Advancing the search for efficacious treatment models requires both a critical analysis of past trials’ flaws and a focus on new, innovative approaches to identifying candidate medications in partnerships with pharmaceutical industry to build a strong medication development infrastructure. As noted by McKetin & Farrell [2], attrition bias is a major contributor to poor quality of existing medication trials for CUD. The authors propose strategies to increase treatment retention. While several of these strategies, such as incentivizing participants, are routinely and successfully used in CUD trials, others certainly deserve more attention. For example, the COVID-19 pandemic has forced researchers to rapidly develop strategies to minimize in-person contacts. As a result, the majority of research settings has now established protocols for virtual visits which reduce participant burden related to travel and allow collecting assessments in real time. Other strategies, such as shortening trial duration or requiring an abstinence period at the beginning of a trial, may be less advisable/generalizable. Medications may not immediately show an effect and, alternatively, early responders may relapse later. Thus, observing participants over an extended time-period seems preferable for making predictions about a medication's ‘real-world’ potential. In addition, an initial abstinence period bears an added relapse risk and may deter patients from continued study participation. Attrition bias can be viewed as a methodological flaw related to poor study design and lack of adequate mechanisms to retain participants. However, the fact that this bias is particularly pronounced in trials that target cocaine [3] may also reflect the severity of impairment among individuals with CUD [4], high impulsivity [5, 6] and the lack of pharmacotherapies effective in treating abstinence-related distress. This brings us back to the need for new mechanisms and innovative models to effectively treat CUD beyond simply aiming at a reduction of cocaine use. Shoptaw et al. [7] note the development of a recombinant humanized anti-cocaine monoclonal antibody [8] as a promising way forward. Particularly long-acting agents may offer a more sustainable model of care. In general, longer-acting or extended-release (ER) formulations (taken once a day) seem preferable, as they show greater adherence compared to immediate-release (IR; dosing multiple times per day) [9] medications in addition to having lower potential for misuse [10-12]. For opioid use disorder, even longer-term ER formulations (e.g. monthly naltrexone or buprenorphine depot injection) have shown a protective effect against relapse to opioid use and are generally well tolerated [13, 14]. Given the high relapse and treatment dropout rates among individuals with CUD, the development of longer-term ER agonist medications should be considered. However, in the case of stimulant medications this raises several clinical and research questions regarding effects on sleep or appetite, tolerance development and cardiovascular risks. We strongly agree with Shoptaw et al.’s [7] call for a high-risk/high-reward strategy to engineer new compounds in partnership with the pharmaceutical industry to build the necessary infrastructure. The National Institute on Drug Abuse (NIDA) [15] and their large Clinical Trials Network (CTN), as well as the Food and Drug Administration (FDA) [16], have expressed their interest in and commitment to supporting the development of medications for treating cocaine/stimulant use disorders. This support is crucial to form a stronger lobby for individuals with CUD and other stimulant use disorders to motivate pharma investment in this area. Advancing science and treatment requires both a critical look back to learn from past successes and failures and an optimistic look forward focusing on the most promising avenues to pursue, notwithstanding that the road may be long and winding, as suggested by Humphreys [17]. Hence, we urge researchers not to give up hope in the journey towards identifying efficacious treatments for CUD. As clinicians we would certainly bring the same message and attitude to our patients who struggle with CUD, often for most of their lives. L.B. is funded by an Erwin Schroedinger Fellowship by the Austrian Science Fund (ASF). The authors have no direct financial competing interests on the topic of the article to declare. S.D.C. has received research funding from Alkermes, BioXcel, Braeburn Pharmaceuticals, Cerecor Inc., Corbus, Go Medical, Intra-cellular Therapies, Janssen and Lyndra. In addition, S.D.C. has consulted for: Alkermes, Charleston Labs, Clinilabs, Collegium, Daiichi Sankyo, Depomed, Egalet, Endo, Epiodyne, Inspirion Delivery Sciences, Janssen, KemPharm, Mallinckrodt, Nektar, Neurolixis, Newron, Opiant, Otsuka, Pfizer and Sun Pharma. She also has received honoraria from the World Health Organization and the US Food and Drug Administration. F.R.L. has received research support from US World Meds and acted as an unpaid consultant for Alkermes, Novartis and US WorldMeds. L.B. and T.C. have no competing interests to report.
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