Problems interpreting 5-HT2B receptor data: do hallucinogens cause cardiac fibrosis?

[Ufostrahlen]

I am currently reading this paper and I have problems with interpreting the 5-HT2B receptor data:

Ray, TS. Psychedelics and the human receptorome. PLOS ONE, 2 Feb 2010, 5 (2), e9019. 791 kB. doi:10.1371/journal.pone.0009019

The paper presents on page 12 the following affinity data for the 5-HT2B receptor:

4.00 DOB, 4.00 MDA, 4.00 Aleph-2, 4.00 2C-B-fly,
4.00 2C-B, 4.00 TMA, 4.00 psilocin, 4.00 TMA-2, 4.00 2C-E,
4.00 2C-T-2, 4.00 4C-T-2, 4.00 MEM, 4.00 DOM, 3.97
mescaline, 3.93 6-F-DMT, 3.91 5-MeO-DIPT, 3.91 DMT, 3.88
DPT, 3.70 DOET, 3.64 MDMA, 3.48 DIPT, 3.32 5-MeO-MIPT,
3.13 DOI, 3.11 LSD, 3.01 lisuride, 2.72 cis-2a, 2.17 SS-2c, 1.81
RR-2b, 0.69 5-MeO-DMT; 0.00 salvinorin A;

Now what does that mean? Has 2C-E, Psilocin, Mescaline & DMT a higher affinity for the 5-HT2B receptor than MDMA or a lesser? I'm asking, because agonism at the 5-HT2B receptor has been linked to cardiac fibrosis. If you could help me interpret the data, it be much appreciated!

Edit: Okay, for adding more confusion, I link: Roth BL (January 2007). "Drugs and valvular heart disease". N. Engl. J. Med. 356 (1): 6–9. doi:10.1056/NEJMp068265. PMID 17202450.

Lisuride, which is an agonist at two related serotonin receptors (5-HT 2 A and 5-HT 2 C )
but is not a 5-HT 2 B agonist, was not associated with valve disease.

So how does the 3.01 5-HT2B value from Ray for lisuride fit in? (see first quote)

Clearly, practitioners should avoid prescribing drugs that are potent 5-HT 2 B –receptor agonists — a growing list of medications that now includes ergot derivatives (ergotamine, methysergide, and dihydroergotamine [..] and amphetamine derivatives [..] MDMA)

And what's up with LSD?

 

[Ufostrahlen]

Okay, I found:

Cardiac fibrosis - Wikipedia

en.wikipedia.org

Cardiac fibrosis
Recreational drugs which also act at 5-HT2B receptors

Several serotonergic recreational drugs, including the empathogens MDA and MDMA ("Ecstasy"),[16] and some hallucinogens such as DOI[17] and bromo-dragonfly,[18] have all been shown to act as 5-HT2B agonists in vitro, but how significant this may be as a risk factor associated with their recreational use is unclear. The piperazine derivative mCPP (a major metabolite of Trazodone) is a 5-HT2B agonist in animal models, but actually behaves as a 5-HT2B antagonist in humans.[19][20][21] One study of human users of "ecstasy" found that they did have heart valve changes suggestive of early cardiac fibrosis, which were not present in non-ecstasy using controls,[22] suggesting that ecstasy use certainly has the potential to cause this kind of heart damage. On the other hand there is no statistical evidence as yet to suggest significant increases in rates of cardiac valvopathies in current or former MDMA users, and it is most likely that as with other 5-HT2B agonists, development of heart valve damage will be highly dependent on the frequency and duration of use and the total cumulative exposure over time, and only a small proportion of the heaviest users are likely to face a substantial risk of heart damage.

The chemist Alexander Shulgin first popularized MDMA and MDA, and he invented DOI and many other recreational drugs that are also 5HT-2B receptor agonists. In 2008 Shulgin underwent surgery to replace a defective aortic heart valve. It is unknown whether or not Shulgin's lifelong use of psychedelic drugs caused the failure of his heart valve.

I still wonder, why the 5-HT2B issue hasn't been addressed regarding hallucinogens. I knew of the MDMA issues, but I wonder why Mescaline, LSD & Psilocin have never been mentioned. At least not as loud as MDMA & cardiac fibrosis...

 

[joedirt]

I actually emailed the PI on this paper awhile back with a few questions and did not get a response...

Peace

 

[Ufostrahlen]

I actually emailed the PI on this paper awhile back with a few questions and did not get a response...

Nice, but I wonder why he didn't respond... I mean you certainly asked the right questions and this topic obliviously deservers clarification/investigation. Have you addressed the Lisuride discrepancy?

