Chewing Gum as a Delivery System for Cannabidiol: A Commentary

Abstract

Background

Despite significant gaps in the research literature, the integration of cannabidiols into chewing gum as a drug delivery system is a novel and promising approach for various cannabinoid therapeutic applications. Chewing gum offers a unique delivery mechanism that may promote both local and systemic effects through the oral mucosa, enhancing the bioavailability and efficacy of cannabinoid medications.

Summary

This commentary explores and delves into the potential of cannabinoid-infused chewing gum, highlighting its putative benefits for managing an array of conditions, including oral health, anxiety, and pain. The therapeutic potential of cannabinoids is explored in the context of their anti-inflammatory, antimicrobial, analgesic, and anxiolytic properties that may be especially impactful in the oral cavity and at the oral-pharyngeal mucosa. Additionally, we reviewed the advantages of using chewing gum for discrete self-medication and rapid onset of salutary effects.

Key Messages

Despite a long-standing widespread history of chewing gum use in general, there is sparse experience and even less clinical research on the effects and possible clinical value of incorporating cannabidiol or any other cannabinoid in a chewing gum product. Despite promising reports, research gaps remain, particularly in understanding the absorption mechanisms, dosing precision, and long-term safety of cannabinoid-based chewing gum. Addressing these challenges will position cannabinoid-infused chewing gum as a versatile and effective drug delivery system for a range of health conditions.

Introduction

Historically, natural gums like chicle were used by the Mayans and Aztecs for health promotion, while cannabis and cannabis-based preparations have been used medicinally worldwide for centuries [1, 2]. Today, chewing gum is marketed for oral hygiene and stress relief, reflecting cultural values around health and wellness [3]. Similarly, the acceptance of medical cannabis and cannabinoids for a broad spectrum of conditions like pain, anxiety, and sleep disorders is growing [4–8]. Combining the social acceptability of chewing gum with the putative therapeutic value of both chewing gum and cannabinoids presents an opportunity for innovative, safe, and efficacious products. However, this initiative presents significant challenges.

The present commentary, then, is based first upon a review of bridging data developed for bioactives in chewing gum other than cannabinoids. We then identify the gaps in the research that need to be addressed to develop a gum delivery system for cannabinoid medicines.

There has only been one published placebo-controlled trial investigating cannabinoid chewing gum as a drug delivery system [9]. The study was a small, randomized, double-blind, placebo-controlled, crossover study in adults with IBS. The intervention consisted of chewable gum containing CBD (50 mg per gum) versus placebo, up to 6 gums per day, with symptom-driven dosing. The duration of each treatment period lasted 3 weeks, with a washout period between phases. Findings: among 32 completers, both CBD and placebo reduced pain slightly, but there was no significant difference between CBD and placebo on primary outcomes (mean difference in 30-min pain reduction: 0.1 on VAS, 95% CI: [–0.3, 0.5], p = 0.61). Safety: the gum was well tolerated, with few mild adverse events. This study provided evidence only suggesting that CBD delivered via chewing gum is feasible and well tolerated over the study duration – but, importantly, efficacy was not demonstrated in this small exploratory trial.

Other cannabinoid-specific supporting evidence includes a Phase II pharmacokinetic pilot. AXIM Biotechnologies reported a single-dose PK study of CanChew gum in healthy volunteers (10 and 30 mg CBD) to optimize dosing for the IBS trial [10]. The study does not appear to have been published in the peer-reviewed literature.

AXIM also conducted a randomized, double-blind, crossover Phase II trial (NCT03003260) of CanChew Plus^® (50-mg CBD gum) versus placebo for IBS symptoms (40 subjects), with completion anticipated by mid-2017 [10]. However, while there are reports that AXIM Biotech conducted clinical research on CanChew Plus for IBS and reported positive preliminary results, these results do not appear to have been published. Moreover, the company’s focus appeared to have shifted, and there is no clear indication that CanChew Plus is currently available on the market. The associated patent (US11406593B2) states that over 99% of CBD was delivered to the oral mucosa after 5 min of chewing – supporting the platform’s delivery potential [11]. However, outside of the Van Orten-Luiten et al. [9] study (2022), no other published peer-reviewed randomized trials examining cannabinoid chewing gums in humans were found.

