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Background and Objective: Although there are several treatments for narcolepsy type 2 and idiopathic hypersomnia, studies that assess amphetamines, symptoms beyond sleepiness, and comparative effectiveness are needed. We performed a randomized, fully blinded, noninferiority trial of modafinil versus amphetamine-dextroamphetamine in these disorders., Methods: Forty-four adults were randomized to modafinil or amphetamine-dextroamphetamine, individually titrated to a maximum of modafinil 200 mg twice daily or amphetamine-dextroamphetamine 20 mg twice daily, for 12 weeks. Primary outcome was change in Epworth from baseline to week 12, with a noninferiority threshold of 2 points. Secondary outcomes were (1) patient global impression of change measures of disease severity, sleepiness, sleep inertia, and cognition; (2) change from baseline in Hypersomnia Severity Index; and (3) change from baseline in Sleep Inertia Questionnaire. Adverse events were compared between groups., Results: Epworth improved 5.0 [± standard deviation (SD) 2.7] points with modafinil and 4.4 (± SD 4.7) with amphetamine-dextroamphetamine; noninferiority of amphetamine-dextroamphetamine was not demonstrated (P = 0.11). Noninferiority of amphetamine-dextroamphetamine was demonstrated for change scores of severity, sleepiness, sleep inertia, Hypersomnia Severity Index, and Sleep Inertia Questionnaire. Dropouts due to adverse events were 31.8% for modafinil (including two severe events) and 9.1% for amphetamine-dextroamphetamine, P = 0.13. Anxiety was more common with modafinil and appetite suppression with amphetamine-dextroamphetamine., Conclusion: Noninferiority of amphetamine-dextroamphetamine to modafinil was not demonstrated for the primary outcome. However, amphetamine-dextroamphetamine was noninferior on multiple secondary measures of disease severity and symptomatology. These data may inform shared decision-making regarding treatment for idiopathic hypersomnia and narcolepsy type 2., Registration: Clinicaltrials.gov Registration (NCT03772314) 12/10/18. ., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

A 47-year-old woman with a history of substance abuse, depression, and insomnia experienced a collapse. Upon arrival at the hospital, the patient displayed low systolic blood pressure, confusion, dehydration, and renal failure. Urine tests confirmed an amphetamine and opioid overdose. Her condition fluctuated with reduced consciousness, myoclonic movements, fever, and suspected psychogenic seizures. Brain magnetic resonance imaging revealed abnormalities in the splenium of the corpus callosum, which later resolved. The patient's condition gradually improved without any specific treatment. This unique case represents the first report of mild encephalopathy/encephalitis with reversible splenial lesions associated with amphetamine and opioid use.

The prevalence of alcohol use disorder was found 75% higher among amphetamine dependent patients. Alcohol and amphetamine alone have nephrotoxicity and hepatoxicity. But, the degree of risk with coabuse of alcohol and amphetamine is unknown. The objective of this study was to assess toxic effects of amphetamine-alcohol co-abuse on the liver and kidney. he present study was a cross-sectional study conducted et al. Amal Hospital for Mental Health, Qassim region, KSA and include one hundred participants. Seventy-five participants were patients hospitalized for the treatment of abuse, and twenty-five participants, were healthy voluntaries, have no history of abuse. An experienced psychiatrist conducted patient interviews and assessed the patients using the DSM-5 criteria. The data from healthy participants were considered as a control. The abuse group was paired with the control group by age and lifestyle. Participants were split into: Group I: Control group (n = 25); Group II: Amphetamine (AMP) abuser group (n = 25); Group III: Alcohol abuser group (n = 25) and Group IV: Combined drug abuser group (AMP and alcohol) (n = 25). The socio-demographic data was collected. Complete medical examination, Body Mass Index and samples of blood and urine were collected from all participants for analytical tests; determination of alcohol and AMP levels, kidney functions and liver functions. The mean BMI values in groups II, III, and IV showed no significant change from the control group. The serum level of albumin and alkaline phosphatase showed significant decrease in all abuser groups. While, alanine transaminase (ALT), Aspartate transaminase (AST) and osteopontin levels showed significant increase in all abuser groups. Fasting blood sugar values showed significant increase in alcohol abusers. On the other hand, it revealed no significant change in AMP and combined groups. The mean values of urea showed no significant change in AMP and alcohol abusers and significant increase in combined drug abuser group. The serum creatinine and all abuser groups showed significant increase in Cystatin C. The alteration in the most of studied biochemical parameters were more than two folds in combined group compared with that of AMP or alcohol groups. Study reveals synergistic liver and kidney toxicity. Amphetamine-alcohol co-abuse significantly heightens kidney and liver toxicity., (© 2024. The Author(s).)

