A critical review of cannabis in medicine and dentistry: A look back and the path forward

1 THE HISTORICAL USE OF CANNABIS

The properties of the marijuana plant (Cannabis sativa) are well documented for its use in textile manufacture, health benefits, and healing properties. The ancient world shows several medical records describing the usage of cannabis as a therapeutic agent by several cultures (Mikuriya, 1969). About 2000 years ago, the Chinese culture used cannabis to gain balance and harmony between Yin and Yang that prevent disease formation. The plant seeds were utilized as a laxative for treating constipation with the advantage that cannabis seeds lack the main active constituent Δ⁹-tetrahydrocannabinol (Δ⁹-THC) but are rich in fatty acids. These fatty acids such as γ-linoleic acid were applied topically to treat several skin conditions and orally for the treatment of atherosclerosis, osteoporosis, and inflammatory-based conditions. In India, the psychoactive effect of cannabis was popular, which supported its broad use with religious and meditation rituals. Moreover, ayurvedic (Hindu/Indian) remedies were used for their analgesic, hypnotic, and antispasmodic properties (Mechoulam & Carlini, 1978). The wide use of cannabis in India has resulted in the spreading of the plant to Arabia for medicinal purposes. It has been reported in Ibn al Badri’s treatise of Hashish, in which Chamberlain of the Caliphate Council’s son in Baghdad, Zahir-ad-din was cured of epilepsy but became dependent on it and used it for the rest of his life (Lozano, 1997; Mechoulam, 1986).

The western world, however, saw the use of cannabis for its medicinal value and recreation usage years later. For much of the 1800s and early 1900s, the active ingredients in cannabis were unknown and it was introduced later by O’Shaughnessy (an Irish physician) and Moreau (a French psychiatrist) in the second half of the 19th century (Aldrich, 1997; Mechoulam & Carlini, 1978). The first scientific conference that discussed cannabis therapeutics was held in Ohio, United States in 1860 (McMeens, 1860), and the first characterization of cannabinol (CBN) was done in 1932 (Cahn, 1932) followed by the chemical synthesis of CBN and cannabidiol (CBD) in 1940 (Adams et al., 1940; Jacob & Todd, 1940). In 1964, the psychoactive constituent of cannabis plant Δ⁹-THC was isolated and partially synthesized (Gaoni & Mechoulam, 1964). Devane et al. (1988) provided evidence for the presence of specific cannabinoid receptors in the rat brain and confirmed the isolation of cannabinoid receptor type 1 (CB1R). Shortly after, Munro et al. (1993) isolated and cloned the second cannabinoid receptor subtype, cannabinoid receptor type 2 (CB2R) in a human promyelocytic cell line (HL60).

In the early 20th century, more than thousands of publications studied the medicinal properties and therapeutic applications of cannabis in multiple disease conditions. Moreover, with the widespread cannabis use in various communities and age groups, healthcare practitioners should be cautious about cannabis’s effects on general public health and how it can affect several diseases. Interestingly, with regard to dental health, it has been reported that marijuana users exhibit more decay, poor oral hygiene, and greater plaque index than noncannabis users. There are also additional intraoral conditions reported with cannabis users that include tongue carcinoma, gingival hyperplasia, xerostomia, uvulitis, and fiery red gingivitis (for excellent reviews see Almadori et al., 1990; Darling & Arendorf, 1992; Versteeg et al., 2008). Therefore, this review will shed light on the cannabinoid receptor system, its endogenous ligands, pharmacology, metabolism, and the current medical/dental dilemma.

2 MATERIALS AND METHODS

3 THE ENDOCANNABINOID SYSTEM (ECS)

The CB1R was initially identified in 1988 in rat brain tissue using tritiated nonselective agonist [³H]-CP-55,940 (Devane et al., 1988) followed by cloning cDNA of CB1R from rat cerebral cortex in 1990 (Matsuda et al., 1990). The following year, human CB1R was isolated from a human brain stem, and it was identified to share 97.3% homology with rat CB1R (Gérard et al., 1991). Using [³H] CP 55,940, it was found that CB1R is mainly condensed in the brain regions, such as basal ganglia, substantia nigra, hippocampus, and cerebellum (Herkenham et al., 1990). Moreover, it was reported by several studies that CB1R demonstrated similar distribution between species, such as the rat, monkey, dog, and pig with minor differences (Herkenham et al., 1990; Mailleux & Vanderhaeghen, 1992; Pertwee, 1997). Additionally, the CB1R has been documented to be expressed in some peripheral tissues at a lower level, such as ileum longitudinal smooth muscles (Croci et al., 1998) and cardiovascular tissues (Szabo et al., 2001; Wagner et al., 2001). The wide distribution of CB1R in the human body suggests a crucial regulatory role in glucose metabolism (Nogueiras et al., 2009), food intake (Ravinet Trillou et al., 2004), neurotransmitter release modulation (through M-type potassium channels) (D. J. Kim & Thayer, 2000; Schweitzer, 2000) cancer (Pisanti et al., 2013) and, more importantly, pain management (Pertwee, 2001).

