ALD-52 and other 1-acylated LSD analogues are Prodrugs for LSD (not directly active)

[sekio]

The data showed that ALD-52, 1P-LSD, and 1B-LSD were very weak partial agonists at the human 5-HT2A compared to LSD. Interestingly, despite showing comparatively high affinity for 5-HT2B and 5-HT2C, the compounds showed no agonist activity at those receptors. This behavior is in contrast to LSD, which is an agonist at recombinant human 5-HT2B and 5-HT2C receptors.

The study also assessed the binding affinity of 1B-LSD for 24 other monoamine receptors. Overall, the data indicated that 1-butanoyl substitution had a detrimental effect on binding to most of the receptors, compared to previously reported data for LSD. The binding affinity at these receptors was 10-100-fold lower than for LSD. The two main exceptions were 1B-LSD binding at the 5-HT2C receptor, as discussed earlier and 5-HT2B.

Study Finds ALD-52, 1P-LSD, and 1B-LSD Are Prodrugs of LSD

Identifying and understanding prodrugs is an essential component of psychedelic drug research.

psychedelicreview.com

This kind of confirms what I initially suspected: the "new" analogs of LSD are functionally the same as LSD... despite having some affintiy for serotonin receptors they do not activate them the same way as LSD does.

Scientific article: https://www.ncbi.nlm.nih.gov/pubmed/31756337

The ergoline d-lysergic acid diethylamide (LSD) is one of the most potent psychedelic drugs. 1-Acetyl-LSD (ALD-52), a derivative of LSD containing an acetyl group on the indole nitrogen, also produces psychedelic effects in humans and has about the same potency as LSD. Recently, several other 1-acyl-substitued LSD derivatives, including 1-propanoyl-LSD (1P-LSD) and 1-butanoyl-LSD (1B-LSD), have appeared as designer drugs. Although these compounds are assumed to act as prodrugs for LSD, studies have not specifically tested this prediction. [...] Although LSD acts as an agonist at 5-HT2 subtypes, ALD-52, 1P-LSD and 1B-LSD have weak efficacy or act as antagonists in Ca2+-mobilization assays. Despite the detrimental effect of 1-acyl substitution on 5-HT2A affinity and efficacy, 1-acyl-substitued LSD derivatives induce head twitches in mice with relatively high potency. High levels of LSD were detected in the plasma of rats after subcutaneous administration of ALD-52 and 1P-LSD, demonstrating these compounds are rapidly and efficiently deacylated in vivo. These findings are consistent with the prediction that ALD-52, 1P-LSD and 1B-LSD serve as prodrugs for LSD.

 

[vecktor]

A result most people predicted.
This work is certainly useful information, apart from the functional assay which uses the wrong downstream messenger to give any properly useful information on psychedelic functional agonism at 5ht2a.

Psychedelic researchers, can you please use use B-arrestin recruitment type assays for in vitro functional, it correlates much more closely with human and animal data for psychedelic activity and it is really easy to do using luminescence.
PLA2, is useful too but a real nightmare to design robust assays around. Antagonism/agonism on PLC IP3 ca2+ assays is not so meaningful or useful.

I want to see ring fluorinated ergolenes explored, 13 F for example to block metabolic oxidation to the dopaminergic metabolite, the chemistry is well beyond the abilities of 1p-LSD cooks.

 

[sekio]

A result most people predicted.

Maybe us ivory-tower intellectuals but if you read some of the threads in PD about LSD analogs there are people who insist they have different characteristics to their "highs". Go figure.

At least there is some concrete research to settle the score.

 

[polymath]

Maybe us ivory-tower intellectuals but if you read some of the threads in PD about LSD analogs there are people who insist they have different characteristics to their "highs". Go figure.

Maybe the subjective quality changes when there's more 5-HT2B or 2C activity at the same time with the 5-HT2A effect. Some other things, including metabotropic glutamate ligands, can alter the effects of psychedelics without causing much psychoactive effect on their own.

 

[Cream Gravy?]

Maybe us ivory-tower intellectuals but if you read some of the threads in PD about LSD analogs there are people who insist they have different characteristics to their "highs". Go figure.

At least there is some concrete research to settle the score.

I think a lot of the 'variations' between the LSD analogue pro-drugs could be metabolism related then. I recall 1A-LSD always being gentler and more colorful than classic LSD personally; yet in a blind trial, I'd be hard pressed to distinguish the two. Perhaps different folks metabolize each substitution a bit different, leading to things such as smoother or harsher come-ups, differing duration, etc. Many say that 1P is much quicker/harsher to come-up, and that could be attributed to people metabolizing 1P into LSD much quicker than say, 1A.

