March was another exceptional month for psychedelics research. The month started with the largest (self-)blinded microdosing study to date. During the course of the month, we continued to learn about placebo effects in different settings. A more theoretical paper suggested several study designs to combat this, or better measure what is caused by placebo, expectancy, drugs, set, and setting. Another study found that the ceremonial setting could fool a large part of the study group who thought they had received ayahuasca. Although very difficult to do, we are discovering more and more about what roles different aspects of the psychedelic experience play.

This was also the case for a large study that proposes a framework for thinking about group-level or community effects during psychedelic ceremonies. The interpersonal relationships (communitas) during the retreats predicted wellbeing and social connectedness four weeks later. A survey on the use of mescaline (which is very much understudied) found that a large majority of the respondents indicated improvements on measures of PTSD, anxiety, and depression after using mescaline.

Other studies investigated the effects of psychedelics on our bodies. Data on nearly 200 healthy participants were pooled to find what predicts responses to MDMA. After controlling for weight, there were no significant differences between the sexes. The activity or expression of CYP2D6 genes/enzymes did predict how much MDMA was found in the blood plasma, which in turn predicted both subjective and physiological effects. A study with LSD and ketanserin found that the former increased sympathetic (fight-or-flight) activity, and the latter parasympathetic (rest-and-digest) activity.

These studies and many can be found in our round-up of psychedelic research of March 2021. An impressive 18 studies are highlighted and we noted 45 more interesting studies. An article can be found for all of the featured articles, about 1/3rd of the rest are also added to the database. See you next month!

Self-blinding citizen science to explore psychedelic microdosing (paper)

This self-blinding experiment (n=191) finds that the placebo and microdosing groups both experienced similar improvements in self-rated psychological well-being and cognitive function (e.g. mood, energy, creativity) after four weeks. This study provides more evidence that microdosing benefits can be attributed to expectancy (placebo) effects.

Published: 2 March 2021

Authors: Balázs Szigeti, Laura Kartner, Allan Blemings, Fernando Rosas, Amanda Feilding, David J. Nutt, Robin L. Carhart-Harris & David Erritzoe

“Microdosing is the practice of regularly using low doses of psychedelic drugs. Anecdotal reports suggest that microdosing enhances well-being and cognition; however, such accounts are potentially biased by the placebo effect. This study used a ‘self-blinding’ citizen science initiative, where participants were given online instructions on how to incorporate placebo control into their microdosing routine without clinical supervision. The study was completed by 191 participants, making it the largest placebo-controlled trial on psychedelics to-date. All psychological outcomes improved significantly from baseline to after the 4 weeks long dose period for the microdose group; however, the placebo group also improved and no significant between-groups differences were observed. Acute (emotional state, drug intensity, mood, energy, and creativity) and post-acute (anxiety) scales showed small, but significant microdose vs. placebo differences; however, these results can be explained by participants breaking blind. The findings suggest that anecdotal benefits of microdosing can be explained by the placebo effect.“

Dose–response relationships of psilocybin-induced subjective experiences in humans (paper)

This meta-analysis (n=349) found that the dose of psilocybin (3-27mg/70kg) correlated positively with positive changes in perception (e.g. ego dissolution). Negative experiences were barely modulated by dose.

Published: 4 March 2021

Authors: Tim Hirschfeld & Timo T. Schmidt

“Background: Psilocybin is the psychoactive component in Psilocybe mushrooms (‘magic mushrooms’). Whether and how the quality of the psilocybin-induced experience might mediate beneficial health outcomes is currently under investigation, for example, in therapeutic applications. However, to date, no meta-analysis has investigated the dose-dependency of subjective experiences across available studies. Aim: Establishing dose–response relationships of the subjective experiences induced by psilocybin in healthy study participants and a comparison of patient groups. Method: We applied a linear meta-regression approach, based on the robust variance estimation framework, to obtain linear dose–response relationship estimates on questionnaire ratings after oral psilocybin administration. Data were obtained from the Altered States Database, which contains data extracted from MEDLINE-listed journal articles that used standardized and validated questionnaires: the Altered States of Consciousness Rating Scale, the Mystical Experience Questionnaire and the Hallucinogen Rating Scale. Results: Psilocybin dose positively correlated with ratings on most factors and scales, mainly those referring to perceptual alterations and positively experienced ego dissolution. Measures referring to challenging experiences exhibited small effects and were barely modulated by dose. Conclusion: Psilocybin intensified almost all characteristics of altered states of consciousness assessed with the given questionnaires. Because subjective experiences are not only determined by dose, but also by individual and environmental factors, the results may only apply to controlled laboratory experiments and not to recreational use. This paper may serve as a general literature citation for the use of psilocybin in experimental and clinical research, to compare expected and observed subjective experiences.”

