Thursday, April 30, 2009

Bedwetting ADHD Kids and Depressed Dads: Is there a connection?

ADHD and Bedwetting (Nocturnal Enuresis): How are the two related?

There is a relatively recent publication that came out within the last couple of weeks on the relatively high rate of occurrence in bed wetting (enuresis) among ADHD children, which I believe is worth sharing. We have previously investigated this ADHD and bed wetting connection (note that bed wetting may be more likely to be seen alongside the inattentive subtype of ADHD). However, this study offers some additional insight into this strange association between the two disorders. Here are some important points worth mentioning:

  • Overlapping Drug Treatment for ADHD and bedwetting: It stands to reason that if a particular drug or agent is effective in treating multiple disorders, there may be a distinct possibility that those two or more disorders may share some type of underlying cause(s) or defect(s). For example, Tofranil or Imipramine, a drug used to treat enuresis and depressive disorders can possibly be useful as a treatment option for ADHD. We have also investigated the potential role of Reboxetine as a potential ADHD treatment in previous entries. Some work has found Reboxetine to be useful in treating therapy-resistant enuresis as well.

  • Prevalence of Enuresis in ADHD: Enuresis refers to urinary incontinence which is limited to the night-time. Additionally, the term is typically limited to individuals over the age of 5 (i.e. a 3-year-old child who frequently pees in their pants would not be considered as suffering from enuresis, at least in the context of this study). The article cites other studies in which the rate of bedwetting (enuresis) in ADHD is as high as 30%, although other studies have it down around 10-20%. Still, compared to the general population, (factoring in things such as the age of the child, of course)the high rate of bed wetting in ADHD is especially noteworthy. There is some evidence from other studies that ADHD and enuresis may be more intricately linked than previously imagined. For example, one particular study has shown that treating urinary incontinence has a higher rates of failure in children with ADHD vs. non-ADHD children.

  • The role of Oppositional Defiant Disorder (ODD) on Bed wetting: The study examine several different psychiatric disorders which frequently occur alongside of (or are comorbid to) ADHD. These include depression, anxiety disorders, obsessive compulsive disorders, tic disorders, nail biting, bruxism (teeth grinding), conduct disorders and oppositional defiant disorders. However, out of all of these different disorders which often appear alongside ADHD, the only one which exhibited a statistically significant correlation to increases in bedwetting was oppositional defiant disorder. Interestingly, oppositional defiant disorders have been associated with bedwetting in other ADHD studies.

    As its name suggests, Oppositional Defiant Disorder is a disorder in which a child exhibits disobedience, irritability and hostility towards authority figures beyond the range of normal age-appropriate behaviors. Of course there is a significant gray area with regards to what is age appropriate, especially when the child's environment is considered. Nevertheless, Oppositional Defiant Disorder (or ODD) is much more than just routine temper tantrums. Oppositional Defiant Disorders may also be associated with auditory processing issues and ADHD. It is somewhat interesting that anxiety disorders, which have also been correlated to oppositional behaviors, did not elicit a significant positive correlation to bed wetting.

  • The autonomic nervous system as a potential underlying cause of ADHD, bedwetting and Oppositional Defiant Disorders: The autonomic nervous system is the part of the nervous system responsible for involuntary muscle actions such as digestive processes, blood vessel contraction, etc. It is subdivided into the sympathetic and parasympathetic nervous systems, which often act in a sort of "push-pull" opposition to each other. For example, the sympathetic nervous system does things such as boosting heart rate and constricting blood vessels, while the parasympathetic nervous system is in charge of activities such as reducing heart rates and relaxing sphincter muscles (which plays a role in bladder control).

    Typically, the sympathetic and parasympathetic components of the nervous system are kept in balance, but this balance may be thrown out of whack and result in numerous disorders. For example, it is believed that the parasympathetic nervous system is over dominant in cases of Oppositional Defiant Disorders (ODD). The study found that for ADHD and Oppositional Defiant Disordered children, functions such as heart rate were controlled excessively (if not almost exclusively) by the parasympathetic portion of the nervous system (while non-ODD and non-ADHD children had both sympathetic and parasympathetic controls operating on their heart rates. This suggests a common underlying imbalance among the different components of the nervous system which is common to ADHD and ODD individuals and often separates them from the non-ADHD'ers. Interestingly, other studies have indicated that bedwetting or generalized incontinence problems may also be caused by an overactive parasympathetic nervous system, which suggests that ADHD, ODD and night-time bedwetting may all share some underlying causes within the nervous system.

  • Connection to Parental Depression: I personally found this observation to be interesting. The study found that the prevalence of bedwetting in ADHD children was higher if the father (but not the mother) of the child was suffering from some sort of major depressive illness. The article did not express an opinion as to whether these depressive symptoms were due in part to the child's bed wetting problems or whether there was some underlying mechanism at work.

  • ADHD medications may Influence Enuresis: The authors highlight some other works in which popular ADHD medications may either increase or decrease the risk of bedwetting in ADHD children. For example, the article highlighted a case study (by the same author) in which treatment with methylphenidate induced nocturnal enuresis. Methylphenidate is one of the most common ADHD drugs, and often goes by the common trade names Ritalin, Concerta, Metadate and Daytrana (the patch form of the drug). Of course this is based on only one individual case, but for those of you who have read this blog on a frequent basis, will know that I like to report on some of these abnormal occurrences (for reference sake, here is an earlier blog post I have done on the possible connection between methylphenidate and excessive talking. While based on an isolated case report, I believe that this zany potential side effect was at least worth a mention). On the flip side, however, the non-stimulant alternative ADHD drug, Atomoxetine (Strattera) can be a useful treatment for enuresis. This blogger would personally like to see additional studies on whether ADHD children with a comorbid bedwetting condition actually saw a better reduction in their ADHD symptoms while on Strattera than while on methylphenidate. If this were the case, then bedwetting may actually served as a useful tip-off as to which type of ADHD medication would work best for that particular child.

