Ketamine, an interoceptive associative agent? Evidence from ketamine-assisted Mindfulness-Oriented Recovery Enhancement for opioid use disorder

Background: Relapse in opioid use disorder (OUD) remains common despite pharmacotherapy. Altered interoceptive processing may contribute to addiction, and ketamine-induced changes in salience and insula-related networks may facilitate mindfulness-based interoceptive learning. Aims: This secondary analysis examined whether ketamine-assisted psychotherapy (KAP) added to Mindfulness-Oriented Recovery Enhancement (MORE) improved interoceptive awareness and whether these changes mediated reductions in opioid craving. Methods: Sixty-eight adults with OUD receiving buprenorphine were randomized to 8 weeks of MORE with or without KAP. Assignment was unblinded, and outcomes were self-reported. Interoception was assessed using ecological momentary assessment (EMA) of body awareness and Multidimensional Assessment of Interoceptive Awareness (MAIA) subscales. Posttreatment EMA data were available for 18 MORE + KAP and 15 MORE participants. Mixed-effects models and path analysis were conducted. Results: Piecewise modeling showed a greater increase in EMA-assessed body awareness salience in MORE + KAP during days 1–35, spanning the pre-dosing and first-ketamine-dose period ( B = 0.039, standard error (SE) = 0.005, p < 0.001). Slopes attenuated during days 36–90 (group × slope-change: B = −0.035, SE = 0.008, p < 0.001), although body awareness remained higher for MORE+KAP through follow-up. MORE + KAP increased MAIA Self-Regulation and Body Listening. A composite of these facets mediated reduced opioid craving at 3 months (indirect effect: B = −11.27, 95% bootstrap confidence interval (CI) [−25.50, −0.25], p = 0.044; κ 2 = 0.378). Conclusions: Adjunctive ketamine was associated with rapid, sustained increases in body awareness salience. Improvements in interoceptive regulatory capacity mediated reduced opioid craving, supporting interoception as a potential mechanism and treatment target in ketamine-augmented mindfulness interventions for OUD. ClinicalTrials.gov: NCT04892251