Adderall Research Articles

Stimulant medications in the management of bulimia nervosa and anorexia nervosa in patients with and without comorbid attention deficit hyperactivity disorder: A systematic review.

People with attentional problems are at increased risk of eating disorders. This paper aimed to systematically review and synthesize the existing evidence on stimulant medication in the management of patients with bulimia nervosa (BN) or anorexia nervosa (AN) with or without comorbid attention deficit hyperactivity disorder (ADHD). A systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. A protocol for the review was registered with Open Science Framework (OSF) Registry and critical appraisal of the literature was conducted using Joanna Briggs Institute (JBI) Critical Appraisal Tools. Thirteen articles met inclusion criteria including two quasi-experimental studies, one randomized controlled trial, four case series, and six case reports. 26 cases were included from studies and 32 from case series/reports. Only two cases from a single case report had a diagnosis of AN, while the remainder had BN. Stimulants included methylamphetamine, lisdexamfetamine, methylphenidate, dextroamphetamine sulphate and mixed amphetamine salt. In nearly all cases of BN there were reported reductions in eating disorder symptoms. The rates of adverse effects were high and included weight loss, decreased appetite, tachycardia, dry mouth, fatigue, insomnia, restlessness, nausea, bruxism, headache, palpitations, blood pressure changes, irritability, anxiety, depressed mood, and diaphoresis. There is currently insufficient evidence to support the use of stimulant medications to treat symptoms of BN or AN. The authors recommend considering screening patients with BN for ADHD.

Extended-Release Mixed Amphetamine Salts for Comorbid Adult Attention-Deficit/Hyperactivity Disorder and Cannabis Use Disorder: A Pilot, Randomized Double-Blind, Placebo-Controlled Trial

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.

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

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

A Single-Blind, Placebo Controlled Trial of Triple Beaded Mixed Amphetamine Salts in DSM-5 Adults With ADHD Assessing Effects Throughout the Day

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.

The Therapeutic Potential of Amphetamine-like Psychostimulants.

This review delves into the therapeutic applications of amphetamine-type stimulants such as lisdexamphetamine dimesylate, mixed amphetamine salts, 3,4-methylenedioxymethamphetamine (MDMA), dextroamphetamine, and phentermine. These compounds have been investigated for their potential in treating a range of psychiatric disorders, including attention deficit hyperactivity disorder (ADHD), drug dependence, post-traumatic stress disorder (PTSD), and obesity. Lisdexamphetamine dimesylate has shown promise in effectively treating ADHD symptoms in both children and adults. Additionally, it has been explored as a potential treatment for drug dependency and withdrawal, demonstrating encouraging results. Mixed amphetamine salts have also exhibited efficacy in reducing ADHD symptoms in adults. Future research should explore their potential use in treating bipolar disorder and cocaine dependence, considering the associated risks and benefits. MDMA-assisted psychotherapy has emerged as an innovative approach to treating PTSD, leading to sustained reductions in symptoms and even promoting post-traumatic growth. Furthermore, it has shown promise in managing anxiety related to life-threatening illnesses. Dextroamphetamine and phentermine have demonstrated efficacy in treating cocaine and opioid dependence, ADHD, and obesity. However, careful consideration and monitoring by medical professionals are essential due to the potential risks and benefits associated with them. In conclusion, amphetamine-type stimulants present a promising avenue for therapeutic interventions in various psychiatric conditions. Nevertheless, further research is necessary to comprehensively understand their mechanisms of action, dosage requirements, and long-term effects in different patient populations.

Psychostimulants prescribed to children for ADHD following distal radius fractures significantly reduce bone density as a function of duration.

