Another Round of Research Shows Ketamine May Help Alcoholism

Deborah Brauser

February 13, 2020

More research suggests a single infusion of ketamine combined with counseling may help alcohol-dependent patients curb their drinking.

In a pilot study of 40 participants, those who were randomly assigned to receive intravenous (IV) ketamine plus outpatient motivational enhancement therapy (MET) showed greater abstinence rates, longer time to relapse, and fewer heavy drinking days than those who received MET plus midazolam.

The findings support a UK study published in November that showed that a single dose of IV ketamine plus therapy that focused on reactivating drinking-related "maladaptive reward memories" reduced drinking urges and alcohol intake more than just ketamine or a placebo infusion alone.

"I think the take-home message is that behavioral treatment can be helpful, but there are vulnerabilities that can get in the way," current study investigator Elias Dakwar, MD, New York State Psychiatric Institute, Columbia University Medical Center, New York City, told Medscape Medical News.

"It's an important area of research to understand in order to make behavioral treatments more effective; and ketamine appears to have the properties to address those vulnerabilities," Dakwar said.

The study was published in the February issue of the American Journal of Psychiatry.

Real-World Approach

Pathologic alcohol use is responsible for an estimated 3.8% of all deaths globally, yet current interventions for alcohol use disorder have limited efficacy, the researchers note.

New treatments with innovative mechanisms would be valuable, they add.

Ketamine is a high-affinity N-methyl-D-aspartate receptor (NMDAR) antagonist.

Previously, research offered "promising results" with the use of ketamine for cocaine use disorder, including increased motivation to quit and decreased craving, Dakwar noted.

"Those results led us to think about how ketamine might be helpful for other substance use disorders, especially given the overlap in clinical vulnerabilities and epidemiology," he said.

The study from the UK researchers was conducted in 90 patients with harmful drinking behavior but who had not been diagnosed with alcohol use disorder.

Dakwar noted that this was "a nontreatment study. None of the people there had alcohol use disorder; they were heavy drinkers. Also, the effects there were fairly modest.

"My interest was how to integrate ketamine into a clinical, real-world framework that could be helpful for people," he added.

The study included 40 participants (52.5% women; 70.3% white; mean age, 53 years) with alcohol dependence whose average consumption was five drinks per day.

All entered a 5-week outpatient program of MET, which involved engaging in strategies to promote motivation and self-directed change.

During the program's second week, the participants were randomly assigned to received a 52-minute IV infusion of ketamine 0.71 mg/kg (n = 17) or the benzodiazepine midazolam 0.025 mg/kg (n = 23).

This ketamine dose was selected "because it was the highest dose tolerated by participants in preliminary studies," the researchers report.

"Midazolam was chosen as the active control because it alters consciousness without any known persistent...effect on alcohol dependence," they add.

The "timeline follow back method" was used to assess alcohol use after treatment. Abstinence was confirmed by measuring urine ethyl glucuronide levels with urine toxicology tests.

Other measures included use of a visual analogue scale, the Clinical Institute Withdrawal Assessment, and the modified Perceived Stress Scale.

Primary Outcome Met

Results showed that 47.1% of the ketamine group and 59.1% of the midazolam group used alcohol during the 21 days after treatment infusion; 17.6% and 40.9%, respectively, had a heavy drinking day.

For the primary outcome measure of alcohol abstinence, the "quadratic effect of time was significant" (P = .004), as was time-by-treatment interaction (P < .001).

Although the model-estimated proportions of alcohol abstinence remained stable for the ketamine group for 21 days post infusion, the proportions decreased significantly for the control group.

The odds of having a heavy drinking day did not change significantly after treatment for the ketamine group (odds ratio [OR], 0.98; P = .74) but increased significantly with each postinfusion day for the midazolam group (OR, 1.19; P < .001).

For the ketamine group, time to relapse was also significantly longer (P = .04).

There were no significant differences between the groups in rates of withdrawal, craving, or stress sensitivity.

A New Direction?

The most common adverse events after treatment were sedation, seen in 12 members of the midazolam group and in eight members of the ketamine group; and headache, seen in four and six members, respectively.

Although two ketamine-group members experienced mild agitation for up to 1 hour post infusion, no incidents of persistent psychoactive effects were reported in either group.

No participants who received ketamine dropped out during the study period; among those who received midazolam, six dropped out.

"These preliminary data suggest new directions in integrated pharmacotherapy-behavioral treatments for alcohol use disorder," the investigators write.

However, a larger patient population will be needed in future research in order to "replicate these promising results," they add.

Dakwar noted that the time to first drink after treatment was comparable between the groups.

"But what was different in the ketamine group was that they didn't continue drinking after that first drink. They didn't initiate heavy drinking, they didn't relapse, they were able to bounce back and stay with the program," he said.

"It was surprising but still consistent with the central hypothesis that ketamine provides this opportunity for setting the foundation for the requisite commitment so that once things become difficult, they're still able to maintain recovery," Dakwar said.

"Provocative Findings"

In an accompanying editorial, Sanjay J. Mathew, MD, Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, Texas, and Rebecca B. Price, PhD, Department of Psychiatry, University of Pittsburgh School of Medicine, Pennsylvania, note that ketamine's effects on abstinence "were robust" in this trial.

"It is also noteworthy that, in spite of recruiting from a population of patients with active and significant substance use history (a group that has routinely been excluded from ketamine trials in depression), no participant showed evidence of new drug-seeking behaviors," Mathew and Price write.

"Overall, these findings are provocative and hypothesis-generating but certainly not definitive because of the small sample size," they add.

Other limitations cited include the short follow-up period and the fact that only half of the participants were available for a 6-month follow-up telephone interview. In addition, generalizability was limited because the population did not have additional medical or psychiatric illnesses or additional substance use disorders, the editorialists write.

Because of the limitations, the investigators "are appropriately circumspect about the immediate clinical implications of this small pilot study."

Still, the results "affirm the potential of rational combinatorial approaches for a vexing medical and public health problem," Mathew and Price conclude.

The study was funded by grants from the National Institute on Alcohol Abuse and Alcoholism and the National Institute on Drug Abuse and by the New York State Psychiatric Institute. The study authors and Price report no relevant financial relationships. Mathew reports serving as a consultant to or having received research support from several companies, including Alkermes, Allergan, Clexio Biosciences, and Janssen. The original article includes a full list of his disclosures.

Am J Psychiatry. 2020;177:125-133. Abstract, Editorial

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