Evaluation of the immune system status and hematological dyscrasias, among amphetamine and cannabis abusers at Eradah Hospital in Qassim, Saudi Arabia.

This cross-sectional study aims to evaluate the immune system status and hematological disturbances among individuals who abuse amphetamines and cannabis. Substance abuse, particularly of amphetamines and cannabis, has been associated with various adverse effects on the body, including potential impacts on the immune system and hematological parameters. However, limited research has been conducted to comprehensively assess these effects in a cross-sectional design. Additionally, fungal infections are on the rise internationally, and immune-compromised people are particularly susceptible. The study will recruit a sample of amphetamine and cannabis abusers (n = 50) at the Eradah Hospital in the Qassim Region of Buraydah and assess their sociodemographic and biochemical variables, including blood indices and differential WBC indices, liver, and kidney profiles. Additionally, 50 sputum samples in total were cultured for testing for fungus infections. To obtain the descriptive statistics, the data was imported into Microsoft Excel and subjected to statistical analysis using SPSS 22.0. Amphetamine and cannabis abuser's sociodemographic variables analysis observed that the majority (52%) were aged 18-30, with 56% in secondary school. Unemployment was a significant issue, and most had no other health issues. The majority (50%) had 5-10 years of abuse, while 32% had less than 5 years, and only 18% had been drug abusers for more than 10 years. There were significant changes (p < 0.001) in all different leukocyte blood cells, including neutrophils, lymphocytes, monocytes, eosinophils, and basophils. Furthermore, a microscopic examination of blood films from individuals who misuse the combination of the medications "amphetamine and cannabis" reveals hazardous alterations in Neutrophils. Out of 50, 35 sputum samples showed positive growth on Sabouraud dextrose agar (SDA) with chloramphenicol antibiotic, indicating a unicellular fungal growth. The present study explores the immune system and hematological disturbances linked to amphetamine and cannabis abuse, providing insights into health risks and targeted interventions. The findings complement previous research on drug users' hematological abnormalities, particularly in white blood cells. Routine hematological tests help identify alterations in homeostatic conditions, improving patient knowledge and preventing major issues. Further research is needed on multi-drug abuse prevention, early detection, and intervention. The cross-sectional design allows for a snapshot of the immune system and hematological status among abusers, laying the groundwork for future longitudinal studies. Key Words: Drug Effect, Immunity, Epidemiology, Oxidative Stress, Inflammation.

Psychosis with use of amphetamine drugs, methylphenidate and atomoxetine in adolescent and adults.

BACKGROUND: Use of psychostimulants and relative drugs has increased worldwide in treatment of attention-deficit hyperactivity disorder (ADHD) in adolescents and adults. Recent studies suggest a potential association between use of psychostimulants and psychotic symptoms. The risk may not be the same between different psychostimulants. OBJECTIVE: To assess whether amphetamine or atomoxetine use is associated with a higher risk of reporting symptoms of psychosis than methylphenidate use in adolescents and adults, particularly in patients with ADHD. METHODS: Using VigiBase, the WHO's pharmacovigilance database, disproportionality of psychotic symptoms reporting was assessed among adverse drug reactions related to methylphenidate, atomoxetine and amphetamines, from January 2004 to December 2018, in patients aged 13-25 years. The association between psychotic symptoms and psychostimulants was estimated through the calculation of reporting OR (ROR). FINDINGS: Among 13 863 reports with at least one drug of interest, we found 221 cases of psychosis with methylphenidate use, 115 with atomoxetine use and 169 with a prescription of an amphetamine drug. Compared with methylphenidate use, amphetamine use was associated with an increased risk of reporting psychotic symptoms (ROR 1.61 (95% CI 1.26 to 2.06)]. When we restricted the analysis to ADHD indication, we found a close estimate (ROR 1.94 (95% CI 1.43 to 2.64)). No association was found for atomoxetine. CONCLUSION: Our study suggests that amphetamine use is associated with a higher reporting of psychotic symptoms, compared with methylphenidate use. CLINICAL IMPLICATIONS: The prescription of psychostimulants should consider this potential adverse effect when assessing the benefit-risk balance.

Prescription Stimulant Use During Pregnancy and Risk of Neurodevelopmental Disorders in Children.

