The 5-HT2B receptor, valvulopathy and the apparent safety of psychedelic drugs

[AA357]

Hi,

Recently I posted a thread in PD about my echocardiogram:
http://www.bluelight.org/vb/threads/763801-Echocardiography-of-a-heavy-2C-E-psychedelic-user

I had a transthoracic echocardiogram with doppler ultrasound (very, very thorough). The procedure lasted 20-30 minutes. My heart is strong and healthy and there are no signs of cardiomyopathy or valvulopathy.

I have been using psychedelics very heavily for the past 12 months: mostly 2C-E (about 2.5g), LSD (about 10mg) and DOM (at least 100mg). I trip multiple times per week and I dose heavily.

I do believe that excessive stimulation of 5HT2B receptors inevitably leads to valvulopathy (as evidenced by the high prevalence of valvulopathy among users of fenfluramine, MDA/MDMA and many ergoloids), but psychedelics don't activate this receptor strongly enough for this to be a realistic concern. Psilocin is probably the most abundant and commonly used psychedelic in the world. It is highly selective for 2B; yet there are no documented cases of psilocin-induced valvulopathy in humans. It is worth mentioning that humans have been eating shrooms for over 7,000 years.

I got a few interesting responses.
One poster commented that 2C-E is only a "weak partial agonist" at 2B and therefore a lot less likely to cause valvulopathy than fenfluramine and MD(M)A. If this is the case then why is methysergide - a partial agonist at 2B with an efficacy similar to that of psilocin - associated with valvulopathy (while psilocin isn't)?
This poster also pointed out that the majority of people who used fenfluramine didn't develop valvulopathy and another poster suggested that my heart is just 'remarkably resiliant' and that my findings don't mean anything.

What gives... are most people genuinely immune/extremely resiliant to 2B-related damage? Is 2B agonism from classical psychedelics really a non-issue or am I just one of those people who could take high doses of fenfluramine for years and get away scot-free?
If every psychedelic user tripped as often as I do, is it really likely that we would start to see a higher prevalence of valvulopathy? I find this extremely hard to believe given that there is no hard evidence out there to support this.

Thanks.

 

[mb-909]

If you want to take a look at a well dicussed thread:

http://www.reddit.com/r/DrugNerds/comments/2mqqww/psilocin_and_5ht2b_agonism_induced_cardiotoxicity/

A lot of information, so it will take some time to totally go through it.

So it's pretty well known that 5-HT2b agonists like fenfluramine, cabergoline and MDMA have the potential to cause the accumulation of collagen in heart valves which results in diseases caused valvulopathies (mostly a failure of the heart valve to completely seal). This was mostly an issue with the first two, which were medications administered daily. Despite lower frequency of use, regular MDMA users' hearts showed abnormalities including aortic regugitation in one retrospective study. However, these subjects had extremely high MDMA use (an average use of 3.6 "tablets" per week for 6 years), so it may not be at all relevant to people who space their rolls for other reasons.
Psilocybin is my favourite drug, and one that I'd like to think I can use relatively frequently without much cause for concern (up to bi-weekly). Unfortunately, compared to other classical hallucinogens it has the worst selectivity for the primary hallucinogenic 5-HT2a receptor over 5-HT2b: its kIs at these receptor are 107.2 nm and 4.6 nm respectively, compared with 127 nm vs 184 nm (DMT), 3.5 nm vs 30 nm (LSD) (values from this review). This study has the affinity data for the DOx class, which all show 5-HT2a selectivity.
My concern is that frequent psilocybin use may result in slight valvular fibrosis which has not been detected yet in users.
I tried to compare the risk associated with regular psilocybin use by means of a very rough estimate from the known threshold of cardiac effects from cabergoline, where 3 mg daily, used as a Parkinson's treatment, increases the risk of clinical valvular heart disease, while 0.5-2 mg twice a week over a 4 year period, taken for prolactinemia, does not seriously increase valvular regurgitation.
This is where there's a lot of extrapolation, but I can't see any other way to make an estimate of the cardiotoxic potential of psilocin:
A typical dose for cabergoline taken twice weekly (~1mg) is about 2 nmol, while a strongish mushroom trip (3.5g cubensis) is around 25 mg of psilocybin, or 120 nmol of psilocin. Both have an oral bioavaliability of around 50%. Their affinities for the 5-HT2b receptor are 1.17 (cabergoline) and 4.6 (psilocin). Their agonist efficacies compared to serotonin are 103% for cabergoline and 43% for psilocin at this receptor. The overall potency (EC50) of the two drugs as 5HT-2b agonists is 13 nM cabergoline and 58 nM for psilocybin. So psilocybin is about 4.5 fold less potent than cabergoline as an agonist here, but we're taking 50x as much. So hypothetically, if you were tripping twice a week, you'd be 10 fold over known non-cardiotoxic levels of a 5-HT2b agonist.
However, these drugs differ enormously in their half life. Psilocin has a half life of around 2.5 hours following oral psilocybin administration, while cabergoline has a half life of ~65 hours (from the prescribing information), so it will be exposed to cardiac fibroblasts for around 25X as long as psilocin. Extrapolating a very long stretch, a weekly mushroom trip is probably not going to cause cardiotoxicity.

