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Recent clinical trials have found that the serotonergic psychedelic psilocybin effectively alleviates anxiodepressive symptoms in patients with life-threatening illnesses when given in a supportive environment. These outcomes prompted Canada to establish legal pathways for therapeutic access to psilocybin, coupled with psychological support. Despite over one-hundred Canadians receiving compassionate access since 2020, there has been little examination of these real-world patients. We conducted a prospective longitudinal survey which focused on Canadians who were granted Section 56 exemptions for legal psilocybin-assisted psychotherapy. Surveys assessing various symptom dimensions were conducted at baseline, two weeks following the session (endpoint), and optionally one day post-session. Participant characteristics were examined using descriptive statistics, and paired sample t-tests were used to quantify changes from baseline to the two-week post-treatment endpoint. Eight participants with Section 56 exemptions (four females, Mage = 52.3 years), all with cancer diagnoses, fully completed baseline and endpoint surveys. Significant improvements in anxiety and depression symptoms, pain, fear of COVID-19, quality of life, and spiritual well-being were observed. Attitudes towards death, medical assistance in dying, and desire for hastened death remained unchanged. While most participants found the psilocybin sessions highly meaningful, if challenging, one reported a substantial decrease in well-being due to the experience. These preliminary data are amongst the first to suggest that psilocybin-assisted psychotherapy can produce psychiatric benefits in real-world patients akin to those observed in clinical trials. Limited enrollment and individual reports of negative experiences indicate the need for formal real-world evaluation programs to surveil the ongoing expansion of legal access to psychedelics.

Do psychedelics affect sexual functioning postacutely? Anecdotal and qualitative evidence suggests they do, but this has never been formally tested. While sexual functioning and satisfaction are generally regarded as an important aspect of human wellbeing, sexual dysfunction is a common symptom of mental health disorders. It is also a common side effect of selective serotonin reuptake inhibitors (SSRIs), a first line treatment for depression. The aim of the present paper was to investigate the post-acute effects of psychedelics on self-reported sexual functioning, combining data from two independent studies, one large and naturalistic and the other a smaller but controlled clinical trial. Naturalistic use of psychedelics was associated with improvements in several facets of sexual functioning and satisfaction, including improved pleasure and communication during sex, satisfaction with ones partner and physical appearance. Convergent results were found in a controlled trial of psilocybin therapy versus an SSRI, escitalopram, for depression. In this trial, patients treated with psilocybin reported positive changes in sexual functioning after treatment, while patients treated with escitalopram did not. Despite focusing on different populations and settings, this is the first research study to quantitively investigate the effects of psychedelics on sexual functioning. Results imply a potential positive effect on post-acute sexual functioning and highlight the need for more research on this.

Psilocybin, a serotonergic psychedelic, is being increasingly researched in clinical studies for the treatment of psychiatric disorders. The relatively lengthy duration of oral psilocybins acute effects (4-6 h) may have pragmatic and cost-effectiveness limitations. Here, we explored the effects of intravenous (IV) N,N-Dimethyltryptamine (DMT), a closely related, but faster-acting psychedelic intervention, on mental health outcomes in healthy volunteers. Data is reported from two separate analyses: (1) A comparison of mental health-related variables 1 week after 7, 14, 18, and 20 mg of IV DMT versus IV saline placebo (n = 13) and, (2) A prospective dataset assessing effects before versus 2 weeks after 20 mg of IV DMT (n = 17). Mental health outcomes included measures of depression severity (QIDS-SR16), trait anxiety (STAI-T), Neuroticism (NEO-FFI), wellbeing (WHO-5), meaning in life (MLQ), optimism (LOT-R), and gratitude (GQ-6). In both the prospective and placebo-controlled datasets, significant improvements in scores of depression were found 1-2 weeks after DMT administration. Significant reductions in trait Neuroticism were only found for the placebo-controlled sample. Finally, changes in depression and trait anxiety correlated with acute peak experiences (assessed via Oceanic Boundlessness). While the use of two separate cohorts in pooled analysis limits the generalizability of these correlational findings, these results suggest that DMT may reduce depressive symptomatology by inducing peak experiences. The short half-life of IV DMT and its potential for flexible dosing via controlled infusions makes it an appealing candidate for psychedelic medicine. Further research in clinical samples is needed to corroborate the therapeutic potential of DMT.

As a proposed mediator between stigma-related stressors and negative mental health outcomes, HIV-related shame has been predictive of increased rates of substance use and difficulties adhering to antiretroviral treatment among people with HIV. These downstream manifestations have ultimately impeded progress toward national goals to End the HIV Epidemic, in part due to limited success of conventional psychotherapies in addressing HIV-related shame. In a pilot clinical trial (N = 12), receipt of psilocybin-assisted group therapy was associated with a large pre-post decrease in HIV-related shame as measured by the HIV and Abuse Related Shame Inventory, with a median (IQR) change of - 5.5 (- 6.5, - 3.5) points from baseline to 3-months follow-up (Z = - 2.6, p = 0.009, r = - 0.75). A paradoxical exacerbation of sexual abuse-related shame experienced by two participants following receipt of psilocybin raises critical questions regarding the use of psilocybin therapy among patients with trauma. These preliminary findings carry potential significance for the future of HIV care.

Abstract As a proposed mediator between stigma-related stressors and negative mental health outcomes, HIV-related shame has been predictive of increased rates of substance use and difficulties adhering to antiretroviral treatment among people with HIV. These downstream manifestations have ultimately impeded progress toward national goals to End the HIV Epidemic, in part due to limited success of conventional psychotherapies in addressing HIV-related shame. In a pilot clinical trial (N = 12), receipt of psilocybin-assisted group therapy was associated with a large pre-post decrease in HIV-related shame as measured by the HIV and Abuse Related Shame Inventory, with a median (IQR) change of − 5.5 (− 6.5, − 3.5) points from baseline to 3-months follow-up (Z = − 2.6, p = 0.009, r = − 0.75). A paradoxical exacerbation of sexual abuse-related shame experienced by two participants following receipt of psilocybin raises critical questions regarding the use of psilocybin therapy among patients with trauma. These preliminary findings carry potential significance for the future of HIV care.

