Modeling Changes of Fatal Xylazine-Involved Drug Overdoses in Connecticut Across Time.

BACKGROUND: Fatal drug overdoses have involved both xylazine and fentanyl. Xylazine is a non-opioid substance used in veterinary medicine. This study aimed to model changes in fatal xylazine-involved drug overdose deaths from 2019 to 2023 in Connecticut using overdose death data from the Office of the Chief Medical Examiner. METHODS: Xylazine-involved drug overdose fatality rates were calculated by number of deaths per year per 100,000 population from 2019 to 2023. We used joinpoint regression modeling to evaluate quarterly overdose rates across age, number of drugs, and drug types with a significance level of p < 0.05. RESULTS: From 2019 to 2023, there were 1116 xylazine-involved fatal overdoses with a cumulative rate of 31.3 deaths per 100,000. Xylazine-involved overdose death rates were significantly higher in Hispanic populations compared to both non-Hispanic White and Black populations (p < 0.05). The joinpoint analyses showed that xylazine-fentanyl mortality rates significantly increased by 0.18 per 100,000 per quarter from 2019 to 2022. Xylazine-fentanyl overdoses involving at least 4 or 5 substances significantly increased. Windham, Hartford, New London, and New Haven counties had the highest xylazine-involved death rates. CONCLUSION: Xylazine-fentanyl deaths increased from 2019 to 2023, and often involved multiple substances (e.g., cocaine, ethanol, benzodiazepines, and oxycodone). Results show Hispanic populations, those aged 35-49, and 50+ experienced high rates of xylazine-fentanyl overdose deaths. Vulnerable populations in Connecticut for special consideration for future intervention and local resource allocation are recommended.

The psychedelic drug DOI reduces heroin motivation by targeting 5-HT2A receptors in a heroin and alcohol co-use model.

There has been a recent renewed interest in the potential use of psychedelic drugs as therapeutics for certain neuropsychiatric disorders, including substance use disorders. The psychedelic drug 2,5-dimethoxy-4-iodoamphetamine (DOI) has demonstrated therapeutic efficacy in preclinical models of opioid use disorder (OUD). Alcohol is commonly co-used in individuals with OUD, but preclinical models that recapitulate this comorbidity are lacking. We developed a polydrug model wherein male and female rats were allowed to self-administer intravenous heroin and oral alcohol (or saccharin control solution) over weeks of behavioral training, and then we conducted a series of progressive ratio tests to assess the animals' motivational state for heroin and alcohol. In this model, motivation for heroin is higher than alcohol, and DOI (0.4 mg/kg) administered prior to testing significantly reduced heroin motivation measured as the animals' break point, or maximum effort the animal is willing to expend to obtain a single infusion of heroin. The 5-HT2A receptor antagonist MDL 100,907 (0.3 mg/kg), but not the 5-HT2C receptor antagonist SB-242084 (0.5 mg/kg), blocked the therapeutic effect of DOI on heroin motivation. No significant effects on alcohol break points were observed, nor did MDL 100,907 or SB-242084 have any effect on break points on their own. These data support the view that psychedelic drugs like DOI may have therapeutic effects on opioid use in individuals with OUD and comorbid alcohol use, by acting as a 5-HT2A receptor agonist.

Changing trends in anabolic-androgenic steroid use within Scottish prisons: Detection, prevalence, and quantitation.

Anabolic-androgenic steroids (AASs) are a subclassification of image performance enhancing drugs (IPEDs). While AAS use is most prevalent among people in athletics, there is also high lifetime prevalence of AAS use among prisoners. This study reports the qualitative detection of AASs in seized samples from the Scottish prisons from 2019-2023. Additionally, methods were developed for the quantitative analysis of AASs using gas chromatography-mass spectrometry (GC-MS) and applied to 61 samples of tablets or powders seized from Scottish prisons between July 2022 and July 2023. Since 2022, there has been an increase in AAS detections in the Scottish prisons. Oxymetholone was the most prevalent AAS, followed by metandienone (methandrostenolone, methandienone), methyltestosterone, oxandrolone, mestanolone (methylandrostanolone), stanozolol, and androstenedione. Multiple AASs were found in 21 samples and 10 samples contained other drugs, including amitriptyline, sertraline, zopiclone, mirtazapine, sildenafil, etizolam, Δ9-tetrahydrocannabinol, and the synthetic cannabinoid MDMB-INACA. Most AAS samples were tablets (77.0%), although they were also detected in powders, herbal material, e-cigarettes, and a fragmented soap bar-type sample. There was a large variation in the concentration of AASs in the tablets and powders seized from the Scottish prisons, demonstrating AASs are another highly variable component of the polydrug use situation in prisons, the effects of which need to be examined further.

