Review Reports - Cannabis, Cannabinoids, and Stroke: Increased Risk or Potential for Protection—A Narrative Review

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Based on the extensive review of the article titled "Cannabis Cannabinoids and Stroke: Increased Risk or Potential for Protection—a Scoping Review" by Caroline Carter et al., I propose the following suggestions for improvement:

1. Clearly define the scope and limitations of the scoping review in the introduction section to help readers understand the breadth and depth of the analyzed studies, including the types of studies (e.g., animal vs. human studies) and the cannabinoids explored. Explain "cannabinoid effects," specifying which cannabinoids and stroke types (ischemic, hemorrhagic) could refine the scope.

2. Provide a more detailed description of the literature search strategy, including databases searched, keywords used, and the inclusion/exclusion criteria to ensure replicability and transparency.

3. Enhance the critical analysis of included studies by discussing the quality of evidence, such as study design, sample size, and potential biases, to give readers a clearer understanding of the strength of the findings.

4. Provide clear definitions for key terms such as "chronic use," "recreational use," and "medical use" to ensure consistency and avoid ambiguity in the interpretation of findings.

5. Where data permits, analyze and discuss the dose-response relationship between cannabis use and stroke risk or protection to provide insights into how different levels of exposure might affect outcomes.

6. Differentiate the effects of various cannabinoids (e.g., THC vs. CBD) on stroke risk and outcomes more clearly, given their distinct pharmacological profiles and potential impacts.

7. Provide a more detailed analysis of potential confounding factors (e.g., use of other substances, underlying health conditions) in the studies reviewed and their impact on the findings.

8. Discuss the influence of age and gender on the relationship between cannabis use and stroke, considering the variability in stroke risk and cannabinoid effects across different populations.

9. Expand the Discussion on the proposed mechanisms of action through which cannabinoids might influence stroke risk and outcomes, incorporating recent scientific findings and theoretical models.

10. Highlight the clinical relevance of the review findings for healthcare professionals, including potential implications for patient counseling, risk assessment, and management strategies.

11. Clearly outline specific gaps in the current literature and propose directions for future research, emphasizing the need for longitudinal studies, clinical trials, and mechanistic studies.

12. Incorporate additional figures and tables to summarize key findings, mechanisms of action, and study characteristics, enhancing the visual appeal and accessibility of the information presented.

13. Discuss the broader public health implications of the findings, including the potential impact of changing cannabis legislation and social attitudes on stroke incidence and outcomes.

14. Refine the conclusion section to summarize the main findings more concisely, their limitations, and their implications for practice and policy, avoiding overgeneralizing results.

Implementing these suggestions should strengthen the manuscript's contribution to the field, providing a more comprehensive, critical, and nuanced overview of the current evidence on the relationship between cannabis use and stroke.

Author Response

Dear Reviewer,

Thank you for taking the time to review our manuscript, and for giving us the time to revise our manuscript. We have made changes according to your suggestions, all of which are listed below and highlighted throughout the manuscript so they can easily be found.

Reviewer 1:

Clearly define the scope and limitations of the scoping review in the introduction section to help readers understand the breadth and depth of the analyzed studies, including the types of studies (e.g., animal vs. human studies) and the cannabinoids explored. Explain "cannabinoid effects," specifying which cannabinoids and stroke types (ischemic, hemorrhagic) could refine the scope.
Response: Thank you for your feedback. However, we would like to clarify that our manuscript is a narrative review. As such, we did not collect specific information on the types of studies (e.g., animal vs. human studies) or delve into the nuances of individual cannabinoids. Our focus is on providing a comprehensive overview of cannabinoid effects in the context of stroke. We will, however, specify that the scope was primarily focused on ischemic stroke as it is the most common etiology and therefore is much better characterized.
Provide a more detailed description of the literature search strategy, including databases searched, keywords used, and the inclusion/exclusion criteria to ensure replicability and transparency.
Response: We acknowledge the importance of transparency and replicability. However, as this is a narrative review, we did not compile a formal literature search strategy. Our approach involved a comprehensive review of existing literature, including relevant studies, reviews, and expert opinions. We apologize for any inconvenience caused by the lack of specific details regarding databases searched, keywords used, or inclusion/exclusion criteria.
Enhance the critical analysis of included studies by discussing the quality of evidence, such as study design, sample size, and potential biases, to give readers a clearer understanding of the strength of the findings.
Response: We appreciate the reviewer’s attention to the quality of evidence. However, it’s essential to note that our review is not a systematic one. Instead, it takes a narrative approach, synthesizing available information from various sources. While we acknowledge the limitations inherent in this methodology, we have aimed to provide a balanced discussion of the findings, considering study design, sample size, and potential biases where applicable.
Provide clear definitions for key terms such as "chronic use," "recreational use," and "medical use" to ensure consistency and avoid ambiguity in the interpretation of findings.
Response: We understand the need for consistency and clarity. Unfortunately, in the context of cannabis, there are no universally accepted definitions for terms such as “chronic use,” “recreational use,” or “medical use.” These terms can vary significantly based on cultural, legal, and clinical contexts. Therefore, we have opted not to impose rigid definitions but rather interpret findings within the broader context of cannabinoid use. We have included a discussion of this phenomenon in our limitations section.

