Journal of Psychopharmacology最新文献

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.

Background: Although psychedelics have regained attention as potential treatment tools for various mental disorders, little research has examined their impact on temporal perception.

Aims: This double-blinded placebo-controlled study aimed to investigate changes in temporal perception under psilocybin, both through performance during the Temporal Bisection Task (TBT) and through subjective self-report scales.

Methods: Twenty-four healthy volunteers were assessed by comparing their performance on two parameters of the TBT -the Bisection Point (BP) and the Just Noticeable Difference (JND) with subjectively reported changes measured using the Hallucinogen Rating Scale (HRS) and the Altered States of Consciousness (ASC) questionnaires.

Results: We observed a rightward shift in BP under psilocybin compared to placebo (t(23) = 2.27, p = 0.033, g = -0.37). This shift corresponded to reports of subjective time slowing down under psilocybin as measured by HRS and ASC. Psilocybin also increased JND compared to placebo (t(23) = 2.48, p = 0.021, g = -0.47), indicating decreased temporal precision. Consistent with previous findings, these effects were significant for durations longer than 2 seconds.

Conclusions: Based on Bayesian framework of timing, we emphasised that psilocybin alters time perception through disruptions in cognitive functions, particularly working memory and attention. We also outlined directions for future research, which would allow us to not only understand time perception under psychedelics better, but help elucidate the role of serotonergic system on timing.Research ID:The research was conducted as part of a clinical trial registered at EudraCT database under the number 2012-004579-37.

Background: Existing tools assess psychedelic experiences, but none specifically measure altered processing of traumatic memories-a key mechanism in trauma-focused therapies and psychotherapy in general. The helioscope effect describes how psychedelics like psilocybin and 3,4-methylenedioxymethamphetamine (MDMA) enable revisiting challenging or traumatic experiences while remaining protected from re-actualization of trauma symptoms. This study introduces and evaluates the Helioscope Questionnaire, a novel scale for assessing memory-related processing during psychedelic experiences.

Method: A cross-sectional, Internet-based survey was administered to 468 individuals (mean age = 32.9; 66.7% male) with self-reported psychedelic/MDMA use.

Results: The final Helioscope Questionnaire comprised 21 items across 3 factors: protection, exposure, and avoidant-distress. A composite Helioscope Score (HS) was derived from protection and exposure subscales. Convergent validity was demonstrated through strong correlations with the Psychological Insight Questionnaire. Discriminant validity was evidenced by moderate associations with the Mystical Experience Questionnaire and a lack of significant correlations with the Challenging Experience Questionnaire. Predictive validity was supported by the HS predicting positive changes in mood and attitude on the Persisting Effects Questionnaire, whereas avoidant-distress predicted negative changes. The scale also demonstrated incremental validity by providing explanatory power beyond established psychedelic effect measures. Additionally, the presence of a trip sitter was associated with stronger HS scores, and MDMA use was linked to reduced avoidant distress.

Conclusions: The Helioscope Questionnaire offers a novel, psychometrically robust tool for assessing therapeutic mechanisms of psychedelic experiences, particularly in relation to processing of difficult memories. Further research in clinical populations is warranted to evaluate its utility in predicting treatment outcomes.

Rationale: Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by social communication difficulties and restricted, repetitive behaviors. Although several pharmacological agents have been trialed, treatments for core features remain limited. Propranolol, a non-selective β₁/β₂-adrenoceptor antagonist (β-blocker, NbN), has shown potential effects across multiple ASD-related domains.

Methods: A narrative review was conducted following Preferred Reporting Items for Systematic reviews and Meta-Analyses principles. Systematic searches in PubMed, Scopus, ScienceDirect, and ProQuest identified 22 studies, of which 15 were included, comprising randomized controlled trials, single-dose psychopharmacological challenge studies, and reviews.

Results: Evidence suggests that propranolol may improve social anxiety, verbal problem-solving, cognitive flexibility, emotional regulation, and behavioral dysregulation. Benefits of facial scanning and verbal fluency have also been described. The drug may attenuate adrenergic hyperarousal and promote parasympathetic dominance. However, most positive findings derive from small samples or single-dose studies, while sustained double-blind trials are scarce. Polypharmacy contexts remain underexplored.

Discussion: Propranolol may serve as an adjunctive therapy in selected ASD cases, particularly when other strategies are insufficient. Its central nervous system penetration and anxiolytic profile support potential clinical use. Emerging evidence suggests that autonomic biomarkers and pharmacogenetic factors (e.g., CYP2D6, ADRB1/2 polymorphisms) could inform patient selection.

Conclusions: Propranolol shows promise in modulating adrenergic activity relevant to several ASD symptom domains. The most consistent evidence supports anxiolytic effects under sustained dosing, whereas cognitive and behavioral findings remain preliminary. Larger, placebo-controlled trials with biomarker integration are needed to clarify efficacy, long-term safety, and clinical positioning. Until then, its use should remain cautious and highly individualized.

