How toxic is Mephedrone?

[jac1999]

has there really been no study on Mephedrone at all? I can't believe that a substance is such wide use now has unknown toxicity.

 

[Ceres]

^ not even tested on rats as far as I'm aware.

 

[vecktor]

toxicity data almost...

What is wierd is that those people who have reported severe reactions had taken it previously at high doses without adverse effects. which inspiredme to look into the likely metabolites

We know little about the metabolism of 4-mmc, I would expect that the metabolites will be the betahydroxy compound (paramethyl ephedrine) the N-demethylated betahydroxy compound (paramethylnorephedrine) more on these later...
and to a lesser extent the metabolites from P450 oxidation of the 4-methyl position;- the hydroxymethyl (benzyl alcohol) and the carboxylic acid this seems more common with the more lipophillic cathinones. all water soluble and so elimination is going to be renal, with limited amounts in other fluids.

I think that the metabolites rather than the drug itself will provide the answer to the toxicity.
the betahydroxy compounds are almost certainly the primary metabolites of mephedrone, and these are known compounds with toxicity data:
ed betahydroxy compound (paramethylnorephedrine) more on these later...
and to a lesser extent the metabolites from P450 oxidation of the 4-methyl position;- the hydroxymethyl (benzyl alcohol) and the carboxylic acid. all water soluble and so elimination is going to be renal, with limited amounts in other fluids.

I think that the metabolites rather than the drug itself will provide the answer to the toxicity.
the betahydroxy compounds are almost certainly the primary metabolites of mephedrone, and these are known compounds with toxicity data:

the primary metabolite paramethyl ephedrine is compound II in the paper below and is 3.4x more toxic than ephedrine in guinea pigs or 2.27 x more toxic than ephedrine in rabbits

A survey of the toxicities reveals no parallelism between the two methods
of determination. There is, however, a remarkable regularity of increase
in the toxicity on intravenous administration of the phenylalkanolamines
with increase in length of the side chain. Another striking fact is the much
greater toxicity of the p-tolyl derivatives (I11 and V) as compared with the
corresponding phenyl products (I1 and IV), which lends support to the
observation of de Burnaga Sanchez'O that p-methylephedrine is about 20%
more toxic than ephedrine.

AMINO-ALCOHOLS. II. HOMOLOGS AND ANALOGS OF PHENYLPROPANOLAMINE
Walter H. Hartung, James C. Munch, W. Allan Deckert, Frank Crossley
J. Am. Chem. Soc., 1930, 52 (8), pp 3317–3322
DOI: 10.1021/ja01371a046

asuming that this metabolite s the primary metabolite,
working from the sc guinea pig LD50 of 175mg/kg using the standard conversion of divide mg/kg by 4 to go from guinea pig to human gives 44mg/kg for this metabolite as the LD50 for humans. an estimate of around 3.3 g for 75kg body weight. people with idiosyncratic metabolism or are taking caffeine as well will die at lower doses.

we know that vanilla cathinone has central half life of 1.5 hrs or so, and that the beta hydroxy compound cathine has a much longer half life 5 hrs or so , extrapolating this to 4-mmc would seem to suggest that repeated redosing of 4-mmc raises the levels of the betahydroxy metabolite, even though plasma levels of 4-mmc do not significantly rise above the initial peak. the longer the redosing continues the more this metabolite accumulates.

4-mmc is also a chiral molecule, unlike ordinary methcathinone it is a mixture of enantiomers, as it is made from 4-methylpropiophenone rather than a chiral precusor. with other cathinones both enantiomers have cardiac activity but only one has significant mental effects. the other enantiomer in 4-mmc is not contributing to the central effects but it is causing cardiovascular effects.

http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1884326

people are taking grams of a drug that metabolises to an ephedrine like compound, a compound that is considerably more toxic than ephedrine in animal models and a metabolite which likely has a much longer half life than 4-mmc, and we wonder why there are problems. the interesting thing is not that there are problems is that they are relatively infequent.

the vendors should have pulled this stuff when adverse effects were first apparent, but they don't give a fuck as long as the money rolls in.

they should also do their homework properly, I got all this with an hour of googling.
I should be a due dilligence consultant, my standard rate is 2K USD per day

please be careful with this stuff, used in moderation it is probably reasonably safe perhaps no worsethan methcathinone itself.

