The NMDA antagonist memantine attenuates the expression of opioid physicaldependence in humans

Rationale: Preclinical observations suggest that NMDA receptor-mediated glu tamatergic neurotransmission is involved in the expression and maintenance of opioid dependence. Objective: The present study evaluated whether memant ine, the clinically available noncompetitive NMDA receptor antagonist, decr eases naloxone-precipitated withdrawal in morphine-dependent humans. Method s: Eight heroin-dependent, non-treatment seeking, inpatient participants we re stabilized on a fixed dose of morphine (30 mg PO qid). Subsequently, the y received a series of challenges with naloxone (0.4 mg, IM) and the severi ty of opioid withdrawal was monitored. Either placebo or memantine (60 mg P O) was given 6 h before each naloxone challenge. A modified multiple baseli ne, across-participants design was used to evaluate the effects of memantin e on the severity of naloxone-precipitated opioid withdrawal. Results: Nalo xone increased ratings and produced physical changes consistent with opioid withdrawal. Memantine attenuated the severity of opioid withdrawal as asse ssed with the Clinical Institute for Narcotic Withdrawal Scale scale. Withd rawal was significantly reduced when naloxone was administered at 6 and 52 h after memantine, but not when administered 126 h (5 days) after memantine . Medication effects, assessed 5 h after memantine administration and befor e naloxone administration, included significant increases in ratings of "st rong" and "good" drug effect, and "I feel sedated", "mellow", and "high". C onclusions: Memantine attenuated the expression of opioid physical dependen ce in humans, indicating that glutamatergic neurotransmission at the NMDA r eceptor site contributes to the maintenance of opioid dependence. This find ing suggests that memantine may be a useful adjunct in the treatment of opi oid dependence.