Psychedelic Research Papers

This double-blind Phase IIb trial (n=147) evaluated the efficacy, safety, and tolerability of esketamine nasal spray versus midazolam in reducing depressive (MDD) symptoms in adolescents at imminent risk for suicide (SI). The study finds that pooled doses of esketamine (56 and 84 mg) significantly reduce depressive symptoms at 24 hours, with common side effects including dizziness, nausea, and dissociation.

This systematic review (s=31) examines the side effects of microdosing LSD and psilocybin, finding that adverse effects are typically dose-dependent, mild, and short-lived. Common side effects include increased blood pressure, anxiety, and cognitive impairment. The review highlights the lack of standardised reporting on side effects and calls for future studies to provide more systematic and transparent assessments.

This neuroimaging study (n=62) investigates how psilocybin (19mg) reorganises brain connectivity in different contexts using fMRI and EEG. Participants were scanned before and after ingestion during rest and naturalistic stimuli (meditation, music, and visual). Under psilocybin, brain activity in eyes-closed states became more similar to eyes-open states, with increased connectivity in associative regions and decreased connectivity in sensory areas. The findings suggest that psilocybin induces a state of "embeddedness," reducing distinctions between self and environment, which may underlie both its subjective and therapeutic effects.

This computational fMRI study (n=15) examines brain dynamics after DMT (iv; 20mg) administration, focusing on the onset of the psychedelic state. It reveals a peak destabilization of brain dynamics around 5 minutes post-administration and identifies a heightened reactivity phase, primarily affecting fronto-parietal and visual regions. The study links these changes to serotonin 5HT2a receptor density, suggesting these dynamics underpin the psychedelic state's complexity and flexibility.

This randomized, double-blind, cross-over study (n=23) investigates LSD (100μg) effects after daily paroxetine (SSRI) or placebo administration in healthy participants. It finds paroxetine reduced negative LSD effects ("bad drug effect," "anxiety," "nausea") while maintaining pleasant effects, and caused higher LSD concentrations (1.4-1.5x) due to CYP2D6 inhibition, suggesting no LSD dose adjustment is needed when combined with CYP2D6-inhibiting SSRIs.

This one-year observational follow-up study (n=66) examined the long-term outcomes of psilocybin (25 mg, 10 mg, 1 mg; COMP360) in treatment-resistant depression (TRD). Median time to depressive relapse was longest in the 25 mg group (92 days) compared to 10 mg (83 days) and 1 mg (62 days), with most participants relapsing by week 12. A post hoc analysis of those entering the follow-up study (n=58) found a more pronounced difference, with the 25 mg group maintaining benefits for 189 days. Adverse events were minimal, with one case of mild suicidal ideation in the 1 mg group.

This systematic review (s=8) analyses completed controlled trials of psychedelics for depression, including psilocybin, LSD, ayahuasca, and DMT, all in Phase II or I/II. It evaluates methodological patterns against the draft European Medicines Agency guideline revision, highlighting challenges such as unblinding, expectancy, and adverse event characterisation, while calling for larger studies to assess long-term efficacy and safety.

This naturalistic longitudinal study (n=66) investigates the long-term effects of ayahuasca on mental health in adults with no prior exposure. Participants attending neo-shamanic ceremonies reported sustained improvements in depression, anxiety, stress, affect, personality traits, spirituality, and relationships up to 12 months. Individuals with depression or anxiety experienced lasting symptom reductions, while those without a diagnosis had short-term benefits. Alcohol and cannabis use decreased only at one month. Findings suggest ayahuasca's mental health benefits persist, with varying trajectories of change over time.

This open-label study (n=10) investigates the effects of single-dose psilocybin (25mg) therapy in adults with severe alcohol use disorder (AUD). It finds significant reductions in alcohol consumption, craving, and increases in self-efficacy over 12 weeks following treatment despite notable between-participant pharmacokinetic variations.

This single-blind, cross-over study (n=28) using MRI in healthy participants found that psilocybin (18.2mg/70kg) significantly decreased cerebral blood flow (CBF) and internal carotid artery (ICA) diameter. In contrast, ketanserin (20mg) had no significant effect. This finding suggests an asymmetric 5-HT2AR modulatory effect on CBF and provides the first in vivo human evidence of psilocybin-induced ICA constriction.

