Psychedelic Research Recap July & August 2022

While many of us had the chance to enjoy a vacation this summer, psychedelic researchers continued their hard work. They continued to unearth more about the therapeutic potential of these compounds. A big real-world study on at-home ketamine therapy finds promising results. At the same time, psilocybin was tested for alcoholism in a double-blind, placebo-controlled study design for the first time.

In case you had some downtime over the summer, hopefully, this overview will get you up to speed with anything you may have missed.

For all the latest papers, check out our database and the ones that weren’t added in our July and August Link Overviews.

Psychedelics put to the test

One of the most significant developments this summer was the results of the first double-blind, active placebo-controlled study to test psilocybin for alcohol use disorder (AUD). Psilocybin significantly reduced the number of heavy drinking days across the 32-week follow-up period. With a large sample size for a clinical trial with psilocybin and positive results, psilocybin-assisted therapy could soon help many more people change their drinking behaviours.

In this open-label study from researchers in Copenhagen, three moderate doses of psilocybin significantly reduced the frequency of the pain-related disorder, chronic cluster headaches (CCH). On average, the frequency was reduced by 30%, while one participant was free from CCHs for 21 weeks. Similar to other psychedelic studies, a reduction in symptoms was associated with changes in functional brain activity.

Ketamine was tested in the emergency department (ED) for the first time in an open-label study. Ketamine infusion significantly reduced suicidal ideation (SI) in patients among patients in the ED. Additionally, the willingness to try ketamine as a treatment was also high among patients and physicians.

In another positive for ketamine, this pilot study found that adopting a ketogenic diet for a period before receiving a series of ketamine infusions significantly improved persisting eating disorder symptoms in participants who had recovered from anorexia nervosa (AN).

The jury’s still out on microdosing

The latest study using the Quantified Citizen app to assess the effects of microdosing psilocybin compared to non-microdoses found small- to medium-sized improvements in mood and mental health over 30 days. Combining psilocybin, lion’s mane mushrooms and niacin was associated with psychomotor improvements in some participants. However, these results should be taken lightly as the study lacked an adequate placebo control, and all participants were unblinded.

A separate study using a double-blind placebo-controlled design explored the effects of microdosing psilocybin (0.5g of dried mushrooms) on several measures. Many participants could correctly identify their experimental condition, and reduced EEG accompanied subsequent effects in the theta band. Contrary to the study above, no evidence was found to support enhanced well-being, creativity and cognitive function, leading Enzo Tagliazucchi and his colleagues to believe that expectation likely underlies the positive effects of microdosing.

The power of real-world evidence

This open-label (real-world evidence) paper (n=1247) argues that at-home sublingual ketamine (tablets for under the tongue) is both safe and effective with finding remission rates of roughly 32% for depression and anxiety. Interestingly, patients only spoke with a ‘guide’ instead of a therapist over video as the study was conducted during Covid. The results look promising, though the study sponsor (Mindbloom) has recently been scrutinised.

Using a survey, researchers at Imperial College London explored the effects the naturalistic use of psychedelics has on symptoms of anxiety and depression, observing reductions in depressive symptoms at 2 and 4 weeks. Furthermore, a medicinal motive, previous psychedelic use, drug dose and the type of acute psychedelic experience were all significantly associated with changes in self-rated depression.

In another survey, the effects psilocybin has on measures of state and trait anxiety among retreat participants with subclinical anxiety levels were assessed. The morning after the ceremony, medium reductions in both state and trait anxiety were observed, and these reductions persisted for 1-week. Higher ratings of ego dissolution and changes in neuroticism were the strongest predictors of these reductions.

Researchers at Johns Hopkins carried out a survey to compare psychedelic-occasioned and non-drug experiences that altered individuals’ beliefs about death. Compared to the psychedelic groups, the non-drug group was more likely to report being unconscious, clinically dead, and that their life was in imminent danger. Interestingly, both groups reported similar changes in death attitudes attributed to the experience, including a reduced fear of death and high ratings of positive persisting effects.

New tools for psychedelic researchers

Rosalind Watts and colleagues were busy developing and validating the Watts Connected Scale (WCS). The WCS measures connectedness across the three domains of connectedness to self, others, and the world. Factor analysis of all WCS items revealed three main factors with good internal consistency, and the WCS showed good construct validity. Acute measures of ‘mystical experience’, ’emotional breakthrough’, and ‘communitas’ correlated positively with post-psychedelic changes in connectedness.

Researchers have begun developing the RElaxed Beliefs Questionnaire (REB-Q) in a trial using a single-blind design with healthy participants. It was shown that confidence in negative self-beliefs decreased after a high dose of psilocybin (25mg) which predicted increases in well-being four weeks later, providing the first psychological (vs neurological) information on the validity of the REBUS model.

The REBUS model was further refined in a separate paper using complex systems theory (CST) to propose that psychedelics act as destabilisers of stuck patterns of thinking (‘attractors’ or ‘overweighted priors’) which could explain both the acute (peak) and subsequent period in which psychedelics can help one get ‘unstuck’.

Using several concepts from statistical physics, this preprint uses the Ising model of brain phase transition to assess fMRI BOLD data from a study where LSD was administered. Analysing individualised Ising temperature increases under the influence of LSD and placebo shows that LSD ingestion shifts the system away from the critical point between paramagnetic and ferromagnetic phases to a more disordered state. Overall, findings suggest that LSD increases the complexity of brain dynamics.

The rest of the studies in July & August

A review of adverse events (AEs) in psychedelic clinical trials found that commonly reported AEs included nausea, headaches and anxiety. At the same time, only one serious AE occurred in a study involving MDMA administration. Results from qualitative studies suggest that psychologically challenging experiences could have therapeutic benefits. Overall, AEs in psychedelic research require more detailed reporting.

In this review, Charles Nichols synthesises our knowledge of psychedelics as anti-inflammatory therapeutics. However, most evidence is in cells (in vitro) and rodents (in vivo); all evidence points towards anti-inflammatory effects, with much of this happening at sub-perceptual (non-hallucinogenic) doses.

Some well-known researchers like Roland Griffiths argue that within the current regulatory framework of the Controlled Substances Act (CSA) (or similar worldwide), the use of psychedelics is severely limited in both the research and recreational settings. By building on the CSA’s framework, the authors argue for rescheduling psychedelic substances.

Michiel van Elk and David Yaden explore the three different analysis levels of psychedelic therapeutic mechanisms; 1) biochemical (e.g. neuroplasticity), 2) neural (e.g. less top-down signalling), and 3) psychological level (e.g. belief change). The authors then map out how the levels can be bridged and provide directions for future studies.

VR may soon be used to alleviate symptoms of depression as this open-label study finds that Psyrreal, a VR experience that mimics the phenomenological components of psychedelic and mystical experiences, can lead to significant reductions in depressive symptoms two weeks after the experiments.

This paper reanalysed fMRI data from a previous open-label study where psilocybin was used to treat treatment-resistant depression (TRD). Dynamic sensitivity analysis identified brain regions transitioning from a depressive brain state to a healthy one which correlated with in vivo density maps of serotonin receptors 5-HT2A and 5-HT1A, providing further evidence for the role of serotonergic signalling in the recovery of depression via psilocybin.