The limited research noted above leaves our analysis to relevant bridging data from R&D efforts with similar bioactive compounds. The prospective development of cannabinoid chewing gum in our analysis, therefore, begins by leveraging pre-existing knowledge about important key questions, such as oral mucosal absorption, formulation stability, and dose precision. For instance, insights from nicotine gum development highlight solutions for optimizing buccal delivery. At the same time, studies on bioactive peptides can inform strategies to enhance bioavailability and maintain structural integrity under salivary conditions. Bridging these insights reduces redundancy, expedites problem-solving, and helps overcome technical challenges, justifying specific cannabinoid-dedicated research in the chewing gum domain.

Experience with Chewing Gum as a Delivery System: Bioavailability during Oral vs. Buccal Exposure

Caffeine in Chewing Gum vs. Capsules

Kamimori et al. [12] (2002) reported a crossover trial in 84 healthy adults comparing Stay Alert^® caffeine chewing gum with caffeine capsules. Results reported included a T_max significantly more rapid with gum (44–80 min) versus capsules (84–120 min; p < 0 0.05). Relative bioavailability ranged from 64 to 77%, increasing to 75–90% when normalized to gum release suggesting more rapid onset and comparable systemic exposure of caffeine with gum.

Loratadine Delivered via Chewing Gum

Noehr-Jensen et al. [13] (2006) compared a single 30-mg loratadine gum to 20-mg tablets: AUC increased nearly 2.7-fold (GMR 2.68; 95% CI: 1.75–4.09), suggesting more drug-reached systemic circulation with the gum. This was reported as likely due to ∼40% buccal absorption of the loratadine in the gum by directly entering the systemic circulation and bypassing first-pass metabolism [13].

Medicated Chewing Gum

Wessel et al. [14] (2016) reviewed potential applications for gum delivery in oral healthcare. Based on a review of the literature, they summarized possible advantages of gum, including promotion of buccal uptake, rapid onset via mucosal absorption, avoidance of first-pass metabolism, and controlled, extended exposure in the oral cavity, which appeared to have been demonstrated for compounds like aspirin, caffeine, and diphenhydramine compared to tablets.

Hydrophilic Gum vs. Hydrophobic CBD: Approaches to Resolving the Chemistry

Hydrophilic Gum vs. Hydrophobic Cannabinoids

Cannabinoids (such as THC/CBD) are hydrophobic, lipophilic, and poorly soluble in water while chewing gum relies on saliva (hydrophilic) for drug release. To bridge this gap, a few strategies have been suggested:

• Lipid‐based nanocarriers: cannabinoids are embedded in lipid nanoparticles with a hydrophilic shell. This approach allows dispersion in saliva while retaining lipophilic cannabinoid payloads – a strategy employed in experimental oromucosal sprays utilizing nanotechnology-based cannabinoids [15].

• Mesoporous carriers with mucoadhesive coatings: preformulation studies have developed cannabidiol-loaded mesoporous systems for buccal use, enhancing mucosal adherence and solubility [16].

• Formulation patents (e.g., WO2009120080): outline chewable compositions that solubilize cannabinoids via carriers and mucoadhesives [17].

These methods may enable the release and absorption of hydrophobic cannabinoids in a hydrophilic oral environment.

The buccal route may help solve water-lipid mismatches by:

• Using mucoadhesive matrices that localize the drug at mucosal surfaces (e.g., fentanyl and buprenorphine lozenges) [18].

• Employing nanoparticles, microemulsions, or lipid-based carriers to enhance solubility and permeability is a standard practice in peptide, hormone therapy, and pain drug development [15].

• Adding penetration enhancers and enzyme inhibitors to films or tablets to protect and facilitate transmucosal delivery is supported by research on transmucosal drug delivery systems [18].

