Evidence for Cannabidiol as a Medication for the Treatment of Neurological, Psychiatric, Behavioral and Substance Use Disorders in Adolescents
Round 1
Reviewer 1 Report
Comments and Suggestions for AuthorsIt is a well-structured comprehensive review paper focusing on the potential therapeutic effects of CBD in adolescence This topic is very important, and in light of its clinical implications this review is timing and helpful. There are few issues that should be addressed by the authors in order to increase the impact of this review, including the addition of missing information.
Minor concerns:
Point 1: Section 3.2 “Schizophrenia”: The following papers suggesting the potential therapeutic effects of adolescent CBD exposure on neurodevelopmental disorders including schizophrenia should be cited
Stark et al., 2021 Pharmacol. Res. 174:105938. doi: 10.1016/j.phrs.2021.10593
Di Bartolomeo et al., 2021 Pharmacol Res 164: 105357. https://doi.org/10.1016/j.phrs.2020.105357
Stark et al., 2020 Biochem Pharmacol. 177:114004 doi: 10.1016/j.bcp.2020.114004.
Stark et al., 2019. Neuropharmacology 146: 212-221.doi: 10.1016/j.neuropharm.2018.11.035
Point 2: Section 3.6 ”Fragile X Syndrome” The following paper suggesting the potential therapeutic effects of adolescent CBD exposure on Fragile X Syndrome should be cited:
Manduca et al., 2024 Pharmacol Res. 203:107176. doi: 10.1016/j.phrs.2024.107176.
Overall, the above papers shown that CBD exposure during sensitive period of the life (i.e. adolescence) may ameliorate the behavioural and molecular alterations, which are similar to those described in subjects suffering of neurodevelopmental disorders such as schizophrenia or Fragile X Syndrome, suggesting that CBD treatment may have potential efficacy to prevent the development of psychopathologies.
Conclusions:
I feel that minor revision is required, especially regarding the above citations to add in the text, which are strictly related to the topic of the MS.
Author Response
Comment 1:
Minor concerns:
Point 1: Section 3.2 “Schizophrenia”: The following papers suggesting the potential therapeutic effects of adolescent CBD exposure on neurodevelopmental disorders including schizophrenia should be cited
Stark et al., 2021 Pharmacol. Res. 174:105938. doi: 10.1016/j.phrs.2021.10593
Di Bartolomeo et al., 2021 Pharmacol Res 164: 105357. https://doi.org/10.1016/j.phrs.2020.105357
Stark et al., 2020 Biochem Pharmacol. 177:114004 doi: 10.1016/j.bcp.2020.114004.
Stark et al., 2019. Neuropharmacology 146: 212-221.doi: 10.1016/j.neuropharm.2018.11.035
Response 1:
Thank you for these comments. The papers noted above in point 1 describe pre-clinical studies/animal models. We have added a brief summary of this information to the introduction. Page 2, paragraph 1, lines 45 and 47.
Comment 2:
Point 2: Section 3.6 ”Fragile X Syndrome” The following paper suggesting the potential therapeutic effects of adolescent CBD exposure on Fragile X Syndrome should be cited:
Manduca et al., 2024 Pharmacol Res. 203:107176. doi: 10.1016/j.phrs.2024.107176.
Overall, the above papers shown that CBD exposure during sensitive period of the life (i.e. adolescence) may ameliorate the behavioural and molecular alterations, which are similar to those described in subjects suffering of neurodevelopmental disorders such as schizophrenia or Fragile X Syndrome, suggesting that CBD treatment may have potential efficacy to prevent the development of psychopathologies.
Response 2:
Thank you for these comments. The papers noted above in point 2 describe pre-clinical studies/animal models. We have added a brief summary of this information to the introduction. Page 2, paragraph 1, lines 45 and 47
Reviewer 2 Report
Comments and Suggestions for AuthorsThe main issue with the manuscript is that it feels more like a general summary of existing studies rather than a focused review that tries to answer an important research question. A good review article should do more than just collect information, it should help readers understand what we already know, what we still don’t know, and how future research can move forward. Right now, the manuscript seems to include almost everything that’s been published on the topic, but without a clear direction or purpose.
I suggest organizing the content in a more focused way. Try to clearly explain the gaps in current knowledge and give enough background about how CBD is thought to work for the condition being discussed. It would also be helpful to add a separate section with future research suggestions and expert opinions. Including summary tables, listing each condition studied, the dose of CBD used, and whether the results were positive or negative, would also make the review more useful for readers.
Author Response
Comment 1:
The main issue with the manuscript is that it feels more like a general summary of existing studies rather than a focused review that tries to answer an important research question. A good review article should do more than just collect information, it should help readers understand what we already know, what we still don’t know, and how future research can move forward. Right now, the manuscript seems to include almost everything that’s been published on the topic, but without a clear direction or purpose.
