Drug and Alcohol Dependence

BackgroundThe efficacy and safety of buprenorphine alone and in combination with naloxone for treatment of opioid dependence were evaluated in Federally-sponsored randomized clinical trials. Meta-analysis of pooled individual participant data provides an opportunity to identify multiple predictors of buprenorphine treatment outcome. MethodsWe selected six buprenorphine efficacy and safety trials from NIDAs Data Share database for analysis. Treatment, sociodemographic, and drug use history variable domains were systematically harmonized and included in analysis. After exclusions, 3,022 participants randomized or enrolled in buprenorphine treatment for opioid dependence (mean (SD) age 36.1 (9.8) years, 33% female, 66% White, 16% Hispanic, 14% Black), were analyzed using a generalized linear mixed model with time-weighted treatment variables and participant covariates. We defined positive urinalysis or self-reported lapse as the primary outcome. ResultsFour treatment variables were significantly associated (p < 0.001) with lapse. Time-weighted dose and time-weighted adaptive dose had greater estimated effects than time-in-trial and time-weighted clinic visit. All treatment variables were novel predictors of lapse. ConclusionsIn a large cohort of trial participants treated with buprenorphine and behavioral counseling for opioid dependence, we identified and ranked four novel treatment factors reflecting components of buprenorphine dose, clinical provider engagement and patient engagement. Additional research to explore the effects of pharmacologic and non- pharmacologic treatment factors, and to explore relations with provider and patient factors will help our understanding of buprenorphine treatment outcomes. Continued analyses of publicly available data will extend discovery and support development of personalized opioid use disorder treatments. Highlights (3 to 5 bullet point max 85 characters each including spaces)O_LITreatment and participant variables were harmonized in six buprenorphine trials C_LIO_LITime-weighted treatment variables were used in a random effects mixed model of lapse C_LIO_LIBuprenorphine dose and three clinical interactions were protective against lapse C_LIO_LISupport of protective treatment factors may improve buprenorphine treatment success C_LI

BackgroundStimulant drug users vary in their substance of choice and may, in some cases, switch up their preferred substance based on availability, cost or other factors. Poly-substance use is rarely assessed in rodent models of drug seeking and this study determined if training drug alters the apparent reinforcing properties of methamphetamine (MA) and -pyrrolidinopentiophenone (-PVP). MethodsFemale and male Wistar rats (N=8 per group) were trained in the intravenous self-administration (IVSA) of -PVP or MA. The impact of dose substitution (0.0125, 0.0250, 0.100, 0.300 mg/kg/infusion) for each training drug was then assessed in all groups under FR and Progressive Ratio schedules of reinforcement. ResultsMale and female rats obtained similar numbers of infusions of MA (0.05 mg/kg/infusion) and of -PVP (0.05 mg/kg/infusion) during acquisition, however more infusions of -PVP than of MA were obtained by each sex. Mean lever discrimination ratios exceeded 80% on the drug-associated lever within 5 training sessions for -PVP groups but were not consistently at this level for either MA group. Drug potency was similar across groups but was less effective in the MA-trained males. ConclusionsInterpretations of sex differences in the acquisition of drug IVSA require caution when dose is not varied across or within group. This study also further confirms that the apparent efficacy of a drug as a reinforcer depends at least partially on the behavioral antecedents, including the identity of the drug used for initial IVSA acquisition.