“Terms such as “users” and “non-users” are often listed without clarification on amount or frequency of usage, and dose dependency is an important factor in relation to cannabis use its link with stroke. “Chronic consumption” has also been listed in several reports without a clear operational definition of what this entails, such as how often and how much one needs to be consuming to fit the criteria of a chronic user”.
Where data permits, analyze and discuss the dose-response relationship between cannabis use and stroke risk or protection to provide insights into how different levels of exposure might affect outcomes.
Response: We have adjusted the section on dose and time dependency to reflect the state of the literature. Much of the categorization in the literature is not standardized and terms like “heavy user” or “light user” can be interpreted in many ways. For example, in early literature, Sally B. Zachariah, (Stroke, 1991) reports a heavy user as someone who smokes “7-14 marijuana cigarettes per day” while recent literature would report on frequency of use more often. Using terms such as “frequent user”, “daily user”, “regular user” etc. This has been identified as a limitation in the literature and we have identified it and reported on it in our manuscript here:

“Terms such as “users” and “non-users” are often listed without clarification on amount or frequency of usage, and dose dependency is an important factor in relation to cannabis use its link with stroke.”
Differentiate the effects of various cannabinoids (e.g., THC vs. CBD) on stroke risk and outcomes more clearly, given their distinct pharmacological profiles and potential impacts.
Response: We would like to thank the reviewer’s suggestion. It has been known that cannabis contains varieties of cannabinoids with most common substances of THC and CBD, and cannabis users generally prefer the strains of the plant with higher THC content due to its primary psychoactive effect. However, the studies on cannabis users did not differentiate the effects of THC and CBD on stroke risk and outcomes. In contrast, the distinct pharmacology profiles, and potential impact of THC (such as influence coagulation, vasoconstriction and platelet aggregation) were studied at preclinical experiments and were described in the section of 2.5. in the current manuscript.
Provide a more detailed analysis of potential confounding factors (e.g., use of other substances, underlying health conditions) in the studies reviewed and their impact on the findings.
Response: Thanks for the reviewer’s suggestion. We had a section 2.4 for Co-consumption in the original manuscript. Although we did not find direct information for the combination of cannabis use and underlying health conditions in the risk of stroke, we added a piece of information regarding a longitudinal cohort study of association of cannabis use and risk of stroke in pregnant women in the section 2.4.
Discuss the influence of age and gender on the relationship between cannabis use and stroke, considering the variability in stroke risk and cannabinoid effects across different populations.
Response: Thank you for your feedback, this was an important comment and we have identified being young and male as a significant factor associated with increased hospitalization following stroke.

“Using the national inpatient sample dataset (2007-2014), Desai et al. identified trends amongst cannabis users and found that there was a 13.92% relative increase in stroke amongst young (18-49 years) cannabis users as compared to non-users. This effect was most noticeable in males and was not observed in females [30]. In summary, young males that use cannabis are more likely to be hospitalized for stroke.”
Expand the Discussion on the proposed mechanisms of action through which cannabinoids might influence stroke risk and outcomes, incorporating recent scientific findings and theoretical models.
Response: Thank you for your comment, we have expanded the section on the proposed mechanisms of action through which cannabinoids might influence stroke and reordered the paragraph for clarity. Now it highlights the role of THC in contributing to cerebrovascular angiopathy. This paragraph was added to the section:

“The cerebero-vascular effect of cannabis was found to be correlated with an increased pulsatility index and systolic velocities, both linked with cerebral vasoconstriction (https://doi.org/10.1007/s11910-021-01113-2). Increasingly, oxidative stress, endothelial damage associated hemodynamic dysfunction, procoagulant effects and mitochondrial dysfunction have been reported to be contributors to cannabis -induced angiopathy. THC, in particular, has been implicated in causing much of brain mitochondrial respiratory chain dysfunction and increases in oxidative stress [62,63,64].”
Highlight the clinical relevance of the review findings for healthcare professionals, including potential implications for patient counseling, risk assessment, and management strategies.
Response: We would like to thank the reviewer for this important suggestion. We added the following paragraph to the section “Limitations and conclusions”:

“Despite the above-mentioned limitations in the available data, it is prudent for healthcare providers to advise patients on the potential risks of recreational cannabis use. According to our literature search, a preventive effect of cannabis use for stroke has not been shown in any study. The higher risk of cannabis-related stroke in younger patients is concerning.”
Clearly outline specific gaps in the current literature and propose directions for future research, emphasizing the need for longitudinal studies, clinical trials, and mechanistic studies.
Response: We added the following paragraph to the final chapter of the manuscript:

“However, more studies are needed to elucidate the exact role of the endocannabinoid system (ECS) in stroke. In particular, the long-term effects of ECS-directed treatment are not known. In particular, the impact of CB2 modulation on systemic immune response is a potential area of concern. Without those mechanistic studies, clinical studies are at high risk of failure and detrimental outcomes.“
Incorporate additional figures and tables to summarize key findings, mechanisms of action, and study characteristics, enhancing the visual appeal and accessibility of the information presented.
Response: Thank you for your comment. We have included a figure that summarizes the MOA of cannabis induced angiopathy (see figure 1).
Discuss the broader public health implications of the findings, including the potential impact of changing cannabis legislation and social attitudes on stroke incidence and outcomes.
Response: The broader public health implications are outside the scope of this narrative review. However, we amended the conclusion section with the following sentences:

