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

[Weltmeister]

Using them weekly (or even more) will probably bring about mental health problems anyway

 

[WSH]

Using them weekly (or even more) will probably bring about mental health problems anyway

Yes, Terence McKenna also tried to use them daily (as a "dietary supplement" as he called it LOL) and he found that within maybe a week he became quite psychotic!

 

[Solipsis]

Using them weekly (or even more) will probably bring about mental health problems anyway

Seems like some sort of heuristic assumption but in my experience, not really not necessarily. The impact the trips have are much more important and can mean that you absolutely need time to integrate them, but I don't get those kinds so dramatic anymore that they really change me, weekly use can be okay IMO, just made me less sketical mostly.

Dosing daily is different and would have to be microdosing which is another topic, or heavy dosing to compensate for tolerance which is also another story. I think Leary et al have also reported on it without anything too serious, but yeah going in heavily requires a strong constitution, and (also @ mentioned mcKenna) sure it will always be hazardous simply because you are not allowing yourself to come up for air, to harmonize the crazy psychedelic with the sober. It just should never start leading a life of it's own.

 

[MocCozmiK]

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!

What about using something like IV psilocin or 4-Aco-dmt weekly? For about about 2 months. Can that use cause heart fibroblast or valvular damage

 

[markosheehan]

Take yohimbine and certain supplements like PQQ and resveratrol and you should be fine.
Why don't you just IV psilocin and then go and get an echo cardiogram and see if there are any changes and if there aren't you can keep doing it. Echo cardiogram are cheap and easy to get and should detect changes in heart structure. If there is a change just stop doing it.

 

[markosheehan]

"Psilocybin is not cardiotoxic due to 5ht2B agonism unless combined with MAO-A inhibitors or taken daily. Usually when drugs have high binding affinity for receptors and you take a high dose OR you get excess serotonin release due to both dual action of 5HT releasing and MAO-inhibitor action ( like cathinones or some research chemicals ). Often you get a cascade reaction - when high levels of neurotransmitters are released due to one receptor another one gets triggered/activated . This is why you have different effects at different dosages.

5HT2B affinity of psilocybin is too low to pose any threat to health. 5HT2B receptor however prevents or decrease serotonin syndrom, that is why people don't get serotonin syndrom from research chemicals unless they thake MAO-inhibitor or anti-depressants along with drugs.

You have to compare to other drugs like research chemicals for example benzofurans like 5-APB and 6-APB are releasers , reuptake inhibitors and have Monoamine oxidase inhibition activity. 6-APB has 5HT2B 3.5 or 3.7 ki value. That one point difference is huge when translated to micromolar saturation between neurons and synapses. Recalling from my head LSD had about around 1 ki value for almost all targeted 5HT receptors which is huge. Psilocybin binds to Serotonin transporters(SERT) and basically bumping endogenous monoamines of SERT, this is pretty much the same mechanism of SSRI.

All the compounds in psilocybin mushrooms are metabolized rather quickly but because it binds to SERT you have a pretty long subjective half-life of the effects. oral passage 163±64 minutes is about the normal half life for psilocybin. That doesn't translate to the 6 hours of effects people feel. If you get some research chemicals with a a half life of 2 hours and are purely releasers, you will stop feeling anything after those 2 hours. Normally it would be about 4 hours but due to downregulation the other half won't really have an effect. Also with psilocybin you have downregulation ( tolerance) so in theory you shouldn't peak after 3 hours.

When it binds to the SERT the SERT will eventually be broken down by MAO-A displacing the psilocybin from the SERT , however if you take MAO-A inhibitors, transporters won't be broken down resulting in more transport across the synaptic cleft. Thus the psilocybin you take only a small fraction will be transported across the synaptic cleft. Taking a MAO-A inhibitor like syrian rue will approximately result in a 3x to 4x increase of psilocybin forwarded to the synapses ( thus resulting in stronger 5HT2B receptor activation. The more Psilocybin reaches the receptors in the synaps the more this 5HT2B receptor will be activated. Also psilocybin has little A1 and A2 affinity. LSD is not a releaser of 5HT but also binds to SERT.

