Journal of Psychopharmacology最新文献

{"title":"Quantitative natural language processing markers of psychoactive drug effects: A pre-registered systematic review.","authors":"Sachin Ahuja, Farida Zaher, Lena Palaniyappan","doi":"10.1177/02698811251319455","DOIUrl":"10.1177/02698811251319455","url":null,"abstract":"<p><p>Psychoactive substances used for recreational purposes have mind-altering effects, but systematic evaluation of these effects is largely limited to self-reports. Automated analysis of expressed language (speech and written text) using natural language processing (NLP) tools can provide objective readouts of mental states. In this pre-registered systematic review, we investigate findings from applying the emerging field of computational linguistics to substance use with specific focus on identifying short-term effects of psychoactive drugs. From the literature identified to date, we note that all the studied drugs - stimulants, 3,4-methylenedioxymethamphetamine (MDMA), cannabis, ketamine and psychedelics - affect language production. Based on two or more studies per substance, we note some emerging patterns: stimulants increase verbosity; lysergic acid diethylamide reduces the lexicon; MDMA increases semantic proximity to emotional words; psilocybin increases positive sentiment and cannabis affects speech stream acoustics. Ketamine and other drugs are understudied regarding NLP features (one or no studies). One study provided externally validated support for NLP and machine learning-based identification of MDMA intoxication. We could not undertake a meta-analysis due to the high degree of heterogeneity among outcome measures and the lack of sufficient number of studies. We identify a need for harmonised speech tasks to improve replicability and comparability, standardisation of methods for curating and analysing speech and text data, theory-driven inquiries and the need for developing a shared 'substance use language corpus' for data mining. The growing field of computational linguistics can be utilized to advance human behavioral pharmacology of psychoactive substances. Achieving this will require concerted efforts towards consistency in research methods.</p>","PeriodicalId":16892,"journal":{"name":"Journal of Psychopharmacology","volume":" ","pages":"940-949"},"PeriodicalIF":5.5,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12371134/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143433373","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Naturalistic use of psychedelics is associated with longitudinal improvements in anxiety and depression during global crisis times.","authors":"Maria Bălăeţ, William Trender, Annalaura Lerede, Peter J Hellyer, Adam Hampshire","doi":"10.1177/02698811251346729","DOIUrl":"10.1177/02698811251346729","url":null,"abstract":"<p><strong>Background: </strong>Mental health implications of COVID-19 drug use patterns are still unclear.</p><p><strong>Methods: </strong>We used data-driven clustering in a large citizen science cohort recruited agnostically to an interest in drug-use to categorise people according to common patterns of drug use and analysed their mental health symptoms (GAD-7 and PHQ-9 items), from recruitment prior to COVID-19 restrictions in 2020 (<i>N</i> = 242,260) to three follow-ups in 2020-2022 (<i>N</i> = 68,416). Mixed effects modelling examined how mental health scores related to drug-use clusters cross-sectionally and how changes in those scores longitudinally related to changes in consumption frequencies.</p><p><strong>Results: </strong>We identified six common patterns of drug use during the COVID-19 pandemic, with cannabis cross cutting most of them. The majority of drug use clusters had worse average mental health scores relative to drug-naive individuals at all timepoints. The average mental health scores of those who used more drugs during the pandemic worsened over time relative to individual baselines. However, psychedelics and cannabis users showed average improvements in depression (β = -0.26 SD, 95% CI: -0.44, -0.08, <i>p</i> = 0.003), anxiety (β = -0.24 SD, 95% CI: -0.41, -0.06, <i>p</i> = 0.007) and overall mental health (β = -0.2 SD, 95% CI: -0.35, -0.04, <i>p</i> = 0.01) from pre-pandemic to January 2022, becoming on par with the drug-naive group. This was not the case for cannabis-only users, whose worse mental health scores persisted.</p><p><strong>Conclusion: </strong>Those who used psychedelics may have experienced some improvements in mental health across the pandemic timeframe, which supports the idea that beneficial effects on mood and anxiety associated with these substances may extend beyond controlled conditions.