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.

Marked Increase in Amphetamine-Related Emergency Department Visits and Inpatient Admissions in Toronto, Canada, 2014-2021.

BACKGROUND: We report emergency department and inpatient amphetamine-related trends focusing on co-occurring substance use and psychiatric diagnoses at the Centre for Addiction and Mental Health, the largest mental health teaching hospital in Canada. METHODS: We describe yearly trends in amphetamine-related Centre for Addiction and Mental Health emergency department visits and inpatient admissions out of all emergency department visits and inpatient admissions between 2014 and 2021, along with proportions of concurrent substance-related admissions and mental/psychotic disorders emergency department visits and inpatient admissions among amphetamine-related contacts; joinpoint regression analyses assessed changes in amphetamine-related emergency department visits and inpatient admissions. RESULTS: Amphetamine-related emergency department visits rose from 1.5% in 2014 to 8.3% in 2021, with a peak of 9.9% in 2020. Amphetamine-related inpatient admissions rose from 2.0% to 8.8% in 2021, with a peak of 8.9% in 2020. Significant increasing trends in the percentage of amphetamine-related emergency department visits happened especially between the second and the fourth quarter of 2014 (quarterly percent change = + 71.4, P <0.01). Similarly, the percentage of amphetamine-related inpatient admissions increased mostly between the second quarter of 2014 and the third quarter of 2015 (quarterly percent change = + 32.6, P <0.01). The proportion of concurrent opioid-related contacts among amphetamine-related emergency department visits and inpatient admission increased markedly between 2014 and 2021; psychotic disorders in amphetamine-related inpatient admissions more than doubled from 2015 to 2021. DISCUSSION: Prevalence of amphetamine use, mostly from methamphetamine, has been increasing in Toronto as have co-occurring psychiatric disorders and opioid use. Our findings highlight the need for increases in accessible efficacious treatments for complex populations with polysubstance use and co-occurring disorders.

Cannabis and Inflammatory Mediators.

INTRODUCTION: Although the recreational cannabis use is expressive worldwide, the literature about medical potential of cannabis extracts, including its anti-inflammatory properties, remains inconclusive. METHODS: We screened all articles, published on the PubMed database, on inflammatory mediators and any information about cannabis use from 1980 to March 2019. RESULTS: Six studies were included, and the main findings were as follows: (i) among healthy volunteers and cannabis users, cannabinoids seemed to decrease the inflammatory response, thus decreasing the immune response, which led to a higher risk of infections; (ii) among patients with multiple sclerosis, cannabinoids seemed to have little impact on the inflammatory markers' levels. DISCUSSION: Although cannabis use can produce immune inflammatory suppression in healthy people, this effect is not robust enough to change inflammatory mediators' levels in situations of highly dysfunctional inflammatory activation. Nevertheless, the impact of cannabinoids in clinical outcomes of these conditions remains to be determined.

Z-Drug Use and Benzodiazepine Use and Misuse Among LGB Populations: The Role of Psychological Distress.

BACKGROUND: Z-drugs (hypnotics such as zolpidem, zopiclone, and zaleplon) and benzodiazepines (BZDs) are sedative medications with misuse liability. The goals of this study are to report the (1) prevalence of past-year any Z-drug use, any BZD use, and any BZD misuse by sexual identity category and psychological distress; (2) associations among these 3 categories between sexual identity and past-year psychological distress; (3) associations among these 3 categories with sexual identity by past-year psychological distress status. METHODS: Data were collected from the National Survey on Drug Use and Health (years 2015-2019 [n = 210,392]), a yearly representative national household survey of the American population. We report prevalences of any Z-drug use, any BZD use, and any BZD misuse by sexual identity and past-year psychological distress status. We ran logistic regressions with complex survey design with the 3 dichotomous variables described above as the dependent variables, stratified and not-stratified by psychological distress. RESULTS: Prevalence of any Z-drug an BZD use and any BZD misuse were higher among LGB (lesbian/gay/bisexual) populations, especially gay men and bisexual women. Psychological distress was positively associated with any Z-drug and BZD use and any BZD misuse. Women were at higher risk of Z-drug (odds ratio [OR], 1.27; 95% confidence interval [CI], 1.18-1.37) and BZD use (OR, 1.64; 95% CI, 1.55-1.73), but lower risk of BZD misuse (OR, 0.82; 95% CI, 0.76-0.88). When stratifying by psychological distress, differences between LGB and heterosexuals were more pronounced among those without past-year psychological distress, especially gay men and bisexual women. CONCLUSIONS: The presence of psychological distress attenuates the disparities between LGB and heterosexual individuals in Z-drug use and BZD use and misuse.

