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.