Cannabidiol and its application in the treatment of oral diseases: therapeutic potentials, routes of administration and prospects

2.1. Overview of pharmacological effects of CBD

2.2. Receptors of CBD

2.3. Distribution and function of CBD receptors in oral cavity

3.1. Periodontal therapy

Periodontal disease is an inflammatory disease caused by plaque that, if left untreated, can lead to the loss of alveolar bone and eventually the loss of teeth. Fortunately, some scholars have found that the endocannabinoid system can regulate the inflammatory response of periodontal ligament cells and inhibit the progression of inflammation, and also plays an important role in the immunosuppression of porphyromonas gingivalis lipopolysaccharide (LPS) [115]. Therefore, the study of the interaction between CBD and oral endocannabinoid system opens up new ideas for the prevention and treatment of periodontal diseases. Oral biofilm is a complex structure formed by continuous accumulation of more than 600 kinds of bacteria [116]. Dental plaque includes supragingival plaque and subgingival plaque. Supragingival plaques mainly contain aerobic bacteria, while subgingival plaques mainly contain anaerobic bacteria [116]. The accumulation of supragingival plaques eventually leads to the formation of subgingival plaques. Some scholars believe that supragingival dental plaque is a reservoir of periodontal pathogens, which may spread to the subgingival area and cause periodontal disease [117]. Therefore, removal of supragingival and subgingival plaque is the key to controlling and treating periodontal diseases. In clinical work, we take different ways to remove plaque on the tooth surface, but cannot effectively inhibit the bacteria that form dental plaque. As a matter of fact, according to the results of in vitro bacterial culture, there are still active bacteria on the treated tooth surface, which increases the difficulty of the treatment and maintenance of periodontal disease. Fortunately, the study of Vasudevan et al. [118] found that adding CBD to polishing powder can effectively improve the tooth polishing effect, and can inhibit and reduce the recombination ability of bacteria and the formation of new dental plaque, which provides ideas for the control of bacteria and the maintenance of periodontal health after plaque removal. In recent years, with the deepening of research, Blaskovich et al. [30] found that CBD also has a selective inhibitory effect on gram-negative bacteria, and CBD does not produce drug resistance. Therefore, the use of CBD in combination with other anti-gram-negative bacteria or facultative anaerobic drugs may have potential application value in periodontal infection control and periodontal health maintenance. In the future, CBD can also be applied to the treatment of periodontal diseases in the form of drug load sustained release, such as the synthesis of CBD complex drugs similar to minocycline hydrochloride (Palio) and the preparation of CBD drug strips in the form of nanofiber scaffolds.

3.2. Endodontic treatment

It is well known that dental caries is the result of a combination of factors, including bacteria in biofilms and plaque (such as Streptococcus mutans or Lactobacillus), regular intake of sugary foods that lead to acid accumulation, and insufficient cleaning of teeth for a long time, among which bacterial factors are the main factors in the development of dental caries. Studies have shown that CBD can significantly inhibit the bacterial activity in dental plaque and biofilm, and can effectively prevent the formation of oral biofilm and dentin decay, and its antibacterial effect is even the same as chlorhexidine [118]. Streptococcus mutans is a common cariogenic bacteria in oral cavity, which can produce lactic acid through the metabolism of carbohydrates, leading to the occurrence and progression of tooth decay. Aqawi et al. [133] found that CBG can reduce the expression of basic metabolic pathways related to the cariogenic properties of Streptococcus mutans biofilm and various genes involved, and proved that CBG has anti-biofilm activity against Streptococcus mutans, making it a potential drug for the prevention and treatment of dental caries. Therefore, CBD, as one of the main components of cannabinoids, may also have potentials in oral antibacterial as CBG, which needs to be verified by researchers. In addition, promoting the mineralization and repair of dental tissue is the key to the treatment of caries. Petrescu et al. [98]combined CBD with vitamin D3 and found that the addition of CBD can better promote the osteogenic differentiation of mesenchymal stem cells and accelerate the formation and mineralization of calcium nodules. These properties suggest that CBD may have potential therapeutic applicability in preventing and treating dental caries. With the progression of dental caries and the exposure to bacterial infection, pulpitis or even tooth loss may occur [134]. CBD, as a non-psychoactive factor, also has potential advantages in the anti-inflammatory analgesia of pulpitis. CBD can act on the endocannabinoid system in oral cavity, thereby inhibiting the release of inflammatory factors and relieving pain [135]. Meanwhile, CBD can effectively relieve anxiety during pain and improve patients’ sleep. In addition, the regeneration of dentin and the preservation of pulp vitality are crucial problems to be faced in endodontic treatment. For example, studies have found that CB1 receptor and CB2 receptor can be expressed in dental pulp cells and tissues, and activation of CB1 receptor can regulate the entry of extracellular Ca2+ and promote the formation of repaired dentin in odontoblast cells [136]. Qi et al. [137]induced the proliferation and differentiation of human dental pulp cells through CBD, and found that CBD could bind to CB2 receptor, promote osteogenic differentiation of human dental pulp cells through MAPK signaling pathway, and enhance the production of type I and Type III collagen, as shown in Fig. 2. The study suggests that CBD may become a new therapeutic product in dental pulp therapy. More importantly, studies have found that the combined use of CBD and moringa significantly reduces the expression level of inflammatory factors, and promotes the vascular neuralization of dental pulp and periodontal stem cells, indicating that CBD is likely to become a key drug in the treatment of dental pulp regeneration while promoting dentin repair [138].

