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.

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.