The Daily Dose • Thursday, June 10, 2021

Psychedelic Neuroscience: Mechanisms and Medicine

Psychedelic Neuroscience: Mechanisms and Medicine

Christian S. Guay, MD

Psychedelic neuroscience is a rapidly evolving field spanning the translational spectrum, from molecular pharmacology through pragmatic clinical trials. In this “International Science Symposium: Psychedelic Neuroscience,” held on May 15 at the IARS 2021 Annual Meeting, world experts shared original data on the mechanisms of psychedelics and explored some of their applications in anesthesiology.

George Mashour, MD, PhD, from University of Michigan, launched the symposium with a brief introduction to the field of psychedelic neuroscience and its relation to anesthesiology through the study of consciousness and overlapping pharmacology.

Boris Heifets, MD, PhD, from Stanford University, started with a principle that unifies diverse psychedelics in medicine: their onset is rapid, yet their effects can last weeks, months or even years after the molecules themselves have been eliminated from the body. Despite this unity, psychedelics exhibit a wide range of biological mechanisms which Dr. Heifets posits are essential to decipher if we are to optimize their clinical use. To this end, his group demonstrated that the prosocial and abuse effects of MDMA operate through parallel independent circuits, suggesting that it may be possible to leverage the therapeutic effects of this drug in the absence of abuse potential. In another mechanistic study, they revealed that the antidepressant effects of ketamine can be reversed with naltrexone in mice, pointing to a role for the opioid system in modulating ketamine’s lasting effects on mood, in addition to its traditional MDMA antagonism. Turning his attention towards humans, Dr. Heifets is now investigating if the psychedelic “trip” is in fact needed to reap the lasting psychological effects of ketamine: an ongoing clinical trial is tracking the antidepressant effects of ketamine when given during general anesthesia, a state which effectively prevents patients from experiencing the acute psychedelic effects of ketamine but may spare its long-term benefits.

Robin Carhart Harris, MD, from Imperial College London, and Katrin Preller, PhD, from Yale School of Medicine, built on Dr. Heifet’s discussion on the neuromechanisms of psychedelics by exploring data specific to the serotonergic system, with an emphasis on the serotonin 2A receptor (5-HT2AR). This widely distributed receptor has been widely studied in the settings of neuroplasticity, brain development, learning and psychological flexibility. In a natural setting, chronic stress primes the serotonergic system and acute stress induces the release of serotonin, leading to neuroplastic modifications and behavioral adaptability, key features in biological evolution. By agonizing 5-HT2AR, psilocybin and LSD may in fact hijack this natural system and enable their users to free themselves from habits of the mind causing a range of psychiatric disorders. This hypothesis is supported by data showing complete blockade of the reported effects of these drugs when coadministered with ketanserin, a 5-HT2AR antagonist. Ketanserin also blocks the increased functional connectivity observed between areas of high 5-HT2AR gene expression caused by psychedelics, adding a converging line of evidence for serotonergic mechanisms.

Psychedelic neuroscience is a rapidly evolving field spanning the translational spectrum, from molecular pharmacology through pragmatic clinical trials. As anesthesiologists, we can expect to care for an increasing number of patients consuming psychedelics and may one day leverage these drugs in our own armamentarium to improve our patients’ health well beyond the perioperative period.