The effect of dextromethorphan on reward-related behaviors: A systematic review of preclinical and clinical evidence.

INTRODUCTION

Extant literature suggests that anhedonia, defined as a loss of the ability to feel pleasure or interest, is subserved by dysregulation of reward processing in the central nervous system. Dextromethorphan (DXM), an uncompetitive N-Methyl-d-Aspartate (NMDA) receptor antagonist and sigma-1 (σ1) receptor agonist, is a glutamatergic modulator with antidepressant properties. The effect of DXM on reward-related outcomes remains inadequately characterized. Herein, we conducted a systematic review of extant literature reporting on the effects of DXM on reward-related behaviors in both preclinical and clinical studies.

METHODS

A systematic search of the literature was conducted on online databases (PubMed, OVID, Scopus, Web of Science) of published articles from inception to January 2025. Preclinical and clinical studies that reported on the effect of DXM on reward outcomes were assessed.

RESULTS

Preclinical studies (n = 13) indicate that administration of DXM attenuates reward-seeking behavior in rats as measured primarily by performance in the conditioned place preference test and behavioral sensitization. In a single human study (n = 1) evaluating DXM in healthy participants (n = 20), self-reported drug-liking for DXM (400 mg/70 kg) was significantly lower in comparison to psilocybin (20 mg and 30 mg) at 7 h after the dosing session.

DISCUSSION: Extant literature suggests that DXM administration attenuates reward-related behaviors in rats. There is a paucity of human studies investigating the effect of DXM on reward outcomes. Future research should prioritize the investigation of the effect of DXM on reward function using validated reward paradigms in persons with anhedonia.