RESUMO
Major depressive disorder (MDD) is a highly prevalent psychiatric disorder, associated with substantial burden and large economical costs. Notwithstanding various conventional antidepressant treatment options, a large portion of depressed people (ca. 30%) fails to respond to first-line treatment, resulting in treatment-resistant depression (TRD). Although non-response to multiple antidepressant interventions is a common outcome, a consensus definition of TRD is not yet available. In practice, TRD is applied when two or more successive treatments with different antidepressants are not working. The last decade's intense research into new medicines for TRD has led to two developments, using typical or serotonergic (psilocybin, ayahuasca) and atypical (glutamatergic) psychedelics (ketamine, esketamine). Both approaches, although via different entrance mechanism, exhibit a fast onset but also long-lasting antidepressant effect far beyond the biological presence of the drug in the body, strongly indicating that downstream mechanisms activated by signaling cascades in the brain are involved. The present chapter describes the clinical development of psilocybin and esketamine for TRD and discusses the problems involved in the use of a proper placebo because of the psychotomimetic (psilocybin) or dissociative (ketamine) effects that interfere with performing "blind" studies. Nevertheless, intranasal esketamine was developed and approved for TRD, whereas psilocybin has shown positive results. Adverse effects and tolerability of both drugs in the dose ranges used are generally acceptable. The emergence of anti-TRD medicines for treatment of a very severe disease is a breakthrough in psychiatry.
Assuntos
Antidepressivos , Transtorno Depressivo Resistente a Tratamento , Alucinógenos , Ketamina , Psilocibina , Humanos , Transtorno Depressivo Resistente a Tratamento/tratamento farmacológico , Alucinógenos/uso terapêutico , Alucinógenos/efeitos adversos , Alucinógenos/farmacologia , Ketamina/uso terapêutico , Ketamina/efeitos adversos , Psilocibina/uso terapêutico , Psilocibina/efeitos adversos , Psilocibina/farmacologia , Antidepressivos/uso terapêutico , Antidepressivos/efeitos adversos , Antidepressivos/farmacologia , Transtorno Depressivo Maior/tratamento farmacológico , Resultado do TratamentoRESUMO
Aspects of the acute experience induced by the serotonergic psychedelic psilocybin predict symptomatic relief in multiple psychiatric disorders and improved well-being in healthy participants, but whether these therapeutic effects are immediate or are based on memories of the experience is unclear. To examine this, we co-administered psilocybin (25 mg) with the amnestic benzodiazepine midazolam in 8 healthy participants and assayed the subjective quality of, and memory for, the dosing-day experience. We identified a midazolam dose that allowed a conscious psychedelic experience to occur while partially impairing memory for the experience. Furthermore, midazolam dose and memory impairment tended to associate inversely with salience, insight, and well-being induced by psilocybin. These data suggest a role for memory in therapeutically relevant behavioral effects occasioned by psilocybin. Because midazolam blocks memory by blocking cortical neural plasticity, it may also be useful for evaluating the contribution of the pro-neuroplastic properties of psychedelics to their therapeutic activity.
Assuntos
Alucinógenos , Midazolam , Psilocibina , Humanos , Psilocibina/administração & dosagem , Psilocibina/farmacologia , Midazolam/administração & dosagem , Midazolam/farmacologia , Alucinógenos/administração & dosagem , Alucinógenos/farmacologia , Masculino , Adulto , Feminino , Memória/efeitos dos fármacos , Adulto JovemRESUMO
Psilocybin has shown promise as a novel pharmacological intervention for treatment of depression, where post-acute effects of psilocybin treatment have been associated with increased positive mood and decreased pessimism. Although psilocybin is proving to be effective in clinical trials for treatment of psychiatric disorders, the information processing mechanisms affected by psilocybin are not well understood. Here, we fit active inference and reinforcement learning computational models to a novel two-armed bandit reversal learning task capable of capturing engagement behaviour in rats. The model revealed that after receiving psilocybin, rats achieve more rewards through increased task engagement, mediated by modification of forgetting rates and reduced loss aversion. These findings suggest that psilocybin may afford an optimism bias that arises through altered belief updating, with translational potential for clinical populations characterised by lack of optimism.
