Cannabinoids, such as CBD and THC, can be taken in a variety of ways, which are often referred to as delivery methods. If you are familiar with cannabinoid-containing therapeutic products, you have likely seen oils, tinctures, and sprays that are designed to be absorbed through the mucosa of the patients’ mouths (cheeks, gums, and under the tongue). You may see these products categorized as sublingual, buccal, oromucosal, or transmucosal. In this article, we will examine the pharmacokinetic properties of this route of administration specifically as it relates to the compound cannabidiol (CBD), as well as discuss considerations for therapeutic use.
Cannabinoids are categorized as Class II drugs under the Biopharmaceutical Classification System, meaning they have poor solubility in aqueous solutions but are highly permeable1. This class of drugs clashes with traditional pharmaceutical formulation standards, but this does not mean they do not have potential therapeutic uses. It does mean, however, that cannabinoid drug product formulations vary significantly from traditional pharmaceuticals.
ADME Principles of Transmucosal Delivery
The term “Pharmacokinetics” refers to the effect your body has on a certain drug that has entered your system. The main concerns of pharmacokinetics are how the body absorbs, distributes, metabolizes, and excretes the drug, commonly referenced as ADME. As mentioned earlier, cannabinoids are delivered via a variety of methods, due in part to the variance in these ADME properties between formulations. Transmucosal delivery of cannabinoids involves drug absorption through the mucosal barrier to achieve systemic circulation2. Transmucosal drug delivery systems have a high patient acceptability rate compared to other available methods.
Once cannabinoids are absorbed, they are distributed throughout the body to specialized receptor sites which are aptly named Cannabinoid-1 receptor and Cannabinoid-2 receptor, or CB1 and CB2 for short. It should be noted that the exact mechanisms of action for cannabidiol is not well-established (there are many). Studies suggest part of CBD’s effectiveness is a result of behaving as an allosteric modulator of cannabinoid receptors3. This means that CBD does not activate either CB1 or CB2, but rather affects the binding availability of primary agonist molecules to these receptors. This behavior is how CBD impacts our bodies’ Endocannabinoid Systems.
The Endocannabinoid System is composed of two G-coupled protein receptors (CB1 & CB2), various endogenous lipid ligands, and the active enzymes that promote biosynthesis and metabolic transformations4.
Cannabinoids consumed via transmucosal delivery bypass first-pass metabolism through the liver. Drugs that undergo the first pass effect experience a reduction in the active concentration of that drug before it reaches systemic circulation, which can mean a higher dose is necessary or that blood concentration levels fluctuate more rapidly5. The bypassing of hepatic first-pass metabolism then leads to higher bioavailability.
It should be noted that with this route of delivery, trace amounts of cannabinoids may be swallowed and would then be exposed to first-pass metabolism through the liver. Patients utilizing transmucosal cannabinoid products should be made aware of this possibility and be advised to wait at least 60-90 seconds before swallowing once the dose has been administered. This time allows the oil-soluble cannabinoids and their carrier to absorb through the mouth and enter the bloodstream.
Even though first-pass metabolism is avoided with this route, the cannabinoids circulating through the bloodstream will still eventually reach the liver to be metabolized and eventually excreted from the system. The metabolic pathway of CBD involves extensive hydroxylation followed by oxidation, which occurs primarily via CYP450 enzymes found in the liver6. Because of this, there is a theoretical concern that CBD can impact the blood concentrations of other drugs that are dependent on CYP450 metabolization. To address this concern, it is recommended to take CBD separately from other medications, allowing approximately 3 hours in between doses to allow for uninhibited metabolization.
Product Considerations
Hemp-sourced cannabinoid products are growing as therapeutic options for many patients, as well as a supplementary addition to daily health and wellness routines. The increasing acceptance of hemp products containing cannabinoids is due in large part to the purported health benefits that consumers are experiencing, as well as recent governmental approvals exemplified through shifting regulations. However, provider and patient due diligence in product selection are still imperative as regulatory product and testing oversight is limited compared to pharmaceutical standards.
When choosing hemp-sourced cannabinoid products, certain factors should be considered. First and foremost, the product should include a Certificate of Analysis (CoA) report from an ISO-certified lab to ensure the product is accurately labeled and free from unlisted contaminants. Products without certification of testing should be considered toxic. The next major consideration is product consistency. Since hemp is an agricultural product, some variance is to be expected between harvest batches, but producers of high-quality hemp products take extra steps to combat this issue. Through the utilization of a single variety of hemp, maintenance of identical farming practices, and enactment of rigorous quality control standards, producers are able to ensure a consistent product profile.
When to Choose Transmucosal Products
People who are using cannabinoid products for the first time are encouraged to use oils intended to be taken this way. Why? One reason is that cannabinoid-rich oils held under the tongue will not only enter the bloodstream ten times faster compared to swallowing capsules or edibles. The more important reason is that people using cannabinoid products must find which dose works best for them. Dosing ranges can vary from 5mg to 500mg (or more) depending on the person and health situation. Finding that optimal serving size is the most important step in the search for cannabinoid-based health. Since other delivery cannot be easily titrated, using sublingual oils as part of any patient’s 30-day dosing plan is recommended.
References:
[1] Center for Drug Evaluation and Research. (n.d.). M9 biopharmaceutics classification system-based Biowaivers. U.S. Food and Drug Administration. Retrieved August 8, 2022, from https://www.fda.gov/regulatory-information/search-fda-guidance-documents/m9-biopharmaceutics-classification-system-based-biowaivers.
[2] Chinna Reddy P, Chaitanya KS, Madhusudan Rao Y. A review on bioadhesive buccal drug delivery systems: current status of formulation and evaluation methods. Daru. 2011;19(6):385-403.
[3] Kathmann, M., Flau, K., Redmer, A. et al. Cannabidiol is an allosteric modulator at mu- and delta-opioid receptors. Naunyn Schmied Arch Pharmacol 372, 354–361 (2006). https://doi.org/10.1007/s00210-006-0033-x
[4] Vemuri, V. K., & Makriyannis, A. (2015). Medicinal chemistry of cannabinoids. Clinical Pharmacology & Therapeutics, 97(6), 553–558. https://doi.org/10.1002/cpt.115
[5] Jiang R, Yamaori S, Takeda S, Yamamoto I, Watanabe K. Identification of cytochrome P450 enzymes responsible for metabolism of cannabidiol by human liver microsomes. Life Sci. 2011;89(5-6):165-170. doi:10.1016/j.lfs.2011.05.018
[6] István Ujváry and Lumír Hanuš. Human metabolites of Cannabidiol: A review on their formation, biological activity, and relevance in therapy. Cannabis and Cannabinoid Research. Dec 2016.90-101. http://doi.org/10.1089/can.2015.0012