Lysergamides LSD prodrugs and potency

[Dr. Trismegistus]

A drug that mirrors, the effects of another drug does not mean that it has the exact same effects it only appears to have the same effects to the user and the observer. When the actual reason for using a specific drug cannot be determined by an observer.I don’t think there is any textbook definition for the way somebody should feel and act when they take LSD 25 unlike an analog LSD knock off.

LSD dopamine, receptors heavily influence dopamine D2 and D4personality traits like novelty seeking, risk-taking, and extraversion by modulating reward sensitivity. Serotonin receptors (5-HT) affect conscientiousness and anxiety, while oxytocin receptors influence trust and bonding. Overall, brain chemistry shapes personality by regulating motivation and behavior

Analog LSD lysergamide derivatives like 1P-LSD primarily acts as a 5-HT2A serotonin receptor agonistin the brain. It acts as a "strong partial agonist" at this receptor, binding tightly and causing significant alterations in cognition, perception, and mood. It also interacts with other serotonin so they are in fact different and have different effects

 

[Dr. Trismegistus]

A drug that mirrors, the effects of another drug does not mean that it has the exact same effects it only appears to have the same effects to the user and the observer.

Anyone who knows a thing or two about acid knows that there are also countless RC analogues or 'pro-drugs' for good old 25. What I am referring to here are the 1-x-LSD variants, and not ETH-LAD, AL-LAD, or anything else.

I understand that these LSD 'pro-drugs' are pretty much indistinguishable from LSD-25, unless you want to delude yourself into thinking they have unique properties; (I would understand a slower come up due to hydrolysis) what I am asking is if they are technically less potent by weight than LSD-25 - because If they are really a 'pro-drug', then the added groups (the propionyl, valeryl, etc.) would have an added weight to the molecule - meaning that their breakdown would result in a lighter version of the final product? If so, could you scientificlly tell exactly how much weaker?

Help me understand.

Though I suppose the only way to know for sure would be to do a true blind test with what is confirmed to be 100ugs of LSD-25 with 100ugs of an LSD prodrug - but then again there will always be issues with set and setting and the subjects involved.

Damn you acid with your enigmatic nature.

LSD dopamine, receptors heavily influence dopamine D2 and D4personality traits like novelty seeking, risk-taking, and extraversion by modulating reward sensitivity. Serotonin receptors (5-HT) affect conscientiousness and anxiety, while oxytocin receptors influence trust and bonding. Overall, brain chemistry shapes personality by regulating motivation and behavior

Analog LSD lysergamide derivatives like 1P-LSD primarily acts as a 5-HT2A serotonin receptor agonistin the brain. It acts as a "strong partial agonist" at this receptor, binding tightly and causing significant alterations in cognition, perception, and mood. It also interacts with other serotonin so they are in fact different and have different effects

 

[Dr. Trismegistus]

Add the molecular weight of the 1-substitution to the molecular weight of LSD to get the new molecular weight of the prodrug, then you can say (these numbers are just for example) something like "Well I added the number up to 150 but LSD's original weight is 100 so I know that for every 3 micrograms of prodrug I will have 2 micrograms of LSD".

Just an example of how to calculate that, not actual numbers there obviously.

I think that depends because the time it takes to peak also depends on transport rates within the gut and/or the blood-brain barrier. A longer alkyl chain may decrease polarity of the molecule which could have the effect of speeding up transport. The time to peak versus chain length may be a U-shaped. This is all just in theory of course.

My problem with LSZ was that it seemed to be rough on the guts and a very highly effective laxative (even ondansetron couldn't keep it under control). A collectors piece rather than fun...

