Psychedelic Research Papers

This pre-print mouse study investigates how psilocybin affects different types of brain cells in the medial frontal cortex (mPFC; decision-making processes and judgement). The research finds that psilocybin increases dendritic spine density in both pyramidal tract (PT) and intratelencephalic (IT) neurons, but only PT neurons are essential for psilocybin's anti-stress effects through 5-HT2A receptor activation.

This randomised feasibility study (n=37) evaluates psilocybin-assisted (microdoses x 6) frontal-midline theta neurofeedback (NF) to improve executive functions (EFs) in participants with psychiatric disorders. Despite no significant improvements in tasks-based EFs, the experimental group reported medium to high gains in daily EFs, indicating the potential benefits of this neuromodulation technique for enhancing daily functioning.

This lab study used different ways of looking at cells to see how the psychedelic drug DOI affects the outer layer of cells (lipid membrane). The study found that DOI is over 100 times stronger than serotonin at disrupting the cell's outer layer, helping small bubble-like structures combine with cells, and making it easier for tiny holes to form in cell membranes. This suggests that psychedelics might affect the brain not just by binding to receptors (their usual known method), but also by physically changing how cell membranes work and help create new connections.

This pre-print, open-label, proof-of-concept trial (n=5) of psilocybin-assisted therapy for fibromyalgia finds the treatment to be well-tolerated, with only transient blood pressure elevations and headaches reported. Secondary outcomes show clinically meaningful improvements in pain severity, pain interference, and sleep disturbance one month after treatment, with all participants reporting some degree of symptom improvement.

This pre-registered randomized placebo-controlled study (n=34) investigates the effects of MDMA (100mg) administration on personality traits and affective states in healthy adults. While no statistical significance was found for the primary hypotheses, medium effect sizes were observed for increased Openness (d = 0.79) and Positive Affect (d = 0.51) 48 hours after MDMA administration compared to placebo.

This internet survey (n=629) examines how psychedelic experiences relate to psychological flexibility and mental well-being in classical psychedelic users. Network analysis shows psychological insight links to acceptance, while mediation analysis reveals psychological flexibility mediates the relationship between psychedelic use and well-being, suggesting experience quality matters more than frequency of use.

This survey study (n=457) explores the relationship between dysfunctional attitudes and well-being in the context of psychedelic-assisted therapy. It finds that post-acute changes in these attitudes significantly influence well-being, with emotional breakthroughs having a greater impact than challenging or mystical experiences.

This post hoc analysis (n=233) of a Phase II RCT investigates the impact of recent antidepressant discontinuation (n=156) on the efficacy of psilocybin in treating treatment-resistant depression (TRD). The study compares outcomes between participants who discontinued antidepressants during screening and those who entered the trial free of these medications, finding no significant relationship between antidepressant discontinuation and worsening depression severity or compromised psilocybin treatment efficacy.

This preprint mouse study (n=29) finds that the serotonin 1B receptor (5-HT1BR) is necessary for psilocybin's antidepressant and anxiolytic effects, independent of its hallucinogenic properties. Using transgenic mice lacking 5-HT1BR and network analysis, the study demonstrates that this receptor influences brain-wide activity patterns and mediates acute and persistent behavioural responses to psilocybin, suggesting a novel mechanism for psilocybin's therapeutic effects.

This retrospective analysis (n=841) of the Prehospital Tranexamic Acid Use for Traumatic Brain Injury trial evaluates the effects of ketamine in subjects with traumatic brain injury (TBI). It finds no significant difference in mortality or disability between ketamine-exposed (15.5%) and unexposed subjects, though ketamine exposure was associated with fewer instances of elevated intracranial pressure and a lower increase in TBI protein biomarkers, despite a higher likelihood of seizure activity in the ketamine group.

This pre-print, double-blind, placebo-controlled crossover study (n=22) investigates the neural effects of 2C-B (20mg) compared to psilocybin (15mg) and placebo using 7T resting-state functional MRI. The results reveal that both 2C-B and psilocybin reduce intra-network connectivity while enhancing between-network connectivity, with 2C-B showing less impact on certain connectivity measures but greater transmodal connectivity.

This online survey (n=233) of autistic participants with high autism quotient scores examines their experiences with psychedelic drugs and perceived changes attributed to their most 'impactful' psychedelic experience. It finds that the majority of participants reported reductions in psychological distress (82%) and social anxiety (78%), and increases in social engagement (70%), while 20% reported undesirable effects such as increased anxiety.

This preprint, naturalistic EEG study (n=29) examines the effects of inhaled synthetic 5-MeO-DMT (12mg) on brain activity in healthy individuals. It finds that 5-MeO-DMT radically reorganises low-frequency neural activity flows, making them incoherent, heterogeneous, and nonrecurring. It also causes broadband activity to exhibit slower, more stable, low-dimensional behaviour with increased energy barriers to rapid global shifts.

This meta-analysis (2024, s=31) examines the correlation between subjective effects and therapeutic outcomes for ketamine (s=23, n=471) and psilocybin (s=8, n=183) in depression and substance use disorder (SUD) treatment. It finds modest mediating effects of subjective experiences on therapeutic outcomes, with psilocybin showing a stronger mediating effect (R² = 24%) compared to ketamine (R² = 5-10%), and a greater mediating effect observed in SUD compared to depression regardless of the substance used.

