
==== Front
J Oral Biol Craniofac Res
J Oral Biol Craniofac Res
Journal of Oral Biology and Craniofacial Research
2212-4268
2212-4276
Elsevier

S2212-4268(24)00125-8
10.1016/j.jobcr.2024.09.001
Article
Unleashing the therapeutic role of cannabidiol in dentistry
Mulla Sayem Anwarhussain sayemmullaa@gmail.com
a⁎
Patil Amit b
Mali Sheetal b
Jain Ashish K. b
Jaiswal Himmat b
Sawant Hitesh Ramdas c
Arvind Ritvi b
Singh Shruti a
a Department of Dentistry, Bharati Vidyapeeth (Deemed to be University), Dental College and Hospital, Navi Mumbai, Maharashtra, India, 400614
b Department of Conservative Dentistry and Endodontics, Bharati Vidyapeeth (Deemed to be University), Dental College and Hospital, Navi Mumbai, Maharashtra, India, 400614
c Department of Orthodontics and Dentofacial Orthopaedics, Bharati Vidyapeeth (Deemed to be University), Dental College and Hospital, Navi Mumbai, Maharashtra, India, 400614
⁎ Corresponding author. Department of Dentistry, Bharati Vidyapeeth (Deemed to be University), Dental College and Hospital, Sector-7, CBD-Belapur, Navi Mumbai, Maharashtra, 400614, India. sayemmullaa@gmail.com
07 9 2024
Sep-Oct 2024
07 9 2024
14 5 649654
18 8 2024
2 9 2024
© 2024 The Authors
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Cannabidiol (CBD) found in Cannabis sativa is a non-psychoactive compound which is capable of binding to CB1 and CB2 receptors. CBD has recently gained interest in dentistry although it has not been explored sufficiently yet. The therapeutic effects of CBD include anti-inflammatory, analgesic, antioxidant, biological and osteoinductive properties. The aim of this review is to highlight these effects with respect to various oral conditions and shed light on the current limitations and prospects for the use of CBD in maintaining oral health.

Graphical abstract

Image 1

Keywords

Cannabis
Anti-inflammatory
Endocannabinoids
Phytocannbinoids
Non-psychoactive
==== Body
pmc1 Introduction

Cannabinoids are molecules that occur naturally in mammals produced by the endocannabinoid system and are known to interact with substances which are endogenous (e.g., 2-arachidonoylglycerol as well as anandamide),1,2 phytocannabinoids (e.g., tetrahydrocannabinol and cannabidiol), or other cannabinoid analogues which are synthetic in nature.3 Cannabidiol (CBD) is a non-psychoactive compound procured from the plant named Cannabis sativa.4

Cannabinoids have the ability to bind to two receptors namely, cannabidiol-1 (CB1) and cannabidiol-2 (CB2); routinely encountered in plasmalemma (cytoplasmic/plasma/cell membrane), axon (nerve fibres) (CB1) and cells of the tissue (CB2).1 Receptors belonging to CB1 are presynaptic when the brain is concerned and are also instrumental in the regulation of mood, memory, appetite, sleep, and pain by their ability to release neurotransmitters. Small quantities of CB1 receptors are also encountered in peripheral tissues such as the heart, testicles, muscles, liver, pancreas, and adipose tissues. CB2 receptors that wring out in the hematopoietic cells and spleen, are thought to be in charge of the cannabidiols’ anti-inflammatory and immunomodulatory effects.2

Several studies and literature reviews have suggested that the therapeutic spectrum of CBD includes its use as an anti-inflammatory,5 anti-oxidant,2 analgesic,6 bone cell differentiation,3,7, 8, 9 antiepileptic, neuroprotection, anti-cancer and anxiolytic agent. It also holds the potential to be used for stress relaxation, relief, and sleep improvement.10 The expression of cannabidiol receptors in various structures present in the oral cavity such as dental pulp stem cells as well as the periodontium opens the portal for its use as a medicinal agent.11, 12, 13 The purpose of this article is to gauge the myriads of applications of CBD in dentistry while also exploring the probable mechanism of action as well as the current limitations in its use. The review will also help the lacunae associated with the use of CBD and allow the researchers as well as clinicians to adapt CBD as a routinely used therapeutic agent in the dental field.

2 Mechanism of action and pharmacology behind cannabidiol

They function by the stimulation of CB1 and CB2 receptors which are within the endocannabinoid system. This is a complex network of organs presents throughout the body aiding in the expression of CB receptors who play a vital role in homeostasis.14 The endocannabinoid system is involved in functions such as pain 15, memory,16 movement,17 appetite,18 metabolism,19 lacrimation, salivation,20 immunity as well as cardiopulmonary functions.21 It is worth noting that the vast majority of the effects of cannabinoids, including psychotropics, are caused by CB1 activation, with CB2 playing a more important role in immune and inflammatory functions (Fig. 1).Fig. 1 Main applications of cannabidiol and its synthetic analogues in dentistry.

