Low-dose esketamine given during surgery for vestibular schwannoma did not reduce pain at rest or with movement in the first 24 hours after the operation. The trial randomly assigned 90 adults to receive either 0.2 mg/kg of esketamine or a placebo after dural closure. Esketamine moderately increased brain activity as measured by the bispectral index for at least 30 minutes after administration, prolonged the time to removal of the breathing tube, and lowered the required dose of remifentanil at that point, but did not affect heart rate, blood pressure, or the time to regain spatial orientation. Rates of nausea and vomiting were similar between groups, and no hallucinations or excessive sedation occurred.
Psychedelics are being tested in over 200 clinical trials as potential treatments for psychiatric disorders, but how they work and their risks are not fully understood. The serotonin 2A receptor (5-HT2AR) is the main target of psychedelics. This study compared psychedelics with non-hallucinogenic analogues using cell and animal experiments, finding that 5-HT2AR signaling through a non-canonical Gi pathway is essential for hallucinogenic effects. Five cryo-electron microscopy structures of 5-HT2AR bound to these drugs were solved. A special contact between non-hallucinogenic analogues and the receptor biased signaling away from Gi. A derivative called DOI-NBOMe showed potent Gq-biased activity and therapeutic effects in mice without causing hallucinations. These findings reveal mechanisms of 5-HT2AR Gi signaling and guide the design of safer psychedelic-based drugs.