Psychedelic Research Papers

This preclinical pharmacology study in rats found that zalsupindole (third-generation psychedelic) produced robust effects on structural and functional neuroplasticity in the prefrontal cortex as well as sustained antidepressant-like responses comparable to or greater than those of ketamine, psilocybin, and DMT, despite lacking any of the acute cellular and behavioural characteristics of hallucinogenic or dissociative compounds.

This open-label pilot trial (n=10) found that psilocybin-assisted therapy (25mg) delivered to terminally ill home hospice patients was feasible and safe, significantly reducing demoralisation scores at week 3, though the emotional intensity of the intervention affected acceptability for some participants.

This open-label Phase IIa trial (n=19, 15 male) found that an 8-week regimen of microdosed LSD (8μg initially, then 6-20μg twice weekly) for major depressive disorder was well-tolerated with no serious adverse events or cardiac valvulopathy, achieved 59.5% reduction in MADRS scores sustained for six months, and had only one withdrawal due to anxiety.

This pre-print double-blind placebo-controlled trial (n=15) found that healthy participants who had a psilocybin-induced psychedelic experience in a therapeutic-like room exhibited more intense mystical-type experiences, longer-lasting psychological benefits, and greater increases in synaptic density than those dosed inside an MRI scanner, indicating that psilocybin's neuroplastic effects are modulated by environmental context.

This real-world safety analysis of esketamine in the United States (n=58,483 patients, 1,486,213 treatment sessions over 58 months) found that sedation, dissociation, and increased blood pressure occurred in 34.7%, 41.0%, and 0.9% of sessions respectively, with serious adverse events in <0.1-0.18% of sessions, suicide rates lower than background rates, and 210 cases of abuse/misuse reported, confirming the established safety profile with no new safety signals identified.

This within-subject, double-blind study (n=22) found that acute administration of methamphetamine (14 mg/70 kg) significantly lowered plasma 2-arachidonoylglycerol concentrations compared to placebo at 150-180 minutes post-administration, whilst MDMA (100 mg) did not affect endocannabinoid levels, and higher anandamide concentrations during the placebo condition correlated with disliking the 'drug effects'.

These two randomised, double-blind, placebo-controlled trials (n=141) conducted in semi-naturalistic settings found that microdosing psilocybin truffles did not significantly affect cognitive control, memory, social cognition, subjective well-being, attention, mood, or self-reported cognitive flexibility compared to placebo. Initial effects in some domains did not remain significant after correcting for multiple comparisons.

This Phase I single-ascending dose, randomised, placebo-controlled, double-blind study (n=48) found that GM-2505, a novel 5-HT2A receptor agonist, demonstrated an acceptable safety profile with mild transient adverse events at intravenous doses up to 20 mg, a half-life of 40-50 minutes, and dose-dependent effects on neuroendocrine hormones, neuropsychological measures, and resting-state electroencephalography similar to other 5-HT2A receptor agonists but with a duration of effects shorter than psilocybin and longer than DMT.

This cross-sectional fMRI study (n=67) found that experienced psychedelic users (≥10 lifetime experiences) showed faster and more accurate recognition of angry facial expressions alongside diminished neural responses to anger in limbic and salience network regions, enhanced responses to happiness in parietal and sensorimotor areas, and reduced emotional differentiation in default mode network regions compared to non-users.

This qualitative study (n=28 interviews) of participants in a psilocybin-assisted therapy trial for cancer-related depression found that therapeutic benefits were closely tied to participants' ability to "surrender" (accepting and remaining open to the experience's intensity and unpredictability), with a safe, supportive, and ethical environment critical to fostering trust and engagement, and preparation and integration key to maximizing benefit, whilst music played a significant but variable role and ceremonial elements added meaning for many despite the clinical setting providing safety.

This open-label pilot trial (n=7) of psilocybin-assisted therapy (2x25mg sessions with preparatory and integration psychotherapy) for treatment-resistant depression found clinically meaningful aggregate reductions in depressive symptoms at 3 weeks (mean change=-7.14; Hedges' g=-1.27) maintained at 20 weeks. Exploratory analyses identified pre-dosing mindset, spiritual experiences, and perceptual shifts, but not expectations, as potential predictors of response, with no serious adverse events.

This secondary analysis of an RCT fMRI study (n=40) of meditation practitioners during a 3-day retreat found that DMT-harmine ('pharmahuasca', 120mg/120mg buccal) increased functional connectivity within the visual network and between visual and attention networks, whilst meditation alone reduced between-network connectivity, with no evidence of prolonged cortical gradient disruption characteristic of acute psychedelic effects, suggesting distinct neural mechanisms for meditation versus psychedelic-augmented meditation.

This double-blind placebo-controlled crossover trial (n=23) compared equimolar doses of MDMA (100mg), MDA (92mg), and their lysine-conjugated prodrugs, finding MDA produced stronger, longer-lasting effects (6.1 vs 4.1 hours) with more psychedelic-like perceptions and adverse effects than MDMA, whilst Lys-MDA successfully delayed onset and peak effects, but Lys-MDMA failed to release MDMA and showed no effects.

This open-label pilot study (n=15) found that outpatient psilocybin-assisted psychotherapy (25mg) with motivational enhancement and acceptance and commitment therapy for methamphetamine use disorder was safe and feasible, with participants showing reduced methamphetamine use from a median of 12 days at screening to 0 days at day 28 and 2 days at day 90 post-treatment.

This double-blind placebo-controlled study (study 1: n=15, study 2: n=20) found that MDMA (100mg) significantly increased global trust in community and society after conversation compared to placebo, whilst methamphetamine (20mg) showed no effects on subjective well-being or social connection measures.

