Cannabinoids, the Blood–Brain Barrier, and Neurodegeneration: Mechanisms, Dysregulation, and Therapeutic Perspectives
, Ludmila Yarmolinsky, Nitzan Sharon, Taima Zeadnaa-Aldda, Shir Dayan, Boris Khalfin and Sigal Fleisher-Berkovich *
Round 1
Reviewer 1 Report
Comments and Suggestions for AuthorsThis is a well-written review article. I do not have major comments but to ask the authors to include a figure showing the chemical structures of cannabinoids etc.
Author Response
Reviewer #1
This is a well-written review article. I do not have major comments, but to ask the authors to include a figure showing the chemical structures of cannabinoids, etc.
Answer
Thank you very much for your opinion. An additional figure is added.
Reviewer 2 Report
Comments and Suggestions for AuthorsThe manuscript addresses a timely and relevant topic by reviewing the interactions between cannabinoids, the endocannabinoid system (ECS), blood–brain barrier (BBB) regulation, and neurodegeneration, and it fits well within the scope of Biomolecules. But the manuscript requires several revisions before it can be considered for publication.
The authors should more explicitly discuss conflicting findings in the literature, particularly the context-dependent protective versus disruptive effects of CB1 signaling at the BBB, and critically evaluate the limitations of commonly used in vitro BBB models and animal models of neurodegeneration. Clear distinctions should be made between mechanistic observations, preclinical efficacy, and translational relevance.
The section on BBB regulation would benefit from clearer organization, with well-defined subsections and the inclusion of an early conceptual framework summarizing ECS–BBB–neurodegeneration interactions.
The review places disproportionate emphasis on CBD and THC, while other phytocannabinoids (e.g., CBG, CBDV, and acidic cannabinoids) are discussed superficially; this imbalance should be justified or corrected.
Statements implying neuroprotective or therapeutic effects based mainly on in vitro or rodent studies should be more carefully qualified, with clear differentiation between symptomatic benefits and true disease-modifying effects.
Finally, the clinical evidence summarized is limited by small sample sizes, heterogeneous designs, and largely symptomatic endpoints; these limitations should be more clearly emphasized, and clinical efficacy should not be overstated.
Author Response
Reviewer #2:
Comments and Suggestions for Authors
The manuscript addresses a timely and relevant topic by reviewing the interactions between cannabinoids, the endocannabinoid system (ECS), blood–brain barrier (BBB) regulation, and neurodegeneration, and it fits well within the scope of Biomolecules. But the manuscript requires several revisions before it can be considered for publication.
Answer
Thank you very much for your opinion.
The authors should more explicitly discuss conflicting findings in the literature, particularly the context-dependent protective versus disruptive effects of CB1 signaling at the BBB and critically evaluate the limitations of commonly used in vitro BBB models and animal models of neurodegeneration. Clear distinctions should be made between mechanistic observations, preclinical efficacy, and translational relevance.
Answer: It was performed; several additions have been made to the text.
The section on BBB regulation would benefit from clearer organization, with well-defined subsections and the inclusion of an early conceptual framework summarizing ECS–BBB–neurodegeneration interactions.
Answer
The review places disproportionate emphasis on CBD and THC, while other phytocannabinoids (e.g., CBG, CBDV, and acidic cannabinoids) are discussed superficially; this imbalance should be justified or corrected.
Answer: It was performed, there are additions in the text and in the conclusion part.
Statements implying neuroprotective or therapeutic effects based mainly on in vitro or rodent studies should be more carefully qualified, with clear differentiation between symptomatic benefits and true disease-modifying effects.
Answer: It was performed, and there are additions in the text
Finally, the clinical evidence summarized is limited by small sample sizes, heterogeneous designs, and largely symptomatic endpoints; these limitations should be more clearly emphasized, and clinical efficacy should not be overstated.
Answer
It was performed.
Reviewer 3 Report
Comments and Suggestions for AuthorsThe manuscript "Cannabinoids, the Blood-Brain Barrier, and Neurodegeneration: Mechanisms, Dysregulation, and Therapeutic Perspectives" by Ben-Shabat et al. deals with still a current topic - cannabinoids. Because their beneficial effects are describing in increasing numbers of publication, the review describes newest results.
The manuscript is written and designed well. The authors make a cross-section of facts and basic knowledge about endocannabinoids and their activites. Because the manuscript is focused particularly on BBB, the authors may add a figure with potential ways how ECs act on BBB level. Figure 2 is good, however, the small letters are not readable. Please, make them bigger.
Author Response
The manuscript "Cannabinoids, the Blood-Brain Barrier, and Neurodegeneration: Mechanisms, Dysregulation, and Therapeutic Perspectives" by Ben-Shabat et al. deals with still a current topic - cannabinoids. Because their beneficial effects are describing in increasing numbers of publication, the review describes newest results.
The manuscript is written and designed well. The authors make a cross-section of facts and basic knowledge about endocannabinoids and their activites. Because the manuscript is focused particularly on BBB, the authors may add a figure with potential ways how ECs act on BBB level. Figure 2 is good, however, the small letters are not readable. Please, make them bigger.
Answer
Thank you for the helpful comment. We added figure 2 to depict the effects of endogenous cannabinoids on BBB. The text in Figure 2 has been enlarged to improve readability, and the updated figure is now included in the revised manuscript.
