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.

The therapeutic alliance between study participants and intervention facilitators is associated with acute effects and clinical outcomes in a psilocybin-assisted therapy trial for major depressive disorder.

We examined if the therapeutic alliance between study participants and intervention facilitators in a psilocybin-assisted therapy (PAT) trial changed over time and whether there were relationships between alliance, acute psilocybin experiences, and depression outcomes. In a randomized, waiting list-controlled clinical trial for major depressive disorder in adults (N = 24), participants were randomized to an immediate (N = 13) or delayed (N = 11) condition with two oral doses of psilocybin (20mg/70kg and 30mg/70kg). Ratings of therapeutic alliance significantly increased from the final preparation session to one-week post-intervention (p = .03, d = .43). A stronger total alliance at the final preparation session predicted depression scores at 4 weeks (r = -.65, p = .002), 6 months (r = -.47, p = .036), and 12 months (r = -.54, p = .014) post-intervention. A stronger total alliance in the final preparation session was correlated with higher peak ratings of mystical experiences (r = .49, p = .027) and psychological insight (r = .52, p = .040), and peak ratings of mystical experience and psychological insight were correlated with depression scores at 4 weeks (r = -.45, p = .030 for mystical; r = -.75, p < .001 for insight). Stronger total alliance one week after the final psilocybin session predicted depression scores at 4 weeks (r = -.85, p < .001), 3 months (r = -.52, p = .010), 6 months (r = -.77, p < .001), and 12 months (r = -.61, p = .001) post-intervention. These findings highlight the importance of the therapeutic relationship in PAT. Future research should explore therapist and participant characteristics which maximize the therapeutic alliance and evaluate its relationship to treatment outcomes. Trial registration: Registration: Clinicaltrials.gov NCT03181529. https://classic.clinicaltrials.gov/ct2/show/NCT03181529.

Unique effects of sedatives, dissociatives, psychedelics, stimulants, and cannabinoids on episodic memory: A review and reanalysis of acute drug effects on recollection, familiarity, and metamemory.

Despite distinct classes of psychoactive drugs producing putatively unique states of consciousness, there is surprising overlap in terms of their effects on episodic memory and cognition more generally. Episodic memory is supported by multiple subprocesses that have been mostly overlooked in psychopharmacology and could differentiate drug classes. Here, we reanalyzed episodic memory confidence ratings from 10 previously published data sets (28 drug conditions total) using signal detection models to estimate two conscious states involved in episodic memory and one consciously controlled metacognitive process of memory: autonoetic retrieval of specific details (recollection), noetic recognition absent of retrieved details (familiarity), and retrospective introspection of memory decisions (metamemory). Sedatives, dissociatives, psychedelics, stimulants, and cannabinoids had unique patterns of effects on these mnemonic processes dependent on whether they impacted encoding, consolidation, or retrieval (the formation, stabilization, and access to memory traces, respectively). Sedatives at encoding reliably impaired both recollection and familiarity but at consolidation enhanced recollection. Dissociatives and cannabinoids at encoding impaired recollection but less reliably impaired familiarity, and cannabinoids at retrieval increased false recollections. These drug-induced encoding impairments occasionally came with metamemory enhancements, perhaps because of less interstimulus interference. Psychedelics at encoding impaired recollection but tended to enhance familiarity and did not impact metamemory. Stimulants at encoding enhanced metamemory, at consolidation impaired metamemory, and at retrieval enhanced familiarity and metamemory. These findings allude to mechanisms underlying the idiosyncratic phenomena of drugs, such as blackouts from sedatives and presque vu from psychedelics. Finally, these findings converge on a model in which memory quantity and stability influence metamemory. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Double-Blind Comparison of the Two Hallucinogens Dextromethorphan and Psilocybin: Experience-Dependent and Enduring Psychological Effects in Healthy Volunteers.

