Nicotine Withdrawal Effects Differ in ADHD Individuals

There is a relatively strong connection between ADHD and drug abuse, with nicotine being one of the most common types of "self-medication". It is believed that ADHD and nicotine addiction share similar neural pathways, although there still remains a fair amount of debate as to the exact underlying mechanisms at work between the two conditions.

One topic of equal intrigue may be the relative effects of withdrawal from nicotine in ADHD vs. non-ADHD individuals. If smoking and ADHD do share overlapping neural pathways, then we might expect that cessation of smoking may have different effects between people with and without ADHD. According to a recent study by Kollins and coworkers on ADHD and smoking abstinence, individuals with ADHD have a much wider array of behaviors with regards to reaction times to specific stimuli and cognitive processing. In other words, smokers with ADHD who temporarily give up nicotine have a greater variety (and hence less predictability) with regards to concentration-related tasks than do non-ADHD smokers. A more detailed explanation of this study follows:

• Giving up cigarettes and other forms of nicotine has a wide range of negative effects such as working memory, attention, and the ability to control or inhibit ones' responses. However, these effect typically subside when one resumes original smoking behaviors. As a result, based on the negative side effects due to decreased cognitive function, quitting smoking can result in a number of disadvantages with regards to brain function.

• Many previous studies have shown that individuals with ADHD are more prone to some of these disadvantages, especially with regards to slower reaction times to external stimuli when abstaining from smoking. This may be one of many reasons why smoking is more popular among individuals with ADHD than within the general population.
  


• For example, using a special computerized test called Conners Continuous Performance Test, to test for reaction time, comparison studies were done between ADHD and non-ADHD smokers under conditions where they were allowed to smoke and conditions where they were required to abstain from smoking (typically starting the previous night before the morning Continuous Performance Test. Briefly, the test consists of pressing a specific key on a computer keyboard when any letter (except for "X") flashes on the computer screen continuously for a period of approximately 15 minutes. If the letter "X" were to appear on the screen, the test subjects were instructed not to press any keys on the keyboard. Reaction times and accuracies were based on these behaviors.

• However, based on the study by Kollins and coworkers on smoking abstinence and ADHD, there is a relatively significant amount of evidence that the above point may not entirely be true. Based on the results of their study, Kollins and coworkers suggest that the average impairment with regards to reaction times during smoking cessation may actually be less for most ADHD smokers when compared to non-ADHD smokers. For example, when deprived of smoking, the reaction time of highest frequency for ADHD smokers was somewhere around 0.3 seconds, while the non-ADHD group was slightly slower (but still significant and measurable), hovering around 0.35 seconds. However, the ADHD group is also more likely to have a few individuals who are prone to lengthy delays in reaction times (as in multiple seconds). Kollins instead attributes this to attention lapses in which the individuals concentration was broken. In other words, it appears that while the majority of individuals with ADHD smokers may actually have faster reaction times than non-ADHD smokers, ADHD smokers have more extreme cases of reaction time delays due to attentional lapses, especially when deprived of nicotine. Therefore, by separating out the "common" cases from the more "extreme" cases in their study, Kollins and coworkers may have uncovered this underlying trend.

• There are several possible causes for these potential attentional lapses due to smoking withdrawal. One may stem from a brain region called the cingulate gyrus, whose approximate location is shown below (region #7, for orignal file source, click here) on the diagram.
  

The actual area is a specific subsection of this region, but we will not go into the detail here. This region, the cingulate gyrus (#7), is in some ways analogous to a gear shifter in a car. If this brain region is underactive (think of a loose gear shifter), then an individual often bounces around from one thought, idea or focus to the next, which is a common characteristic of ADHD. Lapses in attention have been attributed to subsections of this cingulate region. On the other hand, generalized overactivity in this brain region often leads to excessive fixation on a particular topic, idea or behavior (think of it as pushing too hard on a gear shift and getting stuck in a gear). This latter condition is often seen in dysfunctions such as obsessive compulsive disorder (OCD). With regards to our topic of discussion, Kollins suggests that this brain region may be the culprit for increased attentional lapses in ADHD smokers.