Importance: Use of medications for attention-deficit/hyperactivity disorder (ADHD) during pregnancy is increasing in the US. Whether exposure to these medications in utero impacts the risk of neurodevelopmental disorders in children is uncertain. Objective: To evaluate the association of childhood neurodevelopmental disorders with in utero exposure to stimulant medications for ADHD. Design, Setting, and Participants: This cohort study included health care utilization data from publicly insured (Medicaid data from 2000 to 2018) and commercially insured (MarketScan Commercial Claims Database data from 2003 to 2020) pregnant individuals aged 12 to 55 years in the US with enrollment from 3 months prior to pregnancy through 1 month after delivery, linked to children. Children were monitored from birth until outcome diagnosis, disenrollment, death, or end of the study (December 2018 for Medicaid and December 2020 for MarketScan). Exposures: Dispensing of amphetamine/dextroamphetamine or methylphenidate in the second half of pregnancy. Main Outcomes and Measures: Autism spectrum disorder, ADHD, and a composite of any neurodevelopmental disorder were defined using validated algorithms. Hazard ratios were estimated comparing amphetamine/dextroamphetamine and methylphenidate to no exposure. Results: The publicly insured cohort included 2 496 771 stimulant-unexposed, 4693 amphetamine/dextroamphetamine-exposed, and 786 methylphenidate-exposed pregnancies with a mean (SD) age of 25.2 (6.0) years. The commercially insured cohort included 1 773 501 stimulant-unexposed, 2372 amphetamine/dextroamphetamine-exposed, and 337 methylphenidate-exposed pregnancies with a mean (SD) age of 31.6 (4.6) years. In unadjusted analyses, amphetamine/dextroamphetamine and methylphenidate exposure were associated with a 2- to 3-fold increased risk of the neurodevelopmental outcomes considered. After adjustment for measured confounders, amphetamine/dextroamphetamine exposure was not associated with any outcome (autism spectrum disorder: hazard ratio [HR], 0.80; 95% CI, 0.56-1.14]; ADHD: HR, 1.07; 95% CI, 0.89-1.28; any neurodevelopmental disorder: HR, 0.91; 95% CI, 0.81-1.28). Methylphenidate exposure was associated with an increased risk of ADHD (HR, 1.43; 95% CI, 1.12-1.82]) but not other outcomes after adjustment (autism spectrum disorder: HR, 1.06; 95% CI, 0.62-1.81; any neurodevelopmental disorder: HR, 1.15; 95% CI, 0.97-1.36). The association between methylphenidate and ADHD did not persist in sensitivity analyses with stricter control for confounding by maternal ADHD. Conclusions and Relevance: The findings in this study suggest that amphetamine/dextroamphetamine and methylphenidate exposure in utero are not likely to meaningfully increase the risk of childhood neurodevelopmental disorders.

Effects of Stimulant Treatment on Changes in Brain Activation During Reward Notifications in Drug Naïve Youth With ADHD.

BACKGROUND: Research examining the potential effects of stimulant exposure in childhood on subsequent development of substance use disorder (SUD) have focused on differences in the brain reward system as a function of risk. METHODS: 18 drug naïve children ages 7 to 12 years (11 High Risk [ADHD + ODD/CD]; 7 Low Risk [ADHD only]), underwent fMRI scans before and after treatment with mixed amphetamine salts, extended release (MAS-XR). We examined correlations between clinical ratings and fMRI activation at baseline and following treatment as a function of risk status. RESULTS: High Risk children had higher activation than Low Risk children at baseline during both the Reward and Surprising Non-Reward conditions. Treatment produced strong differential effects on brain activation pertinent to group and reward outcome. CONCLUSIONS: Findings support the hypothesized role of reward mechanisms in SUD risk, and suggest that stimulant treatment may have differential effects on reward processing in relation to SUD risk.

Associations between short-term ambient temperature exposure and emergency department visits for amphetamine, cocaine, and opioid use in California from 2005 to 2019.

