CBD and the liver: hepatic enzymes, interactions and thresholds for caution

At high doses, CBD can raise liver enzymes; at everyday consumption doses, the signal is weak but not zero, especially where another treatment is involved. The most solid data come from Epidiolex, a purified cannabidiol approved for certain rare epilepsies. In its trials, ALT elevations beyond three times the upper limit of normal affected roughly 13% of patients at 10-20 mg/kg/day, and around 12% at 25 mg/kg/day. These figures concern very high therapeutic doses, under strict medical supervision, in patients who are often on multiple medicines, and bear no relation to the exposure from a commercially sold CBD oil.

The enzyme elevations observed on Epidiolex are dose-dependent, early (typically within the first two weeks) and, in the vast majority of cases, reversible. The marker monitored is ALT, an enzyme released into the blood when liver cells are under stress. A reassuring point: these elevations generally return to normal within one to two weeks after stopping or reducing the dose, with no case of liver failure reported in this setting. Two factors clearly increase the risk: concomitant valproate use and transaminases already elevated at baseline.

CBD changes the speed at which the liver metabolises other molecules, by inhibiting key cytochromes P450 (CYP3A4, CYP2C19) as well as UGT enzymes. The result is what is known as the "grapefruit effect": by slowing their elimination, CBD can raise the blood concentrations of other substances, increasing both their effect and their adverse effects (CDER). This interaction, more than any direct toxicity, is the most relevant risk for a consumer who is on medication. Antiepileptics such as valproate, anticoagulants and certain immunosuppressants with a narrow therapeutic margin warrant particular attention.

The gap in exposure between Epidiolex and everyday consumption is considerable. The doses associated with the liver signal range from 10 to 25 mg/kg/day, that is 700 to 1750 mg per day for a 70 kg adult. Wellness consumption is more in the region of 20 to 50 mg per day, an order of magnitude 15 to 80 times lower. Safety data at intermediate doses of 200 to 400 mg per day remain limited, however, for lack of long-term human trials at those levels, which calls for nuance rather than dismissing all concern.

People on long-term treatment come first, because of the risk of interaction via the cytochromes P450. People with a known liver disease or with already elevated transaminases make up the other sensitive group. In practice: seek advice from a doctor or pharmacist before starting anything with a narrow therapeutic margin, report any liver history, and see a doctor in case of unusual fatigue, nausea or dark urine. Our article on the legal framework for CBD in France sets out the general precautions to know before any use.

Research converges on a twofold message: CBD is not innocuous at high doses, but the liver risk at everyday doses remains poorly quantified. A randomised trial by CDER, the FDA's centre for drug evaluation, specifically studied the safety of CBD. A phase I trial conducted in healthy adults also documented abnormal liver function tests on cannabidiol, without establishing a danger at wellness doses (Watkins et al., *Clinical Pharmacology & Therapeutics*, 2021).

Does CBD damage the liver?

At the very high doses of a medicine such as Epidiolex, CBD can raise liver enzymes in 12 to 13% of patients, generally reversibly. At everyday consumption doses, the signal is weak.

At what dose does the liver signal appear?

The documented signal concerns 10 to 25 mg/kg/day, that is 700 to 1750 mg for a 70 kg adult, far above the 20-50 mg of wellness consumption.

Does CBD interact with my medicines?

Yes. CBD inhibits the cytochromes CYP3A4 and CYP2C19, which can increase the concentrations of other medicines. Molecules with a narrow therapeutic margin require particular vigilance.

Who should seek advice before taking CBD?

People on long-term treatment, those with a known liver disease or elevated transaminases, and those taking valproate are the most concerned by this caution.