Psychedelic Research Recap November 2022
Throughout November, we gained some fascinating new insights into the potential of psychedelic medicine as researchers from some of the world’s leading institutions published their work. The month brought with it exciting new psychedelic research and some long-awaited results.
Most notably, the official results of COMPASS Pathways’ Phase II trial exploring the use of psilocybin in treating treatment-resistant depression (TRD) were finally published.
Antidepressants were found to weaken the effects of psilocybin, while ketanserin has the potential to stop an LSD trip.
Psilocybin remains popular among researchers
Almost one year ago, COMPASS Pathways published the topline results from the world’s largest study with psilocybin to date. Evidence for the antidepressant effects of its COMP360 psilocybin formulation sent a wave of excitement through the psychedelic community and beyond. However, the positive effects were overshadowed by the reporting of serious adverse events. Now, we have the official results of the largest clinical trial with a psychedelic to date.
After testing three different doses of psilocybin alongside supportive therapy, a significant reduction in depressive symptoms (MADRS, 12-point drop from baseline of 32) was observed after three weeks. This reduction was significantly greater in the 25mg group vs the 1mg (placebo) group. The response (>50% drop in MADRS score) in the 25mg group dropped from 37% at 3 weeks to 20% at 12 weeks.
You can find out more about the results of this trial, the adverse events and what COMPASS has planned next in our summary.
By reanalysing data, researchers at Imperial College London (ICL) found that music-evoked emotions are increased after treatment with psilocybin (25mg). This finding correlates with decreased anhedonia (inability to feel pleasure). fMRI measures also showed a decrease in connectivity (FC) between the nucleus accumbens (NAc, music-related area) and the default mode network (DMN).
Other researchers at ICL found that body mass index (BMI) doesn’t predict the intensity of the response to psilocybin after analysing data from three trials. They suggest a fixed dosing schedule may be preferable in future trials with psilocybin.
Natasha Mason and colleagues at Maastricht University explored the effects psilocybin (12mg/70kg) has on a range of inflammatory markers associated with stress-related psychiatric disorders. 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.
A survey from researchers at Johns Hopkins found that the probability of weaker psilocybin effects was higher for SSRIs than non-serotonergic antidepressants in participants taking psilocybin with an antidepressant. Additionally, the weakening effect of antidepressants on psilocybin waned between 3-6 months after discontinuation.
In participants experiencing cluster headaches, psilocybin reduced the frequency of cluster headaches. The effect was not significant, while the intensity of the acute experience didn’t impact the outcome.
Other psychedelics put to the test
By analysing data from previous studies, increasing LSD doses were found to be positively correlated with ratings on most factors and scales on the Altered States of Consciousness Rating Scale (ASC) and the Mystical Experience Questionnaire (MEQ), with the strongest responses for visionary phenomena such as audio-visual synesthesia and altered imagery, followed by positively perceived ego dissolution comprising depersonalization and derealization phenomena.
A pre-print used data from two double-blind, randomized controlled trials to model whole-brain effective connectivity (EC) data and compare it to the previously reported functional connectivity (FC) data gathered following LSD administration.
LSD was found to decrease brain connectivity and increase self-inhibition in certain brain regions after modelling whole-brain effective connectivity (EC) data and comparing it to previously reported functional connectivity (FC) data gathered following LSD administration. EC and FC offer promise as clinically-relevant biomarkers for LSD effects.
In another trial, ketanserin (40mg) administered one hour after LSD (100µg) reversed the effects cutting down the trip from an average of 8.5 to 3.5 hours, making it the first study to show that ketanserin can effectively stop/halt an ongoing psychedelic trip.
MDMA-AT was found to significantly reduce Chronic Pain Grade Scale (CPGS) scores for pain intensity and disability by assessing the effects of MDMA-assisted therapy (MDMA-AT) on measures of chronic pain using data from a Phase II study exploring MDMA-AT for PTSD. The greatest reduction in severity was observed in the highest pain cluster (n=9, p<0.05), and reductions in pain intensity were highest in the medium pain cluster (n=11, p<0.05).
Real-world data leads to new insights
In participants that had recently attempted suicide, a single dose of intravenous (IV) ketamine led to significant and rapid reductions across all measures of suicidality, with the largest effect sizes observed up to five days post-infusion. Reductions in suicidality were maintained up to six months after the infusion.
