A review of amphetamine extended release once-daily options for the management of attention-deficit hyperactivity disorder

ABSTRACT

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.

KEYWORDS:

• Amphetamine
• ADHD
• dextroamphetamine
• delivery
• extended-release
• once-daily treatment

1. Introduction

Attention deficit hyperactivity disorder (ADHD) is the most common behavioral disorder of childhood, with prevalence rates reported to be 6–10% [1]. One of the earliest descriptions in the medical literature was a case series reported by Sir George F. Still (better known for Still’s disease) in which he described ‘nervous children’ with symptoms of impulsiveness, inattention and poor self-control [2]. Management of this condition was largely symptomatic. In 1937 Bradley first reported the use of a newly approved drug, Benzedrine (racemic amphetamine sulfate), in treating children with behavior disorders [3]. Bradley was using the drug as treatment for headaches in children who had undergone pneumoencephalography as part of their evaluation. He noted that their troublesome behavior became more subdued, and this was seen as an overall improvement in their behavior. He conducted later studies [4] describing beneficial effects on motivation, output, and socially appropriate behavior. Over the past century there has been significant progress and change in the description of what we now call ADHD as well as our understanding of and use of amphetamine in treating the condition. Amphetamine medications are now considered as first or second line options for medical treatment of ADHD [5].

While amphetamine was first synthesized in Germany in 1887, its first medically oriented synthesis was by Japanese chemists working with the herbal medicine ephedra. This led to the isolation of l-ephedrine. The sympathomimetic actions of ephedrine were found to be similar to adrenaline [6,7], and it was initially marketed in the US and Europe for use as a decongestant and treatment for asthma. Attempts to develop a more effective drug led to amphetamine receiving a patent for its use as a medicine despite its uncertain indications. The patent rights were assigned to Smith, Kline and French (SKF) and the company promoted further clinical development. Early human trials indicated that it had little benefit as a decongestant but did seem to promote a feeling of well-being and wakefulness. This led to its use as a treatment for narcolepsy. Normal controls in some early studies reported improvements in energy and a sense that their cognitive skills were also improved. SKF then supported several studies in adults to determine what effects amphetamine might have on neurocognitive skills in addition to mood [8]. By the late 1940s the dextrorotatory isomer dextroamphetamine had been confirmed as the major mediator of the effects on attention, mood and appetite and was being marketed as Dexedrine. It continued to be marketed as a treatment for depression and as a weight loss drug through the 1960s. However, abuse of amphetamine drugs was reported in the 1930s and their widespread use during World War II made this more problematic [9]. In the 1970 UN Convention on Psychotropics amphetamines were scheduled as controlled substances due to their risk for addiction.

Meanwhile, the condition of children with behavioral concerns continued to be refined with the description of hyperkinetic reaction of childhood in the second edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM) in 1968. This was revised to attention deficit disorder with or without hyperactivity in 1980 in the DSM III, and further to attention deficit hyperactivity disorder (ADHD) in DSM-III revised in 1987 and has continued as such in the current DSM-5. As the disorder became more clearly specified and increasingly diagnosed, questions arose regarding what constituted the best treatment. There were good studies demonstrating benefits of stimulant medication such as amphetamine, and also evidence of effectiveness of non-medical treatments comprised of behavior management techniques. The Multi-modal Treatment of ADHD (MTA) study was undertaken in the late 1990s to attempt to answer this question [10]. The study found that ‘carefully crafted medication management was superior to behavioral treatment.’ Part of this careful medication management was the use of three times a day dosage schedules that provided medication benefit for as much of the daytime hours as possible without causing unacceptable reduction in appetite and growth, or in sleep disruption. The response from the pharmaceutical industry has been the development of numerous options of once daily extended release, prolonged acting stimulant medications. In this expert opinion drug profile we aim to provide a review of the amphetamine extended release medications currently available, summarize their overall efficacy in treating ADHD, discuss common issues in dosing and managing side effects, and provide some suggestions regarding their use in clinical practice. In preparing this review, we conducted a broad PubMed search with no language or date restrictions using the terms amphetamine, dextroamphetamine, ADHD, extended release, and once-daily treatment. The authors examined the results of this search strategy and then focused on review articles and clinical trials in preparing this review.

2. Pharmacological profile of amphetamine

Racemic amphetamine consists of dextro- and levo- isomers. Amphetamines act as a full agonist of trace amine-associated receptor 1 (TAAR1), a G-protein coupled receptor (GPCR) present in CNS neurons, specifically in monoaminergic regions of the brain including the substantia nigra, dorsal raphe nucleus and ventral tegmental area, the hypothalamus, amygdala, nucleus of the solitary tract, and the parahippocampal region and subiculum [11]. Activation of this receptor inhibits the reuptake and subsequent transport of norepinephrine and dopamine back into the presynaptic neurons in the CNS [12]. This effectively increases the concentration, and therefore availability, of norepinephrine and dopamine in the synaptic cleft. Additionally, amphetamines directly inhibit vesicular monoamine transporters (VMAT1 and VMAT2), further increasing neurotransmitter (dopamine, norepinephrine, and serotonin to a lesser extent) availability in the synaptic cleft.

