N&PD Moderators: Skorpio
MDMA effects on Aromatic L-amino acid decarboxylase
organicshroom
Bluelighter
I am just wondering if the enzyme responsible for the synthesis of serotonin from 5-Hydroxytryptophan is significantly damaged or deactivated following a dose of MDMA? If so, is this reversible or are new enzymes required to be synthesized before serotonin production can commence days following mdma exposure?
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LuxEtVeritas
Bluelighter
^ Tryptophan hydroxylase converts Tryptophan to 5-HTP, not 5-HTP to SE
Aromatic L-amino acid decarboxylase converts 5-HTP to SE which i do not think MDMA affects adversely to any significant degree
for reference of the related:
http://www.ncbi.nlm.nih.gov/pubmed/2568404?dopt=Abstract
http://www3.interscience.wiley.com/journal/119368978/abstract
organicshroom
Bluelighter
Why I ask is because I'm trying to make sense of the typical delayed comedown I get from a session of mdma. It typically hits 48-72 hours after the initial dose. It would make sense that the deactivation of Tryptophan hydroxylase would contribute to this comedown period as little 5htp would be synthesized from tryptophan days following the mdma exposure, so heavy 5-htp supplementation would be required.
But in my experience, even with 200mg each day of supplementation for a few days following the mdma dose I still experience the same degree of comedown, instead possibly delaying it further. From this I suspect a deactivation of Aromatic L-amino acid decarboxylase too could be playing a role, in both the lack of synthesis for serotonin and dopamine. Also I heard that people who supplement with 5htp can become depleted in dopamine, maybe also due to this enzyme burning out? Next time I will supplement with both l-dopa and 5htp to see if has any effect on my terrible tuesday.
LuxEtVeritas
Bluelighter
is 5-HTP at 200mg for the days following making no difference at all?
organicshroom
Bluelighter
The following 2 days it does without a dout(most notably the next day), but during this period I don't get any significant depression anyhow. It's not until day 3 when it hits, and it hits rather suddenly which to me suggests that its certainly an issue with SE system. Even with 5htp supplementation I can not avoid this period, which only last a day at the most anyway. Yes, lower doses of mdma (<120mg) I can avoid this episode, but my desired total dose over a session is usually around 120-180mg, which seems to be the tipping point at which it effects me days after. I don't consider this a particularly irresponsible dose, hence why I am trying to understand the mechanism behind the Tuesday blues.
LuxEtVeritas
Bluelighter
hmmm...confusing
obviously i doubt as would be needed to be the case I assume that AAAD is mostly working for the first two days than simply crashes out to such a degree
organicshroom
Bluelighter
Is a considerate amount of down regulation to the 5-ht receptors likely after a single moderate session of mdma?
LuxEtVeritas
Bluelighter
^ than he would still have some notable negative effects right after comedown
any major dude
Bluelight Crew
good question. I've had this exact same thing happen to me. I rarely use MDMA anymore, but remember this happening to me when I used it frequently. A few weeks ago I took 100mg MDMA for the first time since the 06-07 new years eve and had the same effect. Dosed sunday around 7:30pm, felt fine monday, had mild depression and general malaise tues-thurs.
organicshroom
Bluelighter
^ Its quite common I believe, this delayed comedown. The Tuesday blues if a dose is typically taken on a Saturday night for example. I think it has little to do with use patterns, so even very moderate use won't avoid this heavy comedown.
If it ain't SE receptor downregulation, then it has to do with the lack of serotonin production(psychological effects aside). I can't find any studies that test for this Aromatic enzyme activity after mdma, but it may be safe to guess that the efficiency of this enzyme would be hindered by mdma exposure, as mdma upsets Tryptophan hydroxylase.
The only way to tell next time is by taking a heavy regime of 5htp consistently for the 3-4days following the mdma dose. For example, 100mg every 3-4 hours each day. This may be necessary to quickly renew SE stores and to over come any inefficiency's in it's synthesis.
I am going to see my doctor about getting Carbidopa, which boost 5htp plasma levels giving it more of a chance to be used by the brain.
^ Supplementing with carbidopa is a fascinating idea...it'd prevent 5-HTP's synthesis into serotonin elsewhere in the body while promoting its synthesis in the brain, since carbidopa can't cross the blood-brain barrier.
(Uninformed opinion follows...)
