Does Tyrosine Supplementation Actually Work for ADHD? (part 2)

Can ADHD symptoms be alleviated by supplementing with the amino acid tyrosine?

This post is a continuation from our introductory one on the effectiveness of tyrosine as an ADHD supplementation strategy.

(Blogger's note: if you do not have the time or the patience to wade through all of this information, I have provided a 7-point summary at the bottom of the page, which goes over the major points of this blog posting. If you do have the time, however, there is a lot of material and valuable research in the posting below surrounding the complex metabolic processes surrounding just one step of the tyrosine supplementation pathway for ADHD treatment).

The theory behind using the amino acid tyrosine to treat ADHD symptoms stems from the fact that tyrosine is a chemical precursor to important neurotransmitters (chemical signaling agents in the nervous system) dopamine and norepinephrine. Dopamine and norephinephrine belong to a class of signaling agents called catecholamines. Numerous studies have shown that imbalances of both of these catecholamine agents exist in most ADHD cases, and the imbalances are often on the low end (i.e. lower levels of dopamine and norepinephrine are found in several critical regions of an ADHD brain when compared to a "normal" brain).

Of course, this is a vast oversimplification of the whole process (which is much more complex), but the basic idea is that we "feed" the brain with higher levels of tyrosine and it is then able to create more of these two neurotransmitters. This idea, of giving the body higher amounts of starting material to use to convert into higher levels of the specific chemicals we want to produce is often referred to as precursor loading.

Unfortunately, as we might imagine, the process of correcting these chemical shortages an imbalances (and solving all of our ADHD problems in the process) is much more complex than popping a few tyrosine supplements. Shown below is a diagram of most of the major chemical "steps" needed to go from tyrosine (written as "L-tyrosine" below) to the catecholamines dopamine and norepinephrine A larger version of the diagram can be found by clicking the figure (in most browsers, or at the original source of the diagram, which can be found here).
We might be asking ourselves the question: Why can't we just supplement with dopamine or norepinephrine catecholamines directly to combat these ADHD-related shortages? The answer has to do with a biochemical entity known as the blood brain barrier.

The blood brain barrier is a special biochemical barrier used to control the transport of nutrients in and out of the brain. It is largely a protective measure, meant to keep toxic chemicals, which may have worked their way into the blood, out of the highly susceptible brain region. However, this blood brain barrier can also keep out some of our desired drug targets or chemical agents, including dopamine. Thus, while tyrosine (or as we'll also see in a later post, L-DOPA) can cross this barrier, dopamine cannot. As a result, we need to start with either tyrosine or L-DOPA on the outside of the blood brain barrier, shuttle these agents into the brain, and then have the brain convert them to the desired compounds.

In today's post, we will be examining the first step of the process in more detail, the conversion of tyrosine (L-tyrosine in the diagram) to L-DOPA:In order for this process to occur efficiently, we need three major components:

1. An ample supply of tyrosine (or L-tyrosine) listed above
   
2. A functional amount of the enzyme tyrosine hydroxylase
3. Sufficient levels of a compound called Tetrahydrobiopterin.

Here's a more in-depth analysis of each of these three factors:

OPTIMIZING FACTOR #1: AN AMPLE SUPPLY OF TYROSINE:

How much tyrosine is necessary to do the job?

Unfortunately, the conversion from tyrosine to L-DOPA is not a particularly efficient process. As a result, higher levels of starting material (tyrosine) are needed. Just to give a very rough overview on the amount of tyrosine we're dealing with here in the context of ADHD treatment, typical daily supplemental doses often fall around 500 to 1500 mg per day, although there is often room for higher doses before toxicity risks set in.

At around 10-12 grams (roughly 10 times this amount), the risk of toxicity often goes way up. Other complications include high blood pressure or skin cancer (the reasons which we'll discuss in later posts), or the use of antidepressant medications, in which recommended tyrosine supplemental levels should be significantly lower (or avoided altogether).

**While tyrosine supplements can be purchased over the counter, PLEASE consult with a physician before doing any type of supplementation. In addition to the ones listed above, there are several other confounding factors which need to be taken into consideration with regards to dosing.


OPTIMIZING FACTOR #2: ADEQUATE FUNCTION OF THE ENZYME TYROSINE HYDROXYLASE

Kinetic studies (studies which measure the speed or rate of chemical reactions) have shown that this first step, L-tyrosine to L-DOPA is the rate limiting step in the tyrosine to dopamine/norepinephrine process. In other words, the "bottleneck" in this conversion process lies within the enzymatic conversion of tyrosine to L-DOPA and involves the tyrosine hydroxylase enzyme.

In addition to the fact that this enzymatic step is the slowest step in the tyrosine to dopamine conversion pathway, the tyrosine hydroxylase enzyme has some additional challenges to overcome. One of these is inhibition by its product, L-DOPA. What does this mean?

Most enzymes or enzyme systems often have some sort of "brakes" or "control switches" too keep them from running non-stop at full speed. In other words, when the body senses that enough of the desired product is attained, it will signal for these enzymes (or other regulatory systems) to either slow down or stop, to keep things balanced and in check (think of what would happen if these feedback systems weren't in place for, say, regulating appetite and feeling full, or getting an adrenaline rush that did not subside when the perceived "threat" was over).

