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 (***).

------------------------------------------------------------------------------------------------
***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.***

-------------------------------------------------------------------------------------------------
***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.
   

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

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

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

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

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

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

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

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

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

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

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

OPTIMIZING FACTOR #1: AN AMPLE SUPPLY OF TYROSINE:

How much tyrosine is necessary to do the job?

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

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

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


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

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

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

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

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

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

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

Getting back to the topic at hand...

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

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

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

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

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

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

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

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

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

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

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


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

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

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

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

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

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

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

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

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

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

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

Can ADHD Symptoms be Cured or Treated via Tyrosine Supplementation?

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

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

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

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

The list goes on, but we get the idea.


THE THEORY BEHIND TYROSINE SUPPLEMENTATION FOR TREATING ADHD:

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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