Background: Inhibitory control deficits are associated with cocaine use disorder (CUD) development and maintenance. Additionally, drug use and inhibitory control can be negatively affected by depressive symptoms, including somatic factors like sleep disturbance and fatigue.

Aim: The current study assessed the relationship between inhibitory control and depressive symptoms among individuals initiating CUD treatment. We examined associations among anti-saccade response inhibition performance, total scores on the Beck Depression Inventory-II (BDI-II), and individual BDI-II items.

Methods: N = 101 patients enrolled in a clinical trial for CUD completed drug-specific anti-saccade and depression (BDI-II) measures prior to treatment. Generalized linear models tested the associations of anti-saccade error rate with stimulus type (cocaine, neutral) and with BDI-II total score. Penalized regression then modeled the error rate among the entire set of BDI-II items to select the most relevant symptom correlates.

Results: Anti-saccade error rates were higher on cocaine relative to neutral trials (p < 0.001), confirming attentional bias. Error rates were positively associated with BDI-II total scores, controlling for demographic and recent cocaine use variables (p < 0.001); this association did not differ by stimulus content (p = 0.742). Among BDI-II items, Loss of Pleasure, Crying, Agitation, Changes in Sleeping Pattern, Concentration Difficulty, Tiredness, and Loss of Interest in Sex were retained by the penalized regression of error rates.

Conclusions: Attentional bias was drug-specific, and overall error rates were strongly related to somatic factors underlying depression in CUD. The association between inhibitory control and depression in CUD may be driven by physiological symptomatology, including sleep impairment and fatigue.

Clinicaltrials: gov:NCT02896712.

Background: The Altered States of Consciousness Scale (3/5D-ASC or 11-ASC) is widely used to assess non-ordinary states of consciousness, particularly for psychedelic research. However, its original dimensional model (3D-ASC within 5D-ASC) and later 11-subscale structure (11-ASC) have a hierarchically incompatible higher/lower-order structure. Although the 11-ASC offers superior model fit, the 3D-ASC remains widely used for summarizing broader experiential domains.

Aims: We wanted to provide an updated, psychometrically revalidated version of the ASC. We tested whether the 42-item 11-ASC could be integrated into a coherent three-dimensional framework. We further hypothesized that this revised model would outperform the original 66-item 3D-ASC while preserving its conceptual clarity.

Methods: Data from 901 5D-ASC questionnaires from 398 healthy participants across 16 randomized, mostly placebo-controlled psychedelic (lysergic acid diethylamide, psilocybin, mescaline, and N,N-dimethyltryptamine) studies were split for exploratory and confirmatory factor analysis. We compared the 3D-ASC and 11-ASC in terms of reliability and model fit, and tested whether the 11-ASC could be summarized within a three-dimensional model.

Results: Ten of the 11 subscales formed three higher-order dimensions-Positive (PosE), Distressing (DisE), and Perceptual (PerE) effects-mirroring the 3D-ASC but with improved fit. We propose this as the 3D-ASCr scale. The Anxiety subscale could not be integrated due to consistent floor effects (low anxiety in the sample), but given its clinical relevance, it is retained within 3D-ASCr (as part of DisE or a standalone subscale).

Conclusion: The 3D-ASCr is an updated version of the ASC and is recommended for use with classic serotonergic psychedelics in both clinical practice and research.

Objective: To investigate the reporting of harms in systematic reviews (SRs) focused on hallucinogen use.

Methods: A search was conducted in May 2022 using MEDLINE, Embase, Epistemonikos, and Cochrane databases to retrieve SRs focused on the use of hallucinogens. Investigators screened the titles and abstracts from the search for study inclusion in a masked, triplicate fashion. Investigators analyzed the included SRs for reported harms linked to hallucinogen use via a pre-established harms reporting assessment. Methodological quality of SRs was graded using the A MeaSurement Tool to Assess Systematic Reviews-2 (AMSTAR-2) in a masked, duplicate manner. Study characteristics for each review were extracted in duplicate. The corrected covered area was measured for SR dyads.

Results: Our search returned 908 articles, and 32 SRs met eligibility criteria for final harms reporting analysis. Of the included reviews, 28 SRs (56.2%) indicated harms as a primary or secondary outcome, 2 SRs (6.3%) reported predetermined methods to grade, collect harms data, or statistically analyze harms. A significant relationship was found between completeness of harm reporting and whether harms were listed as a primary or secondary outcome.

Conclusion: Harms were largely underreported in scientific literature regarding hallucinogen use, despite many studies designating them as a primary or secondary outcome. Inadequate reporting is unlikely to provide credible evidence used to evaluate the benefit-harm trade-off. Therefore, steps should be taken to improve the reporting of harms in studies concerning hallucinogen use.