Blossom Pulse Archive
What happened in psychedelic research in 2023
514 events from 2023, dated by when they happened rather than when we logged them. Papers as they published, trials starting and finishing, programme milestones, and the news coverage around them, grouped by week.
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Week of 25 December 2023
Open-label, single-group Phase II study (n=15) of psilocybin-assisted psychotherapy for treatment-resistant depression: two 25 mg oral dosing sessions (6 weeks apart) with preparatory and integrative therapy over 12 weeks.
PsilocybinThis single-arm, open-label trial (n=14) will investigate the effects of Ketamine Assisted Psychotherapy (KAP) on individuals with Post Traumatic Stress Disorder (PTSD).
KetamineKetamine administration after traumatic brain injury was not associated with increased mortality or greater disability despite being given to more severely injured patients. Ketamine exposure correlated with fewer episodes of elevated intracranial pressure and smaller rises in TBI protein biomarkers, but a higher incidence of seizures and, in the intracranial haemorrhage subgroup, more cardiac events.
KetamineDepressive DisordersPTSDChronic PainTraumatic Brain Injury (TBI)Neurological InjuryRandomised, blinded Phase I study (n=15) comparing low-dose (100 µg/kg) and high-dose (300 µg/kg) psilocybin to lorazepam (1 mg) in participants with moderate–severe OCD; dosing weekly with masked exposure across phases.
PsilocybinDouble-blind, randomized, parallel-group Phase III study (n=30) comparing single 25 mg oral psilocybin + psychotherapy vs 250 mg niacin active placebo with pre- and post-dose psychotherapy for depression and burnout in frontline healthcare clinicians.
Psilocybin
Week of 18 December 2023
This combined analysis of two cohorts (n=311) compared intravenous ketamine (KET-IV) and intranasal esketamine (ESK-NS) in the treatment of Treatment-Resistant Depression (TRD). The study found that KET-IV (n=171) had larger effect sizes and higher response rates than ESK-NS (n=140), although both significantly reduced depressive symptoms. Despite KET-IV having more reported side effects, its discontinuation rate due to adverse events was not significantly higher than ESK-NS.
KetamineEsketamineMajor Depressive Disorder (MDD)Treatment-Resistant Depression (TRD)Depressive DisordersSuicidalitySafety & Risk ManagementThis survey (n=1022) investigated the correlation between set and setting variables in psychedelic therapy with psychopathology, well-being, and personality. Findings suggest that growth motivations, natural settings, and the presence of significant others predict positive outcomes. In contrast, problematic motivations are associated with greater psychopathology and lower well-being.
MDMATreatment-Resistant Depression (TRD)Depressive DisordersPTSDAnxiety DisordersSubstance Use Disorders (SUD)Palliative & End-of-Life DistressSet & SettingInterpersonal Functioning & Social ConnectednessAcross two cross-sectional studies (n = 54 and n = 306), the authors show that ayahuasca-induced personal death (APD) experiences occur in over half of ceremony participants and are typically intense, transformative events associated with a greater sense of transcending death and certainty in continuity of consciousness. APDs were not linked to demographics, personality or psychopathology but were associated with increased environmental concern and improved coping and life fulfilment, suggesting they may contribute to psychedelics’ long-term beneficial effects.
AyahuascaVeteransPersonality & Trait FactorsThis systematic review and meta-analysis (s=6; 2023) assessed the role of psychedelics in treating alcoholism (AUD). LSD and any psychedelic therapy showed enhanced odds of achieving abstinence or reducing alcohol consumption in randomised, double-blind, placebo-controlled trials. However, the study highlights methodological weaknesses in the literature. It suggests that while promising, definitive statements about the value of psychedelics in treating AUD are precluded, emphasizing the need for future trials with greater rigour.
LSDAlcohol Use Disorder (AUD)SuicidalityNeurocognitive DisordersSubstance Use Disorders (SUD)In a phase 2 open‑label trial, a single 25 mg dose of psilocybin given in a group therapy setting with one‑to‑one therapist support was safe and feasible in 30 patients with cancer and major depressive disorder, with no psilocybin‑related serious adverse events. The treatment produced a large reduction in depressive symptoms (mean 19.1‑point decrease; 80% sustained response; 50% remission at week 1 maintained through 8 weeks), suggesting clinical efficacy warranting further study.
PsilocybinAnxiety DisordersDepressive DisordersSuicidalityMajor Depressive Disorder (MDD)Chronic PainHeadache Disorders (Cluster & Migraine)Palliative & End-of-Life DistressSafety & Risk ManagementIn interviews with 28 cancer patients with major depressive disorder, a combined model of psilocybin‑assisted simultaneous individual and group therapy was generally judged acceptable and was felt to enhance perceived safety, preparedness, connection and opportunities for self‑transcendence and compassion. Participants emphasised the therapeutic framework, the complementary value of individual sessions, and careful attention to group size and interaction structure as key factors influencing acceptability and scalability in cancer care.
PsilocybinDepressive DisordersAdolescentsMajor Depressive Disorder (MDD)Palliative & End-of-Life DistressHealthy VolunteersInterpersonal Functioning & Social ConnectednessAnxiety Disorders
Week of 11 December 2023
This retrospective analysis (n=5061) of FAERS data on esketamine from 2019 to 2023 reveals 117 adverse reactions. In addition to known adverse events, new signals like flashback, tachyphylaxis, and autoscopy were identified. Suicidal ideation and attempts were relatively high, emphasizing the need for vigilance, while issues related to nasal administration, such as monitoring procedure errors and discomfort, were highlighted.
KetamineEsketamineAdolescentsTreatment-Resistant Depression (TRD)Depressive DisordersSubstance Use Disorders (SUD)SuicidalitySafety & Risk ManagementNuminus Wellness’s Cedar Clinical Research will participate in one of multiple sites for the Phase 2b study, which will assess different doses and the safety and efficacy of intranasal synthetic 5-MeO-DMT. The trial follows the US Food and Drug Administration’s Investigational New Drug approval for this short-acting psychedelic approach.
5-MeO-DMTDMTDepressive DisordersRandomised, double-blind, placebo-controlled Phase I trial (n=38) assessing safety, tolerability, PK and PD of IV and IM SPL028 (deuterated DMT fumarate) in healthy participants; optional Part B (MDD) did not take place.
DMTThis open-label, lead-in Phase II study is intended to gather supportive data on the safety and effectiveness of manualized MDMA-assisted psychotherapy as a treatment for PTSD, with two open-label MDMA-assisted therapy sessions per participant (flexible dosing 80–180 mg per session).
MDMAThis randomized, double-blind, placebo-controlled study (n=160) aims to evaluate the safety, tolerability, and efficacy of Psilocybin-Assisted Psychotherapy (APEX-002-A02) in treating severe depression among adults with Post-Traumatic Stress Disorder (PTSD).
PsilocybinAnalysing free-text reports from psychedelic users and survey data from users and non‑users, the study identified 52 distinct perceived personality‑change themes that aggregated into eight higher‑order factors and showed that openness, extraversion and neuroticism predict interest in and outcomes of psychedelic use. These results support a tentative holistic model in which baseline personality, drug type and setting interact to produce diverse, clinically relevant personality changes, and they point to directions for prospective research and psychedelic‑assisted therapies.
