Adverse Events in Studies of Classic Psychedelics: A Systematic Review and Meta-Analysis.

Importance: A clear and comprehensive understanding of risks associated with psychedelic-assisted therapy is necessary as investigators extend its application to new populations and indications. Objective: To assess adverse events (AEs) associated with classic psychedelics, particularly serious AEs (SAEs) and nonserious AEs (NSAEs) requiring medical or psychiatric evaluation. Data Sources: The search for potentially eligible studies was conducted in the Scopus, MEDLINE, PsycINFO, and Web of Science databases from inception through February 8, 2024. Study Selection: Two independent reviewers screened articles of classic psychedelics (lysergic acid diethylamide [LSD], psilocybin, dimethyltryptamine [DMT], and 5-methoxy-N,N-dimethyltryptamine [5-MeO-DMT]) involving administration in clinical or research contexts. Data Extraction and Synthesis: AE data were extracted and synthesized by 2 reviewers and were used for random-effects meta-analysis of AE frequency and heterogeneity. Risk of bias assessment focused on AE ascertainment (eg, systematic assessment and quality of follow-up). Main Outcomes and Measures: A hybrid approach was used for capture of all reported AEs following high-dose classic psychedelic exposure and confirmatory capture of AEs of special interest, including suicidality, psychotic disorder, manic symptoms, cardiovascular events, and hallucinogen persisting perception disorder. AEs were stratified by timescale and study population type. Forest plots of common AEs were generated, and the proportions of participants affected by SAEs or NSAEs requiring medical intervention were summarized descriptively. Results: A total of 214 unique studies were included, of which 114 (53.3%) reported analyzable AE data for 3504 total participants. SAEs were reported for no healthy participants and for approximately 4% of participants with preexisting neuropsychiatric disorders; among these SAEs were worsening depression, suicidal behavior, psychosis, and convulsive episodes. NSAEs requiring medical intervention (eg, paranoia, headache) were similarly rare. In contemporary research settings, there were no reports of deaths by suicide, persistent psychotic disorders, or hallucinogen persisting perception disorders following administration of high-dose classic psychedelics. However, there was significant heterogeneity in the quality of AE monitoring and reporting. Of 68 analyzed studies published since 2005, only 16 (23.5%) described systematic approaches to AE assessment, and 20 studies (29.4%) reported all AEs, as opposed to only adverse drug reactions. Meta-analyses of prevalence for common AEs (eg, headache, anxiety, nausea, fatigue, and dizziness) yielded comparable results for psilocybin and LSD. Conclusions and Relevance: In this systematic review and meta-analysis, classic psychedelics were generally well tolerated in clinical or research settings according to the existing literature, although SAEs did occur. These results provide estimates of common AE frequencies and indicate that certain catastrophic events reported in recreational or nonclinical contexts have yet to be reported in contemporary trial participants. Careful, ongoing, and improved pharmacovigilance is required to understand the risk and benefit profiles of these substances and to communicate such risks to prospective study participants and the public.

Centering and flourishing: an online intervention study assessing the effects of a Christian contemplative practice on stress-reduction and human flourishing.

Despite widespread engagement in contemplative religious practices, comparatively little research has been conducted on their potential effects on well-being. Furthermore, few studies have focused on how an explicitly religious framing may impact the outcomes of such practices. In this online randomized controlled trial (N = 702), we tested the well-being effects of a contemplative prayer practice called Centering Prayer on self-identifying Christians. We compared 1) presenting the practice with an explicitly religious framing (experimental condition), 2) presenting the practice without an explicitly religious framing (active control), and 3) presenting simple instructions to reflect on the day, without any instructions regarding a meditation-like practice (passive control). After randomization into one of these three conditions, participants were asked to complete their assigned practice daily for 28 days. We hypothesized that the religious framing version of the practice would increase well-being over the active and passive control conditions. Well-being was assessed at three follow-up time points: one day, one week, and one month after the practice period. We found no group differences between the conditions on our primary outcome measure of well-being at one-week post-intervention. Each group increased in well-being from baseline to follow-up. We found significant group differences on acute measures of spiritual experience, the Mystical Experience Questionnaire (MEQ-30) and Daily Spiritual Experience Questionnaire (DSES). These results suggest that a religious framing may not enhance well-being effects but may alter spiritual outcomes related to contemplative practices.

