Next Article in Journal
A Novel Germline Mutation of ADA2 Gene in Two “Discordant” Homozygous Female Twins Affected by Adenosine Deaminase 2 Deficiency: Description of the Bone-Related Phenotype
Next Article in Special Issue
The CB2 Receptor as a Novel Therapeutic Target for Epilepsy Treatment
Previous Article in Journal
Evidence for Protein–Protein Interaction between Dopamine Receptors and the G Protein-Coupled Receptor 143
Previous Article in Special Issue
Development of [18F]LU14 for PET Imaging of Cannabinoid Receptor Type 2 in the Brain
 
 
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Cannabinoids Drugs and Oral Health—From Recreational Side-Effects to Medicinal Purposes: A Systematic Review

by Luigi Bellocchio 1,*,†, Alessio Danilo Inchingolo 2,†, Angelo Michele Inchingolo 2,†, Felice Lorusso 3,*,†, Giuseppina Malcangi 2, Luigi Santacroce 2, Antonio Scarano 3, Ioana Roxana Bordea 4,*, Denisa Hazballa 2,5, Maria Teresa D’Oria 2,6, Ciro Gargiulo Isacco 2,7,8, Ludovica Nucci 9, Rosario Serpico 9, Gianluca Martino Tartaglia 10, Delia Giovanniello 11, Maria Contaldo 9,‡, Marco Farronato 10,‡, Gianna Dipalma 2,‡ and Francesco Inchingolo 2,‡
1
INSERM, U1215 NeuroCentre Magendie, Endocannabinoids and Neuroadaptation, University of Bordeaux, 33063 Bordeaux, France
2
Department of Interdisciplinary Medicine, University of Study “Aldo Moro”, Policlinico, 70124 Bari, Italy
3
Department of Medical, Oral and Biotechnological Sciences, University of Chieti-Pescara, 66100 Chieti, Italy
4
Department of Oral Rehabilitation, Faculty of Dentistry, Iuliu Hațieganu University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania
5
Kongresi Elbasanit, Rruga: Aqif Pasha, 3001 Elbasan, Albania
6
Department of Medical and Biological Sciences, University of Udine, via delle Scienze, 206, 33100 Udine, Italy
7
Human Stem Cells Research Center HSC, Ho Chi Minh 70000, Vietnam
8
Embryology and Regenerative Medicine and Immunology at Pham Chau Trinh, University of Medicine, Hoi An 51300, Vietnam
9
Multidisciplinary Department of Medical-Surgical and Dental Specialties, University of Campania Luigi Vanvitelli, via Luigi de Crecchio, 680138 Naples, Italy
10
UOC Maxillo-Facial Surgery and Dentistry, Department of Biomedical, Surgical and Dental Sciences, School of Dentistry, Fondazione IRCCS Ca Granda, Ospedale Maggiore Policlinico, University of Milan, 20100 Milan, Italy
11
Hospital A.O.S.G. Moscati, Contrada Amoretta, cap, 83100 Avellino, Italy
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work as co-first authors.
These authors contributed equally to this work as co-last authors.
Int. J. Mol. Sci. 2021, 22(15), 8329; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22158329
Submission received: 15 July 2021 / Revised: 1 August 2021 / Accepted: 2 August 2021 / Published: 3 August 2021

Abstract

:
Background: marijuana, the common name for cannabis sativa preparations, is one of the most consumed drug all over the world, both at therapeutical and recreational levels. With the legalization of medical uses of cannabis in many countries, and even its recreational use in most of these, the prevalence of marijuana use has markedly risen over the last decade. At the same time, there is also a higher prevalence in the health concerns related to cannabis use and abuse. Thus, it is mandatory for oral healthcare operators to know and deal with the consequences and effects of cannabis use on oral cavity health. This review will briefly summarize the components of cannabis and the endocannabinoid system, as well as the cellular and molecular mechanisms of biological cannabis action in human cells and biologic activities on tissues. We will also look into oropharyngeal tissue expression of cannabinoid receptors, together with a putative association of cannabis to several oral diseases. Therefore, this review will elaborate the basic biology and physiology of cannabinoids in human oral tissues with the aim of providing a better comprehension of the effects of its use and abuse on oral health, in order to include cannabinoid usage into dental patient health records as well as good medicinal practice. Methods: the paper selection was performed by PubMed/Medline and EMBASE electronic databases, and reported according to the PRISMA guidelines. The scientific products were included for qualitative analysis. Results: the paper search screened a total of 276 papers. After the initial screening and the eligibility assessment, a total of 32 articles were considered for the qualitative analysis. Conclusions: today, cannabis consumption has been correlated to a higher risk of gingival and periodontal disease, oral infection and cancer of the oral cavity, while the physico-chemical activity has not been completely clarified. Further investigations are necessary to evaluate a therapeutic efficacy of this class of drugs for the promising treatment of several different diseases of the salivary glands and oral diseases.

1. Introduction

Cannabis, also known as marijuana, has always been one of the illicit drugs most commonly used at recreational levels worldwide [1]. On the other hand, medical use of this plant dates back more than 2000 years ago and has been described in almost all of the ancient cultures [2]. Recreational and ritual use of cannabis and its derived compounds (called cannabinoids) has an important historical meaning, mostly due to the various psychological and physiological effects on the human body, particularly the intense euphoria experience. At the same time, cannabinoids have always been provided to patients, for pain treatment and management, as well as treatment for other types of diseases. Phyto-cannabinoids have been proposed as dietary supplements to improve the gastrointestinal tract function [3,4,5,6]. However, acute and long-term cannabinoid intoxication has several adverse effects which span from unconscious health problems such as tachycardia, immune depression and increased cancer risk [7] to motor impairment and catalepsy [8], interference with cognitive function, panic attacks and a higher risk of developing psychosis [9]. In regard to therapeutic administration, the cannabinoids reported a clinical capability towards anxiety and depressive symptoms regulation [10].
In recent years, many states legalized and promoted the use of cannabinoids for therapeutical purposes, and in some states recreational cannabis became legal and its prevalence markedly rose [11]. Given the present and future increase in health issues related to cannabinoid consumption, it is mandatory for oral healthcare providers and dentists to know and understand the oral effects of cannabis.
This review briefly summarized the components of cannabis and the endocannabinoid system, as well as its cellular and molecular mechanisms of biological cannabis action in human cells and biologic activities on tissues. We will also look into oropharyngeal tissue expression of cannabinoid receptors together with a putative association of cannabis to several oral diseases. Therefore, this review elaborates the basic biology and physiology of cannabinoids in human oral tissues, with the aim of providing a better comprehension of the effects of its use and abuse on oral health, in order to include cannabinoid usage into dental patient health records as well as good medicinal practice.

1.1. Cannabinoids and Their Biological Effects

1.1.1. Phyto-Cannabinoids

The Cannabis sativa plant contains more than 500 components. Amongst them, more than 100 compounds which possess an aromatic hydrocarbon have been identified and called cannabinoids [12]. All these cannabinoids have bind-described bind/activate cannabinoid receptors [13,14]. The plant-derived cannabinoids are also called phyto-cannabinoids, in order to distinguish them from synthetic cannabinoids and endogenous counterparts (endocannabinoids). Among phyto-cannabinoids there are three major compounds derived from cannabigerol-type (CBG) molecules, delta-9-tetrahydrocannabinol (THC, the main psychoactive compounds from cannabis), cannabinol (CBN), and cannabidiol (CBD) [15]. They were isolated and structurally identified by nuclear magnetic resonance as well as by mass spectrometry [16]. The majority of phyto-cannabinoids are characterized by different affinities to cannabinoid receptors, despite possessing the basic structural types described above.
THC, a highly hydrophobic and lipophilic compound, is the most abundant in cannabis [17]. This compound binds to both cannabinoid receptors with similar affinities for CB1 and CB2 (both Ki values are around 40 nM), but has been shown to possess less intrinsic affinity to CB2 than CB1 [14]. THC administration to animal models as well as to human subjects highlighted the enormous and potent psychoactive properties of this compound, with a plethora of effects on locomotion, anxiety, pain, cognition and reality perception [1,18]. On the other hand, CBD has always been considered to be an isomer of THC devoid of psychoactive activity. When compared to THC, CBD has significantly lower affinity for CB1 and CB2 receptors, with Ki values at M levels (in nM for THC) [14], but several other brain targets and molecular effectors have been proposed for this compound other than cannabinoid receptors, including numerous classical ion channels, receptors, transporters, and enzymes (reviewed in [19]). However, some CBD effects at these targets in in vitro assays only manifest at high concentrations, which may be difficult to achieve in vivo, particularly given CBD’s relatively poor bioavailability [20]. Several reports also suggest that CBD might also affect the bioavailability, receptor binding and molecular actions of THC [21].
CBN is a product of THC metabolism and has only mild psychoactive activity if compared to its parental molecule [22] with higher affinity to CB2 than CB1 receptors. To date, there are three main forms of cannabis consumption: marijuana, hashish, and hash oil [23]. Hemp, a preparation of cannabis dried leaves and flowers, contains 0.5%–5% THC. On the other hand, cannabis flower heads compressed to form small light brown or black blocks, so called hashish, contains 2%–20% THC. The recently formulated hash oil, which is an oily liquid derived from hashish, can include up to 15%–50% THC and represents the highest percentage obtained in natural products so far [23].

1.1.2. Synthetic Cannabinoids

Historically, the use of the marijuana-derived Δ9-THC as well as synthetic analogues was actually the golden tool for the discovery and characterization of CB1 [24]. Among the synthetic cannabinoid agonists, we will briefly mention some of them, since they are widely used in experimental models (Figure 1). HU-210, characterized by a like-3 ring structure as in THC, is the most potent synthetic compound belonging to the HU series and was first synthesized and characterized in Israel. Bi- and tricyclic analogs of Δ9-THC, such as CP-55,940, characterize the second group of CB1 agonists used in pharmacological studies. As a third group of ligands, amino-alkylindols, such as WIN-55,212, exhibit potent CB1 agonistic activity [12].
All the above reported compounds also show some ability to bind and activate CB2 receptors. Amongst the selective CB1 agonists, ACEA (arachidonoyl-2′-chloroethanolamide) is the first one ever characterized and has a very potent and extremely selective CB1 agonist without activity at CB2 [25]. Synthetic ligands showing antagonistic properties at the cannabinoid receptors have been developed in the past. The compounds specific to CB1 and most widely used in both pre-clinical and clinical studies are SR141716 [26], AM251 [27] and AM281 [28]. Instead, CB2 receptor antagonists such as SR144528 and AM630 have different actions on effector cells and tissues by targeting the receptors [29]. Finally, two classes of compounds are normally used to interfere with the endocannabinoid system, although not acting directly on cannabinoid receptors. These compounds are represented by inhibitors of endocannabinoid re-uptake, such as AM 404 [30], VDM-11, UCM-707 and OMDM-2 [31], and by inhibitors of anandamide hydrolysis, such as URB532, URB597 [32]. More recently, synthetized compounds are the two inhibitors of 2-AG degradation, such as JZL184 and JZL195 [33,34]. These classes of compounds seem to have been shown to selectively increase the concentration of endocannabinoids, possibly avoiding some of the side effects due to generalized cannabinoid receptor activation by direct agonists.

1.1.3. Cannabinoid Receptors

CB1, the first identified cannabinoid receptor identified, was cloned in rat, human and mouse tissues [24,35,36]. The characterization and the cloning of the other well-known cannabinoid receptors, designated CB2, were subsequently also realized in the three species [37,38].
The analysis of the primary amino acid sequence of CB1 and CB2 receptors led to assigning them to the large family of G protein-coupled receptors (GPCRs). A combination of mutagenesis experiments and three dimensional models of these two receptors identified important structural determinants of the structure/function relationships and ligand binding/effector triggering (reviewed in [39]). CB1 and CB2 are encoded by different genes but possess 44% amino acid homology. In humans, CB1 was preferentially localized in the brain and the spinal cord but nowadays is accepted to be ubiquitously expressed throughout the body [14]. In contrast, CB2 is expressed at high levels in leukocytes, neutrophils, keratinocytes, the spleen, natural killer cells, and, at a lower extent, in the muscle, liver, intestines and testes [40], as well as in the adipose tissue [41]. However, the second isoform of CB2 seems to be present in additional tissues, especially in the brain and kidney [40]. Although CB1 and CB2 are well known and characterized, numerous pharmacological studies suggest the existence of additional cannabinoid receptors. Recent data point to two other GPCRs, G protein-coupled receptor 55 (GPR55) and G protein-coupled receptor 119 (GPR119) as novel potential cannabinoid receptors (reviewed [42]), besides the transient receptor potential vanilloid type 1 (TRPV1) ion channel, which is well-known to bind some endocannabinoid ligands. The human orphans GPR55 and GPR119, originally identified through a bioinformatic approach [43], were both cloned in mice, rats and humans [44]. The human GPR55 shares only 14% sequence identity with the CB1 and CB2 receptors and is mainly expressed in the brain (caudate and putamen, cerebellum) [44,45]. Thus, GPR55 might be involved in learning, memory, and motor function given its high expression in the brain, especially the basal ganglia and cerebellum [44,45]. The human GPR119 is encoded by a protein of 335 amino acids, and isoforms of this receptor are present in various mammalian species [44]. Expression profiles of GPR119 mRNA receptor seem to be restricted to the pancreas, fetal liver and gastrointestinal tract in humans [46,47].

