Estrogen receptor beta signaling enhances extinction memory recall for heroin-conditioned cues in a sex- and region-specific manner.

Return to use, or relapse, is a major challenge in the treatment of opioid use disorder (OUD). Relapse can be precipitated by several factors, including exposure to drug-conditioned cues. Identifying successful treatments to mitigate cue-induced relapse has been challenging, perhaps due to extinction memory recall (EMR) deficits. Previously, inhibition of estradiol (E2) signaling in the basolateral amygdala (BLA) impaired heroin-cue EMR. This effect was recapitulated by antagonism of BLA estrogen receptors (ER) in a sex-specific manner such that blocking ERα in males, but ERß in females, impaired EMR. However, it is unclear whether increased E2 signaling, in the BLA or systemically, enhances heroin-cue EMR. We hypothesized that ERß agonism would enhance heroin-cue EMR in a sex- and region-specific manner. To determine the capacity of E2 signaling to improve EMR, we pharmacologically manipulated ERß across several translationally designed experiments. First, male and female rats acquired heroin or sucrose self-administration. Next, during a cued extinction session, we administered diarylpropionitrile (DPN, an ERß agonist) and tested anxiety-like behavior on an open field. Subsequently, we assessed EMR in a cue-induced reinstatement test and, finally, measured ERß expression in several brain regions. Across all experiments, females took more heroin and sucrose than males and had greater responses during heroin-cued extinction. Administration of DPN in the BLA enhanced EMR in females only, driven by ERß's impacts on memory consolidation. Interestingly, however, systemic DPN administration improved EMR for heroin cues in both sexes across several different tests, but did not impact sucrose-cue EMR. Immunohistochemical analysis of ERß expression across several different brain regions showed that females only had greater expression of ERß in the basal nucleus of the BLA. Here, in several preclinical experiments, we demonstrated that ERß agonism enhances heroin-cue EMR and has potential utility in combatting cue-induced relapse.

Novel psychoplastogen DM506 reduces cue-induced heroin-seeking and inhibits tonic GABA currents in the Prelimbic Cortex.

Opioid use disorder is a major public health crisis that is manifested by persistent drug-seeking behavior and high relapse frequency. Most of the available treatments rely on targeting opioid receptors using small molecules that do not provide sustained symptom alleviation. Psychoplastogens are a novel class of non-opioid drugs that produce rapid and sustained effects on neuronal plasticity, intended to produce therapeutic benefits. Ibogalogs are synthetic derivatives of iboga alkaloids that lack hallucinogenic or adverse side effects. In the current study, we examine the therapeutic potential of DM506, a novel ibogalog lacking any cardiotoxic or hallucinogenic effects, in cue-induced seeking behavior following heroin self-administration. At a single systemic dose of 40 mg/kg, DM506 significantly decreased cue-induced seeking in both male and female rats at abstinence day 1 (AD1) following heroin self-administration. Upon re-testing for cue-induced seeking at AD14, we found that males receiving DM506 continued to show decreased cue-induced seeking, an effect not observed in females. Since there is evidence of psychedelics influencing tonic GABA currents, and opioid and psychoplastogen-mediated neuroadaptations in the medial prefrontal cortex (PrL) underlying its functional effects, we performed patch-clamp recordings on PrL slices of drug-naïve rats with an acute application or chronic incubation with DM506. Tonic GABA current was decreased in slices incubated with DM506 for 2 h. qPCR analysis did not reveal any differences in the mRNA levels of GABAA receptor α and δ subunits at AD14 in heroin and saline self-administered animals that received vehicle or DM506 at AD1. Overall, our data indicate that DM506 attenuates cue-induced heroin seeking and inhibits tonic GABA current in the prelimbic cortex.

A novel tramadol-polycaprolactone implant could palliate heroin conditioned place preference and withdrawal in rats: behavioral and neurochemical study.

