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BackgroundNovel treatments for substance use disorders are needed. Acute bouts of exercise can improve mood states and craving in nonclinical populations. Exercise effects in those with polysubstance dependence are understudied; controlled trials are needed. ObjectiveThis protocol describes a clinical study examining the short-term psychological effects of 2 types of physical activity, soccer and circuit training, in patients with substance use disorders. Effects will be compared with a nonexercise control group. Specific aims are to investigate whether there are differences between the activities and the duration of changes. MethodsThis study is a short-term multicenter randomized control trial with a crossover design. Patients consecutively admitted to 4 inpatient treatment centers were invited to participate in 3 conditions, each lasting 45 minutes, within one week. The order of the conditions was randomized. There were a total of 5 assessments, taken at baseline, immediately before each condition, immediately after each condition, and 1, 2, and 4 hours postintervention, enabling patterns of change over time to be observed. Psychological effects were assessed with self-report questionnaires, which included scales for craving, state anxiety, positive and negative affect, self-esteem, and mood. Exercise intensity was assessed with the Borg Rating of Perceived Exertion scale and a heart rate monitor (Polar M200; Polar Electro Ltd). Cortisol was assessed in saliva before and 4 hours after the intervention. ResultsA total of 39 patients were included in the study. Data collection was completed in 2019. ConclusionsWe anticipate larger improvements in the intervention groups than among controls, indicating positive psychological effects during and after exercise. The study will add clinically relevant information about the short-term psychological effects of exercise in the treatment of substance use disorders, using activities that are easily accessible in different clinical settings. Trial RegistrationGerman Clinical Trials Register DRKS00018869; https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00018869 International Registered Report Identifier (IRRID)DERR1-10.2196/18553