Psychedelics Research Recap April 2021
Psychedelic research in April pitted psychedelics against SSRIs, gave mice a break from tripping, and found new psychedelics. As we’re awaiting the full results of the MAPS Phase III MDMA trial data, let’s look back at the research of last month.
Psychedelics pitted against antidepressants
This month’s most important and most debated study investigated psilocybin (2 high doses) and Escitalopram (six weeks). The double-blind study investigated the effects on depression and found psilocybin to do better on most measures. The main (pre-registered) measure, a self-reported depression questionnaire, unfortunately, didn’t show significant differences between both groups.
Find our analysis and links to many other commentaries on the page dedicated to this paper.
What if we can have our cake without experiencing that we ate it?
Is it possible to part the positive long-term effects of psychedelics from the acute effects? A new study in mice finds that pretreating them with ketanserin blocks before giving them psilocybin did precisely that.
Psychological support (as per the ACE model) is possibly one of the big drivers in the psilocybin vs. SSRI trial’s success. And mice are not men. But perhaps, non-hallucinogenic psychedelics (which may need a new name/classification) can be part of our mental healthcare toolbox. In my opinion, even then, we shouldn’t forget the societal and personal causes of (and solutions to) depression.
Discovering molecules that may be non-hallucinogenic might get a lot easier with PsychLight. This innovative technique that highlights serotonin receptor activity has already been used in mice and can predict hallucinogenic potential. Part of the same team is also responsible for tabernanthalog, another non-hallucinogen with anti-addictive potential.
May there already be some psychedelics out there that scientists should get their hands on? A search through online fora identified nearly 1000 previously unknown psychedelic molecules. The new Shulgins are already out there, in the lab, and out in the wild.
Bipolar depression and psychedelics
Bipolar depression (BD; previously manic depression) affects about a third as many people as (major) depression (MDD). Currently, there is very little research on the use and safety of psychedelics for those suffering from BD.
Two recent reviews cover ketamine and psilocybin use for BD. The studies with ketamine look promising. A review investigated the data from six studies with 135 participants. It found a response for 61% of patients versus only 5% in the placebo control group.
A pre-print investigated the use of psilocybin and the risk of activating mania. The 15 case studies, of which four involved psilocybin, showed that there is indeed a risk. A study from last February also highlighted the risk of combining lithium (commonly used by those with BD) and psychedelics.
More studies with ketamine
Ketamine could be used for the treatment of PTSD finds a new review. A study from January showed a response in 67% of patients, but the effects weren’t sustained a month later.
The cognitive function of patients receiving ketamine treatment was also investigated. The study showed only minor differences between those with MDD or PTSD and healthy control subjects. It also found that baseline cognitive function didn’t predict clinical outcomes.
The final ketamine study this month is an opinion article that investigates how ketamine works. It argues that the fast-acting antidepressant effects are a product of heterogeneous (enhancing and suppressing) neuroplasticity.
Putting ayahuasca into context
A large international survey with nearly 6900 participants investigated the influence of context and setting on mental health and wellbeing outcomes. A combination of motivation, ceremony, and support variables predict these outcomes in a new model proposed in this paper.
An updated review of ayahuasca for substance use disorders (SUDs; e.g., alcoholism found that it helped people (and mice) consume fewer substances and improve mental health and wellbeing scores.
The studies in this review weren’t double-blind placebo-controlled (RCT) trials. However, more and more RCT studies with ayahuasca are being conducted.
One such study this month found, counter to earlier research, that ayahuasca didn’t reduce the recognition of fearful face stimuli. Researchers use this as an indication of social cognition. One possible explanation of the null-finding could be the dose used in the study.
Three other studies reported outcomes from studies with ayahuasca. The first showed varying changes in sub-scores on a depression scale. The second investigated the intent of Western users of ayahuasca (and also reported positive effects on SUDs). And the third analyzed seven case studies of adverse reactions for first-time users.
The rest of the psychedelic studies
A very well-controlled study finds both positive and negative effects on creativity during and after the use of psilocybin. Although not much love has been given to the Default Mode Network (DMN), this study found that decreased integrity of the DMN was the strongest predictor of the found effects.
Microdosing psilocybin increased awe and aesthetic experiences for a group of 30 participants. The researchers point out that many of them were aware that they received a placebo or psilocybin, and expectancy effects could be at play again.
A final look inside the brain shows us that LSD and psilocybin reduce the top-down hierarchical organization.
Seasoned researchers way in on how psychedelic research can be conducted in the future. One paper argues for more real-world data and digital health solutions. A second speaks specifically about psychedelics and end-of-life care. And a third paper highlights ethical and legal issues that therapists face when working with psychedelics.
Nearing completion at Blossom
This month we added 22 new papers that came out this month (and highlighted 44 more). In the background, we’ve been adding about 100 more papers. This means that we’re nearing the (preliminary) completion of the database. In a few days, we will update our roadmap and show what is in store for Blossom.
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Papers Published in April 2021
23 studies from the Blossom database published this month.