In 1993, the CB2R was discovered and characterized using a human promyelocytic leukemic cell line (HL60). Initially, CB2R was named as a peripheral cannabinoid receptor because of the high expression in peripheral immune cells, such as spleen’s macrophages (Munro et al., 1993). B-cells, natural killer cells, monocytes, neutrophils, and T cells (Galiègue et al., 1995). However, recent advances in research tools and techniques led to the identification of CB2R in the brain microglia during inflammatory conditions (Kearn & Hilliard, 1997). The amino acid residues in the CB2R structure showed more diversity in the C-terminus region among different species (human, rat, mouse) (Brown et al., 2002; Griffin et al., 2000). The limited distribution of CB2R in the immune cells suggests that this receptor plays an important regulatory role in inflammation and serves as a novel target for multiple neuroinflammatory disease conditions, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and multiple sclerosis (MS) (Mecha et al., 2016).

The two cannabinoid receptors belong to the superfamily of G-protein-coupled receptors (GPCRs—Class A, Figure 1) that have seven transmembrane alpha-helices with a glycosylated N-terminus and intracellular C-terminus (Bramblett et al., 1995). The homology between the CB1/2 receptors is approximately 44% in the amino acid sequence and 68% in the ligand-binding site (Munro et al., 1993). The first endogenous ligand for the cannabinoid receptors was discovered from the porcine brain two years after the discovery of CB1R and named arachidonoyl ethanolamide (anandamide, AEA). The binding studies of AEA demonstrated a high binding affinity toward CB1R and it also exhibited similar psychoactive properties of Δ⁹-THC when tested in rodents (Devane et al., 1992). In 1995, the second endogenous cannabinoid ligand 2-arachidonoylglycerol (2-AG) was discovered and isolated from the canine gut (Mechoulam et al., 1995) and both ligands are lipids analogs that are synthesized on-demand after physiological or pathogen stimuli.

4 THE PHARMACOLOGY OF CANNABINOID LIGANDS

5 PHYTOCANNABINOIDS

The female plant of C. sativa contains hundreds of various lipid-soluble compounds that share CBRs as molecular targets. The two molecules Δ⁹-THC and CBD are the most studied pCBs in literature. At CB1R, the affinity of Δ⁹-THC is ranging from 5 to 80.3 nM and it demonstrated a comparable low nanomolar range affinity (K_i = 3–75 nM) at CB2R. Additionally, it has been reported that the Δ⁹-THC pharmacological profile at CB1 and CB2 receptors can range from partial/full agonist to antagonist depending on receptor density and coupling efficiency of downstream effectors. Thus, in certain tissues that have high expression of cannabinoid receptors (i.e., CB1R in substantia nigra and globus pallidus), agonist activity is predicted (Pertwee, 2005). While, several other reported investigations showed that Δ⁹-THC behaved as antagonists in tissues that showed low expression level or coupling efficiency of both receptors, reviewed in Pertwee (1997, 2005, 2008). For example, using hippocampal cultures, the application of 100 nM of THC reversed the effect of 2-AG on synaptic activity in a dose-dependent manner (Kelley & Thayer, 2004). Additionally, it has been reported by Bayewitch et al. that THC behaved as a weak CB2R antagonist in Chinese hamster ovary cells (Bayewitch et al., 1996). Bhattacharyya et al. reported that in males the acute anxiety produced by THC is modulated in the right amygdala while processing fearful stimuli that are positively correlated with the extent of local CB1 receptors’ availability (Bhattacharyya et al., 2017).

Moreover, CBD demonstrated a micromolar affinity range toward CBRs relative to Δ⁹-THC, with K_i values ranging from 4350 to greater than 10,000 nM at CB1R and slightly higher affinity (K_i ranging from 2399 to 10,000 nM) at CB2R. In terms of functional activity, multiple reports have shown that CBD antagonizes the agonist activity of CP 55,940 and R-(+) WIN55212 and in some cases, it behaves as an inverse agonist at CB1R depending on the used concentration. At CB2R, CBD behaved as an inverse agonist with promising anti-inflammatory properties in murine microglia and macrophages, reviewed in Pertwee (2004, 2008). The synthetic pathway of Δ⁹-THC, CBD, and some other pCBs (i.e., cannabichromene [CBC]) share cannabigerol (CBG) as the main precursor that converts via specific synthase enzymes (e.g., Δ⁹-THC synthase, CBD synthase, or CBC synthase) into various pCBs.

