Psilocybin Therapy (PT) is being increasingly studied as a psychiatric intervention. Personality relates to mental health and can be used to probe the nature of PT's therapeutic action. In a phase 2, double-blind, randomized, active comparator controlled trial involving patients with moderate-to-severe major depressive disorder, we compared psilocybin with escitalopram, over a core 6-week trial...
Psilocybin therapy for depression has started to show promise, yet the underlying causal mechanisms are not currently known. Here, we leveraged the differential outcome in responders and non-responders to psilocybin (10 and 25 mg, 7 days apart) therapy for depression-to gain new insights into regions and networks implicated in the restoration of healthy brain dynamics. We used large-scale brain...
Integrating independent but converging lines of research on brain function and neurodevelopment across scales, this article proposes that serotonin 2A receptor (5-HT2AR) signalling is an evolutionary and developmental driver and potent modulator of the macroscale functional organization of the human cerebral cortex. A wealth of evidence indicates that the anatomical and functional organization...
Abstract Mystical-like states of consciousness may arise through means such as psychedelic substances, but may also occur unexpectedly during near-death experiences (NDEs). So far, research studies comparing experiences induced by serotonergic psychedelics and NDEs, along with their enduring effects, have employed between-subject designs, limiting direct comparisons. We present results from an...
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...
5-MeO-DMT is a tryptamine being developed as a potential antidepressant that may display a distinct therapeutic mechanism due to its unique pharmacology and subjective effects compared to typical psychedelics. In this article, we parallel the relatively distinct phenomenology and behavioral effects of the acute and post-acute effects of 5-MeO-DMT to those induced by epileptiform activity,...
Abstract Application of complexity measures to neurophysiological time series has seen increased use in recent years to identify neural correlates of global states of consciousness. Lempel-Ziv complexity is currently the de-facto complexity measure used in these investigations. However, by simply counting the number of patterns, this measure theoretically takes its maximum value for data that...
The role of the thalamus in mediating the effects of lysergic acid diethylamide (LSD) was recently proposed in a model of communication and corroborated by imaging studies. However, a detailed analysis of LSD effects on nuclei-resolved thalamocortical connectivity is still missing. Here, in a group of healthy volunteers, we evaluated whether LSD intake alters the thalamocortical coupling in a...
A growing body of work shows that autonomic signals provide a privileged evidence-stream to capture various aspects of subjective and neural states. This work investigates the potential for autonomic markers to track the effects of psychedelics — potent psychoactive drugs with important scientific and clinical value. For this purpose, we introduce a novel Bayesian framework to estimate the...
The non-selective serotonin 2A (5-HT2A) receptor agonist lysergic acid diethylamide (LSD) holds promise as a treatment for some psychiatric disorders. Psychedelic drugs such as LSD have been suggested to have therapeutic actions through their effects on learning. The behavioural effects of LSD in humans, however, remain incompletely understood. Here we examined how LSD affects probabilistic...
N,N-dimethyltryptamine (DMT) is a psychedelic compound that is being studied as a therapeutic option in various psychiatric disorders. Due to its short half-life, continuous infusion of DMT has been proposed to extend the psychedelic experience and potential therapeutic effects. The primary aim of this work was to design an infusion protocol for DMT based on a desired level of psychedelic...
Abstract 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,...
Abstract 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...
Abstract Rationale Therapeutic administration of psychedelics has shown significant potential in historical accounts and recent clinical trials in the treatment of depression and other mood disorders. A recent randomized double-blind phase-IIb study demonstrated the safety and efficacy of COMP360, COMPASS Pathways’ proprietary synthetic formulation of psilocybin, in participants with...
Abstract The human brain is a complex system, whose activity exhibits flexible and continuous reorganisation across space and time. The decomposition of whole-brain recordings into harmonic modes has revealed a repertoire of gradient-like activity patterns associated with distinct brain functions. However, the way these activity patterns are expressed over time with their changes in various...
Psilocybin therapy is receiving attention as a mental health intervention with transdiagnostic potential. In line with psychotherapeutic research, qualitative research has highlighted the role of reductions in experiential avoidance (and increases in connectedness) within psilocybin therapy. However, no quantitative research has examined experiential avoidance as a mechanism underlying...
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...
We conducted a meta-analysis using individual participant data from three, two-dose psilocybin trials for depression (N = 102) with the aim of assessing the risk of symptom worsening. Clinically significant symptom worsening occurred for a minority of participants in the psilocybin and escitalopram conditions (∼10%) and for a majority of participants in the waitlist condition (63.6%). Using...
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Psychedelic-assisted psychotherapy with psilocybin is an emerging therapy with great promise for depression, and modern psychedelic therapy (PT) methods incorporate music as a key element. Music is an effective emotional/hedonic stimulus that could also be useful in assessing changes in emotional responsiveness following PT. Brain responses to music were assessed before and after PT using...
Lysergic acid diethylamide (LSD) is an atypical psychedelic compound that exerts its effects through pleiotropic actions, mainly involving 1A/2A serotoninergic (5-HT) receptor subtypes. However, the mechanisms by which LSD promotes a reorganization of the brain's functional activity and connectivity are still partially unknown. Our study analyzed resting-state functional magnetic resonance...
To understand how pharmacological interventions can exert their powerful effects on brain function, we need to understand how they engage the brain’s rich neurotransmitter landscape. Here, we bridge microscale molecular chemoarchitecture and pharmacologically induced macroscale functional reorganization, by relating the regional distribution of 19 neurotransmitter receptors and transporters...
Psychedelics offer a profound window into the functioning of the human brain and mind through their robust acute effects on perception, subjective experience, and brain activity patterns. In recent work using a receptor-informed network control theory framework, we demonstrated that the serotonergic psychedelics lysergic acid diethylamide (LSD) and psilocybin flatten the brain's control energy...
Background: In a recent clinical trial examining the comparative efficacy of psilocybin therapy (PT) versus escitalopram treatment (ET) for major depressive disorder, 14 of 16 major efficacy outcome measures yielded results that favored PT, but the Quick Inventory of Depressive Symptomatology, Self-Report, 16 items (QIDS-SR 16 ) did not. Aims: The present study aims to (1) rationally and...
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...