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MDMA Pharmacology Notes

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G_Chem

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I’d like this thread to serve as a place to discuss the nuances of MDMA’s pharmacology.

First I was wondering why oral MDMA has more love to it then other ROA’s and found this article.

The effect of 3,4-methylenedioxymethamphetamine (MDMA, ?ecstasy?) and its metabolites on neurohypophysial hormone release from the isolated rat hypothalamus - PMC

Methylenedioxymethamphetamine (MDMA, “ecstasy”), widely used as a recreational drug, can produce hyponatraemia. The possibility that this could result from stimulation of vasopressin by MDMA or one of its metabolites has been investigated in vitro. ...
www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov

This shows the metabolites HMMA and others have a significant hormone impact (including oxytocin the love hormone) compared to MDMA alone. These metabolites form more with oral administration.


Next, I’ve always wondered why product that smelled of safrole felt better than not. This may be why?..

www.sciencedirect.com

Inhibition of human cytochrome P450 enzymes by the natural hepatotoxin safrole

The hepatotoxin, safrole is a methylenedioxy phenyl compound, found in sassafras oil and certain other essential oils. Recombinant cytochrome P450 (CY…
www.sciencedirect.com www.sciencedirect.com

It sounds like safrole may be a decent enzyme inhibitor.

Edit in more later.

-GC
 
It appears oral in dosing is best. They didn't compare to plugging. But for this be study I agree oral is tried and true.

Did I comprehend that right?

Back when I used to abuse ecstacy, I am would take a pill, then an hour or hour and a half in, mate of mine and I, would chop up a pill in lines and snort it. It was intense but just added a bit intensity, headrush to the expirience. Haven't done that in over twenty years since about may 2000. I prefer a smoother experience. having done that, and just about all of the entacogens I've done had plenty stimulation and no need for more intensity. It can be intense enough in public.
 
Innerpeace said:
It appears oral in dosing is best. They didn't compare to plugging. But for this be study I agree oral is tried and true.

Did I comprehend that right?

Back when I used to abuse ecstacy, I am would take a pill, then an hour or hour and a half in, mate of mine and I, would chop up a pill in lines and snort it. It was intense but just added a bit intensity, headrush to the expirience. Haven't done that in over twenty years since about may 2000. I prefer a smoother experience. having done that, and just about all of the entacogens I've done had plenty stimulation and no need for more intensity. It can be intense enough in public.
Click to expand...

Yup that’s what I got from it. HMMA and friends are higher with oral over any other ROA I believe.

I agree, snorting while intense lacks what I’m looking for in a roll. I used to primarily snort it when I first started cuz back then I snorted anything I could get my hands on.

-GC
 
G_Chem said:
Yup that’s what I got from it. HMMA and friends are higher with oral over any other ROA I believe.

I agree, snorting while intense lacks what I’m looking for in a roll. I used to primarily snort it when I first started cuz back then I snorted anything I could get my hands on.

-GC
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I snorted coke a few times and at least one time it was enjoyable. Furthermore I'm a fast-paced person at times other times I'm real slow I kind of got stuck with these genetics my mom she's on the super slow calm side I wouldn't say slow but she's super duper calm her whole family's like that my dad's Energizer Bunny on crack. I came out in between there and sometimes I'm slow real calm and sometimes I get anxious and anxiety and stuff. So I believe a lot of these drugs that increase certain receptors are genetic it depends on your genetics whether you'll respond better to them. Something like THC maybe a few times a week seems a mellow me out when I've been working too hard and under stress and stuff just a bowl one small bowl usually is good enough for that too much and it makes seems to make me like lazy and unmotivated.

I've been tricked twice into snorting meth and one time I was tricked in the drinking Zulu juice it was the remains of meth or something and a drunk I thought it was vodka I was 18 years old at the party is the first time I did it and so that's three times people trick me into that and it was horrible it was terrible and I don't recommend meth.

Sorry if I have a lot of grammar mistakes.

