Archives of toxicology
March 31, 2026
Kamil Jurowski, Damian Kobylarz, Maciej Noga
Serotonergic tryptamines, including psilocin, psilocybin, DMT, and 5-MeO-DMT, are increasingly used medically and recreationally, but experimental toxicity data are scarce. A comprehensive computational assessment using nine validated QSAR models evaluated six tryptamines for acute toxicity, organ effects, cardiotoxicity, genotoxicity, irritation, and estrogenic activity. All compounds were classified as high toxicological concern (Cramer Class III). Predicted oral LD50 values ranged from 100 to 500 mg/kg, indicating moderate to high acute toxicity. Cardiovascular and gastrointestinal systems were primary targets (≥90% predicted effect). DMT and 5-MeO-DMT showed the highest predicted hERG inhibition (IC50 20–45 µM), suggesting cardiotoxic potential, while psilocybin showed lower risk (IC50 ≈760 µM). Most tryptamines were predicted non-mutagenic and non-endocrine active.
eLife
March 31, 2026
Jessica L Maltman, Javier González-Maeso
Exposure to psilocin, the active metabolite of the psychedelic psilocybin, increases structural complexity and strengthens synaptic connections in human neurons derived from stem cells. These changes suggest enhanced neuroplasticity at the cellular level.
The British Journal of Psychiatry
March 30, 2026
1 citation
Psychedelics like psilocybin are being explored as a new treatment for depression, but their use requires psychological support alongside the drug. There is debate about the exact role of this support and who should deliver it, which affects how these treatments could be implemented in public health services like the National Health Service. The authors outline a model for delivering psychological support in publicly funded settings and call for further research to identify the essential elements of support. They emphasize that implementation must be based on high-quality evidence and ensure equitable access for all patients, not just those who can pay.
Zenodo (CERN European Organization for Nuclear Research)
March 30, 2026
A therapist manual for psilocybin-assisted therapy developed for the EPIsoDE trial provides a structured psychotherapeutic framework for treating treatment-resistant depression. The manual outlines therapist qualifications, training, and a therapist dyad model, along with guidance on preparatory, dosing, and integration sessions. It emphasizes set and setting, describes the acute psilocybin experience including beneficial and challenging states, and offers self-regulation techniques like breathing exercises. A distinctive feature is the structured use of music during dosing sessions via a phase-specific block system. The manual also includes safety monitoring procedures and standardized checklists to enhance transparency and reproducibility in psychedelic research.
Substance use & misuse
March 28, 2026
Graeme Knibb, Ruby Ward, Paul Christiansen et al.
People who use psilocybin for therapeutic or personal growth reasons tend to experience less self-stigma—the internalization of negative societal beliefs—while those who use it for social recreation tend to experience more self-stigma. In a survey of 239 people with prior psilocybin experience, three distinct motives emerged: social recreation, experiential enhancement, and therapeutic growth. Greater therapeutic growth motives were linked to lower self-stigma across cognitive, affective, and behavioral dimensions, and also to more frequent psilocybin use. Social recreation motives predicted higher self-stigma. Experiential enhancement showed no significant association with self-stigma. The results suggest that why people use psilocybin may shape how they internalize stigma, with implications for other substances and for clinical use.
bioRxiv : the preprint server for biology
March 27, 2026
James D. Johnson, Runyi Tian, Yasaman Etemadi et al.
Psilocybin preferentially dampens well-consolidated aversive sensory representations in the auditory cortex, rather than fresh associations, without broadly affecting auditory processing or new aversive learning. Using longitudinal two-photon calcium imaging in awake mice, psilocybin selectively reduced responses to aversive stimuli and earlier-established aversive-associated tones, while reward responses and responses to newly aversive-associated tones remained unaffected. At the population level, psilocybin acutely increased coordination across tone-responsive neurons, then later reduced it selectively among neurons encoding the aversive-associated tone. These results suggest psilocybin reshapes sensory representations of learned valence associations, potentially explaining its benefits in affective and trauma-related disorders.
