Dear Dr. Lu,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

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Thank you for submitting your manuscript entitled “ Comparative efficacy of non-pharmacological interventions for individuals with cannabis use disorder: a systematic review and network meta-analysis protocol”  to PLOS ONE .

Your manuscript has now been evaluated by three reviewers. Both reviewers identified issues that require careful attention before the manuscript can be further considered for publication. Therefore, I invite you to submit a revised version addressing all comments raised by the reviewers in a detailed and point-by-point response letter.

In your revision, please ensure that all methodological, reporting, and conceptual concerns are fully addressed, with corresponding changes clearly incorporated into the manuscript where appropriate. Please also indicate precisely where each modification was made.

We look forward to receiving your revised manuscript and response to the reviewers’ comments.

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We look forward to receiving your revised manuscript.

Kind regards,

Alberto Souza Sá Filho, Ph.D

Academic Editor

PLOS One

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When you resubmit, please ensure that you provide the correct grant numbers for the awards you received for your study in the ‘Funding Information’ section.

4. Thank you for stating the following financial disclosure:

This research was supported by Peak-Shaping Project under Guangzhou University of Chinese Medicine's Action Plan for Double First-Class and High-Level Disciplinary Development (GZY2025ZJ18); Guangdong Provincial Higher Education Innovation Team Project(2025KCXTD011); Shenzhen Medical Research Fund(C2501027); and Research and Practice on Optimization Strategies for a Clinical Recommendation System for Non-Pharmacological Interventions in Substance Use Disorders Driven by Large Language Models(A3-0317-25-109-009).

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This research was supported by Peak-Shaping Project under Guangzhou University of Chinese Medicine's Action Plan for Double First-Class and High-Level Disciplinary Development (GZY2025ZJ18); Guangdong Provincial Higher Education Innovation Team Project(2025KCXTD011); and Shenzhen Medical Research Fund(C2501027)

We note that you have provided funding information that is not currently declared in your Funding Statement. However, funding information should not appear in the Acknowledgments section or other areas of your manuscript. We will only publish funding information present in the Funding Statement section of the online submission form.

Please remove any funding-related text from the manuscript and let us know how you would like to update your Funding Statement. Currently, your Funding Statement reads as follows:

This research was supported by Peak-Shaping Project under Guangzhou University of Chinese Medicine's Action Plan for Double First-Class and High-Level Disciplinary Development (GZY2025ZJ18); Guangdong Provincial Higher Education Innovation Team Project(2025KCXTD011); Shenzhen Medical Research Fund(C2501027); and Research and Practice on Optimization Strategies for a Clinical Recommendation System for Non-Pharmacological Interventions in Substance Use Disorders Driven by Large Language Models(A3-0317-25-109-009).

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6. If the reviewer comments include a recommendation to cite specific previously published works, please review and evaluate these publications to determine whether they are relevant and should be cited. There is no requirement to cite these works unless the editor has indicated otherwise. \

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions?

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

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2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses??>

Reviewer #1: Yes

Reviewer #2: Partly

Reviewer #3: Yes

Reviewer #4: Yes

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3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable??>

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

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4. Have the authors described where all data underlying the findings will be made available when the study is complete??>

The PLOS Data policy

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

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5. Is the manuscript presented in an intelligible fashion and written in standard English??>

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

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Please use the space provided to explain your answers to the questions above and, if applicable, provide comments about issues authors must address before this protocol can be accepted for publication. You may also include additional comments for the author, including concerns about research or publication ethics.

You may also provide optional suggestions and comments to authors that they might find helpful in planning their study.

Reviewer #1: 1- The manuscript refers to an “8-tier methodological framework.” Please provide a concise description or schematic to ensure readers understand how interventions will be categorized and compared.

2- While primary outcomes are well defined, secondary outcomes include diverse measures (QoL, withdrawal, adverse events). Consider clarifying how heterogeneity across scales will be handled beyond standardization, particularly for QoL instruments.

3- The rationale for excluding quasi-experimental, adaptive, and cross-over designs is reasonable, but a brief explanation of how this exclusion may affect comprehensiveness would strengthen transparency.

4- The current statement indicates data will be available upon request. To align with PLOS ONE’s policy, please clarify whether the minimal dataset will be deposited in a public repository upon completion.

5- Minor grammatical and stylistic edits would improve readability (e.g., streamline long sentences in the introduction and methods).

This protocol is methodologically sound and addresses a critical gap in comparative evidence for CUD interventions. With minor clarifications and improvements in reporting, it will provide a strong foundation for the planned systematic review and network meta-analysis. I recommend minor revisions to enhance clarity and compliance with journal standards.

Reviewer #2: 1. The population definition is too broad for cannabis use disorder

The protocol claims to study individuals with CUD, but the eligibility criteria allow inclusion of participants who used cannabis in the past month and had at least one cannabis-related problem. That is not equivalent to a formal diagnosis of CUD, cannabis dependence, or cannabis abuse. This could introduce major clinical heterogeneity and weaken the applicability of the findings.

The authors should separate formally diagnosed CUD from broader “problematic cannabis use” populations, or at least plan subgroup or sensitivity analyses by diagnostic certainty.

2. Age criteria are unclear and potentially inconsistent

The table defines adults as age ≥16 years, and later the manuscript discusses adolescents and young adults. In many jurisdictions, 16-year-olds are adolescents, not adults. The authors also plan a sensitivity analysis excluding adolescent trials, but the main inclusion criteria already mix adolescents and adults.

