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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.

Importance: Stimulants (methylphenidate and amphetamines) are often prescribed at unlicensed doses for adults with attention-deficit/hyperactivity disorder (ADHD). Whether dose escalation beyond US Food and Drug Administration recommendations is associated with positive risk benefits is unclear., Objective: To investigate the impact, based on averages, of stimulant doses on treatment outcomes in adults with ADHD and to determine, based on averages, whether unlicensed doses are associated with positive risk benefits compared with licensed doses., Data Sources: Twelve databases, including published (PubMed, Cochrane Library, Embase, Web of Sciences) and unpublished (ClinicalTrials.gov) literature, up to February 22, 2023, without language restrictions., Study Selection: Two researchers independently screened records to identify double-blinded randomized clinical trials of stimulants against placebo in adults (18 years and older) with ADHD., Data Extraction and Synthesis: Aggregate data were extracted and synthesized in random-effects dose-response meta-analyses and network meta-analyses., Main Outcome Measures: Change in ADHD symptoms and discontinuations due to adverse events., Results: A total of 47 randomized clinical trials (7714 participants; mean age, 35 (SD, 11) years; 4204 male [56%]) were included. For methylphenidate, dose-response curves indicated additional reductions of symptoms with increments in doses, but the gains were progressively smaller and accompanied by continued additional risk of adverse events dropouts. Network meta-analyses showed that unlicensed doses were associated with greater reductions of symptoms compared with licensed doses (standardized mean difference [SMD], -0.23; 95% CI, -0.44 to -0.02; very low certainty of evidence), but the additional gain was small and accompanied by increased risk of adverse event dropouts (odds ratio, 2.02; 95% CI, 1.19-3.43; moderate certainty of evidence). For amphetamines, the dose-response curve approached a plateau and increments in doses did not indicate additional reductions of symptoms, but there were continued increments in the risk of adverse event dropouts. Network meta-analysis did not identify differences between unlicensed and licensed doses for reductions of symptoms (SMD, -0.08; 95% CI, -0.24 to 0.08; very low certainty of evidence)., Conclusions and Relevance: Based on group averages, unlicensed doses of stimulants may not have positive risk benefits compared with licensed doses for adults with ADHD. In general, practitioners should consider unlicensed doses cautiously. Practitioners may trial unlicensed doses if needed and tolerated but should be aware that there may not be large gains in the response to the medication with those further increments in dose. However, the findings are averages and will not generalize to every patient.

Introduction: Attention deficit/hyperactivity disorder (ADHD) with co-occurring substance use disorder (SUD) is associated with poor treatment outcomes. Two randomized controlled trials, utilizing robust doses of stimulants, demonstrated a significant effect on treatment outcomes in patients with ADHD/SUD. This study aimed to investigate differences in executive functioning and explore the dose-dependent effect of OROS-methylphenidate (MPH) in patients with comorbid ADHD and amphetamine use disorder (ADHD+AMPH) and patients with ADHD only., Methods: Three groups (ADHD+AMPH, ADHD only, and healthy controls) were assessed repeatedly with a neuropsychological test battery. An exploratory within-subject single-blinded design was employed where the ADHD only group received a maximum dose of 72 mg OROS-MPH, the ADHD+AMPH group a maximum dose of 180 mg, whereas the healthy subjects did not receive any study medication. Both ADHD groups received the same dose titration up to 72 mg OROS-MPH., Results: The ADHD+AMPH group demonstrated a significantly poorer motor inhibition and spatial working memory and reported more severe ADHD symptoms compared to the ADHD only group. 