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.

Modafinil: An alternative treatment for ADHD and comorbid substance abuse?

Can Modafinil (Provigil) Replace Stimulant Medications in Adult ADHD where stimulant drug abuse is a concern?

It is a Catch-22 of the ADHD world. An individual is suffering from severe ADHD symptoms and appropriate stimulant medications may help remedy some of the negative side effects of the disorder. However, due to the high prevalence of substance abuse in ADHD (some officials put the rate of comorbid substance abuse as high as to 30% in the ADHD population), including stimulant medications such as amphetamines, treatment of ADHD symptoms via stimulant medications cannot, by nature of the comorbid substance abuse disorder, be a treatment option.

The appearance of (relatively) novel non-stimulant medication alternatives such as Strattera (atomoxetine), have offered individuals with ADHD another treatment alternative. However, the results are often mixed. Strattera often works well with the inattentive-dominated forms of the disorder, but the positive results are often not as pronounced for the more hyperactive or impulsive forms of ADHD, especially if comorbid disorders such as conduct-related issues surface.

Another alternative may be a completely different type of drug, which, while not a stimulant in its own right, can act on or exhibit pseudo-stimulant properties. It appears that in at least some cases, Modafinil (Provigil) may be the type of drug we're looking for in these cases.

**Blogger's note: The extent of the study highlighting this case for Modafinil treatment for ADHD and comorbid amphetamine abuse is intended for adult treatment only. Given the relative scarcity of research on medication options for adult ADHD symptoms (compared to those designed more for children), this post is designed for offering a possible treatment alternative for ADHD in adults. Nevertheless, some recent studies have shown promising results of Modafinil as an ADHD treatment method for children and adolescents.

It is important to note, that while not initially designed as an ADHD-specific medication (and not a stimulant in its own right), Modafinil does share at least some degree of overlap with several stimulant agents for ADHD treatment. One is its regulation of catecholamines (important neuro-signaling chemical agents, whose balance in and out of neuronal cells is crucially important for regulating attention, hyperactive and impulsive behaviors, and locomotor control). As far as its mode of action and metabolism (clinical pharmacokinetics of Modafinil) are concerned, drug-drug interactions between Modafinil and several ADHD stimulant medications such as methylphenidate or dexamphetamine (Dexedrine) appear to be limited.

A background note on addiction potentials of ADHD drugs: This section is an aside, and is meant to serve as some background information and to clear up potential confusion surrounding ADHD medications and their addiction potentials. The next four paragraphs may be skipped if you are pressed for time.

While I cannot stress enough the importance of regulating neuro-chemical balance for both the onset of ADHD as well as drug addiction (which are affected by pharmacological agents such as ADHD medications, in varying forms), it is the rate of action for which these chemical changes take place which typically drives a particular drug's addiction potential.

Unfortunately, this last fact is often lost in much of the literature surrounding ADHD treatment (especially those which promote non-pharmaceutical treatments for the disorder). For example, many "natural" ADHD treatment books and websites frequently start out by asserting (erroneously) that methylphenidate is the equivalent of crack cocaine, and promotes later drug abuse and addiction.

While this blogger is a personal advocate for natural approaches to treating ADHD whenever possible (and without compromising overall treatment effectiveness in ADHD treatment), he wants to make it clear that significant differences do exist between ADHD medications and stimulant street drugs. One of the most telling signs of this is the rate of uptake and clearance of drug-like agents into and out of the brain, respectively. In general, the quicker a substance is taken up into the central nervous system and the faster it clears the brain, the more likely this chemical agent will elicit a "high" and an increased tendency towards substance dependence.

ADHD medications like Ritalin, while having some degree of overlap in structure and net effects of action as cocaine, are specifically designed to have a much slower rate of release and clearance, significantly reducing their abuse potential compared to cocaine. We have previously discussed Ritalin (methylphenidate) vs. cocaine addiction potentials in earlier posts.


Modafinil: Modes of action and addiction potential:

The reason I am providing all of this information is the fact that the successful regulation and softening of rapid spikes and clearances of chemical peaks is a crucial component to curbing the drug addiction process. It is believed that modafinil may work so well at reducing drug cravings by targeting this very mechanism. Unlike many stimulant medications which can produce some type of "high" (especially if abused by snorting or injection, or taken at abnormally high doses), Modafinil has a low abuse potential, and offers several other advantages over methylphenidate.

