Genes, Omega-3's, Alcohol and ADHD

In our last discussion, we were exploring the theory behind omega-3 fatty acid supplementation for ADHD, and alluded to the fact that there may be some genes at work involving this process. Additionally, there is some evidence that alcohol use can inhibit the effectiveness of some of the enzymes that are coded for by these genes, and possibly be a factor in the onset of ADHD. We will be exploring these associations in this blog post.

Omega-3 fatty acids are crucial for our overall well being for a number of reasons, with many of them being tied to maintaining the structure of all different types of cells in our bodies. Among these omega-3's are alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). ALA converts to EPA (and eventually DHA) through a series of steps, several of which use the enzymes governed by the genes listed above. A summary of this process is highlighted below (original file source here):

The diagram above may look quite complicated, but we're just focusing on a few of the objects listed above.

As a quick side note: a lot of the other objects on this diagram above are showing the role these omega-3's and omega-6's play in the inflammatory process of immune reactions. This discussion is beyond the range of this post, but I have included it to illustrate that omega-3 and omega-6 fatty acids play a critical role in regulating a number of different functions and systems. Omega-3 imbalances can lead to immune dysfunction, which is thought to be one of the reasons why individuals with ADHD, who often have lower blood levels of omega-3's than their peers, are also more likely to have immune system disorders such as allergies. This ADHD/allergy connection will be explored in the future. Also, notice that omega-3's and omega-6's use the same enzymes. This is important, and was discussed at length in the previous post.

The section on the left of the above diagram describes how one omega-3 fatty acid is converted to another, for example, the a-linolenic acid (top left) eventually makes its way to forming EPA (fourth one down on the left), which eventually is converted to DHA (last one in the left column). Bringing our attention to the center, we see a series of enzymes with names like ∆6 desaturase, elongase, etc. These enzymes play a major role in the actual chemical conversion process of one type of omega-3 fatty acid to another.

Keep your attention on the enzymes that have the key term desaturase in their title. These are the ones we need to be concerned about when dealing with the aforementioned genes and alcohol. Without these enzymes functioning at their highest level, the incorporation of dietary omega-3's into the actual structure of the cell membrane is significantly. Genetic differences and the presence of external factors (such as alcohol or other types of fats) can significantly impair the function of these enzymes and slow the conversion process (and ultimately uptake and incorporation into cell membranes) of these critical omega-3's.

A number of these desaturase enzymes are all coded from a specific genetic region located on the 11th chromosome in humans, located at the 11q25 region (chromosomes have 2 "arms", a "p" and a "q", the numbering refers to relative location on that arm, so "11q25" refers to the 25th region on the "q" arm on the 11th chromosome). Interestingly, this region is located near the 11q22 region, which has been linked to ADHD. The closer two genetic regions are, the higher the chances they will be co-transmitted (passed on together from parent to child). In other words, gene forms which are located near each other on a chromosome are more likely to be passed on together, suggesting the possibility that the 11q22 ADHD region may in fact be influenced by some of the genes from nearby 11q25 region.

Brookes and coworkers did a study on the association between these desaturase genes and ADHD (on a personal note, I would like to acknowledge the authors of this particular study. Much of the information in these past two posts is gleaned from their work, and this paper provided a great starting point for much of my research for this post). They found that the 11q25 region contained three genes which code for desaturase enzymes located next to each other: Fatty Acid Desaturase 1, Fatty Acid Desaturase 2, and Fatty Acid Desaturase 3 (abbreviated as FADS1, FADS2 and FADS3, respectively). These genes each exist in different forms, called alleles, which have slightly different DNA configurations (which can differ by as little as one letter in the DNA "code").

Key findings from the Brookes study: This group saw a significant difference in the prevalence of ADHD stemming from two different alleles in the FADS2 gene. It appears that a single point difference was all it took to boost the likelihood of association with ADHD. Individuals with ADHD were significantly more likely to have the "C" form of the FADS2 gene than the "T" form of the gene at marker 498793 (this number just gives the detailed location on which spot of the DNA this form can be found).

