The aim of this study was to assess the influence of sex on diagnostic stability in first-episode psychosis during the first year of follow-up. This was a prospective, observational study of 256 patients with FEP, of whom 188 (73.4

BACKGROUND AND HYPOTHESIS:Patients with first-episode psychosis (FEP) frequently experience early metabolic alterations, including antipsychotic-induced weight gain (AIWG) and fasting glucose dysregulation. Birth weight (BW), a marker of the intrauterine environment and development, and its genetic proxy-the polygenic risk score for BW (PRSBW)-may influence these trajectories. This study investigated whether PRSBW and BW are associated with the progression of AIWG and fasting glucose levels over 24 months in individuals with FEP. STUDY DESIGN:A total of 277 FEP patients with genetic, BW and longitudinal metabolic data were included. Linear mixed-effects models assessed associations of BW and the PRSBW with mean AIWG and glucose, as well as interactions with time. BW was analyzed both as a continuous variable and categorically (Lower/Higher vs. Intermediate BW). STUDY RESULTS:BW was significantly associated with mean AIWG across 24 months (p=.009), with higher BW linked to greater AIWG. In contrast, neither BW nor the PRSBW were associated with mean fasting glucose levels. Significant time×BW and time×PRSBW interaction effects emerged for AIWG (p=2.2e-06 and p=4.6e-04, respectively), indicating steeper AIWG trajectories in individuals with higher BW or PRSBW. CONCLUSIONS:Our findings suggest that both BW and PRSBW influence the progression of AIWG in early stages of psychosis, reinforcing the role of early-life, both environmental and genetic, factors in shaping metabolic vulnerability. The consistent association between BW-related markers and AIWG highlights their potential value for early risk stratification and targeted prevention of adverse metabolic outcomes.

The study of brain morphology parameters in patients with first-episode psychosis (FEP) could help detect early brain footprints related to this disease and its predominant symptomatology. We examined gray matter (GM) volume, cortical thickness (CT), gyrification index (GI), and sulcus depth (SD) differences between patients with FEP and healthy control (HC) participants. We also investigated the associations of these brain parameters with symptomatology in FEP. Our sample consisted of 182 participants, 105 patients with FEP and 77 HC. All participants had a brain structural image acquired with a 3T scanner. Symptomatology was assessed with the Positive and Negative Syndrome Scale (PANSS), considering both the original 3-factor structure and an alternative 5-factor structure proposed by Emsley. Patients with FEP showed reduced GM volume than HC in the anterior cingulate gyrus and adjacent regions. We also found that greater SD of the intraparietal sulcus was associated with more severe negative symptomatology in FEP. This association was found with the total score of this subscale and several of its items. Additionally, lower SD and lower CT in the right parietal lobe were associated with a higher Emsley's excited factor score, which includes items related to manic symptoms. Our results suggest that an abnormal depth of the intraparietal sulcus may be an indicator of impaired functioning of this region, which may in turn be associated with social and emotional issues. Overall, SD seems to provide relevant information on the brain morphology of FEP, making it a promising marker for the early stages of psychosis.

Background: Approximately 20-30% of patients with schizophrenia fail to respond to antipsychotic treatment and are considered treatment resistant (TR). Although clozapine is the treatment of choice in these patients, in real-world clinical settings, clinicians often delay clozapine initiation, especially in first-episode psychosis (FEP). Aim: The main aim of this study was to describe prescription patterns for clozapine in a sample of patients diagnosed with FEP and receiving specialized treatment at a university hospital. More specifically, we aimed to determine the following: (1) the proportion of patients who received clozapine within two years of disease onset, (2) baseline predictors of clozapine use, (3) time from starting the first antipsychotic to clozapine initiation, (4) concomitant medications, and (5) clozapine-related adverse effects. Methods: All patients admitted to a specialized FEP treatment unit at our hospital between April 2013 and July 2020 were included and followed for two years. The following variables were assessed: baseline sociodemographic characteristics; medications prescribed during follow-up; clozapine-related adverse effects; and baseline predictors of clozapine use. We classified the sample into three groups: clozapine users, clozapine-eligible, and non-treatment resistant (TR). Results: A total of 255 patients were consecutively included. Of these, 20 (7.8%) received clozapine, 57 (22.4%) were clozapine-eligible, and 178 (69.8%) were non-TR. The only significant variable associated with clozapine use at baseline was the Global Assessment of Functioning (GAF) score (R2 = 0.09, B = -0.07; OR = 0.94; 95% CI: 0.88-0.99; p = 0.019). The median time to clozapine initiation was 55.0 (93.3) days. The most common side effect was sedation. Conclusions: A significant proportion (30.2%) of patients in this cohort were treatment resistant and eligible for clozapine. However, only 7.8% of the sample received clozapine, indicating that this medication was underprescribed. A lower baseline GAF score was associated with clozapine use within two years, suggesting that it could be used to facilitate the early identification of patients who will need treatment with clozapine, which could in turn improve treatment outcomes. Published by Elsevier Espana, S.L.U. on behalf of Sociedad Espanola de Psiquiatr & imath;a y Salud Mental (SEPSM).

