How toxic is Mephedrone?

[swilow]

I think people are blowing the safety threat of mephedrone way out of proportion. There have been only 3 or 4 recorded deaths from the drug
.

Oh, is that all? Sweet 8)

Stick to LSD.

 

[nuke]

Wait. I thought that you said that MA was more neurotoxic than MDMA at 'equivalent' (not sure...typical dose to typical dose? I'm sure isn't per-milligram...that comparison'd be silly, unless I misunderstood you), suggesting that a DA flood in the presence of moderate 5ht efflux presents greater neurotoxicity than a moderate flood of 5ht and sizable release of DA. Thus, it does not follow that a higher ratio of 5ht to dopamine release reliably marks the magnitude of neurotoxicity.

I would imagine that people will tolerate a level of neurotoxicity equivalent to MDMA (yes, non-neurotoxic would be ideal. . .). Given your above hypothesis, 4MMC should exert less neurotoxicity than MDMA, in terms of that occurring via simultaneous DA and 5ht release (it could of course do other bad things). Of course, if that hypothesis is false, 4MMC could be way worse.

I think that threatening death, amputation, etc. is bad enough.

ebola

A dose by dose comparison perhaps isn't that silly... Let's say that the effective concentration to release dopamine for amphetamine requires 20mg of dextroamphetamine or 10mg of dextro-methamphetamine... Compare this to the slightly less lipophilic (-)-cathinone/(-)-methcathinone which is active around 40mg/20mg. From the EC50s you can see that 4-Methylamphetamine is at least 1/5 or so as active as a dopamine releaser, so you'd expect the equivalent dose around 100mg or more. The average dose of methedrone is around 200mg (usually higher), which is about what you'd expect if you were estimating. So who's to say at these doses you're not producing a similar release of DA/NE, yet at the same time vastly producing more serotonin release? This are all pretty similarly sized compounds in terms of molecular weight too, so there's not really that much difference between the molar concentrations vs. mass dosages. The beta-Keto group of the cathinones is always probably going to reduce the affinity for SERT and thusly 5HT release, but with the huge advantage in release garnered by the addition of the 4-Methyl group in 4-Methylamphetamine as well as the potency of methylone and its substitution of MDMA I don't think it's too far off in believing that 4-MMC can produce a large amount of 5HT efflux.

You can check out the EC50s for MDMA and pCA, too:

EC50 DA/NE/5HT nM
(±)-MDMA 376 ± 16, 77.4 ± 3.4, 56.6 ± 2.1

MDMA is preferential for 5HT release over DA release by quite a lot (though I'm pretty sure the NE release is probably reinforcing and plays a role in it's abuse potential), but it's well known MDMA exhibits a not so nice neurotoxicology profile as well. p-Chloroamphetamine is roughly equipotent to or slightly than MDMA in terms of generating 5HT efflux, which would also make it roughly equivalent to 4-Methylamphetamine in that regards. So this would put 4-Methylamphetamine between meth and MDMA in terms of DA/NE/5HT release. Whether you trust that as safe or not is up to you.

(The bit on pCA mediated efflux: "Serotonin-transporter mediated efflux: A pharmacological analysis of amphetamines and non-amphetamines" Neuropharmacology)

 

[Operation Atlas]

I wish we had these numbers for mephedrone itself, instead of having to try to compare analogues.

It is obviously subjective, but I definitely feel like mephedrone has very little action on serotonin and is active much more with dopamine and norepinephrine. I'm quite surprised that methcathinone is so heavy on serotonin. Maybe the two compounds aren't as closely related as I had assumed.

Unlike most other chemicals with a similar structure, 4-MA's action on serotonin release is very low. Since we know that 4-MA is para-substituted like mephedrone, maybe mephedrone is very low on serotonin release as well. That would back up my subjective observations, but there's obviously very little we have to go in in this respect.

When it comes to how all this effects neurotoxicity, we won't know until somebody does a real animal study. However, there's not much of a rebound or hangover associated with mephedrone use, like there is with amphetamines and especially mdma. I'm not exactly sure about the correlation, but it is my understanding that this is a good indicator of neurotoxicity.