I'm no chemist though nor is this normally a forum I would post in, I just thought I'd draw attention to that. Like me, I'm either lacking or have a lot of whatever that enzyme is that metabolizes tramadol and DXM, as I can take a tenth of the dose needed for either of those and get wayyyy too high. 20mg of O-DSMT will leave me an itchy, balled up nauseous mess.

 

[polymath]

I'm no chemist though nor is this normally a forum I would post in, I just thought I'd draw attention to that. Like me, I'm either lacking or have a lot of whatever that enzyme is that metabolizes tramadol and DXM, as I can take a tenth of the dose needed for either of those and get wayyyy too high. 20mg of O-DSMT will leave me an itchy, balled up nauseous mess.

You lucky bastard

 

[Cream Gravy?]

You lucky bastard

It is nice for O-DT lol. With DXM I can't take it at all because it's frightening at 30mg even. But I can make 5g of O-DT last like, a year, dosing daily. Crazy.

 

[S.J.B.]

I think a lot of the 'variations' between the LSD analogue pro-drugs could be metabolism related then. I recall 1A-LSD always being gentler and more colorful than classic LSD personally; yet in a blind trial, I'd be hard pressed to distinguish the two. Perhaps different folks metabolize each substitution a bit different, leading to things such as smoother or harsher come-ups, differing duration, etc. Many say that 1P is much quicker/harsher to come-up, and that could be attributed to people metabolizing 1P into LSD much quicker than say, 1A.

You're probably right that the duration of the come-up, along with the action of different metabolites not contributing significantly to 5-HT action but maybe affecting body load, etc., can make the experience different to some extent than with LSD, but you're probably also right that people probably wouldn't be able to tell the difference in a blinded trial. There are drugs that people swear are drastically different that they can't tell apart under blinded conditions, heroin and hydromorphone being a notable example.

 

[checktest]

I bet the metabolism does alter some of the timings, even if the vast majority/ whole of the experience is driven by the same agent. Then again, some people say different color M&Ms taste differently.

In vitro metabolic fate of nine LSD-based new psychoactive substances and their analytical detectability in different urinary screening procedures - Analytical and Bioanalytical Chemistry

The market of new psychoactive substances (NPS) is characterized by a high turnover and thus provides several challenges for analytical toxicology. The analysis of urine samples often requires detailed knowledge about metabolism given that parent compounds either may be present only in small...

link.springer.com

https://www.tandfonline.com/doi/full/10.1080/03602532.2019.1638931

PubMed

PubMed® comprises more than 38 million citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full text content from PubMed Central and publisher web sites.

www.ncbi.nlm.nih.gov

Indolealkylamines: Biotransformations and Potential Drug–Drug Interactions - PMC

Indolealkylamine (IAA) drugs are 5-hydroxytryptamine (5-HT or serotonin) analogs that mainly act on the serotonin system. Some IAAs are clinically utilized for antimigraine therapy, whereas other substances are notable as drugs of abuse. In the ...

www.ncbi.nlm.nih.gov

CYP1A2 has a fairly large amount of polymorphisms (slow, intermediate, rapid) and varied inducibility in the general human population, let alone effects from smoking and caffeine/ dietary factors. Especially in some groups.

CYP3A4 studies seems to have more phenotypic variability than genetic, though plenty of drugs factor in.

Pretty rapid metabolism mentioned.

Also PPIs like omeprazole and other drugs people use may be using could alter the timings, if it were more significant.

For tramadol, CYP2D6 ultrarapid metabolism combined with impaired glucuronidation (whatever ones) maybe could have it lasting longer. And whatever that solute carrier that may be involved in some.

[I apparently have some glucoronidation higher level metabolism for at least some. Took 300 mg lamotrigine and still had low enough levels that my psych asked if I was taking it. Bumped to 400 and more.]

 

[novaveritas]

Maybe us ivory-tower intellectuals but if you read some of the threads in PD about LSD analogs there are people who insist they have different characteristics to their "highs". Go figure.

At least there is some concrete research to settle the score.

ALD-52 come up is qualitatively different to LSD, maybe due to better absorbtion distribution and kinetics, or more gradual increase in LSD levels or ALD-52 is missing some anti target that acid hits, the main show is essentially the same.
Do all these different varieties metabolize at the same rate to LSD? What enzyme cleaves them to acid? Do some people not have the enzyme and will not get anything from ALD-52?