Psychedelics in neurosurgery: Potential utility in prevention, perioperative care, pain management, and neurorehabilitation

Background: Neurosurgical patients carry a high and frequently undertreated burden of psychological suffering, acute and chronic pain, and neurological deficits amenable to recovery. The resurgence of psychedelic research has produced relevant evidence in adjacent fields, but its applicability to neurosurgery has not been systematized. This review synthesizes that evidence across prevention, perioperative care, pain management, and neurorehabilitation, and delineates the safety considerations specific to neurosurgery.

Methods: Narrative review structured around a population, intervention, comparator, outcome, and time question, covering 2020–2026. The classic serotonergic psychedelics (psilocybin, lysergic acid diethylamide [LSD], N,N-dimethyltryptamine, ayahuasca, 5-methoxy-N,N-dimethyltryptamine, and mescaline), the iboga alkaloid ibogaine, the entactogen 3,4-methylenedioxymethamphetamine, and the dissociatives ketamine and esketamine were examined. Randomized controlled trials, systematic reviews, meta-analyses, and high-quality mechanistic studies were prioritized.

Results: No trial has administered these agents in neurosurgical cohorts, so all evidence is indirect. Psilocybin- assisted therapy produces substantial, durable reductions in cancer-related depression, anxiety, and existential distress. LSD is anxiolytic; parenteral tryptamines act rapidly in depression; ibogaine improved disability, post- traumatic stress, and cognition after traumatic brain injury but carries arrhythmia risk. Perioperative ketamine and esketamine show antidepressant and opioid-sparing effects. Classic psychedelics promote neuroplasticity and are neuroprotective in preclinical models.

Conclusion: A biologically plausible basis exists for exploring these agents in neurosurgery, but direct evidence is absent and translation is constrained by the seizure threshold, hemodynamic and cerebrovascular effects, perioperative serotonergic interactions, and the need for structured psychological support. Perioperative esketamine and psilocybin for neuro-oncological distress are the most feasible starting points. Purpose-designed neurosurgical trials are required.