New Research on CBD and The Liver
New research claims that the use of cannabidiol (CBD) can damage the liver, and could have adverse side-effects when used with the over the counter drug acetaminophen. Are these claims warranted and what are the results from these studies really saying? Our Director or Research and Education Dr. Jonny Lisano breaks down the science behind it.
Written by: Dr. Jonny Lisano, Ph.D.
Recently, concern has arisen within the CBD industry and consumers alike over the findings from two research studies recently published in the journal Molecules. These studies were performed by a lab cohort from the University of Arkansas for Medical Sciences. The primary aim of these studies was to assess the potential liver toxicity of CBD-rich cannabis extract in mice and assess if there are any negative interactions with the common over-the-counter drug acetaminophen, better known as Tylenol. In this article, we will break down the results of each of these studies, discuss their implications, how they pertain to you, as well as teach you some general concepts when interpreting research studies such as these.
Are High Doses of CBD Toxic to the Liver?
The first study, “Hepatotoxicity of a Cannabinoid-Rich Cannabis Extract in the Mouse Model” was published in April of 2019 (Ewing et al. 2019a). The primary goal of this study was to determine if a single, large dose of CBD or high, daily doses administered for 10-days caused liver damage in mice. There were two primary reasons that this study arose. The first being recent findings from the Università della Campania in Italy which found that doses of CBD induced DNA damage in two human-derived cell lines (don’t worry, we will be discussing that study in a future blog post). Secondly, given the widespread availability of CBD as a food additive and new dietary ingredient, it is imperative to determine what level of consumption could lead to toxic effects.
So, how much CBD can be consumed before it becomes toxic to the body? In this study, a single, large dose of CBD was administered at doses of 246 mg/kg, 738 mg/kg and 2460 mg/kg to three separate groups of mice. In layman’s terms, they administered 246, 738, and 2460 mg of CBD for every kilogram of the animal’s body weight. I know, your first thought is “Holy cow! That is a ton of CBD!”, but there is something that we first need to discuss before we proceed any further with the results of this study, and that is the concept of human and mouse equivalent doses in research, or “allometric scaling” to take into account the vastly different metabolisms between humans and mice.
Dosing: Why use an animal model, and why are these doses so high?
For ethical reasons (sorry, mice!), toxicity studies like these can’t be performed in humans due to the unknown side-effects and the possible lethal effects of the previously un-researched compounds being tested. While it might seem intuitive to base the dose of a drug solely on body weight, and to keep this dose consistent across species, there are large differences in metabolism between species (human vs. mouse), and these must be accounted for when comparing doses. The surface area of the animal/human needs to be taken into account when discussing pharmacokinetics, or the movement of compounds throughout the body. This is because the size of a body can greatly affect the body’s ability to respond to a drug. If toxic effects of a drug are observed in animals, a “conversion factor” must be used to determine at what dose these effects would present themselves in humans. In converting doses between mice and humans a factor of 12.3 is used. For example, consider a compound was administered to a mouse at a dose of 12.3 mg/kg. The human equivalent dose would be 1 mg/kg. Conversely, as it is in this article, if a compound was administered at 2 mg/kg in humans the mouse equivalent dose would be 24.6 mg/kg (2 x 12.3).
Now that you better understand the concept of human and mouse equivalent dosing let’s look back at the doses administered to the mice in this study. Mouse doses of 246, 738 and 2460 mg/kg would equal doses of 20, 60 and 200 mg/kg respectively. For ease of interpretation, we will only use the human equivalent doses (HED) for the remainder of this article (i.e 20, 60 and 200 mg/kg) unless otherwise specified. If we were to administer even the lowest dose of 20 mg/kg to a 150 lb human that would equate to roughly 1,364 mg of CBD, or more than two full 600mg, 2oz bottles of 6° Wellness full-spectrum oil. Now I’m sure you’re thinking to yourself, ”What are these doses based on?”. That’s a great question. The 20 mg/kg dose is based on two clinical trials for the drug EPIDIOLEX, the first FDA approved plant-derived CBD medicine used for the treatment of seizures associated with Lennox-Gastaut syndrome or Dravet syndrome (two forms of severe childhood epilepsy). The other doses of 60 and 200 mg/kg were based off 3x and 10x the highest recommended dose to truly test if CBD would elicit toxic effects at even the highest limit of consumption. As a side note, it would take almost 23 bottles of our 600 mg full spectrum oil to reach the 200 mg/kg dose in a 150 lb adult (which would be toxic)… Wowza!
