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 for ADHD Actually Work? (Part 6)

Can we use tyrosine as an effective supplement to treat ADHD symptoms?

We have dedicated the last five postings on the role of tyrosine and its metabolism, and how imbalances of this common amino acid may dictate, in part, some of the symptoms related to ADHD.

Just for refreshers, here's a diagram of the overall conversion process and metabolism of tyrosine. We have spoken through the first three steps (and the corresponding enzymes and required chemical nutrients) in the process:

Here's a quick recap on our last 5 discussions on ADHD and tyrosine:

Post #1 on ADHD and tyrosine: We examined the overall theory and background behind the use of tyrosine as an ADHD treatment strategy. We saw how it is a chemical precursor to important neurotransmitters (neuro-signaling chemicals responsible for communication among brain cells and the central nervous system) such as dopamine and norepinephrine. We also introduced the concept of the blood-brain barrier, a biochemical barrier which controls the transport of drugs, nutrients and toxins in and out of the brain.

Post #2 on ADHD and tyrosine: here we analyzed the first step of tyrosine metabolism, in which tyrosine is converted to another compound L-DOPA (a common treatment method for Parkinson's patients). This step heavily involves the enzyme tyrosine hydroxylase. However, in order to optimize function of this conversion process, the tyrosine hydroxylase enzyme requires certain vitamins and minerals to act as "co-factors" or "helpers". These include iron, vitamin C, magnesium, zinc, folic acid (namely folate or vitamin B9) and overall adequate antioxidant levels. Secondary nutrients (necessary for enzymes which lead up to the formation of some of the products used by the tyrosine hydroxylase enzyme) include copper, and (as we'll see later on in the tyrosine metabolic pathway), vitamin B12. Deficiencies in one or more of these nutrients could potentially compromise this enzyme's function. Since this first step is actually the slowest (rate-determining) step of the whole tyrosine metabolism process with regards to converting tyrosine to the neurotransmitters dopamine and norepinephrine, making sure we have adequate resources of these "helper" nutrients is crucial to our success.

Post #3 on ADHD and tyrosine: We can essentially bypass this first step of tyrosine to L-DOPA conversion altogether if we just decided to supplement directly with L-DOPA instead. But is L-DOPA more effective than tyrosine as a treatment method for ADHD, or are there some serious drawbacks to this strategy? This third post evaluates and compares both tyrosine and L-DOPA options and compares both their effectiveness as ADHD treatment agents and their comparative safety issues in several different categories.

Post #4 on ADHD and tyrosine: In this post, we examined the second major step of the conversion process in tyrosine metabolism, the conversion of L-DOPA to dopamine. This step requires use of the enzyme DOPA decarboxylase. Like the tyrosine hydroxylase enzyme in the step before it, DOPA decarboxylase also requires nutrient co-factors to optimally function. The main nutrient requirement of this enzyme, however, is a specific form of vitamin B6, known in this case as pyridoxal phosphate. In addition to requiring adequate vitamin B6 levels to function properly, we also saw that other amino acids (namely tryptophan), can actually interfere and even compete with this process, so the post ended with the recommendation to avoid taking in tryptophan-rich foods (which were listed in this fourth post) at the same time as tyrosine was being supplemented.

in post #5 on ADHD and tyrosine supplementation, we examined the conversion process of dopamine to norepinephrine. It is important to note that this process is NOT universal across the body, or even throughout all regions of the brain and central nervous system, for that matter. However, since both dopamine and norepinephrine both can play major roles with regards to ADHD and the symptoms of the disorder, this enzymatic conversion process is still of importance. The enzyme used here for this step of the tyrosine metabolic pathway is called dopamine beta hydroxylase. Interestingly, the gene coding for this enzyme (which goes by the same name, the dopamine beta hydroxylase gene and is located on the ninth human chromosome), has been implicated as a potential hereditary factor for ADHD. Like the aforementioned tyrosine hydroxylase the dopamine beta hydroxylase enzyme is heavily dependent on ascorbic acid (vitamin C) as a cofactor, and heavy utilization of this enzyme (especially without adequate antioxidant pools in place to help regenerate the vitamin) can use up the body's overall supply of vitamin C.

