Clinical effects of wasabi extract containing 6-MSITC on myalgic encephalomyelitis/chronic fatigue syndrome: an open-label trial

This open-label trial enrolled adult outpatients with ME/CFS who visited the Department of Psychosomatic Medicine, International University of Health and Welfare (IUHW) hospital and the IUHW Narita hospital and who satisfied the following criteria: (1) insufficient improvement of general conditions three months after conventional treatment (provided at our hospitals to minimize bias due to the natural course and the effect of preceding treatments), (2) between 20 and 70 years of age, and (3) the subject’s performance state (PS) was between 3 and 8 [16, 17]; patients were asked to fill out the questionnaire by themselves and visit the hospital at least once a month. Patients were excluded if their fatigue was due to physical disease such as liver, kidney, heart, respiratory, endocrine, autoimmune, or malignant disease, severe anemia, electrolyte abnormalities, obesity, or pregnancy. Patients were also excluded if they had taken or were currently taking 6-MSITC-containing supplements.

The combination of treatments provided at our hospitals was described previously [18, 19]. In brief, they included (a) instructions on self-pacing and life guidance, e.g. tips to minimize crash and post-exertional malaise (PEM), reduce maladaptive coping behavior as well as improve adaptive and fatigue-relieving behaviors; (b) psychotherapy to reduce guilt, self-blame, worthlessness or helplessness; (c) pharmacotherapy for comorbid physical diseases such as functional gastrointestinal disorders, fibromyalgia, orthostatic intolerance, and psychiatric diseases such as mood and anxiety disorders as well as insomnia; (d) Kampo, traditional Japanese herbal medicines, to improve general condition and energy; (e) treatments to reduce stress and elicit relaxation; and (f) environmental rearrangement at home, the workplace, or school. The combination of interventions varied from person to person, taking into account background factors that may be involved, motivation, energy and cognitive limits.

The diagnosis of ME/CFS was made when patients met the following case definitions and diagnostic criteria: the 1994 Fukuda case definition of CFS [20], the 2005 Canadian clinical case definition of ME/CFS [1], the 2011 International Consensus Criteria for ME [2], the 2015 diagnostic criteria for ME/CFS or systemic exertion intolerance disease [3], and the 2017 Japanese clinical diagnostic criteria for ME/CFS [17]. All patients met these 5 case definitions or diagnostic criteria, with the exception of one subject who was later confirmed to have bipolar disorder after initiation of the study and was subsequently excluded from analysis.

Assessments were made pre- and post-treatment, i.e., on the first and last day of the 12-week 6-MSITC treatment. During this period, patients were asked to take 6 capsules that contained 6-MSITC (1.6 mg per capsule), i.e., two capsules after each meal, for 12 weeks. On the day of assessment, patients underwent medical interview, physical examinations, measurement of mechanical pain thresholds, active standing tests, and blood draws. Thereafter, they filled out questionnaires (described below) and provided narrative impressions of their condition. During the treatment period, we did not change their prescriptions except to prescribe non-steroidal anti-inflammatory drugs as needed. 6-MSITC was provided by Teijin Co. Ltd.

Results are presented as the mean ± standard deviation (SD). Normality in the data distribution was evaluated by the Kolmogorov–Smirnov test. Differences in continuous variables pre- and post-treatment were assessed by a parametric paired samples Student’s t-test or a non-parametric paired samples Wilcoxon signed-rank test, as appropriate. Differences in categorical variables were assessed by the Fisher’s exact test or paired samples McNemar’s test, as appropriate. Effect sizes (ES) for significant differences in the values were calculated using Cramer’s V, Cohen’s d, or rank-biserial correlation, as appropriate. Multiple linear regression analysis performed using the enter method was conducted to examine whether changes in predictor variables were associated with changes in PS scores. Statistical significance was set at p < 0.05, and all tests were two-tailed. Data were analyzed using SPSS v.21.0 and Jamovi v.2.2.5.

Twenty patients agreed to participate in the study. Among them, five patients were excluded from the final analysis because they withdrew from participation due to fear that they would not be able to change their drug regimen after the study began (n = 2), hospitalization due to disease which was not related to ME/CFS (n = 1), mood changes that were subsequently diagnosed as bipolar disorder (n = 1), and inability to appear at the hospital on the scheduled day due to quarantine for coronavirus disease-2019 (n = 1). Thus, we assessed the data from a total of 15 patients (3 males and 12 females). Their ages ranged from 20 to 58 years (37.5 ± 12.1 years). The mean duration of illness after onset was 5.1 ± 4.0 years. Twelve patients developed ME/CFS suddenly after flu-like episodes (post-infectious type). Five patients had comorbid fibromyalgia.