I suggest organizing the content in a more focused way. Try to clearly explain the gaps in current knowledge and give enough background about how CBD is thought to work for the condition being discussed. It would also be helpful to add a separate section with future research suggestions and expert opinions.
Response 1:
We have extensively reorganized the manuscript according to the reviewer’s suggestions. We now include information on how CBD is thought to work for each condition described. Our Discussion gives suggestions for future research. See Discussion on page 11-12, lines 451-472.
Comment 2:
Including summary tables, listing each condition studied, the dose of CBD used, and whether the results were positive or negative, would also make the review more useful for readers.
Response 2:
We have included a summary table as described by the reviewer. See the table at the end of the manuscript text pages 12-18.
Reviewer 3 Report
Comments and Suggestions for AuthorsThe subject is currently something of a “hot topic”, and this study makes significant contributions.
To improve the quality of the manuscript, consider the following revisions:
- Include the following figure or chart to present data more clearly and enhance understanding:
- A diagram illustrating the role of CBD in adolescent medication.
- In line 345, references were cited in the conclusion section. The discussion and conclusion sections should be presented separately.
- Several registered medications are used in adolescents; however, a more comprehensive discussion is needed to highlight the significance of CBD-based treatments compared to these registered drugs.
Author Response
Comment 1:
The subject is currently something of a “hot topic”, and this study makes significant contributions.
To improve the quality of the manuscript, consider the following revisions:
- Include the following figure or chart to present data more clearly and enhance understanding: A diagram illustrating the role of CBD in adolescent medication.
Response 1:
We have developed a summary table describing the impacts and side effects of CBD for each condition discussed. See table at the end of the manuscript text on pages 12-18.
Comment 2:
In line 345, references were cited in the conclusion section. The discussion and conclusion sections should be presented separately.
Response 2:
We have separated the Discussion and Conclusion sections. See pages 11-12, lines 451-485
Comment 3:
Several registered medications are used in adolescents; however, a more comprehensive discussion is needed to highlight the significance of CBD-based treatments compared to these registered drugs.
Response 3:
We have added a paragraph to the Discussion section that more clearly indicates the distinction between CBD medications with an official indication and unregulated over the counter products. See pages 11-12, lines 467-472
Reviewer 4 Report
Comments and Suggestions for AuthorsPresent manuscript reviews case reports and clinical trials studying CBD as medication applied in various central nervous or central nervous related conditions and in miscellaneous diseases.
The topic of this manuscript is extremely important for scientific community. Since there is a growing body of evidence regarding medical application of CBD, this review will be a helpful paper to get a structured data about recent novelties.
Present manuscript reviews case reports and clinical trials studying CBD as medication applied in various central nervous or central nervous related conditions and in miscellaneous diseases.
The topic of this manuscript is extremely important for scientific community. Since there is a growing body of evidence regarding medical application of CBD, this review will be a helpful paper to get a structured data about recent novelties.
The title of manuscript is very promising with a clear goal and focus. However, in the abstract the authors are narrowing their review on central nervous system related diseases with special focus on effect on brain development of long-term CBD use. Furthermore, the in the main text lot of case reports and clinical trials are summarised. The study involved population widely varying in age and in studied medical conditions.
Although the current study has merits, this manuscript must be improved.
I would like to add several comments about the content and style of the manuscript.
1.) Reconsider use of more adequate title reflecting more on the content of the manuscript.
2.) Rephrase the last part of the abstract referring to the brain development, since this part is not discussed sufficiently and evidence is not provided in the manuscript supporting it.
3.) Since present study focuses on CBD, it might be a bit misleading if effects of non-CBD cannabinoids are discussed. For example, in section 2.5 the cited reference is a review. Citing review would not be problem itself; however, it is not clear which described effect is belonging to study carried out with CBD and which effect is coming from other cannabinoids or Cannabis sativa extract. I strongly suggest to re-check the entire review for these, potentially misleading data. Please analyse and cite the original primary studies instead of reviews.
4.) Your study is going to be an extremely useful review paper. Please, add more specific data supporting your statements. Fo example, in section 2.3 ‘fewer adverse effects’ term is mentioned; however, it would be more useful to know which significant adverse effects were reported from which effects were less frequent when lower dose was applied.
5.) The references are cited next to the title of the section. It would be more effective and accurate to cite the reference in the text itself where the specific data from the referred study is mentioned.
The manuscript is written in excellent English and style. I have few recommendations only:
- Use en-dash to indicate intervals (e.g. 3–19 years or 25–150 mg).