 

[joedirt]

Good question. Here is the email I sent him

My name is XXXXXXX, I'm a medicinal chemist that has a side interest in the work you recently published. I was wondering if you happened to have the relative affinity profiles for serotonin, dopamine, and norepinephrine, and anandamide to match the panel of psychedelics you screened? What I'm thinking is it might be very useful to look at how the binding profile of these compounds differs from their natural neurotransmitters.

BTW I consider your paper ground breaking. It's been common knowledge for far to long that psychedelics elicit their response solely at the 5HT1a and 5HT2a receptors. I'm sure you must be aware of Dr Shulgins work. It would be awesome to take a study like your across the complete panel of known neurotransmitter receptors as well as all the compounds from Shulgins books TIHKAL and PIHKAL.

Sincerely
XXXXX

 

[joedirt]

One other thing to note. He is a zoologist and not a pharmacologist or med chemists... I'd like to see some follow up to his work to be honest...

 

[Ufostrahlen]

Too bad he didn't answer. The idea of studying the TIHKAL/PIHKAL compounds is good and a necessary task. The new acquired knowledge about 5-HT2B receptors now worries me
I don't take 5-HT2B receptors binding compounds too often (1-2x a month, threshold dose), but 2C-E playing in the same league as MDMA baffles me a bit. The psychedelic community should start a kickstarter campaign for an investigative study. I honestly doubt the numbers. McKenna did a study in 1989 where the discrepancy between DOB and Mescaline 5-HT2B values is huge, where Ray suggests identical affinities. The same applies for TMA and Psilocin. This definitely needs further research!

 

[Kohan]

Ya i have this study, the thing about the 1 ,2 ,3 ,4 scale is weird. The values less then 2 would be non-perceptible, then 4 would be totally perceptible or something like that. Of course it isn't potency cause LSD is way more potent then mescaline or even psilocin ..

It should be mention that Dr. Shulgin did have a heart valve operation not tooo long ago.

Psychedelic are less studied than MDMA and very much less abused then the latter.
Thus less psychedelic's cardiac fibrosis crisis in our emergency, thus less investigations.


I would love to see the receptor affinity for the new Nbomes and analogue like 5-Meo-AMT.
Would love to see what receptors is killing our youth.



Much love

 

[endlessness]

I think we`d hear about a lot more cases of cardiac issues related to psychedelics if that was so. Didn`t they investigated the health, including of heart, of the ayahuasca users in Brazil for the Hoasca project and found no damage? I`d have to check on that publication again. LSD has also been around long enough and people have taken enough that they`d probably be dropping like flies if it was such a neat correlation.

Taking "ecstasy" of unknown purity in uncontrolled conditions of possibly poor nutrition, excessive exercise and dehydration is hardly a valid assessment for the damage MDMA can cause to the heart.

The Shulgin heart problem example is purely anecdotical and a cherry pick, it does not indicate anything by itself. Did these people care to check Shulgin`s medical history, relevant genetic components, eating/exercise habits and other things, before even thinking of bringing up that example?

But yes, please keep us informed if you guys/gals research more on this issue and if there are more related papers.

 

[Auxin]

Well bitch, that took me a minute to figure out.
[Correct me if I'm wrong, anyone who was fore-thinking enough to take biochemistry in college...]
In this guys 0 to 4 system the numbers are not binding affinities! For each drug its the relative binding affinity based on a drugs affinity to the receptor to which it has the highest affinity, on a arbitrary(?) scale based on a negative logarithmic measure of actual binding affinity.
Said in another way, if a compound has a ranking of 4 for 5-HT2b that just means that of the receptor affinities tested for in that compound its highest observed affinity was to 5-HT2b, regardless of the actual physical affinity.

Like if you test joe and bob for cheeseburger and hamburger affinity.
joe eats a cheeseburger every day and a hamburger once a week, on this 0-4 scale joes cheeseburger affinity is 4
bob eats a cheeseburger every month and a hamburger twice a year, bobs cheeseburger affinity is also 4
4 alone wont tell us who is eating way too many damned cheeseburgers, only how well cheeseburgers are loved relative to hamburgers.

So the data presented wont say which compounds are likely to be a real-world problem if 5-HT2b agonism of psychedelics is linked to heart valvulopathy, right? We'd need the raw K(i) data, which he didnt include.

I got that right, ya? :lol:

 

[nen888]

..the compound may have a high binding affinity to a particular receptor subtype, but will almost always show binding affinities to other subytypes (even if weaker), and usually other classes of receptor, as well as having other actions..

any given compound has multiple receptor/inhibition activity, multiple actions..
which may in part explain the widely differing physiological and/or subjective actions of compounds which share a particular high binding affinity to a given receptor..