Psychedelic Research Recap December 2022

This December, one big trial on psilocybin for depression came out. Unlike other trials, the dose was relatively modest, given once, and the results were impressive. A new theory on psychological pathologies was proposed (from a star-studded team). And we cover 29 more papers including one on ‘paradoxical wakefulness’ in rats given 5-MeO-DMT.

A single dose of psilocybin led to remission in 54% of those with depression

Can psychedelics be an effective treatment for depression? It’s a question with many aspects, from efficacy to costs and delivery. A positive signal was generated last month where 54% of patients in a study were in remission (scoring low on the MADRS) 14 days after a single dose of psilocybin (16mg).

The study is the first double-blind, placebo-controlled study to do so with a relatively low dose (vs 25-30mg in other studies). It also showed a greater response than the COMPASS Pathways study from last month (37% at three weeks – so not directly comparable). There were relatively few adverse events, showing that going as high as possible might not always be the best way.

The study adds to the relatively sparse literature of randomized, controlled trials (RCTs) with psilocybin. Other studies, such as the EPIsoDE trial (currently ongoing), will help fill in the details.

A new model of psychopathology, based on psychedelic research

A theory-building article by Robin Carhart-Harris and colleagues revives a classical bridging construct, canalization, to describe a new model of a general factor of psychopathology. The model distinguishes between two types of plasticity: TEMP (Temperature or Entropy Mediated Plasticity) and canalization. TEMP relates to increased model variance, while canalization relates to increased model precision.

The model proposes that “pathological” phenotypes develop through mechanisms of canalization as a defensive response to adversity and associated distress. Canalization entrenches in psychopathology, narrowing the phenotypic statespace as the individual becomes expert in their pathology. TEMP, combined with psychological support, may be able to counter canalization. The model raises questions about the adaptiveness of canalization and offers concrete experiments to test its hypotheses.

Looking not at psychopathology, but non-ordinary states of consciousness, Chris Timmermann and colleagues propose a unified neurophenomenological (NP) approach to studying non-ordinary states of consciousness (psychedelics, meditation, hypnosis). By focusing on the experience (phenomenology; e.g. interviews) and combining it with neurophysiological measures, a rich explanatory framework could emerge.

Also published in December is a paper on ‘insight’, showing that insight is a core component in psychotherapy and meditation, a key process underlying the emergence of delusions in schizophrenia, and a factor in the therapeutic effects of psychedelics as well as being commonly studied in problem-solving literature.

Looking at the experience and perspective on psychedelics

Looking at the brain can give insights into how psychedelics work, and we cover more of those studies below. But getting qualitative interview data can also help us discover why they work (and why not for some). One study did this for patients who recovered from treatment-resistant depression after ketamine infusions.

Another study investigated the effects of San Pedro with a focus on the Altered States of Consciousness (11D-ASC) measure. The participants, engaging in ceremonial use, showed changes on all subscales of the measure with moderate scores of ego-dissolution, and a complete mystical experience in two-thirds of participants.

Those seeking out ibogaine for substance use disorders (SUDs) reported on their subjective experiences in another interview study. The themes focus on psychological effects such as transpersonal experiences, autobiographical memories, and personal insights. Similar positive findings are reported in a trial with psilocybin for those suffering from cancer and related depression.

The perspective about psychedelics, for those who haven’t done them, can show what barriers or misconceptions are out there. An interview study asked veterans, all with traumatic brain injuries (TBIs, an understudied but promising area for psychedelics), about psychedelic-assisted therapy (PAT). Before presenting info (about current medical developments), they were neutral, after they had significantly more positive views on psychedelic drugs (3.2 out of 5), interest in PAT (3.7), and would support medical PAT (4.3).

The perspective of healthcare professionals (of which many know nothing about psychedelic, yet) is also essential. A review provides information for this professional group with an overview of practical considerations for psilocybin therapy, focusing on patient safety.

Looking back in history, we can see the actual perspective of practising therapists who used psychedelics. A review explores low-dose psychedelic use (75-125μg) LSD with multiple sessions (5-8x) in combination with talk therapy. 15 years of use in Europe in the 1960s is explored to define the features of psycholytic therapy.

