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BioRxiv : the Preprint Server For... May 2024Psilocybin, ketamine, and MDMA are psychoactive compounds that exert behavioral effects with distinguishable but also overlapping features. The growing interest in using...
Psilocybin, ketamine, and MDMA are psychoactive compounds that exert behavioral effects with distinguishable but also overlapping features. The growing interest in using these compounds as therapeutics necessitates preclinical assays that can accurately screen psychedelics and related analogs. We posit that a promising approach may be to measure drug action on markers of neural plasticity in native brain tissues. We therefore developed a pipeline for drug classification using light sheet fluorescence microscopy of immediate early gene expression at cellular resolution followed by machine learning. We tested male and female mice with a panel of drugs, including psilocybin, ketamine, 5-MeO-DMT, 6-fluoro-DET, MDMA, acute fluoxetine, chronic fluoxetine, and vehicle. In one-versus-rest classification, the exact drug was identified with 67% accuracy, significantly above the chance level of 12.5%. In one-versus-one classifications, psilocybin was discriminated from 5-MeO-DMT, ketamine, MDMA, or acute fluoxetine with >95% accuracy. We used Shapley additive explanation to pinpoint the brain regions driving the machine learning predictions. Our results support a novel approach for screening psychoactive drugs with psychedelic properties.
PubMed: 38826215
DOI: 10.1101/2024.05.23.590306 -
British Journal of Pharmacology Jun 2024Demand for new antidepressants has resulted in a re-evaluation of the therapeutic potential of psychedelic drugs. Several tryptamines found in psilocybin-containing...
BACKGROUND AND PURPOSE
Demand for new antidepressants has resulted in a re-evaluation of the therapeutic potential of psychedelic drugs. Several tryptamines found in psilocybin-containing "magic" mushrooms share chemical similarities with psilocybin. Early work suggests they may share biological targets. However, few studies have explored their pharmacological and behavioural effects.
EXPERIMENTAL APPROACH
We compared baeocystin, norbaeocystin and aeruginascin with psilocybin to determine if they are metabolized by the same enzymes, similarly penetrate the blood-brain barrier, serve as ligands for similar receptors and modulate behaviour in rodents similarly. We also assessed the stability and optimal storage and handling conditions for each compound.
KEY RESULTS
In vitro enzyme kinetics assays found that all compounds had nearly identical rates of dephosphorylation via alkaline phosphatase and metabolism by monoamine oxidase. Further, we found that only the dephosphorylated products of baeocystin and norbaeocystin crossed a blood-brain barrier mimetic to a similar degree as the dephosphorylated form of psilocybin, psilocin. The dephosphorylated form of norbaeocystin was found to activate the 5-HT receptor with similar efficacy to psilocin and norpsilocin in in vitro cell imaging assays. Behaviourally, only psilocybin induced head twitch responses in rats, a marker of 5-HT-mediated psychedelic effects and hallucinogenic potential. However, like psilocybin, norbaeocystin improved outcomes in the forced swim test. All compounds caused minimal changes to metrics of renal and hepatic health, suggesting innocuous safety profiles.
CONCLUSIONS AND IMPLICATIONS
Collectively, this work suggests that other naturally occurring tryptamines, especially norbaeocystin, may share overlapping therapeutic potential with psilocybin, but without causing hallucinations.
PubMed: 38825326
DOI: 10.1111/bph.16466 -
The Primary Care Companion For CNS... May 2024The Psychiatric Consultation Service at Massachusetts General Hospital sees medical and surgical inpatients with comorbid psychiatric symptoms and conditions. During...
The Psychiatric Consultation Service at Massachusetts General Hospital sees medical and surgical inpatients with comorbid psychiatric symptoms and conditions. During their twice-weekly rounds, Dr Stern and other members of the Consultation Service discuss diagnosis and management of hospitalized patients with complex medical or surgical problems who also demonstrate psychiatric symptoms or conditions. These discussions have given rise to rounds repors that will prove useful for clinicians practicing at the interface of medicine and psychiatry. .
Topics: Humans; Psilocybin; Hallucinogens; Mental Disorders
PubMed: 38815272
DOI: 10.4088/PCC.23f03652 -
Clinical Case Reports Jun 2024Long-COVID syndrome lacks effective holistic treatment options. We present a case of a 41-year-old fully vaccinated female with Long-COVID syndrome who obtained...
KEY CLINICAL MESSAGE
Long-COVID syndrome lacks effective holistic treatment options. We present a case of a 41-year-old fully vaccinated female with Long-COVID syndrome who obtained significant symptomatic relief after self-medicating with psilocybin and MDMA.
