Friday, March 12, 2010

ADHD and Vitamin D Deficiency: Any Evidence?

Is there any link between vitamin D levels and ADHD? A review of the current evidence:

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, it does not necessarily mean that this deficiency is the cause of ADHD (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.

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 Pubmed (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.

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. 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. Nevertheless, here are some possible ways in which vitamin D may help in cases of ADHD or related disorders:

  • Vitamin D can boost levels of the antioxidant glutathione in the brain. One way that vitamin D does this is by regulating an enzyme called gamma-glutamyl transpeptidase, 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 omega-3's) are frequently administered for ADHD and related disorders. Given the high makeup of these omega-3 fatty acids in the brain, and their susceptibility to oxidation and damage in the central nervous system, protecting them by boosting antioxidant levels (either directly or indirectly) is a good bet.

  • One of the current theories surrounding ADHD is that it is (at least partially) an energy deficiency syndrome, 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.

    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 vitamin D works by targeting multiple enzymes 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.

  • Vitamin D may play a role in catecholamine synthesis. Catecholamines include the neurotransmitters dopamine and norepinephrine, 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).

  • Vitamin D boosts the effects of an enzyme called choline acetyltransferase in the mammalian brain. This enzyme is used in the manufacture of another neurotransmitting agent called acetylcholine. Acetylcholine is thought to play a major role in maintaining a state of sustained attention, 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.

  • Learning and memory deficits, 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 synaptic plasticity, 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.

  • Problems with fine motor control are sometimes seen as a secondary characteristic in a fraction of the ADHD population. These problems may be exacerbated in a vitamin D deficient state.

  • Perhaps the strongest correlation, however, may be between vitamin D and depressive-like symptoms, particularly those associated with seasonal affective disorders (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 ADHD and SAD in an earlier post.

    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.
To summarize: 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 vitamin D intake can be found here.

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Thursday, February 25, 2010

Do Tyrosine Supplements for ADHD Actually Work? (part 8)

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. 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.

(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).

We have spent the past seven postings on the pathway of tyrosine metabolism and the implications of supplementing with this amino acid nutrient (and its derivatives for ADHD). But does it actually work?

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:

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.

Potential advantages of tyrosine supplementation for ADHD:

  • Tyrosine is a precursor to common neurotransmitters believed to be involved in ADHD (neurotransmitters are chemicals involved in various signaling or messaging processes in the nervous system) dopamine, norepinephrine 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.

  • Tyrosine can readily cross the blood brain barrier. This barrier has been discussed extensively elsewhere, but, in summary, the blood brain barrier is responsible for the passage of nutrients and metabolic products in and out of the brain (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.

  • As a "natural" and common amino acid, tyrosine is something the body already is accustomed to metabolizing through the diet. Note that tyrosine shares several enzymes and transporters with other amino acids and nutrients.

  • Numerous anecdotal reports have found tyrosine to be useful for comorbid (co-existing) disorders to ADHD, such as depression. 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.

  • Tyrosine is a good starting point for nutrient-based treatments in metabolic disorders involving the amino acid phenylalanine (such as phenylketonuria). 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).

  • Numerous anecdotal reports involving tyrosine supplementation for ADHD symptoms have indicated positive results (at least initially, we will see, however, that many of these benefits are often short-lived).

  • Many physicians have (and continue to) prescribe tyrosine for ADHD 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.)

  • Tyrosine may be used in conjunction with medications for ADHD 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). In this blogger's opinion, this may be the strongest potential use of tyrosine (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.

  • 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).

  • The enzymes responsible for tyrosine metabolism 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.

Disadvantages to tyrosine supplementation for ADHD:

  • Beneficial responses of tyrosine for ADHD treatment are often short lived (and usually disappear within 2 to 4 weeks, as the body appears to "adapt" or tolerate the higher levels of tyrosine supplementation.

  • In most cases, the imbalances of dopamine and norepinephrine are believed to be due as much to the transporters (or agents which shuttle these chemical in and out of the neuronal cells) or receptors (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, genetics appears to play a role as to the extent of how a certain transporter or receptor functions, and genes may even affect dosage requirements for certain ADHD medications (such as Adderall, or Strattera). 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.

