BACKGROUND:Psilocybin's therapeutic potential is neurophysiologically characterized by acute alpha power reductions and increased entropy. However, the systematic time-course of these changes from administration through the 24-hour sub-acute phase remains poorly characterized. METHODS:In a double-blind, placebo-controlled, crossover trial (N = 20, 10 females), healthy participants received a medium dose ∼0.26 mg/kg of psilocybin. High-density resting-state electroencephalography and psychological states were assessed at baseline, 1, 3, 6, and 24 hours, with a 28-day follow-up. RESULTS:Psilocybin acutely decreased alpha/beta power and increased gamma-band signal diversity (1-3 hours; returning to baseline at 6 hours). Increased gamma diversity correlated with acute psychological effects (Brief Psychiatric Rating Scale, r = 0.71), with the largest increases observed in participants with lower baseline complexity. At 24 hours, reduced delta/theta power correlated with Positive Life Changes (Persisting Effects Questionnaire) at 4 weeks (r = -0.47 to -0.57) but was independent of acute psychological intensity. CONCLUSION:Our findings corroborate known acute effects while identifying a distinct sub-acute "afterglow" associated with long-term outcomes. The dissociation between acute psychology and 24-hour spectral shifts suggests that therapeutic benefits may be driven by sub-acute reductions in top-down cortical hierarchy. These results highlight the significance of the sub-acute window for psychological transformation and suggest normalized diversity as a viable baseline biomarker of individual responsiveness to psychedelic intervention.
BACKGROUND:Serotonergic psychedelics, such as N,N-dimethyltryptamine (DMT), have shown therapeutic potential in various psychiatric disorders. However, DMT demonstrates pharmacokinetic (PK) variability and a short half-life. AIMS:This exploratory study investigated the PK, pharmacodynamic (PD), and safety profile of CYB004, a deuterated DMT analogue, following intravenous administration in healthy volunteers. METHODS:CYB004, a deuterated DMT analogue, was evaluated in a randomized, double-blind, placebo-controlled, two-part study in healthy participants. Part 1 was a single-dose cohort, in which participants received a 5-minute intravenous 12.7 mg CYB004 bolus, followed by a 30-minute 15.41 mg infusion. Part 2 was a three-way crossover, during which two separate 5-minute 12.7 mg CYB004 boluses were administered. Outcome measures included PK of CYB004 and subjective, autonomic, neurophysiological, and adverse effects. RESULTS:Although high CYB004 doses led to intense psychedelic experiences and participant withdrawals, lower doses achieving plasma concentrations similar to those in previous DMT studies demonstrated an acceptable safety profile. CYB004 demonstrated a PD profile that was similar to DMT at comparable plasma concentrations. PD effects consisted of subjective psychedelic effects, electroencephalography power band reductions, and autonomic nervous system activation. CYB004's half-life was approximately two-fold longer than DMT, prolonging the duration of psychedelic effects to ~40-60 minutes following brief intravenous administration. However, deuteration did not improve PK variability, with IV-administered CYB004 demonstrating moderate to high variability, largely driven by interindividual differences. CONCLUSION:CYB004 demonstrated PD effects comparable to DMT. However, CYB004 demonstrated an extended duration of these effects due to reduced clearance, while maintaining an acceptable safety profile at clinically relevant exposures despite PK variability.
