This systematic review aims to synthesize the current literature on the effect of cannabinoids, focusing on their analgesic, anti-inflammatory, and properties for bone healing. Cannabinoids, the active compounds found in the cannabis plant, have gained increasing attention in medical science due to their potential therapeutic benefits. The clinical importance of cannabinoids lies in their ability to modulate a range of medical conditions, particularly those for which conventional treatments may be limited or ineffective. Cannabinoids interact with the endocannabinoid system (ECS) to modulate pain and inflammation, with CBD showing unique advantages through its interaction with TRPV1 and serotonin receptors [40]. These mechanisms align with existing evidence and support CBD as a safer alternative to opioids and NSAIDs, as cannabinoids have demonstrated significant potential in controlling postoperative pain and inflammation [3,41].

Cannabinoids have been increasingly used as part of pain management strategies, particularly for chronic pain conditions such as cancer pain, neuropathic pain (e.g., diabetic neuropathy, multiple sclerosis), orofacial pain [42,43], fibromyalgia, arthritis, and chronic lower back pain [44,45]. Tetrahydrocannabinol (THC) modulates pain perception through CB1 receptor activation, reducing pain transmission in the central nervous system [46]. Cannabidiol (CBD), on the other hand, exerts anti-inflammatory effects by decreasing pro-inflammatory markers such as TNF-α and IL-6 via indirect ECS modulation and interaction with TRPV1 receptors, leading to reduced pain perception [47]. In clinical studies, patients treated with CBD experienced a 30% reduction in postoperative pain within 24 h compared to those treated with NSAIDs, suggesting that cannabinoids provide an effective non-opioid alternative for pain management [48]. However, the administration of cannabidiol (CBD) as therapy for orofacial pain or oral ulcers should aim to achieve a clinical effect with minimal side effects. Both acute and chronic CBD treatments were tested on human oral cells, with acute treatment showing more significant effects than chronic treatment, particularly in fibroblasts. Concentrations of CBD ≥50 μM were found to be highly cytotoxic, inducing apoptosis and reducing cell migration. These findings suggest that further investigation is needed to evaluate the dose- and time-dependent effects of CBD to identify the optimal therapeutic dose. In the study of Umpreecha C. [33], the authors showed that topical 0.1% cannabidiol (CBD) had no allergic reactions or side effects.

Other clinical indications include neurological disorders (e.g., epilepsy, multiple sclerosis, especially for spasticity and muscle spasms, Parkinson’s disease, for motor symptoms and tremors, Alzheimer’s disease), anxiety and mood disorders, and inflammatory and autoimmune diseases (e.g., rheumatoid arthritis, Crohn’s disease, ulcerative colitis, psoriasis) [49,50,51].

Subgroup analysis revealed both consistencies and notable variabilities across the included studies. The analgesic and anti-inflammatory effects of cannabidiol (CBD) were consistently observed across clinical, preclinical, and in vitro models, particularly in managing orofacial pain and periodontitis. However, variability emerged in the context of bone healing, where outcomes depended on the cannabinoid type, delivery route, and study model. For instance, while preclinical studies reported enhanced bone regeneration and reduced resorption following CBD or CB2 receptor agonist administration, clinical evidence remains limited and less conclusive. Moreover, oral and topical routes of cannabinoid delivery demonstrated different degrees of efficacy, with topical applications showing faster localized pain relief and fewer side effects. These findings underscore the importance of stratified analysis to identify which cannabinoid formulations and administration methods are most effective for specific oral conditions, ultimately strengthening the validity and clinical applicability of the overall findings.

Moreover, additional specificity regarding the different types of cannabinoids studied could help contextualize the therapeutic implications more precisely. Among the studies included in this review, cannabidiol (CBD) was the most frequently investigated compound, noted for its non-psychoactive profile and broad anti-inflammatory, analgesic, and regenerative effects. Only one study explored tetrahydrocannabinol (THC) [24]. Synthetic analogs, such as HU-308 (a selective CB2 receptor agonist) and methanandamide (Meth-AEA, a CB1 agonist), were also evaluated in preclinical models, with findings suggesting significant anti-inflammatory and osteoprotective effects. This distinction between phytocannabinoids (CBD, THC) and synthetic analogs (e.g., HU-308, Meth-AEA) is important, as they differ in receptor selectivity, side effect profiles, and potential clinical applications. Greater granularity in future research comparing these agents head-to-head would be valuable in determining their optimal use in dental and oral surgical contexts.