V

 

[vecktor]

weak MAO-B activity of Nor 4-MMC
pretty weak, 100 uM IC50 for Nor 4-MMC at MAO-B, betahydroxy Norephedrine a possible 4-MMC metablite has a 12 uM IC50 at MAO-A about 4-6 times worse than moclobemide.
unfortunately all the compounds tested were primary amines

though for those interested para-alkylthio cathinones would be a very very bad idea.

Bioorganic & Medicinal Chemistry
Volume 12, Issue 15, 1 August 2004, Pages 4055-4066

doi:10.1016/j.bmc.2004.05.033

MAO inhibition by arylisopropylamines: the effect of oxygen substituents at the β-position

Mauricio Osorio-Olivaresa, Marcos Caroli Rezendea, , , Silvia Sepúlveda-Bozab, Bruce K Casselsc and Angélica Fierroa

aFacultad de Quı́mica y Biologı́a, Universidad de Santiago, Casilla 40, Correo 33, Santiago, Chile

bFacultad de Ciencias Médicas, Universidad de Santiago, Casilla 442, Correo 2, Santiago, Chile

cMillennium Institute for Advanced Studies in Cell Biology and Biotechnology and Departamento de Quı́mica, Facultad de Ciencias, Universidad de Chile, Las Palmeras 3425, Santiago, Chile

Received 26 January 2004; revised 17 May 2004; accepted 26 May 2004. Available online 22 June 2004.
Abstract

Twenty-nine arylisopropylamines, substituted at the β-position of their side chain by an oxo, hydroxy, or methoxy group, were evaluated in vitro as MAO-A and MAO-B inhibitors. The oxo derivatives (`cathinones') were in general less active as MAO-A inhibitors than the corresponding arylisopropylamines, but exhibited an interesting MAO-B inhibiting activity, which was absent in the hydroxy, methoxy, and β-unsubstituted analogues. These results suggest that selective affinity for the two MAO isoforms in this family of compounds is modulated not only by the aryl substitution pattern but also by the side-chain substituents on the arylalkylamine scaffold.

Twenty-nine arylisopropylamines with an oxo, hydroxy, or methoxy side-chain β-substituent were prepared and evaluated in vitro as MAO-A and MAO-B inhibitors.

 

[Coolio]

they should also do their homework properly, I got all this with an hour of googling.
I should be a due dilligence consultant, my standard rate is 2K USD per day

V

Thanks for your efforts man.

 

[Tryptamite]

Yeah thanks for the info Vector.

 

[kong]

Are there drugs that could be taken as emergency antidotes to severe vasoconstriction?

Viagra comes to mind...but I'm sure there are others.

Obviously a hospital would be in the cards for me personally if I had any doubts, but if an antidote exists and can be used safely I'd like to use it as soon as possible in the event of an adverse reaction.

I didn't notice any vasoconstriction with mephedrone, but I only took it up to 350mg and the effect it had on my heart left me with no desire to repeat the experience.

I am more worried about the DOX series as those tend to numb my extremities the most.

 

[Coolio]

Yeah, I would love to know if there is an uncontrolled antidote to drug-induced vasoconstriction, preferably with no effects of its own.

 

[mr.grey]

please be careful with this stuff, used in moderation it is probably reasonably safe perhaps no worsethan methcathinone itself.

V

Thank's a lot Vecktor for all this information!
What would you consider as a moderate amount?
Something like 200-400mg per night or (much) less?

I have contact with two vendors and based on the information I have received from them plus some rough extrapolation, I would say that around 8-10kg of Mephedrone (maybe even more) are sold in europe every week.
With a dose of 200mg, this would mean that 50.000 doses are consumed every week.
Based on that amount I think that the reports of worrying side effects are quite low, but on the other hand I'm not sure how many of the affected people actually report their problems.
Does anyone have information how long it usually took scientists in the past to start researching a new drug?
I would really appreciate if some labs would do some research on that stuff soon, so we actually know what we're dealing with.

Have such studies be done with Methylone already?
I'd guess so, but if anyone has an actualy link on some, that would be awesome.

