Methylene Blue - used for over a century in Psychiatry, also handy for your fish tank

According to the packaging:-

Effective against a range of fungal and bacterial infections

•          Increases the oxygen-carrying capacity of fish

•          Can be used as an antiseptic directly onto wounds

•          For use in tropical and cold water aquariums

 

Our reader Dragos recently let us all know about his success with very low doses of Methylene Blue (MB).  I think this came as a surprise to many, but actually there is nothing new about using this old pigment as a therapy in psychiatry.  Much is known about its modes of action.

 

What is Methylene Blue?

In 1876, German chemist Heinrich Caro synthesized methylene blue (MB) for the first time in history.  It was used as a dye for textiles. Around the same time, it was found that MB is capable of staining cells by binding to their structures, in addition, sometimes inactivating bacteria. This discovery prepared the way for biological or medical studies related to MB. Numerous scientists applied it to a variety of animal and bacterial studies, importantly Paul Ehrlich introduced it to humans in 1891 as an anti-malarial agent.

I was interested to see why it is used in aquariums, in particular the reference to increases the oxygen-carrying capacity of fish.

Methemoglobinemia (MetHb) is a rare blood disorder that affects how red blood cells deliver oxygen throughout your body.

A common way to treat  MetHb  in humans is to reduce methemoglobin levels using  Methylene blue (MB). Another common treatment, not surprisingly, is to give oxygen.

If you want to increase oxygen levels in the fish in your aquarium you put MB in the water.

More oxygen in your blood would improve exercise endurance meaning you would delay the point at which your mitochondria become unable to keep producing ATP efficiently.

I did some investigation and there is indeed a trend towards people using methyl blue to improve their sporting performance. It is mocked in some newspapers because it makes your tongue turn blue. It makes for good pictures on Instagram.     

The effect will be similar to those long distance cyclists who take beetroot juice, but the mechanism is different.

Be aware that just like beetroot may dye what comes out of your body bright red, MB may give you a hint of blue.

  

Improved Mitochondrial Function

One of the known effects of Methylene Blue (MB) is on the mitochondria.

In numerous papers it has been discussed how MB improves brain mitochondrial respiration.

In neurological disorders such as Alzheimer’s disease, traumatic brain injury, depression, stroke, Parkinson’s disease and some autism, mitochondria contribute to the disorder through decreased energy production and excessive production of reactive oxygen species (ROS).

This subject does get rather complex but in short methylene blue is able to perform alternative electron transport, bypassing parts of the electron transport chain.

In autism terms this means that some people diagnosed with a lack of Complex 1, 2, 3 or 4 in their mitochondria, might want to pay particular attention to how Methylene Blue might be helpful.

Improved mitochondrial function is another reason why sportsmen might want to use MB to enhance their performance.

As we have seen with other enhancing drugs like the Russian Meldonium, the US Diamox and the new US super ketone products, the military do end up using these products.  If you see a picture of a navy seal with a blue tongue you will know where it came from!

 

Methylene Blue inhibits Monoamine Oxidase (MAO)

MAOIs act by inhibiting the activity of monoamine oxidase, thus preventing the breakdown of monoamine neurotransmitters and thereby increasing their availability. There are two types of monoamine oxidase, MAO-A and MAO-B. MAO-A preferentially deaminates serotonin, melatonin, epinephrine, and norepinephrine. MAO-B preferentially deaminates phenethylamine and certain other trace amines; in contrast, MAO-A preferentially deaminates other trace amines, like tyramine, whereas dopamine is equally deaminated by both types.

Methyl blue is a reversible selective MAO-A inhibitor and so has antidepressant properties (it gives you more feel good serotonin). This interesting drug has several other pharmacological actions, including inhibition of nitric oxidase synthase (NOS), and guanylate cyclase and so its antidepressant properties should not be solely ascribed to inhibition of MAO-A. 

Inhibition of neuronal nitric oxide synthase and soluble guanylate cyclase prevents depression-like behaviour in rats exposed to chronic unpredictable mild stress

Beyond treating depression MAOIs (Monoamine oxidase inhibitors) have been found to be effective in the treatment of panic disorder, social phobia, mixed anxiety disorder and depression, bulimia, and post-traumatic stress disorder, as well as borderline personality disorder, and Obsessive Compulsive Disorder (OCD).

MAOIs appear to be particularly effective in the management of bipolar depression.

