Tryptamines 4-AcO vs 4-HO Compound Effect Differences v. Settling the Eternal 4-sub Tryptamine Debate

[arrall]

I've seen this debate around for years but never gotten a definitive answer on it. Some say 4-AcOs are prodrugs for their respective 4-HOs (but also have their own active effects), some have told me that 4-AcOs are just inactive prodrugs with differing effects and durations explained by pharmokinetics, and some think that 4-AcO compounds are their own thing entirely (Like how 5-MeOs, 4-HOs, and base tryptamines all differ.)

For those who have experienced 4-AcOs and 4-HOs of the same base tryptamine:
What differences did you notice in effect? How much does the duration differ? Do you think that 4-AcOs are active/inactive prodrugs for 4-HOs or in a league of their own?
Feel free to compare the 4-subs with 5-MeOs, base tryptamines, etc. while you're at it.

I'm thinking of writing up a formal survey for people to fill out if there's enough interest in this question. With a decent sample size, we can settle the debate once and for all!

 

[Mjäll]

I can only compare 4-AcO-DMT to psilocin mushrooms. I found the AcO version less overwhelming, less anxiety-inducing, less somatically uncomfortable and with a warmer nostalgic feeling. The experiential differences were subtle enough to plausibly belong in the realm of suggestion, but not so subtle that i can confidently deny the existence of actual pharmacological differences. Maybe the experiential differences can never be that subtle anyway, owing to the ever-shifting and intense nature of the psychedelic experience itself.

So i'm deeply neutral and undecided i guess

 

[arrall]

I can only compare 4-AcO-DMT to psilocin mushrooms. I found the AcO version less overwhelming, less anxiety-inducing, less somatically uncomfortable and with a warmer nostalgic feeling. The experiential differences were subtle enough to plausibly belong in the realm of suggestion, but not so subtle that i can confidently deny the existence of actual pharmacological differences. Maybe the experiential differences can never be that subtle anyway, owing to the ever-shifting and intense nature of the psychedelic experience itself.

I haven't tried 4-AcO yet but you named the differences that I notice between eating cubensis and taking 4-HOs (4-HO-MET, primarily) - minus the individual quirks of each 4-HO, of course. I would attribute most of the effect differences you noted to 1. Significantly reduced nausea and body load due to not having to consume plant matter & 2. The numerous alkaloids present in psilocybin mushrooms which - as you probably know but others may not - primarily contain 4-PO-DMT/psilocybin in addition to 4-HO-DMT/psilocin, and (in smaller quantities) many other compounds. The fact that we know little to nothing about many identified alkaloids and so many of these alkaloids remain unidentified makes comparing mushrooms to RCs very difficult.

@Xorkoth is one of the few people on here who has tried isolated 4-HO-DMT, so he probably has some interesting insights on this.

 

[G_Chem]

Yea my only experience with tryptamine pro-drugs also is 4-AcO-DMT compared with a wide variety of psilocybin/psilocin mushrooms. They honestly feel like two different drugs to me.

4-AcO-DMT is much easier to handle overall, the visuals and thought process resembles DMT more so than mushrooms, the duration is often much shorter, and the depth not quite as rich n deep.

Mushrooms I need much more preparation, it takes my mind into places 4-AcO never has. Can be a little rough and frightening at times in comparison. Also the duration just keeps going and going, mushrooms don’t seem to like to let go of my brain.

Kinda sad I’m down to the last of my 4-AcO.. I regret giving it all away now Sometimes I give a little too much. I think I’d prefer it for some chill camping adventures over mushrooms.

-GC

 

[Pfafffed]

I've posted on this at length on here before several times (and recently,) so I won't bore you by rehashing it. What I will say is that I believe that there's enough empirical evidence out there to say that at least some AcO substitutions are definitively active. That much is settled. If you can vaporize or inject a drug intravenously, bypassing first pass metabolism, and it is immediately active, then it isn't solely a prodrug. It doesn't depend on metabolism to be effective. That doesn't mean that it isn't partially or completely metabolized into a different drug when taken orally, just that it isn't necessary for it to be active.

