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 groups will be: (1) non-drug-users (NDUs), (2) current opioid/stimulant users (COSUs), and current marijuana users (CMUs). All groups will be roughly matched for socioeconomic status and neighborhoods of residence. Each participant will attend a 5-hour initial study visit and a 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 and utilization), physical and mental health (including quality of life, dental health, pain, sexual function, sleep, HIV, trauma). The biological component will consist of samples of urine (for drugs of abuse, cotinine, microalbumin), breath (for alcohol and carbon monoxide), saliva (for alpha-amylase and cortisol), and blood (for liver function, kidney function, HGBA1C, DHEA-S, lipids, CRP, pre-albumin, cortisol, and lipid biomarkers). Blood for genetics will be obtained at Visit 1 or Visit 2. Blood and urine for the levamisole secondary study will be collected at Visit 1 and/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; lipid biomarkers; medical, psychiatric, and social determinants of health; hematologic markers corresponding to medical conditions; measure of cumulative stress burden (allostatic load); personality assessment; and the relationships among levels of autoantibodies, levamisole, and cocaine metabolites. Individuals who choose not return for a 12-month Visit #2 will be asked to complete a 45-minute telephone visit #2. Individuals in Group 1 (NDU) will also be offered an optional 8-hour laboratory stress session (472 Stress Exposure and Response Session A: 472 SEARSA). The 472 SEARSA session will occur on a separate day, under a separate consent, and will consist of color-vision testing and the Paced Auditory Serial Addition Task (PASAT-C), a psychological stressor. The 472 SEARSA session replicates the 09-DA-N020 Stress Exposure and Response Session A, which is conducted with methadone-maintained opioid-dependent participants, and will thereby provide a non-drug-using neighborhood-matched control group for comparison of stressor reactivity and color vision. 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 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 provide urine and breath samples, complete questionnaires, and upload data from their devices.