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Moving on to our sixth post in our series on ADHD and tyrosine, however, we need to investigate the next step of the process, the conversion of norepinephrine to epinephrine (adrenaline). Keep in mind that this process is not universal, it is dependent on an enzyme called phenylethanolamine methyltransferase, or PNMT for short. Interestingly, the gene which "codes" for this enzyme, also called PNMT, has been linked to a common behavioral sub-component of ADHD called cognitive impulsivity. The PNMT gene is located on the 17th human chromosome.

In contrast to the other main type of ADHD-styled impulsivity, known as aggressive behavioral impulsivity (which is more characterized by arguing, having a short temper, conflicts with peers and adults, and the like, which is more characteristic of oppositional defiant and conduct disorders, and is seen more in the hyperactive/impulsive or combined ADHD subtypes), cognitive impulsivity often has more academic than behavioral inhibitions.

Symptoms of cognitive impulsivity deal more with things such as having trouble waiting in line, struggling with maintaining a continuous focus on school assignments, inability to complete schoolwork, and being prone to every little distraction (a chirping bird outside, the sound of cars passing by on a nearby road, etc.). Cognitive impulsivity is therefore more reflective of the inattentive subtype of ADHD (which is often more frequently seen in girls, and is often more easy to overlook than the other subtypes of ADHD).

It is interesting to note that differences in parent and teacher evaluations often occur over this type of impulsivity, since this type of behavior is often much more visible in a classroom setting. Therefore, if a large discrepancy occurs between the parent and teacher rating scales, which are usually used to help diagnose and assess ADHD, cognitive impulsivity (and possibly even the factor of the PNMT gene) may, in part, be to blame. (Please take this last statement as a possible explanation for this type of behavior and not as an excuse or a "cop-out" for a child's poor performance in school!)

Returning from our aside on the possible genetic relationship between the Phenylethanolamine N-methyltransferase (PNMT) enzyme function and cognitive impulsive ADHD-like behavior, let's return to the chemical process and nutrient requirements of this enzyme. To us visualize this step of the process, here is a chemical depiction of the norepinephrine to epinephrine conversion:Even if you're not a chemist, do you see how the norepinephrine molecule added a methyl (CH3) group on to the right end of it to get epinephrine? This is the working of the Phenylethanolamine N-Methyltransferase (PNMT) enzyme.

However, the source of this methyl (CH3) group to be added to the molecule needs to come from somewhere. This is where an essential nutrient called S-adenosyl-methionine (as depicted in the diagram above by the downward arrow) comes into play.

S-adenosyl-methionine often goes by other shorter names in the literature and in the grocery aisle, it is often referred to simply as SAMe or just "SAM". We will refer to it as "SAMe" from this point onward.

SAMe is one of the hot new supplements out in the health food aisles these days, and while this blogger personally believes that this nutrient is a bit overhyped, it does offer a number of unique benefits which can possibly cover a whole array of disorders. It is a chemically-modified version of the amino acid methionine. The ability of SAMe to pass on or "donate" a methyl (CH3) group to another molecule (as in the above process where norepinephrine is converted to epinephrine) is a relatively rare property among dietary nutrients, so SAMe does have a number of biochemical implications as a potential supplementation strategy.

As far as psychiatric disorders are concerned, SAMe is a particularly well-known natural supplement for treating depression, and can often have a faster onset than several types of prescription medications (it can also be used in conjunction with antidepressant medications in several cases to augment these medications' effectiveness). SAMe has also been implicated as a potential treatment strategy for other neurological disorders such as Alzheimer's and Parkinson's diseases. However, while anecdotal evidence for SAMe's use in ADHD is moderately strong in some cases, very few reported clinical studies have been done on SAMe for ADHD. One very small study on SAMe and ADHD (only 8 people!) showed relatively positive results, however.

