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Comment by derefr | Hacker News Reader

There are a number of substances that act like alcohol in the brain, but which are not fundamentally antithetical to animal cellular biochemistry the way ethanol is. Most-all GABA-A agonist drugs fall into this class.

I've always been curious how harmful these drugs would be under a profile of long-term recreational abuse, when contrasted with alcohol. I have a sense that you'd be far better off being addicted to such drugs, than you would being an alcoholic. Similar to how vaping, no matter its absolute health consequences, could still be beneficial relative to smoking tobacco, if that would be your alternative.

Maybe if we could figure out how to make an aqueous GABA-A agonist with a really high LD50, we could see the development of a "synthahol" in our lifetimes?

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You’re hung up on GABA, but it has little to do with alcohol other than being part of the physiology of physical dependence.

LD50 for benzos is already “really high” - that is not an issue. Alcohol affects other neurotransmitter pathways other than GABA. That isn’t even the one responsible for the psychological dependence. So a GABA-A agonist with a high LD50 exists in multiple (benzos), but it’s not an alcohol substitute. There is a reason why these medications are used for acute withdrawal, but are not used for treating dependence.

Also, being addicted to benzos is far more debilitating than the “vaping” equivalent - this has been well studied since they had their heyday in the 70s. They’re quite harmful for chronic use except in very limited circumstances.

Maybe synthahol might be a thing - I mean you’re probably closer with something like ecstasy - but a GABA agonist isn’t it.

Benzodiazepines (Xanax, Valium, etc.) are basically that - GABAergics with very high LD50. They're positive allosteric modulators, rather than direct agonists, but the pharmacological action is similar. But benzos wouldn't be a good alcohol substitute - they're often described as less "fun" than alcohol by people who use them recreationally, they're more prone to delusions of sobriety (possibly because it's missing the other non-GABA effects of alcohol that help us gauge drunkenness), can be very addictive, and there's some link between long term benzo use and modest elevation of cancer risk, especially brain cancer.

I still found benzos "fun" but they definitely made me more sleepy and chilled out than alcohol. The disinhibition is still there which is where I suppose the "fun" comes from. The memory loss was far more extreme for me than alcohol though, which eventually made me stop taking them.

David Nutt shares your hypothesis and is working on such a substance [1].

I agree with you that something like chronic Diazepam abuse is probably less harmful to the body than a similar alcohol habit - but I'm skeptical (but hopeful) one could design an effective, recreationally-useful GABA-ergic drug that didn't come with the baseline shift and rebound anxiety (and in the limit, seizure/death) usually associated.

You can already choose to abuse pills in contrast to alcohol, and it's generally not very pretty either.

[1] https://www.theguardian.com/science/2019/mar/26/an-innocent-...

I'm pretty sure Dr Nutt was/is trying to market a synthanol product, which even had an "antidote" to get you sober again quickly.

Realistically his chance of any nation (especially a western one) legalising such a thing is very slim indeed, at least in the medium term. Which is a real shame, as alcohol causes huge harm to society.

We have plenty 'safe' GABA-A agonist, the issue is alcohol's greatest risk and greatest hard is dependence. The health effects in non-addiction scenarios are not related to its function as a GABA-A agonist but rather the specific metabolism of ethanol produces toxic metabolites.

The withdrawal from any type of GABA antagonist/PAM type drug can be lethal. The acute and long term side effects of ethanol discourage abuse.

Also acute overdoses of the safe benzo/Z-drugs are strange & alarming since you can put yourself into a 24-48 hour coma but recover pretty quickly.

You’re hung up on GABA, but it has little to do with alcohol other than being part of the physiology of physical dependence.

Also, being addicted to benzos is far more debilitating than the “vaping” equivalent. They’re quite harmful for chronic use except in very limited circumstances.

Maybe synthahol might be a thing - I mean you’re probably closer with something like ecstasy - but a GABA agonist isn’t it.

I've never tried it, but I heard a lot of folks take GHB as an alternative to alcohol, and that it has the same effects, but without the hangover. I also heard you have to be really careful with dosing, as you only need a very small amount of the stuff.

Be careful with that. The hangover provides a negative feedback that keeps the vast majority of (any)-alcohol consumers from becoming addicted. Now leave that out and see what happens.

Note: Alcohol hangover is not the same as the immediate withdrawal symptoms of other drugs that let‘s you crave for taking another hit shot whatever. It‘s caused by the myriad of trash by-products in metabolizing ethanol, not for the lack of alcohol. (and for certain alcohols additional also tannins, aroma substances and similar - think of whiskey and cheap wine)

And, I suppose, more simply, the diabetus! Pickles * beer^2 * burger * fries = (sugar * fat)^2 = pike of insulin over several hours * abundance of bad fats that the liver is supposed to absorb. I do realize not every alcohol binging happens in this form, but it’s the classic modern/hipster form. Any such behavior, even without alcohol, would turn the liver upside down.

Acid ketosis is linked to increased GABA levels in the brain, so you could always work out or go on a keto diet to get similar effects.

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