ADHD Meds: Stimulants vs. Non-Stimulants and What Trials Show

ADHD meds come in two FDA-approved classes. Stimulants contain forms of methylphenidate or amphetamine, and the four non-stimulants are Strattera (atomoxetine), Intuniv (guanfacine), Kapvay (clonidine) and Qelbree (viloxazine)^[3]. Both are approved to help reduce the symptoms of ADHD, which center on inattention, hyperactivity and impulsivity^[3].

The evidence base is large. A 2018 network meta-analysis in The Lancet Psychiatry pooled 133 double-blind randomized trials and found that every drug studied beat placebo on clinician-rated symptoms in children and adolescents at about 12 weeks^[1]. The American Academy of Pediatrics (AAP) puts the average effect size at 1.0 for stimulants and 0.7 for non-stimulants^[2].

Stimulants account for most real-world use. In a 2023 CDC survey, 33.4% of U.S. adults with current ADHD had taken a prescription stimulant in the past year, against 5.9% who took a non-stimulant^[7]. Prescription trends and the recent stimulant shortage are covered in ADHD medication statistics; this guide covers what the drugs are and what the research says about them.

The FDA's approved list contains only these stimulants and four non-stimulants, so supplements and over-the-counter products marketed for focus are not FDA-approved ADHD treatments^[3].

Stimulants have the larger evidence base; the AAP describes the non-stimulants as newer drugs with considerably less supporting research^[2]. The FDA names Ritalin and Concerta (methylphenidate), Adderall (amphetamine/dextroamphetamine) and Dexedrine (dextroamphetamine) as common examples^[4].

Vyvanse (lisdexamfetamine) is a prodrug that the body converts to dextroamphetamine. It is approved for ADHD in adults and children 6 and older, and for moderate to severe binge eating disorder in adults^[6].

Release format also differs. Immediate-release stimulants are usually taken two or three times a day, and extended-release versions once a day^[4].

Response varies by person. The AAP reports that about 40% of children respond to both methylphenidate and amphetamine, and about 40% respond to only one^[2]. In the MTA study, more than 70% of children and adolescents responded to methylphenidate when a full range of doses was tried^[2].

Every prescription stimulant carries the FDA's Boxed Warning on misuse, abuse and addiction, and Vyvanse is a prodrug of amphetamine, a Schedule II controlled substance^[4][6].

Four non-stimulants have FDA approval for ADHD: atomoxetine, guanfacine, clonidine and viloxazine^[3]. Atomoxetine and viloxazine are selective norepinephrine reuptake inhibitors, while extended-release guanfacine and clonidine are alpha-2 adrenergic agonists^[2][5].

The evidence for them is thinner. The AAP rates it sufficient but less strong than for stimulants, in the order atomoxetine, extended-release guanfacine, then extended-release clonidine, with effect sizes around 0.7 for all three^[2].

Viloxazine was first approved in 2021^[5], after the AAP guideline was published in 2019^[2]. Its labeling was revised in April 2022 and now covers adults and children 6 and older^[5].

Extended-release guanfacine and clonidine are the only drugs with enough evidence to win FDA approval as add-ons to a stimulant^[2]. Because blood pressure can rebound when they are stopped abruptly, the AAP says they should be tapered^[2].

For children aged 4 to 5, no non-stimulant has been studied enough to be recommended^[2]. The AAP names methylphenidate as the first-line medication only after behavioral parent training, and notes that its evidence in this age group has not reached the level needed for FDA approval^[2]. The ADHD in children page covers diagnosis rates in that group.

No single drug is best for everyone, but the largest comparative analysis does rank them. Weighing efficacy and tolerability together, Cortese and colleagues concluded that the evidence "supports methylphenidate in children and adolescents, and amphetamines in adults, as preferred first-choice medications for the short-term treatment of ADHD"^[1].

Amphetamines produced the largest symptom reductions on clinician ratings, beating modafinil, atomoxetine and methylphenidate in head-to-head comparisons in both age groups^[1]. They were also harder to tolerate: dropout due to side effects was higher than with placebo in children (odds ratio 2.30) and adults (odds ratio 3.26)^[1].

Teacher ratings were narrower. Only methylphenidate and modafinil beat placebo in the teacher-rated comparisons available^[1]. Modafinil is not on the FDA's list of approved ADHD drugs^[3].

The main gap is time. The analysis found insufficient data at 26 and 52 weeks^[1]. The AAP also found too little evidence to support pharmacogenetic tests for picking a drug and does not recommend them^[2].