The normal dose of psilocybin will not result in for example fibrosis of heartvalves. The saturation is just too low and the half life too short. You cannot redose psilocybin over and over like research chemicals due this mechanism.Binding to A1 and A2 ( adrenergic ) receptors also cause sudden heart failure , hyperthrophy and myraid of other problems due to overstimulation of the parasympathic nerves. LSD has pretty strong affinity for dopamine and adrenergic receptors which probably would the main cause of cardiotoxicity.

Fenfluramine is a very potent 5HT2B agonist and its metabolite is also such agonist , it is both a releaser ( cause vesicles or boutons to release 5HT or other mono amines) and reuptake inhibitor ( causing transporters not to reuptake 5HT back into the neuron). Fenfluramine is cardiotoxic as hell because of this dual or triple mechanism, 5-APB and 6-APB ( triple mechanism) are probably very cardiotoxic as well because it also cause depletion of serotonin in vesicles. Psilocybin does not cause depletion because it only binds to transporters thus resulting in lower 5HT saturation than potent releasers i described before, psilocybin mimics serotonin on the transporters. It just not comes down to pure affinity values.

If you use a releaser which depletes the vesicles storing mono amines like serotonin, once the vesicle gets depleted or near depletion it gets destroyed/deleted - this is especially the case when you use a reuptake inhibitor and/or MAOI because serotonin gets only released and forwarded , not moved back into the neuron. Psilocybin mimics serotonin and binds to a transporter instead of emptying the vesicles( mono amine or 5HT storage. Re uptake inhibtors do not cause empyting and deletion of storage vesicles they only cause a lower density of certain receptors on long term due to downregulation. Drugs that depletes vesicles like most research chemicals cause a increase in receptor density probably because after drug use you have both 1. downregulation and 2. less serotonin coming off vesicles due to deletion of boutons/vesicles and 3. MAO inhibition being active for some time ( 5 and 6-APB also have MAO-inhibition)"

no one seems to mention psilocin is not a serotonin releaser

 

[serotonin2A]

"Psilocybin is not cardiotoxic due to 5ht2B agonism unless combined with MAO-A inhibitors or taken daily. Usually when drugs have high binding affinity for receptors and you take a high dose OR you get excess serotonin release due to both dual action of 5HT releasing and MAO-inhibitor action ( like cathinones or some research chemicals ). Often you get a cascade reaction - when high levels of neurotransmitters are released due to one receptor another one gets triggered/activated . This is why you have different effects at different dosages.

5HT2B affinity of psilocybin is too low to pose any threat to health. 5HT2B receptor however prevents or decrease serotonin syndrom, that is why people don't get serotonin syndrom from research chemicals unless they thake MAO-inhibitor or anti-depressants along with drugs.

You have to compare to other drugs like research chemicals for example benzofurans like 5-APB and 6-APB are releasers , reuptake inhibitors and have Monoamine oxidase inhibition activity. 6-APB has 5HT2B 3.5 or 3.7 ki value. That one point difference is huge when translated to micromolar saturation between neurons and synapses. Recalling from my head LSD had about around 1 ki value for almost all targeted 5HT receptors which is huge. Psilocybin binds to Serotonin transporters(SERT) and basically bumping endogenous monoamines of SERT, this is pretty much the same mechanism of SSRI.

All the compounds in psilocybin mushrooms are metabolized rather quickly but because it binds to SERT you have a pretty long subjective half-life of the effects. oral passage 163±64 minutes is about the normal half life for psilocybin. That doesn't translate to the 6 hours of effects people feel. If you get some research chemicals with a a half life of 2 hours and are purely releasers, you will stop feeling anything after those 2 hours. Normally it would be about 4 hours but due to downregulation the other half won't really have an effect. Also with psilocybin you have downregulation ( tolerance) so in theory you shouldn't peak after 3 hours.