Methylene blue treatment for residual symptoms of bipolar disorder: randomised crossover study

Background: Residual symptoms and cognitive impairment are among important sources of disability in patients with bipolar disorder. Methylene blue could improve such symptoms because of its potential neuroprotective effects.

Aims: We conducted a double-blind crossover study of a low dose (15 mg, 'placebo') and an active dose (195 mg) of methylene blue in patients with bipolar disorder treated with lamotrigine.

Method: Thirty-seven participants were enrolled in a 6-month trial (trial registration: NCT00214877). The outcome measures included severity of depression, mania and anxiety, and cognitive functioning.

Results: The active dose of methylene blue significantly improved symptoms of depression both on the Montgomery-Åsberg Depression Rating Scale and Hamilton Rating Scale for Depression (P = 0.02 and 0.05 in last-observation-carried-forward analysis). It also reduced the symptoms of anxiety measured by the Hamilton Rating Scale for Anxiety (P = 0.02). The symptoms of mania remained low and stable throughout the study. The effects of methylene blue on cognitive symptoms were not significant. The medication was well tolerated with transient and mild side-effects.

Conclusions: Methylene blue used as an adjunctive medication improved residual symptoms of depression and anxiety in patients with bipolar disorder.

 

Methylene Blue activates oxidative stress response genes via Nrf2

One of the antioxidant effects of MB is activation of the redox switch Nrf2.  In the paper below it is also mentioned that MB has a beneficial against tau proteins. Amyloid and tau proteins clog up the brain in Alzheimer’s and as a result MB has been proposed as a therapy for dementia. 

Methylene blue upregulates Nrf2/ARE genes and prevents tau-related neurotoxicity

Methylene blue (MB, methylthioninium chloride) is a phenothiazine that crosses the blood brain barrier and acts as a redox cycler. Among its beneficial properties are its abilities to act as an antioxidant, to reduce tau protein aggregation and to improve energy metabolism. These actions are of particular interest for the treatment of neurodegenerative diseases with tau protein aggregates known as tauopathies. The present study examined the effects of MB in the P301S mouse model of tauopathy. Both 4 mg/kg MB (low dose) and 40 mg/kg MB (high dose) were administered in the diet ad libitum from 1 to 10 months of age. We assessed behavior, tau pathology, oxidative damage, inflammation and numbers of mitochondria. MB improved the behavioral abnormalities and reduced tau pathology, inflammation and oxidative damage in the P301S mice. These beneficial effects were associated with increased expression of genes regulated by NF-E2-related factor 2 (Nrf2)/antioxidant response element (ARE), which play an important role in antioxidant defenses, preventing protein aggregation, and reducing inflammation. The activation of Nrf2/ARE genes is neuroprotective in other transgenic mouse models of neurodegenerative diseases and it appears to be an important mediator of the neuroprotective effects of MB in P301S mice. Moreover, we used Nrf2 knock out fibroblasts to show that the upregulation of Nrf2/ARE genes by MB is Nrf2 dependent and not due to secondary effects of the compound. These findings provide further evidence that MB has important neuroprotective effects that may be beneficial in the treatment of human neurodegenerative diseases with tau pathology.

 

MB to treat inflammation and pain via sodium ion channels and iNOS

MB abates inflammation by suppressing nitric oxide production, and ultimately relieves pain in arthritis and colitis.  

MB suppresses the iNOS/NO-mediated inflammatory signaling by directly downregulating inducible NO synthase (iNOS).

Nitric oxide (NO) is a free radical which, in reactions with various molecules causes multiple biological effects, some good and some harmful.

It is produced by a reaction involving one of three enzymes iNOS, eNOS and nNOS.  i = inducible, n = neuronal and e = endothelial

iNOS is a major downstream mediator of inflammation.

eNOS is very helpful because it can widen blood vessels and so reduce blood pressure and increase blood flow.

nNOS is found in the brain and the peripheral nerve system where it has several important functions.  

MB may impede pain transmission by dampening neuronal excitability elicited by voltage-gated sodium channels (VGSCs).  You would then think that in people with seizures due to malfunctioning sodium channels, MB might be beneficial; for example Nav1.1 in Dravet syndrome. 

