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This paper deals with the numerical threshold stability of a nonlinear age-space structured heroin transmission model. A semi-discrete system is established by spatially domain discretization of the original nonlinear age-space structured model. A threshold value is proposed in stability analysis of the semi-discrete system and named as a numerical basic reproduction number. Besides the role it plays in numerical threshold stability analysis, the numerical basic reproduction number can preserve qualitative properties of the exact basic reproduction number and converge to the latter while stepsizes vanish. A fully discrete system is established via a time discretization of the semi-discrete system, in which an implicit-explicit technique is implemented to ensure the preservation of the biological meanings (such as positivity) without CFL restriction. Some numerical experiments are exhibited in the end to confirm the conclusions and explore the final state. • A numerical scheme is constructed for nonlinear age-structured reaction-diffusion models. • A numerical stability threshold is proposed in numerical stability analysis. • The numerical stability threshold we proposed can preserve qualitative properties of the exact stability threshold. [ABSTRACT FROM AUTHOR]

The variation in improvement among individuals with addiction after abstinence is a critical issue. Here, we aimed to identify robust multimodal markers associated with high response to 8-month abstinence in the individuals with heroin use disorder (HUD) and explore whether the identified markers could be generalized to the individuals with methamphetamine use disorder (MUD). According to the median of craving changes, 53 individuals with HUD with 8-month abstinence were divided into two groups: higher craving reduction and lower craving reduction. At baseline, clinical variables, cortical thickness and subcortical volume, fractional anisotropy (FA) of fibers and resting-state functional connectivity (RSFC) were extracted. Different strategies (single metric, multimodal neuroimaging fusion and multimodal neuroimaging-clinical data fusion) were used to identify reliable features for discriminating the individuals with HUD with higher craving reduction from those with lower reduction. The generalization ability of the identified features was validated in the 21 individuals with MUD. Multimodal neuroimaging-clinical fusion features with best performance was achieved an 87.1 ± 3.89% average accuracy in individuals with HUD, with a moderate accuracy of 66.7% when generalizing to individuals with MUD. The multimodal neuroimaging features, primarily converging in frontal regions (e.g., the left superior frontal (LSF) thickness, FA of the LSF-occipital tract, and RSFC of left middle frontal-right superior temporal lobe), collectively contributed to prediction alongside dosage and attention impulsiveness. In this study, we identified the validated multimodal frontal neuroimaging markers associated with higher response to long-term abstinence and revealed insights for the neural mechanisms of addiction abstinence, contributing to clinical strategies and treatment for addiction. [ABSTRACT FROM AUTHOR]

To explore the efficacy and mechanisms of stimulating the nucleus accumbens (NAc) in heroin-addicted mice using focused ultrasound and microbubbles (MBs). The conditioned place preference (CPP) method was employed to establish a heroin-addicted mice model. Mice were randomized into control (C), heroin (H), heroin + ultrasound (H + U) and H + U + MBs. Ultrasound (2 MHz fundamental frequency, 1.34 MPa peak-negative pressure, 1 MHz pulse repetition frequency, 5% duty cycle, 15 min/d, over 2 d) was applied to stimulate the NAc in the latter 2 groups. Whereas H + U + MBs received an injection of sulfur hexafluoride MBs during the stimulation. Subsequently, CPP scores, open-field test (OFT), and elevated plus-maze test (EPMT) were conducted to assess behavioral changes in addiction memory, anxiety and exercise status. HE staining was performed to detect pathological structures. Neurotransmitters such as dopamine (DA), serotonin (5-HT) and glutamate (Glu) were detected using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Transmission electron microscopy (TEM) was used to observe ultrastructural changes of synapses in NAc. Immunohistochemistry (IHC) was utilized to detect Cleaved Caspase-3 in the NAc region. Western blotting (WB) was used to detect the protein expression of Cleaved Caspase-3, Bax and Bcl-2 in NAc. HE staining showed small patches of erythrocyte exudation were observed in the NAc and adjacent areas in H + U + MBs. The CPP scores of H + U + MBs were lower (p < 0.05) than H. After ultrasound treatment, all indices of the OFT and EPMT in H + U + MBs were significantly higher than H (p < 0.05). UPLC-MS/MS revealed that the levels of DA, 5-HT and Glu in H + U + MBs were lower than H (p < 0.01). TEM showed decrease the number of synapses (p < 0.05), and noticeable swelling of mitochondria, membrane damage, as well as damage to the cristae. Further detection by IHC and WB showed that the pro-apoptotic proteins Cleaved Caspase-3 and Bax increased and Bcl-2 decreased as anti-apoptotic proteins after ultrasound combined with MBs (p < 0.05). Focused ultrasound combined with MBs stimulate the NAc can weaken the addictive memory and improve anxiety of heroin-related mice. The mechanical effect of ultrasound combined with the cavitation effect may be a potential treatment for addiction. [ABSTRACT FROM AUTHOR]

Individuals with opioid use disorder (OUD) have been reported to show abnormal brain metabolism and impaired coupling among brain networks such as the default mode network (DMN), salience network (SN), and executive control network (ECN). However, the characteristics of brain glucose metabolism and its related functions in the brain networks in individuals with OUD remain unknown. Thirty-six individuals with OUD and thirty matched healthy controls (HCs) were recruited in this integrated positron emission tomography/magnetic resonance imaging (PET/MRI) study. Differences in glucose metabolism were analyzed by using 18F-fluorodeoxyglucose (18F-FDG), and the corresponding coupling characteristics of the individuals with OUD were also analyzed. The individuals with OUD showed widespread bilateral hypometabolism in the middle temporal gyrus (MTG), superior temporal gyrus, angular gyrus, supramarginal gyrus, inferior parietal lobe, Rolandic operculum, and left insula, but obvious hypermetabolism in the brainstem and left cerebellum. Meanwhile, in individuals with OUD, the hypometabolism of right MTG which is included in the DMN was accompanied by decreased coupling with the left superior frontal gyrus and right superior parietal gyrus which are included in the ECN. Furthermore, individuals with OUD showed a positive correlation between the duration of heroin use and glucose metabolism of the left MTG. The individuals with OUD were characterized by widespread bilateral hypometabolism in the temporal and parietal regions but obvious hypermetabolism in the brainstem and left cerebellum. The results suggest that the hypometabolism in the temporal and parietal regions might be related to DMN dysfunction and the hypermetabolism in the brainstem and left cerebellum may be compensate for other brain regions showing hypometabolism. In particular, hypometabolism in the self-referential-related DMN regions in OUD might attenuate their relationships with the inhibitory-control-related ECN regions. These findings highlight the importance of evaluating the metabolic and functional profiles of the right MTG in future studies on the treatment of OUD. [ABSTRACT FROM AUTHOR]

Opioid-involved deaths are continuing to increase across the United States, exceeding 100,000 for the first time in 2021. Contamination with, and intentional use of, synthetic opioids such as fentanyl are a major driver of this increase. Utilizing self-report substance use data of patients being treated in the emergency department (ED) can be useful to determine which substances patients are intentionally seeking. 1) Examine changes in self-reported illicit substance use (including fentanyl) over time; 2) Examine changes in the co-occurrence of self-reported fentanyl with other illicit substance use over time. All patients presenting to the study EDs that answered anything other than "never" on the National Institute on Drug Abuse Quick Screen and were seen by a peer recovery specialist in the ED between July 1, 2020 and December 31, 2022 were included for analysis. The substance of use as reported by each patient was recorded by the peer recovery specialist. Differences in substance use by type over time were examined using chi-squared tests of proportions. There were 7568 patients that met inclusion criteria. Self-reported fentanyl (1760%; p < 0.0001) and cocaine (82%; p = 0.034) use increased, whereas heroin use (16%; p < 0.0001) decreased. Self-reported fentanyl and cocaine use has increased significantly in South Carolina ED patients between 2020 and 2022. Given the high morbidity and mortality associated with fentanyl and fentanyl analog use, further measures to identify these patients and provide harm reduction and treatment from the ED setting are warranted. [ABSTRACT FROM AUTHOR]