Assuntos
Comportamento Animal , Psilocibina , Animais , Psilocibina/farmacologia , Ratos , Masculino , Comportamento Animal/efeitos dos fármacos , Otimismo , Alucinógenos/farmacologia , Simulação por Computador , Reversão de Aprendizagem/efeitos dos fármacos , Recompensa , Reforço PsicológicoRESUMO
A variety of classic psychedelics and MDMA have been shown to enhance fear extinction in rodent models. This has translational significance because a standard treatment for post-traumatic stress disorder (PTSD) is prolonged exposure therapy. However, few studies have investigated psilocybin's potential effect on fear learning paradigms. More specifically, the extents to which dose, timing of administration, and serotonin receptors may influence psilocybin's effect on fear extinction are not understood. In this study, we used a delay fear conditioning paradigm to determine the effects of psilocybin on fear extinction, extinction retention, and fear renewal in male and female mice. Psilocybin robustly enhances fear extinction when given acutely prior to testing for all doses tested. Psilocybin also exerts long-term effects to elevate extinction retention and suppress fear renewal in a novel context, although these changes were sensitive to dose. Analysis of sex differences showed that females may respond to a narrower range of doses than males. Administration of psilocybin prior to fear learning or immediately after extinction yielded no change in behavior, indicating that concurrent extinction experience is necessary for the drug's effects. Cotreatment with a 5-HT2A receptor antagonist blocked psilocybin's effects for extinction, extinction retention, and fear renewal, whereas 5-HT1A receptor antagonism attenuated only the effect on fear renewal. Collectively, these results highlight dose, context, and serotonin receptors as crucial factors in psilocybin's ability to facilitate fear extinction. The study provides preclinical evidence to support investigating psilocybin as a pharmacological adjunct for extinction-based therapy for PTSD.
Assuntos
Relação Dose-Resposta a Droga , Extinção Psicológica , Medo , Alucinógenos , Psilocibina , Psilocibina/farmacologia , Medo/efeitos dos fármacos , Animais , Extinção Psicológica/efeitos dos fármacos , Masculino , Feminino , Alucinógenos/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Receptores de Serotonina/efeitos dos fármacos , Receptores de Serotonina/metabolismo , Condicionamento Clássico/efeitos dos fármacosRESUMO
Obsessive-compulsive disorder (OCD) is a chronic mental disease that affects approximately 2% of the population. Obsessions and compulsions are troublesome for patients and may disturb their everyday activities. The pathogenesis of this disease is still not fully elucidated, but dysfunctions of serotonin-, dopamine- and glutamate-mediated neurotransmission together with early maladaptive schemas seem of importance. Pharmacological treatment includes drugs affecting the serotoninergic, dopaminergic, and glutamatergic systems, such as selective serotonin reuptake inhibitors (SSRIs). Providing that up to 40% of patients with OCD are resistant to the currently available medications, there is a need for novel and effective therapies. Recent discoveries suggest that psilocybin, a non-physically addictive psychoactive substance, may ameliorate disease symptoms. When used in appropriate doses and under strict clinical control, psilocybin appears as a valuable treatment for OCD. This narrative article provides a thorough overview of OCD's etiology, current treatment options, and the emerging evidence supporting psilocybin's efficacy in managing OCD symptoms.
Assuntos
Alucinógenos , Transtorno Obsessivo-Compulsivo , Psilocibina , Humanos , Transtorno Obsessivo-Compulsivo/tratamento farmacológico , Psilocibina/uso terapêutico , Psilocibina/farmacologia , Alucinógenos/uso terapêutico , Alucinógenos/farmacologia , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , AnimaisRESUMO
Alcohol is a harmful drug, and reducing its consumption is a significant challenge for users. Furthermore, alcohol dependence is often treatment-resistant, and no completely effective treatment model is available for chemical dependence. Classic psychedelics, such as LSD, psilocybin, and ayahuasca have been used in different clinical and pre-clinical trials, demonstrating promising pharmacotherapeutic effects in the treatment of treatment-resistant psychopathological conditions, such as addiction, especially related to alcohol dependence. In this work, we conducted a narrative review of the emerging research regarding the potential of psychedelics for alcohol use disorder treatment. Psychedelic substances have demonstrated potential for treating drug addiction, especially AUD, mostly by modulating neuroplasticity in the brain. Given that serotonergic psychedelics do not produce physical dependence or withdrawal symptoms with repeated use, they may be considered promising treatment options for managing drug use disorders. However, certain limitations could be found. Although many participants achieve positive results with only one treatment dose in clinical studies, great inter-individual variability exists in the duration of these effects. Therefore, further studies using different doses and experimental protocols should be conducted to enhance evidence about psychedelic substances.
