Spironolactone for ME/CFS in a Patient Homozygous for rs5522 (I180V): A Case Report

Abstract

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a

debilitating condition with no consistently effective treatment. The mineralocorticoid

receptor variant rs5522 (I180V) is associated with enhanced MR response to cortisol and

altered stress responsiveness, but has not been linked to ME/CFS treatment response.

Case: A 49-year-old woman with 29 years of treatment-resistant ME/CFS was found to be

homozygous for rs5522. Following initiation of spironolactone, she experienced

unprecedented improvement: restorative sleep within 48 hours for the first time in 29 years

and complete resolution of post-exertional malaise within 3 days. However, as

spironolactone dose increased from 25mg to 200mg daily, severe progressive fluid

retention forced discontinuation. Laboratory findings at peak showed aldosterone 138

ng/dL and renin 110 ng/mL/h (19 times normal) despite persistent low sodium,

demonstrating extreme compensatory response to MR blockade. After discontinuation,

labs normalized but the dramatic clinical improvement was lost. The patient subsequently

restarted spironolactone at 25mg daily combined with GLP-1 receptor agonist and low-

dose naltrexone (4.5mg), achieving sustained clinical benefit without the adverse

compensatory response seen at higher doses.

Conclusion: MR overactivity drives ME/CFS in this patient and likely many others. The loss

of benefit when high-dose treatment was discontinued represents both tragedy and

roadmap: the treatment works but cannot be tolerated at full dose because the body

mounts extreme evolutionary defense. Low-dose MR blockade (25mg daily) combined with

anti-inflammatory intervention provides benefit without triggering existential threat

response, representing an optimal therapeutic approach.