Carvedilol as a treatment for serotonin syndrome?

[MeDieViL]

It has been shown to reverse mdma induced hyperthermia, serotonin increases body temperature trough the 5ht2a receptor, so therefor my question.

Carvedilol reverses hyperthermia and attenuates rhabdomyolysis induced by 3,4-methylenedioxymethamphetamine (MDMA, Ecstasy) in an animal model.
Sprague JE1, Moze P, Caden D, Rusyniak DE, Holmes C, Goldstein DS, Mills EM.
Author information
Abstract
OBJECTIVE:
Hyperthermia is a potentially fatal manifestation of severe 3,4-methylenedioxymethamphetamine (MDMA, Ecstasy) intoxication. No proven effective drug treatment exists to reverse this potentially life-threatening hyperthermia, likely because mechanisms of peripheral thermogenesis are poorly understood. Using a rat model of MDMA hyperthermia, we evaluated the acute drug-induced changes in plasma catecholamines and used these results as a basis for the selection of drugs that could potentially reverse this hyperthermia.
DESIGN:
Prospective, controlled, randomized animal study.
SETTING:
A research institute laboratory.
SUBJECTS:
Male, adult Sprague-Dawley rats.
INTERVENTIONS:
Based on MDMA-induced changes in plasma catecholamine levels, rats were subjected to the nonselective (beta1 + beta2) adrenergic receptor antagonists propranolol or nadolol or the alpha1- + beta1,2,3-adrenergic receptor antagonist carvedilol before or after a thermogenic challenge of MDMA.
MEASUREMENT AND MAIN RESULTS:
Plasma catecholamines levels 30 mins after MDMA (40 mg/kg, subcutaneously) were determined by high-pressure liquid chromatography and electrochemical detection. Core temperature was measured by a rectal probe attached to a thermocouple. Four hours after MDMA treatment, blood was drawn and serum creatine kinase levels were measured as a marker of rhabdomyolysis using a Vitros analyzer. MDMA induced a 35-fold increase in norepinephrine levels, a 20-fold increase in epinephrine, and a 2.4-fold increase in dopamine levels. Propranolol (10 mg/kg, intraperitoneally) or nadolol (10 mg/kg, intraperitoneally) administered 30 mins before MDMA had no effect on the thermogenic response. In contrast, carvedilol (5 mg/kg, intraperitoneally) administered 15 mins before or after MDMA prevented this hyperthermic response. Moreover, when administered 1 hr after MDMA, carvedilol completely reversed established hyperthermia and significantly attenuated subsequent MDMA-induced creatine kinase release.
CONCLUSION:
These data show that alpha1 and beta3-adrenergic receptors may contribute to the mediation of MDMA-induced hyperthermia and that drugs targeting these receptors, such as carvedilol, warrant further investigation as novel therapies for the treatment of psychostimulant-induced hyperthermia and its sequelae.

Or is this purely related to its cardiocalming effects?

Carvedilol inhibits the cardiostimulant and thermogenic effects of MDMA in humans
CM Hysek,1 Y Schmid,1 A Rickli,1 LD Simmler,1 M Donzelli,1 E Grouzmann,2 and ME Liechti1
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Abstract
BACKGROUND AND PURPOSE

The use of ±3,4-methylenedioxymethamphetamine (MDMA, ‘ecstasy’) is associated with cardiovascular complications and hyperthermia.

EXPERIMENTAL APPROACH

We assessed the effects of the α1- and β-adrenoceptor antagonist carvedilol on the cardiostimulant, thermogenic and subjective responses to MDMA in 16 healthy subjects. Carvedilol (50 mg) or placebo was administered 1 h before MDMA (125 mg) or placebo using a randomized, double-blind, placebo-controlled, four-period crossover design.

KEY RESULTS

Carvedilol reduced MDMA-induced elevations in blood pressure, heart rate and body temperature. Carvedilol did not affect the subjective effects of MDMA including MDMA-induced good drug effects, drug high, drug liking, stimulation or adverse effects. Carvedilol did not alter the plasma exposure to MDMA.