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Sunday, April 26, 2009

Strattera (Atomoxetine) response may be affected by SLC6A2 gene

About a month ago, we were discussing the ADHD gene SLC6A2. Located on the 16th human chromosome, different variations of this SLC6A2 gene are believed to play at least somewhat of a determining factor as to the genetic predisposition towards attention deficit hyperactivity disorders (ADHD). We saw that this gene was also correlated to anxiety and depression-like symptoms (which commonly occur along many ADHD patients) and that these genetic factors were slightly stronger in girls.

Atomoxetine (Strattera) is a non-stimulant alternative to medication treatment for ADHD. Unlike most stimulant medications, which interfere and regulate the pathways of the neurotransmitter dopamine, atomoxetine acts upon the pathway of the neuro-signaling agent norepinephrine. While dopamine-related stimulant medications for ADHD can worsen accompanying anxiety and depressive-like disorders (extreme caution is necessary when prescribing stimulants if a severe co-illness of anxiety or depression is present alongside ADHD), Strattera has shown to extremely beneficial in the co-treatment of depressive-like illnesses, especially when used alongside the SSRI class of antidepressant drugs.

A recent publication in the journal Neuropsychopharmacology highlights the potential connection between variations of the "ADHD gene" SLC6A2 and the effectiveness Strattera (Atomoxetine) for treating ADHD.

It is important to remember that for most genes, there are slight variations in the different forms within the human population. For most, these small changes in DNA do not result in any major physiological differences, but for some, even a change of one or two units of DNA can make a huge impact on biological functions, such as response to a specific medication. We have previously discussed how both the Catechol O-Methyltransferase (COMT) and CREM genes, may both dictate different dosing levels for ADHD medications.

Based on the SLC6A2 and Strattera study, it appears that individuals with specific gene variations of the SLC6A2 gene had a significantly more positive response to atomoxetine (based on a common behavioral rating process typically used to assess ADHD and related disorders), than were others with different variations of the gene. These effects were seen even when another gene (the CYP2D6 gene, located on the 22nd human chromosome and is responsible for the metabolism of atomoxetine/Strattera) was taken into account.

We will hopefully discuss these findings in more detail later, but the main point to drive home from all of this is the concept of how individual gene variation (i.e., which specific forms of a particular gene one has), can play a major role in predicting whether:

  1. An individual will even respond to particular drug (such as Strattera for ADHD), and
  2. Whether that individual's particular forms of these genes predispose him or her to requiring a higher (or lower) than normal dosage level than otherwise physiologically similar individuals to achieve the desired effects.

This blogger personally believes that we have just begun to scratch the surface in investigating the power of gene-medication interactions, and how these interactions will shape the landscape for ADHD treatment.

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Thursday, April 23, 2009

Phenylketonuria (PKU) or ADHD?

ADHD vs. Phenylketonuria: A possible misdiagnosis?

If you’ve never heard or seen the term phenylketonuria (PKU) before, you are not alone. However, here’s a quick experiment. Go look at the back of a 2-Liter bottle of diet soda. Near the bottom of the back label, you will probably see a small warning label that says something along the line of “Phenylketonurics: contains phenylalanine” (individuals with phenylketonuria are often referred to as phenylketonurics).

The reason that this warning is on the back of only diet sodas and not regular ones is because the artificial sweetener Aspartame (Nutrasweet) contains the amino acid phenylalanine as one of its two primary components. When phenylketonurics, take in large amounts of this artificial sweetener, they get a large buildup of this amino acid in their bloodstream which they have trouble clearing. As a result, they often suffer a number of physiological problems, in, but not limited to, the nervous system.

The conversion process of phenylalanine to dopamine and how it relates to ADHD:

Phenylketonurics are those individuals who, for typically genetically predetermined reasons, are unable to break down and process the amino acid phenylalanine. This process actually has several implications that can relate to ADHD. We have spoken extensively about the neurochemical dopamine in various other posts. In general, chemical imbalances of this important neurotransmitter are frequently at the helm of ADHD and related disorders (typically shortages of dopamine are found in the "gaps" between neuronal cells, and most stimulant medications for ADHD work by resetting dopamine levels within these gaps). As we can see below, the body can actually manufacture this important brain chemical from various sources or starting materials, including phenylalanine (providing that the individual is capable of manufacturing all of the necessary enzymes in the conversion process. For PKU patients, this conversion process is hindered, and typically leads to shortages of dopamine). A rough sketch of the conversion process is listed below:

So what’s the point?

I have highlighted the chemical changes above, using different colors to represent the enzymes used and the chemical changes that these enzymes are responsible for (note the red and blue colors). As we can see above, the first step of the metabolism of phenylalanine to dopamine is done by adding a hydroxyl ("OH") group to phenylalanine, converting it to another amino acid, tyrosine. The chemical change is highlighted in red. (As an interesting side note, tyrosine is sometimes used as an ADHD supplement or auxiliary to medication treatment, even though the effectiveness of tyrosine for treating ADHD is questionable. Note that if one with PKU were to start with tyrosine, they would bypass the step of the chemical process of converting phenylalanine to tyrosine, which would help with the deficient enzyme phenylalanine hydroxylase. This enzyme will be addressed further down in the post).