Background: Recent epidemiological data has shown a sharp increase in stimulant use among older adults, which is notable as older adults may be especially vulnerable to their cardiovascular effects. Results of recent studies have shown an increase in cardiovascular events among older adults using stimulants; however, little data exists comparing cardiovascular safety of these agents head-to-head. Objective: To determine if the incidence of serious cardiovascular events, including myocardial infarction (MI), stroke/transient ischemic attack (TIA), or arrhythmia, are different in patients taking amphetamine/dextroamphetamine compared with patients taking methylphenidate. Methods: Retrospective chart review of veterans 50 years and older at the Veterans Affairs North Texas Health Care System (VANTHCS) who were first prescribed a stimulant between 2015 and 2021. The primary outcome was the difference in composite cardiovascular events between amphetamine/dextroamphetamine and methylphenidate. Secondary outcomes were the composite cardiovascular endpoints compared individually (MI, stroke/TIA, or arrhythmia). Hazard ratios were calculated based off of a time-to-event analysis displayed using a Kaplan-Meier curve for primary and secondary outcomes. Results: 466 veterans were screened for inclusion, 30 were excluded, and 436 were included. There was no difference found in composite cardiovascular events between the 241 veterans in the amphetamine/dextroamphetamine group and the 195 veterans in the methylphenidate group with 12 (5%) vs 8 (4.1%) events respectively ( P = .6635). There was also no difference in time-to-event analysis ( P = .4966). Conclusion: In elderly veterans, there was no difference found in incidence of major cardiovascular events with the use of amphetamine/dextroamphetamine compared with methylphenidate., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Attention deficit hyperactive disorder (ADHD) medication use rises among women of childbearing age and during pregnancy. Little is known on the safety of amphetamine stimulants for ADHD treatment during breastfeeding. Most data on the safety of these medications are from recreational abuse of methamphetamine. This study followed children (N = 13) exposed to amphetamine stimulants during breastfeeding. Assessments by Pediatric Quality of Life and Denver Developmental Scale evaluated neurodevelopment and outcomes. Study results showed normal neurodevelopment with no significant adverse effects. Findings suggest amphetamines are likely compatible with breastfeeding; however larger studies are needed., Competing Interests: Declaration of competing interest The authors have no relevant financial or non-financial interests to disclose., (Copyright © 2024 Elsevier B.V. All rights reserved.)

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., (© 2024. The Author(s).)

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.

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., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. Published by BMJ.)

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., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Iliyan Ivanov—no conflicts, Beth Krone—in the last 3 years was a consultant for Signant Health, Mind Tension, Hippo T&C, and Maxis Health, Kurt Schulz—no conflicts, Riaz Shaik—no conflicts, Muhammad Parvaz—no conflicts, Jeffrey Newcorn—in the last three years J.H.N. was a consultant/advisory board member for Adlon Therapeutics, Cingulate Therapeutics, Corium, Hippo T&C, Ironshore, Lumos, Medice, MindTension, Myriad, NLS, OnDosis, Otsuka, Rhodes, Shire/Takeda, Signant and Supernus; he received research support from Adlon, Otsuka, Shire, Supernus; honoraria for disease state lectures from Otsuka and Shire, and served as a consultant for the US National Football League.

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.

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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

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., Competing Interests: Declaration of conflicting interestsThe authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: RR, LF, HM, NM, and SP have none to declare; MD reports receiving personal fees from Eisai Ltd, Otsuka, Winterlight Labs, and the Ontario Brain Institute; CAB is founder and CEO of Sequence2Script Inc.; WGH is a consultant to AbbVie, and Translational Life Sciences; and CGS is a consultant to Clearmind Medicine.

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.

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., Competing Interests: Conflict of interest No conflict declared., (Copyright © 2023 Elsevier B.V. All rights reserved.)

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.

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)-β1, 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., (© The Author(s) 2022. Published by Oxford University Press on behalf of CINP.)

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., (Copyright: © 2023 Permanyer.)

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., (© The Author(s) 2022. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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., Competing Interests: Competing interests: None., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

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., (© Copyright 2022 Physicians Postgraduate Press, Inc.)

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., (Copyright © 1964–2022 by MedWorks Media Inc, Los Angeles, CA All rights reserved. Printed in the United States.)

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., (© 2021. The Author(s).)

The objective of this study was to determine the prevalence of amphetamine-type stimulant use and associated factors among methadone maintenance treatment (MMT) patients. In 2018, a cross-sectional study was conducted on 967 MMT patients at two methadone clinics in Ho Chi Minh City that serve Vietnamese patients. Amphetamine-type stimulant use was assessed by rapid urine test and face-to-face interview using the Alcohol, Smoking, Substance Involvement Screening Test (ASSIST) tool. The prevalence of amphetamine-type stimulant use assessed by urine test was 25.4%. According to ASSIST, the prevalence of moderate and high risk amphetamine-type stimulant use was 15.5% and 1.1%, respectively. Amphetamine-type stimulant use and hazardous use were more prevalent in younger patients, having a part-time job, drug injection, having a lower score of self-health assessment, treated with a higher dose of methadone and missing methadone dose in the past 3 months. By contrast, patients who were HIV positive were less likely to use amphetamine-type stimulants. Cannabis and heroin use were significantly associated with amphetamine-type stimulant use (OR = 1.46; 95% CI: 1.38-8.67; and OR = 1.50; CI: 1.04-2.18, respectively) and hazardous use (OR = 4.07; CI: 1.67-9.92; and OR = 2.38; CI: 1.56-3.63, respectively). Screening and interventions are needed to cope with this issue on time, particularly in young patients, having drug injection and concurrent drugs user groups.

