Drug and Alcohol Dependence

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.

BackgroundIn response to the recent and growing shift from injecting opioids to smoking fentanyl, an increasing number of syringe services programs (SSPs) in the USA are distributing safer smoking supplies. A recent federal ban prevents SSPs from using federal funding to procure safer smoking supplies. There is a lack of research on safer smoking supply distribution and harm reduction outcomes. Therefore, we assessed the relationship between distribution of safer smoking supplies by SSPs and levels of participant engagement and naloxone distribution. MethodsWe used data from the 2023 National Survey of Syringe Services Programs (NSSSP) (N=429), which measured services delivered in 2022. SSPs reported whether they distributed safer smoking pipes (yes/no). We examined the relationship between safer smoking pipe distribution and two outcomes: the number of participant encounters and naloxone doses distributed. ResultsThere were 187 SSPs (43.6%) that distributed pipes for smoking to participants. Compared to SSPs that did not distribute pipes, those that distributed pipes reported more participant encounters (aRR=1.49, 95% CI: 1.09-2.02) and naloxone dose distribution (aRR=1.21, 95% CI: 0.89-1.65), though this latter finding was not statistically significant. ConclusionsFindings showed SSPs distributing safer smoking pipes had more participant engagement and naloxone distribution. To maximize their full individual and population-level health benefits, SSPs should be supported technically, legally, and financially to implement safer smoking supply distribution for their participants. HighlightsO_LIIn 2022, 44% of syringe services programs (SSPs) distributed safer smoking pipes. C_LIO_LIMore community-based organizations distributed pipes than public health or health care programs. C_LIO_LIDistribution of safer smoking pipes was associated with more participant encounters. C_LI

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.

Novel therapies are needed to improve smoking cessation outcomes in people with opioid use disorder (OUD), as they are far more likely to smoke cigarettes (70-90%) compared to the general population (11.6%) and demonstrate poorer response to smoking cessation interventions. This pilot study was the first to explore the impact of a single day (four sessions) of accelerated intermittent theta burst stimulation (iTBS) (1800 pulses/session) versus sham iTBS on the left dorsolateral prefrontal cortex (L.dlPFC) in people with OUD who smoke tobacco cigarettes (n=8 received iTBS, n=7 received sham iTBS). Resting state functional connectivity (rsFC) was acquired at baseline and after the fourth session. Attentional bias for cigarette and opioid cues, and craving assessments were completed at baseline, and after the first and fourth sessions. Connectivity between the L.dlPFC seed and a cluster comprising the left anterior supramarginal gyrus (SMG) showed a significant group x time interaction, with planned comparisons showing a greater increase at follow-up with iTBS compared to sham iTBS (t12=6.37, beta=0.40, p<0.001). Cigarette cue attentional bias showed a significant group x session interaction (t82=2.34, p=0.02), with planned comparisons revealing a decrease after iTBS and an increase after sham iTBS. No effect of iTBS was observed for opioid cue attentional bias. Cigarette craving decreased with both iTBS and sham iTBS but did not show a significant group x session interaction. These results are promising but need to be interpreted with caution, given the limited sample size and multiple comparisons. Future trials could examine the effects of increased doses of iTBS (e.g., more days of accelerated iTBS) to identify the dosing required to promote smoking cessation among individuals with OUD effectively.

The United States is in the midst of an opioid overdose epidemic. A prior report using the Center for Disease Controls Wide-ranging Online Data for Epidemiologic Research (WONDER) database discovered that opioid overdoses decreased by 24.8% from 1999 to 2010 in states with medical cannabis (MC+) relative to those without (MC-). The present study evaluated any differences following MC legislation on WONDER reported opioid overdoses, corrected for population, from 1999 to 2017 using an interrupted time series. Overdoses were significantly higher in MC+ states from 2012-2017. The slope of opioid overdose deaths over time increased significantly post-implementation in states without MC (3-years Pre = 0.1 {+/-} 0.1, 3-years Post = 0.7 {+/-} 0.2, t(16) = 2.88, p [&le;] .011). Overdose deaths showed a non-significant elevation in states with MC (Pre = 1.3 {+/-} 0.3, Post = 2.8 {+/-} 0.8, t(11) = 2.01, p = .069). Post-legalization slopes were significantly higher in MC+ than MC- (t(11.95) = 2.70, p < .05). Overall, any impact of medical cannabis laws on opioid overdoses appears modest. There are other confounds (e.g. death determination reporting quality) which differ non-randomly among states and are non-trivial to account for in ecological investigations of cannabis policy. Alternatively, the potency of fentanyl analogues may obscure any protective effects of MC against illicit opioid harms.