Assuntos
Alcoolismo , Alucinógenos , Humanos , Alucinógenos/uso terapêutico , Alucinógenos/administração & dosagem , Alcoolismo/tratamento farmacológico , Animais , Psilocibina/uso terapêutico , Psilocibina/farmacologia , Psilocibina/administração & dosagem , Dietilamida do Ácido Lisérgico/uso terapêutico , Dietilamida do Ácido Lisérgico/farmacologia , Dietilamida do Ácido Lisérgico/administração & dosagemRESUMO
There is growing interest in the therapeutic potential of psilocybin for the treatment of a wide variety of medical problems, and even for the promotion of wellbeing among healthy individuals. Interestingly, among the many proposed indications, both obesity and anorexia nervosa (AN) have been discussed. However, the effect of psilocybin on appetitive behavior and metabolism is not well known. Here, we report the effects of psilocybin on body weight, intake and output, body composition, and metabolic function among lean male and female wild-type mice. In the days immediately following treatment, both male and female mice receiving a single intraperitoneal dose of psilocybin were consistently heavier than saline controls, with no effect of psilocybin on intake or output. Co-administration of the 5-HT2A/2C receptor antagonist ketanserin had no effect on this outcome. Body composition analysis revealed that psilocybin significantly increased lean and water mass among males, with a similar trend among females. A metabolic panel revealed increased creatine kinase (CK), aspartate aminotransferase (AST), and chloride among male and female psilocybin treated mice. Together, these findings begin to investigate the potential mechanisms of psilocybin's effects on body weight and metabolic measures. Such understanding will be critical for the safe, efficacious, and well-informed use of psilocybin in clinical and non-clinical settings.
Assuntos
Composição Corporal , Peso Corporal , Psilocibina , Animais , Feminino , Masculino , Camundongos , Composição Corporal/efeitos dos fármacos , Psilocibina/farmacologia , Peso Corporal/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Alucinógenos/farmacologia , Ketanserina/farmacologia , Ingestão de Alimentos/efeitos dos fármacos , Caracteres SexuaisRESUMO
BACKGROUND: Major depressive disorder (MDD) is a leading cause of disability worldwide across domains of health and cognition, affecting overall quality of life. Approximately one third of individuals with depression do not fully respond to treatments (e.g., conventional antidepressants, psychotherapy) and alternative strategies are needed. Recent early phase trials suggest psilocybin may be a safe and efficacious intervention with rapid-acting antidepressant properties. Psilocybin is thought to exert therapeutic benefits by altering brain network connectivity and inducing neuroplastic changes that endure for weeks post-treatment. Although early clinical results are encouraging, psilocybin's acute neurobiological effects on neuroplasticity have not been fully investigated. We aim to examine for the first time how psilocybin acutely (intraday) and subacutely (weeks) alters functional brain networks implicated in depression. METHODS: Fifty participants diagnosed with MDD or persistent depressive disorder (PDD) will be recruited from a tertiary mood disorders clinic and undergo 1:1 randomization into either an experimental or control arm. Participants will be given either 25 mg psilocybin or 25 mg microcrystalline cellulose (MCC) placebo for the first treatment. Three weeks later, those in the control arm will transition to receiving 25 mg psilocybin. We will investigate whether treatments are associated with changes in arterial spin labelling and blood oxygenation level-dependent contrast neuroimaging assessments at acute and subacute timepoints. Primary outcomes include testing whether psilocybin demonstrates acute changes in (1) cerebral blood flow and (2) functional brain activity in networks associated with mood regulation and depression when compared to placebo, along with changes in MADRS score over time compared to placebo. Secondary outcomes include changes across complementary clinical psychiatric, cognitive, and functional scales from baseline to final follow-up. Serum peripheral neurotrophic and inflammatory biomarkers will be collected at baseline and follow-up to examine relationships with clinical response, and neuroimaging measures. DISCUSSION: This study will investigate the acute and additive subacute neuroplastic effects of psilocybin on brain networks affected by depression using advanced serial neuroimaging methods. Results will improve our understanding of psilocybin's antidepressant mechanisms versus placebo response and whether biological measures of brain function can provide early predictors of treatment response. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT06072898. Registered on 6 October 2023.
