Introduction. In this invited review, we are honored to have Dr/Professor Alvin Berger describe the current challenge of poor bioavailability of CBD, and how bioavailability can be improved by various means, including use of medium chain triglycerides (MCTs). Dr. Berger is a published expert on lipids including MCTs, with academic, industrial and commercial experience. He has also published landmark papers on endocannabinoids and phytocannabinoids in prestigious journals with Raphael Mechoulam and Vincenzo Di Marzo, leaders in the cannabinoid field.
Definitions of solubility, absorption, and bioavailability. Solubility is the ability of a substance to be dissolved. Some nutrients are not dissolved, but evenly dispersed as fine particles with mixing or sonication. Bioavailability is the uptake of a drug or nutrient by our organs. As it is challenging to measure levels of a nutrient in an organ (requiring a biopsy in humans), a surrogate is to measure levels in whole blood, plasma, or serum. Once the molecule of interest is in the blood circulation, it can exert biological actions by binding to receptors (such as cannabinoid receptors CB1 and CB2 in the endocannabinoid system; and non-cannabinoid receptors like serotonin receptor 5-HT1A, GPR55, and μ- and δ-opioid receptors). If a nutrient is not properly solubilized or dispersed, this can contribute to poor bioavailability. Other factors contributing to poor bioavailability are: poor absorption during digestion (uptake of nutrient from the digestive tract to the blood circulation); degradation during digestion; excretion to the stool or urine; and being metabolized or broken down before reaching target organs. In recent years, drugs and nutrients (such as CBD) have become more lipophilic (fat loving), with poor solubility, unless special emulsifiers and other technologies are employed.
CBD focus. CBD has attracted significant interest due to lack of psychotropic activity, and anti-inflammatory, anti-oxidative, anti-necrotic, pro-sleep, anticonvulsant, anxiolytic, and anti-pain properties . CBD displays a favorable safety and tolerability profile in humans making it a promising candidate for combatting epilepsy, Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, Crohn’s disease, society anxiety disorder, and schizophrenia. In June 2018, highly purified CBD Epidiolex®, a CBD oil preparation, was approved by the FDA for seizures associated with Lennox-Gastaut syndrome or Dravet syndrome. CBD is widely used as a popular food supplements and also topically for a range of complaints. The CBD market will grow to $2.1 billion for US consumer sales by 2020.
Bioavailability of CBDs. CBD can be obtained orally, sub-lingually (under the tongue), and by injection, vaporization, rectal suppositories, and inhalation. Oral bioavailability of CBD is very low (13–19%)  due to: limited aqueous solubility; extensive first pass metabolism (after passing through the intestine, the substance is converted to an inactive form at the liver); and renal (kidney) excretion of metabolites . Despite extensive use of CBD, there is little data on its absorption, distribution, metabolism, and excretion, and rates thereof (together, known as pharmacokinetics or PK). Understanding PK is necessary to optimize bioavailability. A challenge in determining bioavailability is high intra (within)- and inter (between)-subject absorption , which can relate to genetic differences, foods consumed with the preparations, and more. Companies must optimize solubility and bioavailability to provide customers with an efficacious product to differentiate themselves from competitors in this increasingly saturated and soon commoditized space. With higher bioavailability, consumers can consume less product to achieve equivalent benefits, and better taste. If CBD crystallizes out of solution, this imparts a bitter and undesirable taste.
Dose effects on bioavailability. Not surprisingly, consuming more CBD leads to a higher blood concentration. But there is a saturation or plateauing (leveling off) effect. For example, maximum blood concentration was similar with 400 mg and 800 mg doses . Moreover, physiological benefits exist at low and high doses (bimodal effects); and these effects can be opposite at different doses, vastly complicating decisions on the optimal dose to consume. At this time, lack of understanding of dose to consume for different conditions is a huge concern, and not a problem easily solved.
Meal effects on bioavailability. Consuming fatty foods (nut butters, oils, full fat dairy, avocado, etc.) prior to consuming a lipophilic substance (like CBD) generally improves absorption and hence bioavailability. Adding oils to CBDs makes the mixture more lipophilic (fat-loving), driving absorption to the chylomicron-lymphatic absorption path, increasing overall bioavailability versus absorption via the hepatic (liver) portal route (system for absorbing hydrophilic [water-loving] substances from the gut to the liver). In one study, consuming a standard breakfast one hour before consuming CBD capsules increased bioavailability . Co-consumption with fatty foods may also lipase activity, which is valuable when lipid components must be cleaved off a molecule’s backbone for maximal absorption (for example, absorption of the fatty acids from the glycerol backbone in triglycerides, the main form of fat in nature); and may increase biliary flow which helps solubilize fatty nutrients in the gut. Consuming CBD with a fatty meal may also decrease any gastrointestinal discomfort basis results with other fatty molecules. Despite the current craze to add lipophilic nutrients to coffee (“bullet-proof”), this is generally ill advised due to more propensity for gastrointestinal absorption and possibly less solubility and associated bioavailability (not to mention, undesirable effects of consuming acidic coffee on an empty stomach).