</p>","PeriodicalId":16892,"journal":{"name":"Journal of Psychopharmacology","volume":" ","pages":"957-967"},"PeriodicalIF":5.5,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12371141/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144326028","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Set and setting of psychedelics for therapeutic use in psychiatry: A systematic review.","authors":"Clémentine Estric, Thomas Duron, Sarah Kabani, Jorge Lopez-Castroman","doi":"10.1177/02698811251338214","DOIUrl":"10.1177/02698811251338214","url":null,"abstract":"<p><p>Psychedelics offer promising outcomes in psychiatry. However, the preparation of participants (set) and the environmental conditions of taking a psychedelic (setting) are not standardized. We describe the set and setting for therapeutic use of psychedelic drugs in people with psychiatric disorders. In this systematic review, articles were identified in the PubMed and Web of Science databases until 12 December 2023. Only clinical trials published in English or French were eligible, and studies using psychedelics for withdrawal were excluded. Sixteen domains of set and setting were assessed covering participant selection, pre- and post-session interventions, monitor presence, environmental management, and end-of-session procedure. Of 4912 articles screened, 27 articles were retained reporting on 25 studies. Thirteen of the included studies reported randomized trials, while 12 were open-label studies, on a total of 763 participants. Studies considered features of set and setting to different extents. Participant selection and the creation of a safe environment were consistently present, but articles were more heterogeneous about reporting monitor training (52%), controlling visual distractors (64%) and creating a pleasant environment (68%). Psilocybin was over-represented (47%). Many key elements were described in each study, but differences in set and setting limit comparability and reproducibility. Harmonizing these aspects would aid the interpretation of future studies and help understand the effect of psychedelics in psychiatry.</p>","PeriodicalId":16892,"journal":{"name":"Journal of Psychopharmacology","volume":" ","pages":"910-929"},"PeriodicalIF":5.5,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144005858","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"What are set and setting: Reducing vagueness to improve research and clinical practice.","authors":"Kyle Patch, William R Smith","doi":"10.1177/02698811251337372","DOIUrl":"10.1177/02698811251337372","url":null,"abstract":"<p><p>Research on the therapeutic potential of psychedelics has surged, prompting a re-examination of the role of set and setting in psychedelic-assisted therapy. Yet, these concepts are vague and typically defined over inclusively. We believe that set and setting research should be methodologically reductionist, focusing on specific components rather than set and setting as such. To that end, we propose the mechanism-first approach, which begins with specific, paradigmatic set and setting components, such as \"openness to the psychedelic experience\" or calming lighting and music. It seeks to understand the mechanisms through which these components affect psychedelic outcomes. Once the mechanisms in paradigmatic cases are understood, researchers can ask whether other mental and environmental factors play the same or similar mechanistic roles. As the process iterates over time, understanding of set and setting expands to include more components. Setting aside the vague, standard definitions of set and setting and focusing, instead, on specific components of set and setting, the mechanism-first approach encourages productive research agendas, focused on specific projects that are mutually informative. To defend it, we outline the problems with standard definitions of set and setting, describe the mechanism-first approach in detail, illustrate it by considering its implications for selected, active research projects, and respond to objections to our approach.</p>","PeriodicalId":16892,"journal":{"name":"Journal of Psychopharmacology","volume":" ","pages":"900-909"},"PeriodicalIF":5.5,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12354155/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144142870","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Investigating the safety and tolerability of single-dose psilocybin for post-traumatic stress disorder: A nonrandomized open-label clinical trial.","authors":"Niall M McGowan, James J Rucker, Rachel Yehuda, Manish Agrawal, Nadav Liam Modlin, Hollie Simmons, Agata Tofil-Kaluza, Shriya Das, Guy M Goodwin","doi":"10.1177/02698811251362390","DOIUrl":"https://doi.org/10.1177/02698811251362390","url":null,"abstract":"<p><strong>Background: </strong>Post-traumatic stress disorder (PTSD) is a debilitating condition for which there are few efficacious treatments. Psilocybin is being studied for use in treatment-resistant depression but has not yet been investigated in PTSD.