I actually tend to anticipate and enjoy the come up after I swallow and entacogen type feeling compound ,it makes me more alert when I take it knowing that the come up is going to be happening sometime soon.
 
G_Chem said:
I’d like this thread to serve as a place to discuss the nuances of MDMA’s pharmacology.

First I was wondering why oral MDMA has more love to it then other ROA’s and found this article.

The effect of 3,4-methylenedioxymethamphetamine (MDMA, ?ecstasy?) and its metabolites on neurohypophysial hormone release from the isolated rat hypothalamus - PMC

Methylenedioxymethamphetamine (MDMA, “ecstasy”), widely used as a recreational drug, can produce hyponatraemia. The possibility that this could result from stimulation of vasopressin by MDMA or one of its metabolites has been investigated in vitro. ...
www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov

This shows the metabolites HMMA and others have a significant hormone impact (including oxytocin the love hormone) compared to MDMA alone. These metabolites form more with oral administration.


Next, I’ve always wondered why product that smelled of safrole felt better than not. This may be why?..

www.sciencedirect.com

Inhibition of human cytochrome P450 enzymes by the natural hepatotoxin safrole

The hepatotoxin, safrole is a methylenedioxy phenyl compound, found in sassafras oil and certain other essential oils. Recombinant cytochrome P450 (CY…
www.sciencedirect.com www.sciencedirect.com

It sounds like safrole may be a decent enzyme inhibitor.

Edit in more later.

-GC
Click to expand...
MDMA itself is quite the inhibitor of CYP2D6, as the carbon in the methylenedioxy group forms a carbene upon oxidative metabolism, which then forms a covalent bond between the enzyme and the drug, inhibiting the enzyme.

Paroxetine shares this mechanism of CYP2D6 inhibition as well. There is even a compound (Piperonyl butoxide), which is given alongside insecticides to inhibit insect CYP enzymes.

The study below claims that the inhibition of CYP2D6 by MDMA is so complete and robust, that it renders the range of different CYP2D6 polymorphisms irrelevant.

While safrole is likely as efficacious as an inhibitor, MDMA is sufficient for complete CYP2D6 inhibition to occur in its own.

MDMA, methamphetamine, and CYP2D6 pharmacogenetics: what is clinically relevant?
 
Skorpio said:
MDMA itself is quite the inhibitor of CYP2D6, as the carbon in the methylenedioxy group forms a carbene upon oxidative metabolism, which then forms a covalent bond between the enzyme and the drug, inhibiting the enzyme.

Paroxetine shares this mechanism of CYP2D6 inhibition as well. There is even a compound (Piperonyl butoxide), which is given alongside insecticides to inhibit insect CYP enzymes.

The study below claims that the inhibition of CYP2D6 by MDMA is so complete and robust, that it renders the range of different CYP2D6 polymorphisms irrelevant.

While safrole is likely as efficacious as an inhibitor, MDMA is sufficient for complete CYP2D6 inhibition to occur in its own.

MDMA, methamphetamine, and CYP2D6 pharmacogenetics: what is clinically relevant?
Click to expand...

What I’m curious to know (and looked briefly but couldn’t find) is if MDMA also non-selectively inhibits other CYP enzymes. It seems safrole inhibits the whole lot, where I only find selective information on which enzymes MDMA inhibits.

This article seems to show other CYP enzymes can pick up the slack if CYP2D6 is tied up.

www.sciencedirect.com

Identification of the human cytochromes P450 involved in the oxidative metabolism of “Ecstasy”-related designer drugs

The human cytochrome P450 (CYP) isozymes catalyzing the oxidative metabolism of the widely abused amphetamine derivatives MDMA (N-methyl-3,4-methylene…
www.sciencedirect.com www.sciencedirect.com

-GC
 
This one’s interesting, it goes over the stereoselective metabolism of MDMA, MDA and MDEA. Notice how we preferentially metabolize S-MDMA over R-MDMA, MDA less so, and strangely MDEA is the opposite where our bodies seem to like the R isomer over the S. This could explain why MDEA was always considered a dud compared to the other two, also has me wondering if pure S-MDEA would be worth a damn.

academic.oup.com

Optical Isomer Analysis of 3,4-Methylenedioxyamphetamine Analogues and their Stereoselective Disposition in Rats

Abstract. Identification of the optical activity and simultaneous analysis of racemates (±) of three hallucinogens, 3,4-methylenedioxyamphetamine (MDA), 3,
academic.oup.com academic.oup.com

Which brings up an interesting discussion, the stereoselective metabolism of these drugs.

