CREM Gene, Melatonin and ADHD

In the past, we have investigated several different ADHD genes, or genes that are believed to play some type of role in the disorder of ADHD. A recent article, titled CREM mutations and ADHD symptoms suggests that another specific gene, called CREM (short for Cyclic Adenosine Monophosphate Responsive Element Modulator), may actually play an integral role in the onset of ADHD and its symptoms as well.

Before we go any further, we must bear in mind that the journal in which this article is located is titled Medical Hypotheses. As the name suggests, we should be careful not to confuse hypothesis with thoroughly-investigated scientific data. However, the arguments are typically well laid out, and many of these hypotheses are in fact well-grounded based on a number of well-researched facts which point in their directions. In other words, a number of scientific studies or findings are often preceded by publications of these hypotheses, so we could very well be at the cusp of a new scientific discovery.

A second point worth mentioning is that the CREM mutation article is actually based on the mouse model. This in itself is not unusual, as numerous other studies on ADHD have used analogous murine models, such as the spontaneously hypertensive rat (SHR) model. Numerous comparison studies have supported the validity of SHR as a relevant and accurate model of ADHD in humans (although a few studies have disagreed, these disagreement studies are relatively small in number, however). Furthermore, based on the high degree of similarity between the DNA sequences in the human and mouse CREM genes, there is also a potentially high degree of functional overlap between the two. As a result, it is highly possible that CREM gene findings in the mouse may carry over well into CREM gene studies in humans. Additionally, mice with mutations in the CREM gene have been shown to exhibit ADHD-like behaviors.

Location of the CREM gene:
If you are not familiar with human genetics, the human genome typically has 23 different chromosomes (which come in pairs, so 46 chromosomes total), which are numbered 1 through 23. Scattered out through these 23 different chromosomes are some 30,000 to 50, 000 total different genes (the number is constantly in debate, but this is typically a good estimate), which means that the average chromosome will typically carry between 1,000 to 2,000 different genes on it. Further numbering and lettering schemes denote more specific locations of these genes on the chromosomes. In humans the CREM gene is located on the 10th chromosome. For a more detailed look at the specific location of the CREM gene, please click here.

The association between CREM function and ADHD:
The CREM gene is believed to play a significant role in regulating the secretion of the hormone melatonin throughout the day. Melatonin, which is chemically similar to another key hormonal and neuro-signaling agent serotonin (serotonin actually converts to melatonin in the body), plays a number of roles, such as the regulation of sleep patterns. Melatonin is typically secreted by a specific gland called the pineal gland. For most individuals, lower levels of melatonin are produced during daylight, while higher levels are produced during darkness, which leads to the feeling of sleepiness. Furthermore, emotional states such as chronic stress can also effect melatonin production and secretion.

The CREM gene is believed to exhibit a controlling mechanism on the melatonin secretion patterns throughout the daily process. However, mutations or deletions (i.e. removal) of the CREM gene can result in a number of changes, such as different melatonin secretion patterns and excessive movement (locomotion) and activity at night. In other words, day/night differentiation is typically reduced if mutant or lower-functioning forms of the CREM gene are present.

The connection to ADHD:
Numerous findings suggest that individuals with ADHD are prone to differences in genes which regulate key chemicals in the neurosignaling process (as well as their receptors, or biological targets to which they bind). These include serotonin, dopamine and norepinephrine. Melatonin levels are also typically different in individuals with ADHD, and these ADHD individuals are more prone to daytime sleepiness due to oversecretion of melatonin. Furthermore, several studies indicate that individuals with ADHD are more prone to sleep disorders and abnormal sleep patterns in general, although a number of other studies have indicated conflicting results to this assertion. As a result, the melatonin regulating activities of CREM may be at work as underlying factors to these melatonin-related sleep disorders.

The role of ADHD medications on regulating melatonin levels:
Abnormal melatonin levels (caused by CREM mutations or other factors) may be able to be offset by common ADHD medications. For example, methylphenidate (Ritalin, Concerta, Daytrana), has been implicated as a potential agent in correcting sleep disorders in children with ADHD. This is somewhat interesting, because it contradicts numerous other findings in which stimulant medications have been shown to interfere with sleep.

**Blogger's note: While there are a number of studies regarding impaired sleep quality due to ADHD stimulant medication, we must remember that strategic timing and lower dosing of stimulant medications can significantly reduce the number of sleep-impairments. Most of the sleep problems, at least in my opinion based on personal experiences, are due to the administration of medication doses which are too high and given too late in the day. Although outnumbered with regards to the current number of publications for or against it, I personally side with the assessment that methylphenidate, when administered at the proper dose and the proper time for real ADHD cases, is actually beneficial for promoting and regulating sleep patterns. Again, I want to reiterate that this is simply my opinion based on personal observations and research.

