Commentary on Ezard et al.: Agonist-based medications for stimulant use disorder—Distinguishing their true colours

Abstract

The study by Ezard et al. [1] is an impactful contribution to the existing knowledge on the role of agonist-based medications (ABMs) for the treatment of psychostimulant use disorders (PSUDs). It adds to evidence on efficacy [2, 3] and safety [3, 4] of this treatment and is innovative in using higher doses of lisdexamfetamine. The results, however, should be interpreted carefully.

The primary outcome did not yield a statistically significant result. The study measured reduction of methamphetamine use during the last 4 weeks of the 12-week follow-up period [1], an outcome that has been adopted by later trials on the topic [5]. Abstinence-based outcomes, such as proportion of participants achieving 3 weeks of abstinence, also did not find statistically significant results. However, the trial found a significant reduction in days of use throughout the whole study, which is noteworthy, given recent attention to non-abstinence outcomes, such as reduction in use, as clinically relevant, for people with substance use disorders [6].

Regarding safety, this study did not find statistically significant differences between groups in adverse events, serious adverse events or any cardiac or psychiatric events—which are commonly associated with psychostimulants and anticipated by prescribers. This adds to mounting evidence of the safety of agonist medications for individuals with PSUDs [4, 7, 8], a major factor to consider their prescription at the community level.

ABMs, including prescription amphetamines, are considered a potential intervention for PSUDs. More recent trials have mitigated longstanding issues such as high attrition rates and inadequate formulation or dosing [5, 9]. This trial is one of the first to evaluate higher dosages of lisdexamfetamine for any PSUDs. Feasibility trials have shown that dosages up to 250 mg of lisdexamfetamine are tolerable and bring no major safety issues [10, 11] for those with PSUDs. This trial is also among the few assessing prescription amphetamines for the treatment of amphetamine-type stimulant use disorder (ATSUD)—a medication class that has shown encouraging results for the treatment of cocaine use disorder, but not sufficiently evaluated for ATSUD.

The burden from stimulants is a pressing issue in many lower-middle income countries (LMICs)—particularly involving cocaine in South America and amphetamine-type stimulants in Southeast Asia [12]. There are currently no approved medications for the treatment of PSUDs by national regulatory agencies while mounting clinical research is being conducted on the development of effective medications to treat PSUDs.

Currently, the best available evidence for PSUDs is for contingency management (CM), a psychosocial intervention that has proven efficacy on promoting abstinence and reducing stimulant use [13, 14]. Despite its efficacy and safety, CM faces implementation challenges [14]—especially in LMICs—because of funding constraint, stigma and a lack of trained professionals [15].

The assessment and future implementation of an effective pharmacological treatment would add to the current therapeutic options especially in areas with elevated prevalence. The #ScaleUp initiative, led by the United Nations Office on Drugs and Crime (UNODC), the World Health Organization (WHO) and the European Union Drugs Agency (EUDA) aims to demonstrate the feasibility of implementing evidence-based psychosocial interventions such as CM in different socio-economic contexts and to support research on new therapeutic approaches for PSUDs [16] through a multisite study. #ScaleUp will contribute to accessibility and diversity of effective treatments for PSUD globally, including LMICs in an equitable way. This is in line with a newly approved resolution of the Commission on Narcotic Drugs [17].

An essential part of the efforts made by #ScaleUp is to coordinate research on pharmacological treatment for PSUDs across study sites and, therefore be able to pool outcome data. The LiMa Trial can inform the development of the #ScaleUp initiative and study protocols as it offers insights and directions about the potential role of ABMs as a therapeutic modality for ATSUD and PSUDs in general.

The study by Ezard et al. [1] does not offer definitive conclusions. Rather, it adds to the existing evidence and raises new questions for future research. Despite the discouraging results for the primary outcome (and most efficacy outcomes), potential uses of ABM in the context of ATSUD include specific scenarios such as acute withdrawal [18] and craving [19]. A recent meta-analysis about ABM for ATSUD has also found mixed results for reduction in ATS use and craving, suggesting a direction on how to explore ABMs as a therapeutic resource to treat ATSUD [3]. Furthermore, the study reinforces mounting evidence suggesting that ABMs for ATSUDs are safer than initially expected.

None.