Psychedelics in Neurosurgery: Promise, Evidence Gaps, and Translational Barriers

Current Evidence: No Direct Trials, Only Indirect Signals

There are currently no published clinical trials administering psychedelic or dissociative agents to neurosurgical patients, according to a 2026 systematic review (OpenAlex W7221103691). The review synthesizes high-quality evidence from adjacent populations—such as oncology and traumatic brain injury (TBI) cohorts—to map potential applications in neurosurgery, but all findings remain indirect.

Psilocybin-assisted therapy has demonstrated substantial and durable reductions in cancer-related depression, anxiety, and existential distress in randomized controlled trials. Similarly, perioperative ketamine and its enantiomer esketamine have shown antidepressant and opioid-sparing effects in surgical and psychiatric populations. LSD, parenteral tryptamines, and ibogaine have also displayed anxiolytic, neuroprotective, and cognitive benefits in non-neurosurgical settings. However, none of these agents have been tested in the context of neurosurgical procedures, where unique physiological and safety considerations apply.

Mechanistic Rationale: Neuroplasticity, Analgesia, and Psychological Relief

The mechanistic rationale for psychedelics in neurosurgery rests on their documented effects on neuroplasticity, mood, and pain modulation. Classic serotonergic psychedelics—including psilocybin, LSD, and N,N-dimethyltryptamine (DMT)—promote synaptogenesis and dendritic growth in preclinical models, suggesting a potential role in neurorehabilitation and recovery from neurological insult.

Ketamine and esketamine, classified as dissociative anesthetics, act as N-methyl-D-aspartate (NMDA) receptor antagonists. They have rapid-acting antidepressant effects and can reduce opioid requirements, which is particularly relevant for neurosurgical pain management. Ibogaine, though associated with arrhythmia risk, has shown improvements in disability and cognition following TBI in early-phase studies.

Notably, the review highlights the non-obvious point that the perioperative period—when patients are most vulnerable to psychological distress and opioid-related complications—may offer a unique window for intervention with agents like esketamine, which already has regulatory approval for depression in some jurisdictions (e.g., U.S. Food and Drug Administration [FDA] approval for intranasal esketamine in 2019).

Policy and Research Implications: Feasible First Targets and Trial Design

The most feasible initial targets for clinical translation, according to the review, are perioperative esketamine for mood and pain, and psilocybin for neuro-oncological distress. These choices are informed by existing regulatory precedents and the relative safety profiles of these compounds in other populations.

However, the review underscores that purpose-designed clinical trials in neurosurgical cohorts are now essential. Such trials must address unique neurosurgical risks, including:

• Seizure threshold modulation (as serotonergic psychedelics may lower seizure thresholds)
• Hemodynamic and cerebrovascular effects (potentially exacerbating perioperative risk)
• Drug-drug interactions with anesthetics and perioperative medications, especially serotonergic agents
• The need for structured psychological support, which may be logistically challenging in acute surgical settings

Regulatory agencies such as the FDA and the European Medicines Agency (EMA) will likely require robust safety data specific to neurosurgical populations before approving any new protocols. The review also notes that institutional review boards (IRBs) may be particularly cautious, given the complexity and acuity of neurosurgical care.

Risks, Unknowns, and Translational Barriers

Translating psychedelic and dissociative agents into neurosurgical practice is constrained by several significant risks and unknowns. The most immediate concerns include the potential for increased seizure risk, hemodynamic instability, and unpredictable interactions with anesthetics or other perioperative drugs. Furthermore, the psychological vulnerability of neurosurgical patients—who may experience delirium, cognitive deficits, or acute distress—raises questions about the appropriateness and timing of psychedelic interventions.

Another underappreciated barrier is the lack of standardized protocols for psychological support in the perioperative setting. While psychedelic-assisted therapy in psychiatric and oncology trials typically involves multiple preparatory and integration sessions, such resources are rarely available in neurosurgical wards. This gap could undermine both safety and efficacy if not addressed in trial design.

Finally, the review highlights the need for careful patient selection criteria, as certain neurosurgical populations (e.g., those with active intracranial bleeding or unstable cardiovascular status) may be at heightened risk from these agents.

Looking Forward: Next Steps for Research and Clinical Translation

The next phase for psychedelics in neurosurgery will require rigorously designed phase 1 and 2 trials, with careful attention to safety monitoring, patient selection, and multidisciplinary collaboration. Early studies are likely to focus on perioperative esketamine for mood and pain, and psilocybin for neuro-oncological distress, leveraging existing evidence and regulatory pathways.

For funders and institutions, the key insight is that translation will require not just pharmacological innovation but also new models of perioperative psychological care. Success will depend on integrating psychiatry, neurology, anesthesiology, and surgical expertise, as well as proactive engagement with regulators and ethics boards. As of October 2026, the field stands at the threshold—plausibility established, but actionable protocols yet to be defined.

How we research: This analysis was prepared by Dr. Alex J. Feldman, MD, PhD (Neuroscience Editor), and reviewed by Dr. Sarah Lin, MD, FRCS, on 2026-10-12. Primary sources include the referenced OpenAlex review and FDA regulatory documents.