2.1. Pharmacodynamics

Dextroamphetamine is a more potent agonist than its enantiomer, levoamphetamine [13]. Early studies determined that the d-isomer dextroamphetamine is responsible for most of the benefits of increased attention and vigilance, reduced motor activity, increased stamina and reduced appetite. This later was found to be due to the isomer promoting greater release of dopamine. The levoamphetamine isomer is associated with more of the side effects of increased heart rate and blood pressure. This was eventually determined to be due to greater release of norepinephrine. As a result, dextroamphetamine was marketed for many years as providing more beneficial activity by not causing the cardiovascular effects that are not pleasurable, especially in patients with depressed or anxious mood. Later research found that increased norepinephrine plays a role in inattentive symptoms, leading to several manufacturers marketing products containing both d-amphetamine and l-amphetamine compounds.

For several decades, clinical benefits of amphetamines have been limited by the pharmacologic half-life of around 4 hours. Although higher doses can produce higher maximum concentrations, they do not affect the half-life of the dose. Therefore, to achieve longer durations of effect, stimulants had to be dosed at least twice daily. Further, these immediate-release doses were found to have their greatest effect shortly after administration, with a rapid decline in effect after reaching peak blood concentrations. The clinical correlation of this was found in comparing math problems attempted and solved between a mixed amphetamine salts preparation (MAS) 10 mg once at 8 am vs 8 am followed by 12 pm [14]. The study also demonstrated the phenomenon of acute tolerance, where even if blood concentrations were maintained over the course of the day, clinical efficacy in the form of math problems attempted and solved would diminish over the course of the day. These findings eventually led to the development of a once daily preparation (MAS XR) [15], which is a composition of 50% immediate-release beads and 50% delayed release beads intended to mimic this twice-daily dosing with only a single administration.

2.2. Pharmacokinetics

The mean elimination half-life of dextroamphetamine is approximately 9 hours in children aged 6–12 years [16]. This contrasts with the longer half-lives seen in adolescents and adults (11 hours and 10 hours, respectively). For levoamphetamine, the elimination half-life is 11 hours for children aged 6 to 12 years. The presence of food has not been found to change the absorption rate of d- or l-amphetamine but has prolonged T_max for MAS XR by 2.5 hours for d-amphetamine and 2.7 hours for l-amphetamine. That said, children showed 30% less systemic exposure to Adderall XR specifically when doses were normalized on a mg/kg basis.

Dextroamphetamine is metabolized in the liver by CYP-450 2D6 at the 4 position of the benzene ring to form 4-hydroxyamphetamine or norephedrine if on the side chain alpha or beta of the benzene ring and later conjugated by sulfotransferase or glucoronyltransferase [17]. Renal excretion varies from 1% to 75% depending on urinary pH. Because amphetamine itself has a pKa of 9.9, urinary recovery is highly affected by urinary pH and urine output. Alkaline urine results in less renal excretion, while acidic urine results in higher excretion. Assuming a normal urinary pH, ½ of the dose of the drug is excreted in the urine as derivatives of alpha-hydroxy-amphetamine with an additional 30–40% of the dose excreted as amphetamine itself [16]. With both of those mechanisms in mind, dysfunction of either the renal or hepatic system can result in slower metabolism and elimination of amphetamine and so result in longer exposure to the drug.

Table 1 summarizes the available extended-release formulations amphetamine formulations currently available on the market and their relevant pharmacokinetics.

Table 1. Pharmacokinetics of available extended-release once-daily amphetamine products.

Drug	Trade Name	Time to peak plasma concentration	Half life	Typical Length of Clinical Effect	Recommended Starting Dose
Mixed amphetamine salts (MAS SLI381) (dextroamphetamine sulfate, dextroamphetamine saccharate, amphetamine sulfate and amphetamine aspartate) [18,19]	Adderall XR	7 hours	9 hours	12 hours	5 mg
SHP465 mixed amphetamine salts (MAS) [20]	Mydayis	2 or 4 hours	<16 hours	Up to 14 hours (adolescents)	12.5 mg
d,l-amphetamine [21,22]	Dyanavel XR (tablet or liquid)	3.9 to 4.5 hours	10.4 to 12.1 hours	Up to 13 hours (adults), up to 12 hours (liquid, children)	2.5 mg
d,l-amphetamine (AMP XR-OS) [23,24]	Adzenys (ODT or liquid)	4–5 hours	9–10 hours	Up to 12 hours	6.3 mg
Dextroamphetamine sulfate [25,26]	Dexedrine Spansule	3 hours	12 hours	8 hours	5 mg
Lisdexamphetamine (prostimulant) [27,28]	Vyvanse	4 hours	8.6 to 9.5 hours	Up to 12 hours (adults)	10 mg
Dextroamphetamine [29,30]	Xelstrym Patch	9 hours (active at 2)	6.4 hours (effect up to 12)	Up to 11 hours (children)	4.5 mg/9 hours
Dextroamphetamine Sulfate [31,32]	Attentin	1.5 hours	10.2 hours	6.5 hours (children)	5 mg

3. Clinical efficacy

Table 2 provides a summary of the relevant data on clinical efficacy of various amphetamine extended-release formulations.

Table 2. Summary table of clinical trial results for amphetamine extended release once-daily tablets.

