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

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

Throughout the last six posts on this blog, all of which were concerned with tyrosine supplementation strategies for ADHD, we alluded to the fact that introducing high levels of tyrosine into the body can precipitate a number of other biochemical processes besides the conversion to dopamine and norepinephrine in the brain of the ADHD patient. For reference, I have included the diagram we've been following for the past six blog posts on ADHD and supplementing with tyrosine (you can click on the diagram below and get a larger picture in most browsers):

As we can see, there are a number of enzymes, processes and intermediate steps involved in just this one pathway of tyrosine. Please note that other nutrients, such as ascorbic acid (a.k.a. vitamin C, which has a number of connections to ADHD) and S-Adenosyl methionine (also known as SAM or SAMe, which has also been discussed in greater detail in relation to ADHD elsewhere) are required in this process.

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

Here is a quick summary of some of the enzymes used and some of the key vitamins and minerals required (either directly or indirectly) to optimize this enzyme's function:

Tyrosine Hydroxylase: (iron, vitamin C, magnesium, zinc, copper, folic acid or folate, niacin). This is perhaps the most important step of the process, in that it is the slowest or "rate-limiting" step. Because of this, we want to make sure all necessary nutrient "co-factors" (helpers) are in place to help move along this "slow" step as fast as possible)

Dopa Decarboxylase: (vitamin B6, zinc. Also note that excessive levels of some other amino acids, such as leucine, isoleucine, valine, and, especially, tryptophan can compromise this step of tyrosine metabolism. Furthermore, buildup of one of the products of tryptophan metabolism, serotonin, can inhibit or begin to shut down the activity of this Dopa Decarboxylase enzyme and compromise our tyrosine-to-dopamine conversion pathway. This spells bad news if we want to attempt to regulate these dopamine levels in an ADHD brain)

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

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

Keep in mind that this list is not extensive. However, the vitamins and minerals are some of the key players in the conversion processes of tyrosine metabolism.

Other Pathways of Tyrosine Metabolism and the Generation of Homocysteine

This is extremely important. A lot of times we get lulled into believing that just because we're using a natural or dietary-based treatment strategy instead of potentially harmful medications, we are immune to negative and/or dangerous side effects typically associated with drugs. However, as a blogger, I urge everyone to reject this idea as quickly as possible. While the side effects as a whole may be a bit more benign or have more room for error for nutrient-based ADHD treatments, going overboard can be just as harmful.

Minerals such as iron, copper and chromium all can be extremely toxic at high levels, and overdosing on certain vitamins (especially the fat soluble ones such as vitamins A and E, which are more difficult to flush out of the system than the water soluble ones), can also be harmful (or even fatal). Even the water-soluble B vitamins can cause problems if overdone (there is a high degree of interaction among most of these, and there is a relatively delicate balance between their levels. Over-supplementing on one, therefore, can greatly compromise the others).

Amino acid supplementation can also be tricky. We mentioned in an earlier posting that chemically similar amino acids often "compete" with each other in areas such as entry into the brain and competition for the same enzymes. As a result, if we go overboard with supplementing on one type of amino acid (such as tyrosine, in the case of ADHD treatment), we need to examine some of the possible repercussions of disturbing the balance of the other amino acids and the products of their metabolism.

Additionally, we need to be aware of other biochemical pathways in the body in which tyrosine is involved. While it may be true that supplementing with tyrosine can boost levels of dopamine and norepinephrine (although the extent of this is debatable, and will be discussed in our final "wrap-up" post), boosting tyrosine intake can result in higher levels some potentially harmful agents such as the compound homocysteine. For this, we will begin by examining the last step of the tyrosine metabolic process (this was covered in the last post in more detail):

Here we see that tyrosine-derived norepinephrine can be converted to epinephrine (adrenaline) in a process which utilizes the enzyme (phenylethanolamine N-methyltransferasePNMT). Even without a chemistry background, we can still see the chemical transformation process above. A methyl (CH3) group was added to the Nitrogen (N) on the right side of the norepinephrine molecule to form norepinephrine. But where does this methyl group come from?

As mentioned in the last post on ADHD and tyrosine, the compound S-Adenosyl Methionine or SAMe, is a very important nutrient in a number of biochemical processes, in that it is able to "donate" (give-up) a CH3 methyl group. This is a relatively rare property among nutrients, and we are just beginning to scratch the surface with regards to the role of this nutrient in treating neurological and psychological disorders such as depression, ADHD and the like.

However, when SAMe does donate it's CH3 methyl group, as in the case above, we are left with homocysteine (please note that there are a few additional steps to go from SAMe to homocysteine, it is not a 1-step conversion process. For simplicity, however, we will not go into these in any further detail. Nevertheless, homocysteine is a major end product of SAMe-related CH3 donor reactions, such as the one given above).

In other words, higher tyrosine (or L-DOPA) levels can make their way to this step of the metabolic process and begin to deplete SAMe levels and lead to high levels of homocysteine. High levels of homocysteine are known as hyperhomocysteinemia, is commonly seen in Parkinson's patients, who often take large amounts of L-DOPA (the second step of tyrosine metabolism in our first diagram in this blog post). Numerous studies have shown that long-term treatment with L-DOPA leads to elevated homocysteine levels in the blood of Parkinson's patients.

Elevated homocysteine levels have been linked from everything from cancer to diabetes to autoimmune disorders to stroke (however, please note that these results are far from unanimous, there are a number of studies showing the contrary for each of the diseases listed. Furthermore, there is still some debate as to whether the high levels of homocysteine are a causal factor for these disorders or just another side effect or symptom of these disorders. Nevertheless, the near-ubiquitous presence of high homocysteine levels in so many diseases across the board should at least suggest that homocysteine-lowering efforts are of great potential benefit, at least in this blogger's opinion).

