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.

Drugs, Genes and ADHD

The Effects Specific "ADHD Genes" Have on Dosing ADHD Medications:

Below is a list of five of the most common medications for ADHD. In order to break down or metabolize these drugs, however, a series of steps must take place for effective absorption, delivery and clearance of these drugs. This process, however, requires a series of enzymatic steps. Generally, when a physician prescribes these drugs, he or she considers factors such as the patient's age, gender, symptom severity and past medication history. However, lost in the shuffle is a lesser-known, but often equally critical factor: the particular genes of the individual. It is these genes which play a large role as to how well these enzymes function (alongside other factors such as the person's nutritional status, as most vitamins and minerals act as chemical "helpers" to these enzymes, and deficiencies can lead to lower enzyme function and sub-optimal metabolic efficiency).

Unfortunately for prescribing physicians, the landscape of enzyme capabilities among the general population is far from uniform. Some individuals naturally possess enzymes or enzyme systems (which are coded for and dependent on the genetic makeup of the particular individual)which are more efficient than others (often by multi fold differences). If these enzymes are essential to drug metabolism (including ADHD medications), then a potentially crucial piece of information may be missing from the physician's repertoire of assessment tools for medicating at the proper dosage.

Much to the dismay of many a frustrated parent of an ADHD child, this often begins the laborious process of adjusting medication dosages through a glorified "guess and check" process. However, due to the need for a relatively small window of effective dosing (especially for psychotropic drugs such as those prescribed for ADHD and related disorders) and unforgiving margins of error in the optimization process, bits of information, such as a child's genetically-dictated levels of drug-metabolizing enzymes could be extremely useful. With the increasing efficiency, lowering costs of and wider availability of genetic screening methods, we may soon be able to predict a child's enzyme levels by their genetic makeup and facilitate the dosing of (and eliminating much of the guess-work from) their medications for ADHD or other disorders, saving both time and money while on the medication circuit.

Given the powerful role of enzymes and enzyme systems (and the specific genes which encode for them) for the delivery, metabolism and clearance of these medications, we should take a look at some of the genetic variations of these enzymes and the implications they may having in assisting the diagnosing physician in the near future for more effectively dosing ADHD medications.

Here are 5 common ADHD drugs (including one which is not prescribed but often used as a "self-medication" tool among the ADHD population), and the genetically-dictated enzymes which can play a role in their metabolism and dosing patterns and levels.

ADHD Drug #1: Strattera (Atomoxetine)

Key enzymes involved and gene of interest: SLC6A2, CYP2D6

We have already investigated another gene believed to have an impact on dosing with Strattera, the SLC6A2 gene. However, in that earlier post, we alluded to another gene responsible for the metabolism of the non-stimulant ADHD drug Atomoxetine. This gene is called CYP2D6. The CYP2D6 gene codes for an important enzyme of the same name (which is an important enzyme produced in the liver). The gene is located on the 22nd human chromosome (the 22q13.1 genetic region to be more specific if you are familiar with genetic markers).

Approximately a dozen different genetic forms (or alleles) of this CYP2D6 gene are seen in individuals of European ancestry. These forms are often designated by a star followed by a number, such as *1 or *4. While these numbers are used for naming purposes, it is worth noting that most individuals of European descent appear to carry either the *1 (the most common), the *2 or the *4 form of this gene. Additionally, *3, *6, and *10 forms are each found in about 1-2 percent of the population.

Interestingly, the *10 form of this gene is found in higher levels in individuals of East-Asian descent. A Chinese study found that a higher frequency of this *10 form in the population (the *10 form shows up in over half of the Chinese population, about 10 times more frequently than in whites), resulted in slower rate of drug metabolism of the ADHD medication Strattera (Atomoxetine) by the CYP2D6 enzyme.

Relevance of the CYP2D6 gene to medicating ADHD with Strattera: The *10 form of the CYP2D6 produces less enzymatic activity than the most common *1 form. This can result in about a 50% increase in Atomoxetine concentration in the blood and duration before clearance, which was seen in the Chinese study. As a result, for individuals with the exclusive *10 form (such as seen in much of the East Asian population), slightly lower or less frequent dosing levels of atomoxetine might be needed to get the same therapeutic effects. This is in agreement with another study suggesting a 50 to 75% dosage reduction of Atomoxetine for those with hepatic impairment (liver dysfunction), as the CYP2D6 enzyme is produced in the liver.

Additionally, this population may be at a slightly greater risk of side effects with the drug due to a slower clearance and greater buildup of the drug. Of course other genes and additional factors in the Atomoxetine pathway certainly play a role, but these genetic variations can still play a significant role in medication dosing strategies.

ADHD drug #2: Adderall (Mixed amphetamine salts)

Genes of interest: Catechol O-Methyltransferase (COMT) gene, Dopamine Transporter Gene (DAT)

In previous posts, we have spoken extensively about a gene called COMT, short for Catechol O-Methyltransferase and its role on dosing for amphetamine-related ADHD medications such as Adderall and Vyvanse. This previous discsussion on COMT and ADHD medication dosing can be found here.

However, there are a few other genes worth noting here for their potential roles in dosing with amphetamine-based ADHD medications such as Adderall. One of these is the Dopamine Transporter gene (DAT), which is located on the 5th human chromosome. This gene also goes by other names such as DAT1 or SLC6A3. The DAT gene codes for an important protein called the Dopamine Transporter protein, which is responsible for shuttling the important brain chemical dopamine in and out of neuronal cells.

