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Fitoterapia Sep 2023Natural psychedelic compounds are emerging as potential novel therapeutics in psychiatry. This review will discuss how natural psychedelics exert their neurobiological... (Review)
Review
Natural psychedelic compounds are emerging as potential novel therapeutics in psychiatry. This review will discuss how natural psychedelics exert their neurobiological therapeutic effects, and how different neurotransmission systems mediate the effects of these compounds. Further, current therapeutic strategies for depression, and novel mechanism of action of natural psychedelics in the treatment of depression will be discussed. In this review, our focus will be on N, N-dimethyltryptamine (DMT), reversible type A monoamine oxidase inhibitors, mescaline-containing cacti, psilocybin/psilocin-containing mushrooms, ibogaine, muscimol extracted from Amanita spp. mushrooms and ibotenic acid.
Topics: Hallucinogens; Depression; Molecular Structure; N,N-Dimethyltryptamine; Neurotransmitter Agents
PubMed: 37490982
DOI: 10.1016/j.fitote.2023.105620 -
ACS Chemical Neuroscience Jan 2024Primary metabolites of mushroom tryptamines, psilocybin and baeocystin (i.e., psilocin and norpsilocin), exhibit potent agonist activity at the serotonin 2A receptor...
Primary metabolites of mushroom tryptamines, psilocybin and baeocystin (i.e., psilocin and norpsilocin), exhibit potent agonist activity at the serotonin 2A receptor (5-HT) but differ in their 5-HT-mediated effects . In particular, psilocin produces centrally mediated psychedelic effects , whereas norpsilocin, differing only by the loss of an -methyl group, is devoid of psychedelic-like effects. These observations suggest that the secondary methylamine group in norpsilocin impacts its central nervous system (CNS) bioavailability but not its receptor pharmacodynamics. To test this hypothesis, eight norpsilocin derivatives were synthesized with varied secondary alkyl-, allyl-, and benzylamine groups, primarily aiming to increase their lipophilicity and brain permeability. Structure-activity relationships for the norpsilocin analogues were evaluated using the mouse head-twitch response (HTR) as a proxy for CNS-mediated psychedelic-like effects. HTR studies revealed that extending the -methyl group of norpsilocin by a single methyl group, to give the corresponding secondary -ethyl analogue (4-HO-NET), was sufficient to produce psilocin-like activity (median effective dose or ED = 1.4 mg/kg). Notably, -allyl, -propyl, -isopropyl, and -benzyl derivatives also induced psilocin-like HTR activity (ED = 1.1-3.2 mg/kg), with variable maximum effects (26-77 total HTR events). By contrast, adding bulkier -butyl or cyclohexyl groups in the same position did not elicit psilocin-like HTRs. Pharmacological assessments of the tryptamine series demonstrated interactions with multiple serotonin receptor subtypes, including 5-HT, and other CNS signaling proteins (e.g., sigma receptors). Overall, our data highlight key structural requirements for CNS-mediated psychedelic-like effects of norpsilocin analogues.
Topics: Mice; Animals; Hallucinogens; Serotonin; Receptors, Serotonin; Brain; Receptor, Serotonin, 5-HT2A
PubMed: 38189238
DOI: 10.1021/acschemneuro.3c00610 -
Journal of Psychopharmacology (Oxford,... May 2024Psilocybin offers new hope for treating mood disorders due to its rapid and sustained antidepressant effects, as standard medications require weeks or months to exert...
BACKGROUND
Psilocybin offers new hope for treating mood disorders due to its rapid and sustained antidepressant effects, as standard medications require weeks or months to exert their effects. However, the mechanisms underlying this action of psilocybin have not been identified.
AIMS
To investigate whether psilocybin has rapid and sustained antidepressant-like effects in mice and investigate whether its potential mechanisms of action are related to promoted neuroplasticity.
METHODS
We first examined the antidepressant-like effects of psilocybin in normal mice by the forced swimming test and in chronic corticosterone (CORT)-exposed mice by the sucrose preference test and novelty-suppressed feeding test. Furthermore, to explore the role of neuroplasticity in mediating the antidepressant-like effects of psilocybin, we measured structural neuroplasticity and neuroplasticity-associated protein levels in the prefrontal cortex (PFC) and hippocampus.