ImportanceDrug overdoses from opioids like fentanyl and heroin and stimulant drugs such as methamphetamine and cocaine are a major cause of mortality in the United States, with potential sex differences across the lifespan. ObjectiveTo determine overdose mortality for specific drug categories across the lifespan of males and females, using a nationally representative state-level sample. DesignState-level analyses of nationally representative epidemiological data on overdose mortality for specific drug categories, across 10-year age bins (age range: 15-74). SettingPopulation-based study of Multiple Cause of Death 2020-2021 data from the Centers of Disease Control and Prevention (CDC WONDER platform). ParticipantsDecedents in the United States in 2020-2021 Main outcome measuresThe main outcome measure was sex-specific rates of overdose death (per 100,000) for: synthetic opioids excluding methadone (ICD-10 code: T40.4; predominantly fentanyl), heroin (T40.1), psychostimulants with potential for misuse, excluding cocaine (T43.6, predominantly methamphetamine; labeled "psychostimulants" hereafter), and cocaine (T40.5). Multiple regression analyses were used to control for ethnic-cultural background, household net worth, and sex-specific rate of misuse of the relevant substances (from the National Survey on Drug Use and Health, 2018-2019). ResultsFor each of the drug categories assessed, males had greater overall overdose mortality than females, after controlling for rates of drug misuse. The mean male/female sex ratio of mortality rate for the separate drug categories was relatively stable across jurisdictions: synthetic opioids (2.5 [95%CI, 2.4-2.7]), heroin, (2.9 [95%CI, 2.7-3.1], psychostimulants (2.4 [95%CI, 2.3-2.5]), and cocaine (2.8 [95%CI, 2.6-2.9]). With data stratified in 10-year age bins, the sex difference generally survived adjustment for state-level ethnic-cultural and economic variables, and for sex-specific misuse of each drug type (especially for bins in the 25-64 age range). For synthetic opioids, the sex difference survived adjustment across the lifespan (i.e., 10-year age bins ranging from 15-74), including adolescence, adulthood and late adulthood. Conclusions and RelevanceThe robustly greater overdose mortality in males versus females for synthetic opioids (predominantly fentanyl), heroin, and stimulant drugs including methamphetamine and cocaine indicate that males who misuse these drugs are significantly more vulnerable to overdose deaths. These results call for research into diverse biological, behavioral, and social factors that underlie sex differences in human vulnerability to drug overdose. Key PointsO_ST_ABSQuestionC_ST_ABSWhat are the current national trends in overdose mortality from opioids (synthetic opioids such as fentanyl, and heroin) and stimulant drugs (psychostimulants such as methamphetamine and cocaine) for males and females, over the lifespan (overall range 15-74 years)? FindingsState-level analyses of data from CDC for 2020-2021 indicate that after controlling for rates of drug misuse, males had significantly greater (2-3 fold) overdose mortality rates than females for synthetic opioids, heroin, psychostimulants and cocaine. These findings were generally consistent across the lifespan, studied as 10-year age bins (especially in the 25-64 age range). MeaningThese data indicate that males who misuse opioids and stimulant drugs are considerably more vulnerable to overdose mortality, compared to females. This finding calls for research on the underlying biological, behavioral, and social factors.

BackgroundRemission from substance use disorders (SUDs) is typically conceptualized as an all-or-none phenomenon. Here, we present a novel construct: proportion of remission (PrR; i.e., the proportion of substances an individual is in remission from relative to lifetime SUD history), a continuous construct that may better capture progress towards recovery in polysubstance use. MethodsIndividuals (n= 2,417) in recovery from SUDs were recruited from International Quit and Recovery Registry (IQRR). Individuals completed a $1000 adjusting amount delay discounting (DD) task, and questions about current and past substance use over the past 12 months and lifetime. We estimated a series of single-level binomial regressions models using PrR as the independent variable and DD, maximum time in recovery, and maximum quit time as dependent variables. In addition, we performed a moderated mediation analysis to understand the relationship between PrR and recovery variables. ResultsWe report that DD, maximum time in recovery, and maximum quit time significantly predicted PrR in individuals with a history of polysubstance use. Further, we found that the relationship between maximum time in recovery and PrR was mediated by the maximum quit time across substances and differed by varying levels of DD. ConclusionResults suggest that longer quit time of any substance is related to improved recovery outcomes, particularly for individuals with low discounting rates. Together, interventions that focus on harm reduction and/or those that modulate DD may lead to improved clinical outcomes (including quit time and PrR) in individuals with a history of polysubstance use.

QuestionThe opioid epidemic causes massive morbidity, and males have substantially greater overdose mortality rates than females. It is unclear whether there are sex-related disparities at different stages in the trajectory of opioid use disorders, in "real world" settings. GoalTo determine sex disparities in non-medical opioid use (NMOU) at the end of outpatient medication-assisted treatment (MAT), using nationally representative data. DesignObservational epidemiological study of publicly funded outpatient MAT programs in the national "Treatment episode data set-discharges" (TEDS-D) for 2019. ParticipantsPersons aged [&ge;]18 in their first treatment episode, in outpatient MAT for use of heroin or other opioids (N=11,549). The binary outcome was presence/absence of NMOU. ResultsIn univariate analyses, males had significantly higher odds of NMOU, compared to females (odds ratio=1.27; Chi2 [df:1]=39.08; uncorrected p<0.0001; p=0.0041 after Bonferroni correction). A multivariable logistic regression detected a male>female odds ratio of 1.19 (95%CI=1.09-1.29; p<0.0001), adjusting for socio-demographic/clinical variables. Several specific conditions were revealed in which males had greater odds of NMOU compared to females (e.g., at ages 18-29 and 30-39; corrected p=0.012, or if they used opioids by inhalation; corrected p=0.0041). ConclusionsThis nationally representative study indicates that males have greater odds of NMOU in their first episode of MAT, indicating more unfavorable outcomes. The study reveals specific socio-demographic and clinical variables under which this sex disparity is most prominent. Highlights*It is unclear if there are sex-related disparities in outcomes for outpatient opioid medication-assisted therapy (MAT), in large-scale "real world" settings. *In this nationally representative "real world" study, adult males had significantly greater odds of non-medical opioid use (NMOU) in the month prior to discharge from their first MAT episode compared to females, adjusting for socio-demographic and clinical variables. Males were at higher risk than females for this undesirable outcome under several conditions (e.g., in younger age categories, or if their route of NMOU was by inhalation. *Sex disparities in MAT outcomes occur under specific conditions that can be examined and potentially addressed, with the goal of improving personalized approaches for OUD.