These relatively established approaches support the plausibility of applying similar techniques to cannabinoid gum formulations. The importance of oral cannabinoid bioavailability and extended buccal exposure: poor oral bioavailability is a fact of cannabinoid chemistry, and the bioavailability of oral cannabinoids ranges between ∼6 and 20% when swallowed due to poor GI uptake [19, 20]. A chewing gum system with its extended buccal delivery has the following advantages:

• A porcine ex vivo study showed CBD accumulated in the oral mucosa and continued to release systemically for hours after removal of a delivery device [16].

• It avoids first-pass metabolism via venous drainage from the oral mucosa [20].

Sustained mucosal exposure may also reduce dose frequency and increase total absorbed drug [16].

Sativex: A Place for Extracts and Implications for Prolonged Buccal Exposure

Sativex (nabiximols), a well-known example of a cannabis extract containing a 1:1 ratio of THC and CBD, is delivered via a buccal spray.

Advantages of Buccal Delivery and Extended Exposure

Unlike oral administration, buccal delivery bypasses the first-pass effect by directly entering systemic circulation via venous drainage from the oral mucosa. There is evidence that cannabinoids can accumulate in the oral mucosa and release slowly over extended periods [16]. This extended exposure offers several benefits:

• Enhanced systemic absorption: slow, steady release allows more cannabinoids to be absorbed via the oral mucosa, increasing overall bioavailability [16].

• Reduced dose variability: prolonged mucosal contact minimizes variability often associated with GI absorption [20].

• Improved therapeutic outcomes: sustained delivery may allow lower overall doses to achieve the desired therapeutic effect, potentially reducing side effects associated with peak concentrations.

Comparison with Sativex

While Sativex delivers cannabinoids buccally, studies suggest that a significant proportion of the spray is swallowed, resulting in partial reliance on enteral absorption [21]. In contrast, a gum designed for prolonged buccal adhesion could maximize absorption through the oral mucosa.

Because of sustained buccal exposure, cannabis extracts in gum formulations have the potential to overcome key limitations of traditional oral and buccal systems, suggesting a pathway for more effective cannabinoid delivery. Importantly, a long release chewing gum delivery system supports the antimicrobial potential of cannabidiol in which membrane disruption and activity against biofilms are augmented by increased mucosal contact [22].

Blaskovich et al. (2021) highlighted CBDs potent activity against Gram-positive bacteria, including drug-resistant strains such as methicillin-resistant Staphylococcus aureus (MRSA) [22]. This activity is primarily attributed to CBDs ability to disrupt bacterial membranes, causing leakage of cytoplasmic content and subsequent bacterial death. CBD also appears to inhibit the formation of biofilms, which are critical for bacterial survival and resistance to conventional antibiotics.

The anti-inflammatory properties of CBD may complement its antimicrobial activity by reducing host immune system damage during infections [23]. Additionally, the efficacy of CBD in combination therapies is being explored, with evidence suggesting synergistic effects when used alongside antibiotics, potentially reducing the required antibiotic doses and lowering the risk of resistance development [24].

Determinants of Stability and Regulatory Implications

The multifactorial determinants of stability in chewing gum are relevant for any R&D process and regulatory approval. We key on several factors, including the nature of the active pharmaceutical ingredients (APIs), excipients, manufacturing process, and packaging. For hydrophobic and thermolabile compounds like cannabinoids, key considerations include the following:

• Protection from oxidation: lipophilic APIs are prone to oxidation, necessitating antioxidant excipients and proper packaging to enhance shelf life [18].

• Moisture content: the gum base and coating must maintain a low moisture content to prevent the hydrolysis or degradation of sensitive APIs [17].

• Homogeneity and uniformity: APIs must remain evenly distributed within the gum matrix to ensure consistent dosing over time.

• Thermal stability: manufacturing processes involving heating should not degrade the active compounds. Cannabinoids, for instance, are known to degrade at elevated temperatures [19].

