Journal of Psychopharmacology最新文献

{"title":"A systematic review and narrative summary of the therapeutic potential of classic serotonergic psychedelics for smoking cessation and reduction.","authors":"Dillon L Glenn, Seung Hee Choi, Rick S Zimmerman","doi":"10.1177/02698811251353251","DOIUrl":"10.1177/02698811251353251","url":null,"abstract":"<p><strong>Background: </strong>Classic serotonergic psychedelics are 5-HT2A partial agonists that induce non-ordinary states of consciousness. Many have demonstrated anti-addictive properties; however, their impact on smoking behaviors remains under-researched. This review provides a synthesis of the therapeutic potential of these compounds in promoting smoking cessation and reduction.</p><p><strong>Methods: </strong>A systematic review of peer-reviewed studies on psychedelics and smoking outcomes, published in English, was conducted. Database searches of PubMed, CINAHL, PsycINFO, and EMBASE resulted in 3547 records. ASReview, an open-source machine-learning tool, was used to improve the screening process. Abstract and initial review screening excluded 2336 articles, leaving 29 full-text articles for review. After further exclusion based on the inclusion of psychedelics and reported outcomes, eight studies were included in the analysis. All studies were assessed for risk of bias using the risk of bias in non-randomized studies of interventions (ROBINS-I) tool.</p><p><strong>Results: </strong>Heterogeneity in the data was observed. All studies showed a serious risk of bias. Psilocybin was the most frequently reported compound (<i>n</i> = 7), followed by lysergic acid diethylamide (LSD; <i>n</i> = 5), mescaline (<i>n</i> = 4), ayahuasca (<i>n</i> = 4), peyote (<i>n</i> = 2), and N,N-dimethyltryptamine (<i>n</i> = 1). Psilocybin, LSD, and ayahuasca revealed preliminary therapeutic potential for facilitating smoking cessation.</p><p><strong>Conclusions: </strong>Current literature on psychedelics' anti-addictive effects on smoking behaviors is promising but limited by weak study designs and low generalizability. Future research should allow for stronger sampling methods to improve statistical power and include comparative groups within experimental or quasi-experimental designs to strengthen inference for causal mechanisms between drug and nondrug influences on smoking outcomes.</p>","PeriodicalId":16892,"journal":{"name":"Journal of Psychopharmacology","volume":" ","pages":"930-939"},"PeriodicalIF":5.5,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144608645","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":"Lifetime classic psychedelic use and headaches: A cross-sectional study.","authors":"Zusanna Bjurenfalk, Alva Cosmo, Otto Simonsson, Caroline Ran","doi":"10.1177/02698811251324372","DOIUrl":"10.1177/02698811251324372","url":null,"abstract":"<p><strong>Background: </strong>Migraine and cluster headache are two primary headache disorders for which conventional treatments are limited. Classic psychedelic substances such as lysergic acid diethylamide (LSD) and psilocybin are potentially promising new treatment candidates for these conditions.</p><p><strong>Aims: </strong>The aim of the present study was to investigate the possible relationship between the lifetime use of classic psychedelics and frequent bad headaches in a large British cohort sample.</p><p><strong>Methods: </strong>Using data (<i>N</i> = 11,419) collected in 1999-2000 as part of the 1958 British National Child Development Study, this cross-sectional study used multiple logistic regression, controlling for a range of potential confounders, to test the hypothesis that lifetime use of classic psychedelics would be associated with lower odds of having frequent bad headaches.</p><p><strong>Results: </strong>Lifetime use of classic psychedelics was associated with 25% lower odds of having frequent bad headaches (adjusted odds ratio = 0.75, 95% CI: 0.59-0.95, <i>p</i> = 0.016).</p><p><strong>Conclusions: </strong>The results of the present study add to the literature suggesting classic psychedelics as a possible future prophylactic treatment option for primary headache disorders.