Neuropsychopharmacology [JOURNAL]
Sun
200 papers
Cue labeling reduces cigarette craving and associated neural activity.
Tabibnia G, Ghahremani DG, Tindle HA … +5 more , Creswell JD, Westbrook C, Kraynak TE, Julson E, London ED
Neuropsychopharmacology · 2026 Apr · PMID 41407867 · Full text
Cigarette craving, triggered by smoking-related cues, significantly contributes to resumption of smoking after cessation. This study investigated whether affect labeling, the cognitive technique of using words to regulat...
Cigarette craving, triggered by smoking-related cues, significantly contributes to resumption of smoking after cessation. This study investigated whether affect labeling, the cognitive technique of using words to regulate emotions, could be adapted to regulate cue-induced craving. Fifty adults who smoked cigarettes daily (24 women, ages 20-65) completed a novel Cue Labeling Task during fMRI. In this task, participants viewed cigarette-cue images under three conditions: cue matching (craving elicitation), cue labeling (experimental condition), and gender labeling (control). In a fourth condition, neutral matching (baseline), they matched neutral images with one another. Participants rated their cigarette craving in each condition. Relative to cue matching, cue labeling elicited lower craving (p < 0.05, Hedges' g = -0.11) and lower activation in the precuneus (Z = -4.5, p < 0.001), a region associated with craving in prior research and in the present study (β = 0.43, p < 0.05). Age moderated these effects. In the older (but not younger) subsample (Johnson-Neyman age cutoff of 46.7 years), craving during cue labeling was lower than cue matching (p < 0.05, g = -0.29) and similar to neutral matching (p > 0.5). Greater age was also associated with lower precuneus activity during cue labeling versus cue matching (Z = -3.8, p < 0.001). Gender labeling did not significantly alter craving compared to cue matching (p > 0.05, g = -0.13); and, although it led to lower precuneus activity (Z = -5.5, p < 0.001), activity in this region was lower during cue labeling than cue matching (Z = -3.9, p < 0.01). These findings suggest that cue labeling, a simple and scalable self-regulation strategy, may reduce cigarette craving and related neural activity, particularly among older midlife adults with nicotine addiction.
Re-engineering the disordered mind: clinical experimentation, dynamical systems, and AI for personalized psychiatry.
Kheirkhah M, Shariatpanahi B, Hahn T … +5 more , Tiruvadi V, Koppe G, Nozari E, Hofmann SG, Jamalabadi H
Neuropsychopharmacology · 2026 Mar · PMID 41407866 · Full text
This perspective proposes a neuropsychiatric model of psychological and psychiatric interventions by reframing treatment as a control engineering problem grounded in dynamical systems theory and artificial intelligence (...
This perspective proposes a neuropsychiatric model of psychological and psychiatric interventions by reframing treatment as a control engineering problem grounded in dynamical systems theory and artificial intelligence (AI). We argue that psychopathology arises from distortions in the geometry of underlying neurobehavioral low-dimensional cognitive-affective manifolds rather than from isolated biological dysfunctions, and we use a formal dynamical framework to show how clinical interventions can be modeled as control inputs that reshape the manifold itself to restore healthy dynamics. To operationalize this approach clinically, we propose a closed-loop, N-of-1 experimental paradigm in which dense longitudinal measurements and strategically designed perturbations are used to train individualized AI surrogate models of a person's manifold. This model supports the simulation of counterfactual interventions and guide the design of optimized, personalized treatments. Active perturbation reduces required sample size dramatically, enabling precise modeling from limited but richly sampled individual data. This engineering-inspired framework reconceptualizes clinical improvement as the restoration of regulatory capacity and resilient trajectories rather than the mere reduction of symptom counts. By integrating dynamical systems theory, AI-based surrogate modeling, and adaptive clinical experimentation, we outline a principled pathway toward personalized neuropsychiatry based on dynamical systems theory and AI.
When the science alone is not enough: embracing our responsibility as science communicators.
Aggarwal N, France L, Puralewski R … +2 more , Parker KJ, Kalin N
Neuropsychopharmacology · 2026 Feb · PMID 41402533 · Full text
The US biomedical research enterprise has led the world in driving medicine forward but now faces unprecedented threats. Systematic efforts to defund and dismantle the academic research infrastructure, compounded by misi...