RESULTS
We observed that a single dose of psilocybin had rapid and sustained antidepressant-like effects in both healthy mice and chronic CORT-exposed mice. Moreover, psilocybin ameliorated chronic CORT exposure-induced inhibition of neuroplasticity in the PFC and hippocampus, including by increasing neuroplasticity (total number of dendritic branches and dendritic spine density), synaptic protein (p-GluA1, PSD95 and synapsin-1) levels, BDNF-mTOR signalling pathway activation (BDNF, TrkB and mTOR levels), and promoting neurogenesis (number of DCX-positive cells).
CONCLUSIONS
Our results demonstrate that psilocybin elicits robust, rapid and sustained antidepressant-like effects which is accompanied by the promotion of neuroplasticity in the PFC and hippocampus.
Topics: Animals; Neuronal Plasticity; Antidepressive Agents; Mice; Prefrontal Cortex; Male; Psilocybin; Hippocampus; Brain-Derived Neurotrophic Factor; Corticosterone; Depression; Mice, Inbred C57BL; TOR Serine-Threonine Kinases; Doublecortin Protein; Behavior, Animal; Disease Models, Animal
PubMed: 38680011
DOI: 10.1177/02698811241249436 -
The British Journal of Psychiatry : the... May 2024Australia has just rescheduled two drugs controlled under the United Nations Psychotropic Drug Conventions, psilocybin and MDMA, as treatments for treatment-resistant... (Review)
Review
Australia has just rescheduled two drugs controlled under the United Nations Psychotropic Drug Conventions, psilocybin and MDMA, as treatments for treatment-resistant depression and post-traumatic stress disorder respectively. This feature explores the reasons for these developments, the opportunities and challenges they provide to psychiatry communities and how along with health systems these communities might respond to these developments.
PubMed: 38764044
DOI: 10.1192/bjp.2024.76 -
International Journal of Molecular... Dec 2023The pathophysiology of depression is related to the reduced volume of the hippocampus and amygdala and hypertrophy of the nucleus accumbens. The mechanism of these...
The pathophysiology of depression is related to the reduced volume of the hippocampus and amygdala and hypertrophy of the nucleus accumbens. The mechanism of these changes is not well understood; however, clinical studies have shown that the administration of the fast-acting antidepressant ketamine reversed the decrease in hippocampus and amygdala volume in depressed patients, and the magnitude of this effect correlated with the reduction in depressive symptoms. In the present study, we attempted to find out whether the psychedelic substance psilocybin affects neurotransmission in the limbic system in comparison to ketamine. Psilocybin and ketamine increased the release of dopamine (DA) and serotonin (5-HT) in the nucleus accumbens of naive rats as demonstrated using microdialysis. Both drugs influenced glutamate and GABA release in the nucleus accumbens, hippocampus and amygdala and increased ACh levels in the hippocampus. The changes in D2, 5-HT1A and 5-HT2A receptor density in the nucleus accumbens and hippocampus were observed as a long-lasting effect. A marked anxiolytic effect of psilocybin in the acute phase and 24 h post-treatment was shown in the open field test. These data provide the neurobiological background for psilocybin's effect on stress, anxiety and structural changes in the limbic system and translate into the antidepressant effect of psilocybin in depressed patients.
Topics: Humans; Animals; Rats; Psilocybin; Ketamine; Limbic System; Glutamic Acid; Antidepressive Agents
PubMed: 38203271
DOI: 10.3390/ijms25010100 -
Annals of the New York Academy of... Jan 2024Music and psychedelics have been intertwined throughout the existence of Homo sapiens, from the early shamanic rituals of the Americas and Africa to the modern use of... (Review)
Review
Music and psychedelics have been intertwined throughout the existence of Homo sapiens, from the early shamanic rituals of the Americas and Africa to the modern use of psychedelic-assisted therapy for a variety of mental health conditions. Across such settings, music has been highly prized for its ability to guide the psychedelic experience. Here, we examine the interplay between music and psychedelics, starting by describing their association with the brain's functional hierarchy that is relied upon for music perception and its psychedelic-induced manipulation, as well as an exploration of the limited research on their mechanistic neural overlap. We explore music's role in Western psychedelic therapy and the use of music in indigenous psychedelic rituals, with a specific focus on ayahuasca and the Santo Daime Church. Furthermore, we explore work relating to the evolution and onset of music and psychedelic use. Finally, we consider music's potential to lead to altered states of consciousness in the absence of psychedelics as well as the development of psychedelic music. Here, we provide an overview of several perspectives on the interaction between psychedelic use and music-a topic with growing interest given increasing excitement relating to the therapeutic efficacy of psychedelic interventions.
