Prescription psychostimulants for cocaine use disorder: A review from molecular basis to clinical approach.

Cocaine use is a public health concern in many countries worldwide, particularly in the Americas and Oceania. Overdose deaths involving stimulants, such as cocaine, have been increasing markedly in North America, especially with concurrent opioid involvement. To date, no pharmacological treatment is available to treat stimulant (including cocaine) use disorders. Prescription psychostimulants (PPs) could be useful to treat cocaine use disorder (CUD) as they share the pharmacological effects with cocaine, as evidenced by a recent meta-analysis that assessed 38 randomized clinical trials (RCTs). PPs were found to promote sustained abstinence and reduce drug use in patients with CUD. The aim of this paper is to provide a narrative review of the clinical pharmacology of PPs and comment on the current stage of evidence supporting PPs to treat CUD. We also propose a model of care that integrates PPs with evidence-based psychosocial interventions (such as cognitive-behavioural therapy [CBT] and contingency management [CM]), a harm reduction approach and case management with social support.

An observational prospective cohort study of naloxone use at witnessed overdoses, Kazakhstan, Kyrgyzstan, Tajikistan, Ukraine.

Objective: To determine whether participation in the United Nations Office on Drugs and Crime (UNODC) and the World Health Organization's (WHO) Stop Overdose Safely (S-O-S) take-home naloxone training project in Kazakhstan, Kyrgyzstan, Tajikistan and Ukraine resulted in naloxone use at witnessed opioid overdoses. Methods: An observational prospective cohort study was performed by recruiting participants in the implementation of the S-O-S project, which was developed as part of the broader S-O-S initiative. Training included instruction on overdose responses and naloxone use. Study participants were followed for 6 months after completing training. The primary study outcome was participants' naloxone use at witnessed overdoses, reported at follow-up. Findings: Between 400 and 417 S-O-S project participants were recruited in each country. Overall, 84% (1388/1646) of participants were interviewed at 6-month follow-up. The percentage who reported witnessing an overdose between baseline and follow-up was 20% (71/356) in Tajikistan, 33% (113/349) in Kyrgyzstan, 37% (125/342) in Ukraine and 50% (170/341) in Kazakhstan. The percentage who reported using naloxone at their most recently witnessed overdose was 82% (103/125) in Ukraine, 89% (152/170) in Kazakhstan, 89% (101/113) in Kyrgyzstan and 100% (71/71) in Tajikistan. Conclusion: Implementation of the UNODC-WHO S-O-S training project in four low- to middle-income countries resulted in the reported use of take-home naloxone at around 90% of witnessed opioid overdoses. The percentage varied between countries but was generally higher than found in previous studies. Take-home naloxone is particularly important in countries where emergency medical responses to opioid overdoses may be limited.

Report on the International Workshop on Drug Prevention and Treatment in Rural Settings Organized by United Nation Office on Drugs and Crime (UNODC) and World Health Organization (WHO).

Very little evidence has been reported in literature regarding the misuse of substances in rural areas. Despite the common perception of rural communities as a protective and risk-mitigating environment, the scientific literature demonstrated the existence of many risk factors in rural communities. The Drug Prevention and Health Branch (DHB) of the United Nations Office on Drugs and Crime (UNODC), and the World Health Organization (WHO), in June 2016, organized a meeting of experts in treatment and prevention of SUDs in rural settings. The content presented during the meeting and the related discussion have provided materials for the preparation of an outline document, which is the basis to create a technical tool on SUDs prevention and treatment in rural settings. The UNODC framework for interventions in rural settings is a technical tool aimed to assist policy makers and managers at the national level. This paper is a report on UNODC/WHO efforts to improve the clinical conditions of people affected by SUDs and living in rural areas. The purpose of this article is to draw attention on a severe clinical and social problem in a reality forgotten by everyone.

Sexual Dysfunction in Men Receiving Methadone Maintenance Treatment: Clinical History and Psychobiological Correlates.

