The Potential of Cannabidiol in the Management of Oral Infections

Abstract

Oral infections, caused by bacterial, fungal, and viral pathogens, are a significant source of dental morbidity and can lead to systemic complications, especially in immunocompromised individuals. Complex microbial interactions and host immune responses drive common conditions such as dental caries, periodontal disease, oral candidiasis, and herpetic lesions. Conventional antimicrobial therapies face limitations due to resistance and adverse effects, prompting interest in alternative treatments. Cannabidiol (CBD), a non-psychoactive compound derived from Cannabis sativa, has emerged as a promising candidate due to its antimicrobial, anti-inflammatory, and immunomodulatory properties. CBD targets various molecular pathways, including cannabinoid receptors, TRP channels, adenosine receptors, and PPARs, contributing to its multifaceted therapeutic effects. It has demonstrated efficacy against oral pathogens such as Streptococcus mutans, Enterococcus faecalis, and Candida albicans, disrupting biofilms and bacterial membranes. Additionally, CBD modulates inflammatory responses by reducing cytokine production and oxidative stress, particularly relevant in chronic conditions like periodontal disease. Emerging evidence also suggests synergistic effects with conventional antimicrobials and benefits in tissue regeneration. This review highlights the therapeutic potential of CBD in managing oral infections, offering a novel approach to overcoming current treatment limitations and guiding future research into safer and more effective oral health interventions.

1. Introduction

1.1. Oral Infections

Oral infections encompass a range of diseases primarily caused by bacterial, fungal, and viral pathogens affecting the hard and soft tissues of the oral cavity. These infections are not only a major cause of dental morbidity but also serve as potential sources of systemic complications, particularly in immunocompromised individuals. The most prevalent oral infections include dental caries, periodontal disease, oral candidiasis, and herpetic lesions. Each condition presents distinct pathophysiological mechanisms, microbial profiles, and clinical manifestations [1,2].

Dental caries is a chronic, multifactorial disease characterized by the demineralization of tooth enamel due to acid production by cariogenic bacteria. Streptococcus mutans is the principal pathogen, capable of metabolizing dietary sugars to produce lactic acid, leading to localized pH reduction and enamel breakdown. If untreated, caries can progress to involve dentin and pulp tissues, causing pulpitis and periapical infections [3]. Periodontal disease encompasses gingivitis and periodontitis, which involve inflammation and destruction of the supporting structures of teeth [4]. Gingivitis, the milder form, is reversible and primarily associated with plaque accumulation. Periodontitis is a more severe condition characterized by periodontal pocket formation, alveolar bone loss, and eventual tooth mobility or loss. The disease is driven by dysbiotic oral microbiota, including Porphyromonas gingivalis, Tannerella forsythia, and Treponema denticola, along with a heightened host immune response that contributes to tissue damage [5]. Oral candidiasis, commonly known as oral thrush, is a fungal infection predominantly caused by Candida albicans. This opportunistic pathogen can shift from a commensal to a pathogenic state under certain conditions, such as immunosuppression, xerostomia, antibiotic use, or poor oral hygiene. Clinically, it presents in various forms, including pseudomembranous (white plaques), erythematous (red, inflamed areas), and hyperplastic lesions. Denture-related stomatitis is a frequent manifestation in elderly populations [6]. Herpes simplex virus type 1 (HSV-1) is responsible for primary herpetic gingivostomatitis and recurrent herpes labialis (cold sores). Primary infection often occurs in childhood and may be asymptomatic or present with painful ulcers, fever, and lymphadenopathy. After primary infection, HSV-1 remains latent in the trigeminal ganglion and may reactivate under stress, illness, or immune suppression. Herpetic lesions are highly contagious and can complicate oral health, especially in immunocompromised patients [7].

In immunocompromised individuals, such as those with HIV/AIDS, undergoing chemotherapy, or post-transplant patients, other pathogens, including Aspergillus, Histoplasma, cytomegalovirus, and Epstein–Barr virus, may cause oral lesions. Additionally, necrotizing ulcerative gingivitis (NUG) and necrotizing ulcerative periodontitis (NUP) are aggressive infections linked to anaerobic bacteria and immune dysfunction [8].

Oral infections, particularly those of odontogenic origin, have the potential to extend beyond the local site and disseminate through the complex network of fascial planes in the head and neck region. In severe cases, these infections can spread from the skull base down to the mediastinum, leading to deep neck space infections and life-threatening complications such as descending necrotizing mediastinitis. This progression is often facilitated by anatomical continuity between fascial spaces and can be exacerbated by delayed diagnosis, inappropriate treatment, or host factors such as immunosuppression. Immunocompromised patients are especially vulnerable, as their reduced ability to contain infection increases the risk of systemic spread, sepsis, and mortality. Therefore, oral infections should not be viewed as benign or self-limiting conditions, and their potential for rapid and severe progression underscores the need for timely, effective, and evidence-based management strategies [9].

