The relationship between impurities and long-term side effects

[badrobot114]

Hi all,

I was thinking to myself - MDMA is supposedly quite neurotoxic, and obviously it has the potential to completely obliterate people. However, when you look at accounts from various therapists and chemists they never seem to mention any problems or exhibit symptoms of severe neurotoxic damage.

Take for instance Alexander Shulgin, he has tested MDMA(and MDA) on himself extensively at various doses and the tolerance tests he performed on himself where he would dose every day for 5 days straight and then dose MDA on the sixth day to check for cross tolerance are well documented in PiHKAL. Yet this clearly hasn't impacted him in a meaningful way(if at all).

We also have accounts from MDMA advocates like Rick Doblin who claims he has taken the drug 100 times over the last 20 years and feels fine.

These are of course anecdotes, but what they have in common is the fact that these people(and we can assume the same about other professionals and therapists who have experimented with MDMA in clinical and experimental contexts) used a properly synthesized product free of any kind of impurity extensively yet report no long-term problems.

So the question i'd like to propose is this - could it be that the harsh long-term effects observed in some recreational users of MDMA stem from compounded oxidative stress created by a combination of MDMA and impurities that act as free radicals?

 

[Pleh]

So the question i'd like to propose is this - could it be that the harsh long-term effects observed in some recreational users of MDMA stem from compounded oxidative stress created by a combination of MDMA and impurities that act as free radicals?

Looking at the outliers of a situation cannot give you a conclusion that will be valid for the majority. There was a study going on a man who consumed 40,000 ecstasy pills in nine years and as you mentioned people can take a lot and seem okay. Someone could also have a bad experience their first or second time.

Generally speaking, consuming pure mdma powder at the correct dosages, and very infrequently, should not cause severe harm to you neither physically nor mentally. However people who are recreational users often cave in to their addictions or tolerances. Looking past improper diet or the harm various forms of administration can have; people can mix it with alcohol, or consume larger doses of impure mdma/ecstasy and this can cause a range of problems.

 

[badrobot114]

I gave those two examples to elucidate my point which is that users of MDMA in the scientific circle don't seem to report long term problems even when their usage patterns are excessive or prolonged which is evidenced by the fact that those lobbying to use MDMA medicinally all have firsthand experience with it, be it from personal use or the treating of patients with it(and remember that in medical use it was a custom procedure that the therapist also dose himself). This leads me to hypothesize that poor synthesis and inactive impurities have a compounding effect on the neurotoxic potential.

Even responsible recreational users sometimes report long term problems and there is a fair share of users that believe MDMA isn't something to be taken with any kind of regularity and should be dosed only a few times throughout a person's life. Where does this dramatic difference in anecdote come from? why does clandestine MDMA appear to be more damaging?

I'm not stating this a fact. This is, as mentioned, just my personal assumption which i'm bringing it up for debate.

 

[JWills20]

Or perhaps MDMA in moderate recreational human doses really isn't that damaging? All accounts of neurotoxicity are usually rats getting their brains fried on monster doses. In reality, i'd be very surprised if the actual impurities (which are minimal - a slight colour change might be a result of a small % of byproduct left in it) of the MDMA itself caused problems. More probable is the pill cocktails of MDMA/amp/caffeine and pills with piperazines or under-researched RCs. However, one or two people on either end of the spectrum (heavy usage no problems vs. first time usage problems) isn't exactly compelling evidence. Nevertheless, epidemiological data (studies that examine the majority of Ecstasy users) actually report a low incidence rate for problems. Or at least that's what Professor Nutt argues.

It appears that some people who experience negative effects from minimal usage are either: A) Very susceptible to the negative consequences of MDMA or B) Experience negative effects as a result of particularly poor drug combinations/ drugs that are not MDMA. The illegality of the whole situation makes it all very hard to objectively analyse. All I can go on is my personal experiences of moderate doses of MDMA which really hasn't caused me issues yet. Whether I will disagree with myself in 10 years is another issue, but I trust my gut instinct at the moment.

 

[angeleyes]

Looking at the outliers of a situation cannot give you a conclusion that will be valid for the majority. There was a study going on a man who consumed 40,000 ecstasy pills in nine years and as you mentioned people can take a lot and seem okay. Someone could also have a bad experience their first or second time.

I read that article and took it with a very hefty dose of salt, I was seriously surprised this man could walk/talk/comprise a thought because there were points he was taking up to 25 a day? Like seriously? Wtf? The biggest case before that was like 20,000 but 40,000 that just seems ridiculous.

Tens of thousands...possible...40,000? Wtf...

If you space out your rolls you are going to be fine, keep within a safe amount that your body is used to, ymmv but less never hurt anyone more.

If people don't binge on MDMA and keep it to rare occasions such as once a month, you really aren't looking at a kind of "MDMA Junkie" (for lack of better term) popping up all over the world compared to meth/heroin users, heaps of people around the world use MDMA infrequently and lead on to have great, successful and very sociable lives.

could it be that the harsh long-term effects observed in some recreational users of MDMA stem from compounded oxidative stress created by a combination of MDMA and impurities that act as free radicals?

