Journal of Psychopharmacology最新文献

Background: Despite considerable interest in the consequences of benzodiazepine and benzodiazepine-related Z-drug (BZDR) use, little is known about whether and how initiation of BZDR treatment relates to the development of alcohol- and drug-related problems.

Aims: This study aimed to examine the association of incident BZDR dispensing with subsequent alcohol- and drug-related problems.

Methods: This nationwide register-based study included demographically matched and co-twin control cohorts. Among all Swedish residents aged older than 10 years and BZDR-naïve by 2007, 960,430 BZDR-recipients with incident dispensation in 2007-2019 and without any recorded pre-existing substance-related conditions were identified and matched (1:1) to non-recipients from the general population. Twin BZDR-recipients (n = 12,048) were linked to 12,579 unexposed co-twins. Outcomes included alcohol and drug use disorders, poisoning, deaths, and related suspected criminal offences. Flexible parametric survival models estimated outcome risks across up to 14 years of follow-up.

Results: In the demographically matched cohort (60% women, median age at BZDR initiation 51 years), incidence rates in BZDR-recipients and non-recipients (per 1000 person-years) were 5.60 versus 2.79 for alcohol-related and 4.15 versus 1.23 for drug-related problems, respectively. In fully adjusted models, relative risks were increased for alcohol- and drug-related problems (adjusted hazard ratio (95% confidence interval): 1.56 (1.53-1.59) and 2.11 (2.05-2.17), respectively). The risks persisted within the co-twin comparison, different follow-ups, and all additional sensitivity analyses.

Conclusions: BZDR initiation was associated with a small but robust increase in absolute and relative risks of developing alcohol- and drug-related problems. The findings contribute to evidence base for making decisions on BZDR treatment initiation.

Functional connectivity (FC) plays a critical role in understanding major depressive disorder (MDD) and treatment mechanisms. Altered FC patterns, particularly within the default mode network (DMN), have been associated with MDD symptoms and therapeutic outcomes. This study systematically reviews the literature on Escitalopram, a selective serotonin reuptake inhibitor (SSRI) with a particular receptor profile, in relation to FC in MDD. A systematic review was conducted using three databases: PubMed, Scopus, and Web of Science. Eleven articles meeting the inclusion criteria were categorized into two groups: treatment effects (six studies) and treatment response prediction (five studies). The six treatment effect studies included 198 patients with MDD and 219 control participants: 205 healthy controls and 14 placebo-treated patients. These studies highlighted Escitalopram's ability to normalize baseline FC disruptions (hypo- or hyperconnectivity), particularly in DMN subsystems. The five treatment prediction studies examined 159 MDD patients, 97 healthy controls, 22 placebo-treated individuals, and 56 non-responders. Poor treatment efficacy was linked to baseline hypoconnectivity in the dorsolateral prefrontal cortex and altered connectivity between the DMN and the frontoparietal network. Overall, Escitalopram treatment appears to restore FC by normalizing both hyperconnectivity and hypoconnectivity patterns associated with MDD, suggesting a rebalancing of network dynamics underlying symptom improvement. Normalization of altered FC patterns after treatment and associations between baseline FC and treatment response suggest FC's potential as a biomarker for understanding and predicting SSRI efficacy.

Background: Ketamine is increasingly used in the United Kingdom in non-clinical settings for its psychoactive effects, with rising reports of harms including hospital admissions, dependence and deaths. In light of current debates surrounding the reclassification of ketamine under the Misuse of Drugs Act 1971, up-to-date surveillance of associated mortality is warranted.

Aims: We aimed to quantify trends in deaths following illicit ketamine use in England, Wales and Northern Ireland, and to examine changes in demographic and contextual characteristics since the last national analysis which comprised illicit ketamine deaths up to 2019.

Methods: Cases where illicit ketamine was detected at post-mortem were extracted from the National Programme on Substance Use Mortality and analysed.

Results: There were 696 deaths identified with illicit ketamine between 1999 and 2024. Annual deaths increased over 10-fold from 2014 (15 deaths) to 2024 (197 projected deaths). Whilst absolute deaths implicating illicit ketamine rose (2014: 6 deaths; 2023: 123 projected deaths), the proportion of deaths where illicit ketamine was implicated in causing death declined (2014: 60.0% of cases; 2024: 42.6% of cases). Concurrently, polydrug use increased (median number of co-administered substances 1999-2004: 3; 2005-2009: 3, 2010-2014: 4, 2015-2019: 6; 2020-2024: 6), and the demographic profile of decedents shifted towards greater deprivation and dependence-related contexts.

Discussion and conclusions: There has been an acceleration in deaths following illicit ketamine in recent years, which are increasingly featuring complex patterns of polydrug use and socio-economic vulnerability. Policy responses must extend beyond single-substance legislative controls to encompass harm reduction, treatment integration, and social support strategies.

Background: In recent years, there has been a resurgence of scientific interest in psychedelics, including psilocybin, for their potential in treating neuropsychiatric disorders. However, the reward-related effects of psilocybin and its impact on behavior remain underexplored.

Aims: We aimed to evaluate the potential rewarding effects of high doses of psilocybin and its effects on rat behavior.

Methods: Sprague-Dawley rats were exposed to the conditioned place preference (CPP) paradigm. Over an 8-day period, rats were administered either psilocybin (10 mg/kg, i.p.) or vehicle (0.9% saline, i.p.) on odd conditioning days, while receiving vehicle (0.9% saline, i.p.) on even conditioning days. The potential rewarding effect induced by psilocybin was assessed 48 hours after the last psilocybin injection. Behavioral assessments, including head twitch, body shaking, grooming, body licking, defecation pellets, and rearing, were conducted during the CPP exposure.