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.

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.

Polysubstance use is rising and linked to heightened overdose rates and increased treatment challenges, further exacerbated by increasing detection of adulterants (e.g., xylazine) in the street drug supply. Harm reduction groups provide sterile syringes in exchange for used ones, creating a unique opportunity to characterize prevalent polysubstance combinations and inform translational and preclinical research We analyzed residues from used syringes (N=3,168) obtained from several harm reduction organizations in Jefferson County, KY (Jan-Dec 2025) for the presence of substances using gas chromatography mass spectrometry (GC-MS). We classified compounds as adulterants (e.g., diphenhydramine [DPH]/Benadryl), byproducts/precursors of synthesis (e.g., 4-ANPP), and recreational drugs (e.g., meth). We excluded byproducts/precursors and determined the most frequent substance and pairs/trios containing one or more recreational substance. Results. Of 3,168 syringes, 2,522 (79.61%) tested positive for substances. Out of those positive, the top recreational substances were meth (n=1,387; 54.99%), fentanyl (n=1,220; 48.37%), and heroin (n=653; 25.89%). Top adulterants were DPH (n=1021; 40.48%), dimethyl sulfone (n=749; 29.69%), and lidocaine (n=736; 29.18%). The most common pairs were DPH+fentanyl (n=670; 26.57%), lidocaine+fentanyl (n=659; 26.13%), dimethyl sulfone+meth (n=621; 24.62%), and fentanyl+heroin (n=484; 19.19%). The most common trios were DPH+lidocaine+fentanyl (n=369; 14.63%), DPH+fentanyl+heroin (n=327; 12.97%), lidocaine+fentanyl+heroin (n=297; 11.77%), diphenhydramine+xylazine+fentanyl (n=273; 10.82%), and meth+lidocaine+fentanyl (n=262; 10.39%). Our findings highlight evolving patterns of multiple-opioid and opioid-stimulant polysubstance use, generating insights that can be rapidly applied to strengthen clinical, preclinical, and translational polysubstance research. These insights allow for investigations into biobehavioral mechanisms and consequences of emerging use patterns, accelerating development of novel therapeutics.

BackgroundPeople who inject drugs (PWID) have high overdose risk. To assess the burden of drug overdose among PWID in light of opioid epidemic-associated increases in injection drug use (IDU), we estimated rates of non-fatal and fatal overdose among PWID living in Organization for Economic Cooperation and Development (OECD) countries using data from 2010 or later. MethodsPubMed, Psych Info, and Embase databases were systematically searched to identify peer-reviewed studies reporting prevalence or rates of recent (past 12 months) fatal or non-fatal overdose events among PWID in OECD countries. Data were extracted and meta-analyzed using random effects models to produce pooled non-fatal and fatal overdose rates. Results57 of 13,307 identified reports were included in the review, with 33/57 studies contributing unique data and included in the meta-analysis. Other (24/57) studies presented overlapping data to those included in meta-analysis. The rates of non-fatal and fatal overdose among PWID in OECD countries were 24.74 per 100 person years (PY) (95% CI: 19.86 - 30.83; n=28; I2=98.5%) and 0.61 per 100 PY (95% CI: 0.32 - 1.16; n=8; I2=93.4%), respectively. The rate of non-fatal overdose was 27.79 in North American countries, 25.71 in Canada, 28.59 in the U.S., and 21.44 in Australia. ConclusionThese findings suggest there is a fatal overdose for every 40 non-fatal overdose events among PWID in OECD countries. The magnitude of overdose burden estimated here underscores the need for expansion of overdose prevention and treatment programs and serves as a baseline estimate for monitoring success of such programs.

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.

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.