Topics: Humans; Hallucinogens; Psilocybin; Music; Mental Disorders
PubMed: 37983198
DOI: 10.1111/nyas.15082 -
Med (New York, N.Y.) Mar 2024Psilocybin-assisted psychotherapy (PAP) has been associated with antidepressant effects. Trials to date have typically excluded participants with complex presentations.... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Psilocybin-assisted psychotherapy (PAP) has been associated with antidepressant effects. Trials to date have typically excluded participants with complex presentations. Our aim was to determine the feasibility of PAP in a complex population, including high levels of treatment resistance in major depressive and bipolar disorder and patients with baseline suicidality and significant comorbidity. We also evaluated flexible repeated doses over a 6-month period.
METHODS
Adults with treatment-resistant depression as part of major depressive or bipolar II disorder without psychosis or a substance use disorder were eligible to participate. Subjects were randomized to immediate treatment or waitlist control, with all eventually receiving PAP. Participants had one, two, or three psilocybin sessions with a fixed dose of 25 mg. Each dose was accompanied by preparation and integration psychotherapy sessions. Acceptability, safety, tolerability, and efficacy were evaluated (this study was registered at ClinicalTrials.gov: NCT05029466).
FINDINGS
Participants were randomized to immediate treatment (n = 16) or delayed treatment (n = 14). 29/30 were retained to the week-2 primary endpoint. Adverse events were transient, with no serious adverse events. Greater reductions in depression severity as measured by the Montgomery-Åsberg Depression Rating Scale (MADRS) were observed in the immediate treatment arm compared to the waitlist period arm with a large hedge's g effect size of 1.07 (p < 0.01). Repeated doses were associated with further reductions in MADRS scores compared to baseline.
CONCLUSIONS
PAP was feasible in complex patients with preliminary antidepressant efficacy and adequate safety and tolerability. Repeated doses were associated with greater reductions in depression severity.
FUNDING
This work was funded by Brain and Cognition Discovery Foundation (BCDF), Usona, and Braxia Scientific.
Topics: Adult; Humans; Psilocybin; Depressive Disorder, Major; Depressive Disorder, Treatment-Resistant; Antidepressive Agents; Psychotherapy
PubMed: 38359838
DOI: 10.1016/j.medj.2024.01.005 -
European Eating Disorders Review : the... Oct 2023Treatment for anorexia nervosa (AN) remains challenging; there are no approved psychopharmacological interventions and psychotherapeutic strategies have variable... (Review)
Review
OBJECTIVE
Treatment for anorexia nervosa (AN) remains challenging; there are no approved psychopharmacological interventions and psychotherapeutic strategies have variable efficacy. The investigation of evidence-based treatments has so far been compounded by an underdeveloped understanding into the neurobiological changes associated with the acute stages of AN. There is converging evidence of deficiencies in neuroplasticity in AN.
METHOD
This paper provides an overview of neuroimaging, neuropsychological, molecular and qualitative findings relating to neuroplasticity in AN, translating these findings to the identification of novel biological and psychotherapeutic strategies.
RESULTS
Novel psychopharmacological approaches that may ameliorate deficiencies in neuroplasticity include medications such as ketamine, psilocybin and human recombinant leptin. Anti-inflammatory medications and brain-derived neurotrophic factor mimetics may emerge as potential treatments following further research. Psychotherapeutic strategies that may target neuroplastic deficiencies, as well as having wider effects on identity, include imagery rescripting, memory specificity training, cognitive remediation therapy, exposure therapies, narrative therapies, cultural interventions (e.g. music and arts therapies) and yoga/mindfulness-based interventions.
CONCLUSIONS
Treatments specifically targeted towards mitigating the neurobiological sequalae of AN are warranted, and emerging neurobiological and neuropsychological research utilising longitudinal designs and large sample sizes, as well as initial feasibility studies, are necessitated to bolster translational efforts.
PubMed: 37823233
DOI: 10.1002/erv.3039 -
BMJ (Clinical Research Ed.) Aug 2023To estimate the effects of providing access to an alcohol intervention based on a smartphone. (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
To estimate the effects of providing access to an alcohol intervention based on a smartphone.
DESIGN
Randomised controlled trial..
SETTING
Four higher education institutions in Switzerland.
PARTICIPANTS
1770 students (≥18 years) who screened positive for unhealthy alcohol use (ie, a score on the alcohol use disorders identification test-consumption (AUDIT-C) of ≥4 for men and ≥3 for women) were randomly assigned by 1:1 allocation ratio in blocks of 10.
INTERVENTION
Providing access to a brief, smartphone based alcohol intervention.