• Kollins and coworkers also found that when the smokers are "satiated" (i.e. allowed to smoke their desired amounts leading up to the reaction-time test), the ADHD smoking group also had relatively faster reaction times when compared to the non-ADHD smoking group. The ADHD smoking group also had a greater variability in reaction times (i.e. more "extreme cases" or extra-long response times) during satiated conditions, but the differences in variation between these "extreme" cases of ADHD and non-ADHD groups' reaction times were less pronounced than during the nicotine abstinence trials.
  

• Finally, it may seem strange that the majority of ADHD smokers appeared to have faster reaction times both with and without smoking. What is even more interesting is that in the nicotine-deprived state, most of the ADHD smokers actually showed a slightly faster reaction time than in the nicotine-satiated state (although the extreme cases of multi-second attention lapses were also greater). One potential explanation of this may be due to the increase in impulsive behaviors, where the individuals attempted to "guess" or predict when the designated letter flashed on the screen (see the previous point about the nature of the Conners Continuous Performance Test). This would be in agreement with fact that nicotine, which is a stimulant and a common form of "self-medication", may help curb impulsive behaviors in ADHD individuals.

• A final take-home message from this study is that it highlights a relatively common and important trend which we must often consider when dealing with ADHD: studies of ADHD groups which deal with response or reaction times have shown data which is more skewed with a higher variability (and hence a lower predictability) than comparative non-ADHD groups. If study sample numbers are small, these highly variable measurements can sometimes throw off the data and lead researchers to the wrong conclusions. In other words, when doing comparative studies between ADHD and non-ADHD individuals, we must be careful to consider these higher degrees of variability and unpredictability in the ADHD groups and factor these in to our calculations and conclusions accordingly. I will be touching on other cases where we see this significantly greater levels of variability and unpredictability in ADHD in future posts.

Does ADHD improve your sense of smell?

Due to a high degree of overlap in symptoms with other disorders, finding accurate ways of differentiating ADHD is of utmost importance. Based on a recent study by Romanos and coworkers, it appears that individuals with ADHD may be able to "sniff out" their disorder. In a publication on Improved Odor Sensitivity in ADHD, Romanos and others found that children with ADHD had significantly better sensitivity for particular odors when compared to their non-ADHD peers. In other words, children with ADHD may be able to better detect minute or trace levels of certain smells when compared to other children. As an interesting aside, the study noted that boys actually had a slight advantage as far as odor detection when compared to girls (which goes against many other study findings which indicate that females have better senses of smell).

However, when these children were investigated in two other "smell" categories, which included discrimination between different smells, and the actual identification of particular agents causing the smell, they should no advantages over their non-ADHD peers. Similar studies have also been done on adults with ADHD, and have shown little to no effect between ADHD and sense of smell. These findings seem to agree with another recent report on olfactory impairments in children with ADHD. This study found that children with ADHD were worse at identifying the nature of particular odors than non-ADHD children. It appears that these deficits are tied to a specific brain region called the orbitofrontal region, the outer section which is approximated by the green region in the diagram below (original file source can be found here). Note that this region has numerous implications with regards to the disorder of ADHD.

To throw another wrinkle into the mix, it appears that stimulant medication treatments for ADHD may negate these olfactory advantages (with regards to the increased ability of ADHD children to detect minute levels of odors better than their peers). The Romanos study also investigated another group of similar age and gendered individuals with ADHD who were on the medication methylphenidate (Ritalin, Concerta, Daytrana, etc.). Like the non-medicated ADHD children, this group all had the combined subtype of ADHD (meaning that both hyperactive/impulsive as well as inattentive symptoms were present to a large extent). They found that the medicated children did not have the improved smell sensitivity that their non-medicated ADHD peers did, but rather had an odor detectability level similar to that of the non-ADHD group. In other words, it appeared that methylphenidate (as well as other ADHD stimulant medications, potentially), may offset any improvements in smell detection in ADHD individuals.