Prescription psychostimulants for the treatment of amphetamine-type stimulant use disorder: A systematic review and meta-analysis of randomized placebo-controlled trials.

BACKGROUND AND AIMS: There is currently no standard of care for pharmacological treatment of amphetamine-type stimulant (ATS) use disorder (ATSUD). This systematic review with meta-analysis (PROSPERO CRD42022354492) aimed to pool results from randomized placebo-controlled trials (RCTs) to evaluate efficacy and safety of prescription psychostimulants (PPs) for ATSUD. METHODS: Major indexing sources and trial registries were searched to include records published before 29 August 2022. Eligible studies were RCTs evaluating efficacy and safety of PPs for ATSUD. Risk of bias (RoB) was assessed using the Cochrane RoB 2 tool. Risk ratio (RR) and risk difference were calculated for random-effect meta-analysis of dichotomous variables. Mean difference and standardized mean difference (SMD) were calculated for random-effect meta-analysis of continuous variables. RESULTS: Ten RCTs (n = 561 participants) were included in the meta-analysis. Trials studied methylphenidate (n = 7), with daily doses of 54-180 mg, and dextroamphetamine (n = 3), with daily doses of 60-110 mg, for 2-24 weeks. PPs significantly decreased end-point craving [SMD  -0.29; 95% confidence interval (CI) = -0.55, -0.03], while such a decrease did not reach statistical significance for ATS use, as evaluated by urine analysis (UA) (RR = 0.93; 95% CI = 0.85-1.01). No effect was observed for self-reported ATS use, retention in treatment, dropout following adverse events, early-stage craving, withdrawal and depressive symptoms. In a sensitivity analysis, treatment was associated with a significant reduction in UA positive for ATS (RR = 0.89; 95% CI = 0.79-0.99) after removing studies with a high risk of bias. In subgroup analyses, methylphenidate and high doses of PPs were negatively associated with ATS use by UA, while higher doses of PPs and treatment duration (≥ 20 weeks) were positively associated with longer retention. CONCLUSIONS: Among individuals with amphetamine-type stimulant use disorder, treatment with prescription psychostimulants may decrease ATS use and craving. While effect size is limited, it may increase with a higher dosage of medications.

The COVID-19 impact and characterization on substance use-related emergency department visits for adolescents and young adults in Canada: Practical implications.

RATIONALE: Coronavirus (COVID-19)-related stressors precipitated the mental health crisis and increased substance use in Canada and worldwide. As the pandemic continues to evolve, monitoring and updating substance use-related ED visit trends is essential to ensure the stability and quality of ED services under the prolonged pandemic timeline. AIMS AND OBJECTIVES: This study examined the trends and characterization of substance use-related ED visits during the pandemic among adolescents and young adults (aged 13-25 years) in Ontario, Canada. METHODS: Descriptive statistics and binary logistic regression analyses were conducted using population-based, repeated cross-sectional data. The volume, patient characteristics (age and sex) and hospital/ED visit features (triage to end time, timing of the visit, triage level and referral source) were compared before (2019) and during COVID-19 (2020 and 2021) by each substance type (alcohol, opioid, cannabis, sedatives, cocaine, stimulants and multiple psychoactive substances). RESULTS: Substance use-related ED visits decreased by 1.5 times during the pandemic compared to the prepandemic level. However, opioid-related ED visits continued to show an increasing trend and did not recover to the prepandemic level in 2021. Moreover, a significant increase in emergent/life-threatening triage levels (Canadian Triage and Acuity Scales 1 and 2) in substance-related ED visits is alarming (2019 = 36.8%, 2020 = 38.7% and 2021 = 38.4%). We also found a general decrease in weekend visits, overnight visits and visits on statutory holidays, and substance use-related ED patients tended to stay longer (over 6 h) in the ED during the pandemic. CONCLUSION: Our findings indicate unmet substance use treatment needs due to the limited accessibility and heightened threshold for ED visits during the pandemic. Providing access to substance treatment/programs outside ED is critical to reducing substance use-related complications presenting in the ED. Also, policies addressing the pandemic-related complexities in the ED and Health Human Resource challenges are warranted.