Comparing Cannabis Use Motivations and Dependence Across Regular Cannabis Users Who Have or Have Not Recently Used Psilocybin.

Introduction: In Colorado, both cannabis and psilocybin are legal and becoming more commonly used. However, there is almost no research detailing the public health concerns regarding negative outcomes (e.g., dependence) of cannabis and psilocybin co-use and motives that may perpetuate these negative outcomes (e.g., coping, boredom). Methods: Using data from a larger observational study on cannabis and metabolic processes, regular cannabis users (use ≥7 times/month; n = 97, 35.1% female, 89.7% WHITE) who used psilocybin in the past 3 months (n = 34) were compared with those who had not used psilocybin in the past 3 months (n = 63) on cannabis dependence as measured by the Marijuana Dependence Scale and endorsement of 12 cannabis motives from the Comprehensive Marijuana Motives Questionnaire. Correlations between motives and dependence were also examined and compared across groups. Results: Findings revealed that individuals who had recently used psilocybin had greater cannabis dependence scores than those who had not used recently [F (1, 95) = 5.53, p = 0.02], and more strongly endorsed that their cannabis use was motivated by enjoyment [F (1, 91) = 4.31, p = 0.04], boredom [F (1, 91) = 9.10, p < 0.01], and availability [F (1, 91) = 9.46, p < 0.01]. Correlations between dependence scores and coping and boredom motives were also significantly positive for both groups (all p values <0.05) whereas positive correlations with experimentation, celebration, and availability motives were only significant for recent psilocybin users (all p values <0.05). Discussion: These results suggest there are motivational differences for cannabis use among those who co-use cannabis and psilocybin, and there may be a greater risk for harm for these individuals.

Motivation and context of concurrent stimulant and opioid use among persons who use drugs in the rural United States: a multi-site qualitative inquiry.

BACKGROUND: In recent years, stimulant use has increased among persons who use opioids in the rural U.S., leading to high rates of overdose and death. We sought to understand motivations and contexts for stimulant use among persons who use opioids in a large, geographically diverse sample of persons who use drugs (PWUD) in the rural settings. METHODS: We conducted semi-structured individual interviews with PWUD at 8 U.S. sites spanning 10 states and 65 counties. Content areas included general substance use, injection drug use, changes in drug use, and harm reduction practices. We used an iterative open-coding process to comprehensively itemize and categorize content shared by participants related to concurrent use. RESULTS: We interviewed 349 PWUD (64% male, mean age 36). Of those discussing current use of stimulants in the context of opioid use (n = 137, 39%), the stimulant most used was methamphetamine (78%) followed by cocaine/crack (26%). Motivations for co-use included: 1) change in drug markets and cost considerations; 2) recreational goals, e.g., seeking stronger effects after heightened opioid tolerance; 3) practical goals, such as a desire to balance or alleviate the effects of the other drug, including the use of stimulants to avoid/reverse opioid overdose, and/or control symptoms of opioid withdrawal; and 4) functional goals, such as being simultaneously energized and pain-free in order to remain productive for employment. CONCLUSION: In a rural U.S. cohort of PWUD, use of both stimulants and opioids was highly prevalent. Reasons for dual use found in the rural context compared to urban studies included changes in drug availability, functional/productivity goals, and the use of methamphetamine to offset opioid overdose. Education efforts and harm reduction services and treatment, such as access to naloxone, fentanyl test strips, and accessible drug treatment for combined opioid and stimulant use, are urgently needed in the rural U.S. to reduce overdose and other adverse outcomes.

Long-acting injectable depot buprenorphine from a harm reduction perspective in patients with ongoing substance use and multiple psychiatric comorbidities: a qualitative interview study.

