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

We have spent a lot of time looking at correlations between vitamins, minerals, omega-3 fatty acids and amino acids (and their deficiencies) and ADHD. However, it is important to note that just because low levels of a particular nutrient are seen alongside the disorder, it does not necessarily mean that this deficiency is the cause of ADHD (i.e. correlation does not imply causation). In other words, the nutrient deficiency and ADHD symptoms might both be secondary effects of a larger primary cause, such as an enzyme deficiency or metabolic dysfunction.

In the case of vitamin D, the association with ADHD is a lot more muddled than with some of the other nutrients which have a relatively strong connection with the disorder (iron, zinc, magnesium, and omega-3 fatty acids to name a few). The amount of information in the literature is relatively scarce, as well. A search in the journal database Pubmed (where this blogger gets most of his articles and information) for "ADHD" and "vitamin D" turns up only a small handful of search results, the majority of which focus on other disorders and only mention ADHD peripherally.

However, given the fact that vitamin D is such a "hot" vitamin and has been a popular supplement as of late, we should investigate some of its potential benefits with regard to ADHD and related disorders. Please keep in mind that many of these points below are more theoretical or speculative, because most of the hard, concrete evidence in well-documented clinical controlled studies simply does not exist at the moment. Nevertheless, here are some possible ways in which vitamin D may help in cases of ADHD or related disorders:

Vitamin D can boost levels of the antioxidant glutathione in the brain. One way that vitamin D does this is by regulating an enzyme called gamma-glutamyl transpeptidase, which plays a role in both the metabolism and recycling of glutathione. We have spoken at length about how antioxidant deficits can worsen ADHD symtpoms, and how fatty acids (namely omega-3's) are frequently administered for ADHD and related disorders. Given the high makeup of these omega-3 fatty acids in the brain, and their susceptibility to oxidation and damage in the central nervous system, protecting them by boosting antioxidant levels (either directly or indirectly) is a good bet.
One of the current theories surrounding ADHD is that it is (at least partially) an energy deficiency syndrome, or is the result of impaired metabolic abilities in key regions of the central nervous system. While highly debatable, this theory holds that impaired glucose metabolism in various parts of the brain may be a major contributing factor to the presence or severity of this disorder.

While this blogger is currently neutral on this deficiency theory, it is interesting to note that vitamin D can help regulate glucose tranport into the brain, which would (at least in theory) improve this possible cause of the disorder. It is believed that vitamin D works by targeting multiple enzymes involved in glucose transport and metabolism. Much more study needs to be done to confirm this assertion, but this may be another potential benefit of boosting vitamin D levels in the ADHD patient.
Vitamin D may play a role in catecholamine synthesis. Catecholamines include the neurotransmitters dopamine and norepinephrine, both of which are believed to be tightly regulated and highly involved in the treatment of ADHD (deficiencies of both dopamine and norepinephrine in the "gaps" between neuronal cells are often seen in cases of ADHD).
Vitamin D boosts the effects of an enzyme called choline acetyltransferase in the mammalian brain. This enzyme is used in the manufacture of another neurotransmitting agent called acetylcholine. Acetylcholine is thought to play a major role in maintaining a state of sustained attention, a critical shortcoming in those with ADHD. In other words, keeping adequate levels of vitamin D could potentially help prop up lower levels of this attention-sustaining neurochemical.
Learning and memory deficits, both of which are heavily present in the ADHD population, have been tied to prenatal vitamin D deficiencies in the rat model. This involves a process called synaptic plasticity, which relates to memory formation in an individual. If this finding extends to humans, it could have serious implications on maintaining adequate vitamin D intake in pregnant women.
Problems with fine motor control are sometimes seen as a secondary characteristic in a fraction of the ADHD population. These problems may be exacerbated in a vitamin D deficient state.
Perhaps the strongest correlation, however, may be between vitamin D and depressive-like symptoms, particularly those associated with seasonal affective disorders (SAD). Please keep in mind, however, that studies on vitamin D levels and depression are highly variable; a number of studies have been done on the topic and found no such linkage between the two. We have previously investigated possible connections between ADHD and SAD in an earlier post.

