Does Tyrosine Supplementation for ADHD Actually Work? (Part 5)

Part 5 on a series of posts on Tyrosine supplements for ADHD Treatment

The amino acid tyrosine is often prescribed as an alternative strategy for treating ADHD, either alone (and often in the place of ADHD stimulant medications), or in combo with one or more medications for the disorder. But how effective is tyrosine really? Is it a valid ADHD treatment method, or just another theoretical supplement strategy that has only minimal positive effects on the disorder?

In the past four posts, we have examined the following metabolic pathway of tyrosine in the conversion process of this amino acid to the neuro-signaling chemicals dopamine, norepinephrine, and epinephrine (adrenaline) and the implications for this on the biochemical factors involved in the onset and treatment of attention deficit hyperactivity disorder.

1. In part 1 of our series on ADHD and tyrosine supplementation, we did a quick overview of the above process, the connection between regional levels of these compounds listed above with regards to the neuro-chemistry of ADHD, and gave a general theoretical basis for tyrosine supplementation (based on its metabolic profile and some of tyrosine's biochemical products and pathways in the body). We also introduced the concept of the blood brain barrier, which is a biochemical barrier that controls the flow of chemical agents into and out of the brain. This blood brain barrier has numerous implications for drug design and therapeutics, and must be dealt with if we are to get the desired compounds, drugs and nutrients into the brain.
   
   
2. In part 2 of the tyrosine and ADHD discussion, we looked at the enzyme Tyrosine Hydroxylase, and the dietary nutrients which were involved in making this enzyme run effectively. Some of the nutrient-based strategy were based on clinical trials, while others were more based on theory.
   
   
3. Part 3 of the ADHD/tyrosine blog series centered around the merits of starting with tyrosine as a supplementation strategy vs. bypassing tyrosine and starting with the second compound in the above pathway, L-DOPA (also called Levodopa). L-DOPA is commonly used as a treatment agent in Parkinson's Disease (which has a moderate degree of overlap with ADHD as far as chemical happenings are concerned), but we investigated the pro's and cons of starting with this agent vs. starting with its precursor tyrosine for treating ADHD.
   
   
4. and finally, Part 4 of the tyrosine postings zeroed in on the second major enzymatic step of the pathway, in which L-DOPA was converted to dopamine. This process is heavily dependent on a class of enzymes called aromatic amino acid decarboxylases, with the main enzyme of focus being a specific type called DOPA decarboxylase. In order for these enzymes to function, however, we discussed their dependence on a compound called pyridoxal phosphate (pyridoxal phosphate is an "active" form of Vitamin B6). We also looked at how competing amino acids and their products (namely the amino acid tryptophan and its product serotonin), actually share these enzyme systems and can interfere with the L-DOPA to dopamine conversion process and sabotage the effectiveness of the tyrosine-driven ADHD treatment strategy.

And now, for part 5: the conversion process of the neurochemical dopamine to another neurochemical, norepinephrine...

*Blogger's note: What follows is a lengthy explanation of why dopamine and norepinephrine are so important for ADHD, and how they interact with specific proteins called "transporters" or "receptors" to regulate their overall levels in key "ADHD" brain regions. If you are short on time, you may want to bypass this long explanatory section which starts and ends with a triple asterisk (***).

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***Begin explanatory section on dopamine and norepinephrine and ADHD

It is important to note, first of all, that this dopamine to norepinephrine conversion is not universal throughout all of the body, or even throughout the whole central nervous system. In many regions of the brain and nervous system, the chemical conversion process and metabolism of tyrosine "stops" at dopamine. However, in other key regions, the necessary enzymes exist to continue on with this conversion process to norepinephrine (and even beyond in some cases).

First, we need to address the all-important question, however: Why is the conversion of dopamine to norepinephrine important with regards to treating ADHD? To answer this question, we must look at some of the neuro-biology (and neuro-genetics) of some of the mechanisms which regulate dopamine and norepinephrine function in the brain:

We have hinted elsewhere that both dopamine and norepinephrine (namely imbalances of these two neuro-signaling agents) play a major role in the pathology of ADHD and its symptoms in most cases. However, it is important to note one very important thing here: many of the studies implicating dopamine and norepinephrine in the pathology of ADHD are often concerned more with the transport process of these two signaling agents into and out of neuronal cells, and are often less concerned with the overall concentrations of these two chemicals in the body or even the central nervous system.

Of course there is some degree of overlap (a vast overall deficiency of dopamine or its precursors, for example, would probably put one at more risk of having a deficit of this chemical in the key target areas of the brain), but we must get past the thinking that incorrectly assumes that if we just boost overall levels of these compounds across the board, then these chemical imbalances will just work themselves out. This is simply not the case, and unfortunately, in this blogger's opinion, many advocates of supplementation instead of medications often fail to address this all-important issue of the transport process.