A variety of studies evidenced a relationship between drug use disorders and sexual dysfunction. In particular, heroin and opioid agonist medications to treat heroin dependence have been found to be associated with erectile dysfunction and reduced libido. Controversial findings also indicate the possibility of factors other than the pharmacological effects of opioid drugs concurring to sexual dysfunction. With the present study, we investigated the link between sexual dysfunction and long-term exposure to opioid receptor stimulation (heroin dependence, methadone maintenance treatment, methadone dosage), the potentially related hormonal changes reflecting hypothalamus-pituitary-gonadal axis function and prolactin (PRL) pituitary release, the role of adverse childhood experiences in the clinical history and the concomitant symptoms of comorbid mental health disorders in contributing to sexual problems. Forty male patients participating in a long-term methadone treatment program were included in the present study and compared with 40 healthy control subjects who never used drugs nor abused alcohol. All patients and controls were submitted to the Arizona Sexual Experiences Scale (ASEX), Child Experiences of Care and Abuse-Questionnaire (CECA-Q) and the Symptom Check List-90 Scale. A blood sample for testosterone and PRL assays was collected. Methadone dosages were recorded among heroin-dependent patients on maintenance treatment. Methadone patients scored significantly higher than controls on the 5-item rating ASEX scale, on CECA-Q and on Symptoms Check List 90 (SCL 90) scale. Testosterone plasma levels were significantly lower and PRL levels significantly higher in methadone patients with respect to the healthy control group. ASEX scores reflecting sexual dysfunction were directly and significantly correlated with CECA-Q neglect scores and SCL 90 psychiatric symptoms total score. The linear regression model, when applied only to addicted patients, showed that methadone dosages were not significantly correlated with sexual dysfunction scores except for 'erectile dysfunction', for which an inverse association was evidenced. Testosterone values showed a significant inverse correlation with ASEX sexual dysfunction scores, CECA-Q neglect scores and psychiatric symptom at SCL 90 among methadone patients. PRL levels were directly and significantly correlated with sexual dysfunction scores, psychiatric symptoms at SCL 90 and CECA-Q neglect scores. Both testosterone and PRL did not correlate with methadone dosages. The present findings appear to support the view of childhood adversities and comorbid psychiatric symptoms contributing to sexual dysfunction and related hormonal changes among methadone patients, challenging the assumption that attributes sexual problems entirely to the direct pharmacological effects of opioid agonist medications.

Analysis of γ-hydroxy butyrate by combining capillary electrophoresis-indirect detection and wall dynamic coating: application to dried matrices.

γ-Hydroxybutyric acid (GHB) is a powerful central nervous system depressant, currently used in medicine for the treatment of narcolepsy and alcohol dependence. In recent years, it has gained popularity among illegal club drugs, mainly because of its euphoric effects as well as doping agent and date rape drug. The purpose of the present work was the development of a rapid analytical method for the analysis of GHB in innovative biological matrices, namely dried blood spots (DBSs) and dried urine spots (DUSs). The analytical method is based on capillary zone electrophoresis with indirect UV absorption detection at 210 nm and capillary wall dynamic coating. The background electrolyte is composed of a phosphate buffer containing nicotinic acid (probe for detection) and cetyltrimethylammonium bromide (CTAB, reversal of electroosmosis in wall dynamic coating). The influence of probe and CTAB concentration, together with buffer pH, on migration time and signal response was investigated. Under the optimized conditions, analytical linearity and precision were satisfactory; absolute recovery values were also high (>90 %); the use of dried matrices (DBSs and DUSs) was advantageous as an alternative matrix to classical ones. No interferences were found either from the most common exogenous or from endogenous compounds. This analytical approach can offer a rapid, precise and accurate method for GHB determination in innovative biological samples, which could be important for screening purposes in clinical and forensic toxicology. Graphical Abstract CE method, by combined indirect UV detection and dynamic coating, for GHB determination in DBSs and DUSs.

Pregabalin reduces cocaine self-administration and relapse to cocaine seeking in the rat.

Pregabalin (Lyrica™) is a structural analog of γ-aminobutyric acid (GABA) and is approved by the FDA for partial epilepsy, neuropathic pain and generalized anxiety disorders. Pregabalin also reduces excitatory neurotransmitter release and post-synaptic excitability. Recently, we demonstrated that pregabalin reduced alcohol intake and prevented relapse to the alcohol seeking elicited by stress or environmental stimuli associated with alcohol availability. Here, we sought to extend these findings by examining the effect of pregabalin on cocaine self-administration (0.25 mg/infusion) and on cocaine seeking elicited by both conditioned stimuli and stress, as generated by administration of yohimbine (1.25 mg/kg). The results showed that oral administration of pregabalin (0, 10 or 30 mg/kg) reduced self-administration of cocaine over an extended period (6 hours), whereas it did not modify self-administration of food. In cocaine reinstatement studies, pregabalin (10 and 30 mg/kg) abolished the cocaine seeking elicited by both the pharmacological stressor yohimbine and the cues predictive of cocaine availability. Overall, these results demonstrate that pregabalin may have potential in the treatment of some aspects of cocaine addiction.

A novel test using dried blood spots for the chromatographic assay of methadone.