Further modifications carry it to the product dopamine, which require two other enzymes (as a side note, the conversion of tyrosine to dopamine, in addition to the two enzymes listed above, also requires an adequate supply of iron. This is one reason why maintaining ample iron stores is necessary in combating ADHD and related disorders, and why an iron deficiency can elicit some of the negative behaviors characteristic of ADHD patients). As an aside, we have previously investigated how iron deficiency can affect both ADHD and sleep disorders and how iron supplementation can potentially offset the toxic effects of lead in ADHD patients.

You'll notice that the first step of the conversion process is blocked for individuals with PKU. This is due to a mutation in the gene that codes for this enzyme, the phenylalanine hydroxylase gene. For reference sake, the phenylalanine hydroxylase gene is located on 12th human chromosome. Remember that it is the mutated form(s) of the gene that can lead to PKU, the vast majority of the human population carries the regular form.

Fortunately, phenylketonuria is a rare genetic disorder, affecting less than one percent of the population. This is due, in part, to the fact that it must be present in both parents to be passed on to a child. It is almost always detected in most newborn screenings. However, it is possible to be missed, especially if a milder form is present. While there are several key differences, some of its symptoms mimic problems that correlate with attention deficit disorders. These include:

  • Hyperactivity
  • Erratic Arm and Leg Movements (can be similar to tics or Tourette's-like behavior, which often accompanies ADHD individuals as a comorbid disorder)
  • Social immaturity and impairment of mental skills
  • Learning disabilities

As we can see, these four traits are classic behaviors seen in many children diagnosed with ADHD. The first two are more characteristic of the hyperactive/impulsive or combined subtypes of ADHD, the fourth is more tied to the inattentive form of the disorder, and the third can fall into any of the categories. Interestingly, both ADHD and PKU disorders share a common brain region of deficit, the prefrontal cortex.

Key Differences Between ADHD and PKU:

As we can see, there are a number of features and methods in place such that the possibility of misdiagnosing ADHD as PKU and PKU as ADHD by a skilled professional is relatively small. However, in addition to PKU, there are genetic deficiencies which result in compromised activity of the phenylaline hydroxylase enzyme by around 5 to 10%. While these deficiencies are milder than in full-fledged phenylketonuria, it does bring up a critical point that intermediate states do exist between being diagnosed with PKU and not having PKU. It is possible that individuals in this potentially vulnerable intermediate state of enzyme deficiency may be more susceptible to disorders such as ADHD. Of course, this is just a personal hypothesis.

Nevertheless, the main goal of this post was to highlight some of the key genetic, physiological and behavioral overlaps of the two disorders. It is my personal belief that looking for common underlying trends between even the most disparate disorders can offer a wealth of information into some of the underlying causes of the individual disorders that we would otherwise miss. In other words, I think we often sell our selves short by not digging "deep" enough in our investigations of the fundamental causes of diseases and disorders such as ADHD and phenylketonuria.

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Friday, April 17, 2009

10 Ways Carnitine can help treat ADHD

Carnitine: The missing link to omega-3 supplementation for ADHD

Carnitine is one of the new "trendy" supplements out there today, due in part to the number of heart-healthy benefits that can be derived from it's usage (often alongside other new popular supplements such as Coenzyme Q10). I am not here to discourage these supplements, I definitely see a number of positives from taking them, but for this post I would like to address the topic on Carnitine and ADHD: Can Carnitine, with all of it's heart-healthy benefits, actually be useful in treating ADHD? Here are 10 possible reasons why carnitine may be a powerful new treatment option for ADHD and related disorders:

As a quick aside: Carnitine, like many other nutrients, can exist in different forms, one of which is acetylcarnitine. This form, actually has a number of metabolic roles, but for the sake of simplicity, I will not go into too much detail about the different forms of carnitine unless absolutely necessary.
  1. Potential for boosting the effectiveness of omega-3 fatty acid supplementation: We have already discussed the theory and applications of omega-3's and their possible benefits as alternative non-pharmaceutical treatment options for ADHD. Nonetheless, despite the recent surge in population of omega-3's (including the ever-popular fish oil supplements), only marginal amounts of improvements as far as behavior and symptom reductions are often seen. A big possibility for this limited effectiveness may actually stem from missing pieces of the puzzle with regards to omega-3 metabolism. This may include a deficiency in carnitine. There is even some speculation that abnormalities in fatty acid metabolism may play a role in autism, and that carnitine levels may play a role in this. Given the degree of inter-relationship between autism and ADHD, this possible connection may be at least worth mentioning. In particular, carnitine plays an important role in the synthesis of the docosahexaenoic acid (DHA), and a carnitine deficiency can result in a reduction of this key nutrient. Like several other important fatty acids, DHA deficency is often seen in ADHD individuals.

  2. Carnitine may be beneficial for "refractory" ADHD (unresponsive to conventional pharmaceutical treatment): This one is somewhat surprising. Typically supplementation and "natural" measures can be tried, but if they fail, the more "heavy-hitting" pharmaceutical treatment options for ADHD are often employed. However, a Dutch study done by Van Oudheusden and Scholte which investigated the efficacy of carnitine in treating children with ADHD mentioned that carnitine was found to be effective in treating ADHD in children who were previously unresponsive to methylphenidate, clonidine or behavioral therapy treatments.