Authors	Drug (s)	Participants	Study Type	Methods	Findings
James et al. 2001 [33]	Adderall, extended-release dextroamphetamine, and dextroamphetamine spansules	Children 6–12 years with DSM-IV defined ADHD (n = 35)	Randomized, double-blind, placebo-controlled, crossover study in research school setting	Children given Adderall XR, immediate release dextroamphetamine, dextroamphetamine Spansules, and placebo. Behavior ratings, locomotor activity measurements, and academic measures obtained over 8 week period.	Dextroamphetamine spansules less effective in morning compared to Adderall but lasted 3–6 hours longer.
Biederman et al. 2002 [34]	Adderall XR	Children 6–12 years with DSM-IV defined ADHD (n = 584)	Multicenter, randomized, double-blind parallel group, placebo-controlled trial	Participants received placebo or 10 mg, 20 mg, or 30 mg Adderall XR for 3 weeks	Conners Global Index Scales for Teachers and Parents revealed significant and dose-related improvement in morning, afternoon, and late afternoon behavior for all active treatment groups versus placebo
McCracken et al. 2003 [14]	Adderall XR	Children 6–12 years with DSM-IV defined ADHD (N = 51)	Randomized, double-blind, crossover study in analog classroom setting	Participants randomly assigned in crossover design to each of five treatment weeks, Adderall XR 10 mg, 20 mg, Adderall 10 mg, and placebo for a week	Dose-dependent improvements noted, only 20- and 30-mg doses showed continued activity at 10.5 and 12 hours for classroom behavior and math test performance versus placebo
McGough et al. 2005 [35]	Adderall XR	Children 6–12 years with DSM-IV defined ADHD (n = 568)	24-month multi-center, open label extension of two placebo-controlled studies of mixed amephetamine salts (MAS XR; Adderall XR)	Participants began treatment with MAS XR 10 mg once daily, with 10-mg weekly dose increases to optimize effectiveness (max 30 mg/d).	Significant improvement (>30%, p < 0.001) in Conners Global Index Scale-Parent Scores maintained during long-term treatment
Ambrosini et al. 2006 [36]	Mixed Amphetamine Salts Extended Release (MAS-XR)	Children 6–12 years with DSM-IV defined ADHD (N = 2968)	9-week prospective, open-label, non-comparative study at 386 sites	Participants with well-controlled ADHD received previous psychostimulant for 2 weeks and then was converted to equivalent once-daily dose of 10-, 20-, or 30-mg MAS XR	Improvement in ADHD behavior 8 and 12 h postdose during the first week of treatment and maintained ( p < 0.0001). MAS XR treatment significantly improved symptoms compared with the baseline stimulant regimen ( p < 0.0001).
Wilson et al. 2006 [37]	Adderall XR, Concerta	Adolescents with ADHD (n = 35, 19 males)	Randomized, double-blind, placebo controlled study designed to compare two extended release stimulants and placebo on ADHD neuropsychological functioning	Adolescents completed three separate assessments (5, 8, 11 pm) on three different days and medications (Concerta, Adderall XR, and Placebo)	Significant effect on impulsivity and memory with both Concerta and Adderall XR (with no significant difference in performance between Concerta and Adderall XR)
Biederman et al. 2005 [38]	Mixed amphetamine salts extended release (MAS XR)	Adults (> or = 18 years) with ADHD (n = 223)	24-month, open-label extension of a 4-week, multicenter, doubule-blind, placebo-controlled, forced-dose-escalation study	Subjects started at 20 mg/day for 1 week with titration up to 60 mg/day for optimal therapeutic effects	ADHD symptoms significantly improved for all subjects measured by change in mean ADHD Rating Scale IV total scores and was sustained up to 24 months
Wigal et al. 2005 [39]	MAS XR (Adderall XR) vs. Atomoxetine (Strattera)	Children 6–12 years with ADHD per DSM-IV (n = 215)	Randomized, double-blind, multicenter, parallel-group, forced-dose-escalation laboratory school study	Subjects randomized to 18 days of treatment with MAS XR or atomoxetine; Atomoxetine dosed in accordance with FDA labeling up to target daily dose of 1.2 mg/kg/d, MAS XR subjects received 10 mg in week 1, 20 mg in week 2, and 30 mg during week 3	Changes in mean SKAMP (Swanson, Kotkin, Agler, M-Flynn and Pelham) deportment scores significantly greater for MAS XR than for atomoxetine at each week
Spencer et al. 2006 [40]	Adderall XR	Adolescents aged 13 to 17 years (n = 258) with ADHD	4-week, randomized, multi-center, double-blind, placebo-controlled, parallel-group, forced-dose titration study	Participants randomized to 1 of 4 active treatments (MAS XR 10, 20, 30, or 40 mg/day) or placebo.	Improvement in mean ADHD-RS-IV total scores for both inattentive and hyperactive-impulsive subscales in all 4 MAS XR treatment groups compared with placebo throughout study
Biederman et al. 2006 [41]	MAS XR vs. Atomoxetine	Girls aged 6 to 12 with ADHD (n = 215)	Post hoc analysis of data from multicenter, 18-day, randomized, double-blind, parallel-group, forced dose-titration, laboratory school study of boys and girls with ADHD	Compared efficacy, tolerability, and time course of effect of increasing doses of MAS XR (10, 20, and 30 mg/day) and atomoxetine (0.5 and 1.2 mg/k/d)	18-day treatment with MAS XR more effective than atomoxetine in terms of ratings of classroom behavior, attention, and academic productivity
Weisler et al. 2006 [42]	MAS XR	Adults>or = 18 with ADHD (N = 250)	Multisite, randomized, double-blind, placebo-controlled, parallel-group, dose-escalation study	Adults given placebo or MAS XR 20, 40, or 60 mg/day for 4 weeks	Reduction of mean ADHD Rating Scale scores; adults with more severe symptoms had greater symptoms reduction with maximum osing;statistically significant (p < .05) improvements in CAARS-S-S (Conners’ Adult ADHD Rating Scale Short Version Self-Report) ADHD index scores occurred at 4- and 12-hours postdose for all MAS XR groups