1.2. Management of Oral Infections

Despite the pivotal role of antimicrobial agents in the management of infectious diseases, including those of the oral cavity, several significant limitations undermine their long-term effectiveness and clinical utility. These challenges span from microbial resistance and limited spectrum of action to adverse effects and impacts on host microbiota. Understanding these limitations is crucial for the development of novel therapeutic approaches, including alternative and adjunctive treatments such as plant-derived compounds and cannabinoids. The most pressing limitation of conventional antimicrobial therapies is the global rise in antimicrobial resistance (AMR) [10]. The overuse and misuse of antibiotics in both medical and dental settings have accelerated the evolution of resistant strains of pathogenic bacteria [11]. In oral health, resistance among organisms such as Streptococcus mutans, Porphyromonas gingivalis, and Aggregatibacter actinomycetemcomitans has been increasingly reported. The emergence of biofilm-associated resistance further complicates treatment, as microorganisms within biofilms exhibit up to 1000-fold greater resistance to antibiotics compared to their planktonic counterparts. This makes standard doses ineffective, necessitating higher concentrations that may not be clinically feasible or safe [12,13,14].

Moreover, many antimicrobial agents exhibit a narrow spectrum of activity, which may not be adequate for polymicrobial infections commonly seen in periodontal disease and other oral conditions. This often leads to incomplete eradication of pathogens, contributing to recurrent infections and chronic inflammation. Furthermore, some antimicrobials may not effectively penetrate infected tissues or biofilms, reducing their therapeutic efficacy [12,13,14]. Systemic antimicrobial therapies can be associated with a range of adverse effects, from mild gastrointestinal disturbances to severe allergic reactions and organ toxicity. Topical agents, while often better tolerated, may still cause local irritation, mucosal desquamation, or alterations in taste. The risk-to-benefit ratio becomes particularly unfavorable in cases where antimicrobial use is prolonged or prophylactic [10,15].

Antimicrobial agents, especially broad-spectrum antibiotics and antiseptics, can disrupt the balance of the commensal oral microbiota. This dysbiosis may predispose patients to opportunistic infections, such as oral candidiasis, and may impair the natural protective functions of the native microbial community. Maintaining microbial homeostasis is essential for oral and systemic health, and indiscriminate antimicrobial use poses a significant threat to this equilibrium. Poor adherence to prescribed antimicrobial regimens, whether due to complex dosing schedules, side effects, or misunderstanding of instructions, can contribute to subtherapeutic drug levels and the selection of resistant strains. This is particularly relevant in dentistry, where short-term prescriptions are common and often inadequately supervised [16]. Also, the pharmaceutical pipeline for new antimicrobial agents has slowed considerably in recent decades. Most new drugs are modifications of existing compounds rather than new classes, offering limited advantages in circumventing existing resistance mechanisms. As a result, clinicians often rely on a shrinking pool of effective therapies, increasing the urgency for alternative strategies. In summary, while antimicrobial therapies remain a cornerstone in the treatment of oral and systemic infections, their growing limitations highlight the need for novel, more targeted, and safer therapeutic options [10]. Adjunctive therapies, including phytochemicals, probiotics, and cannabinoids such as CBD, are under increasing investigation for their potential to address these gaps in treatment [17].

The search for novel therapeutic agents to address the limitations of conventional antimicrobial therapies has led to increased scientific interest in phytochemicals, particularly cannabinoids. Among these, CBD, a non-psychoactive compound derived from Cannabis sativa, has gained attention for its broad-spectrum antimicrobial, anti-inflammatory, and immunomodulatory properties. While historically studied for its neuroprotective and anxiolytic effects, recent preclinical and in vitro studies have highlighted CBD’s potential as a therapeutic compound in preventing and treating oral infections [18,19].

CBD interacts with multiple molecular targets, including cannabinoid receptors (CB1, CB2), transient receptor potential (TRP) channels, adenosine receptors, and peroxisome proliferator-activated receptors (PPARs). These interactions contribute to its anti-inflammatory, analgesic, and antimicrobial activities, making it a promising candidate for managing oral cavity infections, where inflammation and polymicrobial biofilms play central roles. Emerging evidence suggests that CBD exhibits direct antimicrobial effects against a range of Gram-positive bacteria, including Streptococcus mutans, a key contributor to dental caries [20,21,22], and Enterococcus faecalis, commonly associated with endodontic failures [19]. Studies have demonstrated that CBD disrupts bacterial membrane integrity, leading to cell lysis, and can inhibit biofilm formation, a critical component of oral pathogenicity [23]. Moreover, CBD has shown activity against fungal pathogens such as Candida albicans, suggesting potential for use in oral candidiasis [19,24]. Oral infections are characterized not only by microbial invasion but also by a dysregulated host immune response [25]. CBD modulates key inflammatory pathways by reducing the production of pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6. It also appears to suppress reactive oxygen species (ROS) production and inhibit NF-κB signaling, thereby limiting tissue destruction and promoting the resolution of inflammation. These effects are particularly relevant in periodontal disease, where chronic inflammation leads to progressive bone and soft tissue loss [26].

“Clinical antimicrobials” will be used throughout to specifically denote antimicrobial agents that are employed in clinical settings for the treatment of human infections. This usage is intended to distinguish such therapeutically applied substances from the broader category of antimicrobials, including any chemical, natural, or synthetic agent that acts against microorganisms, regardless of context or application. This terminology aims to avoid ambiguity and clearly differentiate the substances used in medical practice from those used in non-clinical settings such as agriculture, industry, or disinfection. In that sense, studies suggest that CBD may act synergistically with clinical antimicrobials, potentially enhancing their efficacy and reducing the required dose. This could be advantageous in combating antimicrobial-resistant strains and minimizing the adverse effects associated with high-dose antibiotic use. Additionally, its incorporation into topical formulations such as mouthwashes, gels, or slow-release strips could provide localized, sustained delivery in the oral cavity [21]. CBD also shows benefits for bone and soft tissue regeneration following oral infections.