Examples of Stability Data from Approved Gum Products

• Nicotine chewing gum: nicotine, a relatively unstable and hygroscopic compound, has been successfully incorporated into gums with stability data meeting regulatory standards. Studies have shown that proper encapsulation in a gum base and the addition of stabilizers (e.g., buffering agents) can maintain nicotine’s stability for 24 months or longer under ambient conditions [18].

• Caffeine chewing gum: caffeine, another example of a hydrophobic API, has demonstrated excellent stability in gum formulations. Packaging innovations and appropriate moisture control have extended the shelf life of such products [17].

Relevance to Cannabinoid Gums

Cannabinoids share many physicochemical characteristics with APIs in nicotine and caffeine gums, such as poor water solubility and susceptibility to degradation. Leveraging similar formulation strategies – including encapsulation within lipid-based carriers, the addition of antioxidants, and advanced packaging – could enhance the stability of cannabinoid gums [15]. Preliminary studies on nanotechnology-based cannabinoid delivery systems suggest that such approaches can also enhance stability during storage and use [16].

Regulatory Implications

For FDA/EMA approval, cannabinoid gum formulations would require robust stability testing under International Council for Harmonization (ICH) guidelines. These tests include real-time and accelerated stability studies to evaluate API degradation, release profiles, and uniformity over time. Addressing these criteria through careful formulation and packaging design is crucial for regulatory success [18].

An Illustration of Regulatory Challenges: The Case of Nicotine Gum

Nicotine gum presents an important though partial illustration of the current regulatory landscape.

Classification and Approval Pathways

• In the USA: nicotine gum is classified as an over the counter (OTC) drug under the FDAs Center for Drug Evaluation and Research (CDER). It must meet the regulatory standards outlined in the OTC drug monograph for smoking cessation aids [18].

• In the EU: the EMA evaluates nicotine gum as a medicinal product under Directive 2001/83/EC for human medicines. Regulatory oversight ensures safety, efficacy, and quality [17].

• Global variations: classification varies globally. For instance, some countries permit OTC sales only for lower doses, while higher doses may require a prescription [18].

Safety and Efficacy Requirements

Nicotine gum must demonstrate safety and efficacy in smoking cessation:

• Clinical trials: double-blind studies consistently show that nicotine gum improves quit rates compared to placebo, particularly for highly dependent smokers [17, 18].

• Safety data: common side effects include gastrointestinal discomfort and oral irritation. Regulatory review includes addiction potential, risk of misuse, and toxicity from excessive use [19].

Manufacturing Standards

• Good manufacturing practices (cGMP): manufacturers must comply with cGMP to ensure the gum’s consistent quality and safety [18].

• Content uniformity: studies confirm that each piece of nicotine gum delivers a precise dose, which is critical for therapeutic efficacy [17].

Labeling and Packaging Regulations

• OTC labeling: US regulations require clear labeling, including usage instructions, contraindications (e.g., not for non-smokers or pregnant individuals), and potential side effects (FDA monograph) [18].

• Child-resistant packaging: accidental ingestion of nicotine can be toxic, necessitating child-resistant packaging for all products [19].

Post-Market Surveillance and Pharmacovigilance

• Regulatory bodies require ongoing monitoring for adverse events to ensure timely detection and response to these events. For example, reports of misuse or addiction have led to updated labeling and safety guidance [17].

• Pharmacovigilance systems detect rare adverse events and long-term risks, ensuring the continued safety of the product [18].

Marketing and Advertising Restrictions

• Health warnings: advertisements must disclose nicotine’s addictive nature and advise users to seek medical support for comprehensive smoking cessation plans [19].

• Nicotine gum advertising cannot imply that it is a complete substitute for counseling or lifestyle modifications [18].

Example Products and Approvals

• Nicorette (Pfizer/J&J) approved globally as a 2-mg and 4-mg gum with extensive clinical data supporting its use [17].

• Habitrol (Novartis) offers similar nicotine gum options with long-standing regulatory approval [18].