Equity and EthicsPersonality & Trait FactorsInterpersonal Functioning & Social ConnectednessMAPS submitted a new drug application to the U.S. Food and Drug Administration for MDMA-assisted therapy, combining MDMA with psychotherapy, to treat PTSD. The FDA may grant Priority Review, but approval would require the DEA to reschedule MDMA for prescription medical use. Numinus plans to offer the therapy if authorised and has expanded its Practitioner Training Program.
MDMAPTSDAlso covered by MAPS, PR Newswire
This open-label Phase II feasibility study (n=12) of manualized MDMA-assisted psychotherapy for moderate-to-severe depression (MDD) included up to two experimental oral MDMA sessions (supplemental dose allowed) and used clinician-rated MADRS change at ~12 weeks as the primary outcome.
MDMAThis review (2023) of 5-MeO-DMT, a tryptamine with unique antidepressant potential, notes its distinct effects compared to typical psychedelics. It draws parallels between 5-MeO-DMT's effects and epileptiform activity, particularly through 5-HT1A receptor interactions, suggesting its therapeutic action may resemble electroconvulsive therapy (ECT).
5-MeO-DMTTreatment-Resistant Depression (TRD)Depressive DisordersAnxiety Disorders
Week of 4 December 2023
Randomised, double-blind, parallel-group Phase 2 trial (n=81 actual) comparing weekly 1-hour inhaled nitrous oxide (25% or 50%) versus placebo (oxygen–air) for Major Depressive Disorder.
Nitrous OxideThis double-blind, randomized, dose-response trial (n=15) aims to assess the pharmacokinetic and pharmacodynamic profiles of RE02, a psychedelic drug, in healthy subjects.
5-MeO-DMTThis EEG study compared non-users and individuals with extensive naturalistic psychedelic use (≥15 lifetime experiences) during presentation of emotional facial expressions. Experienced users showed reduced early ERP responses (N170/N200) to fearful faces—suggesting diminished automatic reactivity to negative stimuli—whereas later attention-related components (P200/P300) did not differ between groups.
Neuroimaging & Brain MeasuresThe investigator-initiated, open-label study was conducted by Dr Scott Aaronson at Sheppard Pratt in Baltimore and funded by Compass Pathways. At week 3, mean MADRS scores fell by 24 points, with 12 participants meeting response criteria and 11 meeting remission criteria. No manic symptoms or unexpected adverse events were reported, though the authors said larger studies are needed.
PsilocybinBipolar DisorderDepressive DisordersAnalysing 2023 data from MDMA-assisted PTSD and psilocybin-assisted MDD trials, the authors show that group therapy markedly reduces clinician time and costs while expanding potential patient access. Group protocols cut clinician costs by 50.9% for MDMA‑PTSD (≈$3,467 per patient) and 34.7% for psilocybin‑MDD (≈$981), potentially freeing 6,711 and 1,159 FTE clinicians respectively and saving up to $10.3 billion and $2.0 billion in the US over 10 years (3% annual discount).
MDMAPsilocybinAnxiety DisordersDepressive DisordersPTSDMajor Depressive Disorder (MDD)Implementation & Service DeliveryHealth Economics & ReimbursementIn a non‑blinded study of six healthy volunteers, 5,6‑methylenedioxy‑2‑aminoindane (MDAI) produced subjective effects comparable with 125 mg MDMA and raised blood pressure and endocrine markers (cortisol, prolactin) but, unlike MDMA, did not increase heart rate or body temperature. MDAI was well tolerated and remained detectable in serum and urine for several days, warranting further clinical investigation of potential medicinal properties.
MDMAHealthy VolunteersThis retrospective registration trial investigates the effectiveness of psychedelic therapy for Treatment Resistant Depression (TRD).
PsilocybinThis safety-feasibility trial (n=2) explored the interaction between psilocybin and buprenorphine in adults with opioid use disorder (OUD). The study found that coadministration of psilocybin and buprenorphine was safely tolerated, with no serious adverse events or significant changes in opioid craving or withdrawal measures. Feasibility challenges led to modifications in the study population and eligibility criteria, emphasizing the need for improved accessibility and overall generalizability.
PsilocybinAlcohol Use Disorder (AUD)Opioid Use Disorder (OUD)Tobacco/Nicotine Use Disorder (TUD)Substance Use Disorders (SUD)Safety & Risk ManagementInterpersonal Functioning & Social ConnectednessPublic Health, Prevention & Behaviour Change
Week of 27 November 2023
This double-blind, randomised, placebo-controlled, crossover trial (n=39) finds a low dose of LSD (26μg) to produce greater positive mood, stimulant-like, and psychedelic effects in people with mild depression (BDI-II≥17) compared to non-depressed controls. Self-rated depression scores decreased more 48 hours after LSD for the mildly depressed group. Both groups showed expected physiological and subjective drug effects. This suggests low-dose LSD may have therapeutic potential for depression.
LSDAnxiety DisordersDepressive DisordersHealthy VolunteersMicrodosingCreativityThis observational cohort study (n=128) will evaluate the sustained effectiveness of intravenous (IV) ketamine for suicidal ideation in adults experiencing a suicidal crisis due to major depressive disorder.
KetamineRandomized, quadruple-blind, parallel-group trial (n=30) testing single oral psilocybin doses (1–30 mg) combined with zolpidem, modafinil, both, or placebo for adults with chronic low back pain.
PsilocybinDouble-blind, randomised, placebo-controlled, within-subject study (n=20) testing six low/microdoses of oral psilocybin (0, 1, 2, 5, 8, 10 mg) in healthy volunteers to identify doses that improve mood, cognition and sleep without hallucinogenic effects.
PsilocybinUsing the Moving Rubber Hand Illusion in patients with psychosis, people with substantial psychedelic experience, and controls (N = 75), the study found that patients with psychosis showed reduced body ownership and sense of agency during volitional action, whereas the psychedelic group—despite reporting enduring subjective changes to selfhood—did not differ from controls on measures of the bodily self. This suggests that psychedelic-induced alterations in self-experience are not reflected in bodily self-processing, while psychosis involves specific disruption of action-related bodily self-processing.
SchizophreniaThis re-analysis study (n=20) investigated the impact of acute LSD (75μg) administration on thalamocortical connectivity in healthy volunteers. The study utilized structural and resting-state fMRI to examine the thalamus at the nucleus-specific level. LSD intake was found to increase functional connectivity between the thalamus's ventral complex, pulvinar, and non-specific nuclei, particularly with sensory cortices such as somatosensory and auditory networks, as well as parts of the associative cortex dense in serotonin type 2A receptors. The study also reported decreased connectivity between the striatum and thalamus.
LSDNeuroimaging & Brain MeasuresHealthy VolunteersThis double-blind experimental study (n=20) compares the effects of high-dose dextromethorphan (DXM; 400mg/70kg) to psilocybin (10, 20, 30mg/70kg) under conditions typical of therapeutic psychedelic trials. DXM and psilocybin showed increases over placebo in ratings of experiences predictive of psychological benefit at 1 week. However, psilocybin's effects were dose-dependent and more favourable, while DXM had poorer physical tolerability.
PsilocybinHealthy VolunteersThis longitudinal study (n=50, confirmatory sample n=55) investigated the use of esketamine in patients with treatment-resistant depression (TRD) and aimed to define distinct response trajectories. The study identified two classes, one representing response and the other non-response, influenced by factors like concomitant benzodiazepine medication, number of depressive episodes, or polarity. After two esketamine administrations, the depression score (MADRS) predicted the 90-day response trajectory with 80% accuracy, suggesting clinicians could use MADRS scores to decide whether to continue treatment in TRD patients.