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., (© Copyright 2021 Physicians Postgraduate Press, Inc.)

Objective: The purpose of this study was to retrospectively investigate the abuse characteristics of amphetamine-type stimulants (ATS) in patients receiving methadone maintenance treatment (MMT) and buprenorphine maintenance treatment (BMT)., Methods: A total of 58 MMT and 51 BMT patients abusing ATS were recruited from the drug maintenance treatment clinic of Ningbo Addiction Research and Treatment Center from January 2018 to December 2019. They were assessed using the amphetamine abuse questionnaire (AAQ), addiction severity index (ASI) and Barratt impulsiveness scale (BIS). Moreover, 40 MMT control patients, 40 BMT control patients and 20 healthy controls were also assessed using the BIS. All information was collected using the amphetamine abuse questionnaire (AAQ), Chinese version of addiction severity index (ASI-C) and Chinese version of Barratt impulsiveness scale (BIS-C) conducted by qualified psychologists., Results: The interval of amphetamine use in the MMT group was shorter than the BMT group ( P < 0.05). The drug use subscale score of ASI was higher in the MMT group than the BMT group ( P < 0.05). The respective and total scores of attentional impulsiveness, motor impulsiveness and non-planning impulsiveness in BIS in the MMT group were all higher than the MMT control group ( P < 0.05). The scores of motor impulsiveness and non-planning impulsiveness in the BMT group were higher than the BMT control group ( P < 0.05). The respective and total scores in BIS in the MMT control group and the BMT control group were all higher than those in the healthy controls., Conclusion: The patients showing amphetamine abuse in maintenance therapy had a greater impulsiveness than those having other simple maintenance treatments, and patients under MMT may be more addicted to amphetamines in comparison with those having BMT., Competing Interests: The authors declare that they have no conflicts of interest., (© 2021 Liu et al.)

Introduction and Aims: There is a lack of evidence regarding mental health disorder prevalence in people who use amphetamine-type stimulants (ATS). This study compares prevalence in Australian young adults who used ATS and young adults who had never used, and examines potential predictors., Design and Methods: Population-based sampling was used to recruit young adults who used ATS (n = 224) and young adults who had never used ATS (n = 125). Thirty-day prevalence of major depressive disorder (MDD), generalised anxiety disorder (GAD), panic disorder (PD), post-traumatic stress disorder (PTSD) and mania/hypomania were assessed using the Composite International Diagnostic Interview Short Scale. Adjusted prevalence ratios (APR) of mental disorders in people who used ATS and the comparison group were examined, and a prediction model was developed for people who used ATS., Results: We found higher prevalence of PD (APR 4.67, 95% confidence interval [CI] 1.14-19.07, P = 0.032) and PTSD (APR 1.68, 95% CI 1.10-2.55, P = 0.016) in people who used ATS, compared to the comparison group, adjusting for sociodemographic variables. Baseline methamphetamine use was positively associated with MDD (ARR 6.45, 95% CI 1.51-27.59, P = 0.012) and GAD (ARR 2.76, 95% CI 1.52-5.02, P = 0.001). Baseline ecstasy use was negatively associated with GAD (ARR 0.52, 95% CI 0.30-0.92, P = 0.025) and PD (ARR 0.15, 95% CI 0.05-0.48, P = 0.001)., Discussion and Conclusion: PTSD and PD appear to be more common in young adults who use ATS. However, the relationship between ATS use and mental disorders is complex, with divergent patterns of association for ecstasy and methamphetamine use. Mental health screening in people using ATS may improve treatment outcomes., (© 2020 Australasian Professional Society on Alcohol and other Drugs.)

Cardio- and neurotoxicity of amphetamines play an important role in worsening morbidity, making the initial evaluation of the patient's status a potentially lifesaving action. The current study hypothesized that the S-100β serum level could predict the severity of acute amphetamine toxicity and the in-hospital outcome. The current study is a prospective cohort study conducted on 77 patients diagnosed with acute amphetamine exposure and referred to Aseer Poison Control Center, Saudi Arabia. The patients admitted to ICU showed significantly higher serum levels of S-100β in comparison to those not admitted (p < 0.05). Moreover, the S-100β level was significantly elevated among patients with prolonged QTc intervals. Receiver-operating characteristic curve of S-100β serum level as an in-hospital outcome predictor showed that at a cutoff value > 0.430 ug/L, the sensitivity of S-100β serum level as severity predictor was 100%, and the specificity was 74.1%. In conclusion, the current study revealed that the S-100β serum level could be used as an outcome predictor in hospital admission cases due to toxic amphetamine exposure and offers an idea about the cardiac and neuronal involvement. This can help select patients who will benefit most from ICU admission and early management and assess the severity of cases in settings where GC-MS is not available.