Fig. 1

Endogenous endocannabinoids act as neuro-regulatory modulators, facilitating retrograde neurotransmission. A post-synaptic neuron releases endocannabinoids, which primarily bind to CB1 receptors on the presynaptic neuron. This binding inhibits presynaptic calcium channel activation and subsequent neurotransmitter release. If the presynaptic neurotransmitters are primarily inhibitory, such as GABA, the overall effect is excitatory, and vice versa. Cannabinoids, particularly Δ-9-tetrahydrocannabinol (THC), have different psychotropic properties depending on where they bind to the central nervous system (Table 1).22Table 1 Different areas and end-effects of cannabidiol.

Table 1Area	End-effect	
Hippocampus	Short-term memory impairment	
Neocortex	Judgement and sensation impairment	
Basal ganglia	Reaction time and movement alteration	
Hypothalamus	Increased appetite	
Nucleus accumbens	Euphoria	
Amygdala	Panic and paranoia	
Cerebellum	Ataxia	
Brainstem	Anti-emesis	
Spinal cord	analgesia	
Peripheral nervous system	Dry mouth, conjunctivitis, tachycardia, hypotension and bradypnea	

3 Routes of administration of cannabidiol

The route of administration for cannabinoids varies. Medical cannabinoids are typically administered orally as capsules or liquid suspensions. Dronabinol is available in capsules with strengths of 2.5 mg, 5 mg, and 10 mg, as well as an oral 5 mg/mL formulation. The medication is typically taken twice daily, 1 h before meals, with titration from the initial dose done gradually based on tolerance and response.23 Nabilone is available as a 1 mg capsule that can be taken twice or three times per day, depending on the provider and patient's preferences. Finally, cannabidiol is available as a 100 mg/mL oral solution that can be taken twice daily, beginning with 2.5 mg/kg/day and titrated based on patient response and tolerance.

Cannabinoids can also be administered via the oral route by incorporating them in food products such as infused teas or oils, or inhaled by smoking cannabis or marijuana.23 Products containing THC are almost always illegal, classified as Schedule I by the US Drug Enforcement Agency (DEA), and thus only available on black markets. However, CBD has gained popularity in recent years and is now available over the counter. Although smoking cannabis has traditionally been the most common method of cannabinoid administration, vaporization with e-cigarettes is becoming more popular, providing a faster, less carcinogenic way of delivering cannabinoids from the lungs into the bloodstream.24 Finally, although sublingual, rectal, ocular, transdermal, and aerosol deliveries have seen research, there is a paucity of literature on their use.

4 Role of cannabidiol in periodontal therapy

CB1 and CB2 receptors are both expressed in periodontal tissues, but their distribution varies depending on the tissue's condition.12 In healthy periodontal tissues, CB1s are abundantly expressed in the periodontal ligament (PDL) and bounteously active in the epithelium than in the PDL.25,26 CB2 receptor expression increases when bacteria are present, whereas in a sterile inflammatory condition, both the receptors are expressed in PDL in high quantities but not in the cementum or the alveolar bone.27 So, it appears that the two receptors' distinct expression patterns are related to various aspects of cellular function, including differentiation and proliferation, inflammatory regulation, and wound healing.28 Numerous investigations have substantiated the involvement of CB2 in the healing of periodontal tissue, specifically in regulating the adhesion and migration of periodontal cells in reaction to signals from the mitogen-activated protein kinase (MAPK) systems and focal adhesion kinase (FAK).26,28, 29, 30

Via the CB2 receptor, the CBD analogue HU-308 regulates the degree of periodontal disease and its effects on gingival tissue, alveolar bone, and salivary function. Because CBD suppresses the RANK/RANKL system and reduces pro-inflammatory cytokine levels, it possesses anti-inflammatory and anti-bone resorption characteristics.31 An alternate strategy for periodontal therapy could use CBD-mediated inhibition of metalloproteinases and/or activation of gingival fibroblasts with healing growth factors.32,33 Due to its antimicrobial activity, CBD has been known to diminish the inflammatory periodontal diseases caused by various bacterial species.34,35 Because CBD speeds up the healing process of common ulcers, it is also a viable pharmaceutical alternative in the treatment of oral mucositis due to its anti-inflammatory qualities, which help to reduce the severity and extent of the lesion.9,36 It has also demonstrated efficacious effects in decreasing the bacterial charge in tooth plaque.25 CBD is also biocompatible and osteoinductive,28,37 as it has been demonstrated to aid in the healing of fractures by triggering the p42/44 pathway in mesenchymal cells, which then undergo osteoblast differentiation at the site of the injury.38