An easy to understand quick conversion table that shows what the equivalant CBD doses are in animals vs. humans at all three experimental doses can be found in Table 1. This table also shows what the relative CBD dose would be in humans of various body weights.
Table 1: Animal to Human Dose Conversion Table
So, what were the results of this first study?
Getting into the nitty-gritty of this first study. After a large dose of CBD extract researchers observed lethargy (sluggishness) lasting 4-5 hours in the 60 mg/kg HED group and up to 24-hours in the 200 mg/kg HED group. However, there were no observable behavioral differences in the 20 mg/kg HED group. The 60 mg/kg HED group did experience swelling of their livers, but in the 20 or 200 mg/kg HED groups there was no observable liver inflammation. Further, researchers observed a significant increase in liver glutathione, a byproduct of oxidative stress, in the 200 mg/kg HED group but not in the other two groups. This indicates that at this dose of CBD there was increased oxidative stress on the liver, which could potentially lead to liver damage. This study also assessed five blood markers to indicate if liver damage was present. Those markers were ALT, AST, ALP, GGT, and total Bilirubin. While none of these markers were elevated in the 20 mg/kg HED group (indicating no liver damage at this dose) both ALT and AST were elevated in the 60 and 200 mg/kg HED group, and total Bilirubin was elevated in the 200 mg/kg HED group. This implies that the two higher doses of CBD tested in this study did result in liver damage.
In the second part of this study, they sought to assess if daily doses of CBD over 10-days affected liver health. For this aspect of the study, researchers administered human equivalent doses of 5, 15 and 50 mg/kg per day for 10 days. This 5 mg/kg dose was based on the initial recommended dose for individuals taking EPIDIOLEX. A dose of 5 mg/kg per day of CBD would equate to consuming roughly 340 mg of CBD per day in a 150 lb adult, or over half of one of 6° Wellness’ 600 mg bottles. Three days into testing all of the animals in the 50 mg/kg group had to be put down due to symptoms of severe toxicity. However, keep in mind that to reach this dose, a 150 lb individual would potentially have to take 3,400 mg of CBD daily to elicit this effect.
All the animals in the lower dose groups survived the 10-day treatment period and did not exhibit any visible signs of toxicity. In the high dose group, liver cells showed signs of extreme swelling but this wasn’t observed in the low dose group. Further, in assessing for markers of liver damage, there were no significant elevations in either of the lower dose groups, but total Bilirubin was elevated in the high dose 50 mg/kg group. These results imply that following daily doses of 50 mg/kg can cause liver swelling and damage, but at the low dose of 5 mg/kg there were no signs of liver inflammation or damage.
So, what does all of this mean?
I know… that is a lot of information to take in. So, let’s summarize the main findings of this study in just a few sentences. The low doses administered in this study produced little if any indication of liver inflammation or damage following either a single dose of 20 mg/kg or 10-days of 5 mg/kg of CBD. At higher single and daily doses of CBD, symptoms of liver inflammation and damage were present. Nevertheless, don’t forget that for these doses to be achieved in a 150 lb human they would need to consume either 13,640 mg in a single dose or 3,400 mg/day over 10 days CBD to achieve these effects.
Can CBD and Acetaminophen be Taken Together?
In follow-up to the first study, the article titled: “Paradoxical Patterns of Sinusoidal Obstruction Syndrome-Like Liver Injury in Aged Female CD-1 Mice Triggered by Cannabidiol-Rich Cannabis Extract and Acetaminophen Co-Administration” aimed to assess if taking CBD extract and acetaminophen, the main active ingredient in TYLENOL, together produced any negative side-effects on the liver (Ewing et al. 2019b). It is well established that high doses of acetaminophen can damage the liver (Larson 2007). And as we previously discussed it was also found that extremely high doses of CBD extract can produce similar damage. To assess this, researchers administered human equivalent doses of 10 and 25 mg/kg per day, equivalent to a 150 lb person taking 682 mg and 1,704 mg CBD respectively, for three days followed by a large dose of acetaminophen on the fourth day. In the 10 mg/kg group, it was found that there was a significant interaction effect between CBD and acetaminophen resulting in a nearly 40% mortality rate of the animals. It was found that this mortality resulted from large scale oxidative stress triggering liver cell death. However, this was not observed in the 25 mg/kg CBD group. In this group, there was a 0% mortality rate suggesting a paradoxical dose-dependent effect.