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Fig. 2. CBD promotes osteogenic differentiation of dental pulp stem cells (DPSC) through the MAPK pathway [137]. CBD, cannabinoid; DPSC, dental pulp stem cells; CB2R, cannabinoid receptor type 2; MAPK, mitogen activated protein kinase; ALP alkaline phosphatase; Runx2, runt-related scripting factor 2; OCN, osteocalcin.

3.3. Oral mucosa therapy

In recent years, with the acceleration of the pace of life and the increase of related risk exposure factors, the incidence of oral mucosal diseases has been increasing. Various opportunistic pathogens, such as Candida albicans, are present in various parts of the human body including the mouth, vagina and lungs. Some studies have found that CBD can change the structure of fungal biofilms by reducing the thickness of fungal biofilms and the production of extracellular polysaccharide (EPS) [139]. Importantly, it can also inhibit the expression of virulence related genes of bacteria and slow down the damage of bacteria to the body [139]. The pathogenicity of fungi is largely attributed to their ability to adhere and accumulate on various surfaces, and novel anti-fungal strategies focus on developing agents that prevent biofilm formation and eradicate existing biofilms. Therefore, it is of great value to explore CBD as an alternative therapy against fungal infections and oral mucosal diseases. It is worth noting that the use of CBD mouthwash and 0. 2% chlorhexidine can better inhibit the formation of bacterial biofilm, and with the extension of time, there will be no mucosal color change and abnormal taste caused by chlorhexidine [118]. Interestingly, researchers have measured bacterial growth over a 24-hour period using CBD alone or in combination with bacitracin (BAC) [118]. It was found that the combination of 2 μg/mLCBD and 16 μg/mLBAC inhibited the growth of Staphylococcus aureus compared to monotherapy with a single compound. The results showed that CBD could enhance the antibacterial action of BAC [122]. Based on this, CBD can also be used as an auxiliary to enhance component of antibacterial agents in the future. In addition, CBD blocks NT-kB, a regulator of immune and inflammatory responses that is often activated by endotoxins from bacterial lipopolysaccharides, and is also able to reduce the production of inflammatory mediators such as interleukins [140]. This anti-inflammatory and antioxidant properties of CBD may be more effective than classical antioxidants [141]. Taken together, these make CBD possible as a potential therapy for the treatment of mucosal inflammation, because CBD is conducive to epithelialization and promotes the healing of ulcerative lesions in the body.

