Tolerability of a single IV administration of a methylene blue challenge in patients with bipolar disorder: preliminary data from a pharmaco-MRI study

Sharp H, Russo A, Colasanti A, Pinna A, Nwaubani P, Marco R

BJPsych open18 Jun 2021

PMCIDPMC8771454PepBankPUB-95806221

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Summary

Aims To summarise the tolerability profile following an infusion of methylene blue (MB), including subjective effects on mood and energy levels and haemodynamic changes, in patients with Bipolar Affective Disorder (BPAD). Background BPAD is associated with mitochondrial dysfunction and impaired cellular energy production. MB is proposed to enhance mitochondria function via rerouting electrons and intracellular reduction of oxidative stress, and is therefore a candidate compound for use as a probe to reveal alterations in brain oxygen metabolism in vivo in patients with BPAD. Although there are reports of MB used as treatment for BPAD, the tolerability and subjective effects of a single IV dose in this population has not yet been defined. Method Using a single-blind, randomised, within-subject design, 7 patients with BPAD on stable pharmacological treatment and 6 healthy controls (HCs) received an infusion of 0.5mg/kg MB and a placebo glucose solution one week apart. Visual Analogue Scales (VAS) assessing ‘Mood’ and ‘Energy’ levels were completed by 11 participants, and blood pressure (BP), heart rate (HR) and any subsequent side effects were recorded before and after infusions. Result A significant, albeit very small, effect of MB on ‘Mood’ levels relative to placebo was demonstrated, independent of groups (change relative to baseline: 5.5% ± 11 increase (placebo) vs -1.6 % ± 9.5 reduction (MB); p = 0.027). Although there was no effect of MB on energy levels in either group, there appeared to be a trend for a general group difference in ‘Energy’ levels across all trials, with lower ratings in BPAD patients (p = 0.058). There was a trend for significantly lower post-infusion HR relative to pre-infusion (-6.4 ± 8.8 bpm, p = 0.07. Diastolic BP was higher (3.0 ± 7.8mmHg, p = 0.039). These effects were independent of groups and drug. The most common side effect with MB was mild/moderate pain at infusion site (n = 10/13), resolving within median 32.5 minutes (IQR 6-102), and discoloured urine in 7/13 subjects lasting median 44.5 hours (IQR 36-59). No difference in frequency of side effects reported between groups. Conclusion Although limited by small sample size, this tolerability analysis demonstrates a acceptable profile of effects of MB on subjective ratings and blood pressure, in both BPAD and HCs. Common side effects of discoloured urine and pain at infusion site are in line with previous reports in the literature. We observed a small effect of MB on mood ratings which could be related to the discomfort experienced during infusion.

CC BYText from Europe PMC. Highlighted sentences are the source of results.

Results from this study7

7 results from studies that gave the peptide. 7 results from people.

