When consumers take CBD orally (as a tincture, drink, capsule, gummies, foods, etc), it has the lowest bioavailability of any delivery method. As little as 6% of CBD reaches its goal when taken on an empty stomach. As a comparison, bioavailability of inhaled CBD (through vaping) is about 31%.
The main reason for its poor uptake is that CBD is fat-soluble (not water-soluble), and this makes it hard for the body to absorb it. Its slow absorption through the intestinal wall means that the stomach’s digestive enzymes and acids destroy much of the CBD before absorption through the intestines and the liver (known as “first-pass metabolism”).
In this article, we summarize the available evidence regarding the bioavailability of CBD related to its gastrointestinal absorption, presystemic elimination, and its susceptibility to metabolic drug interactions.
In biopharmaceutical terms, CBD is a “class 2 compound”, meaning that it has very low water solubility and the body’s metabolism easily eliminates it in the gut. Low-water soluble substances are usually highly soluble in fats (lipophilic). Therefore, experts recommend to take class 2 compounds with a high-fat meal to increase their solubilization in the gut.
In the case of the FDA/EMA approved CBD medicine, the oral CBD solution has a sesame-oil-base to help overcome the poor bioavailability. Regardless, it still only achieves 6 to 19% bioavailability after taking the drug in a fasting state.
When consumers take CBD with a high-fat meal (840–860 calories), plasma CBD concentration dramatically increases 4.9-fold. In addition, taking CBD with a high-fat meal not only increases bioavailability, but also reduces the variability of absorption seen between different individuals.
As such, the large variability in absorption (empty stomach vs. with a high-fat meal) observed could lead to different CBD effects if taken inconsistently around meal-times.
Once CBD enters the bloodstream, the liver acts to metabolize and convert it into a form that can be easily transported and excreted. However, CBD is a “high-clearance drug”, meaning that the liver extracts and removes about 70–75% of it in the first pass before CBD could reach the systemic circulatory system.
The bioavailability of CBD is also dose-dependent, and we see a decrease in bioavailability at extremely high doses (>3000 mg). This is primarily due to CBD’s poor water solubility, which limits its rapid absorption. Fortunately, the effect is less pronounced in doses in the approved range (10 to 20 mg/kg/day).
With the liver being so efficient in removing CBD, researchers have looked to increase the gastrointestinal absorption of CBD to improve its overall bioavailability. By adding lipids (e.g. oils) to the formulation increases CBD bioavailability by 2.5 times compared with no lipids added.
Scientists have also found that the simultaneous addition of lipids substantially improves CBD bioavailability by stimulating/activating the intestine lymphatic transport system. As such, this assists in enhancing CBD uptake to over 30% uptake of CBD (almost on par with vaping).
Scientists speculate that this different route of absorption may also reduce or avoid the liver’s metabolism of CBD. Lymph flows from the gut walls to the mesenteric lymph nodes and then via the mesenteric and thoracic ducts into the systemic circulation. As such, CBD dissolved in the lymph bypasses the liver’s first-pass metabolism and removal, and thus increasing bioavailability.
A further study noted that the main compound produced after the first-pass metabolism is 7-hydroxy-CBD, which still maintains some of CBD’s beneficial properties. Therefore, measures of CBD bioavailability (post-liver-metabolism) may, in fact, underestimate CBD’s activity still present in the circulation.
In addition, due to its lipophilic properties, taking CBD regularly can result in the accumulation of CBD in the body’s fatty-tissues for up to 2–3 weeks after oral ingestion. This CBD is more slowly released back into the circulation and via the liver for elimination.
Watch this 7:43 minute video about CBD bioavailability
Given its high liver clearance, interactions with other drugs that inhibit liver metabolizing enzymes can also affect CBD metabolism. In the liver, CBD is metabolized by cytochrome P450 enzymes (CYP3A4 and CYP2C19). When a CYP3A4 inhibitor was combined with CBD mouth spray, CBD’s exposure doubled. On the other hand, when an enzyme promoter was given, CBD exposure decreased by 60%. However, no studies have taken this further by investigating CYP3A4 inducers with other orally administered CBD.
The enzyme CYP2C19 appears to be responsible for the metabolism of CBD to 7-hydroxy-CBD, but the mechanism is unclear. Some studies, however, show that CBD has a dose-dependent inhibiting effect on CYP2C19 , which has important consequences. CYP2C19 is involved in the metabolism of several prescription drugs for heartburn and reflux such as omeprazole, lansoprazole, phenytoin, diazepam, and escitalopram. Therefore, CBD can interfere with the effectiveness of these drug treatments.
A greater understanding of CBD’s absorption and metabolism could enable the development of new formulations. This would allow better and more consistent bioavailability of future CBD products and reduce the unevenness in clinical response.
Perucca E, Bialer M. Critical Aspects Affecting Cannabidiol Oral Bioavailability and Metabolic Elimination, and Related Clinical Implications. CNS Drugs. 2020 Aug;34(8):795-800. doi: 10.1007/s40263-020-00741-5. PMID: 32504461