Psilocybin and lysergic acid diethylamide (LSD) experiences can range from very positive to highly challenging (e.g., fear, grief, and paranoia). These challenging experiences contribute to hesitancy toward psychedelic-assisted psychotherapy among health care providers and patients. Co-use of 3,4-Methylenedioxy methamphetamine (MDMA) with psilocybin/LSD anecdotally reduces challenging experiences and enhances positive experiences associated with psilocybin/LSD. However, limited research has investigated the acute effects of co-use of MDMA and psilocybin/LSD. In a prospective convenience sample (N = 698) of individuals with plans to use psilocybin/LSD, we examined whether co-use of MDMA with psilocybin/LSD (n = 27) is associated with differences in challenging or positive experiences. Challenging experiences were measured using the Challenging Experiences Questionnaire and positive experiences were measured using the Mystical Experience Questionnaire and single-item measures of self-compassion, compassion, love, and gratitude. Potentially confounding variables were identified and included as covariates. Relative to psilocybin/LSD alone, co-use of psilocybin/LSD with a self-reported low (but not medium-high) dose of MDMA was associated with significantly less intense total challenging experiences, grief, and fear, as well as increased self-compassion, love and gratitude. Co-use of psilocybin/LSD and MDMA was not associated with differences in mystical-type experiences or compassion. Findings suggest co-use of MDMA with psilocybin/LSD may buffer against some aspects of challenging experiences and enhance certain positive experiences. Limitations include use of a convenience sample, small sample size, and non-experimental design. Additional studies (including controlled dose-response studies) that examine the effects and safety of co-administering MDMA with psilocybin/LSD (in healthy controls and clinical samples) are warranted and may assist the development of personalized treatments.

Several phase II studies have demonstrated that psilocybin-assisted therapy shows therapeutic potential across a spectrum of neuropsychiatric conditions, including major depressive disorder (MDD). However, the mechanisms underlying its often persisting beneficial effects remain unclear. Observational research suggests that improvements in psychological flexibility may mediate therapeutic effects. However, no psychedelic trials to date have substantiated this finding in a clinical sample. In an exploratory placebo-controlled, within-subject, fixed-order study, individuals with moderate to severe MDD were administered placebo (n = 19) followed by psilocybin (0.3 mg/kg) (n = 15) 4 weeks later. Dosing sessions were embedded within a manualized psychotherapy that incorporated principles of Acceptance and Commitment Therapy. Depression severity, psychological flexibility, mindfulness, and values-congruent living were measured over a 16-weeks study period. Psychological flexibility, several facets of mindfulness, and values-congruent living significantly improved following psilocybin and were maintained through week 16. Additionally, improvements in psychological flexibility and experiential acceptance were strongly associated with reductions in depression severity following psilocybin. These findings support the theoretical premise of integrating psilocybin treatment with psychotherapeutic platforms that target psychological flexibility and add to emerging evidence that increasing psychological flexibility may be an important putative mechanism of change in psilocybin-assisted therapy for MDD and potentially, other mental health conditions. [ABSTRACT FROM AUTHOR]

Abstract Psychedelic substances induce profound alterations in consciousness. Careful preparation is therefore essential to limit adverse reactions, enhance therapeutic benefits, and maintain user safety. This paper describes the development of a self-directed, digital intervention for psychedelic preparation. Drawing on elements from the UK Medical Research Council (MRC) framework for developing complex interventions, the design was informed by a four-factor model of psychedelic preparedness, using a person-centred approach. Our mixed-methods investigation consisted of two studies. The first involved interviews with 19 participants who had previously attended a ‘high-dose’ psilocybin retreat, systematically exploring their preparation behaviours and perspectives on the proposed intervention. The second study engaged 28 attendees of an ongoing psilocybin retreat in co-design workshops, refining the intervention protocol using insights from the initial interviews. The outcome is a co-produced 21-day digital course (Digital Intervention for Psychedelic Preparation (DIPP)), that is organised into four modules: Knowledge–Expectation, Psychophysical–Readiness, Safety–Planning, and Intention–Preparation. Fundamental components of the course include daily meditation practice, supplementary exercises tied to the weekly modules, and mood tracking. DIPP provides a comprehensive and scalable solution to enhance psychedelic preparedness, aligning with the broader shift towards digital mental health interventions.

In this study, for the first time, we explored a dataset of functional magnetic resonance images collected during focused attention and open monitoring meditation before and after a five-day psilocybin-assisted meditation retreat using a recently established approach, based on the Mapper algorithm from topological data analysis. After generating subject-specific maps for two groups (psilocybin vs. placebo, 18 subjects/group) of experienced meditators, organizational principles were uncovered using graph topological tools, including the optimal transport (OT) distance, a geometrically rich measure of similarity between brain activity patterns. This revealed characteristics of the topology (i.e. shape) in space (i.e. abstract space of voxels) and time dimension of whole-brain activity patterns during different styles of meditation and psilocybin-induced alterations. Most interestingly, we found that (psilocybin-induced) positive derealization, which fosters insightfulness specifically when accompanied by enhanced open-monitoring meditation, was linked to the OT distance between open-monitoring and resting state. Our findings suggest that enhanced meta-awareness through meditation practice in experienced meditators combined with potential psilocybin-induced positive alterations in perception mediate insightfulness. Together, these findings provide a novel perspective on meditation and psychedelics that may reveal potential novel brain markers for positive synergistic effects between mindfulness practices and psilocybin. [ABSTRACT FROM AUTHOR]

Psychedelic substances induce profound alterations in consciousness. Careful preparation is therefore essential to limit adverse reactions, enhance therapeutic benefits, and maintain user safety. This paper describes the development of a self-directed, digital intervention for psychedelic preparation. Drawing on elements from the UK Medical Research Council (MRC) framework for developing complex interventions, the design was informed by a four-factor model of psychedelic preparedness, using a person-centred approach. Our mixed-methods investigation consisted of two studies. The first involved interviews with 19 participants who had previously attended a ‘high-dose’ psilocybin retreat, systematically exploring their preparation behaviours and perspectives on the proposed intervention. The second study engaged 28 attendees of an ongoing psilocybin retreat in co-design workshops, refining the intervention protocol using insights from the initial interviews. The outcome is a co-produced 21-day digital course (Digital Intervention for Psychedelic Preparation (DIPP)), that is organised into four modules: Knowledge–Expectation, Psychophysical–Readiness, Safety–Planning, and Intention–Preparation. Fundamental components of the course include daily meditation practice, supplementary exercises tied to the weekly modules, and mood tracking. DIPP provides a comprehensive and scalable solution to enhance psychedelic preparedness, aligning with the broader shift towards digital mental health interventions. [ABSTRACT FROM AUTHOR]

