Scientific Research

Psilocybin, the naturally occurring psychedelic compound produced by hallucinogenic mushrooms, has received attention due to considerable clinical evidence for its therapeutic potential to treat various psychiatric and neurodegenerative indications. However, the underlying molecular mechanisms remain enigmatic, and few studies have explored its systemic impacts. We provide the first experimental evidence that psilocin (the active metabolite of psilocybin) treatment extends cellular lifespan and psilocybin treatment promotes increased longevity in aged mice, suggesting that psilocybin may be a potent geroprotective agent.

Atrophy of neurons in the prefrontal cortex (PFC) plays a key role in the pathophysiology of depression and related disorders. The ability to promote both structural and functional plasticity in the PFC has been hypothesized to underlie the fast-acting antidepressant properties of the dissociative anesthetic ketamine. Here, we report that, like ketamine, serotonergic psychedelics are capable of robustly increasing neuritogenesis and/or spinogenesis both in vitro and in vivo. These changes in neuronal structure are accompanied by increased synapse number and function, as measured by fluorescence microscopy and electrophysiology. The structural changes induced by psychedelics appear to result from stimulation of the TrkB, mTOR, and 5-HT2A signaling pathways and could possibly explain the clinical effectiveness of these compounds. Our results underscore the therapeutic potential of psychedelics and, importantly, identify several lead scaffolds for medicinal chemistry efforts focused on developing plasticity-promoting compounds.

This paper reviews safety considerations for human research with classical hallucinogens (psychedelics). Although these compounds are relatively safe physiologically and are not considered drugs of dependence, their administration involves unique psychological risks, including acute distress ('bad trips') and rare prolonged psychoses. The authors outline safeguards to minimize risk: careful screening (including exclusion of volunteers with personal or family history of psychotic or severe psychiatric disorders), thorough preparation, a safe physical environment, and continuous interpersonal support from trained monitors. Follow-up should probe for hallucinogen persisting perception disorder. When conducted with these guidelines, persisting adverse reactions are rare; incautious research may jeopardize participant safety and future work. Carefully conducted studies can inform treatment of psychiatric disorders and advance basic science.

A double-blind, randomized, active placebo-controlled pilot study was conducted to examine safety and efficacy of lysergic acid diethylamide (LSD)-assisted psychotherapy in 12 patients with anxiety associated with life-threatening diseases. Treatment included drug-free psychotherapy sessions supplemented by two LSD-assisted psychotherapy sessions 2 to 3 weeks apart. The primary outcome measure was State-Trait Anxiety Inventory (STAI) trait anxiety at 2 months after treatment end. Secondary outcomes included STAI state anxiety, Beck Depression Inventory, and a quality of life questionnaire. At 2-month follow-up, positive trends were found for the primary outcome, with an effect size of 1.28. Significant positive changes were observed in secondary outcome measures. No serious adverse events were reported. This pilot study found positive trends in the reduction of anxiety after two sessions of LSD-assisted psychotherapy, warranting larger controlled studies.

Randomized, double-blind, placebo-controlled phase II crossover trial of LSD-assisted therapy in patients with anxiety, with and without life-threatening illness. Two dosing sessions were paired with structured psychotherapy and integration. Anxiety and depression ratings improved through follow-up with generally mild, transient adverse effects, supporting further controlled trials.

Lysergic acid diethylamide (LSD) is the prototypical psychedelic drug, but its effects on the human brain have never been studied before with modern neuroimaging. Here, three complementary neuroimaging techniques: arterial spin labeling (ASL), blood oxygen level-dependent (BOLD) measures, and magnetoencephalography (MEG), implemented during resting state conditions, revealed marked changes in brain activity after LSD that correlated strongly with its characteristic psychological effects. Increased visual cortex cerebral blood flow (CBF), decreased visual cortex alpha power, and a greatly expanded primary visual cortex (V1) functional connectivity profile correlated strongly with ratings of visual hallucinations, implying that intrinsic brain activity exerts greater influence on visual processing in the psychedelic state, thereby defining its hallucinatory quality. LSD's marked effects on the visual cortex did not significantly correlate with the drug's other characteristic effects on consciousness, however. Rather, decreased connectivity between the parahippocampus and retrosplenial cortex (RSC) correlated strongly with ratings of "ego-dissolution" and "altered meaning," implying the importance of this particular circuit for the maintenance of "self" or "ego" and its processing of "meaning." Strong relationships were also found between the different imaging metrics, enabling firmer inferences to be made about their functional significance. This uniquely comprehensive examination of the LSD state represents an important advance in scientific research with psychedelic drugs at a time of growing interest in their scientific and therapeutic value. The present results contribute important new insights into the characteristic hallucinatory and consciousness-altering properties of psychedelics that inform on how they can model certain pathological states and potentially treat others.