Returning to the diagram here (see below), we see that one of the end products (that's what the curvy arrow means) of this interaction between the PNMT enzyme and the SAMe nutrient is another compound called homocysteine.

We have alluded to this potentially harmful pro-inflammatory compound in some of our previous posts on tyrosine supplementation, and also examined homocysteine in more detail in post further back dealing with ADHD, alcoholism and nutrient deficiencies. As a natural byproduct of this norepinephrine to epinephrine conversion process, we must make sure that we are able to keep levels of homocysteine in check. We will see how we can potentially counter this with B vitamins and other nutrients in our next blog post on ADHD and tyrosine supplementation.

However, the three main points we should take away from this post on tyrosine supplements and ADHD are as follows:

• The conversion process of tyrosine to epinephrine does not occur in all cells, even in the brain and central nervous system. Many regions (even those associated with ADHD) "stop" with dopamine in the overall metabolic process of tyrosine.
  

• For the brain regions that do accommodate the norepinephrine to epinephrine conversion process, an adequately functioning enzyme called Phenylethanolamine N-Methyltransferase (or PNMT) is required.
  

• In order for the PNMT enzyme to do its job in converting norepinephrine to epinephrine (adrenaline), adequate supplies of the nutrient S-Adenosyl-methionine (SAMe) are required. This process, however, can leave us with a potentially hazardous byproduct called homocysteine, which must be kept in check to reduce the risk of "inflammatory" diseases such as cancer or cardiovascular disorders. Nutritional intervention strategies must be put in place to help prevent unwanted accumulation of this homocysteine. This is part of the "cleanup process" of the tyrosine supplementation strategy for ADHD, and will be discussed at length in the next blog posting.
  

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.

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.
   

Does Tyrosine for ADHD Actually Work as a Supplementation Strategy? (part 3)

Can we treat ADHD symptoms via Tyrosine supplementation?

This is the 3rd post in our series of discussions regarding ADHD and supplementation with the amino acid tyrosine. Some physicians (and ADHD patients) swear by it, but the results in the literature and clinical studies are often muddled. Why is this the case?

Over the past few postings, I have been going over the metabolic pathway of how the body converts the amino acid tyrosine to our desired brain chemicals of dopamine and norepinephrine. Imbalances of both dopamine and norepinephrine are typically seen in ADHD, and this imbalance is the target of most ADHD medications (especially the stimulants) during their modes of action.

Here is the metabolic pathway on Tyrosine to Dopamine and Norephinephrine again (you can click on the image to get a larger view, or see the original image source here):

In our first post on ADHD and tyrosine supplementation, we went through the overview of this pathway. In our last posting, we went through the first step of the process: the conversion of tyrosine (also referred to as L-tyrosine) to DOPA (also referred to as L-DOPA, Levodopa and a number of trade names such as Dopar, Laradopar or Sinemet), and the enzymes and nutrient co-factors involved in this conversion process. L-DOPA is a common treatment method for patients with Parkinson's Disease.

I was going to start with the next step of the process today: the conversion of L-DOPA to dopamine, and the major enzymes involved. However, one of our readers from the previous posting on the conversion of Tyrosine to L-DOPA, posed an excellent question on a topic I failed to address (which may be on the minds of several readers). As a result, I will dedicate the remainder of this post to this question and save the next step of the tyrosine to dopamine pathway for the next blog entry.

LynneC asked about the advantages of supplementing with tyrosine vs. supplementing directly with L-DOPA. As we saw in the previous posting on tyrosine supplementation for ADHD, the tyrosine to dopamine conversion requires one major enzyme (tyrosine hydroxylase) and several secondary enzymes (to produce some of the compounds needed to help the tyrosine hydroxylase enzyme to function properly), as well as nutrient co-factors such as iron, zinc, magnesium, and even antioxidants or reducing agents such as vitamin C.

Further complicating the issue, we saw that individual variation across the gene pool leads to different forms of this tyrosine hydroxylase enzyme, some of which are notably more effective or "potent" than others. In other words, some people are more disposed to having an efficient metabolic conversion of tyrosine to L-DOPA than others.