    What's interesting is that this group found a strong connection between plasma carnitine levels and a reduction in behavior problems (i.e., those children who were able to build up higher levels of carnitine in the blood were more likely to show direct benefit with regards to ADHD symptoms, while those with lower blood levels exhibited more severe ADHD-like behavior). This strongly suggests the carnitine/ADHD connection and also highlights the fact that there is a relatively wide degree of variation among individuals as far as carnitine storage and metabolism is concerned. Even more interesting, this same group found that when carnitine treatment was discontinued, the negative ADHD symptoms re-appeared relatively soon (within 3-4 weeks), but upon re-administration of the previous carnitine doses, the behavioral problems quickly subsided again.

  3. Potential for use for both inattentive and hyperactive/impulsive ADHD: The same study on carnitine treatment for ADHD noted that a decrease in aggression and conduct problems (which are often comorbid to or co-occur with the more hyperactive/impulsive side of ADHD) upon treatment with carnitine. Not to be outdone, another study found that carnitine was more useful in treating the inattentive subtype of ADHD. Interestingly, the inattentive ADHD study found that individuals with the combined subtype ADHD subtype (which includes high levels of both the inattentive and hyperactive/impulsive behaviors) actually showed a worsening of symptoms upon treatment with carnitine.

    It's important to note that the Dutch study did see some improvement in inattentive symptoms as well, so it appears (at least for now), that carnitine may be more of benefit towards treating the inattentive aspects of ADHD. This may actually be in line with other studies which link carnitine treatment to increased energy (individuals with the inattentive form of ADHD are often more likely associated to be more lethargic as opposed to the bouncing-off-the-walls behavior typically exhibited by the hyperactive/impulsive or combined ADHD subtypes).

  4. Carnitine as a memory booster: I am personally hesitant to suggest supplementation with generalized memory boosters for ADHD (multiple ADHD websites love to do this), due to the distinct nature of the disorder. Nevertheless, individuals with ADHD do typically exhibit deficiencies in working memory, and some studies on carnitine on memory improvement are of interest. There is evidence that memory improvement from carnitine treatment may be seen in certain sub-populations. For example, carnitine treatment improved visual memory and attention in Down Syndrome patients, but the same effects were not seen in non-Down Syndrome individuals. Additionally, carnitine has also been shown to be useful in Alzheimer's dementia. The possibility that unique subsections of the population may be particularly receptive is intriguing, to say the least.

  5. Carnitine may play a role in reducing toxicity of other psychiatric medications: We have previously addressed the possible association of ADHD and epilepsy. Valproic acid, an anti-epileptic medication (which is also used in treating bipolar disorders, which often has a fair amount of overlap with ADHD itself) has risks of toxicity. However, carnitine treatment of Valproic acid toxicity has been shown in a recent study. In general, carnitine can also help the body clear toxic carboxylic acids from its cells.

  6. Carnitine's lack of addiction potential compared to stimulant ADHD medications: One of the classic problems with many medications (including ADHD stimulant medications) is the potential for addiction. In general, addiction potential is increased by rapid uptake into and rapid clearance by the brain. Although much more rare than prescription medications, herbs and supplements may also be addiction forming. However, there is a relatively slow uptake of carnitine into the brain, which reduces its addiction potential to virtually zero. While not entirely significant (addictions of similar types of nutrients are almost non-existent), it is worth mentioning, if for no other reason than to inform those who are looking for non-prescription alternatives to ADHD some of the benefits to nutrient supplementation.

  7. Acetyl-carnitine may offer the brain an alternative energy source during glucose shortages: Multiple studies have found glucose deficiencies in key specific brain regions in ADHD patients. A study found that glucose can actually inhibit the uptake of acetyl-carnitine into the brain, indicating a similar metabolic pathway. This conclusion of acetyl-carnitine as an alternative energy source was reached by the authors, however, it has been backed up by a body of research from numerous other studies. This seems to indicate that carnitine and its various forms may offer a viable means of alternative energy for glucose-starved ADHD brains.

  8. Carnitine plays a role in acetylcholine (and possibly dopamine) synthesis: Acetylcholine is an important neuro-transmitter in the brain. While it often takes a back seat to more well-known ADHD-related neuro-signaling agents such as dopamine and norepinephrine, several stimulant drugs which alleviate ADHD symptoms may target acetylcholine-dependent pathways (interestingly, nicotine appears to have a high degree of interaction with the acetylcholine receptors, and is often a popular drug of choice in ADHD individuals, often as a means to "self-medicate").

    It appears that carnitine can help offset acetylcholine deficiencies in the brain, especially with regards to neuro-degenerative diseases. These effects can be even more pronounced if carnitine is co-administered with other key nutrients such as S-Adenosylmethionine (SAMe) and N-Acetylcysteine (NAc). To do these other two nutrients justice with regards to their effects on ADHD and related disorders or illness, they will need to be covered in their own separate posts. Finally, it appears that carnitine also affects dopamine-related pathways as well, which has numerous potential implications for ADHD, given that dopamine shortages and metabolic differences in key brain regions are often associated with the disorder.

  9. Improved circulation via administration of carnitine (and vitamin E?): There is a mounting body of evidence that supports the assertion that individuals with ADHD have reduced bloodflow to key regions of the brain necessary for maintaining focus, eliminating distractions and maintaining attention to specific tasks. Certain ADHD medications, such as methylphenidate (Ritalin, Concerta, Metadate, Daytrana), can actually alter patterns of cerebral bloodflow in ADHD patients. It appears that carnitine can also improve blood flow to brain tissue (the study refers to the term "ischemia", which is simply a reduction of blood supply via blood vessels). These effects may possibly be increased even further, when combined with vitamin E, as highlighted in the same study. Carnitine can also help reduce ischemia to the spinal cord.

