Impairment of the GABAergic system in the anterior insular cortex of heroin-addicted males.

Opioid addiction is a global problem, causing the greatest health burden among drug use disorders, with opioid overdose deaths topping the statistics of fatal overdoses. The multifunctional anterior insular cortex (AIC) is involved in inhibitory control, which is severely impaired in opioid addiction. GABAergic interneurons shape the output of the AIC, where abnormalities have been reported in individuals addicted to opioids. In these neurons, glutamate decarboxylase (GAD) with its isoforms GAD 65 and 67 is a key enzyme in the synthesis of GABA, and research data point to a dysregulation of GABAergic activity in the AIC in opioid addiction. Our study, which was performed on paraffin-embedded brains from the Magdeburg Brain Bank, aimed to investigate abnormalities in the GABAergic function of the AIC in opioid addiction by densitometric evaluation of GAD 65/67-immunostained neuropil. The study showed bilaterally increased neuropil density in layers III and V in 13 male heroin-addicted males compared to 12 healthy controls, with significant U-test P values for layer V bilaterally. Analysis of confounding variables showed that age, brain volume and duration of formalin fixation did not confound the results. Our findings suggest a dysregulation of GABAergic activity in the AIC in opioid addiction, which is consistent with experimental data from animal models and human neuroimaging studies.

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.

Compulsivity and Inhibitory Control Deficits in Abstinent Individuals With Heroin Addiction and Their Biological Siblings Compared With Unrelated Healthy Control Participants.

BACKGROUND: Compulsivity represents the performance of persistent and repetitive acts despite negative consequences and is considered one of the critical mechanisms for drug addiction. Although compulsivity-related neurocognitive impairments have been linked to addiction, it remains unclear whether these deficits might have predated drug abuse as potential familial susceptibilities. METHODS: A large sample of 213 adult participants were recruited, including 70 abstinent individuals addicted to heroin (HAs), 69 unaffected biological siblings of the HAs (siblings), and 74 unrelated healthy control participants. Compulsivity-related neurocognitive functions were evaluated using the intradimensional/extradimensional set-shift task and a probabilistic reversal learning task. Compulsive traits were measured by the Obsessive-Compulsive Inventory-Revised. Inhibitory control was assessed using the stop signal task and Stroop Color and Word Test. Network models for group recognition were conducted using multilayer perceptron neural networks. RESULTS: Data indicated that both HAs and siblings performed worse than healthy control participants on compulsivity-related aspects (i.e., shifting and reversal learning functions) and inhibitory control and had higher levels of self-reported compulsive traits. Furthermore, neural models revealed that a possible 3-facet clustering of neurocognitive deficits was linked to both HAs and siblings. CONCLUSIONS: Our findings suggest that deficits in shift reversal and inhibitory control aspects and elevated compulsive traits, shared by HAs and their unaffected siblings, may putatively represent conceivable markers associated with familial vulnerabilities implicated in the development of heroin dependence.

Inverse pattern of GABAergic system impairment in the external versus internal globus pallidus in male heroin addicts.

Opioid addiction is a global problem that has been exacerbated in the USA and Europe by the COVID-19 pandemic. The globus pallidus (GP) plays a prominent neurobiological role in the regulation of behaviour as an output station of the striato-pallidal system. GABAergic large projection neurons are the main neuronal type in the external (EGP) and internal (IGP) parts of the GP, where addiction-specific molecular and functional abnormalities occur. In these neurons, glutamate decarboxylase (GAD) with isoforms GAD 65 and 67 is a key enzyme in GABA synthesis, and experimental studies suggest GAD dysregulation in the GP of heroin addicts. Our study, which was performed on paraffin-embedded brains from the Magdeburg Brain Bank, aimed to investigate abnormalities in the GABAergic function of large GP neurons by densitometric evaluation of their GAD 65/67-immunostained thick dendrites. The study revealed a bilaterally decreased fibres density in the EGP paralleled by the increase in the IGP in 11 male heroin addicts versus 11 healthy controls (significant U-test P values). The analysis of confounding variables found no interference of age, brain volume, and duration of formalin fixation with the results. Our findings suggest a dysregulation of GABAergic activity in the GP of heroin addicts, which is consistent with experimental data from animal models and plays potentially a role in the disturbed function of basal ganglia circuit in opioid addiction.