A novel test has been developed for the analysis of methadone in dried blood spot specimens from patients undergoing methadone maintenance treatment. An isocratic reversed-phase high-performance liquid chromatography method with coulometric detection has been optimized for the determination of methadone. The clean-up of dried blood spots was performed by means of an original microextraction by packed sorbent procedure after microwave-assisted extraction of the drug with a suitable solvent. Extraction yields were satisfactory, always being higher than 90.0 %. The calibration curve was linear over the 4-500 ng mL(-1) concentration range. The method had satisfactory sensitivity (limit of quantitation of 4 ng mL(-1)), precision (relative standard deviation less than 5.8 %), selectivity and accuracy (recovery greater than 87.0 %). It was successfully applied to dried blood spot samples collected from heroin-addicted patients undergoing methadone maintenance therapy at dosages between 40 and 240 mg day(-1). The statistical analysis (Bland-Altman plot) showed that the results were in good agreement with those found from the analysis of plasma samples obtained from the same patients. Thus, the method has proved to be suitable for the monitoring of methadone by means of dried blood spots.

Psychobiological responses to unpleasant emotions in cannabis users.

Aim of this paper is to investigate the psychobiological reactions to experimentally induced negative emotional states in active marijuana-dependent smokers and whether changes in emotional reactivity were reversed by prolonged abstinence. Twenty-eight patients were randomly included into group A (fourteen active marijuana-dependent smokers) or group B (fourteen abstinent marijuana-dependent subjects). Emotional response evaluation of group B subjects was assessed after 6 months of abstinence. Fourteen healthy volunteers, matched for age and sex, were used as controls. Psychometric and emotional response evaluations were performed by administering Symptoms Check List-90 and State-Trait Anxiety Inventory Y-1 (STAI). Neutral and unpleasant set of pictures selected from the international affective picture system and the Self-Assesment Manikin procedure (SAM) have been used to determine ratings of pleasure and arousal. Before and after the experimental session, blood samples were collected to determine ACTH and cortisol plasma levels. Active cannabis users displayed significantly higher levels of pleasantness SAM scores and lower levels of arousal SAM scores compared to abstinent cannabis users and controls in response to emotional task. In a close parallel with psychological data, hormonal findings indicate a persistent hyperactivity of hypothalamus-pituitary-adrenal (HPA) axis in cannabis users, particularly among active marijuana smokers, and an impaired hormonal reaction to negative emotions, in comparison with healthy subjects. The capacity of the HPA axis to respond to stressful stimuli/negative emotions seems to be only partially recovered after 6 months of abstinence. Ours findings, although obtained in a small number of subjects, suggest an association between active cannabis use, subjective reduced sensitivity to negative emotions and threat and HPA axis dysfunction.

Violent Behaviours among Adolescents and Young Adults: Association with Psychoactive Substance Use and Parenting Styles.

This study extends existing research on the relationship between psychoactive substance use among young people and violent behaviour, by evaluating the possible effect of the modification of parenting in a nationally representative sample of 14,685 Italian students drawn from the 2019 wave of the ESPAD Italia survey (51% male; mean age about 17 years). Parental dimensions considered in the study were rule-setting, monitoring, and emotional support, as well as the possible absence of a parent. Relative risk ratios and binary logistic regressions were used to estimate the associations separately for adolescents (15-17) and young adults (18-19). Overall, parental rule-setting, perceived parental monitoring, and emotional support were protective factors for substance use, and the strength of this relationship increased with the frequency of use. Among adolescents, the absence of a parent represented a risk factor. In both age groups, the odds of engaging in violent behaviour was increased among those reporting alcohol intoxication and substance use and the greater the frequency of use, the greater the increase in the odds. As parental monitoring and emotional support decreased, the odds of engaging in violent behaviour increased (except in the case of lower parental support among young adults), while the opposite applies to parental rule-setting. The odds of engaging in violent behaviour were increased among those reporting the absence of a parent only in the adolescent age group. Parental rule-setting was found to have an effect only among adolescents, increasing the odds of violent behaviour among frequent drinkers. Our results might be helpful to signal adolescents who would be more prone to adopt violent behaviour in order to target prevention policies.

Early parent-child interactions and substance use disorder: An attachment perspective on a biopsychosocial entanglement.