Substance use disorder is a growing public health challenge in the United States. People who use drugs may be more vulnerable to ambient heat due to the effects of drugs on thermoregulation and their risk environment. There have been limited population-based studies of ambient temperature and drug-related morbidity. We examined short-term associations between daily ambient temperature and emergency department (ED) visits for use or overdose of amphetamine, cocaine and opioids in California during the period 2005 to 2019. Daily ZIP code-level maximum, mean, and minimum temperature exposures were derived from 1-km data Daymet products. A time-stratified case-crossover design was used to estimate cumulative non-linear associations of daily temperature for lag days 0 to 3. Stratified analyses by patient sex, race, and ethnicity were also conducted. The study included over 3.4 million drug-related ED visits. We found positive associations between daily temperature and ED visits for all outcomes examined. An increase in daily mean temperature from the 50th to the 95th percentile was associated with ED visits for amphetamine use (OR = 1.072, 95% CI: 1.058, 1.086), cocaine use (OR = 1.044, 95% CI: 1.021, 1.068 and opioid use (OR = 1.041, 95% CI: 1.025, 1.057). Stronger positive associations were also observed for overdose: amphetamine overdose (OR = 1.150, 95% CI: 1.085, 1.218), cocaine overdose (OR = 1.159, 95% CI: 1.053, 1.276), and opioid overdose (OR = 1.079, 95% CI: 1.054, 1.106). In summary, people who use stimulants and opioids may be a subpopulation sensitive to short-term higher ambient temperature. Mitigating heat exposure can be considered in harm reduction strategies in response to the substance use epidemic and global climate change.

Association of clozapine treatment and rate of methamphetamine or amphetamine relapses and abstinence among individuals with concurrent schizophrenia spectrum and amphetamine use disorder: A retrospective cohort study.

BACKGROUND: Preliminary evidence suggest clozapine is associated with more favorable impact on concurrent substance use disorder related outcomes in patients with concurrent schizophrenia spectrum disorders (SSD). At the same time, there is a dearth of evidence with regards to clozapine outcomes in the context of concurrent methamphetamine or amphetamine use disorder (MAUD). AIMS: To examine whether clozapine use decreases rate of methamphetamine or amphetamine (MA) relapses and increases the likelihood of maintaining abstinence from any MA use. METHODS: A descriptive-analytic retrospective cohort study was conducted on individuals with SSD-MAUD in an inpatient provincial treatment and rehabilitation center for concurrent disorders. Antipsychotic exposure was categorized as "on clozapine" or "on other antipsychotic(s)." Data were collected using electronic health records. Logistic regression was used to examine association of clozapine treatment with likelihood of complete abstinence from MA use for the duration of antipsychotic exposure. Negative binomial regression was used to examine association of clozapine treatment with rate of MA relapses for the duration of antipsychotic exposure. RESULTS: The majority of the 87 included patients were male. Ethnicity was diverse, with the largest groups self-identifying as Indigenous and European. Clozapine use was both associated with increased likelihood of maintaining abstinence from MA use (adjusted odds ratio (aOR) = 3.05, 95% confidence intervals (CI) = 1.15-8.1, p = 0.025), and decreased rate of MA relapses (aRR = 0.45, 95% CI = 0.25-0.82, p = 0.009) for the duration of antipsychotic exposure. Co-prescription of psychostimulants was associated with increased rate of MA relapses (aRR = 2.43, 95% CI = 1.16-5.10, p = 0.019). CONCLUSION(S): In this study, clozapine use compared with other antipsychotics in SSD was associated with improved outcomes related to severe concurrent MAUD. Co-prescription of psychostimulant medications was associated with a poor outcome.

Amphetamine-type Stimulants: Novel Insights into their Actions and use Patterns.

This review focuses on the effects and mechanisms of action of amphetamine-type stimulants (ATS) and their adverse effects on the cardiovascular, nervous, and immune systems. ATS include amphetamine (AMPH), methamphetamine (METH, "crystalmeth," or "ice"), methylenedioxymethamphetamine (MDMA, "ecstasy," or "Molly"), MDMA derivatives (e.g., methylenedioxyamphetamine [MDA] and methylenedioxy-N-ethylamphetamine [MDEA]), khat, and synthetic cathinones. The first section of this paper presents an overview of the historical aspects of ATS use, their initial clinical use, and regulations. The second part reviews the acute and chronic impact and the most salient clinical effects of ATS on the central nervous and cardiovascular systems, skin, and mouth. The chemical structure, pharmacokinetics, and classic and non-canonical pharmacological actions are covered in the third section, briefly explaining the mechanisms involved. In addition, the interactions of ATS with the central and peripheral immune systems are reviewed. The last section presents data about the syndemic of ATS and opioid use in the North American region, focusing on the increasing adulteration of METH with fentanyl.

Mucocutaneous alterations and complications in amphetamine abusers: a narrative review.