Using growth mixture modelling and the QIDS-SR as the measure of depression, this study successfully replicated the same three antidepressant treatment response trajectories from a community sample of depressed patients receiving IV ketamine. A history of childhood maltreatment was associated with more optimal treatment outcomes for patients reporting a severe level of depression at baseline, and measures of suicidality followed similar improvement patterns.
A significant reduction in depressive symptoms was observed using the PHQ-9 and GAD-7 from baseline to last the last treatment in a sample of participants with treatment-resistant depression (TRD) receiving esketamine.
This survey study found that reactivations (flashbacks) are common with 5-MeO-DMT use. These reactivations were generally perceived as positive, with only some reporting them as negative. The change of reactivations was higher for those using 5-MeO-DMT in a structured setting, female, and older at the time of first use.
Novel insights, new reviews & the rest
This review proposes that psychedelic-induced alterations in low-level sensory dimensions of experience are not entirely causally reducible to alterations in high-level dimensions, but rather co-occur in a dialogical interplay and play a causally relevant role in determining high-level alterations and therapeutic outcomes.
Through interviews, this study finds that participants treated with esketamine were often overwhelmed, lacked preparation, or couldn’t let go of control. The authors suggest that more support (prep, during, after) can help patients ‘let go’ and achieve better outcomes.
A new method offers a fast and effective way to assess the kinetics of methylone, MDMA and their metabolites.
This survey found that 33% of participants reported a symptom of HPPD (e.g. intensified colours after the trip is finished), but only 3% reported the symptoms as disturbing. The study also finds that the personality trait absorption predicts increases in magical thinking at the end-point (4 weeks).
Papers Published in November 2022
24 studies from the Blossom database published this month.
Classic psychedelics, health behavior, and physical health
In a US-representative sample (N = 2,822), lifetime use of classic psychedelics was associated with healthier tobacco- and diet-related behaviours, and among users greater psychological insight during their most insightful psychedelic experience predicted healthier exercise habits, healthier BMI and better diet (with some alcohol-related improvements). Although causality cannot be inferred, the results suggest psychological insight from classic psychedelic experiences may facilitate positive health-behaviour change, particularly for weight management.
Reactivations after 5-methoxy-N,N-dimethyltryptamine use in naturalistic settings: An initial exploratory analysis of the phenomenon’s predictors and its emotional valence
In a survey of 513 non‑clinical 5‑MeO‑DMT users, reactivations were more likely among women, older initiates, those with higher education and those dosing in structured group settings. Higher mystical experience scores, greater wellbeing and prior non‑drug non‑dual experiences predicted neutral or positive valence, suggesting reactivations are often benign or beneficial in this sample, though further work is needed to identify predictors of negative outcomes.
Changes in music-evoked emotion and ventral striatal functional connectivity after psilocybin therapy for depression
In patients with treatment-resistant depression, two-dose psilocybin therapy increased music-evoked pleasure that correlated with reductions in anhedonia and produced a post‑treatment decrease in nucleus accumbens functional connectivity with default mode network‑like regions during music listening, suggesting a neural mechanism for enhanced musical reward.
Holding on or letting go? Patient experiences of control, context, and care in oral esketamine treatment for treatment-resistant depression: A qualitative study
This qualitative IPA study of 17 patients with treatment‑resistant depression found that the key determinant of esketamine session experience and subsequent outcomes was patients’ ability to “let go” of control during overwhelming psychoactive effects, which was strongly shaped by preparation, emotional/physical support, and the treatment setting. The authors recommend better pre‑session education, optimised settings and targeted training for nurses/support staff to facilitate surrender and improve quality of care.
The effect of ketamine on cognition, anxiety, and social functioning in adults with psychiatric disorders: A systematic review and meta-analysis
This meta-analysis (n=1,298) explored the effects ketamine has on cognition, anxiety, quality of life, and social functioning in adults with psychiatric disorders. Ketamine was found to have positive effects on depression, anxiety and social functioning but not with respect to cognition and quality of life.