Predicting Reactions to Psychedelic Drugs: A Systematic Review of States and Traits Related to Acute Drug Effects (paper)

This review (14 studies) found that traits of absorption, openness, acceptance, and surrender correlated with more positive and mystical (MEQ30) experiences. Gender didn’t predict drug effects, but possible biomarkers are serotonin receptor binding potential, executive network node diversity, and right anterior cingulate cortex volume.

Published: 5 March 2021

Authors: Jacob S. Aday, Alan K. Davis, Cayla M. Mitzkovitz, Emily K. Bloesch & Christopher C. Davoli

“Psychedelic drugs are increasingly being incorporated into therapeutic contexts for the purposes of promoting mental health. However, they can also induce adverse reactions in some individuals, and it is difficult to predict before treatment who is likely to experience positive or adverse acute effects. Although consideration of setting and dosage as well as excluding individuals with psychotic predispositions has thus far led to a high degree of safety, it is imperative that researchers develop a more nuanced understanding of how to predict individual reactions. To this end, the current systematic review coalesced the results of 14 studies that included baseline states or traits predictive of the acute effects of psychedelics. Individuals high in the traits of absorption, openness, and acceptance as well as a state of surrender were more likely to have positive and mystical-type experiences, whereas those low in openness and surrender or in preoccupied, apprehensive, or confused psychological states were more likely to experience acute adverse reactions. Participant sex was not a robust predictor of drug effects, but 5-HT2AR binding potential, executive network node diversity, and rACC volume may be potential baseline biomarkers related to acute reactions. Finally, increased age and experience with psychedelics were individual differences related to generally less intense effects, indicating that users may become slightly less sensitive to the effects of the drugs after repeated usage. Although future well-powered, placebo-controlled trials directly comparing the relative importance of these predictors is needed, this review synthesizes the field’s current understanding of how to predict acute reactions to psychedelic drugs.“

The DMT and Psilocin Treatment Changes CD11b+ Activated Microglia Immunological Phenotype (paper)

This study on neuronal-glial cells (CD11b+ microglia, from mice) found that the direct application of psilocin (a metabolite of psilocybin) and DMT, led to increased capacity for the cells to fulfill their immune responses. Specifically, it reduced levels of TLR4, p65, CD80 proteins (markers of the immune response), and upregulated TREM2 (neuroprotective receptor).

Published (pre-print): 8 March 2021

Authors: Urszula Kozłowska, Aleksandra Klimczak, Kalina Wiatr & Maciej Figiel

“Psychedelics are new, promising candidate molecules for clinical use in psychiatric disorders such as Treatment-Resistant Depression (TRD) and Post Traumatic Stress Disorder (PTSD). They were recently also proposed as molecules supporting neural tissue repair by anti-inflammatory properties. Here we reported that two classic psychedelics, DMT and psilocin, can influence microglial functions by reducing the level of TLR4, p65, CD80 proteins, which are markers of the immune response, and upregulat TREM2 neuroprotective receptor. Psilocin also secured neuronal survival in the neuron-microglia co-culture model by attenuating the phagocytic function of microglia. We conclude that DMT and psilocin regulate the immunomodulatory potential of microglia. Of note, psychedelics were previously reported as a relatively safe treatment approach. The demonstrated regulation of inflammatory molecules and microglia phagocytosis suggests that psychedelics or their analogs are candidates in the therapy of neurological disorders where microglia and inflammation significantly contribute to pathogenic disease mechanisms.“

Blinding and Expectancy Confounds in Psychedelic Randomised Controlled Trials (paper)

This systematic review argues that de-blinding (breaking blind) in randomized controlled trials (RCTs) of psychedelic therapies is leading to a (not defined/measurable) over-estimation of the outcomes (outside clinical trials). The authors suggest measures to tackle this and to use caution interpreting the existing RCTs.