180 mg OROS-MPH was associated with a significant improvement in executive functioning in the dual diagnosis group. However, the exploratory study design and recruitment issues do not allow for any conclusion to be drawn regarding the effect of 180 mg OROS-MPH., Conclusion: Patients with ADHD+AMPH present with more severe neurocognitive deficits compared to ADHD only. The effect of 180 mg OROS-MPH on cognition in patients with ADHD+AMPH was inconclusive. Future studies should consider recruitment issues and high drop-out rates in this study population., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Background: This meta-analysis (PROSPERO-ID: CRD42022362962), pooled effect estimates of outcomes, from placebo-controlled randomized clinical trials (RCTs) examining bupropion efficacy and safety for amphetamine-type stimulant use disorder (ATSUD) treatment., Method: Electronic databases were searched for records published to October 31st, 2022, including MEDLINE, CINAHL, PsycINFO, EBM Reviews, EMBASE, PubMed, Web of Science, trial registries. Inclusion criteria were RCTs comparing bupropion to placebo in ATSUD. Cochrane RoB2 tool and GRADE evidence certainty assessment were employed. Outcomes included amphetamine-type stimulant (ATS) use by urinalysis, retention in treatment, treatment adherence, ATS craving, addiction severity, depressive symptom severity, drop-out following adverse events (AEs), and serious AEs. Random-effect meta-analysis was conducted presenting standardized mean difference (SMD), risk ratio (RR), and risk difference (RD)., Results: Eight RCTs (total N=1239 participants) were included. Bupropion compared to placebo was associated with reduced ATS use (RR: 0.90; 95% CI: 0.84, 0.96), end-of-treatment ATS craving (SMD: -0.38; 95%CI: -0.63, -0.13), and adherence (RR: 0.91; 95%CI: 0.84, 0.99). Subgroup analysis showed greater reduction in ATS use with longer trial duration (12 weeks) (RR: 0.85; 95%CI: 0.78, 0.93) and greater reduction in end-of-treatment ATS craving in studies with mixed ATS use frequency (SMD: -0.46; 95%CI: -0.70, -0.22) and male-only samples (SMD: -1.26; 95%CI: -1.87, -0.65)., Conclusion: Bupropion showed a significant modest reduction in ATS use and ATS craving (both rated as very low-quality evidence), larger in males (craving), and with longer treatment (ATS use). These results may inform future studies. More research is warranted on who might benefit from bupropion as ATSUD treatment., Competing Interests: Declaration of Competing Interest PB is the site PI for upcoming trial on psychostimulants for the treatment of methamphetamine use disorder. CGS is a consultant at Clearmind Medicine. NE has received funding from the Australian National Health and Medical Research Council (NHMRC) to conduct a study examining lisdexamfetamine for the treatment of MAUD (APP1109466). KS has received funding from the National Centre for Clinical Research on Emerging Drugs (NCCRED) to conduct a pilot study of lisdexamfetamine for methamphetamine withdrawal (NCCRED is funded by the Australian Government Department of Health [4-EH8ULD4]). BLF has obtained funding from Pfizer Inc. (GRAND Awards, including salary support) for investigator-initiated projects. BLF has obtained funding from Indivior for a clinical trial sponsored by Indivior. BLF has in-kind donations of cannabis products from Aurora Cannabis Enterprises Inc. and study medication donations from Pfizer Inc. (varenicline for smoking cessation) and Bioprojet Pharma. BLF was also provided a coil for a Transcranial magnetic stimulation (TMS) study from Brainsway. BLF has obtained industry funding from Canopy Growth Corporation (through research grants handled by the Centre for Addiction and Mental Health and the University of Toronto), Bioprojet Pharma, Alcohol Countermeasure Systems (ACS), Alkermes, and Universal Ibogaine. BLF has participated in a session of a National Advisory Board Meeting (Emerging Trends BUP-XR) for Indivior Canada and has been a consultant for Shinogi. DJA receives study material from Cardiol Therapeutics and Exka for clinical trials funded by the Quebec Ministry of Health and Social Services. All other authors declare no conflict of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Prevailing frameworks propose that a key feature of attention-deficit/hyperactivity disorder (ADHD) is lower motivation. An important component of motivation is the willingness to engage in cognitively or physically effortful behavior. However, the degree to which effort sensitivity is impaired in ADHD has rarely been tested, and the efficacy of stimulant medication in ameliorating any such impairments is unclear. Here, we tested 20 individuals with ADHD (11 males, 9 females) who were managed with amphetamine-based medication (dexamfetamine, lisdexamfetamine), and 24 controls (8 males, 16 females). Individuals with ADHD were tested over two counterbalanced sessions, ON and OFF their usual amphetamine-based medication. In each session, participants performed an effort-based decision-making task, in which they were required to choose how much cognitive or physical effort they were willing to engage in return for reward. Our results revealed three main findings. First, individuals with