BACKGROUND: Long-acting injectable depot buprenorphine may increase access to opioid agonist treatment (OAT) for patients with opioid use disorder in different treatment phases. The aim of this study was to explore the experiences of depot buprenorphine among Swedish patients with ongoing substance use and multiple psychiatric comorbidities. METHOD: Semi-structured qualitative interviews were conducted with OAT patients with experience of depot buprenorphine. Recruitment took place at two OAT clinics with a harm reduction focus, specializing in the treatment of patients with ongoing substance use and multiple comorbidities. Nineteen participants were included, 12 men and seven women, with a mean age of 41 years (range 24-56 years), and a mean of 21 years (5-35 years) of experience with illicit substance use. All participants had ongoing substance use and psychiatric comorbidities such as ADHD, anxiety, mood, psychotic and eating disorders. Interviews were transcribed verbatim. Thematic content analysis was conducted both manually and using qualitative data analysis software. RESULTS: Participants reported social benefits and positive changes in self-perception and identity. In particular, depot buprenorphine contributed to a realization that it was possible to make life changes and engage in activities not related to substance use. Another positive aspect that emerged from the interviews was a noticeable relief from perceived pressure to divert OAT medication, while some expressed the lack of income from diverted oral/sublingual OAT medication as a negative, but still acceptable, consequence of the depot buprenorphine. Many participants considered that the information provided prior to starting depot buprenorphine was insufficient. Also, not all patients found depot buprenorphine suitable, and those who experienced coercion exhibited particularly negative attitudes towards the medication. CONCLUSIONS: OAT patients with ongoing substance use and multiple psychiatric comorbidities reported clear benefits of depot buprenorphine, including changes in self-perception which has been theorized to play an important role in recovery. Clinicians should consider the specific information needs of this population and the extensive diversion of traditional OAT medications in this population to improve the treatment experience and outcomes. Overall, depot buprenorphine is a valuable treatment option for a population in need of harm reduction and may also contribute to psychological changes that may facilitate recovery in those with the greatest need.

Prevalence and factors associated with polydrug use among clients seeking treatment for alcohol misuse.

INTRODUCTION: The aim of this paper was to examine the client and psychosocial characteristics associated with polydrug use in patients with alcohol misuse as their primary drug of concern (PDC) seeking treatment from substance use treatment centres. METHODS: Self-report surveys were undertaken with clients attending 1 of 34 community-based substance use treatment centres across Australia with alcohol as their PDC. Survey items included client's socio-demographic characteristics, level of alcohol dependence, use of other drugs including tobacco, health and wellbeing factors including health-related quality of life. The factors associated with polydrug use (alcohol use concurrent with at least one other drug) were examined. RESULTS: In a sample of 1130 clients seeking treatment primarily for alcohol problems, 71% reported also using another drug. The most frequently used drug was tobacco (50%) followed by cannabis (21%) and benzodiazepines (15%). Excluding tobacco use, 35% of participants reported polydrug use. Factors associated with any polydrug use were younger age, lower education levels, lower levels of mental health related quality of life and housing risk (i.e., risk of eviction or experienced homelessness in past 4 weeks). When tobacco was excluded, factors associated with polydrug use were age, lower physical and mental health-related quality of life, and housing risk. DISCUSSION AND CONCLUSIONS: Most adults seeking treatment for alcohol misuse as their PDC reported using another drug in addition to alcohol. Treatment services should be designed accordingly to maximise the likelihood of treatment engagement and success.

A study into the nature and extent of polydrug use in driving recidivism behavior.