EsketamineKetamineDepressive DisordersTreatment-Resistant Depression (TRD)Bipolar DisorderThis observational, case-only study (n=25) will investigate the self-administered therapeutic use of psychedelics in people with psychiatric disorders.
This single-group assignment trial (n=6) aims to evaluate the feasibility and preliminary efficacy of ketamine as a treatment for patients with Opioid Use Disorder (OUD) and comorbid depression (OUDCD).
KetamineFor the year ended 31 August 2023, Numinus reported revenue of C$23.2 million, up 256.9% year on year, and gross profit of C$8.4 million. Its clinics provided 82,373 appointments, while more than 400 learners joined its certification pathway and the company facilitated 36 clinical research trials. Numinus also partnered with MAPS to offer MDMA-assisted therapy experiential opportunities for practitioners.
MDMADouble-blind, placebo-controlled, randomised single-dose cohorts (n=64 across cohorts A–G) and an open-label multiple-dose cohort (J) investigating safety and serum pharmacokinetics of IV GH002 (5‑MeO‑DMT) in healthy volunteers.
5-MeO-DMTThe first direct head-to-head study will randomly assign about 400 participants across Yale-affiliated, Emory University, University of Michigan and community sites to IV ketamine or esketamine nasal spray. Researchers will assess depression and anxiety symptoms, treatment satisfaction, drug response and tolerability in real-world settings.
EsketamineKetamineAnxiety DisordersDepressive DisordersThis review (2023) discusses the potential integration of classic psychedelic-assisted therapies (PAT) into current clinical practices for substance use disorders (SUDs). With promising results from initial studies, the authors suggest that classic psychedelic-assisted therapies could become legally available options for SUD patients in the future. The article outlines contemporary evidence-based treatments for SUDs and proposes that classic psychedelic-assisted therapies can be broadly compatible with existing mainstream SUD treatment paradigms, offering a new avenue for exploration in addressing these disorders.
Substance Use Disorders (SUD)Public Health, Prevention & Behaviour ChangeThis Phase II interventional trial (n=60) aims to investigate whether psilocybin affects synaptic vesicular density (SVD) in individuals with amnestic Mild Cognitive Impairment (aMCI) compared to healthy participants.
PsilocybinThis is a Phase II, multi-centre, randomized, double-blind, parallel-group, dose-finding study to assess the effect of four doses of MM-120 (25, 50, 100 or 200 μg LSD freebase-equivalent) for the treatment of anxiety symptoms in subjects diagnosed with generalized anxiety disorder (GAD).
LSDThis open-label within-subject study (n=10) compared the oral administration of a capsule (containing DMT and harmine) with combined intranasal administration of an oromucosal harmine tablet and an intranasal DMT spray at two doses. The research aimed to improve the pharmacokinetics and tolerability profiles of ayahuasca-analogue formulations. Results indicate that the combined buccal/intranasal administration substantially attenuated common side effects and yielded significantly improved pharmacokinetic profiles. This suggests it may be an innovative approach for the safe and patient-oriented administration of DMT/harmine for treating affective disorders.
AyahuascaDepressive DisordersHealthy VolunteersSafety & Risk ManagementMedicinal Chemistry & Drug DevelopmentPersonality & Trait Factors
Week of 20 November 2023
This first longitudinal case study reports that a single inhaled dose of toad‑derived 5‑MeO‑DMT produced rapid, clinically significant and sustained reductions in PTSD symptoms, hopelessness and suicide risk in a 23‑year‑old woman, with the participant endorsing a complete mystical experience and no drug‑related serious adverse events. Improvements persisted for 12 months but were accompanied by acute nausea, overwhelming subjective effects and later night terrors.
5-MeO-DMTPTSDSuicidalitySafety & Risk ManagementThis double-blind, randomized, dose-response trial (n=15) aims to assess the pharmacokinetic and pharmacodynamic profiles of RE02, a psychedelic drug, in healthy subjects.
5-MeO-DMTThis systematic review of 52 human studies summarises drug–drug interactions between classic psychedelics (LSD, psilocybin, mescaline, DMT, 5‑MeO‑DMT) and various psychotropic and recreational drugs, finding heterogeneous outcomes — attenuated, potentiated or unchanged effects — with few serious adverse events reported beyond isolated case reports. The paper provides a comprehensive synthesis of clinical evidence and discusses potential molecular mechanisms underlying these interactions.
AyahuascaLSD5-MeO-DMTDMTMescalinePsilocybinAdolescentsDepressive DisordersAnxiety DisordersSafety & Risk ManagementMedicinal Chemistry & Drug Development
Week of 13 November 2023
In a retrospective survey of 160 people, a naturalistic psychedelic experience was associated with significant reductions in drinking days per week and AUDIT scores and with increased psychological flexibility. Greater reductions in alcohol use were linked to higher baseline AUD severity and lower baseline psychological flexibility, and were associated with the intensity of the mystical experience and with increases in psychological flexibility.
Alcohol Use Disorder (AUD)Public Health, Prevention & Behaviour ChangeSubstance Use Disorders (SUD)Phase I triple-blind, random-order, 3-period crossover in healthy volunteers (n=25) comparing MDMA 120 mg + 60 mg booster (2 h), MDMA 120 mg + placebo, and placebo + placebo to assess duration of acute subjective, physiological and endocrine effects.
MDMAThis cross-sectional survey (n=517) assessed the psychometric properties of the Spiritual Well-Being Scale (SWBS) concerning existential well-being (EWB) and religious well-being (RWB). The study found that the RWB factor exhibited superior psychometric indices for validity, group discrimination, and reliability, showing a U-shaped pattern in the association between psychedelics and spiritual well-being, where non-users and frequent users had higher RWB and EWB indices than occasional users.
The UK research will include COMP 006, a trial comparing 25mg, 10mg and 1mg doses of COMP360 across sites including the new Centre for Mental Health Research and Innovation at Maudsley Hospital. The centre was established by Compass Pathways, South London and Maudsley NHS Foundation Trust and King’s College London IoPPN to advance psychedelic research and new mental health care models.
PsilocybinDepressive DisordersTreatment-Resistant Depression (TRD)Also covered by Kcl
This interventional trial (n=3) will assess the efficacy and safety of esketamine for the treatment of Rett Syndrome (RTT) in children aged 5 to 10 years.
Esketamineatai Life Sciences reported third-quarter 2023 results from New York and Berlin, with $209.0 million in cash, cash equivalents and short-term investments as of 30 September. The company said funding is expected to support operations into the first half of 2026, while RL-007’s Phase 2b results are expected in the second half of 2024 and a Phase 1b VLS-01 study is planned for the first half of 2024.
DMTHealthy VolunteersRandomised, parallel-group study (n=82 actual) comparing a single high-dose psilocybin session (30 mg/70 kg) plus CBT versus standard transdermal nicotine patch plus CBT for nicotine-dependent smokers.
PsilocybinIn a cross-sectional internet convenience sample of 770 self‑selecting Norwegian adults reporting a memorable classic psychedelic experience (predominantly psilocybin), most used psychedelics for recreational or therapeutic reasons and reported self‑perceived improvements in mental health and substance‑use symptoms, with many preparing, processing and integrating the experience though few received therapist support. Adverse reactions were generally mild and short‑lived but lasted one year or more in 4.2% of participants, including persistent flashbacks in 2.9%.
