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 the 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 response 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 Buy ketamine USA in heavy drinking and addictive disorders, potentially via modification of glutamatergic dysregulation or mTOR-mediated downstream effects on neural plasticity. 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 to be mutually exclusive. Indeed the greatest treatment benefits may be seen through a 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.