Research into the use of psilocybin for the treatment of psychiatric disorders is a growing field. Nevertheless, robust brain–behavior relationships linking psilocybin-induced brain changes to subjective drug-induced effects have not been established. Furthermore, it is unclear if the acute neural effects are dependent on individual heterogeneity in baseline characteristics. To address this, we assessed the effects of three oral doses of psilocybin vs. placebo on cerebral blood flow (CBF) using arterial spin labeling in healthy participants (N = 70; n = 31, 0.16 mg/kg; n = 10, 0.2 mg/kg; n = 29, 0.215 mg/kg). First, we quantified psilocybin-induced changes in relative and absolute CBF. Second, in an exploratory analysis, we assessed whether individual baseline characteristics and subjective psychedelic experience are associated with changes in CBF. Psychological and neurobiological baseline characteristics correlated with the psilocybin-induced reduction in relative CBF and the psilocybin-induced subjective experience. Furthermore, the psilocybin-induced subjective experience was associated with acute changes in relative and absolute CBF. The results demonstrated that inter-individual heterogeneity in the neural response to psilocybin is associated with baseline characteristics and shed light on the mechanisms underlying the psychedelic-induced altered state. Overall, these findings help guide the search for biomarkers, paving the way for a personalized medicine approach within the framework of psychedelic-assisted therapy. [ABSTRACT FROM AUTHOR]

Previous research has suggested that classical psychedelics can foster significant and enduring changes in personality traits and subjective wellbeing. Despite the lack of evidence for adverse effects on mental health stemming from psychedelic use, concerns persist regarding the capacity of these substances to modulate information processing and attitudes towards factual data. The aim of the present study was to investigate the propensity for accepting alternative facts and the general treatment of knowledge within a sample of 392 participants, 233 of whom reported at least a single incidence of psychedelic use in their lifetime. To do this, we leveraged step-wise methods of linear modelling investigating effects of demographics, psychiatric conditions and concomitant drug use. Our findings revealed a moderate positive association between psychedelic use and beliefs in alternative facts, as well as the specific belief that facts are politically influenced. However, no links were found for favouring intuition over evidence when confirming facts. Among other investigated drugs, only alcohol was negatively associated with beliefs in alternative facts. Taken together, our results support the link between psychedelic use and non-conformist thinking styles, which can be attributed to the psychological effects of the drugs themselves, but may also mirror a common trait related to unconventional beliefs and illicit substance use. [ABSTRACT FROM AUTHOR]

Recent controversies have arisen regarding claims of uncritical positive regard and hype surrounding psychedelic drugs and their therapeutic potential. Criticisms have included that study designs and reporting styles bias positive over negative outcomes. The present study was motivated by a desire to address this alleged bias by intentionally focusing exclusively on negative outcomes, defined as self-perceived 'negative' psychological responses lasting for at least 72 h after psychedelic use. A strong justification for this selective focus was that it might improve our ability to capture otherwise missed cases of negative response, enabling us to validate their existence and better examine their nature, as well as possible causes, which could inspire risk-mitigation strategies. Via advertisements posted on social media, individuals were recruited who reported experiencing negative psychological responses to psychedelics (defined as classic psychedelics plus MDMA) lasting for greater than 72 h since using. Volunteers were directed to an online questionnaire requiring quantitative and qualitative input. A key second phase of this study involved reviewing all of the submitted cases, identifying the most severe—e.g., where new psychiatric diagnoses were made or pre-existing symptoms made worse post psychedelic-use—and inviting these individuals to participate in a semi-structured interview with two members of our research team, during which participant experiences and backgrounds were examined in greater depth. Based on the content of these interviews, a brief summary of each case was compiled, and an explorative thematic analysis was used to identify salient and consistent themes and infer common causes. 32 individuals fully completed an onboarding questionnaire (56% male, 53% < age 25); 37.5% of completers had a psychiatric diagnosis that emerged after their psychedelic experience, and anxiety symptoms arose or worsened in 87%. Twenty of the seemingly severer cases were invited to be interviewed; of these, 15 accepted an in-depth interview that lasted on average 60 min. This sample was 40% male, mean age = 31 ± 7. Five of the 15 (i.e., 33%) reported receiving new psychiatric diagnoses after psychedelic-use and all fifteen reported the occurrence or worsening of psychiatric symptoms post use, with a predominance of anxiety symptoms (93%). Distilling the content of the interviews suggested the following potential causal factors: unsafe or complex environments during or surrounding the experience, unpleasant acute experiences (classic psychedelics), prior psychological vulnerabilities, high- or unknown drug quantities and young age. The current exploratory findings corroborate the reality of mental health iatrogenesis via psychedelic-use but due to design limitations and sample size, cannot be used to infer on its prevalence. Based on interview reports, we can infer a common, albeit multifaceted, causal mechanism, namely the combining of a pro-plasticity drug—that was often 'over-dosed'—with adverse contextual conditions and/or special psychological vulnerability—either by young age or significant psychiatric history. Results should be interpreted with caution due to the small sample size and selective sample and study focus. [ABSTRACT FROM AUTHOR]

The objective of the current study was to investigate the associations between lifetime classic psychedelic use and cardiometabolic diseases. Using data from the National Survey on Drug Use and Health (2005-2014), the present study examined the associations between lifetime classic psychedelic use and two types of cardiometabolic disease: heart disease and diabetes. Respondents who reported having tried a classic psychedelic at least once in their lifetime had lower odds of heart disease in the past year (adjusted odds ratio (aOR) = 0.77 (0.65-0.92), p = .006) and lower odds of diabetes in the past year (adjusted odds ratio (aOR) = 0.88 (0.78-0.99), p = .036). Classic psychedelic use might be beneficial for cardiometabolic health, but more research is needed to investigate potential causal pathways of classic psychedelics on cardiometabolic diseases.