Journal of Pain and Symptom Management
March 27, 2026
Ana Cláudia Mesquita Garcia, Geovanna Maria Isidoro, Cremilson de Paula Silva
For people with serious illness, psychedelic experiences can transform how they relate to their own finitude. Before the experience, death is a dominant threat, marked by fear and an illness-centered identity. During the psychedelic state, expanded consciousness enables transcendence—symbolic encounters with death, ego expansion, spiritual unity, and emotionally challenging experiences—which allow people to reinterpret suffering as transformative and reconstruct their personal narratives. Afterward, finitude becomes integrated into life with greater acceptance of mortality, reduced death anxiety, and a revaluation of life priorities. The process does not eliminate suffering but involves its traversal and integration, supporting existential adaptation at the end of life.
eLife
March 27, 2026
Malin Schmidt, Anne Hoffrichter, Mahnaz Davoudi et al.
3 citations
Psilocin, the psychoactive metabolite of psilocybin, increases BDNF abundance in human cortical neurons derived from induced pluripotent stem cells via the 5-HT2A receptor. Transcriptomic profiling shows gene expression changes that prime neurons for neuroplasticity. Morphologically, psilocin enhances neuronal complexity and increases synaptic proteins, especially in the postsynaptic compartment. Functionally, it leads to increased excitability and enhanced synaptic network activity. These findings suggest psilocin induces a state of enhanced neuronal plasticity, which may explain its therapeutic potential in neuropsychiatric disorders involving synaptic dysfunction.
PsyArXiv
March 26, 2026
preprint
An open-label extension of a Phase II randomized controlled trial examined the safety and efficacy of psilocybin-assisted therapy for alcohol use disorder. Participants who had received either psilocybin or placebo in the main trial were offered two open-label psilocybin sessions. The treatment was well tolerated, with no serious adverse events attributed to psilocybin. Heavy drinking days decreased substantially from baseline, and the reduction was sustained through the 32-week follow-up. The findings suggest that psilocybin-assisted therapy may produce durable reductions in alcohol consumption among individuals with alcohol use disorder.
Communications Biology
March 26, 2026
Veronica Mäki-marttunen
1 citation
Psilocybin, a psychedelic compound that activates 5HT2a serotonin receptors, alters the speed and pattern of traveling waves of neural activity across the cortex. Using fMRI data from a publicly available dataset, researchers found that psilocybin increased the propagation speed of infraslow cortical activity, which was linked to greater overall functional connectivity and a contraction of the principal gradient—a measure of how brain regions are organized along a sensory-to-association axis. The distribution of 5HT2a receptors in the cortex may help explain these changes. The results connect large-scale brain activity patterns, global neural events, and receptor action, offering insights into how psychedelics produce their effects.
Brain sciences
March 26, 2026
Piotr Skalski, Katarzyna Pękacka-falkowska, Agnieszka Pluto-Prądzyńska et al.
Psilocybin shows rapid and sustained antidepressant and anxiolytic effects, with benefits also observed in addiction treatment. However, conventional randomized controlled trials (RCTs) may not adequately capture the therapeutic complexity of psilocybin, which depends on pharmacological action as well as contextual, psychological, and interpersonal factors. This critical narrative review of the ten most cited clinical studies from 2015 to 2025 identified significant methodological limitations, including selection bias, challenges in placebo design and blinding, small sample sizes, and underrepresentation of diverse populations. Real-world evidence studies revealed heterogeneous response patterns and insights unattainable through RCTs alone. Comprehensive evaluation requires larger and more diverse trials, long-term follow-up, standardized psychotherapeutic protocols, and integration of real-world evidence.
Mini reviews in medicinal chemistry
March 24, 2026
Shivaputra A Patil, Holly C Hunsberger
Psilocybin, a naturally occurring psychedelic derived from Psilocybe mushrooms, is experiencing renewed interest for treating mental health disorders, addiction, and cancer-related depression, and its benefits are expanding into brain injury and lifespan due to its ability to enhance neuroplasticity. Its psychoactive effects arise from psilocin acting as a partial agonist at the 5-HT2A receptor. After the FDA's breakthrough therapy designation for treatment-resistant depression in 2018 and major depressive disorder in 2019, large-scale synthesis became a major challenge, requiring complex multi-step processes with strict temperature control and hazardous reagents. Modified versions of Hofmann's original method now enable kilogram-scale production for clinical trials. This mini review covers the history, chemistry, pharmacology, and therapeutic use of psilocybin in depression.