BackgroundXylazine is a veterinary tranquilizer found in the unregulated drug supply in the United States. It appears alone or as an adulterant in fentanyl ("tranq dope"). Xylazines symptomatology is well described and includes skin and soft tissue damage, bradycardia, and loss of consciousness. However, little is known about whether and how substance use behaviors have changed as xylazines presence in street drugs has grown. MethodsWe conducted semi-structured in-depth interviews with people with recent overdose reversal experiences in two mid-sized midwestern cities (n=52). Interviews were part of a larger study on naloxone administration behaviors. Participants were asked about their knowledge and perceptions of local drug supply trends. Transcript data were analyzed using the rigorous and accelerated data reduction technique. ResultsParticipants preferred fentanyl and heroin without xylazine. Most participants discussed adjusting opioid use toward safer practices: using less in amount or frequency, abstaining or seeking treatment, alternating use (e.g., ingesting xylazine only at night), or changing route of administration from injecting to smoking, snorting, or boofing (ingesting anally). Motivations for changes in use included not experiencing intended opioid agonist effects, fear of physical health risks, loss of functionality and productivity, and overdose concerns. ConclusionFindings suggest that xylazine is encouraging reduced fentanyl and heroin use. Our results corroborate laboratory, clinical, and behavioral studies showing that xylazine, which causes severe health harms, may also, paradoxically, be protective against fatal overdose. More research is needed on this phenomenon in light of recent downward trends in overdose mortality.

BackgroundOpioid use disorder (OUD) is a major public health crisis. Patients initial exposure to opioids often comes from prescribed medications. Predicting which of these patients will develop OUD remains challenging. Prior evidence from various substances suggest that initial subjective responses influence addiction risk, however these studies have used relatively small cohorts and have not led to the development of widespread tools to predict OUD risk. MethodsWe used a cohort of 141,897 adult research participants to perform a retrospective observational study of self-reported subjective responses to prescription opioids. We collected demographics, subjective positive (e.g., euphoria), subjective negative (e.g., nausea), and analgesic responses as well as self-reported OUD. ResultsPositive subjective effects, particularly "Like Overall", "Euphoric", and "Energized", were the strongest predictors of OUD. For example, the odds-ratio for individuals responding "Extremely" for "Like Overall" was 36.5. The sensitivity and specificity of this single question was excellent (ROC=0.87). Negative effects and analgesic effects were much less predictive. We developed a two-question decision tree ("When you first took opioid pain medication, to what extent did you like the way they made you feel overall?" and "When you first took opioid pain medication, to what extent did you experience an unpleasant itchy feeling?"), that can identify a small high-risk subset with 78.5% prevalence of OUD and a much larger low-risk subset with 1.2% prevalence of OUD. ConclusionsScreening for subjective responses can identify high-risk individuals who would benefit from tailored interventions.

Introduction The market shift from heroin to illicitly-manufactured-fentanyl in North America led to surging opioid mortality. However, limited information exists about the doses of illicit fentanyl regularly consumed. We examined purity of fentanyl samples and estimate the typical daily oral milligrams of morphine equivalent (MME). Methods Leveraging community-based drug checking data from Los Angeles, we ascertained the purity of 509 samples of fentanyl collected between September 2023 and January 2026 using liquid chromatography mass spectrometry. We assessed typical consumption quantity and routes of administration among 47 respondents who reported regularly using fentanyl. We estimate bioavailability and MME conversion factors from literature. To estimate daily MME, incorporating all parameter uncertainty, we used a bootstrapping model with 1,000,000 draws, with sensitivity analyses to assess the impact of factors including the correlation between purity and quantity. Results Among participants, the mean daily consumption of fentanyl was 1.07 grams (95% prediction interval: 0.03g-4.00g). Illicit fentanyl products had a mean fentanyl purity of 12.47% (0.23%-38.80%), and the mean estimated bioavailability based on routes of administration was 50.82% (30.64%-76.75%). The mean estimated IV fentanyl to PO morphine MME conversion factor was 1:183.15 (1:71.85 - 1:294.21)., The mean estimated daily consumption in our sample was 8,887.55 MME (156.56 MME-41,761.3 MME) Conclusions Under all plausible estimation scenarios, individuals consuming illicit fentanyl in Los Angeles on average use a quantity of MME several orders of magnitude higher than clinical guidelines or typical methadone doses. This likely contributes to high overdose mortality, high opioid tolerance, and more difficult methadone and buprenorphine induction.

