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Translational Psychiatry Dec 2023Alcohol Use Disorder (AUD) adversely affects the lives of millions of people, but still lacks effective treatment options. Recent advancements in psychedelic research... (Randomized Controlled Trial)
Randomized Controlled Trial
Alcohol Use Disorder (AUD) adversely affects the lives of millions of people, but still lacks effective treatment options. Recent advancements in psychedelic research suggest psilocybin to be potentially efficacious for AUD. However, major knowledge gaps remain regarding (1) psilocybin's general mode of action and (2) AUD-specific alterations of responsivity to psilocybin treatment in the brain that are crucial for treatment development. Here, we conducted a randomized, placebo-controlled crossover pharmaco-fMRI study on psilocybin effects using a translational approach with healthy rats and a rat model of alcohol relapse. Psilocybin effects were quantified with resting-state functional connectivity using data-driven whole-brain global brain connectivity, network-based statistics, graph theory, hypothesis-driven Default Mode Network (DMN)-specific connectivity, and entropy analyses. Results demonstrate that psilocybin induced an acute wide-spread decrease in different functional connectivity domains together with a distinct increase of connectivity between serotonergic core regions and cortical areas. We could further provide translational evidence for psilocybin-induced DMN hypoconnectivity reported in humans. Psilocybin showed an AUD-specific blunting of DMN hypoconnectivity, which strongly correlated to the alcohol relapse intensity and was mainly driven by medial prefrontal regions. In conclusion, our results provide translational validity for acute psilocybin-induced neural effects in the rodent brain. Furthermore, alcohol relapse severity was negatively correlated with neural responsivity to psilocybin treatment. Our data suggest that a clinical standard dose of psilocybin may not be sufficient to treat severe AUD cases; a finding that should be considered for future clinical trials.
Topics: Humans; Rats; Animals; Psilocybin; Alcoholism; Default Mode Network; Hallucinogens; Brain; Ethanol; Magnetic Resonance Imaging; Recurrence
PubMed: 38097569
DOI: 10.1038/s41398-023-02690-1 -
Frontiers in Neuroscience 2023Psilocybin, a naturally occurring hallucinogenic component of magic mushrooms, has significant psychoactive effects in both humans and rodents. But the underlying...
Psilocybin, a naturally occurring hallucinogenic component of magic mushrooms, has significant psychoactive effects in both humans and rodents. But the underlying mechanisms are not fully understood. Blood-oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI) is a useful tool in many preclinical and clinical trials to investigate psilocybin-induced changes of brain activity and functional connectivity (FC) due to its noninvasive nature and widespread availability. However, fMRI effects of psilocybin on rats have not been carefully investigated. This study aimed to explore how psilocybin affects resting-state brain activity and FC, through a combination of BOLD fMRI and immunofluorescence (IF) of EGR1, an immediate early gene (IEG) closely related to depressive symptoms. Ten minutes after psilocybin hydrochloride injection (2.0 mg/kg, i.p.), positive brain activities were observed in the frontal, temporal, and parietal cortex (including the cingulate cortex and retrosplenial cortex), hippocampus, and striatum. And a region-of-interest (ROI) -wise FC analysis matrix suggested increased interconnectivity of several regions, such as the cingulate cortex, dorsal striatum, prelimbic, and limbic regions. Further seed-based analyses revealed increased FC of cingulate cortex within the cortical and striatal areas. Consistently, acute psilocybin increased the EGR1 level throughout the brain, indicating a consistent activation thought the cortical and striatal areas. In conclusion, the psilocybin-induced hyperactive state of rats is congruent to that of humans, and may be responsible for its pharmacological effects.