3.4. Oral tumor therapy

The antitumor activity of CBD is mainly mediated by plasma membrane-associated receptors, such as GPR55 and TRPV1/2. Relevant studies have found that GPR55 is a key factor in tumor progression, and CBD as a GPR55 antagonist can counteract its role in promoting tumor cell growth, thereby inhibiting tumor progression [164]. A recent study showed that CBD can induce autophagy in glioma stem cells in a TRPV2-dependent manner, and this pathway is regulated by the AKT/mTOR network, in which Beclin-1 protein plays a central role [165]. In addition, the sensitivity of tumor cells to chemotherapy drugs is induced by the action of CBD on TRPV2 [166]. CBD can also be used as a novel GPR12 reverse agonist to inhibit cAMP accumulation stimulated by structurally active GPR12 and regulate the adhesion of metastatic tumor cells [167]. Tumor progression is accompanied by the generation of a large number of microvessels, and the oral cavity is an environment with rich blood circulation, and tumors are often accompanied by rapid metastasis and progression. In recent years, studies have found that CBD has a strong anti-angiogenesis ability in vitro, which can interfere with the protein expression of various regulators involved in the angiogenesis process. As studies have shown, CBD can down-regulate the expression of VEGF, inhibit hypoxia-inducible factor-1 α in U87-MG glioma cells, and inhibit cell angiogenesis under hypoxia environment [158]. On this basis, if CBD drugs that act on GPR12 and down-regulate the angiogenesis of cancer cells can be developed, certain breakthroughs may be made in the treatment of oral cancer invasion. In addition, the activation of the immune system plays an important role in the suppression of tumor cells, and a clinical study found that CBD can stimulate the immune system and enhance the sensitivity of tumor cells to killer cells [168]. More importantly, advanced oral and maxillofacial tumors are often accompanied by severe chronic pain. The use of CBD can better control pain, relieve anxiety and help patients sleep, and patients will not develop drug dependence. Allosteric regulation plays an important role in the signal transduction mechanisms of many proteins, which favor proteins that enhance (i. e., positive allosteric regulators) or reduce (i. e., negative allosteric regulators) activity [169]. At present, it has been reported that CBD can play a certain allosteric regulatory role through at least three plasma membrane targets (GPR55, CB1 and TRPV1), which lays a foundation for CBD to develop drugs for the treatment of oral tumors. In terms of products, at present, epididymol (containing CBD) sold by GW Pharmaceuticals is prescribed as an adjuvant for the treatment of glioma [170].

3.5. Temporomandibular joint treatment

In recent years, the incidence age of oral temporomandibular joint diseases has gradually shown a trend of younger. Factors such as bad oral habits, life and mental pressure have become the important reasons for the occurrence of temporomandibular joint diseases, among which temporomandibular joint disorders (TMD) are the most common. TMD is often associated with restricted mouth opening, swelling, and pain. A study in 2012 found that CBD is an excellent blocker, blocking nerve conduction [171]. In addition, Hammell et al. [172] administered CBD to a rat model of arthritis and found that CBD significantly reduced joint swelling, spontaneous pain, immune cell infiltration, and synovial thickening in a dose-dependent manner. This means that CBD can be used to treat TMD. In mammals, TRPV1 immunoreactivity is located in the injurious primary afferent nerve that innervates the knee joint. After inflammation, TRPV1 expression is not only increased in the primary afferent nerve, but is also detected in synovial cells, which secrete lubrication into the synovial space and function as local immune cells [173]. Therefore, TRPV1 acts as one of CBD’s receptors, and CBD desensitization to TRPV1 may interrupt further progression of this cycle [174], [175]. In conclusion, CBD’s special pharmacological effect may bring good news for the treatment of TMD patients. In addition, CBD has good antibacterial and promoting the migration and osteogenic differentiation of mesenchymal stem cells (MSCs), which will also be a major research highlight in promoting the healing and repair of articular cartilage in the future. Of course, these still need to be excavated and explored by researchers in the future.

3.6. Treatment of maxillofacial bone tissue defect

Bone defects caused by oral and maxillofacial trauma, tumor, radioactive osteonecrosis, jaw osteomyelitis and congenital defects have a great impact on patients’ psychology and physiology [176]. The regeneration and repair of oral and maxillofacial region has always been the focus and difficulty in the field of stomatology. The presence of cannabinoid receptors in bone has brought new ideas for the regeneration and repair of bone defects. CB1 and CB2 receptors are expressed in bone and regulate bone homeostasis in humans. The expression level of CB1 receptor in bone cells is very low, while the expression level of CB1 receptor increases with age, and the upregulation of CB1 receptor expression can protect against age-related bone loss and osteoporosis [177]. CB2 receptor polymorphism is associated with osteoporosis and bone strength. CB2 receptor, as the main receptor of CBD, plays an important role in bone tissue regeneration and repair (such as stimulating cell proliferation and activity). Some studies have found that CBD stimulates bone formation and inhibits bone absorption by acting on CB2 receptors, activating CB2 receptors [178]. These effects may lead to new bone formation and improved biomechanical properties of bone tissue, making CBD a suitable therapeutic adjuvant for bone loss caused by oral and maxillofacial surgery or trauma. For example, in our current study, we extracted human jaw bone marrow mesenchymal stem cells for culture, proving that a certain concentration of CBD can promote the proliferation and biomineralization of human jaw bone marrow mesenchymal stem cells. Furthermore, human jawbone marrow mesenchymal stem cells and CBD were loaded together on the electrospinning fiber scaffold to construct an extracellular matrix (ECM) space supporting cell growth, and to study its influence on the repair and healing of bone defects, providing a basis for the future clinical application of CBD, as shown in Fig. 3.