The CREM mutations and ADHD symptoms authors referred to a small study they did on the effects of methylphenidate on lowering melatonin levels. Based on these (extremely limited) findings, it is possible that melatonin regulation via methylphenidate treatment may be a contributing factor to the drug's effect on sleep performance. However, we should be careful not to put too much stock into this finding, since melatonin levels are highly variable among individuals (i.e. comparison of absolute melatonin concentrations between individuals is often ineffective, and intra-individual fluctuation of melatonin levels occur throughout the day anyway).

While the hypothesis that the CREM gene (which, as mentioned, is located on the 10th chromosome in humans) may play a significant factor in regulating melatonin levels and affecting ADHD behavior is predominantly theoretical at this point, I personally believe that this possible connection is at least worth mentioning. Additionally, potential gene/medication interaction studies may emerge, such as studies involving different methylphenidate dosage requirements based on the different CREM gene mutations. We have discussed analogous gene/medication interaction studies in previous posts such as the one entitled ADHD Genes Influence Medication Dosage . We should remain on the lookout for future studies on the possible connections among these different areas.

Gender, Age and Subtype Effects on ADHD Comorbid Disorders

We have spoken extensively on some of the related or comorbid disorders associated with ADHD ("Comorbid" here refers to an accompanying disorder that frequently occurs alongside ADHD. These may include disorders such as depression, Tourette's Syndrome, allergies, substance abuse problems and the like). The topic of this post is to investigate whether there is a pronounced gender effect on these comorbid disorders; in other words, whether boys and girls are more prone to a particular disorder comorbid to ADHD based on their gender. As we will see later, age and ADHD subtype effects are also important factors with regards to comorbid disorders.

Much of this info was taken from an article titled Gender Differences in ADHD Subtype Comorbidity by Levy and coworkers. Here is a summary of some of the main points in the study:

• Approximately half to over three quarters of ADHD children carry some type of comorbid behavior disorder. These include oppositional defiant and conduct disorders, learning disabilities and communication disorders (including speech and reading difficulties). Additionally, many exhibit anxiety disorders such as generalized anxiety disorders or separation anxiety disorders.

• Additionally, ADHD has traditionally been separated into three different forms or subtypes: inattentive, hyperactive/impulsive, or combined (a combination of the other two subtypes). All three subtypes are heavily skewed towards the boys, which outnumber girls from anywhere around 2:1 to 5:1 (some studies skew this gender difference even higher, up around 10:1). Based on the study by Levy and coworkers, here is an approximate distribution (numbers indicate overall percentages among the study population, which includes non-ADHD individuals) among the prevalence of the three subtypes for both genders:
  

As we can see, all three subtypes are skewed heavily in favor of the boys.

• Of the three subtypes listed above, it appears that the subtype (again, perhaps not surprisingly) most associated with comorbid disorders (listed in the first point) is the combined subtype.
  

• There appears to be a discrepancy between the genders as far as internal/external symptoms of ADHD and related disorders. Some studies have suggested a general trend in which many of the symptoms or problems of girls with ADHD and related disorders are more internalized (i.e., they do not outwardly manifest themselves as readily as boys), which may contribute to the skewed gender differences mentioned above. On the contrary, the same study suggests that external or outward symptoms are more apparent in boys, which may compound this effect.

• Reading disabilities are, perhaps not surprisingly, more common in children with ADHD. It appears that reading disabilities correlate more to "internal" symptoms in girls and "external" symptoms in boys with ADHD, however, reading disorders appear to have very little overlap with conduct or oppositional behaviors such as aggression or delinquent behavior. Furthermore, reading difficulties appear to be more related to the inattentive side of the disorder of ADHD than the hyperactive/impulsive side of the disorder. In other words, the inattentive and combined ADHD subtypes are significantly more likely to have problems with reading than the exclusive hyperactive/impulsive subtype for both genders. It appears that reading difficulties and inattentive behavior may have an even stronger correlation in girls.

• Furthermore, with regards to reading and speech disabilities, there is a strong gender difference for non-ADHD individuals. However, once the disorder of ADHD is introduced, the gender difference becomes less of a factor (this holds for all three ADHD subtypes). This may at least suggest, that ADHD symptoms may override or overpower what appears to be more subtle gender differences with regards to speech and reading disorders.