CONCLUSIONS AND IMPLICATIONS

α1- and β-Adrenoceptors contribute to the cardiostimulant and thermogenic effects of MDMA in humans but not to its psychotropic effects. Carvedilol could be useful in the treatment of cardiovascular and hyperthermic complications associated with ecstasy use.

Toward directed therapy for amphetamine-mediated hyperthermia: is carvedilol worth raving about?

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[serotonin2A]

The hyperthermia is due to vasoconstriction of peripheral vasculature, which impairs heat regulation. Beta receptors can counteract that because they are expressed in the vasculature. But carvediol cannot block most 5-HT2A response, just this one in particular.

 

[MeDieViL]

MDMAs induced serotonin release must play a big role in the hyperthermia, if it completely reverses it then surely it must work against serotonin syndrome somehow, atleast some heating caused y the 5ht2a receptor.

Or do you mean sero induced hyperthermia is caused by 5ht2a induced vasoconstriction? while that can play a role it causes hyperthermia trough other mechanisms too otherwise ppl with vasoconstriction would drop dead all over the place if thats causes life treatening heating.

just looking that it appears to completely reverse it

 

[serotonin2A]

MDMAs induced serotonin release must play a big role in the hyperthermia, if it completely reverses it then surely it must work against serotonin syndrome somehow, atleast some heating caused y the 5ht2a receptor.

I don't understand your logic here. Serotonin works on 14 different receptors. Serotonin syndrome is not caused by 5-HT2A activation. If a drug can block one effect of serotonin then that doesn;t imply that it can block any other effects of serotonin. It depends on the receptors involved in the effect.

Or do you mean sero induced hyperthermia is caused by 5ht2a induced vasoconstriction?

MDMA-induced hyperthermia is caused by activation of 5-HT2A and alpha-adrenergic receptors. Both of those receptors reduce blood flow to the extremities, which inhibits thermoregulation (when the body gets hot, peripheral blood flow increases so that more heat can be transferred from blood to the environment). Carvedilol works because it counteracts the vasoconstriction.

while that can play a role it causes hyperthermia trough other mechanisms too otherwise ppl with vasoconstriction would drop dead all over the place if thats causes life treatening heating.

The vasoconstriction-induced hyperthermia isn't why people die -- it is because they are also running around, not drinking enough water, and because MDMA also affects thermoregulation in the hypothalamus. So the problem is that there are high levels of activity in people with compromised thermoregulation, which can be fatal. Hyperthermia combined with overactivity causes rhabdomyolysis due to muscle degeneration, resulting in kidney failure and death.

In terms of your general proposal, hyperthermia is not a defining symptom of serotonin syndrome. Carvedilol can reverse MDMA-induced hyperthermia through a downstream action. But carvediol doesn't specifically block any of the effects of serotonin. You can also cool the people with ice and that will also treat the hyperthermia. That doesn't imply that cooling people with serotonin syndrome would be effective.

 

[MeDieViL]

AFAIK serotonin syndrome, the deadly aspect is what i refer to offcourse is caused by 5ht2a activation.

life treatening heating.
The vasoconstriction-induced hyperthermia isn't why people die it is because they are also running around, not drinking enough water, and because MDMA also affects thermoregulation in the hypothalamus. So it is the high levels of activity in people with compromised thermoregulation that proves fatal. They end up getting rhabdomyolysis due to muscle degeneration, which causes kidney failure and death

Thia doesnt explain the anecdotes of ppl that took those old bad xtc tablets and were sitting outside sweating like crazy, i also noticed sweating a ton on mdma related substances and im pretty sure there wasnt much more vasoconstriction then on a stim overdose even.

