Ritalin and Cocaine: Similarities and Differences

We have previously investigated some of the similarities between the chemistry and modes of action of Ritalin and cocaine. In this past post, however, we looked more at the rates of uptake and metabolism of the two drugs and investigated a side-by-side structural comparison.

I was originally planning on continuing with posts on Daytrana, which is very similar to the more common ADHD medications Ritalin and Concerta (it is actually comprised of the same chemical agent, methylphenidate. However, I recently saw an interesting article on the topic of methylphenidate, cocaine and nicotine, and the mechanism of interaction between these different stimulants. As a result, in lieu of the Daytrana postings, I would like to discuss these findings in the next couple of posts.

Here are seven key points to be aware of regarding the similarities and differences between methylphenidate and cocaine:

1. SIMILARITY: Uptake patterns into the brain: Both methylphenidate and cocaine enter the brain at similar rates and target similar specific regions of the brain. When injected, around 7.5% of the injected compound makes it into the brain tissue for each compound at similar rates (peak uptake only takes around 2 to 8 minutes for cocaine and 4 to 10 minutes for methylphenidate in the injected form, oral administration, which will be discussed later, is significantly longer, especially for methylphenidate). The most favored target region of the brain is the striatum for both cocaine and methylphenidate (see brain diagram below). In fact, several studies have indicated that the two drugs share a number of target binding sites within the brain, to the point where the ADHD medication methylphenidate has actually been used as a treatment option for cocaine abuse.
   
   
2. Brain Regions Targeted by each drug: In addition to similar uptake patterns in the brain between the two drugs, there is a relatively large degree of overlap for particular brain regions targeted. However, there is at least one notable exception, which bears relevance to our discussion. On an interesting note, the method of delivery not only affects the speed of uptake of a drug (injected is almost always faster than snorted, which is almost always faster than ingested), but also the actual brain regions targeted by the drug. For example, another brain region, called the Nucleus Accumbens (see image below for approximate location) is targeted by cocaine and injected methylphenidate. However, when methylphenidate, such as Ritalin, Concerta or Metadate is taken orally, this nucleus accumbens region is not targeted (at least not anywhere near the level of injection).
   
   The nucleus accumbens is believed to play an important role in the addiction potential of a number of drugs, including many stimulant medications. Thus, proper use of the methylphenidate medication actually bypasses a key brain region believed to be critically involved in the "high" or addiction process of a stimulant drug. This highlights a major difference in the pharmacology between Ritalin and cocaine.
   
3. Key Difference between methylphenidate and cocaine: Rate of clearance from the striatum region of the brain: As mentioned in an earlier post, the addiction potential of a drug is typically correlated to the rate of exit or clearance from the brain. In other words, drugs that linger in the brain's receptors for extended periods of time are often much less addicting than ones which exhibit a short and rapid spike in their brain levels and then a quick drop-off in their concentration in the brain. In the striatum, the rate of clearance takes about 90 minutes for methylphenidate, and only 20 minutes for cocaine. If we go by peak concentration duration (i.e. the amount of time the highest concentration typically lasts in the brain before going back down), we see that methylphenidate's peak lasts around 15 to 20 minutes, while cocaine's is a fleeting 2 to 4 minutes. In both cases, the higher dissipation of the drug from high levels in the brain is much more pronounced in cocaine, giving this drug a much more addiction-worthy effect over methylphenidate (even when methylphenidate is abuses and either snorted or injected, it still cannot match the rates of clearance of cocaine).
   
   
4. Potency of the two drugs: The following may seem surprising at first. With regards to specific brain targets, methylphenidate is almost twice as potent as cocaine. We have discussed at length the role of the dopamine transporter protein (DAT), and its role in ADHD and related disorders. Essentially, this DAT protein is responsible for retaining a proper balance of the important brain chemical dopamine in and out of nerve cells. For individuals with ADHD, this balance is often skewed, typically with too much dopamine being taken up into the neuron cells and not enough in the gaps between the cells. Many stimulant medications remedy this problem by essentially binding to and plugging up the dopamine transporter proteins in the nervous system, which inhibits their abilities to shuttle dopamine into the cells. As a result of this medication-effected correction, dopamine balance can be somewhat restored. As a frame of reference, based on some of the current literature, it takes often takes at least a 60% saturation of these dopamine transporters with a drug to elicit the "high" (of course, there is a significant degree of variation between individuals).
   