LSDPsilocybinAdolescentsDepressive DisordersAnxiety DisordersSubstance Use Disorders (SUD)
Week of 6 November 2023
This randomised controlled parallel group Phase II trial (n=24) evaluated the safety and efficacy of mdma for post-traumatic stress disorder.
MDMAUsing quantitative textual analysis of open-ended reports from first-time ayahuasca users (9 with treatment-resistant depression, 20 healthy controls), the study identified five core experiential clusters—altered states of consciousness, cognitive changes, somatic alterations, auditory experiences and visual perceptual content—and found that participants with depression reported more aversive bodily reactions. These findings align with central axes of the psychedelic experience and may inform therapeutic applications of ayahuasca.
AyahuascaDepressive DisordersTreatment-Resistant Depression (TRD)Healthy VolunteersGH Research had $228.7 million in cash and related assets at 30 September 2023 and expects funding into 2026. Its Phase 2b GH001-TRD-201 trial is enrolling about 80 people across 20 sites in seven European countries, with top-line data expected in Q3 or Q4 2024. The FDA requested further inhalation toxicology, device verification and investigator brochure updates before lifting the hold on GH001-HV-106.
5-MeO-DMTDMTDepressive DisordersHealthy VolunteersTreatment-Resistant Depression (TRD)The authors introduce a Bayesian framework to estimate heart-rate entropy (and Bayesian mean HR and HRV) under psychedelics and apply it to data from LSD, DMT, psilocybin and sub‑anaesthetic ketamine. They report consistent increases in mean HR, high‑frequency HRV and heart‑rate entropy during the psychedelic state, with heart‑rate entropy predicting subjective dimensions and correlating with brain entropy, suggesting a cost‑efficient autonomic marker for tracking subjective and neural psychedelic effects.
LSDDMTKetaminePsilocybinThis qualitative study (n=15) explores the perspectives of ayahuasca ceremony leaders, primarily from the West/Global North, on the suitability of ceremonial ayahuasca use for individuals with eating disorders (EDs). The analysis identifies categories such as screening for EDs, purging and dietary restrictions, potential risks, and complementarity with conventional ED treatment. The findings suggest the need for careful screening and extra support to ensure safe and beneficial ayahuasca ceremony experiences for individuals with EDs.
AyahuascaEating DisordersEarly‑Phase interventional dose-ranging study (n=40) assessing LSD single doses (25–200 µg) to quantify 5‑HT2A receptor occupancy in healthy participants using [11C]CIMBI‑36 PET/MR.
LSDThis review (2023) examines ibogaine as a potential treatment for substance use disorders (SUDs). The lack of randomised, controlled studies on its safety and efficacy and the elusive mechanisms of action have been barriers to clinical use. The review suggests that ibogaine and its metabolite, noribogaine (NOR), modulate multiple targets associated with SUDs, emphasizing a complex, multi-target approach to understanding its pharmacology.
IbogaineTobacco/Nicotine Use Disorder (TUD)Substance Use Disorders (SUD)Medicinal Chemistry & Drug DevelopmentThis mini‑review argues that 5‑HT2A activation is only one facet of serotonergic psychedelic action, which also involves other serotonin receptors (5‑HT1A, 5‑HT2C), neurotrophin receptors (e.g. TrkB), promotion of neuroplasticity and possible protein post‑translational modifications. It highlights efforts to develop non‑hallucinogenic derivatives that retain therapeutic neuroplastic effects while minimising the intense psychedelic experience.
LSDPsilocybinAnxiety DisordersDepressive DisordersPTSDSubstance Use Disorders (SUD)Eating DisordersChronic PainAdaptive, non-randomised Phase I healthy volunteer study (target n=15) testing IV psilocybin 2 mg (2‑ or 10‑minute infusions) with or without 0.2 mg oral clonidine to identify regimens that permit dosing during sleep.
PsilocybinThis study measures the safety and efficacy of repeated low dose MM-120 as treatment for ADHD in adults: a multi-center, randomized, double-blind, placebo-controlled trial.
LSDThis randomised controlled trial (n=45) evaluates a 55-minute psychedelic-like VR intervention (Psyrreal) versus a non-psychedelic VR analogue and a conditional waitlist in adults with clinical depression.
This multi-site open-label study assesses the efficacy and safety of 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy in participants who were enrolled in a parent study for the treatment of posttraumatic stress disorder (PTSD).
MDMAThis perspective article (2023) discusses the ethical considerations of providing post-trial access (PTA) in psychedelic clinical trials. It highlights the unique aspects of psychedelic trials, such as the legal status of psychedelics, the researcher-participant relationship, and the extended therapeutic process, as factors supporting the case for introducing PTA. The authors also advocate for a broader focus on post-trial care beyond access and provide an overview of potential provisions for psychedelic clinical trials, emphasizing the development of infrastructure for the post-legalisation psychedelic medicine ecosystem.
Equity and EthicsThis review (2023) examines the interest in ibogaine's therapeutic potential for substance use disorders over three decades (1993-2022). The study identifies a linear growth of publications in the first and third decades, with academic research centers in the United States and Canada being the most productive. Major keywords shifted from cocaine, tobacco, morphine, and alcohol in the first two decades to opioids and psychedelics in the third decade, indicating evolving research trends.
IbogaineOpioid Use Disorder (OUD)Substance Use Disorders (SUD)
Week of 30 October 2023
Randomised, Phase I parallel study (n=18) testing single and repeated oral psilocybin (10 mg) vs diphenhydramine placebo across two sessions ~7 days apart to assess effects on migraine headache burden and mechanisms.
PsilocybinThe company expects initial topline data from COMP005 in summer 2024 and from COMP006 in mid-2025, while topline data from its Phase 2 PTSD study are expected by the end of 2023. The financing could provide up to approximately $285 million in total proceeds, supporting clinical development and preparation for a potential FDA filing.
PsilocybinPTSDOpen-label, single-group Phase II study (n=10) assessing a single 25 mg oral dose of psilocybin for adults with MDD and co-occurring BPD to evaluate safety and efficacy.
PsilocybinRandomised, double-blind, parallel-group study (n=30) testing a single oral dose of psilocybin (0.36 mg/kg) versus active placebo (dextromethorphan 2.6 mg/kg) for fibromyalgia.
PsilocybinDouble-blind, randomised, multi-site trial (n=66) comparing two psilocybin sessions (30 mg; second session 30 or 40 mg) versus active placebo niacin (150 mg; second session 150 or 200 mg) plus CBT for smoking cessation.
PsilocybinThis double-blind placebo-controlled paper (n=60) explores the effects psilocybin (12mg/70kg) has on a range of inflammatory markers associated with stress-related psychiatric disorders. Blood samples, MRI and questionnaires were used to assess different aspects of the immune response. Psilocybin immediately reduced levels of the inflammation-inducing TNF-α while other markers were unchanged. After seven days, TNF-α returned to baseline while levels of IL-6 and CRP were reduced in the psilocybin group, which were associated with more persisting positive mood and social effects.
PsilocybinHealthy VolunteersDepressive DisordersPTSDSubstance Use Disorders (SUD)Neuroimaging & Brain MeasuresImmunology & InflammationThis systematic review (s=51) examines fMRI studies on the acute effects of psychedelics like psilocybin, LSD, and ketamine on the human brain. The review highlights significant methodological inconsistencies across studies, including 54% not meeting contemporary Type I error correction or motion artefact control standards. Despite these limitations, convergent findings indicate that psilocybin and LSD affect the connectivity architecture of the sensorimotor-association cortical axis, while ketamine increases activation in the dorsomedial prefrontal cortex.