Frontiers in Neuroscience
March 23, 2026
Malkanthi Evans, Andrew Charrette
Psychedelic therapies show promise for treatment-resistant depression, PTSD, anxiety, and substance-use disorders, but significant methodological and ethical challenges remain. Issues include inadequate masking in trials, expectancy effects, and reproducibility concerns. Early-phase studies indicate rapid symptom improvement, supported by neuroimaging insights, but large multisite trials with harmonized protocols and long-term follow-up are still needed. The role of psychotherapy in psychedelic-assisted treatment is debated; some developers include only psychological support. Subjective aesthetic experiences—perceptual richness, emotional resonance, beauty—are strongly linked to emotional breakthroughs and clinical outcomes. Neuroimaging shows DMT modulates brain connectivity in socio-emotional circuits. Psilocybin promotes emotional openness and cognitive flexibility. Future research must clarify mechanisms, optimize protocols, and ensure safety and generalizability.
EvidenzUpdate
March 22, 2026
Denis Nößler
A methodologically rigorous randomized controlled trial (EPIsoDE) found that psilocybin did not significantly improve the primary endpoint—a 50% or greater reduction on the HAMD17 depression scale—in patients with treatment-resistant depression. Secondary signals were encouraging but difficult to interpret due to broken blinding and expectation effects. An accompanying editorial and review explain why psychedelics may appear more effective in studies than they actually are.
Discover Mental Health
March 19, 2026
Àlvar Farré-colomés, Olga Rublinetska, Óscar Soto-Angona
This review gathers all available fMRI evidence from psilocybin studies. Twenty unique datasets were identified, five of which included participants diagnosed with depression. Dropout rates were high, and most studies lacked follow-up scanning timepoints. Research has concentrated on the amygdala, anterior cingulate cortex, and prefrontal cortex as key regions involved in psilocybin's effects. However, methods and designs across studies are inconsistent. More research is needed to clarify psilocybin's impact on the human brain and its potential to enhance psychotherapy outcomes.
Journal of Raman Spectroscopy
March 19, 2026
Mingyu Sun, Xiaoyu Zhao, Fandi Kong et al.
A Raman spectroscopy method combined with machine learning can rapidly and non-destructively identify psilocybin, the psychoactive compound in magic mushrooms. Theoretical Raman spectra predicted by density functional theory matched experimental spectra from fresh and heat-treated Psilocybe cubensis samples, establishing characteristic fingerprint features. Among feature extraction methods, competitive adaptive reweighted sampling (CARS) selected the most discriminative variables. An XGBoost model, optimized with Bayesian tuning and balanced via SMOTE, was integrated into a Bagging framework with KNN, SVM, and Decision Tree. The final model achieved 0.984 accuracy, 0.984 F1-score, and 0.976 ROC AUC, showing strong stability under storage conditions. This approach enables rapid, accurate, cost-effective, and contamination-free psilocybin detection for food safety and toxic mushroom screening.
JAMA Psychiatry
March 18, 2026
1 citation
A guided psychedelic experience with psilocybin may treat refractory depression by inducing a mystical experience, rather than through a simple biological drug effect. The text suggests that the therapeutic benefit could stem from the profound, transformative nature of the experience, as conceptualized by William James.
JAMA Psychiatry
March 18, 2026
9 citations
A phase 2b randomized clinical trial tested 25 mg of psilocybin with psychotherapy against a 5 mg dose and a placebo (nicotinamide) in 144 adults aged 25 to 65 with treatment-resistant depression who had stopped antidepressants. The primary outcome—a 50% or greater reduction in depression scores at six weeks—was not statistically significant: 17.0% of those receiving 25 mg responded, versus 12.5% on 5 mg and 10.6% on placebo. Exploratory analyses suggested a clinically meaningful reduction in depressive symptoms with the 25 mg dose. The treatment was generally well tolerated, but safety signals included higher reports of suicidal ideation on dosing days and two serious adverse reactions, one case of hallucinogen persisting perception disorder.
