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Journal articleBaumann S, Carhart-Harris R, Nutt D, et al., 2022,
Evidence for tolerance in psychedelic microdosing from the self-blinding microdose trial
<p>Microdosing is the practice of regularly using very low doses of psychedelic drugs. Anecdotal reports suggest that it may enhance well-being, creativity and cognition. Here, we use data from a self-blinding microdose trial, a large (n=240) placebo-controlled citizen science trial of microdosing to investigate whether tolerance develops during microdosing. We conceptualized tolerance as the relationship between correct microdose guess probability and the number of previous microdoses taken within the trial’s timeframe: if tolerance develops then, correct microdose guess probability should decrease with more microdoses taken. Mixed linear regression models show that correct microdose guess probability decreases with number of microdoses taken (mean±se: -.017±.007; p=.009**), suggesting that tolerance developed. Secondary post-hoc analysis revealed that this tolerance was present with LSD/LSD-analogue microdoses (mean±se: -.026±.007; p&lt;.001**), but not with psilocybin microdoses (mean±se: .013±.014; p=.36). These results suggest that microdosers may need to periodically suspend their microdosing routine to avoid tolerance and that psilocybin may be better suited for long-term microdosing protocols.</p>
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Journal articleSingleton SP, Luppi AI, Carhart-Harris RL, et al., 2022,
Receptor-informed network control theory links LSD and psilocybin to a flattening of the brain's control energy landscape
, NATURE COMMUNICATIONS, Vol: 13- Cite
- Citations: 12
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Journal articleVohryzek J, Cabral J, Lord L-D, et al., 2022,
Brain dynamics predictive of response to psilocybin for treatment-resistant depression
<title>Abstract</title> <p>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 (10mg and 25mg, 7 days apart) therapy for depression - to gain new insights into regions and networks implicated in the restoration of healthy brain dynamics. We used whole-brain modelling to fit the spatiotemporal brain dynamics at rest in both responders and non-responders before treatment. Dynamic sensitivity analysis of systematic perturbation of these models enabled us to identify specific brain regions implicated in a transition from a depressive brain state to a heathy one. Binarizing the sample into treatment responders (> 50% reduction in depressive symptoms) versus non-responders enabled us to identify a subset of regions implicated in this change. Interestingly, these regions correlate with in vivo density maps of serotonin receptors 5-HT<sub>2A</sub> and 5-HT<sub>1A</sub>, which psilocin, the active metabolite of psilocybin, has an appreciable affinity for, and where it acts as a full-to-partial agonist. Serotonergic transmission has long been associated with depression and our findings provide causal mechanistic evidence for the role of brain regions in the recovery from depression via psilocybin.</p>
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Journal articleBarba T, Buehler S, Kettner H, et al., 2022,
Effects of psilocybin versus escitalopram on rumination and thought suppression in depression
, BJPSYCH OPEN, Vol: 8, ISSN: 2056-4724- Author Web Link
- Cite
- Citations: 5
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Journal articleGirn M, Roseman L, Bernhardt B, et al., 2022,
Serotonergic psychedelic drugs LSD and psilocybin reduce the hierarchical differentiation of unimodal and transmodal cortex
, NEUROIMAGE, Vol: 256, ISSN: 1053-8119- Cite
- Citations: 15
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Journal articleLuppi AI, Hansen JY, Adapa R, et al., 2022,
Mapping Pharmacologically-induced Functional Reorganisation onto the Brain’s Neurotransmitter Landscape
<jats:title>Abstract</jats:title><jats:p>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 reorganisation, by relating the regional distribution of 19 neurotransmitter receptors and transporters obtained from Positron Emission Tomography, and the regional changes in functional MRI connectivity induced by 10 different mind-altering drugs: propofol, sevoflurane, ketamine, LSD, psilocybin, DMT, ayahuasca, MDMA, modafinil, and methylphenidate. Our results reveal that psychoactive drugs exert their effects on brain function by engaging multiple neurotransmitter systems. The effects of both anaesthetics and psychedelics on brain function are organised along hierarchical gradients of brain structure and function. Finally, we show that regional co-susceptibility to pharmacological interventions recapitulates co-susceptibility to disorder-induced structural alterations. Collectively, these results highlight rich statistical patterns relating molecular chemoarchitecture and drug-induced reorganisation of the brain’s functional architecture.</jats:p>
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Working paperZeifman R, Spriggs M, Kettner H, et al., 2022,
From Relaxed Beliefs Under Psychedelics (REBUS) to Revised Beliefs After Psychedelics (REBAS): preliminary development of the RElaxed Beliefs Questionnaire (REB-Q)
, Publisher: PsyArXivBackground: The Relaxed Beliefs Under pSychedelics (REBUS) model proposes that serotonergic psychedelics decrease the precision weighting of neurobiologically-encoded beliefs, and offers a unified account of the acute and therapeutic action of psychedelics. Although REBUS has received some neuroscientific support, little research has examined its psychological validity. We conducted a preliminary examination of two psychological assumptions of REBUS: (a) psychedelics foster acute relaxation and post-acute revision of confidence in mental-health-relevant beliefs; (b) this relaxation and revision facilitates positive therapeutic outcomes and is associated with the entropy of EEG signals (an index of neurophysiological mechanisms relevant to REBUS). Method: Healthy individuals (N=11) were administered 1 mg and 25 mg psilocybin 4-weeks apart. Confidence ratings for personally held negative and positive beliefs were obtained before, during, and 4-weeks after dosing sessions. Acute entropy and self-reported subjective experiences were measured, as was well-being (before and 4-weeks after dosing sessions). Results: Confidence in negative self-beliefs decreased following 25 mg psilocybin and not following 1 mg psilocybin. Entropy and subjective effects under 25 mg psilocybin correlated with decreases in negative self-belief confidence (acute and 4-weeks after dosing). Particularly strong evidence was seen for a relationship between decreases in negative self-belief confidence and increases in well-being at 4-weeks. Conclusions: We report the first empirical evidence that the relaxation and revision of negative self-belief confidence mediates positive psychological outcomes; a psychological assumption of REBUS. Replication within larger and clinical samples remains necessary. We also introduce a new measure, the Relaxed BEliefs Questionnaire (REB-Q), for examining the robustness of these preliminary findings and the utility of the REBUS model.