This pre-print, multimodal study (n=18) investigates psilocybin’s (5mg and 10mg) effects on perception and brain dynamics using psychophysics, ultra-high field fMRI, and computational modelling. It finds that psilocybin alters contextual perception in the Ebbinghaus illusion, modifies cortical responses to visual stimuli, and proposes a computational model linking these changes, suggesting altered contextual computations as a potential general mechanism of psychedelic action.

This theory-building paper proposes the ALBUS (Altered Beliefs Under Psychedelics) model as an extension of the REBUS hypothesis, suggesting that 5-HT2A receptor activation can lead to both relaxation (REBUS) and strengthening (SEBUS) of beliefs depending on dosage and context. The authors draw parallels between psychedelic states and lucid dreaming, focusing on mechanisms of conscious perception, dreaming, and memory.

This pre-print neuroimaging study (n=38) investigates the effects of MDMA and LSD on striatal connectivity (brain area, movement, and reward systems) using resting-state fMRI. The study finds that while neither drug significantly altered within-network connectivity of the striatum, both substances caused significant changes in connectivity with other brain regions, such as MDMA reducing connectivity between the limbic striatum and the amygdala and LSD increasing connectivity between the associative striatum and the frontal, sensorimotor, and visual cortices.

This survey (n=30) of psychedelic researchers identifies key research gaps in psychedelic harm and safety. It highlights the need to define types of harm, their predictors, and effective treatments. It also calls for better post-psychedelic support, including online resources, peer support, therapy, and psychiatric care. The authors advocate for increased funding, suggesting that psychedelic investors and companies allocate 1% of their investments to safety measures.

This qualitative analysis of Erowid.org experience reports (n=279) examines the temporal structure (organisation of time) of psilocybin experiences, focusing on the 'come-up' and 'come-down' phases. The study finds that the onset phase typically resembles an acute stress reaction with negative feelings. In contrast, the descending phase is characterised by positive feelings similar to post-stress recovery, suggesting a potentially important therapeutic mechanism.

This single-blind, randomized, two-arm, factorial, dose-finding study (n=16) investigates the pharmacokinetic and pharmacodynamic interactions between DMT and harmine in an ayahuasca-inspired ('pharmahuasca') formulation. Participants received six dose combinations (0–120 mg DMT, 0–180 mg harmine) via a transmucosal delivery system. Results show dose-dependent subjective effects lasting 4–5 hours, with peak plasma levels (Cmax) of 33 ng/mL for DMT and 49 ng/mL for harmine. Harmine increased DMT bioavailability and plasma half-life while altering its metabolism. The formulation demonstrated a favourable safety profile, supporting its potential for further clinical testing in affective disorders.

This secondary analysis (n=321) of the ESCAPE-TRD trial compared work productivity loss (WPL) and related costs in patients with treatment-resistant depression (TRD) receiving esketamine nasal spray (56mg or 84mg) versus quetiapine (atypical antipsychotic) extended release, both combined with an oral antidepressant. By week 8, WPL decreased by 30.3% with esketamine and 17.3% with quetiapine, leading to a cost savings difference of $156 per week. By week 32, WPL reductions were 45.3% (esketamine) and 32.5% (quetiapine), with a weekly cost savings difference of $153.

This prospective, longitudinal study (n=679) examined the effects of psilocybin use on emotional experiences, particularly feelings of shame and guilt. The study found that while most participants had positive experiences with psilocybin, acute feelings of shame or guilt were common (68%), and the ability to work through these feelings positively correlated with well-being in the weeks following use. On average, psilocybin resulted in a small but significant decrease in trait shame, which was maintained for 2-3 months after use, though in a minority of participants (30%), trait shame increased.

This systematic review and meta-analysis (s=87; 2025) finds esketamine's efficacy as an adjunctive therapy for treatment-resistant depression (TRD) to be modest (effect size 0.15-0.23) and comparable to atypical antipsychotics, with no significant effect on suicidality. The review raises concerns about esketamine's abuse potential and unknown long-term effects. It also highlights regulatory issues, including deaths and emerging suicidality during clinical trials.

This single-blind (n=11) study with healthy participants shows that confidence in negative self-beliefs decreased after a high dose of psilocybin (25mg) which predicted increases in well-being four weeks later. This provides the first psychological (vs neurological) information on the validity of the REBUS model.