If this is the case, why should we mess with tyrosine at all? Shouldn't we just bypass this first step of the process entirely and start with L-DOPA? Here are a few things to consider:

1. Supplement Availability: L-Tyrosine is available over-the-counter. However (until relatively recently), L-DOPA required a prescription. This is not the case anymore, however, as L-DOPA supplements are available in countries like the United States (I believe that a prescription is still required in Canada, however, but I could be wrong).
   
   Blogger's note: Even though both of these agents are available without a prescription, this blogger believes is is EXTREMELY important for you to talk to your physician before giving either of these supplements a try.
   
   Both tyrosine and L-DOPA can undergo biochemical transformations via a number of different pathways (i.e. not just in the conversion to catecholamines in the brain such as dopamine and norepinephrine). Both can interact with other medications (especially certain classes of anti-depressants known as MAOI's or monoamine oxidase inhibitors), as well as with each other, and overdosing is possible. Additionally, individuals with certain forms of cancer (especially skin cancers) or eye disorders such as glaucoma are typically instructed to avoid both treatments entirely. PLEASE check with a physician before starting either of these as a therapy for ADHD or ANY other reason.
   
   ADVANTAGE with regards to ADHD treatment: Tyrosine
   
   


2. Cost: I did a quick search on the costs of both supplements (keep in mind that brand names, strengths and quantities can cause extreme variation), and from what I've seen, L-DOPA often costs somewhere from about $65 to $150 US dollars for 100 tablets. Please note that L-DOPA typically comes in a combination form of Levodopa and another compound called Carbidopa (Carbidopa greatly aids in the absorption of Levodopa and helps minimize unwanted side-reactions of the Levodopa drug, so almost all standard formulas now exist in this Levodopa/Carbidopa tandem). For tyrosine, the cost is much lower, as I've seen ads online for a bottle of 100 capsules (500 mg strength, note that many individuals who supplement with tyrosine take doses around this level 3 times a day) for only $2 to $3 dollars a bottle. Clearly, the cost of taking L-tyrosine is much lower.
   
   ADVANTAGE for treating ADHD: Tyrosine
   
   


3. Step in the conversion pathway: In the previous post, we saw how certain enzymes (tyrosine hydroxylase) and nutrient "co-factors" (co-factors essentially function as "helpers" to the enzyme, making it function more effectively. If these co-factors are missing or deficient, the enzyme is often compromised, and the metabolic conversion process is reduced. In this blogger's opinion, co-factor shortages are one of the most overlooked reasons why natural, dietary or supplementation strategies for ADHD treatment often fail), such as iron, zinc, magnesium, and vitamin C are needed, either directly or indirectly to aid the process.
   
   ADVANTAGE for ADHD treatment: L-DOPA*
   * Starting directly with L-DOPA bypasses these factors or complications (but poses its own set of challenges, as we'll see later in this post, more about this in a minute).



4. Transportability across the blood-brain barrier: We talked at length about the blood-brain barrier in the past two posts, but to recap: The blood-brain barrier is a biochemical barrier designed to keep potentially hazardous or toxic compounds (that accidentally get into the blood) from getting into the brain (where these substances are often much more devastating). It also acts like a sort of "filtering" system, controlling or regulating the transport of "good" compounds in the brain, reducing the risk of imbalances from these chemicals.
   
   Unfortunately (especially for drug manufacturers), this barrier also blocks out many potential therapeutic agents, so drugs targeting specific brain regions must be chemically designed to pass through this blood-brain barrier to be effective. It is worth noting that both tyrosine and L-DOPA can cross through this barrier, so both are acceptable methods of delivery to increase or balance out dopamine and norepinephrine levels in the brain.
   
   On a side note (and mentioned in our previous discussions on the matter), dopamine and norepinephrine typically are NOT able to pass through the blood brain barrier, meaning that these compounds need to be manufactured inside of the brain. This is why we cannot supplement with either of these agents directly.
   
