Psilocybin-induced changes in cerebral blood flow are associated with acute and baseline inter-individual differences.

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.

Comparing Neural Correlates of Consciousness: From Psychedelics to Hypnosis and Meditation.

BACKGROUND: Pharmacological and nonpharmacological methods of inducing altered states of consciousness (ASCs) are becoming increasingly relevant in the treatment of psychiatric disorders. While comparisons between them are often drawn, to date no study has directly compared their neural correlates. METHODS: To address this knowledge gap, we directly compared 2 pharmacological methods (psilocybin 0.2 mg/kg orally [n = 23] and lysergic acid diethylamide [LSD] 100 µg orally [n = 25]) and 2 nonpharmacological methods (hypnosis [n = 30] and meditation [n = 29]) using resting-state functional connectivity magnetic resonance imaging and assessed the predictive value of the data using a machine learning approach. RESULTS: We found that 1) no network reached significance in all 4 ASC methods; 2) pharmacological and nonpharmacological interventions of inducing ASCs showed distinct connectivity patterns that were predictive at the individual level; 3) hypnosis and meditation showed differences in functional connectivity when compared directly and also drove distinct differences when jointly compared with the pharmacological ASC interventions; and 4) psilocybin and LSD showed no differences in functional connectivity when directly compared with each other, but they did show distinct behavioral-neural relationships. CONCLUSIONS: Overall, these results extend our understanding of the mechanisms of action of ASCs and highlight the importance of exploring how these effects can be leveraged in the treatment of psychiatric disorders.

Corrigendum to 'Single-dose psilocybin-assisted therapy in major depressive disorder: a placebo-controlled, double-blind, randomised clinical trial'.

[This corrects the article DOI: 10.1016/j.eclinm.2022.101809.].

Single-dose psilocybin-assisted therapy in major depressive disorder: A placebo-controlled, double-blind, randomised clinical trial.

Background: Psilocybin has been suggested as a novel, rapid-acting treatment for depression. Two consecutive doses have been shown to markedly decrease symptom severity in an open-label setting or when compared to a waiting list group. To date, to our knowledge, no other trial compared a single, moderate dose of psilocybin to a placebo condition. Methods: In this double-blind, randomised clinical trial, 52 participants diagnosed with major depressive disorder and no unstable somatic conditions were allocated to receive either a single, moderate dose (0.215 mg/kg body weight) of psilocybin or placebo in conjunction with psychological support. MADRS and BDI scores were assessed to estimate depression severity, while changes from baseline to 14 days after the intervention were defined as primary endpoints. The trial took place between April 11th, 2019 and October 12th, 2021 at the psychiatric university hospital in Zürich, Switzerland and was registered with clinicaltrials.gov (NCT03715127). Findings: The psilocybin condition showed an absolute decrease in symptom severity of -13.0 points compared to baseline and were significantly larger than those in the placebo condition (95% CI -15.0 to -1.3; Cohens' d = 0.97; P = 0.0011; MADRS) and -13.2 points (95% CI; -13.4 to -1.3; Cohens' d = 0.67; P = 0.019; BDI) 14 days after the intervention. 14/26 (54%) participants met the MADRS remission criteria in the psilocybin condition. Interpretation: These results suggest that a single, moderate dose of psilocybin significantly reduces depressive symptoms compared to a placebo condition for at least two weeks. No serious adverse events were recorded. Larger, multi-centric trials with longer follow-up periods are needed to inform further optimisation of this novel treatment paradigm. Funding: The study was funded by the Swiss National Science Foundation, Crowdfunding, the Swiss Neuromatrix Foundation, and the Heffter Research Institute.

Psychedelic-Assisted Therapy for Substance Use Disorders and Potential Mechanisms of Action.

Substance use disorders (SUD) represent a significant public health issue with a high need for novel and efficacious treatment options. In light of this high unmet need, recent results reporting beneficial outcomes of psychedelic-assisted therapy in SUD are particularly relevant. However, several questions remain with regard to this treatment approach. The clinical mechanisms of action of psychedelic substances in the treatment of SUD are not well understood. Closing this knowledge gap is critical to inform and optimize the psychotherapeutic embedding of the acute substance administration. In this chapter, we discuss potential mechanisms that have implications on psychotherapeutic approaches including induced neuroplasticity, alterations in brain network connectivity, reward and emotion processing, social connectedness, insight, and mystical experiences. Furthermore, we outline considerations and approaches that leverage these mechanisms in order to optimize the therapeutic embedding by maximizing synergy between substance effects and psychotherapy. Understanding the mechanisms of action, developing psychotherapeutic approaches accordingly, and evaluating their synergistic efficacy in scientific studies will be critical to advance the framework of psychedelic-assisted therapy for addiction, create evidence-based approaches, and achieve the best treatment outcome for patients with SUD.

The Predictive Value of Impulsivity and Risk-Taking Measures for Substance Use in Substance Dependent Offenders.

Impulsivity and risk-taking are known to have an important impact on problematic substance use and criminal behavior. This study examined the predictive value of baseline self-report and behavioral impulsivity and risk-taking measures [Delay Discounting Task (DDT), Balloon Analogue Risk Task (BART) and Behavioral Inhibition, Behavioral Activation Scale (BIS/BAS)] in 12-months follow-up substance use outcomes (e.g., use of alcohol, cannabis and other substances) and criminal recidivism (yes/no). Participants were 213 male offenders with a substance use disorder (SUD) under probation supervision. Bivariate regression analyses showed that BIS and BAS levels were associated (respectively) with the use of alcohol and cannabis. Multiple regression analysis showed that BIS was negatively associated with alcohol use at follow-up, whereas cannabis use at baseline and BAS predicted cannabis use at follow-up. At a trend level, interactions between delay discounting and risk-taking, and interactions between baseline cannabis use and BAS and BART predicted cannabis use at follow-up. Other substance use at follow-up was solely predicted by baseline other substance use. Overall, the findings provide marginal support for the predictive utility of impulsivity and risk-taking in accounting for variability in substance use among offenders with a SUD. This may be partly explained by the fact that only a limited number of psychological factors was assessed in this study. The studied population consists of a severe group, in which relapse into substance use or criminal behavior likely is related to complex, interacting biopsychosocial factors, of which impulsivity measures play a relatively small part.