November 26, 2019

expert reaction to study using ketamine for problem drinking

Research, published in Nature Communications, reports the use of ketamine to reduce problem drinking by pharmacologically rewriting drinking memories.

Dr Rupert McShane, Consultant psychiatrist at Oxford Health NHS Foundation Trust, Associate Professor, University of Oxford, and spokesperson for the Royal College of Psychiatrists, said:

“If the findings of this study were replicated, it could be very important. At its broadest, it could imply that habits of thinking could be provoked and then usefully disrupted by a single ketamine infusion.  If proven, this would have many therapeutic applications.  

“However, the major problem with the study, which is acknowledged by the authors, is that the three groups being compared were not similar in terms of how much they were drinking.  This is just an unlucky quirk which sometimes happens when participant are randomly put into groups.  What it means is that the key result could have happened because those drinking the most will also, statistically, have tended to reduce their drinking the most. So, unfortunately, we cannot really be sure about how to interpret the data.

“When this happens, the only way to be confident about the result is for someone else to do the study again.  Given the possibilities here, I’m excited to see the result of that replication study.”

Prof Celia Morgan, Professor of Psychopharmacology, University of Exeter, said:

“This is an interesting study that elaborates on some other work from the 1980s showing ketamine may help people reduce alcohol use. Although these people were not alcoholics unlike earlier work so it remains to be seen if this memory procedure could weaken memories in this group. Ketamine overall reduced drinking but this was greater in people who had been shown a beer cue before which is said to reactivate a memory and make it vulnerable to destabilisation.

“The idea is really intriguing and follows up other work blocking drug use behaviours by using similar drugs to interfere with reconsolidation in animals. More recently people have tried this in humans but the findings of which have so far been mixed. The problem being that in humans we cannot see whether this is truly reconsolidation being blocked or some other process. We really have no idea about the time course or dose of ketamine required to block this so we need a lot more work on this and ideally some way of testing if this is reconsolidation or some other process related to thinking about the cues.

“The fact that these are people who drink a fair amount but not daily, and who don’t meet criteria for alcohol use disorder means that the use as a treatment has to be tested. People in the study who drank less beer went on to drink more wine so this also may limit use as a treatment. Ketamine is an addictive substance and associated with harms to bladder and a risk of accidents, so we have to be cautious when using it in groups who are prone to addictive behaviours.

“But this is important work trying to drive the science of ketamine and memory forwards.”

Prof Matt Field, Professor of Psychology, University of Sheffield, said:

“This study demonstrates that in problem drinkers, administration of ketamine at the same time as a brief procedure to disrupt alcohol-related “maladaptive reward memories” (MRM) leads to reductions in alcohol craving and the anticipated enjoyment of alcohol. These promising findings are certainly worthy of further investigation. However, the authors’ claim that they have found “meaningful, lasting reductions in alcohol consumption outside of the lab after a single brief manipulation (that) are unprecedented in alcohol research” should be interpreted with some caution.

“This is because the group of participants who received ketamine alongside the MRM procedure tended to drink more alcohol than the control groups at baseline (and therefore their consumption was more likely to decline, a phenomenon known as regression to the mean). More importantly, it can be seen that all participants (including participants in both of the control groups) tended to reduce their alcohol consumption over the 9-month follow-up period, as is common with problem drinkers such as the people who took part in this study. Indeed, at the 6-month follow-up, both control groups appear to be drinking LESS alcohol than the ketamine + MRM group. At 9-month follow-up, the groups are drinking at comparable levels but this seems to be because alcohol consumption sharply declined in the ketamine & MRM group between 6 and 9 months, for reasons that the authors cannot explain. This can be seen in Figure 2c on page 5.

“In summary, these are promising findings but the strong claim that ketamine & MRM leads to ’unprecedented’ long-lasting reductions in alcohol consumption are not justified on the basis of this data. Further investigation with a larger sample size and preregistration of methods and hypotheses before data collection begins is needed to support this claim”.

‘Ketamine can reduce harmful drinking by pharmacologically rewriting drinking memories’ by Ravi Das et al. was published in Nature Communications at 16:00 UK time on Tuesday 26th November. 

DOI: 10.1038/s41467-019-13162-w

Declared interests

Dr Rupert McShane: Advisory Boards for Janssen and Sage. Participating as a trial site in 2 Janssen trials of esketamine. I run an NHS, and an NHS-self-pay ketamine clinic in Oxford Health NHS Foundation Trust.

Prof Celia Morgan: “I did used to be in that lab but wasn’t directly involved with the work. I examined the PhD student who did this as part of her PhD.”

Prof Matt Field: “I have no conflicts of interest to declare.”