This review aims to elucidate environmental and genetic factors, as well as their epigenetic and neuroendocrine moderators, that may underlie the association between early childhood experiences and Substance Use Disorders (SUD), through the lens of parental attachment. Here we review those attachment-related studies that examined the monoaminergic systems, the hypothalamic pituitary adrenal stress response system, the oxytoninergic system, and the endogenous opioid system from a genetic, epigenetic, and neuroendocrine perspective. Overall, the selected studies point to a moderating effect of insecure attachment between genetic vulnerability and SUD, reasonably through epigenetic modifications. Preliminary evidence suggests that vulnerability to SUDs is related with hypo-methylation (e.g. hyper-expression) of high-risk polymorphisms on the monoaminergic and hypothalamic pituitary adrenal system and hyper-methylation (e.g. hypo-expressions) of protective polymorphisms on the opioid and oxytocin system. These epigenetic modifications may induce a cascade of neuroendocrine changes contributing to the subclinical and behavioural manifestations that precede the clinical onset of SUD. Protective and supportive parenting could hence represent a key therapeutic target to prevent addiction and moderate insecure attachment.

Alcohol use disorders among adult children of alcoholics (ACOAs): Gene-environment resilience factors.

Both genetic and early environmental factors contribute to the pathogenesis of Alcohol Use Disorder (AUD). Gender and psychopathology symptoms might further moderate this association, resulting in an impairment of both the dopaminergic and serotoninergic pathways that sustain the binge, withdrawal and craving cycle. In a sample of of adult children of alcoholic parents (ACOAs) (n = 107) we compared those with and without an AUD, on socio-demographic variables, adverse childhood experiences, psychopathology symptoms and two polymorphisms associated with an impaired serotoninergic and dopaminergic neurotransmission (5HTTLPR and Taq1A/DRD2). A logistic regression revealed that an early caring environment might lower the risk of developing an AUD. When controlling for the actual psychopathology symptoms, being male and having the genotype associated with an impaired dopaminergic neurotransmission were still associated with AUD. Results were confirmed by an unsupervised approach that showed how the clusters characterised by being male and having the high risk genotypes were still associated with AUD compared to being female without the unfavourable dopamine genotype.Our results point to the need for implementing prevention strategies aimed at creating a caring environment especially in those families with an alcoholic parent. We further suggest that psycho-education as a symptom recognition and avoiding self-medication could improve the outcome in those subjects at higher risk, especially males.

Simultaneous determination of disulfiram and bupropion in human plasma of alcohol and nicotine abusers.

An isocratic high-performance liquid-chromatographic method has been developed for the simultaneous determination of disulfiram and bupropion in human plasma samples. Analyses were carried out on a C(8) reversed-phase column using a mobile phase composed of 50% acetonitrile and 50% aqueous phosphate buffer, containing triethylamine. Diode-array detection was used, operating at a wavelength of 250 nm. For the clean-up of plasma samples, a solid phase extraction procedure, based on C(2) cartridges, was implemented. Extraction yields of the analytes were satisfactory, being always higher than 84%. The calibration curve was linear over the 5-500 ng mL(-1) plasma concentration range for both disulfiram and bupropion. The method showed a high sensitivity (limit of detection of 1.5 ng mL(-1)) and satisfactory precision, selectivity and accuracy. The application to human plasma samples obtained from some alcohol and nicotine abusers also gave good results.

Buprenorphine-based regimens and methadone for the medical management of opioid dependence: selecting the appropriate drug for treatment.

Maintenance therapy with methadone or buprenorphine-based regimens reduces opioid dependence and associated harms. The perception that methadone is more effective than buprenorphine for maintenance treatment has been based on low buprenorphine doses and excessively slow induction regimens used in early buprenorphine trials. Subsequent studies show that the efficacy of buprenorphine sublingual tablet (Subutex®) or buprenorphine/naloxone sublingual tablet (Suboxone®) is equivalent to that of methadone when sufficient buprenorphine doses, rapid induction, and flexible dosing are used. Although methadone remains an essential maintenance therapy option, buprenorphine-based regimens increase access to care and provide safer, more appropriate treatment than methadone for some patients.

Buprenorphine in maintenance treatment: experience among Italian physicians in drug addiction centers.

The aim of this study was to assess the attitudes of Italian physicians regarding buprenorphine and its clinical use approximately 6 years after the medication was introduced into clinical practice. The sample consisted of 305 randomly selected physicians, working in public centers of drug addiction. In Italy buprenorphine seems a valid tool in the field of drug addiction treatment, although it is far from replacing methadone even though it seems to guarantee better compliance. Interviewees follow clinical experience more than international guidelines, with pharmaceutical company representatives as the most cited source for information about the medication. The data also suggests a need for the development of formal guidelines for treatment with buprenorphine in Italy.

Subtyping patients with heroin addiction at treatment entry: factor derived from the Self-Report Symptom Inventory (SCL-90).