LSD dopamine, receptors heavily influence dopamine D2 and D4personality traits like novelty seeking, risk-taking, and extraversion by modulating reward sensitivity. Serotonin receptors (5-HT) affect conscientiousness and anxiety, while oxytocin receptors influence trust and bonding. Overall, brain chemistry shapes personality by regulating motivation and behavior

Analog LSD lysergamide derivatives like 1P-LSD primarily acts as a 5-HT2A serotonin receptor agonistin the brain. It acts as a "strong partial agonist" at this receptor, binding tightly and causing significant alterations in cognition, perception, and mood. It also interacts with other serotonin so they are in fact different and have different effects

 

[foodcrisis]

So how would I know if I am getting just good LSD or this heavenly ALD-52 LSD? ...Or is ald52 just ..LSD and not any analogs?

I'm asking because as far as I can tell .my gel tabs have been consistent with blotters from the past, and they never have a taste. Are all analogs bitter? Or just the nbomes or whatever?
Fucking acid, wish I could try all of the analogs but then again my tasteless stuff seems to be the real deal.?

ald52 is one of the analogues and the analogues don't have a taste. any body correct me if i'm wrong.

i dunno how common it is to put analogues on gel tabs. most of the analogues just come from the research site type places or sites claiming to be i'm pretty sure. a lot of people claim to get real LSD25, but who knows cause common tests don't distinguish between analogues. from what i understand though a lot of lsd25 is still being made.

 

[Dr. Trismegistus]

ald52 is one of the analogues and the analogues don't have a taste. any body correct me if i'm wrong.

i dunno how common it is to put analogues on gel tabs. most of the analogues just come from the research site type places or sites claiming to be i'm pretty sure. a lot of people claim to get real LSD25, but who knows cause common tests don't distinguish between analogues. from what i understand though a lot of lsd25 is still being made.

Dr. Trismegistus​

A drug that mirrors, the effects of another drug does not mean that it has the exact same effects it only appears to have the same effects to the user and the observer. Ever heard of the expression smoke and mirrors? Well, it’s a trick.

LSD dopamine, receptors heavily influence dopamine D2 and D4personality traits like novelty seeking, risk-taking, and extraversion by modulating reward sensitivity. Serotonin receptors (5-HT) affect conscientiousness and anxiety, while oxytocin receptors influence trust and bonding. Overall, brain chemistry shapes personality by regulating motivation and behavior

Analog LSD lysergamide derivatives like 1P-LSD primarily acts as a 5-HT2A serotonin receptor agonistin the brain. It acts as a "strong partial agonist" at this receptor, binding tightly and causing significant alterations in cognition, perception, and mood. It also interacts with other serotonin so they are in fact different and have different effects

 

[xdrc]

If you see HTR in rats as indicative of strength of psychedelia in humans, this study should offer some clue:

Analytical and behavioral characterization of 1‐hexanoyl‐LSD (1H‐LSD) - PMC

The development of lysergic acid diethylamide (LSD) derivatives and analogs continues to inform the design of novel receptor probes and potentially new medicines. On the other hand, a number of newly developed LSD derivatives have also emerged as ...

pmc.ncbi.nlm.nih.gov

The pro-drugs seem less potent per mol (not mass!) already than LSD based on this data, so you likely need more than the mass of the 1-acyl residue to get to the same strength.

The activity of 1H‐LSD is roughly equivalent to the potency of ALD‐52 (ED50 = 297.2 nmol/kg), 1P‐LSD (ED50 = 349.6 nmol/kg), 1V‐LSD (ED50 = 373 nmol/kg), and 1cP‐LSD (ED50 = 430 nmol/kg) when they were tested under similar experimental conditions.

In previous studies, LSD induced the HTR with an ED50 of 132.8 nmol/kg, making 1H‐LSD about one‐third as potent as LSD in mice. However, the extent to which the relative potencies of LSD and 1H‐LSD in mice can be extrapolated to humans is unclear. For LSD and a large series of structurally diverse psychedelic drugs, there is a robust correlation (r = 0.9448) between their potencies (ED50 values) in the HTR assay mice and their potencies as psychedelic drugs in humans. However, if N 1‐substituted lysergamides act as prodrugs; then, the relationship between psychedelic drug potencies in mice and humans may not extend to N 1‐substituted lysergamides because there may be considerable cross‐species variations in their potency due to potential differences in the identity, expression level, and tissue distribution of the enzymes responsible for the hydrolysis to LSD.