Reviewer 4 Report
Comments and Suggestions for AuthorsThe manuscript provides a review of the complex relationship between the endocannabinoid system (ECS), the blood-brain barrier (BBB) and neurodegenerative diseases (NDDs). Overall, the manuscript is well written and structured, and the conclusions are supported by the cited literature. However, a few major issues regarding classification, clarity and concision must be addressed before publication.
- The authors declared: "This review looks at the links between cannabinoids, the blood-brain barrier, and neurodegeneration". However, there is no dedicated section on methodology (e.g. search strategy, databases, inclusions/exclusions, quality assessment). This is indispensable for a review.
- Although the authors mention side effects in the introduction, they are not addressed in subsequent sections. A concise subsection on safety and tolerability should be added, covering the following topics: neutral vs. acidic cannabinoids; psychotropic effects; specific risks to the blood-brain barrier; CB1 receptor-mediated endothelial stress; and adverse events in clinical trials.
- Some concepts, such as the ECS's role in BBB regulation, are repeated across sections. Please delete any duplicate text.
- Figure 1: Standardise the visual presentation of the figure. Use a clear legend to explain that means 'increase' or 'upregulation', and ¯ means 'decrease' or 'downregulation'. Ensure that the explanation in the caption or main text (lines 168–177) is fully consistent with the visual representation in the figure.
- Revise Table 2 to include columns for study design, sample size, dose/route, duration, primary outcomes and adverse events..
- Table 1 and Figure 2 are presented without clear citations in the text. Please add the reference in the text and ensure that it is correctly formatted.
Author Response
The manuscript provides a review of the complex relationship between the endocannabinoid system (ECS), the blood-brain barrier (BBB) and neurodegenerative diseases (NDDs). Overall, the manuscript is well written and structured, and the conclusions are supported by the cited literature. However, a few major issues regarding classification, clarity and concision must be addressed before publication.
The authors declared: "This review looks at the links between cannabinoids, the blood-brain barrier, and neurodegeneration". However, there is no dedicated section on methodology (e.g. search strategy, databases, inclusions/exclusions, quality assessment). This is indispensable for a review.
Answer:
Section 2 “Methods” was added. We performed a structured literature search using several electronic databases (Science Direct, Google Scholar, PubMed and Scopus). The search strategy was designed to determine the relationship between ECS, BBB and cannabinoids in the context of neurodegeneration on the basis of multiple criteria sorting methods [13]. The keywords were searched alone or in combination with Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, multiple sclerosis. The manuscripts published between 2000 and 2025 were chosen for possible inclusion in the present work. Narrative reviews, case reports or case series with 5 patients or less, letters, and editorials were excluded. A set of original research publications was obtained, and a comprehensive analysis of the interrelationship between cannabinoids, the blood-brain barrier and neurodegeneration were performed.
Although the authors mention side effects in the introduction, they are not addressed in subsequent sections. A concise subsection on safety and tolerability should be added, covering the following topics: neutral vs. acidic cannabinoids; psychotropic effects; specific risks to the blood-brain barrier; CB1 receptor-mediated endothelial stress; and adverse events in clinical trials.
Answer
An additional section (7. Side effects) was added. Adverse effects of cannabinoids intake on almost all body systems are well-known; their durations and severity depend on many factors, for example, age, sex, concentrations of the cannabinoids and so on [154]. Acidic cannabinoids show mild side effects, while neutral cannabinoids are associated with severe side effects, including psychoactivity [155]. For example, side effects of THC may be various psychoactive effects, tachycardia, dry mouth and red eyes and so on [156]. It is mostly unclear whether cannabinoids crossing the BBB create specific risk to it. In fact, it has been demonstrated in cell and animal models that THC induces BBB damage, it is partly connected with CB1 activation and triggering the oxidative stress response [17]. All adverse events reported in clinical trials are reflected in table 2.
Some concepts, such as the ECS's role in BBB regulation, are repeated across sections. Please delete any duplicate text.
Answer
“The primary role of the BBB is to preserve CNS homeostasis and protect the brain by restricting the entry of circulating chemicals and pathogens [98–100]. During neuroinflammatory conditions, the BBB function becomes compromised, leading to increased barrier permeability and facilitating the influx of peripheral and central immune cells that can exacerbate neuronal injury.” was deleted from the part ”Neuroprotective and Therapeutic Roles of Phytocannabinoids”.
Figure 1: Standardise the visual presentation of the figure. Use a clear legend to explain that -means 'increase' or 'upregulation', and ¯ means 'decrease' or 'downregulation'. Ensure that the explanation in the caption or main text (lines 168–177) is fully consistent with the visual representation in the figure.
Answer: it is performed.
Revise Table 2 to include columns for study design, sample size, dose/route, duration, primary outcomes and adverse events.
Answer: it is performed.
Table 1 and Figure 2 are presented without clear citations in the text. Please add the reference in the text and ensure that it is correctly formatted.
Answer: Thank you for your opinion. It was performed.
Round 2
Reviewer 2 Report
Comments and Suggestions for AuthorsThe manuscript has been improved in clarity, structure, and the discussion is now better balanced and appropriately framed for a review article. The revised version adequately addresses the previous comments and is suitable for publication.
Reviewer 4 Report
Comments and Suggestions for AuthorsThe authors fairly answered reviewer' questions.
From my side, submission can be accepted for publication
