tag:blogger.com,1999:blog-27366120522950998422024-03-17T22:59:35.292-04:00ADHD treatmentsThis blog is all about the exploration of ADHD! We will investigate the causes, symptoms and conventional (as well as unconventional) treatments for ADHD.The ADHD Treatment Guidehttp://www.blogger.com/profile/00747782650821771627noreply@blogger.comBlogger111125tag:blogger.com,1999:blog-2736612052295099842.post-17956716065303419162010-03-12T14:12:00.004-05:002010-03-12T17:38:13.641-05:00ADHD and Vitamin D Deficiency: Any Evidence?<strong><em>Is there any link between vitamin D levels and ADHD? A review of the current evidence:</em></strong><br /><br />We have spent a lot of time looking at correlations between vitamins, minerals, omega-3 fatty acids and amino acids (and their deficiencies) and ADHD. However, it is important to note that just because low levels of a particular nutrient are seen alongside the disorder,<em> it does not necessarily mean that this deficiency is the cause of ADHD </em>(i.e. correlation does not imply causation). In other words, the nutrient deficiency and ADHD symptoms might both be secondary effects of a larger primary cause, such as an enzyme deficiency or metabolic dysfunction. <br /><br />In the case of vitamin D, the association with ADHD is a lot more muddled than with some of the other nutrients which have a relatively strong connection with the disorder (iron, zinc, magnesium, and omega-3 fatty acids to name a few). The amount of information in the literature is relatively scarce, as well. A search in the journal database <a href="http://www.ncbi.nlm.nih.gov/pubmed"><span style="color:#3333ff;">Pubmed</span></a> (where this blogger gets most of his articles and information) for "ADHD" and "vitamin D" turns up only a small handful of search results, the majority of which focus on other disorders and only mention ADHD peripherally.<br /><br />However, given the fact that vitamin D is such a "hot" vitamin and has been a popular supplement as of late, we should investigate some of its potential benefits with regard to ADHD and related disorders. <em>Please keep in mind that many of these points below are more theoretical or speculative, because most of the hard, concrete evidence in well-documented clinical controlled studies simply does not exist at the moment</em>. Nevertheless, here are some possible ways in which vitamin D may help in cases of ADHD or related disorders:<br /><br /><ul><li>Vitamin D can boost levels of the <a href="http://www.ncbi.nlm.nih.gov/pubmed/11893522"><span style="color:#3333ff;">antioxidant glutathione in the brain</span></a>. One way that vitamin D does this is by regulating an enzyme called <a href="http://www.ncbi.nlm.nih.gov/pubmed/10428085"><span style="color:#3333ff;"><em>gamma-glutamyl transpeptidase</em></span></a>, which plays a role in both the metabolism and recycling of glutathione. We have spoken at length about how antioxidant deficits can worsen ADHD symtpoms, and how fatty acids (namely <a href="http://adhd-treatment-options.blogspot.com/2009/01/omega-3-fatty-acids-and-adhd-theory.html"><span style="color:#3333ff;">omega-3's</span></a>) are frequently administered for ADHD and related disorders. Given the high makeup of these omega-3 fatty acids in the brain, and their <a href="http://adhd-treatment-options.blogspot.com/2009/09/omega-3-oxidation-in-adhd-problem-with.html"><span style="color:#3333ff;">susceptibility to oxidation</span></a> and damage in the central nervous system, protecting them by boosting antioxidant levels (either directly or indirectly) is a good bet. <br /><br /></li><li>One of the current theories surrounding ADHD is that it is (at least partially) an <a href="http://www.ncbi.nlm.nih.gov/pubmed/11513813"><span style="color:#3333ff;">energy deficiency syndrome</span></a>, or is the result of impaired metabolic abilities in key regions of the central nervous system. While highly debatable, this theory holds that impaired glucose metabolism in various parts of the brain may be a major contributing factor to the presence or severity of this disorder. <br /><br />While this blogger is currently neutral on this deficiency theory, it is interesting to note that vitamin D can help regulate glucose tranport into the brain, which would (at least in theory) improve this possible cause of the disorder. It is believed that <a href="http://www.ncbi.nlm.nih.gov/pubmed/8397307"><span style="color:#3333ff;">vitamin D works by targeting multiple enzymes</span></a> involved in glucose transport and metabolism. Much more study needs to be done to confirm this assertion, but this may be another potential benefit of boosting vitamin D levels in the ADHD patient. <br /><br /></li><li><a href="http://www.ncbi.nlm.nih.gov/pubmed/6288172"><span style="color:#3333ff;">Vitamin D may play a role in catecholamine synthesis</span></a>. Catecholamines include the neurotransmitters <strong>dopamine</strong> and <strong>norepinephrine</strong>, both of which are believed to be tightly regulated and highly involved in the treatment of ADHD (deficiencies of both dopamine and norepinephrine in the "gaps" between neuronal cells are often seen in cases of ADHD). <br /><br /></li><li><a href="http://www.ncbi.nlm.nih.gov/pubmed/3753932"><span style="color:#3333ff;">Vitamin D boosts the effects of an enzyme called <em><strong>choline acetyltransferase</strong></em></span></a> in the mammalian brain. This enzyme is used in the manufacture of another neurotransmitting agent called <strong>acetylcholine</strong>. Acetylcholine is thought to play a major role in maintaining a state of <a href="http://www.ncbi.nlm.nih.gov/pubmed/10808142"><span style="color:#3333ff;">sustained attention</span></a>, a critical shortcoming in those with ADHD. In other words, keeping adequate levels of vitamin D could potentially help prop up lower levels of this attention-sustaining neurochemical. <br /><br /></li><li><a href="http://www.ncbi.nlm.nih.gov/pubmed/15922058"><span style="color:#3333ff;">Learning and memory deficits</span></a>, both of which are heavily present in the ADHD population, have been tied to prenatal vitamin D deficiencies in the rat model. This involves a process called <strong>synaptic plasticity</strong>, which relates to memory formation in an individual. If this finding extends to humans, it could have serious implications on maintaining adequate vitamin D intake in pregnant women. <br /><br /></li><li>Problems with fine motor control are sometimes seen as a secondary characteristic in a fraction of the ADHD population. These problems may be <a href="http://www.ncbi.nlm.nih.gov/pubmed/18056830"><span style="color:#3333ff;">exacerbated in a vitamin D deficient state</span></a>. <br /><br /></li><li>Perhaps the strongest correlation, however, may be between <a href="http://www.ncbi.nlm.nih.gov/pubmed/18761297"><span style="color:#3333ff;">vitamin D and depressive-like symptoms</span></a>, particularly those associated with <a href="http://www.ncbi.nlm.nih.gov/pubmed/10888476"><span style="color:#3333ff;">seasonal affective disorders</span></a> (SAD). Please keep in mind, however, that studies on vitamin D levels and depression are highly variable; a number of studies have been done on the topic and found no such linkage between the two. We have previously investigated possible connections between <a href="http://adhd-treatment-options.blogspot.com/2009/05/adhd-and-seasonal-affective-disorder.html"><span style="color:#3333ff;">ADHD and SAD</span></a> in an earlier post. <br /><br />This may make intuitive sense, since vitamin D production is triggered by sunlight, so in the dark winter months, the levels of this vitamin are often much lower (this may also be a major contributing factor as to why illnesses run so much more rampant during the winter months). In other words, vitamin D supplementation may be particularly useful in individuals with ADHD who also have co-occuring depressive or anxiety-ridden symptoms.</li></ul><strong>To summarize: </strong>Vitamin D does not have as many pronounced direct effects on ADHD as do some of the other vitamins, minerals, fatty acids and amino acids we have previously discussed. Nevertheless, the vitamin does seem to have multiple neurodevelopmental and neuroregulatory properties, and may go well with comorbid disorders such as schizophrenia, speech difficulties, memory problems, and (perhaps most strongly) depressive symptoms. Please keep in mind, however, that it may not be possible to simply "supplement these problems away" with extra vitamin D. This blogger just wants to point out that a deficiency in this vitamin often manifests itself in many ways, some of which closely parallel ADHD or related disorders. Nevertheless, supplementing may not be a bad idea, especially if you live in an area that gets minimal sunlight for part of (or all of) the year. Some rough guidelines for <a href="http://dietary-supplements.info.nih.gov/factsheets/vitamind.asp"><span style="color:#3333ff;">vitamin D intake can be found here</span></a>.The ADHD Treatment Guidehttp://www.blogger.com/profile/00747782650821771627noreply@blogger.com163tag:blogger.com,1999:blog-2736612052295099842.post-78882836084162213972010-02-25T20:37:00.012-05:002010-02-26T22:17:18.724-05:00Do Tyrosine Supplements for ADHD Actually Work? (part 8)<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjIMYqj8WYqOJJTlQT35Q9YlxrDykeIz2fd5ETw92Kg1MYtf6UeuwlI3Ex_07RUkv0jgkfdvrr6pZ2Dr13YeSX656fFEnnQyIB5EGfnfmjKthTf_EMHJw5zCaZ50DB32EKLtCJMi1LCglY/s1600-h/ADHD+tyrosine+co-supplements.jpg"><img id="BLOGGER_PHOTO_ID_5442724567081172450" style="DISPLAY: block; MARGIN: 0px auto 10px; WIDTH: 253px; CURSOR: hand; HEIGHT: 400px; TEXT-ALIGN: center" alt="" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjIMYqj8WYqOJJTlQT35Q9YlxrDykeIz2fd5ETw92Kg1MYtf6UeuwlI3Ex_07RUkv0jgkfdvrr6pZ2Dr13YeSX656fFEnnQyIB5EGfnfmjKthTf_EMHJw5zCaZ50DB32EKLtCJMi1LCglY/s400/ADHD+tyrosine+co-supplements.jpg" border="0" /></a><em></em><br /><br /><br /><em>Blogger's note: If you are interested in taking tyrosine as a supplement for ADHD or related disorders, the above diagram is a summary of the key nutrients which interact or play a role in tyrosine metabolism. In this blogger's opinion, we want to avoid deficiencies (or, in some cases, excesses) of any of these nutrients. If you are in a rush and do not want to read this whole posting, this table may be a good starting point. I have listed a number of links at the bottom to other sites as far as recommended daily intakes are concerned for the majority of these nutrients.</em> <em>This list is by no means extensive, but this will hopefully highlight the major impact factors in maximizing the benefits of tyrosine supplementation as an ADHD treatment strategy. </em><br /><em></em><br /><em>(If the above diagram is not easily visible, most browsers will allow you to left-click the image to get a blow-up version, or you should be able to right-click the image with your mouse and view the image in a new window).</em><br /><br />We have spent the past seven postings on the pathway of <a href="http://adhd-treatment-options.blogspot.com/2010/01/does-tyrosine-supplementation-actually.html"><span style="color:#3333ff;">tyrosine metabolism</span></a> and the implications of supplementing with this amino acid nutrient (and its derivatives for ADHD). But does it actually work?<br /><br />For the last seven postings, we have been examining the following metabolic pathway of tyrosine. Included are the major enzymes and key nutrients responsible for this process to occur efficiently:<br /><br /><br /><img id="BLOGGER_PHOTO_ID_5442755089257369922" style="DISPLAY: block; MARGIN: 0px auto 10px; WIDTH: 176px; CURSOR: hand; HEIGHT: 400px; TEXT-ALIGN: center" alt="" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjvfpxqYDhB_GVCMPgr-jOv34vnvvmKmWVXd6UFgmiSHu9XfKXLGzSTMCwbtA8eLGnW-SWWB7ikxwBZntFqHYSn0IWKaQLqPzqZyZ_TGW_ePD7NcD6V6s4sK9dQfSC6jreek7CGG0vqdfY/s400/ADHD+tyrosine+to+dopamine.PNG" border="0" /><br />Here's a brief review of the evidence for (and against) tyrosine supplementation. Much has been covered in the previous 7 blog posts, but some is new. Links to the studies (or summaries of the studies if the full article is not available) are provided in most cases.<br /><br /><strong><em>Potential </em>advantages of tyrosine supplementation for ADHD:</strong><br /><br /><ul><li><strong><a href="http://adhd-treatment-options.blogspot.com/2010/01/does-tyrosine-supplementation-actually.html"><span style="color:#3333ff;">Tyrosine is a precursor to common neurotransmitters believed to be involved in ADHD</span></a></strong> (neurotransmitters are chemicals involved in various signaling or messaging processes in the nervous system) <a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2738337/"><span style="color:#3333ff;">dopamine, norepinephrine</span></a> and epinephrine (adrenaline). Imbalances (typically shortages) in the regions or "gaps" between neuronal cells of these chemicals often occur in ADHD and related disorders, so the idea with tyrosine is that it can theoretically boost levels of these deficiencies and potentially help correct this imbalance.<br /><br /></li><li><strong><a href="http://www.ncbi.nlm.nih.gov/pubmed/10736373"><span style="color:#3333ff;">Tyrosine can readily cross the blood brain barrier</span></a></strong>. This barrier has been discussed extensively elsewhere, but, in summary, the blood brain barrier is responsible for the <a href="http://www.ncbi.nlm.nih.gov/pubmed/2698167"><span style="color:#3333ff;">passage of nutrients and metabolic products in and out of the brain</span></a> (and also helps keep harmful agents out of the brain). L-DOPA, a derivative of tyrosine, and the first major product of tyrosine metabolism in most cases, is also able to make it across the blood brain barrier. Most of the major products beyond this point cannot, making tyrosine (or L-DOPA) potential supplementation agents which can be taken orally. </li><br /><br /><li>As a "natural" and common amino acid, <strong>tyrosine is something the body already is accustomed to metabolizing through the diet</strong>. Note that tyrosine shares several enzymes and transporters with other amino acids and nutrients. </li><br /><br /><li>Numerous anecdotal reports have found tyrosine to be useful for <strong>comorbid</strong> (co-existing)<strong> disorders</strong> <strong>to ADHD</strong>, such as <a href="http://www.ncbi.nlm.nih.gov/pubmed/3026151"><span style="color:#3333ff;">depression</span></a>. Given the high frequency of comorbid disorders associated with ADHD, tyrosine's versatility may potentially give us some "2-for-1" deals with regards to helping treat multiple symptoms or disorders at once. </li><br /><br /><li>Tyrosine is a good starting point for nutrient-based treatments in metabolic disorders involving the amino acid <strong>phenylalanine</strong> (such as <strong><a href="http://www.ncbi.nlm.nih.gov/pubmed/19622700"><span style="color:#3333ff;">phenylketonuria</span></a></strong>). Phenylalaline is converted to tyrosine in a fashion similar to how tyrosine is converted to L-DOPa, via an enzyme-based chemical modification called hydroxylation (in which an "OH" chemical group is added to the molecule). </li><br /><br /><li>Numerous anecdotal reports involving tyrosine supplementation for ADHD symptoms have indicated <strong>positive results</strong> (at least initially, we will see, however, that many of these benefits are often short-lived). </li><br /><br /><li><strong>Many physicians have</strong> (and continue to)<strong> prescribe tyrosine for ADHD</strong> and related disorders, and, in many anecdotal cases, the individuals taking the tyrosine have seen marked improvement in a matter of days regarding ADHD symptoms (focus, impulse control, decrease in hyperactivity, etc.) </li><br /><br /><li><strong><a href="http://www.ncbi.nlm.nih.gov/pubmed/1760749"><span style="color:#3333ff;">Tyrosine may be used in conjunction with medications for ADHD</span></a></strong> and other related disorders. In other words, it may boost their effects (although this may be a double-edged sword, as some of these drugs are potent, so co-supplementation with tyrosine can possibly increase their side-effects and risks by several orders of magnitude in some cases). <em>In this blogger's opinion, this may be the strongest potential use of tyrosine</em> (as opposed to supplementation on it's own, which may often be short-lived). I personally believe that we often grossly underestimate the effects of supplements on medications, tyrosine's effects on stimulants (and other drugs targeting various types of dopamine-related pathways) are no exception. </li><br /><br /><li>Tyrosine supplements are typically easily metabolized and cleared from the body, lessening potential side effects from residual metabolites (which is the case for several drugs). </li><br /><br /><li>The <a href="http://adhd-treatment-options.blogspot.com/2010/02/does-tyrosine-supplementation-for-adhd_12.html"><span style="color:#3333ff;">enzymes responsible for tyrosine metabolism</span></a> are often dependent on vitamin and mineral nutrients, and can be much more effective if adequate levels of these nutrients are supplied. I have provided a table of some of these key nutrients in a table at the bottom (and top) of this posting.<br /></li></ul><p><strong></strong> </p><p><strong>Disadvantages to tyrosine supplementation for ADHD:</strong> </p><ul><li>Beneficial responses of <a href="http://www.ncbi.nlm.nih.gov/pubmed/3300376"><span style="color:#3333ff;">tyrosine for ADHD treatment are often short lived</span></a> (and usually disappear within 2 to 4 weeks, as the body appears to "adapt" or tolerate the higher levels of tyrosine supplementation. </li><br /><br /><li>In most cases, the imbalances of dopamine and norepinephrine are believed to be due as much to the <a href="http://www.ncbi.nlm.nih.gov/pubmed/20088618"><span style="color:#3333ff;">transporters</span></a> (or agents which shuttle these chemical in and out of the neuronal cells) or <a href="http://www.ncbi.nlm.nih.gov/pubmed/20172533"><span style="color:#3333ff;">receptors</span></a> (places on the cells where the dopamine or norepinephrine bind). Most ADHD medications (including the stimulants) typically work by blocking, modifying or reversing the modes of action of these transporters in an attempt to restore a proper "inside" vs. "outside" chemical balance. Interestingly, <a href="http://www.ncbi.nlm.nih.gov/pubmed/15059031"><span style="color:#3333ff;">genetics</span></a> appears to play a role as to the extent of how a certain transporter or receptor functions, and <a href="http://adhd-treatment-options.blogspot.com/2009/10/drugs-genes-and-adhd.html"><span style="color:#3333ff;">genes may even affect dosage requirements for certain ADHD medications</span></a> (such as <a href="http://adhd-treatment-options.blogspot.com/2008/12/adhd-genes-influence-medication-dosage.html"><span style="color:#3333ff;">Adderall</span></a>, or <a href="http://adhd-treatment-options.blogspot.com/2009/04/strattera-atomoxetine-response-may-be.html"><span style="color:#3333ff;">Strattera</span></a>). <em>In other words, blasting the body with high levels of tyrosine in hopes of using it as a precursor does not necessarily remediate these transporter issues</em>. </li><br /><br /><li>Localization is a problem. Imbalances of dopamine and norepinephrine in ADHD are often seen only in a <a href="http://www.ncbi.nlm.nih.gov/pubmed/19698780"><span style="color:#3333ff;">handful of specific brain regions</span></a>, so flooding the whole system with tyrosine may not be conducive to zeroing in on these target brain regions. Interestingly, however, the synthesis of <strong>monoamine</strong> neurotransmitters such as <strong>dopamine</strong> and <strong>norepinephrine</strong> may not be tied down entirely to specific brain regions, as there may be some <a href="http://www.ncbi.nlm.nih.gov/pubmed/19358813"><span style="color:#3333ff;">flexibility</span></a> as to where these chemicals are generated based on the demands (and failures) of other parts of the brain and central nervous system.<br /><br /></li><li>While side effects may potentially be lower, tyrosine (or L-DOPA) does have some metabolites which can be harmful at high levels. The pro-inflammatory agent <a href="http://adhd-treatment-options.blogspot.com/2010/02/do-tyrosine-supplements-for-adhd.html"><span style="color:#3333ff;">homocysteine</span></a> is one such example, and has been discussed at length in a previous tyrosine for ADHD blog post. </li><br /><br /><li>While anecdotal reports on the benefits of tyrosine supplementation for ADHD treatment abound, the actual number of published studies showing positive results for tyrosine (especially in the last 10-20 years) is surprisingly low. </li><br /><br /><li>As mentioned earlier, <a href="http://www.ncbi.nlm.nih.gov/pubmed/12933350"><span style="color:#3333ff;">tyrosine can "compete" with other amino acids</span></a> such as tryptophan, valine, leucine and isoleucine for entry into the brain, because they share a similar system of transporters. In fact, there are a number of parallels between the <a href="http://adhd-treatment-options.blogspot.com/2010/02/does-tyrosine-for-adhd-actually-work-a.html"><span style="color:#3333ff;">tyrosine to dopamine/norepinephrine pathway and the tryptophan to serotonin pathway</span></a>, in that they share similar enzymatic processes. In other words, it is possible to create imbalances or reduce the effectiveness of one amino acid (and its desired products of metabolism) if the presence of a competing amino acid is too high. This interference is often seen especially in the tyrosine/tryptophan and can potentially promote imbalances in the serotonin to dopamine ratios. </li><br /><br /><li>Genetic disorders (which are relatively uncommon) or nutrient deficiencies can hamper the efficiency of several enzymes required for tyrosine metabolism. Even being short in one nutrient can cause problems. Given the nutritional status of many with ADHD, this may be a grave problem. As a result, there are numerous opportunities for the tyrosine supplement to be compromised.<br /></li></ul><strong>Ways to improve the effectiveness of tyrosine supplementation for ADHD:<br /></strong><br />As a blogger on the subject, I always try to remain neutral (many times, however, this can be extremely difficult). When researching the stories and studies on tyrosine supplementation for ADHD, the one thing that continuously caught my attention was the degree of discord between the studies on tyrosine supplementation for ADHD (most of which showed no significant improvement) and the number of clinicians who prescribed it (and individuals who reported benefits from tyrosine). Again, this disagreement may be due to a number of things (differences between study conditions and the treated individuals, co-treatment with ADHD medications, the placebo effect, immediate vs. long-term effects, etc.), so we need to be very careful when making a comparison.<br /><br />Having said all of this, and weighing everything I've read and researched, I admit (as a blogger) to being skeptical about the overall effectiveness of the whole tyrosine supplementation thing for ADHD. There just don't seem to be enough positive studies grounded in <span style="FONT-STYLE: italic">long-term</span> improvements which tyrosine. Nevertheless, the number of positive reports on tyrosine from individuals are too great to ignore in most cases, so an outright condemnation of tyrosine for ADHD is by no means warranted.<br /><br />It is important to note that none of the studies I've seen (both those supporting or refuting the idea of tyrosine for ADHD) have paid much attention into controlling for the co-factors of the enzymes responsible for metabolizing tyrosine. Just as a reminder, co-factors are essentially vitamins, minerals and other nutrients which are used to help enzymes function properly (or at least more efficiently).<br /><br />So if we do decide to begin a tyrosine supplementation program, we should make sure we have adequate levels of the following nutrients (I have listed the major nutrients, and where it helps in the tyrosine metabolic processes. It is important to note that this list is not 100% complete, there are several other nutrients which play a role indirectly in the process, but I am just highlighting the major ones I've come across in the studies I've seen on the metabolic pathways of tyrosine to dopamine, norepinephrine and epinephrine):<br /><br /><br /><p><img id="BLOGGER_PHOTO_ID_5442723447991251266" style="DISPLAY: block; MARGIN: 0px auto 10px; WIDTH: 253px; CURSOR: hand; HEIGHT: 400px; TEXT-ALIGN: center" alt="" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjv8Zf4PQlYB2ddE4NzG6WAYPZrnK5eMm-OvUiqzhGZwctsES_4dEvKXsY2NyMTWFYzKuR3kcdOMvNH9JQksyNao-H3mwkZhyphenhyphenIv3Cce-9xaokDJKOavqfEXiRy7J8aWsDAriNhyphenhyphenTMHFeuk/s400/ADHD+tyrosine+co-supplements+2.JPG" border="0" /> </p><br /><p><strong>Here are some links to recommended daily levels of the following nutrients and "cofactors" which can potentially affect the outcome of tyrosine supplementation for ADHD:</strong><br /></p><ul><li><a href="http://dietary-supplements.info.nih.gov/factsheets/iron.asp"><span style="color:#3333ff;">Iron</span></a></li><li><a href="http://dietary-supplements.info.nih.gov/factsheets/zinc.asp"><span style="color:#3333ff;">Zinc</span></a></li><li><a href="http://dietary-supplements.info.nih.gov/factsheets/magnesium.asp"><span style="color:#3333ff;">Magnesium</span></a></li><li><a href="http://lpi.oregonstate.edu/infocenter/minerals/copper/"><span style="color:#3333ff;">Copper</span></a></li><li><a href="http://lpi.oregonstate.edu/infocenter/vitamins/vitaminB6/"><span style="color:#3333ff;">Vitamin B6</span></a></li><li><a href="http://lpi.oregonstate.edu/infocenter/vitamins/vitaminB12/"><span style="color:#3333ff;">Vitamin B12</span></a></li><li><a href="http://lpi.oregonstate.edu/infocenter/vitamins/fa/"><span style="color:#3333ff;">Folic Acid</span></a></li><li><a href="http://lpi.oregonstate.edu/infocenter/vitamins/vitaminC/"><span style="color:#3333ff;">Vitamin C</span></a></li><li>(no official doses have been set for S-Adenosyl Methionine or SAMe, as this can be produced in the body, a ballpark supplemental dose for SAMe is around 100-200 mg twice a day, but of course varies per individual)</li></ul><p><br /><strong>A quick summary of this blogger's overall thoughts and advice on tyrosine supplementation for ADHD:</strong><br /><br /></p><ul><li>There are (surprisingly) few well-controlled clinical studies which show tyrosine to be an effective long-term strategy for treating ADHD. In spite of this, tyrosine supplements are often prescribed by a number of physicians (seemingly in a disproportionate manner when compared to other agents with more promising clinical studies). This disparity is at least noteworthy. </li><br /><br /><li>For those (few) studies who do tout the benefits of tyrosine supplements for ADHD, the symptom improvements are often short-lived (often only a few short weeks). </li><br /><br /><li>However, this blogger personally believes that many of the studies may have shown minimal effects due (at least in part) to the fact that many of the other nutritional "puzzle pieces" (such as those given in the tables above) were either neglected or not necessarily in place. These vitamin and mineral-based cofactors can play a huge role in the metabolic conversion of tyrosine to its desired products, and has been discussed at length in the seven previous blog posts on tyrosine and ADHD. Had these studies incorporated some of these co-treatment strategies, some of the results might possibly have been different. </li><br /><br /><li><em>Please note that while "natural", tyrosine supplementation is not always benign</em>. Health risks, such as amino acid imbalances (due to the competitive nature of several amino acids with tyrosine to get into the brain), cardiovascular issues and even some types of cancers (which are often more associated with a derivative of tyrosine, L-DOPA, however) are very real. Additionally, biochemical side effects of tyrosine metabolism also exist, and can be magnified greatly if rampant tyrosine supplementation is undertaken. The pro-inflammatory agent homocysteine is one such example. However, nutrient-based treatments via B vitamins can often offset a potential homocysteine buildup. </li><br /><br /><li>The dosages for tyrosine supplementation can vary widely ranging from as low as 100 milligrams all the way up to 5000 milligrams (or more, toxicity often begins to set in around 10,000 mg, but this of course widely varies by individual). 2-3 supplements of 500-1000 mg/day is typical in a number of cases (lower doses are almost always a must for children), but dosing should always be under the guidance of a physician. </li><br /><br /><li>Most of the tyrosine supplemental strategies hinge or ride on the theory that ADHD is a dopamine or norepinephrine deficiency issue. However, much of the evidence on the disorder seems to indicate that the transport of these chemical neurotransmitters across neuronal cell membranes and an imbalance of the "inside-the-cell" vs. "outside-the-cell-in-the-gaps-between-neuronal-cell" concentrations of these agents is the real culprit. <em>In other words, flooding the body with tyrosine in hopes that it will generate more dopamine and norepinephrine will not necessarily address this basis of imbalance. </em></li><br /><br /><li>This blogger personally believes that tyrosine supplementation may be of much greater benefit if used <em>in conjunction</em> with a medication (often a stimulant or other dopamine "releasing" agent). <em>Please note that these supplement-drug interactions may be extremely potent, so please only do this under the supervision of a physician. </em></li></ul>In other words, tyrosine supplementation for ADHD treatments is theoretically viable, and has had numerous success stories. Maintaining adequate intake of the nutrient cofactors listed in the tables above helps supply the body's enzymes with the tools they need to metabolize tyrosine most effectively. When dietary intake of these nutrients is sufficient, and tyrosine is wisely used in conjunction with proper pharmaceutical agents, this blogger personally believes that there may be great tangible benefits with regards to ADHD symptoms and treatment.The ADHD Treatment Guidehttp://www.blogger.com/profile/00747782650821771627noreply@blogger.com48tag:blogger.com,1999:blog-2736612052295099842.post-12262427124515003802010-02-18T11:46:00.010-05:002010-02-20T00:26:35.695-05:00Do Tyrosine Supplements for ADHD Actually Work? (part 7)<span style="FONT-STYLE: italic; FONT-WEIGHT: bold">Homocysteine Buildup: The (Potential) Dark Side of Tyrosine and L-DOPA Supplementation for ADHD</span><br /><br />Throughout the last six posts on this blog, all of which were concerned with tyrosine supplementation strategies for ADHD, we alluded to the fact that introducing high levels of tyrosine into the body can precipitate a number of other biochemical processes besides the conversion to dopamine and norepinephrine in the brain of the ADHD patient. For reference, I have included the diagram we've been following for the past six blog posts on ADHD and supplementing with tyrosine (you can click on the diagram below and get a larger picture in most browsers):<br /><p><img style="TEXT-ALIGN: center; MARGIN: 0px auto 10px; WIDTH: 176px; DISPLAY: block; HEIGHT: 400px; CURSOR: hand" id="BLOGGER_PHOTO_ID_5440163791817865026" border="0" alt="" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhBCj-g23tYQx3znwAmN9EU9ygvKmGC61Jlq7T40LKuQ_Or1nudb9yqXSEYCVMiZN0OZZ0Z3khyh38f3n1aCJ4Osh9HZr3jcRSEf0BwyuOJaQ8CNzby8Tm-Int8Umwx8-de6kgonBHkCzA/s400/ADHD+tyrosine+to+dopamine.PNG" />As we can see, there are a number of enzymes, processes and intermediate steps involved in just this one pathway of tyrosine. Please note that other nutrients, such as <span style="FONT-WEIGHT: bold">ascorbic acid</span> (a.k.a. <span style="FONT-WEIGHT: bold">vitamin C</span>, which has a number of connections to ADHD) and <span style="FONT-WEIGHT: bold">S-Adenosyl methionine</span> (also known as <span style="FONT-WEIGHT: bold">SAM</span> or <span style="FONT-WEIGHT: bold">SAMe</span>, which has also been discussed in greater detail in relation to ADHD elsewhere) are required in this process.<br /><br />Also, a number of enzymes are required to make this process go.<br /><br />Here is a quick summary of some of the enzymes used and some of the key vitamins and minerals required (either directly or indirectly) to optimize this enzyme's function:<br /><br /><a style="COLOR: rgb(51,51,255)" href="http://adhd-treatment-options.blogspot.com/2010/01/does-tyrosine-supplementation-actually_28.html"><span style="FONT-STYLE: italic; FONT-WEIGHT: bold">Tyrosine Hydroxylase</span></a><span style="FONT-WEIGHT: bold">: </span>(<span style="FONT-WEIGHT: bold">iron</span>, <span style="FONT-WEIGHT: bold">vitamin C</span>, <span style="FONT-WEIGHT: bold">magnesium</span>, <span style="FONT-WEIGHT: bold">zinc</span>, <span style="FONT-WEIGHT: bold">copper</span>, <span style="FONT-WEIGHT: bold">folic acid</span> or <span style="FONT-WEIGHT: bold">folate</span>, <span style="FONT-WEIGHT: bold">niacin</span>). This is perhaps the most important step of the process, in that it is the slowest or "rate-limiting" step. Because of this, we want to make sure all necessary nutrient "co-factors" (helpers) are in place to help move along this "slow" step as fast as possible)</p><p><a style="COLOR: rgb(51,51,255)" href="http://adhd-treatment-options.blogspot.com/2010/02/does-tyrosine-for-adhd-actually-work-a.html"><span style="FONT-STYLE: italic; FONT-WEIGHT: bold">Dopa Decarboxylase</span></a>: (vitamin B6, zinc. Also note that excessive levels of some other amino acids, such as leucine, isoleucine, valine, and, especially, <span style="FONT-WEIGHT: bold">tryptophan</span> can compromise this step of tyrosine metabolism. Furthermore, buildup of one of the products of tryptophan metabolism, <span style="FONT-WEIGHT: bold">serotonin</span>, can inhibit or begin to shut down the activity of this <span style="FONT-STYLE: italic">Dopa Decarboxylase</span> enzyme and compromise our tyrosine-to-dopamine conversion pathway. This spells bad news if we want to attempt to regulate these dopamine levels in an ADHD brain)<br /><br /><a style="COLOR: rgb(51,51,255)" href="http://adhd-treatment-options.blogspot.com/2010/02/does-tyrosine-supplementation-for-adhd.html"><span style="FONT-STYLE: italic; FONT-WEIGHT: bold">Dopamine Beta Hydroxylase</span></a>: (<span style="FONT-WEIGHT: bold">vitamin C</span>, but also requires additional antioxidants to "recycle" the used vitamin C) </p><p><a style="COLOR: rgb(51,51,255)" href="http://adhd-treatment-options.blogspot.com/2010/02/does-tyrosine-supplementation-for-adhd_12.html"><span style="FONT-STYLE: italic; FONT-WEIGHT: bold">Phenylethanolamine N-methyltransferase</span></a>: (<span style="FONT-WEIGHT: bold">S-Adenosyl-methionine</span> or <span style="FONT-WEIGHT: bold">SAMe</span>)<br /><br />Keep in mind that this list is not extensive. However, the vitamins and minerals are some of the key players in the conversion processes of tyrosine metabolism.<br /><br /><span style="FONT-WEIGHT: bold">Other Pathways of Tyrosine Metabolism and the Generation of Homocysteine<br /></span><br />This is extremely important. A lot of times we get lulled into believing that just because we're using a natural or dietary-based treatment strategy instead of <span style="FONT-STYLE: italic">potentially</span> harmful medications, we are immune to negative and/or dangerous side effects typically associated with drugs. However, as a blogger, I urge everyone to reject this idea as quickly as possible. While the side effects as a whole may be a bit more benign or have more room for error for nutrient-based ADHD treatments, going overboard can be just as harmful.<br /><br />Minerals such as <a href="http://dietary-supplements.info.nih.gov/factsheets/iron.asp"><span style="color:#3333ff;">iron</span></a>, <a href="http://www.nlm.nih.gov/medlineplus/druginfo/natural/patient-copper.html"><span style="color:#3333ff;">copper</span></a> and <a href="http://dietary-supplements.info.nih.gov/factsheets/chromium.asp#h8"><span style="color:#3333ff;">chromium</span></a> all can be extremely toxic at high levels, and overdosing on certain vitamins (especially the fat soluble ones such as <a href="http://dietary-supplements.info.nih.gov/factsheets/vitamina.asp"><span style="color:#3333ff;">vitamins A</span></a> and <a href="http://ods.od.nih.gov/factsheets/VitaminE.asp"><span style="color:#3333ff;">E</span></a>, which are more difficult to flush out of the system than the water soluble ones), can also be harmful (or even fatal). Even the water-soluble B vitamins can cause problems if overdone (there is a high degree of interaction among most of these, and there is a relatively delicate balance between their levels. Over-supplementing on one, therefore, can greatly compromise the others).<br /><br />Amino acid supplementation can also be tricky. We mentioned in an earlier posting that chemically similar amino acids often "compete" with each other in areas such as entry into the brain and competition for the same enzymes. As a result, if we go overboard with supplementing on one type of amino acid (such as tyrosine, in the case of ADHD treatment), we need to examine some of the possible repercussions of disturbing the balance of the other amino acids and the products of their metabolism.<br /><br />Additionally, we need to be aware of other biochemical pathways in the body in which tyrosine is involved. While it may be true that supplementing with tyrosine can boost levels of dopamine and norepinephrine (although the extent of this is debatable, and will be discussed in our final "wrap-up" post), boosting tyrosine intake can result in higher levels some potentially harmful agents such as the compound <span style="FONT-WEIGHT: bold">homocysteine</span>. For this, we will begin by examining the last step of the tyrosine metabolic process (this was covered in the last post in more detail):<br /></p><img style="TEXT-ALIGN: center; MARGIN: 0px auto 10px; WIDTH: 264px; DISPLAY: block; HEIGHT: 209px; CURSOR: hand" id="BLOGGER_PHOTO_ID_5440162930384513490" border="0" alt="" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhg6ckhf0vWEg2cM5L7sLHy3fllFBrW-lZamVSLjYEJFlXOTqutm_mdCTez3Tke-GIrdPWP9LgfxVfRnNyxUmLi4odyVtw5jK3okp-KwKXViRCnYUEwUBa9lakPwOSkKJqkg0UhAQPTZ1I/s400/tyrosine+supplement+ADHD+homocysteine.PNG" />Here we see that tyrosine-derived <span style="FONT-WEIGHT: bold">norepinephrin</span>e can be converted to <span style="FONT-WEIGHT: bold">epinephrine</span> (<span style="FONT-WEIGHT: bold">adrenaline</span>) in a process which utilizes the enzyme (<span style="FONT-STYLE: italic; FONT-WEIGHT: bold">phenylethanolamine N-methyltransferasePNMT</span>). Even without a chemistry background, we can still see the chemical transformation process above. A methyl (CH3) group was added to the Nitrogen (N) on the right side of the norepinephrine molecule to form norepinephrine. But where does this methyl group come from?<br /><br />As mentioned in the <a href="http://adhd-treatment-options.blogspot.com/2010/02/does-tyrosine-supplementation-for-adhd_12.html"><span style="color:#3333ff;">last post on ADHD and tyrosine</span></a>, the compound <span style="FONT-WEIGHT: bold">S-Adenosyl Methionine</span> or <span style="FONT-WEIGHT: bold">SAMe</span>, is a very important nutrient in a number of biochemical processes, in that it is able to "donate" (give-up) a CH3 methyl group. This is a relatively rare property among nutrients, and we are just beginning to scratch the surface with regards to the role of this nutrient in treating neurological and psychological disorders such as depression, ADHD and the like.<br /><br />However, when SAMe does donate it's CH3 methyl group, as in the case above, we are left with homocysteine (<span style="FONT-STYLE: italic">please note that there are a few additional steps to go from SAMe to homocysteine, it is not a 1-step conversion process. For simplicity, however, we will not go into these in any further detail. Nevertheless, homocysteine is a major end product of SAMe-related CH3 donor reactions, such as the one given above</span>).<br /><br />In other words, higher tyrosine (or L-DOPA) levels can make their way to this step of the metabolic process and begin to deplete SAMe levels and lead to high levels of homocysteine. High levels of homocysteine are known as hyperhomocysteinemia, is commonly seen in Parkinson's patients, who often take large amounts of L-DOPA (the second step of tyrosine metabolism in our first diagram in this blog post). Numerous studies have shown that long-term treatment with <a style="COLOR: rgb(51,51,255)" href="http://www.ncbi.nlm.nih.gov/pubmed/18505360">L-DOPA leads to elevated homocysteine levels</a> in the blood of Parkinson's patients.<br /><br /><p>Elevated homocysteine levels have been linked from everything from <a href="http://www.ncbi.nlm.nih.gov/pubmed/19075131"><span style="color:#3333ff;">cancer</span></a> to <a href="http://www.ncbi.nlm.nih.gov/pubmed/19967264"><span style="color:#3333ff;">diabetes to autoimmune disorders</span></a> to <a href="http://www.ncbi.nlm.nih.gov/pubmed/19228852"><span style="color:#3333ff;">stroke</span></a> (<em>however, please note that these results are far from unanimous, there are a number of studies showing the contrary for each of the diseases listed. Furthermore, there is still some debate as to whether the high levels of homocysteine are a causal factor for these disorders or just another side effect or symptom of these disorders. Nevertheless, the near-ubiquitous presence of high homocysteine levels in so many diseases across the board should at least suggest that homocysteine-lowering efforts are of great potential benefit, at least in this blogger's opinion</em>).</p><p>With regards to ADHD, the actual role of homocysteine is, admittedly, much more murky. While the mechanisms and overall physiology of an ADHD brain vs. a Parkinson's brain show acute differences (In ADHD, chemical imbalances between the "inside" and "outside" regions of a neuron exist, which can be chemically modified via medications which target the proteins which shuttle this neuro-transmitting agents in and out of the cells. In Parkinson's, however, the imbalances are caused by cell death and neuronal degeneration, requiring overall higher levels of neurotransmitters like dopamine need to be supplied via chemical precursor agents like L-DOPA), the fact that the two disorders both share similar treatment methods should (in this blogger's opinion) at least sound a warning bell that some of the negative effects for one might also be prevalent in the other. </p><p>Surprisingly, there are very few studies (at least to the best of this blogger's knowledge) on homocysteine levels in the ADHD population, so it is difficult to get a good read on the subject. Nevertheless, given some of the points made earlier on tyrosine or L-DOPA supplementation or treatment and homocysteine buildup, we should at least examine some of the ways to reduce high homocysteine levels. Fortunately (at least in most cases), homocysteine-lowering efforts often respond very well to vitamin and mineral based treatments via supplementation or food fortification. At the center of this are the some of the well-known B vitamins.</p><p><strong>B vitamin-based nutritional "weapons" which can combat potentially high homocysteine levels arising from tyrosine or L-DOPA supplementation:</strong> </p><ul><li><strong>Vitamin B6</strong> (whose "active" form is known as <strong>pyridoxal phosphate</strong>. For simplicity, we will just be referring to this compound by its common vitamin name, vitamin B6)</li><li><strong>Cobalamin</strong> (a version of <strong>vitamin B12</strong>) </li><li><strong>Folate</strong> (a derivative of <strong>Folic Acid</strong> or <strong>Vitamin B9</strong>. For simplicity, as in the diagram below, we will just refer to this modified form of folate as "folic acid", but please note that there is a modest chemical difference here)<br /></li></ul><p><img style="TEXT-ALIGN: center; MARGIN: 0px auto 10px; WIDTH: 400px; DISPLAY: block; HEIGHT: 336px; CURSOR: hand" id="BLOGGER_PHOTO_ID_5440160859107550210" border="0" alt="" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEi95pan66sAcxJT1YoGSwDzUhJEq7buGTHLlR8NVBjoVySxEUHeqA3mmf0aEo4Ut402k1oqOPCe5DAbXD9tyAo90HFTHnFoXIJIv0v-4rZGNutbRLNAKI5W-vbfkmVhB-8p52jZ4807XLE/s400/ADHD+TYROSINE+HOMOCYSTEINE+PATHWAY.png" /><br />While the above diagram may look extremely complicated and "busy", please try not to get distracted. The first four "steps" at the top (the arrows simply refer to a metabolic pathway by showing the gradual transformation of one tyrosine-based compound to the next. We have discussed each of these steps in great detail in the previous postings) have already been covered extensively. </p><p>The last step, the conversion of norepinephrine to epinephrine was discussed in the last posting on ADHD and tyrosine. The curved arrow simply refers to the fact that the norepinephrine to epinephrine conversion requires another nutrient-based compound <strong>SAMe</strong>. The norepinephrine essentially "steals" a methyl (CH3) group from SAMe, leaving SAMe to transform into another compound S-Adenosylhomocysteine (which then proceeds to our "dreaded" homocysteine). <em>To put it another way, in order to make the norepinephrine to epinephrine conversion, the valuable nutrient SAMe must be "sacrificed" to a more potentially harmful compound homocysteine.</em> </p><p>If this SAMe to homocysteine conversion process is not kept in check, we run the potential risk of homocysteine buildup. However, based on the diagram above (look at the far right side of the diagram for this part), there are 2 different ways to "dump off" high levels of homocysteine by converting it to other more benign compounds. However, each of these two "paths" requires at least one type of B vitamin. </p><p><strong>Path #1: conversion of homocysteine to the amino acid cysteine: </strong>This is actually a multi-step process, but for the sake of brevity and simplicity, I have left out some of the middle steps. The two major points of note here as follows:</p><ol><li>This process requires a specific enzyme called <strong><em>cystathione beta-synthase</em></strong> (don't worry about remembering this enzyme, just remember that this enzyme requires a form of <strong>vitamin B6</strong> as a cofactor or "helper to function). Thus, to optimize this vitamin B6-based conversion process, we want to make sure that we don't have any deficiencies of this vitamin. Please note that we already mentioned the need for vitamin B6 in another step of the tyrosine supplementation process for ADHD, the conversion of <a href="http://adhd-treatment-options.blogspot.com/2010/02/does-tyrosine-for-adhd-actually-work-a.html"><span style="color:#3333ff;">L-DOPA to dopamine</span></a>. Thus, it is doubly important that we don't come up short on this vitamin.<br /><br />A rough summary of recommended dosage levels for B6 will be given at the end of this post (<em>Blogger's note: not to go into too much detail here, but this homocysteine to cysteine conversion process is also dependent on another amino acid called <strong>serine</strong>. I have not included serine as an essential nutrient because serine deficiencies are rare. However, there are some genetic disorders in which serine synthesis is compromised. Seizures and related symptoms are common among those with this </em><a href="http://www.serine.org/"><span style="color:#3333ff;"><em>genetic defect on serine metabolism</em></span></a>).<br /><br /></li><li>The conversion of homocysteine to cysteine is (largely) <strong>irreversible</strong>. This is good news if we want to "dump off" homocysteine levels and not have to worry about the process chemically finding its way back to homocysteine (at least not through this pathway). </li></ol><p><strong>Path #2: the conversion of homocysteine to the amino acid methionine: </strong>While path #1 is dependent on one type of B vitamin (B6), this pathway is dependent on 2 different B's: a form of <strong>vitamin B12</strong> and a derivative of <strong>folic acid</strong> (<strong>vitamin B9</strong>). Without going into too much detail, this process requires a <strong>methyl</strong> (<strong>CH3</strong>) "donor" (which, in this case, is the <strong><em>modified</em> form of folic acid</strong> here. This is very similar to like way the nutrient <strong>SAMe</strong> acts in helping the conversion from norepinephrine to epinephrine as mentioned earlier).<br /><br />Please note that, unlike the last case, this process is <strong>chemically reversible</strong> (which means that the process can go backwards and regenerate homocysteine to a certain extent). This process also requires a special enzyme called <em><strong>homocysteine methyltransferase</strong>.</em> Again, don't worry too much about this enzyme, just note that it requires a form of <strong>vitamin B12</strong> to function.<br /><br /><em>To summarize: if we want to keep the "cycle" going to avoid homocysteine buildup by converting homocysteine to methionine, we need 2 different B vitamins: The folic acid as the chemical modifier, and vitamin B12 to help the enzyme involved in the process to function properly.</em> </p><p>Perhaps not surprisingly, taking B12 (also known as <strong>cobalamin</strong>) and a form of folic acid (<strong>folate</strong>) together has shown to be advantageous in a number of cases. <a style="COLOR: rgb(51,51,255)" href="http://www.ncbi.nlm.nih.gov/pubmed/15804266">Combinations of folate and cobalamin</a> have also shown to be useful in reducing homocysteine levels in those treated with L-DOPA. </p><p>A quick summary on using B vitamins to reduce potential homocysteine buildup from tyrosine (or L-DOPA) supplementation:</p><ul><li><strong>Homocysteine</strong> can be an inflammatory compound that is produced indirectly as a result of tyrosine metabolism. High levels of this compound have been linked to a wide number of diseases and health risks.<strong><br /><br /></strong></li><li><strong>Vitamin B6</strong> can be used to help "shunt" homocysteine to a common (and typically less-harmful) amino acid known as <strong>cysteine</strong>. This process is (essentially) <strong>irreversible</strong>. B6 is also a requirement for an earlier step of the tyrosine or L-DOPA metabolic process, the <a href="http://adhd-treatment-options.blogspot.com/2010/02/does-tyrosine-for-adhd-actually-work-a.html"><span style="color:#3333ff;">conversion of L-DOPA to dopamine</span></a>.<br /><br /></li><li><strong>Vitamin B12</strong> and <strong>folic acid</strong> can both assist in the conversion of homocysteine to another amino acid, methionine. Unlike the cysteine conversion process above, this process is <strong>reversible</strong>, meaning that it is possible to "work" backwards towards homocysteine in a bi-directional pathway.<br /><br /></li><li>Because of the importance of these 3 B vitamin-derived factors in the prevention of homocysteine buildup, it is imperative that we try to avoid shortages of these agents at all costs (<em>but be careful about over-supplementing</em>, B vitamins work best in specific ratios, and overdosing on one can compromise the functions of the other, as we have noted in previous posts on <a href="http://adhd-treatment-options.blogspot.com/2009/01/adhd-alcoholism-and-nutrient.html"><span style="color:#3333ff;">ADHD and nutrient deficiencies</span></a>).<br /><br /></li><li>Here are some good sites which list the suggested daily amounts for <a href="http://dietary-supplements.info.nih.gov/factsheets/folate.asp"><span style="color:#3333ff;">folic acid (folate)</span></a>, <a href="http://dietary-supplements.info.nih.gov/factsheets/vitaminb6.asp"><span style="color:#3333ff;">vitamin B6</span></a> and <a href="http://dietary-supplements.info.nih.gov/factsheets/vitaminb12.asp"><span style="color:#3333ff;">vitamin B12</span></a>. Going slightly higher is often fine (as these agents have relatively high "ceilings" between recommended amounts and toxicity levels), but try to keep the <em>ratio</em> of these different B vitamins as close to the same as in the recommended amounts as possible. Again, please make sure your physician is in the know if you choose to supplement with anything significantly above the recommened levels. </li></ul><p>This is our second-to-last post on ADHD and tyrosine. The last one on tyrosine supplementation strategies for ADHD will give a recap of all the key enzymes, nutrients, and chemical intermediates we've covered throughout the past seven postings. It will also provide a summary of what the main studies on exactly how effective tyrosine supplements really are based on clinical studies. Finally, we will briefly mention how tyrosine may be able to augment the effects of common ADHD stimulant medications.<br /></p>The ADHD Treatment Guidehttp://www.blogger.com/profile/00747782650821771627noreply@blogger.com41tag:blogger.com,1999:blog-2736612052295099842.post-90296833338097183342010-02-12T17:31:00.008-05:002010-02-12T20:01:31.811-05:00Does Tyrosine Supplementation for ADHD Actually Work? (Part 6)<span style="font-style: italic; font-weight: bold;">Can we use tyrosine as an effective supplement to treat ADHD symptoms?</span><br /><br />We have dedicated the last five postings on the role of tyrosine and its metabolism, and how imbalances of this common amino acid may dictate, in part, some<span style="font-style: italic;"> </span>of the symptoms related to ADHD.<br /><br />Just for refreshers, here's a diagram of the overall conversion process and metabolism of tyrosine. We have spoken through the first three steps (and the corresponding enzymes and required chemical nutrients) in the process:<br /><a onblur="try {parent.deselectBloggerImageGracefully();} catch(e) {}" href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjyYPE-NM6BYCm-xrOOdVCmP4bKeucF8RxBlO9AcatV4uHTln_j-jzphkpBEd4iLSVfaPFhzxXJ9iFsFdtWlAU6D6ptn6iEg4GNc_FACwGwW75o5SbaL59kENWI4Y3EOOgn4ln79tq9JKQ/s1600-h/ADHD+tyrosine+L-DOPA+dopamine.PNG"><img style="margin: 0px auto 10px; display: block; text-align: center; cursor: pointer; width: 264px; height: 323px;" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjyYPE-NM6BYCm-xrOOdVCmP4bKeucF8RxBlO9AcatV4uHTln_j-jzphkpBEd4iLSVfaPFhzxXJ9iFsFdtWlAU6D6ptn6iEg4GNc_FACwGwW75o5SbaL59kENWI4Y3EOOgn4ln79tq9JKQ/s400/ADHD+tyrosine+L-DOPA+dopamine.PNG" alt="" id="BLOGGER_PHOTO_ID_5437504398542790290" border="0" /></a><br />Here's a quick recap on our last 5 discussions on ADHD and tyrosine:<br /><br /><a style="color: rgb(51, 51, 255);" href="http://adhd-treatment-options.blogspot.com/2010/01/does-tyrosine-supplementation-actually.html"><span style="font-weight: bold;">Post #1 on ADHD and tyrosine:</span></a> We examined the overall theory and background behind the use of tyrosine as an ADHD treatment strategy. We saw how it is a chemical precursor to important neurotransmitters (neuro-signaling chemicals responsible for communication among brain cells and the central nervous system) such as dopamine and norepinephrine. We also introduced the concept of the <span style="font-weight: bold;">blood-brain barrier</span>, a biochemical barrier which controls the transport of drugs, nutrients and toxins in and out of the brain.