Opioid overdose deaths in 2021 were the highest ever, driven by fentanyl and polysubstance use. The aim of the study was to characterize drug use, assessed by urine drug screens (UDSs), in patients with untreated opioid use disorder (OUD) presenting to 28 emergency departments (EDs) nationally and by region. We analyzed UDSs from patients enrolled in the CTN-0099 ED-INNOVATION (Emergency Department-Initiated Buprenorphine Validation) trial between July 12, 2020 and March 9, 2022. Participants were adult ED patients with OUD not engaged in addiction treatment with a UDS positive for an opioid, but negative for methadone. Sites were divided into "East" and "West" regions. A UDS was available for all 925 enrolled participants, 543 from East and 382 from West. Fentanyl was in 702 specimens (76%) (n = 485 [89%] East vs. n = 217 [57%] West; p < 0.01) and was the only opioid in 269 (29%). After fentanyl, the most common opioids were morphine (presumably heroin; n = 411 [44%]; n = 192 [35%] East vs. n = 219 [57%] West; p < 0.01) and buprenorphine (n = 329 [36%]; n = 186 [35%] East vs. n = 143 [37%] West; p = 0.32). The most common drugs found with opioids were stimulants (n = 545 [59%]), tetrahydrocannabinol (n = 417 [45%]), and benzodiazepines (n = 151 [16%]). Amphetamine-type stimulants were more common in West (n = 209 [55%] vs. East (n = 125 [23%]). Cocaine was more common in East (n = 223 [41%]) vs. West (n = 82 [21%]). The presence of multiple drugs was common (n = 759 [82%]). Most participants had UDS specimens containing multiple substances; a high proportion had fentanyl, stimulants, and buprenorphine. Regional differences were noted. Given the increased risk of death with fentanyl and polysubstance use, ED providers should be providing risk reduction counseling, treatment, and referral. [ABSTRACT FROM AUTHOR]

Cost-effectiveness analysis of two 12-week contingency management (CM) schedules targeting heroin abstinence or attendance at weekly keyworker appointments for opioid agonist treatment compared with treatment as usual (TAU). A cost-effectiveness analysis was conducted alongside a cluster randomized trial of 552 patients from 34 clusters (drug treatment clinics) randomly allocated 1:1:1 to opioid agonist treatment plus weekly keyworker appointments with (1) CM targeted at heroin abstinence (CM abstinence), (2) CM targeted at on-time attendance at weekly appointments (CM attendance), or (3) no CM (TAU). The primary cost-effectiveness analysis at 24 weeks after randomization took a societal cost perspective with effects measured in heroin-negative urine samples. At 24 weeks, mean differences in weekly heroin-negative urine results compared with TAU were 0.252 (95% confidence interval [CI] −0.397 to 0.901) for CM abstinence and 0.089 (95% CI −0.223 to 0.402) for CM attendance. Mean differences in costs were £2562 (95% CI £32-£5092) for CM abstinence and £317 (95% CI −£882 to £1518) for CM attendance. Incremental cost-effectiveness ratios were £10 167 per additional heroin-free urine for CM abstinence and £3562 for CM attendance with low probabilities of cost-effectiveness of 3.5% and 36%, respectively. Results were sensitive to timing of follow-up for CM attendance, which dominated TAU (better outcomes, lower costs) at 12 weeks, with an 88.4% probability of being cost-effective. Probability of cost-effectiveness remained low for CM abstinence (8.6%). Financial incentives targeted toward heroin abstinence and treatment attendance were not cost-effective over the 24-week follow-up. Nevertheless, CM attendance was cost-effective over the treatment period (12 weeks), when participants were receiving keyworker appointments and incentives. • There is evidence that contingency management (CM) may be an effective strategy in heroin treatment; nevertheless, there is limited evidence of cost-effectiveness. • CM is not a cost-effective strategy for promoting heroin abstinence and treatment engagement in England. • Further research into the duration and the target of incentives is needed before CM could be considered value for money in English drug treatment services. [ABSTRACT FROM AUTHOR]

Recessions, poverty, and unemployment have been associated with opioid use. However, these measures of financial hardship may be imprecise, limiting our ability to understand this relationship. We tested associations between relative deprivation and non-medical prescription opioid use (NMPOU) and heroin use among working-age adults (ages 18–64) during the Great Recession. Our sample included working-age adults in the 2005–2013 United States National Survey of Drug Use and Health (n = 320,186). Relative deprivation compared the lowest limit of participants' income category to the national 25th percentile individual income for people with similar socio-demographic characteristics (race and ethnicity, gender, year). We distinguished the period before (1/2005-11/2007), during (12/2007-06/2009), and after (07/2007-12/2013) the Great Recession. We estimated odds of past-year NMPOU and heroin use for each past-year exposure (i.e., relative deprivation, poverty, unemployment) using separate logistic regressions adjusting for individual-level covariates (gender, age, race/ethnicity, marital status, and education) and national-level annual Gini coefficient. Our results show that NMPOU was higher among people experiencing relative deprivation (aOR = 1.13, 95% CI = 1.06–1.20), poverty (aOR = 1.22, 95% CI = 1.16–1.29), and unemployment (aOR = 1.42, 95% CI = 1.32–1.53) between 2005 and 2013, as was heroin use (aORs = 2.54, 2.09, 3.55, respectively). The association between relative deprivation and NMPOU was modified by recession timing, and was significantly higher after the Recession (aOR = 1.21, 95% CI = 1.11–1.33). Relative deprivation was associated with higher odds of NMPOU and heroin use, and higher odds of NMPOU after the Great Recession. Our findings suggest contextual-level factors may modify the relationship between relative deprivation and opioid use, and support the need for new measures of financial hardship. [ABSTRACT FROM AUTHOR]

As a drug of abuse tightens its hold on addicted individuals, aspects of life that once brought pleasure lose their appeal while attention and motivation are turned toward acquiring drug. In a rodent model of self-administration and reward devaluation, we previously showed that animals that suppress intake of a drug-paired saccharin cue show greater addiction-like behaviors, as well as increased gene-expression of elements of the corticotropin releasing factor (CRF) pathway in the prefrontal cortex (mPFC), hippocampus (Hipp), and ventral tegmental area (VTA). In the present study, we explored whether the observed differences in components of the CRF signaling pathway were a function of self-administration or devaluation of the cue. Moreover, as an increasing body of work illustrates, functional and molecular hemispheric differences in reward pathway components, we examined whether these CRF pathway components exhibited hemispheric differences in response to heroin administration. Over a period of 7 trials, 30 male rats received brief access to saccharin followed by passive (IP) injection of heroin (n = 20) or saline (n = 10). Saccharin intakes between large saccharin suppressors (LS; 12 animals) and small suppressors (SS; 8 animals) were statistically different after trial 1 and separated further with ensuing trials. We then assessed gene expression for components of the CRF pathway in the mPFC, Hipp, VTA, Amygdala, and nucleus accumbens (NAc). Within the Hipp, LS showed greater expression of CRF binding protein (CRFbp). No differences were observed in the mPFC, VTA, NAc or Amygdala. Several hemisphere differences in CRF signaling pathway genes were detected. These findings indicate that avoidance of the experimenter delivered heroin-paired saccharin cue, do not recapitulate findings observed for avoidance of the iv self-administered heroin-paired saccharin cue, at least in terms of the expression of genes within the CRF pathway, and provide further evidence that consideration should be given to hemisphere differences when exploring molecular phenomena. [ABSTRACT FROM AUTHOR]

Addiction is a disease of brain-reward circuitry whereby attention, motivation, memory and emotional systems become enslaved to the goal of seeking and acquiring drug, instead of responding to the natural rewards for which these systems evolved. At the intersection of reward/limbic structures, the medial prefrontal cortex (mPFC) receives and consolidates signals regarding environment and orchestrates the most appropriate response (i.e., decision-making and attention). As such, mPFC function plays a critical role in the vulnerability or resilience to drug addiction. In our model of drug-induced reward devaluation, an outbred group of Sprague-Dawley rats parsed into two distinct drug-taking phenotypes: those, referred to as small suppressors (SS) that readily ingest a heroin-paired sweet cue and then take little drug, and those, referred to large suppressors (LS), that avoid the heroin-paired cue, but then respond greatly for the drug of abuse. In the present study, we analyzed the mPFC transcriptome of rats from these divergent groups to discover differences in gene expression that underlie these distinct phenotypes. Genes found to be differentially expressed were those associated with schizophrenia and dopamine signaling, signal transduction, development and synaptic plasticity. These genes may underlie the circumstance whereby some individuals succumb to addiction, while others do not, and may reveal new pharmacological targets for the treatment of drug addiction. [ABSTRACT FROM AUTHOR]

Law enforcement officer (LEO) administered naloxone is an effective intervention for treating prehospital opioid overdoses. Our objective is to determine the rate and factors associated with adverse behavioral effects and efficacy following LEO naloxone administration. This is a retrospective cohort study of patients treated with naloxone law enforcement over 5 years in one county EMS system. Law enforcement officers utilized intranasal 4 mg/0.1 mL for suspected opioid overdose. Data were acquired from forms completed by LEO following administration of naloxone. We performed descriptive statistics. Univariate regression analysis with a primary outcome of improved neurological status and a secondary outcome of patient irritability/combativeness post-naloxone. A total of 597 cases of LEO administered naloxone were reported. Naloxone was felt to be effective by the LEO in 370 (62%) of these cases with 6 (1%) exhibiting combativeness and 57 (10%) having the composite outcome of irritability or combativeness. The perceived rate of efficacy was higher when an opioid, rather than a non-opioid agent was suspected (239/346 [67%] vs. 83/165 [50%], OR 2.21, 95% CI 1.51–3.23), and for heroin and fentanyl specifically. Suspected fentanyl exposure was the only variable associated with our secondary outcome of irritability or combativeness (7/22 [32%] vs. 45/489 [9%], OR 4.60, 95% CI 1.78–11.8). LEO administered naloxone remains an effective intervention for overdose victims, with higher perceived efficacy when opioids are specifically implicated. Combativeness is rare following LEO naloxone administration. Further research is needed to understand a relationship between suspected fentanyl intoxication and post-naloxone behavioral disturbances. • Law enforcement officers administered naloxone for 597 patients with possible opioid overdose. • In 370 (62%) of cases, naloxone was effective. • In 6 cases (1%), patients exhibited combativeness, and in 57 cases (10%), they were irritable or combative. • Cases where fentanyl was the suspected intoxicant were associated with irritability following naloxone reversal, but the causality of this relationship is unknown. [ABSTRACT FROM AUTHOR]

