Mitochondrial Compound

Methylene Blue

Methylthioninium chloride

Evidence TierDWADA NOT PROHIBITED

tuneTypical Dose

Evidence varies by indication. Human studies used oral doses around 195 to 280 mg or supervised IV protocols rather than a standard nootropic regimen

watchEffect Window

Acute (≈1 hour) for cognitive-task measures. Approximately 1 month for extinction retention after post-session dosing. Weeks–months for mood endpoints in adjunct protocols

check_circleCompliance

WADA NOT PROHIBITED

Overview

Clinical Summary

Methylene blue has small human signals for acute memory-task performance and for strengthening learning after successful exposure therapy sessions, but evidence is limited, results vary by context, and interaction risk (serotonin syndrome) is clinically significant.

Human research does show a few real signals, including modest acute memory-task effects, extinction-learning augmentation after successful exposure therapy, and some psychiatric or perioperative findings in supervised settings. But those details sit beside the much more important safety story: clinically relevant MAOI interactions, G6PD-related hemolysis risk, and major uncertainty around the purity and concentration of nonmedical products.

Low-dose methylene blue can act as a mitochondrial redox cycler supporting cellular energy metabolism in active neural networks. It also has clinically relevant MAOI activity that drives serotonin-syndrome interaction risk with serotonergic medications and certain opioids.

Outcomes

What This Is Expected To Influence

Primary Outcomes

  • Modest acute improvement in short-term memory retrieval in one small healthy-adult study (single dose).
  • Context-dependent strengthening of extinction learning when administered post-session in one phobia study.

Secondary Outcomes

  • Adjunct improvement in residual depression/anxiety symptoms in bipolar disorder (cognition not significantly improved).
  • Neutral prespecified primary-analysis results in a large Alzheimer’s disease phase 3 trial of a related formulation.
  • Reduced postoperative delirium/early cognitive dysfunction in an IV surgical protocol (medical setting).

Safety

Contraindications and Interactions

Contraindications

  • G6PD deficiency
  • Pregnancy (avoid unless clearly necessary in emergency medical use)
  • Severe hypersensitivity to methylene blue/thiazine dyes

Side effects

  • Urine/stool discoloration
  • Nausea
  • Dizziness
  • Dysgeusia
  • Sweating
  • Headache
  • Skin discoloration

Interactions

  • Serotonergic psychiatric medications (SSRIs/SNRIs/TCAs/MAOIs and others)
  • Serotonergic opioids and dextromethorphan
  • Other MAOIs

Avoid if

  • Pregnancy/lactation without clinician direction
  • G6PD deficiency
  • Current serotonergic drug use
  • Unstable cardiovascular disease
  • Severe hepatic/renal impairment without supervision

Evidence

Study-level References

methylene-blue-SRC-001Randomized, double-blind, placebo-controlled human study
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Rodriguez P, Zhou W, Barrett DW, et al. "Multimodal Randomized Functional MR Imaging of the Effects of Methylene Blue in the Human Brain." Radiology. 2016;281(2):516-526. doi:10.1148/radiol.2016152893. PMID:27351678. https://pubmed.ncbi.nlm.nih.gov/27351678/

Population: Healthy adults

Dose protocol: Single oral dose ~280 mg (≈4 mg/kg), neuroimaging and cognitive-task assessment ~1 hour post-dose

Key findings: Modest favorable signal on memory retrieval accuracy and task-related neuroimaging markers

Notes: Small sample. Acute outcomes. Limited external replication for real-world performance.

Paper content

Modest favorable signal on memory retrieval accuracy and task-related neuroimaging markers

methylene-blue-SRC-002Randomized, double-blind, placebo-controlled human study
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Telch MJ, Bruchey AK, Rosenfield D, et al. "Effects of post-session administration of methylene blue on fear extinction and contextual memory in adults with claustrophobia." Am J Psychiatry. 2014;171(10):1091-1098. doi:10.1176/appi.ajp.2014.13101407. PMID:25018057. https://pubmed.ncbi.nlm.nih.gov/25018057/

Population: Adults with marked claustrophobic fear undergoing extinction training

Dose protocol: Single 260 mg dose immediately post-session, follow-up at ~1 month

Key findings: Conditional benefit (improves when session successful, may worsen when unsuccessful). Contextual memory improved at follow-up

Notes: Moderation by session success. Single-session protocol. Population-specific.

Paper content

Conditional benefit (improves when session successful; may worsen when unsuccessful); contextual memory improved at follow-up

methylene-blue-SRC-003Double-blind randomized crossover study
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Alda M, McKinnon M, Blagdon R, et al. "Methylene blue treatment for residual symptoms of bipolar disorder: randomised crossover study." Br J Psychiatry. 2017;210(1):54-60. doi:10.1192/bjp.bp.115.173930. PMID:27284082. https://pubmed.ncbi.nlm.nih.gov/27284082/

Population: Bipolar disorder patients on lamotrigine with residual symptoms

Dose protocol: 195 mg/day vs 15 mg/day over months

Key findings: Improved depression/anxiety ratings. Cognitive outcomes not significant

Notes: Low-dose comparator rather than inert placebo. Adjunct-only setting.

