Daytrana Dosing Equivalents to Ritalin and Concerta

Methylphenidate remains one of the most popular choices of medications for individuals with ADHD. However, the combination of dosing difficulties and negative side effects connected with oral administration left room for an alternate form of delivery: the methylphenidate transdermal delivery system, more commonly known as Daytrana. Currently, this medication is prescribed for children with ADHD and not adults, although it is sometimes prescribed off-label for adults with ADHD and related disorders.

If you are not familiar with Daytrana as a method of treatment for ADHD, you are not alone. It is a relatively new medication, introduced in 2006. It consists of the drug methylphenidate, the same chemical compound used in the more common ADHD medications Ritalin and Concerta. It is currently the only ADHD medication available in the patch form.

We will begin a series of posts exploring this new player in the world of ADHD, but I would like to start off with just providing a table of approximate dosing equivalents between Daytrana and the more common forms of methylphenidate, Ritalin and Concerta. A rough comparison, obtained from an article by Arnold and coworkers in the journal Pediatrics titled Treating Attention-Deficit/Hyperactivity Disorder with a Stimulant Transdermal Patch: The Clinical Art.

Please note that there are four different patch sizes of Daytrana currently available, which, based on the pharmacokinetics of a 6-12 year old child, correspond to four different doses of both the immediate release methylphenidate (note this 2nd-to last column corresponds to a Ritalin immediate release dose that given 3 times/day) and an osmotic-based release form of methylphenidate (Concerta). The patch is typically placed on the relatively inconspicuous location of the child's hip, and should be administered to the same site on a daily basis for consistency (different locations can actually affect the releasing dosage patterns of the patch)

Typical wear is for 9 hours, which is why the 9-hour dosing equivalents are given. However, the theoretical maximum dose per patch (which is the delivery rate times a 24-hour period) is also given. However, anything beyond a 9-hour dose is typically considered "off-label" use for Daytrana. These delivery rates of dosing for the different patch sizes are slower than the other forms of methylphenidate, as we will see in future posts. Nevertheless, I have included them to illustrate the patch size/dosing rate relationship for Daytrana. Note that the patch area and delivery rate follow a linear relationship, which is indicative of a uniform distribution of the drug across the surface of the patch which provides approximately 2.2 mg of methylphenidate content per square centimeter of patch area (over a 24 hour period).

We will be going into much more detail about the modes of action and functional differences of the Daytrana form of the drug methylphenidate (especially the differences between this patch form and the conventional "pill" form) as well as highlight some of the advantages and disadvantages of this new form of treatment for ADHD in the next few posts. Topics addressing the difficulties of an oral delivery system (we have hinted at some of the problems of food or drug metabolism and the ensuing consequences due to digestive issues such as celiac disease and ADHD symptoms) will also be discussed in the very-near future. In the meantime, a good overview of Daytrana, as evaluated by the FDA can be found here.

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.

ADHD Genes Influence Medication Dosage

This blog originally began by exploring seven different genes that were thought to be tied to ADHD. However, there is another gene of interest, that was not on that list, which is also believed to be a key factor in how much of a stimulant medication is needed for treating a person with ADHD. The gene in question is referred to as COMT, which is short for Catechol O-Methyltransferase. COMT "codes" for an important enzyme by the same name in humans, the Catechol O-Methyltransferase protein.

The COMT gene is located on the 22nd human chromosome in the q11 region (don't worry too much about the exact location, "q11" simply refers to a more detailed location on the 22nd chromosome. Keep in mind that the COMT is just one of the 30,000 to 50,000 plus genes, which are spread out over 23 pairs of chromosomes in humans. The point here is simply that one slight change to one gene can have profound effects on the way the body handles stimulant drugs such as amphetamines).

It is interesting to note that this genetic region has also been tied to other disorders which either occur alongside of ADHD (that is they are comorbid to ADHD) or have some symptom overlap with the disorder. These include schizophrenia, bipolar disorders, and even panic disorders. Additionally, there have been studies which tied in this genetic region to eating disorders including anorexia.

Like many proteins (enzymes are a specific class of proteins), the COMT enzyme can exist in several different forms in the human population. In one segment of the enzyme (the 158th amino acid from the end), an individual can either have the amino acid valine (often abbreviated as "Val" or simply "V") present or the amino acid methionine (also abbreviated "Met" or "M")present. In humans of European background, only about 15-20% carry the Met form of the COMT gene in both copies of their 22nd chromosome.

However, the minority of individuals who do carry this rarer "Met" form in both chromosomes generally require smaller doses of stimulants such as amphetamines for regulating ADHD symptoms. A brief explanation follows below:

Blogger's note: the majority of this information comes from a 2003 publication in the journal PNAS (Procedings of the National Academy of Sciences) in the USA by Mattay and Coworkers. A copy of this article may be found here. Please keep in mind that the description below is a simplified version of what is in the original article. If you have a scientific or medical background, I encourage you to follow the link above and check out the original article. Otherwise, the descriptions below give a fairly good overview of the content of the article.

• Individuals with ADHD often have lower free levels* of the important brain signaling agent dopamine (see region #1 in the figure below) in a region near the front of their brains called the prefronal cortex (PFC). However, evidence has also shown that if dopamine levels are too high (region #3 in the figure), then problems can occur also. It is hypothesized that free dopamine levels in the prefrontal cortex follow a sort of upside-down "U"-shaped curve. For maximum effectiveness via medications or other treatment options, you want to be at the highest point on the curve (region #2 in the figure). Please refer to the illustration below:
  

* Please note: "free levels" here refers to levels of the brain chemical dopamine that are not taken up by neuron cells. Dopamine can be shuttled in and out of the cells from the area outside the cells. For individuals with ADHD, the amount of dopamine outside of the cells in this "free" space is often lower than in other individuals. Many ADHD stimulant medications (such as amphetamines) counteract this effect by reducing the transport of dopamine into the surrounding cells, or even reversing the process. This artificially boosts dopamine concentrations outside the cells and offsets some of the negative chemical effects of ADHD or related disorders.

