The Potential of Cannabidiol in the Management of Oral Infections
Round 1
Reviewer 1 Report
Comments and Suggestions for AuthorsReview:
The manuscript, “The Potential of Cannabidiol in the Management of Oral Infections”, presents a timely and comprehensive overview of cannabidiol (CBD) as a potential therapeutic agent in the treatment of oral infections. The review effectively compiles preclinical and emerging clinical data supporting CBD’s antimicrobial, anti-inflammatory, and immunomodulatory activities, particularly in diseases such as periodontitis, mucositis, and candidiasis. The author highlights the advantages of novel delivery systems – such as nanoparticles, hydrogels, and inserts – for improving CBD’s bioavailability and targeting in oral tissues. Importantly, the manuscript addresses the current limitations in the field, including the lack of standardized formulations, variability in study designs, and insufficient long-term human data. These issues are appropriately emphasized as key barriers to the clinical translation of CBD in dentistry. The review also explores future perspectives, such as the potential for combination therapies and the need for regulatory alignment. Nonetheless, the manuscript would benefit from a more critical differentiation between in vitro/preclinical evidence and clinical applicability. Additional discussion on the pharmacokinetics of CBD in the oral cavity, along with patient-centered outcomes (e.g., pain, quality of life), would enrich the narrative. Clarifying the language in some sections, especially in terms of technical phrasing and cohesion, would improve overall readability. Overall, the article makes a valuable contribution to cannabinoid-based oral therapeutics and underscores the need for well-designed clinical trials and standardized delivery approaches. Addressing the mentioned points would further enhance its scientific rigor and practical relevance.
However, to strengthen the data and ensure clarity, the suggested revisions should be fully addressed.
Major revisions
Lines 137, 318, and 532:
The author state: “Studies suggest that CBD may act synergistically with conventional antimicrobials, potentially enhancing their efficacy and reducing the required dose.” Antibiotics (in the strict sense): originally defined as natural substances produced by microorganisms (such as bacteria or fungi) that inhibit or kill other microorganisms, especially bacteria. In contrast, antimicrobials represent a broader category and include any agent – whether of protozoan, animal, plant, semi-synthetic, or synthetic origin –capable of killing or inhibiting the growth of any type of microorganism. This inconsistency must be thoroughly addressed. Therefore, the author should carefully review the entire manuscript to avoid conveying misleading conceptual information.
In Section 6. Challenges and Future Perspectives (should be corrected to Section 7. Challenges and Future Perspectives): Lack of a concluding sentence. The passage ends abruptly after listing items “i–iii.” A transitional or concluding sentence would strengthen the argument and improve flow. Suggested addition: “Together, these strategies may enhance the therapeutic utility of CBD while mitigating potential limitations related to efficacy and microbial resistance.”
Minor revisions
Lines 100 to 101:
Rewrite the sentence for:
“This is particularly relevant in the dental setting, where short-term prescriptions are common and often taken without adequate supervision [15].” to “This is particularly relevant in dentistry, where short-term prescriptions are common and often inadequately supervised [15].” In this way, the text is presented in a more fluid way.
Lines 141 and 142:
Rewrite the sentence for:
“CBD also has benefits in bone and soft tissues, increasing regeneration after oral infections.” to “CBD also shows benefits for bone and soft tissue regeneration following oral infections.”
Line 180:
Rewrite the sentence for:
“Replace “Cannabis sativa L..” with “Cannabis sativa L.”, or alternatively, replace “L.” with “Linnaeus”
Line 186:
Rewrite the sentence for:
“…terpenephenolic…” to “…terpenophenolic…”
Line 204:
Rewrite the sentence for:
“…biofilms, a major virulence factor…” to “…biofilms, which are a major virulence factor...”
Line 206:
Rewrite the sentence for:
“CBD’s lipophilic structure allows it to integrate into microbial cell membranes…” to "The lipophilic structure of CBD enables its integration into microbial membranes...”
