Journal of Psychopharmacology

ObjectivesCombined oral contraceptive (COC) use is linked to increased depression risk, potentially via serotonergic pathways. This study examined whether serotonin 2A/2C receptor (5-HT2AR/5-HT2CR) brain binding differs between healthy women using COCs and non-users. Methods71 healthy women had been scanned with either [18F]Altanserin (17 COC users, 22 non-users) or [11C]Cimbi-36 Positron Emission Tomography (17 COC users, 15 non-users). Multiple linear regression and latent variable models were used to assess associations between COC use and neocortical 5-HT2AR and subcortical-HT2AR/5-HT2CR binding, respectively.. Analyses were performed on data pooled across both radiotracers and on each tracer, separately. ResultsIn pooled analyses across both tracers, COC use was not significantly associated with 5-HT2AR binding in the neocortex (-7.7%, 95% CI [-18.9;5.2], p=0.22), nor with 5-HT2AR/5-HT2CR in subcortical regions (-7.8, 95% CI [-21.7;7.7], p=0.31). In [11C]Cimbi-36-only analyses, COC use was associated with -12.6% (95% CI [-22.1;-1.9], p=0.02) lower 5-HT2AR binding in neocortex and -23.5% lower 5-HT2AR/5-HT2CR binding in subcortical regions (95% CI [-35.6;-9.1], p=0.002). No significant differences were observed in the [18F]Altanserin-only analyses. ConclusionThe [11C]Cimbi-36 data indicated lower cortical 5-HT2AR and subcortical 5-HT2AR/5-HT2CR binding in COC users compared to non-users, but this was not observed in the [18F]Altanserin data. This may reflect better signal-to-noise properties of [11C]Cimbi-36 and the fact that it binds more selectively to the high-affinity, biologically active receptor state. These results offer potential mechanistic insights into the depression risk associated with COC use and may have implications for treatments targeting 5-HT2AR/5-HT2CR, underscoring the need for replication and further investigation. Highlights1) COC use was associated with lower 5-HT2AR/CR brain binding in Cimbi-36 PET data 2) COC use was not associated with 5-HT2AR brain binding in [18F]Altanserin PET data 3) We speculate if lower 5-HT2AR/CR levels may affect treatments targeting 5-HT2AR/CR

BackgroundA common feature of Cannabis use disorder (CUD) is an intense reactivity to cannabis cues, which are becoming increasingly visible due to growth in the decriminalization, accessibility and marketing of cannabis products. The brains automatic reactivity to cannabis cues can trigger craving and subsequent use. This study aimed to test neural activity during cannabis cue-induced craving in non-treatment seeking individuals with moderate-to-severe CUD, with past attempts to cut down/quit. MethodsThe study examined 65 individuals with moderate-to-severe CUD and 43 controls, with a fMRI cannabis cue-induced craving task and assessment of mental health, substance use, and cognitive testing. Group differences in neural cue-induced craving were examined, adjusting for age and sex; correlations with cannabis use characteristics were assessed, accounting for recent substance use. ResultsIndividuals with a CUD relative to controls showed greater brain activity during cannabis cue-induced craving in the superior/middle occipital, medial/lateral OFC, anterior/posterior cingulate, cerebellar, hippocampus, middle temporal and lateral parietal cortices (p < .05; cluster k > 10, FWE-corrected). Greater occipital/cerebellar activity correlated with greater subjective arousal towards cannabis images and cannabis withdrawal scores, while anterior cingulate/inferior parietal activity negatively correlated with urinary level of 11-Nor-9-carboxy-{Delta}9-tetrahydrocannabinol:creatinine (ps<.05). ConclusionsExposure to cannabis cues can elicit greater activity within salience evaluation/attention, motivation and disinhibition pathways of addiction neurocircuitry in people with moderate-to-severe CUD, consistent with prominent neuroscientific theories of addiction and findings with other substances. Interventions which can suppress brain activity in salience and attention circuits during cannabis-induced craving may help reduce craving and subsequent use.

