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Molecular Psychiatry Jun 2024Visual alterations under classic psychedelics can include rich phenomenological accounts of eyes-closed imagery. Preclinical evidence suggests agonism of the 5-HT2A...
Visual alterations under classic psychedelics can include rich phenomenological accounts of eyes-closed imagery. Preclinical evidence suggests agonism of the 5-HT2A receptor may reduce synaptic gain to produce psychedelic-induced imagery. However, this has not been investigated in humans. To infer the directed connectivity changes to visual connectivity underlying psychedelic visual imagery in healthy adults, a double-blind, randomised, placebo-controlled, cross-over study was performed, and dynamic causal modelling was applied to the resting state eyes-closed functional MRI scans of 24 subjects after administration of 0.2 mg/kg of the serotonergic psychedelic drug, psilocybin (magic mushrooms), or placebo. The effective connectivity model included the early visual area, fusiform gyrus, intraparietal sulcus, and inferior frontal gyrus. We observed a pattern of increased self-inhibition of both early visual and higher visual-association regions under psilocybin that was consistent with preclinical findings. We also observed a pattern of reduced inhibition from visual-association regions to earlier visual areas that indicated top-down connectivity is enhanced during visual imagery. The results were analysed with behavioural measures taken immediately after the scans, suggesting psilocybin-induced decreased sensitivity to neural inputs is associated with the perception of eyes-closed visual imagery. The findings inform our basic and clinical understanding of visual perception. They reveal neural mechanisms that, by affecting balance, may increase the impact of top-down feedback connectivity on perception, which could contribute to the visual imagery seen with eyes-closed during psychedelic experiences.
PubMed: 38862674
DOI: 10.1038/s41380-024-02632-3 -
Frontiers in Psychiatry 2024It is important to understand how mental health practitioners view recent findings on psychedelic-assisted psychotherapy (PAP) as there is potential this treatment may...
INTRODUCTION AND AIM
It is important to understand how mental health practitioners view recent findings on psychedelic-assisted psychotherapy (PAP) as there is potential this treatment may be incorporated into clinical practice. The aim of our study was to explore how psychiatrists who are not involved in psychedelic research and who are located in the European region perceive psychedelics and PAP.
METHODS
We conducted online semi-structured interviews with 12 psychiatry specialists and psychiatry trainees from 8 European countries. Data were analyzed using a general inductive approach informed by codebook thematic analysis.
RESULTS
Based on the interviews, we developed four main themes and 14 sub-themes, including (1) Psychedelics hold potential, (2) Psychedelics are dangerous, (3) Future of psychedelics is uncertain, and (4) Psychiatry is ambivalent toward psychedelics.
DISCUSSION
Our respondents-psychiatrists acknowledged the potential of PAP but remained cautious and did not yet perceive its evidence base as robust enough. Education on psychedelics is lacking in medical and psychiatric training and should be improved to facilitate the involvement of mental health experts in decision-making on PAP.
PubMed: 38855648
DOI: 10.3389/fpsyt.2024.1411234 -
BioRxiv : the Preprint Server For... Jun 2024Preclinical and human studies indicate psilocybin may reduce perseverant maladaptive behaviors, including nicotine and alcohol seeking. Such studies in the opioid field...
Preclinical and human studies indicate psilocybin may reduce perseverant maladaptive behaviors, including nicotine and alcohol seeking. Such studies in the opioid field are lacking, though opioids are involved in more >50% of overdose deaths. Psilocybin is an agonist at the serotonin 2A receptor (5-HTR), a well-documented target for modulation of drug seeking, and evidence suggests 5-HTR agonists may dampen motivation for opioids. We sought to investigate the therapeutic efficacy of psilocybin in mediating cessation of opioid use and maintenance of long-lasting abstinence from opioid seeking behavior in a rat model of heroin self-administration (SA). Psilocybin or 5-HTR antagonists ketanserin and volinanserin were administered systemically to rats prior to SA of 0.075 mg/kg/infusion of heroin, or relapse following forced abstinence. Psilocybin did not alter heroin taking, but a single exposure to 3.0 mg/kg psilocybin 4-24 hours prior to a relapse test blunted cue-induced heroin seeking. Conversely, 5-HTR antagonists exacerbated heroin relapse. To begin to elucidate mechanisms of psilocybin, drug-naïve rats received psilocybin and/or ketanserin, and tissue was collected from the prefrontal cortex (PFC), a region critical for drug seeking and responsive to psilocybin, 24 hours later for RNA-sequencing. 3.0 mg/kg psilocybin regulated ~2-fold more genes in the PFC than 1.0 mg/kg, including genes involved in the cytoskeleton and cytokine signaling. Ketanserin blocked >90% of psilocybin-regulated genes, including the IL-17a cytokine receptor, . Psychedelic compounds have reported anti-inflammatory properties, and therefore we performed a gene expression array to measure chemokine/cytokine molecules in the PFC of animals that displayed psilocybin-mediated inhibition of heroin seeking. Psilocybin regulated 4 genes, including , and a subset of genes correlated with relapse behavior. Selective inhibition of PFC IL-17a was sufficient to reduce heroin relapse. We conclude that psilocybin reduces heroin relapse and highlight IL-17a signaling as a potential downstream pathway of psilocybin that also reduces heroin seeking.