I think you guys are overestimating the dangers of peripheral vasoconstriction. You don't really have to worry about vasoconstriction unless it keeps up for a significant period of time (>12 hours), which is extremely unlikely with responsible use of the drug. Obviously this can be a problem with the idiots who are doing two-week benders on it, but almost anything would be dangerous when consumed in those levels, so I don't think there's anything special about mephedrone in this regard.

The main cardiovascular risk with these types of drugs is with the heart itself due to tachycardia and subsequent arrhythmias. Mephedrone doesn't appear to be too heavy on the central cardiovascular system, and would most likely be much safer than most amphetamines due to reflex bradycardia because of said vasoconstriction. The only other related compound that I'm aware of that has similar vasoconstrictive properties is pseudoephedrine, which as we know is pretty safe. Even pseudoephedrine has some small risks in tachycardia, palpitations and arrhythmia- but it is still safe enough to be over the counter. I wouldn't be surprised if Mephedrone's cardiovascular risk lined up favorably to that of pseudoephedrine.

 

[nuke]

Unlike most other chemicals with a similar structure, 4-MA's action on serotonin release is very low. Since we know that 4-MA is para-substituted like mephedrone, maybe mephedrone is very low on serotonin release as well. That would back up my subjective observations, but there's obviously very little we have to go in in this respect.

Huh? 4-MA is as potent of a serotonin release as MDMA or pCA.

When it comes to how all this effects neurotoxicity, we won't know until somebody does a real animal study. However, there's not much of a rebound or hangover associated with mephedrone use, like there is with amphetamines and especially mdma. I'm not exactly sure about the correlation, but it is my understanding that this is a good indicator of neurotoxicity.

I don't really get hangovers from methamphetamine or MDMA unless I use crazy amounts and avoid sleep, but that doesn't mean it's not toxic.

The main cardiovascular risk with these types of drugs is with the heart itself due to tachycardia and subsequent arrhythmias. Mephedrone doesn't appear to be too heavy on the central cardiovascular system, and would most likely be much safer than most amphetamines due to reflex bradycardia because of said vasoconstriction. The only other related compound that I'm aware of that has similar vasoconstrictive properties is pseudoephedrine, which as we know is pretty safe. Even pseudoephedrine has some small risks in tachycardia, palpitations and arrhythmia- but it is still safe enough to be over the counter. I wouldn't be surprised if Mephedrone's cardiovascular risk lined up favorably to that of pseudoephedrine.

I would, being that mephedrone is probably a strong 5HT releaser and that it may in the long term cause cardiac valve damage. It's like fenfluramine and phentermine all in one drug, with a shorter half life but higher abuse potential. We don't even known if it's a 5HT2B agonist either (like norphenfluramine), but the structure is fairly similar.

 

[Operation Atlas]

Huh? 4-MA is as potent of a serotonin release as MDMA or pCA.

Compared to amphetamine analogues.

I would, being that mephedrone is probably a strong 5HT releaser and that it may in the long term cause cardiac valve damage. It's like fenfluramine and phentermine all in one drug, with a shorter half life but higher abuse potential.

It doesn't matter how much 5ht it releases, it matters whether it binds to HTR2B receptors. This is also only really a problem with long-term usage, as with phen-fen when prescribed for daily use. Mephedrone also has a much shorter half-life than either of these two chemicals.

As long as you don't give mephedrone to fat people on a daily basis, I think the cardiovascular risks are very small.

 

[vecktor]

I think you guys are overestimating the dangers of peripheral vasoconstriction. You don't really have to worry about vasoconstriction unless it keeps up for a significant period of time (>12 hours), which is extremely unlikely with responsible use of the drug. Obviously this can be a problem with the idiots who are doing two-week benders on it, but almost anything would be dangerous when consumed in those levels, so I don't think there's anything special about mephedrone in this regard.

