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Comment by RobotToaster | Hacker News Reader

It's this https://en.wikipedia.org/wiki/Xanomeline/trospium_chloride

> M4 and M1 receptor stimulation indirectly rebalances dopaminergic and glutamatergic circuits involved in the symptoms associated with neurological and neuropsychiatric diseases such as schizophrenia and Alzheimer's disease.

Whoa. Wonder if that's being evaluated?

Yes, it's being tested for autism as well.

I wonder what their hopes are for autism. I think the detail-oriented (or at least logic-oriented) thinking at least is an intrinsic part of brain development in autistics, but I wonder if it'll ever be possible to control certain other symptoms of autism through medication.

It could very well become a cost/reward analysis thing since Autism is a spectrum disorder. People who are high-functioning will probably be fine without the drug, but people who are, for example, non-verbal may be more willing to take it.

I'm assuming such a drug would have drastic drawbacks in terms of how Autistic people think. Similar to other drugs that address mental state, they might not feel like themselves.

> I'm assuming such a drug would have drastic drawbacks in terms of how Autistic people think. Similar to other drugs that address mental state, they might not feel like themselves.

Knowing how I think, and how I use knowledge, I'm not sure that I'd be better at anything if a drug altered my ability to think in detail. Even if something made me non-autistic like magic, I have a lifetime of autistic knowledge that is structured differently than what a non-autistic brain would need. I could have to learn everything all over again if I were to become unable to comprehend/assemble the logical building blocks that I normally use to do everything.

So I have to assume the drug doesn't actually attempt to treat the core defining trait of autism and only attempts to treat some of the side effects.

As far as I'm aware, even though autism is a spectrum, every brain that is autistic has a particularly distinctive redistribution of connections, which is what results in basically everything. This redistribution is likely what results in the overly logical/analytical thinking (whether it's bottom-up or top-down), although I don't think anyone's been able to prove or disprove that, it's just a correlation.

Right, but we need to consider outcomes. If such a drug could help those who can't take care of themselves, take care of themselves, that's a very good outcome. An outcome for someone like you wouldn't be very good so it doesn't matter much. But for some, this could be the difference between being institutionalized forever versus living a somewhat independent life.

Co-administration of an agonist and an antagonist for the same pharmacophore seems like an interesting approach.

Looks like the antagonist is only outside the brain, so it works to counteract the side-effects, pretty cool.

I wanted sort of the opposite of this for opioids - work in the body, not the brain. There's been a few attempts but non that passed trials.

> I wanted sort of the opposite of this for opioids - work in the body, not the brain

That's already how some anti-diarrheals work like loperamide. And some anticonstipation drugs like oral naloxone and methylnaltrexone that work as peripheral or locally-acting antagonists

Yes but loperamide doesn't alleviate pain, which maybe just that opioids only alleviate pain if they do reach the brain, but I did see trials for non-bbb crossing ones that were for pain so not sure what's going on there.

It's possible that the analgesic and euphoric effects of opioids are one and the same. In other words, it's centrally dampening the experience of pain, both physical and mental. One is experienced as analgesia and the other as pleasure, but both may share the same mechanism, making one impossible without the other.

Would the opposite (work in the brain but not the body) also be a healthier alternative for people addicted to getting high on opiates?

A controversial and hypothetical drug which might help addicts would be a companion drug that somehow prevented the development of tolerance. I know nothing about the brain so that's probably laughably impossible, but if it existed it could cheapen the cost of a habit and lead to fewer ODs because they would have no need to chase their tolerance to feel the same effects. It would certainly have other side effects because someone could essentially just remain high 24/7 (in the extreme case).

Yeah, because it is the high they are after, but not working in the brain would make opioids completely useless for depression and anxiety (for which it really does wonders).

My want is for relieving pain in the body without making me feel high, I actually assumed you want it in the body not brain, as the brain effects are the feel-good effects, but really not sure or familiar with how they work.

Ibuprofen and acetaminophen may already be that option.

https://www.aafp.org/pubs/afp/issues/2018/0301/p348.html

I believe there are other studies besides this that points to these two OTC pain relievers as being 'just as good' as opiates.

I have went through most NSAIDs, they do not compare to opiates at all, and when I mean all, I am referring to prescription-only NSAIDs, too. There was a time when I mixed diclofenac, naproxen, and ibuprofen, too, none of them helped (separately and mixed). Kratom, however, did.

If I were to have fever, I would not take opiates though, I do not think they reduce inflammation or fever.

Maybe they work on some small subset of pain similarly, but they really are incomparable.

Opiates could near make you not feel your arm being chopped off, ibuprofen couldn’t prevent a light pinch from hurting.

There are prescription-grade NSAIDs that make Advil look like candy, but they're admittedly still not as heavy-hitting as bona fide painkillers. Great for inflammatory pain though.

They're also typically pretty rough on your GI systems. Though it's worth the trade-off, usually

Not just your GI, but they increase your risk of cardiovascular issues as well, among many others, whereas opiates do not cause any of those horrible side-effects. Dose matters, it does matter with NSAIDs, too, if I pop 10 acetaminophen, you can rest assured I will have liver cirrhosis.

Ha, also yes. Unfortunately I know this too well, but my GI systems are worse than the average person's :P

And there's even topical ibuprofen (or related nsaids)

I personally do not feel high on opiates and I tried most of them, I might be in the minority here.

Would you mind elaborating on what you've used / your experiences? I'm curious (without wanting to encourage further use) how definite it is that they don't make you high as opposed to that you need higher (no pun intended) doses to get high than other people. Are they effective at relieving physical pain for you?

It wouldn't surprise me if either were true - it's definitely the case that different people need different opiate doses to get the same effects (even for their first dose, not considering developed tolerance), I've known people for whom OTC (over the counter, no prescription needed) cocodamol - 8mg codeine + 500mg paracetamol, x1-2 per dose - contained enough codeine for them to feel a bit high, meanwhile other people like me need prescription strength (30-60mg) codeine to feel any benefits at all, and don't feel remotely high from it.

I also had a friend once who literally couldn't get high from weed, it has no effect on him - at least up to the amount tested, which was him smoking & vaping several grams of a strong strain of cannabis that got the rest of the room extremely high with much less of it. He tried on various other occasions, included edibles from a coffeeshop in Amsterdam, never any effects.

I have tried oxycodone (40 mg, went way above 80 mg too) and it did not make me high at all, people talk about a state of bliss and whatnot but I have never experienced it.

Most substances do not affect me the way they affect others; I have depression & anxiety and I have tried almost all antidepressants (along with mood stabilizers) to no effect.

I suspect it may have to do with my brain lesions (I have MS), but I am not quite sure.

That said, opiates do help with my physical symptoms, and only them, unfortunately.

> people like me need prescription strength (30-60mg) codeine to feel any benefits at all, and don't feel remotely high from it.

It is interesting though. Oxycodone is way stronger than codeine, and 80 mg is considered a very high dose yet it does not make me high, with or without tolerance.

You might have a genetic abnormality in the P450 family: https://www.ncbi.nlm.nih.gov/books/NBK574601/

My sister has defective P450 and your experience is the same as hers with opiates and other drugs, e.g. they are entirely ineffective when taken orally.

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