1.1.4. Biological Effects of Cannabinoids via Their Receptors

Cannabinoids exert their physiological and pathophysiological effects mainly by binding to various cannabinoid receptors and triggering different signaling pathways (Figure 2). Here, we will mainly focus on the best described amongst them, which is the CB1 receptor [48]. The central mechanism of action of CB1, when activated, is to inhibit adenylate cyclase, a second messenger system, in a dose-dependent manner via Gi/o proteins, which reduce intracellular levels of cyclic adenosine monophosphate (cAMP) [49,50]. This turn results in a downregulated activity of cAMP-dependent protein kinase (PKA), which in turn reflects on downstream signaling pathways, such as ion channels, and electrical properties of the cell, triggering several mitogen-activated protein kinases (MAPK) [51].
Amongst other signaling pathways which have been shown to play a key role in the cellular and behavioral effects of THC PI3K/Akt signaling, the mTOR pathway and neurosteroid synthesis are worth mentioning (reviewed in [48]). Furthermore, a series of recent studies point out that apart from their canonical plasma-membrane localization and signaling, CB1 receptors are also associated with mitochondrial membranes in several cell types. Activation of these subcellular receptor pools tremendously impacts cell bioenergetic status, resulting in important behavioral and physiological alterations [52,53,54,55,56,57].

1.2. Oral and Craniofacial Cannabinoid Receptors

1.2.1. Tongue

Several studies found the expression of both CB1 and CB2 receptors in the human tongue [58]. Immunohistochemical positive CB1 and CB2 immunoreactivity throughout the full thickness of the epithelium has been found in the epithelial cells of the tongue and in circumvallate and fungiform papillae [59]. Moreover, both CB2 and TRPV1 receptors have been described in epithelial cells adjacent to taste buds and in the basal layers of tongue epithelium [60,61,62].
However, how cannabinoids are involved in tongue functions is still unclear. To date, the elegant series of studies performed by Yoshida and colleagues showed that administration of both exogenous agonists and endogenous cannabinoids increases gustatory nerve responses to sweeteners, as well as behavioral responses to sweet–bitter mixtures, and electrophysiological responses of taste receptor cells to sweet compounds [60,61,63,64,65,66,67,68,69]. Interestingly, genetic and pharmacological receptor blockades highlight an exclusive role of CB1 receptors in the aforementioned cannabinoid effects [60,61]. The pathophysiological status of the tongue has been recently associated with cannabinoid receptor expression levels. Indeed, several pieces of evidence found a higher expression of both CB1 and CB2 receptors in patients suffering from mobile tongue squamous cell carcinoma (SCC) [70]. Moreover, higher levels of TRPV1 and CB2 are also associated with a reduction in CB1 expression levels, which have been described in the epithelial cells of the tongue from patients with burning mouth syndrome [59]. These last observations are in line with the role of cannabinoid receptors in cancer [71] and inflammation [72], which will be treated in the next session.

1.2.2. Salivary Glands

Salivary glands express both CB1 and CB2 receptors with specific patterns [73,74,75,76,77,78,79,80,81,82,83,84,85,86]. CB1 receptors have been detected in the major salivary glands, however their expression was not observed in the acinous cells but were restricted to the striated duct cells near to the apical membrane [87]. CB2 receptors instead have been visualized mainly in myoepithelial cells surrounding the acini, where the production and release of saliva takes place, as well as in neurons of ganglia from the secretory ducts (Figure 3) [88]. Cannabinoid receptor expression in salivary glands has been shown to be under the control of several factors, including food quantity and quality and noradrenergic tone [74,88]. For instance, in the submandibular gland, basolateral membranes of ductal cells primarily express CB1 which, however, is also found in the serous cells of mixed acini according to dietary status [88]. Several pieces of evidence from the Elverdin lab pointed out a negative action of both CB1 and CB2 receptor activation in the regulation of saliva secretion [89,90,91,92,93], which might explain the dry mouth sensation always experienced by heavy cannabis users [11]. These sets of findings were supported by another study showing that endogenous cannabinoid anandamide, by activating CB1 receptors expressed in rat parotid glands, triggers cAMP accumulation. This results in amylase release with subsequent Na+ –K+–ATPase inhibition and impacts upon salivary gland functions [73].

1.2.3. Pulp Tissue

Although in dental pulp tissues only few reports succeed in the detection of CB1 receptor expression, several reports pinpoint out a therapeutical role of cannabinoids in this oral tissue. Indeed, CB1 receptors have been found at the pulp–dentin border, especially located on the nerve terminals impinging into the dental pulp tissue, and this pattern of expression was maintained in nerve fibers of symptomatic painful dental pulp [94]. Given the well-known role of neurotransmitter suppressors in basically all kinds of transmission [95], together with the presence of CB1 receptors on these nerve terminals cannabinoids might represent a good therapeutic target for diseases with dental pain. Another target of cannabinoid-based medicine in the dental pulp might be dentin repair/regeneration. Indeed, functional CB1 receptors have also been reported in human odontoblasts [96]. Cannabinoid treatment of rat odontoblasts has been shown to promote the formation of “reparative dentin” by modulating extracellular Ca2+ entry [97], which might be the mechanism for CB1-mediated dental pulp tissue repair via the matrix metalloproteinase–2 activation in dental pulp cells [98,99,100,101,102].

1.2.4. Periodontal Tissue

In periodontal tissues, several reports have suggested a role for both CB1 and CB2 receptors in pathological conditions, such as inflammation and wound healing [103,104,105]. Indeed, CB1 are expressed at a significantly higher level than CB2 receptors in both epithelium and periodontal ligaments (PDL) in periodontal tissues from healthy subjects. Furthermore, there is a switch in receptor expression (downregulation of CB1 and overexpression of CB2 receptor) within the PDL following bacterial inflammation. On the other hand, sterile inflammation strongly increases CB1 and CB2 expression in the PDL, but not in the alveolar bone nor in the cementum [103].
Periodontal tissue cannabinoid receptors have been suggested to differentially regulate cell growth and differentiation, inflammatory processes, and tissue healing [104,106,107,108,109,110,111,112,113,114,115], indicating that distinct expression patterns of CB1 and CB2 in PDL may be representative of distinct cellular function [104,106,107,108,109]. For instance, Liu et al. showed that cannabinoids, by activating FAK and MAPK signaling in a CB2-dependent manner, trigger periodontal cell adhesion and migration [104], which provides evidence for therapeutic potential of cannabinoid compounds in periodontal regeneration and wound healing, possibly associated with the anti-inflammatory actions of CB1 receptor activation, via NF-kappaB pathway inhibition in the periodontal tissue, as reported by Nakajima and colleagues [109].

1.2.5. Oral Mucosa

At a histological level, oral mucosa is made by a stratified squamous epithelium and underlying connective tissues. Although no direct report on cannabinoid receptor expression in oral mucosa has yet been provided, CB1 and CB2 have been shown to be functionally expressed by skin epithelial cells, suggesting a putative role in modulating several cellular functions in the mucosa epithelium [116]. Indeed CB1 and CB2 receptor activation exerts opposite effects on human epidermal keratinocyte proliferation and differentiation [117,118,119,120,121,122,123,124,125,126,127]. As previously mentioned, CB1, CB2 and TRPV1 receptors are indeed identified in the connective tissue from the lamina propria layer from the oral mucosa especially on salivary glands, blood vessels, nerve endings, and immune cells belonging to this tissue [59]. However, there is to date a poor scientific description of cannabinoid receptor expression in the oral mucosa, an issue that will need to be addressed since oral mucosa is the first line of tissue interacting with cannabinoids during marijuana consumption. Thus, exploring the physiological and pathophysiological role of cannabinoids on oral mucosal health and diseases might represent the way to improve cannabis-based medicine or mitigate side effects of cannabis recreational consumption. The aim of the present investigation was to evaluate the cannabinoids and their biological effects through a systematic review of the literature.

2. Materials and Methods

2.1. Patient and Public Involvement

The present investigation evaluated the effects of cannabinoids on oral health associated with recreational using and therapeutic purposes through a systematic review of the literature.
No patients have been involved in the present study, while no investigational ethical considerations are associated with the present paper.

2.2. Search Strategy

The study PICO question has been summarized in Table 1, and the scope of the present investigation was to evaluate the effectiveness of cannabinoids derived adjuvant for the treatment of different diseases of the oral cavity such as: dry mouth, tooth caries, periodontal and gingival diseases, oral hygiene maintenance, oral cancer and oral tissue diseases.
The paper search and selection was conducted independently by two expert reviewers (F.I. and F.L.), and a Boolean database search has been conducted in the Pubmed (MEDLINE) and EMBASE electronic databases without any time limitations. The key words search indicators are presented in Table 2: (cannabinoids AND dry mouth); (cannabinoids AND caries); (cannabinoids AND periodontal diseases); (cannabinoids AND oral hygiene); (cannabinoids AND oral cancer); (cannabinoids AND oral tissue diseases). Moreover, a manual paper search was conducted to improve the article pool; the duplicates were removed after the title evaluation. The abstracts were manually evaluated to perform an initial screening of the articles identified and the final selection was performed with the full text of the papers in order to conduct the eligibility for the qualitative analysis. At the end of the process, the papers selected were categorized according to the reference data, year of publication, type of the study, patients treated, test and control group treatments, follow-up, and study effectiveness.

2.3. Inclusion and Exclusion Criteria

For the present investigation, for the qualitative analysis full-length articles written in English language were considered, as well as literature reviews and meta-analyses, randomized and non-randomized clinical trials, case reports and case series. The exclusion criteria for the evaluations were: editorial letters, book chapters and conference proceedings.

2.4. Study Selection

The full texts were recorded and evaluated for all the papers included in the present systematic review. Each one was studied independently according to the inclusion and exclusion criteria mentioned above. The majority of the papers were in the English language; we only choose the ones in which the drilling technique was performed following the guidelines of the burst producer. The minimum follow up period was set to three weeks.

2.5. Data Extraction

For the qualitative synthesis of the studies included, the following data were considered: the drug description, the design of the study, the experimental model, the administration protocol, and the effectiveness of the study.

3. Results and Discussion

3.1. Articles Selection Process

The entire article identification, initial screening, eligibility assessment criteria and qualitative analysis processes are described in Figure 4. The initial screening process retrieved a total of 276 articles. The papers identified were merged, and after the initial screening a total of 162 articles were excluded. The eligibility assessment was performed and a total of 59 manuscripts were excluded from the articles pool: 53 off topic papers, 3 book chapters, 1 editorial letter and 2 congress proceedings. A total of 31 articles were selected for the qualitative synthesis.

3.2. Cannabinoids Drugs for the Treatment of Dry Mouth

A total of four studies were included about cannabinoid use and dry mouth disease. Darling et al. reported the only cross-sectional study conducted on 300 patients that reported cannabinoids consumption by smoking (Table 3) [129]. The subjects included reported nicotinic stomatitis in a total of four cannabis consumers but not smokers. A higher incidence of leukoedema and dry mouth was evident in cannabis users compared to the control groups. The other studies were conducted on animals: two papers on rat models [89,92] and one article on pigs [88]. Pirino et al. evaluated the cannabinoid receptor expressions CB1 and CB2 after a dietary supplement administration on 32 pigs, reporting an influence of the expression of salivary ducts and secretion of the mandibular glands related to endocannabinoids activity (Table 3).

3.3. Cannabinoids and Dental Caries

A total of three studies were included about the topic of cannabinoids and dental caries. Two articles reported a clinical study on humans: a case report [130] and a retrospective cohort trial [131]. Grafton et al. [130] reported a clinical report of a low compliance of a marijuana smoker that submitted to a tooth extraction procedure with a high incidence of dental caries. Ditmyer et al. [131] reported through a retrospective cohort study on 66,941 subjects an increase of the prevalence and severity of dental caries in patients that declared tobacco/marijuana administration. In vitro, Liu et al. [104] reported that delta-9-tetrahydrocannabinol (THC) promoted periodontal cell adhesion and migration in wound tissue healing (Table 4).

3.4. Cannabinoids and Periodontal Diseases

A total of 10 articles were included about the topic of cannabinoids and periodontal diseases: two clinical studies, three studies only in vitro, one study only in vivo on rats and three articles with both in vitro/in vivo on rats. Thomson et al. [132] reported in patients affected by periodontitis that the cannabis smoking may be a risk factor for periodontal disease independent from the tobacco use, while Shariff et al. [133] showed that cannabis smoking was correlated to deeper probing depths, increased clinical attachment loss and higher risk for severe periodontitis. Nogueira-Filho et al. [134] reported on rats that cannabis smoke exposure may impact alveolar bones by increasing bone loss, while in other studies the administration of synthetic cannabinoid derived molecules such as anandamide (AEA)/2-arachidonoylglycerol (2-AG)+ AM251, AM630 and HU-308 seems to be correlated with an increased activity and proliferation of human gingival fibroblasts, a lower bone loss by the inhibition of the RANK/RANKL expression, and anti-inflammatory and osteoprotective effects on the oral tissue in vivo [107,135,136,137]. In studies conducted on human periodontal fibroblasts (HPLF) and human gingival fibroblasts, the cannabinoids exhibited a strong inhibition of pro-inflammatory molecules such as LPS, TNF-α, and IL-1β expression [106,107,108] (Table 5).

