Subanesthetic Ketamine for the Treatment of Depression

Disclaimer: This article is intended solely for informational and educational purposes only. It does not constitute medical advice.

Since ketamine’s approval by the FDA in the 1970s as an anesthetic, it has been used widely in anesthesia. However, research emerged in the 1990s suggesting antidepressant effects. By the 2010s, it saw widespread off-label use by physicians for its efficacy in patients with treatment-resistant depression (TRD). In 2019, after sufficient clinical trials, the FDA approved esketamine (Spravato), the S-enantiomer of ketamine, at subanesthetic doses for treatment-resistant depression. Racemic ketamine, by contrast, lacks FDA approval for depression and is prescribed off-label without a standardized, depression-specific federal safety framework comparable to Spravato's.

Ketamine's greatest efficacy in treating depression occurs at subanesthetic doses, typically a serum level between 70–200 ng/mL, far below anesthetic levels of 2000–3000 ng/mL. The strongest evidence supports a 40 minute infusion to reach these levels, typically in a clinical setting where unexpected side effects can be managed (Wilkinson et al., JAMA Psychiatry, 2024). These potential side effects include specific qualities of ketamine that complicate its regulation: its production of perceptual disturbances and dissociative effects. These characteristics are part of why the FDA requires patient monitoring after Spravato administration and why abuse and diversion must be mitigated. The FDA strictly prohibits at-home administration of Spravato (Wilkinson et al., JAMA Psychiatry, 2024).

Racemic ketamine, by contrast, remains largely unregulated, since it is still only FDA-approved as an anesthetic, and trials of racemic ketamine are far fewer and less powered compared to those of Spravato. Even so, prescribing of it rose roughly 500% between 2017 and 2022. Meanwhile, between 2019 and 2021, ketamine overdose rates rose by 81% (Levinstein et al., 2025).

Spravato is further regulated on several levels: it carries a boxed warning (citing sedation, dissociation, respiratory depression, and abuse), it may only be dispensed and administered in settings certified under a Risk Evaluation and Mitigation Strategy (REMS), and it requires at least 2 hours of post-administration monitoring, including pulse oximetry, under direct observation. None of these patient protections exist for racemic ketamine, which has no drug safety program (Wilkinson et al., JAMA Psychiatry, 2024).

These safeguards are grounded in a consistent adverse-effect profile. In a large community cohort receiving IV ketamine for TRD, the most common events were drowsiness, dizziness, and dissociation, and 44.3% met criteria for treatment-emergent hypertension (Rodrigues et al., Expert Opinion on Drug Safety, 2020). Long-term risks, like tolerance, misuse, and consequences of repeated high-dose exposure, remain poorly characterized (Köhler-Forsberg et al., JAMA, 2019).

The differences in FDA approval also affect what patients pay. Since racemic ketamine is prescribed off-label for depression, patients often have to pay out of pocket, while esketamine is more likely to be covered by insurance.

At the state level, regulation adds another layer of complexity. Most states restrict ketamine relatively aggressively, while a minority, including New York, Utah, and Oregon, explicitly permit supervised off-label treatment in medical facilities. Meanwhile, direct-to-consumer telehealth platforms ship ketamine for home use with far less oversight than the esketamine REMS. Moving forward, the regulation of ketamine must balance maintaining access to medically proven uses of ketamine with improving safety protections associated with various forms of ketamine and gathering more efficacy and safety data on novel applications of subanesthetic doses.

References

Wilkinson ST, Palamar JJ, Sanacora G. The Rapidly Shifting Ketamine Landscape in the US. JAMA Psychiatry. 2024;81(3):221–222. doi:10.1001/jamapsychiatry.2023.4945

Levinstein MR, Budinich RC, Bonaventura J, Schatzberg AF, Zarate CA Jr, Michaelides M. Redefining Ketamine Pharmacology for Antidepressant Action: Synergistic NMDA and Opioid Receptor Interactions?. Am J Psychiatry. 2025;182(3):247-258. doi:10.1176/appi.ajp.20240378

Köhler-Forsberg O, Cusin C, Nierenberg AA. Evolving Issues in the Treatment of Depression. JAMA. 2019;321(24):2401–2402. doi:10.1001/jama.2019.4990