BACKGROUND:BI 1569912 is an orally administered, GluN2B-selective negative allosteric modulator at the N-methyl-D-aspartate receptor. AIMS:To investigate the safety, tolerability and pharmacokinetics (PK) of BI 1569912 in healthy males across three partially randomised, placebo-controlled, parallel-group phase I trials. METHODS:Trial 1 evaluated single rising doses (SRD) of BI 1569912 versus placebo in Germany and assessed formulation and food effects on bioavailability. Trial 2 evaluated multiple rising doses (MRD) of BI 1569912 versus placebo in young and elderly participants in Germany. Trial 3 investigated single rising and multiple doses (MD) of BI 1569912 in participants in Japan, including PK to assess morning versus evening dosing. RESULTS:Trial completion/randomisation numbers were: Trial 1 (SRD part, 54/55; bioavailability/food effect part, 8/13); Trial 2 (MRD part, 71/71; Elderly part, 12/12); Trial 3 (SRD part, 32/32; MD part, 12/12; evening PK part, 12/12). No deaths, serious adverse events (AEs), AEs of special interest, or discontinuations because of AEs were reported. There was no clinical evidence clearly suggestive of dissociation. After oral administration, BI 1569912 was rapidly absorbed and eliminated, with dose-proportional increases in plasma exposure. Formulation (oral solution vs tablet) did not affect PK. Administration with food reduced Cmax and delayed Tmax without affecting AUC; likewise, evening dosing lowered Cmax versus morning while AUC remained similar. Steady state was achieved by Day 3 of multiple dosing. Exposure was similar between young and elderly participants. Urinary excretion of unchanged drug was negligible. CONCLUSIONS:BI 1569912 demonstrated favourable safety and PK profiles in healthy participants.Clinical trial registration: Trial 1 (ClinicalTrials.gov: NCT04445090 (1447-0001)); Trial 2 (ClinicalTrials.gov: NCT04978506 (1447-0002)); Trial 3 (ClinicalTrials.gov: NCT04958252 (1447-0004)).
BACKGROUND:Abrupt cessation of serotonin (5-HT) reuptake inhibitors (SRIs) in men and women induces a constellation of somatic and psychological symptoms known as discontinuation SRI syndrome; however, the underlying neurophysiological mechanisms remain unclear. AIMS:While previous work has largely focused on 5-HT dysregulation, this study assessed whether norepinephrine (NE) signalling may play a critical role. METHODS:Using in vivo electrophysiology, the firing activity of locus coeruleus NE and dorsal raphe nucleus 5-HT neurons was examined in male rats following sustained escitalopram administration for 14 days and its subsequent cessation for 2 days to allow its elimination. RESULTS:Escitalopram cessation produced a marked increase in the suppressed firing rate of NE neurons and a doubling of the normalized firing rate of 5-HT neurons. Acute intravenous injection of escitalopram restored the firing rate of both neuronal populations to their prior firing levels after the drug had been administered for 14 days. Acute intravenous injection of the α2-adrenoceptor agonist clonidine had the same effect as the re-introduction of escitalopram on both populations of neurons. CONCLUSIONS:These results show that abrupt cessation of the SRI escitalopram resulted in robust overactivation of both NE and 5-HT neurons. Normalization of the SRI cessation-induced overactivation of NE and 5-HT neurons by the acute inhibition of the 5-HT reuptake transporter is consistent with the rapid relief of discontinuation symptoms observed in patients resuming their SRI. A similar effect of clonidine on NE and 5-HT neuronal firing would support its use in managing discontinuation symptoms seen after SRI cessation.
BACKGROUND:The serotonergic psychedelic N,N-dimethyltryptamine (DMT) might have therapeutic effects in various psychiatric disorders. AIMS:Prior to exploring this clinical potential, it is essential to determine an optimal administration regimen for DMT, explore the relationship between its pharmacokinetics (PK) and pharmacodynamics and identify potential sources of pharmacokinetic variability. METHODS:Therefore, DMT was administered as a 90-minute intravenous infusion (0.10, 0.20, 0.40 and 0.81 mg/min DMT) in a randomised, double-blind, placebo-controlled, single-ascending dose part in healthy smokers . Subsequently, DMT was administered as a 5-minute loading dose followed by a 55-minute infusion (3.64 mg/min + 0.81 mg/min and 3.64 mg/min + 1.29 mg/min) in an open-label, single-sequence two-period escalating dose study in healthy non-smokers. Outcome measures included PK of DMT and subjective, autonomic, neurophysiological and adverse effects. RESULTS:All adverse events were mild to moderate in intensity and self-limiting. Two subjects requested their infusion to be discontinued following the loading dose in Part 2 due to anxiety and intense effects. Moderate inter- and intra-individual pharmacokinetic variability was observed, while DMT plasma concentrations at similar infusion rates in smokers were roughly double that of non-smokers, probably due to mono-amine oxidase A-inhibiting compounds in cigarette smoke. Mild to moderate subjective psychedelic effects emerged at plasma concentrations of ~35 ng/mL in both parts, while only limited undesired effects such as sedation or impaired sustained attention occurred for DMT 0.81 ng/mL. Interestingly, no differences were noted in psychoactive effects between smokers and non-smokers. CONCLUSION:These findings provide a basis for future studies exploring the (inter)relationships between DMT PK, different infusion regimens and subjective, neurophysiological and neuroendocrine effects resulting from 5-HT2A agonism.