- Unify the use of RCT abbreviation through entire text.
- Unify the use of ‘double blind’ or ‘double-blind’ through entire text.
- Check the reference list and apply consistent style (i.e. using of capital letters only/sentence case/capitalise the first letter only in title or journal name). Check for the missing page numbers of article id (e.g. reference #28).
I would be honoured if the authors would consider my comments on the present manuscript.
Author Response
Comment 1:
Present manuscript reviews case reports and clinical trials studying CBD as medication applied in various central nervous or central nervous related conditions and in miscellaneous diseases.
The topic of this manuscript is extremely important for scientific community. Since there is a growing body of evidence regarding medical application of CBD, this review will be a helpful paper to get a structured data about recent novelties.
Present manuscript reviews case reports and clinical trials studying CBD as medication applied in various central nervous or central nervous related conditions and in miscellaneous diseases.
The topic of this manuscript is extremely important for scientific community. Since there is a growing body of evidence regarding medical application of CBD, this review will be a helpful paper to get a structured data about recent novelties.
The title of manuscript is very promising with a clear goal and focus. However, in the abstract the authors are narrowing their review on central nervous system related diseases with special focus on effect on brain development of long-term CBD use. Furthermore, the in the main text lot of case reports and clinical trials are summarised. The study involved population widely varying in age and in studied medical conditions.
Response 1:
Thank you for this comment. We have changed the title of the manuscript to, “Evidence for Cannabidiol as a Medication for Adolescents in the treatment of neurologic, psychiatric, behavioral and substance use disorders”. See page 1, lines 1-4. We have included more information, including descriptions of the pathophysiology of disorders (when known) and the CBD mechanisms that are thought to underlie the benefits. To make the manuscript more concise, we have eliminated the section on “miscellaneous conditions”. See redacted text pages 10-11, lines 415-450. While the research regarding the impact of CBD on cancer, metabolic disorders and inflammatory diseases and other conditions is very compelling, they now are a bit out of scope for this paper which focuses on common problems in children and adolescents.
Comment 2:
Although the current study has merits, this manuscript must be improved.
I would like to add several comments about the content and style of the manuscript.
Reconsider use of more adequate title reflecting more on the content of the manuscript.
Response 2:
We have changed the title, as above. See page 1, lines 1-4.
Comment 3:
Rephrase the last part of the abstract referring to the brain development, since this part is not discussed sufficiently and evidence is not provided in the manuscript supporting it.
Response 3:
We have revised the abstract to make a clear distinction between CBD pharmaceuticals and unregulated CBD preparations that are available over the counter. See page 1, lines 21-32. We have also added a reference to a review of the role of endocannabinoids on brain development to the introduction. See page 2, lines 49-51.
Comment 4:
Since present study focuses on CBD, it might be a bit misleading if effects of non-CBD cannabinoids are discussed. For example, in section 2.5 the cited reference is a review. Citing review would not be problem itself; however, it is not clear which described effect is belonging to study carried out with CBD and which effect is coming from other cannabinoids or Cannabis sativa extract. I strongly suggest to re-check the entire review for these, potentially misleading data. Please analyse and cite the original primary studies instead of reviews.
Response 4:
Thank you for pointing this out. Some of the studies that were included tested substances that were not pure CBD. In all cases, we have noted the substance that was tested (eg “high CBD cannabis) exactly as it is noted in the paper.
Comment 5:
Your study is going to be an extremely useful review paper. Please, add more specific data supporting your statements. Fo example, in section 2.3 ‘fewer adverse effects’ term is mentioned; however, it would be more useful to know which significant adverse effects were reported from which effects were less frequent when lower dose was applied.
Response 5:
We have extensively reorganized the manuscript and we have added more specific information throughout, including the presumed mechanistic underpinnings for each condition.
Comment 6:
The references are cited next to the title of the section. It would be more effective and accurate to cite the reference in the text itself where the specific data from the referred study is mentioned.
The manuscript is written in excellent English and style. I have few recommendations only:
- Use en-dash to indicate intervals (e.g. 3–19 years or 25–150 mg).
- Unify the use of RCT abbreviation through entire text.
- Unify the use of ‘double blind’ or ‘double-blind’ through entire text.
- Check the reference list and apply consistent style (i.e. using of capital letters only/sentence case/apitalize the first letter only in title or journal name). Check for the missing page numbers of article id (e.g. reference #28).
I would be honoured if the authors would consider my comments on the present manuscript.
Response 6:
Thank you, We are happy to conform to the style of the journal.
Round 2
Reviewer 2 Report
Comments and Suggestions for AuthorsAuthors have substantially improved the quality of the manuscript, and I have no further comments for the authors.
