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.

Serum brain-derived neurotrophic factor in relation to craving and duration of abstinence in patients with heroin dependence-A case-control study.

BACKGROUND AND OBJECTIVES: Addiction is a chronic disorder that comes with emotional and financial burdens. Several neurobiological factors were correlated to opiate-use disorder which is brain-derived neurotrophic factor (BDNF). BDNF has been found to be involved in long-term potentiation of synaptic strength, a mechanism that is thought to motivate both natural adaption mechanisms as well as the development of addictive behavior. In this study, we aimed to address the relation between BDNF serum level and heroin craving and the effect of duration of abstinence on them. METHODS: A case study was conducted on 80 subjects from Kasr Al-Ainy Psychiatry and Addiction Treatment Hospital with a history of heroin dependence and were divided into two groups: Group A had 40 active heroin-dependent subjects while in Group B, 40 subjects with 1-year heroin abstinence. Severity of addiction was assessed by the addiction severity index, heroin craving was measured by Brief Substance Craving Scale and serum BDNF level was investigated using an enzyme-linked immunosorbent assay. RESULTS: The findings show that active heroin users had significantly higher serum BDNF which is associated with high heroin craving in comparison to the abstinent group. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: This study revealed a significant positive correlation between serum BDNF levels and craving in active heroin users versus 1-year abstinent subjects. It is the first study to address the relationship between craving and serum BDNF level in a 1-year abstinent participants. These findings help to determine the brain alterations associated with illness and recovery in heroin dependence.

Relapse risk revealed by degree centrality and cluster analysis in heroin addicts undergoing methadone maintenance treatment.

BACKGROUND: Based on hubs of neural circuits associated with addiction and their degree centrality (DC), this study aimed to construct the addiction-related brain networks for patients diagnosed with heroin dependence undertaking stable methadone maintenance treatment (MMT) and further prospectively identify the ones at high risk for relapse with cluster analysis. METHODS: Sixty-two male MMT patients and 30 matched healthy controls (HC) underwent brain resting-state functional MRI data acquisition. The patients received 26-month follow-up for the monthly illegal-drug-use information. Ten addiction-related hubs were chosen to construct a user-defined network for the patients. Then the networks were discriminated with K-means-clustering-algorithm into different groups and followed by comparative analysis to the groups and HC. Regression analysis was used to investigate the brain regions significantly contributed to relapse. RESULTS: Sixty MMT patients were classified into two groups according to their brain-network patterns calculated by the best clustering-number-K. The two groups had no difference in the demographic, psychological indicators and clinical information except relapse rate and total heroin consumption. The group with high-relapse had a wider range of DC changes in the cortical-striatal-thalamic circuit relative to HC and a reduced DC in the mesocorticolimbic circuit relative to the low-relapse group. DC activity in NAc, vACC, hippocampus and amygdala were closely related with relapse. CONCLUSION: MMT patients can be identified and classified into two subgroups with significantly different relapse rates by defining distinct brain-network patterns even if we are blind to their relapse outcomes in advance. This may provide a new strategy to optimize MMT.

Cognitive Enhancer Donepezil Attenuates Heroin-Seeking Behavior Induced by Cues in Rats.