   With regards to potency, we see that both cocaine and methylphenidate love to bind to these dopamine transporter proteins. To shut down the function of these dopamine transporter proteins to 50% of their original function (a common way of measuring the potency of a drug in pharmaceutical and laboratory testing), a 640 nanomolar concentration was needed for cocaine, while only a 390 nanomolar concentration was needed for methylphenidate to do the trick. If you're not familiar with these units of concentration, don't worry. These numbers work out to very small amounts (around the neighborhood of only 0.001 grams of drug per liter of fluid). I just put the numbers out there to show that only about half the amount of methylphenidate was needed to share the same effects with cocaine (i.e. the methylphenidate is approximately twice as potent for this particular process).
   
   
5. Difference between Ritalin and Cocaine: DAT saturation levels and perceived high: The relative saturation of these dopamine transporters are also believed to play a role in the "high" of stimulant drugs such as methylphenidate and cocaine. However, research by Volkow and coworkers found that while the level of saturation of the dopamine transporters with cocaine correlated with the "high" associated with this drug, the methylphenidate drug tells a different story. As mentioned previously, the reinforcing effects of a drug including the "high" typically correlate with the rate of clearance from the brain.
   
   We have also seen that methylphenidate clears much more slowly than cocaine. However, in the case of methylphenidate, the diminished effects of the the high occurred long before the drug had fully cleared from the dopamine transporter. In other words, there appears to be a relatively strong connection between the binding of cocaine to the dopamine transporter proteins and the perceived "high" but the effects are much less pronounced with methylphenidate. This highlights a major difference between methylphenidate and cocaine and at least suggests the possibility of a difference in mechanisms between the two stimulants.
   
   
6. Divergence in metabolic patterns between methylphenidate and cocaine: Furthering this issue a bit more, there is some evidence that the pathway of the two drugs is almost identical for the first part of the journey into the system, but their modes of action split off at some point when it comes to dopamine transporter occupancy and the corresponding reinforcement effects (see sketch below).
   
   
   
7. Difference between methylphenidate and cocaine: Drug lingering and tolerance: The persistence of methylphenidate on the dopamine transporter proteins may result in more than its reduction of abuse potential. It also appears that this "lingering" of the drug on these dopamine transporter proteins may also play a significant role in the phenomena of tolerance to methylphenidate.
   
   Acute tolerance to methylphenidate is nothing new. Newer formulations of the drug (Concerta, Metadate) were designed in part to address the problem of the reappearance of ADHD symptoms by ramping up and releasing increased levels of the drug throughout the day. This is important, because, the effects of methylphenidate appear to be best felt when its levels are climbing or building up, and not stabilizing (i.e. you do not want a constant level of methylphenidate throughout the day, but rather a constantly increasing one to maintain the same effects). Essentially, this is "micro-tolerance" to methylphenidate and is seen on a daily level. The ideal dosing strategy for methylphenidate typically entails a morning dosage which is approximately 50% of an evening dosage, i.e. a "ramping" effect of the drug throughout the day is often needed to maintain the desired results.
   
   It is suggested that this tolerance to methylphenidate may be due, at least in part to its continued presence and relatively slow clearance in specific areas, such as on the dopamine transporter proteins. Other faster-clearing drugs, such as cocaine, do not exhibit this property. However, given the fact that cocaine tolerance is also common, it is unlikely that the whole "dopamine transporter saturation" theory can fully address the issue of tolerance for stimulant drugs. Volkow and coworkers explored this role of blocking dopamine transporters with methylphenidate and the perceived high in greater detail. Nevertheless, at least in this blogger's personal opinion, the lingering effect of methylphenidate still plays some degree of significance to the process of tolerance to the drug, and the need for ramping its dosage to treat disorders such as ADHD.