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Fig. 3. Effect of CBD on human jaw bone marrow mesenchymal stem cells (h-JBMMSCs) and future application strategies. The h-JBMMSCs and CBD were C-ES to prepare fibrous bone tissue scaffolds for bone defect regeneration and repair. CBD, cannabidiol; ECM, extracellular matrix; h-JBMMSCs, human jaw bone marrow mesenchymal stem cells.

3.7. Treatment of other oral diseases

In addition to this, CBD also plays an important role in other aspects of the mouth. Angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2) are the key viral channels of oral, lung and intestinal epithelial cells and important pathways of SARS-CoV2 invasion [191]. Studies have reported that in the presence of oral ECS, CBD can down-regulate the expression of oral ACE2 and TMPRSS2 [192]. Therefore, the use of CBD-containing products, such as mouthwashes, to down-regulate ACE2 and TMPRSS2 may serve as a preventive strategy for COVID-19 infection. In addition, CBD, as a drug for the treatment of epilepsy, plays an important role in regulating mental state, relieving mental stress and promoting sleep in patients, and the use of CBD may be of great value in the treatment of oral related psychiatric diseases, such as burning mouth syndrome, trigeminal neuralgia and hysteria. It is worth noting that CBD, with its good antibacterial and bone-promoting ability, may also have certain therapeutic potential in the future in promoting implant bone adhesion and preventing and treating implant mucosal and peripheral inflammation.

4.1. Oral administration

For most therapeutic molecules, the oral route is the most common and patient preferred route of administration. Because its main advantages include convenience, ease of use, self-management and non-invasiveness [193]. Currently, a variety of oral CBD preparations are available, such as oil drops and capsule oils [205]. Oral administration usually takes place through the mouth, pharynx, esophagus, stomach, duodenum, small intestine, and large intestine. Among them, the gut plays a key role in the absorption of drug molecules. However, the physicochemical properties of drug molecules, such as water solubility, stability, lipophilicity, fraction size and crystallinity, affect the degree of drug absorption. Therefore, the high lipophilicity of CBD may precipitate directly in the gastrointestinal tract, leading to CBD malabsorption and low drug availability [195]. In animal models of mice, dogs, horses, and dairy calves, there was a delay ranging from 2 to 7 hours in reaching a predetermined peak plasma concentration of CBD after oral administration [194], [196], [205], [213], [233], [234]. The low absorption of CBD in the blood limits the therapeutic effectiveness of acute central neurological diseases of the brain. This delay in the treatment of sudden oral and maxillofacial cancer pain means that early prophylactic administration may be necessary. Some scholars have proposed that the absorption of CBD can be improved by taking it with a high-fat diet [235]. In other areas, after taking CBD orally, the researchers detected CBD in the brains of rats and mice, as well as in synovial fluid and joint tissue (articular cartilage and subpatellar fat pads) in horses and guinea pigs [236], [237]. The location of CBD after oral administration, as well as the distribution of its action receptors as described above, support CBD’s potential use in central nervous system diseases and musculoskeletal pain. In particular, it supports the treatment of joint tissue areas by oral administration, which makes it possible to treat oral temporomandibular joint diseases.

4.2. Sublingual administration

The tongue is the most flexible organ in the mouth, and its abundant taste buds and blood vessels play a key role in it. The mucosa under the tongue is very thin and accompanied by a large number of capillaries, which provides the basis for systemic treatment with drugs. Therefore, sublingual administration is one of the important ways to treat local or systemic diseases [202]. Vitetta et al. [238] found that CBD was rapidly absorbed within 1 hour when ingested sublingual, but bioavailability was not reported. So sublingual administration is feasible for the treatment of local or systemic acute symptoms, and can be used to relieve the pain of oral mucosal diseases, oral muscle spasms, oral area infections, and tongue cancer symptoms. For example, some researchers have classified CBD and THC as 1;1 Mix to make an oral mucosal spray to relieve moderate to severe multiple sclerosis spasms [202]. However, the inevitable entry of CBD into the intestinal system during sublingual ingestion means that the ultimate pharmacological pathway of CBD is still controversial. It is necessary to adopt a standardized and standardized way to conduct research on the pharmacological pathway of CBD in order to determine the best route of CBD administration. Secondly, sublingual ingestion of CBD will be affected by oral saliva and swallowing. In order to ensure the continuity of sublingual CBD uptake and drug effectiveness, it is necessary to extend the retention time of CBD mucosa in the form of mucosal adhesives [238]. This method can be used to treat local oral ulcers and associated mucosal lesions. Secondly, the discovery of oral cannabinoid receptors also makes it possible for sublingual CBD to treat oral tongue diseases (such as burning mouth syndrome and fungal glossitis, etc.) and salivary gland diseases (such as Schergren syndrome, salivary gland inflammation and salivary gland secretion abnormalities, etc.).