With regard to their oral effects, Gu et al. examined the influence of physiologically relevant doses of CBD, CBN, and THC (1.0 μg/ml) on the immune response induced by oral pathogens, Porphyromonas gingivalis, Filifactor alocis, and Treponema denticola. CBD, CBN, and THC exhibited the suppression of P. gingivalis-induced cytokines while enhancing interleukin 10 (IL-10, an anti-inflammatory cytokine). Similar responses with the phytocannabinoids were also seen in F. alocis- and T. denticola-exposed human monocytes and human gingival keratinocytes. Interestingly, phytocannabinoid doses ≥5.0 μg/ml compromised cell viability, but efficiently inhibited the growth of P. gingivalis and F. alocis. Additionally, in a transient oral infection model, CBD was able to suppress P. gingivalis-induced innate immune markers in wild-type mice, but not in CB2R-deficient mice (Gu et al., 2019). Although the phytocannabinoids can exert anti-inflammatory effects, misuse of cannabis products could enhance PD and systemic diseases by promoting microbial dysbiosis via direct toxic effects on specific oral bacteria, suppression of the innate immune response to periodontal pathogens, and compromising oral cell vitality (Gu et al., 2019).

In animal studies, CBD has been shown to decrease nociception by inhibiting FAAH (fatty acid enzyme hydrolase that breaks down endocannabinoids) and consequently increasing AEA (endogenous cannabinoid). Therefore, AEA readily binds to CB1 and TRPV1 receptors, promoting analgesia while decreasing the nociception via TRPV1 receptors (Crivelaro do Nascimento et al., 2020; Peres et al., 2018). Moreover, CBD demonstrated the ability to enhance adenosine signaling by blocking its uptake and might be one of the mechanisms by which CBD modulates inflammation (Carrier et al., 2006). The NF-κB is known to regulate the expression of genes associated with the pro-inflammatory response (IL-1β, tumor necrosis factor [TNF-α], IL-6) and cyclooxygenase-2 (COX-2). Interestingly, the number of cannabinoids and terpenes found in the hemp plant can inhibit NF-κB directly or indirectly reducing inflammatory cytokines, thus attenuating inflammation (Morales et al., 2017; Simão da Silva et al., 2011; Kunnumakkara et al., 2018). Meanwhile, several cannabinoids (Muller et al., 2019) and flavonoids (Nakamura et al., 2016) found in the hemp plant activate transient receptor potential ankyrin 1 (TRPA1) (involved with cold hypersensitivity, acidic pH, hyperalgesia), while several cannabinoids activate the transient receptor potential vanilloid (TRPV) and rapidly desensitize the ion channel making them insensitive to mechanical, thermal, and chemical stimulation (Muller et al., 2019).

In MS patients, the mixture of THC: CBD oro-mucosal spray has been used to treat pain and sleep disturbance in a randomized controlled trial in 2005. Cannabinoids adjunctive treatment demonstrated significant improvement in the pain and sleep disturbance in MS patients compared to the control group (Rog et al., 2005). Interestingly, a harmony in opioids and cannabinoid pathways exists; the antinociception measured in rats using high dose morphine or high dose THC was subjected to development of tolerance including receptor desensitization. Meanwhile, a low dose combination of both morphine and Δ⁹-THC combination (0.75 mg/kg each, morphine subcutaneous and Δ⁹-THC intraperitoneal) twice daily for 6.5 days circumvented the development of tolerance, while exhibiting antinociception (Smith et al., 2007). The use of phytocannabinoids in combination with opioids could potentially aid in the management of chronic pain in treating a variety of pain conditions.

6 SYNTHETIC CANNABINOIDS

Several studies have reported the beneficial effects of synthetic cannabinoids in treating multiple disease conditions. In particular, CB2R agonists demonstrated a promising ability to attenuate neuroinflammation in multiple disease models (Leleu-Chavain et al., 2012). For instance, HU-308 was discovered in 1999 and characterized as a selective CB2R agonist lacking CB1R activity (Hanuš et al., 1999). Application of HU-308 in inflammatory models demonstrated anti-inflammatory properties in vitro and in vivo studies (Gómez-Gálvez et al., 2016; Taylor et al., 2015). Additionally, as reported in the literature, synthetic CB2R agonists are the most extensively studied ligands in the cannabinoids field (Aghazadeh Tabrizi et al., 2016). However, more recently, CB2R inverse agonists have emerged as a new potential therapeutic approach to treat neuroinflammation as reviewed by Lunn et al. (2008).

