What is wrong with the MDMA available today?

[indigoaura]

Hi @MBaggott, welcome! Thanks for contributing.

I do not recall a lot of discussion of the liver over the last 212 pages.

I have seen someone on MDMA have a seizure due to interference at the CYP2D6 level with a prescription drug they were taking at the same time. So, I certainly believe that CYP2D6 is a significant factor in how MDMA is processed/felt.

If I am understanding you right, you are suggesting that old MDMA may have had byproducts that competed with CYP2D6 and thus allowed greater amounts of MDMA into the bloodstream? Couldn't the same effect be achieved by raising the dose of MDMA?

There have been some more recent studies of the CYP2D6 human mutants that show that the genetic mutations have no notable effect on MDMA metabolism. I would have to look for those articles as I don't have the link ready. I do recall someone sharing it waaaay back in the thread.

We've gone back and forth a lot in the thread about whether it is possible the old MDMA had active contaminants that improved the roll. However, if that was the case it would mean that pure MDMA was not "magical" in the sense that we are discussing. That is hard to believe, though. Surely Shulgin's synthesis was relatively pure?

 

[MBaggott]

Yes, you're understanding my theory correctly. I would also hypothesize that you can't easily imitate the effects with higher dose, but that's more speculative. People without cyp2d6 have faster rises in blood concentrations, while high doses seem to delay the time to peak.

I'm relying on the largest dataset available for my inferences (Matthias Liechti's lab, look at the linked paper), which leads to slightly different conclusions from the Barcelona group results, which you may be remembering and which had a much smaller N. Importantly, everyone agrees that 2D6 isn't a safety issue. What I'm suggesting is inhibiting it and/or other enzymes can modestly but significantly modify the quality of MDMA effects.

Sasha's MDMA was likely pure, but how many people are comparing his MDMA to modern?

 

[thegreenhand]

There is a mechanism where some of the transporters operate in reverse, as I recall from the Dacesafe slide show. However, serotonin release has always been theorized to be the primary reason for MDMA's effects, although obviously the reason for the effects is multi-faceted.

If you have not seen it before, this is a great visual: https://dancesafe.org/drug-information/ecstasy-slideshow/

What this article specifically points out, however, is that one of the primary means of PTSD treatment appears to be the direct result of the 5-HT transporters, and when they are blocked, that effect no longer occurs. Since other articles have already demonstrated that synthesis impurities in microgram ranges are blocking those 5-HT transporters, (https://sci-hub.tw/https://doi.org/10.1124/jpet.105.084426) this leads me to conclude that the loss of effects we are noticing may be due to something similar.

I will also say this...I do not personally buy into the idea that oxytocin is primarily responsible for the MDMA euphoria and empathy. Oxytocin release is in overdrive during childbirth. I've been present to witness several childbirths, and let me tell you...nobody is rolling. Nobody feels good. I'm sure it contributes to the overall experience, but I think focusing on oxytocin as the source of MDMA magic is barking up the wrong tree.

Well yes what the serotonin/5HT transport does is remove serotonin/5HT from the synaptic cleft and place the neurotransmitter back into vesicles in the presynaptic cell’s axon. If this ran in reverse it would lead to serotonin release from the presynaptic cell which as you said is the primary action. We’re saying the same thing it looks like.

I think this is promising and according to the study about synthesis impurities the two candidates would be:

1,3-bis (3,4-methylenedioxyphenyl)-2-propanamine

N-formyl- 1,3-bis (3,4-methylenedioxyphenyl)-prop-2-yl-amine

Would any chemistry geeks in here know how hard these would be to assay?

 

[G_Chem]

Apologies for jumping in this thread without reading the entire thread.

As several have said, the difference between batches is never enantiomers.

Oxytocin is not likely to be a good biomarker for the effects of interest. As indigoaura implies, it is at best necessary but not sufficient. We also don't really know if blood levels after MDMA correlate with brain levels. Plus, the vasoconstriction from MDMA breaks red blood cells during blood draws which falsely inflates oxytocin concentrations. I basically don't believe any of the human studies measuring oxytocin for this reason.

