Lipidomic Evidence for Cannabidiol-Induced Remodeling of Cellular Lipid Composition in SH-SY5Y Cells

Cannabidiol (CBD) is increasingly discussed in relation to neurodegenerative disorders, including Alzheimer’s disease (AD), yet its effects on cellular lipid profiles remain poorly understood. Using targeted lipidomics, we investigated whether CBD alters the lipidome of SH-SY5Y wildtype (wt) cells and whether the principal phosphatidylcholine response is also observed in cells expressing amyloid precursor protein with the Swedish mutation (APPswe). CBD induced a broad, class-specific lipid response. Total diacyl and ether-linked phosphatidylcholines increased. Within these classes, many species with lower degrees of unsaturation increased, whereas several highly polyunsaturated ether-linked phosphatidylcholines declined. Lysophosphatidylcholines were broadly reduced, total sphingomyelin abundance declined, free carnitine decreased, and most measured acylcarnitine species also declined. Together, in wt cells, these changes are consistent with a relative shift toward a less polyunsaturated lipid profile. CBD-associated changes in both phosphatidylcholine classes were also observed in stably APPswe-expressing SH-SY5Y cells. Because the affected lipid classes have been implicated in AD-related lipid dysregulation, these findings link CBD exposure to an AD-relevant lipid context and provide a rationale for investigating the functional consequences of this response in more complex neurodegeneration-relevant models.