ABSTRACT
Long-COVID, a syndrome persisting after the acute phase of coronavirus disease 2019 (COVID-19), lacks effective holistic treatment options. We present a case of a 41-year-old fully vaccinated female with Long-COVID syndrome who obtained significant symptomatic relief by self-prescribing psilocybin and MDMA. Future research is needed to assess safety and efficacy.
PubMed: 38813452
DOI: 10.1002/ccr3.8791 -
Journal of Neurophysiology Jul 2024Psilocybin is a serotonergic psychedelic believed to have therapeutic potential for neuropsychiatric conditions. Despite well-documented prevalence of perceptual...
Psilocybin is a serotonergic psychedelic believed to have therapeutic potential for neuropsychiatric conditions. Despite well-documented prevalence of perceptual alterations, hallucinations, and synesthesia associated with psychedelic experiences, little is known about how psilocybin affects sensory cortex or alters the activity of neurons in awake animals. To investigate, we conducted two-photon imaging experiments in auditory cortex of awake mice and collected video of free-roaming mouse behavior, both at baseline and during psilocybin treatment. In comparison with pre-dose neural activity, a 2 mg/kg ip dose of psilocybin initially increased the amplitude of neural responses to sound. Thirty minutes post-dose, behavioral activity and neural response amplitudes decreased, yet functional connectivity increased. In contrast, control mice given intraperitoneal saline injections showed no significant changes in either neural or behavioral activity across conditions. Notably, neuronal stimulus selectivity remained stable during psilocybin treatment, for both tonotopic cortical maps and single-cell pure-tone frequency tuning curves. Our results mirror similar findings regarding the effects of serotonergic psychedelics in visual cortex and suggest that psilocybin modulates the balance of intrinsic versus stimulus-driven influences on neural activity in auditory cortex. Recent studies have shown promising therapeutic potential for psychedelics in treating neuropsychiatric conditions. Musical experience during psilocybin-assisted therapy is predictive of treatment outcome, yet little is known about how psilocybin affects auditory processing. Here, we conducted two-photon imaging experiments in auditory cortex of awake mice that received a dose of psilocybin. Our results suggest that psilocybin modulates the roles of intrinsic neural activity versus stimulus-driven influences on auditory perception.
Topics: Animals; Auditory Cortex; Mice; Psilocybin; Hallucinogens; Male; Mice, Inbred C57BL; Neurons; Auditory Perception; Acoustic Stimulation
PubMed: 38810366
DOI: 10.1152/jn.00124.2024 -
Frontiers in Psychiatry 2024Intense interest surrounds current research on psychedelics, particularly regarding their potential in treating mental health disorders. Various studies suggest a link... (Review)
Review
Intense interest surrounds current research on psychedelics, particularly regarding their potential in treating mental health disorders. Various studies suggest a link between the subjective effects produced by psychedelics and their therapeutic efficacy. Neuroimaging evidence indicates an association of changes in brain functional connectivity with the subjective effects of psychedelics. We conducted a review focusing on psychedelics and brain functional connectivity. The review focused on four psychedelic drugs: ayahuasca, psilocybin and LSD, and the entactogen MDMA. We conducted searches in databases of MEDLINE, Embase, APA PsycInfo and Scopus from inception to Jun 2023 by keywords related to functional connectivity and psychedelics. Using the PRISMA framework, we selected 24 articles from an initial pool of 492 for analysis. This scoping review and analysis investigated the effects of psychedelics on subjective experiences and brain functional connectivity in healthy individuals. The studies quantified subjective effects through psychometric scales, revealing significant experiences of altered consciousness, mood elevation, and mystical experiences induced by psychedelics. Neuroimaging results indicated alterations in the functional connectivity of psychedelics, with consistent findings across substances of decreased connectivity within the default mode network and increased sensory and thalamocortical connectivity. Correlations between these neurophysiological changes and subjective experiences were noted, suggesting a brain network basis of the psychedelics' neuropsychological impact. While the result of the review provides a potential neural mechanism of the subjective effects of psychedelics, direct clinical evidence is needed to advance their clinical outcomes. Our research serves as a foundation for further exploration of the therapeutic potential of psychedelics.
PubMed: 38807690
DOI: 10.3389/fpsyt.2024.1386321 -
BioRxiv : the Preprint Server For... May 2024Intracellular calcium (Ca) is ubiquitous to cell signaling across all biology. While existing fluorescent sensors and reporters can detect activated cells with elevated...
