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

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

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

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

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

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

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

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


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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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