Gene Variations Which Affect Attention Control

A couple weeks ago, I posted some information on a specific gene thought to be connected with ADHD called COMT (short for Catechol-O-Methyltransferase). This gene is located on the 22nd human chromosome, and can exist in different forms. What is important to note is that the amount of stimulant medication necessary for effective dosing for ADHD and related disorders is often dependent on which forms of this gene an individual possesses. To view this (somewhat lengthy) post on COMT, please click here.

In this previous post, I mentioned that the COMT gene codes for an enzyme which goes by the same name. This COMT enzyme has two forms of interest with regards to our discussion, the "Met" form and the "Val" form. "Met" and "Val" are short for Methionine and Valine, respectively, which are two different amino acids seen at the 158th spot on the COMT enzyme.

The reason that this is so important and relevant to the topic of ADHD is that this relatively small difference in enzyme composition can have a huge effect on how much of a stimulant medication is required to reach peak chemical efficiency in a region of the brain called the prefrontal cortex.

The prefrontal cortex is located in the brain behind the forehead, and is heavily associated with the disorder of ADHD. What a recent study found was that individuals with the "Met" form of the enzyme often require significantly less "assistance" from stimulant medications to reach peak efficiency in this critical brain region during cognitive tasks, than do individuals with the "Val" form of the enzyme. To illustrate this, please refer to the diagram below, which was seen in this previous post.:




Now it appears that, in addition to the prefrontal cortex region of the brain, these two variations in this COMT gene are responsible for what goes on in other brain regions as well. This region is called the cingulate cortex. The region of this brain section which we are most interested in for this discussion is about 2/3 of the way back, closer to the center of the brain. This region of interest is around area 31 on this brain map below, which is referred to as the dorsal cingulate. Here, the word "dorsal" means "back", and the word "cortex" refers to the outer layer. As a reference, the prefrontal cortex area of the previous discussion of interest is around region 9 of the brain map below:
There are a couple of differences worth mentioning between these two brain regions. The prefrontal cortex region mentioned in the previous post is responsible for functions such as working memory (which is explained in more detail here), as well as screening out unimportant information and inhibiting inappropriate responses. We can see how this is relevant to ADHD, as improper function on this region can lead to excessive distraction by unimportant stimuli and poor impulse control. To use the analogy of a car, we might think of this brain region as a type of "braking system" for the brain.

If the prefrontal cortex region acts as the brakes, the cingulate region of the brain can be thought of as a type of "gear shifter". In addition to being relevant to ADHD, this cingulate region of the brain can also be a major factor in disorders such as OCD (Obsessive Compulsive Disorder). In the case of OCD, the cingulate region is overactive. As an analogy, think of pushing on a gear shift with too much force that the vehicle gets "stuck" in a specific gear. In the same sense, individuals with OCD often get "stuck" on a certain fixation whether it be washing one's hands repeatedly, counting cracks on a sidewalk, or repeatedly checking to make sure the oven is off.

As an interesting aside, there has been some interesting discussions on the role of the cingulate region of the brain with regards to governing events involving motor control such as hand movements. This may be one of the reasons why individuals with ADHD often have poor handwriting and difficulty taking notes.


There are some differences in chemical function between these two brain regions (the cingulate and the prefrontal cortex) as well. For the prefrontal cortex region, there are relatively few receptors and transporters for the brain chemical dopamine. Dopamine is a key ingredient for proper signaling between neurons, and a specific balance of this chemical inside and outside of nerve cells is critical for proper function. For individuals with ADHD, there is often a shortage of dopamine in the areas in between nerve cells, so this inside-outside balance is off. Many stimulant medications work to "correct" this imbalance by blocking the transport of dopamine from the outside of cells to the inside of cells in specific regions of the brain. In contrast to the prefontal cortex region of the brain, where there are relatively few of these dopamine transporting and receiving agents, the cingulate region of the brain has a much higher concentration of these dopamine-regulating areas.

The reason that the COMT enzyme is so relevant to all of this, is that this enzyme is capable of metabolizing and breaking down the chemical dopamine. We have previously seen that the "Val" form of this enzyme is more effective at metabolizing dopamine than the "Met" form. As a result, individuals who exclusively have the "Val" form, are often more prone to a shortage of free dopamine than individuals with the "Met" version.