Developing an Ethics and Policy Framework for Psychedelic Clinical Care: A Consensus Statement.

Importance: As government agencies around the globe contemplate approval of the first psychedelic medicines, many questions remain about their ethical integration into mainstream medical practice. Objective: To identify key ethics and policy issues related to the eventual integration of psychedelic therapies into clinical practice. Evidence Review: From June 9 to 12, 2023, 27 individuals representing the perspectives of clinicians, researchers, Indigenous groups, industry, philanthropy, veterans, retreat facilitators, training programs, and bioethicists convened at the Banbury Center at Cold Spring Harbor Laboratory. Prior to the meeting, attendees submitted key ethics and policy issues for psychedelic medicine. Responses were categorized into 6 broad topics: research ethics issues; managing expectations and informed consent; therapeutic ethics; training, education, and licensure of practitioners; equity and access; and appropriate role of gatekeeping. Attendees with relevant expertise presented on each topic, followed by group discussion. Meeting organizers (A.L.M., I.G.C., D.S.) drafted a summary of the discussion and recommendations, noting points of consensus and disagreement, which were discussed and revised as a group. Findings: This consensus statement reports 20 points of consensus across 5 ethical issues (reparations and reciprocity, equity, and respect; informed consent; professional boundaries and physical touch; personal experience; and gatekeeping), with corresponding relevant actors who will be responsible for implementation. Areas for further research and deliberation are also identified. Conclusions and Relevance: This consensus statement focuses on the future of government-approved medical use of psychedelic medicines in the US and abroad. This is an incredibly exciting and hopeful moment, but it is critical that policymakers take seriously the challenges ahead.

Unveiling the underlying structure of awe in virtual reality and in autobiographical recall: an exploratory study.

Over the last two decades, awe has attracted the attention of an increasing number of researchers. The use of virtual reality has been identified as one of the most effective techniques for eliciting awe, in addition to more personalized methods for inducing emotion, such as autobiographical recall. However, previous measures of awe were unable to uncover the hidden structure of this experience. Awe experience scale (AWE-S) has been validated as a comprehensive measure of contingent awe in English, providing new opportunities for analysis. In this two-phases study, we investigated whether the latent structure of the experience of awe evoked by the autobiographical recall technique (Study 1) overlapped with that induced by exposing participants to a validated virtual reality awe-eliciting training (Study 2). The original English AWE-S structure held both in autobiographical recall induction and virtual reality-based elicitation. Despite evidence of overlap between English and Italian structures, low correlations were found between Italian trait measures used to test the concurrent validity of the AWE-S in the Italian sample and AWE-S state dimensions. This study highlights cultural differences in awe experience, trait, and state variations, and provides new insights into the standardized induction of this emotion through simulated environments.

Psychedelic Experiences Increase Mind Perception but do not Change Atheist-Believer Status: A Prospective Longitudinal Study.

Recent studies suggest psychedelic use may be associated with changes in a variety of beliefs or belief-like states, including increased 1) mind perception, 2) non-naturalistic beliefs, and 3) Atheist-Believer status (e.g. believer, agnostic, or nonbeliever). We conducted a prospective longitudinal study among participants (N = 657) who planned to have a psilocybin experience outside a laboratory setting. We asked participants about their beliefs concerning mind perception of various entities, specific metaphysical positions, and Atheist-Believer status both before (and after their experience. Replicating previous findings, we observed increases in mind perception across a variety of living and non-living targets (e.g. plants, rocks). However, we found little to no change in metaphysical beliefs (e.g. dualism) or Atheist-Believer status. Taken together, these findings contrast with those from cross-sectional studies that psilocybin experiences result in changes to Atheist-Believer status and non-naturalistic beliefs but support the relevance of mind perception and mentalization.

