Participants in DEI will perform their exercise sessions on a Life Fitness 95T-seriesTreadmill (Schiller Park, IL). Prescribed exercise doses and intensities will be ramped over the initial 3 weeks of the study to allow for a gradual familiarization to the study protocol and the accompanying physical demands (see Table 1). Exercise intensity will be based on a percentage of the maximum heart rate (HR) achieved during the baseline maximal exercise test. The 12 kilocalories*kilogram of bodyweight^-1 * week^-1 (KKW) weekly exercise dose was chosen to approximate public health dose guidelines http://www.health.gov/paguidelines (i.e., approximately 30-50 min, 3-5 days per week). Participants will be scheduled to complete their weekly exercise dose over three exercise sessions. However, additional exercise sessions can be scheduled for those needing more than three sessions per week to achieve their target dose.

During the supervised exercise sessions, participants will perform an active warm-up for 5 minutes prior to initiation of the exercise prescription. Polar RS 400 HR monitors (Kempele, Finland) will be used to continuously monitor participants' heart rate (HR) throughout the exercise session to ensure that they are within their target HR zone (i.e., 70-85% of an individual's HR_max). Typically, participants can achieve a HR of 70-85% by either walking briskly at an incline or by running at zero incline. The speed and/or grade of the treadmill will be continually adjusted to maintain participant HR within the target HR zone while allowing the participants some flexibility in customizing their exercise session. A global Rating of Perceived Exertion (RPE), assessed using Borg's RPE scale, will be taken at the conclusion of each exercise session. At the completion of the exercise session, participants will perform an active cool down (0 grade and 50-70% of speed) until their HR returns to within 15% of their resting value. Participants will then be led through a 5-10 minute stretching routine.

During the continuation phase, participants will complete one supervised exercise session per week at the CTP exercise facility with the remainder of their exercise dose to be completed in unsupervised exercise sessions. Exercise Facilitators will aid the participant in identifying a safe location for completing their unsupervised sessions, scheduling these sessions, and planning other practical concerns related to engaging in exercise during the continuation phase. Participants will also receive assistance in developing measured exercise courses to allow for estimates of time and distance covered at each unsupervised session. Participants will record a global RPE score at the end of each unsupervised exercise session.

Those who are not safe to exercise, including those with greater than Stage 1 hypertension will not be randomized. Prior to each exercise session, participants will sit undisturbed for 5 minutes before assessment of their resting heart rate and blood pressure (BP). If a participant's resting HR is ≥ 100, it will be re-measured after an additional 5-minute rest period. If a participant's resting HR remains ≥ 100, the exercise session will be rescheduled for another day. Likewise, if a participant's resting BP is ≥ 160/100, it will be re-measured after an additional 5-minute rest period. If a participant's resting BP remains ≥ 160/100, the exercise session will be rescheduled for another day. During the session, BP will be assessed after 5 minutes to monitor for adverse responses to the onset of the exercise. BP will continue to be monitored if an exaggerated acute response is observed (i.e., SBP > 200 mmHg). The exercise session will be halted if an extreme BP response (SBP > 250 mmHg or remains unchanged despite an increase in workload, or DBP increase > 15 mmHg) is observed. Following the cool down, a final BP will be taken before the participant is cleared to leave the facility. Guidelines are also present for referral to appropriate medical care and additional physician clearance based on blood pressure readings.

At screening, standard demographic information will be collected from all participants (e.g., gender, race, ethnicity, etc.). Contact information will be obtained and updated monthly and additionally as needed. DSM-IV-TR alcohol and substance abuse and dependence will be assessed with the substance use modules of the World Health Organization (WHO) Composite International Diagnostic Interview (CIDI) (Version 2.1)[⁵⁵,⁵⁶]. Additional DSM-IV Axis I diagnostic information will be obtained using the MINI International Neuropsychiatric Interview (MINI)[⁵⁷].

Medical history will be obtained using a self-report medical history form designed to collect information about history and/or treatment of medical conditions, such as heart disease, high blood pressure, diabetes, and cancer. The form also assesses allergies, past surgeries, tobacco and alcohol use, family history of medical conditions, medical symptoms over the past 30 days, and prior and concomitant medications. Additionally, participants will complete the Self-Administered Comorbidity Questionnaire (SCQ)[⁵⁸] and the Physical Activity Readiness Questionnaire (PAR-Q)[⁵⁹]. Medical personnel will conduct a medical history and physical exam, and laboratory tests (chemistry, hematology, lipid profile, and urinalysis) will be obtained as part of the medical screening process.