PURPOSE: Opioid use disorder is a significant global problem. Chronic heroin use is associated with impairment of cognitive function and conscious control ability. The cholinergic system can be disrupted following heroin administration, indicating that activation of the cholinergic system may prevent chronic heroin misuse. Donepezil as an inhibitor of cholinesterase has been reported to clinically improve cognition and attention. In this study, the inhibition of heroin self-administration and heroin-seeking behaviours by donepezil were evaluated in rats. METHODS: Rats were trained to self-administer heroin every four hours for 14 consecutive days under a fixed ratio 1 (FR1) reinforcement schedule, then underwent withdrawal for two weeks. A progressive ratio schedule was then used to evaluate the relative motivational value of heroin reinforcement. After withdrawal, a conditioned cue was introduced for the reinstatement of heroin-seeking behaviour. Donepezil (0.3-3 mg/kg, i.p.) was used during both the FR1 heroin self-administration and progressive ratio schedules. Immunohistochemistry was used to investigate the mechanism of action of donepezil in the rat brain. RESULTS: Pre-treatment with high dose donepezil (3 mg/kg) but not low doses (0.3-1 mg/kg) significantly inhibited heroin self-administration under the FR1 schedule. Donepezil decreased motivation values under the progressive ratio schedule in a dose-dependent manner. All doses of donepezil (1-3 mg/kg) decreased the reinstatement of heroin seeking induced by cues. Correlation analysis indicated that the inhibition of donepezil on heroin-seeking behaviour was positively correlated with an increased expression of dopamine receptor 1 (D1R) and dopamine receptor 2 (D2R) in the nucleus accumbens (NAc) and increased expression of choline acetyltransferase (ChAT) in the ventral tegmental area (VTA). CONCLUSIONS: The present study demonstrated that donepezil could inhibit heroin intake and heroin-seeking behaviour. Further, donepezil could regulate dopamine receptors in the NAc via an increase of acetylcholine. These results suggested that donepezil could be developed as a potential approach for the treatment of heroin misuse.

The motives and methods of methamphetamine and 'heroin' co-use in West Virginia.

BACKGROUND: Opioid and methamphetamine co-use is increasing across the USA with overdoses involving these drugs also rising. West Virginia (WV) has led the US in opioid overdose death rates since at least 2013 and rising co-use of methamphetamine with opioids has played a greater role in deaths over the last 5 years. METHODS: This study used rapid ethnography to examine methods and motivations behind opioids and methamphetamine co-use from the viewpoint of their consumers. Participants (n = 30) were people who injected heroin/fentanyl also using methamphetamine who participated in semi-structured interviews. RESULTS: We found multiple methods of co-using opioids and methamphetamine, whether alternately or simultaneously and in varying order. Most prioritized opioids, with motives for using methamphetamine forming three thematic categories: 'intrinsic use', encompassing both inherent pleasure of combined use greater than using both drugs separately or for self-medication of particular conditions; 'opioid assisting use' in which methamphetamine helped people manage their existing heroin/fentanyl use; and 'reluctant or indifferent use' for social participation, reflecting methamphetamine's low cost and easy availability. CONCLUSIONS: Methamphetamine serves multiple functions among people using opioids in WV. Beliefs persist that methamphetamine can play a role in preventing and reversing opioid overdose, including some arguments for sequential use being protective of overdose. 'Reluctant' uptake attests to methamphetamine's social use and the influence of supply. The impact on overdose risk of the many varied co-use patterns needs further investigation.

Assessing the Role of Corticothalamic and Thalamo-Accumbens Projections in the Augmentation of Heroin Seeking in Chronically Food-Restricted Rats.

Drug addiction is a chronic disorder characterized by compulsive drug seeking, and involves repetitive cycles of compulsive drug use, abstinence, and relapse. In both human and animal models of addiction, chronic food restriction increases rates of relapse. Our laboratory has reported a robust increase in drug seeking following a period of withdrawal in chronically food-restricted rats compared with sated controls. Recently, we reported that activation of the paraventricular nucleus of the thalamus (PVT) abolished heroin seeking in chronically food-restricted rats. However, the precise inputs and outputs of the PVT that mediate this effect remain elusive. The goal of the current study was to determine the role of corticothalamic and thalamo-accumbens projections in the augmentation of heroin seeking induced by chronic food restriction. Male Long-Evans rats were trained to self-administer heroin for 10 d. Next, rats were removed from the self-administration chambers and were subjected to a 14 d withdrawal period while sated (unlimited access to food) or mildly food-restricted (FDR). On day 14, rats were returned to the self-administration context for a 3 h heroin-seeking test under extinction conditions during which corticothalamic and thalamo-accumbens neural activity was altered using chemogenetics. Surprisingly, chemogenetic activation or inhibition of corticothalamic projections did not alter heroin-seeking behavior. Chemogenetic activation of thalamo-accumbens shell, but not core, projectors attenuated heroin seeking in FDR rats. The results indicate an important role for the PVT to nucleus accumbens shell projections in the augmentation of heroin seeking induced by chronic food restriction.SIGNIFICANCE STATEMENT Relapse to heroin use is one of the major obstacles in the treatment of opiate addiction. Triggers for relapse are modulated by environmental challenges such as caloric restriction. Elucidating the brain mechanisms that underlie relapse is critical for evidence-based treatment development. Here we demonstrate a critical role for the input from the paraventricular thalamus (PVT), a hub for cortical, sensory, and limbic information, to the nucleus accumbens shell (an area known to be important for reward and motivation) in the augmentation of heroin seeking in food-restricted rats. Our findings highlight a previously unknown role for the PVT in heroin seeking following a period of abstinence.