Frontiers in Computer Science
March 16, 2026
A computational model using explainable artificial intelligence can optimize single-dose psilocybin treatment protocols by creating personalized patient simulations. The framework, tested on three public datasets (7 participants from a neuroimaging dataset, 53 from a multimodal mental disorder dataset, and aggregated results from 10 clinical trials), achieved 94.7% prediction accuracy and 89.3% explainability scores in simulated environments. The model also demonstrated 92.8% precision in predicting treatment response patterns and a 73.4% reduction in carbon footprint. These results are entirely from simulated data and require clinical validation before any practical use.
Child and Adolescent Psychiatry and Mental Health
March 13, 2026
Marc-Antoine Crocq, Philippe Auby
The recent approval of esketamine for adults has renewed interest in psychedelic compounds for psychiatric use, but their relevance for children and adolescents is unclear. This review examines the rationale for investigating classic serotonergic psychedelics (e.g., psilocybin, LSD), the entactogen MDMA, and dissociative compounds like ketamine and esketamine in young populations. Ongoing and planned trials primarily involve adolescents aged 16 years and older, driven by unmet needs in child and adolescent psychiatry, where few medications are approved and therapeutic response is often unsatisfactory. Potential targets include anorexia nervosa, autism spectrum disorder symptoms, obsessive-compulsive disorder, resistant depression, and severe PTSD. Translation to pediatric populations requires caution due to developmental vulnerabilities and limited long-term safety data.
Journal of Psychopharmacology
March 13, 2026
Francisco A. Moreno, Katja Ehrmann Allen, Christopher B. Wiegand et al.
3 citations
Psilocybin, a psychedelic compound, was generally well-tolerated and reduced obsessive-compulsive disorder (OCD) symptoms in a small clinical trial. No serious adverse events, psychotic symptoms, or changes in suicide severity occurred. Psilocybin, but not placebo, significantly lowered scores on the Yale-Brown Obsessive Compulsive Scale. After eight weeks of treatment including at least four high doses, 73.3% of participants responded (at least 35% reduction in symptoms), and 40% achieved remission. Benefits diminished but remained substantial at six months. Higher cumulative doses were linked to greater symptom reduction. Larger trials are needed to confirm efficacy and refine protocols.
JAMA
March 12, 2026
Joshua C. Black, Gabrielle E. Bau, Ryan R. Cook et al.
2 citations
After Oregon and Colorado decriminalized psilocybin, 12-month use of the substance increased in both states. The survey data show that the estimated prevalence of past-year psilocybin use rose in Oregon and Colorado compared with the period before decriminalization. The findings suggest that decriminalization policies are associated with higher rates of psilocybin use.
March 11, 2026
Jason B Luoma, Kim Hoffman, Adie Wilson-Poe et al.
preprint
Oregon's early psilocybin facilitator workforce is relatively diverse, with many holding existing healthcare licenses, though training expenses pose a moderate-to-severe financial strain for most. The mean tuition across 16 active training programs was $9,359, half offered diversity scholarships, and the mean planned session price was $1,388. Facilitators most commonly specialized in trauma, mental disorders, consciousness exploration, and spirituality, and most were satisfied with training while requesting ongoing opportunities. These findings inform future policy and program development for a diverse and effective workforce.
Figshare
March 11, 2026
Jenna Houff, Andrew Williams, Obie Allen et al.
A single dose of psilocybin reduced preference for larger rewards and increased the time taken to choose them in rats, effects that were not tied to delay length and thus not indicative of altered impulsivity. Forty-eight hours after administration, psilocybin also increased the density of activated parvalbumin inhibitory interneurons surrounded by perineuronal nets in the dorsomedial prefrontal cortex. The findings suggest psilocybin decreases appetitive motivation by activating these specific inhibitory neurons.