Years ago, I did quite a few posts on famotidine as I personally experienced great relief from this chemical, which could not possibly be explained by its anti-acid mechanism. Much to my surprise, it turned out that famotidine was capable of lowering PTH, prolactin and, above all, serotonin. Then, during the pandemic, a number of studies came out suggesting that famotidine has an anti-COVID effect and also lowered risk of both severe disease and death from COVID. The anti-serotonin effects undoubtedly played a big role in those benefits. However, famotidine also seemed to increase my endurance when climbing stairs or biking, which I suspected was due to another, yet unknown, mechanism of famotidine.
The study below shows that in humans, famotidine is an inhibitor of the so-called organic cation transported type II (OCTN2), which is a major mechanism of action of the drug Meldonium / Mildronate. The latter drug is mostly known as an inhibitor of the synthesis of the amino acid L-carnitine, and this inhibition leads to reduced oxidation of long-chain fatty acids in the mitochondria. This inhibition of fatty acid oxidation (FAO) is perhaps the main reason Meldonium has an ergogenic effect, which led to WADA labeling the drug as a doping agent and banning it from competitive sports. Since the ban, several high -profile athletes were caught using it and received various penalties. The most famous such case was probably the one with the tennis player Maria Sharapova. The main mechanism through which Meldonium depletes L-carnitine was thought to be through inhibition of the carnitine-synthesizing enzyme gama-butyrobetaine oxygenase (BBOX). However, we also ingest carnitine from food sources and that circumvents the BBOX inhibition pathway, but Meldnoium still maintains its FAO inhbition potency even in the presence of sufficient carnitine intake from food. Meldodium was synthesized back in the 1970s by a team of medical professionals from the Latvian Soviet Socialist Republic (LSSR), presently the independent country of Latvia. A number of former students of the original inventors of Meldonium banded together and formed an institute dedicated to the study of Meldonium and the synthesis of new and improved versions of the drug. I mentioned in a few interviews that my research group synthesized several new and improved versions of Meldonium and our work was informed/inspired by the work of those Latvian researchers. In any event, the Lavian group demonstrated that the cellular concentrations of carnitine are much more sensitive to OCTN2 inhibition than BBOX inhibition, by at least an order of magnitude. Namely, most of the carnitine inside the cell is transported into the cell by OCTN2 rather than synthesized de-novo. As such, OCTN2 inhbition by Meldonium explain most of its effects on FAO. Furthermore, other OCTN2 inhibitors (valproic acid, aspirin, progesterone, etc) have also been shown to have effects similar to Meldonium when it comes to FAO inhibition. Well, the study below now adds famotidine to the list of OCTN2 inhibitors and it seems that it is a rather potent one at that. If this finding is confirmed in other studies, it would make famotidine not only an ergogenic substance, but may explain a good deal of its beneficial effects in studies on lipid-driven conditions such as diabetes, cancer, Alzheimer, etc. Interestingly enough, the study demonstrates OCTN2 inhibition effectiveness of famotidine within regularly used pharmacological doses (20mg, twice daily), despite in-vitro studies suggesting that famotidine doses on the order of several grams daily would be needed to achieve those effects.
https://pubmed.ncbi.nlm.nih.gov/41145993/
“…The results of this study indicate that subjects taking famotidine require significantly greater amounts of supplemental L-carnitine than those not taking famotidine in order to maintain a free carnitine level within the normal range. The molecular weight of free carnitine is 161.2, and it is not protein-bound. Free carnitine is primarily filtered through the renal glomeruli, and >90% of filtered free carnitine is reabsorbed in the renal tubules via OCTN2 (Evans and Fornasini 2003; Stanley 2004). The reported IC50 value for famotidine as an OCTN2 inhibitor is 1,920 μM (Glube et al. 2007), suggesting that it exerts only a relatively minor inhibitory effect. However, the findings of this study indicate that famotidine administration can affect L-carnitine supplementation in replacement therapy, thereby consequently having a significant impact on free carnitine concentrations. The urinary excretion rate of unchanged famotidine is reportedly in the range 21.0 to 44.0% (Inotsume et al. 1989; Gao et al. 1991). Despite its high IC50 value, the relatively high urinary excretion rate suggests that a possible effect of famotidine on OCTN2-mediated reabsorption cannot be ruled out.”
