Influence of combined treatment with naltrexone and memantine on alcohol drinking behaviors: a phase II randomized crossover trial

Abstract

Glutamate and opioid systems play important roles in alcohol drinking behaviors. We examined if combined treatment with the NMDA antagonist memantine and the opioid antagonist naltrexone, when compared with naltrexone alone, would have a greater influence on alcohol drinking behaviors. Fifty-six, non-treatment-seeking heavy drinkers, with alcohol dependence and a positive family history (FHP) of alcoholism, participated in a randomized, double-blind, crossover trial, including two 6–8 days treatment periods, separated by a 6-day washout, and 3 alcohol drinking paradigm (ADP) sessions. After the first baseline (BAS) ADP1 session, participants were randomized to receive either naltrexone (NTX; 50\u2009mg/day)\u2009+\u2009placebo memantine, or NTX (50\u2009mg/day)\u2009+\u2009memantine (MEM; 20\u2009mg/day), during the first treatment period, following which they completed ADP2. After a 6-day washout, participants were crossed over to the treatment they did not receive during the first treatment period, following which they completed ADP3. During each ADP, participants received a priming drink of alcohol followed by 3 1-hour, self-administration periods during which they had ad-lib access to 12 drinks. Individually, both NTX and NTX\u2009+\u2009MEM, when compared to BAS ADP1, significantly reduced the number of drinks consumed ( p ’s\u2009<\u20090.001) and craving ( p ’s\u2009<\u20090.001). When comparing NTX\u2009+\u2009MEM vs. NTX on number of drinks consumed, there was a significant treatment* sequence interaction ( p \u2009=\u20090.004). Specifically, when NTX\u2009+\u2009MEM followed NTX alone, NTX\u2009+\u2009MEM resulted in a further reduction in drinking (mean: −1.94; 95% CI: −2.6, −0.8, p \u2009=\u20090.0005). However, when NTX alone followed NTX\u2009+\u2009MEM, NTX alone did not lead to further reduction in drinking (mean: 0.59; 95% CI: −0.67, 1.43, p \u2009=\u20090.47). Similar patterns were observed for alcohol craving; specifically, a significant reduction in craving was observed when NTX\u2009+\u2009MEM followed NTX alone ( p \u2009=\u20090.009), but craving reduction was maintained when NTX\u2009+\u2009MEM was followed by NTX alone. Neither treatment condition significantly influenced alcohol-induced stimulation or sedation. Memantine (at a dose of 20\u2009mg/day) enhances the efficacy of naltrexone (50\u2009mg/day) in reducing alcohol drinking and craving among FHP drinkers with beneficial effects that appear to carryover after discontinuation of memantine treatment.