  10. Carnitine helps maintain cell membrane integrity: Numerous diseases and disorders are the result of damages to (or "leaky") cell membranes. These membranes are comprised mainly of fats, with several different proteins interspersed among the fatty acids. Ample omega-3 fatty acids play a critical role in maintaining a structure to the cell membranes, which is one of the reasons why adequate carnitine levels are so beneficial. However, fatty acids are prone to oxidation (think of a damage similar to rusting or corrosion, but within the body), so adequate antioxidant levels are needed to maintain these key components of cell structure and overall health.

    In addition to its numerous other roles, carnitine is considered to be an antioxidant. Dietary deficiencies, as well as environmental stresses can leave these membranes prone to damage, resulting in a whole slew of potential diseases and disorders, such as increased risks of viral infections, allergies, buildup of cellular toxins, impairment of blood flow (this is actually related to our previous point on carnitine and ischemia) etc. In addition, cells contain inner membranes, whose structure and function can also be dependent on carnitine.
How much carnitine should we be taking, especially for ADHD?
This is a good question, which, unfortunately, does not carry a straight answer. There is no official "RDA" for carnitine at the moment. One group studying carnitine metabolism suggested a recommended daily dose of carnitine to be 200 mg/day. The Dutch study used a dose that was proportional to the patient's body weight, 100 mg of carnitine/kg body weight to be precise. This corresponded to a maximum of 4 grams of carnitine (note that this study was done in children) for the study. Dosage at this level corresponded to about a doubling in plasma carnitine concentration. With regards to side effects, there were relatively few, although one individual discontinued the study due to onset of a strange odor emanating from his skin. It was believed that this may be due to a buildup of a compound known as trimethylamine, which has a characteristic fishy, ammonia-like smell.

However, some of the effects in other studies were seen at only a fraction of these doses, such as some reporting effects such as significant improvements in attention at only 25 mg carnitine/kg body weight. 50 mg/kilogram body weight was the dosage used in a study that found carnitine to be effective in combating hyperactivity. These studies are simply rough estimates for amounts needed to suppress inattentive and hyperactive/impulsive behaviors associated with ADHD. As far as safety and toxicity issues are concerned, there are few published reports about dangerously high levels of carnitine. For a one-year study on the effects of carnitine for ADHD boys, a daily dose of 1 gram per day was found to be safe. This study recommended 20-50 mg carnitine per kg of body weight, which is roughly one fifth to one half of the levels used in the Dutch study.

Regional/Geographic effects on carnitine supplementation for ADHD: A mult-site study on the effects of carnitine on ADHD by Arnold and co-workers made an interesting observation. They studied the effects of carnitine on ADHD symptoms in children in 10 different sites across the United States, and found that significantly more pronounced effects were seen in 3 sites in Ohio and northern Kentucky. All of these sites were about 150 miles northwest of the Allegheny Mountains. The other parameters (age range, demographics, ethnicity, ADHD symptom scores, doses of carnitine, etc.) were similar to the other sites, and the researchers in the study offered no explanation for the findings and suggested the difference to be merely coincidental. While this is obviously a possibility, this blogger offers a possible explanation: the potential effects of interaction between carnitine and minerals or heavy metals.

One possibility may have to do with magnesium deficiency in this particular region. Some studies note that the soil in the Allegheny region is deficient in magnesium due to erosion or poor soil management. It is possible that this magnesium depletion in the soil may result in a higher prevalance to dietary magnesium deficiency in these geographic regions. We have demonstrated the effects of magnesium deficiency in ADHD in several previous posts, such as one on Magnesium Deficiency and Childhood ADHD. However, we have also seen that magnesium can often work in conjunction with other vitamins, minerals and antioxidants in treating ADHD as well. These highlights can be found in an earlier post on magnesium combination treatments and ADHD.

Some research has found that magnesium can boost the activity of the enzyme Acetyl-CoA carboxylase, which plays a significant role in fatty acid biosynethesis. A fatty derivative of carnitine can also push this same enzyme along. It is possible, therefore, that carnitine supplementation may take over some of the roles of the depleted magnesium, thereby freeing up magnesium for some of the other ADHD-fighting fuctions as previously noted. Of course this is just a personal hypothesis, but this blogger earnestly believes that there are a number of carnitine-mineral interactions that have not been studied extensively that warrant further investigation.

Carnitine does not act in isolation:
If you get nothing else out of this post or any of the other posts in this blog dealing with nutrition strategies for ADHD, please remember this: nutrient therapies often do not work because not all the pieces are in place. In other words, the different nutrients are highly interdependent, and a missing piece or two can sabotage the whole system. I personally believe that this is why a number of ADHD supplementation strategies do not work to their full potentials, because they are often missing key ingredients. Instead, for ADHD combination treatments to be effective, it is vital that we begin to understand all of the individual steps of nutrient metabolism and their affiliation with the disorder.

