Cannabis: Pharmacology, Medical Usage and Oral and Dental Implications

Introduction
Cannabis refers to drug products produced from plants of the genus Cannabis. 1 One of the most commonly used recreational drugs, 2 cannabis is capable of producing feelings of euphoria and relaxation in users. 3 While historically cannabis has been an illegal substance, in many countries there has been increasing acceptance of its usage with many jurisdictions decriminalizing, deregulating, and even legalizing its usage. 4 Routes of utilization of cannabis include inhalational, edibles, oils and topical. 5 In Canada, cannabis was federally legalized for recreational use with the passing of the Cannabis Act, but was previously available for medicinal usage. 6 While it is unclear whether the legalization will result in increased usage of cannabis, the dental professional should be aware of cannabis and its properties, and how it may affect dental treatment and patient health. Here we review the pharmacology of cannabis, its medical usage, its effects on the oral cavity, and implications for dentistry.

Pharmacology of Cannabis

Pharmacodynamics
Δ9-Tetrahydrocannaibnol (THC) is the primary source of the pharmacological effects of cannabis, responsible for the generation of both its medical benefits and its recreational effects. 7 The majority of these effects are through agonistic or antagonistic actions at cannabinoid receptors. There are two primary receptors, namely CB1 and CB2, both of which are G-protein coupled receptors. Endogenous compounds for the cannabinoid receptors include arachidonylethanolamide (anandamide) and 2-arachidonylglycerol. Both these agents are suspected neurotransmitters and neuromodulators.

CB1 receptors are found mainly in nerve tissues while CB2 receptors are found primarily in immune cells. CB1 receptors are also present on peripheral tissues including endocrine glands, leucocytes, spleen, heart, urinary tract, gastrointestinal tract, and reproductive tract. Activation of CB1 receptors produces the ‘classic’ marijuana effects on psyche and circulation, while activation of CB2 does not. THC has equal affinity to CB1 and CB2, while synthetic cannabinoids may have differing affinity. The activation of the endocannabinoid system results in widespread effects, summarized in Table 1.

Pharmacokinetics
The pharmacokinetics of THC varies depending on the route of administration. 7 Here we describe the most common methods of administration, namely inhalational and orally, and follow THC from absorption, to distribution, to metabolism, to elimination.

For inhaled cannabis, THC is rapidly detected in blood plasma after first inhalation, with peaking of concentration in 3-10 minutes with a bioavailability of approximately 10-35%. 7 For oral cannabis, THC absorption is irregular, resulting in plasma concentrations peaking after 1-2 hours, in contrast with inhaled cannabis. 7 Degradation of THC occurs in the stomach and there is significant first-pass effect in the liver, resulting in significantly lower bioavailability compared to inhaled cannabis. 7 Following absorption, THC is distributed with approximately 90% in blood plasma and 10% in red blood cells. 7 95-99% of THC in the blood plasma is bound to plasma proteins. 7 THC readily penetrates vascular tissues, including the liver, fat, and heart. 7 Metabolism of THC occurs largely in the liver, by the cytochrome p450 complex before the metabolites are eliminated in the urine and feces. 7 Of note, elimination is slowed by the fact that THC is slow to be released into the blood stream following uptake by body tissues, resulting in an elimination half-life of 20-30 hours. 7

Medical Usage of Cannabis
While many claims have been made about the medical effects of cannabis and cannabinoids, there remains controversy within the literature as to which effects are clinically significant and statistically corroborated; cannabis and cannabinoids should not be viewed as a panacea. Its medical usage is related to its known effects such as appetite stimulation, relaxation, and euphoria. A complete detailing of all medical uses of cannabis and cannabinoids is beyond the scope of this article and we focus here primarily on the usages that are most common, namely for nausea and vomiting, pain, spasticity, and sleep disorders.

Amongst cancer patients, there is some evidence to support the usage of cannabis for the treatment of nausea and vomiting. 8,9 Embase, Cochrane library, bibliographies Amongst patients suffering from HIV/AIDS, cannabis and cannabinoids have been shown to stimulate appetite, 9 as well as the treatment of neuropathic pain. 10 In the general population, there is some evidence to support the usage of cannabis and cannabinoids for chronic pain. 9,11,12 The treatment of spasticity in patients suffering from conditions like multiple sclerosis also demonstrates evidence supporting its use. 9,12 For patients suffering from sleep disorders, there is evidence to support the usage of cannabis and cannabinoids in improving quality of sleep. 9

Oral Manifestations
There are several documented effects of cannabis on the oral cavity.