Amphetamines are the second most commonly used illicit drug worldwide. Amphetamine use can result in significant cutaneous morbidity. This review highlights the dermatological manifestations of amphetamine abuse.

Amphetamine-Related Fatalities and Altered Brain Chemicals: A Preliminary Investigation Using the Comparative Toxicogenomic Database.

Amphetamine is a psychostimulant drug with a high risk of toxicity and death when misused. Abuse of amphetamines is associated with an altered organic profile, which includes omega fatty acids. Low omega fatty acid levels are linked to mental disorders. Using the Comparative Toxicogenomic Database (CTD), we investigated the chemical profile of the brain in amphetamine-related fatalities and the possibility of neurotoxicity. We classified amphetamine cases as low (0-0.5 g/mL), medium (>0.5 to 1.5 g/mL), and high (>1.5 g/mL), based on amphetamine levels in brain samples. All three groups shared 1-octadecene, 1-tridecene, 2,4-di-tert-butylphenol, arachidonic acid (AA), docosahexaenoic acid (DHA), eicosane, and oleylamide. We identified chemical-disease associations using the CTD tools and predicted an association between DHA, AA and curated conditions like autistic disorder, disorders related to cocaine, Alzheimer's disease, and cognitive dysfunction. An amphetamine challenge may cause neurotoxicity in the human brain due to a decrease in omega-3 fatty acids and an increase in oxidative products. Therefore, in cases of amphetamine toxicity, a supplement therapy may be needed to prevent omega-3 fatty acid deficiency.

Priming effects of a slot machine game and amphetamine on probabilistic risk-taking in people with gambling disorder and healthy controls.

INTRODUCTION: The Game of Dice Task (GDT) captures probabilistic risk-taking, which is an important feature of addictions and integral to gambling disorder (GD). No research appears to have assessed effects of gambling-specific priming manipulations or the pharmacological basis of such effects on the GDT. AIMS: To investigate effects of slot machine gambling (Slots) and d-amphetamine (AMPH; 20 mg) on risk-taking in people with GD and healthy controls (HCs) (n = 30/group). The role of dopamine (DA) was assessed by pre-treating participants with the D2 receptor (D2R)-preferring antagonist, haloperidol (HAL; 3-mg) or mixed D1R-D2R antagonist, fluphenazine (FLU; 3-mg). HYPOTHESES: Slots and AMPH will each increase risk-taking based on fewer (less probable) possible outcomes selected (POS) and poorer net monetary outcomes (NMO; gains minus losses) on the GDT, with stronger effects in Group GD. If DA mediates these effects, outcomes will vary with pre-treatment. METHOD: Participants attended a pre-experimental baseline session and 4 test sessions. Antagonist Group (HAL, FLU) was manipulated between-participants. Pre-treatment (antagonist, placebo) was manipulated within-participants and counterbalanced over sessions for Slots and AMPH test phases. Moderator/mediator effects of trait and neuropsychological factors and GD severity (South Oaks Gambling Screen; SOGS) were explored via covariance. RESULTS: AMPH led to an escalation in risky POS over trial blocks in both groups, regardless of pre-treatment. Cognitive inflexibility (high perseveration-proneness) moderated this effect in Group HC. In Group GD, SOGS selectively predicted riskier POS on AMPH sessions. Group GD achieved poorer NMO vs. Group HC on the pre-experimental baseline and Placebo-Slots sessions. Group HC selectively displayed poorer NMO on the Antagonist-Slots session. CONCLUSIONS: The GDT can detect behavioral and pharmacological priming effects. Cognitive inflexibility and symptom severity moderate AMPH-induced risk-taking in HC and GD participants, respectively. Sensitization-related "wanting" of risk may contribute to the latter effect in people with GD.

Amphetamines modulate fentanyl-depressed respiration in a bidirectional manner.