Line 216:
Rewrite the sentence for:
“CBD enhances the efficacy of conventional antibiotics...” to “CBD has been shown to enhance the efficacy of conventional antibiotics...”
Lines 220 and 221:
Rewrite the sentence for:
“Although less extensively studied, CBD also exhibits antifungal activity…” to “CBD also exhibits antifungal activity, although this has been less extensively studied…”
Lines 251 to 253:
Rewrite the sentence for:
“Concerning CBD sublingual absorption, CBD is placed under the tongue and is absorbed through the highly vascularized sublingual mucosa.” to “In sublingual administration, CBD is placed under the tongue and absorbed through the highly vascularized mucosa.” In this way, the text is presented in a more fluid way.
Lines 254 to 256:
Rewrite the sentence for:
“Concerning buccal absorption, it offers a slower but sustained absorption pathway through the inner cheek, …” to “Buccal absorption offers a slower but sustained route through the inner cheek, …” In this way, the text is presented in a more fluid way.
Lines 260 and 261:
Rewrite the sentence for:
“Once absorbed, CBD, due to its lipophilic nature, readily diffuses through cell membranes...” to “Due to its lipophilic nature, CBD readily diffuses through cell membranes once absorbed...”
Lines 261 and 162:
Rewrite the sentence for:
“Studies suggest that after mucosal absorption, CBD may distribute effectively into the gingival epithelium…” to “Studies suggest that following mucosal absorption, CBD may distribute effectively to the gingival epithelium…”
Lines 284 and 285:
Rewrite the sentence for:
“...under investigation to optimize pharmacokinetics and therapeutic outcomes in oral diseases [37].” to “...being investigated to optimize both pharmacokinetic properties and therapeutic outcomes in oral health [37].” In this way, the text is presented in a more fluid way.
Line 295:
Rewrite the sentence for:
“...on hydroxyapatite and enamel-like surfaces [19,20].” to “...on hydroxyapatite-coated and enamel-analogous surfaces [19,20].”
Line 298:
Rewrite the sentence for:
“…notorious...” to “...noted…”
Lines 315 and 316:
Rewrite the sentence for:
“CBD-treated Candida biofilms show reduced adhesion...” to “CBD treatment reduces Candida biofilm adhesion...” In this way, the text is presented in a more fluid way.
Line 321:
Rewrite the sentence for:
“…"does not appear to induce significant microbial resistance…” to “…has not been associated with significant microbial resistance…”
Line 346:
Rewrite the sentence for:
“...performs...” to “...favors...”
Lines 452 and 453:
Rewrite the sentence for:
“…pathogens like Porphyromonas gingivalis and Streptococcus mutans and modulation of local inflammation [73].” to “...pathogens such as Porphyromonas gingivalis and Streptococcus mutans, along with modulation of local inflammation [73].”
Lines 456 and 457:
Rewrite the sentence for:
“...CBD, maintaining therapeutic levels and supporting tissue regeneration and microbial control [74].” to “... CBD, thereby maintaining therapeutic levels and supporting both tissue regeneration and microbial control [74].”
Line 462:
Rewrite the sentence for:
“...localized high...” to “...high localized...”
Lines 471 and 472:
Rewrite the sentence for:
“In Table 2 the main CBD delivery methods...” to “Table 2 summarizes the main CBD delivery methods...”
Line 487:
Rewrite the sentence for:
“Differences in CBD delivery (e.g., oil, gel, rinse, systemic), ...” to “Differences in CBD delivery methods (e.g., oils, gels, rinses, or systemic administration), ...”
Lines 489 and 490:
Rewrite the sentence for:
“…studies are limited to acute outcomes...” to “…studies assess only acute outcomes...”
Lines 491 and 492:
Rewrite the sentence for:
“...are open-label or uncontrolled...” to “...are either open-label or lack appropriate control groups...”
Line 493:
Rewrite the sentence for:
“...across regions limits...” to “...across jurisdictions limits ...”