Published (pre-print): 9 March 2021

Authors: Suresh Muthukumaraswamy, Anna Forsyth & Thomas Lumley

“There is increasing interest in the potential for psychedelic drugs such as psilocybin, LSD and ketamine to treat a number of mental health disorders. To gain evidence for the therapeutic effectiveness of psychedelics, a number of randomised controlled trials (RCTs) have been conducted using the traditional RCT framework and these trials have generally shown promising results, with large effect sizes reported. However, in this paper we argue that estimation of treatment effect sizes in psychedelic clinical trials are likely over-estimated due to de-blinding of participants and high levels of response expectancy generated by RCT trial contingencies. The degree of over-estimation is at present difficult to estimate. We conduct systematic reviews of psychedelic RCTs and show that currently reported RCTs have failed to measure and report expectancy and malicious de-blinding. In order to overcome these confounds we argue that RCTs should routinely measure de-blinding and expectancy and that careful attention should be paid to the clinical trial design used and the instructions given to participants to allow these confounds to be estimated and removed from effect size estimates. We urge caution in interpreting effect size estimates from extant psychedelic RCTs.”

A placebo-controlled study of the effects of ayahuasca, set and setting on mental health of participants in ayahuasca group retreats (paper)

This double-blind placebo-controlled study (n=30) controlled for expectation bias in a naturalistic ayahuasca ceremony. The use of ayahuasca led to more emotional empathy, but both groups improved as much on symptoms of depression, anxiety, and stress. Noted should be that the dosage of ayahuasca was relatively low (14-21mg DMT, 2-4x lower than usual).

Published: 10 March 2021

Authors: Malin V. Uthaug, Natasha L. Mason, Stefan W. Toennes, Johannes T. Reckweg, Elizabeth B. de Sousa Fernandes Perna, Kim P. C. Kuypers, Kim van Oorsouw, Jordi Riba & Johannes G. Ramaekers

“Ayahuasca is a plant concoction containing N,N-dimethyltryptamine (DMT) and certain β-carboline alkaloids from South America. Previous research in naturalistic settings has suggested that ingestion of ayahuasca can improve mental health and well-being; however, these studies were not placebo-controlled and did not control for the possibility of expectation bias. This naturalistic observational study was designed to assess whether mental health changes were produced by ayahuasca or by set and setting. Assessments were made pre- and post-ayahuasca sessions in 30 experienced participants of ayahuasca retreats hosted in the Netherlands, Spain, and Germany. Participants consumed ayahuasca (N = 14) or placebo (N = 16). Analysis revealed a main effect of time on symptoms of depression, anxiety, and stress. Compared to baseline, symptoms reduced in both groups after the ceremony, independent of treatment. There was a main treatment × time interaction on implicit emotional empathy, indicating that ayahuasca increased emotional empathy to negative stimuli. The current findings suggest that improvements in mental health of participants of ayahuasca ceremonies can be driven by non-pharmacological factors that constitute a placebo response but also by pharmacological factors that are related to the use of ayahuasca. These findings stress the importance of placebo-controlled designs in psychedelic research and the need to further explore the contribution of non-pharmacological factors to the psychedelic experience.”

On the Relationship between Classic Psychedelics and Suicidality: A Systematic Review (paper)

This review (64 studies) investigated the literature and found no clear relationship (finding correlation both ways, and non-significant results) between non-clinical use of psychedelics and suicidality. There is preliminary evidence for acute and sustained decreases in suicidality after psychedelic therapy.

Published: 11 March 2021

Authors: Richard J. Zeifman, Nikhita Singhal, Leah Breslow & Cory R. Weissman

“Use of classic psychedelics (e.g., psilocybin, ayahuasca, and lysergic acid diethylamide) is increasing, and psychedelic therapy is receiving growing attention as a novel mental health intervention. Suicidality remains a potential safety concern associated with classic psychedelics and is, concurrently, a mental health concern that psychedelic therapy may show promise in targeting. Accordingly, further understanding of the relationship between classic psychedelics and suicidality is needed. Therefore, we conducted a systematic review of the relationship between classic psychedelics (both non-clinical psychedelic use and psychedelic therapy) and suicidality. We identified a total of 64 articles, including 41 articles on the association between non-clinical classic psychedelic use and suicidality and 23 articles on the effects of psychedelic therapy on suicidality. Findings on the association between lifetime classic psychedelic use and suicidality were mixed, with studies finding positive, negative, and no significant association. A small number of reports of suicide and decreased suicidality following non-clinical classic psychedelic use were identified. Several cases of suicide in early psychedelic therapy were identified; however, it was unclear whether this was due to psychedelic therapy itself. In recent psychedelic therapy clinical trials, we found no reports of increased suicidality and preliminary evidence for acute and sustained decreases in suicidality following treatment. We identify some remaining questions and provide suggestions for future research on the association between classic psychedelics and suicidality.“

