Multiple studies have demonstrated that a single administration of ketamine can rapidly, but transiently, alleviate depressive symptoms as well as thoughts of suicide. Interestingly, ketamine’s effect may be more potent in depressed individuals with a family history of alcoholism. Can ketamine help individuals with problematic consumption of alcohol who do not exhibit depressive symptoms? Two recent studies addressed this question.
In an article published in the American Journal of Psychiatry, Elias Dakwar and colleagues describe a study utilizing a single 52-minute infusion of ketamine in conjunction with several weeks of motivational enhancement therapy. Individuals with alcohol use disorder who received the ketamine infusion had improved rates of abstinence, prolonged time to relapse, and fewer days of heavy drinking than individuals with alcohol use disorder who received an infusion of midazolam. (Midazolam was used as an active control because, like ketamine, it alters consciousness. Midazolam is not thought to have long-lasting effects on alcohol dependence, however.) During the 21 days following the infusion, 41% of the midazolam group abstained from alcohol compared to 53% in the ketamine-treated group. During the same period, 41% of the midazolam group experienced a heavy drinking day compared to 18% in the ketamine group. (A heavy drinking day was defined as more than four drinks per day for men and more than three drinks for women.) The odds of a heavy drinking day increased with each day post-infusion for the midazolam group but did not change significantly for the ketamine group.
The authors acknowledge that this study is preliminary and has several limitations. The sample was small: 23 individuals were in the midazolam group (six of whom dropped out before the end of the study) and 17 in the ketamine group. The study was also of short duration; longer follow-up would have provided important information about the longer-term effectiveness of ketamine in preventing relapse.
In a second study published in Nature Communications, Ravi Das and colleagues used a single infusion of ketamine to interfere with memory reconsolidation related to drinking cues in a group of young adults (55 men and 35 women) with harmful/hazardous drinking patterns. Individuals with problematic substance use develop learned associations between environmental cues related to the substance and expectations of reward from consumption of the substance. For example, when individuals with histories of problematic drinking see pictures of alcoholic beverages, they recall prior experiences with alcohol and these memories reinforce their urge to drink. These retrieved memories can be modified by administering ketamine during the initiation of the memory retrieval process. This procedure is thought to make these memories less reinforcing.
In the Das et al. study, when ketamine was administered without initiating recall of alcohol-related memories, there was a decrease in alcohol use during the first week after the procedure and at all time points during the 9-month follow-up period. This result is consistent with the results of the Dakwar et al. study discussed above, although subjects in the Das et al. study did not meet the criteria for alcohol use disorder. When ketamine was administered in a manner that interfered with the reconsolidation of alcohol-related memories, the effect of ketamine was substantially larger. These results suggest that ketamine might help decrease the use of alcohol in those with problematic drinking through two different mechanisms.
The knowledge that recalled memories undergo a process of reconsolidation and that reconsolidation is susceptible to modification was gained from preclinical neuroscience research. Therapeutic application of this finding in studies such as those discussed here is an example of translating findings from basic science research into treatments. As more is learned about brain function, more science-based therapies will be discovered.
This post was written by Eugene Rubin MD, Ph.D. and Charles Zorumski, MD
Dakwar, E., Levin, F., Hart, C.L., Basaraba, C., Choi, J., Pavlicova, M., Nunes, E.V. (2020). A single ketamine infusion combined with motivational enhancement therapy for alcohol use disorder: a randomized midazolam-controlled pilot trial. Am J Psychiatry. 177:125-133.
Das, R.K., Gale, G., Walsh, K., Hennessey, V.E., Iskandar, G., Mordecai, L.A., Brandner, B., et al. (2019 Nov 26). Ketamine can reduce harmful drinking by pharmacologically rewriting drinking memories. Nat Commun. 10(1):5187. doi: 10.1038/s41467-019-13162-w.