The main cardiovascular risk with these types of drugs is with the heart itself due to tachycardia and subsequent arrhythmias. Mephedrone doesn't appear to be too heavy on the central cardiovascular system, and would most likely be much safer than most amphetamines due to reflex bradycardia because of said vasoconstriction. The only other related compound that I'm aware of that has similar vasoconstrictive properties is pseudoephedrine, which as we know is pretty safe. Even pseudoephedrine has some small risks in tachycardia, palpitations and arrhythmia- but it is still safe enough to be over the counter. I wouldn't be surprised if Mephedrone's cardiovascular risk lined up favorably to that of pseudoephedrine.

if there is reflex bradycardia why is the reported pulse rate of users rediculously high?
Mr cardiovascular genius can you explain how vasoconstriction and consequent reduced blood supply to the heart muscle combined with tachycardia and increased oxygen demand by the cardiac muscle is a good thing?
Also can you explain the prevalence of pains in the chest and in the left arm, also the reports of people who have used the drug heavily having severe brethlessness.

Mephedrone is IMHO a shitty stick drug, but each to their own, maybe it is a worthwhile drug if you have access to discount cardiovascular implants???

 

[nuke]

Compared to amphetamine analogues.

Right, but it doesn't concern you that putting a methyl in the 4-position increases the affinity for the 5HT release 33 fold? That's a hell of a lot more than n-methylation increases the affinity (a bit over 2 fold). N-methylation of (-)-cathinone to (-)-methcathinone decreases the concentration needed to achieve 5HT release from 2,366 to 1772 nm, not as dramatic as the difference from AMP to METH but still considerable. I don't think it's far off to think that the 4-position methylation may achieve a remarkable increase in serotonin release for methcathinone. And it's already known methcathinone is a neurotoxin, too.

It doesn't matter how much 5ht it releases, it matters whether it binds to HTR2B receptors. This is also only really a problem with long-term usage, as with phen-fen when prescribed for daily use. Mephedrone also has a much shorter half-life than either of these two chemicals.

As long as you don't give mephedrone to fat people on a daily basis, I think the cardiovascular risks are very small.

Yes, it does matter how much 5HT is released as methamphetamine has an affinity for the 5HT2B receptor that is undetectable (Ki database entry #48555, >10 µM) yet causes pulmonary arterial hypertension and cardiac valve proliferation. Aside from that, it's still very possible that mephedrone is a 5HT2B agonist as is.

 

[Operation Atlas]

if there is reflex bradycardia why is the reported pulse rate of users rediculously high?
Mr cardiovascular genius can you explain how vasoconstriction and consequent reduced blood supply to the heart muscle combined with tachycardia and increased oxygen demand by the cardiac muscle is a good thing?
Also can you explain the prevalence of pains in the chest and in the left arm, also the reports of people who have used the drug heavily having severe brethlessness.

Mephedrone is IMHO a shitty stick drug, but each to their own, maybe it is a worthwhile drug if you have access to discount cardiovascular implants???

I haven't seen any reports of "rediculously high" heart rates. In order to be of any concern, it'd have to be >150bpm for more than a half hour. My resting pulse rate on the stuff is usually 90-110bpm, which is high but certainly not enough to cause heart damage.

Obviously extreme levels of vasoconstriction aren't great for your heart, but the vessels near your heart are fucking huge, and aren't going to cut off blood supply to any part of your heart absent a blockage of some kind. The only thing that will happen is increased peripheral resistance, which increases blood pressure, which will immediately cause the heart to slow down (reduce cardiac output).

If you go on a mephedrone binge, you WILL get chest pains- I've never defended usage of this stuff for more than a 8 hour period. It'd be pretty much the same as if you were jogging for a day straight- unless your heart's in really great condition, keeping it at >120bpm for a long period of time is not good for it.

I haven't seen any reports of breathlessness- the only reason this would happen in a cardiac situation is if there is fluid buildup in the lungs due to compromised heart function, probably in the right ventricle. I don't see that happening, and if anything mephedrone would probably reduce any fluid buildup in the lungs. The breathlessness is most likely due to the ROA more than anything.

I'm not trying to say that this stuff is great for you, I'm just trying to argue that you guys are way overestimating the dangers of this drug. By saying such outlandish things people aren't going to listen to you and are just going to do the drug anyhow. People need to be aware that there are levels of responsible usage and that there are levels of irresponsible usage, and I think we should be concentrating on keeping people from using irresponsibly, instead of keeping them from using at all. Applying shit sticks and whatnot just makes you sound like reefer madness fear mongers.

