Journal of Psychopharmacology最新文献

Rationale: Classical psychedelics-a broad class of compounds that include psilocybin, lysergic acid diethylamide, dimethyltryptamine, and mescaline-have shown significant promise for the treatment of mental health conditions in recent clinical trials. Organizations such as the National Network of Depression Centers (NNDCs) can play a pivotal role in uniting researchers and clinicians working in this field to explore and synthesize existing evidence as well as characterize emerging challenges.

Objectives: We outline several categories of challenges that have emerged in the context of clinical trials with psychedelic drugs, drawing from our collective empirical observations as well as the extant literature. While these challenges have been presented in the context of clinical trial environments, many of them are likely to persist if and when psychedelic treatments become approved and are implemented in psychiatric clinical practice.

Results: We describe four categories of challenges in the context of clinical trial participants-(1) treatment nonresponse, (2) expectancy effects and functional unblinding, (3) post-session psychological difficulties, and (4) contagion effects-and provide management strategies for study teams to mitigate associated risks.

Conclusions: Classical psychedelics show therapeutic promise as mental health treatments. Studying them properly presents unique and unprecedented challenges that require researchers to develop sophisticated strategies to navigate nonresponse, expectancy effects, functional unblinding, post-session psychological issues, and possible contagion effects to responsibly advance this field. The NNDC and similar organizations are well-positioned to guide best practices and ensure the responsible advancement of this promising field.

Background: Affective biases are central to mood and anxiety disorders, with individuals often interpreting ambiguous facial expressions more negatively. Adaptation paradigms, where exposure to emotional stimuli shifts perception, provide a tool to separate perceptual from decisional biases, but have not been used to study emotional biases relevant to affective disorders.

Aims: To determine whether affective biases in facial emotion perception arise from perceptual or decisional processes, and to examine how these biases are modulated by individual differences in negative affect.

Methods: Eighty participants completed emotion and identity discrimination tasks before and after adaptation. Participants made binary judgements of morphed facial expressions (happy/sad) and identities (Bonny/Sheila), followed by confidence ratings. Logistic and Gaussian functions were used to estimate adaptation effects from shifts in the point of subjective equality (PSE) and peak uncertainty.

Results/outcomes: Adaptation produced repulsive aftereffects: exposure to happy faces biased perception towards sadness, and vice versa, with analogous effects for identity. Correlated shifts in PSE and uncertainty indicated a perceptual rather than decisional origin. Negative affect (derived from Beck Depression Inventory and State Trait Anxiety Inventory-trait questionnaires) moderated this relationship, such that individuals higher in negative affect showed stronger perceptual biases towards sadness.

Conclusions/interpretation: Findings suggest that negative affect modulates low-level perceptual encoding of emotional expressions. This supports cognitive neuropsychological models positing that antidepressants first target early perceptual biases and highlight perceptual encoding as a potential mechanism underlying affective biases in mood and anxiety disorders.

Introduction: Managing depression during pregnancy requires balancing maternal health and fetal safety. As drugs for depression are often used alongside other medications, understanding if these combinations relate to teratogenic risks is important. This study explored patterns of major congenital malformations (MCMs), including congenital heart defects (CHDs), following first-trimester drugs for depression, alone, or with co-medications.

Methods: Using Danish national registry data, we analyzed 674,154 pregnancies, of which 2.2% were exposed to first-trimester drugs for depression. We compared MCMs and CHD occurrences in pregnancies exposed to these drugs, alone or with co-medications, to nonexposed pregnancies and generated estimates to explore potential associations and interactions.

Results: Exploratory assessments suggested that overall MCM risk among pregnancies exposed to drugs for depression was similar to nonexposed pregnancies (adjusted odds ratio (95% confidence interval): 1.05 (0.96-1.15)), while CHD risk appeared higher (1.26 (1.08-1.47). Certain co-medications showed signals warranting further study, including possible increases in MCM risk with antihistamines (1.64 (1.14-2.28)) and levothyroxine (1.72 (1.12-2.53)) and a potential decrease with opioids (0.51 (0.27-0.86). For CHDs, drugs for psychosis (1.67 (1.01-2.60)), nonsteroidal anti-inflammatory/antirheumatic medications (2.07 (1.23-3.25)), topical corticosteroid (2.07 (1.02-3.71)), and progesterone (2.01 (1.06-3.45)) showed patterns potentially indicating elevated risk.

Conclusion: This study provides exploratory insights into how first-trimester use of drugs for depression, alone or with selected co-medications, may relate to MCM and CHD patterns. These findings suggest potential interactions but could also result from confounding or chance. Further research is needed to support clinical decision-making.

