The Degradation Pathways of Cannabinoids and How to Manage Them – Part 1

In the first of two articles, Broughton, a regulatory consultancy currently focused on EU and UK cannabis regulation, discusses the susceptibility of cannabinoids to degrade and summarizes the main degradation pathways of the primary cannabinoid products on the market: THC and CBD.

The degradation pathways of these products are reviewed with consideration of the potential impact on product efficacy, consumer safety, and regulatory and legal compliance. A high-level review of how these degradation pathways may impact different dosage forms is provided, along with a consideration of how the formation of these breakdown products may be mitigated.

These two articles form a high-level synopsis of cannabinoid degradation, an important consideration for manufacturers working with these products to comply with key regulations or with the intention of submitting regulatory dossiers.

You can read part two here.

Introduction

Cannabinoids are naturally occurring compounds found in the Cannabis sativa plant that can interact with cannabinoid receptors in the endocannabinoid system that trigger a biological response.

These compounds are delivered to the body in many ways, such as medicinal or wellness products licensed under specific regulatory pathways, or the novel foods or cosmetics legislation. They may be used to treat or relieve various illnesses. Some examples include seizures linked to specific diseases, tuberous sclerosis, multiple sclerosis, anxiety, and general pain. There are over 60 cannabinoids; in consumer goods, the most common are tetrahydrocannabinol (THC) and cannabidiol (CBD).

Since the UK legalized medical cannabis in 2018, coupled with an increased awareness of the natural health and wellness solutions offered by these products, the industry has seen a growing demand for cannabinoid products. As the cannabinoids industry grows, it is essential that these products are thoroughly characterized and that there is a comprehensive understanding of the stability and potential breakdown or degradation products.

Cannabinoids are labile compounds that may easily degrade under thermal, light exposure, or oxidative conditions. Depending on the delivery mechanism and storage, some of these products may be more prone to degradation. Understanding the stability of these products and their degradation compounds is essential from a patient or consumer safety viewpoint. The medicinal products must maintain efficacy and all products must have no toxicological impact on the consumer from breakdown products. Additionally, not understanding how these products perform over their shelf life may result in legal implications where manufacturers find themselves in breach of the law and potentially subject to criminal sanctions.

Although CBD is considered legal for consumer use in many applications when manufactured in a controlled manner, it is critical to ensure the THC content is less than one milligram (mg) per container. There is also a maximum allowed THC concentration in the industrial hemp raw material; for instance, in Europe, the limit is set at 0.3% dry weight basis. There is the potential for CBD to degrade to THC, which is a Class B controlled drug under Part II, Schedule 2, of the Misuse of Drugs Act 1971. This example highlights the importance of understanding degradation pathways in cannabinoid products.

The scope of this whitepaper covers cannabinoids before consumption. The potential degradation of cannabinoids in vivo is outside the scope of this paper.

Stability/shelf-life studies

Stability studies, commonly referred to as shelf-life studies, are an assessment of a product’s performance over time when stored under various environmental conditions. Physicochemical and microbiological tests are also often carried out. These tests may include but are not limited to the assessment of:

• Levels of the active ingredient.
• Purity.
• Degradation products.
• Appearance.
• Water content.
• Uniformity of dose.
• pH.
• Microbiological contamination.

For cannabinoid products on the market via the medical pathway, novel foods, or cosmetic legislation, stability assessment is a mandatory requirement to substantiate the assigned shelf life. THC and CBD products may be licensed via the medical route. However, as per current legislation, only CBD products may be approved via the novel food or cosmetic regulatory pathways.

Evaluation of the degradation products involves critical stability indicating tests. These tests are vital quality parameters over the shelf life of cannabinoid products due to:

• Susceptibility of these products to readily degrade under light, thermal or oxidative conditions.
• Potential for loss of efficacy due to degradation of the active ingredient responsible for triggering the pharmacological response.
• Toxicology of degradation products may not be fully characterized.
• Potential for the formation of illegal compounds.

Degradation pathways of cannabinoids

The formation of cannabinoids starts with the enzymatic transformation of olivetolic acid, an organic compound in Cannabis sativa, into cannabigerolic acid (CBGA), a phytocannabinoid acid that is the primary precursor to phytocannabinoids. Further enzymatic processes in the Cannabis sativa plant convert CBGA to the phytocannabinoid acids, Δ⁹-tetrahydrocannabinolic acid (Δ⁹-THCA-A), cannabidiolic acid (CBDA), and cannabichromene acid ((±)-CBCA).