The COVID-19 pandemic has had a devastating impact on the health and wellbeing of the global population. This paper presents the results of a longitudinal transcultural study that was begun at the peak of the pandemic (in April, 2020). An online survey was used to collect data from English-, Spanish-, and Portuguese-speaking participants. The survey collected information about sociodemographics, lifestyle activities, COVID-19-related circumstances, and drug use (with an emphasis on hallucinogenic drugs), as well as involving psychometric questionnaires. Users of hallucinogenic drugs had higher psychological well-being and lower scores on psychopathology scales, both at baseline and during follow-ups. This difference was larger when users were distinguished by frequency of use, as regular users scored higher on psychological well-being and lower on psychopathology scales. Subjects with more psychological distress had lower scores for all scales of post-traumatic growth, but if they were regular hallucinogens users, they had higher scores for post-traumatic growth. When comparing the results between cultural contexts, heterogeneous results were obtained. There were more English-speaking regular users of hallucinogenic drugs. Further research should analyse the potential role of hallucinogens in large-scale catastrophes, with a special focus on post-traumatic growth. [ABSTRACT FROM AUTHOR]

A renewed interest in the use of psychedelics for treating obsessive compulsive disorder (OCD) has emerged in the last 20 years. But pre-clinical and clinical evidence remain scarce, and little is known about the factor determining the magnitude and persistence of the therapeutic effect. We therefore designed a retrospective online survey to explore, in the general population using psychoactive drugs, their impact on OCD symptoms. We also assessed the attitude of the participants towards the substance in term of frequency of intakes. In a sample of 174 participants, classic psychedelics were reported as the only substances effective at reducing OCD symptoms. In classic psychedelics users, symptoms reduction was associated with the intensity of acute effects, itself correlated to the dose. Reports on the persistence of the therapeutic effect varied from weeks to months, but we could not find any predicting factor. Finally, the occurrence and frequency of subsequent intakes, which seemed to be limited in our sample, were predicted by the magnitude and persistence of the therapeutic effect, respectively. Our observations support the hypothesis of classic psychedelics efficacy in reducing OCD symptoms but a careful evaluation of the persistence of this effect is still needed. [ABSTRACT FROM AUTHOR]

In medical trials, 'blinding' ensures the equal distribution of expectancy effects between treatment arms in theory; however, blinding often fails in practice. We use computational modelling to show how weak blinding, combined with positive treatment expectancy, can lead to an uneven distribution of expectancy effects. We call this 'activated expectancy bias' (AEB) and show that AEB can inflate estimates of treatment effects and create false positive findings. To counteract AEB, we introduce the Correct Guess Rate Curve (CGRC), a statistical tool that can estimate the outcome of a perfectly blinded trial based on data from an imperfectly blinded trial. To demonstrate the impact of AEB and the utility of the CGRC on empirical data, we re-analyzed the 'self-blinding psychedelic microdose trial' dataset. Results suggest that observed placebo-microdose differences are susceptible to AEB and are at risk of being false positive findings, hence, we argue that microdosing can be understood as active placebo. These results highlight the important difference between 'trials with a placebo-control group', i.e., when a placebo control group is formally present, and 'placebo-controlled trials', where patients are genuinely blind. We also present a new blinding integrity assessment tool that is compatible with CGRC and recommend its adoption. [ABSTRACT FROM AUTHOR]

Psychedelic microdosing describes the ingestion of near-threshold perceptible doses of classic psychedelic substances. Anecdotal reports and observational studies suggest that microdosing may promote positive mood and well-being, but recent placebo-controlled studies failed to find compelling evidence for this. The present study collected web-based mental health and related data using a prospective (before, during and after) design. Individuals planning a weekly microdosing regimen completed surveys at strategic timepoints, spanning a core four-week test period. Eighty-one participants completed the primary study endpoint. Results revealed increased self-reported psychological well-being, emotional stability and reductions in state anxiety and depressive symptoms at the four-week primary endpoint, plus increases in psychological resilience, social connectedness, agreeableness, nature relatedness and aspects of psychological flexibility. However, positive expectancy scores at baseline predicted subsequent improvements in well-being, suggestive of a significant placebo response. This study highlights a role for positive expectancy in predicting positive outcomes following psychedelic microdosing and cautions against zealous inferences on its putative therapeutic value.

Psychedelic drugs, including lysergic acid diethylamide (LSD) and other agonists of the serotonin 2A receptor (5HT2A-R), induce drastic changes in subjective experience, and provide a unique opportunity to study the neurobiological basis of consciousness. One of the most notable neurophysiological signatures of psychedelics, increased entropy in spontaneous neural activity, is thought to be of relevance to the psychedelic experience, mediating both acute alterations in consciousness and long-term effects. However, no clear mechanistic explanation for this entropy increase has been put forward so far. We sought to do this here by building upon a recent whole-brain model of serotonergic neuromodulation, to study the entropic effects of 5HT2A-R activation. Our results reproduce the overall entropy increase observed in previous experiments in vivo, providing the first model-based explanation for this phenomenon. We also found that entropy changes were not uniform across the brain: entropy increased in all regions, but the larger effect were localised in visuo-occipital regions. Interestingly, at the whole-brain level, this reconfiguration was not well explained by 5HT2A-R density, but related closely to the topological properties of the brain's anatomical connectivity. These results help us understand the mechanisms underlying the psychedelic state and, more generally, the pharmacological modulation of whole-brain activity. [ABSTRACT FROM AUTHOR]

Considering contradictory findings of previous investigations and growing prevalence of psychological disorders, we investigated association between dietary total fat and omega-3 fatty acids intake with serum brain-derived neurotrophic factor (BDNF) levels, depression, anxiety and psychological distress in Iranian adults. Using a multistage cluster random sampling method, 533 middle-aged adults were included in this cross-sectional study. A validated semi-quantitative 168-item food frequency questionnaire was used to examine dietary intakes. A 12-h fasting blood sample was drawn to measure serum BDNF. Serum BDNF values in the first decile were considered low level. Hospital Anxiety and Depression Scale (HADS) and General Health Questionnaire (GHQ) were used to assess depression, anxiety and psychological distress. A U-shaped relationship between fat intake and prevalence of anxiety and distress was found. The third quartile of fat intake compared to the first quartile was significantly related to 80% decreased odds of depression (OR = 0.20, 95% CI 0.05–0.80), in fully-adjusted model. Participants in the third quartile of fat intake compared to those in the first quartile had significantly 45% lower odds for distress, in the crude model (OR = 0.55, 95% CI 0.33–0.92); however, this association disappeared after considering confounders. There was no significant association between omega-3 fatty acids intake and odds of depression, anxiety or distress. Prevalence of low-BDNF values was higher in participants with depression, as compared to non-depressed subjects (14.9 vs. 9%; P = 0.06). This cross-sectional study illustrated a U-shaped relationship between fat intake and prevalence of anxiety and distress. Moderate intake of fat was related to lower odds of depression. Prevalence of low-BDNF values was slightly higher in subjects with depression compared to non-depressed individuals. [ABSTRACT FROM AUTHOR]