Tyrosine hydroxylase is one such enzyme, meaning that when large amounts of dopamine or norepinephrine are eventually produced from tyrosine, the body actually begins to shut down this enzyme-regulated conversion process. Numerous studies have shown this, as tyrosine hydroxylase is inhibited by catecholamines.

In addition, other enzymes also work on tyrosine hydroxylase and help turn it "on" or "off". As a result, bombarding the system with high amounts of tyrosine will not generate equally high levels of neurotransmitters, because this feedback system is in place (and we haven't even mentioned some of the potentially harmful effects of doing this, which will be discussed in later posts).

***Blogger's note: It is not my intention as a blogger to try to dazzle or confuse anyone by using all of this technical and scientific jargon. Rather, I simply want to share how much is really going on behind the scenes when we play with the levels of just one type of supplement, like tyrosine. Having said this, I personally feel that a lot of false hope is created by advocates of supplement treatment for ADHD, as these proponents often over-simply these complexities and exaggerate the overall efficacy of these "natural" ADHD treatments. I personally would like to see more non-medication treatments tried out for ADHD management, but it is a disservice to anyone if these non-drug treatment options for ADHD aren't addressed with a similar level of scrutiny.

Getting back to the topic at hand...

Further clouding the tyrosine hydroxylase enzyme issue is the fact that there are several different forms of this enzyme which exist across the population. The enzyme tyrosine hydroxylase is actually coded for by a gene on the 11th human chromosome, which goes by the same name, the tyrosine hydroxylase gene.

It is important to note that slightly different versions of this gene among the human population actually result in slightly different versions of the tyrosine hydroxylase enzyme. A growing body of evidence suggests that individuals with certain genetic variations of this tyrosine hydroxylase enzyme are more prone to certain psychiatric disorders. While it appears that ADHD is not as strongly connected to this gene and enzyme as other disorders (such as schizophrenia or Parkinson's), it is important to note that ADHD does share some degree of biochemical overlap with some of the disorders mentioned.

It is important to note that this tyrosine hydroxylase enzyme does not act in isolation. As mentioned in the previous post, many enzymes require special "helping" agents called co-factors, which are needed to help stabilize the enzyme or system of enzymes and influence their chemical functionality.

Many vitamins and minerals serve as co-factors for various enzymes. In the case of tyrosine hydroxylase, a major necessary nutrient co-factor is iron. As we will see later, iron has all sorts of implications with regards to the dopamine synthesis pathway. This has effects on both ADHD, as well as common comorbid (co-occurring) disorders to ADHD, including sleep disorders such as Restless Legs Syndrome. In other words, it is imperative that adequate dietary intake of iron in necessary to provide the body with enough of this vital nutrient to allow enzymes such as tyrosine hydroxylase function properly.

The tyrosine hydroxylase enzyme is bound to iron. You may remember from high school or college chemistry classes that iron typically exists in two major form, the ferrous form (a "+2" positive charge) or a ferric form (a "+3" positive charge). It turns out that these two forms of iron actually exhibit major effects on the function of this tyrosine hydroxylase enzyme.

Blogger's note: The following explanation will contain a fair amount of chemistry jargon. If you have any sort of science background, you might find it interesting, if not, please skim the next few paragraphs, and we'll meet up at the bottom where I summarize these findings and applications of this info:

As mentioned above, ferrous iron is the less positively charged (or, in chemical terms, less "oxidized") form of iron, while ferric is the more positively charged or more oxidized version of iron. Both of these forms can be embedded in the tyrosine hydroxylase enzyme. It turns out, however, that it is the less-oxidized ferrous form of the iron (+2) that is required for the enzyme to convert tyrosine to L-DOPA.

On the flipside, the more oxidized ferric form of the iron (+3 charge) is actually the form of the enzyme which plays a major role in shutting down the enzyme's production by catecholamines, as in the process of feedback inhibition mentioned above.

Overgeneralizing and oversimplifying a bit here, it is advantageous for our system to keep this iron in the tyrosine hydroxylase state at the less-oxidized ferrous form if we want to keep the enzyme running (again, this is a gross oversimplification, but the general idea holds).

If you've been reading this blog for awhile, you may have come across a post a few weeks ago entitled 10 Ways Vitamin C helps treat ADHD symptoms. In this posting, we discussed some of the interactions between vitamin C and iron, and how the vitamin can not only aid in the absorption of iron (thus helping to boost iron levels necessary for proper enzyme function) but also to act as an antioxidant on the iron.

Branching off of this idea, maintaining the necessary antioxidant pools via vitamin C or other antioxidants (which will be discussed shortly), we can help keep the iron in the tyrosine hydroxylase enzyme in the reduced ferrous state and aid in the tyrosine to dopamine conversion pathway. Some earlier mammalian studies have found that activity of the tyrosine hydroxylase enzyme is compromised in a state of severe vitamin C deficiency (scurvy), with the probable culprit being the inability to maintain the reduced (+2) ferrous state. In other words, vitamin C can influence ferrous iron levels, which then influences the tyrosine hydroxylase enzyme.