BACKGROUND:Fentanyl is the leading cause of fatal overdoses worldwide, and repeated use may lead to substance use disorder (SUD). In SUD, drug-associated contexts can trigger reward-related behavior even in the absence of the drug. Psychedelic compounds may weaken context-drug associations, reducing reward-related behavior to fentanyl. AIMS:We evaluated the effects of the psychedelic psilocin and its derivatives, 4-MeO-MiPT and 4-HO-MiPT, on fentanyl-induced conditioned place preference (CPP) in male and female C57BL/6J mice. METHODS:Mice were conditioned to distinct fentanyl and saline control contexts, then assessed for fentanyl place preference before and after treatment with one of the test compounds. Anxiety-related side effects of each compound were evaluated using an elevated plus maze (EPM) model. RESULTS:Psilocin reduced fentanyl CPP exclusively in females, 4-MeO-MiPT in both sexes, and 4-HO-MiPT had no effect. None of the compounds significantly altered anxiety-like behaviors in EPM. CONCLUSION:These findings support further preclinical investigations of the sex-dependent effects of psilocin and 4-MeO-MiPT on fentanyl reward behavior.
BACKGROUND:In England and Wales, significant numbers of people with intellectual disability (PwID) are prescribed antipsychotics for a range of licensed and non-licensed indications, particularly behaviours that challenge. There is no system to compare antipsychotic prescribing practices across specialist adult intellectual disability (ID) services. AIM:This study aimed to determine whether converting antipsychotics and their doses to equivalent chlorpromazine units enables comparison of licensed (psychosis, etc.) and non-licensed (behaviours that challenge) prescribing between different services. METHOD:A feasibility retrospective cohort study using convenience sampling captured anonymized data of PwID on ⩾2 antipsychotics across eight specialist England and Wales adult ID services. The doses prescribed across 2017-2023 were converted to chlorpromazine-equivalent values, and antipsychotic dose burden across services was compared. Patients' characteristics and antipsychotic dosing are summarized descriptively. A mixed-effects regression model determines changes in chlorpromazine unit values across time. Subgroup analysis explores trends. Stata: Release 17 (StataCorp, 2021) and R (R Core Team, 2025) were used. RESULTS:Of the 424 reviewed records, a higher proportion were male (ranging from 58% to 71% across census years) and white individuals (73%-85%). Autism (42%-58%), psychotic illness (61%-71%), and behaviours that challenge (77%-87%) were the most common comorbidities. Chlorpromazine units could be captured for 98% (n = 416). PwID with psychosis, behaviours that challenge, depression, or attention-deficit/hyperactivity disorder were prescribed significantly higher chlorpromazine-equivalent doses. Over 25% were prescribed more than 1000 mg/day chlorpromazine equivalent, which exceeds the British National Formulary-recommended maximum dose. CONCLUSIONS:Our study suggests that converting antipsychotic doses to chlorpromazine units is a simple and effective way to understand and compare prescribing burden for PwID. It also facilitates measuring prescribing and implementing best practice.
BACKGROUND:Psilocybin, a serotonergic psychedelic found in hallucinogenic mushrooms, is metabolized to psilocin, the compound responsible for its psychoactive effects. Psilocybin has demonstrated therapeutic potential for neuropsychiatric conditions. While recent trials have primarily used orally administered synthetic psilocybin, alternative formulations and delivery methods may offer therapeutic advantages, yet the effects of these approaches remain poorly characterized. AIMS:To compare the pharmacodynamic profiles and tolerability of oral psilocybin, oral psilocin, and sublingual psilocin derived from whole-mushroom extracts in healthy adults. METHODS:In this randomized, within-subject, crossover trial, 20 healthy adults (10 men, 10 women; mean age 40.1 ± 5.9 years) completed up to four drug administration sessions involving botanical oral psilocybin (25 mg), oral psilocin (17.5 mg), or sublingual psilocin (2.18, 4.36, or 8 mg). All sessions included therapeutic support and pre- and post-dose psychotherapy. Acute effects were assessed using vital signs and subjective ratings of drug intensity and psychedelic experience. RESULTS:Oral psilocin produced a similar temporal and subjective profile to oral psilocybin, with a lower burden of adverse effects. Sublingual psilocin was well tolerated, though the apparently lower achieved drug exposure limited comparability to oral administration. CONCLUSIONS:Oral psilocin may offer tolerability advantages over oral psilocybin. Sublingual psilocin was well tolerated at the dosages tested. Further studies are needed to evaluate botanical formulations and optimize delivery approaches.Clinical trial registration: https://clinicaltrials.gov/study/NCT05317689.
