Hexaraphane/6-MSITC in ME/CFS: Findings From a 12-Week Open-Label Trial

“It feels as though my mind is constantly covered in fog, and I cannot think.” “I struggle to find words.” “If I exert myself, I may be confined to bed for days afterward.” These overlapping symptoms occur in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). No effective treatment has been established for this difficult-to-treat condition¹, ². A clinical study has examined whether hexaraphane/6-MSITC, a food-derived compound found in Japanese wasabi, could influence some of its symptoms.

The study reviewed here was published in Biopsychosocial Medicine in 2022 by Professor Takakazu Oka of the International University of Health and Welfare and colleagues. Fifteen people with ME/CFS who had not improved sufficiently with conventional treatment received hexaraphane/6-MSITC for 12 weeks. The researchers assessed pre-post changes in cognitive function, pain, vitality, and other outcomes.

What You Will Learn

• What ME/CFS is and why it is difficult to treat
• How a 12-week open-label study in 15 people who had not improved with conventional treatment reported significant pre-post changes in brain fog, headache frequency, and cognitive-test performance
• Why the antioxidant and anti-inflammatory properties of hexaraphane/6-MSITC have been proposed as possible contributors, while the mechanism remains unconfirmed

What Is ME/CFS?

ME/CFS is a condition characterized by severe fatigue lasting at least six months that does not resolve with rest. It can involve diverse and overlapping symptoms, including brain fog, or cognitive dysfunction; post-exertional malaise (PEM); and pain. No effective treatment has been established¹, ², ³. For a broader overview, see Symptoms, Causes, Diagnosis, and Research in ME/CFS.

Hexaraphane/6-MSITC: An Anti-Inflammatory and Antioxidant Compound From Japanese Wasabi

Hexaraphane/6-MSITC is a relatively uncommon isothiocyanate found in the rhizome of Japanese wasabi. Previous research has reported several relevant biological effects:

• Anti-inflammatory activity: Suppression of inflammatory signaling in macrophages, a type of immune cell⁴, ⁵
• Antioxidant activity: Reduction of oxidative stress in experimental studies⁶, ⁷, ⁸
• Modulation of neuroinflammation: Reduced brain inflammation in a viral-infection model⁹
• Cognitive findings: Reduced memory impairment in an Alzheimer’s disease mouse model⁸ and reported cognitive findings in a randomized controlled trial of cognitively healthy middle-aged and older adults¹⁰

Because oxidative stress and neuroinflammation have been implicated in ME/CFS, the research team hypothesized that these reported properties might influence its symptoms.

Previous research

In a 2017 pilot study by Dr. Nakatomi and colleagues at the former Osaka City University Hospital, 18 people with ME/CFS received hexaraphane/6-MSITC for one to three months. General improvement was observed in six participants and marked improvement in two※11. However, dose and duration differed among participants, and individual symptoms were not evaluated in detail. The present study addressed some of these limitations by using a fixed dose and fixed duration.

Against this background, Professor Oka and colleagues conducted a clinical study to examine hexaraphane/6-MSITC systematically in people with ME/CFS.

A 12-Week Clinical Study in 15 People With ME/CFS

Study Design

This was an open-label trial, an early-stage design used to explore a potential intervention.

Open-label trial

A clinical study in which both participants and researchers know what substance is being administered. Because there is no placebo group, expectation-related effects cannot be excluded. Confirmation of efficacy therefore requires a placebo-controlled, double-blind randomized controlled trial.

• Design: Open-label pre-post study
• Participants: 15 people with ME/CFS; 3 men and 12 women; aged 20–58 years; mean age 37.5 years. Mean severity was PS 6.8, indicating that most participants needed to rest at home for more than half of each week.
• Mean duration of illness: 5.1 years after onset
• Trigger: Twelve participants developed the condition after a viral infection.
• Comorbidity: Five participants also had fibromyalgia.
• Key inclusion condition: Participants had not improved sufficiently after at least three months of conventional treatment.
• Intervention: Hexaraphane/6-MSITC at 9.6 mg/day, given as six 1.6 mg capsules—two after each meal. A dose of 9.6 mg is approximately equivalent to the amount of hexaraphane/6-MSITC in 20 g of Japanese wasabi rhizome.
• Duration: 12 weeks
• Measures: Performance status (PS), fatigue scales, sleep, subjective pain and pressure-pain threshold, subjective cognition and Trail Making Test Part A (TMT-A), standing tests, psychological measures including POMS2 and the Hospital Anxiety and Depression Scale, and quality of life measured with SF-36
• Institution: Department of Psychosomatic Medicine, International University of Health and Welfare Hospital
• Registration number: jRCTs 031190205

The study tested many outcomes simultaneously without adjustment for multiple comparisons. Individual p-values should therefore be interpreted cautiously.

Results

After 15 participants who had not improved sufficiently with conventional treatment received 9.6 mg/day of hexaraphane/6-MSITC for 12 weeks, the exploratory analysis found statistically significant pre-post changes in several outcomes. These findings came from an uncontrolled study and should not be treated as definitive evidence of efficacy.

1. Cognitive measures improved significantly from baseline

Brain fog and cognitive dysfunction are among the symptoms with the greatest effect on daily life in ME/CFS. Both subjective ratings and an objective cognitive test changed significantly from baseline.

NRS, or Numerical Rating Scale

A self-reported score on which a participant rates symptom severity from 0, meaning none, to 10, meaning the worst possible.

p-value

A statistical measure used to assess whether an observed difference would be unlikely under a specified null hypothesis. A value below 0.05 is often treated as statistically significant, although interpretation also depends on study design, sample size, and the number of comparisons.