IntroductionThe primary psychoactive component in marijuana is tetrahydrocannabinol (THC), which acts on receptors, such as cannabinoid 1 (CB1), that are distributed broadly throughout the brain. THC interferes with synaptic plasticity and neurogenesis and impacts the brains macrostructure, specifically white matter where CB1 receptors are abundant. The current study aims to investigate whether callosal morphology differs depending on how much experience individuals have with marijuana. MethodsThis is a quantitative between-group corpus callosum morphology analysis using cohort study data. The data for this study (n = 144) came from the S1200 Release from the Washington University - University of Minnesota Human Connectome Project Consortium (WU-Minn HCP). Marijuana use was quantified using self-reports and grouped as (1) no use, (2) low use, and (3) high use. T1-weighted MRI brain images were obtained and then processed using SPM12 and MATLAB. Each corpus callosum was manually traced and automatically separated into seven callosal areas according to the Witelson parcellation scheme. The resulting area measures were compared between the three groups, while covarying for total brain volume. ResultsOur ANCOVA analysis was significant (F(2, 145) = 4.38, p = .014), and posthoc tests revealed a significantly smaller anterior midbody in the high marijuana use group compared to the no marijuana use group (p = .012). ConclusionSmaller callosal areas in the high use marijuana group suggest that heavy cannabis may be related to weaker interhemispheric connectivity. Future research is required to replicate the current findings using well-powered designs.

BackgroundAnesthetic agents including ketamine and nitrous oxide have shown antidepressant properties when appropriately dosed. Our recent open-label trial of propofol, an intravenous anesthetic known to elicit transient positive mood effects, suggested that it may also produce robust and durable antidepressant effects when administered at a high dose that elicits an electroencephalographic (EEG) burst-suppression state. Here we report findings from a randomized controlled trial (NCT03684447) that compared two doses of propofol. We hypothesized greater improvement with a high dose that evoked burst suppression versus a low dose that did not. MethodsParticipants with moderate-to-severe, treatment-resistant depression were randomized to a series of 6 treatments at low versus high dose (n=12 per group). Propofol infusions were guided by real-time processed frontal EEG to achieve predetermined pharmacodynamic criteria. The primary and secondary depression outcome measures were the 24-item Hamilton Depression Rating Scale (HDRS-24) and the Patient Health Questionnaire (PHQ-9), respectively. Secondary scales measured suicidal ideation, anxiety, functional impairment, and quality of life. ResultsTreatments were well tolerated and blinding procedures were effective. The mean [95%-CI] change in HDRS-24 score was -5.3 [-10.3, -0.2] for the low-dose group and -9.3 [-12.9, -5.6] for the high-dose group (17% versus 33% reduction). The between-group effect size (standardized mean difference) was -0.56 [-1.39, 0.28]. The group difference was not statistically significant (p=0.24, linear model). The mean change in PHQ-9 score was -2.0 [-3.9, -0.1] for the low dose and -4.8 [-7.7, -2.0] for the high dose. The between-group effect size was -0.73 [-1.59, 0.14] (p=0.09). Secondary outcomes favored the high dose (effect sizes magnitudes 0.1 - 0.9) but did not generally reach statistical significance (p>0.05). ConclusionsThe medium-sized effects observed between doses in this small, controlled, clinical trial suggest that propofol may have dose-dependent antidepressant effects. The findings also provide guidance for subsequent trials. A larger sample size and additional treatments in series are likely to enhance the ability to detect dose-dependent effects. Future work is warranted to investigate potential antidepressant mechanisms and dose optimization.