Line 502:
Rewrite the sentence for:
“6. Challenges and Future Perspectives” to “7. Challenges and Future Perspectives”
Line 305:
Rewrite the sentence for:
“…lack placebo control, or are limited by short follow-up periods [16,60].” to “…lack placebo controls, or have short follow-up periods [16,60].”
Lines 520 and 521:
Rewrite the sentence for:
“...purity, presence of other cannabinoids (e.g., THC, CBG), delivery format (gels, rinses, patches, nanoparticles).” to “...purity, the presence of other cannabinoids (e.g., THC, CBG), and delivery format (e.g., gels, rinses, patches, nanoparticles).”
Lines 523 and 524:
Rewrite the sentence for:
“...complicating dose selection for clinical use.” to “...complicating the selection of appropriate doses for clinical use.”
Line 536:
Rewrite the sentence for:
“7. Conclusions” to “8. Conclusions”
Lines 544 to 546:
Rewrite the sentence for:
“...key components in the pathogenesis and treatment of oral infections such as dental caries, periodontal disease, and candidiasis.” to “...key factors in the pathogenesis and treatment of oral infections, including dental caries, periodontal disease, and candidiasis.”
Lines 548 and 549:
Rewrite the sentence for:
“...including limited high-quality human studies, inconsistent formulations and dosing strategies, and regulatory barriers.” to “...including the lack of high-quality human studies, inconsistency in formulations and dosing strategies, and persistent regulatory barriers.”
Line 553:
Rewrite the sentence for:
“...standardized, pharmaceutically...” to “...standardized and pharmaceutically...”
Lines 554 to 556:
Rewrite the sentence for:
“...CBD holds the potential to address unmet clinical needs and complement existing antimicrobial strategies in the management of oral infectious diseases.” to “...CBD holds significant potential to address unmet clinical needs and complement existing antimicrobial strategies in managing oral infectious diseases.”
Comments on the Quality of English LanguageThe English could be improved to more clearly express the research.
Author Response
Reviewer 1
Answers for reviewer 1:
Dear reviewer
Thank you very much for your helpful and important comments which were taken into consideration and responded to below and marked on the manuscript in blue.
Comment 1: Lines 137, 318, and 532:
The author state: “Studies suggest that CBD may act synergistically with conventional antimicrobials, potentially enhancing their efficacy and reducing the required dose.” Antibiotics (in the strict sense): originally defined as natural substances produced by microorganisms (such as bacteria or fungi) that inhibit or kill other microorganisms, especially bacteria. In contrast, antimicrobials represent a broader category and include any agent – whether of protozoan, animal, plant, semi-synthetic, or synthetic origin –capable of killing or inhibiting the growth of any type of microorganism. This inconsistency must be thoroughly addressed. Therefore, the author should carefully review the entire manuscript to avoid conveying misleading conceptual information.
Answer: The entire text was changed, reviewed, and changed according to the comment. Changes were done and marked in blue throughout the entire document and particularly on pages 4.
Comment 2: In Section 6. Challenges and Future Perspectives (should be corrected to Section 7. Challenges and Future Perspectives): Lack of a concluding sentence. The passage ends abruptly after listing items “i–iii.” A transitional or concluding sentence would strengthen the argument and improve flow. Suggested addition: “Together, these strategies may enhance the therapeutic utility of CBD while mitigating potential limitations related to efficacy and microbial resistance.”
Answer: The text was changed according to the comment. Changes were done and marked in blue on page 14.
Comment 3: Lines 100 to 101:
Rewrite the sentence for:
“This is particularly relevant in the dental setting, where short-term prescriptions are common and often taken without adequate supervision [15].” to “This is particularly relevant in dentistry, where short-term prescriptions are common and often inadequately supervised [15].” In this way, the text is presented in a more fluid way.
Answer: The text was changed according to the comment. Changes were made and marked in blue on page 3.
Comment 4: Lines 141 and 142:
Rewrite the sentence for:
“CBD also has benefits in bone and soft tissues, increasing regeneration after oral infections.” to “CBD also shows benefits for bone and soft tissue regeneration following oral infections.”.