Effects of psilocybin microdosing on awe and aesthetic experiences: a preregistered field and lab-based study
In a preregistered combined field- and lab-based study, psilocybin microdosing increased self-reported awe in response to videos of funny animals and moving objects compared with placebo. However, about two-thirds of participants broke blind, and exploratory analyses suggest expectancy effects may largely drive these subjective benefits.
Ketamine for bipolar depression: a systematic review
This review (2021; s=6; n=135) found that ketamine (35mg/70kg; 1-6 doses) achieved a response (>50% reduction) on a score of depression for 61% of those suffering from bipolar depression (BD), compared to 5% for placebo.
Effects of ayahuasca and its alkaloids on substance use disorders: an updated (2016-2020) systematic review of preclinical and human studies
This review (2021; s=9) of ayahuasca for substance use disorders (SUDs; e.g. alcoholism) found improvements in both rodents and humans who were suffering from SUDs (also on scores of anxiety and depression). The human studies were observational (vs RCTs) thus lacking the power to (confidently) infer causality.
Ketamine: Promising Path or False Prophecy in the Development of Novel Therapeutics for Mood Disorders?
This commentary review (2014) highlights the strength of evidence from recent proof-of-concept studies of ketamine which bear promise for the rapid treatment of depression which currently lacks efficient treatment alternatives. However, the authors disagree about the underlying mechanism mediating these effects and doubt whether there is a sufficient degree of preclinical evidence to warrant the initiation of novel treatment approaches or widespread availability of the drug in clinical settings.
The psychology of philosophy: Associating philosophical views with psychological traits in professional philosophers
This survey study (n=314) investigated professional philosophers' worldviews in relation to psychological traits, such as personality, well-being, lifestyle, transformative life experiences, and psychedelic use. Amongst other results, they found an association between Hard Determinism (no free will) and more depression -; as well as lower life satisfaction, and that psychedelics use was associated with non-realist/subjective view of moral and aesthetic value judgments, while transformative or self-transcendent experiences predicted theism and idealism as their worldview.
Rapid Onset of Intranasal Esketamine in Patients with Treatment Resistance Depression and Major Depression with Suicide Ideation: A Meta-Analysis
This meta-analysis (s=7; n=1488) of double-blind placebo-controlled studies with those suffering from depression (MDD; TRD) and suicidal ideation (SI) found that esketamine (24-84mg) significantly improved scores on a measure of depression (MADRS) over the placebo up to 28 days alter, the SI scores were only significant within the first 24 hours.
Can pragmatic research, real-world data and digital technologies aid the development of psychedelic medicine?
The paper argues that conventional confirmatory trials alone are insufficient to establish safety and best practice for psychedelic therapy and risks being overtaken by hype and regulation. It recommends complementing these trials with pragmatic trials, real‑world data initiatives and digital health technologies to accelerate discovery of optimal, personalised, safe and cost‑efficient treatment protocols.
A Qualitative Study of Intention and Impact of Ayahuasca Use by Westerners
This qualitative study interviewed 41 Western participants about their intentions for, and sustained impacts of, facilitated group ayahuasca experiences. Participants reported a wide range of enduring benefits—including improvements in mental health, substance use, health behaviours, relationships, sense of self, creativity, somatic and physical symptoms, nature connectedness and spirituality—while two participants reported problematic experiences likely related to set and setting; the authors discuss implications for research and practice within a humanistic framework.
Influence of Context and Setting on the Mental Health and Wellbeing Outcomes of Ayahuasca Drinkers: Results of a Large International Survey
Using a large international survey (n=6,877), the study found that ceremony and ritual characteristics, additional support practices and drinkers’ motivations are significantly associated with acute spiritual/insight experiences and longer-term mental health and wellbeing outcomes, with mediation by intermediate variables such as personal insights and spiritual experience. Generalised structural equation modelling indicates these set-and-setting factors can be optimised in naturalistic and clinical contexts to enhance therapeutic benefits.
Effects of Ayahuasca on the Recognition of Facial Expressions of Emotions in Naive Healthy Volunteers: A Pilot, Proof-of-Concept, Randomized Controlled Trial
In a pilot randomised controlled trial of 22 healthy volunteers, a single dose of ayahuasca produced no significant acute or prolonged change in recognition of facial expressions of emotion compared with placebo. The brew was generally well tolerated but showed time-dependent alkaloid degradation (notably DMT), which—alongside dosing, learning effects and sample characteristics—may account for the negative finding and indicates future trials should ensure alkaloid stability.
Trial of Psilocybin versus Escitalopram for Depression
This double-blind placebo-controlled study (n=59) compared psilocybin (2x25mg; 3 weeks apart) to escitalopram (SSRI) over a six-week period and found large improvements in depression scores for those suffering from depression (MDD) in both groups. On the main measure of depression, the QIDS-SR-16, there was no significant difference between both groups. The study did find significant differences, favoring psilocybin, on the HAM-D-17, MADRS, avoidance, flourishing, wellbeing, and suicidality.
