What Causes Liver Damage?
The liver is an organ of extreme importance in our bodies; it helps the body synthesize or metabolize the majority of nutrients, vitamins, and minerals. More importantly, its main function is to get rid of all of the toxic compounds in our bodies along with removing any of the administered drugs in order to prevent us from getting intoxicated.
There are many factors that would affect the liver’s ability and function, including an unhealthy lifestyle, excessive alcohol drinking, taking certain drugs or drug overdose, or some liver viruses. These factors contribute to the irreversible damage to the liver, making it unable to perform its function as intended.
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The 5 stages of liver damage
Liver damage is generally categorized into five stages based on the nature of the liver injury. They include:
- Stage 0: Healthy liver
- Stage 1: The initial phase of liver damage (reversible). Reversible liver damage means that the liver can return back to its original function if the offending agent is removed
- Stage 2: Moderate liver damage (reversible)
- Stage 3: Significant liver damage (reversible)
- Stage 4: Severe liver damage or liver cirrhosis (irreversible). At this stage, the liver becomes unfunctional and can’t return back to normal even if the offending agent is removed.
The effect of many drugs on the liver has been an area of interest to many researchers in the past. However, with the recent increase in the use of cannabidiol (CBD) for the treatment of many medical conditions, one is not sure whether CBD protects against liver damage or causes it. Therefore, many research studies have been conducted to look into this particular point to make sure that the safety of this compound is guaranteed.
Is there an Interaction between CBD and the Liver?
CBD is one of the many cannabinoid compounds that are derived from the plant Cannabis sativa. Unlike tetrahydrocannabinol (THC), CBD does not possess any of the psychoactive properties of THC, so it does not get you high. Also, CBD has attained great attention in the past decade because of its potential therapeutic properties in treating many health problems, including pain and inflammation.
Epidiolex, a drug that contains CBD, is the only approved drug by the FDA to be used in certain cases of drug-resistant epileptic syndromes. That being said, CBD oil is being used by a great proportion of the American population as a dietary supplementation or as an over-the-counter product for a wide range of purposes. CBD oil has been used for pain management, stress relief, sleep aid, depression management, neuroprotection, and many other indications.
The typical dose of CBD that has been approved in people with epilepsy ranges from 10 to 20 mg/kg/day; however, the higher doses of this drug has been the most commonly used ones. With the increase in CBD dose, it is feared that this would lead to serious adverse events/side-effects, particularly with the long-term use of CBD.
Several researchers have examined the side-effects of CBD at higher doses, and they found that the most commonly reported adverse events were somnolence, diarrhea, reduced appetite, fatigability, and less frequently, increased serum aminotransferases (liver enzymes). Because of the increase in the liver enzymes with the use of high doses of CBD, the potential hepatoxicity of CBD was warranted to be studied. Meanwhile, a well-conducted animal study reported that CBD is protective against liver damage and would not cause hepatotoxicity, and this added to the confusion regarding the effects of CBD on the liver.
As a result, the question of whether CBD is safe and free of major side-effects, including hepatotoxicity, at the doses that are frequently used in dietary supplementations was raised. This question will be addressed in detail in the upcoming sections while discussing the major findings of both animal and human research studies.
Is CBD Protective Against Liver Damage or Cause it?
There is a paucity of well-designed animal studies that examine the safety of oral CBD in the purified form. The majority of available studies investigate the safety of CBD along with THC extracts. In a 90-day toxicity profile study, rats were administered with an extract that contains 25% CBD. Rats received different doses of the extracts, including 100, 360, and 720 mg/kg/day. No increase in serum liver enzymes was noted in rats receiving the 100 and 360 mg/kg/day dose of the extract. Meanwhile, rats that were given the higher doses (720 mg/kg/day) had a three-fold increase in their liver enzymes. After 28 days from the trial end-point, it was noted that the level of liver enzymes returned back to normal. It should be noted that the extract also contains THC at higher concentrations, which may be the cause of the significant increase in liver enzymes. Eventually, the authors of this animal research concluded that the hepatic side-effects of this extract were generally mild and reversible, even at high doses of cannabidiol (180 mg CBD; 720 mg/kg/day of the extract), during the 90-day period of the study.