Amphetamine produces a multiplicity of well-documented end-order biochemical, pharmacological and biobehavioural effects. Mechanistically, amphetamine downregulates presynaptic and postsynaptic striatal monoamine (primarily dopaminergic) systems, producing alterations to key brain regions which manifest as stereotyped ridged behaviour which occurs under both acute and chronic dosing schedules and persists beyond detoxification. Despite evidence of amphetamine-induced visual attentional dysfunction, no conceptual synthesis has yet captured how characteristic pharmaco-behavioural processes are critically implicated via these pathways, nor described the potential implications for safety-sensitive behaviours. Drawing on known pathomechanisms, we propose a cross-disciplinary, novel conceptual functional system framework for delineating the biobehavioural consequences of amphetamine use on visual attentional capacity and discuss the implications for functional and behavioural outcomes. Specifically, we highlight the manifest implications for behaviours that are conceptually driven and highly dependent on visual information processing for timely execution of visually-guided movements. Following this, we highlight the potential impact on safety-sensitive, but common behaviours, such as driving a motor vehicle. The close pathophysiological relationship between oculomotor control and higher-order cognitive processes further suggests that dynamic measurement of movement related to the motion of the eye (gaze behaviour) may be a simple, effective and direct measure of behavioural performance capabilities in naturalistic settings. Consequently, we discuss the potential efficacy of ocular monitoring for the detection and monitoring of driver states for this drug user group, and potential wider application. Significance statement: We propose a novel biochemical-physiological-behavioural pathway which delineates how amphetamine use critically alters oculomotor function, visual-attentional performance and information processing capabilities. Given the manifest implications for behaviours that are conceptually driven and highly dependent on these processes, we recommend oculography as a novel means of detecting and monitoring gaze behaviours during naturalistic tasks such as driving. Real-word examination of gaze behaviour therefore present as an effective means to detect driver impairment and prevent performance degradation due to these drugs., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

BACKGROUND Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder that manifests in early childhood. Pharmacotherapy, including psychostimulants, is considered the cornerstone of ADHD management. Although stimulants have been associated with adverse effects, sedation following the administration of an amphetamine-based stimulant is an extremely rare adverse effect. CASE REPORT We report the case of a 6-year-old boy presenting with ADHD and a history of autism spectrum disorder (ASD). After discussing treatment options with his parents, he was started on a low dose of a methylphenidate medication. He was unable to tolerate the medication due to anorexia, insomnia, and irritability despite multiple adjustments in the dosages. A trial of immediate-release mixed amphetamine salts was initiated, starting from a low dose. The boy developed sedation and lethargy shortly after the administration of this medication. CONCLUSIONS Sedation is a rare adverse drug reaction to mixed amphetamine salts. Clinicians should proactively monitor for the possible adverse effects in patients with ASD and ADHD, including unexpected symptoms such as sedation. Reporting of adverse drug reactions should be encouraged to promote the post-marketing surveillance of medications.

Study Objective: Concurrent use of amphetamine-type stimulants among individuals with opioid use disorder can exacerbate social and medical harms, including overdose risk. The study evaluated rates of amphetamine-type stimulant use among patients with untreated opioid use disorder presenting at emergency departments in Baltimore, MD; New York, NY; Cincinnati, OH; and Seattle, WA., Methods: Emergency department (ED) patients with untreated opioid use disorder (N=396) and enrolled between February 2017 and January 2019 in a multisite hybrid type III implementation science study were evaluated for concurrent amphetamine-type stimulant use. Individuals with urine tests positive for methamphetamine, amphetamine, or both were compared with amphetamine-type stimulant-negative patients., Results: Overall, 38% of patients (150/396) were amphetamine-type stimulant positive; none reported receiving prescribed amphetamine or methamphetamine medications. Amphetamine-type stimulant-positive versus -negative patients were younger: mean age was 36 years (SD 10 years) versus 40 years (SD 12 years), 69% (104/150) versus 46% (114/246) were white, 65% (98/150) versus 54% (132/246) were unemployed, 67% (101/150) versus 49 (121/246) had unstable housing, 47% (71/150) versus 25% (61/245) reported an incarceration during 1 year before study admission, 60% (77/128) versus 45% (87/195) were hepatitis C positive, 79% (118/150) versus 47% (115/245) reported drug injection during 1 month before the study admission, and 42% (62/149) versus 29% (70/244) presented to the ED for an injury. Lower proportions of amphetamine-type stimulant-positive patients had cocaine-positive urine test results (33% [50/150] versus 52% [129/246]) and reported seeking treatment for substance use problems as a reason for their ED visit (10% [14/148] versus 19% [46/246]). All comparisons were statistically significant at P<.05 with the false discovery rate correction., Conclusion: Amphetamine-type stimulant use among ED patients with untreated opioid use disorder was associated with distinct sociodemographic, social, and health factors. Improved ED-based screening, intervention, and referral protocols for patients with opioid use disorder and amphetamine-type stimulant use are needed., (Copyright © 2020 American College of Emergency Physicians. Published by Elsevier Inc. All rights reserved.)

