LONGECITY

Hey guys,

I just want to know if I am interpreting this correctly. I am taking Tianeptine for its antidepressive activity which is related to its glutamatergic effects. If caffeine interferes with Tianeptines glutamatergic activity this would mean it could potentially diminish the antidepressive properties.

In recent work, Uzbay and colleagues found that tianeptine attenuated pentylenetetrazole (PTZ)-induced seizures [196,197,198] in rodents, which is consistent with its known mode of action to reduce excessive glutamatergic activity. Importantly, the investigators found that the latter effect was blocked by the administration of caffeine, a nonspecific adenosine receptor antagonist, and 8-cyclopentyl-1,3-dipropylxanthine, an A1 receptor-specific antagonist.

I don't know about this MOA specifically, but caffeine may impair hippocampal neurogenesis, which is presumably important to reverse the hippocampal shrinkage seen in depression. I recall reading that tianeptine is second only to NSI-189 in triggering neurogenesis.
See:
α2-glycine Receptors Modulate Adult Hippocampal Neurogenesis and Spatial Memory

Pharmacological inhibition of GlyRs by strychnine or picrotoxin decreased the proliferation of ANSCs[adult neural stem cells], both in vivo and in vitro. Mice knockout for glra2, the gene coding for the GlyR α2 subunit, were determined to display impaired AHN, and this phenomenon was accompanied by deficits in spatial memory.

Caffeine Inhibition of Ionotropic Glycine Receptors

Tested against the EC(50) of each GlyR subtype, the order of caffeine potency (IC(50)) is: alpha2beta (248 +/- 32 microm) alpha3beta (255 +/- 16 microm) > alpha4beta (517 +/- 50 microm) > alpha1beta(837 +/- 132 microm).

Drug distribution studies with microdialysis II. Caffeine and theophylline in blood, brain and other tissues in rats

Caffeine (20 mg/kg) [HED 3.3 mg/kg] was found to be evenly distributed with a free concentration of approximately 120 μM.

To summarize, caffeine strongly inhibits the glycine receptor associated with neurogenesis, and it would reach the EC50 at about 6-7 mg/kg, which is within the intake range of even a moderate coffee drinker. It may, consequently, impact the effectiveness of tianeptine as an AD.
Edited by StevesPetMacaque, 05 July 2020 - 11:11 PM.

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Thanks for your insights! Do you think that limiting intake to 100-150mg daily would still have negative effects?

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Though based on a chain of research, this is still indirect speculation. You should also note that there is some evidence that drinking coffee is associated with positive health in old age, though I have only seen correlational studies and not interventional ones. My suspicion in that regard is, if you have poor mental health, caffeine becomes anxiogenic, leading to selection bias.

Nevertheless, it can't be too strong of an effect, or we'd probably know about it with such a widely consumed beverage. (Then again, consider the mystery of the optimal level of alcohol intake.) My estimate based on the above studies is that the IC50 would be hit around 400 - 1000 mg/day, so 100-150 mg is probably OK. (I try to limit myself to 1.5 cups daily, but I have a bad habit of ramping up my consumption over time.) Also, you could try sweetening your coffee with glycine rather than sugar - it's cheap enough to buy in bulk, and it tastes pleasantly sweet.