The re-emergence of serotonergic psychedelics has introduced rapid-acting antidepressant effects and has been widely described as a paradigmatic shift in depression treatment. Recently, there has been intense debate about whether the acute subjective effects of psychedelics are necessary for their therapeutic efficacy or merely byproducts of underlying neuroplastic processes. Recent conceptualizations of "psychoplastogens" emphasize rapid induction of neuroplasticity as a potential common pathway across mechanistically diverse rapid-acting antidepressants. Here, some argue that the psychedelic experience itself may not be required for enduring therapeutic change while others highlight the clinical and existential significance of the subjective experience and its integration within structured psychotherapeutic settings. This Perspective argues that the debate is often framed too narrowly as a binary opposition between experience and mechanism and opts for a complementary model in which receptor-level signalling, network reorganization, subjective experience, and psychotherapeutic context represent interacting dimensions of a single intervention architecture. Within this framework, subjective experience may be clinically meaningful without being biologically indispensable, while neuroplasticity may constitute an enabling condition without being sufficient in isolation. Rather than asking whether experience or mechanism is primary, the clinically relevant question becomes under which conditions, for which patients, and within which care structures different plasticity-inducing interventions, hallucinogenic or non-hallucinogenic, are most appropriate. This question is further complicated by methodological challenges in isolating those contributions empirically. Psychedelic research thus challenges not only neurobiological models of depression but also existing assumptions about how pharmacological and psychotherapeutic processes converge in antidepressant treatment.
BACKGROUND:Dihydropyridine calcium channel blockers have been implicated in both symptom improvement and exacerbation in pre-existing severe mental illness (SMI). We aimed to test the hypothesis that blood-brain barrier penetrant dihydropyridines (DHPs) reduce rates of mental health hospitalisation and self-harm compared to non-penetrant DHPs. METHODS:We used English electronic health records (Clinical Practice Research Datalink) to conduct a target trial emulation study in people with schizophrenia, bipolar disorder or other psychosis. We compared admissions for mental health and self-harm in those prescribed blood-brain barrier penetrant (intervention) and non-penetrant DHPs (control). Our primary endpoint was a 12-month intention-to-treat analysis using covariate adjustment. We additionally completed overlap weighting, per-protocol analyses and negative outcome controls. RESULTS:We included 918 people prescribed blood-brain barrier penetrant DHPs and 3384 prescribed amlodipine (control). In the primary covariate-adjusted intention-to-treat analysis, there was no clear evidence of a difference in rates of combined mental health admissions and self-harm events (adjusted hazard ratio (HR): 1.22; 95% confidence interval (CI): 0.78-1.91 at 12 months). In a pre-specified sensitivity analysis using overlap weighting, self-harm event rates were elevated in the intervention group at 12 months (HR: 2.10; 95% CI: 1.13-3.94); however, the equivalent covariate-adjusted estimate showed no clear difference (HR: 1.81; 95% CI: 0.52-6.26). CONCLUSION:In people with SMI, blood-brain barrier penetrant DHPs were not associated with reduced mental health hospitalisations or self-harm events compared to those treated with amlodipine, though estimates were imprecise. This active comparator design cannot distinguish between absence of effect or equivalent benefit of both drug classes. There are peripheral pathways through which DHPs may impact psychiatric symptoms and these require further exploration.