As was previously mentioned, CBD has anti-inflammatory qualities and can lessen the loss of alveolar bone in periodontitis that is produced.33,35 Pharmacologically, CBD can have therapeutic, analgesic, or anti-inflammatory effects by selectively activating CB2 receptors, which avoids the side effects brought on by activating CB1 receptors.5 The way these anti-inflammatory qualities behaved looked to be comparable to other endogenous cannabinoids, such anandamide. Specifically, it has been demonstrated that anandamide is present, regulated along the course of periodontal disease, and has a role in the inhibition of pro-inflammatory mediators. Additionally, it might have a role in the physiological defense of periodontal tissues against severe inflammation.32 Moreover, it can decrease the synthesis of inflammatory mediators like interleukins and block NT-kB, a regulator of the immunological and inflammatory response that is typically triggered by endotoxins made from bacterial lipopolysaccharides.5 It has also been demonstrated to lessen oxidative and nitrosative stress, interfere with neutrophil and macrophage migration, and block or regulate the synthesis of cytokines, chemokines, and pro-inflammatory growth factors.2 Similar to endocannabinoids, CBD has been shown to exhibit anti-inflammatory properties at cannabinoid receptors, either directly or indirectly. This finding may have intriguing therapeutic ramifications. According to a different study, CBD may exacerbate gingival fibrosis by raising the synthesis of fibronectin, transforming growth factor-b, and gingival fibroblasts while lowering the activity and production of matrix metalloproteinase. It has been demonstrated that, within 24 h, low amounts of CBD can raise transforming growth factor beta levels by as much as 40 %, suggesting that CBD may inadvertently encourage fibrosis. Additionally, CBD may raise anandamide levels, which through CB1 or other receptors may encourage fibrosis.32

5 Role of cannabidiol in oral medicine

The oral mucous membrane is the main tissue of the oral cavity that interacts with CBD. Oral mucosal epithelial cells have been shown to exhibit CB1 and CB2 receptors. Human epithelial keratinocytes proliferate and differentiate more when exposed to CB2 receptors than when exposed to CB1 receptors.39

There are CB1 and CB2 receptors found all the way down to the lamina propria's connective tissue. They also indicate their presence in the tongue's taste buds and epithelial cells, which are primarily controlled by the physiological and pathological circumstances of the tongue.40 When burning mouth syndrome is present, CB1 receptor expression is downregulated and CB2 expression is upregulated. Furthermore, as both CB1 and CB2 receptor expression has been demonstrated to be elevated, it appears that ECS activation is involved in oncological disorders like mobile tongue squamous cell carcinoma.41,42

The existence of CB1 and CB2 receptors in dental pulp is poorly understood, yet they are identified in nerve fibers which are sympathetic in nature as well as on the surface of pulp tissue where they border dentin 43. Human odontoblasts also contain CB1s, and these cells may react to immunological stimuli.44,45 In fact, TRPV1-mediated extracellular Ca2+ ion passage (TRPV1) via extrusion Na+-Ca2+ exchangers (NCXs) are made possible by activation of these receptors and the cyclic adenosine monophosphate (cAMP) signaling that follows.46 This promotes the formation of a dentin bridge secondary in nature as a response to stimuli generated through the odontoblasts. The salivary glands include different locations for CB1 and CB2 receptors. The main salivary glands' striatal duct cells produce CB1, while the cells which are acinar cells—specifically, the myoepithelial cells—express CB2, which is involved in saliva secretion.47,48 It is interesting to note that food type and quantity appear lto govern the residence and dispersal of CB1s in salivary glands,49 and both CB1 and CB2 receptors influence salivary secretions.50, 51, 52

CBD has dose-responsive analgesic and anti-inflammatory effects; however, optimal dosages for potential antioxidant and anti-inflammatory effects have not yet been determined.9,38,53 The synthesis of mediators of pro-inflammation that cause diseases such oral mucositis may be altered by CBD's powerful anti-inflammatory, antioxidant, and analgesic effects compared to conventional antioxidants.9 Due to the favorable epithelial alterations that CBD produced in ulcer lesions in vivo, it may one day be employed as a therapeutic to treat the symptoms of mucositis. One crucial factor that could affect this tissue response is CBD's potential capacity to affect keratinocytes without having any negative side effects. The anti-inflammatory qualities of CBD did not hasten the healing of wounds.36

In an in-vivo study, the synthetic analogue HU-308 decreased gingival tissues' loss of alveolar bone and mediators of inflammation, which are elevated when lipopolysaccharide-induced periodontitis cases without therapy are considered. The primary localized impact is a result of CB2 receptor activation, which decreases osteoclastogenesis and promotes osteoblast cell differentiation. According to this, CB2 receptor signaling acts directly on bone cells to stop bone loss while also preventing pro-reabsorption cytokines from being expressed.31

Research has demonstrated that CBD possesses potent antibacterial qualities, effectively diminishing bacterial strain colonies in the oral cavity along with two biofilms. Higher concentrations of this drug prevent Porphyromonas gingivalis and Filifactor alocis from growing, two crucial members of the subgingival microbiota.34 Tooth plaque is a steady, biofilm with an organized structure housing plethora of microorganisms responsible for periodontitis, gingivitis, and tooth cavities. Since Gram-positive bacteria make up most of the pathogens found in dental or oral biofilms, they may be more susceptible to the effects of CBD, which has been shown to reduce bacterial colonies more in comparison to other oral hygiene methods. Although, due to the microbial diversity of dental biofilms, the effectiveness of CBD may vary from person to person.35

6 Role of cannabidiol in trauma and surgery

Due to its biological and osteoinductive characteristics, CBD, either by itself or in conjunction with other medications, has been shown to reliably and efficiently enhance microglial cell migration and bone differentiation via the ECS.33 Bone cells and skeletal sympathetic nerves both include the ECS, and cannabinoids are crucial for maintaining bone mass homeostasis.54 In this case, it appears that CBD increases the expression of the PLOD1 gene, which leads to rise in the maturation of collagen, expression of bone protein, along with mineralization.7,38 Because of the potential for better bone tissue biomechanical qualities and neobone development, CBD is a fitting therapeutic subordinate for loss of bone resulting from trauma or surgery.