Modafinil does have a relatively positive track record for mitigating substance abuse disorders. For example, the administration of Modafinil can attenuate cocaine dependence. In contrast, methylphenidate (Ritalin, Concerta, Metadate, Daytrana), while being very effective as an ADHD treatment, does little to curb comorbid substance abuse disorders in ADHD patients. Unfortunately, the effectiveness of Modafinil on treating comorbid substance abuse disorders in individuals with ADHD may be limited to specific drugs. For example similar positive effects of Modafinil on nicotine dependence appear to be less pronounced.

Modafinil may also offer advantages over traditional stimulants as well. As a cognitive enhancement type of pharmacological agent, modafinil may be useful in improving the work performance of adults with ADHD by improving short-term memory and visual recall, impulse control, and spatial skills (all of which are frequent deficits in children and adults with ADHD). Additionally, similar improvements were seen in individuals with schizophrenia, suggesting the diversity of modafinil's range of performance in cognitive improvement. These improvements are typically not seen in individuals unaffected by psychological disorders, further supporting the evidence that modafinil is less likely to be abused recreationally in the general population.

The potential implications of modafinil for ADHD treatment may be further reaching than the details outlined in the original article (and basis of this post, highlighting the effects of modafinil on amphetamine abuse in adult ADHD). For example, modafinil, as a vigilance-promoting medication, can offset an afternoon dip in arousal state (which has implications on many of the shorter-acting stimulant medications, which begin to wear off around this time). This may be useful for individuals with sleep disorders (which are common in ADHD), as well as regulating circadian rhythms. In a post earlier this month, we investigated the relationship between ADHD and seasonal affective disorders, and hinted at the association between ADHD and disruption in circadian rhythms.


Potential future implications of Modafinil as an ADHD treatment alternative:

Additionally, while Modafinil may offer benefits for the whole ADHD spectrum, this blogger hypothesizes that it may be most useful for treating the inattentive subtype of the disorder. Some reasons for this are as follows:

• Activity patterns and circadian rhythms may often be associated with ADHD subtype. For example, "morning people" with ADHD may have a tendency to fall into the more hyperactive/impulsive group, while "eveningness" is more of an inattentive ADHD trait, suggesting more of a disruption in the circadian rhythms of inattentive ADHD'ers.
• Additionally, non-stimulants often have somewhat of a better track record with the inattentive subtype of ADHD compared to the more hyperactive/impulsive subtypes. The uses of the non-stimulant atomoxetine (Strattera), highlight this general trend. While atomoxetine treatments often result in drastic improvements in all ADHD subtypes, negative side effects are often less seen in the inattentive subtype.
• Compared to stimulants, non-stimulant medications for ADHD often do a better job at not exacerbating comorbid disorders such as obsessive compulsive or anxiety disorders (which are often more common to the ADHD inattentive subtype). Additionally, Modafinil treatment can be useful in treating adults with ADHD and a history of mood disorders.
• Modafinil offers advantages over methylphenidate as far as fewer side effects including appetite suppression, sleep disturbances and heart rate dysfunction (orthostatic tachycardia, which essentially is significant changes in heart rhythms based on postural changes, such as standing up quickly from a seated position).
• Anecdotal evidence, as noted by the Modafinil and amphetamine abuse study mentioned earlier, also suggests that Modafinil may be a useful treatment method for "refractory" cases, or individuals who have consistently shown poor response to other treatment medications and interventionary measures.
  
• Finally, it is important to note (and this was also touched on in the Modafinil and amphetamine abuse study), that Modafinil treatment may be better suited for the more "controlled" abusers of stimulants. In other words, better effects might be seen for adults who regularly take illegal stimulant drugs such as amphetamines as a conscious effort to "self-medicate" for their ADHD, as opposed to an out-of-control drug addict who craves the drugs on a non-scheduled basis.

Given the high propensity of comorbid disorders when deciding on treatment for ADHD, as well as practicality issues concerning the administration of medicinal agents for treatment of the disorder in adults, I see a fair amount of potential for Modafinil's "off-label" usage as a treatment alternative to stimulants in adults with ADHD.

Does Blood Type Affect ADHD?

