Longitudinal experiences of Canadians receiving compassionate access to psilocybin-assisted psychotherapy.

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.

Effects of Psychedelics in Older Adults: A Prospective Cohort Study.

OBJECTIVE: Affective symptoms such as anxiety, low mood, and loneliness are prevalent and highly debilitating symptoms among older adults (OA). Serotonergic psychedelics are currently investigated as novel interventions for affective disorders, yet little is known regarding their effects in OA. We investigated the mental health effects and psychological mechanisms of guided psychedelic group experiences in OA and a matched sample of younger adults (YA). METHODS: Using a prospective observational cohort design, we identified 62 OA (age ≥60 years) and 62 matched YA who completed surveys two weeks before, a day, two weeks, four weeks, and six months after a psychedelic group session. Mixed linear regression analyses were used to investigate longitudinal well-being changes, as well as baseline, acute, and post-acute predictors of change. RESULTS: OA showed post-psychedelic well-being improvements similar to matched YA. Among baseline predictors, presence of a lifetime psychiatric diagnosis was associated with greater well-being increases in OA (B = 6.72, p = .016 at the four-week key-endpoint). Compared to YA, acute subjective psychedelic effects were less intense in OA and did not significantly predict prospective well-being changes. However, relational experiences before and after psychedelic sessions emerged as predictors in OA (r(36) = .37,p = 0.025). CONCLUSIONS: Guided psychedelic group sessions enhance well-being in OA in line with prior naturalistic and controlled studies in YA. Interestingly, acute psychedelic effects in OA are attenuated and less predictive of well-being improvements, with relational experiences related to the group setting playing a more prominent role. Our present findings call for further research on the effects of psychedelics in OA.

Long-term benefits to psychological health and well-being after ceremonial use of Ayahuasca in Middle Eastern and North African immigrants and refugees.

Background: Refugees and immigrants can experience complex stressors from the process of immigration that can have lasting and severe long-term mental health consequences. Experiences after ayahuasca ingestion are shown to produce positive effects on psychological wellbeing and mental health, including anecdotal reports of improved symptoms of trauma and related disorders. However, data on the longitudinal health impact of naturalistic ayahuasca use in Middle Eastern and North African (MENA) immigrant and refugee populations is limited. Aims: The current longitudinal online survey study was conducted to gather prospective data on ceremonial ayahuasca use in a group (N = 15) of primarily female MENA immigrants and refugees and to provide further insight into the patterns and outcomes surrounding that use. The study sought to assess self-reported changes in physical and mental health, well-being, and psychological functioning, examine relationships between aspects of individual mindset (e.g., psychedelic preparedness) prior to ayahuasca use and observed outcomes during (e.g., subjective drug effects) and afterwards (i.e., persisting effects), characterize risks and negative experiences, and describe trauma exposure and personal history. Results/Outcomes: Our findings revealed ceremonial use of ayahuasca is associated with significant improvements in mental health, well-being, and psychological functioning, including reductions in depression, anxiety, and shame, and increases in cognitive reappraisal and self-compassion. Most participants reported no lasting adverse effects and experienced notable positive behavioral changes persisting months after ingestion. Conclusion/Interpretation: While preliminary, results suggest naturalistic ayahuasca use might hold therapeutic potential for MENA populations exposed to trauma prior to and during the process of migration.

Psychiatric risks for worsened mental health after psychedelic use.

BACKGROUND: Resurgent psychedelic research has largely supported the safety and efficacy of psychedelic therapy for the treatment of various psychiatric disorders. As psychedelic use and therapy increase in prevalence, so does the importance of understanding associated risks. Cases of prolonged negative psychological responses to psychedelic therapy seem to be rare; however, studies are limited by biases and small sample sizes. The current analytical approach was motivated by the question of whether rare but significant adverse effects have been under-sampled in psychedelic research studies. METHODS: A "bottom margin analysis" approach was taken to focus on negative responders to psychedelic use in a pool of naturalistic, observational prospective studies (N = 807). We define "negative response" by a clinically meaningful decline in a generic index of mental health, that is, one standard error from the mean decrease in psychological well-being 4 weeks post-psychedelic use (vs pre-use baseline). We then assessed whether a history of diagnosed mental illness can predict negative responses. RESULTS: We find that 16% of the cohort falls into the "negative responder" subset. Parsing the sample by self-reported history of psychiatric diagnoses, results revealed a disproportionate prevalence of negative responses among those reporting a prior personality disorder diagnosis (31%). One multivariate regression model indicated a greater than four-fold elevated risk of adverse psychological responses to psychedelics in the personality disorder subsample (b = 1.425, p < 0.05). CONCLUSION: We infer that the presence of a personality disorder may represent an elevated risk for psychedelic use and hypothesize that the importance of psychological support and good therapeutic alliance may be increased in this population.