ADHD had lower motivation relative to controls to invest effort in both the cognitive and physical domains. Second, amphetamine increased motivation uniformly across both domains. Finally, the net effect of amphetamine treatment was to mostly restore motivation across both domains of effort relative to healthy controls. These data provide clear evidence for a heightened sensitivity to both cognitive and physical effort in ADHD, and reveal the efficacy of amphetamine-based drugs in restoring effort sensitivity to levels similar to controls. These findings confirm the existence of reduced motivational drive in ADHD, and more broadly provide direct causal evidence for a domain-general role of catecholamines in motivating effortful behavior. SIGNIFICANCE STATEMENT A core feature of attention-deficit/hyperactivity disorder (ADHD) is thought to be a heightened aversion to effort. Surprisingly, however, the degree to which effort sensitivity is impaired in ADHD has rarely been tested. More broadly, the relative efficacy of catecholamines in motivating the investment of cognitive and physical effort is unclear. We tested 20 individuals with ADHD ON and OFF amphetamines, and compared their behavior on an effort-based decision-making task to 24 controls. When tested OFF medication, the ADHD group was less cognitively and physically motivated than controls. However, amphetamines led to a comparable increase in motivation across both domains. This demonstrates the efficacy of catecholamines in facilitating domain-general effort, and highlights the broader potential of such drugs to treat disorders of motivation., (Copyright © 2023 Chong et al.)

Background: Attention-deficit and hyperactivity disorder (ADHD) is frequently diagnosed in patients with substance use disorders (SUDs), including opioids. There remains concern about the safety and efficacy of prescription amphetamines (PAs) and their impact on effectiveness of opioid use disorder (OUD) treatment with buprenorphine., Objectives: To assess the effect of PAs on OUD buprenorphine treatment retention and/or SUD-related emergency admission or drug-related poisonings., Methods: We used a retrospective cohort design with a secondary analysis of data from Merative MarketScan Commercial and Multi-State Medicaid Databases from 1 January 2006 to 31 December 2016. Individuals included were aged 12-64 years, had an OUD diagnosis and were prescribed buprenorphine. Our analysis used multivariable Cox regression to evaluate the relationship between PA receipt and time to buprenorphine discontinuation. The second part focused on subsamples of buprenorphine initiators who had either (1) any SUD-related emergency admissions or (2) drug-related poisoning. These outcomes were modelled as a function of PA exposure using conditional logistic regression models as part of a within-person, case-crossover design., Findings: Our sample had 90 269 patients with OUD (mean age 34.2 years (SD=11.3)) who initiated buprenorphine. Being prescribed a PA was associated with improved buprenorphine retention among individuals both with (adjusted HR (aHR) 0.91 (95% CI 0.86 to 0.97)) and without a concurrent psychostimulant use disorder (PSUD) (aHR 0.92 (95% CI 0.90 to 0.93))., Conclusions: PA use was associated with improved buprenorphine retention in people with OUD with and without co-occurring PSUD. The risks of acute SUD-related events and drug-related poisonings associated with PA use did not differ when comparing PA-using days with days without PA use., Clinical Implications: Patients with OUD on buprenorphine should receive treatment with a PA when indicated., Competing Interests: Competing interests: AB received grants from National Institutes of Health (NIH), research support and medication samples from Alkermes, and consulting fees from OpheliaHealth, a telehealth provider for opioid use disorder. FRL reported consulting for Major League Baseball, receiving grants from the National Institutes of Health (NIH) and Substance Abuse and Mental Health Services Administration (SAMHSA), receiving a salary from the New York State Psychiatric Institute, and receiving non-financial support from US World Meds, Alkermes and Indivior outside the submitted work and serving as an uncompensated member of scientific advisory boards of Alkermes, Indivior, Novartis International, Teva Pharmaceutical Industries and US WorldMeds. RAG reported receiving grants from the NIH and Arnold Ventures during the conduct of the study, consulting for Janssen Pharmaceuticals and receiving personal fees for grant reviews from the NIH outside the submitted work., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. Published by BMJ.)