In response to your actual question, cutters/adulterants definitely and will always complicate things. They are cutters of the pure product usually unknown to users, which is why it is important to test due to things like piperazines/PMA, someone recently posted that there is a distinct correlation between how bad the comedown is and how hot someone was during their roll (overheating during roll = oxidative stress = worse comedown).

Tbh I'd say that when I have sweated my balls off at a club there have been times where my comedowns were worse, placebo/fact take it as you will.


Overall like there's going to be cutters in every form of drug in one way or another (speed growing/manufacturing/bulking etc), theoretically if someone was to only use pure MDMA 100% throughout their lives and were a 6 foot 5 90kg fit bulk 30 year old man with a good brain clean drug past that did 200mg of MDMA once a month for the next 10 years, I am sure that any side effects would be fairly minimal and could easily be tolerated with in a day to day life.

 

[badrobot114]

I want to clarify - i'm a firm believer that responsible, moderate use of tested and clean MDMA carries few/none long term problems. This is a purely hypothetical discussion about the possibility that impurities(small as they may be) compound the possible nerve damage.

It just seems logical to me that even a small % of impurity can have a compounding effect in a scenario where the brain is already under oxidative stress and generally in a very vulnerable state.

Whether or not the various impurities that can be present in MDMA can cross into the brain and act as free radicals is the real question i suppose.

 

[angeleyes]

Let's get a chainsaw and some MD and get a little crazy as we see how radical shit gets when we cross into the brain mwahahahaha

 

[TheMedic]

Perhaps it's the fact that many users are also poly drug users who tend to take massive dosages of mdma voluntarily with amps , caffeine , etc.

Imo an individual should NEVER combine any substance with something else to give the human mind a break. Even marijuana I disapprove of any users who take it on the come down. The combination of all substances have a much better chance of impairing cognitive abilities than just mdma alone.

stay safe

 

[JWills20]

I want to clarify - i'm a firm believer that responsible, moderate use of tested and clean MDMA carries few/none long term problems. This is a purely hypothetical discussion about the possibility that impurities(small as they may be) compound the possible nerve damage.

It just seems logical to me that even a small % of impurity can have a compounding effect in a scenario where the brain is already under oxidative stress and generally in a very vulnerable state.

Whether or not the various impurities that can be present in MDMA can cross into the brain and act as free radicals is the real question i suppose.

Can I just clarify the question: Is it whether impurities within the MDMA itself cause more damage? Or impurities independent of MDMA (such as piperazines, research chems, amps etc) cause the damage?

From what I gather, you're asking about impurities within MDMA, of which the effect would be negligible really. The free radicals you talk about aren't actually a metabolite of the drug, rather a result of serotonin depletion in the presence of high dopamine (as induced by high doses of MDMA). The theory: serotonin is low, dopamine is high, dopamine binds to the serotonin site where it shouldn't be, turns into a destructive chemical which selectively destroys the serotonin cell. The actual metabolism, and subsequent metabolites of MDMA, are not thought to play a role in it's toxicity. So, I'd be very surprised if a few byproducts changed much apart from a slightly reduced amount of MDMA per molecule weight. Unless anyone could provide a reason why byproducts within MDMA would be particularly damaging, I don't see why they would be. In reality, if you buy some MDMA off the street and it is not a clear colour, but it tests solidly, it's really not that far off pharmaceutical MDMA.

 

[Folley]

I've always used the term adulterants for drugs like piperazines/meth/cathinones.. helps clear up any confusion with by-product impurities leftover from chemical reactions.



However;

When excess hypochlorite was used in the reaction, a second, unexpected, compound was formed. Use of the listed instrumentation identified the new material as 2-chloro-4,5-methylenedioxyamphetamine, a compound not previously identified in the forensic literature.

http://www.ncbi.nlm.nih.gov/pubmed/23116634

Chlorinated amphetamines are typically very neurotoxic, see PCA and DCA.


Another impurity found is MDDM.. although not too much is known about it's effects, it would seem to be less neurotoxic than MDMA (offering a different opinion)

Very little data exists about the pharmacological properties, metabolism, and toxicity of MDDM. This compound is however occasionally encountered as an impurity in 3,4-methylenedioxy-N-methylamphetamine (MDMA) which has been synthesized by methylation of MDA using methylating reagents such as methyl iodide. An excess of reagent or a reaction temperature that is too high results in some double methylation of the amine nitrogen, yielding MDDM as well as MDMA. The presence of MDDM as an impurity can thus reveal which synthetic route was used to manufacture seized samples of MDMA.
http://en.wikipedia.org/wiki/Methylenedioxydimethylamphetamine

MDP2P would also seem to be an impurity found in MDMA, and it has been shown to promote "programmed cell death"
http://www.ncbi.nlm.nih.gov/pubmed/15763947





Other byproducts found in MDMA can be anything from mercury and aresenic to industrial solvents.. to assume that is anything other than harmful is foolish IMO. The real question is, how harmful is it? I think in the average batch of MDMA, it's not going to make an impact that is anywhere even near what the MDMA metabolites themselves will do.