Methylphenidate and mixed amphetamine salts (MAS) are psychostimulant medications widely prescribed for various psychiatric disorders. Although these medications are known to adversely impact bone mineral content and density, as well as biomechanical integrity during skeletal development in rats, their effect on bone density in children remains largely unknown. The primary aim of this work was to investigate the effects of methylphenidate and MAS on bone density following distal radius fractures in pediatric populations, and secondarily assess any impact on healing. The retrospective case-control study was designed to assess fracture healing in patients treated with stimulant drugs and matched controls. For the primary outcome, X-rays ( n = 188) were evaluated using an optical density image analysis technique to compare bone density throughout the bone healing process. Results showed that methylphenidate and MAS significantly reduced bone healing by approximately 20% following distal radius fractures in these children. The data also suggested that duration of psychostimulant use played a role in bone healing; the longer the treatment (1-5 years), the lower the bone density was observed (by approximately 52%) as compared to controls (no medication). However, subjects taking these drugs for longer than 5 years did not show a significant difference. Our results suggested that children taking psychostimulants for up to 5 years had slower bone healing following distal radius fractures. Orthopedic surgeons planning elective surgeries should be cognizant of this as a potential issue in recovery after any elective bone procedures and preoperatively optimize bone health as well as counsel patients and their families.

Switching patterns of immediate-release forms of generic mixed amphetamine salts products among privately and publicly insured individuals aged 15-64 years in the United States, 2013-2019.

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. 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. 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. 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.

0584 Sodium Oxybate Treatment Patterns in Narcolepsy Patients: A Propensity Score–Matched Cohort Study Subanalysis

Abstract Introduction Sodium oxybate (SXB) is strongly recommended for treatment of narcolepsy. Patients treated with available immediate-release oxybates are required to awaken for a second dose 2.5–4 hours after the bedtime dose to cover a full night of sleep. This study characterized SXB treatment patterns and discontinuation in narcolepsy patients. Methods Mayo Clinic patients from 1975–2020 were identified using an electronic health record–based search. Patients with ≥1 narcolepsy-specific ICD-9/-10 code and ≥1 diagnostic mention of narcolepsy in clinical notes (identified using a natural-language-processing [NLP] algorithm) were included. NLP was used to identify SXB non-use events with manual chart reviews performed to characterize reasons for discontinuation, switching, or missing the second dose and effects of missing the second dose. Results Of the patients with narcolepsy prescribed SXB (n=351; mean age at first diagnosis code observed at Mayo Clinic, 32 y [IQR: 23.2–46.1]; 65.5% female; 92.3% white), 113 (32.2%) had clinical notes indicating discontinuation of SXB, with 71 (20.2%) including reasons for discontinuation. The most common reasons for discontinuation (n≥5) included lack of efficacy (n=11), side effects (n=10), gastrointestinal side effects (n=10), neurological side effects (n=9), psychiatric side effects (n=8), lack of access (insurance/cost, n=10), and resolution/absence of cataplexy (n=5). Mentions of switching from SXB to other drugs (n=12 patients) included switching to stimulants (mixed amphetamine salts, n=3; dextroamphetamine, n=2; methylphenidate, n=1), sedative hypnotics (zolpidem, n=2), antidepressants (mirtazapine, n=1), and wake-promoting agents (solriamfetol, n=1). Of the 38 patients (10.8%) with mentions of missing the second nightly SXB dose, reasons were recorded for 24 (63.2%), including inability to wake up (n=14), forgetting the second dose (n=3), and having to wake up early the following day (n=3). Consequences of missing the second dose were recorded for a small subset (increased cataplexy, n=4; lower daytime alertness, n=3; awakens earlier, n=1; tiredness, n=1). Conclusion Limited data are available regarding real-world use of SXB. This novel study used a combination of NLP algorithm and manual chart review to identify difficulties patients have with the second, middle-of-the night immediate-release oxybate dose and patient-experienced consequences of not adhering to the prescribed dosing regimen. Support (if any) Avadel Pharmaceuticals

Risk of Major Malformations in Infants After First-Trimester Exposure to Stimulants: Results From the Massachusetts General Hospital National Pregnancy Registry for Psychiatric Medications.

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. 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. 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. Although preliminary, this analysis from an ongoing pregnancy registry provides reassurance that these stimulants do not appear to have major teratogenic effects. ClinicalTrials.gov identifier: NCT01246765 .