Baseline power of theta oscillations predicts mystical-type experiences induced by DMT (paper)

This EEG study (n=35) showed that the baseline power of theta oscillations (associated with mind-wandering) negatively correlated with the intensity of mystical-type (MEQ30) experiences after smoking DMT.

Published (pre-print): 12 March 2021

Authors: Enzo Tagliazucchi, Federico Zamberlan, Federico Cavanna, Laura Alethia de la Fuente, Celeste Romero, Yontatan Sanz Perl & Carla Pallavicini

“N,N-Dimethyltryptamine (DMT) is a classic psychedelic capable of inducing short-lasting but profound changes in consciousness. As with other psychedelics, the experience induced by DMT strongly depends upon contextual factors, yet the neurobiological determinants of this variability remain unknown. We combined wireless electroencephalography and source imaging to map changes in neural oscillations elicited by inhaled DMT. Furthermore, we found that the power of frontal and temporal theta oscillations was inversely correlated with scales indexing feelings of unity and transcendence, which are an integral part of the phenomenology of mystical-type experiences. Finally, we established the robustness of these results using a machine learning model for regression trained and tested following a cross-validation procedure. Our results are consistent with the observation that the state of mind prior to consuming a psychedelic drug influences the ensuing subjective experience of the user. We also suggest that priming subjects to reduce their theta power before administration of a serotonergic psychedelic could enhance the likelihood of inducing mystical-type experiences, leading to sustained positive effects in well-being and improving the outcome of therapeutic interventions.”

Combining Psychedelic and Mindfulness Interventions: Synergies to Inform Clinical Practice (paper)

This perspective article proposes various synergies between mindfulness practice and psychedelics. The authors argue that psychedelics can form the compass (direction setting) and mindfulness the vehicle (integration).

Published: 16 March 2021

Authors: Jake E. Payne, Richard Chambers & Paul Liknaitzky

“Psychedelic and mindfulness interventions have been shown to improve mental ill-health and wellbeing, with a range of clinical processes and effects in common. However, each appear to contain specific challenges in the context of mental health treatment. In this Perspective, we focus on a set of distinct affordances, “useful differences”, within psychedelic and mindfulness interventions that might address common challenges within the other intervention. Accordingly, we propose a set of applied synergies, indicating specific ways in which these two promising interventions might be combined for greater benefit. Metaphorically, on the journey toward mental health and wellbeing, we propose that psychedelic treatments may serve the role of Compass (initiating, motivating, and steering the course of mindfulness practice), with mindfulness interventions serving the role of Vehicle (integrating, deepening, generalizing, and maintaining the novel perspectives and motivation instigated by psychedelic experience). We outline a set of testable hypotheses and future research associated with the synergistic action of psychedelic and mindfulness interventions toward improved clinical outcomes.”

Acute and Sustained Reductions in Loss of Meaning and Suicidal Ideation Following Psilocybin-Assisted Psychotherapy for Psychiatric and Existential Distress in Life-Threatening Cancer (paper)

This follow-up study (n=11) of psilocybin-assisted therapy for anxiety and depression, found that it also significantly reduced suicidal ideation (SI) and loss of meaning (LoM) up to the 4.5 years follow-up.