I don't think these effective dosages are comparable to what happens in humans, as you certainly do not need more than twice the amount of ALD-52 or 1P-LSD in humans to get a similar strength as LSD. But they may be indicative of a trend that more material is needed than to account for the residue.

 

[Didgital]

f so, could you scientificlly tell exactly how much weaker?

Molecular weight of LSD (as a freebase) is 323.4g/mol

Molecular weight of ALD-42 (as a freebase) is 364.47g/mol
Molecular weight of 1P-LSD (as a freebase) is 379.5g/mol
Molecular weight of 1V-LSD (as a freebase) is 407.5g/mol

Dividing the molecular weight of LSD by the weight of it's analogue gives a % of how much of that analogue breaks down into LSD.
323.4/364.47 = .887 x 100 = 88.7% ALD
323.4/379.5 = .852 x 100 = 85.2% 1P
323.4/407.5 = .794 x 100 = 79.4% 1V

So if you're taking 100 micrograms of 1V, that is equivalent to taking 79.4 micrograms of LSD. It's scientifically that much weaker.

If you wanted to calculate the equivalency of each analogue to 100 micrograms of LSD simply divide that number of micrograms by the percentage and then again by 100 to g

100/88.7/100 = 112.7 micrograms of ALD-52 is equivalent to 100 micrograms LSD
100/85.2/100 = 117.4 ug 1P is equivalent to 100 ug LSD
100/79.4/100 = 126 ug 1V is equivalent to 100 ug LSD

 

[xdrc]

In theory, you'd need to account for the mass of the tartrate salt too (as doses are typically measured not as freebase but the salt), and perhaps even include some solvent complexes (iirc when recrystallised from MeOH LSD hemitartrate complexes with two molecules methanol). And then there is above indication that the conversion is not full or inefficient. IIRC in metabolic studies of these compounds some metabolites with intact 1-acyl group are found too which would likely be mostly inactive when hydrolysed, which may be a reason for the discrepancies in molar doses as discussed in my previous comment.

In practice, nobody knows the exact dosing and composition of their tabs anyways

 

[Allylbenzene]

...in my experience I've tended to find ALD-52 to be dependably delightful. I'm certainly not going to pretend that it's anything other than subjective bias

There are countless ALD-52 fanclubs (groups/threads/posts etc) where people adamantly favour ALD-52 which they commonly describe as more relaxed & easy-going compared to LSD. Others argue that it's merly an inactive prodrug (and reference studies) but imo there's something else going on which might involve it being an active prodrug.

 

[Didgital]

In theory, you'd need to account for the mass of the tartrate salt too (as doses are typically measured not as freebase but the salt), and perhaps even include some solvent complexes (iirc when recrystallised from MeOH LSD hemitartrate complexes with two molecules methanol). And then there is above indication that the conversion is not full or inefficient. IIRC in metabolic studies of these compounds some metabolites with intact 1-acyl group are found too which would likely be mostly inactive when hydrolysed, which may be a reason for the discrepancies in molar doses as discussed in my previous comment.

In practice, nobody knows the exact dosing and composition of their tabs anyways

The math wouldn't change as long as the salts are the same form.

 

[4DQSAR]

I think we should be looking harder at the (S,S)-2,4-dimethylazetidine homologue of LSD. That rigid and chiral example MAY hint at the optimal lopophilic pocket. Possibly it may be easier to go there via the NBOMes as I think I've seen example where the ortho methoxy benzyl motif was substituted with a thiophen-2-ylmethyl.

If it IS active, are the thioamides of LSD then also 'novel'? I think it strongly suggests that it's a lone-pair interaction be it the O or the S. But so little is known, for now we can only seek to find a hypothesis and to design experiments to lend a weight of evidence.

