Experimental design and methods: This is a three-group observational study with a cross-sectional component and a longitudinal component: each participant will be assessed in two visits spaced approximately 12 months apart. The three main groups will be: (1) non-drug-users (NDUs), (2) current opioid/stimulant users [(COSUs) comprised of two subgroups: treatment seeking (COSU-TS) and non-treatment seeking (COSU-NTS)], and current marijuana users (CMUs). All groups will be roughly matched for socioeconomic status and neighborhoods of residence. Each participant will attend a 3-5-hour initial study visit and a 3-5-hour 12 month visit #2. The study visits will include a questionnaire component and a biological-sample component. Questionnaires will cover substance use, stress, social stability (including healthcare access/utilization, and neighborhood environment), physical and mental health (including quality of life, HIV, and trauma). The biological component will consist of samples of urine (for drugs of abuse and cotinine), breath (for alcohol and carbon monoxide). Blood for genetics will be obtained at Visit 1 or Visit 2. The primary outcome measures will be lifetime substance-misuse history (cross-sectional component) and changes in drug-use status across the 12 months between visits (longitudinal component). Secondary outcome measures will include: biological assessments of drug use; medical, psychiatric, social determinants of health; and impulsivity and decision-making factors. Individuals who choose not to return for a 12-month Visit #2 will be asked to complete a 45-minute telephone visit #2. In the HON EMA/GMA secondary study participants will carry a smartphone and a GPS unit (if necessary) for up to 4 weeks after completing Visit 1. Event-triggered entries will be initiated by participants (1) each time that they use a drug (COSU) or marijuana and/or alcohol (NDU, CMU, and Unclassified) and (2) each time they feel overwhelmed, anxious, or stressed more than usual. Participants will also make 5 random-signal-triggered recordings per day and one brief end of day recording. During this study participants will also come to the clinic once a week to complete compliance visits.