To study the effects of resveratrol on heroin addiction-related behaviors and to preliminarily explore the possible intervention mechanism of resveratrol in heroin dependence. The effects of resveratrol on heroin withdrawal symptoms were observed by naloxone; The effect of resveratrol on heroin reward memory acquisition was detected by CPP paradigm; The effect of resveratrol on the mental excitability of heroin was tested by open field experiment; The effect of resveratrol on heroin spatial learning and memory was tested by water maze test. Western blot was used to detect Sirtuin 1 (SIRT1) Expression of brain-derived neurotrophic factor (BDNF), glial cell derived neurotrophic factor (GDNF), and postsynaptic density protein (PSD95). The behavioral results showed that the withdrawal behavior of the resveratrol intervention group was reduced compared with the heroin chronic dependence group (P <0.05), and the shift score of the conditioned place preference test of the resveratrol intervention group was reduced compared with the heroin chronic dependence group (P <0.05) The spatial learning and memory ability of the water maze in the resveratrol intervention group was improved compared with the heroin chronic dependence group (P <0.05), and the mental excitability of the resveratrol intervention group was lower than that of the heroin chronic dependence group (P <0.05), but higher than that of the saline group (P <0.05); SIRT1 The expression levels of BDNF, GDNF and PSD95 protein were significantly increased (P <0.05). The behavioral results of this study suggest that resveratrol can be used as a potential drug to treat heroin dependence. At the same time, SIRT1 The expression of BDNF, GDNF, and PSD95 increased; SIRT1, BDNF, GDNF, and PSD95 play an essential role in heroin addiction. [ABSTRACT FROM AUTHOR]

• We surveyed 681 people who used unregulated opioids in Vancouver, Canada (2021–22). • 74 % reported prescription of preferred opioids could reduce unregulated opioid use. • These participants had a heightened overdose risk (e.g., benzodiazepine exposure). • The most commonly reported preferences were diacetylmorphine and fentanyl patches. • Recent prescriptions for diacetylmorphine (6 %) and fentanyl patches (13 %) were low. Many people who use drugs in the United States and Canada continue to access the contaminated unregulated drug supply, resulting in the ever-escalating overdose epidemic. In Canada, even in areas where healthcare providers are authorized to prescribe alternatives to the unregulated supply (e.g., prescribed safer supply), availability and accessibility are low. We sought to characterize the needs of people who use unregulated opioids in Vancouver, Canada by asking them whether access to any pharmaceutical opioids would reduce their use of unregulated opioids, and if so, which pharmaceutical opioids they preferred. We analyzed data from participants who self-reported using unregulated opioids in three Vancouver-based prospective cohort studies between 2021 and 2022. We employed multivariable logistic regression to identify factors associated with reporting a preferred pharmaceutical opioid to reduce unregulated opioid use. Of 681 eligible participants, 504 (74.0 %) identified a preferred pharmaceutical opioid to reduce unregulated opioid use. The most commonly reported preferred opioids included: diacetylmorphine (42.9 %), fentanyl patches (11.1 %), and fentanyl powder (10.5 %). Overall, 5.6 % of participants who identified diacetylmorphine, 12.5 % of participants who identified fentanyl patches, and no participants who identified fentanyl powder as their preferred opioids reported receiving prescriptions of them. In multivariable analysis, exposure to benzodiazepines through unregulated drug use (adjusted odds ratio [AOR] = 2.57; 95 % confidence interval [CI] = 1.69–3.90), and receipt of prescribed safer supply of opioids without opioid agonist therapy (OAT; AOR = 2.66; 95 % CI = 1.12–6.36) within the past six months were significantly associated with reporting a preferred pharmaceutical opioid. Three-quarters of participants reported that receiving prescribed pharmaceutical opioids of their preference could reduce their use of unregulated opioids; however, the proportions of those actually being prescribed their preferred opioids were very low. Further, these participants were also more likely to report exposure to benzodiazepine-adulterated drugs. Our findings provide important implications for future safer supply programs. [ABSTRACT FROM AUTHOR]

While randomized-controlled trials have shown that heroin-assisted treatment (HAT) is superior to methadone maintenance alone in treatment of refractory clients, little is known about client factors associated with retention in HAT in routine care. This retrospective cohort study assessed predictors of retention in first treatment episode among a consecutive cohort of clients admitted to HAT in Denmark from 2010 to 2018, who could be matched to the Danish population register and for whom a Short Form Health Survey (SF-36) was available at admission (N = 432). The study derived predictors from client self-reports at intake and administrative data available in national registers. Cox proportional hazards regression modelled retention in treatment. The one-year retention rate was 69.63 % (95 % CI 65.06 %–73.74 %), and the median time in treatment was 2.45 years (95 % CI, 1.83–3.12). Bivariate analyses showed that retention was lower for clients who had recent cocaine or benzodiazepine use and among those who had experienced an overdose in the year prior to enrollment in HAT. Age below 40, recent illegal activity, poorer emotional wellbeing, previous residential treatment experience, and previous intensive outpatient treatment were also predictors of dropout from HAT. This observational study found that retention in HAT in routine care was similar to rates observed in randomized-controlled trials conducted in other countries. The results suggest that addressing polysubstance use as part of the HAT program may promote long-term retention, as may directing resources to certain subgroups identified at intake, including clients under 40 years and those who report recent criminal activity, emotional problems, or overdoses. The findings that previous residential treatment and intensive outpatient treatment were associated with dropout were unexpected. • High one-year retention in HAT in a routine care setting, similar to RCTs. • History of emotional problems, criminal activity, or overdoses increases dropout risk. • Addressing polysubstance use directly may improve retention in HAT. [ABSTRACT FROM AUTHOR]

Maintenance therapy with buprenorphine and methadone is the gold standard pharmacological treatment for opioid use disorder (OUD). Despite these compounds demonstrating substantial efficacy, a significant number of patients do not show optimal therapeutic responses. The abuse liability of these medications is also a concern. Here we used rats to explore the therapeutic potential of the new long-acting pan-opioid agonist Cebranopadol in OUD. We tested the effect of cebranopadol on heroin self-administration and yohimbine-induced reinstatement of heroin seeking. In addition, we evaluated the abuse liability potential of cebranopadol in comparison to that of heroin under fixed ratio 1 (FR1) and progressive ratio (PR) operant self-administration contingencies. Oral administration of cebranopadol (0, 25, 50 μg/kg) significantly attenuated drug self-administration independent of heroin dose (1, 7, 20, 60μg/inf). Cebranopadol also reduced the break point for heroin (20 μg/inf). Finally, pretreatment with cebranopadol significantly attenuated yohimbine-induced reinstatement of drug seeking. In abuse liability experiments under FR1 contingency, rats maintained responding for heroin (1, 7, 20, 60μg/inf) to a larger extent than cebranopadol (0.03, 0.1, 0.3, 1.0, 6.0μg/inf). Under PR contingency, heroin maintained responding at high levels at all except the lowest dose, while the break point (BP) for cebranopadol did not differ from that of saline. Together, these data indicate that cebranopadol is highly efficacious in attenuating opioid self-administration and stress-induced reinstatement, while having limited abuse liability properties. Overall, the data suggest clinical potential of this compound for OUD treatment. • Methadone and buprenorphine are the goldstandard therapies in OUD. Their abuse liability is a concern. • Cebranopadol, a first-in-class opioid agonist that also activates the NOP receptor, is in phase-III for pain. • Cebranopadol reduces the motivation for heroin self-administration and heroin seeking. • Results demonstrate a low abuse liability of cebranopadol in rat self-administration experiments. • Cebranopadol is candidate for immediate clinical investigation in OUD disorder patients. [ABSTRACT FROM AUTHOR]