Here’s an article showing when MDMA metabolizes into MDA there is a higher ratio of S-MDA to R-MDA.

www.sciencedirect.com

Stereochemistry of the metabolism of MDMA to MDA

The chiral derivatizing reagent N-trifluoroacetyl-L-propyl chloride (LPTC) was used to form diastereomers of 3,4-methylenedioxymethamphetamine (MDMA) …
www.sciencedirect.com www.sciencedirect.com

This is interesting as S-MDA is supposed to be like an intense condensed version of MDMA. I’ve always felt this also had some contribution to oral MDMA’s effects as well.

I don’t know but have many of you heard of the phenomenon of MDMA having a shorter duration when more is taken? Ive heard from many people over the years that while larger doses increase the intensity of the effects, the drop off is sooner and more intense as well. This could also be explained by S-MDA.

My experience with MDA is that there is two distinct periods of effect, from the two very different optical isomers. The initial intense euphoric part lasts only 3-4 hours then quickly tapers off into the long lasting trippy stimmy afterglow. The initial part is the S-MDA and it indeed is shorter than MDMA which often is 4-6.

This next one is a great one, although sadly the result of a fatality. The deceased had twice as much S-MDA to R-MDA in the blood. While this one extrapolates the increased R-MDMA found was due to preferential metabolism of S-MDMA, I’m going to assume the S-MDA was still there in high amounts as the body wasn’t able to properly metabolize the dose taken (hence death) and didn’t have the ability to demethylenate. (Bad for them, good for us to get a better idea of the S-MDA to R-MDA ratios.)

www.sciencedirect.com

Distribution of 3,4-methylenedioxymethamphetamine (MDMA) and 3,4-methylenedioxyamphetamine (MDA) stereoisomers in a fatal poisoning

This communication presents the quantitation and differential distribution of the enantiomers of 3,4-methylenedioxymethamphetamine (MDMA) and its phys…
www.sciencedirect.com www.sciencedirect.com

-GC
 
I have only scanned these articles, but to address the issue of safrole potentially inhibiting liver enzymes...super interesting...

If we are talking about P450, then adding grapefruit juice would theoretically mimic this effect, as grapefruit juice also inhibits P450. I have always heard how grapefruit juice potentiates a roll, but have been hesitant to try it due to an ER incident with a friend of mine involving CYP2D6.
 
This one is interesting…

www.sciencedirect.com

Nicotine and modafinil combination protects against the neurotoxicity induced by 3,4-Methylenedioxymethamphetamine in hippocampal neurons of male rats

MDMA (3,4-Methylenedioxymethamphetamine) is a common recreational drug of abuse which causes neurodegeneration. Nicotine and modafinil provide antioxi…
www.sciencedirect.com www.sciencedirect.com

It appears both modafinil and nicotine protects against MDMA induced neurotoxicity. It makes me wonder if other stimulants at low dosages could afford similar protection.

-GC
 
REAL pure MDMA is great but one Chemical tops that.... utterly the Bugatti Veyron of Stims and Empathogens ! Figure out what it is....Legendary and I know guy who raved on it! What an experience he had ...:p;)
My opinion it's 6 -APB.....Thank You Stimsim BENZO FURY real thing -------
Happy Dance GIF
 
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Idk if I posted this before but I often talk of how the 3month rule is completely arbitrary and there’s no harm in having 2night sessions so long as certain rules are followed (one being only having at most 6-7 sessions a year average). I’ve proven plenty how it’s safe from a neurotoxicity standpoint in another thread but many think the high will be dulled as well.