Metabolic and functional substrates of impulsive decision-making in individuals with heroin addiction after prolonged methadone maintenance treatment.

Elevated impulsivity has been frequently reported in individuals with opioid addiction receiving methadone maintenance therapy (MMT), but the underlying neural mechanisms and cognitive subprocesses are not fully understood. We acquired functional magnetic resonance imaging (fMRI) data from 37 subjects with heroin addiction receiving long-term MMT and 33 healthy controls who performed a probabilistic reversal learning task, and measured their resting-state brain glucose using fluorine-18-fluorodeoxyglucose positron emission tomography (18F-FDG PET). Subjects receiving MMT exhibited significantly elevated self-reported impulsivity, and computational modeling revealed a marked impulsive decision bias manifested as switching more frequently without available evidence. Moreover, this impulsive decision bias was associated with the dose and duration of methadone use, irrelevant to the duration of heroin use. During the task, the switch-related hypoactivation in the left rostral middle frontal gyrus was correlated with the impulsive decision bias while the function of reward sensitivity was intact in subjects receiving MMT. Using prior brain-wide receptor density data, we found that the highest variance of regional metabolic abnormalities was explained by the spatial distribution of µ-opioid receptors among 10 types of neurotransmitter receptors. Heightened impulsivity in individuals receiving prolonged MMT is manifested as atypical choice bias and noise in decision-making processes, which is further driven by deficits in top-down cognitive control, other than reward sensitivity. Our findings uncover multifaceted mechanisms underlying elevated impulsivity in subjects receiving MMT, which might provide insights for developing complementary therapies to improve retention during MMT.

Malmö Treatment Referral and Intervention Study (MATRIS)-36-month follow-up on retention and substance use among patients referred from needle exchange to opioid agonist treatment-The role of stimulant use at baseline.

INTRODUCTION: Opioid use disorder (OUD) is the leading cause of overdose morbidity and mortality globally. Retention in opioid agonist treatment (OAT) is crucial as it effectively reduces overdose mortality among individuals suffering from OUD. Previous research on treatment retention among heroin-dependent individuals referred from needle exchange programs (NEP) to OAT is scarce, and with predictors for retention in OAT being somewhat inconclusive, further investigations into this subject is of great interest. The aim of our study was to assess 36-month treatment outcomes-defined as retention and illicit drug abstinence-and predictors of OAT discontinuation. METHODS: This is a longitudinal cohort study of 71 study subjects successfully referred from a NEP to OAT. Participants were included between October 2011 and April 2013 and followed for 36 months. The study collected data from a structured baseline interview and from patient records, including laboratory data. RESULTS: At the 36-month follow-up, retention was 51 % (n = 36), with mean days in treatment of 422 for those who discontinued treatment. Amphetamine use during the 30 days before inclusion was positively correlated with treatment discontinuation (AOR 1.22 [95 % CI 1.02-1.46]). No statistically significant association with retention was seen for gender, age, suicide attempt prior to treatment, or benzodiazepine use during 30 days prior to treatment. Opiate use and use of other substances were reduced over time, with major reductions occurring during the first 6 months. CONCLUSIONS: Hitherto, baseline factors predicting retention in OAT have been insufficiently demonstrated. Active referral from NEP to OAT is effective when it comes to long-term retention and reduction of substance use while in treatment. Except from use of amphetamine, the use of other substances prior to OAT was not associated with treatment discontinuation. Further and in-depth analyses of baseline predictors are of importance for OAT retention.

Characteristics of Stress Sensitivity in Heroin Use Disorder Patients during Their Opioid Agonist Treatment.