Contaminants from the synthesis seem like a plausible theory to me. But I would suggest they are more likely to be altering metabolism in the gut and liver than changing effects in the brain. There are admittedly a few contaminants that are known to bind to reuptake transporters (see Pifli et al 2005 doi:10.1124/jpet.105.084426). But I doubt these are ever make it into the brain in high enough concentrations to matter.

I'd more readily believe contaminants alter metabolism. There must be many that are substrates for cyp2d6 and other enzymes. A reason I think altered metabolism could strongly affect the roll is because we know MDMA hits people who lack cyp2d6 differently from normal metabolizers. You can see this in Figure 2 of Schmidt et al 2016 (link below). Even though cyp2d6 gets inhibited by MDMA, it likely eats up a few tens of mg of MDMA first. Without any 2d6, you get a faster peak and a different ratio of MDMA to crappy physiologically active metabolites. And keep in mind that any biproducts of synthesis don't need to make it into the brain to have these effects, they only need to compete with MDMA for enzymes in the gut.

Now, if this theory is true, it may be that pure MDMA is actually less "enjoyable" than MDMA with some enzyme substrates/inhibitors thrown in. In which case, maybe you need a tiny dose of dextromethorphan or something a few hours before the MDMA to recover the magic of yesteryear's MDMA.

schmid2016 mdma cyp2d6.pdf

drive.google.com

Hey man appreciate you stopping in

Explain how “MDMA breaks red blood cells to inflate oxytocin counts” as that sounds like some inaccurate information to me.

And for those that do believe the data (to be fair if your statement was true other researchers would be altering the way they study oxytocin) here’s a piece that shows Prolactin isn’t alone in making individuals want to “cuddle puddle.”

“and both exogenous OT (oxytocin) and MDMA increase “adjacent lying”, thought to be indicative of prosocial behavior (Ramos et al., 2013)”

So it seems oxytocin can also make you wanna lay next to and trust other individuals.

Idk the absolute trust of MDMA just screams oxytocin and the blood levels which peak at 90-120min correlate perfectly with the pro-social/trusting aspect of the experience.

-GC

 

[G_Chem]

Well yes what the serotonin/5HT transport does is remove serotonin/5HT from the synaptic cleft and place the neurotransmitter back into vesicles in the presynaptic cell’s axon. If this ran in reverse it would lead to serotonin release from the presynaptic cell which as you said is the primary action. We’re saying the same thing it looks like.

I think this is promising and according to the study about synthesis impurities the two candidates would be:

1,3-bis (3,4-methylenedioxyphenyl)-2-propanamine

N-formyl- 1,3-bis (3,4-methylenedioxyphenyl)-prop-2-yl-amine

Would any chemistry geeks in here know how hard these would be to assay?

The strange thing about these impurities is they are formed in the Leuckart synthesis I believe. Leuckart was king during the 90’s up until early 2000’s it was switched and I don’t think anyone feels the MDMA back then was lackluster.

Leuckart also has the product which seems to most reliably produce positive effects. When reading the Hive there’s chemists in there which claim the Leuckart was the reason the old 90’s product was next level good even though it wasn’t all that pure relative to today.

I personally don’t think those two impurities are the problem. What that study DOES show us is that out of 12 somewhat randomly selected impurities found in MDMA (of which there are 100’s/1000’s) 2 of them had significant psychoactive properties.

This means if researchers took the time to study others I can guarantee we’d find our problem.

-GC

 

[thegreenhand]

Hi @MBaggott, welcome! Thanks for contributing.

I do not recall a lot of discussion of the liver over the last 212 pages.

I have seen someone on MDMA have a seizure due to interference at the CYP2D6 level with a prescription drug they were taking at the same time. So, I certainly believe that CYP2D6 is a significant factor in how MDMA is processed/felt.

If I am understanding you right, you are suggesting that old MDMA may have had byproducts that competed with CYP2D6 and thus allowed greater amounts of MDMA into the bloodstream? Couldn't the same effect be achieved by raising the dose of MDMA?

There have been some more recent studies of the CYP2D6 human mutants that show that the genetic mutations have no notable effect on MDMA metabolism. I would have to look for those articles as I don't have the link ready. I do recall someone sharing it waaaay back in the thread.

We've gone back and forth a lot in the thread about whether it is possible the old MDMA had active contaminants that improved the roll. However, if that was the case it would mean that pure MDMA was not "magical" in the sense that we are discussing. That is hard to believe, though. Surely Shulgin's synthesis was relatively pure?