PubMed: 37287797
DOI: 10.3389/fnins.2023.1168911 -
Journal of Psychopharmacology (Oxford,... Mar 2024Though microdosing psychedelics has become increasingly popular, its long-term effects on cardiac health remain unknown. Microdosing most commonly involves ingesting... (Review)
Review
Though microdosing psychedelics has become increasingly popular, its long-term effects on cardiac health remain unknown. Microdosing most commonly involves ingesting sub-threshold doses of lysergic acid diethylamide (LSD), psilocybin, or other psychedelic drugs 2-4 times a week for at least several weeks, but potentially months or years. Concerningly, both LSD and psilocybin share structural similarities with medications which raise the risk of cardiac fibrosis and valvulopathy when taken regularly, including methysergide, pergolide, and fenfluramine. 3,4-Methylenedioxymethamphetamine, which is also reportedly used for microdosing, is likewise associated with heart valve damage when taken chronically. In this review, we evaluate the evidence that microdosing LSD, psilocybin, and other psychedelics for several months or more could raise the risk of cardiac fibrosis. We discuss the relationship between drug-induced cardiac fibrosis and the 5-HT2B receptor, and we make recommendations for evaluating the safety of microdosing psychedelics in future studies.
Topics: Humans; Hallucinogens; Psilocybin; Cardiotoxins; Lysergic Acid Diethylamide; Fibrosis
PubMed: 38214279
DOI: 10.1177/02698811231225609 -
Fungal Biology Apr 2022Therapeutic use of psilocybin has become a focus of recent international research, with preliminary data showing promise to address a range of treatment-resistant mental... (Review)
Review
Therapeutic use of psilocybin has become a focus of recent international research, with preliminary data showing promise to address a range of treatment-resistant mental health conditions. However, use of psilocybin as a healing entheogen has a long history through traditional consumption of mushrooms from the genus Psilocybe. The forthcoming adoption of new psilocybin-assisted therapeutic practices necessitates identification of preferred sources of psilocybin; consequently, comprehensive understanding of psilocybin-containing fungi is fundamental to consumer safety. Here we examine psilocybin producing fungi, discuss their biology, diversity, and ethnomycological uses. We also review recent work focused on elucidation of psilocybin biosynthetic production pathways, especially those from the genus Psilocybe, and their evolutionary history. Current research on psilocybin therapies is discussed, and recommendations for necessary future mycological research are outlined.
Topics: Agaricales; Biology; Psilocybe; Psilocybin
PubMed: 35314062
DOI: 10.1016/j.funbio.2022.01.003 -
Frontiers in Psychiatry 2023Psilocybin may help treat obsessive-compulsive disorder (OCD). To date, only one open-label study of psilocybin for OCD exists, necessitating further investigation with...
Safety, tolerability, and clinical and neural effects of single-dose psilocybin in obsessive-compulsive disorder: protocol for a randomized, double-blind, placebo-controlled, non-crossover trial.
BACKGROUND
Psilocybin may help treat obsessive-compulsive disorder (OCD). To date, only one open-label study of psilocybin for OCD exists, necessitating further investigation with a randomized controlled design. The neural correlates of psilocybin's effects on OCD have also not been studied.
OBJECTIVES
This first-of-its-kind trial aims to evaluate the feasibility, safety, and tolerability of psilocybin in the treatment of OCD, provide preliminary evidence on the effects of psilocybin on OCD symptoms, and elucidate neural mechanisms that may mediate psilocybin's effects on OCD.
DESIGN
We use a randomized (1:1), double-blind, placebo-controlled, non-crossover design to examine the clinical and neural effects of either a single dose of oral psilocybin (0.25 mg/kg) or active placebo-control agent (250 mg of niacin) on OCD symptoms.
METHODS AND ANALYSIS
We are enrolling 30 adult participants at a single site in Connecticut, USA who have failed at least one trial of standard care treatment (medication/psychotherapy) for OCD. All participants will also receive unstructured, non-directive psychological support during visits. Aside from safety, primary outcomes include OCD symptoms over the past 24 h, assessed by the Acute Yale-Brown Obsessive-Compulsive Scale and Visual Analog Scale ratings. These are collected by blinded, independent raters at baseline and the primary endpoint of 48 h post-dosing. Total follow-up is 12 weeks post-dosing. Resting state neuroimaging data will be collected at baseline and primary endpoint. Participants randomized to placebo will be offered the chance to return for an open-label dose of 0.25 mg/kg.
ETHICS STATEMENT
All participants will be required to provide written informed consent. The trial (protocol v. 5.2) was approved by the institutional review board (HIC #2000020355) and registered with ClinicalTrials.gov (NCT03356483).