7 Role of cannabidiol in odontalgia (toothache)

Odontalgia, or toothache, is a debilitating condition that is frequently the primary complaint of patients who visit the dentist. Although many non-opioid-based preparations, such as nonsteroidal anti-inflammatory drugs (NSAIDS), acetaminophen, and others, are prescribed, their role and effectiveness in relieving odontogenic pain are limited.55 To combat this, Chrepa et al. conducted a randomized clinical trial and found that oral CBD can be an effective analgesic medication for odontalgia.56 Murphy and Hayes demonstrated that the pure CBD drug "Epidiolex" can effectively treat acute dental pain 55. However, it is imperative to note that CBD would only serve as temporary bridges until definitive dental care, such as endodontic therapy or exodontia, could be performed. It is also crucial to note that, like any other drug, CBD can cause side effects that patients should be aware of beforehand. These include sedation, abdominal pain, diarrhoea, and elevated liver enzyme levels.57

8 Role of cannabidiol in endodontic therapy (direct hooding)

In order to prevent pulpitis, odontalgia, and necrosis in cases of traumas and/or deep caries, it is imperative to encourage odontogenesis.58 Since the dental pulp expresses CBD receptors, CBD have the ability to induce odontogenic or osteogenic differentiation. This process stimulates the migration, proliferation, as well as dental pulp stem cells differentiation, increasing the mineralization and synthesis of collagen and having a protective effect on pulp vitality.44,59,60 Moreover, TNF-alpha is inhibited by CBD, which also prevents stem cell differentiation. TNF-alpha, interleukin (IL)-1beta, and IL-6 are pro-inflammatory cytokines that are reduced by CBD,54 and CBD activates CB1 receptors in odontoblasts to promote extracellular Ca2+ entry and the production of reparative dentin 61,62.

RUNX family transcription factor 2 (RUNX2), Osteopontin (OPN), intercellular adhesion molecule 1 (ICAM-1), Vascular Endothelial Growth Factor-Based angiostatics (VEGFR1), dentinal matrix acid phosphoprotein 1 (DMP-1), dentin sialophosphoprotein (DSPP), and alkaline phosphatase (ALP) are among the angiogenic and odontogenic genes whose expression is increased by CBD.59,63,64

9 Role of cannabidiol in constitutional conditions involving the oral cavity

Oral mucositis is one of the most horrifying and excruciating side effects of radiation and chemotherapy. Owing to its antioxidant qualities, CBD might lessen oxidative stress, which is connected to oral mucositis.65 Additionally, nausea and vomiting are common in cancer patients, and these symptoms can change the oral microbiota by causing inflammation of the oral mucosa and enamel erosion from the acidity of gastric secretions. It has been demonstrated that CBD lessen this negative effect of cancer treatments.66,67 In preclinical research, CBD have also been shown to lessen arthritis-related pain and inflammation, which is advantageous if the temporomandibular joint (TMJ) is affected.68 For instance, CBD suppresses T-cell proliferation, which stops the generation of interferon (IFN) along with tumor necrosis factor (TNF) as well as the onset of autoimmune rheumatoid arthritis mediated by Th1.69

Owing to its profound properties of antioxidation and anti-inflammation, CBD encompasses several positive impacts when it comes to hyperglycemia. It's interesting to note that chronic ECS overactivation has been connected to both type 2 diabetes and obesity,70,71 suggesting that CBD may have therapeutic applications in the treatment of type 2 diabetes. In fact, oral health is greatly impacted by this pathological condition, especially when it comes to diabetes-related oral infections.66 Lastly, randomized, placebo-controlled trials proves CBD to be effective in treating epilepsy, with a notable decrease in the frequency of seizures.72,73 CBD may improve dental health because it reduces the risk of damage and injury to the tissues of the oral cavity as well as lips, which are frequent during epileptic seizures.74

10 Present limitations in the use of cannabidiol in dentistry

The lack of a defined legal framework governing CBD quality could lead to a variety of production methods and uneven CBD preparation efficacy.75 The components of natural goods obtained from plants vary widely due to the variability of conditions seen in the environment; therefore, the standard and amount of these products extracted naturally depend on various factors such vegetation, geographic location, as well as the circumstances present during extraction.76 As a result, different substances that affect therapeutic action may be present in a natural formulation. When it comes to the analytical methods employed to describe the products, there is no set procedure. Thus, in terms of product value and therapeutic effects, it is important to take into account the fluctuation associated with the jurisdiction of the source, condition of storage as well as devising or manufacture of these materials while also considering the potential contaminations.77

11 Future prospects

Researching the behavior, dosage, and mode of action of CBD is crucial, especially when it comes to dental applications. Standardized techniques for extracting CBD are unquestionably necessary, as is the standardization of in-vitro and in-vivo testing. It is necessary to assess the cytocompatibility and biocompatibility of CBD side by side. Finally, in order to assess this substance, clinical and laboratory trials ought to be conducted. It is also important to assess if patients find CBD to be acceptable.10

12 Conclusion

CBD are potent non-psychoactive drug which when used in appropriate proportions under proper guidelines hold the potential to drastically change the current state of dental sciences. However, future researches are imperative focusing on the nature, mechanism, formulations as well as modes of administration to understand this drug thoroughly. Nonetheless, due to its properties such as anti-inflammation, antioxidation, biological nature, analgesia as well as osteoinduction; it is a drug with promising future in dentistry.