(The assumption here that a short exposure to a high concentration agonist has the same effects as a longer, lower level of agonism is pretty implausible but I can't see an alternative.)
EDIT: Check out the data in my comment below regarding bromocriptine for a more pharmacologically and pharmacokinetically similar drug to psilocybin reported

Sources: Comment by Herperderperton on reddit

 

[serotonin2A]

Psilocin isn't highly selective for 5-HT2B. It would have to show >100-fold higher affinity for 5-HT2B vs any other receptor and that isn't the case.

 

[atara]

Psilocin is a partial agonist at 5-ht2b; methysergide is metabolized to methylergometrine. Additionally psilocin is functionally selective at all of the targets where we've thought to check. Additionally LSD & DOM have quite low 5-ht2b affinity relative to their 5-ht2a/1a/2c affinities.

 

[Zeds(NCO2CH2CH3)2]

Ok we need to not focus as much on the affinity and recognize the dosage rate of fenfen as taken in the studies which cited the toxicity. 5ht2b utilizes different intracellular pathways with contribute to fibrotic changes as far as I know thereby causing this issue. I have a feeling Fenfen has more pristine PK and distribution then all the above examples listed..

 

[MocCozmiK]

Serotonin2a and atara - You say that psilocin is a partial agonist of the 5HT2b receptor. Do you have any sources to cite? If so can you please provide them. I am asking not to prove anyone wrong or argue what "I" think. I am looking for legitimate sources and claims and proof for investigational reasons.

Sorry I bumped this thread but I am looking and researching as much as I can on this subject. And in my research I have found many interesting facts regarding Psilocins affinity for the 5HT2B receptor

 

[serotonin2A]

Serotonin2a and atara - You say that psilocin is a partial agonist of the 5HT2b receptor. Do you have any sources to cite? If so can you please provide them. I am asking not to prove anyone wrong or argue what "I" think. I am looking for legitimate sources and claims and proof for investigational reasons.

Sorry I bumped this thread but I am looking and researching as much as I can on this subject. And in my research I have found many interesting facts regarding Psilocins affinity for the 5HT2B receptor

There are a few studies that have conducted functional assays. Here is one:

http://www.sciencedirect.com/science/article/pii/S0960894X05008735?via=ihub

I can dig up others if that is not sufficient.

 

[MocCozmiK]

Thank you for that source. Do you have anymore. I have a few. I am worried that the use of psilocin intravenously had caused me some sort of valvular heart issue. The sources I have read said that psilocin had high affinity for 5HT2B receptor.
So now I am concerned.

 

[Volsam]

Imo what else is important is the half-life of the chemical that acts on 5HT-2B receptor. Fenfluramine's half-life, for example, is about 20 hours. So that's about 30-40 hours of non-stop activation of 5HT-2B receptors in the body, compare to about 3 hours of half-life for Psilocin, so 4-7 hours of acting.

 

[Solipsis]

It does make sense that it would be a combination of how long you have a 5-HT2B agonist in your blood from a dose, how big the dose is, and how high the efficacy at that receptor.

Not sure how often IV psilocin we're talking about, but if it just on occasion then it should be fine: IV or other ROAs should not matter for psilocin ending up in your blood apart from IV being more potent (so you probably required a lower dose to offset / compensate for that). This fibrosis seems like a developmental problem, similar to some hypertrophy that grows over time if 5HT2B is activated often. Not sure but it sounds unlikely that incidental use would cause acute cases of such fibrosis?

Psilocin may have high affinity for 5-HT2B but it doesn't last all that long and the activity at 5-HT2A allows you to need a dose that is not in the hundreds of mg's. Some stimulant that lasts all day and is efficacious at 5-HT2B and that requires taking hundreds of mg's to get an effect mediated by unrelated MOAs seem much worse. Not sure what the affinity or efficacy of MDMA for 5-HT2B is, but considering the doses are not low it could be more of an issue by comparison, even worse if you take MDA or perhaps certain longer acting benzofurans regularly...

LSD and DOM sound particularly okay since despite their durations the efficacy is expected to be low and the doses are also quite low.

It's not necessarily easy to quantitatively compare the harm using that efficacy x duration x dose (x frequency of use of course) formula - you think it gives a fair approximation? It might not, if there is some threshold above which you especially get fibrosis, in a non-linear fashion. If it's linear it could give a fair idea?