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Journal articleNayak SM, Bari BA, Yaden DB, et al., 2022,
A Bayesian Reanalysis of a Trial of Psilocybin versus Escitalopram for Depression
<p>Objectives: To perform a Bayesian reanalysis of a recent trial of psilocybin (COMP360) versus escitalopram for Major Depressive Disorder (MDD) in order to provide a more informative interpretation of the indeterminate outcome of a previous frequentist analysis.Design: Reanalysis of a two-arm double-blind placebo controlled trial.Participants: Fifty-nine patients with MDD.Interventions: Two doses of psilocybin 25mg and daily oral placebo versus daily escitalopram and 2 doses of psilocybin 1mg, with psychological support for both groups.Outcome measures: Quick Inventory of Depressive Symptomatology–Self-Report (QIDS SR-16), and three other depression scales as secondary outcomes: HAMD-17, MADRS, and BDI-1A.Results: Using Bayes factors and ‘skeptical priors’ which bias estimates towards zero, for the hypothesis that psilocybin is superior by any margin, we found indeterminate evidence for QIDS SR-16, strong evidence for BDI-1A and MADRS, and extremely strong evidence for HAMD-17. For the stronger hypothesis that psilocybin is superior by a ‘clinically meaningful amount’ (using literature defined values of the minimally clinically important difference), we found moderate evidence against it for QIDS SR-16, indeterminate evidence for BDI-1A and MADRS, and moderate evidence supporting it for HAMD-17. Furthermore, across the board we found extremely strong evidence for psilocybin’s non-inferiority versus escitalopram. These findings were robust to prior sensitivity analysis.Conclusions: This Bayesian reanalysis supports the following inferences: 1) that psilocybin did indeed outperform escitalopram in this trial, but not to an extent that was clinically meaningful—-and 2) that psilocybin is almost certainly non-inferior to escitalopram. The present results provide a more precise and nuanced interpretation to previously reported results from this trial, and support the need for further research into the relative efficacy of
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Journal articleCarhart-Harris R, Daws RE, Nutt D, 2022,
A critique of: Skepticism About Recent Evidence that Psilocybin Opens Depressed Minds
<p>This document details an authors' response to a critique of their work entitled: Skepticism About Recent Evidence that Psilocybin Opens Depressed Minds.</p>
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Journal articleDaws R, Timmermann C, Giribaldi B, et al., 2022,
Increased global integration in the brain after psilocybin therapy for depression
, Nature Medicine, Vol: 28, ISSN: 1078-8956Psilocybin therapy shows antidepressant potential, but its therapeutic actions are not well understood. We assessed the sub-acute impact of psilocybin on brain function in two clinical trials of depression. The first was an open-label trial of orally administered psilocybin (10mg and 25mg, 7 days apart) in treatment-resistant depression (TRD). fMRI was recorded at baseline and one day after the 25mg dose. Beck’s depression inventory (BDI) was the primary outcome measure (MR/J00460X/1). The second trial was a double-blind phase 2 randomised control trial (DB-RCT) comparing psilocybin therapy with escitalopram. Major depressive disorder (MDD) patients received either: 2 x 25mg oral psilocybin, 3 weeks apart, plus 6 weeks of daily placebo (‘psilocybin-arm’); or 2 x 1mg oral psilocybin, 3 weeks apart, plus 6 weeks of daily escitalopram [10-20mg] (‘escitalopram-arm’). fMRI wasrecorded at baseline and 3 weeks after the 2nd psilocybin dose (NCT03429075). In both trials, the antidepressant response to psilocybin was rapid, sustained and correlated with decreases in functional MRI (fMRI) brain network modularity, implying that psilocybin’s antidepressant action may depend on a global increase in brainnetwork integration. Network cartography analyses indicated that 5-HT2A receptor rich higher-order functional networks became more functionally inter-connected and flexible post psilocybin. The antidepressant response to escitalopram was milder and no changes in brain network organisation were observed. Consistent efficacy related brain changes, correlating with robust antidepressant effects across two studies, suggest an antidepressant mechanism for psilocybin therapy: Global increases in brain network integration.
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