Competing interests

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Funding/support

Nil.

Ethical considerations

Not applicable.

Patient/participant declaration of consent statement

Not applicable.

Data availability statement

All the data collected is available with the corresponding author upon request.

Patient/parent/guardian's consent

Not applicable.

Sources of funding

None.

Ethical clearance

Not required.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgements

None.
==== Refs
References

1 Rossi F. Siniscalco D. Luongo L. The endovanilloid/endocannabinoid system in human osteoclasts: possible involvement in bone formation and resorption Bone 44 2009 476 484 10.1016/j.bone.2008.10.056 19059369
2 Pisanti S. Maria A. Ciaglia E. Pharmacology & Therapeutics Cannabidiol: state of the art and new challenges for therapeutic applications Pharmacol Ther 175 2017 133 150 10.1016/j.pharmthera.2017.02.041 28232276
3 Dragos A. Ondine L. Alexandru M. Cannabinoids and bone regeneration Drug Metab Rev 51 2019 65 75 10.1080/03602532.2019.1574303 30702341
4 Amin M.R. Ali D.W. Pharmacology of medical cannabis Adv Exp Med Biol 1162 2019 151 165 10.1007/978-3-030-21737-2_8 31332738
5 Burstein S. Cannabidiol (CBD) and its analogs: a review of their effects on inflammation Bioorg Med Chem 23 2015 1377 1385 10.1016/j.bmc.2015.01.059 25703248
6 Pavanini S. Lauriola S. Mottola A. Cocchi R. Il sistema endocannabinoide: attuali conoscenze e potenziali applicazioni in odontostomatologia Intal Oral Surg 10 2011 66 68 10.1016/j.ios.2010.11.004
7 Kamali A. Oryan A. Hosseini S. Cannabidiol-loaded microspheres incorporated into osteoconductive sca ff old enhance mesenchymal stem cell recruitment and regeneration of critical-sized bone defects Mater Sci Eng C 101 2019 64 75 10.1016/j.msec.2019.03.070
8 Kogan N.M. Melamed E. Wasserman E. Cannabidiol, a major non-psychotropic cannabis constituent enhances fracture healing and stimulates lysyl hydroxylase activity in osteoblasts J Bone Miner Res 30 2015 1905 1913 10.1002/jbmr.2513 25801536
9 Whyte L. Ford L. Ridge S. Cameron G. Rogers M. Ross R. Cannabinoids and bone: endocannabinoids modulate human osteoclast function in vitro Br J Pharmacol 165 2012 1584 2597 10.1111/j.1476-5381.2011.01519.x 21913895
10 David C. Elizalde-Hernández A. Barboza A.S. Cardoso G.C. Santos M.B. Cannabidiol in dentistry: a scoping review Dent J 10 2022 193 10.3390/dj10100193
11 Cuba L. Salum F. Guimarães F. Cherubini K. Borghetti R. de Figueriredo M. Cannabidiol on 5-FU-induced oral mucositis in mice Oral Dis 26 2020 1483 1493 10.1111/odi.13413 32400905
12 Konermann A. Jäger A. Held S.A. Brossart P. Schmöle A. In vivo and in vitro identification of endocannabinoid signaling in periodontal tissues and their potential role in local pathophysiology Cell Mol Neurobiol 37 2017 1511 1520 10.1007/s10571-017-0482-4 28289947
13 Miyashita K. Oyama T. Sakuta T. Tokuda M. Torii M. Anandamide induces matrix metalloproteinase-2 production through cannabinoid-1 receptor and transient receptor potential vanilloid-1 in human dental pulp cells in culture J Endod 38 2012 786 790 10.1016/j.joen.2012.02.025 22595113
14 Sheikh N.K. Dua A. Cannabinoids 2023 StatPearls Publishing Treasure Island (FL)
15 Calignano A. La Rana G. Loubet-Lescoulié P. Piomelli D. A role for the endogenous cannabinoid system in the peripheral control of pain initiation Prog Brain Res 129 2000 471 482 10.1016/s0079-6123(00)29034-1 11098711
16 Castellano C. Rossi-Arnaud C. Cestari V. Costanzi M. Cannabinoids and memory: animal studies Curr Drug Targets: CNS Neurol Disord 2 2003 389 402 10.2174/1568007033482670 14683467
17 Rodríguez de Fonseca F. Del Arco I. Martín-Calderón J. Gorriti M. Navarrao M. Role of the endogenous cannabinoid system in the regulation of motor activity Neurobiol Dis 5 1998 483 501 10.1006/nbdi.1998.0217 9974180
18 Gómez R. Navarro M. Ferrer B. A peripheral mechanism for CB1 cannabinoid receptor-dependent modulation of feeding J Neurosci 22 2002 9612 9617 10.1523/jneurosci.22-21-09612.2002 12417686