OBJECTIVE: Polydrug use has become a frequent pattern of drug consumption in Europe, and this is considered a particularly dangerous risk factor for impaired driving. In Italy, persons whose license has been revoked or suspended due to the use of psychoactive drugs can reapply for a new driving license, depending on the judgment of the relevant local medical committee (CML). To regain a revoked license, offenders must remain drug free throughout an observation period. An important problem with enforcement of impaired driving is recidivism. The aim of the present study is to analyze the influence of polydrug use on driving recidivism. METHOD: We report the findings of several years' experience at the forensic toxicology laboratory of the University of Macerata. Hair samples collected over a 7-year period by the CML from drug users were analyzed for cocaine, opiates, and cannabis using gas chromatography-mass spectrometry. RESULTS: Three hundred thirty-five of the tested subjects were recidivists. Recidivism was more frequent among monodrug users (81%) compared with polydrug users (19%), but logistic regression showed that polydrug use is certainly a risk factor for recidivism compared to monodrug use (odds ratio [OR] = 1.99). The sex and age distribution of recidivist subjects showed a strong predominance of males in both groups, but there were no sex differences. There were more recidivist polydrug users than recidivist monodrug users in the younger age groups (OR = 2.012). Cocaine use was most prevalent in the recidivist monodrug group. All drugs analyzed were demonstrated to be a risk factor for recidivism among monodrug users, whereas only the cocaine and cannabis combination was shown to be a risk factor for recidivism among polydrug users (OR = 1.65 versus cocaine; OR = 1.30 versus Δ9-tetrahydrocannabinol). Almost all polydrug users became monodrug users, and cocaine was the most frequently detected drug in the subsequent test during the monitoring phase. CONCLUSIONS: Our results show that polydrug use increases the risk of impaired driving recidivism and represents a considerable threat to road safety.

The significance of information variables in polydrug use by adolescents: insights from a cross-sectional study in Tarragona (Spain).

Substance use, especially among adolescents, is a significant public health concern, with profound implications for physical and psychological development. This study aimed to evaluate the quantity and sources of information available to adolescents regarding polydrug use. A cross-sectional survey was conducted in Tarragona involving adolescents with an average age of 16.44 years. This study assessed the number of substances used (alcohol, cigarettes, and cannabis) in the past month, along with information sources related to substance use. Monitored sources (e.g., schools, parents, and mass media) and unmonitored sources (e.g., peers, siblings, internet) were distinguished. In addition, four individual and four environmental control variables were considered. Multinomial logistic regression analysis revealed that incorporating variables related to adolescents' substance use information and its sources enhanced the explanatory model, surpassing control variables. The degree of information about substance use did not significantly explain consumption patterns, but the number of information sources, both monitored and unmonitored, did. The unmonitored sources were associated with increased polydrug use. Conversely, greater reliance on supervised sources for information was linked to reduced single-substance and polydrug use. This protective effect increased with an increase in the number of substances used. In conclusion, information obtained from monitored sources acts as a deterrent to substance consumption, consistent with findings suggesting that greater health literacy among adolescents discourages substance use. Conversely, this study suggests that information from more informal sources may encourage heavier polydrug use, aligning with reports indicating that adolescents with a more comprehensive understanding of substance use consequences tend to engage in heavier drug use.

Impact of OPRM1 (Mu-opioid Receptor Gene) A112G Polymorphism on Dual Oxycodone and Cocaine Self-administration Behavior in a Mouse Model.

The use of mu-opioid receptor (MOP-r) agonists such as oxycodone together with cocaine is prevalent, and deaths attributed to using these combinations have increased. RATIONALE: It is unknown if functional single nucleotide polymorphisms (SNPs), such as the OPRM1 (MOP-r gene) SNP A118G, can predispose individuals to more dual opioid and psychostimulant intake. The dual self-administration (SA) of MOP-r agonists and cocaine has not been thoroughly examined, especially with regard to neurobiological changes. OBJECTIVES: We examined oxycodone SA and subsequent dual oxycodone and cocaine SA in male and female A112G (A/G and G/G, heterozygote and homozygote, respectively) mice, models of human A118G carriers, versus wild-type (A/A) mice. METHODS: Adult male and female A/G, G/G and A/A mice self-administered oxycodone (0.25 mg/kg/infusion, 4hr/session, FR 1.) for 10 consecutive days (sessions 1-10). Mice then self-administered cocaine (2 hr) following oxycodone SA (4 hr, as above) in each session for a further 10 consecutive days (sessions 11-20). Message RNA transcripts of 24 reward-related genes were examined in the dorsal striatum. RESULTS: Male and female A/G and G/G mice had greater oxycodone SA than A/A mice did in the initial 10 days and in the last 10 sessions. Further, A/G and G/G mice showed greater cocaine intake than A/A mice. Dorsal striatal mRNA levels of Pdyn, Fkbp5, Oprk1, and Oprm1 were altered following oxycodone and cocaine SA. CONCLUSIONS: These studies demonstrated that this functional genetic variation in Oprm1 affected dual opioid and cocaine SA and altered specific gene expression in the striatum.