A number of stimulant drugs used to treat ADHD and related disorders work, at least in part, by interacting with this dopamine transporter (DAT) to correct a dopamine imbalance (in general, individuals with ADHD often have too little dopamine in the regions between brain cells or neurons in key regions of the brain. Many stimulant ADHD drugs remedy this by blocking the shuttling of dopamine back into the cells, keeping adequate amounts in these "gaps").

Interestingly, on a side note, the DAT gene has been implicated (in conjunction with another dopamine-related gene called DRD4) in IQ levels an behavior problems.

Like the genes mentioned above, DAT exists in a wide number of different forms across the human gene pool. Some forms appear to increase ones predisposition to ADHD and various neurophysiological or behavioral disorders and have earned the moniker "high risk alleles" (remember, an "allele" is simply a specific form of a gene which varies within the population).

A study on families of ADHD children found that a specific form of the DAT gene which included a 480 base pair repeat (simply a repeating section of DNA which is 480 DNA "letters" long) allele was associated with greater severity of ADHD symptoms, especially in the combined ADHD subtype (which includes high levels of both inattentive and hyperactive/impulsive symptoms as opposed to a predominance of one).

Potentially, individuals with ADHD who carry this "high-risk allele" of the DAT gene (which is a substantial portion of the general population) may require slightly higher levels of medication dosage with amphetamine-based stimulants than their "lower-risk" counterparts. These differences may be even more pronounced if the individual carries the "Val" form of the COMT gene, mentioned in a previous post (given the current body of research on the subject, the contributions of the COMT gene dwarf those of the DAT gene with regards to governing amphetamine dosage levels).

ADHD drug #3 Vyvanse (lisdexamfetamine dimesylate)

Gene of Interest: Trypsinogen

Due to its chemical proximity to amphetamines (Vyvanse is essentially an "inactivated" form of the drug Dexedrine, which is an isolation of one of the potent components of Adderall). A special chemical "tag" is linked to the active part of the drug, which must be chemically cleaved to release the active form of Vyvanse (think of it as essentially breaking a seal to free up the drug) into its functional amphetamine-based product. Naturally, the genes listed above (and the enzymes which they encode) which metabolize amphetamines are of substantial interest for potentially influencing the effectiveness of ADHD treatment with Vyvanse as well.

However, the actual cleaving process of releasing the active component of Vyvanse is equally as important. If the drug is not freed, then it cannot be effectively metabolized.

Several enzymes which are called upon to metabolize the other ADHD drugs in this post do NOT appear to have a significant effect on Vyvanse. These include CYP2A6, CYP2B6 (both for nicotine), and CYP2D6 (for Strattera). This is good news for those who are already taking medications, as Vyvanse's relative independence of these drug-metabolizing enzymes means fewer adverse drug-drug interactions.

As far as genetics go, the genes coding for the breakage of de-activating chemical tag placed on Vyvanse may be of most importance, especially since this breakage (or "hydrolysis") is believed to be the slowest (or rate-determining) step in metabolizing Vyvanse for ADHD. The de-activating "tag" attached to Vyvanse is none other than the amino acid lysine. While the exact mechanism of cleaving this link is not fully known, one enzyme in particular may be extremely relevant to this process.

Trypsin is an extremely common digestive enzyme produced predominantly in the pancreas. It is responsible for breaking up chemical linkages much like that of the one used to de-activate Vyvanse. Thus, a genetically-governed deficiency of the trypsin enzyme could lead to a severely hampered absorption (and subsequent metabolism and clearance of the ADHD drug Vyvanse).

Trypsin is actually coded for by a series of enzymes, often referred to as Trypsinogen, which located on the 7th human chromosome (in the "q35" region of the chromosome to be more exact). Individuals with pancreatic deficiencies, including pancreatitis have been tied down to having mutations in this trypsinogen gene.

Therefore, while this genetic region on the 7th chromosome hasn't been sufficiently studied with regards to Vyvanse (at least to the best of this blogger's current knowledge), this blogger personally believes that aberrations in the region of the Trypsinogen gene on this 7th human chromosome may be a worthwhile place to look for genetic response-based differences to the ADHD medication Vyvanse.

ADHD drug #4: Concerta/Ritalin/Daytrana/Biphentin (methylphenidate)

Genes of Interest: Carboxylesterase 1 (also referred to as "CES1"), DAT (refer to ADHD drug #2: Adderall section for DAT's genetic location)

Carboxylesterase 1: Although the affected form of this enzyme, which is coded for by a gene on the 16th chromosome, is relatively rare, some key studies have indicated that deficiencies in the CES1 enzyme can be coded from specific forms of this gene. These rare, low-functioning gene-mutation forms of Carboxylesterase 1 result in extremely poor methylphenidate metabolism, resulting in a buildup of abnormally high levels of the drug in individuals with this enzymatically-deficient form.

In addition to their effects on amphetamines such as Adderall or Dexedrine, variations (often referred to in the literature as "polymorphisms") in the DAT gene also play a role in the response to methylphenidate. A Korean study found that a specific allele (the 10-repeat allele, which is the same form as the "high-risk" 480 base-pair allele mentioned earlier in the amphetamines section) predicted a poor response to methylphenidate.

Interestingly, however, several Irish studies suggest the exact opposite: the "high-risk" 10-repeat 480 base pair form of the DAT gene may produce larger amounts of the DAT protein (which shuttles essential dopamine out of the gaps between the cells, the opposite effect of what one wants if they suffer from ADHD), so the higher levels of expression of this transporter may make it a better candidate for methylphenidate.

