Cannabidiol (CBD) is known as one of the most therapeutically promising cannabinoids in medicine today. Currently, however, adequate studies assessing CBD as a drug solution (instead of as a plant extract) are still lacking. This information is critical for drug researchers and manufacturers in the pharmaceutical industry who are interested in developing stable and effective cannabinoid therapeutics. A recent, 2020 scientific study led by Sánchez and colleagues, conducted an investigation into CBD stability as a drug solution and discovered some notable findings regarding three important factors that a CBD drug solution’s stability: temperature, type of solvent used, and photosensitivity or light exposure.1 The study is titled, “Stability characteristics of cannabidiol for the design of pharmacological, biochemical and pharmaceutical studies” and utilizes an established High-Performance Liquid Chromatography (HPLC) assay to quantify CBD in solution and in simulated physiological conditions, instead of as a plant extract.1 This report will explore the findings of this study and observe their clinical implications and therapeutic significance for the world at large.
How Stable Is An Aqueous Drug Solution Of CBD?
There are a few important factors to consider when evaluating CBD as an aqueous solution. This particular study assessed the stability of CBD in both water and ethanol, as well as evaluated the stability of CBD in physiological conditions. The study determined that “in simulated physiological conditions (pH 7.4 and 37 °C) 10% of CBD was degraded within 24 h. These studies indicate that CBD is highly unstable, and this should be taken into account in the development of in vitro and in vivo studies of CBD activity and in the pharmaceutical development of dosage forms.”1 What factors exactly affect CBD stability? The study identifies three key factors that are important to our discussion.
3 Key Factors That Affect CBD Stability As An Aqueous Drug Solution
There are three key factors regarding the stability of an aqueous drug solution of CBD that are notably pointed out by Sánchez and colleagues in their study: temperature, type of solution (ethanol versus water), and photosensitivity/light exposure. In regards to temperature, it notes that, “at room temperature, CBD was highly unstable.”1 Cooler temperatures are likely more ideal to preserve the chemical and consequent pharmacological activity of a CBD drug solution — the researchers found that, “at 5°C it was stable for at least 12 months.”1 Furthermore, the researchers found that CBD was significantly more stable in an ethanol solution compared to when water was used as a solvent. To quote the scientists, “the solvent influences CBD stability, and the latter is more stable in ethanol than in aqueous medium.”1 Finally, the CBD drug solution was found to be sensitive to oxidation and light. The researchers stated that the “photolytic reaction seems to be oxidative.” Whereas in acidic conditions CBD would cyclize to THC, oxidation leads to the formation of a quinone compound. For drug makers, these factors are all critical to consider when attempting to create a reliable, consistent, and efficacious drug solution of CBD.
A Note About Limited Oral CBD Bioavailability & A Novel Self-Emulsifying Drug Delivery System
To give the reader an idea of just how important and challenging it is to create a durable, effective, and stable drug featuring a lipophilic (fat-loving) cannabinoid compound like CBD, consider the poor oral bioavailability of CBD in humans.2 This is due to the lipophilic nature of cannabinoids like CBD in general, as well as the extensive first-pass metabolism that takes place within the liver. The latter is variable depending on the individual and, as such, highlights the importance of establishing stable, titrated levels of CBD in any drugs being designed. Knaub and colleagues, in a 2019 study, conducted research to overcome these limitations by developing “a novel self-emulsifying drug delivery system (SEDDS) based on VESIsorb® formulation technology incorporating CBD, as Hemp-Extract…(SEDDS-CBD).”2 Researchers found that, by using this novel new delivery method, “single oral administration of SEDDS-CBD led to a 4.4-fold higher Cmax and a 2.85-/1.70-fold higher AUC0–8h/AUC0–24h compared to the reference formulation.”2 That is to say that the researchers determined this new drug delivery system was able to boost CBD concentrations in subjects that consumed it by over four times that of the reference solution, quantified and validated by area under the curve analysis. Researchers in this study also found drug levels reached maximum plasma levels in substantially less time (one hour instead of three) when compared to the reference formulation that utilized MCT oil. Thus, this new “self-emulsifying” drug delivery system for CBD allows for higher concentrations of CBD to be bioavailable or useable by the body and these concentrations are also reached at a faster rate! Perhaps even more curious in the field of CBD stability and cannabinoid drug design studies is the “father of cannabis science,” Raphael Mechoulam, and his most recent contributions to this field.
Mechoulam Stabilizes Therapeutic Cannabidiolic Acid More Potent Than THC, CBD
Mechoulam’s recently patented acid-based cannabinoid molecule, EPM 301, has significant implications for CBD research and drug development, in part, due to its unique stability.3 The cannabidiolic acid at the center of Mechoulam’s discovery is particularly innovative because it is a methyl ester many times more potent than THC or CBD, as well as a precursor to those cannabinoids which are formed later in the plant’s life cycle.3 Until now, it was thought that these acid-based cannabinoid molecules were too unstable to be used in any meaningful way during drug development. However, Mechoulam and his team’s use of the chemical process called esterification allowed them to stabilize this potent molecule, which exhibits similar beneficial effects to that of THC and CBD, but without any unwanted side effects noted thus far. The novel use of esterification by Mechoulam to stabilize acid-based cannabinoids is a noteworthy case study in cannabinoid-based drug development.
The current difficulties within the field of cannabinoid research should not deter a foray into these compounds, by any means. Given the lack of information and research into human endocannabinoid systems, it should be recognized that as we continue to learn more about cannabinoids, this knowledge will only help to elucidate our own, endogenous lipid-based system. With the complexities of the Cannabis plant as a spur to research and understanding, along with its promising applications within the field of medicine, new modalities for preserving and delivering these compounds in the most efficacious manner will continue to occur. With the murky legal waters opening up research possibilities, and the overreaching availability of CBD products, further study will hopefully pave the way for a legitimate and effective compound that can be scientifically acknowledged and recognized.
- Fraguas-Sánchez, A. I., Fernández-Carballido, A., Martin-Sabroso, C. & Torres-Suárez, A. I. Stability characteristics of cannabidiol for the design of pharmacological, biochemical and pharmaceutical studies. J. Chromatogr. B 1150, 122188 (2020).
- 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 24, (2019).
- Hasse, J. More Potent Than CBD, THC: Dr. Raphael Mechoulam Explains His Latest Discovery. Forbes https://www.forbes.com/sites/javierhasse/2020/07/12/dr-mechoulam/.