The US biomedical research enterprise has led the world in driving medicine forward but now faces unprecedented threats. Systematic efforts to defund and dismantle the academic research infrastructure, compounded by misinformation and questionable public support for science, have already impeded innovation and discouraged students from pursuing careers in research and healthcare, which ultimately will harm patients. This moment calls on us, as scientists and physicians, to effectively communicate the relevance of our research to the public and elected officials and ensure that the value of basic, translational, and clinical scientific inquiry in developing novel treatments for debilitating medical and psychiatric conditions is fully appreciated. In this Perspective, we highlight concrete, actionable steps to robustly engage in science communication, grassroots advocacy, and early education efforts to rejuvenate the vigorous research environment that is essential to the health and well-being of the public.
Females have shorter scalp-to-cortex distances and receive stronger TMS electrical fields: Implications for clinical treatment.
McCalley DM, Cadicamo NJ, Weijerman F … +4 more , Tenekedjieva LT, Alzheimer’s Disease Neuroimaging Initiative, Knutson B, Padula CB
Neuropsychopharmacology · 2026 Mar · PMID 41398077 · Full text
The strength of a given transcranial magnetic stimulation (TMS) pulse decays rapidly with distance. Male and female bone structure reliably differs by the shape of the frontal bone, mandible, and inion. Given the morphol...
The strength of a given transcranial magnetic stimulation (TMS) pulse decays rapidly with distance. Male and female bone structure reliably differs by the shape of the frontal bone, mandible, and inion. Given the morphology of these structures constitutes much of the scalp-to-cortex distance (STCD), we hypothesized that females have shorter STCDs and thereby receive stronger TMS electrical field strengths, relative to males. Head models (n = 411; 197 female, 214 male) were constructed from MRIs of healthy participants (ages 18-90). STCD and peak electrical field strength were measured at 50 EEG 10-20 sites (SimNIBSv3.2). Linear models (bootstrapped and Benajamini-Hochberg multiple comparison-corrected) evaluated the influence of sex on STCD and electrical field strength. Females had significantly shorter STCDs at 27/50 sites and stronger TMS electrical fields at 18/50. When normalized by data collected at the motor cortex, females had significantly shorter STCD at 40/49 sites and stronger TMS electrical fields at 29/49 sites. The largest effect size differences were detected at the frontal, temporal, and occipital poles, and the cerebellum. Interestingly, STCD at the motor cortex was not different between sexes, suggesting the motor cortex-based dosing strategies produce unequal electrical fields between sexes. These data provide a mathematically grounded explanation for sex-differences in clinical outcome and may be relevant to other modalities that depend on electromagnetic signals (e.g., EEG, MEG).
Amygdala reactivity to threat, negative facial perception, and risk of future psychiatric hospitalizations: a longitudinal study in major depressive and bipolar disorders.
Miskowiak KW, Ozenne B, Kjærstad HL … +9 more , Fisher PM, Beaman EE, Dam VH, Ysbæk-Nielsen AT, Knudsen GM, Kessing LV, Macoveanu J, Frøkjær VG, Sankar A
Neuropsychopharmacology · 2026 Feb · PMID 41398076 · Full text
Biased neural and behavioral responses to emotional information, specifically threat-related amygdala and fusiform hyperactivity and negative bias in the recognition of facial expressions, have emerged as potential bioma...
Biased neural and behavioral responses to emotional information, specifically threat-related amygdala and fusiform hyperactivity and negative bias in the recognition of facial expressions, have emerged as potential biomarkers of responses to short-term intervention outcomes in major depressive disorder (MDD) and bipolar disorder (BD). However, investigating the influence of these biomarkers on the risk of longer-term adverse outcomes, over at least a year, may provide valuable insights for developing tailored interventions to improve outcomes in these often recurrent and persistent disorders. Thus, we examined whether threat-related amygdala and fusiform responses, and negative biases in facial expression recognition were associated with a one-year risk of psychiatric hospitalizations. The study participants were 112 individuals diagnosed with either BD (n = 62) or MDD (n = 50), who underwent functional magnetic resonance imaging during an emotion face processing task and behavioral assessments of negative emotional biases. Longitudinal data on psychiatric hospitalizations for up to one-year after the participants' study inclusion were obtained using the Danish registers. The analyses were conducted using a Cox regression model, adjusting for demographics, and clinical variables such as prior hospitalizations, diagnoses, illness chronicity, baseline symptoms, and medication. The results showed that left amygdala hyperactivity to fearful vs. happy faces (HR = 14.05, 95% CI: 1.17-168.26, p = 0.037), and increased speed in recognizing negative vs. positive facial expressions (HR = 20.75, 95% CI: 4.13-104.11, p = 0.0002), were significantly associated with subsequent psychiatric hospitalizations. Future studies are needed to explore whether targeting negative threat biases, such as through psychotherapeutic interventions, might help reduce overall disease burden, and potentially decrease societal costs associated with hospitalizations in these conditions.