This may make intuitive sense, since vitamin D production is triggered by sunlight, so in the dark winter months, the levels of this vitamin are often much lower (this may also be a major contributing factor as to why illnesses run so much more rampant during the winter months). In other words, vitamin D supplementation may be particularly useful in individuals with ADHD who also have co-occuring depressive or anxiety-ridden symptoms.

To summarize: Vitamin D does not have as many pronounced direct effects on ADHD as do some of the other vitamins, minerals, fatty acids and amino acids we have previously discussed. Nevertheless, the vitamin does seem to have multiple neurodevelopmental and neuroregulatory properties, and may go well with comorbid disorders such as schizophrenia, speech difficulties, memory problems, and (perhaps most strongly) depressive symptoms. Please keep in mind, however, that it may not be possible to simply "supplement these problems away" with extra vitamin D. This blogger just wants to point out that a deficiency in this vitamin often manifests itself in many ways, some of which closely parallel ADHD or related disorders. Nevertheless, supplementing may not be a bad idea, especially if you live in an area that gets minimal sunlight for part of (or all of) the year. Some rough guidelines for vitamin D intake can be found here.

Blogger's note: If you are interested in taking tyrosine as a supplement for ADHD or related disorders, the above diagram is a summary of the key nutrients which interact or play a role in tyrosine metabolism. In this blogger's opinion, we want to avoid deficiencies (or, in some cases, excesses) of any of these nutrients. If you are in a rush and do not want to read this whole posting, this table may be a good starting point. I have listed a number of links at the bottom to other sites as far as recommended daily intakes are concerned for the majority of these nutrients. This list is by no means extensive, but this will hopefully highlight the major impact factors in maximizing the benefits of tyrosine supplementation as an ADHD treatment strategy.

(If the above diagram is not easily visible, most browsers will allow you to left-click the image to get a blow-up version, or you should be able to right-click the image with your mouse and view the image in a new window).

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

For the last seven postings, we have been examining the following metabolic pathway of tyrosine. Included are the major enzymes and key nutrients responsible for this process to occur efficiently:

Here's a brief review of the evidence for (and against) tyrosine supplementation. Much has been covered in the previous 7 blog posts, but some is new. Links to the studies (or summaries of the studies if the full article is not available) are provided in most cases.

Potential advantages of tyrosine supplementation for ADHD:

Tyrosine is a precursor to common neurotransmitters believed to be involved in ADHD (neurotransmitters are chemicals involved in various signaling or messaging processes in the nervous system) dopamine, norepinephrine and epinephrine (adrenaline). Imbalances (typically shortages) in the regions or "gaps" between neuronal cells of these chemicals often occur in ADHD and related disorders, so the idea with tyrosine is that it can theoretically boost levels of these deficiencies and potentially help correct this imbalance.
Tyrosine can readily cross the blood brain barrier. This barrier has been discussed extensively elsewhere, but, in summary, the blood brain barrier is responsible for the passage of nutrients and metabolic products in and out of the brain (and also helps keep harmful agents out of the brain). L-DOPA, a derivative of tyrosine, and the first major product of tyrosine metabolism in most cases, is also able to make it across the blood brain barrier. Most of the major products beyond this point cannot, making tyrosine (or L-DOPA) potential supplementation agents which can be taken orally.

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

Numerous anecdotal reports have found tyrosine to be useful for comorbid (co-existing) disorders to ADHD, such as depression. Given the high frequency of comorbid disorders associated with ADHD, tyrosine's versatility may potentially give us some "2-for-1" deals with regards to helping treat multiple symptoms or disorders at once.

Tyrosine is a good starting point for nutrient-based treatments in metabolic disorders involving the amino acid phenylalanine (such as phenylketonuria). Phenylalaline is converted to tyrosine in a fashion similar to how tyrosine is converted to L-DOPa, via an enzyme-based chemical modification called hydroxylation (in which an "OH" chemical group is added to the molecule).

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

Many physicians have (and continue to) prescribe tyrosine for ADHD and related disorders, and, in many anecdotal cases, the individuals taking the tyrosine have seen marked improvement in a matter of days regarding ADHD symptoms (focus, impulse control, decrease in hyperactivity, etc.)