Answer: The text was changed according to the comment. Changes were made and marked in blue on page 4.
Comment 5: Line 180:
Rewrite the sentence for:
“Replace “Cannabis sativa L..” with “Cannabis sativa L.”, or alternatively, replace “L.” with “Linnaeus”.
Answer: The text was changed according to the comment. Changes were made and marked in blue on page 5.
Comment 6: Line 186:
Rewrite the sentence for:
“…terpenephenolic…” to “…terpenophenolic…”
Answer: The text was changed according to the comment. Changes were made and marked in blue on page 5.
Comment 7: Line 204:
Rewrite the sentence for:
“…biofilms, a major virulence factor…” to “…biofilms, which are a major virulence factor...”
Answer: The text was changed according to the comment. Changes were made and marked in blue on page 6.
Comment 8: Line 206:
Rewrite the sentence for:
“CBD’s lipophilic structure allows it to integrate into microbial cell membranes…” to "The lipophilic structure of CBD enables its integration into microbial membranes...”
Answer: The text was changed according to the comment. Changes were made and marked in blue on page 6.
Comment 9: Line 216:
Rewrite the sentence for:
“CBD enhances the efficacy of conventional antibiotics...” to “CBD has been shown to enhance the efficacy of conventional antibiotics…”
Answer: The text was changed according to the comment. Changes were made and marked in blue on page 6.
Comment 10: Line 220 and 221:
Rewrite the sentence for:
“Although less extensively studied, CBD also exhibits antifungal activity…” to “CBD also exhibits antifungal activity, although this has been less extensively studied…”
Answer: The text was changed according to the comment. Changes were made and marked in blue on page 6.
Comment 11: Line 251 and 253:
Rewrite the sentence for:
“Concerning CBD sublingual absorption, CBD is placed under the tongue and is absorbed through the highly vascularized sublingual mucosa.” to “In sublingual administration, CBD is placed under the tongue and absorbed through the highly vascularized mucosa.” In this way, the text is presented in a more fluid way.
Answer: The text was changed according to the comment. Changes were made and marked in blue on page 6.
Comment 12: Line 254 and 256:
Rewrite the sentence for:
“Concerning buccal absorption, it offers a slower but sustained absorption pathway through the inner cheek, …” to “Buccal absorption offers a slower but sustained route through the inner cheek, …” In this way, the text is presented in a more fluid way.
Answer: The text was changed according to the comment. Changes were made and marked in blue on page 7.
Comment 13: Line 260 and 261:
Rewrite the sentence for:
“Once absorbed, CBD, due to its lipophilic nature, readily diffuses through cell membranes...” to “Due to its lipophilic nature, CBD readily diffuses through cell membranes once absorbed...”
Answer: The text was changed according to the comment. Changes were made and marked in blue on page 7.
Comment 14: Line 261 and 262:
Rewrite the sentence for:
“Studies suggest that after mucosal absorption, CBD may distribute effectively into the gingival epithelium…” to “Studies suggest that following mucosal absorption, CBD may distribute effectively to the gingival epithelium…”
Answer: The text was changed according to the comment. Changes were made and marked in blue on page 7.
Comment 15: Line 284 and 285:
Rewrite the sentence for:
“...under investigation to optimize pharmacokinetics and therapeutic outcomes in oral diseases [37].” to “...being investigated to optimize both pharmacokinetic properties and therapeutic outcomes in oral health [37].” In this way, the text is presented in a more fluid way.
Answer: The text was changed according to the comment. Changes were made and marked in blue on page 7.
Comment 16: Line 295:
Rewrite the sentence for:
“...on hydroxyapatite and enamel-like surfaces [19,20].” to “...on hydroxyapatite-coated and enamel-analogous surfaces [19,20].”
Answer: The text was changed according to the comment. Changes were made and marked in blue on page 7.
Comment 17: Line 298:
Rewrite the sentence for:
“…notorious...” to “...noted…”
Answer: The text was changed according to the comment. Changes were made and marked in blue on page 7.
