PROJECT SUMMARY/ABSTRACT We propose to investigate motivations for methamphetamine injection, associations of its co-use with fentanyl and infectious disease risk, and the underlying causes of death for methamphetamine overdose in San Francisco (SF) and Oakland (OAK), California. All major indicators point to a steep increase in methamphetamine use in the United States (US). From 2015 to 2018, 1.6 million US adults reported past- year methamphetamine use, of which 22% reported injecting methamphetamine. When the US experienced a large increase in methamphetamine use in the late 1990s and 2000s, the motivations for its use and attendant health risks were well characterized. However, the introduction of illicitly made fentanyl into drug markets in the US in the past 5 years has significantly altered the context in which methamphetamine is now used. What is being termed the “fourth wave of the opioid epidemic” is a surge in co-use of fentanyl and methamphetamine. Anecdotal evidence suggests that fentanyl and its analogs are so potent that people are motivated to co-use methamphetamine to overcome the heavy sedation that accompanies fentanyl use. Consequently, our understanding of the motivations for methamphetamine injection must be updated within this new context. We also need to update our understanding of how people who inject methamphetamine are at increased risk for infectious diseases during the fentanyl era. While the data from the 1990s and 2000s showed increased syringe sharing and sexual risks, it is unclear whether these persist in the new wave of methamphetamine injection and its co-use with fentanyl. As opposed to opioid overdose deaths, which are caused by respiratory depression, we know little about the distribution of underlying causes of death in methamphetamine overdoses. The only US epidemiological study showed that the most common additional causes of death were cerebral hemorrhage (15%) and cardiac conditions (6%). That study predated the co- use of fentanyl, after which overdose deaths have surged. If we do not know why people who use methamphetamine are dying, we cannot address how to prevent such deaths. Aim 1: To characterize motivations for methamphetamine injection. Aim 2: To assess the association of methamphetamine and fentanyl co-use with infectious disease risk behaviors. Aim 3: To determine the distribution of underlying causes of death among people whose cause of death includes acute methamphetamine toxicity. To achieve Aims 1 and 2, we will recruit a community-based cohort of 800 people who inject drugs using targeted sampling methods in SF and OAK. We will conduct surveys at baseline and monthly for 6 months, using 7- day timeline follow-back methods. To achieve Aim 3, we will determine cause of death of all overdose fatalities involving methamphetamine from 2016 to 2024 by reviewing medical examiner records in SF (estimated N=500). Findings will provide rigorous empirical evidence to policymakers, health departmen...