Perhaps boofing some mehDMA would allow for a comparison

 

[thegreenhand]

The strange thing about these impurities is they are formed in the Leuckart synthesis I believe. Leuckart was king during the 90’s up until early 2000’s it was switched and I don’t think anyone feels the MDMA back then was lackluster.

Leuckart also has the product which seems to most reliably produce positive effects. When reading the Hive there’s chemists in there which claim the Leuckart was the reason the old 90’s product was next level good even though it wasn’t all that pure relative to today.

I personally don’t think those two impurities are the problem. What that study DOES show us is that out of 12 somewhat randomly selected impurities found in MDMA (of which there are 100’s/1000’s) 2 of them had significant psychoactive properties.

This means if researchers took the time to study others I can guarantee we’d find our problem.

-GC

Ya know what you’re probably right. We may be stuck waiting awhile for academia to come around on this particular problem

 

[psy997]

Perhaps boofing some mehDMA would allow for a comparison

Plugging has been done and seemingly has no effect on MehDMA. It's still just as Meh.

 

[indigoaura]

@MBaggott , so theoretically, something like that grapefruit Rave gum could have the CYP2D6 effects you think may be beneficial?

My point in bringing up Shulgin is that he definitely experienced the magic of MDMA. This shit that I keep getting is not magical, by any stretch of the imagination. I think it would have been an entry in Pikhal that did not warrant much additional exploration.

I still think that the blocking of SERT/DAT/NET transporters would explain a lot of what we are noticing. It would also explain the variation in "meh" experiences based on which transporters were being blocked and to what extent. In the Pifl C. article it is stated that, "If added 4 min before MDMA to the superfusion buffer, 12 and 13 concentration-dependently suppressed the release induced by 3 uM MDMA in NET-, SERT-, and DAT-expressing cells" (p. 350). Only 100 uM of compound 12 "suppressed MDMA-induced release mediated by the DAT to levels slightly beneath basal efflux" (p. 350).

In other words, very small amounts of these compounds were having an extreme impact.

 

[draculic acid69]

The strange thing about these impurities is they are formed in the Leuckart synthesis I believe. Leuckart was king during the 90’s up until early 2000’s it was switched and I don’t think anyone feels the MDMA back then was lackluster.

Leuckart also has the product which seems to most reliably produce positive effects. When reading the Hive there’s chemists in there which claim the Leuckart was the reason the old 90’s product was next level good even though it wasn’t all that pure relative to today.

I personally don’t think those two impurities are the problem. What that study DOES show us is that out of 12 somewhat randomly selected impurities found in MDMA (of which there are 100’s/1000’s) 2 of them had significant psychoactive properties.

This means if researchers took the time to study others I can guarantee we’d find our problem.

-GC

If an impurity is the culprit then it would mean it's a route specific problem and like I said earlier
once we determine whether meh is
made via one specific method vs multiple methods we can prove/disprove the cause being
an impurity.quickest way to do that
is test multiple samples of meh to see how it was made.

 

[indigoaura]

I personally don’t think those two impurities are the problem. What that study DOES show us is that out of 12 somewhat randomly selected impurities found in MDMA (of which there are 100’s/1000’s) 2 of them had significant psychoactive properties.

I agree with this. I think one (several) of the newer synthesis methods have produced an impurity that is doing something similar. It is blocking transporter uptake, probably on SERT and DAT transporters. They did clarify at one point in the article that some of these impurities were coming about due to a backdoor method of making a precursor. I will try to find the quote.

For that matter, the impurity may already be present in some kind of mass produced precursor being sold in bulk. Anyone using that precursor is getting the impurity which is making it into the MDMA.

As for the whole boofing thing... not opposed to trying it, simply to see if my stomach issues would respond differently to a different ROA. But, I doubt it is going to have an impact.

 

[indigoaura]

@draculic acid69

While some impurities are route specific, others may appear in multiple synthesis routes. This paper goes into a variety of impurities related to synthesis routes: https://sci-hub.tw/10.1016/j.forsciint.2012.10.006

And, there are so many subtleties in the routes of synthesis...one person's slight variation may be responsible for an impurity that is not present in a properly performed synthesis otherwise.