<br /><br /><a style="color: rgb(51, 51, 255);" href="http://adhd-treatment-options.blogspot.com/2010/01/does-tyrosine-supplementation-actually_28.html"><span style="font-weight: bold;">Post #2 on ADHD and tyrosine:</span></a> here we analyzed the first step of tyrosine metabolism, in which tyrosine is converted to another compound <span style="font-weight: bold;">L-DOPA</span> (a common treatment method for Parkinson's patients). This step heavily involves the enzyme <span style="font-style: italic; font-weight: bold;">tyrosine hydroxylase</span>. However, in order to optimize function of this conversion process, the tyrosine hydroxylase enzyme requires certain vitamins and minerals to act as "co-factors" or "helpers". These include <span style="font-weight: bold;">iron</span>, <span style="font-weight: bold;">vitamin C</span>, <span style="font-weight: bold;">magnesium</span>, <span style="font-weight: bold;">zinc</span>, <span style="font-weight: bold;">folic acid</span> (namely <span style="font-weight: bold;">folate</span> or <span style="font-weight: bold;">vitamin B9</span>) and overall adequate antioxidant levels. Secondary nutrients (necessary for enzymes which lead up to the formation of some of the products used by the <span style="font-style: italic;">tyrosine hydroxylase</span> enzyme) include <span style="font-weight: bold;">copper</span>, and (as we'll see later on in the tyrosine metabolic pathway), <span style="font-weight: bold;">vitamin B12</span>. Deficiencies in one or more of these nutrients could potentially compromise this enzyme's function. Since this first step is actually the slowest (rate-determining) step of the whole tyrosine metabolism process with regards to converting tyrosine to the neurotransmitters dopamine and norepinephrine, making sure we have adequate resources of these "helper" nutrients is crucial to our success.<br /><br /><a style="color: rgb(51, 51, 255);" href="http://adhd-treatment-options.blogspot.com/2010/02/does-tyrosine-for-adhd-actually-work-as.html"><span style="font-weight: bold;">Post #3 on ADHD and tyrosine:</span></a> We can essentially bypass this first step of tyrosine to L-DOPA conversion altogether if we just decided to supplement directly with L-DOPA instead. But is L-DOPA more effective than tyrosine as a treatment method for ADHD, or are there some serious drawbacks to this strategy? This third post evaluates and compares both tyrosine and L-DOPA options and compares both their effectiveness as ADHD treatment agents and their comparative safety issues in several different categories.<br /><br /><a style="color: rgb(51, 51, 255);" href="http://adhd-treatment-options.blogspot.com/2010/02/does-tyrosine-for-adhd-actually-work-a.html"><span style="font-weight: bold;">Post #4 on ADHD and tyrosine:</span></a> In this post, we examined the second major step of the conversion process in tyrosine metabolism, the conversion of L-DOPA to dopamine. This step requires use of the enzyme <span style="font-style: italic; font-weight: bold;">DOPA decarboxylase</span>. Like the <span style="font-style: italic;">tyrosine hydroxylase</span> enzyme in the step before it, <span style="font-style: italic;">DOPA decarboxylase</span> also requires nutrient co-factors to optimally function. <span style="font-style: italic;">The main nutrient requirement of this en</span><span style="font-style: italic;">zyme, however, is a specific form of </span><span style="font-weight: bold; font-style: italic;">vitamin B6</span><span style="font-style: italic;">, known in this case as </span><span style="font-weight: bold; font-style: italic;">pyridoxal phosphate</span>. In addition to requiring adequate vitamin B6 levels to function properly, we also saw that other amino acids (namely <span style="font-weight: bold;">tryptophan</span>), can actually interfere and even compete with this process, so the post ended with the recommendation to <span style="font-style: italic;">avoid taking in tryptophan-rich foods</span> (which were listed in this fourth post)<span style="font-style: italic;"> at the same time as tyrosine was being supplemented</span>.<br /><br />in <a style="color: rgb(51, 51, 255);" href="http://adhd-treatment-options.blogspot.com/2010/02/does-tyrosine-supplementation-for-adhd.html"><span style="font-weight: bold;">post #5 on ADHD and tyrosine supplementation</span></a>, we examined the conversion process of dopamine to norepinephrine. It is important to note that this process is NOT universal across the body, or even throughout all regions of the brain and central nervous system, for that matter. However, since both dopamine and norepinephrine both can play major roles with regards to ADHD and the symptoms of the disorder, this enzymatic conversion process is still of importance. The enzyme used here for this step of the tyrosine metabolic pathway is called <a style="color: rgb(51, 51, 255); font-weight: bold; font-style: italic;" href="http://adhd-treatment-options.blogspot.com/2010/02/does-tyrosine-supplementation-for-adhd.html">dopamine beta hydroxylase</a>. Interestingly, the gene coding for this enzyme (which goes by the same name, the <span style="font-weight: bold; font-style: italic;">dopamine beta hydroxylase gene</span> and is located on the ninth human chromosome), has been implicated as a <a style="color: rgb(51, 51, 255);" href="http://adhd-treatment-options.blogspot.com/2008/09/adhd-gene4-dopamine-beta-hydroxylase.html">potential hereditary factor for ADHD</a>. Like the aforementioned <span style="font-style: italic;">tyrosine hydroxylase</span> <span style="font-weight: bold;">the dopamine </span><span style="font-style: italic; font-weight: bold;">beta hydroxylase </span><span style="font-weight: bold;">enzy</span><span style="font-weight: bold;">me is heavily dependent on ascorbic acid (vitamin C) as a cofactor<span style="font-weight: bold;">, </span></span>and heavy utilization of this enzyme (especially without adequate antioxidant pools in place to help regenerate the vitamin) can use up the body's overall supply of vitamin C.<span style="font-weight: bold;"><span style="font-weight: bold;"> </span></span><br /><br />-----------------------------------------------------------------------------------------------<br /><br /><span style="font-weight: bold;">Moving on to our sixth post in our series on ADHD and tyrosine</span>, however, we need to investigate the next step of the process, the conversion of norepinephrine to epinephrine (adrenaline). Keep in mind that this process is not universal, it is dependent on an enzyme called <span style="font-weight: bold; font-style: italic;">phenylethanolamine methyltransferase</span>, or <span style="font-weight: bold; font-style: italic;">PNMT </span>for short.<span style="font-weight: bold;"> </span>Interestingly, the gene which "codes" for this enzyme, also called <span style="font-style: italic;">PNMT</span>, has been linked to a common behavioral sub-component of ADHD called <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/18937842"><span style="font-weight: bold;">cogniti</span></a><a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/18937842"><span style="font-weight: bold;">ve impulsivity</span></a>. The <span style="font-style: italic;">PNMT</span> gene is located on the <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=171190">17th human chromosome</a>.<br /><br />In contrast to the other main type of ADHD-styled impulsivity, known as <span style="font-weight: bold;">aggressive behavioral impulsivity</span> (which is more characterized by arguing, having a short temper, conflicts with peers and adults, and the like, which is more characteristic of oppositional defiant and conduct disorders, and is seen more in the hyperactive/impulsive or combined ADHD subtypes), cognitive impulsivity often has more academic than behavioral inhibitions.<br /><br />Symptoms of cognitive impulsivity deal more with things such as having trouble waiting in line, struggling with maintaining a continuous focus on school assignments, inability to complete schoolwork, and being prone to every little distraction (a chirping bird outside, the sound of cars passing by on a nearby road, etc.). <span style="font-style: italic;">Cognitive impulsivity is therefore more reflective of the inattentive subtype of ADHD</span> (which is often more frequently seen in girls, and is often more easy to overlook than the other subtypes of ADHD). <span style="font-style: italic;"><span style="font-style: italic;"> </span></span><br /><br />It is interesting to note that differences in parent and teacher evaluations often occur over this type of impulsivity, since this type of behavior is often much more visible in a classroom setting<span style="font-style: italic;">. </span>Therefore, if a large discrepancy occurs between the parent and teacher rating scales, which are usually used to help diagnose and assess ADHD, cognitive impulsivity (and possibly even the factor of the <span style="font-style: italic;">PNMT</span> gene) <span style="font-weight: bold;">may</span>, in part, be to blame. (Please take this last statement as a possible explanation for this type of behavior and not as an excuse or a "cop-out" for a child's poor performance in school!)<br /><br />Returning from our aside on the possible genetic relationship between the <span style="font-style: italic;">Phenylethanolamine N-methyltransferase</span> (<span style="font-style: italic;">PNMT</span>) enzyme function and cognitive impulsive ADHD-like behavior, let's return to the chemical process and nutrient requirements of this enzyme. To us visualize this step of the process, here is a chemical depiction of the norepinephrine to epinephrine conversion:<a onblur="try {parent.deselectBloggerImageGracefully();} catch(e) {}" href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgk8Zf0YTpYgaL7g_PKq1Ci3ywE5nAFGgvP8LKgi4CNn0uhHudmzul9neChJNF1R9SbMpdXFlEYsBIMeOPoJ9_yHzioDS4uxIBgLqx2AfhV3_KWI__AHFzmkQQT2APiLOZ1wELAgsXm22U/s1600-h/tyrosine+supplementation+ADHD+norepinephrine+to+epinephrine+enzyme.PNG"><img style="margin: 0px auto 10px; display: block; text-align: center; cursor: pointer; width: 264px; height: 209px;" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgk8Zf0YTpYgaL7g_PKq1Ci3ywE5nAFGgvP8LKgi4CNn0uhHudmzul9neChJNF1R9SbMpdXFlEYsBIMeOPoJ9_yHzioDS4uxIBgLqx2AfhV3_KWI__AHFzmkQQT2APiLOZ1wELAgsXm22U/s400/tyrosine+supplementation+ADHD+norepinephrine+to+epinephrine+enzyme.PNG" alt="" id="BLOGGER_PHOTO_ID_5437505591983293810" border="0" /></a>Even if you're not a chemist, do you see how the norepinephrine molecule added a methyl (CH3) group on to the right end of it to get epinephrine? This is the working of the <span style="font-weight: bold; font-style: italic;">Phenylethanolamine N-Methyltransferase</span> (<span style="font-style: italic; font-weight: bold;">PNMT</span>) enzyme.<br /><br />However, the source of this methyl (CH3) group to be added to the molecule needs to come from somewhere. This is where an essential nutrient called <span style="font-weight: bold;">S-adenosyl-methionine</span> (as depicted in the diagram above by the downward arrow) comes into play.<br /><br />S-adenosyl-methionine often goes by other shorter names in the literature and in the grocery aisle, it is often referred to simply as <span style="font-weight: bold;">SAMe</span> or just "<span style="font-weight: bold;">SAM</span>". We will refer to it as "SAMe" from this point onward.<br /><br />SAMe is one of the hot new supplements out in the health food aisles these days, and while this blogger personally believes that this nutrient is a bit overhyped, it does offer a number of unique benefits which can possibly cover a whole array of disorders. It is a chemically-modified version of the amino acid <span style="font-weight: bold;">methionine</span>. The ability of SAMe to pass on or "donate" a methyl (CH3) group to another molecule (as in the above process where norepinephrine is converted to epinephrine) <span style="font-style: italic;">is a relatively rare property among dietary nutrients</span>, so SAMe does have a number of biochemical implications as a potential supplementation strategy. <br /><br />As far as psychiatric disorders are concerned, <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/12420702">SAMe is a particularly well-known natural supplement for treating depression</a>, and can often have a faster onset than several types of prescription medications (it can also be used in conjunction with antidepressant medications in several cases to augment these medications' effectiveness). SAMe has also been implicated as a potential treatment strategy for other neurological disorders such as <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/19276539">Alzheimer's</a> and <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/11104210">Parkinson's</a> diseases. However, while anecdotal evidence for SAMe's use in ADHD is moderately strong in some cases, very few reported clinical studies have been done on SAMe for ADHD. One very small study on<a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/2236465"> SAMe and ADHD</a> (only 8 people!) showed relatively positive results, however.<br /><br />Returning to the diagram here (see below), we see that one of the end products (that's what the curvy arrow means) of this interaction between the <span style="font-style: italic;">PNMT</span> enzyme and the SAMe nutrient is another compound called <span style="font-weight: bold;">homocyste</span><span style="font-weight: bold;">ine</span>.<br /><a onblur="try {parent.deselectBloggerImageGracefully();} catch(e) {}" href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjz6b1TZ1-FyMW6bBFWkoQKa8FhS4o6vct6FSTYteMpM0W7B2yaABwFUprENnPEjLRL1K6qV4HbztO8ucdim-reuLIgco7jYVuhWu4HQX5FifviCv9B0rDINBpAnM5-kyz1yzwIJyPIl10/s1600-h/tyrosine+supplementation+ADHD+norepinephrine+to+epinephrine+enzyme.PNG"><img style="margin: 0px auto 10px; display: block; text-align: center; cursor: pointer; width: 264px; height: 209px;" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjz6b1TZ1-FyMW6bBFWkoQKa8FhS4o6vct6FSTYteMpM0W7B2yaABwFUprENnPEjLRL1K6qV4HbztO8ucdim-reuLIgco7jYVuhWu4HQX5FifviCv9B0rDINBpAnM5-kyz1yzwIJyPIl10/s400/tyrosine+supplementation+ADHD+norepinephrine+to+epinephrine+enzyme.PNG" alt="" id="BLOGGER_PHOTO_ID_5437526245905048274" border="0" /></a><br />We have alluded to this potentially harmful pro-inflammatory compound in some of our previous posts on tyrosine supplementation, and also examined homocysteine in more detail in post further back dealing with <a style="color: rgb(51, 51, 255);" href="http://adhd-treatment-options.blogspot.com/2009/01/adhd-alcoholism-and-nutrient.html">ADHD, alcoholism and nutrient deficiencies</a>. As a natural byproduct of this norepinephrine to epinephrine conversion process, we must make sure that we are able to keep levels of homocysteine in check. We will see how we can potentially counter this with B vitamins and other nutrients in our next blog post on ADHD and tyrosine supplementation.<br /><br />However, the three main points we should take away from <span style="font-style: italic;">this </span>post on tyrosine supplements and ADHD are as follows:<br /><br /><ul><li>The conversion process of tyrosine to epinephrine does not occur in all cells, even in the brain and central nervous system. Many regions (even those associated with ADHD) "stop" with dopamine in the overall metabolic process of tyrosine.<br /></li></ul><ul><li>For the brain regions that do accommodate the norepinephrine to epinephrine conversion process, an adequately functioning enzyme called<span style="font-style: italic;"> <span style="font-weight: bold;">Phenylethanolamine N-Methyltransferase</span></span><span style="font-weight: bold;"> </span>(or <span style="font-style: italic; font-weight: bold;">PNMT</span>) is required.<br /></li></ul><ul><li>In order for the <span style="font-style: italic;">PNMT</span> enzyme to do its job in converting norepinephrine to epinephrine (adrenaline), adequate supplies of the nutrient <span style="font-weight: bold;">S-Adenosyl-methionine</span> (<span style="font-weight: bold;">SAMe</span>) are required. This process, however, can leave us with a potentially hazardous byproduct called <span style="font-weight: bold;">homocysteine</span>, which must be kept in check to reduce the risk of "inflammatory" diseases such as cancer or cardiovascular disorders. Nutritional intervention strategies must be put in place to help prevent unwanted accumulation of this homocysteine. This is part of the "cleanup process" of the tyrosine supplementation strategy for ADHD, and will be discussed at length in the next blog posting.<br /></li></ul>The ADHD Treatment Guidehttp://www.blogger.com/profile/00747782650821771627noreply@blogger.com21tag:blogger.com,1999:blog-2736612052295099842.post-14009472165366241922010-02-11T18:13:00.006-05:002010-02-11T21:12:53.326-05:00Does Tyrosine Supplementation for ADHD Actually Work? (Part 5)<span style="font-style: italic; font-weight: bold;">Part 5 on a series of posts on Tyrosine supplements for ADHD Treatment</span><br /><br />The amino acid tyrosine is often prescribed as an alternative strategy for treating ADHD, either alone (and often in the place of ADHD stimulant medications), or in combo with one or more medications for the disorder. But how effective is tyrosine really? Is it a valid ADHD treatment method, or just another theoretical supplement strategy that has only minimal positive effects on the disorder?<br /><br />In the past four posts, we have examined the following metabolic pathway of tyrosine in the conversion process of this amino acid to the neuro-signaling chemicals <span style="font-weight: bold;">dopamine, </span><span style="font-weight: bold;">norepinephrine</span>, and <span style="font-weight: bold;">epinephrine</span> (<span style="font-weight: bold;">adrenaline</span>) and the implications for this on the biochemical factors involved in the onset and treatment of <span style="font-weight: bold;">attention de</span><span style="font-weight: bold;">ficit hyperactivity disorder</span>.<a onblur="try {parent.deselectBloggerImageGracefully();} catch(e) {}" href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiVkmj_LQvluBaro5i7YyYXy4v38AOWC5gA8Q1ArFdjnrp_9XZoCwMRm9fNw4-uLhGKCHHyGMaiZTBG768nxfRjZRGslrXiIWj0uTPAOBPj3NNsH41btWjDk2zCWhI7prm2_ZFuH8XTiOc/s1600-h/ADHD+tyrosine+to+dopamine.PNG"><img style="margin: 0px auto 10px; display: block; text-align: center; cursor: pointer; width: 176px; height: 400px;" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiVkmj_LQvluBaro5i7YyYXy4v38AOWC5gA8Q1ArFdjnrp_9XZoCwMRm9fNw4-uLhGKCHHyGMaiZTBG768nxfRjZRGslrXiIWj0uTPAOBPj3NNsH41btWjDk2zCWhI7prm2_ZFuH8XTiOc/s400/ADHD+tyrosine+to+dopamine.PNG" alt="" id="BLOGGER_PHOTO_ID_5437130125036767890" border="0" /></a><ol><li><a style="color: rgb(51, 51, 255);" href="http://adhd-treatment-options.blogspot.com/2010/01/does-tyrosine-supplementation-actually.html"><span style="font-weight: bold;">In part 1 of our series on AD</span><span style="font-weight: bold;">HD and tyrosine supplementation</span></a>, we did a quick overview of the above process, the connection between regional levels of these compounds listed above with regards to the neuro-chemistry of ADHD, and gave a general theoretical basis for tyrosine supplementation (based on its metabolic profile and some of tyrosine's biochemical products and pathways in the body). We also introduced the concept of the <span style="font-weight: bold;">blood brain barrier</span>, which is a biochemical barrier that controls the flow of chemical agents into and out of the brain. This blood brain barrier has numerous implications for drug design and therapeutics, and must be dealt with if we are to get the desired compounds, drugs and nutrients into the brain.<br /><br /></li><li><a style="color: rgb(51, 51, 255);" href="http://adhd-treatment-options.blogspot.com/2010/01/does-tyrosine-supplementation-actually_28.html"><span style="font-weight: bold;">In part 2 of the tyrosine and ADHD discussion</span></a>, we looked at the enzyme <span style="font-style: italic;">Tyrosine Hydroxylase</span>, and the dietary nutrients which were involved in making this enzyme run effectively. Some of the nutrient-based strategy were based on clinical trials, while others were more based on theory.<br /><br /></li><li><a style="color: rgb(51, 51, 255);" href="http://adhd-treatment-options.blogspot.com/2010/02/does-tyrosine-for-adhd-actually-work-as.html"><span style="font-weight: bold;">Part 3 of the ADHD/tyrosine blog series</span></a> centered around the merits of starting with tyrosine as a supplementation strategy vs. bypassing tyrosine and starting with the second compound in the above pathway, <span style="font-weight: bold;">L-DOPA</span> (also called <span style="font-weight: bold;">Levodopa</span>). L-DOPA is commonly used as a treatment agent in Parkinson's Disease (which has a moderate degree of overlap with ADHD as far as chemical happenings are concerned), but we investigated the pro's and cons of starting with this agent vs. starting with its precursor tyrosine for treating <span style="font-weight: bold;">ADHD</span>. <br /><br /></li><li>and finally, <a style="color: rgb(51, 51, 255);" href="http://adhd-treatment-options.blogspot.com/2010/02/does-tyrosine-for-adhd-actually-work-a.html"><span style="font-weight: bold;">Part 4 of the tyrosine</span></a> postings zeroed in on the second major enzymatic step of the pathway, in which L-DOPA was converted to dopamine. This process is heavily dependent on a class of enzymes called <span style="font-weight: bold; font-style: italic;">aromatic amino acid decarboxylases</span>, with the main enzyme of focus being a specific type called <span style="font-weight: bold; font-style: italic;">DOPA decarboxylase</span>. In order for these enzymes to function, however, we discussed their dependence on a compound called <span style="font-weight: bold;">pyridoxal</span> <span style="font-weight: bold;">phosphate</span> (pyridoxal phosphate is an "active" form of Vitamin B6). We also looked at how competing amino acids and their products (namely the amino acid tryptophan and its product serotonin), actually share these enzyme systems and can interfere with the L-DOPA to dopamine conversion process and sabotage the effectiveness of the tyrosine-driven ADHD treatment strategy.</li></ol><span style="font-style: italic;"><span style="font-weight: bold;">And now, for part 5: the conversion process of the neurochemical </span></span><span style="font-weight: bold; font-style: italic;">dopamine</span><span style="font-style: italic; font-weight: bold;"> to another neurochemical, </span><span style="font-weight: bold; font-style: italic;">norepinephrine</span><span style="font-style: italic;"><span style="font-weight: bold;">...<br /><br />*Blogger's note: </span>What follows is a lengthy explanation of why dopamine and norepinephrine are so important for ADHD, and how they interact with specific proteins called "<span style="font-weight: bold;">transporters</span>" or "<span style="font-weight: bold;">receptors</span>" to regulate their overall levels in key "ADHD" brain regions. If you are short on time, you may want to bypass this long explanatory section which starts and ends with a triple asterisk (***).<br /><br />------------------------------------------------------------------------------------------------<br />***Begin explanatory section on dopamine and norepinephrine and ADHD<br /><span style="font-weight: bold;"></span></span><br />It is important to note, first of all, that this dopamine to norepinephrine conversion is not universal throughout all of the body, or even throughout the whole central nervous system. In many regions of the brain and nervous system, the chemical conversion process and metabolism of tyrosine "stops" at dopamine. However, in other key regions, the necessary enzymes exist to continue on with this conversion process to norepinephrine (and even beyond in some cases).<br /><br />First, we need to address the all-important question, however:<span style="font-style: italic;"> <span style="font-weight: bold;">Why is the conversion of dopamine to norepinephrine important with regards to treating ADHD?</span></span> To answer this question, we must look at some of the neuro-biology (and neuro-genetics) of some of the mechanisms which regulate dopamine and norepinephrine function in the brain:<br /><br />We have hinted elsewhere that both dopamine and norepinephrine (namely imbalances of these two neuro-signaling agents) play a major role in the pathology of ADHD and its symptoms in most cases. However, it is important to note one very important thing here: many of the studies implicating dopamine and norepinephrine in the pathology of ADHD are often concerned <span style="font-weight: bold;">more</span> with the <span style="font-weight: bold;">transport process</span> of these two signaling agents into and out of neuronal cells, and are often less concerned with the overall concentrations of these two chemicals in the body or even the central nervous system.<br /><br />Of course there is some degree of overlap (a vast overall deficiency of dopamine or its precursors, for example, would probably put one at more risk of having a deficit of this chemical in the key target areas of the brain), <span style="font-weight: bold; font-style: italic;">but we must get past the thinking that incorrectly assumes that if we just boost overall levels of these compounds across the board, then these chemical imbalances will just work themselves out</span>. This is simply not the case, and unfortunately, in this blogger's opinion, many advocates of supplementation instead of medications often fail to address this all-important issue of the transport process.<br /><br />Among the many different ways of transporting dopamine and norepinephrine in and out of the neuronal cells, we must look at two key players: the receptors and the transporters.<br /><br /><span style="font-weight: bold;">#1) The receptors:</span><br /><br />The receptors (in a nutshell), are located on the outside of a cell (in this case, the neuronal cells in the brain), and are the place where signaling agents such as dopamine, norepinephrine, histamine, etc. essentially "dock" onto the cell. Proper functioning of these receptors is especially important with regards to disorders such as ADHD. We have even looked at some of the specific genes which code for these receptors, and have analyzed how <span style="font-style: italic;">certain genetic forms of these "receptor genes" are often associated with a higher likelihood of having ADHD.</span><br /><br />For example, some of the earliest posts on this blog looked at specific genes that coded for dopamine receptors, such as the <a style="color: rgb(51, 51, 255);" href="http://adhd-treatment-options.blogspot.com/2008/08/seven-genes-associated-with-adhd.html"><span style="font-style: italic; font-weight: bold;">Dopamine D4 receptor gene (DRD4)</span></a> and the <a style="color: rgb(51, 51, 255); font-weight: bold;" href="http://adhd-treatment-options.blogspot.com/2008/09/adhd-gene-2-drd5.html"><span style="font-style: italic;">Dopamine D5 receptor gene (DRD5)</span></a> . The <span style="font-style: italic;">DRD4</span> gene is believed to be one of the most "heavily" influencing genes out there with regards to ADHD genes, while the <span style="font-style: italic;">DRD5</span> gene, while showing a somewhat weaker genetic connection to ADHD overall, seems to show a bit more of a specific connection to the inattentive component of ADHD (as opposed to the hyperactive/impulsive component of the disorder). <br /><br />With regards to genetics and chemical receptors for the neuro-chemical norepinephrine, it appears that there are also some genes which may affect this norepinephrine-receptor relationship. There is some evidence for a specific gene called <a style="color: rgb(51, 51, 255);" href="http://adhd-treatment-options.blogspot.com/2009/06/adhd-gene-adra1a-good-target-for.html"><span style="font-style: italic; font-weight: bold;">ADRA1A</span></a>. <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?cmd=entry&id=104221"><span style="font-style: italic;">ADRA1A</span> is a gene located on the 8th human chromosome</a>, and is believed to code for a specific receptor of norepinephrine. In fact, there are some implications that having a particular form of this <a style="color: rgb(51, 51, 255);" href="http://adhd-treatment-options.blogspot.com/2009/06/adhd-gene-adra1a-good-target-for.html"><span style="font-style: italic;">ADRA1A</span> gene may even influence the effectiveness of medications such as <span style="font-weight: bold;">clonidine</span></a> (which is a drug often used to treat hypertension, but is sometimes used "off-label" as an ADHD treatment medication. Clonidine has a different mode of action than the typical stimulants, but has found some success as a second or third level treatment method for certain types of ADHD). <span style="font-weight: bold; font-style: italic;"><br /><br />It is important to note that several of the most common ADHD medications target (either directly or indirectly) these transporters, which influences the overall balance of dopamine and norepinephrine in and out of cells. </span>In other words, if we want to truly replace drugs with nutrition for treating ADHD, we need to overcome this receptor problem (at least in theory). <span style="font-style: italic;">This is why (in the blogger's opinion) nutrition-based treatments often come up short, because while they may be able to influence production and overall levels of neuro-signaling agents such as dopamine and norepinephrine they are often nowhere near as chemically "potent" at modifying the transporter issues</span>. If you're interested, an earlier post talked about some of the specific genes, receptors and transporters, and how some of these <a style="color: rgb(51, 51, 255);" href="http://adhd-treatment-options.blogspot.com/2009/10/drugs-genes-and-adhd.html">"ADHD genes" may even play a specific role on how we should dose ADHD medications</a>.<br /><br /><span style="font-weight: bold;">#2) The transporters</span><br /><br />Switching gears away from dopamine and norepinephrine receptors, we must also examine another important class of proteins which regulate dopamine and norepinephrine levels both inside and outside of neuronal cells. These are called "transporters". As their name suggests, these agents essentially go one step further in the process by shuttling neuro-signaling chemicals such as dopamine and norepinephrine both into and out of cells. <span style="font-style: italic;">In other words, these dopamine and norepinephrine tranporters also play a vital role in the process. </span><br /><br />We can talk about these transporters all day (and we have, in other previous posts on this blog!), but for sake of brevity, I should just mention that specific genes for <a style="color: rgb(51, 51, 255);" href="http://adhd-treatment-options.blogspot.com/2008/09/adhd-gene3-dat.html">dopamine transporters</a> (called the <span style="font-style: italic; font-weight: bold;">dopamine transporter gene</span> or <span style="font-weight: bold; font-style: italic;">DAT</span>), and for <a style="color: rgb(51, 51, 255);" href="http://adhd-treatment-options.blogspot.com/2009/03/adhd-gender-and-slc6a2-gene.html">norepinephrine transporters</a> (called the <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=163970"><span style="font-style: italic;">norepinephrine transporter gene</span> or <span style="font-weight: bold; font-style: italic;">NET</span></a>, however, it is also referred to by another completely different name: <span style="font-style: italic; font-weight: bold;">SLC6A2</span>) both have been studied extensively with regards to their genetic influences on ADHD and related disorders. As mentioned earlier, these transporters often play major roles in medication responses, and may even be linked to co-occurring disorders in ADHD, such as <a style="color: rgb(51, 51, 255);" href="http://adhd-treatment-options.blogspot.com/2009/01/adhd-and-bulimia-connection.html">bulimia</a>, <a style="color: rgb(51, 51, 255);" href="http://adhd-treatment-options.blogspot.com/2009/02/ritalin-vs-cocaine-addiction-potential.html">drug addiction</a>, <a style="color: rgb(51, 51, 255);" href="http://adhd-treatment-options.blogspot.com/2009/04/strattera-atomoxetine-response-may-be.html">anxiety disorders</a>, etc.<br /><br /><span style="font-weight: bold;">*In other words, </span><span style="font-style: italic; font-weight: bold;">these receptors and transporters (as well as the influences they carry on regulating neurochemical levels) are some of the main reasons why ADHD is believed to be so genetically influenced.***</span><br /><br />-------------------------------------------------------------------------------------------------<br />***End explanatory section on the importance of regulating dopamine and norepinephrine levels in ADHD. The rest of the post is concerned with the dopamine to norepinephrine conversion process, and starts immediately below:<br /><br /><br /><br />Here is a chemical representation of the dopamine to norepinephrine conversion process (don't worry if you're not a chemist, just look at some of the names of the compounds, enzymes and nutrients involved in the process, we will discuss all of these in thorough detail below):<br /><br /><a onblur="try {parent.deselectBloggerImageGracefully();} catch(e) {}" href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEioquCg94cMvwWH27XNB4FHx6K9bXRvdnUg70FyLy5ThuZTncmcjCY2pC3-Bs8zmZbLV4rGzyIUxJkZWlSk5VV4DPyVQK8A0uBb9SpXvbkuRbKa_KQ4XlIgRuXHO6pP5EZKv_f0L0Dx-Z4/s1600-h/tyrosine+ADHD+dopamine+to+norepinephrine.PNG"><img style="margin: 0px auto 10px; display: block; text-align: center; cursor: pointer; width: 263px; height: 187px;" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEioquCg94cMvwWH27XNB4FHx6K9bXRvdnUg70FyLy5ThuZTncmcjCY2pC3-Bs8zmZbLV4rGzyIUxJkZWlSk5VV4DPyVQK8A0uBb9SpXvbkuRbKa_KQ4XlIgRuXHO6pP5EZKv_f0L0Dx-Z4/s400/tyrosine+ADHD+dopamine+to+norepinephrine.PNG" alt="" id="BLOGGER_PHOTO_ID_5437136822813638418" border="0" /></a><br />From the above picture, we should note the two main components which need to be addressed in the dopamine to norepinephrine conversion process:<br /><ol><li>The enzyme <span style="font-weight: bold; font-style: italic;">Dopamine Beta Hydroxylase</span>, and</li><li>The nutrient <span style="font-weight: bold;">ascorbic acid</span> (aka <span style="font-weight: bold;">vitamin C</span>), especially with its regard to oxygen (O2), as depicted above.<span style="font-style: italic; font-weight: bold;"></span></li></ol><span style="font-style: italic; font-weight: bold;">Dopamine Beta Hydroxylase</span> <span style="font-weight: bold;">enzyme</span>: We have examined <span style="font-style: italic; font-weight: bold;">Dopamine Beta Hydroxylase</span> (often abbreviated as <span style="font-weight: bold; font-style: italic;">DBH</span>) several times in previous posts. The <a style="color: rgb(51, 51, 255);" href="http://adhd-treatment-options.blogspot.com/2008/09/adhd-gene4-dopamine-beta-hydroxylase.html">gene coding for the <span style="font-style: italic;">DBH</span></a> enzyme (of which the gene shares the same name, "<span style="font-weight: bold; font-style: italic;">DBH</span>") is located on the 9th human chromosome. This enzyme is responsible for adding a <span style="font-weight: bold;">hydroxyl</span> (-OH) group off of the dopamine molecule, which leaves us with the new neuro-chemical <span style="font-weight: bold;">norepinephrine</span>. Note that this is the second time in the overall conversion process of tyrosine to L-DOPA to dopamine to norepinephrine that an "OH" group was added, the first being the work of an "OH" onto the hexagon ring of tyrosine to convert it to L-DOPA (see first diagram in this blog post if this is confusing). <span style="font-style: italic;"><br /><br />*Please note: It is important to note that <span style="font-weight: bold;">oxygen</span> is required for this step to work, as an oxygen atom is transferred from O2 to the dopamine molecule. In order for this chemical conversion to work, however, another agent (vitamin C) is required. This is where ascorbic acid (vitamin C) comes in</span>:<span style="font-weight: bold;"><br /><br />Ascorbic Acid (vitamin C):</span> We mentioned vitamin C in an earlier post, in that it can play a "helper" role in the <a style="color: rgb(51, 51, 255);" href="http://adhd-treatment-options.blogspot.com/2010/01/does-tyrosine-supplementation-actually_28.html">conversion of tyrosine to L-DOPA</a>, a process which utilizes the enzyme <span style="font-style: italic; font-weight: bold;">tyrosine hydroxylase</span>. <span style="font-style: italic; font-weight: bold;">Tyrosine hydroxylase</span> is dependent on iron, but the efficacy of the enzyme requires iron to operate in the "reduced" form as opposed to the "oxidized" form (the reduced form has iron in a "+2" positively charged state, and in the "oxidized" form, iron exists in the even more positively charged "+3" state. In nature how positively or negatively charged a certain element is can have drastic effects on its biological function. In the case of the <span style="font-style: italic;">tyrosine hydroxylase enzyme</span>, and the metabolism of tyrosine, this is no exception). Much of this "helper" role of vitamin C was due to the ability of the vitamin to keep the iron in the desired "+2" state. Some studies have found this <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/13171"><span style="font-style: italic;">tyrosine hydroxylase</span> enzyme to be significantly compromised in vitamin C deficient states (as in scurvy)</a>.<br /><br />However, while <span style="font-style: italic;">tyrosine hydroxylase</span> the enzyme <span style="font-style: italic;">Dopamine Beta Hydroxylase</span> appears to be even more heavily dependent on vitamin C, as mentioned in an earlier blog entry titled: <a style="color: rgb(51, 51, 255);" href="http://adhd-treatment-options.blogspot.com/2009/12/10-ways-vitamin-c-helps-treat-adhd.html"><span style="font-style: italic; font-weight: bold;">10 Ways Vitamin C Helps Treat ADHD Symptoms</span></a> (this was mentioned in point #9). For the conversion process of tyrosine to L-DOPA, much of vitamin C's usage was due to its antioxidant status, but for this <span style="font-style: italic;">dopamine beta hydroxylase</span> enzyme, which is used to convert dopamine to norepinephrine, vitamin C is used more of as a "co-factor" or "helper" to the enzyme.<br /><br />As mentioned above, vitamin C must be "sacrificed" to get the oxygen atom from the O2 molecule and onto the dopamine molecule to convert it to norepinephrine. The end result of this "sacrifice" is a different oxidized form of the vitamin, which is known as <span style="font-weight: bold;">dehydroascorbate</span>.<br /><br />This brings up another important point. We have seen in the past how vitamin C is often an "altruistic" agent in ADHD treatment, in that it frequently sacrifices itself for the well-being of other nutrients of importance to ADHD. For example, we've spoken at length about the problem of oxidation of omega-3 fatty acids (since omega-3 supplementation is a common ADHD supplementation strategy, this damaging oxidation process can be quite severe if not controlled for), and <a style="color: rgb(51, 51, 255);" href="http://adhd-treatment-options.blogspot.com/2009/09/omega-3-oxidation-in-adhd-problem-with.html">how vitamin C can help in preventing omega-3 oxidation in ADHD treatment cases</a>. Vitamin <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/9808773">C often helps "recycle" other antioxidants such as vitamin E</a> (which is much more fat-soluble than vitamin C, so it is often recommended for antioxidant treatment strategies for ADHD that vitamins C and E are used in tandem). <br /><br />Please note, then, that since vitamin C is used in the dopamine to norepinephrine pathway, and that it is essentially "lost" in the process (unless it is returned to its native ascorbic acid form by another antioxidant, such as <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/7844111">glutathione</a>), it is crucial that we maintain adequate levels of vitamin C. Furthermore, since vitamin C is a water soluble vitamin, it gets removed from the system quite easily. Therefore, it is imperative that we maintain adequate pools of this vitamin through diet or supplementation. A rough estimate of daily <a style="color: rgb(51, 51, 255);" href="http://lpi.oregonstate.edu/infocenter/vitamins/vitaminC/">vitamin C requirements can be found here</a>.<br /><br />However, since toxicity is rarely an issue with vitamin C (<a style="color: rgb(51, 51, 255);" href="http://lpi.oregonstate.edu/infocenter/vitamins/vitaminC/">see the upper limits of the vitamin here</a>, and note how much of a ceiling there is between the recommended levels and the upper limit), going slightly higher (i.e. 2 times the recommended amount) is rarely a problem. Therefore, this blogger personally recommends that since the vitamin is useful in at least 2 different parts of the tyrosine to dopamine and norepinephrine conversion process (involving both the <span style="font-style: italic;">tyrosine hydroxylase</span> enzyme for the conversion of tyrosine to L-DOPA and the <span style="font-style: italic;">dopamine beta hydroxylase</span> enzyme-driven conversion of dopamine to norepinephrine), those wishing to try tyrosine supplementation for ADHD should maintain adequate (if not slightly higher than "adequate") levels of the vitamin.<br /><br />We will wrap up our discussion of tyrosine supplementation for treating ADHD in the next few blog posts. We will look briefly at the norepinephrine to epinephrine conversion process, but focus more on some of the potentially harmful side-products of tyrosine metabolism, including the potential buildup of the pro-inflammatory agent <span style="font-weight: bold;">homocysteine</span>. Finally, we will finish with a final post on the blogger's thoughts on the whole process, recap the different nutrients needed to optimize enzyme function for overall tyrosine metabolism, and look at possible ways in which, instead of being used completely in isolation, tyrosine supplementation could also be used as an <span style="font-style: italic;">adjunct</span> or <span style="font-style: italic;">accessory</span> treatment to common ADHD medications, possibly optimizing their function and improving their effectiveness in treating ADHD and related disorders. <br /><span style="font-style: italic;"><span style="font-style: italic;"><span style="font-style: italic;"><br /></span></span></span>The ADHD Treatment Guidehttp://www.blogger.com/profile/00747782650821771627noreply@blogger.com76tag:blogger.com,1999:blog-2736612052295099842.post-89039612225106809042010-02-10T19:56:00.013-05:002010-02-10T22:07:53.315-05:00Does Tyrosine for ADHD Actually Work as a Supplementation Strategy?(part 4)We're attempting to answer the major question: <span style="font-style: italic;">Can ADHD symptoms be reduced via controlled supplementation with the amino </span><span style="font-style: italic;">acid tyrosine?</span><br /><br />This is the fourth in an in-depth multi-part blog series on how and why this amino acid is so frequently prescribed and used off-label as an ADHD treatment method. Reviews and literature findings are mixed, but some physicians (and parents and individuals with ADHD themselves) swear by tyrosine as a hugely successful treatment strategy for ADHD. We have spent the last three posts examining:<ol><li>The different enzymes and enzyme systems used in tyrosine metabolism</li><li>Which (if any) nutrient "helpers" or "co-factors" are required by these enzyme systems to function properly, and </li><li>The implications these have on the neuro-biology of ADHD</li></ol>I've included the following diagram in the last few posts, which highlights the major steps and intermediate products involved in the conversion process of tyrosine to dopamine and norepinephrine (the two desired targets of tyrosine supplementation with regards to ADHD treatment).<br /><a onblur="try {parent.deselectBloggerImageGracefully();} catch(e) {}" href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhpKv7sQCMs8vxQ5EwWyOZTo4q4jzD-_yVfmyvFjcfaDvZpOg2wWDMO32PLaWq1UVJ7O0o653Cj9LKTc6cT23nXOjhSlTwHrETQhHBvKEPQU9UARHBtJlQ1ZM4ZViEv0AJV1x1SAensQKY/s1600-h/ADHD+tyrosine+to+dopamine.PNG"><img style="margin: 0px auto 10px; display: block; text-align: center; cursor: pointer; width: 176px; height: 400px;" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhpKv7sQCMs8vxQ5EwWyOZTo4q4jzD-_yVfmyvFjcfaDvZpOg2wWDMO32PLaWq1UVJ7O0o653Cj9LKTc6cT23nXOjhSlTwHrETQhHBvKEPQU9UARHBtJlQ1ZM4ZViEv0AJV1x1SAensQKY/s400/ADHD+tyrosine+to+dopamine.PNG" alt="" id="BLOGGER_PHOTO_ID_5436786828316876450" border="0" /></a>As a quick recap:<ol><li>In <a style="color: rgb(51, 51, 255);" href="http://adhd-treatment-options.blogspot.com/2010/01/does-tyrosine-supplementation-actually.html">tyrosine and ADHD post #1</a>, we gave a general overview of the process and the roles of dopamine and norepinephrine on ADHD biology. We also looked at how tyrosine enters the brain, and which mechanisms are important for facilitating its transport to the desired targets for therapeutic effects with regards to ADHD (Please note that different forms of tyrosine exist, but the form most common in nature and in chemistry in general is referred to as "L-tyrosine". When this blog mentions "tyrosine", it is this "L" form we are referring to in all cases unless specified otherwise).<br /><br /></li><li>In the <a style="color: rgb(51, 51, 255);" href="http://adhd-treatment-options.blogspot.com/2010/01/does-tyrosine-supplementation-actually_28.html">second post on ADHD and tyrosine</a>, we focused on the first step of the process, the conversion of tyrosine to L-DOPA. This step heavily utilizes a specific enzyme called <span style="font-style: italic;"><span style="font-weight: bold;">tyrosine hydroxylase</span>. Tyrosin</span><span style="font-style: italic;">e Hydroxylase</span> is dependent on adequate supplies of certain nutrients such as <span style="font-weight: bold;">iron</span>, <span style="font-weight: bold;">magnesium,</span> <span style="font-weight: bold;">zinc</span>, <span style="font-weight: bold;">tetrahydrobiopterin</span>, and adequate levels of <span style="font-weight: bold;">vitamin C</span> (and antioxidants in general). While rampant supplementation is not necessary, inadequate levels of any of these agents (as well as a few others, such as copper) could potentially compromise the function of the <span style="font-style: italic;">tyrosi</span><span style="font-style: italic;">ne hydroxylase</span> enzyme. It is important to note that the <span style="font-weight: bold;">convers</span><span style="font-weight: bold;">ion of tyrosine to L-</span><span style="font-weight: bold;">DOPA is typically the slowest and rate-limiting step of the whole tyrosine metab</span><span style="font-weight: bold;">olism and conversion pr</span><span style="font-weight: bold;">ocess to dopamine and norepinephrine</span>. Thus, compromising this first conversion step can be potentially the most devastating with regards to impaired tyrosine metabolism for ADHD. This was why the post was a bit lengthy with regards to advocating for nutritional sufficiency.<br /><br /></li><li>The<a style="color: rgb(51, 51, 255);" href="http://adhd-treatment-options.blogspot.com/2010/02/does-tyrosine-for-adhd-actually-work-as.html"> third post on tyrosine and ADHD</a> focused more on the question as to whether we could bypass the first step of the chemical process outlined above <span style="font-style: italic;">ent</span><span style="font-style: italic;">irely</span> by supplementing with L-DOPA (the second major step of the tyrosine conversion process) directly. We discussed the pro's and con's of using each (tyrosine or L-DOPA) as a starting point for ADHD treatment. </li></ol><span style="font-weight: bold;">This brings us to today's post: the co</span><span style="font-weight: bold;">n</span><span style="font-weight: bold;">version of L-DOPA to dopamine. </span><span>This process is heavily dependent on an enzyme known as <span style="font-weight: bold; font-style: italic;">DOPA decarboxylase</span>. Here are some of the main components which need to be in pl</span><span>ace for this enzymatic conversion process to occur with efficiency:</span><br /><br /><span style="font-style: italic; font-weight: bold;">DOPA decarboxylase</span> belongs to a particular class of enzymes called <span style="font-style: italic; font-weight: bold;">aromatic amino acid decarboxylases</span>. The term" aromatic" here refers to a particular type of "ring" structure in the chemical compound (if you don't have a background in organic chemistry, take a look at the chemical depictions of <span style="font-weight: bold;">tyrosine</span>, <span style="font-weight: bold;">L-DOPA</span> and <span style="font-weight: bold;">dopamine</span> shown below:<br /><br /><a onblur="try {parent.deselectBloggerImageGracefully();} catch(e) {}" href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEh7zWZg5dBVOSCYQL-mQI9KNh9jfb6tiW4Ij1anQle5YQE2rH61RiS6kjMlYPQz7TAxeQFAVaN9iPvbv_W8JOLY_TN7CTPJxLNbMrn7cK5D1Rp3ywP-euzU_ug99CrkYK96cHAAH8FQrBo/s1600-h/ADHD+tyrosine+L-DOPA+dopamine.PNG"><img style="margin: 0px auto 10px; display: block; text-align: center; cursor: pointer; width: 264px; height: 323px;" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEh7zWZg5dBVOSCYQL-mQI9KNh9jfb6tiW4Ij1anQle5YQE2rH61RiS6kjMlYPQz7TAxeQFAVaN9iPvbv_W8JOLY_TN7CTPJxLNbMrn7cK5D1Rp3ywP-euzU_ug99CrkYK96cHAAH8FQrBo/s400/ADHD+tyrosine+L-DOPA+dopamine.PNG" alt="" id="BLOGGER_PHOTO_ID_5436796484285573618" border="0" /></a><br /><span style="font-style: italic;">***A quick note on the chemical processes shown above and below: If you're not a chemist, don't worry, just look at what's chan</span><span style="font-style: italic;">ging in the pictures above and below, which represents the chemical structure of these different</span><span style="font-style: italic;"> molecules involved in the tyrosine to dopamine conversion process. That hexagon-like structure on the left side of these molecules, (with the -OH groups coming off of it) is what makes these compounds "aromatic".<br /></span><br /><span style="font-style: italic;">The enzyme tyrosine hydroxylase simp</span><span style="font-style: italic;">ly adds another "-OH group" to the top-left side this hexagonal ring to make L-DOPA out of tyrosine. The chemical process of this conversion was the point of discussion in our </span><span style="font-style: italic;">second blog </span><span style="font-style: italic;">post on ADHD and tyrosine supplementation. Our next enzyme-driven step leaves this "</span><span style="font-style: italic;">aromatic" hexagonal ring alone, and instead works on chemically modifying the right side of the molecule, as we'll see in a second. </span>***<br /><br />The term originally comes from the fact that chemicals with this type of built-in structure often gave off a particular <span style="font-style: italic;">aroma</span>. <span style="font-style: italic;">Aromatic amino acid decarboxylases</span> essentially take a carbon dioxide off of these six-membered rings, which greatly changes the chemical properties and reactivity of the chemical compound in most cases. (Do you see how the right end of the molecule L-DOPA is "chopped off" to get to dopamine in the step shown below? That is the work of these <span style="font-style: italic;">decarboxylase</span> enzymes).<br /><a onblur="try {parent.deselectBloggerImageGracefully();} catch(e) {}" href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgZO9MgJrlFS3frpo8PgSx3jyXPMlYbf55dXOFu93nLahfUCIooGzyp_xgKqmZVWE_6GlhVrhSEvXsikVpaUSV9DbipAmGyM_lfGgQwK5sai-D8vh1Ri0zJGRRP5-fegtpvBjiazTGscDY/s1600-h/tyrosine+ADHD+L-DOPA+to+dopamine+DOPA+decarboxylase.PNG"><img style="margin: 0px auto 10px; display: block; text-align: center; cursor: pointer; width: 264px; height: 188px;" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgZO9MgJrlFS3frpo8PgSx3jyXPMlYbf55dXOFu93nLahfUCIooGzyp_xgKqmZVWE_6GlhVrhSEvXsikVpaUSV9DbipAmGyM_lfGgQwK5sai-D8vh1Ri0zJGRRP5-fegtpvBjiazTGscDY/s400/tyrosine+ADHD+L-DOPA+to+dopamine+DOPA+decarboxylase.PNG" alt="" id="BLOGGER_PHOTO_ID_5436814501310529490" border="0" /></a><br />Of these decarboxylase enzymes (there are several different variations), the "best" one for this conversion process is called<span style="font-weight: bold;"> </span><span style="font-style: italic; font-weight: bold;">DOPA decarboxylase</span>.<br /><br />Although <span style="font-style: italic;">DOPA decarboxylase</span> can be indirectly affected by several different nutrients (specifically shortages of nutrients), <span style="font-style: italic;">the main one involved in this step is called </span><span style="font-weight: bold;"><span style="font-style: italic;">pyridoxal phosphate</span>.</span> <span style="font-style: italic;">Pyridoxal phosphate is the chemically "active" form of </span><span style="font-weight: bold; font-style: italic;">vitamin B6</span><span style="font-style: italic;">.</span><br /><br />We have spoken about the merits of vitamin B6 with regards to ADHD and how it works in conjunction with other nutrients in previous posts. For example, <a style="color: rgb(51, 51, 255);" href="http://adhd-treatment-options.blogspot.com/2009/04/10-ways-zinc-can-combat-adhd.html">getting B6 into this desired pyridoxal phosphate form requires zinc</a> (another reason why adequate zinc levels are necessary for optimal tyrosine metabolism). It also appears that <a style="color: rgb(51, 51, 255);" href="http://adhd-treatment-options.blogspot.com/2008/11/treating-adhd-with-magnesium-and.html">vitamin B6 works well alongside magnesium as an ADHD treatment combination strategy</a>. Finally, <a style="color: rgb(51, 51, 255);" href="http://adhd-treatment-options.blogspot.com/2009/09/omega-3-oxidation-in-adhd-problem-with.html">vitamin B6 plays a role in the metabolism of omega-3 fatty acids</a> (omega-3 rich fish oil is a common "natural" treatment method for ADHD)<br /><br />Because of its vital role as a "co-factor" or "helper" of the <span style="font-style: italic;">DOPA decarboxylase</span> enzyme, which is responsible for converting L-DOPA to dopamine, <span style="font-style: italic;">it is imperative that we avoid shortages of this essential B vitamin</span>. A rough estimate of recommended daily intake levels of vitamin B6 can be found <a style="color: rgb(51, 51, 255);" href="http://ods.od.nih.gov/factsheets/vitaminb6.asp">here</a>. Keep in mind that over 100 different other enzymes also depend on vitamin B6 and its derivatives, so keeping adequate stores of this vitamin is essential.