Accurate Education – Cannabidiol (CBD): CBD Pharmacokinetics

Oral Use of CBD (Edibles)

Oral bioavailability of CBD is estimated to be only 6-19% due to significant first-pass metabolism of CBD in the liver.  Cmax and AUC following oral administration are also dose dependent. A dose of 10mg CBD has a mean Cmax of 2.5 ng/mL at 1.27 hours, and a dose of 400 or 800 mg has a mean Cmax of 181 ng/mL (at 3.0 hours) and 114 ng/mL (at 1.5 hours) for 400 mg, and 221 ng/mL (at 3.0 hours) and 157 ng/mL (at 4.0 hours) for 800 mg. A dose of 800 mg oral CBD in a small study reported a mean Cmax of 78 ng/mL and mean Tmax of 3.0 hours . Although, an increase in dose corresponds with an increase in Cmax, the Cmax between the higher doses of CBD does not greatly differ, suggesting a saturation effect between 400 and 800 mg.

In other words, there appears to be little benefit in exceeding single oral CBD doses of 400-800 mg.

In another study, one hour after oral capsule administration containing 5.4 mg CBD in males and females, mean Cmax was reported as 0.93 ng/mL (higher for female participants than male). In those who ate a standard breakfast meal 1 hour after the capsules, there was a slightly increased mean Cmax to 1.13 ng/mL. CBD remained detectable in the blood for 3–4 hours after administration. This is also demonstrated in animal studies; co-administration of lipids with oral CBD increased systemic availability by almost 3-fold in rats while  a pro-nanoliposphere self-emulsifying formulation formulation increased oral bioavailability by about 3- 6-fold.

Research evaluating the bioaccessibility of CBD with and without food  showed that lipase enzyme activity and fatty acid absorption increased
in the presence of bile salts. In the fed-state digestion revealed significantly higher micelle formation with CBD compared to the fasted state.  The increase in bioaccessibility of CBD with food can be explained by the fact that micelle formation from hydrolyzed lipids aid in bioaccessibility of hydrophobic molecules which depends on the food matrix and the presence of lipase and bile salts. This understanding has lead to the design of new formulations that enhance absorption of CBD and other lipophyllic compounds.

Because CBD oil is highly lipophilic and therefore very poorly soluble in water, it is not absorbed well with oral ingestion (80% or more of ingested CBD is not absorbed. Additionally, THC and CBD are prone to extensive first pass mechanisms, meaning that the liver metabozizes a very significant proportion of these compounds immediately upon absortion from the gut before entering the blood. These absorption factors result in low and erratic, variable oral bioavailability, only a small fraction – less than 10% – of orally ingested CBD  actually enter a cells where they exert their medical properties (true also for other cannabinoids and terpenes in marijuana).  Instead, CBD remains in the blood until it passes through the liver and is metabolized.

New formulations of CBD are appearing on the market that offer enhanced water solubility and absorption that provide greater bioavaiability. These products include liposomal formulations,  nano-sized formulations and self emulsifying formulations. Furthermore, some formulations supplement with compounds such as peperine that enhance bioavaliability with other mechanisms.

Liposomal CBD

Liposomal technology provides a method used to enable medications to be better absorbed from the gut and into cells. It is a technology commonly used in nutriceutical supplements, including products described elsewhere on this website (See: Meriva and Siliphos). Liposomes are small sacs with membranes made of phospholipids – the same type of membrane that encloses the cells in our bodies. Liposomal formulations involves enclosing individual drug molecules like CBD inside liposomes, which facilitates their entry into cells in the same way the body transports its own substances into and out of cells. Thus, liposomal CBD is more efficiently used by the body, estimated at possibly 4-5 times more efficiently.

Advantages of Liposomal CBDs

1. 1. 1. Encapsulates the active ingredients and delivers them directly into the cell;
      2. Reduces the breakdown of the CBD (avoids first pass metabolism by the liver); and 
      3. It improves the percentage of bioavailable CBD, as the full concentration can be absorbed

Nano Formulations

In general, cells can absorb particles only up to 50 nanometers (billionths of a meter) in diameter. Because CBD is hydrophobic and fatty, it binds with itself to a certain extent, creating chains of CBD that are too large to be absorbed by cells. Recent technology sometimes referred to as nano-amplification allows for the separation of CBD molecules  from each other.  Individually, CBD molecules are about 10-15 nanometers in diameter so that nano-forms of CBD are better absorbed by cells with less wastage.

Self-Nano Emulsifying Drug Delivery Systems (SNEDDS)

Self-nano emulsifying drug delivery systems (SNEDDS) increase the oral bioavailability of poorly water-soluble drugs by multiple mechanisms in concert including:

1. 1. 1. Improvement in drug’s solubility
      2. Reduced intra-enterocyte metabolism by CYP P450 enzymes
      3. Reduced P-glycoprotein (P-gp) efflux activity
      4. Reduced hepatic first-pass metabolism bypass via lymphatic absorption

Transdermal Route

The steady-state blood concentrations of transdermal CBD maintain throughout 48 hours of gel application, starting to decline at about 6 hours after gel removal, indicating a skin reservoir effect in guinea pigs. The skin reservoir property of CBD is because of the high lipophilic property of the drug that makes it easier to cross the stratum corneum but makes it difficult to traverse through the aqueous dermis.

Because THC is more lipophilic than CBD, the skin reservoir effect is higher with THC, but steady-state blood concentrations of THC are lower than those achieved with CBD. With the use of the enhancer, CBD is delivered up to 3.7 times better than without, suggesting this would be the case with transdermal THC.

CBD Metabolism

CBD Metabolism

CBD metabolism is similar to that of THC, with primary hydroxylation to 7-hydroxy cannabidiol (7-OH-CBD), the major pharmacologically active metabolite which is further converted to the inactive metabolite 7-COOH-CBD. After this step there is further liver metabolism and subsequent fecal, and, to a lesser extent, urinary, excretion of the additional metabolites. Little is known about the pharmacological activity of the metabolites of CBD in humans.   

CBD is reportedly metabolized primarily by the liver enzymes CYP2C19 and CYP3A4, and additionally CYP1A1, CYP1A2, CYP2C9 and CYP2D6. A 2021 study concluded that both CYP2C19 and CYP2C9 are involved in CBD metabolism to the active metabolite 7-OH-CBD.  CYP2C19 enzyme activity in the formation of 7-OH-CBD  is not associated with CYP2C19 genetic variants (genotypes) which is consistent with factors besides CYP2C19 polymorphism influence CYP2C19 activity and CBD 7-hydroxylation. While CYP3A provides the greatest contribution to overall CBD clearance through other oxidative pathways, CYP3A does not contribute significantly to production of 7-OH-CBD. Metabolism also occurs in extra-hepatic tissues that have CYP450 enzymes, including the small intestine and brain.

CBD and THC Metabolism

 It has been reported that CBD  inhibits THC metabolism but it is believed that the pharmacokinetics of THC are not meaningfully affected by CBD, except for a slight slowing of the metabolism of 11-OH- THC to THC-COOH. Co-administration of CBD does not significantly affect the total clearance, volume of distribution, or terminal elimination half-lives of THC or its metabolites.