It is believed that the dopamine system and pathways play a critical role in smell differences between ADHD children and their peers. Keep in mind that methylphenidate and most other stimulants for ADHD work by increasing the concentration of the neurotransmitter dopamine in the areas between neuronal cells, by reducing the transport of this important brain chemical into the cells themselves (individuals with ADHD often have an imbalance between the dopamine levels inside and outside of these neurons, and often have insufficient dopamine levels in the surrounding areas outside the neuron cells). Dopamine levels have been shown to have a protective effect on olfactory neurons (neurons related to smell). Chemical alterations of dopamine levels, such as those introduced by methylphenidate or other ADHD stimulants may therefore interfere with odor sensitivities in key regions of smell such as the olfactory bulb region of the brain.

On a final note, the findings by Romanos and coworkers are of potential interest because of the fact that many neuropsychiatric disorders are accompanied by a sharp decrease in odor detection and sense of smell. These include Parkinson's Disease, obsessive-compulsive disorder (OCD), schizophrenia, autism, and depression. Because of this, it may be possible to use odor sensitivity tests to help differentiate between ADHD and other neuropsychiatric disorders, at least in children. Although we have seen that there is some conflicting evidence surrounding studies, it appears that we could, at least in theory, administer some type of smell test of trace levels of specific odorous chemical agents that are undetectable to the majority of the child population and see whether the potential ADHD candidate could detect these minute traces. Furthermore, it would be interesting to see whether other stimulant medications besides methylphenidate have the same effects on curbing the increased odor sensitivities exhibited in ADHD children.

Do ADHD Stimulant Drugs Stunt Growth?

Here are seven questions or factors we need to address to assess the validity of studies on ADHD stimulant medications and their effects on growth:

1. Is there a history of prior stimulant medication use? Surprisingly, a number of studies on the inhibitory effects of ADHD stimulant medications either neglect or downplay the fact that children in their studies had a previous history of stimulant medication usage for their conditions. This can seriously confound effects, for if a child was taking a stimulant medication previously, he or she may still be on track for a lower baseline growth rate. Furthermore, if a child was taken off stimulant medications recently, there remains the possibility that his or her system is beginning to play "catch-up" by displaying a greater-than-normal increase in growth following a medication "holiday". In either case, baseline readings are skewed, and these effects muddy the accuracy of current stimulant medication studies on growth effects. Poulton and Nanan make this observation in their article on prior treatments with stimulant medication and growth in children with ADHD. They go on to say that growth is an accurate indicator of prior treatment with stimulant medication.
   
   
2. Beware of the pretreatment bias with regards to effectiveness of stimulant medications: Poulton and Nanan also warned about the natural bias of individuals with a previous treatment history of stimulants in that they have already proven to have a greater tolerance to potential side effects (otherwise they would have likely discontinued earlier stimulant treatments) and an overall higher levels of compliance and positive response to stimulant medications. This too, can give a potential "false positive" with regards to evaluating the effectiveness of current stimulant medication treatments for ADHD.
   
   
3. Do untreated children and adolescents with ADHD have different growth patterns than non-affected children? This is also a much-neglected consideration. Spencer and coworkers performed a study in which they saw a slower growth rate in the earlier years for children with ADHD, which was followed by a significantly later "catch" up period. In other words, compared to non-ADHD children, individuals with ADHD may be more predisposed to being "late bloomers", even when they are unmedicated. This potential difference in growth patterns between ADHD'ers and non-ADHD'ers, while still highly debatable, should at least raise the question as to whether delays in growth patterns for medicated individuals with ADHD can actually be attributed to the medications or to the nature of the disorder itself (or a combination of both).
   
