Marijuana and cannabinoid use in clinical oral and maxillofacial surgery: a scoping review

Introduction

Marijuana has been consumed for thousands of years with the first evidence of its medicinal use occurring around 400 AD (1). Consumption of marijuana was unregulated in the United States until the first federal restriction on cannabis was enacted by the Marihuana Tax Act of 1937. Since then, legislation has remained a strong regulator of marijuana use for recreational or medical purposes. The Controlled Substances Act of 1970 created the first drug scheduling system listing Marijuana as a schedule 1 substance along with heroin. However, due to legislative changes over the past decade, marijuana is now legalized for medical use in 35 states and Washington DC for adults over age 21 (2-4) (Table 1). Of the remaining 15 states, 7 of these (i.e., Georgia, Indiana, Iowa, Kentucky, Texas, Virginia, and Wisconsin) have legalized low-∆-9-tetrahydrocannabinol (THC) cannabidiol (CBD) oil (up to 5% THC) for medical use (2). As a result, only 8 states have yet to legalize any form of marijuana or CBD for medical or recreational use, which may decrease by the end of 2021 based on pending legislation (2). Consequently, the increase in legal marijuana use provides an opportunity for researchers to investigate the therapeutic potential of medical marijuana, as well as to better characterize the physiologic effects of recreational marijuana.

Specifically, “marijuana” refers to parts of the Cannabis sativa plant from which it is derived, which contain the highest concentrations of the primary psychoactive compound, THC, while the term “cannabis” refers to all parts of the C. sativa plant (5,6). Marijuana contains approximately 450 distinct compounds, including 60 cannabinoids (5,6). THC and CBD are two of the main cannabinoids which are most commonly studied. To date, there have been hundreds of clinical trials and studies on medical marijuana and cannabinoids for conditions such as epileptic seizures, Parkinson’s disease, ulcerative colitis, cognitive dysfunction, opioid use disorder, acute and chronic pain (7). However, it is unclear how well studied marijuana is in the context of oral and maxillofacial surgery (OMFS), as well as intravenous (IV) sedation, which is an integral part of the OMFS specialty. Our study sought to characterize the literature on marijuana in OMFS, including treatment outcomes and side effects, with the hypothesis that there is likely a paucity of studies available on this topic. We hope this study will serve as a foundation for future research on marijuana in OMFS, especially as legislation around medical marijuana use grows increasingly relaxed throughout the United States (2). We present the following article in accordance with the PRISMA-ScR reporting checklist (available at https://joma.amegroups.com/article/view/10.21037/joma-21-7/rc).

Materials and methods

We conducted a scoping review of the literature relating marijuana or cannabinoids to clinical OMFS. This review complied with the Preferred Reporting Items for Systematic Reviews and Meta-analyses extension for Scoping Reviews (PRISMA-ScR) reporting checklist.

Our search of relevant studies included ClinicalTrials.gov, PubMed, and Web of Science databases dating from inception until 11/1/2021. Various key words were utilized for the search including oral surg*, TMJ, temporomandibular, dentoalveolar, orthognathic surgery, dental extraction, dental, dentistry AND cannabi*, tetrahydroxy*, marijuana. MeSH terms were also used where available. Studies that assessed the relationship of cannabinoids or marijuana with oral surgery procedures were considered for inclusion (see Figure 1). We excluded papers not written in English, those involving animal models, and those without interventional arms. Titles and abstracts were screened by two independent researchers (LY Tang and AR Emery) from 1/10/2021 to 11/10/2021 with disagreements reviewed and decided upon by author (J Wang). Although the aforementioned protocol was designed a priori, no formal protocol registration was performed.

Figure 1 Flow diagram of included articles.

The outcome variables for the clinical trials included the clinical trial number, title of the study, principal investigator (PI) name/author names, PI specialty, study topic, study type, sample size, study start date, study end date, study sponsor, primary outcome, and results reported on ClinicalTrials.gov. The outcome variables for the non-clinical trials included study name, authors, study topic, study type, sample size, date of accepted publication, intervention, primary outcome, and results. No studies meeting the inclusion criteria were excluded. The data presented in this study is publicly available and thus did not require institutional review board approval.

Results

Eleven studies were identified that met the inclusion criteria, with 2 studies described within a single publication (8). There were 7 prospective studies including 4 clinical trials (Table 2) and 3 randomized control trials (RCTs) not registered as clinical trials. There were also 4 observational studies (i.e., retrospective cohorts) identified (Table 3). The topics covered by these studies included acute post-dental extraction pain, temporomandibular joint (TMJ) pain and myofascial pain, extraction socket wound healing, IV sedation anesthetic requirements, IV sedation physiologic responses and observations, including cardiovascular responses. The sample sizes ranged from 10 to 151 patients. In total, two studies found that cannabinoids may improve pain (9,10), while two studies failed to demonstrate improved pain control with cannabinoids (11,12). Additionally, 3 studies reported that cannabinoids had adverse effects on vital signs (8,13,14), with another study noting increased anesthetic requirements for cannabinoid users (15). Lastly, 1 study reported no difference in post-operative healing after dental extractions for cannabinoid and non-cannabinoid users (16).

