Department of Psychiatry, UCSD

Mania is a defining feature of bipolar disorder, although its pathophysiology remains incompletely understood. Multiple substances are known to precipitate mania in susceptible individuals. Here we describe the case of a 22-year-old male with no prior psychiatric history, who was hospitalized due to mania three times within four months. Each relapse corresponded to either increasing or restarting creatine supplementation. The patient met DSM-5-TR criteria for bipolar I disorder. However, the full and rapid recovery with each episode, similar symptoms in a first-degree relative that resolved on cessation, and the consistent temporal relationship with creatine supplementation raise the possibility that creatine contributed to precipitating these symptoms. Causality was rated as probable on the Naranjo Adverse Drug Reaction Probability Scale. This case suggests a possible link between creatine supplementation and mania. It also highlights the importance of screening for supplement use in patients presenting new-onset mood symptoms and offers ideas for further research.

The Reln gene encodes the extracellular glycoprotein Reelin that regulates synaptic plasticity and activity-dependent gene expression with implication in several neuropsychiatric disorders, including substance use disorder. Although reduction of Reln expression has been associated with altered responses to psychostimulants and cannabinoids, its role in opioid-evoked behaviors has not been investigated. Here, we tested whether Reln haploinsufficiency alters behavioral and molecular responses to the synthetic opioid fentanyl. Heterozygous Reeler (Reln+/-) mice and wild-type littermates were assessed using complementary contingent and non-contingent models of fentanyl exposure, including multi-phase fentanyl intravenous self-administration paradigm, conditioned place preference paradigm, locomotor assays, and dorsal striatal immediate early gene expression. Reln haploinsufficiency did not alter acquisition, extinction, or cue-induced fentanyl seeking during self-administration, indicating stable opioid reinforcement and relapse-like behavior. Following acute, passive fentanyl exposure, Reln+/- mice exhibited enhanced fentanyl-induced locomotion and Fos immunoreactivity in the dorsal striatum, while fentanyl conditioned place preference remained unchanged. Together, these findings demonstrate that Reln haploinsufficiency does not modify opioid reinforcement or cue-driven drug seeking but enhances acute drug-evoked neuronal activation in the dorsal striatum. These results identify Reln as a modulatory factor in opioid-responsive neural circuits rather than in the associative learning processes underlying opioid reinforcement.

OBJECTIVE: Individuals with anorexia nervosa (AN) share premorbid traits with Parkinson's Disease (PD) (e.g., anxiety) and exhibit a two-fold relative risk of a reported family history of PD. Published estimates of intra- and inter-disorder genetic architecture were extracted and compared prior to conducting novel analyses to provide evidence for cross-disorder genetic risk. METHODS: National register or meta-analytic familial, twin, and common variant genome-wide studies were searched; estimates and findings were extracted and compared. Novel cross-disorder conditional and conjunctional false discovery rate analyses were performed. RESULTS: Sibling relative risks and additive genetic estimates of the two disorders were similar. AN had greater common variant heritability than PD whether measured via infinitesimal model (linkage disequilibrium score regression, LDSC) or causal mixture model (MiXeR). AN had greater polygenicity than PD (mean (SD) 2.50E-03 (1.64E-04) versus 2.72E-4 (1.47E-05), p < 0.001), but lower discoverability than PD (4.20E-05 (2.69E-06) versus 1.40E-04 (6.95E-06), p < 0.001). Global genetic correlation was significant (e.g., bivariate LDSC r_g = 0.10, p = 0.0033). Novel analyses identified cross-disorder enrichment, and cross-disorder risk at chr3p21.31. CONCLUSIONS: Cross-disorder AN and PD research identified shared risk variants at chr3p21.31, genes and mechanisms (e.g., conditioning, fear, and reward) linked to a shared endophenotype.

Background: Adolescent substance use is a continued public health concern. The objective of this manuscript is to detail the prevalence of substance use, polysubstance use, and investigate sex differences in the Adolescent Brain Cognitive Development (ABCD) Study from ages 9-17. Methods: 11,880 youth across the U.S., recruited at ages 9-10, completed annual study visits from September 2016 to January 2024. The ABCD 6.0 data release comprises baseline to year-6 data. Lifetime and annual substance use prevalence rates, sex differences, and polysubstance use are described and analyzed. Results: Past-year substance use prevalence increased with age; 38% report lifetime use by age 16. Alcohol, cannabis, and nicotine were the most reported substances. There were non-significant differences observed between unweighted trends and census-weighted trends. More boys reported substance use prior to age 12, then from age 13 onward, more girls reported use. Polysubstance use analyses detail the occurrence of the most shared substance use patterns and divergent reports across the sexes. Conclusions: Descriptively, these prevalence rates mirror other national surveys showing increases in reported use across early adolescence, with alcohol, cannabis, and nicotine being the most used substances. Unique sex differences and polysubstance use prevalence rates are contextualized alongside prior national reports of these behaviors in the U.S. Understanding the latest prevalences, specifically in a well-phenotyped cohort, helps to guide knowledge for continued analysis of antecedents and sequelae of substance use on health.