Additionally, it appears that the onset of ADHD stemming from prenatal alcohol exposure may be somewhat genetic as well. For individuals who were exposed to alcohol via maternal consumption during pregnancy, there is some nominal evidence linking "G" allele instead of the "C" allele at two different locations on the FADS1 gene was correlated with a higher likelihood of being diagnosed with ADHD. However, the authors concluded that this connection was only "speculative".

This possible ADHD/genetics/fatty acid consumption/alcohol exposure connection is somewhat intriguing. The study established a strong ADHD connection to a specific allele of the FADS2 gene on the 11th chromosome, and also cited a number of other studies on the effects of omega-3 consumption on ADHD symptoms, but the connections with alcohol are more strained. Nevertheless, the findings from other studies offer support for this possible alcohol association with these other factors:

1. We have seen before that omega-3 fatty acid deficiencies are more prevalent in individuals with ADHD. The previous post describes the process of how omega-3's affect cell membrane integrity, which, in turn, can effect the passage of key chemical signaling agents such as dopamine (which has repeatedly been found to deficient in specific brain regions of ADHD individuals). The desaturase enzymes, which are products of the genes listed above are partly responsible for the process of omega-3 metabolism and incorporation into the cell membranes.



2. Different alleles (alternate forms of a gene) can result in slightly different forms of these enzymes, some of which are more efficient than others. In other words, enzymes coded for by one form of a gene are somewhat better at metabolizing omega-3's and incorporating them into cells than the "alternate" enzymes coded for from the "alternate" forms of the gene. As a result, small changes in the gene code in these aforementioned regions can indirectly affect the efficiency of omega-3-to-membrane incorporation.



3. Several studies have pointed to the the connection between alcohol and fatty acid metabolism in animal models of ADHD.



4. It also appears that an individual may be able to "recover" from some of the negative effects on cognition due to alcohol exposure by an increase in dietary omega-3's. This includes increasing maternal dietary levels of omega-3's during pregnancy (based on animal model studies).
   

To summarize the whole post (as well as the previous one), it appears that omega-3 fatty acid metabolism plays a major role in ADHD. This is thought to be at least in part to the effects of omega-3's on maintaining cell membrane structure and integrity and their effects on regulating levels of the brain signaling agent dopamine (which is a crucial neurotransmitter and is often deficient in ADHD cases). However, properly functioning enzymes are required for these steps. Desaturase enzymes are coded for by a genetically "hot" region for ADHD on the 11th chromosome in humans. Different versions of these genes can result in a reduction in enzyme function and potentially affect the way these omega-3's are metabolized. In mammals, alcohol exposure can also lead to reduced desaturase enzyme activity. Additionally, there is at least some evidence that alcohol can increase the likelihood of specific forms of FADS1 gene giving rise to ADHD. This may be due to the two factors combining to reduce desaturase enzyme activity to a point where omega-3 metabolism falls past a hypothetical "break-point" resulting in a sharp increase in the onset of ADHD and other related disorders.

We have been focusing heavily on the ADHD and alcoholism connection for the past couple of weeks. We will be investigating a few more studies on this connection in the upcoming posts.

Does Lead Exposure Cause ADHD?

Many of these findings were based off of an original journal article regarding prenatal tobacco and lead exposure and the onset of ADHD by Braun and coworkers in the December 2006 issue of the journal Environmental Health Perspectives. For a quick synopsis of this article on lead and ADHD, please click here. Interestingly, this same group also published more recent papers on the effects of lead on conduct disorders, which are often comorbid to ADHD cases. This should be especially relevant for pregnant or nursing mothers. For more information on ADHD and pregnancy, please check out the collection of posts on this blog addressing the topic, which can be found here.

While the relevance of several studies regarding the effects of lead on ADHD and cognitive dysfunction is called into question, often because the lead-levels reflect a much higher exposure than what is often faced by the general population, a relatively large study done recently indicates that even moderately high blood lead levels show a strong correlation with ADHD. This suggests either one of two things:

• Other unknown or "hidden" factors were present in the lead-based studies which were the major contributors to impaired mental function and disorders such as ADHD. Even with lower lead levels, these under riding factors were still present, and therefore the major contributing causes to the disorder were still present.