In the present study, performed on a sample of Heroin Use Disorder (HUD) patients undergoing Opioid Agonist Treatment (OAT), we attempted to explore the relationships between stress sensitivity and heroin addiction-related clinical aspects. HUD patients' stress sensitivity was evaluated with the Heroin/PTSD-Spectrum questionnaire (H/PSTD-S). The Drug Addiction History Questionnaire (DAH-Q), the Symptomatological Check List-90 (SCL-90), and The Behavioural Covariate of Heroin Craving inventory (CRAV-HERO) were all used, as were the Deltito Subjective Wellness Scale (D-SWS), a self-report scale evaluating subjective well-being; the Cocaine Problem Severity Index (CPSI), a questionnaire determining the extent of a cocaine problem; and the Marijuana Craving Questionnaire (MC-Q), an instrument assessing craving for cannabinoids. We checked correlations between stress sensitivity and the extent of HUD clinical features and compared patients with and without problematic stress sensitivity. H/PTSD-S was positively correlated with patients' income, altered mental status, legal problems, the lifetime different treatments index, the current treatment load index, and all SCL-90 indexes and factors. Regarding subjective well-being, stress sensitivity negatively correlated with the contrast best week (last five years) index. Patients with high-stress sensitivity were females with a low income. They exhibited a more severe mental status at treatment entry, greater difficulty in working adaptation, and legal problems during treatment. Additionally, these patients showed a higher level of psychopathology, more impairment in well-being, and more risky behaviours during treatment. Stress sensitivity, as H/PTSD-S, must be considered an outcome of HUD. HUD's addiction history and clinical features are significant risk factors for H/PTSD-S. Therefore, social and behavioural impairment in HUD patients could be considered the clinical expression of the H/PTSD spectrum. In summary, the long-term outcome of HUD is not represented by drug-taking behaviours. Rather, the inability to cope with the contingent environmental conditions is the key feature of such a disorder. H/PTSD-S, therefore, should be seen as a syndrome caused by an acquired inability (increased salience) concerning regular (daily) life events.

The effect of repetitive transcranial magnetic stimulation on electroencephalography microstates of patients with heroin-addiction.

The effects of transcranial magnetic stimulation in treating substance use disorders are gaining attention; however, most existing studies used subjective measures to examine the treatment effects. Objective electroencephalography (EEG)-based microstate analysis is important for measuring the efficacy of transcranial magnetic stimulation in patients with heroin addiction. We investigated dynamic brain activity changes in individuals with heroin addiction after transcranial magnetic stimulation using microstate indicators. Thirty-two patients received intermittent theta-burst stimulation (iTBS) over the left dorsolateral prefrontal cortex. Resting-state EEG data were collected pre-intervention and 10 days post-intervention. The feature values of the significantly different microstate classes were computed using a K-means clustering algorithm. Four EEG microstate classes (A-D) were noted. There were significant increases in the duration, occurrence, and contribution of microstate class A after the iTBS intervention. K-means classification accuracy reached 81.5%. The EEG microstate is an effective improvement indicator in patients with heroin addiction treated with iTBS. Microstates were examined using machine learning; this method effectively classified the pre- and post-intervention cohorts among patients with heroin addiction and healthy individuals. Using EEG microstate to measure heroin addiction and further exploring the effect of iTBS in patients with heroin addiction merit clinical investigation.

Environmental enrichment facilitates electric barrier induced heroin abstinence after incubation of craving in male and female rats.

BACKGROUND: Treatment strategies that aim to promote abstinence to heroin use and reduce vulnerability to drug-use resumption are limited in sustainability and long-term efficacy. We have previously shown that environmental enrichment (EE), when implemented after drug self-administration, reduces drug-seeking and promotes abstinence to cocaine and heroin in male rats. Here, we tested the effects of EE on abstinence in an animal conflict model in males and females, and after periods where incubation of craving may occur. METHODS: Male and female rats were trained to self-administer heroin followed by 3 or 21 days of a no-event-interval (NEI). Following NEI, rats were permanently moved to environmental enrichment (EE) or new standard (nEE) housing 3 days prior to resuming self-administration in the presence of an electric barrier adjacent to the drug access lever. Electric barrier current was increased daily until rats ceased self-administration. RESULTS: We found that 21 days of NEI led to significantly greater heroin self-administration and a trend toward shorter latencies to emit the first active lever press in the first abstinence session compared to 3 days of NEI. EE, when compared to nEE, led to longer latencies in the first abstinence session. Also, EE groups of both sexes and in both NEIs achieved abstinence criteria in significantly fewer numbers of sessions. CONCLUSIONS: EE facilitates abstinence in males and females and after periods where incubation of craving may occur. This suggests that EE may benefit individuals attempting to abstain from heroin use and may aid in the development of long term treatment strategies.

