THC and CBD Produce Largely Non-Overlapping Molecular Effects Across Species and Tissues

CBD datasets showed more differentially expressed genes and enriched pathways across species. CBD effects clustered by administration route and species and were enriched for inflammation suppression, zinc homeostasis, and cell cycle regulation. THC signatures were more variable but consistently affected antioxidant activity, neuronal myelination, and synaptic signaling. THC altered endocannabinoid genes mainly in brain tissue, while CBD affected them in both central and peripheral tissues.

Curation and analysis of 105 THC and CBD RNA-sequencing and microarray datasets from NCBI GEO across mammalian species (human, rhesus macaque, mouse, rat). Meta-analysis identified common gene signatures, with pathway enrichment, network analysis, and disease association analysis.

Despite being the two main cannabinoids, THC and CBD are often discussed interchangeably. This comprehensive molecular comparison shows they affect fundamentally different biological pathways, supporting the need to consider them as distinct therapeutic agents.

This is one of the most comprehensive molecular comparisons of THC and CBD to date. The finding that their effects are largely non-overlapping has implications for product formulation, clinical trials, and understanding why different cannabis products produce different effects.

Analysis of existing datasets introduces heterogeneity in experimental conditions. Different doses, exposure durations, and tissue types across studies. Transcriptomic changes do not always translate to functional outcomes. Publication bias toward certain tissues and species.