Comment · Wed, March 20, 2013
MDMA Supplementation
Original post in this thread
MisterYouAreSoDumb · 205 points
Ok, I did promise that I would make another post regarding supplementation to mitigate MDMA induced neurotoxicity. I have just been putting it off. Since my last post, I have gathered more information regarding my theory about MDA metabolism being the main cause of MDMA's neurotoxic effects. I will try to not get into that in this post, and keep this mostly about supplementation. As seems to be the norm with me, this may be long winded. Obviously everything I put on this list is not necessary. I will be placing supplements into different categories, with reasonings and references. I will let you decide which ones will be a part of your regimen.
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Essential Supplements:
* Alpha Lipoic Acid- This is one that everyone should be taking. It is a powerful antioxidant that scavenges reactive oxygen and nitrogen species. It also has a nice benefit of regenerating other vitamins, like C, after redox cycling. It exists in two enantiomers, R-ALA and S-ALA. R-ALA is the biologically active isomer that we are looking for. Most supplements a…
What they were answering
AskQGetA · 1 points
How did you determine that inhibition of CYP3A4 prevents MDA metabolism? The study you referred to contains this illustration which seems to imply that CYP1A2 and CYP2D6 play a bigger role, but since these are crucial to ridding MDMA from the body, they shouldn't be tampered with.
Edit: Now I'm confused. This study has the following graph which does show that MDMA is metabolised into MDA by CYP3A4 alone. Might the first be a misprint, or an interpretation error on my part?
u/MisterYouAreSoDumb
The study you referred to contains this illustration which seems to imply that CYP1A2 and CYP2D6 play a bigger role
Wow, that's an oversight on their part. They have the figure backwards!! The primary route of metabolism is CYP2D6, leading to O-demethylation. The secondary route is CYP3A4, leading to N-demethylation. Rats primary metabolism is via CYP2D1 (Their CYP3A4 equivalent). This is why rats show higher toxicity than humans.
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http://www.ncbi.nlm.nih.gov/pubmed/20388857
>inhibition of CYP2D6 activity
by MDMA could result in metabolic compensation by CYP1A2
and CYP3A4 in vivo (Lin et al., 1992; Kreth et al., 2000; Maurer et
al., 2000; O’Mathuna et al., 2008). This result means that the role of
CYP3A4 could become more important than CYP2D6 in MDMA
metabolism at higher concentrations.
>Our results are in
contrast with a study by Carmo et al. (2006) who described that the
CYP3A4 enzyme did not enhance MDMA toxicity in Chinese hamster
lung fibroblast V79 cells transfected with individual P450 enzymes.
This difference might indicate that cell-specific properties play
an additional role in the cytotoxicity of MDMA or its metabolites.
This fits right into my theory. The methylated metabolites are much more hepatotoxic, but do not cross the blood brain barrier. The N-demethylated metabolites are much more neurotoxic.
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http://www.ncbi.nlm.nih.gov/pubmed/19628751
>These results, which are consistent with those of Escobedo et al.
(2005), suggest that HHMA and HMMA do not readily penetrate the
blood-brain barrier (either in their free form or as sulfate or glucuronic
conjugates) and indicate that there is little or no brain metabolism of
MDMA to HHMA or HMMA. Taken together, these observations and those of others (Steele et al., 1991; Escobedo et al., 2005) cast doubt
on the view that HHMA and HMMA are directly involved in MDMA
neurotoxicity (Goni-Allo et al., 2008) but leave open the possibility
that MDA or a catechol-thioether metabolite of MDMA might be
involved.
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http://www.ncbi.nlm.nih.gov/pubmed/18074122
>This is the first report showing a direct
relationship between core body temperature and MDMA
metabolism. This finding has implications on both the
temperature dependence of the mechanism of MDMA
neurotoxicity and human use, as hyperthermia is often
associated with MDMA use in humans.
>plasma concentrations
of MDA, HMMA, or HMA were significantly
higher in those rats administered at 30°C. As shown in Fig. 5a, lowering ambient temperature to
15°C afforded an almost complete protection against
MDMA-induced serotonergic deficits produced at a standard
ambient temperature of 21.5°C. Under these experimental
conditions, hyperthermia was abolished (Fig. 5b and c). In contrast, raising ambient temperature exacerbated both the
acute hyperthermic effect and long-term loss of 5-HT and 5-
HIAA content in different rat brain regions. Accordingly, plasma concentrations of MDA,
HMMA, and HMA in rats treated at 15°C were significantly
lower than those found in rats treated at 21.5°C.
Temperature increases lead to increased metabolism to MDA and it's O-demthylated metabolites. It all fits!
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but since these are crucial to ridding MDMA from the body, they shouldn't be tampered with.
No way! I want to prevent all metabolism. They are not crucial to ridding MDMA from the body. MDMA is excreted unchanged in the urine. You can increase this excretion by increasing urinary acidity. I do this with grapefruit juice and emergen-C packets. CYP3A4 is the primary pathway to MDA. However, CYP1A2 is a secondary pathway. Both are inhibited by grapefruit juice.