With regards to ADHD, the actual role of homocysteine is, admittedly, much more murky. While the mechanisms and overall physiology of an ADHD brain vs. a Parkinson's brain show acute differences (In ADHD, chemical imbalances between the "inside" and "outside" regions of a neuron exist, which can be chemically modified via medications which target the proteins which shuttle this neuro-transmitting agents in and out of the cells. In Parkinson's, however, the imbalances are caused by cell death and neuronal degeneration, requiring overall higher levels of neurotransmitters like dopamine need to be supplied via chemical precursor agents like L-DOPA), the fact that the two disorders both share similar treatment methods should (in this blogger's opinion) at least sound a warning bell that some of the negative effects for one might also be prevalent in the other.

Surprisingly, there are very few studies (at least to the best of this blogger's knowledge) on homocysteine levels in the ADHD population, so it is difficult to get a good read on the subject. Nevertheless, given some of the points made earlier on tyrosine or L-DOPA supplementation or treatment and homocysteine buildup, we should at least examine some of the ways to reduce high homocysteine levels. Fortunately (at least in most cases), homocysteine-lowering efforts often respond very well to vitamin and mineral based treatments via supplementation or food fortification. At the center of this are the some of the well-known B vitamins.

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

• Vitamin B6 (whose "active" form is known as pyridoxal phosphate. For simplicity, we will just be referring to this compound by its common vitamin name, vitamin B6)
• Cobalamin (a version of vitamin B12)
• Folate (a derivative of Folic Acid or Vitamin B9. For simplicity, as in the diagram below, we will just refer to this modified form of folate as "folic acid", but please note that there is a modest chemical difference here)
  

While the above diagram may look extremely complicated and "busy", please try not to get distracted. The first four "steps" at the top (the arrows simply refer to a metabolic pathway by showing the gradual transformation of one tyrosine-based compound to the next. We have discussed each of these steps in great detail in the previous postings) have already been covered extensively.

The last step, the conversion of norepinephrine to epinephrine was discussed in the last posting on ADHD and tyrosine. The curved arrow simply refers to the fact that the norepinephrine to epinephrine conversion requires another nutrient-based compound SAMe. The norepinephrine essentially "steals" a methyl (CH3) group from SAMe, leaving SAMe to transform into another compound S-Adenosylhomocysteine (which then proceeds to our "dreaded" homocysteine). To put it another way, in order to make the norepinephrine to epinephrine conversion, the valuable nutrient SAMe must be "sacrificed" to a more potentially harmful compound homocysteine.

If this SAMe to homocysteine conversion process is not kept in check, we run the potential risk of homocysteine buildup. However, based on the diagram above (look at the far right side of the diagram for this part), there are 2 different ways to "dump off" high levels of homocysteine by converting it to other more benign compounds. However, each of these two "paths" requires at least one type of B vitamin.

Path #1: conversion of homocysteine to the amino acid cysteine: This is actually a multi-step process, but for the sake of brevity and simplicity, I have left out some of the middle steps. The two major points of note here as follows:

1. This process requires a specific enzyme called cystathione beta-synthase (don't worry about remembering this enzyme, just remember that this enzyme requires a form of vitamin B6 as a cofactor or "helper to function). Thus, to optimize this vitamin B6-based conversion process, we want to make sure that we don't have any deficiencies of this vitamin. Please note that we already mentioned the need for vitamin B6 in another step of the tyrosine supplementation process for ADHD, the conversion of L-DOPA to dopamine. Thus, it is doubly important that we don't come up short on this vitamin.
   
   A rough summary of recommended dosage levels for B6 will be given at the end of this post (Blogger's note: not to go into too much detail here, but this homocysteine to cysteine conversion process is also dependent on another amino acid called serine. I have not included serine as an essential nutrient because serine deficiencies are rare. However, there are some genetic disorders in which serine synthesis is compromised. Seizures and related symptoms are common among those with this genetic defect on serine metabolism).
   
   
2. The conversion of homocysteine to cysteine is (largely) irreversible. This is good news if we want to "dump off" homocysteine levels and not have to worry about the process chemically finding its way back to homocysteine (at least not through this pathway).

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

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

To summarize: if we want to keep the "cycle" going to avoid homocysteine buildup by converting homocysteine to methionine, we need 2 different B vitamins: The folic acid as the chemical modifier, and vitamin B12 to help the enzyme involved in the process to function properly.

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

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

• Homocysteine can be an inflammatory compound that is produced indirectly as a result of tyrosine metabolism. High levels of this compound have been linked to a wide number of diseases and health risks.
  
  
• Vitamin B6 can be used to help "shunt" homocysteine to a common (and typically less-harmful) amino acid known as cysteine. This process is (essentially) irreversible. B6 is also a requirement for an earlier step of the tyrosine or L-DOPA metabolic process, the conversion of L-DOPA to dopamine.
  
  
• Vitamin B12 and folic acid can both assist in the conversion of homocysteine to another amino acid, methionine. Unlike the cysteine conversion process above, this process is reversible, meaning that it is possible to "work" backwards towards homocysteine in a bi-directional pathway.
  
  
• Because of the importance of these 3 B vitamin-derived factors in the prevention of homocysteine buildup, it is imperative that we try to avoid shortages of these agents at all costs (but be careful about over-supplementing, B vitamins work best in specific ratios, and overdosing on one can compromise the functions of the other, as we have noted in previous posts on ADHD and nutrient deficiencies).
  
  
• Here are some good sites which list the suggested daily amounts for folic acid (folate), vitamin B6 and vitamin B12. Going slightly higher is often fine (as these agents have relatively high "ceilings" between recommended amounts and toxicity levels), but try to keep the ratio of these different B vitamins as close to the same as in the recommended amounts as possible. Again, please make sure your physician is in the know if you choose to supplement with anything significantly above the recommened levels.

This is our second-to-last post on ADHD and tyrosine. The last one on tyrosine supplementation strategies for ADHD will give a recap of all the key enzymes, nutrients, and chemical intermediates we've covered throughout the past seven postings. It will also provide a summary of what the main studies on exactly how effective tyrosine supplements really are based on clinical studies. Finally, we will briefly mention how tyrosine may be able to augment the effects of common ADHD stimulant medications.