Methylene Blue Application to Lessen Pain: Its Analgesic Effect and Mechanism

Methylene blue (MB) is a cationic thiazine dye, widely used as a biological stain and chemical indicator. Growing evidence have revealed that MB functions to restore abnormal vasodilation and notably it is implicated even in pain relief. Physicians began to inject MB into degenerated disks to relieve pain in patients with chronic discogenic low back pain (CDLBP), and some of them achieved remarkable outcomes. For osteoarthritis and colitis, MB abates inflammation by suppressing nitric oxide production, and ultimately relieves pain. However, despite this clinical efficacy, MB has not attracted much public attention in terms of pain relief. Accordingly, this review focuses on how MB lessens pain, noting three major actions of this dye: anti-inflammation, sodium current reduction, and denervation. Moreover, we showed controversies over the efficacy of MB on CDLBP and raised also toxicity issues to look into the limitation of MB application. This analysis is the first attempt to illustrate its analgesic effects, which may offer a novel insight into MB as a pain-relief dye. 

Nicotinic acetylcholine receptors

The modulation of nicotinic acetylcholine receptors (nAChRs) has been suggested to play a role in the pathogenesis of various neurodegenerative diseases. 

MB acts as a non-competitive antagonist on α7 nAChRs.

Well known drugs that act in a similar way include the Alzheimer’s drug Memantine and Ketamine. Recall that intranasal Ketamine has been used in autism. 

Substances  with the opposite effect include nicotine, choline and of course

Amyloid beta, the marker of Alzheimer's disease.

Note that some people need to block α7 nAChRs and some people need to activate them. 

Methylene blue inhibits the function of α7-nicotinic acetylcholine receptors

FDA Drug Safety Communication: Serious CNS reactions possible when methylene blue is given to patients taking certain psychiatric medications

A list of the serotonergic psychiatric medications that can interact with methylene blue can be found here. 

• Methylene blue can interact with serotonergic psychiatric medications and cause serious CNS toxicity.
• In emergency situations requiring life-threatening or urgent treatment with methylene blue (as described above), the availability of alternative interventions should be considered and the benefit of methylene blue treatment should be weighed against the risk of serotonin toxicity. If methylene blue must be administered to a patient receiving a serotonergic drug, the serotonergic drug must be immediately stopped, and the patient should be closely monitored for emergent symptoms of CNS toxicity for two weeks (five weeks if fluoxetine [Prozac] was taken), or until 24 hours after the last dose of methylene blue, whichever comes first.
• In non-emergency situations when non-urgent treatment with methylene blue is contemplated and planned, the serotonergic psychiatric medication should be stopped to allow its activity in the brain to dissipate. Most serotonergic psychiatric drugs should be stopped at least 2 weeks in advance of methylene blue treatment. Fluoxetine (Prozac), which has a longer half-life compared to similar drugs, should be stopped at least 5 weeks in advance.
• Treatment with the serotonergic psychiatric medication may be resumed 24 hours after the last dose of methylene blue.
• Serotonergic psychiatric medications should not be started in a patient receiving methylene blue. Wait until 24 hours after the last dose of methylene blue before starting the antidepressant.
• Educate your patients to recognize the symptoms of serotonin toxicity or CNS toxicity and advise them to contact a healthcare professional immediately if they experience any symptoms while taking serotonergic psychiatric medications or methylene blue.

Conclusion 

Rather surprisingly, this therapy from the fish tank may have wide ranging effects on the autistic brain and in those with dementia, bipolar etc.

Possible benefits might include:

·        Improved production of ATP (energy) in the brain

·        Reduced oxidative stress in the brain

·        Reduced nitrosative stress

·        Reduced inflammation

·        Improved mood (due to increased serotonin)

·        Improved memory and cognitive function

·        Reduction in obsessive behaviors

In one of the papers, they comment that “methylene blue modulates functional connectivity in the human brain”.

It seems to work for Dragos.  You can also see that people on Reddit use it for issues like ADHD. 

 

Note the FDA warning:

Do not combine Methylene Blue with serotonergic psychiatric medications, because of the risk of serotonin syndrome (i.e., serotonin toxicity).

Sensory Gating in Autism, Particularly Asperger's

Sensory gating is an issue in autism, schizophrenia and ADHD.   It is the neurological process of filtering out redundant or unnecessary stimuli in the brain; like the child who sits in his classroom and gets bothered by the noise of the clock on the wall.  He is unable to filter out and ignore this sound. He becomes preoccupied by the sound and cannot concentrate on his work.

There are also sometimes advantages to not filtering out environmental stimuli, because you would have more situational awareness and notice things that others miss.

An example of sensory gating is the fact that young children are not waken by smoke detectors that have high pitched siren, but are waken by a recorded human voice telling them there is a fire and to wake up.