IntroductionMedical cannabis use has expanded rapidly, yet long-term real-world safety data remain limited. We evaluated adverse-event (AE) frequency, severity, and predictors in a US telehealth registry of medical cannabis patients over one year. MethodsWe analyzed 14,313 adults who completed intake between June-August 2024. Patients reported any of 30 prespecified adverse events (AEs) and rated each on a 0-10 impact scale. Weekly exposure was estimated as (days/week) x (serving size) and categorized into quintiles. We computed AE rates per 100 patients with binomial 95% confidence intervals (CI) and tested linear trends. Univariate logistic regressions assessed 20 candidate predictors within chronic-pain and anxiety subgroups. We then applied LASSO to select multivariate predictors, combining these with age, sex, race/ethnicity, smoking, and unhealthy-weeks in final logistic models. Marginal predicted-probability curves were generated across exposure, stratified by subgroup, sex, race, and age. ResultsOverall, 2.6% of patients reported [&ge;]1 AE. The most common symptoms were increased appetite (23.8%), fatigue (20.3%), and anxiety (19.9%) with mean impact <4/10. In adjusted models, having been to the doctor because of their condition remained the sole AE predictor for patients with anxiety (OR 4.03, 95% CI: 2.44-6.87); age was a significant predictor for patients with chronic pain (OR 0.981, 95% CI: 0.97-0.99). Marginal curves remained flat ([~]2-3% AE probability) across weekly cannabis exposure. Ad hoc analysis of non-missing-at-random data suggests possible AE rates are in line with current literature. DiscussionIn this large cohort, AEs were infrequent and mild, and weekly cannabis frequency did not independently increase odds. Healthcare engagement likely reflects underlying health complexity driving AE reporting. These findings support the safety of medical cannabis.

BackgroundEvidence indicates that prescription drug monitoring programs (PDMPs) reduce demand for substance use disorder (SUD) treatment among the general population, perhaps by minimizing the risk of SUD onset through limiting access to prescribed opioids. Little is known about PDMP effects on SUD treatment among people who inject drugs (PWID), a population at high overdose risk. MethodsUsing four waves (2012, 2015, 2018, and 2022) of National HIV Behavioral Surveillance (NHBS), we conducted two-way fixed-effect modelling of associations of state-level "mandated review" PDMP policies and individual-level (1) SUD treatment utilization, and (2) unmet demand for SUD treatment among 24,518 PWID in 13 states. We tested effect modification by race/ethnicity. ResultsPDMPs were associated with an 8 percentage-point increase in the probability of unmet demand for SUD treatment in the sample as a whole (95% CI: 3.0, 12.0). PDMP implementation was also associated with an increased Black, Indigenous, Latinx, and other people of color (BILPOC) vs. White gap in the probability of unmet demand, from a 3.0 percentage-point gap in non-PDMP states (95% CI: 1.0, 5.0) to a 9 percentage-point gap in PDMP states (95% CI: 7.0, 11.0). ConclusionsPDMPs may increase racial/ethnic inequities in SUD treatment access. To strengthen PDMP effectiveness, supply reduction policies must be accompanied by enhanced access to SUD treatment and other services for PWID, particularly among BILPOC PWID.

