Psilocybin, a psychedelic compound, has fast-acting antidepressant-like effects in mice. Using tests of hedonic behavior and a drug that blocks hallucinogenic 5-HT2A receptors, the results suggest that altered perception may not be required for its therapeutic benefits. Psilocybin also strengthens connections between brain cells in regions involved in reward and emotion processing. These findings indicate it may be possible to retain psilocybin's antidepressant actions while minimizing alterations in consciousness.
A single low dose of the ketamine metabolite (2R,6R)-hydroxynorketamine (HNK) produces rapid antidepressant-like effects in mice without blocking NMDA glutamate receptors (NMDARs), unlike ketamine itself. At a dose of 10 mg/kg, which triggers antidepressant-related behavioral and cellular responses, (2R,6R)-HNK reaches hippocampal concentrations of about 8 µM—far below the levels needed to inhibit NMDARs in vitro. The dose required to prevent NMDA-induced lethality was 228 mg/kg for (2R,6R)-HNK versus 6.4 mg/kg for ketamine, indicating weak NMDAR inhibition. These findings suggest that (2R,6R)-HNK's antidepressant effects occur through alternative molecular targets, potentially avoiding ketamine's adverse effects such as dissociation and abuse potential.