A Tale of Two Specialties: Repurposing Anesthetics for Psychiatric Disorders

Christian S. Guay, MD

The target organ of anesthesia is the brain, and anesthesiologists induce altered states of consciousness every day. Can this expertise with psychoactive molecules be leveraged to develop new therapeutic protocols for psychiatric disorders? And can anesthesiologists and psychiatrists effectively collaborate to alleviate the suffering of some of our most vulnerable patients? In the session, co-sponsored by the Association of University Anesthesiologists (AUA), “Update on Repurposing Anesthetics for Psychiatric Disorders,” experts discussed three promising drugs in this emerging field: nitrous oxide, psilocybin and propofol on Saturday, April 15 at the IARS 2023 Annual Meeting.

Peter Nagele, MD, Professor of Anesthesia and Critical Care, Professor of Psychiatry and Behavioral Neuroscience and Chair of the Department of Anesthesiology at the University of Chicago, has been instrumental in the quest to repurpose nitrous oxide for treatment-resistant depression (TRD). Inspired by ketamine’s rapid therapeutic effect in TRD, Dr. Nagele wondered whether another N-methyl-D-aspartate (NMDA)-receptor antagonist, nitrous oxide (N₂O), could achieve similar results. Since his first proof-of-concept trial, published in Biological Psychiatry in 2014, there have been four more reports to support the rapid and persisting therapeutic effects of N₂O in patients with TRD. Most studies use a standard dental anesthesia apparatus to deliver 25-50% N₂O for one hour, with depression scale scores improving within hours and sustaining for up to two weeks. However, not all patients respond to the therapy, and approximately a quarter of patients report adverse events such as nausea and dissociative states. Considering these positive preliminary results, additional studies are studying N₂O as an adjuvant therapy for patients with depression that is partially responsive to standard antidepressants. Efforts are also underway to understand the underlying neurological mechanisms, which appear to involve connectivity in the anterior cingulate cortex and other brain areas previously implicated in major depressive disorder.

Psilocybin is another promising molecule being repurposed for psychiatric disorders, most recently gaining significant press coverage for a 2022 publication in NEJM showing that a single 25 mg dose can reduce depression scale scores in patients with TRD. In addition to TRD, psilocybin is also being tested in patients with alcohol use disorder, smoking cessation, cluster headaches and chronic pain. Boris Heifets, MD, PhD, Assistant Professor of Anesthesiology, Perioperative and Pain Medicine and, by courtesy, of Psychiatry and Behavioral Sciences at Stanford University, is studying psilocybin and other rapid-acting psychoactive molecules across the translational spectrum, from basic to clinical neuroscience. The basic therapeutic mechanisms of psilocybin are likely multifaceted, from anti-inflammatory effects and circuit-specific neuroplasticity to enhanced cognitive flexibility and transformative subjective life experiences.

Dr. Heifets is conducting basic science in rodent models using an unbiased whole-brain imaging approach, while also preparing a randomized clinical trial to test whether a psilocybin is effective to treat chronic low back pain in humans. Most experimental paradigms for psilocybin in humans include a preparation phase, dosing phase and integration phase, merging psychotherapy with pharmacotherapy to induce effective and long-lasting effects. However, a burning question remains: is the subjective psychedelic experience necessary to reap the therapeutic benefits? To help address this question, Dr. Heifets is collaborating with George Mashour, MD, PhD, Robert B. Sweet Professor of Anesthesiology, Professor of Neurosurgery and Chair of Anesthesiology at the University of Michigan, to anesthetize patients with propofol during a psilocybin “trip” and assessing whether they still exhibit a therapeutic response. These experiments truly highlight the power of cross-pollinating anesthesiology with psychiatry.

Ben Palanca, MD, PhD, Associate Professor of Anesthesiology at Washington University in St. Louis, concluded the session with a preview of one of the most exciting ongoing studies at the nexus of anesthesiology and psychiatry: Slow Wave Induction by Propofol to Eliminate Depression (SWIPED). The interface of sleep and anesthesia has long been recognized. Likewise, the association of sleep disruption and depression was described centuries ago. With the advent of electroencephalography, we now know that slow wave sleep in particular is disrupted in patients suffering from depression, and that many antidepressants increase slow wave sleep. Experiments in animal models have shown that propofol-induced slow wave anesthesia can help rodents recover from sleep deprivation. Dr. Palanca’s trial combines these lines of evidence, investigating whether propofol infusion sessions can promote subsequent slow wave sleep and induce an antidepressant response in elderly patients, with clinical follow-up at 17, 30 and 80 days postinfusion. Preliminary results are encouraging and a small case series has already been published. Dr. Palanca also holds an appointment in the Department of Psychiatry at Washington University School of Medicine and has fostered many productive relationships with practicing psychiatrists, exemplifying how anesthesiologists can forge cross-specialty collaborations to solve some of the most challenging problems in modern medicine.