An adolescent hangover: astrocyte dysfunction in paraventricular thalamus promotes adult anxiety after alcohol exposure in adolescent mice.
Sonsini G, Marchant NJ
Neuropsychopharmacology · 2026 Mar · PMID 41387571 · Full text
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Acute stress induces changes in epigenome-wide DNA methylation.
Zillich L, Czernin NS, Salvador OC … +6 more , Hummel EM, Pauli P, Reif A, Deckert J, Domschke K, Schiele MA
Neuropsychopharmacology · 2026 Mar · PMID 41387570 · Full text
Stress plays a significant role in the development of mental and somatic disorders by dysregulating the hypothalamic-pituitary-adrenal (HPA) axis. Epigenetic mechanisms, particularly DNA methylation (DNAm), are assumed t...
Stress plays a significant role in the development of mental and somatic disorders by dysregulating the hypothalamic-pituitary-adrenal (HPA) axis. Epigenetic mechanisms, particularly DNA methylation (DNAm), are assumed to mediate this relationship, with increasing evidence linking stress experience to DNAm changes, though the longitudinal effects of acute stress remain unclear. Here, 122 healthy individuals underwent the Maastricht Acute Stress Test (MAST). Salivary samples for cortisol measurements were taken at seven time points from before to 45 min after stress induction, and blood was drawn for DNAm analyses before and 45 min after. Cortisol reactivity was predicted by baseline DNAm using robust linear models, and a mixed linear model was performed to investigate DNAm changes over time. Downstream analyses included identifying differentially methylated regions (DMRs) and overrepresented Gene Ontology (GO) Terms. A total of 120 CpG sites and four DMRs were associated with cortisol reactivity, with chromatin modifiers among the top findings. Longitudinal epigenome-wide changes were observed at 32 CpG sites and four DMRs. Overrepresented GO terms were related to learning, cognition, and synaptic processes. Two thyroid-related genes, TTR and TSHR, were observed among the top hits. These findings highlight the association between acute stress and DNAm, suggesting DNAm levels to be related to cortisol reactivity and acute stress to influence DNA methylation patterns dynamically. Key genes involved in thyroid function and transcriptional regulation were implicated in the stress response. Further research with larger samples and multi-omics approaches is needed to confirm these findings, assess their long-term stability, and explore their functional relevance.
Aberrant effective connectivity during working memory performance in schizotypal personality disorder and schizophrenia: A spectrum approach.
Hazlett EA, Fiore VG, Shafritz KM … +12 more , Ng S, Aladin S, Kowalchyk ML, Dolgopolskaia ES, Russo DL, Chan CC, Perez-Rodriguez MM, Haznedar MM, Kahn RS, McClure MM, Goldstein KE, Szeszko PR
Neuropsychopharmacology · 2026 Mar · PMID 41381851 · Full text
Working memory (WM) deficits play a prominent role in schizophrenia and have been linked to aberrant frontal-parietal functional connectivity. Schizotypal personality disorder (SPD) is a schizophrenia-spectrum disorder t...