OPTIMIZING FACTOR #3: THE NEED FOR TETRAHYDROBIOPTERIN (and cofactors necessary for the regeneration of this tetrahydrobiopterin)

We have seen that vitamin C can help stabilize the tyrosine hydroxylase enzyme. However, the main factor in regular tyrosine to dopamine conversion stems from a compound known as tetrahydrobiopterin, which is often abbreviated as BH4. Tetrahydrobiopterin (along with molecular oxygen) is a major cofactor of the tyrosine hydroxylase enzyme, and responsible for the addition of the hydroxyl (-OH) group to the tyrosine molecule to produce L-DOPA.

This compound is manufactured in the human body, so (except in the case of rare genetic or metabolic disorders) supplementation with tetrahydrobiopterin or its chemical precursors is not necessary. However, its synthesis (from its own series of enzymes) is dependent on adequate levels of nutrient cofactors including magnesium and zinc. Prolonged deficiencies in either or both of these minerals can therefore potentially inhibit the synthesis of tetrahydrobiopterin, and, indirectly, the tyrosine to dopamine conversion process. Please note that we have discussed both magnesium and zinc in great detail with regards to the roles they play in the onset and treatment of ADHD.

In addition to the indirect relationship between tetrahydrobiopterin and ADHD due to the impact on dopamine synthesis, tetrahydrobiopterin is important in numerous other functions as well. For example, low levels of tetrahydrobiopterin in the body have been associated with hypertension and other types of cardiovascular dysfunction.

If tetrahydrobiopterin (BH4) is the predominant compound for the tyrosine hydroxylase enzyme function, is vitamin C still potentially useful in the process?

While BH4 is a more powerful regulator of the tyrosine hydroxylase enzyme in the tyrosine to L-DOPA ADHD treatment pathway, there is some evidence that vitamin C can "help the helper". A much older study, done way back in the 1970's suggests the benefits of vitamin C on the synthesis of catecholamines like dopamine and norepinephrine. The reason given in this article is the role of vitamin C in recycling or regenerating functional forms of the tetrahydrobiopterin compound.

The whole concept of vitamin C recycling other nutrients is not new to this blog and its discussions. We have mentioned how vitamin C can "recycle" other antioxidants such as vitamin E, and how this can have an indirect impact on nutritional treatment strategies for ADHD.

To summarize the key points and suggestions which should be taken away from this the blog post:

1. Do not overdose on Tyrosine supplementation. For reference, a ballpark estimate on dosing is often somewhere around 500 to 1500 mg per day, but please do not start any type of supplementation without consulting with a physician.
   
   
2. Tyrosine hydroxylase is the key enzyme in the conversion of tyrosine to L-DOPA. It is contains iron which must be kept in the reduced (+2) state to function properly. Naturally, this means that the enzyme can be compromised if an iron deficiency is present. Recommended daily intake levels for iron can be found here.
   
   
3. It is believed that this tyrosine hydroxylase enzyme can be aided by maintaining ample levels of antioxidants such as vitamin C in the diet. Keeping antioxidant levels up to speed aids in maintaining this necessary form of the iron for the enzyme to function properly. In other words, the enzyme is intricately connected to antioxidant balances in the body. This is an often overlooked side-component of ADHD treatment via tyrosine supplementation. here is a link for the recommended daily intake for vitamin C.
   
   
4. Tyrosine hydroxylase is inhibited by its own products, the catecholamines (which include dopamine and norepinephrine, two of our later "targets" in the above diagrammed pathways). This means that we cannot expect to get high levels of dopamine in the brain by mega-supplementing with tyrosine, because this process shuts itself off.
   
   
5. Therefore, excessive tyrosine supplementation (beyond the level recommended by your physician) is essentially ineffective, and potentially harmful.
   
   
6. The main helper of the tyrosine hydroxylase enzyme, however, is the compound tetrahyrobiopterin. This is manufactured in the body, so supplementation for this is not necessary (except in the case of a few rarel genetic or metabolic disorders). Tetrahydrobiopterin and molecular oxygen (O2) supply the enzyme with the proper tools to convert the tyrosine to L-DOPA by chemically adding a hydroxyl (-OH) group, which can be seen in the diagrams near the top of the post.
   
   
7. Tetrahydrobiopterin synthesis is dependent on nutrient cofactors including zinc and magnesium. Recommended daily amounts can be found here for zinc and here for magnesium.
   

In our next post, we will be looking at the second major step of the conversion process from the tyrosine to dopamine pathway. This will rely heavily on enzymes known as decarboxylases. We will be looking at how these enzymes work, what nutrients (or co-factors) they need, and examine to see if there are any interfering factors or side-effects involved, as a way to optimize this process of tyrosine supplementation as an ADHD treatment strategy.

Does Tyrosine Supplementation Actually Work for ADHD? (part 1: theory and background)

Can ADHD Symptoms be Cured or Treated via Tyrosine Supplementation?