This blog has often discussed the wide range of genetic influences on ADHD and related disorders. Some of the ADHD genes we have previously investigated include:

• DAT1 gene (often referred to simply as "DAT", possibly related to Tourette's and eating disorders such as bulimia)
• MAOA gene (likely has gender-specific effects, also tied to autism, bipolar and anxiety disorders)
• COMT gene (can affect dosage levels of ADHD stimulant medications, and possibly have an impact on brain regions responsible for attentional control)
• SLC6A2 gene (also called "NET" or "norepinephrine transporter gene", may affect the response to Strattera, also related to posture and eating disorders such as anorexia)
• SLC6A4 gene (often has a greater potential effect on males with ADHD, associated with autism)
• Protogenin gene (possibly related to ADHD and reading disabilities)
• DRD4 gene (also may be related to schizophrenia, alcoholism, and resistance to Parkinson's)
• Fatty acid desaturase genes (may play a role in deficiencies in omega-3 levels in ADHD)
• CREM gene (may be related to hormonal regulation, including the sleep-related melatonin)
• Serotonin receptor 1B gene (may be more associated with the inattentive subtype of ADHD)

Additionally, some of these genes may work together in combo. For example, a combination of specific variations in the DAT1 gene and the DRD4 gene may associate with IQ and behavioral disorders as they relate to ADHD.

The main point of all of these examples was not to overwhelm anyone, but rather to highlight the intricate relationship between genetics and ADHD heritability.

Adding to this extensive list may be a new set of genes related to blood types and ADHD.

**For a quick synopsis of blood types, please consult the italicized paragraphs below. Otherwise you may skip to the next paragraph highlighting a new study on blood type and ADHD.

Human blood types are often classified by the "ABO" system. "A" and "B" refer to immune-regulating factors and play a major role in blood transfusions. These blood types are acquired from our parents and can come in dominant and recessive forms. Genes for blood type can be found on the 9th human chromosome.

They are the two main (or dominant) forms of immune-regulating blood factors. Additionally, A and B can be "codominant", that is an individual can have a mixture of the two. For these "codominant" individuals, their blood type is labeled "AB". If an individual has neither "A" nor "B", he or she is labeled as an "O".

In essence, if you have a specific letter(s), you can donate blood to individuals who share your same letters (there are actually other important factors and donor restrictions besides this, such as the "Rh factor", but for sake of simplicity, we will just discuss "ABO" for the moment). For example, a person with type "A" blood could donate to another person who has "A" or "AB" because both "A" and "AB" would recognize the "A" component. They could not donate to a "B" or an "O" blood type because these individuals' bodies would not be able to recognize the "A", resulting in a severe immuno-rejection problem.

An "O" could donate to and "A", a "B", an "AB", or another "O" (again, there are detailed exceptions to this generalization), because "O" does not have either of the "A" or "B" markers on it, so the recipient's body would not see anything "foreign" about this. This makes "O" carriers better candidates for blood donation. On the flip side, and individual with type "AB" could take blood from and "A", a "B", an "AB" or an "O" since their blood already recognizes the "markers". This makes AB candidates better recipients for blood.

In addition to an individual's blood type governing the blood transfusion process, blood types may also confer resistance or susceptibility to certain bodily dysfunctions or diseases. For example, type "A" individuals may be naturally more prone to cancers of the digestive system, and individuals with type "O" are more prone to cholera, plagues, or even malaria (interestingly, they may be more prone to be preferred targets of mosquitoes, compared to the other blood types).

Overview of an original study on ADHD and blood types:
Returning to our main discussion, it appears that certain blood types may also be related to an increased likelihood of childhood ADHD or related disorders. A Chinese study recently came out which sought to investigate whether certain blood types were actually more likely to be affiliated with ADHD. The results, while preliminary, should nevertheless pique some interest on the topic among professionals.

Here are some of the major highlights of the study:

• Blood types (using the "ABO" format) were taken from 96 children and their parents, to determine the heritability patterns of blood types.
• Both ADHD and non-ADHD children were observed in the study, and their blood types were broken down.
• The study found that children who did have ADHD were more likely to have inherited either the "A" or "O" type blood from their parents.
• Conversely, children who inherited the type "B" blood (which would include either the "B" or "AB" form) were less likely to be diagnosed with ADHD.