Gabapentin Use Among Individuals Initiating Buprenorphine Treatment for Opioid Use Disorder.

Importance: Gabapentin prescriptions have drastically increased in the US due to off-label prescribing in settings such as opioid use disorder (OUD) treatment to manage a range of comorbid conditions and withdrawal symptoms, despite a lack of evidence. Objective: To assess the purpose and associated risks of off-label gabapentin use in OUD treatment. Design, Setting, and Participants: This retrospective recurrent-event case-control study with a crossover design used administrative claims data from MarketScan Commercial and Multi-State Medicaid databases from January 1, 2006, to December 31, 2016. Individuals aged 12 to 64 years with an OUD diagnosis and filling buprenorphine prescriptions were included in the primary analysis conducted from July 1, 2022, through June 1, 2023. Unit of observation was the person-day. Exposures: Days covered by filled gabapentin prescriptions. Main Outcomes and Measures: Primary outcomes were receipt of gabapentin in the 90 days after initiation of buprenorphine treatment and drug-related poisoning. Drug-related poisonings were defined using codes from International Classification of Diseases, Ninth Revision, and International Statistical Classification of Diseases and Related Health Problems, Tenth Revision. Results: A total of 109 407 patients were included in the analysis (mean [SD] age, 34.0 [11.2] years; 60 112 [54.9%] male). Among the 29 967 patients with Medicaid coverage, 299 (1.0%) were Hispanic, 1330 (4.4%) were non-Hispanic Black, 23 112 (77.1%) were non-Hispanic White, and 3399 (11.3%) were other. Gabapentin was significantly less likely to be prescribed to Black or Hispanic patients, and more likely to be prescribed to female patients, those with co-occurring substance use or mood disorders, and those with comorbid physical conditions such as neuropathic pain. Nearly one-third of persons who received gabapentin (4336 [31.1%]) had at least 1 drug-related poisoning after initiating buprenorphine treatment, compared with 13 856 (14.5%) among persons who did not receive gabapentin. Adjusted analyses showed that days of gabapentin use were not associated with hospitalization for drug-related poisoning (odds ratio, 0.98 [95% CI, 0.85-1.13]). Drug-related poisoning risks did not vary based on dosage. Conclusions and Relevance: Gabapentin is prescribed in the context of a myriad of comorbid conditions. Even though persons receiving gabapentin are more likely to have admissions for drug-related poisoning, these data suggest that gabapentin is not associated with an increased risk of drug-related poisoning alongside buprenorphine in adjusted analyses. More data on the safety profile of gabapentin in OUD settings are needed.

Drug overdose deaths in Brazil between 2000 and 2020: an analysis of sociodemographics and intentionality.

OBJECTIVES: To examine drug overdose records in Brazil from 2000 to 2020, analyzing trends over time in overdoses and overall sociodemographic characteristics of the deceased. METHODS: Using data from the Brazilian Mortality Information System (Sistema de Informações sobre Mortalidade), we identified records from 2000-2020 in which the underlying cause-of-death was one of the following codes: X40-X45 (accidental poisoning), X60-X65 (intentional poisoning), or Y10-Y15 (undetermined intentionality poisoning). The Brazilian dataset included 21,410 deaths. We used joinpoint regression analysis to assess changes in trends over time. RESULTS: People who died of drug overdoses in Brazil between 2000 and 2020 had a mean age of 38.91 years; 38.45% were women, and 44.01% were identified as White. Of the overdose deaths, 44.70% were classified as intentional and 32.12% were classified as unintentional. Among the identified drugs, stimulants were the most common class. However, most records did not report which drug was responsible for death. CONCLUSION: Sociodemographic trends in overdose deaths in Brazil must guide country-specific policies. Nevertheless, data collection protocols must be improved, particularly regarding the drug used in overdoses.

Overdose deaths involving non-BZD hypnotic/sedatives in the USA: Trends analyses.