Gaps in Research: What Is Needed to Support Development of Chewing Gum as a Delivery System for Cannabinoids

Absorption Mechanisms

Oral mucosal variability: one significant gap lies in understanding the variability of oral mucosal absorption among individuals. Factors such as mucosal thickness, saliva composition, and oral pH may influence drug uptake, yet these remain insufficiently studied [18, 19]. Variability in saliva production and enzymatic activity also affects the release and absorption of cannabinoids, potentially leading to inconsistent therapeutic outcomes [17].

Buccal vs. GI absorption: while buccal absorption bypasses first-pass metabolism, swallowed cannabinoids are subject to hepatic degradation, reducing bioavailability to less than 5% [16]. Detailed comparative studies evaluating the interplay between buccal and gastrointestinal absorption when using chewing gum are necessary to optimize formulations [21].

Guidelines for Dosing

While it is known that medical cannabinoid doses are generally much lower than those used recreationally, precise dosing guidelines tailored to the variety of therapeutic indications for gum-based delivery remain largely undefined. Specific areas for further investigation include:

Wide-ranging therapeutic dosing, but few formal guidelines: clinical studies have examined CBD dosing from 1 to 50 mg/kg/day across indications – anxiety, epilepsy, psychosis, and substance use disorders – though regimens vary widely and lack consensus [25, 26]. A Delphi panel recommends “start low and go slow”: initiating with 10 mg/day CBD, titrating up to 40 mg/day, then adding small increments of THC if needed [27]. Yet, none of these guidelines are specific to gum formulations – nor do they account for distinct mucosal pharmacokinetics.

Formulation and administration route profoundly affect bioavailability, hence dosing: oral CBD has highly variable and low bioavailability (∼6% fasted), which can increase dramatically when taken with food – up to sixfold or more [28]. Patented CBD gum demonstrates rapid mucosal transfer – with over 99% of released CBD absorbed through the oral mucosa within 5 min [29]. Yet, peer-reviewed controlled trials of CBD chewing gum are lacking, and current human data are absent – highlighting a dearth of clinical validation for dose and efficacy in gum format.

High inter-individual variability complicates dosing: clinical data across populations – from healthy volunteers to chronic pain patients – show significant variability in effective dose, response, and safety [25, 30]. Body weight, metabolic profile, disease state, and route-specific absorption influence systemic exposure, underscoring the challenge of defining standard dosages for chewing gum delivery.

Dosing Precision and Consistency

Achieving precise dosing with chewing gum is challenging due to multiple variables, including specific indication, gender, age, chewing behavior, and saliva production. Controlled-release systems for gum are underexplored, particularly for lipophilic drugs like cannabinoids, which may require innovative formulations to ensure consistent delivery and dose [15]. We have added a detailed discussion of gaps in the dosing research, which is outlined below.

In sum, although broad dosing ranges for oral and mucosal cannabinoid therapies exist, there remains a striking lack of specific, evidence-based dosing regimens for chewing gum formulations across therapeutic indications. Well-designed, dose-ranging clinical trials are crucial for establishing effective, safe, and standardized gum-based cannabinoid therapies.

Drug Stability and Formulation Challenges

Heat stability and shelf life: cannabinoids are chemically unstable when exposed to heat, light, and oxygen. Ensuring stability during manufacturing, storage, and use is a significant challenge [17]. Comprehensive data on the stability of cannabinoids in gum formulations over extended periods are lacking.

Flavor and texture impacts: balancing flavor-masking agents with cannabinoid stability remains an underexplored area. Cannabinoids’ natural bitterness and aroma often require masking agents, which can affect drug release and stability. Optimizing this balance involves advanced research in food and pharmaceutical sciences [18].

User Compliance and Behavior Studies

Chewing behavior variation: chewing behavior varies significantly across demographics and cultures, reflecting coping styles and/or personality traits. Studies investigating how these behaviors affect cannabinoid release and absorption are limited [19].

Patient preference: research into user preferences for chewing gum as a drug delivery method is sparse, particularly among specific populations like children, older adults, or those with psychiatric conditions. Understanding the needs and preferences of these cohorts may enhance compliance and therapeutic outcomes [18].