IntroductionThe purity, accessibility, and affordability of illicit methamphetamine has 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. MethodsFrom August 2024-April 2025, self-reported daily methamphetamine consumption was assessed among n=68 individuals. Methamphetamine samples (n=112) were analyzed for purity using liquid chromatography-mass spectrometry. Percent bioavailability by route of administration and stimulant equivalency were obtained from literature. A simulation model leveraging bootstrapping was used to estimate MOAE. ResultsThe average reported daily methamphetamine consumption was 0.96g (median 0.36g; range 0.1g-4.0g). Average purity was 71.6% (median 75.5%; range 0.1%-95.0%). Given estimated average bioavailability of 52.0% when smoked, 79.3% when insufflated, 67.2% orally or inserted rectally, and a 2:1 amphetamine-methamphetamine equivalency, the average consumer used 1,549.0 MOAE daily (median 516.6; range 1.3-10,112.0). DiscussionWe estimate that consumers of methamphetamine in Los Angeles use an average daily stimulant dose (>1,500 MOAE) that is 25-fold higher than the maximum typical recommended clinical dose of mixed amphetamine salts (60mg). This may help explain the limited efficacy of prescription stimulant treatment for methamphetamine use disorder, which typically employs considerably lower quantities. Given this high dose, these findings shed light on the rising incidence of methamphetamine-related sequalae, such as psychosis, cardiovascular complications, and sudden death. Although exposure quantification is commonplace for alcohol and tobacco use disorders, uncertainties in illicit drug markets has complicated this practice for most illicit drugs. This study supports leveraging emerging information from drug checking programs so that clinicians can approximate exposure quantification.

BackgroundLong-acting injectable buprenorphine (LAIB) has been positioned as a potentially transformative option for opioid use disorder (OUD), in part because patient experiences reported in qualitative studies emphasize reduced daily burden, increased "freedom," reduced stigma, and fewer pressures related to diversion--while also noting barriers such as insufficient information, early adverse experiences, and concerns about coercion. MethodsWe conducted a cross-sectional online survey of adults recruited from the Behavioral Health Research Panel (BHRP). Eligibility included age [&ge;]18, English literacy, and OUD diagnosis or problematic opioid use within the past 5 years. Survey content assessed buprenorphine experience, knowledge and attitudes toward LAIB, attribute preferences, and open-text feedback. Descriptive statistics were generated; analyses were stratified by buprenorphine experience (experienced vs naive). ResultsAmong 105 participants, 82.9% reported prior buprenorphine use, and 17.1% were buprenorphine-naive. Overall, 53.3% preferred a long-acting injection regimen (weekly/monthly/3-monthly) versus 46.7% preferring a daily oral tablet/film. Convenience and adherence-related themes (e.g., not missing doses, fewer visits) drove LAIB preference, while oral-route preference and concerns about side effects and safety were prominent among those favoring oral formulations. ConclusionsIn this national convenience sample, preferences were nearly evenly split between daily oral and long-acting injectable buprenorphine regimens, with a slight overall preference for LAIB. Findings align with the qualitative literature, emphasizing the practical and psychosocial benefits of LAIB, alongside persistent needs for improved education, shared decision-making, and attention to tolerability, safety perceptions, and cost/coverage barriers.

BackgroundEvaluating the opioid use disorder (OUD) care cascade can improve OUD treatment retention and care. ObjectivesTo identify risk and protective factors for retention among patients in OUD treatment. MethodsWe conducted a retrospective cohort study among patients diagnosed with OUD using data from the Rhode Island (RI) All-Payer Claims Database from 2011 to 2019. Patients who initiated treatment (Stage 2) were classified into sub-stages of retention (Stage 3) corresponding to multistate modeling states capturing early retention (sub-stage 1), short and long-term retention (sub-stage 2), and short and long-term disengagement (sub-stage 3). The association of baseline characteristics with state transitions were evaluated. ResultsA cohort of 6,939 RI residents diagnosed with OUD included 41% aged 40 to 60 years, 57.6% male, and 70.8% Medicaid beneficiaries. In sub-stage 1, cannabis (Relative risk ratios (RRR) = 1.16; 95% confidence interval (CI) = 1.04,1.29) and cocaine use disorders (RRR=1.15; 95% CI=1.05,1.25) increased early disengagement risk after engagement. Medicaid beneficiaries were less likely to experience early disengagement (RRR=0.81; 95% CI =0.76,0.87). In sub-stage 2, alcohol (RRR=1.29; 95% CI=1.13,1.47) or cocaine use disorders (RRR=1.18; 95% CI=1.01,1.40) increased risk of disengagement among patients in the retention states. In sub-stage 3, tobacco (RRR=1.10; 95% CI=1.01,1.21) and alcohol (RRR=1.14; 95% CI=1.03,1.27) use disorders were associated with re-engagement from disengaged states. ConclusionThe multistate model applied to a cohort of patients initiating medication for OUD led to the identification of factors associated with treatment engagement and retention. These results may guide strategies to sustain treatment among OUD patients.