Working memory (WM) deficits play a prominent role in schizophrenia and have been linked to aberrant frontal-parietal functional connectivity. Schizotypal personality disorder (SPD) is a schizophrenia-spectrum disorder that is biologically related to schizophrenia, but with less marked WM impairment. Comparing network dynamics during WM performance among individuals with schizophrenia-spectrum disorders could enhance our understanding of risk and resilience factors on a spectrum of illness severity. We used dynamic causal modeling (DCM) to identify changes in effective connectivity among the lateral-prefrontal cortex (lPFC), anterior-cingulate cortex (ACC) and parietal cortex (PC) associated with WM load during an N-back task in healthy controls (HC; N = 42), individuals with SPD (N = 28), and schizophrenia patients (N = 35). The main findings indicate that N-Back task difficulty (i.e. increasing WM load) significantly modulated connectivity between the ACC and PC, but in different directions depending on diagnostic group. In HC, WM load modulated PC-to-ACC effective connectivity, whereas in schizophrenia, WM load modulated effective connectivity in the opposite direction (i.e. ACC-to-PC). In SPD, no clear directionality emerged between ACC and PC, suggesting an intermediate or mixed pattern of connectivity. In schizophrenia, greater ACC-to-PC connectivity was associated with greater negative and positive symptom severity; a pattern that was also evident in the combined cohort of individuals with SPD and schizophrenia. These findings indicate that the normal pattern of PC-to-ACC effective connectivity modulated by WM load is abnormal in the schizophrenia spectrum which is consistent with abnormalities in processing that instigate early involvement of the ACC for conflict monitoring.
Corticosterone accelerates behavioral inflexibility via plasticity-related gene expression in the dorsal striatum.
Murphy MD, Krick KS, Zhang S … +1 more , Heller EA
Neuropsychopharmacology · 2026 Feb · PMID 41366066 · Full text
Behavioral flexibility allows organisms to modify actions based on new information, such as shifts in reward value or availability, and is promoted by the dorsomedial striatum (DMS). In contrast, behavioral inflexibility...
Behavioral flexibility allows organisms to modify actions based on new information, such as shifts in reward value or availability, and is promoted by the dorsomedial striatum (DMS). In contrast, behavioral inflexibility provides efficiency and automaticity in familiar contexts, and is promoted by the dorsolateral striatum (DLS). Importantly, chronic elevation of the primary stress hormone, corticosterone (CORT) in rodents or cortisol in humans, impairs behavioral flexibility through dendritic atrophy in the DMS, and promotes inflexible behavioral response strategies through dendritic outgrowth in the DLS. However, understanding of changes in gene expression underlying behavioral inflexibility is lacking. We used a food-motivated operant task in male and female mice to define gene changes that accompany the shift to inflexible behavior with CORT. We discovered that CORT-accelerated loss of behavioral flexibility is accompanied by decreased DMS- and increased DLS-specific synaptic plasticity gene expression, and that distinct genes are either differentially expressed or spliced in the transition to inflexible behavior. Splicing analysis suggests that repressed activity in the DMS during the transition to inflexible behavior may reflect both reduced expression and increased degradation of plasticity-related mRNA transcripts. Finally, given the ability of CORT to influence histone acetylation, we defined CORT-mediated H3K9ac enrichment profiles associated with synaptic plasticity gene regulation stratified by sex and striatal subregion. This study is the first to define CORT-driven epigenetic regulation in the DMS and DLS during the CORT-accelerated transition from flexible to inflexible behavior in male and female mice.
ENX-104: a selective and potent DD receptor antagonist enhances dopamine neurotransmission and reward responsiveness in translational rodent models.
Vadodaria KC, Serrats J, Brubaker W … +5 more , Kangas BD, Pizzagalli DA, Garvey DS, Sudarsan V, Vanover KE
Neuropsychopharmacology · 2026 May · PMID 41354763 · Full text
Anhedonia, characterized by a diminished reactivity to pleasurable stimuli, is a core symptom across multiple neuropsychiatric disorders, including major depressive disorder. Disruptions in dopaminergic neurotransmission...
Anhedonia, characterized by a diminished reactivity to pleasurable stimuli, is a core symptom across multiple neuropsychiatric disorders, including major depressive disorder. Disruptions in dopaminergic neurotransmission and dysfunction within the mesolimbic dopaminergic circuitry are key contributors to reward processing deficits. We hypothesized that low receptor occupancy-mediated antagonism of presynaptic inhibitory D/D receptors could enhance dopaminergic neurotransmission and, in turn, improve reward responsiveness, a behavioral phenotype implicated in anhedonia. For this purpose, we developed ENX-104, a highly selective and potent D/D receptor antagonist with favorable CNS pharmacokinetics, characterized by high brain penetrance and rapid plasma clearance. In preclinical studies, ENX-104 produced sustained increases in dopamine levels in the nucleus accumbens in rats. In the Probabilistic Reward Task (PRT), a preclinical model of reward responsiveness reverse-translated for rats from human studies designed to objectively quantify subdomains of anhedonia, ENX-104 enhanced reward responsiveness at low doses corresponding to approximately 10-50% D/D receptor occupancy. Predictably, higher doses (65-80% receptor occupancy) were associated with antipsychotic-like effects in the rat conditioned avoidance response assay, while extrapyramidal side effects, such as catalepsy, emerged only at much higher occupancies ( > 80% receptor occupancy). Our integrated pharmacokinetic-pharmacodynamic modeling suggests that a once-daily oral dosing regimen of ENX-104 could enable low D/D receptor occupancies, potentially offering a novel therapeutic approach for the treatment of psychiatric conditions characterized by deficits in reward responsiveness.
