Multi-Modal Profiling Reveals Contrasting Immunomodulatory Effects of Recreational Marijuana Used Alone or with Tobacco in Youth with HIV.

The evolving legal landscape has increased marijuana accessibility across the United States, including for medical use to manage clinical symptoms among people with HIV. The effects of marijuana use remain understudied in youth with HIV (YWH), who face lifelong antiretroviral therapy (ART) and an elevated risk of developing comorbidities. This study applied a multi-modal approach, including plasma biomarker analysis, peripheral blood cell phenotyping, and transcriptome profiling, to examine the effects of recreational marijuana alone, tobacco alone, or marijuana combined with tobacco in virally suppressed YWH (≤50 RNA copies/mL) on ART compared to youth without HIV and YWH who used no substance. Marijuana use alone was associated with elevated IL-10 levels and normalization of pro-inflammatory genes and pathways, suggesting an immunomodulatory effect. Conversely, tobacco use alone or combined with marijuana was linked to increased IL-1β levels and heightened pro-inflammatory responses, including upregulation of genes involved in inflammasome activation. This study is the first to demonstrate GPR15 upregulation and potential marijuana-associated epigenetic modulation in HIV-suppressed youth. The findings identify potential markers for early detection of inflammation-related comorbidities in YWH, particularly among those exposed to tobacco and underscore the need for targeted profiling to guide personalized monitoring and early substance use intervention strategies for YWH.