Prevalence and blood concentrations of benzodiazepines and opioids in opioid-positive death investigations in Ontario, Canada, from 2017 to 2021.

The aim of this study was to investigate the incidence of benzodiazepines in opioid-positive death investigations, including trends in frequency and combination of drugs, as well as demographic data and blood concentrations, where available. Additionally, naloxone concentrations in polysubstance compared to opioid-only cases were analyzed. This was a retrospective study that consisted of all post-mortem toxicology cases in Ontario, Canada, from January 01, 2017, to December 31, 2021, with an opioid finding in any analyzed autopsy specimen. There were 11,033 death investigations identified. The overall rate of benzodiazepine co-involvement was 54.5%. Males accounted for the majority of cases (71%), and the most affected age group was 30- to 39-year-olds. The most frequently detected opioid was fentanyl and the most frequently detected benzodiazepine was etizolam, which was also the most frequently observed opioid/benzodiazepine combination. Findings related to differences in concentrations of opioids when naloxone was also present were mostly non-significant, except for methadone. The rate of benzodiazepine detection with opioids grew faster than opioid detections overall, potentially due to the increasingly toxic drug supply. Detection of novel psychoactive drugs fluctuated more unpredictably than opioids and benzodiazepines associated with clinical use. These findings can help inform policy decisions by public health agencies in exploring harm reduction efforts, for example, education and drug-checking services.

Polydrug Use Typologies of Regular Ecstasy Users Visiting Electronic Dance Music Events: A Latent Class Analysis.

INTRODUCTION: Polydrug use patterns among young adults using ecstasy vary, as well as their willingness to change them. Polydrug use patterns are likely associated with different adverse health outcomes. It is unknown whether polydrug use patterns of young adults who use ecstasy are similar in different countries. This study aims to identify and compare polydrug use patterns and willingness to change them of young adults that use ecstasy in the United Kingdom (UK) and the Netherlands (NL), two countries with a high prevalence of ecstasy use and a large electronic dance music (EDM) scene. METHODS: The data from the online cross-sectional Electronic Music Scene Survey were used in a latent class analysis. The binary indicators used in the estimation were past-year substance use of 21 different substances. The sample consisted of young adult ecstasy users that regularly visit EDM events (age 18-34). RESULTS: A total of 1,077 respondents from the UK (age M = 23.1) and 1,178 from the NL (age M = 23.7) that regularly visit EDM events were included in the analyses. In both countries, three polydrug use patterns of ecstasy users were identified based on Bayesian Information Criterion fit indices: a traditional polydrug use class (UK: 28%; NL: 40%), a stimulant and ketamine polydrug use class (UK: 48%; NL: 52%), and an extensive polydrug use class (UK: 24%; NL: 8%) characterized by substantial use of stimulants, depressant, and psychedelic substances. Overall, young adults that used ecstasy in the UK consumed 3,4-methylenedioxymeth-amphetamine (MDMA) more often as powder/crystalline and at higher dosages compared to young adults in the NL who preferred MDMA tablets. Regardless of polydrug class or country, most respondents indicated that they had the intention to reduce but not quit their use. CONCLUSION: In both countries, structurally similar polydrug use patterns among young adults that use ecstasy were found, while the use frequencies of individual substances and preferred MDMA form varied between the countries.

Exploring the Decision-Making Process behind Illicit Drug Use at Music Festivals.