Assessing clinical symptoms in First Episode Psychosis (FEP) is essential for guiding treatment decisions and predicting outcomes. The Positive and Negative Syndrome Scale (PANSS-30) is widely used for this purpose; however, its length limits feasibility in routine clinical practice. The PANSS-6, a shorter version, represents a promising alternative, though its performance in FEP populations remains underexplored. This study evaluated the predictive abilities of PANSS-30 and PANSS-6 for clinical remission, functional remission, and relapse over a 2-year follow-up in a Spanish cohort of 193 FEP patients. Data were derived from the PEPs Project, with PANSS-30 assessments conducted at baseline and at 2, 6, 12, and 24 months; PANSS-6 scores were calculated from PANSS-30 at the same visits. Clinical remission, functional remission, and relapse were defined using established criteria. Logistic regression and ROC-AUC analyses assessed predictive and discriminatory performance. Agreement between the Remission in Schizophrenia Working Group (RSWG) for PANSS-30 and PANSS-6 remission criteria was near-perfect at 1 and 2 years (κ ≥ 0.98). PANSS-6 demonstrated stronger predictive associations and similar discriminatory performance to PANSS-30 for clinical and functional remission, while its performance for relapse over two years was similar. In conclusion, the PANSS-6 is a reliable and efficient tool for assessing clinical outcomes in FEP, offering similar predictive accuracy to PANSS-30 while being more practical for routine use due to its shorter administration time.

Inflammatory changes have been widely reported in psychosis. Cannabis use has been consistently related to increased risk of psychosis, earlier onset, higher rates of relapse and poorer treatment response. However, it is unclear how cannabis use interacts with brain inflammatory changes in psychosis. In this cross-sectional study we used diffusion imaging to measure extracellular free water in the brain (FW), a measure that has been associated with inflammation, in 62 individuals with recent onset psychosis (ROP) and 38 controls, with and without cannabis use. Past cannabis use was associated with lower FW in controls, and conversely, to elevated FW in ROP. This group x past cannabis use interaction was found significant in average GM (p = 0.049), and in cortical regions, including the temporal lobe expanding to parietal regions (TFCE p-FWE < 0.05). Within ROP, antipsychotic exposure was related to lower FW in gray matter and white matter only in the non-cannabis users, with no significant association in cannabis users (p interaction in WM = 0.005, in GM = 0.073). Our results demonstrate a differential effect of cannabis use on FW, a surrogate marker of neuroinflammatory processes and suggest that past cannabis use may influence the effects of antipsychotic medication on the brain. However, given the cross-sectional design and moderate sample size, causal interpretations are limited, and further longitudinal studies are warranted.

Growing evidence places the gestational period as a unique moment of heightened neuroplasticity in adult life. In this longitudinal study spanning pre, during, and post pregnancy, we unveil a U-shaped trajectory in gray matter (GM) volume, which dips in late pregnancy and partially recovers during postpartum. These changes are most prominent in brain regions associated with the Default Mode and Frontoparietal Network. The U-shaped trajectory is predominantly linked to gestational factors, as it only presents in gestational mothers and correlates with fluctuations in estrogens over time. Finally, the mother's mental health status mediates the relationship between postpartum GM volume recovery and maternal attachment at 6 months postpartum. This research sheds light on the complex interplay between hormones, brain development, and behavior during the transition to motherhood. It addresses a significant knowledge gap in the neuroscience of human pregnancy and opens new possibilities for interventions aimed at enhancing maternal health and well-being.