  • Localization is a problem. Imbalances of dopamine and norepinephrine in ADHD are often seen only in a handful of specific brain regions, so flooding the whole system with tyrosine may not be conducive to zeroing in on these target brain regions. Interestingly, however, the synthesis of monoamine neurotransmitters such as dopamine and norepinephrine may not be tied down entirely to specific brain regions, as there may be some flexibility as to where these chemicals are generated based on the demands (and failures) of other parts of the brain and central nervous system.

  • 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 homocysteine is one such example, and has been discussed at length in a previous tyrosine for ADHD blog post.

  • 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.

  • As mentioned earlier, tyrosine can "compete" with other amino acids 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 tyrosine to dopamine/norepinephrine pathway and the tryptophan to serotonin pathway, 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.

  • 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.
Ways to improve the effectiveness of tyrosine supplementation for ADHD:

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.

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 long-term 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.

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).

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):

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:

A quick summary of this blogger's overall thoughts and advice on tyrosine supplementation for ADHD:

  • 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.

  • 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).

  • 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.

  • Please note that while "natural", tyrosine supplementation is not always benign. 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.

  • 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.

  • 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. 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.

  • This blogger personally believes that tyrosine supplementation may be of much greater benefit if used in conjunction with a medication (often a stimulant or other dopamine "releasing" agent). Please note that these supplement-drug interactions may be extremely potent, so please only do this under the supervision of a physician.
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.

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Thursday, February 18, 2010

Do Tyrosine Supplements for ADHD Actually Work? (part 7)

Homocysteine Buildup: The (Potential) Dark Side of Tyrosine and L-DOPA Supplementation for ADHD

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):

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 ascorbic acid (a.k.a. vitamin C, which has a number of connections to ADHD) and S-Adenosyl methionine (also known as SAM or SAMe, which has also been discussed in greater detail in relation to ADHD elsewhere) are required in this process.

Also, a number of enzymes are required to make this process go.

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:

Tyrosine Hydroxylase: (iron, vitamin C, magnesium, zinc, copper, folic acid or folate, niacin). 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)

Dopa Decarboxylase: (vitamin B6, zinc. Also note that excessive levels of some other amino acids, such as leucine, isoleucine, valine, and, especially, tryptophan can compromise this step of tyrosine metabolism. Furthermore, buildup of one of the products of tryptophan metabolism, serotonin, can inhibit or begin to shut down the activity of this Dopa Decarboxylase 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)

Dopamine Beta Hydroxylase: (vitamin C, but also requires additional antioxidants to "recycle" the used vitamin C)

Phenylethanolamine N-methyltransferase: (S-Adenosyl-methionine or SAMe)

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.

Other Pathways of Tyrosine Metabolism and the Generation of Homocysteine

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 potentially 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.

Minerals such as iron, copper and chromium all can be extremely toxic at high levels, and overdosing on certain vitamins (especially the fat soluble ones such as vitamins A and E, 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).

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.

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 homocysteine. 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):

Here we see that tyrosine-derived norepinephrine can be converted to epinephrine (adrenaline) in a process which utilizes the enzyme (phenylethanolamine N-methyltransferasePNMT). 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?

As mentioned in the last post on ADHD and tyrosine, the compound S-Adenosyl Methionine or SAMe, 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.

However, when SAMe does donate it's CH3 methyl group, as in the case above, we are left with homocysteine (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).

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 L-DOPA leads to elevated homocysteine levels in the blood of Parkinson's patients.

Elevated homocysteine levels have been linked from everything from cancer to diabetes to autoimmune disorders to stroke (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).

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.

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.

B vitamin-based nutritional "weapons" which can combat potentially high homocysteine levels arising from tyrosine or L-DOPA supplementation:

  • Vitamin B6 (whose "active" form is known as pyridoxal phosphate. For simplicity, we will just be referring to this compound by its common vitamin name, vitamin B6)
  • Cobalamin (a version of vitamin B12)
  • Folate (a derivative of Folic Acid or Vitamin B9. 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)

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.

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 SAMe. 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). 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.

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.

