ethanol

Alcoholic drinks are popular in most of the world. Excessive consumption of them is also a major public health problem. Bans have been attempted, sometimes successfully, sometimes unsuccessfully, but some people argue that alcohol plays a necessary role in social interactions.

Alcoholic drinks contain ethanol, which is metabolized to acetaldehyde, which is metabolized to acetate. In cells, ethanol is mostly unreactive but can bind to receptors. Acetaldehyde reacts with lots of stuff, mostly reversibly but sometimes irreversibly. Small amounts of acetate are essentially irrelevant, mostly providing calories.

Acetaldehyde can inactivate enzymes by causing crosslinking. Large amounts of it are generally bad. We can separate out the effects of ethanol itself and acetaldehyde by looking at people who metabolize acetaldehyde slowly.

About 50% of people of Northeast Asian descent have a dominant mutation in their acetaldehyde dehydrogenase gene, making this enzyme less effective, which causes the alcohol flush reaction, also known as Asian flush syndrome. A similar mutation is found in about 5–10% of blond-haired blue-eyed people of Northern European descent. In these people, acetaldehyde accumulates after drinking alcohol, leading to symptoms of acetaldehyde poisoning, including the characteristic flushing of the skin and increased heart and respiration rates. Other symptoms can include severe abdominal and urinary tract cramping, hot and cold flashes, profuse sweating, and profound malaise. Individuals with deficient acetaldehyde dehydrogenase activity are far less likely to become alcoholics, but seem to be at a greater risk of liver damage, alcohol-induced asthma, and contracting cancers of the oro-pharynx and esophagus due to acetaldehyde overexposure.

Wikipedia

alternatives to ethanol

Ethanol is what's in drinks because it's produced naturally by a common type of fermentation, it prevents growth of most harmful microbes, and the yeast produced has some nutritional value. But our modern industrial civilization is no longer bound by such prosaic concerns. Can we do better?

ether

Studies, including that of an ether addict in 2003, have shown that ether causes dependence; however, the only symptom observed was a will to consume more ether. No withdrawal symptoms were prevalent.

Wikipedia

Diethyl ether has the same direct effect as ethanol, but mostly isn't metabolized in the body. Some of it gets metabolized (by a monooxygenase) by oxidation to (ethanol + acetaldehyde), but more of it gets exhaled. Thus, it's similar to what ethanol without acetaldehyde production would be like.

Diethyl ether isn't expensive to make, and there's lots of knowledge about its effects because it was widely consumed in the past. But it does have some problems:

  • It's volatile and has a strong smell, so it's obnoxious to other people.
  • It has fairly low water solubility, ~6%.
  • Above 2% in air, it's inflammable.
  • Pure diethyl ether exposed to oxygen can slowly form explosive peroxides.
  • It's already been banned most places, and unbanning things might be harder than not banning them.

butanol

At sub-lethal doses, 1-butanol acts as a depressant of the central nervous system, similar to ethanol: one study in rats indicated that the intoxicating potency of 1-butanol is about 6 times higher than that of ethanol, possibly because of its slower transformation by alcohol dehydrogenase.

— Wikipedia

Some butanol occurs naturally in fermented products. Yeasts could be engineered to produce mostly butanol instead of ethanol, but the maximum practical concentration from fermentation is low, ~1%. If it's 6x as effective as ethanol, then 1% would be enough for drinks. It would then provide a similar effect to ethanol with less aldehyde production.

Its boiling point is 118C, and its water solubility is 7%, so it wouldn't evaporate much. The odor is OK, like fruity alcohol, but it's detectable at much lower levels than ethanol. Apparently, the odor is less pleasant at higher concentrations, and hedonically neutral at 300 ppm.

Some naturally occuring microbes produce butanol together with acetone. The acetone could be distilled out relatively easily.