Faraone et al. 2007 [43]	MAS XR (Adderall XR) vs. Atomoxetine (Strattera)	Children ages 6 to 12 with ADHD per DSM-IV criteria (n = 215)	Analysis of data from randomized, double-blind, multicenter, parallel-group, forced-dose-escalation laboratory school study	Statistical modeling used to forecast the levels of efficacy that might be observed during 8-week treatment extension	Similar pattern to Wigal et al., 2005; MAS XR expected to be more effective that Atomoxetine
Biederman et al. 2007 [44]	MAS XR and Lisdexamfetamine dimesylate (LDX)	Children 6–12 years with ADHD per DSM-IV criteria (n = 52)	Randomized, double-blind, placebo- and active-controlled crossover study in classroom environment comparing the efficacy and safety of LDX with placebo, with MAS XR included as reference arm	Open-label administration of MAS XR for 3 weeks, titrated from 10 mg/d based on clinical response, subsequently transitioned to LDX based on MAS XR optimized dose. Participants then crossed over such that each subject received 1 week of placebo, 1 week of MAS XR, and 1 week of LDX.	Subjects treated with MAS XR had significant decreases in mean SKAMP-DS scores as compared with placebo (unable to compare LDX and MAS XR)
Spencer et al. 2008 [45]	Triple-Bead Mixed Amphetamine Salts (Mydadis)	Adults ages 18 to 55 years with ADHD per DSM-IV-TR Criteria (N = 272)	7-week, randomized, double-blind, multicenter, placebo-controlled, parallel-group, dose-optimization study	Subjects randomly assigned to triple-bead MAS (12.5 mg) or placebo	Significant improvement versus placebo in ADHD-RS-IV total score change, CGI (Clinical Global Impressions Scale)-Improvement, TASS (Time-Sensitive ADHD Symptom Scale) total score at 13–16 hours post-dose, BADDS (Brown Attention-Deficit Disorder Scale) total score, all AIM-A (Adult ADHD Impact Module) domains, and ADHD-RS-IV subscales, demonstrating extended duration of efficacy and improvements in executive functioning and Quality of LIfe
Mikami et al. 2009 [46]	Extended release amphetamine salts, osmotic-release methylphenidate and routine limited medication regimen	Male (n = 19) and female (n = 16) adolescents, ages 16–19 with ADHD	Randomized, double-blind crossover study	Participants randomly assigned to either 1 day dcourse of OROS MPH followed by a 17 day course or se-AMPH ER, or the reverse sequence	Medication appears similarly effective between males and females
Stein et al. 2011 [47]	Long-acting extended-release dexmethylphenidate (ER d-MPH) versus ER mixed amphetamine salts (ER MAS)	Children and adolescents ages 9 to 17 with ADHD (n = 56)	8-week, double-blind, crossover study	Participants administered three dose conditions of ER d-MPH and ER MAS (10, 20, and 25–30 mg) sequentially from lowest dose to highest dose with a randomized week of placebo in each period. 50% started with ER d-MPH and 50% started with ER MAS	80% demonstrated reliable change on ADHD-RS-IV at the highest dose level of ER MAS compared with 79% when receiving ER d-MPH; 3% of the responders were preferential responders to only one of the stimulant formulations
Wigal et al. 2018 [48]	SHP465 vs. immediate-release MAS (MAS IR)	Adults (>or = 18) with ADHD Rating Scale, Version IV scores ≥ 24 (n = 86)	Participants randomized to MAS (50 or 75 mg), placebo, or 25 mg MASI-R in double-blind, three-period, crossover study using a simulated adult workplace environment	Following 7-day treatment period, efficacy assessed 16 h postdose using the Permanent Product Measure of Performance (PERMP) and ADHD-RS-IV scores based on clinician ratings of counselor observations using the Time Segment Rating system and participant self-report	MAS (50/75 mg) resulted in significantly improved PERMPT total scores versus placebo, no significant difference between MAS (50/75) and MAS IR
Wigal et al. 2019 [49]	SHP465 versus placebo and MAS IR	Adolescents ages 13–17 years with ADHD having ADHD rating Scale, Version IV total scores ≥ 24 (n = 84)	Randomized, 3-period, 3-treatment crossover study in laboratory classroom setting	Efficacy assessed on last day of each 7-day treatment period using PERMP, SKAMP, and participant self report	PERMP total scores favored MAS XR over placebo at all time points
Adler et al. 2020 [50]	SHP465 versus placebo	Adults ages 18–55 years with ADHD per DSM-IV-TR criteria and baseline ADHD-RS-IV scores ≥ 24 (for the dose-optimization study; Spencer et al. 2008) or ≥ 32 for the fixed-dose study (Frick et al. 2020)	Post hoc analyses of response and remission rates on data from placebo-controlled MAX-XR dose-optimization (12.5–75 mg) and fixed-dose (25–75 mg) studies	Response and remission rates analyzed in addition to potential mediating factors	MAS XR associated with greater response and remission rates at the final treatment week and/or study endpoint. Remission rates comparable when examining based on sex and age.
Mattingly et al. 2020 [51]	SHP465 versus placebo	Children ages 6–12 years with DSM-5 defined ADHDD; 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 (n = 89)	Randomized double-blind, placebo-controlled, fixed-dose study at 27 sites	Participants received 6.25 mg SHP465 MAS once daily or placebo for 4 weeks	MAS 6.25 mg well tolerated but not superior to placebo
Frick et al. 2020 [52]	SHP465 versus placebo	Adults with ADHD-RS-IV total scores ≥ 32 (n = 405)	Double-Blind, Randomized, Forced-Dose Trial	Participants randomized to 6 weeks of SHP465 (25, 50, or 75 mg) or placebo	Significant improvement in ADHD-RSI-IV total scores for SHP465, no significant differences between SHP465 dosages
Brown et al. 2022 [53]	SHP465 versus placebo	Adults ages 18–55 years with ADHD per DSM-IV-TR criteria and baseline ADHD-RS-IV scores ≥ 24 (for the dose-optimization study; Spencer et al. 2008) or ≥ 32 for the fixed-dose study (Frick et al. 2020)	Post hoc analyses on data from placebo-controlled MAX-XR dose-optimization (12.5–75 mg) and fixed-dose (25–75 mg) studies	Treatment response assessed using Brown Attention-Deficit Disorder Scale (BADDS)	Improvement in executive function measured by BADDS response rates was 2-fold greater than MAS XR versus placebo