4.3. Intravenous administration

Intravenous injection is a common drug delivery method in clinical practice. Intravenous administration can quickly reach the therapeutic concentration of the drug throughout the body, and can effectively maintain the therapeutic effect. And it can quickly make the drug directly into the systemic circulation, bypassing the first pass of metabolism, and has positive therapeutic significance for patients with shock, pain or acute infection [203]. For example, Xu et al. [198] injected 10 mg CBD into each kg of mice intravenously and found that the drug concentration in the body quickly reached 18 times that of oral administration. Similarly, Meyer et al. [199] demonstrated that intravenous CBD was found to reach drug action concentrations in humans within 10 minutes. However, CBD is a highly lipophilic drug with low solubility and is difficult to administer intravenously by proportionally mixing it with saline. Therefore, this means that CBD can only be administered intravenously if it is soluble in lipids (such as soybean oil and fat emulsions, etc.), organic solvents (anhydrous ethanol) and polymers (polyethylene glycol) [199], [200], [201]. These solvents will have more or less toxic effects on the body, which is obviously difficult to meet the clinical principles of treatment, and most of the current experiments only stay in the animal experiment research stage. In addition, in terms of the clearance rate of drugs in vivo, Paudel et al. [200] conducted relevant studies on rats, and the results showed that the CBD plasma concentration decreased from 3596 ng/mL to 18. 9 ng/mL and 9 ng/mL respectively in 1 h and 2 h. This means that in order to maintain the therapeutic concentration of CBD in the body for a certain time in the future, it has to be repeatedly administered on time and quantitatively, which is obviously not in line with the non-invasive and convenient clinical treatment. Therefore, intravenous administration is difficult to choose for the treatment of oral diseases, and other ways of administration for oral diseases may be more routine in the future.

4.4. Transdermal administration

The skin is the body’s largest organ and consists of three layers: the epidermis, dermis, and subcutaneous tissue. The skin not only plays an important role in protecting the body and maintaining physiological functions, but also plays a key role in drug therapy. Local skin administration can be defined as the local treatment of skin diseases, while transdermal administration is the use of the skin as the site of local and systemic administration [239]. Transdermal administration has two main advantages over oral administration: low patient compliance requirements and high cost effectiveness; This is followed by a lower first-pass metabolic rate and the ability to terminate the drug delivery system at any time [240]. According to relevant studies, transdermal administration of CBD drugs has a good therapeutic effect in the persistent treatment of rat models with chronic inflammation, such as arthritis [193]. Some researchers also use CBD in band-Aids, creams and gels for wound treatment. For example, Lodzki et al. [215], after applying 3%w/w CBD patch on the skin of mice, found a large amount of CBD accumulation in the skin of mice. Interestingly, after transdermal, CBD was also detected in other locations, such as the buttock skin, abdominal skin, muscle, liver, and pancreas of mice. Transdermal delivery gives the advantage of storing drugs locally in the skin and maintaining drug concentrations over a period of time. For example, Paudel et al. [200] found the transdermal reservoir effect of CBD in the skin of guinea pigs. Steady-state CBD levels of 6. 3 ng/mL were reached 15. 5 hours after gel application and continued for 48 hours [200]. This phenomenon is very useful in the treatment of local skin lesions, infections and tumors. However, transdermal administration cannot enter the systemic circulation as quickly as intravenous administration to exert systemic effects. First, the drug needs to pass through multiple layers of tissue, and when it passes through the lipophilic stratum corneum, it accumulates and is difficult to penetrate deep. Second, it takes time to reach and cross the blood-brain barrier, and the clearance of drugs as described above after entering the systemic circulation is also very high. Therefore, the treatment of some oral and maxillofacial chronic local diseases is more suitable, systemic and acute symptoms of disease treatment is often limited.

