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We received funding through the National Institutes on Drug Abuse\u2019s Helping to End Addiction Long-Term (HEAL) initiative to conduct longitudinal qualitative research on polysubstance use among people experiencing homelessness (PEH) in San Francisco, California. An Intersectional Risk Environment Framework was used to examine the interaction between social, structural, and environmental factors and overdose vulnerability. During the data collection period, San Francisco implemented multiple policies that increased the criminalization of PEH, and several service organizations closed or had limited services, necessitating a combination of methods to capture structural and community shifts in real-time. We recruited participants from community partner sites in four San Francisco neighborhoods to obtain a diverse study sample, enrolling 66 participants. We conducted semi-structured qualitative interviews, starting with baseline and life history interviews, and six-month follow-up. We recruited a subset of participants to take part in photovoice and ethnographic activities. All study visits were compensated. Our study approach centered participant autonomy and expertise throughout the research process. We employed a combination of multiple intentional and innovative methods designed to build trust at the community and participant levels, improve data quality, and enhance study retention including: (1) meaningful long-term reciprocal community engagements with stakeholders and service delivery organizations; (2) diverse, intersectional recruitment and equitable compensation to promote autonomy; (3) conducting life history interviews that addressed intersectional trauma histories after the first baseline interview; (4) addressing follow-up challenges with compensated check-ins, establishing a study community-based location, and hiring a community consultant; and (5) facilitating deep phenomenological data collection through photovoice and ethnography. 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