2-FMA Cardiotoxicity Warning Legit?

[ericzx]

I have come across this post (see post #30):

http://www.bluelight.org/vb/threads/648663-Best-stimulant-RC-Study-Aid/page2

The poster claims his friend was taking 2-FMA regularly for over a year ... and then developed some major heart valve problem that required surgery. Quoting:

"My buddy basically summed up that if you take 2-FMA as regularly as he did (daily for probably about a year) cardio-toxic phenethylamines build up so slowly in your body to the point where you don't even notice the effects until there is enough of these toxic chemicals to cause serious heart damage."

... Something to do with the way 2-FMA was metabolized, accumulating in fatty tissue ...

BS or no?

I have found various online accounts of people using 2-FMA daily for months, reporting no symptoms ... in fact less cardiovascular symptoms than that of Adderall/amps. I've been taking 40mg Vyvanse daily for over 5 years ... now having tried 2-FMA it feels A LOT less strenuous on my cardiovascular system, much smoother.

My blood pressure is actually lower (120/70 range) on 2-FMA ... heart rate 95-100 T+1:00 into the first dose, then subsiding to the high 80s range. Blood pressure continuously normal/low, versus continuously borderline normal with Vyvanse.

BUT ... that would have nothing to do with the potential cardiotoxicity if 2-FMA metabolites cause some sort of structural heart problem (which may be asymptomatic) ...

QUESTION:

Does anyone know if 2-FMA metabolites bind to the 5-HT2B receptor?

Can any chem/bio majors weigh in on how 2-FMA is metabolized?

* I'm assuming if 2-FMA metabolites have 5-HT2B affinity than this would be present in other fluoroamphetamine analogues ... or no?
Thanks!

 

[ericzx]

An update:

I've come across this thread: http://zoklet.net/bbs/archive/index.php/t-178757.html

RE: the 4-fluoroamphetamines

A poster warning:

"Be aware that 4-fluoroamphetamines may very well bind with 5HT2a receptors on the mitral valve chordae tendineae. If so, then cellular proliferation is likely, which can inturn result in a leaky heart valve. Many drugs have been removed from the market because of this effect.
Fenfluramine was removed for this purpose because the issue arises when people use it everyday..."

With a rebuttal:

Sounds like total bullshit to me.
Fenfluramine and other drugs were withdrawn because they strongly bind to the 5-HT2B receptor, which are most widely expressed on the heart valves. Repeated agonism at this receptor causes the valves to thicken, which ultimately leads to heart failure over time.
@ "cellular proliferation" due to acute administration of a 2B agonist. If that were true, psilocin, LSD, DMT, DOx, and nearly every psychedelic (besides mescaline) would seriously fuck your heart after a single dose, as they are all potent 2B agonists.
Yes, eating a 2B agonist everyday is incredibly harmful over time, but I'm willing to bet that without an extra 2,5-dimethoxy substituent on 4-FA (making DOF (http://en.wikipedia.org/wiki/2,5-Dimethoxy-4-fluoroamphetamine)), you're not going to get any significant 2B agonism.
Moar about 2B here (http://www.zoklet.net/bbs/showthread.php?t=150810)

There is also a poster in the same thread claiming he's taken 4-FA regularly since 2009 (posted 7/2011), so roughly 2 years ... reporting no negative symptoms ....

Various posters here also (for regular 2-FMA use):

[Wynardtage]

I've used 2-FMA 3-4 times a week for like 9 months or so now. I have noticed no adverse health effects except for some weight loss.

[Mercc96]

I used around 60-80mg each day , for about 3 months and everything was fine, it just felt a little weird after a while. A friend of mine binged on the stuff (300-500mg a day) and got the vasoconstriction and massive mood swings as you would imagine.

Another on this thread:

i really believe 2fma is very overlooked chem. never a issue sleepin if really sleepy after a few hours. i have taken around 50 too 100 mg a day for over two months straight. no bad side effects, that is the only issue with it.

It appears those with adverse effects generally experience them on the first try or first few days after taking high-doses (consistent with amphetamines in general). But in terms of long-term cardiotoxicity, no major health problems/complaints with (seemingly responsible) chronic users have been reported ... other than that one sketchy 'my friend said' case in my first post.

