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 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.