Discussion

Our study provides an overview of the current marijuana and cannabinoid research in OMFS. As hypothesized for our primary outcome, the number of qualifying studies was small with a total of 11 studies being identified. In the future, studies related to both cannabinoids and oral surgery will likely be more common and will be essential for treating a patient population that now has legal access to cannabinoids. Our secondary outcomes relate to the outcomes of each study which are detailed in Tables 2,3, and explained in the sections below.

Routes of cannabinoid administration

Cannabinoids have been formulated for administration by a variety of routes including inhalation, oral, sublingual, IV, intramuscular, and topical use (17,18). However, among the 7 prospective studies included in the present paper (8-12,16,19), oral administration of cannabinoids was the most common mode observed in all except 3 of them with 1 using IV THC (8) and 2 using topical CBD (10,16). One ongoing clinical trial that is currently in the recruiting phase plans to administer CBD and hemp oil under the tongue for 1 minute followed by swallowing (19). The study using IV THC assessed its effects on the cardiovascular system during IV sedation (8). Unlike oral administration of cannabinoids, sublingual and IV administration bypass the liver and thus avoid first-pass metabolism, which otherwise reduces the bioavailability of the active cannabinoid compounds. The 4 observational studies enrolled patients based on positive THC toxicology or self-reported marijuana use, which most likely included inhalational use or edibles, although it was not specified. The route of marijuana administration is important to consider for evaluating drug effect, especially given the variety of administration routes throughout the literature (12). The field of OMFS is especially susceptible to the routes of drug administration given the proximity of oral surgical sites (i.e., sources of pain) to medication taken orally, sublingually, applied topically, or inhaled through the mouth. Future studies may seek to better characterize the how each form of cannabinoid administration can affect OMFS patients and explore which route of administration works best for certain procedures.

Pain

Among the 11 marijuana and cannabinoid-focused studies identified in the OMFS literature, 6 of them assessed pain alleviation. Previous research has shown that cannabinoids likely possess analgesic, anxiolytic, antispasmodic muscle relaxing, anti-inflammatory and anticonvulsant properties (20). The opioid epidemic provided motivation to find alternative pain-relieving modalities, leading many to consider cannabinoids (21). Dental extractions historically represent one of the most common OMFS procedures and sources of patient discomfort requiring prescription pain medications, thus representing a potential role for cannabinoids (22). In 2011, Bacci et al. conducted a staged split-mouth study comparing 300 mg of a cannabinoid receptor ligand known as Normast (i.e., palmitoylethanolamide) versus no Normast for patients undergoing third molar extractions (9). They concluded that Normast improved postoperative pain based on visual analog scale (VAS). However, the study’s objective assessment of pain was severely limited by participant drop-out rate and heterogeneous post-operative non-steroidal anti-inflammatory drug (NSAID) consumption. The study also identified a delayed onset of edema in the Normast group compared to control suggesting Normast may delay edema formation following extraction. A phase 3 study is currently studying the pain-relieving effects of oral CBD drops at 2 different concentrations versus Tylenol and Ibuprofen versus placebo for patients following dental extraction (23). This study may elucidate whether CBD can serve as a safe adjunct to NSAIDs and Tylenol following tooth extraction, instead of needing to prescribe narcotics. Conducting prospective studies and working to increase study protocol compliance may allow stronger conclusions to be drawn about the potential of cannabinoids to treat post-extraction dental pain.

In 2011, a RCT evaluated the effects of preoperatively administering GW842166 (an experimental cannabinoid and CB2 selective agonist) versus ibuprofen and placebo prior to mandibular third molar surgical extraction. Unfortunately, no clinically meaningful analgesic benefit of GW842166 was found (12). The authors attributed the lack of observed benefit to subtherapeutic plasma drug concentrations potentially from high protein-binding of the drug that was also previously seen in rat and human studies. Higher drug doses or administration in more bioavailable forms (e.g., intramuscular or IV) could potentially increase drug concentrations within the blood stream to a therapeutic or effective level. The same authors also suggested increasing the exposure time of the drug to its CB2 receptor to elicit an effect response. CB2 selective agonists, like GW842166, which lack the psychotropic effects of CB1 agonists, and thus may be preferred and worth pursuing more. In 2012, another experimental cannabinoid, AZD1940 (CB1 and CB2 agonist), given preoperatively was tested against placebo and Naproxen prior to mandibular third molar tooth extraction (11). The study concluded that AZD1940 did not result in reduced post-operative pain. Despite a lack of convincing evidence of the effects of these experimental cannabinoids, there is still hope for increasing their efficacy through alternative routes of administration and dosing. Also, as additional opioids are discovered, a focus on the receptor selectivity (i.e., CB1 vs. CB2) may also alter therapeutic effects, as well as, potential side effects.

