In volume 1, we discovered a sobering fact: oral bioavailability of cannabinoids is poor. On an A-F scale, we gave it a D. But as Albert Einstein said, “Reality is merely an illusion, albeit a very persistent one.” Fortunately, it’s possible to bend the reality of oral bioavailability.
Combining a high-fat meal with cannabinoids produces major improvements in bioavailability. Zgair et al (2016) observed a 2.5- to 3-fold increase in systemic exposure of THC and CBD when administered to rats with sesame oil (mostly long-chain triglycerides).  A 2019 study published in Epilepsia examined eight human patients; a high-fat meal prior to CBD capsules amplified maximum concentration 14-fold and area-under-the-curve 4-fold. 
Maximum concentration, or cmax, refers to the highest amount of a substance (i.e., CBD) that reaches circulation. Area-under-the-curve, or AUC, reflects total exposure over time. In this 2019 study, CBD not only reached levels 14 times higher than fasted baseline — it also multiplied total exposure by four.  In terms of bioavailability, this is a big deal.
[Graphic 2: U.S. National Library of Medicine]
The FDA-approved CBD isolate drug Epidiolex® echoes this phenomenon. Look no further than the safety label: “Coadministration of EPIDIOLEX with a high-fat/high-calorie meal increased Cmax by 5-fold, AUC by 4-fold, and reduced the total variability, compared with the fasted state in healthy volunteers.”
This bioavailability miracle is likely due to the phenomenon of “intestinal lymphatic transport.” When ingested, fats are broken down and form chylomicrons (CM), or lipid-protein particles. These particles have strong affinity for cannabinoids. Cannabinoids jump on the CM bus, so to speak. Those that make it (an estimated 1/3) bypass first-pass metabolism. They enter circulation through intestinal lymphatic transport.  Instead of portal circulation and relentless pounding from the liver, these cannabinoids enter circulation through lymph. 
This is not the same as simply infusing cannabinoids in oil carriers. The purpose of extraction/infusion into fats is decarboxylation and solubility. Achieving peak CM levels appears to require significant fat content, such as that found in medium- to high-fat meals. [1,4]
Another promising adventure concerns liposomal formulations. Liposomes are lipid nanoparticles that serve as carriers or transporters for a whole range of pharmaceuticals. [3,5] Essentially, they are phospho-lipid ‘bubbles’ capable of delivering encased lipids (e.g., cannabinoids) into aqueous solutions. This gives cannabinoids the surface appearance of being “water-soluble” although they are not.
[Graphic 3: SuperManu]
Remember, cannabinoids are fat-loving, water-hating molecules. The phospho-lipids in a liposome have hydrophilic (water-loving) heads and hydrophobic (water-hating) tails. The bi-layer (two layers back-to-back) means lipids can be trapped inside. Liposomes may thereby help protect cannabinoids from first-pass metabolism and increase rates of absorption substantially. It also appears that liposomes increase CM and lymphatic transport (like high-fat meals) although this mechanism of action is unclear. 
Recently, several companies have patented liposomal cannabinoid products designed to enhance absorption. Marketing that says ‘water-soluble’ likely relates to liposomes; cannabinoids are never water soluble, but may appear as such when encased in a liposome. Challenges associated with this technology include manufacturing difficulties (such as drug loading), variable stability, and cost. 
The marketing surrounding cannabinoid products can be dizzying. Terms like enhanced absorption, superior delivery, and even water-soluble all point to bioavailability. Overall, bioavailability is how much of the cannabinoids we dose actually reach the bloodstream. Due to their lipophilic nature, oral cannabinoids receive a D in bioavailability. But a high-fat meal or liposomal technology can boost this grade up to a B. And that’s worth pinning on the fridge.
- Zgair, Atheer et al. “Dietary Fats and Pharmaceutical Lipid Excipients Increase Systemic Exposure to Orally Administered Cannabis and Cannabis-based Medicines.” American Journal of Translational Research, 8, no. 8, 2016, pp. 3448-59. Journal Impact Factor = 2.829, Times Cited = 14 (ResearchGate)
- Birnbaum, Angela K., et al. “Food Effect on Pharmacokinetics of Cannabidiol Oral Capsules in Adult Patients with Refractory Epilepsy.” Epilepsia, vol. 60, no. 8, 2019, pp. 1586–1592, doi:10.1111/epi.16093. Journal Impact Factor = 5.562, Times Cited = 2 (ResearchGate)
- Ahn, Hyeji, and Ji-Ho Park. “Liposomal Delivery Systems for Intestinal Lymphatic Drug Transport.” Biomaterials Research, vol. 20, no. 1, 2016, doi:10.1186/s40824-016-0083-1. Journal Rank = 0.828, Times Cited = 12 (ResearchGate)
- Zgair, Atheer, et al. “Oral Administration of Cannabis with Lipids Leads to High Levels of Cannabinoids in the Intestinal Lymphatic System and Prominent Immunomodulation.” Scientific Reports, vol. 7, no. 1, June 2017, doi:10.1038/s41598-017-15026-z. Journal Impact Factor = 4.525, Times Cited = 10 (ResearchGate)
- Bruni, Natascia, et al. “Cannabinoid Delivery Systems for Pain and Inflammation Treatment.” Molecules, vol. 23, no. 10, 2018, p. 2478, doi:10.3390/molecules23102478. Journal Impact Factor = 3.060, Times Cited = 3 (ResearchGate)