Attention Deficit Hyperactivity Disorder (ADHD) medication is increasingly being used during pregnancy. Concerns have been raised as to whether ADHD medication has long-term adverse effects on the offspring. The authors investigated whether in utero exposure to ADHD medication was associated with adverse long-term neurodevelopmental and growth outcomes in offspring. The population-based cohort study in the Danish national registers included 1,068,073 liveborn singletons from 1998 to 2015 followed until any developmental diagnosis, death, emigration, or December 31, 2018. Children of mothers who continued ADHD medication (methylphenidate, amphetamine, dexamphetamine, lisdexamphetamine, modafinil, atomoxetine, clonidine) during pregnancy and children of mothers who discontinued ADHD medication before pregnancy were compared using Cox regression. Main outcomes were neurodevelopmental psychiatric disorders, impairments in vision or hearing, epilepsy, seizures, or growth impairment during childhood or adolescence. In total, 898 children were exposed to ADHD medication during pregnancy compared to 1270 children whose mothers discontinued ADHD medication before pregnancy. After adjustment for demographic and psychiatric characteristics of the mother, no increased risk of any offspring developmental disorders was found combined (aHR 0.97, 95% CI 0.81 to 1.17) or for separate subcategories. Similarly, no increased risk was found for any sub-categories of outcomes in the negative control or sibling controlled analyses. Neurodevelopment and growth in offspring do not differ based on antenatal exposure to ADHD medication. These findings provide reassurance for women with ADHD who depend on ADHD medication for daily functioning and who consider continuing medication in pregnancy., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: First-in-human studies to test the efficacy and safety of human embryonic stem cells (hESC)-derived dopaminergic cells in the treatment of Parkinson's disease (PD) are imminent. Pre-clinical studies using hESC-derived dopamine neuron transplants in rat models have indicated that the benefits parallel those shown with fetal tissue but have thus far failed to consider how ongoing L-DOPA administration might impact on the graft., Objective: To determine whether L-DOPA impacts on survival and functional recovery following grafting of hESC-derived dopaminergic neurons., Methods: Unilateral 6-OHDA lesioned rats were administered with either saline or L-DOPA prior to, and for 18 weeks following surgical implantation of dopaminergic neural progenitors derived from RC17 hESCs according to two distinct protocols in independent laboratories., Results: Grafts from both protocols elicited reduction in amphetamine-induced rotations. Reduced L-DOPA-induced dyskinesia preceded the improvement in amphetamine-induced rotations. Furthermore, L-DOPA had no effect on overall survival (HuNu) or dopaminergic neuron content of the graft (TH positive cells) but did lead to an increase in the number of GIRK2 positive neurons., Conclusion: Critically, we found that L-DOPA was not detrimental to graft function, potentially enhancing graft maturation and promoting an A9 phenotype. Early improvement of L-DOPA-induced dyskinesia suggests that grafts may support the handling of exogenously supplied dopamine earlier than improvements in amphetamine-induced behaviours indicate. Given that one of the protocols will be employed in the production of cells for the European STEM-PD clinical trial, this is vital information for the management of patients and achieving optimal outcomes following transplantation of hESC-derived grafts for PD.