The use of low sub-hallucinogenic doses of psychedelics ("microdosing") has gained popularity in recent years. Although anecdotal reports claim multiple benefits associated with this practice, the lack of placebo-controlled studies limits our knowledge of microdosing and its effects. Moreover, research conducted in laboratory settings might fail to capture the motivation of individuals engaged in microdosing protocols. We recruited 34 individuals planning to microdose with psilocybin mushrooms (Psilocybe cubensis), one of the materials most frequently used for this purpose. Following a double-blind placebo-controlled design, we investigated the effects of 0.5 g dried mushrooms on subjective experience, behavior, creativity, perception, cognition, and brain activity. The reported acute effects were significantly more intense for the active dose compared to the placebo, which could be explained by unblinding. For the other measurements, we observed either null effects or a trend towards cognitive impairment and, in the case of EEG, towards reduced theta band spectral power. Our findings support the possibility that expectation effects underlie at least some of the anecdotal benefits attributed to microdosing with psilocybin mushrooms.

Psilocybin is a classic psychedelic and a novel treatment for mood disorders. Psilocybin induces dose-dependent transient (4-6 hours) usually pleasant changes in perception, cognition, and emotion by non-selectively agonizing the 5-HT2A receptors and negatively regulating serotonin reuptake, and long-term positive antidepressant effect on mood and well-being. Long-term effects are ascribed to the psychological quality of the acute experience, increase in synaptodensity and temporary (1-week) down-regulation of 5-HT2A receptors. Electroencephalography, a non-invasive neuroimaging tool, can track the acute effects of psilocybin; these include the suppression of alpha activity, decreased global connectivity, and increased brain entropy (i.e. brain signal diversity) in eyes-closed resting-state. However, few studies investigated how these modalities are affected together through the psychedelic experience. The current research aimed to evaluate the psilocybin intoxication temporal EEG profile. 20 healthy individuals (10 women) underwent oral administration of psilocybin (0.26 mg/kg ) as part of a placebo-controlled cross-over study, resting-state 5-minute eyes closed EEG was obtained at baseline and 1, 1.5, 3, 6, and 24 hours after psilocybin administration. Absolute power, relative power spectral density (PSD), power envelope global functional connectivity (GFC), Lempel-Ziv complexity (LZ), and a Complexity via State-Space Entropy Rate (CSER) were obtained together with measures of subjective intensity of experience. Absolute power decreased in alpha and beta band, but increased in delta and gamma frequencies. 24h later was observed a broadband decrease. The PSD showed a decrease in alpha occipitally between 1 and 3 hours and a decrease in beta frontally at 3 hours, but power spectra distribution stayed the same 24h later. The GFC showed decrease acutely at 1, 1.5, and 3 hours in the alpha band. LZ and showed an increase at 1 and 1.5 hours. Decomposition of CSER into functional bands shows a decrease in alpha band but increase over higher frequencies. Further, complexity over a source space showed opposing changes in the Default Mode Network (DMN) and visual network between conditions, suggesting a relationship between signal complexity, stimulus integration, and perception of self. In an exploratory attempt, we found that a change in gamma GFC in DMN correlates with oceanic boundlessness. Psychological effects of psilocybin may be wrapped in personal interpretations and history unrelated to underlying neurobiological changes, but changes to perception of self may be bound to perceived loss of boundary based on whole brain synchrony with the DMN in higher frequency bands.

BackgroundAbrupt cessation of therapy with a selective serotonin reuptake inhibitor (SSRI) is associated with a discontinuation syndrome, typified by numerous disabling symptoms including anxiety. Surprisingly little is known of the behavioural effect of SSRI discontinuation in animals. AimHere, the effect of SSRI discontinuation on anxiety-like behaviour was systematically investigated in mice. MethodsExperiments were based on a 3-arm experimental design comprising saline, continued SSRI and discontinued SSRI. Mice were assessed 2 days after SSRI discontinuation over a 5 day period using the elevated plus maze (EPM) and other anxiety tests. ResultsAn exploratory experiment found cessation of paroxetine (12 days) was associated with decreased open arm exploration and reduced total distance travelled, in male but not female mice. Follow-up studies confirmed a discontinuation effect on the EPM in male mice after paroxetine (12 days) and also citalopram (12 days). Mice receiving continued paroxetine (but not citalopram) also showed decreased open arm exploration but this was dissociable from effects of discontinuation. The discontinuation response to paroxetine did not strengthen after 28 days treatment but was absent after 7 days treatment. A discontinuation response was not decernable in other anxiety and fear-learning tests applied 3-5 days after treatment cessation. Finally, discontinuation effects on the EPM were typically associated with decreased locomotion on the test. However, separate locomotor testing implicated anxiety-provoked behavioural inhibition rather than a general reduction in motor activity. ConclusionOverall, the current study provides evidence for a short-lasting behavioural discontinuation response to cessation of SSRI treatment in mice.

