Beyond Cannabinoids

Cannabis pharmacology has been dominated by a cannabinoid-centric paradigm that attributes therapeutic effects primarily to Δ9-tetrahydrocannabinol (THC), cannabidiol (CBD), and related cannabinoids acting through CB₁ and CB₂ receptors. While this framework explains aspects of neuromodulation, it has been overextended to account for systemic, metabolic, and organ-protective effects that fall outside the mechanistic scope of cannabinoid receptor signaling.Olivetol and its precursor, olivetolic acid, are biosynthetically indispensable intermediates in cannabinoid production and are unavoidably present in all cannabinoid-rich extracts due to shared biosynthesis and non-selective extraction processes [1–4]. Despite this inevitability, these phenolic compounds have been largely excluded from pharmacological attribution. This omission persists even though alkylresorcinols and related phenolics exhibit robust antioxidant, anti-inflammatory, mitochondrial-protective, autophagy-inducing, metabolic-regulatory, and organ-protective effects across multiple preclinical models [5–14].These effects are mediated through conserved intracellular pathways, including AMPK, Nrf2, NF-κB, autophagy, and mitochondrial quality-control systems, rather than extracellular cannabinoid receptors. These mechanisms align closely with the systemic therapeutic outcomes historically attributed to cannabis and resolve inconsistencies that persist under a cannabinoid-centric model.This review advances a reattribution framework proposing that a substantial portion of cannabis’ therapeutic effects are more accurately explained by olivetol-mediated intracellular regulation. This correction is not speculative but arises from convergent biochemical, mechanistic, and pharmacokinetic evidence. Reattributing cannabis therapeutics to olivetol restores internal coherence to cannabis pharmacology and establishes a more accurate foundation for future research and therapeutic development.