BACKGROUND: Addiction is a relapsing chronic condition in which psychiatric phenomena play a crucial role. Psychopathological symptoms in patients with heroin addiction are generally considered to be part of the drug addict's personality, or else to be related to the presence of psychiatric comorbidity, raising doubts about whether patients with long-term abuse of opioids actually possess specific psychopathological dimensions. METHODS: Using the Self-Report Symptom Inventory (SCL-90), we studied the psychopathological dimensions of 1,055 patients with heroin addiction (884 males and 171 females) aged between 16 and 59 years at the beginning of treatment, and their relationship to age, sex and duration of dependence. RESULTS: A total of 150 (14.2%) patients with heroin addiction showed depressive symptomatology characterised by feelings of worthlessness and being trapped or caught; 257 (24.4%) had somatisation symptoms, 205 (19.4%) interpersonal sensitivity and psychotic symptoms, 235 (22.3%) panic symptomatology, 208 (19.7%) violence and self-aggression. These dimensions were not correlated with sex or duration of dependence. Younger patients with heroin addiction were characterised by higher scores for violence-suicide, sensitivity and panic anxiety symptomatology. Older patients with heroin addiction showed higher scores for somatisation and worthlessness-being trapped symptomatology. CONCLUSIONS: This study supports the hypothesis that mood, anxiety and impulse-control dysregulation are the core of the clinical phenomenology of addiction and should be incorporated into its nosology.

Socioeconomic Status, Parental Education, School Connectedness and Individual Socio-Cultural Resources in Vulnerability for Drug Use among Students.

BACKGROUND AND AIMS: Families who live in a disadvantaged socioeconomic situation frequently face substandard housing, unsafe neighborhoods, inadequate schools and more stress in their daily lives than more affluent families, with a host of psychological and developmental consequences that can hinder their children's development in many ways. However, the measurement of socioeconomic status among youth and its link with different forms of illicit substance use is challenging and still unclear. This paper extends existing research on the relationship between socioeconomic status and illicit drug use among adolescents by focusing on three different patterns of use (experimental, episodic and frequent) and making use of two indicators to improve the measurement of individual socioeconomic characteristics in a big sample of European students. METHODS: Data were drawn from the European school Survey Project on Alcohol and other Drugs (ESPAD), which, since 1995, collects comparable data among 15-to-16-year-old students to monitor trends in drug use and other risk behaviors across Europe. The sample comes from 28 countries that participated in the 2015 data collection. The consumption of cannabis, cocaine and heroin are considered, and the related patterns are identified based on the frequency of use. Family characteristics at student level are defined through two dimensions: parental educational level and perceived socioeconomic status. Multivariate multilevel mixed-effects logistic regression was performed in order to measure the association between individual characteristics and vulnerability for drug use. RESULTS: Some patterns of use, episodic and frequent in particular, were found strongly associated with a lower socioeconomic status and lower parental education. CONCLUSIONS: Our results suggest that drug policies should be combined with actions aimed at removing barriers to social inclusion that are attributable to the socioeconomic background of adolescents.

Implementation and Evaluation of a Psychoactive Substance Use Intervention for Children in Afghanistan: Differences Between Girls and Boys at Treatment Entry and in Response to Treatment.

Psychoactive substance use among children in Afghanistan is an issue of concern. Somewhere around 300,000 children in the country have been exposed to opioids that either parents directly provided to them or by passive exposure. Evidence-based and culturally appropriate drug prevention and treatment programs are needed for children and families. The goals of this study were to: (1) examine lifetime psychoactive substance use in girls and boys at treatment entry; and (2) examine differential changes in substance use during and following treatment between girls and boys. Children ages 10-17 years old entering residential treatment were administered the Alcohol, Smoking and Substance Involvement Screening Test for Youth (ASSIST-Y) at pre- and post-treatment, and at three-month follow-up. Residential treatment was 45 days for children and 180 days for adolescents and consisted of a comprehensive psychosocial intervention that included education, life skills, individual and group counseling and, for older adolescents, vocational skills such as embroidery and tailoring. Girls and boys were significantly different regarding lifetime use of five substances at treatment entry, with girls less likely than boys to have used tobacco, cannabis, stimulants, and alcohol, and girls more likely than boys to have used sedatives. Differences between boys and girls were found for past-three-month use of four substances at treatment entry, with girls entering treatment with higher past-three-month use of opioids and sedatives, and boys with higher past-three-month use of tobacco, cannabis, and alcohol. Change over the course of treatment showed a general decline for both girls and boys in the use of these substances. Girls and boys in Afghanistan come to treatment with different substance use histories and differences in past-three-month use. Treatment of children for substance use problems must be sensitive to possible differences between girls and boys in substance use history.