3.5. Cannabinoids and Oral/Neck Cancer

A total of 13 articles were included about the topic of cannabinoids and oral/neck cancer development: three literature reviews [138,139,140], four in vitro studies [141,142,143,144], one case series, and five case–control and cohort studies [145,146,147,148,149]. The studies [138,145,147,148,149] that evaluated marijuana consumption reported that the smoking habitude has been correlated to a carcinogen induction with no completely clarified chemical and physical pathogenesis, while Rosenblatt et al. [146] demonstrated a similar oral cancer incidence between test and control with no cannabis smoke evidence. The studies [141,142,143,144] that considered cannabinoids supplements in vitro reported a capability to inhibit the growth of different cancer cells lineages, including aggressive and chemotherapy-resistant variants of lung cancers (Table 6).

3.6. Cannabis and Oral Tissue Diseases

A total of two studies were included for the qualitative synthesis: a literature review [11] and a cross-sectional study on humans [129]. Versteeg et al. [11] reported that the cannabis smoking habit has been correlated with an increased incidence of xerostomia, leukoedema and a higher prevalence of Candida albicans infections. Darling et al. [129] reported a high incidence of nicotinic stomatitis associated with cannabis consumers with no tobacco use.

3.7. Cannabis Consumption and Effect on Oral Health

Cannabis abuse has always been known to impact on proper oral health status. Several compounds assume that cannabis smoke will possibly put cannabis users to a higher risk of dry mouth, dental caries, soft tissue disease, poor oral hygiene, periodontal disease and even oral cancer by changing the physiology of the oral environment (Figure 5). On the other hand, cannabis might represent a good pain management tool for dental anesthesia as well as post-operative management.

3.8. Dry Mouth

Cannabis use can lead to xerostomia by reducing salivary flow. Dry mouth associated with cannabis abuse is reported to be similar to the one after cigarette smoking, and in most subjects dry mouths appear immediately after cannabis use [129]. Cannabis use has always been associated with dry mouth and hypo-salivation via a CB1/CB2 receptor-mediated THC effect on the salivary glands cholinergic transmission [89,92]. THC has also been shown to importantly reduce submandibular salivary flow induced by electrical stimulation in dogs [150]. These findings may help to better understand the mechanisms of reduced saliva production, which eventually lead cannabis smokers to xerostomia.

3.9. Caries

Amongst the main dental complication of cannabis use, an increased incidence of caries has frequently been reported. This is probably mediated by several factors, which might include less saliva production, poor oral hygiene and higher plaque scores. Indeed, cannabis smokers have been shown to present a higher number of DMF teeth scores with a greater accumulation of plaque [130]. Another study, after correcting some confounding factors such as exposure to second-hand smoke, gender and race/ethnicity, reported an increased prevalence and severity of dental caries among marijuana users [131]. However, one has to also take into account the potential beneficial roles of cannabinoids on dental pulp diseases and regeneration/repair [104,106,107,108,109], which will be discussed in the next section.

3.10. Periodontal Diseases

To date, a potential link between cannabis use and periodontal disease is supported only by a limited and inconsistent literature background. Some studies tend to suggest chronic cannabis use as a potential risk factor for periodontal diseases including gingival leukoplakia, gingival hyperplasia, alveolar bone loss and gingivitis [132]. Additionally, a US Survey supports an incidence of more severe periodontitis associated with recreational cannabis use [133]. Higher bone loss and lower bone density were associated with marijuana smoke inhalation (MSI) in rats following ligature-induced periodontitis [134] with, however, no significant histological differences.
On the other hand, no association between cannabis smoking and periodontitis was found in another groups of studies. For example, no significant associations between cannabis use and periodontitis have been found in adolescent populations [151]. Moreover, in mice with ligature-induced periodontitis, cannabinoids have been shown to protect them from periodontal diseases, as CBD/THC injection strongly reduced pro-inflammatory cytokine levels and PMN cell motility as well as less furcation bone loss [137].
Several pieces of evidence against the causative effects of cannabinoids on periodontal disease are given by the well-known role of the endocannabinoid system in periodontal healing, as mentioned previously. Cannabinoids, by activating CB1/CB2 receptors, promote the proliferation of gingival fibroblasts in periodontal healing [107], and methanandamide and HU308, selective CB1 and CB2 receptor agonists, are able to dampen LPS-induced periodontitis in vitro and in vivo [135,136], especially by attenuating alveolar bone loss and increased inflammatory mediator. Moreover, administration of CBD inhibited RANK/RANKL expression resulting in a diminished bone resorption and pro-inflammatory cytokine in the periodontal tissue [137]. Thus, these findings highlight different receptor and molecular mechanisms on periodontal disease, which are all in support of an anti-inflammatory and protective effects of cannabinoids.
Multiple factors and research designs might explain the conflicting findings for the link between cannabis use and periodontal disease. First, patients presented several risk factors apart from cannabis use such as age, systemic health, concurrent tobacco smoking and oral hygiene. Second, individuals had different amounts, frequencies, duration, and modes of administration of cannabis use. Third, the effects of cannabis use on oral tissues and oral health have been described only in limited reports; thus, more well-designed studies will be needed to address these issues.

3.11. Oral Hygiene

Cannabis abusers, as well as cigarette smokers, normally have poor oral hygiene and higher plaque scores, increasing the likelihood of caries and periodontal disease [152]. Unfortunately, it is difficult to determine whether neglect of oral hygiene and failure to seek regular preventative dental care might be the causes directly linking cannabis use to oral uncleanliness. One study showed that increasing amounts of drug used was not associated with a lower oral hygiene index, or decayed, missing and filled teeth (DMF–T) [129]. As cannabis users often also abuse tobacco and alcohol, this relationship is of course hard to disentangle.

3.12. Oral Cancer

Although still unclear, an association between marijuana use and oral cancer has been recently proposed. Indeed, cannabis smoke increases the possibility of developing oral cancer, since it contains similar carcinogens as in tobacco. Some studies indicate that cannabis use increases oral premalignant lesions such as leukoplakia and erythroplakia, especially on the anterior floor of the mouth and the tongue [129,138]. Cannabis smoking has also been suggested to be a possible cause of tongue carcinoma [138,145,146], and marijuana smokers have been found with epithelial dysplasia in the buccal mucosa [129]. A strong association between cannabis use and head and neck cancer has also been reported among younger patients [145,147]. Furthermore, frequent, forever and long duration marijuana use increases significantly the possibility of developing oropharyngeal cancer [147].
However, other studies failed to associate cannabis use to head and neck cancer [139,148,149,153]. Moreover, a case-control study with strict control for confounding factors, such as birth year, education, sex, cigarette and alcohol consumption, showed no association between oral squamous cell carcinoma before and after cannabis consumption [146], indicating that conflicting results may be due to different methods used, and a lack of quality research. Targeting the cannabinoid system represents a potential therapeutic target in the treatment of several types of cancer [140]. Cannabinoid agonists prevent cancer cell progression, reducing tumor growth and metastasis in at least in two ways: by inhibiting cancer cell proliferation and/or inducing autophagy and cell apoptosis [143,144] by suppressing cancer cell migration [141,142]. Thus, the potential of therapeutic targeting of cannabinoid receptors in oral cancers should not be neglected.

3.13. Other Oral Tissue Diseases

Cannabis smoking may also result in lesions in the oral soft tissue. Stomatitis with leukoedema and hyperkeratosis are often found in the buccal mucosa of cannabis smokers, probably resulting from the high temperature of the smoke or the specific chemicals inhaled [129]. Moreover, due to their poor oral/denture hygiene and nutritional deficiency, heavy cannabis users are also more prone to Candida albicans infections [11].

3.14. Potential Therapeutic Application of Cannabinoids on Oral Health

As mentioned before, its anti–oxidant, anti–inflammatory and analgesic properties have allowed CBD to be proposed as a therapeutic and safe drug for use in oral mucositis [154], Thus, this recent proposition of CBD use in dentistry will surely open the way to studies on the use of cannabinoids in oral mucositis and other oral mucosal diseases caused by oxidative stress, chemotherapy, or radiotherapy.
There are many considerations of the role of marijuana’s effect with dental anesthesia, especially as a pain management tool for surgical analgesia as well as post-operative management. In a study done by Holdcroft et al., capsules of THC and CBD were given to patients following major operations [155]. Pain relief and mood, measured by eight assessments trough a visual scale, showed that these capsules reduced demands and extended the lag time for rescue analgesia (morphine) in patients; the optimal dosage, to avoid dose-related side effects such as dizziness and sedation, was ten milligram [155]. This and other studies showed morphine-sparing effects of cannabis, which are crucial as opioid compounds have high abuse potential and fatal risks [156], indicating the potential use of marijuana as an analgesic alternative with positive future implications for the dental field.

4. Conclusions

Although there is a long history of cannabis use, the knowledge of the effects of cannabis on human health has only been enriched in recent decades. The discovery of synthetic cannabinoids, cannabinoid receptors and the endocannabinoid system has paved the way for better understanding of several effects of cannabis on the human brain and body. Given the present and future increase in health issues related to recently legalized cannabinoid consumption, it is mandatory for oral healthcare providers and dentists to know and understand both the adverse and beneficial oral effects of cannabis. It is critical for oral healthcare providers to be aware of a patient’s status, to recognize the potential risks, and to seek the best treatment options.
The most common way of consuming cannabis, marijuana smoking, has several direct and indirect deleterious effects on oral cavities; however, the evidence linking cannabis to oral/dental diseases is contradictory and at best limited. This is often related to different personal risk factors, as well as the lack of details in marijuana usage information.
Innovative compounds active on selective cannabinoids receptors could be useful for the treatment of numerous systemic disease and novel implications in several pathologies.
Well-designed research controlling for confounding factors are needed in the future, and more basic and clinical research should be designed to understand the mechanisms of action of cannabis. This will allow us to precisely target the systemic and oral effects in a more specific manner, by developing synthetic agonists, antagonists and more general modulators of the endocannabinoid system. This will largely benefit patients by developing new therapeutic approaches to increase treatment efficacy and to reduce the side effects.

Author Contributions

Conceptualization: L.B., F.I., G.D.; methodology: L.B., F.I., A.D.I., A.M.I., F.L., G.M., L.S., A.S.; software: L.B., I.R.B., D.H., M.T.D., L.N., G.M.T., D.G.; validation: F.I., G.M.T., A.S.; formal analysis: L.N., C.G.I., L.B., R.S., F.I.; investigation: G.M., F.L., A.D.I., A.M.I., F.I., A.S., G.M.T., M.F., D.G., M.C.; data curation, L.B., F.L.; writing—original draft preparation: L.B., F.I.; writing—review and editing: F.I., F.L., A.D.I., G.D., A.M.I.; All authors have read and agreed to the published version of the manuscript. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted.

Funding

The authors declared no external funding for the present research.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

All experimental data to support the findings of this study are available contacting the corresponding author upon request.

