The journey to recovery from addiction is marked by various obstacles, including the notable risk of relapse. Interestingly, medications designed for other health concerns might inadvertently heighten this risk. Brief encounters with stimulant drugs, for instance, can reawaken cravings and trigger relapse, a process known as “priming.” Although the effects of cocaine priming are well acknowledged, the implications of methylphenidate use, primarily for Attention-Deficit Hyperactivity Disorder (ADHD), are less certain. Beyond its therapeutic application, methylphenidate (also known as Ritalin ®) is often utilized for recreation or as a ‘cognitive enhancer,’ notably among college students. Furthermore, methylphenidate’s role as a potential treatment for cocaine addiction is under scrutiny, with mixed evidence regarding its effectiveness and the risk of provoking cocaine cravings. The combination of methylphenidate with drugs like fluoxetine, prescribed for concurrent ADHD and depression, further complicates the issue, potentially mimicking the neurochemical impact of cocaine and sparking relapse in those recovering from stimulant use.
In a groundbreaking study led by Professor Michela Marinelli from the University of Texas and Professor Heinz Steiner from Rosalind Franklin University, with their team members Joel Beverley, also from Rosalind Franklin University, and Dr. Lorissa Lamoureux from the University of Illinois, researchers have uncovered that methylphenidate alone or combined with fluoxetine can potentially reignite cocaine-seeking behaviors in rats. This finding raises significant concerns about the risk of relapse for former cocaine users taking such drugs.
Professor Marinelli stated, “Methylphenidate is commonly prescribed to treat ADHD and is also taken for non-medical purposes as a recreational drug or ‘cognitive enhancer’. Combined exposure to methylphenidate and selective serotonin reuptake inhibitors such as fluoxetine can also occur, such as in the treatment of ADHD with depression comorbidity or when patients taking fluoxetine use methylphenidate for non-medical purposes.” She further explained the critical need for this investigation in humans, “It is unclear if such exposure could subsequently increase the risk for relapse in former cocaine users.”
The study meticulously tested the reinstatement of cocaine-seeking behavior in rats previously conditioned to self-administer cocaine, then subjected to withdrawal. The conditions simulated potential human scenarios of relapse among former cocaine users.
For the experimental procedure, the team introduced the rats to cocaine self-administration, followed by a period of extinction where cocaine was no longer available, mimicking a withdrawal phase. They then tested for reinstatement of cocaine-seeking behavior triggered by acute intraperitoneal injections of either vehicle, fluoxetine, methylphenidate, a combination of methylphenidate and fluoxetine, or cocaine directly. The doses of methylphenidate used were reflective of both therapeutic levels and those potentially misused for recreational or cognitive enhancing purposes, while the doses of fluoxetine were chosen based on their known effects to reduce behavioral markers of depression. This approach allowed the researchers to explore the potential risks associated with both therapeutic and non-medical use of these drugs in triggering cocaine relapse.
Professor Steiner elaborated on the findings, “Our main finding is that rats that self-administered cocaine and then underwent withdrawal and extinction of cocaine-seeking behavior showed reinstatement of cocaine-seeking behavior after a challenge injection of methylphenidate or methylphenidate + fluoexetine, at levels comparable to those seen after a challenge injection of cocaine.”
These results highlight the complex interplay between therapeutic drugs and their potential to activate underlying drug-seeking tendencies, especially in individuals with a history of psychostimulant use. It emphasizes the necessity for careful consideration and monitoring when prescribing these medications to those at risk of relapse. The implications of this research extend beyond the clinical setting, urging a reevaluation of how medications for ADHD and depression are administered to individuals with a past of cocaine use. The study not only sheds light on the biological underpinnings of drug relapse but also calls for a more nuanced approach to treating co-occurring mental health issues in former substance users.
JOURNAL REFERENCE
L. Lamoureux, J. Beverley, H. Steiner, M. Marinelli, “Methylphenidate with or without fluoxetine triggers reinstatement of cocaine seeking behavior in rats”, Neuropsychopharmacology.
DOI: https://doi.org/10.1038/s41386-023-01777-z.
ABOUT THE AUTHORS
Dr. Michela Marinelli is an Associate Professor of Neuroscience at the University of Texas at Austin, with affiliate appointments in the Department of Neurology, the Department of Psychiatry and Behavioral Sciences, and in the Division of Pharmacology and Toxicology. Dr. Marinelli obtained her B.S. in Pharmacy at the University of Rome “La Sapienza” (Italy) and her Ph.D. in Neuroscience and Pharmacology at the University of Bordeaux 2 (France). After a post-doctoral training in the United States, she was hired as an Assistant Professor by the INSERM (the French equivalent to the American NIH). Three years later, in 2003, she was recruited by the Dept. of Cellular & Molecular Pharmacology, at Rosalind Franklin University of Medicine & Science, in North Chicago. After ten years at that University, she moved to the University of Texas at Austin, where she currently works. Dr. Marinelli’s main research seeks to understand the neurobiological bases of drug addiction. The team uses a “systems approach”, which means that they examine and integrate different levels of information to understand how systems work and interact. These variables are studied in rodent models, and they range from the cellular and molecular level to the whole animal level. Dr. Marinelli has published over 50 publications in peer-reviewed journals and her work has been cited over 8000 times.
Dr. Heinz Steiner is a Full Professor of Cellular and Molecular Pharmacology at the Chicago Medical School, Rosalind Franklin University of Medicine and Science, and a Principal Investigator in the Stanson Toshok Center for Brain Function and Repair at Rosalind Franklin University. Dr. Steiner received his M.S. in Biology from the Swiss Federal Institute of Technology (ETH) in Zurich, Switzerland, and his Ph.D. in Physiological Psychology from the University of Dusseldorf, Germany. After post-doctoral work at the National Institute of Mental Health, Bethesda, he was a Research Assistant Professor in the Department of Anatomy and Neurobiology at the University of Tennessee, College of Medicine and The Center for Neuroscience in Memphis. He joined the faculty in the Department of Cellular and Molecular Pharmacology at the Chicago Medical School in 2000, and was department chair from 2011-2022. Dr. Steiner’s research focuses on the functional organization of the basal ganglia and related brain systems, especially on the role of the neurotransmitters dopamine and serotonin in the regulation of basal ganglia – cortical interactions. One of the main objectives of his work is to understand how treatments with dopaminergic and serotonergic drugs produce changes in gene regulation in the basal ganglia and their consequences for drug addiction and other brain disorders. Dr. Steiner is the senior editor of the “Handbook of Basal Ganglia Structure and Function” and a co-editor of Elsevier’s “Handbook of Behavioral Neuroscience” series.