Exploratory investigation of a patient-informed low-dose psilocybin pulse regimen in the suppression of cluster headache: Results from a randomized, double-blind, placebo-controlled trial
An exploratory randomised, double‑blind, placebo‑controlled trial of a patient‑informed low‑dose psilocybin pulse regimen for cluster headache found no statistically significant reduction in attack frequency overall, although a moderate overall effect size (d = 0.69) and a large, sustained effect in chronic patients (d = 1.25) were observed. Psilocybin was well tolerated, therapeutic effects did not correlate with acute psychotropic intensity, and the authors conclude larger definitive trials are warranted.
Methylone and MDMA Pharmacokinetics Following Controlled Administration in Humans
In a first controlled human study, oral methylone (50–200 mg) showed rapid, dose‑proportional (linear) pharmacokinetics with Cmax and AUC increasing proportionally, Tmax ≈1.5–2 h and t1/2 ≈6–7 h. A validated LC–MS/MS assay quantified methylone, MDMA and metabolites and found the primary metabolite HMMC had much lower exposure (Cmax ~10–14× and AUC ~21–29× lower) and faster kinetics than the parent drug.
The Altered States Database: Psychometric data from a systematic literature review
This paper (2022) presents the development of the Altered State Database (ASDB). The ASDB was developed through a systematic literature review of psychometric questionnaire data on subjective experiences of altered states of consciousness (ASC). The ASDB allows for the calculation of comparable psychometric values of ASC experiences and of dose-response relationships of substances inducing ASC.
ARC: a framework for access, reciprocity and conduct in psychedelic therapies
In a within‑subjects intravenous LSD versus placebo study using computational reinforcement‑learning modelling, LSD increased reward (and to a lesser extent punishment) learning rates and reduced stimulus stickiness, producing greater exploration while leaving simple win‑stay/lose‑shift measures unchanged. These effects indicate heightened plasticity that could facilitate the revision of maladaptive associations in clinical psychedelic therapy.
Adverse effects of ayahuasca: Results from the Global Ayahuasca Survey
A global survey of 10,836 ayahuasca users reported high rates of acute physical effects (69.9%, chiefly vomiting) and medium-term psychological effects (55.9%), though most users framed psychological effects as part of a positive integration process and only small proportions required medical (2.3%) or professional (≈12%) help. Risk factors for physical adverse effects included older age at first use, physical health conditions, greater use, prior substance use disorder and unsupervised settings, while mental health effects were linked to anxiety disorders, physical conditions and stronger spiritual experiences but were less common in religious contexts, suggesting targets for screening, support and policy.
Body mass index (BMI) does not predict responses to psilocybin
Pooled analysis of three therapeutic trials using a fixed 25 mg psilocybin dose found that BMI did not predict acute psychedelic intensity, mystical experiences, perceptual changes, emotional breakthroughs, or two‑week improvements in well‑being, with Bayesian evidence supporting the null. These results support the use of a standardised fixed therapeutic dose rather than routine weight‑adjusted dosing.
Psychedelic-Assisted Therapy for People with Eating Disorders
This review (2022) offers food for thought on the potential use of psychedelic-assisted therapy for treating eating disorders, particularly anorexia nervosa, using up-to-date research.
More than meets the eye: The role of sensory dimensions in psychedelic brain dynamics, experience, and therapeutics
This pre-print (2022) reviews the current body of evidence surrounding the effects psychedelics have on low-level sensory dimensions of experience, and corresponding brain dynamics, particularly visual dimensions. It is proposed that psychedelic-induced alterations in low-level sensory dimensions of experience are not entirely causally reducible to alterations in high-level dimensions, but rather co-occur in a dialogical interplay and play a causally relevant role in determining high-level alterations and therapeutic outcomes.
A Psychoanalytic Perspective on Psychedelic Experience
This perspective (2022) provides an understanding of the psychedelic experience through 1) ego dissolution and mystical states, 2) hyperassociative states, and 3) the role of set and setting.
Ketanserin reverses the acute response to LSD in a randomized, double-blind, placebo-controlled, crossover study in healthy subjects
In a randomized, double-blind, placebo-controlled crossover study in 24 healthy subjects, a single 40 mg oral dose of the 5‑HT2A antagonist ketanserin given one hour after 100 µg LSD rapidly reversed the acute psychedelic response—shortening subjective effect duration from 8.5 to 3.5 hours and attenuating visual/auditory alterations, ego dissolution, cardiovascular effects and mydriasis—without altering LSD pharmacokinetics or BDNF elevations. These findings support that LSD’s acute effects depend on 5‑HT2A receptor occupancy and indicate ketanserin can serve as a planned or rescue agent to shorten or mitigate LSD experiences in research and therapy.