Maximal exercise testing will be conducted during the screening process to examine cardiorespiratory responses in order to rule out ischemic response to exercise (with its implications of cardiovascular disease), to identify participants for whom exercise might be hazardous, and to provide data for the exercise prescription. The test will be repeated at the end of the 12-week acute phase (or during an early termination visit). A trained technician will process the test data and a report will be generated that contains the following information: 1) participant's symptoms before, during, and after testing; 2) maximal heart rate achieved and percent of predicted maximal heart rate achieved; 3) time on treadmill and estimated maximal metabolic equivalent (METS) achieved; and 4) ECG interpretation. A designated medical staff member will be responsible for reviewing the participant's medical history and evaluating results from the medical exam, maximal testing, and lab results to determine whether or not the participant is medically cleared to exercise.

Eligible participants complete a comprehensive baseline assessment. Since there are numerous baseline assessments, these may be distributed over more than one day if necessary. The frequency and type of ongoing assessments are equivalent in both groups, with the exception of blood pressure and heart rate obtained for exercise participants prior to every supervised exercise session. Descriptions of ongoing study assessments are described by category below (as well as in Table 2).

The Timeline Followback [⁴⁸,⁴⁹] and Substance Use Diary (SUD) will be used to acquire information on alcohol and drug use, including cocaine and other stimulants. The TLFB is a semi-structured interview that uses a calendar to prompt participants to provide retrospective estimates of their daily drug use over a specified period of time that can vary up to 12 months before the interview date. The measure provides prompts to facilitate accurate recollection of use behavior. The SUD, a pocket calendar given to participants at the beginning of the study to prospectively record substance use, will assist with accurate recall when completing the TLFB at each study visit.

Qualitative urine drug screens (UDS) will be conducted at baseline, three times a week in the first 12 weeks, and once a week in the subsequent 6 months. The screen will test for the following substances: marijuana, cocaine, opiates, amphetamine, methamphetamine, benzodiazepines, barbiturates, methadone, methylenedioxymethamphetamine (MDMA, Ecstasy), and oxycodone. UDSs will also be used to corroborate information on the TLFB.

The Addiction Severity Index-Lite (ASI-Lite) will be administered by research staff to examine multiple domains that are commonly affected by substance use, including medical, employment/self-support, alcohol/drug use, legal status, family/social, and psychiatric status [⁶⁰]. Stimulant craving (cocaine, methamphetamine, and other stimulants) will be assessed using the Stimulant Craving Questionnaire-Brief (STCQ-Brief; adapted from Sussner et al. [⁶¹] and derived from the 10-item Cocaine Craving Questionnaire-Brief and the original 46-item Cocaine Craving Questionnaire-Now [⁶²]). Signs and symptoms of stimulant (cocaine, methamphetamine, and other stimulants) abstinence will be evaluated using the Stimulant Selective Severity Assessment (SSSA; adapted from Kampman et al. [⁶³]). Baseline nicotine dependence will be evaluated using the Fagerstrom Test for Nicotine Dependence (FTND)[⁶⁴,⁶⁵] and number of cigarettes smoked per day will be captured on the TLFB.

Symptoms of depression will be measured by the Quick Inventory of Depressive Symptomatology - Clinician Rated version (16-item)[^66-70], and the Snaith-Hamilton Pleasure Scale (SHAPS)[⁷¹] will be used to measure anhedonia. Suicidality and related symptoms will be evaluated throughout the study using the Concise Health Risk Tracking - Self-Report (CHRT-SR), and the Concise Associated Symptoms Tracking - Self-Report (CAST-SR).

Psychosocial assessments will include the Quality of Life Enjoyment and Satisfaction Questionnaire Short Form (Q-LES-Q-SF [⁷²]), the Short-Form Health Survey (SF-36 [⁷³,⁷⁴]), and the Pain Frequency, Intensity and Burden Scale (P-FIBS). Assessments of cognitive function will include the Stroop Color and Word Test [⁷⁵,⁷⁶], a measure of attention response inhibition, and the MGH Cognitive and Physical Functioning Questionnaire (CPFQ [⁷⁷]), a measure of subjective cognitive function. The Wechsler Test of Adult Reading (WTAR [⁷⁸]) will be administered at baseline to assess premorbid intelligence.

Physiological measures include height, weight, body mass index (BMI), and waist circumference. For those participants in the exercise intervention, resting heart rate and blood pressure will be obtained prior to each exercise session using the Exercise Readiness Form in order to evaluate safety to exercise. Resting heart rate and blood pressure will be obtained for all participants during the maximal exercise test. The maximal exercise will be repeated at week 13 to assess change in fitness.

The Treatment Participation Questionnaire (TPQ), a five-item self-report that assesses the participant's likelihood of remaining in treatment for substance abuse and continuing to attend study visits, will be administered at baseline and then weekly thereafter. Since this study is designed as an intent-to-treat study, subjects will be encouraged to complete assessments regardless of their status in their treatment programs or their engagement in the study intervention.

