Psychedelic Research Papers

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.

This repeated-measures dose-dependent study (n=19) investigates DMT's subjective and neural dynamics under naturalistic conditions. Participants received 20mg or 40mg doses of freebase DMT in a blinded, counterbalanced design, with EEG data and time-resolved subjective measures collected. The 40mg dose produced more intense visual hallucinations and emotional responses. Neural analyses revealed alpha power and permutation entropy were most associated with subjective experiences, whereas lempel-ziv complexity was less predictive, challenging prior assumptions about its role in psychedelic states.

This phenomenological study (n=23) investigates DMT-induced immersive experiences and encounters with autonomous presences during fMRI scanning. Using micro-phenomenological interviews, it identifies structural features and temporal dynamics of DMT experiences, highlighting layered sensory, spatial, self-related, and social effects that extend beyond ego dissolution or mystical experiences.

This re-analysis of an RCT (n=51) investigates the effects of psilocybin-assisted therapy on empathy in depressed patients. Participants received either a single psilocybin dose (15mg/70kg) or placebo within a 4-week psychological support programme. Psilocybin significantly improved emotional empathy, particularly towards positive stimuli, for up to two weeks compared to placebo.

This re-analysis of the COMPASS Phase IIb trial (n=233) investigates the relationships between psilocybin dose, psychedelic experiences, and therapeutic outcomes in treatment-resistant depression. Participants received a single dose of 25, 10, or 1 mg of psilocybin (COMP360) with psychological support. Higher doses produced stronger psychedelic effects, and reductions in depression (MADRS scores) at Week 3 correlated most strongly with dimensions of Oceanic Boundlessness (r = −0.508), Visual Restructuralization (r = −0.516), and Emotional Breakthrough Inventory (r = −0.637). Findings suggest the quality and intensity of psychedelic experiences mediate therapeutic outcomes and support dose-response mechanisms.

This re-analysis of a single-blind, fixed-order trial (n=28) investigates the effects of a single high-dose psilocybin (25 mg) on personality traits in psychedelic-naïve healthy volunteers. It finds significant reductions in neuroticism one month post-administration, moderated by subjective experience meaningfulness and ego dissolution, suggesting psilocybin catalyses lasting personality changes with therapeutic potential.

This systematic review (2024; s=9) of healthcare workers' attitudes and knowledge about psychedelic-assisted therapy for patients with serious illness finds polarized views, with most acknowledging potential benefits but desiring further education and a stronger evidence base.

This review (2024) examines the recent approval by the Australian Therapeutic Goods Administration (TGA) of psilocybin for treatment-resistant depression (TRD) and MDMA for PTSD, effective 1 July 2023. It highlights the campaign led by Mind Medicine Australia and supported by leading researchers and institutions, as well as implications for future approvals and psychedelic drug development pathways.

This double-blind, randomized, placebo-controlled, crossover study (n=22) investigates the dose-dependent effects and pharmacokinetics of continuous intravenous DMT infusions over 120 minutes. It finds dose-proportional pharmacokinetics, a rapid onset of subjective effects that plateaus at 30 minutes, and a ceiling effect for positive effects at 1.8 mg/min. Higher doses (2.4 mg/min) induce anxiety and ego dissolution. Moderate acute tolerance and successful self-titration for desired effects were observed.

This systematic review (s=45) on psychedelic-assisted psychotherapy for mental disorders finds that psychological interventions are reported with low completeness and high heterogeneity. It also finds that MDMA studies are more homogeneous, with greater procedural detail.

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 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.