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Background: Adults with ADHD benefit from treatment with extended-release (ER) formulations that provide symptom control for the entire day. Some patients are advised to supplement their extended-release medication with an immediate-release (IR) medication later in the day if they need to prolong its effects. Given that several FDA-approved ER formulations are available and many individual patient variables may affect efficacy, the purpose of this study was to identify reliable predictors of the tendency for patients to supplement their daily ER medication with an IR medication., Methods: This retrospective study analyzed data from medical treatment records of adults with ADHD who received at least one ER psychostimulant (amphetamine or methylphenidate preparations) for at least six months between November 2022 and June 2024 (N = 417). Data from their intake evaluations, pre-visit measures of depression, anxiety, and ADHD via validated self-report scales, and post-visit clinician evaluations were compiled from their electronic medical records and the Qualtrics API. The association between Dyanavel XR, IR supplementation, and patient variables were investigated by backward stepwise linear regressions modeled using the variable groupings: (1) side effects reported at baseline, (2) side effects reported after 90 days, and (3) change in depression, anxiety, and ADHD symptoms from baseline to 90 days using assessment scale scores., Results: Compared to the other amphetamine and methylphenidate ER medications, only Dyanavel XR resulted in lower IR supplementation at 90 days. This relationship held when controlling for baseline IR use. Regardless of whether patients supplemented with an IR, they demonstrated improved ADHD symptoms as measured by the ADHD Symptom and Side Effect Tracking (ASSET) scale after 90 days (d = 0.68 in patients with IR, d = 0.39 in patients without IR). Dyanavel XR was significantly associated with reduced IR supplementation at 90 days compared to the pooled group of patients taking other ER medications (χ 2  = 4.320, Nagelkerke R 2  = 0.039, p = .038). The CGI-I score at baseline was also significantly associated with supplementation at 90 days (r = .14, p = .010). No other baseline variable was independently associated with IR supplementation. Along with being on Dyanavel XR, improved ADHD and anxiety symptom presentation from the baseline to the 90-day visit predicted reduced IR supplementation (ASSET change: t = 2.377, p = .018; GAD-2 change: t = -2.543, p = .011; Dyanavel XR: t = -2.112, p = .035)., Conclusion: These analyses support Dyanavel XR as a monotherapy for the daily management of ADHD in adults compared with other ER medications. Considering its tendency to reduce IR supplementation and its relationship with improved ADHD and anxiety symptoms, Dyanavel XR may simplify treatment regimens and improve outcomes., Clinical Trial Number: Not applicable., Competing Interests: Declarations. Ethics approval and consent to participate: The research presented in this manuscript has received ethics approval from Oakland University Institutional Review Board (IRB) under reference number IRB-FY2024-321. All methods were performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. All participants involved in this study provided informed consent and gave permission for their de-identified data to be used in undisclosed future research prior to their participation, and secondary research use of their information was deemed ethical by the responsible IRB. Consent for publication: Patients gave written consent for data publication. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background and Hypothesis: The dopamine theory of schizophrenia suggests that antipsychotics alleviate symptoms by blocking dopamine D2/3 receptors, yet a significant subset of patients does not respond adequately to treatment. To investigate potential predictors, we evaluated d-amphetamine-induced dopamine release and 1-year clinical outcomes in 21 antipsychotic-naive patients with first-episode schizophrenia., Study Design: Twenty-one antipsychotic-naive patients (6 female) underwent dopamine D2/3 receptor radioligand [11C]-(+)-PHNO positron emission tomography. For estimating dopamine release, scans were performed with and without d-amphetamine pretreatment. The Positive and Negative Syndrome Scale was performed at regular intervals over 1 year while receiving treatment in a naturalistic setting (Clinical Trial Registry: EUDRACT 2010-019586-29)., Study Results: A group analysis revealed no significant differences in d-amphetamine-induced dopamine release between patients with or without clinically significant improvement. However, d-amphetamine-induced dopamine release in ventral striatum was significantly associated with reductions in positive symptoms (r = 0.54, P = .04; uncorrected P-values); release in globus pallidus correlated with a decrease in PANSS negative (r = 0.58, P = .02), general (r = 0.53, P = .04), and total symptom scores (r = 0.063, P = .01). Higher dopamine release in substantia nigra/ventral tegmental area predicted larger reductions in general symptoms (r = 0.51, P = .05). Post-amphetamine binding in putamen correlated positively with negative symptom scores at baseline (r = 0.66, P = .005) and throughout all follow-up visits., Conclusions: These exploratory results support a relationship between d-amphetamine-induced dopamine release and the severity and persistence of symptoms during the first year of psychosis., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.)

Objective: To determine if treatment of co-occurring adult ADHD and Cannabis Use Disorder (CUD) with extended-release mixed amphetamine salts (MAS-ER) would be effective at improving ADHD symptoms and promoting abstinence., Method: A 12-week randomized, double-blind, two-arm pilot feasibility trial of adults with comorbid ADHD and CUD ( n  = 28) comparing MAS-ER (80 mg) to placebo. Main outcomes: ADHD: ≥30% symptom reduction, measured by the Adult ADHD Investigator Symptom Rating Scale (AISRS). CUD: Abstinence during last 2 observed weeks of maintenance phase., Results: Overall, medication was well-tolerated. There was no significant difference in ADHD symptom reduction (MAS-ER: 83.3%; placebo: 71.4%; p  = .65) or cannabis abstinence (MAS-ER: 15.4%; placebo: 0%; p  = .27). MAS-ER group showed a significant decrease in weekly cannabis use days over time compared to placebo ( p  < .0001)., Conclusions: MAS-ER was generally well-tolerated. The small sample size precluded a determination of MAS-ER's superiority reducing ADHD symptoms or promoting abstinence. Notably, MAS-ER significantly reduced weekly days of use over time., 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: Frances R. Levin receives research support from NCATS, SAMHSA, US World Meds, and Aelis Pharmaceuticals. She also receives medication from Indivior for research and royalties from APA publishing. In addition, Dr. Levin served as a nonpaid member of a Scientific Advisory Board for Alkermes, Indivior, Novartis, Teva, and US WorldMeds and is a consultant to Major League Baseball. John J Mariani has served as a consultant to Indivior, Inc. Martina Pavlicova has no conflicts to report. C. Jean Choi has no conflicts to report. Cale Basaraba has no conflicts to report. Amy L. Mahony has no conflicts to report. Daniel J. Brooks has no conflicts to report. Christina A. Brezing has no conflicts to report. Nasir Naqvi has no conflicts to report.

The prevalence of stroke and traumatic brain injury is increasing worldwide. However, current treatments do not fully cure or stop their progression, acting mostly on symptoms. Amphetamine and methylphenidate are stimulants already approved for attention deficit hyperactivity disorder and narcolepsy treatment, with neuroprotective potential and benefits when used in appropriate doses. This review aimed to summarize pre-clinical and clinical trials testing either amphetamine or methylphenidate for the treatment of stroke and traumatic brain injury. We used PubMed as a database and included the following keywords ((methylphenidate) OR (Ritalin) OR (Concerta) OR (Biphentin) OR (amphetamine) OR (Adderall)) AND ((stroke) OR (brain injury) OR (neuroplasticity)). Overall, studies provided inconsistent results regarding cognitive and motor function. Neurite outgrowth, synaptic proteins, dendritic complexity, and synaptic plasticity increases were reported in pre-clinical studies along with function improvement. Clinical trials have demonstrated that, depending on the brain region, there is an increase in motor activity, attention, and memory due to the stimulation of the functionally depressed catecholamine system and the activation of neuronal remodeling proteins. Nevertheless, more clinical trials and pre-clinical studies are needed to understand the drugs' full potential for their use in these brain diseases namely, to ascertain the treatment time window, ideal dosage, long-term effects, and mechanisms, while avoiding their addictive potential., (© 2024 Walter de Gruyter GmbH, Berlin/Boston.)

Introduction: The dextroamphetamine transdermal system (d-ATS) is a stimulant patch recently approved by the United States (U.S.) Food and Drug Administration for the treatment of attention-deficit/hyperactivity disorder (ADHD)., Areas Covered: The composition of the d-ATS, pharmacokinetics, and metabolism are presented along with data from dermal trials evaluating the tolerability of patch application at various skin sites. Efficacy and safety data from a laboratory classroom study in children and adolescents including effect sizes are assessed. Pharmacokinetic-pharmacodynamic modeling of variable wear times is also discussed., Expert Opinion: Although stimulants are recommended as first-line treatment for ADHD in the U.S. some patients may have difficulty swallowing intact tablets and capsules, or dislike the taste or texture of chewable, oral disintegrating, or liquid formulations. The d-ATS fills an unmet need for those with ADHD who are unable or prefer not to take medication orally. Varying wear time of the d-ATS also gives flexibility in length of stimulant effect which may be useful for patients with changing schedules. However, dermal discomfort must be considered in addition to the usual amphetamine side effects when prescribing the d-ATS. Patient and provider experience will determine how frequent the use of d-ATS becomes.