I don't know if taking such heavy amounts of 5-HTP is a great idea; the only rate-limiting step is the aforementioned decarboxylation, which is less restrictive than the rate-limiting step for tryptophan. You'd either end up with a ridiculous amount of serotonin or you'd deactivate all of your AAAD in the production of serotonin from 5-HTP.
organicshroom
Bluelighter
^ I don't believe Aromatic L-amino acid decarboxylase to be a rate limited step, so I assume it keeps on catalyzing the reaction until it burns out. Taking a large dose of 5htp is necessary in circumstances after MDMA exposure, but I wouldn't say it would be healthy in a normal situation, as I think it sacrifices dopamine synthesis(Though they state large doses of 5-htp can be well tolerated). Taking L-Dopa with 5htp would be recommended to overcome this, but then you may reach a point where the decarboxylase enzyme is burnt out. Though I'm not sure if the limit of this enzyme can be reached in a healthy person?
I wonder why it is that taking 5-HTP sacrifices dopamine synthesis, as you say. Is it perhaps because they're both competing for decarboxylation by AAAD? It'd be great if someone could weigh in with some expertise on the following questions:
EDIT: Ok, heh, I just realized that I reposed the original question of the thread. Perhaps it's better to ask by what specific mechanism AAAD converts 5-HTP into 5-HT, in order to better understand if there's any competition with L-DOPA or if stores of AAAD can be depleted.
I've read the excess 5-HTP is metabolized and excreted, but this may be because there simply isn't enough remaining AAAD to convert it into 5-HT. Would taking carbidopa, because it allows for more targeted serotonin production, reintroduce the problem of ending up with excess serotonin? This may also exacerbate the problem of dopamine, since more in-brain AAAD will be occupied with synthesizing 5-HTP into serotonin, assuming that L-DOPA and 5-HTP compete with each other for synthesis via AAAD.
Yes, tryptophan hydroxylase is the rate-limiting step for the conversion of tryptophan to serotonin due to what I'm assuming is the fast reaction time and availability of aromatic amino acid decarboxylase. Nevertheless, when you're converting 5-HTP to serotonin and your only reaction is the decarboxylation, then the decarboxylation becomes a rate-limiting step by default...I suppose this depends on your definition of how limiting a step should be to be considered "rate-limiting" -- it's possible that an abundance of AAAD or its nature (e.g. not being deactivated after decarboxylation) renders this "rate-limiting" null.
At the risk of being lame, may I present a Wikipedia reference:
http://en.wikipedia.org/wiki/Aromatic-L-amino-acid_decarboxylase
I couldn't find a cited source on the part that I was interested in. 
In any case, the problem with taking excesses of 5-HTP would originate in the conversion of 5-HT to 5-HTP via AAAD, whether or not it's a rate-limiting step. If the mechanism by which 5-HTP->5-HT conversion is limited is via depletion of AAAD, then I imagine this would create problems for dopamine synthesis as well. Of course, if the mechanism is something else and there's sufficient AAAD for every biological pathway (or it's not deactivated in the decarboxylation), then taking more 5-HTP would be inconsequential to the problem of dopamine production.
tryp2fun
Bluelighter
Well, the situation with AADC is a bit more complicated than it might seem. It has amine oxidase (MAO) activity as well as decarboxylase activity.
Furthermore, AADC is inactivated during turnover of the amine oxidase activity with serotonin and other biogenic amines.
Finally, AADC reacts with alpha-methylDOPA to produce 3,4-dihydroxyphenylacetone, which is an irreversible inactivator of AADC.
Putting these bits of data together, one might hypothesize that MDMA might either be a substrate for oxidative deamination to 3,4-methylenedioxyphenylacetone by AADC, or by the MAOs, and that compound could result in the irreversible loss of AADC activity.
organicshroom
Bluelighter
^ Nice work.
Where does it suggest that 3,4-methylenedioxyphenylacetone destroys AADC? If this is so, then we have good evidence that will support the deactivation of AADC after MDMA exposure. Another question would then remain, to what degree is the deactivation compared to the concentration of 3,4-methylenedioxyphenylacetone?
organicshroom
Bluelighter
Yes, it's easy to understand now why some people may experience severe comedowns from MDMA, even from a moderate dose. Not only is your serotonin low days later but also could be your dopamine stores too. So it's like a double hit, this is then potentated by either a naturally low AAAD(AADC) activity and/or a significant enough dose of MDMA to render the enzyme inactive.
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tryp2fun
Bluelighter
Well, the data only show that 3,4-dihydroxyphenylacetone inactivates AADC. 3,4-methylenedioxyphenylacetone is very similar in structure to 3,4-dihydroxyphenylacetone, so it could also inactivate AADC. The inactivation involves reaction of the acetone portion of the molecule. Also, I think that MDMA is metabolized to 3,4-dihydroxyphenylacetone by CYP-450 and MAO.
