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Psychedelic Research Bulletin: March 2023

March reflected the blossoming of psychedelic research with 23 new articles covered. In this recap, we reflect on the new microdosing study, detailed brain measures under the influence of psychedelics, a null result with psilocybin for depression, and meditation x psychedelics.

On finding null results

If you find a significant result (p-value <0.05), you’re saying that chance alone is likely not the driver of the result. Suppose a statistically significant result isn’t found. In that case, it’s customary to say that the null hypothesis (usually meaning no difference between the two experimental groups) is true (or not rejected).

Several published studies have shown a statistical difference between therapy alone and therapy plus psychedelics. However, a new study of psilocybin (21mg/70kg) in 19 participants shows no statistically significant difference between the two groups: both had improved depression scores.

Though this is a small study, it might signal that the magnitude of psychedelic-assisted therapy (PAT) is less pronounced than previously believed. Participants guessed correctly when they had received psilocybin, so blinding is still an issue in this study. In the discussion, the authors also highlight that some participants believed they hadn’t done the session correctly, indicating that multiple dosings (as is employed in some ongoing studies) might be a better (but costlier) regimen.

On the note of null findings, an even smaller study with ten participants finds no significant difference between arketamine and placebo (no therapy given in the trial) in those with treatment-resistant depression (TRD).

An analysis of health outcomes of nearly 300 patients finds a trend, but again no significant effect, towards lower healthcare costs in those treated with esketamine for treatment-resistant depression.

Acute benefits of microdosing

In a positive signal for the benefits of microdosing, an at-home study of repeated microdoses of LSD (10μg) finds higher scores for creativity, connectedness, energy, and other wellness ratings. The study started with a dosing session in the lab, but the subsequent 13 doses were taken at home (over six weeks).

A common critique of microdosing studies in the lab is that the artificial condition and convoluted tasks don’t reflect the real-world settings in which people microdose. Thinking about multiple uses of a brick (building a wall, throwing contest, etc.) and doing an April fools joke for your newsletter are two very different ways of looking at creativity.

This study combines the strength of both designs, standardizing the dose (usually guessed in at-home studies) and being taken outside the lab. Still, the study finds no enduring changes in mood and cognition outside of the dosing days.

An interview study looked specifically at the experiences of those who microdosed. It identified three themes: 1) seeking a solution: agency and rationale; 2) microdosers as scientists; 3) catalysing desirable and beneficial effects.

case study of microdosing for Lyme disease (30,000 cases per year in the US) showed improvements in a man who microdosed with psilocybin. A possible explanation could lie in the anti-inflammatory effects that psilocybin possesses, though results from one case study need to be studied in a larger trial.

Peering into the brain on psychedelics

A star-studded team of researchers combined EEG and fMRI measures to look at the brain before, during, and after the administration of DMT. EEG is helpful as it provides good information over time (high temporal resolution) but at low display resolution. fMRI provides more details (high spatial resolution) but is less suited for observing temporal changes. By combining both techniques, researchers can gain a more complete understanding of brain activity.

The team found that DMT increased global functional connectivity (GFC), network disintegration and desegregation, and a compression of the principal cortical gradient. These changes were associated with the brain’s transmodal association pole, which is linked to species-specific psychological advancements and high expression of 5-HT2A receptors.

For an in-depth analysis of these results, see the excellent substack newsletter from Andrew Gallimore.

pre-print article investigated the effects of psilocybin on brain activity (this time with fMRI only) and found that function connectomes (FCs) become more idiosyncratic, especially in the default-mode network (DMN). Looking specifically at the DMN, the researchers find reduced within-DMN activity and more connectivity with attentional systems.

The third psychedelic where new analyses were done is ayahuasca. A re-analysis found an increase in the average information parity in the brain networks of individuals, particularly in the limbic system and frontal cortex regions. By comparing resting-state functional brain networks of individuals before and after ingesting ayahuasca, the study utilized complex network theory and calculated pairwise information parity to quantify functional, statistical symmetries between brain region connectivity.

And a fourth analysis, now of LSD, found modifications in serotonin receptor-rich areas. The local signal amplitude and functional connectivity increased in the DMN and attention networks (rich in serotonin 2a receptors). A decrease was seen in limbic areas (with many serotonin 1a receptors).

Together, these studies help map out the changes happening in the brain under the influence of psychedelics. Findings from here can help identify what changes correlate with improvements in (mental) health outcomes and help develop novel psychedelics.

Meditation, psychological insight, and psychedelics

large survey of over 2,800 people finds a correlation between lifetime classical psychedelic use and a higher frequency of current mindfulness meditation (but not compassion meditation) practice. When analysing psychological insight (an aspect of the acute psychedelic experience), a correlation with both types of meditation was found.

Psychedelics and meditative practices share many characteristics. Two essays explore the benefit of including meditation and philosophical perspectives and PAT. The first essay argues that incorporating the Tibetan framework of view, meditation, and action may enhance the efficacy of PAT. The second essay proposes integrating metaphysical experiences from PAT with metaphysics, offering a Metaphysics Matrix Questionnaire to aid in this process.

third essay takes issue with evolutionary spirituality, a cultural frame for psychedelics in Western culture, which suggests that human evolution can be guided towards creating higher beings through techniques like psychedelics and eugenics. It identifies five ethical limitations of this tradition, including spiritual narcissism and contempt for less-evolved masses, before suggesting responses to these limitations.

field study dives deep into the experience of ‘self’ after DMT inhalation. It’s the second analysis, whereas the first looked at the ‘other’, and reports (in great detail) on five categories of breakthrough experiences, including the onset of effects, bodily, sensorial, psychological, and emotional effects.

Other studies that published in March

An open-label study of psilocybin (25mg) finds significant effects of psilocybin plus therapy for the treatment of body dysmorphic disorder (BDD), an obsessive preoccupation with misperceptions of appearance. Seven out of 12 participants showed a response (>30% decrease on a measure of BDD). Two reviews from last year suggested using psychedelics for BDD, and this small study provides a positive signal.

Another open-label trial, this time without psychedelics but with Psyreal, a VR experience that mimics the phenomenological components of psychedelic and mystical experiences, finds it alleviates depressive symptoms in people with mild-to-moderate depression.

retrospective analysis, from within a larger trial, finds that patients with borderline personality disorder (BPD) comorbid with TRD had reduced symptoms of depression, borderline personality, suicidality, and anxiety after treatment with ketamine.

Another analysis of the Global Drug Survey finds a positive relationship between LSD and psilocybin used for self-treatment, and well-being outcomes, particularly insight and mood. A quarter of respondents reported adverse effects.

Mice treated with a non-hallucinogenic LSD analogue (2-bromo-LSD) showed neuronal structural plasticity and active coping behaviour. The main benefit of the analogue is that it doesn’t activate the 5-HT2B receptor associated with cardiac valvulopathy (disease of heart valves).

review of ibogaine research details animal studies and the human use of ibogaine in stopping addiction. Studies are few and far between, and clinical trials are only now being started.

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