The serotonergic psychedelics psilocybin, LSD and DMT hold great promise for the development of new treatments for psychiatric conditions such as major depressive disorder, addiction and end-of-life anxiety. Previous studies in both animals and humans have confirmed the effects of these drugs on neuronal activity and plasticity. However, the understanding of the mechanisms of action of these substances is limited. Here we show rapid effects of psychedelics on presynaptic properties, using live cell imaging at the level of single synapses in primary rat cortical neurons. Using the genetically encoded reporter of synaptic vesicle fusion synaptopHluorin, we detected a reduced fraction of synaptic vesicles that fused in response to mild or strong electrical stimulation 3-30 min after application of serotonergic psychedelics. These effects were transient and no longer present 24 h after treatment. While DMT only reduced the total recycling pool, LSD and psilocin also reduced the size of the readily releasable vesicle pool. Imaging with the sensors for glutamate, iGluSnFR, and presynaptic calcium, synGCaMP6, showed that while psilocin and DMT increased evoked glutamate release, LSD and psilocin reduced evoked presynaptic calcium levels. Interestingly, psilocin also affected short-term plasticity leading to a depression of responses to paired stimuli. The rapid and drug-specific modulation of glutamatergic neurotransmission described in this study may contribute to distinct anxiolytic and antidepressant properties of serotonergic psychedelics.
- MeSH
- halucinogeny * farmakologie MeSH
- krysa rodu rattus MeSH
- kultivované buňky MeSH
- kyselina glutamová * metabolismus MeSH
- LSD farmakologie MeSH
- mozková kůra * účinky léků metabolismus cytologie MeSH
- neurony * účinky léků metabolismus MeSH
- potkani Sprague-Dawley MeSH
- psilocybin farmakologie MeSH
- serotoninové látky farmakologie MeSH
- synaptické vezikuly účinky léků metabolismus MeSH
- tryptaminy farmakologie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND: Recent years show an exponential increased interest ("renaissance") in the use of psychedelics for the treatment of mental disorders and broader. Some of these treatments, such as psilocybin for depression, are in the process of formal regulation by regulatory bodies in the US (FDA) and Europe (EMA), and as such on the brink of real-world implementation. In the slipstream of these developments increasing commercial initiatives are taking shape. The European Psychiatric Association (EPA) acknowledges both the therapeutic potential of psychedelic substances and the challenges for both research and clinical implementation. Steps need to be taken toward a well-balanced policy based upon sound scientific evidence and research, aiming at safe, ethical responsible integration of psychedelic therapy available for all patients who can potentially benefit. METHODS: In this EPA policy paper, we highlight the potential benefits, and also the challenges of psychedelic treatments, which can be relevant for the future real-world implementation of these treatments. RESULTS: In addition to an overview of the current evidence and hypotheses of working mechanisms of psychedelic treatment, this policy paper specifically highlights the importance of the psychosocial components of the treatment as well as the ethical and professional aspects playing a role in real-world implementation. CONCLUSIONS: Four recommendations are formulated for further research and clinical implementation.
- MeSH
- duševní poruchy * farmakoterapie MeSH
- halucinogeny * terapeutické užití MeSH
- lidé MeSH
- psilocybin terapeutické užití farmakologie MeSH
- psychiatrie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Geografické názvy
- Evropa MeSH
OBJECTIVE: To determine the relationships between psilocybin dose, psychedelic experiences, and therapeutic outcome in treatment-resistant depression. METHODS: For treatment-resistant depression, 233 participants received a single dose of 25, 10, or 1 mg of COMP360 psilocybin (a proprietary, pharmaceutical-grade synthesized psilocybin formulation, developed by the sponsor, Compass Pathfinder Ltd.) with psychological support. The resulting psychedelic experience (Five-Dimensional Altered States of Consciousness questionnaire [5D-ASC] and Emotional Breakthrough Inventory [EBI]) were measured. These proximal variables and outcome 3 weeks post-administration (change in Montgomery-Åsberg Depression Rating Scale [MADRS]) were explored using correlation analysis. RESULTS: The mean intensity of psychedelic effects was dose-related, but distributions of scores for different doses overlapped considerably. Depression response correlated with select aspects of the psychedelic experience overall and for individual doses. At the 25 mg dose, 5D-ASC dimensions Oceanic Boundlessness (Pearson correlation coefficient r = -0.508) and Visual Restructuralization (r = -0.516), and EBI (r = -0·637) were the variables with the strongest correlation to the Week 3 change from Baseline in MADRS score. LIMITATIONS: The existence of correlation does not establish causation and exploratory findings require further replication, preferably in larger independent samples. CONCLUSIONS: The intensity of psychedelic experience overlaps widely across doses and mitigates the risk of unblinding to dose. Correlations between psychedelic experience and outcome suggest specificity in psilocybin's mechanism of action. Quality and intensity of psychedelic experience may be a measure of pharmacodynamic effect and reveal an effective dose response phenomenon for single oral doses.