Estudio de seguimiento de 35 años de pacientes admitidos a tratamiento con metadona entre 1982-1984 en Asturias, España / A 35-year follow-up study of patients admitted to methadone treatment between 1982-1984 in Asturias, Spain

El objetivo fue evaluar el estado de una población dependiente a la heroína 35 años después de su primera inscripción en un tratamiento de mantenimiento con metadona (TMM). Se utilizó un protocolo ad hoc para evaluar morbilidad, consumo y tratamiento de la adicción en la muestra de supervivientes. Se calculó la razón de mortalidad estandarizada (RME) con un intervalo de confianza (IC) del 95%. Un total de 214 pacientes ingresaron en TMM entre 1982 y 1984 en el Servicio de Salud Pública de Asturias. Se recibió información sobre 195 sujetos, de los cuales 146 habían fallecido. Los hombres representaron el 77,5% de la cohorte del estudio. Durante el período de seguimiento de 35 años, la RME fue de 11,75 (IC 95% = 9,95 – 13,77). En la muestra de supervivientes, el 5,7% todavía estaba inscrito en TMM; el virus de inmunodeficiencia humana (VIH) se diagnosticó en un 38,77% y la hepatitis B/C en un 73,46%; el consumo actual de heroína se informó en un 4,1%. No hubo diferencias de género en la mortalidad o la condición de VIH y hepatitis B/C. Ninguna de las mujeres consumía heroína en el seguimiento de 35 años en comparación con el 5,26% de los hombres. En conclusión, nuestro estudio confirma la alta tasa de mortalidad a largo plazo, incluso después de la inscripción en TMM. (AU)

The objective was to evaluate outcomes in a heroin-dependent population 35 years after first enrolment in methadone maintenance treatment (MMT). An ad hoc protocol was used to assess drug misuse, treatment, and drug-related morbidity in the survivor sample. The standardized mortality ratio (SMR) and 95% confidence interval (CI) were calculated. A total of 214 heroin-dependent patients entered MMT between 1982 and 1984 in the Asturias Public Health Service. Information was received on 195 subjects, of whom 146 were deceased. Men accounted for 77.5% of the study cohort. Over the 35-year follow-up period, the SMR was 11.75 (95% CI = 9.95 – 13.77). In the survivor sample, 5.7% were still enrolled in MMT; human immunodeficiency virus (HIV) was diagnosed in 38.77% and hepatitis B/C in 73.46%. No differences were found between sexes in mortality or HIV and hepatitis B/C status. None of the female survivors were using heroin at the 35-year follow-up compared with 5.26% of males. In conclusion, our study confirms the high long-term mortality rate of heroin addicts, even after enrollment in MMT. (AU)

Prefrontal-habenular microstructural impairments in human cocaine and heroin addiction.

The habenula (Hb) is central to adaptive reward- and aversion-driven behaviors, comprising a hub for higher-order processing networks involving the prefrontal cortex (PFC). Despite an established role in preclinical models of cocaine addiction, the translational significance of the Hb and its connectivity with the PFC in humans is unclear. Using diffusion tractography, we detailed PFC structural connectivity with the Hb and two control regions, quantifying tract-specific microstructural features in healthy and cocaine-addicted individuals. White matter was uniquely impaired in PFC-Hb projections in both short-term abstainers and current cocaine users. Abnormalities in this tract further generalized to an independent sample of heroin-addicted individuals and were associated, in an exploratory analysis, with earlier onset of drug use across the addiction subgroups, potentially serving as a predisposing marker amenable for early intervention. Importantly, these findings contextualize a plausible PFC-Hb circuit in the human brain, supporting preclinical evidence for its impairment in cocaine addiction.

