I asked David Nicholas if 1p-lsd is a prodrug for lsd.

[WeGotTheWay]

Is 1P-lsd A Prodrug To LSD?


Al-LAD and LSZ are known LSD analogs that were being sold online for the last few years. However, earlier this year these substances were banned in the UK as part of the Misuse of Drugs Act 1971 (Amendment) (No. 2) Order 2014. To no one’s surprise, a new LSD analog appeared shortly after the ban; 1P-LSD.


1P-LSD is a molecule from the same family as LSD. It gets its name from the propionyl group that is bound to the nitrogen of the polycyclic indole group of LSD. 1P-LSD is considered homologous to ALD-52; the latter contains an acetyl group bound to CH3-CO-R instead of the propionyl group. The structure of 1P-LSD contains a polycylic group, and it has a bicyclic hexahydroindole that is bound to a bicyclic quinoline group.


1P-LSD acts as a partial antagonist to 5-HT2A. The psychedelic effects of the molecule are believed to come from 1P-LSD’s effects with the 5-HT2A receptors. However, how this results in a psychedelic experience is still not clear. It has been theorized around the internet that 1P-LSD may be a prodrug to LSD. This theory has been judged likely untrue, because of a few factors. It has both a shorter duration, subtly distinct subjective effects and an extremely close potency which are three things which are rarely associated with a prodrug in regards to the drug it’s compared to.


We asked David E Nichols a few questions regarding this subject. Dr Nichols is the founding president of the Heffter Research Institute, a non-profit that researches medical uses for of psychedelic hallucinogens. He has been working in the psychoactive field since 1969, and was involved in the first human trials for MDMA under Alexander Shulgin.


Is 1P-LSD a prodrug to LSD?


David Nichols:


It is a prodrug, and is hydrolyzed in the body to LSD. A publication just came out in Drug Testing and Analysis.


Can a prodrug be more potent than their parent chemical?


David Nichols:


No, a prodrug won’t generally be more potent than the actual parent drug. In some cases, e.g. heroin, which is a prodrug for morphine, will get into the brain faster and at a higher concentration than morphine will; 10 mg of heroin would have more effect than 10 mg of morphine. But that is the exception.


As a prodrug, 1P-LSD becomes similar to LSD in its effects only after it’s been metabolized. While the debate for which new drugs will take over the market rages on, this interesting analogue of an old favorite is making its presence known.

 

[Xorkoth]

It seems odd to think that there is a single exception to the rule. If diacetylmorphine reaches the brain faster and stronger than the drug it is a prodrug for, why couldn't some other thing do that too?

For what it's worth I find 1p-LSD to be slower and less powerful than LSD. I just found that one statement to be a bit off.

 

[Bagseed]

as far as I know, this is only the case if you use diacetylmorphine iv. orally it's probably no better than morphine, and morphine itself isn't that bioavailable orally. also diacetylmorphine is psychoactive in it's own right which 1p-LSD probably isn't.

I also don't think it's the single exception, but rather that there are few (pro-)drugs that work like this.

 

[Thorns Have Roses]

I also don't think it's the single exception, but rather that there are few (pro-)drugs that work like this.

There are a bunch, think inactive prodrugs like GBL, lisdexamphetamine, or levodopa. Also, caffeine's primary metabolite, paraxanthine, is as potent as the parent compound.

diacetylmorphine is psychoactive in it's own right

IIRC, diacetylmorphine is very weak, however it rapidly breaks down into the far more active 6-monoacetylmorphine (and the not so active 3-monoacetylmorphine, μ opioid activity here relying on a 3-hydroxy group, so that 3-acetyl is no good), and from there to morphine.

If diacetylmorphine reaches the brain faster and stronger than the drug it is a prodrug for, why couldn't some other thing do that too?

GBL packs a quicker harder punch than GHB, in spite of its inactivity, for the same reason as heroin, it is more lipophilic than its desirable metabolite and it has an extremely short metabolic half-life.

 

[Kapitan]

Here's the relevant part of the paper that he refers to:

Other N1-substituted lysergamides undergo extensive N1-dealkylation in vivo,[73–75]and it is possible that 1P-LSD is hydrolyzed to LSD. Indeed, ALD-52 is equipotent with LSD in humans[76]and is considered to serve as a pro-drug, although this does not seem to have ever been confirmed empirically. In order to gaininitial insights into the potential for hydrolysis, 1P-LSD was exposed to incubation in human serum at 37°C followed by LC-MS analysis in selective ion monitoring mode. As shown in the SupportingInformation, LSD detection was observed under a variety of exposure times. Follow-up studies are currently being conducted to compare the affinity and selectivity of LSD and 1P-LSD at 5-HT receptors, and to determine whether 1P-LSD is hydrolyzed to LSD in vivo.

I found this to be a little bit surprising; amide bonds are usually really stable. If you pull up the SI, the evidence for this supposed hydrolysis on any kind of reasonable timescale is a little shaky. They do LCMS in human serum on samples at 1h, 2h, 3h and 24h. They don't actually show the integrals on their EIC, but it looks like less than 1% is converted after 1h, and still much less than 50% after 24h. Maybe that could account for part of the action of this drug, but if I had to guess, I'd say that most of the effect is probably due to the parent compound.

But I dunno -- I'm not a biochemist.

 

[Xorkoth]

as far as I know, this is only the case if you use diacetylmorphine iv. orally it's probably no better than morphine, and morphine itself isn't that bioavailable orally. also diacetylmorphine is psychoactive in it's own right which 1p-LSD probably isn't.

I also don't think it's the single exception, but rather that there are few (pro-)drugs that work like this.

Everyone said the same about 4-AcO-DMT when it came out, on the basis that 4-PO-DMT (psilocybin) appears to be a simple pro-drug for psilocin (4-HO-DMT). But myself and a great many other people find 4-HO-DMT (which I have had pure synthetic of) and 4-AcO-DMT to be very dissimilar. I have a hunch it's not so uncommon. Why is 1p-LSD probably not active on its own? What's the basis for this statement?

 

[Bagseed]

I've read that Nichols said that ALD-52 won't be active at 5HT-2A because of the bulkiness of the acetyl group, it simply wouldn't fit the receptor properly. propionyl is even bulkier than acetyl thus it shouldn't fit either. at least that's how I understood it