Assuntos
Afeto , Encéfalo , Transtorno Depressivo Maior , Psilocibina , Ensaios Clínicos Controlados Aleatórios como Assunto , Humanos , Psilocibina/uso terapêutico , Psilocibina/efeitos adversos , Psilocibina/administração & dosagem , Psilocibina/farmacologia , Afeto/efeitos dos fármacos , Encéfalo/diagnóstico por imagem , Encéfalo/efeitos dos fármacos , Encéfalo/fisiopatologia , Transtorno Depressivo Maior/tratamento farmacológico , Imageamento por Ressonância Magnética , Fatores de Tempo , Resultado do Tratamento , Adulto , Plasticidade Neuronal/efeitos dos fármacos , Adulto Jovem , Masculino , Antidepressivos/uso terapêutico , Feminino , Pessoa de Meia-IdadeRESUMO
A single dose of psilocybin, a psychedelic that acutely causes distortions of space-time perception and ego dissolution, produces rapid and persistent therapeutic effects in human clinical trials1-4. In animal models, psilocybin induces neuroplasticity in cortex and hippocampus5-8. It remains unclear how human brain network changes relate to subjective and lasting effects of psychedelics. Here we tracked individual-specific brain changes with longitudinal precision functional mapping (roughly 18 magnetic resonance imaging visits per participant). Healthy adults were tracked before, during and for 3 weeks after high-dose psilocybin (25 mg) and methylphenidate (40 mg), and brought back for an additional psilocybin dose 6-12 months later. Psilocybin massively disrupted functional connectivity (FC) in cortex and subcortex, acutely causing more than threefold greater change than methylphenidate. These FC changes were driven by brain desynchronization across spatial scales (areal, global), which dissolved network distinctions by reducing correlations within and anticorrelations between networks. Psilocybin-driven FC changes were strongest in the default mode network, which is connected to the anterior hippocampus and is thought to create our sense of space, time and self. Individual differences in FC changes were strongly linked to the subjective psychedelic experience. Performing a perceptual task reduced psilocybin-driven FC changes. Psilocybin caused persistent decrease in FC between the anterior hippocampus and default mode network, lasting for weeks. Persistent reduction of hippocampal-default mode network connectivity may represent a neuroanatomical and mechanistic correlate of the proplasticity and therapeutic effects of psychedelics.