Background: There is sparse knowledge on overdose deaths resulting from non-benzodiazepines and gabapentinoids usage. We examined overdose death rate across demographics categories and the overdose death trends over time. Methods: Using data from the National Center for Health Statistics (USA), we identified 21,167 persons that died with an overdose ICD code as the underlying cause of death and had a T42.6/T42.7 ICD code, which include gabapentinoids and z-drugs, among their multiple causes of death. The overdose death rate was calculated per 100,000 persons for every year between 2000 and 2018. We used joinpoint regression analyses to assess trends over time. Results: We identified a rise in the proportion of deaths with a T42.6/T42.7 ICD code between 2000 and 2006 (yearly change: +0.06) and between 2006 and 2015 (yearly change: +0.32). From 2000 to 2008, the proportion of deaths with any other T code rose significantly (yearly change: +3.56). Between 2008 and 2018, there was also a significant rise (yearly change: +1.31). From 2000 to 2015, the proportion of deaths with a T42.6/T42.7 ICD code with any other T code rose (yearly change: +2.58). From 2000 to 2015, the proportion of deaths with a T42.6/T42.7 ICD code with a concurrent benzodiazepine T code rose (yearly change: +1.98). From 2000 to 2005, the proportion of alcohol T codes rose non-significantly (yearly change: +0.35). Finally, the proportion of alcohol T codes fell significantly between 2008 and 2018 (yearly change: - 0.74). Interpretation: Deaths due to non-benzodiazepine hypnotics and gabapentinoids increased significantly over the last two decades. Clinicians should not assume that replacing benzodiazepines and opioids with these medications necessarily lowers risk to the patient. Funding: This study was funded by an internal grant from the Columbia University President's Global Innovation Fund (PI: Martins).

Differences in use of inhalants among sexual minorities in the USA in 2015-2018.

OBJECTIVES: Inhalants are substances with underestimated abuse potential associated with cardiac problems, dizziness, seizures, and decreased level of consciousness. Inhalants are commonly used by the LGB population, who are vulnerable to their harms. US epidemiologic inhalants data are scarce. The aims of this study are to: i) investigate associations between inhalant use and sexual identity groups; ii) examine associations with use of other drugs among lesbian/gays who use inhalants. METHODS: Data came from the 2015-2018 NSDUH (n = 168,560). Participants ages 18 or older were asked if they had used any inhalants in their lifetime and past-year. We investigated the associations between inhalant use with sexual identity categories heterosexual, lesbian/gay, and bisexual using logistic regression models with complex survey design. RESULTS: Total prevalences of lifetime and past-year use of inhalants were 9.4% and 0.5%, respectively. Lesbian/gay population (L/G) and bisexuals (B) reported higher odds of lifetime (L/G: aOR = 3.71, 95%CI = [3.19,4.30], B: aOR = 1.82, 95%CI = [1.64,2.03) and past-year (L/G: aOR = 11.57, 95%CI = [8.95,14.96], B: aOR = 2.81, 95%CI = [2.02,3.92]) inhalant use compared to heterosexuals. Among L/G, men had higher odds of lifetime (aOR = 4.11, 95%CI = [3.06,5.52]) and past-year (aOR = 15.67, 95%CI = [7.27,33.76]) inhalant use versus women. Use of marijuana (aOR = 2.76, 95%CI = [1.48,5.16]), other illegal drugs (aOR = 2.70, 95%CI = [1.60,4.56]), and non-medical use of psychotherapeutics (aOR = 2.67, 95%CI = 1.77,4.05) were associated with past-year use of inhalants among L/G. CONCLUSION: LGB population is at elevated risk of inhalant use and of concurrent use with other drugs. Gay men had significantly higher odds of inhalant use compared to lesbians and bisexuals. Informative and in-site harm reduction measures are warranted to prevent harms from inhalant use.

Treatment compliance and risk and protective factors for suicide ideation to completed suicide in adolescents: a systematic review.