Do ADHD Treatments Improve Executive Behavior Beyond Core ADHD Symptoms in Adults? Evidence From Systematic Analysis of Clinical Trials.

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.

Treatment of ADHD: Drugs, psychological therapies, devices, complementary and alternative methods as well as the trends in clinical trials.

Attention-deficit/hyperactivity disorder (ADHD) is one of the most common neurodevelopmental disorders having a high influence on social interactions. The number of approved treatments and clinical trials for ADHD have increased markedly during the recent decade. This analytical review provides a quantitative overview of the existing pharmacological and non-pharmacological methods of ADHD treatments investigated in clinical trials during 1999-2021. A total of 695 interventional trials were manually assessed from clinicaltrial.gov with the search term « ADHD», and trial data has been used for analysis. A clear majority of the studies investigated non-pharmacological therapies (∼80%), including many behavioral options, such as social skills training, sleep and physical activity interventions, meditation and hypnotherapy. Devices, complementary and other alternative methods of ADHD treatment are also gaining attention. The pharmacological group accounts for ∼20% of all the studies. The most common drug classes include central nervous system stimulants (e.g., methylphenidate hydrochloride, lisdexamfetamine dimesylate, amphetamine sulfate, mixed amphetamine salts, a combination of dexmethylphenidate hydrochloride and serdexmethylphenidate chloride), selective noradrenaline reuptake inhibitors (atomoxetine, viloxazine), and alpha2 adrenergic receptor agonists (guanfacine hydrochloride, clonidine hydrochloride). Several studies investigated antidepressants (e.g., bupropion hydrochloride, vortioxetine), and atypical antipsychotics (e.g., quetiapine, aripiprazole) but these are yet not approved by the FDA for ADHD treatment. We discuss the quantitative trends in clinical trials and provide an overview of the new drug agents and non-pharmacological therapies, drug targets, and novel treatment options.

The Use of Brexpiprazole Combined With a Stimulant in Adults With Treatment-Resistant Attention-Deficit/Hyperactivity Disorder.

This is the first controlled pharmacologic study in either adults or children with uncomplicated, treatment-resistant attention-deficit/hyperactivity disorder (ADHD). This study augmented stimulant therapy with the atypical antipsychotic brexpiprazole. The Food and Drug Administration preapproved primary outcome measure (Conners' Adult ADHD Rating Scale [CAARS]) showed no drug-placebo differences. Often studies showing no efficacy on the prestudy, defined primary outcome variable go unpublished. While this is decried, publishing studies with equivocal results remains rare. This reanalysis highlights trends in secondary measures having implications for treatment and research regarding treatment resistant ADHD. Initially, 559 stimulant-naive and 174 prior stimulant nonresponders received methylphenidate osmotic-release oral system, dexmethylphenidate hydrochloride, lisdexamfetamine, or mixed amphetamine salts. After 5 weeks, 168 stimulant-naive patients and 68 prior stimulant nonresponders who failed treatment were randomized to brexpiprazole or placebo in a 2:1 ratio while the remaining were on the stimulant. Outcome was measured with the CAARS, Montgomery-Asberg Depression Rating Scale, Beck Depression Inventory, Clinical Global Impression, and the Wender-Reimherr Adult Attention Deficit Disorder Scale (WRAADDS). The WRAADDS contains 2 factors: attention and emotional dysregulation. Stimulant-naive patients showed no improvement with adjunctive brexpiprazole. Prior stimulant nonresponders displayed no brexpiprazole effect on the CAARS, Montgomery-Asberg Depression Rating Scale, or Beck Depression Inventory. In contrast, the WRAADDS detected a trend in treatment benefit, primarily through emotional dysregulation symptoms. Adverse effects on brexpiprazole and placebo were equivalent. Brexpiprazole might be effective in ADHD adults who are nonresponders to 2 or more stimulants. Future trials in treatment-resistant ADHD should use a 1:1 randomization and use a measure of ADHD symptoms that includes emotional dysregulation.