   
4. Do "drug holidays" work? This is actually comprised of several questions and considerations. It is not uncommon for parents or prescribing physicians to allow for "drug holidays" for unmedicated ADHD children. These holidays can vary from a few days to longer periods such as an entire summer vacation. If the period of these drug holidays is long enough, such as in a summer-long study by Gittleman-Klein and coworkers on methylphenidate and growth, significant changes may be seen. This study saw a relative increase in weight but not in height following a summer off of medication of the stimulant methylphenidate (Ritalin). Of potential interest was the observation that following a second holiday from medication the following summer, a relative increase in height but not in weight was observed. It is entirely possible that the duration and frequency of drug holidays may effect the two parameters (height and weight) in slightly different fashions. Another article by Poulton suggests the possibility that height gains may take longer to remedy because gains in weight may drive subsequent growth in height.
   
   
5. Does the type of stimulant medication make a difference? In a preliminary sense, it appears that the answer would be "yes". For example, it appears that the stimulant drug dexamphetamine (d-amphetamine, also called by common name Dexedrine) has a greater inhibitory effect on growth during the first year of treatment than does methylphenidate (Ritalin, Concerta, Daytrana).
   
   
6. What is the typical extent of growth impairments due to stimulant medications? We need to be careful on this one, especially with regards to some of the earlier factors and considerations mentioned above. Nevertheless, a review of the literature seems to indicate a relative deficit in growth of around 1 cm per year for up to about 3 years which can be attributed to stimulant medication treatment. Furthermore, it appears that weight may be even more affected than height due to stimulant medication treatment, although it also appears that weight differences are easier to remediate than height differences and therefore pose less of a concern.
   
   
7. Are the growth changes due to stimulant medication temporary or permanent? Although hotly debatable, it appears that growth impairments due to prescribed stimulant medication usage is more of a short-term effect. A follow-up study of medicated ADHD children into adulthood indicated that even at moderately-high doses of the stimulant medication methylphenidate (45 mg/day average), medicated children with ADHD eventually reached normal final heights when compared to controls. It is worth mentioning, however, that these children eventually discontinued their medications. It is unclear as to what the effects may have been had they continued on with the methylphenidate usage into adulthood (especially since there has been a sharp trend towards continuing stimulant medication treatment into adulthood for adult ADHD).

Ritalin vs. Cocaine: Addiction Potential of Methylphenidate

If you were to read the opening couple of pages of most natural or alternative treatment books on ADHD, you would likely find some version of the following argument: "Ritalin is chemically similar to cocaine and amphetamines and studies have shown it has a high addiction potential". There actually is a fair amount of truth to that statement, but the latter half leaves out some equally important information concerning the nature of these studies.

This post is not meant to be a pro-stimulant drug message, I certainly do see some apparent risks for many ADHD medications, especially concerning young children and their developing nervous systems. However, I also feel that we should carefully examine the nature of many of these "anti-methylphenidate" studies and evaluate the relevancy of their findings. To facilitate this discussion, I have taken data from a serious of research articles on the topic of habit-forming potentials of methylphenidate (Ritalin, Concerta, Daytrana, etc.) and have attempted to box together some of the overlapping information with relevant conclusions that are, to the best of my ability, as unbiased as possible. Here are some key points worth noting:

• Chemical similarity to cocaine and amphetamines. The chemical structure of methylphenidate is given below. As a comparison, the structure of methamphetamine is also given. I realize that the majority of readers here are not organic chemists, so I have highlighted the similar regions of the two molecules (which is a relatively big overlap as far as chemical structure and function is concerned). The purple/red regions below highlight chemically similar regions between the two drugs, while the green/blue areas show chemical differences. For brevity and simplicity, I have not included the structure of cocaine, because there are fewer obvious similarities between the chemical structures of methylphenidate and cocaine. Just realize that there are chemical and functional similarities between the two drugs.

• A huge factor in a drug's addiction potential rests on how fast the drug can both enter and leave the brain. In short, the faster the entry and the faster the clearance of the drug from the brain, the greater the "high" and the greater the addiction potential. We have seen this before in earlier posts, such as the one on Vyvanse for ADHD treatment. The chart below summarizes some of the key comparisons between methylphenidate and cocaine (most of the data comes from studies by Volkow and coworkers on brain entry and clearance times of cocaine vs. methylphenidate:

We can see from the chart above that cocaine and methylphenidate show similarly quick routes of entry into the brain when administered intravenously (note that this is not the typical route for taking methylphenidate for ADHD patients). However, note that the clearance time from the brain is significantly longer for methylphenidate than cocaine (half-life is a common measuring tool, which refers to the amount of time it takes for half the drug to clear the system). Also note that when methylphenidate is taken in the appropriate manner (orally), the time to arrive at a peak concentration (based on a mammalian model) is significantly longer as well. Both the longer clearance time and times to peak concentrations play a crucial role in reducing the involved "high" and addiction potential for methylphenidate, when compared to drugs such as methamphetamines and cocaine.