OBJECTIVE: To review the literature regarding adolescent suicide risk and explore the associations between treatment compliance (expressed as a concept including measured adherence to treatment and/or mental health service utilization) and risk and protective factors for suicidal behavior (SB), as well as the association between treatment compliance and reattempts. METHODS: PubMed, LILACS, and Google Scholar were searched using the following terms: (adolescent*) AND (suicide*) AND (risk factor OR protective factors) AND (treatment compliance OR treatment attrition OR treatment adherence OR treatment drop out OR treatment retention OR mental health utilization). We retrieved studies that focused on the relation of treatment compliance to risk and protective factors for SB and that had only adolescent samples. RESULTS: Of 4,841 articles, 30 original articles were selected for review. Most studies indicated high mental health service (MHS) utilization and poor treatment adherence by SB patients. Social minority status and conduct disorder were associated with less treatment adherence, while female sex, parental perceived need for treatment, and major depression were associated with greater treatment adherence. Inpatient and intensive emergency care after SA and family interventions improved MHS utilization and treatment compliance. However, we found no substantial protective effect of treatment compliance against reattempts. CONCLUSION: Effective treatment planning for compliance requires considering psychopathology, treatment planning, and social, familial, and individual factors.

Prescription psychostimulants for the treatment of stimulant use disorder: a systematic review and meta-analysis.

RATIONALE: Agonist-based pharmacologic intervention is an accepted approach in treatment of opioid and tobacco use disorders. OBJECTIVES: We conducted a systematic review and meta-analysis to evaluate usefulness of an agonist approach as treatment of (psycho)stimulant use disorder (PSUD). METHODS: We reviewed PubMed/Medline, LILACS, and ClinicalTrials.gov databases searching for randomized, double-blind, placebo-controlled, parallel-design studies evaluating outcomes of individuals treated for cocaine- or amphetamine-type substance use disorder. We combined results of all trials that included the following prescription psychostimulants (PPs): modafinil, methylphenidate, or amphetamines (mixed amphetamine salts, lisdexamphetamine, and dextroamphetamine). The combined sample consisted of 2889 patients. Outcomes of interest included the following: drug abstinence (defined as 2-3 weeks of sustained abstinence and the average maximum days of consecutive abstinence), percentage of drug-negative urine tests across trial, and retention in treatment. We conducted random-effects meta-analyses and assessed quality of evidence using the GRADE system. RESULTS: Thirty-eight trials were included. Treatment with PPs increases rates of sustained abstinence [risk ratio (RR) = 1.45, 95% confidence interval (CI) = (1.10, 1.92)] and duration of abstinence [mean difference (MD) = 3.34, 95% CI = (1.06, 5.62)] in patients with PSUD, particularly those with cocaine use disorder (very low-quality evidence). Prescription amphetamines were particularly efficacious in promoting sustained abstinence in patients with cocaine use disorder [RR = 2.44, 95% CI = (1.66, 3.58)], and higher doses of PPs were particularly efficacious for treatment of cocaine use disorder [RR = 1.95, 95% CI = (1.38, 2.77)] (moderate-quality evidence). Treatment with prescription amphetamines also yielded more cocaine-negative urines [MD = 8.37%, 95% CI = (3.75, 12.98)]. There was no effect of PPs on the retention in treatment. CONCLUSION: Prescription psychostimulants, particularly prescription amphetamines given in robust doses, have a clinically significant beneficial effect to promote abstinence in the treatment of individuals with PSUD, specifically the population with cocaine use disorder.

Drug overdose deaths in Brazil between 2000 and 2020: an analysis of sociodemographics and intentionality

Objectives: To examine drug overdose records in Brazil from 2000 to 2020, analyzing trends over time in overdoses and overall sociodemographic characteristics of the deceased. Methods: Using data from the Brazilian Mortality Information System (Sistema de Informações sobre Mortalidade), we identified records from 2000-2020 in which the underlying cause-of-death was one of the following codes: X40-X45 (accidental poisoning), X60-X65 (intentional poisoning), or Y10-Y15 (undetermined intentionality poisoning). The Brazilian dataset included 21,410 deaths. We used joinpoint regression analysis to assess changes in trends over time. Results: People who died of drug overdoses in Brazil between 2000 and 2020 had a mean age of 38.91 years; 38.45% were women, and 44.01% were identified as White. Of the overdose deaths, 44.70% were classified as intentional and 32.12% were classified as unintentional. Among the identified drugs, stimulants were the most common class. However, most records did not report which drug was responsible for death. Conclusion: Sociodemographic trends in overdose deaths in Brazil must guide country-specific policies. Nevertheless, data collection protocols must be improved, particularly regarding the drug used in overdoses.