The pain management aspect of synthetic cannabinoids also shows great potential by alternating opioid and cannabinoid treatment, which could be therapeutically advantageous. The Δ⁹-THC analog, HU-210 enhances antinociceptive effects of morphine, when injected into the periaqueductal gray, preventing the development of tolerance, while enhancing morphine antinociception (Wilson et al., 2008). Additionally, selective modulation of the CB2R by AM1241 (agonist) caused the release of β-endorphin from keratinocytes, decreasing pain by local neuronal μ-opioid receptors (Ibrahim et al., 2005). These studies demonstrate antinociception through G-protein-coupled mechanisms by enhancing the opioid system leading to either improvement in opioid effects or by the local release of β-endorphin by CB2R. In our previous studies, we have investigated the therapeutic potential of selective CB2R ligands to regulate chronic inflammation in PD. Our studies were mainly focused on investigating the immunomodulation properties of synthetic CB2R agonist HU-308, and the CB2R inverse agonist SMM-189 in stimulated primary human periodontal ligament fibroblasts (hPDLFs) in which synthetics could provide benefits in PD (Abidi et al., 2018). Moreover, other related findings showed that HU-308 has prohomeostasis effects by inducing anti-inflammatory and osteoprotective properties in oral tissues of rats with LPS-induced PD (Ossola et al., 2016). These studies, along with others (Ossola et al., 2020; Zhang et al., 2020), highlight the important role of the ECS in oral and systemic health. Moreover, the cytokine and chemokine inhibition profiles of HU-308 (agonist) and SMM-189 (inverse agonist) were investigated in activated hPDLFs, and study results showed that CB2R ligands are viable candidates for the development of a new therapeutic intervention for PD (Figure 2) (Abidi et al., 2020).

7 CLINICAL PHARMACOKINETICS AND PHARMACODYNAMICS OF CANNABINOIDS

8 PHARMACODYNAMICS

The impact of the cannabis products has also influenced cultural acceptance that includes smoking various forms of cannabis strains (e.g., Green crack, Sour diesel, etc.) due to presumed health benefits. Healthcare professionals, especially dentists may observe a higher incidence and progression of cannabis-related oral health problems. Although the impact of hemp/CBD oil on oral health is unknown, marijuana is considered a risk factor for periodontal disease since it impairs immune response and compromises the healing of tissues (Tomar & Asma, 2000). The well-known associated effects with marijuana usage are increased somnolence, appetite, and potent immunomodulatory effects that may be the underlying reason why cannabis users have more dental decay, poor oral hygiene, and greater plaque index than nonusers (Darling & Arendorf, 1992a; Shariff et al., 2017). Cannabis use has resulted in other documented intraoral conditions, including tongue carcinoma, gingival hyperplasia, xerostomia, uvulitis, and fiery red gingivitis (Almadori et al., 1990; Christie & Chesher, 1994; Rees, 1992; Rawal et al., 2012; Versteeg et al., 2008). Cessation of cannabis use along with nonsurgical and surgical therapies improved clinical and radiographic findings for a patient demonstrating a localized severe form of PD (Momen-Heravi & Kang, 2017). Meanwhile, it is noteworthy that smoking (i.e., cigarettes) is a risk factor for developing periodontal disease; therefore, smoking cannabis products (ElSohly & ElSohly, 2007) (i.e., carbon monoxide, acetaldehyde, nitrosamines, and polycyclic aromatic hydrocarbons) poses a similar risk (Mayol et al., 2021). Although cannabis use is associated with poor oral health, cannabis use is not associated with other physical health problems in early midlife. However, tobacco use was associated with poor lung function, systemic inflammation, and metabolic health in early midlife (Meier et al., 2016).

Although cannabis has been associated with various oral conditions and adverse effects, it is generally well tolerated by most individuals. However, abuse of cannabis and/or products could result in an oral manifestation of diseases and possibly other conditions that are consistent with the well-established role of the ECS and the cannabinoid receptors regulating immune response (Pacher & Mechoulam, 2011) modulation of T-cells, B-cells, production of inflammatory cytokines, chemokines, and cell migration (Croxford & Yamamura, 2005; Klein et al., 2003; Tanasescu & Constantinescu, 2010). The current shortcomings in our clinical understanding of marijuana exist largely due to incomplete knowledge of the complex biological activities of the phytocannabinoids and limited clinical studies. Other possible challenges are the limited scientific access to cannabis products and the lack of current consumer testing due to regulations and policies, resulting in limited data availability. For these reasons, the effects of many pCBs on the oral cavity are largely unknown, and what is available is focused on either Δ⁹-THC (the psychotropic agent in marijuana) or CBD. It is very important to understand that the C. sativa plant contains many known pCBs, but little is known about their biological activity (Andre et al., 2016). In addition to cannabinoids, the cannabis plant also has terpenes, phenolic compounds including flavonoids that may modulate the overall health outcomes (Andre et al., 2016) and/or interact with other pCBs to produce opposing or enhancing (i.e., “entourage effect: The whole plant is better than the sum of its parts”) effects on the ECS (Laprairie et al., 2015; Pertwee, 2008; Russo, 2011) (Table 1).

