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Nature Communications Mar 2024Psilocybin, the natural hallucinogen produced by Psilocybe ("magic") mushrooms, holds great promise for the treatment of depression and several other mental health...
Psilocybin, the natural hallucinogen produced by Psilocybe ("magic") mushrooms, holds great promise for the treatment of depression and several other mental health conditions. The final step in the psilocybin biosynthetic pathway, dimethylation of the tryptophan-derived intermediate norbaeocystin, is catalysed by PsiM. Here we present atomic resolution (0.9 Å) crystal structures of PsiM trapped at various stages of its reaction cycle, providing detailed insight into the SAM-dependent methylation mechanism. Structural and phylogenetic analyses suggest that PsiM derives from epitranscriptomic N-methyladenosine writers of the METTL16 family, which is further supported by the observation that bound substrates physicochemically mimic RNA. Inherent limitations of the ancestral monomethyltransferase scaffold hamper the efficiency of psilocybin assembly and leave PsiM incapable of catalysing trimethylation to aeruginascin. The results of our study will support bioengineering efforts aiming to create novel variants of psilocybin with improved therapeutic properties.
Topics: Psilocybin; Phylogeny; Hallucinogens; Agaricales; Psilocybe
PubMed: 38548735
DOI: 10.1038/s41467-024-46997-z -
Brain Sciences Mar 2024This study aims to provide an overview of pharmacological trials that examine the neurocognitive effects of psychedelics among healthy individuals and patients with... (Review)
Review
OBJECTIVE
This study aims to provide an overview of pharmacological trials that examine the neurocognitive effects of psychedelics among healthy individuals and patients with post-traumatic stress disorder (PTSD) or major depressive disorder (MDD).
METHODS
The Preferred Reporting Items for Systematic Reviews (PRISMA) was used as a guide to structure and report the findings for this review. A literature search included the MEDLINE database up until December 2022. We included randomized or open-label human studies of MDMA, psilocybin, mescaline, LSD, DMT, or cannabis reporting non-emotionally charged neurocognitive outcomes ("cold cognition") measured through validated neuropsychological tests.
RESULTS
A total of 43 full-text papers on MDMA (15), cannabis (12), LSD (6), psilocybin (9), DMT/ayahuasca (1), and mescaline (0) were included, mostly on healthy subjects. A single article on MDMA's effects on cognition in subjects with PTSD was included; there were no studies on psychedelics and neurocognition in MDD. Most of the studies on healthy subjects reported detrimental or neutral effects on cognition during the peak effect of psychedelics with a few exceptions (e.g., MDMA improved psychomotor function). Performance on the type of neurocognitive dimension (e.g., attention, memory, executive function, psychomotor) varies by type of psychedelic, dosage, and cognitive testing.
CONCLUSIONS
Small samples and a lack of uniformed methods across studies preclude unequivocal conclusions on whether psychedelics enhance, decrease, or have no significant effect on cognitive performance. It is foreseen that psychedelics will soon become an available treatment for various psychiatric disorders. The acute and long-term effects on cognition caused by psychedelics should be assessed in future studies.
PubMed: 38539636
DOI: 10.3390/brainsci14030248 -
Journal of Fungi (Basel, Switzerland) Mar 2024The species of (Hymenogastraceae, Agricales) are commonly recognized as wood-decaying fungi. Certain members of this genus have been identified as psilocybin-producing...
The species of (Hymenogastraceae, Agricales) are commonly recognized as wood-decaying fungi. Certain members of this genus have been identified as psilocybin-producing mushrooms. exhibits a diverse range and has a global distribution. In this study, a total of seventy-eight specimens were gathered from ten provinces in China. A comprehensive molecular phylogenetic analysis was conducted, employing gene sequences including ITS, nrLSU, nrSSU, , , and . Additionally, morphological examinations were also carried out. The phylogenetic topology of from this study generally agreed with previous studies and facilitated the identification of all those specimens. As a result, eleven species, including five newly discovered ones named , , , , and , were recognized. Significantly, four of the five newly identified species are native to the Xizang Autonomous Region, emphasizing their specialization in this distinctive habitat. This research contributes to our comprehension of diversity and lays the groundwork for the conservation and sustainable utilization of resources.
PubMed: 38535228
DOI: 10.3390/jof10030220 -
Scientific Reports Mar 2024In this study, for the first time, we explored a dataset of functional magnetic resonance images collected during focused attention and open monitoring meditation before...
