As you mention, most SSRI ads specifically note that it is thought to work by inhibiting serotonin reuptake...maybe. There isn't even strong proof that serotonin plays the part popularly believed.

But SSRIs work for many people, and do seem to have an effect, so the theoretical is good enough for now.

> As you mention, most SSRI ads specifically note that it is thought to work by inhibiting serotonin reuptake...maybe. There isn't even strong proof that serotonin plays the part popularly believed.

The "chemical imbalance" theory hasn't been taken seriously for decades. It's a myth that psychiatrists think that SSRIs are compensating for low serotonin. We've known for a long time that the actual anti-depressant effects come from somewhere downstream that isn't fully understood yet. This isn't really a new discovery. We've known from the start that SSRIs inhibit serotonin reuptake within hours of taking the first dose, but the full antidepressant effect can lag by weeks.

That doesn't mean that serotonin isn't involved in the therapeutic action of SSRIs, though. Occupying around 80% of the serotonin transporters is necessary to bring about the antidepressant effects of different SSRIs. So we do know that inhibiting serotonin reuptake is almost certainly the mechanism that kicks off the chain of events that ultimately produces the antidepressant effect, but we also know that the antidepressant effect doesn't come directly from this inhibition.

This is a good article that explains debunks the myth that psychiatry believes the "chemical imbalance" or "low serotonin" theories: https://www.psychiatrictimes.com/view/debunking-two-chemical...

Because SSRIs take weeks to work, it is theorized that they actual modify DNA expression and other things that are slow to action.

Serotonin itself has little to do with depression at the synaptic level

Yes, that's true; like you say, no one even quite knows how SSRIs work, so this looks promising! Hopefully future studies show similar effects without some of the SSRI side effects

Don't disregard scientific knowledge like that. Many (albeit not all) drugs have been extensively tested at least by close to exhaustively testing receptor binding sensitivity. Except for the extremely rare drugs that have very atypical action mechanism it allows to understand to a decent extent what it does pharmacologically. But also, understanding how a drug work isn't necessary for taking the risk of trying it given that most CNS (except DRA) drugs are "safe" especially if combined with potent neuroprotectors (anti oxidants, NMDA antagonists, etc) However even if the risk is low, I don't understand your motive to try it. The only one would be to advance scientific knowledge by self testing. But if the motive is for egoistic and not altruistic then there are much more proved antidepressants out there with small side effect profiles.

Oh - I muddled my phrasing - I agree with you, I was saying I would try a medication with historical, industry and regulatory backing even if we didn't understand exactly how it worked - not the saffron. That being said, I'm now planning to make paella...

why aren't DRA safe?

Well it was a simplification. I know that many dopamine releasing agents are safe, such as amantadine. However when a drug is a DRA + a dopamine reuptake inhibitor or worse reverse the transport of dopamin reuptake through TRAAR and / or is a dopamin agonist then there is a risk of neurotoxicity and of durably lowering dopamin receptor density in the brain. This also apply for other monoamines but to a lesser extent. Most of drugs that have this combination of action are https://en.m.wikipedia.org/wiki/Substituted_phenethylamine Some are safe such as D-amphetamine (Adderall, Vyvanse) but most have an unknown risk. Note that you can regrow lost receptors to some extent with e.g Uridine.