Results: Psilocybin did not induce CPP in rats, highlighting its lack of reinforcing effects under these conditions. However, this regimen of administration led to modifications in the behavioral profile during CPP test by increasing head twitching, wet-wet-dog shaking, and defecation pellets and decreasing grooming, body licking, and rearing compared to the vehicle group. Importantly, 48 hours after the final psilocybin injection, no behavioral differences were observed between psilocybin and vehicle groups.

Conclusion: Psilocybin at this regimen (10 mg/kg, every other day) does not induce CPP, but induces changes in behavior, which disappear 48 hours after the last injection. More research is needed to better evaluate the addiction liability of psychedelics using different paradigms, doses, and protocols.

Background: The empathogen and psychostimulant 3,4-methylenedioxymethamphetamine (MDMA) is thought to boost both subjective well-being and social connection. Although MDMA is considered to enhance social connection to a greater extent than other stimulant drugs, few studies have compared MDMA to other stimulants. In addition, previous studies have focused on social positivity effects (e.g., increased trust) for specific in-lab interaction partners without considering more generalized social positivity effects (e.g., trust in one's community).

Aims: We tested the effects of MDMA on subjective ratings of well-being and global social connection, including feelings of trust toward one's community and society. The effects of MDMA were compared to a prototypic stimulant, methamphetamine (MA).

Methods: Across two studies, we examined differences in subjective well-being and global social well-being 90 minutes after a conversation on MDMA (study 1; N = 15; 100 mg) and after a conversation on MA (study 2; N = 20; 20 mg) compared to a placebo.

Results: After MDMA, participants reported significantly higher global trust, t(14) = -2.583, p = 0.022, and marginally higher self-worth, t(14) = -2.000, p = 0.065, compared with after the placebo. Furthermore, MA did not alter scores of subjective well-being and social connection.

Conclusions: Our findings extend previous research by demonstrating that MDMA increases feelings of trust in the social world beyond lab-specific interaction partners. These findings are consistent with user reports of generalized social well-being effects and support the idea that MDMA may have clinical value from a social psychological perspective.

Background: Although classic psychedelic trials show therapeutic potential, the limited diversity of participants raises concerns about generalizability and safety.

Aims: This study assesses the representation of race, ethnicity, and sex in interventional clinical trials of psilocybin and lysergic acid diethylamide (LSD) to evaluate disparities in participant diversity.

Methods: We conducted a cross-sectional analysis of interventional trials registered on ClinicalTrials.gov up to 12 January 2025 that focused on classic psychedelics (psilocybin, psilocin, LSD, DMT, 5-MeO-DMT, and mescaline). Eligible trials were phases 2-4 and targeted psychiatric disorders or symptoms. Trials involving only healthy participants were excluded. Two reviewers extracted trial-level data independently; discrepancies were resolved by consensus.

Results: Nine eligible trials included eight with psilocybin and one with LSD. In the psilocybin trials (n = 501), the age of participants ranged from 34.3 to 56.3 years; 47.7% were women. White participants accounted for 87.2%, while Black participants accounted for 3.0%, and Asian individuals accounted for 5.0%. Ethnicity was reported in 4 of 8 psilocybin trials (n = 134), with 13.4% identifying as Hispanic or Latino. In four U.S.-only trials(n = 139), participation-to-population ratios (PPRs) confirmed the underrepresentation of Black (PPR = 0.317) and Asian participants (PPR = 0.799). The LSD trial (n = 11) included older adults (average age: 51.7 years) who did not provide any information on race or origin.

Conclusions: The limited diversity in psychedelic trials demonstrates the need for broader recruitment. Without better representation, the safety and efficacy of these therapies remain uncertain. Standardized reporting and targeted strategies are essential to ensure equity.

As psychedelic clinical trials expand in scale and influence, foundational challenges in trial design have come into sharper focus. In this commentary, we examine three interrelated issues: 1) the failure of blinding in psychedelic trials, 2) the potential of alternate controls including dose-response designs as an empirical workaround, and 3) the persistent ambiguity surrounding psychosocial control conditions. We argue that efforts to preserve traditional placebo-controlled frameworks are often inadequate due to the unmistakable subjective effects of psychedelics and the therapeutic relevance of those effects themselves. Instead, we highlight alternative designs including graded dose comparisons and unblinded comparative efficacy studies as pragmatic paths forward. Finally, we outline a proposal for empirically isolating the role of psychotherapy in psychedelic treatment, emphasizing the need for operational definitions, fidelity monitoring, and careful risk mitigation. These issues are unlikely to be resolved by any single design; rather, progress will require triangulating evidence across multiple imperfect but complementary methodologies.

Background: 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.

Methods: 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.

Results: Heterogeneity in the data was observed. All studies showed a serious risk of bias. Psilocybin was the most frequently reported compound (n = 7), followed by lysergic acid diethylamide (LSD; n = 5), mescaline (n = 4), ayahuasca (n = 4), peyote (n = 2), and N,N-dimethyltryptamine (n = 1). Psilocybin, LSD, and ayahuasca revealed preliminary therapeutic potential for facilitating smoking cessation.

Conclusions: 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.

Background: 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.

Aims: 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.

Methods: Using data (N = 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.

Results: 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, p = 0.016).

Conclusions: The results of the present study add to the literature suggesting classic psychedelics as a possible future prophylactic treatment option for primary headache disorders.