Structural violence and the need for compassionate use of methadone in Mexico.

BACKGROUND: Epidemiological data from Mexico have documented an increase in heroin use in the last decade. However, there is no comprehensive care strategy for heroin users, especially those who have been accused of a crime. The objective of this study was to describe the heroin and methadone use of intravenous heroin users of both sexes who have been in jail, to offer evidence for the formulation of health policy. METHODS: This study used an ethnographic approach, with open-ended interviews carried out from 2014 to the present. Heroin users of both sexes attending a private methadone clinic in Mexico City were invited to participate. The sample was non-probabilistic. All interviews were audiotaped and transcribed, and narratives were analyzed using thematic analysis. RESULTS: Participants in this study were 33 users of heroin, two of them women, who had been in prison. They ranged in age from 33 to 62 years, had used heroin for a period of 13-30 years, and were from three states: Michoacan, Oaxaca, and Mexico City. Three principal categories of analysis were structured: 1. Pilgrimage for help (dynamics of the drama of suffering, pain, and time through health care spaces); 2) methadone use as self-care; and 3) accessibility to methadone treatment. The impossibility of access to methadone treatment is a condition which motivates users in their journey. The dynamics of methadone use are interpreted as a form of self-care and care to avoid substance use. Reducing the psychological, physical, and harmful effects of the substance allows them to perform daily activities. The inability to access treatment leads to a significant effect on users who experience structural violence. CONCLUSION: Compassionate methadone treatment and holistic attention should be considered as a way to meet patients' needs and mitigate their suffering, based on public health policy that allows for human rights-based care.

Can the migration process influence the clinical expression of heroin use disorder in migrants to Italy?

BACKGROUND: For some time now, there has been a strong consensus that the migration process can influence the onset, course, development, outcome, and clinical aspects of psychiatric pathologies. METHODS: In this study, we have analyzed the influence of the migration process on the clinical expression of heroin use disorder (HUD). In a naturalistic case-control study, we compared, both at univariate and multivariate level, 30 migrant HUD (M-HUD) patients with 30 age/gender-matched Italian HUD (IT-HUD) patients. We also analyzed demographic data, drug addiction history, psychopathological symptoms, addictive behavior, and emotional reactivity to life events. RESULTS: Compared with IT-HUD pairs, at HUD Agonist Opioid Treatment, M-HUD patients were characterized by inadequate income and the presence of legal problems. They were more frequently at stage 3 of heroin addiction, with a concomitantly less frequent use of stimulants. Their age at the onset of heroin use was greater than that of subjects in the IT-HUD group. HUD post-traumatic stress disorder spectrum was present and was more severe in all M-HUD patients, but grief reactions and maladaptive behavior were the most discriminant traits. No differences were found in terms of addictive behaviors related to heroin craving or with respect to the severity/typology of psychopathology specific to HUD. CONCLUSIONS: The migratory process does not seem to be correlated with addictive behaviors or with psychopathology specific to HUD. It partly affects HUD history, and specifically correlates with emotional reactivity to loss and traumatic life events, so suggesting that in M-HUD individuals, the link between the migratory syndrome and HUD is very close.