Impairment in social functioning is a common source of morbidity across many mental health disorders, yet there is a dearth of effective and easily implemented interventions to support social functioning. MDMA/ecstasy and classic psychedelics (psilocybin, LSD, peyote, mescaline) represent two potential treatments for impairments in social functioning, as evidence suggests these compounds may be supportive for alleviating social difficulties. Using a nationally representative sample of U.S. adults from the National Survey on Drug Use and Health (2015–2019) (N = 214,505), we used survey-weighted multivariable ordinal and logistic regression to examine the associations between lifetime use of the aforementioned compounds and impairments in social functioning in the past year. Lifetime MDMA/ecstasy use was associated with lowered odds of three of our four social impairment outcomes: difficulty dealing with strangers (aOR 0.92), difficulty participating in social activities (aOR 0.90), and being prevented from participating in social activities (aOR 0.84). Lifetime mescaline use was also associated with lowered odds of difficulty dealing with strangers (aOR 0.85). All other substances either shared no relationship with impairments in social functioning or conferred increased odds of our outcomes. Future experimental studies can assess whether these relationships are causal. [ABSTRACT FROM AUTHOR]

More and more people are under high pressure in modern society, leading to growing mental disorders, such as antenatal depression for pregnant women. Antenatal depression can affect pregnant woman's physical and psychological health and child outcomes, and cause postpartum depression. Therefore, it is essential to detect the antenatal depression of pregnant women early. This study aims to predict pregnant women's antenatal depression and identify factors that may lead to antenatal depression. First, a questionnaire was designed, based on the daily life of pregnant women. The survey was conducted on pregnant women in a hospital, where 5666 pregnant women participated. As the collected data is unbalanced and has high dimensions, we developed a one-class classifier named Stacked Auto Encoder Support Vector Data Description (SAE-SVDD) to distinguish depressed pregnant women from normal ones. To validate the method, SAE-SVDD was firstly applied on three benchmark datasets. The results showed that SAE-SVDD was effective, with its F-scores better than other popular classifiers. For the antenatal depression problem, the F-score of SAE- SVDD was higher than 0.87, demonstrating that the questionnaire is informative and the classification method is successful. Then, by an improved Term Frequency-Inverse Document Frequency (TF-IDF) analysis, the critical factors of antenatal depression were identified as work stress, marital status, husband support, passive smoking, and alcohol consumption. With its generalizability, SAE-SVDD can be applied to analyze other questionnaires. [ABSTRACT FROM AUTHOR]

Suicide is one of the leading causes of death amongst adolescents and decades of research have failed to curb suicide rates within this population. There is thus a need to better understand factors that correlate with adolescent suicidal thoughts and behaviors (STBs). MDMA/ecstasy and classic psychedelics represent two areas for exploration, as use of these substances has been associated with both increased and lowered odds of STBs. Thus, the goal of this study was to test the associations between MDMA/ecstasy and classic psychedelics (psilocybin, peyote, mescaline, LSD) and STBs in a nationally representative sample of U.S. adolescents. We tested these associations in a sample of adolescents aged 12–17 years old from the National Survey on Drug Use and Health (2004–2019) (N = 262,617) using survey-weighted multivariable logistic regression models. Lifetime psilocybin use was associated with lowered odds of lifetime suicidal thinking, planning, and attempts (aOR range 0.77–0.85). Conversely, LSD was associated with increased odds of these same outcomes (aOR range 1.20–1.35). MDMA/ecstasy, peyote, and mescaline did not share associations with STBs. Our study demonstrates that individual classic psychedelics share varying relationships to STBs among adolescents. Future cross-sectional and longitudinal studies are needed to further elucidate the link between classic psychedelic use and STBs in youth. [ABSTRACT FROM AUTHOR]

Although there is research interest to assess attitudes on psychedelics, no validated instrument exists for this purpose. We aimed to develop and examine the psychometric properties of the Attitudes on Psychedelics Questionnaire (APQ) in a sample of the Croatian general population. A cross-sectional, web-based survey among the general population was conducted on 1153 participants (62.1% female, 77.7% with a graduate or high school degree, 15.1% health care workers). We assessed participants' ability to recognize psychedelic substances using a short knowledge test. The APQ consists of 20 items with four sub-scales: Legal Use of Psychedelics, Effects of Psychedelics, Risk Assessment of Psychedelics, and Openness to Psychedelics. This model demonstrated best fit in a confirmatory factor analysis. Total scale reliability was excellent (McDonald's ω = 0.949, 95% CI = 0.944–0.953). A strong correlation with a similar unvalidated measure (r = 0.885, P < 0.001) demonstrated convergent validity. We observed an association between attitudes and knowledge on psychedelics (r = 0.494, P < 0.001). Younger age, male gender, and lower educational status were associated with higher APQ scores. The APQ is valid, reliable, and could be applied in assessing educational interventions, patients' treatment outcomes, and the attitudes of different groups of experts. We encourage further validation of the APQ in English. [ABSTRACT FROM AUTHOR]

Psychedelic compounds have been linked to salutary mental health outcomes in both naturalistic and clinical settings; however, current research on psychedelics suffers from a lack of inclusion and focus on racial and ethnic minorities. Thus, the goal of our study was to assess whether race and ethnicity moderate the associations that naturalistic lifetime MDMA (3,4-Methylenedioxymethamphetamine) use and psilocybin use share with past month psychological distress and past year suicidality (ideation and planning). Using data from the National Survey on Drug Use and Health (NSDUH) (2008–2019) (N = 484,732), we conducted survey-weighted multivariable logistic regression to conduct interaction tests and to assess the associations that MDMA use and psilocybin use share with the aforementioned outcomes for each racial and ethnic group. Race and ethnicity significantly moderated the associations between MDMA and psilocybin use and psychological distress and suicidality. For White participants, MDMA and psilocybin use conferred lowered odds of all distress and suicidality outcomes. For racial and ethnic minority participants, the associations between psychedelic use and suicidality were far fewer. These findings invite further research into the impact of race, ethnicity, and other identity factors (e.g., socioeconomic status, sexual/gender minority status) on the effects of psychedelic substances. [ABSTRACT FROM AUTHOR]