Just from this post alone, we have seen that carnitine has potential interactions with:

Omega-3 fatty acids
Vitamin E and other antioxidants
S-Adenosylmethionine (SAMe)
N-Acetylcysteine (NAc)
Coenzyme Q10
Valproic acid (and other medications often used to ADHD or disorders which often show up alongside of it)

The point is, is that the various ADHD medications and treatment alternatives do not exist in a vacuum. One of the goals of this blog is to further elucidate the many interactions and factors at work in the different treatment strategies for ADHD. We need to consider all possible food-food, drug-drug, food-drug, food-supplement, drug-supplement and supplement-supplement interactions in order to tailor an effective treatment method for any individual. It is my belief that only then will we be truly able to see consistently effective individual treatments for ADHD and related disorders.

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Sunday, April 12, 2009

10 Ways Zinc can Combat ADHD

Here are 10 reasons why zinc may be an effective treatment method for ADHD and related disorders:

  1. Protection against oxidative damage of omega-3 fatty acids: We've previously discussed the role of omega-3's and their use as a treatment option for ADHD. However, the downside to this is that these fats (along with many others) are prone to oxidation. As a result, dietary antioxidants are needed to preserve these effects. According to a work by Villet and coworkers, zinc may be beneficial in retarding this omega-3 fatty acid oxidation process. As a result, zinc may be a good supplement to go alongside omega-3 treatment for ADHD.

  2. Conversion of Vitamin B6 to its active form: We have mentioned the role of vitamin B6 and its role in the treatment of ADHD, including how B6 can work alongside another key nutrient, magnesium. Zinc is needed to convert the inactive form of the vitamin B6, pyridoxine, to the active form pyridoxal phosphate. Thus, zinc is needed in vitamin B6 metabolism.

  3. Production of melatonin: Melatonin is a hormone we have also discussed earlier with regards to its effects on ADHD in an earlier post titled CREM gene, melatonin and ADHD. It appears that melatonin deficiencies may be attributed to a shortage of zinc. In short, melatonin plays a role in regulating the important neuro-chemical signaling agent dopamine, which is a key neurotransmitter involved in the symptoms and treatment strategies for ADHD.

  4. Zinc can modulate or affect thyroid function, especially when melatonin is a factor: We have also discussed how thyroid dysfunction may closely mimic ADHD symptoms, and highlighted the importance of iodine to combat this . Now it appears that imbalanced melatonin levels may disrupt the thyroid. However, zinc may combat the negative effects of excessive melatonin on thyroid function. Combining this point with the previous one, we now see that zinc may be needed not only for the production of melatonin, but can actually be used to reel in this hormone when excessive melatonin levels lead to unwanted side effects such as thyroid dysfunction. Thus, it appears that zinc may play a role of double duty with regards to regulating melatonin production and curbing the negative effects of its excess.

  5. Production of serotonin: This piggy-backs on the vitamin B6 role highlighted in point number 2 above. ADHD is often considered a disorder associated with the neurochemicals dopamine and norepinephrine. However, serotonin may also play a role in this disorder. For individuals who exhibit anxiety and depressive symptoms alongside their ADHD (which is surprisingly common), a serotonin deficiency is often partly to blame. Serotonin is synthesized in the body from the amino acid tryptophan. However, for this conversion process to go through, sufficient and functional vitamin B6 is required for serotonin to be formed by the tryptophan conversion process via a special type of enzyme known as aromatic amino acid decarboxylase. As previously mentioned, zinc is needed for functional vitamin B6, and therefore plays an indirect role in the synthesis of serotonin. Thus, zinc may be extremely important in individuals with ADHD and comorbid (co-occurring) depression or depressive-like symptoms.

  6. Reduction of hyperactivty, impulsivity and antisocial behavioral symptoms: For direct treatment of ADHD, it appears that zinc may be more effective in treating the hyperactive/impulsive aspects of the disorder than the inattentive portion of the disorder. This study also noted the effectiveness of zinc for older children and children with a higher body mass index, which at least suggests that the effectiveness of zinc as a treatment for children with ADHD may increase as the child ages and grows.

  7. Zinc may also play a role in the process of brain waves associated with ADHD as well as other disorders: We have already investigated differences and discrepancies in the brain wave patterns of ADHD children, including how these may actually be tied to an individual's genes. Information processing, which is often impaired in ADHD individuals, is believed to be tied to a brain pattern known as N2 (which is short for second negative wave, no need to concern ourselves with the exact details of this process here). Some research suggests that N2 mediated information processing may be negatively affected by zinc deficiency. This relates to unwanted attentional shifting (i.e. distraction) to irrelevant stimuli. In other words, N2 is related to the "novelty effect" of a specific stimulus or change in stimuli. As an interesting aside, N2 brain patterns are thought to be affected by serotonin, which, as mentioned in point #5, is indirectly tied to zinc levels. Based on this, it is at least plausible that zinc may play an integral role in this mechanism of distraction.

  8. Boosting the effectiveness of ADHD medications: While we have reported on this in an earlier post on zinc and Ritalin, I believe it is worth repeating here. Multiple studies suggest that zinc can boost the effectiveness of methylphenidate for treating ADHD and related disorders. This may be of importance with regards to reducing some of the negative side effects associated with the drug. Many of these negative side effects often don't set in at the lower doses of the various forms of the drug, but instead, begin to appear with greater frequencies at higher doses. Taking this into account, it seems reasonable (at least in this blogger's opinion) that concurrent treatment with zinc may be enough to hold some of these methylphenidate dosages below the threshold of some of these negative symptoms, thereby increasing the tolerability of this common ADHD drug.