The authors should clearly define age groups and decide whether the review is about adults, adolescents, or both. If both are included, age should be treated as a major effect modifier in the NMA.

3. Outcomes are not sufficiently well defined

The primary outcomes are confusing. The abstract lists efficacy, acceptability, and cannabis-use days as primary outcomes. The methods describe efficacy as both abstinence and days of cannabis use. The table lists point abstinence, cannabis-use days, and retention. Secondary outcomes then include cannabis-use frequency over the past 30 days, which overlaps with cannabis-use days.

The authors should define one clear hierarchy of outcomes. For example:

Primary benefit outcome: biochemically verified abstinence at end of treatment.

Primary harm/acceptability outcome: all-cause dropout or treatment discontinuation.

Secondary outcomes: days of cannabis use, cannabis-related problems, dependence severity, craving, withdrawal, mood symptoms, adverse events.

4. Intervention node classification is underdeveloped

The eight intervention categories are potentially useful, but the node-building rules are not precise enough. For example, “combined interventions” may include CBT plus MET, CBT plus CM, MET plus CM, family therapy plus CM, or psychosocial intervention plus neuromodulation. These are clinically very different and may not be valid as one node.

The authors should provide explicit rules for classifying multicomponent interventions, including how they will handle intensity, duration, therapist contact, delivery mode, group versus individual format, digital versus face-to-face delivery, and co-interventions.

5. Statistical methods contain internal inconsistencies

The statistical section needs substantial revision. The authors describe a frequentist NMA but refer to “credible intervals,” which are usually Bayesian. They also mention weighted least squares with REML and then say they will apply the DerSimonian-Laird random-effects model. REML and DerSimonian-Laird are different estimators and should not be presented as the same approach.

6. GRADE and imprecision rules require clarification

The GRADE plan is ambitious but not always clear. The manuscript mentions minimally clinically important differences, decision thresholds, and absolute effects, but the actual thresholds are not defined. The authors should specify the MID or decision threshold for each outcome before analysis.

The statement that outcomes informed by a single trial with a large statistically significant effect will be considered “high risk of bias due to potential small-sample effects” is conceptually unclear. Small-study effects relate more directly to imprecision, publication bias, or small-study bias, not necessarily risk of bias.

Reviewer #3: The introduction of the study was carefully written, using relevant epidemiological data to situate the problem statement. Currently used interventions, mainly non-pharmacological treatments, were also presented. Nevertheless, although the work focuses on non-pharmacological treatment, current pharmacological treatments may be presented and evaluated, as in the non-pharmacological studies. Additionally, the authors may present some merits and demerits of the pharmacological treatments, which may skewed the study towards non-pharmacological interventions in the first instance.

The methodology is rigorous and dense, providing all relevant information to ensure reproducibility. The lack of language restrictions in the search strategies may raise questions, particularly with conclusions, as specific meanings may be lost in translations. Authors should justify why there were no restrictions on language. Also, on line 105, “from inception to 30 December, 2025”, the study period appears to have passed, or the authors may have made a typographical error.

The authors appear to intermix the future tense (will) and the past tense, resulting in some confusion as to whether the work has already been carried out or is a protocol to be carried out.

A sample of the data extraction form (line 185) should be included.

Lines 194 to 196: Please include a reference or justify why the control groups are split evenly. What are the implications if the groups are uneven?

Reviewer #4: This manuscript presents a protocol designed to evaluate and rank the efficacy of several non-pharmacological interventions across different methodological and intervention categories, intending to inform clinical decision-making.

The proposed systematic review and network meta-analysis of randomized controlled trials comparing non-pharmacological interventions with control conditions in individuals with cannabis use disorder is potentially valuable for the fields of addiction medicine, psychiatry, and behavioral medicine. The study is also well positioned to clarify the relative effects of neurotherapeutic modalities in cannabis use disorder.

However, few issues should be addressed to improve the manuscripts clarity and completeness.

First, some acronyms are not defined at their first mention. For example, rTMS and tDCS should be fully written out when they first appear in the manuscript, followed by the abbreviation in parentheses.

Secondly, although this is a protocol, the manuscript would be strengthened if the authors could include any preliminary findings, pilot observations, or feasibility data, where available. If preliminary results are not yet available, the authors should explicitly state this and explain how the protocol will ensure methodological rigor.

Lastly, the authors should briefly discuss possible methodological pitfalls and alternative strategies. For example, they may consider how they would address limited numbers of eligible randomized controlled trials, high heterogeneity across interventions, inconsistent outcome measures, small sample sizes, or disconnected networks in the network meta-analysis. A contingency plan/ alternative approach would improve confidence in the feasibility and robustness of the proposed approach.

Overall, the protocol addresses an important and clinically relevant question in CUD. With improved acronym definition, clearer justification of feasibility, and a brief discussion of alternative methodological approaches in the event of anticipated limitations, the manuscript would be strengthened.

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Reviewer #1: Yes:  Sura Saad Abdullah

Reviewer #2: No

Reviewer #3: No

Reviewer #4: No

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Comparative efficacy of non-pharmacological interventions for individuals with cannabis use disorder: a systematic review and network meta-analysis protocol

PONE-D-26-23451R1

Dear Dr. Lu

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

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Kind regards,

Alberto Souza Sá Filho, Ph.D

Academic Editor

PLOS One