OR

• The sensitivity to lead exposure in children is even higher than previously thought.

An important question we should be asking ourselves is "Does lead exposure beyond a certain point trigger specific ADHD symptoms, or is there an increase in ADHD behavior across the board?".

ADHD is often defined by two major components, the hyperactive/impulsive component and the inattentive component. Based on a recent publication by Nigg and coworkers in the February 2008 Journal of Biological Psychiatry, it appears that the hyperactive/impulsive component of ADHD predominates based on exposure to lead.

Interestingly, the children investigated in the study above were of the inattentive subtype or the combined subtype (both inattentive and hyperactive/impulsive) of ADHD. Based on these results, it is my personal opinion that a child who, under other circumstances may otherwise be of the ADHD inattentive subtype, could instead fall into the ADHD Combined Subtype if he/she is exposed to a specific quantity of lead during the prenatal or early childhood stages of development. Furthermore, I propose that, had the individuals in the study have been of the predominantly Hyperactive/Impulsive Subtype of ADHD, the results would have shown that lead exposure beyond a critical thresh hold would have exacerbated the already-negative hyperactive behaviors for this particular subtype.

In addition to the negative effects surrounding the hyperactive elements of ADHD, the study also found a correlation between low-level lead exposure and child IQ's. This, of course, has been a hotly debated topic for years. While other factors may clearly be at work (lead exposure is often higher in areas with lower socioeconomic status, which is also a factor often correlated with lower IQ scores), the results of numerous studies, many of them recent, still support a strong possible connection.

Theoretically, then, by significantly reducing the prenatal or early-developmental exposure to lead, a child may be at least partially shielded from negative symptoms such as a lower IQ and hyperactive behavior. However, for individuals with the predominantly inattentive form of ADHD, these lead-restrictive measures would be less effective in addressing their inattentive behaviors. Therefore, it is my opinion that reducing lead exposure due to prenatal intervention, iron therapy, or, even possibly chelation methods (both of which will be discussed in future posts), would be most effective for treating the Hyperactive/Impulsive and Combined subtypes of ADHD and less effective for the Predominantly Inattentive ADHD Subtype.

While we should be careful not to overplay or overhype the lead/ADHD connection (especially given the fact that overall lead exposure risks have gone down throughout most of the world in recent years due to the uses of unleaded gasoline and lead-based paint, among other things), it is important to recognize that there is still a statistically significant connection between the two, at least according to a number of recent studies. The Nigg paper, mentioned above, found a strong correlation with hyperactive ADHD-like behavior at much lower lead levels (much closer to the average levels found in much of the United States) than those in most previous studies. This information is particularly important to pregnant mothers, since it has been demonstrated that the negative effects of lead, and other heavy metals and toxins are more harmful on developing brains and nervous systems than to mature ones. The protective effects of reducing lead exposure to mitigate the negative symptoms of ADHD, should not, in this blogger's opinion, be overlooked.

In the next post, we will be discussing how treatment or supplementation with iron may be able to offset some of these harmful effects of early lead exposure on ADHD, should they occur.

Iodine deficiency or ADHD?

We have alluded to the fact in previous posts that ADHD symptoms can sometimes either be triggered or mimicked by nutrient deficiencies. If this is the case, then we can argue that by increasing the levels of these nutrients via food intake or supplements could ameliorate some of the negative features of the disorder.

While vitamin, mineral, protein and omega 3 fatty acid deficiencies often steal the spotlight for dietary intervention strategies for ADHD, there is another, less-heralded connection and treatment that deserves considerable attention. According to multiple journal articles, reviews and studies, there appears to be a correlation between an iodine deficiency and an increased likelihood of developing ADHD.

One such study on ADHD and iodine was published in the Journal of Endocrinology and Metabolism in 2004 by Vermiglio and coworkers. This study found that mothers who were iodine deficient were more likely to give birth to children with ADHD. While numerous nutritional deficiencies are often predominantly linked to Third World countries, Iodine deficiencies are surprisingly common in industrialized nations. Although little attention is often paid to this topic, the results of an iodine deficiency can be quite severe.