 

[Ximot]

I am really thinking twice now whether I should really order this drug

 

[vecktor]

^
sadly the academic research is usually done a few years after the substance is illegalised, it was for methcathinone and 4-MTA.

an interesting point about the absolute incidence of adverse effects, I would be interested to know how often adverse effects, such as numbness or coldness of the extremities, excessive heart rate, headache, occur.
if 50,000 doses are being consumed a week it would appear to be 1 in 10,000 to 1 in 50,000 based on reported problems the true incidence could be higher. this is several orders of magnitude more often than MDMA, where well over 500,000 doses a week are being consumed in Europe. 4-MTA was about 1 in 25,000 doses resulting in severe complications.

as for what is a moderate dose/ or use? I don't know. but I would suggest levels that as an absolute maximum, no more than around 200-300mg per session and 5-7 days between sessions as a detox period, any more than that and the ephedrine like metabolite is accumulating. if it is like ephedrine frequent use will also raise the risk of cardiovascular problems, stroke heart attack etc. and ephedrine's cardiovascular toxicity effects young people too

Ephedrine use has been linked to numerous severe incidents in one report on ephedrine:

Of most concern were the "sentinel" events, which were based on documentation that: 1) an adverse event had occurred; 2) the subject had consumed ephedra within 24 hours prior to the event or a toxicological examination showed ephedrine or one of its associated products in the blood or urine; and 3) an adequate investigation had evaluated for and excluded other causes. A total of 21 sentinel events were identified with prior ephedra consumption: two deaths, four myocardial infarctions, nine strokes, one seizure, and five psychiatric cases.* About half of all sentinel events occurred in persons aged 30 years or younger, although this could easily reflect patterns of spontaneous reporting.

http://nccam.nih.gov/news/alerts/ephedra/working-group.htm

there is not an easy way to deal with the vasoconstrictive properties, in studies with cathinone the vasoconstrictive properties were found to be at least partially working through a mechanism other than adrenergic agonism, perhaps indirectly through epithelin or other peptide?

I personally wouldn't touch this stuff with fastandbulbous's metaphorical shitty stick

does anyone know what enzyme reduces cathinones to hydroxy compounds?

the other question I have is how many half lives of the metabolite should one wait before redosing to avoid excessive accumulation of the metabolite? I think 4 half lives, guessing about 20hrs? that way only an eigth of the previous doses metabolite is present as a background level.

next I shall be looking at 4-fluoromethcathinone, and also the particularly worrying beta keto DOB and betaketo 2CB, which both look like a real disasters.

 

[MurphyClox]

does anyone know what enzyme reduces cathinones to hydroxy compounds?

AFAIK, the exact enzyme was not studied in detail. But such a metabolic reactions usually take place in liver microsomes, and are performed by dehydrogenases, carbonyl reductases or CYP450s.
- Murphy

 

[flacky]

Yeah, I would love to know if there is an uncontrolled antidote to drug-induced vasoconstriction, preferably with no effects of its own.

Maybe Yohimbine would work due to its effects at the adrenergic receptors?

Simply having a vasodilator would be counterproductive. The best thing to do is to attack the actual mechanism by doing the reverse of it on the same receptor. (kind of like how using a stimulant won't stop a Heroin OD, but Naloxone will).

I'd be worried, though about Yohimbine's 5-HT receptor affinity in conjunction with this drug, though. Anyone want to weigh in on this? I mean, this is probably the only OTC preparation which will have an effect on the adrenergic receptors (which are probably the receptors which are responsible for Mephedrone's vasoconstrictive properties).

 

[pofacedhoe]

Maybe Yohimbine would work due to its effects at the adrenergic receptors?

Simply having a vasodilator would be counterproductive. The best thing to do is to attack the actual mechanism by doing the reverse of it on the same receptor. (kind of like how using a stimulant won't stop a Heroin OD, but Naloxone will).

I'd be worried, though about Yohimbine's 5-HT receptor affinity in conjunction with this drug, though. Anyone want to weigh in on this? I mean, this is probably the only OTC preparation which will have an effect on the adrenergic receptors (which are probably the receptors which are responsible for Mephedrone's vasoconstrictive properties).

the thought of yohimbine with mephedrone goes through me

 

[flacky]

Well, it might be the only OTC option of countering Mephedrone-related vasoconstriction. The common theory ATM is a hydroxy-metabolite's action on the adrenergic receptors. Yohimbine could counter that. I mean, can you think of any other OTC adrenergic agents?

 

[pofacedhoe]

^no but personally i think medical emergencies involving vasoconstriction are the domain of a doctor. i know things (but would lack confidence in solving a drug based medical emergency with more drugs off my own bat)yet not eough as also a doctor would have access to something a bit more effective with less peripheral side effects.

as not everone experiences the same effects from drugs i.e beta blockers and the paradoxical response, i would assume that people getting a random medical crisis may have slightly different body style (at the genetic level) and therefore maybe more unussual reactions to things. they might be fine and this may work but i would rather have a doctor solve the emergency of my friend than risk doing more damage to them myself.

if a situation is serious then running the risk of law enforcement is something i would do to help my friend and i'm not a person to panic or place my faith in the authorities-they have yet to acheive any help with my bipolar, its been up to me to find a life that works. but i am afraid of playing doctors and nurse when a person needs the real thing.

