Psychedelic Research Papers

This secondary analysis of an open-label study (n=30) of male Veterans with traumatic brain injury found that greater intensity of mystical experiences during magnesium-ibogaine treatment was associated with larger reductions in PTSD severity both immediately and one month post-treatment, as well as greater reductions in peak alpha frequency at one month.

This open-label study (n=9) found that an encapsulated DMT-harmala alkaloid product (pharmahuasca) produced dose-dependent mystical experiences that exceeded those reported in most previous ayahuasca studies and were associated with beneficial persisting psychological effects in healthy volunteers.

This secondary analysis of two placebo-controlled studies (n=27) found that DMT shifts brain oscillations away from criticality towards subcritical regimes in alpha and adjacent frequency bands, increasing entropy whilst reducing complexity, with these shifts in theta and alpha bands correlating with the intensity of self-dissolution experiences.

This secondary analysis (n=26) of adults with treatment-resistant depression from an open-label psilocybin-assisted psychotherapy trial found statistically significant improvements in processing speed and executive function at two weeks post-treatment, with gains on Trail Making Tests remaining significant after adjusting for depressive symptoms; however, reliable change indices showed that the proportion of participants achieving meaningful improvement (4.2–12.5%) did not exceed chance expectations, suggesting observed gains may reflect practice effects rather than genuine procognitive benefits.

This preclinical rat study (n=24; 8 rats per group) shows that a single dose of psilocybin (1.0 mg/kg) or the selective 5-HT2A receptor agonist 25CN-NBOH (1.5 mg/kg) reduces immobility in the forced-swim test, with effects persisting for at least three months. Electrophysiology of medial prefrontal cortex (mPFC) Layer 5 neurons reveals long-lasting functional, but not structural, plasticity—characterised by changes in resting membrane potential, neuronal firing rates, and excitatory synaptic input. In contrast, dendritic spine density and gene-expression markers related to synaptic structure remain unchanged, indicating enduring functional alterations rather than persistent structural modifications.

This qualitative study (n=40) of healthy males following a double-blind placebo-controlled trial of LSD microdosing (10µg every third day for 6 weeks) found participants reported effects across emotions and mood, social life, mindfulness, cognition and creativity, and physiological domains, with key themes including openness to experiences and bidirectionality of effects, alongside reports of changes in anxiety suggesting important considerations for patient selection and dose optimisation.

This Phase I double-blind placebo-controlled trial (n=32) using microphenomenology interviews found that intranasal 5-MeO-DMT produced dose-dependent subjective effects with rapid onset peaking at 8-15 minutes and return to baseline by 45-60 minutes, characterised by minimal visual effects but strong emotional and bodily experiences, including emotional breakthroughs and personal insights.

This magnetoencephalogram study (n=50) found that long-term ayahuasca users showed neurophysiological markers of death-denial at unconscious levels despite reporting less implicit and explicit fear-of-death than controls and meditators, suggesting ayahuasca alters conscious but not automatic processing of death-related thoughts.

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.