Partial agonist just means it's not as efficacious as the corresponding endoligand (serotonin here), right? So 'partial agonist' doesn't necessarily equal low efficacy and shouldn't be too impressive of a term here, it's just not super high efficacy. Correct?

The affinity of methylergonovine for 5-HT2B is really high by the way, even compared to norfenfluramine, and higher than 5-HT which makes it a full agonist / superagonist.

 

[serotonin2A]

The affinity of methylergonovine for 5-HT2B is really high by the way, even compared to norfenfluramine, and higher than 5-HT which makes it a full agonist / superagonist.

Whether or not a ligand is a full agonist depends on efficacy and has nothing to do with affinity.

 

[Solipsis]

Alright that was really foolish since I tried that make that point a sentence earlier To be fair, I may have read that it is indeed highly efficacious in the same source:

Methysergide acts as a partial agonist at the 5-HT2B receptor, while the metabolite methylergonovine has even greater affinity and efficacy.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2695569/

Hmm apparently methylergonovine has a lower 5-HT2B Kact than 5-HT, but turns out not to be a full agonist after all unless I'm mistaken:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2695569/table/T3/

 

[serotonin2A]

Alright that was really foolish since I tried that make that point a sentence earlier To be fair, I may have read that it is indeed highly efficacious in the same source:



https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2695569/

Hmm apparently methylergonovine has a lower 5-HT2B Kact than 5-HT, but turns out not to be a full agonist after all unless I'm mistaken:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2695569/table/T3/

Yes, according to the table, methylergonovine has 40% efficacy at 5-HT2B, making it a partial agonist.

 

[Cotcha Yankinov]

Just for the sake of argument, could it be the case that a receptor is coupled to 4 different pathways, only one of which may cause problematic proliferation of fibroblasts, and a ligand that appears to have 25% efficacy meausred across the signaling cascades is technically a full agonist (biased ligand) with respect to the fibrosis pathway in question?

Essentially, could a biased ligand that is a full agonist for whatever it is biased for appear to be a partial agonist if a study isn't carefully conducted?

Worst case scenario the ligand is a super agonist at the fibrosis cascade (if there is a particular fibrosis cascade) but if compared against the activation of pathways that serotonin produces a response in, it appears to be a partial agonist.

I've never really found anything about how fibroblasts actually get activated - do the fibroblasts express 5-HT2B or something?

 

[serotonin2A]

Just for the sake of argument, could it be the case that a receptor is coupled to 4 different pathways, only one of which may cause problematic proliferation of fibroblasts, and a ligand that appears to have 25% efficacy meausred across the signaling cascades is technically a full agonist (biased ligand) with respect to the fibrosis pathway in question?

Essentially, could a biased ligand that is a full agonist for whatever it is biased for appear to be a partial agonist if a study isn't carefully conducted?

Worst case scenario the ligand is a super agonist at the fibrosis cascade (if there is a particular fibrosis cascade) but if compared against the activation of pathways that serotonin produces a response in, it appears to be a partial agonist.

I've never really found anything about how fibroblasts actually get activated - do the fibroblasts express 5-HT2B or something?

The situation you described is always a possibility, but agonists are assumed to be unbiased unless other evidence emerges.

Fibroblasts express 5-HT2B receptors.

 

[Cotcha Yankinov]

So theoretically a 5-HT2B agonist could cause fibrosis wherever there are fibroblasts?

Some ecstasy users have reported issues with compression neuropathy (sometimes severe) and weird musculoskeletal issues with onset just after ecstasy use, consistent with myofascial problems. I've always wondered if a 5-HT2B agonist could contribute to developing tissue fibrosis that could compress peripheral nerves, but all I've ever really heard about is cardiac fibrosis. Unfortunately it's not like nerve conduction studies pick up nerve compression until there is degeneration, whereas VHD is probably quite more apparent diagnostically.

I imagine a scenario where there is heavy overuse of a muscle group and inflammation (whatever conditions lead to natural fibroblast activation) and then the 5-HT2B agonist potentiates things. I wonder if just as Toll-Like Receptors can be upregulated on "activated microglia", if receptors/cascades that ultimately lead to fibrosis can be upregulated on "activated" fibroblasts, especially in a vulnerable population (people with weird collagen and hypermobility syndrome comes to mind).

 

[MocCozmiK]

It does make sense that it would be a combination of how long you have a 5-HT2B agonist in your blood from a dose, how big the dose is, and how high the efficacy at that receptor.

Not sure how often IV psilocin we're talking about, but if it just on occasion then it should be fine: IV or other ROAs should not matter for psilocin ending up in your blood apart from IV being more potent (so you probably required a lower dose to offset / compensate for that). This fibrosis seems like a developmental problem, similar to some hypertrophy that grows over time if 5HT2B is activated often. Not sure but it sounds unlikely that incidental use would cause acute cases of such fibrosis?

