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Psychedelic Research Bulletin: 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 IIb 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 29% 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 Blossom’s summary.

By reanalysing data, researchers at Imperial College London 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 Imperial 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.

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, females, and those who were older at the time of first use.

Novel insights, new reviews, etc.

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.

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).

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