This open-label exploratory study (n=9) tested three Acacia-based ayahuasca-like formulations in healthy volunteers with prior ayahuasca experience. In a cross-over design, two formulations (1 mg/kg DMT + 4 mg/kg harmalas) were given to five adults, while a third (ACL-010) was given to four adults at two dosages. All formulations were safe and well-tolerated, with no serious adverse events. Subjective experiences were similar to traditional ayahuasca, and ACL-010 was rated as comparable or more beneficial.

This three-arm open-label study (n=84) found that ayahuasca-assisted meaning reconstruction therapy (A-MR) produced significantly greater reductions in severe grief compared to meaning reconstruction therapy alone (d=0.86) or no treatment (d=1.07), with the A-MR group showing the largest effect size (d=2.44) and additional improvements in prolonged grief symptoms, post-traumatic growth, and quality of life.

This randomised, placebo-controlled study (n=48) examining LSD microdosing (15 μg) for analgesia in healthy participants found no significant pain-relieving effects on pain tolerance or subjective pain perception using the Cold Pressor Task. LSD increased blood pressure, which correlated with pain tolerance, and post-hoc analysis in participants without ceiling effects suggested marginal improvements in pain tolerance and reduced unpleasantness only after the first dose, indicating that 15 μg may be below the threshold for consistent analgesic effects.

This neuroscience reanalysis (n=25) of two earlier studies used connectome harmonic decomposition to analyse how DMT affects brain function across the structural connectome (white matter pathways), finding that DMT reshapes the connectome harmonic repertoire and increases repertoire entropy similarly to other psychedelics (psilocybin, LSD, ketamine), and importantly demonstrating for the first time that energy spectrum differences and repertoire entropy measures correlate with subjective experience intensity in a time-resolved manner, revealing close coupling between connectome harmonics and conscious experience under psychedelics.

This Phase IIb randomised, double-blind, placebo-controlled trial (n=198) found that single doses of 100 µg and 200 µg of MM120 (lysergide D-tartrate) significantly reduced anxiety symptoms at 4 weeks in adults with moderate to severe generalised anxiety disorder (GAD), with dose-dependent effects and adverse events including visual perceptual changes, nausea, and headache.

This pre-clinical mouse study tested chronic administration of serotonin, d-fenfluramine, or subhallucinogenic doses of LSD on cardiovascular health. Serotonin and d-fenfluramine caused ventricular thickening and valve regurgitation, respectively, while LSD produced no significant ventricular or valvular changes. Receptor binding assays showed LSD, psilocybin, and norfenfluramine had similar affinity for 5-HT2B, but LSD’s activation was short-lived, providing no evidence of heart remodeling with prolonged low-dose LSD.

This decision analysis model study (n=1000 simulated PTSD patients) evaluates the cost-effectiveness of group MDMA-assisted therapy with supplemental individual therapy for PTSD in Ukraine. It finds treatment costs $1.1M, averts 19.2 deaths, and gains 717 QALYs over 3 years, with an incremental cost-effectiveness ratio of $1537 per QALY. From a societal perspective, the intervention generates $2.6M in net savings, and scaling to 50% of eligible patients over 10 years could save 48,000 lives and gain 1.5M QALYs.

This Phase II, nonrandomized open-label trial (n=22) tested a single 25 mg dose of psilocybin with psychological support in adults with PTSD. It found the treatment to be safe and well-tolerated, with common side effects such as headache, nausea, crying, and fatigue resolving quickly. Clinically meaningful reductions in PTSD symptoms were observed at weeks 4 and 12, alongside improvements in functioning and quality of life.

This double-blind placebo-controlled trial (n=35) found that psilocybin-assisted psychotherapy (25mg) significantly reduced depression and anxiety symptoms in adults with life-threatening illnesses compared to an active placebo (100mg niacin), with benefits sustained at 26 weeks and improvements in spiritual well-being, quality of life, demoralisation, and death anxiety.

This cost-effectiveness analysis found that psilocybin-assisted therapy (PAT) for treatment-resistant depression (TRD) may offer economic value at $5,000 or less per treatment course, yielding an incremental cost-effectiveness ratio of $117,517 per QALY gained over 12 months, with cost-effectiveness highly sensitive to treatment price (95% probability at $3,000 vs 1% at $10,000).

This open-label retreat study (n=21) of veterans with traumatic brain injuries tested dried psilocybin mushrooms (1.5–5g) in two ceremonies over six days. Four weeks later, PTSD, depression, and anxiety scores fell by 50%, 65%, and 28% respectively, while EEG showed reduced delta/theta power and increased alpha/beta coherence, suggesting improved emotional regulation and cognition.

This case-control fMRI study (n=38 males) found that long-term ayahuasca users showed significantly higher psychological resilience scores and altered emotional brain reactivity patterns compared to controls. Machine learning algorithms achieved 75% accuracy in distinguishing users from non-users.

This secondary analysis of an RCT (n=30) found that a DMT/harmine combination (pharmahuasca) significantly impaired convergent thinking while showing trend-level reductions in divergent thinking fluency and elaboration. It also uniquely disrupted creative process transitions from incubation to illumination during a real-world painting task, suggesting that psychedelics alter creative pathways rather than uniformly enhance creativity.

This rodent study found that the nonhallucinogenic psychoplastogen tabernanthalog (TBG) promotes cortical neuroplasticity and sustained antidepressant effects through the same 5-HT2A, TrkB, mTOR, and AMPA receptor pathway as psychedelics, but without inducing the immediate glutamate burst or immediate early gene activation previously thought necessary for psychedelic-induced neuroplasticity.

This review (2025) of the Swiss limited access scheme describes how approximately 100 physicians treated 723 patients with MDMA, LSD, or psilocybin in 2024, with patients typically receiving 2-4 psychedelic-assisted therapy sessions within 12 months for treatment-resistant conditions.