Published: 18 March 2021

Authors: Stephen Ross, Gabrielle Agin-Liebes, Sharon Lo, Richard J. Zeifman, Leila Ghazal, Julia Benville, Silvia Franco Corso, Christian Bjerre Real, Jeffrey Guss, Anthony Bossis & Sarah E. Mennenga

“People with advanced cancer are at heightened risk of desire for hastened death (DHD), suicidal ideation (SI), and completed suicide. Loss of Meaning (LoM), a component of demoralization, can be elevated by a cancer diagnosis and predicts DHD and SI in this population. We completed a randomized controlled trial in which psilocybin-assisted psychotherapy (PAP) produced rapid and sustained improvements in depression, demoralization, and hopelessness in people with cancer. Converging epidemiologic and clinical trial findings suggests a potential antisuicidal effect of this treatment. To probe our hypothesis that PAP relieves SI through its beneficial impacts on depression and demoralization (LoM in particular), we performed secondary analyses assessing within- and between-group differences with regard to LoM and an SI composite score. Among participants with elevated SI at baseline, PAP was associated with within-group reductions in SI that were apparent as early as 8 h and persisted for 6.5 months postdosing. PAP also produced large reductions in LoM from baseline that were apparent 2 weeks after treatment and remained significant and robust at the 6.5 month and 3.2 and 4.5 year follow-ups. Exploratory analyses support our hypothesis and suggest that PAP may be an effective antisuicidal intervention following a cancer diagnosis due to its positive impact on hopelessness and demoralization and its effects on meaning-making in particular. These preliminary results implicate psilocybin treatment as a potentially effective alternative to existing antidepressant medications in patients with cancer that are also suicidal, and warrant further investigation in participants with elevated levels of depression and suicidality.”

Neural Correlates of the Shamanic State of Consciousness (paper)

This brain imaging (EEG) study (n=37) found that the shamanic practitioners showed significant differences to control participants on an altered states of consciousness scale (OAV) and EEG measures. Their brainwaves resembled that of earlier data on those under the influence of psychedelics but still were identified as unique, often stronger, patterns.

Published: 18 March 2021

Authors: Emma R. Huels, Hyoungkyu Kim, UnCheol Lee, Tarik Bel-Bahar, Angelo V. Colmenero, Amanda Nelson, Stefanie Blain-Moraes, George A. Mashour & Richard E. Harris

“Psychedelics have been recognized as model interventions for studying altered states of consciousness. However, few empirical studies of the shamanic state of consciousness, which is anecdotally similar to the psychedelic state, exist. We investigated the neural correlates of shamanic trance using high-density electroencephalography (EEG) in 24 shamanic practitioners and 24 healthy controls during rest, shamanic drumming, and classical music listening, followed by an assessment of altered states of consciousness. EEG data were used to assess changes in absolute power, connectivity, signal diversity, and criticality, which were correlated with assessment measures. We also compared assessment scores to those of individuals in a previous study under the influence of psychedelics. Shamanic practitioners were significantly different from controls in several domains of altered states of consciousness, with scores comparable to or exceeding that of healthy volunteers under the influence of psychedelics. Practitioners also displayed increased gamma power during drumming that positively correlated with elementary visual alterations. Furthermore, shamanic practitioners had decreased low alpha and increased low beta connectivity during drumming and classical music and decreased neural signal diversity in the gamma band during drumming that inversely correlated with insightfulness. Finally, criticality in practitioners was increased during drumming in the low and high beta and gamma bands, with increases in the low beta band correlating with complex imagery and elementary visual alterations. These findings suggest that psychedelic drug-induced and non-pharmacologic alterations in consciousness have overlapping phenomenal traits but are distinct states of consciousness, as reflected by the unique brain-related changes during shamanic trance compared to previous literature investigating the psychedelic state.”

Examining changes in personality following shamanic ceremonial use of ayahuasca (paper)

This open-label study (n=256) found that directly after an ayahuasca retreat, and three months later, the personality of the participants was changed. The strongest finding was for neuroticism, but noted should be that there was no control group.

Published: 23 March 2021

Authors: Brandon Weiss, Joshua D. Miller, Nathan T. Carter & W. Keith Campbell

“The present study examines the association between the ceremonial use of ayahuasca—a decoction combining the Banistereopsis caapi vine and N,N-Dimethyltryptamine-containing plants—and changes in personality traits as conceived by the Five-Factor model (FFM). We also examine the degree to which demographic characteristics, baseline personality, and acute post-ayahuasca experiences affect personality change. Participants recruited from three ayahuasca healing and spiritual centers in South and Central America (N = 256) completed self-report measures of personality at three timepoints (Baseline, Post, 3-month Follow-up). Informant-report measures of the FFM were also obtained (N = 110). Linear mixed models were used to examine changes in personality and the moderation of those changes by covariates. The most pronounced change was a reduction in Neuroticism dz self-reportT1–T2 =  − 1.00; dz self-reportT1–T3 =  − .85; dz informant-reportT1–T3 =  − .62), reflected in self- and informant-report data. Moderation of personality change by baseline personality, acute experiences, and purgative experiences was also observed.”