Further studies could focus on CBD’s anti-inflammatory and regenerative properties, as it promotes bone regeneration and accelerates osseointegration by activating CB2 receptors, a topic particularly relevant for dental implantology [52,53]. This activation stimulates osteoblast activity while inhibiting osteoclast-mediated bone resorption. Preclinical studies have shown that CBD accelerates callus formation, enhances bone density, and improves the biomechanical strength of regenerated tissue. Additionally, CBD’s interaction with PLOD1, an enzyme crucial for collagen stabilization, contributes to the mechanical resilience of bone tissue [54]. These findings underscore the significant potential of cannabinoids as adjuvant therapies to improve outcomes in dental implantology and support their broader role in regenerative medicine and surgical applications. In addition, the synergistic effects between cannabinoids, terpenes, and flavonoids, known as the entourage effect, significantly enhance the therapeutic potential of individual compounds [55]. For instance, beta-caryophyllene, a terpene, acts as a CB2 receptor agonist, complementing CBD’s anti-inflammatory properties, while flavonoids like quercetin enhance antioxidant and anti-inflammatory effects, further reducing pain and inflammation. Preclinical models have shown that combining CBD with terpenes, such as myrcene, enhances cellular permeability, improving pain and inflammation control [56]. Additionally, CBD’s anxiolytic effects, mediated through its interaction with serotonin 5-HT1A receptors, help manage preoperative anxiety, which can positively influence surgical outcomes [57]. Clinical studies indicate that CBD treatment can reduce anxiety by up to 40% compared to a placebo, improving patient comfort and facilitating smoother postoperative recovery [58]. These findings highlight CBD’s potential as a holistic therapeutic option in dentistry, While the current findings highlight the promising therapeutic potential of cannabinoids—particularly CBD—in managing orofacial pain, oral inflammation, and promoting bone healing, their immediate integration into dental practice remains premature. Although several preclinical studies have demonstrated consistent analgesic and anti-inflammatory effects, and a few human trials report favorable outcomes with minimal side effects, the overall clinical evidence is still limited by small sample sizes, variability in dosing, cannabinoid formulations, and outcome measures. Furthermore, most randomized controlled trials evaluated short-term effects, and therefore long-term safety, optimal dosing protocols, and drug interactions remain unclear. Therefore, while these results offer a compelling rationale for further research, especially in dental pain and postoperative management, more large-scale, standardized clinical trials are required before cannabinoids can be fully endorsed as routine adjuncts in dental care.

Furthermore, as with every drug, also CBDs caused adverse effects included sedation (calmness or relaxation), diarrhea, and abdominal pain [59]. Nevertheless, they were resolved quickly or with minor interventions. Moreover, chronic treatments with concentrations of CBD ≥ 50 μM were found to be highly cytotoxic, inducing apoptosis and reducing cell migration [60].

This stated the need to evaluate the dose- and time-dependent effects of CBD to identify the optimal therapeutic dose.

This systematic review has several limitations that must be acknowledged. First, the included studies were highly heterogeneous in terms of study design, cannabinoid type (CBD, THC, CB1/CB2 agonists, cannabis smoke), administration route (topical, oral, systemic), and outcome measures. Second, more than half of the studies included were preclinical (animal or in vitro), and nine of the animal studies were judged to have a high risk of bias, weakening the strength of the evidence base. Third, although four randomized controlled trials were included, one was rated as moderate risk of bias and they evaluated different conditions (e.g., acute dental pain, myofascial pain, and oral ulcers), reducing the generalizability of findings. Finally, due to the variability in outcome reporting and the lack of standardized effect size data, meta-analysis could not be performed, limiting quantitative synthesis.