</p><p><strong>Aims: </strong>The trial's primary outcome was to investigate the safety and tolerability of single-dose psilocybin in participants with PTSD.</p><p><strong>Methods: </strong>This was a Phase 2, nonrandomized, open-label, multicenter trial. Secondary outcomes were changes in PTSD symptoms (Clinician-Administered PTSD Scale for DSM-5 (CAPS-5); PTSD Checklist for DSM-5 (PCL-5)), functional impairment (Sheehan Disability Scale; SDS) and quality of life (EQ-5D-5L index score).</p><p><strong>Results: </strong>Amongst the 22 participants enrolled (63.6% female; mean (SD) age, 39.0 (7.91) years), there was a total of 117 treatment-emergent adverse events (TEAEs); 70 (59.8%) were reported on administration day, of which 64/70 (91.4%) resolved by the end of the next day. TEAEs commonly included headache (<i>n</i> = 11; 50.0%), nausea (<i>n</i> = 8; 36.4%), crying (<i>n</i> = 6; 27.3%) and fatigue (<i>n</i> = 6; 27.3%). There were no serious TEAEs or TEAEs leading to study withdrawal. Pre-post comparisons indicated a clinically meaningful change from Baseline in mean CAPS-5 total score at Week 4 (-29.9 (14.06)) and Week 12 (-29.5 (15.43)), which was associated with the intensity of psychedelic experience on Day 1. PCL-5 scores showed symptom reduction was rapid and sustained until Week 12. SDS total score and EQ-5D-5L index score showed similar improvements.</p><p><strong>Conclusions: </strong>Psilocybin at a dose of 25 mg, administered with psychological support, may be safe, well-tolerated and associated with symptomatic improvement in adults with PTSD. Further investigation is warranted.</p><p><strong>Clinical trial registration: </strong>ClinicalTrials.gov Identifier: NCT05312151(https://clinicaltrials.gov/study/NCT05312151).</p>","PeriodicalId":16892,"journal":{"name":"Journal of Psychopharmacology","volume":" ","pages":"2698811251362390"},"PeriodicalIF":5.5,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144958524","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dose-response efficacy and safety of lumateperone in bipolar depression: A preliminary meta-analysis of randomized controlled trials.","authors":"Chih-Wei Hsu, Yu-Kang Tu, Kuo-Chuan Hung, Chih-Sung Liang, Ping-Tao Tseng, Yang-Chieh Brian Chen","doi":"10.1177/02698811251364389","DOIUrl":"https://doi.org/10.1177/02698811251364389","url":null,"abstract":"<p><strong>Background: </strong>The optimal lumateperone dose for bipolar depression remains uncertain.</p><p><strong>Aims: </strong>To examine its dose-response relationship for efficacy and safety.</p><p><strong>Methods: </strong>We systematically searched major databases to 1 July 2025. Efficacy outcomes included change in depression severity, global illness severity, quality of life, responder, and remitter rates. Safety outcomes included all-cause dropout, discontinuations due to adverse event (AE), treatment-emergent AE, mania, suicidality, extrapyramidal symptoms, body weight, lipid profile, and fasting glucose. A one-step dose-response meta-analysis generated effect sizes, reported as standardized mean differences (SMDs) and risk ratios (RRs) with 95% confidence intervals (CIs).</p><p><strong>Results: </strong>Three randomized controlled trials involving 1454 patients showed that a 42-mg daily dose of lumateperone significantly improved depressive symptoms (SMD = -0.26; 95% CI: -0.51, -0.02), Clinical Global Impression-Bipolar-Severity (CGI-BP-S) overall bipolar illness (SMD = -0.31; 95% CI: -0.45, -0.16), CGI-BP-S bipolar depression (SMD = -0.33; 95% CI: -0.48, -0.17), quality of life (SMD = 0.22; 95% CI: 0.07, 0.36), and responder rate (RR = 1.27; 95% CI: 1.05, 1.53), but not remitter rate (1.06; 95% CI: 0.81, 1.38). Compared with placebo, discontinuation due to AE significantly increased at the 42 mg dose (RR = 3.12; 95% CI: 1.68, 5.80), but not at 28 mg (1.58; 95% CI: 0.25, 9.89). Moreover, dropout rates (42 mg RR = 1.15; 95% CI: 0.76, 1.73) and other safety outcomes did not exhibit a dose-response trend.</p><p><strong>Conclusions: </strong>Preliminary evidence suggests that 42 mg daily of lumateperone may provide clinical benefit in bipolar depression, yet the higher rate of AE-related discontinuation warrants caution in practice. However, current data remain limited, requiring further studies to establish the optimal dosing range balancing efficacy and safety.