   ADVANTAGE for ADHD: A draw. Both Tyrosine and Levodopa can cross the blood-brain barrier**
   
   **We will see in the next few points, how this "tie" between the two may not be entirely true.
   
   
5. "Target" specificity: Here is where the real difference lies. In the past few posts, we have been vague with regards to the specific brain regions in which chemical imbalances of dopamine and norepinephrine are found in the ADHD brain. It is important to note, that these deficiencies/imbalances are not uniform throughout the body (or even the brain) in the ADHD individual.
   
   Certain brain regions are frequently identified as target sites of chemical imbalances (which typically exist as deficits, not excesses) of the neurotransmitters dopamine and norepinephrine. By no means is this list extensive, but two brain regions which are commonly associated with shortages of these signaling chemicals are the striatum and the prefrontal cortex (as an interesting aside, these 2 brain regions have been found to be proportionally smaller in ADHD individuals according to some studies and bloodflow patterns to the prefrontal cortex have been found to be different in the ADHD brain vs. the brains of patients with other disorders such as Obsessive Compulsive disorders).
   Shown above is a picture of an individual's brain. We are looking from the top down on a patient facing forward (the front is towards the top of the page). Several key "ADHD brain regions" are highlighted. The rough location of the prefrontal cortex, shown in brown, is a major region of importance where ADHD treatment is of concern. The green, red and blue regions represent approximate locations of sub-components of a brain region collectively called the corpus striatum. Both the prefrontal cortex and the corpus striatum regions of the brain are thought to be common sites of imbalance of the brain chemicals dopamine and and norepinephrine.
   
   Getting back to our main point here, however, is the fact that supplementation with tyrosine typically reaches its targets with much more specificity than does L-DOPA. In other words, if target region specificity is what we're after, then supplementation with tyrosine shows a slightly better track record, at least according to the literature reviewed by this blogger. Keep in mind, however, that this assertion hinges on only a few older studies, and the findings are far from definite.
   
   SLIGHT ADVANTAGE for treating ADHD: Tyrosine
   
   


6. Fewer negative side effects: This ties in with the previous point, to a certain extent. L-DOPA, is, and continues to be, a treatment for Parkinson's, and not designed specifically for ADHD. However, in addition to being a chemical precursor to dopamine and norepinephrine, L-DOPA can also be converted to the agent melanin (which is responsible for skin pigmentation, among other things). The problem with this, however, is the fact that this conversion process can sometimes go overboard, and result in rapid generation and buildup of this (and related) compounds, increasing the risk of melanoma and related skin cancers.
   
   The actual magnitude of this L-DOPA/skin cancer association, however, is often questionable. While higher rates of skin cancer are seen in Parkinson's patients treated with L-DOPA, this finding is often negated by the fact that the cancer was present before the start of the L-DOPA treatment. Furthermore, general medical recommendations are often to refrain from L-DOPA or tyrosine supplementation in Parkinson's patients who are in various stages of these cancers. In other words, tyrosine may not be much better in this regard.
   
   Both tyrosine and L-DOPA have limitations, and potentially negative interactions. This includes kidney and liver dysfunctions, cases of depression where specific anti-depressants called MAOI's (short for monoamine oxidase inhibitors) are taken (both tyrosine and L-DOPA can negatively interact with MAOI function).
   
   Possible buildup of the compound homocysteine (a pro-inflammatory agent which has been implicated in everything from heart disease and cardiovascular disorders to depressive symptoms to cancer) can also be linked to tyrosine and L-DOPA intake, because both can serve as chemical precursors to this potentially dangerous compound. We will see how homocysteine ties in to all of this within the next few posts (as we work our way down the tyrosine to dopamine and norepinephrine pathway), and how its buildup can be reduced by taking in adequate levels of certain B vitamins and other nutrients. More on this later.
   