Acknowledgments

No acknowledgment to declare.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Karila, L.; Roux, P.; Rolland, B.; Benyamina, A.; Reynaud, M.; Aubin, H.-J.; Lancon, C. Acute and Long-Term Effects of Cannabis Use: A Review. Curr. Pharm. Des. 2014, 20, 4112–4118. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  2. Bridgeman, M.B.; Abazia, D.T. Medicinal Cannabis: History, Pharmacology, and Implications for the Acute Care Setting. P T A Peer-Rev. J. Formul. Manag. 2017, 42, 180–188. [Google Scholar]
  3. Martínez, V.; De-Hond, A.I.; Borrelli, F.; Capasso, R.; Del Castillo, M.D.; Abalo, R. Cannabidiol and Other Non-Psychoactive Cannabinoids for Prevention and Treatment of Gastrointestinal Disorders: Useful Nutraceuticals? Int. J. Mol. Sci. 2020, 21, 3067. [Google Scholar] [CrossRef] [PubMed]
  4. Charitos, I.A.; Gagliano-Candela, R.; Santacroce, L.; Bottalico, L. The Cannabis Spread throughout the Continents and its Therapeutic Use in History. Endocr. Metab. Immune Disord. Drug Targets 2021, 21, 407–417. [Google Scholar] [CrossRef] [PubMed]
  5. Santacroce, L.; Topi, S.; Haxhirexha, K.; Hidri, S.; Charitos, I.A.; Bottalico, L. Medicine and Healing in the Pre-Socratic—A Brief Analysis of Magic and Rationalism in Ancient Herbal Therapy. Endocr. Metab. Immune Disord. Drug Targets 2021, 21, 282–287. [Google Scholar] [CrossRef]
  6. Charitos, I.A.; Gagliano-Candela, R.; Santacroce, L.; Bottalico, L. Venoms and poisonings during the centuries. A narrative review. Endocr. Metab. Immune Disord. Drug Targets 2020, 20, 1–13. [Google Scholar] [CrossRef] [PubMed]
  7. Hall, W.; Degenhardt, L. Adverse health effects of non-medical cannabis use. Lancet 2009, 374, 1383–1391. [Google Scholar] [CrossRef]
  8. Prashad, S.; Filbey, F.M. Cognitive motor deficits in cannabis users. Curr. Opin. Behav. Sci. 2017, 13, 1–7. [Google Scholar] [CrossRef] [Green Version]
  9. Hasan, A.; Von Keller, R.; Friemel, C.M.; Hall, W.; Schneider, M.; Koethe, D.; Leweke, F.M.; Strube, W.; Hoch, E. Cannabis use and psychosis: A review of reviews. Eur. Arch. Psychiatry Clin. Neurosci. 2019, 270, 403–412. [Google Scholar] [CrossRef] [PubMed]
  10. Vieira, G.; Cavalli, J.; Gonçalves, E.C.D.; Braga, S.F.P.; Ferreira, R.S.; Santos, A.R.S.; Cola, M.; Raposo, N.R.B.; Capasso, R.; Dutra, R.C. Antidepressant-Like Effect of Terpineol in an Inflammatory Model of Depression: Involvement of the Cannabinoid System and D2 Dopamine Receptor. Biomolecules 2020, 10, 792. [Google Scholar] [CrossRef]
  11. Versteeg, P.; Slot, D.; Van Der Velden, U.; Van Der Weijden, G. Effect of cannabis usage on the oral environment: A review. Int. J. Dent. Hyg. 2008, 6, 315–320. [Google Scholar] [CrossRef] [PubMed]
  12. Mechoulam, R.; Hanuš, L.O.; Pertwee, R.; Howlett, A. Early phytocannabinoid chemistry to endocannabinoids and beyond. Nat. Rev. Neurosci. 2014, 15, 757–764. [Google Scholar] [CrossRef] [PubMed]
  13. Atakan, Z. Cannabis, a complex plant: Different compounds and different effects on individuals. Ther. Adv. Psychopharmacol. 2012, 2, 241–254. [Google Scholar] [CrossRef] [Green Version]
  14. Howlett, A. International Union of Pharmacology. XXVII. Classification of Cannabinoid Receptors. Pharmacol. Rev. 2002, 54, 161–202. [Google Scholar] [CrossRef]
  15. Mechoulam, R. Chemistry of Cannabis. Psychotr. Agents 1982, 55, 119–134. [Google Scholar] [CrossRef]
  16. Gaoni, Y.; Mechoulam, R. Isolation, Structure, and Partial Synthesis of an Active Constituent of Hashish. J. Am. Chem. Soc. 1964, 86, 1646–1647. [Google Scholar] [CrossRef]
  17. Garrett, E.R.; Hunt, C. Physicochemical Properties, Solubility, and Protein Binding of Δ9 -Tetrahydrocannabinol. J. Pharm. Sci. 1974, 63, 1056–1064. [Google Scholar] [CrossRef]
  18. Panlilio, L.V.; Justinova, Z. Preclinical Studies of Cannabinoid Reward, Treatments for Cannabis Use Disorder, and Addiction-Related Effects of Cannabinoid Exposure. Neuropsychopharmacology 2017, 43, 116–141. [Google Scholar] [CrossRef]
  19. Bih, C.I.; Chen, T.; Nunn, A.V.W.; Bazelot, M.; Dallas, M.; Whalley, B.J. Molecular Targets of Cannabidiol in Neurological Disorders. Neurotherapeutics 2015, 12, 699–730. [Google Scholar] [CrossRef] [Green Version]
  20. Millar, S.A.; Stone, N.L.; Yates, A.S.; O’Sullivan, S.E. A Systematic Review on the Pharmacokinetics of Cannabidiol in Humans. Front. Pharmacol. 2018, 9, 1365. [Google Scholar] [CrossRef] [PubMed]
  21. Pisanti, S.; Malfitano, A.M.; Ciaglia, E.; Lamberti, A.; Ranieri, R.; Cuomo, G.; Abate, M.; Faggiana, G.; Proto, M.C.; Fiore, D.; et al. Cannabidiol: State of the art and new challenges for therapeutic applications. Pharmacol. Ther. 2017, 175, 133–150. [Google Scholar] [CrossRef]
  22. Jagannathan, R. Identification of Psychoactive Metabolites from Cannabis sativa, Its Smoke, and Other Phytocannabinoids Using Machine Learning and Multivariate Methods. ACS Omega 2020, 5, 281–295. [Google Scholar] [CrossRef]
  23. Joshi, S.; Ashley, M. Cannabis: A joint problem for patients and the dental profession. Br. Dent. J. 2016, 220, 597–601. [Google Scholar] [CrossRef] [PubMed]
  24. Matsuda, L.A.; Lolait, S.J.; Brownstein, M.J.; Young, A.C.; Bonner, T.I. Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nat. Cell Biol. 1990, 346, 561–564. [Google Scholar] [CrossRef] [PubMed]
  25. Hillard, C.J.; Manna, S.; Greenberg, M.J.; DiCamelli, R.; Ross, R.A.; Stevenson, L.A.; Murphy, V.; Pertwee, R.; Campbell, W.B. Synthesis and characterization of potent and selective agonists of the neuronal cannabinoid receptor (CB1). J. Pharmacol. Exp. Ther. 1999, 289, 1427–1433. [Google Scholar] [PubMed]
  26. Rinaldi-Carmona, M.; Barth, F.; Héaulme, M.; Shire, D.; Calandra, B.; Congy, C.; Martinez, S.; Maruani, J.; Néliat, G.; Caput, D.; et al. SR141716A, a potent and selective antagonist of the brain cannabinoid receptor. FEBS Lett. 1994, 350, 240–244. [Google Scholar] [CrossRef] [Green Version]
  27. Gatley, S.; Gifford, A.N.; Volkow, N.D.; Lan, R.; Makriyannis, A. 123I-labeled AM251: A radioiodinated ligand which binds in vivo to mouse brain cannabinoid CB1 receptors. Eur. J. Pharmacol. 1996, 307, 331–338. [Google Scholar] [CrossRef]
  28. Lan, R.; Liu, Q.; Fan, P.; Lin, S.; Fernando, S.R.; McCallion, D.; Pertwee, R.; Makriyannis, A. Structure—Activity Relationships of Pyrazole Derivatives as Cannabinoid Receptor Antagonists. J. Med. Chem. 1999, 42, 769–776. [Google Scholar] [CrossRef]
  29. Bie, B.; Wu, J.; Foss, J.F.; Naguib, M. An overview of the cannabinoid type 2 receptor system and its therapeutic potential. Curr. Opin. Anaesthesiol. 2018, 31, 407–414. [Google Scholar] [CrossRef]
  30. Beltramo, M.; Stella, N.; Calignano, A.; Lin, S.Y.; Makriyannis, A.; Piomelli, D. Functional Role of High-Affinity Anandamide Transport, as Revealed by Selective Inhibition. Science 1997, 277, 1094–1097. [Google Scholar] [CrossRef] [Green Version]
  31. DE Lago, E.; Ligresti, A.; Ortar, G.; Morera, E.; Cabranes, A.; Pryce, G.; Bifulco, M.; Baker, D.; Fernandez-Ruiz, J.; Di Marzo, V. In vivo pharmacological actions of two novel inhibitors of anandamide cellular uptake. Eur. J. Pharmacol. 2004, 484, 249–257. [Google Scholar] [CrossRef]
  32. Kathuria, S.; Gaetani, S.; Fegley, D.; Valiño, F.; Duranti, A.; Tontini, A.; Mor, M.; Tarzia, G.; La Rana, G.; Calignano, A.; et al. Modulation of anxiety through blockade of anandamide hydrolysis. Nat. Med. 2002, 9, 76–81. [Google Scholar] [CrossRef]
  33. Long, J.Z.; Li, W.; Booker, L.; Burston, J.J.; Kinsey, S.G.; Schlosburg, J.E.; Pavon, F.J.; Serrano, A.; Selley, D.E.; Parsons, L.H.; et al. Selective blockade of 2-arachidonoylglycerol hydrolysis produces cannabinoid behavioral effects. Nat. Chem. Biol. 2008, 5, 37–44. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  34. Long, J.Z.; Nomura, D.K.; Vann, R.E.; Walentiny, D.M.; Booker, L.; Jin, X.; Burston, J.J.; Sim-Selley, L.J.; Lichtman, A.H.; Wiley, J.; et al. Dual blockade of FAAH and MAGL identifies behavioral processes regulated by endocannabinoid crosstalk in vivo. Proc. Natl. Acad. Sci. USA 2009, 106, 20270–20275. [Google Scholar] [CrossRef] [Green Version]
  35. Gérard, C.M.; Mollereau, C.; Vassart, G.; Parmentier, M. Molecular cloning of a human cannabinoid receptor which is also expressed in testis. Biochem. J. 1991, 279, 129–134. [Google Scholar] [CrossRef]
  36. Chakrabarti, A.; Onaivi, E.S.; Chaudhuri, G. Cloning and sequencing of a cDNA encoding the mouse brain-type cannabinoid receptor protein. DNA Seq. 1995, 5, 385–388. [Google Scholar] [CrossRef] [PubMed]
  37. Munro, S.; Thomas, K.; Abu-Shaar, M. Molecular characterization of a peripheral receptor for cannabinoids. Nat. Cell Biol. 1993, 365, 61–65. [Google Scholar] [CrossRef] [PubMed]
  38. Shire, D.; Calandra, B.; Rinaldi-Carmona, M.; Oustric, D.; Pessegue, B.; Bonnin-Cabanne, O.; Le Fur, G.; Caput, D.; Ferrara, P. Molecular cloning, expression and function of the murine CB2 peripheral cannabinoid receptor. Biochim. Biophys. Acta (BBA) Gene Struct. Expr. 1996, 1307, 132–136. [Google Scholar] [CrossRef]
  39. Shim, J.-Y. Understanding Functional Residues of the Cannabinoid CB1 Receptor for Drug Discovery. Curr. Top. Med. Chem. 2010, 10, 779–798. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  40. Liu, Q.-R.; Pan, C.-H.; Hishimoto, A.; Li, C.-Y.; Xi, Z.-X.; Llorente-Berzal, A.; Viveros, M.-P.; Ishiguro, H.; Arinami, T.; Onaivi, E.S.; et al. Species differences in cannabinoid receptor 2 (CNR2gene): Identification of novel human and rodent CB2 isoforms, differential tissue expression and regulation by cannabinoid receptor ligands. Genes Brain Behav. 2009, 8, 519–530. [Google Scholar] [CrossRef]
  41. Roche, R.; Hoareau, L.; Bes-Houtmann, S.; Gonthier, M.-P.; Laborde, C.; Baron, J.-F.; Haffaf, Y.; Cesari, M.; Festy, F. Presence of the cannabinoid receptors, CB1 and CB2, in human omental and subcutaneous adipocytes. Histochem. Cell Biol. 2006, 126, 177–187. [Google Scholar] [CrossRef]
  42. Shahbazi, F.; Grandi, V.; Banerjee, A.; Trant, J.F. Cannabinoids and Cannabinoid Receptors: The Story so Far. iScience 2020, 23, 101301. [Google Scholar] [CrossRef]
  43. Fredriksson, R.; Lagerström, M.C.; Lundin, L.-G.; Schiöth, H.B. The G-Protein-Coupled Receptors in the Human Genome Form Five Main Families. Phylogenetic Analysis, Paralogon Groups, and Fingerprints. Mol. Pharmacol. 2003, 63, 1256–1272. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  44. Ryberg, E.; Larsson, N.; Sjögren, S.; Hjorth, S.; Hermansson, N.-O.; Leonova, J.; Elebring, T.; Nilsson, K.; Drmota, T.; Greasley, P.J. The orphan receptor GPR55 is a novel cannabinoid receptor. Br. J. Pharmacol. 2007, 152, 1092–1101. [Google Scholar] [CrossRef]
  45. Ross, R.A. The enigmatic pharmacology of GPR55. Trends Pharmacol. Sci. 2009, 30, 156–163. [Google Scholar] [CrossRef]
  46. Hansen, H.S.; Rosenkilde, M.M.; Holst, J.J.; Schwartz, T.W. GPR119 as a fat sensor. Trends Pharmacol. Sci. 2012, 33, 374–381. [Google Scholar] [CrossRef] [PubMed]
