Research on Oral CBD: Tackling Bioavailability and Formulation Challenges

Research on Oral CBD: Tackling Bioavailability and Formulation Challenges

 As today's email was opened, the February 2024 preprint issue of the Journal of Drug Delivery Science and Technology brought forth exciting new research regarding the study and advancement of both formulations and delivery systems to make CBD work better for consumers. The lengthy paper entitled Oral delivery of cannabidiol: Revealing the formulation and absorption challenges was at the top of my list to review. As the Researcher OG, one of my main objections is to make these very complex studies more straightforward to understand by breaking them down into a more reader-friendly version. 


Cannabidiol (CBD) has emerged as a compound of significant interest in the pharmaceutical and nutraceutical fields due to its therapeutic potential and safety profile. Despite its growing popularity and application, particularly in the form of oral dosage, there remain substantial challenges in formulating CBD for efficient and consistent drug delivery. This review investigates the complexities associated with the oral bioavailability of CBD, examining its physicochemical properties, gastrointestinal absorption, systemic circulation, and the metabolic and excretory pathways it undergoes.

Cannabidiol (CBD), a primary non-psychoactive cannabinoid derived from Cannabis and other plant species, has garnered attention for its wide array of pharmacological applications. Notable among these are its anticonvulsant properties, with prescription drugs like Epidiolex® and Sativex® being prominent examples. Additionally, CBD is integrated into various food items and oils within the US Market and beyond due to its potential shown in research and reputed online claims of its benefits in alleviating anxiety, stress, and pain and promoting relaxation and sleep. Despite a market evaluation exceeding the anticipated billions, the development of oral CBD products remains hindered by challenges in stability and bioavailability.

CBD Physicochemical Properties and Oral Delivery Challenges

CBD's chemical instability, particularly in acidic environments, poses significant formulation challenges. This instability leads to low bioavailability, as CBD undergoes substantial degradation and extensive metabolism, which affects its efficacy and consistency as a therapeutic agent. 

The key to enhancing oral bioavailability lies in addressing these stability issues and improving the compound's permeability across biological membranes.

Acidic Conditions: CBD can undergo degradation in acidic environments, such as the stomach, after oral administration. This degradation often leads to the conversion of CBD into other cannabinoids, such as Δ9-tetrahydrocannabinol (Δ9-THC) and cannabinol (CBN), which can alter its intended therapeutic effects and profile. 

Temperature and Light Exposure: High temperatures and exposure to UV light can accelerate the degradation process, reducing the concentration of active CBD available for absorption. 


CBD has the attention of healers and healthcare professionals globally
CBD has the attention of healers and healthcare professionals globally


Impact on Bioavailability

The bioavailability of a drug refers to the proportion of the drug that enters the systemic circulation when introduced into the body and is thus available for therapeutic action. CBD's instability directly impacts its bioavailability:

Degradation Leading to Lower Concentrations: The chemical degradation of CBD in acidic environments reduces the amount of intact CBD that reaches systemic circulation. This reduction translates to lower bioavailability, meaning less CBD is available to exert its therapeutic effects. 

First-Pass Metabolism: After oral administration, CBD undergoes extensive first-pass metabolism in the liver, further broken down before reaching the systemic circulation. This metabolism, coupled with its instability, further decreases its overall bioavailability. 

Research and Formulation Strategies

Given these challenges, research has focused on developing strategies to improve the stability and, consequently, the bioavailability of CBD:

Protective Formulations: Scientists are exploring various formulation strategies to protect CBD from acidic degradation. These include encapsulation techniques like liposomes or polymer-based nanoparticles that can shield CBD as it passes through the stomach. 

Alternative Routes of Administration: To circumvent the acidic environment of the stomach, alternative routes of administration, such as sublingual or transdermal delivery systems, are being investigated. These methods can bypass the gastrointestinal tract, potentially improving bioavailability. 

Co-Administration with Absorption Enhancers: Some studies suggest co-administering CBD with certain substances that can enhance absorption and stabilize the compound. For instance, combining CBD with lipid-based carriers has improved its solubility and resistance to acidic degradation.

Absorption, Distribution, Metabolism, and Excretion (ADME) of CBD

The absorption of CBD in the gastrointestinal tract is inconsistent, partly due to its low solubility and permeability. Once absorbed, CBD undergoes extensive first-pass metabolism, forming various metabolites with their pharmacological activities. 