<br /><br />In addition to keeping up necessary vitamin B6 levels to help the <span style="font-style: italic;">DOPA decarboxylase</span> enzyme's ability to function properly in the second major chemical step of tyrosine metabolism, we must also mention an often-overlooked issue with the enzyme: the interaction of <span style="font-style: italic;">DOPA decarboxylase</span> with another common neurochemical signaling agent called <span style="font-weight: bold;">serotonin</span>.<br /><br />Serotonin is generated from another important amino acid called <span style="font-weight: bold;">tryptophan</span>. Tryptophan (like tyrosine) is an aromatic amino acid, and the two amino acids have several structural and functional similarities. While this may sound like a good thing at first, it can lead to some problems.<br /><br />One of these problems is the fact that if two chemicals share similar structural characteristics, enzymes which act on one may also act on the other. If the structural characteristics are close enough, the two agents can even compete for the same enzymes, or effectively block each other off or crowd each other out.<br /><br /><span style="font-style: italic;">This is precisely what can happen with the amino acid tryptophan and its product serotonin. </span> The tryptophan to serotonin process <span style="font-style: italic;">also</span> uses these aromatic amino acid decarboxylase enzymes (and interestingly, also uses vitamin B6 as a cofactor in the process. This is yet <span style="font-style: italic;">another</span> reason why we want to keep B6 levels up to speed!).<br /><br />**A generalized conversion process of tryptophan to serotonin is shown below. Note that this pathway is analogous to the tyrosine to dopamine pathway in a number of ways, including the addition of a hydroxyl (-OH) group in the first step and a decarboxylation (essentially the removal of carbon dioxide) in the second step, which utilizes both the aromatic amino acid decarboxylase enzymes and pyridoxal phosphate (vitamin B6). Do you see how these two processes can easily be in competition with each other for resources (the enzymes as well as the vitamin B6).<a onblur="try {parent.deselectBloggerImageGracefully();} catch(e) {}" href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEh1u_7-QY-eGmNsvao0FCPJ0o9B3zIXk4HJdPV96f2903ycj0DuB9b8DJ1_RL0i0TC-dm7U7x_bU3ThBXI7c6iTFqP043KvzE59qv5nxhLAH63bwEzb7-aZKhja4OUlqefabopRToIGhNw/s1600-h/tyrosine+ADHD+tryptophan+to+serotonin+conversion+pathway.png"><img style="margin: 0px auto 10px; display: block; text-align: center; cursor: pointer; width: 332px; height: 400px;" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEh1u_7-QY-eGmNsvao0FCPJ0o9B3zIXk4HJdPV96f2903ycj0DuB9b8DJ1_RL0i0TC-dm7U7x_bU3ThBXI7c6iTFqP043KvzE59qv5nxhLAH63bwEzb7-aZKhja4OUlqefabopRToIGhNw/s400/tyrosine+ADHD+tryptophan+to+serotonin+conversion+pathway.png" alt="" id="BLOGGER_PHOTO_ID_5436807581582058962" border="0" /></a><span style="font-weight: bold;">Additionally, the end product of the above process, <a style="color: rgb(51, 51, 255);" href="http://www.jbc.org/content/271/39/23954.abstract">serotonin, can also effectively shut the enzyme </a></span><a style="color: rgb(51, 51, 255);" href="http://www.jbc.org/content/271/39/23954.abstract"><span style="font-style: italic; font-weight: bold;">DOPA decarboxylase</span></a><span style="font-weight: bold;"><a style="color: rgb(51, 51, 255);" href="http://www.jbc.org/content/271/39/23954.abstract"> down</a>.</span> This process, in which an enzyme is essentially shut down by its final products, is often used in the body to keep from overproducing one particular kind of substance. It is known as <span style="font-weight: bold;">feedback inhibition</span>, and is a very common and crucial process for retaining chemical balances in the body.<br /><br />However, if large amounts of tryptophan are present, not only can the crowd out tyrosine for the <span style="font-style: italic;">dopa decarboxylase enzyme</span>, but the final product of this tryptophan (serotonin), can essentially shut the enzyme down for both processes. In other words, it's a double-whammy for tyrosine, along with the implications for its use as an ADHD treatment strategy.<br /><br />Actually, make that a triple-whammy. Remember how we mentioned that chemical compounds of similar structure can often crowd each other out? <span style="font-weight: bold;">It turns out that <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/15930466">tyrosine and tryptophan both compete with each other for transport into the brain</a>.</span> In the first post on this topic, we talked about the <a style="color: rgb(51, 51, 255);" href="http://adhd-treatment-options.blogspot.com/2010/01/does-tyrosine-supplementation-actually.html">blood brain barrier</a>, and how crossing this biochemical barrier was needed to successfully deliver the drug or nutrient-based treatment to the desired brain regions.<br /><br />This is not meant to blast tryptophan or serotonin. Both chemicals are crucial to a number of important bodily functions. Rather, it is the timing of the administration of these nutrients with which we should be careful. The main strategy here is to try to avoid taking tryptophan-rich foods alongside tyrosine supplements. Some foods which are <a style="color: rgb(51, 51, 255);" href="http://www.nutritiondata.com/foods-000079000000000000000.html">high in tryptophan can be found here</a>. Keep in mind, however, that many of these tryptophan-rich foods may also be high in tyrosine (such as wild game and several types of seeds like pumpkin seeds). Some of the more tryptophan-concentrated foods are milk, turkey, and legumes (chick peas, peanuts, etc.), so it would be a good idea to refrain from these rich sources of tryptophan for a couple of hours on either side of tyrosine supplementation.<br /><br />So with regards to the second major step of tyrosine supplementation, the conversion of L-DOPA, we should remember these 2 main things:<br /><br /><ol><li>Keep up adequate levels of vitamin B6 to help the DOPA decarboxylase enzyme function at peak efficiency.<br /></li><li>Try to avoid taking in tryptophan-rich foods anytime near the time you take your tyrosine supplements. This will help you avert most of the competitive biochemical processes between these two nutrients, and can ultimately improve the efficacy of tyrosine as an ADHD treatment strategy.<br /></li></ol>The ADHD Treatment Guidehttp://www.blogger.com/profile/00747782650821771627noreply@blogger.com15tag:blogger.com,1999:blog-2736612052295099842.post-85450750129356032662010-02-05T20:58:00.006-05:002010-02-07T19:38:31.949-05:00Does Tyrosine for ADHD Actually Work as a Supplementation Strategy? (part 3)<div><strong><em>Can we treat ADHD symptoms via Tyrosine supplementation?</em></strong><br /><div><br />This is the 3rd post in our series of discussions regarding ADHD and supplementation with the amino acid <strong>tyrosine</strong>. Some physicians (and ADHD patients) swear by it, but the results in the literature and clinical studies are often muddled. <em>Why is this the case?</em><br /><br />Over the past few postings, I have been going over the metabolic pathway of how the body converts the amino acid tyrosine to our desired brain chemicals of dopamine and norepinephrine. Imbalances of both dopamine and norepinephrine are typically seen in ADHD, and this imbalance is the target of most ADHD medications (especially the stimulants) during their modes of action.<br /><br />Here is the metabolic pathway on Tyrosine to Dopamine and Norephinephrine again (you can click on the image to get a larger view, or see the original image source <a href="http://en.wikipedia.org/wiki/File:Catecholamines_biosynthesis.svg"><span style="color: rgb(51, 51, 255);">here</span></a>):<br /></div><p><img style="margin: 0px auto 10px; text-align: center; width: 176px; display: block; height: 400px;" id="BLOGGER_PHOTO_ID_5434946184748549794" alt="" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhZnIIytZjoA6Q5DnmaK5TFmdJC0u5xgHhoB6JIy9eREaVZUArXyt6v6JmqIhks3gWrElFeKZsQe1iTBlJL12S9XhXL31RuNScYARftlffHcGSTmCOqELveqJDWCesGfXiru7eHQGHpgg4/s400/ADHD+tyrosine+to+dopamine.PNG" border="0" />In our first post on <a href="http://adhd-treatment-options.blogspot.com/2010/01/does-tyrosine-supplementation-actually.html"><span style="color: rgb(51, 51, 255);">ADHD and tyrosine supplementation</span></a>, we went through the overview of this pathway. In our <a href="http://adhd-treatment-options.blogspot.com/2010/01/does-tyrosine-supplementation-actually_28.html"><span style="color: rgb(51, 51, 255);">last posting</span></a>, we went through the first step of the process: the conversion of tyrosine (also referred to as L-tyrosine) to DOPA (also referred to as <strong>L-DOPA</strong>, <strong>Levodopa</strong> and a number of trade names such as <strong>Dopar</strong>, <strong>Laradopar</strong> or <strong>Sinemet</strong>), and the enzymes and nutrient co-factors involved in this conversion process. L-DOPA is a common treatment method for patients with Parkinson's Disease. </p><p>I was going to start with the next step of the process today: the conversion of L-DOPA to dopamine, and the major enzymes involved. However, one of our readers from the <a href="http://adhd-treatment-options.blogspot.com/2010/01/does-tyrosine-supplementation-actually_28.html"><span style="color: rgb(51, 51, 255);">previous posting</span></a> on the conversion of Tyrosine to L-DOPA, posed an excellent question on a topic I failed to address (which may be on the minds of several readers). As a result, I will dedicate the remainder of this post to this question and save the next step of the tyrosine to dopamine pathway for the next blog entry. </p><p>LynneC asked about <em>the advantages of supplementing with tyrosine vs. supplementing directly with L-DOPA. </em>As we saw in the previous posting on <a href="http://adhd-treatment-options.blogspot.com/2010/01/does-tyrosine-supplementation-actually_28.html"><span style="color: rgb(51, 51, 255);">tyrosine supplementation for ADHD</span></a>, the tyrosine to dopamine conversion requires one major enzyme (<em><strong>tyrosine hydroxylase</strong></em>) and several secondary enzymes (to produce some of the compounds needed to help the <span style="font-style: italic;">tyrosine </span>hydroxylase enzyme to function properly), as well as nutrient co-factors such as <strong>iron,</strong> <strong>zinc</strong>, <strong>magnesium</strong>, and even antioxidants or reducing agents such as <strong>vitamin C</strong>.<br /><br />Further complicating the issue, we saw that individual variation across the gene pool leads to different forms of this <span style="font-style: italic;">tyrosine hydroxylase</span> enzyme, some of which are notably more effective or "potent" than others. In other words, some people are more disposed to having an efficient metabolic conversion of tyrosine to L-DOPA than others. </p><p>If this is the case, why should we mess with tyrosine at all? Shouldn't we just bypass this first step of the process entirely and start with L-DOPA? Here are a few things to consider:<br /></p><ol><li><strong>Supplement Availability:</strong> L-Tyrosine is available over-the-counter. However (until relatively recently), L-DOPA required a prescription. This is not the case anymore, however, as L-DOPA supplements are available in countries like the United States (I believe that a prescription is still required in Canada, however, but I could be wrong).<br /><br /><em>Blogger's note: Even though both of these agents are available without a prescription, this blogger believes is is <strong>EXTREMELY</strong> <strong>important for you to talk to your physician before giving either of these supplements a try</strong>.<br /><br />Both tyrosine and L-DOPA can undergo biochemical transformations via a number of different pathways (i.e. not just in the conversion to catecholamines in the brain such as dopamine and norepinephrine). Both can interact with other medications (especially certain classes of anti-depressants known as <strong>MAOI's</strong> or <strong>monoamine oxidase inhibitors</strong>), as well as with each other, and overdosing is possible. <strong>Additionally, individuals with certain forms of cancer (especially skin cancers) or eye disorders such as glaucoma are typically instructed to avoid both treatments entirely</strong>. PLEASE check with a physician before starting either of these as a therapy for ADHD or ANY other reason.</em><br /><br /><strong>ADVANTAGE with regards to ADHD treatment: Tyrosine</strong><br /><br /></li><br /><li><strong>Cost:</strong> I did a quick search on the costs of both supplements (keep in mind that brand names, strengths and quantities can cause extreme variation), and from what I've seen, <strong>L-DOPA often costs somewhere from about $65 to $150 US dollars for 100 tablets</strong>. Please note that L-DOPA typically comes in a combination form of Levodopa and another compound called <strong>Carbidopa </strong>(<a href="http://home.caregroup.org/clinical/altmed/interactions/Drugs/L-Dopa.htm"><span style="color: rgb(51, 51, 255);">Carbidopa greatly aids in the absorption of Levodopa</span></a> and helps minimize unwanted side-reactions of the Levodopa drug, so almost all standard formulas now exist in this Levodopa/Carbidopa tandem). For tyrosine, the cost is much lower, as I've seen ads online for a bottle of 100 capsules (500 mg strength, note that many individuals who supplement with tyrosine take doses <em>around</em> this level 3 times a day) for only <strong>$2 to $3 dollars a bottle</strong>. Clearly, the cost of taking L-tyrosine is much lower.<br /><br /><strong>ADVANTAGE for treating ADHD: Tyrosine</strong><br /><br /></li><br /><li><strong>Step in the conversion pathway:</strong> In the previous post, we saw how certain enzymes (<em><strong>tyrosine hydroxylase</strong></em>) and nutrient "co-factors" (co-factors essentially function as "helpers" to the enzyme, making it function more effectively. If these co-factors are missing or deficient, the enzyme is often compromised, and the metabolic conversion process is reduced. <em>In this blogger's opinion, co-factor shortages are one of the most overlooked reasons why natural, dietary or supplementation strategies for ADHD treatment often fail</em>), such as <strong>iron</strong>, <strong>zinc</strong>, <strong>magnesium</strong>, and <strong>vitamin C </strong>are needed, either directly or indirectly to aid the process.<br /><br /><strong>ADVANTAGE for ADHD treatment: L-DOPA</strong>*<br />* Starting directly with L-DOPA bypasses these factors or complications (but poses its own set of challenges, as we'll see later in this post, more about this in a minute). </li><br /><br /><li><strong>Transportability across the blood-brain barrier:</strong> We talked at length about the blood-brain barrier in the past two posts, but to recap: The blood-brain barrier is a biochemical barrier designed to keep potentially hazardous or toxic compounds (that accidentally get into the blood) from getting into the brain (where these substances are often much more devastating). It also acts like a sort of "filtering" system, controlling or regulating the transport of "good" compounds in the brain, reducing the risk of imbalances from these chemicals.<br /><br />Unfortunately (especially for drug manufacturers), this barrier also blocks out many potential therapeutic agents, so drugs targeting specific brain regions must be chemically designed to pass through this blood-brain barrier to be effective. It is worth noting that both tyrosine and L-DOPA can cross through this barrier, so both are acceptable methods of delivery to increase or balance out dopamine and norepinephrine levels in the brain.<br /><br />On a side note (and mentioned in our previous discussions on the matter), dopamine and norepinephrine typically are NOT able to pass through the blood brain barrier, meaning that these compounds need to be manufactured inside of the brain. This is why we cannot supplement with either of these agents directly.<br /><br /><strong>ADVANTAGE for ADHD: A draw. Both Tyrosine and Levodopa can cross the blood-brain barrier**<br /><br />**</strong>We will see in the next few points, how this "tie" between the two may not be entirely true.<br /><br /></li><li><strong>"Target" specificity:</strong> Here is where the real difference lies. In the past few posts, we have been vague with regards to the specific brain regions in which chemical imbalances of dopamine and norepinephrine are found in the ADHD brain. It is important to note, that these deficiencies/imbalances are not uniform throughout the body (or even the brain) in the ADHD individual.<br /><br />Certain brain regions are frequently identified as target sites of chemical imbalances (which typically exist as deficits, not excesses) of the neurotransmitters <strong>dopamine</strong> and <strong>norepinephrine</strong>. <em>By no means is this list extensive</em>, but two brain regions which are commonly associated with shortages of these signaling chemicals are the <strong>striatum</strong> and the <strong>prefrontal cortex</strong> (as an interesting aside, these <a href="http://adhd-treatment-options.blogspot.com/2009/03/2-key-brain-regions-which-are-smaller.html"><span style="color: rgb(51, 51, 255);">2 brain regions have been found to be proportionally smaller in ADHD individuals</span></a> according to some studies and <a href="http://adhd-treatment-options.blogspot.com/2009/01/adhd-vs-ocd-brain-regions-and-bloodflow.html"><span style="color: rgb(51, 51, 255);">bloodflow patterns to the prefrontal cortex</span></a> have been found to be different in the ADHD brain vs. the brains of patients with other disorders such as Obsessive Compulsive disorders). <img style="margin: 0px auto 10px; text-align: center; width: 332px; display: block; height: 400px;" id="BLOGGER_PHOTO_ID_5434979220485499842" alt="" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEj_VLnOwWwnPBSFo8HS0gybaNboDCKwgzk6E4VkWb7N-q54IMKu5IYfbPWrIS_XZLiDILZ1zmz_Gp4gjr_CFurz9B0Zmw-yzvd8mIAGLfwC-5gWspdVlimmPiTlyqcYS-PPg-krsdVtvpY/s400/ADHD+tyrosine+supplementation+striatum+prefrontal+cortex.jpg" border="0" /><br />Shown above is a picture of an individual's brain. We are looking from the top down on a patient facing forward (the front is towards the top of the page). Several key "ADHD brain regions" are highlighted. The rough location of the <span style="color: rgb(153, 51, 0);"><strong>prefrontal cortex</strong><span style="color: rgb(0, 0, 0);">, shown in <span style="color: rgb(153, 51, 0);"><strong>brown</strong></span>, is a major region of importance where ADHD treatment is of concern. The <span style="color: rgb(0, 153, 0);"><strong>green</strong></span>, <span style="color: rgb(255, 0, 0);"><strong>red</strong></span> and <span style="color: rgb(51, 51, 255);"><strong>blue</strong></span> regions represent approximate locations of sub-components of a brain region collectively called the <strong>corpus striatum</strong>. Both the prefrontal cortex and the corpus striatum regions of the brain are thought to be common sites of imbalance of the brain chemicals <a href="http://www.ncbi.nlm.nih.gov/pubmed/15691523"><span style="color: rgb(51, 51, 255);">dopamine</span></a> and and <a href="http://www.ncbi.nlm.nih.gov/pubmed/19445548"><span style="color: rgb(51, 51, 255);">norepinephrine</span></a>.<br /><br /></span></span>Getting back to our main point here, however, is the fact that supplementation with <em><a href="http://pharmrev.aspetjournals.org/content/32/4/315.abstract"><span style="color: rgb(51, 51, 255);">tyrosine typically reaches its targets with much more specificity than does L-DOPA</span></a></em>. In other words, <strong>if target region specificity is what we're after, then supplementation with tyrosine shows a slightly better track record</strong>, at least according to the literature reviewed by this blogger. <em>Keep in mind, however, that this assertion hinges on only a few older studies, and the findings are far from definite.<br /><br /></em><strong>SLIGHT ADVANTAGE for treating ADHD: Tyrosine</strong><br /><br /></li><br /><li><strong>Fewer negative side effects:</strong> This ties in with the previous point, to a certain extent. L-DOPA, is, and continues to be, a treatment for Parkinson's, and not designed specifically for ADHD. However, in addition to being a chemical precursor to dopamine and norepinephrine, L-DOPA can also be converted to the agent <span style="font-weight: bold;">melanin</span> (which is responsible for skin pigmentation, among other things). The problem with this, however, is the fact that this conversion process can sometimes go overboard, and result in rapid generation and buildup of this (and related) compounds, <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/19789839">increasing the risk of melanoma and related skin cancers</a>.<br /><br />The actual magnitude of this <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/20063399">L-DOPA/skin cancer association, however, is often questionable</a>. While higher rates of skin cancer are seen in Parkinson's patients treated with L-DOPA, this finding is often negated by the fact that the cancer was present <span style="font-style: italic;">before</span> the start of the L-DOPA treatment. Furthermore, general medical recommendations are often to refrain from L-DOPA or tyrosine supplementation in Parkinson's patients who are in various stages of these cancers. In other words, tyrosine may not be much better in this regard.<br /><br />Both tyrosine and L-DOPA have limitations, and potentially negative interactions. This includes kidney and liver dysfunctions, cases of depression where specific anti-depressants called MAOI's (short for monoamine<span style="font-weight: bold;"> </span>oxidase<span style="font-weight: bold;"> inhibitors</span>) are taken (both tyrosine and L-DOPA can negatively interact with MAOI function).<br /><br />Possible <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/15804266">buildup of the compound <span style="font-weight: bold;">homocysteine</span></a> (a pro-inflammatory agent which has been implicated in everything from heart disease and cardiovascular disorders to depressive symptoms to cancer) can also be linked to tyrosine and L-DOPA intake, because both can serve as chemical precursors to this potentially dangerous compound. We will see how homocysteine ties in to all of this within the next few posts (as we work our way down the tyrosine to dopamine and norepinephrine pathway), and how its buildup can be reduced by taking in adequate levels of certain <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/15261610">B vitamins</a> and other nutrients. More on this later.<br /><br />In the meantime, please realize that there are hundreds of different ways tyrosine and L-DOPA levels can affect the body, so trying to classify one as "safer" is not necessarily so cut-and-dry. However, in this blogger's opinion, tyrosine, since it is a naturally occurring dietary food-source, has the advantage of over L-DOPA in that it is one step closer to "nature". Tyrosine <span style="font-style: italic;">is</span> typically less potent than L-DOPA, so a higher dosage of tyrosine is typically required to get the same effects (in other words, we shouldn't be comparing, say a 500 mg dose of tyrosine with a 500 mg dose of L-DOPA, the effects of L-DOPA at this dose would be much more pronounced).<br /><br />Furthermore, as we have seen in the last post on <a style="color: rgb(51, 51, 255);" href="http://adhd-treatment-options.blogspot.com/2010/01/does-tyrosine-supplementation-actually_28.html">tyrosine and ADHD</a>, the enzyme-mediated conversion of tyrosine to L-DOPA is actually limited or shut off by the generation of the catecholamine "end-products" <span style="font-weight: bold;">dopamine </span>and <span style="font-weight: bold;">norepinephrine</span>. When high levels of these compounds are generated under normal conditions, these <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/16105651">catecholamine compounds actually bind to and inhibit the enzyme <span style="font-style: italic;">tyrosine hydroxylase</span></a> (which converts tyrosine to L-DOPA), thereby limiting further tyrosine to dopamine conversion.<br /><br /><span style="font-style: italic;">In other words, it appears that tyrosine has slightly better designed "control-switches" to keep its end products in check than does L-DOPA</span>. We may be splitting hairs here (since both tyrosine and L-DOPA are natural metabolites of the body, both can be quite safe <span style="font-style: italic;">if the correct levels are taken and none of the pre-existing conditions exist or competing medications are being used</span>), but according to all of the information this blogger currently has, <span style="font-style: italic;">tyrosine supplementation for ADHD treatment seems to be the safer bet here</span>.<br /><br /><span style="font-weight: bold;">ADVANTAGE</span>: Tyrosine (just make sure to consult with a physician before trying this supplement, even though it is readily available over-the-counter).<br /><br /></li><br /><li><strong>Overall effectiveness and potency: </strong><strong style="font-weight: normal;">While both L-Dopa and tyrosine have often been prescribed for ADHD as more natural or "gentler" alternatives to pharmaceuticals, and "success" stories abound on individual cases, the overall literature tends to be less praise-worthy. From the studies this blogger has seen most of them show a temporary boost in effectiveness, but the positive results are often short-lived. Tolerance generally seems to be an issue, as in the case of a small study on direct <a style="color: rgb(51, 51, 255);" href="http://ajp.psychiatryonline.org/cgi/content/abstract/144/8/1071">tyrosine treatment for ADHD</a>. In this study, the effectiveness of tyrosine wore off after 2 weeks. A similar study was done with <a style="color: rgb(51, 51, 255);" href="http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6TBV-45Y22VX-9W&_user=10&_coverDate=02%2F28%2F1982&_rdoc=1&_fmt=high&_orig=search&_sort=d&_docanchor=&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=7b66eed85284a941020ecddae7b398bc">L-DOPA (levodopa) on ADHD boys</a>, and the results were similar. Initially, there was a positive response, but these results were also short lived.<br /><br />Curiously, most of these studies involving direct tyrosine or L-Dopa dependent treatment of ADHD are relatively old ones, most of which took place in the early 1980's (many were done by the same research group). There currently does not seem to be a whole lot of new material on this topic (at least to the best of this blogger's current knowledge).<br /><br />Furthermore, neither of these studies co-supplemented with the aforementioned nutrient "cofactors" to help with the metabolism and conversion to dopamine or norepinephrine. There is no telling what the status of <span style="font-weight: bold;">magnesium</span>, <span style="font-weight: bold;">zinc</span>, <span style="font-weight: bold;">iron</span>, or antioxidant levels (all of which can have an effect on tyrosine metabolism, as we've seen in the previous post on <a style="color: rgb(51, 51, 255);" href="http://adhd-treatment-options.blogspot.com/2010/01/does-tyrosine-supplementation-actually_28.html">tyrosine supplementation for ADHD</a>).<br /><br />Additionally, another nutrient called <span style="font-weight: bold;">pyridoxal phosphate</span> also plays a role in the next step of the chemical conversion process of L-DOPA to dopamine (pyridoxal phosphate is a derivative of <span style="font-weight: bold;">vitamin B6</span> which is used to help the enzyme <span style="font-style: italic; font-weight: bold;">dopa decarboxylase </span>to function properly. We will be investigating this nutrient/enzyme pairing in the next post, when we look at the next step of the dopamine conversion process). </strong>Levels of this key ingredient (at least in this blogger's opinion) need to be factored in when we evaluate the true merits of tyrosine or L-DOPA treatment for ADHD and related disorders.<br /><br /><span style="font-weight: bold;">ADVANTAGE as an ADHD treatment method: </span>Too close to call. In addition to their individual usage, tyrosine/L-DOPA/carbidopa (we will discuss why this <span style="font-weight: bold;">carbidopa</span> compound is often used alongside L-DOPA in the next section) can be used <span style="font-style: italic;">together to boost each others' effectiveness. </span>Anecdotal reports laud the effectiveness of tyrosine/L-DOPA/carbidopa in combination as an effective ADHD treatment, but again, detailed clinical trials <span style="font-weight: bold;">specifically designating ADHD </span>are relatively scarce. In other words, although the literature findings on the subject seem to be scarce and somewhat discouraging, additional factors (such as the extra nutrients and enzyme co-factors which we are currently laying out) could possibly lead to more effective studies with more promising results on the topic of ADHD treatment via tyrosine and/or L-DOPA supplementation.<br /></li></ol><div></div></div>The ADHD Treatment Guidehttp://www.blogger.com/profile/00747782650821771627noreply@blogger.com18tag:blogger.com,1999:blog-2736612052295099842.post-11162521206345974382010-01-28T19:48:00.008-05:002010-01-29T04:13:56.159-05:00Does Tyrosine Supplementation Actually Work for ADHD? (part 2)<span style="font-style: italic; font-weight: bold;">Can ADHD symptoms be alleviated by supplementing with the amino acid tyrosine? </span><br /><br />This post is a continuation from our introductory one on the effectiveness of tyrosine as an ADHD supplementation strategy.<br /><br /><span style="font-style: italic;">(Blogger's note: if you do not have the time or the patience to wade through all of this information, I have provided a 7-point summary at the bottom of the page, which goes over the major points of this blog posting. If you do have the time, however, there is a lot of material and valuable research in the posting below surrounding the complex metabolic processes surrounding just one step of the tyrosine supplementation pathway for ADHD treatment). </span><br /><br />The theory behind using the amino acid tyrosine to treat ADHD symptoms stems from the fact that tyrosine is a chemical precursor to important neurotransmitters (chemical signaling agents in the nervous system) <span style="font-weight: bold;">dopamine</span> and <span style="font-weight: bold;">norepinephrine</span>. Dopamine and norephinephrine belong to a class of signaling agents called <a style="color: rgb(51, 51, 255);" href="http://en.wikipedia.org/wiki/Catecholamine"><span style="font-weight: bold;">catecholamines</span></a>. Numerous studies have shown that <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/11864734">imbalances of both of these catecholamine agents exist in most ADHD cases</a>, and the imbalances are often on the low end (i.e. lower levels of dopamine and norepinephrine are found in several critical regions of an ADHD brain when compared to a "normal" brain).<br /><br />Of course, this is a vast oversimplification of the whole process (which is much more complex), but the basic idea is that we "feed" the brain with higher levels of tyrosine and it is then able to create more of these two neurotransmitters. This idea, of giving the body higher amounts of starting material to use to convert into higher levels of the specific chemicals we want to produce is often referred to as <span style="font-weight: bold;">precursor loading</span>.<br /><br />Unfortunately, as we might imagine, the process of correcting these chemical shortages an imbalances (and solving all of our ADHD problems in the process) is much more complex than popping a few tyrosine supplements. Shown below is a diagram of most of the major chemical "steps" needed to go from tyrosine (written as "L-tyrosine" below) to the catecholamines dopamine and norepinephrine A larger version of the diagram can be found by clicking the figure (in most browsers, or at the original source of the diagram, which can be found <a style="color: rgb(51, 51, 255);" href="http://en.wikipedia.org/wiki/File:Catecholamines_biosynthesis.svg">here</a>).<em><strong><br /></strong></em><a onblur="try {parent.deselectBloggerImageGracefully();} catch(e) {}" href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEg4yvK44RAVXocAM2Ru194Pojvu5nD1SSF3bXOTWlLAg0a3VxNMbg2Xw5C1qiKGbTT5bjHL3Tyq9AupEr_7wntFRUe7qkJQs8oeAsPrFaDLp-4Z2_uxMcf1zP0Lc9lYHnjSskWpXrD_3GE/s1600-h/ADHD+tyrosine+to+dopamine.PNG"><img style="margin: 0px auto 10px; display: block; text-align: center; cursor: pointer; width: 176px; height: 400px;" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEg4yvK44RAVXocAM2Ru194Pojvu5nD1SSF3bXOTWlLAg0a3VxNMbg2Xw5C1qiKGbTT5bjHL3Tyq9AupEr_7wntFRUe7qkJQs8oeAsPrFaDLp-4Z2_uxMcf1zP0Lc9lYHnjSskWpXrD_3GE/s400/ADHD+tyrosine+to+dopamine.PNG" alt="" id="BLOGGER_PHOTO_ID_5431963351769421570" border="0" /></a>We might be asking ourselves the question: <span style="font-style: italic;">Why can't we just supplement with dopamine or norepinephrine catecholamines directly to combat these ADHD-related shortages?</span> The answer has to do with a biochemical entity known as the <span style="font-weight: bold;">blood brain barrier</span>.<br /><br />The blood brain barrier is a special biochemical barrier used to control the transport of nutrients in and out of the brain. It is largely a protective measure, meant to keep toxic chemicals, which may have worked their way into the blood, out of the highly susceptible brain region. However, this blood brain barrier can also keep out some of our desired drug targets or chemical agents, including dopamine. Thus, <span style="font-style: italic;">while tyrosine (or as we'll also see in a later post, L-DOPA) can cross this barrier, dopamine cannot</span>. As a result, we need to start with either tyrosine or L-DOPA on the <span style="font-weight: bold;">outside</span> of the blood brain barrier, shuttle these agents <span style="font-weight: bold;">into</span> the brain, and then have the brain convert them to the desired compounds.<br /><br />In today's post, we will be examining the first step of the process in more detail, the conversion of tyrosine (L-tyrosine in the diagram) to L-DOPA:<a onblur="try {parent.deselectBloggerImageGracefully();} catch(e) {}" href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEixRX0_c42U7xD8ox-SUj1OjVBR8GpOM7wLhwylKv8jPDq2_CGU-rEd1_XvmOh3ypEEFZkyA-X1x-68pIT6NYh6rC9_2-1ovvXdq711z6_OS6UYQq5ahHW5AnNoWigMoph74JEPXVIxo6k/s1600-h/ADHD+tyrosine+to+L-DOPA+tyrosine+hydroxylase.png"><img style="margin: 0px auto 10px; display: block; text-align: center; cursor: pointer; width: 264px; height: 203px;" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEixRX0_c42U7xD8ox-SUj1OjVBR8GpOM7wLhwylKv8jPDq2_CGU-rEd1_XvmOh3ypEEFZkyA-X1x-68pIT6NYh6rC9_2-1ovvXdq711z6_OS6UYQq5ahHW5AnNoWigMoph74JEPXVIxo6k/s400/ADHD+tyrosine+to+L-DOPA+tyrosine+hydroxylase.png" alt="" id="BLOGGER_PHOTO_ID_5431963929064057874" border="0" /></a>In order for this process to occur efficiently, we need three major components:<br /><ol><li>An ample supply of tyrosine (or L-tyrosine) listed above<br /></li><li>A functional amount of the enzyme <span style="font-style: italic; font-weight: bold;">tyrosine hydroxylase</span></li><li>Sufficient levels of a compound called <span style="font-weight: bold;">Tetrahydrobiopterin.</span></li></ol>Here's a more in-depth analysis of each of these three factors:<br /><br /><span style="font-weight: bold;">OPTIMIZING FACTOR #1: AN AMPLE SUPPLY OF TYROSINE:</span><br /><br />How much tyrosine is necessary to do the job?<br /><br />Unfortunately, the conversion from tyrosine to L-DOPA is not a particularly efficient process. As a result, higher levels of starting material (tyrosine) are needed. Just to give a <span style="font-style: italic;">very rough</span> overview on the amount of tyrosine we're dealing with here in the context of ADHD treatment, typical daily supplemental doses often fall around <a style="color: rgb(51, 51, 255);" href="http://www.umm.edu/altmed/articles/tyrosine-000329.htm">500 to 1500 mg per day</a>, although there is often room for higher doses before toxicity risks set in.<br /><br />At around 10-12 grams (roughly 10 times this amount), the risk of toxicity often goes way up. Other complications include high blood pressure or skin cancer (the reasons which we'll discuss in later posts), or the use of antidepressant medications, in which recommended tyrosine supplemental levels should be significantly lower (or avoided altogether). <span style="font-weight: bold;"><br /><br />**While tyrosine supplements can be purchased over the counter, PLEASE consult with a physician before doing any type of supplementation. In addition to the ones listed above, there are several other confounding factors which need to be taken into consideration with regards to dosing. </span><br /><br /><span style="font-weight: bold;"><br />OPTIMIZING FACTOR #2: ADEQUATE FUNCTION OF THE ENZYME <span style="font-style: italic;">TYROSINE HYDROXYLASE</span></span><br /><br />Kinetic studies (studies which measure the speed or rate of chemical reactions) have shown that this first step, L-tyrosine to L-DOPA is the <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/19396395"><span style="font-weight: bold;">rate limiting step</span></a> in the tyrosine to dopamine/norepinephrine process. In other words, the "bottleneck" in this conversion process lies within the enzymatic conversion of tyrosine to L-DOPA and involves the<span style="font-style: italic;"> tyrosine hydroxylase</span> enzyme.<br /><br />In addition to the fact that this enzymatic step is the slowest step in the tyrosine to dopamine conversion pathway, the <span style="font-style: italic;">tyrosine hydroxylase</span> enzyme has some additional challenges to overcome. One of these is inhibition by its product, L-DOPA. What does this mean?<br /><br />Most enzymes or enzyme systems often have some sort of "brakes" or "control switches" too keep them from running non-stop at full speed. In other words, when the body senses that enough of the desired product is attained, it will signal for these enzymes (or other regulatory systems) to either slow down or stop, to keep things balanced and in check (think of what would happen if these feedback systems weren't in place for, say, regulating appetite and feeling full, or getting an adrenaline rush that did not subside when the perceived "threat" was over).<br /><br /><span style="font-style: italic;">Tyrosine hydroxylase</span> is one such enzyme, meaning that when large amounts of dopamine or norepinephrine are eventually produced from tyrosine, the body actually begins to shut down this enzyme-regulated conversion process. Numerous studies have shown this, as <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/16105651"><span style="font-style: italic;">tyrosine hydroxylase</span> is inhibited by catecholamines</a>.<br /><br />In addition, <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/15569247">other enzymes also work on<span style="font-style: italic;"> tyrosine hydroxylase</span></a> and help turn it "on" or "off". As a result, bombarding the system with high amounts of tyrosine will not generate equally high levels of neurotransmitters, because this feedback system is in place (and we haven't even mentioned some of the potentially harmful effects of doing this, which will be discussed in later posts).<br /><br /><span style="font-style: italic;">***Blogger's note: It is not my intention as a blogger to try to dazzle or confuse anyone by using all of this technical and scientific jargon. Rather, I simply want to share how much is really going on behind the scenes when we play with the levels of just one type of supplement, like tyrosine. Having said this, I personally feel that a lot of false hope is created by advocates of supplement treatment for ADHD, as these proponents often over-simply these complexities and exaggerate the overall efficacy of these "natural" ADHD treatments. I personally <span style="font-weight: bold;">would</span> like to see more non-medication treatments tried out for ADHD management, but it is a disservice to anyone if these non-drug treatment options for ADHD aren't addressed with a similar level of scrutiny.</span><br /><br />Getting back to the topic at hand...<br /><br />Further clouding the <span style="font-style: italic;">tyrosine hydroxylase</span> enzyme issue is the fact that there are several different forms of this enzyme which exist across the population. The enzyme <span style="font-style: italic;">tyrosine hydroxylase</span> is actually coded for by a gene on the <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=191290">11th human chromosome</a>, which goes by the same name, the <span style="font-style: italic; font-weight: bold;">tyrosine hydroxylase</span> gene. <span style="font-style: italic;"><br /><br />It is important to note that slightly different versions of this gene among the human population actually result in slightly different versions of the tyrosine hydroxylase enzyme.</span> A growing body of evidence suggests that individuals with certain genetic variations of this <span style="font-style: italic;">tyrosine hydroxylase</span> enzyme are more <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/8822146">prone to certain psychiatric disorders</a>. While it appears that ADHD is not as strongly connected to this gene and enzyme as other disorders (such as schizophrenia or Parkinson's), it is important to note that ADHD <span style="font-weight: bold;">does</span> share some degree of biochemical overlap with some of the disorders mentioned.<br /><br />It is important to note that this <span style="font-style: italic;">tyrosine hydroxylase</span> enzyme does not act in isolation. As mentioned in the previous post, many enzymes require special "helping" agents called <span style="font-weight: bold;">co-factors</span>, which are needed to help stabilize the enzyme or system of enzymes and influence their chemical functionality.<br /><br />Many vitamins and minerals serve as co-factors for various enzymes. In the case of <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/16112186"><span style="font-style: italic;">tyrosine hydroxylase</span>, a major necessary nutrient co-factor is <span style="font-weight: bold;">iron</span></a>. As we will see later, iron has all sorts of implications with regards to the dopamine synthesis pathway. This has effects on both ADHD, as well as common comorbid (co-occurring) disorders to ADHD, including sleep disorders such as <a style="color: rgb(51, 51, 255);" href="http://adhd-treatment-options.blogspot.com/2009/03/iron-levels-sleep-disorders-and-adhd.html">Restless Legs Syndrome</a>. In other words, it is imperative that adequate dietary intake of iron in necessary to provide the body with enough of this vital nutrient to allow enzymes such as <span style="font-style: italic;">tyrosine hydroxylase</span> function properly.<br /><span style="font-weight: bold;"><span style="font-weight: bold;"><span style="font-weight: bold;"><br /></span></span></span>The <span style="font-style: italic;">tyrosine hydroxylase</span> enzyme is bound to iron. You may remember from high school or college chemistry classes that iron typically exists in two major form, the <span style="font-weight: bold;">ferrous</span> form (a "+2" positive charge) or a <span style="font-weight: bold;">ferric</span> form (a "+3" positive charge). It turns out that these two forms of iron actually exhibit major effects on the function of this <span style="font-style: italic;">tyrosine hydroxylase</span> enzyme. <span style="font-weight: bold;"><span style="font-weight: bold;"><span style="font-weight: bold;"><br /><br /></span></span></span><span style="font-style: italic;">Blogger's note:</span><span style="font-weight: bold;"><span style="font-weight: bold;"><span style="font-weight: bold;"> </span></span></span><span style="font-style: italic;">The following explanation will contain a fair amount of chemistry jargon. If you have any sort of science background, you might find it interesting, if not, please skim the next few paragraphs, and we'll meet up at the bottom where I summarize these findings and applications of this info<span style="font-weight: bold;">:<br /></span></span><span style="font-weight: bold;"></span><br />As mentioned above, ferrous iron is<span style="font-style: italic;"><span style="font-weight: bold;"> </span></span>the less positively charged (or, in chemical terms, less "oxidized") form of iron, while ferric is the more positively charged or more oxidized version of iron. Both of these forms can be embedded in the <span style="font-style: italic;">tyrosine hydroxylase</span> enzyme. It turns out, however, that it is the less-oxidized <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1945184/pdf/nihms-13158.pdf"><span style="font-weight: bold;">ferrous form</span> of the iron (+2) that is required for the enzyme to convert tyrosine to L-DOPA</a>. <span style="font-weight: bold;"><span style="font-weight: bold;"><span style="font-weight: bold;"><br /><br /></span></span></span>On the flipside, the more oxidized <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1945184"><span style="font-weight: bold;">ferric</span> form of the iron</a><span style="font-weight: bold;"><span style="font-weight: bold;"><span style="font-weight: bold;"> </span></span></span>(+3 charge) is actually the form of the enzyme which plays a major role in <span style="font-weight: bold;">shutting down</span> the enzyme's production by catecholamines, as in the process of feedback inhibition mentioned above.<br /><br />Overgeneralizing and oversimplifying a bit here, it is advantageous for our system to keep this iron in the <span style="font-style: italic;">tyrosine hydroxylase</span> state at the <span style="font-weight: bold;">less-oxidized</span> ferrous form if we want to keep the enzyme running (again, this is a gross oversimplification, but the general idea holds).<br /><br />If you've been reading this blog for awhile, you may have come across a post a few weeks ago entitled <a style="color: rgb(51, 51, 255);" href="http://adhd-treatment-options.blogspot.com/2009/12/10-ways-vitamin-c-helps-treat-adhd.html"><span style="font-style: italic;">10 Ways Vitamin C helps treat ADHD symptoms</span></a>. In this posting, we discussed some of the interactions between vitamin C and iron, and how the vitamin can not only aid in the absorption of iron (thus helping to boost iron levels necessary for proper enzyme function) but also to act as an antioxidant on the iron.<br /><br /><span style="font-style: italic;">Branching off of this idea, maintaining the necessary antioxidant pools via vitamin C or other antioxidants (which will be discussed shortly), we can help keep the iron in the tyrosine hydroxylase enzyme in the <span style="font-weight: bold;">reduced ferrous state</span> and aid in the tyrosine to dopamine conversion pathway</span>. Some earlier mammalian studies have found that activity of the <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/13171"><span style="font-style: italic;">tyrosine hydroxylase</span> enzyme is compromised in a state of severe vitamin C deficiency (scurvy)</a>, with the probable culprit being the inability to maintain the reduced (+2) ferrous state. <span style="font-weight: bold;">In other words, vitamin C can influence ferrous iron levels, which then influences the tyrosine hydroxylase enzyme. </span><br /><br /><span style="font-weight: bold;"><br />OPTIMIZING FACTOR #3: THE NEED FOR TETRAHYDROBIOPTERIN (and cofactors necessary for the regeneration of this tetrahydrobiopterin)</span><br /><br />We have seen that vitamin C can help stabilize the <span style="font-style: italic;">tyrosine hydroxylase</span> enzyme. However, the main factor in regular tyrosine to dopamine conversion stems from a compound known as <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/14216443"><span style="font-weight: bold;">tetrahydrobiopterin</span></a>, which is often abbreviated as <span style="font-weight: bold;">BH4</span>. Tetrahydrobiopterin (along with molecular oxygen) is a major cofactor of the <span style="font-style: italic;">tyrosine hydroxylase enzyme</span>, and responsible for the addition of the hydroxyl (-OH) group to the tyrosine molecule to produce L-DOPA.<br /><br />This compound is manufactured in the human body, so (except in the case of rare genetic or metabolic disorders) supplementation with tetrahydrobiopterin or its chemical precursors is not necessary. However, its synthesis (from its own series of enzymes) is dependent on adequate levels of nutrient <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/10727395">cofactors including magnesium and zinc</a>. Prolonged deficiencies in either or both of these minerals can therefore potentially inhibit the synthesis of tetrahydrobiopterin, and, indirectly, the tyrosine to dopamine conversion process. Please note that we have discussed both <a style="color: rgb(51, 51, 255);" href="http://adhd-treatment-options.blogspot.com/2008/11/magnesium-combination-treatments-for.html">magnesium</a> and <a style="color: rgb(51, 51, 255);" href="http://adhd-treatment-options.blogspot.com/2009/04/10-ways-zinc-can-combat-adhd.html">zinc</a> in great detail with regards to the roles they play in the onset and treatment of ADHD.<br /><br />In addition to the indirect relationship between tetrahydrobiopterin and ADHD due to the impact on dopamine synthesis, tetrahydrobiopterin is important in numerous other functions as well. For example, low levels of tetrahydrobiopterin in the body have been associated with <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/19042039">hypertension and other types of cardiovascular dysfunction</a>.<br /><br /><span style="font-style: italic;">If tetrahydrobiopterin (BH4) is the predominant compound for the tyrosine hydroxylase enzyme function, is vitamin C still potentially useful in the process?</span><br /><br />While BH4 is a more powerful regulator of the <span style="font-style: italic;">tyrosine hydroxylase</span> enzyme in the tyrosine to L-DOPA ADHD treatment pathway, there is some evidence that vitamin C can "help the helper". A much older study, done way back in the 1970's suggests the benefits of <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1177509/pdf/biochemj00613-0203.pdf">vitamin C on the synthesis of catecholamines</a> like dopamine and norepinephrine. The reason given in this article is the role of vitamin C in recycling or regenerating functional forms of the tetrahydrobiopterin compound.<br /><br />The whole concept of vitamin C recycling other nutrients is not new to this blog and its discussions. We have mentioned how <a style="color: rgb(51, 51, 255);" href="http://adhd-treatment-options.blogspot.com/2009/12/10-ways-vitamin-c-helps-treat-adhd.html">vitamin C can "recycle" other antioxidants such as vitamin E</a>, and how this can have an indirect impact on nutritional treatment strategies for ADHD.<br /><span style="font-weight: bold;"><br />To summarize the key points and suggestions which should be taken away from this the blog post:</span><br /><ol><li>Do not overdose on Tyrosine supplementation. For reference, a ballpark estimate on dosing is often somewhere around 500 to 1500 mg per day, but <span style="font-weight: bold;">please</span> do not start any type of supplementation without consulting with a physician.<br /><br /></li><li><span style="font-style: italic;">Tyrosine hydroxylase</span> is the key enzyme in the conversion of tyrosine to <span style="font-weight: bold;">L-DOPA</span>. It is contains iron which must be kept in the reduced (+2) state to function properly. Naturally, this means that the enzyme can be compromised if an iron deficiency is present. Recommended daily intake levels for iron can be found <a style="color: rgb(51, 51, 255);" href="http://dietary-supplements.info.nih.gov/factsheets/iron.asp">here</a>.<br /><br /></li><li>It is believed that this <span style="font-style: italic;">tyrosine hydroxylase</span> enzyme can be aided by maintaining ample levels of antioxidants such as vitamin C in the diet. Keeping antioxidant levels up to speed aids in maintaining this necessary form of the iron for the enzyme to function properly. In other words, the enzyme is intricately connected to antioxidant balances in the body. <span style="font-style: italic;">This is an often overlooked side-component of ADHD treatment via tyrosine</span> <span style="font-style: italic;">supplementation</span>. here is a link for the recommended daily intake for <a style="color: rgb(51, 51, 255);" href="http://lpi.oregonstate.edu/infocenter/vitamins/vitaminC/">vitamin C</a>.<br /><br /></li><li><span style="font-style: italic;">Tyrosine hydroxylase </span>is inhibited by its own products, the catecholamines (which include dopamine and norepinephrine, two of our later "targets" in the above diagrammed pathways). This means that we cannot expect to get high levels of dopamine in the brain by mega-supplementing with tyrosine, because this process shuts itself off.<br /><br /></li><li>Therefore, <span style="font-style: italic;">excessive</span> tyrosine supplementation (beyond the level recommended by your physician) is essentially ineffective, and potentially harmful.<br /><br /></li><li>The main helper of the <span style="font-style: italic;">tyrosine hydroxylase</span> enzyme, however, is the compound <span style="font-weight: bold;">tetrahyrobiopterin</span>. This is manufactured in the body, so supplementation for this is not necessary (except in the case of a few rarel genetic or metabolic disorders). Tetrahydrobiopterin and molecular oxygen (O2) supply the enzyme with the proper tools to convert the tyrosine to L-DOPA by chemically adding a hydroxyl (-OH) group, which can be seen in the diagrams near the top of the post.<br /><br /></li><li>Tetrahydrobiopterin synthesis is dependent on nutrient cofactors including zinc and magnesium. Recommended daily amounts can be found <a style="color: rgb(51, 51, 255);" href="http://lpi.oregonstate.edu/infocenter/minerals/zinc/">here for zinc</a> and <a style="color: rgb(51, 51, 255);" href="http://lpi.oregonstate.edu/infocenter/minerals/magnesium/">here for magnesium</a>.