Here's an EPA summary of 1-butanol rat studies. In rats, high doses can cause neurotoxicity and fetal problems. Comparing to mass of ethanol in beer relative to human weight, no problems were found at 0.6 beers/day but some were found at 1.5 beers/day. Considering that 1-butanol has ~6x the apparent intoxicating effect of ethanol in rats, that makes sense if those effects come from the same mechanism as the psychoactive effects of alcohol. However, it's not clear what the rate of (butanal -> butyrate) is in humans compared to (acetaldehyde -> acetate), and if it's proportionately slower, then butanol might not be significantly less problematic than ethanol.

2-methyl-2-butanol

Does this have similar effects to ethanol? Yes, but it's stronger, and some people have been (illegally) using it recreationally.

Since this is a tertiary alcohol (with the oxygen bonded to a carbon with 3 carbons on it) it can't be metabolized by dehydrogenation to an aldehyde, which is one way to avoid aldehyde production. However, that means it lasts too long, leaving people intoxicated for ~2 days. Also, the smell/taste is somewhat bad.

It's worth noting that tertiary alcohols produce the same effect too despite steric issues being plausible.

ethoxyethanol & butoxyethanol

You might think these are safe because they're used in eg some paint solvents, but no, they're somewhat toxic. I wish companies would stop using them in consumer products.

cyclic ethers

We can't use longer hydrocarbons than diethyl ether or butanol because solubility in water gets too low, so how about cyclic ethers?

Would cyclic ethers have the same effect? I'm pretty sure they would. If butanol is stronger than ethanol, and diethyl ether also works, then the mechanism must involve molecules fitting inside a protein hydrophobic pocket with a carboxylic acid group inside it that hydrogen bonds to an ether or alcohol. The effect then probably comes from protein conformational changes from that type of hydrophobic pocket being stabilized. Cyclic ethers would be more conformationally restricted than diethyl ether, yes, but I doubt that would matter here.

Tetrahydrofuran is a 5-member ring, less volatile than diethyl ether and miscible with water, but it's toxic, presumably because it can be metabolized to 1,4 dialdehyde which can react irreversibly in a Paal–Knorr reaction. For the same reasons it's miscible with water, high concentrations also disrupt various biological membranes by acting as a surfactant. It's also somewhat expensive to make, and very flammable, and it has a tendency to form peroxides.

oxane

Oxane is a 6-member ring. 8% solubility in water and a 88 C boiling point are high enough. Like how pentanediol is much safer than butanediol, oxane metabolites are safer than tetrahydrofuran metabolites. The odor is "pungent sweet ethereal".

As it's a bigger molecule than tetrahydrofuran, and pentanediol costs more than butanediol, you might expect this to be more expensive to make, but it's actually cheaper, with 2 practical routes:

  • propene + formaldehyde
  • -> (dihydropyran + butadiene + butanal) in a Prins + Diels-Alder reaction using solid acid catalyst
  • -> dihydropyran hydrogenation

The inputs are very cheap, and those side products are more valuable than the inputs.

  • furfural
  • -> hydrogenation to tetrahydrofurfuryl alcohol
  • -> rearrangement on Al2O3 to dihydropyran
  • -> dihydropyran hydrogenation

Furfural is made from biomass, so it's renewable, which I guess is considered good?

I don't want to be like a high school chemistry teacher handling liquid mercury with their bare hands in a classroom to show how it's not absorbed through the skin and all those people afraid of it are just dumb and yes that's a thing that happened. Even asking my dentist to use articaine instead of their usual choice makes me worry I'm overlooking something, which is just silly. But I'm quite confident that pure oxane is safer for humans than ethanol, so I think people should be able to have some high-oxane entertainment if they want. My main concern is that it could last too long; it should be cleared faster than 2-methyl-2-butanol, but because it's less volatile and more soluble than diethyl ether, it wouldn't be exhaled as quickly.

regulations

I think it makes sense for some country with a high rate of alcohol flush reaction to legalize using 1-butanol or oxane as a substitute for ethanol in drinks served at bars and restaurants. If that works out well, people could go from there. However, I'm not sure what would lead to a country doing that...hmm...isn't it a shame that some Japanese salarymen and OLs can't be socially pressured by their bosses into consuming psychoactive substances at company drinking parties merely because they have an adverse reaction? Clearly, this is a societal problem that demands rectification, and if it can't be fixed socially it should be fixed chemically.