Comment 18: Line 315 and 316:
Rewrite the sentence for:
“CBD-treated Candida biofilms show reduced adhesion...” to “CBD treatment reduces Candida biofilm adhesion...” In this way, the text is presented in a more fluid way.
Answer: The text was changed according to the comment. Changes were made and marked in blue on page 8.
Comment 19: Line 321:
Rewrite the sentence for:
“…"does not appear to induce significant microbial resistance…” to “…has not been associated with significant microbial resistance…”
Answer: The text was changed according to the comment. Changes were made and marked in blue on page 8.
Comment 20: Line 346:
Rewrite the sentence for:
“...performs...” to “...favors...”
Answer: I am really sorry, but I could not find it.
Comment 21: Line 452 and 453:
Rewrite the sentence for:
“…pathogens like Porphyromonas gingivalis and Streptococcus mutans and modulation of local inflammation [73].” to “...pathogens such as Porphyromonas gingivalis and Streptococcus mutans, along with modulation of local inflammation [73].”
Answer: The text was changed according to the comment. Changes were made and marked in blue on page 11.
Comment 22: Line 456 and 457:
Rewrite the sentence for:
“...CBD, maintaining therapeutic levels and supporting tissue regeneration and microbial control [74].” to “... CBD, thereby maintaining therapeutic levels and supporting both tissue regeneration and microbial control [74].”
Answer: The text was changed according to the comment. Changes were made and marked in blue on page 12.
Comment 23: Line 462:
Rewrite the sentence for:
“...localized high...” to “...high localized...”
Answer: The text was changed according to the comment. Changes were made and marked in blue on page 12.
Comment 24: Line 471 and 472:
Rewrite the sentence for:
“In Table 2 the main CBD delivery methods...” to “Table 2 summarizes the main CBD delivery methods...”
Answer: The text was changed according to the comment. Changes were made and marked in blue on page 12.
Comment 25: Line 487:
Rewrite the sentence for:
“Differences in CBD delivery (e.g., oil, gel, rinse, systemic), ...” to “Differences in CBD delivery methods (e.g., oils, gels, rinses, or systemic administration), ...”
Answer: The text was changed according to the comment. Changes were made and marked in blue on page 13.
Comment 26: Line 489 and 490:
Rewrite the sentence for:
“…studies are limited to acute outcomes...” to “…studies assess only acute outcomes...”
Answer: The text was changed according to the comment. Changes were made and marked in blue on page 13.
Comment 27: Line 491 and 492:
Rewrite the sentence for:
“...are open-label or uncontrolled...” to “...are either open-label or lack appropriate control groups...”
Answer: The text was changed according to the comment. Changes were made and marked in blue on page 13.
Comment 28: Line 493:
Rewrite the sentence for:
“...across regions limits...” to “...across jurisdictions limits ...”
Answer: The text was changed according to the comment. Changes were made and marked in blue on page 13.
Comment 29: Line 502:
Rewrite the sentence for:
“6. Challenges and Future Perspectives” to “7. Challenges and Future Perspectives”
Answer: The text was changed according to the comment. Changes were made and marked in blue on page 13.
Comment 30: Line 305:
Rewrite the sentence for:
“…lack placebo control, or are limited by short follow-up periods [16,60].” to “…lack placebo controls, or have short follow-up periods [16,60].”
Answer: The text was changed according to the comment. Changes were made and marked in blue on page 13.
Comment 31: Line 520 and 521:
Rewrite the sentence for:
“...purity, presence of other cannabinoids (e.g., THC, CBG), delivery format (gels, rinses, patches, nanoparticles).” to “...purity, the presence of other cannabinoids (e.g., THC, CBG), and delivery format (e.g., gels, rinses, patches, nanoparticles).”
Answer: The text was changed according to the comment. Changes were made and marked in blue on page 14.
Comment 32: Line 523 and 524:
Rewrite the sentence for:
“...complicating dose selection for clinical use.” to “...complicating the selection of appropriate doses for clinical use.”