Naturalistic Use of Mescaline Is Associated with Self-Reported Psychiatric Improvements and Enduring Positive Life Changes (paper)

This survey study (n=452) found that the use of mescaline led to improvements in scores on clinical conditions (anxiety 80%, depression 86%, PTSD & AUD 76%). Those who scored higher on acute mystical experience (MEQ30), ego dissolution, and psychological insight had larger improvement than those who scored lower.

Published: 23 March 2021

Authors: Gabrielle Agin-Liebes, Trevor F. Haas, Rafael Lancelotta, Malin V. Uthaug, Johannes G. Ramaekers & Alan K. Davis

“Mescaline is a naturally occurring psychoactive alkaloid that has been used as a sacrament by Indigenous populations in spiritual ritual and healing ceremonies for millennia. Despite promising early preliminary research and favorable anecdotal reports, there is limited research investigating mescaline’s psychotherapeutic potential. We administered an anonymous online questionnaire to adults (N = 452) reporting use of mescaline in naturalistic settings about mental health benefits attributed to mescaline. We assessed respondents’ self-reported improvements in depression, anxiety, post-traumatic stress disorder (PTSD), and alcohol and drug use disorders (AUD and DUD). Of the respondents reporting histories of these clinical conditions, most (68–86%) reported subjective improvement following their most memorable mescaline experience. Respondents who reported an improvement in their psychiatric conditions reported significantly higher ratings of acute psychological factors including mystical-type, psychological insight, and ego dissolution effects compared to those who did not report improvements (Cohen’s d range 0.7 – 1.5). Many respondents (35–50%) rated the mescaline experience as the single or top five most spiritually significant or meaningful experience(s) of their lives. Acute experiences of psychological insight during their mescaline experience were associated with increased odds of reporting improvement in depression, anxiety, AUD and DUD. Additional research is needed to corroborate these preliminary findings and to rigorously examine the efficacy of mescaline for psychiatric treatment in controlled, longitudinal clinical trials.”

Psychedelic Communitas: Intersubjective Experience During Psychedelic Group Sessions Predicts Enduring Changes in Psychological Wellbeing and Social Connectedness (paper)

This prospective survey study (n=886) of those participating in a psychedelic ceremony, validated the adapted Communitas Scale and found that positive interpersonal experiences (including personal sharing) correlated with positive outcomes (psychological wellbeing & social connectedness).

Published: 25 March 2021 (we also featured this research when the pre-print was out in January 2021)

Authors: Gabrielle Agin-Liebes, Trevor F. Haas, Rafael Lancelotta, Malin V. Uthaug, Johannes G. Ramaekers & Alan K. Davis

“Background: Recent years have seen a resurgence of research on the potential of psychedelic substances to treat addictive and mood disorders. Historically and contemporarily, psychedelic studies have emphasized the importance of contextual elements (‘set and setting’) in modulating acute drug effects, and ultimately, influencing long-term outcomes. Nevertheless, current small-scale clinical and laboratory studies have tended to bypass a ubiquitous contextual feature of naturalistic psychedelic use: its social dimension. This study introduces and psychometrically validates an adapted Communitas Scale, assessing acute relational experiences of perceived togetherness and shared humanity, in order to investigate psychosocial mechanisms pertinent to psychedelic ceremonies and retreats. Methods: In this observational, web-based survey study, participants (N = 886) were measured across five successive time-points: 2 weeks before, hours before, and the day after a psychedelic ceremony; as well as the day after, and 4 weeks after leaving the ceremony location. Demographics, psychological traits and state variables were assessed pre-ceremony, in addition to changes in psychological wellbeing and social connectedness from before to after the retreat, as primary outcomes. Using correlational and multiple regression (path) analyses, predictive relationships between psychosocial ‘set and setting’ variables, communitas, and long-term outcomes were explored. Results: The adapted Communitas Scale demonstrated substantial internal consistency (Cronbach’s alpha = 0.92) and construct validity in comparison with validated measures of intra-subjective (visual, mystical, challenging experiences questionnaires) and inter-subjective (perceived emotional synchrony, identity fusion) experiences. Furthermore, communitas during ceremony was significantly correlated with increases in psychological wellbeing (r = 0.22), social connectedness (r = 0.25), and other salient mental health outcomes. Path analyses revealed that the effect of ceremony-communitas on long-term outcomes was fully mediated by communitas experienced in reference to the retreat overall, and that the extent of personal sharing or ‘self-disclosure’ contributed to this process. A positive relationship between participants and facilitators, and the perceived impact of emotional support, facilitated the emergence of communitas. Conclusion: Highlighting the importance of intersubjective experience, rapport, and emotional support for long-term outcomes of psychedelic use, this first quantitative examination of psychosocial factors in guided psychedelic settings is a significant step toward evidence-based benefit-maximization guidelines for collective psychedelic use.”