In particular, completion time on TMT-A—the Trail Making Test Part A, which requires participants to connect numbers in sequence—declined by approximately 28%, from 53.0 seconds before treatment to 38.1 seconds after treatment. This value moved closer to reported averages for healthy adults: 29 ± 8 seconds for people in their 20s and 30s and 30 ± 8 seconds for those in their 40s. The result suggests an improvement in objective test performance, but the absence of a control group prevents the change from being attributed conclusively to hexaraphane/6-MSITC.

2. Pain-related measures changed

Headache frequency declined from 4.1 to 3.0 episodes per week, and muscle-pain frequency declined from 4.1 to 2.4 episodes per week. Pressure-pain thresholds—the amount of pressure at which pain begins—also increased.

3. Vitality and quality-of-life measures increased

The POMS2 vitality score increased from 46.9 to 50.0. General health perception and vitality on the SF-36 health-related quality-of-life scale also increased significantly, with p < 0.05 for each. These findings were consistent with subjective reports such as feeling more motivated or wanting to be more active.

4. Performance status improved significantly from baseline

Mean PS, an indicator of activity in daily life, changed from 6.8 before treatment to 6.3 after treatment, with p = 0.014. PS improved in 6 of the 15 participants and was unchanged in the other 9. Two participants reached a PS below 3, a level below the diagnostic threshold used for ME/CFS in the study.

5. Fatigue scores did not change significantly

No statistically significant change was observed in the CFS-11, the 11-item Chalder Fatigue Scale, which changed from 22.0 to 20.5, or in the fatigue NRS, which changed from 5.9 to 5.5.

Two interpretations are possible.

Interpretation 1, proposed by the research team: Participants who had previously been largely confined to bed may have increased their activity. They may therefore have been able to do more while still experiencing fatigue from that additional activity. In a regression analysis, improvement in PS was predicted not by fatigue scores but by improvements in TMT-A performance and the POMS2 tension score.

Interpretation 2: Hexaraphane/6-MSITC may simply have had no effect on fatigue itself. Any effects may have been selective for domains such as cognition or pain and limited for fatigue, a core symptom of ME/CFS.

A placebo-controlled trial is required to distinguish between these possibilities.

6. Effects on orthostatic intolerance and sleep were limited

Standing-test patterns did not change significantly overall. At the individual level, one participant changed from a postural orthostatic tachycardia syndrome pattern to a normal pattern, and one changed from orthostatic hypotension to a normal pattern. Sleep outcomes were also limited: the Pittsburgh Sleep Quality Index changed from 10.9 to 9.3, without a statistically significant difference.

7. Safety

No serious adverse events were reported during the 12-week intervention.

Participants’ Perceptions

Fourteen of the 15 participants reported that they felt the treatment had been effective, particularly with respect to cognitive function and brain fog. Although PS improved in only 6 participants, some whose PS remained unchanged reported relief in individual symptoms such as brain fog or pain.

The following quotations are subjective comments from participants published in the original paper by Oka and colleagues in 2022. They describe individual experiences and do not establish efficacy.

Participant A

“My mind used to feel constantly dull and clouded, but now there are more periods when the brain fog clears. I used to struggle to organize my words, but I can do that now. The sensation of heat in my head and back whenever I tried to think has also subsided.”

Participant B

“My mind used to feel foggy all the time, and I felt as though I had no ability to think or remember. Now I feel clearer. I am still far from how I was when I was healthy, but I have improved considerably and daily life has become easier. I can understand conversations and find words more readily.”

Participant C

“Because the brain fog has decreased, I can now do several things at once, such as cooking. I used to be unable to remember even three- or four-digit numbers, but now I can. I can also listen to music again.”

These reports were directionally consistent with changes in measures such as TMT-A and pressure-pain threshold. However, agreement between subjective and objective measures does not eliminate placebo effects, practice effects, regression to the mean, or other sources of bias in an open-label study.

Discussion: Why Might Cognitive Function and Pain Have Changed?

Hexaraphane/6-MSITC has reported antioxidant and anti-inflammatory effects, including modulation of neuroinflammation. The research team proposed that these properties may have reduced oxidative stress¹² and neuroinflammation¹³ implicated in ME/CFS, contributing to changes in cognition and pain. The authors also raised the hypothesis that oral intake might affect the gut microbiome and influence symptoms through the gut–brain axis¹⁴. These remain hypotheses and require further testing.

Fatigue scores did not change significantly. Because changes were observed in cognitive, pain, and vitality measures, hexaraphane/6-MSITC may act selectively on certain symptom domains. The mechanism remains a question for future research.

Significance and Limitations

A notable aspect of this study is that it included participants with severe symptoms who had not improved after at least three months of conventional treatment. The reported changes in brain fog and cognitive-test performance are relevant because cognitive dysfunction is a disabling symptom of ME/CFS with limited treatment options. The study also reported no serious adverse events over 12 weeks, and a separate high-dose study reported safety at 16 mg/day for four weeks.

However, several limitations are substantial. The study was open-label and had no placebo control, so placebo effects and other biases cannot be excluded. The sample comprised only 15 participants, and the findings cannot be generalized without larger studies. Long-term effects are unknown, although 10 of the 15 participants continued taking hexaraphane/6-MSITC after the trial. The mechanism remains unclear and requires investigation using blood biomarkers and other measures. The study also did not formally assess effects on PEM, although some participant reports may be relevant to that symptom.

A placebo-controlled, double-blind randomized controlled trial is necessary before efficacy can be established.

This article summarizes an academic paper and does not claim that any specific product treats ME/CFS. People experiencing symptoms of ME/CFS should consult a medical professional. Access to clinicians experienced in ME/CFS remains limited, but searching for a dedicated ME/CFS clinic may help identify an appropriate facility.

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