• The type of methylphenidate administered may also play a role in the addiction potential. There is a general trend towards prescribing longer-lasting sustained release versions of methylphenidate over the original immediate-release version (although cost is also a factor, with the longer-release versions typically carrying a higher price tag). At the 20 and 40 mg levels, one study showed that the immediate-release version of methylphenidate produced a higher degree of addictive level effects than the longer-release version, although this was based on more qualitative subjective measurements than hard, concrete numerical data.

• On somewhat of an interesting note, it appears that the reinforcing effects of methylphenidate may be much more pronounced in the case of sleep deprivation. One study indicated that methylphenidate only produced reinforcing effects when study participants were limited to 4 hours of sleep the previous night. Given the fact that sleep problems and disturbances are remarkably common in individuals with ADHD, this may actually lend a fair amount of support to potential for abuse among ADHD individuals. However, I personally believe that, based on the other points regarding individuals with ADHD, this population is still relatively "safe" from stimulant medication abuse when the medication is administered and taken in a proper manner.

• We have spoken extensively on the role of Dopamine Transporter (DAT) proteins and their role on governing levels of dopamine, a key neuro-signaling agent which is thought to be critically involved with regards to the onset and symptoms of ADHD. In short, DAT proteins are responsible for shuttling dopamine into and out of neuronal cells and maintaining an overall balance of this important chemical. Individuals with ADHD are thought to have more of these DAT proteins in their brain systems, which results in lower levels of dopamine in the areas between nerve cells, a phenomena which is commonly seen in cases of ADHD and related disorders. DAT proteins are therefore common targets of many ADHD stimulant drugs, which typically act by binding to these DAT proteins and reduce their shuttling effects, which, in turn, helps restore higher dopamine levels in these key regions between nerve cells. It is hypothesized that drugs, even at low doses (such as 20 mg methylphenidate) which bind to and saturate these DAT proteins may contribute to some of the "high" associated with these drugs. However, other findings have contradicted this, with regards to the role of the DAT proteins on "highs" associated with stimulant medications such as methylphenidate.

• Finally, in what may be the most important piece of the puzzle with regards to addictions and ADHD stimulant medications, there was a review done by Kollins which examined the nature of pre-existing studies on the abuse potential of methylphenidate. Kollins noted that a large number of the studies which suggested high addiction potentials for methylphenidate and related subjects gathered their data from non-ADHD individuals. This is important to note, especially considering some of the aforementioned differences between ADHD individuals and non-ADHD individuals with regards to chemical balances (such as the dopamine levels) and hard-wiring issues (such as a higher density of Dopamine Transporter Proteins or DAT's in individuals with ADHD). While this should not be grounds for immediate dismissal of these findings, the lack of studies on actual ADHD patients should raise some serious questions as to whether methylphenidate deserves its "guilty" label with regards to addiction potential. Of course, these studies provide ample evidence to support the assertion that ADHD medications such as methylphenidate can be abused if they are taken by the wrong individuals (non-ADHD patients, such as healthy individuals with few to no signs of ADHD as well as generalized drug abusers), but there appears to be an overall lack of evidence to support the claim that needy patients who do suffer from ADHD will turn into stimulant abusers if they begin to take methylphenidate at prescription-based levels.

