By Renata Vardanega
Dr. Renata Vardanega graduated in 2011 from the Universidade Reginal Integrada in Erechim, Brazil, in Food Engineering, and finished her PhD in Food Engineering in 2016 at the University of Campinas, Brazil. She has dedicated her work to the optimization of green extraction processes to obtain bioactive compounds from different matrices and to the development of strategies to improve the bioaccessibility of these bioactive compounds, resulting in more than 50 articles, 7 book chapters and 2 patents. Dr. Vardanega worked at a Brazilian company of Cannabis products, where she was responsible for the manufacturing processes of pharmaceutical active ingredients. As Researcher at the University of Minho, in Braga, Portugal, she is currently investigating strategies to modulate the bioavailability of cannabinoids in edible products by evaluating in vitro digestion, cytotoxicity, and in vivo pharmacokinetics.
By António A. Vicente
Prof. Antonio Vicente graduated in 1994 from the Portuguese Catholic University in Porto, Portugal, in Food Engineering, and finished his Ph.D. in Chemical and Biological Engineering in 1998 at the UMinho, in Braga, Portugal. He received his Habilitation in Chemical and Biological Engineering from the UMinho in 2010. Since early in his career, he has maintained close contact with the food industry, and he is involved in more than 40 research projects together with industrial and academic partners, either as participant or as project leader. His main research interests include: micro and nanotechnology applied to Food Technology, using different structures (nano-)multi-layered films and coatings, (nano)emulsions, (nano)particles, and (nano)gels, all in the form of food-grade materials; and in vitro digestion systems for the evaluation of what happens to foods in the gastrointestinal tract.
The promotion of CBD's benefits has become incrementally greater, with a plethora of products on the shelves. CBD is available in various forms and concentrations, which can be confusing for customers who want to start using it. One of the main questions consumers ask is: "How much CBD should be taken to achieve the desired effect?" The answer is not straightforward, as it depends heavily on the method of consumption.
The most well-known way to consume CBD is by smoking or vaporizing cannabis. However, for those who prefer not to smoke or vaporize, CBD can be taken in other forms, such as orally (CBD capsules), sublingually (by placing extracts or candies under the tongue for absorption through the saliva glands), or topically (in lotions and creams).
Each method of introducing CBD into the body results in different amounts of CBD reaching the bloodstream to produce an active effect. This is known as CBD bioavailability, which refers to the percentage of a substance that is absorbed into the bloodstream and made available for use by the body. Understanding how bioavailability varies based on the method of consumption is key to determining the best CBD product for each individual to achieve the desired effects.
Many people are accustomed to taking medications and supplements orally, making this one of the most preferred methods for consuming CBD. However, oral CBD takes longer to produce effects since absorption occurs through the digestive system, and it has relatively low bioavailability, typically ranging from 6–20%1. This is primarily due to the "first-pass effect," whereby CBD is metabolized in the liver before entering the bloodstream. In practical terms, this means that higher doses of CBD must be consumed to achieve the desired effects. As CBD is increasingly used not only for treating health conditions but also for general well-being, numerous edible CBD products have been launched. However, these face challenges relating to the low bioavailability of orally-ingested CBD. To address this issue, we are working on strategies to improve the oral bioavailability of CBD.
The CBDHIGHBIO project, funded by the European Commission and hosted at the University of Minho in Portugal, focuses on this goal. The first approach involves incorporating CBD into lipid-based delivery systems. These systems can divert the absorption away from the liver, where much of the CBD is metabolized, thus increasing the compound's solubility in aqueous media, enhancing its absorption in the body. The specific delivery systems we are using include nanoemulsions (NE) and nanostructured lipid carriers (NLC).
Nanoemulsions are mixtures whereby tiny droplets (in the nanometer range) of oil are dispersed in water, stabilized by an emulsifier. NE is commonly used to improve the absorption and effectiveness of hydrophobic substances like CBD, as these tiny droplets can be absorbed more easily by the body. NLCs, on the other hand, are lipid-based carriers made from a combination of solid and liquid lipids, also stabilized by an emulsifier. Like NE, NLCs increase the absorption of lipophilic substances, but they offer an additional advantage: their solid lipid component provides enhanced stability.
Our early results showed that CBD was highly compatible with these delivery systems. It was fully encapsulated within the carriers and remained stable during four weeks of storage.2,3 Additionally, the cytotoxicity potential of the delivery systems was evaluated using Caco-2 cells, and no cellular damage was observed from the NE or NLC. In fact, when CBD was incorporated into these nanosystems, its cytotoxicity potential was drastically reduced, probably because of the protective effect of the particles.
These CBD-loaded nanosystems were also subjected to in vitro digestion, simulating the digestive process in the mouth, stomach, and intestine, thus providing an indication of CBD bioavailability. The results showed an increase of at least 20% in bioavailability when CBD was incorporated into both NE and NLC, compared to a control sample of CBD oil. However, it is important to interpret these in vitro results with caution, as the model does not account for certain metabolic processes, such as liver metabolism, for example, which further reduces CBD bioavailability. To gather more accurate data, preclinical assessments of CBD bioavailability in mice are planned as the next phase of this study.
The second approach we are exploring to enhance oral bioavailability involves combining CBD with piperine, a substance found in black pepper known for its bioenhancer properties. Piperine boosts the bioavailability of other compounds by inhibiting liver enzymes responsible for breaking down substances like CBD. The bioenhancing effect of piperine on CBD will also be evaluated in the preclinical study on mice.
In addition to the variability of the CBD bioavailability caused by the form of intake, individual variability in CBD bioavailability is another important factor to consider, as it can significantly influence the effects of CBD on different people. Factors such as age, metabolism, body weight, diet, and even genetic differences can all impact on how much CBD is absorbed into the bloodstream and how long it remains active in the body. Additionally, variations in liver enzyme activity, gut health, and overall digestion can alter how CBD is metabolized. This variability makes it difficult to establish a one-size-fits-all dosage.
A clear understanding of the factors influencing the levels of different cannabis compounds that reach systemic circulation is critical for designing cannabis edibles with consistent biological effects, but this is still rarely considered in the current generation of commercial products. Improving our knowledge of the metabolism of edible cannabis after oral ingestion is closely linked to the safety of consuming these products. Due to the limited understanding of how food carriers affect the pharmacokinetics and bioavailability of CBD, it is still difficult to design an effective delivery system that ensures both appropriate bioavailability and consumer safety. Therefore, a comprehensive understanding of the digestion of CBD-loaded nanosystems is essential for the reliable development of cannabis edibles.
In conclusion, enhancing the oral bioavailability of CBD is crucial for optimizing its therapeutic effects, especially given the increasing demand for convenient and effective CBD products. Through innovative approaches such as lipid-based delivery systems like NE and NLC, as well as the use of bioenhancers like piperine, we are making significant progress in overcoming the limitations of traditional oral consumption. As we move forward with preclinical studies, our findings hold promise for the development of more efficient, safe CBD products that can improve both health and well-being for a broad range of consumers.
References:
1. Perucca y Bialer, 2020. 10.1007/s40263-020-00741-5
2. Vardanega et al., 2024. https://doi.org/10.1016/j.foodchem.2023.138295
3. Vardanega et al., 2024. https://doi.org/10.1016/j.foodres.2024.114498