Adults are treated with the same two classes, and the trial evidence favors amphetamines. In the 2018 meta-analysis, amphetamines, methylphenidate, bupropion and atomoxetine all beat placebo in adults on clinician ratings, while modafinil did not^[1]. Methylphenidate, atomoxetine and modafinil were less well tolerated than placebo in adults, a gap not seen in children^[1].

Several products carry explicit adult indications, including Vyvanse and Qelbree^[6][5]. The adult Qelbree dose range runs higher than the pediatric one, to a maximum of 600 mg once daily versus 400 mg for children^[5].

In the 2023 CDC survey, 50.4% of adults with current ADHD had been prescribed ADHD medication in the past year^[7]. Since March 2020, 30.5% had used telehealth to get an ADHD prescription, under temporary federal flexibilities for prescribing stimulants remotely that began during the COVID-19 pandemic^[7].

Adult prevalence and diagnosis figures are on the ADHD in adults page.

The AAP lists appetite loss, abdominal pain, headaches and sleep disturbance as the most common short-term effects of stimulants^[2]. The FDA adds irritability, fast heart rate and high blood pressure^[4].

On average, heart rate rises by 1 to 2 beats per minute and blood pressure by 1 to 4 mm Hg, but 5% to 15% of people show larger increases^[2]. The AAP states that stimulants have not been shown to raise the risk of sudden death beyond that seen in children who do not take them^[2].

Growth is a known effect in children. In the MTA study, height ended 1 to 2 cm below predicted adult height, mostly among children on higher, more consistent doses^[2]. Hallucinations and other psychotic symptoms are uncommon but significant^[2].

Why some people get talkative on ADHD meds

The Vyvanse label lists logorrhea, or excessive talking, among the less frequently reported adverse reactions that led to discontinuation in a pediatric trial^[6]. Research on how often stimulants make people more talkative, and why, is limited.

Non-stimulant side effects

Atomoxetine can cause initial sleepiness, stomach upset and decreased appetite, and carries an FDA boxed warning for suicidal thoughts^[2]. Qelbree carries a boxed warning on suicidal thoughts and behaviors, and its most common adverse reactions in adults were insomnia, headache, sleepiness, fatigue, nausea, decreased appetite, dry mouth and constipation^[5].

Extended-release guanfacine and clonidine are associated with sleepiness, dry mouth, dizziness, irritability, a slow heart rate and low blood pressure^[2].

Misuse and sharing

The FDA's 2023 update to the class-wide Boxed Warning followed a review finding that 56% to 80% of people who misuse prescription stimulants get them from friends or family^[4]. Past-year nonmedical use was highest among young adults aged 18 to 25 (4.1% to 7.5%) and among adolescents and young adults diagnosed with ADHD (14% to 32%)^[4].

Trial data beyond 12 weeks are sparse^[1], so long-term evidence comes mainly from national registries. A Swedish case-control study of 278,027 people with ADHD found that each additional year of medication use was associated with a 4% higher risk of cardiovascular disease, especially hypertension and arterial disease^[9].

That risk increase was concentrated in the first 3 years of cumulative use and then held steady over up to 14 years of follow-up^[9].

A second Swedish cohort of 148,578 people found that starting medication within 3 months of diagnosis was associated with lower all-cause mortality over 2 years (hazard ratio 0.79)^[8]. The difference came mainly from deaths due to unnatural causes, a category that includes injuries and accidental poisonings (hazard ratio 0.75)^[8].

Both findings are associations. Registry designs cannot fully separate the effect of a drug from differences between people who take it and people who do not.

Stopping ADHD meds has measurable effects, but not for everyone. In a 2019 randomized trial in the American Journal of Psychiatry, 94 children and adolescents who had taken methylphenidate for more than 2 years either continued it or were tapered to placebo^[10].

After 7 weeks, 40.4% of the discontinuation group had worsened, compared with 15.9% of those who stayed on the drug^[10]. The authors concluded that some patients can stop without deterioration, which supports periodic checks on whether medication is still needed^[10].

The Vyvanse label describes physical dependence. After abrupt discontinuation or a dose cut following prolonged use of CNS stimulants, it lists withdrawal signs including low mood, depression, fatigue, vivid unpleasant dreams, insomnia or oversleeping, increased appetite, and slowed movement or agitation^[6].

For guanfacine and clonidine, the AAP recommends tapering to avoid rebound hypertension^[2].