An incredible new experimental study from University College London has found a specifically timed infusion of ketamine can effectively rewrite maladaptive reward memories. In this study a number of subjects with harmful alcohol behaviours significantly reduced their drinking for several months following a single ketamine treatment.
Ketamine was originally developed as a novel anaesthetic in the mid 20th century but its potent disassociative effects rendered it unsuitable for broad human uses. More recently the drug has been experiencing a renaissance after its rapid anti-depressant effects were discovered.
Following on from some landmark Russian research in the 1980s exploring ketamine’s potential for treating a variety of addictive disorders, including alcoholism, a new study is suggesting the drug can potentially disrupt the encoding of reward memories when administered after addictive urges have been primed.
“Learning is at the heart of why people become addicted to drugs or alcohol,” explains Ravi Das, lead author on the new research. “Essentially, the drug hijacks the brain’s in-built reward-learning system, so that you end up associating environmental ‘triggers’ with the drug. These produce an exaggerated desire to take the drug. Unfortunately, once these reward memories are established, it’s very difficult to re-learn more healthy associations, but it’s vital in order to prevent relapse.”
Based on the prior efficacy ketamine had shown treating alcoholism, the new research hypothesized the drug to have the capacity to rewrite maladaptive reward memories (MRMs) if administered at the moment the brain was reconsolidating those memories. To experimentally test this hypothesis the researchers recruited 90 subjects with harmful drinking behaviors. The subjects all self reported heavy drinking (an average consumption of 74 units of alcohol per week) but had no preexisting clinical diagnoses of alcoholism.
To activate a reward memory the researchers presented the subjects with a glass of beer. Before being allowed to drink the beer the subjects were tasked with rating their anticipated pleasure after viewing a series of drinking related images. To destabilize the reward memory the researchers unexpectedly took the beer away from the subjects before they could drink it. The idea is that this process would trigger the reconsolidation of an MRM, creating a short window of time where ketamine could be administered to disrupt the rewriting of the association.
The cohort was randomly split into three groups: one group received an active ketamine infusion immediately after the reward memory activation, another group received a placebo infusion after the memory activation, and a third group received a ketamine infusion in the absence of any MRM activation.
The results revealed the group receiving the ketamine after reward memory activation reported significant reductions in drinking days per week and overall volume of alcohol consumed. The results also impressively held strong for the entire nine-month follow-up period. Interestingly, the group receiving the ketamine without memory activation did report a reduction in drinking behaviors, however, those results were not as strong as those administered the drug alongside MRM activation.
The researchers are cautious in noting the study was only intended as an experimental proof-of-concept, and therefore does not have the rigor of an official clinical trial. This underpins reservations voiced by some experts in over-interpreting the study’s conclusions. The University of Exeter’s Celia Morgan, who did not work on this new research, suggests the ideas explored here are intriguing but it’s early days in understanding exactly how this kind of memory consolidation disruption actually works in humans.
“The problem being that in humans we cannot see whether this is truly reconsolidation being blocked or some other process,” says Morgan. “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.”
Rupert McShane, from the University of Oxford, is also wary of over-excitement in interpreting these results. He suggests until the study is effectively replicated one cannot be sure how relevant these results can be.
“… 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,” says McShane, who did not work in the new research. “This is just an unlucky quirk which sometimes happens when participants 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.”
It is undeniably early days for the field of memory manipulation but this new research is certainly not the first study to explore ways to pharmacologically edit our memories. Earlier this year an impressive study, led by a team of Spanish scientists, investigated whether a commonly used anesthetic called propofol could weaken, or even erase, the reconsolidation of negative memories.
The research was inspired by the commonly seen side-effect of short-term memory loss in patients following general anesthesia. The small proof-of-concept study discovered that administering propofol directly after the reactivation of specific memories did indeed tend to impair the recall of those memories in the days following. This research was primarily exploring whether negative memories linked to PTSD could be effectively suppressed, or rewritten, by interrupting the reconsolidation process with a specific drug.
So, while this new ketamine study somewhat feels like it is tinkering on the fringes of science fiction, with its drug-induced concepts of memory manipulation, it is underpinned by an impressive body of pre-existing research. And, if the scientists can first verify, then optimize, this process, it has the promising ability to be easily deployed to help millions of people suffering from different forms of addiction.
“This is a first demonstration of a very simple, accessible approach, so we hope that with more research into optimizing the method, this could be turned into a helpful treatment for excessive drinking, or potentially for other drug addictions,” says Das.
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