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

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

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

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

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

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

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

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

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

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

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

Other Pathways of Tyrosine Metabolism and the Generation of Homocysteine

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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.