This preprint open-label study (n=20) examines the effects of ketamine infusions (35mg/70kg, 6x) on biological ageing markers in individuals with depression (MDD) or PTSD. It finds reductions in epigenetic age as measured by OMICmAge, GrimAge V2, and PhenoAge biomarkers, as well as significant changes in Epigenetic Biomarker Proxies (EBPs) and surrogate protein markers following a 2-3 week treatment course. The study also reports expected decreases in depression and PTSD scores as measured by PHQ-9 and PCL-5.

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 randomized, double-blind, placebo-controlled, crossover study (n=16) investigates the dose-dependent acute effects, pharmacokinetics, and mechanism of action of mescaline (100-800mg; 5x) in healthy subjects. It finds that mescaline induces dose-dependent subjective effects, increases blood pressure and heart rate, and has dose-proportional pharmacokinetics, with effects primarily mediated by 5-HT2A receptors as demonstrated by ketanserin co-administration.

This open-label trial (n=15) evaluates the efficacy and safety of psilocybin (25mg) in veterans with severe treatment-resistant depression (TRD). It finds that 60% of participants met response criteria and 53% met remission criteria at 3 weeks post-treatment, with 47% maintaining response and 40% maintaining remission at 12 weeks.

This randomized, double-blind, placebo-controlled study (n=68) assesses the prosocial, entactogen effects of ketamine (35mg/70kg) in participants with treatment-resistant depression (TRD). Ketamine increased pleasure from social interactions and helping others, lasting for one week post-treatment. In a rodent experiment, ketamine-treated rats showed increased protective behaviour towards their cage mates, indicating entactogen effects.

This double-blind, placebo-controlled study (n=40) investigates the effect of DMT-harmine ('pharmahuasca') on meditative states during a 3-day retreat with experienced meditators. It finds that participants who received DMT-harmine reported greater mystical-type experiences, non-dual awareness, and emotional breakthrough during acute effects, as well as greater psychological insight one day later, compared to the placebo group.

This open-label single ascending dose Phase I trial (n=25) determines the maximum tolerated dose (MTD) of oral pharmaceutical-grade harmine (component of ayahuasca brew) in healthy adults. It finds that doses <189mg/70kg can be administered with minimal or no adverse events, while doses >189mg/70kg are associated with vomiting, drowsiness, and limited psychoactivity.

This re-analysis of a single-blind study (n=17) investigates the role of the autonomic nervous system in DMT-induced peak experiences (20mg, iv). It finds that balanced activity between the "fight-or-flight" and "rest-and-digest" systems (sympathovagal coactivation) is linked to stronger feelings of spirituality and insight during DMT sessions and improved well-being two weeks later. The study also notes that a person's nervous system (sympathovagal) balance before taking DMT can predict how insightful their experience will be.

This comparative study (n=56) investigates the relationship between antidepressant effects and acute drug effects of LSD and psilocybin in 28 patients undergoing psychedelic-assisted therapy (PAT) in Switzerland and 28 healthy volunteers from a randomized, double-blind crossover trial. The study finds similar ratings of overall drug effect and mystical experience across groups, but lower ratings of ego dissolution in patients. It identifies relaxation during PAT sessions as the greatest predictor of antidepressant outcomes.

This case study (n=1) finds that a single low dose of 5 µg (0.38µg/kg) of 1cp-LSD on a 13-year-old female dog with a history of separation-related behavioural problems significantly reduced anxiety after two hours. No adverse effects or signs of a psychedelic experience were observed during the 5.5-hour trial.

This 6-month follow-up of a Phase II, double-blind, randomized controlled trial (n=59) finds sustained improvements in depressive symptoms for both psilocybin therapy (PT) and escitalopram treatment (ET) for moderate-to-severe major depressive disorder (MDD). PT shows greater improvements in psychosocial functioning, meaning in life, and psychological connectedness compared to ET at the 6-month follow-up.

This open-label study (n=4) investigated the effects of low-dose oral psilocybin (5-10mg) with psychological support in patients with chronic short-lasting unilateral neuralgiform headache attacks (SUNHA). The study aimed to assess cognitive effects, safety, tolerability, and impact on headache severity and frequency, but was terminated early due to recruitment difficulties.

This survey (n=319) of psychedelic users measured personality traits using the Ten-Item Personality Inventory (TIPI) and a simplified Risk Taking Index (RTI). The study finds participants scored higher than norms on all Big Five traits except Extraversion, and on all dimensions of risk-taking. Personality structure was linked to psychedelic experience characteristics such as feelings of fear, love, peace, and perceptions of contact with transcendent forces.

This retrospective survey (n=143) of Amazon Mechanical Turk participants who self-administered psilocybin identifies factors related to mystical experiences (MEs) and challenging experiences. The study finds a state of surrender predicts MEs, while preoccupation predicts challenging experiences, explaining 66% and 56% of the variance in ME and dread scores, respectively. Mystical experiences during the session also relate to long-term positive changes.

This mixed-design study (n=48) finds significant increases in agreeableness and reductions in neuroticism post-ayahuasca administration (n=24), sustained at 6-month follow-up, with trait level increases in openness also observed at follow-up. The study also reports an association between greater perceived mystical experience and increased reductions in neuroticism.

This double-blind, placebo-controlled, crossover trial (n=28) finds that LSD (100μg), d-amphetamine (40mg), and MDMA (125mg) reduced network integrity in healthy volunteers. LSD uniquely reduced default-mode network integrity and showed more pronounced effects on network segregation and seed-based connectivity compared to amphetamines.