Answer: The text was changed according to the comment. Changes were made and marked in blue on page 14.
Comment 33: Line 536:
Rewrite the sentence for:
“7. Conclusions” to “8. Conclusions”
Answer: The text was changed according to the comment. Changes were made and marked in blue on page 14.
Comment 34: Line 544 to 546:
Rewrite the sentence for:
“...key components in the pathogenesis and treatment of oral infections such as dental caries, periodontal disease, and candidiasis.” to “...key factors in the pathogenesis and treatment of oral infections, including dental caries, periodontal disease, and candidiasis.”
Answer: The text was changed according to the comment. Changes were made and marked in blue on page 14.
Comment 35: Line 548 and 549:
Rewrite the sentence for:
“...including limited high-quality human studies, inconsistent formulations and dosing strategies, and regulatory barriers.” to “...including the lack of high-quality human studies, inconsistency in formulations and dosing strategies, and persistent regulatory barriers.”
Answer: The text was changed according to the comment. Changes were made and marked in blue on page 14.
Comment 36: Line 553:
Rewrite the sentence for:
“...standardized, pharmaceutically...” to “...standardized and pharmaceutically...”
Answer: The text was changed according to the comment. Changes were made and marked in blue on page 14.
Comment 37: Line 554 to 556:
Rewrite the sentence for:
“...CBD holds the potential to address unmet clinical needs and complement existing antimicrobial strategies in the management of oral infectious diseases.” to “...CBD holds significant potential to address unmet clinical needs and complement existing antimicrobial strategies in managing oral infectious diseases.”
Answer: The text was changed according to the comment. Changes were made and marked in blue on page 14.
Comment 38: English was revised throughout the entire document and marked in blue.
Author Response File: 
Author Response.pdf
Reviewer 2 Report
Comments and Suggestions for AuthorsDear Author,
First of all, I want to express my congratulations for the scientific work. the topic is very interesting and brings new directions for using the Cannabidiol in oral infections management. It is well known that oral infections management is very complex and challenging and new methods must be found in order to minimize the life threatening potential.
The review, even if is a narative one, is very well structured and the informations are presented in a clear way.
On the introduction section please discuss the potential of oral infections to evolve and and spread along the fascial planes of the neck from the skull base to the mediastinum, being potentially life-threatening, as presented in the introduction part of this article: https://doi.org/10.3390/biomedicines11061710 . It is very important not to minimize the risk of death from the oral infections specially in immunocompromised patients.
Because the topics presented in the introduction are very exhaustive, I recommend to introduce subheadings in order to be more accesibile to the reader.
On the second section, I recommend if it is possible a figure that represents the chemical aspects of the Cannabidiol.
I appreciate the table regarding the CBD effects.
Author Response
Reviewer 2
Answers for reviewer 2:
Dear reviewer
Thank you very much for your helpful and important comments, which were taken into consideration and responded to below and marked on the manuscript in green.
Comment 1: On the introduction section please discuss the potential of oral infections to evolve and and spread along the fascial planes of the neck from the skull base to the mediastinum, being potentially life-threatening, as presented in the introduction part of this article: https://doi.org/10.3390/biomedicines11061710 . It is very important not to minimize the risk of death from the oral infections specially in immunocompromised patients..
Answer: The text was changed according to the comment. Changes were made and marked in green on page 2.
Comment 2: Because the topics presented in the introduction are very exhaustive, I recommend to introduce subheadings in order to be more accesibile to the reader.
Answer: The text was changed according to the comment. Changes were made and marked in green on page 2 and 3.
Comment 3: On the second section, I recommend if it is possible a figure that represents the chemical aspects of the Cannabidiol.
Answer: Figure 2 was added.
Comment 4: I appreciate the table regarding the CBD effects.
Answer: Thanks for the nice comment.
Author Response File: Author Response.pdf
Round 2
Reviewer 2 Report
Comments and Suggestions for AuthorsThe manuscript has been improved and can be published in present form.