Due to the extensive nature of this topic, we will be investigating the answer to this question over a number of consecutive blog posts. First, some background on tyrosine, and why it is often a suggested (and even prescribed) on a relatively frequent basis by clinicians for treatment of ADHD and related disorders:

The appeal of a natural ADHD treatment strategy such as supplementation with tyrosine or other amino acids in lieu of drugs:

As a parent, teacher or guardian of an ADHD child (or possibly as ADHD sufferers ourselves), we often have an inherent bias against medications for the attention deficit hyperactivity disorders. This is quite understandable. After all, who really wants to "drug" themselves or their child, especially if a more "natural" benign treatment method is currently available? While many of the claims against ADHD medications are either fabricated (as an example, while many "natural" ADHD treatment websites often love to assert otherwise, Ritalin is not the equivalent to crack cocaine) or over-hyped, there are definitely legitimate concerns and risks surrounding medication treatments for the disorder. Potential complications include:

• Negative side effects, including potential cardiovascular effects, and even rare bizarre ones
  
• Addiction potential (spoken especially of stimulants)
  
• Mis-dosing risks (either over or under-dosing on medications) and numerous in-born or genetic factors which can lead to dosing difficulties
  
• Medication safety issues
  
• Potential complications with ADHD comorbid disorders such as Tourette's and tic disorders, obsessive compulsive disorders (OCD), anxiety disorders, bedwetting, etc.
• Negative effects on dietary habits, including appetite suppression (with the potential for stunting growth and development), eating disorders, and sleep or sleep-related disorders
  
• Costs of medications and other treatment strategies for ADHD
  
• The idea that medications only treat the symptoms of the disorders as opposed to the root of the problem
• Relative lack of evidence on possible long-term side-effects of adhd medications
• Possible damages on brain development
  

The list goes on, but we get the idea.


THE THEORY BEHIND TYROSINE SUPPLEMENTATION FOR TREATING ADHD:

1. There is an imbalance of brain chemicals dopamine and norepinephrine in the ADHD brain:

One of the basic premises of ADHD is that it is caused by a chemical imbalance of certain neurotransmitters in the brain, including dopamine and norepinephrine. While the following description is a gross over-simplification of the process involved, the current theory is that the balance of the brain chemical dopamine inside vs. outside of brain cells is out of whack in certain key "ADHD" brain regions.

(As a side note, here is a link to some of main brain regions believed to be "different" between the ADHD and non-ADHD population, as well as another earlier post on the difference between an ADHD brain and an OCD (obsessive compulsive disorder) brain. Additionally, variations among individuals involving specific "ADHD genes" may play a role in dopamine level differences. Please take each post with a grain of salt, as they are more generalizations and examples than non-negotiable absolutes).

Again, this is a great oversimplification of a complicated process, but the general idea is that most ADHD medications (the stimulants in particular) work by either directly or indirectly increasing the levels of dopamine outside of the neuronal cells in the brain and restoring this imbalance. Please note, however, that this generalized "dopamine deficiency" theory of ADHD is by no means a consensus among the medical profession and is being challenged by some professionals.

2. Direct dietary supplementation with dopamine for ADHD treatment is ineffective:

Our first thought might be to just try to supplement the body with large amounts of dopamine to try to correct this neuro-chemical imbalance. The problem with this strategy is that we have to deal with an entity known as the Blood Brain Barrier.

In a nutshell, the Blood Brain Barrier is a barrier meant to prevent potentially harmful agents in the blood from making their way into the brain. In other words, it is a crucial protective measure which is vital to the survival of our bodies and respective nervous systems from the rapid influx of potentially harmful agents. The problem is that this barrier also screens out a number of potentially helpful agents, including many types of therapeutic drugs (this is one of the biggest challenges in the design of psychiatric medications, in addition to acting on their targets, these drugs must be able to actually get into the brain in the first place).

Unfortunately, it has long been known that the chemical dopamine itself does not have a particularly sound affinity for the blood brain barrier (although a number of "tricks" involving manipulation of protein "transporters" in and around the brain, as well as using slightly modified related compounds have been used to increase levels of this important neurochemical). As a result, direct unaided dopamine supplementation for ADHD does not work. Enter the amino acid tyrosine.

3. The amino acid tyrosine is a chemical precursor to both dopamine and norepinephrine.

Unlike dopamine, the amino acid tyrosine can cross the blood brain barrier (under the right conditions). The following diagram highlights the general pathway (including chemical intermediates) from tyrosine (listed as "L-tyrosine" in the diagram) all the way to dopamine, norepinephrine, and even epinephrine (adrenaline):
(Please note, the diagram depicted above is a reproduction of a larger image originally found here. The blogger apologizes for the low quality of the image depicted here; feel free to check out the larger image in the link above if needed.)

The attempt to generate higher levels of dopamine and norepinephrine by supplying the body with the dopamine and norepinephrine precursor tyrosine is an example of what is known in medicine as precursor loading. As we will see later on, precursor loading strategies are often a mixed bag of rewards and risks, with varying degrees of overall effectiveness. This blogger intentionally wishes to remain neutral on the subject at hand here, with the goal in mind of providing unbiased information advocating both for and against tyrosine treatment for ADHD.

You do not need to be a biochemist or know chemical structures or pathways; the above picture is just simply a visual tool to demonstrate that there are a number of steps in the conversion process of tyrosine to dopamine and norepinephrine. Using the above diagram for reference, we will see that there are a number of "hoops" we need to jump through in order to make tyrosine supplementation worthwhile as a possible ADHD treatment. We will break this down into smaller steps in the next collection of posts and summarize the overall potential (as well as review what the current literature has to say on this process) at the very end.