Getting into the weed-the genetics of cannabis use in modern America.
Agrawal A
Neuropsychopharmacology · 2026 Feb · PMID 41331104 · Full text
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The hippocampus as a central hub in ketamine's antidepressant action: from molecules to circuit rewiring.
Park D, Lee G, Kim B … +2 more , Seong M, Kim JW
Neuropsychopharmacology · 2026 Feb · PMID 41299093 · Full text
Ketamine has emerged as a rapid-acting antidepressant that challenges classical monoaminergic frameworks and highlights the importance of synaptic and circuit-level plasticity in mood regulation. This review examines the...
Ketamine has emerged as a rapid-acting antidepressant that challenges classical monoaminergic frameworks and highlights the importance of synaptic and circuit-level plasticity in mood regulation. This review examines the hippocampus as a key site through which ketamine exerts both rapid and sustained antidepressant effects. We synthesize evidence showing that ketamine enhances hippocampal synaptic plasticity via mechanisms including NMDAR blockade of spontaneous neurotransmission, BDNF-TrkB signaling, MeCP2-dependent transcriptional priming, and adult neurogenesis. Molecular modulators such as Reelin, which influence NMDAR signaling and synaptic function, may also shape the efficacy of ketamine in a subset of individuals. Importantly, these hippocampal effects occur in coordination with broader network interactions, particularly with the medial prefrontal cortex and lateral habenula, allowing for circuit-level integration of antidepressant responses. Notably, ketamine's therapeutic actions are dissociable from normalization of hypothalamic-pituitary-adrenal (HPA) axis function, underscoring a shift away from neuroendocrine-based models. By integrating molecular, synaptic, and systems-level findings, this review provides a hippocampus-centered framework for understanding ketamine's antidepressant mechanisms and outlines novel strategies for circuit-informed, fast-acting antidepressant development.
Orbitofrontal BDNF puts the brakes on alcohol intake and relapse.
McGinty JF
Neuropsychopharmacology · 2026 Feb · PMID 41291004 · Full text
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The impact of collider bias on genetic prediction in psychotic disorders.
Asim A, Yang Y, PsyCourse Study … +7 more , Heilbronner U, Schulze T, Lencz T, Vassos E, Clouston SAP, Kotov R, Jonas K
Neuropsychopharmacology · 2026 Jan · PMID 41266786 · Full text
Polygenic risk scores (PRS) have potential utility as biomarkers of psychiatric disorders. However, the potential utility of some PRS has been much clearer than others. The schizophrenia PRS has been consistently associa...
Polygenic risk scores (PRS) have potential utility as biomarkers of psychiatric disorders. However, the potential utility of some PRS has been much clearer than others. The schizophrenia PRS has been consistently associated with diagnosis, symptom severity, and other correlates of schizophrenia. Yet despite the close genetic correlation (r = 0.69) between bipolar disorder and schizophrenia, the bipolar (BP) PRS has been inconstantly associated with clinical course and outcomes. We hypothesize that common sample selection strategies induce collider bias between the SZ and BP PRS, in turn moderating the association between the BP PRS and clinical outcomes. Collider bias is illustrated in three effects. First, it is shown that clinical characteristics used in sample ascertainment (i.e. case status, treatment history) are a function of the SZ and BP PRSs. Second, selecting on these clinical characteristics biases the correlation between the BP and SZ PRSs. Third, selection on these clinical characteristics in turn moderates the association between the BP PRS and clinical outcomes. Effects were tested in three samples: UK Biobank (N = 337,420), a population-based sample; PsyCourse (N = 1,594), a case-control cohort of individuals with mood and psychotic disorders; and the Suffolk County Mental Health Cohort (N = 378), a first-admission psychosis cohort. In all three samples, SZ and BP PRSs were significantly correlated with case status or treatment history. In addition, correlations between SZ and BP PRS were biased in samples selected by case status or treatment history. Finally, conditioning analyses on case status moderated, and in some cases reversed, associations between the BP PRS and clinical outcomes. It is important to understand the impact of this and other forms of selection bias in evaluating PRS as biomarkers of psychiatric disorders, particularly when the intended application is populations enriched for high genetic risk.
