A single oral dose of methylphenidate, a stimulant commonly used to treat attentive-deficit/hyperactivity disorder (ADHD), modifies abnormal circuitry in the brain, a finding that may help improve self-control and reduce craving in cocaine-addicted individuals.
In a small proof-of-concept study, investigators at Mount Sinai School of Medicine in New York City found that short-term methylphenidate administration “can, at least transiently, remodel abnormal circuitry relative to the pathophysiologic characteristics of cocaine addiction.”
“We have done earlier research that showed oral methylphenidate improved brain function in cocaine addicts who were performing certain cognitive tasks, such as ignoring emotionally distracting words and resolving a cognitive conflict,” senior author Rita Z. Goldstein, PhD, professor of psychiatry and neuroscience, told Medscape Medical News.
Similar to cocaine, methylphenidate increases dopamine and norepinephrine activity in the brain, but when it is given orally, it takes longer to reach peak effect.
“This gives it a lower potential for abuse, and by extending dopamine’s action, it enhances signaling to improve certain cognitive functions, including information processing and attention. In this study, we wanted to determine whether methylphenidate will also improve the network and communication between different neural networks in those same individuals while they were not performing any tasks,” Dr. Goldstein said.
The study was published online June 26 in JAMA Psychiatry.
Strong Suggestion of Benefit
Led by Anna Konova, a doctoral candidate at Stony Brook University, in New York, the study included 18 cocaine-addicted volunteers who were randomly assigned to receive a single oral dose of methylphenidate 20 mg or placebo at each of 2 study sessions.
At each session, the volunteers underwent resting-state functional magnetic resonance imaging (fMRI) to examine changes in mesocorticolimbic connectivity immediately after drug administration, before onset of effect, and 120 minutes later, during peak onset of effect.
The researchers found that methylphenidate decreased connectivity of the ventral striatum with the dorsal striatum, areas of the brain that have been strongly implicated in the formation of habits, including compulsive drug seeking and craving.
fMRI imaging also showed that methylphenidate strengthened connectivity between several corticolimbic and corticocortical connections, areas of the brain involved in regulating emotions and exerting control over behaviors and that are known to be disrupted in cocaine addiction.
“This study showed that mesocorticolimbic connectivity is susceptible to dopaminergic manipulation in cocaine use disorders. We found positive effects after just a single dose,” Dr. Goldstein said.
“Our scans showed very robust enhancement of the communication between those control regions of the brain, and also a reduction in communication between the regions of the brain that characterize addiction.
“Now we need to test whether we could use it in treatment, along with cognitive behavioral therapy or cognitive remediation, to enhance self-control, and give it not just once but perhaps once a week for a few weeks to see if it would help decrease drug use. My lab is going to undertake this next step because these imaging results are so suggestive of benefit,” she added.
Many Trials, Many Failures
Commenting on the study for Medscape Medical News, Mark Willenbring, MD, founder and director of Allina Mental Health in Saint Paul, Minnesota, said it is a very good proof of concept.
“This work does advance the scientific understanding of interactions among neural circuits and goes beyond looking at a specific area alone. It looks at disordered connections between different functional areas of the brain, and it is pretty exciting that methylphenidate could normalize some of those key abnormalities in those areas of the brain,” said Dr. Willenbring, who specializes in addiction treatment.
“So far, finding medications to effectively treat addictions, cocaine in particular, has been very elusive,” he said.
“NIDA [the National Institute on Drug Abuse] has thrown millions of dollars into clinical trials for many different candidate medications that were based on animal studies, and none of them have panned out,” he said.
“But I think that the overall strategy of agonist therapy, as opposed to antagonist therapy, is likely to lead to better results. Examples are buprenorphine or methadone for opioid addiction, and varenicline for smoking cessation. Agonist therapy is likely to be of benefit, and this study supports that it could have real effects on the areas of the brain that are involved in addiction behavior, as shown on functional MRI.”
Dr. Goldstein, Anna Konova, and Dr. Willenbring report no relevant financial relationships. The study was sponsored by the National Institute on Drug Abuse.
JAMA Psychiatry. Published online June 26, 2013. Abstract