Improvements in well-being following naturalistic psychedelic use and underlying mechanisms of change in older adults: A prospective cohort study.

Affective symptoms such as anxiety, low mood, and loneliness are prevalent and highly debilitating symptoms among older adults (OA). Serotonergic psychedelics are novel experimental interventions for affective disorders, yet little is known regarding their effects in OA. Using a prospective cohort design, we identified 62 OA (age ≥ 60 years) and 62 matched younger adults (YA) who completed surveys two weeks before, and one day, two weeks, four weeks, and six months after a guided psychedelic group session in a retreat setting. Mixed linear regression analyses revealed significant well-being improvements in OA and YA, amplified in OA with a history of a psychiatric diagnosis. Compared to YA, acute subjective psychedelic effects were attenuated in OA and did not significantly predict well-being changes. However, a psychosocial measure of Communitas emerged as a predictor in OA, suggesting that the relational components in psychedelic group settings may hold particular value for OA.

Brain substates induced by DMT relate to sympathetic output and meaningfulness of the experience.

N,N-Dimethyltryptamine (DMT) is a serotonergic psychedelic, known to rapidly induce short-lasting alterations in conscious experience, characterized by a profound and immersive sense of physical transcendence alongside rich and vivid auditory distortions and visual imagery. Multimodal neuroimaging data paired with dynamic analysis techniques offer a valuable approach for identifying unique signatures of brain activity - and linked autonomic physiology - naturally unfolding during the altered state of consciousness induced by DMT. We leveraged simultaneous fMRI and EKG data acquired in 14 healthy volunteers prior to, during, and after intravenous administration of DMT, and, separately, placebo. fMRI data was preprocessed to derive individual dynamic activity matrices, reflecting the similarity of brain activity in time, and community detection algorithms were applied on these matrices to identify brain activity substates; EKG data was used to derive continuous heart rate. We identified a brain substate occurring immediately after DMT injection, characterized by increased superior temporal lobe activity, and hippocampal and medial parietal deactivations under DMT. Results revealed that hippocampus and medial parietal cortex hypoactivity correlated with scores of meaningfulness of the experience. During this first post-injection substate, increased heart rate under DMT correlated negatively with the meaningfulness of the experience and positively with hippocampus/medial parietal deactivation. These results suggest a chain of influence linking sympathetic regulation to hippocampal and medial parietal deactivations under DMT, which combined, may contribute to positive mental health outcomes related to self-referential processing following psychedelic administration.

The Relationship Between Changes in Mindfulness and Subsequent Changes in Well-Being Following Psychedelic Use: Prospective Cohort Study.

This study demonstrates that changes in mindfulness predict subsequent changes in well-being in a data set including individuals who recently engaged in psychedelic use.

Psychedelics and sexual functioning: a mixed-methods study.

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 one's 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.

Interactions between classic psychedelics and serotonergic antidepressants: Effects on the acute psychedelic subjective experience, well-being and depressive symptoms from a prospective survey study.

BACKGROUND: There is growing evidence for the therapeutic effects of psychedelics. However, it is still uncertain how these drugs interact with serotonergic antidepressants (serotonin reuptake inhibitors (SRIs)). OBJECTIVE: This study explores the interaction between psychedelics and SRIs in terms of therapeutic effects. The objective is to compare acute psychedelic effects and subsequent changes in well-being and depressive symptoms among 'SRI -' individuals (not on psychiatric medication) and 'SRI +' individuals (undergoing SRI treatment). METHODS: Using prospective survey data, the study employs multivariate analysis of covariance (MANCOVA) and linear mixed effect models to analyse subjective differences and changes in well-being and depressive symptoms pre- and post-psychedelic experiences. RESULTS: Results indicate that 'SRI -' participants experience significantly more intense subjective effects compared to 'SRI +' participants (F = 3.200, p = 0.016) in MANCOVA analysis. Further analysis reveals 'SRI -' individuals report stronger mystical (18.2% higher, p = 0.048), challenging (50.9% higher, p = 0.001) and emotional breakthrough experiences (31.9% higher, p = 0.02) than 'SRI +' individuals. No differences are observed in drug-induced visual effects (p = 0.19). Both groups exhibited similar improvements in well-being and depressive symptoms after the psychedelic experience. CONCLUSION: Individuals presumed to be on serotonergic antidepressants during psychedelic use display reduced subjective effects but similar antidepressant effects compared to those not undergoing SRI treatment. Further controlled research is needed to comprehend the interplay between serotonergic antidepressants and psychedelics, illuminating potential therapeutic benefits and limitations in clinical contexts.