  47. Overton, H.A.; Fyfe, M.C.T.; Reynet, C. GPR119, a novel G protein-coupled receptor target for the treatment of type 2 diabetes and obesity. Br. J. Pharmacol. 2008, 153, S76–S81. [Google Scholar] [CrossRef] [Green Version]
  48. Busquets-Garcia, A.; Bains, J.; Marsicano, G. CB1 Receptor Signaling in the Brain: Extracting Specificity from Ubiquity. Neuropsychopharmacology 2017, 43, 4–20. [Google Scholar] [CrossRef] [PubMed]
  49. Felder, C.C.; Joyce, K.E.; Briley, E.M.; Mansouri, J.; Mackie, K.; Blond, O.; Lai, Y.; Ma, A.L.; Mitchell, R.L. Comparison of the pharmacology and signal transduction of the human cannabinoid CB1 and CB2 receptors. Mol. Pharmacol. 1995, 48, 443–450. [Google Scholar]
  50. Demuth, D.G.; Molleman, A. Cannabinoid signalling. Life Sci. 2006, 78, 549–563. [Google Scholar] [CrossRef]
  51. Derkinderen, P.; Valjent, E.; Toutant, M.; Corvol, J.-C.; Enslen, H.; Ledent, C.; Trzaskos, J.; Caboche, J.; Girault, J.-A. Regulation of Extracellular Signal-Regulated Kinase by Cannabinoids in Hippocampus. J. Neurosci. 2003, 23, 2371–2382. [Google Scholar] [CrossRef]
  52. Bénard, G.; Massa, F.; Puente, N.; Lourenço, J.; Bellocchio, L.; Soria-Gómez, E.; Matias, I.; Delamarre, A.; Metna-Laurent, M.; Cannich, A.; et al. Mitochondrial CB1 Receptors Regulate Neuronal Energy Metabolism. Nat. Neurosci. 2012, 15, 558–564. [Google Scholar] [CrossRef]
  53. Hebert-Chatelain, E.; Desprez, T.; Serrat, R.; Bellocchio, L.; Soria-Gomez, E.; Busquets-Garcia, A.; Zottola, A.C.P.; Delamarre, A.; Cannich, A.; Vincent, P.; et al. A cannabinoid link between mitochondria and memory. Nat. Cell Biol. 2016, 539, 555–559. [Google Scholar] [CrossRef]
  54. Koch, M.; Varela, L.; Kim, J.G.; Kim, J.D.; Hernández-Nuño, F.; Simonds, S.; Castorena, C.M.; Vianna, C.R.; Elmquist, J.K.; Morozov, Y.; et al. Hypothalamic POMC neurons promote cannabinoid-induced feeding. Nat. Cell Biol. 2015, 519, 45–50. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  55. Jimenez-Blasco, D.; Busquets-Garcia, A.; Hebert-Chatelain, E.; Serrat, R.; Vicente-Gutierrez, C.; Ioannidou, C.; Gómez-Sotres, P.; Lopez-Fabuel, I.; Resch-Beusher, M.; Resel, E.; et al. Glucose metabolism links astroglial mitochondria to cannabinoid effects. Nat. Cell Biol. 2020, 583, 603–608. [Google Scholar] [CrossRef]
  56. Ballini, A.; Santacroce, L.; Cantore, S.; Bottalico, L.; Dipalma, G.; De Vito, D.; Saini, R.; Inchingolo, F. Probiotics Improve Urogenital Health in Women. Open Access Maced. J. Med Sci. 2018, 6, 1845–1850. [Google Scholar] [CrossRef] [Green Version]
  57. Pham, V.H.; Gargiulo Isacco, C.; Nguyen, K.C.D.; Le, S.H.; Tran, D.K.; Nguyen, Q.V.; Pham, H.T.; Aityan, S.; Pham, S.T.; Cantore, S.; et al. Rapid and Sensitive Diagnostic Procedure for Multiple Detection of Pandemic Coronaviridae Family Members SARS-CoV-2, SARS-CoV, MERS-CoV and HCoV: A Translational Research and Cooperation between the Phan Chau Trinh University in Vietnam and University of Bari “Aldo Moro” in Italy. Eur. Rev. Med. Pharmacol. Sci. 2020, 24, 7173–7191. [Google Scholar] [CrossRef]
  58. Hossain, M.Z.; Ando, H.; Unno, S.; Kitagawa, J. Targeting Peripherally Restricted Cannabinoid Receptor 1, Cannabinoid Receptor 2, and Endocannabinoid-Degrading Enzymes for the Treatment of Neuropathic Pain Including Neuropathic Orofacial Pain. Int. J. Mol. Sci. 2020, 21, 1423. [Google Scholar] [CrossRef] [Green Version]
  59. Borsani, E.; Majorana, A.; Cocchi, M.A.; Conti, G.; Bonadeo, S.; Padovani, A.; Lauria, G.; Bardellini, E.; Rezzani, R.; Rodella, L.F. Epithelial expression of vanilloid and cannabinoid receptors: A potential role in burning mouth syndrome pathogenesis. Histol. Histopathol. 2014, 29, 523–533. [Google Scholar] [CrossRef] [PubMed]
  60. Yoshida, R.; Ohkuri, T.; Jyotaki, M.; Yasuo, T.; Horio, N.; Yasumatsu, K.; Sanematsu, K.; Shigemura, N.; Yamamoto, T.; Margolskee, R.; et al. Endocannabinoids selectively enhance sweet taste. Proc. Natl. Acad. Sci. USA 2009, 107, 935–939. [Google Scholar] [CrossRef] [Green Version]
  61. Yoshida, R.; Niki, M.; Jyotaki, M.; Sanematsu, K.; Shigemura, N.; Ninomiya, Y. Modulation of sweet responses of taste receptor cells. Semin. Cell Dev. Biol. 2013, 24, 226–231. [Google Scholar] [CrossRef]
  62. Moon, Y.W.; Lee, J.-H.; Yoo, S.B.; Jahng, J.W. Capsaicin receptors are colocalized with sweet/bitter receptors in the taste sensing cells of circumvallate papillae. Genes Nutr. 2009, 5, 251–255. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  63. Ehrenfest, D.M.D.; Del Corso, M.; Inchingolo, F.; Charrier, J.-B. Selecting a relevant in vitro cell model for testing and comparing the effects of a Choukroun’s platelet-rich fibrin (PRF) membrane and a platelet-rich plasma (PRP) gel: Tricks and traps. Oral Surgery Oral Med. Oral Pathol. Oral Radiol. Endodontol. 2010, 110, 409–411. [Google Scholar] [CrossRef]
  64. Ballini, A.; DiPalma, G.; Isacco, C.G.; Boccellino, M.; Di Domenico, M.; Santacroce, L.; Nguyễn, K.C.; Scacco, S.; Calvani, M.; Boddi, A.; et al. Oral Microbiota and Immune System Crosstalk: A Translational Research. Biology 2020, 9, 131. [Google Scholar] [CrossRef]
  65. Santacroce, L.; Charitos, I.A.; Ballini, A.; Inchingolo, F.; Luperto, P.; De Nitto, E.; Topi, S. The Human Respiratory System and its Microbiome at a Glimpse. Biology 2020, 9, 318. [Google Scholar] [CrossRef]
  66. Inchingolo, F.; Martelli, F.S.; Isacco, C.G.; Borsani, E.; Cantore, S.; Corcioli, F.; Boddi, A.; Nguyễn, K.C.; De Vito, D.; Aityan, S.K.; et al. Chronic Periodontitis and Immunity, Towards the Implementation of a Personalized Medicine: A Translational Research on Gene Single Nucleotide Polymorphisms (SNPs) Linked to Chronic Oral Dysbiosis in 96 Caucasian Patients. Biomedicines 2020, 8, 115. [Google Scholar] [CrossRef] [PubMed]
  67. Inchingolo, F.; Santacroce, L.; Ballini, A.; Topi, S.; DiPalma, G.; Haxhirexha, K.; Bottalico, L.; Charitos, I.A. Oral Cancer: A Historical Review. Int. J. Environ. Res. Public Health 2020, 17, 3168. [Google Scholar] [CrossRef] [PubMed]
  68. Topi, S.; Santacroce, L.; Bottalico, L.; Ballini, A.; Inchingolo, A.D.; Dipalma, G.; Charitos, I.A.; Inchingolo, F. Gastric Cancer in History: A Perspective Interdisciplinary Study. Cancers 2020, 12, 264. [Google Scholar] [CrossRef] [Green Version]
  69. Boccellino, M.; Di Stasio, D.; DiPalma, G.; Cantore, S.; Ambrosio, P.; Coppola, M.; Quagliuolo, L.; Scarano, A.; Malcangi, G.; Borsani, E.; et al. Steroids and growth factors in oral squamous cell carcinoma: Useful source of dental-derived stem cells to develop a steroidogenic model in new clinical strategies. Eur. Rev. Med. Pharmacol. Sci. 2019, 23, 8730–8740. [Google Scholar] [CrossRef]
  70. Theocharis, S.; Giaginis, C.; Alexandrou, P.; Rodríguez, J.; Tasoulas, J.; Danas, E.; Patsouris, E.; Klijanienko, J. Evaluation of cannabinoid CB1 and CB2 receptors expression in mobile tongue squamous cell carcinoma: Associations with clinicopathological parameters and patients’ survival. Tumor Biol. 2015, 37, 3647–3656. [Google Scholar] [CrossRef]
  71. Dariš, B.; Verboten, M.T.; Knez, Ž.; Ferk, P. Cannabinoids in cancer treatment: Therapeutic potential and legislation. Bosn. J. Basic. Med. Sci. 2019, 19, 14–23. [Google Scholar] [CrossRef]
  72. Nagarkatti, P.; Pandey, R.; Rieder, S.A.; Hegde, V.L.; Nagarkatti, M. Cannabinoids as novel anti-inflammatory drugs. Futur. Med. Chem. 2009, 1, 1333–1349. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  73. Busch, L.; Sterin-Borda, L.; Borda, E. Expression and biological effects of CB1 cannabinoid receptor in rat parotid gland. Biochem. Pharmacol. 2004, 68, 1767–1774. [Google Scholar] [CrossRef] [PubMed]
  74. Thoungseabyoun, W.; Tachow, A.; Pakkarato, S.; Rawangwong, A.; Krongyut, S.; Sakaew, W.; Kondo, H.; Hipkaeo, W. 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. 2017, 81, 160–166. [Google Scholar] [CrossRef] [PubMed]
  75. Santacroce, L.; Di Cosola, M.; Bottalico, L.; Topi, S.; Charitos, I.; Ballini, A.; Inchingolo, F.; Cazzolla, A.; Dipalma, G. Focus on HPV Infection and the Molecular Mechanisms of Oral Carcinogenesis. Viruses 2021, 13, 559. [Google Scholar] [CrossRef]
  76. Santacroce, L.; Inchingolo, F.; Topi, S.; Del Prete, R.; Di Cosola, M.; Charitos, I.A.; Montagnani, M. Potential beneficial role of probiotics on the outcome of COVID-19 patients: An evolving perspective. Diabetes Metab. Syndr. Clin. Res. Rev. 2021, 15, 295–301. [Google Scholar] [CrossRef]
  77. Signorini, L.; Ballini, A.; Arrigoni, R.; De Leonardis, F.; Saini, R.; Cantore, S.; De Vito, D.; Coscia, M.F.; Dipalma, G.; Santacroce, L.; et al. Evaluation of a nutraceutical product with probiotics, vitamin d, plus banaba leaf extracts (Lagerstroemia speciosa) in glycemic control. Endocr. Metab. Immune Disord. Drug Targets 2020, 20, 1–11. [Google Scholar] [CrossRef]
  78. Signorini, L. Probiotics May Modulate the Impact of Aging on Adults. J. Biol. Regul. Homeost. Agents 2020, 34, 1601–1606. [Google Scholar] [CrossRef] [PubMed]
  79. Isacco, C.G.; Ballini, A.; De Vito, D.; Nguyen, K.C.D.; Cantore, S.; Bottalico, L.; Quagliuolo, L.; Boccellino, M.; Di Domenico, M.; Santacroce, L. Rebalance the Oral Microbiota as Efficacy Tool in Endocrine, Metabolic, and Immune Disorders. Endocr. Metab. Immune Disord. Drug Targets 2020, 18, 466–469. [Google Scholar] [CrossRef]
  80. Santacroce, L.; Sardaro, N.; Topi, S.; Pettini, F.; Bottalico, L.; Cantore, S.; Cascella, G.; Del Prete, R.; DiPalma, G.; Inchingolo, F. The pivotal role of oral microbiota in health and disease. J. Biol. Regul. Homeost Agents 2020, 34, 733–737. [Google Scholar]
  81. Supplement, D.; Isacco, C.G.; Ballini, A.; Paduanelli, G.; Inchingolo, A.D.; Nguyen, K.C.D.; Inchingolo, A.M.; Pham, V.H.; Aityan, S.K.; Schiffman, M.; et al. Bone decay and beyond: How can we approach it better. J. Biol. Regul. Homeost Agents 2020, 33, 143–154. [Google Scholar]
  82. Supplement, D.; Scarano, A.; Puglia, F.; Cassese, R.; Mordente, I.; Amore, R.; Ferraro, G.; Sbarbati, A.; Russo, F.L.; Lucchina, A.G.; et al. Hyaluronic acid fillers in lip augmentation procedure: A clinical and histological study. J. Biol. Regul. Homeost Agents 2020, 33, 103–108. [Google Scholar]
  83. Inchingolo, A.; Inchingolo, A.; Bordea, I.; Malcangi, G.; Xhajanka, E.; Scarano, A.; Lorusso, F.; Farronato, M.; Tartaglia, G.; Isacco, C.; et al. SARS-CoV-2 Disease through Viral Genomic and Receptor Implications: An Overview of Diagnostic and Immunology Breakthroughs. Microorganisms 2021, 9, 793. [Google Scholar] [CrossRef] [PubMed]
  84. Scarano, A.; Inchingolo, F.; Lorusso, F. Facial Skin Temperature and Discomfort When Wearing Protective Face Masks: Thermal Infrared Imaging Evaluation and Hands Moving the Mask. Int. J. Environ. Res. Public Health 2020, 17, 4624. [Google Scholar] [CrossRef]