9 CANNABINOIDS AND DRUG INTERACTIONS

As a dental or medical practitioner, several concerns may rise as the patient might use cannabis products along with other frequently used or prescribed medications in dentistry like nonsteroidal anti-inflammatory agents (NSAIDs), local anesthetics, antimicrobial agents (antibiotics, antifungal, antiviral), corticosteroids, and antianxiety/sedative agents that could interact with cannabis or hemp extracts. For instance, the CYP3A4 is responsible for metabolism for almost a quarter of all drugs (Basheer & Kerem, 2015), and acetaminophen, lidocaine-mepivacaine, nystatin, benzodiazepines are all mainly metabolized by CYP3A4. Additionally, CYP2D6 metabolizes many antidepressants, opioids, antipsychotics, while CYP2C9 is known to oxidize ibuprofen (Xie et al., 2012). Considering that CBD and THC both affect these enzymes, CBD in particular, by inhibition of CYP3A4, CYP2D6 (Yamaori et al., 2011), and CYP2C9 (Jiang et al., 2013) consequently affects the metabolism of many other drugs. Therefore, CBD and THC use could greatly affect the serum level of drugs that are metabolized by CYP3A4, CYP2D6, CYP2C9, including many dental drugs and other classes of drugs like SSRIs, opioids, antimicrobials, anxiolytics, and antipsychotics  (Qian et al., 2019) (Figure 3). Additionally, clinical trials with Epiodiolex report interactions with CYP1A2 (caffeine), CYP2B (bupropion), UGT1A9, UGT2B7, and clinically significant interactions with CYP2C8 and CYP2C9 (Phenytoin) when coadministered (Biosciences, 2018). The most significant adverse reaction (≥10% of an effect than placebo) seen in the patients receiving CBD included transaminase elevation (hepatocellular injury), while other significant effects included somnolence, decreased appetite, fatigue, vomiting, rash, insomnia, poor quality sleep, and infections (Biosciences, 2018).

Clinicians should be cautious when the patient is either taking cannabis or hemp-based products as many metabolic pathways may be affected and there may be potential drug interactions that exist between cannabis-hemp products and conventional medicine. There is a clear indication for the use of cannabinoids for the unmet clinical needs, but like most medications, cannabinoids can also produce adverse effects and toxicity. Several reviews have focused on the therapeutic and adverse effects of CBD with conclusions of CBD being generally safe but need more investigation (Machado Bergamaschi et al., 2011) and CBD’s safety profile is better when compared to other antiepileptic and antipsychotics (Iffland & Grotenhermen, 2017). More recently, Huestis et al. (2019) reviewed CBD for its adverse effects and toxicity. In their review, the preclinical studies had shown adverse events negatively impacting cardiovascular, hepatocellular, hormonal changes, decreased fertility, alterations of in vitro cell viability, and P-glycoprotein effects; however, these effects occurred when doses exceeded 200 mg/kg/day, which is far above the 50 mg/kg/day suggested in antiepileptic clinical studies. It is important to note that the clinical trial data has reported only a few incidences of cardiovascular and reproductive effects. Cannabis and hemp-based products seem to be well tolerated by the body; however, it is not risk-free but may be relatively safer than some prescription and/or narcotic drugs (Foster et al., 2019). Additionally, the significantly high doses of CBD or the route of administration (IP or IV) can also alter overall cannabinoid content; therefore, the chances of adverse effects can increase that need to be monitored with hemp or CBD-rich oils.

10 LEGAL STATUS AND CANNABINOID PRODUCTS

Under current federal law (United States), possession of cannabis is illegal, where cannabis is categorized under schedule I drug status. However, many states have allowed the use of cannabis (marijuana) for medical and recreational purposes, while also decriminalizing it (MARIJUANA-OVERVIEW, 2017). In the Agriculture Improvement Act or the Farm Bill of 2018, FDA explicitly preserves the authority over industrial hemp or “hemp” defined as C. sativa L with Δ⁹-THC (psychotropic) content to be no more than 0.3% on a dry weight basis, while separating marijuana as an independent identity, removing hemp from being a control substance. Hemp is being marketed for various CBD-rich or hemp oil-rich products (oral oil drops, capsules, topical lotions, creams, and teas) that are seeing considerable commercial growth. According to Forbes magazine, it is estimated that US sales of hemp/CBD products will exceed $20 billion by 2024. The current CBD/hemp oil industry boasts the effects of CBD to improve a variety of conditions like pain (Good et al., 2019), migraines, and other inflammatory conditions (Burstein, 2015). Moreover, in recent findings, CBD oils may aid in reducing opioid addiction. A clinical study reported that among patients using opioids for pain management, CBD hemp extract significantly provided chronic pain relief along with the reduction of opioid use and improved sleep quality among CBD-treated patients (Capano et al., 2020). The hemp/CBD oils affect the body by modulating receptor systems specifically targeting the ECS (Croxford & Yamamura, 2005; Jean-Gilles et al., 2015; Klein et al., 2003). The main ingredients found in hemp oils are CBD along with other cannabinoids, terpenoids, and polyphenolics (flavonoids) that exhibit a synergistic effect on the body termed the “Entourage Effect.”