In this study, for the first time, we explored a dataset of functional magnetic resonance images collected during focused attention and open monitoring meditation before and after a five-day psilocybin-assisted meditation retreat using a recently established approach, based on the Mapper algorithm from topological data analysis. After generating subject-specific maps for two groups (psilocybin vs. placebo, 18 subjects/group) of experienced meditators, organizational principles were uncovered using graph topological tools, including the optimal transport (OT) distance, a geometrically rich measure of similarity between brain activity patterns. This revealed characteristics of the topology (i.e. shape) in space (i.e. abstract space of voxels) and time dimension of whole-brain activity patterns during different styles of meditation and psilocybin-induced alterations. Most interestingly, we found that (psilocybin-induced) positive derealization, which fosters insightfulness specifically when accompanied by enhanced open-monitoring meditation, was linked to the OT distance between open-monitoring and resting state. Our findings suggest that enhanced meta-awareness through meditation practice in experienced meditators combined with potential psilocybin-induced positive alterations in perception mediate insightfulness. Together, these findings provide a novel perspective on meditation and psychedelics that may reveal potential novel brain markers for positive synergistic effects between mindfulness practices and psilocybin.
Topics: Humans; Psilocybin; Meditation; Brain; Brain Mapping; Hallucinogens
PubMed: 38531905
DOI: 10.1038/s41598-024-55726-x -
South African Medical Journal =... Nov 2023Healthcare providers face the challenging task of managing patients who suffer from chronic nociplastic pain conditions. Pain is a multidimensional experience, and the... (Review)
Review
Healthcare providers face the challenging task of managing patients who suffer from chronic nociplastic pain conditions. Pain is a multidimensional experience, and the current approach to managing people in chronic pain often fails to meet the needs of these patients. Novel ways of treating people who suffer from chronic nociplastic pain with classic psychedelic agents may offer a new lens through which to approach their pain. Lysergic acid diethylamide (LSD) and psilocybin are both serotonergic agents with a long history of use in treating people with chronic pain and mental health disorders. The new wave of research into psychedelics for major depressive disorder provides an opportunity to investigate and understand the potential for incorporating these drugs into chronic pain management pathways. This narrative review presents healthcare workers with a framework to understand the method of action of these drugs in chronic nociplastic pain pathways and a brief history into their use. We conducted an online search using Pubmed with keywords 'chronic pain' AND/OR 'psilocybin' AND/OR 'lysergic acid diethylamide' AND/OR 'psychedelics' with no date limit applied. We identified further articles that contained information on the neuroscience of psychedelics and the serotonergic system using Google Scholar. During the final stages of writing the article, the latest publications on psychedelics and chronic pain in leading pain journals were again included to update the information.
Topics: Humans; Hallucinogens; Psilocybin; Lysergic Acid Diethylamide; Chronic Pain; Depressive Disorder, Major; South Africa
PubMed: 38525640
DOI: 10.7196/SAMJ.2023.v113i11.814 -
Journal of Psychopharmacology (Oxford,... May 2024There is growing evidence for the therapeutic effects of the psychedelic drug psilocybin for major depression. However, due to the lack of safety data on combining... (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND
There is growing evidence for the therapeutic effects of the psychedelic drug psilocybin for major depression. However, due to the lack of safety data on combining psilocybin with selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) and concerns that there may be a negative interaction on efficacy, participants enrolling in psychedelic trials are usually required to discontinue SNRI/SNRIs prior to enrolling.
AIMS
Using data from a recent clinical trial examining the comparative efficacy the psychedelic drug psilocybin (P) combined with approximately 20 h of psychological support to a 6-week (daily) course of the SSRI escitalopram plus matched psychological support for major depressive disorder, we explored the effects of discontinuing SSRI/SNRIs prior to study enrolment on study outcomes.
METHODS
Exploratory post hoc analyses using linear mixed effects model were performed to investigate the discontinuation effect on various validated depression symptom severity scales and well-being. The impact of SSRI/SNRIs discontinuation on the acute psychedelic experience was also explored.
RESULTS/OUTCOMES
In the psilocybin group, there was a reduced treatment effect on all outcome measures for SSRI/SNRIs discontinuers compared with unmedicated patients at trial entry. However, no effects of discontinuation on measures of the acute psychedelic experience were found.
