# Mechanistic Assessment of N-Acetylcysteine as an Antioxidant Therapy for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Through Dose Response and Treatment Target Engagement

> **NIH NIH R01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2020 · $586,263

## Abstract

ABSTRACT
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is an unexplained multisystem/multisymptom
disorder characterized by severe and debilitating fatigue for which there are currently no validated diagnostic
tests nor accepted therapies. The present proposal focuses on exploring a naturally occurring and widely
available dietary supplement, N-acetylcysteine (NAC) – a prodrug for in situ synthesis of the primary
intracellular antioxidant, glutathione (GSH) – as a highly promising treatment for ME/CFS. Driving this
exploratory clinical trial are recent compelling preliminary findings by the applicants which showed that 4
weeks of daily supplements of 1800mg of NAC (a) alleviated a significant in vivo brain GSH deficit in patients
with ME/CFS as measured directly with proton magnetic resonance spectroscopy (1H MRS) (b) ameliorated
ME/CFS symptoms and (c) decreased the levels of plasma markers of oxidative stress in ME/CFS patients
while eliciting no changes in healthy controls. The significance of these novel findings is that they represent the
clearest and most direct evidence to date that NAC has the ability to spur in situ synthesis and restoration of
brain GSH levels, and that GSH regulates its own synthesis through a "feedback inhibition" mechanism
whereby GSH synthesis is turned on or off depending whether tissue GSH levels are low or normal,
respectively. The main objective of the present proposal is to further investigate through a double-blind,
placebo-controlled, randomized clinical trial, the mechanism(s) of in situ GSH synthesis control by
administering different doses of NAC or placebo only to ME/CFS patients shown by 1H MRS to have a
significant cortical GSH deficit at baseline. We postulate that this narrow requirement for a GSH deficit at
baseline will represent a cohort selection refinement that would identify patients who would be most likely to
show cortical GSH elevations in response to NAC treatment because GSH synthesis would not be feedback-
inhibited. The expectation is that if successfully completed, the proposed study would advance our
understanding of the mechanism(s) of action of NAC in in vivo cortical GSH synthesis, confirm oxidative
stress as a viable treatment target for dietary NAC, and establish changes in 1H MRS measures of cortical
GSH and in plasma markers of oxidative stress as biomarkers of treatment target engagement and of
therapeutic response and, importantly, suggest optimal experimental conditions (cohort selection criteria, NAC
dose) that would be suitable for use in future full-scale efficacy clinical trials of NAC for treatment of ME/CFS or
other conditions in which redox imbalance has been postulated.

## Key facts

- **NIH application ID:** 9982469
- **Project number:** 1R01NS116887-01
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Dikoma C Shungu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $586,263
- **Award type:** 1
- **Project period:** 2020-07-15 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9982469

## Citation

> US National Institutes of Health, RePORTER application 9982469, Mechanistic Assessment of N-Acetylcysteine as an Antioxidant Therapy for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Through Dose Response and Treatment Target Engagement (1R01NS116887-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9982469. Licensed CC0.

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