What does this all mean?

Several studies have indicated that the cingulate region is very important in monitoring conflict and regulating behavioral control as well as governing challenging decision making processes. With regards to our discussion here, if an individual is taking an online exam and a cricket is chirping outside, the cingulate region is in part responsible for which "stimulus" is more worthy of attention. Therefore, this cingulate region of the brain plays an important role with regards to attentional control.


A brief recap of the study on COMT gene variations on the cingulate brain region:

A comprehensive study was done by Blasi and coworkers to investigate the differences between the "Met" and "Val" forms of the COMT gene with regards to attentional control. They found that individuals who had both copies of the "Val" form of the COMT gene (remember that humans typically possess two copies of a gene, one coming from each parent) had much more difficulty maintaining attention than did individuals who had both copies of the "Met" form of the gene. Individuals who had one "Val" form and one "Met" form fell in between.


Blasi's group found that in order to maintain attention for a prolonged period of time (i.e. screening out distracting stimuli that interfere with the desired task at hand), the "Val" individuals had much more activity going on in this cingulate region of the brain. In other words, this cingulate brain region had to work harder (i.e. was less efficient) for the individuals who had both copies of the "Val" form of the COMT gene, than for those who had one copy of each. Individuals who were fortunate to have both copies of the COMT gene be of the "Met" form showed the most efficient (i.e. less work needed) cingulate region of the brain, and were more effective at maintaining attention to the desired task at hand.


What is interesting to note is that this group tested the subjects on different tasks which required varying degrees of attentional control. This was done by asking the individuals to analyze the relative orientation of different sized arrows on a computer screen (see here for the the diagrams used in the study). Notice that there are three different sizes of arrows, in which seven small arrows make up a medium sized arrow and six medium sized arrows comprise a large arrow. Subjects were asked to answer which direction a given-sized arrow (either "small", "medium" or "large") was facing. Note that for the "easy" attention tasks, all 3 sizes of arrows were pointing in the same direction, while in the "medium" and "hard" attention-based tasks, the different-sized arrows were pointing in different directions.


Results of the attention-based study: The study found that the genetic effects were much more pronounced for the difficult attention control tasks than for the easier tasks. In other words, individuals with the "Met" forms of the COMT gene had a much less difficult time with this task than did individuals with the "Val" forms of the COMT gene (that is the cingulate region of the "Met" individuals required less brain activity to complete the task than the cingulate region of the "Val" individuals).

This is analogous to the results from a brain activity study involving the differences in the "Val" and "Met" gene forms on a working memory task, which utilized the prefrontal cortex region of the brain (you can find the blog post on this study here). Based on this prefrontal cortex study, the more difficult the working memory task, the more pronounced the difference between the "Met" and "Val" individuals (like in the cingulate study, the "Val" individuals' brains had to work harder). Brain activity in both studies was determined by measuring changes in blood flow to these brain regions required to complete the task, using an oxygen-detecting system (larger increases in blood and oxygen flow to a specific brain region signify harder work by that portion of the brain).


Key differences between the two brain regions regarding Val and Met differences:

While the two studies of the two different brain regions and their respective tasks (the prefrontal cortex and working memory tasks vs. the cingulate region and attention control tasks) shared a high degree of overlap in their results, there were some key differences:

• While individuals with the "Val" form of the COMT gene required greater effort in their prefrontal cortex region of their brains (as detected by blood oxygen sensors) than those with the "Met form", this overall increase in effort did not correspond to worse performances in the tests by the "Val" individuals. In other words, for tasks involving working memory, it appears that while "Val" individuals have to work harder, they can still perform at comparable levels of accuracy to "Met" individuals. However, "Val" individuals may have a more difficult time when it comes to the cingulate region, as there was a connection between an increase in required brain activity and actual performance on these tasks. In other words, "Val" individuals could be out of luck when it comes to matching performances with their "Met" counterparts when it comes to functioning during very difficult attention-maintaining tasks. Of course this is not to say that practice, training and medication treatment cannot overcome at least some of this inherent genetic disadvantage.