Other surgical specialties outside of OMFS have also considered cannabinoids for the treatment of acute pain. For example, a 2020 meta-analysis (24) of 8 RCTs and 4 observational studies assessed the utility of cannabinoids for post-surgical pain following various types of surgery (i.e., cardiac, general, neurological, orthopedic, urologic, vascular and 2 RCTs on dental extraction (11,12). They found that the addition of cannabinoids to analgesics did not improve acute post-surgical pain. Similarly, another 2020 meta-analysis of 6 RCTs using cannabinoids for acute post-surgical pain (25), including 2 RCTs on dental extraction (11,12), found a small but significant improvement of subjective pain scores with intramuscular cannabinoid administration and less so with oral administration. The mixed results of these studies regarding the efficacy of cannabinoids for acute post-surgical pain calls for additional high-level studies, such as RCTs, to draw more convincing conclusions. Given the different pain experiences associate with various types of surgery, future studies investigating cannabinoids administration for OMFS procedures would be most informative for OMFS practitioners.

Chronic pain, including both cancer pain and non-cancer pain subtypes, have also been studied (26). A 2015 systematic review of chronic nonmalignant neuropathic pain found that cannabinoids may provide effective analgesia in conditions refractory to other pain modalities (27). A 2019 clinical trial evaluating the use of cannabis cream applied to skin over bilateral masseter muscles found a significant decrease in myofascial pain and in masseter muscle activity measured by surface electromyography (sEMG) compared to placebo (10). One active clinical trial investigating TMJ and myofascial pain will hopefully provide insight into any potential therapeutic cannabinoids may hold for such pain, which is often chronic in nature (19). The current authors are hopeful that a continued interest in cannabinoids will elucidate any analgesic properties that cannabinoids may have for treating TMJ pain and myofascial pain (28), which are difficult to control forms of pain within OMFS.

Anesthetic requirement

The IV anesthetic requirement associated with recreational marijuana users has also been studied. A 2019 retrospective cohort of self-described marijuana users versus non-users undergoing dental extractions under IV sedation found that marijuana users consumed a higher average amount of propofol in milligrams per minute (15). These findings suggest pharmacokinetic variations in OMFS patients based on experience with marijuana. As a result, OMFS providers who quantify marijuana use during pre-sedation evaluations may be able to predict intraoperative sedation requirements for each patient, and even determine if a patient is fit for outpatient sedation.

Vital signs, cardiovascular effects, and perioperative observations

The effects of THC and cannabinoids on normal physiology, especially cardiovascular effects, is also important information for OMFS providers. A 2019 retrospective cohort study of adult patients sought to characterize the effects of THC on vital signs during IV sedation with IV versed (midazolam) and IV Fentanyl. The patients were placed in the experimental arm if they tested positive for urine THC and put in the control group if they tested negative (13). Patients who tested positive had statistically significant higher mean arteriolar pressure percentage change and lower heart rate percentage change at 10 minutes into surgery than the group testing negative for THC. However, there was no significant change in the respiratory rate. These findings suggest that there may be different physiologic responses to IV sedation for patients who use marijuana compared to those who do not.

Another study by Gregg et al. (1976) investigated the cardiovascular effects of cannabinol during oral surgery (8). They compared presurgical administration of IV THC to diazepam and placebo and found that the higher dose of IV THC (i.e., 0.044 mg/kg, compared to 0.022 mg/kg) resulted in higher peak heart rate, syncopal-like episodes of hypotension around 4–8 minutes after administration, and elevated blood pressure at 25 minutes after administration. They also noted that one patient, who received the 0.044 mg/kg dose of THC, had a reduction in their preoperative arrhythmia for 1 hour after administration. By contrast, the preoperative arrhythmias increased for 4 of the patients in the 0.022 mg/kg group. The paper by Gregg et al. also conducted a retrospective study of 10 patients undergoing IV general anesthesia for tooth extraction and found that those who endorsed THC use within 72 hours of their procedure demonstrated a sustained post-operative tachycardia for an average of 38 minutes after the end of anesthesia compared to 7 minutes in the control group. These observations are important considerations as marijuana, and cannabinoids, become more available for both recreational and medicinal purposes. Understanding the physiologic effects will help providers counsel patients and also prepare for any perturbations in vital signs attributable to marijuana exposure.