Rationale: N-methyl-D-aspartate receptor-mediated dissociatives and serotonergic hallucinogens are being increasingly used in therapeutic interventions that involve nonordinary states of consciousness and may represent a unique mental health paradigm wherein pharmacologically induced experiences are conducive to psychological well-being. Objective: The aim of this study was to further understand how the phenomenological and health-promoting effects of high-dose dextromethorphan (DXM) compared to psilocybin in the same participants when administered under experimental conditions that are typical of therapeutic psychedelic trials. Methods: Single, acute oral doses of DXM (400 mg/70 kg), psilocybin (10, 20, 30 mg/70 kg), and inactive placebo were administered under double-blind and psychologically supportive conditions to 20 healthy participants with histories of hallucinogen use. Ratings of personal meaning, spiritual significance, psychological challenge, and psychological insight attributed to acute drug experiences were assessed 7 h (at session end) and 1 week after each drug administration. Persisting psychological effects were assessed 1 week after each drug administration. Results: High-dose DXM and psilocybin produced similar increases over placebo in ratings of drug experience that was predictive of psychological benefit at 1 week, even when expectancy effects were minimized. These effects tended to favor psilocybin in a dose-dependent manner and were limited by poor physical tolerability for DXM. Conclusions: This analysis suggests the utility of exploring clinical applications of dissociatives that occur within the supportive contexts that are characteristic of psychedelic research and that prioritize the optimization of psychologically valuable drug experiences. This study was registered with ClinicalTrials.gov (NCT02033707).

Naturalistic psilocybin use is associated with persisting improvements in mental health and wellbeing: results from a prospective, longitudinal survey.

Introduction: The classic psychedelic psilocybin, found in some mushroom species, has received renewed interest in clinical research, showing potential mental health benefits in preliminary trials. Naturalistic use of psilocybin outside of research settings has increased in recent years, though data on the public health impact of such use remain limited. Methods: This prospective, longitudinal study comprised six sequential automated web-based surveys that collected data from adults planning to take psilocybin outside clinical research: at time of consent, 2 weeks before, the day before, 1-3 days after, 2-4 weeks after, and 2-3 months after psilocybin use. Results: A sample of 2,833 respondents completed all baseline assessments approximately 2 weeks before psilocybin use, 1,182 completed the 2-4 week post-use survey, and 657 completed the final follow-up survey 2-3 months after psilocybin use. Participants were primarily college-educated White men residing in the United States with a prior history of psychedelic use; mean age = 40 years. Participants primarily used dried psilocybin mushrooms (mean dose = 3.1 grams) for "self-exploration" purposes. Prospective longitudinal data collected before and after a planned psilocybin experience on average showed persisting reductions in anxiety, depression, and alcohol misuse, increased cognitive flexibility, emotion regulation, spiritual wellbeing, and extraversion, and reduced neuroticism and burnout after psilocybin use. However, a minority of participants (11% at 2-4 weeks and 7% at 2-3 months) reported persisting negative effects after psilocybin use (e.g., mood fluctuations, depressive symptoms). Discussion: Results from this study, the largest prospective survey of naturalistic psilocybin use to date, support the potential for psilocybin to produce lasting improvements in mental health symptoms and general wellbeing.

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.

Single-Dose Psilocybin Treatment for Major Depressive Disorder: A Randomized Clinical Trial.