- MeSH
- deprese nereagující na léčbu * farmakoterapie MeSH
- depresivní porucha unipolární farmakoterapie MeSH
- dospělí MeSH
- dvojitá slepá metoda MeSH
- halucinogeny * aplikace a dávkování farmakologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- psilocybin * farmakologie aplikace a dávkování MeSH
- psychiatrické posuzovací škály MeSH
- výsledek terapie MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- randomizované kontrolované studie MeSH
RATIONALE: Mescaline is a classical psychedelic compound with a phenylethylamine structure that primarily acts on serotonin 5-HT2A/C receptors, but also binds to 5-HT1A and 5-HT2B receptors. Despite being the first psychedelic ever isolated and synthesized, the precise role of different serotonin receptor subtypes in its behavioral pharmacology is not fully understood. OBJECTIVES: In this study, we aimed to investigate how selective antagonists of 5-HT2A, 5-HT2B, 5-HT2C, and 5-HT1A receptors affect the behavioral changes induced by subcutaneous administration of mescaline (at doses of 10, 20, and 100 mg/kg) in rats. METHODS: We used adult male Wistar rats in all our experiments. We evaluated locomotor activity using the open field test, and assessed sensorimotor gating deficits by measuring prepulse inhibition (PPI) of acoustic startle reaction (ASR). RESULTS: While the highest dose of mescaline induced hyperlocomotion (p < 0.001), which almost all the other antagonists reversed (p < 0.05-0.001), the PPI deficits were selectively normalized by the 5-HT2A antagonist (p < 0.05-0.01). The 5-HT2C antagonist partially reversed the small PPI deficit induced by lower doses of mescaline (p = 0.0017). CONCLUSION: Our findings suggest that mescaline-induced changes in behavior are primarily mediated by the 5-HT2A receptor subtype, with less pronounced contributions from the 5-HT2C receptor. The other antagonists had limited effects.
- MeSH
- antagonisté serotoninových receptorů 5-HT2 farmakologie MeSH
- antagonisté serotoninu farmakologie MeSH
- chování zvířat * účinky léků MeSH
- halucinogeny farmakologie aplikace a dávkování MeSH
- krysa rodu rattus MeSH
- lokomoce účinky léků MeSH
- meskalin * farmakologie MeSH
- pohybová aktivita účinky léků MeSH
- potkani Wistar * MeSH
- prepulsní inhibice účinky léků MeSH
- receptor serotoninový 5-HT2A * metabolismus účinky léků MeSH
- receptor serotoninový 5-HT2C * metabolismus účinky léků MeSH
- úleková reakce účinky léků MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- MeSH
- deprese * farmakoterapie MeSH
- halucinogeny MeSH
- lidé MeSH
- výzkumní pracovníci MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- osobní vyprávění MeSH
There are currently no pharmacological treatments for cocaine use disorder. Recently there has been a great deal of interest in the potential of psychedelic drugs such as psilocybin to treat psychiatric disorders. Human studies have indicated that a single administration of psilocybin can have long-lasting effects. Few preclinical studies have examined a role for psilocybin in addiction models. The goal of the current study was to determine whether psilocybin would enhance extinction following cocaine self-administration in male and female mice and rats and thus result in an attenuation of cue-induced drug-seeking. In experiments in mice, 16 female and 19 male mice underwent 8d of cocaine self-administration (0.5 mg/kg/infusion) and extinction training. Immediately following extinction trials, mice were injected with vehicle or 1.0 mg/kg psilocybin. Following the conclusion of extinction training, mice were tested for cue-induced reinstatement. In experiments in rats, 24 female and 23 male rats underwent 15d of cocaine self-administration (0.8 mg/kg/infusion) and extinction training. Immediately following extinction trials, rats were injected with vehicle, 1.0 mg/kg psilocybin, or 2.5 mg/kg psilocybin. Following the conclusion of extinction training, rats were tested for cue-induced reinstatement. Psilocybin administered following extinction trials had no effect, as both female and male mice and rats demonstrated significant cue-induced reinstatement. These data suggest that psilocybin is ineffective at altering cocaine-seeking behavior in the paradigm and doses used in the current study. It remains to be seen whether treatment with psilocybin under different conditions may be useful in the long-standing goal of finding pharmacotherapies to treat CUD.
- MeSH
- autoaplikace * MeSH
- chování při shánění drogy * účinky léků MeSH
- extinkce (psychologie) * účinky léků MeSH
- halucinogeny * farmakologie aplikace a dávkování MeSH
- inhibitory vychytávání dopaminu farmakologie aplikace a dávkování MeSH
- kokain * farmakologie aplikace a dávkování MeSH
- krysa rodu rattus MeSH
- myši inbrední C57BL MeSH
- myši MeSH
- operantní podmiňování účinky léků MeSH
- podněty * MeSH
- pohlavní dimorfismus MeSH
- poruchy spojené s užíváním kokainu farmakoterapie psychologie MeSH
- potkani Sprague-Dawley MeSH
- psilocybin * farmakologie aplikace a dávkování MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- MeSH
- duševní poruchy farmakoterapie MeSH
- halucinogeny * terapeutické užití MeSH
- lidé MeSH
- mezinárodní spolupráce MeSH
- posttraumatická stresová porucha * farmakoterapie MeSH
- psychotropní léky terapeutické užití MeSH
- stresové poruchy z válečných bojů farmakoterapie MeSH
- vystavení válce škodlivé účinky MeSH
- zákonodárství lékové MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- novinové články MeSH
- Geografické názvy
- Česká republika MeSH
- Evropa MeSH
- Ukrajina MeSH
- MeSH
- dostupnost zdravotnických služeb MeSH
- duševní poruchy epidemiologie farmakoterapie MeSH
- halucinogeny terapeutické užití MeSH
- lidé MeSH
- posttraumatická stresová porucha farmakoterapie MeSH
- psychiatrie * organizace a řízení statistika a číselné údaje trendy MeSH
- psychotropní léky terapeutické užití MeSH
- zákonodárství lékové MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- novinové články MeSH
- MeSH
- halucinogeny ekonomika terapeutické užití MeSH
- klinická studie jako téma MeSH
- lidé MeSH
- nádory komplikace psychologie MeSH
- psilocybin * ekonomika terapeutické užití MeSH
- vyvíjení léků MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- novinové články MeSH
- rozhovory MeSH