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

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

This is the fourth in an in-depth multi-part blog series on how and why this amino acid is so frequently prescribed and used off-label as an ADHD treatment method. Reviews and literature findings are mixed, but some physicians (and parents and individuals with ADHD themselves) swear by tyrosine as a hugely successful treatment strategy for ADHD. We have spent the last three posts examining:

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

I've included the following diagram in the last few posts, which highlights the major steps and intermediate products involved in the conversion process of tyrosine to dopamine and norepinephrine (the two desired targets of tyrosine supplementation with regards to ADHD treatment).
As a quick recap:

1. In tyrosine and ADHD post #1, we gave a general overview of the process and the roles of dopamine and norepinephrine on ADHD biology. We also looked at how tyrosine enters the brain, and which mechanisms are important for facilitating its transport to the desired targets for therapeutic effects with regards to ADHD (Please note that different forms of tyrosine exist, but the form most common in nature and in chemistry in general is referred to as "L-tyrosine". When this blog mentions "tyrosine", it is this "L" form we are referring to in all cases unless specified otherwise).
   
   
2. In the second post on ADHD and tyrosine, we focused on the first step of the process, the conversion of tyrosine to L-DOPA. This step heavily utilizes a specific enzyme called tyrosine hydroxylase. Tyrosine Hydroxylase is dependent on adequate supplies of certain nutrients such as iron, magnesium, zinc, tetrahydrobiopterin, and adequate levels of vitamin C (and antioxidants in general). While rampant supplementation is not necessary, inadequate levels of any of these agents (as well as a few others, such as copper) could potentially compromise the function of the tyrosine hydroxylase enzyme. It is important to note that the conversion of tyrosine to L-DOPA is typically the slowest and rate-limiting step of the whole tyrosine metabolism and conversion process to dopamine and norepinephrine. Thus, compromising this first conversion step can be potentially the most devastating with regards to impaired tyrosine metabolism for ADHD. This was why the post was a bit lengthy with regards to advocating for nutritional sufficiency.
   
   
3. The third post on tyrosine and ADHD focused more on the question as to whether we could bypass the first step of the chemical process outlined above entirely by supplementing with L-DOPA (the second major step of the tyrosine conversion process) directly. We discussed the pro's and con's of using each (tyrosine or L-DOPA) as a starting point for ADHD treatment.

This brings us to today's post: the conversion of L-DOPA to dopamine. This process is heavily dependent on an enzyme known as DOPA decarboxylase. Here are some of the main components which need to be in place for this enzymatic conversion process to occur with efficiency:

DOPA decarboxylase belongs to a particular class of enzymes called aromatic amino acid decarboxylases. The term" aromatic" here refers to a particular type of "ring" structure in the chemical compound (if you don't have a background in organic chemistry, take a look at the chemical depictions of tyrosine, L-DOPA and dopamine shown below:


***A quick note on the chemical processes shown above and below: If you're not a chemist, don't worry, just look at what's changing in the pictures above and below, which represents the chemical structure of these different molecules involved in the tyrosine to dopamine conversion process. That hexagon-like structure on the left side of these molecules, (with the -OH groups coming off of it) is what makes these compounds "aromatic".

The enzyme tyrosine hydroxylase simply adds another "-OH group" to the top-left side this hexagonal ring to make L-DOPA out of tyrosine. The chemical process of this conversion was the point of discussion in our second blog post on ADHD and tyrosine supplementation. Our next enzyme-driven step leaves this "aromatic" hexagonal ring alone, and instead works on chemically modifying the right side of the molecule, as we'll see in a second. ***

The term originally comes from the fact that chemicals with this type of built-in structure often gave off a particular aroma. Aromatic amino acid decarboxylases essentially take a carbon dioxide off of these six-membered rings, which greatly changes the chemical properties and reactivity of the chemical compound in most cases. (Do you see how the right end of the molecule L-DOPA is "chopped off" to get to dopamine in the step shown below? That is the work of these decarboxylase enzymes).

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

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

We have spoken about the merits of vitamin B6 with regards to ADHD and how it works in conjunction with other nutrients in previous posts. For example, getting B6 into this desired pyridoxal phosphate form requires zinc (another reason why adequate zinc levels are necessary for optimal tyrosine metabolism). It also appears that vitamin B6 works well alongside magnesium as an ADHD treatment combination strategy. Finally, vitamin B6 plays a role in the metabolism of omega-3 fatty acids (omega-3 rich fish oil is a common "natural" treatment method for ADHD)

Because of its vital role as a "co-factor" or "helper" of the DOPA decarboxylase enzyme, which is responsible for converting L-DOPA to dopamine, it is imperative that we avoid shortages of this essential B vitamin. A rough estimate of recommended daily intake levels of vitamin B6 can be found here. Keep in mind that over 100 different other enzymes also depend on vitamin B6 and its derivatives, so keeping adequate stores of this vitamin is essential.

In addition to keeping up necessary vitamin B6 levels to help the DOPA decarboxylase enzyme's ability to function properly in the second major chemical step of tyrosine metabolism, we must also mention an often-overlooked issue with the enzyme: the interaction of DOPA decarboxylase with another common neurochemical signaling agent called serotonin.

Serotonin is generated from another important amino acid called tryptophan. Tryptophan (like tyrosine) is an aromatic amino acid, and the two amino acids have several structural and functional similarities. While this may sound like a good thing at first, it can lead to some problems.

One of these problems is the fact that if two chemicals share similar structural characteristics, enzymes which act on one may also act on the other. If the structural characteristics are close enough, the two agents can even compete for the same enzymes, or effectively block each other off or crowd each other out.

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

**A generalized conversion process of tryptophan to serotonin is shown below. Note that this pathway is analogous to the tyrosine to dopamine pathway in a number of ways, including the addition of a hydroxyl (-OH) group in the first step and a decarboxylation (essentially the removal of carbon dioxide) in the second step, which utilizes both the aromatic amino acid decarboxylase enzymes and pyridoxal phosphate (vitamin B6). Do you see how these two processes can easily be in competition with each other for resources (the enzymes as well as the vitamin B6).Additionally, the end product of the above process, serotonin, can also effectively shut the enzyme DOPA decarboxylase down. This process, in which an enzyme is essentially shut down by its final products, is often used in the body to keep from overproducing one particular kind of substance. It is known as feedback inhibition, and is a very common and crucial process for retaining chemical balances in the body.

