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Here's a side project David and I have been looking into, which others might have useful input on...
As I understand it, thyroid hormone levels are approximately-but-accurately described as the body's knob for adjusting "overall metabolic rate" or the subjective feeling of needing to burn energy. Turn up the thyroid knob, and people feel like they need to move around, bounce their leg, talk fast, etc (at least until all the available energy sources are burned off and they crash). Turn down the thyroid knob, and people are lethargic.
That sounds like the sort of knob which should probably typically be set higher, today, than was optimal in the ancestral environment. Not cranked up to 11; hyperthyroid disorders are in fact dangerous and unpleasant. But at least set to the upper end of the healthy range, rather than the lower end.
... and that's nontrivial. You can just dump the relevant hormones (T3/T4) into your body, but there's a control system which tries to hold the level constant. Over the course of months, the thyroid gland (which normally produces T4) will atrophy, as it shrinks to try to keep T4 levels fixed. Just continuing to pump T3/T4 into your system regularly will keep you healthy - you'll basically have a hypothyroid disorder, and supplemental T3/T4 is the standard treatment. But you better be ready to manually control your thyroid hormone levels indefinitely if you start down this path. Ideally, one would intervene further up the control loop in order to adjust the thyroid hormone set-point, but that's more of a research topic than a thing humans already have lots of experience with.
So that's thyroid. We can tell a similar story about cortisol.
As I understand it, the cortisol hormone system is approximately-but-accurately described as the body's knob for adjusting/tracking stress. That sounds like the sort of knob which should probably be set lower, today, than was optimal in the ancestral environment. Not all the way down; problems would kick in. But at least set to the lower end of the healthy range.
... and that's nontrivial, because there's a control loop in place, etc. Ideally we'd intervene on the relatively-upstream parts of the control loop in order to change the set point.
We'd like to generalize this sort of reasoning, and ask: what are all the knobs of this sort which we might want to adjust relative to their ancestral environment settings?
We're looking for signals which are widely broadcast throughout the body, and received by many endpoints. Why look for that type of thing? Because the wide usage puts pressure on the signal to "represent one consistent thing". It's not an accident that there are individual hormonal signals which are approximately-but-accurately described by the human-intuitive phrases "overall metabolic rate" or "stress". It's not an accident that those hormones' signals are not hopelessly polysemantic. If we look for widely-broadcast signals, then we have positive reason to expect that they'll be straightforwardly interpretable, and therefore the sort of thing we can look at and (sometimes) intuitively say "I want to turn that up/down".
Furthermore, since these signals are widely broadcast, they're the sort of thing which impacts lots of stuff (and is therefore impactful to intervene upon). And they're relatively easy to measure, compared to "local" signals.
The "wide broadcast" criterion helps focus our search a lot. For instance, insofar as we're looking for chemical signals throughout the whole body, we probably want species in the bloodstream; that's the main way a concentration could be "broadcast" throughout the body, rather than being a local signal. So, basically endocrine hormones.
Casting a slightly wider net, we might also be interested in:
... and of course for all of these there will be some control system, so each has its own tricky question about how to adjust it.
With some coaxing, we got a pretty solid-sounding list of endocrine hormones out of the LLMs. There were some obvious ones on the list, including thyroid and cortisol systems, sex hormones, and pregnancy/menstruation signals. There were also a lot of signals for homeostasis of things we don't particularly want to adjust: salt balance, calcium, digestion, blood pressure, etc. There were several inflammation and healing signals, which we're interested in but haven't dug into yet. And then there were some cool ones: oxytocin (think mother-child bonding), endocannabinoids (think pot), satiety signals (think Ozempic). None of those really jumped out as clear places to turn a knob in a certain direction, other than obvious things like "take ozempic if you are even slightly overweight" and the two we already knew about (thyroid and cortisol).
Then there were neuromodulators. Here's the list we coaxed from the LLMs:
Of those, serotonin immediately jumps out as a knob you'd probably want to turn to the "plentiful resources" end of the healthy spectrum, compared to the ancestral environment. That puts the widespread popularity of SSRIs in an interesting light!
Moving away from chemical signals, brain waves (alpha waves, theta oscillations, etc) are another potential category - they're oscillations at particular frequencies which (supposedly) are widely synced across large regions of the brain. I read up just a little, and so far have no idea how interesting they are as signals or targets.
Shifting gears, the biggest dead end so far has been parasympathetic tone, i.e. overall activation level of the parasympathetic nervous system. As far as I can tell, parasympathetic tone is basically Not A Thing: there are several different ways to measure it, and the different measurements have little correlation. It's probably more accurate to think of parasympathetic nervous activity as localized, without much meaningful global signal.
Anybody see obvious things we're missing?
Psilocybin’s effect on human brain synaptic plasticity, which for example could help in the treatment of substance use disorders or treatment-resistant major depressive disorder in appropriate settings. Beyond the curative aspects it may also increase creativity and divergent thinking, but the risks should also be considered and may not outweigh the benefits if it's not for addressing a disorder under professional guidance. It's legal status also varies from region to region.