MDMAKetaminePsilocybinNeuroimaging & Brain MeasuresThis parallel-group, double-blinded, randomised controlled trial (n=35) investigates a single 25 mg oral psilocybin dose plus structured psychotherapy versus active placebo (100 mg niacin) for depression and anxiety in terminally ill patients.
PsilocybinThis naturalistic, open-label, single-arm intervention trial (n=162) conducted by Royal North Shore Hospital assesses add-on intranasal esketamine (Spravato) for adults with major depressive disorder.
KetamineThe investigators will compare 3 groups (ketamine + naltrexone vs ketamine alone vs placebo) in an 8-week randomised, double-blind, placebo-controlled trial (n=65) of repeated IV ketamine (0.5 mg/kg weekly x4) for comorbid MDD and AUD.
Ketamine
Week of 23 October 2023
This Phase IV interventional trial (n=60) aims to investigate the effectiveness of intraoperative ketamine in reducing postoperative depressive symptoms in patients undergoing lumbo-peritoneal shunt insertion.
KetamineThis single-blind, placebo-controlled crossover study (n=11) investigated a novel administration method for DMT involving a bolus injection followed by a constant-rate infusion to extend the experience over 30 minutes. Results demonstrate that the method was safe and maintained stable subjective effects, although the plateauing of psychological effects despite rising plasma concentrations suggests the development of acute tolerance.
DMTAnxiety DisordersMedicinal Chemistry & Drug DevelopmentOpen-label, parallel-group, randomised trial (withdrawn; ACTUAL n=0) comparing adjunctive intranasal esketamine versus adjunctive aripiprazole in veterans with treatment-resistant depression over up to 6 months; primary endpoint remission at 6 weeks.
EsketamineThis open-label, dose-ranging clinical trial (n=50) aims to determine the feasibility, tolerability, and safety of weekly oral ketamine for PTSD over six weeks with follow-up assessments.
KetamineThis systematic review indicates that MDMA generally increases sexual desire and, when orgasm occurs, intensifies its pleasure in both sexes, while producing mixed effects on arousal and potentially impairing erectile and ejaculatory function in men. However, heterogeneous methods and largely qualitative outcome measures limit the strength of these conclusions.
MDMARandomised, triple-blind, crossover early-phase study (n=43) comparing single oral MDMA 125 mg, methamphetamine 20 mg, and placebo in healthy volunteers to assess social motivation, social ability, and neural indices of social function.
MDMAThis Phase I intervention trial (n=120) investigates whether stimulating the serotonin system influences pro-social behaviour compared to stimulating the dopamine system in healthy individuals; single-dose psilocybin (15 mg), MDMA (100 mg) or methylphenidate (60 mg) in a double-blind randomized parallel design.
PsilocybinMDMAIn a US-representative sample (N=2,822), lifetime naturalistic psychedelic use was associated with more lifetime unusual visual experiences and a 1.3% self-reported rate of hallucinogen persisting perception disorder, but not with greater past-two-week psychotic symptoms overall. There was an interaction with family history: psychedelic users with a family history of psychotic or bipolar disorders reported higher recent psychotic symptoms, whereas users without such a family history reported lower symptoms.
Bipolar DisorderDepressive DisordersSchizophreniaThis mixed‑methods study of 608 people reporting extended difficulties after psychedelic use found common problems—anxiety and fear, existential struggle, social disconnection and depersonalisation/derealisation—with about one third affected for over a year and one sixth for more than three years. Shorter duration was associated with knowing the dose and drug type and with lower acute difficulty, while a narrower range of difficulties was linked to taking the drug in a guided setting, with implications for harm reduction.
PsilocybinAnxiety DisordersSchizophreniaSafety & Risk ManagementThis Phase II, single-center trial (n=56) investigates the efficacy, safety, and tolerability of up to two doses of psilocybin (25mg) administered at an interval of 9 to 10 weeks in patients with Major Depressive Disorder (MDD) and cancer.
PsilocybinIn a randomised controlled pilot study of 26 individuals with PTSD, subanesthetic ketamine (vs midazolam) did not increase resting‑state functional connectivity between the amygdala and medial prefrontal cortex subregions. Instead, ketamine induced a transient decrease in vmPFC–amygdala connectivity, challenging prior correlational links between dissociation and fronto‑limbic overconnectivity.
KetamineNeuroimaging & Brain MeasuresPTSDContrary to the prevailing view that psychedelics increase pyramidal cell excitability via 5‑HT2A receptors, this study shows multiple classes of psychedelics dose‑dependently suppress intrinsic excitability of prefrontal pyramidal neurons by enhancing M‑current potassium channels independently of 5‑HT2A activation, with extracellular application producing larger effects than intracellular. Machine‑learning modelling indicates M‑current activation interacts with other mechanisms to markedly reduce excitability and shorten working‑memory timespan, implying modulation of ubiquitous ion channels may drive homeostatic changes that contribute to broad therapeutic benefits.
Week of 16 October 2023
This open-label prospective study (n=25) evaluated esketamine nasal spray (ESK-NS) treatment for treatment-resistant depression (TRD). Over three months, patients reported early and sustained improvements in depression, anhedonia, and suicidality, while clinicians detected improvements that varied at different time points.
KetamineEsketamineTreatment-Resistant Depression (TRD)Depressive DisordersAnxiety DisordersSuicidalityIn representative longitudinal samples from the US and UK, self-reported psychedelic use over a two-month period was associated with greater increases in days of mindfulness meditation, and among users the subjective experience of insight predicted increases in both mindfulness and loving‑kindness/compassion practice. Higher baseline engagement in loving‑kindness/compassion meditation was associated with less intense subjective feelings of death or dying during participants' most intense psychedelic experience, suggesting psychedelics may promote meditation uptake while some meditation practices could buffer challenging psychedelic experiences.
Palliative & End-of-Life DistressInterpersonal Functioning & Social ConnectednessDepressive DisordersAnxiety DisordersThis triple-masked, randomised, placebo-controlled trial (n=40) of adults with major depressive disorder (MDD) found no short-term effect on depression severity (measured by MADRS) after a single dose of intravenous ketamine (35mg/70kg) compared to placebo (saline) during anaesthesia for routine surgery.
KetamineAnxiety DisordersDepressive DisordersMajor Depressive Disorder (MDD)This placebo-controlled study (n=13) investigated the effects of ketamine (3.5-35mg/70kg) on altered states of consciousness (ASCs) and their neural mechanisms. It examined the impact of different doses of ketamine on emotional task-evoked brain activity and various components of dissociation and ASCs. The study found that ketamine-induced ASCs had differential effects on brain activity, with higher depersonalization relieving negative brain states, while dissociative amnesia exacerbated insula activity. These results may provide insights into how specific dissociative states predict the response to ketamine in individuals with depression.
KetamineDepressive DisordersAnxiety DisordersNeuroimaging & Brain MeasuresThis observational cohort study (n=40), conducted by Yale University, aims to explore the long-term effects of ketamine for treating depression in Parkinson's disease (PD) and assess the impact of Cognitive Behaviour Therapy (CBT) on maintaining the effects of ketamine.
KetamineThis uncontrolled, single-arm, naturalistic study (n=162) aims to evaluate the positioning of Esketamine Treatment (PoET) for symptom management in adults with major depressive disorder (MDD).
