Cannabinoids as Adjuncts in Periodontal Therapy

Periodontal disease is highly prevalent around the globe, affecting approximately 538 million people worldwide. In the United States, 64.7 million adults age 30 and older (or 46% of the population) are impacted.^1–4 As chronic disorders of the periodontium, periodontal conditions can be prevented or addressed with many treatment modalities and adjuncts.^5,6 In some instances, adjunctive local and systemic antibiotic therapies and even surgery may be necessary. A new and emerging modality, however — cannabidiol (CBD) — may help reduce the inflammatory response associated with this chronic destructive disease. 

Used for centuries, the cannabis plant has both medicinal and recreational purposes.⁷ Its two principal compounds — tetrahydrocannabinol (THC) and CBD — are referred to as cannabinoids.^7–9 More than 100 types of cannabinoids exist. They are classified as: 

• Endogenous (a substance created within the body) or endocannabinoids (produced in humans and animals and used as lipid messengers)
• Synthetic
• Phytocannabinoid (from stalks, seeds, leaves and flowers of the cannabis plant)

In addition to THC and CBD, other cannabinoids include cannabinol (CBN), cannabigerol (CBG), and cannabichromene (CBC).^7–9 

Cannabinoids are a group of secondary metabolites that act on the cellular cannabinoid receptors (CB1 and CB2) throughout the body’s endocannabinoid system. These receptors possess lipophilic ligands derived from arachidonic acid, an essential fatty acid that is necessary for chemical messaging.¹⁰ The CB1 receptor is most abundant in the cerebellum, hippocampus and basal ganglia of the brain, and is also located in peripheral sites, such as the heart, lungs, adrenal glands and peripheral neurons. In addition, CB1 receptors are found in retinal, fat, intestinal and reproductive tissues.¹⁰ The CB2 receptor is chiefly expressed in immune cells (e.g., the spleen, tonsils and thymus) and has been shown to exert anti-inflammatory effects on leukocytes.¹¹ Recent evidence indicates the CB2 receptor is also present in central nervous tissue, and both receptors are known to bind endocannabinoids and phytocannabinoids.^10,11 Unlike CBD, THC acts mainly on the CB1 receptor of the central nervous system and contributes to psychotropic effects, such as alterations in mood, behavior, thoughts and perception. 

Because it has anti-inflammatory, antimicrobial, immunomodulatory and antioxidant properties, CBD prevents inflammation; it also helps regulate the immune system and protects cells from tissue damage.^8,12 Various forms of CBD have been used effectively to prevent and reduce seizures in patients with severe pediatric epilepsy, help quell anxiety, treat insomnia, and alleviate chronic pain associated with cancer, nausea, neuropathic causes and multiple sclerosis.^8,12–14 Studies have shown CBD provides protective effects in those who have experienced stroke and in patients with Alzheimer’s disease who have amyloid plaques; additionally, CBD may even help patients with Huntington disease and Parkinson disease.¹² Cannabinoids such as CBD have demonstrated antimicrobial effects against pathogenic bacteria, including methicillin-resistant Staphylococcus aureus, Streptococcus pneumoniae and Clostridioides difficile.^15,16 

Supporting Research

The inflammatory response of periodontal disease directly impacts systemic health. Inflammation, whether chronic or acute, results in a host response. Activation of the inflammatory (innate) and/​or immune (adaptive) system triggers the body to initiate a series of protective responses, including the secretion of sulcular fluid composed primarily of leukocytes, enzymes and other cellular elements. The stimulation of the inflammatory response system is largely responsible for tissue destruction in periodontitis. 

Cytokines, prostaglandins and matrix metalloproteinases are among several biochemical mediators that initiate tissue destruction and bone loss in chronic inflammatory disease.¹⁷ The anti-inflammatory, antibacterial and immunomodulatory properties of CBD have prompted researchers to investigate its ability to combat periodontal conditions. 

Napimoga et al¹⁸ induced periodontitis in rats and compared treatment with CBD versus a saline control. In this in vivo study, the control group did not receive a suture, but did receive the saline injection. In the two other groups, a suture was placed around the mandibular first molar and the rats were either (depending on group) injected with saline or CBD (5 mg/​kg). After 30 days, the animals were euthanized and the right and left mandibular areas were reviewed to determine bone loss. The gingival tissues were also removed, and interleukin-1β levels, tumor necrosis factor levels, and neutrophil infiltration were evaluated. Compared to the control group, the results showed the rats that received daily intraperitoneal injections with CBD for 30 days had less alveolar bone loss, and the gingival tissue demonstrated decreased neutrophil migration. Reduced neutrophil migration signifies a depression in pro-inflammatory markers, suggesting that modulation of the host response by CBD may be an alternative to traditional periodontal treatment approaches. 