<br /></li></ol><span style="font-style: italic;">In our next post, we will be looking at the second major step of the conversion process from the tyrosine to dopamine pathway. This will rely heavily on enzymes known as </span><span style="font-weight: bold; font-style: italic;">decarboxylases</span><span style="font-style: italic;">. We will be looking at how these enzymes work, what nutrients (or co-factors) they need, and examine to see if there are any interfering factors or side-effects involved, as a way to optimize this process of tyrosine supplementation as an ADHD treatment strategy. </span><br /><span style="font-weight: bold;"></span>The ADHD Treatment Guidehttp://www.blogger.com/profile/00747782650821771627noreply@blogger.com14tag:blogger.com,1999:blog-2736612052295099842.post-39350211242121869922010-01-15T21:10:00.006-05:002010-01-16T00:06:18.353-05:00Does Tyrosine Supplementation Actually Work for ADHD? (part 1: theory and background)<span style="font-weight: bold; font-style: italic;">Can ADHD Symptoms be Cured or Tr</span><span style="font-weight: bold; font-style: italic;">eated via Tyrosine Supplementation?</span><br /><br />Due to the extensive nature of this topic, we will be investigating the answer to this question over a number of consecutive blog posts. First, some background on tyrosine, and why it is often a suggested (and even prescribed) on a relatively frequent basis by clinicians for treatment of ADHD and related disorders:<br /><span style="font-weight: bold;"><br />The appeal of a natural ADHD treatm</span><span style="font-weight: bold;">ent strategy such as supplementation with tyrosine or other amino acids in lieu of drugs:</span><br /><br />As a parent, teacher or guardian of an ADHD child (or possibly as ADHD sufferers ourselves), we often have an inherent bias against medications for the attention deficit hyperactivity disorders. This is quite understandable. After all, who really wants to "drug" themselves or their child, especially if a more "natural" benign treatment method is currently available? While many of the claims against ADHD medications are either fabricated (as an example, while many "natural" ADHD treatment websites often love to assert otherwise, <a style="color: rgb(51, 51, 255);" href="http://adhd-treatment-options.blogspot.com/2009/04/ritalin-and-cocaine-similarities-and.html">Ritalin is <span style="font-style: italic;">not</span> the equivalent to crack cocaine</a>) or over-hyped, there are definitely legitimate concerns and risks surrounding medication treatments for the disorder. Potential complications include:<br /><ul><li>Negative side effects, including <a style="color: rgb(51, 51, 255);" href="http://adhd-treatment-options.blogspot.com/2008/10/are-adhd-stimulant-drugs-bad-for-your.html">potential cardiovascular effects</a>, and even <a style="color: rgb(51, 51, 255);" href="http://adhd-treatment-options.blogspot.com/2009/02/excessive-talking-as-potential.html">rare bizarre ones</a><br /></li><li><a style="color: rgb(51, 51, 255);" href="http://adhd-treatment-options.blogspot.com/2008/10/how-addictive-is-ritalin.html">Addiction potential</a> (spoken especially of stimulants)<br /></li><li><a style="color: rgb(51, 51, 255);" href="http://adhd-treatment-options.blogspot.com/2008/12/adhd-genes-influence-medication-dosage.html">Mis-dosing risks</a> (either over or under-dosing on medications) and numerous in-born or genetic factors which can lead to <a style="color: rgb(51, 51, 255);" href="http://adhd-treatment-options.blogspot.com/2009/10/drugs-genes-and-adhd.html">dosing difficulties</a><br /></li><li><a style="color: rgb(51, 51, 255);" href="http://adhd-treatment-options.blogspot.com/search/label/medication%20safety%20issues">Medication safety issues</a><br /></li><li>Potential complications with ADHD comorbid disorders such as <a style="color: rgb(51, 51, 255);" href="http://adhd-treatment-options.blogspot.com/2008/10/do-adhd-stimulant-meds-worsen-tourettes.html">Tourette's and tic disorders</a>, <a style="color: rgb(51, 51, 255);" href="http://adhd-treatment-options.blogspot.com/2009/01/adhd-vs-ocd-brain-regions-and-bloodflow.html">obsessive compulsive disorders (OCD)</a>, <a style="color: rgb(51, 51, 255);" href="http://adhd-treatment-options.blogspot.com/2009/05/methylphenidate-anxiety-and-adhd-how-do.html">anxiety disorders</a>, <a style="color: rgb(51, 51, 255);" href="http://adhd-treatment-options.blogspot.com/2009/04/bedwetting-adhd-kids-and-depressed-dads.html">bedwetting</a>, etc.</li><li>Negative effects on dietary habits, including <a style="color: rgb(51, 51, 255);" href="http://adhd-treatment-options.blogspot.com/2008/11/benefits-and-risks-of-different.html">appetite suppression</a> (with the potential for <a style="color: rgb(51, 51, 255);" href="http://adhd-treatment-options.blogspot.com/2009/02/do-adhd-stimulant-drugs-stunt-growth.html">stunting growth and development</a>), <a style="color: rgb(51, 51, 255);" href="http://adhd-treatment-options.blogspot.com/2009/01/adhd-and-bulimia-connection.html">eating disorders</a>, and <a style="color: rgb(51, 51, 255);" href="http://adhd-treatment-options.blogspot.com/2009/03/methylphenidate-vs-atomoxetine-adhd.html">sleep</a> or <a style="color: rgb(51, 51, 255);" href="http://adhd-treatment-options.blogspot.com/2009/03/iron-levels-sleep-disorders-and-adhd.html">sleep-related disorders</a><br /></li><li><a style="color: rgb(51, 51, 255);" href="http://adhd-treatment-options.blogspot.com/2009/02/economic-impact-of-adhd.html">Costs</a> of medications and other treatment strategies for ADHD<br /></li><li>The idea that medications <span style="font-style: italic;">only treat the </span><span style="font-style: italic;">symptoms</span> of the disorders as opposed to the root of the problem</li><li>Relative lack of evidence on <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/18777967">possible long-term side-effects of adhd medications</a></li><li>Possible <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/16494852"><span style="color: rgb(51, 51, 255);">damages on brain development</span><br /></a></li></ul>The list goes on, but we get the idea.<br /><br /><span style="font-weight: bold;"><br />THE THEORY BEHIND TYROSINE SUPPLEMENTATION FOR TREATING ADHD:</span><br /><br /><span style="font-style: italic; font-weight: bold;">1. There is an imbalance of brain chemicals dopamine and norepinephrine in the ADHD brain:</span><br /><br />One of the basic premises of ADHD is that it is caused by a chemical imbalance of certain neurotransmitters in the brain, including <span style="font-weight: bold;">dopamine</span> and <span style="font-weight: bold;">norepinephrine</span>. While the following description is a gross over-simplification of the process involved, <span style="font-style: italic;">the current theory is that the balance of the brain chemical dopamine in</span><span style="font-style: italic;">side vs. outside of brain cells is out of whack in certain key "ADHD" brain regions</span>.<br /><br />(As a side note, here is a link to some of main <a style="color: rgb(51, 51, 255);" href="http://adhd-treatment-options.blogspot.com/2009/03/do-adhd-kids-use-their-brain-regions.html">brain regions believed to be "different" between the ADHD and non-ADHD population</a>, as well as another earlier post on the difference between an <a style="color: rgb(51, 51, 255);" href="http://adhd-treatment-options.blogspot.com/2009/01/adhd-vs-ocd-brain-regions-and-bloodflow.html">ADHD brain and an OCD</a> (obsessive compulsive disorder) brain. Additionally, variations among individuals involving specific "<a style="color: rgb(51, 51, 255);" href="http://adhd-treatment-options.blogspot.com/2009/01/gene-variations-which-effect-attention.html">ADHD genes</a>" may play a role in dopamine level differences. Please take each post with a grain of salt, as they are more generalizations and examples than non-negotiable absolutes).<br /><br />Again, this is a great oversimplification of a complicated process, <span style="font-style: italic;">but the general idea is that most ADHD medications (the stimulants in particular) work by either directly or indirectly increasing the levels of dopamine outside of the neuronal cells in the brain and restoring this imbalance</span>. Please note, however, that this generalized "dopamine deficiency" theory of ADHD is by no means a consensus among the medical profession and is being <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/18986716">challenged</a> by some professionals.<br /><br /><span style="font-style: italic;"><span style="font-weight: bold;">2. Direct dietary supplementation </span></span><span style="font-style: italic;"><span style="font-weight: bold;">with dopamine for ADHD treatment is ineffective:<br /><br /></span></span>Our first thought might be to just try to supplement the body with large amounts of dopamine to try to correct this neuro-chemical imbalance. The problem with this strategy is that we have to deal with an entity known as the <span style="font-weight: bold;">Blood Brain Barrier</span>. <span style="font-style: italic;"><span style="font-weight: bold;"><br /></span></span><br />In a nutshell, the Blood Brain Barrier is a barrier meant to prevent potentially harmful agents in the blood from making their way into the brain. In other words, it is a crucial protective measure which is vital to the survival of our bodies and respective nervous systems from the rapid influx of potentially harmful agents. The problem is that this barrier also screens out a number of potentially helpful agents, including many types of therapeutic drugs (this is one of the biggest challenges in the design of psychiatric medications, in addition to acting on their targets, these drugs must be able to actually get into the brain in the first place).<br /><br />Unfortunately, it has long been known that the chemical <a style="color: rgb(51, 51, 255);" href="http://www.nature.com/nature/journal/v228/n5269/abs/228358a0.html">dopamine <span style="font-style: italic;"><span style="font-weight: bold;">itself</span> </span>does not have a particularly sound affinity for the blood brain barrier</a> (although a number of "tricks" involving manipulation of protein "transporters" in and around the brain, as well as using slightly modified related compounds have been used to increase levels of this important neurochemical). <span style="font-weight: bold;">As a result, direct unaided dopamine su</span><span style="font-weight: bold;">pplementation for ADHD does not work.</span> Enter the amino acid tyrosine<span style="font-style: italic;"><span style="font-weight: bold;">.<br /><br />3. The amino acid tyrosine is a chemical precursor to both dopamine and norepinephrine.<br /></span></span><br />Unlike dopamine, the amino acid<span style="font-weight: bold;"> tyrosine can </span>cross the blood brain barrier (under the right conditions). The following diagram highlights the general pathway (including chemical intermediates) from tyrosine (listed as "L-tyrosine" in the diagram) all the way to <span style="font-weight: bold;">dopamine</span>, <span style="font-weight: bold;">norepinephrine</span>, and even <span style="font-weight: bold;">epinephrine</span> (adrenaline): <a onblur="try {parent.deselectBloggerImageGracefully();} catch(e) {}" href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgak3YCIB4vEW9XkFP5Bmre2dNbMFlNLyIG1zBhOTpaxPViCfybt4wl4mGod0HA4Yt2ZA8AuQtvq0Bt3HftWXk9nXneDYuGVQrMWA8UOE_DmIW-FJSMBW5cLf2rhDFddIj5FCK_Bdyexes/s1600-h/ADHD+tyrosine+to+dopamine.PNG"><img style="margin: 0px auto 10px; display: block; text-align: center; cursor: pointer; width: 251px; height: 572px;" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgak3YCIB4vEW9XkFP5Bmre2dNbMFlNLyIG1zBhOTpaxPViCfybt4wl4mGod0HA4Yt2ZA8AuQtvq0Bt3HftWXk9nXneDYuGVQrMWA8UOE_DmIW-FJSMBW5cLf2rhDFddIj5FCK_Bdyexes/s400/ADHD+tyrosine+to+dopamine.PNG" alt="" id="BLOGGER_PHOTO_ID_5427180561219858530" border="0" /></a><br /><span style="font-style: italic;"><span style="font-weight: bold;">(Please note, the diagram depicted above is a reproduction of a larger image originally found <a style="color: rgb(51, 51, 255);" href="http://upload.wikimedia.org/wikipedia/commons/0/08/Catecholamines_biosynthesis.svg">here</a>. The blogger apologizes for the low quality of the image depicted here; feel free to check out the larger image in the link above if needed.)<br /><br /></span></span><span><span>The attempt to generate higher levels of dopamine and norepinephrine by supplying the body with the dopamine and norepinephrine precursor tyrosine is an example of what is known in medicine as <span style="font-weight: bold;">precursor loading</span>. As we will see later on, precursor loading strategies are often a mixed bag of rewards and risks, with varying degrees of overall effectiveness. This blogger intentionally wishes to remain neutral on the subject at hand here, with the goal in mind of providing unbiased information advocating both for and against tyrosine treatment for ADHD.<br /><br />You do <span style="font-weight: bold;">not</span> need to be a biochemist or know chemical structures or pathways<span style="font-style: italic;">;</span><span style="font-style: italic;"> the above picture is just simply a visual tool to demonstrate that there are a number of steps in the conversion process of tyrosine to dopamine and norepinephrine</span>. Using the above diagram for reference, we will see that there are a number of "hoops" we need to jump through in order to make tyrosine supplementation worthwhile as a possible ADHD treatment. We will break this down into smaller steps in the next collection of posts and summarize the overall potential (as well as review what the current literature has to say on this process) at the very end.<br /><br />I have broken down some of the major steps of this process, which need to be considered to maximize the effectiveness of this tyrosine treatment for ADHD. Each of these steps will be addressed in the next few posts:<br /><br /></span></span><ol><li>The supplement must be able to cross the blood brain barrier. This process involves special "transporters", and can be influenced by outside factors, including other dietary amino acids. This will be discussed in the next post.<br /><br /></li><li>In order to proceed on to dopamine, tyrosine must first be converted into an intermediate called <span style="font-weight: bold;">L-dopa</span> (please note that L-dopa can cross the blood brain barrier as well, and is sometimes used as a prescribed supplement for ADHD treatment in its own right. This will be discussed later on, including advantages or disadvantages of supplementing with L-dopa vs. supplementing with tyrosine).<br /><br /></li><li>In order to convert to L-dopa, tyrosine requires the enzyme <span style="font-style: italic; font-weight: bold;">Tyrosine Hydroxylase</span>, as well as <span style="font-weight: bold;">cofactors</span> ("helpers" to the enzyme), which will be discussed in detail in a later section.<br /><br /></li><li>In order to convert from L-dopa to dopamine, a class of enzymes known as <span style="font-style: italic; font-weight: bold;">decarboxylases</span> is needed. This too, requires cofactors (which in this case are specific vitamin and mineral derivatives) to operate properly. It is important to note that deficiencies in these nutrients can severely inhibit this step of the process (and, in the blogger's opinion, can be a seriously overlooked reason for the relative ineffectiveness of tyrosine supplementation in a number of cases, and that simply maintaining adequate levels of these nutrients could greatly aid the process in this crucial step). Again, these challenges will be discussed at a later time.<br /><br /></li><li>Norepinephrine imbalances are also seen in many ADHD cases, so the dopamine to norepineprhine conversion process is also important. This, too, requires specific enzymes and cofactors.<br /><br /></li><li>It is also critical that we don't overlook side reactions in the process. <span style="font-style: italic;">As we might expect, tyrosine can convert to a number of other things in the body besides dopamine</span>, and the enzymes and systems involved in these pathways often "compete" with one another, each with its own accompanying side effects. These competing processes can cause potential problems,<span style="font-style: italic;"> including the depletion of several crucial vitamins and minerals</span> (the B vitamins in particular) and may also cause a buildup of potentially harmful biochemical products (such as <span style="font-weight: bold;">homocysteine</span>). <span style="font-style: italic; font-weight: bold;">Perhaps not surprisingly, some of these key vitamins and minerals used up by the above metabolic processes are often found to be deficient in the general ADHD population.</span><br /><br />We have investigated some of these <a style="color: rgb(51, 51, 255);" href="http://adhd-treatment-options.blogspot.com/2009/01/adhd-alcoholism-and-nutrient.html">B vitamin and homocysteine effects with respect to ADHD in an earlier post</a>. The point here is this: <span style="font-style: italic;">if we flood our system with tyrosine, we must realize that we are feeding the first step of a whole slew of biochemical products in addition to our desired end products of dopamine and norepinephrine. </span><span>We must account for these effects and do everything possible nutritionally to minimize the potential harm of chemical imbalances caused by these processes. </span></li></ol>Of course there are other factors besides these six, but hopefully, we can start to see that supplementation with this amino acid in hopes of treating ADHD (or at least reducing symptoms of the disorder) has numerous complications, as well as potential drawbacks and limitations. However, this blogger feels that if we are to have a go with tyrosine supplementation, all the other pieces of this metabolic puzzle (nutrients, enzyme systems and otherwise) must be firmly in place to maximize the effectiveness of this ADHD treatment strategy. <span style="font-style: italic;">While this is certainly a tall order, it is my aim as a blogger to both highlight these necessary puzzle pieces and give potential ways to optimize their effectiveness in the next few posts. </span><span style="font-style: italic;"><br /></span>The ADHD Treatment Guidehttp://www.blogger.com/profile/00747782650821771627noreply@blogger.com56tag:blogger.com,1999:blog-2736612052295099842.post-21681149722447391312009-12-28T21:18:00.014-05:002010-01-12T19:55:52.965-05:0010 Ways Vitamin C helps treat ADHD Symptoms<strong><u>How Vitamin C can be an Effective Treatment Method for ADHD</u></strong><br /><br />We have previously discussed nutritional treatment methods for ADHD, including other "10 Ways" posts for <a href="http://adhd-treatment-options.blogspot.com/2009/04/10-ways-carnitine-can-help-treat-adhd.html"><span style="color:#3333ff;">carnitine</span></a> and <a href="http://adhd-treatment-options.blogspot.com/2009/04/10-ways-zinc-can-combat-adhd.html"><span style="color:#3333ff;">zinc</span></a>. However, vitamin C, while often associated as being more of an immune-boosting and heart healthy antioxidant vitamin, may also play a crucial (and often underrated) role in taming the negative symptoms associated with Attention Deficit Hyperactivity Disorder, or ADHD.<br /><br />Before we go any further, I must establish the appropriate context as to how we should interpret this blog post. Some of the following information on vitamin C surrounds more of the <em>potential ways in which </em>the vitamin can interact with the causative mechanisms of ADHD, and is more <em>speculative</em> than that of evidence-based controlled clinical trials. Other abilities or utilizations of the vitamin (such as <a href="http://www.ncbi.nlm.nih.gov/pubmed/19209525"><span style="color:#3333ff;">vitamin C's ability to boost iron absorption</span></a>, or the vitamin C-dependence of various enzymes required to metabolize ADHD medications or parallel nutrition strategies) are well-documented and better established.<br /><br />Having said that, out of these following 10 reasons for vitamin C supplementation for treating ADHD, around 3 to 4 are well-grounded on clinical evidence, about 3 to 4 are plausible arguments, but with potentially great limiting factors, and 3 to 4 are possible, <em>but largely hypothetical at the current time</em>. <em>It is the intent of the blogger not to persuade or advocate the rampant consumption of megadoses of this vitamin, but rather to illustrate the complexities of our metabolic systems as to how such a basic vitamin can be tied into so many ADHD-relevant processes.</em><br /><br />Based on the conclusions of the various research papers which I am about to highlight in this posting, it appears that high levels of vitamin C supplementation will do <em>little</em> to alleviate ADHD symptoms, especially when compared to efficacy other nutrients with better track records such as <a href="http://adhd-treatment-options.blogspot.com/2009/01/omega-3-fatty-acids-and-adhd-theory.html"><span style="color:#3333ff;">omega-3's</span></a>, <a href="http://adhd-treatment-options.blogspot.com/2009/03/iron-levels-sleep-disorders-and-adhd.html"><span style="color:#3333ff;">iron</span></a>, <a href="http://adhd-treatment-options.blogspot.com/2008/11/magnesium-deficiency-and-childhood-adhd.html"><span style="color:#3333ff;">magnesium</span></a> and <a href="http://adhd-treatment-options.blogspot.com/2009/04/10-ways-zinc-can-combat-adhd.html"><span style="color:#3333ff;">zinc</span></a>. <em>Based on (often substantially) greater piles of evidence, stronger claims can generally be made for a correlation between deficiencies of these aforementioned nutrients and ADHD severity than for the connection between ADHD and levels of vitamin C. </em><br /><br />Instead, this post is meant more as an advocate for the maintenance of recommended (or slightly higher) levels of vitamin C and avoiding deficiencies (which can decrease the processes optimized by this vitamin). <em>Thus, it appears to be more accurate if we view vitamin C as an <strong>auxiliary</strong> or <strong>secondary co-treatment strategy for ADHD</strong> via natural dietary methods and <strong>not</strong> <strong>as a stand-alone ADHD treatment</strong>. </em>This is important to remember as we work through this post and see some of vitamin C's potential (but not always decisively proven) "natural" ADHD treatment options.<br /><br />We must also acknowledge that vitamin C exists in two major forms: the common (non-oxidized) form of the vitamin, also called <strong>ascorbic acid</strong>, or the oxidized form <strong>Dehydroascorbic Acid </strong>or DHA (<em>Blogger's note: please don't confuse this vitamin-C derived "DHA" with the omega-3 fatty acid <strong>docosahexaenoic acid</strong>, which is also commonly abbreviated as DHA. They are two <u>entirely</u> different molecules. We have discussed the significance of this </em><a href="http://adhd-treatment-options.blogspot.com/2009/09/omega-3-oxidation-in-adhd-problem-with.html"><span style="color:#3333ff;"><em>important omega-3</em></span></a><em> earlier posts</em>).<br /><br />As we will see later in this post, the two different forms of the vitamin have extremely different properties in several cases, including their methods of transport and uptake into the brain (while it may seem counterintuitive, given the fact that we often associate "oxidized" with being bad in the body, it is the <em>oxidized</em> DHA form of the vitamin actually has a number of advantages over the reduced form with regards to brain uptake).<br /><br />Without further ado, here are 10 documented ways (as well as two "possibilities") in which this important vitamin can help with ADHD. While some of these may seem obvious, others appear to have a more obscure, but equally important role or function as an ADHD treatment method:<br /><br /><br /><ol><li><strong>Vitamin C offers protection against fatty acid oxidation</strong>, including the important omega-3's which are a popular treatment and supplement for ADHD. While omega-3 supplementation remains a popular treatment method among "natural" ADHD treatment advocates, its overall effectiveness remains questionable.<br /><br />The <a href="http://adhd-treatment-options.blogspot.com/2009/01/omega-3-fatty-acids-and-adhd-theory.html"><span style="color:#3333ff;">theory behind omega-3 treatments for ADHD</span></a> can be found in an earlier posting, but in a nutshell, the brain and central nervous system are comprised of cells with very high omega-3 fat content, and must be constantly supplied with either these fats themselves or chemical precursors to these fats (which can then be converted into these essential nutrients). These fats play a critical role in coating the outer layers of the "messenger" signaling portions of the brain, and the development of these protective layers (called <strong>myelination</strong>) is especially pronounced in adolescence.<br /><br />High levels of overall brain development and re-wiring occurs during the adolescent stages, and in multiple cases, <em>this process is delayed in the ADHD population</em>. Therefore, the idea holds that we should be supplementing this process along by feeding the brain these important omega-3 rich foods and nutrients.<br /><br />However, one of the fundamental problems is the fact that fatty acids (including omega-3's in particular) are especially susceptible to damage through chemical process of oxidation. We have alluded to this in earlier discussions on <a href="http://adhd-treatment-options.blogspot.com/2009/09/omega-3-oxidation-in-adhd-problem-with.html"><span style="color:#3333ff;">omega-3 oxidation and ADHD</span></a>. Numerous studies have shown that dietary antioxidant intervention can greatly alleviate this problem. <em>In this blogger's opinion, failure to recognize this important factor of antioxidant protection for omega-3 fatty acids is one of the biggest saboteurs of omega-3 intervention as an ADHD treatment.</em><br /><br />As far as antioxidant protection strategies of fatty acids are concerned, vitamin C is often <em>not</em> the best choice. As a water-soluble vitamin, the interactions with the much less water soluble omega-3 fatty acids are potentially limited. However, vitamin C can "sacrifice" itself and help boost levels of other important antioxidants in the body that <em>can</em> have a greater impact on omega-3 fatty acid protection and cell membrane viability. Among these are vitamin E and glutathione (which will be addressed later on in this posting, when we talk about antioxidant recycling).<br /><br />However, we may be beginning to see that vitamin C could be an effective co-treatment to fatty acids in its own right, at least according to some recent studies. One study (which, unfortunately paid more attention to the fatty acid component and had vitamin C as more of an auxiliary co-treatment) suggested that <a href="http://www.ncbi.nlm.nih.gov/pubmed/16314082"><span style="color:#3333ff;">vitamin C can boost the efficacy of flax oil</span></a> (a popular omega-3 rich dietary choice) as an ADHD treatment measure. Clearly, this was just one study, and more research is warranted, but <em>the significance of protecting these all-important dietary fats found at high concentrations in the brain and nervous system cannot be understated</em>. </li><br /><li><strong>Vitamin C acts as a potent neuroprotective agent</strong> (important for neurological disorders including ADHD). It may sound surprising, but <a href="http://www.ncbi.nlm.nih.gov/pubmed/17066209"><span style="color:#3333ff;">nerve endings in the brain have the second highest concentration of vitamin C in the body</span></a> (behind only the adrenal glands, which produce adrenaline, which we will mention later in this post when discussing vitamin C and catecholamines). Current research appears to illuminate the protective role of vitamin C, specifically in its oxidized DHA form and when used <a href="http://www.ncbi.nlm.nih.gov/pubmed/19266157"><span style="color:#3333ff;">in conjunction with vitamin D3</span></a>, against a specific type of oxidative damage on the brain called <strong>ischemia </strong>(reduced blood supply to a particular brain region, which can be brought on, by other things, oxidative damage).<br /><br />The relevance to ADHD here is that ischemia is a surprisingly common <em>environmental</em> cause of the disorder, especially during early (neonatal) development. It is believed by some researchers that oxidative damage which causes this ischemic reduction of blood supply may bring on ADHD symptoms by <a href="http://www.ncbi.nlm.nih.gov/pubmed/14995087"><span style="color:#3333ff;">interfering with biological targets (or receptors)</span></a> in the brain for the important neurotransmitting chemical <strong><a href="http://en.wikipedia.org/wiki/Dopamine"><span style="color:#3333ff;">dopamine</span></a></strong>. <em>In other words, for those individuals suffering from reduced blood flow to these brain regions earlier in life, the important signaling chemical dopamine has trouble finding its mark in the brain, results in the attenuation of attention span and longer reaction timing</em> (for more information on ADHD and reaction timing, please see the earlier post: <em><a href="http://adhd-treatment-options.blogspot.com/2009/03/do-adhd-kids-use-their-brain-regions.html"><span style="color:#3333ff;">Do ADHD Kids Use their brain regions differently?</span></a></em>).<br /><br />While the basis for ischemia treatment for ADHD via vitamin C supplementation is more hypothetical at the moment, the fact that treatment with this vitamin can counteract a major environmental cause of the disorder suggests that vitamin C may be a viable treatment method for this aspect of ADHD and related disorders. </li><br /><li><strong>Vitamin C helps "recycle" and maintain pools of other crucial antioxidants</strong> such as vitamin E, polyphenols (potent antioxidants found in fruits, vegetables, wines and teas), <strong>glutathione</strong> (which is manufactured in the body and is the body's <a href="http://www.ncbi.nlm.nih.gov/pubmed/18538422"><span style="color:#3333ff;">standard antioxidant of choice</span></a>), and products of the antioxidant enzyme <em><strong>superoxide dismutase</strong></em> or <em><strong>SOD</strong></em>.<br /><br />We have alluded to this message in point number 1 above. Several studies have found abnormally <a href="http://www.ncbi.nlm.nih.gov/pubmed/18644422"><span style="color:#3333ff;">low antioxidant levels</span></a> (and high "pro-oxidant" levels) in ADHD subjects. It appears that increasing dietary antioxidant intake may at least partially reduce this trend.<br /><br />For example, boosting intake of a form of vitamin E called <a href="http://www.ncbi.nlm.nih.gov/pubmed/18757191"><span style="color:#3333ff;"><strong>gamma-tocopherol </strong>can reduce the oxidation of important fatty acids in ADHD subjects</span></a> (although it is worth mentioning that gamma-tocopherol is not the most bio-available form of vitamin E, that honor goes to another form of the vitamin called <strong><a href="http://www.fasebj.org/cgi/content/full/13/10/1145"><span style="color:#3333ff;">alpha-tocopherol</span></a></strong>). <em>It is worth mentioning that <a href="http://www.ncbi.nlm.nih.gov/pubmed/18309774"><span style="color:#3333ff;">vitamin C and vitamin E work extremely well together as an antioxidant tandem</span></a>, and help spare the pool of the body's antioxidant reserves from depletion. Therefore co-administration of these two vitamins is highly recommended</em>.<br /><br />Collective research appears to indicate that raising the <a href="http://www.ncbi.nlm.nih.gov/pubmed/18205981"><span style="color:#3333ff;">total antioxidant levels in the body</span></a> can offset some of the negative symptoms of ADHD and related disorders. We've already mentioned the importance of preventing oxidation of the fatty acids (lipids) of the cell walls, including the membranes of brain cells (which are rich in the omega-3's).<br /><br />Secondary to its role in preventing fatty acid oxidation, vitamin C can counteract the oxidation of minerals (including iron and copper) which may often be used as dietary supplements for ADHD treatments. <em>As in the case of omega-3 fatty acid supplementation, the risk of increased oxidative damage due to these mineral supplements is an often overlooked negative side effect of this common "natural" ADHD treatment strategy.</em><br /><br />Due, in part to its high concentration in brain tissue and susceptibility to oxidation, <a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2756717"><span style="color:#3333ff;">iron is prone to causing oxidative damage to the brain</span></a>. Maintaining adequate levels of vitamin C (as well as vitamin E, polyphenols and glutathione) can offset much of this potential damage. We will see this more in point #5 below.<br /><br />Finally, an often-overlooked side effect of most medications (including ADHD stimulant medications) is the potential for these medications to cause oxidative damage. For example, the common <a href="http://www.ncbi.nlm.nih.gov/pubmed/16494852"><span style="color:#3333ff;">ADHD stimulant methylphenidate (Ritalin, Concerta, Daytrana) was found to cause oxidative stress in young rat brains</span></a>, and highlights the possibility that long-term administration of these agents may leave key targeted "ADHD" brain regions more susceptible to oxidative damage.<br /><br />This observation was more evident in younger rats undergoing development and brain maturation, which may translate into analogous effects in the developing brains of children. Thus, children may be susceptible to harmful oxidative damage in the brain via consistent use of common ADHD stimulant medication, increasing their need for higher levels of vitamin C and other antioxidants.<br /><br />Of course, we should not put too much stock into just one or two studies; and that this conclusion is being drawn prematurely by ramblings of an over-anxious blogger :) <em>but we may seriously need to investigate this often overlooked possibility of ADHD medication based oxidative brain damage in children, and the possible amelioration of these dagmages via treatment with dietary antioxidants such as vitamins C and E.</em><br /><br /></li><li><strong>Vitamin C can potentially counteract the effects of lead on ADHD-like states:</strong> Numerous studies have linked in increase in ADHD symtpoms and behaviors with higher lead levels (although it is worth mentioning that numerous studies out there refute this association as well, so there is far from a consensus surrounding this issue). We have seen previously that <a href="http://adhd-treatment-options.blogspot.com/2008/12/using-iron-to-combat-effects-of-lead-in.html"><span style="color:#3333ff;">iron may counteract lead</span></a> and potentially alleviate some of these negative lead-based effects. When used in conjunction with other nutrients such as the mineral <a href="http://www.ncbi.nlm.nih.gov/pubmed/19357318"><span style="color:#3333ff;">zinc and the amino acids taurine, methionine and glycine</span></a>, vitamin C may reduce lead-derived learning and memory impairments (in the rat model), features which offer at least some semblance to common deficits in the disorder of ADHD.<br /><br /></li><li><strong>Vitamin C can boost absorption of key minerals which are often deficient in the ADHD population.</strong> One possible explanation for the ability of vitamin C to counteract the effects of lead may be the role of <a href="http://www.ncbi.nlm.nih.gov/pubmed/11509108"><span style="color:#3333ff;">vitamin C in boosting iron absorption</span></a>, especially in iron deficient states. Some studies strongly recommend the <a href="http://www.ncbi.nlm.nih.gov/pubmed/15743017"><span style="color:#3333ff;">co-administration of these two nutrients</span></a>.<br /><br />As an aside, please note that there is a healthy debate surrounding the possibility of <a href="http://www.ncbi.nlm.nih.gov/pubmed/14728718"><span style="color:#3333ff;">vitamin C/iron combinations acting as potentially destructive <em>pro</em>-oxidants</span></a>. Based on <a href="http://www.ncbi.nlm.nih.gov/pubmed/18852484"><span style="color:#3333ff;">current trends in the literature</span></a>, however, it appears that most of these negative effects are seen more <em>in vitro</em>, or in cell cultures, but not <em>in vivo</em>, or in the body. Interestingly, this potential double-edged sword of ascorbic acid form of vitamin C (as either a pro-oxidant or antioxidant) may be strongly tied to the <a href="http://www.ncbi.nlm.nih.gov/pubmed/19209525"><span style="color:#3333ff;">concentration or levels of the vitamin</span></a>, in that vitamin C is reported to act more like a <em>pro-oxidant at lower levels</em> and an <em>antioxidant at higher levels</em>. This may explain some of the discrepancy surrounding the pro vs. anti-oxidant effects of vitamin C when coupled with iron or other minerals.<br /><br />We have discussed the prominence of iron deficiencies in the ADHD population and the role of this critical nutrient for treating the disorder, such as the role of <a href="http://www.ncbi.nlm.nih.gov/pubmed/19393285"><span style="color:#3333ff;">iron in the synthesis of neurotransmitters such as dopamine</span></a>.<br /><br />Additionally, common disorders common to ADHD such as Restless legs Syndrome and <a href="http://adhd-treatment-options.blogspot.com/2009/03/iron-levels-sleep-disorders-and-adhd.html"><span style="color:#3333ff;">sleep disorders</span></a> may be attributed to deficiencies in iron levels. Therefore, <em>vitamin</em> <em>C may serve as a secondary protection strategy against iron deficiencies and subsequent worsening of ADHD symptoms.</em><br /><br />I realize that it can be difficult to make sense of and keep separate the various iron/vitamin C interactions, so to summarize some of the main points of these associations:<br /><br />1) Vitamin C can aid in the body's absorption of iron.<br />2) Vitamin C can interact with iron and keep the iron from being oxidized, but...<br />3) This process can cause an <em>oxidized form of vitamin C itself</em>. This oxidized vitamin C species can potentially cause damage in its own right if unchecked (but can be recycled back to the antioxidant form of the vitamin by other antioxidants in the body).<br />4) In general, lower levels of vitamin C tend to have more of a "pro-oxidant" effect, while the antioxidant effects of vitamin C often predominate at higher levels of the vitamin.<br /><br /></li><li><strong>Higher vitamin C levels have been tied to improvements in visuo-spatial abilities as well as </strong><a href="http://www.ncbi.nlm.nih.gov/pubmed/8031738"><span style="color:#3333ff;"><strong>non-verbal intelligence</strong></span></a> (both of which are often deficient in the ADHD population). As a reference, non-verbal intelligence includes skills such as being able to read or pick up on non-verbal social cues such as reading facial expressions and associating them with another person's mood, as well as distinguishing differences and inflections in tone of voice. It is important to note that non-verbal learning disabilities often accompany ADHD symptoms, and are often seen across the autistic spectrum (which mirrors ADHD symptoms in a number of ways).<br /><br />The correlation between vitamin C and non-verbal abilities is more strained than some of the other associations mentioned in this piece, but this blogger has found a few documented studies pointing out this possible affiliation. The whole vitamin C association with non-verbal deficits might be part of a bigger picture, in that deficits in <a href="http://www.ncbi.nlm.nih.gov/pubmed/8031738"><span style="color:#3333ff;">non-verbal IQ scores seems to be correlated with low total <em>overall</em> antioxidant levels</span></a>.<br /><br />On the flipside, the correlation between non-verbal deficits and the vitamin C antioxidant in particular appears to be <a href="http://www.ncbi.nlm.nih.gov/pubmed/8031738"><span style="color:#3333ff;">more prominent in </span></a><em><a href="http://www.ncbi.nlm.nih.gov/pubmed/8031738"><span style="color:#3333ff;">boys</span></a> </em>(compare this to a later section of this post where we will see that ADHD symptoms may be more tied to abnormalities in blood glucose levels in <em>girls</em>). <em>In other words, the effects of vitamin C supplementation may have different levels of effectiveness with regards to gender and comorbid conditions (but please note that much more additional study must be done to validate this general claim).</em><br /><br /></li><li><strong>Beyond the physical anti-aging benefits commonly associated with the vitamin,</strong> <a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2674290/"><span style="color:#3333ff;"><strong>vitamin C has shown to exhibit potent intellectual anti-aging benefits</strong></span></a> (making it a good candidate for adult ADHD cases). While the publication cited above is given in the context of the neurodegenerative disorder Alzheimer's Disease, we should take note that there is a significant overlap between ADHD and Alzheimer's (beyond just the attentional deficits).<br /><br />For example, genes (and the enzymes they code for) we have previously mentioned as being associated with ADHD are also believed to be affiliated with <a href="http://www.ncbi.nlm.nih.gov/pubmed/17851196"><span style="color:#3333ff;">Alzheimer's</span></a>. These include "ADHD" genes and enzymes such as <a href="http://adhd-treatment-options.blogspot.com/2009/03/adhd-gender-and-comt-gene.html"><span style="color:#3333ff;"><em>COMT</em></span></a><em> </em>and the<em> </em><a href="http://adhd-treatment-options.blogspot.com/2008/09/adhd-gene-5-serotonin-transporter-gene.html"><span style="color:#3333ff;"><em>Serotonin Transporter gene</em></span></a>. <em>Given the fact that the two disorders share a significant genetic and enzyme system overlap, as well as similarities between the features of the two disorders (as well as some anecdotal evidence for higher rates of neurodegenerative disease susceptibility in the ADHD population), this blogger suggests that the two disorders may also share effective treatment strategies utilizing vitamin C.<br /><br /></em></li><li><strong>Vitamin C's important role as a cofactor in important enzymes relevant to ADHD and related disorders:</strong> This is one of the less obvious (but extremely important) ways in which vitamin C treatment could benefit the individual with ADHD. Typically when we think of "cofactors" (agents which help the enzymes and enzyme systems in the body operate at peak efficiency), we often think of B vitamins or trace minerals such as zinc, iron, or magnesium.<br /><br /><em>However, it is important to get out of our heads the notion that vitamin C's mode of action as an ADHD treatment strategy is confined to its role as a "generic" antioxidant</em>. Several enzymes whose function is linked to ADHD (often through the metabolism of other nutrients or pharmaceutical agents) require it as an essential cofactor to improve their function. One of these is the enzyme <em><strong>Dopamine Beta Hydroxylase</strong></em>, which will be discussed in more detail in the next point.<br /><br /></li><li><strong>Vitamin C is important in the conversion process of dopamine to norepinephrine:</strong> This is relevant to both drug and nutritionally based treatment methods for ADHD (dopamine and norepinephrine are key neurotransmitters in the brain and nervous system and are often unbalanced in ADHD cases. Many ADHD medications (in particular the stimulants) work by regulating the production and transport of these two chemicals by targeting key enzymes and proteins made for transporting both of these agents.<br /><br />As mentioned above, one such enzyme for this conversion is the enzyme <em>Dopamine Beta Hydroxylase</em> (or <em>DBH</em>). We have investigated the importance of the gene that codes for this enzyme, the <a href="http://adhd-treatment-options.blogspot.com/2008/09/adhd-gene4-dopamine-beta-hydroxylase.html"><em><span style="color:#3333ff;">Dopamine Beta Hydroxylase gene</span></em></a>, and its significance with regards to ADHD in earlier posts.<br /><br />Synthesis of other <strong>catecholamines</strong> (chemicals which are manufactured in the body from the amino acid <strong>tyrosine</strong>, which were alluded to in an earlier post on the drug <a href="http://adhd-treatment-options.blogspot.com/2009/05/modafinil-alternative-treatment-for.html"><span style="color:#3333ff;">modafinil for adult ADHD treatment</span></a> and will be discussed further at the end of this post) such dopamine, norepinephrine and adrenaline) takes place in vitamin C rich regions of the body, including the adrenal glands as well as various brain regions.<br /><br />Keep in mind that the concentrations of vitamin C required for the enzymes in these brain regions to work optimally are around <a href="http://www3.interscience.wiley.com/cgi-bin/fulltext/122538616/HTMLSTART"><span style="color:#3333ff;">40 times higher than the typical vitamin C concentration in the blood</span></a>. As a result, an effective transport system to get this higher concentration in the brain is necessary, which leads to the next function of the <strong>Blood Brain Barrier (BBB):</strong><br /><br /></li><li><strong>Vitamin C has multiple well-designed ways to get into the brain through the Blood Brain Barrier and its levels are tightly regulated:</strong> The Blood Brain Barrier is an important barrier that is designed to limit or prevent potentially harmful substances in the blood from crossing over into the brain, while allowing a controlled passage of nutrients into the brain. We have alluded to this barrier in the last post with regards to its role in the passage of metals such as <a href="http://adhd-treatment-options.blogspot.com/2009/12/can-zinc-and-selenium-counteract.html"><span style="color:#3333ff;">selenium, zinc and mercury</span></a> and the subsequent effects on ADHD.<br /><br />Compounds which are water soluble, such as vitamin C, have an inherently more difficult passage through this critical barrier owing to size and solubility issues (in general, the blood brain barrier naturally favors the transport of <em>less</em> water soluble agents). However, there are a number of ways around this potential problem.<br /><br />In biology and medicine, the term <strong>homeostasis<em> </em></strong>refers to stability or resistance to uncontrolled fluctuation. The transport systems of the blood brain barrier seem to be well-suited for vitamin C, owing in part to the fact that the optimal levels of key proteins that transport the vitamin into the brain fall work at <a href="http://www3.interscience.wiley.com/cgi-bin/fulltext/122538616/HTMLSTART"><span style="color:#3333ff;">peak efficiency around the standard concentration of vitamin C in the blood</span></a> (this is not the case for all nutrient transporters).<br /><br />For example one of these proteins is called the <strong>Sodium-dependent Vitamin C Transporter-2</strong> (or <strong>SVCT-2</strong>) allows vitamin C to be transported into the brain from the blood and maintain the much higher brain concentration of the vitamin. In fact, different transport methods exist (and, to some degree are even more favorable) if vitamin C is in the oxidized form (i.e. it has already fulfilled its role as an antioxidant by "sacrificing" itself to keep harmful oxidation from occuring to something else, such as an omega-3 fatty acid).<br /><br />It is important to note that because of these tight regulatory mechanisms which safeguard levels of vitamin C both in and out of the brain, rampant supplementation with vitamin C will not change its levels in the brain to a high degree. In other words, our bodies are typically well-adapted at holding onto this vitamin and maintaining appropriate levels of this key nutrient in the brain. This provides argument against the merits of high levels of supplementation (not to say that higher levels are necessarily harmful, just that this will be of limited effect). Nevertheless, we still should strive to avoid shortages of this vitamin. </li></ol><p><strong>**Two other possible advantages of boosting vitamin C intake for ADHD:</strong> Please note that these next two suggestions are more of a personal hypothesis of the blogger and less validated by adequate research. Nevertheless, they may be at least worth a mention:</p><ol><li><strong>Vitamin C may help regulate blood glucose levels in ADHD patients:</strong> Several studies seem to indicate that <a href="http://www.ncbi.nlm.nih.gov/pubmed/8489322"><span style="color:#3333ff;">glucose metabolism in the brains of ADHD children</span></a> is lower in multiple regions. It appears that these effects may be even more pronounced in <a href="http://neuro.psychiatryonline.org/cgi/content/full/10/2/168"><span style="color:#3333ff;">girls and women with ADHD</span></a> (although this blogger believes that the whole brain glucose metabolism differences are a bit overhyped, a number of other studies, which are simply not mentioned in most ADHD treatment books, found little to no metabolic differences. Nevertheless, I believe there is still sufficient evidence that, while smaller than what most other "ADHD experts" assert, there is still a significant difference in these metabolic patterns).<br /><br />Additionally, these differences may become more <a href="http://www.ncbi.nlm.nih.gov/pubmed/9608405"><span style="color:#3333ff;">pronounced with age</span></a>, suggesting a potentially greater necessity for intervention among adult ADHD cases. Again, women in particular may be more affected, according to the current body of research. <em>It is important to note that the evidence for vitamin C supplementation for improving brain glucose metabolic efficiency for ADHD patients is more hypothetical than experimental at the moment.</em><br /><br />What we do know is that there are pronounced interactions with vitamin C and glucose regulation, such as <a href="http://www.jacn.org/cgi/content/full/17/2/105"><span style="color:#3333ff;">vitamin C treatment for diabetic conditions</span></a>. However, we may at the wrong end of a "chicken-or-the-egg" type of dilemna, since significant evidence points towards lower <a href="http://www.ncbi.nlm.nih.gov/pubmed/8918139"><span style="color:#3333ff;">vitamin C concentrations in diabetic-like conditions</span></a>. This is likely due, in part, to the oxidative stress caused on the body by the diabetic state (and the subsequent consumption or depletion of vitamin C stores).<br /><br />Again, most of these studies are done on diabetic conditions in the blood outside of the nervous system, but some of these effects (at least in theory) could carry over to glucose regulation in the brain. However, this blogger readily admits that this possibility is somewhat tenuous.<br /><br /></li><li><strong>Vitamin C can improve circulation, including to brain regions:</strong> Again, this is more on a theoretical note. In addition to its proposed role as a blood sugar regulating measure (see above), <a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC81230/"><span style="color:#3333ff;">vitamin C may also help regulate blood pressure</span></a> and subsequent circulatory capabilities to key brain regions. Again, the evidence supporting this assertion is much weaker than the original 10 points listed, above, but in this blogger's personal opinion, this may be another positive side effect of vitamin C treatment for ADHD.</li></ol><p>It is important to realize that the body of research supporting these claims for utilizing vitamin C as an ADHD treatment strategy is all over the spectrum (from merely hypothetical ponderings to consistently verified controlled research studies). </p><p>At the moment, the strongest arguments for vitamin C treatment as a remedy to ADHD symptoms seem to be in protecting cells in the brain and nervous system from oxidative damage either directly via vitamin C's antioxidant capabilities or secondarily via vitamin C's ability to help regulate or "recycle" levels of other antioxidants, such as vitamin E (which much more effective at protecting the omega-3 rich regions of the brain from fatty acid oxidation) and glutathione. <strong>In other words, vitamin C is a great way to augment the ever-popular omega-3 fatty acid supplementation strategy for ADHD</strong> (and is unfortunately often overlooked by prescribing physicians).</p><p>While these effects are perhaps the most widely known among the health field, two other factors such as vitamin C's role in ADHD management are also well-documented and potentially on par with its role as a generalized antioxidant. Vitamin C is an important co-factor (enzyme helper) in a number of metabolic processes surrounding the disorder of ADHD, and is key to both the synthesis of important neurotransmitters such as <strong>dopamine</strong> and<strong> norepinephrine</strong> (which are often off-kilter in the ADHD population). </p><p>Thus, it may be a beneficial adjunct therapy for <strong>precursor loading </strong>(taking high levels of a nutrient which the body can then convert to the desired compound) with the amino acid <strong>tyrosine</strong> (which the body converts to dopamine and eventually norepinephrine via a series of enzyme-dependent steps, some which utilize vitamin C. In theory we're giving the body more starting material to work with to increase the output of these important neuro-signaling chemicals of clinical relevance to ADHD and related disorders. Please keep in mind that the literature seems to be split at the moment about the overall effectiveness of these precursor loading methods with regards to these ADHD treatment strategies). </p><p>In conclusion, maintaining adequate levels of vitamin C (for the recommended daily amounts of vitamin C, check <a href="http://lpi.oregonstate.edu/infocenter/vitamins/vitaminC/"><span style="color:#3333ff;">here</span></a>) is an often overlooked treatment method for a variety of diseases and disorders beyond the common cold. While perhaps not as promising as some of the other nutritionally-based treatment strategies for ADHD which have been mentioned in the past in this blog, such as <a href="http://adhd-treatment-options.blogspot.com/2009/04/10-ways-carnitine-can-help-treat-adhd.html"><span style="color:#3333ff;">carnitine</span></a>, <a href="http://adhd-treatment-options.blogspot.com/2009/04/10-ways-zinc-can-combat-adhd.html"><span style="color:#3333ff;">zinc</span></a>, <a href="http://adhd-treatment-options.blogspot.com/2009/01/omega-3-fatty-acids-and-adhd-theory.html"><span style="color:#3333ff;">omega-3 fatty acids</span></a>, <a href="http://adhd-treatment-options.blogspot.com/2009/03/iron-levels-sleep-disorders-and-adhd.html"><span style="color:#3333ff;">iron</span></a>, or <a href="http://adhd-treatment-options.blogspot.com/2008/11/magnesium-combination-treatments-for.html"><span style="color:#3333ff;">magnesium</span></a> and <a href="http://adhd-treatment-options.blogspot.com/2008/11/treating-adhd-with-magnesium-and.html"><span style="color:#3333ff;">B vitamins</span></a>, this simple and relatively inexpensive treatment method may pay dividends in the long run. </p><p>Furthermore, with low risks of toxicity due to its highly water-soluble nature (overdosing on vitamin C usually results in little more than temporary bouts of diarrhea which are quickly reversible when the vitamin intake is scaled back), the payoff/risk factors are favorable for regular usage of vitamin C as an <em>auxiliary </em>or <em>supplementary</em> method of nutritionally-based ADHD treatment. </p>The ADHD Treatment Guidehttp://www.blogger.com/profile/00747782650821771627noreply@blogger.com30tag:blogger.com,1999:blog-2736612052295099842.post-41996009003590658002009-12-16T17:58:00.012-05:002009-12-21T02:23:01.078-05:00Can Zinc and Selenium Counteract Mercury's Effects on ADHD and Autism?