Psilocybin, a psychedelic compound that mimics serotonin by binding to 5-HT2A receptors, shows preliminary promise for treating depression. Neuroimaging indicates it reduces default mode network activity while increasing connectivity across brain regions. Since 2011, five clinical studies involving 139 patients have reported 60% of participants experiencing significant symptom reduction (ranging from 58% to 83%), though these studies are limited by small samples and methodological variability. One recent trial found no significant difference in antidepressant effects between psilocybin and the conventional drug escitalopram. Over 50 further studies are registered, including a phase 2 multicenter trial for treatment-resistant depression. Rigorous future research is needed.
Regularly ingesting a non-hallucinogenic dose of LSD, known as microdosing, is reported by advocates to provide long-lasting psychological benefits without altering consciousness. Despite promising preliminary findings, few clinical studies exist, including interviews, an open-label study, and a cross-sectional study. Recent pharmacokinetic findings may improve future study interpretation and replicability. A proposed neurobiological mechanism from preclinical research involves rebalancing hippocampal 5-HT2/5-HT1A signaling and associated plasticity, which appears to bias emotional processing toward positive information and reduce responses to fearful stimuli. Neuroimaging suggests psychedelics may influence connectivity between cortical areas responsible for maintaining the sense of self.