This review aims to explore the potential of CBD, which exhibits promising antimicrobial, anti-inflammatory, and immunomodulatory properties in oral infections. By integrating recent preclinical findings, the review assesses CBD’s role in modulating oral microbiota, inhibiting biofilm formation, and alleviating inflammation, offering a novel perspective on adjunctive therapy for oral infections. Ultimately, this review aims to bridge current therapeutic gaps and inform future research directions in the development of safer, more effective treatments for oral infectious diseases.

In Figure 1, the main applications of CBD and its synthetic analogues in dentistry are shown.

2. Chemical and Pharmacological Aspects of Cannabidiol

CBD, whose chemical structure is represented in Figure 2, is a major non-psychoactive phytocannabinoid derived from the plant Cannabis sativa L. First isolated in 1940, CBD has garnered increasing scientific attention for its wide-ranging therapeutic properties, including anti-inflammatory, analgesic, anxiolytic, antioxidant, and antimicrobial effects. Unlike delta-9-tetrahydrocannabinol (THC), the principal psychoactive component of cannabis, CBD does not induce intoxication and has a favorable safety profile, making it a promising candidate for various clinical applications [27].

CBD is a terpenophenolic compound with the molecular formula C₂₁H₃₀O₂ and a molecular weight of 314.46 g/mol. Structurally, it is a bicyclic compound featuring a resorcinol moiety and a pentyl side chain. In the cannabis plant, CBD is synthesized from cannabigerolic acid (CBGA) through the action of CBD synthase, resulting in cannabidiolic acid (CBDA), which is subsequently decarboxylated to CBD via heat or light exposure. CBD exerts its biological effects through complex interactions with multiple molecular targets, as follows: (i) Cannabinoid Receptors: CBD has low affinity for the classical cannabinoid receptors CB1 and CB2, but modulates their activity indirectly. It acts as a negative allosteric modulator of CB1, potentially reducing the psychoactive effects of THC, and may exert partial agonistic or antagonistic actions at CB2. (ii) Transient Receptor Potential (TRP) Channels: CBD activates the TRPV1, TRPV2, and TRPA1 channels, which are involved in pain perception, inflammation, and thermoregulation. (iii) Serotonin Receptors: it acts as a partial agonist at the 5-HT1A receptor, contributing to its anxiolytic and neuroprotective properties. (iv) PPARγ Activation: CBD activates peroxisome proliferator-activated receptor gamma (PPARγ), influencing inflammatory and metabolic pathways. (v) Adenosine Signaling: CBD inhibits adenosine reuptake, leading to increased adenosine signaling and associated anti-inflammatory and cardioprotective effects [27].

CBD displays broad-spectrum antimicrobial activity, particularly against Gram-positive bacteria, and has shown efficacy in disrupting biofilms, which are a major virulence factor in many oral and systemic infections [24,28].

The lipophilic structure of CBD enables its integration into microbial membranes, where it causes structural disruption and increased membrane permeability (membrane disruption). This leads to the leakage of cellular contents, impaired membrane potential, and ultimately, cell death. Electron microscopy studies have revealed morphological damage in bacterial membranes treated with CBD, supporting this mechanism [29].

Biofilms are dense microbial communities that confer resistance to antibiotics and host defenses. CBD has been shown to inhibit biofilm formation and reduce established biofilms, particularly in oral pathogens such as Streptococcus mutans and Enterococcus faecalis. This anti-biofilm effect may be attributed to CBD’s interference with quorum sensing pathways and extracellular polymeric substance (EPS) production [19,24,28].

CBD has been shown to enhance the efficacy of conventional clinical antibiotics in some settings, potentially through synergistic interactions that facilitate greater microbial susceptibility. For example, CBD has been reported to potentiate the effects of antibiotics like bacitracin and erythromycin, possibly by facilitating antibiotic entry into bacterial cells or by disrupting resistance mechanisms [30]. CBD also exhibits antifungal activity, although this has been less extensively studied against Candida albicans and related species, likely via similar membrane-disruptive mechanisms [24]. Some evidence suggests antiviral effects, although these remain to be fully elucidated in oral contexts [31].

CBD’s anti-inflammatory effects arise from its ability to modulate both innate and adaptive immune responses, particularly in tissues affected by chronic or acute inflammation, such as the oral mucosa and periodontium. CBD reduces the expression and secretion of key pro-inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and interleukin-6 (IL-6). This occurs through the downregulation of transcription factors such as NF-κB and AP-1, which are central regulators of inflammation. In inflamed tissues, the excessive production of ROS contributes to cellular damage and perpetuates the inflammatory response. CBD exhibits antioxidant properties, reducing ROS levels and oxidative stress in immune and epithelial cells, thereby helping to preserve tissue integrity. CBD influences various immune cells involved in inflammation, including macrophages, neutrophils, and T cells. It has been shown to suppress macrophage activation, reduce neutrophil recruitment, and promote a shift from pro-inflammatory M1 to anti-inflammatory M2 macrophage phenotypes. Additionally, CBD may induce regulatory T cell activity, contributing to immune homeostasis. CBD’s interaction with TRPV1 and adenosine A2A receptors further contributes to its anti-inflammatory effects. TRPV1 activation has been linked to reduced nociceptive signaling and inflammation, while adenosine receptor engagement leads to immunosuppressive and tissue-protective effects [32,33].