** A caveat concerning the findings and reproducibility of this study: It is important to note that the study population was relatively small, especially for a study of this magnitude which seeks to identify general trends between blood types and their relative association with co-existing disorders. Some blood types can be relatively rare, for example, in the United States, only around 10% of the population has type "B" blood and only about 15% has the "B" in any form (types B or AB). Although blood types vary extensively all over the world, certain types tend to predominate, which requires large populations to be studies to ensure all groups are sufficiently represented. Thus, small population studies can easily produce skewed results. Nevertheless, I personally believe this study was a good starting point.

**Blogger's personal notes/opinions on these findings:

I found this study to be interesting. Unfortunately, I could not read the whole article (the majority is in Chinese!), but the possibility of blood typing being related to ADHD would be a major breakthrough, if these results are able to be consistently replicated with larger population studies.

My first thought was that maybe some nearby gene related to ADHD might be influencing the blood type/ADHD connection, but no significant genes associated with ADHD exist on the 9th chromosome (at least to the best of my knowledge after conducting a search of OMIM for the term "ADHD", a national database which ties down diseases and disorders to known genetic regions). However, genes which are located far apart from each other, even on completely different chromosomes can also work in tandem, so genetic relationships between ADHD genes and blood type genes cannot be ruled out entirely.

Another option may be some type of indirect connection between blood type and ADHD. For example, the article notes that individuals who have the "O" or "A" blood type alleles are more prone to ADHD. Other sources note that individuals with type "O" are more prone to developing intestinal and gastric ulcers, and that individuals with type "A" are more prone to cancers of the digestive system (such as cancers of the esophagus, pancreas and stomach). This may signify that these blood types (compared to those who have "B" or "AB" blood) may be more prone to digestive problems.

Digestive disorders can result in poor nutrient absorption (we have discussed nutrient deficiencies in ADHD in number of previous posts), which may leave one more prone to ADHD symptoms. Additionally, digestive dysfunctions can actually lead to an increased likelihood of developing food allergies, as potential allergens are less likely to be broken down or "chewed up" than by a properly-functioning digestive system. Furthermore, we have also explored the possibility that acid accumulation can make its way into the brain regions and have an impact on neurological symptoms including ADHD-like behaviors. This was discussed in a recent post investigating the high prevalence of ADHD in children who suffer from frequent ear infections.

While these possibilities are strictly hypothetical at the moment I firmly believe that we should further explore the possibility of specific blood types as possible underlying causes or risk factors for developing ADHD.

ADHD and Balance Impairment: Visual and Inner Ear Deficiencies

Balance dysfunctions and visual or vestibular deficiencies: Uncommon comorbids in the ADHD spectrum:

When we think of comorbid disorders to ADHD, we often envision disorders which can be diagnosed psychiatrically. Common examples such as depression, anxiety, Obsessive Compulsive Disorders (OCD), oppositional defiant disorders, and conduct disorders often come to mind. In addition, it is perhaps no surprise that learning disabilities are relatively common in children and adults with ADHD. If we do delve into physical comorbid disorders, things like Tourette's and tics may come to mind. For those skilled in the diagnosis and treatment of ADHD, even non-trivial comorbids such as bedwetting and sleep disorders may be apparent.

However, there is another impairment that often goes along with the ADHD population, especially in children. Sensory processing disorders are often seen in the ADHD population, especially in children. This includes more "physical" dysfunctions including the ability of the child to maintain balance and equilibrium. To the frustrated parent of coach of an ADHD child, this may introduce another complication with regards to sports or other activities which involve coordination and balance, such as basketball, baseball, tennis, soccer, gymnastics, musical instruments, dance, etc.

The aim of this post is to investigate and discuss impairments in balance function in children with the disorder, We will be citing and highlighting some key studies in the overlap between ADHD and balance dysfunctions (especially relating to functions derived from visual and tactile signals) and look for possible underlying causes and treatment methods:

Brain regions involved in Balance Dysfunction in the ADHD Child:

Most experts often cite specific "hot spot" regions of the brain for the ADHD patients. Among these, the prefrontal cortex part of the brain often receives the most attention. Less pronounced, however, are the studies associating the cerebellum, and their implications on ADHD. For a reference to the Prefrontal Cortex and Cerebellum brain regions, please consult the brain diagrams below:

Shown above is a human brain. The Cerebellum region, which plays a major role in governing balancing functions and may be compromised in a significant subsection of ADHD children, is shown in purple in the top picture. The area highlighted in orange in the bottom drawing roughly corresponds to the prefrontal cortex region of the brain, which plays a major role in impulse control. Deficiencies in blood flow and overall activity of this prefrontal cortex region of the brain are often seen in children (and adults) with ADHD, and may be responsible for some of the difficulties in filtering out comments and actions for appropriateness.

