1 Volume 24 2025 e255518 Original Research Braz J Oral Sci. 2025;24:e255518http://dx.doi.org/10.20396/bjos.v24i00.8675518 1 School of Dentistry, Universidad de la República, Montevideo, Uruguay. 2 Structural Genomics Laboratory, Technological Development Center, Federal University of Pelotas, Pelotas, RS, Brazil. 3 Department of Restorative Dentistry, Federal University of Pelotas, RS, Brazil. Corresponding author: Luiz Alexandre Chisini. Post-Graduate Program in Dentistry, Department of Restorative Dentistry, 457, Gonçalves Chaves. Pelotas, room 502 - RS - Brazil ZIP: 96015-360. e-mail: alexandrechisini@gmail.com Editor: Dr. Altair A. Del Bel Cury Received: January 16, 2024 Accepted: December 12, 2024 The therapeutic effect of cannabidiol in oral mucosa lesions: a scoping review of in vivo and clinical studies Matias Mederos1 , Luana Carla Salvi2 , Luiz Alexandre Chisini3* Aim: This study aims to analyze the potential therapeutic effect of cannabidiol use on oral mucosa lesions in clinical and in vivo studies. Methods: A scoping review was conducted considering the question: “Is there a therapeutic effect of the use of cannabidiol (CBD) on lesions of the oral mucosa?”. Four distinct databases were searched (PubMed/MEDLINE, Embase, Web of Science, and Scopus) and gray literature until August 2023. Original clinical and in vivo studies were included, involving human and animal subjects where CBD was applied topically to the oral mucosa or administered systemically for the treatment of lesions or superficial/deep alterations of the oral mucosa. Results: A total of 610 records were found in the initial searches. Twelve studies were assessed in full text for eligibility and five studies were excluded. Seven studies were included in this review. Five studies were conducted with in vivo design and only two studies had clinical design in humans. Considering results from in vivo studies, all of them presented better clinical results for oral mucosa lesion groups treated with CBD-based therapy compared to placebo. Regarding histological features, four studies found statistically significant improvement in CBD-based therapy and only one study did not find a significant improvement. For clinical studies, all studies presented positive clinical results (primarily regarding pain control) in the use of CBD-based therapies. Conclusion: CBD appears effective in treating oral mucosa lesions (oral mucositis, ulcers, burning mouth syndrome). CBD-based therapies can reduce inflammation in vivo studies and hold promise for pain control and lesion healing in oral mucosa lesions in clinical studies. However, the limited number of clinical trials, heterogeneity in cannabis-based therapies, and a lack of standardized protocols underscore the need for further rigorous, interdisciplinary research to establish consistent dosing and assess the efficacy of various cannabinoids in treating oral mucosa conditions. Keywords: Cannabis. Cannabidiol. Oral ulcer. Pathology, oral. https://orcid.org/0000-0002-1561-2283 https://orcid.org/0000-0001-5809-8272 https://orcid.org/0000-0002-3695-0361 2 Mederos et al. Braz J Oral Sci. 2025;24:e255518 Introduction Cannabis sativa L. is an herbaceous plant from the Cannabaceae family that has been used by humans for many years in many parts of the world1. Cannabinoids are found within the active metabolites that they contain2. The most well-known canna- binoids are delta-9-tetrahydrocannabinol (THC), with psychotropic effects, and can- nabidiol (CBD), without psychotropic effects. The absence of psychotropic effects in CBD is the main reason why it is chosen for medicinal purposes2,3. Studies have shown that CBD has anti-inflammatory properties in humans4,5, antioxidants6,7, and analgesic effects8,9. The human body can synthesize metabolites similar to THC and CBD, such as anan- damide, which is why these molecules are referred to as endocannabinoids10. Spe- cific receptors for these molecules (cannabinoids) are distributed throughout the body’s tissues; thus, forming a true internal communication network that the litera- ture has defined as the endocannabinoid system11,12. The large number of endocan- nabinoid receptors in living organisms results in different therapeutic possibilities and varied forms of administration with therapeutic purposes, which can be deliv- ered systemically through oral consumption in the form of tablets13, by lung inhala- tion from cigarettes or vaporizers14-16, and by topically applied directly to the skin or oral mucosa17,18. There is a tendency towards an increase in topical use on the skin, being poten- tially effective for the treatment of uncommon pathologies, such as granuloma- tous pyoderma and epidermolysis bullosa19,20. The use of Cannabinoids for the treatment of oral mucosa lesions has limited evidence with contradictory results among studies21,22. CBD was able to inhibit the production of TNF-α and IL-1β