3.1. Clinical efficacy in children

The clinical efficacy of amphetamine extended release once-daily tablets has been well established in the pediatric population. The first study to establish efficacy was conducted by James et al. [33] and involved a randomized, double-blind, placebo-controlled, crossover study on 35 children ages 6–12 years of age with ADHD. Children were given either MAS, immediate-release dextroamphetamine, dextroamphetamine extended-release capsules (Spansules), or placebo, and behavior ratings, locomotor activity measurements, and academic measures were obtained over an 8-week period. The study found that although the dextroamphetamine capsules were less effective in the morning compared to immediate-release MAS, the overall duration of action was 3–6 hours longer. It was also found that although parent behavior ratings and locomotor activity improved with all three drugs over a 2-hour period, the number of math problems completed correctly 4 hours after dosing were only significantly increased by the dextroamphetamine extended-release capsules.

Following the success of the first amphetamine-based extended-release formulation, SLI381, also known as MAS XR, was developed and has also demonstrated significant benefit in the pediatric population in multiple studies [14,34–36,39,41,43,44,46]. In a multicenter, randomized, double-blind parallel group, placebo-controlled trial involving 584 children ages 6–12, Biederman et al. [34] found that there was a dose-related improvement in Conners Global Index Scales for teachers and parents for all active treatment groups versus placebo and was effective throughout the morning, afternoon, and late afternoon, thus eliminating the need for school administration of stimulants as had been the previous standard of care, allowing for the completion of homework activities and improved participation in after school athletic and social activities and family life. Dose-dependent benefits were also seen in a randomized, double-blind crossover study in an analog classroom study of 51 children with ADHD 6–12 years of age in a study by McCracken et al. [14]. In this study, MAS XR was shown to have continued activity at 10.5 and 12 hours for classroom behavior and math test performance versus placebo.

On a larger scale, two prospective studies have confirmed the benefits of MAS XR in the pediatric population. McGough et al. [35] conducted a 24-month multi-center, open-label extension of two previous placebo-controlled studies [14,34] on 568 children ages 6–12 with ADHD and found that the significant improvement (>30%, p < 0.001) in Conners Global Scale Index Scale-Parent Scores were maintained during 24 months of treatment. Subsequently, Ambrosini et al. completed a 9-week prospective, open-label, non-comparative study at 386 sites involving 2968 children ages 6–12 with ADHD during which participants with well-controlled ADHD on a different psychostimulant were converted to equivalent once-daily dosing of 10-, 20-, or 30 mg of MAS XR [36]. The group found improvements in ADHD-related behaviors 8 and 12 hours post dose during the first week of treatment and was subsequently maintained (p < 0.0001). MAS XR treatment was also noted to significantly improve symptoms compared to the patients baseline stimulant regimens (p < 0.0001).

In comparing MAS XR to other medications on the market for ADHD, superiority has been demonstrated in comparison to Atomoxetine in both a large group of both girls and boys ages 6–12 with ADHD [36]as well as specifically girls ages 6–12 with ADHD [41]. Faraone et al. [43] utilized statistical modeling to forecast the levels of efficacy that might be seen during an 8-week treatment extension of the study described by Wigal et al. [39] and again found MAS XR to be superior in terms of efficacy. Stein et al. [47] also compared long-acting extended release dexmethylphenidate to MAS XR during an 8-week, double-blind crossover study in a group of children and adolescents ages 9 to 17 with ADHD (n = 56) and found that 80% demonstrated reliable change on ADHD-RS-IV at the highest dose level of MAS XR compared with 79% when receiving ER d-MPH.

A newer drug on the market, Mydayis (also known as SHP465), has demonstrated tolerability but in a randomized, double-blind, placebo-controlled, fixed-dose study at 27 sites involving 42 children aged 6–12 years with ADHD was not found to be superior to placebo [51].