The inter-relationship between attention and balance/coordination: The strong association of the prefrontal cortex and cerebellum regions of the brain:

Many studies involving brain regions and ADHD often miss this connection. The relationship between these brain regions may go a long ways in explaining ADHD comorbid disorders as well, especially the more "physical" ones such as speech complications, developmental coordination disorders, etc. While perennial "hot spot" brain regions, such as the prefrontal cortex, are frequently mentioned in studies involving brain activity in ADHD, this particular brain region is actually intricately interconnected with the cerebellum (as well as another key brain region, the basal ganglia. The role of the basal ganglia in kids with ADHD has been discussed previously in other postings, but in general, the basal ganglia tell how fast a person "idles". 'Type A' personalities, such as workaholics, individuals with OCD and overly focused individuals typically have overactive basal ganglia, whereas many with ADHD often exhibit underactive basal ganglia.).

We have already mentioned that the balance-governing regions of the brain (the cerebellum) is interconnected with a key impulse-control region of the brain (the prefrontal cortex or PFC). We also mentioned that impulsivity is a characteristic of the Hyperactive-impulsive and Combined ADHD subtypes (as opposed to the more inattentive forms of the disorder). Interestingly, the prevalence of balance dysfunction cases seems to predominate in the combined subtype of ADHD (main paper as reference source). This correlation lends further credence to the hypothesis that the balance-governing and impulse-governing regions of the brain may be "co-affected" in the case of the balance-deficient, hyper-impulsive ADHD child.

Key points concerning balance related deficiencies and ADHD:

• ADHD is often associated with developmental delays. Indeed, studies highlighting a delay in cortical maturation in children with ADHD suggests that children and teens with the disorder may fall "behind the curve". By its own very nature, the vestibular system often does not fully develop until the age of 15, so immature development in this brain region may result in deficiencies in this system throughout almost the entire span of childhood in an individual with ADHD.


• Additionally, EEG and imaging studies have also demonstrated relative deficiencies in both size and activity (by measuring blood flow patterns) in various brain regions of ADHD children. These include the cerebellum and the caudate nucleus. Both are interconnected and associate with the "ADHD region" of the prefrontal cortex (PFC). This PFC region plays a major role in the impulse-control process and deficiencies in its function can result in a weak self-regulatory system of impulsive behaviors (which are hallmark characteristics of ADHD, especially in the hyperactive/impulsive and Combined subtypes).


• The cerebellum gathers input from visual, vestibular (inner ear), and somatosensory (mainly tactile senses, such as perceived through the skin and internal organs) systems. As we can imagine, a defect in one or more of these information-obtaining sensory systems, and the cerebellum (as well as the interconnected region of the PFC) may be compromised. Thus ADHD and sensory deficits may be intricately related.


• Taking this one step further, we may wish to explore the link between ADHD and sensory disorders, including processing disorders and sensory integration disorders. One thing is for sure, however: ADHD is not simply limited to deficits in the PFC!


• The vestibular system also plays a crucial role in what is known as "gaze stabilization" (i.e., stabilizing the focus on a particular fixed object when you yourself are moving). The very nature of "gazing" obviously has visual implications as well, so a deficiency in the vestibular component of gaze stabilization may also affect visual input success as well. Interestingly (an perhaps not surprisingly), visual input deficiencies are also seen at high rates in children with ADHD.
  
  This may actually serve as one of the key contributing factors as to why maintaining attention (to, say, a teacher), may be so difficult for ADHD kids, because they literally are having trouble focusing their visual attention (gaze) on their target of interest (i.e. a teacher standing up in class giving a lecture), especially if the child is already fidgeting around in their seat. In other words, there may be some inherent deficiency in this particular component of the attention span, and needs to be addressed further in the near future.