As shown in Table 10, multiple linear regression analysis indicated that improvements in Trail Making test time (ΔTMT-A) and the POMS-2 tension score were predictive factors for improvement in the PS level (ΔPS) of these patients. This model accounted for 42% of the variance of the ΔPS and was a good fit for the data (F₂ = 4.4, p = 0.038). The distribution of the residuals satisfied the normality assumptions (Fig. 1a). There was no multicollinearity detected between the tested variables (tolerance < 10), no outliers (Cook’s distance < 1; standard residuals <  ± 3.3), and the independence assumption was satisfied (1.5 < Durbin-Watson < 3). The homoscedasticity was not violated by the Breusch-Pagan test (p = 0.235). The associations between the estimated marginal means with a 95% confidence interval for the ΔPS and ΔTMT-A are shown in Fig. 1b.

It is noteworthy that 6-MSITC improved PS in patients who had not significantly improved after more than 3 months of conventional treatment at our hospitals. The 2017 Japanese clinical diagnostic criteria for ME/CFS [17] requires that the patient have a PS of 3 or higher; therefore, prior to intervention, the PS of all patients was 3 or greater. After 12 weeks of treatment, PS decreased in 6 patients; in 2 patients, PS decreased to less than 3, but the changes in PS of 6 patients were to grades 1 or 2, so not necessarily complete recovery. Further studies are needed to determine if longer-term administration of 6-MSITC can reduce PS even more.

In contrast to PS, there were no significant changes in CFS-11 scores or NRS scores for fatigue. Prior to conducting this study, we anticipated that 6-MSITC would also improve fatigue. These contradictory results might be attributed, at least in part, to the fact that patients who had been almost bedridden regained some ability to move, perform routine household chores, and begin working. It is reasonable for patients to feel more fatigued, especially after exertion, than when they almost never leave their bed. Such patients recorded higher levels of fatigue three months later, despite being more active. Another explanation could be that fatigue is not the only contributor to PS. In fact, multiple regression analysis demonstrated that the TMT-A and POMS-2 tension scores were predictors of improvement in PS.

Unrefreshing sleep is another common symptom of ME/CFS. The present study found that 14 of 15 patients (93.3%) had poor sleep quality, which is comparable to a previous study conducted in Japan that demonstrated that 84 out of 88 (95.5%) patients experienced poor sleep [31]. In the present study, despite one patient (S11) reporting an improvement in sleep quality after 6-MSITC treatment, it did not change PSQI scores significantly. Therefore, the effects of 6-MSITC on sleep seem to be minimal.

ME/CFS patients also complain of many pain symptoms, such as headache, myalgia, arthralgia, and pharyngeal pain. Among these, 6-MSITC significantly improved the frequency of headache and myalgia. These effects may be related to an improvement in PPT. The PPT of patients with ME/CFS in this study was lower than that of healthy subjects at the posterior neck region (38.9 – 39.9 kPa) [32], suggesting that patients in this study were more sensitive to pain than healthy subjects. Therefore, the improvement in PPT by 6-MSITC represents a beneficial change for patients with ME/CFS. However, it is unclear why the PPT improved only on the right side. Our previous study also showed a more significant improvement of PPT on the right occiput than left occiput after practicing autogenic training, a relaxation-inducing technique, in healthy subjects [33]. Thus, if 6-MSITC has some relaxing effects, it is reasonable that PPT would improve on the right occiput and reduce the frequency of headaches and myalgia.

Neurocognitive symptoms and brain fog are also disabling symptoms for patients with ME/CFS. To our surprise, 6-MSITC treatment greatly improved the cognitive function of patients with ME/CFS in the present study. 6-MSITC improved the subjective severity of brain fog, difficulty finding appropriate words, and photophobia. In accordance with these improvements, many patients (S1, S3, S6, S7, S11, S13, S18) described in detail how their cognitive problems were resolved. The scores on the TMT-A, a frontal lobe function test, were worse in ME/CFS patients than in healthy subjects prior to treatment, but 6-MSITC was found to significantly improve scores. To date, effective treatments for neurocognitive symptoms and brain fog in patients with ME/CFS have been limited. Therefore, 6-MSITC might represent a meaningful treatment option for reliving their symptoms.