ImportanceHeroin addiction and related mortality impose a devastating toll on society, with little known about the neurobiology of this disease or its treatment. Poor inhibitory control is a common manifestation of prefrontal cortex (PFC) impairments in addiction, and its potential recovery following treatment is largely unknown in heroin (or any drug) addiction. ObjectiveTo study inhibitory control brain activity in iHUD and HC, before and after 15 weeks of inpatient treatment in the former. DesignA longitudinal cohort study (11/2020-03/2022) where iHUD and HC underwent baseline and follow-up fMRI scans. Average follow-up duration: 15 weeks. SettingThe iHUD and HC were recruited from treatment facilities and surrounding neighborhoods, respectively. ParticipantsTwenty-six iHUD [40.6{+/-}10.1 years; 7 (29.2%) women] and 24 age-/sex-matched HC [41.1{+/-}9.9 years; 9 (37.5%) women]. InterventionFollowing the baseline scan, inpatient iHUD continued to participate in a medically-assisted program for an average of 15 weeks (abstinence increased from an initial 183{+/-}236 days by 65{+/-}82 days). The HC were scanned at similar time intervals. Main Outcomes and MeasuresBehavioral performance as measured by the stop-signal response time (SSRT), target detection sensitivity (d, proportion of hits in go vs. false-alarms in stop trials), and brain activity (blood-oxygen level dependent signal differences) during successful vs. failed stops in the stop signal task. ResultsAs we previously reported, at time 1 and as compared to HC, iHUD exhibited similar SSRT but impaired d [t(38.7)=2.37, p=.023], and lower anterior and dorsolateral PFC (aPFC, dlPFC) activity (p<.001). Importantly, at time 2, there were significant gains in aPFC and dlPFC activity in the iHUD (group*session interaction, p=.002); the former significantly correlated with increases in d specifically in iHUD (p=.012). Conclusions and RelevanceCompared to HC, the aPFC and dlPFC impairments in the iHUD at time 1 were normalized at time 2, which was associated with individual differences in improvements in target detection sensitivity. For the first time in any drug addiction, these results indicate a treatment-mediated inhibitory control brain activity recovery. These neurobehavioral results highlight the aPFC and dlPFC as targets for intervention with a potential to enhance self-control recovery in heroin addiction. Key pointsO_ST_ABSQuestionC_ST_ABSDoes inhibitory control brain function, a common impairment in drug addiction, recover with treatment in inpatient individuals with heroin use disorder (iHUD)? FindingsIn this longitudinal cohort study, 26 inpatient iHUD and 24 healthy controls (HC) performed a stop-signal task during functional MRI twice, separated by an average of 15 weeks. In the iHUD, we found lower anterior and dorsolateral prefrontal cortex (comprising the cognitive control network) signaling at baseline, which increased after 15 weeks of treatment, as associated with behavioral improvements. MeaningAs the opioid epidemic continues, our results indicate potential therapeutic targets to enhance neural function underlying self-control in heroin addiction.

BackgroundFactors influencing cessation include biopsychosocial characteristics, treatments and responses to treatment. The first cessation trial designed to assess cessation disparities between African American and White cigarette smokers demonstrated that socioeconomic, treatment, psychosocial and smoking characteristics explained cessation disparities. Ongoing translational efforts in precision cessation treatment grounded in genetically informed biomarkers have identified cessation differences by genotype, metabolism, ancestry and treatment. MethodsIn planned analyses, we evaluated six smoking-related measures, demographic and socioeconomic covariates, and prospective abstinence (7-day point prevalence at 12 weeks with bupropion, nicotine replacement and counseling treatments). We assessed concurrent and predictive validity in two covariate models differing by inclusion of Office of Management and Budget (OMB) race/ethnicity or genomic ancestry. ResultsWe studied Pharmacogenetic Study participants (N=456, mean age 49.5 years, 41.5% female, 7.4% African American, 9.4% Multiracial, 6.5% Other, and 6.7% Hispanic). Cigarettes per day (OR=0.95, P<.001), Fagerstrom score (OR=0.89, P<=.014), Time-To-First-Cigarette (OR=0.75, P<=.005) and predicted urinary nicotine metabolite ratio (OR=0.57, P<=.039) were associated with abstinence. OMB African American race (ORs from 0.31 and 0.35, p-values<=.007) and African genomic ancestry (ORs from 0.21 and 0.26, p-values<=.004) were associated in all abstinence models. ConclusionsFour smoking-related measures exhibited association with abstinence, including predicted nicotine metabolism based on a novel genomic model. African genomic ancestry was independently associated with reduced abstinence. Treatment research that includes social, psychological, treatment and biological factors is needed to reduce cessation disparities. ImplicationsO_LIThis is the first application of a statistical learning model of the urinary nicotine metabolite ratio to cessation. Results are concordant with biochemical and genetic models of the plasma nicotine metabolite ratio in multiethnic samples. C_LIO_LIThe urinary ratio exhibits the largest standardized effect size of four smoking-related measures associated with cessation (time-to-first cigarette, total Fagerstrom score and cigarettes per day were the others). C_LIO_LIThe social construct of African American race and genomic African ancestry are significant covariates in all cessation models. C_LIO_LIResults point to social and biological mechanisms requiring investigation in larger samples to understand and reduce cessation health disparities. C_LI