Valuing the Acute Subjective Experience.

Psychedelics, including psilocybin, and other consciousness-altering compounds such as 3,4-methylenedioxymethamphetamine (MDMA), currently are being scientifically investigated for their potential therapeutic uses, with a primary focus on measurable outcomes: for example, alleviation of symptoms or increases in self-reported well-being. Accordingly, much recent discussion about the possible value of these substances has turned on estimates of the magnitude and duration of persisting positive effects in comparison to harms. However, many have described the value of a psychedelic experience with little or no reference to such therapeutic benefits, instead seeming to find the experience valuable in its own right. How can we make sense of such testimony? Could a psychedelic experience be valuable even if there were no persisting beneficial effects? If so, how? Using the concept of psychological richness, combined with insights from the philosophy of aesthetics and the enhancement literature, this essay explores potential sources of value in the acute subjective experience, apart from the value derived from persisting beneficial effects.

Large language models could change the future of behavioral healthcare: a proposal for responsible development and evaluation.

Large language models (LLMs) such as Open AI's GPT-4 (which power ChatGPT) and Google's Gemini, built on artificial intelligence, hold immense potential to support, augment, or even eventually automate psychotherapy. Enthusiasm about such applications is mounting in the field as well as industry. These developments promise to address insufficient mental healthcare system capacity and scale individual access to personalized treatments. However, clinical psychology is an uncommonly high stakes application domain for AI systems, as responsible and evidence-based therapy requires nuanced expertise. This paper provides a roadmap for the ambitious yet responsible application of clinical LLMs in psychotherapy. First, a technical overview of clinical LLMs is presented. Second, the stages of integration of LLMs into psychotherapy are discussed while highlighting parallels to the development of autonomous vehicle technology. Third, potential applications of LLMs in clinical care, training, and research are discussed, highlighting areas of risk given the complex nature of psychotherapy. Fourth, recommendations for the responsible development and evaluation of clinical LLMs are provided, which include centering clinical science, involving robust interdisciplinary collaboration, and attending to issues like assessment, risk detection, transparency, and bias. Lastly, a vision is outlined for how LLMs might enable a new generation of studies of evidence-based interventions at scale, and how these studies may challenge assumptions about psychotherapy.

Strong Bipartisan Support for Controlled Psilocybin Use as Treatment or Enhancement in a Representative Sample of US Americans: Need for Caution in Public Policy Persists.

The psychedelic psilocybin has shown promise both as treatment for psychiatric conditions and as a means of improving well-being in healthy individuals. In some jurisdictions (e.g., Oregon, USA), psilocybin use for both purposes is or will soon be allowed and yet, public attitudes toward this shift are understudied. We asked a nationally representative sample of 795 US Americans to evaluate the moral status of psilocybin use in an appropriately licensed setting for either treatment of a psychiatric condition or well-being enhancement. Showing strong bipartisan support, participants rated the individual's decision as morally positive in both contexts. These results can inform effective policy-making decisions around supervised psilocybin use, given robust public attitudes as elicited in the context of an innovative regulatory model. We did not explore attitudes to psilocybin use in unsupervised or non-licensed community or social settings.

IUPHAR-review: The integration of classic psychedelics into current substance use disorder treatment models.

Substance use disorders (SUDs) have an enormous impact on public health. With classic psychedelic-assisted therapies showing initial promise in treating multiple SUDs, it is possible that these treatments will become legally available options for patients with SUDs in the future. This article highlights how classic psychedelic-assisted therapies might be integrated into current clinical practice. We first describe contemporary evidence-based treatments for SUDs and highlight how classic psychedelic-assisted therapies might fit within each treatment. We suggest that classic psychedelic-assisted therapies can be integrated into most mainstream evidence-based SUD treatments that are currently used in clinical settings, indicating broad compatibility of classic psychedelics with contemporary SUD treatment paradigms.