Psychopathological manifestations and cognitive impairments are core features of psychotic disorders. Polygenic risk scores (PRS) offer insights into the relationships between genetic vulnerability, symptomatology, and cognitive impairments. This study used a network analysis to explore the connections between PRS, cognition, psychopathology, and overall functional outcomes in individuals experiencing a first episode of psychosis (FEP). The study sample comprised 132 patients with FEP. Genetic data were used to construct PRS for mental disorders and cognitive traits via PRS-continuous shrinkage. We conducted comprehensive clinical and neuropsychological assessments at 2 months post-diagnosis and again at a 2-year follow-up. A network analysis was performed to generate two distinct networks and their centrality indices, encompassing 19 variables across domains such as symptoms, cognition, functioning, and PRS. Variables were grouped within related domains, and stronger relationships were observed within domains than between them. PRS for schizophrenia showed weak negative associations with attention, working memory, and verbal memory, while PRS for cognitive performance showed weak positive associations with attention. Negative symptoms were negatively associated with functioning and verbal memory at both the 2-month and 2-year assessments, as well as with social cognition at 2 years. Poor functioning was moderately related to greater severity of Positive and Negative Syndrome Scale dimensions. This study identified pathways linking PRS, cognition, symptoms, and functioning, suggesting that genetic risk may serve as a marker of vulnerability and disorder progression. The findings also highlight the importance of considering genetic predispositions alongside clinical and cognitive factors to better understand the heterogeneity of psychotic disorders.

BACKGROUND:Obstetric complications (OCs) are associated with cognitive and brain abnormalities observed in patients with schizophrenia. Gyrification, a measure of cortical integrity sensitive to events occurring during the prenatal and perinatal periods, is also altered in first-episode psychosis (FEP). We examined the relationship between OCs and gyrification in FEP, as well as whether gyrification mediates the relationship between OCs and cognition. METHODS:We examined differences in the Local Gyrification Index (LGI) for the frontal, parietal, temporal, occipital, and cingulate cortices between 139 FEP patients and 125 healthy controls (HCs). Regression analyses explored whether OCs and diagnosis interact to explain LGI variation. Parametric mediation analyses were conducted to assess the effect of LGI on the relationship between OCs and cognition for FEP and HC. RESULTS:Significant LGI differences were observed between FEP patients and HC in the left parietal and bilateral cingulate and occipital cortices. There was a significant interaction between OCs and diagnosis on the left cingulate cortex (LCC) that was specific to males (p = 0.04) and was driven by gestational rather than intrauterine OCs.In HCs, OCs had a direct effect on working memory (WM) (p = 0.048) in the mediation analysis, whereas in FEP, we observed no significant effect of OCs on either verbal or WM. CONCLUSIONS:OCs interact with diagnosis to predict LCC gyrification, such that males with FEP exposed to OCs exhibit the lowest LGI. OCs influence WM, and LCC gyrification may mediate this relation only in HC, suggesting a differential neurodevelopmental process in psychosis.