3.2. Clinical efficacy in adolescents

A few studies have also evaluated the clinical efficacy of MAS XR in adolescents with ADHD specifically. In a 4-week, randomized, multi-center, double-blind, placebo-controlled, parallel-group, forced-dose titration study, Spencer et al.) randomized 258 adolescents ages 13 to 17 to one of four active treatments consisting of either MAS XR 10, 20, 30, or 40 mg/day or placebo [40]. The group found an overall improvement in mean ADHD-RS-IV scores for both inattentive and hyperactive subscales in all 4 MAS XR treatment groups compared with placebo throughout the study. Wilson et al. completed a randomized, double-blind, placebo-controlled trial designed to compare two extended-release stimulants (OROS methylphenidate (OROS MPH), MAS XR) to placebo on measures of neuropsychological functioning [37]. During this study, adolescents completed three separate assessments (5, 8, and 11 pm) on three different days and three different medications (either OROS MPH, MAS XR, or placebo). The group found that there was a significant effect on impulsivity and memory with both OROS MPH and MAS XR without a significant difference in performance between the two medications.

As a result of increasing interest on the potential differences in clinical efficacy of psychostimulants on males versus females, Mikami et al. [46] conducted a randomized, double-blind crossover study in adolescents ages 16–19 with ADHD. Participants were randomly assigned to either 1 day course of OROS methylphenidate followed by a 17-day course of MAS XR, or the reverse sequence. Ultimately, medication appeared to be similarly effective between males and females.

In the adolescent population, SHP465 has shown some promise as an ‘extra’ extended-release formulation. In a randomized, 3-period, 3-treatment crossover study in a laboratory classroom setting involving 84 adolescents aged 13–17 with ADHD, SHP465 has demonstrated superiority versus placebo and MAS IR as assessed by Product Measure of Performance total score, ADHD symptoms based on participant self-report, Swansons, Kotskin, angler, M-Flynn, and Pelham Scale, as well as Revised Conner’s Parent Rating Scale [49].

3.3. Clinical efficacy in adults

There have been relatively fewer studies evaluating the efficacy of amphetamine extended release once daily tablets in the adult population. The first published study to evaluate the safety and efficacy of MAS XR in adults was conducted by Weisler et al. [42]. In this multisite, randomized, double-blind, placebo-controlled, parallel-group, dose-escalation study on adults aged 18 or older with ADHD (n = 250), MAS XR was found to be both safe and effective for adults with ADHD as measured by the ADHD Rating Scale and Conners’ Adult ADHD Rating Scale Short Version Self-Report (CAARS-S-S) with a noted dose-dependent response. Biederman et al. [38] subsequently conducted a 24-month, open-label extension of the study published by Weisler et al. [42] and found sustained improvement as measured by change from baseline in mean ADHD-RS-IV scores up to 24 month.

In 2008, Spencer et al. published the results of a 7-week, randomized double-blind, multicenter placebo-controlled parallel-group, dose-optimization study evaluating the safety and efficacy of a new amphetamine extended-release formulation on the market, SHP465, in the adult population (n = 272) [45]. There was a noted significant improvement versus placebo in ADHD-RS-IV total score change, CGI (Clinical Global Impressions Scale)-Improvement, TASS (Time-Sensitive ADHD Symptom Scale) total score at 13–16 hours post-dose, BADDS (Brown Attention-Deficit Disorder Scale) total score, all AIM-A (Adult ADHD Impact Module) domains, and ADHD-RS-IV subscales, demonstrating extended duration of efficacy and improvements in executive functioning and Quality of Life. Data from this study supported an extended duration of efficacy of the triple-bead amphetamine formulation up to 16 hours, demonstrating a longer period of efficacy in contrast to MAS XR and thus fulfilling a need in the market for adults with ADHD presumably requiring medications with a longer duration of action in contrast to the time periods required for children with ADHD.

In a randomized, double-blind study of SHP465 in 86 adults using a simulated workplace design Wigal et al. [48] found that SHP465 resulted in a significantly improved Permanent Product Measure of Performance Total Score. Additional studies of SHP465 in the adult population have also demonstrated greater response and remission rates versus placebo in adults with ADHD [50]. Frick et al. [52] conducted a double-blind, randomized, forced-dose trial with 405 adults with ADHD and found a significant improvement in ADHD-RS-IV total scores for SHP465Mydayis with no significant differences between dosages. Subsequently, post hoc analyses on data from the Spencer et al. [45] and Frick et al. [52] studies showed improvement in executive function as measured by the Brown Attention-Deficit Disorder Scale (BADDS) [53].

3.4. Other uses of amphetamine extended release in individuals with ADHD

Extended-release amphetamine tablets have also been studied in individuals with ADHD with comorbid anxiety [54] as well as cocaine use disorder and other substance use disorders [55–57]. Gabriel et al. [54] completed a small study (n = 32) on adults with confirmed diagnoses of generalized anxiety and comorbid ADHD. All patients had significant symptoms of anxiety and had failed to respond to 8-week trials of Serotonin Reuptake Inhibitors (SSRIs) or Norepinephrine Reuptake inhibitors (SNRIs). All patients subsequently received Adderall XR as adjuncts to either an SSRI or SNRI and were followed for 12 weeks after which it was found a significant reduction in both symptoms of anxiety and ADHD at 8 weeks (as measured by the Hamilton Anxiety Scale, the Clinical Global Impression Severity subscale and the ADHD Self-Report Scale) followed by a significant reduction in their disability score at 12 weeks (as measured by Sheehan’s Disability scale).