I have broken down some of the major steps of this process, which need to be considered to maximize the effectiveness of this tyrosine treatment for ADHD. Each of these steps will be addressed in the next few posts:

1. The supplement must be able to cross the blood brain barrier. This process involves special "transporters", and can be influenced by outside factors, including other dietary amino acids. This will be discussed in the next post.
   
   
2. In order to proceed on to dopamine, tyrosine must first be converted into an intermediate called L-dopa (please note that L-dopa can cross the blood brain barrier as well, and is sometimes used as a prescribed supplement for ADHD treatment in its own right. This will be discussed later on, including advantages or disadvantages of supplementing with L-dopa vs. supplementing with tyrosine).
   
   
3. In order to convert to L-dopa, tyrosine requires the enzyme Tyrosine Hydroxylase, as well as cofactors ("helpers" to the enzyme), which will be discussed in detail in a later section.
   
   
4. In order to convert from L-dopa to dopamine, a class of enzymes known as decarboxylases is needed. This too, requires cofactors (which in this case are specific vitamin and mineral derivatives) to operate properly. It is important to note that deficiencies in these nutrients can severely inhibit this step of the process (and, in the blogger's opinion, can be a seriously overlooked reason for the relative ineffectiveness of tyrosine supplementation in a number of cases, and that simply maintaining adequate levels of these nutrients could greatly aid the process in this crucial step). Again, these challenges will be discussed at a later time.
   
   
5. Norepinephrine imbalances are also seen in many ADHD cases, so the dopamine to norepineprhine conversion process is also important. This, too, requires specific enzymes and cofactors.
   
   
6. It is also critical that we don't overlook side reactions in the process. As we might expect, tyrosine can convert to a number of other things in the body besides dopamine, and the enzymes and systems involved in these pathways often "compete" with one another, each with its own accompanying side effects. These competing processes can cause potential problems, including the depletion of several crucial vitamins and minerals (the B vitamins in particular) and may also cause a buildup of potentially harmful biochemical products (such as homocysteine). Perhaps not surprisingly, some of these key vitamins and minerals used up by the above metabolic processes are often found to be deficient in the general ADHD population.
   
   We have investigated some of these B vitamin and homocysteine effects with respect to ADHD in an earlier post. The point here is this: if we flood our system with tyrosine, we must realize that we are feeding the first step of a whole slew of biochemical products in addition to our desired end products of dopamine and norepinephrine. We must account for these effects and do everything possible nutritionally to minimize the potential harm of chemical imbalances caused by these processes.

Of course there are other factors besides these six, but hopefully, we can start to see that supplementation with this amino acid in hopes of treating ADHD (or at least reducing symptoms of the disorder) has numerous complications, as well as potential drawbacks and limitations. However, this blogger feels that if we are to have a go with tyrosine supplementation, all the other pieces of this metabolic puzzle (nutrients, enzyme systems and otherwise) must be firmly in place to maximize the effectiveness of this ADHD treatment strategy. While this is certainly a tall order, it is my aim as a blogger to both highlight these necessary puzzle pieces and give potential ways to optimize their effectiveness in the next few posts.

10 Ways Vitamin C helps treat ADHD Symptoms

How Vitamin C can be an Effective Treatment Method for ADHD

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

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

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

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

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

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

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

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

1. Vitamin C offers protection against fatty acid oxidation, including the important omega-3's which are a popular treatment and supplement for ADHD. While omega-3 supplementation remains a popular treatment method among "natural" ADHD treatment advocates, its overall effectiveness remains questionable.
   
   The theory behind omega-3 treatments for ADHD can be found in an earlier posting, but in a nutshell, the brain and central nervous system are comprised of cells with very high omega-3 fat content, and must be constantly supplied with either these fats themselves or chemical precursors to these fats (which can then be converted into these essential nutrients). These fats play a critical role in coating the outer layers of the "messenger" signaling portions of the brain, and the development of these protective layers (called myelination) is especially pronounced in adolescence.
   
   High levels of overall brain development and re-wiring occurs during the adolescent stages, and in multiple cases, this process is delayed in the ADHD population. Therefore, the idea holds that we should be supplementing this process along by feeding the brain these important omega-3 rich foods and nutrients.
   
   However, one of the fundamental problems is the fact that fatty acids (including omega-3's in particular) are especially susceptible to damage through chemical process of oxidation. We have alluded to this in earlier discussions on omega-3 oxidation and ADHD. Numerous studies have shown that dietary antioxidant intervention can greatly alleviate this problem. In this blogger's opinion, failure to recognize this important factor of antioxidant protection for omega-3 fatty acids is one of the biggest saboteurs of omega-3 intervention as an ADHD treatment.
   
   As far as antioxidant protection strategies of fatty acids are concerned, vitamin C is often not the best choice. As a water-soluble vitamin, the interactions with the much less water soluble omega-3 fatty acids are potentially limited. However, vitamin C can "sacrifice" itself and help boost levels of other important antioxidants in the body that can have a greater impact on omega-3 fatty acid protection and cell membrane viability. Among these are vitamin E and glutathione (which will be addressed later on in this posting, when we talk about antioxidant recycling).
   
   However, we may be beginning to see that vitamin C could be an effective co-treatment to fatty acids in its own right, at least according to some recent studies. One study (which, unfortunately paid more attention to the fatty acid component and had vitamin C as more of an auxiliary co-treatment) suggested that vitamin C can boost the efficacy of flax oil (a popular omega-3 rich dietary choice) as an ADHD treatment measure. Clearly, this was just one study, and more research is warranted, but the significance of protecting these all-important dietary fats found at high concentrations in the brain and nervous system cannot be understated.