Introduction Diagnostic stability is a controversial issue in first episode psychosis (FEP) due to heterogenous symptoms and unclear affective symptoms. Differencing affective and non-affective psychoses is important as treatment strategies are different. Initial affective symptomatology has low specificity for predicting the subsequent diagnosis of affective psychosis. Sex has proven to be relevant for clinical and functional outcomes but it remains unclear how sex may contribute to diagnosis switch of FEP. Objectives To determine the role of sex in diagnostic stability in a sample of FEP after 1-year follow-up. Methods Diagnoses of FEP patients from Hospital del Mar of Barcelona were assessed at baseline and 1 year after. Univariate analyses was perfomed for all diagnoses and dichotomic variable (affective/non-affective). Logistic regression model was perfomed to know which variables predict diagnosis switch. Results 256 patients were enrolled. No differences were found at baseline between completers and non-completers (Table 1). No significant differences between men and women at baseline diagnosis were found, neither all diagnoses (p=0.274) nor the dichotomic variable affective/non-affective (p=0.829) (Table 2AB). Significant differences were found at 1-year follow-up between men and women, for all diagnoses (p=0.043) and the dichotomic variable (p=0.039). Sex was the only variable that predicted diagnosis switch (Figure 1), PANSS, CDSS, YMRS, GAF and cannabis did not. Table 1. Baseline characteristics of participants Completers (n=188) Non-completers (n=68) p Women (n, %) 71 (37.8) 30 (44.1) 0.111 Age (M, IQR) 24 (20-28) 22 (20-28) 0.899 Cannabis use (M, IQR) 5.5 (0-18) 7 (0-21) 0.231 DUP (M, IQR) 45 (12.5-130) 36 (11.25-115.75) 0.213 PANSS (m, sd) 44.55 (10.17) 40.93 (10.42) 0.761 CDSS (M, IQR) 2 (0-7) 3 (0-5.5) 0.199 YMRS (m, sd) 19 (9.64) 17.6 (9.15) 0.845 GAF (M, IQR) 30 (25-50) 30 (25-35) 0.114 TABLE 2A and 2B. Diagnosis comparison (n, %) Baseline 1-year follow-up Men Women Total Men Women Total Psychosis NOS 69 (59) 39 (54.9) 108 (57.4) 28 (23.9) 10 (14.1) 38 (20.2) Schizophreniform disorder 22 (18.8) 16 (22.5) 38 (20.2) 14 (12 9 (12.7) 23 (12.2) Induced psychosis 4 (3.4) 0 (0) 4 (2.1) 15 (12.8) 4 (5.6) 19 (10.1) Affective psychosis 17 (14.5) 9 (12.7) 26 (13.8) 24 (20.5) 25 (35.2) 49 (26.1) Schizophrenia 0 (0) 0 (0) 1 (0.4) 30 (25.6) 14 (19.7) 44 (23.4) Brief psychotic disorder 5 (4.3) 7 (9.9) 12 (6.4) 6 (5.1) 8 (11.3) 14 (7.4) Baseline 1-year follow-up Men Women Total Men Women Total Affective psychosis 17 (14.5) 9 (12.7) 26 (13.8) 24 (20.5) 25 (35.2) 49 (26.1) Non-affective psychosis 100 (85.5) 62 (87.3) 162 (86.2) 93 (79.5) 46 (64.8) 139 (73.9) Image: Conclusions Sex has proven to be the main predictor of switching initial diagnosis of FEP. Disclosure of Interest None Declared

Background. Polygenic risk scores for educational attainment (PRSEA), cognitive reserve (CR), and clinical symptoms are associated with functioning in first-episode psychosis (FEP). Nevertheless, the mechanisms underlying their complex interaction are yet to be explored. This study assessed the mediating role of CR and clinical symptoms, both negative (NS) and positive (PS), on the interrelationship between PRS(EA )and functionality, one year after a FEP. Methods. A total of 162 FEP patients underwent clinical, functional, and genetic assessments. Using genome-wide association study summary results, PRS(EA )were constructed for each individual. Two mediation models were performed. The parallel mediation model explored the relationship of PRSEA with functionality through CR and clinical symptoms. The serial mediation model tested a causal chain of the three mediators: CR, NS, and PS. Mediation analysis was performed using the PROCESS function V.4.1 in SPSS V.22. Results. A serial mediation model revealed a causal chain for PRSEA > CR > NS > Functionality (beta = -0.35, 95%CI [-0.85, -0.04], p < 0.05). The model fit the data satisfactorily (CFI = 1.00; RMSEA = 0.00; SRMR = 7.2 x 10-7). Conversely, no parallel mediation was found between the three mediators, PRSEA and functionality and the model poorly fit the data (CFI = 0.30; RMSEA = 0.25; SRMR = 0.11). Conclusions. Both CR and NS mediate the relationship between PRSEA and functionality at one-year follow-up, using serial mediation analysis. This may be relevant for prevention and personalized early intervention to reduce illness impact and improve functional outcomes in FEP patients.