BACKGROUND: The opioid epidemic remains one of the most pressing public health crises facing the United States. Fentanyl and related synthetic opioid agonists have largely driven the rising rates of associated overdose deaths, in part, because of their surreptitious use as substitutes for other opioids and as adulterants in psychostimulants. Deaths involving opioids typically result from lethal respiratory depression, and it is currently unknown how co-use of psychostimulants with opioids affects respiratory toxicity. Considering psychostimulant overdoses have increased over 3-fold since 2013, and half of those co-involved opioids, this is a cardinal question. METHODS: Naloxone, d-amphetamine (AMPH), and (±)-methamphetamine (METH) were evaluated for their effects on basal and fentanyl-depressed respiration. Minute volume (MVb) was measured in awake, freely moving mice via whole-body plethysmography to quantify fentanyl-induced respiratory depression and its modulation by dose ranges of each test drug. RESULTS: Naloxone immediately reversed respiratory depression induced by fentanyl only at the highest dose tested (10 mg/kg). Both AMPH and METH exhibited bidirectional effects on MVb under basal conditions, producing significant (p ≤ 0.05) depressions then elevations of respiration as dose increased. Under depressed conditions the bidirectional effects of AMPH and METH on respiration were exaggerated, exacerbating and then reversing fentanyl-induced depression as dose increased. CONCLUSIONS: These results indicate that co-use of amphetamines with fentanyl may worsen respiratory depression, but conversely, monoaminergic components of the amphetamines may possibly be exploited to mitigate fentanyl overdose.

Association Between Inflammatory Cytokines, Executive Function, and Substance Use in Patients With Opioid Use Disorder and Amphetamine-Type Stimulants Use Disorder.

BACKGROUND: Long-term opioid and amphetamine-type stimulants (ATS) abuse may affect immunological function and impair executive function. We aimed to determine whether biomarkers of inflammation and executive function were associated with substance use in individuals with opioid use disorder (OUD) and ATS use disorder (ATSUD). The interactions between these biomarkers were also explored. METHODS: We assessed plasma cytokines [tumor necrosis factor (TNF)-α, C-reactive protein (CRP), interleukin (IL)-8, IL-6, transforming growth factor (TGF)-ß1, brain-derived neurotrophic factor (BDNF), and executive function in terms of the Wisconsin Card Sorting Test (WCST) and Continuous Performance Test (CPT) in OUD and ATSUD patients and healthy controls (HC). OUD and ATSUD patients were followed for 12 weeks, and their urine morphine and amphetamine tests, cytokine levels, and executive function were repeatedly measured. RESULTS: We enrolled 483 patients and 145 HC. Plasma TNF-α, CRP, IL-8, IL-6, and BDNF levels and most subscale scores on the WCST and CPT significantly differed between OUD and ATSUD patients and HC. Increased TNF-α levels and more perseveration error on the WCST were significantly associated with more urine drug-positive results and less abstinence. Plasma IL-6 and CRP levels were significantly negatively correlated with WCST and CPT performance. CONCLUSION: OUD and ATSUD patients had more inflammation and worse executive function than HC. Inflammatory markers and WCST performance were associated with their urinary drug results, and higher inflammation was associated with poor executive function. Studies on regulating the inflammatory process and enhancing executive function in OUD and ATSUD are warranted.

Sleep Deprivation & Amphetamine Induced Psychosis.

Objectives: To explore the relationship between sleep deprivation and amphetamine-induced psychosis. Methods: The patient group included 78 patients with a diagnosis of amphetamine (Captagon)-induced psychosis. The control group included 49 patients with no current or past history of amphetamine (Captagon)-induced psychosis. All study subjects underwent the following: a demographic sheet, a structured clinical interview for SM-IV (SCID 1), a drug use questionnaire, a questionnaire to explore any relationship between sleep deprivation and Captagon-induced psychosis, routine medical investigation, and urine screening for detection of drugs. Results: The patient group showed significantly higher both regular and maximum daily doses of Captagon. Patients showed more periods of sleep deprivation with the use of Captagon in comparison to controls, especially with the increase of the Captagon dose. Patients believed that the occurrence and termination of sleep deprivation were the cause of the start and end of psychotic experiences (more so than the increase and decrease or stoppage of Captagon doses). Conclusion: sleep deprivation plays an essential role in the development of psychotic symptoms in patients who are using Captagon.

Randomized, Double-Blind, Placebo-Controlled, Fixed-Dose Study to Evaluate the Efficacy and Safety of Amphetamine Extended-Release Tablets in Adults With Attention-Deficit/Hyperactivity Disorder.