Reliable variability in subjective responses to parenteral hydromorphone administration: empirical confirmation of an opioid non-responder phenotype.
Ellis JD, Towers EB, Dunn KE … +8 more , Tsang S, Speed T, Lerman SF, Mei M, Lynch W, Strain EC, Smith MT, Finan PH
Neuropsychopharmacology · 2026 Jan · PMID 41254414 · Full text
A subset of individuals without a history of prolonged or problematic opioid use demonstrate attenuated subjective responses to orally administered opioids despite physiological and analgesic responses. This phenotype ma...
A subset of individuals without a history of prolonged or problematic opioid use demonstrate attenuated subjective responses to orally administered opioids despite physiological and analgesic responses. This phenotype may confer elevated risk for greater analgesic requests and physiologic dependence, but it is unclear if this is driven by differences in route of administration. This study evaluated responses to cumulative dosing of parenteral hydromorphone, versus placebo, in persons without a history of significant opioid use to further identify and characterize this subgroup. Individuals without opioid use disorder (N = 82) were exposed to a cumulative hydromorphone dosing procedure, during which they completed measures of subjective effects and were assessed for physiological opioid responses. Linear mixed effects regressions were used to examine changes in subjective and physiological measures as a function of responder phenotype, drug condition, and time. Approximately 31.7% of the sample were classified as Opioid Non-Responders. These individuals had attenuated changes in subjective responses to hydromorphone relative to other participants, despite equivalent physiological responses. Race and sex did not predict Opioid Responder status. These findings confirm the presence of a "Opioid Non-Responder" phenotype for the first time in the context of a cumulative, parenteral dosing paradigm. Further research is warranted to elucidate the clinical implications and potential risk or protective factors underlying this phenotype.
Altered amygdala and striatal responsivity and prediction error encoding of temporal reward dynamics in post-trauma psychopathology.
Enten LK, DeMarco A, Kline R … +5 more , Globisch FM, Dunsmoor JE, Cisler JM, Nemeroff CB, Fonzo GA
Neuropsychopharmacology · 2026 Apr · PMID 41249466 · Full text
Diminished positive affect is a hallmark of post-trauma psychopathology (PTP), e.g. posttraumatic stress disorder and major depressive disorder, yet the circuit dysfunction underlying these PTP symptoms is poorly underst...
Diminished positive affect is a hallmark of post-trauma psychopathology (PTP), e.g. posttraumatic stress disorder and major depressive disorder, yet the circuit dysfunction underlying these PTP symptoms is poorly understood. Computational models offer a powerful framework to probe learning processes by linking such processes to brain activity in regions involved in updating reward predictions. Here, we examined fMRI neural responsivity to temporal prediction errors-deviations in timing of expected reward delivery-and applied a temporal difference (TD) learning model to characterize model-based prediction error neural encoding in individuals with PTP (N = 45; 32 females) and trauma-exposed healthy controls (N = 45; 25 females). Participants learned that a visual cue reliably predicted timing of a primary reward (oral juice bolus). To induce temporal prediction errors, we introduced occasional "catch" trials, which unexpectedly extended the cue-outcome interval. Compared to controls, the PTP group showed blunted activation in the left amygdala and putamen to reward receipt at unexpected vs. expected times and blunted deactivation to reward absence at unexpected vs. expected times (corrected p's < 0.05). Interestingly, attenuated amygdala deactivation was associated with lower anhedonia (ρ = -0.50, p < 0.001), suggesting a possible mechanism for preserving hedonic capacity. Model-based fMRI revealed diminished amygdala and putamen prediction error encoding at reward delivery in PTP but exaggerated insula and putamen encoding at cue presentation (corrected p's < 0.05). We provide new evidence of disrupted PTP amygdala-striatal reward responsivity and computational learning signals, demonstrating an unrecognized pervasiveness of dysfunction extending to the fundamental learning domain of cue-reward timing.