19 Di Marzo V. Melck D. Bisogno T. De Petrocellis L. Endocannabinoids: endogenous cannabinoid receptor ligands with neuromodulatory action Trends Neurosci 21 1998 521 528 10.1016/s0166-2236(98)01283-1 9881850
20 Nallapaneni A. Liu J. Karanth S. Pope C. Pharmacological enhancement of endocannabinoid signaling reduces the cholinergic toxicity of DIISOPROPYLFLUOROPHOSPHATE Neurtoxicology 29 2008 1037 1043 10.1016/j.neuro.2008.08.001
21 Pandey R. Mousawy K. Nagarkatti M. Nagarkatti P. Endocannabinoids and immune regulation Pharmacol Res 60 2009 85 92 10.1016/j.phrs.2009.03.019 19428268
22 Mouhamed Y. Vishnyakov A. Qorri B. Therapeutic potential of medicinal marijuana: an educational primer for health care professionals Drug Healthc Patient Saf 10 2018 45 66 10.2147/DHPS.S158592 29928146
23 Taylor B.N. Mueller M. Sauls R.S. Cannaboinoid Antiemetic Therapy 2023 StatPearls Publishing Treasure Island (FL)
24 Hartman R.L. Brown T.L. Milavetz G. Controlled cannabis vaporizer administration: blood and plasma cannabinoids with and without alcohol Clin Chem 61 2015 850 869 10.1373/clinchem.2015.238287 26019183
25 Jirasek P. Jusku A. Simanek V. Frankova J. Storch J. Vacek J. Cannabidiol and periodontal inflammatory disease : a critical assessment Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 166 2022 155 160 10.5507/bp.2022.012 35332345
26 Liu C. Qi X. Alhabeil J. Lu H. Zhou Z. Activation of cannabinoid receptors promote periodontal cell adhesion and migration J Clin Periodontol 46 2019 1264 1272 10.1111/jcpe.13190 31461164
27 Raphael-Mizrahi B. Gabet Y. The cannabinoids effect on bone formation and bone healing Curr Osteoporos Rep 18 2020 433 438 10.1007/s11914-020-00607-1 32705630
28 Kozono S. Matsuyama T. Krishna K. Involvement of the endocannabinoid system in periodontal healing Biochem Biophys Res Commun 394 2010 928 933 10.1016/j.bbrc.2010.03.080 20233580
29 Wang J. Miyazu M. Xiang P. Li S. Sokabe M. Naruse K. Stretch-induced cell proliferation is mediated by FAK-MAPK pathway Life Sci 76 2005 2817 2825 10.1016/j.lfs.2004.10.050 15808882
30 Cariccio V.L. Scionti D. Raffa A. Treatment of periodontal ligament stem cells with MOR and CBD promotes cell survival and neuronal differentiation via the PI3K/akt/mTOR pathway Int J Mol Sci 19 2018 2341 10.3390/ijms19082341 30096889
31 Ossola C.A. Surkin P.N. Mohn C.E. Elverdin J.C. Fernández-Solari J. Anti-inflammatory and osteoprotective effects of cannabinoid-2 receptor agonist HU-308 in a rat model of lipopolysaccharide-induced periodontitis J Periodontol 87 2016 725 734 10.1902/jop.2016.150612 26846967
32 Rawal S. Dabbous Mk Tipton D. Effect of cannabidiol on human gingival fibroblast extracellular matrix metabolism: MMP production and activity, and production of fibronectin and transforming growth factor β J Periodontol 47 2012 320 329 10.1111/j.1600-0765.2011.01435.x
33 Napimoga M.H. Benatti B.B. Lima F.O. Cannabidiol decreases bone resorption by inhibiting RANK/RANKL expression and pro-inflammatory cytokines during experimental periodontitis in rats Int Immunopharm 9 2009 216 222 10.1016/j.intimp.2008.11.010
34 Gu Z. Singh S. Niyogi R.G. Marijuana-derived cannabinoids trigger a CB2/PI3K Axis of suppression of the innate response to oral pathogens Front Immunol 10 2019 1 13 10.3389/fimmu.2019.02288 30723466
35 Stahl V. Vasudevan K. Comparison of efficacy of cannabinoids versus commercial oral care products in reducing bacterial content from dental plaque: a preliminary observation Cureus 12 2020 1 12 10.7759/cureus.6809
36 Klein M. De Quadros De Bortolli J. Guimarães F.S. Salum F.G. Cherubini K. de Figueiredo M.A.Z. Effects of cannabidiol, a Cannabis sativa constituent, on oral wound healing process in rats: clinical and histological evaluation Phytother Res 32 2018 2275 2281 10.1002/ptr.6165 30088305
37 Nakajima Y. Furuichi Y. Biswas K.K. Endocannabinoid, anandamide in gingival tissue regulates the periodontal inflammation through NF-κB pathway inhibition FEBS Lett 580 2006 613 619 10.1016/j.febslet.2005.12.079 16406050
38 Petrescu N.B. Jurj A. Sorițău O. Cannabidiol and vitamin D3 impact on osteogenic differentiation of human dental mesenchymal stem cells Méd 56 2020 1 23 10.3390/medicina56110607
