Comment · Sat, October 7, 2017
This amazing MDMA damage mitigation post by /u/MisterYouAreSoDumb is four years old now. Have there been any discoveries since that warrant an update?
What they were answering
WonkyHonky69 · 17 points
I just took note of something from /u/MisterYouAreSoDumb 's post. He cited drinking grapefruit juice as a way to inhibit the enzyme CYP3A4. He included a flow chart of the metabolizing enzymes showing that CYP3A4 converts MDMA-->MDA. The thought process was that by drinking GFJ, you would reduce the conversion of MDMA to MDA (which was shown to be significantly more neurotoxic, albeit indirectly), and allow it to follow it's other metabolic pathway to HHMA. However, his illustration runs counter to the one in a paper he cited in his supplementation post:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2663855/
Here is the specific chart: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2663855/figure/F1/
Using this info, it shows that CYP3A4 is involved in MDMA-->HHMA and MDA-->HHA. This would mean that GFJ before consuming MDMA would lead to both prolonged serum MDMA and MDA.
So MDMA and MDA injected directly into the brain show NO neurotoxicity. Individuals with lower CYP2D6 enzyme show higher levels of neurotoxicity.
This makes sense if I'm interpreting the chart correctly (Good chance I'm not). To me, it looks like the CYP enzyme written on top is the primary metabolizer (bigger font). If that interpretation is correct, CYP2D6 would be the main guy for converting MDMA-->HHMA and MDA-->HHA, so individuals with lower CYP2D6 would have prolonged MDMA and MDA concentrations…
u/MisterYouAreSoDumb
This is the main study I was referencing in my post:
Non-linear pharmacokinetics of MDMA \(‘ecstasy’\) in humans
You can see the O-demethylation to HMMA is from CYP2D6, and the N-demethylation to MDA is from CYP3A4. However, more recent studies have shown that CYP3A4 is only a minor pathway for N-demethylation. It's actually CYP1A2, CYP2B6, and CYP2C19 that are responsible for the majority of N-demethylation in humans. Your study shows CYP1A2, but not CYP2B6 and CYP2C19.
In conclusion, the results indicate that CYP1A2, CYP2C19, and CYP2B6 contribute to the conversion of MDMA to MDA in humans. Additionally, genetic polymorphisms in CYP2C19 may play a role in the clinical toxicity of MDMA.
The thing is that grapefruit juice inhibits all those enzymes as well.
The effect of grapefruit juice on drug disposition
Bergamottin inhibits multiple CYP isoforms, including CYP1A2, CYP1B1, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4, and CYP3A5.
I've known about this for a bit. People have PMed me many times about the more recent studies regarding the primary CYP enzymes. I also knew that GFJ inhibited those enzymes as well, and it really did not change the gist of my postulations. So I decided to just leave it be for the time being. I wrote that post back in 2012. I was working off older studies, and I did not have full access to as many studies as I do now. So there were certainly holes in things. I always meant to get back around to making a new one. I just never seem to have enough time, and I always get drawn into long-winded arguments in comments and PMs when I do. So I avoid doing it now. I had time to go back and forth with people for hours on end back then. I don't anymore, unfortunately.
The main idea behind my theory is still valid. N-demethylation to MDA is the thing we want to inhibit. It is looking more like CYP1A2, CYP2C19, and CYP2B6 are the targets for that, rather than just CYP3A4. However, grapefruit juice inhibits them all. Even so, I have shied away from recommending GFJ in recent years, and focused more on addressing the oxidative substances themselves. Not that I think GFJ is bad to take. Everything still points to it helping. I just have focused more on the antioxidant side of things recently.
I never intended for those posts to be taken as gospel, or even as completely settled theories, even though many people have taken them that way over the years. I meant them to be a starting place for a larger discussion, and to let people know what I found to have worked. I still think MDMA-induced neurotoxicity is a multifaceted mechanism, and body temperature has always been an exacerbating factor. Toxic metabolites do still seem to be the primary driver of 5-HT system toxicity, and α-Methyldopamine from MDA seems to be the most potent at causing that damage. I have not seen anything yet that would convince me that is not the case. Other mechanisms/metabolites do cause other damage; like excitotoxicity and hepatotoxicity. So focusing solely on one thing is not ideal. That's why it needs a multifaceted approach to addressing each one. Antioxidants and vitamin C/E to hit the oxidative substances, magnesium to help prevent excess calcium from entering neurons, mitochondrial support to ensure your body has enough ATP to keep cells regulated, water and electrolytes to stay hydrated, and monitoring of body temperatures. Preventing the metabolism still seems to be a good idea, but addressing everything else should be sufficient to protect oneself.