October was a relatively quiet month for psychedelic research. Nonetheless, we still gained some valuable new insights into the world of psychedelics. Natural language processing (NLP) was used to successfully predict clinical outcomes using data from a trial exploring psilocybin on treatment-resistant depression (TRD); but only after the first psilocybin session had taken place. The first real-world study assessing esketamine for TRD yielded positive results. At the same time, new evidence suggests people who microdose may build up a tolerance.
Psychedelics put to the test
Surprisingly, there have been no published studies assessing the effectiveness of esketamine outside of the laboratory setting despite its legal availability in certain circumstances until now. This real-world study using Spravato (esketamine, up to 84mg, multiple dosings) found the response rate (64%) and rate of remission (41%) to be similar to findings from clinical trials at the three-month mark.
A separate study found that ketamine tablets were safe to use and significantly reduced both depression and anxiety in a relatively large sample of participants (n=664) taking the tablets at home.
Researchers at Maastricht University published the preprint from another naturalistic study where they used fMRI to assess functional connectivity (FC, how areas of the brain communicate) in members of the Santo Daime church following ayahuasca intake. Changes in FC were similar across participants and less unique than previously thought.
At the University of Copenhagen, researchers used the Mystical Experience Questionnaire to assess the association between psilocybin-induced lasting increases in mindfulness and the mystical experience. Using the Mindful Attention and Awareness Scale (MAAS) to measure mindfulness after three months, MAAS scores were found to be positively correlated with MEQ scores indicating that the phenomenology of the psilocybin experience induces a shift toward mindful living.
Reanalysing old data leads to new insights
Researchers affiliated with COMPASS Pathways used natural language processing (NLP) to assess the audio from psychological support sessions in the COMP360 trial for TRD. The NLP model used predicted clinical outcomes with high accuracy (85%). COMPASS plans to explore the use of NLP in their upcoming world-first Phase III trials of COMP360 for TRD, which they announced earlier in October.
At Imperial College London, researchers reanalysed data from a placebo-controlled citizen science microdosing study to investigate whether tolerance develops during microdosing. After conceptualizing tolerance as the decreasing probability of correctly guessing active microdoses with more microdoses, models showed that correct microdose guess probability decreased with the number of microdoses taken (p=0.09), indicating tolerance developed.
By reanalysing data from the TRANSFORM-1 and TRANSFORM-2 trials, researchers from Janssen Pharmaceuticals found that treating participants with esketamine plus an antidepressant improved symptoms of depression regardless of their baseline irritability level and increased odds of achieving a response.
A brain imaging study examined the difference between those who regularly used ayahuasca and control subjects. It found evidence for a thicker corpus callosum (the section that connects brain regions), but this effect didn’t survive multiple comparisons.
Looking inside the brain
A comprehensive review from some of the world’s experts explains the neural basis of how psychedelics work. It covers serotonin receptors, changes in structural plasticity, and the long-term effects of psychedelics. The discussion covers the future of psychedelics, including non-hallucinogenic compounds.
A separate review explores how psychedelics modulate the brain’s Default Mode Network (DMN). While we see an acute disruption within the DMN and increased functional connectivity between resting-state networks, it’s still too early to say exactly how these changes correlate with well-being outcomes.
Researchers have produced a nuanced mechanism through which MDMA alleviates the symptoms of PTSD. This mechanism relates to the increase of brain-derived neurotrophic factor (BDNF) in fear memory learning pathways which act together with MDMA’s pro-social effects to explain the therapeutic effects of MDMA.
Ethical considerations going forward
This review outlines recommendations for current practice in preparatory sessions in substance-assisted psychotherapy (SAPT), providing information on safety measures and screening procedures, preparation of set and setting, session contents, methods, roles, prerequisites, and appropriate conduct of therapists.
Data from the US National Survey on Drug Use and Health was used to explore the associations between naturalistic lifetime MDMA and psilocybin use. Race and ethnicity significantly moderated the associations between MDMA and psilocybin use and psychological distress and suicidality. For white participants, MDMA and psilocybin use lowered the odds of all distress, whereas these associations were far fewer for racial and ethnic minorities.
A review of early psychedelic studies from the first wave of psychedelic research finds that most would not pass ethical review today. The errors made in early research largely involved people of colour and related to issues around dosing, lack of consent, inadequate setting, and lack of scientific hypotheses. The authors make restorative justice and cultural competency suggestions.
Reviews & the rest
A meta-analysis found that the standard mean difference for electroconvulsive therapy (ECT), when compared to ketamine in treating depression, suggests ECT is more efficacious than ketamine for depression severity.
In a separate meta-analysis, researchers found that psilocybin, LSD and ayahuasca all led to short and long-term reductions in depressive symptoms when administered with psychological support in the clinical setting.
This review uses preclinical and clinical research to explore mescaline’s pharmacological and behavioural effects. The pharmacological mechanisms of mescaline are similar to those of other classical psychedelics, i.e. binding at the 5HT2A receptor. Mescaline can improve well-being and mental health conditions, particularly alcohol use disorder.
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