39 Maccarrone M. Di Rienzo M. Battista N. The endocannabinoid system in human keratinocytes: evidence that anandamide inhibits epidermal differentiation through CB1 receptor-dependent inhibition of protein kinase C, activating protein-1, and transglutaminase J Biol Chem 278 2003 33896 33903 10.1074/jbc.M303994200 12815050
40 Borsani E. Majorana A. Cocchi M.A. Epithelial expression of vanilloid and cannabinoid receptors: a potential role in burning mouth syndrome pathogenesis Histol Histopathol 29 2014 523 533 10.14670/HH-29.10.523 24190005
41 Theocharis S. Giaginis C. Alexandrou P. Evaluation of cannabinoid CB1 and CB2 receptors expression in mobile tongue squamous cell carcinoma: associations with clinicopathological parameters and patients' survival Tumour Biol 37 2016 3647 3656 10.1007/s13277-015-4182-8 26459312
42 Rosenblatt K.A. Daling J.R. Chen C. Sherman K.J. Schwartz S.M. Marijuana use and risk of oral squamous cell carcinoma Cancer Res 64 2004 4049 4054 10.1158/0008-5472.CAN-03-3425 15173020
43 Beneng K. Renton T. Yilmaz Z. Yiangou Y. Anand P. Cannabinoid receptor CB1-immunoreactive nerve fibres in painful and non-painful human tooth pulp J Clin Neurosci 17 2010 1476 1479 10.1016/j.jocn.2010.04.005 20705472
44 Que K. He D. Jin Y. Expression of cannabinoid type 1 receptors in human odontoblast cells J Endod 43 2017 283 288 10.1016/j.joen.2016.10.004 27989582
45 Navarro-Siaz L. Bernal-Cepeda L. Castellanos J. Immune challenges upregulate the expression of cannabinoid receptors in cultured human odontoblasts and gingival fibroblasts Acta Odontol Latinoam 35 2022 80 89 10.54589/aol.35/2/80 36260938
46 Tsumura M. Sobhan U. Muramatsu T. TRPV1-mediated calcium signal couples with cannabinoid receptors and sodium-calcium exchangers in rat odontoblasts Cell Calcium 52 2012 124 136 10.1016/j.ceca.2012.05.002 22656960
47 Thoungseabyoun W. Tachow A. Pakkarato S. Immunohistochemical localization of cannabinoid receptor 1 (CB1) in the submandibular gland of mice under normal conditions and when stimulated by isoproterenol or carbachol Arch Oral Biol 81 2017 160 166 10.1016/j.archoralbio.2017.05.003 28549258
48 Pirino C. Cappai M. Maranesi M. The presence and distribution of cannabinoid type 1 and 2 receptors in the mandibular gland: the influence of different physical forms of diets on their expression in piglets J Anim Physiol Anim Nutr 102 2018 e870 e876 10.1111/jpn.12848
49 Yoshida R. Ohkuri T. Jyotaki M. Endocannabinoids selectively enhance sweet taste Proc Natl Acad Sci U S A 107 2010 935 939 10.1073/pnas.0912048107 20080779
50 Prestifilippo J.P. Fernández-Solari J. Medina V. Rettori V. Elverdin J.C. Role of the endocannabinoid system in ethanol-induced inhibition of salivary secretion Alcohol Alcohol 44 2009 443 448 10.1093/alcalc/agp040 19589828
51 Prestifilippo J.P. Fernández-Solari J. De La Cal C. Inhibition of salivary secretion by activation of cannabinoid receptors Exp Biol Med 231 2006 1421 1429 10.1177/153537020623100816
52 Andreis K. Billingsley J. Naimi Shirazi K. Cannabinoid CB1 receptors regulate salivation Sci Rep 12 2022 1 13 10.1038/s41598-022-17987-2 34992227
53 Scionti D. Diomede F. Marchisio M. Cannabidiol modulates the immunophenotype and inhibits the activation of the inflammasome in human gingival mesenchymal stem cells Front Physiol 7 2016 559 27932991
54 Bellocchio L. Inchingolo A.D. Inchingolo A.M. Cannabinoids drugs and oral health—from recreational side-effects to medicinal purposes: a systematic review Int J Mol Sci 22 2021 8329 10.3390/ijms22158329 34361095
55 Murphy S. Hayes E. Cannabidiol - an effective analgesic for toothache? Evid Base Dent 2024 10.1038/s41432-024-01007-5 Online ahe
56 Chrepa V. Villasenor S. Mauney A. Kotsakis G. Macpherson L. Cannabidiol as an alternative analgesic for acute dental pain J Dent Res 103 2024 235 242 10.1177/00220345231200814 37910667
57 Theken K. Hersh E. Cannabidiol for toothache: ups, downs, and regulatory considerations J Dent Res 103 2024 225 226 10.1177/00220345231223691 38347664