Vasudevan and Stahl^19–21 conducted three studies on human subjects using dental plaque from patients with varying levels of periodontal disease. The investigators examined CBD’s antibacterial properties in toothpaste, mouthrinse and tooth polishing powder. In the first study, the researchers compared cannabinoids and toothpaste products to identify the efficiency of cannabinoids in reducing oral bacteria.¹⁹ This was the first known study to test samples of human dental plaque with CBD. The authors compared the antibacterial activity of 12.5% cannabinoids (CBD, CBC, CBN, CBG and cannabigerolic acid) against two well-known brands of toothpaste. Broth agar-prepared petri dishes were subdivided into four sections, and each section was smeared with an individual cannabinoid or toothpaste. Plaque samples were collected from human interdental spaces and spread on each section. The samples were incubated at 37° C for 24 hours. After incubation, total bacteria counts were taken for each section and compared. The CBD-treated and all other cannabinoid-treated samples demonstrated less colony-forming growth than the toothpaste-treated samples, with CBN and CBC proving the most effective in reducing total bacterial growth. This study suggests that cannabinoids, including CBD, may be an effective antimicrobial agent against dental plaque-associated bacteria. 

In the second study, Vasudevan and Stahl²⁰ conducted a randomized controlled trial comparing the bactericidal activity of cannabinoid-infused mouthrinses against total-culturable bacterial content from human dental plaque samples. The infused mouthrinses contained less than 1% of either CBD or CBG and were compared against a mouthrinse containing 0.2% chlorhexidine (higher than traditionally prescribed) and two commercially available mouthrinses: one containing essential oils with alcohol, and one with fluoride/​potassium nitrate without alcohol. Plaque samples were collected from interdental spaces and processed for in vitro assay. Using both the agar well diffusion method (30 μl undiluted mouthrinse) and disc diffusion method (15 μl undiluted mouthrinse), plaque samples were spread on the petri dishes and incubated at 37° C for 36 hours. After incubation, the authors measured the zone of inhibition. The in vitro assay was performed three times for each mouthrinse. Compared to chlorhexidine, the CBD-infused mouthrinse exhibited superior bactericidal action against bacterial plaque. While CBG also demonstrated greater inhibition of bacterial content than chlorhexidine, the difference was not statistically significant. The two commercially available mouthrinse did not show any significant antimicrobial activity. This study supports cannabinoids’ antibacterial activity against bacterial content in dental plaque. 

In the third Vasudevan and Stahl²¹ study, regular tooth polishing powder was supplemented with CBD to determine if supragingival and subgingival bacteria-forming colonies would be suppressed. Synthetic CBD was added to sodium bicarbonate tooth polishing powder at an equal 1% weight​-to-weight ratio. The teeth of the 12 subjects were polished with either the CBD-infused polishing powder or the control, noninfused polishing powder. Two tooth-polishing machines were used to prevent cross-contamination with CBD. Oral plaque was collected from identical interdental spaces both pre- and posttreatment. The plaque was prepared for in vitro assay and the broth agar plates smeared with samples. The samples were incubated at 37° C and colony-forming units of bacteria were analyzed after 36 hours. The results suggested the noninfused powder was only effective in removing dental plaque from gingival spaces and had no effect on the inhibition of colony-forming units. Conversely, teeth polished with the CBD-infused powder showed a significant reduction in colony-forming bacteria. 