 

[arrall]

I've posted on this at length on here before several times (and recently,) so I won't bore you by rehashing it. What I will say is that I believe that there's enough empirical evidence out there to say that at least some AcO substitutions are definitively active. That much is settled. If you can vaporize or inject a drug intravenously, bypassing first pass metabolism, and it is immediately active, then it isn't solely a prodrug. It doesn't depend on metabolism to be effective. That doesn't mean that it isn't partially or completely metabolized into a different drug when taken orally, just that it isn't necessary for it to be active.

Thank you, and excellent point that I was not aware of. True inactive prodrugs (e.g. Vyvanse) have a bit of a delay with all administration routes. I'm far more interested in the effects differences than the prodrug debate, so I'll go take a look at some of your posts to see said comparisons.
EDIT: Excellent comparison below

4-HO-MET: a deeper, smoother, more sedating and emotional version of 4-AcO-MET's cold, crystal clear eye candy. They're both childlike, but 4-HO-MET is deeper and warmer and more interesting, while 4-AcO-MET is more recreational and refreshing. The internet consensus is that 4-HO-MET is a gem, now supplanting 4-HO-MiPT and 4-AcO-DMT as the internet's favorite 4-sub.

4-xxx-DET: No idea, no internet consensus

4-xxx-DPT: No idea. The internet says that it's shallow and easygoing compared to N,N-DPT. Also a pain in the ass to get the dose right due to inconsistent bioavailability. Some people insufflate it because of this. Tremory/seizurey maybe with some muscle side-effects, although these don't appear to be common side effects.

4-xxx-EPT: Light, pastel confection. They lie to you, telling me everything is right with the world even when it definitely isn't. They're kind to me, but also not challenging or insightful.

4-xxx-MiPT: Impossible to classify. Is it primal or cyberpunk digital? Is it rich or thin? Is it alien or organic? I don't know. They definitely make me enjoy things: my body, food, touch, and narrative. I find them recreational and not insightful, but they can really bring attention and emotion to interpersonal relationships, refreshing appreciation for the love you feel for those that are important to you. Sometimes it all goes sideways and you just end up kinda stoned.

4-xxx-MPT: A warm, gilded relative of 4-xxx-DMT. Baroque and rich, this has depth without being as confronting. It's less harsh, but less earthy and grounded. Is it as honest? That I don't know. Sometimes it whiffs completely and is just a generic, blunting tryptamine like 4-xxx-MALT.

N,N-DPT: It's had books written about it. It's a mega-classic on par with the classical biggies. It's also pretty polarizing--people love it or hate it. I will likely never take it a second time, but I respect it. Again with the tremors. You may not want to explore this if you are nervous about possible seizures, although it appears to have a pretty good safety record all in all.

N,N-EPT: The lightest psychedelic that I've ever used that I would still call a psychedelic, and that's when vaporized. Intimidates absolutely no one. Feels lovely in the body. Erotic and gentle. Not very visual at all, and not very insightful. Still very pleasant if you aren't looking to get your world rocked.

It depends on you. It seems like people fall into one of three camps.
1) All 4 substituted tryptamines are indistinguishable from psilocybin. There's no real difference.
2) 4-substituted tryptamines have individual variation, but there's no difference between hydroxy and acetoxy substitutions at the 2-position.
3) 2) 4-substituted tryptamines have individual variation, and there's a noticeable difference between hydroxy and acetoxy substitutions at the 2-position. This can be potency, duration, or subjective effects.

This is an oversimplification, of course. I fall into category 3. So far, acetoxy subs have been smoother, lighter, more electric, more stimulating, and more shallow. Hydroxy subs have been foggier, bumpier, more muddled, deeper, less jittery, and more insightful.

This holds true for miprocin and mipracetin. I don't really like miprocin (although I want to.) Mipracetin has all of the benefits of miprocin, but yet it seems thinner and more hollowed out, lacking miprocin's richness. Mipracetin lasts longer for me.

 

[ecstacylover]

Psilocybin was way different than 4-AcO-DMT for me, or any other 4-sub for that matter. The visual effects were unlike anything I've encountered since, almost like viewing the world through a distorted fish-eye lens. Completely devoid of color, everything took on shades of dark grey. It also felt much more insightful and more stripping of cultural associations. 4-AcO-DMT felt much dreamier and more like the other 4-subs I've tried.

I saw a study where psilocybin cannot be detected in the bloodstream when taken orally (first blood samples taken 15 minutes in), so I question how much of a pharmacological difference there is here. Definitely would help to better understand the activity of other alkaloids present as @arrall suggested.