Importance: Psilocybin shows promise as a treatment for major depressive disorder (MDD). Objective: To evaluate the magnitude, timing, and durability of antidepressant effects and safety of a single dose of psilocybin in patients with MDD. Design, Setting, and Participants: In this phase 2 trial conducted between December 2019 and June 2022 at 11 research sites in the US, participants were randomized in a 1:1 ratio to receive a single dose of psilocybin vs niacin placebo administered with psychological support. Participants were adults aged 21 to 65 years with a Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition diagnosis of MDD of at least 60 days' duration and moderate or greater symptom severity. Exclusion criteria included history of psychosis or mania, active substance use disorder, and active suicidal ideation with intent. Participants taking psychotropic agents who otherwise met inclusion/exclusion criteria were eligible following medication taper. Primary and secondary outcomes and adverse events (AEs) were assessed at baseline (conducted within 7 days before dosing) and at 2, 8, 15, 29, and 43 days after dosing. Interventions: Interventions were a 25-mg dose of synthetic psilocybin or a 100-mg dose of niacin in identical-appearing capsules, each administered with psychological support. Main Outcomes and Measures: The primary outcome was change in central rater-assessed Montgomery-Asberg Depression Rating Scale (MADRS) score (range, 0-60; higher scores indicate more severe depression) from baseline to day 43. The key secondary outcome measure was change in MADRS score from baseline to day 8. Other secondary outcomes were change in Sheehan Disability Scale score from baseline to day 43 and MADRS-defined sustained response and remission. Participants, study site personnel, study sponsor, outcome assessors (raters), and statisticians were blinded to treatment assignment. Results: A total of 104 participants (mean [SD] age, 41.1 [11.3] years; 52 [50%] women) were randomized (51 to the psilocybin group and 53 to the niacin group). Psilocybin treatment was associated with significantly reduced MADRS scores compared with niacin from baseline to day 43 (mean difference,-12.3 [95% CI, -17.5 to -7.2]; P <.001) and from baseline to day 8 (mean difference, -12.0 [95% CI, -16.6 to -7.4]; P < .001). Psilocybin treatment was also associated with significantly reduced Sheehan Disability Scale scores compared with niacin (mean difference, -2.31 [95% CI, 3.50-1.11]; P < .001) from baseline to day 43. More participants receiving psilocybin had sustained response (but not remission) than those receiving niacin. There were no serious treatment-emergent AEs; however, psilocybin treatment was associated with a higher rate of overall AEs and a higher rate of severe AEs. Conclusions and Relevance: Psilocybin treatment was associated with a clinically significant sustained reduction in depressive symptoms and functional disability, without serious adverse events. These findings add to increasing evidence that psilocybin-when administered with psychological support-may hold promise as a novel intervention for MDD. Trial Registration: ClinicalTrials.gov Identifier: NCT03866174.

Translation and Initial Psychometric Evaluation of Spanish Versions of Three Psychedelic Acute Effects Measures: Mystical, Challenging, and Insight Experiences.

This study translated and tested the psychometric properties of acute psychedelic effects measures among Spanish-speaking people. The Psychological Insight Questionnaire (PIQ), Challenging Experiences Questionnaire (CEQ), and Mystical Experiences Questionnaire (MEQ) were translated before being incorporated into a web-based survey. We recruited native Spanish-speakers (N = 442; Mage = 30.8, SD = 10.9; Latino/Latina = 62%; Hispanic = 91.4%; male = 71.5%) to assess their previous experience with one of two psychedelics (LSD = 58.4%; Psilocybin = 41.6%) and their acute and enduring effects. Confirmatory factor analysis (confirming factor structure based on the English version) revealed a good fit for the MEQ, PIQ and the CEQ. Repeating our analysis in each drug subsample revealed consistency in factor structure for each assessment tool. Construct validity was supported by significant positive associations between the PIQ and MEQ, and between the PIQ and MEQ and changes in cognitive fusion and negative associations between changes in prosocial behaviors. As a signal of predictive validity, persisting effects (PEQ) were strongly related to scores on the MEQ and PIQ. Findings demonstrate that the Spanish versions of these measures can be reliably employed in studies of psychedelic use or administration in Spanish-speaking populations.

Assessing the risk of symptom worsening in psilocybin-assisted therapy for depression: A systematic review and individual participant data meta-analysis.

We conducted a meta-analysis using individual participant data from three, two-dose psilocybin trials for depression (N = 102) with the aim of assessing the risk of symptom worsening. Clinically significant symptom worsening occurred for a minority of participants in the psilocybin and escitalopram conditions (∼10%) and for a majority of participants in the waitlist condition (63.6%). Using data from the two trials with control arms, the psilocybin arm showed a lower likelihood of symptom worsening versus waitlist, and no difference in the likelihood of symptom worsening versus escitalopram. The limitation of a relatively small sample size should be addressed in future studies.

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.

Belief changes associated with psychedelic use.