Another Irish study may help resolve some of this discrepancy. It found that individuals with the so-called "high-risk" form of the DAT gene mentioned above exhibit a more positive response to treatment with methylphenidate with regards to treating their attentional symptoms based on the left side of the brain. Left sided inattention can be a reflection of brain damage or brain asymmetry, the latter being a common trait in the ADHD population. It should be worth noting that methylphenidate has been an effective treatment method for improving cognitive processes for those suffering from traumatic brain injuries.

Given the fact that in the amphetamine section we mentioned that the DAT gene was more connected to the Combined ADHD subtype (the original article specifically stated that the association did not hold for the strictly inattentive ADHD subtype). If this holds true, then we may have discovered a potentially significant gene/medication/ADHD subtype association.

It is this blogger's current hypothesis that the "high-risk"/480 base pair/10-repeat allele form of the DAT gene might predispose one to a MORE FAVORABLE response to methylphenidate treatment if inattention is the most persistent ADHD symptom (as in the predominantly inattentive ADHD subtype). Conversely, if the hyperactive/impulsive behavior either predominates or is largely present in an individual (such as in the hyperactive/impulsive or combined ADHD subtypes, respectively), then the "high-risk" label holds for this particular gene type, and the methylphenidate response potential goes down.

In other words, if large amounts of hyperactivity are present (which is the case in most ADHD children, as the combined subtype is by far the most common form), then this "high-risk" form of the DAT gene hampers methylphenidate's effectiveness, whereas if hyperactivity is largely absent, then the response to methylphenidate is actually more favorable. If this hypothesis were to hold true, then we could screen youngsters for this form of the gene and keep them far away from methylphenidate if they were bouncing off the walls, whereas if the exhibited more of an inattentive "space cadet" type of behavior then methylphenidate might be a good first choice of pharmaceutical treatment. Of course this theory could be completely off-base, but given this blogger's current knowledge and exposure to the current literature, this may be a plausible explanation.

Another possible explanation for this discrepancy between Irish and Korean studies: We have already seen that specific forms of certain genes can be found at considerably higher levels such as the *10 form of the CYP2D6 gene mentioned above with regards to the East Asian population. Keep in mind that this gene form was associated with the metabolism of Strattera (which exhibits a significantly different mode of operation than do stimulants such as methylphenidate or mixed amphetamine salts). However, there are a number of so-called ADHD genes which have been implicated with the disorder. The current thought here is that some genes exhibit a more powerful influence on physical or behavioral traits than do others. In other words, some genes simply act more "powerfully" than others. This is known as epistasis ("Epistasis" roughly means "standing upon").

***As a side note, please don't confuse "epistasis" with the whole dominant/recessive "big A/little a" (Aa) gene thing you probably learned about in middle school biology. Dominant/recessive refers to different forms of the SAME gene, whereas epistasis refers to DIFFERENT genes. For example, let's say, hypothetically that there was a rare gene for green hair located on the 20th human chromosome. However, a more "powerful" gene, say on the 14th chromosome codes for brown hair. This brown hair gene in this case would be epistatic, meaning that it would overpower the effects of the green hair gene altogether. This phenomena is quite common in genetics.

Getting back to our discussion, this blogger hypothesizes that there may be one or more other unidentified genes in either the Korean or Irish population which are epistatic to the DAT gene with regards to the methylphenidate response. If this was true, then it's quite possible that the effects of these hypothetical yet-to-be-identified genes might "mask" or override the effects of the DAT gene, and that the association with the "high-risk allele" may be largely coincidental rather than causative. Given the state of the current research on current "heavyweight" genes such as the COMT gene mentioned earlier, it is entirely possible that the overall level of contribution among specific "high-risk" DAT alleles might be less significant than many of these studies seem to indicate.

Of course the discrepancy could just as easily be attributed to small sampling sizes, slight differences in experimental methods or uncontrolled variables in the experiment (or a complete lack of true association between methylphenidate and the DAT gene at all, although given the current body of literature, this last assertion seems highly unlikely).

ADHD drug #5: Nicotine:

Genes of interest: CYP2A6, CYP2B6

I have included this drug due to the high rates of smoking among those with ADHD. As with alcohol, nicotine is often widely used as a form of self-medication for those with ADHD. Some research even suggests that individuals with ADHD exhibit a different response to nicotine and that nicotine withdrawal may produce different patterns in certain critical brain regions between ADHD'ers and the general population. Interestingly, there are some genetic regions which may tie into this behavior.

With regards to nicotine metabolism, 2 genes appear to stand out in particular: CYP2A6 and CYP2B6 (note the similarity in nomenclature between these and the gene/enzyme mentioned above for Strattera metabolism CYP2D6. This is not an accident, as all three of these belong to the same "superfamily" of enzymes and carry many similar chemical and functional similarities). Out of these, the CYP2A6 (hereafter abbreviated as "2A6") enzyme is responsible for the lion's share of nicotine metabolism. It is coded for by by a gene of the same name, located in the "q13.2" region on the 19th human chromosome.

Like the 2D6 gene for Strattera, the 2A6 gene can exist in multiple different forms. Some 2A6 gene forms produce higher levels of the 2A6 enzyme than others. Other forms of 2A6 are less efficient, which results in a slower breakdown and clearance of nicotine. As a result, the nicotine stays in the body longer, and less of it is typically required. As a result individuals with these less efficient forms (called "slow metabolizers") of the 2A6 genes are less likely to develop nicotine addictions.

The relevance of these 2A6 genes on ADHD: The stimulating effects of nicotine are believed to be a major contributing factor to the higher prevalence of smoking among the ADHD population. If this is true, then slow metabolizers of nicotine may not derive the full effect of nicotine self-medication for attentional deficits, at least not as immediately as the fast metabolizers. On the flipside, they have lower cravings (like with virtually all stimulant drugs, the speed and rate of uptake and clearance of nicotine is a major factor in its addiction potential) and are exposed to less tobacco and often find it easier to quit smoking.