Among the many different ways of transporting dopamine and norepinephrine in and out of the neuronal cells, we must look at two key players: the receptors and the transporters.

#1) The receptors:

The receptors (in a nutshell), are located on the outside of a cell (in this case, the neuronal cells in the brain), and are the place where signaling agents such as dopamine, norepinephrine, histamine, etc. essentially "dock" onto the cell. Proper functioning of these receptors is especially important with regards to disorders such as ADHD. We have even looked at some of the specific genes which code for these receptors, and have analyzed how certain genetic forms of these "receptor genes" are often associated with a higher likelihood of having ADHD.

For example, some of the earliest posts on this blog looked at specific genes that coded for dopamine receptors, such as the Dopamine D4 receptor gene (DRD4) and the Dopamine D5 receptor gene (DRD5) . The DRD4 gene is believed to be one of the most "heavily" influencing genes out there with regards to ADHD genes, while the DRD5 gene, while showing a somewhat weaker genetic connection to ADHD overall, seems to show a bit more of a specific connection to the inattentive component of ADHD (as opposed to the hyperactive/impulsive component of the disorder).

With regards to genetics and chemical receptors for the neuro-chemical norepinephrine, it appears that there are also some genes which may affect this norepinephrine-receptor relationship. There is some evidence for a specific gene called ADRA1A. ADRA1A is a gene located on the 8th human chromosome, and is believed to code for a specific receptor of norepinephrine. In fact, there are some implications that having a particular form of this ADRA1A gene may even influence the effectiveness of medications such as clonidine (which is a drug often used to treat hypertension, but is sometimes used "off-label" as an ADHD treatment medication. Clonidine has a different mode of action than the typical stimulants, but has found some success as a second or third level treatment method for certain types of ADHD).

It is important to note that several of the most common ADHD medications target (either directly or indirectly) these transporters, which influences the overall balance of dopamine and norepinephrine in and out of cells. In other words, if we want to truly replace drugs with nutrition for treating ADHD, we need to overcome this receptor problem (at least in theory). This is why (in the blogger's opinion) nutrition-based treatments often come up short, because while they may be able to influence production and overall levels of neuro-signaling agents such as dopamine and norepinephrine they are often nowhere near as chemically "potent" at modifying the transporter issues. If you're interested, an earlier post talked about some of the specific genes, receptors and transporters, and how some of these "ADHD genes" may even play a specific role on how we should dose ADHD medications.

#2) The transporters

Switching gears away from dopamine and norepinephrine receptors, we must also examine another important class of proteins which regulate dopamine and norepinephrine levels both inside and outside of neuronal cells. These are called "transporters". As their name suggests, these agents essentially go one step further in the process by shuttling neuro-signaling chemicals such as dopamine and norepinephrine both into and out of cells. In other words, these dopamine and norepinephrine tranporters also play a vital role in the process.

We can talk about these transporters all day (and we have, in other previous posts on this blog!), but for sake of brevity, I should just mention that specific genes for dopamine transporters (called the dopamine transporter gene or DAT), and for norepinephrine transporters (called the norepinephrine transporter gene or NET, however, it is also referred to by another completely different name: SLC6A2) both have been studied extensively with regards to their genetic influences on ADHD and related disorders. As mentioned earlier, these transporters often play major roles in medication responses, and may even be linked to co-occurring disorders in ADHD, such as bulimia, drug addiction, anxiety disorders, etc.

*In other words, these receptors and transporters (as well as the influences they carry on regulating neurochemical levels) are some of the main reasons why ADHD is believed to be so genetically influenced.***

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***End explanatory section on the importance of regulating dopamine and norepinephrine levels in ADHD. The rest of the post is concerned with the dopamine to norepinephrine conversion process, and starts immediately below:



Here is a chemical representation of the dopamine to norepinephrine conversion process (don't worry if you're not a chemist, just look at some of the names of the compounds, enzymes and nutrients involved in the process, we will discuss all of these in thorough detail below):


From the above picture, we should note the two main components which need to be addressed in the dopamine to norepinephrine conversion process:

1. The enzyme Dopamine Beta Hydroxylase, and
2. The nutrient ascorbic acid (aka vitamin C), especially with its regard to oxygen (O2), as depicted above.

Dopamine Beta Hydroxylase enzyme: We have examined Dopamine Beta Hydroxylase (often abbreviated as DBH) several times in previous posts. The gene coding for the DBH enzyme (of which the gene shares the same name, "DBH") is located on the 9th human chromosome. This enzyme is responsible for adding a hydroxyl (-OH) group off of the dopamine molecule, which leaves us with the new neuro-chemical norepinephrine. Note that this is the second time in the overall conversion process of tyrosine to L-DOPA to dopamine to norepinephrine that an "OH" group was added, the first being the work of an "OH" onto the hexagon ring of tyrosine to convert it to L-DOPA (see first diagram in this blog post if this is confusing).