Harnessing psilocybin: antidepressant-like behavioral and synaptic actions of psilocybin are independent of 5-HT2R activation in mice
Psilocybin produces rapid antidepressant-like behavioural effects and enhances synaptic connectivity in mouse brain regions involved in reward and emotion. These therapeutic and synaptic actions occur despite blockade of prohallucinatory 5‑HT2A receptors, suggesting antidepressant mechanisms can be dissociated from its perceptual effects.
Ketamine For Post-Traumatic Stress Disorders And Its Possible Therapeutic Mechanism
This review (2021) investigates the possibility of ketamine being used to treat Post-Traumatic Stress Disorder (PTSD).
Mapping an Agenda for Psychedelic-Assisted Therapy Research in Patients with Serious Illness
This paper (2021) represents the outcomes of several brainstorming sessions, interviews, etc. with many of the leading psychedelic researchers that maps out the direction that the field may take with regards to the use of psychedelics for those with serious illness (end-of-life care).
Acute cognitive effects of single-dose intravenous ketamine in major depressive and posttraumatic stress disorder
A single subanesthetic IV ketamine infusion produced large, rapid reductions in depressive symptoms in people with MDD or PTSD at 2 hours and 1 day. Ketamine caused transient declines in attention, executive function and verbal memory at 2 hours that resolved by 1 day (attention impairment was greater in patients than controls), did not affect working memory, and cognitive changes were unrelated to antidepressant response.
Psilocybin in end of life care: Implications for further research
This commentary (2016) examines the study design and the outcome measures of two randomised controlled studies that used psilocybin to treat mood and anxiety in patients undergoing palliative care. It can be concluded that the experiences of salience, meaningfulness, and healing that accompany the powerful spiritual experiences elicited by psilocybin, mediate the antidepressant and anxiolytic outcomes measures. Future investigations may investigate these phenomena in their own right, as well as replicate these findings in diverse clinical populations that aim to implement more robust blinding measures.
Spontaneous and deliberate creative cognition during and after psilocybin exposure
In a double-blind, placebo-controlled study, psilocybin (0.17 mg/kg) produced time- and construct-specific effects on creativity: acutely it increased spontaneous creative insights while impairing deliberate task-based creativity, and seven days later it increased the number of novel ideas. Ultrahigh-field multimodal imaging showed these acute and persisting effects were predicted by within- and between-network connectivity of the default mode network, implicating DMN dynamics in psychedelic modulation of creative cognition.
Ethical and legal issues in psychedelic harm reduction and integration therapy
The paper analyses the ethical and legal risks therapists face when supporting clients who use prohibited psychedelics and argues that a harm‑reduction framework enables clinicians to mitigate those risks. It recommends pre‑ and post‑experience sessions and practical strategies so therapists can help clients minimise harms and maximise therapeutic benefit while striving to remain within legal and ethical boundaries.
Evaluating the Risk of Psilocybin for the Treatment of Bipolar Depression: A Systematic Review of Published Case Studies
A systematic review of published case reports identified 17 cases suggesting psilocybin (and related psychedelics) can precipitate manic episodes in people with bipolar disorder, indicating a real but poorly quantified risk. The authors conclude that, despite limited data, carefully controlled trials using modern set-and-setting safeguards and targeting lower-risk groups (e.g. bipolar II) are urgently needed.
Epidemiology of hospitalizations with hallucinogen use disorder: a 17-year U.S. National study
This long-term study (17 years) assessed time-trends and outcomes of hallucinogen use disorder per 100,000 in the US. Hallucinogen use disorders hospitalizations were common and increased from 1998-2014. Modifiable patient and hospital factors can reduce this burden.
3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for victims of sexual abuse with severe post-traumatic stress disorder: an open label pilot study in Brazil
This open-label clinical pilot study (n=3) investigated the efficacy of MDMA-assisted psychotherapy (75 mg in the 1st session, 75 or 125 mg in the 2nd and 3rd sessions) for patients suffering from severe post-traumatic stress disorder due to sexual abuse. One showed small but clinically significant improvement, one showed moderate improvement, and one showed strong improvement, with regard to diagnostic symptoms for PTSD.
A Dendrite-Focused Framework for Understanding the Actions of Ketamine and Psychedelics
This opinion article (2021) postulates that ketamine and psychedelics substances enact their rapid fast-acting antidepressant effects by means of promoting neuroplasticity in a heterogeneous manner, by enhancing or suppressing dendritic excitability across different parts of the cellular membrane. Although precise measurements of this pharmacological effect across the entire dendritic tree are currently still lacking, the authors hypothesize that the spatial mismatches in the opposing effects of these drugs drive neuroplasticity at specific dendritic hotspots, depending on the microcircuitry of their respective target neurons.
Increased sensitivity to strong perturbations in a whole-brain model of LSD
This in silico modelling study, based on fMRI data from healthy volunteers (n=14) administered LSD (75 μg), investigated brain-wide dynamical stability. It finds that LSD shifts the brain towards a more unstable, complex state, with the most significant dynamical changes occurring in the limbic, visual, and default mode networks.