Introduction: Amphetamine preparations are one of the two categories of stimulant medications approved for the treatment of attention deficit hyperactivity disorder (ADHD). Optimal treatment of ADHD aims to reduce core symptoms for as much of the waking hours as possible, leading to longer-acting delivery formats. In addition, the pediatric population commonly has difficulty swallowing pills and manufacturers have developed a variety of options to facilitate this concern. These include chewable tablets, capsules that may be sprinkled on soft food, liquids and transdermal patches., Areas Covered: This article reviews the once-daily extended-release preparations currently available for amphetamine compounds, their pharmacodynamics, and common adverse effects., Expert Opinion: There is an extensive evidence base supporting use of amphetamine preparations in the treatment of ADHD. Rapid onset of action and a favorable side effect profile make these widely used. The availability of once-daily extended-release chewable tablets, capsules that can be opened and sprinkled, and liquid formulations provides clinicians with multiple options to meet the specific needs of patients with difficulty swallowing whole pills.

Background: The prosocial compound ± 3,4-methylenedioxymethamphetamine (MDMA) is an amphetamine derivative that has shown promise as an adjunct to psychotherapy in the treatment of post-traumatic stress disorder. MDMA increases positive responses to social images, and it has been suggested that the ability of MDMA to positively bias social perception may underlie its therapeutic efficacy as a psychotherapy adjunct. However, the effect of the compound on affective responses to positive or negative social feedback has not been tested., Aims: In this study, we aimed to test the effects of MDMA compared to placebo and the prototypical stimulant, methamphetamine (MA), on responses to positive and negative social feedback., Methods: This was a double-blind, placebo-controlled, crossover trial (NCT03790618), comparing the effects of two doses of MDMA (0.75 mg/kg, 1.5 mg/kg) to both placebo and MA (20 mg) on responses to a personalized social feedback task, similar to a dating app, in healthy adult volunteers ages 18-40 ( N  = 36, 18 women, 18 men)., Results/outcomes: The high dose of MDMA increased positive affective responses to social feedback., Conclusions/interpretations: These findings suggest one process by which MDMA may facilitate social connection. Further work is needed to understand how MDMA affects responses to more generalized types of social feedback and to understand these effects in clinical populations., Competing Interests: Declaration of conflicting interestsHdW is on the board of PharmAla Biotech, Inc. and is a consultant to Awakn Life Sciences and Gilgamesh Pharmaceuticals. DTH is currently employed by Tonix Pharmaceuticals.

Objective: To examine the effects of triple beaded mixed amphetamine salts (TB MAS) on ADHD and executive dysfunction symptoms throughout the day in adults with DSM-5 ADHD., Method: This was a 6 week, single-blind, placebo-lead in trial of TB MAS (12.5-37.5 mg/day); all participants received 2 weeks of single-blind placebo); one individual was a placebo responder and was discontinued. One of these 18 dropped after 1 week on 12.5 mg/day, while all others completed the trial and received 37.5 mg/day TB MAS., Results: There were significant effects of TB MAS on all clinical measures, including investigator overall symptoms (AISRS); self-report overall (ASRS), time-sensitive ADHD (TASS) scores throughout the day, impairment (CGI) and executive function scores (BRIEF-A). TB MAS was generally well tolerated., Conclusions: This study extends prior findings of TB MAS to adults with DSM-5 ADHD; it further re-validates findings of efficacy of TB MAS throughout the day., 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: 3 year Disclosures: Lenard A. Adler MD: has received Grant/Research support to NYU Grossman School of Medicine from Shire/Takeda, Otsuka Pharmaceuticals, Corium; Consultant to Supernus Pharmaceuticals, Bracket/Signant, SUNY, Neurocentria, National Football League, Major League Baseball, Otsuka; Royalty payments (as inventor) from NYU Grossman School of Medicine for license of adult ADHD scales and training materials since 2004.; Deepti Anbarasan MD, Taylor Sardoff BA, Terry Leon RN, Caleb A. Massimi BA have all declared no potential conflicts of interest; 3 year Disclosures: Richard Gallagher Ph.D:Research Support from NIMH and IES; Royalties from Guilford Press and NYU Grossman School of Medicine (latter for Children’s Organizational Skills Scale Project).; In the past year, Dr. Faraone received income, potential income, travel expenses continuing education support and/or research support from Aardvark, Aardwolf, AIMH, Tris, Otsuka, Ironshore, Kanjo, Johnson & Johnson/Kenvue, KemPharm/Corium, Akili, Supernus, Atentiv, Noven, Sky Therapeutics, Axsome and Genomind. With his institution, he has US patent US20130217707 A1 for the use of sodium-hydrogen exchange inhibitors in the treatment of ADHD. He also receives royalties from books published by Guilford Press: Straight Talk about Your Child’s Mental Health, Oxford University Press: Schizophrenia: The Facts and Elsevier: ADHD: Non-Pharmacologic Interventions. He is Program Director of www.ADHDEvidence.org and www.ADHDinAdults.com. Dr. Faraone is supported by the European Union’s Horizon 2020 research and innovation program under grant agreement No 965381; NIMH grants U01AR076092-01A1, 1R21MH1264940, R01MH116037; 1R01NS128535 – 01; Oregon Health and Science University, Otsuka Pharmaceuticals, Noven Pharmaceuticals Incorporated, and Supernus Pharmaceutical Company.

Objective: Stimulant medications are the main treatment for Attention Deficit Hyperactivity Disorder (ADHD), but overall treatment efficacy in adults has less than a 60% response rate. This study aimed to identify neural and cognitive markers predictive of longitudinal improvement in response to stimulant treatment in drug-naïve adults with ADHD., Method: We used diffusion tensor imaging (DTI) and executive function measures with 36 drug-naïve adult ADHD patients in a prospective study design., Results: Structural connectivity (measured by fractional anisotropy, FA) in striatal regions correlated with ADHD clinical symptom improvement following stimulant treatment (amphetamine or methylphenidate) in better medication responders. A significant positive correlation was also found between working memory performance and stimulant-related symptom improvement. Higher pre-treatment working memory scores correlated with greater response., Conclusion: These findings provide evidence of pre-treatment neural and behavioral markers predictive of longitudinal treatment response to stimulant medications in adults with ADHD., 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: Dr. Joseph Biederman has received research support from the following sources: AACAP, Feinstein Institute for Medical Research, Food & Drug Administration, Genentech, Headspace Inc., NIDA, Pfizer Pharmaceuticals, Roche TCRC Inc., Sunovion Pharmaceuticals Inc., Takeda/Shire Pharmaceuticals Inc., Tris, and NIH. Joseph Biederman’s program has received departmental royalties from a copyrighted rating scale used for ADHD diagnoses, paid by Biomarin, Bracket Global, Cogstate, Ingenix, Medavent Prophase, Shire, Sunovion, and Theravance; these royalties were paid to the Department of Psychiatry at MGH. Joseph Biederman has a US Patent (#14/027,676) for a non-stimulant treatment for ADHD, a US Patent (#10,245,271 B2) on a treatment of impaired cognitive flexibility, and a patent pending (#61/233,686) on a method to prevent stimulant abuse. Joseph Biederman was a consultant for Akili, Avekshan, Jazz Pharma, and Shire/Takeda. He received research support from Lundbeck AS and Neurocentria Inc. Through MGH CTNI, he participated in a scientific advisory board for Supernus. Dr. Mai Uchida received honoraria from Mochida Pharmaceuticals and American Physician’s Institute, received royalties for the book, “Ask The Geniuses About The Future” (Magazine House Publishing) and provided consultations to Guidepoint and Moderna. Dr. Hung, Ms. Green, Ms. Kelberman, Ms. Gaillard, Mr. Cappella, Ms. Rudberg, and Dr. Gabrieli has no disclosures to report.

Background: NLS-3 or (R, R) enantiomer of phacetoperane (levophacetoperane) is the reverse ester of methylphenidate, a well-documented psychostimulant marketed for the treatment of attention-deficit/hyperactivity disorder (ADHD) since the end of 1950s. Launched in Canada and Europe by Specia Rhône-Poulenc and Rhodia, marketed as Lidepran® (8228 R.P.), for the treatment of obesity and depression, phacetoperane became an increasingly popular psychiatric medication from 1959 to 1967. Previous data supported that the stimulant effect of phacetoperane differed from those of other medications acting on the catecholamine system (e.g., methylphenidate, amphetamine), with an advantage of benefit/risk balance., Method: The goal of this study is to characterize the binding profile of NLS-3 using in vitro and in vivo assays and hypothesize potential therapeutic uses considering all available data., Results: A complete binding profile assay confirmed the potential benefit of phacetoperane with a higher benefit/risk compared to other stimulants. NLS-3 synthesis resulted from phenylketone, which is also used for the synthesis of methylphenidate. It differs from that used by Rhône-Poulenc SA laboratories, allowing the possibility of individualizing several enantiomers not synthesized previously. The present review also confirmed extensive clinical use of the compound in almost one thousand children and adolescents in large dose ranges with fewer side effects versus comparative treatments. Furthermore, levophacetoperane was found to be generally well-tolerated by the subjects., Conclusion: NLS-3 could be a safer and more potent alternative to stimulants for patients with ADHD., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Introduction: There has been a pronounced increase in the use of Schedule II stimulants to treat attention-deficit hyperactivity disorder (ADHD) in the United States over the last two decades. Interestingly, chronic medical cannabis (MC) use can present with cognitive impairments that resemble ADHD symptoms. This study aimed to determine if MC legalization increased prescription stimulant distribution., Methods: Information on the distribution of methylphenidate, amphetamine, and lisdexamfetamine for 2006 to 2021 was extracted from the Drug Enforcement Administration's comprehensive database and the three-year population-corrected slopes of stimulant distribution before and after MC program implementation were compared., Results: We found a significant main effect of time ( p <0.001); however, contrary to the hypothesis, the sales status of states' MC, did not influence slopes of distribution ( p =0.391). There was a significantly large interaction effect of time and MC sales status on slopes of distribution ( p <0.001). Slopes of distribution rates of stimulants were significantly lower in states that proceeded to legalize MC prior to MC program implementation than those states that did not ( p =0.022). After MC program implementation, however, the distribution rates of the Schedule II stimulants were not significantly different when comparing states with MC sales to those without ( p =0.355)., Discussion: These findings suggest that MC program legalization did not contribute to certain states having rapid increases in Schedule II stimulant distribution rates over time. Other factors, including the liberalization of the adult ADHD diagnostic criteria in the DSM-5 and the introduction of Binge Eating Disorder, also likely contributed to elevations in stimulant distribution., Competing Interests: BJP’s research is supported by the Pennsylvania Academic Clinical Research Center and the Health Resources and Services Administration (D34HP31025). Prior (2019–2021) osteoarthritis research was supported by Pfizer and Eli Lilly. The other authors have no disclosures., (Thieme. All rights reserved.)