Preliminary evidence for the importance of therapeutic alliance in MDMA-assisted psychotherapy for posttraumatic stress disorder.

Background: MDMA-assisted psychotherapy (MDMA-AP) is a combined psychotherapeutic and pharmacologic intervention that shows promise in the treatment of posttraumatic stress disorder (PTSD). Although therapeutic alliance has been established as a key predictor across psychotherapies and is emphasised within MDMA-AP treatment manuals, research has not yet examined the relationship between therapeutic alliance and MDMA-AP treatment outcomes.Objective: Examine whether therapeutic alliance predicts changes in PTSD symptoms following MDMA-AP.Method: Twenty-three individuals with chronic PTSD participated in a MDMA-AP clinical trial that included a randomised (MDMA vs. placebo) and open-label phase. The present analyses focused on participants who were administered MDMA over the course of the randomised and open-label phases (n = 22). Therapeutic alliance was assessed using the Working Alliance Inventory at sessions baseline (pre-session 3) and sessions 4 and 9. PTSD symptoms were assessed using the Clinician Administered PTSD Scale and the Impact of Events Scale-Revised.Results: Controlling for baseline clinician-assessed PTSD severity, therapeutic alliance at sessions 4 and 9 (but not baseline) significantly predicted post-MDMA-AP clinician-assessed PTSD severity. Controlling for baseline self-reported PTSD severity, therapeutic alliance at baseline (although this did not survive correction for multiple comparisons) and sessions 4 and 9 predicted post-MDMA-AP self-reported PTSD severity.Conclusions: The present results provide the first preliminary evidence for the relationship between the therapeutic alliance and treatment outcomes within MDMA-AP for PTSD. These findings highlight the important role of psychotherapy, and common psychotherapeutic factors, within MDMA-AP. Replication in studies with larger and more diverse clinical samples remain necessary.Trial registration: ClinicalTrials.gov identifier: NCT00090064.

Among individuals with chronic posttraumatic stress disorder, therapeutic alliance predicted changes in posttraumatic stress disorder severity following MDMA-assisted psychotherapy.Therapeutic alliance may play a key role in facilitating therapeutic improvement within MDMA-assisted psychotherapy.Further research remains necessary to confirm these preliminary findings and the role of therapeutic alliance in MDMA-assisted psychotherapy.

The ego in psychedelic drug action - ego defenses, ego boundaries, and the therapeutic role of regression.

The ego is one of the most central psychological constructs in psychedelic research and a key factor in psychotherapy, including psychedelic-assisted forms of psychotherapy. Despite its centrality, the ego-construct remains ambiguous in the psychedelic literature. Therefore, we here review the theoretical background of the ego-construct with focus on its psychodynamic conceptualization. We discuss major functions of the ego including ego boundaries, defenses, and synthesis, and evaluate the role of the ego in psychedelic drug action. According to the psycholytic paradigm, psychedelics are capable of inducing regressed states of the ego that are less protected by the ego's usual defensive apparatus. In such states, core early life conflicts may emerge that have led to maladaptive ego patterns. We use the psychodynamic term character in this paper as a potential site of change and rearrangement; character being the chronic and habitual patterns the ego utilizes to adapt to the everyday challenges of life, including a preferred set of defenses. We argue that in order for psychedelic-assisted therapy to successfully induce lasting changes to the ego's habitual patterns, it must psycholytically permeate the characterological core of the habits. The primary working principle of psycholytic therapy therefore is not the state of transient ego regression alone, but rather the regressively favored emotional integration of those early life events that have shaped the foundation, development, and/or rigidification of a person's character - including his or her defense apparatus. Aiming for increased flexibility of habitual ego patterns, the psycholytic approach is generally compatible with other forms of psychedelic-assisted therapy, such as third wave cognitive behavioral approaches.

