Mephedrone science

[vecktor]

A New thread,
the idea is that unlike the previous how 'toxic is mephedrone' thread the discussion here stays high level and to the point. the other thread is now extremely unwieldy and difficult to extract the useful information from the other drivel.

no trip reports.

 

[vecktor]

mephedrone analysis

Mephedrone Analytical data. In French

Is 4-methylephedrone, an “Ecstasy” of the twenty first century?


Olivier Roussel1, Martine Perrin1, Philippe Herard1, Marc Chevance1, Patrick Arpino2

Abstract – A capsule, presumed to contain ecstasy, was seized in 2007 and transmitted to the laboratory of the IRCGN
for confirmation purpose. However, after chemical analysis using ion mobility spectrometry, gas chromatographyelectron
ionisation mass spectrometry (GC-EI/MS), nuclear magnetic resonance spectroscopy (NMR), and liquid
chromatography, electrospray ionisation mass spectrometry (LC-ESI/MS), the substance was identified as 4-
methylephedrone and not as ecstasy. This case was an example of the development of new addictive drugs, specifically
designed to by-pass current legislation, and generally called ‘designer drugs’.
Key words: 4-methylephedrone, NMR, GC-MS, LC-ESI/MS

http://www.ata-journal.org/articles/ata/pdf/first/ata09028.pdf

 

[vecktor]

Human and rat metabolism

Mephedrone metabolism.

looks like my earlier prediction of the paramethyl ephedrine metabolite is correct, although it also makes paramethyl norephedrine by N-demethylation.

from what I am hearing mephedrone users should expect more bad news over the following months.

please use this stuff in strict moderation if you must use it, if you can't moderate your consumption don't take it at all. It is not looking good at the moment.
vecktor

. Metabolism of the new designer drug mephedrone
and toxicological detection of the beta keto designer drugs
mephedrone, butylone and methylone in urine
M.R. Meyer, F.T. Peters, H.H. Maurer
Department of Experimental and Clinical Toxicology, Saarland University,
D-66421 Homburg (Saar), Germany

Introduction: Beta keto (bk) designer drugs are a new class of drugs of
abuse. In contrast to mephedrone (2-methylamino-1-p-tolylpropane-1-one),
the metabolism of butylone (2-methylamino-1-(3,4-methylenedioxyphenyl)
butan-1-one, bk-MBDB) and methylone (3,4-methylenedioxymethcathinone,
bk-MDMA) has already been investigated. So far, these designer drugs have
not yet been included in our systematic toxicological analysis (STA).

Aim: The first aim of the presented work was to study the metabolism of
mephedrone and to incorporate all of the above-mentioned bk-designer drugs
into our STA. The second aim was to check for suitability of our rat model
by comparing incurred rat urine samples with human urine samples from
mephedrone and butylone users.

Methods: For the metabolism study, urine samples from male Wistar rats
(20 mg/kg BW) were extracted (liquid-liquid or Isolute Confirm HCX
cartridges) after enzymatic cleavage of conjugates. After extraction and
acetylation, the metabolites were separated and identified by GC–MS in
the electron ionisation and in the positive chemical ionisation mode. For
toxicological detection, a common users dose corresponding to 1 mg/kg
BW were administered to rats and urine was collected over a 24 h period.
Human urine submitted to our laboratory for toxicological analysis was
collected approximately 6 hours after intake of an unknown amount of
butylone and mephedrone. The rat and human urine samples were analyzed
using our STA based on an acid hydrolysis followed by liquid-liquid
extraction, acetylation and analysis via full-scan GC-MS. Finally, the
results from the metabolism and screening studies in rats were compared
to those obtained from the patients’ urine to verify the suitability of the
used rat model.

Results: Analysis of the rat and human samples revealed the following
main metabolic steps for mephedrone: N-demethylation to the primary
amine, reduction of the keto moiety to the respective alcohol and oxidation
of the tolyl moiety to the corresponding alcohols and carboxylic acids. The
metabolites of butylone and mephedrone detected in rat urine could also be
found in human urine samples. Using our STA, the parent compounds and
N-demethyl metabolites could be detected in rat urine after a common user’s
dose as well as in the patients’ urine samples in the case of mephedrone and
butylone.

Conclusion: Besides the elucidation of the metabolism of the new designer
drug mephedrone, we were able to show, that our STA was suitable to proof
S1-23

Ann Toxicol Anal. 2009; 21(S1) Abstracts
an intake of at least butylone and/or mephedrone in human urine. These
examples showed again that the used rat model was suitable to predict the
qualitative metabolism and detectability of drugs in human urine.
Keywords: designer drugs, butylone, mephedrone, methylone, metabolism

http://www.ata-journal.org/articles/...ta2009s102.pdf

 

[boohigh]

May I guess that paramethyl-ppa would be very dangerous stuff to have in system ?