BackgroundCannabis use is highly prevalent among people who use unregulated drugs. While daily cannabis use has been hypothesized to provide protective effects through substitution or tolerance mechanisms, the relationship between cannabis use frequency and overdose risk remains poorly understood, particularly for infrequent users. MethodsWe conducted a secondary analysis of cross-sectional interview data from people who use unregulated drugs in Vancouver, British Columbia, collected during the fentanyl crisis (November 2019-July 2021; n=657). Binary logistic regression examined associations between self-reported cannabis use frequency (five categories: less than monthly, 1-3 times per month, weekly, more than weekly and daily) and non-fatal overdose in the preceding six months. Daily use served as the reference category. Models adjusted for age, gender, ethnicity, homelessness, mental health, HIV status, incarceration and daily use of alcohol, opioids, fentanyl, cocaine and stimulants. ResultsAmong 657 participants, 95 (14.5%) reported non-fatal overdose in the past six months. In adjusted models with daily cannabis use as the reference, infrequent cannabis use was associated with significantly increased odds of overdose: use 1-3 times per month (aOR=3.17, 95% CI: 1.50-6.69, p=.002) and more than weekly use (aOR=3.13, 95% CI: 1.70-5.76, p<.001) showed approximately three-fold increased odds compared to daily use. Less frequent use showed non-significant trends in the same direction (less than monthly: aOR=1.73, 95% CI: 0.89-3.37, p=.109; weekly: aOR=1.44, 95% CI: 0.59-3.51, p=.421). Sensitivity analysis restricted to participants with daily stimulant or fentanyl use (n=148) revealed even stronger associations. ConclusionsInfrequent cannabis use was associated with substantially increased overdose risk compared to daily use. This frequency-dependent relationship, with infrequent users at highest risk, likely reflects tolerance differences: infrequent users lack tolerance to synergistic cannabis-opioid effects. These findings were completely obscured in preliminary analyses that dichotomized cannabis use as daily versus less-than-daily, demonstrating how analytical choices can mask critical public health insights. Current harm reduction approaches, including cannabis distribution programs, should incorporate frequency-dependent risk communication and develop strategies to protect infrequent users who may be at heightened overdose risk.

ObjectivesPeople experiencing homelessness are at increased risk for addiction, with substance use both a cause and response to homelessness. Street Medicine (SM) programs provide decentralized, low-barrier care to people experiencing homelessness and have begun to offer medication for opioid use disorder (MOUD). Literature on MOUD initiation via SM is nascent. This study investigated the impact of SM-initiated MOUD on ED utilization among people experiencing homelessness in a mid-sized US city. MethodsWe completed a retrospective medical record review of patients initiated on buprenorphine in 2023 by the SM program. Age, gender, prescription refill status, and emergency department (ED) utilization were recorded. Outcome measures were the number of overdose-related, opioid use disorder (OUD)-related, and all-cause ED visits in the 12 months before versus 12 months after buprenorphine initiation. ResultsIn the year prior to buprenorphine initiation, 115 patients had 221 cumulative ED visits, 79 of which were OUD-related. In the year following initiation, cumulative ED visits declined to 191, of which 44 were related to OUD (p<0.05). Overdose-related ED visits decreased from 26 to 13. In terms of prescription renewal, 44% of subjects renewed, 13% via SM and 31% via another provider. ConclusionsBuprenorphine initiation by a SM program was associated with a significant decline in OUD-related ED visits and insignificant reductions in overdose-related and total ED visits. These conclusions support SM-initiated buprenorphine as a strategy for reducing opioid-related ED utilization while encouraging sustained engagement in care. SM programs represent promising avenues to initiate buprenorphine and reduce OUD-related morbidity in the unhoused population.