Assuntos
Encéfalo , Alucinógenos , Rede Nervosa , Psilocibina , Adolescente , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem , Encéfalo/citologia , Encéfalo/diagnóstico por imagem , Encéfalo/efeitos dos fármacos , Encéfalo/fisiologia , Mapeamento Encefálico , Rede de Modo Padrão/citologia , Rede de Modo Padrão/diagnóstico por imagem , Rede de Modo Padrão/efeitos dos fármacos , Rede de Modo Padrão/fisiologia , Alucinógenos/farmacologia , Alucinógenos/administração & dosagem , Voluntários Saudáveis , Hipocampo/citologia , Hipocampo/diagnóstico por imagem , Hipocampo/efeitos dos fármacos , Hipocampo/fisiologia , Imageamento por Ressonância Magnética , Metilfenidato/farmacologia , Metilfenidato/administração & dosagem , Rede Nervosa/citologia , Rede Nervosa/diagnóstico por imagem , Rede Nervosa/efeitos dos fármacos , Rede Nervosa/fisiologia , Psilocibina/farmacologia , Psilocibina/administração & dosagem , Percepção Espacial/efeitos dos fármacos , Percepção do Tempo/efeitos dos fármacos , EgoRESUMO
Several fungi belonging to the genus Psilocybe, also called "magic mushrooms", contain the hallucinogenic drugs psilocybin and psilocin. They are chemically related to serotonin (5-HT). In addition to being abused as drugs, they are now also being discussed or used as a treatment option for depression. Here, we hypothesized that psilocybin and psilocin may act also on cardiac serotonin receptors and studied them in vitro in atrial preparations of our transgenic mouse model with cardiac myocytes-specific overexpression of the human 5-HT4 receptor (5-HT4-TG) as well as in human atrial preparations. Both psilocybin and psilocin enhanced the force of contraction in isolated left atrial preparations from 5-HT4-TG, increased the beating rate in isolated spontaneously beating right atrial preparations from 5-HT4-TG and augmented the force of contraction in the human atrial preparations. The inotropic and chronotropic effects of psilocybin and psilocin at 10⯵M were smaller than that of 1⯵M 5-HT on the left and right atria from 5-HT4-TG, respectively. Psilocybin and psilocin were inactive in WT. In the human atrial preparations, inhibition of the phosphodiesterase III by cilostamide was necessary to unmask the positive inotropic effects of psilocybin or psilocin. The effects of 10⯵M psilocybin and psilocin were abrogated by 10⯵M tropisetron or by 1⯵M GR125487, a more selective 5-HT4 receptor antagonist. In summary, we demonstrated that psilocin and psilocybin act as agonists on cardiac 5-HT4 receptors.
Assuntos
Átrios do Coração , Camundongos Transgênicos , Psilocibina , Receptores 5-HT4 de Serotonina , Psilocibina/farmacologia , Psilocibina/análogos & derivados , Animais , Humanos , Receptores 5-HT4 de Serotonina/metabolismo , Receptores 5-HT4 de Serotonina/genética , Átrios do Coração/efeitos dos fármacos , Átrios do Coração/metabolismo , Masculino , Contração Miocárdica/efeitos dos fármacos , Alucinógenos/farmacologia , Alucinógenos/toxicidade , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Camundongos , Agonistas do Receptor 5-HT4 de Serotonina/farmacologia , Frequência Cardíaca/efeitos dos fármacos , FemininoRESUMO
BACKGROUND: Treatment-Resistant Depression (TRD) challenges psychiatric treatment, with existing guidelines covering only a subset of augmentation strategies. METHODS: A network meta-analysis following PRISMA guidelines examined the efficacy and safety of TRD treatments, analyzing 72 randomized controlled trials from eight databases, assessing response and remission rates, tolerability, and safety through the Cochrane Risk of Bias Tool and CINeMA framework. FINDINGS: Including 12,105 participants, the analysis highlighted ECT, Ketamine, Esketamine, and Psilocybin as superior first-line treatments due to their optimal balance between effectiveness and tolerability. Brexpiprazole and Quetiapine showed no significant efficacy over placebo in response rates, while Esketamine and Psilocybin exhibited lower tolerability. INTERPRETATION: The results advocate for ECT, Ketamine, Esketamine, and Psilocybin as preferred treatments for TRD, guiding clinical practice with evidence-based recommendations for enhancing treatment outcomes. This study underscores the importance of considering both efficacy and safety in selecting augmentation strategies for TRD.