Objective: To evaluate the efficacy and safety of amphetamine extended-release tablets (AMPH ER TAB) in adults with attention-deficit/hyperactivity disorder (ADHD).Methods: In a 5-week forced-dose titration phase, subjects were randomized to either oral double-blind AMPH ER TAB 5-mg starting dose or matching placebo, once daily in the morning. Safety and efficacy assessments were completed weekly. After visit 3, subjects received 20 mg for 14 ± 3 days before visit 5. At visit 5, efficacy assessments included the administration of serial Permanent Product Measure of Performance (PERMP) tests predose and at 0.5, 1, 2, 4, 8, 10, 12, 13, and 14 hours postdose. The primary efficacy endpoint was the mean PERMP Total score (PERMP-T) across postdose time points during the visit 5 serial PERMPs. Safety was monitored by adverse events (AEs) assessed at each visit, Columbia Suicide Severity Rating Scale (C-SSRS), vital signs, weight, physical examination, and assessment of sleep, appetite, mood, and psychotic AEs. The study was conducted from February 2019 to October 2019.Results: Of 130 randomized subjects, 127 were in the intent-to-treat (ITT) population and 91 completed the study. The mean PERMP-T across all postdose time points at visit 5 was statistically significantly higher in the AMPH ER TAB group than in the placebo group (302.8 vs 279.6; P = .0043). Numerical differences favoring AMPH ER TAB were seen at all time points, with statistically significant improvements in the AMPH ER TAB group at 30 minutes and 1, 2, 4, 8, and 13 hours postdose, although the 10-, 12-, and 14-hour time points were not significant. Common AEs included decreased appetite, insomnia, and dry mouth. The majority of treatment-emergent AEs were mild to moderate in severity, and no serious AEs, as defined by the US Food and Drug Administration, were reported.Conclusions: AMPH ER TAB demonstrated efficacy in treatment of symptoms of ADHD in adults, with an anticipated safety profile.Trial Registration: ClinicalTrials.gov identifier: NCT03834766.

Cardiovascular Outcomes Among Older Individuals With Depression Prescribed Amphetamines: A Retrospective Cohort Study.

BACKGROUND: Prescription amphetamines are utilized for treatment of depression in older adults, yet cardiovascular risks in this population are not well described. The purpose of this study is to evaluate risk of cardiovascular events among adults aged 65 and older with depression who were prescribed amphetamines. METHODS: We conducted a retrospective matched cohort study utilizing the TriNetx database and statistical software. The 1:1 propensity score matching technique was performed using logistic regression to balance the baseline characteristics of the population. Inclusion criteria were a diagnosis of depression and age 65 years and older. We excluded individuals with an adverse cardiovascular event or diagnosis of attention deficit and hyperactivity disorder prior to enrollment. Individuals were followed from January 1, 2018 to December 31, 2020. Those prescribed an amphetamine were considered exposed and others served as controls. We used descriptive statistics and calculated risk ratios to assess the relationship between amphetamine prescriptions and cardiovascular events in these cohorts. RESULTS: There were 4 434 included in the exposed cohort and 4 434 matched controls in the unexposed group. The cohort exposed to amphetamines had higher high-density lipoprotein along with lower low-density lipoprotein, total cholesterol, hemoglobin A1C, systolic blood pressure, and body mass index than the control group, but increased risk of cardiovascular events (risk ratio: 8.9; 95% confidence interval: 6.39, 12.48). CONCLUSIONS: Amphetamines offer potential benefits to people with depression; however, these data suggest increased risk of cardiovascular events among older individuals. Additional research is warranted to fully characterize risk among subpopulations of older adults and inform patient-provider decision making.

Risk of psychosis in illicit amphetamine users: a 10 year retrospective cohort study.

QUESTION: Amphetamine use is a risk factor for psychosis, which imposes a substantial burden on society. We aimed to investigate the incidence of psychosis associated with illicit amphetamine use and whether rehabilitation treatments could influence the psychosis risk. STUDY SELECTION AND ANALYSIS: A retrospective cohort study was conducted using the population based Taiwan Illicit Drug Issue Database (TIDID) and the National Health Insurance Research Database (NHIRD), from 2007 to 2016. We identified 74 601 illicit amphetamine users as the amphetamine cohort and 2 98 404 subjects as the non-amphetamine cohort. The incidence rate of newly diagnosed psychosis was the main outcome. Cox proportional hazards models were applied to assess the effects of amphetamine, and the Kaplan-Meier method was used to estimate the cumulative psychosis incidence curves. FINDINGS: Illicit amphetamine users were 5.28 times more likely to experience psychosis than those without illicit drug use records. The risk was higher for subjects with multiple arrests for amphetamine use. A greater hazard ratio (HR) magnitude was observed in female patients. We also observed a significant decrease in the risk of psychosis in patients receiving rehabilitation treatments during deferred prosecution (adjusted HR 0.74, 95% CI 0.61 to 0.89). CONCLUSIONS: Illicit amphetamine use was associated with an increased incidence of psychosis. The risk was identified across all age groups, particularly in women and in those arrested multiple times, and was inversely correlated with rehabilitation treatments for amphetamine misuse.