58 Luiz de Oliveira da Rosa W. Machada da Silva T. Fernando Demarco F. Piva E. Fernandes da Silva A. Could the application of bioactive molecules improve vital pulp therapy success? A systematic review J Biomed Mater Res 105 2017 941 956 10.1002/jbm.a.35968
59 Qi X. Liu C. Li G. Investigation of in vitro odonto/osteogenic capacity of cannabidiol on human dental pulp cell J Dent 109 2021 103673 10.1016/j.jdent.2021.103673
60 Yu L. Zeng L. Zhang Z. Cannabidiol rescues TNF-α-inhibited proliferation, migration, and osteogenic/odontogenic differentiation of dental pulp stem cells Biomolecules 13 2023 118 10.3390/biom13010118 36671503
61 European Society of Endodontology (ESE) developed by.Duncan H. Galler K. Tomson P. Simon S. El-Karim I. Management of deep caries and the exposed pulp Int Endod J 52 2019 949 973 10.1111/iej.13128 30985944
62 Sáez M.D.M. López G.L. Atlas D. de la Casa M.L. Evaluation of pH and calcium ion diffusion from calcium hydroxide pastes and MTA Acta Odontol Latinoam 30 2017 26 32 28688183
63 Schmuhl E. Ramer R. Salamon A. Peters K. Hinz B. Increase of mesenchymal stem cell migration by cannabidiol via activation of p42/44 MAPK Biochem Pharmacol 87 2014 489 501 10.1016/j.bcp.2013.11.016 24304686
64 Smith A.J. Smith J.G. Shelton R.M. Cooper P.R. Harnessing the natural regenerative potential of the dental pulp Dent Clin 56 2012 589 601 10.1016/j.cden.2012.05.011
65 Cuba L. Salum F. Cherubini K. Figueiredo M. Cannabidiol: an alternative therapeutic agent for oral mucositis? J Clin Pharm Therapeut 42 2017 245 250 10.1111/jcpt.12504
66 Rock E.M. Limebeer C.L. Pertwee R.G. Mechoulam R. Parker L.A. Therapeutic potential of cannabidiol, cannabidiolic acid, and cannabidiolic acid methyl ester as treatments for nausea and vomiting Cannabis Cannabinoid Res 6 2021 266 274 10.1089/can.2021.0041 34115951
67 Good P. Haywood A. Gogna G. Oral medicinal cannabinoids to relieve symptom burden in the palliative care of patients with advanced cancer: a double-blind, placebo-controlled, randomised clinical trial of efficacy and safety of 1:1 delta-9-tetrahydrocannabinol (THC) and cannabidiol BMC Palliat Care 18 2019 110 10.1186/s12904-019-0494-6 31810437
68 Frane N. Stapleton E. Iturriaga C. Ganz M. Rasquinha V. Duarte R. Cannabidiol as a treatment for arthritis and joint pain: an exploratory cross-sectional study J Cannabis Res 4 2022 10.1186/s42238-022-00154-9
69 Malfait A. Gallily R. Sumariwalla P. The nonpsychoactive cannabis constituent cannabidiol is an oral anti-arthritic therapeutic in murine collagen-induced arthritis Proc Natl Acad Sci U S A 97 2000 9561 9566 10.1073/pnas.160105897 10920191
70 Di Marzo V. The endocannabinoid system in obesity and type 2 diabetes Diabetologia 51 2008 1356 1367 10.1007/s00125-008-1048-2 18563385
71 Weiss L. Zeira M. Reich S. Cannabidiol lowers incidence of diabetes in non-obese diabetic mice Autoimmunity 39 2006 143 151 10.1080/08916930500356674 16698671
72 Lattanzi S. Trinka E. Striano P. Highly purified cannabidiol for epilepsy treatment: a systematic review of epileptic conditions beyond dravet syndrome and lennox–gastaut syndrome CNS Drugs 35 2021 265 281 10.1007/s40263-021-00807-y 33754312
73 Cannabidiol Samanta D. A review of clinical efficacy and safety in epilepsy Pediatr Neurol 96 2019 24 29 10.1016/j.pediatrneurol.2019.03.014 31053391
74 Nonato E.R. Borges M.A. Oral and maxillofacial trauma in patients with epilepsy prospective study based on an outpatient population Arq Neuropsiquiatr 69 2011 491 495 10.1590/S0004-282X2011000400016 21755128
75 Koturbash I. MacKay D. Cannabidiol and other cannabinoids: from toxicology and pharmacology to the development of a regulatory pathway J Diet Suppl 17 2020 487 492 10.1080/19390211.2020.1796886 32715797
76 Bernardini S. Tiezzi A. Laghezza Masci V. Ovidi E. Natural products for human health: an historical overview of the drug discovery approaches Nat Prod Res 32 2018 1926 1950 10.1080/14786419.2017.1356838 28748726
77 Abubakar A.R. Haque M. Preparation of medicinal plants: basic extraction and fractionation procedures for experimental purposes J Pharm BioAllied Sci 12 2020 1 10 10.4103/jpbs.JPBS_175_19 32801594