IntroductionN,N-Dimethyltryptamine (DMT), a naturally occurring psychedelic tryptamine contained in the indigenous ayahuasca brew has shown antidepressant effects. This Phase 2a clinical trial investigates for the first time the efficacy of isolated DMT in treatment-resistant depression (TRD). MethodsSix TRD patients participated in an open-label, fixed-order, dose-escalation study, receiving a lower (15 mg) and then a higher (60 mg) dose of vaporized DMT in a single-day session. Depression severity was assessed using the Montgomery-Asberg Depression Rating Scale (MADRS) and the Patient Health Questionnaire-9 (PHQ-9) up to one-month post-dosing. ResultsSignificant reductions in MADRS and PHQ-9 scores were noted from Day 1 to M1. The mean MADRS score variation from baseline to D7 was -22 points and -17 points at M1. PHQ-9 scores also showed significant decreases, mirroring the MADRS results. By D7, 83.33% of patients responded to treatment, with 66.67% achieving remission. At M1, 66.67% maintained response, and 50% maintained remission. DiscussionThe rapid onset and sustained antidepressant effects of vaporized DMT align with the paradigm of rapid-acting antidepressants to be used in the scope of interventional psychiatry. The non-invasive route and short-acting nature of DMT offer practical advantages, potentially enhancing accessibility to psychedelic treatments. Clinical Trial registrationClinicaltrials.gov NCT06094907

ObjectivesKetamines prohedonic properties have been linked to enhanced reward-related brain activation during the early post-infusion phase. Its effects during the subacute period ([~]2-24 h post-infusion), when psychotomimetic symptoms fade and neuroplastic adaptations emerge, are less well characterised. This study assessed ketamines subacute effects on reward processing using the Monetary Incentive Delay (MID) task. MethodsIn a randomised, placebo-controlled, crossover study, 28 healthy participants received 0.5 mg/kg racemic ketamine or placebo via 40-minute intravenous infusion. Functional magnetic resonance imaging (fMRI) was acquired [~]5 h post-infusion. Plasma concentrations of ketamine and norketamine were obtained for individual area under the curve (AUC) estimation. Analyses focused on the contrast between expected and actual trial outcomes. ResultsAt five hours post-infusion, ketamine did not significantly modulate MID task-related brain activation, despite pronounced subjective drug effects. Pharmacokinetic modelling confirmed expected ketamine and norketamine profiles, but neither drug exposure (AUC) nor subjective measures correlated with neural activation. ConclusionsProhedonic effects of ketamine may not sufficiently manifest in MID task-related activation in healthy individuals [~]5 hours after infusion. The lack of significant effects provides valuable extension of the existing literature, as ketamines effects might be confined to a more acute time window or differ in clinical populations.