Xerostomia and Plaque
Many pharmaceutical agents are known to cause xerostomia in patients and cannabis is no exception. The primary compound responsible for xerostomia is THC which inhibits the action of acetylcholine. 14 Dry-mouth is reported by many users and in the literature as a prominent acute effect of cannabis use. 15,16,17 The decreased production of saliva has a negative effect on the oral cavity because of its necessary function of buffering and irrigating the oral cavity. This can lead to increased plaque retention, and also longer periods of decreased pH creating a cariogenic environment. One study found that cannabis and tobacco users had higher incidences of caries on smooth surfaces compared to tobacco-only users. 3,4 However, this cannot be attributed to salivary changes alone. In addition, the user of cannabis also report behavioural changes that are conducive to developing caries: increased consumption of cariogenic foods, less frequent brushing, and fewer dental visits. 17,18 The combination of behavioural changes and physiological changes caused by cannabis use places cannabis users at an increased risk of developing caries.

Periodontal Health
Periodontal health is often compromised in cannabis users due to a variety of factors such as: decreased salivary production, infrequent oral hygiene and consumption of cariogenic foods. The combination of these factors affect periodontal health because they increase the amount of plaque in the oral cavity. Meier et.al reported that long term use of cannabis was linked with poorer periodontal health in young adults, even when controlling for other factors such as tobacco use, childhood health, and childhood socioeconomic status. 19 Furthermore, smoking cannabis can cause acute gingival inflammation due to the production of harmful hydrocarbons that are produced during combustion of cannabis, similar to that of tobacco smoking. 20 This effect may be limited to the smoked administration of cannabis and not other forms of delivery. No published articles were found which have examined the differences between the forms of delivery and their effect on the periodontium. Shariff et.al found self-reported cannabis users had a higher number of periodontal probing (PD) depths exceeding 4mm, with more sites and increased severity of clinical attachment loss (CAL) than non-self-reported cannabis users. 21 The effects of cannabis on periodontal health necessitates chronic and long term use as two different surveys on adolescents reported opposing results on the relationship between cannabis and poorer periodontal health. 19,22,23 With increasing prevalence of cannabis use and associated compounds, it is vital that more research is needed about cannabis use and its effects on oral health, so that oral healthcare professionals can provide optimal care for patients in a changing healthcare system.

Oral Cancer
The risk of smoking tobacco and oral cancer has been well noted and well documented in the literature, but the effects of cannabis smoke and usage are not so clear. Cannabis combustion has twice as many carcinogenic hydrocarbons as tobacco smoke, which is associated with increased leukoedema and pre-malignant lesions. 20,24,25 Other studies have found a strong link between cannabis smoking and more aggressive cancers, especially in younger patients. 24 While certain papers have shown a link between cannabis usage and increased pre-malignant lesions and leukoedema, none of them were able to report an association between cannabis and oral cancer. Furthermore, cannabinoids have shown some potential protective effects against tongue cancers as well as antineoplastic activity against head and neck cancers. 25,26

Dental Implications

Dental Clinic Environment, Anxiety, and Consent
As cannabis gains acceptance due to its recent legalization in Canada, healthcare professionals such as dentists need to be aware of the problems that it can cause on their clinical practice and patient health. One such problem with cannabis is the potential for intoxication. Individuals who are intoxicated may present with reduced cognition, and in these situations, treatment cannot be administered because of the lack of conscious consent given by the patient. 15,27 While some cannabis users report being more relaxed after consumption, there are individuals that report elevated anxiety. 14,27 Visiting the dentist is an uncomfortable event for some individuals, and if they respond to cannabis with elevated levels of anxiety, this may be stressful for oral healthcare professionals as well. This may complicate treatments and procedures for oral healthcare professionals and the patients themselves. Management of cannabis intoxication is outlined below in Table 2.

Even with the recent legalization of marijuana in Canada, there are portions of our population that may still feel uncomfortable talking about marijuana or disclosing their use of it. It is vital that dentists and oral healthcare professionals do not ostracize or target patients for their beliefs or use of it, but rather provide a support and open environment where the patient feels secure about discussing this topic so that optimal oral healthcare can be delivered. For example, when intoxication may be an issue, the clinician must stress to the patient that the cessation of marijuana consumption is not because of the clinician’s views on the drug, but due to the problems that it presents to providing adequate treatment such as consent, drug interactions, and adverse effects. The discussion will be successful if the clinician provides an environment where the patient feels supported and not maligned by the oral healthcare team. Patients who use marijuana recreationally should have a discussion centered around the problems that cannabis and its pharmacological compounds can have on treatment and oral health status: such as drug interactions, hypertension, tachycardia, dry mouth, reduced periodontal health, etc. For those that use marijuana and its compounds for medical purposes, conversations with the patient’s physician may be needed to understand the patient’s use of the drug and how both parties can work together to maintain good overall and oral health given the patient’s current health situation.

