Abstract “Our Healing Journey: A Cultural and Traditional Response to the Opioid Epidemic” Generally, there are greater negative consequences associated with substance misuse among American Indian and Alaska Native (AI/AN) adults, even when rates of substance use abstinence are higher across the two groups (i.e., alcohol). Substance use rates among AI/AN adults compared to non-Hispanic Whites (NHW) vary. Due to ongoing settler-colonialism, health inequities related to substance use on the applicant reservation persist. Opioid poisoning on the reservation has increased by 159% from 68 (2019) to 176 and the reservation has the highest naloxone administration rate in the state, 193.4 per 100,000 people compared with 84.7 per 100,000 people. Locally focused strategies have been identified and implemented to address and alleviate the impact of the opioid and methamphetamine epidemic on the reservation. At the applicant outpatient treatment facility, community-focused, culturally grounded, evidence-based, and innovative solutions rooted in the teachings of the Medicine Wheel have been implemented. The Medicine Wheel is a holistic framework representing the spiritual, mental, physical, and emotional domains necessary to living a balanced and healthy life. It signifies the balance in the four directions, the four seasons, and the stages of life, along with representing the relationship to self, family, community, the environment, and land, as well as the larger societal context. Therefore, we propose to respond to the public health crisis by building up our research infrastructure and skills and expanding our culturally centered response by employing community-driven strategies. Together, our team has the culturally grounded program development, evaluation, and research experience necessary to complete the activities outlined in the proposal. The proposed aims will follow the Medicine Wheel teachings and incorporate emotional, physical, mental and spiritual focus areas. The specific aims include: 1) Mental—Develop the infrastructure to track individual and community outcomes related to this proposal, including poisonings, treatment seeking, treatment retention, and well-being. 2) Emotional, Physical, Spiritual—Refine the proposed integration of the EHR, evidence-based practices, cultural, and CAM evaluations, by assessing community interest in these interventions, identifying barriers to implementation, and creating a comprehensive model and supporting documents for implementation, and determine outcomes for analysis. 3) Emotional, Physical, Mental, Spiritual—Pilot our intervention and study the feasibility of our approach and collect preliminary data for a larger study to examine and measure the menu of strategies and solutions (e.g., traditional plant medicines, CAM, harm reduction strategies) to address outcomes including but not limited to anxiety, depression, sleep, substance use and abstinence, fatal and non-fatal drug poisonings, engagement and retention, pain management, overall feelings of well-being. No previous research has investigated the combination of traditional Indigenous medicines, CAM, harm reduction, and Western evidence-based strategies on substance use, pain management, and well-being among AI/AN communities. Building our research infrastructure by partnering with the NRRN and other T/NASOs, along with the activities described in the proposal, will allow us to develop a research portfolio and collect the pilot data for the submission of future NIH research proposals that prioritizes culture, well-being and is strength-based. Our work will make a national impact by adding to the research on the rapid response necessary to inform long-term research and services for other rural Tribal communities, many of whom are bearing a disproportionate burden of the opioid epidemic.