Cocaine is a powerfully addictive substance that with repeated use leads to rewiring of the brain’s reward system. We have described the brain mechanisms underlying the development of addiction in an earlier blog post.

A person addicted to cocaine develops a craving for it, and this craving can take over a person’s life.

Unfortunately, the addiction-mediated rewiring of brain pathways may not reverse even after many years of being drug free. The craving for cocaine may never go away, and there are no consistently effective medications to treat it. Elias Dakwar and colleagues from Columbia University have been interested in exploring treatments for substance abuse, and they recently published a paper in the journal, Molecular Psychiatry examining the effect of ketamine on cocaine self-administration.

Why ketamine? Ketamine has been shown to have rapidly acting antidepressant properties. The mechanism of this effect may involve this drug’s ability to increase neuroplasticity—the ability to make brain cell connections more flexible. Would this property of ketamine help temporarily diminish the effects of the cocaine-induced abnormal rewiring that leads to craving?

Participants in this study consisted of 20 volunteers who were addicted to and actively using crack cocaine. They were hospitalized for six days during each of three different study periods. On the fourth day of each hospitalization, the participants received one of three treatments by intravenous infusion: ketamine, placebo (saline), or a so-called active placebo—in this case, midazolam. Midazolam was considered to be an active placebo because the participants could tell that they had received an active agent, but at the dose used, midazolam is not thought to influence cocaine craving.

One day after receiving the study drug or placebo, the participant was offered a choice between immediate access to crack cocaine or money that would be paid the following day. Each participant was presented with this choice five times throughout the test day. It had been previously established that the amount of cocaine and the amount of monetary reward were such that a treatment that decreased cravings would shift an individual’s preference from smoking cocaine to receiving money. 

When participants received either saline or midazolam the day prior to testing, they chose cocaine instead of money an average of 4.3 out of 5 times. When they received ketamine the day prior to testing, they chose cocaine only 1.6 times out of the 5 offerings. In other words, the single infusion of ketamine diminished the measure of craving for cocaine the next day by two-thirds. Although this effect of ketamine wore off within a few days for most participants, two participants maintained abstinence from cocaine for an entire two-week follow-up period.

This finding is remarkable, and hopefully it will be confirmed by other investigators. If it turns out to be reproducible, then a new avenue of research into treatments for addiction may ensue. It is possible that ketamine interferes temporarily with the abnormal brain pathways associated with addiction. If so, can this effect be made permanent? 

While the Dakwar study is likely to generate considerable interest, it is also important to proceed cautiously in terms of potential clinical use of ketamine-like drugs. Ketamine is known to induce acute psychotic symptoms in otherwise normal adults, and it is an abused drug in its own right. The temporary nature of the changes raise the possibility that repeated infusions of ketamine (or ketamine-like drugs) will be needed to produce more sustained effects in individuals with cocaine addiction, but we know little about the longer-term consequences of repeated ketamine infusions at the present time.

Studies of ketamine for major depression are proceeding rapidly, and important lessons will be learned from these studies. It will also be interesting to determine whether the beneficial effects of ketamine in cocaine addiction (provided they can be replicated in subsequent studies) will translate to benefits in other substance use disorders. Despite these significant limitations, we may be entering an era in which acute infusion treatments become more common in psychiatry across a range of illnesses.

This column was co-written by Eugene Rubin MD, Ph.D. and Charles Zorumski MD.

References

Dakwar, E., Hart, C.L., Levin, F.R., Nunes, E.V., & Foltin, R.W. (2017). Molecular Psychiatry, 22, 76-81.

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