3. Overview of Pharmacokinetics Relevant to Oral Tissues

While the systemic pharmacokinetics of CBD have been studied in various formulations and routes of administration, its behavior within the oral cavity, including absorption, distribution, metabolism, and elimination (ADME), requires special consideration due to the unique anatomy and physiology of oral tissues [34,35].

CBD can be administered via multiple routes, including oral ingestion, sublingual application, buccal sprays, and topical formulations. Among these, sublingual and buccal delivery systems are of particular relevance for oral health applications, as they allow direct absorption into the oral mucosa, bypassing first-pass metabolism in the liver and improving systemic bioavailability [36]. In sublingual administration, CBD is placed under the tongue and absorbed through the highly vascularized mucosa. The onset of action typically occurs within 15–45 min, with bioavailability ranging from 13% to 35%, depending on the formulation and individual variability [37]. Buccal absorption offers a slower but sustained route through the inner cheek, which can be advantageous for prolonged local exposure to oral tissues, especially in the management of localized infections or inflammation. These mucosal routes allow CBD to reach oral tissues directly, potentially achieving higher local concentrations compared to systemic administration [38].

Due to its lipophilic nature, CBD readily diffuses through cell membranes once absorbed and accumulates in lipid-rich tissues. Studies suggest that following mucosal absorption, CBD may distribute effectively to the gingival epithelium, periodontal ligament, and alveolar bone, where it can exert antimicrobial and anti-inflammatory effects. In periodontal disease, where tissue penetration and modulation of the host immune response are critical, localized delivery systems (e.g., CBD-loaded gels or nanoparticles) may further enhance tissue-specific bioavailability and therapeutic efficacy [39,40].

While hepatic metabolism (via CYP450 enzymes) is dominant in systemic CBD processing, enzymatic activity in the oral cavity may contribute to local metabolism. Salivary enzymes, along with microbial enzymes in the oral microbiota, can potentially alter CBD structure or activity before systemic absorption. However, the extent and clinical relevance of these local metabolic transformations remain underexplored [41]. CBD and its metabolites are ultimately eliminated through urine and feces after systemic absorption. However, in oral applications, particularly topical or intraoral slow-release systems, CBD may remain in contact with mucosal surfaces or within biofilms for extended periods, enhancing local retention and efficacy. Salivary flow, pH, and formulation viscosity are key factors influencing residence time. Formulations such as mucoadhesive films, mouth rinses, or biodegradable inserts are being explored to maximize retention and minimize washout by saliva or swallowing [27].

Given its pharmacokinetic profile, CBD offers several advantages for oral health applications, as follows: (i) rapid onset and localized action via sublingual or buccal routes; (ii) bypassing first-pass metabolism, improving systemic and local bioavailability; and (iii) potential for site-specific delivery in periodontal pockets or mucosal lesions. Novel delivery systems such as CBD-infused dental gels, mucoadhesive patches, nanocarriers, and biodegradable strips are being investigated to optimize both pharmacokinetic properties and therapeutic outcomes in oral health [38].

4. Antimicrobial Properties of Cannabidiol

4.1. In Vitro Evidence

One of the most studied targets of CBD in oral microbiology is Streptococcus mutans, the primary etiological agent in dental caries. In vitro experiments have shown that CBD can significantly reduce the growth and metabolic activity of S. mutans, including its ability to form biofilms and produce acid, both of which are critical to cariogenicity [20,38,42]. CBD appears to disrupt bacterial membrane integrity and inhibit quorum sensing pathways, thereby reducing bacterial communication and biofilm formation. Other in vitro studies have demonstrated that CBD can reduce established S. mutans biofilms and prevent their formation on hydroxyapatite-coated and enamel-analogous surfaces [20,21].

CBD has also exhibited inhibitory effects against several Gram-negative anaerobic bacteria involved in periodontal disease, including Porphyromonas gingivalis, Aggregatibacter actinomycetemcomitans, and Fusobacterium nucleatum. These pathogens are noted for their resistance to conventional antibiotics and their role in chronic inflammation and tissue destruction [43,44].

In vitro MIC and MBC values for CBD against these species fall within therapeutically relevant ranges, with some studies reporting minimum inhibitory concentrations comparable to chlorhexidine [45]. CBD has also been shown to attenuate lipopolysaccharide (LPS)-induced inflammatory responses in human gingival fibroblasts, suggesting both direct and indirect therapeutic benefits in periodontal disease [46].

Endodontic infections, particularly those involving Enterococcus faecalis, present significant treatment challenges due to biofilm formation and antibiotic resistance. In vitro models have demonstrated that CBD exhibits antimicrobial activity against E. faecalis, with the potential to enhance root canal disinfection. CBD’s ability to disrupt biofilms within dentinal tubules and reduce viable bacterial counts suggests potential use as an adjunct in root canal irrigants or intracanal medicaments [12,19,47].