Also consider this one from a regular mega-doser (no major health problems it appears):

I've been doing 2-FMA for about 2 months. I need to take about 500mg to get a decent high now. The high is no where near as good as what it was at first. There was a lot of euphoria at first, now it's almost straight jittery stimulation...

What's the verdict?

Can any chem/bio/pharm expert/student weigh in on this?

 

[endotropic]

Fenfluramine and other drugs were withdrawn because they strongly bind to the 5-HT2B receptor, which are most widely expressed on the heart valves. Repeated agonism at this receptor causes the valves to thicken, which ultimately leads to heart failure over time.

This is accurate. That means you have two types of drugs that you need to watch out for: 5-HT2B agonists, and serotonin releasing drugs (the serotonin itself will bind to the 5-HT2Br in the heart valves causing the same problem). I don't know if 2-fma has either of those actions, but if it does, then this sort of toxicity should be expected.

This is only a problem with chronic regular dosing. It's also the sort of problem that won't be immediately obvious without a thorough heart scan, or until cardiac function is severely compromised.

 

[ericzx]

This is accurate. That means you have two types of drugs that you need to watch out for: 5-HT2B agonists, and serotonin releasing drugs (the serotonin itself will bind to the 5-HT2Br in the heart valves causing the same problem). I don't know if 2-fma has either of those actions, but if it does, then this sort of toxicity should be expected.

This is only a problem with chronic regular dosing. It's also the sort of problem that won't be immediately obvious without a thorough heart scan, or until cardiac function is severely compromised.

Oh okay thanks!

So we know from existing research: "4-FA does not cause long-lasting depletion of brain serotonin, unlike its analogues 4-CA and 4-BA.^[4] This is thought to "reflect the inability of the fluoro-compound to be metabolized in the same way as the other haloamphetamines."^[5].

Would this extend similarly to the 2-F(M)A series?

Also, how accurate would this statement be:

... without an extra 2,5-dimethoxy substituent on 4-FA (making DOF (http://en.wikipedia.org/wiki/2,5-Dim...oroamphetamine)), you're not going to get any significant 2B agonism.

?

 

[endotropic]

Oh okay thanks!

So we know from existing research: "4-FA does not cause long-lasting depletion of brain serotonin, unlike its analogues 4-CA and 4-BA.^[4] This is thought to "reflect the inability of the fluoro-compound to be metabolized in the same way as the other haloamphetamines."^[5].

Would this extend similarly to the 2-F(M)A series?

I thought that 5-HT releasing drugs only cause long lasting 5-HT depletion when they also release dopamine, as the dopamine gets sucked up by the 5-HT transporter and causes oxidative damage to the 5-HT neurons. I really don't know anything about the sort of metabolic toxicity mentioned there.

Also, how accurate would this statement be:

... without an extra 2,5-dimethoxy substituent on 4-FA (making DOF (http://en.wikipedia.org/wiki/2,5-Dim...oroamphetamine)), you're not going to get any significant 2B agonism.

?

I'm skeptical that anyone understands the SAR of the 5-HT2B receptor well enough to make that claim with 100% certainty. Lacking the results of an actual binding assay with this drug at this receptor I wouldn't make any assumptions about what activity it might or might not have.

 

[InterestingFACT]

All amphetamines are going to be mildly cardiotoxic. My best guess is that 2-fma's toxicity would be a result of its long duration--meaning that accumulation of the drug in fatty tissues would be possible with dosing on consecutive days.

I've also heard it hypothesized that both the extra methyl group (vs 2fa) and the fluorine substitution (vs regular amp or methamp) would work to increase lipophilicity, therefore increasing accumulation of the drug in fatty tissues.

All of this would tend to suggest that it would be the constant presence of 2-fma in your body (even after you no longer feel effects) that would be damaging. As far as I know, 2-fma is probably not significantly metabolized by your body, so any metabolites are unlikely to play an important role in side effects.