BACKGROUND:Despite the diverse nature of clinical trajectories after a first episode of psychosis, few baseline characteristics have been predictive of clinical improvement, and the neurobiological underpinnings of this heterogeneity remain largely unknown. Elevated extracellular free water (FW) in the brain is a diffusion imaging measure that has been consistently reported in different phases of psychosis that may indicate a neuroinflammatory state. However, its predictive capacity in terms of clinical outcomes is unknown. METHODS:We used diffusion imaging to determine FW and tissue-specific fractional anisotropy (FA-t) in first-episode psychosis. Forty-seven participants were categorized as clinical improvers (n = 26) if they achieved a 20% decrease in total Brief Psychiatric Rating Scale score at 12 months. To determine the predictive capacity of FW and FA-t, these measures were introduced in a stepwise logistic regression model to predict clinical improvement. For measures that survived the model, regional between-group differences were also investigated in cortical surface or white matter tracts, as applicable. RESULTS:Both higher gray matter FW (odds ratio 1.698; 95% CI, 1.134-2.542) and FA-t (odds ratio, 1.358; 95% CI, 0.905-2.038) predicted improver status. FW in gray matter was also linearly correlated with the Brief Psychiatric Rating Scale total score at the 12-month follow-up. When we examined regional specificity, we found that improvers showed greater FW predominantly in temporal regions and higher FA-t values in several white matter tracts, including the bilateral longitudinal superior fasciculus. CONCLUSIONS:Our results show that elevated FW in gray matter and FA-t predict further clinical improvement during the initial phases of psychosis. The potential roles of brain inflammatory processes in predicting clinical improvement are discussed.

AIM:People at clinical high risk (CHR) for psychosis are a heterogeneous population in regard to clinical presentation and outcome. It is unclear, however, if their baseline clinical characteristics can be used to construct orthogonal subgroups that differ in their clinical trajectory to provide early identification of individuals in need of tailored interventions. METHODS:We used latent profile analysis (LPA) to determine the number of distinct clinical profiles within the CHR population using the NAPLS-3 dataset, focusing on the clinical features incorporated in the NAPLS psychosis risk calculator (including age, unusual thought content and suspiciousness, processing speed, verbal learning and memory function, social functioning decline, life events, childhood trauma, and family history of psychosis). We then conducted a between-profile comparisons of clinical trajectories based on psychotic and depressive symptoms as well as substance use disorder (SUD) related features over time. RESULTS:Two distinct profiles emerged. One profile, comprising approximately 25% of the sample, was significantly older, displayed better cognitive performance, experienced more types of traumatic and undesirable life events, exhibited a greater decline in functioning in the past year, and was more likely to have relatives with psychosis. This group showed worse positive symptoms and SUD-related features over time, although groups did not differ in the proportion of individuals who developed psychosis. CONCLUSIONS:LPA results suggest CHRs can be segregated into two profiles with different clinical trajectories. Characterizing individuals within these clinical profiles may help understand the divergent outcomes of this population and ultimately facilitate the development of specialized interventions.

BACKGROUND:The clinical course following a first episode of schizophrenia (FES) is often characterized by recurrent relapses, resulting in unfavorable clinical and functional outcomes. Inflammatory dysregulation has been implicated in relapse risk; however, the predictive value of inflammatory blood cells in clinically remitted patients after a FES has not been previously explored. METHODS:In this study, we closely monitored 111 patients in remission after a FES until relapse or a three-year follow-up endpoint. The participants were recruited from the multicenter 2EPS Project. Data on inflammatory blood cells and ratios were collected at baseline and at the time of relapse or after three years of follow-up. RESULTS:Monocyte counts (OR = 1.91; 95 % CI = 1.07-3.18; p = 0.009) and basophil counts (OR = 1.09; 95 % CI = 1.01-1.12; p = 0.005) at baseline were associated with an increased risk of relapse, while the platelet-lymphocyte ratio (OR = 0.98; 95 % CI = 0.97-0.99; p = 0.019) was identified as a protective factor. However, after adjusting for cannabis and tobacco use during the follow-up, only monocyte counts (OR = 1.73; 95 % CI = 1.03-2.29; p = 0.027) and basophil counts (OR = 1.08; 95 % CI = 1.01-1.14; p = 0.008) remained statistically significant. ROC curve analysis indicated that the optimal cut-off values for discriminating relapsers were 0.52 × 10^9/L (AUC: 0.66) for monocytes and 0.025 × 10^9/L (AUC: 0.75) for basophils. When considering baseline inflammatory levels, no significant differences were observed in the inflammatory biomarkers at the endpoint between relapsers and non-relapsers. CONCLUSION:This study provides evidence that higher monocyte and basophil counts measured at remission after a FES are associated with an increased risk of relapse during a three-year follow-up period.