Other studies have also focused on the perioperative changes seen in patients who consume marijuana. One retrospective cohort by Mechas et al. (2018) of 50 IV sedation cases noted that 26 patients required preoperative albuterol for asthma or to improve lung sounds to auscultation (14). They also reported that 31 patients received glycopyrrolate to prevent consequences of secretions including aspiration, bronchospasm, or laryngospasm. Diazepam reduced the intraoperative use of other medications such as propofol, fentanyl, and ketamine. Having excluded 3 patients for marijuana use within a few hours of their planned procedure, the authors of that study advocated for delaying elective procedures 24 hours from the last marijuana consumption to ensure informed consent is possible. They also advocated for more careful cardiovascular and respiratory monitoring during and after surgery. Finally, they report the antiemetic effect of marijuana occurs briefly after consumption, which is unlikely to benefit the patient undergoing surgery at least 24 hours later. Knowing these physiologic trends will equip OMFS practitioners to competently manage such physiologic perturbations among marijuana users to keep patients safe. Future studies may seek to quantify and correlate the amount of marijuana consumed with the amount of physiologic perturbation observed.

Wound healing

Cannabinoids have also been shown to have immunomodulatory effects, including inhibition of interleukin-6 (IL-6), an upregulator of pathways in microglial cells that decrease inflammation (29). A 2019 study by Puisys et al. found that post-extraction use of oral amoxicillin and chlorhexidine rinse had no difference in outcomes (i.e., pain, swelling intensity, alveolar osteitis, tolerance of post-operative healing, and overall assessment of satisfaction) compared to those that used phytocannabinoid-CBD gel intraorally and extraorally along with chlorhexidine rinse (16). This study suggests similar effects on post-extraction healing caused by cannabinoids and antibiotics. However, this study may have been confounded by administration of chlorhexidine rinse to both groups that may be responsible for similar outcomes. The proposition of cannabinoids imposing anti-inflammatory effects is intriguing, but calls for more robust head-to-head comparisons of cannabinoids against controls, such as antibiotics, for validation.

Risks of marijuana use

Despite recent legalizations, the medical use of marijuana still remains controversial. According to Volkow et al. (2014), short term adverse effects include impaired memory, impaired motor coordination, altered judgement, paranoia and psychosis (30). Long term impacts include altered brain development and cognitive impairment (30). Long-term marijuana use can also lead to dependence with 9% of overall users and 17% of those who begin using marijuana in adolescence becoming addicted (30). Furthermore, the THC content of marijuana has steadily increased from about 3% in the 1980s to 12% in 2012, which may have led to more emergency department visits (17). Also, marijuana can have complex drug interactions with other painkillers or anesthetic drugs, and the precise mechanism of these interactions is still unclear. These potential risks must be considered in the context of alternative treatments, such as opioids, which also carry the risk of addiction. Legalizing marijuana for medical use may potentially lower the rate of opioid prescriptions and mortalities, although this idea calls for greater investigative efforts for understanding (21).

Limitations of the study

This study is limited by the inclusion of only studies written in English. It is also limited by the quality of the studies with 4 of the 11 being observational studies and the remaining 7 RCTs having relatively small sample sizes (i.e., 10–151). Patient drop out and lack of compliance with preset trial protocols also impaired the success of some studies (9,14).

Conclusions

In conclusion, very few studies have evaluated the role of marijuana and cannabinoids in OMFS and we only identified 11 studies in the English literature. Two of these studies found that cannabinoids may improve pain (9,10), two studies failed to demonstrate improved pain control with cannabinoids (11,12), 3 studies reported that cannabinoids had adverse effects on vital signs (8,13,14), 1 study reported increased anesthetic requirements for cannabinoid users (15), 1 study reported no difference in post-operative healing after dental extractions for cannabinoid and non-cannabinoid users (16), and 1 study is ongoing (23). Given the liberalization of marijuana laws over the past decade leading to an increase in recreational and medical marijuana use, more patients are expected to have tried or actively use cannabinoids prior to interaction with OMFS providers. Future studies will be essential to understanding the effects and potential therapeutic benefits of these substances and medications, particularly their clinical implications. This study will hopefully lay the foundation for guiding future studies aimed at elucidating the role and impact cannabinoids may have within the OMFS scope of practice.

Statement of clinical relevance

The effects of marijuana and cannabinoids in OMFS is vastly understudied, thus necessitating future research to better elucidate its pain-relieving potential, effects on wound healing, and physiologic perturbations, particularly during anesthesia.

Acknowledgments

Funding: None.

Footnote

Reporting Checklist: The authors have completed the PRISMA-ScR reporting checklist. Available at https://joma.amegroups.com/article/view/10.21037/joma-21-7/rc

Conflicts of Interest: The authors have completed the ICMJE uniform disclosure form (available at https://joma.amegroups.com/article/view/10.21037/joma-21-7/coif). JW serves an unpaid editorial board member of Journal of Oral and Maxillofacial Anesthesia from August 2021 to July 2023. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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