Adolescent use of amphetamine and its closely related, methylated version methamphetamine, is alarmingly high in those who use drugs for nonmedical purposes. This raises serious concerns about the potential for this drug use to have a long-lasting, detrimental impact on the normal development of the brain and behavior that is ongoing during adolescence. In this review, we explore recent findings from both human and laboratory animal studies that investigate the consequences of amphetamine and methamphetamine exposure during this stage of life. We highlight studies that assess sex differences in adolescence, as well as those that are designed specifically to address the potential unique effects of adolescent exposure by including groups at other life stages (typically young adulthood). We consider epidemiological studies on age and sex as vulnerability factors for developing problems with the use of amphetamines, as well as human and animal laboratory studies that tap into age differences in use, its short-term effects on behavior, and the long-lasting consequences of this exposure on cognition. We also focus on studies of drug effects in the prefrontal cortex, which is known to be critically important for cognition and is among the later maturing brain regions. Finally, we discuss important issues that should be addressed in future studies so that the field can further our understanding of the mechanisms underlying adolescent use of amphetamines and its outcomes on the developing brain and behavior., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Introduction: The assessment of the abuse potential of CNS-active drugs is a regulatory requirement. Drug discrimination is one of the nonclinical tests that contribute to this assessment by providing information on a drug's potential to induce a discriminative stimulus comparable to that of a known drug of abuse., Aim: The objective was to validate drug discrimination in the rat for the purpose of supporting regulatory submissions for novel drugs with potential cannabinoid-like activity., Methods: Ten female Lister hooded rats were trained to discriminate no-drug from Δ 9 -THC (1.5 mg/kg, IP) under a FR10 schedule of reinforcement. Once trained, a Δ 9 -THC dose-response curve was obtained using doses of 0.25, 0.75, 1.5, and 3 mg/kg, IP. This was followed by evaluation of amphetamine (0.3 mg/kg, SC); morphine (3 mg/kg, IP); midazolam (2.5 mg/kg, PO); and the synthetic cannabinoids WIN55,212-2 (0.75 to 2 mg/kg, IP), CP-47,497 (0.5 to 2 mg/kg, IP), and JWH-018 (1 mg/kg, IP) for their discriminative stimulus similarity to Δ 9 -THC., Results: Pharmacological specificity was demonstrated by achieving the anticipated dose-response curve for Δ 9 -THC, and a vehicle-like response for the non-cannabinoid drugs. Although full generalisation was obtained for JWH-018, in contrast to published literature, WIN55,212-2 and CP-47,497 failed to generalise to Δ 9 -THC., Discussion: Based on the literature review performed in light of the results obtained, contrasting and unpredictable behavioural responses produced by cannabinoids in animals and humans raises the question of the reliability and relevance of including drug discrimination and self-administration studies within an abuse potential assessment for novel cannabinoid-like drugs., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Attention deficit hyperactivity disorder (ADHD) affects approximately 3% of adults globally. Many pharmacologic treatments options exist, yet the comparative benefits and harms of individual treatments are largely unknown. We performed a systematic review and network meta-analysis to assess the relative effects of individual pharmacologic treatments for adults with ADHD., Methods: We searched English-language published and grey literature sources for randomized clinical trials (RCTs) involving pharmacologic treatment of ADHD in adults (December 2018). The primary outcome was clinical response; secondary outcomes were quality of life, executive function, driving behaviour, withdrawals due to adverse events, treatment discontinuation, serious adverse events, hospitalization, cardiovascular adverse events, and emergency department visits. Data were pooled via pair-wise meta-analyses and Bayesian network meta-analyses. Risk of bias was assessed by use of Cochrane's Risk of Bias tool, and the certainty of the evidence was assessed by use of the GRADE framework., Results: Eighty-one unique trials that reported at least one outcome of interest were included, most of which were at high or unclear risk of at least one important source of bias. Notably, only 5 RCTs were deemed at overall low risk of bias. Included pharmacotherapies were methylphenidate, atomoxetine, dexamfetamine, lisdexamfetamine, guanfacine, bupropion, mixed amphetamine salts, and modafinil. As a class, ADHD pharmacotherapy improved patient- and clinician-reported clinical response compared with placebo (range: 4 to 15 RCTs per outcome); however, these findings were not conserved when the analyses were restricted to studies at low risk of bias, and the certainty of the finding is very low. There were few differences among individual medications, although atomoxetine was associated with improved patient-reported clinical response and quality of life compared with placebo. There was no significant difference in the risk of serious adverse events or treatment discontinuation between ADHD pharmacotherapies and placebo; however, the proportion of participants who withdrew due to adverse events was significantly higher among participants who received any ADHD pharmacotherapy. Few RCTs reported on the occurrence of adverse events over a long treatment duration., Conclusions: Overall, despite a class effect of improving clinical response relative to placebo, there were few differences among the individual ADHD pharmacotherapies, and most studies were at risk of at least one important source of bias. Furthermore, the certainty of the evidence was very low to low for all outcomes, and there was limited reporting of long-term adverse events. As such, the choice between ADHD pharmacotherapies may depend on individual patient considerations, and future studies should assess the long-term effects of individual pharmacotherapies on patient-important outcomes, including quality of life, in robust blinded RCTs., Registration: PROSPERO no. CRD 42015026049., Competing Interests: Don Husereau has provided advice and analysis for Eli Lilly Canada and Purdue Canada Inc. He is also an expert advisor for the Ontario Ministry of Health and Long Term Care. Alice Charach has received a limited one-time speaker honorarium from Janssen, Inc. She has no additional biomedical financial interests or potential conflicts of interest to declare. Ms. Skidmore is a paid information consultant/contractor to the Ottawa Hospital Heart Institute. Muhammad Mamdani has served as a member of an advisory board for Hoffman La Roche, Pfizer, Novartis, GlaxoSmithKline and Eli Lilly Canada. None declared for JE, AJ, SK, C.E., SH, ZB, ET, DC, or GW. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Dopamine (DA) in medial prefrontal cortex is crucial in extinction of aversive or appetitive experiences. Although attention has been mostly focused on the infralimbic area of prefrontal cortex, a role of the prelimbic (PL) area has been envisaged pointing to DA transmission in the extinction of drug conditioned behavior. Evidence shows that DA exerts its action also via both D1 and D2 receptor subtypes. Here we investigated the effects of D1 and D2 receptor agonist microinfusion in the PL cortex of C57BL/6J mice on expression and extinction of amphetamine-induced conditioned place preference (CPP), in order to ascertain the effects of selective vs concomitant receptor subtypes stimulation. SKF38393 and Quinpirole were used at doses not impairing expression of amphetamine-induced CPP on the day of infusion. Acute infusion of each agonist alone did not affect extinction in subsequent days in comparison with Vehicle-treated mice, while concomitant infusion of both agonists produced a clear-cut advance of extinction of preference for the compartment previously paired with amphetamine. These results show that concomitant stimulation of D1 and D2 receptors in PL is required to foster extinction suggesting a synergic action between receptors or a heteromeric receptor involvement., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objective: To describe our experience with amphetamine/dextroamphetamine salts (AMP) as a treatment for delayed orgasm/anorgasmia (DO/AO)., Methods: We identified patients with DO/AO from September 2017 to September 2019. Baseline characteristics and patient-reported orgasmic latency time (OLT) were recorded. After extensive screening, patients were treated with AMP. Validated questionnaires were administered including International Index of Erectile Function, quantitative Androgen Deficiency in the Aging Male and Adult ADHD Self-Report Scale. OLT change, adverse effects, and patient satisfaction were assessed. Baseline characteristics were compared using chi-squared test. OLT changes were compared with one-way ANOVA. Multivariable logistic regression was performed to identify predictors of treatment success. P < 0.05 was statistically significant., Results: Seventeen men received AMP - 6 of 17 (35.3%) for AO and 11 of 17 (64.7%) for DO, with median follow-up 1.0 year (interquartile range [IQR] 1.0 year). Amongst responders, AMP improved subjective experience of sex in 8 of 17 (47.1%) patients (2/6 with AO). Of those, 6 of 17 (35.3%; 1/6 with AO) experienced reduced OLT or increased frequency of orgasm. Non-responders were older than responders, with median age 69.5 (IQR 4.3) vs 61.0 years (IQR 12.3; P = 0.024). There were no other significant differences in baseline characteristics among responders. Of note, 6 of 8 (75%) responders and 8 of 9 (88.9%) non-responders failed other treatment modalities prior to AMP. Among responders with DO and improved OLT, mean OLT decreased by 72.3% (40.7 to 11.1 minutes, P = 0.049) during intercourse. Minimal side effects were noted including insomnia and jitters, each in one patient respectively., Conclusion: AMP as a treatment for AO/DO merits further investigation. Measurable improvements in OLT or frequency of orgasm occurred in more than a third of patients. Larger prospective multicenter studies with strict inclusion and exclusion criteria are warranted., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. No potential conflicts of interest were disclosed.