 

[vecktor]

Mephedrone metabolite toxicity

Taken from an earlier post

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 inspired me 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
Quote: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.

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/art...?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 worse than methcathinone itself.

V

AMINO-ALCOHOLS. II. HOMOLOGS AND ANALOGS OF PHENYLPROPANOLAMINE
Walter H. Hartung, J. Am. Chem. Soc., 1930, 52 (, pp 3317–3322
DOI: 10.1021/ja01371a046

http://pubs.acs.org/doi/abs/10.1021/ja01371a046

 

[MurphyClox]

What puzzles me most is that the numerous evidence for mephedrone's toxicity (resp. of its metabolites) in form of purple knees, joints and fingers should practically be enough to persuade the consumers. But nonetheless, people keep on denying the facts.

It doesn't surprise me that Vecktor's suggestion revealed to be true but why the hell do we need such sophisticated reference for it? What the hell makes this drugs so special that folks constantly deny the danger of it?

I don't know the answer


BIG UPS to Vecktor for providing the info!

- Murphy

 

[vecktor]

May I guess that paramethyl-ppa would be very dangerous stuff to have in system ?

I suggest it is at least as bad as ephedrine, causing hypertension and vasoconstriction.

 

[vecktor]

ephedrine toxicity

working on the basis that ephedrine and 4-methylephedrine have a similar toxicological profile we can use ephedrine data to get an idea of the problems long term mephedrone use is going to have. There is a strong possibility that mephedrone also causes neurological damage as well as the ephedrine like peripheral effects.

CMAJ • March 5, 2002; 166 (5)

Ephedrine is a sympathomimetic
drug prescribed as a nasal decongestant,
with properties similar to epinephrine;
its effects on both α- and β-adrenergic
receptors and its central effects resemble
those of amphetamines (see figure).7
The adverse effects of ephedrine are hypothesized
to be related to coronary
artery constriction, vasospasm, shortening
of cardiac refractory periods allowing
re-entrant cardiac arrhythmias,
hypertension-induced subarachnoid hemorrhage,
cerebral artery vasoconstriction
and sympathomimetic-induced
platelet activation.

full article free access http://www.cmaj.ca/cgi/reprint/166/5/633

Norpseudoephedrine aka phenylpropanolamine adverse reactions also includes discussion of ephedrine toxicity
Adverse Drug Reaction Bulletin:
August 1984 - Volume 107 - Issue 1 - ppg 396-399

Phenylpropanolamine resembles ephedrine in
activity but is said to cause less CNS stimulation. As
well as being a constituent in cold remedies, it has also
been used as an appetite suppressant. There are many
reports of hypertension following its use as an appetite
suppressant, but even single doses of 50mg
phenylpropanolamine contained in a cold remedy were
sufficient to increase the diastolic blood pressure in
12% of subjects to over 100 mm Hg . Stroke
following the ingestion of large doses of
phenylpropanolamine is a well recognized
complication12. Myocardial injury has been reported
in three previously healthy young patients following
phenylpropanolamine ingestion13. In one of these
cases ischaemic chest pain occurred following ingestion
of a single capsule containing phenylpropanolamine
50mg, chlorpheniramine 4mg, and belladonna
alkaloids 0.2mg. In the other two cases, myocardial
damage was associated with very large doses of
phenylpropanolamine ingested as a deliberate drug
overdose.

http://journals.lww.com/adversedrug..._Reactions_To_Sympathomimetics_in_Cold.1.aspx

more ephedrine related toxicity

The RAND report, commissioned by the National Institutes of Health (NIH), was able to identify sentinel events related to ephedra and ephedrine consumption. For ephedra containing products, the following were identified as sentinel events: two deaths, three myocardial infarctions, nine cerebrovascular accidents, three seizures, and five psychiatric cases. For ephedrine consumption, sentinel events included: three deaths, two myocardial infarctions, two cerebrovascular accidents, one seizure, and three psychiatric cases. The symptoms described in the psychiatric cases included psychosis, hallucinations, delusions, homicidal intent, insomnia and paranoia. Between ephedra and ephedrine, 50 additional cases were identified as possible sentinel events. Another study, funded by the National Center for Complementary and Alternative Medicine (NCCAM), released preliminary results on the relative safety of ephedra compared with other herbal products. The study found that the relative risk for an adverse reaction from ephedra was more than 100 times greater compared with other herbs.

https://www.clevelandclinicmeded.com/medicalpubs/pharmacy/marapr2003/ephedra.htm

 

[boohigh]

So, if these metabolic pathway are shared with all bk-PEAs, should all this beta-keto stimulants have such a dangerous impact on body? I think yes, given the fact that the dosages are very big, and typical user consume 0.6 ~ 1.5 gramm in session. These happens vith methcathinone, alpha-PPP.
Btw, would this tertietary alpha-PPP be metabolised to PPA ?