• Based on the hypothetical upside-down "U" curve above, most individuals with ADHD would naturally fall somewhere around region 1, that is, the amounts of free dopamine (see *'ed section above for explanation on this) are below the optimal level. In other cases, free dopamine levels can be too high (region 3 above), and can lead to anxiety, depression, or even schizophrenia-related symptoms.


• The enzyme COMT mentioned above is responsible for breaking down free dopamine between neuron cells by converting it to another compound (called 3-methoxytyramine. The exact process of this is beyond the scope of this post, just remember that COMT enzyme functionally lowers the levels of free dopamine in between neuronal cells by converting it to the 3-methoxytyramine).

• Additionally, it appears that the "Val" form of the enzyme mentioned above, is approximately 3 times more active than the "Met" form of the enzyme. As a result, more dopamine is typically converted to the 3-methoxytyramine product mentioned above for individuals who have the "Val " form of the gene. Therefore, individuals who have the "Met" form of the enzyme COMT often have higher baseline levels of free dopamine in the front brain region than do those with the "Val" form of the COMT enzyme.
  

To help visualize this, in the case of the graph below, individuals with the "Met" form of the COMT enzyme would be closer to region 2 (optimal dopamine-based function in the PFC region of the brain) than do individuals with the "Val" form (who would be closer to region 1 in the graph below).

• This prefrontal cortex region of the brain is an important region of the brain to analyze for individuals with ADHD, because it is responsible for areas of cognitive function such as working memory (i.e. not simply "memorizing" facts, but being able to retrieve and utilize them). This is a function of higher level thinking, and is typically much more taxing in individuals with ADHD and related disorders.


• A well-known task used as a diagnostic tool for disorders involving the prefrontal cortex region is called the Wisconsin Card Sorting Test, which measures the learning process of matching specific cards based on common features (for more information on the Wisconsin Card Sorting Test, please click here). Studies have shown that different forms of COMT genes (the "Met" and "Val" forms described above) can affect performance on this test.
  
• Based on results from Mattay and coworkers, it appears that individuals who had copies of the Met form of the COMT gene in both pairs of their 22nd chromosomes did significantly better on the Wisconsin Card Sorting Test (which suggests a better, more efficient functioning in the PFC brain region with regards to working memory) than did individuals who possessed the Val form of the COMT gene for both chromosomes. However, after treatment with amphetamines, individuals with the Val forms of the gene significantly improved on the test, while individuals with the Met forms of the gene did noticeably worse. Therefore, we see that treatment with amphetamine stimulant medications can boost cognitive function for one type of the COMT gene, while the same (relatively low amount) can significantly reduce cognitive performance efficiency with another form of the same gene.

• Interestingly, based on animal model studies, it appears that tasks which require the use of the working memory listed above is connected to a boost free dopamine levels in the prefrontal cortex region of the brain to a certain degree. It is unclear as to whether this holds across the board, but it at least suggests the possibility that an organized "brain workout" program which regularly challenges the brain by utilizing the working memory may be a potential powerful supplement to treatment with stimulant medications for treating ADHD. This appears to be a wide-open topic of future study. Regardless of whether this previous hypothesis holds true, the working memory vs. dopamine connection will be a key factor which we will see later in this post.
  
• As mentioned above, stimulant medications such as amphetamines Adderall, Dexedrine, and Vyvanse (once metabolized), can cause a boost in signaling via increased free dopamine levels between neuron cells. Returning to our hypothetical upside-down "U" curve for a moment, we can see that proper amphetamine dosage may push an individual to the optimal (read "most efficient") dopamine-based signaling in the PFC region of the brain for an ADHD patient:

As we can see above, treatment with amphetamines (AMP) can shift the dopamine-based signaling process in this prefrontal cortex region of the brain. Note that if the drug dosing is too high ("Met high AMP" arrow), we can "over-correct" the level of peak functioning of the Prefrontal Cortex (PFC) region in the brain, which is thought to worsen the severity of symptoms for ADHD and related disorders. In this particular case above, the low Amphetamine dose was close to perfect for individuals with the "Met" form of the COMT gene, whereas higher doses of amphetamine were preferable for those with the "Val" form of the COMT gene.

This can result in a paradox for treatment via stimulant medications, that is too much stimulant medication can often result in similar effects as those caused by too little. For a further explanation of this, please check out Dr. Charles Parker's blog entry on the therapeutic window of stimulant medications. Unfortunately, given the similarity of symptoms, prescribing physicians sometimes make the mistake of thinking that they are under-dosing when they are really overdosing. The results of this may lead the patient even further away from the "optimized" region of PFC function, and actually, and unknowingly worsen their ADHD symptoms.

• Before going any further, I need to clarify a bit with regards as to what constitutes "optimum" PFC function. As mentioned, the PFC or Prefrontal Cortex region of the brain is thought to be involved with the disorder ADHD. As I've mentioned earlier, individuals with ADHD often have lower-than-normal levels of dopamine, as well as norepinephrine (which is a chemical cousin to adrenaline) which are both key agents for signaling throughout the nervous system. Given the fact that this brain region has a relatively low number of dopamine transporter proteins, the COMT enzyme's level of activity becomes even more significant, since it has fewer proteins to "compete" with to regulate free dopamine levels. For other signaling agents such as norepinephrine, there are more of these transporter proteins available, so these become much less of a factor with regards to ADHD and related disorders. As a result, it appears that when we want to address and regulate signaling in the prefrontal cortex region of the brain, dopamine is the main agent of concern.
  
