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Psychedelic Research Bulletin: September 2023

In September 2023, the second Phase III study from MAPS was published, showing more than two-thirds of those treated with MDMA-assisted psychotherapy no longer met DSM-5 criteria for PTSD. With 104 participants, the study complements the first Phase III study and marks the transition to the next step in psychedelic research, the FDA approval process.

Next to MAPS’ landmark study, we were also treated to the largest prospective survey of people using psychedelics outside the clinical setting. In settings outside the lab, respondents generally found benefits such as reduced alcohol misuse, better emotional regulation, and improved spiritual well-being. The data could serve as a counterpoint towards recent negative news around self-experimentation with psychedelics.

September was another productive month for psychedelic research, with 25 articles (and full summaries for paying members) added to the database (nearing 2000 articles). In this recap, we also cover exciting news about psychedelics and our immune system, the surprising similarity between MDMA and methamphetamine, and how to prevent history from repeating itself.

For all the latest papers, check out Blossom’s database and those that weren’t added in its September Link Overview.

The Final Clinical Step for MDMA-assisted Therapy

The long-awaited second Phase III clinical trial provides further evidence that MDMA-assisted therapy (MDMA-AT) can significantly reduce symptoms of post-traumatic stress disorder (PTSD). The randomized, placebo-controlled trial involved 104 participants with moderate to severe PTSD. After three sessions of MDMA-AT or placebo plus therapy, the MDMA group showed significantly greater reductions in PTSD symptoms on the CAPS-5 scale and functional impairment on the Sheehan Disability Scale.

Remarkably, 86.5% of the MDMA group showed a clinically meaningful response, and 71.2% no longer met diagnostic criteria for PTSD after treatment. MDMA-AT was also well-tolerated, with mostly mild to moderate side effects reported. Though a history of suicide risk was common, suicidal ideation did not increase with MDMA treatment.

The results support and extend previous Phase II and III(a) trials showing MDMA-AT can provide lasting relief for PTSD when combined with therapy. The data from the Phase III trials will now go to the FDA, which is expected to come back with a decision in late 2024. This marks the final clinical step and the start of a thousand more steps between these positive results and MDMA-AT’s eventual (relatively) widespread availability.

Further down the line, MDMA-AT might become an available treatment for adolescents. A focus group study with 19 participants found generally unfavourable attitudes from parents, clinicians, and youth. Still, after explaining the therapy, all but one person supported its potential use. Studies with ketamine and adolescents, of which one was published last month, generally find no unexpected adverse effects (e.g. on cognition).

Naturalistic Psilocybin Use Outcomes

An extensive survey of people using psilocybin mushrooms in naturalistic settings found persisting improvements in symptoms of anxiety, depression, and alcohol misuse after psilocybin use. Participants also reported increased well-being, spirituality, cognitive flexibility, and extraversion after psilocybin. However, a minority (11% in the weeks after) experienced persistent adverse effects like mood fluctuations. This is the most extensive prospective study of naturalistic psilocybin use, adding to evidence of the therapeutic potential while highlighting the importance of safeguards.

smaller survey and interview study dove into the long-term negative effects of psychedelics. The study identified potential causal factors, such as unsafe or complex environments during or surrounding the experience, prior psychological vulnerabilities, high or unknown drug quantities, and young age.

Other recent psychedelic studies further demonstrate shifting attitudes and insights. A 7-year follow-up survey showed a significant positive change in American psychiatrists’ opinions about psychedelics. In 2016, only 29% expressed belief in the therapeutic potential of psychedelics, but that rose to 81% in 2023. Acceptance is growing, but risks remain.

One survey linked psychedelic use to greater belief in alternative facts, especially around politics, though psychedelic users did not favour intuition over evidence. As we expand access, education on benefits and risks is essential.

This is How the Cookie Crumbles

Doing psychedelic science is hard. Funding is difficult, treatment is intensive, and bias is pervasive. Michiel van Elk and Eiko Fried identify ten pressing problems facing the field, grouped into easy, moderate, and complex issues. Taking a sample from the moderate problems, the researchers talk about – well – sample size (generally relatively small), selection bias, and the lack of long-term follow-up. The checklist provided in the article serves as an excellent summary of their recommendations.

Still, progress has been made in psychedelic research. One helpful set of tools has been the introduction of neuroimaging. An article we previously covered as a pre-print now reviews the landscape and highlights PET and (f)MRI’s contributions to the field. At the same time, much discussion still exists around the exact mechanisms that psychedelics work through.

One of the proposed mechanisms that psychedelics work through is by improving neuroplasticity. A viewpoint article tries to pinpoint the definition of neuroplasticity. Yet, it shows that it can mean many things, and one should be wary of using it without defining the term. Another commentary takes a different route, investigating the neurobiological mechanisms underlying meaningfulness induced by psychedelics.

The Psychedelic Experiments from September 2023

double-blind study with 60 healthy volunteers investigated the effects of psilocybin 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.

What is the influence of MDMA on feeling connected with someone else? Researchers found that, versus placebo, there was a stronger connection with MDMA, which correlated with raised oxytocin levels. Interestingly, in another group, the researchers looked at the effects of methamphetamine (meth) versus placebo and also found an increase in connectedness. This time, there was no correlation with oxytocin levels (which were still raised). Though MDMA is currently uniquely being researched as an ’empathogen’, the study shows that other drugs – generally considered the ‘bad’ ones – can also enhance feelings of connectedness.

An open-label study with psilocybin-assisted therapy for alcoholism found that showing a nature-themed video during the sessions was safe and didn’t lead to negative outcomes. The researchers also suggest that it could reduce cardiovascular risks, but with an open-label design and only 20 participants, it’s hard to conclude much from the study.

All Other Psychedelic Studies of September 2023

With 25 articles added (and 76 more in Blossom’s link overview), there is too much to talk about in detail, so here is a quick primer on the other studies:

  • study compared ayahuasca users in Sante Daime and neo-shamanic groups and found some participant differences (e.g. on personality).
  • Treating veterans (SOFV) in Mexico with ibogaine and 5-MeO-DMT is once again shown to be effective in reducing PTSD symptoms and improving quality of life. Another study investigated what factors predicted outcomes in the study group.
  • Predicting if someone will respond to therapy could be a good way to stop unnecessary future treatments. One study looked at 50 participants being treated with esketamine and found that after two sessions, the depression score (MADRS) predicted the 90-day response with 80% accuracy.
  • 7-year follow-up to a survey of psychiatrists’ attitudes towards psychedelics finds them being much more receptive than in 2016.
  • Experts were consulted about the exclusion of those with psychotic disorders from psychedelic research and generally agreed that without support, it would be unwise to include them. Still, they agreed that PAT might benefit some in this group.
  • Lately, there haven’t been many developments in the group model of psychedelic-assisted therapies. A study on Indigenous elders and ketamine therapy highlights challenges and possible benefits.
  • mice study with DPT finds that it can prevent seizures in a mouse model of Fragile X Syndrome.
  • Infusing DMT to achieve a certain psychedelic intensity has been recently achieved after years of speculation. The infusion protocol has now been published.

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