Purpose: Immediate-release forms of generic mixed amphetamine salts (MAS) have been the subject of passive surveillance reports signaling lack of effectiveness. We examined switching patterns that might suggest whether long-term users of specific MAS are more likely to switch away or switch back after use of the MAS of interest in the FDA's Sentinel Distributed Database., Methods: We required at least 60-day continuous supply of selected MAS grouped by Abbreviated New Drug Application (ANDA) to describe patterns of switching away from and to generics approved under the ANDAs of interest among individuals ages 15-64 years with attention deficit hyperactivity disorder or narcolepsy during 2013-2019., Results: We observed the greatest number of treatment episodes for ANDA 040422 (n = 525 771), followed by ANDA 202424 (n = 181 693), ANDA 040439 (n = 62 363), ANDA 040440 (n = 21 143), and ANDA 040480 (n = 8792). Of those with switches away from their original ANDA, episodes initiated on generic products under ANDA 040422 (48.6%) and ANDA 202424 (43.0%) were most likely to switch back, while those initiated on generic product under ANDA 040480 were least likely (24.1%). Of those episodes with switches to a generic under an ANDA of interest, about one-third (range 27.1% to 37.0%) switched back to the same product. These switches back had a median time to switch of about 30 days., Conclusions: These descriptive analyses, although subject to limitations, did not suggest increased switching away or switching back after use of the generics of interest. Continued post-marketing surveillance is warranted., (© 2023 John Wiley & Sons Ltd. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Lithium carbonate (LiCO) is a mainstay therapeutic for the prevention of mood-episode recurrences in bipolar disorder (BD). Unfortunately, its narrow therapeutic index is associated with complications that may lead to treatment non-compliance. Intriguingly, lithium orotate (LiOr) is suggested to possess unique uptake characteristics that would allow for reduced dosing and mitigation of toxicity concerns. We hypothesized that due to differences in pharmacokinetics, LiOr is more potent with reduced adverse effects. Dose responses were established for LiOr and LiCO in male and female mice using an amphetamine-induced hyperlocomotion (AIH) model; AIH captures manic elements of BD and is sensitive to a dose-dependent lithium blockade. LiCO induced a partial block of AIH at doses of 15 mg/kg in males and 20 mg/kg in females. In contrast, LiOr elicited a near complete blockade at concentrations of just 1.5 mg/kg in both sexes, indicating improved efficacy and potency. Prior application of organic anion transport inhibitors, or inhibition of orotate uptake into the pentose pathway, completely blocked the effects of LiOr on AIH while sparing LiCO effects, confirming differences in transport and compartmentalization between the two compounds. Next, the relative toxicities of LiOr and LiCO were contrasted after 14 consecutive daily administrations. LiCO, but not LiOr, elicited polydipsia in both sexes, elevated serum creatinine levels in males, and increased serum TSH expression in females. LiOr demonstrates superior efficacy, potency, and tolerability to LiCO in both male and female mice because of select transport-mediated uptake and pentose pathway incorporation., Competing Interests: Declaration of competing interest Dr. Bekar and Mr. Pacholko report no biomedical financial interests or potential conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Attention-deficit/hyperactivity disorder (ADHD) is a common neurobehavioral disorder with symptoms that may persist in up to 90% of adults diagnosed during childhood and continue to cause significant impairment throughout the lifespan. In the United States (US), amphetamine and methylphenidate formulations have been available to treat ADHD for several decades. Only one nonstimulant, atomoxetine, was available for the treatment of ADHD in adults until recently. In April 2022, a second nonstimulant, viloxazine extended-release (VLX-ER), became available in the US for the treatment of adult ADHD. Efficacy was previously established in placebo-controlled trials in children and adolescents., Areas Covered: VLX-ER is a norepinephrine reuptake inhibitor with serotonin activity. The efficacy in adults, adverse event profile, pharmacokinetics, drug-drug interactions, and metabolism of VLX-ER are reviewed., Expert Opinion: Despite the availability of effective pharmacological treatments for ADHD, many patients discontinue treatment in less than 1 year. Stimulants are effective in more than 80% of patients; however, some may have difficulty tolerating them. Although there were no head-to-head studies, the effect size of VLX-ER in an adult efficacy trial was lower than has been shown for stimulants. Nevertheless, the approval of VLX-ER adds another effective ADHD treatment option for adults.

With the proliferation of synthetic drugs, research on the mechanism of action of addictive drugs and treatment methods is of great significance. Among them, methamphetamine (METH) is the most representative amphetamine synthetic drug, and the treatment of METH addiction has become an urgent medical and social problem. In recent years, the therapeutic effects of Chinese herbal medicines on METH addiction have gained widespread attention because of their non-addictiveness, multiple targets, low side effects, low cost, and other characteristics. Previous studies have identified a variety of Chinese herbal medicines with effects on METH addiction. Based on the research on METH in recent years, this article summarizes the mechanism of action of METH as the starting point and briefly reviews the Chinese herbal medicine-based treatment of METH., (© 2023. The Chinese Journal of Integrated Traditional and Western Medicine Press and Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose/background: The prevalence of attention-deficit/hyperactivity disorder in adult females is 3% to 4%. Attention-deficit/hyperactivity disorder is highly comorbid with other psychiatric disorders such as mood, anxiety, and substance use disorders. For reproductive-aged women, the treatment of attention-deficit/hyperactivity disorder with stimulant medications may be considered during pregnancy or breastfeeding, although historically, data are lacking to inform these decisions. The aim of this investigation was to determine the risk of major malformations in infants after first-trimester prescription stimulant exposure in a small but rigorously characterized sample., Methods/procedures: The Massachusetts General Hospital National Pregnancy Registry for Psychiatric Medications systematically ascertains information from pregnant females including demographic information, medical and psychiatric history, use of prescription medications, and other information relevant to fetal outcomes. Participants provide verbal informed consent and are interviewed twice during gestation and again at approximately 3 months postpartum. The primary outcome of interest is the presence of a major malformation identified within 6 months after birth. Redacted cases of major malformations are reviewed by a dysmorphologist blinded to medication exposure., Findings/results: A total of N = 1988 women were eligible for this analysis, including the following exposures: n = 173 to mixed amphetamine salts; n = 40 to lisdexamfetamine; n = 45 to methylphenidate; n = 3 to dexmethylphenidate; and n = 1755 controls. The odds ratio of a major malformation among infants after first-trimester exposure to any stimulant was 0.39 (95% confidence interval, 0.09-1.61) compared with controls. There were no major malformations observed in infants exposed to lisdexamfetamine, methylphenidate, or dexmethylphenidate., Implications/conclusions: Although preliminary, this analysis from an ongoing pregnancy registry provides reassurance that these stimulants do not appear to have major teratogenic effects., Trial Registration: ClinicalTrials.gov identifier: NCT01246765 ., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

We sought to understand the effect of current treatments for attention deficit hyperactivity disorder (ADHD) on executive functioning deficits, which are often comorbid with ADHD, via a systematic analysis of adult ADHD treatment studies evaluating change in behavioral measures beyond the core symptoms of Diagnostic and Statistical Manual of Mental Disorders ADHD. The standardized mean difference for behavioral measures of executive functioning was determined from controlled trials of adults with ADHD and compared with effects on core ADHD symptoms. Several studies of atomoxetine revealed small to large standardized mean differences. Nonreplicated studies revealed small to medium effects for triple-bead mixed amphetamine salts, lisdexamfetamine, and forms of cognitive behavioral therapy. Proportional effect versus core ADHD symptoms ranged from 0.78 to 1.16 for atomoxetine, and from 0.65 to 1.44 across all the studies. ADHD treatments have effects on executive functioning behavior beyond core ADHD symptoms in adults. Clinicians can measure and treat this morbidity using available clinical tools., (© 2023, The American College of Clinical Pharmacology.)