BACKGROUND: Psychedelic use is anecdotally associated with belief changes, although few studies have tested these claims. AIM: Characterize a broad range of psychedelic occasioned belief changes. SURVEY: A survey was conducted in 2374 respondents who endorsed having had a belief changing psychedelic experience. Participants rated their agreement with belief statements Before and After the psychedelic experience as well as at the time of survey administration. RESULTS: Factor analysis of 45 belief statements revealed five factors: "Dualism," "Paranormal/Spirituality," "Non-mammal consciousness," "Mammal consciousness," and "Superstition." Medium to large effect sizes from Before to After the experience were observed for increases in beliefs in "Dualism" (ß = 0.72), "Paranormal/Spirituality" (ß = 0.90), "Non-mammal consciousness" (ß = 0.72), and "Mammal consciousness" (ß = 0.74). In contrast, negligible changes were observed for "Superstition" (ß = -0.18).). At the individual item level, increases in non-physicalist beliefs included belief in reincarnation, communication with the dead, existence of consciousness after death, telepathy, and consciousness of inanimate natural objects (e.g., rocks). The percentage of participants who identified as a "Believer (e.g., in Ultimate Reality, Higher Power, and/or God, etc.)" increased from 29% Before to 59% After." At both the factor and individual item level, higher ratings of mystical experience were associated with greater changes in beliefs. Belief changes assessed after the experience (an average 8.4 years) remained largely unchanged at the time of survey. CONCLUSIONS: A single psychedelic experience increased a range of non-physicalist beliefs as well as beliefs about consciousness, meaning, and purpose. Further, the magnitude of belief change is associated with qualitative features of the experience.

Clinical Trial Design Challenges and Opportunities for Emerging Treatments for Opioid Use Disorder: A Review.

Importance: Novel treatments for opioid use disorder (OUD) are needed to address both the ongoing opioid epidemic and long-standing barriers to existing OUD treatments that target the endogenous µ-opioid receptor (MOR) system. The goal of this review is to highlight unique clinical trial design considerations for the study of emerging treatments for OUD that address targets beyond the MOR system. In November 2019, the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) public-private partnership with the US Food and Drug Administration sponsored a meeting to discuss the current evidence regarding potential treatments for OUD, including cannabinoids, psychedelics, sedative-hypnotics, and immunotherapeutics, such as vaccines. Observations: Consensus recommendations are presented regarding the most critical elements of trial design for the evaluation of novel OUD treatments, such as: (1) stage of treatment that will be targeted (eg, seeking treatment, early abstinence/detoxification, long-term recovery); (2) role of treatment (adjunctive with or independent of existing OUD treatments); (3) primary outcomes informed by patient preferences that assess opioid use (including changes in patterns of use), treatment retention, and/or global functioning and quality of life; and (4) adverse events, including the potential for opioid-related relapse or overdose, especially if the patient is not simultaneously taking maintenance MOR agonist or antagonist medications. Conclusions and Relevance: Applying the recommendations provided here as well as considering input from people with lived experience in the design phase will accelerate the development, translation, and uptake of effective and safe therapeutics for individuals struggling with OUD.

Subtypes of the psychedelic experience have reproducible and predictable effects on depression and anxiety symptoms.

BACKGROUND: Subjective experiences seem to play an important role in the enduring effects of psychedelic experiences. Although the importance of the subjective experience on the impact of psychedelics is frequently discussed, a more detailed understanding of the subtypes of psychedelic experiences and their associated impacts on mental health has not been well documented. METHODS: In the current study, machine learning cluster analysis was used to derive three subtypes of psychedelic experience in a large (n = 985) cross sectional sample. RESULTS: These subtypes are not only associated with reductions in anxiety and depression symptoms and other markers of psychological wellbeing, but the structure of these subtypes and their subsequent impact on mental health are highly reproducible across multiple psychedelic substances. LIMITATIONS: Data were obtained via retrospective self-report, which does not allow for definitive conclusions about the direction of causation between baseline characteristics of respondents, qualities of subjective experience, and outcomes. CONCLUSIONS: The present analysis suggests that psychedelic experiences, in particular those that are associated with enduring improvements in mental health, may be characterized by reproducible and predictable subtypes of the subjective psychedelic effects. These subtypes appear to be significantly different with respect to the baseline demographic characteristics, baseline measures of mental health, and drug type and dose. These findings also suggest that efforts to increase psychedelic associated personal and mystical insight experiences may be key to maximizing beneficial impact of clinical approaches using this treatment in their patients.