OBJECTIVEN-methyl D-aspartate Receptor (NMDAR) antagonist antidepressants have known potential for abuse liability. The aim of this study was to evaluate the abuse liability of D-cycloserine (DCS), using a self-administration paradigm in which DCS was tested in its efficacy in substituting for ketamine in ketamine-dependent rats. METHODSA standard Intravenous self-administration study was conducted in Male adult Sprague-Dawley rats. model to study compounds abuse liability. Potential for self-administration was assessed in ketamine-habituated subjects. Subjects were trained to press a lever to obtain food, prior to connection of the lever to intravenous drug administration apparatus. DCS was provided for self-infusion by test subjects at doses of 1.5, 5.0, and 15mg/kg per lever press. RESULTSS-Ketamine was seen to substitute for ketamine and to result in self-administration at the same frequency. DCS was not seen to result in any self-administration at any of the test doses. The self-infusion behavior of DCS was the same as that of saline. CONCLUSIONC-cycloserine, an a mixed agonist/antagonist of the NMDAR glycine site, which has been shown to have antidepressant and anti-suicidal properties in clinical studies has no apparent potential for abuse liability in a standard rodent self-administration model.

Considering the ever-increasing use of ketamine as a rapid-acting and efficacious agent for difficult-to-treat affective disorders, it is paramount that clinicians understand pharmacological interactions between ketamine and other drugs commonly used in unipolar and bipolar depression. Anticonvulsants appear of particular interest in this context, as some (valproate, lamotrigine, carbamazepine, pregabalin, gabapentin) are widely employed as mood-stabilisers and/or anxiolytics, while others are still commonly encountered due to the significant comorbidity between affective disorders and epilepsy. This is the protocol for a scoping review aiming to comprehensively collect evidence regarding pharmacodynamic and pharmacokinetic interactions between ketamine (and its enantiomers) and anticonvulsants. Our review was designed in accordance with the PRISMA Extension for Scoping Reviews (PRISMA-ScR). PubMed, Embase, PsycINFO, ProQuest and ClinicalTrials.gov will be searched for relevant papers. Primary and non-primary research of any design will be included to ensure comprehensiveness. All data will be synthetised and presented in narrative form. We anticipate that our results will provide useful insight for clinicians and highlight gaps in knowledge that may be explored in future research.

BackgroundQuetiapine is an antipsychotic drug with unique pharmacological properties approved for the treatment of schizophrenia, bipolar disorder, and augmentation for major depressive disorder. In routine clinical practice, it is also frequently prescribed for conditions such as insomnia, anxiety, and psychomotor agitation. Italfarmaco (ITF) Group has developed an innovative oral suspension formulation of quetiapine; its composition, optimized in viscosity and stability, aims to facilitate administration and dosing across a wide range of patient profiles, particularly those requiring low doses or those with difficulty swallowing, limited manual dexterity, or cognitive impairment. ObjectiveThis study aimed to evaluate the pharmacokinetic (PK) profile of this innovative oral suspension formulation of quetiapine compared to the immediate-release tablets. MethodsA single-dose, open-label, randomized, two-sequence, two-treatment, two-period cross-over pivotal study was conducted in 43 healthy subjects under fasting conditions. Volunteers received a single 25 mg dose of quetiapine, administered either as an oral suspension or as an immediate-release film-coated tablet, with an appropriate washout between treatments. The PK performance of the two formulations was compared, maximum plasma concentration (Cmax), time to reach Cmax (tmax), area under the curve (AUC), and overall bioavailability. Plasmatic quetiapine levels were measured by validated high performance liquid chromatography (HPLC) methods blinded to the dosing randomization scheme. ResultsQuetiapine oral suspension demonstrated pharmacokinetic bioequivalence to the reference tablet in terms of Cmax and AUC. It exhibited faster absorption, being detectable in plasma within 10 minutes following oral administration, with a median tmax of 0.75 h compared to 1.02 h for the immediate-release tablet. Calculating the median tmax difference for each subject shows that quetiapine oral suspension reaches peak plasma concentration about 30 minutes faster than the immediate-release tablet. ConclusionThis novel quetiapine oral suspension formulation addresses key unmet needs in psychiatric pharmacotherapy treatment by combining a favorable pharmacokinetic profile with a patient-centered design. It enables precise dose titration of the drug and promotes faster absorption, thereby potentially achieving a more rapid onset of action. This formulation facilitates administration and dosing flexibility, an advantage for all patients, especially for the ones requiring low doses. KEY POINTSO_LIItalfarmaco (ITF) has developed an innovative oral suspension formulation of quetiapine. C_LIO_LIThis novel quetiapine oral suspension formulation enables precise dose titration of the drug and promotes faster absorption, thereby potentially achieving a more rapid onset of action. C_LIO_LIITF quetiapine suspension formulation is intended to address key unmet needs in antipsychotic pharmacotherapy treatment by combining a favorable pharmacokinetic profile with a patient-centered design. C_LI