Attention-deficit hyperactivity disorder (ADHD) and bipolar disorder (BD) are often comorbid in patients and can have significant overlap in symptoms. Because of this common comorbidity and often overlapping symptoms, accurate diagnoses can be difficult. The standard treatment for these comorbid disorders is a mood stabilizer with the possibility of adding a psychostimulant. However, research suggesting treatment for comorbid disorders with a psychostimulant without a mood stabilizer is lacking. Here, we present two cases where mixed amphetamine salts, which are traditionally avoided in those with BD, were effectively used without a mood stabilizer to treat comorbid BD and ADHD in both patients. The outcome of this case series serves to motivate future investigations which are needed to validate treatment with a psychostimulant without a mood stabilizer for the treatment of comorbid BD and ADHD., (Published by Oxford University Press on behalf of the Association of Military Surgeons of the United States 2021. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Background: Attention deficit hyperactivity disorder (ADHD) is a major problem in children and adolescents, characterised by age-inappropriate levels of inattention, hyperactivity, and impulsivity, and is associated with long-term social, academic, and mental health problems. The stimulant medications methylphenidate and amphetamine are the most frequently used treatments for ADHD, but these are not always effective and can be associated with side effects. Clinical and biochemical evidence suggests that deficiencies of polyunsaturated fatty acids (PUFA) could be related to ADHD. Research has shown that children and adolescents with ADHD have significantly lower plasma and blood concentrations of PUFA and, in particular, lower levels of omega-3 PUFA. These findings suggest that PUFA supplementation may reduce the attention and behaviour problems associated with ADHD. This review is an update of a previously published Cochrane Review. Overall, there was little evidence that PUFA supplementation improved symptoms of ADHD in children and adolescents., Objectives: To compare the efficacy of PUFA to other forms of treatment or placebo in treating the symptoms of ADHD in children and adolescents., Search Methods: We searched 13 databases and two trials registers up to October 2021. We also checked the reference lists of relevant studies and reviews for additional references., Selection Criteria: We included randomised and quasi-randomised controlled trials that compared PUFA with placebo or PUFA plus alternative therapy (medication, behavioural therapy, or psychotherapy) with the same alternative therapy alone in children and adolescents (aged 18 years and under) diagnosed with ADHD., Data Collection and Analysis: We used standard Cochrane methods. Our primary outcome was severity or improvement of ADHD symptoms. Our secondary outcomes were severity or incidence of behavioural problems; quality of life; severity or incidence of depressive symptoms; severity or incidence of anxiety symptoms; side effects; loss to follow-up; and cost. We used GRADE to assess the certainty of evidence for each outcome., Main Results: We included 37 trials with more than 2374 participants, of which 24 trials were new to this update. Five trials (seven reports) used a cross-over design, while the remaining 32 trials (52 reports) used a parallel design. Seven trials were conducted in Iran, four each in the USA and Israel, and two each in Australia, Canada, New Zealand, Sweden, and the UK. Single studies were conducted in Brazil, France, Germany, India, Italy, Japan, Mexico, the Netherlands, Singapore, Spain, Sri Lanka, and Taiwan. Of the 36 trials that compared a PUFA to placebo, 19 used an omega-3 PUFA, six used a combined omega-3/omega-6 supplement, and two used an omega-6 PUFA. The nine remaining trials were included in the comparison of PUFA to placebo, but also had the same co-intervention in the PUFA and placebo groups. Of these, four trials compared a combination of omega-3 PUFA plus methylphenidate to methylphenidate. One trial each compared omega-3 PUFA plus atomoxetine to atomoxetine; omega-3 PUFA plus physical training to physical training; and an omega-3 or omega-6 supplement plus methylphenidate to methylphenidate; and two trials compared omega-3 PUFA plus dietary supplement to dietary supplement. Supplements were given for a period of between two weeks and six months. Although we found low-certainty evidence that PUFA compared to placebo may improve ADHD symptoms in the medium term (risk ratio (RR) 1.95, 95% confidence interval (CI) 1.47 to 2.60; 3 studies, 191 participants), there was high-certainty evidence that PUFA had no effect on parent-rated total ADHD symptoms compared to placebo in the medium term (standardised mean difference (SMD) -0.08, 95% CI -0.24 to 0.07; 16 studies, 1166 participants). There was also high-certainty evidence that parent-rated inattention (medium-term: SMD -0.01, 95% CI -0.20 to 0.17; 12 studies, 960 participants) and hyperactivity/impulsivity (medium-term: SMD 0.09, 95% CI -0.04 to 0.23; 10 studies, 869 participants) scores were no different compared to placebo. There was moderate-certainty evidence that overall side effects likely did not differ between PUFA and placebo groups (RR 1.02, 95% CI 0.69 to 1.52; 8 studies, 591 participants). There was also moderate-certainty evidence that medium-term loss to follow-up was likely similar between groups (RR 1.03, 95% CI 0.77 to 1.37; 13 studies, 1121 participants)., Authors' Conclusions: Although we found low-certainty evidence that children and adolescents receiving PUFA may be more likely to improve compared to those receiving placebo, there was high-certainty evidence that PUFA had no effect on total parent-rated ADHD symptoms. There was also high-certainty evidence that inattention and hyperactivity/impulsivity did not differ between PUFA and placebo groups. We found moderate-certainty evidence that overall side effects likely did not differ between PUFA and placebo groups. There was also moderate-certainty evidence that follow-up was similar between groups. It is important that future research addresses the current weaknesses in this area, which include small sample sizes, variability of selection criteria, variability of the type and dosage of supplementation, and short follow-up times., (Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Excess dopamine release in the dorsal striatum (DS) is linked to psychosis. Antipsychotics are thought to work by blocking striatal D2 dopamine receptors, but they lack efficacy for the negative and cognitive symptoms of schizophrenia. These observations and the fact that increasing brain-wide dopamine improves cognition have fueled the dogma that excess dopamine is not involved in negative and cognitive symptoms. However, this idea has never been explicitly tested with DS-pathway specificity. To determine if excess DS dopamine is involved in cognitive and negative symptoms, we selectively re-expressed excitatory TRPV1 receptors in DS-projecting dopamine neurons of Trpv1 knockout mice. We treated these mice with capsaicin (TRPV1 agonist) to selectively activate these neurons, validated this approach with fiber photometry, and assessed its effects on social interaction and working memory, behavioral constructs related to negative and cognitive symptoms. We combined this manipulation with antipsychotic treatment (haloperidol) and compared it to brain-wide dopamine release via amphetamine treatment. We found that selectively activating DS-projecting dopamine neurons increased DS (but not cortical) dopamine release and increased locomotor activity. Surprisingly, this manipulation also impaired social interaction and working memory. Haloperidol normalized locomotion, but only partially rescued working memory and had no effect on social interaction. By contrast, amphetamine increased locomotion but did not impair social interaction or working memory. These results suggest that excess dopamine release, when restricted to the DS, causes behavioral deficits linked to negative and cognitive symptoms. Future therapies should address this disregarded role for excess striatal dopamine in the treatment-resistant symptoms of psychosis., (© 2022. The Author(s), under exclusive licence to American College of Neuropsychopharmacology.)

Background: In recent years, amphetamine-type-stimulants (ATS) have been extensively misused in South-East Asia, inducing major problems among methadone-maintenance-treatment (MMT) patients. Objective: We examine ATS-misuse prevalence and its determinants among MMT patients in East-Coast-Malaysia. Methods: A retrospective-observational study was conducted on government-subsidized medication for opioid-use-disorder (MOUD) treatment clinics involving 292 MMT-patients (98% males) who were selected using a multilevel-proportional-stratified random sampling technique. Information obtained during the mandatory monitoring procedure from January 1 to December 31 2019, was utilized to determine ATS misuse prevalence from consecutive random urine drug screening. The determinants associated with its use, namely sociodemographics, social networks, comorbidities, and pharmacological assessments were analyzed via a logistic model. Results: Overall, 52.2% of the MMT-patients (95% CI: 0.42-0.54) had misused ATS at least once during their methadone treatment. These misusing patients were active smokers, hepatitis B and C seronegative, concurrently misused opioids, and had received suboptimum prescribed doses of methadone. Multiple logistic regression analysis demonstrated that the odds of misusing ATS during methadone treatment were 37 times higher among those who concurrently misused opioids (AOR: 37.60, 95% CI: 14.03-100.74) and 12 times higher among those who received suboptimal methadone doses (<60 mg/day) (AOR: 12.24, 95% CI: 5.58-25.43). Conclusion: This study demonstrated the significant prevalence of ATS misuse among MMT-patients in East-Coast-Malaysia, especially among patients who were prescribed suboptimal doses of methadone and/or demonstrated concomitant opioid-misuse. Stringent urine-monitoring is crucial to prevent diversion to ATS misuse. Nonetheless, to avoid negligence and improve physician engagement, the relevant authorities should immediately plan a comprehensive national-standard training module comprising support activities for professional methadone-prescribers.