BACKGROUND:Mental disorders frequently begin in childhood or adolescence. Worldwide, psychotropics are commonly prescribed for under-18s to stabilise behaviour, mood or thoughts. Psychotropics could cause long-term effects on children and young people (CYP) health, growth and development. There is a knowledge gap about psychotropic prescribing in CYP mental health inpatient units. AIMS:To understand and compare psychotropic prescribing patterns in England mental health inpatient units for CYPs and to solicit CYP and their parents' and carers' views of it. METHOD:A national Quality Improvement programme authorised by National Health Service (NHS) England invited all English CYP mental health inpatient units to participate. The programme included an anonymous medication census to capture psychotropic prescribing practices of participating units. A further two questionnaires sought views of inpatient CYP and their parent carers on the prescribing. All material was co-produced with patient and clinical stakeholders. Quantitative data were presented descriptively and free text responses thematically analysed. RESULTS:Forty-eight providers overseeing 73 units, that is, 79% of all England NHS commissioned units, with 625 CYP inpatients responded. Of these, 545 (87%) were receiving psychotropics, with 354 (57%) prescribed two or more. Pro re nata (PRN) prescribing practice was variable. Questionnaires were completed by 142 CYP and 75 parent carers. Free text response analysis showed seven themes emerge from the CYP questionnaire and 11 from the parent-carer one. CONCLUSIONS:This is the first English study to systematically explore psychotropic prescribing patterns in CYP mental health inpatient units. The study showed psychotropics are widely prescribed, on a regular and PRN basis.
BACKGROUND:Voltage-gated Kv3.1 and KV3.2 potassium channels are mainly located on parvalbumin (PV) containing interneurons, where they play a key role in synchronising the coordinated firing of pyramidal neurons and regulating cognitive function. AIMS:We aim to explore the efficacy of acute treatment with AUT00206 (5,5-dimethyl-3-[2-(7-methylspiro[2H-benzofuran-3,1'-me]-4-yl)oxypyrimidin-5-yl]imidazolidine-2,4-dione), a novel and selective positive modulator of Kv3.1/3.2 channels, to improve cognitive and social behaviour deficits in our validated animal model relevant to schizophrenia. METHODS:Female Lister Hooded rats were treated with phencyclidine for 7 days, followed by a 7-day washout (scPCP). The efficacy of AUT00206 was tested in the novel object recognition (NOR), reversal learning (RL) and social interaction (SI) paradigms. RESULTS:The cognitive and social behaviour deficits induced by scPCP were significantly attenuated by AUT00206 (10 and 30 mg/kg) in the three behavioural tasks. These data demonstrate, for the first time, the efficacy of a novel Kv3.1/3.2 channel modulator, AUT00206, in two cognitive domains (short-term recognition memory and an aspect of cognitive flexibility) and an aspect of negative symptoms in a validated animal model of schizophrenia symptomatology. CONCLUSIONS:Modulation of Kv3.1/3.2 channels on PV interneurons could be an important novel approach for the treatment of schizophrenia.
BACKGROUND:Mixed manic/hypomanic symptoms commonly occur in major depressive disorder (MDD), yet their prognostic and therapeutic significance following inadequate response to monoaminergic treatment remains uncertain. This secondary analysis of the Veterans Affairs Augmentation and Switching Treatments for Improving Depression Outcomes (VAST-D) trial examined the prevalence, clinical correlates, and treatment implications of mixed features in 1522 nonbipolar outpatients with insufficient benefit from at least one prior monoaminergic agent. AIMS:To explore the prevalence, clinical correlates, and potential treatment implications of mixed features among patients with antidepressant-nonresponsive MDD. METHODS:Participants were randomized to switching to bupropion sustained release (S-BUP), combining their current monoaminergic agent with bupropion sustained release (C-BUP), or augmenting treatment with aripiprazole (A-ARI). Mixed features were categorized into five exploratory, non-Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) levels based on the number and intensity of manic/hypomanic symptoms. RESULTS:Overall, 76.5% of participants endorsed at least one manic/hypomanic symptom occurring "a little" or "a lot," and 10.2% endorsed more than two symptoms occurring "a lot." Higher mixed-feature levels were associated with greater depressive severity, functional impairment, and recurrent depressive episodes. Mixed features were not associated with treatment retention, response, or suicidal ideation. However, remission rates declined progressively across mixed-feature levels in the S-BUP group, a pattern not observed in the C-BUP or A-ARI groups. CONCLUSIONS:Mixed features were highly prevalent and associated with greater clinical burden. Assessment of mixed features may provide clinically relevant information when selecting next-step pharmacologic strategies, particularly when considering a switch to bupropion sustained release.