  85. Scarano, A.; Inchingolo, F.; Rapone, B.; Festa, F.; Tari, S.R.; Lorusso, F. Protective Face Masks: Effect on the Oxygenation and Heart Rate Status of Oral Surgeons during Surgery. Int. J. Environ. Res. Public Health 2021, 18, 2363. [Google Scholar] [CrossRef]
  86. Inchingolo, F.; Tatullo, M.; Abenavoli, F.M.; Marrelli, M.; Inchingolo, A.D.; Villabruna, B.; Inchingolo, A.M.; Dipalma, G. Severe Anisocoria after Oral Surgery under General Anesthesia. Int. J. Med Sci. 2010, 7, 314–318. [Google Scholar] [CrossRef] [Green Version]
  87. Dall’Aglio, C.; Mercati, F.; Pascucci, L.; Boiti, C.; Pedini, V.; Ceccarelli, P. Immunohistochemical localization of CB1 receptor in canine salivary glands. Vet. Res. Commun. 2010, 34, 9–12. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  88. Pirino, C.; Cappai, M.G.; Maranesi, M.; Tomassoni, D.; Giontella, A.; Pinna, W.; Boiti, C.; Kamphues, J.; Dall’Aglio, C. 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. 2017, 102, e870–e876. [Google Scholar] [CrossRef] [PubMed]
  89. Prestifilippo, J.P.; Fernández-Solari, J.; De La Cal, C.; Iribarne, M.; Suburo, A.M.; Rettori, V.; McCann, S.M.; Elverdin, J.C. Inhibition of Salivary Secretion by Activation of Cannabinoid Receptors. Exp. Biol. Med. 2006, 231, 1421–1429. [Google Scholar] [CrossRef] [PubMed]
  90. Fernandez-Solari, J.; Prestifilippo, J.; Vissio, P.; Ehrhart-Bornstein, M.; Bornstein, S.; Rettori, V.; Elverdin, J. Anandamide injected into the lateral ventricle of the brain inhibits submandibular salivary secretion by attenuating parasympathetic neurotransmission. Braz. J. Med Biol. Res. 2009, 42, 537–544. [Google Scholar] [CrossRef] [Green Version]
  91. 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. 2009, 44, 443–448. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  92. Prestifilippo, J.; Medina, V.; Mohn, C.; Rodriguez, P.; Elverdin, J.; Fernandez-Solari, J. Endocannabinoids mediate hyposalivation induced by inflammogens in the submandibular glands and hypothalamus. Arch. Oral Biol. 2013, 58, 1251–1259. [Google Scholar] [CrossRef]
  93. Cantore, S.; Ballini, A.; Saini, R.; De Vito, D.; Altini, V.; Saini, S.R.; Pustina-Krasniqi, T.; Xhajanka, E.; Isacco, C.G.; DiPalma, G.; et al. Efficacy of a combined sea salt-based oral rinse with xylitol against dental plaque, gingivitis, and salivary Streptococcus mutans load. J. Biol. Regul. Homeost. Agents 2018, 32, 1593–1597. [Google Scholar]
  94. 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. 2010, 17, 1476–1479. [Google Scholar] [CrossRef] [PubMed]
  95. Szabo, B.; Schlicker, E. Effects of Cannabinoids on Neurotransmission. In Cannabinoids; Springer: Berlin/Heidelberg, Germany, 2005; pp. 327–365. [Google Scholar]
  96. Que, K.; He, D.; Jin, Y.; Wu, L.; Wang, F.; Zhao, Z.; Yang, J.; Deng, J. Expression of Cannabinoid Type 1 Receptors in Human Odontoblast Cells. J. Endod. 2017, 43, 283–288. [Google Scholar] [CrossRef] [PubMed]
  97. Tsumura, M.; Sobhan, U.; Muramatsu, T.; Sato, M.; Ichikawa, H.; Sahara, Y.; Tazaki, M.; Shibukawa, Y. TRPV1-mediated calcium signal couples with cannabinoid receptors and sodium–calcium exchangers in rat odontoblasts. Cell Calcium 2012, 52, 124–136. [Google Scholar] [CrossRef]
  98. 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. 2012, 38, 786–790. [Google Scholar] [CrossRef]
  99. Lorusso, F.; Inchingolo, F.; DiPalma, G.; Postiglione, F.; Fulle, S.; Scarano, A. Synthetic Scaffold/Dental Pulp Stem Cell (DPSC) Tissue Engineering Constructs for Bone Defect Treatment: An Animal Studies Literature Review. Int. J. Mol. Sci. 2020, 21, 9765. [Google Scholar] [CrossRef]
  100. Ballini, A.; Cantore, S.; Scacco, S.; Perillo, L.; Scarano, A.; Aityan, S.K.; Contaldo, M.; Nguyen, K.C.D.; Santacroce, L.; Syed, J.; et al. A comparative study on different stemness gene expression between dental pulp stem cells vs. dental bud stem cells. Eur. Rev. Med Pharmacol. Sci. 2019, 23, 1626–1633. [Google Scholar] [CrossRef]
  101. Mancinelli, R.; Di Filippo, E.; Tumedei, M.; Marrone, M.; Fontana, A.; Ettorre, V.; Giordani, S.; Baldrighi, M.; Iezzi, G.; Piattelli, A.; et al. Human Dental Pulp Stem Cell Osteogenic Differentiation Seeded on Equine Bone Block with Graphene and Melatonin. Appl. Sci. 2021, 11, 3218. [Google Scholar] [CrossRef]
  102. Ballini, A.; Gnoni, A.; De Vito, D.; DiPalma, G.; Cantore, S.; Isacco, C.G.; Saini, R.; Santacroce, L.; Topi, S.; Scarano, A.; et al. Effect of probiotics on the occurrence of nutrition absorption capacities in healthy children: A randomized double-blinded placebo-controlled pilot study. Eur. Rev. Med. Pharmacol. Sci. 2019, 23, 8645–8657. [Google Scholar] [CrossRef]
  103. Konermann, A.; Jäger, A.; Held, S.A.E.; 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. 2017, 37, 1511–1520. [Google Scholar] [CrossRef] [PubMed]
  104. Liu, C.; Qi, X.; Alhabeil, J.; Lu, H.; Zhou, Z. Activation of cannabinoid receptors promote periodontal cell adhesion and migration. J. Clin. Periodontol. 2019, 46, 1264–1272. [Google Scholar] [CrossRef] [PubMed]
  105. Cantore, S.; Ballini, A.; De Vito, D.; Martelli, F.S.; Georgakopoulos, I.; Almasri, M.; Dibello, V.; Altini, V.; Farronato, G.; DiPalma, G.; et al. Characterization of human apical papilla-derived stem cells. J. Boil. Regul. Homeost. Agents 2017, 31, 901–910. [Google Scholar]
  106. Abidi, A.; Presley, C.S.; Dabbous, M.; Tipton, D.A.; Mustafa, S.M.; Moore, B.M. Anti-inflammatory activity of cannabinoid receptor 2 ligands in primary hPDL fibroblasts. Arch. Oral Biol. 2018, 87, 79–85. [Google Scholar] [CrossRef]
  107. Kozono, S.; Matsuyama, T.; Biwasa, K.K.; Kawahara, K.-I.; Nakajima, Y.; Yoshimoto, T.; Yonamine, Y.; Kadomatsu, H.; Tancharoen, S.; Hashiguchi, T.; et al. Involvement of the endocannabinoid system in periodontal healing. Biochem. Biophys. Res. Commun. 2010, 394, 928–933. [Google Scholar] [CrossRef] [PubMed]
  108. Cariccio, V.L.; Scionti, D.; Raffa, A.; Iori, R.; Pollastro, F.; Diomede, F.; Bramanti, P.; Trubiani, O.; Mazzon, E. 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. 2018, 19, 2341. [Google Scholar] [CrossRef] [Green Version]
  109. Nakajima, Y.; Furuichi, Y.; Biswas, K.K.; Hashiguchi, T.; Kawahara, K.-I.; Yamaji, K.; Uchimura, T.; Izumi, Y.; Maruyama, I. Endocannabinoid, anandamide in gingival tissue regulates the periodontal inflammation through NF-κB pathway inhibition. FEBS Lett. 2006, 580, 613–619. [Google Scholar] [CrossRef] [Green Version]
  110. Ballini, A.; Cantore, S.; Farronato, D.; Cirulli, N.; Inchingolo, F.; Papa, F.; Malcangi, G.; Inchingolo, A.D.; DiPalma, G.; Sardaro, N.; et al. Periodontal disease and bone pathogenesis: The crosstalk between cytokines and porphyromonas gingivalis. J. Boil. Regul. Homeost. Agents 2015, 29, 273–284. [Google Scholar]
  111. Abenavoli, F.M.; Inchingolo, A.D.; Inchingolo, A.M.; Dipalma, G.; Inchingolo, F. Periodontal Neoformations and Myocarditis Onset: Is It More than a Simple Coincidence? J. Biol. Regul. Homeost Agents 2019, 33, 987–989. [Google Scholar] [PubMed]
  112. Cantore, S.; Ballini, A.; De Vito, D.; Abbinante, A.; Altini, V.; DiPalma, G.; Inchingolo, F.; Saini, R. Clinical results of improvement in periodontal condition by administration of oral probiotics. J. Biol. Regul. Homeost Agents 2018, 32, 1329–1334. [Google Scholar] [PubMed]
  113. Ballini, A.; Cantore, S.; DiPalma, G.; De Vito, D.; Saini, R.; Saini, S.R.; Georgakopoulos, P.; Isacco, C.G.; Inchingolo, F.; De Vito, D. Anti-calculus efficacy of Periogen® oral rinse in gingivitis patients. J. Biol. Regul. Homeost Agents 2019, 33, 52–55. [Google Scholar] [PubMed]
  114. Cantore, S.; Mirgaldi, R.; Ballini, A.; Coscia, M.F.; Scacco, S.; Papa, F.; Inchingolo, F.; Dipalma, G.; De Vito, D. Cytokine Gene Polymorphisms Associate with Microbiogical Agents in Periodontal Disease: Our Experience. Int. J. Med Sci. 2014, 11, 674–679. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  115. Scarano, A.; Crincoli, V.; Di Benedetto, A.; Cozzolino, V.; Lorusso, F.; Vulpiani, M.P.; Grano, M.; Kalemaj, Z.; Mori, G.; Grassi, F.R. Bone Regeneration Induced by Bone Porcine Block with Bone Marrow Stromal Stem Cells in a Minipig Model of Mandibular “Critical Size” Defect. Stem Cells Int. 2017, 2017, 1–9. [Google Scholar] [CrossRef]
  116. Bíró, T.; Tóth, B.I.; Haskó, G.; Paus, R.; Pacher, P. The endocannabinoid system of the skin in health and disease: Novel perspectives and therapeutic opportunities. Trends Pharmacol. Sci. 2009, 30, 411–420. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  117. Maccarrone, M.; Di Rienzo, M.; Battista, N.; Gasperi, V.; Guerrieri, P.; Rossi, A.; Finazzi-Agrò, A. The Endocannabinoid System in Human Keratinocytes. J. Biol. Chem. 2003, 278, 33896–33903. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  118. Paradisi, A.; Pasquariello, N.; Barcaroli, D.; Maccarrone, M. Anandamide Regulates Keratinocyte Differentiation by Inducing DNA Methylation in a CB1 Receptor-dependent Manner. J. Biol. Chem. 2008, 283, 6005–6012. [Google Scholar] [CrossRef] [Green Version]
  119. Scarano, A.; Lorusso, F.; Staiti, G.; Sinjari, B.; Tampieri, A.; Mortellaro, C. Sinus Augmentation with Biomimetic Nanostructured Matrix: Tomographic, Radiological, Histological and Histomorphometrical Results after 6 Months in Humans. Front. Physiol. 2017, 8, 565. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  120. Scarano, A.; Valbonetti, L.; Marchetti, M.; Lorusso, F.; Ceccarelli, M. Soft Tissue Augmentation of the Face with Autologous Platelet-Derived Growth Factors and Tricalcium Phosphate. Microtomography Evaluation of Mice. J. Craniofacial Surg. 2016, 27, 1212–1214. [Google Scholar] [CrossRef]
  121. Bordea, I.; Xhajanka, E.; Candrea, S.; Bran, S.; Onișor, F.; Inchingolo, A.; Malcangi, G.; Pham, V.; Inchingolo, A.; Scarano, A.; et al. Coronavirus (SARS-CoV-2) Pandemic: Future Challenges for Dental Practitioners. Microorganisms 2020, 8, 1704. [Google Scholar] [CrossRef]
  122. Scarano, A.; Noumbissi, S.; Gupta, S.; Inchingolo, F.; Stilla, P.; Lorusso, F. Scanning Electron Microscopy Analysis and Energy Dispersion X-ray Microanalysis to Evaluate the Effects of Decontamination Chemicals and Heat Sterilization on Implant Surgical Drills: Zirconia vs. Steel. Appl. Sci. 2019, 9, 2837. [Google Scholar] [CrossRef] [Green Version]
  123. Maglione, M.; Bevilacqua, L.; Dotto, F.; Costantinides, F.; Lorusso, F.; Scarano, A. Observational Study on the Preparation of the Implant Site with Piezosurgery vs. Drill: Comparison between the Two Methods in terms of Postoperative Pain, Surgical Times, and Operational Advantages. BioMed. Res. Int. 2019, 2019, 8483658. [Google Scholar] [CrossRef] [Green Version]
  124. Scarano, A.; Inchingolo, F.; Lorusso, F. Environmental Disinfection of a Dental Clinic during the Covid-19 Pandemic: A Narrative Insight. BioMed. Res. Int. 2020, 2020, 8896812. [Google Scholar] [CrossRef] [PubMed]