Background: Illicit substance use is common at music festivals. One could question whether festival attendees deliberately plan to take drugs at such events or whether their illicit (poly)drug use is provoked by specific circumstances, such as the presence of peers or a general belief that others are using drugs at the festival. Objectives: The present study implemented the prototype willingness model, which is a model that assesses whether illicit drug use at music festivals is rather a rational or a more spontaneous decision-making process. Results: A three-wave panel survey was conducted, questioning festival attendees before (n = 304, 60.86% males), during, and after music festival visits. In total, 186 people (59.68% males) between 18 and 55 years (M = 27.80 years; SD = 8.19) completed all three surveys, of which 62.9% had taken one or more different illicit substances at the festival. Positive attitudes toward illicit drug consumption were most firmly related to attendees' intentions to take drugs at festivals. Additionally, the more festival visitors identified themselves with the prototype of an attendee using drugs, the more likely they were to be willing to use them. The perceived presence of illicit substances at such events was also strongly related to the actual behavior. Conclusion: The findings suggest that illicit drug use at music festivals relates to both a rational choice and an unplanned one.

Effects of combined exposure to ethanol and delta-9-tetrahydrocannabinol during adolescence on synaptic plasticity in the prefrontal cortex of Long Evans rats.

Significant exposure to alcohol or cannabis during adolescence can induce lasting disruptions of neuronal signaling in brain regions that are later to mature, such as the medial prefrontal cortex (mPFC). Considerably less is known about the effects of alcohol and cannabis co-use, despite its common occurrence. Here, we used male and female Long-Evans rats to investigate the effects of early-life exposure to ethanol, delta-9-tetrahydrocannabinol (THC), or their combination on high frequency stimulation (HFS)-induced plasticity in the prelimbic region of the mPFC. Animals were injected daily from postnatal days 30-45 with vehicle or THC (escalating doses, 3-20 mg/kg) and allowed to drink vehicle (0.1% saccharin) or 10% ethanol immediately after each injection. In vitro brain slice electrophysiology was then used to record population responses of layer V neurons following HFS in layer II/III after 3-4 weeks of abstinence. We found that THC exposure reduced body weight gains observed in ad libitum fed rats, and reduced intake of saccharin and ethanol. Compared to controls, there was a significant reduction in HFS-induced long-term depression (LTD) in rats exposed to either drug alone, and an absence of LTD in rats exposed to the drug combination. Bath application of indiplon or AR-A014418, which enhance GABAA receptor function or inhibit glycogen synthase kinase 3ß (GSK3ß), respectively, suggested the effects of ethanol, THC or their combination were due in part to lasting adaptations in GABA and GSK3ß signaling. These results suggest the potential for long-lasting adaptations in mPFC output following co-exposure to alcohol and THC.

Development of an intervention to manage benzodiazepine dependence and high-risk use in the context of escalating drug related deaths in Scotland: an application of the MRC framework.

BACKGROUND: Scotland has the highest rate of drug related deaths (DRD) in Europe. These are deaths in people who use drugs such as heroin, cocaine, benzodiazepines and gabapentinoids. It is a feature of deaths in Scotland that people use combinations of drugs which increases the chance of a DRD. Many deaths involve 'street' benzodiazepines, especially a drug called etizolam. Many of the 'street' benzodiazepines are not licensed in the UK so come from illegal sources. People who use opiates can be prescribed a safer replacement medication (e.g., methadone). While guidance on management of benzodiazepines use highlights that there is little evidence to support replacement prescribing, practice and evidence are emerging. AIM: To develop an intervention to address 'street' benzodiazepines use in people who also use opiates. METHODS: The MRC Framework for Complex Interventions was used to inform research design. Co-production of the intervention was achieved through three online workshops with clinicians, academics working in the area of substance use, and people with lived experience (PWLE). Each workshop was followed by a PWLE group meeting. Outputs from workshops were discussed and refined by the PWLE group and then further explored at the next workshop. RESULTS: After these six sessions, a finalised logic model for the intervention was successfully achieved that was acceptable to clinicians and PWLE. Key components of the intervention were: prescribing of diazepam; anxiety management, sleep, and pain; and harm reduction resources (locked box and a range of tips), personal safety conversations, as well as a virtual learning environment. CONCLUSION: A co-produced intervention was developed for next stage clinical feasibility testing.

Effects of combined exposure to ethanol and delta-9-tetrahydrocannabinol during adolescence on synaptic plasticity in the prefrontal cortex of Long Evans rats.