Estimation of the impact of changing drug-use trend on HIV, hepatitis C and syphilis epidemics among people who use synthetic drug-only, polydrug and heroin-only during 2005-2035 in China: modelling study.

OBJECTIVE: The rapid expansion of the recreational drug market becomes a global health concern. It is worrying that the bacterial and viral infection epidemics linking to drug use may worsen accordingly. This study aimed to estimate the impacts of changing trend and behaviours of using heroin only, synthetic drug (SD) only and polydrug (using SD and heroin concurrently) on HIV, hepatitis C virus (HCV) and syphilis epidemics among people who use drugs in China by 2035. METHODS: We constructed a compartmental model to estimate HIV, HCV and syphilis epidemics in the dynamic drug-use trend by three scenarios: SD-only use, heroin-only use and polydrug use based on Monte Carlo simulations. The parameters for the model were collected from a comprehensive literature search. RESULTS: Our model estimated that polydrug use led to the highest HIV and HCV prevalence among three drug-use patterns. The prevalences were projected to increase from 10.9% (95% CI 10.2% to 11.5%) and 61.7% (95% CI 59.4% to 62.5%) in 2005 to 19.0% (95% CI 17.3% to 20.7%) and 69.1% (95% CI 67.3% to 69.5%), respectively, in 2035 among people using polydrug. Similarly, HIV and HCV prevalence in the SD-only group were projected to increase from 0.4% (95% CI 0.3% to 0.4%) and 19.5% (95% CI 19.4% to 21.7%) to 1.8% (95% CI 1.4 to 2.1%) and 33.7% (95% CI 33.2% to 34.9%) in 2005-2035. Conversely, HIV prevalence in the heroin-only group was projected to decrease from 8.0% (95% CI 7.6% to 8.1%) to 2.2% (95% CI 2.0% to 2.3%) in 2005-2035. Syphilis prevalence was estimated to remain unchanged in all population groups within this time frame. It was projected that the proportion of HIV transmitted by sexual transmission will increase compared with unsafe injection transmission in all people who use drugs from 2005 to 2035. CONCLUSION: Our modelling suggests that polydrug use is projected to lead to the highest HIV and HCV disease burden by 2035, and the proportion of HIV transmitted by sexual transmission will increase. Current HIV intervention among people using heroin seems effective according to our estimation.

The Impact of Childhood Emotional Abuse on Pain Interference Among People with Chronic Pain who Inject Drugs in Vancouver, Canada.

OBJECTIVE: High levels of chronic pain interference with daily activities are known to negatively impact quality of life. Although mental health conditions have been associated with pain interference and child abuse, research has been mixed regarding it acting as a mediator, with even less known among people who inject drugs. Therefore, we sought to explore childhood emotional abuse and pain interference among this population. METHODS: Data were derived from two prospective cohort studies of community-recruited people who inject drugs in Vancouver, Canada, between June 2014 and November 2016. We employed multivariable generalized estimating equations to examine the relationship between childhood emotional abuse and pain interference in the past six months. We also conducted a mediation analysis to examine whether mental health disorder diagnoses mediated this association. RESULTS: Among 822 eligible participants, 341 (41.5%) reported childhood emotional abuse. In a multivariable analysis, experiencing childhood emotional abuse remained independently associated with pain interference (adjusted odds ratio = 1.33, 95% confidence interval [CI] = 1.05-1.70) after adjusting for a range of confounders. Results from the mediation analysis yielded a statistically significant positive average causal mediation effect (ß = 0.01, 95% CI = 0.001-0.02). Approximately 12% of the effect was due to mediation. CONCLUSIONS: Our results demonstrate among people who inject drugs with chronic pain, those who experienced childhood emotional abuse were more likely to report pain interference, which was partially mediated by mental health disorder diagnosis history. These findings highlight the importance of incorporating screening and appropriate treatment for mental illness into chronic pain treatment.

Heroin delay discounting and impulsivity: Modulation by DRD1 genetic variation.