• When it comes to task performance requiring attention and working memory, it appears that differences in dopamine-governed signaling processes (such as those arising from "Val" or "Met" forms of the COMT gene), it appears that accuracy differences in performing tasks is more pronounced in cingulate regions of the brain, where differences in speed, reaction time and even premature decision-making are more evident in the prefrontal cortex region of the brain.
  
  
• Within the context of this post, it suggests that "Val" individuals are more prone to slower processing, poor reaction timing and impulse control on tasks involving the prefrontal cortex (such as tapping into working memory in tasks such as recalling and utilizing stored information such as math formulas or physics equations), and more likely to be error-prone with regards to tasks involving the cingulate region (such as discriminating between multiple conflicting stimuli and maintaining attention to the "correct" one).
  
  
• Taking the above one step further, this possibly suggests that if an untreated ADHD individual who has the "Val" version of both genes was taking a physics test, he or she could likely perform in a comparable manner to that of a similar individual with the "Met" form, if he or she had extra test time. This is because this type of test would likely involve working memory (i.e. recalling and then using an appropriate formula for a particular physics problem). However, if a continuous external distraction was present (such as a loud air conditioner or a flickering light or an attractive member of the opposite sex seated nearby), having extra test time would be less likely to even the playing field for our poor "Val" individual. This of course, may be stretching and over-simplifying quite a bit (of course we know that there are way more factors involved than just this), but these somewhat subtle genetic differences could possibly have some implications when it comes to discerning and providing accommodations for individuals with learning disabilities, especially in an academic or work environment.
  

These findings have medication implications as well. Based on the Prefrontal Cortex / Working Memory studies with regards to the "Val" and "Met" forms of the COMT gene, we have seen that differences in ADHD medication dosage are affected, with "Val's" typically requiring more stimulant medications than "Met's" to achieve optimal dopamine balance. However, in the cingulate brain region, another key signaling chemical called serotonin also comes into play. As mentioned previously, the cingulate region is thought to play a role in OCD, and medications of the antidepressant variety (which often boost serotonin levels and can actually indirectly reduce dopamine production, as serotonin and dopamine can sometimes act in a "push-pull" manner, where an increase in one can decrease the other) are often utilized as a medication treatment option.

This is why medication treatment strategies, can get hairy with regards to this cingulate region. On one hand, we want to tune down the dopamine-destroying effects of the "Val" form of the COMT gene in an attempt to regulate attentional control, while at the same time keep this cingulate region in check so a chemical imbalance of serotonin doesn't force this region into overdrive and result in or exacerbate OCD behavior. That is why some of these studies tying down the effects of variations of specific genes to specific brain regions can be such useful tools in determining medication levels.

I am personally convinced that in the future, individual genetic screens will become more commonplace and will play much more of a role in governing the selection and dosage of specific ADHD medications. As we begin to pin down more and more gene forms to specific regions of the brain, we will certainly be armed with more tools to fine-tune individual treatments for ADHD and related disorders and eliminate some of the guess-work in selecting medications and other treatment options.

ADHD Gene#3: DAT

ADHD Genes

ADHD Gene #3: Dopamine Transporter Gene (DAT, SLC6A3), Human Chromosome #5

There have been a number of recent postings on genes thought to be connected with ADHD. Previous ones discussed include the ADHD form of the Dopamine D4 receptor Gene (DRD4), the ADHD form of the Dopamine D5 Receptor Gene (DRD5), and, to a lesser degree, the DRD2 ADHD gene. However, one of the most intriguing ADHD genes is a gene called the Dopamine Transporter Gene, abbreviated as DAT. An ADHD form (also called allele), of this gene, which is located on the 5th chromosome in humans, has been tabbed. The ADHD gene DAT has been discussed in another recent post, where it has been tied to a mutated form of a protein called the dopamine transporter protein that "shuttles" an important brain chemical, called dopamine, in and out of neuron cells. While the regular form of this protein functions, normally, the mutated form causes it to run in the opposite direction at high speed, significantly changing the distribution of the dopamine chemical throughout the brain. This balance can result in extreme ADHD symptoms, and has also been seen in bipolar individuals.