Prophylactic action of ayahuasca in a non-human primate model of depressive-like behavior
This primate study (n=12) found that ayahuasca (at 3 points in time) led to better resilience to being separated from the family groups. The animals that had received ayahuasca (n=6) showed no indication of anhedonia (inability to feel pleasure) and showed higher cortisol reactivity (positive).
Safety and effectiveness of intranasal esketamine for treatment-resistant depression: a real-world retrospective study
This retrospective analysis (n=171) examined the effectiveness of esketamine in participants with treatment-resistant depression (TRD). A significant reduction in depressive symptoms was observed using the PHQ-9 and GAD-7 from baseline to last the last treatment.
MDMA-assisted therapy is associated with a reduction in chronic pain among people with post-traumatic stress disorder
In an exploratory analysis of 32 participants from a Phase 2 open‑label trial of manualised MDMA‑assisted therapy for PTSD, 84% reported chronic pain and 75% reported pain‑related disability. MDMA‑AT was associated with significant reductions in pain intensity, disability and overall Chronic Pain Grade Scale severity in the high‑pain subgroup and reduced pain intensity in the medium‑pain subgroup, supporting further investigation of MDMA‑AT for comorbid chronic pain.
Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression
This double-blind active-placebo controlled trial (n=233) tested the effect of a single dose of psilocybin (25/10/1mg) with supportive therapy for treatment-resistant depression. The primary endpoint at three weeks finds a significant reduction in depressive symptoms (MADRS, 12-point drop from baseline of 32) that was significantly greater in the 25mg group vs the 1mg (placebo) group (6.6 points larger drop). The response (>50% drop in MADRS score) in the 25mg group dropped from 37% at 3 weeks to 20% at 12 weeks.
Acute and enduring effects of naturalistic psychedelic use among Indigenous peoples in Canada and the United States
This survey study (n=66) explored the effects of naturalistic psychedelic use on recalled psychological distress and trauma symptoms among Indigenous peoples living in the United States and Canada who had experienced racial trauma. The most commonly used psychedelics were psilocybin, MDMA and LSD. Participants recalled experiencing fewer symptoms of depression, anxiety, stress, trauma, symptoms of discrimination, and alcohol use in the 30 days after (vs. before) the psychedelic experience
Arketamine, a new rapid-acting antidepressant: A historical review and future directions
This review (2022) highlights the potential of arketamine (the 'right-handed' part of ketamine) as an antidepressant. Though studies less than ketamine (or esketamine, the 'left-handed' part), arketamine potentially has fewer side effects and more potent antidepressant effects.
Ketamine use in pediatric depression: A systematic review
This systematic review (n=46; s=6) examined the efficacy and safety of ketamine for the treatment of pediatric depression (mean age=15.7 y/o). Findings suggested that ketamine, administered intravenously at doses ranging from 35mg/70kg to 140-490mg/70kg, significantly reduced depressive symptoms without severe adverse events.
Psychedelics and schizophrenia: Distinct alterations to Bayesian inference
This analysis of neuroimaging (M/EEG) compares data from patients with schizophrenia (n=29) and healthy volunteers under the influence of LSD (75μg, n=17) or ketamine (n=19). It finds that although both show increased neural signal diversity, only for those with schizophrenia did it increase the precision (weighting) of sensory information. Both groups increase 'bottom-up' signalling, but of a different kind.
The effect of lysergic acid diethylamide (LSD) on whole-brain functional and effective connectivity
Using regression dynamic causal modelling of resting-state fMRI in a randomized placebo-controlled crossover (n=45), LSD produced widespread increases in interregional effective connectivity and reduced self-inhibition — except in occipital regions where interregional connectivity decreased and self-inhibition increased — consistent with a perturbation of the brain's excitation/inhibition balance. Both effective connectivity and functional connectivity distinguished LSD from placebo with high accuracy (EC 91.11%, FC 85.56%), indicating their promise as clinically relevant biomarkers.