Background and Aims: The North American overdose crisis is increasingly characterized by complex polysubstance use alongside a transition from injecting to smoking unregulated opioids. However, transitions involving multiple substances remain understudied. We characterized longitudinal transitions in the route of administration and frequency of heroin, fentanyl, and methamphetamine use and examined whether these transitions differed by multilevel factors hypothesized to influence patterns of polysubstance use and routes of administration over time. Design: People who inject drugs (PWID) enrolled in a cohort study completed baseline surveys (October 2020-2021) and three biannual follow-up visits (through April 2023). Setting: San Diego, California, and Tijuana, Baja California. Participants: Among 612 PWID, median age was 43 years; most were male (74%), Hispanic, Latino, or Mexican (72%), and San Diego residents (67%). Measurements: Based on past six-month substance use behaviors reported at each visit, we categorized participants according to six indicators over time: low- (< weekly) and high-frequency ([&ge;] weekly) smoking and injecting of heroin, fentanyl, and methamphetamine. We then used latent transition analysis (LTA) to identify distinct subgroups of participants with respect to these indicators at baseline and examine transitions between them over 18 months. We fit models with 2-5 subgroups, selecting the final model based on fit and interpretability and used multiple-groups LTA to examine differences in subgroup transitions by multilevel factors. Findings: We identified four subgroups: Subgroup 1 (Heroin-Methamphetamine Polyroute), characterized by high-frequency heroin and methamphetamine smoking and injection, included 22% of participants at baseline but 0% at 18 months. Subgroup 2 (Methamphetamine-dominant Smoking), characterized by high-frequency methamphetamine smoking, accounted for 14% of participants at baseline and 18 months. Subgroup 3 (Fentanyl-Methamphetamine Smoking), characterized by high-frequency fentanyl and methamphetamine smoking, included 4% of participants at baseline and 21% at 18 months. Subgroup 4 (Heroin-dominant Injecting), characterized by high-frequency heroin injection, included 61% of participants at baseline and 65% at 18 months. Participants in Subgroup 1 primarily transitioned to Subgroups 3 and 4 over time. Larger increases in Subgroup 3 prevalence occurred for participants who, at baseline, experienced homelessness, resided in San Diego (vs. Tijuana), received syringes from a syringe services program, and overdosed in the past six months. Conclusions: PWID in this region increasingly transitioned from high-frequency heroin and methamphetamine injection toward fentanyl and methamphetamine smoking, likely reflecting shifts in drug availability. Results highlight the need for multilevel interventions that address health harms resulting from polysubstance smoking alongside continued injection.

BackgroundAlthough alcohol outlet density (AOD) is associated with drinking behaviors in the general population, little evidence exists about this relationship among people who inject drugs (PWID). Establishing this connection is particularly important, as alcohol use exacerbates the risk of opioid overdose. This study investigated 1) the association between ZIP code-level AOD and binge drinking among PWID who use opioids, and 2) the potential moderating effect of race/ethnicity on the AOD-binge drinking relationship. MethodsThis analysis linked 2018 National HIV Behavioral Surveillance (NHBS) data and 2016 ZIP code-level AOD data from the ZIP Code Business Pattern survey. Hierarchical generalized linear models quantified the association between AOD and binge drinking, overall and by race/ethnicity. ResultsOf 9,660 PWID, 27% reported recent binge drinking. For Hispanic/Latinx and White PWID, increases in AOD were associated with a 1% and 3% increase in the odds of binge drinking, respectively (p < 0.05); AOD was unrelated to binge drinking among Black PWID. However, when AOD was set to the median, binge drinking probability was highest among Black PWID (PP: 0.28, 95% CI: 0.24-0.33). ConclusionsReducing AOD may decrease binge drinking among White and Latinx PWID. Our results suggest, however, that this strategy alone may be not be effective among Black PWID. Holistic strategies targeting structural determinants of alcohol and opioid co-use among Black PWID are needed to address inequities in drug-related harms.

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

Drug overdose deaths in the United States reached record levels during the fentanyl era before recently declining. A plausible hypothesis is that a sudden drop in fentanyl purity beginning in 2023 caused the downturn in overdose mortality. We evaluated this hypothesis by replicating a published analysis with regional overdose data, using models that account for time trends and autocorrelation, and negative control indicators to test for spurious correlation. When fentanyl purity was rising, the national purity series did not track overdose increases in most regions and showed only a modest association in the West. When both purity and mortality later declined, the observed associations were also seen with unrelated macroeconomic indicators that shared the same time pattern. National fentanyl purity alone does not provide a sufficient explanation for recent overdose declines.

