Effects of USP Methylene Blue on Cognitive and fMRI Brain Activity

NCT ID: NCT01836094

Last Updated: 2017-04-11

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: EARLY_PHASE1
• Total Enrollment: 36 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-08-31
• Study Completion Date: 2016-03-31

Brief Summary

The purpose of the study is to evaluate whether low-dose USP methylene blue (MB) will: i) improve short-term memory retention in a delayed match-to-sample task, ii) reduce reaction time in a psychomotor vigilance test, and iii) enhance responses to a visual-motor task as measured by functional magnetic resonance imaging (fMRI).

A single low-dose MB or placebo will be orally administered to self-declared healthy adults using double-blind study design. Non-invasive fMRI data will be acquired before and after MB administration in the same subjects. Each study will take 2-3 hours, inclusive of an hour break in between.

Detailed Description

Self-declared healthy adult volunteers will be studied using a double-blind, placebo-controlled design. After informed consent and familiarity with the tasks and the MRI environment, the subject will enter an MRI scanner and perform the following 3 tasks:

Delayed match-to-sample task: The subject views an object for a few seconds. After a few (variable) seconds, the subject is presented with two patterns and the subject needs to press the left or right button based on whether the picture on the left or the right is the same as the previous picture. The correct and incorrect answers are recorded. A few of these trials will be cycled, lasting about 5-10 mins.

Psychomotor vigilance test: The subject will receive a visual cue to press a button as fast as possible. The reaction time is recorded. A false start is when the subject presses before the visual cue and that trial is not counted. The subject is instructed to avoid a false start. A few of these trials will be cycled, lasting about 5-10 mins.

Visual-motor task: The subject is instructed to tap his/her 4 fingers against the thumb every second and cycle through the 4 fingers, in synchrony with an alternating visual checkerboard patterns. A few of these trials will be cycled, lasting about 5-10 mins.

For calibration of the fMRI signal, fMRI data will also be acquired during a brief (3-5 mins) inhalation of 5% CO2 in air.

fMRI measurements will be made before intervention. The subject comes out of the scanner, orally ingests the USP MB or placebo, and waits for an hour (break). The same measurements will then be repeated.

fMRI data acquisition: The MRI pulse sequences include standard and non-invasive anatomical MRI for co-registration, blood flow and blood-oxygen-level dependent (BOLD) fMRI. fMRI will image changes in regional brain activity associated with these tasks.

In addition, one week after the fMRI study, the subject will be emailed a short questionnaire (which takes a few minutes to answer) and the responses can be returned via email.

Data analysis: Standard fMRI analysis will be analyzed using established fMRI software. Statistical parametric analysis will be performed to generate activation maps. Task-evoked changes in brain activities will be analyzed and contrasted between placebo and MB conditions in the same subjects. Paired t-test will be used for group comparison with P < 0.05 (with bonferroni correction) considered statistically significant.

Expected results: The investigators predict that, compared to placebo, MB will: i) improve short-term memory retention in a delayed match-to-sample task by memory performance and enhanced fMRI responses in the prefrontal cortex-hippocampus, ii) reduce reaction time in a psychomotor vigilance test and enhanced fMRI responses within a cortical sustained attention network and the motor systems, and iii) enhance responses in the visual and motor cortices.

Power analysis: Sample sizes were calculated for a power of 80%, alpha = 0.05 to detect statistical difference between MB and placebo. The investigators estimate they will need 40 subjects (complete studies) and thus will recruit 50 subjects to account for potential failed studies.

Conditions

Brain Activity

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: BASIC_SCIENCE
• Blinding Strategy: DOUBLE

Study Groups

Methylene Blue

Methylene Blue, 280mg, oral, one time

Group Type: EXPERIMENTAL

Methylene Blue (USP grade, 280mg oral)

Intervention Type: DRUG

Placebo

FD\&C Blue No. 2 (food dye), oral, one time

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

oral, one time

Interventions

Methylene Blue (USP grade, 280mg oral)

Intervention Type: DRUG

Placebo

oral, one time

Intervention Type: DRUG

Other Intervention Names

USP Methylene Blue, Phenothiazin-5-ium, 3, 7-bis (dimethylamino)-chloride, trihydrate; FD&C Blue No. 2 (food dye)