Co-use of MDMA with psilocybin/LSD may buffer against challenging experiences and enhance positive experiences.

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.

Human brain effects of DMT assessed via EEG-fMRI.

Psychedelics have attracted medical interest, but their effects on human brain function are incompletely understood. In a comprehensive, within-subjects, placebo-controlled design, we acquired multimodal neuroimaging [i.e., EEG-fMRI (electroencephalography-functional MRI)] data to assess the effects of intravenous (IV) N,N-Dimethyltryptamine (DMT) on brain function in 20 healthy volunteers. Simultaneous EEG-fMRI was acquired prior to, during, and after a bolus IV administration of 20 mg DMT, and, separately, placebo. At dosages consistent with the present study, DMT, a serotonin 2A receptor (5-HT2AR) agonist, induces a deeply immersive and radically altered state of consciousness. DMT is thus a useful research tool for probing the neural correlates of conscious experience. Here, fMRI results revealed robust increases in global functional connectivity (GFC), network disintegration and desegregation, and a compression of the principal cortical gradient under DMT. GFC × subjective intensity maps correlated with independent positron emission tomography (PET)-derived 5-HT2AR maps, and both overlapped with meta-analytical data implying human-specific psychological functions. Changes in major EEG-measured neurophysiological properties correlated with specific changes in various fMRI metrics, enriching our understanding of the neural basis of DMT's effects. The present findings advance on previous work by confirming a predominant action of DMT-and likely other 5-HT2AR agonist psychedelics-on the brain's transmodal association pole, i.e., the neurodevelopmentally and evolutionarily recent cortex that is associated with species-specific psychological advancements, and high expression of 5-HT2A receptors.

Among psychedelic-experienced users, only past use of psilocybin reliably predicts nature relatedness.

BACKGROUND: Past research reports a positive relationship between experience with classic serotonergic psychedelics and nature relatedness (NR). However, these studies typically do not distinguish between different psychedelic compounds, which have a unique psychopharmacology and may be used in specific contexts and with different intentions. Likewise, it is not clear whether these findings can be attributed to substance use per se or unrelated variables that differentiate psychedelic users from nonusers. AIMS: The present study was designed to determine the relative degree to which lifetime experience with different psychedelic substances is predictive of self-reported NR among psychedelic-experienced users. METHODS: We conducted a combined reanalysis of five independent datasets (N = 3817). Using standard and regularized regression analyses, we tested the relationship between degree of experience with various psychedelic substances (binary and continuous) and NR, both within a subsample of psychedelic-experienced participants as well as the complete sample including psychedelic-naïve participants. RESULTS/OUTCOMES: Among people experienced with psychedelics, only past use of psilocybin (versus LSD, mescaline, Salvia divinorum, ketamine, and ibogaine) was a reliable predictor of NR and its subdimensions. Weaker, less reliable results were obtained for the pharmacologically similar N,N-dimethyltryptamine (DMT). Results replicate when including psychedelic-naïve participants. In addition, among people exclusively experience with psilocybin, use frequency positively predicted NR. CONCLUSIONS/INTERPRETATION: Results suggest that experience with psilocybin is the only reliable (and strongest) predictor of NR. Future research should focus on psilocybin when investigating effects of psychedelic on NR and determine whether pharmacological attributes or differences in user expectations/use settings are responsible for this observation.

Effects of psilocybin versus escitalopram on rumination and thought suppression in depression.

BACKGROUND: Major depressive disorder is often associated with maladaptive coping strategies, including rumination and thought suppression. AIMS: To assess the comparative effect of the selective serotonin reuptake inhibitor escitalopram, and the serotonergic psychedelic psilocybin (COMP360), on rumination and thought suppression in major depressive disorder. METHOD: Based on data derived from a randomised clinical trial (N = 59), we performed exploratory analyses on the impact of escitalopram versus psilocybin (i.e. condition) on rumination and thought suppression from 1 week before to 6 weeks after treatment inception (i.e. time), using mixed analysis of variance. Condition responder versus non-responder subgroup analyses were also done, using the standard definition of ≥50% symptom reduction. RESULTS: A time×condition interaction was found for rumination (F(1, 56) = 4.58, P = 0.037) and thought suppression (F(1,57) = 5.88, P = 0.019), with post hoc tests revealing significant decreases exclusively in the psilocybin condition. When analysing via response, a significant time×condition×response interaction for thought suppression (F(1,54) = 8.42, P = 0.005) and a significant time×response interaction for rumination (F(1,54) = 23.50, P < 0.001) were evident. Follow-up tests revealed that decreased thought suppression was exclusive to psilocybin responders, whereas rumination decreased in both responder groups. In the psilocybin arm, decreases in rumination and thought suppression correlated with ego dissolution and session-linked psychological insight. CONCLUSIONS: These data provide further evidence on the therapeutic mechanisms of psilocybin and escitalopram in the treatment of depression.