Drug dependence is a chronic brain disease characterized by craving and recurrent episodes of relapse. Tramadol HCl is a promising agent for withdrawal symptoms management, considering its relatively low abuse potential and safety. Oral administration, however, is not preferred in abstinence maintenance programs. Introducing an implantable, long-lasting formula is suggested to help outpatient abstinence programs achieve higher rates of treatment continuation. Tramadol implants (T350 and T650) were prepared on polycaprolactone polymer ribbons by the wet method. Male Wistar rats were adapted to heroin-conditioned place preference (CPP) at escalating doses (3-30 mg/kg, intraperitoneally, for 14 days). Implants were surgically implanted in the back skin of rats. After 14 days, the CPP score was recorded. Naloxone (1 mg/kg, intraperitoneally) was used to induce withdrawal on day 15, and symptoms were scored. Elevated plus maze and open field tests were performed for anxiety-related symptoms. Striata were analyzed for neurochemical changes reflected in dopamine, 3,4-dihydroxyphenyl acetic acid, gamma-aminobutyric acid, and serotonin levels. Brain oxidative changes including glutathione and lipid peroxides were assessed. The tramadol implants (T350 and T650) reduced heroin CPP and limited naloxone-induced withdrawal symptoms. The striata showed increased levels of 3,4-dihydroxyphenyl acetic acid, and serotonin and decreased levels of gamma-aminobutyric acid and dopamine after heroin withdrawal induction, which were reversed after implanting T350 and T650. Implants restore the brain oxidative state. Nonsignificant low naloxone-induced withdrawal score after the implant was used in naive subjects indicating low abuse potential of the implants. The presented tramadol implants were effective at diminishing heroin CPP and withdrawal in rats, suggesting further investigations for application in the management of opioid withdrawal.

Bedside urine testing for fentanyl in self-reported heroin users in a tertiary Brisbane emergency department.

OBJECTIVE: To determine if patients presenting to our toxicology unit following self-reported heroin use had positive urine immunoassay testing for fentanyl or its analogues. METHODS: Urine samples from consenting patients were tested at the bedside for the presence of opiates or fentanyl and its analogues. RESULTS: Over a 30-month period, 58 patients were recruited. All samples tested positive for opiates, but none tested positive for fentanyl or its analogues. CONCLUSION: In patients presenting to our toxicology unit in Brisbane, we did not find any cases where the urine of patients self-reporting heroin exposure tested positive for fentanyl or its analogues.

Changes in injecting versus smoking heroin, fentanyl, and methamphetamine among people who inject drugs in San Diego, California, 2020-2023.

BACKGROUND: Amidst an increasingly toxic drug supply in North America, people who inject drugs may be transitioning to smoking them. We aimed to assess changes in injecting and smoking opioids and methamphetamine among a cohort of people who inject drugs from San Diego, California. METHODS: Over five six-month periods spanning October 2020-April 2023, we assessed prevalence of injecting and smoking opioids or methamphetamine and whether participants used these drugs more frequently by smoking than injecting. Multivariable Poisson regression via generalized estimating equations was used to examine time trends. RESULTS: Of 362 participants, median age was 40 years; a minority were female (29%), Hispanic/Latinx/Mexican (45%), and housed (33%). Among this cohort, of whom 100% injected (and 84% injected and smoked) in period one (October 2020-April 2021), by period five (November 2022-April 2023), 34% only smoked, 59% injected and smoked, and 7% only injected. By period five, the adjusted relative risk (aRR) of injecting opioids was 0.41 (95% Confidence Interval [CI]: 0.33, 0.51) and the aRR for injecting methamphetamine was 0.50 (95% CI: 0.39, 0.63) compared to period one. Risks for smoking fentanyl rose significantly during period three (aRR=1.44, 95% CI: 1.06, 1.94), four (aRR=1.65, 95% CI: 1.24, 2.20) and five (aRR=1.90, 95% CI: 1.43, 2.53) compared to period one. Risks for smoking heroin and methamphetamine more frequently than injecting these drugs increased across all periods. CONCLUSIONS: Opioid and methamphetamine injection declined precipitously, with notable increases in smoking these drugs. Research is needed to understand the health consequences of these trends.

Prolonged diacetylmorphine take-home during the COVID-19 pandemic-Results of a retrospective cohort study.

