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Researchers have found that a single high dose of methylphenidate may increase the risk of relapse in individuals who have previously used cocaine. This study, published in the journal Neuropsychopharmacology, utilized a rodent model to investigate the effects of methylphenidate on relapse behavior, providing new insights into the potential dangers of this commonly prescribed drug.
Methylphenidate (commonly known by its brand name, Ritalin) is a stimulant drug primarily prescribed for the treatment of attention-deficit hyperactivity disorder (ADHD). It works by increasing the levels of certain neurotransmitters in the brain, namely dopamine and norepinephrine, which helps improve focus, attention, and behavioral control. While its medical benefits are well-documented, methylphenidate is also known for its potential misuse. College students, for example, often use it as a cognitive enhancer to boost concentration and stay awake for extended periods.
Previous studies suggested that while methylphenidate could be beneficial in treating cocaine addiction, it might also inadvertently provoke cravings and relapse, similar to the effects of cocaine itself. Additionally, the use of methylphenidate in combination with fluoxetine, a selective serotonin reuptake inhibitor (SSRI) commonly used to treat depression, was of particular interest. Fluoxetine alters serotonin levels, and combining it with methylphenidate could potentially mimic the effects of cocaine more closely.
One of the researcher’s curiosity about the increasing use of methylphenidate in children with ADHD led the team to investigate its potential for causing stimulant addiction.
“The interest started many years ago, from a creative graduate student I worked with in Dr. Frank White’s lab: Cindy Brandon. Cindy had school-aged children and noticed that more and more children at school were being diagnosed with ADHD and treated with methylphenidate,” explained study author Michela (Micky) Marinelli, an associate professor at the University of Texas at Austin.
“She wondered if this could pose a risk to develop stimulant addiction and she set out to study this in rodent models. She found that rats are not likely to self-administer very low doses of cocaine (they are too low to have an effect) but they will self-administer these low doses of cocaine if they have been previously exposed to methylphenidate (Brandon et al., 2001). She continued this line of research as a postdoctoral fellow in Dr. Heinz Steiner’s lab. Dr. Steiner was an expert in studying gene expression and together they found that methylphenidate alters gene expression in the brain in ways that were similar to cocaine, but not quite the same.”
“Dr. Steiner noted that methylphenidate elevates dopamine and norepinephrine, but not serotonin (cocaine elevates all three),” Marinelli said. “So he asked: what would happen if people taking methylphenidate also take antidepressant drugs like selective serotonin-reuptake inhibitors (SSRIs), which elevate serotonin. Would the methylphenidate + SSRI combination become cocaine-like?”
“He studied this by examining gene expression in the brain and found that indeed, this combination created changes in gene expression that were similar to those caused by cocaine. From there, we wrote a grant together to study the risk of combining methylphenidate and SSRIs. One of our questions was to determine if this combination could increase risk of relapse, in individuals (rats) that had self-administered cocaine in the past.”
“At this point in time, methylphenidate started to be taken not just in the clinic, as a medication for ADHD but also recreationally or as a ‘cognitive enhancer’ so we set out to examine both low and high doses of methylphenidate, to mimic (as much as possible in a rat) doses used in the clinic (low doses) vs. those used recreationally or as a cognitive enhancer (high doses),” Marinelli explained.
To investigate the effects of methylphenidate, the researchers used a controlled laboratory setting with male Sprague Dawley rats. These rats were chosen because their biological and behavioral responses can model human addiction patterns effectively.
Juvenile rats were trained to self-administer cocaine. This phase simulated the initiation of drug use during adolescence, which is a critical period for the onset of substance abuse in humans. The rats were given access to cocaine and learned to associate a specific action (nose poking) with receiving the drug.
After a period of cocaine self-administration, the rats underwent a withdrawal phase, followed by an extinction phase. During extinction, cocaine was no longer available, and the rats’ cocaine-seeking behavior gradually decreased. This process aimed to extinguish the learned drug-seeking behavior.
Following the extinction phase, the rats were subjected to reinstatement tests. They were given a single high dose of methylphenidate or a combination of methylphenidate and fluoxetine to see if these drugs would trigger a relapse in cocaine-seeking behavior. The researchers measured the rats’ responses to determine if the drugs prompted them to resume their cocaine-seeking actions.
The primary finding was that a single high dose of methylphenidate could indeed trigger a relapse in cocaine-seeking behavior. This was particularly evident when comparing the rats’ responses before and after the administration of methylphenidate. The rats that received a high dose of methylphenidate demonstrated a marked increase in their cocaine-seeking actions, suggesting that the drug can reinstate addictive behaviors even after a period of abstinence.
The researchers also compared the relapse-inducing potential of methylphenidate with that of cocaine. The results showed that the relapse behavior induced by a high dose of methylphenidate was comparable to that triggered by cocaine itself. This similarity underscores the potent nature of methylphenidate in provoking addictive behaviors.
“One needs caution extrapolating studies in rodents to human,” Marinelli told PsyPost. “But at least in rats, if one has previously taken cocaine, taking methylphenidate can push that individual (rat) to seek cocaine again. This happens at high doses of methylphenidate, comparable to those used recreationally or as a cognitive enhancer.”
Interestingly, the addition of fluoxetine, a selective serotonin reuptake inhibitor, did not significantly alter the relapse-inducing effects of methylphenidate. The researchers found that whether the rats were given methylphenidate alone or in combination with fluoxetine, the relapse behavior was similar. This indicates that while methylphenidate’s impact on relapse is robust, fluoxetine does not exacerbate or mitigate this effect.
“We were surprised that adding a SSRI (fluoxetine) to methylphenidate did not exacerbate the effects of methylphenidate,” Marinelli said. “The effects we saw were due to methylphenidate alone.”
As with all research, however, there are some caveats to note. The study focused on the effects of a single, acute dose of methylphenidate, which simulates short-term recreational use. The long-term effects of chronic methylphenidate use remain unknown. The rats used in the study did not have ADHD, which means the results may not fully translate to humans with ADHD who are prescribed methylphenidate.
“It will be important to examine how much this work translates to human populations,” Marinelli noted. “These are difficult to study as, unlike rats, they are not in a controlled environment, where we can determine the dose, duration, and manner in which they are exposed to different drugs or medications or treatments.”
“When I teach about addiction in summer camps or to undergraduate students, I ask how many of them know of someone who has taken methylphenidate as a cognitive enhancer. Almost all raise their hand. When I then ask them if any of them have, nobody raises their hand – so self-reported use of methylphenidate might be difficult to obtain. Anonymous questionnaires are helpful, but not if one wants to obtain more information from a person, which is only done face-to-face.”
The study, “Methylphenidate with or without fluoxetine triggers reinstatement of cocaine seeking behavior in rats,” was authored by Lorissa Lamoureux, Joel Beverley, Heinz Steiner, and Michela Marinelli.