 

[ColtDan]

i used to get heavy heart beats/louder heart for a few days after doing the really smelly meph. since ive stopped doing that stuff ive not suffered from it. a potentially useful bit of information for anyone that does do the smelly stuff. avoid that shit. it also gave me minor visuals

 

[vecktor]

I'm not trying to say that this stuff is great for you, I'm just trying to argue that you guys are way overestimating the dangers of this drug. By saying such outlandish things people aren't going to listen to you and are just going to do the drug anyhow. People need to be aware that there are levels of responsible usage and that there are levels of irresponsible usage, and I think we should be concentrating on keeping people from using irresponsibly, instead of keeping them from using at all. Applying shit sticks and whatnot just makes you sound like reefer madness fear mongers.

Bluelight is not some consensus based organisation, there are people who can take different positions on various things, that is the beauty of it.

I don't care if people take this drug or not , or responsably or irresponsably, it is their decision, just like it is my decision, based on what I can see, NOT to take this drug.
Just as it would be my judgment based on what I have seen in your posts not to rely on you for medical information.

I truly hope I am wrong with the hazards of mephedrone, sadly I think that time will prove me right.

 

[ebola?]

A dose by dose comparison perhaps isn't that silly... Let's say that the effective concentration to release dopamine for amphetamine requires 20mg of dextroamphetamine or 10mg of dextro-methamphetamine... Compare this to the slightly less lipophilic (-)-cathinone/(-)-methcathinone which is active around 40mg/20mg. From the EC50s you can see that 4-Methylamphetamine is at least 1/5 or so as active as a dopamine releaser, so you'd expect the equivalent dose around 100mg or more.

I was thinking of a comparison with MA. Okay, I meant that x milligrams vs. x milligrams didn't make sense, so you have something way more sophisticated here. BUT, wouldn't making this comparison between MA and MDMA entail a ridiculous dose of MDMA? Is that why we can say that MA is more neurotoxic, as no one takes a dose of MDMA that releases as much DA as typical doses of MA?

I don't think it's too far off in believing that 4-MMC can produce a large amount of 5HT efflux.

I was likely unclear. I don't doubt 5ht efflux for 4MMC (I'd be surprised if it didn't ), but I wondered why we'd expect it to be significantly worse than MDMA.

p-Chloroamphetamine is roughly equipotent to or slightly than MDMA in terms of generating 5HT efflux

Okay...I thought p-CA was SUPER neurotoxic, like MPTP but for neurons w/ 5ht receptors. Is there an additional mechanism?

(The bit on pCA mediated efflux: "Serotonin-transporter mediated efflux: A pharmacological analysis of amphetamines and non-amphetamines" Neuropharmacology)

Thanks. This layperson needs edumacation.

ebola

 

[nuke]

I was thinking of a comparison with MA. Okay, I meant that x milligrams vs. x milligrams didn't make sense, so you have something way more sophisticated here. BUT, wouldn't making this comparison between MA and MDMA entail a ridiculous dose of MDMA? Is that why we can say that MA is more neurotoxic, as no one takes a dose of MDMA that releases as much DA as typical doses of MA?

Well, MDMA analogues that are pretty much selective for 5HT release like MBDB are still self-administered in rats. It may simply be that the subjective high and desired amount/type of effects is different between METH and MDMA so the dosing is different because something fundamentally different is achieved. But then again, maybe DA really has shit all to do with the related neurotoxicity of MDMA and NE release is a bigger part of the picture (catecholamine transporters are promiscuous), and the subjective effect is just from this specific combination, or maybe the 5HT2A/5HT2C receptor agonism really impact subjective effect and monoamine release in specific areas of the brain that you can't learn about from looking about how many monoamines a cell releases when exposed to such and such chemical. It gets convoluted, which is why this mostly remains a estimate.