Opioid use during pregnancy and subsequent neonatal opioid withdrawal syndrome (NOWS) have been associated with poor developmental outcomes including cognitive functioning. Less is known about the underlying molecular effects of prenatal opioid exposure and subsequent withdrawal; however, given the recent increase in NOWS cases, there is a pressing need to better understand these effects, which may partially explain cognitive deficits that have been observed in both preclinical NOWS models and patients with NOWS. This study evaluated the effects of prenatal heroin exposure and subsequent precipitated withdrawal symptoms on microglial reactivity in the nucleus accumbens (NAc), dorsal hippocampus (HC), and ventral tegmental area (VTA) in rat neonates, as well as cognitive functioning at three developmental time points using the Morris Water Maze (MWM) task. Heroin or saline (2 mg/kg) was randomly assigned and administered to six pregnant Sprague Dawley rat dams via osmotic minipump. A total of 63 rat neonates underwent naloxone-precipitated (5 mg/kg, subcutaneous injection) withdrawal testing at postnatal day 10 (PN10). Following withdrawal testing, neonates were randomly assigned to undergo perfusion and subsequent immunohistochemistry experiments to fluoresce Iba-1 for microglia detection, or to undergo the MWM task at three separate developmental time points (PN21–23; PN37; PN60) for cognitive testing. Results suggest that in-utero heroin exposure led to an increase in ultrasonic vocalizations during naloxone-precipitated withdrawal; a sensitive index of withdrawal in rat neonates. Additional results suggest increased microglial reactivity in the HC and VTA, but not the NAc, as well as reduced performance during the MWM in the group exposed to heroin in-utero. Together, these data suggest that in-utero opioid exposure is associated with microglial reactivity in brain regions associated with learning and memory, and may be associated with later cognitive deficits. Further research is needed to characterize these findings, which may inform future therapeutic strategies for this vulnerable population. • In utero heroin exposure increased ultrasonic vocalizations in rat neonates during naloxone-precipitated withdrawal. • Heroin-exposed rat neonates had increased microglia density in the dorsal hippocampus and ventral tegmental area. • Rat neonates exposed to heroin in utero showed reduced spatial and learning memory in the Morris Water Maze test. [ABSTRACT FROM AUTHOR]

Controls on essential/precursor chemicals from commercial companies have been associated with many large downturns in illicit drug markets and attendant problems. My colleagues and I brought this to light in the studies that are the subject of Giommoni's review. McKetin et al. in an earlier review considered several of our studies on chemical controls for methamphetamine, all centered in North America. Giommoni discusses not only those studies but also our later work on chemical controls for cocaine and heroin. This later work evaluates US essential/precursor chemical policies targeting illicit drug producers outside of North America, and it examines impacts on illicit drug availability and use (the studies reviewed by McKetin et al. predominantly focused on outcomes such as drug-related hospitalizations, arrests, and treatment). Giommoni's review is a new resource that will help make the varied topics in essential/precursor chemical control research more accessible to many readers. After noting this, I discuss some common methodological misconceptions about our studies. For example, our studies generally used multi-replication interrupted time series analysis, a research design among the most powerful of all quasi-experimental designs. Authors, however, typically discuss the studies as if they used single-intervention interrupted time series analysis, a less powerful design. Multi-replication and single-intervention interrupted time series analyses also differ regarding likely confounders; awareness of this is critical to accurately assessing our findings and critiquing alternative explanations. Finally, I note that commercial chemical companies function as the silent, albeit usually unwitting, partners in the large-scale production of several illicit drugs, including fentanyl. And many governments are implementing essential/precursor chemical controls to help stymie this partnership. But they are doing so largely without evaluation and study—a poor policy practice. To remedy this, I suggest establishing multi-disciplinary applied research teams to help assess, guide and improve essential/precursor chemical control efforts. [ABSTRACT FROM AUTHOR]

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 GABA A 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. • DM506, derived from ibogamine, attenuates heroin seeking in a sex-specific manner. • DM506 inhibits tonic GABA currents in the prelimbic cortex. • DM506 does not influence α&δ GABA A subunit mRNAs in the prelimbic cortex. [ABSTRACT FROM AUTHOR]

Low-threshold substance use treatment programs may help overcome barriers for marginalized individuals. The aims of this study were to 1) describe participant characteristics and treatment outcomes for a multi-site, Philadelphia-based mobile program providing street-based buprenorphine initiation, stabilization, and referral to ongoing care and 2) examine associations between patient characteristics and successful linkage. We conducted a retrospective cohort study of patients receiving buprenorphine through Prevention Point Philadelphia's mobile overdose response program from 9/2020–12/2021. We abstracted electronic medical record data, including patient characteristics, mobile program treatment, and care linkage. We used descriptive statistics to characterize the sample and assessed the association between patient characteristics and successful care linkage using multi-variable logistic regression. Two hundred thirty-seven patients initiated buprenorphine in the program across six sites. Mean age was 46. Participants were majority men (67 %); 59 % identified as Black, 33 % identified as White, and 15 % reported Hispanic ethnicity. Most were publicly insured (74 %) and 30 % were unstably housed. Basedline engagement in primary care (32 %), psychiatric treatment (5 %), and counseling (2 %) were low. Most participants reported heroin or fentanyl use at intake (87 %), with high rates of IV drug use (37 %)., and co-occurring substance use and prior buprenorphine treatment experience were common.. 86 % completed ≥1 mobile follow-up visit, and 69 % completed ≥4 mobile program visits. 51 % of patients attended at least one visit at an outside site, and 30 % had ≥2 visits for buprenorphine prescriptions at an outside site. 35 % of the referrals were internal, meaning they went to University-based practices staffed by the mobile unit physicians. In a multivariable logistic regression model, internal referral was associated with significantly increased odds of effective care linkage (aOR 2.47, 95 % CI 1.20–5.09). Targeted community outreach with low-threshold substance use care facilitated treatment access among marginalized individuals. Participants showed high levels of engagement with the mobile program, but rates of outside care linkage, while comparable to retention in other low-threshold models, were lower. The only predictor of effective care linkage was referral to brick-and-mortar clinics staffed by mobile unit physicians. These findings support the importance of outreach beyond traditional health care settings to engage high-risk patients with OUD. • Low-threshold programs may overcome treatment barriers for marginalized patients. • We describe outcomes in a Philadelphia mobile buprenorphine treatment program. • The program engaged high-risk patients with limited connection to health services. • Engagement at the mobile site was high, but linkage outside the program was lower. • Referrals to clinics staffed mobile program physicians had higher linkage rates. [ABSTRACT FROM AUTHOR]

• Direct injection allowed fast LC-MS/MS analysis of illicit drugs in WW. • DI presents similar LOQs and lower matrix effect than the SPE method. • Interlaboratory exercise supports the reliability of the DI approach. • Method would allow reporting data for most cities of a large monitoring campaigns. • Methodology promotes easier logistic and prompt reporting of results. The determination of illicit drugs in urban influent wastewater (IWW) enables the monitoring of spatial and temporal drug usage trends and assessment of community lifestyle habits. The increasing number of wastewater surveillance studies has emphasized the necessity for the development of rapid, high-throughput methods that maintain high quality data. This work evaluates the use of a dilute-and-shoot methodology, based on direct injection (DI) of centrifuged samples, as an alternative approach to the widely applied sample pre-treatment based on solid-phase extraction, for the liquid chromatography-tandem mass spectrometry determination of seven widely consumed illicit drugs and their metabolites in IWW (amphetamine; cocaine metabolite, benzoylecgonine; ketamine; 3,4-methylenedioxymethamphetamine (MDMA); methamphetamine; cannabis metabolite, 11-nor-9-carboxy-delta-9-tetrahydrocannabinol (THC COOH); heroin metabolite, 6-acetylmorphine (6-MAM)). Comparison of both approaches in terms of matrix effects, sensitivity and accuracy, demonstrates the DI method suitability to correctly quantify these analytes in IWW, with a limit of quantification lower than 30 ng L−1 for most compounds. After validation of the method and participation in an interlaboratory exercise, the DI method was applied to the analysis of 54 IWW samples collected from different Spanish wastewater treatment plants. Additionally, quality controls were incorporated in each analysis batch to support the DI method applicability and robustness. The use of a 10 μL-DI reduces time-consuming sample preparation, analysis time and measurement uncertainty. Moreover, it supports green chemistry by reducing the consumption of organic solvents and it facilitates logistics by collecting, transporting, and storing less sample volume. The methodology is therefore especially appropriate for monitoring illicit drugs in large wastewater-based epidemiology sampling campaigns or when fast near real-time results are needed. [Display omitted] [ABSTRACT FROM AUTHOR]

