Non-Psychoactive Cannabis Extract Disrupts Reinstatement and Reconsolidation in Cocaine-Induced Conditioned Place Preference in Mice

Cocaine use disorder (CUD) remains a significant global health issue, with no FDA-approved pharmacological treatments. Cannabidiol (CBD), a non-psychoactive phytocannabinoid primarily derived from Cannabis sativa L., has demonstrated promising results in preclinical research to disrupt the consolidation and retrieval of drug-associated memories, thereby reducing relapse behaviors linked to substance use disorders such as cocaine dependence. This study evaluates the effects of a non-psychoactive cannabis extract (NPCE) on the reinstatement and reconsolidation of cocaine-induced conditioned place preference (CPP) in CD1 male mice—processes that, to our knowledge, have not been previously examined. The results showed that NPCE significantly inhibited both priming -induced and stress-induced reinstatement of cocaine-induced CPP, suggesting its potential to disrupt drug-associated memories. Additionally, NPCE effectively impaired the reconsolidation of cocaine-induced CPP, suggesting an effect on memory reconfiguration lasting at least two weeks. Additionally, NPCE alone did not produce any effect on CPP acquisition. These findings underscore the potential of NPCE, in targeting memory-related mechanisms underlying cocaine addiction, specifically in the reconsolidation and reinstatement. These results indicated that NPCE may reduce relapse risk by modulating drug-reward memories, potentially through interactions with CB1 receptors and other molecular signaling pathways like serotonergic receptors. This research contributes to the growing body of evidence, which suggests that cannabinoids, particularly non-psychoactive extracts, could offer novel therapeutic options for treating CUD. Further studies are needed to explore the individual effects of other cannabinoids on cocaine dependence and to assess clinical applicability of these findings.