Intracellular calcium (Ca) is ubiquitous to cell signaling across all biology. While existing fluorescent sensors and reporters can detect activated cells with elevated Ca levels, these approaches require implants to deliver light to deep tissue, precluding their noninvasive use in freely-behaving animals. Here we engineered an enzyme-catalyzed approach that rapidly and biochemically tags cells with elevated Ca in vivo. Ca-activated Split-TurboID (CaST) labels activated cells within 10 minutes with an exogenously-delivered biotin molecule. The enzymatic signal increases with Ca concentration and biotin labeling time, demonstrating that CaST is a time-gated integrator of total Ca activity. Furthermore, the CaST read-out can be performed immediately after activity labeling, in contrast to transcriptional reporters that require hours to produce signal. These capabilities allowed us to apply CaST to tag prefrontal cortex neurons activated by psilocybin, and to correlate the CaST signal with psilocybin-induced head-twitch responses in untethered mice.
PubMed: 38798353
DOI: 10.1101/2023.09.06.556431 -
Psychopharmacology May 2024Psychedelic-assisted psychotherapy (PAP) has emerged as a potential treatment for a variety of mental health conditions, including substance use disorders and... (Review)
Review
RATIONALE
Psychedelic-assisted psychotherapy (PAP) has emerged as a potential treatment for a variety of mental health conditions, including substance use disorders and depression. Current models of PAP emphasize the importance of psychotherapeutic support before, during, and after ingestion of a psychedelic to maximize safety and clinical benefit. Despite this ubiquitous assumption, there has been surprisingly little empirical investigation of the "psychotherapy" in PAP, leaving critical questions about the necessary and sufficient components of PAP unanswered.
OBJECTIVES
As clinical trials for psychedelic compounds continue the transition from safety- and feasibility-testing to evaluating efficacy, the role of the accompanying psychotherapy must be better understood to enhance scientific understanding of the mechanisms underlying therapeutic change, optimize clinical outcomes, and inform cost-effectiveness.
RESULTS
The present paper first reviews the current status of psychotherapy in the PAP literature, starting with recent debates regarding "psychotherapy" versus "psychological support" and then overviewing published clinical trial psychotherapy models and putative models informed by theory. We then delineate lessons that PAP researchers can leverage from traditional psychotherapy research regarding standardizing treatments (e.g., publish treatment manuals, establish eligibility criteria for providers), identifying mechanisms of change (e.g., measure established mechanisms in psychotherapy), and optimizing clinical trial designs (e.g., consider dismantling studies, comparative efficacy trials, and cross-lagged panel designs). Throughout this review, the need for increased research into the psychotherapeutic components of treatment in PAP is underscored.
CONCLUSIONS
PAP is a distinct, integrative, and transdisciplinary intervention. Future research designs should consider transdisciplinary research methodologies to identify best practices and inform federal guidelines for PAP administration.
PubMed: 38782821
DOI: 10.1007/s00213-024-06620-x -
Psychiatry Research Jul 2024
Meta-Analysis
Topics: Humans; Psilocybin; Depressive Disorder, Treatment-Resistant; Hallucinogens; Treatment Outcome
PubMed: 38781672
DOI: 10.1016/j.psychres.2024.115960 -
The European Journal of Neuroscience May 2024Psychoactive substances obtained from botanicals have been applied for a wide variety of purposes in the rituals of different cultures for thousands of years. Classical... (Review)
Review
Psychoactive substances obtained from botanicals have been applied for a wide variety of purposes in the rituals of different cultures for thousands of years. Classical psychedelics from N,N'-dimethyltryptamine, psilocybin, mescaline and various lysergamides cause specific alterations in perception, emotion and cognition by acting through serotonin 5-HT receptor activation. Lysergic acid diethylamide, the first famous breakthrough in the field, was discovered by chance by Albert Hoffman in the Zurich Sandoz laboratory in 1943, and studies on its psychoactive effects began to take place in the literature. Studies in this area were blocked after the legislation controlling the use and research of psychedelic drugs came into force in 1967, but since the 1990s, it has started to be a matter of scientific curiosity again by various research groups. In particular, with the crucial reports of psychotherapy-assisted psilocybin applications for life-threatening cancer-related anxiety and depression, a new avenues have been opened in the treatment of psychiatric diseases such as treatment-resistant depression and substance addictions. An increasing number of studies show that psychedelics have a very promising potential in the treatment of neuropsychiatric diseases where the desired efficiency cannot be achieved with conventional treatment methods. In this context, we discuss psychedelic therapy, encompassing its historical development, therapeutic applications and potential treatment effects-especially in depression, trauma disorders and substance use disorders-within the framework of ethical considerations.
PubMed: 38773750
DOI: 10.1111/ejn.16421