</p>","PeriodicalId":16892,"journal":{"name":"Journal of Psychopharmacology","volume":" ","pages":"968-975"},"PeriodicalIF":5.5,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12371135/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143604937","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":"Behavioral effects of three synthetic tryptamine derivatives in rodents.","authors":"Rebecca D Hill, Ritu A Shetty, Nathalie Sumien, Jeanne Priddy, Michael J Forster, Michael B Gatch","doi":"10.1177/02698811251330737","DOIUrl":"10.1177/02698811251330737","url":null,"abstract":"<p><strong>Aims: </strong>New synthetic tryptamine derivatives have emerged in the underground market. They act on serotonin receptors mimicking the effects of hallucinogenic drugs such as DOM. The DEA has identified three tryptamine derivatives of concern, 5-MeO-DBT, 5-Cl-DMT, and 4-OH-MiPT.</p><p><strong>Methods: </strong>Swiss Webster mice were tested for locomotor activity. Discriminative stimulus effects were tested in male Sprague-Dawley rats trained to discriminate DOM (0.5 mg/kg, 30-min pretreatment) from vehicle (0.9% saline).</p><p><strong>Results: </strong>In the locomotor activity tests, DOM (ED₅₀ = 4.8 mg/kg) produced a 40-100-min depressant phase. 5-MeO-DBT (ID₅₀ = 16.5 mg/kg; ED₅₀ = 0.074 mg/kg) had a 50-min depressant phase and a 100-min stimulant phase. 5-Cl-DMT (ID₅₀ = 12.3 mg/kg; ED₅₀ = 6.1 mg/kg) produced a 20-40-min depressant phase and a 30-min stimulant phase. 4-OH-MiPT (ID₅₀ = 5.8 mg/kg; ED₅₀ = 0.6 mg/kg) had a 30-130-min depressant phase and a 50-minute stimulant phase. In the drug discrimination assay, 4-OH-MIPT (ED₅₀ = 0.77 mg/kg) was fully substituted, whereas 5-Cl-DMT partially substituted for the discriminative stimulus effects produced by DOM (ED₅₀ = 0.23 mg/kg). 5-MeO-DBT failed to substitute for the discriminative stimulus of DOM. 5-CL-DMT and 5-MeO-DBT decreased response rate.</p><p><strong>Conclusion: </strong>The locomotor depressant effects of the three synthetic tryptamine derivatives were similar to DOM, but not as potent. In the drug discrimination assay, only 4-OH-MIPT was substituted fully for DOM. These results support the possibility that 4-OH-MIPT has abuse liability similar to DOM, whereas 5-MeO-DBT and 5-Cl-DMT may not.</p>","PeriodicalId":16892,"journal":{"name":"Journal of Psychopharmacology","volume":" ","pages":"1007-1013"},"PeriodicalIF":5.5,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143780321","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":"Examining mystical experiences as a predictor of psilocybin-assisted psychotherapy for treatment-resistant depression.","authors":"Ryan M Brudner, Erica Kaczmarek, Marc G Blainey, Christian Schulz-Quach, Shakila Meshkat, Zoe Doyle, Orly Lipsitz, Hilary Offman, Rickinder Sethi, Geneva Weiglein, Roger S McIntyre, Joshua D Rosenblat","doi":"10.1177/02698811251346697","DOIUrl":"10.1177/02698811251346697","url":null,"abstract":"<p><strong>Background: </strong>Psilocybin-assisted psychotherapy (PAP) is a promising treatment for various psychiatric disorders. However, the exact biological and psychological mechanisms of action of PAP remain to be determined. Examining predictors of PAP outcomes may help identify necessary processes for positive treatment outcomes. Mystical experiences are considered a key aspect of the subjective effects of ingesting psilocybin. Mystical experiences have been observed to be possibly predictive of positive outcomes in psilocybin treatments. Therefore, some argue that mystical-type experiences are necessary to achieve therapeutic benefits.</p><p><strong>Aims: </strong>The current study examines mystical experiences as a predictor of antidepressant treatment outcomes in PAP, in a complex clinical sample.</p><p><strong>Methods: </strong>Participants included 31 individuals with a primary diagnosis of major depressive disorder (MDD) or Bipolar II Disorder (BDII), with treatment resistance to symptoms of their disorder. Participants had one, two, or three PAP treatments with a fixed dose of 25 mg of psilocybin. Depressive symptoms were measured at baseline, at a pre-dose visit and at 2 weeks post-dosing. The presence of mystical experiences was measured on the dosing day after the acute effects had resolved.</p><p><strong>Results: </strong>For the first psilocybin dose, participants with greater levels of mystical experiences exhibited a greater antidepressant effect from PAP. This effect was not found at the second or third doses.</p><p><strong>Conclusion: </strong>These results provide preliminary support for the hypothesis that mystical experiences have therapeutic importance in PAP and extend the literature to include a clinical sample of individuals with treatment-resistant depression in the context of MDD or BDII.