A few studies have also evaluated changes in driving patterns in individuals receiving extended-release amphetamine products. Cox et al. [58] conducted a randomized, double-blind placebo-controlled, crossover study with 35 adolescent drivers with ADHD in which drivers were compared on a simulator after taking 72 mg of OROS methylphenidate, 30 mg of MAS XR, or placebo. The authors’ primary outcome measure, the Impaired Driving Score, improved following OROS methylphenidate versus placebo and MAS XR; however, MAS XR demonstrated no statistical improvement over placebo. In a randomized, double-blind, placebo-controlled, crossover study of simulated driving performance with MAS XR 50 mg/day and atomoxetine 80 mg/day in adults ages 19 to 25 with ADHD found that adults administered either drug had improved overall driving performance versus placebo up to 12 hours after dosing [59].

A final emerging area of interest relates to the potential benefits in health-related quality of life of individuals receiving extended-release amphetamine products as part of a treatment regimen to address their ADHD symptoms. Sallee et al. [60] evaluated 2,968 children ages 6–12 years with ADHD in a prospective, open-label multicenter, non-comparative community assessment study and found the MAS XR resulted in an improvement in health-related quality of life (HRQL) as assessed by the Pediatric Quality of Life Inventory ™ 4.0 (PedsQL™) following 7 weeks of treatment. Improvements in the quality of life have also been found in the literature for adults with ADHD [61,62].

4. Safety and tolerability

A synthesis of common and serious adverse effects is provided in Table 3. Although appetite suppression was found as a common side effect for most of the long-acting stimulants in around 10–40% of study participants, weight loss was relatively rare, occurring 1–4% of the time depending on the stimulant less than a kilogram on average [33]. Notably, studies found that, at least for MAS-XR, only appetite suppression was consistently a dose-related side effect [14,34,35]. Less commonly, although still significant in most studies still focusing on MAS-XR, was insomnia occurring at a rate of about 2–30% [40,41,44,45]). Most often, this was mild-to-moderate in intensity [40], but in some cases it was more severe and lead to discontinuation for a handful of subjects [36,48].

Table 3. Safety and tolerability [33], [35], [61–66].

Generic Name	Trade Name	Common Adverse Effects	Serious Adverse Effects
Mixed Amphetamine salts, extended release double bead system (MAS-XR) [34,36]	Adderall XR	Decreased appetite (22%), Insomnia (17%), abdominal pain (14%), vomiting (7%), headache (4%)	Emotional lability (9%), Dizziness (2%), hostility (0.8%)
SHP465 mixed amphetamine salts, extended release triple bead system (SHP465 MAS) [20]	Mydayis	Decreased appetite (22%), Insomnia (8%)	Decreased weight (5%), irritability (6%), dizziness (4%), depression (1%), seizure, hemoptysis
D,L-amphetamine extended release [22]	Dyanavel XR	Dry mouth, decreased appetite, weight loss, nausea, stomach pain (3.8%), trouble sleeping, emotional lability, increased heart rate	Epistaxis (3.8%)
Mixed amphetamine salts extended release (MAS ER) [63]	Adzenys	Decreased appetite (22%), insomnia (17%), abdominal pain (14%)	Weight loss (4%), emotional lability (9%)
Dextroamphetamine [25]	Dexedrine Spansule	Decreased appetite, insomnia, headache, tremors, tachycardia	Dizziness, decreased seizure threshold, blurred vision and other vision changes
Lisdexamphetamine [27]	Vyvanse	Decreased appetite (39%), insomnia, (22%), upper abdominal pain (12%), irritability (10%)	Dizziness (5%), affect lability (3%), anorexia (2%)
Dextroamphetamine [29]	Xelstrym patch	Decreased appetite (12%), insomnia (8%), headache (6%), abdominal pain/vomiting (4%)	Affect lability (3%), irritability (2%)
Dextroamphetamine sulfate [32]	Attentin	Decreased appetite (14%), depressed mood (2%), abdominal pain (1%)	Decreased weight (1%)

Of note, vital signs and growth parameters most often had modest, non-significant changes, even when measured over up to 2 years of treatment [35,42,43].

Most of the studies compared the frequency of Adverse Events or Treatment Emergent Adverse Events (TEAE’s) in subjects taking the Mixed Amphetamine Salts, Extended Release (MAS-ER) with that of subjects taking placebo. There were, however, three studies that compared MAS-ER with another product that had been used to treat ADHD for years [37,43,44]. Wilson et al. [37] compared the efficacy of MAS-ER and OROS MPH on ADHD symptoms but did not compare severity or frequency of Adverse Events. Faraone et al. [43] compared MAS-XR with Atomoxetine in School-aged Children with ADHD. In terms of adverse events, it was found that effects on weight, height and BMI all occurred in the first year of treatment. Finally, Biederman et al. [44] compared MAS ER with Lisdexamfetamine Dimesylate in children with ADHD. In the double-blind part of the study 16% of subjects on Lisdexamfetamine reported AE’s while 18% of subjects on MAS ER reported AE’s as compared to 15% of those on placebo.

5. Regulatory affairs

Amphetamine effects on mood elevation and perceived fatigue reduction led to extensive use by the military during World War II. This subsequently led to similarly common abuse after the war, with reports of widespread addiction in the US, Germany, Japan and Great Britain. Efforts to reduce this problem led to regulations enacted to limit their prescription and better monitor their use. By the late 1960s these activities led to greater control of amphetamine prescriptions and a reduction in their use [8]. Today, there are wide variances in availability and access across countries.