BackgroundConducting longitudinal infectious disease research during armed conflicts is important for understanding transmission dynamics and preventing outbreaks. War in Ukraine started in 2014, with the escalation to full-scale invasion in 2022, resulting in massive population displacement, infrastructure destruction, mobility restriction for men, and reduced access to healthcare. The ANCHOR (Analysis of Network Composition, Health Outcomes, and Resilience) study, launched in November 2024, examines how war- and displacement-driven changes affect social networks, HIV risks, and HIV care engagement. Here, we report implementation challenges and adaptations as practical lessons that may inform infectious disease surveillance and research in conflict settings.MethodsANCHOR is a cohort study conducted in Kyiv and Lviv in 2024–2026 that enrolled sexual minority men (SMM) using respondent-driven sampling, with 6- and 12-month follow up of participants testing positive for HIV. Data collection included structured behavioral and social network interviews, HIV rapid testing, viral load (VL) assessment, and HIV genetic sequencing.ResultsA total of 1,199 SMM were enrolled; of those, 87 tested positive for HIV. Challenges of conducting a research study in an ongoing conflict were identified during the first month of recruitment and prompted protocol revision, incorporating online screening, oral consent, remote interviews, video-assisted HIV self-testing, flexible biospecimen collection. These changes enabled safe completion of study recruitment ahead of the anticipated schedule (within 8 instead of 18 months). Interview follow-up rate was 94% (82/87) at both 6-and 12-month, accompanied by successful biospecimen collection in 61/87 and 45/87 cases at 6-month and 12-month follow-up, respectively.ConclusionsFlexible adaptations in response to the war conditions preserved study integrity and safety of study participants and staff. Availability of various modes of biospecimen collection allowed successful completion of clinical and genomic components of the study, including VL testing and HIV molecular epidemiology analyses despite logistical, infrastructural, and security constraints. Longitudinal biospecimen collection remained challenging due to the ongoing migration and displacement. Lessons from the ANCHOR study can support continuity of infectious disease research in conflict settings and among populations facing barriers to participation. Some of these adaptations may also be applicable to routine infectious disease surveillance, although their utility requires further evaluation.

OBJECTIVES: The purity, accessibility, and affordability of illicit methamphetamine have increased in recent decades, which has been linked to rising rates of methamphetamine-involved overdoses, psychosis, cardiovascular events, and other health consequences. Nevertheless, information about the quantity of methamphetamine used by regular consumers has been limited, despite the potential clinical utility of exposure quantification. METHODS: From August 2024 to April 2026, self-reported daily methamphetamine consumption was assessed among n = 94 individuals in Los Angeles County. Methamphetamine samples (n = 256) were analyzed for purity using liquid chromatography-mass spectrometry. Bioavailability by route of administration and stimulant equivalency were obtained from the literature. A simulation model leveraging bootstrapping with 1,000,000 draws was used to estimate oral amphetamine milligram equivalents (AME). RESULTS: The average reported methamphetamine consumption was 1.09 g daily (95% prediction interval: 0.07-4.00). Average purity was 84.52% (95% PI: 14.90%-100.00%). Given estimated average bioavailability of 66.41% (95% PI: 39.35%-85.24%), the average consumer used an estimated 1432.54 AME daily (95% PI: 35.74-6973.05). CONCLUSIONS: We estimate that consumers of methamphetamine in Los Angeles use an average daily stimulant dose (nearly 1500 oral AME) about 25-fold higher than the maximum typical recommended clinical dose of mixed amphetamine salts (60 mg). This may help contextualize why prescription stimulant treatment trials using substantially lower doses have shown limited efficacy. Given this high dose, these findings shed light on the rising incidence of methamphetamine-related sequelae, such as psychosis, cardiovascular complications, and sudden death. Although exposure quantification is commonplace for alcohol and tobacco use disorders, uncertainties in illicit drug markets have complicated this practice for most illicit drugs. This study supports leveraging emerging information from drug checking programs so that clinicians can approximate exposure quantification.

Adolescents experience extensive neurocognitive development, with cannabis use potentially impacting developmental trajectories. Here, we comprehensively assess the influence of adolescent cannabis use onset on neurocognitive trajectories and consider how recent delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) may influence neurocognition. We use the large, diverse longitudinal Adolescent Brain Cognitive Development (ABCD) Study dataset, combining self-reported substance use with objective toxicological tests (hair, urine, breath, oral fluid). Longitudinal mixed methods of the full cohort (n = 11,036, ages 9-17; 47% Female/53% Male) investigate time-varying cannabis onset on neurocognitive performance. Primary model covariates include sociodemographics, family history of substance use disorder, prenatal substance exposure, early psychopathology, other substance use, and nesting for participant ID, study site, and family ID. Secondarily, in participants with repeat toxicological hair testing (n = 645; 38% Female/62% Male) at ages 12-16, we consider the influence of THC v. CBD v. Controls. Primary models included false discovery rate corrections (FDR-p < .05) while secondary models were interpreted at p < .01. Cannabis group interacted with age to show altered neurocognitive trajectories across domains (immediate recall and delayed memory, processing speed, inhibitory control, visuospatial processing, language, and working memory; βs = -0.11- -0.52). Secondary models indicated hair-identified THC exposure*age predicted worse episodic memory than in Controls (β = -0.60, p = .007), with no difference between CBD exposed and Controls. Data suggest those who use cannabis show likely pre-existing better cognitive performance during late childhood, with reduced improvement or flattened trajectories over time. These neurocognitive trajectories in youth (ages 9-17) who initiate cannabis use were demonstrated after accounting for within-person change and numerous known confounds and improving accuracy in identifying cannabis use through incorporating toxicological measures. Continued monitoring of this cohort will clarify cannabinoid-cognition relationships into young adulthood, including the impact of timing of cannabis use initiation.