 

[perpetualdawn]

Re ALD-52 (vs LSD)
- very weak affinity on 5-ht1a
- it seems to have lower affinity on 5-ht2a, but still active
- it seems to have much higher affinity on 5-ht2c, possibly antagonist


So itself ALD-52 seems to be psychoactive.

But it probably converts very quickly to LSD (I think I read 15mins in rat studies) - so if it has a different feel thank LSD, you'd expect it to be most noticeable in the come-up. Of course there could be complex things going on that we don't understand - like maybe humans metabolize it very differently than rats do. Or maybe when and ALD-52 molecule is bound in a receptor site it cant deacetylate (no idea if that makes sense chemically/biologically)

 

[4DQSAR]

@perpetualdawn - tritate that amide? After all, didn't a Japanese team use NaBT4 on BOL-148 thus creating a radioligand?

Sure, we know that a few deuterated examples of certain medicines were shown to differ a bit, but with FMRI, it seems the shortest route between two points.

 

[iom]

I'm generally a big proponent of the hypothesis that pharmacokinetics can have a significant impact on the qualitative effects of a substance. This may be partly due to differing temporal-spatial distribution of the compound within different parts of the body and brain but also due to what I suspect are time-dependent differences in the signaling cascades that follow from receptor activation. This implies that pharmacokinetic differences could absolutely be felt well beyond the come-up phase. This also implies that the theoretical separation of "pharmacology" and "pharmacokinetics" is not a neat and clean as we might like to suppose.

 

[xdrc]

The math wouldn't change as long as the salts are the same form.

Tartaric acid: 150 g/mol. "Hemitartrate" thus 75 g/mol.

(323 + 75)/(364 + 75) ≠ 323/364.


You can't shorten sums in fractions like that. If you could, the mass of freebase LSD wouldn't matter either It's only like ~2 % difference and I'd assume nobody in the world would be able to lay tabs more accurate than that, yet alone discern the differences.

 

[4DQSAR]

@iom - it seems that mean receptor occupancy time is critical. My own pet hypothesis is that it's the binding-unbinding cycle that is a loci of subjective activity.

 

[Didgital]

Tartaric acid: 150 g/mol. "Hemitartrate" thus 75 g/mol.

(323 + 75)/(364 + 75) ≠ 323/364.


You can't shorten sums in fractions like that. If you could, the mass of freebase LSD wouldn't matter either It's only like ~2 % difference and I'd assume nobody in the world would be able to lay tabs more accurate than that, yet alone discern the differences.

What i meant was the ratio wouldnt change, meaning whether its a salt or a freebase ALD (fb or tartrate) is 88.7% active

I am all too familiar w the nuances of hemisalts trust me

 

[4DQSAR]

@perpetualdawn - Affinity ≠ efficacy. Do we have EC50 values as in vivo is often the better measure than in vitro?

 

[Esperighanto]

There are countless ALD-52 fanclubs (groups/threads/posts etc) where people adamantly favour ALD-52 which they commonly describe as more relaxed & easy-going compared to LSD. Others argue that it's merly an inactive prodrug (and reference studies) but imo there's something else going on which might involve it being an active prodrug.

I have run into it once so far, so I can only speak from a single experience which is far too few to have a take, but it was exceptionally strange to have acid take so goddamn long to finish coming up.

 

[perpetualdawn]

@perpetualdawn - Affinity ≠ efficacy. Do we have EC50 values as in vivo is often the better measure than in vitro?

Yes and in the case of 5-ht2c with ALD-52 it's meant to be an antagonist or at least a non-agonist. I don't remember what EC50 means so not sure and I already lost track of the source I was looking at

edit nm here it is: https://researchonline.ljmu.ac.uk/id/eprint/11815/1/NEUROPHARM-D-19-00561R1_accepted_uncorrected.pdf