2. Vitamin C acts as a potent neuroprotective agent (important for neurological disorders including ADHD). It may sound surprising, but nerve endings in the brain have the second highest concentration of vitamin C in the body (behind only the adrenal glands, which produce adrenaline, which we will mention later in this post when discussing vitamin C and catecholamines). Current research appears to illuminate the protective role of vitamin C, specifically in its oxidized DHA form and when used in conjunction with vitamin D3, against a specific type of oxidative damage on the brain called ischemia (reduced blood supply to a particular brain region, which can be brought on, by other things, oxidative damage).
   
   The relevance to ADHD here is that ischemia is a surprisingly common environmental cause of the disorder, especially during early (neonatal) development. It is believed by some researchers that oxidative damage which causes this ischemic reduction of blood supply may bring on ADHD symptoms by interfering with biological targets (or receptors) in the brain for the important neurotransmitting chemical dopamine. In other words, for those individuals suffering from reduced blood flow to these brain regions earlier in life, the important signaling chemical dopamine has trouble finding its mark in the brain, results in the attenuation of attention span and longer reaction timing (for more information on ADHD and reaction timing, please see the earlier post: Do ADHD Kids Use their brain regions differently?).
   
   While the basis for ischemia treatment for ADHD via vitamin C supplementation is more hypothetical at the moment, the fact that treatment with this vitamin can counteract a major environmental cause of the disorder suggests that vitamin C may be a viable treatment method for this aspect of ADHD and related disorders.


3. Vitamin C helps "recycle" and maintain pools of other crucial antioxidants such as vitamin E, polyphenols (potent antioxidants found in fruits, vegetables, wines and teas), glutathione (which is manufactured in the body and is the body's standard antioxidant of choice), and products of the antioxidant enzyme superoxide dismutase or SOD.
   
   We have alluded to this message in point number 1 above. Several studies have found abnormally low antioxidant levels (and high "pro-oxidant" levels) in ADHD subjects. It appears that increasing dietary antioxidant intake may at least partially reduce this trend.
   
   For example, boosting intake of a form of vitamin E called gamma-tocopherol can reduce the oxidation of important fatty acids in ADHD subjects (although it is worth mentioning that gamma-tocopherol is not the most bio-available form of vitamin E, that honor goes to another form of the vitamin called alpha-tocopherol). It is worth mentioning that vitamin C and vitamin E work extremely well together as an antioxidant tandem, and help spare the pool of the body's antioxidant reserves from depletion. Therefore co-administration of these two vitamins is highly recommended.
   
   Collective research appears to indicate that raising the total antioxidant levels in the body can offset some of the negative symptoms of ADHD and related disorders. We've already mentioned the importance of preventing oxidation of the fatty acids (lipids) of the cell walls, including the membranes of brain cells (which are rich in the omega-3's).
   
   Secondary to its role in preventing fatty acid oxidation, vitamin C can counteract the oxidation of minerals (including iron and copper) which may often be used as dietary supplements for ADHD treatments. As in the case of omega-3 fatty acid supplementation, the risk of increased oxidative damage due to these mineral supplements is an often overlooked negative side effect of this common "natural" ADHD treatment strategy.
   
   Due, in part to its high concentration in brain tissue and susceptibility to oxidation, iron is prone to causing oxidative damage to the brain. Maintaining adequate levels of vitamin C (as well as vitamin E, polyphenols and glutathione) can offset much of this potential damage. We will see this more in point #5 below.
   
   Finally, an often-overlooked side effect of most medications (including ADHD stimulant medications) is the potential for these medications to cause oxidative damage. For example, the common ADHD stimulant methylphenidate (Ritalin, Concerta, Daytrana) was found to cause oxidative stress in young rat brains, and highlights the possibility that long-term administration of these agents may leave key targeted "ADHD" brain regions more susceptible to oxidative damage.
   
   This observation was more evident in younger rats undergoing development and brain maturation, which may translate into analogous effects in the developing brains of children. Thus, children may be susceptible to harmful oxidative damage in the brain via consistent use of common ADHD stimulant medication, increasing their need for higher levels of vitamin C and other antioxidants.
   
   Of course, we should not put too much stock into just one or two studies; and that this conclusion is being drawn prematurely by ramblings of an over-anxious blogger :) but we may seriously need to investigate this often overlooked possibility of ADHD medication based oxidative brain damage in children, and the possible amelioration of these dagmages via treatment with dietary antioxidants such as vitamins C and E.
   
   
4. Vitamin C can potentially counteract the effects of lead on ADHD-like states: Numerous studies have linked in increase in ADHD symtpoms and behaviors with higher lead levels (although it is worth mentioning that numerous studies out there refute this association as well, so there is far from a consensus surrounding this issue). We have seen previously that iron may counteract lead and potentially alleviate some of these negative lead-based effects. When used in conjunction with other nutrients such as the mineral zinc and the amino acids taurine, methionine and glycine, vitamin C may reduce lead-derived learning and memory impairments (in the rat model), features which offer at least some semblance to common deficits in the disorder of ADHD.
   