Aside from that MDMA is fairly specific towards serotonergic neuron neurotoxicity while METH will kill off both serotonergic neurons and dopaminergic neurons (and I'm pretty sure there was a study recently specifying it did nothing good for norepinephrinergic neurons as well). How to extrapolate the neurotoxicity between the two is hard to say exactly: METH is about 10 fold as potent a neurotoxin as MDMA, but they have different neuronal selectivity, different monoamine releasing patterns and different affinities for various 5HT receptors.

I was likely unclear. I don't doubt 5ht efflux for 4MMC (I'd be surprised if it didn't ), but I wondered why we'd expect it to be significantly worse than MDMA.

Well, in terms of 5HT release it could possibly be similar to MDMA (who knows really, just reaching around in the dark, maybe slightly less). But the thing is the ratios involved for say DA:5HT and NE:5HT release don't seem to be in good ranges as far as toxicology goes. We haven't heard a lot of glowing things about 4-Methylamphetamine, and it's smack in the middle. I'm not sure that say, 4-Chloroamphetamine is going to be much different. I mean, hydrophobic interactions, slightly larger van der Waals radius, but otherwise they tend to act fairly similar (as can be made out with the potency of the 2C/3C psychedelic phenethylamines). The electronegativity for Cl is a little higher, so you know, you could maybe guess a slightly higher affinity for the DA/NE transporter, but the para-Bromine analogue has a very similar electronegativity to carbon yet similarly a awful toxicology profile to p-CA.

Even the source of the monoamine release data is important too, as human dopamine cell lines have indicated a many fold higher affinity of (+)-METH for the human dopamine transporter as compared to rat dopamine cell lines. The proteins/enzymes between organisms, even closely related ones, are rarely perfectly equivalent to eachother. I think these were for human cells, though the paper with 4-MA/3-MA had slightly different efflux values for DA/NE for d-AMPH as per usually given, with them near equipotent which is slightly strange.

Okay...I thought p-CA was SUPER neurotoxic, like MPTP but for neurons w/ 5ht receptors. Is there an additional mechanism?

I mean, METH is pretty hideously neurotoxic but its damage seems localized to areas of the brain that don't generally impact motor control, so even if you damage dopaminergic cells, you may not always get the same results. pCA is strongly neurotoxic although if I recall correctly it was tried in humans in the 50's. Not sure what the results were exactly. The earlier studies that evaluated the toxicology had found that the mechanisms by which it produced neurotoxicity were distinct from those of METH and MDMA, though I'm not sure what the significance of that is exactly. What seems pretty clear is that things that release DA/NE and 5HT together, even with ratios moderately favouring one or the other, seem to be very good at producing neurotoxicity whereas agents that don't do not. There's still a great need for the production of more evidence, though.

One experiment that could be done to evaluate the 5HT release of mephedrone is to monitor the temperature of the user before and after the ingesting of the drug. 5HT releasers generally always elevate temperature.

 

[Amberthefrog]

Some great posts in here, specially by vecktor. I've sampled the stuff twice, both times loving it and experiencing pretty much no negative effects. After reading the stuff about a potential beta-hydroxyl metabolite though, I'm not going to touch the stuff again. Even if it's probably fairly safe to take it infrequently at low end doses, the list of potential risks involved seems too great to make the experience worth it. Maybe one day if toxicity research is done, till then bye-bye. Glad I sampled it though, very enjoyable, unique experience. What has shocked be is the apparent rise in usage in the UK over the past few months. 5 months back I had only heard about this stuff on the internet, now I have spoken to numerous people who have tried it.

I'm not trying to say that this stuff is great for you, I'm just trying to argue that you guys are way overestimating the dangers of this drug. By saying such outlandish things people aren't going to listen to you and are just going to do the drug anyhow. People need to be aware that there are levels of responsible usage and that there are levels of irresponsible usage, and I think we should be concentrating on keeping people from using irresponsibly, instead of keeping them from using at all. Applying shit sticks and whatnot just makes you sound like reefer madness fear mongers.

Stupid post.