Safety and Concerns

The market is flooded with commercially available CBD and THC products designed for therapeutic, medicinal and recreational purposes.^7,8,12–16 These products are distributed in various forms, including oils, candies, gummies, balms, lotions, capsules, incense/​herbal blends, and sprays. Such products can be purchased online and at many retail stores and dispensaries.^7,22–24 

Although THC and CBD are both cannabinoids, they should not be used interchangeably. Products containing doses greater than 0.3% dry weight of THC (the legal dose in the United States) elicit the high commonly associated with marijuana, whereas CBD products containing less than the legal dose of THC do not cause psychotropic reactions.^7,24 

Additionally, CBD has a safer profile than THC, which can alter cardiovascular functions, body temperature, or psychomotor or psychological function.¹² Also worth noting is that while CBD oil (sometimes referred to as hemp oil) and hemp seed oil are easily confused, hemp seed oil does not contain any cannabinoids (CBD or THC).²⁴ 

Standard levels of CBD, THC and other cannabinoids allowed in products have not been established. The majority of CBD products are not regulated by the U.S. Food and Drug Administration (FDA) and the only FDA-approved CBD product is a prescription medication used to treat severe seizures in children.²⁵ Products manufactured without undergoing FDA review are subject to inconsistent quality control, no guarantee on the accuracy or level of the active ingredients, and the user’s/​prescriber’s inability to verify the safety and efficacy of the product.²⁵ In fact, some products have been found to contain mold, pesticides and heavy metals.²⁶ Inaccurate labeling and marketing of CBD and other cannabis-derived products place consumers’ and patients’ health and safety at risk.^23–25 

Conclusion 

Although controlled and limited to small sample sizes, emerging research is promising and supports the adjunctive use of CBD, as well as other cannabinoids, in treating periodontal disease. Continued trials are needed to support CBD’s validity in combating periodontal disease and should be expanded to include other types of cannabinoids and modalities. The studies discussed in this article did not include THC or actual marijuana smoking, as smoking cannabis/​marijuana has deleterious effects on gingival tissue and increases the risk of head and neck cancers.²⁷ 

Practitioners should be mindful that each individual’s host response will be different and is contingent on the patient’s health and other factors. Because the majority of CBD products are not FDA regulated, it is imperative to understand their ingredients, risks and benefits prior to speaking with patients. Consideration of preexisting conditions and interaction of prescribed pharmaceutical drugs is critical in determining the effect of CBD on periodontal conditions. Moreover, patients should be advised to consult their physician before use to discuss potential adverse reactions. 

Oral health professionals can stay up to date on the most current regulations and state laws related to cannabis and cannabis-derived products by visiting the FDA’s Regulation of Cannabis and Cannabis-Derived Products page (https:/​/​bit.ly/​3jPCnJz),²⁵ and the National Conference of State Legislatures’ State Medical Marijuana Laws page (https:/​/​bit.ly/​3yJP0vV).²⁸  

Key Takeaways

• Limited evidence suggests a new and emerging adjunctive modality — cannabinoids, including cannabidiol (CBD) — may help reduce the inflammatory response associated with periodontal disease.
• Because it has anti-inflammatory, antimicrobial, immunomodulatory and antioxidant properties, CBD prevents inflammation; it also helps regulate the immune system and protects cells from tissue damage.^8,12
• Napimoga et al¹⁸ induced periodontitis in rats and compared treatment with CBD versus a saline control. The results showed the rats that received daily intraperitoneal injections with CBD had less alveolar bone loss, and the gingival tissue demonstrated decreased neutrophil migration. 
• Reduced neutrophil migration signifies a depression in pro-inflammatory markers, indicating that modulation of the host response by CBD may be an alternative to traditional periodontal treatment approaches. 
• In addition, research by Stahl and Vasudevan¹⁹ suggests that cannabinoids, including CBD, may be an effective antimicrobial agent against pathogens associated with dental plaque.

