The effect of dextromethorphan on reward-related behaviors: A systematic review of preclinical and clinical evidence.
Kayla M Teopiz, Gia Han Le, Sabrina Wong, Roger S McIntyre
Journal of Affective Disorders April 1, 2026 DOI: 10.1016/j.jad.2025.120836 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Systematic review Peer reviewed |
|---|---|
| Population | Rats and healthy human participants |
| Interventions | Dextromethorphan Psilocybin |
| Dose | 400 mg/70 kg |
| Topics | Depression |
| Keywords | Anhedonia Anticipatory Antidepressant Consummatory Dextromethorphan Drug-liking Glutamate Methamphetamine Morphine Nicotine Reward |
| Key findings | Dextromethorphan attenuates reward-seeking behavior in rats and shows lower drug-liking compared to psilocybin in healthy humans. |
Abstract
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. 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. 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. 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.
Comparable studies
Other systematic reviews and meta-analyses on depression, most cited first.
Citations in the library
Cited by 2
- Psilocybin for Anhedonia in Unipolar and Bipolar Depression: A Systematic Review of Clinical and Preclinical Evidence Journal of Psychiatric Research October 1, 2026
- Intracellular Crosstalk Between NMDA and Sigma-1 Receptors: A Novel Mechanistic Insight Relevant to Neuropsychiatric Pharmacotherapy Cells September 17, 2026
Cites 8
- Synthesizing the Evidence for Ketamine and Esketamine in Treatment-Resistant Depression: An International Expert Opinion on the Available Evidence and Implementation American Journal of Psychiatry March 17, 2021
- A New Perspective on the Anti-Suicide Effects With Ketamine Treatment Journal of Clinical Psychopharmacology December 12, 2015
- Subjective features of the psilocybin experience that may account for its self-administration by humans: a double-blind comparison of psilocybin and dextromethorphan. Psychopharmacology August 1, 2020
- Efficacy of dextromethorphan for the treatment of depression: a systematic review of preclinical and clinical trials Expert Opinion on Emerging Drugs January 2, 2021
- Ketamine treatment for anhedonia in unipolar and bipolar depression: a systematic review. European Neuropsychopharmacology September 1, 2024
and 3 more in the library