While ketamine is already approved for treatment resistant depression in adult patients, its efficacy and safety profile for its use in adolescence still needs further investigations. Preclinical studies proved dose- and sex-dependent effects induced by ketamine during adolescence, but few studies have evaluated the short- and long-term safety profile of ketamine at the doses necessary to induce its antidepressant-like effects. The present study aimed at evaluating the antidepressant-like effects of ketamine (1, 5 or 10 mg/kg; vs. vehicle; 1 vs. 7 days) during adolescence in naive or early-life stressed (i.e., maternal deprivation) rats of both sexes in the forced-swim or novelty-suppressed feeding tests. Safety was evaluated by measuring the psychomotor- and reinforcing-like responses induced by adolescent ketamine. In addition, long-term safety was evaluated in adulthood at the level of cognitive performance, or addiction liability (induced by a challenge dose of ketamine in rats treated with adolescent ketamine). The main results reinforced the potential for ketamine as an antidepressant for adolescence, but at different dose ranges for each sex. However, some safety concerns emerged for adolescent female rats (i.e., signs of sensitization at the dose used as antidepressant) and adult male rats (i.e., addiction liability when re-exposed to ketamine in adulthood), suggesting the need for caution and further research before moving forward the use of ketamine as an antidepressant for adolescence.

ObjectiveTo evaluate the effectiveness of repeated at-home ketamine treatments for depression, generalized anxiety, and social anxiety and assess safety in terms of adverse effects and tendency towards long-term use. MethodsThis retrospective analysis included patients with depression, generalized anxiety, and/or social anxiety who received ketamine treatment (delivered at-home via low-dose, sublingual lozenges) through a private telehealth provider. Data was collected between May 2022 and April 2023. The primary outcome was change in depression, generalized anxiety, and social anxiety symptoms from baseline to three follow-up time points, measured via Patient Health Questionnaire (PHQ-9), Generalized Anxiety Disorder Assessment (GAD-7), and Social Anxiety Disorder Severity Scale (SAD-D-10), with analysis subgroups established based on baseline diagnosis. Secondary outcomes included side effects, adverse events, long-term use, well-being improvements, and comparison of outcomes between treatment-resistant and non-resistant depression cases. ResultsOf 431 patients (mean [SD] age, 43.6 [10.9] years; 49.2% women), 81 (18.8%) reported minor side effects resolving within 24 hours, and 397 concluded treatment in [&le;] 6 months. Statistically significant improvement on the primary outcome was observed at all follow-ups in all three subgroups (p < 0.001). No significant differences were found between treatment-resistant and non-resistant depression outcomes. ConclusionsRepeated sublingual ketamine significantly reduced depression, generalized anxiety, and social anxiety with no major adverse events and minimal tendency towards long-term use observed. These findings prompt further exploration of ketamine as an alternative or adjunct to medications such as SSRIs and benzodiazepines to minimize response delays and dependence risk.