• If an individual is at a non-optimal PFC function level (either to the left or the right of the "peak" of the upside-down U curve, their performance on cognitive tasks such as working memory becomes much less efficient and much more difficult. As a result, tasks such as recalling and using the memory function for a higher level task can become extremely taxing to both an untreated individual with ADHD (who are often "left" of optimal) on the curve or depression or anxiety-related disorders (who sometimes fall to the "right" of optimal) on the upside-down U curve. Either way, their brains must work harder than an average person's to accomplish the desired task.

• However, various treatment options such as nutritional approaches or medications can lead either of these two individuals to closer to optimal PFC levels (that is closer to the top or "peak" of the upside-down U curve shown above). However, over-compensating via over-medication or other means can push an individual back down the "U"-curve away from optimal brain function.
  
• The level of exertion or difficulty in this region of the brain can actually be measured by advanced processes such as fMRI (which stands for Functional Magnetic Resonance Imaging). A form of fMRI called BOLD fMRI (BOLD stands for "Blood Oxygen Level Dependent") can detect via imaging processes changes in the amount of oxygen required of neurons in a certain brain region to perform a given task.
  
• If the PFC region in the brain is at sub-optimal function (less efficient), then a greater degree of exertion in that region in the brain is required to carry out a task, and a greater oxygen requirement is needed. This greater demand shows up on the BOLD fMRI. However, if the PFC region of the brain is pushed towards a more optimal level (closer to the top of the upside-down U curve), then this brain region is more efficient and requires less oxygen to perform the same task.

• As a result, BOLD fMRI can be used to determine how medications or other external stimuli can influence brain function and efficiency.
  
• Continuing on with the study on the COMT gene variations, we must also investigate the effects that cognitive tasks such as working memory, when combined with medication effects, have on the efficiency of the Prefrontal Cortex (PFC) region of the brain. Here's another example using our favorite upside-down-U-curve, for a hypothetical individual with ADHD. We will see some of the potential outcomes when three factors are all combined: Genetics (the "Met" or the "Val" form of the COMT gene), Amphetamine dosage levels (high AMP or low AMP) and Cognitive challenge via working memory (WM) tasks:

From here we should be able to spot three trends:

1. Due to the fact that their overall activity of the COMT enzyme is lower (which leads to less conversion of dopamine to the 3-methoxytyramine and higher free levels of dopamine in the region between neuronal cells in the PFC region of the brain) , individuals with the "Met" form of the COMT gene are closer to the optimal efficiency in the brain's PFC region. This often reduces the severity of ADHD symptoms when cognitive tasks are required.
2. The use of stimulant medications such as amphetamines can also boost the dopamine-based signaling to closer-to-optimal levels up to a point. For individuals with the Met form of the gene, low levels of amphetamine (low AMP), and a working memory task (+WM), the balance was at the top of the curve, and at optimal function for the PFC brain region. However, excessive medication can cause an individual to slide back down the other side of the "mountain", as seen in the figure above for the individual with the "Met" form of the gene and high levels of amphetamine (AMP) treatment for a cognitive task involving working memory (WM).
3. We see that utilizing cognitive tasks such as working memory can also push an individual to the right of the curve listed above. In fact, as tasks become more mentally challenging, the individual may continue to move further and further to the right on the curve. Therefore, if faced with a relatively easy working memory task, an individual may operate at near-peak PFC function (i.e. near the top of the curve), but for higher-level working memory challenges, this same individual will begin to fall down the right side of the curve, away from optimal function.

This should raise several issues, which prescribing physicians often face. Do we want to medicate more for behavioral related issues, or for improving cognitive performance? This becomes a serious problems, as incongruencies are often seen between parent and teacher evaluations for the same individual. Given the fact that cognitive tasks such as working memory are more utilized in certain subjects such as mathematics, logic and physical sciences, we can see the effects of too little or too much medication (as well as specific gene forms such as "Met" or "Val" for the COMT gene) can have on an individual.

By no means are these results or observations quantitative. In other words, you can't simply plug in an individual's gene form ("Met" or "Val" for the COMT gene), and level of difficulty of upcoming cognitive tasks into an equation to find out the perfect level of stimulant medication required to achieve optimum performance in the PFC region of the brain. However, the take-home message is this: clearly there is an intersection of genetics, medication dosage effects and degree of cognitive challenge which must be optimized for peak mental function. These must all be considered as relevant factors when attempting to treat an individual with ADHD.

Evaluation of Vyvanse for ADHD Treatment

A new drug called Vyvanse (Lisdexamfetamine) has entered the world of ADHD stimulant medications relatively recently. Vyvanse was originally marketed as an ADHD treatment for children, but has recently been approved by the FDA for adult and adolescent use this past April. A cousin of the popular ADHD medications Dexedrine and Adderall, Vyvanse includes some key modifications from these other meds. Some reports (unverified) suggest that Shire Pharmaceuticals, the makers of Vyvanse, are pushing this new drug aggressively over Adderall XR. While Adderall is a chemical mixture of amphetamine salts including enantiomers, Vyvanse only contains the one enantiomer thought to be more "active".