CONCLUSION
Discontinuation of SSRI/SNRIs before psilocybin might diminish response to treatment; however, as we did not test SSRI/SNRI continuation in our trial, we cannot infer such causation. Moreover, the exploratory nature of the analyses makes them hypothesis generating, and not confirmatory. A controlled trial of SSRI/SNRI discontinuation versus continuation prior to psilocybin is urgently required.
Topics: Humans; Psilocybin; Depressive Disorder, Major; Adult; Male; Selective Serotonin Reuptake Inhibitors; Female; Hallucinogens; Escitalopram; Middle Aged; Treatment Outcome; Drug Therapy, Combination
PubMed: 38520045
DOI: 10.1177/02698811241237870 -
RSC Medicinal Chemistry Mar 2024Psilocybin analogues have been synthesized comprising a non-hydrolysable P-C bond to evaluate the biological activity and the selectivity towards 5-HTR, 5-HTR and the...
Psilocybin analogues have been synthesized comprising a non-hydrolysable P-C bond to evaluate the biological activity and the selectivity towards 5-HTR, 5-HTR and the TNAP receptor. No activity was observed towards the phosphatase, however all compounds showed good binding affinity for 5-HTR and 5-HTR and one compound showed a higher selectivity towards 5-HTR than psilocin.
PubMed: 38516602
DOI: 10.1039/d4md00043a -
Brain Communications 2024This scientific commentary refers to 'Brain dynamics predictive of response to psilocybin for treatment-resistant depression', by Vohryzek ....
This scientific commentary refers to 'Brain dynamics predictive of response to psilocybin for treatment-resistant depression', by Vohryzek . (https://doi.org/10.1093/braincomms/fcae049).
PubMed: 38515441
DOI: 10.1093/braincomms/fcae067 -
Brain Communications 2024Psilocybin therapy for depression has started to show promise, yet the underlying causal mechanisms are not currently known. Here, we leveraged the differential outcome...
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 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 healthy 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 density maps of serotonin receptors 5-hydroxytryptamine 2a and 5-hydroxytryptamine 1a, 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.
PubMed: 38515439
DOI: 10.1093/braincomms/fcae049 -
Journal of Pain Research 2024Amid a lack of effective chronic pain treatments, psychedelics have gained attention as a potential solution, although their Schedule 1 classification poses challenges.... (Review)
Review
INTRODUCTION
Amid a lack of effective chronic pain treatments, psychedelics have gained attention as a potential solution, although their Schedule 1 classification poses challenges. Psychedelics, such as lysergic acid diethylamide (LSD) and psilocybin, have gained popularity as alternatives and adjuncts for chronic pain treatment. Studies suggest that they may modulate pain processing through agonism primarily at the serotonin receptor, 5-HT. One of the first of its nature, we present an artificial intelligence (AI)-powered scoping review primarily focusing on evaluating psychedelics for chronic pain conditions such as cluster headache, phantom limb pain, and fibromyalgia.
METHODS
In accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines, we used an AI-powered comprehensive search strategy utilizing the ChatGPT4.0 Bing chat to search Medline, Embase, Cochrane, and Google Scholar for articles addressing chronic pain. The query was performed on June 1, 2023, focusing on psychedelics for chronic, non-cancer pain including headache disorders. Inclusion criteria were English-only, peer-reviewed articles involving human participants >18 years, focusing on chronic pain conditions (eg, phantom limb pain and cluster headache), using LSD, 2.5-dimethoxy-4-bromophenethylamine (2C-B), N, N-dimethyltryptamine (DMT), psilocybin, or mescaline. Exclusion criteria were reviews, editorials, and opinion articles and studies focusing on tetrahydrocannabinol/cannabis and/or ketamine.
RESULTS
A total of 186 unique database entries were retrieved, of which nine studies were included in the scoping review. These included four case reports/series, an open-label study, a cohort study, two online surveys, and a randomized, double-blind, placebo-controlled trial. They comprised three studies addressing phantom limb pain, four addressing cluster headaches, and two addressing fibromyalgia, spinal cord injury, complex regional pain syndrome, and lumbar radiculopathy.
CONCLUSION
Psychedelics may have potential in alleviating pain symptoms secondary to a multitude of chronic pain conditions. However, further randomized, double-blind, placebo-controlled trials are needed to further explore and evaluate the role of psychedelics in chronic, non-cancer pain.
PubMed: 38496341
DOI: 10.2147/JPR.S439348