The MAOI-Methylene Blue Connection: A Breakthrough in Mood Enhancement

The sun is shining, a cool breeze hits your face. Your mind is at ease and centered.

Everything seems just right. You feel in the zone. You feel centered. But like all sensations, emotions, and feelings, this moment won't last. Like all moments before and after it, they will arise and then pass by... like a cloud in the sky. 

For most of us -- except those precious few who have the concept of dynamic equanimity down to a science -- countless factors will make your mood swing radically through the day. Too much work, too many responsibilities, crying children, crying husbands, etc. The struggle is real…

But hey! There is good news! Other than implementing healthy habits like plenty of sleep, exercise, a good diet, and a regular meditation practice, there are some exciting molecules that can help us stay mentally strong by optimizing our brain chemistry.

And surprise! Methylene blue (MB) is one of them. Although we are not suggesting you change or stop any of your medications unless you speak to your healthcare provider, MB may very well lift your mood and, in early clinical trials, it is showing promise in treating certain psychiatric and neurological disorders.

Let's, once again, launch back into the Blueniverse...

Beating the blues with more blue

MB is a unique compound. Low-dose MB stimulates energy metabolism via increased mitochondrial activity since it serves as an electron cycler acting as both a donor and acceptor. You can check out this post to better understand how. Since brain cells (neurons) are always hungry for energy, MB creates a beneficial synergistic loop supporting and optimizing them.

MB also activates metabolism and oxygen consumption in the brain, creating a temporary low-oxygen local environment that, in consequence, increases blood flow and glucose uptake via nitric oxide production and glycolysis, respectively [1].

MB also displays antioxidant properties and can reduce the formation of reactive oxygen species (ROS) and inflammation in the brain; this helps to protect neurons and other cells from oxidative stress-induced damage [2].

It has also been shown in animals that MB displays a therapeutic effect in traumatic brain injury, reducing neuronal death and reversing the damage to the blood-brain barrier (BBB); the BBB being a sort of filter protecting the brain from potentially harmful components in the blood [3].

If this wasn’t compelling enough, MB also shows several advantages in the psychiatry/neurobiology fields:

• Penetrates the BBB and can easily reach therapeutic concentrations in the brain whether given by buccal, oral, or IV
• Increases neuron metabolism and reduces brain inflammation
• Low cost and easy to dose

MB is currently used for various medical applications, including as a treatment for malaria, infectious shock, carbon monoxide or cyanide poisoning, and methemoglobinemia, a condition in which the blood cannot transport oxygen effectively. 

Additionally, it is being investigated as a potential treatment for certain psychiatric and neurological disorders, such as depression, anxiety, and Alzheimer's disease [2]. However, research on using MB as a treatment for these conditions is still in the early stages and more studies are needed to determine its safety and efficacy.

Can methylene blue work as a mood regulator?

Clinical trial results using MB in treating mood disorders have been promising. MB showed favorable outcomes for patients with bipolar disorder and severe depression [4,5]. It uses several mechanisms to trigger these positive effects, but one is the most distinctive.

MB is a known monoamine oxidase inhibitor (MAOI) [6]. Monoamine oxidases (MAO) are enzymes (there are two of them, see below) primarily found in the central nervous system (CNS) that break down certain neurotransmitters including serotonin, norepinephrine, and dopamine. 

Quick reminder: Neurotransmitters are like traveling messengers across our neurons that regulate neuron activation. These are required fundamental molecules in our brain, constantly being produced and removed to control our body’s functions and feelings. 

By inhibiting the activity of MAO, MAOIs such as MB increase the levels of these neurotransmitters, which can positively affect how we feel.

• Serotonin regulates mood, anxiety, appetite, and sleep. Low serotonin levels have been associated with depression and anxiety.
• Norepinephrine can control mood, attention, and the body's response to stress. Low norepinephrine levels have been associated with depression and attention deficit disorder (ADD).
• Dopamine is associated with movement, motivation, memory, and reward. Low dopamine levels have been linked to Parkinson's disease and ADD.