PubMed: 38854027
DOI: 10.1101/2024.05.28.596205 -
BioRxiv : the Preprint Server For... May 2024Exploring the intricate relationship between brain's structure and function, and how this affects subjective experience is a fundamental pursuit in neuroscience....
Exploring the intricate relationship between brain's structure and function, and how this affects subjective experience is a fundamental pursuit in neuroscience. Psychedelic substances offer a unique insight into the influences of specific neurotransmitter systems on perception, cognition and consciousness. Specifically, their impact on brain function propagates across the structural connectome - a network of white matter pathways linking different regions. To comprehensively grasp the effects of psychedelic compounds on brain function, we used a theoretically rigorous framework known as connectome harmonic decomposition. This framework provides a robust method to characterize how brain function intricately depends on the organized network structure of the human connectome. We show that the connectome harmonic repertoire under DMT is reshaped in line with other reported psychedelic compounds - psilocybin, LSD and ketamine. Furthermore, we show that the repertoire entropy of connectome harmonics increases under DMT, as with those other psychedelics. Importantly, we demonstrate for the first time that measures of energy spectrum difference and repertoire entropy of connectome harmonics indexes the intensity of subjective experience of the participants in a time-resolved manner reflecting close coupling between connectome harmonics and subjective experience.
PubMed: 38853985
DOI: 10.1101/2024.05.30.596410 -
Journal of Psychiatric Research May 2024Psilocybin-assisted psychotherapy (PAP) is a promising treatment option for depression, with randomized controlled trials (RCTs) providing preliminary support for its... (Review)
Review
BACKGROUND
Psilocybin-assisted psychotherapy (PAP) is a promising treatment option for depression, with randomized controlled trials (RCTs) providing preliminary support for its safety and efficacy. However, there is a lack of consistency across existing treatment protocols and psychotherapeutic approaches. The objective of this review is to summarize and compare current psychotherapy methods of PAP in treating depression and distress in life-threatening illnesses. We sought to comprehensively summarize published psychotherapy protocols from clinical trials to provide insights for future practices.
METHODS
A systematic search of four databases (Embase, MEDLINE, PsycINFO, CINAHL) for data relating to psychotherapy protocols was conducted by two independent reviewers.
RESULTS
In total, our search identified 1869 articles; after removing duplicates, we screened 1107 articles. We included 70 articles in the full-text review and determined that 28 were eligible for the final review. All protocols include sessions before (preparatory) and after (integration) the psychedelic dosing session with supportive monitoring. However, there was substantial variability and inconsistencies in all other aspects of therapy protocols (e.g., duration and number of sessions, model of therapy). Additionally, significant limitations were identified in the frequent need for more clarity in the description of therapeutic approaches.
CONCLUSION
In published clinical trials, PAP has consisted of preparation, supportive dosing, and integration sessions. Beyond this basic framework, significant heterogeneity and lack of clarity were identified in reported psychotherapy protocols, meaning a validated and universally agreed upon protocol for PAP currently does not exist. Future studies should more clearly define and report psychotherapeutic components to identify the safest and most efficacious approaches to PAP.
PubMed: 38850581
DOI: 10.1016/j.jpsychires.2024.05.051 -
PeerJ 2024Psilocybin and related tryptamines have come into the spotlight in recent years as potential therapeutics for depression. Research on the mechanisms of these effects has...