<span style="FONT-WEIGHT: bold">Mercury, an unwanted side-effect of the omega-3 rich fish oil treatment strategy for both ADHD and autistic spectrum disorders may be counteracted by Selenium and Zinc:<br /><br /></span>It's a catch-22 of the ADHD world. We've been told to feed ourselves and our kids as much of the omega-3 rich cold water fish as we can muster in order to balance their dietary fats and the subsequent hormonal effects. On the other hand, we're supposed to curb our fish product consumption for fear of mercury. Are there any other options beyond digging into our wallets for the pricey low-mercury wild organic salmon of the Pacific<span style="FONT-WEIGHT: bold"><span style="FONT-WEIGHT: bold"><span style="FONT-WEIGHT: bold"></span></span></span>?<br /><br /><span style="FONT-WEIGHT: bold">Why mercury is so toxic for the brain:</span><br /><br />In general, (as one would probably expect) if a metal or compound can be cleared from the body easily, then the risk of toxicity is generally much lower. However, if the material cannot be easily cleared from the system, it can begin to build up in specific tissues or regions of the body.<br /><br />Unfortunately, the brain is one of those target organs that has an almost magnetic pull for the heavy metal. While the digestive system can partially metabolize mercury into organic mercury-containing compounds, these compounds can make their way across the protective blood-brain barrier (a barrier meant to restrict the access of chemicals in the blood from passing into the brain, however, several harmful organic compounds can make their way across this barrier with relative ease).<br /><br />In general, fatty acids penetrate the blood brain barrier relatively well, and these important fish fats and oils can make perfect delivery vehicles for some of these toxic compounds. In other words, mercury in fish and fish oil products can be exceptionally hard to isolate or remove from the brain.<br /><br />Further complicating the matter is the problem of oxidation, especially in the brain tissue. While all organs and tissues of the body can suffer from oxidative damage (think of the biochemical equivalent of rusting or corrosion), <em>the brain, due to its high fat content, is especially susceptible to this harmful oxidation</em>. It is here in the brain that the mercury can become trapped and promote these dangerous oxidative processes.<br /><br /><strong>Mercury and corn syrup: A hidden danger for the ADHD child?</strong><br /><strong></strong><br />The sugar/hyperactivity debate has been around for ages, although most of the recent evidence often refutes this commonly held assertion. Nevertheless, several nutritionists swear by their convictions about this association. So who is right?<br /><br /><em>This blogger personally believes that there is an association between sugar and ADHD-like symptoms, but this connection is likely due to secondary factors. Let me explain:</em><br /><br /><em>Consumption of high concentrations of sugary foods and beverages can be a metabolically taxing and stressful process on the body. The enzyme systems necessary to metabolize high quantities of sugars are dependent on an ample supply of vitamin and mineral "cofactors" (these will be discussed in more detail later on in this post), or agents that help the enzymes function propertly. </em><br /><em></em><br /><em>If overtaxed (as by consuming large quantities of soda or candy, for example), these vitamin and mineral cofactors can be rapidly depleted. Common cofactors such as </em><a href="http://www.ncbi.nlm.nih.gov/pubmed/18800899"><span style="color:#3333ff;"><em>iron, copper, zinc and selenium</em></span></a><em> can be depleted in glucose (sugar) metabolism. </em><br /><em></em><br /><em>Interestingly, </em><a href="http://www.ncbi.nlm.nih.gov/pubmed/16190793"><span style="color:#3333ff;"><em>deficiencies in zinc</em></span></a><em> and iron (especially when </em><a href="http://adhd-treatment-options.blogspot.com/2009/03/iron-levels-sleep-disorders-and-adhd.html"><span style="color:#3333ff;"><em>comorbid sleep disorders</em></span></a><em> including </em><a href="http://www.ncbi.nlm.nih.gov/pubmed/17644481"><span style="color:#3333ff;"><em>restless legs syndrome</em></span></a><em> are present alongside the ADHD) are common in the ADHD population. In fact, iron may be the underpinning biological factor in an alleged </em><a href="http://www.ncbi.nlm.nih.gov/pubmed/19223043"><span style="color:#3333ff;"><em>genetic link between ADHD and restless legs syndrome</em></span></a><em>. We will be discussing the role of selenium in ADHD shortly. </em><br /><em></em><br /><em>Additionally, this depletion can have an effect on the antioxidant levels of the individual including a lowering of levels of pools of the important antioxidant </em><a href="http://www.ncbi.nlm.nih.gov/pubmed/18800899"><span style="color:#3333ff;"><em>reduced glutathione</em></span></a><em> (we will be investigating the importance of glutathione later on in this post). There is some evidence of ADHD symptoms in adults being at least partially attributed to </em><a href="http://www.ncbi.nlm.nih.gov/pubmed/18644422"><span style="color:#3333ff;"><em>antioxidant imbalance</em></span></a><em>. </em><br /><em></em><br /><em>In addition, the insulin rush, surge and fallout from consumption of a sugary meal can also wreak havoc on hormonal balances (including adrenaline, a chemical cousin to several neuro-chemical agents which are often seen to be off-kilter in most ADHD cases). We will save this discussion and go into more detail on the role of sugar consumption and hyperactivity and attentional deficits in later posts.</em><br /><br />Returning to the main topic of our post (from our tangent here!), some forms of sugar may also have other hidden dangers with relevance to our post here on mercury and ADHD and related disorders. The processing and manufacturing of high fructose corn syrup (one of the most common and readily available sweetening agents in North America and much of the Westernized world), may actually leave <a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2773803/"><span style="color:#3333ff;">detectable levels of mercury</span></a> in the sweetener (which, the study also attributes to causing a zinc loss). <br /><br />As a result, consumption of high levels of corn syrup at least has the potential to up our intake of mercury. <em>If the mercury/autism/ADHD connection holds true, then this is one more (indirect) way in which sugary foods can increase the risk of inattention and hyperactivity associated with the disorder. </em><br /><strong></strong><br /><br /><span style="FONT-WEIGHT: bold">Can chelation therapy be used to effectively remove the mercury in our systems?</span><br /><br />Our first thought might be to enlist the help of chemical agents which could pull the mercury or other toxic (and easily oxidizable metals) out of our systems.<br /><br />A <a style="COLOR: rgb(51,51,255)" href="http://www.ncbi.nlm.nih.gov/pubmed/19860886">recent study</a> has highlighted some possible alternatives on the mercury-fish-ADHD dilemma. One of the strategies involves the use of <span style="FONT-WEIGHT: bold">chelating</span> materials. The word "chelate" comes from the Greek word "claw", and refers to an important chemical property in which a non-metallic compound can tightly bind to or "pick" up a specific type of metal and pull it away. <span style="FONT-WEIGHT: bold"><br /><br />Ethylenediamenetetraacetic Acid</span> or <span style="FONT-WEIGHT: bold">EDTA</span>, is one of the most well-known chelating agents for removing metals and mineral deposits from hard water, and even has some reported health implications for removing crusty hardening from human arteries.<br /><br />In theory, it sounds like this may be a good treatment option for removing toxic metals or oxidizing agents from the brains and digestive tracts of children with ADHD and related disorders (i.e. the autism-mercury controversy?).<br /><br />On the flip side, chelation therapy can be dangerous, especially for children, due, in part, to the fact that the chelating agents are often non-specific for their target metals. This highlights a classic problem in medical research, the rift between theory and practice.<br /><br />For example, some versions or derivatives of EDTA can "pick up" or remove significant amounts of the important mineral calcium (which, in addition to its role in skeletal function is an extremely important mineral in regulating heart rhythms, and optimizing nervous system function, among other things) along with the desired heavy metals lead and mercury. Cases of <a style="COLOR: rgb(51,51,255)" href="http://www.ncbi.nlm.nih.gov/pubmed/18949650">deaths due to this chelation therapy for autism</a> have been reported, and recent <a style="COLOR: rgb(51,51,255)" href="http://www.ncbi.nlm.nih.gov/pubmed/19017902">clinical trials for chelation therapy for autism have been halted</a>. <span style="FONT-WEIGHT: bold"></span><br /><br /><span style="FONT-WEIGHT: bold">Enzyme systems: Nature's alternatives to organic chelating agents?</span><br /><br />Fortunately, our bodies contain a number of powerful enzymes which not only can protect our brain and other important organs from oxidative damage, but actually help remove harmful or toxic materials from our systems.<br /><br />However, in order for these enzymes to work at optimal levels, they must be constantly equipped with adequate levels of helpful nutrients or <span style="FONT-WEIGHT: bold">cofactors</span>. Cofactors, often come in the form of our dietary vitamins and minerals, such as <a style="COLOR: rgb(51,51,255)" href="http://adhd-treatment-options.blogspot.com/2009/04/10-ways-zinc-can-combat-adhd.html">zinc</a>, <a style="COLOR: rgb(51,51,255)" href="http://adhd-treatment-options.blogspot.com/2009/03/iron-levels-sleep-disorders-and-adhd.html">iron</a>, <a style="COLOR: rgb(51,51,255)" href="http://adhd-treatment-options.blogspot.com/2008/11/magnesium-combination-treatments-for.html">magnesium</a>, <a style="COLOR: rgb(51,51,255)" href="http://adhd-treatment-options.blogspot.com/2008/11/treating-adhd-with-magnesium-and.html">vitamin B6</a>, <a style="COLOR: rgb(51,51,255)" href="http://adhd-treatment-options.blogspot.com/2009/01/adhd-alcoholism-and-nutrient.html">vitamin B12</a>, <a style="COLOR: rgb(51,51,255)" href="http://adhd-treatment-options.blogspot.com/2009/01/omega-3-fatty-acids-and-adhd-theory.html">vitamin C</a>, etc., and are required by numerous enzymes in order for the enzymes to work at peak efficiency. Not surprisingly, several of these cofactors have been discussed for their relevance to ADHD in earlier postings of this blog (see links on nutrients listed above)<br /><br />This is why nutrient deficiencies can be so hazardous, because literally hundreds or even thousands of enzyme systems may be in jeopardy if our bodies are deficient in just a handful of nutrients.<br /><br />Two of these important enzyme system and enzyme products are the<span style="FONT-WEIGHT: bold"> <em>metallothionein</em></span> enzyme and the peptide <span style="FONT-WEIGHT: bold">glutathione</span> (which is not an enzyme, but is synthesized via several enzymes and is sensitive to the balance between oxidant and antioxidant levels).<br /><br />Metallothionein has been implicated in a number of studies concerning the enzyme's relationship to <a href="http://www.ncbi.nlm.nih.gov/pubmed/19161050"><span style="color:#3333ff;">autism</span></a>. One theory holds that children with autism have either lower levels of this enzyme or higher levels of antibodies to the enzyme (in which the body essentially attacks its own enzyme system as part of the idea of autism being an auto-immune disorder).<br /><br />While a small amount or research out there supports these claims, it is important to note that these findings are far from universal. In fact, most of the recent body of literature refutes the claim outright. One <a style="COLOR: rgb(51,51,255)" href="http://www.ncbi.nlm.nih.gov/pubmed/16771783">study</a> in particular negated both the observation that metallothionein was lower in autistic children or that higher levels of antibodies to the enzyme were present in autistic children. On the other hand, <a style="COLOR: rgb(51,51,255)" href="http://www.ncbi.nlm.nih.gov/pubmed/16264412">lower levels of the antioxidant glutathione are often seen in cases of autism</a>.<br /><br />(<span style="FONT-STYLE: italic">Blogger's note: the reason I'm going into so much detail about autism is because the high degree of <a style="COLOR: rgb(51,51,255)" href="http://www.ncbi.nlm.nih.gov/pubmed/19016613">symptomal overlap between ADHD and disorders of the autistic spectrum</a>, as well as the high degree of overlap between <a style="COLOR: rgb(51,51,255)" href="http://www.ncbi.nlm.nih.gov/pubmed/18208598">nutrient deficiencies concerning the two disorders</a>). </span><br /><br /><strong>The role of selenium and zinc in the processes of the enzyme metallothionein and the antioxidant glutathione:<br /></strong><br />We have seen in previous cases how boosting levels of one metal in the body can offset the negative effects of another such as the case of <a style="COLOR: rgb(51,51,255)" href="http://adhd-treatment-options.blogspot.com/2008/12/using-iron-to-combat-effects-of-lead-in.html">iron combatting the harmful effects of lead in ADHD</a>.<br /><br />It appears that the metallothionein function in autism is intricately tied to <a style="COLOR: rgb(51,51,255)" href="http://www.ncbi.nlm.nih.gov/pubmed/19280374">copper-zinc ratios</a>, and an excess of copper (or deficiency of zinc) can hinder this enzyme's effectiveness (the presence of heavy metals such as mercury are believed to be at least partially responsible for this skewed zinc-to-copper ratio). Interestingly, significantly <a href="http://www.ncbi.nlm.nih.gov/pubmed/19875267"><span style="color:#3333ff;">higher copper to zinc ratios have also been seen in ADHD children</span></a> in recent studies. In addition, the transport or delivery of zinc to its desired targets may be dependent on the antioxidant functions of <a style="COLOR: rgb(51,51,255)" href="http://www.healing-arts.org/children/mtpromotion.htm">glutathione and the mineral selenium</a>.<br /><br />While <a href="http://www.ncbi.nlm.nih.gov/pubmed/19875267"><span style="color:#3333ff;">copper</span></a> and <a href="http://www.ncbi.nlm.nih.gov/pubmed/19344299"><span style="color:#3333ff;">zinc</span></a> balances have been studied extensively with their relationship to ADHD (here's an earlier post on <a href="http://adhd-treatment-options.blogspot.com/2009/04/10-ways-zinc-can-combat-adhd.html"><span style="color:#3333ff;">ten ways zinc can counteract ADHD symptoms</span></a>, or how <a href="http://adhd-treatment-options.blogspot.com/2008/11/using-zinc-to-boost-ritalins.html"><span style="color:#3333ff;">zinc can boost the effectiveness of ADHD medications</span></a>), selenium may be a "sleeper" as far as important minerals for ADHD symptom treatment goes. <br /><br />While selenium is unlikely to unseat "heavyweight" minerals such as <a href="http://adhd-treatment-options.blogspot.com/2009/04/10-ways-zinc-can-combat-adhd.html"><span style="color:#3333ff;">zinc</span></a>, <a href="http://adhd-treatment-options.blogspot.com/2009/03/iron-levels-sleep-disorders-and-adhd.html"><span style="color:#3333ff;">iron</span></a> and <a href="http://adhd-treatment-options.blogspot.com/2008/11/magnesium-deficiency-and-childhood-adhd.html"><span style="color:#3333ff;">magnesium</span></a> for ADHD treatment, selenium is an important mineral for maintaining proper antioxidant balances, either directly (as an antioxidant itself) or indirectly (via its <a href="http://www.ncbi.nlm.nih.gov/pubmed/9776375"><span style="color:#3333ff;">incorporation into selenium-dependent enzymes</span></a>). The latter is evidenced by a number of important enzymes such as the dependence of the <a href="http://www.ncbi.nlm.nih.gov/pubmed/12394641"><span style="color:#3333ff;">important antioxidant enzyme <em>glutathione peroxidase</em> on selenium</span></a>. <br /><br />However, given selenium's wide range of potential benefits (<a href="http://www.ncbi.nlm.nih.gov/pubmed/9776375"><span style="color:#3333ff;">selenium has been implicated as an anti-cancer agent</span></a> in a number of studies), it appears that this often unheralded mineral may be a useful auxiliary agent in ADHD treatment. <br /><br />To conclude this message, we must remember that nutrients often work best in combos, not in isolation. <em>This (in this blogger's humble opinion), is why so many nutritional methods which attempt to combat ADHD often fail, in that they often fail to see this interconnection between nutrient interactions. They often instruct the individual to ramp up the dosage of only one or two nutrient which are believed to be deficient, and neglect to take into account the important roles of these supporting nutrient systems as a whole. </em><br /><br />We have seen in other postings how <a href="http://adhd-treatment-options.blogspot.com/2009/09/omega-3-oxidation-in-adhd-problem-with.html"><span style="color:#3333ff;">omega-3 fatty acids often work well with antioxidants</span></a>, as well as <a href="http://adhd-treatment-options.blogspot.com/2009/04/10-ways-carnitine-can-help-treat-adhd.html"><span style="color:#3333ff;">omega-3's and carnitine for treating ADHD</span></a> via nutritional methods. <a href="http://adhd-treatment-options.blogspot.com/2009/09/omega-3-oxidation-in-adhd-problem-with.html"><span style="color:#3333ff;">Vitamin C can work in tandem with vitamin E</span></a> as an antioxidant supplement duo, and recent evidence suggests that <a href="http://www.ncbi.nlm.nih.gov/pubmed/16314082"><span style="color:#3333ff;">vitamin C and flax oil</span> </a>may also be a good combo for ADHD as well. Several studies have indicated that <a href="http://adhd-treatment-options.blogspot.com/2008/11/treating-adhd-with-magnesium-and.html"><span style="color:#3333ff;">magnesium works well with Vitamin B6</span></a> (as well as other B vitamins) as an ADHD treatment method. <a href="http://adhd-treatment-options.blogspot.com/2009/04/10-ways-zinc-can-combat-adhd.html"><span style="color:#3333ff;">Zinc may also work well with omega-3's as well as vitamin B6</span></a>, and now, as we have seen, potentially with selenium, as an antidote to mercury's oxidative and toxic effects. <br /><br />It is imperative that we recognize the importance of these nutrients both alone and in combination, including their potential abilities to counteract chemical agents which may either cause or exacerbate ADHD symptoms.The ADHD Treatment Guidehttp://www.blogger.com/profile/00747782650821771627noreply@blogger.com8tag:blogger.com,1999:blog-2736612052295099842.post-45750577635073203042009-12-15T19:55:00.005-05:002009-12-15T20:13:18.462-05:00ADHD Subtype Differences and Stress<span style="font-weight: bold;font-family:georgia;" >Why ADHD Subtypes Matter: Inattentive vs. Hyperactive-Impulsive ADHD and the Cortisol Response to Stress</span><br /><br /><span style=";font-family:";" ><span style="font-family:georgia;">There is growing evidence that the three traditional subtypes of ADHD (Inattentive ADHD, Hyperactive-Impulsive ADHD and the Combined ADHD subtype) may in fact, be more accurately classified as separate disorders altogether. Although the ADHD sub typing method is still likely to persist, new biochemical studies have begun to shine light on some of the physiological differences associated with the three distinct ADHD subtypes. </span><b style="font-family: georgia;"><br /><br /></b><span style="font-family:georgia;">Significant </span><a style="font-family: georgia;" href="http://www.ncbi.nlm.nih.gov/pubmed/19225245"><span style="color: rgb(51, 51, 255);">outward expressional differences among the different subtypes</span></a><span style="font-family:georgia;"> can be seen, such as a more passive, less self-directed behaviors among the predominantly inattentive subtypes and more novelty seeking, stubborn and non-compliant behaviors once the hyperactivity component is added in. Perhaps this is not surprising, given the definition of impulsivity. Nevertheless, differences in accompanying disorders comorbid to ADHD also lend credence to the idea of separating the subtypes out into unique stand-alone disorders.<br /><br />It has even been posited that the </span><a style="font-family: georgia;" href="http://www.ncbi.nlm.nih.gov/pubmed/19308723"><span style="color: rgb(51, 51, 255);">disorder be subdivided further based on accompanying comorbid conditions</span></a><span style="font-family:georgia;">, but at the moment this sub-classification seems unlikely. Along with </span><a style="font-family: georgia;" href="http://adhd-treatment-options.blogspot.com/2009/02/gender-age-and-subtype-effects-on-adhd.html"><span style="color: rgb(51, 51, 255);">comorbid conditions, age and gender differences among the ADHD subtypes</span></a><span style="font-family:georgia;"> have also been postulated. </span><b style="font-family: georgia;"><br /><br /></b><span style="font-family:georgia;">Although outward behavioral expressions and phenotypes suggest stronger distinctions among the ADHD subtypes, it is the physiological and biochemical differences among these subtypes which may offer some of the most convincing evidence that a further re-classification of the disorder is warranted. </span><b style="font-family: georgia;"><br /><br /></b><span style="font-family:georgia;">It is possible, for instance, that symptoms such as hyperactivity may predominate more than inattentive behaviors from prior medical problems such as </span><a style="font-family: georgia;" href="http://adhd-treatment-options.blogspot.com/2009/05/childhood-ear-infections-and-adhd-why.html"><span style="color: rgb(51, 51, 255);">childhood ear infections</span></a><span style="font-family:georgia;"> (which might seem counterintuitive, given that we would expect ear infections to promote hearing loss and compromise the attention side of the disorder more than the hyperactive-impulsive components). However, evidence for the biological differences of ADHD subtypes often goes well beyond earlier exposures to diseases and external stressors.</span><b style="font-family: georgia;"><br /><br /></b><span style="font-family:georgia;">Getting to the meat of this issue are some recent studies on what is known as the HPA axis of the nervous system and the effects of this. "HPA" stands for hypothalamic-pituitary-adrenal, which include three essential components of the nervous system, which plays an extensive role in the fight-or-flight response in humans. So how does this tie in to ADHD?</span><br /><span style="font-family:georgia;"><br />One of the key components of this HPA axis is hormonal fluctuation. The chemical cortisol (you may have heard of cortisol from all of those late night TV and radio ads blasting cortisol for its contribution to body fat) is actually a stress-related hormone, meaning that the body produces it in response to internal or external stressors.</span><br /><br /><span style="font-family:georgia;">The kicker here is that there is now at least some evidence that the production of this </span><a style="font-family: georgia;" href="http://www.ncbi.nlm.nih.gov/pubmed/19294447"><span style="color: rgb(51, 51, 255);">cortisol hormone may be variable among the different ADHD subtypes</span></a><span style="font-family:georgia;">.<br /><br />It appears that children with the predominantly inattentive component of the disorder are more likely to exhibit a high cortisol response to stress while those with the more hyperactive/impulsive subtypes (just to avoid confusion, the study actually looked at the </span><i style="font-family: georgia;">combined ADHD subtype</i><span style="font-family:georgia;">, which includes the hyperactive component, and not the much rarer hyperactive-impulsive subtype) may have a significantly lower boost in the stressor hormone.<br /><br />This may not be all surprising, given the tendency and stereotype of the inattentive ADHD kids as being more lazy, overweight couch potatoes, while the hyperactive-impulsive kids are associated with being rail-thin fidgety and bouncing off the walls.</span><br /><br /><span style="font-family:georgia;">While this study seems to fit the bill and make sense, it is important that we try not to read too much into these results. After all, a number of other studies on the subject found little to no subtype difference with regards to HPA or the cortisol response. However, another recent study did advance this HPA notion a bit further. </span><b style="font-family: georgia;"><br /><br /></b><span style="font-family:georgia;">This study, done by </span><a style="font-family: georgia;" href="http://www.ncbi.nlm.nih.gov/pubmed/19899671"><span style="color: rgb(51, 51, 255);">Maldonado and coworkers</span></a><span style="font-family:georgia;">, found that ADHD children who exhibited more of the hyperactive-impulsive traits of the disorder</span><b style="font-family: georgia;"> had lower cortisol response levels to stressors than did the inattentive symptom dominated groups. </b><span style="font-family:georgia;">It is important to note that the HPA/cortisol/impulsivity association has been studied extensively in the literature.<br /><br />For example, an earlier study on </span><a style="font-family: georgia;" href="http://www.ncbi.nlm.nih.gov/pubmed/12950115"><span style="color: rgb(51, 51, 255);">ADHD children in Korea</span></a><span style="font-family:georgia;">, the researchers concluded that "the blunted HPA axis response to stress is related to the impulsivity in patients with ADHD", as evidenced by higher error rates on attention-based tasks.</span><span style="font-family:georgia;"> </span><span style="font-family:georgia;">To put it another way, a higher HPA axis response (including the secretion of the cortisol hormone) is thought to be advantageous as far as attention symptoms are concerned.</span><span style="font-family:georgia;"><br /><br />As an interesting side note, this blunted HPA activity subsequent "dulling" of the fight-or-flight response among the ADHD population may, in part, explain the high percentage of ADHD'ers in stressful occupations such as firefighters, EMT's, ER physicians, and combat personnel and the like. In other words, due to the reduced HPA response among most of the ADHD population, ADHD'ers are less likely to be overwhelmed in stressful situations, and may actually be at an advantage in occupations such as these. </span><b style="font-family: georgia;">Remember, ADHD can have its advantages!<br /><br /></b><span style="font-family:georgia;">Further muddying the waters with respect to cortisol and the HPA axis and ADHD is the presence of comorbid disorders. Another recent publication addressed this issue and found that for </span><a style="font-family: georgia; color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/19132527">boys with ADHD</a><span style="font-family:georgia;">, the presence of a comorbid anxiety disorder was likely to </span><i style="font-family: georgia;">raise</i><span style="font-family:georgia;"> the cortisol levels in response to stress for the child, but the presence of an oppositional or disruptive behavioral comorbid disorder showed a tendency to </span><i style="font-family: georgia;">lower</i><span style="font-family:georgia;"> the cortisol response to stress in the ADHD child. </span><b style="font-family: georgia;"><br /><br /></b><span style="font-family:georgia;">These findings show agreement with some of the earlier statements made above, given that </span><a style="font-family: georgia;" href="http://adhd-treatment-options.blogspot.com/2009/02/gender-age-and-subtype-effects-on-adhd.html"><span style="color: rgb(51, 51, 255);">comorbid anxiety disorders</span></a><span style="font-family:georgia;"> are often hallmark characteristics of either the inattentive or combined sub-components of ADHD, while oppositional or conduct disorders are seen at higher frequency with the hyperactive/impulsive or combined ADHD subtypes.</span><br /><i style="font-family: georgia;"><br />Blogger's personal note: The concept of oppositional behaviors in ADHD is somewhat interesting. It appears that there may be much more going on under the surface with regards to ADHD and oppositional/conduct disorders and dysfunction within the nervous system. These behaviors may be associated with seemingly unrelated functions among the ADHD population such as bedwetting. I don't mean to sound like a "conspiracy theorist", but for an interesting read on the subject, this blogger personally recommends an earlier post entitled <a style="color: rgb(51, 51, 255);" href="http://adhd-treatment-options.blogspot.com/2009/04/bedwetting-adhd-kids-and-depressed-dads.html">Bedwetting ADHD Kids and Depressed Dads: Is there a Connection?</a></i><br /><span style="font-family:georgia;"><br />Returning to our topic of discussion here, it is important to remember that in the first study mentioned, it was the hyperactive-impulsive children who showed more of a blunted cortisol response to stressors, so these observations from research groups in three different countries all seem to be reaching similar conclusions. </span><b style="font-family: georgia;"><br /><br /></b><span style="font-family:georgia;">In conclusion, we should take away from these studies that the different ADHD subtypes may exhibit distinct hormonal response differences, as well as neuro-chemical activity differences between the ADHD and the non-ADHD populations.</span><b style="font-family: georgia;"> </b><span style="font-family:georgia;">In general the more hyperactivity and/or impulsivity we see, the lesser the HPA-derived cortisol response e would expect to see in reaction to stressful situations.<br /><br />We can also see that comorbid disorders alongside the ADHD may either further dampen this HPA activity and cortisol response (as in the case of oppositional disorders), or counteract the ADHD response by boosting HPA activity and cortisol levels (as in the example of many anxiety disorders). The take-home message is this: ADHD subtype differences and the presence of comorbid disorders can play a pivotal role in the hormonal fluctuations among the ADHD population.</span><o:p></o:p></span><p></p> <p class="MsoNormal"><span style=";font-family:";" ><o:p> </o:p></span></p>The ADHD Treatment Guidehttp://www.blogger.com/profile/00747782650821771627noreply@blogger.com24tag:blogger.com,1999:blog-2736612052295099842.post-19484817425568198472009-11-08T13:10:00.003-05:002009-11-08T15:15:29.600-05:00"Dirty" Electricity and ADHD<span style="font-weight: bold;">Could fixing your power sources help clear up ADHD symptoms?</span><br /><br />We often hear about the health impacts of prolonged exposure to electrical and magnetic fields, including those involving cognitive deficits, neuro-developmental difficulties, and increased cancer risks. We would come to expect that some of these same invisible forces may also be at work with disorders such as ADHD.<br /><br />In previous posts, we have covered how <a style="color: rgb(51, 51, 255);" href="http://adhd-treatment-options.blogspot.com/2009/05/adhd-and-seasonal-affective-disorder.html">full-spectrum light exposure</a> (within the context of seasonal affective disorders) can influence ADHD severity and symptomology. <br /><br />In my reading, I recently came across an article from a few years back that caught my attention. This <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/17178585">article</a> was from the journal Electromagnetic Biology and Medicine, and involved a phenomenon known as "<a style="color: rgb(51, 51, 255);" href="http://www.dirtyelectricity.org/">dirty electricity</a>". The authors posited that this type of electricity, which occurs when electricity passes through several types of electronic devices such as computers or microwaves, which creates a more "noisy" spectrum (think of the analogy of a river or stream that picks up waste and debris along the way of its course) than "clean" electricity, may be a factor in a wide array of diseases and disorders ranging from <span style="font-style: italic;">diabetes</span> to <span style="font-style: italic;">multiple sclerosis</span>, to <span style="font-style: italic;">asthma</span>, to <span style="font-style: italic;">fibromyalgia</span> to neurological dysfunction (including balancing difficulties as well as <span style="font-style: italic;">ADHD</span>-like behaviors and symptoms). <br /><br /><span style="font-style: italic;">Although ADHD was not the main concern of the article </span>(which focused more heavily on the diabetic and MS complications associated with this dirty electricity)<span style="font-style: italic;">, the importance of maintaining appropriate blood sugar levels to the brains of ADHD patients should at least warrant further investigation into the matter.</span> <br /><br />By no means do I believe that this "dirty" electricity is a predominant contributing factor to a child's (or adult's) ADHD, but I did want to at least make the blogosphere aware that this may be an overlooked area of treatable potential. Some of the results of the study were intriguing to say the least.<br /><br />For example, the authors found that:<br /><ul><li>Fatigue among individuals in a building "sick" from dirty electricity is much more common than previously believed. Due to their size and range of appliances and power consumption patterns, schools are often prime candidates for being vulnerable to this dirty electricity phenomena. Fatigue and overall sickness in students and teachers may be significantly reduced if special electrical filters (called <span style="font-weight: bold;">Graham/Stetzer </span>or <span style="font-weight: bold;">GS </span>filters) are utilized. Similar results have been found in other related <a style="color: rgb(51, 51, 255);" href="http://www.electricalpollution.com/documents/Havas&Stetzer_revised.pdf">studies</a> (please keep in mind that several of these are somewhat biased, i.e. published by the makers of these electrical filters. <span style="font-style: italic;">For reference, this blogger has absolutely no affiliation with Graham Stetzer and does not receive any type of compensation from the makers of these filters</span>).</li></ul><ul><li>Stress from electrical sources <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/16189829">reduces the binding ability of insulin</a> to its targets in the body, which can result in <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/17178585">lower insulin sensitivity</a> (much like the pattern of insulin resistance seen in the onset of <a style="color: rgb(51, 51, 255);" href="http://en.wikipedia.org/wiki/Diabetes_mellitus_type_2">type 2 diabetes</a>). <br /></li></ul><ul><li>Furthermore, exposure to higher levels of electromagnetic fields results in an increase in production of <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/15515027">"stress" proteins</a> in the body. The degree of this varies, as a number of individuals carry more of a hypersensitivity to electrical fields than others. This high level of inter-individual variability makes it difficult to set concrete limits on safety concerns surrounding <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/17495668">electromagnetic exposure</a>. <br /></li></ul><ul><li>Additionally, the <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/17178585">original article</a> cited a case of significant improvement in balance and walking ability in and individual with multiple sclerosis following the "cleaning" of electricity in his area by using the electrical filters. Much like the phenomena of birds flying into more windows in areas near power lines (which can interfere with the bird's internal magnetic-based sense of direction), it is possible that cleaning up the power supply may have similar effects on humans. <br /></li></ul><span style="font-weight: bold;">Please note:</span> it's important not to get too excited or attempt to draw too many theoretical conclusions based on these observations. Keep in mind that this individual was diagnosed with MS and it was just a case study. Nevertheless, given the previously mentioned association between ADHD and early infections the inner ear (which affects balance and coordination), the potential influence of electrical fields may somehow tie in to all of this as well. This is simply a working hypothesis of the blogger at the moment. <br /><br />However, given the fact that abnormal <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/9334553">glucose metabolism</a> and blood sugar levels are typically depressed or less stable in the brains of ADHD patients as well as the possible connection between ADHD and areas involved with the balancing regions of the nervous system, the effects of electrical fields on the disorder may be larger than we previously realized.<br /><br />**As an interesting aside, many of the brain glucose studies of ADHD patients have found that glucose metabolic differences are often more pronounced in <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/8083143">girls</a> and <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/9608405">women</a> with the disorder than boys or men. It stands to reason (at least on a theoretical basis, but not to prematurely draw any conclusions) that similar gender-based differences may exist with regards to blood sugar levels in the brain as a result of exposure to electromagnetic fields of "dirty" electricity. <br /><br />Again, to reiterate that this blogger has no affiliation with the filters nor receives any compensation for endorsement of these products, it <span style="font-style: italic;">may</span> be useful to investigate how "dirty" the power in your home, school or office really is, especially if you or a loved one have ADHD or one of the related complications listed in the <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/17178585">original article</a>. <br /><br />**For reference sake, the cost of a meter for measuring dirty electricity runs somewhere from 100 to 150 US dollars (at least based off of what this blogger has seen), and the filters are about 35 US dollars apiece (not surprisingly the companies often recommend sets of 20 for an average home, bringing the grand total up over 800 US dollars. Not a small sum, of course!).<br /><br />As of now, this blogger is undecided whether the negative impact of dirty electricity is enough to warrant the pricey purchase of these power cleanup methods and devices. The main point for this post was simply bring a lesser-known phenomena of electrical pollution and highlight at least some of the <span style="font-style: italic;">theoretical</span> basis for exacerbating attentional deficits and ADHD symptoms. <br /><br />Given the widely-encompassing health risks covering various diseases and disorders (listed in the <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/17178585">original article</a> and beyond ADHD), it may be worthwhile to spend some time in more personal investigation on the topic. <br /><br /><span style="font-style: italic;">Nevertheless, these little-known connection (such as those between power lines and blood sugar levels) should serve to highlight the fact that ADHD is a multi-faceted disorder, and its symptoms may be governed by an ever-widening array of influential factors. </span>The ADHD Treatment Guidehttp://www.blogger.com/profile/00747782650821771627noreply@blogger.com8tag:blogger.com,1999:blog-2736612052295099842.post-13379110577201974722009-10-20T16:23:00.010-04:002009-10-26T21:59:08.475-04:00Treating ADHD by Floating in Salt Water?<div style="font-weight: bold;"><em>Can Floating in Salt Water Near Body Temperature be Used as an Effective, Natural ADHD Treatment?</em></div><br /><div>One of the things I enjoy most about researching and writing this blog is that I get a chance to review the literature of some pretty zany diagnostic and treatment methods for ADHD. I often wonder what is going through the minds of some of these researchers as they concoct these seemingly eccentric modes of treatment for the disorder. </div><br /><div></div><div>This blog has covered some of these seemingly bizarre treatments, including <a href="http://adhd-treatment-options.blogspot.com/search/label/mirrors%20for%20treating%20ADHD"><span style="color: rgb(51, 51, 255);">treating ADHD with mirrors</span></a>, <a href="http://adhd-treatment-options.blogspot.com/2009/01/genes-and-adhd-brainwave-patterns.html"><span style="color: rgb(51, 51, 255);">EEG manipulated ADHD treatment</span></a>, <a href="http://adhd-treatment-options.blogspot.com/2009/05/adhd-and-seasonal-affective-disorder.html"><span style="color: rgb(51, 51, 255);">light therapy for ADHD with seasonal affective disorders</span></a>, and the effectiveness of <a href="http://adhd-treatment-options.blogspot.com/2009/02/cost-effectiveness-of-adhd-treatments.html"><span style="color: rgb(51, 51, 255);">behavioral therapy measures for ADHD</span></a>, and hinted at other treatments such as <a href="http://www.ncbi.nlm.nih.gov/pubmed/18198165"><span style="color: rgb(51, 51, 255);">vestibular stimulation for ADHD</span></a>. </div><br /><div></div><div>A recent <a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2740119/"><span style="color: rgb(51, 51, 255);">article</span></a> in <em>Cases Journal </em>on treating a patient with ADHD and Asperger's by flotation sessions in a tank of salt water struck me as particularly bizarre, but piqued my curiosity. However, the justifications and apparent effectiveness of these measures suggests that further investigation may be warranted. Before we all decide to take a prolonged trip to the Dead Sea, we should investigate the methods of this treatment process and check for scientific evidence behind its claims. Below is a summary of the process, and some of the major points the article's authors conjured up to validate the effects of this form of ADHD treatment.</div><div></div><ul><li>As the name of the journal title suggests, this was a case report on a single individual, and not a controlled clinical study. However, I have repeated given my opinion on how case studies, although statistically inferior to controlled trials, should retain a place in novel medical treatments.</li><br /><li>The patient was a 36 year-old woman co-diagnosed with ADHD and Asperger's (although keep in mind that many diagnostic methods forbid the co-diagnosis of ADHD with anything along the Autistic Spectrum, including Asperger's. However, many clinicians often ignore this guideline and have no problem with diagnosing a person with these two comorbid disorders).</li><br /><li>The study authors noted that a number of the alternative treatments which previously showed promise hinged on triggering arousal levels (mirrors, EEG, etc.). It is well documented that deficiencies within <a href="http://www.ncbi.nlm.nih.gov/pubmed/18591484"><span style="color: rgb(51, 51, 255);">arousal levels are common in the ADHD</span></a> population. Hence, a sensory stimulation via flotation in a water tank may possibly show promise as an alternative ADHD treatment. </li><br /><li>The <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/8003591">flotation device</a> is essentially a covered tank (to minimize the impact of outside sources of stimulation) containing highly concentrated salt water (to enable easier floating and buoyancy) at near-body temperature (to reduce tactile stimulation due to a temperature difference between the person's body and outside environment). Keep in mind that this water is typically only 8 inches to a foot (20 to 30 centimeters) deep, and its high salt content (much higher than the ocean) allows one to float easily without touching the bottom of the tank. This method, called <em>flotation-Restricted Environmental Stimulation Technique</em> or <em><a href="http://www.ncbi.nlm.nih.gov/pubmed/8003591"><span style="color: rgb(51, 51, 255);">flotation-REST</span></a></em>, has been shown to be an effective stress-reliever and relaxation method. A total of 19 flotation treatment sessions were done within the span of about a year. </li><br /><li>The authors found five key components (arousal control, inhibition/activity regulation, sensory integration and interpretation, cognitive abilities, and emotional abilities) of ADHD behavior to be positively affected by flotation.<br /></li></ul><ol><li><span style="font-weight: bold;">Arousal control:</span> As mentioned previously, <a href="http://www.ncbi.nlm.nih.gov/pubmed/17166762"><span style="color: rgb(51, 51, 255);">arousal levels have been shown to be a significant component of ADHD</span></a> (and it can be either over or under-arousal). The flotation-REST method apparently addresses the arousal problem and normalizes this state by providing an environment which screens out most visual and tactile environmental stimulants. </li><br /><li><span style="font-weight: bold;">Activity regulation/inhibitory control of physical processes:</span> Often a hallmark characteristic of ADHD is the difficulty with inhibition control or <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/19627998">impulsivity</a> with regards to physical movements, especially in younger children. Impulsively grabbing at objects or persons is a common occurrence among children with the disorder (as almost any parent of and ADHD child can attest!). The <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2740119/">salt water/ADHD treatment case study</a> highlights that the salt water flotation/isolation therapy may alleviate some of this behavior due to it's effect on allowing the individual to "internalize" their focus on their physical movements, which may build up more regulatory ability of motor control and enhance the ability to restrict inappropriate physical impulses.<br /><br /></li><li><span style="font-weight: bold;">Sensory integration:</span> We have previously alluded to the possible connection between ADHD and sensory integration (in the context of <a style="color: rgb(51, 51, 255);" href="http://adhd-treatment-options.blogspot.com/2009/05/adhd-and-balance-impairment-visual-and.html">balance impairment and inner-ear dysfunction on ADHD</a>) disorders. Additionally, numerous studies on fine motor skill deficiencies, such as <a style="color: rgb(51, 51, 255);" href="http://adhd-treatment-options.blogspot.com/2009/05/adhd-and-handwriting-whats-connection.html">handwriting and ADHD</a> have been covered this blog and <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/17982901">studied in the literature</a>. It appears (at least in theory, according to the case study and journal article) that the flotation experience in a sensory restricted environment <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2740119">enhances the patient's sensory integration abilities</a> by depriving external sensory stimuli, leaving room for the person in the salt water tank more time to focus and coordinate his or her senses.<br /><br /></li><li><span style="font-weight: bold;">Improvements in cognitive abilities for ADHD patients:</span> We have discussed <a style="color: rgb(51, 51, 255);" href="http://adhd-treatment-options.blogspot.com/2009/05/methylphenidate-anxiety-and-adhd-how-do.html">cognitive abilities in ADHD</a> (as related to pharmacological treatment strategies) in previous posts, and there are numerous studies on comorbid <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/19825866">cognitive deficits in those with ADHD</a>. Furthermore, some posit a cognitive energy deficiency as the underlying cause to ADHD, identified as a <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/10654654">cognitive-energetic model</a> of the disorder. These deficiencies are believed to be at least partially remedied or improved by the flotation in salt water treatment, mainly due to the distraction-free environment being conducive to periods of prolonged concentration and enhanced thinking without interruption. According to the article, many of these benefits continue after the individual is out of the tank even for a period of a few weeks (of which these effects then begin to taper off).<br /><br /></li><li><span style="font-weight: bold;">Imrovements in personal emotional abilities:</span> <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/11853351">Emotional abilities</a>, especially as they relate to inter-personal interactions and relationships can also be a common deficit in individuals with ADHD. The flotation technique is believed to improve this aspect as well, as it provides an environment of personal self-acceptance which can then be transferred to <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2740119/">improved relationships with others and their emotions</a>.<br /></li></ol>In conclusion, we should probably not go running out to buy a big shark tank (minus the shark of course!) just yet. Remember, this was just one simple case study done in Sweden of a 36-year old woman with comorbid Asperger's. Obviously further study is warranted, and there are a number of loose ends that must be tied up before this alternative treatment method is accepted and goes mainstream. Future studies on the effectiveness of this treatment for children with the disorder would be especially useful. Nevertheless, this <span style="font-weight: bold;">Flotation Restricted Environment Stimulation Technique </span>(<span style="font-weight: bold;">flotation REST</span>) has shown to be useful in other areas of psychological function, including as a <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/8003591">relaxation/stress reduction</a> method.<br /><br />Thus, (in this blogger's personal opinion) this flotation REST technique may be especially good for ADHD'ers who suffer from high levels or irritability or have comorbid anxiety or depressive qualities (perhaps not those with claustrophobia or hydrophobia though!). Individuals with ADHD who have responded well to Wellbutrin or other antidepressant medications may be especially good candidates for this flotation treatment, at least in theory based on our current observations at the time.<br /><br />Additionally, it is worth the re-mention that the woman of the case study had co-morbid (co-existing) Asperger's and was already on an antidepressant medication throughout the whole course of the study. This may be good news for those who suffer from co-morbid disorders, as well as the fact that this flotation REST technique seems to be relatively compatible with medication treatment. Thus supplemental treatment by flotation in salt water near body temperature may be a good adjunctive measure for individuals with ADHD and a wide spectrum of comorbid disorders.The ADHD Treatment Guidehttp://www.blogger.com/profile/00747782650821771627noreply@blogger.com16tag:blogger.com,1999:blog-2736612052295099842.post-46879352894179960872009-10-11T14:07:00.019-04:002009-10-18T21:23:36.683-04:00Drugs, Genes and ADHD<div><span style="font-weight: bold; font-style: italic;">The Effects Specific "ADHD Genes" Have on Dosing ADHD Medications:</span><br /><br />Below is a list of five of the most common medications for ADHD. In order to break down or metabolize these drugs, however, a series of steps must take place for effective absorption, delivery and clearance of these drugs. This process, however, requires a series of enzymatic steps. Generally, when a physician prescribes these drugs, he or she considers factors such as the patient's age, gender, symptom severity and past medication history. However, lost in the shuffle is a lesser-known, but often equally critical factor: the particular genes of the individual. It is these genes which play a large role as to how well these enzymes function (alongside other factors such as the person's nutritional status, as most vitamins and minerals act as chemical "helpers" to these enzymes, and deficiencies can lead to lower enzyme function and sub-optimal metabolic efficiency). </div><br /><br /><div>Unfortunately for prescribing physicians, the landscape of enzyme capabilities among the general population is far from uniform. Some individuals naturally possess enzymes or enzyme systems (which are coded for and dependent on the genetic makeup of the particular individual)which are more efficient than others (often by multi fold differences). If these enzymes are essential to drug metabolism (including ADHD medications), then a potentially crucial piece of information may be missing from the physician's repertoire of assessment tools for medicating at the proper dosage. </div><br /><br /><div>Much to the dismay of many a frustrated parent of an ADHD child, this often begins the laborious process of adjusting medication dosages through a glorified "guess and check" process. However, due to the need for a relatively small window of effective dosing (especially for psychotropic drugs such as those prescribed for ADHD and related disorders) and unforgiving margins of error in the optimization process, bits of information, such as a child's genetically-dictated levels of drug-metabolizing enzymes could be extremely useful. With the increasing efficiency, lowering costs of and wider availability of genetic screening methods, we may soon be able to predict a child's enzyme levels by their genetic makeup and facilitate the dosing of (and eliminating much of the guess-work from) their medications for ADHD or other disorders, saving both time and money while on the medication circuit.<br /></div><br /><br /><div>Given the powerful role of enzymes and enzyme systems (and the specific genes which encode for them) for the delivery, metabolism and clearance of these medications, we should take a look at some of the genetic variations of these enzymes and the implications they may having in assisting the diagnosing physician in the near future for more effectively dosing ADHD medications. </div><br /><br /><div>Here are 5 common ADHD drugs (including one which is not prescribed but often used as a "self-medication" tool among the ADHD population), and the genetically-dictated enzymes which can play a role in their metabolism and dosing patterns and levels.