4.5. Intranasal administration

Thousands of years ago, ancient people had records of intranasal administration of drugs to treat diseases. The earliest record of nasal drug delivery dates from the 16th century BC, with ancient Egyptians inhaling steam from the heated herb Hyoscyamus niger to ease breathing difficulties [241]. Some drugs for nasal delivery are well established and have been in use for decades. Nasal administration is non-invasive and can be self-administered by the patient. Major challenges of nasal administration include controlling particle/droplet size, the small amount of mucosal fluid available for drug dissolution, removal of undissolved particles, the effects of disease on respiratory anatomy and physiology, and local metabolic enzymes [193], [242]. However, compared with oral administration, the enzyme activity of the nasal cavity is relatively lower than that of the gastrointestinal tract, which can avoid drug degradation caused by the harsh environment of the gastrointestinal tract (such as stomach acidity, digestive enzymes, food contents). In addition, it has a well-vascularized and thin mucous membrane that allows passive diffusion into the blood and enhances drug absorption [206], [207]. Therefore, intranasal administration is ideal for local treatments such as allergic rhinitis. Paudel et al. [200] developed various nasal preparations, and found in the rat model study that CBD preparations were absorbed quickly in the nasal cavity (t Max ≤10 min), avoiding the degradation of CBD in the gastrointestinal tract. However, the current research only stays in the animal research stage, and future human clinical studies still need to be carried out, of course, which requires a large number of animal experiments in the early stage to determine its safety and effectiveness. In addition, the nasal cavity can also be used for systemic administration, depending on the nasal mucosa and the large number of capillaries in the lungs. However, this requires the molecular size of inhaled drugs to be limited, and generally (>5μm) drug particles have difficulty entering the lungs [193]. Therefore, nasal treatments in 5–10μm drugs are common in nasal products [193]. The nasal sense of smell and the trigeminal nerve pathway are connected to the brain, and perhaps in the future, the nasal administration of CBD is a potential treatment for central nerve diseases of the brain (such as trigeminal neuralgia and Bell’s palsy).

4.6. Other routes of administration

In addition to the routes described above, a number of other routes may also be used for systemic CBD administration, such as pulmonary, eye, ear, and recto-vaginal administration. Pulmonary administration is ideal for the treatment of respiratory diseases because it achieves high drug concentrations directly and quickly at the target site and can be administered throughout the body [193]. The ancient Chinese have records of using opium to treat severe coughs, diarrhea, and pain [193]. However, although smoking marijuana can get molecules into the lungs and brain quickly, the toxic products produced are far more powerful than the drug. Certainly this is not in accordance with the law and clinical treatment basis. In addition, formulation strategies using CBD dry powder need to overcome the challenges of poor wettability and low solubility, both of which are due to the high lipophilicity of the drug. Therefore, aerodynamic small particles should be generated for deep lung deposition to facilitate whole-body delivery of CBD [243]. When drugs are administered through the eye, the first thing that comes to mind is the treatment of glaucoma. The ocular route is mainly used for local treatment, but systemic absorption of the eye is also possible due to the elevation of the conjunctival vessels [236]. CBD, which is usually highly lipophilic, can be absorbed into the aqueous humor through the cornea and then enter the systemic circulation to play a therapeutic role [244]. At present, there are no studies on the administration of CBD in the eye, but Chiang et al. [226] studied THC administration in the eye of rabbits. Owing to the chemical similarity of CBD and THC, it is possible to systematically deliver CBD through the eye, but this is something that needs to be studied and validated. In patients where oral and inhalation administration is not possible, systemic administration in the rectum or vagina may also be attempted in the form of suppositories. However, it is difficult to achieve drug concentration in this way. For example, some scholars tried to study the PK curve of 100 mg CBD suppository in healthy dogs, and the results showed that the plasma CBD level was below the quantitative limit, so the data could not be analyzed [208]. Perhaps in the future CBD could be attempted to be administered through the rectum like diazepam and levetiracetam for rapid and effective seizure treatment, but this needs to be studied. Vaginal administration of CBD has not yet been reported, but oral Bethell’s disease is often accompanied by vaginal ulcers, and vaginal CBD suppository treatment may be a major research highlight. In addition, CBD drug injection therapy in local areas is also an important way of CBD administration in the future, such as direct injection therapy for TMD joint cavity, inflammatory space of myofascial and pus cavity.