• There is a significant association between generalized anxiety disorders and ADHD for both genders. Gender differences for the combined ADHD subtype were especially pronounced, with rates among females with the combined ADHD subtype being significantly higher than the combined subtype males. In addition, the combined subtype was more associated with generalized anxiety for both genders (when compared to the inattentive subtype), which suggests that hyperactivity/impulsivity may play some sort of role in generalized anxiety for both genders.
  

• With regards to separation anxiety disorders (such as from parents or loved ones), it also appears that there is a higher correlation to girls with ADHD, especially with regards to the inattentive ADHD subtype. For boys, the separation anxiety disorders were highest for the combined ADHD subtype. The study suggested that separation anxiety disorders may be a sign of immaturity for both genders, and may be indicative of later "internalizing" problems in girls. Furthermore, this assertion is in agreement with several studies which associate ADHD with a delay in maturity.
  

• Based on the two findings above, in which girls with the inattentive ADHD subtype had higher rates of separation anxiety disorders and girls with the combined subtype having increased rates of generalized anxiety disorders (both of which are considered more "internal" symptoms) than their male peers, it may be suggest that screening for ADHD in girls who exhibit anxiety disorders may be beneficial, in that it may reveal underlying comorbid ADHD and offset some of the skew among gender differences and ADHD.

• Finally, age has been shown to be an important factor with regards to symptoms and severity of ADHD comorbid disorders. In this study, comparisons were done between the younger (ages and and under) and older (ages 11 and older) children in the study population. For males, the prevalence of most of the comorbid disorders (speech and reading difficulties, oppositional defiance, generalized and separation anxieties) decreased with age, with the notable exception being conduct disorders, which increased with age. For females, age was less of a factor for all of the comorbid disorders listed above with the exception of Separation Anxiety Disorders, which decreased with age (supporting the earlier assertion that this disorder is tied to maturity levels and would naturally decrease as a child gets older). In addition, inattentive symptoms associated with ADHD actually increased with age for the female population of the study. This was the exception to the overall trend of decreasing ADHD symptoms with age, which was seen in the other two subtypes for females and all three subtypes for males.
  

I would like to conclude with a final note of personal opinion. I firmly believe that when screening, diagnosing and attempting to treat ADHD and comorbid disorders, we employ far too little emphasis on the gender differences surrounding these disorders. This can lead to several potential problems such as stereotyping or pigeon-holing certain behaviors (i.e. attributing hyperactivity/impulsivity as being a "male" characteristic and either intentionally or unintentionally overlooking these symptoms or behaviors in girls).

In addition, it appears that girls may have a higher prevalence of the more "internal" comorbid disorders such as anxiety, which are often more difficult to detect than the more outward comorbid disorders of oppositional defiance and conduct disorders. This may play a major part in the gender discrepancy of ADHD diagnosis, which may leave a number of girls with ADHD undiagnosed and untreated.

Additionally, the more "internalized" nature of female cases may also lead to a lack of diagnosis and treatment for comorbid disorders associated with ADHD as well. The Levy study pointed this out, citing the discrepancy between referrals for ADHD-related reading disabilities. Reading disorders for boys were more likely to be associated with some of these outward characteristics, while girls with reading disorders exhibited more of the aforementioned "inward" traits. As a result, the rates of referral for boys with reading disabilities (based on their overall representation in the population) was almost twice that of girls.

Furthermore, this study by Levy, as well as several others, indicate that there are several (sometimes unusual or counter intuitive) associations between gender, and ADHD subtype and the expression of symptoms of specific comorbid disorders. For example, attributing an increase in Separation Anxiety disorders to younger females with the Inattentive ADHD subtype or Conduct Disorders to the Combined ADHD subtype in males may give us some possible insight as to which subpopulations of ADHD children are most "at risk" for developing some of the aforementioned comorbid disorders.

Since several of these comorbid disorders carry their own lines of medication and other treatments, the subclassification of ADHD children based on age, gender and subtype may be especially beneficial with regards to developing successful individualized treatment plans. I firmly believe that by separating out and subcategorizing ADHD and its comorbid disorders based on factors such as age, gender and subtype whenever possible could lead to a new a wealth of information for diagnosing and treating ADHD and its associated comorbid disorders.

Excessive Talking as a Potential Methylphenidate Side Effect

Methylphenidate (Ritalin, Concerta, Daytrana) is one of the most common stimulant medications prescribed for ADHD. However, there have been several questions as to its side effects. Studies have been conducted on the effects of methylphenidate which include excessive talking, cardiac abnormalities, hallucinations, bruxism (teeth grinding), movement disorders, psychotic and manic-like symptoms, appetite suppression, and temporary weight and growth reduction.