However, if large amounts of tryptophan are present, not only can the crowd out tyrosine for the dopa decarboxylase enzyme, but the final product of this tryptophan (serotonin), can essentially shut the enzyme down for both processes. In other words, it's a double-whammy for tyrosine, along with the implications for its use as an ADHD treatment strategy.

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

This is not meant to blast tryptophan or serotonin. Both chemicals are crucial to a number of important bodily functions. Rather, it is the timing of the administration of these nutrients with which we should be careful. The main strategy here is to try to avoid taking tryptophan-rich foods alongside tyrosine supplements. Some foods which are high in tryptophan can be found here. Keep in mind, however, that many of these tryptophan-rich foods may also be high in tyrosine (such as wild game and several types of seeds like pumpkin seeds). Some of the more tryptophan-concentrated foods are milk, turkey, and legumes (chick peas, peanuts, etc.), so it would be a good idea to refrain from these rich sources of tryptophan for a couple of hours on either side of tyrosine supplementation.

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

1. Keep up adequate levels of vitamin B6 to help the DOPA decarboxylase enzyme function at peak efficiency.
   
2. Try to avoid taking in tryptophan-rich foods anytime near the time you take your tyrosine supplements. This will help you avert most of the competitive biochemical processes between these two nutrients, and can ultimately improve the efficacy of tyrosine as an ADHD treatment strategy.
   

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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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ADHD, Alcoholism and Nutrient Deficiencies

This will probably be the last blog post on the ADHD and alcoholism connection. We have investigated the connection between ADHD and alcoholism with regards to:

• Size and function of specific brain regions, such as the corpus callosum.


• The prevalence of ADHD in children of male alcoholics


• The theory behind omega-3 fatty acids, which are often deficient in ADHD and maintain cell structure and function


• How specific genes which encode for desaturase enzymes, can actually interact with alcohol and and omega-3 fatty acids and all combine to influence the likelihood of ADHD.

Now we will investigate another potential connection between the disorders of ADHD and alcoholism, which involves alcohol-induced deficiencies of key vitamins and minerals which are often deficient in individuals with ADHD. We will list some of these key nutrients below:


Magnesium: (Here are recommended daily magnesium intake levels)

We have posted on this nutrient extensively in the past. For example, there is relatively strong evidence of a connection between magnesium deficiency and childhood ADHD. Additionally, there are a number of disorders which occur alongside of ADHD, which are called comorbid disorders. Magnesium levels are thought to influence some of these ADHD comorbid disorders as well. Co-treatment with vitamin B6 has been shown to boost magnesium's effects for ADHD treatment as well. Finally, I have outlined some other nutrient treatment combinations thought to boost the effectiveness of magnesium for ADHD.

Magnesium deficiencies are also common in chronic alcoholics. There are several potential reasons for this including decreased absorption and increased urinary loss of magnesium, dietary deficiencies as alcohol calorically replaces magnesium-rich foods, and decreased retention due to liver dysfunction. Unfortunately, the actual process of quitting alcohol use can also result in magnesium shortages. This is due to the alcohol withdrawal process in which results in fatty acid composition changes and the buildup of compounds in a process called ketoacidosis. These compositional changes during the alcohol withdrawal process can result in products which bind to magnesium and reduce its serum levels. A review by Krishnel and coworkers on the efficacy of intravenous vitamins for alcoholics in the emergency department touted the benefits of oral magnesium supplementation for admitted alcoholic patients.


Thiamine (also spelled "thiamin"): (Here are recommended daily thiamin intake levels).

There are several studies pointing towards a connection between chronic alcohol abuse and thiamine deficiency, although the scope of these effects is still under debate. Thiamine deficiency has been implicated for a disorder called Wernicke's encephalopathy. Wernicke's encephalopathy does have some overlap in symptoms with ADHD, such as impaired short-term memory, but beyond this, there is little connection between the two disorders. One thing to note about thiamine is that while there is minimal research done on the possible connection between its deficiency and ADHD, thiamine does play a major role in the process of glucose metabolism. Individuals with ADHD have often shown sub-average blood glucose levels to several key brain regions. Some studies have even implicated a potential risk of thiamine depletion caused by rapid glucose administration (such as through IV treatment).


Vitamin B-6: (Here are recommended daily vitamin B-6 intake levels)

Vitamin B-6 has had numerous implications for both the causes and treatment of ADHD. B6 has been shown to assist and boost the effects of magnesium in treating ADHD. Vitamin B6 has an "active form", which is often referred to as pyridoxal phosphate (PLP).

Chronic alcoholism can lead to a condition known as hyperhomocysteinemia. This disorder is the result of excessive buildup of the compound homocysteine. Homocysteine has been implicated as a major factor in a number of cardiovascular and inflammatory diseases and is a leading culprit of stroke and arterial damage. In addition to these disorders, high homocysteine levels are thought to play an indirect role in the onset of ADHD.

Vitamin B-6, vitamin B-12 and folic acid all play a role in regulating homocysteine levels. In fact, there is thought to be a minimal level for each of vitamin B6, B12 and folate to combat excessive homocysteine levels. Below is a rough sketch of how homocysteine is converted to the more benign and extremely important bodily antioxidant glutathione. This is important, because ADHD individuals have often been shown to have lower than normal levels of this ubiquitous antioxidant (as well as antioxidant levels in general). Upping the conversion of homocysteine to glutathione through B vitamin-dependent pathways therefore presents two different therapeutic measures for the ADHD sufferer.


At this point, there is no need to familiarize yourself with the intermediate steps in the process, just note that the "active" form of vitamin B-6, Pyridoxal phosphate or PLP is needed in not one, but two different steps of this conversion process. Low levels of this key nutrient can lead to a backup of homocysteine as this process is severely hampered.