Ethical Issues Regarding Nonsubjective Psychedelics as Standard of Care.

Evidence suggests that psychedelics bring about their therapeutic outcomes in part through the subjective or qualitative effects they engender and how the individual interprets the resulting experiences. However, psychedelics are contraindicated for individuals who have been diagnosed with certain mental illnesses, on the grounds that these subjective effects may be disturbing or otherwise counter-therapeutic. Substantial resources are therefore currently being devoted to creating psychedelic substances that produce many of the same biological changes as psychedelics, but without their characteristic subjective effects. In this article, we consider ethical issues arising from the prospect of such potential "nonsubjective" psychedelics. We are broadly supportive of efforts to produce such substances for both scientific and clinical reasons. However, we argue that such nonsubjective psychedelics should be reserved for those special cases in which the subjective effects of psychedelics are specifically contraindicated, whereas classic psychedelics that affect subjective experience should be considered the default and standard of care. After reviewing evidence regarding the subjective effects of psychedelics, we raise a number of ethical concerns around the prospect of withholding such typically positive, meaningful, and therapeutic experiences from most patients.

Psychedelic-Assisted Therapy for People with Eating Disorders.

PURPOSE OF REVIEW: A growing body of research suggests psychedelic-assisted therapy (PAT) may be safe and effective for a variety of mental health conditions. Among these, eating disorders have been a recent target of interest. This review provides an up-to-date summary of the potential mechanisms and use of PAT in people diagnosed with eating disorders, with a focus on anorexia nervosa. RECENT FINDINGS: Classic psychedelics may have transdiagnostic efficacy through several mechanisms relevant to eating disorder pathology. Interest in, and efforts to increase access to PAT are both high. Early clinical trials are focused on establishing the safety and utility of this treatment in eating disorders, and efficacy remains unclear. High-quality published data to support the use of PAT for people with eating disorders remains lacking. Recent studies however suggest PAT has the potential to augment the efficacy of current interventions for these difficult-to-treat conditions.

Preparing for the Bursting of the Psychedelic Hype Bubble.

This Viewpoint presents impediments to the clinical application of psychedelics created by extreme shifts in public perception while advocating further study and encouraging the dispute of claims not supported by available evidence.

Comparison of psychedelic and near-death or other non-ordinary experiences in changing attitudes about death and dying.

Both psychedelic drug experiences and near-death experiences can occasion changes in perspectives on death and dying, but there have been few direct comparisons of these phenomena. This study directly compared psychedelic occasioned and non-drug experiences which altered individuals' beliefs about death. Individuals who reported an experience that altered their beliefs about death occasioned by either a psychedelic drug or a near-death or other non-ordinary experience completed an online survey. Circumstances of the experience, mystical and near-death subjective features, changes in attitudes about death, and other persisting effects were evaluated. The study sample (n = 3192) included five groups: non-drug near-death or other non-ordinary experiences (n = 933), and drug experiences occasioned by lysergic acid diethylamide (LSD) (n = 904), psilocybin (n = 766), ayahuasca (n = 282), or N,N-dimethyltryptamine (DMT) (n = 307). Analyses of differences in experiences were adjusted statistically for demographic differences between groups. Compared to the psychedelic groups, the non-drug group was more likely to report being unconscious, clinically dead, and that their life was in imminent danger. The groups were remarkably similar in the reported changes in death attitudes attributed to the experience, including a reduced fear of death and high ratings of positive persisting effects and personal meaning, spiritual significance, and psychological insight. Although both psychedelic and non-drug participants showed robust increases on standardized measures of mystical and near-death experiences, these measures were significantly greater in the psychedelic participants. Non-drug participants were more likely to rate their experiences as the single most meaningful of their lives. Comparing across psychedelic substances, ayahuasca and DMT groups tended report stronger and more positive enduring consequences of the experience than the psilocybin and LSD groups, which were largely indistinguishable. These data provide a detailed characterization and comparison of psychedelic occasioned and non-drug experiences that changed attitudes about death and suggest the importance of future prospective psychedelic administration studies.