When it binds to the SERT the SERT will eventually be broken down by MAO-A displacing the psilocybin from the SERT , however if you take MAO-A inhibitors, transporters won't be broken down resulting in more transport across the synaptic cleft. Thus the psilocybin you take only a small fraction will be transported across the synaptic cleft. Taking a MAO-A inhibitor like syrian rue will approximately result in a 3x to 4x increase of psilocybin forwarded to the synapses ( thus resulting in stronger 5HT2B receptor activation. The more Psilocybin reaches the receptors in the synaps the more this 5HT2B receptor will be activated. Also psilocybin has little A1 and A2 affinity. LSD is not a releaser of 5HT but also binds to SERT.

The normal dose of psilocybin will not result in for example fibrosis of heartvalves. The saturation is just too low and the half life too short. You cannot redose psilocybin over and over like research chemicals due this mechanism.Binding to A1 and A2 ( adrenergic ) receptors also cause sudden heart failure , hyperthrophy and myraid of other problems due to overstimulation of the parasympathic nerves. LSD has pretty strong affinity for dopamine and adrenergic receptors which probably would the main cause of cardiotoxicity.

Fenfluramine is a very potent 5HT2B agonist and its metabolite is also such agonist , it is both a releaser ( cause vesicles or boutons to release 5HT or other mono amines) and reuptake inhibitor ( causing transporters not to reuptake 5HT back into the neuron). Fenfluramine is cardiotoxic as hell because of this dual or triple mechanism, 5-APB and 6-APB ( triple mechanism) are probably very cardiotoxic as well because it also cause depletion of serotonin in vesicles. Psilocybin does not cause depletion because it only binds to transporters thus resulting in lower 5HT saturation than potent releasers i described before, psilocybin mimics serotonin on the transporters. It just not comes down to pure affinity values.

If you use a releaser which depletes the vesicles storing mono amines like serotonin, once the vesicle gets depleted or near depletion it gets destroyed/deleted - this is especially the case when you use a reuptake inhibitor and/or MAOI because serotonin gets only released and forwarded , not moved back into the neuron. Psilocybin mimics serotonin and binds to a transporter instead of emptying the vesicles( mono amine or 5HT storage. Re uptake inhibtors do not cause empyting and deletion of storage vesicles they only cause a lower density of certain receptors on long term due to downregulation. Drugs that depletes vesicles like most research chemicals cause a increase in receptor density probably because after drug use you have both 1. downregulation and 2. less serotonin coming off vesicles due to deletion of boutons/vesicles and 3. MAO inhibition being active for some time ( 5 and 6-APB also have MAO-inhibition)"

no one seems to mention psilocin is not a serotonin releaser

There are a number of misstatements and factually incorrect information in your post.

First, psilocybin is a prodrug for psilocin, so it makes no sense to expect the half-life of psilocybin to match its subjective duration.

Second, you are not correct about psilocybin having no risk of cardiotoxicity. Psilocybin may not have extremely high 5-HT2B affinity, but its active metabolite psilocin does have high affinity for 5-HT2B receptors (Ki = 4.6 nM).

Direct 5-HT2B agonism is sufficient to produce cardiotoxicity, as evidenced by the fact that some ergot alkaloids (e.g., ergotamine and methysergide, which do not release 5-HT) are cardiotoxic. Even for drugs that act as mixed 5-HT2B agonists and 5-HT releasers only the former mechanism will come into play because released 5-HT can't bind to 5-HT2B receptors that are occupied by a direct agonist.

You wrote at length about the importance of the interaction between psilocybin/psilocin and SERT, but in actuality this interaction is unlikely to occur in vivo. Psilocin has micromolar affinity for SERT (Ki = 3801 nM), but it has nM affinity for 5-HT2A receptors (Ki = 25 nM), meaning that it is unlikely to produce appreciable SERT inhibition in vivo. The concentration of psilocin in the body is in the hundreds of nM range, which is consistent with a mechanism-of-action involving 5-HT2A receptors, but too low to produce appreciable interaction with SERT.