Indigenous Peoples have cultivated and protected natural psychoactive medicines through ceremony, kinship, and spiritual responsibility across generations, yet their long-standing contributions have often been marginalized through extractive research, commercialization, and policy exclusion. It is Indigenous communities that have stewarded and gained expertise working with psychoactive medicines for centuries, yet they remain underrepresented within the scientific discourse. This commentary advances the case for reciprocal and equitable collaboration in psychedelic science, grounded in Indigenous sovereignty, cultural and intellectual property rights, and governance. Drawing on traditions involving ayahuasca, psilocybin, peyote, and iboga, we illustrate how Indigenous methodologies, including ritual, community-based practices, and ecological approaches, offer insights critical to both safety and efficacy. We argue that research and policy must embed free, prior, and informed consent, equitable benefit-sharing, and Indigenous leadership. Such efforts require moving past tokenistic inclusion toward meaningful collaboration and systemic change in psychedelic research that is both scientifically rigorous and culturally just. We conclude by calling for more formal, transparent, and globally legitimate convening processes, such as those modeled on WHO global consultations, that can bring Indigenous leaders, researchers, and policymakers together in dialogue. These steps represent profound acts of inclusion essential for these medicines to realize their full potential to heal and transform.

Background: Multi-criteria decision analysis (MCDA) has been used to quantify drug harms in the United Kingdom, the European Union, Australia, and New Zealand. This paper presents the result of an MCDA conducted in Canada, with the aim of informing Canadian drug policy and contributing to public understanding of drugs' relative harms.

Methods: A panel composed of 20 experts from six provinces determined 16 drugs to evaluate on 16 dimensions of harm (ten representing harm to people who use the drug; six representing harm to others). At a two-day decision conference, the panel scored each drug on a scale of 0-100 for each harm criterion, then weighted the relative importance of each criterion.

Results: This analysis of drug harms in Canada found that alcohol causes the most harm overall, with a cumulative weighted score of 79. It was followed by tobacco (45), nonprescription opioids (33), cocaine (19), methamphetamine (19), and cannabis (15). The finding that alcohol causes the most harm is consistent with the results of previous MCDA drug harm studies.

Conclusion: These harm scores express population-level harm rather than individual-level "harmfulness." They reflect not only a drug's pharmacological risk profile but also the current policy context in Canada. The high score for alcohol underscores a failure to adopt policies to address alcohol-related harms, despite the known health harms and the existence of proven policy measures. More broadly, when developing drug policies, governments should consider the harm-both individual and societal-caused by drugs and by the laws and regulations that govern them.

Background: Changes in well-being, personality, and personal values have been documented post-psilocybin; however, evidence from placebo-controlled trials is limited.

Aims: To examine the effects of psilocybin versus placebo on psychiatric symptoms, personality, and personal values in healthy participants. Potential mediators were also explored.

Methods: This secondary analysis used data from a phase I, double-blind, randomised, placebo-controlled trial testing a single dose of 10 mg (n = 30) or 25 mg psilocybin (n = 30) versus an inert placebo (n = 29) in 89 healthy participants. Effects of psilocybin on personality (Neo Five-Factor Inventory; NEO-FFI), psychiatric symptoms (Symptom Checklist-90; SCL-90), and values (Life Changes Inventory; LCI) at short- (day 8) and long-term follow-up (day 85) were analysed using mixed-effects models. Group differences in cognitive flexibility (Intra-Extra Dimensional Set Shift task; IED) at day 8 were analysed using a Kruskal-Wallis test. Potential mediating effects of the acute psychedelic experience (Five-Dimensional Altered States of Consciousness Questionnaire; 5D-ASC) were explored.

Results: No between-group differences were found on the NEO-FFI, SCL-90, or IED. Both psilocybin groups showed greater LCI absolute change scores at both follow-up points compared to placebo. The 5D-ASC oceanic boundlessness subscale partially mediated these changes. Oceanic boundlessness also fully or partially mediated differences across several LCI subscales, and auditory alterations mediated differences on one subscale.

Conclusions: The acute psychedelic experience, namely oceanic boundlessness and, to a lesser extent, auditory alterations, mediates self-reported changes in values in healthy volunteers. Findings from this exploratory study are tentative and should be replicated in larger samples.

Background: Cariprazine is a second-generation antipsychotic approved for treating schizophrenia, acute manic/mixed, and depressive episodes associated with bipolar I disorder, and as adjunctive treatment in major depressive disorder (MDD). Antipsychotic treatment is often associated with metabolic alterations, including weight gain, dyslipidemia, and increased risk of type 2 diabetes and cardiovascular disease.

Aims: We conducted a systematic review and meta-analysis to synthesize study results on the effects of cariprazine on glucose and lipid homeostasis, as well as weight, in persons living with affective disorders.

Methods: Using the Covidence platform, we included 19 studies for the systematic review and 4 randomized controlled studies for the meta-analysis. This study is registered with the International Platform of Registered Systematic Review and Meta-analysis Protocols under protocol number 2025100044. Six meta-analyses focused on patients with bipolar disorder (BD), and six meta-analyses focused on patients with MDD, evaluating changes in weight, cholesterol, and glucose for both cariprazine 1.5 and 3 mg.

