Research Shows Evidence of Methylphenidate Provoking Relapse in Former Cocaine Users

In a study that was originally published late last year, researchers unveiled the risks for former cocaine users who may relapse by taking methylphenidate.

Methylphenidate is used as a treatment for attention-deficit hyperactivity disorder (ADHD), and is often recognized through brands such as Aptensio XR, Concerta/Concerta XR-ODT, Jornay PM, and most commonly, Ritalin. As a stimulant drug, these medicines increase brain neurotransmitters such as dopamine and norepinephrine, to help a patient achieve better focus and behavior control. To a lesser degree, methylphenidate can also be used to treat narcolepsy as well.

Methylphenidate is currently a Schedule III substance in the U.S., and has a history of misuse. According to Psypost.org, college students sometimes use methylphenidate to help them focus. Although methylphenidate has shown some promise in studies as a treatment to help people abusing cocaine, it comes with a few concerning side effects such as cravings and relapse. Researchers also found that methylphenidate use in conjunction with fluoxetine (a treatment for depression) actually mirrors the effects of cocaine.

The study entitled “Methylphenidate with or without fluoxetine triggers reinstatement of cocaine seeking behavior in rats,” was originally published in the December 2023 issue of Neuropsychopharmacology, and lead by researchers Lorissa Lamoureux, Joel Beverly, Heinz Steiner, and Michela Marinelli.

Study author Michela “Micky” Marinelli works at the University of Texas as an associate professor, and explained the history behind this unique study topic. “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,” Marinelli explained. “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.”

She added that according to Dr. Steiner’s research, methylphenidate elevates just dopamine and norepinephrine in the brain, but cocaine elevates those two as well as serotonin. Because of these similarities. “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?”

Dr. Steiner observed gene expressions in the brain, which revealed the answer to his questions. Together, Dr. Stein and Marinelli wrote a grant study revealing the risks of using both a methylphenidate and an SSRI. “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.

In the most recent study, researchers studied male Sprague Dawley rats in a controlled setting. Rats were trained to self-administer cocaine as a way to mimic youth cocaine use. This was followed by a withdrawal phase when cocaine access was removed, where rats exhibited “cocaine-seeking behavior,” which included “nose poking” whenever they would receive the cocaine. Then an extinction phase followed, where the rats would learn to no longer exhibit that behavior.

The next step included giving the rats either a high dose of methylphenidate or a combined dose of methylphenidate and fluoxetine to see if the rats would relapse and begin exhibiting cocaine-seeking behavior once again. “One needs caution extrapolating studies in rodents to human,” Marinelli said to PsyPost in an interview. “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.”

Researchers also observed that there was no significant difference between rats who took methylphenidate alone, or the combined methylphenidate with fluoxetine, showing that fluoxetine doesn’t impact the effect. “We were surprised that adding a SSRI (fluoxetine) to methylphenidate did not exacerbate the effects of methylphenidate,” said Marinelli. “The effects we saw were due to methylphenidate alone.”

It’s easier to study rats in an isolated, controlled environment versus studying humans, which leaves much to be desired in human observations. “It will be important to examine how much this work translates to human populations,” said Marinelli. “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.”

The rats also did not have ADHD, which could lead to different results in a human trial. “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.”