</p>","PeriodicalId":16892,"journal":{"name":"Journal of Psychopharmacology","volume":" ","pages":"950-956"},"PeriodicalIF":5.5,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12371138/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144540597","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":"OAV and 5D-ASC for Brazilian Portuguese: A validation and adaptation study.","authors":"Rafael S Rodrigues, Isabel Wießner, Dimitri Daldegan-Bueno, Bheatrix Bienemann, Alexandre Pontual, Luís Fernando Tófoli, Daniel C Mograbi","doi":"10.1177/02698811251344685","DOIUrl":"10.1177/02698811251344685","url":null,"abstract":"<p><strong>Background: </strong>This study aimed to validate and culturally adapt the Altered States of Consciousness Rating Scale (OAV) and Five Dimensional-Altered States of Consciousness Questionnaire (5D-ASC) for Brazilian Portuguese to measure altered states of consciousness in the context of psychedelic research.</p><p><strong>Methods: </strong>A parallel back-translation model was employed with expert reviews to ensure linguistic and cultural accuracy. The finalized version was pre-tested with 10 participants and subsequently included in an online survey. This survey was completed by 3762 respondents recounting their psychedelic experiences. Exploratory factor analysis and confirmatory factor analysis were conducted to identify the factor structure and validate the scales. Internal consistency and convergent validity were assessed through correlation with the Mystical Experience Questionnaire (MEQ) and Ego Dissolution Inventory (EDI).</p><p><strong>Results: </strong>The analyses confirmed an 11-factor structure for the OAV and a 6-factor structure for the 5D-ASC, both exhibiting strong internal consistency (α > 0.76). Significant correlations were observed between OAV and 5D-ASC factors and the MEQ and EDI, indicating solid convergent validity. Differences in factor scores were noted depending on the substance, setting, and meditation frequency, with higher oceanic boundlessness and anxious ego-dissolution scores for ayahuasca and dimethyltryptamine experiences.</p><p><strong>Conclusions: </strong>The validated scales demonstrated reliable psychometric properties for the Brazilian context. The results highlight cultural aspects influencing subjective experiences with psychedelics. Limitations include sample homogeneity and potential recall bias. Future research should involve more diverse samples to confirm and extend these findings.</p>","PeriodicalId":16892,"journal":{"name":"Journal of Psychopharmacology","volume":" ","pages":"990-1006"},"PeriodicalIF":5.5,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144528486","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":"Pharmacokinetics and pharmacodynamics of sublingual microdosed lysergic acid diethylamide in healthy adult volunteers.","authors":"James D Morse, Soo Hee Jeong, Robin J Murphy, Suresh D Muthukumaraswamy, Rachael L Sumner","doi":"10.1177/02698811251330747","DOIUrl":"10.1177/02698811251330747","url":null,"abstract":"<p><strong>Introduction: </strong>Microdosing is the practice of taking psychedelic drugs at doses that produce no or minimal perceptible subjective or behavioural effects. This study investigated the pharmacokinetics and pharmacodynamics of microdosed lysergic acid diethylamide (LSD).</p><p><strong>Methods: </strong>This was a Phase 1 double-blind placebo-controlled parallel-groups trial with 80 healthy male volunteers (four withdrawals due to anxiety). Plasma samples were taken at 0.5, 1, 2, 4 and 6 h after 10 µg sublingual LSD and analysed with liquid chromatography-tandem mass spectrometry (LC-MS/MS). LSD pharmacokinetics were modelled. Population analyses were performed using nonlinear mixed effects models. Heart rate and a visual analogue scale ('feel effect') were used to describe LSD pharmacodynamics. The effect of the relevant cytochrome P450 (CYP) genotype on LSD pharmacokinetics was qualitatively assessed. Plasma and serum levels of brain-derived neurotrophic factor (BDNF) were evaluated.</p><p><strong>Results: </strong>A one-compartment model best described LSD pharmacokinetics. Mean (95% confidence interval): elimination clearance = 7.78 L/h/70 kg (6.75-8.77), central volume of distribution = 32.9 L/70 kg (30.1, 36.0). Maximal concentration (0.20 µg/L), time to maximal concentration (1.51 h) and elimination half-life (3.08 h). The maximal increase in heart rate and visual analogue scale was small (<15%) compared to baseline estimates limiting the modelling. Two of the participants withdrawn from the study due to anxiety had intermediate-weak CYP2D6 activity. CYP2D6, CYP1A6, CYP2B6 and CYP2C9 qualitatively appeared to influence concentration. No evidence of alterations of peripheral BDNF with microdosing was found.