SERT isn't broken down by MAO.

MAO inhibitors don't release serotonin, but rather increase the amount of serotonin that is stored and released in vesicles.

No studies have ever examined whether MAO inhibitors alter brain levels of psilocybin, so I'm not sure where you are getting these numbers. Psilocybin probably doesn't even get into the brain due to its chemical properties, so studies would be looking at psilocin and not psilocybin, but in any case you are citing an experiment that has yet to be conducted.

LSD does not bind to SERT.

 

[markosheehan]

well how come there have been no studies linking psilocin to being cardiotoxic. we all know so well what drugs are cardiotoxic so why cant we say psilocin is cardiotoxic? ECG is not affected by psilocin administration

 

[Cotcha Yankinov]

I imagine you would have to have a pretty significant lifetime usage of mushrooms, but perhaps it could be noted in people who microdose daily long term or people who have taken large doses a few times a week for many years.

But I'm not aware of a study that has checked for fibrosis in chronic hallucinogen users (only ecstasy users). It seems like mental side effects could limit the lifetime dosage of hallucinogens while some people may be able to chronically abuse substituted amphetamines.

One issue is that people develop some valvular heart disease as they age anyways.

In the case of substituted amphetamines, there is a case report or two of cardiac fibrosis from E but I'm not sure about this one study showing valvular heart disease in young adult ecstasy abusers. About 30% of the young adults in that study had some (mild) valvular heart disease with 0% in the control group. Hard to say whether or not we should take that study with a grain of salt.

 

[serotonin2A]

well how come there have been no studies linking psilocin to being cardiotoxic. we all know so well what drugs are cardiotoxic so why cant we say psilocin is cardiotoxic? ECG is not affected by psilocin administration

Because compared to something like fenfluramine, very few people ingest psilocybin. Furthermore, fenfluramine was taken chronically, whereas psilocybin is typically used much more sporadically. So even if psilocybin can cause valvulopathy, it is unlikley that there would be more than a few cases that have occurred.

Even if psilocybin use has induced valvulopathy in a few individuals, it is unlikely that such effects would be linked back to psilocybin. Valvulopathy can occur spontaneously, and the doctors treating such patients might not be aware of the psilocybin use. Even if they were aware of psilocybin use, linking the valvulopathy back to psilocybin would be extremely difficult because the population of psilocybin users is very small, meaning that it would be extremely difficult to demonstrate a link.

 

[markosheehan]

psilocins efficacy to the receptor is very small .

many people take psilocybin . people have been taking it for hundreds of years

we know 5 apb is cardiotoxic for this reason so why would we not know psilocin is cardiotoxic.

mdma has a value of 550 for the receptor but is still cardiotoxic for this reason and suggests there is more to consider than just affinity like the downstream activation profile of psilocin.

do you know what value DMT has? on wiki it says its .108 but on the PDSp database it says its 550

could one take yohimbine before taking psilocin to downregulate the receptor. yohimbine is quite selective for 5ht2b comapred to 2a and 2c so shouldnt affect the experience too much

 

[Cotcha Yankinov]

Maybe APBs and MDMA are full agonists at 5-HT2B, and can also be used in much more abusive patterns than traditional hallucinogens.

But it could just be an observational issue, and maybe some people who have 500 lifetime uses of mushrooms do have some increased risk of VHD.

I don't know about taking a 5-HT2B agonist to downregulate 5-HT2B. Seems like if yohimbine could appreciably downregulate 5-HT2B then it could appreciably activate 5-HT2B, which defeats the purpose.

 

[markosheehan]

Yohimbine is a antagonist not agonist.
If you took the yohimbine right before you took psilocin it would down regulate no?
It would be a bad idea to take yohimbine the day before as than it would be up regulated after and then when you take the psilocin it would be bad.

I would be surprised if 500 life time uses of psilocin spread out increased VHD. If you live to 80 that's means you would be taking a dose every 58 days. I've looked up reports of drug induced VHD and it always has in the report usually daily abuse for years.
Some one should do them echo cardiograms already.