Disruptions in social decision-making are becoming evident in many psychiatric conditions. These are studied using paradigms investigating the psychological mechanisms underlying interpersonal interactions, such as the Ultimatum Game (UG). Rejection behaviour in the UG represents altruistic punishment - the costly punishment of norm violators - but the mechanisms underlying it require clarification. To investigate the psychopharmacology of UG behaviour, we carried out two studies with healthy participants, employing serotonergic agonists: psilocybin (open-label, within-participant design, N = 19) and 3,4-methylenedioxymethamphetamine (MDMA; placebo-controlled, double-blind, crossover design, N = 20). We found that both MDMA and psilocybin reduced rejection of unfair offers (odds ratio: 0.57 and 0.42, respectively). The reduction in rejection rate following MDMA was associated with increased prosociality (R2 = 0.26, p = 0.025). In the MDMA study, we investigated third-party decision-making and proposer behaviour. MDMA did not reduce rejection in the third-party condition, but produced an increase in the amount offered to others (Cohen's d = 0.82). We argue that these compounds altered participants' conceptualisation of 'social reward', placing more emphasis on the direct relationship with interacting partners. With these compounds showing efficacy in drug-assisted psychotherapy, these studies are an important step in the further characterisation of their psychological effects.

Psilocybin microdosing involves repeated self-administration of mushrooms containing psilocybin at doses small enough to not impact regular functioning. Microdose practices are diverse and include combining psilocybin with substances such as lion's mane mushrooms (Hericium erinaceus; HE) and niacin (vitamin-B3). Public uptake of microdosing has outpaced evidence, mandating further prospective research. Using a naturalistic, observational design, we followed psilocybin microdosers (n = 953) and non-microdosing comparators (n = 180) for approximately 30 days and identified small- to medium-sized improvements in mood and mental health that were generally consistent across gender, age and presence of mental health concerns, as we all as improvements in psychomotor performance that were specific to older adults. Supplementary analyses indicated that combining psilocybin with HE and B3 did not impact changes in mood and mental health. However, among older microdosers combining psilocybin, HE and B3 was associated with psychomotor improvements relative to psilocybin alone and psilocybin and HE. Our findings of mood and mental health improvements associated with psilocybin microdosing add to previous studies of psychedelic microdosing by using a comparator group and by examining the consistency of effects across age, gender, and mental health. Findings regarding the combination of psilocybin, HE and B3 are novel and highlight the need for further research to confirm and elucidate these apparent effects. [ABSTRACT FROM AUTHOR]

Psilocybin is a hallucinogenic compound that is showing promise in the ability to treat neurological conditions such as depression and post-traumatic stress disorder. There have been several investigations into the neural correlates of psilocybin administration using non-invasive methods, however, there has yet to be an invasive study of the mechanism of action in awake rodents. Using multi-unit extracellular recordings, we recorded local field potential and spiking activity from populations of neurons in the anterior cingulate cortex of awake mice during the administration of psilocybin (2 mg/kg). The power of low frequency bands in the local field potential was found to significantly decrease in response to psilocybin administration, whilst gamma band activity trended towards an increase. The population firing rate was found to increase overall, with just under half of individual neurons showing a significant increase. Psilocybin significantly decreased the level of phase modulation of cells with each neural frequency band except high-gamma oscillations, consistent with a desynchronization of cortical populations. Furthermore, bursting behavior was altered in a subset of cells, with both positive and negative changes in the rate of bursting. Neurons that increased their burst firing following psilocybin administration were highly likely to transition from a phase-modulated to a phase unmodulated state. Taken together, psilocybin reduces low frequency oscillatory power, increases overall firing rates and desynchronizes local neural activity. These findings are consistent with dissolution of the default mode network under psilocybin, and may be indicative of disruption of top-down processing in the acute psychedelic state. [ABSTRACT FROM AUTHOR]

Psilocybin with psychological support is showing promise as a treatment model in psychiatry but its therapeutic mechanisms are poorly understood. Here, cerebral blood flow (CBF) and blood oxygen-level dependent (BOLD) resting-state functional connectivity (RSFC) were measured with functional magnetic resonance imaging (fMRI) before and after treatment with psilocybin (serotonin agonist) for treatment-resistant depression (TRD). Quality pre and post treatment fMRI data were collected from 16 of 19 patients. Decreased depressive symptoms were observed in all 19 patients at 1-week post-treatment and 47% met criteria for response at 5 weeks. Whole-brain analyses revealed post-treatment decreases in CBF in the temporal cortex, including the amygdala. Decreased amygdala CBF correlated with reduced depressive symptoms. Focusing on a priori selected circuitry for RSFC analyses, increased RSFC was observed within the default-mode network (DMN) post-treatment. Increased ventromedial prefrontal cortex-bilateral inferior lateral parietal cortex RSFC was predictive of treatment response at 5-weeks, as was decreased parahippocampal-prefrontal cortex RSFC. These data fill an important knowledge gap regarding the post-treatment brain effects of psilocybin, and are the first in depressed patients. The post-treatment brain changes are different to previously observed acute effects of psilocybin and other 'psychedelics' yet were related to clinical outcomes. A 'reset' therapeutic mechanism is proposed.