Aims: To investigate Western Australian (WA) data on the relationship between the prescription of Amphetamine-Type Stimulants (ATS), and the non-medical use of prescription ATS and other forms of meth/amphetamine, for both adults (18+) and minors (<18)., Design and Methods: Two WA specific data sources were identified. The Stimulant Regulatory Scheme provided comprehensive ATS prescribing data from 2004 until 2017, and Australian Secondary School Alcohol and Drug (ASSAD) surveys provided details of non-medical prescription ATS use by WA adolescents (12-17). Other data sources included National Drug Strategy Household Surveys (NDSHS), the Pharmaceutical Benefits Scheme (PBS), and the National Wastewater Drug Monitoring Program (NWDMP)., Results: Over 95% of WA ATS prescribing has been for the treatment of Attention Deficit Hyperactivity Disorder (ADHD). WA adults have consistently received prescription ATS at a much higher rate than other Australian adults. The most recent published data reported that in 2017 WA adults were 2.6 times as likely as other Australian adults to be supplied an ATS for ADHD. Drug treatment, NDSHS and NWDMP data indicate that WA adult rates of non-medical meth/amphetamine use have also regularly exceeded the Australian rate. Furthermore, the little data that exist on the non-medical use of prescription ATS by Australian adults suggests that it may also be disproportionately common in WA. From 1993 until 2002 the proportion of WA minors prescribed ATS grew rapidly and was the highest in Australia. Following regulatory reforms prescribing rates declined. By 2010 they were approximately half the 2002 rate. Over a similar timeframe there was a 72% fall in WA adolescent self-reported, past-week, non-medical amphetamine use. Since 2011 WA minor ATS prescribing rates have rebounded significantly. Unfortunately, useful data on adolescent meth/amphetamine use since 2011 is not available. Nonetheless, two ASSAD snapshots, in 2005 and 2017, suggest that more WA adolescents use prescription ATS non-medically than medically., Discussion and Conclusion: The data for WA adults suggest a correlation, but does not establish a causal connection, between ATS prescribing and the non-medical use of ATS and other forms of meth/amphetamine. Although it is clear that there is significant illicit prescription ATS use by WA adolescents, little is known about the contribution that the prescription of ATS makes to subsequent meth/amphetamine and other drug use. There is a critical need for research that investigates long-term, population-wide patterns and individual experiences of both those prescribed ATS and the broader population, to inform policy, prevention and treatment responses., (© 2020 Australasian Professional Society on Alcohol and other Drugs.)

