By Noel Gardner M.D., M.Div.
At the effective but low, recommended dose of Methylene Blue in Best365 Lab’s oral products (30 mg/day preferably in divided doses) there is NO chance that it would cause a clinically significant serotonin syndrome when given with a therapeutic dose (or even excessive dose) of an SSRI or SNRI anti-depressant). Here are the essential facts:
1. The risk assessments leading to strong warnings about MB regarding serotonin syndrome are a result that, until the recent appearance of oral MB, it was almost exclusively given by intravenous infusions at much higher doses, and then for limited indications.
2. These much higher doses led to serious serotonin syndromes in some cases. Serotonin syndromes result from excessive serotonin in the brain (an important neurotransmitter) that resulted from the blockage of the enzymes that normally break down and inactivate the serotonin molecule. This was to maintain the proper neurotransmitter balance. These enzymes are called mono-amine oxidases (MAOs). The very first antidepressants increased the availability of the neurotransmitters serotonin and norepinephrine that were needed to treat depression did this by potently blocking these enzymes and thus inactivating them. These mono amine oxidase inhibitors were very effective in treating depression. However, these antidepressants blocked these enzymes irreversibly and permanently, and the body needs 2-3 weeks to synthesize new enzymes after stopping the antidepressant. As a result, serotonin levels temporarily soared and took an extended time to be restored to normal. These mechanisms were not well understood during the 1950s-1980s and therefore, even though these antidepressants were rarely used, when they were used, patients also needed the urgent utilization of intravenous MB, serious serotonin syndromes resulted. MB is NOT like these irreversible inhibitors of these enzymes (MAOIs). While MB is an inhibitor of this MAO enzyme, it is a reversible one that readily comes off the enzyme and is cleared completely in approximately 24 hours rather than the 2-3 weeks caused by the old antidepressants that are no longer prescribed.
3. The risk of serotonin syndrome with oral MB at the FDA approved doses of SSRIs and SNRIs with the 10 -30mg of MB recommended in Best365Labs products is essentially zero. There are several well-established reasons for this:
a. Until recently, virtually all dosing of methylene blue was by intravenous routes needed to treat the serious and often immediate life-threatening conditions for which it was FDA approved. This urgency required IV rather than oral dosing.
b. Intravenous dosing of MB achieves near-instant peak concentration with 100% bioavailability. It immediately enters the systemic circulation by-passing the gut and liver circulation where oral MB is metabolized by multiple mechanisms. Thus, only a part of the MB ends up in general arterio-venous circulation. For this reason, oral MB is significantly less likely to cross the blood-brain barrier and end up in the central nervous system where the problems with the serotonin syndrome are generated. (see Peter C, et al. Pharmacokinetics and organ distribution of intravenous and oral methylene blue. European Journal of Clinical Pharmacology. 2000. P 247-50.)
c. Oral MB takes 1-2 hours to be absorbed and thus has substantially lower bioavailability.
d Once in general circulation MB has a short serum half-life (the amount of time to eliminate 50% of the drug from the body) of about 5-6 hours (not the almost 1 week for the irreversible MAO inhibitors).
e. Extensive pharmacokinetic studies show that whole blood concentrations of oral vesus IV MB are widely different. The same dose of MB can differ by a factor of up to 1:100. (see prior reference).
4. Final reassurance. In 2018, a group of general hospital neuropsychiatrists published a review of the entire world’s medical literature on MB and serotonin syndrome. They located a total of 50 cases. 48 of the 50 cases were when MB was given IV as described above. Only one case involved an oral intake of MB and that was at high dose. This one case included multiple serotonergic agents. The one oral MB case was reported to be mild and resolved quickly, needing only minimal supportive care. It had no long term adverse effects. (see Zuschlag et.al, Psychosomatics, 59;6 Nov-Dec, 2018).
Conclusion:
The very modest doses of MB in Best 365 Labs MB when used as recommended create NO risk for a clinically significant serotonin syndrome, period.