Background: Over the past decade, the number of individuals requiring medical care for amphetamine-related psychosis has increased., Objective: This study aims to examine the psychological characteristics of amphetamine psychosis in drug-addicted patients depending on the length of drug exposure and compared to patients diagnosed with paranoid schizophrenia., Methods: The study was carried out in psychiatric clinic No. 1 in Kyiv (Ukraine) in 2019, involving 107 patients. Of all the participants, 50 were included in Group 1 (methamphetamine psychosis) and 57 - in Group 2 (paranoid schizophrenia). All patients were treated with medication to relieve exacerbating symptoms. They underwent extensive testing to determine the impairment severity of cognitive function, attention, and task performance during remission., Results: In Group 1, the timing of onset for paranoid symptoms depends on the length of amphetamine exposure (Spearman correlation coefficient = 0.89). The efficacy and dynamics of drug treatment in Group 2 were similar to patients in Group 1. However, the effect of reduction in Group 2 was achieved only in 4 months. Delusions, emotional disturbances, hallucinations in patients of Group 1 occurred 2.3 times more frequently than in Group 2 (p ≤ 0.05). The patients of Group 1 are characterized by the presence of disorders related to the affective and behavioral components., Conclusion: All reported exacerbations are related to amphetamine use. Patients in Group 1 learned a smaller number of words compared to those in Group 2. Besides, a large number of errors and difficulties with shifting focus were recorded., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Impulsive-compulsive behaviours manifest in a substantial proportion of subjects with Parkinson's disease. Reduced ventral striatum dopamine receptor availability, and increased dopamine release is noted in patients with these symptoms. Prior studies of impulsivity suggest that midbrain D2 autoreceptors regulate striatal dopamine release in a feedback inhibitory manner, and in healthy populations, greater impulsivity is linked to poor proficiency of this inhibition. This has not been assessed in a Parkinson's disease population. Here, we applied 18F-fallypride PET studies to assess striatal and extrastriatal D2-like receptor uptake in a placebo-controlled oral dextroamphetamine sequence. We hypothesized that Parkinson's disease patients with impulsive-compulsive behaviours would have greater ventral striatal dopaminergic response to dextroamphetamine, and that an inability to attenuate ventral striatal dopamine release via midbrain D2 autoreceptors would underlie this response. Twenty patients with Parkinson's disease (mean age = 64.1 ± 5.8 years) both with (n = 10) and without (n = 10) impulsive-compulsive behaviours, participated in a single-blind dextroamphetamine challenge (oral; 0.43 mg/kg) in an OFF dopamine state. All completed PET imaging with 18F-fallypride, a high-affinity D2-like receptor ligand, in the placebo and dextroamphetamine state. Both voxelwise and region of interest analyses revealed dextroamphetamine-induced endogenous dopamine release localized to the ventral striatum, and the caudal-medial orbitofrontal cortex. The endogenous dopamine release observed in the ventral striatum correlated positively with patient-reported participation in reward-based behaviours, as quantified by the self-reported Questionnaire for Impulsivity in Parkinson's disease Rating Scale. In participants without impulsive-compulsive behaviours, baseline midbrain D2 receptor availability negatively correlated with ventral striatal dopamine release; however, this relationship was absent in those with impulsive-compulsive behaviours. These findings emphasize that reward-based behaviours in Parkinson's disease are regulated by ventral striatal dopamine release, and suggest that loss of inhibitory feedback from midbrain autoreceptors may underlie the manifestation of impulsive-compulsive behaviours., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose/background: Acute hyperkinetic movement disorders have been reported with the concomitant use of attention-deficit/hyperactivity disorder (ADHD) stimulants and antipsychotics in children and adolescents. We analyzed postmarketing reports of suspected acute hyperkinetic movement disorder associated with concomitant use of ADHD stimulants and antipsychotics., Methods/procedures: We searched for postmarketing reports of acute hyperkinetic movement disorders associated with concomitant use of ADHD stimulants-antipsychotics in the US Food and Drug Administration Adverse Event Reporting System through December 6, 2019. PubMed and EMBASE were also searched for acute hyperkinetic movement reports with the concomitant use of ADHD stimulants-antipsychotics through January 13, 2020., Findings/results: We identified 36 cases resulting in acute hyperkinetic movement disorder associated with the concomitant use of ADHD stimulants-antipsychotics, 19 of which were also identified in the medical literature. From an ADHD stimulant perspective, methylphenidate products accounted for the largest number of cases (n = 23 [64%]), followed by amphetamine products (n = 9 [25%]) and atomoxetine (n = 4 [11%]). From an antipsychotic perspective, all 36 cases were reported with second-generation antipsychotics, particularly risperidone (n = 20 [56%]). Most of the cases were reported in boys (n = 31 [86%]) aged 6 to 12 years (n = 27 [75%]). Approximately 53% of the cases reported a time to onset within 24 hours of the drug change. Acute dystonic reactions (n = 27 [75%]) were the most frequently reported movement disorder., Implications/conclusions: As outlined in changes to the US prescribing information for all methylphenidate and risperidone products, health care professionals should be aware that changes to this combination may be associated with a pharmacodynamic drug-drug interaction resulting in acute hyperkinetic movement disorder., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Rationale: Methylphenidate (MPH) and mixed D,L-amphetamine salts (MASs; Adderall) were previously found to have unreliable effects on judgment and decision processes., Objective: We predicted that MPH and MASs have a specific effect of reducing heuristic responses, which should lead to increased performance on the cognitive reflection test (CRT). The CRT is considered to be a testbed for heuristic versus deliberative response modes., Methods: We recruited a sample of 15,361 individuals using the Prolific Academic crowdsourcing platform. From this initial pool, our final sample consisted of 294 participants (125 MPH users and 169 MASs users) who conformed to the study criteria and completed the experimental tasks. Tasks were performed on days where participants were either medicated or not, allowing to assess the effect of medication status., Results: There was a strong positive effect of taking MPH on CRT scores (Cohen's d = 0.40) which was not qualified by frequency of MPH usage, ADHD symptoms, and demographic factors. There was also a somewhat weaker effect for MASs (Cohen's d = 0.07). No effects of MPH and MASs were recorded for risk-taking and numeracy., Conclusions: The results indicate that MPH enhances decision-making in tasks where heuristic responses typically bias it., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: Assess executive function (EF) improvement with SHP465 mixed amphetamine salts (MAS) extended-release in adults with attention-deficit/hyperactivity disorder (ADHD) using responder analyses of the Brown Attention-Deficit Disorder Scale (BADDS)., Methods: Post hoc analyses examined data from placebo-controlled SHP465 MAS dose-optimization (12.5-75 mg) and fixed-dose (25-75 mg) studies. Treatment response was assessed using two definitions (BADDS total score at endpoint <50 [no EF impairment] vs. ≥50 [impaired]; BADDS total score at endpoint relative to the in-treatment 90% CI range for baseline total score [below the range = improved])., Results: Response rates (SHP465 MAS vs. placebo) favored SHP465 MAS (all nominal p < .0001) in the dose-optimization (BADDS <50: 41.9% vs. 19.2%; below 90% CI range: 57.4% vs. 29.6%) and fixed-dose (BADDS <50: 51.9% vs. 16.7%; below 90% CI range: 70.6% vs. 32.3%) studies., Conclusion: Improvement in EF measured by BADDS response rates was approximately 2-fold greater with SHP465 MAS than placebo.

Background: Given the limited treatment options for younger children with attention-deficit/hyperactivity disorder (ADHD), a clinical study for SHP465 treatment was warranted., Objectives: We aimed to evaluate the pharmacokinetics, safety, and tolerability of SHP465 mixed amphetamine salts (MAS) 6.25 mg after multiple once-daily doses in children aged 4-5 years with ADHD., Methods: In this open-label multicenter study, SHP465 MAS 6.25 mg once daily was administered for 28 days to children aged 4-5 years with ADHD; baseline ADHD Rating Scale-5 total score ≥ 28 (boys) or ≥ 24 (girls) and Clinical Global Impression-Severity scale score ≥ 4. Blood samples were collected in the pharmacokinetic-rich group predose on day 1 week 1 and day 7 week 4 (predose, postdose at 2, 5, 8, 12, 16, 24, and 48 hours); and in the pharmacokinetic-sparse group predose on day 1 weeks 1, 2, and 3 and 24 hours postdose on day 7 week 4 . Key pharmacokinetic parameters included maximum plasma drug concentration (C max ), plasma trough drug concentration, time to C max during a dosing interval (t max ), area under the concentration-time curve from time 0 to time of last collected sample, area under the concentration-time curve over the dosing interval (24 h) at steady state (AUC tau,ss ), first-order rate constant associated with the terminal phase of elimination, terminal half-life (t 1/2 ), total clearance of drug from plasma after oral administration, and apparent volume of distribution at steady state. Safety endpoints included treatment-emergent adverse events and vital signs., Results: Mean ± standard deviation age and body mass index of 24 participants (66.7% male) were 4.8 ± 0.41 years and 17.2 ± 3.18 kg/m 2 , respectively. The most common ADHD was the combined presentation (91.7%); ratings were 50% markedly ill and 45.8% moderately ill on the Clinical Global Impression-Severity scale. Plasma d-amphetamine and l-amphetamine steady state was attained by predose on treatment day 8, consistent with the half-life. Peak steady-state plasma concentration (median t max ) for both d-amphetamine and l-amphetamine occurred at 7.92 h postdose on day 7 week 4 and thereafter declined monoexponentially, with a geometric mean t 1/2 of 10.4 and 12.3 h for d-amphetamine and l-amphetamine, respectively. For both d-amphetamine and l-amphetamine, C max and AUC tau,ss were comparable between children aged 4 years (n = 3) and children aged 5 years (n = 8) regardless of sex. In total, 14 treatment-emergent adverse events were reported by 45.8% (11/24) of participants. Five treatment-emergent adverse events, reported for four (16.7%) participants, were considered treatment related; affect lability occurred in two (8.3%) participants, and insomnia, accidental overdose, and increased blood pressure each occurred in one (4.2%) participant., Conclusions: In children aged 4-5 years with ADHD, following multiple once-daily administrations of SHP465 MAS 6.25 mg, the pharmacokinetic profile of plasma d-amphetamine and l-amphetamine was generally consistent among participants. Between-individual variability of plasma d-amphetamine and l-amphetamine steady-state exposure was low to moderate. SHP465 MAS was generally well tolerated in this study., Trial Registration: ClinicalTrials.gov, NCT03327402 (31 October, 2017)., (© 2021. The Author(s).)

