Considering rationales for use in defining subgroups for the treatment of stimulant use disorder

We followed the series of systematic reviews of pharmacotherapy for stimulant use disorder by Chan et al. with interest and were intrigued by their most recent meta-analysis (1), focusing on treatment options for a subgroup of patients with comorbid opioid use disorder. Although the results were largely negative, we laud the authors for their attempt to study specific subgroups within the heterogeneous population of people with stimulant use disorder. The burden of stimulant use is increasing globally (2), and patients with concurrent opioid use disorder represent only one of many potentially important subpopulations. The concept of studying subgroups separately within stimulant use disorder has been gaining traction (3,4), and many substance use and demographic variables have been suggested as a means to separate distinct populations for study (3,4). We believe, however, that characterizing individual rationales for stimulant use and distinguishing patients based on these rationales may have important clinical implications.

Qualitative literature (5–7) has mirrored our clinical experience suggesting that people often use stimulants for a specific functional goal. Effects being sought may include mental alertness, weight loss, sexual enhancement, and synergy with other drugs, among others. When stimulant replacement trials are unsuccessful, parallels are often drawn with opioid agonist treatment (OAT). However this comparison overlooks a key difference between the chronic use of opioids and stimulants: a common endpoint that drives a significant component of opioid use is staving off withdrawal, which agonist therapies treat extremely effectively. Although withdrawal can similarly be experienced with frequent stimulant use, the factors driving continued use may be more nuanced and often have functional undertones.

We propose that stratifying patients based on the function being sought from stimulants will be central to determining what treatment will be effective. For example, some OAT patients may use illicit stimulants to counteract the sedating effects of OAT (5). Prescription psychostimulants may help achieve this effect, which could explain the weak signal for reduction in use with psychostimulants seen in this meta-analysis (1). Furthermore, by mitigating side effects of OAT, psychostimulants may keep patients engaged in treatment for opioid use disorder (8). The potential value in studying subgroups has also been signaled in mirtazapine trials that demonstrated reduction in methamphetamine use among men who have sex with men commonly using methamphetamine for sexual enhancement (9,10). This is contrasted with the largely negative antidepressant trials among the methamphetamine-using population as a whole (11), though a similar effect of mirtazapine in other populations is yet to be explored. Furthermore, for precariously housed patients using stimulants as a survival mechanism, the best approach may not be pharmacotherapy at all, but rather addressing their housing needs (12,13).

We encourage investigators to consider using specific reasons for use as inclusion criteria or covariates in future trials for stimulant use disorder to permit elucidation of promising results in select subgroups and to facilitate focused meta-analyses. We commend Chan et al. for their novel approach in this meta-analysis for stimulant use disorder pharmacotherapy.