BACKGROUND: Dopamine D1 receptors (encoded by DRD1) are implicated in drug addiction and high-risk behaviors. Delay discounting (DD) procedures measure decisional balance between choosing smaller/sooner rewards vs larger/later rewards. Individuals with higher DD (rapid discounting) are prone to maladaptive behaviors that provide immediate reinforcement (eg, substance use). DRD1 variants have been linked with increased DD (in healthy volunteers) and opioid abuse. This study determined whether four dopaminergic functional variants modulated heroin DD and impulsivity. METHODS: Substance use, DD, and genotype data (DRD1 rs686 and rs5326, DRD3 rs6280, COMT rs4680) were obtained from 106 current heroin users. Subjects completed an array of DD choices during two imagined conditions: heroin satiation and withdrawal. Rewards were expressed as $10 heroin bag units, with maximum delayed amount of 30 bags. Delays progressively increased from 3 to 96 hours. RESULTS: DRD1 rs686 (A/A, n = 25; G/A, n = 56; G/G, n = 25) was linearly related to the difference in heroin DD (area under the curve; AUC) between the heroin satiation and withdrawal conditions; specifically, G/G homozygotes had a significantly smaller (satiation minus withdrawal) AUC difference score had higher drug-use impulsivity questionnaire scores, relative to A/A homozygotes, with G/A intermediate. DRD3 and COMT variants were not associated with these DD and impulsivity outcomes. CONCLUSION: DRD1 rs686 modulated the difference in heroin DD score between pharmacological states and was associated with drug-use impulsivity. These data support a role of DRD1 in opioid DD and impulsive behaviors.

The role of the paraventricular nucleus of the thalamus in the augmentation of heroin seeking induced by chronic food restriction.

Drug addiction is a chronic disorder that is characterized by compulsive drug seeking and involves cycling between periods of compulsive drug use, abstinence, and relapse. In both human addicts and animal models of addiction, chronic food restriction has been shown to increase rates of relapse. Previously, our laboratory has demonstrated a robust increase in drug seeking following a period of withdrawal in chronically food-restricted rats compared with sated rats. To date, the neural mechanisms that mediate the effect of chronic food restriction on drug seeking have not been elucidated. However, the paraventricular nucleus of the thalamus (PVT) appears to be a promising target to investigate. The objective of the current study was to examine the role of the PVT in the augmentation of heroin seeking induced by chronic food restriction. Male Long-Evans rats were trained to self-administer heroin for 10 days. Rats were then removed from the training chambers and experienced a 14-day withdrawal period with either unrestricted (sated) or mildly restricted (FDR) access to food. On day 14, rats underwent a 1-hour heroin-seeking test under extinction conditions, during which neural activity in the PVT was either inhibited or increased using pharmacological or chemogenetic approaches. Unexpectedly, inhibition of the PVT did not alter heroin seeking in food-restricted or sated rats, while enhancing neural activity in the PVT-attenuated heroin seeking in food-restricted rats. These results indicate that PVT activity can modulate heroin seeking induced by chronic food restriction.

Case Series: Rapid Induction Onto Long Acting Buprenorphine Injection for High Potency Synthetic Opioid Users.

BACKGROUND AND OBJECTIVES: Highly potent synthetic opioids (HPSO) are increasingly responsible for opioid overdose deaths in the United States. METHODS: In an open-label, uncontrolled trial to test the feasibility of extended-release buprenorphine (BXR) injection treatment of heroin-using individuals with opioid use disorder testing positive for HPSO, participants were enrolled and began an induction with sublingual BXR (n = 5). During the induction, ancillary medications (clonidine, clonazepam, zolpidem, and prochlorperazine) were provided for breakthrough opioid withdrawal symptoms. RESULTS: Two participants received the BXR injection on the second day of the induction and three participants on the third day. DISCUSSION AND CONCLUSION: All five participants were retained at least 1-month postinduction. SCIENTIFIC SIGNIFICANCE: It may be feasible to provide BXR treatment to HPSO-positive heroin users rapidly to achieve clinical stabilization. (Am J Addict 2020;00:00-00).