Over the past decade, treatment for opioid use disorder has expanded to include long-acting injectable and implantable formulations of medication for opioid use disorder (MOUD), and integrated treatment models systematically addressing both behavioral and physical health. Patient preference for these treatment options has been underexplored. Gathering data on OUD treatment preferences is critical to guide the development of patient-centered treatment for OUD. This cross-sectional study assessed preferences for long-acting MOUD and integrated treatment using an online survey. An online Qualtrics survey assessed preferences for MOUD formulation and integrated treatment models. The study recruited participants (n = 851) in October and November 2019 through advertisements or posts on Facebook, Google AdWords, Reddit, and Amazon Mechanical Turk (mTurk). Eligible participants scored a two or higher on the opioid pain reliever or heroin scales of the Tobacco, Alcohol Prescription Medication and other Substance Use (TAPS) Tool. Structured survey items obtained patient preference for MOUD formulation and treatment model. Using stated preference methods, the study assessed preference via comparison of preferred options for MOUD and treatment model. In the past year, 824 (96.8 %) participants reported non-prescribed use of opioid pain relievers (mean TAPS score = 2.72, SD = 0.46) and 552 (64.9 %) reported heroin or fentanyl use (mean TAPS score = 2.73, SD = 0.51). Seventy-four percent of participants (n = 631) reported currently or previously receiving OUD treatment, with 407 (48.4 %) receiving MOUD. When asked about preferences for type of MOUD formulation, 452 (53.1 %) preferred a daily oral formulation, 115 (13.5 %) preferred an implant, 114 (13.4 %) preferred a monthly injection and 95 (11.2 %) preferred a weekly injection. Approximately 8.8 % (n = 75) would not consider MOUD regardless of formulation. The majority of participants (65.2 %, n = 555) preferred receiving treatment in a specialized substance use treatment program distinct from their medical care, compared with receiving care in an integrated model (n = 296, 34.8 %). Though most participants expressed willingness to try long-acting MOUD formulations, the majority preferred short-acting formulations. Likewise, the majority preferred non-integrated treatment in specialty substance use settings. Reasons for these preferences provide insight on developing effective educational tools for patients and suggesting targets for intervention to develop a more acceptable treatment system. • 851 participants completed a web-based survey on OUD treatment preferences. • 53 % of participants preferred short-acting oral MOUD to long-acting formulations. • 65 % of participants preferred receiving treatment in a non-integrated treatment model. • Results support expanding access to a range of OUD treatment options. [ABSTRACT FROM AUTHOR]

In this work, a novel biosensing platform was fabricated based on modification of a rotating glassy carbon electrode (GCE) with chitosan-ionic liquid (Ch-IL) composite film, electrochemical synthesis of gold palladium platinum trimetallic three metallic alloy nanoparticles (AuPtPd NPs) onto its surface, and electrosynthesis of dual templates molecularly imprinted polymers (MIPs) where morphine (MO) and codeine (COD) used as template molecules. The AuPtPd NPs were synthesized under different electrochemical conditions, and surfaces of electrodes were investigated by digital image processing, and the best electrode was chosen. Effects of experimental variables on response of the biosensor to MO and COD were optimized by a central composite design (CCD), and under optimized conditions (concentration of the phosphate buffered solution (PBS): 0.09 M, pH of the PBS: 3.21–3.2, time of immersion: 204.8–205 s, and rotation rate: 2993.51–3000 rpm) the biosensor responses to MO and COD were individually calibrated (1–20 pM for MO and 0.5–12 pM for COD), three-way calibrated by PARASIAS, PARAFAC2, and MCR-ALS, and validated in the presence of ascorbic acid and uric acid as uncalibrated interference. Finally, performance of the biosensor in simultaneous determination of MO and COD in the presence of ascorbic acid and uric acid as uncalibrated interference in human serum samples were verified and compared with the results of HPLC-UV as the reference method which guaranteed it as a reliable method. • A novel electrochemical biosensor was fabricated for simultaneous determination of morphine and codeine. • Image processing, experimental design, and multi-way calibration supported the biosensor. • Interference caused by ascorbic acid and uric acid were tackled by exploiting second-order advantage. • The biosensor assisted by MCR-ALS was successful in analysis of serum samples. • Performance of the intelligent biosensor was admirable and comparable with the reference method. [ABSTRACT FROM AUTHOR]

Background: Emotion dysregulation is a crucial component of substance use disorders in predisposition, maintenance, and relapse. Emotional regulation strategies are an important factor in emotion dysregulation. However, studies on heroin use disorder (HUD) patients' ability to use emotion regulation strategies are scarce.Methods: Time-frequency-based analyses were used to compare the power of 33 patients with HUD and 28 healthy controls to elucidate whether patients with HUD have abnormal neural oscillations during passive viewing and emotion regulation strategies. Using the standardized low-resolution brain electromagnetic tomography algorithm (sLORETA), we estimated the possible sources of the anomalous band power.Results: Compared to patients with HUD, healthy controls showed a stronger decrease in the power of the delta/theta band across all task conditions. The effect peaked at approximately 1300-1900 ms after stimulus onset and varied by task condition. The estimation of sLORETA suggested the frontal, parietal, and limbic lobes as possible generators.Limitations: We cannot exclude the potential influence of additional factors, such as sex, depression and anxiety levels, and polysubstance use, on the results.Conclusions: Patients with HUD have blunted arousal and impaired ability to use emotion regulation strategies. The abnormal patterns described above may be the underlying neurophysiological basis for this dysfunction. Future studies could combine different approaches to improve emotion dysregulation in patients with HUD to promote treatment outcomes. [ABSTRACT FROM AUTHOR]

Opioid use disorder (OUD), like other substance use disorders (SUDs), is widely understood to be a disorder of persistent relapse. Despite the use of three FDA-approved medications for OUD, typically in conjunction with behavioral treatments, relapse rates remain unacceptably high. Whereas medication assisted therapy (MAT) reduces the risk of opioid overdose mortality, the benefits of MAT are negated when people discontinue the medications. Currently approved medications present barriers to efficient use, including daily visits to a treatment center or work restrictions. With spiking increases in opioid relapse and death, it is imperative to identify new treatments that can reduce the risk of relapse. Recent evidence suggests that glucagon-like peptide-1 receptor agonists (GLP-1RAs), currently FDA-approved to treat obesity and type two diabetes, may be promising candidates to reduce relapse. GLP-1RAs have been shown to reduce relapse in rats, whether elicited by cues, drug, and/or stress. However, GLP-1RAs also can cause gastrointestinal malaise, and therefore, in humans, the medication typically is titrated up to full dose when initiating treatment. Here, we used a rodent model to test whether cue- and drug-induced heroin seeking can be reduced by the GLP-1RA, liraglutide, when the dose is titrated across the abstinence period and prior to test. The results show this titration regimen is effective in reducing both cue-induced heroin seeking and drug-induced reinstatement of heroin seeking, particularly in rats with a history of high drug-taking. Importantly, this treatment regimen had no effect on either circulating glucose or insulin. GLP-1RAs, then, appear strong candidates for the non-opioid prevention of relapse to opioids. [ABSTRACT FROM AUTHOR]

[Display omitted] • Opioid prescription drug abuse is an epidemic. • The social impact of the deterrent opioids remains uncertain. • Abusers seek heroin and other deadly illicit drugs at an alarming rate. • Government should control opioid manufacturing and its distribution. • Research should focus on nonaddictive opioids and non-opioids, as well as targeted therapy of addiction. The primary tools to alleviate the opioid epidemic in the USA include strict Federal and State laws on opioid prescriptions, tracking opioid medications, accountability of the opioid manufacturers and physicians, as well as boosting public awareness. Although abuse-deterrent opioids have in part lowered the incidence of opioid abuse, many post-marketing studies are still pending and some products have been recalled or terminated. Moreover, some studies show that the current deterrent opioid products might potentially force the abusers to seek more-powerful and deadly illicit drugs that can lead to toxicity and hepatitis C infections. Along with all the positive developments, there remains a strong need to discover and develop nonaddictive opioids and comparable non-opioid alternatives for acute pain management. [ABSTRACT FROM AUTHOR]

Information regarding the metabolism of illicit drugs is under urgent need for toxicological assessment. Its development, however, is limited by the currently available animal models. To this end, we proposed three-dimensional (3D) HepaRG spheroids as an in vitro model to study the effects of illicit drugs on hepatic cytochrome P450 (CYP450) enzymes and potential drug-drug interactions (DDIs). By comparing the results from animal and cell experiments, we confirmed the significant impact of heroin, morphine, tetrahydrocannabinol, and fentanyl on CYP450 enzymes, and the 3D spheroids results were in good agreement with the animal results for 2B6, 2C19, 2D6. Using 3D HepaRG spheroids, we demonstrated DDIs between heroin as a 2B6 perpetrator and clinical medicine for cancer, depression, and illicit drug withdrawal. Specifically, the clearance rate of 5.4 μM bupropion was increased by 214 % under DDI with 5 µM heroin, highlighting the importance of DDI pre-screening and individualized medication guidance for illicit drug users. This research contributes to the growing body of evidence regarding the metabolic toxicity of illicit drugs and suggests 3D HepaRG spheroids as a high-throughput and cost-efficient platform for DDI analysis. • Induction of CYP450 by illicit drugs was evaluated in animal and cellular models. • Using 3D HepaRG spheroids to study the effects of illicit drugs on CYP450. • Predicting potential DDIs between heroin and clinical medicine. [ABSTRACT FROM AUTHOR]