ImportanceRecently, the Food and Drug Administration gave pre-marketing approval to algorithm based on its purported ability to identify genetic risk for opioid use disorder. However, the clinical utility of the candidate genes comprising the algorithm has not been independently demonstrated. ObjectiveTo assess the utility of 15 variants in candidate genes from an algorithm intended to predict opioid use disorder risk. DesignThis case-control study examined the association of 15 candidate genetic variants with risk of opioid use disorder using available electronic health record data from December 20, 1992 to September 30, 2022. SettingElectronic health record data, including pharmacy records, from Million Veteran Program participants across the United States. ParticipantsParticipants were opioid-exposed individuals enrolled in the Million Veteran Program (n = 452,664). Opioid use disorder cases were identified using International Classification of Disease diagnostic codes, and controls were individuals with no opioid use disorder diagnosis. ExposuresNumber of risk alleles present across 15 candidate genetic variants. Main Outcome and MeasuresPredictive performance of 15 genetic variants for opioid use disorder risk assessed via logistic regression and machine learning models. ResultsOpioid exposed individuals (n=33,669 cases) were on average 61.15 (SD = 13.37) years old, 90.46% male, and had varied genetic similarity to global reference panels. Collectively, the 15 candidate genetic variants accounted for 0.4% of variation in opioid use disorder risk. The accuracy of the ensemble machine learning model using the 15 genes as predictors was 52.8% (95% CI = 52.1 - 53.6%) in an independent testing sample. Conclusions and RelevanceCandidate genes that comprise the approved algorithm do not meet reasonable standards of efficacy in predicting opioid use disorder risk. Given the algorithms limited predictive accuracy, its use in clinical care would lead to high rates of false positive and negative findings. More clinically useful models are needed to identify individuals at risk of developing opioid use disorder. Key PointsO_ST_ABSQuestionC_ST_ABSHow well do candidate genes from an algorithm designed to predict risk of opioid use disorder, which recently received pre-marketing approval by the Food and Drug Administration, perform in a large, independent sample? FindingsIn a case-control study of over 450,000 individuals, the 15 genetic variants from candidate genes collectively accounted for 0.4% of the variation in opioid use disorder risk. In this independent sample, the SNPs predicted risk at a level of accuracy near random chance (52.8%). MeaningCandidate genes from the approved genetic risk algorithm do not meet standards of reasonable clinical efficacy in assessing risk of opioid use disorder.

BackgroundThe variation in purity of illicitly manufactured fentanyl has been theorized to be a key driver of overdose. However, data on the purity of illicitly manufactured fentanyl in the United States typically comes from law enforcement seizures and is rarely available at the consumer-level, which is most relevant to overdose risk. MethodsSamples were analyzed from a community-based drug checking program operating at four geographic sites in Los Angeles County, California 2023 Q1 to 2025 Q2. Participants answered an anonymous survey about sample characteristics. Qualitative and quantitative analyses were conducted leveraging directly-observed mass spectrometry (DART-MS) and Liquid chromatography mass spectrometry (LC/MS) respectively. LC/MS quantified a panel of compounds including fentanyl and fluorofentanyl. Composite fentanyl purity was estimated by adding the percent mass of fentanyl and fluorofentanyl. ResultsA total of 353 samples had either fentanyl, fluorofentanyl, or both, quantified. Average purity was 10.0%, SD 11.1%, range 0.1%-64.9%. Samples expected to be fentanyl (n=308) had higher average purity (10.9%) compared to those expected to be heroin (n=24, average purity=2.7%) or other drugs. Powder samples (n=318) had higher average concentration (10.8%) compared to pills (n=11, 1.4%) or tar (n=22, 3.2%). Of expected-fentanyl samples, 42.5% (n=117) had a fentanyl purity of less than 5%, while 17.5% (n=51) had purity over 20%. ConclusionsWe found high variation in fentanyl purity among consumer-level samples sold as fentanyl, which may explain overdose among people with opioid tolerance. Fentanyl concentration was lower among samples sold as heroin, other drugs, or in pill form, and was particularly low among expected non-opioid drugs.

Background and PurposeFentanyls and nitazenes are opioid receptor agonists responsible for a large number of opioid overdose deaths. Here, we compared the potency, dissociation kinetics and antagonism by naloxone at the receptor of several fentanyl and nitazene analogues and compared them to morphine and DAMGO. Experimental ApproachIn vitro assays of G protein activation and signalling and arrestin recruitment were performed. AtT20 cells expressing receptors were loaded with a membrane potential dye and changes in fluorescence used to determine agonist potency, dissociation kinetics and susceptibility to antagonism by naloxone. BRET experiments were undertaken in HEK293T cells expressing opioid receptors, to assess Gi protein activation and {beta}-arrestin 2 recruitment. Key ResultsThe rate of agonist dissociation from the receptor varied, with morphine, DAMGO, alfentanil and fentanyl dissociating rapidly whereas isotonitazene, etonitazene, ohmefentanyl and carfentanil dissociated slowly. Slowly dissociating agonists were more resistant to antagonism by naloxone. For carfentanil, the slow rate of dissociation was not due to G protein receptor kinase-mediated arrestin recruitment as its rate of dissociation was not affected by inhibition of GRKs with Compound 101. The in vitro relative potencies of fentanyls and nitazenes compared to morphine were much lower than that previously observed in in vivo experiments. Conclusions and ImplicationsWith fentanyls and nitazenes, that slowly dissociate from the opioid receptor, antagonism by naloxone is pseudo competitive. In overdoses involving fentanyls and nitazenes higher doses of naloxone may be required for reversal than those normally used to reverse heroin overdose. What is already knownO_LI"Fentanyls" and "nitazenes" are potent agonists at the opioid receptor. C_LI What does this study addO_LISome fentanyls and nitazenes dissociate slowly and are less sensitive to naloxone antagonism C_LI What is the clinical significanceO_LIMore naloxone may be required to reverse overdoses involving fentanyls and nitazenes C_LI