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: Psychostimulants are first-line pharmacological treatments for attention deficit hyperactivity disorder (ADHD), although symptom reduction varies widely between patients and these individual differences in treatment response are poorly understood. The authors sought to examine whether the resting-state functional connectivity within and between cingulo-opercular, striato-thalamic, and default mode networks was associated with treatment response to psychostimulant medication, and whether this relationship changed with development., Methods: Patients with ADHD (N=110; 196 observations; mean age at first observation, 10.83 years, SD=2.2) and typically developing control subjects (N=142; 330 observations; mean age at first observation, 10.49 years, SD=2.81) underwent functional neuroimaging on up to five occasions during development (age range, 6-17 years). For patients, symptoms were assessed on and off psychostimulant medication (methylphenidate-based treatments: N=132 observations, 67%; amphetamine-based treatments: N=64 observations, 33%) using the Diagnostic Interview for Children and Adolescents for parents. Linear mixed-effects models examined whether resting-state connectivity was associated with treatment response and its interaction with age. Comparisons with typically developing control subjects were performed to contextualize any significant associations., Results: Resting-state connectivity within the cingulo-opercular network was associated with a significant interaction between treatment response and age. Specifically, worse responses to treatment compared with better responses to treatment among patients and compared with typically developing control subjects were associated with an atypical increase in cingulo-opercular connectivity with increasing age from childhood to adolescence., Conclusions: This work delineates how resting-state connectivity may be associated over development with response to psychostimulants in ADHD. Functioning and development within the cingulo-opercular network may warrant further investigation as a contributor to differential response to psychostimulants.

This study evaluated a battery of pain-stimulated, pain-depressed, and pain-independent behaviors for preclinical pharmacological assessment of candidate analgesics in mice. Intraperitoneal injection of dilute lactic acid (IP acid) served as an acute visceral noxious stimulus to produce four pain-related behaviors in male and female ICR mice: stimulation of 1) stretching, 2) facial grimace, 3) depression of rearing, and 4) depression of nesting. Additionally, nesting and locomotion in the absence of the noxious stimulus were used to assess pain-independent drug effects. These six behaviors were used to compare effects of two mechanistically distinct but clinically effective positive controls (ketoprofen and oxycodone) and two negative controls that are not clinically approved as analgesics but produce either general motor depression (diazepam) or motor stimulation (amphetamine). We predicted that analgesics would alleviate all IP acid effects at doses that did not alter pain-independent behaviors, whereas negative controls would not. Consistent with this prediction, ketoprofen (0.1-32 mg/kg) produced the expected analgesic profile, whereas oxycodone (0.32-3.2 mg/kg) alleviated all IP acid effects except depression of rearing at doses lower than those that altered pain-independent behaviors. For the negative controls, diazepam (1-10 mg/kg) failed to block IP acid-induced depression of either rearing or nesting and only decreased IP acid-stimulated behaviors at doses that also decreased pain-independent behaviors. Amphetamine (0.32-3.2 mg/kg) alleviated all IP acid effects but only at doses that also stimulated locomotion. These results support utility of this model as a framework to evaluate candidate-analgesic effects in a battery of complementary pain-stimulated, pain-depressed, and pain-independent behavioral endpoints. SIGNIFICANCE STATEMENT: Preclinical assays of pain and analgesia often yield false-positive effects with candidate analgesics. This study used two positive-control analgesics (ketoprofen, oxycodone) and two active negative controls (diazepam, amphetamine) to validate a strategy for distinguishing analgesics from nonanalgesics by profiling drug effects in a battery of complementary pain-stimulated, pain-depressed, and pain-independent behaviors in male and female mice., (Copyright © 2021 by The American Society for Pharmacology and Experimental Therapeutics.)

Objective: Binge-eating disorder (BED) disrupts dopamine neuron function, in part by altering dopamine transporter (DAT) activity. This study characterized the effects of high-fat bingeing on presynaptic dopamine terminals and tested the hypothesis that acute low-dose amphetamine would restore DAT function., Methods: C57BL/6 mice were given limited access (LimA) to a high-fat diet (2 h/d, 3 d/wk) or standard chow (control). After 6 weeks, ex vivo fast-scan cyclic voltammetry was used to characterize dopamine-terminal adaptations in the nucleus accumbens. Prior to undergoing fast-scan cyclic voltammetry, some mice from each group were given amphetamine (0.5 mg/kg intraperitoneally)., Results: Escalation of high fat intake, termed bingeing, occurred in the LimA group and coincided with increased phasic dopamine release, reduced dopamine uptake rates, and increased dopamine receptor 2 (D 2 ) autoreceptor function. Acute amphetamine selectively reversed dopamine uptake changes in the LimA group and restored the potency of amphetamine to inhibit uptake., Conclusions: High-fat bingeing enhanced dopaminergic signaling in the nucleus accumbens by promoting phasic dopamine release and reducing clearance. This study's data show that amphetamine was efficacious in restoring impaired DAT function caused by high-fat bingeing but did not reduce dopamine release to normal. These presynaptic changes should be considered if amphetamine-like dopamine releasers are used as treatments for BED., (© 2021 The Authors. Obesity published by Wiley Periodicals LLC on behalf of The Obesity Society (TOS).)

Purpose: This single-dose pivotal study evaluated the pharmacokinetics of amphetamine extended-release oral suspension (AMPH EROS) under fasted and fed conditions and the relative bioavailability of AMPH EROS and immediate-release mixed amphetamine salts (IR MAS) in adults. Methods: This open-label, randomized, three-period, three-treatment, six-sequence crossover study enrolled 30 healthy adult participants who were randomly assigned to receive either 1 dose of AMPH EROS 18.8 mg under fed or fasted conditions or 30 mg of IR MAS under fasted conditions. Participants crossed over with a 7-day washout period between each of the three periods. Plasma samples were measured for C max , AUC 0- t , AUC 0-5 , AUC 5- t , and AUC 0-∞ for comparative bioavailability. Results: The geometric mean ratios for C max , AUC 0- t , and AUC 0-∞ were within the 90% confidence limits [80.0%, 125.0%] for comparable bioavailability. There was no food effect for AMPH EROS. Both the AMPH EROS and IR MAS formulations were generally well tolerated with no serious adverse events reported. Conclusions: The bioavailability of a single dose of AMPH EROS was comparable to two 15 mg doses of IR MAS, given 4 hr apart, with no food effect or safety concerns observed.

BACKGROUND Little is known regarding the sociodemographic and clinical characteristics of emergency department (ED) patients with untreated opioid use disorder (OUD) and the relationship of those characteristics with whether they were seeking a referral to substance use treatment at the time of their ED visit. METHODS Using data collected from 2/2017-1/2019 from participants enrolled in Project ED Health (CTN-0069), we conducted a cross-sectional analysis of patients with untreated moderate to severe OUD presenting to one of four EDs in Baltimore, New York City, Cincinnati, or Seattle. Sociodemographic and clinical correlates, and International Classification of Diseases Tenth Revision (ICD-10) diagnosis codes related to opioid withdrawal, injection-related infection, other substance use, overdose, and OUD of those seeking and not seeking a referral to substance use treatment on presentation were compared using univariate analyses. RESULTS Among 394 study participants, 15.2 % (60/394) came to the ED seeking a referral to substance use treatment. No differences in age, gender, education, health insurance status or housing stability were detected between those seeking and not seeking referral to substance use treatment. Those seeking a referral to substance use treatment were less likely to have urine toxicology testing positive for amphetamine [17 % (10/60) vs 31 % (104/334), p = 0.023] and methamphetamine [23 % (14/60) vs 40 % (132/334), p = 0.017] compared to those not seeking a referral. CONCLUSION Most patients with untreated OUD seen in the EDs were not seeking a referral to substance use treatment. Active identification, treatment initiation, and coding may improve ED efforts to address untreated OUD., (Copyright © 2020 Elsevier B.V. All rights reserved.)

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.)