BackgroundN,N-Dimethyltryptamine (DMT) is a short acting psychedelic tryptamine found naturally in many plants and animals. Few studies to date addressed the neural and psychological effects of DMT alone, either administered intravenously or inhaled in freebase form, and none conducted in natural settings. AimsOur primary aim was to study the acute effects of inhaled DMT in natural settings, focusing on questions tuned to the advantages of conducting field research, including the effects of contextual factors (i.e. "set" and "setting"), the possibility of studying a comparatively large number of subjects, and the relaxed mental state of participants consuming DMT in familiar and comfortable settings. MethodsWe combined state-of-the-art wireless electroencephalography (EEG) with psychometric questionnaires to study the neural and subjective effects of naturalistic DMT use in 35 healthy and experienced participants. ResultsWe observed that DMT significantly decreased the power of alpha (8-12 Hz) oscillations throughout all scalp locations, while simultaneously increasing power of delta (1-4 Hz) and gamma (30-40 Hz) oscillations. Gamma power increases correlated with subjective reports indicative of mystical-type experiences. DMT also increased/decreased global synchrony and metastability in the gamma/alpha band, and resulted in widespread increases in signal complexity. ConclusionsOur results are consistent with previous studies of psychedelic action in the human brain, while at the same time suggesting potential EEG markers of mystical-type experiences in natural settings, thus highlighting the importance of investigating these compounds in the contexts where they are naturally consumed.

BackgroundBehavioural studies in animal models represent a critical component of psychiatric drug development. Positive results in animal studies have identified novel therapeutic targets for major depressive disorder (MDD) but efficacy in humans has largely not been borne out in clinical trials. A possible reason for this failed translation is inappropriate dose selection and the engagement of mechanisms not directly relevant to antidepressant effects in patients. MethodsWe first used PubMed to identify preclinical rodent studies in two assays used to assess antidepressants; the conventional forced swim test, (FST) and more recently developed affective bias test, (ABT). Dose ranges were extracted, as well as information about subjects, timing and route of administration, and justification and efficacy of dose(s). Dose ranges were compared against calculated animal equivalent doses. ResultsThe median FST dose across all antidepressants was 10mg/kg, with median doses for each drug exceeding the relevant animal equivalent dose by 1.5-25x. In contrast, effective doses in the ABT showed closer alignment to those used clinically. In the second study, 232 ketamine and 202 fluoxetine papers involving MDD-related research in rodents were reviewed. The median dose was 10mg/kg for both drugs, exceeding animal equivalent doses by 1.6-3.2x and 3.2-6.5x for ketamine and fluoxetine, respectively. ConclusionsThe results indicate pervasive use of antidepressant doses in conventional models of MDD that may not correspond with doses used in clinical practice. We discuss the implications of using doses which exceed therapeutic levels and the potential to engage receptors and underlying mechanisms which are not relevant to clinical effects.

Background and PurposeSerotonergic psychedelic drugs are under renewed investigation for the potential treatment of several psychiatric disorders. While all serotonergic psychedelics have 5-HT2A receptor activity, the explanation for why some 5-HT2A receptor agonists are not psychedelic is unknown. To address this question, we investigated the 5-HT2A receptor signalling bias and efficacy of a panel of psychedelics and non-psychedelics. Experimental ApproachG -coupled (Ca2+ and IP) and {beta}-arrestin2 signalling effects of eight chemically diverse psychedelics (psilocin, 5-MeO-DMT, LSD, mescaline, 25B-NBOMe and DOI) and non-psychedelics (lisuride and TBG) were characterised using SH-SY5Y cells expressing recombinant human 5-HT2A receptors. Measurements of signalling efficacy and bias were derived from dose-responses curves for each agonist, compared to 5-HT. Follow-up experiments sought to confirm the generality of findings using rat C6 cells expressing endogenous 5-HT2A receptors. Key ResultsIn SH-SY5Y cells, all psychedelics were partial agonists at both 5-HT2A receptor signalling pathways and none showed significant signalling bias. In comparison, in SH-SY5Y cells the non-psychedelics lisuride and TBG were not distinguishable from psychedelics in terms of biased agonist properties, but both exhibited the lowest 5-HT2A receptor signalling efficacy of all drugs tested, a result confirmed in C6 cells. Conclusion and ImplicationsIn summary, all psychedelics tested were unbiased, partial 5-HT2A receptor agonists. Importantly, the non-psychedelics lisuride and TBG were discriminated from psychedelics, not through biased signalling but rather by relatively low efficacy. Thus, 5-HT2A receptor signalling efficacy and not bias provides a possible explanation for why some 5-HT2A receptor agonists are not psychedelic.