Context: Researchers conducted extensive investigations of hallucinogens in the 1950s and 1960s. By the early 1970s, however, political and cultural pressures forced the cessation of all projects. This investigation reexamines a potentially promising clinical application of hallucinogens in the treatment of anxiety reactive to advanced-stage cancer. Objective: To explore the safety and efficacy of psilocybin in patients with advanced-stage cancer and reactive anxiety. Design: A double-blind, placebo-controlled study of patients with advanced-stage cancer and anxiety, with subjects acting as their own control, using a moderate dose (0.2 mg/kg) of psilocybin. Setting: A clinical research unit within a large public sector academic medical center. Participants: Twelve adults with advanced-stage cancer and anxiety. Main Outcome Measures: In addition to monitoring safety and subjective experience before, during, and after treatment with psilocybin, 5 subscales of the Profile of Mood States, the State-Trait Anxiety Inventory, and a Quality of Life Inventory were administered the day before, day of, and 1 day, 2 weeks, and 6 months after treatment with psilocybin. Results: Safe physiological and psychological responses were documented during treatment sessions. There were no clinically significant adverse events with psilocybin. The State-Trait Anxiety Inventory trait anxiety subscale demonstrated a significant reduction in anxiety at 1 and 3 months after treatment. The Beck Depression Inventory revealed an improvement of mood that reached significance at 6 months; the Profile of Mood States identified mood improvement after treatment with psilocybin that approached but did not reach significance. Conclusions: This study established the feasibility and safety of administering moderate doses of psilocybin to patients with advanced-stage cancer and anxiety. Some of the data revealed a positive trend toward improved mood and anxiety. These results support the need for more research in this long-neglected field.

This integrative review presents classic psychedelics (serotonin 2A receptor agonists such as LSD, psilocybin, and mescaline) research findings on epidemiology, mechanisms, acute subjective effects, therapeutic efficacy, and potential risks. Data were critically evaluated in terms of study design, methods, and impact. Classic psychedelics are not considered drugs of dependence. They present low physiological risk, although cardiovascular effects in hypertensive or cardiac patients should be researched further. Epidemiologic studies associate classic psychedelic use with lower psychological distress, suicidality, and alcohol and drug use disorders. Preliminary data suggest safety and potential efficacy for mood, anxiety, and substance use disorders. The subjective effects of mystical experience are implicated in therapeutic efficacy. However, more research with diverse populations is needed to examine therapeutic mechanisms, particularly how individual differences (demographics, genetics, personality) and session variables (context, expectations, rapport) might moderate outcomes, safety issues, and therapeutic methods.

Background: Psilocybin is a serotonin receptor agonist that occurs naturally in some mushroom species. Recent studies have assessed the therapeutic potential of psilocybin for various conditions, including end-of-life anxiety, obsessive-compulsive disorder, and smoking and alcohol dependence, with promising preliminary results. Here, we aimed to investigate the feasibility, safety, and efficacy of psilocybin in patients with unipolar treatment-resistant depression. Methods: In this open-label feasibility trial, 12 patients (six men, six women) with moderate-to-severe, unipolar, treatment-resistant major depression received two oral doses of psilocybin (10 mg and 25 mg, 7 days apart) in a supportive setting. There was no control group. Psychological support was provided before, during, and after each session. The primary outcome measure for feasibility was patient-reported intensity of psilocybin's effects. Patients were monitored for adverse reactions during the sessions and subsequent clinic and remote follow-up. Depressive symptoms were assessed with the 16-item Quick Inventory of Depressive Symptoms (QIDS) and 17-item Hamilton Depression Rating scale (HDRS) at baseline, and 1 week and 3 months after treatment, with additional QIDS assessments 2, 3, and 5 weeks after treatment. The QIDS at 1 week after treatment was the primary efficacy outcome. Findings: Psilocybin's acute psychedelic effects typically became detectable 30-60 min after dosing, peaked 2-3 h after dosing, and subsided to negligible levels at least 6 h after dosing. Mean self-rated intensity (on a 0-1 scale) was 0.51 for the 10 mg session and 0.75 for the 25 mg session. Psilocybin was well tolerated by all patients, and no serious or unexpected adverse events occurred. The adverse reactions we noted were transient anxiety during drug onset (all patients), transient confusion or thought disorder (nine patients), mild and transient nausea (four patients), and transient headache (four patients). Relative to baseline, depressive symptoms were markedly reduced 1 week and 3 months after high-dose treatment. Findings suggest that psilocybin might have value as a treatment option for patients with treatment-resistant depression. Interpretation: This small-scale feasibility study led to a clinical trial in a larger population.