CBD has also been shown to inhibit the growth of fungal pathogens, particularly Candida albicans, which is commonly associated with denture stomatitis and oral candidiasis. In vitro assays reveal that CBD reduces fungal cell viability, inhibits hyphal transformation, and disrupts biofilm integrity. CBD treatment reduces Candida biofilm adhesion to acrylic surfaces, indicating potential utility in preventing prosthesis-associated infections [24,48].

Preliminary studies suggest that CBD may act synergistically with clinical antimicrobials, such as bacitracin or erythromycin, potentially enhancing their efficacy and overcoming bacterial resistance [49]. Moreover, repeated exposure to sub-inhibitory concentrations of CBD has not been associated with significant microbial resistance, a promising feature for long-term use in oral care products [50].

4.2. Anti-Inflammatory Effects in Oral Infection Models

Preclinical evidence from in vitro and in vivo oral infection models supports its potential as an adjunctive treatment in managing inflammation-associated oral pathologies [51].

CBD has been shown to significantly downregulate pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and interleukin-6 (IL-6) in human gingival fibroblasts (HGFs) and periodontal ligament (PDL) cells exposed to bacterial components like Porphyromonas gingivalis lipopolysaccharide (LPS) [52]. The proposed mechanism is that CBD suppresses the nuclear translocation of nuclear factor-kappa B (NF-κB), a key transcription factor in the inflammatory cascade, thereby reducing cytokine gene expression and inflammatory mediator release. In LPS-stimulated HGFs, CBD treatment led to a significant reduction in IL-6 and prostaglandin E2 (PGE2) levels, indicating a dampened inflammatory response [53].

Reactive oxygen species (ROS) are key contributors to inflammation-induced tissue damage in oral infections. CBD has demonstrated antioxidant activity by reducing ROS production and enhancing the expression of endogenous antioxidant enzymes, such as superoxide dismutase (SOD) and glutathione peroxidase (GPx), in inflamed oral tissues [54]. In vitro models of oxidative stress in oral epithelial cells show that CBD attenuates ROS levels following bacterial or inflammatory stimulation, suggesting a protective role in oral mucosal and periodontal health [38,51].

CBD exerts immunomodulatory effects by influencing the behavior of key immune cells involved in oral inflammation, including macrophages, neutrophils, and T cells. CBD reduces the expression of inducible nitric oxide synthase (iNOS) and the production of nitric oxide (NO) in activated macrophages, favoring a shift from the pro-inflammatory M1 to the anti-inflammatory M2 phenotype. CBD has been shown to decrease Th1/Th17-mediated responses while promoting regulatory T cell activity, which could contribute to immune homeostasis in chronic inflammatory settings such as periodontitis [55].

Animal studies provide further evidence for CBD’s anti-inflammatory role in oral tissues. In rat models of ligature-induced periodontitis, the topical or systemic administration of CBD reduced inflammatory infiltrates, lowered cytokine expression in gingival tissues, and preserved alveolar bone levels compared to untreated controls. Histological analysis of periodontal tissues revealed decreased inflammatory cell infiltration and collagen degradation in CBD-treated groups. Similar anti-inflammatory effects have been observed in peri-implant mucositis models, where CBD treatment reduced peri-implant inflammatory markers and improved soft tissue healing [38,56].

Given its non-psychoactive profile, minimal toxicity, and broad anti-inflammatory effects, CBD represents a promising adjunct in the treatment of oral inflammatory diseases. Delivery strategies currently under exploration include CBD-infused mouth rinses, topical gels, periodontal films, and biodegradable microspheres for targeted drug release into inflamed periodontal sites with potential for clinical translation.

4.3. Preclinical and Clinical Studies

The therapeutic application of CBD in oral infections has garnered increasing interest, supported by a growing body of preclinical research. These studies have evaluated CBD’s efficacy in reducing microbial burden, alleviating pain, and modulating inflammatory responses. Although promising, the current findings are derived from diverse models, ranging from in vitro and ex vivo tissue cultures to animal experiments and preliminary human trials, each contributing distinct insights into CBD’s potential as an adjunctive treatment in dentistry.

Rodent models of oral disease, particularly ligature-induced periodontitis and oral mucositis, have been widely used to assess CBD’s therapeutic impact [57]. Periodontitis models in rats demonstrated that both systemic and local CBD administration reduced inflammatory infiltrates, decreased alveolar bone loss, and downregulated pro-inflammatory cytokines such as IL-1β and TNF-α. Bone preservation was confirmed by micro-CT and histological analyses [56,57].

CBD has been tested on human gingival fibroblasts (HGFs), periodontal ligament cells, and oral epithelial cells, often stimulated with Porphyromonas gingivalis LPS or pro-inflammatory cytokines. The outcomes consistently show reduced expression of COX-2, IL-6, IL-8, and MMPs after CBD treatment. In ex vivo models using extracted human gingival tissue, topical CBD application reduced inflammatory cytokine release and preserved epithelial integrity [52].