References

1. Nazir M, Al-Ansari A, Al-Khalifa K, Alhareky M, Gaffar B, Almas K. Global prevalence of periodontal disease and lack of its surveillance. Scientific World Journal. 2020;2020:2146160. 
2. U.S. Centers for Disease Control and Prevention. Gum Disease. Available at: http/​:/​/​www.cdc.gov/​oralhealth/​fast-facts/​gum-disease/​index.html. Accessed September 8, 2021. 
3. World Health Organization. Oral Health. Available at: https:/​/​www.who.int/​news-room/​fact-sheets/​detail/​oral-health. Accessed September 8, 2021.
4. Janakiram C, Dye BA. A public health approach for prevention of periodontal disease. Periodontol 2000. 2020;84:202–214. 
5. Gasner NS, Schure RS. Periodontal disease. Available at: https:/​/​www.ncbi.nlm.nih.gov/​books/​NBK554590/​. Accessed September 8, 2021. 
6. Könönen E, Gursoy M, Gursoy UK. Periodontitis: a multifaceted disease of tooth-supporting tissues. J Clin Med. 2019;8:1135. 
7. Karas JA, Wong LJ, Paulin OK, et al. The antimicrobial activity of cannabinoids. Antibiotics (Basel). 2020;9:406. 
8. Larsen C, Shahinas J. Dosage, efficacy and safety of cannabidiol administration in adults: a systematic review of human trials. J Clin Med Res. 2020;12:129–141.
9. Chilakapati J, Farris FF. Cannabinoids. In: Wexler P, ed. Encyclopedia of Toxicology. 3rd ed. Cambridge, Mass: Academic Press; 2014:649–654. 
10. Reggio PH. Endocannabinoid binding to the cannabinoid receptors: what is known and what remains unknown. Curr Med Chem. 2010;17:1468–1486. 
11. Turcotte C, Blanchet MR, Laviolette M, Flamand N. The CB2 receptor and its role as a regulator of inflammation. Cell Mol Life Sci. 2016;73:4449–4470. 
12. Campos AC, Fogaça MV, Sonego AB, Guimarães FS. Cannabidiol, neuroprotection and neuropsychiatric disorders. Pharmacol Res. 2016;112:119–127.
13. Russo EB. Cannabinoids in the management of difficult to treat pain. Ther Clin Risk Manag. 2008;4:245–259. 
14. Khaleghi M. New arthritis foundation guidelines on CBD use could be first of many more to come. Altern Ther Health Med. 2020;26(S1):8–11. 
15. Appendino G, Gibbons S, Giana A, et al. Antibacterial cannabinoids from cannabis sativa: a structure-activity study. J Nat Prod. 2008;71:1427–1430. 
16. Blaskovich MA, Kavanagh AM, Elliott AG, et al. The antimicrobial potential of cannabidiol. Commun Biol. 2021;4:7. 
17. Gehrig JS, Willmann DE. Foundations of Periodontics for the Dental Hygienist. 5th ed. New York: Lippincott, Williams & Wilkins; 2020. 
18. Napimoga MH, Benatti BB, Lima FO, et al. Cannabidiol decreases bone resorption by inhibiting RANK/​RANKL expression and pro-inflammatory cytokines during experimental periodontitis in rats. Int Immunopharmacol. 2009;9:216–222. 
19. Stahl V, Vasudevan K. Comparison of efficacy of cannabinoids versus commercial oral care products in reducing bacterial content from dental plaque: a preliminary observation. A Cureus. 2020;12:e6809.
20. Vasudevan K, Stahl V. Cannabinoids infused mouthwash products are as effective as chlorhexidine on inhibition of total-culturable bacterial content in dental plaque samples. J Cannabis Res. 2020;2:20. 
21. Vasudevan K, Stahl V. CBD-supplemented polishing powder enhances tooth polishing by inhibiting dental plaque bacteria. J Int Soc Prev Community Dent. 2020;10:766–770. 
22. Vandrey R, Dunn KE, Fry JA, Girling ER. A survey study to characterize use of spice products (synthetic cannabinoids). Drug Alcohol Depend. 2012;120:238–241. 
23. Fitzcharles MA, Clauw DJ, Hauser W. A cautious hope for cannabidiol (CBD) in rheumatology care. Arthritis Care Res (Hoboken). 2020;10:1002.
24. VanDolah HJ, Bauer BA, Mauck KF. Clinicians’ guide to cannabidiol and hemp oils. Mayo Clin Proc. 2019;94:1840–1851.
25. U.S. Food and Drug Administration. FDA Regulation of Cannabis and Cannabis-Derived Products, Including Cannabidiol (CBD). Available at: https:/​/​bit.ly/​3jPCnJz. Accessed September 8, 2021. 
26. Hurd YL. Leading the next CBD wave — safety and efficacy. JAMA Psychiatry. 2020;77:341–342. 
27. American Dental Association. Cannabis: Oral Health Effects. Available at: https:/​/​www.ada.org/​en/​member-center/​oral-health-topics/​cannabis-oral-health-effects. Accessed September 8, 2021.
28. National Conference of State Legislatures. State Medical Marijuana Laws. Available at: https:/​/​bit.ly/​3yJP0vV. Accessed September 8, 2021.

From Decisions in Dentistry. October 2021;7(10):12-15.