any major dude
Bluelight Crew
The way I understand it, yes, and ND is for no data or missing data. 0.00 is for values of Ki >10,000nM
-
N&PD Moderators: Skorpio
Psychedelics and the Human Receptorome
- Thread starter any major dude
- Start date
The way I understand it, yes, and ND is for no data or missing data. 0.00 is for values of Ki >10,000nM 
Dondante
Bluelighter
- Joined
- Dec 6, 2005
- Messages
- 1,638
In my opinion, the paper accomplishes exactly what it aims to accomplish, which is to serve as a reference and foundation for future research. There are significant limitations, which may not have been clearly articulated by the author, but are likely evident to those with a rudimentary understanding of pharmacology. Let me preface the following by saying that I have no more than a rudimentary understanding of pharmacology.
The bulk of this paper is based on affinity data. The only functional data is found in one supplemental table, which consists of EC50 and Emax for Ca++ mobilization relative to 5-HT at the 5-HT2A and 5-HT2C receptors. Here, it is clear that mescaline is a full agonist at the 5-HT2A receptor (EC50: 87.6-208.4 nM; Emax:100% ). Adding to the limitations of this assay mentioned in the paper, calcium mobilization is only one measure of activity, which is to say that taking this data at face value ignores the concept of functional selectivity (i.e. whether certain downstream signaling pathways are preferentially activated via agonist activity).
nuke
Bluelighter
- Joined
- Nov 7, 2004
- Messages
- 4,190
I'm guessing the study was intended to look at the selectivity of various commonly used psychotropic ligand standards, especially psychedelics. These compounds may have just been included as controls.
Please stop spouting out expletives and other enraged linguistics that are devoid of any practical scientific value. It helps no one, evaluates nothing and serves to make you look inordinate.
As rocknroll said, affinity assays can be dramatically different in human receptors, hell, even in different isoforms of human receptors. The use of different hot ligands will change the results, too. A shortcoming of the study is no functional assays, but he probably has been working on this for a while. If you're concerned about his methodology and results, why don't you just e-mail him? He's using the same assay method as was developed by Glennon.
Let's, for instance, compare Ray's data to the data in the PDSP (Ray did not list his exact methodology in the paper, so I don't know what hot ligands he's using to assay activity):
They are, for the most part, in agreement with the literature.
It's also not all that surprising that MDMA has no huge 5HT2 affinity, since the active metabolite MDA has been fingered for its psychedelic activity for a long time.Last edited:The aggregation methods (the npK's and log sigmas) are a bit unlike what I'm used to reading in these types of papers. I understand the mathematics, but I also understand that once you start using unconventional algorithms (and nested, to boot), statistical legerdemain is less noticeable.gravitymonk
Greenlighter
- Joined
- Jun 1, 2009
- Messages
- 48
I'm a little disappointed that the only 4-xx-DMT in the study was psilocin. It would be interesting to see whether 4-AcO-DMT had a different receptor profile.
dread
Bluelighter
vortex30
Bluelighter
No, 4-aco-dmt is converted to 4-ho-dmt quite quickly, so obviously the same chemical will have the same effect. If 4-aco-dmt cross the blood-brain-barrier (which I'm not sure it does), it would be broken down very quickly by Monoamine oxidase. 4-aco-dmt is essentially 4-ho-dmt, difference in effects come down to how quick/slow you metabolize it.psood0nym
Bluelighter
4-AcO-DMT must cross the blood-brain barrier if the IV reports of powerful near-immediate effects are to be made sense of. Is there enough deacetylase or whatever in our brain or blood to convert the prodrug that 4-AcO supposedly is to 4-ho-DMT so fast? (Please reply in the B&D 4-AcO-DMT thread if you have an explanation, because this is off topic but I'm genuinely curious.)Last edited:
dread
Bluelighter
Probably. That's exactly how IV:ing heroin works: you inject it, it crosses the BBB quick with the acetyls, and enzymes in the brain shitcan the acetyls, allowing it to bind.psood0nym
Bluelighter
^Thanks! There's been talk of AcO's being active on their own and not being prodrugs in PD for years. But if there's a high concentration of deacetylazing enzymes in the brain that work quickly and are necessary for the active 4-ho metabolite "to bind," that makes sense of a lot. You should have posted in those threads earlier. It would have prevented a lot of pointless ignorant posts, including mine!
any major dude
Bluelight Crew
ha! i've been involved in that conversation as well i believe... thanks for the info
Hammilton
Bluelighter
- Joined
- Sep 2, 2008
- Messages
- 3,435
I didn't note any issue with MDMA's supposed lack of 5HT2a affinity. Given the effects, that's rather obvious. What is retarded is the supposed lack of SERT affinity given that everyone else has found it.
This study has no real value. Comparing agonists to antagonists is bound to give useless results. There are a fair number of studies available that find antagonists like ketanserin binding in a site significantly different from the agonist pocket. One study I found in the blacklight database found that only about 30% overlap between the two sites.
So what exactly is the point of taking a bunch of numbers that aren't useful in determing actual affinity? I'm not seeing any.
The funny thing is how empty the conversation here has been. Accepting these numbers, when they're so obviously flawed, as if they have real meaning. Anything that's finding MDMA to have no measurable affinity to SERT or DiPT no 5HT2a affinity should raise a red flag.
Hammilton
Bluelighter
- Joined
- Sep 2, 2008
- Messages
- 3,435
100,000nM is extremely low affinity - no affinity for practical purposes. Look at what most studies find for affinities to these receptors. Even the document rocknroll714 quotes has 2 studies w/ >10,000 affinity, and 4 with affinities that are more reasonable for a drug commonly dosed @ 75-250mg. Interestingly, it's the assays w/ human SERT that have the really oddball results. And no, doses of 75-250mg should not remotely correlate with affinities that high. er... rather low.
Dondante
Bluelighter
- Joined
- Dec 6, 2005
- Messages
- 1,638
This study did not report any affinities >10,000 nM...I don't know where the 100,000 nM figure came from. Regardless, the functional assay for mescaline at 5-HT2A found an EC50 around 200 nM relative to 5-HT. I'm not sure I understand the discrepancy with the affinity values relative to 3H-ketanserin, but I suppose the results of the binding assay depend on the affinity of the hot ligand.
Anyway, I had some down time last week and made this figure showing 5-HT2A/1A affinity ratios. Obviously, this is the least surprising conclusion of the paper (since there is already evidence regarding the profiles of phens vs. trypts), but I found it satisfying to see it in graph form. It will be interesting to find out what effect other 5-HT receptors have on the phenomenology of the psychedelic experience ... and SERT and DA, alpha2, and sigma receptors too.
*These data points are from published data gathered by the PDSP, not tested by the PDSP.
Also, I left out DOET, because the high 1A affinity doesn't make sense to me. I should ask them to repeat that experiment...
Hammilton
Bluelighter
- Joined
- Sep 2, 2008
- Messages
- 3,435
By the way, if you read the wiki page on this ray guy, he seems like quite an oddball, even for psychedelic science.
re: 100,000nM, yeah, 10K was the obvious number. But even 10,000nM is essentially inactive. Anything over 5,000nM is ridiculously not potent. The numbers reported for mescaline aren't in line with its relatively low potency. Much of mescaline's in vivo potency is due to MAO, as any inhibition increases its potency quite a bit.
