Regular Empathogen Use and Heart Valve Disease?

[Lady Codone]

As a fan of stimulant/empathogens, the fear of pulmonary hypertension/heart valve disease is always in the back of my mind. (There's tons of research linking 5HT2b agonists like fenfluramine with these conditions...something about it triggering overgrowth of cardiac tissue by latching onto serotonin receptors on the heart or smtg).

Obviously, occasional MDMA use is unlikely to cause a chronic health condition like heart valve disease. But what about daily/regular use of less potent empathogens like 4-FA, methylone or 4-EMC? Is there something different about fenfluramine that triggers these problems, or are all empathogens equally cardiotoxic? Are there any supplements or lifestyle changes that can help offset this specific type of cardiac damage?

Sorry if this is in the wrong section. I can't seem to find anything about this topic online. (Please avoid talk of neurotoxicity or other side effects, as there's plenty of discussion about that already).

 

[sekio]

Norfenfluramine is a particularly strong selective 5-ht2b agonist that caused the phen-fen shit, & it was administered in chronic dosing.

Lots of drugs have notable affinity for 5-ht2b but none of these is cardiotoxic per se. At least other toxicity like serotonin depletion or psychosis sets in before your heart valves go.

From PLoS ONE:

5ht2b: 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, 0.69 5-MeO-DMT

Larger number = greater affinity for the receptor. However most of these drugs have been demonstrated to not be notably valvotoxic in the course of human use.

It is also important to note that just because a compound binds tightly to a receptor does not always mean it will activate it.

Tl;dr: Norfenfluramine was something like >150% serotonin's efficacy at 5-ht2b, and was fairtly selective. Most psychedelics aren't anywhere near as selective or efficacious at 5-ht2b, and few people use them every day like fenfluramine was Rx'd.

 

[Dr. Drugs]

Actually, there's reason to believe that recreational serotonergics can cause heart valve damage. A 2003 study showed that MDMA and MDA can cause heart valve damage cells in-vitro, causing the same type of damage as seen in fenfluramine use.
Link: http://www.ncbi.nlm.nih.gov/pubmed/12761331

A 2007 study found multiple signs of valve damage in a cohort of MDMA users (n=29). http://www.ncbi.nlm.nih.gov/pubmed/17950805

Eight subjects (28%) who took MDMA had abnormal echocardiographic results using the United States Food and Drug Administration's criteria for appetite suppressant-induced valvular heart disease, compared with none in the control group (p = 0.0045). Six (21%) subjects had mitral regurgitation of 1/4 and 4 (14%) of > or =2/4, compared with none in the control group (p = 0.002). The mean mitral regurgitant area ratios (jet/atrium) were 12 +/- 9.8% and 5 +/- 1.3%, respectively (p = 0.007). Tricuspid regurgitation > or =2/4 was present in 13 MDMA users (45%) and absent in controls (p <0.001). The mean tricuspid regurgitant area ratios were 19 +/- 9.5% and 9 +/- 4.5%, respectively (p <0.001). Four MDMA users (14%) had mild aortic regurgitation (p = 0.11). Valvular "strands" were present in 6 MDMA users (21%) and in none of the controls (p = 0.02). In conclusion, MDMA may lead to mild to moderate valvular heart disease and valvular strands.

So, basically, there's a decent chance that MDMA and probably most of the empathogenic RC's cause a certain amount of heart valve damage. How much, exactly,. is hard to say. Daily use is definitely going to be more dangerous than occasional, so take it easy.

It's interesting to note that Alexander Shulgin had heart valve replacement surgery in 2008. It's impossible to know whether it was caused by his long-time use of serotonergic drugs or just old age, but it's something to think about.

 

[Achten]

I like MDMA, MDAI and a whole range of psychedelics a LOT, but nearly everyday usage ?
I can trip two days in a row but after that it gets boring, doesn't feel right.
Are your trips more or less equally strong ? Or have you noticed like a lower maximum high, after long repeated use ?

 

[pofacedhoe]

the big question is what about mephedrone which people were taking with far greater regularity than mdma?

 

[golden1]

If it was due to the sole fact of serotonin release wouldn't mao-a inhibitors cause a similar effect on the growth of heart valves? I know there is a clear difference, but both raise the serotonin that would be binding to heart 5ht2b receptors, no? So, it would have to be the compound's affinity itself @ 5ht2b making them cardiotoxic.. atleast from how I'm seeing it now.

 

[Dr. Drugs]

If it was due to the sole fact of serotonin release wouldn't mao-a inhibitors cause a similar effect on the growth of heart valves? I know there is a clear difference, but both raise the serotonin that would be binding to heart 5ht2b receptors, no? So, it would have to be the compound's affinity itself @ 5ht2b making them cardiotoxic.. atleast from how I'm seeing it now.

That's how I understand it as well. It seems like the damage is caused by 5-HT2b agonists other than 5-HT itself.
For example, SSRI's aren't associated with heart valve damage. (citation: PMID 11305992) They raise serotonin levels (the 5-HT transporter is expressed in the heart too) but don't have significant affinity for 5-HT2b themselves.

 

[deckmunki]

the big question is what about mephedrone which people were taking with far greater regularity than mdma?

Good question. I got myself into a pretty bad cycle of chronic use too. This paragraph in Wikipeeja suggests a similar level of serotonin increase for mephedrone as MDMA, although the page itself is light on figures (I didn't check the source for details - too lazy, plus nobody ever lies on Wikipedia, right...?)

http://en.wikipedia.org/wiki/Mephedrone#Pharmacology

 

[sekio]

Serotonin release does not cause cardiotoxicity. Direct overactivation of 5-HT2b does.

