Transcriptomic Evidence of Acquired Cannabis Hypersensitivity in Cannabinoid Hyperemesis Syndrome

Background Cannabinoid hyperemesis syndrome (CHS) is a paradoxical and increasingly prevalent disorder characterized by recurrent vomiting in people with chronic cannabis use. Despite its growing clinical impact, the underlying mechanisms remain poorly understood. Methods A genome-wide RNA sequencing was used to characterize transcriptomic differences and identify potential pathways involved in CHS pathogenesis. In this pilot study, whole blood RNA sequencing was performed on 7 patients with CHS and 7 matched controls. Differentially expressed genes (DEGs) were identified, annotated and analyzed by automated and manual analysis. RNA sequences were further analyzed by digital isotyping for HLA Class I and II allele usage. Results CHS was associated with marked activation of the adaptive immune system, including upregulation of B-cell related immunoglobin transcripts and altered expression of T cell, monocyte, and neutrophil-related transcripts. DEGs also suggested increased matrix degradation, and reduced adhesion and protease inhibitor transcripts, consistent with impaired gut barrier function. Digital HLA isotyping revealed increased MHC Class I expression, Class II allele restriction, and down-regulation of IgE receptor transcripts, a known response to elevated IgE levels in allergic hypersensitivity. Conclusions Together, these findings suggest that CHS may represent an acquired, gut-restricted, immune-mediated hypersensitivity response to cannabis. This transcriptomic analysis provides new mechanistic insights into CHS and lays groundwork for future studies to identify biomarkers, clarify immune triggers, and develop targeted therapies.