Paper content

Improved depression/anxiety ratings; cognitive outcomes not significant

methylene-blue-SRC-004Exploratory double-blind randomized placebo-controlled dose-finding trial
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Wischik CM, Staff RT, Wischik DJ, et al. "Tau aggregation inhibitor therapy: an exploratory phase 2 study in mild or moderate Alzheimer's disease." J Alzheimers Dis. 2015;44(2):705-720. doi:10.3233/JAD-142874. PMID:25550228. https://pubmed.ncbi.nlm.nih.gov/25550228/

Population: Mild/moderate Alzheimer’s disease

Dose protocol: Multiple daily dose arms, outcomes assessed at ~24 weeks with blinded extensions

Key findings: Benefits reported at an intermediate dose on selected outcomes. Higher dose delivery impaired by absorption limitations

Notes: Exploratory design. Multiplicity. Formulation/absorption constraints.

Paper content

Benefits reported at an intermediate dose on selected outcomes; higher dose delivery impaired by absorption limitations

methylene-blue-SRC-005Randomized, controlled, double-blind, parallel-arm phase 3 trial
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Gauthier S, Feldman HH, Schneider LS, et al. "Efficacy and safety of tau-aggregation inhibitor therapy in patients with mild or moderate Alzheimer's disease: a randomised, controlled, double-blind, parallel-arm, phase 3 trial." Lancet. 2016;388(10062):2873-2884. doi:10.1016/S0140-6736(16)31275-2. PMID:27863809. https://pubmed.ncbi.nlm.nih.gov/27863809/

Population: Mild/moderate Alzheimer’s disease

Dose protocol: Twice-daily dosing at two active levels vs control, assessment over ~65 weeks

Key findings: Neutral in prespecified primary analysis

Notes: Large sample and prespecified coprimary outcomes reduce random error. Post-hoc signals require cautious interpretation.

Paper content

Neutral in prespecified primary analysis

methylene-blue-SRC-006Prospective randomized open-label clinical trial
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Deng Y, Wang R, Li S, et al. "Methylene blue reduces incidence of early postoperative cognitive disorders in elderly patients undergoing major non-cardiac surgery: An open-label randomized controlled clinical trial." J Clin Anesth. 2021;68:110108. doi:10.1016/j.jclinane.2020.110108. PMID:33091706. https://pubmed.ncbi.nlm.nih.gov/33091706/

Population: Elderly patients undergoing major non-cardiac surgery

Dose protocol: IV 2 mg/kg after induction vs saline, postoperative assessment

Key findings: Favorable vs control in the protocol. Adverse events comparable

Notes: Open-label. Single-center/context-specific. IV hospital-only protocol.

Paper content

Favorable vs control in the protocol; adverse events comparable

methylene-blue-SRC-007Regulatory drug-safety communication
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U.S. Food and Drug Administration. "FDA Drug Safety Communication: Serious CNS reactions possible when methylene blue is given to patients taking certain psychiatric medications." July 26, 2011 (updated Oct 20, 2017). https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-serious-cns-reactions-possible-when-methylene-blue-given-patients

Population: Patients receiving methylene blue while on serotonergic psychiatric medications

Dose protocol: Case reports and safety synthesis and recommendations

Key findings: High-risk interaction pathway. Serious and fatal cases reported

Notes: Pharmacovigilance signal plus mechanistic plausibility. Not an efficacy trial.

Paper content

High-risk interaction pathway; serious and fatal cases reported

methylene-blue-SRC-008Prescribing information (drug label)
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DailyMed. "METHYLENE BLUE injection, solution" (U.S. prescribing information; boxed warning, contraindications, and interaction sections). https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=4f222ee5-df03-46d5-a060-c63565b7186f

Population: IV use for methemoglobinemia

Dose protocol: Weight-based IV dosing, boxed warning on serotonin syndrome, contraindication in G6PD deficiency

Key findings: Clear safety constraints. Interaction and hemolysis risks emphasized

Notes: Label reflects regulated-risk framing. Route-specific but interaction biology is generalizable.

Paper content

Clear safety constraints; interaction and hemolysis risks emphasized

methylene-blue-SRC-009Regulatory product information
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electronic Medicines Compendium (emc). "Methylthioninium chloride Proveblue 5 mg/ml solution for injection - Summary of Product Characteristics (SmPC)." Updated July 1, 2024. https://www.medicines.org.uk/emc/product/6898/smpc

Population: IV emergency administration and interaction framework

Dose protocol: Safety and interaction sections detail MAOI activity, serotonergic/opioid interaction risk, and monitoring issues

Key findings: High interaction salience. Monitoring recommended

Notes: Medical-use context. Nonetheless informative for risk assessment.

Paper content

High interaction salience; monitoring recommended

methylene-blue-SRC-010National safety advisory
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Therapeutic Goods Administration (Australia). "Imported unregistered methylene blue products" (Safety advisory). Published September 25, 2025. https://www.tga.gov.au/safety/safety-alerts/imported-unregistered-methylene-blue-products

Population: Consumer exposure to imported/unregistered oral products promoted for cognitive/mood/anti-ageing

Dose protocol: Advisory highlights quality, safety, and interaction risks. Advises against unsupervised use

Key findings: High caution, risk-focused

Notes: Advisory is not an efficacy evaluation. Emphasizes real-world product risk.

Paper content

High caution; risk-focused

methylene-blue-SRC-011Prohibited-substance list (anti-doping standard)
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World Anti-Doping Agency (WADA). "2026 Prohibited List" (in force January 1, 2026). https://www.wada-ama.org/en/resources/2026-prohibited-list

Population: Competitive sports anti-doping compliance

Dose protocol: Name-based check for prohibited status

Key findings: Not prohibited by exact-name check

Notes: Anti-doping risk can still arise from contamination, mislabeling, or evolving rules.

Paper content

Not prohibited by exact-name check

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