It remains to be seen whether cathinones bind to 5-ht2b. My gut instinct is they do not.

 

[al-laddin]

Norfenfluramine is a particularly strong selective 5-ht2b agonist that caused the phen-fen shit, & it was administered in chronic dosing.

Lots of drugs have notable affinity for 5-ht2b but none of these is cardiotoxic per se. At least other toxicity like serotonin depletion or psychosis sets in before your heart valves go.

From PLoS ONE:


Larger number = greater affinity for the receptor. However most of these drugs have been demonstrated to not be notably valvotoxic in the course of human use.

It is also important to note that just because a compound binds tightly to a receptor does not always mean it will activate it.

Tl;dr: Norfenfluramine was something like >150% serotonin's efficacy at 5-ht2b, and was fairtly selective. Most psychedelics aren't anywhere near as selective or efficacious at 5-ht2b, and few people use them every day like fenfluramine was Rx'd.

So in the chart it states both MDA and psilocin have the same affinity to 5ht2b. MDMA is not listed but Im going to take a shot in the dark and assume its at 4.0 or more considering the heart damage articles DR. DRugs linked too. That or MDMA is far more "abused" than say mushrooms or other drugs that effect 5ht2b. Are just a few points higher or lower significant here? I mean LSD is at a low 3.11. How much safer for the heart valve does this number suggest? And does LSDs receptor promiscuity have any effect on the heart toxicity level? Does this have to do with receptor affinity ratio maybe in the same way as the ratio of CBD to THC in cannabis effects how psychoactive the said strain is? For example from my understanding you can have a plant that is very high in THC but for it to be strongly psychoactive the CBD levels must remain low. Perhaps a particular psychedelics high binding affinity to 5ht2b may be negated by said drugs balanced binding to other 5ht receptors?

 

[Black]

Serotonin release does not cause cardiotoxicity. Direct overactivation of 5-HT2b does.

It remains to be seen whether cathinones bind to 5-ht2b. My gut instinct is they do not.

how would they then release serotonin?

from the supporting data from this paper:

of course that's only affinity data and gives no indication of efficacy.

as expected, (the more popular/pleasant) empathogens have an affinity here, while the stimulants do not.
the only thing that really confuses me is MDAI...

 

[sekio]

how would they then release serotonin?

Binding to SERT or 5ht1a or any number of other serotonin-related protiens?

 

[Black]

Binding to SERT or 5ht1a or any number of other serotonin-related protiens?

binding to sert afaik doesn't result in serotonin release. sert is necessary for 5-ht2b-mediated release and of course reuptake inhibition increases the available 5-ht, but i don't know how affecting only the transporter could result in release.
5-ht1a is interesting, being an inhibitory autoreceptor, it would need an antagonist to release serotonin that way. same with 5-ht1b.
that's still no explanation for mdai (no affinity there either, in fact, now that i'm looking at the whole table again, they found no affinity for anything except alpha2 receptors. that doesn't look quite right...)

 

[WSH]

binding to sert afaik doesn't result in serotonin release. sert is necessary for 5-ht2b-mediated release and of course reuptake inhibition increases the available 5-ht, but i don't know how affecting only the transporter could result in release.

Yes, MDMA binds to both 5-ht2b and SERT and when 5-ht2b is selectively antagonized, the 5-ht-release is completely abolished, therefore it's clear that the SERT binding isn't enough for release, both SERT binding AND 5-ht2b-agonism are necessary for 5-ht-release:
http://www.ncbi.nlm.nih.gov/pubmed/18337424

 

[endotropic]

Yes, MDMA binds to both 5-ht2b and SERT and when 5-ht2b is selectively antagonized, the 5-ht-release is completely abolished, therefore it's clear that the SERT binding isn't enough for release, both SERT binding AND 5-ht2b-agonism are necessary for 5-ht-release:
http://www.ncbi.nlm.nih.gov/pubmed/18337424

That was my understanding as well, but how do reconcile the lack of 5-HT2B affinity (shown above) with the known 5-HT releasing effects of MDAI?

 

[Black]

Yes, MDMA binds to both 5-ht2b and SERT and when 5-ht2b is selectively antagonized, the 5-ht-release is completely abolished, therefore it's clear that the SERT binding isn't enough for release, both SERT binding AND 5-ht2b-agonism are necessary for 5-ht-release:
http://www.ncbi.nlm.nih.gov/pubmed/18337424

i thought SERT-binding was not necessary for serotonin release. i sadly cannot find a source now, but iirc the apb's have no affinity for SERT and release serotonin in (at least) a similar magnitude. to me it looks like binding to 5-ht2b is enough for SERT reversal atm.

@endotropic
i'll save myself some typing and paste a little chart about mdai (that's hopefull not going to take up too much space) :

that it has no affinity at all for any serotonin receptor and neither for SERT sounds a bit fishy to me. also these supplementary data just consist of a table with numbers without any explanation (i still imagine that if they didn't test receptors with this compound, they'd put n.d. instead of 0). do we have some independant data on mdai? some nichols paper?

edit: the original image did take up too much space.

 

[WSH]

i sadly cannot find a source now, but iirc the apb's have no affinity for SERT and release serotonin in (at least) a similar magnitude.

6-apb has an affinity of about 2700nm @ SERT and 5-apb about 800nm, but yes, it's true that the importance of the SERT binding isn't clear, the only thing we know for sure is that 5-ht2b-agonism is absolutely necessary for mdma's 5-ht-release.