Tyrosine may be used in conjunction with medications for ADHD and other related disorders. In other words, it may boost their effects (although this may be a double-edged sword, as some of these drugs are potent, so co-supplementation with tyrosine can possibly increase their side-effects and risks by several orders of magnitude in some cases). In this blogger's opinion, this may be the strongest potential use of tyrosine (as opposed to supplementation on it's own, which may often be short-lived). I personally believe that we often grossly underestimate the effects of supplements on medications, tyrosine's effects on stimulants (and other drugs targeting various types of dopamine-related pathways) are no exception.

Tyrosine supplements are typically easily metabolized and cleared from the body, lessening potential side effects from residual metabolites (which is the case for several drugs).

The enzymes responsible for tyrosine metabolism are often dependent on vitamin and mineral nutrients, and can be much more effective if adequate levels of these nutrients are supplied. I have provided a table of some of these key nutrients in a table at the bottom (and top) of this posting.

Disadvantages to tyrosine supplementation for ADHD:

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

In most cases, the imbalances of dopamine and norepinephrine are believed to be due as much to the transporters (or agents which shuttle these chemical in and out of the neuronal cells) or receptors (places on the cells where the dopamine or norepinephrine bind). Most ADHD medications (including the stimulants) typically work by blocking, modifying or reversing the modes of action of these transporters in an attempt to restore a proper "inside" vs. "outside" chemical balance. Interestingly, genetics appears to play a role as to the extent of how a certain transporter or receptor functions, and genes may even affect dosage requirements for certain ADHD medications (such as Adderall, or Strattera). In other words, blasting the body with high levels of tyrosine in hopes of using it as a precursor does not necessarily remediate these transporter issues.

Localization is a problem. Imbalances of dopamine and norepinephrine in ADHD are often seen only in a handful of specific brain regions, so flooding the whole system with tyrosine may not be conducive to zeroing in on these target brain regions. Interestingly, however, the synthesis of monoamine neurotransmitters such as dopamine and norepinephrine may not be tied down entirely to specific brain regions, as there may be some flexibility as to where these chemicals are generated based on the demands (and failures) of other parts of the brain and central nervous system.
While side effects may potentially be lower, tyrosine (or L-DOPA) does have some metabolites which can be harmful at high levels. The pro-inflammatory agent homocysteine is one such example, and has been discussed at length in a previous tyrosine for ADHD blog post.

While anecdotal reports on the benefits of tyrosine supplementation for ADHD treatment abound, the actual number of published studies showing positive results for tyrosine (especially in the last 10-20 years) is surprisingly low.

As mentioned earlier, tyrosine can "compete" with other amino acids such as tryptophan, valine, leucine and isoleucine for entry into the brain, because they share a similar system of transporters. In fact, there are a number of parallels between the tyrosine to dopamine/norepinephrine pathway and the tryptophan to serotonin pathway, in that they share similar enzymatic processes. In other words, it is possible to create imbalances or reduce the effectiveness of one amino acid (and its desired products of metabolism) if the presence of a competing amino acid is too high. This interference is often seen especially in the tyrosine/tryptophan and can potentially promote imbalances in the serotonin to dopamine ratios.

Genetic disorders (which are relatively uncommon) or nutrient deficiencies can hamper the efficiency of several enzymes required for tyrosine metabolism. Even being short in one nutrient can cause problems. Given the nutritional status of many with ADHD, this may be a grave problem. As a result, there are numerous opportunities for the tyrosine supplement to be compromised.

Ways to improve the effectiveness of tyrosine supplementation for ADHD:

As a blogger on the subject, I always try to remain neutral (many times, however, this can be extremely difficult). When researching the stories and studies on tyrosine supplementation for ADHD, the one thing that continuously caught my attention was the degree of discord between the studies on tyrosine supplementation for ADHD (most of which showed no significant improvement) and the number of clinicians who prescribed it (and individuals who reported benefits from tyrosine). Again, this disagreement may be due to a number of things (differences between study conditions and the treated individuals, co-treatment with ADHD medications, the placebo effect, immediate vs. long-term effects, etc.), so we need to be very careful when making a comparison.

Having said all of this, and weighing everything I've read and researched, I admit (as a blogger) to being skeptical about the overall effectiveness of the whole tyrosine supplementation thing for ADHD. There just don't seem to be enough positive studies grounded in long-term improvements which tyrosine. Nevertheless, the number of positive reports on tyrosine from individuals are too great to ignore in most cases, so an outright condemnation of tyrosine for ADHD is by no means warranted.