From a REBUS perspective it makes sense that plant material vs. powder could lead to differently perceived experiences even if the active components are the same. Once you start relaxing a lot of other high-level beliefs, suddenly the distinction between a plant and powder gains influence and could more strongly impact how the experience is interpreted/constructed. Although for many people the distinction of plant vs. powder probably carries a large influence to begin with.

If you can vaporize or inject a drug intravenously, bypassing first pass metabolism, and it is immediately active, then it isn't solely a prodrug. It doesn't depend on metabolism to be effective.

The sentiment I've encountered is that esterases are present in the bloodstream, and if their concentration and/or rate is high enough, you still wouldn't have a significant amount of the ester reaching the brain. Succinylcholine administered IV is 90-95% hydrolyzed before it reaches tissue, so the reaction can happen quickly, at least in some cases.

Interesting paper in 2020 on 4-sub SAR showed that 4-AcO-DPT and 4-AcO-MPT are more potent in mice than their hydroxy counterparts. To your point, this can't be explained if the ester was rapidly hydrolyzed, so at the very least there can be significant differences in AcO vs. HO brain uptake (caveat: species differences exist w.r.t esterase activity). They also showed the AcO esters of all major 4-subs have 5-HT2A Gq efficacy, although it was generally over an order of magnitude weaker than the corresponding hydroxy.

At least for the AcO's vs. HO's, this supports the notion that there is a distinction and that it might not just be kinetic either.

 

[damfino]

Comparing 4-AcO-DMT to mushrooms I definitely found 4-AcO to be noticeably different. The visuals were more geometric (I can see the similarities to DMT) but less colorful. They developed to a certain point then more or less looped for the duration of the experience accompanying a whirring noise that built up and released as they did so. The periodic release felt as if all physical material disintegrated into something in-between the Apple startup noise and aum (432Hz) which was quite an experience, pretty benevolent. I don't recall ever experiencing that level of persistence or influence from auditory hallucinations on mushrooms, however it was not unlike a couple experiences I've had with LSD (but with LSD the whirring always seemed to be stuck in a persistent build up, nearly drove me mad at points). The colorful rapidly dynamic landscapes I associate with mushrooms still occurred at points but in general they seemed much more transient and less colorful / dull. The thought of movement was quite unappealing and proved to be more difficult and couch-locking than with any mushroom experience. In contrast with others descriptions I actually found 4-AcO-DMT to last considerably longer than even my most high dose mushroom experiences. So to surmise the differences I'd say 4-AcO-DMT is less dynamic, more thought-loopy, and a bit more dull, while something about its presentation seemed to feel more "medicinal" to me. I see what people mean with less overwhelming but I'm a bit neutral on this point, maybe less anxiety but I barely get much anxiety on mushrooms anyways.

 

[Pfafffed]

Just a quick clarifying note here:

psilocybin = 4-PO-DMT
psilocin = 4-HO-DMT
psilacetin = 4-AcO-DMT

 

[Zopiclone bandit]

My experience has been with 4-AcO-DMT & 4-HO-MET

4-AcO-DMT gave me the most insane 2nd visual ever (only smoking N,N-DMT gave better effects) but it lasted for a few mins, a tree took off like a rocket out the ground & exploded in the sky, it then rained colours I've never seen before onto my window then vanished. The rest of the trip was a heavy bodyload & an uneasy feeling in the body. I personally didn't rate Aco-DMT to mushrooms, give me 5 grams of Welsh Liberty caps any day.

4-HO-MET is imho the best thing out there for tripping, the visual effects are insane, everything takes on a cartoon look to it, the sky turned blue, purple, yellow, I watched a skyrise block of flats bounce around like a accordion, I watched a firework display one evening next to a bonfire & I nearly melted my brain. I could go on & on, something VERY SPECIAL is happening in the brain when you take a good dose of 4-HO-MET.

 

[ryanegg]

Only tried 4-AcO-DMT smoked, then after having a very mild dose of libs a few days later, I did find some similarities. Being short of libs, I remember thinking of topping up with a quick pipe of AcO as I wanted to go a bit deeper.