 

[pofacedhoe]

it clearly has a large effect on 5ht, if you have ever tried ssri's e.g. citalopram it has an overlap of effect- the massive effect on colours in vision when using mephedrone (you dont get this with speed or coke to anywhere near the same degree). this is probably responsible for people comparing its effects to mdma-the way a thing makes you feel can be used to compare to known effects of other things you have tried

it also has a large adrenaline effect (hence the feeling of adrenaline rush after a line and the micro willy álá amphetamine) and a moderate dopamine effect ( if you have been taking coke it feels seriously weak in euphoria by comparison). if you have done a lot of stimulants you can guage what a new stimulant is doing with a degree of accuracy...

 

[phillop]

First study I have seen in journal about it, thought it would do well here. And if anyone can access the full article and not just the abstract and upload it or PM me it that would be VERY much appreciated. As I dont think the dosage in the abstact is right, or its very misleading in some way.

CLINICAL TOXICOLOGY Volume: 47 Issue: 7 Pages: 733-733 Meeting Abstract: 153 Published: 2009

153. Recreational Use of 4-Methylmethcathinone (4-MMC) Presenting with Sympathomimetic Toxicity and Confirmed by Toxicological Screening

Wood DM,1,2 Davies S,3 Puchnarewicz M,3 Button J,3 Archer R,4 Ramsey J,3,5 Lee T,3 Holt DW,3 Dargan PI.1,2 1Clinical Toxicology, Guy’s and St Thomas’ Poisons Unit, London, United Kingdom; 2King’s Health Partners, London, United Kingdom; 3Analytical Unit, St George’s, University of London, London, United Kingdom; 4Kingston University, Kingston upon Thames, United Kingdom; 5TICTAC Communications, St George’s, University of London, London, United Kingdom.

Introduction: Leaves of the Khat plant (Catha Edulis) are widely chewed by the Somali community for their stimulant properties. This is due to release of cathinone from the leaves on chewing. Extraction from khat and/ or synthesis of cathinone and the related alkaloid methcathinone are controlled under the UK Misuse of Drugs Act, 1971. However, other cathinone derivatives such as 4-methylmethcathinone (4-MMC, mepherdone) are not currently controlled. 4-MMC is promoted as “safe and legal” alternative to classified recreational drugs. We report the first case of toxicity related to 4-MMC confirmed by toxicological screening. Case report: A 22 year old man presented after oral ingestion of 200mg and subcutaneous injection of 3.8g of 4- MMC. He developed palpitations and blurred vision shortly after use. On arrival in the ED he had sympathomimetic features (agitation, 7mm dilated pupils, HR 105, BP 177/111 mmHg). His temperature was 36.3°C and he had normal tone with no clonus. EKG showed a sinus tachycardia only. He was treated with 1mg of oral lorazepam. His sympathomimetic features settled within 6 hours of presentation. Serum and urine samples taken at the time of presentation were sent for toxicological analysis. Toxicological Screening Screening methods were developed for 4-MMC using in-house derivatives of cathinone and methcathinone checked for purity by Nuclear Magnetic Resonance. Samples were screened using Gas Chromatography with Mass Spectrometry. The only substance detected was 4-MMC; no other drugs or alcohol were detected. Liquid chromatography with tandem Mass Spectrometry was used to confirm and quantitate 4-MMC, the serum concentration was 0.15mg/L.

Conclusion: We report the first case of confirmed, lone, use of 4-MMC resulting in sympathomimetic toxicity. Clinical toxicologists should be aware of the potential for use of these compounds in patients presenting with sympathomimetic toxicity.

 

[dread]

subcutaneous injection of 3.8g of 4- MMC.

W T F

 

[phillop]

W T F

^ I know! I would have thought that even half of that would give someone a heart attack. Thats why we need the full paper. The abstract implies it was done at once, but he may have taken it over a longer time period.

Either way, 3.8 grams is a hell of a lot to do in one session no matter what timescale or ROA.

 

[dread]

With a subcutaneous injection, no less... Try injecting 3.8 grams of anything under your skin with one dose... :D

 

[Jamshyd]

ANY drug that make you think its ok to S.C. 3.8g is obviously not safe for you .

 

[vecktor]

the 3.8g number is a typo. it would be next to impossible to inject that much sc.

I would guess the true number is some round gram number minus the 200mg that was snorted so probably 800mg.