Methods to increase solubility of CBDs. These include: self-emulsifying drug delivery system (SEDDS) ; self nano-emulsifying drug delivery systems (SNEDDS) ; utilization of liposomes and lipospheres (coating CBD in lipid particles) ; and solubilizing CBDs in oils such medium chain triglycerides (MCT) and other oils . An emulsion is a thermodynamically stable system comprising oil, water, and a surfactant or emulsifier, and have been used to effectively deliver highly lipophilic drugs and nutrients. Solubilization in MCTs will be our focus herein.
MCTs defined. MCTs consist of fatty acids of chain length 6-10 carbons, esterifed (attached) to a glycerol (glycerin) backbone. In a typical triglyceride in a vegetable oil, the chain lengths would be 16-20 carbons. Fatty acids of chain length 6-10 are classified as a saturated fat for labeling purposes, but do not behave like longer chain fatty acids with 12 or more carbons, because medium chain fatty acids (MCFA) are absorbed via the hepatic portal system; whereas longer chain fatty acids are absorbed via the lymphatic system. MCFA are rapidly and efficiently absorbed, and MCT have been used since the 1980s by athletes, and in recent years by the masses for weight management, energy, cognition and increasingly solubilization of hard to solubilize nutrients (and drugs). MCTs are used topically (labeled as caprylic-capric tryglycerides- C8/10) to increase penetration through the skin’s stratum corneum outer layer.
Solubilizing CBDs in MCT oils. Bioavailability of CBDs can be improved with various techniques. MCTs advantage is providing a healthy oil that is not stored as body fat, but rather burned for energy at the liver or preferentially converted to beneficial ketone bodies, providing sustained energy, glycemic control, weight management, and cognitive benefits. These benefits may be additive or possibly synergistic (greater than the sum of the parts) with CBDs. MCTs can increase bioavailability of CBDs by increasing solubilization in liquid products and in the gut , and by minimizing first pass metabolism (liver degradation). MCTs and their derivatives can also increase bioavailability by forming SEDDS and SNEDDS with drugs and nutrients [10-12]. A practical advantage of solubilizing CBDs with MCTs are the very long shelf life of MCTs, with typical re-test dates being 3 years. Stability is high because there are no double bonds in high quality C8/10 MCTs to oxidize. Oxidation is a major concern with some vegetable oils and fish oils, imparting bad taste and undesirable health effects. Despite reports in lay media, there is little evidence MCTs have anti-microbial properties; rather it is the monoglyceride or fatty acid component of MCTs that have anti-microbial properties [13, 14].
Types of MCTs used to solubilize CBD. Companies purchasing LifeSense Products’CBD Solubilizer (containing C8 MCTs) report they have internal data demonstrating C8 MCTs solubilize CBDs better than C8/10 MCTs; and claim better bioavailability with the former. Dr. Berger is not aware of formal studies proving this. However, C8 fatty acids and C8 MCTs do have different polarity than those from C8/10, so such differences are conceivable. Another advantage of C8 over mixtures of C8/10 is the former leads to larger increases in beneficial plasma ketone bodies, which is expected to translate to better weight management, sustained energy, cognition and other conditions correlated with increased ketone bodies .
Solubilizing CBDs in coconut oil. Despite marketing claims from the Coconut Oil Board and companies with vested interests, coconut oil is not a rich source of MCTs (and should not be called an MCT oil) as it contains predominately the longer chain C12 fatty acid (lauric acid; esterified to glycerol), and C12 is less polar (more hydrophobic, water resisting) than the C8 and C10 fatty acids (esterified to glycerol) found in true MCT oils . Coconut oil contains only 5-15% C8/10 fatty acids. C8 MCTs (such as LifeSense Products’ CBD solubilizer) contain 95+ percent C8, with up to 5% C10, and minimal C6 and C12. In C8/10 MCTs, the ratio of C8:C10 is 60:40 or 70:30. It is very likely coconut oil would solubilize CBDs differently than C8/10 MCTs; and physiologically coconut oil behaves mostly like other long chain fats, accumulating in adipose tissue and having adverse affects on LDL (bad) cholesterol in high amounts; moreover, coconut oil can impart a soapy taste to products .
Water soluble CBD and powdered CBD. Using previously described techniques, water soluble CBD oil appeared on the market beginning in 2016. CBD added to oil would appear as oil droplets in the water. To produce a single phase, CBD can be dispersed into oil to create an emulsion by: using surfactants to lower surface tension between two liquids; and by using emulsifiers to mix the two liquids. An emulsifier such as lecithin contains a hydrophilic head (the polar group in lecithin) and a hydrophobic tail (fatty acid chains in lecithin). The head contacts the water, the tail contacts the oil. If additional emulsifiers are added to MCT oil, an added benefit may be further increases in CBD absorption and bioavailability, tracking with greater increases in ketone bodies and plasma C8/C10 fatty acids (and also less stomach upset in sensitive individuals . Similarly, mixtures of powdered CBD and powdered C8 MCT oil (the latter from LifeSense Products) are manufactured with emulsifiers for addition to aqueous vehicles, offering the convenience of a powder. Such powders can be mixed with other nutritional powders.