in macrophages present in gingival ulcers in an in vitro experiment23. A CBD spray has inhibited inflammation, reduced pain, and accelerated the healing of oral ulcers in mice17. On the other hand, a systematic review evaluating the effects of canna- bis extracts on oral ulcers did not demonstrate a statistical difference between Cannabis sativa and the control group24. In addition to its therapeutic properties, it has been demonstrated that plant-based medicines have fewer side effects and therefore present a valid and safe alternative to conventional treatments22,25,26, justifying their choice. Despite promising results in the dental field, few pathological entities of the oral mucosa have been evaluated through the use of cannabis for their therapeutic poten- tial22. Furthermore, there is no consensus in the literature on what is the optimal dosage to select for each case22. Previous studies, such as those focusing on oral mucositis related to chemotherapy and radiotherapy, have indicated CBD’s potential for managing oral lesions; however, limited research exists on its application across a broader spectrum of oral mucosal pathologies. This gap highlights the need for a more comprehensive investigation into CBD’s effects and dosage efficacy for vari- ous oral lesions27. Therefore, the objective of this scoping review was to analyze the potential therapeutic effect of cannabidiol use on oral mucosa lesions in clinical and in vivo studies. 3 Mederos et al. Braz J Oral Sci. 2025;24:e255518 Methods This review was reported following the PRISMA to scoping reviews28. The study regis- tration was performed in the OSF (10.17605/OSF.IO/CN53D). Study design We chose a scoping review approach instead of a systematic review, aligning with guidance that recommends scoping reviews when there is a need to map, report, and discuss various characteristics rather than address a specific research question pre- cisely29. Consequently, scoping reviews do not aim to provide a critically appraised and synthesized answer to a particular question29, providing a general overview of existing content, and establishing future directions for studies and gaps in literature30-32. Review question and searches The present scoping review was conducted considering the question: “Is there a ther- apeutic effect of the use of cannabidiol on individuals or animals with lesions of the oral mucosa?”. The question followed the acronym PCC framework33: Population: Individuals or animals with alteration or pathology in the oral mucosa. Concept: The healing effect of soft tissue being measured using clinical or histological criteria that follow: Clinical: 1) Ulcer size; 2) Presence and severity of Oral Mucositis; 3) Pain (burning mouth syndrome and UAO); 4) Levels of anxiety and depression (burning mouth syndrome); 5) Quality of life; 6) Satisfaction with the intervention. Histological: 1) Edema, hyperemia, and presence of inflammatory infiltrate; 2) Hematological cell count (leukocytes, erythrocytes, and platelets); 3)Activity of antioxidant enzymes and oxidative stress; 4) Increase of cytokines, TNF and IL-6; 5) Size of ulcers, cellular positivity and epi- thelial thickness; 6) Average fluorescence intensity; 7) Cellular viability; 8) Cell apoptosis rate; 9) Expression levels and nuclear translocation of Nrf2; 10) Protein expression levels. Context: Application of cannabidiol extract. A structured search was carried out in PubMed/MEDLINE, Embase, Web of Science, and Scopus, until August 2023. Keywords and MeSH terms were used to build the search syntax of each database. Details of all strategies in each database are dis- played in Table 1. Table 1. Search summary used according to the databases Database Syntax Pubmed (Oral ulcer OR ulcer OR ulceration OR aphthous OR stomatitis OR burning mouth síndrome) AND (cannabis OR cannabidiol) Embase ((Oral ulcer) OR (ulcer) OR (ulceration) OR (aphthous) OR (stomatitis) OR (burning mouth síndrome)) AND ((cannabis) OR (cannabidiol)) Scopus ALL(“Oral ulcer” OR “ulcer” OR “ulceration” OR “aphthous” OR “stomatitis” OR “burning mouth síndrome”) AND ALL(“cannabis” OR “cannabidiol”) Web of Science TS=(Oral ulcer OR ulcer OR ulceration OR aphthous OR stomatitis OR burning mouth síndrome) AND TS=(cannabis OR cannabidiol) 4 Mederos et al. Braz J Oral Sci. 2025;24:e255518 The search approach involved the utilization of pertinent keywords and entry terms associated with MeSH Terms, adapted to the structure of each individual database. The detailed search strategy can be found in Table 1. The gathered records were imported into EndNote™ software (Thomson Reuters, Rochester, New York, NY) to create a virtual library. Duplicate studies were identified and removed. Two indepen- dent reviewers (MM and LAC) assessed the titles and abstracts of all papers. Gray literature was manually explored in the 100 first hits of Google Scholar using the fol- lowing syntax: ((Oral ulcer) AND ((cannabis) OR (cannabidiol)). The same reviewers proceeded to evaluate the full-text articles and resolve any discrepancies through dis- cussion to reach a consensus. Eligibility criteria Were included: (1) Original published articles, (2) In vivo or clinical studies in humans or animals, (3) studies using CBD in either commercial or experimental extract form, (4) studies applying CBD topically to the oral mucosa or systemically for the treatment of lesions or superficial/deep alterations of the oral mucosa. Were not included: (1) Letters to the editor and reviews, (2) in vitro studies, (3) studies where mucosal lesions were treated with therapies other than CBD, (4) studies focusing on skin lesions, (5) studies addressing ulcers in areas of the body other than the oral cavity, (6) studies investigating the use of cannabis for the treatment of pain and other conditions not localized to the oral cavity. Data collection Data extraction was performed independently by the same reviewers using a pre- defined electronic spreadsheet. The following data were extracted: author data, year of publication, details of the model used (for in vivo studies), description of the type of study (for clinical studies), study groups, evaluated variables, biological context, and main results of analyzed studies, the main active component of the evaluated therapy, the origin of the product (commercial or experimental), delivery vehicle and the con- centration/doses applied. Strategy for data synthesis The extensive variability in materials and methods, particularly concerning study design and outcome evaluation within the included articles, led to the formation of numerous smaller subcategories of results. This diversity precluded any attempt at quantitative analysis. Consequently, a comprehensive descriptive analysis of the results was conducted, organizing the studies into two main groups: in vivo studies and clinical studies, further categorized based on their specific oral lesions. Results A total of 610 records were found in the initial searches and two additional records in gray literature (Figure 1). After the exclusion of duplicates, 508 manuscripts remained for title and abstract screening. Twelve studies were assessed in full text for eligibil- ity, and five studies were excluded. Table 2 presents the reasons for the exclusion of these papers. Seven studies were included in this review. 5 Mederos et al. Braz J Oral Sci. 2025;24:e255518 Fi gu re 1 . P ris m a flo w d ia gr am Id en tif ic at io n of s tu di es v ia d at ab as es a nd re gi st er s Id en tif ic at io n of s tu di es v ia o th er m et ho ds Re co rd s id en tif ie d fr om : G ra y Li te ra tu re (2 ) Re co rd s id en tif ie d fr om *: Da ta ba se s (n = 4 ) Re gi st er s (n = 6 10 ) Re po rts s ou gh t f or re tri ev al (n = 2 ) Re po rts s ou gh t f or re tri ev al (n = 1 2) Re po rts n ot re tri ev ed (n = 0 ) Re co rd s sc re en ed (n = 5 08 ) Re po rts n ot re tri ev ed (n = 0 ) Re po rts a ss es se d fo r el ig ib ili ty (n = 2 ) Re po rts a ss es se d fo r el ig ib ili ty (n = 1 2) St ud ie s in cl ud ed in re vi ew (n = 7 ) Re po rts e xc lu de d: In v itr o st ud ie s (n = 2 ) Re po rts e xc lu de d* * (n = 4 96 ) Re po rts e xc lu de d: Re vi ew s (n = 1 ) In v itr o st ud ie s (n = 1 ) N o ev al ua te th e ef fe ct on o ra l m uc os a (n = 1 ) Ap pl ic at io n on s ki n (n = 2 ) Re po rts e xc lu de d be fo re s cr ee ni ng : Du pl ic at e re co rd s re m ov ed (n = 1 02 ) Re co rd s m ar ke d as in el ig ib le by a ut om at io n to ol s (n = 0 ) Re co rd s re m ov ed fo r ot he r r ea so ns (n = 0 ) Identification Screening Included 6 Mederos et al. Braz J Oral Sci. 2025;24:e255518 Table 2. Excluded studies and their reasons Studies Exclusion reasons Cuba et al.27 Review Kongkadee et al.23 in vitro study Darling et al.34 Not evaluate the effect on oral mucosa Serpell et al.35 and Jiménez-Rodríguez et al.36 Application on skin Study characteristics The majority (n=5, 71.4%) of included studies were carried out with in vivo designs17,18,37-39 and only two studies had clinical designs13,40. The studies were published between 2018 and 2023 and the study authors were from China, Brazil, Italy, and Thailand. The oral mucosal pathologies analyzed included oral ulcers, oral mucositis, and burning mouth syndrome. CBD was the most commonly used active component, only one study evaluated the application of CBD together with THC13. Details of study charac- teristics and their respective clinical and histological results are displayed in Table 3 and discussed in the next subtopics. The forms of application reported in studies were systemic, through intraper- itoneal and intravenous injection or oral consumption of an extract. Additionally, topical application was reported, using an oral spray by dripping directly onto the oral mucosa. The variables evaluated were mostly at the histological level, such as inflammation degree, hematological cell count, cellular activity, oxidative activity, and rate of cellular apoptosis. At a clinical level, the dimensions of the lesion, pain, and level of anxiety and depression were evaluated. Most of the studies (n=6; 85.7%) used experimental cannabis-based therapies (Table 4) and only one used a com- mercial medication: Bediol®. 