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naraburns  nihil supernum  1yr ago (text post)   5953 thread views

Small-Scale Question Sunday for January 22, 2023

Do you have a dumb question that you're kind of embarrassed to ask in the main thread? Is there something you're just not sure about?

This is your opportunity to ask questions. No question too simple or too silly.

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When should we privilege the phenomenological over the pharmacological?

There are herbal remedies that people swear induce some certain desired state. Scientists attempt to discover the underlying chemical structures that induce the state, but they don’t always get it right. I’ve come across some interesting cases of this. There’s valerian root, which only recently was found to interact with adenosine (having previously been discarded as an insomnia treatment). There’s California Poppy, which was only recently discovered to contain Reticuline, which in turn was only recently discovered to induce an opioid response in the brain. There are all sorts of things going on with cannabis which are not related to THC but instead implicate a THC/CBD synergy and plausibly the addition of chemical structures known as terpenes. There are the essential oil studies that clearly indicate certain odors induce alertness (bitter lemon) or relaxation (lavender). Then there’s the science of things like serotonin which are hardly understood at all — only recently did we learn that tryptophan will selectively unbind with albumin at the blood brain barrier, and only recently has the consensus shifted to serotonin deficiency lacking a role in depression (although I have my own views on this).

Essentially, if a person asserts “the aerial parts of the Phenomena Logicila plant make me happy”, and a scientist looking at a paper finds no clear mechanism for this to occur… what do we say? The science is never conclusive or half-finished, and maybe the person has a unique physiological or genetic profile that corresponds to the feeling. What should a reasonable person do?

Empirical results > logic and theoretical mechanisms. The most clear demonstration of this is general anaesthesia, which continues to lack an agreed-upon theoretical mechanism, makes no logical sense, and yet very clearly works. Anything less than taking empirical results above neat theories ceases to be science.

Is there a relatively simple explanation somewhere about why anesthesia makes no sense? I keep hearing this without anyone ever going into details, and it sounds like exactly the kind of thing I would find very amusing.

So there's this way to get a human, and knock them out, that's safe! And not only that, but while they've lost consciousness, they have no memory of this happening. And they don't feel pain. And then, once the anaesthesia wears off, they wake up, almost entirely side-effect free! When the closest alternative is to whack someone in the head hard enough that they fall unconscious, which is significant more dangerous, it sure awfully convenient. The sum effects are equivalent to a coma or severe brain damage, but entirely reversible! Like it is some specific procedure that exists purely for the purpose of enabling surgery. How nonsensical it is for the body to have the ability to do this, given there would be no possible use for this back when we wandered the savanna 100,000 years ago? And yet, we do have this ability. A hidden off switch that can be controllably flicked with a few relatively easy to acquire gases.

Aliens?

More seriously, is it that we don't understand how it works, or why it evolved?

There are competing hypotheses for how it works, but nothing conclusive.

I'm not certain to understand what your goal is with that question,

a pharmacological causative model is heuristically useful to make predictions, about effectiveness for condition X and to establish a safety, tolerance, toxicity and interaction profile.

All those things are useful but mostly unecessary for the layman.

If there is a non-negligible community that takes plant X since years in quantity Y and that doesn't report huge terrifying side effects and that they report potent effectiveness then its probably worth a try for acute use although for long term use there will always be a toxicity/accelerated ageing question but in many cases we never know for certain however in most cases we do know reasonably somewhat the safety profiles.

It has actually become very rare to find phytochemicals that have not been extensively studied regarding their pharmacology and hence the causative model is often well established assuming you take time to research the research.

But beyond annecdtotal evidence, doing a blind test scientific trial about wether X is effective for Y, e.g. depression is very cheap and therefore even without said causative model we often know wether X has elicited a potent response for Y in N people empirically following precise protocol.

