Systematic Review: Ketamine’s Psychiatric Role, Safety, and Policy Gaps

Ketamine’s Expanding Role in Psychiatry: Key Findings from a 2026 Systematic Review

A 2026 systematic review (OpenAlex W7215047767) consolidates evidence on ketamine’s clinical applications, safety profile, and regulatory challenges, reflecting its rapid ascent from anesthetic to psychiatric intervention. The review, which analyzed 106 peer-reviewed articles across PubMed, SCOPUS, and PsycINFO, confirms ketamine’s established use in anesthesia and its growing off-label use for treatment-resistant depression (TRD), post-traumatic stress disorder (PTSD), anxiety, and bipolar disorder. This synthesis is particularly timely as clinicians, researchers, and policymakers grapple with the drug’s expanding footprint in both regulated and non-traditional care environments.

Mechanisms of Action: From NMDA Antagonism to Network-Level Effects

Ketamine exerts its psychiatric effects primarily as an N-methyl-D-aspartate (NMDA) receptor antagonist, but its downstream impact is far-reaching. The review details how ketamine’s blockade of NMDA receptors leads to increased glutamate release, activation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, and upregulation of brain-derived neurotrophic factor (BDNF). These molecular changes promote synaptogenesis and neuroplasticity, with additional signaling through the mammalian target of rapamycin (mTOR) pathway. At the systems level, ketamine alters connectivity within large-scale brain networks, including the default mode network, which is implicated in mood, cognition, and self-referential thought. This mechanistic complexity underpins both its rapid antidepressant effects and its dissociative, sometimes psychotomimetic, side effects.

Clinical Applications and Off-Label Expansion

Ketamine is FDA-approved as an anesthetic, but its psychiatric use is largely off-label, with the notable exception of esketamine (the S-enantiomer) nasal spray for TRD. The review highlights robust evidence supporting intravenous ketamine for TRD, with response rates often exceeding those of conventional antidepressants in acute settings. However, evidence for other indications—such as PTSD, anxiety disorders, and bipolar depression—remains preliminary, often limited to small trials or open-label studies. Notably, the review surfaces a non-obvious challenge: the heterogeneity of dosing regimens and administration routes (intravenous, intramuscular, oral, sublingual, and intranasal) complicates both research synthesis and clinical standardization, with implications for reproducibility and safety monitoring.

Safety, Monitoring, and the Rise of Telehealth Prescribing

Ketamine’s safety profile is characterized by acute dissociation, transient cardiovascular effects, and, with chronic or high-dose use, risks of cystitis, hepatotoxicity, and cognitive impairment. The review draws attention to the proliferation of telehealth services prescribing oral and sublingual ketamine, especially since the COVID-19 pandemic relaxed certain telemedicine regulations. This shift has enabled broader access but also introduced new risks, including insufficient patient monitoring, diversion, and unstandardized protocols. A concrete example not widely discussed in competitor analyses is the lack of consensus on remote screening for psychiatric contraindications—such as a history of psychosis or substance use disorder—which may elevate risk in virtual care models. The review calls for urgent development of standardized telehealth protocols and post-marketing surveillance systems to track outcomes in these rapidly evolving settings.

Ethical, Public Health, and Policy Implications

The review integrates ethical and public health perspectives, emphasizing the societal consequences of expanding ketamine access outside traditional medical settings. Key concerns include the potential for recreational misuse, disparities in access, and the challenge of balancing innovation with patient safety. The authors underscore gaps in current knowledge, particularly regarding long-term outcomes, comparative effectiveness against other interventions, and the impact of different delivery models on safety and efficacy. For policymakers, these gaps highlight the need for adaptive regulatory frameworks, real-world data collection, and ongoing stakeholder engagement as the field evolves.

Looking Forward: Research and Regulatory Priorities

Future research must address unresolved questions about optimal dosing, duration of benefit, and risk mitigation strategies, especially in community and telehealth contexts. The review’s synthesis suggests that as ketamine’s psychiatric use expands, interdisciplinary collaboration—across neuroscience, clinical trials, public health, and ethics—will be essential to ensure both innovation and safety. Policymakers and funders should prioritize studies that directly compare administration routes, monitor long-term outcomes, and evaluate telehealth-specific risks, as these factors will shape the next phase of ketamine’s integration into mental health care.

How we research: This article was written by Dr. Alex Morgan, MD, PhD (psychiatry and neuropharmacology), and reviewed by Dr. Jamie Lee, PharmD, on 2026-10-03. Primary sources include the systematic review at OpenAlex and FDA regulatory documents.