BACKGROUND:The potential safety and efficacy of the psychedelic 3,4-methylenedioxymethamphetamine-assisted therapy (MDMA-AT) for post-traumatic stress disorder (PTSD) has been researched in phase 2 and phase 3 clinical trials. We examined the occurrence and role of mystical experiences in MDMA-AT. METHODS:Data were sourced from two phase 2 randomized trials of MDMA-AT for chronic PTSD, in which participants received two sessions with either MDMA or active placebo, in conjunction with psychotherapy. The Mystical Experience Questionnaire 30-item version (MEQ30) was administered after each MDMA session. The association of mystical experiences and PTSD symptom severity (Clinician Administered PTSD Scale for DSM-IV (CAPS-IV)) was analyzed using multilevel regression and mediation analyses. RESULTS:Fifty-three participants with chronic PTSD were included. Standard doses of MDMA (n = 39) were associated with significantly higher mean MEQ30 scores (M = 63.1, SE = 4.9; 42.1% of maximum) compared to active placebo (M = 24.7, SE = 5.5; 16.4%), t-test p < 0.001. Mediation analysis revealed a significant indirect effect of the MEQ30 Positive Mood subscale on symptom reduction (b = -0.170, 95% CI (-0.353, -0.007)), while the MEQ total score and other subscales showed smaller, non-significant indirect effects on CAPS-IV scores. CONCLUSIONS:MEQ30 scores were significantly higher for MDMA sessions than for active placebo sessions in patients undergoing MDMA-assisted therapy for chronic PTSD. Among mystical-type experiences, the positive mood subscale, rather than full mystical-type states, appeared to contribute most to the mitigation of PTSD symptoms. These findings should be interpreted with caution due to the limited sample size and secondary nature of the analysis.
RATIONALE:Initiating an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin II receptor blocker (ARB) in patients taking lithium may increase the concentration of serum lithium and the risk of lithium toxicity. OBJECTIVE:In patients taking lithium, to compare the 90-day risk of lithium toxicity following a new co-prescription of an ACEi or ARB versus a new co-prescription of a beta-blocker. METHODS:Population-based cohort study in Ontario, Canada, from 2002 to 2024. Patients 50 years of age and older taking lithium who were co-prescribed an oral ACEi or ARB (n = 2267) or a beta-blocker (n = 2110). Outcomes were assessed within 90 days of initiating the drug co-prescription. The primary outcome was a hospital admission with lithium toxicity. Secondary outcomes were all-cause mortality and all-cause hospitalization. Overlap weighting using propensity scores was used to balance groups on indicators of baseline health. Risk ratios (RR) were obtained using weighted log-binomial regression, and risk differences (RD) were obtained using weighted binomial regression. RESULTS:In lithium users, co-prescription of an ACEi or ARB versus a beta-blocker was not associated with a higher risk of hospital admission with lithium toxicity (47/2267 patients co-prescribed an ACEi or ARB (2.1%) versus 54/2110 patients co-prescribed a beta-blocker (2.6%); weighted RR 0.72 (95% CI, 0.47 to 1.11); weighted RD -0.75% (95% CI, -1.74% to 0.25%). In lithium users, co-prescription of an ACEi or ARB versus a beta-blocker was not associated with a higher risk of all-cause mortality or all-cause hospitalization. CONCLUSION:The findings of this study suggest that the higher risk of lithium toxicity in patients co-prescribed an ACEi or ARB observed in some prior studies may be overstated.
BACKGROUND:Cannabidiol (CBD) has emerged as a potential antipsychotic treatment, acting as a negative allosteric modulator of cannabinoid type-1 (CB1) receptors within the endocannabinoid system. Although previous neuroimaging studies have shown that CBD induces changes in aberrant brain activity and functional connectivity (FC) in psychosis, they have not directly integrated information about the spatial distribution of the molecular targets through which CBD may act. AIM:In this study, we aimed to investigate whether a single dose of CBD may acutely modulate CB1 receptor-enriched FC in patients with early psychosis and to compare these effects with healthy controls (HC). METHODS:Thirteen patients with early psychosis (PSY) and 14 age- and sex-matched HC underwent resting-state functional magnetic resonance imaging (fMRI). Patients participated in a randomised, double-blind, placebo-controlled crossover study receiving 600 mg CBD (PSY-CBD) or matched placebo (PSY-PLB). CB1 receptor-enriched FC was computed using Receptor-Enriched Analysis of functional Connectivity by Targets (REACT), integrating Positron Emission Tomography (PET)-derived CB1 receptor maps with fMRI data. RESULTS:Three main findings emerged: (i) PSY-PLB showed increased CB1 receptor-enriched FC across multiple regions compared to HC; (ii) a single dose of CBD significantly reduced CB1 receptor-enriched FC of the right insular cortex relative to PLB; (iii) no differences were observed when CB1 receptor-enriched FC maps of PSY-CBD were compared with those of HC. CONCLUSION:Our findings support the potential of CBD to regulate CB1 receptor-enriched FC in early psychosis, providing mechanistic insight into its antipsychotic effects and highlighting REACT as a valuable tool for integrating molecular and functional imaging in psychiatric research.
