Effect of conditioned stimuli-triggered memory retrieval-extinction in patients with methamphetamine use disorder

Methamphetamine (METH) is a widely abused stimulant that affects the central nervous system. The persistent maladaptive conditioned stimuli (CS, drug cues)-drug associative memories represent a primary factor precipitating relapse. Interfering with the reconsolidation of these memories may help disrupt and modify these maladaptive CS-drug associations, potentially reducing their influence on drug-seeking behavior. The present study explored the effect of CS-triggered memory retrieval-extinction on METH craving, potentially offering a new treatment strategy for addiction. This was a single-center, randomized, controlled trial involving individuals with METH use disorder (MUD). Participants completed one of three interventions on consecutive days (days 2 and 3): CS-triggered memory retrieval followed by extinction after a 10-min interval, CS-triggered memory retrieval followed by extinction after a 6-h interval, or extinction without prior retrieval. Self-report cue-induced craving for METH, salivary cortisol and sympathetic responses were measured at baseline (day 1), post intervention (day 4) and two follow-up timepoints (days 34 and 184), with cue-induced craving and salivary cortisol as primary outcomes. Ninety-eight MUD individuals (mean age 28.15 ± 6.31) were analyzed. After two-day's interventions, cue-induced METH craving (time × cue interaction: F_(1,94) = 60.02, p < 0.001) reduced in all groups. Results from follow-up data indicated, when the extinction was performed 10 min, but not 6 h after memory retrieval or no retrieval, the intervention decreased experimental cue-induced METH craving (intervention × time × cue: F_(2,94) = 14.32, p < 0.001; intervention: F_(2,94) = 24.28, p < 0.001) and saliva cortisol increases (F_(2,90) = 9.51, p < 0.001), with effects lasting up to 6-month follow-up. The results revealed a substantial reduction in cue-elicited craving and saliva cortisol in the retrieval-10 min-extinction group over the 6-month follow-up. These findings provide compelling evidence that a brief reconsolidation-based intervention can effectively diminish METH-related craving and cortisol levels, underscoring its potential as a supportive measure in METH treatment. Salivary cortisol is a readily accessible and sensitive biomarker for evaluating intervention effects.