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Amphetamine mixed salts, XR (generic) – Adderall, Adderall XR (brand)

The Pharmacogenetic Impact on the Pharmacokinetics of ADHD Medications.

ADHD is a common condition in both children and adults. The most prescribed medications for the treatment of ADHD include methylphenidate, mixed amphetamine salts, atomoxetine, guanfacine, and clonidine. While each of these medications have their own distinct pharmacokinetic profile, the extent to which pharmacogenetics effects their pharmacokinetic parameters is best described in atomoxetine, followed by methylphenidate. Atomoxetine is predominantly metabolized by cytochrome p450 2D6 (CYP2D6), while methylphenidate is metabolized by carboxylesterase 1 (CES1). Both CYP2D6 and CES1 have multiple variants resulting in varying levels of enzyme activity; however, to date, the functional consequence of variants and alleles for CYP2D6 is better characterized as compared to CES1. Regarding CYP2D6, individuals who are poor metabolizers prescribed atomoxetine experience up to ten-fold higher exposure as compared to normal metabolizers at comparable dosing. Additionally, individuals prescribed methylphenidate with the rs71647871 variant may experience up to 2.5-fold higher exposure as compared to those without. Having this pharmacogenetic information available may aid clinicians and patients when choosing medications and doses to treat ADHD.

The effect of methylphenidate and mixed amphetamine salts on cognitive reflection: a field study.

Methylphenidate (MPH) and mixed D,L-amphetamine salts (MASs; Adderall) were previously found to have unreliable effects on judgment and decision processes. 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. 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. 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. The results indicate that MPH enhances decision-making in tasks where heuristic responses typically bias it.

Mixed Amphetamine Salts Without a Mood Stabilizer for Treating Comorbid Attention-Deficit Hyperactivity Disorder and Bipolar Disorder: Two Case Reports.

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.

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A single-dose, comparative bioavailability study comparing amphetamine extended-release oral suspension with extended-release mixed amphetamine salts capsules.

To evaluate the relative bioavailability of a single dose of amphetamine extended-release oral suspension (AMPH EROS) compared with a single dose of extended-release mixed amphetamine salts (ER MAS) in healthy, fasted adult subjects. The study population consisted of healthy adult volunteers. The study drug used in this study was 7.5mL of 2.5mg/mL AMPH EROS equivalent to 18.8mg of amphetamine base administered after an overnight fast of at least 10hours. AMPH EROS comprises a 3.2:1 enantiomeric ratio of d-amphetamine to l-amphetamine. The reference product was one 30mg ER MAS capsule (equivalent to 18.8mg of amphetamine base). Relative bioavailability between the products was determined by a statistical comparison of the area under the curve and maximum concentration (Cmax) for d-amphetamine and l-amphetamine. PK (PK) blood samples were collected prior to dosing (0-hour) and at 1, 2, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, 10, 12, 14, 16, 24, 36, 48, and 60hours after drug administration, totaling 20 samples in each period. The mean subject age was 35.0 (standard deviation ±8) years, and the overall study population comprised 19 (63.3%) males and 11 (36.7%) females. The contrasts for geometric mean ratios for all assessed PK parameters (for both l- and d-amphetamine) between the test article AMPH EROS and reference product ER MAS fell within the prescribed 80% to 125% limits. The overall PK profile of single-dose AMPH EROS 7.5mL was found to be comparable with a single dose of oral ER MAS 30mg.

Improved Executive Function in Adults Diagnosed With Attention-Deficit/ Hyperactivity Disorder as Measured by the Brown Attention-Deficit Disorder Scale Following Treatment With SHP465 Mixed Amphetamine Salts Extended-Release: Post Hoc Analyses From 2 Randomized, Placebo-Controlled Studies

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.

Pharmacologic treatment of attention deficit hyperactivity disorder in adults: A systematic review and network meta-analysis.

BackgroundAttention 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.MethodsWe 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.ResultsEighty-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.ConclusionsOverall, 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.RegistrationPROSPERO no. CRD 42015026049