So, what do we take away from this second article? Well, first and foremost there is strong evidence to suggest that administration of CBD in high doses can interact with the common over the counter drug acetaminophen, like TYLENOL, that could potentially produce harmful effects. However, it’s important to put into context both the doses of CBD and acetaminophen used in this study. To reach the low dose of CBD used in this study, a 150 lb individual would have to take more than an entire 600 mg, 2oz bottle in one sitting (we don’t recommend doing that) for three consecutive days followed by 2,200 mg of acetaminophen at once. That would be the equivalent of taking 7 regular strength TYLENOL all at once. On their website, TYLENOL recommends taking 2 regular-strength tablets every 4-6 hours and to not exceed more than 10 tablets in 24-hours. That means to achieve this dose an individual would only have to take 70% of the maximum daily recommended dose at once to experience these effects. These are important findings, as many people who are taking CBD for pain relief may also be taking other drugs such as TYLENOL, and although either one in isolation is relatively safe, the two combined could possibly lead to toxic effects.
What are some of the major limitations of these studies?
The studies are somewhat limited by the content of the CBD extract used. The extract was not pure CBD and still contained concentrations of other cannabinoids like THC. Further, to produce the concentrate hexane was used as the extraction solvent. While the majority of the hexane was boiled off at 80°C to activate the cannabinoids there was still residual hexane (< 0.5%) present in the final extract, which is quite a bit. 0.5% would be the same as half the amount of CBD in a 600mg, 2oz bottle of CBD (600mg CBD in 60 ml of oil = 1% CBD). It has been well known for more than 30-years that hexane is toxic to the liver, even at low concentrations, as described in “Hepatotoxic effects elicited by n-hexane or n-heptane” published back in 1988 (Goel et al. 1988). It’s possible that some of the toxic effects observed in these studies could be in part due to hexane exposure. Unfortunately, many companies providing CBD extracts use hexane in their extraction process as well, because it is easy, and very cheap. Now, you’re probably wondering “Is there any hexane present in the products provided by 6° Wellness?”. The short and long answer to that is… absolutely not. We use a CO2 extraction method, which leaves no volatile residues. Further, our products are tested by an independent third-party lab for not only hexane residuals but many other residual chemicals as well. As always, we want to ensure that we provide you with the highest quality product possible.
While it would take an extraordinary amount of CBD alone, or moderate doses of CBD and acetaminophen together to produce the effects described in these studies, it is always important to consider all medications and supplements you are taking at the same time. Unfortunately, research in this area is still limited. If you’re worried about cross-reactive effects of your medications and supplements, always consult your personal physician before adding it to your daily routine so they can monitor your health and any acute changes in your personal physiology.
It is always important to remember that you can have too much of a good thing. While CBD has many proposed benefits, when consumed in extreme amounts it could potentially have negative side effects. Just like Ibuprofen and TYLENOL can help subside inflammation and pain, both can cause damage to the kidneys and liver if consumed in excess. Therefore, we recommend you always track your CBD intake, and only use pure products from 6° Wellness verified by a third party laboratory. Your health is always our top priority, and that is why we strive to provide you with the highest quality products possible.
The media and science alike have a tendency to exaggerate scientific findings, and we know research articles can sometimes be intimidating to interpret. Their titles can be long and complex, and sometimes it’s difficult to make sense of the doses and methods being used. Don’t let that scare you, take ownership of your health and make an effort to dig deeper than the surface. If there is ever an article on CBD and health that you need help interpreting reach out to us at firstname.lastname@example.org and we will do our best to provide our unbiased interpretation in future blog posts like this.
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