However if you're eating some nasty, unwashed black goop... yeah, there probably is a large correlation with impurities and side effects.

 

[badrobot114]

Can I just clarify the question: Is it whether impurities within the MDMA itself cause more damage? Or impurities independent of MDMA (such as piperazines, research chems, amps etc) cause the damage?

From what I gather, you're asking about impurities within MDMA, of which the effect would be negligible really. The free radicals you talk about aren't actually a metabolite of the drug, rather a result of serotonin depletion in the presence of high dopamine (as induced by high doses of MDMA). The theory: serotonin is low, dopamine is high, dopamine binds to the serotonin site where it shouldn't be, turns into a destructive chemical which selectively destroys the serotonin cell. The actual metabolism, and subsequent metabolites of MDMA, are not thought to play a role in it's toxicity. So, I'd be very surprised if a few byproducts changed much apart from a slightly reduced amount of MDMA per molecule weight. Unless anyone could provide a reason why byproducts within MDMA would be particularly damaging, I don't see why they would be. In reality, if you buy some MDMA off the street and it is not a clear colour, but it tests solidly, it's really not that far off pharmaceutical MDMA.

That is actually not entirely accurate, MDMA causes a sharp rise in the level of free radicals in the brain - first and foremost through the increases in extracellular neurotransmitters, yes, but also through specific metabolites like alpha-methyldopamine which reacts with gluthatione in the body to create a very toxic metabolite with a very long name(it is actually this metabolite largely believed to be the cause of nerve damage), or MDA which is a known serotonergic neurotoxin.

Folley brought up some pretty nasty byproducts that can be found in impure MDMA(mercury for example, which is actually a very toxic substance to have in the body, and mercury poisoning is know to cause brain damage) - and while on their own they might not be doing much damage, when introduced in the context of MDMA in which there is already a rise in free radicals and overwhelming of the body's natural defenses they can become much more damaging. Think about the compounded neurotoxic effects of meth and MDMA taken together, only milder.

@Folley - I agree the impurities themselves are probably much less harmful than the metabolites of the MDMA itself. However, when the brain is already under oxidative stress and vulnerable these impurities put additional stress on the brain - whereas in the absence of such impurities the body might be able to handle the stress MDMA creates at reasonable doses -MUCH- better.

We can, for the sake of the argument, roughly compare this with medical use of meth. People prescribed Desoxyn typically stay on it for years with escalating doses(people prescribed 40-60mg a day is very common despite the max recommended dosage being 25mg a day). Yet they don't run into any of the problems Meth abusers run into(yes, it's a very crude comparison because Meth abusers take obscene doses while depriving the body of food and sleep, but it's a good example of how the body is able to deal with oxidative insults from amphetamine derivatives quite efficiently given a pure product and good physical maintenance).

 

[JWills20]

That is actually not entirely accurate, MDMA causes a sharp rise in the level of free radicals in the brain - first and foremost through the increases in extracellular neurotransmitters, yes, but also through specific metabolites like alpha-methyldopamine which reacts with gluthatione in the body to create a very toxic metabolite with a very long name(it is actually this metabolite largely believed to be the cause of nerve damage), or MDA which is a known serotonergic neurotoxin.

Folley brought up some pretty nasty byproducts that can be found in impure MDMA(mercury for example, which is actually a very toxic substance to have in the body, and mercury poisoning is know to cause brain damage) - and while on their own they might not be doing much damage, when introduced in the context of MDMA in which there is already a rise in free radicals and overwhelming of the body's natural defenses they can become much more damaging. Think about the compounded neurotoxic effects of meth and MDMA taken together, only milder.

@Folley - I agree the impurities themselves are probably much less harmful than the metabolites of the MDMA itself. However, when the brain is already under oxidative stress and vulnerable these impurities put additional stress on the brain - whereas in the absence of such impurities the body might be able to handle the stress MDMA creates at reasonable doses -MUCH- better.

We can, for the sake of the argument, roughly compare this with medical use of meth. People prescribed Desoxyn typically stay on it for years with escalating doses(people prescribed 40-60mg a day is very common despite the max recommended dosage being 25mg a day). Yet they don't run into any of the problems Meth abusers run into(yes, it's a very crude comparison because Meth abusers take obscene doses while depriving the body of food and sleep, but it's a good example of how the body is able to deal with oxidative insults from amphetamine derivatives quite efficiently given a pure product and good physical maintenance).

The MDMA itself doesn't metabolize into alpha-methyldopamine though, or at least I didn't think it did (A google search didn't help, feel free to post something on this). I was always under the impression that MDMA itself is relatively non-toxic (just like LSD), rather the acute depletion of serotonin can cause toxicity. Conversely, alcohol as an example metabolizes into acetadelhyde (or something with a name like that, cba to google) which is directly toxic to the liver. Your point about MDA is kind of mute considering that only a tiny proportion of MDMA (like 7%.) actually metabolizes into MDA. Such a small conversion would be unlikely to really influence much.