Path #1: conversion of homocysteine to the amino acid cysteine: 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:

  1. This process requires a specific enzyme called cystathione beta-synthase (don't worry about remembering this enzyme, just remember that this enzyme requires a form of vitamin B6 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 L-DOPA to dopamine. Thus, it is doubly important that we don't come up short on this vitamin.

    A rough summary of recommended dosage levels for B6 will be given at the end of this post (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 serine. 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 genetic defect on serine metabolism).

  2. The conversion of homocysteine to cysteine is (largely) irreversible. 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).

Path #2: the conversion of homocysteine to the amino acid methionine: While path #1 is dependent on one type of B vitamin (B6), this pathway is dependent on 2 different B's: a form of vitamin B12 and a derivative of folic acid (vitamin B9). Without going into too much detail, this process requires a methyl (CH3) "donor" (which, in this case, is the modified form of folic acid here. This is very similar to like way the nutrient SAMe acts in helping the conversion from norepinephrine to epinephrine as mentioned earlier).

Please note that, unlike the last case, this process is chemically reversible (which means that the process can go backwards and regenerate homocysteine to a certain extent). This process also requires a special enzyme called homocysteine methyltransferase. Again, don't worry too much about this enzyme, just note that it requires a form of vitamin B12 to function.

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.

Perhaps not surprisingly, taking B12 (also known as cobalamin) and a form of folic acid (folate) together has shown to be advantageous in a number of cases. Combinations of folate and cobalamin have also shown to be useful in reducing homocysteine levels in those treated with L-DOPA.

A quick summary on using B vitamins to reduce potential homocysteine buildup from tyrosine (or L-DOPA) supplementation:

  • Homocysteine 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.

  • Vitamin B6 can be used to help "shunt" homocysteine to a common (and typically less-harmful) amino acid known as cysteine. This process is (essentially) irreversible. B6 is also a requirement for an earlier step of the tyrosine or L-DOPA metabolic process, the conversion of L-DOPA to dopamine.

  • Vitamin B12 and folic acid can both assist in the conversion of homocysteine to another amino acid, methionine. Unlike the cysteine conversion process above, this process is reversible, meaning that it is possible to "work" backwards towards homocysteine in a bi-directional pathway.

  • 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 (but be careful about over-supplementing, 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 ADHD and nutrient deficiencies).

  • Here are some good sites which list the suggested daily amounts for folic acid (folate), vitamin B6 and vitamin B12. Going slightly higher is often fine (as these agents have relatively high "ceilings" between recommended amounts and toxicity levels), but try to keep the ratio 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.

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.

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Friday, February 12, 2010

Does Tyrosine Supplementation for ADHD Actually Work? (Part 6)

Can we use tyrosine as an effective supplement to treat ADHD symptoms?

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 of the symptoms related to ADHD.

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:

Here's a quick recap on our last 5 discussions on ADHD and tyrosine:

Post #1 on ADHD and tyrosine: 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 blood-brain barrier, a biochemical barrier which controls the transport of drugs, nutrients and toxins in and out of the brain.

Post #2 on ADHD and tyrosine: here we analyzed the first step of tyrosine metabolism, in which tyrosine is converted to another compound L-DOPA (a common treatment method for Parkinson's patients). This step heavily involves the enzyme tyrosine hydroxylase. 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 iron, vitamin C, magnesium, zinc, folic acid (namely folate or vitamin B9) and overall adequate antioxidant levels. Secondary nutrients (necessary for enzymes which lead up to the formation of some of the products used by the tyrosine hydroxylase enzyme) include copper, and (as we'll see later on in the tyrosine metabolic pathway), vitamin B12. 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.

Post #3 on ADHD and tyrosine: 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.

Post #4 on ADHD and tyrosine: 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 DOPA decarboxylase. Like the tyrosine hydroxylase enzyme in the step before it, DOPA decarboxylase also requires nutrient co-factors to optimally function. The main nutrient requirement of this enzyme, however, is a specific form of vitamin B6, known in this case as pyridoxal phosphate. In addition to requiring adequate vitamin B6 levels to function properly, we also saw that other amino acids (namely tryptophan), can actually interfere and even compete with this process, so the post ended with the recommendation to avoid taking in tryptophan-rich foods (which were listed in this fourth post) at the same time as tyrosine was being supplemented.

in post #5 on ADHD and tyrosine supplementation, 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 dopamine beta hydroxylase. Interestingly, the gene coding for this enzyme (which goes by the same name, the dopamine beta hydroxylase gene and is located on the ninth human chromosome), has been implicated as a potential hereditary factor for ADHD. Like the aforementioned tyrosine hydroxylase the dopamine beta hydroxylase enzyme is heavily dependent on ascorbic acid (vitamin C) as a cofactor, 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.