This study proves otherwise and goes along pretty much with what I’ve been saying. A second night roll can be better than the first.


-GC
 
F.U.B.A.R. said:
DOM, aka STP by any chance?
Click to expand...
Nah combination of actual 6-APB and 2C-B now you are really talking about tripping and rolling --that is one of a kind experience. He did his Post speech and feelings on you tube and no question he was trashed hard. and he was so used to doing all the stims including actual real Molly. He did this on a Saturday evening and was not able to do the video till Tuesday and still looked completely baked. Doubt still on there but he did say he was wired for all 3 days and would never do that combo again. I have done both separately and can probably imagine what kind of rush and trip one would experience doing both in quantity. Definitely want right kind of people around you ..do it at a Stoner festival yes, Rave perhaps , Night club taking chances but at Music Festival --you might not be the only one there doing it! That's about it.:eek::rofl::devils:
 
hardtack said:
Nah combination of actual 6-APB and 2C-B now you are really talking about tripping and rolling --that is one of a kind experience. He did his Post speech and feelings on you tube and no question he was trashed hard. and he was so used to doing all the stims including actual real Molly. He did this on a Saturday evening and was not able to do the video till Tuesday and still looked completely baked. Doubt still on there but he did say he was wired for all 3 days and would never do that combo again. I have done both separately and can probably imagine what kind of rush and trip one would experience doing both in quantity. Definitely want right kind of people around you ..do it at a Stoner festival yes, Rave perhaps , Night club taking chances but at Music Festival --you might not be the only one there doing it! That's about it.:eek::rofl::devils:
Click to expand...

You said "one chemical".

You've misled us all you blighter...
 
G_Chem said:
Idk if I posted this before but I often talk of how the 3month rule is completely arbitrary and there’s no harm in having 2night sessions so long as certain rules are followed (one being only having at most 6-7 sessions a year average). I’ve proven plenty how it’s safe from a neurotoxicity standpoint in another thread but many think the high will be dulled as well.

This study proves otherwise and goes along pretty much with what I’ve been saying. A second night roll can be better than the first.


-GC
Click to expand...
For the first time in my life, last year in 2021, I tried rolling two nights in a row on the less than stellar product. Had a great time both nights. Not planning to make it a habit, as I had never done it before in 20+ years of rolling, but it was nice to know that at a special event with multiple nights, I would have that option available.
 
indigoaura said:
For the first time in my life, last year in 2021, I tried rolling two nights in a row on the less than stellar product. Had a great time both nights. Not planning to make it a habit, as I had never done it before in 20+ years of rolling, but it was nice to know that at a special event with multiple nights, I would have that option available.
Click to expand...

Yea honestly I often feel better after a two night session, but maybe it’s also the vast quantities of psychedelics often consumed in conjunction ;)

3 nights has always ended up with some decent depression after, not sure why the difference. I think it comes down to a taxing of the antioxidant system.

-GC
 
Yeah, I was mixing LSD, 2CB, and MDMA all weekend. It was a great time, and I would do it again. Three days would def. be too much.
 
indigoaura said:
Yeah, I was mixing LSD, 2CB, and MDMA all weekend. It was a great time, and I would do it again. Three days would def. be too much.
Click to expand...

I was thinking on it more today. For me at least the day between is usually full of sleep. I pretty much sleep all day wake up for an hour or two then dose again. It seems like such fiend like behavior but it’s the only drug I use in such a way and for the reason of knowing that second night can reach truly epic proportions.

I remember @Hilopsilo describing it well, I think me and him get similar types of MDxx and use in a similar manner. That second night it’s like you’re almost relaxed into it more. It usually hits harder in all the right ways, much more inhibition.

Next weekend I’ll be doing a two nighter so I’ll report back but I’m sure I’ll walk away feeling great.

-GC
 
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