BACKGROUND
Psilocybin and related tryptamines have come into the spotlight in recent years as potential therapeutics for depression. Research on the mechanisms of these effects has historically focused on the direct effects of these drugs on neural processes. However, in addition to such neural effects, alterations in peripheral physiology may also contribute to their therapeutic effects. In particular, substantial support exists for a gut microbiome-mediated pathway for the antidepressant efficacy of other drug classes, but no prior studies have determined the effects of tryptamines on microbiota.
METHODS
To address this gap, in this preliminary study, male Long Evans rats were treated with varying dosages of oral psilocybin (0.2 or 2 mg/kg), norbaeocystin (0.25 or 2.52 mg/kg), or vehicle and their fecal samples were collected 1 week and 3 weeks after exposure for microbiome analysis using integrated 16S ribosomal DNA sequencing to determine gut microbiome composition.
RESULTS
We found that although treatment with neither psilocybin nor norbaeocystin significantly affected overall microbiome diversity, it did cause significant dose- and time-dependent changes in bacterial abundance at the phylum level, including increases in and , and decreases in .
CONCLUSION AND IMPLICATIONS
These preliminary findings support the idea that psilocybin and other tryptamines may act on the gut microbiome in a dose- and time-dependent manner, potentially identifying a novel peripheral mechanism for their antidepressant activity. The results from this preliminary study also suggest that norbaeocystin may warrant further investigation as a potential antidepressant, given the similarity of its effects to psilocybin.
Topics: Animals; Gastrointestinal Microbiome; Male; Rats, Long-Evans; Tryptamines; Rats; Feces; Psilocybin; Administration, Oral; Antidepressive Agents
PubMed: 38846751
DOI: 10.7717/peerj.17517 -
Acta Crystallographica. Section E,... May 2024The title compound, CHNO, is a hy-droxy-substituted mono-amine alkaloid, and the primary metabolite of the naturally occurring psychedelic compound psilocybin....
The title compound, CHNO, is a hy-droxy-substituted mono-amine alkaloid, and the primary metabolite of the naturally occurring psychedelic compound psilocybin. Crystalline forms of psilocin are known, but their characterization by single-crystal structure analysis is limited. Herein, two anhydrous polymorphic forms (I and II) of psilocin are described. The crystal structure of polymorphic Form I, in space group 2/, was first reported in 1974. Along with the redeterm-ination to modern standards and unambiguous location of the acidic H atom and variable-temperature single-crystal unit-cell determinations for Form I, the Form II polymorph of the title compound, which crystallizes in the monoclinic space group 2/, is described for the first time. The psilocin mol-ecules are present in both forms in their phenol-amine tautomeric forms (not resolved in the 1974 report). The mol-ecules in Forms I and II, however, feature different conformations of their ,-dimethyl ethyl-ene substituent, with the N-C-C-C link in Form I being and in Form II being , allowing the latter to bend back to the hydroxyl group of the same mol-ecule, leading to the formation of a strong intra-molecular O-H⋯N hydrogen bond between the hydroxyl moiety and ethyl-amino-nitro-gen group. In the extended structure of Form II, the mol-ecules form one-dimensional strands through N-H⋯O hydrogen bonds from the indole group to the oxygen atom of the hydroxyl moiety of an adjacent mol-ecule. Form II exhibits whole-mol-ecule disorder due to a pseudo-mirror operation, with an occupancy ratio of 0.689 (5):0.311 (5) for the two components. In contrast, Form I does not feature intra-molecular hydrogen bonds but forms a layered structure through inter-molecular N-H⋯O and O-H⋯N hydrogen bonds.
PubMed: 38845717
DOI: 10.1107/S2056989024004201 -
Addiction (Abingdon, England) Jun 2024The turn of the century brought a resurgence of interest in psychedelics as a treatment for addiction and other psychiatric conditions, accompanied by extensive positive...