Co-exposure of cannabinoids with amphetamines and biological, behavioural and health outcomes: a scoping review of animal and human studies.

RATIONALE: The growing prevalence of psychostimulant (including amphetamine) use and associated health harms, with limited treatment options, present a global challenge. There is an increasing availability and medical applications of cannabinoids, and growing interest in their therapeutic potential for addictive disorders. OBJECTIVES: The objective of this study is to review available data regarding cannabis/cannabinoid co-use or exposure on amphetamine-related outcomes. METHODS: Towards the present scoping review, we systematically searched four databases (Medline, Web-of-Science, CINAHL Plus and PsycInfo) using cannabis/cannabinoid and amphetamine text-terms identifying peer-reviewed, English-language studies published in 2000-2020 involving multiple methods approaches among both human and animal study samples, assessing the association of co-use/administration of cannabis/cannabinoids products with non-medical amphetamines on biological, behavioural or health outcomes. RESULTS: Twenty-five articles were included. Pre-clinical studies (n = 15) found mostly protective effects of single or repeated cannabinoids administration on rodents in amphetamine addiction models, amphetamine-induced models of human mental disorders (e.g. schizophrenia) and amphetamine-induced neurotoxicity. Human studies (n = 10) were more heterogeneously designed (e.g. cross-sectional, case-control, longitudinal) and assessed natural ongoing cannabis and methamphetamine use or dependence, showing mostly enhanced harms in a diversity of outcomes (e.g. mental health, methamphetamine use, cognition). CONCLUSIONS: While human studies suggest cannabis use as an adverse risk factor among non-medical amphetamine users, pre-clinical studies suggest therapeutic potential of cannabinoids, especially cannabidiol, to alleviate amphetamine addiction and harms, including treatment outcomes. Given increasing psychostimulant harms but lack of care options, rigorous, high-quality design studies should aim to translate and investigate pre-clinical study results for potential therapeutic benefits of cannabinoids for amphetamine use/abuse in human subjects.

A Randomized, Double-Blind, Placebo-Controlled Trial to Evaluate the Efficacy and Safety of AR19, a Manipulation-Resistant Formulation of Amphetamine Sulfate, in Adults With Attention-Deficit/Hyperactivity Disorder.

Objective: To assess the efficacy and safety of AR19 in the treatment of attention-deficit/hyperactivity disorder (ADHD) diagnosed by DSM-5 criteria in adults from 18 through 55 years of age. AR19 is a pellets-in-capsule, immediate-release amphetamine sulfate investigational formulation with physical and chemical barriers designed to resist manipulation to deter snorting, smoking, and intravenous injection.Methods: This randomized, double-blind, placebo-controlled, fixed-dose, forced titration, multicenter trial investigated the safety and efficacy of AR19 from September 2018 to April 2019. Study participants were randomized and titrated to 20 mg or 40 mg AR19 daily or placebo. Study medication was dosed once in the morning and again 4 to 6 hours later for a period of 5 weeks. The primary efficacy measure was the total score on the Adult ADHD Investigator Symptom Rating Scale (AISRS).Results: Participants (N = 320) were randomized and received at least 1 dose of study medication. Demographics and baseline characteristics were similar across treatment groups. The least squares mean treatment differences versus placebo (97.5% CI) were -7.2 (-11.3 to -3.1) for the AR19 20-mg group and -7.3 (-11.4 to -3.2) for the AR19 40-mg group (each P < .001). The most common treatment-emergent adverse events occurring in participants in the AR19 treatment groups were insomnia, dry mouth, decreased appetite, palpitations, headache, and tachycardia and are consistent with the known safety profile of amphetamine sulfate.Conclusions: AR19 demonstrated efficacy on all endpoints and was generally well tolerated, supporting the efficacy and safety of AR19 20 mg and 40 mg in adults with ADHD.Trial Registration: ClinicalTrials.gov Identifier: NCT03659929.