Psilocybin has been shown to be a powerful, long-lasting antidepressant in human clinical trials and in rodent models. Although rodents have commonly been used to model psychiatric disorders, Drosophila have neurotransmitter systems similar to mammals and many comparable brain structures involved in similar behaviors. The forced swim test (FST), which has been used extensively to evaluate compounds for antidepressant efficacy, has recently been adapted for Drosophila. The fly FST has potential to be a cost-effective, high-throughput assay for evaluating potential antidepressants. For this study we pharmacologically validated the fly FST using methamphetamine, DL-α-methyltyrosine, and the antidepressant citalopram. While methamphetamine and DL-α-methyltyrosine altered overall locomotor activity in the Drosophila Activity Monitor System (DAMS), they had no significant impact on measures of immobility in the FST. Conversely, chronic citalopram decreased measures of immobility in the FST in both sexes without increasing DAMS activity. We used the validated FST to evaluate the antidepressant-like effects of high (3.5 mM) and low (0.03 mM) doses of psilocybin. Both doses of psilocybin significantly reduced measures of immobility in male flies, but not females. 0.03 mM had an effect size comparable to chronic citalopram, and 3.5 mM had an effect size approximately twice that of chronic citalopram. [ABSTRACT FROM AUTHOR]

With a growing body of research highlighting the therapeutic potential of experiential phenomenology which diminishes egoic identity and increases one's sense of connectedness, there is significant interest in how to elicit such 'self-transcendent experiences' (STEs) in laboratory contexts. Psychedelic drugs (YDs) have proven particularly effective in this respect, producing subjective phenomenology which reliably elicits intense STEs. With virtual reality (VR) emerging as a powerful tool for constructing new perceptual environments, we describe a VR framework called 'Isness-distributed' (Isness-D) which harnesses the unique affordances of distributed multi-person VR to blur conventional self-other boundaries. Within Isness-D, groups of participants co-habit a shared virtual space, collectively experiencing their bodies as luminous energetic essences with diffuse spatial boundaries. It enables moments of 'energetic coalescence', a new class of embodied intersubjective experience where bodies can fluidly merge, enabling participants to include multiple others within their self-representation. To evaluate Isness-D, we adopted a citizen science approach, coordinating an international network of Isness-D 'nodes'. We analyzed the results (N = 58) using 4 different self-report scales previously applied to analyze subjective YD phenomenology (the inclusion of community in self scale, ego-dissolution inventory, communitas scale, and the MEQ30 mystical experience questionnaire). Despite the complexities associated with a distributed experiment like this, the Isness-D scores on all 4 scales were statistically indistinguishable from recently published YD studies, demonstrating that distributed VR can be used to design intersubjective STEs where people dissolve their sense of self in the connection to others. [ABSTRACT FROM AUTHOR]

Opioid use disorder (OUD) is a major source of morbidity and mortality in the U.S. and there is a pressing need to identify additional treatments for the disorder. Classic psychedelics (psilocybin, peyote, mescaline, LSD) have been linked to the alleviation of various substance use disorders and may hold promise as potential treatments for OUD. The aim of this study was to assess whether the aforementioned classic psychedelic substances conferred lowered odds of OUD. Furthermore, this study aimed to replicate and extend findings from Pisano et al. (2017) who found classic psychedelic use to be linked to lowered odds of OUD in a nationally representative sample. We used recent data from the National Survey on Drug Use and Health (2015–2019) (N = 214,505) and multivariable logistic regression to test whether lifetime use (yes/no) of classic psychedelics was associated with lowered odds of OUD. Lifetime psilocybin use was associated with lowered odds of OUD (aOR: 0.70; 95% CI [0.60, 0.83]). No other substances, including other classic psychedelics, were associated with lowered odds of OUD. Additionally, sensitivity analyses revealed psilocybin use to be associated with lowered odds of seven of the 11 DSM-IV criteria for OUD (aOR range: 0.66–0.83). Future clinical trials and longitudinal studies are needed to determine whether these associations are causal. [ABSTRACT FROM AUTHOR]

What is the level of consciousness of the psychedelic state? Empirically, measures of neural signal diversity such as entropy and Lempel-Ziv (LZ) complexity score higher for wakeful rest than for states with lower conscious level like propofol-induced anesthesia. Here we compute these measures for spontaneous magnetoencephalographic (MEG) signals from humans during altered states of consciousness induced by three psychedelic substances: psilocybin, ketamine and LSD. For all three, we find reliably higher spontaneous signal diversity, even when controlling for spectral changes. This increase is most pronounced for the single-channel LZ complexity measure, and hence for temporal, as opposed to spatial, signal diversity. We also uncover selective correlations between changes in signal diversity and phenomenological reports of the intensity of psychedelic experience. This is the first time that these measures have been applied to the psychedelic state and, crucially, that they have yielded values exceeding those of normal waking consciousness. These findings suggest that the sustained occurrence of psychedelic phenomenology constitutes an elevated level of consciousness - as measured by neural signal diversity.

The original article can be found online at https://doi.org/10.1038/s41598-024-55726-x.Correction to: ScientificReportshttps://doi.org/10.1038/s41598-024-55726-x, published online 26 March 2024The original version of this Article contained an error in the name of author Berit Singer which was incorrectly given as Singer Berit.The original Article has been corrected.By Berit Singer; Daniel Meling; Matthias Hirsch-Hoffmann; Lars Michels; Michael Kometer; Lukasz Smigielski; Dario Dornbierer; Erich Seifritz; Franz X. Vollenweider and Milan ScheideggerReported by Author; Author; Author; Author; Author; Author; Author; Author; Author; Author [Extracted from the article]

Cocaine Use Disorder (CUD) is a significant public health problem associated with elevated morbidity and mortality within the United States. Current behavioral treatments have limited efficacy and there are currently no FDA approved pharmacological treatments for CUD. Classic psychedelics might be associated with lowered odds of substance misuse and may effectively treat various forms of addiction. Thus, the goal of this study is to assess protective associations that lifetime use of classic psychedelics may share with CUD within a nationally representative sample of the U.S. We used data from The National Survey on Drug Use and Health (NSDUH) (2015–2019) and conducted survey-weighted multivariable logistic regression to test whether each of four classic psychedelics (peyote, mescaline, psilocybin, LSD) conferred lowered odds of CUD and its related 11 sub-criteria. Participants were 214,505 adults in the NSDUH (2015–2019) aged 18 and older. Peyote conferred lowered odds of CUD, reducing the odds of CUD by over 50% (aOR: 0.47). All other substances (including other classic psychedelics) either shared no association to CUD or conferred increased odds of CUD. Furthermore, sensitivity analyses revealed peyote to confer sharply lowered odds of the majority (seven of 11) of CUD criteria as well (aOR range: 0.26–0.47). Peyote use is associated with lowered odds of CUD. Future inquiries into third variable factors (i.e., demographic/personality profiles of individuals who use peyote, motivational/contextual factors surrounding peyote use) that may underlie our observed associations may reveal protective factors that can inform treatment development for CUD. Additionally, future longitudinal studies can shed further light on whether there is a temporal link between peyote use and lowered odds of CUD. [ABSTRACT FROM AUTHOR]