The turn of the century brought a resurgence of interest in psychedelics as a treatment for addiction and other psychiatric conditions, accompanied by extensive positive media attention and private equity investment. Government regulatory bodies in Australia, Israel, Canada and the United States now permit use of psychedelics for medical purposes. In the United States, citizen action and corporate financing have led to petitions and ballot initiatives to legalize psilocybin and other psychedelics for medical and recreational use. Given this momentum, policymakers must grapple with important questions that define whether and how psychedelics are made available to the public, as well as how companies produce and promote them. The current push to broaden the production, sale, and use of psychedelics bears many parallels to the movement to legalize cannabis in the United States and other nations-most notably, the use of poorly-evidenced therapeutic claims to create a de facto recreational market via the health care system. Experience with cannabis highlights the value of debating the question of legalization for nonmedical use as such rather than misrepresenting it as a medical issue. The lessons of cannabis policy also suggest a need to challenge hyping of psychedelic research findings; to promote rigorous clinical research on dosing and potency; to minimize the influence of for-profit industry in shaping policies to their economic advantage; and to coordinate federal, state, and local governments to regulate the manufacture, sale and distribution of psychedelic drugs (regardless of whether they are legalized for medical and/or recreational use).
PubMed: 38845381
DOI: 10.1111/add.16575 -
Journal of Clinical and Experimental... Jun 2024Psilocybin, a naturally occurring serotonergic agonist in some mushroom species, has shown promise as a novel, fast-acting pharmacotherapy seeking to overcome the... (Review)
Review
INTRODUCTION
Psilocybin, a naturally occurring serotonergic agonist in some mushroom species, has shown promise as a novel, fast-acting pharmacotherapy seeking to overcome the limitations of conventional first-line antidepressants. Studying psilocybin effects on cognition and emotional processing may help to clarify the mechanisms underlying the therapeutic potential of psilocybin and may also support studies with people suffering from depression. Thus, this review aims to provide a comprehensive overview of the current literature regarding the effects of psilocybin on these two key areas in both healthy and depressed populations.
METHOD
A systematic search was performed on 29 January 2024, in the PubMed, EBSCOhost, Web of Science and SCOPUS databases. After duplicates removal, study selection was conducted considering pre-specified criteria. Data extraction was then performed. The quality assessment of the studies was carried out using the Cochrane Collaboration tools for randomized (RoB 2.0) and non-randomized (ROBINS-I) controlled trials.
RESULTS
Twenty articles were included, with 18 targeting healthy adults and two adults with depression. Results point to impairments within attentional and inhibitory processes, and improvements in the domains of creativity and social cognition in healthy individuals. In the population with depression, only cognitive flexibility and emotional recognition were affected, both being enhanced. The comparison of outcomes from both populations proved limited.
CONCLUSIONS
Psilocybin acutely alters several cognitive domains, with a localized rather than global focus, in a dose- and time-dependent manner. However, the significant methodological constraints call for further research, in the context of depression and with standardized protocols, with longitudinal studies also imperative.
PubMed: 38842300
DOI: 10.1080/13803395.2024.2363343 -
Journal of Fluency Disorders May 2024Stuttering poses challenges to social, occupational, and educational aspects of life. Traditional behavioral therapies can be helpful but effects are often limited....
Stuttering poses challenges to social, occupational, and educational aspects of life. Traditional behavioral therapies can be helpful but effects are often limited. Pharmaceutical treatments have been explored but there are no FDA-approved treatments for stuttering. Interest has grown in the potential use of classic psychedelics, including psilocybin and LSD, which have shown effectiveness in treating disorders with similar symptoms (e.g., anxiety, depression, PTSD). The potential effects of psychedelics on stuttering have not been explored. We conducted a preliminary investigation of self-identified stutterers who report their experiences taking classic psychedelics on the online messaging forum, Reddit. We qualitatively analyzed 114 publicly available posts, extracting meaningful units and assigning descriptor codes inductively. We then deductively organized responses into an established framework of psychedelics which includes behavioral, emotional, cognitive, belief-based, and social effects. These effects were subsequently grouped under organizing themes (positive, negative, neutral). Descriptive statistics revealed that the majority of users (74.0%) reported positive overall short-term effects particularly related to behavioral and emotional change (e.g., reduced stuttering and anxiety), but negative (9.6%), mixed (positive and negative; 4.8%), and neutral overall experiences (11.6%) were also reported. The results support the possibility that psychedelics may impact stuttering, but caution must be applied in their interpretation given the entirely uncontrolled research setting and potential adverse health effects of psychedelics as reported elsewhere. While these results do not encourage the use of psychedelics by stutterers, they suggest that future work could examine the impact of psychedelics on stuttering under supervised and in clinically controlled settings.
PubMed: 38833909
DOI: 10.1016/j.jfludis.2024.106062