*Please note: It is important to note that oxygen is required for this step to work, as an oxygen atom is transferred from O2 to the dopamine molecule. In order for this chemical conversion to work, however, another agent (vitamin C) is required. This is where ascorbic acid (vitamin C) comes in:

Ascorbic Acid (vitamin C): We mentioned vitamin C in an earlier post, in that it can play a "helper" role in the conversion of tyrosine to L-DOPA, a process which utilizes the enzyme tyrosine hydroxylase. Tyrosine hydroxylase is dependent on iron, but the efficacy of the enzyme requires iron to operate in the "reduced" form as opposed to the "oxidized" form (the reduced form has iron in a "+2" positively charged state, and in the "oxidized" form, iron exists in the even more positively charged "+3" state. In nature how positively or negatively charged a certain element is can have drastic effects on its biological function. In the case of the tyrosine hydroxylase enzyme, and the metabolism of tyrosine, this is no exception). Much of this "helper" role of vitamin C was due to the ability of the vitamin to keep the iron in the desired "+2" state. Some studies have found this tyrosine hydroxylase enzyme to be significantly compromised in vitamin C deficient states (as in scurvy).

However, while tyrosine hydroxylase the enzyme Dopamine Beta Hydroxylase appears to be even more heavily dependent on vitamin C, as mentioned in an earlier blog entry titled: 10 Ways Vitamin C Helps Treat ADHD Symptoms (this was mentioned in point #9). For the conversion process of tyrosine to L-DOPA, much of vitamin C's usage was due to its antioxidant status, but for this dopamine beta hydroxylase enzyme, which is used to convert dopamine to norepinephrine, vitamin C is used more of as a "co-factor" or "helper" to the enzyme.

As mentioned above, vitamin C must be "sacrificed" to get the oxygen atom from the O2 molecule and onto the dopamine molecule to convert it to norepinephrine. The end result of this "sacrifice" is a different oxidized form of the vitamin, which is known as dehydroascorbate.

This brings up another important point. We have seen in the past how vitamin C is often an "altruistic" agent in ADHD treatment, in that it frequently sacrifices itself for the well-being of other nutrients of importance to ADHD. For example, we've spoken at length about the problem of oxidation of omega-3 fatty acids (since omega-3 supplementation is a common ADHD supplementation strategy, this damaging oxidation process can be quite severe if not controlled for), and how vitamin C can help in preventing omega-3 oxidation in ADHD treatment cases. Vitamin C often helps "recycle" other antioxidants such as vitamin E (which is much more fat-soluble than vitamin C, so it is often recommended for antioxidant treatment strategies for ADHD that vitamins C and E are used in tandem).

Please note, then, that since vitamin C is used in the dopamine to norepinephrine pathway, and that it is essentially "lost" in the process (unless it is returned to its native ascorbic acid form by another antioxidant, such as glutathione), it is crucial that we maintain adequate levels of vitamin C. Furthermore, since vitamin C is a water soluble vitamin, it gets removed from the system quite easily. Therefore, it is imperative that we maintain adequate pools of this vitamin through diet or supplementation. A rough estimate of daily vitamin C requirements can be found here.

However, since toxicity is rarely an issue with vitamin C (see the upper limits of the vitamin here, and note how much of a ceiling there is between the recommended levels and the upper limit), going slightly higher (i.e. 2 times the recommended amount) is rarely a problem. Therefore, this blogger personally recommends that since the vitamin is useful in at least 2 different parts of the tyrosine to dopamine and norepinephrine conversion process (involving both the tyrosine hydroxylase enzyme for the conversion of tyrosine to L-DOPA and the dopamine beta hydroxylase enzyme-driven conversion of dopamine to norepinephrine), those wishing to try tyrosine supplementation for ADHD should maintain adequate (if not slightly higher than "adequate") levels of the vitamin.

We will wrap up our discussion of tyrosine supplementation for treating ADHD in the next few blog posts. We will look briefly at the norepinephrine to epinephrine conversion process, but focus more on some of the potentially harmful side-products of tyrosine metabolism, including the potential buildup of the pro-inflammatory agent homocysteine. Finally, we will finish with a final post on the blogger's thoughts on the whole process, recap the different nutrients needed to optimize enzyme function for overall tyrosine metabolism, and look at possible ways in which, instead of being used completely in isolation, tyrosine supplementation could also be used as an adjunct or accessory treatment to common ADHD medications, possibly optimizing their function and improving their effectiveness in treating ADHD and related disorders.

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.