Open-label, nonrandomized trial of a single 25 mg dose of synthetic psilocybin with structured psychotherapy in adults with treatment-resistant bipolar II depression. Depressive symptoms improved at 3 and 12 weeks, with no significant increase in mania or suicidality, supporting further controlled studies in this population.

Six-month follow-up letter to the 2016 open-label feasibility study of psilocybin with psychological support in treatment-resistant depression. Depressive symptom reductions (e.g., QIDS, HDRS) observed acutely and at 3 months persisted in a substantial proportion of participants at 6 months, with some cases of partial or full relapse, highlighting both durability and limits of effect. No new serious adverse events emerged. Findings support further controlled trials and exploration of maintenance strategies (e.g., additional therapeutic integration or booster dosing). NOTE: DOI pending confirmation; current metadata is provisional.

Single-group proof-of-concept study (N=10) evaluating psilocybin-assisted therapy (one or two dosing sessions integrated with Motivational Enhancement Therapy) in DSM-IV alcohol-dependent adults. Significant post-psilocybin increases in abstinent days and reductions in heavy drinking were maintained through 36-week follow-up. Greater acute subjective intensity during the first psilocybin session predicted larger subsequent reductions in alcohol use, craving, and improved abstinence self-efficacy, suggesting experiential (possibly mystical-type) factors mediate therapeutic change. No serious treatment-related adverse events occurred. Findings support controlled randomized trials to investigate efficacy, psychological and neurobiological mechanisms, and optimal integration strategies for alcohol use disorder.

Background Proper assessment of the harms caused by the misuse of drugs can inform policy makers in health, policing, and social care. We aimed to apply multicriteria decision analysis (MCDA) modelling to a range of drug harms in the UK. Method: Members of the Independent Scientific Committee on Drugs, including two invited specialists, met in a 1-day interactive workshop to score 20 drugs on 16 criteria: nine related to the harms that a drug produces in the individual and seven to the harms to others. Drugs were scored out of 100 points, and the criteria were weighted to indicate their relative importance. Findings: MCDA modelling showed that heroin, crack cocaine, and metamfetamine were the most harmful drugs to individuals (part scores 34, 37, and 32, respectively), whereas alcohol, heroin, and crack cocaine were the most harmful to others (46, 21, and 17, respectively). Overall, alcohol was the most harmful drug (overall harm score 72), with heroin (55) and crack cocaine (54) in second and third places. Interpretation: These findings lend support to previous work assessing drug harms, and show how the improved scoring and weighting approach of MCDA increases the differentiation between the most and least harmful drugs. However, the findings correlate poorly with present UK drug classification, which is not based simply on considerations of harm.

Background: Microdosing psychedelics is the practice of consuming very low, sub-hallucinogenic doses of a psychedelic substance, such as lysergic acid diethylamide (LSD) or psilocybin-containing mushrooms. According to media reports, microdosing has grown in popularity, yet the scientific literature contains minimal research on this practice. There has been limited reporting on adverse events associated with microdosing, and the experiences of microdosers in community samples have not been categorized. Methods: In the present study, we develop a codebook of microdosing benefits and challenges (MDBC) based on the qualitative reports of a real-world sample of 278 microdosers. Results: We describe novel findings, both in terms of beneficial outcomes, such as improved mood (26.6%) and focus (14.8%), and in terms of challenging outcomes, such as physiological discomfort (18.0%) and increased anxiety (6.7%). We also show parallels between benefits and drawbacks and discuss the implications of these results. We probe for substance-dependent differences, finding that psilocybin-only users report the benefits of microdosing were more important than other users report. Conclusions: These mixed-methods results help summarize and frame the experiences reported by an active microdosing community as high-potential avenues for future scientific research. The MDBC taxonomy reported here informs future research, leveraging participant reports to distil the highest-potential intervention targets so research funding can be efficiently allocated. Microdosing research complements the full-dose literature as clinical treatments are developed and neuropharmacological mechanisms are sought. This framework aims to inform researchers and clinicians as experimental microdosing research begins in earnest in the years to come.