Effects of UGT2B7 rs7662029 and rs7439366 polymorphisms on sublingual buprenorphine metabolism in heroin addicts: An improved PCR-RFLP assay for the detection of rs7662029 polymorphism.

This study aimed to determine the effects of UGT2B7 rs7662029 and rs7439366 polymorphisms on plasma buprenorphine (BUP) concentration and different treatment responses in a sample of 109 patients with opioid use disorder (OUD) treated with sublingual BUP/naloxone. Polymorphisms were analysed by PCR-RFLP. Plasma concentrations of BUP and its metabolite norbuprenorphine were detected by LC-MS/MS. Craving, withdrawal, depression and anxiety were measured by appropriate scales. OUD patients with rs7439366 CC or rs7662029 GG genotypes had significantly lower dose-normalized (BUP/D) and dose/kg-normalized BUP (BUP/D.kg-1) levels than those who were CT or AA carriers. Significant associations between UGT2B7 rs7662029 and increased craving (p = 0.037) and withdrawal symptoms (p = 0.029) were detected. Our findings were pointing to an important role of UGT2B7 in the metabolism of sublingual BUP/naloxone in the heroin addicts for the first time. A novel PCR-RFLP assay was developed for the determination of UGT2B7 rs7662029 polymorphism, based on utilizing novel restriction enzyme.

Laser meridian massage decreased craving in men with opioid use disorder on methadone maintenance treatment.

BACKGROUND: The incidence of opioid use disorder (OUD) is increasing worldwide, and the opioid-related overdose crisis is currently a major global challenge. This study investigated the effects of adjuvant laser meridian massage (LMM) in men with OUD undergoing methadone maintenance treatment (MMT). METHODS: A case-controlled study was conducted from February 2019 to April 2020. Fourteen men with OUD on MMT were enrolled from an addiction treatment center as an experimental group. An age-matched control group comprising 13 men was also enrolled. The experimental group received LMM on the back, including over the Bladder meridian and Governor Vessel, three times weekly for 4 weeks. The control group received only MMT. Urinary morphine levels, patients' self-reports of the number of episodes or days of heroin use, and visual analog scale scores for heroin craving/refusal to use heroin during the previous week were evaluated. Quality of life was reported using the Short Form (SF)-12v2. RESULTS: The experimental group showed a significant decrease in heroin use (p < 0.05), whereas the control group showed a significant increase in heroin craving (p < 0.05). The SF-12v2 Health Survey revealed a significant improvement in physical health in the experimental group (P < 0.05). CONCLUSION: The results of this study suggest that laser meridian massage can be considered a safe, well-tolerated, and potentially useful adjuvant intervention for opioid use disorder.

Ribosomal DNA transcription is increased in the left nucleus accumbens of heroin-dependent males.

Opioid addiction is a worldwide problem accentuated in the USA and European countries by the COVID-19 pandemic. The nucleus accumbens (NAc) plays an outstanding neurobiological role in opioid addiction as a part of the striatum and key component of brain reward system. The striatal GABAergic medium spiny projection neurons (MSNs) are the main neuronal type in the NAc where addiction-specific synaptic plasticity occurs. The activity of ribosomal DNA (rDNA) transcription is crucial for neural plasticity and molecular studies suggest its increase in the NAc of heroin addicts. Silver-stained argyrophilic nucleolar organizer region (AgNOR) areas visualised in neuronal nuclei in paraffin-embedded brain sections are reliable morphological estimators of rDNA transcription and thus surrogate markers for the activity of brain regions. Our study revealed increased AgNOR areas in MSNs of the left NAc in 11 heroin addicts versus 11 healthy controls from the Magdeburg Brain Bank (U-test P = 0.007). No differences were observed in another investigated part of the striatum, namely the head of caudate nucleus, which is located closely to the NAc. The results were not confounded by significant differences in the age, brain volume and time of formalin fixation existing between compared groups. Our findings suggest an increased NAc activity in heroin addicts, which is consistent with human and animal experimental data.