There may be times when sensory overload in autism is not a case of too much volume from each of the senses, but rather too many inputs being processed by the brain, instead of some just being ignored.  It is more a case of information overload.

Note that this blog has already covered hypokalemic sensory overload in some depth, which is treatable.

Much is known about sensory gating because it has long been known to be a problem in schizophrenia.

An EEG (Electroencephalography) test measures your brain waves / neural oscillations. Many people with autism have EEGs, but mainly those in which epilepsy is a consideration.

In the world of the EEG, the P50 is an event occurring approximately 50 millisecond after the presentation of an auditory click.  The P50 response is used to measure sensory gating, or the reduced neurophysiological response to redundant stimuli.

Abnormal P50 suppression is a biomarker of schizophrenia, but is present in other disorders, including Asperger’s, post-traumatic stress disorder (PTSD) and traumatic brain injury (TBI).

In more severe autism abnormal P50 suppression was found not to be present in one study.  This might be because cognition and the senses are dimmed by the excitatory-inhibitory imbalance.

More broadly, sensory gating is seen as an issue in wider autism and ADHD.

Correcting P50 gating

It is known that α7 nicotinic acetylcholine receptor (α7 nAChR) agonists can correct the impaired P50 gating. It is also known that people with schizophrenia have less expression of this receptor in their brains than typical people.

One short term such agonist is the nicotine released from smoking.  This likely contributes to why people with schizophrenia can be heavy smokers.  The effect is thought to last for about 30 minutes.

Clinical trials using Tropisetron, a drug that is a α7 nAChR agonist and used off-label to treat fibromyalgia, have shown that it can correct defective P50 gating and improve cognitive function in schizophrenia.

An alternative α7 nAChR agonist that is widely available is varenicline, a drug approved to help people stop smoking.

So you might expect varenicline to improve P50 gating and improve cognition. You might also expect it to help people with fibromyalgia and indeed some other people with chronic inflammation, as shown by elevated inflammatory cytokines.

You may recall that the α7 nAChR is the key to stimulating the vagus nerve and this should be beneficial to many people with inflammatory conditions (from arthritis to fibromyalgia).

Brief Report: Initial Trial of Alpha7-Nicotinic Receptor Stimulation in Two Adult Patients with Autism Spectrum Disorder

Abnormalities in CHRNA7, the alpha7-nicotinic receptor gene, have been reported in autism spectrum disorder. These genetic abnormalities potentially decrease the receptor’s expression and diminish its functional role. This double-blind, placebo-controlled crossover study in two adult patients investigated whether an investigational receptor-specific partial agonist drug would increase the inhibitory functions of the gene and thereby increase patients’ attention. An electrophysiological biomarker, P50 inhibition, verified the intended neurobiological effect of the agonist, and neuropsychological testing verified a primary cognitive effect. Both patients perceived increased attention in their self-ratings. Alpha7-nicotinic receptor agonists, currently the target of drug development in schizophrenia and Alzheimer Disease, may also have positive clinical effects in autism spectrum disorder.

α7-nicotinic acetylcholine receptor agonists for cognitive enhancement in schizophrenia

A role for H3 and HI histamine receptors

It has also been suggested that histamine plays a role in sensory gating via the H1 and H3 receptors.

It had also been thought H3 receptors could be targeted to improve cognition in schizophrenia, but that research really did not go anywhere.

Meclizine enhancement of sensorimotor gating in healthy male subjects with high startle responses and low prepulse inhibition.

Histamine H₁ receptor systems have been shown in animal studies to have important roles in the reversal of sensorimotor gating deficits, as measured by prepulse inhibition (PPI). H₁-antagonist treatment attenuates the PPI impairments caused by either blockade of NMDA glutamate receptors or facilitation of dopamine transmission. The current experiment brought the investigation of H₁ effects on sensorimotor gating to human studies. The effects of the histamine H₁ antagonist meclizine on the startle response and PPI were investigated in healthy male subjects with high baseline startle responses and low PPI levels. Meclizine was administered to participants (n=24) using a within-subjects design with each participant receiving 0, 12.5, and 25 mg of meclizine in a counterbalanced order. Startle response, PPI, heart rate response, galvanic skin response, and changes in self-report ratings of alertness levels and affective states (arousal and valence) were assessed. When compared with the control (placebo) condition, the two doses of meclizine analyzed (12.5 and 25 mg) produced significant increases in PPI without affecting the magnitude of the startle response or other physiological variables. Meclizine also caused a significant increase in overall self-reported arousal levels, which was not correlated with the observed increase in PPI. These results are in agreement with previous reports in the animal literature and suggest that H₁ antagonists may have beneficial effects in the treatment of subjects with compromised sensorimotor gating and enhanced motor responses to sensory stimuli.