 

[vecktor]

So, if these metabolic pathway are shared with all bk-PEAs, should all this beta-keto stimulants have such a dangerous impact on body? I think yes, given the fact that the dosages are very big, and typical user consume 0.6 ~ 1.5 gramm in session. These happens vith methcathinone, alpha-PPP.
Btw, would this tertietary alpha-PPP be metabolised to PPA ?

It does occur but I believe it is a minor pathway with pyrrolidine compounds:



Journal of Chromatography B Volume 796, 2003, Pages 253-266

Metabolism of the new designer drug α-pyrrolidinopropiophenone (PPP) and the toxicological detection of PPP and 4′-methyl-α-pyrrolidinopropiophenone (MPPP) studied in rat urine using gas chromatography-mass spectrometry


Dietmar Springera, Giselher Fritschib and Hans H. Maurer

R,S-α-pyrrolidinopropiophenone (PPP) is a new designer drug with assumed amphetamine-like effects which has appeared on the illicit drug market. The aim of this study was to identify the PPP metabolites using solid-phase extraction, ethylation or acetylation as well as to develop a toxicological detection procedure in urine using solid-phase extraction, trimethylsilylation and gas chromatography–mass spectrometry (GC–MS). Analysis of urine samples of rats treated with PPP revealed that PPP was extensively metabolized by hydroxylation of the pyrrolidine ring with subsequent dehydrogenation to the corresponding lactam, hydroxylation of the aromatic ring in position 4′ or double dealkylation of the pyrrolidine ring to the corresponding primary amine (cathinone) partly followed by reduction of the keto group to the corresponding secondary alcohol (norephedrines). As cathinone and the norephedrine diastereomers are also formed after intake of other drugs of abuse or medicaments, special attention must be paid to the detection of the unequivocal metabolite 2″-oxo-PPP as an unambiguous proof for the intake of PPP. The hydroxy groups were found to be partly conjugated. Based on these data, PPP could be detected in urine via its metabolites by full-scan GC–MS using mass chromatography for screening and library search for identification by comparison of the spectra with reference spectra. The same toxicological detection procedure can be applied to other designer drugs of the pyrrolidinophenone type, like MOPPP, MDPPP, MPHP, and MPPP. The detection of the latter will also be presented here

doi:10.1016/j.jchromb.2003.07.008

 

[Tomer]

Vecktor, helpful insight, much appreciated. If done in moderation, though, nothing even above 200mg's in a sitting, is there any cause for concern? Maybe once a week, twice at the most, but taking a few weeks in-between sittings. Thanks.

Tomer

 

[MeDieViL]

What puzzles me most is that the numerous evidence for mephedrone's toxicity (resp. of its metabolites) in form of purple knees, joints and fingers should practically be enough to persuade the consumers. But nonetheless, people keep on denying the facts.

It doesn't surprise me that Vecktor's suggestion revealed to be true but why the hell do we need such sophisticated reference for it? What the hell makes this drugs so special that folks constantly deny the danger of it?

I don't know the answer


BIG UPS to Vecktor for providing the info!

- Murphy

I personally do not think mephedrone is that bad when taken in normal doses, just as with ephedrine it would be safe in normal doses but incredibly bad in overdose.

Ephedrine is a popular BB supplement that definatly can be used safely. The biggest problem with mephedrone is that it leaves you wanting for more so many ppl get trapped in taking overdoses that cause severe vasoconstriction. Mephedrone is definatly not recommend for ppl that cannot control their use.

@Vecktor, i apreciate the info your providing.

 

[vecktor]

Vecktor, helpful insight, much appreciated. If done in moderation, though, nothing even above 200mg's in a sitting, is there any cause for concern? Maybe once a week, twice at the most, but taking a few weeks in-between sittings. Thanks.

Tomer

For certain, low doses and infrequent use is vastly safer than the the binge approach and is unlikely to do you any real lasting damage, even rather toxic drugs in moderation do little noticeable damage, however, I personally do not think it is wise to take mephedrone at all.