It is important to note that none of the studies I've seen (both those supporting or refuting the idea of tyrosine for ADHD) have paid much attention into controlling for the co-factors of the enzymes responsible for metabolizing tyrosine. Just as a reminder, co-factors are essentially vitamins, minerals and other nutrients which are used to help enzymes function properly (or at least more efficiently).

So if we do decide to begin a tyrosine supplementation program, we should make sure we have adequate levels of the following nutrients (I have listed the major nutrients, and where it helps in the tyrosine metabolic processes. It is important to note that this list is not 100% complete, there are several other nutrients which play a role indirectly in the process, but I am just highlighting the major ones I've come across in the studies I've seen on the metabolic pathways of tyrosine to dopamine, norepinephrine and epinephrine):

Here are some links to recommended daily levels of the following nutrients and "cofactors" which can potentially affect the outcome of tyrosine supplementation for ADHD:

Iron
Zinc
Magnesium
Copper
Vitamin B6
Vitamin B12
Folic Acid
Vitamin C
(no official doses have been set for S-Adenosyl Methionine or SAMe, as this can be produced in the body, a ballpark supplemental dose for SAMe is around 100-200 mg twice a day, but of course varies per individual)

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

There are (surprisingly) few well-controlled clinical studies which show tyrosine to be an effective long-term strategy for treating ADHD. In spite of this, tyrosine supplements are often prescribed by a number of physicians (seemingly in a disproportionate manner when compared to other agents with more promising clinical studies). This disparity is at least noteworthy.

For those (few) studies who do tout the benefits of tyrosine supplements for ADHD, the symptom improvements are often short-lived (often only a few short weeks).

However, this blogger personally believes that many of the studies may have shown minimal effects due (at least in part) to the fact that many of the other nutritional "puzzle pieces" (such as those given in the tables above) were either neglected or not necessarily in place. These vitamin and mineral-based cofactors can play a huge role in the metabolic conversion of tyrosine to its desired products, and has been discussed at length in the seven previous blog posts on tyrosine and ADHD. Had these studies incorporated some of these co-treatment strategies, some of the results might possibly have been different.

Please note that while "natural", tyrosine supplementation is not always benign. Health risks, such as amino acid imbalances (due to the competitive nature of several amino acids with tyrosine to get into the brain), cardiovascular issues and even some types of cancers (which are often more associated with a derivative of tyrosine, L-DOPA, however) are very real. Additionally, biochemical side effects of tyrosine metabolism also exist, and can be magnified greatly if rampant tyrosine supplementation is undertaken. The pro-inflammatory agent homocysteine is one such example. However, nutrient-based treatments via B vitamins can often offset a potential homocysteine buildup.

The dosages for tyrosine supplementation can vary widely ranging from as low as 100 milligrams all the way up to 5000 milligrams (or more, toxicity often begins to set in around 10,000 mg, but this of course widely varies by individual). 2-3 supplements of 500-1000 mg/day is typical in a number of cases (lower doses are almost always a must for children), but dosing should always be under the guidance of a physician.

Most of the tyrosine supplemental strategies hinge or ride on the theory that ADHD is a dopamine or norepinephrine deficiency issue. However, much of the evidence on the disorder seems to indicate that the transport of these chemical neurotransmitters across neuronal cell membranes and an imbalance of the "inside-the-cell" vs. "outside-the-cell-in-the-gaps-between-neuronal-cell" concentrations of these agents is the real culprit. In other words, flooding the body with tyrosine in hopes that it will generate more dopamine and norepinephrine will not necessarily address this basis of imbalance.

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

In other words, tyrosine supplementation for ADHD treatments is theoretically viable, and has had numerous success stories. Maintaining adequate intake of the nutrient cofactors listed in the tables above helps supply the body's enzymes with the tools they need to metabolize tyrosine most effectively. When dietary intake of these nutrients is sufficient, and tyrosine is wisely used in conjunction with proper pharmaceutical agents, this blogger personally believes that there may be great tangible benefits with regards to ADHD symptoms and treatment.

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Friday, March 12, 2010

ADHD and Vitamin D Deficiency: Any Evidence?

Thursday, February 25, 2010

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

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