Investigating the sources of balance impairment in children with ADHD:
In order to clarify where I am coming from on this, I will highlight an extremely recent publication in the Journal of Pediatrics by Shum and Pang. This study investigated the different systems of balance in children, including somatosensory (balance governed by tactile features), visual, and vestibular (inner ear and the sense of equilibrium). They tested approximately 50 children (ages 6-12) with ADHD for balance discrepancies by isolating each of the three systems listed above to test sensory organizations of balance. A highlight of the study can be seen below:

Instruments/Methods of the study:

1. A platform which can induce a feeling of motion on a child who stands upon it (this disrupts the somatosensory component of balance, forcing the child to use their visual or vestibular functions to compensate for the somatosensory impairment).
2. Surrounding scenery which can visually give the illusion of motion. This forces the child to use their vestibular and somatosensory methods of equilibrium, as the visual sense is disrupted. Another variation of this is to have the child perform with their eyes closed.
3. A combination of the two methods above will isolate the vestibular component of balance, as both the somatosensory and visual sources of balance are now both compromised.
4. A total of six different environmental conditions were performed to isolate one or more senses of balance. The researchers noted which of the three modes of balance were most likely to be compromised in the ADHD children. The findings are highlighted below:
   

While balance-related issues can stem from visual discrepancies, somatosensory issues (i.e. the sensations of touch and pressure from the skin and even internal organs), and vestibular (inner ear) imbalances, it appears that ADHD children are most likely to suffer from visual imbalances. This is closely followed, however, by deficits in vestibular function. Somatosensory difficulties appear to occur in ADHD children as well, but the role of this system is likely to be much smaller than for the other 2.

Possible academic implications of balance dysfunction and ADHD: Does the source of an ADHD child's balance deficiency affect his or her sensory learning style? The following points are simply the result of this blogger thinking out loud. Nevertheless, these might be some good topics of future study, as balance difficulties may be useful in evaluating academic strategies.

• These findings on balance may even extend to the classroom and affect the learning environment of an ADHD child. Given the above, abnormalities in these areas may even affect a child's mode of learning and learning style. While these assertions simply remain personal hypotheses of this blogger, a child with visual discrepancies leading to balancing difficulties may also be deficient in visual perception and therefore struggle in a visual-dominated learning environment. He or she may gravitate towards a more auditory or kinesthetic style of learning.
  

• Conversely, it is also possible that vestibular-regulated balance dysfunctions, which stem from the inner ear may actually extend to a child's auditory learning capabilities. Again, this remains a hypothesis, but given the fact that severe childhood ear infections can affect both balance and hearing (as well as ADHD symptoms, see previous post on childhood ear infections and ADHD), a child with vestibular-related balance deficiencies may also have more difficulty in a predominantly auditory-based learning environment. This may spell bad news if an ADHD child's teacher engages in more auditory discussions or as the child moves up to high school and college courses where an auditory lecture is the more common form of teaching and communication.
  

• A double-whammy?: Given the fact that children with ADHD may suffer from both vestibular and visual (and even somatosensory) information processing for balance, it leads us to wonder if the child may also have learning deficits in 2 of the 3 major forms of learning (visual, auditory or kinesthetic). If this is the case, trying to accommodate an ADHD child's education could be extremely difficult, if he or she must heavily rely on only one predominant mode of acquiring and processing information.
  
  For example, if a child were to undergo a study similar to the one listed above, and it turns out that he or she is weak in both the visual and vestibular forms of balance, and (this is a big "if" and is only hypothetical at the moment) the whole balance governing/learning style hypothesis holds true, he or she may have to rely on a predominantly kinesthetic form of learning. While this child may succeed in hands-on learning subjects (i.e. frog dissection or wood shop class), he or she may have an exceedingly difficult time in other subjects such as algebra or history where hands-on-learning opportunities are more difficult to implement.
  
  

• The role of balance and sensory stimulation may have even greater-reaching academic implications. Another study just came out recently investigating the role of posture stability (i.e. how well a person stabilizes their center of balance) on ADHD and dyslexia. The study found that comorbid ADHD symptoms greatly influenced the effects of posture stability in dyslexic individuals, which may even have implications to affecting the reading environment of the individuals with dyslexia. It's important to keep in mind that this study involved adults instead of children, but the fact that ADHD may play such an integrated role into sensory modulation of other disorders into adulthood may signify the deep level of inter-relationship between cognitive function and sensory motor stimulation.
  

Vestibular Stimulation as an alternative form of ADHD Treatment?: As an interesting aside, there has been some pronounced effect on treating ADHD symptoms with a non-pharmaceutical alternative method called vestibular stimulation. We will be addressing the validity of these findings and their potential for practical usage in a later discussion.