Background: Stimulant medications are commonly prescribed for the treatment of attention-deficit/hyperactivity disorder; however, they also have high potential for diversion and misuse. We estimated national stimulant dispensing trends from 2014 to 2019 and differences in dispensing by age, sex, state, prescriber specialty, payor type, patient copay, and stimulant type., Methods: We calculated rates of stimulant dispensing using IQVIA National Prescription Audit (NPA) New to Brand, NPA Regional, and NPA Extended Insights data, which provide dispensing estimates from approximately 49,900 pharmacies representing 92 % of prescriptions dispensed in the United States. Average annual percent change (AAPC) from 2014 to 2019 was analyzed using Joinpoint regression., Results: From 2014 to 2019, the national annual rate of stimulant dispensing increased significantly from 5.6 to 6.1 prescriptions per 100 persons. Rates differed by prescription stimulant type, with increases occurring among both amphetamine-type stimulants and long-acting stimulants. Rates among females (AAPC = 3.6 %; P = 0.001) and adults aged 20-39 years (AAPC=6.7 %; P = 0.002), 40-59 years (AAPC=9.7 %; P < 0.001), and ≥60 years (AAPC = 6.9 %; P = 0.001) increased significantly during the study period. Stimulant dispensing rates varied substantially across states, ranging from 1.0 per 100 in Hawaii to 13.6 per 100 in Alabama., Conclusions: National stimulant dispensing rates increased from 2014 to 2019, driven by notable increases among females and adults aged ≥20 years. These trends should be considered when prescribing stimulants given growing concerns over prescription stimulant diversion, misuse, and related health harms., (Published by Elsevier B.V.)

Objectives: In a previous pivotal study of children and adolescents (aged 6-17 years) with attention-deficit/hyperactivity disorder (ADHD), dose-optimized SHP465 mixed amphetamine salts (MAS) extended-release (12.5-25 mg once daily) was superior to placebo in reducing ADHD symptoms. This study evaluated the efficacy, tolerability, and safety of 6.25 mg SHP465 MAS once daily (one-half the lowest approved dose for adolescents and adults) versus placebo in children aged 6-12 years with ADHD. Methods: Children (aged 6-12 years) with Diagnostic and Statistical Manual of Mental Disorders, Fifth edition-defined ADHD; baseline ADHD-Rating Scale, Fifth Edition, Child, Home Version total scores (ADHD-RS-5-HV-TS) ≥28; and baseline Clinical Global Impressions-Severity scores ≥4 were eligible. Participants received 6.25 mg SHP465 MAS once daily or placebo for 4 weeks. The primary (ADHD-RS-5-HV-TS change from baseline at week 4) and key secondary (Clinical Global Impressions-Improvement [CGI-I] score at week 4) efficacy end points were assessed using linear mixed-effects models for repeated measures. Safety and tolerability assessments included treatment-emergent adverse events (TEAEs) and vital sign changes. Results: Of 89 randomized participants, 83 completed the study (placebo, n  = 41; SHP465 MAS, n  = 42). At week 4, the least squares mean (95% confidence interval) treatment differences (SHP465 MAS-placebo) were not statistically significant for ADHD-RS-5-HV-TS change (-1.9 [-6.8 to 3.1], p  = 0.451; effect size [ES] = 0.17) or CGI-I score (-0.1 [-0.5 to 0.3], nominal p  = 0.597; ES = 0.12). The percentage of participants reporting TEAEs was 16.3% with placebo and 24.4% with SHP465 MAS. The most frequently reported TEAEs (placebo; SHP465 MAS) were headache (7.0%; 4.4%) and decreased appetite (4.7%; 2.2%). Minimal increases in blood pressure were observed with SHP465 MAS at the final on-treatment assessment. Conclusions: SHP465 MAS 6.25 mg once daily (one-half the lowest dose approved for adolescents and adults) was well tolerated in children aged 6-12 years but was not superior to placebo in reducing ADHD symptoms, suggesting that this dose of SHP465 MAS was subtherapeutic in this age group. The Clinical Trial Registration number: NCT03325881.

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.

Objective: To investigate the effectiveness of stimulants in patients with depression, by using naturalistic outcome measures, such as psychiatric admissions, psychiatric bed-days and incidents of intentional self-harm or suicide attempts., Methods: Via linkage of the Danish nationwide health registers, we identified all patients with a diagnosis of depression initiating stimulants, including methylphenidate, modafinil, amphetamine, dexamphetamine or lisdexamphetamine, from 1995 to 2012. We used a mirror-image model to test whether redemption of a stimulant prescription was associated with a reduction in psychiatric admissions, inpatient days and incidents of intentional self-harm or suicide attempts. Specifically, the number of these outcomes in the 2 years leading up to redemption of a stimulant prescription was compared to the two subsequent years. Similar outcomes were used in a reverse mirror-image model to investigate the effect of stimulant termination., Results: A total of 3354, 935 and 105 patients diagnosed with depression redeemed prescriptions for methylphenidate, modafinil or amphetamine/dexamphetamine/lisdexamphetamine, respectively. Initiation of methylphenidate was not associated with a significant change in psychiatric admissions (mean: -0.02 admissions, p  = 0.11) or inpatient days (mean: 0.13 days, p  = 0.74). Similar findings were made for modafinil and the amphetamines. In addition, no clinically relevant change in psychiatric admissions or inpatient days was found after termination of a stimulant. After initiation of methylphenidate, the incidents of self-harm or suicide attempts were reduced by 54%, from 68 to 31 events ( p  = 0.004). No significant change in incidents of self-harm or suicide attempts were found for modafinil or the amphetamines., Conclusion: This nationwide study, using naturalistic outcomes, does not support the use of stimulants in patients with depression. However, the use of methylphenidate was associated with a 54% reduction in incidents of self-harm or suicide attempts, indicating that methylphenidate may potentially be useful in patients with depression with suicidal- or self-harming behaviour. However, further studies are needed, before any firm conclusions can be made.

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

Amphetamine (AMPH), mainly used in the treatment of attention deficit hyperactivity disorder and narcolepsy, has weight loss properties, although with detrimental cardiovascular effects. In this issue, Mahú et al. (2020) describe the effect of a new derivative of AMPH, "PEGyAMPH," a brain-spared anti-obesity drug that alters sympathetic activity without cardiovascular side effects., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: The rodent Continuous Performance Test (rCPT) is an analogue of human CPTs where mice have to discriminate between target and non-target stimuli. The rCPT offers a readout of attentional performance and impulsive behaviour. This study aimed to determine if female C57BL/6 J mice could be trained in the rCPT since previously published rCPT studies have only used male mice and to study whether the effects of methylphenidate (MPH), atomoxetine (ATX), and dexamphetamine (AMPH) on attention and impulsivity depend on baseline (reference) levels of performance., Methods: 48 female mice underwent rCPT training. Effects of MPH (1, 2, and 3 mg/kg), ATX (1, 3, and 5 mg/kg) and AMPH (0.3, 0.6, and 1 mg/kg) were assessed in a variable stimulus duration probe. Drugs were administered intraperitoneally and sequentially tested following a Latin-square design. Data were analysed using a repeated measurements mixed effect model and reference-dependent effects were studied., Results: ATX and AMPH improved performance as seen by increases in discriminability. These improvements were a result of a decreased false-alarm rate. AMPH showed a reference-dependent effect, improving the task performance of low-performing mice and decreasing the performance of high-performing mice. MPH also showed this reference-dependent effects, albeit to a lesser extent. ATX and AMPH decreased premature responses and increased response criterion, but no reference-dependent effects were observed for these parameters., Conclusion: This study presents a novel method to analyse baseline-dependent effects. It shows that the rCPT can be successfully used in pharmacological studies in female mice and demonstrates that the effect of ADHD medication is in line with the inverted U-shape theory of performance-arousal relationship., Competing Interests: Declaration of Competing Interest Authors LSL and LA are currently employed at H. Lundbeck A/S. Author MCP was employed at University of Copenhagen but conducted the experiments at the animal facilities at H. Lundbeck A/S as part of an academic collaboration between both institutions. None of the authors have any conflict of interest pertaining the methods used or the drugs tested in this study., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: Evaluate the efficacy and tolerability of triple-bead mixed amphetamine salts (MAS) in ADHD. Method: Adults with ADHD Rating Scale IV (ADHD-RS-IV) total scores ≥32 were randomized to 6 weeks of triple-bead MAS (25, 50, or 75 mg) or placebo. The primary endpoint was ADHD-RS-IV total score change from baseline at end of study (EOS). Results: Least squares mean (95% confidence interval [CI]) treatment differences for ADHD-RS-IV total score changes from baseline to EOS significantly favored triple-bead MAS (all doses combined: -10.6 [-13.2, -8.0]; p < .0001); there were no significant differences between triple-bead MAS dosages. The most frequently reported TEAEs with triple-bead MAS (all doses combined) included insomnia, decreased appetite, and dry mouth. Mean ± SD pulse and systolic blood pressure increases at EOS were 3.5 ± 10.33 bpm and 0.3 ± 10.48 mmHg with triple-bead MAS (all doses combined). Conclusion: Triple-bead MAS significantly reduced adult ADHD symptoms; the safety profile was consistent with previous triple-bead MAS studies.