At least two alleles or forms of the 2A6 gene (using the "star/number" nomencalture us used in 2D6 for Strattera earlier in this blog), have been shown to coincide with slower rates of nicotine metabolism. They are 2A6*2 and 2A6*4 (these two forms are actually referred to as "null alleles" meaning that the 2A6 enzyme they code for has no activity).

Additionally, there are noticeable differences in the frequencies of these forms across different ethnicities among the global population. For example, these "slow metabolizing" gene/enzyme forms of are found in higher percentages in individuals of Asian ancestry (around 20%) compared to those of European descent (around 8%).

With regards to ADHD behavior, it is likely that people possessing these *2 or *4 forms of the CYP2A6 gene, may be less likely to use nicotine as a self-medication tool for their ADHD, or at least use the drug in lower doses, due to its lesser effects. On the flipside, however, there is another allele of the 2A6 gene, referred to as CYP2A6*1B. This version of the 2A6 nicotine metabolism gene actually promotes greater activity of the nicotine metabolizing enzyme, and speeds up the processing and clearance of the drug. As a result, individuals who possess this relatively rare CYP2A6 form may be more prone to more frequent use and abuse of nicotine, and individuals with ADHD who attempt to self-medicate with this drug may cycle through their nicotine more rapidly if they carry this *1B form of the gene.

Interestingly, another drug, bupropion (Wellbutrin), which is an anti-depressant often used off-label to treat more "depressive" forms of ADHD is a relatively common anti-smoking drug. Given the fact that a number of ADHD'ers who typically do not respond well to stimulants, but do respond to Wellbutrin may fall in this smoking category, it is possible that the fast metabolizers (i.e. the *1B individuals), may be good candidates for Wellbutrin, not only to stop smoking, but possibly also to treat unwanted ADHD symptoms.

Alleles of the CYP2B6 gene and enzyme with regards to nicotine and ADHD:

Shifting gears for a minute, we see that the CYP2B6 gene (as well as the enzyme which it encodes) also may also play a unique role in ADHD. The CYP2B6 gene is located on the 19th human chromosome (in the 13.2 region of the 19th, to be more specific). For individuals who lack CYP2A6 enzyme activity because of the reduced-activity or even "null" alleles, the enzyme CYP2B6 can metabolize nicotine in its place (it turns out that CYP2D6, the enzyme responsible for Strattera metabolism can also do the trick). For those who need to metabolize nicotine, but lack an effective CYP2A6 enzyme system, this is good news (however, this "B6" enzyme only functions at about 10% of the level of the "A6" enzyme, so B6 is not a very efficient "backup" for A6).

Beyond its role as a "backup" for the CYP2A6 enzyme, CYP2B6 may also be of clinical significance with regards to ADHD and similar disorders. In contrast to "A6", whose enzymes are predominantly generated in the liver, the CYP2B6 generated enzymes are expressed in brain tissue. With regards to the differences in neurochemistry and neurological functioning of the ADHD brain, the role of CYP2B6 is therefore potentially noteworthy.

Additionally, as we have discussed in earlier posts regarding ADHD and alcoholism, the 2B6 enzyme apparently also plays a role in alcoholism, and individuals who express higher levels of this genetically-encoded CYP2B6 enzyme in their brains may be more sensitive to alcohol, nicotine and other centrally acting drugs. The study even suggests that individuals with high levels of this gene-coded enzyme may be more prone to damages induced from these common chemical agents, including possible higher susceptibility to cancer.

For reference (using the "star" notation again), genetic forms of CYP2B6 which typically yield higher levels of this enzyme in the brain include the CYP2B6*4 (which shows up in about a third of the European popluation) form and the CYP2B6*9 (which is present in about a quarter of those of European descent) form. Again, don't worry too much about the specifics of these "starred" variants, just know that if you were to get a genetic screen and had one of these two enzymatic forms, you may be more sensitive to nicotine as a self-treatment ADHD "medication".

What this means is that ADHD individuals who harbor the higher-expressing "*4" and "*9" forms of the CYP2B6 enzyme in their brains may be more sensitive to chemical agents such as nicotine, and these same individuals may be more likely to suffer the toxic effects of this popular form of ADHD "self-medication".

In conclusion, we should note that some of these genes (such as DAT) have been well-studied and have repeatedly shown to be associated factor in proper dosing of ADHD medications. Others, however, such as the trypsinogen gene for Vyvanse are more at the theoretical level at the moment. However, this blogger believes that in the next couple of decades, (due in part to our expanding knowledge of the human genetic code and functional genomics), genetic screens will become foutinely more commonplace as a necessary tool for both prescribing and dosing medications. With regards to this general trend, psychotropic medications for disorders such as ADHD should be no exception.

Omega-3 Oxidation in ADHD: A Problem with Supplementation?

Here are 4 reasons why omega-3/fish oil/flax seed oil often fails for treating ADHD and how some simple strategies can maximize omega-3 supplementation's effectiveness for therapeutic treatment of the disorder:

One of the most common recent trends in the natural treatment world of ADHD is omega-3 fatty acid supplementation. A number of studies appear to provide at least a theoretical basis for omega-3 fatty acid supplementation for ADHD as a valid natural treatment option. Fish oils, flax oils, and a variety of marine and seed oils are are showing up and rapidly disappearing off the shelves in grocery and health food stores.