BACKGROUND AND AIMS: Legal regulations for dispensing in Swiss heroin-assisted treatment were relaxed during the COVID-19 pandemic, allowing prolonged take-home of up to 7 days instead of two to reduce patient contact and the risk of infection. Our study aimed to measure the consequences of this new practice. DESIGN, SETTING AND PARTICIPANTS: This was a retrospective cohort study set in Switzerland's largest outpatient centre for opioid agonist therapy. One hundred and thirty-four (72.4%) of the 185 patients receiving oral diacetylmorphine (DAM) participated in the study. MEASUREMENTS: Through the utilization of electronic medication prescription and dispensing software, as well as the electronic medical record, the following data were extracted to explore the potential consequences: dose of DAM, the number of antibiotic therapies, emergency hospitalizations and incarcerations. Age, gender, prescriptions for psychotrophic drugs and additional prescription for injectable DAM were tested to assess an increased risk of losing prolonged take-home privileges. Data in the year since prolonged take-home (period 2) were compared with data from the equivalent prior year (period 1). FINDINGS: DAM take-home was not associated with a change in DAM dose (P = 0.548), the number of emergency hospitalizations (P = 0.186) or the number of incarcerations (P = 0.215); 79.1% of all patients were able to maintain their extended take-home privileges. However, patients who had injectable DAM experienced significant reductions in their prolonged take-home privileges. CONCLUSION: Allowing patients to take home oral diacetylmorphine for up to 7 days as treatment for opioid use disorder does not appear to pose any demonstrable health risk. It is generally manageable for the large majority of patients. However, careful consideration of prolonged take-home for patients with additional injectable diacetylmorphine is recommended, as these patients are more likely to lose take-home privileges.

FDA Issues Warning About 'Gas Station Heroin'.

The highly addictive dietary supplement mimics opioid effects.

Pan-striatal reduction in the expression of the astrocytic dopamine transporter precedes the development of dorsolateral striatum dopamine-dependent incentive heroin seeking habits.

The emergence of compulsive drug-seeking habits, a hallmark feature of substance use disorder, has been shown to be predicated on the engagement of dorsolateral striatal control over behaviour. This process involves the dopamine-dependent functional coupling of the anterior dorsolateral striatum (aDLS) with the nucleus accumbens core, but the mechanisms by which this coupling occurs have not been fully elucidated. The striatum is tiled by a syncytium of astrocytes that express the dopamine transporter (DAT), the level of which is altered in individuals with heroin use disorder. Astrocytes are therefore uniquely placed functionally to bridge dopamine-dependent mechanisms across the striatum. Here we tested the hypothesis that exposure to heroin influences the expression of DAT in striatal astrocytes across the striatum before the development of DLS-dependent incentive heroin seeking habits. Using Western-blot, qPCR, and RNAscope™, we measured DAT protein and mRNA levels in whole tissue, culture and in situ astrocytes from striatal territories of rats with a well-established cue-controlled heroin seeking habit and rats trained to respond for heroin or food under continuous reinforcement. Incentive heroin seeking habits were associated with a reduction in DAT protein levels in the anterior aDLS that was preceded by a heroin-induced reduction in DAT mRNA and protein in astrocytes across the striatum. Striatal astrocytes were also shown to be susceptible to direct dopamine- and opioid-induced downregulation of DAT expression. These results suggest that astrocytes may critically regulate the striatal dopaminergic adaptations that lead to the development of incentive heroin seeking habits.

Inhibition of SIRT1 in the nucleus accumbens attenuates heroin addiction-related behavior by decreasing D1 neuronal autophagy.