Identifying behavioral and biological predictors of cannabis vapor self-administration in rats.
Park GI, Malena AN, Glodosky NC … +7 more , Fisher ZDG, Cuttler C, Lightfoot SHM, Baglot SL, Murray C, Hill MN, McLaughlin RJ
Neuropsychopharmacology · 2026 Jun · PMID 41238696 · Full text
The recent wave of recreational cannabis legalization in the US has underscored the importance of identifying predictors of individual variability in cannabis use. While a subset of recreational cannabis users will go on...
The recent wave of recreational cannabis legalization in the US has underscored the importance of identifying predictors of individual variability in cannabis use. While a subset of recreational cannabis users will go on to meet diagnostic criteria for cannabis use disorder, many do not, making it critical to characterize traits that confer both vulnerability and resilience. However, progress in identifying relevant predictors has been hindered by limited mechanistic insight and a lack of translationally relevant animal models of cannabis use. To address this, we employed a rat model of cannabis vapor self-administration that uses whole-plant cannabis extract and mimics the intrapulmonary route of intake typically used in humans. Using this model, we sought to identify behavioral and biological predictors of motivation to self-administer vaporized cannabis. Male and female Long-Evans rats (N = 48) underwent a battery of assays indexing behavioral domains aligned with the NIMH Research Domain Criteria (RDoC) prior to self-administration training. After four weeks of cannabis vapor self-administration (1 h sessions daily), motivation for cannabis vapor was assessed via a 3-h fixed ratio escalation (FRE) procedure. A series of linear regressions revealed that Social Processes, Arousal/Regulatory Systems, Cognition, and Positive Valence domains significantly predicted the number of cannabis vapor deliveries earned during the FRE test. Specifically, higher basal corticosterone (CORT), lower morning anandamide, impaired set-shifting performance, superior visual cue discrimination, and more social grooming during adolescence each predicted responding for cannabis. The Negative Valence domain was not a significant predictor. A multivariate machine learning approach combining principal component analysis and permutation importance further identified basal CORT and set-shifting performance as the strongest predictors of responding for vaporized cannabis. These findings highlight individual differences in stress regulation and cognitive flexibility as possible risk factors for cannabis use propensity and demonstrate the utility of leveraging RDoC framework for identifying relevant phenotypes in rodents that may extend across human psychiatric conditions.
Polydrug overdose mortality caused by synthetic opioids and stimulants: current sex- and age-specific trajectories in United States national data for 2018-2024.
Butelman ER, Huang Y, Shastry S … +3 more , Manini AF, Goldstein RZ, Alia-Klein N
Neuropsychopharmacology · 2026 Apr · PMID 41238695 · Full text
Recent years have shown increases in overdose (OD) mortality caused by polydrug exposure to synthetic opioids such as fentanyl and stimulants such as methamphetamine or cocaine. The goal of this study is to understand th...
Recent years have shown increases in overdose (OD) mortality caused by polydrug exposure to synthetic opioids such as fentanyl and stimulants such as methamphetamine or cocaine. The goal of this study is to understand the recent trajectory in this polydrug OD mortality, especially as associated with decedents' sex and age. We carried out a cross-sectional analysis of national data for persons aged 15-74, from CDC WONDER for 2018-2024 (data for 2024 are considered provisional at the time of analysis). The outcome measure was OD mortality/100,000 population; annual data for 2018-2024 were analyzed with joinpoint regression, and the most recent years (2023-2024) were analyzed with ANOVA and multiple linear regression. Males had greater polydrug OD mortality caused by synthetic opioids and stimulants compared to females, across 2018-2024. Sex-specific joinpoint regressions detected increases in these polydrug OD after 2018, then decreases from 2023 in males, and from 2022 in females. For these polydrug OD, the mean annual percent change (APC) in 2024 versus 2023 was -36% and -31% in males and females, respectively. For synthetic opioids without stimulants, OD trends in 2024 versus 2023 were similar to those for polydrug OD (-42% and -39% APC in males and females, respectively). However, OD for stimulants without synthetic opioids showed relatively smaller changes (-3% and -2% APC in males and females, respectively). Stratification into 10-year age groups for polydrug OD revealed that mortality peaked at age 35-44 and then declined at older ages. Recent decreases in polydrug OD mortality were observed across age groups, with joinpoints detected in 2022 or 2023. These findings indicate that after increases from 2018 onward, polydrug OD mortality caused by synthetic opioids and stimulants exhibited substantial decreases in both males and females in the most recent data for 2024, across a broad age range. Because relatively smaller changes were observed in OD mortality caused by stimulants without synthetic opioids in this time period, the decreases in polydrug OD mortality are more likely to be caused by changes in exposure, prevention or intervention strategies focused on opioids rather than on stimulants. While this polydrug OD mortality has decreased in 2024, it remains at concerning levels.