A quick side note on enantiomers: Entantiomers are essentially "mirror images" of the same chemical compound, like a person's left and right hand. The body, like most objects in nature, react differently to and often heavily prefer one "mirror image" over the other. Certain ADHD medications such as Focalin, have already employed this technique. Focalin is an isolation of only one of the two mirror images that make up Ritalin, another popular ADHD medication. In addition, the ADHD medication Dexedrine also employs this mirror-image selectivity regarding its composition.

The second major difference between Vyvanse and other amphetamines such as Adderall, is that Vyvanse is listed as a "pro-drug". A pro-drug is essentially an inactive form of a drug, which, when broken down or metabolized by the body, releases the active drug form. Vyvanse contains an amphetamine which is chemically linked to an amino acid (a building block component of proteins) called lysine. In the body, this chemical linkage is severed by special enzymes which separate Vyvanse into the amphetamine drug and leftover lysine fragment (which is easily disposed of, since lysine is a naturally occurring amino acid in its own right).

***Blogger's note: I will be citing a number of studies previously conducted on the drug lisdexamfetamine. Keep in mind that this is a relatively new drug, so it does not have the history of a drug such as methylphenidate. Nevertheless, I have tried to keep a good balance of sample studies on the drug to report on. The list of studies mentioned and referred to here, are by no means exclusive! While not all of the studies used the Vyvanse brand of the drug, I will be using the terms "Vyvanse" and lisdexamfetamine interchangeably throughout the post.

***Additionally, please do not take this information as official medical advice. I am simply trying to highlight some of the pluses and minuses of the drug and arm you with information so you can better consult with your physician on the merits of this drug.

This chemically-modified form carries several apparent advantages for Vyvanse:

• Since the lysine link must be cleaved to release the active form of the amphetamine drug, Vyvanse naturally lasts longer in the system than do straight amphetamines. While most other stimulant medications rely on the capsules encasing the drugs to slowly dissolve and thereby slow down the release of the drug, Vyvanse already has what is essentially a controlled release built in to the drug itself. As a result, a single dose taken early in the day can last up until the evening hours, which allows individuals to avoid the hassle or stigma of needing to take the medication during the work or school day.

• Most of amphetamines problems stem from their addiction potentials. Generally, the faster the amphetamine gets into the blood stream and gets into (as well as out of), the brain, the greater the "high", and the more addiction-forming the drug. Again, by its built-in slow release mechanism, Vyvanse enters the blood (as well as the nervous system) at a slower, more controlled pace, thereby reducing its addiction potential. Even when snorted or injected, lisdexamfetamine exhibits notably reduced addiction potentials, when compared to other amphetamine-based stimulants. For example, when injected via IV, subjects who took Vyvanse needed 1-3 hours to feel the drug effects while isolated d-amphetamine (analogous to Dexedrine) felt the effects in only 15 minutes.

• Due largely in part to the fact that Vyvanse's drug effect needs to be "activated" biochemically, it is poses less risk for tampering and related abuses (i.e., crushing and snorting) as well.

Additionally, Vyvanse also carries some other distinctive advantages:

• While many drugs effectiveness are often dependent on the level of acidity in the stomach and intestinal tract, Vyvanse appears to be only mildly affected. It dissolves quickly in the gastro-intestinal tract, and its solubility is minimally affected by digestive pH.

• The presence of food only results in a slight delay in Vyvanse's absorption. When taken alongside a fatty meal (fatty foods generally impede the absorption process, as they themselves are slow to clear the gastro-intestinal tract) the delay in amphetamine release from Vyvanse was only about an hour. This was in contrast to around a 2.5 hour delay when Adderall was taken with fatty foods. As a result, Vyvanse appears to be less affected by the presence of food than other well-known amphetamines, suggesting an increased versatility as an ADHD stimulant medication treatment.


• This next statement is the blogger's opinion and is not supported by direct evidence. Nevertheless I believe this is a topic worthy of investigation: In a previous blog post, we discussed celiac disease and how it can ravage the digestive tract and result in ADHD-like symptoms. While these symptoms are likely the result of a different path than ADHD caused by genetic or environmental factors, it may be worth noting that Vyvanse may alleviate some of these inattentive symptoms better than other ADHD medications, due to the fact that it may absorb better in a digestive system damaged by celiac disease or the pH changes which often accompany it (poorly digested carbohydrates can alter the pH in the digestive system immensely). While this will not treat the underlying cause of celiac disease, it may mask the some of the ADHD-like symptoms better than other medications. This assertion is simply a personal hypothesis and is yet to be studied or verified.

• In addition to its resiliency regarding foods and digestive pH, it appears that Vyvanse may be less susceptible to negative drug-drug interactions than many other agents. Many medications target a key metabolic system referred to as Cytochrome P450. While to complex to discuss in detail in the limited scope of this post, the P450 system of proteins plays an integral role in drug metabolism, the body's antioxidant levels, and regulation of toxicities, it appears that the effects of the drug lisdexamfetamine on the P450 system are minimal. Since many drugs do operate via this system, Lisdexamfetamine should therefore pose less of a threat regarding negative drug-drug interactions.

• The drug apparently has a good track record as far as behavioral improvements and attention span are concerned. A study was done using a rating scale called SKAMP (which stands for the initials of its creators: Swanson, Kotkin, Agler, M-Flynn and Pelham), which is used to determine classroom behavior. According to the study using this particular rating scale, measurable improvements were seen in both attention span and classroom conduct for periods of up to 12 hours after taking their last dose of lisdexamfetamine. Prolonged behavioral changes are typically not seen to this degree, and the fact that the subjects were diagnosed and medicated previously suggest the potential effectiveness of Lisdexamfetamine even for "stubborn" ADHD cases.