Along with all of the pronounced cardiovascular improvements, a number of concerned parents are reaching for these omega-3's as natural treatment options for other dysfunctions, including ADHD and depression. A number of journal articles and research studies seem to support the use of omega-3 fatty acid supplementation as a viable alternative treatment method for attention deficit and or hyperactivity disorders (although not, perhaps at the complete level of stimulant medications).

Lost in the shuffle, however, is the million dollar question: Does omega-3 supplementation actually work in practice?

A number of parents will quickly jump to one side or another on this issue. Some swear by the effects, while others have written off this treatment alternative altogether.

I would like to distill some of the information I have gathered on the subject for this blog post. I personally believe that manipulation and treatment strategies for disorders such as ADHD using dietary fats is still in its infancy. Beyond their caloric content and to a degree beyond most other foodstuffs, fatty acids are often capable of making or breaking our systems hormonally and metabolically. Omega-3's are no different.

Recent findings suggest that fatty acid imbalances in children with ADHD may not be due as much to fatty acid intake, but rather a difference in metabolism of these fats.

In my personal line of work, I have seen at least 4 major factors (there are certainly more beyond these 4, for sure), which can severely hamper the effectiveness of omega-3 fatty acid treatment for ADHD and related disorders. They are:

1. Insufficient nutrient cofactors (or "helpers" for the enzymes that metabolize fatty acids). These include key vitamins and minerals, many whose supplementation, coincidentally, is often linked to improvement in ADHD symptoms.
2. Genetic factors in which lower amounts of of active enzymes key in the omega-3 metabolic pathway are present: A relatively new body of research suggests that individuals with ADHD manufacture different levels of these enzymes than the general population. This is one of many ways in which genetics may play a factor in the disorder.
3. Multiple fats competing for the same enzymes and pathways: The metabolism of different types of fatty acids can be complex. Different fats often share the same enzymes to form their respective products, so an imbalance in dietary intake of certain fats often means an imbalance in their products. This can have wide-reaching effects, such as a heightened state of inflammatory processes and disorders (such as heightened allergies), which coincidentally or not, are often seen at higher rates in ADHD patients. In other words, supplementation with omega-3 fats may be offset if a person's diet also contains high levels of "competing" fats.
   
4. Fatty acid oxidation: One of the most damaging negative side effects. Omega-3's, as great as they are for overall cell health, are often especially prone to oxidative damage. This damage, of course, can be at least partially stopped by ensuring that the body has adequate stores of antioxidant nutrients which are capable of acting on cell membranes and other common destinations of omega-3's.
   

Having highlighted these 4 factors on how well we can maximize the "omega-3 effect" on ADHD and related disorders, we can see that one of them (genetics) is largely beyond our control. However, we can also see that 3 of these 4 factors do fall under our control, at least somewhat, by dietary intervention. Add on these 3 helping factors, and you increase the chance of reducing unwanted ADHD symptoms and behaviors through omega-3 manipulation.

Before we begin, let's get a brief background on omega-3's and other fatty acids and how they relate to disorders such as ADHD.

A background on fatty acid ratios and ADHD:

You may be familiar with some of the following fatty acid "buzzwords" being thrown around recently: ALA, DHA, EPA, etc. These are simply abbreviations of much more lengthy names of major types of fatty acid which are either obtained in the diet or produced by metabolism of other fats.

Here is a quick summary on some of these important fatty acids and why they may be important with regards to ADHD and related disorders:

ALA: Short for Alpha Linolenic Acid, ALA is an omega-3 fatty acid. It can be obtained via dietary means including green vegetables, walnuts, soybeans and several types of seeds (kiwi seeds, flax seed or linseed are especially high in ALA).

One of the main reasons ALA is so important is that it can be converted to other key fatty acids such as EPA and DHA, which will be addressed shortly (essentially it acts as starting material for these other fats). It is therefore relatively versatile among the omega-3's, so maintaining adequate levels of this fat is important. It is important to keep in mind, however, that this conversion process is relatively inefficient, even with the help of important enzymes. As a result, many choose to supplement with these other fats which occur "down the line" directly. Nevertheless, due to its nutritive properties and versatility, maintaining adequate pools of ALA through consumption of the above-mentioned dietary staples is of great potential use.

DHA: Short for Docosahexaenoic Acid, DHA is another important omega-3 fat. It is found in green vegetables as well, as well as several types of meat and animal products (including milk from free range animals who graze on greens instead of feed lots). Of the omega-3's DHA is one of the most critical fatty acids for optimal brain health and nervous function. Low levels of DHA have been linked to cognitive decline and neurodegenerative diseases such as Alzheimer's Disease. DHA is also important for eye health, but is also susceptible to oxidation (which will be discussed in the last section). Interestingly, DHA is believed to play a role in protecting the nervous system from oxidative stress.

EPA: Short for Eicosapentaenoic Acid (not the Environmental Protection Agency, although this fat does play a protective role in several key functions!), EPA is another important omega-3 fatty acid. It is found in significant levels in breast milk (another major plus to breast-feeding) and oily fish such as sardines, mackerel, cod liver and salmon. Most of the fish oil treatments for ADHD rely heavily on this omega-3. It is important to note that this omega-3 is not often found in high levels in farmed fish who obtain their food primarily from non-algae sources. This is because it is the algae itself, which contains most of the EPA.

EPA is unique in that it's effect may be more far-reaching than many other omega-3's. At least some research suggests EPA has a protective effect against depressive disorders including suicide, inflammatory conditions (DHA does this as well, making both EPA and DHA good potential candidates for ADHD patients with a concurrent inflammatory condition such as allergies), and may even combat certain types of cancer.