5.1. Challenges and possible solutions

Some drawbacks and challenges may limit the research and application of CBD. First, although there is evidence that CBD can be used to treat oral diseases, the scientific evidence for its use in dentistry is limited. The application of CBD in the treatment of oral diseases has almost no scientific literature and patent records [245]. Therefore, in order for CBD to be truly applied to all aspects of the dental medicine field, further rigorous, standard and sound scientific studies are needed to confirm their safety, tolerability, efficacy, optimal dosage and optimal delivery system in the treatment of dental diseases. Including from CBD extraction, purity control and the unification of the way of administration, in vitro and in vivo studies in a strictly standardized manner. In addition, for its safety and rationality, researchers are encouraged to try to start with the development of dental products such as toothpaste, mouthwash and floss for oral health maintenance. Currently, most studies have been conducted in animal models (mice, rats, and rabbits), which means that these results may differ histologically and pathologically from those in humans, which can only be instructive [116]. Therefore, it is necessary to conduct similar studies in large animals such as primates to further verify the safety and effectiveness of CBD. Secondly, most of the research on CBD in tumors focuses on tumors of the nervous system, digestive system and respiratory system, while the research on oral tumors is very urgent [246]. At present, there are only a few studies on tongue squamous cell carcinoma [247] and salivary gland cell carcinoma [118] in oral tumor research. It is worth noting that most clinically available anticancer drugs are non-selective, coupled with the complexity of the tumor itself and the associated tumor microenvironment, as well as the unknown side effects of CBD and the lack of long-term experimental studies, which limit its clinical application in the treatment of tumors. In conclusion, there remain numerous obstacles and challenges in the utilization of CBD for the treatment of oral diseases. For example, the anti-inflammatory effects of CBD in the treatment of periodontitis are intricately linked with immunosuppression. Long-term immunosuppression can disrupt the body’s immune regulatory mechanisms, creating imbalances. Moreover, the distribution of oral endocannabinoid systems throughout different regions of the mouth makes it challenging to ensure that CBD provides a precise therapeutic benefit in targeted tissue. Consequently, from a comprehensive perspective, further research on the optimal administration mode of CBD is warranted to promote precision treatment. Furthermore, there has been a lack of randomized clinical trials with an intervention placebo control, posing a significant challenge for the reliable evaluation of the efficacy of CBD in the management of oral inflammatory diseases [248]. It is worth noting that the anti-inflammatory activity of CBD in the oral cavity depends not only on its effect on periodontal tissue, but also on its interaction with oral microbiota, especially surrounding pathogens. This means that the specific mechanism of CBD in the treatment of oral inflammatory diseases and oral mucosal infectious diseases still needs a lot of research to confirm, and it is also convenient for rational clinical application in the future. In addition, the research on CBD in tooth pulp only stays in the in vitro cell experiment, and the future in vivo experiment is still the mining point of research. Of course, relevant studies have shown that CBD has certain pharmacological effects in anti-inflammatory and analgesic aspects, but its clinical treatment in the temporomandibular joint is still blank and remains in the animal experimental stage. But overall the future is promising, with the Drug Enforcement Administration reclassifying CBD as a drug with low abuse potential, expanding CBD’s research potential in the treatment of oral diseases. At the same time, a large number of studies have shown that the distribution and action of receptors acted by CBD in the mouth make CBD very likely to solve many problems in the treatment of oral diseases. However, more studies on the mechanism of CBD and its receptors are also needed in the future to further lay the foundation for the precision treatment of CBD.

The fact that CBD is allowed for clinical use and deregulated does not assure patients of the quality, effective dose, purity and absence of chemical or microbial contamination of the product itself. It means that CBD pharmaceutical products must be mandatory, like other drugs, need to ensure safety, effectiveness and quality standards of product licensing to protect public health, and all products that have been marketed without permission are illegal and must be withdrawn [21]. It is worth noting that CBD has been approved for use in patients in many countries, and there is still a lack of clinically relevant research and evidence-based medicine in oral medicine, which means that the available evidence is of low quality and prone to the risk of bias [249]. In addition, although we have discussed the possible administration routes of CBD, this is actually achieved based on a large number of animal experimental studies and in-depth analysis of the safety, effectiveness and rationality of various administration routes, and there is a long way to go in the future. Including tracking the long-term clinical efficacy and side effects of CBD, the frequency and extent of adverse reactions may also increase with the increase of dose. Of course, through the summary of the drug administration route, it provides a research idea and reference value for the future application of CBD in the treatment of oral diseases. For example, we found that CBD has high lipophilic properties, and we can carry out drug loading applications in the form of nanocarriers [193]. Among them, liposome is an effective nanocarrier composed of phospholipid bilayer, which can encapsulate hydrophilic and lipophilic drugs, and can provide a good choice for drug delivery of CBD. In addition, the solubility of CBD can be improved through various formulations, such as the use of cyclodextrins [250], [251], [252], mesoporous silica [253], polymers [200], [254], self-emulsifying drug delivery systems [255], [256], [257], [258], and other nanomaterials [259], [260], [261]. By increasing the solubility of CBD through these formulations, oral bioavailability can be improved. At the same time, the different routes of administration indicate the therapeutic range and action characteristics of the drug. According to the type and degree of oral diseases, comprehensive treatment with different or multiple drug administration routes can be adopted. For example, some oral mucosal diseases can be treated effectively and safely simply by gargling and sublingual ingestion of drugs. However, for oral and maxillofacial tumors, we have to take a variety of administration routes such as oral, intravenous and transdermal administration to ensure the concentration and persistence of the drug. In addition, oral and maxillofacial symptoms involved in central nervous system disorders often require continuous drug treatment to maintain their therapeutic effects and prevent recurrence, which can be achieved through intranasal or inhalation administration, as both of these methods allow for non-invasive self-administration [193]. Transdermal administration provides a consistent and stable drug concentration that reduces the frequency of administration and is ideal for the treatment of local oral mucosal lesions, tumors, and infections. In other ways, inhalation of CBD can achieve faster and higher drug absorption than transdermal routes because of the large surface area of the respiratory epithelium. This can be used to treat acute central nervous system symptoms, such as pain and anxiety attacks. Nasal administration can act on the central nervous system quickly, and it also provides a way to treat oral and maxillofacial trigeminal neuralgia. In short, to treat any disease quickly and effectively in order to achieve effective disease management, it is necessary to find an optimal route of CBD administration. But this process obviously has a long way to go and is full of unknowns and challenges. In conclusion, the clinical application of CBD will not be achieved overnight, and it is hoped that these challenges will be addressed through multidisciplinary collaboration among clinicians, pharmacological researchers and biomedical engineers.