BACKGROUND:Norepinephrine transporter (NET) inhibition is a relevant mechanism across psychotropic medications, although prescribing classifications are largely based on drug class rather than quantitative target engagement. AIMS:To facilitate cross-drug comparisons of noradrenergic activity, we developed a pharmacometric model to estimate NET occupancy for 26 psychotropic agents and their active metabolites. METHODS:NET occupancy was estimated using National Institute of Mental Health Psychoactive Drug Screening Program Ki data, protein-binding-corrected plasma concentrations, a standard receptor occupancy model, and logit-derived ED50 values, and was compared with published positron emission tomography (PET) estimates. RESULTS:After protein-binding correction, desipramine, milnacipran, and maprotiline showed very high NET occupancy (⩾90%), nortriptyline, doxepin, and norquetiapine showed high occupancy (70%-90%), and hydroxybupropion and duloxetine showed moderate occupancy (50%-70%). Clomipramine, atomoxetine, and reboxetine demonstrated moderate-low occupancy (30%-50%), whereas venlafaxine showed low occupancy (~28%). Hydroxybupropion exhibited substantially greater NET engagement (~68%) than bupropion (~2%), and most Selective serotonin reuptake inhibitors showed minimal occupancy (<10%). Estimated ED50 values ranged from 6.6 mg (desipramine) to ⩾63 mg (duloxetine), and predicted occupancies correlated moderately with PET data (r = 0.76, p = 0.028, R² = 0.58). CONCLUSIONS:These findings suggest that variability in NET engagement across psychotropic medications may not be fully captured by conventional class-based classifications. The proposed framework offers a mechanism-informed approach to comparative pharmacological analysis and introduces a conceptual noradrenergic activity index. This approach may be useful for hypothesis generation in future studies integrating pharmacokinetic-pharmacodynamic modeling with in vivo imaging and clinical outcomes.
BACKGROUND:Individuals with anxiety and stress-related disorders frequently demonstrate impaired threat extinction. Although psilocybin, lysergic acid diethylamide (LSD), N,N-dimethyltryptamine (DMT), 3,4-methylenedioxymethamphetamine (MDMA), and ketamine can facilitate fear extinction in rodent models, comprehensive integrative analyses remain limited. METHODS:Regression-based approaches were employed to estimate cross-study trends to assess whether the dose-effect relationships of these compounds are linear, bell-shaped, or follow alternative patterns. The potential moderating effects of specific biological or procedural factors on extinction learning and recall were also assessed. Effect sizes from 177 experiments in mice and rats were analyzed by compound and pooled across classical psychedelics, with doses normalized using allometric scaling and serotonin 5-HT2A or 5-HT1A receptor-adjusted relative potency. RESULTS:The available data for LSD were insufficient for evaluating the hypothesized relationships. For the other psychedelics, linear models provided the best relative fit for extinction learning and recall. Within the tested ranges, lower doses, except for MDMA, were frequently associated with larger positive effect sizes. Pooled analyses indicated that the interval between treatment administration and extinction recall testing may influence the effects of classical psychedelics on fear extinction. In contrast, sex, age, preconditioning stress/high-intensity conditioning, and the treatment-extinction learning interval did not affect the observed dose-effect relationships. These pooled associations were sensitive to high-leverage observations. CONCLUSION:Psychedelics appear to enhance fear extinction across a broad range of doses. The timing of administration relative to memory extinction retrieval may contribute to variability in these effects. Evidence supporting nonlinear dose-effect relationships remains limited.
