Commentary on Ezard et al.: Prescribed psychostimulant medications for methamphetamine use disorder – an urgent path forward

Over the last decade, methamphetamine-related hospitalizations, emergency visits and fatalities have steadily increased in the USA [1], highlighting a growing public health crisis. Despite these trends, no medication for stimulant (methamphetamine or cocaine) use disorder (StUD) has yet received approval by the US Food and Drug Administration (FDA). While psychosocial interventions effectively reduce stimulant use [2], their adoption in community settings in the USA remains challenging [3, 4].

Given the critical gap in treatments for StUD, researchers and clinicians have looked to the medical model used in opioid use disorder (OUD) care, where the prescribed opioid agonists methadone and buprenorphine serve as first-line therapies – reducing illicit opioid use, lowering overdose risk and improving quality of life. This successful approach prompted parallel efforts to explore agonist-based treatments for methamphetamine and cocaine use disorders, with prescription amphetamines and methylphenidate as the main candidates. Although initial attempts with prescribed amphetamines as substitution therapy in the 1960s–1970s were unsuccessful, owing to safety concerns, subsequent efforts in the 1990s in the UK – drawing on methadone maintenance experience – showed more favorable outcomes [5]. Around the same time in the USA, case series and early controlled studies [6, 7] indicated the feasibility, safety and benefits of an agonist-based approach for StUD, prompting calls for further systematic research [8]. This debate on the merits of such an approach has persisted for the past three decades [9].

Over that period, numerous controlled trials, and subsequent systematic reviews and meta-analyses, have explored agonist-like medications in StUD treatment; with prescription amphetamines demonstrating promise for cocaine use disorder, and with methylphenidate showing benefits in methamphetamine use disorder [10-14]. The latest study by Ezard and colleagues [15] adds to this body of evidence by indicating that high-dose prescription amphetamines can have small but significant benefit for individuals with severe methamphetamine use. Generally, higher doses of stimulant medications have produced more favorable outcomes than lower doses [11, 14], indicating a dose–response relationship, consistent with an agonist-type mechanism. This highlights the importance of dose optimization and calls for caution when interpreting negative findings from lower-dose trials. Nonetheless, high attrition rates, heterogeneity in outcomes and difficulties with medication blinding contribute to the overall low quality of evidence [11].

Although safety has been a key concern in repurposing stimulants for StUD, clinical trials to date indicate that severe adverse events are no more frequent in participants receiving prescribed stimulants than among those given placebo [11, 14]. Ezard et al. [15] have added further support to the safety of an agonist approach by demonstrating the tolerability of lisdexamfetamine at doses of up to three times the maximum approved dosage for other indications (70 mg/d). These findings suggest some degree of tolerance among regular amphetamine users, mirroring the tolerance seen with high-dose methadone in OUD treatment. Nevertheless, prescribers may be hesitant to use higher stimulant doses, echoing methadone underdosing practices, owing to safety concerns. At the same time, higher doses of prescribed stimulants could carry greater adverse-effect risks than opioid agonists, emphasizing the need for careful patient selection until additional real-world data are available.

High dropout rates remain a major hurdle in StUD clinical trials, reflecting the real-world difficulties of patient retention. Unlike opioid agonists, prescription stimulants have shown little impact on keeping patients in care [11, 14], and Ezard et al. [15] similarly found no improvement in retention with lisdexamfetamine under minimal psychosocial support. As psychosocial interventions can help reduce dropout [2], combining them with agonists might be considered to maximize treatment benefits [16].

Drawing on systematic evidence, in 2023 leading US professional societies released guidelines [17] recommending that clinicians consider long-acting amphetamine and methylphenidate formulations for StUD, particularly in individuals with co-occurring attention-deficit/hyperactivity disorder (ADHD), and noting that doses at or above the FDA-approved maximum for ADHD may provide stronger benefits. In light of these guidelines and the urgent public health need in the USA, there is growing support for community-based prescription stimulant treatment for StUD, particularly in addiction specialty settings [17, 18], which has also gained traction internationally [19]. However, implementing treatment in clinical settings must be accompanied by rigorous effectiveness, pragmatic, and implementation research, to identify which populations benefit most and how to maximize safety and adherence, refine individualized dosing, explore the impact of concurrent behavioral intervention and determine treatment duration, for sustained benefits.

Finally, by adopting a medication-based treatment for StUD, we can reduce stigma, encourage more individuals to enter treatment, and better integrate care within mainstream healthcare and psychiatry, particularly for patients who face multiple co-occurring conditions.

Adam Bisaga is the sole author of this commentary.

None.

No funding to report.