Clinical data remain limited; few studies mainly focus on the following: (i) Topical CBD in Oral Pain and Inflammation: a randomized controlled trial (RCT) reported that topical CBD oil applied to aphthous ulcers resulted in reduced pain intensity and faster healing compared to placebo [58]. (ii) CBD Mouthwash: pilot studies evaluating CBD-infused oral rinses demonstrated significant reductions in plaque indices and gingival inflammation, with efficacy comparable to chlorhexidine and fewer side effects [45,59]. (iii) Systemic CBD in Mucositis: a case series in oncology patients undergoing chemotherapy suggested that systemic CBD could reduce the severity and duration of oral mucositis, although larger trials are needed [60].

CBD treatment across various models has yielded consistent therapeutic outcomes, as follows: (i) Infection reduction and antibacterial and antifungal effects were observed in vitro and in vivo, especially against S. mutans, E. faecalis, and Candida albicans. While few human studies directly quantify pathogen load, plaque and biofilm reduction has been noted [19,20,28,43]. (ii) Pain relief: both animal models and small clinical trials suggest analgesic effects, attributed to CBD’s interaction with TRPV1 and adenosine receptors, reducing nociceptive signaling and peripheral sensitization [61,62]. (iii) Reduction in inflammatory markers: CBD downregulated key inflammatory mediators, including TNF-α, IL-1β, IL-6, and COX-2, while also modulating oxidative stress markers such as nitric oxide and ROS [55].

Table 1. CBD effect in different oral infections.

	Target Pathogen/Condition	Mechanism/Details	References
In vitro evidence	Streptococcus mutans (Dental caries)	Inhibits growth, acid production, and biofilm formation. Disrupts membrane integrity; inhibits quorum sensing; prevents biofilm on hydroxyapatite and enamel-like surfaces.	[20,21,38,42]
	Porphyromonas gingivalis, Aggregatibacter actinomycetemcomitans, Fusobacterium nucleatum (Periodontal pathogens)	Inhibits growth and biofilm formation. MIC and MBC values comparable to chlorhexidine; attenuates LPS-induced inflammation in gingival fibroblasts.	[43,44,45,46]
	Enterococcus faecalis (Endodontic infections)	Reduces biofilms and viable counts in dentinal tubules. Enhances root canal disinfection; potential use in irrigants or intracanal medicaments.	[12,19,47]
	Candida albicans (Oral candidiasis)	Reduces viability, hyphal transformation, and biofilm integrity. Reduces adhesion to acrylic surfaces; potential against denture stomatitis and oral candidiasis.	[24,48]
	Antimicrobial Resistance (general)	Synergistic effects with antibiotics (e.g., bacitracin, erythromycin); does not induce resistance.	[49,50]
Anti-Inflammatory Effects in Oral Infection Models	Inflammation in oral cells (HGFs, PDLs)	Reduces TNF-α, IL-1β, IL-6, PGE2. Inhibits NF-κB translocation and cytokine gene expression.	[52,53]
	Oxidative Stress	Decreases ROS; increases SOD and GPx expression. Antioxidant action in oral epithelial cells.	[38,51,54]
	Immune Modulation	Reduces iNOS and NO; shifts macrophages to M2 phenotype. Suppresses pro-inflammatory immune responses.	[55]
Animal/ Preclinical Studies	Periodontitis, Mucositis	Reduces inflammation, cytokines (IL-1β, TNF-α), and preserves bone and tissue. Systemic and topical CBD effective; confirmed by micro-CT and histology.	[38,56,57]
Clinical Studies	Aphthous Ulcers	Reduces pain and accelerates healing. Topical CBD application in RCT.	[58]
	CBD Mouthwash	Reduces plaque and gingival inflammation. Comparable to chlorhexidine, fewer side effects.	[45,59]
	Mucositis (Oncology)	Decreases severity and duration of oral mucositis. Case series in chemotherapy patients.	[60]
	Pain Relief	Analgesic effects via TRPV1 and adenosine receptors. Reduces nociceptive signaling and peripheral sensitization.	[61,62]

summarizes the effects of CBD in several studies on oral infections.

5. CBD Delivery Methods for Oral Infections: Current Strategies and Therapeutic Potential

To maximize the therapeutic efficacy of CBD in the context of oral infection management, the route of administration is crucial. This section discusses the primary CBD delivery methods tailored to oral infections, highlighting their pharmacological advantages and practical limitations.

5.1. Topical Delivery Systems

Topical administration is a preferred strategy for localized oral infections due to its ability to deliver high concentrations of CBD directly to the site of infection, minimizing systemic exposure.

5.1.1. Mucoadhesive Gels and Ointments

CBD-infused gels can be applied to inflamed or ulcerated oral mucosa, periodontal pockets, or peri-implant tissues. Mucoadhesive formulations enhance residence time, facilitating sustained release and deeper tissue penetration. In preclinical models, these gels have reduced microbial load and downregulated pro-inflammatory cytokines (e.g., IL-1β, IL-6), aiding in infection control and tissue healing [63].

5.1.2. Mouth Rinses

CBD-containing mouthwashes provide a convenient method to address generalized microbial colonization and gingival inflammation. Studies have reported significant reductions in plaque accumulation and gingival bleeding, with efficacy comparable to chlorhexidine. However, short retention time due to salivary dilution remains a limitation, potentially necessitating repeated administration [45,59].