I was reading through all this stuff myself, before I decided to pull the trigger on it. Of course the best recommendation in keeping with harm reduction would be that you stay away from the stuff until there's more research proving its safety. That being said, I have personally concluded that it isn't significantly dangerous with intermittent usage. However I would strongly advice you not to use it daily for long periods of time (Ie. I wouldn't replace your Vyvanse with it--that's what I originally planned to do, but I thought better of it.)

 

[ericzx]

All amphetamines are going to be mildly cardiotoxic. My best guess is that 2-fma's toxicity would be a result of its long duration--meaning that accumulation of the drug in fatty tissues would be possible with dosing on consecutive days.

I've also heard it hypothesized that both the extra methyl group (vs 2fa) and the fluorine substitution (vs regular amp or methamp) would work to increase lipophilicity, therefore increasing accumulation of the drug in fatty tissues.

All of this would tend to suggest that it would be the constant presence of 2-fma in your body (even after you no longer feel effects) that would be damaging. As far as I know, 2-fma is probably not significantly metabolized by your body, so any metabolites are unlikely to play an important role in side effects.

I was reading through all this stuff myself, before I decided to pull the trigger on it. Of course the best recommendation in keeping with harm reduction would be that you stay away from the stuff until there's more research proving its safety. That being said, I have personally concluded that it isn't significantly dangerous with intermittent usage. However I would strongly advice you not to use it daily for long periods of time (Ie. I wouldn't replace your Vyvanse with it--that's what I originally planned to do, but I thought better of it.)

Thanks. Yes this is what I wanted to get at, as a Vyvanse replacement. So I guess it's time to pull the plug.

By the way, would you know of other more-researched chems that could be a good Vyvanse replacement? (Or safe to take half-time e.g. 2 weeks Vyvanse, 2 weeks replacement chem? ... say MPA? ...

 

[InterestingFACT]

Thanks. Yes this is what I wanted to get at, as a Vyvanse replacement. So I guess it's time to pull the plug.

By the way, would you know of other more-researched chems that could be a good Vyvanse replacement? (Or safe to take half-time e.g. 2 weeks Vyvanse, 2 weeks replacement chem? ... say MPA? ...

My first thought would be to that you use regular 2fa (not 2fma)--just dosed twice daily (like taking Dexedrine twice a day vs taking vyvanse once). If I'm right and the danger in 2fma has to do with it's long half-life, then 2fa is probably not very dangerous since there would be less accumulation from day to day. Of course we still no next to nothing objectively about it's safety profile.

I can't see MPA substituting for vyvanse. It's long acting, but it's apparently very dirty at higher doses--ie it's more adrenergic than dopaminergic. It's been in use for a while though, and I don't think there have been many reports of complications.

Ethylphenidate probably has similar properties to methylphenidate--though IME it feels unhealthy, so does methylphenidate and that is apparently quite remarkably safe. It's short acting and has horrible comedowns though, so I couldn't recommend it.

Tbh, in terms of effects, I think 2-fma has the best potential out there as a vyvanse-like drug. It's just too bad we don't know more about it's safety--keep in mind that people have had heart problems after methamphetamine or amphetamine use too, and we don't know if this is a fluke. I'm fairly confident that you're not going to have complications after using it for two weeks, but who knows if it's having a cumulative effect. If I were in your position (I pretty much am), I would try to keep usage to a minimum. Cycling with vyvanse isn't a bad idea. Another suggestion would be to take half a vyvanse with a low dose of 2fma. Also if it's about the cost of vyvanse, I think extended release Dexedrine is significantly cheaper (though I way prefer the smooth release of vyvanse to the staged release crap in other xr meds).

 

[SONN]

Did anyone ever figure out if this is true? is 2-FMA worse for your heart than regular amphetamine or meth?

 

[dopamimetic]

It would be very nice to read more about that certain case and the theory behind, and to have the material used by this guy analyzed. Somehow I doubt that pure and reasonably dosed 2-FMA can be any worse than your average meth, or even speed, but yes - this warning actually made me to drop the 2-FMA too. It's just too much to loose. But it would be unfortunate if this proves wrong and makes people switch to more harmful alternatives (like MPA for example, maybe).

Nevertheless, 2-FA might be a good alternative that does not last as long.

By the way, would you know of other more-researched chems that could be a good Vyvanse replacement?