   
5. Vitamin C can boost absorption of key minerals which are often deficient in the ADHD population. One possible explanation for the ability of vitamin C to counteract the effects of lead may be the role of vitamin C in boosting iron absorption, especially in iron deficient states. Some studies strongly recommend the co-administration of these two nutrients.
   
   As an aside, please note that there is a healthy debate surrounding the possibility of vitamin C/iron combinations acting as potentially destructive pro-oxidants. Based on current trends in the literature, however, it appears that most of these negative effects are seen more in vitro, or in cell cultures, but not in vivo, or in the body. Interestingly, this potential double-edged sword of ascorbic acid form of vitamin C (as either a pro-oxidant or antioxidant) may be strongly tied to the concentration or levels of the vitamin, in that vitamin C is reported to act more like a pro-oxidant at lower levels and an antioxidant at higher levels. This may explain some of the discrepancy surrounding the pro vs. anti-oxidant effects of vitamin C when coupled with iron or other minerals.
   
   We have discussed the prominence of iron deficiencies in the ADHD population and the role of this critical nutrient for treating the disorder, such as the role of iron in the synthesis of neurotransmitters such as dopamine.
   
   Additionally, common disorders common to ADHD such as Restless legs Syndrome and sleep disorders may be attributed to deficiencies in iron levels. Therefore, vitamin C may serve as a secondary protection strategy against iron deficiencies and subsequent worsening of ADHD symptoms.
   
   I realize that it can be difficult to make sense of and keep separate the various iron/vitamin C interactions, so to summarize some of the main points of these associations:
   
   1) Vitamin C can aid in the body's absorption of iron.
   2) Vitamin C can interact with iron and keep the iron from being oxidized, but...
   3) This process can cause an oxidized form of vitamin C itself. This oxidized vitamin C species can potentially cause damage in its own right if unchecked (but can be recycled back to the antioxidant form of the vitamin by other antioxidants in the body).
   4) In general, lower levels of vitamin C tend to have more of a "pro-oxidant" effect, while the antioxidant effects of vitamin C often predominate at higher levels of the vitamin.
   
   
6. Higher vitamin C levels have been tied to improvements in visuo-spatial abilities as well as non-verbal intelligence (both of which are often deficient in the ADHD population). As a reference, non-verbal intelligence includes skills such as being able to read or pick up on non-verbal social cues such as reading facial expressions and associating them with another person's mood, as well as distinguishing differences and inflections in tone of voice. It is important to note that non-verbal learning disabilities often accompany ADHD symptoms, and are often seen across the autistic spectrum (which mirrors ADHD symptoms in a number of ways).
   
   The correlation between vitamin C and non-verbal abilities is more strained than some of the other associations mentioned in this piece, but this blogger has found a few documented studies pointing out this possible affiliation. The whole vitamin C association with non-verbal deficits might be part of a bigger picture, in that deficits in non-verbal IQ scores seems to be correlated with low total overall antioxidant levels.
   
   On the flipside, the correlation between non-verbal deficits and the vitamin C antioxidant in particular appears to be more prominent in boys (compare this to a later section of this post where we will see that ADHD symptoms may be more tied to abnormalities in blood glucose levels in girls). In other words, the effects of vitamin C supplementation may have different levels of effectiveness with regards to gender and comorbid conditions (but please note that much more additional study must be done to validate this general claim).
   
   
7. Beyond the physical anti-aging benefits commonly associated with the vitamin, vitamin C has shown to exhibit potent intellectual anti-aging benefits (making it a good candidate for adult ADHD cases). While the publication cited above is given in the context of the neurodegenerative disorder Alzheimer's Disease, we should take note that there is a significant overlap between ADHD and Alzheimer's (beyond just the attentional deficits).
   
   For example, genes (and the enzymes they code for) we have previously mentioned as being associated with ADHD are also believed to be affiliated with Alzheimer's. These include "ADHD" genes and enzymes such as COMT and the Serotonin Transporter gene. Given the fact that the two disorders share a significant genetic and enzyme system overlap, as well as similarities between the features of the two disorders (as well as some anecdotal evidence for higher rates of neurodegenerative disease susceptibility in the ADHD population), this blogger suggests that the two disorders may also share effective treatment strategies utilizing vitamin C.
   
   
8. Vitamin C's important role as a cofactor in important enzymes relevant to ADHD and related disorders: This is one of the less obvious (but extremely important) ways in which vitamin C treatment could benefit the individual with ADHD. Typically when we think of "cofactors" (agents which help the enzymes and enzyme systems in the body operate at peak efficiency), we often think of B vitamins or trace minerals such as zinc, iron, or magnesium.
   
   However, it is important to get out of our heads the notion that vitamin C's mode of action as an ADHD treatment strategy is confined to its role as a "generic" antioxidant. Several enzymes whose function is linked to ADHD (often through the metabolism of other nutrients or pharmaceutical agents) require it as an essential cofactor to improve their function. One of these is the enzyme Dopamine Beta Hydroxylase, which will be discussed in more detail in the next point.
   
   
9. Vitamin C is important in the conversion process of dopamine to norepinephrine: This is relevant to both drug and nutritionally based treatment methods for ADHD (dopamine and norepinephrine are key neurotransmitters in the brain and nervous system and are often unbalanced in ADHD cases. Many ADHD medications (in particular the stimulants) work by regulating the production and transport of these two chemicals by targeting key enzymes and proteins made for transporting both of these agents.
   