</p>","PeriodicalId":16892,"journal":{"name":"Journal of Psychopharmacology","volume":" ","pages":"2698811251364389"},"PeriodicalIF":5.5,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144958488","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacological characterisation of psilocybin and 5-MeO-DMT discriminative cues in the rat and their translational value for identifying novel psychedelics.","authors":"Guy A Higgins, Cam MacMillan, Ines de Lannoy, Carolyn Tyler, Malik Slassi","doi":"10.1177/02698811251361453","DOIUrl":"https://doi.org/10.1177/02698811251361453","url":null,"abstract":"<p><strong>Background and aims: </strong>Drug discrimination procedures have made important contributions to the pre-clinical investigation of psychedelic drugs, such as psilocybin, lysergic acid diethylamide (LSD), N,N-dimethyltryptamine (DMT) and 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT). One of the most important being to highlight the critical role of central 5-HT2A receptor agonism as a mediator of hallucinogenic activity, and secondly, drugs that fully generalise to a 5-HT2A receptor agonist cued drug discrimination in rodents, may elicit hallucinogenic activity in humans, showing a forward translational value. However, there is relatively little information about how clinical exposures associated with hallucinations back-translate to generalisation profiles in the rat.</p><p><strong>Methods: </strong>The present series of experiments utilised two cohorts of male Sprague-Dawley rats, one trained to a psilocybin (0.5 mg/kg SC) cue, and the second trained to a 5-MeO-DMT (1 mg/kg SC) cue.</p><p><strong>Results: </strong>Tests of substitution and antagonism supported the primary role of 5-HT2A and 5-HT1A receptors, respectively, in the mediation of each cue. Plasma exposures of psilocin required for generalisation to the psilocybin cue (5-52 ng/mL) overlapped with clinical exposures associated with perceptual effects in humans. With respect to DMT and LSD, higher exposures were required in the rat compared to humans. Time-course studies using an approximate ED90 dose of each psychedelic showed differing temporal profiles in terms of duration of drug-lever generalisation, with LSD > psilocybin > 5-MeO-DMT ⩾ DMT, showing good agreement with clinical experience. With the exception of LSD, there was a good temporal association between plasma exposure and drug lever generalisation. The disconnect noted for LSD is mirrored by similar findings in the clinic.</p><p><strong>Conclusions: </strong>In summary, the present studies both support and extend the value of the drug discrimination assay as a translational approach to the pre-clinical study of psychedelic drugs.</p>","PeriodicalId":16892,"journal":{"name":"Journal of Psychopharmacology","volume":" ","pages":"2698811251361453"},"PeriodicalIF":5.5,"publicationDate":"2025-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144958561","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Appraisal of the validity of preclinical investigations to predict the efficacy of psychedelic drugs as fast-acting antidepressants.","authors":"S Clare Stanford","doi":"10.1177/02698811251360754","DOIUrl":"https://doi.org/10.1177/02698811251360754","url":null,"abstract":"<p><p>Each incident of failure of a novel drug to translate from preclinical experiments into the clinic increases the pressure to justify the use of animals in these experiments and for the interpretation of findings to be valid and convincing. This is especially the case with research of psychedelics, because they have already been tested extensively in humans. One reason for failure to translate is that preclinical research findings and conclusions are rarely, if ever, confirmed independently. Another is an incautious interpretation of the validity of the animal models that are used, in respect of their relevance to the human disorder of interest and its treatment. This article discusses both these points in the context of preclinical investigations of psychedelics as fast-acting antidepressants, but the generic points are relevant to other human disorders as well.</p>","PeriodicalId":16892,"journal":{"name":"Journal of Psychopharmacology","volume":" ","pages":"2698811251360754"},"PeriodicalIF":5.5,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144958533","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Acute cannabidiol (CBD), tetrahydrocannabinol (THC) and their mixture (THC:CBD) exert differential effects on brain activity and blood flow in rats: A translational neuroimaging study.","authors":"Eilidh MacNicol, Michelle Kokkinou, Maria Elisa Serrano Navacerrada, Donna-Michelle Smith, Jennifer Li, Camilla Simmons, Eugene Kim, Michel Mesquita, Loreto Rojo Gonzalez, Tierney Andrews, Sally Loomis, Royston A Gray, Volker Knappertz, Benjamin J Whalley, Andrew C McCreary, Steven Cr Williams, David Virley, Diana Cash","doi":"10.1177/02698811251360745","DOIUrl":"https://doi.org/10.1177/02698811251360745","url":null,"abstract":"<p><strong>Background: </strong>Cannabis constituents, including Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), show distinct pharmacological profiles with therapeutic relevance for neurological and psychiatric conditions. THC exerts euphoric effects primarily via CB1 receptor activation, while CBD displays non-euphoric properties affecting various pathways.