Neuroscientists have devoted efforts to explore potential brain recovery after prolonged abstinence in heroin users (HU). However, not much is known about whether frontostriatal circuits can recover after prolonged abstinence in HU. An eight-month longitudinal study was carried out for HU. Two MRI scans were obtained at baseline (HU1) and 8-month follow-up (HU2). The functional and structural connectivities of dorsal and ventral frontostriatal pathways were measured by resting-state functional connectivity (RSFC) and diffusion tensor imaging (DTI). Correlation analyses were employed to reveal the associations between neuroimaging and behavioral changes. Results suggested that relative to healthy controls (HCs), HU1 showed lower fractional anisotropy (FA) in the right dorsolateral prefrontal cortex (DLPFC)-to-caudate tracts and medial orbitofrontal cortex (mOFC)-to-nucleus accumbens (NAc) tracts as well as decreased RSFC in the left mOFC-NAc circuits. Longitudinal results revealed reduced craving and enhanced cognitive control in HU2 compared with HU1. After prolonged abstinence, HU2 showed increased FA values in the right DLPFC-caudate and mOFC-NAc tracts as well as increased RSFC strength in the bilateral mOFC-NAc circuits compared with HU1. In addition, changes in RSFC and FA values in the right mOFC-NAc circuit were negatively correlated with craving score changes. Similarly, negative correlations were also found between changes of RSFC in the bilateral DLPFC-caudate circuits and TMT-A scores. We provided scientific evidence for brain recovery of the dorsal and ventral frontostriatal circuits in HU after prolonged abstinence, and these circuits may be potential neuroimaging biomarkers for cognition and craving changes. • Reduced craving and improved cognition were observed in heroin users (HU) after 8-month of abstinence. • Increased RSFC and FA values of frontostriatal were demonstrated in HU after 8 months of abstinence. • ΔRSFC and ΔFA values in the dorsal and ventral circuit were associated with improved cognition and decreased craving. • Time line (baseline and eight-month follow-up) produced a significant main effect. [ABSTRACT FROM AUTHOR]

Impaired behavioral inhibition is a critical factor in drug addiction and relapse. Repetitive transcranial magnetic stimulation (rTMS) reduces the craving of heroin-addicted individuals for drug-related cues. However, it is unclear whether this technique also improves impaired behavioral inhibition and how improved behavioral inhibition affects craving. The intermittent theta-burst stimulation (iTBS) has been recently shown to be non-inferior relative to rTMS for depression. Here, we aim to investigate the effect of iTBS on heroin-addicted individuals' behavioral inhibition and cue-induced craving and the relationship between the alteration of behavioral inhibition and craving. 42 of 56 initially recruited individuals with the heroin-use disorder in the abstinent-course treatment were randomized to undergo active or sham iTBS to the left dorsolateral prefrontal cortex and received three daily iTBS treatments for 10 consecutive days. We measured participants' performance during a two-choice oddball task (80% standard and 20% deviant trials) and heroin-related cue-induced craving before and immediately after treatment. The group that received active iTBS showed significantly improved two-choice oddball task performance after 10 days of intervention compared to both pre-intervention and the group who received sham iTBS. Similarly, a significant reduction in cue-induced craving was observed after following the intervention in the active iTBS group but not the sham iTBS group. The moderation model indicated that iTBS categories play a significant moderating role in the relationship between accuracy cost changing and altered cue-induced craving. The iTBS treatment protocol positively affects behavioral inhibition in patients with heroin addiction. Improvements in behavioral inhibition can substantially reduce craving. • iTBS treatment protocol can enhance behavioral inhibition of heroin use disorder. • iTBS targeting prefrontal cortex reduce cue-induced craving in heroin use disorder. • Improvements in behavioral inhibition can be a predictive factor of treatment outcome. • Improving cognitive control functions could have therapeutic implications in drug addiction. [ABSTRACT FROM AUTHOR]

• Cocaine-fed larvae developed less in length and weight than the control. • Heroin-fed larvae had a more sluctuating development than the control. • Combination-fed larvae seemed to favour the effects of cocaine rather than heroin. • Cocaine and combination-fed larvae increased second and third instar stages, but shorten pupation and accelerate eclosion. • Heroin increases second instar stage and pupation. Insects present on or near decomposing bodies are collected by forensic entomologists and used to estimate the post-mortem interval. Drugs metabolized by a person before death may affect the rate of development of insects feeding on the corpse. This study aimed to determine the effects of cocaine and heroin main metabolites on the development rate of the Calliphora vomitoria (Diptera: Calliphoridae) and their implications on minimum post-mortem interval determination. Groups of 250 eggs each were placed into four separate pots of 150 g of minced pork meat being either un-spiked, or spiked with benzoylecgonine, morphine, or a combination of both. Larval length (mm) and weight (mg) measurements were taken twice daily and the rate of development of the insects' life cycle was monitored until eclosion. Results show that cocaine-fed larvae developed less in length and weight than the control group. Heroin-fed larvae showed a more fluctuating pattern, being smaller and lighter than the control group for most of their larval cycle, but overtaking them in both parameters towards pupation. Combination-fed larvae seemed to favour the effects of cocaine. The three conditions also had a significant impact on the length of the insects' life cycle. Cocaine and drug combination treatments increased the length of the second and third instar stages, but led to the shortening of pupation and accelerated eclosion. Conversely, heroin treatment led to lengthier pupation. Interestingly, the effects of the drug combination seemed to mirror more precisely those of cocaine. These findings indicate that both cocaine and heroin, singularly and in combination, have sizable effects on blowflies' development rates, potentially biasing post-mortem interval estimations. [ABSTRACT FROM AUTHOR]

Individuals who are addicted to drugs often face unfavourable social conditions and difficulty with social adaptation. Both may be closely related to impaired social cognitive ability. This study posits that social cognitive impairments likely arise from blunted social reward processing in drug users. This study aimed to explore the electrophysiological mechanism of social reward processing in people who abstain from using heroin (heroin abstainers). Twenty-eight male heroin abstainers and 27 matched controls completed the social incentive delay task. At the same time, their corresponding behaviour and electroencephalography data were recorded. The feedback-related negativity (FRN) elicited by positive outcomes was significantly more positive than that elicited by negative outcomes for the healthy controls. However, no significant difference in FRN was found between negative and positive outcomes among the heroin abstainers. There was no significant difference in P3 (a positive event-related potential component after FRN) elicited by negative and neutral outcomes in the heroin abstainers. Meanwhile, negative outcomes elicited greater P3 than neutral outcomes in the healthy controls. In addition, this study also found that withdrawal time was negatively correlated with the difference wave of FRN for the heroin abstainers. Heroin abstainers may be hyposensitive to the processing of social reward outcomes. In other words, they may have insufficient motivation to acquire social rewards. Abnormal social reward processing found in heroin abstainers can be improved with an increase in abstinence time. These results deepen our understanding of the social reward impairments associated with chronic drug use. • Heroin abstainers may be hyposensitive to the processing of social reward outcomes. • Abnormal social reward processing found in heroin abstainers can be improved with an increase in abstinence time. • This study deepen our understanding of the social reward impairments associated with chronic drug use. [ABSTRACT FROM AUTHOR]

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. • Psychedelic drug DOI reduces heroin, but not alcohol, motivation in polydrug rats. • The serotonin 5-HT2A receptor antagonist MDL 100,109 blocked this DOI effect. • A 5-HT2C receptor antagonist did not block the effect of this modest dose of DOI • Serotonin 5-HT2A receptor agonists could be a promising treatment for opioid misuse. [ABSTRACT FROM AUTHOR]

Concurrent use of heroin and cocaine (known as the "speedball") prevails among substance use disorder populations, especially in opioid-dependent individuals, with severe consequences and a high fatality rate. Little is known about the patterns and correlations of the concurrent use of heroin and cocaine. It is vital to investigate such a polydrug use in both humans and animals to uncover concomitant toxicity and the cause of fatal overdose (death). In this study, we aimed to shed some light on the role of cocaine in the etiology of heroin-related deaths in the context of molecular pharmacokinetics (PK). For the purpose, a high-performance liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) method for simultaneous determination of heroin, cocaine, and their metabolites in whole blood was developed and fully validated in accordance with the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) guidelines. Then, this method was used to analyze heroin, cocaine, and their metabolites in blood from the rats intraperitoneally administered non-lethal 10 mg/kg heroin or 20 mg/kg cocaine alone, or their combination that is lethal with a proximal mortality of 33 %. The obtained results from the rats that experienced the lethal toxicity revealed that the concurrent use of heroin and cocaine significantly increased the risk of fatality from overdose. Heroin significantly slowed down the elimination of cocaine and its main metabolites in blood, while cocaine significantly enhanced heroin metabolism from 6-monoacetylmorphine (6-MAM) to morphine. Similar elimination half-lives for other heroin metabolites were observed. These findings are reported for the first time in this study, facilitating our understanding of the polysubstance metabolism and severe consequences produced by the polydrug use. • The PKs of heroin and cocaine co-use were investigated by using a LC-MS/MS method. • Simultaneous use of heroin and cocaine increased the risk of fatality from overdose. • Heroin delayed and inhibited metabolism of cocaine. • Cocaine affected two main steps of heroin metabolism inconsistently. [ABSTRACT FROM AUTHOR]