<br /><br /><u><span style="font-weight: bold;">ADHD Drug #1: Strattera (Atomoxetine)</span><br /></u><br /><strong>Key enzymes involved and gene of interest:</strong> <em><strong>SLC6A2</strong></em>, <strong><em>CYP2D6</em></strong></div><br /><div align="left">We have already investigated another gene believed to have an impact on dosing with <a href="http://adhd-treatment-options.blogspot.com/2009/04/strattera-atomoxetine-response-may-be.html"><span style="color: rgb(51, 51, 255);">Strattera, the <em><strong>SLC6A2</strong> gene</em></span></a>. However, in that earlier <a href="http://adhd-treatment-options.blogspot.com/2009/04/strattera-atomoxetine-response-may-be.html"><span style="color: rgb(51, 51, 255);">post</span></a>, we alluded to another gene responsible for the metabolism of the non-stimulant ADHD drug Atomoxetine. This gene is called <em><strong>CYP2D6</strong></em>. The <em>CYP2D6</em> gene codes for an important enzyme of the same name (which is an important enzyme produced in the liver). The gene is located on the 22nd human chromosome (the <a href="http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=124030"><span style="color: rgb(51, 51, 255);">22q13.1 genetic region</span></a> to be more specific if you are familiar with genetic markers).<br /><br />Approximately a dozen different genetic forms (or alleles) of this <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/9012401"><span style="font-style: italic;">CYP2D6</span> gene</a> are seen in individuals of European ancestry. These forms are often designated by a star followed by a number, such as *1 or *4. While these numbers are used for naming purposes, it is worth noting that most individuals of European descent appear to carry either the *1 (the most common), the *2 or the *4 form of this gene. Additionally, *3, *6, and *10 forms are each found in about 1-2 percent of the population.<br /><br />Interestingly, the *10 form of this gene is found in higher levels in individuals of East-Asian descent. A Chinese study found that a higher frequency of this *10 form in the population (the *10 form shows up in over half of the Chinese population, about 10 times more frequently than in whites), resulted in slower rate of drug metabolism of the ADHD medication Strattera (Atomoxetine) by the <span style="font-style: italic;">CYP2D6</span> enzyme.<br /><br /><strong>Relevance of the <em>CYP2D6 </em>gene to medicating ADHD with Strattera:</strong> The *10 form of the CYP2D6 produces less enzymatic activity than the most common *1 form. This can result in about a <a href="http://www.ncbi.nlm.nih.gov/pubmed/17610534"><span style="color: rgb(51, 51, 255);">50% increase in Atomoxetine concentration in the blood</span></a> and duration before clearance, which was seen in the Chinese study. As a result, for individuals with the exclusive *10 form (such as seen in much of the East Asian population), slightly lower or less frequent dosing levels of atomoxetine might be needed to get the same therapeutic effects. This is in agreement with another study suggesting a 50 to 75% dosage reduction of <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/12621383">Atomoxetine for those with hepatic impairment</a> (liver dysfunction), as the <span style="font-style: italic;">CYP2D6</span> enzyme is produced in the liver.<br /><br />Additionally, this population may be at a slightly greater risk of side effects with the drug due to a slower clearance and greater buildup of the drug. Of course other genes and additional factors in the Atomoxetine pathway certainly play a role, but these genetic variations can still play a significant role in medication dosing strategies.<br /><br /><strong><u>ADHD drug #2: Adderall (Mixed amphetamine salts)</u></strong> </div><br /><div align="left"><strong>Genes of interest: <em>Catechol O-Methyltransferase</em> (<em>COMT</em>) <em>gene</em>, <em>Dopamine Transporter Gene</em> (<em>DAT</em>)</strong></div><br /><div align="left">In previous posts, we have spoken extensively about a gene called <em><strong><a href="http://adhd-treatment-options.blogspot.com/2008/12/adhd-genes-influence-medication-dosage.html"><span style="color: rgb(51, 51, 255);">COMT</span></a></strong></em>, short for <strong><em>Catechol O-Methyltransferase </em></strong>and its role on dosing for amphetamine-related ADHD medications such as <strong>Adderall</strong> and <strong>Vyvanse</strong>. This previous discsussion on <em>COMT</em> and ADHD medication dosing can be found <a href="http://adhd-treatment-options.blogspot.com/2008/12/adhd-genes-influence-medication-dosage.html"><span style="color: rgb(51, 51, 255);">here</span></a>. </div><br /><div align="left">However, there are a few other genes worth noting here for their potential roles in dosing with amphetamine-based ADHD medications such as Adderall. One of these is the <a href="http://adhd-treatment-options.blogspot.com/2008/09/adhd-gene3-dat.html"><span style="color: rgb(51, 51, 255);"><em><strong>Dopamine Transporter gene</strong></em> (<strong><em>DAT</em></strong>)</span></a>, which is located on the <a href="http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=126455"><span style="color: rgb(51, 51, 255);">5th human chromosome</span></a>. This gene also goes by other names such as <strong><em>DAT1</em></strong> or <em><strong>SLC6A3</strong></em>. The <strong><em>DAT</em></strong> gene codes for an important protein called the <strong><em>Dopamine Transporter</em></strong> protein, which is responsible for shuttling the important brain chemical dopamine in and out of neuronal cells. </div><br /><div align="left">A number of stimulant drugs used to treat ADHD and related disorders work, at least in part, by interacting with this dopamine transporter <a href="http://www.ncbi.nlm.nih.gov/pubmed/18416663"><span style="color: rgb(51, 51, 255);">(DAT) to correct a dopamine imbalance</span></a> (in general, individuals with ADHD often have too little dopamine in the regions between brain cells or neurons in key regions of the brain. Many stimulant ADHD drugs remedy this by blocking the shuttling of dopamine back into the cells, keeping adequate amounts in these "gaps").</div><br /><div align="left">Interestingly, on a side note, the <em><strong>DAT</strong></em> gene has been implicated (in conjunction with another dopamine-related gene called <strong><em>DRD4</em></strong>) in <a href="http://adhd-treatment-options.blogspot.com/2009/05/adhd-iq-and-gene-combinations.html"><span style="color: rgb(51, 51, 255);">IQ levels an behavior problems</span></a>. </div><br /><div align="left">Like the genes mentioned above, <em>DAT</em> exists in a wide number of different forms across the human gene pool. Some forms appear to increase ones predisposition to ADHD and various neurophysiological or behavioral disorders and have earned the moniker "high risk alleles" (remember, an "allele" is simply a specific form of a gene which varies within the population). </div><br /><div align="left">A study on families of ADHD children found that a specific form of the <em>DAT </em>gene which included a <a href="http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=9837830"><span style="color: rgb(51, 51, 255);">480 base pair repeat</span></a> (simply a repeating section of DNA which is 480 DNA "letters" long) allele was associated with greater severity of ADHD symptoms, especially in the combined ADHD subtype (which includes high levels of both inattentive and hyperactive/impulsive symptoms as opposed to a predominance of one). </div><br /><div align="left">Potentially, individuals with ADHD who carry this "high-risk allele" of the <em>DAT</em> gene (which is a substantial portion of the general population) may require slightly higher levels of medication dosage with amphetamine-based stimulants than their "lower-risk" counterparts. These differences may be even more pronounced if the individual carries the <a href="http://adhd-treatment-options.blogspot.com/2008/12/adhd-genes-influence-medication-dosage.html"><span style="color: rgb(51, 51, 255);">"Val" form of the <em>COMT gene</em></span></a>, mentioned in a <a href="http://adhd-treatment-options.blogspot.com/2008/12/adhd-genes-influence-medication-dosage.html"><span style="color: rgb(51, 51, 255);">previous post</span></a> (given the current body of research on the subject, the contributions of the <em>COMT</em> gene dwarf those of the <em><strong>DAT</strong></em> gene with regards to governing amphetamine dosage levels). </div><br /><div align="left"><strong><u>ADHD drug #3 Vyvanse (lisdexamfetamine dimesylate)<br /><br /></u></strong></div><span style="font-weight: bold;">Gene of Interest: </span><span style="font-style: italic; font-weight: bold;">Trypsinogen</span><br /><br />Due to its chemical proximity to amphetamines (Vyvanse is essentially an "inactivated" form of the drug Dexedrine, which is an isolation of one of the potent components of Adderall). A special chemical "tag" is linked to the active part of the drug, which must be chemically cleaved to release the active form of Vyvanse (think of it as essentially breaking a seal to free up the drug) into its functional amphetamine-based product. Naturally, the genes listed above (and the enzymes which they encode) which metabolize amphetamines are of substantial interest for potentially influencing the effectiveness of ADHD treatment with Vyvanse as well. <br /><br />However, the actual cleaving process of releasing the active component of Vyvanse is equally as important. If the drug is not freed, then it cannot be effectively metabolized.<br /><br />Several enzymes which are called upon to metabolize the other ADHD drugs in this post <span style="font-weight: bold;">do NOT</span> appear to have a significant <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/17407369">effect on Vyvanse</a>. These include <span style="font-style: italic;">CYP2A6</span>, <span style="font-style: italic;">CYP2B6 </span>(both for nicotine), and <span style="font-style: italic;">CYP2D6</span> (for Strattera). This is good news for those who are already taking medications, as Vyvanse's relative independence of these drug-metabolizing enzymes means fewer adverse drug-drug interactions.<br /><br />As far as genetics go, the genes coding for the breakage of de-activating chemical tag placed on Vyvanse may be of most importance, especially since this breakage (or "hydrolysis") is believed to be the slowest (or rate-determining) step in <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/17407369">metabolizing Vyvanse for ADHD</a>. The de-activating "tag" attached to Vyvanse is none other than the amino acid lysine. While the exact mechanism of cleaving this link is not fully known, one enzyme in particular may be extremely relevant to this process.<br /><br /><a style="color: rgb(51, 51, 255);" href="http://en.wikipedia.org/wiki/Trypsin"><span style="font-weight: bold;">Trypsin</span></a> is an extremely common digestive enzyme produced predominantly in the pancreas. It is responsible for breaking up chemical linkages much like that of the one used to de-activate Vyvanse. <span style="font-style: italic;">Thus, a genetically-governed deficiency of the trypsin enzyme could lead to a severely hampered absorption (and subsequent metabolism and clearance of the ADHD drug Vyvanse). </span><br /><br />Trypsin is actually coded for by a series of enzymes, often referred to as <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=276000"><span style="font-style: italic; font-weight: bold;">Trypsinogen</span>, which located on the 7th human chromosome</a> (in the "<a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/Omim/getmap.cgi?l276000">q35</a>" region of the chromosome to be more exact). Individuals with pancreatic deficiencies, including <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/8841182">pancreatitis have been tied down to having mutations in this <span style="font-style: italic;">trypsinogen</span> gene</a>.<br /><br /><span style="font-style: italic;">Therefore, while this genetic region on the 7th chromosome hasn't been sufficiently studied with regards to Vyvanse (at least to the best of this blogger's current knowledge), this blogger personally believes that aberrations in the region of the Trypsinogen gene on this 7th human chromosome may be a worthwhile place to look for genetic response-based differences to the ADHD medication Vyvanse. </span><br /><div align="left"><strong><u></u></strong><br /></div><div align="left"><strong><u>ADHD drug #4: Concerta/Ritalin/Daytrana/Biphentin (methylphenidate)<br /><br /></u></strong> </div><span style="font-weight: bold;">Genes of Interest<span style="text-decoration: underline;"><span style="font-style: italic;"></span></span><a href="http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=114835"><span style="font-style: italic;"></span></a>: <span style="font-style: italic;">Carboxylesterase 1</span> </span>(also referred to as "<span style="font-weight: bold; font-style: italic;">CES1</span>"), <span style="font-style: italic; font-weight: bold;">DAT</span> (refer to ADHD drug #2: Adderall section for DAT's genetic location)<br /><br /><span style="font-style: italic; font-weight: bold;">Carboxylesterase 1: </span>Although the affected form of this enzyme, which is coded for by a gene on the <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=114835">16th chromosome</a>, is relatively rare, some key studies have indicated that deficiencies in the <span style="font-style: italic;">CES1</span> enzyme can be coded from specific forms of this gene. These rare, low-functioning <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2427248/">gene-mutation forms of <span style="font-style: italic;">Carboxylesterase 1</span></a> result in extremely poor methylphenidate metabolism, resulting in a buildup of abnormally high levels of the drug in individuals with this enzymatically-deficient form.<br /><br /><div align="left">In addition to their effects on amphetamines such as Adderall or Dexedrine, variations (often referred to in the literature as "polymorphisms") in the <em>DAT</em> gene also play a role in the <a href="http://www.ncbi.nlm.nih.gov/pubmed/15059031"><span style="color: rgb(51, 51, 255);">response to methylphenidate</span></a>. A Korean study found that a specific allele (the 10-repeat allele, which is the same form as the "high-risk" 480 base-pair allele mentioned earlier in the amphetamines section) predicted a <a href="http://www.ncbi.nlm.nih.gov/pubmed/15572278"><span style="color: rgb(51, 51, 255);">poor response to methylphenidate</span></a>. </div><br /><div align="left">Interestingly, however, several Irish studies suggest the exact opposite: the "high-risk" 10-repeat 480 base pair form of the <em>DAT </em>gene may produce larger amounts of the <em>DAT</em> protein (which shuttles essential dopamine out of the gaps between the cells, the opposite effect of what one wants if they suffer from ADHD), so the <a href="http://www.ncbi.nlm.nih.gov/pubmed/12898575"><span style="color: rgb(51, 51, 255);">higher levels of expression of this transporter</span></a> may make it a <em>better</em> candidate for methylphenidate. </div><br /><div align="left">Another Irish study may help resolve some of this discrepancy. It found that individuals with the so-called "high-risk" form of the <em>DAT</em> gene mentioned above exhibit a more positive response to treatment with methylphenidate with regards to treating their <a href="http://www.ncbi.nlm.nih.gov/pubmed/16123773"><span style="color: rgb(51, 51, 255);"><em>attentional</em> symptoms based on the <em>left</em> side of the brain</span></a>. <em>Left sided inattention</em> can be a reflection of brain damage or <a href="http://www.ncbi.nlm.nih.gov/pubmed/19733838"><span style="color: rgb(51, 51, 255);">brain asymmetry</span></a>, the latter being a common trait in the ADHD population. It should be worth noting that <a href="http://www.ncbi.nlm.nih.gov/pubmed/15166683"><span style="color: rgb(51, 51, 255);">methylphenidate has been an effective treatment method</span></a> for improving cognitive processes for those suffering from traumatic brain injuries. </div><br /><div align="left">Given the fact that in the amphetamine section we mentioned that the <em>DAT</em> gene was more connected to the Combined ADHD subtype (the <a href="http://www.ncbi.nlm.nih.gov/pubmed/9837830"><span style="color: rgb(51, 51, 255);">original article</span></a> specifically stated that the association did not hold for the strictly inattentive ADHD subtype). <strong>If this holds true, then we may have discovered a potentially significant gene/medication/ADHD subtype association.</strong> </div><br /><div align="left"><em>It is this blogger's current hypothesis that the "high-risk"/480 base pair/10-repeat allele form of the DAT gene might predispose one to a MORE FAVORABLE response to methylphenidate treatment if inattention is the most persistent ADHD symptom (as in the predominantly inattentive ADHD subtype). Conversely, if the hyperactive/impulsive behavior either predominates or is largely present in an individual (such as in the <strong>hyperactive/impulsive</strong> or <strong>combined</strong> ADHD subtypes, respectively), then the "high-risk" label holds for this particular gene type, and the methylphenidate response potential goes down. </em></div><br /><div align="left"><em>In other words, <strong>if large amounts of hyperactivity are present</strong> (which is the case in most ADHD children, as the combined subtype is by far the most common form), then this "high-risk" form of the DAT gene <strong>hampers methylphenidate's effectiveness</strong>, whereas <strong>if</strong> <strong>hyperactivity is largely absent, then the response to methylphenidate is actually more favorable</strong>. If this hypothesis were to hold true, then we could screen youngsters for this form of the gene and keep them far away from methylphenidate if they were bouncing off the walls, whereas if the exhibited more of an inattentive "space cadet" type of behavior then methylphenidate might be a good first choice of pharmaceutical treatment. Of course this theory could be completely off-base, but given this blogger's current knowledge and exposure to the current literature, this may be a plausible explanation. </em></div><br /><div align="left"><em>Another possible explanation for this discrepancy between Irish and Korean studies:</em> We have already seen that specific forms of certain genes can be found at considerably higher levels such as the *10 form of the <em>CYP2D6</em> gene mentioned above with regards to the East Asian population. Keep in mind that this gene form was associated with the metabolism of Strattera (which exhibits a significantly different mode of operation than do stimulants such as methylphenidate or mixed amphetamine salts). However, there are a number of so-called <em>ADHD genes </em>which have been implicated with the disorder. The current thought here is that some genes exhibit a more powerful influence on physical or behavioral traits than do others. In other words, some genes simply act more "powerfully" than others. This is known as <em><strong><a href="http://en.wikipedia.org/wiki/Epistasis"><span style="color: rgb(51, 51, 255);">epistasis</span></a></strong></em> ("Epistasis" roughly means "standing upon"). </div><br /><div align="left">***<em>As a side note, please don't confuse "epistasis" with the whole dominant/recessive "big A/little a" (Aa) gene thing you probably learned about in middle school biology. Dominant/recessive refers to different forms of the SAME gene, whereas epistasis refers to DIFFERENT genes. For example, let's say, hypothetically that there was a rare gene for green hair located on the 20th human chromosome. However, a more "powerful" gene, say on the 14th chromosome codes for brown hair. This brown hair gene in this case would be <strong>epistatic</strong>, meaning that it would overpower the effects of the green hair gene altogether. This phenomena is quite common in genetics.</em></div><br /><div align="left">Getting back to our discussion, this blogger hypothesizes that there may be one or more other unidentified genes in either the Korean or Irish population which are epistatic to the <em>DAT</em> gene with regards to the methylphenidate response. If this was true, then it's quite possible that the effects of these hypothetical yet-to-be-identified genes might "mask" or override the effects of the <em>DAT</em> gene, and that the association with the "high-risk allele" may be largely coincidental rather than causative. Given the state of the current research on current "heavyweight" genes such as the <em>COMT</em> gene mentioned earlier, it is entirely possible that the overall level of contribution among specific "high-risk" <em>DAT</em> alleles might be less significant than many of these studies seem to indicate. </div><br /><div align="left">Of course the discrepancy could just as easily be attributed to small sampling sizes, slight differences in experimental methods or uncontrolled variables in the experiment (or a complete lack of true association between methylphenidate and the <em>DAT</em> gene at all, although given the current body of literature, this last assertion seems highly unlikely). <em><br /></em><br /><u><strong>ADHD drug #5: Nicotine:</strong></u> </div><br /><div align="left"><span style="font-weight: bold;">Genes of interest:</span> <strong><em>CYP2A6</em>, <em>CYP2B6</em></strong></div><br /><div align="left"><strong></strong>I have included this drug due to the high rates of smoking among those with ADHD. As with alcohol, nicotine is often widely used as a form of self-medication for those with ADHD. Some research even suggests that individuals with ADHD exhibit a different response to nicotine and that <a href="http://adhd-treatment-options.blogspot.com/2009/02/nicotine-withdrawal-effects-differ-in.html"><span style="color: rgb(51, 51, 255);">nicotine withdrawal</span></a> may produce different patterns in certain critical brain regions between ADHD'ers and the general population. Interestingly, there are some genetic regions which may tie into this behavior. </div><p>With regards to nicotine metabolism, 2 genes appear to stand out in particular: <em><strong>CYP2A6</strong></em> and <strong><em>CYP2B6</em></strong> (note the similarity in nomenclature between these and the gene/enzyme mentioned above for Strattera metabolism <strong><em>CYP2<u>D</u>6</em></strong>. This is not an accident, as all three of these belong to the same "superfamily" of enzymes and carry many similar chemical and functional similarities). Out of these, the <em>CYP2A6</em> (hereafter abbreviated as "<em>2A6</em>") enzyme is responsible for the lion's share of nicotine metabolism. It is coded for by by a gene of the same name, located in the <a href="http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=122720"><span style="color: rgb(51, 51, 255);">"q13.2" region on the 19th human chromosome</span></a>. </p><p>Like the <em>2D6</em> gene for Strattera, the <em>2A6</em> gene can exist in multiple different forms. Some <em>2A6</em> gene forms produce higher levels of the <em>2A6</em> enzyme than others. Other forms of <em>2A6</em> are less efficient, which results in a slower breakdown and clearance of nicotine. As a result, the nicotine stays in the body longer, and less of it is typically required. <em>As a result individuals with these less efficient forms (called "slow metabolizers") of the 2A6 genes are less likely to develop nicotine addictions.</em> </p><p><strong>The relevance of these <em>2A6</em> genes on ADHD: </strong>The stimulating effects of nicotine are believed to be a major contributing factor to the higher prevalence of <a href="http://www.ncbi.nlm.nih.gov/pubmed/11694203"><span style="color: rgb(51, 51, 255);">smoking among the ADHD</span></a> population. If this is true, then slow metabolizers of nicotine may not derive the full effect of nicotine self-medication for attentional deficits, at least not as immediately as the fast metabolizers. On the flipside, they have lower cravings (like with virtually all stimulant drugs, the speed and rate of uptake and clearance of nicotine is a major factor in its addiction potential) and are exposed to less tobacco and often find it easier to quit smoking. </p><p>At least two alleles or forms of the <em>2A6</em> gene (using the "star/number" nomencalture us used in <em>2D6 </em>for Strattera earlier in this blog), have been shown to coincide with <a href="http://www.ncbi.nlm.nih.gov/pubmed/19169923"><span style="color: rgb(51, 51, 255);">slower rates of nicotine metabolism</span></a>. They are <em>2A6*2</em> and <em>2A6*4 </em>(these two forms are actually referred to as "null alleles" meaning that the <em>2A6</em> enzyme they code for has no activity)<strong><em>.<br /></em></strong></p><p><strong><em> </em></strong>Additionally, there are noticeable differences in the frequencies of these forms across <a href="http://www.ncbi.nlm.nih.gov/pubmed/15475735"><span style="color: rgb(51, 51, 255);">different ethnicities</span></a> among the global population. For example, these "slow metabolizing" gene/enzyme forms of are found in <a href="http://www.ncbi.nlm.nih.gov/pubmed/16952495"><span style="color: rgb(51, 51, 255);">higher percentages</span></a> in individuals of Asian ancestry (around 20%) compared to those of European descent (around 8%). </p><p>With regards to ADHD behavior, it is likely that people possessing these <span style="font-weight: bold;">*2 or *4</span> <span style="font-weight: bold;">forms of the </span><em style="font-weight: bold;">CYP2A6 </em><span style="font-weight: bold;">gene</span>, may be <span style="font-weight: bold;">less</span> <span style="font-weight: bold;">likely</span> <span style="font-weight: bold;">to use nicotine as a self-medication tool</span> <span style="font-weight: bold;">for their ADHD</span>, or at least use the drug in lower doses, due to its lesser effects. On the flipside, however, there is another allele of the <em>2A6</em> gene, referred to as <em><a href="http://www.ncbi.nlm.nih.gov/pubmed/17522595"><span style="color: rgb(51, 51, 255);">CYP2A6*1B</span></a></em>. This version of the <em>2A6</em> nicotine metabolism gene actually promotes greater activity of the nicotine metabolizing enzyme, and speeds up the processing and clearance of the drug. As a result, individuals who possess this relatively rare <em>CYP2A6</em> form may be more prone to more frequent use and abuse of nicotine, and individuals with ADHD who attempt to self-medicate with this drug may cycle through their nicotine more rapidly if they carry this <span style="font-style: italic;">*1B</span> form of the gene.<br /></p><p>Interestingly, another drug, bupropion (Wellbutrin), which is an anti-depressant often used off-label to treat more "depressive" forms of ADHD is a relatively common anti-smoking drug. Given the fact that a number of ADHD'ers who typically do not respond well to stimulants, but do respond to Wellbutrin may fall in this smoking category,<span style="font-weight: bold;"> it is possible that the fast metabolizers (i.e. the *1B individuals), may be good candidates for Wellbutrin</span>, not only to stop smoking, but possibly also to treat unwanted ADHD symptoms.</p><p><strong>Alleles of the <em>CYP2B6</em> gene and enzyme with regards to nicotine and ADHD:</strong><br /></p><p>Shifting gears for a minute, we see that the <span style="font-style: italic;">CYP2B6</span> gene (as well as the enzyme which it encodes) also may also play a unique role in ADHD. The <span style="font-style: italic;">CYP2B6</span> gene is located on the <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=123930">19th human chromosome</a> (in the 13.2 region of the 19th, to be more specific). For individuals who lack <em>CYP2</em><u>A</u><em>6</em> enzyme activity because of the reduced-activity or even "null" alleles, the <a href="http://www.ncbi.nlm.nih.gov/pubmed/17112802"><span style="color: rgb(51, 51, 255);">enzyme <em>CYP2<u>B</u>6 </em>can metabolize nicotine in its place</span></a> (it turns out that <span style="font-style: italic;">CYP2D6</span>, the enzyme responsible for Strattera metabolism can also do the trick). For those who need to metabolize nicotine, but lack an effective <em>CYP2A6</em> enzyme system, this is good news (however, this "B6" enzyme only functions at about 10% of the level of the "A6" enzyme, so B6 is not a very efficient "backup" for A6).<br /></p><p>Beyond its role as a "backup" for the <span style="font-style: italic;">CYP2A6</span> enzyme, <span style="font-style: italic;">CYP2B6 </span>may also be of clinical significance with regards to ADHD and similar disorders. In contrast to "A6", whose enzymes are predominantly generated in the liver, the <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/12814665"><span style="font-style: italic;">CYP2B6</span> generated enzymes are expressed in brain tissue</a>. With regards to the differences in neurochemistry and neurological functioning of the ADHD brain, the role of <span style="font-style: italic;">CYP2B6</span> is therefore potentially noteworthy.<br /></p><p>Additionally, as we have discussed in earlier posts regarding <a style="color: rgb(51, 51, 255);" href="http://adhd-treatment-options.blogspot.com/2009/01/adhd-alcoholism-and-nutrient.html">ADHD and alcoholism</a>, the <span style="font-style: italic;">2B6</span> enzyme apparently also plays a role in alcoholism, and individuals who express <span style="font-style: italic;">higher</span> levels of this genetically-encoded <span style="font-style: italic;">CYP2B6</span> enzyme in their brains may be <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/12814665">more sensitive to alcohol, nicotine and other centrally acting drugs</a>. The study even suggests that individuals with high levels of this gene-coded enzyme may be more prone to damages induced from these common chemical agents, including possible higher susceptibility to cancer. <span style="font-weight: bold; font-style: italic;"><br /></span></p><p>For reference (using the "star" notation again), genetic forms of <span style="font-style: italic;">CYP2B6</span> which typically yield higher levels of this enzyme in the brain include the <a style="color: rgb(51, 51, 255); font-weight: bold;" href="http://www.ncbi.nlm.nih.gov/pubmed/11470993"><span style="font-style: italic;">CYP2B6*4</span></a> (which shows up in about a <span style="font-weight: bold;">third</span> of the European popluation) form and the <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/11243870"><span style="font-weight: bold;">CYP2B6*9</span></a> (which is present in about a <span style="font-weight: bold;">quarter</span> of those of European descent) form. Again, don't worry too much about the specifics of these "starred" variants, just know that if you were to get a genetic screen and had one of these two enzymatic forms, you may be more sensitive to nicotine as a self-treatment ADHD "medication". </p><p><span style="font-weight: bold; font-style: italic;">What this means is that ADHD individuals who harbor the higher-expressing "*4" and "*9" forms of the CYP2B6 enzyme in their brains may be more sensitive to chemical agents such as nicotine, and these same individuals may be more likely to suffer the toxic effects of this popular form of ADHD "self-medication".</span><br /></p><p>In conclusion, we should note that some of these genes (such as <span style="font-style: italic;">DAT</span>) have been well-studied and have repeatedly shown to be associated factor in proper dosing of ADHD medications. Others, however, such as the <span style="font-style: italic;">trypsinogen</span> gene for Vyvanse are more at the theoretical level at the moment. However, this blogger believes that in the next couple of decades, (due in part to our expanding knowledge of the human genetic code and functional genomics), genetic screens will become foutinely more commonplace as a necessary tool for both prescribing and dosing medications. With regards to this general trend, psychotropic medications for disorders such as ADHD should be no exception.<span style="font-weight: bold;"><span style="font-weight: bold;"><span style="font-weight: bold;"><br /></span></span></span></p><span style="font-weight: bold;"><span style="font-weight: bold;"><span style="font-weight: bold;"></span></span></span>The ADHD Treatment Guidehttp://www.blogger.com/profile/00747782650821771627noreply@blogger.com48tag:blogger.com,1999:blog-2736612052295099842.post-54051485559866516082009-09-08T23:18:00.009-04:002009-09-10T00:30:23.769-04:00Omega-3 Oxidation in ADHD: A Problem with Supplementation?<div><span style="font-weight: bold;">Here are 4 reasons why omega-3/fish oil/flax seed oil often fails for treating <span class="blsp-spelling-error" id="SPELLING_ERROR_0">ADHD</span> and how some simple strategies can maximize omega-3 <span class="blsp-spelling-error" id="SPELLING_ERROR_1">supplementation's</span> effectiveness for therapeutic treatment of the disorder:</span><em></em></div><br /><div> </div>One of the most common recent trends in the natural treatment world of <span class="blsp-spelling-error" id="SPELLING_ERROR_2">ADHD</span> is omega-3 fatty acid supplementation. A number of studies appear to provide at least a theoretical basis for <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/16777670">omega-3 fatty acid supplementation for ADHD</a> as a valid natural treatment option. Fish oils, flax oils, and a variety of marine and seed oils are are showing up and rapidly disappearing off the shelves in grocery and health food stores.<br /><br /><div> </div>Along with all of the pronounced cardiovascular improvements, a number of concerned parents are reaching for these omega-3's as natural treatment options for other dysfunctions, including <span class="blsp-spelling-error" id="SPELLING_ERROR_3">ADHD</span> and depression. A number of journal articles and research studies seem to support the use of omega-3 fatty acid supplementation as a viable alternative treatment method for attention deficit and or hyperactivity disorders (although not, perhaps at the complete level of stimulant medications).<br /><br />Lost in the shuffle, however, is the million dollar question: <span style="font-style: italic;">Does omega-3 supplementation actually work in practice?</span><br /><br />A number of parents will quickly jump to one side or another on this issue. Some swear by the effects, while others have written off this treatment alternative altogether.<br /><br />I would like to distill some of the information I have gathered on the subject for this blog post. I personally believe that manipulation and treatment strategies for disorders such as <span class="blsp-spelling-error" id="SPELLING_ERROR_4">ADHD</span> using dietary fats is still in its infancy. Beyond their caloric content and to a degree beyond most other foodstuffs, fatty acids are often capable of making or breaking our systems hormonally and metabolically. Omega-3's are no different.<br /><br /><div>Recent findings suggest that fatty acid imbalances in children with <span class="blsp-spelling-error" id="SPELLING_ERROR_5">ADHD</span> may not be due as much to fatty acid intake, but rather a <a href="http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=18275609"><span style="color: rgb(51, 51, 255);">difference in metabolism of these fats</span></a>. </div><br /><br />In my personal line of work, I have seen at least 4 major factors (there are certainly more beyond these 4, for sure), which can severely hamper the effectiveness of omega-3 fatty acid treatment for <span class="blsp-spelling-error" id="SPELLING_ERROR_6">ADHD</span> and related disorders. They are:<br /><br /><ol><li>Insufficient nutrient <span style="font-style: italic;"><span class="blsp-spelling-error" id="SPELLING_ERROR_7">cofactors</span> </span>(or "helpers" for the enzymes that metabolize fatty acids). These include key vitamins and minerals, many whose supplementation, coincidentally, is often linked to improvement in <span class="blsp-spelling-error" id="SPELLING_ERROR_8">ADHD</span> symptoms.</li><li>Genetic factors in which lower amounts of of active enzymes key in the omega-3 metabolic pathway are present: A relatively new body of research suggests that individuals with <span class="blsp-spelling-error" id="SPELLING_ERROR_9">ADHD</span> manufacture different levels of these enzymes than the general population. This is one of many ways in which genetics may play a factor in the disorder. </li><li>Multiple fats competing for the same enzymes and pathways: The metabolism of different types of fatty acids can be complex. Different fats often share the same enzymes to form their respective products, so an imbalance in dietary intake of certain fats often means an imbalance in their products. This can have wide-reaching effects, such as a heightened state of inflammatory processes and disorders (such as heightened allergies), which coincidentally or not, are often seen at higher rates in <span class="blsp-spelling-error" id="SPELLING_ERROR_10">ADHD</span> patients. In other words, supplementation with omega-3 fats may be offset if a person's diet also contains high levels of "competing" fats.<br /></li><li>Fatty acid oxidation: One of the most damaging negative side effects. Omega-3's, as great as they are for overall cell health, are often especially prone to <span class="blsp-spelling-error" id="SPELLING_ERROR_11">oxidative</span> damage. This damage, of course, can be at least partially stopped by ensuring that the body has adequate stores of antioxidant nutrients <span style="font-style: italic;">which are capable of acting on cell membranes and other common destinations of omega-3's</span>.<br /></li></ol>Having highlighted these 4 factors on how well we can maximize the "omega-3 effect" on <span class="blsp-spelling-error" id="SPELLING_ERROR_12">ADHD</span> and related disorders, we can see that one of them (genetics) is largely beyond our control. However, we can also see that 3 of these 4 factors do fall under our control, at least somewhat, by dietary intervention. Add on these 3 helping factors, and you increase the chance of reducing unwanted <span class="blsp-spelling-error" id="SPELLING_ERROR_13">ADHD</span> symptoms and behaviors through omega-3 manipulation.<br /><br />Before we begin, let's get a brief background on omega-3's and other fatty acids and how they relate to disorders such as <span class="blsp-spelling-error" id="SPELLING_ERROR_14">ADHD</span>.<br /><br /><div> </div><div> </div><div> </div><strong>A background on fatty acid ratios and <span class="blsp-spelling-error" id="SPELLING_ERROR_15">ADHD</span>:</strong><br /><div><strong></strong> </div><br /><div>You may be familiar with some of the following fatty acid "buzzwords" being thrown around recently: <strong>ALA</strong>, <strong><span class="blsp-spelling-error" id="SPELLING_ERROR_16">DHA</span></strong>, <strong>EPA</strong>, etc. These are simply abbreviations of much more lengthy names of major types of fatty acid which are either obtained in the diet or produced by metabolism of other fats. </div><br /><div> </div>Here is a quick summary on some of these important fatty acids and why they may be important with regards to <span class="blsp-spelling-error" id="SPELLING_ERROR_17">ADHD</span> and related disorders:<br /><div> </div><br /><div><span style="font-weight: bold;">ALA:</span> Short for <span style="font-weight: bold;">Alpha <span class="blsp-spelling-error" id="SPELLING_ERROR_18">Linolenic</span> Acid</span>, ALA is an omega-3 fatty acid. It can be obtained via dietary means including green vegetables, walnuts, soybeans and several types of seeds (kiwi seeds, flax seed or linseed are especially high in ALA).<br /><br />One of the main reasons ALA is so important is that it can be converted to other key fatty acids such as <span style="font-weight: bold;">EPA</span> and <span style="font-weight: bold;"><span class="blsp-spelling-error" id="SPELLING_ERROR_19">DHA</span></span>, which will be addressed shortly (essentially it acts as starting material for these other fats). It is therefore relatively versatile among the omega-3's, so maintaining adequate levels of this fat is important. It is important to keep in mind, however, that this conversion process is relatively inefficient, even with the help of important enzymes. As a result, many choose to supplement with these other fats which occur "down the line" directly. Nevertheless, due to its nutritive properties and versatility, maintaining adequate pools of ALA through consumption of the above-mentioned dietary staples is of great potential use.<br /><br /><span style="font-weight: bold;"><span class="blsp-spelling-error" id="SPELLING_ERROR_20">DHA</span>:</span> Short for <span style="font-weight: bold;"><span class="blsp-spelling-error" id="SPELLING_ERROR_21">Docosahexaenoic</span> Acid</span>, <span class="blsp-spelling-error" id="SPELLING_ERROR_22">DHA</span> is another important omega-3 fat. It is found in green vegetables as well, as well as several types of meat and animal products (including milk from free range animals who graze on greens instead of feed lots). Of the omega-3's <span class="blsp-spelling-error" id="SPELLING_ERROR_23">DHA</span> is one of the most critical fatty acids for optimal brain health and nervous function. Low levels of <span class="blsp-spelling-error" id="SPELLING_ERROR_24">DHA</span> have been linked to cognitive decline and <span class="blsp-spelling-error" id="SPELLING_ERROR_25">neurodegenerative</span> diseases such as <a style="color: rgb(51, 51, 255);" href="http://www.jci.org/articles/view/25420">Alzheimer's Disease</a>. <span class="blsp-spelling-error" id="SPELLING_ERROR_26">DHA</span> is also important for eye health, but is also susceptible to oxidation (which will be discussed in the last section). Interestingly, <span class="blsp-spelling-error" id="SPELLING_ERROR_27">DHA</span> is believed to play a role in protecting the nervous system from <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/15912889"><span class="blsp-spelling-error" id="SPELLING_ERROR_28">oxidative</span> stress</a>.<br /></div><br /><div> </div><span style="font-weight: bold;">EPA:</span> Short for <span style="font-weight: bold;"><span class="blsp-spelling-error" id="SPELLING_ERROR_29">Eicosapentaenoic</span> Acid</span> (not the Environmental Protection Agency, although this fat does play a protective role in several key functions!), EPA is another important omega-3 fatty acid. It is found in significant levels in breast milk (another major plus to breast-feeding) and oily fish such as sardines, <span class="blsp-spelling-corrected" id="SPELLING_ERROR_30">mackerel</span>, cod liver and salmon. Most of the fish oil treatments for <span class="blsp-spelling-error" id="SPELLING_ERROR_31">ADHD</span> rely heavily on this omega-3. It is important to note that this omega-3 is not often found in high levels in farmed fish who obtain their food primarily from non-algae sources. This is because it is the algae itself, which contains most of the EPA.<br /><br />EPA is unique in that it's effect may be more far-reaching than many other omega-3's. At least some research suggests EPA has a protective effect against depressive disorders including <a style="color: rgb(51, 51, 255);" href="http://www.journals.elsevierhealth.com/periodicals/bps/article/PIIS0006322304007061/abstract">suicide</a>, <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/19602399">inflammatory conditions</a> (<span class="blsp-spelling-error" id="SPELLING_ERROR_32">DHA</span> does this as well, making both EPA and <span class="blsp-spelling-error" id="SPELLING_ERROR_33">DHA</span> good potential candidates for <span class="blsp-spelling-error" id="SPELLING_ERROR_34">ADHD</span> patients with a concurrent inflammatory condition such as allergies), and may even combat certain types of <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/19566923">cancer</a>.<br /><br />As an interesting aside, there is also some evidence that EPA (at very high doses) may interact with an important type of enzyme called <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/16978661"><span style="font-style: italic;"><span class="blsp-spelling-error" id="SPELLING_ERROR_35">CYP</span>2D6</span></a>. This enzyme is actually responsible for metabolizing a number of drugs including amphetamines (for <span class="blsp-spelling-error" id="SPELLING_ERROR_36">ADHD</span>) and a number of antidepressants (including Prozac or <span class="blsp-spelling-error" id="SPELLING_ERROR_37">fluoxetine</span> as well as <span class="blsp-spelling-error" id="SPELLING_ERROR_38">Tofranil</span> or <span class="blsp-spelling-error" id="SPELLING_ERROR_39">imipramine</span>), so extremely high doses of EPA may actually interfere with these medications. Additionally, some studies suggest that higher levels of <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/11237929">EPA may reduce levels of natural killer cells</a> (which play a big role in fighting off invading foreign bodies) in older adults. However, to reiterate, most of these observations were seen at high doses beyond the common range of dietary or supplemental levels.<br /><br /><span style="font-style: italic;"><span class="blsp-spelling-error" id="SPELLING_ERROR_40">Blogger's</span> note: I found an excellent review article about </span><a style="color: rgb(51, 51, 255); font-style: italic;" href="http://www.lipidworld.com/content/pdf/1476-511X-8-33.pdf">ALA, EPA and <span class="blsp-spelling-error" id="SPELLING_ERROR_41">DHA</span></a><span style="font-style: italic;"> for those of you who are interested. It can be found </span><a style="color: rgb(51, 51, 255); font-style: italic;" href="http://www.lipidworld.com/content/pdf/1476-511X-8-33.pdf">here</a><span style="font-style: italic;">. Although a bit lengthy and technical, it greatly expands on our above discussion. </span><br /><br />Now that we have given some background into some of the key omega-3 fatty acids and their functional roles, let's return to the four factors listed in the beginning of this blog on how omega-3 <span class="blsp-spelling-error" id="SPELLING_ERROR_42">supplementation's</span> effectiveness can be hindered.<br /><br /><div><span style="font-style: italic; font-weight: bold;">Factor #1: Insufficient supporting nutrients for the conversion process:</span><br />The ALA to <span class="blsp-spelling-error" id="SPELLING_ERROR_43">DHA</span> and EPA conversion process involves a number of steps and a number of enzymes. These enzymes, however, do not function in a vacuum, but rather rely on a number of common vitamin and mineral "<span style="font-weight: bold;"><span class="blsp-spelling-error" id="SPELLING_ERROR_44">cofactors</span></span><span style="text-decoration: underline;"></span>" to optimize their function. Some of these <a style="color: rgb(51, 51, 255);" href="http://en.wikipedia.org/wiki/Cofactor_%28biochemistry%29"><span class="blsp-spelling-error" id="SPELLING_ERROR_45">cofactors</span></a> necessary to optimize function of these fatty acid conversion enzymes include magnesium, zinc, vitamin B6, and vitamin C. We have seen in previous posts how <a style="color: rgb(51, 51, 255);" href="http://adhd-treatment-options.blogspot.com/2008/11/magnesium-combination-treatments-for.html">magnesium</a>, <a style="color: rgb(51, 51, 255);" href="http://adhd-treatment-options.blogspot.com/2009/04/10-ways-zinc-can-combat-adhd.html">zinc</a>, and <a style="color: rgb(51, 51, 255);" href="http://adhd-treatment-options.blogspot.com/2008/11/treating-adhd-with-magnesium-and.html">vitamin B6</a> supplementation may be helpful in <span class="blsp-spelling-error" id="SPELLING_ERROR_46">ADHD</span> cases, especially if nutrient deficiencies are suspected.</div><br /><div> </div><br /><div><span style="font-weight: bold; font-style: italic;">Factor #2: Deficiencies in the enzyme systems themselves: </span><br />Another possibility in the fatty acid metabolic differences in individuals with <span class="blsp-spelling-error" id="SPELLING_ERROR_47">ADHD</span> may be due to malfunctioning or lower enzyme activity, even if the above mentioned <span class="blsp-spelling-error" id="SPELLING_ERROR_48">cofactors</span> are in place. Lending credence to this hypothesis is the fact that certain forms of genes responsible for "coding" for these important enzymes are seen at higher levels in <span class="blsp-spelling-error" id="SPELLING_ERROR_49">ADHD</span> patients. One of these genes is called fatty acid <span class="blsp-spelling-error" id="SPELLING_ERROR_50">desaturase</span> 2 gene, or <span style="font-style: italic; font-weight: bold;">FADS2. </span></div><div> </div><br /><div>It's important to note 2 things here: </div><div> </div><br /><div>1. The <em>FADS2</em> gene is believed to code for an important enzyme <a style="color: rgb(51, 51, 255);" href="http://en.wikipedia.org/wiki/Desaturase"><em>delta-6 <span class="blsp-spelling-error" id="SPELLING_ERROR_51">desaturase</span></em></a>. This enzyme is critical in several fatty acid conversion processes, such as ALA to <span class="blsp-spelling-error" id="SPELLING_ERROR_52">DHA</span>. As we will see in the next section, this same enzyme, <em>delta-6 <span class="blsp-spelling-error" id="SPELLING_ERROR_53">desaturase</span></em> is also used in another fatty acid conversion process, LA to AA. </div><br /><div> </div><br /><div>2. At least some genetic evidence suggests that some forms of the <em>FADS2</em> gene are seen at abnormally high rates in individuals with <span class="blsp-spelling-error" id="SPELLING_ERROR_54">ADHD</span>. This hints at a potential association between <a href="http://www.ncbi.nlm.nih.gov/pubmed/16893529"><span style="color: rgb(51, 51, 255);"><span class="blsp-spelling-error" id="SPELLING_ERROR_55">ADHD</span> and the <em>FADS2</em> gene</span></a>. </div><br />Please keep in mind that these genetic factors are a bit more tenuous than the other ones. This is good news, because it suggests that even more control of the disorder may lie in the diet instead of the genes (at least with regards to omega-3 levels and <span class="blsp-spelling-error" id="SPELLING_ERROR_56">ADHD</span>). However, it is also important to note that the body of research on this topic is constantly shifting and changing.<br /><div> </div><br /><div> </div><br /><div><strong>Factor #3 on omega-3 supplementation for <span class="blsp-spelling-error" id="SPELLING_ERROR_57">ADHD</span>: Different fats share the same enzyme (<span style="font-style: italic;">delta-6 <span class="blsp-spelling-error" id="SPELLING_ERROR_58">desaturase</span></span>):</strong></div><br /><div> </div><br /><div>Factor #1 tells us that if we want to be serious about getting the most out of omega-3 <span class="blsp-spelling-error" id="SPELLING_ERROR_59">supplementation</span> for <span class="blsp-spelling-error" id="SPELLING_ERROR_60">ADHD</span> and related disorders, we had better make sure that we are supplying the enzymes which churn out this important omega-3 conversion process with the necessary nutrients or "<span class="blsp-spelling-error" id="SPELLING_ERROR_61">cofactors</span>" (vitamins C and B6, magnesium and zinc, to name a few). Without these helping nutrients in place, the enzymes cannot do their job nearly as effectively, and many of the <span class="blsp-spelling-error" id="SPELLING_ERROR_62">nutritionally</span> based benefits of omega-3's may be lost. </div><br /><div> </div><br /><div>Factor #2 states that expression of some of these enzymes (and the subsequent activity level of these fatty-acid <span class="blsp-spelling-error" id="SPELLING_ERROR_63">metabolizing</span> enzymes, such as <span style="font-style: italic;">delta-6 <span class="blsp-spelling-error" id="SPELLING_ERROR_64">desaturase</span></span><a style="color: rgb(51, 51, 255); font-style: italic;" href="http://en.wikipedia.org/wiki/Desaturase"><em></em></a>) is contingent on specific genes, such as the <em>FADS2 gene</em>. Certain forms of this gene are believed to appear at higher levels in the <span class="blsp-spelling-error" id="SPELLING_ERROR_65">ADHD</span> population. <span class="blsp-spelling-error" id="SPELLING_ERROR_66">Unfortunately</span>, this is a genetic factor, meaning that there is little we can do about this process. </div><br /><div> </div><br /><div>However, a third factor with regards to <span class="blsp-spelling-error" id="SPELLING_ERROR_67">manipulating</span> enzyme systems involved in omega-3 fatty acid <span class="blsp-spelling-error" id="SPELLING_ERROR_68">supplementation</span> and subsequent metabolism <em>is</em> within our control, at least to a certain extent. This involves tilting the scale or balance of dietary fats which compete for the same enzyme system. Let me explain:</div><br /><div> </div><br /><div>The typical conversion of the omega-3 fatty acid <span style="font-weight: bold;">ALA</span> (<span style="font-weight: bold;">alpha <span class="blsp-spelling-error" id="SPELLING_ERROR_69">linolenic</span> acid</span>, see description at the top of this post) to the important fatty acid <span style="font-weight: bold;"><span class="blsp-spelling-error" id="SPELLING_ERROR_70">DHA</span></span> utilizes the enzyme <span style="font-style: italic;">delta-6 <span class="blsp-spelling-error" id="SPELLING_ERROR_71">desaturase</span></span>. Yes, this is the same delta-6 <span class="blsp-spelling-error" id="SPELLING_ERROR_72">desaturase</span> enzyme which is coded by the <span style="font-style: italic;">FADS2</span> gene in factor #2 (and whose expression may, at least indirectly be associated with <span class="blsp-spelling-error" id="SPELLING_ERROR_73">ADHD</span> by genetic factors). However, the conversion of other fats in the body also share this enzyme for their conversion process (think of 2 <span class="blsp-spelling-error" id="SPELLING_ERROR_74">construction</span> workers who need to share the same power tool at the same time, but for completely different sections of the project). One of these other "competing" fats is <span style="font-weight: bold;"><span class="blsp-spelling-error" id="SPELLING_ERROR_75">linoleic</span> acid</span> (abbreviated as "<span style="font-weight: bold;">LA</span>", be careful, unlike alpha <span class="blsp-spelling-error" id="SPELLING_ERROR_76">linole</span><em>n</em><span class="blsp-spelling-error" id="SPELLING_ERROR_77">ic</span> acid, this fat is spelled without the "n"). <strong>LA</strong> requires this same enzyme delta-6 <span class="blsp-spelling-error" id="SPELLING_ERROR_78">desaturase</span> to undergo a conversion process to another important product called <strong><span class="blsp-spelling-error" id="SPELLING_ERROR_79">arachidonic</span> acid</strong> (<strong>AA</strong>)<strong>. </strong></div><br /><div><strong></strong> </div><br /><div>Please don't get too tripped up on all of these lengthy names, terms and <span class="blsp-spelling-error" id="SPELLING_ERROR_80">abbreviations</span>. The important thing to remember here, is that many different processes, including <span class="blsp-spelling-error" id="SPELLING_ERROR_81">metabolizing</span> different types of fats, often share the same enzyme systems. As a result, these different fats often "compete" for the same enzymes, and significant dietary imbalances of one type of fat over another may often lead to an imbalance of "output" or products of these fatty acids. </div><br /><div> </div><br /><div><span style="font-weight: bold;"><span class="blsp-spelling-error" id="SPELLING_ERROR_82">Arachidonic</span> acid</span> (a non-omega 3 fatty acid) is responsible for a number of necessary processes, including some of the <span class="blsp-spelling-error" id="SPELLING_ERROR_83">inflammatory</span> responses described earlier, but it is important to note that it is possible to build up an over-abundance of this, which can play a role in the buildup of unnecessary or chronic levels of <span class="blsp-spelling-error" id="SPELLING_ERROR_84">inflammation</span>. This is believed to be at least partly responsible for <span class="blsp-spelling-error" id="SPELLING_ERROR_85">inflammatory</span> diseases and disorders such as allergies (as an interesting side note, allergies are seen at higher levels in individuals with <span class="blsp-spelling-error" id="SPELLING_ERROR_86">ADHD</span> than within the general population). </div><br /><div> </div><br /><div>To summarize this point, the conversion of alpha-<span class="blsp-spelling-error" id="SPELLING_ERROR_87">linolenic</span> acid (ALA, which is an omega-3) to <span class="blsp-spelling-error" id="SPELLING_ERROR_88">DHA</span> must "compete" alongside the <span class="blsp-spelling-error" id="SPELLING_ERROR_89">Linoleic</span> acid (LA, a non omega-3) to <span class="blsp-spelling-error" id="SPELLING_ERROR_90">Arachidonic</span> acid pathway for the same enzyme (<em>delta-6 <span class="blsp-spelling-error" id="SPELLING_ERROR_91">desaturase</span></em>). If excessive amounts of non omega-3 fatty acids are consumed (which is typical in most Western diets), then this crucial ALA to <span class="blsp-spelling-error" id="SPELLING_ERROR_92">DHA</span> process is hampered. Of course an imbalance on the other side (too many omega-3's) is also a possible, but given the dietary makeup in much of the <span class="blsp-spelling-error" id="SPELLING_ERROR_93">industrialized</span> world, this is often highly unlikely. </div><br /><div> </div><br /><div>So, to summarize Factor#3: <em>Omega-3 <span class="blsp-spelling-error" id="SPELLING_ERROR_94">supplementation</span>, such as with fish oil, <span class="blsp-spelling-error" id="SPELLING_ERROR_95">flaxseed</span> oil or ALA is often compromised by the concurrent intake of high amounts of other fats, throwing off the delicate balance of dietary fatty acid intake.