The serotonergic hallucinogen psilocybin has shown potential as a treatment for psychiatric conditions like alcohol use disorder (AUD) and depression in clinical studies. Epigenetic mechanisms, including DNA methylation, are hypothesized to contribute to its lasting therapeutic benefits. In this exploratory study, we present the first methylome-wide analysis...
Psilocybin is a hallucinogen with complex neurobiological and behavioral effects. Underlying these effects are changes in brain neuroplasticity. We hypothesized psilocybin given during adolescence, a time of heightened neuroplasticity, particularly in the forebrain, would affect emotional behavior and the associated underlying neuroanatomy, neurocircuitry, a...
Emerging evidence suggests that classical psychedelics may offer therapeutic potential for opioid use disorder (OUD) by alleviating key hallmarks such as altered reward processing and dependence. However, the mechanisms behind these effects remain unclear. Our data demonstrate that a single administration of the psychedelic psilocybin (PSI) reduces condition...
Abstract For many, cognitive and affective health declines through typical aging. Although cognitive and affective symptoms are often studied in isolation, they share substantial overlap, and arise, in part, from common biological processes. Aging is accompanied by diminished neural plasticity, heightened neuroinflammation, and widespread alterations in the ...
The serotonergic hallucinogen psilocybin has shown potential as a treatment for psychiatric conditions like alcohol use disorder (AUD) and depression in clinical studies. Epigenetic mechanisms, including DNA methylation, are hypothesized to contribute to its lasting therapeutic benefits. In this exploratory study, we present the first methylome-wide analysis...
ABSTRACT Acyloxymethyl (ACOM) derivatives of tryptamines such as the psychedelic drug psilocin and the anti-migraine drug sumatriptan bear potential as prodrugs. Previous synthetic approaches suffer from insufficient chemoselectivity between the desired functionalization of the phenolic (psilocin) or sulfonamide (sumatriptan) groups versus other reactive gro...
Mental disorders are a representative type of brain disorder, including anxiety, major depressive depression (MDD), and autism spectrum disorder (ASD), that are caused by multiple etiologies, including genetic heterogeneity, epigenetic dysregulation, and aberrant morphological and biochemical conditions. Psychedelic drugs such as psilocybin and lysergic acid...
Psilocybin, a psychedelic compound found in specific hallucinogenic mushrooms, is known to induce changes in visual perception and experience in humans. However, there is little knowledge of the molecular mechanisms through which psilocybin affects vision-associated regions in the brain, such as the visual cortex. The current study determined both psilocybin...
The recent renaissance in research on psychedelics such as psilocybin has highlighted their therapeutic potential including their lasting influences on brain function. Here we report that a single systemic administration of the serotonergic psychedelic psilocybin can durably promote social behaviour in the Cntnap2-knockout mouse model of autism. This effect ...
Abstract The Psilocybe cubensis SAM-dependent methyltransferase, PsiM, catalyzes the last step in the biosynthesis of psilocybin. Likely evolved from monomethylating RNA methyltransferases, PsiM acquired a key amino acid exchange in the secondary sphere of the active site, M247 N, which is responsible for its capacity to dimethylate. Two variants, PsiM N247M...
For 3000 years, psychedelics have been used in religious contexts to enhance spiritual thinking, well-being, and a sense of community. In the last few years, a renaissance in the use of psychedelic drugs for mental disorders has occurred in Western society; consequently, a pressing scientific need to elucidate the intricate mechanisms underlying their action...
Abstract 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 resolut...
Alcohol abuse is a leading risk factor for the public health burden worldwide. Approved pharmacotherapies have demonstrated limited effectiveness over the last few decades in treating alcohol use disorders (AUD). New therapeutic approaches are therefore urgently needed. Historical and recent clinical trials using psychedelics in conjunction with psychotherap...
There has recently been a resurgence of interest in psychedelic compounds based on studies demonstrating their potential therapeutic applications in treating post-traumatic stress disorder, substance abuse disorders, and treatment-resistant depression. Despite promising efficacy observed in some clinical trials, the full range of biological effects and mecha...
Introduction The 5-HT2A agonist classic psychedelic, psilocybin (O-phosphoryl-4-hydroxy-N,N-dimethyltryptamine) is a tryptophan, indole-based alkaloid present in up to 2% of certain hallucinogenic “magic” mushroom species; typically Psilocybe azurescens, semilanceata, and cyanescens,. In addition, mushrooms may contain psilocin (4-hydroxy-N,N-dimethyltryptam...
IntroductionTreatment outcomes for PTSD with current psychological therapies are poor, with very few patients achieving sustained symptom remission. A number of authors have identified physiological and immune disturbances in Post Traumatic Stress Disorder (PTSD) patients, but there is no unifying hypothesis that explains the myriad features of the disorder....
4-Acetoxy-N,N-dimethyltryptamine (4-AcO-DMT, psilacetin, O-acetylpsilocin) is a synthetic tryptamine with psychedelic properties. Psilacetin may also act as precursor drug of psilocin, similar to psilocybin, but little is known about its metabolism. In this study, the phase I and phase II in vitro metabolism of 4-AcO-DMT was investigated with pooled human li...
Psilocybin and its direct precursor baeocystin are indole alkaloids of psychotropic Psilocybe mushrooms. The pharmaceutical interest in psilocybin as a treatment option against depression and anxiety is currently being investigated in advanced clinical trials. Here, we report a biocatalytic route to synthesize 6-methylated psilocybin and baeocystin from 4-hy...
Psilocybe mushrooms are best known for their l-tryptophan-derived psychotropic alkaloid psilocybin. Dimethylation of norbaeocystin, the precursor of psilocybin, by the enzyme PsiM is a critical step during the biosynthesis of psilocybin. However, the "magic" mushroom Psilocybe serbica also mono- and dimethylates l-tryptophan, which is incompatible with the s...
A unifying mechanism for abused drugs has been proposed previously from the standpoint of electron transfer. Mescaline can be accommodated within the theoretical framework based on redox cycling by the catechol metabolite with its quinone counterpart. Electron transfer may play a role in electrical effects involving the nervous system in the brain. This appr...