• Kollins does conclude with some more relevant (at least in this blogger's opinion) concerns surrounding the use of methylphenidate for ADHD. He questions the impact of methylphenidate and related drugs with regards to:

1. Their impact on brain development, especially in young children (a topic in which there is still relatively little conclusive data available).
2. How dopamine level changes due to these medications may alter the dopamine system, including the levels of dopamine transporter proteins (DAT proteins).
3. The role of early stimulant exposure on latter stimulant abuse (although Kollins notes that early treatment with appropriate stimulants may actually have a protective effect against latter stimulant abuse).

For the most part, I am in agreement with this line of thinking. It is my opinion that we should shift our focus away from the fears of addiction potentials with regards to stimulant medications taken via appropriate doses and methods for ADHD and related disorders, and instead shift our attentions to the effects of these substances on the developing nervous systems of young children. We have seen that methylphenidate has several built-in safety measures with regards to reducing its abuse potential. Furthermore, I personally believe that there are much greater potential risks of stimulant medications with regards to their effects on the critical early neural developmental stages (such as those in the first 5 years of life) than to overall addiction potentials of these substances, and that our research focuses with regards to overall safety of these medications should shift in this direction.

Genes and Low Birth Weight Combine to Increase Risk of Conduct Problems Alongside ADHD

In the past, we have investigated the role of the COMT gene and its effects on the onset and severity of ADHD cases. Now it appears that this gene may play a role not only in the ADHD itself, but conduct or behavior disorders which often occur alongside (or are comorbid to) of ADHD.

Recall from earlier posts that COMT (which is short for Catechol O-Methyltransferase) refers to both a gene and an enzyme protein encoded by the gene, which is responsible for maintaining a balance of neurotransmitters such as dopamine in key regions of the brain. In essence, the COMT enzyme is responsible for breaking down levels of free dopamine in the prefrontal cortex region of the brain (the area highlighted in orange). Keep in mind that in another key brain region, called the striatum, another series of enzymes called the dopamine transporter (DAT) proteins play a greater regulatory role in maintaining dopamine levels. However, in the prefrontal cortex region of the brain (see area below), the COMT gene and COMT enzymes play a much greater role in regulating the balance of key neurotransmitters necessary for communication between brain cells.

The prefrontal cortex region of the brain is approximated by the area in orange in the figure above. Note that we are looking from the left side of the brain of an individual facing to his or her left. The numbering system refers to a subseries of brain regions from which this original figure was taken.

As a reference, the striatum region of the brain can be seen in the green areas of the figure below (original file source here):

Returning to our discussion on the COMT gene and the prefrontal cortex region of the brain, it is important to note that there are two main "flavors" of this gene and subsequent enzyme, the "Val" and the "Met" (I've mentioned previously in other posts what "Val" and "Met" stand for, but as a quick summary: "Val" is short for valine, and "Met" is short for methionine, both of which are common amino acids found in almost every protein in our bodies. However, these two amino acids exhibit slightly different biochemical properties, and a simple substitution of one for the other can actually result in significant changes as to how a protein functions. For the COMT enzyme, which is a special type of protein, the simple change from a "Val" to a "Met" or vice versa can actually dictate how efficient the whole enzyme becomes). COMT enzymes comprised of the "Val" form are actually 3-4 times more efficient at breaking down dopamine in key brain regions such as the prefrontal cortex, which results in overall lower levels of neurotransmitters such as dopamine.

Since individuals with ADHD are often deficient in free levels of dopamine in the prefontal cortex region of the brain, having the "Val" form of the COMT gene often poses a greater risk of exhibiting ADHD behavior. We have seen the effects of this Met/Val difference with regards to cognitive tasks and even the effects of these different gene forms on the onset of alcoholism-related ADHD symptoms. For example, on a post on gene variations and attentional control, we saw that individuals with the "Met" form of the gene (and enzyme) had improved attention-related control than those with the "Val" form.

With regards to conduct disorders comorbid to ADHD, it also appears that the lower dopamine levels associated with the "Val" forms of these enzymes is also a major determining factor in the childhood onset of anti-social behavior and conduct disorders. Furthermore, it appears that environmental factors and this "Val" form genetic factor can actually interact and combine, to increase the risk of an individual with ADHD in developing some sort of conduct problem to go alongside his or her ADHD symptoms.

