Psychedelic Research Papers

This systematic review (2024) and meta-analysis (s=44) finds that medium/high doses of LSD yield higher ratings of visionary restructuralisation than psilocybin. It also reports that psychedelics strengthen between-network functional connectivity and diminish within-network connectivity, and that LSD induces more inositol phosphate formation at the 5-HT2A receptor than DMT or psilocin, while receptor selectivity differences remain negligible.

This perspective article (2024) for investigators at academic medical centres in the United States provides recommendations for establishing psychedelic research programs. It highlights challenges including funding, regulatory approvals, sourcing controlled substances, preparing study spaces, managing controlled substances, and engaging the local community, and offers strategies to anticipate and surmount these obstacles.

This double-blind randomized trial (n=30) finds that psilocybin therapy significantly reduces symptoms of depression in clinicians after frontline work during the COVID-19 pandemic. Psilocybin (25mg) showed greater reductions in depression (MADRS scores) and PTSD symptoms compared to the niacin control, though PTSD findings were not statistically significant.

This review (2024) examines the effects of classic psychedelics (e.g., LSD, psilocybin, DMT) and non-classic psychedelics (e.g., ketamine, MDMA) on neuroplasticity. Drawing on preclinical and clinical studies, it discusses molecular, structural, and functional changes induced by these agents, highlighting their potential to re-open developmental windows (hyper-plasticity) and increase nervous system sensitivity to stimuli (meta-plasticity). Translating findings to humans remains challenging, but emerging tools like PET radioligands and multimodal approaches offer promise for future research.

This robustness analysis of the ESCAPE-TRD Phase IIIb trial (n=676) investigates esketamine nasal spray versus quetiapine extended release for treatment-resistant depression (TRD). Esketamine significantly outperformed quetiapine in achieving remission at week 8 (MADRS ≤10) and maintaining relapse-free status through week 32, with hazard ratios favouring esketamine (HR: 1.658–1.711, p < 0.001).

This observational study (n=24) examines the acute effects of ayahuasca on memory in experienced Santo Daime members (>500 lifetime uses). Findings show ayahuasca enhances memory accuracy and recollection while not impacting familiarity or false memory, suggesting β-carboline activity may drive selective improvements in hippocampal-dependent processes.

This randomized, double-blind, psychoactive-controlled study (n=12) compared intramuscular ketamine (35-70mg/70kg) to fentanyl (50μg) in treatment-resistant OCD patients, with 10 participants completing the trial. The study found dose-dependent reductions in OCD symptoms (Y-BOCS scores) for ketamine compared to fentanyl, with effects lasting up to 168 hours, though two participants dropped out due to dissociative effects.

This meta-analysis (s=29) examines the effects of psychedelics (including ketamine and MDMA) and two other 'psychoplastogens' on peripheral BDNF levels in humans. It finds no significant changes in BDNF levels post-administration (SMD=0.024, p=0.64), regardless of drug, dose, participant age, or psychiatric condition. Studies with better-controlled designs report smaller effect sizes, and later timepoints show minimal increases in BDNF. The authors conclude that peripheral BDNF is likely not a reliable marker of rapid neuroplasticity and recommend neuroimaging or stimulation-based methods for future research.

This review (2024) highlights preclinical research from the past 15 years showing that ketamine and psychedelics trigger dendritic spine growth in cortical pyramidal neurons, enhancing neural plasticity. It compares the longitudinal effects of psychoactive drugs, emphasizing rapid-onset and sustained structural plasticity as key features of rapid-acting antidepressants, and discusses gaps in understanding and prospects for other interventions like rTMS.

This subgroup analysis of a trial on treatment-resistant depression (n=4) evaluates the safety and efficacy of psilocybin (25 mg) in individuals with Bipolar II disorder. Results show a reduction in MADRS scores from 32.5 at baseline to 21.3 at 6 months, with no emergent mania, hypomania, or psychosis, suggesting potential improvement in depressive symptoms.

This pre-print cross-over, placebo-controlled trial (n=14) assesses the effects of escalating doses of 3-MMC (25, 50, 100mg) on vital signs, neurocognitive function, state of consciousness, appetite, and drug desire. Results show dose-dependent increases in heart rate and blood pressure (not clinically significant), enhanced neurocognitive task performance, and mild dissociative and psychedelic effects. Participants reported decreased appetite and transient increases in liking and wanting 3-MMC. Low to moderate doses were well tolerated and safe, with potential risks associated with high doses.