Moving on to our sixth post in our series on ADHD and tyrosine, 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 phenylethanolamine methyltransferase, or PNMT for short. Interestingly, the gene which "codes" for this enzyme, also called PNMT, has been linked to a common behavioral sub-component of ADHD called cognitive impulsivity. The PNMT gene is located on the 17th human chromosome.

In contrast to the other main type of ADHD-styled impulsivity, known as aggressive behavioral impulsivity (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.

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.). Cognitive impulsivity is therefore more reflective of the inattentive subtype of ADHD (which is often more frequently seen in girls, and is often more easy to overlook than the other subtypes of ADHD).

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. 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 PNMT gene) may, 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!)

Returning from our aside on the possible genetic relationship between the Phenylethanolamine N-methyltransferase (PNMT) 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: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 Phenylethanolamine N-Methyltransferase (PNMT) enzyme.

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 S-adenosyl-methionine (as depicted in the diagram above by the downward arrow) comes into play.

S-adenosyl-methionine often goes by other shorter names in the literature and in the grocery aisle, it is often referred to simply as SAMe or just "SAM". We will refer to it as "SAMe" from this point onward.

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 methionine. 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) is a relatively rare property among dietary nutrients, so SAMe does have a number of biochemical implications as a potential supplementation strategy.

As far as psychiatric disorders are concerned, SAMe is a particularly well-known natural supplement for treating depression, 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 Alzheimer's and Parkinson's 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 SAMe and ADHD (only 8 people!) showed relatively positive results, however.

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 PNMT enzyme and the SAMe nutrient is another compound called homocysteine.

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 ADHD, alcoholism and nutrient deficiencies. 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.

However, the three main points we should take away from this post on tyrosine supplements and ADHD are as follows:

  • 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.
  • For the brain regions that do accommodate the norepinephrine to epinephrine conversion process, an adequately functioning enzyme called Phenylethanolamine N-Methyltransferase (or PNMT) is required.
  • In order for the PNMT enzyme to do its job in converting norepinephrine to epinephrine (adrenaline), adequate supplies of the nutrient S-Adenosyl-methionine (SAMe) are required. This process, however, can leave us with a potentially hazardous byproduct called homocysteine, 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.

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Thursday, February 11, 2010

Does Tyrosine Supplementation for ADHD Actually Work? (Part 5)

Part 5 on a series of posts on Tyrosine supplements for ADHD Treatment

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?

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 dopamine, norepinephrine, and epinephrine (adrenaline) and the implications for this on the biochemical factors involved in the onset and treatment of attention deficit hyperactivity disorder.

  1. In part 1 of our series on ADHD and tyrosine supplementation, 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 blood brain barrier, 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.

  2. In part 2 of the tyrosine and ADHD discussion, we looked at the enzyme Tyrosine Hydroxylase, 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.

  3. Part 3 of the ADHD/tyrosine blog series 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, L-DOPA (also called Levodopa). 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 ADHD.

  4. and finally, Part 4 of the tyrosine 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 aromatic amino acid decarboxylases, with the main enzyme of focus being a specific type called DOPA decarboxylase. In order for these enzymes to function, however, we discussed their dependence on a compound called pyridoxal phosphate (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.
And now, for part 5: the conversion process of the neurochemical dopamine to another neurochemical, norepinephrine...

*Blogger's note:
What follows is a lengthy explanation of why dopamine and norepinephrine are so important for ADHD, and how they interact with specific proteins called "transporters" or "receptors" 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 (***).

***Begin explanatory section on dopamine and norepinephrine and ADHD

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).