Solubilizing different phytocannabinoids in MCT. Cannabis sativa plant contains more than a hundred different phytocannabinoid compounds, CBD being one. Hemp seed oil and full spectrum CBDs contain numerous phytocannabinoids and terpenoids. Some of these are structurally similar with similar polarity (charge) and may have similar solubility as CBD; but not all phytocannabinoids and terpenoids can be expected to solubilize equivalently in a given oil or bioavailability enhancer system. Thus, companies should make solubility measurements on their complex mixtures in MCTs. On the biological side, an advantage of complex phytocannabinoid systems are the “entourage” effects where non-receptor binding lipids decrease degradation of receptor-binding phytocannabinoids [17, 18]. As THC is structurally similar to CBD, systems that maximize solubility and bioavailability of CBD may do the same for THC and levels of blood THC should ideally be measured for each formulation developed .
Conclusions. MCTs alone and in SEDDs formulations are increasingly used to increase solubility and oral bioavailability of CBDs. This allows manufacturers to provide a product that is more potent biologically (also providing a competitive commercial advantage); and at the same time, provides for the independent (possibly synergistic) benefits of C8/10 MCT oils.
- Nakano, Y., et al., Development of a novel nanoemulsion formulation to improve intestinal absorption of cannabidiol. Medical Cannabis and Cannabinoids, 2019. 2(1): p. 35-42.
- Mechoulam, R., L.A. Parker, and R. Gallily, Cannabidiol: an overview of some pharmacological aspects. J Clin Pharmacol, 2002. 42(S1): p. 11s-19s.
- Huestis, M.A., Human cannabinoid pharmacokinetics. Chem Biodivers, 2007. 4(8): p. 1770-804.
- Knaub, K., et al., A novel self-emulsifying drug delivery system (SEDDS) based on Vesisorb(®) formulation technology improving the oral bioavailability of cannabidiol in healthy subjects. Molecules (Basel, Switzerland), 2019. 24(16): p. 2967.
- Millar, S.A., et al., A systematic review on the pharmacokinetics of cannabidiol in humans. Front. Pharmacol., 2018. 9: p. 1365-1365.
- Bruni, N., et al., Cannabinoid delivery systems for pain and inflammation treatment. Molecules, 2018. 23(10).
- Elgart, A., et al., Improved oral bioavailability of BCS class 2 compounds by self nano-emulsifying drug delivery systems (SNEDDS): the underlying mechanisms for amiodarone and talinolol. Pharm Res, 2013. 30(12): p. 3029-44.
- Zgair, A., et al., Dietary fats and pharmaceutical lipid excipients increase systemic exposure to orally administered cannabis and cannabis-based medicines. Am J Transl Res, 2016. 8(8): p. 3448-59.
- Feeney, O.M., et al., 50 years of oral lipid-based formulations: Provenance, progress and future perspectives. Adv. Drug Deliv. Rev., 2016. 101: p. 167-194.
- Niu, Z., et al., Lipid-based nanocarriers for oral peptide delivery. Adv. Drug Deliv. Rev., 2016. 106, Part B: p. 337-354.
- Rao, P.J. and H. Khanum, A green chemistry approach for nanoencapsulation of bioactive compound – Curcumin. Food Sci. Technol., 2016. 65: p. 695-702.
- Tripathi, C.B., et al., Systematic development of optimized SNEDDS of artemether with improved biopharmaceutical and antimalarial potential. Drug Deliv, 2016. 23(9): p. 3209-3223.
- Umerska, A., et al., Antibacterial action of lipid nanocapsules containing fatty acids or monoglycerides as co-surfactants. Eur J Pharm Biopharm, 2016. 108: p. 100-110.
- Berger, A., Coconut Oil – Is it ACTUALLY Good for You? 2019: Amazon Digital Services LLC.
- Vandenberghe, C., et al., Tricaprylin alone increases plasma ketone response more than coconut oil or other medium-chain triglycerides: an acute crossover study in healthy adults. Curr Dev Nutr, 2017. 1(4): p. e000257.
- Courchesne-Loyer, A., et al., Emulsification increases the acute ketogenic effect andbioavailability of medium-chain triglycerides in humans: protein, carbohydrate, and fat metabolism. Curr Dev Nutr, 2017. 1(7): p. e000851.
- Di Marzo, V., et al., Trick or treat from food endocannabinoids? Nature, 1998. 396(6712): p. 636-7.
- Berger, A., et al., Anandamide and diet: inclusion of dietary arachidonate and docosahexaenoate leads to increased brain levels of the corresponding N-acylethanolamines in piglets. Proc Natl Acad Sci U S A, 2001. 98(11): p. 6402-6.