DISCUSSION
This study may represent an advance in our ability to treat refractory OCD, and pave the way for future studies of neurobiological mechanisms of OCD that may respond to psilocybin.
PubMed: 37181888
DOI: 10.3389/fpsyt.2023.1178529 -
Journal of Psychopharmacology (Oxford,... Aug 2022Postpartum depression (PPD) is a major public health concern and has, at its core, a sense of maternal 'disconnection' - from the self, the infant, and the support... (Review)
Review
BACKGROUND
Postpartum depression (PPD) is a major public health concern and has, at its core, a sense of maternal 'disconnection' - from the self, the infant, and the support system. While PPD bears similarities with MDD, there is increasing evidence for its distinct nature, especially with the unique aspect of the mother-infant relationship. Current treatment modalities for PPD, largely based on those used in major depressive disorder (MDD), have low remission rates with emerging evidence for treatment resistance. It is, therefore, necessary to explore alternative avenues of treatment for PPD.
OBJECTIVE
In this narrative review, we outline the potential therapeutic rationale for serotonergic psychedelics in the treatment of PPD, and highlight safety and pragmatic considerations for the use of psychedelics in the postpartum period.
METHODS
We examined the available evidence for the treatment of PPD and the evidence for psychedelics in the treatment of MDD. We explored safety considerations in the use of psychedelics in the postpartum period.
RESULTS
There is increasing evidence for safety, and encouraging signals for efficacy, of psilocybin in the treatment of MDD. Psilocybin has been shown to catalyse a sense of 'reconnection' in participants with MDD. This effect in PPD, by fostering a sense of 'reconnection' for the mother, may allow for improved mood and maternal sensitivity towards the infant, which can positively impact maternal role gratification and the mother-infant relationship.
CONCLUSION
Psychedelic assisted therapy in PPD may have a positive effect on the mother-infant dyad and warrants further examination.
Topics: Depression, Postpartum; Depressive Disorder, Major; Female; Hallucinogens; Humans; Mothers; Psilocybin
PubMed: 35638179
DOI: 10.1177/02698811221093793 -
Translational Psychiatry Aug 2022Psilocybin and other serotonergic psychedelics have re-emerged as therapeutics for neuropsychiatric disorders, including addiction. Psilocybin induces long-lasting...
Psilocybin and other serotonergic psychedelics have re-emerged as therapeutics for neuropsychiatric disorders, including addiction. Psilocybin induces long-lasting effects on behavior, likely due to its profound ability to alter consciousness and augment neural connectivity and plasticity. Impaired synaptic plasticity in obesity contributes to 'addictive-like' behaviors, including heightened motivation for palatable food, and excessive food seeking and consumption. Here, we evaluate the effects of psilocybin on feeding behavior, energy metabolism, and as a weight-lowering agent in mice. We demonstrate that a single dose of psilocybin substantially alters the prefrontal cortex transcriptome but has no acute or long-lasting effects on food intake or body weight in diet-induced obese mice or in genetic mouse models of obesity. Similarly, sub-chronic microdosing of psilocybin has no metabolic effects in obese mice and psilocybin does not augment glucagon-like peptide-1 (GLP-1) induced weight loss or enhance diet-induced weight loss. A single high dose of psilocybin reduces sucrose preference but fails to counter binge-like eating behavior. Although these preclinical data discourage clinical investigation, there may be nuances in the mode of action of psychedelic drugs that are difficult to capture in rodent models, and thus require human evaluation to uncover.
Topics: Animals; Energy Metabolism; Feeding Behavior; Hallucinogens; Humans; Mice; Obesity; Psilocybin; Weight Loss
PubMed: 35953488
DOI: 10.1038/s41398-022-02103-9 -
Frontiers in Psychiatry 2023Methamphetamine use disorder is a chronic relapsing condition associated with substantial mental, physical, and social harms and increasing rates of mortality.... (Review)
Review
Methamphetamine use disorder is a chronic relapsing condition associated with substantial mental, physical, and social harms and increasing rates of mortality. Contingency management and psychotherapy interventions are the mainstays of treatment but are modestly effective with high relapse rates, while pharmacological treatments have shown little to no efficacy. Psilocybin-assisted psychotherapy is emerging as a promising treatment for a range of difficult-to-treat conditions, including substance use disorders; however, no studies have yet been published looking at psilocybin-assisted psychotherapy in the treatment of methamphetamine use disorder. Here we review the rationale for psilocybin-assisted psychotherapy as a potential treatment for this indication, and describe practical considerations based on our early experience designing and implementing four separate clinical trials of psilocybin-assisted psychotherapy for methamphetamine use disorder.
