The Rise of Non-Stimulant ADHD Treatments: A Paradigm Shift?

For decades, stimulant medications have led attention-deficit/hyperactivity disorder (ADHD) treatment, but limitations such as suboptimal response rates, comorbid contraindications, and abuse potential are prompting a shift. This article explores the growing role of non-stimulant therapies, including FDA-approved agents such as atomoxetine, guanfacine, clonidine, and viloxazine. With once-daily dosing, reduced risk for abuse, and greater suitability for patients with sleep disturbances or tics, non-stimulants offer compelling alternatives or adjuncts. The article also looks ahead to emerging compounds in late-stage development and highlights the potential for more personalized, mechanism-targeted ADHD care.  

The Emergence of Stimulants for ADHD

Stimulant medications and behavioral interventions have been the foundation of ADHD treatment in children for over 45 years.¹ In 1937, Charles Bradley reported that benzedrine improved behavior in children with behavior problems, and dextroamphetamine was approved for these problems in the same year. Methylphenidate was introduced in 1954, with agents such as Ritalin® seeing increased use while amphetamine use declined. By 1977, 62 placebo-controlled studies had shown the efficacy and general safety of stimulant medications. By 1999, more than 300 well-designed studies had confirmed their benefits. Hundreds more have been published since, supporting their use in persons aged 4 years and older, with the proviso that they are taken at therapeutic doses.¹

Shortcomings of Stimulants

Still, stimulants have important limitations that have become apparent over time, limitations that have led to increased use of non-stimulants and encouraged efforts to develop new classes of ADHD therapy. In particular, 25% to 30% of individuals treated with stimulants either do not experience adequate symptom control or are unable to tolerate these agents. Stimulant use may also be problematic in patients with certain comorbid conditions, including mood disorders (anxiety and/or depression), tics, and sleep or eating disorders. Additional concerns arise in patients needing 24-hour symptom coverage,² as most stimulants have a limited daily duration of action.^2,3 Stimulants are Schedule II substances that carry a substantial risk of nonmedical use or abuse and diversion. In fact, nearly 60% of college undergraduates with active stimulant prescriptions report giving their medication away or selling it. In children, long-term continuous stimulant use has been associated with modest reductions in adult height and increased body weight and body mass index.²

Non-Stimulants: The Paradigm Shift

Non-stimulants currently approved by the US Food and Drug Administration (FDA) for ADHD include the selective norepinephrine reuptake inhibitor (SNRI) atomoxetine, extended-release formulations of the alpha-2 adrenergic receptor agonist clonidine, the alpha-2A adrenergic receptor agonist guanfacine, and the multimodal agent viloxazine, which is an SNRI with serotonergic activity. Among these, only atomoxetine and viloxazine are approved for adult use.^2,4 

As an alternative to stimulants, non-stimulants offer a longer duration of action with once-daily administration (except for clonidine) that allows for around-the-clock symptom control. These agents improve core ADHD symptoms without the dopaminergic activation seen with stimulants that can disrupt sleep.³ In particular, guanfacine and clonidine have calming effects that make them suitable for patients with sleep disorders.^3,5 Non-stimulants act more gradually on norepinephrine, which helps prevent late-day rebound hyperactivity. They are effective in patients with disruptive behavior disorders, tics or Tourette’s disorder, and they are not Schedule II drugs with notable abuse potential.³ Notably, augmentation of stimulants can extend the duration of symptom control and allow for a lower stimulant dose.^3,6 Non-stimulants—in particular, guanfacine and clonidine—are also well suited for patients with sleep disorders.⁵

What the Future Holds

The number of non-stimulant options in the ADHD armamentarium is expected to grow, with agents in Phase 2 and/or Phase 3 development that include monoamine reuptake inhibitors (dasotraline, centanafadine SR, OPC-64005, solriamfetol), receptor modulators (fasoracetam, metadoxine, and oxytocin), and multimodal agents nabiximols (delta-9-tetrahydrocannabinol [THC] + cannabidiol [CBD]) and vortioxetine, along with a lower-abuse-potential stimulant, mazindol controlled release (Schedule IV).^2,7,8 L-methylfolate supplementation has also been examined in adults with ADHD.⁸

Among 90 eligible randomized controlled trials evaluating new agents, centanafadine was the only treatment with replicated positive outcomes across multiple trials (n=4), but effect sizes were small (0.24 to 0.40). Positive results from single trials were also reported for mazindol, OPC-64005, and solriamfetol. Some nonpharmacological interventions also demonstrated positive results, including neurostimulation (repetitive transcranial magnetic stimulation [rTMS], transcranial direct current stimulation [tDCS]), physical activity, dialectical behavioral therapy-based group treatment, internet-based cognitive behavioral therapy, mindfulness-based cognitive therapy, and a self-guided psychological internet-delivered intervention.⁸

Because stimulants have demonstrated large effect sizes in randomized controlled trials for improving core ADHD symptoms, it is unlikely that new agents will surpass them in overall efficacy.⁷ Nonetheless, these emerging treatments may provide similar or improved tolerability.⁷ Moreover, by targeting biological mechanisms that are disrupted in specific subgroups of individuals with ADHD, these agents may represent a step toward more personalized, precision-based pharmacologic approaches rather than a universal one-size-fits-all treatment strategy.⁷

References

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2. Cutler AJ, Mattingly GW, Jain R, O'Neal W. Current and future nonstimulants in the treatment of pediatric ADHD: monoamine reuptake inhibitors, receptor modulators, and multimodal agents. CNS Spectr. 2022;27(2):199-207. doi:10.1017/S1092852920001984
3. Mechler K, Banaschewski T, Hohmann S, Häge A. Evidence-based pharmacological treatment options for ADHD in children and adolescents. Pharmacol Ther. 2022;230:107940. doi:10.1016/j.pharmthera.2021.107940
4. Qelbree. Prescribing information. Supernus Pharmaceuticals. Revised January 2025. Accessed May 12, 2025. https://www.supernus.com/sites/default/files/Qelbree-Prescribing-Info.pdf
5. Neuchat EE, Bocklud BE, Kingsley K, et al. The role of alpha-2 agonists for attention deficit hyperactivity disorder in children: A review. Neurol Int. 2023;15(2):697-707. doi:10.3390/neurolint15020043
6. Dey A, Do TL, Almagor D, Khullar A. Managing comorbid sleep issues in patients with attention-deficit/hyperactivity disorder. CMAJ. 2025;197(12):E323-E324. doi:10.1503/cmaj.241262
7. Nageye F, Cortese S. Beyond stimulants: a systematic review of randomised controlled trials assessing novel compounds for ADHD. Expert Rev Neurother. 2019;19(7):707-717. doi:10.1080/14737175.2019.1628640
8. Veronesi GF, Gabellone A, Tomlinson A, Solmi M, Correll CU, Cortese S. Treatments in the pipeline for attention-deficit/hyperactivity disorder (ADHD) in adults. Neurosci Biobehav Rev. 2024;163:105774. doi:10.1016/j.neubiorev.2024.105774