• The same study also employed a mathematics-based test called PERMP (short for Permanent Product Measure of Performance). Notable improvements were seen in both both speed and accuracy on this test following a 5-week amphetamine treatment program. Lisdexamfetamine's positive effects on this cognitive task peaked around 4.5 hours after the last dose was administered and held relatively steady for the next 7-8 hours. The results of this study suggest that Lisdexamfetamine can improve the inattentive and behavioral symptoms of ADHD as well as enhance cognitive performance abilities for a prolonged period of time. This suggests great potential for use as a "school drug".

• A study on adult stimulant drug abusers by Jasinski and Krishnan presented at the 2006 US Psychiatric and Mental Health Congress found that the study's subjects found Lisdexamfetamine to be much less "likable" than other amphetamines, further suggesting a reduced addiction potential for an already-at-risk group.

• When taken around breakfast time (7:30-8:00 a.m.), Vyvanse showed remarkable "staying power" throughout the day, based on results from a behavioral rating scale taken in the mid-morning, afternoon and evening time (the last being around 6:00 p.m.). This is good news for teachers and parents, and suggests a more gradual tapering-off of effects, and a lesser "rebound effect", in which negative symptoms rapidly reappear, often within the hours of 4 and 6 p.m.

• Amphetamine levels delivered via the lisdexamfetamine system are thought to stabilize within about 5 days. This is good news, especially since many ADHD medications can take up to 3 weeks to normalize their effects.

• Lisdexamfetamine is apparently processed and broken down in an efficient manner, and is typically cleared from the body without system buildup.

• Lisdexamfetamine has also shown more consistency than many other drugs as far as less variation from patient to patient. While this is neither good or bad by itself, it does suggest a greater inherent stability in that it appears to be less susceptible to the effects of other bodily functions which are variable from person-to-person. As a result, I see this greater predictability will make it a preferable choice for many prescribing physicians. Of course, the flip side is that ADHD is an extremely complex and multi-faceted disorder, and clinicians may fall into the trap of seeing a "one-size-fits-all" solution and begin to treat Lisdexafetamine as a fall-back, default prescription.
  

This blog, of course, is not designed to sound like some sort of promotional "infomercial" touting all of the benefits of Vyvanse while leaving out potential risk factors. To keep things balanced, I have included some of the negative attributes of this particular stimulant medication as well:

• While the study by Jasinski and Krishnan on the reduced "likability" of Vyvanse was encouraging, it is not recommended for individuals with a history of drug abuse, as previous non-prescription drugs can interfere with its effectiveness.

• Additionally, Vyvanse reduces the presence of a key enzyme in the body which is targeted by anti-depressants called monoamine oxidase. A number of anti-depressants called monoamine oxidase inhibitors (MAOI's) also target this enzyme and reduce its presence. Due to the potentially harmful combination of amphetamines and MAOI's, these MAOI drugs should not be taken alongside Vyvanse. Please note that certain substances, such as cigarettes, and even turmeric or curry (in large doses) can also have potentially negative effects with Vyvanse.

• Slight elevations in heart rate and blood pressure (mainly the diastolic pressure, which is the smaller of the two numbers and represents the blood pressure at the "resting" phase of the heart) and slight changes in heart rhythms were seen with Vyvanse, especially in the upper dose (70 mg) levels. However, this is a relatively common occurrence within the family of stimulant medications. For further information, please see the earlier post Are ADHD Stimulant Drugs Bad for your Heart?

• Like most stimulant medications used to treat ADHD, appetite suppression was also a common side effect (this is due, in part, to increased levels of free dopamine, an important signaling agent in the nervous system, which, also plays a role in the feeling of "fullness" in an individual. By artificially boosting free levels of this neuro-chemical, a reduction of hunger symptoms are often seen), even at the lower 30 mg doses. However, actual weight loss did not become a huge symptom until the upper levels (around 70 mg doses) were approached.

• Insomnia can also be a problem with Vyvanse, even at lower doses. As a result, it is advised to give this medication as early in the day as possible.

• The "classic" side effects (that almost all medications now somehow seem to evoke!) such as headache, nausea, vomiting, etc. all remained relatively low until the 70 mg level was approached.

• Keep in mind that this drug still functions as a stimulant, and is therefore inherently better-suited for the more inattentive or impulsive forms of ADHD. Given the negative interactions with the MAOI class of antidepressants and the fact that stimulant drugs in general can worsen depressive symptoms, I recommend that extreme caution be used when prescribing this medication for individuals with comorbid ("comorbid" means "occurring alongside of") depressive symptoms alongside their attention deficit disorder.

Medication Doses Available:

30 mg, 50 mg and 70 mg were the original strengths available, but recently 20 mg, 40 mg and 60 mg doses have been added. The amount of amphetamine delivered in Vyvanse compared to Dexedrine approximately a 5:2 ratio. For example, 50 mg of Vyvanse corresponds roughly to 20 mg Dexedrine, 25 mg Vyvanse to 10 mg Dexedrine, etc. 30 mg is often a starting point for children, but doses can be carefully ramped up under the guidance of a physician. In general, it appears that many of the negative side effects can be kept at bay by staying under the 70 mg amount.

A quick side note: For another good source of information on medication dosages, I recommend the blog of Dr. Charles Parker. His blog can be found here. Additionally, he talks about a paradox called the therapeutic window. This is interesting to note, because sometimes ADHD medications which are prescribed at too high of a dosage actually result in ADHD symptoms to re-emerge and give the false impression of underdosage. You can check out this blog article here.