Statistically speaking, there is a weaker correlation between the above form of the gene and ADHD behavior than the previous two genes. Nevertheless, this gene serves as an important target for stimulant medications (such as Ritalin) for both rats and humans. A number of studies have been done on an analogous gene in mice has shown that altering this gene function resulted in a noticeable increase in hyperactivity and decrease in behavioral inhibition and control.

Remember, two ADHD genes mentioned in previous posts, the DRD4 ADHD gene, and the DRD5 ADHD gene are both thought to be more affiliated with the inattentive component of ADHD. In contrast, individuals with the DAT gene mentioned in this posting, above are more prone to hyperactivity and behavioral inhibition problems associated with ADHD. We will soon discuss the various components and subtypes of ADD and ADHD in later posts, but for now, please keep in mind that a number of different genes may be at work within and ADHD individual.

There is still a fair amount of research to be done on this gene, but for now, we can cautiously assume that there is a correlation between forms of this DAT gene, located on the 5th human chromosome, and ADHD.

ADHD genes

ADHD Protein on "Speed"?

ADHD treatment options and resources

New mutation found on an "ADHD gene"

I was going to post some more information on the second ADHD gene on the list, but I recently came across a very interesting article on genetic mutations and ADHD, which can be found here.
The original study was recently published in the July 9, 2008 issue of the Journal of Neuroscience by the groups of Aurelio Galli and Randy Blakely. Several subtypes of ADHD are thought to be caused by an imbalance in the levels of of dopamine, an extremely important chemical found in the brain and nervous system that regulates proper neural functioning. There is an ideal balance between the amount of dopamine that is stored in neurons and the amount that is present in the "gaps" between different neuron cells.

It is here, that a critical protein comes into play. A special protein called the Dopamine Transporter (DAT) protein acts as a type of "shuttle" or "ferry" that helps balance dopamine levels inside and outside of the neuronal cells by aiding in the transport of dopamine in and out of the cells. This protein is actually "coded" for by the third ADHD gene on the list of a recent post.

It is strongly suggested that individuals diagnosed with ADHD have lower than normal levels of this dopamine in the gaps between neuron cells. As a result, a number of ADHD drugs focus on this DAT "shuttle" in an attempt to manipulate its ability to clear dopamine to the cells (think of the analogy of building a dam to trap and collect a stream of water in a region where it is scarce). In essence, this helps "fix" the problem of the low dopamine levels in this space, which is associated with ADHD.

Here is where it gets interesting. A rare mutation causes this shuttling DAT protein to essentially run in reverse at high speeds. Instead of "mopping up" dopamine and carrying it into the surrounding neurons, this mutated form of the protein essentially "squeezes" dopamine out of the cells and into the open space. This mutant protein actually functions in a very similar way to amphetamines such as the popular ADHD drug Adderall (which, incidentally, is chemically similar and has a similar, but much more benign, mode of function as the drug "Speed"). Here lies the paradox-- we would think that this mutated transporter protein, which behaves like a drug used to treat ADHD would be beneficial for ADHD individuals. However, the opposite is true. Individuals which possessed this mutation exhibited noticeable ADHD behavior.

Further complicating the issue is the fact that Adderall, while behaving much like this mutation by making the DAT shuttle run backwards, actually blocks some of the key negative effects of the mutation. Think of it as an almost homeopathic-like solution, treating "like" with "like". Ritalin, another ADHD medication which, in turn, can counteract the ability of Adderall to make this shuttle protein move backwards. For sake of brevity, I will save this discussion for a later post in the near future!

Finally, it is also interesting to note that this DAT mutation is very rare. Outside of this study, only one other case had been seen by the researchers, that of a bipolar girl. I found this interesting because it is sometimes difficult to distinguish differences between ADHD and pediatric bipolar disorders. The overlap of this mutation between the two disorders may lend some credence to underlying genetic mechanisms that both disorders seem to share.

ADHD treatment options and resources