OUTCOME MEASURES
The primary outcome studied was number of standard drinks per week at six months and the secondary outcome was number of heavy drinking days (past 30 days). Additional outcomes were maximum number of drinks consumed on one occasion, alcohol related consequences, and academic performance. Follow-up assessments occurred at months three, six, and 12. Data were analysed by intention to treat and by using generalised linear mixed models with random intercepts for the recruitment site and participants nested within the recruitment site, and with intervention ( control), time (three months six months; 12 months six months), and baseline outcome values as fixed effects.
RESULTS
Between 26 April 26 2021 and 30 May 2022, 1770 participants (intervention group (n=884); control group (n=886)) were included. Mean age was 22.4 years (standard deviation 3.07); 958 (54.1%) were women; and 1169 (66.0%) were undergraduate students, 533 (30.1%) were studying for a master's degree, 43 (2.4%) were studying for a doctorate, and 25 (1.4%) were students of other higher education programme. The baseline mean number of standard drinks per week was 8.59 (standard deviation 8.18); the baseline number of heavy drinking days was 3.53 (4.02). Of 1770 participants, follow-up rates were 1706 (96.4%) at three months, 1697 (95.9%) at six months, and 1660 (93.8%) at 12 months. Of 884 students randomly assigned to the intervention group, 738 (83.5%) downloaded the smartphone application. The intervention had a significant overall effect on the number of standard drinks per week (incidence rate ratio 0.90 (95% confidence interval 0.85 to 0.96)), heavy drinking days (0.89 (0.83 to 0.96)), and the maximum number of drinks consumed on one occasion (0.96 (0.93 to 1.00), P=0.029), indicating significantly lower drinking outcomes in the intervention group than in the control group during the follow-up period. The intervention did not affect alcohol related consequences or academic performance.
CONCLUSIONS
Providing access to the smartphone application throughout the 12 month follow-up was effective at limiting the average drinking volume of university students who had self-reported unhealthy alcohol use at baseline.
TRIAL REGISTRATION
ISRCTN 10007691.
Topics: Male; Humans; Female; Young Adult; Adult; Smartphone; Alcohol Drinking; Alcoholism; Secondary Prevention; Universities; Ethanol; Students
PubMed: 37586742
DOI: 10.1136/bmj-2022-073713 -
Current Opinion in Psychiatry Jul 2024The pace of psychedelic treatments continues to increase. Regulation and coherent clinical guidance have not been established. A philosophical divide limits effective... (Review)
Review
PURPOSE OF REVIEW
The pace of psychedelic treatments continues to increase. Regulation and coherent clinical guidance have not been established. A philosophical divide limits effective resolution of a practice delivery quandary: is this primarily a pharmacological or psychotherapeutic intervention?
RECENT FINDINGS
Lykos (formerly MAPS) has submitted its new drug application (NDA) request to the FDA for 3-4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for PTSD and is expecting a response by the summer of 2024. Australia endorsed psilocybin and MDMA for regulated use in 2023. Multiple phase II and III clinical trials are also being conducted in the United States and Europe to study the use of psilocybin. Currently, Colorado and Oregon have legalized psilocybin in different manners. In Colorado, plants containing psilocybin, ibogaine, dimethyltryptamine (DMT) and mescaline (other than peyote) are now legal to possess, share and cultivate. Guidelines for regulated treatment with psilocybin containing mushrooms are in process with service delivery to begin early in 2025. In Oregon, clients must complete a preparation session with a licensed facilitator before consuming psilocybin products at a licensed service center. A prescription is not required. It is expected that other states will follow suit with a ballot measure likely in Massachusetts this year. Additionally, in the United States, the DEA, state boards, pharmaceutical distributors, and professional liability carriers all share mounting concerns about the in-home use of compounded ketamine used as a psychedelic therapeutic via remote prescribing.
SUMMARY
Psychedelic treatments are rapidly entering the mainstream of medical care delivery in the United States. Clinical guidelines are urgently needed to ensure well tolerated practice and coherent regulation. The delivery of this guidance is limited by a core philosophical disagreement. Resolution of this conflict will be needed to deliver coherent clinical guidelines. Current research and clinical experience provide a solid foundation for practical clinical guidance and the introduction of psychedelics into healthcare.
Topics: Hallucinogens; Humans; Psilocybin; Psychotherapy; United States; N-Methyl-3,4-methylenedioxyamphetamine; Stress Disorders, Post-Traumatic
PubMed: 38726805
DOI: 10.1097/YCO.0000000000000946