Since the thyroid gland and the hormones it secretes are heavily dependent on this key nutrient, low levels of iodine can lead to problems such as poor circulation and body temperature regulation, reduced energy levels, inhibited brain development and dysfunction, improper calcium levels in the blood and bones, and impaired immune function.

In a nutshell, the study examined the rates of ADHD in children who lived in 2 different regions, a relatively Iodine-rich region (where iodine deficiencies were more commonplace) and and Iodin-poor region. The 10-year study, which had a relatively small sample size, found that the rates of ADHD born to mothers at risk for facing an iodine deficiency was significantly higher than the rates of those born to mothers in a more iodine-sufficient environment. Furthermore, IQ scores were statistically lower in the low-iodine group.

We need to be careful not to lump ADHD into a general category of cognitive decline. After all, a very large percentage of individuals with the disorder are of average or above-average intelligence.

The overall mechanism of low iodine and the onset of ADHD is not completely clear, but there is a known correlation between low hormone levels (those secreted by the thyroid gland) and ADHD. Other studies, including one in the New England Journal of Medicine, have shown that individuals with a built-in resistance to thyroid hormones have higher incidences of ADHD. Individuals with a specific genetic mutation to the thyroid receptor-beta gene, are resistant to specific thyroid hormones and have roughly 3 times the risk of developing ADHD than the general population.

In the low iodine study, it appears that there was a bias towards hyperactive and impulsive behavior (as opposed to inattentive behavior), but with the small sample size used in the study, we should not put too much weight into this possible connection. Nevertheless, it is at least worth mentioning. Additionally, abnormal weight gain can also be a sign of an iodine deficiency, so an unexplained increase in weight accompanied by an increase in ADHD symptom severity may be due to an iodine deficiency and thyroid dysfunction.

Simple clinical tests can be done to determine whether an individual is iodine deficient and/or has thyroid dysfunction. One of the most common measuring devices is testing for the levels of TSH or Thyroid Stimulating Hormone. If an individual has underactive thyroid function (such as that caused by insufficient iodine intake), then the body tries to compensate for this by boosting thyroid function through increasing levels of TSH. Therefore, high levels of TSH correlate with an abnormally low thyroid function. Not surprisingly, in the pregnancy study on ADHD and iodine deficiency, mothers of ADHD children typically had elevated levels of TSH.

So how do we boost dietary iodine levels quickly and efficiently (the recommended daily amount is 150 micrograms, if that number means anything to you!)? One of the easiest ways is to replace common refined table salt with either iodized salt, or iodine-rich sea salt. Ocean fish and seaweed are also good bets as iodine-rich food sources.

One particularly good piece of information is that the developing fetus is surprisingly resilient to early stages of iodine deficiency in the mother if the iodine deficiency is corrected before the third trimester of pregnancy. Since the effects of an iodine deficient diet can be severe to both mother and child, I highly recommend pregnant mothers to switch to iodized salts or sea salt during the pregnant and nursing stages. This simple practice can significantly reduce the risk of ADHD and cognitive dysfunction in their child's future.

Do ADHD Medications Cause Birth Defects?

ADHD Medications and Pregnancy

Do ADHD Medications Cause Birth Defects?

Due to the impulsive tendencies of adults with ADHD (currently thought to be as high as 4% of the general adult population), one would expect higher rates of unplanned pregnancies among this subgroup of the adult population. This is, in fact, often the case. As a result, it is worth investigating whether women with ADHD, who are often on medications are posing hazardous risks to their babies by taking these drugs during pregnancy. Although this area of ADHD medications and birth defects has not been studied extensively, here are some following observations and guidelines to go by:

Since some of the most common primary forms of ADHD medications are amphetamine-based stimulant drugs (such as Adderall), it is necessary to mention the fact that amphetamine usage during pregnancy has been shown to correlate with a reduction in birth weights of these children. However, other factors of growth, such as head size or birth length were unchanged, and the birth weight reduction amounts were often significantly less than a pound compared to newborns of non-users of amphetamines (or less than a 5% difference on average). Another relatively large study done primarily on the stimulant dextroamphetamine (Dexedrine), showed no significant difference in birth weights or the prevalence of birth defects.