Significant exposure to alcohol or cannabis during adolescence can induce lasting disruptions of neuronal signaling in brain regions that are later to mature, such as the medial prefrontal cortex (mPFC). Considerably less is known about the effects of alcohol and cannabis co-use, despite its common occurrence. Here, we used male and female Long-Evans rats to investigate the effects of early-life exposure to ethanol, delta-9-tetrahydrocannabinol (THC), or their combination on high frequency stimulation (HFS)-induced plasticity in the prelimbic region of the mPFC. Animals were injected daily from postnatal days 30 to 45 with vehicle or THC (escalating doses, 3-20 mg/kg) and allowed to drink vehicle (0.1% saccharin) or 10% ethanol immediately after each injection. In vitro brain slice electrophysiology was then used to record population responses of layer V neurons following HFS in layer II/III after 3-4 weeks of abstinence. We found that THC exposure reduced body weight gains observed in ad libitum fed rats, and reduced intake of saccharin and ethanol. Compared to controls, there was a significant reduction in HFS-induced long-term depression (LTD) in rats exposed to either drug alone, and an absence of LTD in rats exposed to the drug combination. Bath application of indiplon or AR-A014418, which enhance GABAA receptor function or inhibit glycogen synthase kinase 3ß (GSK3ß), respectively, suggested the effects of ethanol, THC or their combination were due in part to lasting adaptations in GABA and GSK3ß signaling. These results suggest the potential for long-lasting adaptations in mPFC output following co-exposure to alcohol and THC.

High-risk polysubstance use among LGBTQ+ people who use drugs in the United States: An application of syndemic theory.

BACKGROUND: Compared to heterosexual and cisgender people, lesbian, gay, bisexual, transgender, queer, and other sexual and gender minority (LGBTQ+) people are more likely to develop problems with high-risk polysubstance use. According to syndemic theory, this disparity in high-risk polysubstance use is produced by the LGBTQ+ community's increased vulnerability to experiencing psychosocial (e.g., discrimination, unwanted sex) and structural (e.g., food insecurity, homelessness) conditions, greater likelihood of coping with concurrent health problems (e.g., human immunodeficiency virus [HIV]), and decreased opportunities to develop protective factors (e.g., social support, resilience). METHODS: Data from 306 LGBTQ+ participants living in the United States (U.S.) with a lifetime history of alcohol and drug use were analyzed; 21.2% reported lifetime problems with 10 different drugs. Bootstrapped hierarchical multiple regression was used to test demographic correlates and syndemic predictors of high-risk polysubstance use. One-way ANOVA and post-hoc comparison tests were used to test subgroup differences by gender. RESULTS: Results indicated that income, food insecurity, sexual orientation-based discrimination, and social support were associated with high-risk polysubstance use, explaining 43.9% of the variance of high-risk polysubstance use. Age, race, unwanted sex, gender identity-based discrimination, and resilience were not significant. Group comparison tests revealed that, compared to nonbinary people and cisgender sexual minority men and women, transgender individuals experienced significantly higher levels of high-risk polysubstance use and sexual orientation-based discrimination but significantly lower levels of homelessness and social support. CONCLUSION: This study provided further evidence for conceptualizing polysubstance use as an adverse outcome of syndemic conditions. Harm reduction strategies, anti-discrimination laws, and gender-affirming residential treatment options should be considered in U.S. drug policy. Clinical implications include targeting syndemic conditions to reduce high-risk polysubstance use among LGBTQ+ people who use drugs.

Intermittent theta burst stimulation to the left dorsolateral prefrontal cortex improves cognitive function in polydrug use disorder patients: a randomized controlled trial.

