(Originally posted by me on DF)
Is MDA Neurotoxicity Really All That Worse Than MDMA?
This is something I've been needing to address for a long time now. It seems over the recent years people have gotten it in their head that MDA is somehow much more neurotoxic than it's brother MDMA. Everyone takes this as fact sadly due to one person in particular, yet no one seems to know the answer why. I've heard everything from it's a little bit more neurotoxic, to 10x more toxic, to it's the sole reason MDMA is neurotoxic (via MDMA to MDA metabolism, this is coming from MisterUAreSoDumb over at reddit, the "one person" I speak of above..)
Sadly in order to do this I'm going to have to kind of call someone out, and that person is misteruaresodumb. People seem to think this guy is the one and only when it comes to information regarding this subject, and the folks over at reddit have taken his misinformation and ran wild with it. He definitely knows a thing or two but obviously seemed to only nit-pick the studies which agreed with his theory. The theory being that MDA is the sole cause for MDMA's neurotoxicity, and that by inhibiting the enzyme responsible for the MDA metabolite the neurotoxicity is completely avoided. He then goes on to promote a massive anti-oxidant supplement regimen as well as enzyme inhibiters, which help him experience zero comedown. (Hint: The enzyme inhibitors likely aren't the ones helping out in this case, I have zero comedowns too as well as zero tolerance buildup after 12 years of MDMA use and only take anti-oxidants.)
To dive deeper in lets examine this theory people seem to have. It is said that MDMA is metabolized into MDA (demethylation) which is then metabolized into alpha-methyldopamine. It is alpha-methyldopamine which people theorize is the cause for the toxicity and while more recent studies seem to agree they are only half correct. (The thioether conjugates of said metabolites being the problem here.) Just as there is an N-methyl analog of MDA (MDMA) there is also an N-methyl analog of alpha-methyldopamine. (N-methyl-alpha-methyldopamine.) Not really sure why people missed this as it's been in the literature for a long time now but only recently has it been more of a main focus (as well as it's non-methylated counterpart) as being the potential cause for the neurotoxicty seen after administration of MDA or MDMA. (Typically in the old literature these two are referred to as HMA and HMMA.)
Both alpha-methyldopamine as well as N-methyl-alpha-methyldopamine thioether conjugates seem to be the cause of neurotoxicity as neither MDA nor MDMA cause toxicity when injected directly into the brain. Both are also negated by anti-oxidants..
So now that we are aware that both of these empathogens produce similarly neurotoxic metabolites, we can pretty much throw that theory out already, but might as well back it up with some more evidence hey?...
Just because they share similarly toxic metabolites doesn't mean there couldn't still be some other possible mechanism which makes MDA more neurotoxic than the rest.
Next lets look at a study which examined a few MDMA analogs and the generation of ROS (reactive oxygen species, negated by anti-oxidants) as well as mitochondrial respiration both a sign of neurotoxicity. The analogs examined were MDA, MDEA and MDMA (but not 3,4-MDMA, supposedly 2,6-MDMA which I think is a potential typo and should read 2,3-MDMA as I've never heard of 2,6-MDMA in any other literature.) The study is ""Elucidate the Neurotoxic Effects of MDMA and its Analogues. April 2014. Karuppagrounder, Bhattacharya, Ahuja, Dhanasekaran."" They even used some known exceedingly neurotoxic substances to help give some perspective, methamphetamine being one of them.
When looking at this study two graphs stick out. In Fig. 4 it shows the reactive oxygen species generated when MDMA and it's analogs were incubated with brain homogenate. What is interesting is that while MDA does generate the most it's not much more in comparison to 2.3-MDMA and MDEA. Probably less than 10% more than the others. It should also be noted that MDEA has always been known as having little in the way of neurotoxicity and for MDA to come close to it when it comes to the formation of ROS free radicals says something.
Next looking at Fig. 5 we see a graph showing the inhibition of mitochondrial respiration. According to the authors this is at least one of the ways neurotoxicity takes place. Looking at the graph it seems MDA of the four substances shown (METH being one of them) has the least effect on mitochondrial respiration!!
Despite this there is still a few things MDA has going against it which need to be mentioned. Recent research seems to show that indeed dopamine uptake into SERT is at least one mechanism by which the above talked about metabolites cause their toxicity. MDA releases more dopamine than any of the others, but this problem can be remedied same as always with anti-oxidants and maintaining a cool body temperature.