5.2. Future prospects

So far, CBD has very few research and patents related to dentistry, and it has a lot of room for dental product development and technology application. First of all, the distribution and existence of cannabinoids and other receptors in the mouth laid the research foundation for CBD treatment of oral diseases. Secondly, a large number of studies have shown that CBD has rich and significant pharmacological effects, such as anti-inflammatory, antioxidant, antibacterial, anti-tumor and neuroprotective aspects [262]. This makes it have positive therapeutic potential in the treatment of oral diseases. In the future, after fully verifying the safety and effectiveness of CBD and establishing a scientific clinical treatment system and program, CBD will bring good news to the treatment of human oral diseases.

The multidisciplinary development has provided a variety of options for the study and application of CBD. Among them, the development of tissue engineering in recent years has provided a reference for CBD loading, release, precision therapy, collaborative therapy and intelligent application. In the future, CBD can be applied in the diagnosis and treatment of oral diseases through tissue engineering technology, such as the research and development of pulp cap agents, regenerative pulp scaffolds, 3D collagen matrix, temporomandibular joint lubrication fluid and jaw defect reconstruction scaffolds. It is even possible to prepare some biomimetic and intelligent 3D nanoscaffolds with 3D printed CBD loads. These scaffolds can be solid, porous, banded, core-shell, hollow, beaded and multi-channel forms to meet the release of CBD in different scenarios and practical applications. By means of electrospinning, 3D printing, hydrogel and nanotechnology, we can give full play to the pharmacological role of CBD to achieve oral and maxillofacial wound repair, tumor treatment, periodontal treatment, dental endodontic treatment and even the prevention and treatment of peri-implant inflammation, as shown in Fig. 4.

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Fig. 4. Schematic diagram of the application of CBD combined with tissue engineering scaffolds in wound healing, periodontal treatment, pulp disease treatment, and anti-tumor therapy. CBD, cannabidiol.

In the future, with the deepening of CBD research and the establishment of its clinical evidence-based medicine, many dental products and patents will be generated. The drug delivery route also requires more specificity and refinement to meet the treatment needs of patients with different oral diseases. As the proportion of older people in the global population increases, so does the need for age-related drug delivery systems for older people, it is particularly important to be able to self-administer drugs and provide simpler, more timely and targeted drug delivery systems [193], [197]. At the same time, in order to improve the administration efficiency and bioavailability of CBD, some physicochemical technologies to promote CBD penetration have also become an indispensable way. For example, in chemical methods, excipients are used to promote the distribution and diffusion of CBD drugs in the skin. Other physical methods include electroacoustic therapy, laser and magnetic energy, and can even be thermal, mechanical and pressure-based techniques [263]. In addition, in order to achieve more convenient and effective delivery and treatment of CBD, the future nanomedicine delivery platform is also the highlight of its research. These include liposomes [264], polymer nanoparticles [265], nanoemulsions [266], solid lipid nanoparticles [267], and nanostructured lipid carriers [268], among others [269]. To sum up, with the in-depth research on CBD and its receptors, the extensive pharmacological effects of CBD will provide a new idea and research value for the treatment of oral diseases, and more practical alternative products for CBD oral treatment may be found in the future. These alternative products will also provide accurate, safe, effective and convenient delivery routes for oral disease treatment.