New mouse study finds level of liver toxicity for CBD
The study, conducted by researchers at the University of Arkansas for Medical Sciences in Little Rock, used a mouse model to look for the level of hepatotoxicity for CBD. The research team was led by Igor Koturbash, PhD and included Bill Gurley, PhD, who performed the dosage calculations.
Calculating the dosages
Those calculations were a key part of the study, Dr Koturbash told NutraIngredients-USA. Almost all of the dosage/safety information that exists about CBD comes from the work done by English company GW Pharma in the development of its drug Epidiolex. The drug was approved last year by the US Food and Drug Administration for the treatment of seizures in two fairly rare forms of childhood epilepsy.
But the development of that drug was unusual, in that it came out of the compassionate usage of CBD to treat children with grave seizure disorders who were not responding to available medications. Dr Koturbash said it was not a typical ground-up drug development process.
The dosage calculations used in the Arkansas study were calculated using a standard model for toxicity dosages in a mouse model. But the wrinkle here was that those dosages were back-calculated from what is already being used in humans, Dr Koturbash said.
“You have to take into account the body size and the metabolism rate,” Dr Koturbash said. “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.”
The study, titled Hepatotoxicity of a Cannabidiol-Rich Cannabis Extract in the Mouse Model, was published at the end of April in the journal Molecules. As with other toxicity investigations, the study included acute and sub-acute phases.
Evidence of liver injury
In the acute phase, mice were gavaged with 0, 246, 738, or 2460 mg/kg of CBD and observed for 24 hours. The mice on the highest dose showed significant increases in liver-to-body weight (LBW) ratios, plasma ALT, AST (enzyme markers for liver damage), and total bilirubin.
In the sub acute phase, the 8-week old mice where gavaged for 10 days with dosages of 0, 61.5, 184.5, or 615 mg/kg for 10 days (sub-acute toxicity). These doses were said to be “the allometrically scaled mouse equivalent doses (MED) of the maximum recommended human maintenance dose of CBD in EPIDIOLEX (20 mg/kg).”
In the sub acute phase, 75% of the mice on the 615 mg dose died or were near death on days three and four. They showed similar manifestations of liver damage (increases in LBW ratios, ALT, AST, and total bilirubin) as did the mice on the highest dose in the acute phase.
Dr Koturbash said the results should be a cause for further investigation of the safety parameters of hemp extracts, especially as they are appearing willy-nilly on the market in a host of delivery forms and at a wide range of dosages. The assertion by product developers in the field that hemp extracts, coming as they do from a plant with a long history of use, are a priori safe should be taken with a grain of salt, he said.
“There is a potential for liver injury. If you look at the Epidolex label, it clearly states a warning for liver injury; it states you have to monitor the liver enzyme levels of the patients. In the clinical trials, 5% to 20% of the patients developed elevated liver enzymes and some patients were withdrawn from the trials,” Dr Koturbash said.
Additional research needed
Writing in Molecules, the researchers stated: "Additional studies are needed to examine the toxicity of chronic low-dose CBD exposure as well as explore CBD’s potential to interact with other medications. Such studies will provide important information regarding the range of CBD doses that can be deemed safe for the purpose of regulatory decision-making."
In addition, the study found that CBD altered a wide host of gene pathways, which raises concerns of its own. The study found that,“CBD differentially regulated more than 50 genes, many of which were linked to oxidative stress responses, lipid metabolism pathways and drug metabolizing enzymes.”
“There is a potential for herb/drug interactions,” he said. (Dr Koturbash said a second study looking at herb/drug interactions with CBD is in the final review phase and will be published shortly.)
As a bottom line, Dr Koturbash said he didn’t want to be seen as trying to torpedo the CBD ship. It may well be proven that the dosages and delivery forms of this ingredient that are coming to market have acceptable safety parameters. In his view that is at the moment a statement of belief, rather than an assertion of fact.
“I don't want to say that CBD is bad and we should ban it. But in my opinion there is clearly not enough research,” he said.
2019, 24(9), 1694. doi: 10.3390/molecules24091694.
Hepatotoxicity of a Cannabidiol-Rich Cannabis Extract in the Mouse Model.
Authors: Koturbash I, et al.
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