This study found that intravenous ketamine following the brief retrieval of maladaptive cue-alcohol memories produced a comprehensive reduction in the reinforcing effects of alcohol among harmful drinkers. A rapid and lasting reduction in number of drinking days per week and volume of alcohol consumed was observed when ketamine followed MRM retrieval/destabilization, with no rebound to baseline observed for at least 9 months following manipulation. Control groups receiving retrieval or ketamine alone did not show such changes in reward-related responses to alcohol, although the latter group did show some reduction in drinking.

This pattern of results is aligned with a therapeutic mechanism grounded in reconsolidation interference. Successful interference with the MRMs that putatively underlie excessive drinking should theoretically allow rapid and lasting dampening of reward responsivity to alcohol cues, reducing motivation to drink and drinking levels. The reductions in drinking attributable to ketamine per se (i.e. without MRM retrieval) are aligned with previous research indicating a potential therapeutic effect of ketamine in heavy drinking and addictive disorders, potentially via modification of glutamatergic dysregulation or mTOR-mediated downstream effects on neural plasticity20. Notably however, the effect of ketamine alone was considerably smaller than when combined with MRM retrieval. We therefore posit that prior MRM reactivation can be a potential catalyst for ketamine’s efficacy in this scenario. Given the negligible additional time investment, discomfort, or clinical burden required to incorporate MRM reactivation, we recommend that this strategy is pursued to develop ketamine-based pharmacotherapies for AUD. This may further prove a fruitful approach in other disorders for which ketamine is currently under investigation and where maladaptive memory is implicated (e.g. depression and PTSD).

The moderate/large associations between blood ketamine and ketamine metabolite levels during the critical ‘reconsolidation window’ in RET + KET are noteworthy, as they represent a potential biomarker for treatment response in a reconsolidation paradigm. That these associations were only seen in the “active” group strongly suggests that reconsolidation blockade was responsible for the remedial effects of the manipulation. Without prior destabilization of MRMs (No RET + KET), acute plasma levels of ketamine, norketamine and dehydroxynorketamine were relatively inconsequential to long term drinking levels. Since responding appeared dose-dependent and given that ketamine is relatively safe even at fully anesthetic doses, future studies may wish to consider using higher doses of ketamine (up to full anaesthesia) to maximize NMDAR saturation and subsequent memory interference.

These results are the first (to our knowledge) to demonstrate that reconsolidation of naturally acquired maladaptive alcohol memories in humans is dependent on NMDAR signaling, and that weakening of alcohol MRMs can be achieved with ketamine following MRM reactivation. The resultant, comprehensive reductions in cue reactivity and meaningful, lasting reductions in alcohol consumption outside of the lab after a single brief manipulation are unprecedented in alcohol research. This speaks to the potential scope of the reconsolidation-interference approach. Current “top-down” (psychosocial) treatment modalities that rely upon incremental learning of new, adaptive cognitive and behavioral patterns to suppress MRMs typically require prolonged treatment over multiple sessions. This presents issues both in terms of therapist burden and service user disengagement and recidivism.

The reconsolidation interference approach instead tackles this issue from the bottom-up, theoretically allowing direct weakening of pathogenic memory mechanisms and more rapid therapeutic gains. This is not to say the two approached need be mutually exclusive. Indeed the greatest treatment benefits may be seen through combination of an initial reconsolidation-based intervention to weaken relapsogenic memories, followed by cognitive-behavioral methods designed to instill more adaptive behaviors and cognitions.

Despite these promising results, several key issues remain that must be addressed through further study and refinement of this approach. Firstly, although ketamine is widely used and safe, particularly at the sub-anesthetic concentrations used here, its dissociative and psychotogenic properties and typical administration route (IV) mean specialist supervision is required and that it may be contraindicated for certain individuals with high schizotypal or dissociative traits. Contemporary advances in drug delivery technologies (e.g. intranasal) and the discovery of less dissociative analogs, spurred by ketamine’s burgeoning use in depression, may be critical in improving the tolerability and acceptability of this approach in substance use disorders. Clearly, the tolerability and potential harms from single-dose ketamine (which we argue are minimal) must be weighed against the health benefits of reduced drinking. Drugs that act as antagonists/inhibitors of other pathways implicated in reconsolidation, such as noradrenergic antagonists may also hold promise for the weakening of maladaptive memories22. Although these remain relatively untested in the context of heavy drinking, meta-analysis suggests that these may be less generally effective in weakening reward memories than NMDAergic compounds16.