Wheter something works trough w downstream action or not has no relevance at all wheter something is effective for the treatment of something, not at all really, that would be like saying that blocking all da recpeptors wont block the effects of amphetamine because its a downstream action and amp still releases its da, sure theres still increased serotonin but if we are gonna talk in that way we could say that everyone is walking up the steps while they cant get trough the door, they are stil coming up, the door is blocked but it doesnt matter thats downstream if that makes sense.

just quick search

haha there we go, 5ht2a controls body temperature besides inducing vasoconstriction

Pharmacol Res. 2016 Jan;103:123-31. doi: 10.1016/j.phrs.2015.11.018. Epub 2015 Nov 24.
5-HT2A receptors control body temperature in mice during LPS-induced inflammation via regulation of NO production.
Voronova IP1, Khramova GM1, Kulikova EA2, Petrovskii DV2, Bazovkina DV2, Kulikov AV3.
Author information
Abstract
G protein-coupled 5-HT2A receptors are involved in the regulation of numerous normal and pathological physiological functions. At the same time, its involvement in the regulation of body temperature (Tb) in normal conditions is obscure. Here we study the effect of the 5-HT2A receptor activation or blockade on Tb in sick animals. The experiments were carried out on adult C57BL/6 mouse males. Systemic inflammation and sickness were produced by lipopolysaccharide (LPS, 0.1mg/kg, ip), while the 5-HT2A receptor was stimulated or blocked through the administration of the receptor agonist DOI or antagonist ketanserin (1mg/kg), respectively. LPS, DOI or ketanserin alone produced no effect on Tb. However, administration of LPS together with a peripheral or central ketanserin injection reduced Tb (32.2°C). Ketanserin reversed the LPS-induced expression of inducible NO synthase in the brain. Consequently, an involvement of NO in the mechanism of the hypothermic effect of ketanserin in sick mice was hypothesized. Administration of LPS together with NO synthase inhibitor, l-nitro-arginine methyl ester (60mg/kg, ip) resulted in deep (28.5°C) and prolonged (8h) hypothermia, while administration of l-nitro-arginine methyl ester alone produced no effect on Tb. Thus, 5-HT2A receptors play a key role in Tb control in sick mice. Blockade of this GPCR produces hypothermia in mice with systemic inflammation via attenuation of LPS-induced NO production. These results indicate an unexpected role of 5-HT2A receptors in inflammation and NO production and have a considerable biological impact on understanding the mechanism of animal adaptation to pathogens and parasites. Moreover, adverse side effects of 5-HT2A receptor antagonists in patients with inflammation may be expected.

Ive had extreme vasoconstriction on stims once and that turns me half blue and freezing cold, quite the opposite of serotonin syndrome.

If you overheat because of just vasoconstriction and running around then i think you must have extremely tight veins and be pumped up on steroids, strychine, amphetamine and someone behind ya with a 9mm

 

[serotonin2A]

Yes, 5-HT2A can influence temperature through other mechanisms (note that in my post above I wrote "MDMA also affects thermoregulation in the hypothalamus"). But that doesn't necessarily mean that central mechanisms play a prominent role in MDMA-induced hyperthermia. It helps to actually read the primary literature before speculating on the mechanism for drug effects.

http://www.ncbi.nlm.nih.gov/pubmed/11606652
http://www.ncbi.nlm.nih.gov/pubmed/12867524
http://www.ncbi.nlm.nih.gov/pubmed/12654345
http://www.ncbi.nlm.nih.gov/pubmed/12867524
http://www.ncbi.nlm.nih.gov/pubmed/15083260

The following article clearly explains the criteria for diagnosing serotonin syndrome:

http://qjmed.oxfordjournals.org/content/96/9/635

You will notice from the chart that hyperthermia doesn't occur in most serotonin syndrome cases and isn't required for diagnosis.

Thia doesnt explain the anecdotes of ppl that took those old bad xtc tablets and were sitting outside sweating like crazy, i also noticed sweating a ton on mdma related substances and im pretty sure there wasnt much more vasoconstriction then on a stim overdose even.