Histamine and acetylcholine receptor involvement in sensorimotor gating: an autoradiography study

The aim of this study was to investigate an established rat model of decreased PPI induced by administration of the NMDA antagonist, dizocilpine and the reversal of this PPI impairment by the histaminergic H1-antagonist, pyrilamine. H1-antagonism is a potential mechanism of the therapeutic effects of the atypical antipsychotic, clozapine, which improves PPI following dizocilpine administration in rats as well as in patients with schizophrenia. In the present study we show that chronic pyrilamine administration prevents the PPI impairment induced by chronic dizocilpine administration, an effect that is correlated with a reduction in ligand-binding potential of H1 receptors in the anterior cingulate and an increase in nicotinic receptor α7 subunit binding in the insular cortex. In light of the functional anatomical connectivity of the anterior cingulate and insular cortex, both of which interact extensively with the core PPI network, our findings support the inclusion of both cortical areas in an expanded network capable of regulating sensorimotor gating.

Histamine H3 Receptor Regulates Sensorimotor Gating and Dopaminergic Signaling in the Striatum.

The brain histamine system has been implicated in regulation of sensorimotor gating deficits and in Gilles de la Tourette syndrome. Histamine also regulates alcohol reward and consumption via H3 receptor (H3R), possibly through an interaction with the brain dopaminergic system. Here, we identified the histaminergic mechanism of sensorimotor gating and the role of histamine H3R in the regulation of dopaminergic signaling. We found that H3R knockout mice displayed impaired prepulse inhibition (PPI), indicating deficiency in sensorimotor gating. Histamine H1 receptor knockout and histidine decarboxylase knockout mice had similar PPI as their controls. Dopaminergic drugs increased PPI of H3R knockout mice to the same level as in control mice, suggesting that changes in dopamine receptors might underlie deficient PPI response when H3R is lacking. Striatal dopamine D1 receptor mRNA level was lower, and D1 and D2 receptor-mediated activation of extracellular signal-regulated kinase 1/2 was absent in the striatum of H3R knockout mice, suggesting that H3R is essential for the dopamine receptor-mediated signaling. In conclusion, these findings demonstrate that H3R is an important regulator of sensorimotor gating, and the lack of H3R significantly modifies striatal dopaminergic signaling. These data support the usefulness of H3R ligands in neuropsychiatric disorders with preattentional deficits and disturbances in dopaminergic signaling.

Conclusion

Other than nicotine, varenicline would seem a good potential therapy for sensory gating.  There are α7-nicotinic acetylcholine receptor agonists in development.

There are many H1 histamine antagonists.  Histamine release in the brain triggers secondary release of excitatory neurotransmitters such as glutamate and acetylcholine via stimulation of H₁ receptors. Centrally acting H1 antihistamines are sedating.

H3 antagonists have stimulant and nootropic effects. Betahistine is an approved drug in this class, there are many research drugs.

The role of histamine dysfunction in sensory and cognitive deficits in schizophrenia

The aim of this study is to investigate the role of the neurotransmitter histamine in sensory and cognitive deficits as they often occur in schizophrenia patients (e.g. hearing voices, planning and memory problems). The ideal location to conduct the study and to obtain a unique learning experience is at the Institute of Psychiatry, London, United Kingdom, where staff comprises of leading experts in the field of schizophrenia and Magnetic Resonance Imaging of pharmacological effects. Current pharmacological treatment of psychotic symptoms including sensory and cognitive deficits remains partially unsuccessful due to side effects and treatment resistance. The neurotransmitter histamine seems to be a very promising target for new treatments. It has been found that histamine neurotransmission is altered in brains of schizophrenics, which may contribute to both the hallucinatory and cognitive symptoms. However, this specific role of histamine has not been investigated before. I will assess the effects of increased histaminergic activity, by administration of betahistine to healthy volunteers, on performance (sensory gating, executive functioning or planning and memory) and associated brain activity using fMRI. Altered performance and brain activity would support the importance of histamine in schizophrenia and would provide a research model and target for new treatments.