Poorer Oral Health
Cannabis has been to shown to cause a myriad of effects on people, but the main concern for dentists is its ability to reduce the amount of salivary flow. The prevalence of cannabis-induced dry mouth will only increase due to recent legalization, and its growing acceptance in the medical communities as a treatment for a variety of conditions. Decreased salivary production has shown to increase plaque retention, and is a risk factor for caries, periodontitis, and candidiasis. Dentists with patients who use cannabis recreationally, or for medical reasons should look to discuss the implications of cannabis on their oral health, and provide alternative solutions to manage the potentially ensuing dry mouth if cannabis cessation is not possible. Increasing the frequency of recall examinations may also be important to maintain an adequate level of oral health for these patients. Given the recent change in legal status for cannabis, it is imperative that more studies be undertaken to fully understand the effects that cannabis and its related compounds have on the oral cavity. For the time being, we know that cannabis usage can alter salivary flow and has shown some evidence of negatively affecting periodontal health, but the scientific community still does not know the full scope of its effects. Thus a call to action is also needed by researchers to investigate such effects and how dental clinicians can navigate cannabis usage within their daily practice. Table 3 summarizes the Dental management of patients with cannabis use.

Drug Interactions
To date, few studies have been conducted to examine the drug interactions of cannabis. However, there may be a few potential interactions given similarities in effects and also metabolism of other drugs. The two most prominent pharmacological agents in marijuana are THC and CBD. Each has different effects and also enzymes targeting it for metabolism. Studies have shown that cytochrome P450 (CYP) enzymes are the primary metabolic enzymes for the THC and CBD. 15,27,28,29 In vitro studies revealed that CYP 2C9 and 3A4 are predicted to be the dominant primary metabolizers of THC, while CYP 2C19 and 3A4 metabolize CBD. 30,31 The in vitro studies were supported by pharmacogenetic data with ketoconazole. 29 Given that these drugs use such prominent enzymes in our liver, the potential for drug interactions is possible, such as NSAIDs and opioids. 27 However, when reviewed the literature, there was no evidence of a drug applicable for its use in dental settings that would alter the metabolism of the compounds in cannabis and vice versa. Studies on human metabolism and drug interactions with cannabis are surely needed in order to minimize the potential for drug interactions.

The pharmacological compounds in cannabis may also cause adverse effects and drug interactions in susceptible patients, if proper care is not taken. For drug interactions specific to those used by dentists, there exists a potential drug interaction between THC and the epinephrine in local anaesthesia. 16,27 THC has been reported to cause tachycardia, and for patients with previous history of myocardial infraction or arrhythmias, this condition may be exacerbated when taking THC and the epinephrine in local anaesthesia. 16,27 Cannabis has also shown to have sedative effects and may show synergism with the   sedatives and anaesthetics used in general anaesthesia for certain dental procedures and patients. 14

Conclusion
In Canada, cannabis was federally legalized for recreational use with the recent passing of the Cannabis Act. While it is unclear whether the legalization will result in increased usage of cannabis, the dental professional should be aware of cannabis and its properties, and how it may affect dental treatment. Here we discussed the various medical usage of Cannabis and its main implications on the oral cavity. Also, we discussed appropriate treatment modifications, so that the dentist can effectively provide standard care to help prevent and treat oral health problems. OH

Oral Health welcomes this original article.

Disclaimer
The authors have no declared financial interests in any company manufacturing the types of products mentioned in this article.