I don't know if determining the synthesis route matters as much as determining WHAT the impurities are.

Test multiple samples of "meh" and see if they contain the same impurities.

 

[MBaggott]

Overall, I don't want to be too specific in my theory. It may not be cyp2d6, although it's a leading candidate. My reference to the 2d6 data is just a demonstration in principle that metabolic interactions can make MDMA effects different. And I think many, if not most, contaminants could compete with MDMA for gut and liver enzymes. The enzymes dealing with the 3,4-methylenedioxy bridge, for example, are likely pretty agnostic to the weird incorrect synthesis stuff on the other side of the molecule.

@indigoaura Don't you think those contaminant concentrations are unreasonably high. Consider that MDMA itself is only at low micromolar concentrations, is it really reasonable to think the contaminants would be higher concentrations than the drug? I don't think it's that likely. As the contaminants are initially lower in the ingested drug, you'd need the contaminants to get actively absorbed or be partitioned into the brain at a much higher brain:blood ratio than MDMA. This is why a pk not pd interaction seems more likely to me.

@G_Chem The general oxytocin problem I describe is pretty well established in the literature. Antibodies used for immunoassay can bind to other proteins and peptides in plasma. This was made clear when oxytocin measured without extraction turned out to be 10–100 fold higher than in extracted samples and extracted vs unextracted levels shown to be uncorrelated. You can find a number of papers on this problem. The specific issues of MDMA aren't as clearly discussed, but you can, for example, read de Wit lab MDMA papers where they mention "outliers ... likely ... because of blood sampling issues resulting in hemolysis". Basically, the insides of red blood cells have things the antibody will stick to. And, if you think about it, vasoconstriction during peak MDMA effects will be correlated with hemolysis, which will be correlated with apparent oxytocin. On the other hand, I do believe the animal studies since they just sacrifice the whole animal to measure oxytocin, which avoids this differential vasoconstriction-induced hemolysis problem.

 

[indigoaura]

@MBaggott Would the amounts matter as much as the affinity for the receptor? Wouldn't the compound with the greater affinity bind to the receptor, even if it is the smaller amount? Also, wouldn't absorption times be a major factor? If the impurity was absorbed quicker and had a higher affinity for the receptor, the MDMA may possibly bind to other receptors instead of the blocked receptor (theoretically).

Assuming it is a metabolic issue due to impurities, how could that be addressed?

 

[MBaggott]

@G_Chem To expand on my previous comments: I think the rat data are solid and I think oxytocin release plays a role in MDMA effects. I question if oxytocin alone, assuming we infused it into the brain, would imitate the MDMA state. For example, the stimulant-like positive mood is also important and does not have a serotonergic/oxytonergic mechanism.

@indigoaura Affinity and concentration both matter. Absorption times should matter less, as the ligands are binding and dissociating from the binding site at set rates; getting there first shouldn't guarantee blockade.

I would like to see a study detecting contaminants in the blood after oral administration of underground MDMA before I would believe they make it through first pass metabolism.

 

[indigoaura]

@MBaggott As a researcher, what do you feel is primarily responsible for "ideal" MDMA effects? When I imagine an ideal MDMA experience, I imagine pro-social behaviors, loss of inhibition, feelings of connection/care/love/euphoria, enhanced sexual drive/feelings (if you are with a person you are attracted to), enhanced tactile sensations, enhanced sound, slight time dilation. Do you feel those are primarily serotonin /dopamine/norepinephrine/oxytocin/prolactin related? All of the above?

What do you personally make of products that do not produce those effects even in new users? Products that appear to be MDMA to GCMS, with no eye dilation at 200 mg, where the user simply sits still and stares, with no urge to talk/connect/touch?

 

[G_Chem]

@G_Chem To expand on my previous comments: I think the rat data are solid and I think oxytocin release plays a role in MDMA effects. I question if oxytocin alone, assuming we infused it into the brain, would imitate the MDMA state. For example, the stimulant-like positive mood is also important and does not have a serotonergic/oxytonergic mechanism.

@indigoaura Affinity and concentration both matter. Absorption times should matter less, as the ligands are binding and dissociating from the binding site at set rates; getting there first shouldn't guarantee blockade.