Characterizing empathy and compassion using computational linguistic analysis.

Many scholars have proposed that feeling what we believe others are feeling-often known as "empathy"-is essential for other-regarding sentiments and plays an important role in our moral lives. Caring for and about others (without necessarily sharing their feelings)-often known as "compassion"-is also frequently discussed as a relevant force for prosocial motivation and action. Here, we explore the relationship between empathy and compassion using the methods of computational linguistics. Analyses of 2,356,916 Facebook posts suggest that individuals (N = 2,781) high in empathy use different language than those high in compassion, after accounting for shared variance between these constructs. Empathic people, controlling for compassion, often use self-focused language and write about negative feelings, social isolation, and feeling overwhelmed. Compassionate people, controlling for empathy, often use other-focused language and write about positive feelings and social connections. In addition, high empathy without compassion is related to negative health outcomes, while high compassion without empathy is related to positive health outcomes, positive lifestyle choices, and charitable giving. Such findings favor an approach to moral motivation that is grounded in compassion rather than empathy. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Acute Subjective Effects of Psychedelics within and Beyond WEIRD Contexts.

Reports of psychedelic experiences may contain similarities and differences across cultural contexts, but most current characterizations and quantifications of psychedelic experiences come from Western medical and naturalistic settings. In this article, we begin with a brief history of the diversity of psychedelic use in non-Western settings. We then compare and contrast accounts of psychedelic experiences within and beyond Western, educated, industrialized, rich, and democratic (WEIRD) contexts. We focus on specific reports of direct testimony of the acute subjective effects of psychedelics experienced across these contexts. We compare themes from each of these various contexts, with special emphasis on psychometric measures such as the mystical experiences questionnaire (MEQ), the five-dimensional altered states of consciousness (5D-ASC) scale, the Survey of God Encounters, and the Survey of Entity Encounters, the Challenging Experiences Questionnaire, and the Inventory of Nonordinary Experiences (INOE). Finally, we offer recommendations for future research to quantify these similarities and differences across cultures to assess them empirically in the future.

Psychedelic Science, Contemplative Practices, and Indigenous and Other Traditional Knowledge Systems: Towards Integrative Community-Based Approaches in Global Health.

As individuals and communities around the world confront mounting physical, psychological, and social threats, three complimentary mind-body-spirit pathways toward health, wellbeing, and human flourishing remain underappreciated within conventional practice among the biomedical, public health, and policy communities. This paper reviews literature on psychedelic science, contemplative practices, and Indigenous and other traditional knowledge systems to make the case that combining them in integrative models of care delivered through community-based approaches backed by strong and accountable health systems could prove transformative for global health. Both contemplative practices and certain psychedelic substances reliably induce self-transcendent experiences that can generate positive effects on health, well-being, and prosocial behavior, and combining them appears to have synergistic effects. Traditional knowledge systems can be rich sources of ethnobotanical expertise and repertoires of time-tested practices. A decolonized agenda for psychedelic research and practice involves engaging with the stewards of such traditional knowledges in collaborative ways to codevelop evidence-based models of integrative care accessible to the members of these very same communities. Going forward, health systems could consider Indigenous and other traditional healers or spiritual guides as stakeholders in the design, implementation, and evaluation of community-based approaches for safely scaling up access to effective psychedelic treatments.

Predicting U.S. county opioid poisoning mortality from multi-modal social media and psychological self-report data.

