CBD and CBG reduce liver fat in mice by activating an unexpected energy backup system
Hebrew University of Jerusalem.
The liver does not usually depend on phosphocreatine for energy. That molecule is the domain of muscles and the brain, tissues that need rapid bursts of power. So when researchers at the Hebrew University of Jerusalem found that two cannabis compounds caused the liver to build up phosphocreatine reserves, they were looking at something unexpected: a metabolic workaround that the organ does not typically employ, activated by compounds from a plant.
The study, led by Prof. Joseph (Yossi) Tam and Dr. Liad Hinden at the School of Pharmacy, tested cannabidiol (CBD) and cannabigerol (CBG), two non-psychoactive compounds from the cannabis plant, in mice with diet-induced fatty liver disease. Both compounds reduced liver fat and improved metabolic markers. But the mechanism went beyond simple fat reduction.
A backup battery for a stressed liver
Metabolic dysfunction-associated steatotic liver disease (MASLD, formerly known as non-alcoholic fatty liver disease) affects roughly one-third of adults worldwide. It is closely tied to obesity, insulin resistance, and high blood pressure. Approved medications remain scarce, and lifestyle changes, while effective, are difficult for many patients to sustain.
When mice on a high-fat diet were treated with CBD or CBG, their livers showed elevated levels of phosphocreatine. This molecule functions as a rapid-access energy reserve, providing ATP on demand when cellular energy supplies are strained. The liver's increased reliance on this system under cannabinoid treatment suggests the organ was deploying an alternative energy strategy to cope with the metabolic stress of fat overload. The researchers describe this as "metabolic remodeling."
Restarting the cellular cleanup crew
The second major finding involved cathepsins, enzymes that operate inside lysosomes, the cell's recycling compartments. In fatty liver disease, lysosomal function is impaired, and the cellular cleanup process slows down. Harmful lipids and waste products accumulate. CBD and CBG restored cathepsin activity, effectively restarting the lysosomal machinery.
With the cleanup crew back at work, the liver was better able to clear triglycerides and ceramides. Ceramides are particularly notable because they are known contributors to insulin resistance and liver inflammation, making their reduction clinically relevant beyond simple fat clearance.
CBG versus CBD: similar but not identical
Both compounds normalized blood sugar levels and improved glucose clearance. But they were not interchangeable. CBG showed a more pronounced effect on several metabolic measures: it reduced body fat mass more substantially, improved insulin sensitivity more robustly, and was particularly effective at lowering total cholesterol and LDL cholesterol. CBD was effective but somewhat less potent on these specific endpoints.
"Our findings identify a new mechanism by which CBD and CBG enhance hepatic energy and lysosomal function," Tam said. "This dual metabolic remodeling contributes to improved liver lipid handling and highlights these compounds as promising therapeutic agents for MASLD."
Mice, not patients
The work was conducted entirely in mice fed a high-fat diet. Mouse models of fatty liver disease are useful for identifying biological mechanisms but do not reliably predict human therapeutic outcomes. Human livers differ in size, metabolic rate, drug processing, and the complexity of the disease itself, which in people develops over years or decades alongside other conditions like diabetes and cardiovascular disease.
The doses used in mouse studies often do not translate directly to human dosing, and cannabinoid metabolism in humans involves additional variables including drug interactions, liver enzyme polymorphisms, and the effects of chronic versus acute administration. CBD products are already widely available as supplements, but the metabolic remodeling observed in this study occurred under controlled experimental conditions that may not be replicated by over-the-counter products of variable quality and dosage.
The phosphocreatine finding is novel and intriguing but needs replication and mechanistic exploration. Whether this energy strategy is beneficial over the long term, or whether it represents a stress response with its own consequences, is not yet clear.
What the study does establish is that CBD and CBG act on fatty liver through mechanisms more sophisticated than simply reducing fat accumulation. They reorganize how the liver handles energy and waste. Whether that reorganization can be translated into a human therapy for MASLD is the question that clinical trials will eventually need to answer.