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.

Psychedelic resting-state neuroimaging: A review and perspective on balancing replication and novel analyses.

Clinical research into serotonergic psychedelics is expanding rapidly, showing promising efficacy across myriad disorders. Resting-state functional magnetic resonance imaging (rs-fMRI) is a commonly used strategy to identify psychedelic-induced changes in neural pathways in clinical and healthy populations. Here we, a large group of psychedelic imaging researchers, review the 42 research articles published to date, based on the 17 unique studies evaluating psychedelic effects on rs-fMRI, focusing on methodological variation. Prominently, we observe that nearly all studies vary in data processing and analysis methodology, two datasets are the foundation of over half of the published literature, and there is lexical ambiguity in common outcome metric terminology. We offer guidelines for future studies that encourage coherence in the field. Psychedelic rs-fMRI will benefit from the development of novel methods that expand our understanding of the brain mechanisms mediating its intriguing effects; yet, this field is at a crossroads where we must also consider the critical importance of consistency and replicability to effectively converge on stable representations of the neural effects of psychedelics.

Turn on, Tune in, and Drop out: Predictors of Attrition in a Prospective Observational Cohort Study on Psychedelic Use.

BACKGROUND: The resurgence of research and public interest in the positive psychological effects of psychedelics, together with advancements in digital data collection techniques, have brought forth a new type of research design, which involves prospectively gathering large-scale naturalistic data from psychedelic users; that is, before and after the use of a psychedelic compound. A methodological limitation of such studies is their high attrition rate, particularly owing to participants who stop responding after initial study enrollment. Importantly, study dropout can introduce systematic biases that may affect the interpretability of results. OBJECTIVE: Based on a previously collected sample (baseline n=654), here we investigated potential determinants of study attrition in web-based prospective studies on psychedelic use. METHODS: Logistic regression models were used to examine demographic, psychological trait and state, and psychedelic-specific predictors of dropout. Predictors were assessed 1 week before, 1 day after, and 2 weeks after psychedelic use, with attrition being defined as noncompletion of the key endpoint 4 weeks post experience. RESULTS: Predictors of attrition were found among demographic variables including age (ß=0.024; P=.007) and educational levels, as well as personality traits, specifically conscientiousness (ß=-0.079; P=.02) and extraversion (ß=0.082; P=.01). Contrary to prior hypotheses, neither baseline attitudes toward psychedelics nor the intensity of acute challenging experiences were predictive of dropout. CONCLUSIONS: The baseline predictors of attrition identified here are consistent with those reported in longitudinal studies in other scientific disciplines, suggesting their transdisciplinary relevance. Moreover, the lack of an association between attrition and psychedelic advocacy or negative drug experiences in our sample contextualizes concerns about problematic biases in these and related data.

Pivotal mental states.

This paper introduces a new construct, the 'pivotal mental state', which is defined as a hyper-plastic state aiding rapid and deep learning that can mediate psychological transformation. We believe this new construct bears relevance to a broad range of psychological and psychiatric phenomena. We argue that pivotal mental states serve an important evolutionary function, that is, to aid psychological transformation when actual or perceived environmental pressures demand this. We cite evidence that chronic stress and neurotic traits are primers for a pivotal mental state, whereas acute stress can be a trigger. Inspired by research with serotonin 2A receptor agonist psychedelics, we highlight how activity at this particular receptor can robustly and reliably induce pivotal mental states, but we argue that the capacity for pivotal mental states is an inherent property of the human brain itself. Moreover, we hypothesize that serotonergic psychedelics hijack a system that has evolved to mediate rapid and deep learning when its need is sensed. We cite a breadth of evidences linking stress via a variety of inducers, with an upregulated serotonin 2A receptor system (e.g. upregulated availability of and/or binding to the receptor) and acute stress with 5-HT release, which we argue can activate this primed system to induce a pivotal mental state. The pivotal mental state model is multi-level, linking a specific molecular gateway (increased serotonin 2A receptor signaling) with the inception of a hyper-plastic brain and mind state, enhanced rate of associative learning and the potential mediation of a psychological transformation.

The potential synergistic effects between psychedelic administration and nature contact for the improvement of mental health.

Therapeutic psychedelic administration and contact with nature have been associated with the same psychological mechanisms: decreased rumination and negative affect, enhanced psychological connectedness and mindfulness-related capacities, and heightened states of awe and transcendent experiences, all processes linked to improvements in mental health amongst clinical and healthy populations. Nature-based settings can have inherently psychologically soothing properties which may complement all stages of psychedelic therapy (mainly preparation and integration) whilst potentiating increases in nature relatedness, with associated psychological benefits. Maximising enhancement of nature relatedness through therapeutic psychedelic administration may constitute an independent and complementary pathway towards improvements in mental health that can be elicited by psychedelics.

More Realistic Forecasting of Future Life Events After Psilocybin for Treatment-Resistant Depression.

Background: Evidence suggests that classical psychedelics can promote enduring changes in personality, attitudes and optimism, as well as improvements in mental health outcomes. Aim: To investigate the effects of a composite intervention, involving psilocybin, on pessimism biases in patients with treatment-resistant depression (TRD). Methods: Patients with TRD (n = 15) and matched, untreated non-depressed controls (n = 15) performed the Prediction Of Future Life Events (POFLE) task. The POFLE task requires participants to predict the likelihood of certain life events occurring within a 30-day period, after which the actual rate of event occurrence is reported; this gives an index of potential pessimism versus optimism bias. Psilocybin was administered in two oral dosing sessions (10 and 25 mg) one week apart. Main outcome measures were collected at baseline and one week after the second dosing session. Results: Patients showed a significant pessimism bias at baseline [t(14) = -3.260, p = 0.006; 95% CI (-0.16, -0.03), g = 1.1] which was related to the severity of their depressive symptoms (rs = -0.55, p = 0.017). One week after psilocybin treatment, this bias was significantly decreased [t(14) = -2.714, p = 0.017; 95% CI (-0.21, -0.02), g = 0.7] and depressive symptoms were greatly improved [t(14) = 7.900, p < 0.001; 95% CI (16.17, 28.23), g = 1.9]; moreover, the magnitude of change in both variables was significantly correlated (r = -0.57, p = 0.014). Importantly, post treatment, patients became significantly more accurate at predicting the occurrence of future life events [t(14) = 1.857, p = 0.042; 95% CI (-0.01, 0.12), g = 0.6] whereas no such change was observed in the control subjects. Conclusion: These findings suggest that psilocybin with psychological support might correct pessimism biases in TRD, enabling a more positive and accurate outlook.

Experienced drug users assess the relative harms and benefits of drugs: a web-based survey.

A web-based survey was used to consult the opinions of experienced drug users on matters related to drug harms. We identified a rare sample of 93 drug users with personal experience with 11 different illicit drugs that are widely used in the UK. Asked to assess the relative harms of these drugs, they ranked alcohol and tobacco as the most harmful, and three "Class A" drugs (MDMA, LSD, and psilocybin) and one class B (cannabis) were ranked as the four least harmful drugs. When asked to assess the relative potential for benefit of the 11 drugs, MDMA, LSD, psilocybin, and cannabis were ranked in the top four; and when asked why these drugs are beneficial, rather than simply report hedonic properties, they referred to potential therapeutic applications (e.g., as tools to assist psychotherapy). These results provide a useful insight into the opinions of experienced drug users on a subject about which they have a rare and intimate knowledge.