 

[flacky]

Trust me, I think it's best in the hands of a doctor too. I'm just answering a question put before me.

 

[vecktor]

^ It is far from certain that an adrenergic antagonist would help in any way, I would have thought that the mechanism is adrenergic agonism, but it might not be, vanilla cathine appear to be able to cause vasoconstriction in an interesting way.

For them to contract the coronary artery by a sympathomimetic action, they would do so via α-adrenoceptors in a similar manner to noradrenaline. Like noradrenaline they would therefore be susceptible to blockade by the α1-adrenoceptor antagonist, prazosin. There was no antagonism of cathinone- or MDMA-induced contractions by prazosin (in the presence of cocaine). The coronary vasoconstrictions by cathinone and MDMA do not therefore appear to be mediated through an indirect sympathomimetic action or via α1-adrenoceptors. This finding contrasts with earlier observations at other sites where cathinone is reported to have indirect amphetamine-like actions by releasing noradrenaline (Kalix, 1983) and MDMA increases blood pressure of anaesthetized rats via α1-adrenoceptors (McDaid and Docherty, 2001).

The mechanism by which cathinone and MDMA cause coronary vasoconstriction cannot be identified from this study but the possibility must be considered that they are releasing other endogenous vasoconstrictors such as angiotensin or endothelin or activating a novel receptor system. The source of such vasoconstrictors, however, is not the endothelium, since removal of the endothelium failed to attenuate the cathinone- and ecstasy-induced contractions. Furthermore, endothelium removal did not enhance the contractions, indicating that they do not concurrently release endothelium-associated vasodilator mediators,

doi:10.1016/j.vph.2007.03.001

 

[kfluxsake]

In response to the paramethyl ephedrine metabolite being 3.4 x as toxic as ephedrine - the statement is pretty arbitrary: are you referring to liver toxicity/neurotoxicity ?

Ephedrine is only v weakly neurotoxic - especially when compared to other amphetamine analogues. Mephedrone is likely a much safer high than mdma (no lipid peroxidation due to depleted 5-HT and related dopamine misplacement) or speed (no significant release - it's a DRI)

Contrbutions above would suggest it is only a weak substrate inhibitor of MAOI. But everything about its effects is telling me otherwise:

1) The relative absence of initial mdma-like 'come up' sensation on further redosing

2) No significant comedown: miraculous considering the undisputed initial serotonergic effect

3) The fact that I experience above effect in its totality despite taking an SSRI daily - something unachievable on mdma

4) Long action perceptible well into next day

 

[vecktor]

In response to the paramethyl ephedrine metabolite being 3.4 x as toxic as ephedrine - the statement is pretty arbitrary: are you referring to liver toxicity/neurotoxicity ?

Ephedrine is only v weakly neurotoxic - especially when compared to other amphetamine analogues. Mephedrone is likely a much safer high than mdma (no lipid peroxidation due to depleted 5-HT and related dopamine misplacement) or speed (no significant release - it's a DRI)

Contrbutions above would suggest it is only a weak substrate inhibitor of MAOI. But everything about its effects is telling me otherwise:

1) The relative absence of initial mdma-like 'come up' sensation on further redosing
and this is evidence of maoi activity- give me a break

2) No significant comedown: miraculous considering the undisputed initial serotonergic effect
yeah you can assign a specific neurochemical action to an experienced effect, bullshit. if that was the case why bother with pharmacology

3) The fact that I experience above effect in its totality despite taking an SSRI daily - something unachievable on mdma
this has absolutely nothing to do with anything, ssris inhibit uptake of MDMA by sert. so how is this evidence of MAOI activity
4) Long action perceptible well into next day
did you read anything about the half life of beta hydroxy amines? how is long action anything like evidence of MAOI activity other drugs which aren't MAOIS can last a while too

so once again we have half baked rubbish being posted.

who suggested anything about neurotoxicity or hepatotoxicity??

the toxicity figures are for killing rabbits and guinea pigs. nothing arbritrary about it, at a dose 3 or so times less than the dose of ephedrine required to kill half the rabbits, half the rabbits died. dead is easy to determine.

this is tiresome.
If people are going to make statements how about they post some fucking evidence, how about the evidence being a bit more solid than "hey man this stuf kinda felt serotoninergic and stuff"

the numbers of adverse events versus doses consumed suggest that mephedrone is not safer than MDMA.