This study aimed to investigate the effects of SIRT1 modulation on heroin addiction-like behavior and its possible biological mechanisms. Wild-type C57BL/6J and Sirt1loxp/loxp D1-Cre mice were used in this experiment, and Sirt1 loxp/loxp D1-Cre(-) mice were used as a control for conditional knockout mice. Mice were divided into saline control and heroin-dependent groups. Behavioral methods were used to record the withdrawal response, conditioned place preference (CPP) changes, and open field test results. Transmission electron microscopy (TEM) was used to observe the structure of autophagosomes in nucleus accumbens (NAc) neurons. The expression of SIRT1 and autophagy-related proteins and genes, such as LC3Ⅱ, ATG5 , and ATG7 , was detected in the NAc of each mouse group via western blot, real-time quantitative PCR (qPCR) analyzes, and immunofluorescence. The results of this experiment showed that compared with the saline group, mice in the wild-type heroin-dependent group showed marked withdrawal symptoms, with more autophagosomes observed in NAc via TEM. Compared with wild-type and Sirt1loxp/loxp D1-Cre(-) heroin-dependent groups, CPP formation was found to be reduced in the conditional knockout mouse group, with a significant decrease in spontaneous activity. Western blot, qPCR, and immunofluorescence results indicated that the expression of LC3Ⅱ, ATG-5, and ATG-7 was significantly reduced in the NAc of the Sirt1loxp/loxp D1-Cre(+) group. It was still, however, higher than that in the saline control group. These results suggest that inhibition of Sirt1 expression may prevent heroin-induced addiction-related behaviors via reducing D1 neuronal autophagy.

Detection of contraband drugs in forensic-correctional mental health services using TeknoScan-a gas chromatography tool.

Substance misuse is a major problem among individuals involved in forensic-correctional mental health services. Urine drug screening detects substance use and deters the entry of contraband into forensic-correctional units, albeit with limitations. For example, a point-of-care urine sample may not be possible and patients can alter or substitute samples to avoid detection, highlighting the role of ancillary tools to detect contraband substances. This study describes the pattern and types of substances detected from environmental samples using a gas chromatographic analyzer (TeknoScan TSI3000) in forensic-correctional populations to model the benefits of similar tools in similar settings. Samples collected over 18 months (January 2020 to June 2021) by trained staff members using the machine were reviewed. During this period, 217 environmental samples were recorded, and 66 (30%) samples were positive for contraband substances, including tetrahydrocannabinol (25%), methamphetamines (19%), and cocaine (16%). Other substances detected include methylene-dioxymethamphetamine, heroin, morphine, lysergic acid diethylamide, tramadol, and methyl-benzoate. Fewer positive samples were detected, especially during the time corresponding with the COVID-19 restriction on the forensic units. TeknoScan was beneficial as an ancillary tool to detect and deter contraband substances. It also provided evidence for risk management. Adequate training is needed for the successful implementation of the tool.

Co-located Heroin Assisted Treatment within primary care: A preliminary analysis of the implications for healthcare access, cost, and treatment delivery in the UK.

BACKGROUND: The UK is experiencing its highest rate of drug related deaths in 25 years. Poor and inconsistent access to healthcare negatively impacts health outcomes for people who use drugs. Innovation in models of care which promote access and availability of physical treatment is fundamental. Heroin Assisted Treatment (HAT) is a treatment modality targeted at the most marginalised people who use drugs, at high risk of mortality and morbidity. The first service-provider initiated HAT service in the UK ran between October 2019 and November 2022 in Middlesbrough, England. The service was co-located within a specialist primary care facility offering acute healthcare treatment alongside injectable diamorphine. METHODS: Analysis of anonymised health records for healthcare costs (not including drug treatment) took place using descriptive statistics prior and during engagement with HAT, at both three (n=15) and six (n=12) months. Primary outcome measures were incidents of wound care, skin and soft tissue infections (SSTIs), overdose (OD) events, unplanned overnight stays in hospital, treatment engagement (general and within hospital care settings) and ambulance incidents. Secondary outcome measures were costs associated with these events. RESULTS: A shift in healthcare access for participants during HAT engagement was observed. HAT service attendance appeared to support health promoting preventative care, and reduce reactive reliance on emergency healthcare systems. At three and six months, engagement for preventative wound care and treatment for SSTIs increased at the practice. Unplanned emergency healthcare interactions for ODs, overnight hospital stays, serious SSTIs, and ambulance incidents reduced, and there was an increase in treatment engagement (i.e. a reduction in appointments which were not engaged with). There was a decrease in treatment engagement in hospital settings. Changes in healthcare utilisation during HAT translated to a reduction in healthcare costs of 58% within six months compared to the same timeframe from the period directly prior to commencing HAT. CONCLUSION: This exploratory study highlights the potential for innovative harm reduction interventions such as HAT, co-located with primary care services, to improve healthcare access and engagement for a high-risk population. Increased uptake of primary healthcare services translated to reductions in emergency healthcare use and associated costs. Although costs of HAT provision are substantial, the notable cost-savings in health care should be an important consideration in service implementation planning.