 

[vecktor]

Ephedrine is a popular BB supplement that definatly can be used safely. The biggest problem with mephedrone is that it leaves you wanting for more so many ppl get trapped in taking overdoses that cause severe vasoconstriction. Mephedrone is definatly not recommend for ppl that cannot control their use.

@Vecktor, i apreciate the info your providing.

I do not agree that ephedrine is safe. The data shows that even low doses of ephedrine are associated with heart and circulatory problems and even death.

 

[MeDieViL]

I do not agree that ephedrine is safe. The data shows that even low doses of ephedrine are associated with heart and circulatory problems and even death.

Interesting, i was not aware of this. I tought the problems with ephedrine was because of dosing too high.
Gonna check out the studies you posted and all the info i can find on ephedrine, thx for the info.

 

[vecktor]

Interesting, i was not aware of this. I tought the problems with ephedrine was because of dosing too high.
Gonna check out the studies you posted and all the info i can find on ephedrine, thx for the info.

smewhere the toxicity meta analysis for ephedrine is free online this is an section of a summary of the studies

Major safety concerns have been associated with ephedra or ephedrine use, including hypertension, tachycardia, CNS excitation, arrhythmia, myocardial infarction, and stroke. In 1997, due to over 800 U.S. reports of serious toxicity (and many more worldwide) including at least 22 deaths in adolescents and young adults, the U.S. Food and Drug Administration (FDA) adopted a policy that ephedra-containing products must: (1) be labeled with all possible adverse effects, including death; (2) contain no more than 8mg of ephedrine per serving; and (3) be used for no more than seven days. The FDA also proposed a maximum daily dose of 24mg, and a ban on ephedra-caffeine combination products (these proposed limits were subsequently withdrawn).

In 2002, Samenuk et al. identified 926 cases of possible ephedra toxicity reported to the Adverse Reaction Monitoring System of the FDA between 1995-1997. In 37 patients, use of ephedra was temporally related to stroke (16 patients), myocardial infarction (10), or sudden death (11). Autopsies performed in patients who experienced sudden death showed a normal heart in one, coronary atherosclerosis in three, and cardiomyopathies in three. In 36 of the 37 patients, use of ephedra was reported to be within the manufacturers' dosing guidelines.

In 2003, a report was prepared by Shekelle et al. on behalf of the RAND Southern California Evidence-based Practice Center for the Agency for Healthcare Research and Quality, U.S. Department of Health and Human Services. This study reviewed available clinical trials, as well as more than 1,500 adverse event reports to the FDA and adverse event reports to the manufacturer Metabolife. Although most prospective trials were not sufficiently large and most adverse event reports were not sufficiently detailed, the authors identified three deaths, two myocardial infarctions, two cerebrovascular accidents, one seizure, and three psychiatric cases that were considered to be "sentinel events" (i.e., strongly tied to ephedra use within 24 hours without other plausible explanations). In addition, 50 other possible sentinel events were identified.

A 2003 analysis by Bent et al. in Annals of Internal Medicine found that products containing ephedra account for 64% of all adverse reactions to herbs in the United States, but only represent 0.82% of herbal product sales. The relative risk for an adverse reaction in a person using ephedra compared with other herbs was extremely high, ranging from 100 (95% CI, 83 to 140) for kava to 720 (95% CI, 520 to 1100) for Ginkgo biloba . It was concluded that ephedra use poses a greatly increased risk of adverse reactions compared with other herbs. A 2003 analysis published in Neurology also found increased risk of stroke associated with ephedra-containing products.

 

[nuke]

Ephedrine is probably dangerous, although I've done insane amounts of it back in the days when I abused drugs along with my brother and am still alive. But, YMMV, there are certainly safer CNS stimulants out there.

Beta-hydroxylated amphetamines are bad news.

 

[fastandbulbous]

What the hell makes this drugs so special that folks constantly deny the danger of it?

Considerable, short lived euphoria and a shortage of MDMA to put it simply. People addicted to it deny it's harmfulness in the same way an alcoholic denies syuch things...

 

[vecktor]

are there any objections to moving the Off Topic posts out of the thread??

 

[vecktor]

Platelet activation

Does anyone know anything about stimulant induced/ sympathomimetic platelet activation? it appears to work through adrenergic receptors and leads to increased clotting.

It is reported for several betahydroxyphenethylamines like ephedrine and phenylpropanolamine, I wonder if mephedrone blue knees have anything to do with ??

If anyone knows how platelet activation happens and the toxic symptoms it causes I'd like to hear it.