7 Mederos et al. Braz J Oral Sci. 2025;24:e255518 Ta bl e 3. S tu dy c ha ra ct er is tic s of th e in cl ud ed s tu di es . Au th or , y ea r, an d co un tr y St ud y de si gn De ta ils o f t he m od el u se d Ex pe rim en ta l gr ou p Co nt ro l g ro up Va ria bl es e va lu at ed Bi ol og ic al co nt ex t M ai n re su lts Kl ei n et a l.37 , 20 18 (B ra zi l) In v iv o Ra t t on gu e ul ce rs w er e cr ea te d m ec ha ni ca lly . 60 in di vi du al s di vi de d in to 3 g ro up s (n =2 0) in a ra nd om iz ed m an ne r. CB D 2% po lyo xy et hy le ns or bi ta n m on oo le at e (T w ee n 80 ) i n sa lin e so lu tio n. Cl in ic : U lc er s iz e ev er y 3 to 7 d ay s H is to lo gy : d eg re e of in fla m m at io n at 3 a nd 7 da ys . Sc ar rin g of o ra l w ou nd s. Cl in ic al : i n th e ce nt er a re a, d im en si on al di ff er en ce s in th e ar ea o f t he u lc er tr ea te d w ith CB D co m pa re d to th e co nt ro l g ro up . H is to lo gi ca l: Af te r 3 d ay s, th e gr ou ps tr ea te d w ith C BD s ho w ed a lo w er d eg re e of in fla m m at io n co m pa re d to th e co nt ro l g ro up . N o di ff er en ce s w er e fo un d be tw ee n gr ou ps a ft er 7 d ay s. Cu ba e t a l.38 , 20 20 (B ra si l) In v iv o M ic e w ith ch em ot he ra py -in du ce d or al m uc os iti s. 90 in di vi du al s di vi de d in to 5 g ro up s (n =1 8) in a ra nd om iz ed m an ne r. CB D Po si tiv e: F U + m ec ha ni ca l t ra um a + pl ac eb o. N eg at iv e: F U + pl ac eb o. Pl ac eb o: T w ee n 80 in sa lin e (0 .2 m l). Cl in ic : U lc er s iz e ev er y 4 to 7 d ay s H is to lo gy : d eg re e of in fla m m at io n, bl oo d ce ll co un t, an d ox id at iv e en zy m es ov er 4 a nd 7 d ay s. Sc ar rin g of o ra l w ou nd s. Cl in ic al : T he s iz e of th e ul ce r i n th e gr ou ps tr ea te d w ith C BD w as s m al le r c om pa re d to th e co nt ro l gr ou p at d ay s 4 an d 7. H is to lo gi ca l: in th e ce nt er a re a, d iff er en ce s in in fla m m at io n le ve ls w er e ob se rv ed b et w ee n th e gr ou ps . G re at er n um be rs o f e ry th ro cy te s an d le uk oc yt es w er e fo un d in th e gr ou ps tr ea te d w ith CB D af te r 4 d ay s, w ith n o di ff er en ce s ob se rv ed af te r 7 d ay s. O xi da tiv e ac tiv ity w as lo w er in th e gr ou ps tr ea te d w ith C BD a ft er 7 d ay s. Q i e t a l.17 , 20 21 (C hi na ) In v iv o Ul ce rs o n th e to ng ue o f ha rd en ed ra ts c re at ed by a ci d et ch in g. In di vi du al s ar e di vi de d in to 3 g ro up s. It d oe s no t s pe ci fy q ua nt ity o r ra nd om iz at io n m et ho d. CB D N /E Cl in ic : U lc er s iz e ev er y 2 an d 4 da ys . H is to lo gy : d eg re e of in fla m m at io n an d ex pr es si on o f cy to ki ne s. Sc ar rin g of o ra l w ou nd s. Cl in ic : T he a pp lic at io n of C BD re du ce d th e si ze o f ul ce rs in a d os e- de pe nd en t m an ne r. H is to lo gi ca l: M uc os a tre at ed w ith C BD sh ow ed a d ec re as e in in fla m m at or y ac tiv ity a nd in th e ex pr es si on o f N LR P3 , I L- 1β , I L- 18 , a nd TN F- α pr ot ei ns . Li e t a l.39 , 2 02 2 (C hi na ) In v itr o an d In vi vo M ic e w ith ch em ot he ra py -in du ce d or al m uc os iti s. 60 in di vi du al s di vi de d in to 5 g ro up s (n =6 ) i n a ra nd om iz ed m an ne r. 5- fl uo ro ur ac il o 5- flu or ou ra ci l + CB D Tw ee n 80 a t 2 % + DM SO * at 3 % + s al in e so lu tio n at 95 % . Cl in ic : s iz e to ng ue ul ce rs . H is to lo gy : c yt ol og ic al re po rt , e xp re ss io n of cy to ki ne s, a nt io xi da nt en zy m es a nd ep ith el ia l t hi ck ne ss , ce ll pr ol ife ra tio n, a nd ap op to si s af te r 4 , 7 , an d 10 d ay s. Sc ar rin g of o ra l w ou nd s. Cl in ic : T he a pp lic at io n of C BD re du ce d th e si ze o f ul ce rs in a d os e- de pe nd en t m an ne r, co m pa re d to th e co nt ro l g ro up . H is to lo gi ca l: Co m pa re d to th e co nt ro l, th er e w er e de cr ea se d le ve ls o f p ro -in fla m m at or y cy to ke ra tin s, in cr ea se d ex pr es si on o f a nt io xi da nt e nz ym es , a nd in cr ea se d ep ith el ia l t hi ck ne ss . A n in cr ea se in c el l pr ol ife ra tio n an d a de cr ea se in c el lu la r a po pt os is w er e al so o bs er ve d. Co nt in ue 8 Mederos et al. Braz J Oral Sci. 2025;24:e255518 Co nt in ua tio n Li u et a l.18 , 20 22 (C hi na ) In v itr o an d In vi vo M ic e w ith ch em ot he ra py -in du ce d or al m uc os iti s. 18 in di vi du al s di vi de d in to 2 g ro up s (n =9 ) i n a ra nd om iz ed m an ne r N an o- m ic el le s w ith fu co id an - de ox yc ho lic (F D) + C BD N an o- m ic el le s w ith FD . Cl in ic al : s iz e of to ng ue u lc er s. H is to lo gy : e xp re ss io n of P -s el ec tin a nd cy to ke ra tin s, de gr ee o f in fla m m at io n, a ft er 2, 4 an d 6 da ys . Sc ar rin g of o ra l w ou nd s. Cl in ic al : T he s iz e of th e ul ce r i n th e gr ou ps tr ea te d w ith C BD w as s m al le r t ha n in th e co nt ro l g ro up . H is to lo gy : G ro up s tre at ed w ith C BD d em on st ra te d lo w er e xp re ss io n of in fla m m at or y fa ct or s an d an ti- in fla m m at or y in fil tra tio n. Ga m bi no e t a l.13 , 20 21 (I ta lia ) Cl in ic Po pu la tio n- ba se d st ud y, pa tie nt s w ith b ur ni ng m ou th s yn dr om e. 17 in di vi du al s w er e se le ct ed b as ed o n in cl us io n cr ite ria in a pr os pe ct iv e st ud y. Ex tra ct : 8 % CB D an d 6. 3% TH C di lu te d in o liv e oi l (p ro po rt io n 1/ 10 g ). - Cl in ic al : A ss es sm en t of p ai n, a nx ie ty , a nd de pr es si on o n da y 0, 4- 12 -2 4 w ee ks Pa in co nt ro l. Cl in ic al : A d ec re as e in o ra l s ym pt om s w as re po rt ed , a lo ng w ith a d ec re as e in a nx ie ty le ve ls . Um pr ee ch a et a l.40 , 2 02 3 (T ha ila nd ia ) Cl in ic Ra nd om , p ar al le l, do ub le -b lin d co nt ro lle d te st . 72 p at ie nt s w ith R AU w er e ra nd om ly d iv id ed in to 3 g ro up s (C BD , T A, p la ce bo ). 0. 1% C BD oi nt m en t. 0. 1% tr ia m ci no lo ne ac et on id e or p la ce bo . Cl in ic al : U lc er s iz e, pa in , i nt er ve nt io n sa tis fa ct io n, a nd qu al ity o f l ife . H ea lin g of o ra l w ou nd s an d pa in co nt ro l. Cl in ic al : G ro up s tre at ed w ith C BD s ho w ed a gr ea te r r ed uc tio n in u lc er s iz e, d ec re as ed p ai n, hi gh er s at is fa ct io n, a nd im pr ov ed q ua lit y of lif e co m pa re d to p la ce bo . N o di ff er en ce s w er e ob se rv ed b et w ee n th e gr ou ps tr ea te d w ith C BD an d TA N /E : D oe s no t s pe ci fy . D M SO : D im et hy l s ul fo xi de . R AU : R ec ur re nt a ph th ou s ul ce r. TA : T ria m ci no lo ne a ce to ni de . 9 Mederos et al. Braz J Oral Sci. 2025;24:e255518 Table 4. Information about cannabis-based therapies used in analyzed studies. Author, year Active component Commercial or experimental Vehicle Klein et al.37, 2018 Synthetic CBD (≥99) Purity (THC Pharm GmbH, Frankfurt, Germany) Commercial 2% polyoxyethylensorbitan monooleate (Tween 80) in saline solution. Cuba et al.38, 2020 Synthetic CBD (≥99) Purity (THC Pharm GmbH, Frankfurt, Germany) Commercial 2% polyoxyethylensorbitan monooleate (Tween 80) in saline solution Qi et al.17, 2021 CBD Experimental N/E Li et al.39, 2022 CBD Experimental Tween 80 at 2% + DMSO* at 3% + saline solution at 95%. Liu et al.18, 2022 CBD Experimental Micella with FD** Gambino et al.13, 2021 CBD y THC Commercial (Bediol®) N/E Umpreecha et al.40, 2023 CBD Experimental N/E N/E: Does not specify. CBD: cannabidiol; THC: delta-9-tetrahydrocannabinol; DMSO*: Dimethyl sulfoxide. FD**: fucoidan-deoxycholic. In vivo studies Five studies utilized an in vivo design17,18,37-39, and all of them presented better clini- cal results for oral mucosa lesion groups treated with CBD-based therapy compared to placebo. Regarding histological features, four studies17,18,37,39 found statistically significant improvement in CBD-based therapy and only one study38 did not find a significant improvement. Three studies investigated oral mucositis and observed a positive effect of CBD com- pared with control groups18,38,39. These studies clinically and histologically evaluated chemotherapy-induced oral mucositis in mice. The therapy was administered intra- peritoneally in amounts of 3, 10, and 30 mg/kg of animal weight, using Tween 80 in saline solution as the vehicle. One study used an intravenous dose (0.2ml of CBD) and a topical application, through direct application to the lesion of 30 µl of CBD in the form of fucoidan-deoxycholic nano micelles. In all three studies, CBD was used as an experimentally derived active component. Considering the clinical outcomes, ulcers treated with CBD showed a greater reduc- tion in size compared to placebo18,38,39. Regarding the histological outcomes, two studies18,39 observed better histological findings in the groups treated with CBD while Cuba et al.38 did not observe statistical differences in histological evaluation between the group treated with CBD and the placebo. Groups treated with CBD showed reduced expression of inflammatory factors and anti-inflammatory infil- trate18, decreased levels of proinflammatory cytokeratins, and increased levels of expression of antioxidant enzymes39. Ulcers on the tongue were investigated in two studies17,37. The ulcers were created (mechanically or with acid) on the tongue of mice17,37. One of them administered 5 10 Mederos et al. Braz J Oral Sci. 2025;24:e255518 and 10 mg/kg of weight of CBD intraperitoneally using