</em> </div><br /><div> </div><br /><div>Finally, there is one other extremely important factor, which is the main topic of this post. Factor #4 involves the fatty acid oxidation process.</div><br /><div> </div><br /><div><span style="font-weight: bold;">Factor #4:</span> <strong>Is <span class="blsp-spelling-error" id="SPELLING_ERROR_96">ADHD</span> an "<span class="blsp-spelling-error" id="SPELLING_ERROR_97">oxidative</span>" condition?</strong></div><br /><div> </div>While numerous studies have linked ADD and <a href="http://www.ncbi.nlm.nih.gov/pubmed/16962757"><span style="color: rgb(51, 51, 255);"><span class="blsp-spelling-error" id="SPELLING_ERROR_98">ADHD</span> to lower blood level ratios of of omega-3's</span> </a>and various essential fatty acids, some others are suggesting that the actual <a href="http://www.ncbi.nlm.nih.gov/pubmed/14609313"><span style="color: rgb(51, 51, 255);"><em>oxidation</em> of these fatty acids</span></a> may also be a problem in children with attention deficit disorders.<br /><div><br />Omega 3's are especially prone to fatty acid oxidation (as anyone who uses pure, untreated omega-3 rich oils can attest, these oils quickly become rancid and have a much shorter shelf-life than the processed "partially hydrogenated" oils). This is actually one of the main reasons why trans fats came about. They are tougher to oxidize by bacterial systems than the "natural" fats and thus have a longer shelf life. Unfortunately, a lot of the health problems stemming from trans-fats is due to many of the same reasons (our bodies aren't quite sure how to process, break down or metabolize these fats).<br /><br />One of the major targets of omega-3's is that they are able to incorporate into cell membranes. In general, omega-3 fatty acids make the cell membranes more flexible or fluid, while other fats often make these same membranes more rigid or hard, which can compromise the integrity of the cell membrane and the overall cell health. However, like omega-3 cooking oils, these cell membranes are constantly exposed to oxidative damage. This includes cells in the nervous system, which are highly "fatty", and thus extremely susceptible to oxidative damage. This is why it is so important to not just provide the nerve cells with abundant supplies of omega-3's to incorporate into their membranes but also <span style="font-style: italic;">protected</span> omega-3's (that is to say, omega-3 fatty acids accompanied by adequate antioxidant protection). <span style="font-style: italic;"><br /><br />Therefore, for disorders involving the nervous system, including ADHD, it is imperative that sufficient antioxidants are available to protect these key cell systems. Simply taking omega-3's, fish oils, etc. in an antioxidant-deficient state is less effective at best, and neuro-damaging at its worst.</span> I personally believe that omitting antioxidant protection is the single-greatest saboteur of omega-3, fish oil, or flax oil supplementation's effectiveness for treating diseases and disorders such as ADHD.<br /></div><br /><div> </div><br /><span style="font-weight: bold;">So which antioxidants should we be taking?</span><br /><br />Vitamin C readily comes to mind as one of the cheapest and most well-known antioxidants. However, one strike against this vitamin is that it typically exists in a water-soluble form (that is, it mixes well with water, and is why it is easily flushed out of the system and needs to be replaced on a daily basis. It is also a main reason why it difficult to overdose on vitamin C, since excess amounts can simply be flushed away with water). Remember that omega-3's are still fats, and that fatty substances often do not mix or interact well with water. Thus, vitamin C, <span style="font-style: italic;">at least in isolation,</span> is not the best option for protecting these essential fats. A fat-soluble antioxidant may be a better option here.<br /><br />Enter vitamin E. Unlike vitamin C, vitamin E is a fat-soluble vitamin, which has a greater potential to interact with fatty substances such as omega-3-laden membranes in the nervous system and other cells. Even better, vitamin E and vitamin C work well in tandem, helping recycle each others' antioxidant pools after countering oxidative-damaging agents in the nervous system and other parts of the body. This is evidenced by a number of studies which indicate that <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/9808773">vitamin C can help recycle vitamin E</a> levels.<br /><br />Recommended daily amounts (and toxic levels) can be found here for <a style="color: rgb(51, 51, 255);" href="http://lpi.oregonstate.edu/infocenter/vitamins/vitaminC/">vitamin C</a> and <a style="color: rgb(51, 51, 255);" href="http://lpi.oregonstate.edu/infocenter/vitamins/vitaminE/">vitamin E</a>.<br /><div><br />Finally, I would like to address one of the more recent "wonder-nutrient" brain foods which may pose therapeutic benefits for ADHD and related disorders: <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/16699814"><span style="font-weight: bold;">Pycnogenol</span>/<span style="font-weight: bold;">pine bark extract</span></a>. There is some debate as to why this may be an effective natural ADHD treatment, but much of the evidence suggests that the effectiveness of <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/16984739">pycnogenol for ADHD lies in its antioxidant properties</a>.<br /></div><div> </div><br /><div>So the key take-home messages from this post are as follows:<br /><ol><li>Omega-3 fatty acids show a significant amount of potential as natural ADHD treatment options (although they are often not nearly as potent as medication treatments in a number of cases).</li><li>Omega-3's rely on enzyme systems to do their job. Genetics can play a role in the functionality and effectiveness in some of these key enzymes.</li><li>In order for these omega-3 metabolizing enzymes to function, nutritional "cofactors" are required. These include most of the B vitamins, vitamin C, and important minerals or metals such as zinc or magnesium. Other cofactors, such as biotin (found in eggs) are also necessary agents to make many of these enzymes run smoothly. Deficiencies in these nutrients compromise enzyme integrity and can ultimately limit the effectiveness of omega-3 supplementation for ADHD and related disorders.</li><li>Omega-3's compete with other fats for many of the same enzymes and enzyme systems. They often produce competing products, so an overall balance of fatty acids is imperative. Taking a couple of fish oil capsules will not be enough to offset a diet chock full of unhealthy saturated or trans fats. Chronic inflammation disorders such as allergies, asthma, etc. can be a sign of (but are by no means the exclusive reason of) omega-3 deficiencies or an indication of an imbalance in fatty acid intake or metabolism.</li><li>It is imperative that these omega-3's be protected by adequate antioxidant levels in the body, as omega-3 fatty acids are often extremely prone to damage by oxidation, especially in the nervous system. Vitamin C/E combos, as well as other powerful antioxidants such as bio-flavonoids in colorful fruits, vegetables, teas, etc. are especially helpful in this regard, and should be taken as seriously as the omega-3's themselves as natural treatment strategies for ADHD.<br /></li></ol></div>The ADHD Treatment Guidehttp://www.blogger.com/profile/00747782650821771627noreply@blogger.com19tag:blogger.com,1999:blog-2736612052295099842.post-51380044375714836822009-06-01T22:37:00.006-04:002009-06-02T01:18:14.607-04:00ADHD gene ADRA1A: A good target for clonidine?<span style="font-weight: bold;">Does the gene <span style="font-style: italic;">ADRA1A</span> affect ADHD comorbid disorders? Is it connected to clonidine's positive response in some ADHD patients?<br /><br /></span>This blog has spent a considerable amount of focus on <a style="color: rgb(51, 51, 255);" href="http://adhd-treatment-options.blogspot.com/2009/05/adhd-iq-and-gene-combinations.html">genes connected with ADHD</a>. Although genetic studies surrounding the disorder are often inconclusive (and often difficult to replicate or even contradictory), the high rate of prevalence of the disorder within families and the strong genetic component of ADHD (this blogger has seen some studies reporting it as high as 90%!), any new findings for genes associated with ADHD can be noteworthy.<span style="font-weight: bold;"><span style="font-weight: bold;"><br /><br /></span></span>Furthermore, the medication treatment options for ADHD can be cumbersome as well. Some medications, such as <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/19203986">clonidine</a>, while not intended to treat the disorder, can often work quite well when applied as an "off-label" treatment for ADHD. The question is why?<br /><br />Gene-drug interactions are an increasingly popular and meaningful component of pharmaceutical research. As we are generally moving in the direction of individualized medication strategies, and away from one-size-fits-all pharmaceutical treatment for disorders as complex and diverse as ADHD, specific genes and the target proteins which they encode, are becoming increasingly relevant in the tailoring of individual treatments for ADHD and related disorders.<span style="font-weight: bold;"><span style="font-weight: bold;"><br /></span></span> <span style="font-weight: bold;"><br />The <span style="font-style: italic;">ADRA1A gene</span> and how it relates to ADHD and other comorbid disorders:</span><span style="font-weight: bold;"><span style="font-weight: bold;"><br /><br /></span></span><a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?cmd=entry&id=104221"><span style="font-style: italic;">ADRA1A</span></a><span style="font-weight: bold;"><span style="font-weight: bold;"> is located on the </span></span>8th human chromosome, which is believed to be one of the "hot" regions for finding genes affiliated with ADHD and related disorders. The "8p" sub-region of the 8th chromosome is believed to be connected to numerous other disorders as well, including psychiatric disorders such as<a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/19204725"> schizophrenia and autism</a>.<br /><br />The gene is also believed to be associated with hypertension, a disorder which is frequently targeted by the anti-hypertensive clonidine. There is some evidence that the actual mechanism of <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/19102884">hypertension as it relates to <span style="font-style: italic;">ADRA1A</span></a> may actually be due to auto-immune related causes. If this is the case, then it may warrant further exploration into other auto-immune disorders, such as allergies (which can elicit ADHD-like symptoms, and are a relatively common comorbid disorder to those diagnosed with ADHD).<br /><br />The <span style="font-style: italic;">ADRA1A</span> gene "codes for" the production of a protein known as the <span style="font-weight: bold; font-style: italic;">alpha 1A-adranergic receptor</span>, which a target of epinephrine (adrenaline) and norepinephrine (noradrenaline). Norepinephrine is an important neuro-signaling agent which is often imbalanced in key regions of the nervous system in many ADHD cases, and is a target of several ADHD medications, including <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/19445548">atomoxetine</a> (Strattera) and stimulant medications such as <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/17020775">amphetamines</a>. The alpha 1A-adranergic receptor has also been implicated in studies of traits common to ADHD. For example, stimulation of this specific receptor has been shown to decrease impulsivity, <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/10501595">improve working memory</a>, and <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/9130297">increase vigilance</a> (in the rat model). This particular <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/19352218">receptor is also a target of clonidine</a>.<br /><br />Given the fact that drug treatment for comorbid disorders can often alleviate some of the co-existing ADHD symptoms as well (and given the fact that ADHD is believed to be connected to circulatory impairments including reduced bloodflow to specific brain regions associated with impulse control), <span style="font-style: italic;">it is possible that those individuals possessing the "wrong" forms of the ADRA1A gene and suffer from hypertensive disorders may be prime candidates for treatment with clonidine to alleviate ADHD symptoms</span>. In other words, specific variations of the <span style="font-style: italic;">ADRA1A</span> gene may make one more or less likely to have a successful response to clonidine as a treatment for not only hypertension, but also co-existing attention deficit and hyperactivity disorders. Additionally, clonidine can also be used to augment the effectiveness of stimulant medication treatments for ADHD and <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/12874489">reduce negative side effects</a>. <span style="font-weight: bold;"><span style="font-weight: bold;"><br /><br /></span></span>Indeed, variations within <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/19352218">three subsections of the gene <span style="font-style: italic;">ADRA1A</span></a> were associated with around a 50% higher likelihood of having ADHD, according to a recent study (although when taken as part of a multi-gene analysis, the effects were not as pronounced). The rate of occurrence of each of these three variations was roughly between 25 and 50% of the study population. In other words, these are not some rare or exotic mutations we're talking about, but relatively common forms of the gene seen in the population (those of European ancestry in particular). <span style="font-weight: bold;"><span style="font-weight: bold;"><br /><br /></span></span><span><span>While not directly related to other disorders sometimes seen alongside ADHD, the genetic proximity of <span style="font-style: italic;">ADRA1A</span> to other genes in the human genome may be noteworthy. For example, <span style="font-style: italic;">ADRA1A</span> is located in the same subsection of the 8th chromosome (<a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/Omim/getmap.cgi?l104221">8p21</a>) as another gene whose mutations may lead to an increased risk of epilepsy<span style="font-weight: bold;">. </span>This may be important, because in general, <span style="font-style: italic;">the closer 2 genes are to each other on a chromosme, the more likely they will be transmitted together from parent to offspring</span>. Thus, a parent who has both the "epilepsy" mutation and the ADHD-specific <span style="font-style: italic;">ADRA1A</span> mutation(s) may stand a greater chance of passing these gene forms on together to their child. As far as treatment is concerned, there is general consensus that clonidine is safe for patients who are diagnosed with co-existing epilepsy, however a few case studies suggest that caution regarding <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/18206800">clonidine and epilepsy</a> may be needed. We have investigated complications in treating <a style="color: rgb(51, 51, 255);" href="http://adhd-treatment-options.blogspot.com/2008/10/adhd-and-comorbid-epilepsy.html">ADHD and comorbid epilepsy</a> in earlier posts. <br /><br />Interestingly, the 8p21 subregion of the 8th chromosome is also home to genetic regions believed to be affiliated with <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=603013">schizophrenia</a>. There is some evidence that clonidine may be an effective augmentative treatment for schizophrenia when used in conjunction with another drug <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/8830068">haloperidol</a>. Thus, for individuals who exhibit symptoms resembling ADHD and schizophrenia, clonidine may be a potentially useful medication strategy to try <span style="font-style: italic;">under medical supervision</span>. </span></span><span style="font-weight: bold;"><span style="font-weight: bold;"><br /><br /></span></span><span><span><span style="font-style: italic;">It is important to note that many of these suggestions are largely hypothetical at the moment. Do not attempt to follow any of these suggestions without medical supervision. </span> Nevertheless, given the complexity and variability of ADHD and the compounding effects of comorbid disorders, it is useful to investigate medication strategies which have shown to be historically useful in treating multiple disorders which can often occur alongside each other. This is particularly useful for ADHD, where constraints are often necessary for medication treatments due to the negative impacts that these ADHD drugs may have on other accompanying disorders. As a result, the potential of clonidine in treating a diverse range of disorders (which may, possibly by way of <span style="font-style: italic;">ADRA1A</span> and other nearby genes share an underlying genetic predisposition), move this traditionally second or third-line medication closer to the forefront as a valid medication-based ADHD treatment option.</span></span><span style="font-weight: bold;"><span style="font-weight: bold;"><span style="font-weight: bold;"> </span><br /></span></span>The ADHD Treatment Guidehttp://www.blogger.com/profile/00747782650821771627noreply@blogger.com13tag:blogger.com,1999:blog-2736612052295099842.post-68157428169733159942009-05-30T20:55:00.011-04:002009-06-01T01:18:46.311-04:00Modafinil: An alternative treatment for ADHD and comorbid substance abuse?<span style="font-style: italic; font-weight: bold;">Can Modafinil (Provigil) Replace Stimulant Medications in Adult ADHD where stimulant drug abuse is a concern?</span><br /><br />It is a Catch-22 of the ADHD world. An individual is suffering from severe ADHD symptoms and appropriate stimulant medications may help remedy some of the negative side effects of the disorder. However, due to the high prevalence of substance abuse in ADHD (some officials put the rate of comorbid <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/15063998">substance abuse as high as to 30% in the ADHD population</a>), including stimulant medications such as amphetamines, treatment of ADHD symptoms via stimulant medications cannot, by nature of the comorbid substance abuse disorder, be a treatment option.<br /><br />The appearance of (relatively) novel non-stimulant medication alternatives such as Strattera (atomoxetine), have offered individuals with ADHD another treatment alternative. However, the results are often mixed. Strattera often works well with the inattentive-dominated forms of the disorder, but the positive results are often not as pronounced for the more hyperactive or impulsive forms of ADHD, especially if comorbid disorders such as conduct-related issues surface.<br /><br />Another alternative may be a completely different type of drug, which, while not a stimulant in its own right, can act on or exhibit pseudo-stimulant properties. It appears that in at least some cases, Modafinil (Provigil) may be the type of drug we're looking for in these cases.<br /><br /><span style="font-style: italic;">**Blogger's note: The extent of the study highlighting this case for <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/18562425">Modafinil treatment for ADHD and comorbid amphetamine abuse</a> is intended for </span><span style="font-weight: bold; font-style: italic;">adult treatment only</span><span style="font-style: italic;">. Given the relative scarcity of research on medication options for adult ADHD symptoms (compared to those designed more for children), this post is designed for offering a possible treatment alternative for ADHD in <span style="font-weight: bold;">adults</span>. </span>Nevertheless, some recent studies have shown promising results of <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/19439364">Modafinil as an ADHD treatment method for children and adolescents</a>. <br /><br />It is important to note, that while not initially designed as an ADHD-specific medication (and not a stimulant in its own right), Modafinil does share at least some degree of overlap with several stimulant agents for ADHD treatment. One is its <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/14658934">regulation of catecholamines</a> (important neuro-signaling chemical agents, whose balance in and out of neuronal cells is crucially important for regulating attention, hyperactive and impulsive behaviors, and locomotor control). As far as its mode of action and metabolism (<a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/12537513">clinical pharmacokinetics of Modafinil</a>) are concerned, drug-drug interactions between Modafinil and several ADHD stimulant medications such as methylphenidate or dexamphetamine (Dexedrine) appear to be limited. <br /><br /><span style="font-weight: bold;">A background note on addiction potentials of ADHD drugs:</span> <span style="font-style: italic;">This section is an aside, and is meant to serve as some background information and to clear up potential confusion surrounding ADHD medications and their addiction potentials. The next four paragraphs may be skipped if you are pressed for time. <br /><br /></span>While I cannot stress enough the importance of regulating neuro-chemical balance for both the onset of ADHD as well as drug addiction (which are affected by pharmacological agents such as ADHD medications, in varying forms), it is the <span style="font-style: italic;">rate</span> <span style="font-style: italic;">of action</span> for which these chemical changes take place which typically drives a particular drug's addiction potential.<br /><br />Unfortunately, this last fact is often lost in much of the literature surrounding ADHD treatment (especially those which promote non-pharmaceutical treatments for the disorder). For example, many "natural" ADHD treatment books and websites frequently start out by asserting (erroneously) that methylphenidate is the equivalent of crack cocaine, and promotes later drug abuse and addiction. <br /><br />While this blogger is a personal advocate for natural approaches to treating ADHD whenever possible (and without compromising overall treatment effectiveness in ADHD treatment), he wants to make it clear that significant differences do exist between ADHD medications and stimulant street drugs. One of the most telling signs of this is the rate of uptake and clearance of drug-like agents into and out of the brain, respectively. In general, the quicker a substance is taken up into the central nervous system and the faster it clears the brain, the more likely this chemical agent will elicit a "high" and an increased tendency towards substance dependence. <br /><br /><span style="font-style: italic;">ADHD medications like Ritalin</span>, while having some degree of overlap in structure and net effects of action as <a style="color: rgb(51, 51, 255);" href="http://adhd-treatment-options.blogspot.com/2009/04/ritalin-and-cocaine-similarities-and.html">cocaine</a>, are <span style="font-style: italic;">specifically designed to have a much slower rate of release and clearance, significantly reducing their abuse potential compared to cocaine</span>. We have previously discussed <a style="color: rgb(51, 51, 255);" href="http://adhd-treatment-options.blogspot.com/2009/02/ritalin-vs-cocaine-addiction-potential.html">Ritalin (methylphenidate) vs. cocaine addiction potentials</a> in earlier posts. <br /><br /><span style="font-weight: bold;"><br />Modafinil: Modes of action and addiction potential:</span><br /><br />The reason I am providing all of this information is the fact that the successful regulation and softening of rapid spikes and clearances of chemical peaks is a crucial component to curbing the drug addiction process. It is believed that modafinil may work so well at reducing drug cravings by targeting this very mechanism. Unlike many stimulant medications which can produce some type of "high" (especially if abused by snorting or injection, or taken at abnormally high doses), <a href="http://www.ncbi.nlm.nih.gov/pubmed/10757254">Modafinil has a low abuse potential</a>, and offers several other advantages over methylphenidate. <br /><br />Modafinil does have a relatively positive track record for mitigating substance abuse disorders. For example, the administration of <a style="color: rgb(51, 51, 255);" href="http://www.nature.com/npp/journal/v30/n1/abs/1300600a.html">Modafinil can attenuate cocaine dependence</a>. In contrast, methylphenidate (Ritalin, Concerta, Metadate, Daytrana), while being very effective as an ADHD treatment, does little to curb comorbid substance abuse disorders in ADHD patients. Unfortunately, the effectiveness of Modafinil on treating comorbid substance abuse disorders in individuals with ADHD may be limited to specific drugs. For example similar positive effects of <a href="http://www.ncbi.nlm.nih.gov/pubmed/18541389">Modafinil on nicotine dependence</a> appear to be less pronounced.<br /><br />Modafinil may also offer advantages over traditional stimulants as well. As a cognitive enhancement type of pharmacological agent, modafinil may be useful in improving the work performance of adults with ADHD by<a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/15121488"> improving short-term memory and visual recall, impulse control, and spatial skills</a> (all of which are frequent deficits in children and adults with ADHD). Additionally, similar improvements were seen in individuals with <a style="color: rgb(51, 51, 255);" href="http://www.nature.com/npp/journal/v29/n7/abs/1300457a.html">schizophrenia</a>, suggesting the diversity of modafinil's range of performance in cognitive improvement. These improvements are typically not seen in individuals unaffected by psychological disorders, further supporting the evidence that modafinil is less likely to be abused recreationally in the general population.<br /><br />The potential implications of modafinil for ADHD treatment may be further reaching than the details outlined in the original article (and basis of this post, highlighting the effects of <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/18562425">modafinil on amphetamine abuse in adult ADHD)</a>. For example, modafinil, as a vigilance-promoting medication, can offset an afternoon dip in arousal state (which has implications on many of the shorter-acting stimulant medications, which begin to wear off around this time). This may be useful for individuals with sleep disorders (which are <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/19110891">common in ADHD</a>), as well as regulating circadian rhythms. In a post earlier this month, we investigated the relationship between <a style="color: rgb(51, 51, 255);" href="http://adhd-treatment-options.blogspot.com/2009/05/adhd-and-seasonal-affective-disorder.html">ADHD and seasonal affective disorders</a>, and hinted at the association between ADHD and disruption in circadian rhythms<span style="font-weight: bold;">. </span><br /><br /><span style="font-weight: bold;"><br />Potential future implications of Modafinil as an ADHD treatment alternative:</span><br /><br />Additionally, while Modafinil may offer benefits for the whole ADHD spectrum, this blogger hypothesizes that it may be most useful for treating the inattentive subtype of the disorder. Some reasons for this are as follows:<br /><ul><li>Activity patterns and circadian rhythms may often be associated with ADHD subtype. For example, "morning people" with ADHD may have a tendency to fall into the more hyperactive/impulsive group, while <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/19387003">"eveningness" is more of an inattentive ADHD trait</a>, suggesting more of a disruption in the circadian rhythms of inattentive ADHD'ers. </li><li>Additionally, non-stimulants often have somewhat of a better track record with the inattentive subtype of ADHD compared to the more hyperactive/impulsive subtypes. The uses of the non-stimulant atomoxetine (Strattera), highlight this general trend. While atomoxetine treatments often result in drastic improvements in all ADHD subtypes, negative side effects are often less seen in the <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/17572882">inattentive subtype</a>. </li><li>Compared to stimulants, non-stimulant medications for ADHD often do a better job at not exacerbating comorbid disorders such as obsessive compulsive or anxiety disorders (which are often more common to the ADHD inattentive subtype). Additionally, Modafinil treatment can be useful in treating adults with <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/18562425">ADHD and a history of mood disorders</a>. </li><li><a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/10757254">Modafinil offers advantages over methylphenidate</a> as far as fewer side effects including appetite suppression, sleep disturbances and heart rate dysfunction (orthostatic tachycardia, which essentially is significant changes in heart rhythms based on postural changes, such as standing up quickly from a seated position). </li><li>Anecdotal evidence, as noted by the Modafinil and amphetamine abuse study mentioned earlier, also suggests that Modafinil may be a useful treatment method for "refractory" cases, or individuals who have consistently shown poor response to other treatment medications and interventionary measures. <br /></li><li>Finally, it is important to note (and this was also touched on in the Modafinil and amphetamine abuse study), that Modafinil treatment may be better suited for the more "controlled" abusers of stimulants. In other words, better effects might be seen for adults who regularly take illegal stimulant drugs such as amphetamines as a conscious effort to "self-medicate" for their ADHD, as opposed to an out-of-control drug addict who craves the drugs on a non-scheduled basis. </li></ul>Given the high propensity of comorbid disorders when deciding on treatment for ADHD, as well as practicality issues concerning the administration of medicinal agents for treatment of the disorder in adults, I see a fair amount of potential for Modafinil's "off-label" usage as a treatment alternative to stimulants in adults with ADHD.The ADHD Treatment Guidehttp://www.blogger.com/profile/00747782650821771627noreply@blogger.com34tag:blogger.com,1999:blog-2736612052295099842.post-75077603141522614002009-05-29T22:01:00.004-04:002009-05-30T00:14:09.952-04:00Does Blood Type Affect ADHD?This blog has often discussed the wide range of genetic influences on ADHD and related disorders. Some of the ADHD genes we have previously investigated include:<br /><br /><ul><li><a href="http://adhd-treatment-options.blogspot.com/2008/09/adhd-gene3-dat.html"><span style="color:#3333ff;"><em>DAT1</em> gene</span></a> (often referred to simply as "<em>DAT</em>", possibly related to <a href="http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=126455"><span style="color:#3333ff;">Tourette's</span></a> and eating disorders such as <a href="http://adhd-treatment-options.blogspot.com/2009/01/adhd-and-bulimia-connection.html"><span style="color:#3333ff;">bulimia</span></a>)</li><li><a href="http://adhd-treatment-options.blogspot.com/2009/03/adhd-gender-and-maoa-gene.html"><span style="color:#3333ff;"><em>MAOA</em> gene</span></a> (likely has gender-specific effects, also tied to autism, bipolar and anxiety disorders)</li><li><a href="http://adhd-treatment-options.blogspot.com/2008/12/adhd-genes-influence-medication-dosage.html"><span style="color:#3333ff;"><em>COMT</em> gene</span></a> (can affect dosage levels of ADHD stimulant medications, and possibly have an impact on <a href="http://adhd-treatment-options.blogspot.com/2009/01/gene-variations-which-effect-attention.html"><span style="color:#3333ff;">brain regions responsible for attentional control</span></a>)</li><li><a href="http://adhd-treatment-options.blogspot.com/2009/03/adhd-gender-and-slc6a2-gene.html"><span style="color:#3333ff;"><em>SLC6A2</em> gene</span></a> (also called "<em>NET</em>" or "<em>norepinephrine transporter gene</em>", may affect the response to Strattera, also related to posture and eating disorders such as <a href="http://www.ncbi.nlm.nih.gov/pubmed/12140790"><span style="color:#3333ff;">anorexia</span></a>)</li><li><a href="http://adhd-treatment-options.blogspot.com/2009/03/adhd-gene-slc6a4-favors-males-over.html"><span style="color:#3333ff;"><em>SLC6A4 </em>gene</span></a> (often has a greater potential effect on males with ADHD, associated with autism)</li><li><a href="http://adhd-treatment-options.blogspot.com/2009/05/adhd-gene-falls-inside-reading.html"><span style="color:#3333ff;"><em>Protogenin </em>gene</span></a> (possibly related to ADHD and reading disabilities)</li><li><a href="http://adhd-treatment-options.blogspot.com/2008/08/seven-genes-associated-with-adhd.html"><span style="color:#3333ff;"><em>DRD4 </em>gene</span></a> (also may be related to schizophrenia, alcoholism, and resistance to Parkinson's)</li><li><a href="http://adhd-treatment-options.blogspot.com/2009/01/genes-omega-3s-alcohol-and-adhd.html"><span style="color:#3333ff;"><em>Fatty acid desaturase </em>genes</span></a> (may play a role in deficiencies in omega-3 levels in ADHD)</li><li><a href="http://adhd-treatment-options.blogspot.com/2009/02/crem-gene-melatonin-and-adhd.html"><span style="color:#3333ff;"><em>CREM </em>gene</span></a> (may be related to hormonal regulation, including the sleep-related melatonin)<em></em></li><li><a href="http://adhd-treatment-options.blogspot.com/2008/09/adhd-gene-6-serotonin-receptor-1b-gene.html"><span style="color:#3333ff;"><em>Serotonin receptor 1B</em> gene</span></a> (may be more associated with the inattentive subtype of ADHD)</li></ul><p>Additionally, some of these genes may work together in combo. For example, a combination of specific variations in the <em>DAT1</em> gene and the <em>DRD4</em> gene may associate with <a href="http://adhd-treatment-options.blogspot.com/2009/05/adhd-iq-and-gene-combinations.html"><span style="color:#3333ff;">IQ and behavioral disorders as they relate to ADHD</span></a>. </p>The main point of all of these examples was not to overwhelm anyone, but rather to highlight the intricate relationship between genetics and ADHD heritability. <br /><br /><strong>Adding to this extensive list may be a new set of genes related to blood types and ADHD.</strong> <br /><em></em><br /><em>**For a quick synopsis of blood types, please consult the italicized paragraphs below. Otherwise you may skip to the next paragraph highlighting a new study on blood type and ADHD.</em><br /><em></em><br /><em>Human blood types are often classified by the "ABO" system. "A" and "B" refer to immune-regulating factors and play a major role in blood transfusions. These blood types are acquired from our parents and can come in dominant and recessive forms. Genes for blood type can be found on the 9th human chromosome. </em><br /><em></em><br /><em>They are the two main (or dominant) forms of immune-regulating blood factors. Additionally, A and B can be "codominant", that is an individual can have a mixture of the two. For these "codominant" individuals, their blood type is labeled "AB". If an individual has neither "A" nor "B", he or she is labeled as an "O". </em><br /><em></em><br /><em>In essence, if you have a specific letter(s), you can donate blood to individuals who share your same letters (there are actually other important factors and donor restrictions besides this, such as the "Rh factor", but for sake of simplicity, we will just discuss "ABO" for the moment). For example, a person with type "A" blood could donate to another person who has "A" or "AB" because both "A" and "AB" would recognize the "A" component. They could not donate to a "B" or an "O" blood type because these individuals' bodies would not be able to recognize the "A", resulting in a severe immuno-rejection problem. </em><br /><em></em><br /><em>An "O" could donate to and "A", a "B", an "AB", or another "O" (again, there are detailed exceptions to this generalization), because "O" does not have either of the "A" or "B" markers on it, so the recipient's body would not see anything "foreign" about this. This makes "O" carriers better candidates for blood donation. On the flip side, and individual with type "AB" could take blood from and "A", a "B", an "AB" or an "O" since their blood already recognizes the "markers". This makes AB candidates better recipients for blood.</em><br /><em></em><br /><em>In addition to an individual's blood type governing the blood transfusion process, <a href="http://anthro.palomar.edu/blood/ABO_system.htm"><span style="color:#3333ff;">blood types may also confer resistance or susceptibility to certain bodily dysfunctions or diseases</span></a>. For example, type "A" individuals may be naturally more prone to cancers of the digestive system, and individuals with type "O" are more prone to cholera, plagues, or even malaria (interestingly, they may be more prone to be preferred targets of mosquitoes, compared to the other blood types). </em><br /><br /><strong>Overview of an original study on ADHD and blood types:</strong><br />Returning to our main discussion, it appears that certain blood types may also be related to an increased likelihood of childhood ADHD or related disorders. A Chinese study recently came out which sought to investigate whether <a href="http://www.ncbi.nlm.nih.gov/pubmed/19470260"><span style="color:#3333ff;">certain blood types were actually more likely to be affiliated with ADHD</span></a>. The results, while preliminary, should nevertheless pique some interest on the topic among professionals. <br /><br />Here are some of the major highlights of the study:<br /><ul><li>Blood types (using the "ABO" format) were taken from 96 children and their parents, to determine the heritability patterns of blood types.</li><li>Both ADHD and non-ADHD children were observed in the study, and their blood types were broken down.</li><li>The study found that children who did have ADHD were more likely to have inherited either the "A" or "O" type blood from their parents.</li><li>Conversely, children who inherited the type "B" blood (which would include either the "B" or "AB" form) were less likely to be diagnosed with ADHD. </li></ul><p>** A caveat concerning the findings and reproducibility of this study: It is important to note that the study population was relatively small, especially for a study of this magnitude which seeks to identify general trends between blood types and their relative association with co-existing disorders. Some blood types can be relatively rare, for example, in the <a href="http://www1.givebloodgivelife.org/education/blood-types/"><span style="color:#3333ff;">United States</span></a>, only around 10% of the population has type "B" blood and only about 15% has the "B" in any form (types B or AB). Although blood types vary extensively all over the world, certain types tend to predominate, which requires large populations to be studies to ensure all groups are sufficiently represented. Thus, small population studies can easily produce skewed results. Nevertheless, I personally believe this study was a good starting point. </p><p>**Blogger's personal notes/opinions on these findings: </p><p>I found this study to be interesting. Unfortunately, I could not read the whole article (the majority is in Chinese!), but the possibility of blood typing being related to ADHD would be a major breakthrough, if these results are able to be consistently replicated with larger population studies. </p><p>My first thought was that maybe some nearby gene related to ADHD might be influencing the blood type/ADHD connection, but no significant genes associated with ADHD exist on the 9th chromosome (at least to the best of my knowledge after conducting a search of <a href="http://www.ncbi.nlm.nih.gov/omim">OMIM</a> for the term "ADHD", a national database which ties down diseases and disorders to known genetic regions). However, genes which are located far apart from each other, even on completely different chromosomes can also work in tandem, so genetic relationships between ADHD genes and blood type genes cannot be ruled out entirely.</p><p>Another option may be some type of indirect connection between blood type and ADHD. For example, the article notes that individuals who have the "O" or "A" blood type alleles are more prone to ADHD. Other sources note that individuals with type "O" are more prone to developing <a href="http://anthro.palomar.edu/blood/ABO_system.htm"><span style="color:#3333ff;">intestinal and gastric ulcers</span></a>, and that individuals with type "A" are more prone to <a href="http://anthro.palomar.edu/blood/ABO_system.htm"><span style="color:#3333ff;">cancers of the digestive system</span></a> (such as cancers of the esophagus, pancreas and stomach). This may signify that these blood types (compared to those who have "B" or "AB" blood) may be more prone to digestive problems. </p><p>Digestive disorders can result in poor nutrient absorption (we have discussed nutrient deficiencies in ADHD in number of previous posts), which may leave one more prone to ADHD symptoms. Additionally, digestive dysfunctions can actually lead to an increased likelihood of developing food allergies, as potential allergens are less likely to be broken down or "chewed up" than by a properly-functioning digestive system. Furthermore, we have also explored the possibility that <a href="http://www.ncbi.nlm.nih.gov/pubmed/17041745"><span style="color:#3333ff;">acid accumulation can make its way into the brain regions</span></a> and have an impact on neurological symptoms including ADHD-like behaviors. This was discussed in a recent post investigating the high prevalence of <a href="http://adhd-treatment-options.blogspot.com/2009/05/childhood-ear-infections-and-adhd-why.html"><span style="color:#3333ff;">ADHD in children who suffer from frequent ear infections</span></a>. </p><p>While these possibilities are strictly hypothetical at the moment I firmly believe that we should further explore the possibility of specific blood types as possible underlying causes or risk factors for developing ADHD. </p>The ADHD Treatment Guidehttp://www.blogger.com/profile/00747782650821771627noreply@blogger.com11tag:blogger.com,1999:blog-2736612052295099842.post-90828342440396211682009-05-27T20:24:00.011-04:002009-05-28T23:57:44.218-04:00ADHD and Balance Impairment: Visual and Inner Ear Deficiencies<strong>Balance dysfunctions and visual or vestibular deficiencies: Uncommon <span class="blsp-spelling-error" id="SPELLING_ERROR_0">comorbids</span> in the <span class="blsp-spelling-error" id="SPELLING_ERROR_1">ADHD</span> spectrum:</strong><div> </div><div> </div><br />When we think of <span class="blsp-spelling-error" id="SPELLING_ERROR_2">comorbid</span> disorders to <span class="blsp-spelling-error" id="SPELLING_ERROR_3">ADHD</span>, we often envision disorders which can be diagnosed <span class="blsp-spelling-error" id="SPELLING_ERROR_4">psychiatrically</span>. Common examples such as depression, anxiety, Obsessive Compulsive Disorders (<span class="blsp-spelling-error" id="SPELLING_ERROR_5">OCD</span>), oppositional defiant disorders, and conduct disorders often come to mind. In addition, it is perhaps no surprise that learning disabilities are relatively common in children and adults with <span class="blsp-spelling-error" id="SPELLING_ERROR_6">ADHD</span>. If we do delve into physical <span class="blsp-spelling-error" id="SPELLING_ERROR_7">comorbid</span> disorders, things like <span class="blsp-spelling-error" id="SPELLING_ERROR_8">Tourette's</span> and tics may come to mind. For those skilled in the diagnosis and treatment of <span class="blsp-spelling-error" id="SPELLING_ERROR_9">ADHD</span>, even non-trivial <span class="blsp-spelling-error" id="SPELLING_ERROR_10">comorbids</span> such as <span class="blsp-spelling-error" id="SPELLING_ERROR_11">bedwetting</span> and sleep disorders may be apparent.<br /><br />However, there is another impairment that often goes along with the <span class="blsp-spelling-error" id="SPELLING_ERROR_12">ADHD</span> population, especially in children. Sensory processing disorders are often seen in the <span class="blsp-spelling-error" id="SPELLING_ERROR_13">ADHD</span> population, especially in children. This includes more "physical" dysfunctions including the ability of the child to maintain balance and equilibrium. To the frustrated parent of coach of an <span class="blsp-spelling-error" id="SPELLING_ERROR_14">ADHD</span> child, this may introduce another complication with regards to sports or other activities which involve coordination and balance, such as basketball, baseball, tennis, soccer, gymnastics, musical instruments, dance, etc.<br /><br />The aim of this post is to investigate and discuss impairments in balance function in children with the disorder, We will be citing and highlighting some key studies in the overlap between <span class="blsp-spelling-error" id="SPELLING_ERROR_15">ADHD</span> and balance dysfunctions (especially relating to functions derived from visual and tactile signals) and look for possible underlying causes and treatment methods:<br /><div> </div><div style="font-weight: bold;"><br />Brain regions involved in Balance Dysfunction in the <span class="blsp-spelling-error" id="SPELLING_ERROR_16">ADHD</span> Child:</div><div>Most experts often cite specific "hot spot" regions of the brain for the <span class="blsp-spelling-error" id="SPELLING_ERROR_17">ADHD</span> patients. Among these, the <span style="font-weight: bold;"><span class="blsp-spelling-error" id="SPELLING_ERROR_18">prefrontal</span> cortex</span> part of the brain often receives the most attention. Less pronounced, however, are the studies associating the <span style="font-weight: bold;">cerebellum</span>, and their implications on <span class="blsp-spelling-error" id="SPELLING_ERROR_19">ADHD</span>. For a reference to the <span class="blsp-spelling-error" id="SPELLING_ERROR_20">Prefrontal</span> Cortex and Cerebellum brain regions, please consult the brain diagrams below:</div><a onblur="try {parent.deselectBloggerImageGracefully();} catch(e) {}" href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjyu6I-x8hlwxjRLTeFksLP9IHcq3OfsDObuBGdmqUANYUL8nxBcoEr5teQRJpGuuLscES9xeCa8dYVPfG24hn_hoWibLKPoy9ViOwB2txGNsSBmO9CVvRf6JQxfAE7j7baf5PRo5nipFg/s1600-h/ADHD+cerebellum+brain+region.png"><img style="margin: 0px auto 10px; display: block; text-align: center; cursor: pointer; width: 360px; height: 262px;" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjyu6I-x8hlwxjRLTeFksLP9IHcq3OfsDObuBGdmqUANYUL8nxBcoEr5teQRJpGuuLscES9xeCa8dYVPfG24hn_hoWibLKPoy9ViOwB2txGNsSBmO9CVvRf6JQxfAE7j7baf5PRo5nipFg/s400/ADHD+cerebellum+brain+region.png" alt="" id="BLOGGER_PHOTO_ID_5341044790685221106" border="0" /></a><a onblur="try {parent.deselectBloggerImageGracefully();} catch(e) {}" href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgvmuYnv00VbocIoSnOwZahg_W2SYDNFxP4-ApEWrlGPFm0tbrSq5NKj9CN7yV1nI9YC5BHsi1l3a1J1qBd-7HChckMvvNHp1i3BWAYu4mX3yDZ4yCc9zFyN8h67PhykMHn39iW59xOPO4/s1600-h/ADHD+OCD+prefrontal+cortex.bmp"><img style="margin: 0px auto 10px; display: block; text-align: center; cursor: pointer; width: 400px; height: 231px;" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgvmuYnv00VbocIoSnOwZahg_W2SYDNFxP4-ApEWrlGPFm0tbrSq5NKj9CN7yV1nI9YC5BHsi1l3a1J1qBd-7HChckMvvNHp1i3BWAYu4mX3yDZ4yCc9zFyN8h67PhykMHn39iW59xOPO4/s400/ADHD+OCD+prefrontal+cortex.bmp" alt="" id="BLOGGER_PHOTO_ID_5341045578489539026" border="0" /></a><span style="font-style: italic;">Shown above is a human brain. The <span style="font-weight: bold;">Cerebellum</span> region, which plays a major role in governing balancing functions and may be compromised in a significant subsection of <span class="blsp-spelling-error" id="SPELLING_ERROR_21">ADHD</span> children, is shown in purple in the top picture. The area highlighted in orange in the bottom drawing roughly corresponds to the <span style="font-weight: bold;"><span class="blsp-spelling-error" id="SPELLING_ERROR_22">prefrontal</span> cortex</span> region of the brain, which plays a major role in impulse control. Deficiencies in blood flow and overall activity of this <span class="blsp-spelling-error" id="SPELLING_ERROR_23">prefrontal</span> cortex region of the brain are often seen in children (and adults) with <span class="blsp-spelling-error" id="SPELLING_ERROR_24">ADHD</span>, and may be responsible for some of the difficulties in filtering out comments and actions for appropriateness.</span><br /><div> </div> <div><span style="font-style: italic;"><br /></span><span style="font-weight: bold;"><br />The inter-relationship between attention and balance/coordination: The strong association of the <span class="blsp-spelling-error" id="SPELLING_ERROR_25">prefrontal</span> cortex and cerebellum regions of the brain:</span><span style="font-style: italic;"><br /><br /></span><span>Many studies involving brain regions and <span class="blsp-spelling-error" id="SPELLING_ERROR_26">ADHD</span> often miss this connection. The relationship between these brain regions may go a long ways in explaining <span class="blsp-spelling-error" id="SPELLING_ERROR_27">ADHD</span> <span class="blsp-spelling-error" id="SPELLING_ERROR_28">comorbid</span> disorders as well, especially the more "physical" ones such as speech complications, developmental coordination disorders, etc. </span><span style="font-style: italic;"> </span><span>While perennial "hot spot" brain regions, such as the <span class="blsp-spelling-error" id="SPELLING_ERROR_29">prefrontal</span> cortex, are frequently mentioned in studies involving brain activity in <span class="blsp-spelling-error" id="SPELLING_ERROR_30">ADHD</span></span><span style="font-style: italic;">, this particular brain region is actually intricately interconnected with the cerebellum</span> (as well as another key brain region, the basal ganglia. The role of the <a style="color: rgb(51, 51, 255);" href="http://adhd-treatment-options.blogspot.com/2009/03/do-adhd-kids-use-their-brain-regions.html">basal ganglia in kids with <span class="blsp-spelling-error" id="SPELLING_ERROR_31">ADHD</span></a> has been discussed previously in other postings, but in general, the basal ganglia tell how fast a person "idles". 'Type A' personalities, such as workaholics, individuals with <span class="blsp-spelling-error" id="SPELLING_ERROR_32">OCD</span> and overly focused individuals typically have <span style="font-style: italic;">over</span>active basal ganglia, whereas many with <span class="blsp-spelling-error" id="SPELLING_ERROR_33">ADHD</span> often exhibit <span style="font-style: italic;">under</span>active basal ganglia.).<br /><br />We have already mentioned that the balance-governing regions of the brain (the cerebellum) is interconnected with a key impulse-control region of the brain (the <span class="blsp-spelling-error" id="SPELLING_ERROR_34">prefrontal</span> cortex or PFC). We also mentioned that <span class="blsp-spelling-error" id="SPELLING_ERROR_35">impulsivity</span> is a characteristic of the Hyperactive-impulsive and Combined <span class="blsp-spelling-error" id="SPELLING_ERROR_36">ADHD</span> subtypes (as opposed to the more inattentive forms of the disorder). Interestingly, the <span style="font-style: italic;">prevalence of balance dysfunction cases seems to predominate in the combined subtype of <span class="blsp-spelling-error" id="SPELLING_ERROR_37">ADHD</span></span> (main paper as reference source). <em>This correlation lends further credence to the hypothesis that the balance-governing and impulse-governing regions of the brain may be "co-affected" in the case of the balance-deficient, hyper-impulsive <span class="blsp-spelling-error" id="SPELLING_ERROR_38">ADHD</span> child.