The problem isn't vasoconstriction in general, it is vasoconstriction of specific cutaneous vascular beds that are required for thermoregulation. Most receptors that induce vasoconstriction act locally (they are expressed by blood vessels). 5-HT2A receptors can contract blood vessels directly, but there are also 5-HT2A receptors in the brain stem and spinal cord that trigger increases in sympathomimetic outflow, which causes vasoconstriction.

Ive had extreme vasoconstriction on stims once and that turns me half blue and freezing cold, quite the opposite of serotonin syndrome.

First off, that is exactly the problem with cutaneous vasoconstriction -- the skin gets cold because there is a lack of bloood flow. That means all the heat is trapped in your organs.
Second, what does any of this have to do with serotonin syndrome? Hyperthermia isn't necessarily a symptom of SS.

Wheter something works trough w downstream action or not has no relevance at all whether something is effective for the treatment of something, not at all really,

It is true that illnesses can be treated by acting downstream from the root cause. Here, carvediol is treating MDMA-induced hyperthermia because it can reduce vasoconstriction, and potentially by affecting thermoregulation through central effects. But serotonin syndrome, by contrast, has nothing to do with either vasoconstriction or thermoregulation (because hyperthermia isn't a primary symptom of SS). So what is the rationale for thinking that carvediol would work downstream from the mechanisms for serotonin syndrome? Carvediol isn't known to block most 5-HT2A-mediated effects.

If you overheat because of just vasoconstriction and running around then i think you must have extremely tight veins and be pumped up on steroids, strychine, amphetamine and someone behind ya with a 9mm

Despite your thinking, that is exactly why people die from MDMA overdose. Read about rhabdymolysis. If you overwork your muscles, especially if they are too hot, the muscle tissue breaks down and releases myoglobin into the bloodstream. The myoglobin can damage the kidneys, which can cause kidney failure, metabolic acidosis, and death. It actually isn't very hard to get rhabydomyolysis. Unfortunately, even jogging has been known to cause rhabdomyolysis. Rhabdomyolysis is one of the main causes of amphetamine and MDMA-induced death.

http://www.ncbi.nlm.nih.gov/pubmed/9355426
http://www.ncbi.nlm.nih.gov/pubmed/8905441

 

[MeDieViL]

Those are a couple of case reports, that doesnt mean its the leading cause of deaht related to serotonin syndrome, when i went raving i jumped around like med sweating like mad, about to collapse and having no drink for fucking 8 hours or something, the ammount of "excercise" without hydration i usually did in a evening is maybe worse then a 6 hour long jog, i only stopped jumping around if i had to gasp for air, and so did my mates, the scene here is a bit more hyperactive then the rave videos ive seen in other other countrys its like a non stop workout session, so i higly doubt that causes alot of deaths except those case reports. And whats a mdma overdose? we all easily took 8 tablets 0f 120mg, imo its pretty much impossible to overdose from mda, i know ppl taking 20 tablets in a evenings, its acute toxiticy is low.

Either way, i should have clarified that with serotonin syndrome i ment te deadly hyperthermia, why else would it be worth discussing?

because hyperthermia isn't a primary symptom of SS

perhaps, but i tought logic would indicate thats the sympton im talking about.

That means all the heat is trapped in your organs.

excuse me if im wrong, but from all the reports ive read, ppl felt extremely hot, ive never heared of someone feeling cold on mdma because the heat is trapped in their orgasms, it allways makes me look like ive been outside in a bloody storm dancing in a hot club

 

[serotonin2A]

when i went raving i jumped around like med sweating like mad, about to collapse and having no drink for fucking 8 hours or something, the ammount of "excercise" without hydration i usually did in a evening is maybe worse then a 6 hour long jog, i only stopped jumping around if i had to gasp for air, and so did my mates, the scene here is a bit more hyperactive then the rave videos ive seen in other other countrys its like a non stop workout session, so i higly doubt that causes alot of deaths except those case reports. And whats a mdma overdose? we all easily took 8 tablets 0f 120mg, imo its pretty much impossible to overdose from mda, i know ppl taking 20 tablets in a evenings, its acute toxiticy is low.