First, we need to address the all-important question, however: Why is the conversion of dopamine to norepinephrine important with regards to treating ADHD? 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:

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 more with the transport process 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.

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), 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. 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.

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.

#1) The receptors:

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 certain genetic forms of these "receptor genes" are often associated with a higher likelihood of having ADHD.

For example, some of the earliest posts on this blog looked at specific genes that coded for dopamine receptors, such as the Dopamine D4 receptor gene (DRD4) and the Dopamine D5 receptor gene (DRD5) . The DRD4 gene is believed to be one of the most "heavily" influencing genes out there with regards to ADHD genes, while the DRD5 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).

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 ADRA1A. ADRA1A is a gene located on the 8th human chromosome, and is believed to code for a specific receptor of norepinephrine. In fact, there are some implications that having a particular form of this ADRA1A gene may even influence the effectiveness of medications such as clonidine (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).

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.
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). 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. If you're interested, an earlier post talked about some of the specific genes, receptors and transporters, and how some of these "ADHD genes" may even play a specific role on how we should dose ADHD medications.

#2) The transporters

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. In other words, these dopamine and norepinephrine tranporters also play a vital role in the process.

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 dopamine transporters (called the dopamine transporter gene or DAT), and for norepinephrine transporters (called the norepinephrine transporter gene or NET, however, it is also referred to by another completely different name: SLC6A2) 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 bulimia, drug addiction, anxiety disorders, etc.

*In other words, 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.***

***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:

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):

From the above picture, we should note the two main components which need to be addressed in the dopamine to norepinephrine conversion process:
  1. The enzyme Dopamine Beta Hydroxylase, and
  2. The nutrient ascorbic acid (aka vitamin C), especially with its regard to oxygen (O2), as depicted above.
Dopamine Beta Hydroxylase enzyme: We have examined Dopamine Beta Hydroxylase (often abbreviated as DBH) several times in previous posts. The gene coding for the DBH enzyme (of which the gene shares the same name, "DBH") is located on the 9th human chromosome. This enzyme is responsible for adding a hydroxyl (-OH) group off of the dopamine molecule, which leaves us with the new neuro-chemical norepinephrine. 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).

*Please note: It is important to note that oxygen 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

Ascorbic Acid (vitamin C):
We mentioned vitamin C in an earlier post, in that it can play a "helper" role in the conversion of tyrosine to L-DOPA, a process which utilizes the enzyme tyrosine hydroxylase. Tyrosine hydroxylase 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 tyrosine hydroxylase enzyme, 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 tyrosine hydroxylase enzyme to be significantly compromised in vitamin C deficient states (as in scurvy).

However, while tyrosine hydroxylase the enzyme Dopamine Beta Hydroxylase appears to be even more heavily dependent on vitamin C, as mentioned in an earlier blog entry titled: 10 Ways Vitamin C Helps Treat ADHD Symptoms (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 dopamine beta hydroxylase enzyme, which is used to convert dopamine to norepinephrine, vitamin C is used more of as a "co-factor" or "helper" to the enzyme.

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 dehydroascorbate.

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 how vitamin C can help in preventing omega-3 oxidation in ADHD treatment cases. Vitamin C often helps "recycle" other antioxidants such as vitamin E (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).

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 glutathione), 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 vitamin C requirements can be found here.

However, since toxicity is rarely an issue with vitamin C (see the upper limits of the vitamin here, 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 tyrosine hydroxylase enzyme for the conversion of tyrosine to L-DOPA and the dopamine beta hydroxylase 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.

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 homocysteine. 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 adjunct or accessory treatment to common ADHD medications, possibly optimizing their function and improving their effectiveness in treating ADHD and related disorders.

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Wednesday, February 10, 2010

Does Tyrosine for ADHD Actually Work as a Supplementation Strategy?(part 4)

We're attempting to answer the major question: Can ADHD symptoms be reduced via controlled supplementation with the amino acid tyrosine?

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:

  1. The different enzymes and enzyme systems used in tyrosine metabolism
  2. Which (if any) nutrient "helpers" or "co-factors" are required by these enzyme systems to function properly, and
  3. The implications these have on the neuro-biology of ADHD
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).
As a quick recap:
  1. In tyrosine and ADHD post #1, 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).

