Psychedelic research shows no sign of slowing down as researchers carried over the New Year’s momentum into February. Over the last month, we saw that psilocybin-assisted therapy’s effects on depression could last for up to 12 months. MDMA-assisted therapy led to reductions in alcohol use in patients with PTSD. At the same time, the first study assessing the effects of MDMA on fear extinction retention took place in healthy adults. Researchers provided us with the foundation for designing safe and effective non-hallucinogenic psychedelic analogues.
Clinical Trials of LSD, Psilocybin, MDMA…
February brought with it the results of many clinical trials involving human participants. Most notably, psilocybin was shown to alleviate symptoms of depression up to 12-months after dosing sessions. LSD was shown to influence the creative process whilst MDMA may have the potential for treating alcohol use disorder, which is often experienced comorbidly alongside PTSD.
The team at Johns Hopkins published the results from a 12-month follow-up (n=24) which assessed the efficacy and safety of psilocybin in depressed participants from a previous trial. A durable antidepressant effect was observed with treatment response (⩾50% reduction in GRID-HAMD score from baseline, Cohen d = 2.4) and rate of remission at 75% and 58%, respectively, at 12 months. No serious adverse events related to psilocybin were observed.
Lead author Dr Natalie Guksayan provided us with an insightful thread related to the results on Twitter. Despite the small sample size, these findings are significant for psilocybin-assisted therapy and psychedelic medicine.
Elsewhere, a double-blind RCT (n=24) assessed the impact LSD (50μg) has on measures of creativity. Near peak drug effects, participants were given several creative tasks to complete. Creativity was then assessed by scoring creativity criteria, calculating divergent thinking and convergent thinking, computing semantic distances and searching for data-driven special features. Compared to placebo, LSD changed several creativity measurements pointing to pattern break, disorganization and meaning which seemed to fundamentally influence creative cognition and behaviour.
We had the chance to catch up with this study’s lead author, Isabelle Wießner, in our latest column with Lucid News.
Isabelle Wießner published another paper (n=24, same participants) that investigated the effects LSD (50 μg) has on a number of measures of cognition in healthy volunteers. It was found that LSD sub-acutely improved visuospatial memory, phonological verbal fluency and impaired cognitive flexibility when compared to placebo suggesting that LSD-assisted therapy may provide a novel treatment in conditions involving memory and language declines.
A similarly designed study with LSD (n=56) explored the effects of four repeated doses of LSD (13 or 26μg) on measures of mood and cognition. LSD administration sessions were separated by 3-4 days. LSD (26μg) produced modest subjective effects but it did not improve mood or affect performance. While LSD was safely administered, low doses of LSD produced negligible changes in mood or cognition in healthy volunteers.
This trial (n=90) assessed patterns of alcohol and substance use in patients receiving MDMA-assisted therapy. MDMA was associated with a significant reduction in Alcohol Use Disorder Identification Test (AUDIT) scores when compared to placebo. Changes in Drug Use Disorder Identification Test (DUDIT) scores did not significantly differ between groups.
In what is a first, a trial (n=34) assessed the effects of MDMA (100mg) following a fear acquisition session, an extinction training session and retention in healthy subjects. There was no difference between extinction training and retention between groups. However, significantly more participants in the MDMA group retained extinction learning compared to the placebo group (p = 0.007).
Researchers assessed clinical predictors of depressive symptom remission and response 24 h and 7 days after racemic ketamine and esketamine infusions in this double-blind RCT (n=61). Depressive symptoms were assessed using the MADRS. The number of treatment failures and the severity of illness were predictors of fewer remissions and responses to depressive symptoms.
A look inside the brain
The team at Imperial College London conducted a neuroimaging study (n=19) that used fMRI and ALFF techniques to assess the brain’s response to music following the administration of psilocybin to participants with treatment-resistant depression. The researchers identified music-related clusters in regions of the brain in which ALFF was significantly correlated with the intensity of subjective effects felt during the dosing sessions implying an elevated response to music following psilocybin therapy.
Researchers at Johns Hopkins used fMRI to compare the effects of a placebo (n=8) or a high dose of psilocybin (n=8). Greater functional connectivity in the default mode network (DMN) was observed in those who received psilocybin. Those who had received psilocybin reported significantly greater meaning, spiritual significance, psychological challenge, and psychological insight than those who had received the placebo.
Important Chemistry
Researchers have provided us with a foundation for the design of safe and effective non-hallucinogenic analogues. Here, they present structures of the serotonin receptor 5-HT2RA bound to psilocin, LSD, serotonin and the non-hallucinogenic analogue lisuride. The researchers were then able to design arrestin-biased ligands that displayed antidepressant-like activity in mice without hallucinogenic effects.
At the University of Basel, researchers explored the effects of several mescaline derivatives, scalines and 3C-scalines, on monoamine receptors in vitro. Scalines and 3C-scalines interacted with the 5-HT2A and 5-HT2C receptors, with preference to the 5-HT2A receptor, and bound with higher affinities (up to 63-fold and 34-fold increase, respectively) when compared to mescaline.
Reviews
The team at Drug Science explores the evidence to assess the psychological and psychiatric risks associated with psychedelics in this review. It was found that medical risks are often minimal and that nearly all of the negative perceptions of psychological risks associated with psychedelics are not supported by the current evidence.
These researchers explore the role and value of the setting in the psychedelic experience and the subsequent therapeutic outcomes. It was found that while the importance of setting is emphasized in the literature, there is yet to be any consistent and rigorous testing of setting and its complexities. There is yet to be a shared consensus on the effects setting has and the mechanism by which it affects outcomes as a result.
In this review, researchers discuss how psychedelics can be used to treat substance use disorders (SUDs) Specifically, the authors discuss the role of different forms of psychotherapy such as psychodynamic and cognitive behavioural.
What went on outside of the lab?
A survey study (n=411) assessed the factors that predict smoking cessation in people who reported quitting or reducing smoking following ayahuasca consumption. Mystical experience and frequency of ayahuasca intake were protective factors, while positive mood (measured by the MEQ30) during the ayahuasca experience was a risk factor. Qualitative analysis revealed eight themes related to the process of smoking cessation/reduction.
This large-scale survey (n=214,505) assessed the associations between lifetime use of classic psychedelics and cocaine use disorder (CUD) within a nationally representative sample of the U.S. Peyote (but not mescaline, the active ingredient in peyote), psilocybin, and LSD use conferred lower odds of CUD.
Another survey (n=511) assessed the contextual factors associated with positive and negative mental health in recreational psychedelic users. Using psychedelics with high frequency and coping with negative affect were found to predict negative mental health. Conversely, using psychedelics in a group setting, with self-expansive intentions, and integrating post-use were found to predict positive mental health.
Researchers took a sociological perspective and discussed issues related to the medicalisation of psychedelic-assisted therapies. Three key areas discussed include the role of advocacy in the advancement of scientific research and the destigmatisation of psychedelics; issues related to medicalisation and pharmaceuticalisation; and integration into healthcare systems.
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