</p><p><strong>Conclusion: </strong>This study provides a population pharmacokinetic model and LC-MS/MS assay that can inform clinical and bioequivalence studies. Relevant CYP genotypes should be studied in larger samples as combined potential biomarkers of response. Microdose-sensitive and reliable pharmacodynamic measures are needed.</p>","PeriodicalId":16892,"journal":{"name":"Journal of Psychopharmacology","volume":" ","pages":"976-989"},"PeriodicalIF":5.5,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12371133/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143999997","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":"Peri-traumatic consumption of classic psychedelics is associated with lower anxiety and post-traumatic responses 3 weeks after exposure.","authors":"Einat Karp Barnir, Zohar Rubinstein, Rany Abend, Shaul Lev-Ran, Lia Naor, Mario Mikulincer","doi":"10.1177/02698811251334025","DOIUrl":"10.1177/02698811251334025","url":null,"abstract":"<p><p>Emerging evidence indicates the therapeutic potential of psychedelic compounds for post-traumatic stress, yet the mechanisms mediating their effects remain unclear. Delineating the effect of psychedelics on traumatic memory formation could shed light on target therapeutic mechanisms. Here, we report on 343 adult survivors of a single, large-scale terrorist attack taking place during a festival in which different psychedelic compounds were consumed, in whom levels of anxiety and post-traumatic symptoms were assessed 3 weeks following the attack. Findings indicated that those who were under the influence of classic psychedelics during the attack reported significantly lower levels of anxiety and post-traumatic responses compared to those who were under the influence of 3,4-methylenedioxymethamphetamine and those who consumed no psychedelics. Furthermore, the protective effects of classic psychedelics for post-traumatic responses manifested more strongly among participants who did not consume additional recreational substances alongside psychedelics. These findings suggest that pharmacologic targets of classic psychedelics may modulate the formation of enduring trauma memories and confer a protective effect against the development of post-traumatic stress and anxiety responses.</p>","PeriodicalId":16892,"journal":{"name":"Journal of Psychopharmacology","volume":" ","pages":"1031-1036"},"PeriodicalIF":5.5,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143989042","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":"Effects of serotonergic psychedelics on synaptogenesis and immediate early genes expression - comparison with ketamine, fluoxetine and lithium.","authors":"Yana Vella, Kateřina Syrová, Aneta Petrušková, Isis Koutrouli, Viera Kútna, Jan Pala, Klára Šíchová, Marek Nikolič, Vladimír Mazoch, Radek Jurok, Martin Kuchař, Zdeňka Bendová, Tomáš Páleníček","doi":"10.1177/02698811251338232","DOIUrl":"10.1177/02698811251338232","url":null,"abstract":"<p><strong>Background: </strong>Recent evidence suggests that psychedelics can induce rapid and long-lasting antidepressant effects. The generally acknowledged explanation for these traits is the phenomenon of neuroplasticity, although the exact underlying molecular mechanisms remain unclear.</p><p><strong>Aims: </strong>This study investigates the effects of psilocin, lysergic acid diethylamide (LSD) and N,N-dimethyltryptamine (DMT) on synaptogenesis and immediate early genes (IEGs) expression in direct comparison with ketamine, fluoxetine and lithium after acute (1 h) and/or prolonged (24 h) treatment in vitro.</p><p><strong>Methods: </strong>Rat primary cortical cultures were treated with 10 µM psilocin, 1 µM LSD, 90 µM DMT, 1 µM ketamine, 10 µM fluoxetine and 5 mM lithium. Analysis of synaptic puncta was performed; puncta of presynaptic marker synapsin I/II, postsynaptic density protein 95 (PSD-95) and their co-localization (established synapse) were assessed 24 h after drug treatment. Next, expressions of IEGs encoding activity-regulated cytoskeleton-associated protein (<i>Arc</i>), early growth response 1 (<i>Egr1</i>), and neuronal PAS (Per-Arnt-Sim) domain protein 4 (<i>Npas4</i>) were analysed 1 and 24 h after drug treatments.