5.1.3. Buccal Films and Patches

These solid dosage forms adhere to the oral mucosa, enabling the controlled release of CBD over extended periods. Their localized effect makes them particularly suitable for treating chronic or recurrent lesions, such as aphthous ulcers or peri-implant mucositis, while reducing the need for frequent dosing [38,64,65].

5.2. Systemic Delivery Approaches

The systemic administration of CBD, while not targeted, may benefit patients with widespread or multifocal oral infections or systemic inflammatory involvement.

5.2.1. Oral Capsules and Edibles

Oral ingestion results in slow onset and low bioavailability (6–10%), primarily due to first-pass metabolism. However, it may support systemic anti-inflammatory responses in severe or generalized infections. Long-term use might also contribute to host immune modulation [27,66].

5.2.2. Sublingual Oils and Tinctures

Sublingual delivery bypasses gastrointestinal degradation, providing faster onset and improved bioavailability (up to 35%). While this method lacks tissue targeting, it may be beneficial as adjunctive therapy for oral pain, swelling, or systemic inflammation associated with infection [37,67].

5.3. Localized Drug Delivery Systems

Emerging localized delivery systems have been developed to increase CBD retention and penetration in infected oral tissues, especially in the treatment of periodontitis and peri-implantitis [38,68].

5.3.1. Nanoparticle-Based Delivery

The encapsulation of CBD into nanoparticles (e.g., polymeric or lipid-based) enhances its solubility, stability, and cellular uptake [69,70,71,72,73]. These systems can be incorporated into gels or solutions for application in periodontal pockets. Studies report enhanced antimicrobial activity against pathogens such as Porphyromonas gingivalis and Streptococcus mutans along with the modulation of local inflammation [74].

5.3.2. Hydrogels and Injectable Systems

Hydrogels allow for minimally invasive, localized delivery into periodontal defects or inflamed tissues. These biodegradable systems gradually release CBD, thereby maintaining therapeutic levels and supporting both tissue regeneration and microbial control [75]. Synergistic effects have been observed in combination with other agents (e.g., chlorhexidine or antibiotics) [38].

5.3.3. Biodegradable Inserts

CBD-loaded inserts can be placed into periodontal pockets or mucosal defects, delivering the drug over days or weeks. This approach ensures high localized concentrations with minimal systemic effects, particularly valuable in managing chronic bacterial biofilms [76].

The bioavailability and pharmacokinetics of CBD vary significantly across delivery routes. For oral infections, the goal is localized drug accumulation, which is most efficiently achieved through topical or site-specific systems. Topical and localized systems have shown superior tissue penetration and therapeutic efficacy, while systemic delivery may serve a complementary role in modulating broader immune responses. Key factors influencing efficacy include the following: (i) formulation pH and solubility; (ii) adhesion to oral tissues; (iii) CBD stability in saliva; and (iv) release kinetics and penetration depth [67].

Table 2. CBD delivery methods tailored to oral infections.

Delivery Systems		Advantages	Disadvantages	References
Topical Delivery Systems	Mucoadhesive Gels and Ointments	Direct application to infection site. Enhances tissue penetration. Reduces inflammation and microbial load.	Limited to accessible areas. May require frequent application	[63]
	Mouth Rinses	Easy to use. Reduces plaque and gingival bleeding.	Short retention time. May need repeated administration.	[45,59]
	Buccal Films and Patches	Adheres to the mucosa. Extended CBD release. Effective for chronic lesions.	Potential discomfort. May detach with saliva or movement.	[38,64,65]
Systemic Delivery Approaches	Oral Capsules/Edibles	Convenient for widespread infections. Supports systemic immune modulation.	Low bioavailability (6–10%). Delayed onset due to first-pass metabolism.	[27,66]
	Sublingual Oils/Tinctures	Avoids first-pass metabolism. Faster onset. Improved bioavailability (up to 35%).	Lacks local targeting. Shorter duration of action.	[37,67]
Localized Drug Delivery Systems	Nanoparticle-Based Delivery	Enhanced solubility and stability. Improved cellular uptake. Strong antimicrobial and anti-inflammatory effects.	Complex formulation. Still under development.	[74]
	Hydrogels/Injectable Systems	Localized, sustained release. Biodegradable and minimally invasive. Supports tissue regeneration.	Requires clinical application. Potential cost and formulation complexity.	[38]
	Biodegradable Inserts	Long-term drug release. Maintains high local concentration. Effective for chronic biofilms.	Invasive placement. May not be suitable for all patients or locations.	[76]

summarizes the main CBD delivery methods tailored to oral infections.

CBD exhibits a favorable safety profile for oral applications at therapeutic doses, but toxicological evaluations specific to oral tissues remain limited. While side effects are generally mild, caution is warranted due to potential drug interactions and the lack of long-term safety data. Regulatory and legal inconsistencies across countries, coupled with quality control issues, represent significant challenges to the clinical integration of CBD into oral health care. Standardized formulations, regulatory oversight, and targeted research will be critical for establishing safe and effective CBD-based therapies in dentistry [38].