EsketamineRandomised Phase I study (n=16) comparing PK/PD and safety of six varying doses of a fixed-combination of DMT and harmine across six study days in healthy volunteers with continuous psychological support.
AyahuascaIn a naturalistic prospective survey of adults with diagnosed or severe ADHD, four weeks of psychedelic microdosing was associated with increased trait mindfulness—specifically the describing and non‑judging facets—and decreased neuroticism, while other Big Five traits remained unchanged. These effects were not altered by concurrent ADHD medication or comorbidity, though placebo‑controlled trials are needed to confirm causality.
MicrodosingPersonality & Trait FactorsThis systematic review analyzed the effects of psilocybin on depressive symptoms in patients diagnosed with life-threatening illnesses or major depressive disorder. The review included 13 studies with a total of 686 participants, and the meta-analysis of 9 studies (596 participants) found a significant and large effect in favor of psilocybin (SMD = -0.78; p<0.001) for reducing depressive symptoms. The review suggests preliminary evidence supporting the antidepressant efficacy of psilocybin-assisted psychotherapy but calls for further studies to assess safety, efficacy, and treatment optimization.
PsilocybinMajor Depressive Disorder (MDD)Depressive DisordersAnxiety DisordersPalliative & End-of-Life DistressSafety & Risk ManagementReanalysis of a placebo‑controlled double‑blind RCT of intravenous ketamine in 31 adults with treatment‑resistant depression found that later age of depression onset predicted a greater antidepressant response three days after infusion, whereas age, sex, baseline severity and dissociative scores showed no association. The authors propose that impaired glutamatergic signalling and reduced neuroplasticity in earlier‑onset cases may explain the diminished ketamine response.
KetamineDepressive DisordersMajor Depressive Disorder (MDD)Treatment-Resistant Depression (TRD)Bipolar DisorderAlcohol Use Disorder (AUD)Substance Use Disorders (SUD)
Week of 9 October 2023
Open-label, single-group pilot (n=16) testing six IV ketamine infusions (0.5 mg/kg) combined with five-session Written Exposure Therapy (WET) to improve and maintain PTSD symptom improvement in chronic PTSD.
KetamineIn healthy volunteers, oral psilocybin produced dose-dependent changes in cerebral blood flow (relative and absolute) that correlated with the intensity of the acute subjective psychedelic experience and with baseline psychological and neurobiological characteristics, revealing marked inter-individual heterogeneity in neural response. These associations point to candidate biomarkers linking baseline traits to psilocybin-induced brain changes and support a personalised medicine approach for psychedelic-assisted therapy.
PsilocybinHealthy VolunteersNeuroimaging & Brain MeasuresThis open-label clinical trial (n=12) aims to assess the feasibility of ketamine-assisted psychotherapy (KAP) for adults with non-operable gastrointestinal (GI) cancers suffering from existential distress.
KetamineThe paper uses ketamine as a case study to show that market and regulatory failures allowed a costly patented intranasal s‑ketamine (Spravato®) to be commercialised while inexpensive generic racemic ketamine—apparently at least as effective—remained under‑evaluated and largely inaccessible. The authors recommend systemic reforms, including commercial incentives, public and public–private funding, reduced regulatory barriers and coordinated international funding, to ensure affordable off‑patent treatments become accessible.
EsketamineKetamineDepressive DisordersAlcohol Use Disorder (AUD)Implementation & Service DeliverySubstance Use Disorders (SUD)This Phase IV, randomised controlled trial (n=30) will evaluate the effectiveness of ketamine and psychotherapy in managing chronic neuropathic pain. Participants aged 18 and older with moderate-to-severe neuropathic pain will be assigned to one of three groups: ketamine hydrochloride (1 mg/kg IV, up to 100 mg) administered on weeks 2, 7, and 12, cognitive behavioural therapy (CBT) combined with mindfulness-based meditation delivered remotely for 16 hours over weeks 1 to 16 with in-person sessions on specified weeks, or a combination of both interventions. The trial aims to assess the feasibility of these treatments, focusing on recruitment and adherence rates, as well as the frequency of adverse events over a two-year period. Participants will be monitored for their response to the interventions, with the primary outcomes including the rate of recruitment, adherence to the treatment protocol, and any adverse events experienced during the study. The trial is sponsored by Unity Health Toronto and is set to conclude in July 2025.
KetamineIn response to inadequate graduate training, this international, bottom-up project produced consensus-based guidelines to equip mental health specialists to support clients around psychedelic experiences. The guidelines define psychedelic integration and provide clinician-friendly information on psychedelic effects, a practical model for integration, theoretical considerations and a catalogue of psychotherapeutic interventions and existing integration models.
Depressive DisordersAnxiety DisordersSet & SettingDouble-blind, randomised, triple-masked, 5-period crossover study (n=20) comparing 0.1 mg LSD base (oral solution), 0.1 mg LSD base (orodispersible film), 0.146 mg LSD tartrate (oral), 0.146 mg LSD tartrate (IV) and placebo in healthy participants to assess bioequivalence and oral bioavailability.
LSDThis semi-naturalistic feasibility study found that psilocybin-assisted frontal-midline theta neurofeedback is practicable without psychological support and produced a trend-level increase in frontal-midline theta alongside significant self-reported improvements in everyday executive functions (working memory, shifting, monitoring, inhibition). However, no objective task-based gains were observed, indicating the need for larger randomised trials with regular sessions and active controls to confirm efficacy and specificity.
PsilocybinMicrodosingNeuroimaging & Brain MeasuresDouble-blind, randomised, controlled perioperative trial (n=200) evaluating a single subanesthetic esketamine dose to reduce postoperative anxiety and depression in adolescents undergoing elective surgery.
EsketamineThis survey (n=1,249) assessed interest in and acceptability of psilocybin use among individuals who have experienced adverse childhood experiences. The study found high interest in psilocybin, and its use was associated with reduced psychological distress among those with more severe childhood adversity, indicating its potential therapeutic benefits for this group.
PsilocybinPTSDAnxiety DisordersSubstance Use Disorders (SUD)Set & SettingRandomised, parallel-group Phase II trial (n≈72) of two-dose psilocybin-assisted psychotherapy (25 mg, optional escalation to 30 mg) versus diphenhydramine active-placebo (75 mg, optional escalation to 100 mg) in adults with GAD; two dosing sessions three weeks apart with preparatory and integrative therapy.
PsilocybinDouble-blind, randomised, parallel Phase II trial (n=293) of oral psilocybin microdosing (4 mg, 11 doses over six weeks) versus caffeine (60 mg) for moderate major depressive disorder.
PsilocybinOpen-label Phase II single-group study (n=14) assessing ascending inhaled DMT (15 mg then 60 mg on a single day) for patients with partial response in depression.
DMT
Week of 2 October 2023
Open-label single-group pilot (n=16 dyads, 8 PTSD+ veterans and their partners) testing MDMA-assisted bCBCT: 8-session therapy with two full-day MDMA sessions for PTSD+ veterans to evaluate preliminary effectiveness on PTSD and relationship functioning.
MDMAThis review (2023) focuses on the role of the ego in psychedelic-assisted psychotherapy (PAT), particularly through a psychodynamic lens. It argues that psychedelics induce regressed states of the ego, allowing for emotional integration of early life events that have shaped a person's character and defence mechanisms. The paper posits that for lasting change, PAT must target the characterological core of the ego's habitual patterns, and it suggests that this psycholytic approach is compatible with other forms of PAT like third-wave cognitive behavioural approaches (CBT/ACT).