Independent brain cortical signatures of risk for adolescent cannabis use and consequences of such use are moderated by sex.
Watts JJ, Navarri X, Conrod PJ
Neuropsychopharmacology · 2026 Jan · PMID 41233604 · Full text
There is an accumulation of evidence linking adolescent cannabis use with variations in brain structure and function, however it remains poorly understood whether cannabis-associated variations in brain structure represe...
There is an accumulation of evidence linking adolescent cannabis use with variations in brain structure and function, however it remains poorly understood whether cannabis-associated variations in brain structure represent pre-existing risk factors or consequences of cannabis use. We investigated whether cannabis use propensity and within-person variations of cannabis use were associated with cortical thickness during adolescence. Adolescents (n = 136, 74 female) completed three neuroimaging sessions and annual assessments from 12 until 17 years of age (with 90% follow-up). Cannabis use was disaggregated into between- (vulnerability) and within-person (time-varying) components using longitudinal multi-level modelling, controlling for age, sex and alcohol use. Across the whole sample, cortical thickness was lower in years when participants' cannabis use exceeded their own average level of cannabis use (F = 3.96, p = 0.047; mean: -0.0023 mm/once-per-week increase). This effect was stronger in males (F = 9.83, p = 0.0017), such that each once-per-week increase in cannabis use was associated with a 0.005 mm reduction in cortical thickness, comparable to 17.9% of the annual rate of cortical thinning (-0.028 mm/year). The strongest within-person effects of cannabis were observed in regions with the greatest expression of CNR1, the gene that codes for the CB1 receptor (sample: rho = -0.33, p = .025; males: rho = -0.5, p = .005). At the between-person level, males (but not females) also exhibited a stable cortical thickness signature associated with propensity towards cannabis use and this signature was present before cannabis exposure. These results highlight the importance of longitudinal analyses using multi-level modelling to disaggregate potential risk factors from potential consequences of substance use.
Psychedelics produce enduring behavioral effects and functional plasticity through mechanisms independent of structural plasticity.
Kramer HM, Hibicke M, Middleton J … +3 more , Jaster AM, Kristensen JL, Nichols CD
Neuropsychopharmacology · 2026 Feb · PMID 41224969 · Full text
Activation of serotonin 2A (5-HT) receptors is thought to underly the long-lasting antidepressant effects of psychedelics such as psilocybin, but beyond that, the molecular and cellular mechanisms involved are not well u...
Activation of serotonin 2A (5-HT) receptors is thought to underly the long-lasting antidepressant effects of psychedelics such as psilocybin, but beyond that, the molecular and cellular mechanisms involved are not well understood. Recent preclinical studies using mice have primarily examined relatively short time points after psychedelic administration, which does not address the long-lasting effects of psilocybin in humans (i.e., several months or more). We utilized a rat experimental system to demonstrate that both psilocybin and the selective 5-HT receptor agonist 25CN-NBOH reduce immobility in the forced swim test without a decrease in effect size for at least three months after a single administration of the psychedelic. There were no overt behavioral differences between psilocybin and 25CN-NBOH treated animals, suggesting 5-HT receptor activation is sufficient to produce long-lasting behavioral changes. Functional cellular plasticity in neurons from the medial prefrontal cortex (mPFC) of these animals was assessed using brain slice electrophysiology. Functional plasticity was evident for both psychedelics several months after treatment, and Layer 5 excitatory pyramidal neurons demonstrated significant changes in resting membrane potential, firing rates, and synaptic excitation. Recorded neurons were examined by microscopy for synaptic density and spine classification, which found no differences between control and psychedelic-treated. Gene expression studies for several presynaptic and postsynaptic markers in the mPFC indicated no differences in expression between groups. Together, our results indicate a single treatment with a psychedelic is sufficient to elicit very long-lasting behavioral and cellular changes through enduring function plasticity rather than structural plasticity.
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