 

[Cotcha Yankinov]

Sorry, I was thinking of guanfacine.

Yohimbine looks like its 5-HT2B antagonism may not be that appreciable because the a2 affinity is so high.

Also, if you're concern is cardiac health, using yohimbine could once again be counterintuitive because of vasoconstriction - not to mention it could ruin the trip.

The thing to remember is that all 80 year olds are going to have some VHD - our valves seem to be guaranteed to lose efficiency with time.

Methamphetamine has been linked to increased risk of Parkinson's disease in some cases - what will probably take a while to uncover is how meth may speed along Parkinson's development in people who will already develop Parkinson's without meth's insults and sleep deprivation.

So in my mind, the concern with 500 lifetime shroom uses is not necessarily that it will cause VHD that the 80 year old would have not seen otherwise, but rather it may worsen VHD to the point where they need surgery for it before they die of other causes.

 

[serotonin2A]

psilocins efficacy to the receptor is very small

Psilocin is a partial 5-HT2B agonist and is just as efficacious as ergotamine, which produces valvuopathy.

many people take psilocybin . people have been taking it for hundreds of years

Yes they have, but not in the same pattern that people take drugs like aminorex and fenfluramine (ie, daily for months or years). But for most of history, medical care was such that no one would notice if a drug like psilocybin was causing people to sustain valve damage; a few people would have just gotten sick and died and no one would have known why.

we know 5 apb is cardiotoxic for this reason so why would we not know psilocin is cardiotoxic.

5-APB use patterns and doses are very different compared to psilocybin. 5-APB also might be more toxic. How does that prove that psilocybin cannot produce valvulopathy?

mdma has a value of 550 for the receptor but is still cardiotoxic for this reason and suggests there is more to consider than just affinity like the downstream activation profile of psilocin.

Affinity values do not really work in vivo the way you are describing. The amount of occupation in vivo depends on the affinity and the tissue concentration. So for some drugs, a Ki of 500 nM may yield a large response, whereas for other drugs it may yield a negligable response. For MDMA, many of the sites it acts on (including SERT) have Ki values in the micromolar range. That is probably why doses of ~100 mg (which is pretty high) have to be taken to produce effects. So a ki of 500 nM is pharmacologically relevant for MDMA.

Another example is PCP and ketamine. From memory, PCP has Ki of ~50 nM, whereas ketamine has a Ki of ~600 nM for NMDA-R. The lower affinity of ketamine is offset by the fact that it is used at higher doses.

do you know what value DMT has? on wiki it says its .108 but on the PDSp database it says its 550

You need to give units or the values are meaningless. If memory serves, 500 nM is probably accurate, but I would have to look.

could one take yohimbine before taking psilocin to downregulate the receptor. yohimbine is quite selective for 5ht2b comapred to 2a and 2c so shouldnt affect the experience too much

Antagonists in general tend to upregulate receptors, not downregulate them. Yohimbine potentially may be selective for 5-HT2B over 5-HT2A, but yohimbine is not a selective 5-HT2B ligand and has high affinity for alpha2-adrenergic sites.

 

[markosheehan]

http://www.ouramazingworld.org/uploads/4/3/8/6/43860587/rickli2016.pdf in this study the activation efficacy was so low they could not get a value for it. it had the lowest efficacy for all the tryptamines and less than LSD aswell. how do you know the efficacy of ergotamines and psilocin are the same?

just based of me i know a lot of people who take psilocybin alot. a lot of them dose 2 times a week easily and i even know microdosers. know one i know or on the internet community has ever had a problem. i lot of the patients taking the drugs could detect the issues. they reported a shortness of breathe and a few other things. if you say this to a doctor they will do a few basic things like ECGs and echocardiograms etc there have been no reports ever of a messed up heart structure in the history of psilocybin intake. even if people dont take it as much as the drugs surely if it was a serious risk there would be at least one report but no never has there been one.