IntroductionThyroid hormones play an essential role in hippocampal development, a key structure in psychosis. However, the role of these hormones in first-episode psychosis (FEP) has received limited attention. It has been hypothesized that thyroid hormones could cause morphological modifications in the hippocampal structure through the upregulation of brain-derived neurotrophic factor (BDNF). In this study, we primarily aimed to determine the relationship between thyroid-stimulating hormone (TSH) levels, peripheral BDNF levels, and hippocampal volume in antipsychotic-naïve FEP patients. We also aimed to determine whether TSH levels were associated with clinical symptomatology.Materials and methodsA total of 50 antipsychotic-naïve FEP patients were included in the study. At baseline, we collected fasting blood samples and registered sociodemographic and clinical variables (substance use, DUP, PANSS, GAF, and CDSS). Structural T1 MRI was performed at baseline to quantify brain volumes. No control group was used for this study.ResultsOf the 50 patients, more than one-third (36%) presented alterations in TSH levels, mainly elevated levels (32% of patients). The TSH levels were inversely correlated with both peripheral BDNF and hippocampal volume. On the multivariate analysis, the model that best predicted the relative hippocampal volume was a single variable model (TSH levels). No significant association was observed between TSH levels and clinical symptomatology.DiscussionThese results suggest that thyroid hormones could have a neuroprotective effect on the hippocampus in FEP patients, possibly through their effect by increasing BDNF concentrations, which could attenuate brain injury and neuroinflammation. Nevertheless, thyroid hormones could also affect hippocampal volume through other pathways.

Obstetric complications (OCs) are key contributors to psychosis risk. However, it is unclear whether they increase psychosis vulnerability independently of genetic risk, in interaction with it, or are a manifestation of psychosis proneness. We examined the role of distinct types of OCs in terms of psychosis risk and tested whether they interact differently with genetic vulnerability, whilst accounting for other known environmental risk factors.

The risk of suicide in first-episode psychosis (FEP) is high. However, there are many unknowns about this phenomenon and the risk factors associated with higher risk are not well-understood. Therefore, we aimed to determine the baseline sociodemographic and clinical factors associated with suicide attempts in FEP patients over two-years after psychosis onset. Univariate and logistic regression analyses were performed. Between April 2013 and July 2020, 279 patients treated at the FEP Intervention Program at our hospital (Hospital del Mar, Spain) were enrolled and 267 completed the follow-up. Of these, 30 patients (11.2%) made at least one suicide attempt, mostly during the untreated psychosis period (17 patients, 48.6%). Several variables-prior history of suicide attempts and low functionality, depression, and feelings of guilt at baseline-were all significantly associated with suicide attempts. These findings suggest that targeted interventions, especially in prodromal stages, could play a key role in identifying and treating FEP patients with a high suicide risk.

Cyclin-dependent kinase 5 (CDK5) is a serine/threonine kinase that has emerged as a key regulator of neurotransmission in complex cognitive processes. Its expression is altered in treated schizophrenia patients, and cannabinoids modulate CDK5 levels in the brain of rodents. However, the role of this kinase, and its interaction with cannabis use in first-episode psychosis (FEP) patients is still not known. Hence, we studied the expression changes of CDK5 and its signaling partner, postsynaptic density protein 95 (PSD95) in olfactory neuroepithelial (ON) cells of FEP patients with (FEP/c) and without (FEP/nc) prior cannabis use, and in a dual-hit mouse model of psychosis. In this model, adolescent mice were exposed to the cannabinoid receptor 1 agonist (CB1R) WIN-55,212–2 (WIN: 1 mg/kg) during 21 days, and to the N-methyl-d-aspartate receptor (NMDAR) blocker phencyclidine (PCP: 10 mg/kg) during 10 days. FEP/c showed less social functioning deficits, lower CDK5 and higher PSD95 levels than FEP/nc. These changes correlated with social skills, but not cognitive deficits. Consistently, exposure of ON cells from FEP/nc patients to WIN in vitro reduced CDK5 levels. Convergent results were obtained in mice, where PCP by itself induced more sociability deficits, and PSD95/CDK5 alterations in the prefrontal cortex and hippocampus than exposure to PCP-WIN. In addition, central blockade of CDK5 activity with roscovitine in PCP-treated mice restored both sociability impairments and PSD95 levels. We provide translational evidence that increased CDK5 could be an early indicator of psychosis associated with social deficits, and that this biomarker is modulated by prior cannabis use.