Psychedelic Research Bulletin: June 2023

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Psychedelic Mechanisms of Action

Two studies in mice are changing how we think about how psychedelics work. The first comes from Gul Dölen’s lab and shows how psychedelics (from ketamine to mescaline) open a ‘social reward learning period’. The seminal work, previously presented at conferences, builds a common bridge between psychedelics. The underlying neurological explanation concerns restoring the oxytocin-mediated long-term depression (lowering) in the nucleus accumbens (part of the ‘reward’ system).

On this level, and also in mice, another groundbreaking study argues that the BNDF (brain-derived neurotropic factor, implicated in neuronal growth) receptor TrkB (‘turk-bee’) is the relevant target for antidepressants. In other words, this pathway is argued to be independently responsible for antidepressant effects from serotonin (5-HT2a) receptor activation. Other labs are attempting to replicate these findings.

Returning to the psychological level, self-compassion is argued to lead to positive outcomes in those treated with psilocybin-assisted therapy for alcohol use disorder (AUD). An interview study finds that trial participants were better able to process emotions related to past events, promoting self-compassion, self-awareness, and feelings of interconnectedness, which laid the foundation for better regulation of negative emotions and improved the quality of relationships.

Another mechanism, the reduction of learned helplessness, is argued for in a review of the psychedelic-assisted therapies literature. The authors argue for the utility of the learned helplessness model in psychedelic research due to its robustness across species, well-described neurobiology, and substantial overlap with neural circuits involved in psychedelic actions.

The question of whether psychedelics lose their magic when combined with other drugs is one for which there are only a few direct comparison studies. A systematic review tries to fill this gap in the literature by diving into all known combinations, including using evidence from research in the 60s. The findings reveal varied effects when psychedelics are combined with other drugs including antidepressants, antipsychotics, anxiolytics, mood stabilizers, and recreational drugs. Adding to this literature is a clinical trial with CBD and ayahuasca where no interaction effects were found.

One of the direct comparisons we have is from the psilocybin vs escitalopram (SSRI) trial. For the latter group, responsiveness to emotional faces was reduced. Another analysis of the same trial finds that in both groups there were significant personality changes (but no significant difference between groups). An online survey also finds that those who use antidepressants (SSRIs/SNRIs) often experience weaker effects than expected when taking psilocybin.

New Data from Psychedelic Trials

Two studies investigated the effects of DMT. The first was another infusion study of DMT in healthy volunteers. Just like in the study published in April, participants tolerated the infusion well. This time the effects were spread out over an even more extended period, up to 90 minutes.

The second study looked at inhaled (vaporized) 5-MeO-DMT (a similar molecule but still very distinct effects) and the antidepressant effects of 6 to 18mg. The study was conducted with 16 people suffering from treatment-resistant depression (TRD) and in both phases eight people participated. The headline result is that in the Phase II (up to three doses) study 87.5% (7 of 8) were in remission seven days after the final administration.

The HOPE trial, where psilocybin-assisted therapy (PAT) is tested in those suffering psychologically from a cancer diagnosis, has published positive findings, including reductions in depressive symptoms. Earlier this year, we already heard about the positive qualitative experiences of participants. The current study confirms earlier positive findings in palliative care but adds that a large part of the treatment was done in a group model.

New results from earlier studies

A re-analysis of a study with psilocybin for depression, this time looking at the EEG measures, finds that EEG theta power doubled in amplitude two weeks after psilocybin administration. The power increase correlated with improvements in depression symptoms, but the main study didn’t find a significant effect versus placebo.

Another re-analysis examines the effects of LSD microdosing (10μcg; 14x; 6w) on sleep in healthy adult male volunteers. This is one of the only clinical trials with microdoses, where the dose is controlled, but participants spend most of the time at home. A sleep tracker showed longer sleep (almost 30 minutes) on the night after microdosing compared to the placebo group.

Sticking with sleep and with re-analyses of trial data, one study looked at daytime and sleep-related declarative memory consolidation in healthy trial participants. The results showed that psilocybin didn’t improve memory consolidation, but importantly, it also didn’t negatively affect memory consolidation.

Finally, an analysis of the interaction between music and a moderate dose of LSD finds that the combination led to changes in the time-varying brain activity of the task-positive state, with music potentially having a long-term influence on the resting state, particularly on states involving task-positive networks. The study concludes that music, as a crucial component of “setting,” may influence the resting state during a psychedelic experience.

Smoking cessation, grief improvement, belief changes and more survey results

In line with prior clinical studies, a survey study of over 150 people finds that after a psychedelic experience, respondents significantly reduced the number of cigarettes smoked. Those who had a (fuller) mystical experience and those who were initially less psychologically flexible improved the most.

An even larger survey study of over 350 people finds improvements in grief symptoms after a psychedelic experience. This was correlated with emotional breakthroughs during the trip and negatively correlated with challenging experiences.

Additionally, a survey of over 1600 people investigated how they integrated ayahuasca experiences. The participants described the integration experiences along three lines: overall appraisal (easy, challenging, or long-term/ongoing), beneficial tools facilitating integration (connecting with a like-minded community, yoga, meditation, journaling), and integration challenges (feeling disconnected or reconciling new understandings with old life). The findings suggest that integration can be challenging and time-consuming, but addressing these challenges may facilitate positive growth.

Bringing together elements of the two previous studies is a survey of 340 people who attended ayahuasca ceremonies and re-experienced adverse life events (e.g. combat-related trauma). Reexperiencing was associated with cognitive reappraisal, psychological flexibility, discomfort during ceremonies, and greater reductions in trait neuroticism post-ceremony.

A pre-print of a longitudinal survey (given over multiple points of time) challenges a long-held finding relating to psychedelics and beliefs. The 650-person survey does find that those who use psychedelics ascribe ‘mind perception’ to more (non-)living targets (e.g. plants, animals) – this was also found in another longitudinal survey. However, participants didn’t change their assessment along the Atheist-Believer scale – contradicting the earlier findings.

Other Studies

Here are the other notable psychedelic studies from June 2023:

• • A review covers ‘placebo’ and proposes a new framework around ‘set and setting’, inspired by the field of psychedelic science.

• • Looking at the methodology of psychedelic trials, a commentary suggests that causal mediation analysis using objective biomarkers could help establish causal pathways between treatment and outcome, providing greater confidence in the efficacy of psychedelic therapies before they are approved as regular medicines.

• • A review of the literature brings together everything we know about psychedelic-assisted therapy for treating addictions.

• • A prospective survey found that participants of an ayahuasca retreat significantly increased in nature-relatedness and -appreciation (and gratitude) one week and one month later. Ratings of the trip on mystical experience and awe correlated weakly with these changes.

• • Psilocybin use has drastically increased (x2) between 2018 and 2021 among young adults. The use of LSD stayed relatively flat, a cohort study of over 11.000 people found.

• • Do we know if microdosing is a placebo? A recent review argues there isn’t enough evidence to claim it’s predominantly so.

• • A small RCT (with 27 people) compared ketamine versus midazolam (benzodiazepine) whilst exposure therapy was given in both groups. The PTSD symptoms improved equally in both groups, but the ketamine group showed lower amygdala and hippocampus reactivation to trauma memories than midazolam recipients.

Finally, an economic analysis assesses the cost-effectiveness of psilocybin-assisted psychotherapy (PAT) versus conventional medication, cognitive behavioural therapy (CBT), and the combination of the two for difficult-to-treat depression (in the UK). The decision model simulates patient outcomes (response, remission, and relapse) and analyses costs and quality-adjusted life years (QALYs) over six months. PAT was not cost-effective unless therapists’ (and drug) prices declined.

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