References

1. Small E, Cronquist A. A Practical and Natural Taxonomy for Cannabis. Taxon. 1976;25(4):405–35.
2. Hall W, Degenhardt L. Prevalence and correlates of cannabis use in developed and developing countries. Curr Opin Psychiatry. 2007 Jul;20(4):393.
3. Green B, Kavanagh D, Young R. Being stoned: a review of self-reported cannabis effects. Drug Alcohol Rev. 2003; 22(4):453–60.
4. Eliason A, Howse RL. A Higher Authority: Canada’s Cannabis Legalization in the Context of International Law [Internet]. Rochester, NY: Social Science Research Network; 2018 Oct [cited 2019 Jan 6]. Report No.: ID 3262773. Available from: https://papers.ssrn.com/abstract=3262773
5. Peters J, Chien J. Contemporary Routes of Cannabis Consumption: A Primer for Clinicians. J Am Osteopath Assoc. 2018 Feb;118(2):67–70.
6. Cox C. The Canadian Cannabis Act legalizes and regulates recreational cannabis use in 2018. Health Policy. 2018 Mar 1;122(3):205–9.
7. Grotenhermen F. Pharmacokinetics and Pharmacodynamics of Cannabinoids. Clin Pharmacokinet. 2003 Apr 1;42(4):327–60.
8. Tramèr MR, Carroll D, Campbell FA, Reynolds DJM, Moore RA, McQuay HJ. Cannabinoids for control of chemotherapy induced nausea and vomiting: quantitative systematic review. BMJ. 2001 Jul 7;323(7303):16.
9. Whiting PF, Wolff RF, Deshpande S, Nisio MD, Duffy S, Hernandez AV, et al. Cannabinoids for Medical Use: A Systematic Review and Meta-analysis. JAMA. 2015 Jun 23;313(24):2456–73.
10. Phillips TJC, Cherry CL, Cox S, Marshall SJ, Rice ASC. Pharmacological Treatment of Painful HIV-Associated Sensory Neuropathy: A Systematic Review and Meta-Analysis of Randomised Controlled Trials. PLOS ONE. 2010 Dec 28;5(12):e14433.
11. Lynch ME, Campbell F. Cannabinoids for treatment of chronic non-cancer pain; a systematic review of randomized trials. Br J Clin Pharmacol. 2011;72(5):735–44.
12. Martín-Sánchez E, Furukawa TA, Taylor J, Martin JLR. Systematic Review and Meta-analysis of Cannabis Treatment for Chronic Pain. Pain Med. 2009 Nov 1;10(8):1353–68.
13. Lakhan SE, Rowland M. Whole plant cannabis extracts in the treatment of spasticity in multiple sclerosis: a systematic review. BMC Neurol. 2009 Dec 4;9(1):59.
14. Grotenhermen F. Pharmacokinetics and Pharmacodynamics of Cannabinoids. Clin Pharmacokinet 2003;42(4):327-60.
15. MacCallum CA, Russo EB. Practical considerations in medical cannabis administration and dosing. Eur J Intern Med. 2018;49:12-9.
16. Cho C, Hirsch R, Johnstone S. General and oral health implications of cannabis use. Australian Dental Journal. 2005;50(2):70-4.
17. Joshi S, Ashley M. Cannabis: A joint problem for patients and the dental profession. Br Dent J. 2016;220(11):597-601.
18. Jager G, Witkamp RF. The endocannabinoid system and appetite: relevance for food reward. Nutr Res Rev. 2014;27(1):172-85.
19. Meier MH, Caspi A, Cerda M, Hancox RJ, Harrington H, Houts R, et al. Associations Between Cannabis Use and Physical Health Problems in Early Midlife: A Longitudinal Comparison of Persistent Cannabis vs Tobacco Users. JAMA Psychiatry. 2016;73(7):731-40.
20. Mofidi A, Fang D, Flores-Mir C. Cannabis and periodontal harm: How convincing is the association? Oral Dis. 2018.
21. Shariff JA, Ahluwalia KP, Papapanou PN. Relationship Between Frequent Recreational Cannabis (Marijuana and Hashish) Use and Periodontitis in Adults in the United States: National Health and Nutrition Examination Survey 2011 to 2012. J Periodontol. 2017;88(3):273-80.
22. Lopez R, Baelum V. Cannabis use and destructive periodontal diseases among adolescents. J Clin Periodontol. 2009;36(3):185-9.
23. Thomson WM, Poulton R, Broadbent JM, Moffitt TE, Caspi A, Beck JD, et al. Cannabis Smoking and Periodontal Disease Among Young Adults. JAMA. 2008;299(6):525-31.
24. Versteeg P, Slot D, Velden Uvd, Weijden Gvd. Effect of cannabis usage on the oral environment: a review. Int J Dent Hygiene. 2008;6:315-20.
25. MR D, TM A. Effects of cannabis smoking on oral soft tissues. Community Dentistry and Oral Epidemiology. 1993;21:78-81.
26. Bryant LM, Daniels KE, Cognetti DM, Tassone P, Luginbuhl AJ, Curry JM. Therapeutic Cannabis and Endocannabinoid Signaling System Modulator Use in Otolaryngology Patients. Laryngoscope Investig Otolaryngol. 2018;3(3):169-77.
27. Beaulieu P. Anesthetic implications of recreational drug use. Can J Anaesth. 2017;64(12):1236-64.
28. de Jonge SW, Gans SL, Atema JJ, Solomkin JS, Dellinger PE, Boermeester MA. Timing of preoperative antibiotic prophylaxis in 54,552 patients and the risk of surgical site infection: A systematic review and meta-analysis. Medicine (Baltimore). 2017;96(29):e6903.
29. Stout SM, Cimino NM. Exogenous cannabinoids as substrates, inhibitors, and inducers of human drug metabolizing enzymes: a systematic review. Drug Metab Rev. 2014;46(1):86-95.
30. Bland TM, Haining RL, Tracy TS, Callery PS. CYP2C-catalyzed delta9-tetrahydrocannabinol metabolism: kinetics, pharmacogenetics and interaction with phenytoin. Biochem Pharmacol. 2005;70(7):1096-103.
31. Richardson TH, Frank Jung, Griffin KJ, Wester M, Raucy JL, Kemper B, et al. A Universal Approach to the Expression of Human and Rabbit Cytochrome P450s of the 2C Subfamily in Escherichia coli. ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS. 1995;323(1):87-96.