Dorsal hippocampal astrocytes mediate the development of heroin withdrawal-enhanced fear learning.

There is a significant co-occurrence of opioid use disorder (OUD) and post-traumatic stress disorder (PTSD) in clinical populations. However, the neurobiological mechanisms linking chronic opioid use, withdrawal, and the development of PTSD are poorly understood. Our previous research has shown that proinflammatory cytokines, expressed primarily by astrocytes in the dorsal hippocampus (DH), play a role in the development of heroin withdrawal-enhanced fear learning (HW-EFL), an animal model of PTSD-OUD comorbidity. Given the role of astrocytes in memory, fear learning, and opioid use, our experiments aimed to investigate their involvement in HW-EFL. Experiment 1 examined the effect of withdrawal from chronic heroin administration on GFAP surface area and volume, and identified increased surface area and volume of GFAP immunoreactivity in the dentate gyrus (DG) following 24-hour heroin withdrawal. Experiment 2 examined astrocyte morphology and synaptic interactions at the 24-hour withdrawal timepoint using an astroglial membrane-bound GFP (AAV5-GfaABC1D-lck-GFP). Although we did not detect significant changes in surface area and volume of GfaABC1D-Lck-GFP labelled astrocytes, we did observe a significant increase in the colocalization of astrocyte membranes with PSD-95 (postsynaptic density protein 95) in the DG. Experiment 3 tested if stimulating astroglial Gi signaling in the DH alters HW-EFL, and our results demonstrate this manipulation attenuates HW-EFL. Collectively, these findings contribute to our current understanding of the effects of heroin withdrawal on astrocytes and support the involvement of astrocytes in the comorbid relationship between opioid use and anxiety disorders.

Glutamatergic neurons in ventral pallidum modulate heroin addiction via epithalamic innervation in rats.

Glutamatergic neurons in ventral pallidum (VPGlu) were recently reported to mediate motivational and emotional behavior, but its role in opioid addiction still remains to be elucidated. In this study we investigated the function of VPGlu in the context-dependent heroin taking and seeking behavior in male rats under the ABA renewal paradigm. By use of cell-type-specific fiber photometry, we showed that the calcium activity of VPGlu were inhibited during heroin self-administration and context-induced relapse, but activated after extinction in a new context. The drug seeking behavior was accompanied by the decreased calcium signal of VPGlu. Chemogenetic manipulation of VPGlu bidirectionally regulated heroin taking and seeking behavior. Anterograde tracing showed that the lateral habenula, one of the epithalamic structures, was the major output region of VPGlu, and its neuronal activity was consistent with VPGlu in different phases of heroin addiction and contributed to the motivation for heroin. VPGlu axon terminals in LHb exhibited dynamic activity in different phases of heroin addiction. Activation of VPGlu-LHb circuit reduced heroin seeking behavior during context-induced relapse. Furthermore, the balance of excitation/inhibition from VP to LHb was shifted to enhanced glutamate transmission after extinction of heroin seeking motivation. Overall, the present study demonstrated that the activity of VPGlu was involved in the regulation of heroin addiction and identified the VPGlu-LHb pathway as a potential intervention to reduce heroin seeking motivation.

Infective Endocarditis in Patients Addicted to Injected Opioid Drugs.