Medicinal Chemistry & Drug DevelopmentThis open-label Phase IIIb trial (n=676) compared the efficacy of esketamine nasal spray and extended-release quetiapine, combined with an SSRI or SNRI, in patients with treatment-resistant depression (TRD). The study found that a significantly higher percentage of patients in the esketamine group achieved remission at week 8 (27.1% vs 17.6%) and had no relapse through week 32 after remission at week 8 (21.7% vs 14.1%). Adverse events were consistent with the established safety profiles of the trial treatments.
EsketamineKetamineDepressive DisordersSchizophreniaMajor Depressive Disorder (MDD)Treatment-Resistant Depression (TRD)Safety & Risk ManagementPublic Health, Prevention & Behaviour ChangeUsing 7 T MRI and morphometric similarity networks in 24 Santo Daime members and matched controls, repeated ayahuasca use was associated with sensorimotor structural differentiation and transmodal de-differentiation across the cortex. These macroscale cortical remodellings spatially correlated with dysregulation of 5‑HT2A and other psychedelic-target genes, and with altered expression of transcription factors and immediate early genes implicated in psychedelic-induced neuroplasticity, suggesting molecular mechanisms scale up to whole-brain organisation.
AyahuascaNeuroimaging & Brain MeasuresNon-randomised single-group pilot (n=16) assessing IV ketamine 0.5 mg/kg (40-minute infusions, four weekly doses) combined with Radically Open DBT in adults with treatment-resistant depression.
KetamineThe programme includes research into group-administered psilocybin for depressed cancer patients, a completed group ketamine-assisted therapy pilot, and an FDA- and IRB-approved follow-up psilocybin project. Numinus will also participate in a five-site study examining ketamine-assisted therapy for end-of-life distress.
KetaminePsilocybinDepressive DisordersRandomised, parallel-group trial (n=60) comparing oral ketamine plus Behavioural Activation Therapy (BAT) vs oral ketamine plus treatment as usual in adults with treatment-resistant major depressive disorder; oral ketamine initial 0.5 mg/kg (up to 2 mg/kg) sipped over 30–60 minutes.
KetamineThis rat study established and validated a regimen for psilocybin microdosing, administering repeated low doses of psilocybin at a level below the psychedelic threshold. The rats tolerated the regimen well without showing signs of anhedonia, anxiety, or altered locomotor activity. Additionally, the treatment imparted resilience against stress, reduced self-grooming behaviours associated with compulsiveness, and increased 5-HT7 receptor expression and synaptic density in the paraventricular nucleus of the thalamus.
PsilocybinDepressive DisordersAnxiety DisordersPalliative & End-of-Life DistressNeuroimaging & Brain MeasuresMicrodosing
Week of 25 September 2023
Open-label, Phase I dose-ranging safety study (n=12) in healthy adults testing single oral doses of SM-001 (0.5, 1.0, 2.0 mL/kg) to assess safety and plasma biomarkers.
AyahuascaThis Phase I/II interventional trial (n=96) will investigate the use of intravenous ketamine for the rapid reduction of suicidality in paediatric patients presenting with suicidal ideation (SI) in the emergency department (ED).
KetamineThis open-label, non-randomized Phase IIa trial (n=18) evaluates the feasibility and safety of MDMA-assisted group therapy for treating PTSD in veterans. Conducted by the Portland VA Research Foundation, the study employs a unique treatment package comprising two once-monthly open-label MDMA sessions combined with non-drug preparatory and integrative therapy, both individual and group-based.
MDMARandomized, open-label, single-blind, non-inferiority Phase IV comparative effectiveness trial (n=1500) comparing ECT versus subanesthetic IV ketamine (0.5 mg/kg) for rapid treatment of acute suicidal depression.
KetamineThis re-analysis of a Phase I randomised controlled trial (n=89) investigated predictors of mystical and challenging experiences in healthy volunteers receiving psilocybin. It finds that dosage was the strongest predictor of intensity for both experience types, while older age was associated with fewer challenging experiences and neuroticism correlated with challenging experiences only at the higher dose.
PsilocybinDepressive DisordersHealthy VolunteersPersonality & Trait FactorsThis observational survey study of university students (n=13,837) explored the association between ADHD symptoms and lifetime psychoactive substance use. It finds a significant correlation between high levels of ADHD symptoms and the use of various substances, including ketamine and psilocybin mushrooms.
KetaminePsilocybinSubstance Use Disorders (SUD)In a sample of 392 participants (233 with lifetime psychedelic use), the study found a moderate positive association between psychedelic use and endorsement of "alternative facts" and the belief that facts are politically influenced, while no link was observed for preferring intuition over evidence and alcohol use was negatively associated with alternative‑fact beliefs. The authors interpret this as evidence that psychedelic use correlates with non‑conformist thinking styles, which may reflect drug effects or pre‑existing unconventional belief traits.
Anxiety DisordersSubstance Use Disorders (SUD)Personality & Trait FactorsImplementation & Service DeliveryThe GH001-TRD-201 trial is approved in seven European countries, with 14 sites initiated and approximately 80 patients expected across 20 sites. Double-blind completion is expected in the third quarter of 2024, with top-line data in the third or fourth quarter. The FDA placed GH001’s IND on clinical hold after citing insufficient information to assess risks to human subjects.
5-MeO-DMTDMTDepressive DisordersHealthy VolunteersTreatment-Resistant Depression (TRD)The National Academy of Medicine will present the award at its annual meeting on 8 October, recognising work that led to Esketamine, approved by the US Food and Drug Administration in 2019. Their 2000 study found improvement within hours and clinical response within 24 hours after a single ketamine dose.
EsketamineKetamineDepressive DisordersOpen-label single-group study (n=17) assessing two oral psilocybin doses (15 mg, then 25 mg at 2 weeks) plus psychotherapy for adults with fibromyalgia.
PsilocybinThis review (2023) discusses the emerging field of psychedelic therapy for psychiatric disorders, emphasizing the potential of classic serotonergic psychedelics like psilocybin and LSD and substances like ketamine, MDMA, and ibogaine. It highlights the role of advanced neuroscientific research methods, particularly neuroimaging using Positron Emission Tomography (PET) and Magnetic Resonance Imaging (MRI), in advancing the understanding of drug and therapy effects on the brain. The article identifies key knowledge gaps, including the relationship between acute and longer-term effects, the precise characterization of effects at the 5-HT2A receptor, and the impact of these compounds on neuroplasticity, and proposes a roadmap for future research to address these questions through multimodal PET/MRI studies.
PsilocybinLSDKetamineMDMAIbogaineDepressive DisordersPTSDSubstance Use Disorders (SUD)Eating DisordersNeuroimaging & Brain MeasuresThis review (2023) discusses the investigation of psychedelics for their therapeutic potential in neuropsychiatric and substance use disorders. Clinical trials have shown promise in alleviating symptoms of depression, anxiety, and reducing nicotine and alcohol use. The underlying molecular mechanisms for these therapeutic effects are not yet fully understood, with ongoing preclinical studies exploring the role of serotonin 5-HT2A receptors and other pathways.
Depressive DisordersAnxiety DisordersTobacco/Nicotine Use Disorder (TUD)Substance Use Disorders (SUD)SchizophreniaThis non-randomized trial (n=100) investigates the psychological, cognitive, and physiological effects of a single session of psychedelic drug exposure with either psilocybin or MDMA in a group setting.