Tween 80 in saline solution as a vehicle, the other study administered 1 and 10 mg/kg directly to the lesion (topi- cal) without specifying the vehicle used. In both studies, experimentally isolated CBD was used as an active component. The observed clinical and histological results were positive17,37. Regarding clinical outcomes, ulcers treated with CBD were smaller in size than those in the placebo group. Histologically, a lower degree of inflammation was observed concerning the control group in the first 3 days (no difference was observed after 7 days)37 and a decrease in inflammatory activity, and in the expression of the proteins NLRP3, IL-1β, IL-18, TNF-α17. Clinical studies Two clinical studies were found and both studies13,40 presented positive clinical results (primarily regarding pain control) in the use of CBD-based therapies. The first of them investigated the effect of cannabidiol extract on humans. It was a prospective single-arm study evaluating burning mouth syndrome. Seventeen patients were evaluated, 14 of whom were female, with an average age was 71 years. The treatment applied was a commercial extract in the form of drops with a concen- tration of 8% CBD and 6.3% THC (Bediol®), prepared with an olive oil-based vehicle. The dosage ranged from 10 to 40 drops daily, divided into two doses each day. The treatment duration ranged from 5 to 13 days. The main variable evaluated was pain, measured using the visual analog scale (VAS). Additionally, the level of anxiety and depression was assessed using the Hospital Anxiety and Depression Scale (HADS) and the Geriatric Depression Scale (GDS). Based on statistical analyses, the results suggest a significant reduction in pain at 4, 12, and 24 weeks compared to the base- line. For anxiety and depression levels, a significant decrease was reported only after 24 weeks compared to baseline. The authors reported that 3 individuals reported diz- ziness the first week, 2 reported headaches (on the 5th and 15th day) and 1 individual reported constipation after 24 days of treatment. Despite this, none of the participants had to abandon the study. The second clinical study analyzed the effect of cannabidiol on recurrent aphthous ulcers (RAU). The study was a randomized, double-blind, controlled clinical trial involving 72 patients with RAU, with ages ranging from 18 to 65 years. Participants were randomly divided into three groups: 0.1% CBD, 0.1% triamcinolone acetonide (TA), and placebo. All therapies were applied topically, directly to the lesions. Oint- ments with corresponding active components were experimentally prepared, without detailing the vehicles used. The ointments were applied with a calibrated applicator (no quantities in weight or volume are specified), three times a day for seven days, before eating. The variables evaluated were the size of the ulcer in millimeters at base- line, 2, 5, and 7 days. Pain was assessed daily using the VAS scale. Satisfaction with the therapy used and quality of life during the treatment were also evaluated, along with any allergic reactions or side effects. The results suggest that the groups treated with CBD showed greater reduction in the size of ulcers, less pain, higher satisfaction, and improved quality of life compared to the placebo group at all times evaluated. No differences were found between the groups treated with CBD and TA. No side effects were reported. 11 Mederos et al. Braz J Oral Sci. 2025;24:e255518 Discussion This study was the first to map the available evidence on the use of cannabidiol in lesions of the oral mucosa. Based on the potential properties of CBD reported in the literature, and the results obtained in the analyzed studies, we can con- sider that (1) the use of CBD appears to be effective in investigated lesions of the oral mucosa (oral mucositis, oral ulcers, and burning mouth syndrome) when using different CBD-based therapies, thus presenting preliminarily positive in vivo results when compared to placebo. Complementary histological analyses in most reports demonstrated that CBD-based therapies appear to reduce the inflamma- tory response in the oral lesions evaluated17,18,37,39; and (2) CBD-based therapies seem to be a promising strategy for pain control in oral mucosa lesions13,40. The different concentrations used have demonstrated similar results, with no signif- icant differences observed between the dosages reported. However, additional studies are needed to confirm these preliminary findings and their interpretations should be carried out with caution. Our findings indicate that the main effect of CBD-based therapies is the potential to improve the healing process and provide significant pain reduction. Indeed, CBD can act through several mechanisms to reduce painful and inflammatory symptoms4. First, CBD can bind to the CB1 and CB2 cannabinoid receptors in the nervous and immune systems, respectively, which can