Long-Term Efficacy and Safety

Chronic use effects: the long-term safety of chewing gum as a cannabinoid delivery system remains underexplored. While the risks of bioaccumulation in fatty tissues may be minimal due to short-term use, the development of tolerance and impacts on dental health require further investigation [16].

Side effect profile: the potential side effects unique to this delivery method, such as local irritation, mucosal damage, dysregulation of the oral microbiome, or unintended digestive effects from swallowed cannabinoids, are not well-documented [21].

Regulatory and Standardization Issues

Lack of regulatory standards: chewing gum lacks specific regulatory standards as a drug delivery vehicle. While the gum base is highly regulated as a food product, additional frameworks are necessary to ensure consistent, safe, and effective cannabinoid formulations [18].

Clinical trial protocols: current clinical trial methodologies are not tailored to evaluate chewing gum as a drug delivery system. Developing protocols to assess efficacy, safety, and user compliance specific to gum delivery remains a significant gap [17].

Targeting and Expanding Use Cases

Use in pediatric and geriatric populations: limited research exists on the suitability of chewing gum for children and older adults. These populations may benefit from safe, chewable formats that simplify administration, but their preferences and individual physiological considerations require dedicated study and likely novel consensus guidelines [15].

Clear Distinction of Salutary Effects from Chewing Gum Itself from Those Observed with CBD-Infused Gum

The development and evaluation of CBD-infused chewing gum necessitates a nuanced understanding of the distinct contributions to health outcomes from the act of chewing itself and from the CBD compound. Chewing gum, even without APIs, has been associated with various benefits, including increased salivary flow, improved oral health, and enhanced cognitive function due to heightened blood flow to the brain [31]. These effects, collectively termed “masticatory-induced benefits,” can confound assessments of CBDs unique properties if not rigorously controlled.

CBD, in contrast, is, of course, a cannabinoid with documented effects on inflammation, pain modulation, and anxiety reduction [32]. When delivered via chewing gum, CBD may benefit from enhanced buccal absorption, thereby bypassing first-pass metabolism and enabling more consistent plasma levels [33]. However, the act of chewing itself may influence the perception of these benefits, particularly in studies with subjective endpoints such as stress reduction or mood enhancement.

To isolate the effects of CBD in gum formulations, future clinical studies should employ rigorous placebo-controlled designs, where one group receives CBD-infused gum and the other receives gum without active ingredients. Furthermore, objective biomarkers (e.g., serum CBD levels, inflammatory markers) in conjunction with pharmacokinetics/pharmacodynamics data should complement subjective measures to ensure validity.

Conclusion

In light of the benefits of chewing gum in and of itself, and in conjunction with the feasibility of delivering reliable dosages of standardized and pure active cannabinoid ingredients with prolonged contact time, biocompatibility, and biodegradable chemical structures, chewing gum may be a versatile and perhaps waiting to be used drug delivery system. Moreover, the emergence of new forms of traditional botanical medicines, along with their broad and sometimes novel indications, seems to call for a versatile, cost-effective, and robust delivery system that can be generalized beyond CBD. Chewing gum products may serve well in this role, and as such, a series of well-designed and comprehensive investigations aimed at the gaps in preclinical and clinical research seem justified.

Conflict of Interest Statement

P.P. and A.W.H. are paid consultants of Aspeya Switzerland SA, and A.M.H., K.V., A.R., and J.H. are employees of Aspeya Switzerland SA.

Funding Sources

This commentary was not supported by any grant, sponsor, or funder.

Author Contributions

Conceptualization: P.P. and A.W.H.; writing – original draft: P.P., A.W.H., A.M.H., and K.V.; and writing – review and editing: P.P., A.W.H., A.M.H., K.V., T.M., A.R., and J.H. All authors have read and agreed to the published version of the manuscript. This is the sole work of the authors and does not necessarily express the opinions of Aspeya Switzerland SA.

Funding Statement

This commentary was not supported by any grant, sponsor, or funder.