PubMed: 36998623
DOI: 10.3389/fpsyt.2023.1123424 -
Frontiers in Psychiatry 2023Psilocybin use has been linked to lowered odds of crime-related outcomes across a host of observational studies. No studies have investigated how these associations may...
INTRODUCTION
Psilocybin use has been linked to lowered odds of crime-related outcomes across a host of observational studies. No studies have investigated how these associations may differ among those of different races and ethnicities.
METHODS
Using a nationally-representative sample of 734,061 adults from the National Survey on Drug Use and Health (2002-2020), we investigated whether race and ethnicity moderate the associations between lifetime psilocybin use and four measures of crime arrests (property crime, assault, serious violence, and miscellaneous crimes).
RESULTS
First, we replicated prior findings and demonstrated that psilocybin confers lowered odds of crime arrests for all four outcomes in question. Second, we demonstrated that race and ethnicity moderate the associations between lifetime psilocybin use and crime arrests for three of our four outcomes. Third, we examined the associations between psilocybin and crime arrests across different races and ethnicities (White, Black, Indigenous, Asian, Multiracial, and Hispanic participants). Psilocybin conferred lowered odds of at least one crime arrest outcome for all racial and ethnic groups except for Black and Hispanic participants.
DISCUSSION
Future investigations should take an intersectional approach to studying the interrelationship of sociodemographic factors, psychedelic use, and crime, examine the structural factors (i.e., systemic racism) that may underlie these results, and investigate whether psychedelics can alleviate mental health disorders that contribute to cycles of recriminalization for communities of color.
PubMed: 37692301
DOI: 10.3389/fpsyt.2023.1169692 -
Journal of Psychopharmacology (Oxford,... Jul 2023The classical psychedelics, psilocybin, peyote, ayahuasca/-dimethyltryptamine, and lysergic acid diethylamide are considered promising new treatments for psychiatric... (Review)
Review
BACKGROUND
The classical psychedelics, psilocybin, peyote, ayahuasca/-dimethyltryptamine, and lysergic acid diethylamide are considered promising new treatments for psychiatric illnesses, such as depression, anxiety, addiction, and obsessive-compulsive disorders. However, their profound and characteristic subjective effects raise concern for distinctive biases in randomized clinical trials.
METHODS
We performed a systematic literature search to identify all clinical trials on classical psychedelics with patient populations to examine descriptive data and determine the risk of bias. Two independent reviewers searched three databases (PubMed, Embase, and APA PsycNet) and extracted information on study design, study population, use of active or inactive placebo, dropouts, evaluation of blinding of intervention, and reporting of expectancy and therapeutic alliance.
RESULTS
We included 10 papers reporting on 10 unique trials. The trials generally included populations that were predominantly white and highly educated. The trials had small samples and considerable dropout. Blinding was either unsuccessful or not reported regardless of type of placebo. Few trials published protocols, statistical analysis plans (SAPs), and outcomes relating to psychotherapy fidelity. All trials but one were rated as high risk of bias.
CONCLUSION
Successful blinding of intervention is a significant challenge in this field. To better accommodate this, we suggest that future trials use a parallel-group design and utilize an active placebo on a psychedelic-naïve population. Future trials should publish trial protocol and SAPs, use clinician-rated outcomes accessed by a blinded rater, evaluate blinding of intervention, and consider measuring expectancy and therapeutic fidelity.
Topics: Humans; Hallucinogens; Randomized Controlled Trials as Topic; Lysergic Acid Diethylamide; Psilocybin; Anxiety Disorders
PubMed: 37403379
DOI: 10.1177/02698811231180276