Comprehensive review of MDMA-assisted therapy for PTSD covering epidemiology and limitations of existing treatments, pharmacology and proposed mechanisms (prosocial effects, fear extinction, memory reconsolidation, critical period plasticity), clinical evidence from Phase II pooled analyses and the first Phase III trial (large effect sizes, remission rates), safety profile (transient cardiovascular and somatic effects, low incidence of serious adverse events), methodological challenges (blinding, expectancy, selection bias, demographic homogeneity), and future directions (scalability, protocol optimization, therapist training, ethical oversight, access and equity). The authors highlight promise for refractory PTSD alongside the need for rigorous long-term efficacy and safety data.

Double-blind, randomized, placebo-controlled cross-over fMRI study (N=25 healthy participants) using spectral dynamic causal modeling to interrogate cortico–striato–thalamo–cortical (CSTC) effective connectivity under placebo, LSD, and ketanserin+LSD conditions. LSD increased thalamus→posterior cingulate cortex effective connectivity (5-HT2A receptor dependent) and decreased ventral striatum→thalamus effective connectivity (5-HT2A independent), consistent with proposed thalamic gating disruption and altered information flow underlying psychedelic phenomenology. Findings refine mechanistic CSTC models of psychedelic action and inform development of 5-HT2A-targeted therapeutics and translational research into psychopathology involving thalamocortical dysconnectivity.

When administered under supportive conditions, psilocybin occasioned experiences similar to spontaneously occurring mystical experiences. At 14-month follow-up, 58% of volunteers rated the experience as among the five most personally meaningful of their lives, and 67% rated it among the top five spiritually significant experiences.

This qualitative study explored the experiences of patients with treatment-resistant depression who received psilocybin-assisted therapy. Participants described a shift from disconnection and avoidance to connection and acceptance, both during the acute experience and in the weeks that followed.

This paper argues that the context in which psychedelics are administered — including the therapeutic relationship, physical environment, and psychological preparation — plays a crucial role in determining outcomes. The authors propose that psychedelics increase sensitivity to context, amplifying the influence of set and setting.

In a study with over 600 participants, preparation quality was identified as one of the strongest predictors of positive psychedelic experiences — more significant than dose or substance type. The findings highlight the importance of psychological preparation and a supportive environment.

An online survey of 1,993 individuals who reported challenging experiences with psilocybin mushrooms found that 84% endorsed benefiting from the experience. Despite the acute difficulty, 76% rated the experience among the top five most personally meaningful, suggesting that challenging psychedelic experiences can lead to positive long-term outcomes.

Using fMRI, this study showed that simply naming emotions — affect labeling — significantly reduces activity in the amygdala, the brain region responsible for processing emotional reactions. The more precise the label, the stronger the effect, suggesting that emotional vocabulary is a powerful self-regulation tool.

This paper proposes guidelines for training psychedelic therapists, emphasizing the need for personal development, ethical awareness, and experiential learning. It highlights that facilitator quality and preparation are critical factors in therapeutic outcomes.

This paper examines the role of set (mindset) and setting (environment) in psychedelic experiences from an extra-pharmacological perspective. It argues that these contextual factors are not merely peripheral but are central determinants of psychedelic outcomes, comparable in influence to the pharmacological action of the substance.

In a double-blind, randomized trial, a high dose of psilocybin produced large and sustained decreases in clinician-rated and self-rated measures of depressed mood and anxiety in patients with life-threatening cancer diagnoses. At 6-month follow-up, approximately 80% showed clinically significant decreases in depression and anxiety.

This paper introduces the Entropic Brain Hypothesis, proposing that the quality of consciousness is indexed by the entropy of brain activity. Psychedelics increase brain entropy, temporarily shifting consciousness to a more flexible, less constrained state — explaining both the therapeutic potential and the phenomenology of psychedelic experiences.

This study provides evidence that music plays a central therapeutic role in psychedelic-assisted therapy. Music experience during psilocybin sessions predicted the quality of the acute experience and therapeutic outcomes at follow-up, with the emotional resonance of music serving as a key mechanism.

This systematic review assessed the current state of microdosing research, analyzing 14 experimental studies with LSD (10-20µg) and psilocybin (sub-3mg). While subtle positive effects on cognition and emotion were observed, the clinical relevance remains uncertain, and the authors call for more rigorous, controlled studies.

This study tracked 98 microdosers over 6 weeks using daily experience sampling. Results showed small but consistent improvements in attention, well-being, and psychological functioning. Participants who kept detailed journals reported greater awareness of subtle effects and more consistent perceived benefits.