CBD Could Cause Liver Damage at High Doses, Says Study

Cannabidiol (CBD) has built up a reputation over the past few years as being the safe, therapeutic part of the cannabis plant. But does it fully deserve this reputation? Or are users of CBD products unknowingly putting themselves at risk of developing harmful side effects? A new scientific research paper suggests as much.

The paper, published in the journal Molecules, details recent work from researchers at the University of Arkansas and the University of Mississippi. Specifically, the paper examines links between CBD doses and the potential for developing “hepatotoxicity” — drug-induced liver damage. 

CBD liver damage in mice

To investigate this CBD hepatotoxicity, researchers designed two experiments. The first, which looked at acute toxicity from a singular dose, gave the mice a dose of either 0, 246, 738, or 2460 mg/kg of CBD. The second experiment examined lower CBD doses over a longer timeframe, which here meant daily doses of either 0, 61.5, 184.5, or 615 mg/kg of CBD over a period of 10 days. 

The paper states that these doses were chosen as they were the “allometrically scaled mouse equivalent doses (MED) of the maximum recommended human maintenance dose of CBD in Epidiolex”, which is an CBD drug used to treat rare forms of epilepsy approved by the US Food and Drug Administration. 

“You have to take into account the body size and the metabolism rate,” study author Dr Igor Koturbash told Nutra Ingredients USA. “There is a formula where you put in the information and how much of a specific compound to use. Is it perfect? No. But in research we like to say that every model is wrong, but some of them are useful.”

In the single dose experiment, the mice on the highest dosage, 2460 mg/kg CBD, became sluggish, lost their appetite, showed significant increases in liver-to-body weight ratios, and marginal body weight loss. The mice were also found to have higher levels of liver enzymes ALT and AST, which are markers for liver damage, and a higher total bilirubin count than normal, which implies the inability of the liver to excrete the pigment normally. 

Mice at the slightly lower 738 mg/kg dose also exhibited lethargy, changes in body weight, increases in liver-to-body weight ratio, and smaller but still significant increases in the liver enzymes ALT and AST. 

In the multi-dose experiment, mice at the highest dose once again exhibit lethargy, loss of appetite, and changes in body weight at the start of the trial period, accompanied by rising ALT, AST and bilirubin levels. However by the end of the third day, four of the six mice being studied at the highest dose were showing signs of severe liver damage and were terminated. The remaining two mice completed the 10 day course on this high dose and exhibited no visible signs of toxicity. None of the mice taking lower doses showed any visible signs of toxicity over the course of the experiment.

As well as these two experiments, the researchers also conducted a gene expression analysis, using an array of more than 80 genes that have been previously recognized as markers of liver toxicity. The researchers found that CBD had the power to regulate more than 50 genes, with the last majority of those affected being so in a dose-dependent manner. 

High dose CBD - is it time to start worrying?

It’s hard to argue with dead mice — at some doses, CBD does indeed cause hepatotoxicity. 

But do consumers need to worry?

As the study says, the doses chosen were calculated to reflect the mouse equivalent of the maximum recommended human dose. But here, the dose equivalent to the maximum human dosage was actually the lowest of the CBD dosages in each experiment, at 246 mg/kg and 61.5 mg/kg respectively. The other dosages were chosen to reflect 3x and 10x the maximum recommended dose for Epidiolex in humans. 

As no signs of visible liver toxicity were seen in either experiment for the lowest dose, this would imply that Epidiolex, and other CBD preparations of a similar recommended dose, are still safe to use. Though, as Dr Koturbash points out in his interview with Nutra Ingredients USA, the Epidiolex packaging does include a warning message which advises people taking other medications that can damage the liver, or have pre-existing liver damage, to consider taking only low doses of Epidiolex, or to not use the product entirely.

“There is a potential for liver injury,” he says. “ If you look at the Epidiolex label, it clearly states a warning for liver injury; it states you have to monitor the liver enzyme levels of the patients.”

Dr Koturbash does not believe that the results of this study imply any sort of immediate danger for people currently taking CBD medication, or using CBD products. Instead, he feels that this research should encourage further investigation of the safety profile of CBD at various doses, and ensure that those people who are bringing CBD products to market check that their advertised dosages are safe for long-term use.