The excretion process of CBD and its metabolites is also a critical aspect, with varying pathways and rates of elimination contributing to the overall pharmacokinetics of CBD.  

Metabolism of CBD

While delving into the excretion process, it's essential to understand that CBD undergoes extensive metabolism, primarily in the liver. The primary enzyme system involved in this metabolism is the cytochrome P450 (CYP450) enzyme system. Here, CBD gets metabolized into various compounds with unique pharmacological properties. These metabolites are primarily hydroxylated and carboxylated compounds.

Excretion Pathways

Renal Excretion (Kidneys):

A portion of CBD and its metabolites get excreted through the kidneys into the urine.

The renal excretion rate is influenced by the pH of the urine, which can affect the metabolites' ionization degree. More acidic urine can lead to increased excretion of specific metabolites.

Biliary Excretion (Liver and Gallbladder):

CBD and its metabolites can also be excreted through the bile, a process governed mainly by the liver and gallbladder.

Following biliary excretion, these compounds may enter the intestine and either be reabsorbed (enterohepatic recirculation) or excreted in the feces.

Factors Influencing Excretion

Dose and Frequency: 

Higher doses or more frequent dosing can lead to increased concentrations of CBD and its metabolites, potentially altering the excretion rates.

Individual Variability: 

Age, genetics, liver, and kidney function can significantly influence how an individual metabolizes and excretes CBD.

Drug Interactions:

Concurrent use of other medications metabolized by the CYP450 enzyme system can affect the metabolism and excretion of CBD.

Rates of Elimination

The rate of elimination for CBD is variable and, in studies, is influenced by the abovementioned factors. The half-life of CBD (the time it takes for half of the drug to get eliminated from the body) can vary significantly. 

Generally, it's estimated to range from a few hours to a couple of days, depending on the mode of administration and individual factors. 

Importance in Therapeutics

Understanding the excretion process of CBD is vital for several reasons:

Dosing Strategies: Knowledge of excretion pathways and rates helps determine appropriate dosing regimens to maintain therapeutic levels of CBD without causing toxicity.

Drug Interactions: Awareness of how CBD is metabolized and excreted aids in predicting interactions with other medications, which is crucial for patient safety.

Personalized Medicine: Recognizing individual variability in excretion can guide customized medicine approaches, tailoring CBD treatment to individual patient needs.

Strategies for Improving Oral Bioavailability

Approaches to enhance CBD's oral bioavailability include lipid-based formulations and food vehicles. These methods aim to stabilize CBD and facilitate its absorption, thus reducing inter- and intra-individual variability in its pharmacokinetics. Further research on novel delivery systems that could optimize CBD's oral bioavailability is warranted. 


While CBD continues to express its potential in various therapeutic areas, developing effective oral dosage forms is imperative for its more comprehensive application. Addressing the challenges in CBD formulation, particularly regarding its stability, absorption, and metabolism, is crucial for maximizing its therapeutic potential.

This review was conducted to provide insights into the complexities of formulating oral CBD with improved bioavailability, contributing to the growing body of knowledge in cannabinoid-based therapeutics.

Author Information

Mike Robinson, Founder of Global Cannabinoid Research Center, is an Internationally known researcher in cannabinoid science, specializing in CBGa and ECS Balance Control.

For further inquiries and discussion, visit


1.) Oral delivery of cannabidiol: Revealing the formulation and absorption challenges, 2024

2.) Mechanism and kinetics of CBDA decarboxylation into CBD in hemp, 2023

3.)  Dosage, Efficacy and Safety of Cannabidiol Administration in Adults: A Systematic Review of Human Trials, 2020

While most research papers will give citations after each statement, that is far less reader-friendly for the everyday consumer. This article provides limited scientific studies but enough to understand that this is 'breaking news' in the world of the Researcher OG, along with a few links (above) that show how this current paper of today came to be. 

When done to investigate the potential for future applications, research is a cascade of studies in which a consumer can easily and quickly become lost.

  -Mike Robinson, Global Cannabis Educator and Creator of ECS Balance Control 

                             CBGa Crumble - The Hash of Hemp

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