Synthetic phenethylamines are widely abused drugs, comprising new psychoactive substances such as synthetic cathinones, but also well-known amphetamines such as methamphetamine and 3,4-methylenedioxymethamphetamine (MDMA, ecstasy). Cathinones and amphetamines share many toxicodynamic mechanisms. One of their potentially life-threatening consequences, particularly of MDMA, is serotonin-mediated hyponatraemia. Herein, we review the state of the art on phenethylamine-induced hyponatremia; discuss the mechanisms involved; and present the preventive and therapeutic measures. Hyponatraemia mediated by phenethylamines results from increased secretion of antidiuretic hormone (ADH) and consequent kidney water reabsorption, additionally involving diaphoresis and polydipsia. Data for MDMA suggest that acute hyponatraemia elicited by cathinones may also be a consequence of metabolic activation. The literature often reveals hyponatraemia-associated complications such as cerebral oedema, cerebellar tonsillar herniation and coma that may evolve to a fatal outcome, particularly in women. Ready availability of fluids and the recommendation to drink copiously at the rave scene to counteract hyperthermia, often precipitate water intoxication. Users should be advised about the importance of controlling fluid intake while using phenethylamines. At early signs of adverse effects, medical assistance should be promptly sought. Severe hyponatraemia (<130 mmol sodium/L plasma) may be corrected with hypertonic saline or suppression of fluid intake. Also, clinicians should be made aware of the hyponatraemic potential of these drugs and encouraged to report future cases of toxicity to increase knowledge on this potentially lethal outcome., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The paper describes three case reports of changes in sexual behavior patterns in male patients who use stimulants (amphetamine and mephedrone). Two of them demonstrate that the consumption of stimulants may lead to hypersexuality and excessive masturbation. Case report three shows that mephedrone use results in such typical stimulant-related subjective effects as the intensification of sensory experiences and sexual arousal. It leads to the loss of interest in sex without mephedrone. In light of the popularity of sex under the influence of drugs, clinicians should be aware of this phenomenon, since it is associated with high-risk sexual behavior. The description of clinical cases on the link between sex and drugs expands our knowledge in this area, leading to more effective treatment interventions.

Background: Stimulant drugs are second only to cannabis as the most widely used class of illicit drug globally, accounting for 68 million past-year consumers. Dependence on amphetamines (AMPH) or methamphetamine (MA) is a growing global concern. Yet, there is no established pharmacotherapy for AMPH/MA dependence. A comprehensive assessment of the research literature on pharmacotherapy for AMPH/MA dependence may inform treatment guidelines and future research directions., Methods: We systematically reviewed the peer-reviewed literature via the electronic databases PubMed, EMBASE, CINAHL and SCOPUS for randomised controlled trials reported in the English language examining a pharmacological treatment for AMPH/MA dependence or use disorder. We included all studies published to 19 June 2019. The selected studies were evaluated for design; methodology; inclusion and exclusion criteria; sample size; pharmacological and (if included) psychosocial interventions; length of follow-up and follow-up schedules; outcome variables and measures; results; overall conclusions and risk of bias. Outcome measures were any reported impact of treatment related to AMPH/MA use., Results: Our search returned 43 studies that met our criteria, collectively enrolling 4065 participants and reporting on 23 individual pharmacotherapies, alone or in combination. Disparate outcomes and measures (n = 55 for the primary outcomes) across studies did not allow for meta-analyses. Some studies demonstrated mixed or weak positive signals (often in defined populations, e.g. men who have sex with men), with some variation in efficacy signals dependent on baseline frequency of AMPH/MA use. The most consistent positive findings have been demonstrated with stimulant agonist treatment (dexamphetamine and methylphenidate), naltrexone and topiramate. Less consistent benefits have been shown with the antidepressants bupropion and mirtazapine, the glutamatergic agent riluzole and the corticotropin releasing factor (CRF-1) antagonist pexacerfont; whilst in general, antidepressant medications (e.g. selective serotonin reuptake inhibitors [SSRIs], tricyclic antidepressants [TCAs]) have not been effective in reducing AMPH/MA use., Conclusions: No pharmacotherapy yielded convincing results for the treatment of AMPH/MA dependence; mostly studies were underpowered and had low treatment completion rates. However, there were positive signals from several agents that warrant further investigation in larger scale studies; agonist therapies show promise. Common outcome measures should include change in use days. Future research must address the heterogeneity of AMPH/MA dependence (e.g. coexisting conditions, severity of disorder, differences between MA and AMPH dependence) and the role of psychosocial intervention.