11 EFFICACY AND SAFETY OF CANNABINOIDS

Many conditions or diseases are considered multifactorial, and individuals who prefer holistic therapy tend to be interested in natural products. Therefore, the use of full-spectrum hemp (whole extract) is gaining the interest of many, which provide a multitargeted treatment, and could potentially have therapeutic advantages. In dental plaque samples, cannabinoid-infused mouthwash (CBD, CBG) was compared to the gold standard 0.2% chlorhexidine digluconate for inhibition of total cultured bacteria (aerobes). The cannabinoids infused mouthwash were equally as effective in decreasing bacterial load and show a promise for oral healthcare use (Vasudevan & Stahl, 2020). Alex Capano et al. investigated the impact of full hemp extract CBD on opioid use and quality of life among chronic pain patients. The concentrations of 15, 30, and 60 mg of CBD were used daily for 8 weeks with very limited side effects and only a few patients were excluded from the study due to adverse effects.

The CBD-rich hemp oil components (may vary based on vendor) other than CBD are usually at small concentrations and are unlikely to cause any severe reactions but do play an important role in the modulation of host immune responses. It is interesting to note that terpenoids like β-caryophyllene that exist in the C. sativa plant have been reported to exist in various other plants and are commonly found in foods like oregano, African black pepper, ginseng, and so forth (Gertsch et al., 2008). β-Caryophyllene has been shown to exert analgesic effects in inflammatory and neuropathic animal pain models (Katsuyama et al., 2013; Klauke et al., 2014). A limited examination of the essential oils from a hemp variety exhibited positive relaxation and anxiolytic effects in the patient population, while it also improved brain wave activity, autonomic nervous system response, and enhanced mood states. The components attributed to these effects include α-pinene, terpinolene, α-humulene, witincludephyllene, and myrcene being main components (Gulluni et al., 2018). A list (Russo, 2011) of cannabinoids: CBD, cannabidiolic acid (CBD-A), THC, tetrahydrocannabinolic acid (THC-A), CBG, cannabigerolic acid (CBG-A), tetrahydrocanncannabigerol), CBC terpiods: α,β- amyrin, α-pinene, α-terpineol, terpinolene, α-humulene, β-caryophyllene, d-limonene, and flavonoids: apigenin, kaempferol, naringenin, quercetin, myricetin, genistein, cannflavin A, B and vitexin can all be found in the cannabis/hemp plant with properties, including but not limited to antinociception, neuroprotection, anti-inflammatory, anxiolytic, antimicrobial, osteoprotective, antihypertensive, and improvement of wound healing and sleep (Nahler, 2018). Moreover, the difference between CBD oil, hemp oil, or cannabis oil is the relative amount of CBD to other phytocannabinoids present in the extract, which can range from small to large portions and are not usually identified from batch to batch. Due to this reason, the commercial content of hemp with regard to CBD and Δ⁹-THC are often incorrectly labeled (Vandrey et al., 2015; Welty et al., 2019).

Additionally, the studies with CBD approved by the FDA for the treatment of seizures in Lennox–Gastaut Syndrome and Dravet Syndrome (Franco & Perucca, 2019) provide better evidence of CBD safety highlighting some risks (discussed later) and a potential for liver injury. Therefore, clinicians interested in recommending hemp/CBD oil for pain, anxiety, or sleep should make sure that the patient does suffer from hepatic diseases. It is worth noting that CBD has been given in significantly high dosing for patients with bipolar, manic episodes, antipsychotic, epilepsy, anticonvulsive ranging from 300 m/day for 6 months, and up to 4 weeks with dosing 1200–1500 mg/day with reported side effects, which include somnolence, decreased appetite, and diarrhea (Cunha et al., 1980; Machado Bergamaschi et al., 2011; A. Zuardi et al., 2010; A. W. Zuardi et al., 1995).