With regards to upper limits and safety measures, based on the studies mentioned above, negative side effects tend to increase around the 70 mg mark. Nevertheless, studies have been done at levels up to 130-150 mg. It is interesting to note that once this high range was reached, the amphetamine concentration in the blood began to taper off. This is good news with regards to the potential for overdose and buildup of toxic levels (note the relatively efficient rate of clearance of Vyvanse mentioned earlier in this post).

As a final word of caution: Remember that Vyvanse is essentially a new delivery method of amphetamines. I have highlighted some of the positives such as lower addiction potential and prolonged modes of action. However, keep in mind that there is often a strong "publication" bias, in that studies which find a drug to be ineffective or even counter-effective are often not reported or published. I therefore urge you to take some of these "glowing" reports on the drug with a grain of salt. Nevertheless, I remain at least cautiously optimistic with regards to the potential merits of lisdexamfetamine for treating ADHD and related disorders. We will be investigating other ADHD medication options shortly in future blog posts.

The Effectiveness of Adderall as an ADHD Medication

Adderall as an ADHD stimulant medication

Adderall is one of the most popular (and currently one of the most "trendy") types of ADHD medication. As a stimulant drug, Adderall is chemically and functionally similar to other ADHD stimulants including Ritalin, Dexedrine, Concerta or Focalin. However, while most of these medications contain either one or two compounds, Adderall technically contains eight. It is a combination of four different types of amphetamines (in the salt form) and their chemical "mirror images".

A bit of a side note on "mirror images" and drug chemistry: For reference sake, consider your left and right hands. They are identical in structure, but mirror images of each other. This mirror image effect plays an important role in pharmacology, and separation of the two mirror images can be extremely important. For example, one mirror image of the pregancy drug Thalidomide was used to treat morning sickness, while the other mirror image was linked to birth defects. Fortunately this grave difference between mirror images is not seen with ADHD stimulant medications. Some ADHD drugs, such as Dexedrine or Focalin only have the "right hand" form, which have different (and often more potent) properties than the "left hand" form. Nevertheless, both mirror images of each of the 4 different amphetamines are seen in Adderall, making it a combination of 8 distinct compounds.

Returning to the main topic, this post will be focusing on the overall effectiveness of the ADHD stimulant Adderall. This information comes from a large review done in 2002 in the Journal of Attention Disorders by Faraone and Biederman. A short synopsis of the orignal article on the medication Adderall and ADHD can be seen here. Please note that these studies focused primarily on the effectiveness of Adderall vs. a placebo and not Adderall vs. other ADHD medications. There actually are studies out there comparing stimulant medications for ADHD, which will be covered soon in later posts.

Also, the form of Adderall used for this review was the standard release version. No slower/extended release (Adderall XR) analyses were covered. Given the time of this publication, Adderall XR data was still scarce. Since 2002, this has changed, and additional insight will be covered in future posts. For now, I will be highlighting some of the main findings of the article below:

• Adderall outperformed the placebo in a statistically significant manner for both academic and behavioral improvements. These improvements were seen by all three monitoring groups: parents, teachers and clinicians, and were consistent, even among the several different ADHD rating systems used by the three groups.
• Additionally, consistency was seen with regards to the effectiveness of Adderall regardless of whether the stimulant medication was administered via fixed-dose (a set dosage for test subjects) or via "best-dose" (the dosing was tailored to the individual by considering the size and gender of the individual, history of other medications taken and the responsiveness to these medications). This suggests the possibility that Adderall may have a more flexible range of effective dosing than most other ADHD drugs.
• The study identified that there is often an inherent clinical bias in reporting the effectiveness of medications because "success" stories in which ADHD medications are effective are naturally published more often than for "failed" studies. A correctional factor (described in the article) was used to counteract this implicit effectiveness bias. Just keep in mind that published results are often not a full representation of data from the full spectrum of studies.
• Adderall treatment (at various doses) appears to be almost as effective in treating aggressive behaviors as in treating ADHD. This spells good news for individuals with ADHD who also exhibit potentially violent or overly-aggressive behavior.
• Although parents, teacher and clinicians all saw improvements with regards to ADHD across the board, the highest levels of measured improvement was typically seen by those in the medical profession. Parent and teacher evaluations showed similar levels of improvements with respect to each other, but their results were often not as pronounced as those done by clinicians.
• In addition to clinician reports giving higher ratings, the mode of measurement for ADHD symptom improvement was also a factor. Symptom ratings scales, refer to a reduction in negative symptoms associated with the disorder. They do not take into effect things such as improvements in school or improvements in social skills, as these are more difficult to monitor as measurable "symptoms".
• By contrast, global ratings also incorporate factors in addition to the symptom ratings. In addition to measuring levels of "sickness" like symptom ratings, global ratings measure more degrees of "wellness", such as the social or academic improvements mentioned above. As a result, global ratings typically offer a wider spectrum and offer a more complete and detailed portrait of improvements following modes of treatment for ADHD. Not surprisingly, due additional improvement categories which can be measured, global ratings typically result in higher rating scores of medication effectiveness than do ADHD symptom studies.
• Based on the layout and distribution of the data, and the overall high level of agreement in the results of multiple unrelated studies, the authors of the article concluded that additional studies on the topic of Adderall medication vs. placebo are unlikely to refute these results.

These results support the idea that ADHD treatments with Adderall are statistically superior to controls (i.e., it is highly unlikely that improvements along the spectrum of undesirable behaviors and effects of ADHD are due to the "placebo effect"). As a result, it is apparent that Adderall has solidified its place as a valid and viable treatment option for ADHD.

Nevertheless, we must now begin to focus on the overall safety of this ADHD drug, and how Adderall stacks up against other ADHD stimulant medications such as Ritalin, Focalin, Concerta, or Dexedrine. Please check for more posts addressing these two key areas in the near future.

