Editorial for the Themed Issue: Addressing the Dual Challenges of Opioid Use Disorder and Chronic Pain in the Context of the Opioid CrisisMehmet Sofuoglu, M.D., Ph.D. 1,2R. Ross MacLean, Ph.D. 1,2Joao P. De Aquino, M.D.1,2,3Yale University School of Medicine, Department of Psychiatry, 300 George Street, New Haven, CT 06511, USAVA Connecticut Healthcare System, 950 Campbell Avenue, West Haven, CT 06516, USAClinical Neuroscience Research Unit, Connecticut Mental Health Center, 34 Park Street, 3rd Floor, New Haven, CT, 06519CORRESPONDING AUTHOR: Mehmet Sofuoglu, VA Connecticut Healthcare System, 950 Campbell Avenue, West Haven, CT 06516, USA

The rise of psychedelics in contemporary medicine has sparked interest in their potential therapeutic applications. While traditionally associated with countercultural movements and recreational use, recent research has shed light on the potential benefits of psychedelics in various mental health conditions. In this review, we explore the emerging role of psychedelics in the management of chronic pain and opioid use disorder (OUD), two critical areas in need of innovative treatment options. Pain control remains a significant clinical challenge, particularly for individuals with OUD and those who receive long-term opioid therapy (LTOT) who develop marked tolerance to opioid-induced analgesia. Despite the magnitude of this problem, there is a scarcity of controlled studies investigating pain management alternatives for these populations. Drawing from preclinical and human evidence, we highlight the potential of psychedelics to act on shared neurobiological substrates of chronic pain and opioid use disorder, potentially reversing pain- and opioid-induced neuroadaptations, such as central sensitization. We elaborate on the multifaceted dimensions of the pain experience (sensory, affective, and cognitive) and their intersections that overlap with opioid-related phenomena (opioid craving and withdrawal), hypothesizing how these processes can be modulated by psychedelics. After summarizing the available clinical research, we propose mechanistic insights and methodological considerations for the design of future translational studies and clinical trials, building on a shared clinical and neurobiological understanding of chronic pain and OUD. Our intention is to provide timely perspectives that accelerate the development and exploration of novel therapeutics for chronic pain and OUD amidst the escalating opioid crisis.