The rise of the opioid abuse epidemic and healthcare challenges to manage pain has resulted in the search for alternative pain therapy. Cannabis or CBD/hemp-rich extract provides a great alternative therapy for the reduction of acute and chronic pain that may also aid in dental pain management. About 9% of the total opioid prescriber population are dentists, of which 45% of opioid prescriptions in the United States are written by dentists (McCauley et al., 2016). While the overall trends of prescribing opioids are decreasing in the United States, there is evidence of increasing rates in dental settings (Gupta et al., 2018; Guy et al., 2017). This issue of opioid prescribing in dentistry is particularly problematic in the United States as the prescriptions written for opioids by US dentists are 37 times greater than those of dentists in England (Suda et al., 2019).

Preclinical studies have demonstrated that cannabinoids (i.e., cannabis plants) enhance the body’s response to pain by binding with the endocannabinoid receptors (Vučković et al., 2018). In 2017, the National Academy of Sciences (NAS) assembled an Expert Review Committee in which they concluded: “there is substantial evidence that cannabis is an effective treatment for chronic pain in adults” (National Academies of Sciences, 2017). Additionally, a systemic review on randomized clinical trials (RCTs) conducted for cannabinoids for medical use provided moderate-quality evidence to support the use of cannabinoids for the treatment of chronic pain and spasticity, while association in short-term adverse effects was found (Whiting et al., 2015). Moreover, the National Academies of Sciences (2017) provided evidence that cannabis is modest in treating pain, discrediting it as a “miracle drug,” and debunking that individuals use it as an excuse to “get high or stoned.” The National Institutes of Health (NIH) has awarded a grant for a prospective cohort study expected to shed light on the understanding of how medical cannabis use affects opioid analgesic use over time, with specific attention to THC/CBD content, adverse events, and other health outcomes (ClinicalTrials.gov Identifier: NCT03268551). For a short excellent review on cannabis/substitute for opiates in the management of chronic pain please read (Carlini, 2018).

There is a growing body of evidence that cannabis can result in synergism and/or additive effects in combination with opioids for the resolution of pain. The indirect stimulation of opioid receptors by CB2R mediated in primary afferent pathways (Ibrahim et al., 2005, 2006) the colocalization of CB1R and μ-opioid receptor in the spinal cord at the first synaptic contact for peripheral nociceptive afferent neurons (Hohmann et al., 1999; Salio et al., 2001) support the synergistic enhancement of opioid analgesia along with the cannabinoids direct analgesic effects. A systemic review on opioid-sparing effects of cannabinoids concluded that findings from clinical studies are inconsistent due to limitations (i.e., lack of placebo control). However, most of the preclinical studies found synergistic effects in which the meta-analyses found the dose of morphine and codeine required to produce the same analgesic effects were lowered by 3.6 and 9.5, respectively, when coadministered with delta-9-THC (Nielsen et al., 2017). Therefore, cannabinoids may provide enormous clinical relevance to practitioners that are looking for effective pain treatment by utilizing opioid-sparing medications to lower opioid doses and dependence thereby reducing opioid-related mortality. Urits et al. reviewed certain cannabinoids and cannabinoid extracts investigating both clinical and preclinical evidence that supported cannabinoid pharmacotherapy for pain (Urits et al., 2019). The CBD dosing in clinical studies has ranged from 5 to 800 mg/day (Fasinu et al., 2016) and the concentrations to determine low or high doses for pain management for phytocannabinoids exhibit U-shaped dose responses (Katsidoni et al., 2013; Kwiatkowska et al., 2004). For instance, studies examining anxiolytic effects of CBD report that a low dose of 3 or 10 mg/kg show anxiolytic and antidepressant effects, while doses of greater than 10–30 mg/kg in mice after 15–30 days did not show the same anxiolytic effects (Schiavon et al., 2016).

Due to the current research barriers and the increase in current cannabis products, the scientific capacity to assess or study many of the currently used cannabis products becomes very difficult. While products, such as nabiximols (an oral spray used to alleviate neuropathic pain and spasticity), are commercialized in 30 countries, including Europe and Canada, have yet to get approval by the Food and Drug Administration (FDA) in the United States. The FDA has shown a commitment to advancing hemp products and is making appropriate additional regulatory pathways to hemp products such as those containing CBD with the intent to protect patients and public health (Hemp Production and the 2018 Farm Bill, in Agriculture, Nutrition, and Forestry, 2019). Therefore, there is an urgent need to increase the awareness of healthcare professionals, especially dental professionals to understand the potential impact of hemp or cannabis products on the quality of life with possible detriment or beneficial outcomes. CBD is also being tested under a dental setting to manage pain after simple tooth extraction (acute inflammatory pain) as a means of alternative pain management for dental patients (ClinicalTrials.gov Identifier: NCT04271917). Additionally, safety concerns do exist with CBD and preclinical studies exhibit potent induction and inhibition of cytochrome P450 (CYP450) (Jiang et al., 2011) (e.g., CYP2C, CYP2D6, and CYP3A isoforms), and limiting dosing of CBD to 30–120 mg/day might be more appropriate for clinicians to reduce drug–drug interactions or complications.