“The legalization of cannabis for recreational and medical use in many jurisdictions contributed to decriminalization and changed the (negative) stigma of cannabis. It is now the mandate of medical research to provide the scientific data for potential beneficial effects or detrimental side effects of this drug. Stroke will be an important area of research on cannabis in the future.”
Refine the conclusion section to summarize the main findings more concisely, their limitations, and their implications for practice and policy, avoiding overgeneralizing results.
Response: Thank you very much again for your advice! We believe that our responses to your comments #10-13 refined the conclusion section significantly. We tried to avoid overgeneralizing our results in the revised version of the conclusion section.

Reviewer 2 Report

Comments and Suggestions for Authors Although being a narrative review, the scientific importance of this paper is obvious. I do have some points to be addressed: 1.- " An ischemic stroke involves loss of brain perfusion due to a blood 79 clot[18]. 9]. Stroke has varying degrees of 81 severity, depending on the localization and size of the infarcted area[14]." please remove this information - it is really trivial 2. Worldwide, ap- 82 proximately 15 million people per year have a stroke. With about 5 million deaths, stroke 83 is the second most common cause of death and a major cause of long-term disability. It is 84 estimated that about 25% of people older than 85 years will develop stroke" - please provide the citation support 3. " ust smoked cannabis had up to a 5× increase in" - please change 5x by 5 times 4. " t was reported that in ¼ of the patients, th" - please change ¼ oby one quarter 5. The information in table 1 is not correct. a) reversible Cerebral Vasoconstriction Syndrome is a brain disorder - i do not understand why is blood pressure at first line of the column b) In none of the 3 condition under coagulation , there is a primary coagulation problem. I think the authors meant to say thrombotic c) If the authors are consider stroke from a mechanism view, I found very strange that hemorrhagic stroke, which can be occur in the context of reversible Cerebral Vasoconstriction is not in the table (DOI: 10.1212/WNL.0000000000001973 ) 6. The explanation of animal studies on neuroprotection is too long. I suggest removing details of time to drug administrations / time from intervention to the measuring of the outcomes- 7- The authors should include as study limitation the narrative nature of the manuscript

Author Response

Dear Reviewer,

Reviewer 2

Although being a narrative review, the scientific importance of this paper is obvious. I do have some points to be addressed:

" An ischemic stroke involves loss of brain perfusion due to a blood 79 clot[18]. 9]. Stroke has varying degrees of 81 severity, depending on the localization and size of the infarcted area[14]." please remove this information - it is really trivial.
Response: Thank you very much for your comment. We have removed this trivial information from the manuscript.
Worldwide, ap- 82 proximately 15 million people per year have a stroke. With about 5 million deaths, stroke 83 is the second most common cause of death and a major cause of long-term disability. It is 84 estimated that about 25% of people older than 85 years will develop stroke" - please provide the citation support
Response: Thank you for bringing to our attention that this has not been referenced. This has been revised in the manuscript, with a reference added from the WHO website.
" just smoked cannabis had up to a 5× increase in" - please change 5x by 5 times.
Response: Thank you for your comment. This has been revised in the manuscript and now reads as “5 times” in place of 5x.
" t was reported that in ¼ of the patients, th" - please change ¼ oby one quarter.
Response: Thank you for your revision. This has been revised in the manuscript and now reads as “one quarter.” In place of ¼.
The information in table 1 is not correct.

a) reversible Cerebral Vasoconstriction Syndrome is a brain disorder – I do not understand why is blood pressure at first line of the column
Response: Thank you for bringing this to our attention, the blood pressure column has been revised to replace with “Vasculature” for better clarity in this section.

b) In none of the 3 condition under coagulation , there is a primary coagulation problem. I think the authors meant to say thrombotic
Response: Thank you for your comment. This part of the table has also been revised to read “Clotting/Thrombosis”
c) If the authors are consider stroke from a mechanism view, I found very strange that hemorrhagic stroke, which can be occur in the context of reversible Cerebral Vasoconstriction is not in the table (DOI: 1212/WNL.0000000000001973 )
Response: See new table
The explanation of animal studies on neuroprotection is too long. I suggest removing details of time to drug administrations / time from intervention to the measuring of the outcomes.
Response: Thank you for your response. This section has been edited and shortened to no longer include the timepoints for drug administrations or outcome measurements.
The authors should include as study limitation the narrative nature of the manuscript.
Response: Thank you for your comment. This limitation has been added into the manuscript limitation section, as follows:

“As there was limited data on the topic of cannabis use and stroke, a systematic or scoping review was not able to be completed, and thus a narrative review was done.”

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

Considering the author's responses to the previous review report, I recommend acceptance in its present form.

Reviewer 2 Report

Comments and Suggestions for Authors

The authors have responded to all my comments.