01HumanRandomized controlled trialEfficacy outcome
Heart rate tended to decrease after infusion in both participant groups, independently of methylene blue or placebo.
In plain wordsHeart rate tended to decrease after infusion with both methylene blue and placebo.
Peptide
Methylene blue
Outcome
No significant changeHeart rate after infusion
Study
n = 13
Comparator
Pre-infusion
Outcome group
Heart function · Cardiovascular
Studied dose
0.5mg/kg · intravenousAs given in this study (human).
Measurements
Post- minus pre-infusion heart rate change
−6.4 bpm
all infusions, independent of group and drug (± 8.8)
Source sentences
Summary
There was a trend for significantly lower post-infusion HR relative to pre-infusion (-6.4 ± 8.8 bpm, p = 0.07.
2 context sentences(design, population, supporting numbers)
Summary · context
These effects were independent of groups and drug.
Summary · context
Using a single-blind, randomised, within-subject design, 7 patients with BPAD on stable pharmacological treatment and 6 healthy controls (HCs) received an infusion of 0.5mg/kg MB and a placebo glucose solution one week apart.
Show in the study text Report a problemFND-9580622103
02HumanRandomized controlled trialEfficacy outcome
Diastolic blood pressure increased after infusion in both participant groups, independently of methylene blue or placebo.
In plain wordsDiastolic blood pressure increased after infusion with both methylene blue and placebo.
Peptide
Methylene blue
Outcome
No significant changeDiastolic blood pressure after infusion
Study
n = 13
Comparator
Pre-infusion
Outcome group
Blood pressure · Cardiovascular
Studied dose
0.5mg/kg · intravenousAs given in this study (human).
Measurements
Post-infusion diastolic blood pressure difference
3 mmHg
all infusions, independent of group and drug (± 7.8)
Source sentences
Summary
Diastolic BP was higher (3.0 ± 7.8mmHg, p = 0.039).
2 context sentences(design, population, supporting numbers)
Summary · context
These effects were independent of groups and drug.
Summary · context
Using a single-blind, randomised, within-subject design, 7 patients with BPAD on stable pharmacological treatment and 6 healthy controls (HCs) received an infusion of 0.5mg/kg MB and a placebo glucose solution one week apart.
Show in the study text Report a problemFND-9580622104
03HumanRandomized controlled trialSafety outcome
With methylene blue, mild or moderate infusion-site pain affected 10/13 participants and resolved within median 32.5 minutes.
In plain wordsWith methylene blue, 10/13 participants had mild or moderate infusion-site pain, which resolved within median 32.5 minutes.
Peptide
Methylene blue
Outcome
Not applicableInfusion-site pain
Study
n = 13
Outcome group
Adverse events · Whole body
Studied dose
0.5mg/kg · intravenousAs given in this study (human).
Measurements
Participants with infusion-site pain
10 participants
MB, of 13 participants
Median time to resolution of infusion-site pain
32.5 minutes
MB
IQR of time to resolution of infusion-site pain
6 to 102 minutes
MB
Source sentences
Summary
The most common side effect with MB was mild/moderate pain at infusion site (n = 10/13), resolving within median 32.5 minutes (IQR 6-102), and discoloured urine in 7/13 subjects lasting median 44.5 hours (IQR 36-59).
1 context sentence(design, population, supporting numbers)
Summary · context
Using a single-blind, randomised, within-subject design, 7 patients with BPAD on stable pharmacological treatment and 6 healthy controls (HCs) received an infusion of 0.5mg/kg MB and a placebo glucose solution one week apart.
Show in the study text Report a problemFND-9580622105
04HumanRandomized controlled trialSafety outcome
With methylene blue, discoloured urine affected 7/13 participants and lasted median 44.5 hours.
In plain wordsWith methylene blue, 7/13 participants had discoloured urine lasting median 44.5 hours.
Peptide
Methylene blue
Outcome
Not applicableDiscoloured urine
Study
n = 13
Outcome group
Adverse events · Kidney and urinary
Studied dose
0.5mg/kg · intravenousAs given in this study (human).
Measurements
Participants with discoloured urine
7 participants
MB, of 13 participants
Median duration of discoloured urine
44.5 hours
MB
IQR of duration of discoloured urine
36 to 59 hours
MB
Source sentences
Summary
The most common side effect with MB was mild/moderate pain at infusion site (n = 10/13), resolving within median 32.5 minutes (IQR 6-102), and discoloured urine in 7/13 subjects lasting median 44.5 hours (IQR 36-59).
1 context sentence(design, population, supporting numbers)
Summary · context
Using a single-blind, randomised, within-subject design, 7 patients with BPAD on stable pharmacological treatment and 6 healthy controls (HCs) received an infusion of 0.5mg/kg MB and a placebo glucose solution one week apart.
Show in the study text Report a problemFND-9580622106
05HumanRandomized controlled trialSafety outcome
Methylene blue side-effect frequency did not differ between bipolar patients and healthy controls.
In plain wordsMethylene blue side-effect frequency did not differ between bipolar patients and healthy controls.
Peptide
Methylene blue
Outcome
No significant changeSide-effect frequency by participant group
Study
n = 13
Comparator
Healthy controls
Outcome group
Adverse events · Whole body
Studied dose
0.5mg/kg · intravenousAs given in this study (human).
Source sentences
Summary
No difference in frequency of side effects reported between groups.
1 context sentence(design, population, supporting numbers)
Summary · context
Using a single-blind, randomised, within-subject design, 7 patients with BPAD on stable pharmacological treatment and 6 healthy controls (HCs) received an infusion of 0.5mg/kg MB and a placebo glucose solution one week apart.
Show in the study text Report a problemFND-9580622107
06HumanRandomized controlled trialEfficacy outcome
In bipolar patients and healthy controls, methylene blue slightly reduced mood ratings relative to placebo.
In plain wordsMethylene blue slightly reduced mood ratings compared with placebo in bipolar patients and healthy controls.
Peptide
Methylene blue
Outcome
DecreaseMood rating
Study
n = 11
Comparator
Placebo glucose solution
Outcome group
Anxiety and mood · Mental health and mood
Studied dose
0.5mg/kg · intravenousAs given in this study (human).
Measurements
Mood change relative to baseline
−1.6%
MB (± 9.5)
Mood change relative to baseline
5.5%
placebo (± 11)
Source sentences
Summary
A significant, albeit very small, effect of MB on ‘Mood’ levels relative to placebo was demonstrated, independent of groups (change relative to baseline: 5.5% ± 11 increase (placebo) vs -1.6 % ± 9.5 reduction (MB); p = 0.027).
1 context sentence(design, population, supporting numbers)
Summary · context
Using a single-blind, randomised, within-subject design, 7 patients with BPAD on stable pharmacological treatment and 6 healthy controls (HCs) received an infusion of 0.5mg/kg MB and a placebo glucose solution one week apart.
Show in the study text Report a problemFND-9580622101
07HumanRandomized controlled trialEfficacy outcome
Methylene blue had no effect on energy ratings in bipolar patients or healthy controls compared with placebo.
In plain wordsMethylene blue did not change energy ratings compared with placebo in bipolar patients or healthy controls.
Peptide
Methylene blue
Outcome
No significant changeEnergy rating
Study
n = 11
Comparator
Placebo glucose solution
Outcome group
Anxiety and mood · Mental health and mood
Studied dose
0.5mg/kg · intravenousAs given in this study (human).
Source sentences
Summary
Although there was no effect of MB on energy levels in either group, there appeared to be a trend for a general group difference in ‘Energy’ levels across all trials, with lower ratings in BPAD patients (p = 0.058).
1 context sentence(design, population, supporting numbers)
Summary · context
Using a single-blind, randomised, within-subject design, 7 patients with BPAD on stable pharmacological treatment and 6 healthy controls (HCs) received an infusion of 0.5mg/kg MB and a placebo glucose solution one week apart.
Show in the study text Report a problemFND-9580622102

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Version 2Current
14 Oct 2026, 05:02 UTC
Study results updated
Version 1
14 Oct 2026, 01:46 UTC
First added · source update from Europe PMC

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