Seems that not everyone likes its profile of effects, but isopropylphenidate has great potential (am using it personally now since 4 months or so). Besides the lack of pushing stimulation (which actually can be a benefit), it has all the positives of MPH and EPH with very few of the negatives. It lasts longer (4-5h vs. 2-3h), comes and goes smoother, has little peripheral / adrenergic effects at all and - maybe the best - no adrenergic "rebound" / lasting stimulation.

I don't know if human studies have been done yet, but it's patented for ADHD and I really hope it becomes available by prescription as soon as possible..

 

[neurotic]

How does the fluorine increase lipophilicity? Genuine question... I thought it'd do the opposite since the C-F bond is polar

 

[The King of Beans]

4-FA definitely causes heart damage over time. I can't even take the stuff anymore. Not sure about 2-fma. But I know 4-fa does from experience of using it.

 

[The King of Beans]

Luckily they say heart damage can be reversed. But you must do all sorts of stuff AND abstain from all drug usage. Which I guarantee once your heart gets bad, you won't want to do the drugs anymore anyway. You might still crave them psychologically, but you will be forced to abstain due to the severe side effects. If I take 4-fa now, i feel as if I am suffocating. There is no euphoria at all anymore, because when you cannot breath, it kills all of the euphoria.

Too bad mdma isn't legal because it isn't bad for the heart like most all these RC's are.

 

[aced126]

How does the fluorine increase lipophilicity? Genuine question... I thought it'd do the opposite since the C-F bond is polar

I would also appreciate an answer for this. Been wondering about it for a while. Here are some stats:

LogP of benzene = 2.13
LogP of fluorobenzene = 2.27

So fluorine substitution on a ring increases logP.

I thought that this would be the result of electron donating and withdrawing effects of fluorine but I've found this to not be the case. Fluorobenzene is less reactive than benzene when undergoing aromatic electrophilic substitution, implying the electron density in the ring is lower than that of benzene. I would've thought this would result in a lower logP but it doesn't. To complicate the situation even more,

LogP of an aliphatic chain with a fluorine substituent is reduced by -0.17

This would imply that the fluorine which pulls electron density from the aliphatic carbon results in a reduced logP. However,

LogP of an aliphatic chain with a chlorine substituent is increased by 0.39
LogP of an aliphatic chain with a bromine substituent is increased by 0.60

So it turns out going down group 7 increases logP on aliphatics a lot. I have no clue why, I'm thinking size of the atom, but how does that lead to better interactions with octan-1-ol rather than water? Finally,

LogP of chlorobenzene = 2.84
LogP of bromobenzene = 2.99

Going down group 7 increases logP on aromatics increases it quite a lot as well. If someone who has a good chemistry knowledge can explain these trends I would be grateful.

 

[belligerent drunk]

You're right, the higher logP of Br and Cl substituted aliphatics is because of their size and decreased electronegativity - the negative charge is very diffuse on the halogens so they don't interact strongly via dipole-dipole etc. The thing is not that they interact stronger with octanol, but they interact much weaker with water because of that. Lipophilic groups or molecules "like" nonpolar solvents not because they interact strongly with them, no the interaction is weak; water/polar solvents on the other hand don't want a weakly interacting particle in their solution as it breaks some solvent-solvent interactions which are much stronger. Fluorine on the other hand is considerably smaller and more electronegative, so the charge is localized enough on it plus the bond is more polarized leading to better hydrophilicity; not by a lot though. Interestingly, perfluoroalkanes are neither lipophilic nor hydrophilic - they hate everybody! I think it comes from the fact that with perfluoro chains, the dipoles are reduced because of cancelling vectors and fluorine is too small to be polarizable enough to interact in any way (London dispersion forces), so they lack strength in all the intermolecular forces making them so weak that even nonpolar solvents don't really want them.

I'm actually not quite sure why fluoroarenes are more lipophilic than without the fluorine. You're correct - fluorobenzene is less reactive due to the inductive effect of fluorine reducing the electrondensity of the ring. I'm only speculating from now on, but perhaps fluorine can't withdraw enough electrondensity (partially due to the electron donating nature) to increase the polarity/dipole of the molecule to offset the increase in the size (H vs F)?