Science

So our mechanistic understanding of how some receptor signaling pathways operate is alright, but you can't look at a molecule and predict its effects with any accuracy until you start actually giving it to people. Advances in the neurosciences haven't given way to advances in psychopharmacology. If anything the opposite has happened since we started doing rational drug design. Brains aren't rational things.

One example: triptans for migraines were developed as 5HT1B/1D specific agonists under the reasoning that migraines are a vascular phenomenon. It turns out that their efficacy in migraine is due to downstream effects on CGRP. Migraines aren't a vascular phenomenon at all. Triptans are still efficacious, but not for the reasons we thought. And it could be that CGRP is just a proxy for something else, or one of multiple pathways involved in migraines. Sticking with serotonin, 5HT2A receptors are associated with the hallucinogenic experience. Activating them seems to be a precondition for an acid trip, say. Except there's lots of 5HT2A agonists that aren't hallucinogenic, and we don't know why or why not. Biased agonism is in vogue right now, or was, but at least for MOR agonists it appears that "biased agonism" is an artifact of the assays used, what they're measuring, and how they're measuring it. If you look for it with different assays, what looked like biased agonism is just partial (unbiased) agonism. Either way: why does it make a difference? Those downstream pathways very quickly turn into black boxes, and the more we study them the less sense they make.

GABA chloride channels do lower neuronal excitability, but beyond being able to say that they raise the activation threshold of specific neurons under specific conditions we can't generalize from that to much of anything useful. The GABAergics we use we discovered entirely by accident. Every single GABAergic that's been trialled following rational drug design principles has been a bust. Vigabatril and tiagabine have tiny niches in the treatment of epilepsy.

Any explanation of why psychoactives do what they do is necessarily going to be post hoc based on whatever the state of the art at the time is and that's always in flux. We don't know what a "normal brain" looks like, or how it works (bearing in mind that "normal" here is a very fuzzy concept). We know what we know about what parts of the brain are responsible for what to the extent we do (and that's more limited than people think, too) from studying people or animals who have had parts of their brains damaged one way or another. That can tell you that a region of the brain is usually associated with this or that, but why? I don't think it's possible to know that. Certainly it's not in the way it's popularly understood to be a tractable problem.

We're social creatures and our experiences can't be neatly reduced to individual neurology except in a few very specific ways. There's a lot of assumptions baked into the neurosciences that rarely get examined (or if you examine them too closely your grant funding magically disappears). Popular understandings of how brains work, and appeals to neuroscience for literally anything else, are a reflection of material conditions and ideologies more than anything else.

steroids?