For medications such as methylphenidate (Ritalin, Concerta), which is not an amphetamine but rather and amphetamine-like stimulant, no significant evidence has shown any connection to birth defects or lower birth weights. However, one study in which the mothers had taken methylphenidate alongside alcohol, cigarettes and other drugs showed higher rates of birth defects, mental impairments and reductions in birth sizes. However, this study had no adequate group of controls, so the effects of the ADHD drug itself could not be determined. Nevertheless, we must leave room for the possibility that this type of stimulant may worsen birth defects triggered by other maternal patterns of substance abuse.

Some other ADHD medications have not been explored in depth in human mothers, but have been investigated in other mammals. For example, in a study done on the non-stimulant ADHD medication Atomoxetine (Strattera) in pregnant rats, it was shown that weight reduction, impaired bone development, and lower offspring survival rates were tied to high levels of this drug. Of course, this was done on a different mammalian system at doses up to 30 times higher than the recommended optimal levels for humans (on a pound-for-pound basis). An even higher relative dose done on rabbits was shown to interfere with development of the circulatory system with the offspring. However, these levels were shown to be significantly over the relative toxic level of the drug in humans.

As a quick side note, I should mention that a small fraction of the population carries an uncommon form of the genetic region CYP 2D6, which, among other things, is connected to the metabolism or breakdown of the Atomoxetine drug. Individuals with this rare form (which can be determined by genetic screens), may be somewhat more at risk than their counterparts. However, individuals with this genetic form would often exhibit adverse effects to the medication early on, and would likely be placed on a different medicated treatment option.

Based on the overall dearth of information involving ADHD medications and pregnancy, we cannot arrive at any definite conclusions about their relative safety in pregnant or nursing mothers. However, if the connection between these medications and birth defects was significant, the results of some of the aforementioned studies would likely have been much more foreboding. As a result, the use of controlled and prescribed medications at appropriate doses are unlikely to pose any sort of major threat in pregnant or nursing mothers. Nevertheless, certain drugs, although much less common as primary modes of treatment for ADHD can be utilized if potential pregnancy or birth defects are a concern.

Medications such as Bupropion (Wellbutrin), have been shown to be useful in treating some forms of ADHD and may be especially effective for individuals who also suffer from depression or those who want to quit smoking. Unfortunately, one of the negative side effects of this medication is that it can increase the risk of seizures (for more information on ADHD and seizures, please check out this earlier post). Nevertheless, aside from some of these potential risks, it appears that Bupropion poses a noticeably smaller role than most stimulants in triggering birth defects.

Additionally, the drug Clonidine, which has shown to be effective in treating ADHD in several cases (especially those cases in which an ADHD comorbid disorder such as Tourette's Syndrome), is also less likely to cause birth defects than stimulants. Clonidine, which also goes by the brand names Catapres and Dixarit, is also used as a treatment for hypertension and can also be used in conjunction with stimulant medications to treat ADHD individuals. This is often done because of the sedative effects of the drug, which, when administered strategically before bedtime, can help calm things down a bit by offsetting the stimulant effects of other ADHD medications. One major caveat with Clonidine, however, is that sudden withdrawal or discontinuation of the drug can cause a rapid and dangerous spike in blood pressure. If Clonidine is to be discontinued, the individual must be gradually weaned off the drug to avoid these negative and harmful side effects.

It is my hope that some of this information will serve as good news to pregnant or soon-to-be pregnant individuals with ADHD. While the information contained here should never be a substitute for personal medical advice, I want you to leave with the fact that, at least as of now, the overall risks of birth defects or complications remain relatively low for most ADHD drugs. This is especially true when other non-prescribed chemical substances are avoided.

ADHD medications and Pregnancy