Opioid poisoning mortality is a substantial public health crisis in the United States, with opioids involved in approximately 75% of the nearly 1 million drug related deaths since 1999. Research suggests that the epidemic is driven by both over-prescribing and social and psychological determinants such as economic stability, hopelessness, and isolation. Hindering this research is a lack of measurements of these social and psychological constructs at fine-grained spatial and temporal resolutions. To address this issue, we use a multi-modal data set consisting of natural language from Twitter, psychometric self-reports of depression and well-being, and traditional area-based measures of socio-demographics and health-related risk factors. Unlike previous work using social media data, we do not rely on opioid or substance related keywords to track community poisonings. Instead, we leverage a large, open vocabulary of thousands of words in order to fully characterize communities suffering from opioid poisoning, using a sample of 1.5 billion tweets from 6 million U.S. county mapped Twitter users. Results show that Twitter language predicted opioid poisoning mortality better than factors relating to socio-demographics, access to healthcare, physical pain, and psychological well-being. Additionally, risk factors revealed by the Twitter language analysis included negative emotions, discussions of long work hours, and boredom, whereas protective factors included resilience, travel/leisure, and positive emotions, dovetailing with results from the psychometric self-report data. The results show that natural language from public social media can be used as a surveillance tool for both predicting community opioid poisonings and understanding the dynamic social and psychological nature of the epidemic.

Psychedelics, Meaningfulness, and the "Proper Scope" of Medicine: Continuing the Conversation.

Psychedelics such as psilocybin reliably produce significantly altered states of consciousness with a variety of subjectively experienced effects. These include certain changes to perception, cognition, and affect,1 which we refer to here as the acute subjective effects of psychedelics. In recent years, psychedelics such as psilocybin have also shown considerable promise as therapeutic agents when combined with talk therapy, for example, in the treatment of major depression or substance use disorder.2 However, it is currently unclear whether the aforementioned acute subjective effects are necessary to bring about the observed therapeutic effects of psilocybin and other psychedelics. This uncertainty has sparked a lively-though still largely hypothetical-debate on whether psychedelics without subjective effects ("nonsubjective psychedelics" or "non-hallucinogenic psychedelics") could still have the same therapeutic impact, or whether the acute subjective effects are in fact necessary for this impact to be fully realized.3,4,5.

Attenuation of psilocybin mushroom effects during and after SSRI/SNRI antidepressant use.

BACKGROUND: Psilocybin is being studied for depression, but little is known about how it interacts with common antidepressants. Limited data suggest that psilocybin's effects may be diminished by serotonergic antidepressants acutely and even after a medication washout period. AIMS: To learn the extent to which antidepressants may diminish the effects of psilocybin-containing mushrooms both concurrently and after discontinuation of antidepressants. METHODS: Online retrospective survey of individuals with use of psilocybin mushrooms (1) with an antidepressant and/or (2) within 2 years of discontinuing an antidepressant. Participants who took mushrooms with an antidepressant and either took the same dose pre-antidepressant or took the same dose with other people not on antidepressant reported the strength of drug effects relative to their expectation. Participants who took mushrooms following discontinuation of an antidepressant also reported the presence of weakened effects. RESULTS: In reports (n = 611) of taking mushrooms with an antidepressant, probabilities [95% CI] of weaker than expected drug effects were 0.47 [0.41-0.54] (selective serotonergic reuptake inhibitors, SSRIs), 0.55 [0.44-0.67] (serotonin norepinephrine reuptake inhibitors, SNRIs) and 0.29 [0.2-0.39] (bupropion). Following SSRI/SNRI discontinuation (n = 1,542 reports), the probability of reduced drug effects was not significantly different from the earliest post-discontinuation timepoint (within 1 week) until 3-6 months, probability = 0.3 [0.20-0.46], p = 0.001. A sensitivity analysis found that removing responses involving fluoxetine, which has an especially long half-life, did not significantly alter this result. CONCLUSIONS: SSRI/SNRIs appear to weaken psilocybin drug effects relative to a non-serotonergic antidepressant. This dampening effect may last as long as 3 months following antidepressant discontinuation.