BackgroundPeople who inject drugs (PWID) have high risk for overdose, but there are no current estimates of overdose rates in this population. We estimated the rates of non-fatal and fatal overdose among PWID living in the U.S. and comparator countries (Canada, Mexico, United Kingdom, Australia), and ratios of non-fatal to fatal overdose, using literature published 01/01/2010 - 09/29/2023. MethodsPubMed, PsychInfo, Embase, and ProQuest databases were systematically searched to identify publications reporting prevalence or rates of recent (past 12 months) non- fatal and fatal overdose among PWID. Non-fatal and fatal overdose rates were meta-analyzed using random effects models. Risk of bias was assessed using an adapted quality assessment tool, and heterogeneity was explored using sensitivity analyses. ResultsOur review included 143 records, with 58 contributing unique data to the meta- analysis. Non-fatal and fatal overdose rates among PWID in the U.S. were 32.9 per 100 person- years (PY) (95% CI: 26.4 - 40.9; n=28) and 1.7 per 100 PY (95% CI: 0.9 - 3.2; n=4), respectively. Limiting the analysis to data collected after 2016 yielded a non-fatal rate of 41.0 per 100 PY (95% CI: 32.1 - 52.5; n=16) and a fatal rate of 2.5 per 100 PY (95% CI: 1.4 - 4.3; n=2) in the U.S. An estimated 5% of overdoses among PWID in the U.S. result in death. Among the analyzed countries, Australia had the lowest non-fatal and fatal overdose rates and the largest ratio of non-fatal to fatal overdose. ConclusionFindings demonstrate substantial burden of non-fatal and fatal overdose among PWID in the U.S. and comparator countries. Scale-up of interventions that prevent overdose mortality and investments in PWID health research are urgently needed.

This study explored whether law enforcement/first responder-reported fentanyl overdose response actions (such as administration of the opioid overdose reversal agent naloxone) differed between overdoses in which xylazine was, versus was not, suspected to be co-involved. Data were drawn from the Pennsylvania State Polices Overdose Information Network (ODIN) for 11,478 suspected fentanyl-involved overdoses, 137 reportedly co-involving xylazine, recorded across Pennsylvania, excluding Philadelphia, January 2018-January 16, 2025. We used relative frequencies, Fishers exact tests, and binomial logistic regression to compare first responders overdose response actions in suspected fentanyl overdoses cases in which xylazine was, versus was not, reportedly co-involved. Naloxone was administered at the scene of 46.0% of the overdoses reportedly involving fentanyl and xylazine, vs. 67.3% of the reported fentanyl-no-xylazine overdoses. Multivariable regression results (among the suspected fentanyl overdoses in ODIN, adjusting for age, sex, race/ethnicity, year, county rurality, and other drugs suspected to be involved) indicated that suspected xylazine co-involvement was associated with 60% lower odds of naloxone administration (Adjusted Odds Ratio, 0.40; 95% Confidence Interval, 0.28-0.57). Observed differences in overdose response based on suspected xylazine co-involvement support the importance of equipping first responders with the tools and training to recognize/manage the distinct challenges of xylazine-fentanyl-involved overdose.

BackgroundIn a profound reversal of prior trends, U.S. drug overdose deaths declined by 26.9% in 2024. Two proposed explanations are: (1) expansion of prevention, treatment, and harm-reduction infrastructure and (2) changes in the illicit fentanyl supply. This study evaluated which hypothesis best aligns with observed changes in drug involvement in overdose mortality. MethodsCDC WONDER multiple-cause-of-death data for 2023 and 2024 were analyzed using complementary approaches. In a preliminary analysis, overdose deaths involving cocaine, methamphetamine, prescription opioids, heroin, and methadone were stratified by fentanyl involvement, and 2024/2023 mortality rate ratios were calculated. The primary analysis used a parsimonious 2x2 design (year x fentanyl involvement) to estimate differential mortality changes. A secondary analysis classified deaths into mutually exclusive strata defined by fentanyl, non-fentanyl opioid, and stimulant involvement, and estimated year-by-drug interaction effects using log-linear Poisson regression. ResultsBetween 2023 and 2024, fentanyl-involved deaths declined by 36.5%; non-fentanyl-involved deaths declined by only 5.3% (p < 0.001). Regression models identified a large year x fentanyl interaction (RR = 0.65), consistent with a fentanyl-specific decline. In contrast, non-fentanyl opioid-involved (RR = 1.04) and stimulant-involved deaths (RR = 1.03) exhibited small relative increases. ConclusionsThe 2023-2024 decline in overdose mortality was confined to fentanyl-involved deaths. These findings are most consistent with supply-side changes affecting fentanyl toxicity rather than more uniform effects of infrastructure expansion. Continued investment in prevention and surveillance, with attention to potential market adaptation toward highly potent synthetic opioids, remains essential.