Fifteen years of heroin-assisted treatment in a Swiss prison-a retrospective cohort study.

BACKGROUND: In the context of the current US opioid crisis and the compelling fact that a quarter to a third of all those addicted to heroin pass through its prisons and jails each year, the care of incarcerated opioid-using individuals (OUI) needs to be improved. AIMS: Little has been published on the effectiveness or outcomes of heroin-assisted treatment (HAT), a treatment option for severely dependent OUI delivered in a prison setting. The aim of this study was therefore to evaluate such treatment since its implementation. The primary objective was to investigate whether heroin-assisted treatment was associated with severe detrimental health outcomes. The secondary objective was to compare the heroin-assisted treatment group with the general prison population in terms of occupational functioning. DESIGN: Retrospective cohort study SETTING: An open prison with 120 places SUBJECTS: Data on 1885 male prisoners with a total of 2239 imprisonment periods between 2000 and 2015 was available. Ninety-seven inmates in heroin-assisted treatment were compared with 1788 inmates from the general prison population (reference group). MEASUREMENTS: Mortality, medical complications (including overdoses), and work performance (days worked, sick days, and monthly wages earned). FINDINGS: Inmates receiving HAT were on average 1 year younger (33.8 vs. 34.9 years), had longer prison stays (7.3 vs. 3.0 months), were more often of Swiss nationality (68.0% vs. 28.9%), and had committed more drug- and property-related offenses (49.5% vs. 23.2% and 63.9% vs. 38.3%, respectively) compared to the reference group. No serious heroin-related medical complication occurred during the 15-year window of observation among inmates with heroin-assisted treatment. Their work performance was comparable to that of the reference group. CONCLUSIONS: This study shows that heroin-assisted treatment can be a valuable treatment option for severely dependent OUI during imprisonment, can be delivered safely by prison health staff over extended periods of time, and allows OUI in treatment to achieve work performance rates comparable to that of the general prison population.

The Affective and Neural Correlates of Heroin versus Cocaine Use in Addiction Are Influenced by Environmental Setting But in Opposite Directions.

Previous studies have shown that individuals with heroin and cocaine addiction prefer to use these drugs in distinct settings: mostly at home in the case of heroin and mostly outside the home in the case of cocaine. Here we investigated whether the context would modulate the affective and neural responses to these drugs in a similar way. First, we used a novel emotional task to assess the affective state produced by heroin or cocaine in different settings, based on the recollections of male and female drug users. Then we used fMRI to monitor neural activity during drug imagery (re-creating the setting of drug use) in male drug users. Consistent with our working hypothesis, the majority of participants reported a shift in the affective valence of heroin from mostly pleasant at home to mostly unpleasant outside the home (p < 0.0001). The opposite shift was observed for cocaine; that is, most participants who found cocaine pleasant outside the home found it unpleasant when taken at home (p < 0.0014). Furthermore, we found a double dissociation, as a function of drug and setting imagery, in BOLD signal changes in the left PFC and caudate, and bilaterally in the cerebellum (all p values <0.01), suggesting that the fronto-striatal-cerebellar network is implicated in the contextualization of drug-induced affect. In summary, we report that the same setting can influence in opposite directions the affective and neural response to psychostimulants versus opiates in humans, adding to growing evidence of distinct substrates for the rewarding effects of these two drug classes.SIGNIFICANCE STATEMENT The rewarding effects of addictive drugs are often thought to depend on shared substrates. Yet, environmental influences can unmask striking differences between psychostimulants and opiates. Here we used emotional tasks and fMRI to explore the influence of setting on the response to heroin versus cocaine in individuals with addiction. Simply moving from one setting to another significantly decreased heroin pleasure but increased cocaine pleasure, and vice versa. Similar double dissociation was observed in the activity of the fronto-striatal-cerebellar network. These findings suggest that the effects of opiates and psychostimulants depend on dissociable psychological and neural substrates and that therapeutic approaches to addiction should take into account the peculiarities of different drug classes and the settings of drug use.