• "Tranq-dope", xylazine-adulterated opioids, has caused many overdose deaths in the US. • Xylazine and opioids act in synergy, increasing the lethality of one another. • We report the first fatal case of xylazine-adulterated heroin in the EU. • Xylazine and its main metabolite were detected in blood and urine by LC-HRMS/MS. • Xylazine should be strictly controlled by public health authorities and toxicologists. The number of xylazine-involved overdose deaths tremendously increased from 2019 onwards in the US. This is due to the "tranq-dope" trend consisting in mixing opioids with the sedative to reduce drug manufacturing costs and enhance their effects. In this study, we report the first fatality involving xylazine-adulterated heroin in the EU. The subject was a 33-year-old Caucasian male with a documented history of drug abuse who was found dead in a public area with puncture marks at the elbow. Peripheral blood and urine were collected at the autopsy and analyzed by liquid chromatography-high-resolution tandem mass spectrometry (LC-HRMS/MS) after protein precipitation. 6-Monoacetylmorphine, total/free morphine, and codeine blood concentrations of 20.3, 236/105, and 38.3 ng/mL, respectively, indicated recent heroin consumption. Methadone blood concentration was below 10 ng/mL. Alprazolam, nordiazepam, and flurazepam blood concentrations were 23.9, 61.4, and 55.0 ng/mL, respectively. Benzoylecgonine blood concentration was below 5 ng/mL. Xylazine blood and urine concentrations were 105 and 72.6 ng/mL, respectively. The combination of central nervous system depressants, i.e., opioids, benzodiazepines, and xylazine, was the principal cause of death by cardiorespiratory failure. The case was promptly reported to the UE Early Warning System on drugs. [ABSTRACT FROM AUTHOR]

The opioid crisis continues to evolve with increasing opioid-related overdose deaths among under-represented minorities. A better understanding of substance use differences in the route of administration for people using heroin and other opioids can lead to targeted strategies and interventions. Using the 2015–2019 Treatment Episode Data Set - Admissions (TEDS-A), a multinomial logistic regression model examined the relationship between race/ethnicity and secondary substance use with route of administration in a subset of 591,078 admissions. For individuals reporting heroin as their primary substance, minoritized clients were both more likely to smoke (NH Blacks RR: 2.28, 95 % CI 2.16–2.41; Hispanic RR: 1.80, 95 % CI: 1.74, 1.87; Other RR: 2.09, 95 % CI: 2.00, 2.20) or inhale heroin (Hispanic RR: 1.82, 95 % CI 1.78–1.85; Other RR: 1.30, 95 % CI 1.25, 1.34) compared to non-Hispanic (NH) Whites. NH Black clients were nearly seven and a half times more likely to report inhaling (RR: 7.45, 95 % CI 7.28, 7.62) heroin over injecting it. Clients were more likely to smoke heroin compared to injection if they reported secondary drug use of methamphetamines (RR: 2.28, 95 % CI 2.21, 2.35) and other opioids (RR: 1.21, 95 % CI 1.15, 1.28). For clients reporting other opioids as their primary substance, Hispanic (RR: 1.33, 95 % CI 1.19, 1.47) and other racial/ethnic minority clients (RR: 2.50, 95 % CI 2.23, 2.79) were more likely to smoke opioids vs take it orally compared to their NH White counterparts. Individuals who reported methamphetamine use as a secondary substance were significantly more than three times as likely to smoke (RR: 3.07, 95 % CI 2.74, 3.45) or inject (RR: 3.36, 95 % CI 3.17, 3.57) compared to orally ingesting opioids, while those who reported cocaine or crack cocaine use were more than twice as likely to inject (RR: 2.22, 95 % CI 2.09–2.36) opioids than taking them orally. Findings demonstrate significant racial and ethnic differences in the route of administration. This work expands on the understanding of the complex nature of polysubstance use in the evolving opioid crisis and the secondary substance use of clients on routes of administration of opioids and heroin, highlighting the need for tailored interventions to address the treatment needs of under-represented minorities. • Route of administration varies by the type of opioid when comparing heroin to other opioids. • Racial and ethnic differences exist in route of administration of heroin and other opioids among those entering treatment. • Route of administration varies with secondary substance use of methamphetamine and cocaine. [ABSTRACT FROM AUTHOR]

A growing body of research indicates that β-caryophyllene (BCP), a constituent present in a large number of plants, possesses significant therapeutic properties against CNS disorders, including alcohol and psychostimulant use disorders. However, it is unknown whether BCP has similar therapeutic potential for opioid use disorders. In this study, we found that systemic administration of BCP dose-dependently reduced heroin self-administration in rats under an FR2 schedule of reinforcement and partially blocked heroin-enhanced brain stimulation reward in DAT-cre mice, maintained by optical stimulation of midbrain dopamine neurons at high frequencies. Acute administration of BCP failed to block heroin conditioned place preference (CPP) in male mice, but attenuated heroin-induced CPP in females. Furthermore, repeated dosing with BCP for 5 days facilitated the extinction of CPP in female but not male mice. In the hot plate assay, pretreatment with the same doses of BCP failed to enhance or prolong opioid antinociception. Lastly, in a substitution test, BCP replacement for heroin failed to maintain intravenous BCP self-administration, suggesting that BCP itself has no reinforcing properties. These findings suggest that BCP may have certain therapeutic effects against opioid use disorders with fewer unwanted side-effects by itself. • β-caryophyllene (BCP) reduces heroin self-administration in rats. • BCP attenuates the expression and extinction of heroin conditioned place preference in female but not male mice. • BCP fails to alter heroin antinociceptive effects in mice. [ABSTRACT FROM AUTHOR]

• Limited research on non-injecting and licit drug use among people who inject drugs. • Diversity in types of drugs and routes of administration used in this population globally. • Licit drug use commonly reported; tobacco was the most widely used drug overall. • Need for increased availability of non-injection harm reduction interventions. A better understanding of global patterns of drug use among people who inject drugs can inform interventions to reduce harms related to different use profiles. This review aimed to comprehensively present the geographical variation in drug consumption patterns among this population. Systematic searches of peer reviewed (PsycINFO, Medline, Embase) and grey literature published from 2008–2022 were conducted. Data on recent (past year) and lifetime drug use among people who inject drugs were included. Data were extracted on use of heroin, amphetamines, cocaine, benzodiazepines, cannabis, alcohol, and tobacco; where possible, estimates were disaggregated by route of administration (injecting, non-injecting, smoking). National estimates were generated and, where possible, regional, and global estimates were derived through meta-analysis. Of 40,427 studies screened, 394 were included from 81 countries. Globally, an estimated 78.1 % (95 %CI:70.2–84.2) and 71.8 % (65.7–77.2) of people who inject drugs had recently used (via any route) and injected heroin, while an estimated 52.8 % (47.0–59.0) and 19.8 % (13.8–26.5) had recently used and injected amphetamines, respectively. Over 90 % reported recent tobacco use (93.5 % [90.8–95.3]) and recent alcohol use was 59.1 % (52.6–65.6). In Australasia recent heroin use was lowest (49.4 % [46.8–52.1]) while recent amphetamine injecting (64.0 % [60.8–67.1]) and recent use of cannabis (72.3 % [69.9–74.6]) were higher than in all other regions. Recent heroin use (86.1 % [78.3–91.4]) and non–injecting amphetamine use (43.3 % [38.4–48.3]) were highest in East and Southeast Asia. Recent amphetamine use (75.8 % [72.7–78.8]) and injecting heroin use (84.8 % (81.4–87.8) were highest in North America while non–injecting heroin use was highest in Western Europe (45.0 % [41.3–48.7]). There is considerable variation in types of drugs and routes of administration used among people who inject drugs. This variation needs to be considered in national and global treatment and harm reduction interventions to target the specific behaviours and harms associated with these regional profiles of use. [ABSTRACT FROM AUTHOR]

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. 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. 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. Opioid and methamphetamine injection declined precipitously, with notable increases in smoking these drugs. Research is needed to understand the health consequences of these trends. • One-third of people who injected drugs at baseline transitioned to smoking only. • The risk of smoking opioids more often than injecting them increased over time. • Smoking methamphetamine more often than injecting it markedly increased over time. • Unregulated injection drug use is likely being supplanted by smoking drug use. [ABSTRACT FROM AUTHOR]