6. Limitations of Current Studies

Despite promising outcomes, current research on CBD in oral infections is constrained by several methodological limitations, as follows: (i) Sample Size: most clinical studies are small-scale trials or case reports, limiting statistical power and generalizability. (ii) Heterogeneity of Formulations: differences in CBD delivery methods (e.g., oils, gels, rinses, or systemic administration), dosage, and purity (full-spectrum vs. isolate) make it difficult to compare results or establish standardized treatment protocols. (iii) Short Study Durations: many studies assess only acute outcomes; there is a lack of long-term data on chronic conditions such as periodontitis or peri-implantitis. (iv) Lack of Blinding and Controls: several trials are either open-label or lack appropriate control groups, introducing potential bias in outcome assessment. (v) Regulatory and Legal Constraints: variability in cannabis legislation across jurisdictions limits the scalability and reproducibility of CBD-related research.

Preclinical and early clinical evidence supports the antimicrobial, anti-inflammatory, and analgesic potential of CBD in the management of oral infections. Outcomes from animal models, ex vivo tissue studies, and small human trials collectively suggest that CBD may serve as an effective adjunct in treating conditions such as periodontitis, mucositis, and oral ulcers. However, larger, well-controlled clinical trials with standardized formulations and dosing protocols are essential to validate these findings and facilitate integration into mainstream dental practice [19,77].

7. Challenges and Future Perspectives

Several scientific, clinical, and regulatory hurdles limit the translation of CBD into routine dental practice. This section addresses the major challenges impeding clinical adoption and highlights key future research directions for integrating CBD into evidence-based oral infection management.

While in vitro and preclinical studies have consistently demonstrated CBD’s antimicrobial and anti-inflammatory effects against common oral pathogens and inflammatory mediators, robust clinical evidence remains scarce [19]. Only a few human studies have explored CBD’s effects on oral health outcomes, and most are small-scale, lack placebo controls, or have short follow-up periods [17,61].

Key gaps include the following: (i) the absence of large randomized controlled trials (RCTs) assessing efficacy in oral infections such as periodontitis or mucositis; (ii) limited data on long-term safety and tolerability of topical or localized CBD use in the oral cavity; and (iii) insufficient evidence on patient-centered outcomes, such as pain reduction, quality of life, and adherence. These limitations hamper the ability to draw firm conclusions on optimal use, safety, and clinical benefit.

Moreover, CBD’s therapeutic effects are highly dose- and formulation-dependent, yet there is no consensus on optimal dosing strategies for oral applications. The currently available products vary widely in CBD concentration and purity, the presence of other cannabinoids (e.g., THC, CBG), and delivery format (e.g., gels, rinses, patches, nanoparticles). This variability affects bioavailability, efficacy, and reproducibility. Moreover, the pharmacokinetics of CBD in oral tissues are not fully understood, complicating the selection of appropriate doses for clinical use. Establishing standardized, validated formulations with consistent pharmacological profiles is essential for advancing CBD as a reliable therapeutic agent in dentistry.

Although CBD has demonstrated antimicrobial activity, particularly against Gram-positive bacteria and biofilm-forming oral pathogens, its spectrum is limited compared to conventional antibiotics. There is also a theoretical risk that indiscriminate or the subtherapeutic use of cannabinoid-based therapies could contribute to resistance development, although this remains to be empirically tested. To enhance efficacy and reduce resistance potential, future strategies may involve the following: (i) combination therapies pairing CBD with existing clinical antimicrobials or antiseptics (e.g., chlorhexidine, metronidazole); (ii) the use of CBD as an adjuvant to reduce inflammation and enhance clinical antimicrobial penetration; and (iii) synergistic formulations with other phytochemicals or probiotic agents to modulate the oral microbiome.

Together, these strategies may enhance the therapeutic utility of CBD while mitigating potential limitations related to efficacy and microbial resistance. Overcoming these challenges through rigorous clinical research, standardized formulations, and integrated therapeutic strategies will be essential for establishing CBD as a safe, effective, and evidence-based adjunct in oral infection management.

8. Conclusions

Oral infections represent a significant global health burden, often leading to both localized dental issues and systemic complications, particularly in vulnerable populations. Traditional clinical antimicrobial therapies, while effective, are increasingly limited by resistance, side effects, and lack of specificity. In this context, cannabidiol (CBD), a non-psychoactive compound derived from Cannabis sativa, offers a promising alternative due to its broad-spectrum antimicrobial, anti-inflammatory, and immunomodulatory properties. Preclinical and in vitro evidence supports CBD’s efficacy in disrupting pathogenic biofilms, reducing inflammatory mediators, and enhancing tissue regeneration, key factors in the pathogenesis and treatment of oral infections, including dental caries, periodontal disease, and candidiasis.

However, despite these encouraging findings, the clinical translation of CBD remains hindered by several challenges, including the lack of high-quality human studies, inconsistency in formulations and dosing strategies, and persistent regulatory barriers. The variability in delivery methods and lack of standardized protocols further complicate the assessment of therapeutic outcomes. To advance CBD as a viable adjunct in oral healthcare, future research must focus on well-designed randomized controlled trials, long-term safety assessments, and the development of standardized and pharmaceutically stable formulations. With rigorous investigation and regulatory alignment, CBD holds significant potential to address unmet clinical needs and complement existing antimicrobial strategies in managing oral infectious diseases.