   As mentioned above, one such enzyme for this conversion is the enzyme Dopamine Beta Hydroxylase (or DBH). We have investigated the importance of the gene that codes for this enzyme, the Dopamine Beta Hydroxylase gene, and its significance with regards to ADHD in earlier posts.
   
   Synthesis of other catecholamines (chemicals which are manufactured in the body from the amino acid tyrosine, which were alluded to in an earlier post on the drug modafinil for adult ADHD treatment and will be discussed further at the end of this post) such dopamine, norepinephrine and adrenaline) takes place in vitamin C rich regions of the body, including the adrenal glands as well as various brain regions.
   
   Keep in mind that the concentrations of vitamin C required for the enzymes in these brain regions to work optimally are around 40 times higher than the typical vitamin C concentration in the blood. As a result, an effective transport system to get this higher concentration in the brain is necessary, which leads to the next function of the Blood Brain Barrier (BBB):
   
   
10. Vitamin C has multiple well-designed ways to get into the brain through the Blood Brain Barrier and its levels are tightly regulated: The Blood Brain Barrier is an important barrier that is designed to limit or prevent potentially harmful substances in the blood from crossing over into the brain, while allowing a controlled passage of nutrients into the brain. We have alluded to this barrier in the last post with regards to its role in the passage of metals such as selenium, zinc and mercury and the subsequent effects on ADHD.
    
    Compounds which are water soluble, such as vitamin C, have an inherently more difficult passage through this critical barrier owing to size and solubility issues (in general, the blood brain barrier naturally favors the transport of less water soluble agents). However, there are a number of ways around this potential problem.
    
    In biology and medicine, the term homeostasis refers to stability or resistance to uncontrolled fluctuation. The transport systems of the blood brain barrier seem to be well-suited for vitamin C, owing in part to the fact that the optimal levels of key proteins that transport the vitamin into the brain fall work at peak efficiency around the standard concentration of vitamin C in the blood (this is not the case for all nutrient transporters).
    
    For example one of these proteins is called the Sodium-dependent Vitamin C Transporter-2 (or SVCT-2) allows vitamin C to be transported into the brain from the blood and maintain the much higher brain concentration of the vitamin. In fact, different transport methods exist (and, to some degree are even more favorable) if vitamin C is in the oxidized form (i.e. it has already fulfilled its role as an antioxidant by "sacrificing" itself to keep harmful oxidation from occuring to something else, such as an omega-3 fatty acid).
    
    It is important to note that because of these tight regulatory mechanisms which safeguard levels of vitamin C both in and out of the brain, rampant supplementation with vitamin C will not change its levels in the brain to a high degree. In other words, our bodies are typically well-adapted at holding onto this vitamin and maintaining appropriate levels of this key nutrient in the brain. This provides argument against the merits of high levels of supplementation (not to say that higher levels are necessarily harmful, just that this will be of limited effect). Nevertheless, we still should strive to avoid shortages of this vitamin.

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

1. Vitamin C may help regulate blood glucose levels in ADHD patients: Several studies seem to indicate that glucose metabolism in the brains of ADHD children is lower in multiple regions. It appears that these effects may be even more pronounced in girls and women with ADHD (although this blogger believes that the whole brain glucose metabolism differences are a bit overhyped, a number of other studies, which are simply not mentioned in most ADHD treatment books, found little to no metabolic differences. Nevertheless, I believe there is still sufficient evidence that, while smaller than what most other "ADHD experts" assert, there is still a significant difference in these metabolic patterns).
   
   Additionally, these differences may become more pronounced with age, suggesting a potentially greater necessity for intervention among adult ADHD cases. Again, women in particular may be more affected, according to the current body of research. It is important to note that the evidence for vitamin C supplementation for improving brain glucose metabolic efficiency for ADHD patients is more hypothetical than experimental at the moment.
   
   What we do know is that there are pronounced interactions with vitamin C and glucose regulation, such as vitamin C treatment for diabetic conditions. However, we may at the wrong end of a "chicken-or-the-egg" type of dilemna, since significant evidence points towards lower vitamin C concentrations in diabetic-like conditions. This is likely due, in part, to the oxidative stress caused on the body by the diabetic state (and the subsequent consumption or depletion of vitamin C stores).
   
   Again, most of these studies are done on diabetic conditions in the blood outside of the nervous system, but some of these effects (at least in theory) could carry over to glucose regulation in the brain. However, this blogger readily admits that this possibility is somewhat tenuous.
   
   
2. Vitamin C can improve circulation, including to brain regions: Again, this is more on a theoretical note. In addition to its proposed role as a blood sugar regulating measure (see above), vitamin C may also help regulate blood pressure and subsequent circulatory capabilities to key brain regions. Again, the evidence supporting this assertion is much weaker than the original 10 points listed, above, but in this blogger's personal opinion, this may be another positive side effect of vitamin C treatment for ADHD.

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

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

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

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

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

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

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

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

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

Why mercury is so toxic for the brain:

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

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

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

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

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

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

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

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

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

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

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

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

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

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


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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

ADHD Subtype Differences and Stress

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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