I would like to see a study detecting contaminants in the blood after oral administration of underground MDMA before I would believe they make it through first pass metabolism.

Thank you for the clarification.

Oxytocin is definitely not the main/only component to MDMA. As I’ve said, we as humans have this insatiable urge to get everything as simplified as possible.

Just like I had a problem with that German researcher who wants to say it’s all Prolactin. MDMA, like other great drugs, is a culmination of many pharmacological factors.

MDMA is oxytocin, it’s prolactin, serotonin, dopamine, NE release, vasopressin, and more that I’m unaware of.. As we see with many other empathogens that if some of these parts are missing the experience is incomplete.

-GC

 

[MBaggott]

@MBaggott As a researcher, what do you feel is primarily responsible for "ideal" MDMA effects? .... Do you feel those are primarily serotonin /dopamine/norepinephrine/oxytocin/prolactin related? All of the above?

I believe all but prolactin are important. I don't think there's enough evidence on prolactin one way or another.

What do you personally make of products that do not produce those effects even in new users? Products that appear to be MDMA to GCMS, with no eye dilation at 200 mg, where the user simply sits still and stares, with no urge to talk/connect/touch?

I haven't encountered this personally, so I don't have a robust theory.

I do think that the core MDMA effect is something more like authenticity or decreased neuroticism than the things we normally list. I think this core effect frees, or disinhibits, people, which facilitates sociability and sensory pleasures and the things we commonly associate with MDMA. But it's also possible to be anxious (this is actually common) or even angry on MDMA. Maybe people can also be authentically and calmly grounded without extraversion and it just seems anomalous to observers.

MDMA is oxytocin, it’s prolactin, serotonin, dopamine, NE release, vasopressin, and more that I’m unaware of.. As we see with many other empathogens that if some of these parts are missing the experience is incomplete.

Yes. An interesting question for me is which parts are needed for therapeutic effects vs recreational effects and does it vary for different people.

 

[indigoaura]

"I haven't encountered this personally, so I don't have a robust theory." Well, if you are quarantined and in need of some light reading, there are 213 pages here that span several years and describe the phenomenon in somewhat excessive detail...

I like how you compared the core state to authenticity. There is an honesty to the state that is lacking from many other altered states. I recall feeling as though I had stepped into reality or into an eternal mode of self that was inaccessible typically.

"An interesting question for me is which parts are needed for therapeutic effects vs recreational effects and does it vary for different people."

One concern I have is that as MDMA moves into mainstream therapeutic settings, that efforts will be made to strip it of every quality except for that which benefits the therapeutic goal; that the whole of that honest/authentic experience may be blunted. Eventually, it will become an elite experience and the value of the individual experience outside of therapy will not be acknowledged.

 

[fasterfb]

I'd more readily believe contaminants alter metabolism. There must be many that are substrates for cyp2d6 and other enzymes. A reason I think altered metabolism could strongly affect the roll is because we know MDMA hits people who lack cyp2d6 differently from normal metabolizers. You can see this in Figure 2 of Schmidt et al 2016 (link below). Even though cyp2d6 gets inhibited by MDMA, it likely eats up a few tens of mg of MDMA first. Without any 2d6, you get a faster peak and a different ratio of MDMA to crappy physiologically active metabolites. And keep in mind that any biproducts of synthesis don't need to make it into the brain to have these effects, they only need to compete with MDMA for enzymes in the gut.

Now, if this theory is true, it may be that pure MDMA is actually less "enjoyable" than MDMA with some enzyme substrates/inhibitors thrown in. In which case, maybe you need a tiny dose of dextromethorphan or something a few hours before the MDMA to recover the magic of yesteryear's MDMA.

@MBaggott , so theoretically, something like that grapefruit Rave gum could have the CYP2D6 effects you think may be beneficial?

@MBaggott Welcome, and thank you for your posts!

Anectodally, I have found grapefruit juice to significantly smooth out and enhance my roll. Apparently, it also slows down/stops the conversion of MDMA into the more neuro-toxic MDA.

@indigoaura

My rave gum has arrived, and I will be giving it a try next week instead of just the grapefruit juice. I'll let you know how it goes!
P.S. I am on no other medications that would be potentiated by CYP2D6 inhibition, so not worried about bad reactions/seizures.