As an interesting aside, there is also some evidence that EPA (at very high doses) may interact with an important type of enzyme called CYP2D6. This enzyme is actually responsible for metabolizing a number of drugs including amphetamines (for ADHD) and a number of antidepressants (including Prozac or fluoxetine as well as Tofranil or imipramine), so extremely high doses of EPA may actually interfere with these medications. Additionally, some studies suggest that higher levels of EPA may reduce levels of natural killer cells (which play a big role in fighting off invading foreign bodies) in older adults. However, to reiterate, most of these observations were seen at high doses beyond the common range of dietary or supplemental levels.

Blogger's note: I found an excellent review article about ALA, EPA and DHA for those of you who are interested. It can be found here. Although a bit lengthy and technical, it greatly expands on our above discussion.

Now that we have given some background into some of the key omega-3 fatty acids and their functional roles, let's return to the four factors listed in the beginning of this blog on how omega-3 supplementation's effectiveness can be hindered.

Factor #1: Insufficient supporting nutrients for the conversion process:
The ALA to DHA and EPA conversion process involves a number of steps and a number of enzymes. These enzymes, however, do not function in a vacuum, but rather rely on a number of common vitamin and mineral "cofactors" to optimize their function. Some of these cofactors necessary to optimize function of these fatty acid conversion enzymes include magnesium, zinc, vitamin B6, and vitamin C. We have seen in previous posts how magnesium, zinc, and vitamin B6 supplementation may be helpful in ADHD cases, especially if nutrient deficiencies are suspected.

Factor #2: Deficiencies in the enzyme systems themselves:
Another possibility in the fatty acid metabolic differences in individuals with ADHD may be due to malfunctioning or lower enzyme activity, even if the above mentioned cofactors are in place. Lending credence to this hypothesis is the fact that certain forms of genes responsible for "coding" for these important enzymes are seen at higher levels in ADHD patients. One of these genes is called fatty acid desaturase 2 gene, or FADS2.

It's important to note 2 things here:

1. The FADS2 gene is believed to code for an important enzyme delta-6 desaturase. This enzyme is critical in several fatty acid conversion processes, such as ALA to DHA. As we will see in the next section, this same enzyme, delta-6 desaturase is also used in another fatty acid conversion process, LA to AA.

2. At least some genetic evidence suggests that some forms of the FADS2 gene are seen at abnormally high rates in individuals with ADHD. This hints at a potential association between ADHD and the FADS2 gene.

Please keep in mind that these genetic factors are a bit more tenuous than the other ones. This is good news, because it suggests that even more control of the disorder may lie in the diet instead of the genes (at least with regards to omega-3 levels and ADHD). However, it is also important to note that the body of research on this topic is constantly shifting and changing.

Factor #3 on omega-3 supplementation for ADHD: Different fats share the same enzyme (delta-6 desaturase):

Factor #1 tells us that if we want to be serious about getting the most out of omega-3 supplementation for ADHD and related disorders, we had better make sure that we are supplying the enzymes which churn out this important omega-3 conversion process with the necessary nutrients or "cofactors" (vitamins C and B6, magnesium and zinc, to name a few). Without these helping nutrients in place, the enzymes cannot do their job nearly as effectively, and many of the nutritionally based benefits of omega-3's may be lost.

Factor #2 states that expression of some of these enzymes (and the subsequent activity level of these fatty-acid metabolizing enzymes, such as delta-6 desaturase) is contingent on specific genes, such as the FADS2 gene. Certain forms of this gene are believed to appear at higher levels in the ADHD population. Unfortunately, this is a genetic factor, meaning that there is little we can do about this process.

However, a third factor with regards to manipulating enzyme systems involved in omega-3 fatty acid supplementation and subsequent metabolism is within our control, at least to a certain extent. This involves tilting the scale or balance of dietary fats which compete for the same enzyme system. Let me explain:

The typical conversion of the omega-3 fatty acid ALA (alpha linolenic acid, see description at the top of this post) to the important fatty acid DHA utilizes the enzyme delta-6 desaturase. Yes, this is the same delta-6 desaturase enzyme which is coded by the FADS2 gene in factor #2 (and whose expression may, at least indirectly be associated with ADHD by genetic factors). However, the conversion of other fats in the body also share this enzyme for their conversion process (think of 2 construction workers who need to share the same power tool at the same time, but for completely different sections of the project). One of these other "competing" fats is linoleic acid (abbreviated as "LA", be careful, unlike alpha linolenic acid, this fat is spelled without the "n"). LA requires this same enzyme delta-6 desaturase to undergo a conversion process to another important product called arachidonic acid (AA).

Please don't get too tripped up on all of these lengthy names, terms and abbreviations. The important thing to remember here, is that many different processes, including metabolizing different types of fats, often share the same enzyme systems. As a result, these different fats often "compete" for the same enzymes, and significant dietary imbalances of one type of fat over another may often lead to an imbalance of "output" or products of these fatty acids.

Arachidonic acid (a non-omega 3 fatty acid) is responsible for a number of necessary processes, including some of the inflammatory responses described earlier, but it is important to note that it is possible to build up an over-abundance of this, which can play a role in the buildup of unnecessary or chronic levels of inflammation. This is believed to be at least partly responsible for inflammatory diseases and disorders such as allergies (as an interesting side note, allergies are seen at higher levels in individuals with ADHD than within the general population).