What you don't seem to realize is that although most people don't experience toxicity from MDMA, that doesn't mean that it does not happen to a minority of users. Even if only 0.01% of users die, that means that out of millions of doses taken per year, several hundred doses would be fatal. Of course it is likely the neither you nor your friends would ever have the pleasure of experiencing MDMA toxicity. According to DAWN data, there were a total of 136,116 emergency room visits related to MDMA in the USA from 2005-2011. Of course, not all the individuals died, but there were hundreds of deaths. Your anecdotal reports are completely meaningless in this discussion, and I don't see the purpose of bringing them up.

It is true that MDMA generally causes hyperthermia and motor activation in most users, but most don't experience rhabdomyolysis. But exactly the same is true for people who play sports or have seizures. Unfortunately, for a certain percentage of the population, hyperthermia and overexertion after taking MDMA (or jogging, or having a seizure) lead to rhabdomyolysis and potentially death. There may be a genetic component. But that doesn't change the fact that hyperthermia and overexerting are the two factors that usually lead to fatalities in MDMA users.

In terms of your disparaging case reports, how else do you think MDMA overdoses become known? Do you think that they run studies with MDMA to see how many of the subjects die after taking it? The fact is, if you read over all the case reports in the literature (and there are many more than I cited) they all show the same mechanism for toxicity.

Either way, i should have clarified that with serotonin syndrome i ment te deadly hyperthermia, why else would it be worth discussing?

Serotonin syndrome and hyperthermia are completely different conditions. That isn't an issue of clarification, it is changing the topic. Posts on the board are often about serotonin syndrome, so it would not be strage to discuss it here.

 

[MeDieViL]

What you don't seem to realize is that although most people don't experience toxicity from MDMA, that doesn't mean that it does not happen to a minority of users. Even if only 0.01% of users die, that means that out of millions of doses taken per year, several hundred doses would be fatal. Of course it is likely the neither you nor your friends would ever have the pleasure of experiencing MDMA toxicity. According to DAWN data, there were a total of 136,116 emergency room visits related to MDMA in the USA from 2005-2011. Of course, not all the individuals died, but there were hundreds of deaths. Your anecdotal reports are completely meaningless in this discussion, and I don't see the purpose of bringing them up.

i didnt post my anecdote as evidence or anything i agree it doesnt mean a thing, i only brought them up because you seem to incline to overusing your muscles causes serotonin syndrome induced hyperthermia and therefor death, you made it sound like its something that happeneds commenly i apologise for my meaningless post.

But how many off those where hospitalised because of serotonin syndrome related hyperthermia? everytime i ended in hospital because of drugs, it was because of a panic attack, or cardiac stress, also how many of those where using drugs in poly related matter? you are talking about jogging inducing this kinda of death which disconnects it even more from the purpose of my topic, discussing serotonin induced dealthly hyperthermia in serotonin syndrome

The fact is, if you read over all the case reports in the literature (and there are many more than I cited) they all show the same mechanism for toxicity.

I dont see any evidence that they sufferered from serotonin syndrome induced hyperthermia, yeah a higher temp can increase death risk but im talking about death directly induced by hyperthermia induced by sero syndrome

 

[MeDieViL]

Serotonin syndrome and hyperthermia are completely different conditions.

Hyperthermia a symption of ss, the symption which makes it a serieus and deadly condition.

 

[serotonin2A]

Hyperthermia a symption of ss, the symption which makes it a serieus and deadly condition.

It really would be helpful for this discussion if you could pick either MDMA toxicity (the origional post was about that) or serotonin syndrome and stick to one of those topics. Because I can't tell if you are switching between topics or if you think MDMA induces serotonin syndrome.

If you read the chart I posted above (the Hunter criteria), that is the official way they evaluate whether someone has serotonin syndrom. The defining symptom of SS is clonus. It is true that some SS patients exhibit hyperthermia, but many do not exhibit elevated body temp. Elevated body temp is very nonspecific and is a symptom of many illnesses. MDMA overdose victims exhibit hyperthermia but rarely display clonus, meaning they ARE NOT suffering from serotonin syndrome.