</p><p><strong>Results: </strong>Psilocin increased synaptic puncta count and induced <i>Arc</i> expression. The effect to promote synaptogenesis was comparable to ketamine and lithium; ketamine additionally increased PSD-95 puncta count. LSD and DMT did not induce any significant effects. Interestingly, fluoxetine had no effect on synaptic puncta count, but upregulated <i>Egr1</i> and <i>Npas4</i>.</p><p><strong>Conclusions: </strong>Psilocin demonstrated synaptogenic effects comparable to those of ketamine and lithium, and acutely upregulated IEG <i>Arc</i> expression, adding another piece of evidence to its profile as a promising therapeutic agent.</p>","PeriodicalId":16892,"journal":{"name":"Journal of Psychopharmacology","volume":" ","pages":"1023-1030"},"PeriodicalIF":5.5,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144173969","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":"Psychedelic-assisted psychotherapy: The need to monitor adverse events.","authors":"Krj Schruers, N K Leibold","doi":"10.1177/02698811251340929","DOIUrl":"10.1177/02698811251340929","url":null,"abstract":"<p><p>The therapeutic use of psychedelics for mental health issues holds considerable promise. However, systematic assessment of adverse events associated with these substances has received relatively little attention. Here, we discuss several considerations concerning the assessment of adverse events in psychedelic-assisted therapies. We discuss the preference for using the term \"adverse effects\" over \"side effects\", as well as the ongoing debate regarding which substances are classified as psychedelic. We also provide recommendations on when and how to assess adverse effects, for example the importance to study them in any kind of therapy involving psychedelics, and using comprehensive monitoring of a wide range of physical parameters in combination with behavioral outcomes and the individual's experience, at baseline and throughout the study. Also, sex-specific differences should be considered. Furthermore, we highlight several significant studies that have addressed these aspects. In summary, psychedelics offer great promise as a potential treatment (add-on) option in psychiatry, but more rigorous assessment of adverse effects is needed to promote safe use and implementation in clinical practice.</p>","PeriodicalId":16892,"journal":{"name":"Journal of Psychopharmacology","volume":" ","pages":"896-899"},"PeriodicalIF":5.5,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12371130/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144111189","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":"Are the LSD-analogs lisuride and ergotamine examples of non-hallucinogenic serotonin 5-HT2A receptor agonists?","authors":"Jan Kehler, Morten Skøtt Thomsen Lindskov","doi":"10.1177/02698811251330741","DOIUrl":"10.1177/02698811251330741","url":null,"abstract":"<p><p>The recent resurgence of classical psychedelic compounds, specifically 5-HT_2A receptor agonists, as potential therapeutics has led to numerous initiatives aimed at better understanding the mechanisms underlying their effects. Psychedelic compounds are commonly known as hallucinogens. One of the major outstanding questions in the field is whether altered states of consciousness-the hallucinogenic or psychedelic experience-is a prerequisite for the therapeutic effect. As a result, several academic and commercial efforts are focused on developing 5-HT_2A receptor agonists that are speculated not to have these consciousness-altering effects. However, these efforts largely rely on chemical analogs of supposedly non-hallucinogenic 5-HT_2A receptor agonists, such as lisuride and ergotamine. Our review of the literature indicates that there is no basis for claiming that lisuride or ergotamine are non-hallucinogenic at relevant concentrations in the brain. This does not invalidate current efforts to produce non-hallucinogenic 5-HT_2A receptor agonists for the potential benefit of patients, but it calls for caution in the reliance on animal data in the pursuit of such compounds and highlights the need for rigorous determination of target engagement in humans before claiming that 5-HT_2A receptor agonists are non-hallucinogenic.</p>","PeriodicalId":16892,"journal":{"name":"Journal of Psychopharmacology","volume":" ","pages":"889-895"},"PeriodicalIF":5.5,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144020705","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}