These phytocannabinoid acids are labile compounds and decarboxylate with heat and over time under ambient conditions. The corresponding neutral phytocannabinoids that result from decarboxylation are (±)Trans-delta-9-Tetrahydrocannabinol (Δ⁹-THC), cannabidiol (CBD), and cannabichromene (CBC). In this part of the degradation process, the degradation pathways and the generation of legally controlled substances are displayed graphically in Figure 1.

Image credit: Cayman.

From a consumer and legal point of view, as the main cannabinoids of interest, the primary focus is on the further degradation pathways of Δ⁹-THC and CBD. The formation and further reaction mechanism of Δ⁹-THC is of high interest due to the controlled status of this compound. Further oxidation and exposure to light of the Δ⁹-THC can result in the formation of cannabinol (CBN) and (±)trans-delta-8-tetrahydrocannabinol (Δ⁸-THC). Although these compounds have various levels of psychoactivity, they are all considered controlled drugs under the MDA in the UK. Products exposed to light are generally exposed to oxidation simultaneously. However, it should be noted that studies of THC degradation with light only have shown no increased quantities of CBN, suggesting an alternative breakdown pathway. It should be noted, light exposure includes the light from the UV rays in direct sunlight but also unnatural light. The oxidative and light reaction mechanism of Δ⁹-THC is shown in Figure 2.

Image credit: Cayman.

Understanding the next steps in the degradation pathways for CBD is crucial for manufacturers to identify and control. Although the THC pathways are meaningful, these compounds are already categorized as controlled substances during the formulation of the products. Therefore, the correct controlled licenses required for manufacture and distribution must be in place. CBD is considered an exempted drug at this point of manufacture when it meets the requirements for an exempted product criteria in Regulation 2 of the UK’s Misuse of Drugs Regulations, 2001.

However, the potential degradation pathways indicated highlighted the potential for CBD to degrade into controlled substances such as Δ⁹-THC and Δ⁸-THC. Under acidic conditions or when exposed to light, CBD degrades to Δ⁹-THC and subsequently to the more stable Δ⁸-THC isomer. Additionally, under basic conditions, the Δ⁹-THC can form two different diastereomeric structures of Δ¹⁰-THC. Further acidic exposure can drive the double bond of either Δ¹⁰-THC diastereomer to isomerize further to the Δ^{6a, 10a}position. This results in the formation of two potential enantiomers Δ^{6a, 10a}-THC⁴. This stage of the reaction mechanism is shown in Figure 3.

Image credit: Cayman.

In addition to the potential loss of efficacy for medicinal products and legal implications for both consumer and medicinal products, there are further risks for manufacturers to consider concerning the degradation of CBD. Another potential degradation pathway for CBD is the formation of phytocannabinoid quinone, specifically for CBD; this involves the aerobic oxidation of CBD to cannabidiol quinone (CBDQ), also referred to as HU-331. This reaction is well known as it forms the basis for the scientific Beam test², but it can also negatively affect consumer products.

Along with the loss of CBD efficacy through this degradation reaction, quinone formation can lead to color changes, most likely a deep purple color, in the product. The formation of such colors and changes in the product’s appearance can result in a poor consumer experience and potentially impact the overall brand perception. Furthermore, some of these compounds are not well understood toxicologically, bringing potential safety unknowns. The formation of CBDQ is shown graphically in Figure 4.

Image credit: Cayman.

These degradation pathways for CBD (Figure 1-4) are the most common pathways likely to occur in an in vitro environment. Therefore, they may represent the environmental conditions the product may be exposed to during manufacture or over the product’s shelf life.

However, this is not an exhaustive list. As innovative formulation methods are applied, and considering CBD’s susceptibility to degradation, there is the potential for new triggers for the degradation pathways. A summary of all known CBD degradation pathways documented in the literature is shown in Figure 5. Although not all these degradation modes will apply to a packaged CBD product, this chart highlights the general degradation potential of CBD and why it is an essential consideration for manufacturers.

Image credit: Cayman.

This overview of the potential degradation pathways for cannabinoids with a focus on THC and CBD emphasizes these products’ lability and susceptibility to degradation. The potential impact of degradation may be loss of efficacy for medicinal products but also impact on the toxicological safety of the product to the consumer and result in a change of the legal classification of the cannabinoid, which may occur during manufacturing processes or over the shelf life of the product.

With this in mind, these products must be characterized at manufacture and monitored with stability studies. The analytical methodology used to assess these products should be validated, quantitative, and stability-indicating to ensure that changes over time are understood.

Additionally, the analytical methods used should be developed and validated at a suitable sensitivity to ensure that any controlled substances can be detected and quantified down to the level specified, one milligram of controlled drug per container and the 0.3% limit for THC in the industrial hemp raw material.

You can read the second part of this Broughton series here.