Revisiting ketamine’s rapid antidepressant effect beyond NMDA antagonism: modulation of endogenous opioid signaling and interactions with glutamatergic-driven neuroplasticity

Introduction

Ketamine produces rapid antidepressant effects in treatment-resistant depression (TRD), with symptom improvement occurring within hours and persisting beyond its short elimination half-life. Current mechanistic models focus on N-methyl-D-aspartate (NMDA) receptor antagonism and subsequent glutamatergic disinhibition, α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) throughput, and downstream brain-derived neurotrophic factor (BDNF) and mammalian target of rapamycin (mTOR)-mediated neuroplasticity. While these proposed mechanisms are backed by considerable evidence and plausibly explain sustained antidepressant gains, they are insufficient to explain ketamine’s early anti-dysphoric and anti-suicidal actions. Growing evidence suggests ketamine and its metabolites may modulate endogenous opioid signalling, raising the possibility that opioid receptors and downstream signaling may be key contributors to rapid affective improvement and interact with glutamatergic pathways.

Aims

The aim of this review was to synthesize preclinical, translational and clinical evidence supporting endogenous opioid involvement in ketamine’s antidepressant response and propose an integrated mechanistic framework linking opioid and glutamatergic systems.

Methods

A narrative review of scientific studies published between 2000 and 2026 was conducted on PubMed, Embase and Scopus using search terms pertaining to ketamine, its metabolites, opioid receptors and opioid receptor antagonists. Relevant preclinical pharmacological studies, murine behavioural models, and human clinical trials were included. Key inferential statistics reported by included studies were also extracted descriptively.

Results

Clinical studies suggest opioid receptor blockade attenuates ketamine antidepressant response. In a randomized double-blind crossover study (n=7), pretreatment with 50 mg naltrexone reduced ketamine response rates from 71% to 0%, prompting early study termination [1]. More recently, Jelen et al. [2] demonstrated that naltrexone pretreatment attenuated both ketamine-induced anterior cingulate glutamatergic activity and antidepressant response, with reduced glutamate and glutamine increase measured by functional magnetic resonance spectroscopy (p = 0.029) and blunted day-1 Montgomery–Åsberg Depression Rating Scale improvement (p = 0.023). Preclinical evidence further supports opioid system involvement. Opioid antagonists blocked ketamine-induced antidepressant-like behavioural effects in rodents [3]. At the molecular level, Gomes et al. [4] demonstrated that ketamine and its metabolites (norketamine and hydroxynorketamine) act as positive allosteric modulators of μ-, δ- and κ-opioid receptors, significantly potentiating endogenous opioid peptide signalling even at nanomolar concentrations that may persist in vivo in tissues days to weeks after ketamine administration, including enhanced GTPγS binding, β-arrestin recruitment and MAPK activation. Notably, 6-hydroxynorketamine displayed robust opioid receptor modulation despite lacking meaningful NMDA receptor affinity, supporting pharmacological relevance of opioid receptor modulation.

Conclusions

Although sparse, emerging evidence supports consideration of opioid receptor signaling as an important contributor to ketamine’s rapid antidepressant effects beyond NMDA-mediated homeostatic neuroplasticity. The findings in this review suggest opioid signalling may modulate ketamine-induced glutamatergic antidepressant mechanisms rather than functioning as an independent parallel pathway. Rather than opposing the glutamatergic model, enhanced opioid signalling may represent an upstream or permissive process that drives acute anti-dysphoric and anti-suicidal effects, while modulating downstream glutamatergic and neuroplastic cascades associated with sustained response. This integrative model proposes that ketamine enhances endogenous opioid signaling, which interacts dynamically with glutamatergic pathways to produce both rapid and durable antidepressant effects in an opioid-dependent manner. However, further in vivo receptor occupancy, pharmacokinetic and neuroimaging studies are required to clarify possible causal mechanisms.

References

1. Williams NR, Heifets BD, Blasey C, et al. Attenuation of Antidepressant Effects of Ketamine by Opioid Receptor Antagonism. Am J Psychiatry. 2018;175(12):1205-1215. doi:10.1176/appi.ajp.2018.18020138
2. Jelen, L.A., Lythgoe, D.J., Stone, J.M. et al. Effect of naltrexone pretreatment on ketamine-induced glutamatergic activity and symptoms of depression: a randomized crossover study. Nat Med 31, 2958–2966 (2025). https://doi.org/10.1038/s41591-025-03800-w
3. Klein ME, Chandra J, Sheriff S, Malinow R. Opioid system is necessary but not sufficient for antidepressive actions of ketamine in rodents. Proc Natl Acad Sci U S A. 2020;117(5):2656-2662. doi:10.1073/pnas.1916570117
4. Gomes I, Gupta A, Margolis EB, Fricker LD, Devi LA. Ketamine and Major Ketamine Metabolites Function as Allosteric Modulators of Opioid Receptors. Mol Pharmacol. 2024;106(5):240-252. Published 2024 Oct 17. doi:10.1124/molpharm.124.000947