*Objectives*

The objectives of this study were to systematically review studies of MBIs for the treatment of ME/CFS symptoms and to report any adverse events reported for these approaches in ME/CFS patients.

#### **2. Materials and Methods**

We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines [33]. The protocol of this systematic review was registered at PROS-PERO (CRD42018085981).

#### *2.1. Population, Intervention, Control, Outcome- Study Design (PICO-S)*

The population of interest was adults ( ≥18 years old) diagnosed or symptom-matched with one of the ME/CFS case definitions (Appendix A, Table A1). Patients with any other conditions were included in this review, as long as they were diagnosed with ME/CFS. Interventions of interest included any of the MBIs listed in Table 1 and any placebo, the standard of care treatment or waiting list as a control group. To be eligible for inclusion, multiple-arm interventional studies were also required to have at least one of the control groups mentioned above.

All outcomes relevant to the signs and symptoms of ME/CFS and quality of life were considered. The outcomes included fatigue, sleep refreshment, pain, anxiety (stress, nervousness, etc.), depression (mood, hopefulness, and helplessness), quality of life, performance (physical, mental, emotional), work-related outcomes (employment, income, etc.), and physical health symptoms such as sore throat, tender lymph nodes, and muscle weakness (Table 1).

Study designs eligible for inclusion were parallel/cross-over/N-of-1 randomized controlled trials (RCTs), controlled clinical trials (CCTs), single-arm experimental (within subject control group), controlled before and after studies, or cohort studies.

#### *2.2. Search Methods*

Five electronic databases (MEDLINE, EMBASE, CINAHL, PsycINFO, and Cochrane Register of Controlled Trials (CENTRAL)) were searched from inception to September 2020. Search terms were based on those presented in Table 1; an example is found in Appendix B. No limitation was implemented in terms of publication dates. English language restriction was applied. The reference lists of included studies, and systematic reviews, were reviewed to identify additional studies.



#### *2.3. Selection of Studies*

Two review authors (MK, DJ) independently screened all the titles and abstracts retrieved from the search in order to identify those that may meet the inclusion criteria. They classified studies as being relevant, possibly relevant and irrelevant. Three reviewers (MK, DJ, SKA) independently assessed the full texts of all relevant and possibly relevant studies to assess inclusion. Discrepancies were resolved by referring to a senior review author (ES, SV).

#### *2.4. Data Collection*

Standardized data extraction forms were used to extract data from full-text articles. Extracted data included general characteristics of the study (first author, publication year, country, settings, design), sample size, age and sex distribution in groups, diagnosis methods, type of MBI and other relevant data including frequency and duration, control (active or passive), primary outcome, secondary outcomes, primary and secondary measurement tools, length of study, follow up period, statistically significant outcomes, and adverse events reported. Data extraction was completed by one reviewer (DJ) and independently verified by a second reviewer (SKA). Disagreements between the authors were resolved by discussion until consensus was reached; if consensus could not be reached, a senior reviewer's opinion was sought.

#### *2.5. Data Analysis*

This systematic review was conducted to determine which outcomes and outcome measures were used in the studies of MBIs for the treatment of ME/CFS patients and whether the interventions were effective. General information of the included studies along with the statistically significant and insignificant outcomes were described. We present the findings of studies using different diagnostic criteria (e.g., Oxford criteria, CDC criteria) separately. We also report whether studies assessed adverse events, their absence or presence, and frequencies. A meta-analysis was not performed due to heterogeneous interventions and outcomes used in the included studies. Cochrane risk of bias assessment tool was used by two independent review authors (SKA, SP) to assess sequence generation, allocation concealment, blinding, incomplete outcome data, selective outcome reporting, and other sources of bias [34] in RCTs. Other study designs including single-arm experimental studies were also appraised by two independent reviewers (SKA, SP) for risk of bias using Cochrane Risk of Bias Assessment Tool for Non-Randomized Studies of Intervention (ACROBAT\_NRSI) which was recently renamed ROBINS-I [35]. Domains for assessing the risk of bias in these studies include bias due to confounding, selection of participants, measurement of interventions, a departure from the intended intervention, missing data, measurement of outcomes, and selection of the reported result.

#### *2.6. Patient Involvement*

Patient engagemen<sup>t</sup> in health research can improve the quality, relevance and impact of the research [36,37]. To recruit patient research partners in this study, a "call for patient representative" letter was developed and distributed among patients, caregivers and advocates. Three patient partners were selected based on their educational background, personal experience, and health status to participate in the study team. They did not receive any financial compensation. They participated regularly in teleconference calls and skype meetings. They also provided feedback and participated in team discussions via email. They contributed to the protocol design, development of the literature search strategy, the condition/diagnosis definitions, and outcome selection.
