The antidepressant effects of the drug (R,S)-ketamine, a mixture of (R)-ketamine (arketamine) and (S)-ketamine (esketamine), are not primarily due to blocking the N-methyl-D-aspartate receptor (NMDAR), despite initial assumptions. Preclinical studies in rodents show arketamine has more potent and longer-lasting antidepressant-like effects than esketamine, even though arketamine binds less strongly to NMDAR. Clinical trials with other NMDAR-blocking compounds failed to produce robust antidepressant effects in humans, indicating rodent findings do not always translate. The exact molecular mechanisms remain unclear. This review covers recent findings on these mechanisms, the possible roles of the brain-gut-microbiota and brain-spleen axes, and arketamine's potential for treating cognitive impairment, Parkinson's disease, osteoporosis, inflammatory bowel diseases, and stroke.
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.