Ketamine Therapy Shows Promise for Alcohol Use Disorder

Ketamine

This is ketamine.

First synthesized at Wayne State University in 1962, the NMDA receptor antagonist was immediately recognized as a promising new anesthetic. The fact that it lacked substantial respiratory depression or the behavioral side-effects that another new agent — PCP — was causing led to rapid clinical use, most notably for surgical anesthesia in the setting of the Vietnam war.

But the recreational use of ketamine, which in sub-anesthetic doses can produce substantial dissociation and hallucination limited wider adoption.

In the year 2000 though, Ketamine got a new lease on life thanks to a paper appearing in Biological Psychiatry that showed a dramatic improvement in depression scores among 7 subjects with severe depression when exposed to ketamine versus placebo.

Ketamine-depression research accelerated, and, in March of 2019, the FDA approved the s-enantiomer of ketamine for treatment-resistant depression, though the efficacy data was not quite as dramatic as some earlier case reports would have you believe.

While we know that ketamine induces anesthesia through antagonism of the NMDA receptor, we don’t know how it treats depression, which limits our ability to predict what, if any, other psychiatric disorders might benefit from ketamine treatment.

This week, we got a bit of early data examining the use of ketamine as a treatment for alcohol use disorder, often co-morbid with depression, in this manuscript, appearing in the American Journal of Psychiatry.

Factorial design

The study is a randomized trial in a 2x2 factorial design.

96 patients were randomized to receive 0.8mg /kg of Ketamine or placebo as well as psychotherapy or alcohol education. The factorial design is an interesting choice here — the authors posit that the dissociation induced by ketamine might facilitate more objectivity and insight during psychotherapy.

The trial is described as double-blind, but don’t hang your hat on that. Participants, by and large, could tell if they were injected with ketamine or saline. In fact, 100% of those randomized to receive ketamine indicated they believed they had received ketamine after the first infusion. This is not surprising given the dose of ketamine used here, which is on par with what recreational users might consider a strong hit — around 75 mgs. Lack of adequate blinding opens up the possibility of placebo effects, which can be very relevant in psychological studies.

The study schedule had participants receive therapy or alcohol education at 7 study visits over 3 months.

During that time they would receive three ketamine or saline infusions. Follow-up occurred at the end of that three-month stint with an additional follow-up at 6 months to assess longevity of treatment effect.

Before I get to the results, a note on these patients. Ketamine studies tend to have rather restrictive inclusion and exclusion criteria — as the drug has some serious side-effects.

Ketamine levels in participants over time

In this case, it’s notable that participants could not be receiving any anti-depressants. There also seems to be a bit of self-selection going on here. 27% of participants had reported using ketamine recreationally in the past and based on this supplemental data showing detectable ketamine levels in a placebo patient, some were still using.

In addition, about half of these participants had previously used psilocybin or LSD.

The primary outcome here was the percent of alcohol-free days over the duration of follow-up.

Primary outcome

Two important findings here. First, you do see a significant improvement in percent of days abstinent from alcohol in the ketamine groups, whether paired with psychotherapy or alcohol education. Perhaps more importantly, you see some evidence of stability of effect. Remember, the last dose of ketamine occurred before week 12 — the next 3 months are just follow-up. Over that time period, the placebo patients return to nearly their baseline alcohol usage. Those exposed to ketamine were faring better.

Of course, this isn’t perfect. Total abstinence was relatively rare in this study — achieved by 48% in the ketamine groups and 33% in the placebo groups — a difference that did not achieve statistical significance.

But I find this line of research hopeful. Not necessarily because it looks like ketamine will be a panacea for refractory psychiatric illness, but because for too long we’ve been unwilling or unable to admit that drugs that have value recreationally may also have value therapeutically. When it comes to psychiatric illness, we may need to set aside our more puritanical impulses.

A version of this commentary first appeared on Medscape.com.

Writing about medicine, science, statistics, and the abuses thereof. Commentator at Medscape. Associate Professor of Medicine at Yale University.

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F. Perry Wilson, MD MSCE

F. Perry Wilson, MD MSCE

Writing about medicine, science, statistics, and the abuses thereof. Commentator at Medscape. Associate Professor of Medicine at Yale University.

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