BACKGROUND: Recent studies intensively explore psilocybin's antidepressant potential, but variables like previous experience, repeated use, setting, and sex remain underexplored. This study examines acute and long-term effects of psilocybin in healthy individuals. METHODS: A double-blind, placebo-controlled, cross-over study included 40 healthy participants (20 females, mean age 38). Each received two doses of psilocybin (0.26 mg/kg) at least 56 days apart (mean 488) in two neuroimaging study arms. Nearly half had previous psychedelic experience. Acute effects were measured using the Altered States of Consciousness Scales (ASCs) and a Visual Analogue Scale (VAS) for emotional valence. The Persisting Effects Questionnaire (PEQ) assessed long-term effects. RESULTS: All results were independent of observed variables such as previous psychedelic experience, repeated use, setting, sex and occupation. Acute effects were moderate on the ASCs, with VAS ratings showing mostly pleasant or fluctuating experiences and only one unpleasant session. All experiences resolved in a positive or neutral state by the session's end. Psilocybin produced lasting positive effects across all PEQ domains, with negligible negative effects. Oceanic Boundlessness (OBN) and Visionary Restructuralization (VRS) correlated with positive outcomes, while Dread of Ego Dissolution (DED), typically associated with fear, did not predict negative effects. The nature of the acute experience (pleasant or mixed) was not linked to the direction or intensity of long-term outcomes. Peak experiences ending in a positive mood were strongly associated with favourable long-term effects. CONCLUSION: Repeated psilocybin administration in healthy individuals induces positive, lasting effects, with challenging experiences in controlled settings not causing adverse outcomes. These findings support psilocybin's psychological safety and its repeated use in clinical trials.

• Keywords
• Healthy population, Previous experience, Psilocybin, Repeated administration, Sex,
• MeSH
• Adult MeSH
• Double-Blind Method MeSH
• Emotions drug effects   MeSH
• Hallucinogens * pharmacology   administration & dosage   MeSH
• Cross-Over Studies MeSH
• Middle Aged MeSH
• Humans MeSH
• Young Adult MeSH
• Psilocybin * pharmacology   administration & dosage   MeSH
• Sex Factors MeSH
• Consciousness drug effects   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Young Adult MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Controlled Clinical Trial MeSH
• Names of Substances
• Hallucinogens * MeSH
• Psilocybin * MeSH

The serotonergic psychedelics psilocybin, LSD and DMT hold great promise for the development of new treatments for psychiatric conditions such as major depressive disorder, addiction and end-of-life anxiety. Previous studies in both animals and humans have confirmed the effects of these drugs on neuronal activity and plasticity. However, the understanding of the mechanisms of action of these substances is limited. Here we show rapid effects of psychedelics on presynaptic properties, using live cell imaging at the level of single synapses in primary rat cortical neurons. Using the genetically encoded reporter of synaptic vesicle fusion synaptopHluorin, we detected a reduced fraction of synaptic vesicles that fused in response to mild or strong electrical stimulation 3-30 min after application of serotonergic psychedelics. These effects were transient and no longer present 24 h after treatment. While DMT only reduced the total recycling pool, LSD and psilocin also reduced the size of the readily releasable vesicle pool. Imaging with the sensors for glutamate, iGluSnFR, and presynaptic calcium, synGCaMP6, showed that while psilocin and DMT increased evoked glutamate release, LSD and psilocin reduced evoked presynaptic calcium levels. Interestingly, psilocin also affected short-term plasticity leading to a depression of responses to paired stimuli. The rapid and drug-specific modulation of glutamatergic neurotransmission described in this study may contribute to distinct anxiolytic and antidepressant properties of serotonergic psychedelics.

• Keywords
• 5‐HT2A, fluorescent sensors, neurotransmitter release, presynaptic, short‐term plasticity, synaptic vesicles,
• MeSH
• Hallucinogens * pharmacology   MeSH
• Rats MeSH
• Cells, Cultured MeSH
• Glutamic Acid * metabolism   MeSH
• Lysergic Acid Diethylamide pharmacology   MeSH
• Cerebral Cortex * drug effects   cytology   metabolism   MeSH
• Neurons * drug effects   metabolism   MeSH
• Rats, Sprague-Dawley MeSH
• Psilocybin pharmacology   MeSH
• Serotonin MeSH
• Synaptic Vesicles drug effects   metabolism   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Hallucinogens * MeSH
• Glutamic Acid * MeSH
• Lysergic Acid Diethylamide MeSH
• Psilocybin MeSH
• Serotonin MeSH

BACKGROUND: Recent years show an exponential increased interest ("renaissance") in the use of psychedelics for the treatment of mental disorders and broader. Some of these treatments, such as psilocybin for depression, are in the process of formal regulation by regulatory bodies in the US (FDA) and Europe (EMA), and as such on the brink of real-world implementation. In the slipstream of these developments increasing commercial initiatives are taking shape. The European Psychiatric Association (EPA) acknowledges both the therapeutic potential of psychedelic substances and the challenges for both research and clinical implementation. Steps need to be taken toward a well-balanced policy based upon sound scientific evidence and research, aiming at safe, ethical responsible integration of psychedelic therapy available for all patients who can potentially benefit. METHODS: In this EPA policy paper, we highlight the potential benefits, and also the challenges of psychedelic treatments, which can be relevant for the future real-world implementation of these treatments. RESULTS: In addition to an overview of the current evidence and hypotheses of working mechanisms of psychedelic treatment, this policy paper specifically highlights the importance of the psychosocial components of the treatment as well as the ethical and professional aspects playing a role in real-world implementation. CONCLUSIONS: Four recommendations are formulated for further research and clinical implementation.

• Keywords
• DMT, LSD, Psychedelics, mental health, methodological challenges, psilocybin, psychiatric disorders,
• MeSH
• Mental Disorders * drug therapy   MeSH
• Hallucinogens * therapeutic use   MeSH
• Humans MeSH
• Psilocybin therapeutic use   pharmacology   MeSH
• Psychiatry MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Geographicals
• Europe MeSH
• Names of Substances
• Hallucinogens * MeSH
• Psilocybin MeSH