Over the past decade, many studies have indicated that adolescence is a critical period of brain development and maturation. The refinement and maturation of the central nervous system over this prolonged period, however, makes the adolescent brain highly susceptible to perturbations from acute and chronic drug exposure. Here we review the preclinical literature addressing the long-term consequences of adolescent exposure to common recreational drugs and drugs-of-abuse. These studies on adolescent exposure to alcohol, nicotine, opioids, cannabinoids and psychostimulant drugs, such as cocaine and amphetamine, reveal a variety of long-lasting behavioral and neurobiological consequences. These agents can affect development of the prefrontal cortex and mesolimbic dopamine pathways and modify the reward systems, socio-emotional processing and cognition. Other consequences include disruption in working memory, anxiety disorders and an increased risk of subsequent drug abuse in adult life. Although preventive and control policies are a valuable approach to reduce the detrimental effects of drugs-of-abuse on the adolescent brain, a more profound understanding of their neurobiological impact can lead to improved strategies for the treatment and attenuation of the detrimental neuropsychiatric sequelae., Competing Interests: Declaration of Competing Interest All authors approve this manuscript and declare no conflict of interest related to this work., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Exposure to synthetic drugs such as amphetamines may lead to significant consequences on the cardiovascular system. The prognosis of young adults with amphetamine-induced cardiomyopathy remains poor. We present 2 young patients (aged <40 years) who developed severe dilated cardiomyopathy after chronic amphetamine use. Thorough psychological evaluations demonstrated favorable features with patients being reliable and committed to their health problems. A left ventricular assist device (HeartMate II; Abbott, Chicago, IL) was implanted in the patients shortly after admission to optimize hemodynamic support and evaluate the potential for recovery. Within less than 1 year, significant improvement was achieved and successful explantation of left ventricular assist device was performed in both patients., (Copyright © 2019 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Objective: In the U.S. ∼33% of children with attention-deficit/hyperactivity disorder (ADHD) are diagnosed during their preschool years (<6 years of age). The majority of these children are treated with a psychopharmacological treatment, despite limited data on pharmacokinetics (PKs), efficacy, or safety of these medications in this population. A phase 4, single-dose open-label study was conducted to assess the PK profile of amphetamine extended-release orally disintegrating tablets (AMP XR-ODT) under fasted conditions in preschool-aged children with ADHD. Methods: Preschool-aged children (aged 4 to <6 years) with a confirmed ADHD diagnosis were enrolled and administered AMP XR-ODT 3.1 mg under fasted conditions. Plasma samples were analyzed for d - and l -amphetamine (AMP) via liquid chromatography-tandem mass spectrometry. Area under the concentration-time curve from time 0 extrapolated to infinity (AUC 0-inf ), area under the concentration-time curve from time 0 to the last measurable plasma concentration (AUC 0-T ), maximum plasma concentration (C max ), time to maximum plasma concentration (T max ), terminal half-life (t 1/2 ), apparent volume of distribution (Vz/F), and apparent clearance (CL/F) for d - and l -AMP and safety were assessed. Results: The PK and safety analyses included 15 preschool-aged children (4 years old, n  = 6; 5 years old, n  = 9); 14 completed the study. Quantifiable plasma concentrations for d - and l -AMP were observed 1.5 hours postdose and throughout the 24-hour sampling period. For d - and l -AMP, mean AUC 0-inf was 315.2 and 104.4 h·ng/mL, AUC 0-T was 296.0 and 96.8 h·ng/mL, t 1/2 was 8.0 and 9.2 hours, C max was 23.0 and 7.0 ng/mL, T max was 3.9 and 4.0 hours, CL/F was 6996.3 and 6837.1 mL/h, and Vz/F was 75,874.5 and 84,140.0 mL, respectively. Adverse events included tachycardia ( n  = 2), neutropenia ( n  = 1), increased alanine aminotransferase ( n  = 1), and aspartate aminotransferase ( n  = 1). Conclusions: AMP XR-ODT 3.1 mg was well tolerated in preschool-aged children, with detectable plasma AMP concentrations over 24 hours, and a PK profile consistent with once-daily dosing.

Objective: The purpose of this study was to compare the pharmacokinetics of a new extended-release amphetamine oral suspension (AMP XR-OS) with a standard extended-release mixed amphetamine salts product, Adderall XR®. Method : In this single-dose, open-label, randomized, two-period, two-treatment crossover study, 42 healthy adult volunteers received 15 mL of AMP XR-OS in one period and a 30 mg Adderall XR capsule in another period (both containing 18.8 mg of amphetamine base) under fasted conditions. Blood samples were analyzed for d - and l -amphetamine concentrations, and pharmacokinetic parameters C max , AUC 0-5 , AUC 5-last , and AUC inf were calculated to determine bioequivalence. Safety was monitored throughout the study. Results : The 90% confidence intervals (CIs) for the log-transformed C max , AUC 0-5 , AUC 5-last , and AUC inf fell within the accepted 80% to 125% range for establishing bioequivalence for d - and l -amphetamine. The most common adverse events were nausea and decreased appetite. Conclusion : AMP XR-OS is bioequivalent to Adderall XR in healthy adult participants.