To summarize this point, the conversion of alpha-linolenic acid (ALA, which is an omega-3) to DHA must "compete" alongside the Linoleic acid (LA, a non omega-3) to Arachidonic acid pathway for the same enzyme (delta-6 desaturase). If excessive amounts of non omega-3 fatty acids are consumed (which is typical in most Western diets), then this crucial ALA to DHA process is hampered. Of course an imbalance on the other side (too many omega-3's) is also a possible, but given the dietary makeup in much of the industrialized world, this is often highly unlikely.

So, to summarize Factor#3: Omega-3 supplementation, such as with fish oil, flaxseed oil or ALA is often compromised by the concurrent intake of high amounts of other fats, throwing off the delicate balance of dietary fatty acid intake.

Finally, there is one other extremely important factor, which is the main topic of this post. Factor #4 involves the fatty acid oxidation process.

Factor #4: Is ADHD an "oxidative" condition?

While numerous studies have linked ADD and ADHD to lower blood level ratios of of omega-3's and various essential fatty acids, some others are suggesting that the actual oxidation of these fatty acids may also be a problem in children with attention deficit disorders.

Omega 3's are especially prone to fatty acid oxidation (as anyone who uses pure, untreated omega-3 rich oils can attest, these oils quickly become rancid and have a much shorter shelf-life than the processed "partially hydrogenated" oils). This is actually one of the main reasons why trans fats came about. They are tougher to oxidize by bacterial systems than the "natural" fats and thus have a longer shelf life. Unfortunately, a lot of the health problems stemming from trans-fats is due to many of the same reasons (our bodies aren't quite sure how to process, break down or metabolize these fats).

One of the major targets of omega-3's is that they are able to incorporate into cell membranes. In general, omega-3 fatty acids make the cell membranes more flexible or fluid, while other fats often make these same membranes more rigid or hard, which can compromise the integrity of the cell membrane and the overall cell health. However, like omega-3 cooking oils, these cell membranes are constantly exposed to oxidative damage. This includes cells in the nervous system, which are highly "fatty", and thus extremely susceptible to oxidative damage. This is why it is so important to not just provide the nerve cells with abundant supplies of omega-3's to incorporate into their membranes but also protected omega-3's (that is to say, omega-3 fatty acids accompanied by adequate antioxidant protection).

Therefore, for disorders involving the nervous system, including ADHD, it is imperative that sufficient antioxidants are available to protect these key cell systems. Simply taking omega-3's, fish oils, etc. in an antioxidant-deficient state is less effective at best, and neuro-damaging at its worst. I personally believe that omitting antioxidant protection is the single-greatest saboteur of omega-3, fish oil, or flax oil supplementation's effectiveness for treating diseases and disorders such as ADHD.

So which antioxidants should we be taking?

Vitamin C readily comes to mind as one of the cheapest and most well-known antioxidants. However, one strike against this vitamin is that it typically exists in a water-soluble form (that is, it mixes well with water, and is why it is easily flushed out of the system and needs to be replaced on a daily basis. It is also a main reason why it difficult to overdose on vitamin C, since excess amounts can simply be flushed away with water). Remember that omega-3's are still fats, and that fatty substances often do not mix or interact well with water. Thus, vitamin C, at least in isolation, is not the best option for protecting these essential fats. A fat-soluble antioxidant may be a better option here.

Enter vitamin E. Unlike vitamin C, vitamin E is a fat-soluble vitamin, which has a greater potential to interact with fatty substances such as omega-3-laden membranes in the nervous system and other cells. Even better, vitamin E and vitamin C work well in tandem, helping recycle each others' antioxidant pools after countering oxidative-damaging agents in the nervous system and other parts of the body. This is evidenced by a number of studies which indicate that vitamin C can help recycle vitamin E levels.

Recommended daily amounts (and toxic levels) can be found here for vitamin C and vitamin E.

Finally, I would like to address one of the more recent "wonder-nutrient" brain foods which may pose therapeutic benefits for ADHD and related disorders: Pycnogenol/pine bark extract. There is some debate as to why this may be an effective natural ADHD treatment, but much of the evidence suggests that the effectiveness of pycnogenol for ADHD lies in its antioxidant properties.

So the key take-home messages from this post are as follows:

1. Omega-3 fatty acids show a significant amount of potential as natural ADHD treatment options (although they are often not nearly as potent as medication treatments in a number of cases).
2. Omega-3's rely on enzyme systems to do their job. Genetics can play a role in the functionality and effectiveness in some of these key enzymes.
3. In order for these omega-3 metabolizing enzymes to function, nutritional "cofactors" are required. These include most of the B vitamins, vitamin C, and important minerals or metals such as zinc or magnesium. Other cofactors, such as biotin (found in eggs) are also necessary agents to make many of these enzymes run smoothly. Deficiencies in these nutrients compromise enzyme integrity and can ultimately limit the effectiveness of omega-3 supplementation for ADHD and related disorders.
4. Omega-3's compete with other fats for many of the same enzymes and enzyme systems. They often produce competing products, so an overall balance of fatty acids is imperative. Taking a couple of fish oil capsules will not be enough to offset a diet chock full of unhealthy saturated or trans fats. Chronic inflammation disorders such as allergies, asthma, etc. can be a sign of (but are by no means the exclusive reason of) omega-3 deficiencies or an indication of an imbalance in fatty acid intake or metabolism.
5. It is imperative that these omega-3's be protected by adequate antioxidant levels in the body, as omega-3 fatty acids are often extremely prone to damage by oxidation, especially in the nervous system. Vitamin C/E combos, as well as other powerful antioxidants such as bio-flavonoids in colorful fruits, vegetables, teas, etc. are especially helpful in this regard, and should be taken as seriously as the omega-3's themselves as natural treatment strategies for ADHD.
   