  2. In the second post on ADHD and tyrosine, we focused on the first step of the process, the conversion of tyrosine to L-DOPA. This step heavily utilizes a specific enzyme called tyrosine hydroxylase. Tyrosine Hydroxylase is dependent on adequate supplies of certain nutrients such as iron, magnesium, zinc, tetrahydrobiopterin, and adequate levels of vitamin C (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 tyrosine hydroxylase enzyme. It is important to note that the conversion of tyrosine to L-DOPA is typically the slowest and rate-limiting step of the whole tyrosine metabolism and conversion process to dopamine and norepinephrine. 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.

  3. The third post on tyrosine and ADHD focused more on the question as to whether we could bypass the first step of the chemical process outlined above entirely 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.
This brings us to today's post: the conversion of L-DOPA to dopamine. This process is heavily dependent on an enzyme known as DOPA decarboxylase. Here are some of the main components which need to be in place for this enzymatic conversion process to occur with efficiency:

DOPA decarboxylase belongs to a particular class of enzymes called aromatic amino acid decarboxylases. 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 tyrosine, L-DOPA and dopamine shown below:

***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 changing in the pictures above and below, which represents the chemical structure of these different 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".

The enzyme tyrosine hydroxylase simply 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 second blog post on ADHD and tyrosine supplementation. Our next enzyme-driven step leaves this "aromatic" hexagonal ring alone, and instead works on chemically modifying the right side of the molecule, as we'll see in a second. ***

The term originally comes from the fact that chemicals with this type of built-in structure often gave off a particular aroma. Aromatic amino acid decarboxylases 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 decarboxylase enzymes).

Of these decarboxylase enzymes (there are several different variations), the "best" one for this conversion process is called DOPA decarboxylase.

Although DOPA decarboxylase can be indirectly affected by several different nutrients (specifically shortages of nutrients), the main one involved in this step is called pyridoxal phosphate. Pyridoxal phosphate is the chemically "active" form of vitamin B6.

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, getting B6 into this desired pyridoxal phosphate form requires zinc (another reason why adequate zinc levels are necessary for optimal tyrosine metabolism). It also appears that vitamin B6 works well alongside magnesium as an ADHD treatment combination strategy. Finally, vitamin B6 plays a role in the metabolism of omega-3 fatty acids (omega-3 rich fish oil is a common "natural" treatment method for ADHD)

Because of its vital role as a "co-factor" or "helper" of the DOPA decarboxylase enzyme, which is responsible for converting L-DOPA to dopamine, it is imperative that we avoid shortages of this essential B vitamin. A rough estimate of recommended daily intake levels of vitamin B6 can be found here. 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.

In addition to keeping up necessary vitamin B6 levels to help the DOPA decarboxylase 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 DOPA decarboxylase with another common neurochemical signaling agent called serotonin.

Serotonin is generated from another important amino acid called tryptophan. 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.

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.

This is precisely what can happen with the amino acid tryptophan and its product serotonin. The tryptophan to serotonin process also uses these aromatic amino acid decarboxylase enzymes (and interestingly, also uses vitamin B6 as a cofactor in the process. This is yet another reason why we want to keep B6 levels up to speed!).

**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).Additionally, the end product of the above process, serotonin, can also effectively shut the enzyme DOPA decarboxylase down. 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 feedback inhibition, and is a very common and crucial process for retaining chemical balances in the body.

However, if large amounts of tryptophan are present, not only can the crowd out tyrosine for the dopa decarboxylase enzyme, 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.

Actually, make that a triple-whammy. Remember how we mentioned that chemical compounds of similar structure can often crowd each other out? It turns out that tyrosine and tryptophan both compete with each other for transport into the brain. In the first post on this topic, we talked about the blood brain barrier, and how crossing this biochemical barrier was needed to successfully deliver the drug or nutrient-based treatment to the desired brain regions.

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 high in tryptophan can be found here. 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.

So with regards to the second major step of tyrosine supplementation, the conversion of L-DOPA, we should remember these 2 main things:

  1. Keep up adequate levels of vitamin B6 to help the DOPA decarboxylase enzyme function at peak efficiency.
  2. 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.

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