  9. Zinc Inhibition of the Dopamine Transporter Protein: This may offer a further explanation as to why zinc is effective in boosting the effectiveness of methylphenidate. We have spoken extensively about the dopamine transporter (DAT) protein and its effects on dopamine levels and ADHD. Several ADHD medications, especially of the stimulant variety (such as methylphenidate), work by inhibiting or blocking DAT. It appears zinc may also act as a natural DAT inhibitor, thereby mimicking the effects of some of the more commonly used drugs.

    In my previous post on zinc and its amplification of Ritalin's effectiveness, I wondered aloud as to whether zinc could be used as an outright substitute for the medication methylphenidate. While still a personal hypothesis, I still believe that for low level doses, zinc may be an ample natural alternative, but, this hypothesis obviously needs to be tested at a clinical level. Nevertheless, I personally believe it to be worthy of investigation.

  10. Zinc as a possible treatment option for juvenile growth impairments: It is suggested that children with ADHD exhibit a delay in the overall growth process. We actually discussed this very topic in an earlier post titled: Do ADHD stimulant drugs stunt growth? Now it appears that zinc may possibly play a role in this. Using a primate model of zinc deficiency, Golub and coworkers found that zinc deficient monkeys showed a slowing of the growth process during what would normally be a period of growth spurt. If this translates into humans, then it is possible that underlying growth and attentional impairments, as well as abnormalities in activity levels (which is sometimes evident in children with ADHD, often more alongside those with the inattentive subtype of the disorder), may actually be due to zinc deficiencies.

    Perhaps on an even more interesting note, the study found that "attention performance was also impaired before the onset of growth retardation". In other words, an attentional deficit may serve as a proverbial canary in the coal mine that a child may suffer from a subsequent delinquency in growth in the upcoming years. As a result, this blogger personally believes that some of these "attentional deficits" may not simply indicate an isolated case of ADHD, but rather serve as a warning of a much larger underlying problem that may be tied to a nutritional deficiency. Furthermore, it is at least possible that the underlying problem of attentional deficits and growth impairments in children with ADHD may be remedied by an intervention strategy that involves adequate dietary zinc or treatment via zinc supplementation.
This list of zinc levels and the direct or indirect relationships to ADHD is by no means extensive. Further connections, such as the relationship between zinc deficiencies and digestive disorders such as Crohn's disease, should also be noted. On an interesting note, a very recent publication came out evaluating the effectiveness of various nutrition supplementation strategies for treatment of ADHD listed zinc as the nutrient of most promise.

Given that zinc deficiencies are common in both Western countries such as the U.K., as well as developing countries such as China it seems evident that ADHD symptoms may be part of a larger picture, a proverbial cry for help due to a widespread nutritional deficiency. In addition to ADHD, other disorders dealing with cognitive development may be susceptible to zinc deficiencies. Of course, a great deal of further study is needed to back up this assertion, but it leads us to wonder exactly how often a case of ADHD is actually due to something as simple as a deficiency in zinc or another common nutrient. We will have further discussions regarding this important mineral in future posts.

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Sunday, April 5, 2009

Ritalin and Cocaine: Similarities and Differences

We have previously investigated some of the similarities between the chemistry and modes of action of Ritalin and cocaine. In this past post, however, we looked more at the rates of uptake and metabolism of the two drugs and investigated a side-by-side structural comparison.

I was originally planning on continuing with posts on Daytrana, which is very similar to the more common ADHD medications Ritalin and Concerta (it is actually comprised of the same chemical agent, methylphenidate. However, I recently saw an interesting article on the topic of methylphenidate, cocaine and nicotine, and the mechanism of interaction between these different stimulants. As a result, in lieu of the Daytrana postings, I would like to discuss these findings in the next couple of posts.

Here are seven key points to be aware of regarding the similarities and differences between methylphenidate and cocaine:

  1. SIMILARITY: Uptake patterns into the brain: Both methylphenidate and cocaine enter the brain at similar rates and target similar specific regions of the brain. When injected, around 7.5% of the injected compound makes it into the brain tissue for each compound at similar rates (peak uptake only takes around 2 to 8 minutes for cocaine and 4 to 10 minutes for methylphenidate in the injected form, oral administration, which will be discussed later, is significantly longer, especially for methylphenidate). The most favored target region of the brain is the striatum for both cocaine and methylphenidate (see brain diagram below). In fact, several studies have indicated that the two drugs share a number of target binding sites within the brain, to the point where the ADHD medication methylphenidate has actually been used as a treatment option for cocaine abuse.

  2. Brain Regions Targeted by each drug: In addition to similar uptake patterns in the brain between the two drugs, there is a relatively large degree of overlap for particular brain regions targeted. However, there is at least one notable exception, which bears relevance to our discussion. On an interesting note, the method of delivery not only affects the speed of uptake of a drug (injected is almost always faster than snorted, which is almost always faster than ingested), but also the actual brain regions targeted by the drug. For example, another brain region, called the Nucleus Accumbens (see image below for approximate location) is targeted by cocaine and injected methylphenidate. However, when methylphenidate, such as Ritalin, Concerta or Metadate is taken orally, this nucleus accumbens region is not targeted (at least not anywhere near the level of injection).