It should also be mentioned that MDA releases more serotonin than MDMA as well. This is the reason why many of the early studies claimed it to be more neurotoxic, but as one very well known MDMA researcher has said before "it's not that the pipes are damaged, they are just empty." Most of these studies examined serotonin concentrations and related data usually a week or so after the experience which is far from long enough to replenish serotonin and allow for downregulation. Studies which wait longer seem to indicate a complete replenishment of serotonin with both MDMA and MDA.
And to finish I'd like to share some anecdotal experience.. As I've said many times before I've been consuming MDxx substances semi-regularly (as regularly as one should safely) for the past 12 years about to go on 13.. I'm grateful to live where I do as not only is MDMA more common than in other parts of the world, but so is MDA. There was once even a time when a local ecstasy producer who is now simply a legend talked about only by the "ol timers" who produced MDMA/MDA and straight MDA tablets. In my opinion true ecstasy is not MDMA but MDMA/MDA combo tablets, there is a clear difference in people's mood, vibe and demeanor comparatively. But enough about the nostalgia..
In a nutshell I've eaten a fair amount of MDA and watched people do the same. I don't feel MDA has done any more or less damage than MDMA. I won't personally take a full dose of just MDA anymore though because as said above it releases much more serotonin than MDMA and subsequently causes a worse serotonin dip than MDMA or MDMA/MDA combined. My preferred dosage is 100mg MDMA and 25mg MDA for true ecstasy. (I feel the same about 5-MAPB another one that releases a shit ton of serotonin.)
What I feel the differences are between MDMA and MDMA/MDA combo is that the combo causes a smoother glide down during the experience, a longer duration, as well as overall a stronger bonding feeling amongst the people around me. The negative though is a more noticeable serotonin dip in the days following but quickly corrects itself as always. While it does create a deeper dip after the experience it also gives one a feeling of satisfaction and is less likely to be compulsively used. (I.E. when MDA is involved I feel overall better long term despite the initial drop in serotonin, and less likely to consume an MDxx soon after.)
So as we can see from the information I've just presented that MDA is likely not too much worse than it's close relatives (ie MDMA.) Despite all this I still believe it is the worst but not by enough to really cause any worry, and definitely not the "sole cause to MDMA's neurotoxicity" as some others seem to wrongly believe. Thank you for reading through this and stay safe out there
Dosage, Frequency, Anti-oxidants, Body Temp. All you ever need to know to keep yourself safe when rolling.. MDMA or MDA.
-GC
Is MDA Neurotoxicity Really All That Worse Than MDMA?
This is something I've been needing to address for a long time now. It seems over the recent years people have gotten it in their head that MDA is somehow much more neurotoxic than it's brother MDMA. Everyone takes this as fact sadly due to one person in particular, yet no one seems to know the answer why. I've heard everything from it's a little bit more neurotoxic, to 10x more toxic, to it's the sole reason MDMA is neurotoxic (via MDMA to MDA metabolism, this is coming from MisterUAreSoDumb over at reddit, the "one person" I speak of above..)
Sadly in order to do this I'm going to have to kind of call someone out, and that person is misteruaresodumb. People seem to think this guy is the one and only when it comes to information regarding this subject, and the folks over at reddit have taken his misinformation and ran wild with it. He definitely knows a thing or two but obviously seemed to only nit-pick the studies which agreed with his theory. The theory being that MDA is the sole cause for MDMA's neurotoxicity, and that by inhibiting the enzyme responsible for the MDA metabolite the neurotoxicity is completely avoided. He then goes on to promote a massive anti-oxidant supplement regimen as well as enzyme inhibiters, which help him experience zero comedown. (Hint: The enzyme inhibitors likely aren't the ones helping out in this case, I have zero comedowns too as well as zero tolerance buildup after 12 years of MDMA use and only take anti-oxidants.)
To dive deeper in lets examine this theory people seem to have. It is said that MDMA is metabolized into MDA (demethylation) which is then metabolized into alpha-methyldopamine. It is alpha-methyldopamine which people theorize is the cause for the toxicity and while more recent studies seem to agree they are only half correct. (The thioether conjugates of said metabolites being the problem here.) Just as there is an N-methyl analog of MDA (MDMA) there is also an N-methyl analog of alpha-methyldopamine. (N-methyl-alpha-methyldopamine.) Not really sure why people missed this as it's been in the literature for a long time now but only recently has it been more of a main focus (as well as it's non-methylated counterpart) as being the potential cause for the neurotoxicty seen after administration of MDA or MDMA. (Typically in the old literature these two are referred to as HMA and HMMA.)
Both alpha-methyldopamine as well as N-methyl-alpha-methyldopamine thioether conjugates seem to be the cause of neurotoxicity as neither MDA nor MDMA cause toxicity when injected directly into the brain. Both are also negated by anti-oxidants..