Expression Quantitative Trait Locus rs6356 Is Associated with Susceptibility to Heroin Addiction by Potentially Influencing TH Gene Expression in the Hippocampus and Nucleus Accumbens.

Opioid addiction is a complicated and highly heritable brain disease. Dysfunction in dopaminergic signaling is involved in the pathogenesis of addictive disorders. Encoding a dopamine synthetase, the tyrosine hydroxylase (TH) gene has long been an interesting candidate in genetic association studies for opioid addiction. However, the mechanisms underlying associations of risk gene variants and opioid addiction remain unknown. In the present study, we first analyzed the association between TH gene variants and susceptibility and traits of heroin addiction in 801 patients with heroin addiction and 930 healthy controls. Methylation levels in the promoter region of the TH gene were detected and compared between the heroin addiction and healthy control groups. To reveal the potential mechanism of the association of TH gene variants and heroin addiction, correlations between the risk TH single nucleotide polymorphism (SNPs) for heroin addiction and the methylation and expression levels of the TH gene were examined. Our results demonstrated that SNP rs6356 was associated with susceptibility to heroin addiction. CpG TH_15 was hypermethylated in the heroin addiction group compared with the healthy control group. Notably, SNP rs6356 was correlated in an allele-specific manner with expression of the TH gene in the hippocampus and nucleus accumbens but not with methylation levels of CpG TH_15. Our findings suggest that the eQTL rs6356 was associated with susceptibility to heroin addiction by potentially affecting the expression of the TH gene in brain regions in the mesocorticolimbic dopamine system, including the hippocampus and nucleus accumbens.

Several nAChRs gene variants are associated with phenotypes of heroin addiction in Chinese Han population.

Heroin addiction is a chronic and complex brain disease. Nicotinic acetylcholine receptors (nAChRs) have been shown as major control points in many of the neurological and physiological disorders involved in heroin addiction. In the present study, thirty-three SNPs across nine nAChR genes were selected and probed for their associations with heroin addiction phenotypes in 801 unrelated northwestern Chinese Han patients. We found that rs2565055 in CHRNA2 gene was associated with daily dose of methadone treatment, and rs2672215, rs2672216 and rs2741865 in CHRNA10 gene were associated with the duration of the transition from first use to dependence (DTFUD). Cox multivariable regression analysis revealed that rs3743075, rs6495309 in CHRNA3, rs2304297 in CHRNA6, and rs1948 in CHRNB4 were associated with sexual desire in patients with heroin addiction. These findings were further supported by the identification of a haplotype block spanning CHRNA5, CHRNA3, and CHRNB4 that is correlated with changes in sexual desire after long-term heroin use. Our findings highlight associations between polymorphisms in nAChRs genes and the phenotypes of heroin addiction in the Chinese Han population. We suggest several nAChRs subunits as potential novel targets for the treatment of heroin addiction.

Assessing brain activity in male heroin-dependent individuals under methadone maintenance treatment: A resting-state fMRI study.

Methadone maintenance treatment (MMT) is recognized as an effective and mainstream alternative treatment for heroin addiction. However, the effect of long-term MMT on the local and global brain activity of heroin-dependent individuals during resting state remains unknown. Twenty-five heroin-dependent individuals under MMT, 26 heroin-dependent individuals after short-term abstinence (HA) and 42 healthy controls (HC) were included in the resting-state functional magnetic resonance imaging study. The craving before and after heroin cue exposure were evaluated among HA and MMT subjects. The difference in craving, regional homogeneity (ReHo) and related functional connectivity were analyzed among the three groups. We found that the craving before and after heroin cue exposure of MMT group was significantly lower than that of HA group. Compared with HA group, the MMT group showed higher ReHo value in the right orbitofrontal cortex and bilateral posterior central cortex. No significant difference in global brain connectivity based on differential ReHo regions was found among the three groups. This study demonstrated the long-term MMT could improve the local activity of executive control and somatosensory brain regions in heroin-dependent individuals. It suggested that MMT might be beneficial to restoring executive control and somatosensory function in the direction towards that of healthy controls.