    The nucleus accumbens is believed to play an important role in the addiction potential of a number of drugs, including many stimulant medications. Thus, proper use of the methylphenidate medication actually bypasses a key brain region believed to be critically involved in the "high" or addiction process of a stimulant drug. This highlights a major difference in the pharmacology between Ritalin and cocaine.
  3. Key Difference between methylphenidate and cocaine: Rate of clearance from the striatum region of the brain: As mentioned in an earlier post, the addiction potential of a drug is typically correlated to the rate of exit or clearance from the brain. In other words, drugs that linger in the brain's receptors for extended periods of time are often much less addicting than ones which exhibit a short and rapid spike in their brain levels and then a quick drop-off in their concentration in the brain. In the striatum, the rate of clearance takes about 90 minutes for methylphenidate, and only 20 minutes for cocaine. If we go by peak concentration duration (i.e. the amount of time the highest concentration typically lasts in the brain before going back down), we see that methylphenidate's peak lasts around 15 to 20 minutes, while cocaine's is a fleeting 2 to 4 minutes. In both cases, the higher dissipation of the drug from high levels in the brain is much more pronounced in cocaine, giving this drug a much more addiction-worthy effect over methylphenidate (even when methylphenidate is abuses and either snorted or injected, it still cannot match the rates of clearance of cocaine).

  4. Potency of the two drugs: The following may seem surprising at first. With regards to specific brain targets, methylphenidate is almost twice as potent as cocaine. We have discussed at length the role of the dopamine transporter protein (DAT), and its role in ADHD and related disorders. Essentially, this DAT protein is responsible for retaining a proper balance of the important brain chemical dopamine in and out of nerve cells. For individuals with ADHD, this balance is often skewed, typically with too much dopamine being taken up into the neuron cells and not enough in the gaps between the cells. Many stimulant medications remedy this problem by essentially binding to and plugging up the dopamine transporter proteins in the nervous system, which inhibits their abilities to shuttle dopamine into the cells. As a result of this medication-effected correction, dopamine balance can be somewhat restored. As a frame of reference, based on some of the current literature, it takes often takes at least a 60% saturation of these dopamine transporters with a drug to elicit the "high" (of course, there is a significant degree of variation between individuals).

    With regards to potency, we see that both cocaine and methylphenidate love to bind to these dopamine transporter proteins. To shut down the function of these dopamine transporter proteins to 50% of their original function (a common way of measuring the potency of a drug in pharmaceutical and laboratory testing), a 640 nanomolar concentration was needed for cocaine, while only a 390 nanomolar concentration was needed for methylphenidate to do the trick. If you're not familiar with these units of concentration, don't worry. These numbers work out to very small amounts (around the neighborhood of only 0.001 grams of drug per liter of fluid). I just put the numbers out there to show that only about half the amount of methylphenidate was needed to share the same effects with cocaine (i.e. the methylphenidate is approximately twice as potent for this particular process).

  5. Difference between Ritalin and Cocaine: DAT saturation levels and perceived high: The relative saturation of these dopamine transporters are also believed to play a role in the "high" of stimulant drugs such as methylphenidate and cocaine. However, research by Volkow and coworkers found that while the level of saturation of the dopamine transporters with cocaine correlated with the "high" associated with this drug, the methylphenidate drug tells a different story. As mentioned previously, the reinforcing effects of a drug including the "high" typically correlate with the rate of clearance from the brain.

    We have also seen that methylphenidate clears much more slowly than cocaine. However, in the case of methylphenidate, the diminished effects of the the high occurred long before the drug had fully cleared from the dopamine transporter. In other words, there appears to be a relatively strong connection between the binding of cocaine to the dopamine transporter proteins and the perceived "high" but the effects are much less pronounced with methylphenidate. This highlights a major difference between methylphenidate and cocaine and at least suggests the possibility of a difference in mechanisms between the two stimulants.

  6. Divergence in metabolic patterns between methylphenidate and cocaine: Furthering this issue a bit more, there is some evidence that the pathway of the two drugs is almost identical for the first part of the journey into the system, but their modes of action split off at some point when it comes to dopamine transporter occupancy and the corresponding reinforcement effects (see sketch below).

  7. Difference between methylphenidate and cocaine: Drug lingering and tolerance: The persistence of methylphenidate on the dopamine transporter proteins may result in more than its reduction of abuse potential. It also appears that this "lingering" of the drug on these dopamine transporter proteins may also play a significant role in the phenomena of tolerance to methylphenidate.

    Acute tolerance to methylphenidate is nothing new. Newer formulations of the drug (Concerta, Metadate) were designed in part to address the problem of the reappearance of ADHD symptoms by ramping up and releasing increased levels of the drug throughout the day. This is important, because, the effects of methylphenidate appear to be best felt when its levels are climbing or building up, and not stabilizing (i.e. you do not want a constant level of methylphenidate throughout the day, but rather a constantly increasing one to maintain the same effects). Essentially, this is "micro-tolerance" to methylphenidate and is seen on a daily level. The ideal dosing strategy for methylphenidate typically entails a morning dosage which is approximately 50% of an evening dosage, i.e. a "ramping" effect of the drug throughout the day is often needed to maintain the desired results.

    It is suggested that this tolerance to methylphenidate may be due, at least in part to its continued presence and relatively slow clearance in specific areas, such as on the dopamine transporter proteins. Other faster-clearing drugs, such as cocaine, do not exhibit this property. However, given the fact that cocaine tolerance is also common, it is unlikely that the whole "dopamine transporter saturation" theory can fully address the issue of tolerance for stimulant drugs. Volkow and coworkers explored this role of blocking dopamine transporters with methylphenidate and the perceived high in greater detail. Nevertheless, at least in this blogger's personal opinion, the lingering effect of methylphenidate still plays some degree of significance to the process of tolerance to the drug, and the need for ramping its dosage to treat disorders such as ADHD.

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