Do ADHD Stimulant Medications Worsen Tourette's and Tic Disorders?

Main Categories: ADHD Stimulant Medications and Comorbid Disorders

In an earlier post, I commented on how Atomoxetine (Strattera) was a good possible medication option for treating ADHD comorbid with Tourette's Syndrome. One of the reasons I gave was that ADHD stimulant medications have been linked to worsening Tourette's cases and tic disorders. But how much of a link is there really between these disorders (which frequently are seen alongside each other, that is they are comorbid disorders).

I examined a review article from a couple years ago recently, and I think that it made some interesting points. Additionally, it did a very thorough investigation on the topic of ADHD, Tourette's and tic disorders, covering a number of previous experiments and journal articles. This review article was from the 2006 journal of Seminars in Pediatric Neurology, researched by G. Erenberg. A link summarizing some major points of this article on Tourette's, ADHD and Stimulant Medications may be found here. I will summarize some other important findings of this article below:

• ADHD has been seen in up to 90% of children with Tourette's, with studies post-1980 studies showing higher percentages that pre-1980 ones
• Although the two disorders are often seen alongside each other, the "form" of ADHD seen alongside Tourette's is the same as the form of ADHD seen without Tourette's
• Increases in the frequency or severity of "tic" disorders (twitching, eye-blinking, etc., and occasional vocal outbursts) have been seen in a number of individuals following treatment with ADHD stimulant medications, but at the population level, these symptoms increases are typically insignificant.
• After 1995, studies with Tourette's often separated out samples with ADHD and those without ADHD. For studies before 1995, this was often not the case. Therefore, studies after 1995 comparing Tourette's, ADHD and combinations of the two are often preferred when studying the two disorders.
• A pre-1995 study (1992), concluded that individuals with Tourette's along with Obsessive Compulsive symptoms had worse attention span, while a post-1995 study (1998) showed that individuals with ADHD and individuals with a combination of ADHD and Tourette's had a worse attention ability than those with only Tourette's. Again, this may have been due to the later addition of the "post-1995 ADHD + Tourette's" subcategory.
• Tourette's Syndrome (TS) is typically not associated with learning disabilities by itself, while ADHD and ADHD with TS are.
• For individuals with Tourette's, ADHD can make tics worse. Additionally, ADHD boosts levels of rage, anxiety, delinquencies and oppositional tendencies in indviduals with TS (i.e., for those with both symptoms, the ADHD is thought to be the one at work for these negative side effects).
• For individuals with Tourette's, aggressive behavior is often not an issue, but if it is accompanied by either ADHD or OCD (Obsessive Compulsive Disorder), aggression is often seen at noticeably higher levels.
• The effectiveness of stimulant medcations for ADHD is typically unaffected by whether the individual also has accompanying TS.
• The Physicians Desk Reference (PDR) includes a warning on individuals with tics (or a parent or sibling with tics) to avoid stimulant medications. This decision was influenced in part by a pre-1995 (1983) study linking ADHD stimulants to the development of tics.
• "Questionable" ADHD stimulant drugs that allegedly boost tic disorders include: Methylphenidate (Ritalin, Concerta, Focalin), Dextropamphetamine (Dexedrine), and Pemoline (Cyclert).
• If an individual has a current or pre-existing condition of tics, then the influence of ADHD stimulant drugs on this tics has produced a host of mixed results.
• Within individuals who have Tourette's Syndrome, tic symptoms are often slow to appear (i.e. it take months or even years for individuals with Tourette's to see tic disorders set in).
• For individuals who take ADHD stimulants and develop tics, the timeframe between starting the medication and developing tics is often relatively long (several months to 1 year, as opposed to immediately). Therefore, if tics show up within a short time-frame in and individual after taking stimulants (less than a month), there is significant possibility that the cause of the tics is medication-related.
• A small sample study demonstrated that methylphenidate (Ritalin, Concerta) was less likely to promote tics than dextroamphetamine (Dexedrine).
• Methylphenidate was shown to be "tic-safe" when combined with another anti-hypertensive agent also used as a non-stimulant medication used for ADHD (clonidine).
• Additionally, minimal research has been done to see whether "anti-tic" medications such as Risperidone or Guanfacine (Tenex) are more or less effective for so-called stimulant-induced tics vs. "natural" tics.

I know I have made a number of "points" summarizing Dr. Erenberg's article on stimulant ADHD medications and tic disorders. However, even if you've skipped down to this point, it seems that based on the research that is currently out there and what we have so far, taking ADHD stimulant medications is relatively safe, even if an individual has Tourette's. Although there is a warning in the Physician's Desk Reference about psycho-stimulant medications worsening tics, the overall effects are relatively small, especially when compared to other disorders that sometimes occur alongside ADHD (such as ADHD and eplilepsy).

Please keep in mind, it is not my intention to try to override this PDR warning or your physician's choice of prescriptions! However, if you are currently diagnosed with ADHD and Tourette's and are on a stimulant medication, please don't run to change your prescription. From the evidence we have currently seen, it appears that ADHD stimulants, especially methylphenidate (currently thought to be one of the safest stimulant medications for ADHD) are still thought to be relatively safe, even for Tourette's. However, keep in mind that if tic disorders are not seen prior to medication, and show up within a month or less, there is a good chance that the ADHD stimulant you were prescribed is to blame. If it is significantly longer (i.e. several months or years), chances are the tics are probably unrelated to the medication. I will continue to investigate these connections and keep on the lookout for more useful articles on the subject matter of ADHD, Tourette's and tic disorders.

How Addictive is Ritalin?