BACKGROUND: Persons who inject drugs and require surgery for infective endocarditis have 2 potentially lethal diseases. Current postoperative rehabilitation efforts seem ineffective in preventing loss to follow-up, injection drug use relapse (relapse), and death. OBJECTIVES: The purpose of this study was to characterize drug use, psychosocial issues, surgical outcome, and postoperative addiction management, as well as loss to follow-up, relapse, and mortality and their risk factors. METHODS: From January 2010 to June 2020, 227 persons who inject drugs, age 36 ± 9.9 years, underwent surgery for infective endocarditis at a quaternary hospital having special interest in developing addiction management programs. Postsurgery loss to follow-up, relapse, and death were assessed as competing risks and risk factors identified parametrically and by machine learning. CIs are 68% (±1 SE). RESULTS: Heroin was the most self-reported drug injected (n = 183 [81%]). Psychosocial issues included homelessness (n = 56 [25%]), justice system involvement (n = 150 [66%]), depression (n = 118 [52%]), anxiety (n = 104 [46%]), and post-traumatic stress disorder (n = 33 [15%]). Four (1.8%) died in-hospital. Medication for opioid use disorder prescribed at discharge increased from 0% in 2010 to 100% in 2020. At 1 and 5 years, conditional probabilities of loss to follow-up were 16% (68% CI: 13%-22%) and 59% (68% CI: 44%-65%), relapse 32% (68% CI: 28%-34%) and 79% (68% CI: 74%-83%), and mortality 21% (68% CI: 18%-23%) and 68% (68% CI: 62%-72%). Younger age, heroin use, and lower education level were predictors of relapse. CONCLUSIONS: Infective endocarditis surgery can be performed with low mortality in persons who inject drugs, but addiction is far more lethal. Risk of loss to follow-up and relapse require more effective addiction strategies without which this major loss to society will continue.

Adult consequences of repeated nicotine and Δ9-tetrahydrocannabinol (THC) vapor inhalation in adolescent rats.

RATIONALE: Use of electronic drug delivery systems (EDDS, "e-cigarettes") to ingest nicotine and Δ9-tetrahydrocannabinol (THC) has surged in adolescents in the USA; five times as many high-school seniors vape nicotine daily using tobacco. At the same time, 19.5% of seniors use cannabis at least monthly, with 12% using EDDS to deliver it. OBJECTIVES: This study was conducted to examine the impact of repeated adolescent vapor inhalation of nicotine and THC in rats. METHODS: Female Sprague-Dawley rats were exposed to 30-min sessions of vapor inhalation, twice daily, from post-natal day (PND) 31 to PND 40. Conditions included vapor from the propylene glycol (PG) vehicle, nicotine (60 mg/mL in the PG), THC (100 mg/mL in the PG), or the combination of nicotine (60 mg/mL) and THC (100 mg/mL). Rats were assessed on wheel activity, heroin anti-nociception and nicotine and heroin vapor volitional exposure during adulthood. RESULTS: Nicotine-exposed rats exhibited few differences as adults, but were less sensitive to anti-nociceptive effects of heroin (1 mg/kg, s.c.). THC- and THC + nicotine-exposed rats were less spontaneously active, and obtained fewer nicotine vapor deliveries as adults. In contrast, THC-exposed rats obtained volitional heroin vapor at rates indistinguishable from the non-THC-exposed groups. Repeated THC exposure also caused tolerance to temperature-disrupting effects of THC (5 mg/kg, i.p.). CONCLUSIONS: These studies further confirm that the effects of repeated vapor exposure to THC in adolescence last into early to middle adulthood, including decreased volitional consumption of nicotine. Effects of repeated nicotine in adolescence were comparatively minor.

Brain-derived neurotrophic factor serum levels as a candidate biomarker for withdrawal in crack heroin dependence.