Please note, however, that this list above is not meant to scare anyone off of this medication. While some side effects appear to be relatively common and well-grounded (such as appetite suppression and temporary growth impairment), many of these side effects are relatively rare, and the results are often based on isolated studies with poor reproducibility. To be fair, methylphenidate has been subject to a number of tests, with the vast majority supporting the claim that it is a relatively safe medication (provided one uses it appropriately as prescribed).

Furthermore, previous entries of this blog have dismissed the notion that methylphenidate carries an addiction potential on the level of cocaine or illegal amphetamines (a claim often erroneously made by many of the anti-medication crowd. Keep in mind that I personally do share many of the same concerns of these groups, but likening a controlled prescription drug with multiple addiction-reducing features to illegal street drugs is both irresponsible and does the overall argument on ADHD medication concerns a disservice in my opinion). Nevertheless, some of the above associations, while limited in scope and supporting data, do seem intriguing. For this post, I would like to briefly assess the results of the first unusual side effect of methylphenidate on the list, the surprising link between methylphenidate and excessive talking.


Before we proceed, we must bear in mind that this association is based on a single case report, and not a controlled clinical study. For those unfamiliar with the differences between the two, a case report is essentially a report of one (or a few) individuals, who exhibit particular symptoms, often in response to a particular medication or treatment strategy. While these reports lack the statistical power and overall scientific magnitude when compared to tightly-controlled clinical studies involving large sample sizes, we should not be quick to dismiss these findings. Individual anomalies, while often statistically small, do offer insight into some of the idiosyncrasies of medication and other forms of treatment, and involve real individuals (who are often in a more "natural" setting than those in clinical trials).

Given the recent advances in genetic studies and innovations in imaging and computational power, we appear to be at the dawn of a medical revolution, in which medication and treatment plans are becoming increasingly tailored towards individuals rather than groups or the general population. I personally believe that because of this general trend, individual case studies will begin to carry more weight and validity among the medical community than they have previously.

While not my intention to digress from the topic of today's post on methylphenidate and excessive talking, I did want to state some of the potential implications of the data accumulated from one particular individual. With regards to the study, here were some of the key findings and observations:

• The case involves a 5-year old Iranian boy who was prescribed methylphenidate (10 mg per day) for extreme hyperactivity and impulsive behavior, two key symptoms of ADHD. Treatment with this dose of methylphenidate produced significant improvements in both impulsivity and hyperactivity.


• Approximately 45 minutes after taking the medication, both parents and teacher reported a sharp increase in excessive talking. These results continued for 3-4 hours, which approximates the duration of effectiveness of methylphenidate (immediate release formula).


• Most interestingly, perhaps, was the apparently direct association between methylphenidate intake and hyper-talkative behavior. The study reported that methylphenidate treatment stopped and was reintroduced on over 20 different occasions within a 7 month period. In all 20 plus cases, the hyper-talkative behavior resumed when methylphenidate treatment was reintroduced. The magnitude of the difference, between talking behavior on and off the medication, while subjective, was significantly pronounced. On a 1-10 scale (done by parents and teachers, with 10 being the highest), the child's talking was around a 2-3 when off the medication and a 7-9 while on it. This extremely high frequency of association and pronounced behavioral differences between methylphenidate and excessive talking strongly attributes the abnormal behavior to the medication.


• The study gives several potential explanations for this association between behavior and medication. For example, methylphenidate, which regulates free dopamine levels and dopamine-related neural function, was shown to regulate word production in individuals with schizophrenia.


• Additionally, methylphenidate has been used to restore talking in patients treated with anesthesia.


• Finally, methylphenidate has been shown to effect the striatal region of the brain (see below, original file source here), which has a regulatory effect on cognitive motor functions, including talking patterns.

The striatum region of the brain (shown in green in the figure above), which has been shown to have a response to methylpenidate, and may be an underlying reason for the connection between methylphenidate and excessive talking.

As mentioned above, we should obviously not put too much stock into one case study on the potential connection between the unusual side effect of excessive talking in response to methylphenidate. However, based on the severity and consistency of the association for the individual and the underlying theoretical basis of the association based on the results of other studies, we should not overlook the observations of this particular study. Furthermore, given the effectiveness of methylphenidate for reducing hyperactive and impulsive ADHD symptoms for this particular child, the fact that excessive talking behaviors (which can be a sign of ADHD-based impulse control problems) suggest the possibility that the methylphenidate treatment may have an effect on shifting the outward expression of symptoms of an underlying ADHD condition such as impulsivity. As a result, a number of questions should be raised on the basis of this study.

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.