Orthostatic intolerance is commonly observed in patients with ME/CFS. On a standing test, some patients may show POTS or OH. The frequency of these orthostatic abnormalities in the present study was almost identical to that in a previous report on Japanese patients [34]. While the present study suggests that 6-MSITC does not have significant effects on general performance in an active standing test, when patients were analyzed individually, one patient who could not complete the standing test prior to treatment gained the ability to remain standing with a normal pattern. Furthermore, one patient with OH and one with POTS also improved to a normal pattern, suggesting improvement in orthostatic intolerance in these patients. In contrast, two patients with a normal pattern prior to treatment developed a pattern of POTS after treatment. Given that the PS of these patients improved, the appearance of POTS must be associated with disease improvement in these subjects. A similar phenomenon had been previously reported [34] in which some patients who showed a normal pattern on a “bad day” exhibited POTS on a “good day”, suggesting that improved condition is associated with the appearance of POTS in some patients. This phenomenon is thought to be due to impaired sympathetic activation on “bad days.” If this is the case, one can hypothesize that impaired sympathetic activation is improved by 6-MSITC treatment, resulting in the appearance of POTS in these patients.

6-MSITC did not change anxiety or depression significantly. However, this study indicated that 6-MSITC significantly improved energy levels, as evidenced by the vigor score in POMS-2 and vitality score in SF-36. This effect may be related to the patients’ impressions, such as “I became more active (S5)” and “I am more motivated (S10)”, and is thus beneficial for patients with ME/CFS.

Currently, it is not fully understood how 6-MSITC improves ME/CFS. In vivo and in vitro studies have demonstrated that 6-MSITC has numerous biological effects, such as anti-inflammatory [7, 8], antiplatelet [35], anti-allergenic [9], antioxidant [10‐12], and anti-cancer [36, 37]. Moreover, peripheral administration of 6-MSITC also has central effects. For example, it inhibits neuroinflammation caused by intraperitoneal administration of polyinosinic:polycytidylic acid (polyI:C), a viral infection model [13], and has neuroprotective effects on nigral dopaminergic [10] and hippocampal neurons [12]. 6-MSITC also improves cognitive function. For example, in a mouse model of Alzheimer’s disease, systemic administration of 6-MSITC for 10 days ameliorated β-amyloid oligomer (Aβ_1-42O)-induced memory impairment [12]. Given that it attenuated Aβ_1-42O-induced hippocampal neuronal cell death [12], hippocampal neuroprotective effects may be involved. In humans, a randomized, double-blind, placebo-controlled trial demonstrated that an eight-week treatment of 6-MSITC improved neurocognitive function, which was assessed by the Stroop Color Word test, in healthy middle-aged and older adults [14].

Oxidative stress [4] and neuroinflammation [5] are thought to be involved in the pathophysiology of ME/CFS. Therefore, one explanation for the beneficial effects of 6-MSITC could be that long-term treatment inhibits oxidative stress and neuroinflammation, thus leading to the improvement of ME/CFS symptoms. Recently, the gut microbiome has been associated with the pathophysiology of ME/CFS, including neuroinflammation and ME/CFS symptoms [6]. Taking this finding into account, another possible mechanism for the effects of 6-MSITC is that long-term oral administration may affect gut microbiota and improve ME/CFS.

We conducted an overdose study in which 10 capsules (16 mg) of 6-MSITC were administered to healthy subjects for 4 weeks to confirm high-dose safety. In a pilot study conducted by Nakatomi et al., they administered 1 (1.6 mg) to 3 (4.8 mg) caps of 6-MSITC daily [15]. Another study conducted by Tanabe et al. administered 9 mg of 6-MSITC to healthy subjects [38]. Based on these studies, we selected a dose of 6 caps (9.6 mg) for administration to our patients. 9.6 mg of 6-MSITC contains approximately 20 g of wasabi (Wasabia japonica, Japanese domestic horseradish) [39].

There are several limitations to this study that should be noted. First, this was an open-label trial with a relatively small number of subjects. Therefore, to confirm the effect of 6-MSITC, it will be necessary to compare the changes in these values with a control group in a randomized, controlled trial with a larger sample size. Second, the long-term effects of 6-MSITC are not known yet. However, due to the beneficial effects of 6-MSITC, 10 out of 15 patients continued to take 6-MSITC after this clinical trial ended. Therefore, we will be able to report the long-term effects of 6-MSITC in the near future. Third, the mechanisms of action of 6-MSITC in patients with ME/CFS are not fully understood yet. To address this question, we will be analyzing blood biomarkers from participants in this study. Fourth, we could not assess the effects of 6-MSITC on post-exertional malaise (PEM), one of the hallmarks of this disease. This is partly due to the lack of a simple method to evaluate PEM in a general outpatient setting. The impressions of patient S1 and S3 suggest that 6-MSITC is also effective for PEM, at least in some patients; thus, it will be important to assess this in a future study. In spite of these limitations, this study identified beneficial effects of 6-MSITC on PS, severity of disease, and several symptoms of ME/CFS, including cognitive problems and brain fog. To date, effective treatments for cognitive impairment and brain fog have yet to be established. Therefore, this study suggests that 6-MSITC may represent a promising treatment option for patients with ME/CFS.