We will include RCTs that have compared a nutritional supplement alone or in combination with a standard treatment with a placebo or another alternative active treatment. Standard treatment is defined as treatment validated by the National Institute for Health and Care Excellence clinical guidelines, whether pharmacological and/or psychological.

We will exclude crossover trials because obsessive ideation and compulsions may evolve over time, and washout periods themselves may induce detrimental effects in the second period of the trial. We will also exclude cluster RCTs because of the potential for identification/recruitment bias and overestimation of the precision of the results.

We will include adults aged ≥18 years with OCD. Participants will be defined as having OCD by using the DSM-5 criteria. We will exclude studies in which participants have organic causes of OCD. Additionally, we will exclude participants with comorbid psychiatric disorders such as schizophrenia, bipolar disorder, depressive disorder, eating disorders, and suicidal behavior. Participants presenting with subthreshold symptoms of depression or anxiety will not be excluded, provided that the diagnostic thresholds for another psychiatric disorder are not met.

Participants with organic causes of OCD, including temporal lobe epilepsy, will be excluded to prevent confusion with neurobiological mechanisms. Individuals with subthreshold depressive or anxiety symptoms will be eligible, provided they do not meet all the diagnostic criteria for another psychiatric disorder. This approach ensures that we retain internal validity while keeping our findings relevant to the diverse OCD population encountered in clinical practice.

We will include nutritional supplementation (eg, vitamin D, vitamin B12, glycine) combined with pharmacological and psychological interventions that have been clinically validated to reduce obsessive-compulsive symptoms.

The comparator will include other nutritional supplements, placebos, or an alternative active drug. Co-interventions will be acceptable in both the intervention and comparison groups provided that they are administered equally across all groups in the trial. If a trial included multiple arms, any arm that met the inclusion criteria will be included.

We will consider intervention durations of 12 weeks or longer because nutritional supplementation is more likely to affect the relevant primary outcomes during this timeframe. We do not impose a limit on the maximum duration of intervention. Studies reporting one or more of our outcomes at least 6 months after the start of the intervention will be included. Therefore, the minimum follow-up duration of the studies will be set at 6 months.

Trials should include a minimum intervention duration of 12 weeks and at least 6 months of follow-up to assess the sustained effects. A sensitivity analysis will also incorporate trials with shorter follow-up periods to assess the robustness of the findings.

The primary and secondary outcomes are defined as outlined below. Trials will not be excluded solely because one or several of our primary or secondary outcome measures are not reported in the publication. However, if none of our primary or secondary outcomes are reported, we will include the trial only for information purposes.

We will search the following electronic databases: MEDLINE through PubMed (National Library of Medicine), Embase through the Elsevier platform, CENTRAL via the Cochrane Library, and ClinicalTrials.gov. We will search these databases since their inception. The research team will design and execute a detailed search strategy by using the same strategy with appropriate adjustments for each database. Search terms will include keywords related to names/clusters of nutritional supplements, cognition, quality of life, psychiatric symptoms, comorbidity, and randomized studies. No restrictions will be imposed on the dates. The initial literature searches of MEDLINE, Embase, and the Cochrane Database of Systematic Reviews began in January 2025. The draft strategies for MEDLINE and Embase are provided in Multimedia Appendix 2.

We will search the reference lists of all identified trials, relevant review studies, and current treatment guidelines to identify additional potentially eligible studies. We will contact the authors of the identified studies and research groups known to be active in pharmacological interventions for OCD to request unpublished material or further information on ongoing studies. The search will be conducted and updated as necessary before publication. We will provide the actual dates of the electronic search during the review stage.

First, 2 researchers will independently screen the titles and abstracts of the studies obtained from the initial searches, masked to each other’s decisions and based on the eligibility criteria. We will obtain the full texts of all potentially relevant reports. Second, these full texts will be examined in detail and screened for eligibility, with the reasons for exclusion recorded. Third, the references of all the considered studies will be manually searched to identify any relevant reports missed by the search strategy. We will examine the full studies and supplementary materials containing data and analyze their general and methodological characteristics and study results. The final versions of the studies available online will also be reviewed.

The authors will be contacted in the case of ambiguity or missing data. Duplicate records will be identified and excluded, and multiple reports from the same study will be collated such that the analysis, rather than individual reports, will serve as the unit of interest in the review. Disagreements will be resolved by consensus or consultation with a third reviewer. If disagreements cannot be resolved, we will categorize the study as “awaiting classification” and contact the authors for clarification. Studies for which relevant data cannot be obtained will also be classified as “awaiting classification.”

Once the searches have been performed, items identified in the databases will be imported into Rayyan software (Rayyan Systems) [18]. Following the recommendations of the PRISMA 2020 declaration [19], a flowchart showing details of the studies included and excluded at each stage of the selection process will be provided.

Data from each report will be used to build evidence tables describing the included studies. A standardized data extraction form will include the following information of interest: first author’s name, year of publication, type of nutritional supplementation (eg, vitamin B12), outcomes (eg, memory, depression), comparison, participant details (eg, diagnostic criteria, age, sex, years of education, comorbidity, risk factors), and maximally adjusted effect sizes, including corresponding 95% CIs, hazard ratios, odds ratios, and relative risks.

When sufficient data are available, random-effects meta-analyses will be performed. Continuous outcomes will be synthesized as standardized mean differences (Hedges g) and dichotomous outcomes as risk ratios with 95% CIs. Heterogeneity will be assessed using the I² statistic, and subgroup analyses will be conducted based on supplement class, dose, and duration. Sensitivity analyses will examine the influence of study quality and follow-up duration. If quantitative synthesis proves unfeasible, results will be summarized narratively by supplement type and clinical outcome.

Subgroup analyses will be performed by supplement class (eg, amino acids, vitamins, fatty acids), dose, and duration of treatment. Implementation in practice may be influenced by variability in supplement quality, dosing guidelines, patient adherence, and placebo effect. These factors will be considered when interpreting the results.

If meta-analysis is not feasible, a structured narrative synthesis will be performed, organized by supplement type, outcome measure (symptom severity, cognition, quality of life), and study quality. Findings will be contextualized in relation to methodological rigor and clinical applicability.

At least 2 researchers will independently assess the risk of bias and the quality of each study, and any disagreements will be resolved by discussion. For the RCTs, we will evaluate the risk of bias in each included study by using the Cochrane Risk of Bias 2.0 tool [20]. This tool considers random sequence generation, allocation concealment, blinding of the participants and outcome assessors, incomplete outcome data, selective outcome reporting, and other potential sources of bias. We will judge the risk of bias for each study based on these criteria and classify the studies as having a low, high, or unclear risk of bias. The quality of the RCTs will also be assessed using the Cochrane Collaboration tool to assess the risk of bias [21]. This scale evaluates 7 items as follows: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective outcome reporting, and other biases [22]. Each item will be scored as high risk, low risk, or unclear risk based on the available evidence. Published trial results will be systematically checked against trial registry entries (eg, ClinicalTrials.gov) to assess for selective reporting of results and potential publication bias.