Background: Polydrug abuse is common among opioid users. Individuals who use both heroin and methamphetamine (MA) have been shown to experience a wide range of cognitive deficits. Previous research shows that repetitive transcranial magnetic stimulation (rTMS) can change cerebral cortical excitability and regulate neurotransmitter concentration, which could improve cognitive function in drug addiction. However, the stimulation time, location, and possible mechanisms of rTMS are uncertain. Methods: 56 patients with polydrug use disorder were randomized to receive 20 sessions of 10 Hz rTMS (n = 19), iTBS (n = 19), or sham iTBS (n = 18) to the left DLPFC. All patients used MA and heroin concurrently. Cognitive function was assessed and several related proteins including EPI, GABA-Aα5, IL-10, etc. were quantified by ELISA before and after the treatment. Results: Baseline RBANS scores were lower than normal for age (77.25; IQR 71.5-85.5). After 20 treatment sessions, in the iTBS group, the RBANS score increased by 11.95 (95% CI 0.02-13.90, p = 0.05). In particular, there were improvements in memory and attention as well as social cognition. Following treatment, serum EPI and GABA-Aα5 were reduced and IL-10 was elevated. The improvement of immediate memory was negatively correlated with GABA-Aα5 (r = -0.646, p = 0.017), and attention was positively correlated with IL-10 (r = 0.610, p = 0.027). In the 10 Hz rTMS group, the improvement of the RBANS total score (80.21 ± 14.08 before vs.84.32 ± 13.80 after) and immediate memory (74.53 ± 16.65 before vs.77.53 ± 17.78 after) was statistically significant compared with the baseline (p < 0.05). However, compared with the iTBS group, the improvement was small and the difference was statistically significant. There was no statistically significant change in the sham group (78.00 ± 12.91 before vs.79.89 ± 10.92 after; p > 0.05). Conclusion: Intermittent theta burst stimulation to the left DLPFC may improve cognitive function in polydrug use disorder patients. Its efficacy appears to be better than that of 10 Hz rTMS. The improvement of cognitive function may be related to GABA-Aα5 and IL-10. Our findings preliminarily demonstrate the clinical value of iTBS to the DLPFC to augment neurocognitive recovery in polydrug use disorders.

Tabernanthalog Reduces Motivation for Heroin and Alcohol in a Polydrug Use Model.

Background: The potential use of psychedelic drugs as therapeutics for neuropsychiatric disorders has been limited by their hallucinogenic properties. To overcome this limitation, we developed and characterized tabernanthalog (TBG), a novel analogue of the indole alkaloids ibogaine and 5-methoxy-N,N-dimethyltryptamine with reduced cardiac arrhythmogenic risk and a lack of classical psychedelic drugs-induced sensory alterations. We previously demonstrated that TBG has therapeutic efficacy in a preclinical model of opioid use disorder (OUD) in rats and in a binge model of alcohol drinking in mice. Alcohol is commonly co-used in ∼35-50% of individuals with OUD, and yet, preclinical models that recapitulate this comorbidity are lacking. Methodology: Here we employed a polydrug model of heroin and alcohol couse to screen the therapeutic efficacy of TBG on metrics of both opioid and alcohol seeking. We first exposed rats to alcohol (or control sucrose-fade solution) in the home-cage (HC), using a two-bottle binge protocol, over a period of 1 month. Rats were then split into two groups that underwent self-administration training for either intravenous heroin or oral alcohol, so that we could assess the impact of HC alcohol exposure on the self-administration of each substance separately. Thereafter, rats began self-administering both heroin and alcohol in the same sessions. Finally, we tested the effects of TBG on break points for heroin and alcohol in a progressive ratio test, where the number of lever presses required to obtain a single reward increased exponentially. Results and Conclusion: TBG effectively reduced motivation for heroin and alcohol in this test, indicating its efficacy is preserved in animals with a history of heroin and alcohol polydrug use.

The Effects of Neighborhood Disorder on Polydrug Use: Examining Depressive Symptoms and Deviant Peer Association as Mediating Mechanisms.

Neighborhood disorder is a risk factor for substance use, but research is limited with regard to the effect of such disorder on polydrug use. Further, research on potential mechanisms underlying this relationship is similarly limited. The current study examined the direct effect of neighborhood disorder on drug use variety and examined deviant peer association and depressive symptoms as mediators among a sample of justice-involved youth. The first three waves of the Pathways to Desistance study were analyzed. Generalized structural equation modeling was used to test for direct and indirect effects of interest. A bootstrap resampling process was used to compute standard errors and significance of hypothesized mediation effects. Findings indicated that greater levels of neighborhood disorder were associated with increased drug use variety. This effect was attenuated by 15% when mediating pathways were included in the model. Only deviant peer association significantly mediated this relationship and accounted for the majority of the total mediating effect. These results indicated that justice-involved youth exposed to neighborhood disorder are at elevated risk for polydrug use and that increased deviant peer association helps to explain this relationship.