Tianeptine PSA on Longecity – Any Legitimacy?

My issue is with the recent posts about tianeptine's μ-opioid affinities, and how they might be the cause of its effects. That, and TLR's business practices. But I will leave that for another time.

As you can see by the numbers I posted, the μ-opioid affinities are much too low to be an issue. Could they be a minor factor in things? Sure, they could be a minor factor. But tianeptine increases dopamine release in multiple parts of the brain, modulates the NMDA/AMPA receptors, and increases up-take of serotonin out of the synapse. So it is much more complicated than simply the low μ-opioid affinities. Anything increasing dopamine in the brain carries the risk of some minor withdrawals. That's because the brain gets used to the increased levels, and reacts badly when they drop upon cessation.

Tianeptine's main actions are modulating the glutamate receptors in the CA3 region of the hippocampus. It's essentially a signal transduction modulator between the various types of glutamate receptors; normalizing the scaling of the amplitude ratio of NMDA receptor to AMPA/kainate receptor-mediated currents. It also increases the presynaptic uptake of serotonin out of the synapse by the SERT. This does not seem to be the primary mechanism, though. And tianeptine is often administered along side SSRIs for treatment-resistant depression. Nevertheless, it is a mediating factor. Tianeptine also increases BDNF in various brain regions. This is where the neurogenic effects come from, and has become a big focus recently with SSRIs, as they also increase BDNF after a few weeks of treatment. Tianeptine has been shown to prevent stress-induced neuroplastic remodeling in the hippocampus. This is most likely due to the glutamate modulation, and due to the increased BDNF. And yes, tianeptine has minor opioid affinities. However, the main nootropic and antidepressant effects are not due to the interaction with the opioid receptors, or we would see more powerful opioids causing the same neurogenetive and antidepressant effects that tianeptine does. Could it be adding some minor antidepressant effects, or increasing the withdrawal for some? Perhaps. But it has 3 times less affinity for the μ-opioid receptors than codeine, which is over the counter in much of the world. It has over 50 times less affinity than kratom. If the effects were due to μ-opioid affinities, we would be seeing much better antidepressant effects in these substances.

So my ultimate point is that it is much more complicated than μ-opioid affinities. The recent uptick in the mention of these mild affinities in tianeptine, is distracting people from the real mechanisms, and getting people to see this as a recreational drug. That is why I feel those posts are doing it a disservice, by either willfully or unknowingly leaving out the more pertinent mechanisms of the substance. So yes, some people have reported some withdrawals from tianeptine. That is to be expected with a substance that increases dopamine, and affects the serotonin and glutamate systems. But it is nothing compared to real opioid withdrawals, and is a lot more nuanced than simply pointing to μ-opioid affinities. Not only that, but only a few people report these withdrawals. Many people take it daily for long periods, and go off it without issue. Perhaps it is a difference in brain chemistry, or perhaps they just define withdrawal as something different. Either way, it should be respected as a substance, just like everything else. I don't think anyone is touting it as side-effect-free. It is merely just a lot better tolerated than other antidepressants out there.