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.

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.