So now that we are aware that both of these empathogens produce similarly neurotoxic metabolites, we can pretty much throw that theory out already, but might as well back it up with some more evidence hey?...
Just because they share similarly toxic metabolites doesn't mean there couldn't still be some other possible mechanism which makes MDA more neurotoxic than the rest.
Next lets look at a study which examined a few MDMA analogs and the generation of ROS (reactive oxygen species, negated by anti-oxidants) as well as mitochondrial respiration both a sign of neurotoxicity. The analogs examined were MDA, MDEA and MDMA (but not 3,4-MDMA, supposedly 2,6-MDMA which I think is a potential typo and should read 2,3-MDMA as I've never heard of 2,6-MDMA in any other literature.) The study is ""Elucidate the Neurotoxic Effects of MDMA and its Analogues. April 2014. Karuppagrounder, Bhattacharya, Ahuja, Dhanasekaran."" They even used some known exceedingly neurotoxic substances to help give some perspective, methamphetamine being one of them.
When looking at this study two graphs stick out. In Fig. 4 it shows the reactive oxygen species generated when MDMA and it's analogs were incubated with brain homogenate. What is interesting is that while MDA does generate the most it's not much more in comparison to 2.3-MDMA and MDEA. Probably less than 10% more than the others. It should also be noted that MDEA has always been known as having little in the way of neurotoxicity and for MDA to come close to it when it comes to the formation of ROS free radicals says something.
Next looking at Fig. 5 we see a graph showing the inhibition of mitochondrial respiration. According to the authors this is at least one of the ways neurotoxicity takes place. Looking at the graph it seems MDA of the four substances shown (METH being one of them) has the least effect on mitochondrial respiration!!
Despite this there is still a few things MDA has going against it which need to be mentioned. Recent research seems to show that indeed dopamine uptake into SERT is at least one mechanism by which the above talked about metabolites cause their toxicity. MDA releases more dopamine than any of the others, but this problem can be remedied same as always with anti-oxidants and maintaining a cool body temperature.
It should also be mentioned that MDA releases more serotonin than MDMA as well. This is the reason why many of the early studies claimed it to be more neurotoxic, but as one very well known MDMA researcher has said before "it's not that the pipes are damaged, they are just empty." Most of these studies examined serotonin concentrations and related data usually a week or so after the experience which is far from long enough to replenish serotonin and allow for downregulation. Studies which wait longer seem to indicate a complete replenishment of serotonin with both MDMA and MDA.
And to finish I'd like to share some anecdotal experience.. As I've said many times before I've been consuming MDxx substances semi-regularly (as regularly as one should safely) for the past 12 years about to go on 13.. I'm grateful to live where I do as not only is MDMA more common than in other parts of the world, but so is MDA. There was once even a time when a local ecstasy producer who is now simply a legend talked about only by the "ol timers" who produced MDMA/MDA and straight MDA tablets. In my opinion true ecstasy is not MDMA but MDMA/MDA combo tablets, there is a clear difference in people's mood, vibe and demeanor comparatively. But enough about the nostalgia..
In a nutshell I've eaten a fair amount of MDA and watched people do the same. I don't feel MDA has done any more or less damage than MDMA. I won't personally take a full dose of just MDA anymore though because as said above it releases much more serotonin than MDMA and subsequently causes a worse serotonin dip than MDMA or MDMA/MDA combined. My preferred dosage is 100mg MDMA and 25mg MDA for true ecstasy. (I feel the same about 5-MAPB another one that releases a shit ton of serotonin.)
What I feel the differences are between MDMA and MDMA/MDA combo is that the combo causes a smoother glide down during the experience, a longer duration, as well as overall a stronger bonding feeling amongst the people around me. The negative though is a more noticeable serotonin dip in the days following but quickly corrects itself as always. While it does create a deeper dip after the experience it also gives one a feeling of satisfaction and is less likely to be compulsively used. (I.E. when MDA is involved I feel overall better long term despite the initial drop in serotonin, and less likely to consume an MDxx soon after.)
So as we can see from the information I've just presented that MDA is likely not too much worse than it's close relatives (ie MDMA.) Despite all this I still believe it is the worst but not by enough to really cause any worry, and definitely not the "sole cause to MDMA's neurotoxicity" as some others seem to wrongly believe. Thank you for reading through this and stay safe out there
Dosage, Frequency, Anti-oxidants, Body Temp. All you ever need to know to keep yourself safe when rolling.. MDMA or MDA.
-GC