Profiles of visuospatial memory dysfunction in opioid-exposed and dependent populations.

BACKGROUND: Chronic opioid exposure is common world-wide, but behavioural performance remains under-investigated. This study aimed to investigate visuospatial memory performance in opioid-exposed and dependent clinical populations and its associations with measures of intelligence and cognitive impulsivity. METHODS: We recruited 109 participants: (i) patients with a history of opioid dependence due to chronic heroin use (n = 24), (ii) heroin users stabilised on methadone maintenance treatment (n = 29), (iii) participants with a history of chronic pain and prescribed tramadol and codeine (n = 28) and (iv) healthy controls (n = 28). The neuropsychological tasks from the Cambridge Neuropsychological Test Automated Battery included the Delayed Matching to Sample (DMS), Pattern Recognition Memory, Spatial Recognition Memory, Paired Associate Learning, Spatial Span Task, Spatial Working Memory and Cambridge Gambling Task. Pre-morbid general intelligence was assessed using the National Adult Reading Test. RESULTS: As hypothesised, this study identified the differential effects of chronic heroin and methadone exposures on neuropsychological measures of visuospatial memory (p < 0.01) that were independent of injecting behaviour and dependence status. The study also identified an improvement in DMS performance (specifically at longer delays) when the methadone group was compared with the heroin group and also when the heroin group was stabilised onto methadone. Results identified differential effects of chronic heroin and methadone exposures on various neuropsychological measures of visuospatial memory independently from addiction severity measures, such as injecting behaviour and dependence status.

Cannabinoid CB1 receptor neutral antagonist AM4113 inhibits heroin self-administration without depressive side effects in rats.

Cannabinoid CB1 receptors (CB1Rs) have been shown to be a promising target in medication development for the treatment of addiction. However, clinical trials with SR141716A (rimonabant, a selective CB1R antagonist/inverse agonist) for the treatment of obesity and smoking cessation failed due to unwanted side effects, such as depression, anxiety, and suicidal tendencies. Recent preclinical studies suggest that the neutral CB1R antagonist AM4113 may retain the therapeutic anti-addictive effects of SR141716A in nicotine self-administration models and possibly has fewer unwanted side effects. However, little is known about whether AM4113 is also effective for other drugs of abuse, such as opioids and psychostimulants, and whether it produces depressive side effects similar to SR141716A in experimental animals. In this study, we demonstrated that systemic administration of AM4113 (3 and 10 mg/kg) dose-dependently inhibited the self-administration of intravenous heroin but not cocaine or methamphetamine, whereas SR141716A (3 and 10 mg/kg) dose-dependently inhibited the self-administration of heroin and methamphetamine but not cocaine. In the electrical brain-stimulation reward (BSR) paradigm, SR141716A (3 and 10 mg/kg) dose-dependently increased the BSR stimulation threshold (i.e., decreased the stimulation reward), but AM4113 had no effect on BSR at the same doses, suggesting that SR141716A may produce aversive effects while AM4113 may not. Together, these findings show that neutral CB1R antagonists such as AM4113 deserve further research as a new class of CB1R-based medications for the treatment of opioid addiction without SR141716A-like aversive effects.

Smoking heroin with cannabis versus injecting heroin: unexpected impact on treatment outcomes.

BACKGROUND: In several countries, especially in Africa, the dominant method of heroin intake is smoking a joint of cannabis laced with heroin. There is no data exploring the impact of smoking heroin with cannabis on treatment outcomes. AIM: To compare treatment outcomes between people who inject heroin and people who smoke heroin with cannabis. METHODOLOGY: Three hundred heroin users were assessed on admission to inpatient rehabilitation and after treatment. We compared drug use, psychopathology, criminality, social functioning and general health between heroin injectors and heroin-cannabis smokers at treatment entry, and at 3 and 9 months after rehabilitation. RESULTS: The sample comprised 211 (70.3%) heroin-cannabis smokers and 89 (29.7%) heroin injectors. Eighty-four percent were followed up at 3 months and 75% at 9 months. At 9 months, heroin-cannabis smokers had a higher proportion of those who relapsed to heroin use compared with intravenous (IV) users (p = 0.036). The median number of heroin use episodes per day was lower for IV users than heroin-cannabis smokers at both follow-up points (p = 0.013 and 0.0019). A higher proportion of IV users was HIV positive (p = 0.002). There were no significant differences in psychopathology, general health, criminality and social functioning between IV users and heroin-cannabis smokers at all three time points. CONCLUSIONS: Heroin users who do not inject drugs but use other routes of administration may have increased risk for relapse to heroin use after inpatient rehabilitation and should therefore have equal access to harm reduction treatment services. Advocating a transition from injecting to smoking heroin in an African context may pose unique challenges.