To understand the real impact of these neurotransmitters on these disorders, studies of suicide victims’ brain samples showed significantly reduced levels of 5-HIAA, the primary metabolite of serotonin, and increased density of α2 adrenoceptors, related to lower norepinephrine release [7]. Although feeling down from time to time cannot be compared to a severe condition such as depression, it is obviously essential to keep the levels of these neurotransmitters optimized. 

Bliss molecules: MAO Inhibitor types and flavors

Given that there are 2 types of MAOs, there are also 2 inhibitor types:

• MAO-A inhibitors primarily target the MAO-A enzyme, leading to increased serotonin, norepinephrine, and dopamine levels.
• MAO-B inhibitors primarily target the MAO-B enzyme, leading to increased dopamine levels.

Several FDA-approved synthetic medicines have been extensively used to treat severe depression, anxiety, and Parkinson’s disease. Tranylcypromine (Parnate), phenelzine (Nardil), and isocarboxazid (Marplan) are MAO-A inhibitors. Selegiline (Eldepryl) and rasagiline (Azilect) are MAO-B inhibitors. 

Interestingly, MAOIs can also be used for controlling blood pressure and other neurological disorders. Obsessive-compulsive disorder, somatoform pain, panic disorder, and schizophrenia have been reported to respond occasionally to treatment with MAOIs [8].

However, these synthetic compounds can cause many adverse side effects, and patients under treatment need a highly regulated diet due to the irreversible binding of these drugs to their cell ligands, although there are a few exceptions [9]. 

Due to this irreversible binding, MAOIs can cause dangerous interactions with certain foods and drinks (sit tight, we’ll get deeper into this below!) and other drugs such as antidepressants, specific pain drugs, cold and allergy medications, and some herbal supplements. 

Foods such as cheese, nuts, chocolate, red wine, and beer have alkaloid and terpenoid compounds that can act as MAO inhibitors.

Plus, there's the well known "cheese effect." Yes, cheese. Here's the low down: Patients already taking MAOIs can experience a severe rise in blood pressure after eating aged cheese. Well, not only cheese but foods rich in a compound called tyramine that is regularly metabolized by MAO. Cured meats, kimchi and other fermented foods, soy sauce and derivatives, and several others can cause serious headaches, confusion, and other related symptoms when combined with MAOIs. 

In addition, multiple herbs and plants, including psychoactives such as ayahuasca (the vine, to be specific) and kava (a MAOI-B inhibitor), have been used to induce mood and sensorium changes across different cultures [8,9]. Even different components of pepper, curry, and green tea have shown high MAO inhibition.

Scientists are still currently investigating whether any of these natural molecules could provide interesting basic chemical skeletons to develop a new class of MAOI drugs that optimize performance [10,11].

Back to MB!

Researchers have renewed interest in MB psychotropic applications [2] since we now know it mainly inhibits MAO-A [7]. More importantly, MB inhibits MAO-A by binding to the enzyme in a reversible way. Once MB concentrations go down, the enzyme can start working again and does not cause any permanent change in its activity. This ability is crucial to avoid one of MAOIs’ most feared side effects, the cheese effect, as mentioned above [12].

MB Precautions 

Be aware, joy seekers! MB should not be used by patients already taking medications affecting the accumulation of serotonin (as serotonergic drugs or selective serotonin/norepinephrine reuptake inhibitors (SSRI/SSRNs)). Combining MB with these drugs can lead to a lethal toxicity effect called serotonin toxicity (ST) that may cause death if left untreated [13,14]. Although this rarely happens, too much joy could actually be dangerous in this case! 

Fortunately, ST is usually resolved by stopping the drug or decreasing the dose without any long-term damage.

Bottom line thoughts

Everybody feels miserable or anxious at times. It’s part of the human condition. However, we can help steer or even trick our brains into staying in that sweet spot for longer periods of time by maintaining healthy levels of neurotransmitters.

Even though more research is needed, MAOIs such as MB can potentially benefit your mood and also have many additional synergistic brain effects. With research still ongoing, scientists still have yet to decide if MB will become the next mainstream treatment for mood disorders or used as a prototype for developing new innovative drugs [16].

For now, if you feel like experimenting, go ahead and try Just Blue, our 16-mg pure pharmaceutical-grade methylene blue buccal troche. 