In another animal study, it was highlighted that the use of CBD is protective against liver damage. CBD has been shown to prevent liver fibrosis, which is the last stage before the liver damage becomes irreversible.
A number of human research studies have investigated the safety and the hepatotoxic potential of CBD among a group of patients with epilepsy who were treated with Epidiolex. Noteworthy, neurological disorders are frequently treated with multiple drugs, and thus, it is difficult to determine whether hepatotoxicity is the result of CBD use or the use of other neurological drugs, such as valproic acid, which is frequently used for the management of epilepsy. Therefore, based on human studies, it is still unclear whether the adverse events on the liver are the result of the use of high CBD doses or due to the concurrent use of valproic acid, which is well-known for causing hepatotoxicity.
In an open-label research study, a total of 162 patients with drug-resistant seizures were treated with oral CBD (2 to 5 mg/kg/day) for a period of 12 weeks. It was noted that, among those who completed the study, 7% had experienced a slight increase in serum transaminases (liver enzymes), while one patient had an excessive increase in serum liver enzymes, and therefore he was withdrawn from the study. Of note, all of the patients were taking valproic acid along with CBD. Therefore, it is difficult to determine if this effect was due to the use of CBD or valproic acid.
In a similar study, 120 children with drug-resistant epileptic syndromes were given CBD orally (20 mg/kg/day) for a period of 14 weeks. A slight increase in liver enzymes occurred in 12 patients. Also, all of them were taking CBD in conjunction with valproic acid. Those patients were withdrawn from the study. Surprisingly, the liver enzymes of 9 out of those 12 patients had returned back to normal while being administered CBD. Therefore, it was suggested that CBD does not cause an increase in liver enzymes or any form of liver damage.
The long-term effects of CBD use were also studied in an extension of an open-label research study. CBD was administered orally (21 mg/kg/day) to 264 patients with epileptic syndromes. Patients were also administered three antiepileptic drugs. After completing the study, the serum levels of liver enzymes were examined, and it was noted that 23 patients had increased liver enzymes (> three times the upper limit of normal). Of particular importance, those patients were also found to have taken valproic acid along with CBD.
Moreover, in a placebo-controlled, double-blinded clinical trial, a total of 76 patients with drug-resistant epilepsy were treated with CBD (20 mg/kg/day), while 73 patients were treated with CBD (10 mg/kg/dose) for a period of 14 weeks. It was noted that 11 patients had a marked increase in liver enzymes, while 3 patients had a slight increase in liver enzymes. Out of the 14 patients who experienced higher liver enzymes, 11 were receiving valproic acid as well. Notably, the liver enzymes of those patients returned back to normal during treatment (5 patients), after the reduction of CBD dose, CBD discontinuation, or after the reduction of the dose of other antiepileptic drugs (9 patients).
Based on the aforementioned studies, it is highly suggested that resultant liver damage (increased liver enzymes) in patients treated with CBD is due to the concurrent use of other antiepileptic medications. That being said, in order to reach decisive conclusions in this matter, CBD needs to be investigated alone. Also, CBD has lately been frequently used in other medical problems. Therefore, it is advised to investigate the safety of CBD in those populations as well. Until more research is conducted, CBD can be used for treating many medical conditions. However, in those using higher doses of CBD, it is advised to monitor their liver enzymes on a monthly basis to avoid any unintended outcomes.
The Take-Home Note:
Based on the available body of evidence, CBD can be safely used in many medical conditions, with minimal and reversible effects on the liver. Until clear-cut evidence has been reached, it is advised to monitor the levels of liver enzymes on a monthly basis, particularly in those receiving very high doses of CBD.
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