Cannabis use disorder (CUD) affects [~]22M people globally and is characterised by difficulties in cutting down and quitting use, but the underlying neurobiology remains unclear. We examined resting-state functional connectivity (rsFC) between regions-of-interest (ROIs) of the addiction neurocircuitry and the rest of the brain in 65 individuals with moderate-to-severe CUD who reported attempts to cut down or quit, compared to 42 controls, and explored the association between rsFC and cannabis exposure and related problems, to elucidate potential drivers of rsFC alterations. The CUD group showed greater rsFC than controls between ROIs implicated in reward processing and habitual substance use (i.e., nucleus accumbens, putamen, pallidum) and occipito/parietal areas implicated in salience processing and disinhibition. Putamen-occipital rsFC correlated with levels of problematic cannabis use and depression symptoms. CUD appears to show neuroadaptations of the addiction neurocircuitry, previously demonstrated in other substance use disorders.

BACKGROUNDKetamine may have antidepressant properties, but its acute psychoactive effects complicate successful masking in placebo-controlled trials. METHODSIn a triple-masked, randomized, placebo-controlled trial, 40 adult patients with major depressive disorder were randomized to a single infusion of ketamine (0.5 mg/kg) or placebo (saline) during anesthesia as usual for routine surgery. The primary outcome was depression severity measured by the Montgomery-[A]sberg Depression Rating Scale (MADRS) at 1, 2, and 3 days post-infusion. The secondary outcome was the proportion of participants with clinical response ([&ge;]50% reduction in MADRS scores) at 1, 2, and 3 days post-infusion. After all follow-up visits, participants were asked to guess which intervention they received. RESULTSMean MADRS scores did not differ between groups at screening or pre-infusion baseline. The mixed-effects model showed no evidence of effect of group assignment on post-infusion MADRS scores at 1 to 3 days post-infusion (-5.82, 95% CI -13.3 to 1.64, p=0.13). Clinical response rates were similar between groups (60% versus 50% on day 1) and comparable to previous studies of ketamine in depressed populations. Secondary and exploratory outcomes did not find statistical separation of ketamine from placebo. 36.8% of participants guessed their treatment assignment correctly; both groups allocated their guesses in similar proportions. One serious adverse event occurred in each group, unrelated to ketamine administration. CONCLUSIONIn adults with major depressive disorder, a single dose of intravenous ketamine delivered during surgical anesthesia had no greater effect than placebo in acutely reducing the severity of depressive symptoms. This trial successfully masked treatment allocation in moderate-to-severely depressed patients using surgical anesthesia. While it is impractical to use surgical anesthesia for most placebo-controlled trials, future studies of novel antidepressants with acute psychoactive effects should make efforts to fully mask treatment assignment in order to minimize subject-expectancy bias. (ClinicalTrials.gov number, NCT03861988)

This international online study (N=759) examined the acute, subacute, and long-term effects of psychedelic drug use on cognitive performance and mental health. Participants completed cognitive tasks assessing working memory, selective attention, and visual/spatial perception, as well as questionnaires assessing mental health outcomes and quality of life. Based on self-reported substance use, participants were classified as non-users, lifetime users, and recent users. Recent users had significantly lower accuracy across all cognitive tasks, and lifetime users had the highest task accuracy without corresponding reaction time deficits. Lifetime use was not associated with long-term cognitive decline. Recent users reported more depressive and dissociative symptoms, whereas lifetime users reported lower scores. Lifetime users scored lower on psychological and social quality of life domains, indicating possible long-term psychosocial effects. These findings highlight the need to differentiate between the acute and long-term effects of psychedelics; lab-controlled, longitudinal studies are needed to enable safe clinical application.