HIV risk behaviours among women who inject drugs in coastal Kenya: findings from secondary analysis of qualitative data.

BACKGROUND: Injecting drug users are at high risk of HIV infection globally. Research related to female drug users is rare in Kenya, yet it is required to inform the development of gender-sensitive HIV prevention and harm reduction services in East Africa, where injecting drug use is on the rise. METHODS: This study aimed to document the nature of HIV risks encountered by women who inject drugs in the Mombasa and Kilifi, Kenya. Secondary data analysis was conducted on an existing dataset from a 2015 primary qualitative study involving 24 interviews and 3 focus group discussions with 45 women who inject drugs. These were complemented with five interviews with key stakeholders involved in the provision of services to women who inject drugs. Guided by the social ecology theory, a thematic analysis was conducted to identify the nature of HIV risks and their underlying determinants. RESULTS: HIV risk behaviours fell into two broad categories: unsafe injecting and unprotected sex. These risks occurred in the form of sharing of needles, unprotected oral, anal, and vaginal sex, sexual assaults, injecting drug use during sex, sex work, and other types of transactional sex. The primary determinants underlying these risks were a low-risk perception, inequitable gender power, economic pressures, and poor availability of needles and condoms. These social-ecological determinants did not exist in isolation, but intersected with each other to create powerful influences which exposed women to HIV. Social-ecological determinants exerted constant influence and created a persistent 'HIV risk environment' that was involuntarily experienced by women. CONCLUSION: Individual, interpersonal, and societal-structural factors intersect to produce HIV risk behaviours. As a minimum, these risks will require a combination of multifaceted micro-level interventions including self-efficacy training, risk assessment skills, couple counselling, and universal access to the recommended harm reduction package. In addition, the current focus on micro-level interventions in Kenya needs to shift to incorporate macro-level interventions, including livelihood, employability, and gender norms-transforming interventions, to mitigate economic and gender-related drivers of HIV risks. In the Kenyan context, injecting drug use during sex work is emerging as an increasingly important HIV risk behaviour needing to be addressed.

Attenuation of response to drug-related cues in male heroin abstainers is modulated by cognitive control mechanisms.

Background: Many research studies reveal that both attentional bias and impaired cognitive control significantly influence heroin addiction. However, limited research has been conducted into how the interplay between attentional bias and cognitive control modulates heroin-seeking behavior. Objectives: A modified version of the flanker task was used to investigate whether attentional bias to drug-related stimuli is modulated by cognitive control mechanisms among heroin users. Methods: Sixty participants (30 male heroin users during their abstinence period and 30 normal controls) responded to the direction of the middle arrow, while ignoring the adjacent arrow and the pictures (drug-related cues and neutral cues) presented as part of the task. Results: The abstinent heroin users had a significantly larger flanker effect under drug-related cues compared to neutral cues, whereas the control group showed no such trend. This effect was primarily influenced by increased reaction times in the presence of drug-related cues relative to neutral cues in the incongruent condition among abstinent heroin users, but not in the control group. Conclusions/Importance: Among abstinent heroin users, attentional bias to drug-related cues was moderated by attentional control. Further, high cognitive control demand was found to reduce heroin users' ability to resist attentional capture from salient, but irrelevant, drug-related information, which may contribute to compulsive drug-seeking behavior and relapse in heroin users.