12 CHALLENGES AND CONSIDERATION FOR UTILIZING CANNABINOID PRODUCTS

The Clinical Guide of CBD and Hemp oil (VanDolah et al., 2019) states that physicians who want to examine CBD and hemp oils need to find the highest-quality product as variations occur in commercial products from the declared amount (Pavlovic et al., 2018). The recommendation of the isolation method includes products extracted by carbon dioxide with no solvents and certified by the US Department of Agriculture with testing performed for pesticides/herbicides. Since hemp seed oil does not contain any of the phytocannabinoids or terpenoids, be aware that the oil being used has nutritious omega-3 fatty acids but lacks cannabinoid content. Additionally, pure CBD oils have been studied much more rigorously but the full spectrum of cannabis products may be beneficial but have not been subjected to more research concerning their safety and efficacy (VanDolah et al., 2019).

Unfortunately, many of the studies with hemp extracts reference only phytocannabinoids and do not address the composition of other phytocompounds. There is also a discrepancy between human and animal studies with regard to the effects of cannabis extracts, in part due to a higher dosage of 8–40 mg/kg in animals compared to human dosage is about 0.25 mg/kg (Katona et al., 2005; Zgair et al., 2017). Additionally, various experiments do not necessarily favor either extracts or pure cannabinoids like CBD/THC. Therefore, the question of a high number of terpenes, flavonoids, and/or CBD/THC ratio would improve specific outcomes remains unknown. The current shortcomings in our understanding of the clinical effects attributed to CBD-rich or hemp oil extracts are largely due to inconsistency of stain, condition of growth, harvest factors, drying, and extraction methods, which have significantly limited clinical publications. Increased literary and scientific support for CBD-rich hemp extracts is on a rise, which should help develop a more coherent and clinically relevant regimen for the restoration of host homeostasis by the management of pain, inflammation, immune responses, and anxiety.

13 CONCLUSION

There is significant interest in C. sativa due to the growing medical and public interest in its use for multiple conditions. The approval of CBD for the treatment of rare epileptic conditions for which the US Drug Enforcement Administration (DEA) changed its status to Schedule V (low abuse potential) has opened CBD’s research potential. There is evidence that shows cannabinoids are clinically relevant in reducing pain symptoms and are a potential avenue for pharmacotherapy as opioid abuse and related deaths remain high in the United States. Due to the heavy reliance on opioids to manage pain following surgeries, the development of nonaddictive analgesics is highly desirable, and a target of interest for the NIH. The pharmacological effects of pure CBD have been studied extensively with several adverse effects seen in both preclinical and clinical settings. Meanwhile, cannabis extracts and hemp products have gained much attention but can vary significantly and lack empirical studies. There are several CBD products (unapproved) sold across the globe without any standardization of CBD or other constituents that claim unproven health effects. Although cannabis or cannabis-related products exhibit anti-inflammatory properties, it is unclear how well hemp/CBD products can replace traditional pain management, or if these products will work in tandem with existing therapies to enhance the effects and reduce the duration of analgesic care. At this point, CBD-rich or hemp oils are considered safe, but CBD’s reported side effects and drug interactions are not negligible and must be considered before therapeutic recommendation. The potential of medical use of cannabis or hemp/CBD still has great interest but its acceptability with practitioners and patients alike is rather low due to incomplete knowledge or bias, which poses several challenges to uptake. As a healthcare professional, it is important to understand that just like common medications are not suitable for every individual, neither is CBD-rich or hemp product. However, since CBD’s efficacy for seizures has been proven, it is likely physicians who are comfortable with CBD usage will recommend off-label use for other conditions. Given the healthcare challenges to manage acute and chronic pain, we are currently investigating CBD-rich hemp extract therapy in patient populations to be used for the reduction of acute and chronic dental pain, while examining specific phytocannabinoids and their respective effects in primary cell cultures to characterize them for a clinical indication and health benefits. Finally, the current shortcomings in understanding the benefits of CBD-rich hemp oils have limitations due to pharmacological and clinical effects not being predictable and profiles of marketed products varying greatly in phytocompounds.

AUTHOR CONTRIBUTIONS

Ammaar H. Abidi and Sahar S. Alghamdi drafted the manuscript, contributed to conception and design, contributed to acquisition, analysis, and interpretation, and critically revised the manuscript. Karen Derefinko drafted the manuscript, contributed to acquisition, analysis, and interpretation, and critically revised the manuscript.

CONFLICTS OF INTEREST

The authors declare no conflicts of interest.