Assuntos
Transtorno Depressivo Resistente a Tratamento , Metanálise em Rede , Ensaios Clínicos Controlados Aleatórios como Assunto , Humanos , Transtorno Depressivo Resistente a Tratamento/tratamento farmacológico , Transtorno Depressivo Resistente a Tratamento/terapia , Antidepressivos/uso terapêutico , Eletroconvulsoterapia , Ketamina/uso terapêutico , Psilocibina/uso terapêutico , Psilocibina/farmacologia , Psilocibina/efeitos adversos , Avaliação de Resultados em Cuidados de SaúdeRESUMO
Stuttering poses challenges to social, occupational, and educational aspects of life. Traditional behavioral therapies can be helpful but effects are often limited. Pharmaceutical treatments have been explored but there are no FDA-approved treatments for stuttering. Interest has grown in the potential use of classic psychedelics, including psilocybin and LSD, which have shown effectiveness in treating disorders with similar symptoms (e.g., anxiety, depression, PTSD). The potential effects of psychedelics on stuttering have not been explored. We conducted a preliminary investigation of self-identified stutterers who report their experiences taking classic psychedelics on the online messaging forum, Reddit. We qualitatively analyzed 114 publicly available posts, extracting meaningful units and assigning descriptor codes inductively. We then deductively organized responses into an established framework of psychedelics which includes behavioral, emotional, cognitive, belief-based, and social effects. These effects were subsequently grouped under organizing themes (positive, negative, neutral). Descriptive statistics revealed that the majority of users (74.0%) reported positive overall short-term effects particularly related to behavioral and emotional change (e.g., reduced stuttering and anxiety), but negative (9.6%), mixed (positive and negative; 4.8%), and neutral overall experiences (11.6%) were also reported. The results support the possibility that psychedelics may impact stuttering, but caution must be applied in their interpretation given the entirely uncontrolled research setting and potential adverse health effects of psychedelics as reported elsewhere. While these results do not encourage the use of psychedelics by stutterers, they suggest that future work could examine the impact of psychedelics on stuttering under supervised and in clinically controlled settings.
Assuntos
Alucinógenos , Psilocibina , Autorrelato , Gagueira , Humanos , Alucinógenos/administração & dosagem , Alucinógenos/uso terapêutico , Gagueira/tratamento farmacológico , Psilocibina/farmacologia , Psilocibina/administração & dosagem , Masculino , Feminino , Dietilamida do Ácido Lisérgico/farmacologia , Dietilamida do Ácido Lisérgico/administração & dosagem , AdultoRESUMO
INTRODUCTION: Psilocybin, a naturally occurring serotonergic agonist in some mushroom species, has shown promise as a novel, fast-acting pharmacotherapy seeking to overcome the limitations of conventional first-line antidepressants. Studying psilocybin effects on cognition and emotional processing may help to clarify the mechanisms underlying the therapeutic potential of psilocybin and may also support studies with people suffering from depression. Thus, this review aims to provide a comprehensive overview of the current literature regarding the effects of psilocybin on these two key areas in both healthy and depressed populations. METHOD: A systematic search was performed on 29 January 2024, in the PubMed, EBSCOhost, Web of Science and SCOPUS databases. After duplicates removal, study selection was conducted considering pre-specified criteria. Data extraction was then performed. The quality assessment of the studies was carried out using the Cochrane Collaboration tools for randomized (RoB 2.0) and non-randomized (ROBINS-I) controlled trials. RESULTS: Twenty articles were included, with 18 targeting healthy adults and two adults with depression. Results point to impairments within attentional and inhibitory processes, and improvements in the domains of creativity and social cognition in healthy individuals. In the population with depression, only cognitive flexibility and emotional recognition were affected, both being enhanced. The comparison of outcomes from both populations proved limited. CONCLUSIONS: Psilocybin acutely alters several cognitive domains, with a localized rather than global focus, in a dose- and time-dependent manner. However, the significant methodological constraints call for further research, in the context of depression and with standardized protocols, with longitudinal studies also imperative.
Assuntos
Cognição , Emoções , Psilocibina , Humanos , Psilocibina/farmacologia , Psilocibina/administração & dosagem , Adulto , Emoções/efeitos dos fármacos , Emoções/fisiologia , Cognição/efeitos dos fármacos , Cognição/fisiologia , Alucinógenos/farmacologia , Depressão/tratamento farmacológicoRESUMO
Background: Psilocybin and related tryptamines have come into the spotlight in recent years as potential therapeutics for depression. Research on the mechanisms of these effects has historically focused on the direct effects of these drugs on neural processes. However, in addition to such neural effects, alterations in peripheral physiology may also contribute to their therapeutic effects. In particular, substantial support exists for a gut microbiome-mediated pathway for the antidepressant efficacy of other drug classes, but no prior studies have determined the effects of tryptamines on microbiota. Methods: To address this gap, in this preliminary study, male Long Evans rats were treated with varying dosages of oral psilocybin (0.2 or 2 mg/kg), norbaeocystin (0.25 or 2.52 mg/kg), or vehicle and their fecal samples were collected 1 week and 3 weeks after exposure for microbiome analysis using integrated 16S ribosomal DNA sequencing to determine gut microbiome composition. Results: We found that although treatment with neither psilocybin nor norbaeocystin significantly affected overall microbiome diversity, it did cause significant dose- and time-dependent changes in bacterial abundance at the phylum level, including increases in Verrucomicrobia and Actinobacteria, and decreases in Proteobacteria. Conclusion and Implications: These preliminary findings support the idea that psilocybin and other tryptamines may act on the gut microbiome in a dose- and time-dependent manner, potentially identifying a novel peripheral mechanism for their antidepressant activity. The results from this preliminary study also suggest that norbaeocystin may warrant further investigation as a potential antidepressant, given the similarity of its effects to psilocybin.