   In the meantime, please realize that there are hundreds of different ways tyrosine and L-DOPA levels can affect the body, so trying to classify one as "safer" is not necessarily so cut-and-dry. However, in this blogger's opinion, tyrosine, since it is a naturally occurring dietary food-source, has the advantage of over L-DOPA in that it is one step closer to "nature". Tyrosine is typically less potent than L-DOPA, so a higher dosage of tyrosine is typically required to get the same effects (in other words, we shouldn't be comparing, say a 500 mg dose of tyrosine with a 500 mg dose of L-DOPA, the effects of L-DOPA at this dose would be much more pronounced).
   
   Furthermore, as we have seen in the last post on tyrosine and ADHD, the enzyme-mediated conversion of tyrosine to L-DOPA is actually limited or shut off by the generation of the catecholamine "end-products" dopamine and norepinephrine. When high levels of these compounds are generated under normal conditions, these catecholamine compounds actually bind to and inhibit the enzyme tyrosine hydroxylase (which converts tyrosine to L-DOPA), thereby limiting further tyrosine to dopamine conversion.
   
   In other words, it appears that tyrosine has slightly better designed "control-switches" to keep its end products in check than does L-DOPA. We may be splitting hairs here (since both tyrosine and L-DOPA are natural metabolites of the body, both can be quite safe if the correct levels are taken and none of the pre-existing conditions exist or competing medications are being used), but according to all of the information this blogger currently has, tyrosine supplementation for ADHD treatment seems to be the safer bet here.
   
   ADVANTAGE: Tyrosine (just make sure to consult with a physician before trying this supplement, even though it is readily available over-the-counter).
   
   


7. Overall effectiveness and potency: While both L-Dopa and tyrosine have often been prescribed for ADHD as more natural or "gentler" alternatives to pharmaceuticals, and "success" stories abound on individual cases, the overall literature tends to be less praise-worthy. From the studies this blogger has seen most of them show a temporary boost in effectiveness, but the positive results are often short-lived. Tolerance generally seems to be an issue, as in the case of a small study on direct tyrosine treatment for ADHD. In this study, the effectiveness of tyrosine wore off after 2 weeks. A similar study was done with L-DOPA (levodopa) on ADHD boys, and the results were similar. Initially, there was a positive response, but these results were also short lived.
   
   Curiously, most of these studies involving direct tyrosine or L-Dopa dependent treatment of ADHD are relatively old ones, most of which took place in the early 1980's (many were done by the same research group). There currently does not seem to be a whole lot of new material on this topic (at least to the best of this blogger's current knowledge).
   
   Furthermore, neither of these studies co-supplemented with the aforementioned nutrient "cofactors" to help with the metabolism and conversion to dopamine or norepinephrine. There is no telling what the status of magnesium, zinc, iron, or antioxidant levels (all of which can have an effect on tyrosine metabolism, as we've seen in the previous post on tyrosine supplementation for ADHD).
   
   Additionally, another nutrient called pyridoxal phosphate also plays a role in the next step of the chemical conversion process of L-DOPA to dopamine (pyridoxal phosphate is a derivative of vitamin B6 which is used to help the enzyme dopa decarboxylase to function properly. We will be investigating this nutrient/enzyme pairing in the next post, when we look at the next step of the dopamine conversion process). Levels of this key ingredient (at least in this blogger's opinion) need to be factored in when we evaluate the true merits of tyrosine or L-DOPA treatment for ADHD and related disorders.
   
   ADVANTAGE as an ADHD treatment method: Too close to call. In addition to their individual usage, tyrosine/L-DOPA/carbidopa (we will discuss why this carbidopa compound is often used alongside L-DOPA in the next section) can be used together to boost each others' effectiveness. Anecdotal reports laud the effectiveness of tyrosine/L-DOPA/carbidopa in combination as an effective ADHD treatment, but again, detailed clinical trials specifically designating ADHD are relatively scarce. In other words, although the literature findings on the subject seem to be scarce and somewhat discouraging, additional factors (such as the extra nutrients and enzyme co-factors which we are currently laying out) could possibly lead to more effective studies with more promising results on the topic of ADHD treatment via tyrosine and/or L-DOPA supplementation.