Evidence Trace, complete trial record
In plain terms
In plain terms: Methylene Blue (low-dose) shows early signals in human research but the evidence is limited -- small trials, surrogate endpoints, or not yet independently replicated. It is an emerging area, not yet a proven one.
Methylene Blue (low-dose)
C
Limited: small, mixed or unreplicated trials
The endpoint this grade is based on: Objectively measured functional outcome, Memory after a single oral dose of about 260 mg, in two small randomized trials from one research group (C). Daily low-dose use for memory or cognition, which is what consumer products supply, has no randomized trial (D Route 1). The one multi-week trial that measured cognition, 195 mg/day for 6 months in bipolar disorder, was null for cognition. The longevity evidence is preclinical.
The evidence as the record states it
Telch et al. (American Journal of Psychiatry, 2014; PMID 25018057): randomized placebo-controlled trial, 42 adults with marked claustrophobic fear, a single 260 mg dose given immediately after six 5-minute exposure sessions; the primary question was retention of fear extinction at one month, better on methylene blue among participants with low end-of-session fear and worse among those with high fear; contextual memory was a secondary measure. Rodriguez et al. (Radiology, 2016; PMID 27351678): 26 healthy adults, randomized double-blind placebo-controlled, one oral dose the authors call low-dose; functional MRI response during attention and short-term memory tasks increased and correct memory retrieval rose 7 percent one hour later. Both trials come from the same laboratory, so neither replicates the other. Alda et al. (British Journal of Psychiatry, 2017; PMID 27284082): double-blind crossover, 37 patients with bipolar disorder on lamotrigine, 195 mg/day against a 15 mg comparator for 6 months; depression and anxiety scores improved, cognitive measures did not. Grade C: small single-dose positives from one group, with the only multi-week cognitive measurement null; daily low-dose use is untested and graded D on its own row. The wider longevity evidence is preclinical.
PMID 25018057 PMID 27351678 PMID 27284082
Evidence by specific use
Memory retrieval and contextual memory after a single oral dose of about 260 mg
Grade C
Telch et al. (Am J Psychiatry, 2014; PMID 25018057): a single 260 mg dose after exposure sessions improved contextual memory as a secondary measure and retention of fear extinction only in people with low end-of-session fear. Rodriguez et al. (Radiology, 2016; PMID 27351678): one oral dose in 26 healthy adults, 7 percent more correct answers on short-term memory retrieval one hour later, with increased functional MRI response. Both trials are from the same University of Texas laboratory, so they are not independent replication. Where cognition was measured over months, 195 mg/day in bipolar disorder changed nothing (Alda et al., 2017; PMID 27284082). Small unreplicated single-dose positives are C.
PMID 25018057 PMID 27351678 PMID 27284082
Daily low-dose methylene blue for memory or cognition
Grade D
No randomized trial has tested daily low-dose methylene blue for memory or cognition in anyone. The positive trials are single doses of about 260 mg from one laboratory, roughly a hundred times what consumer low-dose products deliver per day, and the one multi-week trial measuring cognition (Alda et al., 2017; PMID 27284082, 195 mg/day) was null. The related methylthioninium compound LMTM failed its phase 3 Alzheimer's trial, a different form and population that does not grade this record. Route 1: untested as sold.
PMID 27284082
Why Grade C and not Grade B
Grade C reflects early or limited human evidence -- small trials, surrogate endpoints, or preliminary findings not yet independently replicated. The evidence points in a promising direction but does not yet meet the standard for Grade B. A single well-powered, independently replicated trial with a meaningful endpoint would move this to Grade B or higher.
What would move this grade
A well-powered randomized trial with an objective, clinically meaningful primary endpoint and at least one independent replication would support Grade B or higher.
How to track whether this is working
For the single-dose use, the trials tested memory at one hour to one month; there is no validated protocol for ongoing use. Urine color change is a harmless compliance marker. Methylene blue is a potent MAOI at doses above 0.5 mg/kg, so combining it with SSRIs, MAOIs or other serotonergic agents carries a risk of serotonin syndrome.