Antidepressant effects of a psychedelic experience in a large prospective naturalistic sample.

BACKGROUND: Over the last two decades, a number of studies have highlighted the potential of psychedelic therapy. However, questions remain to what extend these results translate to naturalistic samples, and how contextual factors and the acute psychedelic experience relate to improvements in affective symptoms following psychedelic experiences outside labs/clinics. The present study sought to address this knowledge gap. AIM: Here, we aimed to investigate changes in anxiety and depression scores before versus after psychedelic experiences in naturalistic contexts, and how various pharmacological, extrapharmacological and experience factors related to outcomes. METHOD: Individuals who planned to undergo a psychedelic experience were enrolled in this online survey study. Depressive symptoms were assessed at baseline and 2 and 4 weeks post-psychedelic experience, with self-rated Quick Inventory of Depressive Symptomatology (QIDS-SR-16) as the primary outcome. To facilitate clinical translation, only participants with depressive symptoms at baseline were included. Sample sizes for the four time points were N = 302, N = 182, N = 155 and N = 109, respectively. RESULTS: Relative to baseline, reductions in depressive symptoms were observed at 2 and 4 weeks. A medicinal motive, previous psychedelic use, drug dose and the type of acute psychedelic experience (i.e. specifically, having an emotional breakthrough) were all significantly associated with changes in self-rated QIDS-SR-16. CONCLUSION: These results lend support to therapeutic potential of psychedelics and highlight the influence of pharmacological and non-pharmacological factors in determining response. Mindful of a potential sample and attrition bias, further controlled and observational longitudinal studies are needed to test the replicability of these findings.

The Watts Connectedness Scale: a new scale for measuring a sense of connectedness to self, others, and world.

RATIONALE: A general feeling of disconnection has been associated with mental and emotional suffering. Improvements to a sense of connectedness to self, others and the wider world have been reported by participants in clinical trials of psychedelic therapy. Such accounts have led us to a definition of the psychological construct of 'connectedness' as 'a state of feeling connected to self, others and the wider world'. Existing tools for measuring connectedness have focused on particular aspects of connectedness, such as 'social connectedness' or 'nature connectedness', which we hypothesise to be different expressions of a common factor of connectedness. Here, we sought to develop a new scale to measure connectedness as a construct with these multiple domains. We hypothesised that (1) our scale would measure three separable subscale factors pertaining to a felt connection to 'self', 'others' and 'world' and (2) improvements in total and subscale WCS scores would correlate with improved mental health outcomes post psychedelic use. OBJECTIVES: To validate and test the 'Watts Connectedness Scale' (WCS). METHODS: Psychometric validation of the WCS was carried out using data from three independent studies. Firstly, we pooled data from two prospective observational online survey studies. The WCS was completed before and after a planned psychedelic experience. The total sample of completers from the online surveys was N = 1226. Exploratory and confirmatory factor analysis were performed, and construct and criterion validity were tested. A third dataset was derived from a double-blind randomised controlled trial (RCT) comparing psilocybin-assisted therapy (n = 27) with 6 weeks of daily escitalopram (n = 25) for major depressive disorder (MDD), where the WCS was completed at baseline and at a 6-week primary endpoint. RESULTS: As hypothesised, factor analysis of all WCS items revealed three main factors with good internal consistency. WCS showed good construct validity. Significant post-psychedelic increases were observed for total connectedness scores (η2 = 0.339, p < 0.0001), as well as on each of its subscales (p < 0.0001). Acute measures of 'mystical experience', 'emotional breakthrough', and 'communitas' correlated positively with post-psychedelic changes in connectedness (r = 0.42, r = 0.38, r = 0.42, respectively, p < 0.0001). In the RCT, psilocybin therapy was associated with greater increases in WCS scores compared with the escitalopram arm (ηp2 = 0.133, p = 0.009). CONCLUSIONS: The WCS is a new 3-dimensional index of felt connectedness that may sensitively measure therapeutically relevant psychological changes post-psychedelic use. We believe that the operational definition of connectedness captured by the WCS may have broad relevance in mental health research.