LSD and ketanserin and their impact on the human autonomic nervous system (paper)

This placebo-controlled randomized, crossover study (n=17) investigated the impact of LSD (100 μg/70kg) and the counteracting influence of the 5-HT2A receptor antagonist ketanserin (40mg/70kg) on the autonomic nervous system within healthy subjects. LSD predominantly increased the sympathetic activity, while ketanserin increased the parasympathetic influence, thus antagonizing the effects of LSD on the autonomic nervous system completely.

Published: 27 March 2021

Authors: Sebastian Olbrich, Katrin H. Preller & Franz X. Vollenweider

“The interest in lysergic acid diethylamide (LSD) has sparked again due to its supposed positive effects on psychopathological conditions. Yet, most research focuses on the actions of LSD on the central nervous system. The interaction with the autonomic nervous system (ANS) has been neglected so far. Therefore, the aim was to assess the effects of LSD and the serotonin 2A receptor antagonist ketanserin on the ANS as assessed by heart rate variability (HRV) measures and their correlation with subjective drug‐induced effects in a randomized, placebo‐controlled crossover trial. Thus, ANS activity was derived from electrocardiogram recordings after intake of placebo, LSD or ketanserin, and LSD by calculating R‐peak‐based measures of sympathetic and parasympathetic activity. Repeated measure ANOVA and partial correlation for HRV measures and subjective experience questionnaires were performed. LSD predominantly increased sympathetic activity, while ketanserin counteracted this effect on the ANS via an increase of parasympathetic tone. Sympathetic activity was positively and parasympathetic activity negatively associated with psychedelic effects of LSD. Furthermore, Placebo HRV measures predicted subjective experiences after LSD intake. The association between trait ANS activity and LSD‐induced subjective experiences may serve as a candidate biomarker set for the effectiveness of LSD in the treatment of psychopathological conditions.”

Prediction of MDMA response in healthy humans: a pooled analysis of placebo-controlled studies (paper)

This pooled-data analysis (n=194) of healthy participants of RCTs with MDMA (75mg-125mg) found that MDMA plasma concentration was the strongest predictor of outcomes. The more active the CYP2D6 enzyme, the lower the plasma concentration. And the higher the score on Openness, the more closeness and two subscales of an altered states of consciousness questionnaire (5D-ASC).

Published: 30 March 2021

Authors: Erich Studerus, Patrick Vizeli, Samuel Harder, Laura Ley & Matthias E. Liechti

Background: 3,4-methylenedioxymethamphetamine (MDMA, “ecstasy”) is used both recreationally and therapeutically. Little is known about the factors influencing inter- and intra-individual differences in the acute response to MDMA. Effects of other psychoactive substances have been shown to be critically influenced by personality traits and mood state before intake. Methods: We pooled data from 10 randomized, double-blind, placebo-controlled, cross-over studies performed in the same laboratory in 194 healthy subjects receiving doses of 75 or 125mg of MDMA. We investigated the influence of drug dose, body weight, sex, age, drug pre-experience, genetics, personality and mental state before drug intake on the acute physiological and psychological response to MDMA. Results: In univariable analyses, the MDMA plasma concentration was the strongest predictor for most outcome variables. When adjusting for dose per body weight, we found that (a) a higher activity of the enzyme CYP2D6 predicted lower MDMA plasma concentration, (b) a higher score in the personality trait “openness to experience” predicted more perceived “closeness”, a stronger decrease in “general inactivation”, and higher scores in the 5D-ASC (5 Dimensions of Altered States of Consciousness Questionnaire) scales “oceanic boundlessness” and “visionary restructuralization”, and (c) subjects with high “neuroticism” or trait anxiety were more likely to have unpleasant and/or anxious reactions. Conclusions: Although MDMA plasma concentration was the strongest predictor, several personality traits and mood state variables additionally explained variance in the response to MDMA. The results confirm that both pharmacological and non-pharmacological variables influence the response to MDMA. These findings may be relevant for the therapeutic use of MDMA.“