The primary analysis will compare the primary outcome between the two treatments taking into account possible variability in the overall level of abstinence between sites. More specifically, we use a mixed normal model with a fixed treatment effect and random terms for site and error. The model considers treatment effect to be the same in each site. P-value less than 0.05 will be considered statistically significant. The assumed treatment effect μ_VIHD-μ_HEC is 0.15. The error standard deviation σ is considered to be in the range between 0.40 and 0.45, and abstinence status within participant is assumed to be correlated across days. The primary endpoint will be analyzed on an intent-to-treat basis, meaning that participants' data will be analyzed according to the group they were randomized to, regardless of the subsequent sequence of events (e.g., noncompliance to the intervention).

Even though the overall level of outcome may differ across sites (i.e. σ_site > 0), the primary analysis removes this variation by adjusting for site in the model. Hence, initial sample size computations are based on value of error standard deviation σ and the sample size estimates are based on a two sample t-test formula. A treatment effect that varies across sites may contribute additional variation and simulations with primary analysis performed for each simulation were used to investigate this possibility. Based on these simulations, and as an additional precaution, we increased initial sample size by 10% to attempt to take into consideration potential treatment effect variability. Based on these considerations, we proposed the trial to enroll 330 participants. Clearly, the proposed sample size depends on accurate estimation of variability σ. We propose to reassess this variability midway through the study, i.e., after approximately 165 participants have enrolled and completed the acute phase of the trial, and may readjust needed sample size if the variance assumption proves incorrect.

We selected the use of aerobic exercise in this trial. While there is some evidence that other types of exercise (e.g., weight training) may be beneficial to individuals with other disorders, such as depression, the preponderance of existing evidence supports the use of aerobic exercise. Furthermore, aerobic exercise has been used in previous interventions involving substance abuse disorders [^7-11,¹⁸].

A 12 KKW dose of exercise was selected for this study for the following reasons: 1) it is consistent with U.S. 2008 Physical Activity Guidelines http://www.health.gov/paguidelines, as well as prior recommendations from groups such as the Centers for Disease Control and Prevention and ACSM [^79-83], the NIH Consensus panel [⁴⁵,⁷⁹,⁸⁰,^82-86], and the U.S. Surgeon General (U.S. Department of Health and Human Services [⁸⁷]); 2) it has been used in previous studies involving physical activity interventions in smokers [⁷,⁹], and in other disorders such as depression [⁵⁴,^88-91], it is consistent with doses associated with biological changes that we hypothesize will impact stimulant use such as alterations of the serotonergic [^92-94] and endocannabinoid systems [⁹⁵], attenuated stress responses [⁹⁶,⁹⁷], and increases in release of BDNF [⁹⁸].

An intensity range of 70-85% of an individual's HR_max was selected for this study. This intensity is above the suggested minimum intensity of 50% of HR_max and within the currently recommended training intensity guidelines for producing physiological adaptations and benefits [⁵¹]. Although higher exercise intensities may produce greater changes in outcomes at a constant dose, for this efficacy trial we want to be certain that we are well within standard exercising ranges for both dose and intensity. By selecting a range of 70-85% of HR_max, we have allowed for some exercising flexibility to increase comfort, while ensuring that all participants are exercising above the minimum recommended threshold.

Alternatively, we could have allowed participants to select their own exercise intensity (i.e., self-selected intensity based on rating of perceived exertion) as long as they achieved the target dose. While this approach would allow significantly greater flexibility for participants, it would likely lead to greater variations in exercise intensity. Another alternative would be to have a fixed exercise intensity (i.e., 80% HR_max) to maximize the standardization of the exercise intervention. However, a fixed intensity would allow little flexibility for participants to find a comfortable exercise level and may, therefore, result in poor adherence and increased drop-outs.

In this study, we recommend that participants complete their prescribed weekly exercise dose over three exercise sessions per week. However, we will allow up to two additional sessions per week in order to accommodate variations in baseline fitness levels. Individuals who are more unfit will have a relatively low caloric expenditure rate when exercising within their relative intensity range (as demonstrated by elevated HRs at low treadmill settings). This will require them to exercise for a greater duration to achieve their weekly exercise dose than individuals who have higher baseline fitness levels. For example, a participant exercising at 70% of their HR_max might require 150 min/week (50 min/session for three sessions/week) to achieve the 12 KKW dose, whereas a less fit participant might require 240 min/week to achieve the same 12 KKW dose due to differences in exercise efficiency and their individual responses to exercise. Therefore, it benefits the second participant to divide their exercise dose among four or five sessions, thereby increasing the feasibility of completing each exercise session and achieving the weekly exercise dose.