Objective: To systematically review the literature on the therapeutic use of amphetamine, lisdexamfetamine and methylphenidate in elderly population with and without dementia., Methods: We conducted two researches on the PubMed, Scopus and Embase using the keywords ("elderly") AND ("amphetamine" OR "methylphenidate" OR "lisdexamfetamine") and then ("Alzheimer" OR "dementia") AND ("amphetamine" OR "methylphenidate" OR "lisdexamfetamine")., Results: Twenty-nine papers met all the eligibility criteria. The results are encouraging as 81.5% of the studies showed clinical improvement of the investigated condition., Conclusion: Amphetamines and methylphenidate are probably effective strategies for different conditions in the elderly population. However, further studies are needed to provide more robust evidence on efficacy, dosage and safety for this population., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: The functional role of dopamine D1 and D2 receptors in gambling disorder (GD) remains unclear., Aims: This study aimed to investigate the role of D1 activation and the moderating effects of impulsivity, a trait linked with weaker D2-mediated inhibition of dopamine release, in GD subjects., Methods: Thirty (nine female) non-comorbid GD subjects with low (LI), moderate (MI), or high impulsivity (HI) received the preferential D2 antagonist haloperidol (HAL; 3 mg) or the mixed D1-D2 antagonist fluphenazine (FLU; 3 mg), on separate sessions before a 15-minute slot machine game or amphetamine (AMPH; 20 mg), in a placebo-controlled, double-blind, counterbalanced design., Results: On their own, HAL and FLU led to linear increases and decreases, respectively, in desire to gamble across increasing levels of impulsivity. The slot machine and AMPH each evoked an inverted-U pattern of desire to gamble across increasing impulsivity. HAL reversed this effect of the game, whereas FLU did not alter post-game desire. HAL and FLU decreased and increased psychostimulant-like effects of the game, respectively, in LI and MI subjects, but consistently reduced these effects in HI subjects. HAL also altered the salience of negative affective words on a reading task, such that greater salience of negative words coincided with lower post-game desire to gamble., Conclusions: D1 receptors appear to gauge the incentive value of gambling in GD subjects. D1 activation has negative reinforcing effects in HI gamblers and positive reinforcing effects in LI gamblers. Medications that activate D1 could curtail chasing in HI gamblers. D1 blockade could benefit HI gamblers whose main concern is craving.

Objective: Sleep problems are common in adults with attention-deficit/hyperactivity disorder (ADHD). The presence of sleep problems at the time of presentation for ADHD treatment could impact the level of improvement in ADHD symptoms or executive function occurring with ADHD pharmacotherapy. Therefore, we examined the influence of baseline sleep quality on the effects of SHP465 mixed amphetamine salts (MAS) extended-release., Methods: Adults (18-55 years) with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision-defined ADHD and baseline ADHD Rating Scale IV (ADHD-RS-IV) total scores ≥ 24 were randomized to once-daily SHP465 MAS (12.5-75 mg) or placebo in a 7-week, double-blind, dose-optimization study. Post-hoc analyses evaluated SHP465 MAS treatment effects on ADHD symptoms, using the ADHD-RS-IV, and executive function, using the Brown Attention-Deficit Disorder Scale (BADDS), based on baseline sleep quality as defined by Pittsburgh Sleep Quality Index (PSQI) scores [sleep quality impaired (PSQI total score > 5; PSQI component scores 2 or 3) versus not impaired (PSQI total score ≤ 5; PSQI component scores 0 or 1)]. Analyses were conducted in the intent-to-treat population., Results: Of 280 enrolled participants, 272 were randomized (placebo, n = 135; SHP465 MAS, n = 137). The intent-to-treat population consisted of 268 participants (placebo, n = 132; SHP465 MAS, n = 136), and 170 participants (placebo, n = 76; SHP465 MAS, n = 94) completed the study. Treatment differences nominally favored SHP465 MAS over placebo in both sleep impairment groups regarding ADHD-RS-IV total score changes (all nominal p < 0.05), except for those with impairment defined by sleep efficiency (p = 0.2696), and regarding BADDS total score changes (all nominal p < 0.05), except for those with impairment defined by sleep duration (p = 0.1332) and sleep efficiency (p = 0.8226). There were no statistically significant differences in SHP465 MAS treatment effects between sleep impairment groups., Conclusions: Improvements in ADHD symptoms and executive function occurred with dose-optimized SHP465 MAS, regardless of baseline impairment in some aspects of sleep in adults with ADHD, with no significant differences observed as a function of sleep impairment., Clinical Trials Registration: ClinicalTrials.gov identifier-NCT00150579.

In the last 15 years, there has been a marked increase in the number of available stimulant formulations with the emphasis on long-acting formulations, and the introduction of several novel delivery systems such as orally dissolving tablets, chewable tablets, extended-release liquid formulations, transdermal patches, and novel "beaded" technology. All of these formulations involve changes to the pharmaceutical delivery systems of the two existing compounds most commonly employed to treat attention-deficit/hyperactivity disorder (ADHD), amphetamine (AMP) and methylphenidate (MPH). In addition to these new formulations, our knowledge about the individual differences in response has advanced and contributes to a more nuanced approach to treatment. The clinician can now make increasingly informed choices about these formulations and more effectively individualize treatment in a way that had not been possible before. In the absence of reliable biomarkers that can predict individualized response to ADHD treatment, clinical knowledge about differences in MPH and AMP pharmacodynamics, pharmacokinetics, and metabolism can be utilized to personalize treatment and optimize response. Different properties of these new formulations (delivery modality, onset of action, duration of response, safety, and tolerability) will most likely weigh heavily into the clinician's choice of formulation. To manage the broad range of options that are now available, clinicians should familiarize themselves in each of these categories for both stimulant compounds. This review is meant to serve as an update and a guide to newer stimulant formulations and includes a brief review of ADHD and stimulant properties.

Introduction: A laboratory classroom study in children aged 6-12 years with attention-deficit/hyperactivity disorder (ADHD) found that racemic amphetamine sulfate (RA-AMPH) significantly improved performance versus placebo from 45 min through 10 h post-dose (NCT01986062). A secondary analysis assessed gender as a potential moderator of response to treatment comparing the ADHD Rating Scale-IV (ADHD-RS-IV) and Swanson, Kotkin, Agler, M-Flynn and Pelham (SKAMP) rating scales., Methods: After 8 weeks of open-label RA-AMPH dose optimization using improvement in ADHD-RS-IV symptoms as a guide, 97 subjects (38 females and 59 males) were randomized to the sequence of 2 weeks of double-blind treatment with the optimized dose of RA-AMPH followed by placebo or vice versa during a laboratory classroom day. Efficacy measures included the SKAMP and the Permanent Product Measure of Performance (PERMP). The average difference for RA-AMPH versus placebo was estimated using least-square (LS) means. Treatment interaction by gender was analyzed using a cross-sectional fixed-effects model., Results: ADHD-RS-IV scores were comparable for males and females at study entry and at the end of open-label treatment. During double-blind treatment, LS mean scores significantly improved for both genders versus placebo on the SKAMP scale and the PERMP (average p < 0.0001 for all post-dose time points). Beginning at baseline, males had significantly higher (worse) SKAMP scores than females but not worse ADHD-RS-IV or PERMP scores., Conclusion: Both genders responded well to treatment with RA-AMPH, with comparable onset and duration of effect. The ADHD-RS-IV and SKAMP scales both measure changes in attention and hyperactive-impulsive behavior, but the SKAMP scale also measures associated disruptive behaviors, such as frustration, lying, and interpersonal conflict, that are more characteristic of oppositional and conduct disorders and more prevalent in boys with ADHD. Therefore, the SKAMP may be more sensitive for measuring the range of symptoms of boys with ADHD than the ADHD-RS-IV., Funding: Arbor Pharmaceuticals, LLC.

Rationale: The rodent Continuous Performance Test (rCPT) is a novel rodent paradigm to assess attention and impulsivity that resembles the human CPT. This task measures the rodents' ability to discriminate between target and non-target stimuli. The effect of attention-deficit/hyperactivity disorder (ADHD) medication on rCPT performance in mice remains to be fully characterized., Objective: To investigate the predictive validity of the mouse rCPT by studying the effects of ADHD medication methylphenidate, atomoxetine, amphetamine, guanfacine, and modafinil in four behavioral subgroups based on performance and impulsivity levels., Methods: Two cohorts of male C57BL/6J mice were used, and the effect of treatment was tested in a variable stimulus duration probe. Performance and impulsive subgroups were made based on discriminability and percentage premature responses, respectively., Results: Methylphenidate, atomoxetine, and amphetamine improved performance in the low-performing animals, with no effect in the high-performers. These improvements were a result of increased hit rate and/or decreased false-alarm rate. Furthermore, these drugs decreased percentage premature responses in the high-impulsive group. Methylphenidate, guanfacine, and modafinil increased premature responses in the low-impulsive group. Modafinil impaired performance in the high-performers by increasing false-alarm rate., Conclusion: The effect of ADHD treatment was dependent on baseline, as seen by increases in performance for the low-performers and decreases in impulsivity for the high-impulsive animals. These results agree with clinical data and may support the inverted U-shaped arousal-performance theory. The rCPT combined with behavioral separation into subgroups has high predictive validity, and our study is a step forward towards establishing the clinical translatability of the rCPT.