Results: Cariprazine showed a minimal impact on the metabolic profile in both BD and MDD. Notably, weight gain was statistically significant in both doses (i.e. 1.5, 3 mg), but in most cases not clinically meaningful. Results indicate that there was no statistically significant shift relative to placebo in fasting glucose, triglycerides, or cholesterol.

Conclusions: Results from this meta-analysis suggest that cariprazine presents a favourable metabolic profile compared to other atypical antipsychotics.

Background: Lysergic acid diethylamide (LSD) has been considered as a potential treatment for depression for over 75 years, but its therapeutic potential has only recently been considered in mainstream psychiatry. Repeated ingestion of low doses of LSD ("microdoses") is thought to reduce depression, but the neurobiology underlying this effect is unknown. We previously reported that low doses of LSD increased event-related potentials (ERPs) during receipt of monetary rewards in healthy adults. LSD also produced more positive subjective effects in participants with mild-to-moderate baseline symptoms of depressed mood, compared to controls.

Aim: In this report, we examined the effects of LSD on reward ERPs in participants with mild-to-moderate depressed mood and in non-depressed controls.

Methods: Participants with subclinical mild-to-moderate depression (N = 20) or controls with minimal symptoms (N = 19) received LSD (26 μg tartrate) or placebo on two sessions. Primary measures were ERPs during a reward task, and secondary measures included self-reported mood during and 48 hours after the sessions.

Results: LSD (vs placebo) increased late positive potential (LPP) amplitude to loss (vs win) reward feedback only in participants with higher baseline depressed mood, suggesting enhanced affective processing given the role of LPP in emotional valuation of reward. This effect of LSD on LPP was associated with its acute positive mood effects, and with lower depressed mood 48-hour after the LSD (vs placebo) session. In the full sample, LSD (vs placebo) decreased feedback-P3 and LPP amplitude to reward (vs neutral) feedback.

Conclusion: Although findings must be interpreted with caution, results support the idea that low doses of LSD have potential anti-depressant effects.

Background: Treatment-resistant schizophrenia (TRS) is associated with alterations in glutamate levels and cerebral blood flow (CBF), and treatment with clozapine appears to have an impact on each of these measures. Here, we examined whether changes in CBF and glutamate levels following clozapine treatment are related.

Methods: Glutamate concentrations in the anterior cingulate cortex (ACC), and striatum (measured using proton magnetic resonance spectroscopy, ¹H-MRS); and whole brain regional CBF maps (measured using pseudo-continuous arterial spin labelling (pCASL)), were examined in a cohort of TRS subjects before and after 12 weeks of treatment with clozapine (baseline: N = 30; week 12: N = 20).

Results: The longitudinal change in striatal glutamate during treatment was positively associated with the longitudinal change in striatal CBF (p < 0.05). In the ACC, higher Glx (glutamate + glutamine) and CBF prior to treatment were associated with greater subsequent improvement in total symptom severity.

Conclusions: These results indicate that there is a direct relationship between changes in glutamate activity and CBF in the striatum following clozapine treatment. Future research could investigate whether glutamate-CBF relationships exist in other stages of psychosis or schizophrenia and during treatment with other antipsychotic medications. Associations with clinical outcomes could be explored in larger samples.

Background: Psilocybin has shown rapid and sustained antidepressant effects in patients with major depressive disorder, yet the neurobiological mechanisms underlying these outcomes remain unclear.

Aims: This study aimed to bridge clinical and preclinical findings by investigating the relationships between 5-HT_2A receptor occupancy (RO) achieved after administration of psilocybin and its effects on behavior and markers of neuroplasticity in mice.

Methods: In vivo 5-HT_2A RO was determined via displacement of [³H]MDL-100,907 in the prefrontal cortex (PFC). To relate RO with behavioral outcomes of psilocybin, we assessed the head twitch response (HTR) acutely and investigated behavior in the elevated zero maze (EZM) and forced swim test (FST) 20-24 hours post-drug. Neuroplastic changes were assessed by measuring α-tubulin post-translational modifications (PTMs) and expression of key synaptic proteins in both the PFC and amygdala.

Results: Psilocybin produced dose-dependent 5-HT_2A RO (RO₅₀ = 0.88 mg/kg) and an inverted-U dose-response in HTR, with peak effects occurring between ~44% and 62% RO. Behaviorally, a 1.5 mg/kg dose increased the open areas ratio in the EZM, while 3 mg/kg reduced immobility in the FST, 20 and 24 hours after dosing, respectively. Both dose levels shifted α-tubulin PTMs toward a more dynamic microtubule state and selectively increased synaptic marker expression in the PFC, not in the amygdala.

Conclusions: These findings suggest that the therapeutic effects of psilocybin could be mediated by dose- and region-specific enhancement of neuronal plasticity, with distinct signatures associated with anxiolytic-like and antidepressant-like properties.