</p><p><strong>Aims: </strong>This study evaluated the effects of THC, CBD, and their combination on brain functional connectivity (FC) and cerebral blood flow (CBF) using multimodal neuroimaging.</p><p><strong>Methods: </strong>Adult male Sprague Dawley rats received intraperitoneal doses of 10 mg/kg THC, 150 mg/kg CBD, 10.8:10 mg/kg THC:CBD, or vehicle. Resting-state blood oxygenation level dependent magnetic resonance imaging and arterial spin labelling assessed FC and CBF, approximately 2 h after drug administration. Graph-theory metrics and seed-based analyses identified connectivity and perfusion alterations, while plasma analyses determined cannabinoid concentrations.</p><p><strong>Results: </strong>THC increased whole-brain FC and clustering coefficient, with elevated CBF in cortical and subcortical regions. CBD decreased FC metrics without affecting CBF, while THC:CBD induced moderate increases in both. Seed-based analysis revealed THC-driven increases in cortical-hippocampal and cortical-striatal connectivity, attenuated in the THC:CBD group. A multivariate combined analysis of FC and CBF revealed a divergent pattern of changes induced by each drug.</p><p><strong>Conclusions: </strong>In conclusion, we show that THC and CBD induce distinct neurophysiological profiles in rats, with THC increasing both connectivity and perfusion, moderated by CBD when combined. These findings corroborate existing knowledge about the effects of cannabinoids on the brain, while also supporting the potential of preclinical functional neuroimaging to delineate cannabinoid-induced endophenotypes, offering insights for therapeutic development.</p>","PeriodicalId":16892,"journal":{"name":"Journal of Psychopharmacology","volume":" ","pages":"2698811251360745"},"PeriodicalIF":5.5,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144958536","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The pharmacology underlying the unique antipsychotic efficacy of clozapine.","authors":"Gavin P Reynolds","doi":"10.1177/02698811251365177","DOIUrl":"10.1177/02698811251365177","url":null,"abstract":"<p><p>Clozapine is unique in being the only recourse for people with schizophrenia not responding to conventional pharmacotherapy with dopamine D2 antagonists and partial agonists. Yet, after half a century of use, the underlying mechanism of clozapine's relatively greater efficacy remains elusive. There have been many hypotheses relating to various neurotransmitter receptors that have not withstood further study, and some that have not been fully investigated. The recent introduction of the xanomeline-trospium combination for the treatment of schizophrenia has renewed interest in muscarinic receptor mechanisms; like xanomeline, clozapine and particularly its metabolite norclozapine reportedly have partial agonist actions at some muscarinic receptor subtypes. In their recent article, Morrison et al. draw attention to this by highlighting hypersalivation, a common feature of clozapine treatment that is not shared by other antipsychotic agents which they suggest to be a result of muscarinic receptor agonism. However the relatively weak muscarinic activity of clozapine, low brain availability of norclozapine and clinical findings from xanomeline combine to provide little support for muscarinic mechanisms underlying the greater efficacy of clozapine. An alternative hypothesis is that of alpha2 adrenergic receptor antagonism, a feature of clozapine pharmacology that may also contribute to clozapine-induced hypersalivation. Clinical findings with adjunctive alpha2 antagonists demonstrate clozapine-like improvements in antipsychotic efficacy, while both preclinical studies with specific alpha2C antagonists and the relatively high and selective antagonism of alpha2C receptors by clozapine provide support for this mechanism for clozapine's unique efficacy.</p>","PeriodicalId":16892,"journal":{"name":"Journal of Psychopharmacology","volume":" ","pages":"2698811251365177"},"PeriodicalIF":5.5,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144883085","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}