ADHD gene ADRA1A: A good target for clonidine?

Does the gene ADRA1A affect ADHD comorbid disorders? Is it connected to clonidine's positive response in some ADHD patients?

This blog has spent a considerable amount of focus on genes connected with ADHD. Although genetic studies surrounding the disorder are often inconclusive (and often difficult to replicate or even contradictory), the high rate of prevalence of the disorder within families and the strong genetic component of ADHD (this blogger has seen some studies reporting it as high as 90%!), any new findings for genes associated with ADHD can be noteworthy.

Furthermore, the medication treatment options for ADHD can be cumbersome as well. Some medications, such as clonidine, while not intended to treat the disorder, can often work quite well when applied as an "off-label" treatment for ADHD. The question is why?

Gene-drug interactions are an increasingly popular and meaningful component of pharmaceutical research. As we are generally moving in the direction of individualized medication strategies, and away from one-size-fits-all pharmaceutical treatment for disorders as complex and diverse as ADHD, specific genes and the target proteins which they encode, are becoming increasingly relevant in the tailoring of individual treatments for ADHD and related disorders.

The ADRA1A gene and how it relates to ADHD and other comorbid disorders:

ADRA1A is located on the 8th human chromosome, which is believed to be one of the "hot" regions for finding genes affiliated with ADHD and related disorders. The "8p" sub-region of the 8th chromosome is believed to be connected to numerous other disorders as well, including psychiatric disorders such as schizophrenia and autism.

The gene is also believed to be associated with hypertension, a disorder which is frequently targeted by the anti-hypertensive clonidine. There is some evidence that the actual mechanism of hypertension as it relates to ADRA1A may actually be due to auto-immune related causes. If this is the case, then it may warrant further exploration into other auto-immune disorders, such as allergies (which can elicit ADHD-like symptoms, and are a relatively common comorbid disorder to those diagnosed with ADHD).

The ADRA1A gene "codes for" the production of a protein known as the alpha 1A-adranergic receptor, which a target of epinephrine (adrenaline) and norepinephrine (noradrenaline). Norepinephrine is an important neuro-signaling agent which is often imbalanced in key regions of the nervous system in many ADHD cases, and is a target of several ADHD medications, including atomoxetine (Strattera) and stimulant medications such as amphetamines. The alpha 1A-adranergic receptor has also been implicated in studies of traits common to ADHD. For example, stimulation of this specific receptor has been shown to decrease impulsivity, improve working memory, and increase vigilance (in the rat model). This particular receptor is also a target of clonidine.

Given the fact that drug treatment for comorbid disorders can often alleviate some of the co-existing ADHD symptoms as well (and given the fact that ADHD is believed to be connected to circulatory impairments including reduced bloodflow to specific brain regions associated with impulse control), it is possible that those individuals possessing the "wrong" forms of the ADRA1A gene and suffer from hypertensive disorders may be prime candidates for treatment with clonidine to alleviate ADHD symptoms. In other words, specific variations of the ADRA1A gene may make one more or less likely to have a successful response to clonidine as a treatment for not only hypertension, but also co-existing attention deficit and hyperactivity disorders. Additionally, clonidine can also be used to augment the effectiveness of stimulant medication treatments for ADHD and reduce negative side effects.

Indeed, variations within three subsections of the gene ADRA1A were associated with around a 50% higher likelihood of having ADHD, according to a recent study (although when taken as part of a multi-gene analysis, the effects were not as pronounced). The rate of occurrence of each of these three variations was roughly between 25 and 50% of the study population. In other words, these are not some rare or exotic mutations we're talking about, but relatively common forms of the gene seen in the population (those of European ancestry in particular).

While not directly related to other disorders sometimes seen alongside ADHD, the genetic proximity of ADRA1A to other genes in the human genome may be noteworthy. For example, ADRA1A is located in the same subsection of the 8th chromosome (8p21) as another gene whose mutations may lead to an increased risk of epilepsy. This may be important, because in general, the closer 2 genes are to each other on a chromosme, the more likely they will be transmitted together from parent to offspring. Thus, a parent who has both the "epilepsy" mutation and the ADHD-specific ADRA1A mutation(s) may stand a greater chance of passing these gene forms on together to their child. As far as treatment is concerned, there is general consensus that clonidine is safe for patients who are diagnosed with co-existing epilepsy, however a few case studies suggest that caution regarding clonidine and epilepsy may be needed. We have investigated complications in treating ADHD and comorbid epilepsy in earlier posts.

Interestingly, the 8p21 subregion of the 8th chromosome is also home to genetic regions believed to be affiliated with schizophrenia. There is some evidence that clonidine may be an effective augmentative treatment for schizophrenia when used in conjunction with another drug haloperidol. Thus, for individuals who exhibit symptoms resembling ADHD and schizophrenia, clonidine may be a potentially useful medication strategy to try under medical supervision.

It is important to note that many of these suggestions are largely hypothetical at the moment. Do not attempt to follow any of these suggestions without medical supervision. Nevertheless, given the complexity and variability of ADHD and the compounding effects of comorbid disorders, it is useful to investigate medication strategies which have shown to be historically useful in treating multiple disorders which can often occur alongside each other. This is particularly useful for ADHD, where constraints are often necessary for medication treatments due to the negative impacts that these ADHD drugs may have on other accompanying disorders. As a result, the potential of clonidine in treating a diverse range of disorders (which may, possibly by way of ADRA1A and other nearby genes share an underlying genetic predisposition), move this traditionally second or third-line medication closer to the forefront as a valid medication-based ADHD treatment option.