This pooled analysis of two Phase II RCTs (n=79) evaluates psilocybin-assisted psychotherapy (PAP/PAT) for cancer-related distress. PAT significantly improves anxiety, depression, interpersonal sensitivity, hostility, obsession–compulsion, and somatization without inducing lasting phobia, paranoia, or psychosis.

This secondary analysis of an open-label, single-blind, Phase IIIb trial (n=676) compares esketamine nasal spray plus an SSRI/SNRI versus extended-release quetiapine plus an SSRI/SNRI for treatment-resistant depression (TRD). It finds esketamine to be superior in achieving remission at week 8 (27.1% vs. 17.6%, p=0.003) and preventing relapse through week 32 (21.7% vs. 14.1%). Adverse events align with known safety profiles.

This secondary analysis of an RCT (n=31) evaluates a novel pharmaceutical formulation of DMT and harmine in healthy male volunteers. The study finds that intranasal DMT and buccal harmine (pharmahuasca) produce consistent pharmacokinetic profiles and safe, well-tolerated effects resembling ayahuasca, with subjective experiences lasting 2–3 hours. This formulation is proposed as a safer, standardised alternative for potential therapeutic use in mental health disorders.

This observational study (n=83) examines factors influencing the effects of individual psilocybin-assisted therapy (PAT) on depression, anxiety, PTSD, and personality traits. Results show that a single high dose of psilocybin reduces symptoms of anxiety, depression, and PTSD over three months while increasing openness and conscientiousness. Mystical experiences, emotional breakthroughs, and personal growth, along with demographic factors, moderate these positive changes.

This preprint, randomized controlled trial (n=25) evaluates the safety and efficacy of psilocybin-assisted psychotherapy (PAP/PAT) combined with mindfulness-based stress reduction (MBSR) for frontline healthcare providers with depression and burnout during the COVID-19 pandemic. Results show greater improvements in depression (QIDS-SR-16), burnout (MBI-HSS-MP), demoralization (DS-II), and connectedness (WCS) in the MBSR+PAP group compared to MBSR alone, with no serious adverse events reported.

This retrospective cohort study (n=14,912) examines healthcare resource use (HRU) and costs among patients with major depressive disorder (MDD) and acute suicidal ideation or behaviour (SI) initiated on esketamine nasal spray, ECT, SGA augmentation, or antidepressant monotherapy in the U.S. Esketamine-treated patients (n=122) had lower acute care HRU (0.59 days) and costs ($1869/month) compared to ECT (3.17 days, $4624) and SGA augmentation (0.92 days, $2163), but higher than monotherapy (0.32 days, $863). Esketamine reduced HRU (58%) and costs (50%) most significantly from baseline.

This secondary analysis of a Phase III trial (n=174) evaluates the effects of subcutaneous ketamine on anxiety in treatment-resistant depression (TRD). Significant reductions in anxiety (HAM-A scores) were observed in cohort 2 with flexible dosing (35-63mg/70kg) but not in cohort 1 with fixed low dosing (35mg/70kg). These effects, mediated by changes in depression (MADRS), were not sustained 4 weeks post-treatment.

This reanalysis of a Phase II study (n=84) investigates the effects of psilocybin-assisted therapy (PAT) on personality traits in alcohol use disorder (AUD). Psilocybin (2x, 25-40mg/70kg; n=44) significantly reduced neuroticism and increased extraversion and openness compared to placebo (diphenhydramine, n=40). Decreased impulsiveness correlated with lower alcohol consumption post-treatment, suggesting PAT may normalize abnormal personality traits in AUD.

This article describes the Compass Psychological Support Model (CPSM) used to support participants with treatment-resistant depression undergoing investigational psilocybin treatment. The CPSM aims to ensure a safe and meaningful psychedelic experience, complemented by therapist training, mentoring, and fidelity assessment to maintain delivery quality and consistency.

This open-label trial (n=12) conducted at Sheppard Pratt Hospital finds that psilocybin (25mg) significantly decreases depressive symptoms in patients with severe treatment-resistant depression (TRD) at 3 weeks (MADRS −15.8) and 12 weeks (MADRS −17.2) post-treatment. Exploratory analyses suggest the Oceanic Boundlessness dimension correlates with antidepressant responses, while patients with comorbid PTSD show reduced antidepressant effects.