BackgroundIntravenous self-administration (IVSA) of opioids by rats has been shown frequently to exhibit no sex differences, in many cases a higher intake of females, and only rarely higher rates in males. A diversity of methodological parameters (opioid identity, training doses, rat strain, session duration) makes it difficult to identify consistent contributions to these outcomes. ObjectiveTo determine if Heterogeneous Stock (HS) rats derived from 8 founder strains differ by sex in the IVSA of opioids. MethodsMale and female Heterogeneous Stock (N=7-8 per sex) rats were permitted to self-administer heroin (20 {micro}g/kg/infusion) in 2 hour sessions under a Fixed Ratio 1 schedule of reinforcement. After acquisition, animals completed sessions in which different infusion doses of heroin (0, 15, 30, 60, 120 {micro}g/kg/infusion), oxycodone (0, 30, 60, 150, 300 {micro}g/kg/infusion) and fentanyl (0, 0.625, 1.25, 2.5, 5.0 {micro}g/kg/infusion) were assessed. Next, animals were evaluated on doses of heroin (15, 30, 60, 120 {micro}g/kg/infusion), oxycodone (30, 60, 150, 300 {micro}g/kg/infusion) and fentanyl (0.625, 1.25, 2.5, 5.0 {micro}g/kg/infusion) under a Progressive Ratio schedule. Anti-nociceptive effects of heroin (0.56-2.4 mg/kg, s.c.) were examined with a warm water tail-withdrawal assay. ResultsFemale HS rats consistently self-administered more infusions of opioids, including heroin during acquisition, all three opioids during FR-1 dose substitution and of oxycodone and fentanyl in the PR procedure. Male rats were moderately more sensitive to the anti-nociceptive effects of heroin. ConclusionsFemale rats drawn at random from a genetically diverse population self-administer opioids at higher rates than their male counterparts.

Background and AimsAlcohol use disorder (AUD) remains a major public health concern, with persistent disparities in access to evidence-based treatment. This study aimed to examine associations between perceived discrimination in healthcare settings (PDHS), patient-clinician communication (PCC), and receipt of treatment for AUD, and compared these with sociodemographic and insurance-related factors. DesignCross-sectional analysis using structural equation modeling (SEM), logistic and multinomial logistic regression, and machine learning approaches including SHapley Additive exPlanations (SHAP). SettingUnited States, using data from the National Institutes of Health All of Us Research Program. ParticipantsA total of 5,287 adults with AUD (mean age 61 years; 57% men), including 71.6% non-Hispanic White, 12.2% Black, and 8.6% Hispanic participants. Insurance coverage included 52% government (Medicaid/Medicare), 37% private, and 21% military with 19% reporting more than one type. MeasurementsPrimary outcomes were receipt of Food and Drug Administration-approved pharmacotherapy and/or psychotherapy for AUD, examined as binary and multinomial outcomes. The primary exposure was PDHS, measured using a 7-item scale (range 7-35), with higher scores indicating more frequent discrimination. PCC, assessed using a 2-item scale (range 2-8) with higher scores indicating poorer communication, was examined as a potential mediator. Models were adjusted for age group, sex at birth, race/ethnicity, insurance type (government, private, military), household income, and Alcohol Use Disorders Identification Test-Consumption (AUDIT-C) scores (range 0-12). FindingsPDHS was associated with poorer PCC ({beta} = 0.209, p < 0.001), although communication was not independently associated with treatment receipt. The indirect pathway from discrimination to treatment via communication was not supported. Military insurance was the strongest predictor of treatment receipt, with 6-7 times higher odds compared with other insurance types. Higher AUDIT-C scores and greater PDHS were also associated with increased likelihood of treatment. In analyses restricted to civilian participants, PDHS showed a stronger association with treatment receipt, while PCC demonstrated more modest effects. Machine learning models identified PDHS, AUDIT-C, and PCC as strong contributors, with the impact of poor communication most pronounced among individuals with lower income. ConclusionsAccess to treatment for alcohol use disorder is most strongly associated with insurance coverage, particularly military insurance. PDHS and PCC also contribute to treatment engagement, with differential effects across socioeconomic groups. These findings highlight the importance of addressing structural and interpersonal barriers to improve equitable access to evidence-based AUD treatment.