ADHD Medications

The controversy and discussion surrounding the safety of medications for ADD and ADHD is nothing new. Among the most common criticisms of these drugs are concerns about their abuse potential and their potential risks of being habit-forming drugs. Methylphenidate (the generic name for Ritalin and Concerta), has often been mentioned in the same sentence as "cocaine", especially among the "anti-medication" and "alternative treatment" sites for ADHD treatment options. While some of these comparisons are definitely warranted, the chemical structures and modes of action of ADHD stimulants such as amphetamines and the amphetamine-like methylphenidate and the illegal street drug cocaine do bear some striking resemblances. However, it is important that we do not get lost in the hype surrounding these relationships, and instead immerse ourselves in only the facts.

In the field of organic chemistry, even minor alterations to a drug's molecular makeup can result in significant functional differences. With this in mind, however, investigation into the abuse potential of stimulant ADHD medications such as Ritalin, Concerta, Daytrana, Adderall, Dexedrine, and Focalin should be carried out in a thorough, unbiased manner. A review article from the Journal of Clinical Psychiatry on the abuse potential of the ADHD drug methylphenidate investigated key properties of the drug that play a major role in abuse potential (such as drug absorption, products produced when the drug is metabolized, and how fast the drug clears from the body). Some key findings of the article on this popular stimulant medication are summarized below:

1. When injected, methylphenidate, cocaine, and d-amphetamine all produced similar reinforcing effects in human subjects (keep in mind that injections produce drug effects that occur much faster than those taken orally in almost all cases)
2. Sleep deprivation boosted the reinforcing effects of methylphenidate.
3. Methylphenidate displayed similar abuse potential to d-amphetamine for a number of studies of the general population (read "non-ADHD" population).
4. PET scans of the brain following methylphenidate and cocaine (when both were injected) showed similar absorption rates and binding levels to their target (called the Dopamine Transporter Protein or DAT. For more more info on the DAT and ADHD, please click here). However, methylphenidate was cleared much more slowly than cocaine, which correlates to a significantly lower addiction potential for the popular ADHD drug. A quick note about this: The faster a drug is absorbed in the brain, the greater the "high" is, typically. Since injections and snorting both get the drug into the system faster than when taken orally, these methods typically lead to much greater highs and addiction potentials. Additionally, the faster this drug is then cleared, the more it is "missed" by the brain, which also results in a greater addiction potential. So for a fast-acting and fast-clearing drug, the addiction potential is typically very high. For comparison sake, methylphenidate takes about 10 minutes to enter the brain when injected (for cocaine, it is about 5 minutes), and then takes about 90 minutes to clear halfway (for cocaine it is around 20 minutes). Thus, due to its slower uptake and even slower clearance rate, methylphenidate runs a much lower risk of being habit-forming than cocaine.
5. Oral administration of methylphenidate is much slower than this, often taking at least 1-2 hours to peak in concentration in the brain. Extended and slow-release versions of the drug (Concerta, Ritalin-SR) reduce the abuse potential even further.
6. Individuals with ADHD are thought to have a higher amount of binding sites (DAT, see point #4) for these stimulant medications than do those without ADHD. According to the author, this makes individuals with ADHD less susceptible than the general population to habit-forming addictions surrounding the use of the stimulant methylphenidate. A more detailed explanation for this is given below:

Further explanation for Item #6 above: Although neuroscientists still disagree over the mechanism of action of both medicated and illegal stimulants, it is believed that when this DAT protein is "plugged up" or "blocked" by these stimulants, it cannot shuttle free amounts of the brain chemical dopamine into the surrounding cells. As a result, the levels of free dopamine between neuronal cells builds up. Since dopamine plays a key role in the "reward" process, it can also play a major role in both "highs" and "addictions" (both of which seek out these "rewards").

If individuals with ADHD have more of these transporter proteins to begin with, they are less likely to oversaturate all of these transporters. As a result, they are less susceptible to this dopamine buildup and the highs and addiction potentials that go along with it. In other words, individuals with ADHD can often accommodate higher levels of stimulant medications such as methylphenidate, making them less susceptible to addiction-level effects.

Based on this article and a number of other sources I have either read or followed, here is my overall take on the topic of addictions to ADHD stimulant medications:

I earnestly believe that when properly diagnosed, properly monitored by a competent physician or related professional, and by proper compliance by the medicated individual, ADHD medications are relatively safe, and the risk of developing an addiction a medication such as methylphenidate is relatively low.

Of course, as we've seen above, individuals who are not diagnosed with ADHD and take methylphenidate for recreational purposes, the potential habit-forming effects of the drug can at least approach the levels of cocaine or amphetamines. Keep in mind that the right medication at the wrong dosage can easily be just as (or even more) damaging than having the wrong medication.

Yes, stimulant drugs prescribed for ADHD are often closely related to cocaine in both chemical structure and mode of function, but the small differences between the two are sufficient enough to form a "safety barrier". Given the fact that so many undiagnosed individuals with ADHD or other related disorders often tend to "self-medicate", the dangers of "un-treatment" are just as real and just as hazardous. Keep in mind that "self-medication" is, by nature, a much more erratic form of treatment and typically abounds in negative side effects.

This is not to say that non-medication treatments should never be explored or considered as viable options for treating ADHD. Many of the so-called "alternative treatments for ADHD" are surprisingly well-grounded and increasingly-researched. However, I remain highly skeptical to those who claim that all cases of ADHD can be handled exclusively and completely by natural means. Natural remedies can be very effective for numerous cases involving ADHD, but their scope and range of applications are somewhat limited.

Please check back later for future posts related to many of these important topics on ADHD!