Psychedelic drug abuse potential assessment research for new drug applications and Controlled Substances Act scheduling.

New medicines containing classic hallucinogenic and entactogenic psychedelic substance are under development for various psychiatric and neurological disorders. Many of these, including psilocybin, lysergic acid diethylamide (LSD), and 3,4-methylenedioxymethamphetamine (MDMA) are Schedule I controlled substances of the United States Controlled Substances Act (US CSA), and similarly controlled globally. The implications of the CSA for research and medicines development, the path to approval of medicines, and their subsequent removal from Schedule I in the US are discussed. This entire process occurs within the framework of the CSA in the US and its counterparts internationally in accordance with international drug control treaties. Abuse potential related research in the US informs the eight factors of the CSA which provide the basis for rescheduling actions that must occur upon approval of a drug that contains a Schedule I substance. Abuse-related research also informs drug product labeling and the risk evaluation and mitigation strategies (REMS) will likely be required for approved medicines. Human abuse potential studies typically employed in CNS drug development may be problematic for substances with strong hallucinogenic effects such as psilocybin, and alternative strategies are discussed. Implications for research, medicinal development, and controlled substance scheduling are presented in the context of the US CSA and FDA requirements with implications for global regulation. We also discuss how abuse-related research can contribute to understanding mechanisms of action and therapeutic effects as well as the totality of the effects of the drugs on the brain, behavior, mood, and the constructs of spirituality and consciousness.

Psilocybin induces spatially constrained alterations in thalamic functional organizaton and connectivity.

BACKGROUND: Classic psychedelics, such as psilocybin and LSD, and other serotonin 2A receptor (5-HT2AR) agonists evoke acute alterations in perception and cognition. Altered thalamocortical connectivity has been hypothesized to underlie these effects, which is supported by some functional MRI (fMRI) studies. These studies have treated the thalamus as a unitary structure, despite known differential 5-HT2AR expression and functional specificity of different intrathalamic nuclei. Independent Component Analysis (ICA) has been previously used to identify reliable group-level functional subdivisions of the thalamus from resting-state fMRI (rsfMRI) data. We build on these efforts with a novel data-maximizing ICA-based approach to examine psilocybin-induced changes in intrathalamic functional organization and thalamocortical connectivity in individual participants. METHODS: Baseline rsfMRI data (n=38) from healthy individuals with a long-term meditation practice was utilized to generate a statistical template of thalamic functional subdivisions. This template was then applied in a novel ICA-based analysis of the acute effects of psilocybin on intra- and extra-thalamic functional organization and connectivity in follow-up scans from a subset of the same individuals (n=18). We examined correlations with subjective reports of drug effect and compared with a previously reported analytic approach (treating the thalamus as a single functional unit). RESULTS: Several intrathalamic components showed significant psilocybin-induced alterations in spatial organization, with effects of psilocybin largely localized to the mediodorsal and pulvinar nuclei. The magnitude of changes in individual participants correlated with reported subjective effects. These components demonstrated predominant decreases in thalamocortical connectivity, largely with visual and default mode networks. Analysis in which the thalamus is treated as a singular unitary structure showed an overall numerical increase in thalamocortical connectivity, consistent with previous literature using this approach, but this increase did not reach statistical significance. CONCLUSIONS: We utilized a novel analytic approach to discover psilocybin-induced changes in intra- and extra-thalamic functional organization and connectivity of intrathalamic nuclei and cortical networks known to express the 5-HT2AR. These changes were not observed using whole-thalamus analyses, suggesting that psilocybin may cause widespread but modest increases in thalamocortical connectivity that are offset by strong focal decreases in functionally relevant intrathalamic nuclei.