Relatedly, although we suggest, based on preclinical research, that NMDAR antagonism is a likely potential mechanism underlying the observed effects, we cannot say with certainty that this is the only system involved in the current study. Ketamine has several targets, including other classes of glutamate receptor and opioid receptors which may have contributed to the observed effects. Although the NMDAR is thought to be the primary ‘gatekeeper’ of memory reconsolidation23, non-NMDA receptors may also represent potential therapeutic targets for reconsolidation going forward.

A primary obstacle to the valid assessment of potential therapeutic reconsolidation-blockers is the lack of standardization in retrieval procedures designed to destabilize MRMs. Indeed, inconsistency in retrieval procedures is the norm in the field and may explain the inconsistency in studies attempting to interfere with memory reconsolidation17,24,25,26,27. We have attempted to address this issue through consistent use and detailed description of our MRM destabilization protocol28. However although effective, our procedure was not necessarily ‘optimal’. Indeed, what constitutes ‘optimal’ retrieval parameters for destabilization of different memory types remains an empirical unknown that must be identified to realize the full potential of reconsolidation as a therapeutic strategy. Currently, when confronted with null results, we are unable to infer whether a failure to block memory reconsolidation, or a failure to destabilize memories a priori was responsible. This is due to the fact that memory destabilization and interference is currently a ‘silent’ process, lacking a valid biomarker. It must thus currently be inferred from successful reductions in behavioral “readouts” of MRM strength, as in the current study. Thus despite the convergent evidence supporting this mechanism, we cannot say for certain that MRM weakening produced the beneficial effects observed here. Future research must tackle this issue directly, with the aim of developing independent biomarkers of memory destabilization. Having established ketamine as a robust, dose-dependent reconsolidation blocker in the current study marks a key step forward in achieving this aim and bringing this therapeutic approach to the clinic.

The participants in the current study showed a clearly harmful and problematic pattern of drinking, equivalent to that seen in clinical AUD, but had not received a formal diagnosis of AUD from a healthcare professional and were not treatment-seeking. There is significant variability in cut-point thresholds for diagnosing AUD from AUDIT scores in a UK drinking population. According to Foxcroft et al’s29 findings, based on mean AUDIT scores many of the sample might be expected to meet criteria for AUD. That the sample did not meet SCID criteria for severe alcohol dependence at screening is therefore noteworthy. This is because the sample scored very highly on measures of heaviness of consumption and effects of bingeing (which contributed greatly to AUDIT scores), but did not display physical symptomatology, extreme distress, inability to perform daily tasks nor morning drinking (which contribute highly to SCID criteria). These discrepancies raise important questions around exactly what is being assessed by alcohol use screening tools and potential response biases (see supplementary discussion). Given the novelty of the experimental manipulation assessed here, immediate assessment in a treatment-seeking sample would have been premature and carried greater potential for iatrogenic harm following a relatively untested intervention. Hazardous/harmful and non-treatment-seeking disordered drinkers are a key target group in their own right, however and the reductions observed here, could have enormous public health implications. Given the high levels of problematic drinking in the current sample, one may reasonably expect similar effects to be observed in a more severely dependent/ treatment-seeking population and there is now a strong rationale to conduct such clinical trials in formally diagnosed populations.

It is worth noting that baseline levels of alcohol consumption in RET + KET tended to be higher than the other two groups. While this difference was not statistically significant, we cannot rule out regression to the mean as a contributing factor to the observed reduction in alcohol consumption. Based on the pattern of results in their entirety, however, this explanation is highly unlikely. The clear and striking complementary reductions in the hedonic and motivational properties of alcohol, drinking frequency (which did not differ at baseline) and the association of these with objective ketamine biomarkers seen in RET + KET, are commensurate with the comprehensive dampening of alcohol reward memory structures that might be expected from successful MRM reconsolidation interference.

Owing to response attrition, power, and sample representativeness decreased throughout follow-up. Follow-up data showed that a self-selecting group of responsive participants. This may explain why the drinking data converge at the 9 month time point, with all groups reporting very similar (albeit much lower than baseline) levels of drinking. Despite this, intention-to-treat analyses did not show any appreciable difference to analyses performed on the available data.

This is the first study to demonstrate interference with the reconsolidation of maladaptive alcohol memories in humans using ketamine. These findings highlight the promise of reconsolidation interference as a therapeutic mechanism in harmful drinking, alcohol and substance use disorders and offers key insights into the therapeutic targets of ketamine, while adding to the burgeoning list of its potential psychiatric indications. The striking apparent dampening of reward structures surrounding alcohol and substantial, lasting reductions in drinking levels highlight that reconsolidation interference may form a key part utility of the next generation of more effective long-term treatments for addictive disorders.