Psychedelics and Health Behavior Change (paper)

This review (2021) explores the prospects of psychedelic substances as facilitators of behavioral change that promote a healthy lifestyle concerning diet, exercise, and substance abuse, through psychological mechanisms such as the relaxation of prior beliefs. The authors emphasize that self-determination, confidence, and interconnectedness as useful concepts to understand how individuals derive positive perspectives and internal motivation from a well-integrated psychedelic experience.

Published (in press): 30 March 2021

Authors: Pedro Teixeira, Matthew Johnson, Christopher Timmermann, Rosalind Watts, David Erritzoe, Hannah Douglass, Hannes Kettner & Robin L. Carhart-Harris

“Healthful behaviors such as maintaining a balanced diet, being physically active, and refraining from smoking have major impacts on the risk of developing cancer, diabetes, cardiovascular diseases, and other serious conditions. The burden of the so-called “lifestyle diseases” – in personal suffering, premature mortality, and public health costs – is considerable. Consequently, interventions designed to promote healthy behaviors are increasingly being studied, e.g. using psychobiological models of behavioral regulation and change. In this article, we explore the notion that psychedelic substances such as psilocybin could be used to assist in promoting positive lifestyle change conducive to good overall health. Psilocybin has a low toxicity, is non-addictive, and has been shown to predict favorable changes in patients with depression, anxiety, and other conditions marked by rigid behavioral patterns, including substance (mis)use. While it is still early days for modern psychedelic science, research is advancing fast and results are promising. Here we describe psychedelics’ proposed mechanisms of action and research findings pertinent to health behavior change science, hoping to generate discussion and new research hypotheses linking the two areas. Therapeutic models including psychedelic experiences and common behavior change methods (e.g., Cognitive Behavior Therapy, Motivational Interviewing) are already being tested for addiction and eating disorders. We believe this research may soon be extended to help promote improved diet, exercise, nature exposure, and also mindfulness or stress reduction practices, all of which can contribute to physical and psychological health and wellbeing.“

Efficacy of ketamine for major depressive episodes at 2, 4, and 6-weeks post-treatment: A meta-analysis (paper)

This meta-analysis (41 studies; 5 at 6-weeks post-treatment) found ketamine to be effective up to 6 weeks later when ketamine was used for the treatment of depressive episodes (MDD, bipolar). The effects found, at all three follow-up points, were large (g = -1.28 to -1.36).

Published: 31 March 2021

Authors: Ashley A. Conley, Amber E. Q. Norwood, Thomas C. Hatvany, James D. Griffith, Kathryn E. Barber

“Rationale: Major depressive episodes are severe mood episodes which occur both in major depressive disorder and bipolar I and II disorder. Major depressive episodes are characterized by debilitating symptoms that often persist and interfere with typical daily functioning. Various treatments exist for major depressive episodes; however, most primary pharmacologic treatments may take weeks to months to provide relief from depressive symptoms. Ketamine is a demonstrated treatment for major depressive episodes, as relief from depressive symptoms can occur rapidly following treatment. Objectives: Prior meta-analyses have been conducted to analyze the effectiveness of ketamine for the treatment of major depressive episodes, but at the time of this writing, no meta-analysis had been conducted to observe ketamine treatment efficacy beyond 2 weeks. Methods: The present meta-analysis evaluated the efficacy of ketamine for the treatment of major depressive episodes; observations of depressive episode severity were analyzed at 2, 4, and 6-weeks post-treatment. Results: The present meta-analysis observed large effects at 2 weeks (g = -1.28), 4 weeks, (g = -1.28), and 6 weeks (g = -1.36) post-treatment. Conclusions: The results from the present meta-analysis indicate that ketamine can be an effective pharmacologic intervention for major depressive episodes, with treatment effects lasting up to 6 weeks post-ketamine administration, which has many positive implications for treatment.“