Empiricisms as always trumps a priori reasoning regarding effort efficiency and indeed people should considering the mostly safe profile of phytochemicals (generalization see e.g. cyclopamide https://en.wikipedia.org/wiki/Cyclopamine#/media/File:Cyclopelamb2.jpg) play much more the lab rats, this would drive very significantly the speed of empirical scientific research and therefore discovery of treatments for ineptly considered incurable diseases.

edit:

only recently did we learn that tryptophan will selectively unbind with albumin at the blood brain barrier

What does that imply? We already knew tryptophan cross the BBB. You mean the competition with tyrosine?

only recently has the consensus shifted to serotonin deficiency lacking a role in depression (although I have my own views on this).

What?

Serotonergics are euphorisant see e.g. MDMA, MDAI, 5MAPB, shrooms, etc

The effect of SSRIs is less intuitive (reduction of sert receptors density) but still sert driven.

No, the original thought on how tryptophan crosses BBB was extremely murky, because it a lesser competitor to other LNAAs. So we knew that we could toggle greater crossing by reducing the competitors (see wurtman lab) by flushing LNAA to to muscle via pure carbohydrate insulin spike (tryptophan stays bound to albumin). We also knew exercise increases serotonin synthesis, and tryptophan depletion decreases this. What was relatively new, I believe from 2015-2018, was that tryptophan selectively unbinds with albumin at the BBB, so the albumin-bound tryptophan will release uniquely there. It’s an example of how we know little about the mechanisms of serotonin. There’s also controversy about whether how important T:LNAA ratio is to sum total T, the mice studies are not clear. Maybe I’ll dig up the metastudy I read a bit ago

Re: serotonin, I don’t actually disagree, but the consensus I read was that “more serotonin” does not decrease depression.

https://www.nature.com/articles/s41380-022-01661-0

The distinction I would make is that these studies are flawed and there is actually very limited ways to organically increase serotonin production in the brain: increasing dietary T:LNAA ratio (also found to be widely healthful per a large Japanese population cohort study, on things like sleep); using fruit to flush LNAA muscle tissue; or exercise (somehow; possibly by using up LNAAs).

There are some other interesting things about this: certain human domesticated crops have higher tryptophan than wild-type; there’s a possibility fruit consumption in humans is kind of evolved to increase serotonin, and certain fruit actually have serotonin itself, like kiwi and strawberry, which is fascinating

Thanks Cafe, that is a great comment, exactly the kind of informatively rich comments the motte desperately lacks.

I will give you a proper answer tomorrow but when I said that tryptophan cross the BBB, I actually meant about 5 hydroxy tryptophan (5htp), which has good bioavailability, cross the BBB and bypass the rate limiting enzyme conversion of L-tryptophan to 5htp (which itself downstream will again be converted to serotonin in a rate limited manner)

1998:

https://pubmed.ncbi.nlm.nih.gov/9727088/

What should a reasonable person do?

Try to confirm that the risks of harm are low and then continue to use them?

My general impression is that part of the reason people like "herbal" and "natural" remedies is due to fear of outsized side-effects from pharmaceuticals and the perception that herbal remedies are less dangerous. I have an aunt who would rather drink chamomile and valerian and tough out insomnia than get hooked on sleeping pills.

If the risk is low and the subjective experience is better...track it and continue?

phytochemicals are extremely interesting actually and a surprisingly high number of synthetic drugs are derivatives or imitations of phytos or endogenous molecules.

People use to joke/ridiculize them but there is nothing more ridicule than a human that ridiculize billion of years parallel bidirectional (both the molecule and the body adapt) optimization of phamacological pathways towards maximizing host or symbionts survival or other advantageous metrics.

The issue with phyto (some can be toxic btw) is that many have bad bioavailability and sometimes suboptimal pharmacokinetics or half-lives.

Both of those problems can be trivially solved, either by bypassing first pass metabolism via vitamin C and or increasing lipophilia absorption via co-administration of omega-3 and or via inhibiting the CYP 450 enzymes via e.g. piperine or grappefruit juice (beware can be dangerous with many synthetic drugs as it potentiate wildly their metabolism hence dose potency, profile and half lives)

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