Low birth weight, which has a number of implications for other disorders, was found to be a good indicator of childhood conduct problems appearing alongside of ADHD in its own right. It is believed that low birth weight is a good indicator of a poor prenatal environment, which is why so many disorders and developmental issues are often associated with low birth weights. Statistically, it was noted that children with low birth weights (less than 2.5 kilograms or 5.5 pounds) were at an increased risk of developing co-existing behavioral problems (conduct disorders) alongside of an ADHD diagnosis. As mentioned before, individuals who were unfortunate enough to have one or more copies of the "Val" version of the COMT gene plus a low birth weight, were statistically more likely to exhibit problems associated with conduct-related disorders.

As a quick reference to the severity of the effects of low birth weight and the "Val" version of the COMT gene, please consult the table below. This data was taken from an article by Thapar and coworkers on the effects of COMT genes and low birth weight on the onset of antisocial behavior in children with ADHD.

Notes on the table above: Relative Conduct Symptom Score refers to the severity of conduct problems which are given a numerical value (higher being more problems). I have assigned the first group a value of 1 as a reference. This refers to individuals who have at least one copy of the "Met" (which, in the cases of ADHD appears to be the "good") form of the COMT gene and enzyme, as well as a normal birth weight. As we can see from the table, having either a low birth weight or both copies of the "Val" (the "bad" form of the COMT gene with regards to ADHD) form resulted in a roughly 50% increase in symptoms of conduct or behavioral problems. However, for individuals who possessed both "Val" forms of the COMT gene and enzyme and had a low birth weight, we can see that conduct symptoms associated with ADHD shot up to over three times the original level. This at least suggests that while both genes and developmental environments can play a significant role in the onset of behavioral problems associated with ADHD, it is when these two factors are combined, that remarkable differences in symptoms begin to appear. In other words, strong gene-environment interactions are associated with antisocial behaviors in individuals with ADHD.

Keep in mind that these findings are somewhat inconclusive. Another research group performed a similar experiment, but was unable to replicate these findings which associated low birth weight and the "Val" form of the COMT genes to an increase in antisocial behavior in children with ADHD. Nevertheless, an additional study tied the presence of "Val" forms of the COMT gene to increased aggressiveness, conduct problems, and criminal behavior in individuals with ADHD. Although the information and conclusions from different studies on these topics remains controversial, the fact that the "Val" form of the COMT gene has been implicated in so many other deficits associated with ADHD, I believe that we should take notice of some of these recent findings.

The term conduct disorder itself has a relatively widespread range of meanings. With regards to ADHD and the content of this post, I consider conduct disorders to include behaviors such as oppositional behaviors towards parents, teachers and other authorities, negative peer interactions, pervasive negative attitudes and interactions towards peers and authorities, and, in more extreme cases, illegal substance abuse, cruelty to animals and other individuals, destruction of property, stealing, and other criminal behaviors (please not that the Thapar article highlighted more of the latter and more severe behaviors on the list when addressing the topic of conduct disorders). Of course, there is a fair degree of ambiguity and a wide range of severity in the behaviors from this list, but I think we can all begin to picture the difference between a child who is merely hyperactive, implulsive and inattentive versus one who has a pervasively antagonistic attitude and behavioral patterns to go along with the classic ADHD symptoms.

The unique thing about antisocial behaviors with regards to ADHD is that they appear to be more genetically heritable than generalized antisocial behaviors, and that ADHD-like hyperactivity can potentiate and worsen the severity of accompanying conduct problems. Furthermore, it appears that children may be much more susceptible to antisocial behaviors arising from damage to the prefrontal cortex than are adults. This article suggests that when two or more factors which each have notable effects on ADHD-related conduct problems or comorbid disorders, the combined effects of two or more of these factors can operate in a synergistic fashion. It is my opinion that many of these genetic and early developmental factors will take on an increasingly powerful role with regards to both the diagnosis and treatment of ADHD and accompanying comorbid disorders such as behavioral and conduct problems.