You may object to that, but the classification has to be like that to avoid nonsensical outcomes. If someone taking prozac develops a fever, by your definition they would have serotonin syndrome. But that would obviously not be correct. By the same token someone who takes MDMA and develops hyperthermia does not have serotonin syndrome.

But how many off those where hospitalised because of serotonin syndrome related hyperthermia?

My point is that almost none of them were. They would only have serotonin syndrome related hyperthermia if they exhibited clonus, and that is very rare in MDMA overdose. The treatment for SS is cyproheptadine and that is not typically used in MDMA overdose.

you are talking about jogging inducing this kinda of death which disconnects it even more from the purpose of my topic, discussing serotonin induced dealthly hyperthermia in serotonin syndrome

You are completely missing my point here. The reason I brought up jogging is to give an example of how some people can have paradoxical reactions to things that most everyone else can do safely. Just because you don't get rhabdomyolysis from MDMA doesnt mean it is not possible.

 

[Cotcha Yankinov]

Medievil, I think serotonin syndrome is pretty hard to achieve unless auto receptors have been down regulated with chronic SSRIs and such, maybe MDMA overdose + lots of 5HTP could cause serotonin syndrome but other than that idk... On these forums I've only heard about stuff in the mild SS spectrum concerning MDMA + pharmaceuticals.

Also I think I already disturb Serotonin2A enough so take it easy on him

 

[MeDieViL]

PMMA in xtc pills used to cause it.

one of my future experiments could be something like mdai, with nardil or parnate and other stuff so im interested, also i would need adronergic blockade for the stim with a powerfull maoi, please leave the warning replys, i know what im doing, ive tried worse stuff

 

[Nagelfar]

why not Fenclonine?

 

[(zonk)]

There are some natural compounds that lower body temperature and i'm wondering if they'd be significantly effective against hyperthermia. 6-gingerol and eriodyctiol(which is a trpv antagonist and a bitterness blocker )

 

[serotonin2A]

why not Fenclonine?

PCPA doesn't work fast enough. It doesn't deplete serotonin in vesicles. The vesicular pool becomes depleted after extended PCPA use, but that doesn't happen immediately.

 

[aced126]

I don't understand your logic here. Serotonin works on 14 different receptors. Serotonin syndrome is not caused by 5-HT2A activation. If a drug can block one effect of serotonin then that doesn;t imply that it can block any other effects of serotonin. It depends on the receptors involved in the effect.



MDMA-induced hyperthermia is caused by activation of 5-HT2A and alpha-adrenergic receptors. Both of those receptors reduce blood flow to the extremities, which inhibits thermoregulation (when the body gets hot, peripheral blood flow increases so that more heat can be transferred from blood to the environment). Carvedilol works because it counteracts the vasoconstriction.

The vasoconstriction-induced hyperthermia isn't why people die -- it is because they are also running around, not drinking enough water, and because MDMA also affects thermoregulation in the hypothalamus. So the problem is that there are high levels of activity in people with compromised thermoregulation, which can be fatal. Hyperthermia combined with overactivity causes rhabdomyolysis due to muscle degeneration, resulting in kidney failure and death.

In terms of your general proposal, hyperthermia is not a defining symptom of serotonin syndrome. Carvedilol can reverse MDMA-induced hyperthermia through a downstream action. But carvediol doesn't specifically block any of the effects of serotonin. You can also cool the people with ice and that will also treat the hyperthermia. That doesn't imply that cooling people with serotonin syndrome would be effective.

Are alpha receptors activated directly by MDMA or by released adrenaline?

 

[serotonin2A]

Are alpha receptors activated directly by MDMA or by released adrenaline?

There is evidence that both mechanisms can occu with MDMAr. But studies haven't worked out whether one or both mechanisms are responsible for the effects of MDMA in the vasculature. Most of the published studies were primarily concerned with the receptor involved, not whether they are directly or indirectly activated.