reduce the perception of pain and modu- late the inflammatory response41. Furthermore, CBD can also inhibit the production of pro-inflammatory cytokines, which are signaling molecules that contribute to inflam- mation. Finally, CBD can interact with other receptors in the body, such as the vanilloid TRPV1 receptor, which is involved in pain transmission, and the PPAR-gamma recep- tor, which can help regulate the inflammatory response41. These combined mecha- nisms may explain the capacity of CBD to reduce painful symptoms and inflammation of lesions of the oral mucosa observed in the present review. Although some studies have used systemic application of CBD13, there is a consensus that the preferred treatment approach is through topical application of medications42. This is because the goal is to achieve a localized and specific treatment of the lesion. In certain situations, such as when considering the severity and intensity of the injury, high recurrence, or lesions that do not heal, or in patients with specific systemic condi- tions, it is possible to implement systemic therapy43-45. However, the long-term admin- istration of some medications has unwanted effects on patients46. Despite this, according to the results of this work, we can observe that the majority of investigated CBD-based therapies for the treatment of lesions in the oral mucosa have been administered through systemic action13,18,37-39, and only in three studies was the treatment of the lesion was carried out through topical application17,18,40. This could be attributed to the fact that the majority of studies were carried out in vivo. In these cases, cannabis was administered intravenously and intraperitoneally for the treatment of oral ulcers and mucositis induced in animal models18,37-39. In the ana- lyzed clinical studies, systemic therapy (oral drops) was used in patients with burning mouth syndrome, while in the other study, a topical application of CBD was used for recurrent aphthous ulcers. 12 Mederos et al. Braz J Oral Sci. 2025;24:e255518 From in vivo studies that administered CBD to oral mucosal lesions17,18, oral muco- sitis and ulcers were evaluated. In one study, a dose of 30 µl of an experimental CBD preparation (1 mg/ml) in the form of nanomicelles was applied, and in the second study, 1 and 10 mg/ml of experimental CBD in the form of a spray was used. For the treatment of mucositis, a decrease in Ly6G, a marker of inflammation, was observed18. CBD reduced the expression of cytidine monophosphate/uridine kinase 2 (CMPK2), which is responsible for inhibiting the generation of oxidized mitochon- drial DNA and suppressing the activation of inflammation17. Furthermore, CBD was able to improve the healing capacity of ulcerative lesions, demonstrating a greater reduction in size and faster healing compared to the control group17,18. At a clinical level, patients with burning mouth syndrome receive a dose of 5 to 20 drops daily, with treatments varying between 5 and 13 days. In this case, a com- mercial preparation in the form of oil (Bediol®) was used, containing 8% CBD and 6.3% THC, diluted in olive oil at a proportion of 1/10 g. The results demonstrated a significant reduction in pain at 4, 12, and 24 weeks compared to baseline13. When an experimental preparation with 0.1% CBD was applied topically to recurrent aph- thous ulcers, a decrease was observed in the perception of pain, improvements in healing times, and in the quality of life reported by patients compared to the placebo group. No significative differences were found in comparison with the control group (0.1% Triamcinolone)40. A case report suggested the effectiveness of oral canna- bis administration for pain in rare skin lesions47. Due to its potential benefits, there is great interest in the use of cannabis for treating different skin conditions, such as psoriasis, pruritus, acne, lupus erythematosus, allergic contact dermatitis, some types of cancer, etc.48-50. Indeed, only one of the clinical studies included administered drops of CBD orally to patients diagnosed with burning mouth syndrome. The authors reported that approximately a third of the participants experienced some adverse effects, such as flushing, headache, and constipation. Despite this, none of the participants had to abandon the study, considering the mild and temporary nature of these effects13. For topical applications on the skin, not all studies detail adverse effects. In several clini- cal studies where cannabis was used for skin lesions topically, no adverse reactions were reported19. In another study, when a single patient was administered cannabis orally, she reported an increase in appetite47. In an observational study conducted on 9 patients with multiple sclerosis, the appearance of white lesions in the oral mucosa was described, which the authors attributed to the alcohol used as a vehicle in the commercial preparation, as