This pooled analysis of two RCTs (n=48) investigates the safety of mescaline in single oral doses of 100–800 mg (96 administrations). Positive subjective effects increased dose-dependently, while autonomic effects were moderate. Adverse effects, including nausea (dose-limiting), were recorded, but no significant issues with liver/kidney function or blood cell counts occurred. "Flashbacks" were reported in 2% of administrations. Mescaline doses up to 800 mg were deemed safe in a controlled clinical setting for healthy participants.

This pharmacokinetic study (n=16 + n=51 data from earlier study) investigates the effects of food on MDMA pharmacokinetics and uses population and physiologically based pharmacokinetic models to simulate clinical dosing regimens. Results show that a high-fat/high-calorie meal delays Tmax but does not alter plasma concentrations, with no clinically meaningful covariates identified. Simulations reveal MDMA is a potent CYP2D6 inhibitor but has negligible impact on drugs sensitive to renal transport, informing drug–drug interaction potential and dosing strategies.

This systematic review (2024) and meta-analysis (s=131) examines the incidence of psychedelic-induced psychosis, focusing on individuals with schizophrenia. It finds an incidence of 0.002% in population studies, 0.2% in UCTs, and 0.6% in RCTs, with 3.8% of UCT participants with schizophrenia developing long-lasting psychotic symptoms. It also reports that 13.1% of those with psychedelic-induced psychosis later developed schizophrenia.

This survey (n=581) evaluates the Psychedelic-related Major Life Changes Questionnaire (P-MLCQ) in people reporting naturalistic psychedelic use. It finds that 82.96% of participants reported major life changes in at least one domain, including goals (53.7%), values (53.53%), and spirituality (49.05%), with changes rated highly positively (M = 4.64/5). Frequency of use correlated with more changes (r = 0.34), while education level was negatively associated with the number of changes (β = -0.137).

This mixed-methods investigation (n=16 psilocybin retreat participants; n=529 online survey respondents) explores strategies for navigating challenging psychedelic experiences and their link to emotional breakthroughs. Three primary strategies—Acceptance and Reappraisal, Sensory Regulation and Physical Interaction, and Social Support and Disclosure—emerged, with the first and third positively associated with emotional breakthroughs. Fear-related challenges were negatively associated with breakthroughs, indicating the need for adaptive coping strategies to optimize therapeutic and safety protocols.

This theoretical framework paper analyses two Phase III trials of MDMA-assisted therapy for PTSD, describing the conceptual underpinnings and therapeutic approach. It explains how the treatment combines three MDMA-facilitated sessions with non-drug psychotherapy sessions, emphasizing the patient's "inner healing intelligence" as the primary change agent and the therapeutic relationship as the core facilitating condition.

This reanalysis of four RCTs (n=96) finds that MDMA (100mg or 125mg) induced hyponatremia in 31% of participants, with none occurring in the fluid-restricted group (n=15) compared to 37% in the unrestricted group (n=81). The study challenges previous understanding by showing hyponatremia correlates with increased oxytocin (433% increase) rather than vasopressin levels, suggesting oxytocin mimics vasopressin's effects in the kidneys.

This meta-analysis (s=5, n=158) of classic psychedelic effects on empathy using the Multifaceted Empathy Test (MET) finds significant enhancement of explicit and implicit emotional empathy, with no effect on cognitive empathy. The analysis covers studies up to November 2023 examining LSD, psilocybin, and ayahuasca.

This placebo-controlled study (n=6) investigates how psilocybin (25mg) affects visual surround suppression compared to placebo (100mg niacin). The study finds increased surround suppression effects under psilocybin, with stronger suppression correlating with more intense subjective visual effects.

This online survey (n=6,193; 2,488 microdosers) examines differences between exclusive microdosers and those who use both micro and macrodoses of psychedelics. The study finds exclusive microdosers were typically older, more likely to be female and non-Caucasian, with psilocybin (74.5%) and LSD (34.4%) being the most commonly used substances, primarily for general wellbeing (73.0%).

This cost-effectiveness analysis compares MDMA-assisted therapy (MDMA-AT) versus placebo with therapy (PT) for chronic PTSD treatment over 5 years. Using a health state-transition model, it finds MDMA-AT to be cost-effective with an ICER of $83,845 per QALY (below the $150,000 willingness-to-pay threshold), despite higher intervention costs ($48,376 vs $12,376), due to reduced healthcare visits and better health outcomes (0.377 QALY increment).

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.