BACKGROUND: Crack heroin is a novel opiate derivative with highly addictive properties and unfamiliar health consequences. It causes a variety of brain dysfunctions that are mediated by neurochemical alterations and abnormal neuroplasticity. Brain-derived neurotrophic factor (BDNF) is a widely recognized biological marker implicated in the neuropathology of substance use during substance use disorder and withdrawal. Its involvement can significantly contribute to the severity of withdrawal symptoms. Hence, this study aimed to evaluate BDNF levels in crack heroin users before and after withdrawal. METHODS: In this cross-sectional study, 148 male participants were recruited and divided into two groups: persons with crack heroin use disorder (n = 74) and the controls (n = 74). The BDNF serum levels were measured in both crack heroin users and control groups upon hospitalization and again after twenty-one days of withdrawal using the enzyme-linked immunosorbent assay. RESULTS: The results demonstrated that BDNF levels in persons with crack heroin use disorder upon admission were significantly lower than the levels observed upon discharge and in the control group (p < 0.05). Additionally, a significant difference in BDNF levels was found between persons with crack heroin use disorder at admission and discharge (p = 0.038). Furthermore, BDNF levels showed an inverse correlation with the daily dose of substance use (r= -0.420, p = 0.03) and the duration of crack heroin use (r= -0.235, p = 0.001). CONCLUSIONS: A progressive increment in BDNF levels during early detoxification is associated with the daily amount of substance use and the duration of substance use. Our findings suggest that changes in BDNF serum levels during crack heroin use disorder and withdrawal could serve as potential biomarkers for assessing the intensity of withdrawal symptoms and substance use-related behaviors.

The genetic susceptibility analysis of TAAR1 rs8192620 to methamphetamine and heroin abuse and its role in impulsivity.

Abnormal genetic polymorphism of trace amine-associated receptor 1 (TAAR1) rs8192620 site has been confirmed to induce methamphetamine (MA) use and drug craving. However, the genetic susceptibility difference between MA addicts and heroin addicts is unknown. This study evaluated genetic heterogeneity of TAAR1 rs8192620 between MA and heroin addicts and elucidated whether rs8192620 genotypes associated with discrepancy in emotional impulsivity, which would help to instruct individualized treatment in addiction via acting on TAAR1 and evaluate risk of varied drug addiction. Participants consisting of gender-matched 63 MA and 71 heroin abusers were enrolled in the study. Due to mixed drug usage in some MA addicts, MA users were further subdivided into 41 only-MA (only MA taking) and 22 mixed-drug (Magu composed of about 20% MA and 70% caffeine) abusers. Via inter-individual single nucleotide polymorphism (SNP) analysis and two-sample t tests, respectively, the genotypic and Barratt Impulsiveness Scale-11 (BIS-11) scores differences between groups were completed. With following genotypic stratification, the differences in BIS-11 scores between groups were analyzed through two-sample t test. Individual SNP analysis showed significant differences in alleles distribution of rs8192620 between MA and heroin subjects (p = 0.019), even after Bonferroni correction. The TT homozygotes of rs8192620 dominated in MA participants, while C-containing genotypes in heroin (p = 0.026). There was no association of genotypes of TAAR1 rs8192620 with addicts' impulsivity. Our research indicates that the TAAR1 gene polymorphism might mediate the susceptibility discrepancy between MA and heroin abuse.

Correlates of Stimulant Use among People Who Use Heroin Undergoing Treatment in Out-Patient Facilities in France, 2010-2020.

Background: Polydrug use has been implicated in driving a "fourth wave" of the overdose crisis in North America, specifically through concurrent use of stimulants and opioids, especially fentanyl. In France, however, heroin has historically been and remains the easiest-to-access opioid, accounting for most drug treatment demand. Whether similar polydrug use is increasing in Western Europe remains understudied, despite severe health implications and potential inadequate public health responses.Methods: We take advantage of a nation-wide dataset containing information on all patients serviced in treatment centers in France from 2010 to 2020. We conduct Poisson regression to determine the main predictors of stimulant use among people who use heroin (PWUH) and opioids (PWUO) generally.Results: Heroin remains the primary opioid within drug treatment in France. A decreasing number of out-patients seeking treatment for heroin use has been accompanied by an increasing trend of stimulant use over time, most commonly with powder cocaine. Our results suggest a significant increase of crack cocaine use among the most vulnerable PWUH. Concurrent use of stimulants among PWUH was positively associated with use of alcohol, cannabis, unprescribed psychotropics and hallucinogens, and negatively with tobacco. Similar results were found for all in-treatment PWUO.Conclusions: Our results uncover heterogeneity in the profiles of PWUH that should be fully acknowledged to ensure better efficiency in substance use clinical practices and policy, while simultaneously drawing attention to trends in concurrent opioid-stimulant use outside North America. We advocate for an extension of the generalized risk framework and its implementation in prevention programs.