  125. Bellocchio, L.; Bordea, I.; Ballini, A.; Lorusso, F.; Hazballa, D.; Isacco, C.; Malcangi, G.; Inchingolo, A.; Dipalma, G.; Inchingolo, F.; et al. Environmental Issues and Neurological Manifestations Associated with COVID-19 Pandemic: New Aspects of the Disease? Int. J. Environ. Res. Public Health 2020, 17, 8049. [Google Scholar] [CrossRef]
  126. Lorusso, F.; Noumbissi, S.; Francesco, I.; Rapone, B.; Khater, A.G.A.; Scarano, A. Scientific Trends in Clinical Research on Zirconia Dental Implants: A Bibliometric Review. Materials 2020, 13, 5534. [Google Scholar] [CrossRef] [PubMed]
  127. Scarano, A.; Lorusso, F.; Di Cerbo, A.; Dds, A.G.L.; Carinci, F. Eradication of hairy mouth after oncological resection of the tongue and floor mouth using a diode laser 808 nm. Postoperative pain assessment using thermal infrared imaging. Lasers Surg. Med. 2019, 51, 516–521. [Google Scholar] [CrossRef]
  128. Hutton, B.; Salanti, G.; Caldwell, D.M.; Chaimani, A.; Schmid, C.H.; Cameron, C.; Ioannidis, J.P.; Straus, S.; Thorlund, K.; Jansen, J.P.; et al. The PRISMA Extension Statement for Reporting of Systematic Reviews Incorporating Network Meta-analyses of Health Care Interventions: Checklist and Explanations. Ann. Intern. Med. 2015, 162, 777–784. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  129. Darling, M.R.; Arendorf, T.M. Effects of cannabis smoking on oral soft tissues. Community Dent. Oral. Epidemiol. 1993, 21, 78–81. [Google Scholar] [CrossRef]
  130. Grafton, S.E.; Huang, P.N.; Vieira, A.R. Dental treatment planning considerations for patients using cannabis. J. Am. Dent. Assoc. 2016, 147, 354–361. [Google Scholar] [CrossRef]
  131. Ditmyer, M.; Demopoulos, C.; McClain, M.; Dounis, G.; Mobley, C. The Effect of Tobacco and Marijuana Use on Dental Health Status in Nevada Adolescents: A Trend Analysis. J. Adolesc. Health 2013, 52, 641–648. [Google Scholar] [CrossRef] [PubMed]
  132. Thomson, W.M.; Poulton, R.; Broadbent, J.; Moffitt, T.; Caspi, A.; Beck, J.D.; Welch, D.; Hancox, R.J. Cannabis Smoking and Periodontal Disease Among Young Adults. JAMA 2008, 299, 525–531. [Google Scholar] [CrossRef] [PubMed]
  133. Shariff, J.A.; Ahluwalia, K.P.; Papapanou, P.N. Relationship Between Frequent Recreational Cannabis (Marijuana and Hashish) Use and Periodontitis in Adults in the United States: National Health and Nutrition Examination Survey 2011 to 2012. J. Periodontol. 2017, 88, 273–280. [Google Scholar] [CrossRef]
  134. Nogueira-Filho, G.R.; Todescan, S.; Shah, A.; Rosa, B.T.; Tunes, U.D.R.; Neto, J.B.C. Impact ofCannabis Sativa(Marijuana) Smoke on Alveolar Bone Loss: A Histometric Study in Rats. J. Periodontol. 2011, 82, 1602–1607. [Google Scholar] [CrossRef]
  135. Ossola, C.A.; Surkin, P.N.; Pugnaloni, A.; Mohn, C.E.; Elverdin, J.C.; Fernandez-Solari, J. Long-term treatment with methanandamide attenuates LPS-induced periodontitis in rats. Inflamm. Res. 2012, 61, 941–948. [Google Scholar] [CrossRef]
  136. Ossola, C.A.; Surkin, P.N.; Mohn, C.E.; Elverdín, 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. 2016, 87, 725–734. [Google Scholar] [CrossRef]
  137. Napimoga, M.H.; Benatti, B.B.; Lima, F.O.; Alves, P.M.; Campos, A.C.; Pena-Dos-Santos, D.R.; Severino, F.P.; Cunha, F.Q.; Guimarães, F.S. Cannabidiol decreases bone resorption by inhibiting RANK/RANKL expression and pro-inflammatory cytokines during experimental periodontitis in rats. Int. Immunopharmacol. 2009, 9, 216–222. [Google Scholar] [CrossRef]
  138. Firth, N. Marijuana use and oral cancer: A review. Oral. Oncol. 1997, 33, 398–401. [Google Scholar] [CrossRef]
  139. Osazuwa-Peters, N.; Boakye, E.A.; Loux, T.M.; Varvares, M.A.; Schootman, M. Insufficient Evidence to Support or Refute the Association between Head and Neck Cancer and Marijuana Use. J. Évid. Based Dent. Pr. 2016, 16, 127–129. [Google Scholar] [CrossRef] [PubMed]
  140. Guzmán, M. Cannabinoids: Potential anticancer agents. Nat. Rev. Cancer 2003, 3, 745–755. [Google Scholar] [CrossRef] [PubMed]
  141. Preet, A.; Ganju, R.K.; Groopman, J.E. Δ9-Tetrahydrocannabinol inhibits epithelial growth factor-induced lung cancer cell migration in vitro as well as its growth and metastasis in vivo. Oncogene 2007, 27, 339–346. [Google Scholar] [CrossRef] [Green Version]
  142. Grimaldi, C.; Pisanti, S.; Laezza, C.; Malfitano, A.M.; Santoro, A.; Vitale, M.; Caruso, M.G.; Notarnicola, M.; Iacuzzo, I.; Portella, G.; et al. Anandamide inhibits adhesion and migration of breast cancer cells. Exp. Cell Res. 2006, 312, 363–373. [Google Scholar] [CrossRef]
  143. Salazar, M.; Carracedo, A.; Salanueva, J.; Hernández-Tiedra, S.; Lorente, M.; Egia, A.; Vázquez, P.; Blázquez, C.; Torres, S.; García, S.; et al. Cannabinoid action induces autophagy-mediated cell death through stimulation of ER stress in human glioma cells. J. Clin. Investig. 2009, 119, 1359–1372. [Google Scholar] [CrossRef] [Green Version]
  144. Nabissi, M.; Morelli, M.B.; Offidani, M.; Amantini, C.; Gentili, S.; Soriani, A.; Cardinali, C.; Leoni, P.; Santoni, G. Cannabinoids synergize with carfilzomib, reducing multiple myeloma cells viability and migration. Oncotarget 2016, 7, 77543–77557. [Google Scholar] [CrossRef] [Green Version]
  145. Donald, P.J. Marijuana Smoking—Possible Cause of Head and Neck Carcinoma in Young Patients. Otolaryngol. Neck Surg. 1986, 94, 517–521. [Google Scholar] [CrossRef] [PubMed]
  146. 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. 2004, 64, 4049–4054. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  147. Marks, M.A.; Chaturvedi, A.K.; Kelsey, K.; Straif, K.; Berthiller, J.; Schwartz, S.; Smith, E.; Wyss, A.; Brennan, P.; Olshan, A.F.; et al. Association of Marijuana Smoking with Oropharyngeal and Oral Tongue Cancers: Pooled Analysis from the INHANCE Consortium. Cancer Epidemiol. Biomark. Prev. 2013, 23, 160–171. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  148. Llewellyn, C.; Linklater, K.; Bell, J.; Johnson, N.; Warnakulasuriya, S. An analysis of risk factors for oral cancer in young people: A case-control study. Oral. Oncol. 2004, 40, 304–313. [Google Scholar] [CrossRef] [PubMed]
  149. Llewellyn, C.; Linklater, K.; Bell, J.; Johnson, N.; Warnakulasuriya, K. Squamous cell carcinoma of the oral cavity in patients aged 45 years and under: A descriptive analysis of 116 cases diagnosed in the South East of England from 1990 to 1997. Oral. Oncol. 2003, 39, 106–114. [Google Scholar] [CrossRef]
  150. McConnell, W.R.; Dewey, W.L.; Harris, L.S.; Borzelleca, J.F. A study of the effect of delta 9-tetrahydrocannabinol (delta 9-THC) on mammalian salivary flow. J. Pharmacol. Exp. Ther. 1978, 206, 567–573. [Google Scholar]
  151. Lopez, R.; Baelum, V. Cannabis use and destructive periodontal diseases among adolescents. J. Clin. Periodontol. 2009, 36, 185–189. [Google Scholar] [CrossRef]
  152. Rees, T.D. Oral Effects of Drug Abuse. Crit. Rev. Oral Biol. Med. 1992, 3, 163–184. [Google Scholar] [CrossRef] [PubMed]
  153. Hashibe, M.; Ford, D.E.; Zhang, Z.-F. Marijuana Smoking and Head and Neck Cancer. J. Clin. Pharmacol. 2002, 42, 103S–107S. [Google Scholar] [CrossRef]
  154. Cuba, L.F.; Salum, F.G.; Cherubini, K.; Figueiredo, M.A.Z. Cannabidiol: An alternative therapeutic agent for oral mucositis? J. Clin. Pharm. Ther. 2017, 42, 245–250. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  155. Holdcroft, A.; Maze, M.; Doré, C.; Tebbs, S.; Thompson, S. A Multicenter Dose-escalation Study of the Analgesic and Adverse Effects of an Oral Cannabis Extract (Cannador) for Postoperative Pain Management. Anesthesiology 2006, 104, 1040–1046. [Google Scholar] [CrossRef] [PubMed]
  156. Romero-Sandoval, E.A.; Fincham, J.E.; Kolano, A.L.; Sharpe, B.N.; Alvarado-Vázquez, P.A. Cannabis for Chronic Pain: Challenges and Considerations. Pharmacother. J. Hum. Pharmacol. Drug Ther. 2018, 38, 651–662. [Google Scholar] [CrossRef]
Figure 1. Summary of the main cannabinoids selective for CB1 and CB2 receptors.
Figure 1. Summary of the main cannabinoids selective for CB1 and CB2 receptors.
Ijms 22 08329 g001
Figure 2. Summary of the signaling pathways associated with cannabinoid administration.
Figure 2. Summary of the signaling pathways associated with cannabinoid administration.
Ijms 22 08329 g002
Figure 3. Salivary glands’ acini and ducts activity associated with cannabinoid administration.
Figure 3. Salivary glands’ acini and ducts activity associated with cannabinoid administration.
Ijms 22 08329 g003
Figure 4. PRISMA flowchart of the article screening and inclusion for the qualitative synthesis [128].
Figure 4. PRISMA flowchart of the article screening and inclusion for the qualitative synthesis [128].
Ijms 22 08329 g004
Figure 5. Oral pathologies and disease involved with cannabinoid exposure and abuse.
Figure 5. Oral pathologies and disease involved with cannabinoid exposure and abuse.
Ijms 22 08329 g005
Table 1. PICO questions explication.
Table 1. PICO questions explication.
PICO
Population\PatientsInterventionComparisonOutcomes
Patient group of interest?What is the main intervention you wish to consider?Is there an alternative intervention to compare?What is the clinical outcome?
Patients that need treatment for dry mouth/caries/periodontal diseases/oral hygiene/oral cancer/oral tissue diseasesTreatment protocol with cannabinoids derived adjuvantsTreatment protocol without cannabinoids derived adjuvantsCan this cannabinoid derived adjuvant provide an higher effectiveness for dry mouth/caries/periodontal diseases/oral hygiene/oral cancer/oral tissue diseases
Table 2. Electronic database Boolean search: keyword strategy.
Table 2. Electronic database Boolean search: keyword strategy.
Search Strategies
Keywords:Advanced search: (cannabinoids AND dry mouth); (cannabinoids AND caries); (cannabinoids AND periodontal diseases); (cannabinoids AND oral hygiene); (cannabinoids AND oral cancer); (cannabinoids AND oral tissue diseases);
DatabasesPubMed/Medline, EMBASE
Table 3. Summary of the studies included according to the cannabinoids and dry mouth.
Table 3. Summary of the studies included according to the cannabinoids and dry mouth.
Cannabinoids and Dry Mouth
AuthorsDrugStudy DesignExperimental ModelAdministration ProtocolResultsTestControlSubjects/SpecimensStudy Time
Darling et al. [129]smokeCross-sectional studyoral tissues health and oral dryness was measured.-nicotinic stomatitiswas reported in four cannabis consumers not tobacco users, Leukoedema and dry mouth was more
evident in cannabis users
cannabis/tobacco/methaqualone smokersControl 1:152 tobacco; Control 2:189 non-smokers300 subjects-
Pirino et al. [88]Dietary supplementsIn vivo on pigsPigs Mandibular glands cannabinoid receptors type 1
(CB1) and cannabinoid receptors type 2 (CB2) expression
Dietary supplements administrationendocannabinoids may
influence the functional activity of the mandibular gland modifying qualitative and/
