What randomized clinical trials are underway testing low‑dose methylene blue for Alzheimer’s disease and what are their endpoints?
Executive summary
Low‑dose methylene blue (and its reduced proprietary forms LMTM/HMTM) remains under active clinical investigation for Alzheimer’s disease (AD) in a small set of randomized trials that focus on short‑term mechanistic brain measures and longer clinical outcomes such as cognition, function and brain atrophy; the most visible ongoing studies include TauRx’s low‑dose monotherapy trials (HMTM/LMTM) and an independent fMRI‑based randomized study of low‑dose methylene blue in aging, MCI and mild AD (MB2) [1] [2]. Endpoints across these trials range from neuroimaging and functional connectivity metrics to standard clinical scales (ADAS‑cog, ADCS‑ADL, ADCS‑CGIC) and whole‑brain/ventricular volume measures that were used in prior LMTM trials [3] [2] [4].
1. The trial landscape: who’s running randomized low‑dose studies now
The principal commercially driven randomized program at present is TauRx’s follow‑on low‑dose monotherapy program testing hydromethylthionine (LMTM, later HMTM) at doses that include a 4 mg twice‑daily regimen; TauRx launched a Phase 2/3 monotherapy trial in 2018 across North America and Europe to enroll roughly 180 people and compare six months of low‑dose HMTM against an active low‑dose methylene blue comparator (4 mg twice weekly) [1]. Independently, an academic randomized, double‑blind, placebo‑controlled trial—listed on ClinicalTrials.gov and described in its protocol as MB2—tests short (2‑week) and intermediate (12‑week) low‑dose methylene blue effects on cerebral blood flow, functional connectivity and cognition in healthy aging, MCI and mild AD participants (the MB2 trial documents and protocol describe fMRI and behavioral endpoints) [2] [5].
2. What “low dose” means in these trials
Low dose in the current randomized programs is not uniform: TauRx’s HMTM monotherapy trials explicitly test a 4 mg twice‑daily schedule (a dose that was part of the company’s strategy to separate active monotherapy from what had functioned as an “active placebo” in prior trials) [1], while academic MB2 work uses small, sub‑pharmacologic dosing intended to probe acute neurovascular and connectivity effects with fMRI over days to weeks (protocol summary in MB2 trial documents) [2] [5]. Reviews of the literature note that methylene blue shows hormetic dose effects—potential benefits at low doses and toxicity at higher ones—which is part of why investigators are explicitly testing lower regimens [6].
3. Primary and secondary endpoints being measured
Across the randomized programs the endpoints split into two camps: mechanism/signal‑finding and clinical efficacy. The MB2 study centers on mechanistic neuroimaging and cognitive/behavioral endpoints—cerebral blood flow, functional connectivity on fMRI, and short‑term memory and attention measures at 2 and 12 weeks [2] [5]. TauRx’s low‑dose monotherapy trials are designed to detect clinical change over months using established dementia instruments and structural MRI biomarkers; the broader literature and trial reports show ADAS‑cog, ADCS‑ADL and ADCS‑CGIC as commonly used cognitive/functional endpoints in methylene blue trials, and whole‑brain and lateral ventricular volumes (WBV, LVV) or regional atrophy have been reported as imaging endpoints in phase II/III LMTM studies [3] [4]. Prior phase trials also reported 6‑month cognitive outcomes and slower brain shrinkage on MRI as notable secondary findings [7] [4].
4. What the evidence so far implies about trial aims and uncertainty
The ongoing randomized efforts are explicitly designed to answer two linked questions: can very low doses of methylene blue produce measurable, plausible biological effects in the brain (blood flow, connectivity, proteostasis) and can those translate into clinically meaningful slowing of cognitive/functional decline and reduction of brain atrophy over months to a year [2] [1]. The literature repeatedly notes mixed past results—phase III LMTM trials failed primary endpoints overall though subgroup and imaging signals were reported—so current low‑dose randomized trials are as much about clarifying dosing, trial design and target population as they are about proving efficacy [4] [6] [8].
5. Limits of available reporting and where to watch next
Public descriptions of the active trials provide protocol level detail (dose, duration, imaging/cognitive endpoints) but peer‑reviewed outcome data for the newest low‑dose monotherapy cohorts remain pending; regulators’ assessment and TauRx’s ongoing analyses will determine whether reported subgroup or imaging signals meet standards for efficacy [1] [6]. Independent fMRI‑based randomized studies will be informative about short‑term mechanistic effects but cannot by themselves establish long‑term clinical benefit, so both kinds of trials must be read together to judge low‑dose methylene blue’s promise [2] [3].