Assuntos
Fezes , Microbioma Gastrointestinal , Ratos Long-Evans , Triptaminas , Animais , Microbioma Gastrointestinal/efeitos dos fármacos , Masculino , Triptaminas/farmacologia , Triptaminas/administração & dosagem , Ratos , Fezes/microbiologia , Psilocibina/farmacologia , Psilocibina/administração & dosagem , Administração Oral , Antidepressivos/farmacologia , Antidepressivos/administração & dosagemRESUMO
Some recent research and commentary have suggested that most or all the effects reported by people who microdose psychedelics may be explained by expectations or placebo effects. In this rapid review, we aimed to evaluate the strength of evidence for a placebo explanation of the reported effects of microdosing. We conducted a PubMed search for all studies investigating psychedelic microdosing with controlled doses and a placebo comparator. We identified 19 placebo-controlled microdosing studies and summarised all positive and null findings across this literature. Risk of bias was assessed using the Cochrane risk-of-bias tool for randomised trials. The reviewed papers indicated that microdosing with LSD and psilocybin leads to changes in neurobiology, physiology, subjective experience, affect, and cognition relative to placebo. We evaluate methodological gaps and challenges in microdosing research and suggest eight reasons why current claims that microdosing is predominately a placebo are premature and possibly wrong: (1) there have been only a small number of controlled studies; (2) studies have had small sample sizes; (3) there is evidence of dose-dependent effects; (4) studies have only investigated the effects of a small number of doses; (5) the doses investigated may have been too small; (6) studies have looked only at non-clinical populations; (7) studies so far have been susceptible to selection bias; and (8) the measured impact of expectancy is small. Considering the available evidence, we conclude that it is not yet possible to determine whether microdosing is a placebo.
Assuntos
Relação Dose-Resposta a Droga , Alucinógenos , Dietilamida do Ácido Lisérgico , Efeito Placebo , Psilocibina , Psilocibina/administração & dosagem , Psilocibina/farmacologia , Humanos , Alucinógenos/administração & dosagem , Alucinógenos/farmacologia , Dietilamida do Ácido Lisérgico/administração & dosagem , Dietilamida do Ácido Lisérgico/farmacologia , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
Major Depressive Disorder (MDD) poses a significant global health burden, with 30-40% patients developing resistance to standard clinical antidepressants, such as selective serotonin reuptake inhibitors and tricyclic antidepressants. In 2016, Carhart-Harris and colleagues reported that psilocybin, the hallucinogenic compound derived from magic mushrooms, exhibits rapid and enduring antidepressant effects in patients with treatment-resistant depression. Subsequent clinical studies have found the therapeutic potential of psilocybin in MDD, depressive episode in bipolar disorder, anorexia, and drug addiction. In 2018 and 2019, the U.S. Food and Drug Administration designated psilocybin as a "breakthrough medicine" for treatment-resistant depression and MDD, respectively. Notably, the side effects of psilocybin are limited to transient and mild issues, such as headache and fatigue, suggesting its safety. In 2023, we published a review on the role of serotonin 5-HT2A receptors in the antidepressant effects of serotonergic psychedelics (Nihon Yakurigaku Zasshi, Volume 158, Issue 3, Page 229-232). Here, we present our study alongside the latest clinical and preclinical research on the antidepressant effects of psilocybin and provide an overview of the potential and issues related to psilocybin therapy.