does it not take time for it to upregulate the receptor? would yohimbine not block 5ht2b receptors and not allow the receptor to be stimulated from the intake of psilocin. you would have to take the psilocin straight after taking the yohimbine.

do you know any alternative psychedelics that would not have the risk of 5ht2b agonism or at least reduced 5ht2b agonism risk

 

[serotonin2A]

http://www.ouramazingworld.org/uploads/4/3/8/6/43860587/rickli2016.pdf in this study the activation efficacy was so low they could not get a value for it. it had the lowest efficacy for all the tryptamines and less than LSD aswell. how do you know the efficacy of ergotamines and psilocin are the same?

Several other studies that have shown that psilocin is a 5-HT2B partial agonist. I'm not sure why Liechti found psilocin to have low activity (they usually do good work), but such a result doesn't make any sense given what we know about the structure-activity relationships of tryptamine effects on 5-HT2B. Think of it this way: Leichti found that DMT is an agonist, and they found that 4-hydroxylated tryptamines are agonists, but magically psilocin is not! That doesn't make a lot of sense. If there were no other studies showing that psilocin was an agonist then it would make sense to assume that this is just a peculiarity of the 5-HT2B receptor, but other studies have shown that psilocin is a partial agonist, so there seems to be some issue with their 5-HT2B assay.

Here are the sources for the data I was referring to:

ergotamine is a 5-HT2B partial agonist (56% efficacy):
http://circ.ahajournals.org/content/circulationaha/102/23/2836.full.pdf?download=true

psilocin is a 5-HT2B partial agonist (45% efficacy):
http://www.sciencedirect.com/science/article/pii/S0960894X05008735

just based of me i know a lot of people who take psilocybin alot. a lot of them dose 2 times a week easily and i even know microdosers. know one i know or on the internet community has ever had a problem. i lot of the patients taking the drugs could detect the issues. they reported a shortness of breathe and a few other things. if you say this to a doctor they will do a few basic things like ECGs and echocardiograms etc there have been no reports ever of a messed up heart structure in the history of psilocybin intake. even if people dont take it as much as the drugs surely if it was a serious risk there would be at least one report but no never has there been one.

It is much more difficult to induce valvulopathy than you are suggesting. There is probably a genetic component that makes certain people susceptible. Some people who took fenfluramine for years never developed valvulopathy.

I get what you are saying and I don't think that most people should worry about this possibility. But for a minority of people there may be some risk.

does it not take time for it to upregulate the receptor? would yohimbine not block 5ht2b receptors and not allow the receptor to be stimulated from the intake of psilocin. you would have to take the psilocin straight after taking the yohimbine.

It may be difficult to ingest enough yohimbine to block 5-HT2B. Yohimbine tends to produce unpleasant effects due to alpha-2 blockade, which limits the dose people would be able or willing to ingest.

do you know any alternative psychedelics that would not have the risk of 5ht2b agonism or at least reduced 5ht2b agonism risk

You probably won't find any, although they could be made. The structure of the 5-HT2A and 5-HT2B receptors are very similar, so they have very similar pharmacology, meaning that ligands tend to show effects at both. It takes some work to design drugs that are selective for one over the other, although it is possible.

 

[Weltmeister]

LSD is pretty selective for 5ht2a over 5ht2b if im not mistaken (Ki 2.7nM vs 30nM)

 

[WSH]

LSD is pretty selective for 5ht2a over 5ht2b if im not mistaken (Ki 2.7nM vs 30nM)

I don't know about binding affinities, but here is a functional assay proving that LSD is unselective (actually slightly selective for 5-ht2b):

Functional characterization of agonists at recombinant human 5-HT2A, 5-HT2B and 5-HT2C receptors in CHO-K1 cells

 

[serotonin2A]

LSD is pretty selective for 5ht2a over 5ht2b if im not mistaken (Ki 2.7nM vs 30nM)

That isn't enough of a difference to claim selectivity. To completely eliminate the possibility of interaction, you need at least 100-fold selectivity.