Eligibility Criteria

Inclusion Criteria

• Age 18 - 65 years, self declared healthy individuals
• English speaker and be able to give consent

Exclusion Criteria

• Contraindication for MRI (pacemaker, metal implants, etc.)
• Claustrophobia
• Pregnant (child-bearing age females will be tested to exclude pregnancy onsite)
• Breast-feeding
• A history of hypersensitivity or allergy to methylene blue, glucose-6-phosphate dehydrogenase deficiency (determined via questionnaire)
• Neurological, mental, or cardiovascular disorders
• Liver, kidney disorders, kidney or liver transplant, hypertension, diabetes, etc.
• Known hypersensitivity to thiazide diuretics and phenothiazines
• A history of a psychotic disorder or panic disorder, violent or suicidal behavior, psychiatric institutionalization or imprisonment
• Any other condition, which in the opinion of the investigator, would put the participant at risk and warrant exclusion from the study
• Methemoglobinemia
• On any psychiatric serotonergic antidepressant medication or drugs of abuse currently or within the last 5 weeks
• History of panic attack
• Color Blindness

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

The University of Texas Health Science Center at San Antonio

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Timothy Q. Duong, Ph.D.

Role: PRINCIPAL_INVESTIGATOR

The University of Texas Health Science Center at San Antonio

Locations

Research Imaging Institute, The University of Texas Health Science Center at San Antonio

San Antonio, Texas, United States

Countries

United States

References

Riha PD, Bruchey AK, Echevarria DJ, Gonzalez-Lima F. Memory facilitation by methylene blue: dose-dependent effect on behavior and brain oxygen consumption. Eur J Pharmacol. 2005 Mar 28;511(2-3):151-8. doi: 10.1016/j.ejphar.2005.02.001.

Reference Type: BACKGROUND

PMID: 15792783 (View on PubMed)

Gonzalez-Lima F, Bruchey AK. Extinction memory improvement by the metabolic enhancer methylene blue. Learn Mem. 2004 Sep-Oct;11(5):633-40. doi: 10.1101/lm.82404.

Reference Type: BACKGROUND

PMID: 15466319 (View on PubMed)

Wrubel KM, Riha PD, Maldonado MA, McCollum D, Gonzalez-Lima F. The brain metabolic enhancer methylene blue improves discrimination learning in rats. Pharmacol Biochem Behav. 2007 Apr;86(4):712-7. doi: 10.1016/j.pbb.2007.02.018. Epub 2007 Mar 6.

Reference Type: BACKGROUND

PMID: 17428524 (View on PubMed)

Wen Y, Li W, Poteet EC, Xie L, Tan C, Yan LJ, Ju X, Liu R, Qian H, Marvin MA, Goldberg MS, She H, Mao Z, Simpkins JW, Yang SH. Alternative mitochondrial electron transfer as a novel strategy for neuroprotection. J Biol Chem. 2011 May 6;286(18):16504-15. doi: 10.1074/jbc.M110.208447. Epub 2011 Mar 18.

Reference Type: BACKGROUND

PMID: 21454572 (View on PubMed)

Lim J, Wu WC, Wang J, Detre JA, Dinges DF, Rao H. Imaging brain fatigue from sustained mental workload: an ASL perfusion study of the time-on-task effect. Neuroimage. 2010 Feb 15;49(4):3426-35. doi: 10.1016/j.neuroimage.2009.11.020. Epub 2009 Nov 24.

Reference Type: BACKGROUND

PMID: 19925871 (View on PubMed)

Bruchey AK, Gonzalez-Lima F. Behavioral, Physiological and Biochemical Hormetic Responses to the Autoxidizable Dye Methylene Blue. Am J Pharmacol Toxicol. 2008 Jan 1;3(1):72-79. doi: 10.3844/ajptsp.2008.72.79.

Reference Type: BACKGROUND

PMID: 20463863 (View on PubMed)

Other Identifiers

NS 13-208

Identifier Type: -

Identifier Source: org_study_id