Amphetamine-based stimulants are classified as controlled substances in Australia [64], Canada [65], and the United States of America [66]. In the US, prescriptions are tracked by central pharmacy reporting systems to minimize the possibility of a person receiving the same prescription from several different prescribers. Quantities are also limited, often to a 30-day supply, to help minimize the number of pills available for diversion. In 2014, the European Medicines Agency (EMA) approved dexamfetamine (dexamed) for second line treatment of ADHD, following methylphenidate [67]. In 2022, Lisdexamfetamine had been approved for use by the EMA for treatment of ADHD in children 6 years and up, when response to methylphenidate is determined to be clinically inadequate [68]. The EMA indicates that treatment must be under the supervision of a specialist in child and adolescent behavior disorders and diagnosis must be made according to DSM criteria. Amphetamine is a strictly controlled substance in Japan. It cannot be prescribed or brought into the country when traveling. Lisdexamfetamine can be brought into the country when traveling but cannot be prescribed in Japan [69].

6. Conclusion

Decades of clinical research and use of amphetamine in racemic and single isomer forms has demonstrated its benefit in treatment of ADHD, with other past use as a treatment for depression and weight loss promotion. Multiple studies showed significant improvement in symptoms of attention deficit hyperactivity disorder with mixed amphetamine salts. Original formulations had a half-life of approximately 4 hours, necessitating twice a day dosing. The technologic improvements that support extended action of this medication have likewise shown benefit in symptom coverage for most of the working day. Side effects are well known, typically mild to moderate and usually manageable with dose adjustment, or changes in the time of administration. For example, taking the medication after a meal may lessen the effect of appetite suppression. Appetite suppression was the most common dose-related side effect of MAS ER. Development of novel medications for ADHD continue to rely on pivotal clinical trials comparing the new medication to existing stimulant medications such as amphetamine, emphasizing the continued effectiveness of this treatment category.

7. Expert opinion

As noted in this review, early use of amphetamines (1930’s−1940’s) was directed toward improving depressed mood and increasing alertness and vigilance, with additional potential for use as an appetite reducing weight loss drug. A combination of the development of improved treatments for depression and concerns of medication abuse led to the sole current approved use for the treatment of ADHD. As the condition once known as hyperkinetic reaction of childhood has evolved into the current attention deficit-hyperactivity disorder, this has led to further clinical research on the benefits of treatment along with continued monitoring of adverse events. The present philosophy toward ADHD treatment is to aim for coverage of ADHD symptoms for as much of the day as possible, balanced by adverse effects that are tolerable and manageable.

Providing daylong coverage of symptoms is ideally best done with once daily dosing, as this promotes best adherence to treatment. With once daily dosing, patients are better able to establish a routine for taking their medication at a regular time (usually breakfast) with greater adherence than dosing two or three times daily. Once daily dosing is also easier to achieve as there is no need to have additional medication at school, with authorization for the school to dispense. This leads to less risk of medication being diverted, as well as helping minimize stigma of having to go to the school nurse for midday medication. Once daily dosing also helps provide privacy for adults surrounding personal health concerns.

The immediate release amphetamine products have a slightly longer half-life than the other stimulant class, the methylphenidates, and this has been a factor in physician choice of treatment before today’s current prolonged acting formats. The progress in delayed-release and extended-release technologies has made this less of a factor in choice and re-focused clinician and patient choice on the pharmacokinetics and overall anticipated length of action. Capsules that can be opened and sprinkled for those who have trouble swallowing pills is another factor, and there are two-bead and three-bead products that provide different duration of action. The extended-release tablet Dyanavel XR can be swallowed whole or chewed, facilitating its use.

The various amphetamine medications are not all interchangeable on milligram-to-milligram basis. There are multiple reasons for this. In the case of the prostimulant lisdexamfetamine, it has to do with metabolism converting the prodrug to the active drug. For other amphetamine preparations it is often due to the use of different amphetamine salt compositions (sulfates and saccharates, for example) which have different pharmacokinetic profiles. In other cases a product may be a single isomer (typically dextroamphetamine) rather than the racemic form containing both dextro- and levoamphetamine. Clinically, this is a minor consideration as the overall medication benefits are the same and the newer delivery systems are the primary factor in providing long-acting clinical action. A more pertinent difference is the presence of the l-isomer as it is associated with more cardiovascular effects of increased pulse and blood pressure. While this is generally not a concern in the pediatric age group, as more adults are diagnosed and treated for ADHD this may be an important consideration in clinician selection of treatment.

Article highlights

• Amphetamine treatment for children’s behavior problems was first described more than 85 years ago and remains the pharmacologic treatment for ADHD with the greatest effect size.

• The difference in the levo- and dextroamphetamine effects on attention, hyperactivity, and impulsivity symptoms as well as their differing adverse effects on appetite, sleep, and the cardiovascular system has led to manufacturers developing a variety of formulations of these compounds.

• With a strong evidence base demonstrating effectiveness in treating ADHD, formulations that help support medication adherence such as once daily extended-release formats have become the preferred choice for clinicians and patients.

• The once daily extended-release amphetamine compounds used to treat ADHD are very effective. Adverse events, namely anorexia, insomnia, dry mouth, headache, and abdominal pain are often dose dependent.

• Once daily extended-release amphetamine formulations have not only demonstrated a positive impact on hyperactivity, impulsivity, and inattention but have also demonstrated evidence of improvement in executive function, health-related quality of life, and driving performance.

Declaration of interest

D Coury has received research grant support from GW Biosciences, Stalicla and Stemina and serves on advisory boards for As You Are, BioRosa, Cognoa, GW Biosciences, MaraBio, Quadrant Bioscience, and Stalicla. None of these activities are related to ADHD or its pharmacologic treatment. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

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Funding

This paper was not funded.