Finally, if we zoom out, we can get a perspective on psychedelic use in the broader population. In the US, teens who used psychedelics were more likely to feel sad or hopeless, suicidal, and use other substances (e.g. ecstasy) too. The use of psychedelics among teens did go down over the period of the study. This was reversed in another study looking at adult use of LSD. This study found an increase of 47% (from 0.6% to 0.9%) in the US.

On the edge of science, novel uses for psychedelics

The research on OCD and psychedelics is limited to one clinical study (with less than a handful currently ongoing). Therefore information from a case study can add to our understanding of how they can be effective. A case study finds that a single dose of psilocybin led to improvements in OCD symptoms and positive changes to the individuals’ emotions, social and work function, and quality of life.

Similarly, psychedelics for eating disorders (EDs) such as anorexia are promising. A review evaluates the potential use of psychedelics in treating body dysmorphic disorder and other eating disorders. Like with OCD, the review (unfortunately) is based on only five studies (of which two are case studies). Several trials for EDs are currently ongoing.

A third area with a lot of potential is the impact of psychedelics on markers of inflammation. A new study finds no significant impact of psilocybin on the biomarkers of inflammation the Copenhagen team measured. This contrasts research published in November, showing reductions in inflammatory markers in a relatively similar design. To dive deeper into this topic, also see our interview with Attila Szabo on psychoneuroimmunology.

Using psychedelics is discouraged for those with bipolar depression (BD). The non-classical psychedelic ketamine is the only one where there is a regular study on BD. A real-world study of 66 patients finds that significant antidepressant effects were measured using the QIDS-SR, and further reductions were observed following each subsequent infusion. The rate of remission was 20% after all infusions.

A survey study of over 500 people finds that 32.2% of participants had new/increasing symptoms after psilocybin trips, prominently manic symptoms, difficulties sleeping and anxiety. However, most participants reported that psilocybin was more helpful than harmful. An interview study of 15 people who had used psilocybin and were experiencing BD identified three overarching themes: Mental Health Improvements, Undesired Mental Health Impacts and Salient Contextual Factors for psilocybin use.

A study in rats finds that microdoses of psilocybin normalise cognitive performance in an object recognition test. This study was done in rats with Fragile X syndrome (a genetic cause of autism, ASD). Though a very early signal, it is (again) one of few studies on this topic.

The other studies that came out in December

Mice that were given 5-MeO-DMT delayed the onset of REM sleep as measured with EEG, and showed behavioural signals (e.g. head twitches) consistent with psychedelic effects, whilst during the waking stage the EEG measures were also showing signs of REM sleep (paradoxical wakefulness).

A review summarises the in-cell, in-animal and available clinical data with the non-hallucinogenic phenylalkylamine analogue Ariadne. It proposes a hypothesis for its lack of hallucinogenic effects and the therapeutic potential of this (unexplored) compound.

Using machine learning on brain data has become more commonplace in the last year. An EEG dataset from a study involving ayahuasca was used to investigate the ability of machine learning and complex network measurements to detect changes in brain activity automatically. After applying machine learning at three different levels of data abstraction, machine learning proved to be consistent with the current literature. It showed the highest accuracy in detecting the correlation of the EEG time series.

Looking at the pharmacokinetics and pharmacodynamics (how psychedelics move through the body over time), a study reports on the effects of orally administrated psilocybin. Maximal psilocin concentrations were 11 ng/ml, 17 ng/ml, and 21 ng/ml after administering 15, 25, and 30 mg psilocybin, respectively, and maximal levels were reached after an average of 2 hours. The duration and intensity of subjective effects were dose-dependent.

Finally, several studies flesh out details on the use and effectiveness of ketamine. One finds a good response in those over the age of 60. Repeated ketamine tablets were effective in self-reported measures of depression and anxiety in healthcare workers. Ketamine was similarly effective in depressed patients with and without melancholy. A review covers the biomarkers of ketamine’s antidepressant effects. Whilst another review proposes that the antidepressant effects observed after ketamine infusions are mainly driven by its acute modulation of reward circuits and sub-acute increase in neuroplasticity. Finally, a retrospective analysis investigates the adverse effects of (es)ketamine such as dissociation from Phase III trial data.