Of the above compounds, the one closest to being legal as an alternative to ethanol is definitely butanol. It's allowed as a flavoring in the US; my understanding is, there's no specific limit but usage must be at the lowest level that accomplishes the purpose (of flavoring).

To me, oxane seems like the best ethanol replacement, followed by butanol. As for oxane regulations, it hasn't really been considered by governments at all.

Really, ethanol in drinks is only allowed because it was used historically; I doubt it would be allowed if it was new. If you look at how drugs are handled...in the US, for example, methylphenidate is obligatory for some kids while ethylphenidate is illegal, and they're basically the same but ethylphenidate is probably slightly better.

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I would worry a lot about taste and "texture", especially if you're going to use industrial processes to remove alcohol and add something else. Alcohol-removed beer and wine exist, but mostly taste terrible. Alcohol-free spirits typically taste like water, so replacing those would have more to do with how well they can hold flavorful compounds in solution.

Terrible-tasting drinks that make you drunk would really only be a replacement for Everclear, and the market for that is fairly small.

For the curious, famous researcher David Nutt is working on alcohol replacements too. He's part of Alcarelle, now called gaba labs and IIRC they bet on benzodiazepine derivatives.

>I think it makes sense for some country with a high rate of alcohol flush reaction to legalize using 1-butanol or oxane as a substitute for ethanol in drinks served at bars and restaurants.

The only downside is that butanol tastes pretty awful.

Do all the butanols taste bad? I see on WP that it notes that 2-butanol has a 'burning flavor' which seems like a drawback, but I don't see any flavor (just 'alcoholic odor') mentioned in 'butanol' (although 1-butanol sounds like it's so easy to get I'd expect it to mention flavor & abuse if it were a viable ethanol substitute).

https://www.psychiatrist.com/pcc/recreational-2-methyl-2-butanol-use-emerging-wave-misuse-ethanol-substitute/

The ingestion of 2M2B is unpleasant: it reportedly has a camphor-like aroma, and it produces a burning sensation in the mouth and throat. Users often dilute it in water or another liquid to mitigate unpleasant effects.

2M2B isn't suitable as an ethanol replacement because:

  • it's metabolized very slowly and isn't exhaled like diethyl ether so it lasts a couple days, which is too long
  • the smell/taste is somewhat bad

...but maybe I should've included it in the post. (As a tertiary alcohol, it can't be dehydrogenated by alcohol dehydrogenase, which is one way to avoid aldehyde production. It's worth noting that tertiary alcohols produce the same effect too despite steric issues being plausible.)

But is it awful at 1-2% in water, mixed with other stuff? Apparently the odor is less pleasant at higher concentrations, and hedonically neutral at 300 ppm.

[-]Dagon4mo3-8

Legal regime is a political, not a chemical, argument. I suspect a more sane (self-consistent) society would ban consumption of ethanol rather than allowing butanol.

How butanol will affect driving and aggression?

Probably about the same as ethanol. The point here is just to get similar effects via the same mechanism but with reduced health issues and hangover severity.

[-]dr_s4mo00

But much like with synthetic meats or plant based substitutes, this would require changing a whole tradition of brewing and distilling, with all the related culture and know how, with chemical synthesis. I don't think this is an impossible sell, but it would only stick if the benefits seemed significant. Butanol sounds like a very marginal improvement; people who dislike alcohol and its dangers will see it as no better, and people who like alcohol will see it as a poor substitute. Not sure if there's enough pull to actually justify the attempt to switch.

for example, methylphenidate is obligatory for some kids while ethylphenidate is illegal, and they're basically the same but ethylphenidate is probably slightly better.

This sounds surprising to me. Can you elaborate on the source and thought process leading you to this?

first, see the wikipedia page for ethylphenidate

Sure!