Attention-deficit/hyperactivity disorder (ADHD) is highly prevalent and associated with opioid use disorder (OUD). Yet, little is known about the mechanisms by which ADHD (which is a heterogeneous construct/diagnosis) might alter the trajectory of OUD outcomes in persons who use heroin. We examined whether ADHD subtypes are related to heroin-use consequences and the extent to which the effects of ADHD on lifetime heroin-use consequences are mediated by two impulsivity factors that may be partly independent of ADHD: foreshortened time perspective and drug-use impulsivity. Individuals who reported regular heroin use (N =250) were screened using the Assessment of Hyperactivity and Attention (AHA), Impulsive Relapse Questionnaire (IRQ), Stanford Time Perception Inventory (STPI), and a comprehensive assessment of lifetime and current substance use and substance-related consequences. This secondary analysis examined whether ADHD or intermediate phenotypes predicted heroin-use consequences. Relative to participants whose AHA scores indicated lifetime absence of ADHD (n =88), those with scores indicating persistent ADHD (childhood and adult, n =62) endorsed significantly more total lifetime heroin-use consequences despite comparable heroin-use severity. Likewise, there was a significant indirect effect of the combined ADHD subtype in childhood on lifetime heroin-use consequences. This effect was mediated by STPI scores indicating less future (and more hedonism in the present) temporal orientation and by IRQ scores indicating less capacity for delaying drug use. The combined ADHD subtype is significantly associated with lifetime heroin-use consequences, and this effect is mediated through higher drug-use impulsivity (less capacity for delay) and lower future temporal orientation. • Mechanisms by which ADHD affect heroin use outcomes are poorly understood. • ADHD and impulsivity phenotypes were assessed in 250 heroin users not in treatment. • Subjects with Persistent ADHD endorsed more heroin-use consequences. • Less future thinking and more drug-use impulsivity mediated childhood ADHD effects. [ABSTRACT FROM AUTHOR]

• Patients make meaning of embodied effects of depot buprenorphine in different ways. • Experiences of depot buprenorphine link to many factors beyond pharmacology. • Psychosocial supports in a wider network of care may still be important to patients. Long-acting injectable depot buprenorphine has become an important treatment option for the management of opioid dependence. However, little is known about patients' experiences of depot buprenorphine and its embodied effects. This qualitative study aims to explore patients' experiences of depot buprenorphine treatment, including how it feels within the body, experiences of dosing cycles across time, and how this form of treatment relies on wider ecologies of care beyond the clinical encounter. Participants were recruited from sites in Sydney, regional New South Wales, and Melbourne, Victoria, Australia. Thirty participants (16 men, 14 women) participated in semi-structured interviews. Participants had histories of both heroin and prescription opioid consumption, and opioid agonist therapy including daily dosing of buprenorphine and methadone. Our analysis illuminates: (1) how patients' expectations and concerns about treatment are linked to past embodied experiences of withdrawal and uncertainty about the effectiveness of depot buprenorphine; (2) the diverse meanings patients attribute to the depot buprenorphine substrate 'under the skin'; and, (3) how depot buprenorphine is embedded within wider ecologies of care, such as counselling and social supports. Our analysis destabilises commonplace assumptions about a linear, causal relationship between the pharmacological action of depot buprenorphine and experiences of treatment. Instead, it highlights patients' variable experiences of depot buprenorphine, tracing the everyday practices, embodied feelings, expectations and wider networks of care that shape patient experiences. We conclude with some reflections on the implications of our analysis for alcohol and other drug treatment, specifically how they might inform the design of client education materials and care. [ABSTRACT FROM AUTHOR]

• Of 100 participants who received BUP-XR treatment, 47 were retained in treatment at 96 weeks. • The median retention time was 90 weeks. • Quality of life and treatment satisfaction improved over time for those retained in treatment. The most recent formulation of buprenorphine treatment is extended-release depot injections (BUP-XR) that are administered subcutaneously by health care professionals. This study aimed to observe treatment outcomes of BUP-XR delivered in standard practice during a 96-week follow-up period in a community setting. This study is an extension of the CoLAB study, a prospective single-arm, multicentre, open label trial (N =100, 7 sites in Australia) among people with opioid dependence who received monthly injections of BUP-XR to evaluate the retention in treatment. Participants were followed for 96 weeks, comprising 48 weeks of the CoLAB study followed by a 48-week extension. Of 100 participants at baseline, 47 were retained on BUP-XR at 96 weeks. The median time retained on monthly depot was 90 weeks. Heroin use (adjusted OR=0.19, P =0.012) in the month prior to baseline was associated with lower odds of retention on BUP-XR. Older age at first opioid use (adjusted OR= 1.08, P =0.009) and longer duration in OAT at baseline (adjusted OR= 1.12, P =0.001) were associated with increased retention. Prevalence of past four-weeks opioid use was estimated at 4% at 96 weeks of treatment (prevalence 0.04, 95%CI: 0.00-0.11) compared to 15% at baseline. Quality of life and medication treatment satisfaction improved over time for those retained in treatment. This is one of the few studies to describe long term (96 week) retention in treatment with BUP-XR in a community setting. It displayed retention rates with 47% of participants completing 96 weeks of treatment with BUP-XR. Patient reported outcomes suggest improvements in client wellbeing. Indivior [Display omitted] [ABSTRACT FROM AUTHOR]

Recent evidence reported that parental-derived phenotypes can be passed on to the next generations. Within the inheritance of epigenetic characteristics allowing the transmission of information related to the ancestral environment to the offspring, the specific case of the trans-generational effects of parental drug addiction has been extensively studied. Drug addiction is a chronic disorder resulting from complex interactions among environmental, genetic, and drug-related factors. Repeated exposures to drugs induce epigenetic changes in the reward circuitry that in turn mediate enduring changes in brain function. Addictive drugs can exert their effects trans-generally and influence the offspring of addicted parents. Although there is growing evidence that shows a wide range of behavioral, physiological, and molecular phenotypes in inter-, multi-, and trans-generational studies, transmitted phenotypes often vary widely even within similar protocols. Given the breadth of literature findings, in the present review, we restricted our investigation to learning and memory performances, as examples of the offspring's complex behavioral outcomes following parental exposure to drugs of abuse, including morphine, cocaine, cannabinoids, nicotine, heroin, and alcohol. • The effects of addictive drugs are transmitted to offspring trans-generationally. • Drug abuse is associated with modification of epigenetic patterns. • Parental exposure to drugs decreases memory ability of their offspring. • Parental morphine exposure could impair memory function in the offspring. • Prenatal exposure to heroin result in decrease dendritic length in their offspring. [ABSTRACT FROM AUTHOR]

Within addiction science, incubation of craving is an operational label used to describe time-dependent increases in drug seeking during periods of drug deprivation. The purpose of this systematic review was to describe the preclinical literature on incubation of craving and the clinical literature on craving measured over extended periods of abstinence to document this translational homology and factors impacting correspondence. Across the 44 preclinical studies that met inclusion criteria, 31 reported evidence of greater lever pressing, nose pokes, spout licks, or time spent in drug-paired compartments (i.e., drug seeking) relative to neutral compartments after longer periods of abstinence relative to shorter periods of abstinence, labelled as "incubation of craving." In contrast, no clinical studies (n = 20) identified an increase in opioid craving during longer abstinence periods. The lack of clinical evidence for increases in craving in clinical populations weakens the translational utility of operationalizing the time-dependent increase in drug-seeking behavior observed in preclinical models as models of incubation of "craving". • Incubation of opioid craving is not observed in clinical research. • Opioid craving decreases in humans over time during periods of abstinence. • The translational utility of the incubation of craving model needs refinement. [ABSTRACT FROM AUTHOR]

[Display omitted] • Current status of fast, rapid and on spot diagnosis of rape drugs. • Techniques including identification of several majorly known drugs are illuminated. • Biosensing methods with their future development and possibilities are summarised in this review. Drugs are extracted from plants and synthetic chemicals for their medicinal values and healing properties, these various drugs present worldwide can be of uncountable importance with each of it having different medicinal values that may help in the treatment of numerous lethal diseases, but on the other hand Illegitimate drug-associated incidents like sexual assaults and traffic accidents are gaining recurrence proportions worldwide. As for the clinical and forensic use to spot the evidences in case of sexual assaults the detection of drugs in biological fluids can be very important. Furthermore, there is widespread drug usage at some crucial workplaces, which can cause serious safety issues. This article would shed some light on the drugs that are widely involved in sexual assaults, as well as the many conventional techniques for detecting illicit drugs that have been developed. Ultraviolet spectroscopy, mass spectrometry (MS), thin layer chromatography, Microcrystalline test, infrared spectrometry, ion mobility spectrometry (IMS), Raman spectroscopy, Xray diffraction, spot/colour test, and immunoassay are some of the more prevalent procedures. These methods are primarily employed to identify illicit drugs, but they are both costly and time-consuming. For the fast diagnosis of these drugs, various sensors such as colorimetric sensors, fluorescence sensors, and electrochemical sensors were developed for most popular rape medications, including cocaine, cannabis, methamphetamine, fentanyl, morphine, heroin, and benzodiazepine (diazepam, oxazepam, clonazepam etc). [ABSTRACT FROM AUTHOR]