Just remember! Please talk to your healthcare provider before starting or stopping any supplement or medication.

BONUS TRACK: The discovery of the cheese effect: check out the funny way this became a real thing by the scientist itself here.

References

[1] Gonzalez-Lima F, Auchter A. Protection against neurodegeneration with low-dose methylene blue and near-infrared light. Front Cell Neurosci. 2015 May 12;9:179. doi: 10.3389/fncel.2015.00179.

[2] Alda M. Methylene Blue in the Treatment of Neuropsychiatric Disorders. CNS Drugs. 2019 Aug;33(8):719-725. doi: 10.1007/s40263-019-00641-3.

[3] Shen J, Xin W, Li Q, Gao Y, Yuan L, Zhang J. Methylene Blue Reduces Neuronal Apoptosis and Improves Blood-Brain Barrier Integrity After Traumatic Brain Injury. Front Neurol. 2019 Nov 8;10:1133. doi: 10.3389/fneur.2019.01133.

[4] Naylor GJ, Smith AH, Connelly P. A controlled trial of methylene blue in severe depressive illness. Biol Psychiatry. 1987 May;22(5):657-9. doi: 10.1016/0006-3223(87)90194-6.

[5] Alda M, McKinnon M, Blagdon R, Garnham J, MacLellan S, O'Donovan C, Hajek T, Nair C, Dursun S, MacQueen G. Methylene blue treatment for residual symptoms of bipolar disorder: randomised crossover study. Br J Psychiatry. 2017 Jan;210(1):54-60. doi: 10.1192/bjp.bp.115.173930. Epub 2016 Jun 9. PMID: 27284082.

[6] Ramsay RR, Dunford C, Gillman PK. Methylene blue and serotonin toxicity: inhibition of monoamine oxidase A (MAO A) confirms a theoretical prediction. Br J Pharmacol. 2007 Nov;152(6):946-51. doi: 10.1038/sj.bjp.0707430.

[7] Delport A, Harvey BH, Petzer A, Petzer JP. Methylene blue and its analogues as antidepressant compounds. Metab Brain Dis. 2017 Oct;32(5):1357-1382. doi: 10.1007/s11011-017-0081-6. Epub 2017 Jul 31. PMID: 28762173.

[8] Chaurasiya ND, Leon F, Muhammad I, Tekwani BL. Natural Products Inhibitors of Monoamine Oxidases-Potential New Drug Leads for Neuroprotection, Neurological Disorders, and Neuroblastoma. Molecules. 2022 Jul 4;27(13):4297. doi: 10.3390/molecules27134297.

[9] Hall-Flavin DK. 2018. MAOIs and diet: Is it necessary to restrict tyramine? Retrieved from: https://www.mayoclinic.org/diseases-conditions/depression/expert-answers/maois/faq-20058035

[10] Mazzio E, Deiab S, Park K, Soliman KF. High throughput screening to identify natural human monoamine oxidase B inhibitors. Phytother Res. 2013 Jun;27(6):818-28. doi: 10.1002/ptr.4795. Epub 2012 Aug 8. PMID: 22887993; PMCID: PMC3521852.

[11] Kong LD, Cheng CH, Tan RX. Inhibition of MAO A and B by some plant-derived alkaloids, phenols and anthraquinones. J Ethnopharmacol. 2004 Apr;91(2-3):351-5. doi: 10.1016/j.jep.2004.01.013.

[12] Finberg JP, Rabey JM. Inhibitors of MAO-A and MAO-B in Psychiatry and Neurology. Front Pharmacol. 2016 Oct 18;7:340. doi: 10.3389/fphar.2016.00340. PMID: 27803666; PMCID: PMC5067815.

[13] FDA. 2017. FDA Drug Safety Communication: Serious CNS reactions possible when methylene blue is given to patients taking certain psychiatric medications. Retrieved from: https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-serious-cns-reactions-possible-when-methylene-blue-given-patients

[14] Ramsay RR, Dunford C, Gillman PK. Methylene blue and serotonin toxicity: inhibition of monoamine oxidase A (MAO A) confirms a theoretical prediction. Br J Pharmacol. 2007 Nov;152(6):946-51. doi: 10.1038/sj.bjp.0707430.