Can the use of psychedelic drugs induce lasting changes in metaphysical beliefs? While it is popularly believed that they can, this question has never been formally tested. Here we exploited a large sample derived from prospective online surveying to determine whether and how beliefs concerning the nature of reality, consciousness, and free-will, change after psychedelic use. Results revealed significant shifts away from 'physicalist' or 'materialist' views, and towards panpsychism and fatalism, post use. With the exception of fatalism, these changes endured for at least 6 months, and were positively correlated with the extent of past psychedelic-use and improved mental-health outcomes. Path modelling suggested that the belief-shifts were moderated by impressionability at baseline and mediated by perceived emotional synchrony with others during the psychedelic experience. The observed belief-shifts post-psychedelic-use were consolidated by data from an independent controlled clinical trial. Together, these findings imply that psychedelic-use may causally influence metaphysical beliefs—shifting them away from 'hard materialism'. We discuss whether these apparent effects are contextually independent. [ABSTRACT FROM AUTHOR]

The use of psychedelic substances at sub-sensorium 'microdoses', has gained popular academic interest for reported positive effects on wellness and cognition. The present study describes microdosing practices, motivations and mental health among a sample of self-selected microdosers (n = 4050) and non-microdosers (n = 4653) via a mobile application. Psilocybin was the most commonly used microdose substances in our sample (85%) and we identified diverse microdose practices with regard to dosage, frequency, and the practice of stacking which involves combining psilocybin with non-psychedelic substances such as Lion's Mane mushrooms, chocolate, and niacin. Microdosers were generally similar to non-microdosing controls with regard to demographics, but were more likely to report a history of mental health concerns. Among individuals reporting mental health concerns, microdosers exhibited lower levels of depression, anxiety, and stress across gender. Health and wellness-related motives were the most prominent motives across microdosers in general, and were more prominent among females and among individuals who reported mental health concerns. Our results indicate health and wellness motives and perceived mental health benefits among microdosers, and highlight the need for further research into the mental health consequences of microdosing including studies with rigorous longitudinal designs. [ABSTRACT FROM AUTHOR]

In this study, for the first time, we explored a dataset of functional magnetic resonance images collected during focused attention and open monitoring meditation before and after a five-day psilocybin-assisted meditation retreat using a recently established approach, based on the Mapper algorithm from topological data analysis. After generating subject-specific maps for two groups (psilocybin vs. placebo, 18 subjects/group) of experienced meditators, organizational principles were uncovered using graph topological tools, including the optimal transport (OT) distance, a geometrically rich measure of similarity between brain activity patterns. This revealed characteristics of the topology (i.e. shape) in space (i.e. abstract space of voxels) and time dimension of whole-brain activity patterns during different styles of meditation and psilocybin-induced alterations. Most interestingly, we found that (psilocybin-induced) positive derealization, which fosters insightfulness specifically when accompanied by enhanced open-monitoring meditation, was linked to the OT distance between open-monitoring and resting state. Our findings suggest that enhanced meta-awareness through meditation practice in experienced meditators combined with potential psilocybin-induced positive alterations in perception mediate insightfulness. Together, these findings provide a novel perspective on meditation and psychedelics that may reveal potential novel brain markers for positive synergistic effects between mindfulness practices and psilocybin., (© 2024. The Author(s).)

Preparing participants for psychedelic experiences is crucial for ensuring these experiences are safe and, potentially beneficial. However, there is currently no validated measure to assess the extent to which participants are well-prepared for such experiences. Our study aimed to address this gap by developing, validating, and testing the Psychedelic Preparedness Scale (PPS). Using a novel iterative Delphi-focus group methodology ('DelFo'), followed by qualitative pre-test interviews, we incorporated the perspectives of expert clinicians/researchers and of psychedelic users to generate items for the scale. Psychometric validation of the PPS was carried out in two large online samples of psychedelic users (N = 516; N = 716), and the scale was also administered to a group of participants before and after a 5-7-day psilocybin retreat (N = 46). Exploratory and confirmatory factor analysis identified four factors from the 20-item PPS: Knowledge-Expectations, Intention-Preparation, Psychophysical-Readiness, and Support-Planning. The PPS demonstrated excellent reliability (ω = 0.954) and evidence supporting convergent, divergent and discriminant validity was also obtained. Significant differences between those scoring high and low (on psychedelic preparedness) before the psychedelic experience were found on measures of mental health/wellbeing outcomes assessed after the experience, suggesting that the scale has predictive utility. By prospectively measuring modifiable pre-treatment preparatory behaviours and attitudes using the PPS, it may be possible to determine whether a participant has generated the appropriate mental 'set' and is therefore likely to benefit from a psychedelic experience, or at least, less likely to be harmed., (© 2024. The Author(s).)

Psilocybin is a classic psychedelic compound that may have efficacy for the treatment of mood and substance use disorders. Acute psilocybin effects include reduced negative mood, increased positive mood, and reduced amygdala response to negative affective stimuli. However, no study has investigated the long-term, enduring impact of psilocybin on negative affect and associated brain function. Twelve healthy volunteers (7F/5M) completed an open-label pilot study including assessments 1-day before, 1-week after, and 1-month after receiving a 25 mg/70 kg dose of psilocybin to test the hypothesis that psilocybin administration leads to enduring changes in affect and neural correlates of affect. One-week post-psilocybin, negative affect and amygdala response to facial affect stimuli were reduced, whereas positive affect and dorsal lateral prefrontal and medial orbitofrontal cortex responses to emotionally-conflicting stimuli were increased. One-month post-psilocybin, negative affective and amygdala response to facial affect stimuli returned to baseline levels while positive affect remained elevated, and trait anxiety was reduced. Finally, the number of significant resting-state functional connections across the brain increased from baseline to 1-week and 1-month post-psilocybin. These preliminary findings suggest that psilocybin may increase emotional and brain plasticity, and the reported findings support the hypothesis that negative affect may be a therapeutic target for psilocybin. [ABSTRACT FROM AUTHOR]