or quantitative activity and CB1 CB2 receptors expression of salivary duct and secretion.
finely ground pellet
(FP), coarsely ground meal (CM), coarsely ground pellet (CP) and coarsely ground extruded (CE)
-32 samples4 weeks
Prestifilippo et al. [89]Right femoral vein administrationIn vitro study/In vivo on ratsSalivary glands histological evaluation/Ducts cell gene expressionIn vivo Salivary Secretion evaluation. In vitro: genes expressionsAEA
decreases saliva secretion in the SMG-acting through CB1 and
CB2 receptors.
anandamide (AEA), forskolin (FRSK), NE-HCl, Chloralose and methacholine (MC)No treatment40 samples3 min, 10 min
Prestifilippo et al. [92]Systemic administration/Intraduct salivary gland administrationIn vitro study/In vivo on ratsSalivary glands histological evaluation/Ducts cell gene expression in the presence of inflammogens (LPS)In vivo Salivary Secretion evaluation. In vitro: genes expressionsendocannabinoids mediate the hyposialia induced by inflammogens
in the SMG and in the brain.
LPS and/or the cannabinoid
receptor antagonist AM251 administration
cannabinoidreceptor antagonist AM251 administration
Table 4. Summary of the studies included according to the cannabinoids and caries lesions.
Table 4. Summary of the studies included according to the cannabinoids and caries lesions.
Cannabinoids and Caries Lesions
AuthorsDrugStudy DesignExperimental ModelAdministration ProtocolResultsTestControlSubjects/SpecimensStudy Time
Grafton et al. [130]Marijuana/Tobacco SmokeCase ReportTooth extraction socket/Dental Caries5 h before the dental treatmentLow patient compliance regarding the cannabis use.--1 subject (29 years old)-
Ditmyer et al. [131]Marijuana/Tobacco SmokeRetrospective cohort studyDental Caries Prevalence Screening High prevalence/severity of dental caries in subjects with tobacco/marijuana administration 66,941 subjects (13–18 years old)8 years
Liu et al. [104]Tetrahydrocannabinol (THC)In vitro studyHuman Periodontal fibroblast (HPLF)Cell culturesTHC promoted periodontal cell adhesion and migration through wound healingTHC 1µMNo treatment-0 h, 3 h, 6 h and 24 h
Table 5. Summary of the studies included according to the cannabinoids and periodontal lesions.
Table 5. Summary of the studies included according to the cannabinoids and periodontal lesions.
Cannabinoids and Periodontal Lesions
AuthorsDrugStudy DesignExperimental ModelAdministration ProtocolResultsTestControlSubjects/SpecimensStudy Time
Kozono et al. [107]EndocannabinoidIn vitro study/In vivo on ratsPeriodontal fibroblasts/periodontal wound healingCell cultureHigher proliferation of human gingival fibroblasts (HGFs) by AEA, that can be
reduced by AM251 and AM630, selective antagonists of CB1 and CB2
anandamide (AEA)/2-arachidonoylglycerol (2-AG)anandamide (AEA)/2-arachidonoylglycerol (2-AG)+ AM251 and AM630, which are selective antagonists of CB1 and CB2,4 specimens0, 3 days, 7 days, 14 days
Thomson et al. [132]Cannabis SmokingProspective cohort studyPeriodontitisCannabis exposureCannabis smoking may be a risk factor for periodontal disease that is
independent of the use of tobacco
1: cannabis some exposure; 2: cannabis high exposure (182; 20.2%).No exposure1037 subjects1 year
Shariff et al. [133]cannabis (marijuana and hashish)Cohort studyPeriodontal examination-Cannabis use was related to with deeper probing depths, more clinical attachment loss and higher odds of having severe periodontitis.Cannabis exposureNon cannabis users1938 subjects1 year
Nogueira-Filho et al. [134]CannabinoidsIn vivo on ratsExperimental periodontitisCannabis exposurecannabis smoke may impact alveolar bone by increasing
bone loss
marijuana smoke inhalationNo exposure30 specimens30 days
Ossola et al. [135]synthetic cannabinoidIn vitro study/In vivo on ratsLipopolysaccharide-Induced Periodontitistopical administration on gingival tissuesanti-inflammatory, osteoprotective and pro-homeostatic effects of HU-308 in oral tissues1: Vehicle; 2: HU-308 (500 ng/mL); 2: LPS/HU-308 (500 ng/mL)No treatment24 specimens45 days
Napimoga et al. [137]Cannabis SmokingIn vivo on ratsLPS Experimental periodontitisVein administrationCannabidiol is related to a lower bone resorption by the inhibition of the RANK/RANKL expression1: vehicle; 2: Cannabidiol (CBD)No treatment30 specimens30 days
Ossola et al. [136]synthetic cannabinoidIn vitro study/In vivo on ratsLipopolysaccharide-Induced Periodontitistopical Meth-AEA
(500 ng/mL)
Beneficial
effects of treatment with Meth-AEA on gingival tissue of rats with periodontitis.
1: synthetic cannabinoid methanandamide (Meth-AEA); 2: LPS/(Meth-AEA); 3: LPSNo treatment24 specimens6 weeks
Abidia et al. [106]CannabinoidIn vitro studyHuman Periodontal fibroblast (HPLF)cannabinoid compounds (10−4–10−6.5 Min cell cultureThe cannabinoids inhibited LPS, TNF-α, IL-1β expression
in hPDLFs though CB2R ligands receptors
cannabinoid (10−4–10−6.5 M) [EC50] -1 h
Lanza Cariccio et al. [108]EndocannabinoidIn vitro studyPeriodontal fibroblastsCells cultureHigher survival capacity and neuronal
differentiation potential of hPDLSCs
treated with Moringin and Cannabidiol
Moringin (MOR)
and Cannabidiol (CBD),
No treatment-24 h, 48 h and 72 h
Nakajima et al. [107]EndocannabinoidIn vitro studyhuman gingival fibroblasts (HGFs)Cells cultureAEA blocked of LPS-triggered NF-jB activation related to hyperinflammatory
response in periodontitis.
Anandamide (AEA)/LPS in different concentrations (0, 1µM, 5µM and 10 µM)--48 h
Table 6. Summary of the studies included according to the cannabinoids and oral and neck cancer.
Table 6. Summary of the studies included according to the cannabinoids and oral and neck cancer.
Cannabinoids and Oral and Neck Cancer
AuthorsDrugStudy DesignExperimental ModelAdministration ProtocolResultsTestControlSubjects/SpecimensStudy Time
Firth et al.Marijuana consumptionLiterature reviewCase report literature overviewSmoking aptitudeThe marijuana mechanisms related to the carcinogen
are not clearly clarified and probably related to, aromatic hydrocarbons, benzo[a]pyrene and
nitrosamines in smoked cannabis
Cannabis consumption/two cases in combination with heavy tobacco use 8 subjects-
Donald et al.Marijuana consumptionCase seriesClinical reportsSmoking aptitudeThe active euphoria-producing agent, 1-9 tetrahydrocannabinol,
has been implicated In altered DNA, RNA, and protein synthesis and consequent
chromosomal aberrations
Cannabis consumption/one cases in combination with heavy tobacco use-6 patients-
Rosenblatt et al.Marijuana consumptioncase–control studyYoung adult populationSmoking aptitude on a large population sampleA similar proportion of case subjects (25.6%) and control subjects
(24.4%) reported ever the use of marijuana
Cannabis consumptionNo tobacco use and no cannabis consumption1022 subjects-
Marks et al.Marijuana consumptionEpidemiological studyINHANCE consortium USA and Latino-America databaseSmoking aptitude on a large population sampleThe associations of marijuana use with oropharyngeal and oral tongue cancer are consistent with
both possible pro- and anticarcinogenic effects of cannabinoids
marijuana smokersNonsmokers9916 subjects
Hashibe et al.Marijuana consumptionCohort studyhigh school students and young adults populationSmoking aptitudemarijuana use was not associated with increased risk of all
cancers or smoking-related cancers.
marijuana smokersNonsmokers64,855 subjects8 years
Llewellyna et al.Marijuana consumptionCohort studyYoung adults <45 years oldSmoking aptitudethe major risk factor for oral cancer was consumption of alcohol or both.
No evidence about marijuana consumption or tobacco
Multifactorial carcinogenic and diet quality analysis-116 subjects7 years
Llewellyna et al.Marijuana consumptionCase control studyIdentification of the majorrisk factors for oral cancer in young adults-fresh fruits and vegetables in the diet appeared to be protective for both males and females. No evidence about marijuana consumption.Multifactorial carcinogenic and diet quality analysis- 7 years
Osazuwa-Peters et al. Literature reviewIdentification of the co-relationship between cannabis consumption and oral cancerSmoking aptitudeInsufficient evidence about the association between head and neck
cancer and marijuana use
marijuana smokersNonsmokers--
Guzman et al.cannabinoids SupplementsLiterature reviewThe cannabinoid derivate as an anticancer agent-Cannabinoids exert palliative effects in
patients with cancer and inhibit tumor growth in laboratory animals.
Cannabinoids in combination with chemotherapeutic
drugs or radiotherapy
---
Nabissi et al.cannabinoids SupplementsIn vitro studymultiplemyeloma cellsCannabinoids/carfilzomib administrationThe Δ9-tetrahydrocannabinol (THC)/cannabidiol (CBD) combination showed strong anti-myeloma activities.Δ9-tetrahydrocannabinol (THC)/Cannabidiol (CBD)- 72 h
Salazar et al.cannabinoids SupplementsIn vitro studyhuman glioma cellsCannabinoids administrationTHC can promote the autophagic death of human and mouse cancer cellsΔ9-tetrahydrocannabinol (THC)--10 days
Grimaldi et al.cannabinoids SupplementsIn vitro studybreast cancer cellsCannabinoids administrationThe cannabinoids showed a slowed down growth of breast carcinoma and inhibited its metastatic diffusionAnandamide (AEA)Control no treatment-21 days
Preet et al.cannabinoids SupplementsIn vitro studylung cancer cell/in vivo on miceCannabinoids administrationtherapeutic use of
THC for the treatment of aggressive and chemotherapy-resistant variants of
lung cancers.
Δ9-tetrahydrocannabinol (THC) 6 samples21 days
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Bellocchio, L.; Inchingolo, A.D.; Inchingolo, A.M.; Lorusso, F.; Malcangi, G.; Santacroce, L.; Scarano, A.; Bordea, I.R.; Hazballa, D.; D’Oria, M.T.; et al. Cannabinoids Drugs and Oral Health—From Recreational Side-Effects to Medicinal Purposes: A Systematic Review. Int. J. Mol. Sci. 2021, 22, 8329. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22158329

AMA Style

Bellocchio L, Inchingolo AD, Inchingolo AM, Lorusso F, Malcangi G, Santacroce L, Scarano A, Bordea IR, Hazballa D, D’Oria MT, et al. Cannabinoids Drugs and Oral Health—From Recreational Side-Effects to Medicinal Purposes: A Systematic Review. International Journal of Molecular Sciences. 2021; 22(15):8329. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22158329

Chicago/Turabian Style

Bellocchio, Luigi, Alessio Danilo Inchingolo, Angelo Michele Inchingolo, Felice Lorusso, Giuseppina Malcangi, Luigi Santacroce, Antonio Scarano, Ioana Roxana Bordea, Denisa Hazballa, Maria Teresa D’Oria, and et al. 2021. "Cannabinoids Drugs and Oral Health—From Recreational Side-Effects to Medicinal Purposes: A Systematic Review" International Journal of Molecular Sciences 22, no. 15: 8329. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22158329

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop