Monday, December 28, 2009

10 Ways Vitamin C helps treat ADHD Symptoms

How Vitamin C can be an Effective Treatment Method for ADHD

We have previously discussed nutritional treatment methods for ADHD, including other "10 Ways" posts for carnitine and zinc. However, vitamin C, while often associated as being more of an immune-boosting and heart healthy antioxidant vitamin, may also play a crucial (and often underrated) role in taming the negative symptoms associated with Attention Deficit Hyperactivity Disorder, or ADHD.

Before we go any further, I must establish the appropriate context as to how we should interpret this blog post. Some of the following information on vitamin C surrounds more of the potential ways in which the vitamin can interact with the causative mechanisms of ADHD, and is more speculative than that of evidence-based controlled clinical trials. Other abilities or utilizations of the vitamin (such as vitamin C's ability to boost iron absorption, or the vitamin C-dependence of various enzymes required to metabolize ADHD medications or parallel nutrition strategies) are well-documented and better established.

Having said that, out of these following 10 reasons for vitamin C supplementation for treating ADHD, around 3 to 4 are well-grounded on clinical evidence, about 3 to 4 are plausible arguments, but with potentially great limiting factors, and 3 to 4 are possible, but largely hypothetical at the current time. It is the intent of the blogger not to persuade or advocate the rampant consumption of megadoses of this vitamin, but rather to illustrate the complexities of our metabolic systems as to how such a basic vitamin can be tied into so many ADHD-relevant processes.

Based on the conclusions of the various research papers which I am about to highlight in this posting, it appears that high levels of vitamin C supplementation will do little to alleviate ADHD symptoms, especially when compared to efficacy other nutrients with better track records such as omega-3's, iron, magnesium and zinc. Based on (often substantially) greater piles of evidence, stronger claims can generally be made for a correlation between deficiencies of these aforementioned nutrients and ADHD severity than for the connection between ADHD and levels of vitamin C.

Instead, this post is meant more as an advocate for the maintenance of recommended (or slightly higher) levels of vitamin C and avoiding deficiencies (which can decrease the processes optimized by this vitamin). Thus, it appears to be more accurate if we view vitamin C as an auxiliary or secondary co-treatment strategy for ADHD via natural dietary methods and not as a stand-alone ADHD treatment. This is important to remember as we work through this post and see some of vitamin C's potential (but not always decisively proven) "natural" ADHD treatment options.

We must also acknowledge that vitamin C exists in two major forms: the common (non-oxidized) form of the vitamin, also called ascorbic acid, or the oxidized form Dehydroascorbic Acid or DHA (Blogger's note: please don't confuse this vitamin-C derived "DHA" with the omega-3 fatty acid docosahexaenoic acid, which is also commonly abbreviated as DHA. They are two entirely different molecules. We have discussed the significance of this important omega-3 earlier posts).

As we will see later in this post, the two different forms of the vitamin have extremely different properties in several cases, including their methods of transport and uptake into the brain (while it may seem counterintuitive, given the fact that we often associate "oxidized" with being bad in the body, it is the oxidized DHA form of the vitamin actually has a number of advantages over the reduced form with regards to brain uptake).

Without further ado, here are 10 documented ways (as well as two "possibilities") in which this important vitamin can help with ADHD. While some of these may seem obvious, others appear to have a more obscure, but equally important role or function as an ADHD treatment method:

  1. Vitamin C offers protection against fatty acid oxidation, including the important omega-3's which are a popular treatment and supplement for ADHD. While omega-3 supplementation remains a popular treatment method among "natural" ADHD treatment advocates, its overall effectiveness remains questionable.

    The theory behind omega-3 treatments for ADHD can be found in an earlier posting, but in a nutshell, the brain and central nervous system are comprised of cells with very high omega-3 fat content, and must be constantly supplied with either these fats themselves or chemical precursors to these fats (which can then be converted into these essential nutrients). These fats play a critical role in coating the outer layers of the "messenger" signaling portions of the brain, and the development of these protective layers (called myelination) is especially pronounced in adolescence.

    High levels of overall brain development and re-wiring occurs during the adolescent stages, and in multiple cases, this process is delayed in the ADHD population. Therefore, the idea holds that we should be supplementing this process along by feeding the brain these important omega-3 rich foods and nutrients.

    However, one of the fundamental problems is the fact that fatty acids (including omega-3's in particular) are especially susceptible to damage through chemical process of oxidation. We have alluded to this in earlier discussions on omega-3 oxidation and ADHD. Numerous studies have shown that dietary antioxidant intervention can greatly alleviate this problem. In this blogger's opinion, failure to recognize this important factor of antioxidant protection for omega-3 fatty acids is one of the biggest saboteurs of omega-3 intervention as an ADHD treatment.

    As far as antioxidant protection strategies of fatty acids are concerned, vitamin C is often not the best choice. As a water-soluble vitamin, the interactions with the much less water soluble omega-3 fatty acids are potentially limited. However, vitamin C can "sacrifice" itself and help boost levels of other important antioxidants in the body that can have a greater impact on omega-3 fatty acid protection and cell membrane viability. Among these are vitamin E and glutathione (which will be addressed later on in this posting, when we talk about antioxidant recycling).

    However, we may be beginning to see that vitamin C could be an effective co-treatment to fatty acids in its own right, at least according to some recent studies. One study (which, unfortunately paid more attention to the fatty acid component and had vitamin C as more of an auxiliary co-treatment) suggested that vitamin C can boost the efficacy of flax oil (a popular omega-3 rich dietary choice) as an ADHD treatment measure. Clearly, this was just one study, and more research is warranted, but the significance of protecting these all-important dietary fats found at high concentrations in the brain and nervous system cannot be understated.

  2. Vitamin C acts as a potent neuroprotective agent (important for neurological disorders including ADHD). It may sound surprising, but nerve endings in the brain have the second highest concentration of vitamin C in the body (behind only the adrenal glands, which produce adrenaline, which we will mention later in this post when discussing vitamin C and catecholamines). Current research appears to illuminate the protective role of vitamin C, specifically in its oxidized DHA form and when used in conjunction with vitamin D3, against a specific type of oxidative damage on the brain called ischemia (reduced blood supply to a particular brain region, which can be brought on, by other things, oxidative damage).

    The relevance to ADHD here is that ischemia is a surprisingly common environmental cause of the disorder, especially during early (neonatal) development. It is believed by some researchers that oxidative damage which causes this ischemic reduction of blood supply may bring on ADHD symptoms by interfering with biological targets (or receptors) in the brain for the important neurotransmitting chemical dopamine. In other words, for those individuals suffering from reduced blood flow to these brain regions earlier in life, the important signaling chemical dopamine has trouble finding its mark in the brain, results in the attenuation of attention span and longer reaction timing (for more information on ADHD and reaction timing, please see the earlier post: Do ADHD Kids Use their brain regions differently?).

    While the basis for ischemia treatment for ADHD via vitamin C supplementation is more hypothetical at the moment, the fact that treatment with this vitamin can counteract a major environmental cause of the disorder suggests that vitamin C may be a viable treatment method for this aspect of ADHD and related disorders.

  3. Vitamin C helps "recycle" and maintain pools of other crucial antioxidants such as vitamin E, polyphenols (potent antioxidants found in fruits, vegetables, wines and teas), glutathione (which is manufactured in the body and is the body's standard antioxidant of choice), and products of the antioxidant enzyme superoxide dismutase or SOD.

    We have alluded to this message in point number 1 above. Several studies have found abnormally low antioxidant levels (and high "pro-oxidant" levels) in ADHD subjects. It appears that increasing dietary antioxidant intake may at least partially reduce this trend.

    For example, boosting intake of a form of vitamin E called gamma-tocopherol can reduce the oxidation of important fatty acids in ADHD subjects (although it is worth mentioning that gamma-tocopherol is not the most bio-available form of vitamin E, that honor goes to another form of the vitamin called alpha-tocopherol). It is worth mentioning that vitamin C and vitamin E work extremely well together as an antioxidant tandem, and help spare the pool of the body's antioxidant reserves from depletion. Therefore co-administration of these two vitamins is highly recommended.

    Collective research appears to indicate that raising the total antioxidant levels in the body can offset some of the negative symptoms of ADHD and related disorders. We've already mentioned the importance of preventing oxidation of the fatty acids (lipids) of the cell walls, including the membranes of brain cells (which are rich in the omega-3's).

    Secondary to its role in preventing fatty acid oxidation, vitamin C can counteract the oxidation of minerals (including iron and copper) which may often be used as dietary supplements for ADHD treatments. As in the case of omega-3 fatty acid supplementation, the risk of increased oxidative damage due to these mineral supplements is an often overlooked negative side effect of this common "natural" ADHD treatment strategy.

    Due, in part to its high concentration in brain tissue and susceptibility to oxidation, iron is prone to causing oxidative damage to the brain. Maintaining adequate levels of vitamin C (as well as vitamin E, polyphenols and glutathione) can offset much of this potential damage. We will see this more in point #5 below.

    Finally, an often-overlooked side effect of most medications (including ADHD stimulant medications) is the potential for these medications to cause oxidative damage. For example, the common ADHD stimulant methylphenidate (Ritalin, Concerta, Daytrana) was found to cause oxidative stress in young rat brains, and highlights the possibility that long-term administration of these agents may leave key targeted "ADHD" brain regions more susceptible to oxidative damage.

    This observation was more evident in younger rats undergoing development and brain maturation, which may translate into analogous effects in the developing brains of children. Thus, children may be susceptible to harmful oxidative damage in the brain via consistent use of common ADHD stimulant medication, increasing their need for higher levels of vitamin C and other antioxidants.

    Of course, we should not put too much stock into just one or two studies; and that this conclusion is being drawn prematurely by ramblings of an over-anxious blogger :) but we may seriously need to investigate this often overlooked possibility of ADHD medication based oxidative brain damage in children, and the possible amelioration of these dagmages via treatment with dietary antioxidants such as vitamins C and E.

  4. Vitamin C can potentially counteract the effects of lead on ADHD-like states: Numerous studies have linked in increase in ADHD symtpoms and behaviors with higher lead levels (although it is worth mentioning that numerous studies out there refute this association as well, so there is far from a consensus surrounding this issue). We have seen previously that iron may counteract lead and potentially alleviate some of these negative lead-based effects. When used in conjunction with other nutrients such as the mineral zinc and the amino acids taurine, methionine and glycine, vitamin C may reduce lead-derived learning and memory impairments (in the rat model), features which offer at least some semblance to common deficits in the disorder of ADHD.

  5. Vitamin C can boost absorption of key minerals which are often deficient in the ADHD population. One possible explanation for the ability of vitamin C to counteract the effects of lead may be the role of vitamin C in boosting iron absorption, especially in iron deficient states. Some studies strongly recommend the co-administration of these two nutrients.

    As an aside, please note that there is a healthy debate surrounding the possibility of vitamin C/iron combinations acting as potentially destructive pro-oxidants. Based on current trends in the literature, however, it appears that most of these negative effects are seen more in vitro, or in cell cultures, but not in vivo, or in the body. Interestingly, this potential double-edged sword of ascorbic acid form of vitamin C (as either a pro-oxidant or antioxidant) may be strongly tied to the concentration or levels of the vitamin, in that vitamin C is reported to act more like a pro-oxidant at lower levels and an antioxidant at higher levels. This may explain some of the discrepancy surrounding the pro vs. anti-oxidant effects of vitamin C when coupled with iron or other minerals.

    We have discussed the prominence of iron deficiencies in the ADHD population and the role of this critical nutrient for treating the disorder, such as the role of iron in the synthesis of neurotransmitters such as dopamine.

    Additionally, common disorders common to ADHD such as Restless legs Syndrome and sleep disorders may be attributed to deficiencies in iron levels. Therefore, vitamin C may serve as a secondary protection strategy against iron deficiencies and subsequent worsening of ADHD symptoms.

    I realize that it can be difficult to make sense of and keep separate the various iron/vitamin C interactions, so to summarize some of the main points of these associations:

    1) Vitamin C can aid in the body's absorption of iron.
    2) Vitamin C can interact with iron and keep the iron from being oxidized, but...
    3) This process can cause an oxidized form of vitamin C itself. This oxidized vitamin C species can potentially cause damage in its own right if unchecked (but can be recycled back to the antioxidant form of the vitamin by other antioxidants in the body).
    4) In general, lower levels of vitamin C tend to have more of a "pro-oxidant" effect, while the antioxidant effects of vitamin C often predominate at higher levels of the vitamin.

  6. Higher vitamin C levels have been tied to improvements in visuo-spatial abilities as well as non-verbal intelligence (both of which are often deficient in the ADHD population). As a reference, non-verbal intelligence includes skills such as being able to read or pick up on non-verbal social cues such as reading facial expressions and associating them with another person's mood, as well as distinguishing differences and inflections in tone of voice. It is important to note that non-verbal learning disabilities often accompany ADHD symptoms, and are often seen across the autistic spectrum (which mirrors ADHD symptoms in a number of ways).

    The correlation between vitamin C and non-verbal abilities is more strained than some of the other associations mentioned in this piece, but this blogger has found a few documented studies pointing out this possible affiliation. The whole vitamin C association with non-verbal deficits might be part of a bigger picture, in that deficits in non-verbal IQ scores seems to be correlated with low total overall antioxidant levels.

    On the flipside, the correlation between non-verbal deficits and the vitamin C antioxidant in particular appears to be more prominent in boys (compare this to a later section of this post where we will see that ADHD symptoms may be more tied to abnormalities in blood glucose levels in girls). In other words, the effects of vitamin C supplementation may have different levels of effectiveness with regards to gender and comorbid conditions (but please note that much more additional study must be done to validate this general claim).

  7. Beyond the physical anti-aging benefits commonly associated with the vitamin, vitamin C has shown to exhibit potent intellectual anti-aging benefits (making it a good candidate for adult ADHD cases). While the publication cited above is given in the context of the neurodegenerative disorder Alzheimer's Disease, we should take note that there is a significant overlap between ADHD and Alzheimer's (beyond just the attentional deficits).

    For example, genes (and the enzymes they code for) we have previously mentioned as being associated with ADHD are also believed to be affiliated with Alzheimer's. These include "ADHD" genes and enzymes such as COMT and the Serotonin Transporter gene. Given the fact that the two disorders share a significant genetic and enzyme system overlap, as well as similarities between the features of the two disorders (as well as some anecdotal evidence for higher rates of neurodegenerative disease susceptibility in the ADHD population), this blogger suggests that the two disorders may also share effective treatment strategies utilizing vitamin C.

  8. Vitamin C's important role as a cofactor in important enzymes relevant to ADHD and related disorders: This is one of the less obvious (but extremely important) ways in which vitamin C treatment could benefit the individual with ADHD. Typically when we think of "cofactors" (agents which help the enzymes and enzyme systems in the body operate at peak efficiency), we often think of B vitamins or trace minerals such as zinc, iron, or magnesium.

    However, it is important to get out of our heads the notion that vitamin C's mode of action as an ADHD treatment strategy is confined to its role as a "generic" antioxidant. Several enzymes whose function is linked to ADHD (often through the metabolism of other nutrients or pharmaceutical agents) require it as an essential cofactor to improve their function. One of these is the enzyme Dopamine Beta Hydroxylase, which will be discussed in more detail in the next point.

  9. Vitamin C is important in the conversion process of dopamine to norepinephrine: This is relevant to both drug and nutritionally based treatment methods for ADHD (dopamine and norepinephrine are key neurotransmitters in the brain and nervous system and are often unbalanced in ADHD cases. Many ADHD medications (in particular the stimulants) work by regulating the production and transport of these two chemicals by targeting key enzymes and proteins made for transporting both of these agents.

    As mentioned above, one such enzyme for this conversion is the enzyme Dopamine Beta Hydroxylase (or DBH). We have investigated the importance of the gene that codes for this enzyme, the Dopamine Beta Hydroxylase gene, and its significance with regards to ADHD in earlier posts.

    Synthesis of other catecholamines (chemicals which are manufactured in the body from the amino acid tyrosine, which were alluded to in an earlier post on the drug modafinil for adult ADHD treatment and will be discussed further at the end of this post) such dopamine, norepinephrine and adrenaline) takes place in vitamin C rich regions of the body, including the adrenal glands as well as various brain regions.

    Keep in mind that the concentrations of vitamin C required for the enzymes in these brain regions to work optimally are around 40 times higher than the typical vitamin C concentration in the blood. As a result, an effective transport system to get this higher concentration in the brain is necessary, which leads to the next function of the Blood Brain Barrier (BBB):

  10. Vitamin C has multiple well-designed ways to get into the brain through the Blood Brain Barrier and its levels are tightly regulated: The Blood Brain Barrier is an important barrier that is designed to limit or prevent potentially harmful substances in the blood from crossing over into the brain, while allowing a controlled passage of nutrients into the brain. We have alluded to this barrier in the last post with regards to its role in the passage of metals such as selenium, zinc and mercury and the subsequent effects on ADHD.

    Compounds which are water soluble, such as vitamin C, have an inherently more difficult passage through this critical barrier owing to size and solubility issues (in general, the blood brain barrier naturally favors the transport of less water soluble agents). However, there are a number of ways around this potential problem.

    In biology and medicine, the term homeostasis refers to stability or resistance to uncontrolled fluctuation. The transport systems of the blood brain barrier seem to be well-suited for vitamin C, owing in part to the fact that the optimal levels of key proteins that transport the vitamin into the brain fall work at peak efficiency around the standard concentration of vitamin C in the blood (this is not the case for all nutrient transporters).

    For example one of these proteins is called the Sodium-dependent Vitamin C Transporter-2 (or SVCT-2) allows vitamin C to be transported into the brain from the blood and maintain the much higher brain concentration of the vitamin. In fact, different transport methods exist (and, to some degree are even more favorable) if vitamin C is in the oxidized form (i.e. it has already fulfilled its role as an antioxidant by "sacrificing" itself to keep harmful oxidation from occuring to something else, such as an omega-3 fatty acid).

    It is important to note that because of these tight regulatory mechanisms which safeguard levels of vitamin C both in and out of the brain, rampant supplementation with vitamin C will not change its levels in the brain to a high degree. In other words, our bodies are typically well-adapted at holding onto this vitamin and maintaining appropriate levels of this key nutrient in the brain. This provides argument against the merits of high levels of supplementation (not to say that higher levels are necessarily harmful, just that this will be of limited effect). Nevertheless, we still should strive to avoid shortages of this vitamin.

**Two other possible advantages of boosting vitamin C intake for ADHD: Please note that these next two suggestions are more of a personal hypothesis of the blogger and less validated by adequate research. Nevertheless, they may be at least worth a mention:

  1. Vitamin C may help regulate blood glucose levels in ADHD patients: Several studies seem to indicate that glucose metabolism in the brains of ADHD children is lower in multiple regions. It appears that these effects may be even more pronounced in girls and women with ADHD (although this blogger believes that the whole brain glucose metabolism differences are a bit overhyped, a number of other studies, which are simply not mentioned in most ADHD treatment books, found little to no metabolic differences. Nevertheless, I believe there is still sufficient evidence that, while smaller than what most other "ADHD experts" assert, there is still a significant difference in these metabolic patterns).

    Additionally, these differences may become more pronounced with age, suggesting a potentially greater necessity for intervention among adult ADHD cases. Again, women in particular may be more affected, according to the current body of research. It is important to note that the evidence for vitamin C supplementation for improving brain glucose metabolic efficiency for ADHD patients is more hypothetical than experimental at the moment.

    What we do know is that there are pronounced interactions with vitamin C and glucose regulation, such as vitamin C treatment for diabetic conditions. However, we may at the wrong end of a "chicken-or-the-egg" type of dilemna, since significant evidence points towards lower vitamin C concentrations in diabetic-like conditions. This is likely due, in part, to the oxidative stress caused on the body by the diabetic state (and the subsequent consumption or depletion of vitamin C stores).

    Again, most of these studies are done on diabetic conditions in the blood outside of the nervous system, but some of these effects (at least in theory) could carry over to glucose regulation in the brain. However, this blogger readily admits that this possibility is somewhat tenuous.

  2. Vitamin C can improve circulation, including to brain regions: Again, this is more on a theoretical note. In addition to its proposed role as a blood sugar regulating measure (see above), vitamin C may also help regulate blood pressure and subsequent circulatory capabilities to key brain regions. Again, the evidence supporting this assertion is much weaker than the original 10 points listed, above, but in this blogger's personal opinion, this may be another positive side effect of vitamin C treatment for ADHD.

It is important to realize that the body of research supporting these claims for utilizing vitamin C as an ADHD treatment strategy is all over the spectrum (from merely hypothetical ponderings to consistently verified controlled research studies).

At the moment, the strongest arguments for vitamin C treatment as a remedy to ADHD symptoms seem to be in protecting cells in the brain and nervous system from oxidative damage either directly via vitamin C's antioxidant capabilities or secondarily via vitamin C's ability to help regulate or "recycle" levels of other antioxidants, such as vitamin E (which much more effective at protecting the omega-3 rich regions of the brain from fatty acid oxidation) and glutathione. In other words, vitamin C is a great way to augment the ever-popular omega-3 fatty acid supplementation strategy for ADHD (and is unfortunately often overlooked by prescribing physicians).

While these effects are perhaps the most widely known among the health field, two other factors such as vitamin C's role in ADHD management are also well-documented and potentially on par with its role as a generalized antioxidant. Vitamin C is an important co-factor (enzyme helper) in a number of metabolic processes surrounding the disorder of ADHD, and is key to both the synthesis of important neurotransmitters such as dopamine and norepinephrine (which are often off-kilter in the ADHD population).

Thus, it may be a beneficial adjunct therapy for precursor loading (taking high levels of a nutrient which the body can then convert to the desired compound) with the amino acid tyrosine (which the body converts to dopamine and eventually norepinephrine via a series of enzyme-dependent steps, some which utilize vitamin C. In theory we're giving the body more starting material to work with to increase the output of these important neuro-signaling chemicals of clinical relevance to ADHD and related disorders. Please keep in mind that the literature seems to be split at the moment about the overall effectiveness of these precursor loading methods with regards to these ADHD treatment strategies).

In conclusion, maintaining adequate levels of vitamin C (for the recommended daily amounts of vitamin C, check here) is an often overlooked treatment method for a variety of diseases and disorders beyond the common cold. While perhaps not as promising as some of the other nutritionally-based treatment strategies for ADHD which have been mentioned in the past in this blog, such as carnitine, zinc, omega-3 fatty acids, iron, or magnesium and B vitamins, this simple and relatively inexpensive treatment method may pay dividends in the long run.

Furthermore, with low risks of toxicity due to its highly water-soluble nature (overdosing on vitamin C usually results in little more than temporary bouts of diarrhea which are quickly reversible when the vitamin intake is scaled back), the payoff/risk factors are favorable for regular usage of vitamin C as an auxiliary or supplementary method of nutritionally-based ADHD treatment.

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Wednesday, December 16, 2009

Can Zinc and Selenium Counteract Mercury's Effects on ADHD and Autism?

Mercury, an unwanted side-effect of the omega-3 rich fish oil treatment strategy for both ADHD and autistic spectrum disorders may be counteracted by Selenium and Zinc:

It's a catch-22 of the ADHD world. We've been told to feed ourselves and our kids as much of the omega-3 rich cold water fish as we can muster in order to balance their dietary fats and the subsequent hormonal effects. On the other hand, we're supposed to curb our fish product consumption for fear of mercury. Are there any other options beyond digging into our wallets for the pricey low-mercury wild organic salmon of the Pacific?

Why mercury is so toxic for the brain:

In general, (as one would probably expect) if a metal or compound can be cleared from the body easily, then the risk of toxicity is generally much lower. However, if the material cannot be easily cleared from the system, it can begin to build up in specific tissues or regions of the body.

Unfortunately, the brain is one of those target organs that has an almost magnetic pull for the heavy metal. While the digestive system can partially metabolize mercury into organic mercury-containing compounds, these compounds can make their way across the protective blood-brain barrier (a barrier meant to restrict the access of chemicals in the blood from passing into the brain, however, several harmful organic compounds can make their way across this barrier with relative ease).

In general, fatty acids penetrate the blood brain barrier relatively well, and these important fish fats and oils can make perfect delivery vehicles for some of these toxic compounds. In other words, mercury in fish and fish oil products can be exceptionally hard to isolate or remove from the brain.

Further complicating the matter is the problem of oxidation, especially in the brain tissue. While all organs and tissues of the body can suffer from oxidative damage (think of the biochemical equivalent of rusting or corrosion), the brain, due to its high fat content, is especially susceptible to this harmful oxidation. It is here in the brain that the mercury can become trapped and promote these dangerous oxidative processes.

Mercury and corn syrup: A hidden danger for the ADHD child?

The sugar/hyperactivity debate has been around for ages, although most of the recent evidence often refutes this commonly held assertion. Nevertheless, several nutritionists swear by their convictions about this association. So who is right?

This blogger personally believes that there is an association between sugar and ADHD-like symptoms, but this connection is likely due to secondary factors. Let me explain:

Consumption of high concentrations of sugary foods and beverages can be a metabolically taxing and stressful process on the body. The enzyme systems necessary to metabolize high quantities of sugars are dependent on an ample supply of vitamin and mineral "cofactors" (these will be discussed in more detail later on in this post), or agents that help the enzymes function propertly.

If overtaxed (as by consuming large quantities of soda or candy, for example), these vitamin and mineral cofactors can be rapidly depleted. Common cofactors such as iron, copper, zinc and selenium can be depleted in glucose (sugar) metabolism.

Interestingly, deficiencies in zinc and iron (especially when comorbid sleep disorders including restless legs syndrome are present alongside the ADHD) are common in the ADHD population. In fact, iron may be the underpinning biological factor in an alleged genetic link between ADHD and restless legs syndrome. We will be discussing the role of selenium in ADHD shortly.

Additionally, this depletion can have an effect on the antioxidant levels of the individual including a lowering of levels of pools of the important antioxidant reduced glutathione (we will be investigating the importance of glutathione later on in this post). There is some evidence of ADHD symptoms in adults being at least partially attributed to antioxidant imbalance.

In addition, the insulin rush, surge and fallout from consumption of a sugary meal can also wreak havoc on hormonal balances (including adrenaline, a chemical cousin to several neuro-chemical agents which are often seen to be off-kilter in most ADHD cases). We will save this discussion and go into more detail on the role of sugar consumption and hyperactivity and attentional deficits in later posts.

Returning to the main topic of our post (from our tangent here!), some forms of sugar may also have other hidden dangers with relevance to our post here on mercury and ADHD and related disorders. The processing and manufacturing of high fructose corn syrup (one of the most common and readily available sweetening agents in North America and much of the Westernized world), may actually leave detectable levels of mercury in the sweetener (which, the study also attributes to causing a zinc loss).

As a result, consumption of high levels of corn syrup at least has the potential to up our intake of mercury. If the mercury/autism/ADHD connection holds true, then this is one more (indirect) way in which sugary foods can increase the risk of inattention and hyperactivity associated with the disorder.

Can chelation therapy be used to effectively remove the mercury in our systems?

Our first thought might be to enlist the help of chemical agents which could pull the mercury or other toxic (and easily oxidizable metals) out of our systems.

A recent study has highlighted some possible alternatives on the mercury-fish-ADHD dilemma. One of the strategies involves the use of chelating materials. The word "chelate" comes from the Greek word "claw", and refers to an important chemical property in which a non-metallic compound can tightly bind to or "pick" up a specific type of metal and pull it away.

Ethylenediamenetetraacetic Acid
or EDTA, is one of the most well-known chelating agents for removing metals and mineral deposits from hard water, and even has some reported health implications for removing crusty hardening from human arteries.

In theory, it sounds like this may be a good treatment option for removing toxic metals or oxidizing agents from the brains and digestive tracts of children with ADHD and related disorders (i.e. the autism-mercury controversy?).

On the flip side, chelation therapy can be dangerous, especially for children, due, in part, to the fact that the chelating agents are often non-specific for their target metals. This highlights a classic problem in medical research, the rift between theory and practice.

For example, some versions or derivatives of EDTA can "pick up" or remove significant amounts of the important mineral calcium (which, in addition to its role in skeletal function is an extremely important mineral in regulating heart rhythms, and optimizing nervous system function, among other things) along with the desired heavy metals lead and mercury. Cases of deaths due to this chelation therapy for autism have been reported, and recent clinical trials for chelation therapy for autism have been halted.

Enzyme systems: Nature's alternatives to organic chelating agents?

Fortunately, our bodies contain a number of powerful enzymes which not only can protect our brain and other important organs from oxidative damage, but actually help remove harmful or toxic materials from our systems.

However, in order for these enzymes to work at optimal levels, they must be constantly equipped with adequate levels of helpful nutrients or cofactors. Cofactors, often come in the form of our dietary vitamins and minerals, such as zinc, iron, magnesium, vitamin B6, vitamin B12, vitamin C, etc., and are required by numerous enzymes in order for the enzymes to work at peak efficiency. Not surprisingly, several of these cofactors have been discussed for their relevance to ADHD in earlier postings of this blog (see links on nutrients listed above)

This is why nutrient deficiencies can be so hazardous, because literally hundreds or even thousands of enzyme systems may be in jeopardy if our bodies are deficient in just a handful of nutrients.

Two of these important enzyme system and enzyme products are the metallothionein enzyme and the peptide glutathione (which is not an enzyme, but is synthesized via several enzymes and is sensitive to the balance between oxidant and antioxidant levels).

Metallothionein has been implicated in a number of studies concerning the enzyme's relationship to autism. One theory holds that children with autism have either lower levels of this enzyme or higher levels of antibodies to the enzyme (in which the body essentially attacks its own enzyme system as part of the idea of autism being an auto-immune disorder).

While a small amount or research out there supports these claims, it is important to note that these findings are far from universal. In fact, most of the recent body of literature refutes the claim outright. One study in particular negated both the observation that metallothionein was lower in autistic children or that higher levels of antibodies to the enzyme were present in autistic children. On the other hand, lower levels of the antioxidant glutathione are often seen in cases of autism.

(Blogger's note: the reason I'm going into so much detail about autism is because the high degree of symptomal overlap between ADHD and disorders of the autistic spectrum, as well as the high degree of overlap between nutrient deficiencies concerning the two disorders).

The role of selenium and zinc in the processes of the enzyme metallothionein and the antioxidant glutathione:

We have seen in previous cases how boosting levels of one metal in the body can offset the negative effects of another such as the case of iron combatting the harmful effects of lead in ADHD.

It appears that the metallothionein function in autism is intricately tied to copper-zinc ratios, and an excess of copper (or deficiency of zinc) can hinder this enzyme's effectiveness (the presence of heavy metals such as mercury are believed to be at least partially responsible for this skewed zinc-to-copper ratio). Interestingly, significantly higher copper to zinc ratios have also been seen in ADHD children in recent studies. In addition, the transport or delivery of zinc to its desired targets may be dependent on the antioxidant functions of glutathione and the mineral selenium.

While copper and zinc balances have been studied extensively with their relationship to ADHD (here's an earlier post on ten ways zinc can counteract ADHD symptoms, or how zinc can boost the effectiveness of ADHD medications), selenium may be a "sleeper" as far as important minerals for ADHD symptom treatment goes.

While selenium is unlikely to unseat "heavyweight" minerals such as zinc, iron and magnesium for ADHD treatment, selenium is an important mineral for maintaining proper antioxidant balances, either directly (as an antioxidant itself) or indirectly (via its incorporation into selenium-dependent enzymes). The latter is evidenced by a number of important enzymes such as the dependence of the important antioxidant enzyme glutathione peroxidase on selenium.

However, given selenium's wide range of potential benefits (selenium has been implicated as an anti-cancer agent in a number of studies), it appears that this often unheralded mineral may be a useful auxiliary agent in ADHD treatment.

To conclude this message, we must remember that nutrients often work best in combos, not in isolation. This (in this blogger's humble opinion), is why so many nutritional methods which attempt to combat ADHD often fail, in that they often fail to see this interconnection between nutrient interactions. They often instruct the individual to ramp up the dosage of only one or two nutrient which are believed to be deficient, and neglect to take into account the important roles of these supporting nutrient systems as a whole.

We have seen in other postings how omega-3 fatty acids often work well with antioxidants, as well as omega-3's and carnitine for treating ADHD via nutritional methods. Vitamin C can work in tandem with vitamin E as an antioxidant supplement duo, and recent evidence suggests that vitamin C and flax oil may also be a good combo for ADHD as well. Several studies have indicated that magnesium works well with Vitamin B6 (as well as other B vitamins) as an ADHD treatment method. Zinc may also work well with omega-3's as well as vitamin B6, and now, as we have seen, potentially with selenium, as an antidote to mercury's oxidative and toxic effects.

It is imperative that we recognize the importance of these nutrients both alone and in combination, including their potential abilities to counteract chemical agents which may either cause or exacerbate ADHD symptoms.

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Tuesday, December 15, 2009

ADHD Subtype Differences and Stress

Why ADHD Subtypes Matter: Inattentive vs. Hyperactive-Impulsive ADHD and the Cortisol Response to Stress

There is growing evidence that the three traditional subtypes of ADHD (Inattentive ADHD, Hyperactive-Impulsive ADHD and the Combined ADHD subtype) may in fact, be more accurately classified as separate disorders altogether. Although the ADHD sub typing method is still likely to persist, new biochemical studies have begun to shine light on some of the physiological differences associated with the three distinct ADHD subtypes.

Significant outward expressional differences among the different subtypes can be seen, such as a more passive, less self-directed behaviors among the predominantly inattentive subtypes and more novelty seeking, stubborn and non-compliant behaviors once the hyperactivity component is added in. Perhaps this is not surprising, given the definition of impulsivity. Nevertheless, differences in accompanying disorders comorbid to ADHD also lend credence to the idea of separating the subtypes out into unique stand-alone disorders.

It has even been posited that the
disorder be subdivided further based on accompanying comorbid conditions, but at the moment this sub-classification seems unlikely. Along with comorbid conditions, age and gender differences among the ADHD subtypes have also been postulated.

Although outward behavioral expressions and phenotypes suggest stronger distinctions among the ADHD subtypes, it is the physiological and biochemical differences among these subtypes which may offer some of the most convincing evidence that a further re-classification of the disorder is warranted.

It is possible, for instance, that symptoms such as hyperactivity may predominate more than inattentive behaviors from prior medical problems such as childhood ear infections (which might seem counterintuitive, given that we would expect ear infections to promote hearing loss and compromise the attention side of the disorder more than the hyperactive-impulsive components). However, evidence for the biological differences of ADHD subtypes often goes well beyond earlier exposures to diseases and external stressors.

Getting to the meat of this issue are some recent studies on what is known as the HPA axis of the nervous system and the effects of this. "HPA" stands for hypothalamic-pituitary-adrenal, which include three essential components of the nervous system, which plays an extensive role in the fight-or-flight response in humans. So how does this tie in to ADHD?

One of the key components of this HPA axis is hormonal fluctuation. The chemical cortisol (you may have heard of cortisol from all of those late night TV and radio ads blasting cortisol for its contribution to body fat) is actually a stress-related hormone, meaning that the body produces it in response to internal or external stressors.

The kicker here is that there is now at least some evidence that the production of this cortisol hormone may be variable among the different ADHD subtypes.

It appears that children with the predominantly inattentive component of the disorder are more likely to exhibit a high cortisol response to stress while those with the more hyperactive/impulsive subtypes (just to avoid confusion, the study actually looked at the
combined ADHD subtype, which includes the hyperactive component, and not the much rarer hyperactive-impulsive subtype) may have a significantly lower boost in the stressor hormone.

This may not be all surprising, given the tendency and stereotype of the inattentive ADHD kids as being more lazy, overweight couch potatoes, while the hyperactive-impulsive kids are associated with being rail-thin fidgety and bouncing off the walls.

While this study seems to fit the bill and make sense, it is important that we try not to read too much into these results. After all, a number of other studies on the subject found little to no subtype difference with regards to HPA or the cortisol response. However, another recent study did advance this HPA notion a bit further.

This study, done by Maldonado and coworkers, found that ADHD children who exhibited more of the hyperactive-impulsive traits of the disorder had lower cortisol response levels to stressors than did the inattentive symptom dominated groups. It is important to note that the HPA/cortisol/impulsivity association has been studied extensively in the literature.

For example, an earlier study on
ADHD children in Korea, the researchers concluded that "the blunted HPA axis response to stress is related to the impulsivity in patients with ADHD", as evidenced by higher error rates on attention-based tasks. To put it another way, a higher HPA axis response (including the secretion of the cortisol hormone) is thought to be advantageous as far as attention symptoms are concerned.

As an interesting side note, this blunted HPA activity subsequent "dulling" of the fight-or-flight response among the ADHD population may, in part, explain the high percentage of ADHD'ers in stressful occupations such as firefighters, EMT's, ER physicians, and combat personnel and the like. In other words, due to the reduced HPA response among most of the ADHD population, ADHD'ers are less likely to be overwhelmed in stressful situations, and may actually be at an advantage in occupations such as these.
Remember, ADHD can have its advantages!

Further muddying the waters with respect to cortisol and the HPA axis and ADHD is the presence of comorbid disorders. Another recent publication addressed this issue and found that for boys with ADHD, the presence of a comorbid anxiety disorder was likely to raise the cortisol levels in response to stress for the child, but the presence of an oppositional or disruptive behavioral comorbid disorder showed a tendency to lower the cortisol response to stress in the ADHD child.

These findings show agreement with some of the earlier statements made above, given that comorbid anxiety disorders are often hallmark characteristics of either the inattentive or combined sub-components of ADHD, while oppositional or conduct disorders are seen at higher frequency with the hyperactive/impulsive or combined ADHD subtypes.

Blogger's personal note: The concept of oppositional behaviors in ADHD is somewhat interesting. It appears that there may be much more going on under the surface with regards to ADHD and oppositional/conduct disorders and dysfunction within the nervous system. These behaviors may be associated with seemingly unrelated functions among the ADHD population such as bedwetting. I don't mean to sound like a "conspiracy theorist", but for an interesting read on the subject, this blogger personally recommends an earlier post entitled Bedwetting ADHD Kids and Depressed Dads: Is there a Connection?

Returning to our topic of discussion here, it is important to remember that in the first study mentioned, it was the hyperactive-impulsive children who showed more of a blunted cortisol response to stressors, so these observations from research groups in three different countries all seem to be reaching similar conclusions.

In conclusion, we should take away from these studies that the different ADHD subtypes may exhibit distinct hormonal response differences, as well as neuro-chemical activity differences between the ADHD and the non-ADHD populations. In general the more hyperactivity and/or impulsivity we see, the lesser the HPA-derived cortisol response e would expect to see in reaction to stressful situations.

We can also see that comorbid disorders alongside the ADHD may either further dampen this HPA activity and cortisol response (as in the case of oppositional disorders), or counteract the ADHD response by boosting HPA activity and cortisol levels (as in the example of many anxiety disorders). The take-home message is this: ADHD subtype differences and the presence of comorbid disorders can play a pivotal role in the hormonal fluctuations among the ADHD population.

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Sunday, November 8, 2009

"Dirty" Electricity and ADHD

Could fixing your power sources help clear up ADHD symptoms?

We often hear about the health impacts of prolonged exposure to electrical and magnetic fields, including those involving cognitive deficits, neuro-developmental difficulties, and increased cancer risks. We would come to expect that some of these same invisible forces may also be at work with disorders such as ADHD.

In previous posts, we have covered how full-spectrum light exposure (within the context of seasonal affective disorders) can influence ADHD severity and symptomology.

In my reading, I recently came across an article from a few years back that caught my attention. This article was from the journal Electromagnetic Biology and Medicine, and involved a phenomenon known as "dirty electricity". The authors posited that this type of electricity, which occurs when electricity passes through several types of electronic devices such as computers or microwaves, which creates a more "noisy" spectrum (think of the analogy of a river or stream that picks up waste and debris along the way of its course) than "clean" electricity, may be a factor in a wide array of diseases and disorders ranging from diabetes to multiple sclerosis, to asthma, to fibromyalgia to neurological dysfunction (including balancing difficulties as well as ADHD-like behaviors and symptoms).

Although ADHD was not the main concern of the article (which focused more heavily on the diabetic and MS complications associated with this dirty electricity), the importance of maintaining appropriate blood sugar levels to the brains of ADHD patients should at least warrant further investigation into the matter.

By no means do I believe that this "dirty" electricity is a predominant contributing factor to a child's (or adult's) ADHD, but I did want to at least make the blogosphere aware that this may be an overlooked area of treatable potential. Some of the results of the study were intriguing to say the least.

For example, the authors found that:

  • Fatigue among individuals in a building "sick" from dirty electricity is much more common than previously believed. Due to their size and range of appliances and power consumption patterns, schools are often prime candidates for being vulnerable to this dirty electricity phenomena. Fatigue and overall sickness in students and teachers may be significantly reduced if special electrical filters (called Graham/Stetzer or GS filters) are utilized. Similar results have been found in other related studies (please keep in mind that several of these are somewhat biased, i.e. published by the makers of these electrical filters. For reference, this blogger has absolutely no affiliation with Graham Stetzer and does not receive any type of compensation from the makers of these filters).
  • Furthermore, exposure to higher levels of electromagnetic fields results in an increase in production of "stress" proteins in the body. The degree of this varies, as a number of individuals carry more of a hypersensitivity to electrical fields than others. This high level of inter-individual variability makes it difficult to set concrete limits on safety concerns surrounding electromagnetic exposure.
  • Additionally, the original article cited a case of significant improvement in balance and walking ability in and individual with multiple sclerosis following the "cleaning" of electricity in his area by using the electrical filters. Much like the phenomena of birds flying into more windows in areas near power lines (which can interfere with the bird's internal magnetic-based sense of direction), it is possible that cleaning up the power supply may have similar effects on humans.
Please note: it's important not to get too excited or attempt to draw too many theoretical conclusions based on these observations. Keep in mind that this individual was diagnosed with MS and it was just a case study. Nevertheless, given the previously mentioned association between ADHD and early infections the inner ear (which affects balance and coordination), the potential influence of electrical fields may somehow tie in to all of this as well. This is simply a working hypothesis of the blogger at the moment.

However, given the fact that abnormal glucose metabolism and blood sugar levels are typically depressed or less stable in the brains of ADHD patients as well as the possible connection between ADHD and areas involved with the balancing regions of the nervous system, the effects of electrical fields on the disorder may be larger than we previously realized.

**As an interesting aside, many of the brain glucose studies of ADHD patients have found that glucose metabolic differences are often more pronounced in girls and women with the disorder than boys or men. It stands to reason (at least on a theoretical basis, but not to prematurely draw any conclusions) that similar gender-based differences may exist with regards to blood sugar levels in the brain as a result of exposure to electromagnetic fields of "dirty" electricity.

Again, to reiterate that this blogger has no affiliation with the filters nor receives any compensation for endorsement of these products, it may be useful to investigate how "dirty" the power in your home, school or office really is, especially if you or a loved one have ADHD or one of the related complications listed in the original article.

**For reference sake, the cost of a meter for measuring dirty electricity runs somewhere from 100 to 150 US dollars (at least based off of what this blogger has seen), and the filters are about 35 US dollars apiece (not surprisingly the companies often recommend sets of 20 for an average home, bringing the grand total up over 800 US dollars. Not a small sum, of course!).

As of now, this blogger is undecided whether the negative impact of dirty electricity is enough to warrant the pricey purchase of these power cleanup methods and devices. The main point for this post was simply bring a lesser-known phenomena of electrical pollution and highlight at least some of the theoretical basis for exacerbating attentional deficits and ADHD symptoms.

Given the widely-encompassing health risks covering various diseases and disorders (listed in the original article and beyond ADHD), it may be worthwhile to spend some time in more personal investigation on the topic.

Nevertheless, these little-known connection (such as those between power lines and blood sugar levels) should serve to highlight the fact that ADHD is a multi-faceted disorder, and its symptoms may be governed by an ever-widening array of influential factors.

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Tuesday, October 20, 2009

Treating ADHD by Floating in Salt Water?

Can Floating in Salt Water Near Body Temperature be Used as an Effective, Natural ADHD Treatment?

One of the things I enjoy most about researching and writing this blog is that I get a chance to review the literature of some pretty zany diagnostic and treatment methods for ADHD. I often wonder what is going through the minds of some of these researchers as they concoct these seemingly eccentric modes of treatment for the disorder.

This blog has covered some of these seemingly bizarre treatments, including treating ADHD with mirrors, EEG manipulated ADHD treatment, light therapy for ADHD with seasonal affective disorders, and the effectiveness of behavioral therapy measures for ADHD, and hinted at other treatments such as vestibular stimulation for ADHD.

A recent article in Cases Journal on treating a patient with ADHD and Asperger's by flotation sessions in a tank of salt water struck me as particularly bizarre, but piqued my curiosity. However, the justifications and apparent effectiveness of these measures suggests that further investigation may be warranted. Before we all decide to take a prolonged trip to the Dead Sea, we should investigate the methods of this treatment process and check for scientific evidence behind its claims. Below is a summary of the process, and some of the major points the article's authors conjured up to validate the effects of this form of ADHD treatment.
  • As the name of the journal title suggests, this was a case report on a single individual, and not a controlled clinical study. However, I have repeated given my opinion on how case studies, although statistically inferior to controlled trials, should retain a place in novel medical treatments.

  • The patient was a 36 year-old woman co-diagnosed with ADHD and Asperger's (although keep in mind that many diagnostic methods forbid the co-diagnosis of ADHD with anything along the Autistic Spectrum, including Asperger's. However, many clinicians often ignore this guideline and have no problem with diagnosing a person with these two comorbid disorders).

  • The study authors noted that a number of the alternative treatments which previously showed promise hinged on triggering arousal levels (mirrors, EEG, etc.). It is well documented that deficiencies within arousal levels are common in the ADHD population. Hence, a sensory stimulation via flotation in a water tank may possibly show promise as an alternative ADHD treatment.

  • The flotation device is essentially a covered tank (to minimize the impact of outside sources of stimulation) containing highly concentrated salt water (to enable easier floating and buoyancy) at near-body temperature (to reduce tactile stimulation due to a temperature difference between the person's body and outside environment). Keep in mind that this water is typically only 8 inches to a foot (20 to 30 centimeters) deep, and its high salt content (much higher than the ocean) allows one to float easily without touching the bottom of the tank. This method, called flotation-Restricted Environmental Stimulation Technique or flotation-REST, has been shown to be an effective stress-reliever and relaxation method. A total of 19 flotation treatment sessions were done within the span of about a year.

  • The authors found five key components (arousal control, inhibition/activity regulation, sensory integration and interpretation, cognitive abilities, and emotional abilities) of ADHD behavior to be positively affected by flotation.
  1. Arousal control: As mentioned previously, arousal levels have been shown to be a significant component of ADHD (and it can be either over or under-arousal). The flotation-REST method apparently addresses the arousal problem and normalizes this state by providing an environment which screens out most visual and tactile environmental stimulants.

  2. Activity regulation/inhibitory control of physical processes: Often a hallmark characteristic of ADHD is the difficulty with inhibition control or impulsivity with regards to physical movements, especially in younger children. Impulsively grabbing at objects or persons is a common occurrence among children with the disorder (as almost any parent of and ADHD child can attest!). The salt water/ADHD treatment case study highlights that the salt water flotation/isolation therapy may alleviate some of this behavior due to it's effect on allowing the individual to "internalize" their focus on their physical movements, which may build up more regulatory ability of motor control and enhance the ability to restrict inappropriate physical impulses.

  3. Sensory integration: We have previously alluded to the possible connection between ADHD and sensory integration (in the context of balance impairment and inner-ear dysfunction on ADHD) disorders. Additionally, numerous studies on fine motor skill deficiencies, such as handwriting and ADHD have been covered this blog and studied in the literature. It appears (at least in theory, according to the case study and journal article) that the flotation experience in a sensory restricted environment enhances the patient's sensory integration abilities by depriving external sensory stimuli, leaving room for the person in the salt water tank more time to focus and coordinate his or her senses.

  4. Improvements in cognitive abilities for ADHD patients: We have discussed cognitive abilities in ADHD (as related to pharmacological treatment strategies) in previous posts, and there are numerous studies on comorbid cognitive deficits in those with ADHD. Furthermore, some posit a cognitive energy deficiency as the underlying cause to ADHD, identified as a cognitive-energetic model of the disorder. These deficiencies are believed to be at least partially remedied or improved by the flotation in salt water treatment, mainly due to the distraction-free environment being conducive to periods of prolonged concentration and enhanced thinking without interruption. According to the article, many of these benefits continue after the individual is out of the tank even for a period of a few weeks (of which these effects then begin to taper off).

  5. Imrovements in personal emotional abilities: Emotional abilities, especially as they relate to inter-personal interactions and relationships can also be a common deficit in individuals with ADHD. The flotation technique is believed to improve this aspect as well, as it provides an environment of personal self-acceptance which can then be transferred to improved relationships with others and their emotions.
In conclusion, we should probably not go running out to buy a big shark tank (minus the shark of course!) just yet. Remember, this was just one simple case study done in Sweden of a 36-year old woman with comorbid Asperger's. Obviously further study is warranted, and there are a number of loose ends that must be tied up before this alternative treatment method is accepted and goes mainstream. Future studies on the effectiveness of this treatment for children with the disorder would be especially useful. Nevertheless, this Flotation Restricted Environment Stimulation Technique (flotation REST) has shown to be useful in other areas of psychological function, including as a relaxation/stress reduction method.

Thus, (in this blogger's personal opinion) this flotation REST technique may be especially good for ADHD'ers who suffer from high levels or irritability or have comorbid anxiety or depressive qualities (perhaps not those with claustrophobia or hydrophobia though!). Individuals with ADHD who have responded well to Wellbutrin or other antidepressant medications may be especially good candidates for this flotation treatment, at least in theory based on our current observations at the time.

Additionally, it is worth the re-mention that the woman of the case study had co-morbid (co-existing) Asperger's and was already on an antidepressant medication throughout the whole course of the study. This may be good news for those who suffer from co-morbid disorders, as well as the fact that this flotation REST technique seems to be relatively compatible with medication treatment. Thus supplemental treatment by flotation in salt water near body temperature may be a good adjunctive measure for individuals with ADHD and a wide spectrum of comorbid disorders.

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Sunday, October 11, 2009

Drugs, Genes and ADHD

The Effects Specific "ADHD Genes" Have on Dosing ADHD Medications:

Below is a list of five of the most common medications for ADHD. In order to break down or metabolize these drugs, however, a series of steps must take place for effective absorption, delivery and clearance of these drugs. This process, however, requires a series of enzymatic steps. Generally, when a physician prescribes these drugs, he or she considers factors such as the patient's age, gender, symptom severity and past medication history. However, lost in the shuffle is a lesser-known, but often equally critical factor: the particular genes of the individual. It is these genes which play a large role as to how well these enzymes function (alongside other factors such as the person's nutritional status, as most vitamins and minerals act as chemical "helpers" to these enzymes, and deficiencies can lead to lower enzyme function and sub-optimal metabolic efficiency).

Unfortunately for prescribing physicians, the landscape of enzyme capabilities among the general population is far from uniform. Some individuals naturally possess enzymes or enzyme systems (which are coded for and dependent on the genetic makeup of the particular individual)which are more efficient than others (often by multi fold differences). If these enzymes are essential to drug metabolism (including ADHD medications), then a potentially crucial piece of information may be missing from the physician's repertoire of assessment tools for medicating at the proper dosage.

Much to the dismay of many a frustrated parent of an ADHD child, this often begins the laborious process of adjusting medication dosages through a glorified "guess and check" process. However, due to the need for a relatively small window of effective dosing (especially for psychotropic drugs such as those prescribed for ADHD and related disorders) and unforgiving margins of error in the optimization process, bits of information, such as a child's genetically-dictated levels of drug-metabolizing enzymes could be extremely useful. With the increasing efficiency, lowering costs of and wider availability of genetic screening methods, we may soon be able to predict a child's enzyme levels by their genetic makeup and facilitate the dosing of (and eliminating much of the guess-work from) their medications for ADHD or other disorders, saving both time and money while on the medication circuit.

Given the powerful role of enzymes and enzyme systems (and the specific genes which encode for them) for the delivery, metabolism and clearance of these medications, we should take a look at some of the genetic variations of these enzymes and the implications they may having in assisting the diagnosing physician in the near future for more effectively dosing ADHD medications.

Here are 5 common ADHD drugs (including one which is not prescribed but often used as a "self-medication" tool among the ADHD population), and the genetically-dictated enzymes which can play a role in their metabolism and dosing patterns and levels.

ADHD Drug #1: Strattera (Atomoxetine)

Key enzymes involved and gene of interest: SLC6A2, CYP2D6

We have already investigated another gene believed to have an impact on dosing with Strattera, the SLC6A2 gene. However, in that earlier post, we alluded to another gene responsible for the metabolism of the non-stimulant ADHD drug Atomoxetine. This gene is called CYP2D6. The CYP2D6 gene codes for an important enzyme of the same name (which is an important enzyme produced in the liver). The gene is located on the 22nd human chromosome (the 22q13.1 genetic region to be more specific if you are familiar with genetic markers).

Approximately a dozen different genetic forms (or alleles) of this CYP2D6 gene are seen in individuals of European ancestry. These forms are often designated by a star followed by a number, such as *1 or *4. While these numbers are used for naming purposes, it is worth noting that most individuals of European descent appear to carry either the *1 (the most common), the *2 or the *4 form of this gene. Additionally, *3, *6, and *10 forms are each found in about 1-2 percent of the population.

Interestingly, the *10 form of this gene is found in higher levels in individuals of East-Asian descent. A Chinese study found that a higher frequency of this *10 form in the population (the *10 form shows up in over half of the Chinese population, about 10 times more frequently than in whites), resulted in slower rate of drug metabolism of the ADHD medication Strattera (Atomoxetine) by the CYP2D6 enzyme.

Relevance of the CYP2D6 gene to medicating ADHD with Strattera: The *10 form of the CYP2D6 produces less enzymatic activity than the most common *1 form. This can result in about a 50% increase in Atomoxetine concentration in the blood and duration before clearance, which was seen in the Chinese study. As a result, for individuals with the exclusive *10 form (such as seen in much of the East Asian population), slightly lower or less frequent dosing levels of atomoxetine might be needed to get the same therapeutic effects. This is in agreement with another study suggesting a 50 to 75% dosage reduction of Atomoxetine for those with hepatic impairment (liver dysfunction), as the CYP2D6 enzyme is produced in the liver.

Additionally, this population may be at a slightly greater risk of side effects with the drug due to a slower clearance and greater buildup of the drug. Of course other genes and additional factors in the Atomoxetine pathway certainly play a role, but these genetic variations can still play a significant role in medication dosing strategies.

ADHD drug #2: Adderall (Mixed amphetamine salts)

Genes of interest: Catechol O-Methyltransferase (COMT) gene, Dopamine Transporter Gene (DAT)

In previous posts, we have spoken extensively about a gene called COMT, short for Catechol O-Methyltransferase and its role on dosing for amphetamine-related ADHD medications such as Adderall and Vyvanse. This previous discsussion on COMT and ADHD medication dosing can be found here.

However, there are a few other genes worth noting here for their potential roles in dosing with amphetamine-based ADHD medications such as Adderall. One of these is the Dopamine Transporter gene (DAT), which is located on the 5th human chromosome. This gene also goes by other names such as DAT1 or SLC6A3. The DAT gene codes for an important protein called the Dopamine Transporter protein, which is responsible for shuttling the important brain chemical dopamine in and out of neuronal cells.

A number of stimulant drugs used to treat ADHD and related disorders work, at least in part, by interacting with this dopamine transporter (DAT) to correct a dopamine imbalance (in general, individuals with ADHD often have too little dopamine in the regions between brain cells or neurons in key regions of the brain. Many stimulant ADHD drugs remedy this by blocking the shuttling of dopamine back into the cells, keeping adequate amounts in these "gaps").

Interestingly, on a side note, the DAT gene has been implicated (in conjunction with another dopamine-related gene called DRD4) in IQ levels an behavior problems.

Like the genes mentioned above, DAT exists in a wide number of different forms across the human gene pool. Some forms appear to increase ones predisposition to ADHD and various neurophysiological or behavioral disorders and have earned the moniker "high risk alleles" (remember, an "allele" is simply a specific form of a gene which varies within the population).

A study on families of ADHD children found that a specific form of the DAT gene which included a 480 base pair repeat (simply a repeating section of DNA which is 480 DNA "letters" long) allele was associated with greater severity of ADHD symptoms, especially in the combined ADHD subtype (which includes high levels of both inattentive and hyperactive/impulsive symptoms as opposed to a predominance of one).

Potentially, individuals with ADHD who carry this "high-risk allele" of the DAT gene (which is a substantial portion of the general population) may require slightly higher levels of medication dosage with amphetamine-based stimulants than their "lower-risk" counterparts. These differences may be even more pronounced if the individual carries the "Val" form of the COMT gene, mentioned in a previous post (given the current body of research on the subject, the contributions of the COMT gene dwarf those of the DAT gene with regards to governing amphetamine dosage levels).

ADHD drug #3 Vyvanse (lisdexamfetamine dimesylate)

Gene of Interest: Trypsinogen

Due to its chemical proximity to amphetamines (Vyvanse is essentially an "inactivated" form of the drug Dexedrine, which is an isolation of one of the potent components of Adderall). A special chemical "tag" is linked to the active part of the drug, which must be chemically cleaved to release the active form of Vyvanse (think of it as essentially breaking a seal to free up the drug) into its functional amphetamine-based product. Naturally, the genes listed above (and the enzymes which they encode) which metabolize amphetamines are of substantial interest for potentially influencing the effectiveness of ADHD treatment with Vyvanse as well.

However, the actual cleaving process of releasing the active component of Vyvanse is equally as important. If the drug is not freed, then it cannot be effectively metabolized.

Several enzymes which are called upon to metabolize the other ADHD drugs in this post do NOT appear to have a significant effect on Vyvanse. These include CYP2A6, CYP2B6 (both for nicotine), and CYP2D6 (for Strattera). This is good news for those who are already taking medications, as Vyvanse's relative independence of these drug-metabolizing enzymes means fewer adverse drug-drug interactions.

As far as genetics go, the genes coding for the breakage of de-activating chemical tag placed on Vyvanse may be of most importance, especially since this breakage (or "hydrolysis") is believed to be the slowest (or rate-determining) step in metabolizing Vyvanse for ADHD. The de-activating "tag" attached to Vyvanse is none other than the amino acid lysine. While the exact mechanism of cleaving this link is not fully known, one enzyme in particular may be extremely relevant to this process.

Trypsin is an extremely common digestive enzyme produced predominantly in the pancreas. It is responsible for breaking up chemical linkages much like that of the one used to de-activate Vyvanse. Thus, a genetically-governed deficiency of the trypsin enzyme could lead to a severely hampered absorption (and subsequent metabolism and clearance of the ADHD drug Vyvanse).

Trypsin is actually coded for by a series of enzymes, often referred to as Trypsinogen, which located on the 7th human chromosome (in the "q35" region of the chromosome to be more exact). Individuals with pancreatic deficiencies, including pancreatitis have been tied down to having mutations in this trypsinogen gene.

Therefore, while this genetic region on the 7th chromosome hasn't been sufficiently studied with regards to Vyvanse (at least to the best of this blogger's current knowledge), this blogger personally believes that aberrations in the region of the Trypsinogen gene on this 7th human chromosome may be a worthwhile place to look for genetic response-based differences to the ADHD medication Vyvanse.

ADHD drug #4: Concerta/Ritalin/Daytrana/Biphentin (methylphenidate)

Genes of Interest: Carboxylesterase 1 (also referred to as "CES1"), DAT (refer to ADHD drug #2: Adderall section for DAT's genetic location)

Carboxylesterase 1: Although the affected form of this enzyme, which is coded for by a gene on the 16th chromosome, is relatively rare, some key studies have indicated that deficiencies in the CES1 enzyme can be coded from specific forms of this gene. These rare, low-functioning gene-mutation forms of Carboxylesterase 1 result in extremely poor methylphenidate metabolism, resulting in a buildup of abnormally high levels of the drug in individuals with this enzymatically-deficient form.

In addition to their effects on amphetamines such as Adderall or Dexedrine, variations (often referred to in the literature as "polymorphisms") in the DAT gene also play a role in the response to methylphenidate. A Korean study found that a specific allele (the 10-repeat allele, which is the same form as the "high-risk" 480 base-pair allele mentioned earlier in the amphetamines section) predicted a poor response to methylphenidate.

Interestingly, however, several Irish studies suggest the exact opposite: the "high-risk" 10-repeat 480 base pair form of the DAT gene may produce larger amounts of the DAT protein (which shuttles essential dopamine out of the gaps between the cells, the opposite effect of what one wants if they suffer from ADHD), so the higher levels of expression of this transporter may make it a better candidate for methylphenidate.

Another Irish study may help resolve some of this discrepancy. It found that individuals with the so-called "high-risk" form of the DAT gene mentioned above exhibit a more positive response to treatment with methylphenidate with regards to treating their attentional symptoms based on the left side of the brain. Left sided inattention can be a reflection of brain damage or brain asymmetry, the latter being a common trait in the ADHD population. It should be worth noting that methylphenidate has been an effective treatment method for improving cognitive processes for those suffering from traumatic brain injuries.

Given the fact that in the amphetamine section we mentioned that the DAT gene was more connected to the Combined ADHD subtype (the original article specifically stated that the association did not hold for the strictly inattentive ADHD subtype). If this holds true, then we may have discovered a potentially significant gene/medication/ADHD subtype association.

It is this blogger's current hypothesis that the "high-risk"/480 base pair/10-repeat allele form of the DAT gene might predispose one to a MORE FAVORABLE response to methylphenidate treatment if inattention is the most persistent ADHD symptom (as in the predominantly inattentive ADHD subtype). Conversely, if the hyperactive/impulsive behavior either predominates or is largely present in an individual (such as in the hyperactive/impulsive or combined ADHD subtypes, respectively), then the "high-risk" label holds for this particular gene type, and the methylphenidate response potential goes down.

In other words, if large amounts of hyperactivity are present (which is the case in most ADHD children, as the combined subtype is by far the most common form), then this "high-risk" form of the DAT gene hampers methylphenidate's effectiveness, whereas if hyperactivity is largely absent, then the response to methylphenidate is actually more favorable. If this hypothesis were to hold true, then we could screen youngsters for this form of the gene and keep them far away from methylphenidate if they were bouncing off the walls, whereas if the exhibited more of an inattentive "space cadet" type of behavior then methylphenidate might be a good first choice of pharmaceutical treatment. Of course this theory could be completely off-base, but given this blogger's current knowledge and exposure to the current literature, this may be a plausible explanation.

Another possible explanation for this discrepancy between Irish and Korean studies: We have already seen that specific forms of certain genes can be found at considerably higher levels such as the *10 form of the CYP2D6 gene mentioned above with regards to the East Asian population. Keep in mind that this gene form was associated with the metabolism of Strattera (which exhibits a significantly different mode of operation than do stimulants such as methylphenidate or mixed amphetamine salts). However, there are a number of so-called ADHD genes which have been implicated with the disorder. The current thought here is that some genes exhibit a more powerful influence on physical or behavioral traits than do others. In other words, some genes simply act more "powerfully" than others. This is known as epistasis ("Epistasis" roughly means "standing upon").

***As a side note, please don't confuse "epistasis" with the whole dominant/recessive "big A/little a" (Aa) gene thing you probably learned about in middle school biology. Dominant/recessive refers to different forms of the SAME gene, whereas epistasis refers to DIFFERENT genes. For example, let's say, hypothetically that there was a rare gene for green hair located on the 20th human chromosome. However, a more "powerful" gene, say on the 14th chromosome codes for brown hair. This brown hair gene in this case would be epistatic, meaning that it would overpower the effects of the green hair gene altogether. This phenomena is quite common in genetics.

Getting back to our discussion, this blogger hypothesizes that there may be one or more other unidentified genes in either the Korean or Irish population which are epistatic to the DAT gene with regards to the methylphenidate response. If this was true, then it's quite possible that the effects of these hypothetical yet-to-be-identified genes might "mask" or override the effects of the DAT gene, and that the association with the "high-risk allele" may be largely coincidental rather than causative. Given the state of the current research on current "heavyweight" genes such as the COMT gene mentioned earlier, it is entirely possible that the overall level of contribution among specific "high-risk" DAT alleles might be less significant than many of these studies seem to indicate.

Of course the discrepancy could just as easily be attributed to small sampling sizes, slight differences in experimental methods or uncontrolled variables in the experiment (or a complete lack of true association between methylphenidate and the DAT gene at all, although given the current body of literature, this last assertion seems highly unlikely).

ADHD drug #5: Nicotine:

Genes of interest: CYP2A6, CYP2B6

I have included this drug due to the high rates of smoking among those with ADHD. As with alcohol, nicotine is often widely used as a form of self-medication for those with ADHD. Some research even suggests that individuals with ADHD exhibit a different response to nicotine and that nicotine withdrawal may produce different patterns in certain critical brain regions between ADHD'ers and the general population. Interestingly, there are some genetic regions which may tie into this behavior.

With regards to nicotine metabolism, 2 genes appear to stand out in particular: CYP2A6 and CYP2B6 (note the similarity in nomenclature between these and the gene/enzyme mentioned above for Strattera metabolism CYP2D6. This is not an accident, as all three of these belong to the same "superfamily" of enzymes and carry many similar chemical and functional similarities). Out of these, the CYP2A6 (hereafter abbreviated as "2A6") enzyme is responsible for the lion's share of nicotine metabolism. It is coded for by by a gene of the same name, located in the "q13.2" region on the 19th human chromosome.

Like the 2D6 gene for Strattera, the 2A6 gene can exist in multiple different forms. Some 2A6 gene forms produce higher levels of the 2A6 enzyme than others. Other forms of 2A6 are less efficient, which results in a slower breakdown and clearance of nicotine. As a result, the nicotine stays in the body longer, and less of it is typically required. As a result individuals with these less efficient forms (called "slow metabolizers") of the 2A6 genes are less likely to develop nicotine addictions.

The relevance of these 2A6 genes on ADHD: The stimulating effects of nicotine are believed to be a major contributing factor to the higher prevalence of smoking among the ADHD population. If this is true, then slow metabolizers of nicotine may not derive the full effect of nicotine self-medication for attentional deficits, at least not as immediately as the fast metabolizers. On the flipside, they have lower cravings (like with virtually all stimulant drugs, the speed and rate of uptake and clearance of nicotine is a major factor in its addiction potential) and are exposed to less tobacco and often find it easier to quit smoking.

At least two alleles or forms of the 2A6 gene (using the "star/number" nomencalture us used in 2D6 for Strattera earlier in this blog), have been shown to coincide with slower rates of nicotine metabolism. They are 2A6*2 and 2A6*4 (these two forms are actually referred to as "null alleles" meaning that the 2A6 enzyme they code for has no activity).

Additionally, there are noticeable differences in the frequencies of these forms across different ethnicities among the global population. For example, these "slow metabolizing" gene/enzyme forms of are found in higher percentages in individuals of Asian ancestry (around 20%) compared to those of European descent (around 8%).

With regards to ADHD behavior, it is likely that people possessing these *2 or *4 forms of the CYP2A6 gene, may be less likely to use nicotine as a self-medication tool for their ADHD, or at least use the drug in lower doses, due to its lesser effects. On the flipside, however, there is another allele of the 2A6 gene, referred to as CYP2A6*1B. This version of the 2A6 nicotine metabolism gene actually promotes greater activity of the nicotine metabolizing enzyme, and speeds up the processing and clearance of the drug. As a result, individuals who possess this relatively rare CYP2A6 form may be more prone to more frequent use and abuse of nicotine, and individuals with ADHD who attempt to self-medicate with this drug may cycle through their nicotine more rapidly if they carry this *1B form of the gene.

Interestingly, another drug, bupropion (Wellbutrin), which is an anti-depressant often used off-label to treat more "depressive" forms of ADHD is a relatively common anti-smoking drug. Given the fact that a number of ADHD'ers who typically do not respond well to stimulants, but do respond to Wellbutrin may fall in this smoking category, it is possible that the fast metabolizers (i.e. the *1B individuals), may be good candidates for Wellbutrin, not only to stop smoking, but possibly also to treat unwanted ADHD symptoms.

Alleles of the CYP2B6 gene and enzyme with regards to nicotine and ADHD:

Shifting gears for a minute, we see that the CYP2B6 gene (as well as the enzyme which it encodes) also may also play a unique role in ADHD. The CYP2B6 gene is located on the 19th human chromosome (in the 13.2 region of the 19th, to be more specific). For individuals who lack CYP2A6 enzyme activity because of the reduced-activity or even "null" alleles, the enzyme CYP2B6 can metabolize nicotine in its place (it turns out that CYP2D6, the enzyme responsible for Strattera metabolism can also do the trick). For those who need to metabolize nicotine, but lack an effective CYP2A6 enzyme system, this is good news (however, this "B6" enzyme only functions at about 10% of the level of the "A6" enzyme, so B6 is not a very efficient "backup" for A6).

Beyond its role as a "backup" for the CYP2A6 enzyme, CYP2B6 may also be of clinical significance with regards to ADHD and similar disorders. In contrast to "A6", whose enzymes are predominantly generated in the liver, the CYP2B6 generated enzymes are expressed in brain tissue. With regards to the differences in neurochemistry and neurological functioning of the ADHD brain, the role of CYP2B6 is therefore potentially noteworthy.

Additionally, as we have discussed in earlier posts regarding ADHD and alcoholism, the 2B6 enzyme apparently also plays a role in alcoholism, and individuals who express higher levels of this genetically-encoded CYP2B6 enzyme in their brains may be more sensitive to alcohol, nicotine and other centrally acting drugs. The study even suggests that individuals with high levels of this gene-coded enzyme may be more prone to damages induced from these common chemical agents, including possible higher susceptibility to cancer.

For reference (using the "star" notation again), genetic forms of CYP2B6 which typically yield higher levels of this enzyme in the brain include the CYP2B6*4 (which shows up in about a third of the European popluation) form and the CYP2B6*9 (which is present in about a quarter of those of European descent) form. Again, don't worry too much about the specifics of these "starred" variants, just know that if you were to get a genetic screen and had one of these two enzymatic forms, you may be more sensitive to nicotine as a self-treatment ADHD "medication".

What this means is that ADHD individuals who harbor the higher-expressing "*4" and "*9" forms of the CYP2B6 enzyme in their brains may be more sensitive to chemical agents such as nicotine, and these same individuals may be more likely to suffer the toxic effects of this popular form of ADHD "self-medication".

In conclusion, we should note that some of these genes (such as DAT) have been well-studied and have repeatedly shown to be associated factor in proper dosing of ADHD medications. Others, however, such as the trypsinogen gene for Vyvanse are more at the theoretical level at the moment. However, this blogger believes that in the next couple of decades, (due in part to our expanding knowledge of the human genetic code and functional genomics), genetic screens will become foutinely more commonplace as a necessary tool for both prescribing and dosing medications. With regards to this general trend, psychotropic medications for disorders such as ADHD should be no exception.

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