Psilocin may have high affinity for 5-HT2B but it doesn't last all that long and the activity at 5-HT2A allows you to need a dose that is not in the hundreds of mg's. Some stimulant that lasts all day and is efficacious at 5-HT2B and that requires taking hundreds of mg's to get an effect mediated by unrelated MOAs seem much worse. Not sure what the affinity or efficacy of MDMA for 5-HT2B is, but considering the doses are not low it could be more of an issue by comparison, even worse if you take MDA or perhaps certain longer acting benzofurans regularly...

LSD and DOM sound particularly okay since despite their durations the efficacy is expected to be low and the doses are also quite low.

It's not necessarily easy to quantitatively compare the harm using that efficacy x duration x dose (x frequency of use of course) formula - you think it gives a fair approximation? It might not, if there is some threshold above which you especially get fibrosis, in a non-linear fashion. If it's linear it could give a fair idea?

Partial agonist just means it's not as efficacious as the corresponding endoligand (serotonin here), right? So 'partial agonist' doesn't necessarily equal low efficacy and shouldn't be too impressive of a term here, it's just not super high efficacy. Correct?

The affinity of methylergonovine for 5-HT2B is really high by the way, even compared to norfenfluramine, and higher than 5-HT which makes it a full agonist / superagonist.

Ok thank you. I feel less anxiety about it now. I understand what you said. The research I have been doing is a lot of science write ups. And they are not so easy for me to understand.

Thanks man

 

[MocCozmiK]

Imo what else is important is the half-life of the chemical that acts on 5HT-2B receptor. Fenfluramine's half-life, for example, is about 20 hours. So that's about 30-40 hours of non-stop activation of 5HT-2B receptors in the body, compare to about 3 hours of half-life for Psilocin, so 4-7 hours of acting.

Good info to know. Thank you

 

[Xzbtya]

The FDA report on the cardiotoxicity of fenfluramine and reasoning for pulling it off the market is relatively interesting: https://www.cdc.gov/mmwr/preview/mmwrhtml/00049815.htm

As of September 30, FDA had received 144 individual, provider-initiated (i.e., "spontaneous") reports involving fenfluramine or dexfenfluramine, with or without phentermine, in association with valvulopathy (this total included the 24 publicly reported cases {1}). Minimal degrees of regurgitation (i.e., trace or mild mitral regurgitation {MR} or trace aortic regurgitation {AR}) are relatively common in the general population and are not generally considered abnormal. Therefore, in this analysis, a case of fenfluramine- or dexfenfluramine-associated cardiac valvulopathy was defined as documented AR of mild or greater severity and/or MR of moderate or greater severity after exposure to these drugs. Of the 132 spontaneous reports with complete information, 113 (86% ) met the case definition. Of these 113 cases, 111 (98% ) occurred among women; the median age of case-patients was 44 years (range: 22-68 years). Of these 113 cases, two (2% ) used fenfluramine alone; 16 (14% ), dexfenfluramine alone; 89 (79% ), a combination of fenfluramine and phentermine; and six (5% ), a combination of all three drugs. None of the cases used phentermine alone. The median duration of drug use was 9 months (range: 1-39 months). Overall, 87 (77% ) of the 113 cases were symptomatic. A total of 27 (24% ) case-patients required cardiac valve-replacement surgery; of these, three patients died after surgery.

Overall the rate of cardiac issues appear to be much higher in female users than male (20% vs 12% ) out of a sample population of 5200. Fenfluramine is also still available in some countries around the world. Someone mentioned the benzofurans earlier. Apparently 5/6-APB are extremely potent agonists of 5HT-2B with Ki's at 14/3.7nM respectively. Compared with norfenfluramine +/- which have values of 10-50nM. From what I can find the affinity of MDMA for 5HT-2 receptors in general is much lower than that of the other compounds I've mentioned with R(-) MDMA having the highest affinity at 3.3uM or 3300nM. So 66 to 330 times less potent than norfenfluramine and almost 1000 times less potent an inhibitor than 5-APB.

Assuming the worst case scenario that they are all agonists in the same way (activating whatever pathway damages the heart), coupled with the percentages of people that actually experienced damage from chronic use of fenfluramine I would venture that chronic psychedelic use is probably more likely to cause other issues before doing damage to your heart. Especially since many of the classical psychedelics are self-limiting in terms of abuse potential. I might steer clear of using those APBs on a regular basis though.

 

[WSH]

It is my opinion that the use of psychedelic 5-ht2b agonists is safe when taken at most weekly.
However, i would NEVER use them more than once week!