Validation of the Psychological Insight Scale: A new scale to assess psychological insight following a psychedelic experience.

INTRODUCTION: As their name suggests, 'psychedelic' (mind-revealing) compounds are thought to catalyse processes of psychological insight; however, few satisfactory scales exist to sample this. This study sought to develop a new scale to measure psychological insight after a psychedelic experience: the Psychological Insight Scale (PIS). METHODS: The PIS is a six- to seven-item questionnaire that enquires about psychological insight after a psychedelic experience (PIS-6) and accompanied behavioural changes (PIS item 7). In total, 886 participants took part in a study in which the PIS and other questionnaires were completed in a prospective fashion in relation to a planned psychedelic experience. For validation purposes, data from 279 participants were analysed from a non-specific 'global psychedelic survey' study. RESULTS: Principal components analysis of PIS scores revealed a principal component explaining 73.57% of the variance, which displayed high internal consistency at multiple timepoints throughout the study (average Cronbach's α = 0.94). Criterion validity was confirmed using the global psychedelic survey study, and convergent validity was confirmed via the Therapeutic-Realizations Scale. Furthermore, PIS scores significantly mediated the relationship between emotional breakthrough and long-term well-being. CONCLUSION: The PIS is complementary to current subjective measures used in psychedelic studies, most of which are completed in relation to the acute experience. Insight - as measured by the PIS - was found to be a key mediator of long-term psychological outcomes following a psychedelic experience. Future research may investigate how insight varies throughout a psychedelic process, its underlying neurobiology and how it impacts behaviour and mental health.

Psychedelic experience dose-dependently modulated by cannabis: results of a prospective online survey.

RATIONALE: Classic psychedelics are currently being studied as novel treatments for a range of psychiatric disorders. However, research on how psychedelics interact with other psychoactive substances remains scarce. OBJECTIVES: The current study aimed to explore the subjective effects of psychedelics when used alongside cannabis. METHODS: Participants (n = 321) completed a set of online surveys at 2 time points: 7 days before, and 1 day after a planned experience with a serotonergic psychedelic. The collected data included demographics, environmental factors (so-called setting) and five validated questionnaires: Mystical Experience Questionnaire (MEQ), visual subscales of Altered States of Consciousness Questionnaire (ASC-Vis), Challenging Experience Questionnaire (CEQ), Ego Dissolution Inventory (EDI) and Emotional Breakthrough Inventory (EBI). Participants were grouped according to whether they had reported using no cannabis (n = 195) or low (n = 53), medium (n = 45) or high (n = 28) dose, directly concomitant with the psychedelic. Multivariate analysis of covariance (MANCOVA) and contrasts was used to analyse differences in subjective effects between groups while controlling for potential confounding contextual 'setting' variables. RESULTS: The simultaneous use of cannabis together with classic serotonergic psychedelics was associated with more intense psychedelic experience across a range of measures: a linear relationship was found between dose and MEQ, ASC-Vis and EDI scores, while a quadratic relationship was found for CEQ scores. No relationship was found between the dose of cannabis and the EBI. CONCLUSIONS: Results imply a possible interaction between the cannabis and psychedelic on acute subjective experiences; however, design limitations hamper our ability to draw firm inferences on directions of causality and the clinical implications of any such interactions.

Can pragmatic research, real-world data and digital technologies aid the development of psychedelic medicine?

Favourable regulatory assessments, liberal policy changes, new research centres and substantial commercial investment signal that psychedelic therapy is making a major comeback. Positive findings from modern trials are catalysing developments, but it is questionable whether current confirmatory trials are sufficient for advancing our understanding of safety and best practice. Here we suggest supplementing traditional confirmatory trials with pragmatic trials, real-world data initiatives and digital health solutions to better support the discovery of optimal and personalised treatment protocols and parameters. These recommendations are intended to help support the development of safe, effective and cost-efficient psychedelic therapy, which, given its history, is vulnerable to excesses of hype and regulation.