it was administered orally51. Despite this, several authors agree that its use is safe19,51. Finally, there is a possibility that the patient may be allergic to both the cannabinoids administered and the additives used in the products, which is why an allergy test is suggested before starting any treatment52. Recently, a group of experts with training and experience in cannabis medicine gen- erated a consensus regarding the most appropriate doses of cannabis administered orally for pain control in various systemic conditions (e.g., neuropathic pain, cancer, multiple sclerosis, osteoporosis, fibromyalgia), suggesting that therapies should always start with doses of pure CBD at 5 mg/kg, and can be gradually increased to a maximum of 40 mg/kg53. It was reported that, if necessary, a combined CBD and THC 13 Mederos et al. Braz J Oral Sci. 2025;24:e255518 therapy can be managed by the professional, adding to the previously indicated CBD dose 2.5 mg/kg of THC, up to a maximum of 40 mg/kg53. In addition to the possible benefits of this type of therapy, it is important to note that many CBD-based prod- ucts available on the market also contain small quantities of other cannabinoids49. This information is relevant for professionals and for the design of research meth- odologies, as often the specific product compositions are not disclosed, which could affect the results obtained and generate unwanted effects due to a lack of information regarding the quality of the products used49. Some authors mention that the application of topical medication for oral lesions pres- ents an extra challenge compared to the skin, due to the presence of saliva and other exudates that produce a washing effect or contamination from the environment54-56. For this reason, various methods have been suggested for the transport and delivery of medicines to mucous membranes, such as the use of patches, hydrogels, micelles, or granules with nanotechnology, which can increase contact time with tissues and concentrations absorbed by them57-60. Other factors that can also influence the for- mulations include concentrations of active components, diluents, and vehicles used in products61,62. These attributes were not evaluated in the current review. Cannabis extracts have been evaluated in vitro skin/mucosa models, demonstrating different penetration capacities depending on the concentration of the active component and the vehicle used13,61,62. We are aware that this study has limitations. These include the number of pub- lished studies available at the time and the heterogeneity in cannabis-based ther- apies applied. Furthermore, few conditions of the oral mucosa have been evalu- ated. More clinical studies need to be conducted, with complete details provided regarding the source of cannabis, the cannabinoids used, concentration, excipients, vehicles, and dosages. A standardized control and follow-up protocol must be rig- orously established in clinical studies to ensure the safety of the therapies used. A consensus must be established regarding the dosages, both topical and systemic; for this reason, other cannabinoids and combined “full spectrum” therapies should be analyzed. Finally, due to the significant development of commercial products and studies using cannabis as medicine, it is recommended to establish interdis- ciplinary research lines to obtain a comprehensive view of conditions, therapies, and evaluated outcomes. Another limitation of the present study is the inclusion of only clinical studies with human participants, which limits our ability to extrap- olate the findings. Additionally, different animals were evaluated in in vivo studies, making direct comparisons between results challenging. Future studies may also enhance search specificity by incorporating additional oral conditions, such as oral mucositis, into the search strategy to ensure broader and more targeted coverage of relevant pathologies. Conclusions We found that CBD appears effective in treating oral mucosa lesions (oral mucositis, ulcers, burning mouth syndrome) using different CBD-based therapies, showing prom- ising in vivo results compared to placebo. Histological analyses indicate that CBD- based therapies can reduce inflammation in these lesions. Moreover, we observed 14 Mederos et al. Braz J Oral Sci. 2025;24:e255518 that CBD-based therapies hold promise for pain control and healing lesions in oral mucosa lesions in clinical studies. Different CBD concentrations yielded similar out- comes, highlighting the need for further studies to validate these preliminary results. Fundings The authors have no funding related to the present review. Conflict of Interest The authors of this work declare that there is no potential conflict of interest. Data availability Datasets related to this article will be available to the corresponding author upon request. 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