PsilocybinMDMAThe authors generated a suite of engineered Htr2a mouse lines—including an Htr2a‑EGFP‑CT‑IRES‑CreERT2 reporter, a humanised Htr2a line and a constitutive Htr2a‑Cre line—that enable independent visualisation of HTR2A receptors and HTR2A‑expressing cells and provide detailed anatomical and cell‑type maps. They validated the lines with psychedelic‑induced behavioural phenotypes and electrophysiology showing extracellular 5‑HT produces an HTR2A‑mediated increase in firing of genetically identified pyramidal neurons, consistent with plasma‑membrane localisation and utility for in vivo studies of psychedelic drug actions.
LSDPsilocybinAnxiety DisordersDepressive DisordersPTSDHeadache Disorders (Cluster & Migraine)Chronic PainThe paper identifies ten key methodological and inferential challenges in contemporary psychedelic research that undermine internal, external, construct and statistical validity and often co‑occur, casting doubt on claims about efficacy and safety. It groups these problems by ease of resolution and provides a roadmap and practical checklist for researchers, journalists, funders and policymakers to improve rigour and better assess whether current optimism about therapeutic potential is warranted.
Major Depressive Disorder (MDD)Depressive DisordersPTSDAnxiety DisordersSubstance Use Disorders (SUD)Palliative & End-of-Life DistressCreativityThe study documents multiple cases of lasting negative psychological responses (≥72 h) after classic psychedelics or MDMA, finding new or worsened psychiatric symptoms—predominantly anxiety—and, from in‑depth interviews, implicating unsafe/complex settings, unpleasant acute experiences, prior vulnerabilities, high or unknown doses and young age as common contributing factors. These findings corroborate the reality of iatrogenic mental health harms following psychedelic use but, given the selective small sample and study design, cannot be used to estimate prevalence.
MDMAAnxiety DisordersThis study (n=44) analyzed Uruguayan ayahuasca users in neo-shamanic and Santo Daime groups through chemical tests, ethnography, and psychometrics. Santo Daime participants scored lower in certain personality traits, possibly due to the neo-shamanic group's treatment or Santo Daime's religious framework. The neo-shamanic group had higher scores in Somesthesia and Perception, likely due to their high-arousal rituals.
AyahuascaAnxiety DisordersSubstance Use Disorders (SUD)Set & SettingPersonality & Trait Factors
Week of 18 September 2023
On 11 September 2023, Lord O’Shaughnessy toured the NIHR King’s Clinical Research Facility and its psychedelic treatment rooms, alongside discussions on industry collaboration, trial diversity and barriers to commercial research. King’s College London outlined strategies to increase funding for novel treatments in severe mental illness and neuroscience, while O’Shaughnessy shared an update on his Independent Review of UK Commercial Clinical Trials.
In controlled semi‑structured dyadic conversations, both MDMA (100 mg) and methamphetamine (20 mg) increased participants' feelings of connectedness relative to placebo. Both drugs elevated oxytocin, but only MDMA's oxytocin increase correlated with subjective closeness, indicating similar behavioural effects may arise from different neuroendocrine mechanisms and demonstrating a sensitive method for measuring pro‑social drug effects in person.
MDMAPTSDThis open-label study (n=86) examined the effectiveness of psychedelic-assisted therapy (PAT) among trauma-exposed Special Operations Forces Veterans (SOFV) in Mexico. Results indicated significant improvements in self-reported PTSD symptoms, depression, anxiety, insomnia severity, post-concussive symptoms, satisfaction with life, psychological flexibility, and cognitive functioning from baseline to one-month follow-up. The combination of ibogaine and 5-MeO-DMT assisted therapy showed potential for providing rapid and lasting improvements in mental health functioning, with effects observed up to six months after treatment.
5-MeO-DMTIbogaineVeteransDepressive DisordersPTSDAnxiety DisordersSuicidalityThis Phase II interventional trial (n=120) explores the effectiveness of MDMA-assisted (80–160 mg per session, with possible supplemental doses) prolonged exposure therapy (COPE) versus niacin control in individuals with comorbid PTSD and alcohol use disorder.
MDMAIn the largest prospective longitudinal survey to date of naturalistic psilocybin use (n=2,833 baseline; 657 at 2–3 months), participants reported sustained reductions in anxiety, depression and alcohol misuse and increases in cognitive flexibility, emotion regulation, spiritual wellbeing and adaptive personality traits after a planned psilocybin experience. A minority (11% at 2–4 weeks; 7% at 2–3 months) reported persisting negative effects such as mood fluctuations or depressive symptoms.
PsilocybinAnxiety DisordersDepressive DisordersAdolescentsSubstance Use Disorders (SUD)Healthy VolunteersSet & SettingPersonality & Trait FactorsPublic Health, Prevention & Behaviour ChangeThis expert consultation study (n=12) investigated the exclusion of individuals with personal or familial histories of psychopathological experiences from most psychedelic clinical trials and treatment programs. Experts in psychiatry, clinical psychology, medicine, and psychedelics were interviewed, and the findings revealed that exclusion criteria may be justified in studies with minimal psychological support. They agreed that psychedelic-assisted psychotherapy, as well as therapy with MDMA and ketamine, might be beneficial for some individuals within this group.
MDMAKetamineSchizophreniaBipolar DisorderPTSDEquity and EthicsDepressive DisordersKarydas, President and Chief Financial Officer of Flare Therapeutics, brings more than two decades of biopharmaceutical and financial leadership experience. She joins as COMPASS progresses a phase 3 COMP360 trial in treatment-resistant depression and phase 2 studies in anorexia nervosa and post-traumatic stress disorder.
PsilocybinEating DisordersPTSDThis mouse study investigated the effects of N,N-dipropyltryptamine (DPT), a psychedelic tryptamine, on audiogenic seizures in a mouse model of fragile X syndrome (genetic cause of autism). DPT was found to prevent seizures at a 10 mg/kg dose completely but not at lower doses (3 or 5.6 mg/kg). Despite being a serotonin receptor agonist, the antiepileptic effects of DPT were not mediated through specific serotonin receptor subtypes (5-HT2A, 5-HT1B, or 5-HT1A), nor through sigma1 receptors.
Major Depressive Disorder (MDD)Depressive DisordersAutism Spectrum Disorder (ASD)In a pilot randomised controlled trial of 20 participants with alcohol use disorder, viewing a nature-themed "Visual Healing" video during preparation and the ascent/descent phases of 25 mg psilocybin sessions was feasible, safe and well tolerated. Compared with standard procedures (eyeshades and music), Visual Healing significantly attenuated peak post‑psilocybin blood pressure increases while producing similar psychedelic effects and reductions in alcohol use.
PsilocybinAnxiety DisordersAlcohol Use Disorder (AUD)Safety & Risk ManagementSet & SettingSubstance Use Disorders (SUD)This pilot program (n=8, +2 Elders) explored the effectiveness and safety of group-based therapy augmented by three sessions of ketamine at a psychedelic dose for Indigenous participants in partnership with Roots to Thrive and the Snuneymuxw First Nation. Thematic analysis of qualitative interviews and feedback revealed participant motivations, perceived barriers, program benefits, and psychedelic experiences. Participants emphasized the importance of Indigenous team members, incorporating traditional healing approaches, and fostering authentic relationships between participants and facilitators, highlighting both challenges and significant program benefits. The article underscores the need for reconciliation efforts within and beyond psychedelic therapies.
KetaminePTSDImplementation & Service Delivery
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