 

[Ismene2]

4aco is my friend, my lover, my Yoko Ono from Basel (think thats where Albert created it). In high doses its orally active DMT with very little nausea. I worship it.

 

[Xorkoth]

Some people report no discernable difference between each pair of hydroxy and acetoxy esters, except perhaps a longer duration with the acetoxy, while others report distinct and replicatable differences. My theory is that the acetoxy esters do cross the BBB and have effects of their own, but we also know with certainty that they indeed metabolize into the hydroxy esters. But individuals have metabolic differences, and different people metabolize them more quickly than others. This results in some people getting a substantial portion of the drugs into the plasma unchanged, getting unique effects for a while until they are metabolized. Whereas others metabolize them so readily that they are getting mostly just hydroxy effects. I know for me, and many others, 4-AcO-DMT is extremely distinct from 4-HO-DMT and mushrooms (I have had the fortune to try all 3, including synthetic, pure 4-HO-DMT). I am 100% certain I could easily differentiate between 4-AcO-DMT and 4-HO-DMT in a blind test, 4-AcO-DMT feels just like oral smoked DMT during the first half, it's very different. Then the second half/plateau is indistinguishable from 4-HO-DMT. But some other people swear they're almost exactly the same.

I don't state this as fact by any means, but it's my working theory.

 

[Ismene2]

I can tell 4aco in a heartbeat - it has a physical sensation you only ever get on oral doses of DMT with an MAOI inhibitor. 4aco is orally active DMT simple as.

 

[Hexagon Sun]

4-aco-dmt was a total winner for sure. It´s a pity that is not available ATM. The psychodelic chemist of the moment are getting lazy...

I haven tried the 4-x-met versions yet but seems promising

And whast the point on the fumaric salts? Are just less potent by weight but more stable, Isnt? So it can last years in a drawer without losing potency... isnt?

 

[blistersinthedark]

I think I've posted it before but 4-AcO-MET and 4-HO-MET are markedly different for me.

The main difference is 4-HO-MET gives me terrible GI discomfort, whereas 4-AcO-MET simply doesn't. So naturally I prefer the latter, as it feels "cleaner". In terms of headspace, stimulation and giddiness, there isn't much of a difference, although 4-AcO-MET is much more readily visual, and possibly more potent (I seem to remember having comparatively little effects from 4-HO-MET, but I only tried it 2-3 times before getting rid of it.)

 

[Xorkoth]

And whast the point on the fumaric salts? Are just less potent by weight but more stable, Isnt? So it can last years in a drawer without losing potency... isnt?

Correct, they're far more stable. Back in the early days, the tryptamines were all commonly available as freebases, and they were notoriously unstable. Then they started producing HCL salts, which were more stable but still would degrade pretty quickly. At some point they started producing fumarate salts and those seem to be able to last practically indefinitely even at room temperature.

 

[Keeloverandfly]

I have only tried 4 ho met and 4 aco met, the former once and the latter thrice. With so little experience it is hard to say, but I found 20mg of aco way more visual than 20mg of ho, both eyes closed and open. I also had lovely body shivers with the aco. The ho I found way less interesting, more shallow. But perhaps the ho, which was a pill pressed by a RC company, was just less accurately dosed, or had lost potency, compared to my aco which I bought as fumurate. In any case I will re up on 4 ho in fumurate form, and get back to you in a year or so… more research necessary!

 

[Didgital]

So... I recently got to try true synthetic 4-HO-DMT fumarate (Psilocin) and I've had some experience with 4-ACO-DMT fumarate (acetylpsilocin).

I found them different from eachother and psilocybe mushrooms.

The psilocin I could feel in 15-20 min and at about 40 min mark it was like getting hit by a truck. It was extremely visual at even 15mg but more like a less hectic ayahuasca trip. It was kind of like a rocketship up and a rocketship down. Main effects were dimishing by hour 3.

The acetylpsilocin was more reminiscent of mushrooms, hitting a little bit slower and in waves. I'm probably an outlier here but 4 aco is more likely to cause GI distress for me than either mushrooms or the 4-HO. 4-HO was extremely smooth on my body though I did actually puke, it was more of a spiritual purge. There was no nausea whatsoever.

 

[Pfafffed]

Thanks for the mini report! Gives me a bit of a judge to try some of the psilocin I squirreled away almost a decade ago. Never got around to it somehow.