Vitamin B-12: (Here are recommended daily vitamin B-12 intake levels)

As mentioned above, vitamin B-12 also plays a critical role in maintaining homocysteine levels. It, along with folate (the "nutritionally active" form of folic acid), actually work together, along with a third compound called betaine) in converting potentially dangerously high levels of homocysteine back to the amino acid methionine. Keep in mind that deficiencies of vitamin B-12 can cause problems with regards to homocysteine buildup as an under balance of vitamin B12 with respect to folate can boost homocysteine levels. Keep this in mind when we proceed to the folic acid discussion, as isolated supplementation with folate can offset the desired B12/folate balance and be counterproductive. A brief diagram of this process can be seen below:

A quick note: If you look at the diagram above, you can see that the process of removing homocysteine by converting it to methionine can actually continue on to another important compound, S-Adenosylmethionine (SAMe). There has been a lot of discussion surrounding SAMe as a possible supplement used to treat ADHD. We will save this discussion for a later time, but it is at least worth mentioning that there have been some very positive things said about this nutrient. Additionally, SAMe has been shown to help protect against liver damage (even to the point of reversing the process), which, as we know, is extremely common in alcoholics. Also note that betaine supplementation can also help offset alcohol-induced liver damage, so the betaine mentioned in the above process is multifunctional with regards to ADHD and alcoholism.

In addition, there may be a connection between vitamin B-12 deficiencies and food allergies (which are often associated with a rise in ADHD-like behaviors themselves). This is in part, due to the connection between B-12 deficiencies and pernicious anemia. This is characterized by a reduction of gastric acid secretion through damage to cells in the stomach called parietal cells. Food allergies, which have been associated with ADHD, can be exacerbated by weak stomach acid levels, as food allergens which are normally broken down by sufficient acid are now present at higher levels. We have seen the effects of damage to the stomach and other digestive organs in the case of our earlier post on celiac disease and its correlation with ADHD symptoms.

***Keep in mind that this B-12/food allergy and ADHD connection is more hypothetical at this point, relatively little published information is available to confirm this indirect connection. Nevertheless, I personally believe that this possible association is at least worth mentioning.

Folic Acid/Folate: (Here are recommended daily folate intake levels)

As alluded to above, we have seen the intricate connection between vitamin B-12 and folate (folic acid is the synthetic form of folate used in food fortification. Within the scope of this post, I am using the two terms interchangeably). With regards to cognitive function and relevant disorders such as ADHD, there is also an important relationship regarding the balance of these two nutrients. For example, a relatively recent study found that for vitamin B-12 deficient individuals, folate is actually connected to folate and reduced cognitive function. However, when ample B-12 levels were available, higher folate levels were protective against cognitive impairment. Thus we see that folate can potentially be a double-edged sword in the war against high homocysteine levels and reduced cognitive function, and that folate's effectiveness is grossly dependent on an adequate vitamin B-12 balance.

Aside from the homocysteine/B-12 connection, it also appears that folate plays other critical roles which can indirectly affect the severity of negative symptoms associated with ADHD. Additionally, folic acid has been found to have a protective effect against formic acid, a neurotoxin. This relationship actually stems from the neurotoxic effects of methanol, which is often found in alcoholic beverages either as a congener (essentially a side product in alcoholic beverages, which actually play a factor in the hangover process), or through endogenous formation (within the body). One of the problems with methanol is that it shares the same enzyme system as ethanol (the main form of alcohol in beverages), but is slower to clear due to a less-efficient metabolic process and can build up to toxic levels in heavy drinkers. However, adequate folate levels in the liver can expedite the methanol metabolism and clearance and reduce levels of the neurotoxin formic acid. In addition to the liver, there is some evidence that folate-derived formic acid metabolism occurs in the mammalian brain as well. Folate is also thought to be connected to the key compound in regulating levels of SAMe (S-Adenosylmethionine). Folate deficiency can lead to reduced levels of SAMe. This is of importance, because in numerous studies S-Adenosylmethionine has been implicated as a potential treatment option for ADHD.


A quick word on homocysteine: We have spent a fair amount of time highlighting the connection between alcohol consumption and homocysteine levels. In fact, chronic alcoholics reported double the serum homocysteine levels as nondrinkers. Hyperhomocysteinemia has also been associated as a major culprit in the process of alcoholism-induced brain shrinkage.

However, it is worth noting that the source of the alcohol may play a critical role with regards to homocysteine levels. A study found that beer consumers had notably lower levels of homocysteine than did consumers of wine or other spirits. While this association was not thoroughly addressed, this is possibly due to the relatively high levels of B vitamins in certain forms of brewer's yeast (which is used in the beer-making process). This is right in line with our study on vitamins B-6 and B-12.

In addition to the nutrients listed above, there are thought to be other nutritional factors at play. For example, chronic alcoholics who are faced with alcohol withdrawal are at increased risk of omega-3 fatty acid oxidation. This oxidative damage can disrupt the omega-6/omega-3 fatty acid balance, which we addressed in an earlier post as being a critical factor in cell membrane integrity. Additionally, alcoholism has been linked to deficiencies in antioxidants such as vitamin C (remember that individuals with ADHD generally have lower total antioxidant levels than their non-ADHD peers). Alcoholic liver damage has also been linked to zinc deficiency. We have investigated the zinc connection to ADHD earlier, namely in the potential ability of zinc to boost the effectiveness of Ritalin, a common ADHD stimulant medication.

Finally, I have alluded a bit to the compound S-Adenosylmethionine (SAMe) in this post. It is an ADHD treatment method of great potential interest. We will be discussing the possible merits of SAMe in the near-future.

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Magnesium Combination Treatments for ADHD

The previous 3 posts have all addressed the role of magnesium in the causes and treatment of ADHD and related disorders. Here I will address some of the guidelines as to how to boost the effectiveness of magnesium treatments in ADHD patients. This will include information on which forms are the best and which other compounds or nutrients, when used in combination with magnesium, can help the absorption and processing of this key mineral. Please keep in mind that these are recommendations and findings compiled from hundreds of medical journal articles and clinical studies. Do not take these suggestions as medical advice until you consult with your physician!

Some guidelines are listed below:

• Based on age, gender and a few other factors, recommended amounts of magnesium levels range from 80 to 420 mg/day. For a detailed breakdown on the amount recommended for you, please check out this link here. Due to the role of estrogen, which helps in the retention of magnesium, females typically require less of this nutrient than males.



• Several forms of magnesium are available. These include magnesium chloride, magnesium oxide, magnesium lactate and magnesium aspartate. A study on human absorption patterns showed that magnesium oxide had much poorer absorption than the other three forms. Other forms include magnesium sulfate, magnesium hydroxide, magnesium acetyltaurinate, magnesium citrate, and magnesium carbonate.


• Of potential interest is the form magnesium acetyltaurinate. This form contains both magnesium and a chemically modified version of the substance taurine. Taurine, which is often seen in energy-boosters and “memory” drinks, has been shown to aid the absorption of magnesium into cells in mammals (as do several other compounds such as vitamin B6). It is important to note that this study was done in rats as opposed to humans, but, due to the high crossover of nutrient absorption and metabolism between the two species, I feel that this finding is at least worth mentioning. Although a rarer (and often more expensive) form of the mineral, magnesium acetyltaurinate may essentially provide “two-for-one” deal, thereby making it superior to other magnesium forms. Note that this conclusion is merely hypothetical at this point and should be treated as such. Nevertheless, with the support of your physician, it may be a strategy worthy of investigation for treatment of ADHD and related disorders.

• In a recent post, we have seen how elevated levels of the compound kynurenine can lead to numerous difficulties and exacerbate the symptoms of ADHD and related disorders. A derivative of niacin (short for nicotinic acid or vitamin B3), which is called nicotinamide, has been shown to reduce the unwanted high levels of kynurenine, especially in the brain. Additionally, it has also been shown to reduce spasms in the blood vessels, thereby improving blood flow to the brain and reducing the likelihood of a brain hemorrhage and stroke. These findings are summarized in a journal article by BL Grimaldi (an abstract of the article can be found here).

• As previously mentioned, vitamin B6 (pyridoxine) can boost the absorption of magnesium. We have seen in an earlier post that zinc can be used to boost the effectiveness of methylphenidate (Ritalin, Concerta), in certain cases. Additionally, zinc is required for optimal function of certain enzymes needed to process vitamin B6 such as pyridoxal kinase. Not surprisingly, zinc deficiencies are common in individuals with ADHD and related comorbid disorders. Vitamin B6 boosts the effectiveness of magnesium, vitamin B3 helps offset the buildup of unwanted levels of kynurenine, which is often seen in magnesium deficient individuals, and zinc aids in the processing of vitamin B6. Thus we're beginning to see how all of these vital nutrients do not act merely in isolation, but rather how they can work together to reduce the negative symptoms of ADHD and related disorders.

• We have seen above that vitamin B3 can offset the buildup of unwanted kynurenine, which can be induced through magnesium deficiency. However, there are other key nutrients which are often reduced through prolonged periods of inadequate magnesium intake. Depleted levels of many antioxidants are often seen and need to be replenished. Among these are vitamin C, vitamin E and glutathione.

• Glutathione, which is manufactured in the body, is among the most widespread and potent antioxidants used in the body. However, in order to stay in it's "de-oxidized" functional form, it needs help from dietary antioxidants. Vitamins C and E work with each other as well as with glutathione to keep adequate "pools" of glutathione available for the body's natural antioxidant defenses. Inadequate levels of glutathione can lead to the onset of numerous diseases, damage to the outer covering of cells and tissues, allergies, asthma, neural dysfunction and a wide array of other disorders. Magnesium deficiencies place unwanted stress on the body and reduce the body's available levels of glutathione. Thus, vitamin C and E are needed to "repair" this damage. Recommended levels of these two vitamins can be found here for vitamin E and here for vitamin C. These levels reflect recent changes in which the recommended doses of both vitamins have been bumped up.

• ***Blogger's note: You may have read a number of references or seen a number of websites for ADHD and multiple other ailments touting the benefits of compounds such as pycnogenol (also known as French Maritime Pine Bark Extract), and grape-seed extract. As of now, I am neutral as far as using products such as these. However, it is important to note that the majority of the benefits derived from treatments such as these are due to their antioxidant effects, which are quite powerful by the way (however, other functions besides mere antioxidant effects have been suggested and are entirely possible). Additionally, these supplements can be quite costly. It is this blogger's opinion that similar effects and benefits can be seen with vitamin C and E supplementation for a cheaper price. Nonetheless, the large number of studies supporting the effectiveness of pycnogenol and grape-seed extract does warrant further investigation and potential success as an ADHD treatment option. With you're doctor's permission, pycnogenol or grape seed extract may be worthy of a trial run.
  

• One final ingredient which is highly recommended for adding to the "pile" of nutrients for ADHD and related treatments is lecithin. The reason I personally hold in in such high regards is that it restores multiple components which may have been compromised by prolonged magnesium deficiency. Among these are essential omega 3 fatty acids (which are often found to be compromised in a wide range of diseases and disorders such as depression, heart disease, asthma, allergies, blood clotting and strokes, ADHD, multiple other neural disorders, Tourette's, chronic inflammation, and a whole slew of other ailments) such as alpha-linolenic acid, which is sometimes abbreviated as ALA.

• Additionally, lecithin provides rich levels of inositol which is a special type of sugar which is often listed as a B-vitamin (however, by definition, it is not, since inositol, unlike vitamins, can be synthesized in the body. Nevertheless, it functionally behaves in a manner similar to several other B vitamins and is therefore sometimes classified as such), as several key agents necessary for proper cellular structure and neuronal function. These agents include phosphatidylcholine (which is needed to maintain cell structure, helps regulate breakdown of fats, and is also used to help cells communicate with each other), phostphatidylinositol (which is also required for cell communication or signaling), and phosphatidyl ethanolamine (which is a fatty tissue found in high concentrations in the brain, spinal cord and throughout the nervous system). Inositol itself is also a key "messenger" by facilitating cell-cell communication.

• In addition to their utilization for cell structure and cell membrane integrity, some of these agents (namely inositol) have been shown to be effective antidepressants, having similar effectiveness and modes of action to the SSRI (selective serotonin re-uptake inhibitor) class of antidepressant medications. A summary of some of these findings can be found in a review by Grimaldi (abstract of article listed here). There is no official recommended amount for lecithin, but two tablespoons of the granular form are often administered by physicians. For good natural sources of lecithin, please click here.

• While it provides many absorption-related benefits, magnesium can reduce the absorption and effectiveness of certain antibiotics such as tetracylcine. If you are taking this antibiotic for a short period of time, you may want to consider temporarily reducing your magnesium intake/supplementation.



• Additionally, people with kidney disorders often have difficulty processing and removing magnesium from the system. It is imperative that this is discussed with a physician before deciding on magnesium supplementation.

The main idea of this post is to introduce to you the importance of including all of the pieces of the nutrient puzzle for treating ADHD and related disorders. A quick list of nutrients which must often be used in conjunction include: magnesium, vitamin B6, vitamin B3 (niacin), zinc, antioxidants (vitamin C and E, pycnogenol, grape-seed extract), and multiple components of lecithin (inositol, omega-3 fatty acids, and neuro-regulating agents and their derivatives). To summarize:

1. Magnesium deficiency is thought to be a common underlying cause to ADHD and related comorbid disorders. Increasing magnesium intake via diet or supplementation can offset some of these problems. Recommended magnesium levels and natural sources can be found here.
2. Vitamin B6 boosts the uptake of magnesium into cells. Additionally, an enzyme which helps absorb vitamin B6, called alkaline phosphatase, requires magnesium to function properly. Therefore, vitamin B6 and magnesium function in a cooperative manner, and enhance each other's effectiveness. Recommended vitamin B6 levels and natural sources can be found here.
3. In addition to magnesium, several enzymes required for the processing and proper metabolism of vitamin B6 need adequate zinc levels to function properly. Recommended zinc levels and natural sources can be found here.
4. Deficiencies of magnesium can lead to a harmful buildup of kynurenine. Treatment with vitamin B3 (niacin), can offset some of these harmful effects. Recommended vitamin B3 (niacin) levels and natural sources can be found here.
5. Magnesium deficiency can cause a depletion of antioxidants (especially glutathione) in the body. Increasing the intake of antioxidants such as vitamin C and vitamin E (which complement each other and work great together in tandem), grape-seed extract or pycnogenol can replenish and restore the proper antioxidant balance to the system. Recommended levels and natural sources can be found here for vitamin C and here for vitamin E. No official levels for grape-seed extract or pycnogenol have been established, but common treatment levels and dosage information can be found here for pycnogenol and here for grape-seed extract.
6. Low magnesium levels can also result in depleted amounts of several key fats or fatty-like substances necessary for proper nerve (as well as other types of) cell structure and function, as well as proper cell-cell communication. Lecithin is a great source of many of these deficient components, and is a good replacement method of treatment. There is no official recommended daily amount for lecithin, but for more information on common dosage levels of lecithin please click here.

You have hopefully seen how these key ingredients all work together and how a deficiency in even one of these can inhibit the effectiveness of the other nutritional agents.

Keep in mind that all of these can be obtained from natural food sources. It is not my intention to turn anyone into a "supplement popper". However, if your dietary patterns leave you prone to deficiencies in any of these nutrients, I do recommend supplementation. However, please check with your doctor before doing any of these treatment suggestions. Also, keep in mind that this list is not extensive. I will be discussing some other essential nutrients (such as iron, whose low levels are often connected to ADHD and related disorders) in future blog posts.

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Dietary Magnesium and ADHD Comorbid Disorders

This is the third in a three-part series on the effects of magnesium intake on ADHD. We have seen previously how ADHD can be associated with dietary magnesium deficiencies, and how supplementation with magnesium can prove helpful. We have also seen that taking in vitamin B6 can boost magnesium's absorption into cells, improving its effectiveness for treating ADHD. The co-dependence of magnesium and vitamin B6 is reciprocated, as the enzyme alkaline phosphatase helps absorb the usable form of vitamin B6 into tissues in the body. This important enzyme requires magnesium to function properly.


We have also seen in previous posts that ADHD is often not an isolated condition. Accompanying symptoms such as Tourette's, bedwetting, sleep disorders, depression, allergies and an array of other comorbid disorders are often seen alongside ADHD. Some of these disorders also show statistically-low blood levels of key nutrients. Although this does not guarantee a common underlying nutritional deficiency as the root cause of both ADHD and these other disorders, it does suggest that we give a closer look to some of these overlapping factors.


In the case of ADHD and Tourette's, we see a shared deficiency in the essential mineral magnesium. Keep in mind that Tourette's has a huge overlap with both the OCD (Obsessive Compulsive Disorder) and ADHD. In fact, some estimates place up to 90% of individuals with Tourette's in the ADHD category. While I personally find that figure to be a little high, it is important that we see the magnitude of overlap of these two comorbid disorders, especially since they both share a noticeable connection with low magnesium levels.


Most of this post draws from information from an article in the journal Medical Hypotheses by BL Grimaldi. A summary can be found here. As the name of the journal suggests, this information is not based on a controlled clinical study, but rather a literature investigation combing through over a dozen different disorders and abnormalities commonly associated with Tourette's. ADHD is one of them, as are other common ADHD comorbid disorders such as allergies, Restless Leg Syndrome, seizures, depression, migraine headaches, teeth-grinding and obsessive compulsive disorder.


While all of these symptoms have some sort of connection to a magnesium or vitamin B6 deficiency, three of the strongest tell-tale signs are migraine headaches, allergies (especially on the skin), and hypersensitivity/hyperexcitability (negative over-reactions to stimuli such as touch. Erratic, jerky movements (not seizure-like, or tic-like, but rather rigid, jerky movements in he body, and the hands in particular) can also be caused by low magnesium levels. A study on magnesium-deficient rats showed high levels of inflammation and redness, especially in the ears. While a similar study (at least to the best of this author's knowledge) has not been done on humans, the prominence and rapid onset of this potentially key tell-tale sign should not be overlooked.


Some other key findings of the article are listed below:

• Magnesium deficiencies correlate with muscle spasms and over-excitability. In the last post, we saw that magnesium deficiencies were more associated with the impulsive or hyperactive components of ADHD than the inattentive component of the disorder.

• Estrogen helps the body take up and store magnesium, which is a big reason why men need higher levels of this key mineral than do women. Interestingly, the relative occurrence of both ADHD and Tourette's is much higher in males than in females.

• There is a genetic region on the 11th chromosome called 11q23 which has been linked to both magnesium retention and loss as well as Tourette's. Interestingly, this genetic region is relatively close to another region called 11q22, which is possibly connected with ADHD, based on some studies. This suggests that, the magnesium deficiency connection may not be entirely dietary, as there may be an underlying genetic factor at work behind low magnesium levels, Tourette's and ADHD. This relationship is relatively strong with magnesium and Tourette's, with the relationship with ADHD being more tenuous.

• We have seen in the last post how vitamin B6 and magnesium serve as complementary ADHD treatments. Additionally, this article mentions that both these key nutrients are essential for an important enzyme called kynurenase. Kynurenase breaks down the compound kynurenine. We do not want to have high levels of kynurenine around, because high levels of this interfere with the balance of a number of brain chemicals which, at imbalanced levels are connected with ADHD, Tourette's and various other related disorders. Two of these important brain chemicals that need to be balanced are GABA (which will be discussed in future posts) and dopamine, which are extremely important neurochemicals tied in to ADHD in a number of different ways.

• Additionally, low levels of kynurenase (and thus high levels of kynurenine) can indirectly result in low levels of the important brain chemical serotonin (which is very important for both specific types of ADHD as well as depression and Obsessive Compulsive Disorders). Several individuals with specific types of ADHD or depression take the supplement L-tryptophan, which is converted to serotonin in the body. Low levels of the enzyme kynurenase can result in a poor tryptophan to serotonin conversion, so inadequate kynurenase levels can invalidate L-tryptophan supplementation effectiveness. Therefore, low levels of magnesium and vitamin B6 can result in compromised activity of a key enzyme that helps maintain balanced levels of important chemicals in key brain regions which are often unbalanced in individuals with ADHD.

• Hormonal surges, especially those that occur during puberty (such as testosterone), can also can lead to an unwanted increase in kynurenine (see previous 2 points for the negative effects of this). This is especially true for vitamin B6 deficiencies. Therefore, it it imperative that adolescents, especially those with or prone to disorders such as ADHD, OCD or Tourette's to make sure they have adequate levels of vitamin B6, either through diet or supplementation. Additional information on sources and recommended levels of this vitamin can be found here.

• Additionally, kynurenine can result in constriction of blood vessels, reducing blood flow to key areas. Since individuals with ADHD often have restricted blood flow to specific brain regions (the frontal region behind the forehead is a common site), higher levels of kynurenine due to magnesium and vitamin B6 deficiencies can contribute to or worsen one of the underlying causes of the disorder.

• Finally, high levels of kynurenine can increase uncontrolled hyperactive behavior and amplify some of the negative effects of caffeine.

• In addition to affecting serotonin levels, low magnesium levels can alter the targets of serotonin, also called serotonin receptors. This can result in migraine headaches, making migraines a possible warning sign of low magnesium levels (it is suggested that up to 50% of migraine cases are connected to significantly low levels of a key form of magnesium).

• For Tourette's-like behavior, stimulant medications used to treat ADHD can exacerbate tics and other symptoms of Tourette's (see a related post on this topic here). This may pose as a problem for the large number of individuals who suffer from both Tourette's and ADHD. These effects are magnified even further if the individual is under some type of physical or emotional stress. Unfortunately, low magnesium levels can also prolong stress or anxiety by tripping some key target regions in the brain such as the amygdala (which is located in the center of the brain and is an important site of emotions and memory generation). As a result, low magnesium levels, combined with ADHD stimulant medications can both lead to and increase the duration of negative anxiety and stress in the body. This in turn can worsen tics and other negative symptoms associated with Tourette's Syndrome.

• Following approximately 2 weeks of magnesium deficiency, histamine and other pro-inflammatory agents begin to appear. The result is often some type of allergic reaction. Not surprisingly, allergies are a common side effect of both ADHD and Tourette's. Interestingly, some of these agents, such as histamine, can counteract some of the functions of vitamin B6, thereby propagating the negative magnesium/B6 deficiency cycle. On top of this, the heightened allergic response can stimulate the anxiety regions in the brain (see the previous point), which in turn, boosts prolonged anxiety and stress levels even further.

• Finally, low magnesium levels can trigger a product called Substance P, which, among other things, can boost itching of the skin, the desire to use profanity (one of the less-frequent, but most-associated signs of Tourette's), and even unhealthy sexual obsession. Not surprisingly, individuals with both Tourette's and ADHD are much more prone to risky sexual behavior. Substance P also reduces the body's ability to absorb an important nutrient called inositol, which is essentially a cross between a sugar and a B vitamin. Inositol plays a number of critical roles, including neural function, balancing fat stores in the liver, detoxifying the body, and preventing cholesterol buildup in arteries. As we can see, reducing the presence or activity of this key nutrient and limiting its absorption into cells due to magnesium and vitamin B6 deficiencies (as well as other factors) can have prolific and far-reaching negative effects on many of the body's systems.

Due to the current length of this post, I will stop here. In the next post, I will wrap up a few more things with magnesium and accompanying nutrients and their critical role in ADHD and related disorders. I just wanted to highlight the fact that these effects are far-reaching, and can have serious implications in the overall health of an individual. One month ago, I knew next-to-nothing about the many roles of magnesium, but as of now, I consider it one of the most underrated nutrients out there. Stay tuned for the next blog post, where we will discuss which forms of this key mineral are the best for supplementation, as well as which other ingredients to take alongside of it to maximize its effectiveness for treating ADHD and some of its comorbid disorders.

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