To me the only relevant passage seems to be this one:

Ethylphenidate is more selective to the dopamine transporter (DAT) than methylphenidate, having approximately the same efficacy as the parent compound,[6] but has significantly less activity on the norepinephrine transporter (NET).[8] Its dopaminergic pharmacodynamic profile is nearly identical to methylphenidate, and is primarily responsible for its euphoric and reinforcing effects.

You said:

methylphenidate is obligatory for some kids while ethylphenidate is illegal, and they're basically the same but ethylphenidate is probably slightly better.

  1. I disagree with "they're basically the same". I mean of course they are more similar together than compared to acetaminophen but I do think that they would probably be different in terms of effect on ADHD or hedonic perception if compared head to head.

  2. I don't see how ethylphenidate would be better. Is it "better in terms of how pleasurable it is"? As in recreationnal use. Because then there's no point in comparing to methylphenidate beging given to kids. And if it's in terms of how good it treats ADHD then I don't know where it's coming from. Is that because it has a stronger per weight impact on dopamine than on norepinephrin? IIRC modafinil has way more of an impact on dopamine than norepinephrine but helps poorly for ADHD.

I really must be missing something. Thank you for helping me out!

Also:

All available data on ethylphenidate's pharmacodynamics are drawn from studies conducted on rodents.

I do think that they would probably be different in terms of effect on ADHD or hedonic perception

Based on?

And if it's in terms of how good it treats ADHD

That's what I meant.

Is that because it has a stronger per weight impact on dopamine than on norepinephrin? IIRC modafinil has way more of an impact on dopamine than norepinephrine but helps poorly for ADHD.

"stronger per weight impact on dopamine"? That's not how drugs or biology work. Every neurotransmitter and hormone has several different receptors that different drugs affect in different ways.

As for reasons you might expect it to be better, you can see this but I suspect I won't be able to explain my actual reasoning to you in an expeditious way.

Based on?

The wikipedia page explicitely states that they don't have the same binding profile and also Ockham's razor as it seems unlikely that two different drugs with two different binding profile perform similarly on ADHD.

"stronger per weight impact on dopamine"? That's not how drugs or biology work. Every neurotransmitter and hormone has several different receptors that different drugs affect in different ways.

I'm aware. I know my sentence did not sound professional but it was on purpose. I think it's true nonetheless : using a more specific sentence would involve naming specific receptors and I don't want to check each of them (MPH, ETH, modafinil). Being specific here doesn't really matter because I'm expressing surprise as to your apparent certainty. Your certainty indicates that you researched those specifics, hence what I was asking.

Regarding the study you linked, I don't find anything relevant to ETH's effectiveness compared to MPH on ADHD.

To clarify because I think I sound rash when really I'm not:

  • I'm surprised you seem to have low uncertainty on ETH being more effective than MPH on ADHD, even though ETH has never been studied on ADHD, never been compared to MPH, possibly never even been studied on humans (?).
  • It is certain that ETH and MPH don't have the same binding profile. I would be extremely surprised if they didn't have a difference in effectiveness in treating ADHD if compared in a head to head RCT. But I don't really have an opinion on which would be better. You seem to do so I'm probably lacking information about some neurotransmitters and ADHD.

PS: actually I do think ETH would perform worse than MPH. But probably not by a large margin. ETH could also be more pleasurable but less tolerable. All of this with very low certainty.

Another example of an ethyl version being potentially better: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7827200/

How is butanol currently regulated?

You might think these are safe because they're used in eg some paint solvents, but no, they're somewhat toxic.

Personally, I would not update towards "substance X is safe for recreational human consumption" from learning that is used as a paint solvent. But then again I never had the urge to drink paint solvent, so I might be atypical. 

(Also, I assume that the solvents evaporate while the paint dries, so the health and safety problem should be confined to the wet paint. Of course, details are likely to depend on a lot of specifics. Probably not appropriate for fingerpaint, at least.)

They've been used in paints that are put on walls in buildings people are using. They then evaporate and are inhaled.

[-]dr_s4mo00

I assume they mostly evaporate when the paint is fresh, a time when it's pointedly not advised that you stand in the rooms taking deep breaths.