Adult-Attention Deficit Hyperactive Disorder Symptoms Seem Not to Influence the Outcome of an Enhanced Agonist Opioid Treatment: A 30-Year Follow-Up.

The role of opioids and opioid medications in ADHD symptoms is still largely understudied. We tested the hypothesis that, in Heroin Use Disorder (HUD), when patients are treated with Agonist Opioid medications (AOT), treatment outcome is associated with the presence of Adult Attention-Deficit/Hyperactive Disorder (A-ADHD) symptomatology. A retrospective cohort study of 130 HUD patients in Castelfranco Veneto, Italy, covering 30 years, was divided into two groups according to the Adult ADHD Self-Report Scale (ASRS) score and compared them using demographic, clinical and pharmacological factors. Survival in treatment was studied by utilizing the available data for leaving treatment and relapsing into addictive behavior and for mortality during treatment as poor primary outcomes. Thirty-five HUD subjects (26.9%) were unlikely to have A-ADHD symptomatology, and 95 (73.1%) were likely to have it. Only current age and co-substance use at treatment entry differed significantly between groups. Censored patients were 29 (82.9%) for HUD patients and 70 (73.9%) for A-ADHD/HUD patients (Mantel-Cox test = 0.66 p = 0.415). There were no significant linear trends indicative of a poorer outcome with the presence of A-ADHD after adjustment for demographic, clinical and pharmacological factors. Conclusions: ADHD symptomatology does not seem to exert any influence on the retention in AOT of HUD patients.

Cranial Nerve Palsy Secondary to Botulism After Black Tar Heroin Use.

INTRODUCTION: Wound botulism (WB) is an uncommon but severe neuromuscular illness caused by the bacterium Clostridium botulinum in an infected wound. There has been a dramatic increase in WB associated with black tar heroin injection in California. CASE DESCRIPTION: A 50-year-old male with heroin abuse presented to the emergency department with a 2-day history of dysphagia and dysarthria. Physical examination revealed slurred speech, inability to manipulate tongue, and slowed eye movements. The patient was also noted to have progressive weakness during hospitalization. Laboratory findings were unremarkable, and further workup, including a computerized tomography scan of the head and soft neck tissue, showed no abnormal findings. Given the history of heroin abuse in Southern California and findings on physical examination, a diagnosis of WB needed to be considered as the differential. The Department of Health was contacted, and treatment was initiated with botulism antitoxin and metronidazole. Despite the treatment, the patient's condition did not improve, and the patient died. The resulting diagnosis was confirmed by C. botulism toxin A found in his serum a few days after the patient died. DISCUSSION: Progressive cranial nerve palsy with symmetric descending paralysis with heroin abuse should raise the suspicion of WB and require prompt diagnosis and treatment. This case highlights raising awareness of the disease could help lead to early diagnosis and treatment.

Elevation of DNA Methylation in the Promoter Regions of the Brain-Derived Neurotrophic Factor Gene is Associated with Heroin Addiction.

To study the potential role of brain-derived neurotrophic factor (BDNF) methylation in heroin addiction, we first detected the methylation level of seven CpG islands that included 106 CpG sites in the promoter regions of BDNF from 120 people addicted to heroin and 113 controls. Methylation quantitative trait locus (mQTL) analysis was then employed to determine the association between the single-nucleotide polymorphism rs6265, a well-known locus shown to be correlated with heroin addiction, and the methylation levels of these CpG sites. Finally, we used the JASPAR database to predict whether transcription factors could bind to these CpG sites. We found that the methylation levels of CpG islands 6 and 7 and the methylation levels of BDNF_45 and BDNF_80 were significantly higher in the heroin addiction group than in the control group. We also found that rs6265 was an mQTL and was associated with the methylation level of BDNF_58. Using the JASPAR database, we found that ALX homeobox 3 (ALX3), achaete-scute family bHLH transcription factor 1 (ASCL1) and aryl hydrocarbon receptor nuclear translocator 2 (ARNT2) could bind to CpG island 6, and ALX3 could bind to CpG island 7. In summary, we showed that increased DNA methylation in the promoter regions of the BDNF gene was associated with heroin addiction in Han Chinese.