</em><br /></div><div> </div><br /><div style="font-weight: bold;">Key points concerning balance related deficiencies and <span class="blsp-spelling-error" id="SPELLING_ERROR_39">ADHD</span>:</div><div> </div><ul><li><span class="blsp-spelling-error" id="SPELLING_ERROR_40">ADHD</span> is often associated with developmental delays. Indeed, studies highlighting a <a style="color: rgb(51, 51, 255);" href="http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=18024590">delay in cortical maturation in children with <span class="blsp-spelling-error" id="SPELLING_ERROR_41">ADHD</span></a> suggests that children and teens with the disorder may fall "behind the curve". By its own very nature, the <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/16700940">vestibular system often does not fully develop until the age of 15</a>, so immature development in this brain region may result in deficiencies in this system throughout almost the entire span of childhood in an individual with <span class="blsp-spelling-error" id="SPELLING_ERROR_42">ADHD</span>.</li><br /><li>Additionally, EEG and imaging studies have also demonstrated <a style="color: rgb(51, 51, 255);" href="http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=18590567">relative deficiencies in both size</a> and activity (<a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/18330739">by measuring blood flow patterns</a>) in various <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/10943967">brain regions of <span class="blsp-spelling-error" id="SPELLING_ERROR_43">ADHD</span> children</a>. These include the cerebellum and the <span class="blsp-spelling-error" id="SPELLING_ERROR_44">caudate</span> nucleus. Both are interconnected and <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/10836557">associate with the "<span class="blsp-spelling-error" id="SPELLING_ERROR_45">ADHD</span> region" of the <span class="blsp-spelling-error" id="SPELLING_ERROR_46">prefrontal</span> cortex</a> (PFC). This PFC region plays a major role in the impulse-control process and deficiencies in its function can result in a weak self-regulatory system of impulsive behaviors (which are hallmark characteristics of <span class="blsp-spelling-error" id="SPELLING_ERROR_47">ADHD</span>, especially in the hyperactive/impulsive and Combined subtypes).</li><br /><li>The cerebellum gathers input from visual, vestibular (inner ear), and <span class="blsp-spelling-error" id="SPELLING_ERROR_48">somatosensory</span> (mainly <span class="blsp-spelling-corrected" id="SPELLING_ERROR_49">tactile</span> senses, such as perceived through the skin and internal organs) systems. As we can imagine, a defect in one or more of these information-obtaining sensory systems, and the cerebellum (as well as the interconnected region of the PFC) may be compromised. Thus <span class="blsp-spelling-error" id="SPELLING_ERROR_50">ADHD</span> and sensory deficits may be intricately related.</li><br /><li>Taking this one step further, we may wish to explore the link between <span class="blsp-spelling-error" id="SPELLING_ERROR_51">ADHD</span> and sensory disorders, including processing disorders and sensory integration disorders. One thing is for sure, however: <span class="blsp-spelling-error" id="SPELLING_ERROR_52">ADHD</span> is not simply limited to deficits in the PFC!</li><br /><li>The vestibular system also plays a crucial role in what is known as "gaze stabilization" (i.e., stabilizing the focus on a particular <span style="font-style: italic;">fixed</span> object when you yourself are moving). The very nature of "gazing" obviously has visual implications as well, so a deficiency in the vestibular component of gaze stabilization may also affect visual input success as well. Interestingly (an perhaps not surprisingly), <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/19446843">visual input deficiencies are also seen at high rates in children with <span class="blsp-spelling-error" id="SPELLING_ERROR_53">ADHD</span></a>.<br /><br />This may actually serve as one of the key contributing factors as to why maintaining attention (to, say, a teacher), may be so difficult for <span class="blsp-spelling-error" id="SPELLING_ERROR_54">ADHD</span> kids, because they literally are having trouble focusing their visual attention (gaze) on their target of interest (i.e. a teacher standing up in class giving a lecture), especially if the child is already fidgeting around in their seat. In other words, there may be some inherent deficiency in this particular component of the attention span, and needs to be addressed further in the near future.</li></ul><span style="font-weight: bold;">Investigating the sources of balance impairment in children with <span class="blsp-spelling-error" id="SPELLING_ERROR_55">ADHD</span>:</span><br />In order to clarify where I am coming from on this, I will highlight an extremely recent publication in the <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/19446843">Journal of Pediatrics by <span class="blsp-spelling-error" id="SPELLING_ERROR_56">Shum</span> and Pang</a>. This study investigated the different systems of balance in children, including <span class="blsp-spelling-error" id="SPELLING_ERROR_57">somatosensory</span> (balance governed by tactile features), visual, and vestibular (inner ear and the sense of equilibrium). They tested approximately 50 children (ages 6-12) with <span class="blsp-spelling-error" id="SPELLING_ERROR_58">ADHD</span> for balance discrepancies by isolating each of the three systems listed above to test sensory organizations of balance. A highlight of the study can be seen below:<br /><br />Instruments/Methods of the study:<br /><ol><li>A platform which can induce a feeling of motion on a child who stands upon it (this disrupts the <span class="blsp-spelling-error" id="SPELLING_ERROR_59">somatosensory</span> component of balance, forcing the child to use their visual or vestibular functions to compensate for the <span class="blsp-spelling-error" id="SPELLING_ERROR_60">somatosensory</span> impairment).</li><li>Surrounding scenery which can visually give the illusion of motion. This forces the child to use their vestibular and <span class="blsp-spelling-error" id="SPELLING_ERROR_61">somatosensory</span> methods of equilibrium, as the visual sense is disrupted. Another variation of this is to have the child perform with their eyes closed.</li><li>A combination of the two methods above will isolate the vestibular component of balance, as both the <span class="blsp-spelling-error" id="SPELLING_ERROR_62">somatosensory</span> and visual sources of balance are now both compromised. </li><li>A total of six different environmental conditions were performed to isolate one or more senses of balance. The researchers noted which of the three modes of balance were most likely to be compromised in the <span class="blsp-spelling-error" id="SPELLING_ERROR_63">ADHD</span> children. The findings are highlighted below:<br /></li></ol>While balance-related issues can stem from visual discrepancies, <span class="blsp-spelling-error" id="SPELLING_ERROR_64">somatosensory</span> issues (i.e. the sensations of touch and pressure from the skin and even internal organs), and vestibular (inner ear) imbalances, it appears that <span class="blsp-spelling-error" id="SPELLING_ERROR_65">ADHD</span> children are most likely to suffer from visual imbalances. This is closely followed, however, by deficits in vestibular function. <span class="blsp-spelling-error" id="SPELLING_ERROR_66">Somatosensory</span> difficulties appear to occur in <span class="blsp-spelling-error" id="SPELLING_ERROR_67">ADHD</span> children as well, but the role of this system is likely to be much smaller than for the other 2.<br /><br /><span style="font-weight: bold;">Possible academic implications of balance dysfunction and <span class="blsp-spelling-error" id="SPELLING_ERROR_68">ADHD</span>: Does the source of an <span class="blsp-spelling-error" id="SPELLING_ERROR_69">ADHD</span> child's balance deficiency affect his or her sensory learning style?</span> The following points are simply the result of this blogger thinking out loud. Nevertheless, these might be some good topics of future study, as balance difficulties may be useful in evaluating academic strategies.<ul><li><span style="font-style: italic;">These findings on balance may even extend to the classroom and affect the learning environment of an <span class="blsp-spelling-error" id="SPELLING_ERROR_70">ADHD</span> child.</span> Given the above, abnormalities in these areas may even affect a child's mode of learning and learning style. While these <span style="font-style: italic;">assertions simply remain personal hypotheses of this blogger</span>, a child with visual discrepancies leading to balancing difficulties may<span style="font-style: italic;"> also be deficient in visual perception and therefore struggle in a visual-dominated learning environment</span>. He or she may gravitate towards a more auditory or <span class="blsp-spelling-error" id="SPELLING_ERROR_71">kinesthetic</span> style of learning.<br /></li></ul><ul><li>Conversely, it is also possible that vestibular-regulated balance dysfunctions, which stem from the inner ear may <span style="font-style: italic;">actually extend to a child's auditory learning capabilities</span>. Again, this remains a hypothesis, but given the fact that <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/18821228">severe childhood ear infections can affect both balance and hearing</a> (as well as <span class="blsp-spelling-error" id="SPELLING_ERROR_72">ADHD</span> symptoms, see previous post on <a style="color: rgb(51, 51, 255);" href="http://adhd-treatment-options.blogspot.com/2009/05/childhood-ear-infections-and-adhd-why.html">childhood ear infections and <span class="blsp-spelling-error" id="SPELLING_ERROR_73">ADHD</span></a>), a child with vestibular-related balance deficiencies may also have more difficulty in a predominantly auditory-based learning environment. This may spell bad news if an <span class="blsp-spelling-error" id="SPELLING_ERROR_74">ADHD</span> child's teacher engages in more auditory discussions or as the child moves up to high school and college courses where an auditory lecture is the more common form of teaching and communication.<br /></li></ul><ul><li>A double-whammy?: Given the fact that children with <span class="blsp-spelling-error" id="SPELLING_ERROR_75">ADHD</span> may suffer from both vestibular and visual (and even <span class="blsp-spelling-error" id="SPELLING_ERROR_76">somatosensory</span>) information processing for balance, it leads us to wonder if the child may also have learning deficits in 2 of the 3 major forms of learning (visual, auditory or <span class="blsp-spelling-error" id="SPELLING_ERROR_77">kinesthetic</span>). If this is the case, trying to accommodate an <span class="blsp-spelling-error" id="SPELLING_ERROR_78">ADHD</span> child's education could be extremely difficult, if he or she must heavily rely on only one predominant mode of acquiring and processing information.<br /><br />For example, if a child were to undergo a study similar to the one listed above, and it turns out that he or she is weak in both the visual and vestibular forms of balance, and (this is a big "if" and is only hypothetical at the moment) the whole balance governing/learning style hypothesis holds true, he or she may have to rely on a predominantly <span class="blsp-spelling-error" id="SPELLING_ERROR_79">kinesthetic</span> form of learning. While this child may succeed in hands-on learning subjects (i.e. frog dissection or wood shop class), he or she may have an exceedingly difficult time in other subjects such as algebra or history where hands-on-learning opportunities are more difficult to implement.<br /><br /></li></ul><ul><li>The role of balance and sensory stimulation may have even greater-reaching academic implications. Another study just came out recently investigating the role of posture stability (i.e. how well a person stabilizes their center of balance) on <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/18830588"><span class="blsp-spelling-error" id="SPELLING_ERROR_80">ADHD</span> and dyslexia</a>. The study found that <span class="blsp-spelling-error" id="SPELLING_ERROR_81">comorbid</span> <span class="blsp-spelling-error" id="SPELLING_ERROR_82">ADHD</span> symptoms greatly influenced the effects of posture stability in dyslexic individuals, which may even have implications to affecting the reading environment of the individuals with dyslexia. It's important to keep in mind that this study involved adults instead of children, but the fact that <span class="blsp-spelling-error" id="SPELLING_ERROR_83">ADHD</span> may play such an integrated role into sensory modulation of other disorders into adulthood may signify the deep level of inter-relationship between cognitive function and sensory motor stimulation.<br /></li></ul><div> </div><div> </div><div><strong>Vestibular Stimulation as an alternative form of <span class="blsp-spelling-error" id="SPELLING_ERROR_84">ADHD</span> Treatment?:</strong> As an interesting aside, there has been some pronounced effect on treating <span class="blsp-spelling-error" id="SPELLING_ERROR_85">ADHD</span> symptoms with a non-pharmaceutical alternative method called <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/18198165"><span style="font-weight: bold;">vestibular stimulation</span></a>. We will be addressing the validity of these findings and their potential for practical usage in a later discussion. </div>The ADHD Treatment Guidehttp://www.blogger.com/profile/00747782650821771627noreply@blogger.com2tag:blogger.com,1999:blog-2736612052295099842.post-44920479603430197942009-05-22T22:24:00.003-04:002009-05-23T00:31:24.874-04:00Childhood Ear Infections and ADHD: Why the link?When we scan the literature for statistics on ADHD and search for early warning signs or tip-offs that a young child may be prone to the disorder, a few common trends seem to pop up again and again. One of these is the high rates of ADHD and attentional difficulties in kids suffering infection of the middle ear (Otitis Media) in early childhood. <br /><br />During early childhood, the actual positioning of the ear canal is still adjusting, the pathway into the middle part of the ear is actually at a flatter angle than in a mature adult. This difference in positioning actually makes younger children much more prone to ear infections than older children or adults. Unfortunately, these infections may increase the risk of further complications down the road, including an increased onset of attentional difficulties, including ADHD. Here is what some of the literature has to say about the ADHD/ear infection connections:<br /><br /><strong>Relationship between middle ear infections and inattention: The basis for inattentive ADHD?</strong><br /><strong></strong><br />The main culprit for <a href="http://www.ncbi.nlm.nih.gov/pubmed/8340473"><span style="color:#3333ff;">attentional deficits is often believed to be the result of hearing loss</span></a> (even mild), early in a child's life due to complications with the middle ear, including infections, allergy-related causes or build-up of fluids in the canal. As a result, the child begins to miss out on verbal cues, and does not develop the same level of response to an adult voice. Auditory deficiencies (including auditory processing disorders) may stem from this key development period, even if the hearing difficulties are only temporary. <br /><br />Not surprisingly, there is a wealth of data associated with hearing loss due to <a href="http://www.ncbi.nlm.nih.gov/pubmed/10668655"><span style="color:#3333ff;">middle ear complications can lead to language processing difficulties</span></a>. We have seen how <a href="http://adhd-treatment-options.blogspot.com/2009/03/adhd-and-auditory-processing-disorders.html"><span style="color:#3333ff;">auditory processing disorders</span></a> can often occur as a comorbid factor in ADHD, and may be linked to seemingly unrelated behaviors including <a href="http://adhd-treatment-options.blogspot.com/2009/02/gender-age-and-subtype-effects-on-adhd.html"><span style="color:#3333ff;">comorbid anxiety and conduct-related disorders</span></a>. <br /><br />It is important to note, however, that other early childhood studies have not seen a link between infection and attentional difficulties (observed by <a href="http://www.ncbi.nlm.nih.gov/pubmed/11331683"><span style="color:#3333ff;">parents, teachers, or clinicians</span></a>). <br /><br />Interestingly, environment may play a huge role in explaining this discrepancy between study results. One study found that children who had <a href="http://www.ncbi.nlm.nih.gov/pubmed/16906002"><span style="color:#3333ff;">middle ear complications early on along with poor home environments</span></a> were significantly more likely to develop attentional difficulties (along the lines of what would be classified as ADHD). <em>Therefore, the effects of early ear infections on compromised attentional difficulties may be significantly reduced if a supportive home environment is maintained for a child</em>. This is good news for parents of children with ear infections. But what about the hyperactive component of ADHD?<br /><br /><strong>The link between hyperactive behaviors and middle ear complications: The basis for hyperactive/impulsive or combined subtype ADHD?</strong><br /><br />While it seems more intuitive that ear infections could lead to auditory problems and subsequent attentional difficulties (especially to auditory cues), the relationship between ear infections and hyperactivity is less inherently obvious. This association would be more relevant to the hyperactive/impulsive and combined subtypes of ADHD. <br /><br />For over 30 years, researchers have linked <a href="http://www.ncbi.nlm.nih.gov/pubmed/740464"><span style="color:#3333ff;">high rates of ear infections and hyperactivity</span></a> (this study used the term "minimal brain dysfunction", a phrase which this blogger has personal objections, nevertheless, it is a relatively common term in the literature). Later studies confirmed these findings, including one which reported the <a href="http://www.ncbi.nlm.nih.gov/pubmed/3568530"><span style="color:#3333ff;">majority of children medicated for hyperactivity had a past history of 10 or more childhood ear infections</span></a>. These numbers were in sharp contrast to the prevalence of ADHD in non-hyperactive children. <br /><br />One thought may be that ADHD which includes a significant hyperactive component (as opposed to the more inattention-dominated form of the disorder) is more likely to be associated with comorbid disorders that correspond to ear infections. We have seen previously that comorbid disorders to ADHD are often related to particular subtypes. <br /><br />For example, <a href="http://adhd-treatment-options.blogspot.com/2009/05/methylphenidate-anxiety-and-adhd-how-do.html"><span style="color:#3333ff;">anxiety</span></a> and depressive-like symptoms are often more likely to co-exist with primarily inattentive ADHD, while <a href="http://adhd-treatment-options.blogspot.com/2009/02/genes-and-low-birth-weight-combine-to.html"><span style="color:#3333ff;">conduct disorders</span></a> are more likely to co-exist if there is a high hyperactive/impulsive behavior (especially in the combined subtype). In general, the prevalence of more severe <a href="http://adhd-treatment-options.blogspot.com/2009/05/adhd-gene-falls-inside-reading.html"><span style="color:#3333ff;">learning disabilities</span></a> is often more associated with the inattention-dominant form of ADHD, while motor <a href="http://adhd-treatment-options.blogspot.com/2008/10/do-adhd-stimulant-meds-worsen-tourettes.html"><span style="color:#3333ff;">tics</span></a> are more likely to be a hyperactive/impulsive trait. Carrying these associations in mind, are the studies linking early ear infections to hyperactivity simply due to associations with hyperactive subtype-dominated comorbid disorders?<br /><br />One particular study found that children with <a href="http://www.ncbi.nlm.nih.gov/pubmed/2304807"><span style="color:#3333ff;">hyperactivity vs. children with learning disabilities</span></a> (and not hyperactivity, remember, learning disabilities are often seen at higher rates in the inattentive forms of the disorder) had similar numbers of total childhood ear infections. However, the <em>timing</em> of the infections did seem to matter. Children with hyperactivity experienced more recent ear infections (within the previous year) compared to the learning disability kids. <br /><br />In other words, the question surrounding hyperactivity and ear infections may be more of a "<em>when</em>" question than a <em>"how many</em>" question. <em>This may also suggest the possibility that hyperactivity due to middle ear troubles may be more of a temporary condition</em> (this is supported by trends as an individual with ADHD ages, typically, the hyperactive symptoms of the disorder begin to subside as a child gets older and reaches adulthood, while the inattentive symptoms are more likely to plateau) <em>as opposed to inattentive problems stemming from ear infections</em>. Severity of the infections may also be a triggering cause or associated warning sign of an increased risk of developing hyperactive behaviors. The same study found that earaches and upper respiratory tract infections were higher in the hyperactive group than in the less-hyper learning disability group. <br /><br /><strong>So what's going on with the connection between ear infections and ADHD-like hyperactivity?:</strong><br />Although none of the above studies mentioned this possibility, as a blogger I have a few ideas on the subject. One of the most probable reasons for the ear infection/hyperactivity correlation may be due to the treatment process of ear infections. Let me explain:<br /><br />Ear infections are typically treated with antibiotics. While these drugs work wonders for most infections, they also can disrupt the healthy bacterial counts in the digestive tract (that is, they kill off many of the "good" bacteria in our digestive systems in addition to the "bad" bacteria which may be causing our infections). <br /><br />If the "good" digestive bacterial counts fall too low, the digestive process is compromised. The absorption and digestion process may suffer, as key nutrients may now be compromised (even if no major dietary changes occur). We have spoken extensively about <a href="http://adhd-treatment-options.blogspot.com/2009/01/adhd-alcoholism-and-nutrient.html"><span style="color:#3333ff;">nutrient deficiencies and ADHD</span></a> as well as <a href="http://adhd-treatment-options.blogspot.com/search/label/Nutrition%20strategies"><span style="color:#3333ff;">ADHD-related nutrition strategies</span></a> in earlier posts. <br /><br />Additionally, if good bacterial counts fall low, incomplete digestion results, which can lead to byproducts such as higher concentrations of organic acids, as well as incomplete breakdowns of potential allergens (which can increase sensitivity to food allergens, among others). These allergens and acids can actually begin to <a href="http://www.ncbi.nlm.nih.gov/pubmed/17041745"><span style="color:#3333ff;">penetrate the blood brain barrier</span></a> and show up in higher concentrations in the brain. Neurological disorders, including abnormal hyperactivity may actually be triggered by digestive imbalances (to a degree beyond what most of us realize). We are just beginning to recognize the huge degree of inter-relationship between the nervous and digestive systems, including <a href="http://www.ncbi.nlm.nih.gov/pubmed/18431066"><span style="color:#3333ff;">brain-gut interactions</span></a>.<br /><br />There has been a longstanding "hot" discussion surrounding <a href="http://www.ncbi.nlm.nih.gov/pubmed/15813284"><span style="color:#3333ff;">food allergies and ADHD</span></a> (as well as possible connections between food allergies and disorders like fibromyalgia and chronic fatigue syndrome), and the disrupted bacterial balance in the digestive system due to frequent antibiotic usage for recurrent ear infections may be a governing factor. This seems to make sense, especially considering the fact that hyperactivity was more linked to <em>recent</em> ear infections (and resultant antibiotic treatment), while the more inattentive behaviors and learning disorders seem to be a more long-standing symptom. Since bacterial counts begin to re-stabilize following antibiotic treatment (if a proper diet is maintained), the food-related hyperactivity may begin to subside, but for recent infections and treatments, the digestive bacteria may still be imbalanced, triggering an onset of ADHD-like hyperactive behaviors.<br /><br />Of course this is just the blogger's personal hypothesis, but it at least seems plausible that the actual treatment for ear infections may play an equally strong role on the high rate of occurrence between ADHD and ear infections.The ADHD Treatment Guidehttp://www.blogger.com/profile/00747782650821771627noreply@blogger.com39tag:blogger.com,1999:blog-2736612052295099842.post-64234681391295420342009-05-17T21:00:00.004-04:002009-05-17T22:34:14.831-04:00Ginkgo biloba for ADHD: A natural herbal treatment alternative?A few weeks ago, I discussed the merits of <a style="color: rgb(51, 51, 255);" href="http://adhd-treatment-options.blogspot.com/2009/05/can-adhd-be-treated-with-ginseng.html">ginseng for treating ADHD</a>. What I did not mention is the fact that this special herb often works even better in tandem with another important "brain herb", <span style="font-weight: bold; font-style: italic;">Ginkgo biloba</span>. It's benefits also extend beyond the nervous system, and the <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/16400219"><span style="font-style: italic;">Ginkgo</span> has been used to treat everything from increasing blood flow to Alzheimer's to glaucoma to hormone replacement to protection against neuronal degradation</a>. While somewhat wary (personally) of using generalized "brain booster" nutrients for ADHD (it is a highly variable disorder of complex etiology and treatment methods), I am interested whenever new research publications arise on the topic. Just this week, a new paper came out on the merits of <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/19441138"><span style="font-style: italic;">Ginkgo </span>biloba as an ADHD treatment option</a>.<br /><br />Here are some of the major points of the publication:<br /><br /><ul><li>Irritability is an often overlooked side effect of ADHD. Medications, especially over-prescription with stimulants such as methylphenidate and amphetamines can increase this unwanted side effect. However, <span style="font-style: italic;">Ginkgo</span> exhibited a positive mollifying effect on irritability for the individuals in the study.<br /><br /></li><li>While one of the knocks against <span style="font-style: italic;">Ginkgo biloba</span> is that it can sometimes result in sedative effects, the study found these to be extremely mild. However, to go along with the irritability-reducing benefits above, <span style="font-style: italic;">Ginkgo</span> was able to improve the individuals' tolerance for frustration (to the degree that this behavior could be measured).<br /><br /></li><li>We have seen previously that oppositional defiant behaviors are often comorbid to ADHD (which can often manifest themselves alongside seemingly unrelated disorders such as <a style="color: rgb(51, 51, 255);" href="http://adhd-treatment-options.blogspot.com/2009/03/adhd-and-auditory-processing-disorders.html">auditory processing disorders</a> or even <a style="color: rgb(51, 51, 255);" href="http://adhd-treatment-options.blogspot.com/2009/04/bedwetting-adhd-kids-and-depressed-dads.html">bedwetting</a>). One of the strongest suits of <span style="font-style: italic;">Ginkgo biloba</span> may actually be in curbing these oppositional behaviors. This suggests that <span style="font-style: italic;">Ginkgo</span> may be effective for the more Hyperactive/Impulsive or Combined Subtypes of ADHD, where comorbid oppositional behaviors are more often seen (as opposed to the predominantly inattentive subtype of the Disorder).<br /><br /></li><li>Nevertheless, <span style="font-style: italic;">Ginkgo biloba</span> appeared to boost symptoms of attention and working memory as well. This may suggest <span style="font-style: italic;">Ginkgo's</span> versatility, and that it could be used universally across the ADHD "spectrum", including for the 3 classic or traditional subtypes of the disorder.<br /><br /></li><li>The study highlights the relative success for co-treatment with methylphenidate and clonidine for individuals with ADHD and comorbid anxiety disorders. The authors suggest a functional comparison between <span style="font-style: italic;">Ginkgo</span> and <span style="font-weight: bold;">clonidine</span>, and hint at its use as an alternative to clonidine/methylphenidate treatment (of course, it is also possible that <span style="font-style: italic;">Ginkgo</span> may be used alongside lower doses of stimulant medications, which could be very useful in reducing unwanted side effects, which are often mild for low doses of stimulants, but typically begin to appear with greater frequency when stimulant dosing is increased). Thus, <span style="font-style: italic;">Ginkgo</span> could possibly act as a side-effect-saving alternative to higher doses of medication.<br /><br /></li><li>As a precautionary measure, due, in part to some of its anti-clotting properties, there is some concern about <span style="font-style: italic;">Ginkgo</span> triggering internal cerebral bleeding. Indeed, other studies have also addressed this possible concern, highlighting issues such as <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/18383637">haemmorrhage risks</a>, as well as herb-drug interactions with <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/17030294"><span style="font-style: italic;">Ginkgo</span> and anti-coagulant medications</a>. <br /><br /></li><li>Keep in mind the extremely small nature of the study (only 6 individuals) should be met with healthy skepticism. However, the results were still notable. Statistically significant reductions in some of the trademark ADHD symptoms (fidgeting, restlessness, inattention, etc.) upon <span style="font-style: italic;">Ginkgo biloba</span> treatment definitely highlight its potential as a more "natural" alternative treatment method for ADHD.<br /></li></ul>The ADHD Treatment Guidehttp://www.blogger.com/profile/00747782650821771627noreply@blogger.com46tag:blogger.com,1999:blog-2736612052295099842.post-46462503111292807702009-05-16T20:07:00.006-04:002009-05-16T21:44:07.435-04:00Why the Menstrual Cycle may affect ADHD Medication Dosing Levels<span style="font-weight: bold;">Do hormonal fluctuations result in variable ADHD medication dosage levels across the menstrual cycle?</span><br /><br />We have investigated the impact of gender on ADHD in a number of earlier posts. We have covered topics such as:<br /><br /><ul><li><a style="color: rgb(51, 51, 255);" href="http://adhd-treatment-options.blogspot.com/2009/05/adhd-methylphenidate-and-blood-sugar.html">Gender Based Metabolic Differences in ADHD brains</a></li></ul><ul><li><a style="color: rgb(51, 51, 255);" href="http://adhd-treatment-options.blogspot.com/2009/03/are-adhd-genes-gender-dependent.html">Gender Dependent ADHD Genes</a>, including <span style="font-style: italic; font-weight: bold;">MAOA</span>, <span style="font-style: italic; font-weight: bold;">SLC6A2</span>, <span style="font-style: italic; font-weight: bold;">SLC6A4</span> and <span style="font-style: italic; font-weight: bold;">COMT</span></li></ul><ul><li><a style="color: rgb(51, 51, 255);" href="http://adhd-treatment-options.blogspot.com/2009/02/gender-age-and-subtype-effects-on-adhd.html">ADHD subtypes and Comorbid Disorders</a></li></ul><br />Clearly, there are a number of boy/girl differences in the root causes, diagnoses and treatment methods for the disorder.<br /><br />However, we need to investigate whether intra-individual differences are also an important factor, especially where medication treatment and medication dosing levels are concerned. Based on a number of studies, <span style="font-style: italic;">it appears that women may actually require different medication dosing levels depending on where they are in their menstrual cycle</span>. Additionally, post-menopausal drugs such as estradiol patches may also alter the drug effects of certain ADHD medications such as amphetamines. The main culprits are most likely fluctuating levels of estrogen and progesterone.<br /><br />Here are brief summaries on some of the relevant studies and their findings. Wherever possible, I will include a link to the original studies:<br /><ul><li>The link between Estradiol treatment and amphetamine medications: This study focused on whether pretreatment with <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/10644899">estradiol played any role in the reaction to amphetamines</a>. The drug used in this study was D-Amphetamine, which would correspond to the medication Dexedrine, however, this is also the predominantly active compound in medications such as <span style="font-weight: bold;">Adderall</span> or <span style="font-weight: bold;">Vyvanse</span> (once this "pro-drug" is metabolized). It is unclear at the moment whether chemical "cousins" to amphetamines, such as methylphenidate (<span style="font-weight: bold;">Ritalin</span>, <span style="font-weight: bold;">Concerta</span>, <span style="font-weight: bold;">Daytrana</span>, <span style="font-weight: bold;">Metadate</span>), also exhibit these fluctuations when combined with estradiol-releasing drugs. <br /><br />The study found that for females who took estradiol-supplementing treatments during the early follicular phase (pre-ovulation) of the menstrual cycle experienced an overall greater "stimulating" effect of the amphetamine medication (taken as 10 mg of amphetamine). <span style="font-style: italic;">This may suggest that a slightly lower dosage during this stage of the menstrual cycle might be warranted, and </span>(as this blogger's personal hypothesis)<span style="font-style: italic;"> may actually affect the addiction potential of ADHD stimulant drugs such as amphetamines.<br /><br /></span></li><li><span style="font-style: italic;"><span style="font-style: italic;"><span style="font-style: italic;"></span></span></span>Another<span style="font-style: italic;"> </span>study by the same group found that estrogen may be responsible for some of the heightened euphoric<span style="text-decoration: underline;"></span> effect felt from amphetamine-based drugs. However, the <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/10445374">hormone progesterone may actually counteract some of this euphoria</a>. During the luteal phase of the menstrual cycle (after ovulation), high levels of both estrogen and progesterone are seen (although levels of both of these taper off going into menstruation), so the effects of estrogen may be curbed.<span style="font-style: italic;"> </span>During the late follicular phase, where progesterone levels are low and estrogen levels begin to spike, the "high" may be at its peak, especially if stimulants are involved. <br /><br /></li><li>A case study found that an <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/15723425">increase in inattentive symptoms coincided cyclically with the menstrual cycle</a> for a patient who was undergoing treatment for newly-diagnosed ADHD with a twice-daily dosing regimen of the stimulant medication <span style="font-weight: bold;">Concerta</span>.<br /><br /></li><li>The findings from these two studies suggest the possibility that a slightly smaller dosing schedule with amphetamine-based ADHD medications (such as Adderall, Vyvanse or Dexedrine) may be warranted during the follicular phase. However, during the luteal phase, when progesterone levels are higher, the amphetamine-based effects are less pronounced. This may correlate to a slightly higher dosing regimen for amphetamine-based treatment for ADHD and related disorders.<br /><br /></li><li>While there is a relatively good theoretical basis for this assertion above, practical consideration measures must also be considered. Based on the relative scarcity of studies (besides the 2 mentioned above) on the amphetamine-menstrual cycle interactions, it is unclear as to how pronounced the medication change should be. <br /><br />For instance, should someone taking 10 mg of Adderall during the follicular phase boost up to 15 mg for the luteal phase? 20 mg? 30 mg? Additionally, hormonal fluctuations vary during the phases themselves, such as the estrogen spike during the late follicular phase. Questions abound, especially when dealing with the brief ovulatory phase as well.<br /><br /></li></ul>This blog post hopefully introduces what may be a new consideration to women who have ADHD and are currently taking stimulant-based medication treatments. Perhaps this posting simply confirms what you have already experienced. <br /><br />Nevertheless, given the fact that administering variable levels of medication based on cyclical patterns such as time of day (<a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/10511066">like ramping up methylphenidate concentrations via controlled release formulations to offset "acute tolerance" based effects</a>), and the fact that <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/16458365">individuals with ADHD may experience seasonal variations in symptoms</a>, at least <span style="font-style: italic;">suggests</span>, that<span style="font-style: italic;"> variable dosing of medications across the near-monthly period of the menstrual cycle may prove to be beneficial treatment strategy for females with ADHD.</span>The ADHD Treatment Guidehttp://www.blogger.com/profile/00747782650821771627noreply@blogger.com14tag:blogger.com,1999:blog-2736612052295099842.post-75248711277438176232009-05-14T12:42:00.006-04:002009-05-14T13:58:32.720-04:00Long Wave Infrared Imaging: A new detection method for ADHD?<strong>Detecting ADHD using the long-wave infrared spectrum:</strong><br /><strong></strong><br />I always enjoy covering new breakthroughs in the diagnosis and treatment methods in the medical field. A new study just came out which may have a number of potential applications to aid in the diagnostic process of ADHD, which I believe is worth sharing. Called Long-Wave Infrared Imaging, this method utilizes the infrared spectrum to detect biological activity (namely bloodflow patterns) via the differences in radiation emitted by these activities. The study, titled <em><a href="http://www.ncbi.nlm.nih.gov/pubmed/19429882"><span style="color:#3333ff;">Sensitivity and Specificity of Longwave Infrared Imaging for Attention-Deficit/Hyperactivity Disorder</span></a></em>, found that this method may be a surprisingly powerful way of separating ADHD from other related disorders, aiding in the always-difficult process of differential diagnosis. <br /><br /><strong>The basics of Long-Wave Infrared Imaging:</strong> <br /><br />The term "long-wave" is a relative term, of course, referring to wavelengths of approximately 10 nanometers (or only one <em>one-hundred millionth</em> of a meter). Differential bloodflow patterns can result in temperature differences by a <em>full degree</em> (Celsius), making this technology useful in tracking bloodflow disorders. A recent publication in the Journal of Medical Physics by <a href="http://www.jmp.org.in/article.asp?issn=0971-6203;year=2009;volume=34;issue=1;spage=43;epage=47;aulast=Bagavathiappan"><span style="color:#3333ff;">Bagathaviappan and coworkers</span></a> suggests describes how this long-wave infrared imaging can detect areas in the circulatory system where bloodflow activity is sluggish or reduced. Typically, these areas appear "cooler" on the spectrum, due to the lack of a new, replenishing blood supply.<br /><br /><strong>Applications for ADHD:</strong><br /><br />A number of studies have confirmed the hypothesis that individuals with <a href="http://www.ncbi.nlm.nih.gov/pubmed/15486990"><span style="color:#3333ff;">ADHD have reduced bloodflow levels marking a recuction of activity to multiple key brain regions</span></a>. Additionally, while several disorders have a number of overlapping symptoms (which can make the diagnostic process more complicated, especially if multiple comorbid disorders are present), differential blood flow patterns to the brain may be able to help make these distinctions. For example, <a href="http://adhd-treatment-options.blogspot.com/2009/01/adhd-vs-ocd-brain-regions-and-bloodflow.html"><span style="color:#3333ff;">blood flow patters to the brains of ADHD and OCD</span></a> (<strong>Obsessive Compulsive Disorders</strong>) can show pronounced differences, which can aid the diagnostic process between these two disorders (while ADHD and OCD are often considered to be on "opposite" ends of the spectrum with regards to neuro-chemical signaling levels, these two disorders can often exhibit similar symptoms, such as a severe impairment in the response to verbal directions. This is especially true in younger children).<br /><br />This technology may even be extended to measuring or predicting which medications may work for an individual diagnosed with ADHD, based on blood flow in specific localized brain regions. Cerebral blood flow patterns may help predict the response to common ADHD drugs such as methylphenidate (Ritalin, Concerta, Metadate, Daytrana). For example, a study by Cho and coworkers found <a href="http://www.ncbi.nlm.nih.gov/pubmed/16839567"><span style="color:#3333ff;">increased blood flow in at least three different brain regions for individuals who showed poor response to methylphenidate treatment</span></a> compared to their peers who did show improvements under the drug. <br /><br />While the medication response study was done utilizing a different type of brain imaging device known as <a href="http://en.wikipedia.org/wiki/Single_photon_emission_computed_tomography"><span style="color:#3333ff;"><strong>SPECT</strong></span></a>, which utilizes gamma rays and radioactive tracers to detect brain activity in 3-dimensional patterns. While SPECT has proven to be an extremely powerful and effectively safe method of detection (the radioactive isotope used in this method is relatively non-invasive and breaks down quickly, and the gamma rays are carefully controlled), concerned parents may still have an inherent fear of the terms "radioactivity" and "gamma rays" tend to shy away from this powerful detection method on their kids. <br /><br />While this blogger personally has a very high opinion about the use of SPECT as a diagnostic tool for ADHD and related disorders, it is at least worth mentioning the possibility that long-wave infrared imaging methods may be a viable alternative method in at least some of these imaging cases (SPECT technology has been around for over 30 years, but the recent advances in computational power resurrected this technology in the very recent past, similar possibilities may abound by this infrared technology, which has been around even longer). <br /><br />Keep in mind that the studies utilizing this range of infrared imaging technologies for detecting and differentiation disorders such as ADHD are still relatively scarce. Nevertheless, long-wave infrared imaging appears (at least in this blogger's personal opinion) to be a powerful diagnostic tool for ADHD and related disorders in the near future.The ADHD Treatment Guidehttp://www.blogger.com/profile/00747782650821771627noreply@blogger.com1tag:blogger.com,1999:blog-2736612052295099842.post-35992826375908307592009-05-09T23:38:00.006-04:002009-05-10T02:08:22.356-04:00ADHD and Seasonal Affective Disorder<span style="font-weight: bold;">ADHD and Seasonal Affective Disorder (SAD):</span> <span style="font-weight: bold;">Are they Linked?</span><br /><br />Is it possible that ADHD is a seasonally fluctuating disorder? It sounds intriguing, but remember, for diagnostic purposes, classic ADHD symptoms such as hyperactivity, impulsiveness and inattentive behaviors (beyond the normal range of age-appropriate behavior) must persist for a set period of time (the typical cutoff is 6 months for most cases). Nevertheless, it is worth investigating whether there is any sort of seasonal pattern to the disorder. If there is, there could be far-reaching implications such as medication dosages (if diagnosed or initially treated during a "high ADHD symptom" period may result in effects of over-medication for the rest of the year, while initial dosing during a "low-tide" season of ADHD symptoms may prove inadequate in the later months).<br /><br />Intuitively, we would probably assume that ADHD symptoms would be worst during the dark winter months, but is there any data to support this hypothesis? As it turns out, there may be. Here are the results of a few relevant studies on the apparent connection between ADHD and seasonal related psychological disorders:<br /><br /><ul><li><span style="font-weight: bold;">Seasonal Affective Disorder (SAD) symptoms overlap and co-exist at higher rates in those with ADHD:</span> A study by Levitan and coworkers on <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/10428184">seasonal affective symptoms in adults with ADHD</a> found that the prevalence of seasonal affective disorders was higher in the ADHD population than in the general population. This study accounted for some of the obvious factors such as geography (someone in Seattle would be more prone to seasonal related disorders than, say, someone in San Diego).<br /><br />Perhaps not surprisingly, the rate of appearance of seasonal affective symptoms was higher in women with ADHD (in general, depressive-like disorders such as SAD are more common in women in general). However, other interesting comparisons were seen, such as the prevalence of seasonal affective symptoms in the inattentive subtype of ADHD (as opposed to the hyperactive/impulsive or "combined" subtypes of the disorder). While this subtype connection may be interesting, it is important to remember that comorbid depression is often seen more in the inattentive-dominant forms of ADHD than the hyperactive-impulsive forms of the disorder.<br /><br /></li><li><span style="font-weight: bold;">Overlap in medication treatments for ADHD and SAD:</span> While we should be careful not to simply lump a bunch of disorders together just because they share similar treatment methods, the relationship between SAD, ADHD and medications such as <span style="font-weight: bold;">buproprion</span> (<span style="font-weight: bold;">Wellbutrin</span>) may be worth noting. Bupropion has shown to be clinically effective in the treatment of a whole spectrum of disorders including <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/17309340">seasonal affective disorders</a>.<br /><br />Additionally, this medication has shown its far-ranging capabilities, due, in part to its success as both an anti-depressant and "pseudo-stimulant" (of course there is a heated debate among professionals as far as whether "Wellbutrin" should even be mentioned in the same sentence as "stimulant", but its unusual, and relatively unknown mode of action keep it from an exclusive anti-depressant label, at least in the classical sense).<br /><br />The reason I personally use the term "pseudo-stimulant" is that <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/17309340">bupropion can function as a dopamine reuptake inhibitor</a> (which is one of the major modes of action of several ADHD stimulant medications and is typically uncharacteristic of most anti-depressants which often predominantly target the brain chemical serotonin). This may be evidenced by <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/11156812">bupropion's relative effectiveness in treating ADHD</a> (please note that bupropion or Wellbutrin is still extensively used in ADHD treatment in place of a stimulant if there is some type of depressive related disorder, however, findings such as the one in this <a style="color: rgb(51, 51, 255);" href="http://ajp.psychiatryonline.org/cgi/content/full/158/2/282">previous study</a> seem to indicated that buproprion may be effective for treating free-standing ADHD <span style="font-style: italic;">without</span> comorbid depression).<br /><br />While again, I should reiterate that similar treatment methods does <span style="font-style: italic;">not</span> <span style="font-style: italic;">necessarily</span> equate to similar disorders or conditions, the relative effectiveness of this medication for treating both disorders at least leaves the door open for the <span style="font-style: italic;">possibility</span> that there exist similar underlying modes of action between ADHD and SAD.<br /><br /></li><li><span style="font-weight: bold;">The connection between ADHD and circadian rhythms:</span> While SAD, by definition is a seasonal (as opposed to daily) issue of cyclical patterns of time, it is worth mentioning that new research is being done with regards to differences in the chronological patterns in the bodies of individuals with ADHD. In other words, <span style="font-style: italic;">there may be an actual scientific explanation behind the reasons why your ADHD child likes to stay up until three in the morning on a consistent basis</span>.<br /><br />There also appears to be an affiliation with daily rhythms and ADHD subtype. For example, while impulsivity is often more associated as a "morning" behavior, the <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/19387003">inattentive subcomponent of ADHD appears to be more affiliated with the evening</a>. This may factor into the differences in sleep patterns and <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/19110891">prevalence of sleep disorders in ADHD children</a>, and may even highlight the daily schedule differences between the ADHD subtypes.<br /><br />If the hypothesis that individuals with ADHD are at least partially predisposed to different patterns of circadian rhythms compared to the general population, it may stand to reason that these same individuals may also be more susceptible to seasonal fluctuations. Some studies confirm this possible "double" association of <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/17954143">ADHD to both seasonal fluctuations and circadian rhythms</a>.<br /><br /></li><li><span style="font-weight: bold;">Overlapping treatment strategy of Light Therapy for ADHD and SAD?:</span> There has been a recent surge of evidence that <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/8984852">light therapy</a>, when administered at the <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/16165105">correct wavelengths</a>, is an effective treatment for seasonal affective disorder (and often with <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/17683643">measurable levels of success</a>), may now be useful for treatment in the ADHD population.<br /><br />As an interesting aside, there may be some unusual side effects of ADHD stimulant medications with regards to light therapy. A case study of a single child noted that there may be a possible connection between <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/18362880">methylphenidate and photophobia</a> (photophobia referring to fear of or excessive sensitivity to the light). Of course this observation was limited to just one patient, but the correlation of the symptoms with methylphenidate treatment at least suggests the possibility that this is a possible (albeit) rare side effect of one of the most popular stimulant medications for ADHD currently on the market.<br /><br /><span style="font-style: italic;">Blogger's side note:</span> it is also worth mentioning that this case report was also published by the same individual who brought us the <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/19153945">interesting case study</a> which became the topic of an earlier post in this blog: <a style="color: rgb(51, 51, 255);" href="http://adhd-treatment-options.blogspot.com/2009/02/excessive-talking-as-potential.html">excessive talking as a potential side effect of methylphenidate treatment</a>. I will refrain from making any comments or conclusions about this, but on a personal note, I actually enjoy reading about some of these unique side effect case studies of the popular drug, and wonder if this will result in an increased level of vigilance with regards to monitoring odd side effects of common ADHD stimulant medications in both clinical studies and individual prescriptions.<br /><br /></li><li><span style="font-weight: bold;">Omega 3 (n-3) fatty acid deficiency: A common underlying factor for both ADHD and seasonal affective disorders? </span>I saved what is perhaps the best explanation for last. It consistently has been shown that individuals with <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/16962757">ADHD are often deficient in omega-3 fatty acids</a>. We have even discussed the <a style="color: rgb(51, 51, 255);" href="http://adhd-treatment-options.blogspot.com/2009/01/omega-3-fatty-acids-and-adhd-theory.html">theory behind omega-3 fatty acid supplementation for ADHD</a> in earlier bloggings. Now it appears that <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/18716175">omega-3 deficiencies may disrupt circadian rhythms</a> as well, possibly due to an impairment in melatonin production (<span style="font-weight: bold;">melatonin</span> is a hormone which is tightly associated with the sleep-wake cycle and hence has implications on the circadian rhythm patterns in a particular individual). <br /><br />This may suggest that omega-3 fatty acid deficiencies may either help cause, or exacerbate the severity of both ADHD and circadian rhythm impairments. Interestingly, there is some evidence that omega-3 supplementation may be beneficial in treating seasonal affective disorders as well. In fact, <a style="color: rgb(51, 51, 255);" href="http://ajp.psychiatryonline.org/cgi/content/full/158/2/328">diets rich in omega-3's</a> may be an underlying reason why <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/10671392">seasonal affective disorders are relatively uncommon in Iceland</a>, which, due to its far-northern location, experiences exceptionally long, dark winters.<br /></li></ul>While I admit that the evidence for the link between ADHD and Seasonal Affective Disorders is nowhere near as strong as for other ADHD comorbid issues (such as Tourette's, anxiety, conduct disorders, and learning disabilities), I still wanted to pass on some of the information out there supporting a possible link between the two disorders. Given the close associations both between depression and seasonal affective disorders, including the argument that <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/18589628">SAD should be labeled as a specific subtype of depression</a>, and the high rate of comorbidity between <a style="color: rgb(51, 51, 255);" href="http://www.ncbi.nlm.nih.gov/pubmed/16135620">ADHD and depressive disorders</a>, there is certainly a possibility that the magnitude of overlap between ADHD and SAD is greater than we might imagine.The ADHD Treatment Guidehttp://www.blogger.com/profile/00747782650821771627noreply@blogger.com10