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Theories for no comedown

I found this article interesting. It mentions that MDMA iself is not neurotoxic when direct cerebral injection did not result in the expected degree of toxicity. The study consists of applying the MDMA and its metabolites to cells to test for relative oxidative toxicity.

Changes in cell viability caused by exposure to MDMA or
its five metabolites were evaluated and compared as shown in
Figure 5. All of the compounds induced a dose-dependent decrease
in cell viability after 24 h of incubation; however, the
catechol-containing metabolites (19-21) were considerably
more toxic to PC12 cells because their IC50 values are significantly
lower than the ones of MDA and MDMA, as determined
by the analysis of all of the IC50 values: IC50 158 uM (NMe-
R-MeDA) < IC50 247 uM (6-OH-R-MeDA) < IC50 416
uM (R-MeDA) , IC50 3365 uM (MDA) < IC50 4464 uM
(MDMA) < IC50 7526 uM (3-O-Me-R-MeDA), decreasing
order of toxicity. The range of concentrations achieved is
believed to occur in vivo after repeated drug usage (57).
Click to expand...

Although N-Me-R-MeDA, 6-OH-R-MeDA, and R-MeDA
have not been undoubtedly established as in ViVo neurotoxic
metabolites of MDMA, it was demonstrated that these metabolites
can account for the toxic properties of this drug. Note that
N-Me-R-MeDA, a metabolite that attains human plasma concentrations
similar to those of MDMA (58), was the most toxic
metabolite, a result that is in agreement with toxicological data
obtained in cardiomyocytes and hepatocytes (9, 59). It is possible
that adducts of these catecholic-containing compounds and major
oxidative metabolites of MDMA could be generated and
participate in its toxic effects (60-62).

... All compounds that possess a substituent in the catechol group
seem to be less toxic than those with free aromatic hydroxyl
groups. The ability of these latter compounds to form reactive
o-quinones, leading to the formation of reactive species, is
thought to represent a critical step in their toxicity, as suggested
by previous studies (63, 64). Furthermore, the oxidation of the
metabolites to their respective aminochromes, which are toxic,
must also be taken in consideration (9). Electrochemical results
fully support and explain the differences observed in terms of
the cytotoxicity of the compounds.
Click to expand...

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?CMD=search&DB=pubmed
 
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It seems to me that the people with more efficient COMT metabolism would suffer less neurotoxicity since the products can no longer form reactive quinone species like alpha-methyldopamine.

And I have no idea what enzyme is responsible for the O-demethylenation.
 
and R-MeDA
Click to expand...

I'm assuming that the above abbrieviation refers to alphamethyldopamine? If that's the case & it's a toxic metabolite then how the fuck did a drug like aldomet (alphamethyl DOPA) get through clinical trials & end up being used to treat hypertension, as the active metabolite of aldomet is alphamethyldopamine.

Unless there was a mighty cock-up in the phase 2/3 trials of aldomet, the only conclusion to be drawn is that those metabolites behave differently in the brains of humans compared with the test species, otherwise lots of people using aldomet for essential hypertension would have developed into e-tards in a very short tiome (the daily dose of aldomet would produce the equivalent amount of metabolite as doing a few pills every day)
 
what in the fuck do people mean when they say 'no comedown'

Every fucking drug has a comedown, its a matter of the drug wearing off, aka 'coming down' from the high.
Whether its unpleasant or not is another story.
 
^ It is assumed that people here are refering to the CRASH that occurs after what you describe as come down. It feels like the opposite of the high preceeding it, and usually lasts longer.

So, I can use morphine once, get really high, come down (by your definition), and feel perfectly fine (if not better) the next day.

Substitute that with E, and you'll have me feeling suicidal for around a week after.
 
fastandbulbous said:
I'm assuming that the above abbrieviation refers to alphamethyldopamine? If that's the case & it's a toxic metabolite then how the fuck did a drug like aldomet (alphamethyl DOPA) get through clinical trials & end up being used to treat hypertension, as the active metabolite of aldomet is alphamethyldopamine.
Click to expand...

Hmm ... good question.
 
Amphetamine is a top seller and popular in most places, despite its reputation for neurotoxicity.
 
^^True.

And from looking at it, it seems that alpha-MeDA is actually a very minor metabolite of alpha-methylDOPA. I didn't see anything about alpha-MeDA being the principally active metabolite.
 
for me there are huge differences between comedowns. with meth they can be almost non-existent or nightmares which last for days. i always think this is a sign that drugs like meth or xtc effect our brain in a way we do not completely understand. a lot of people in drug forums have a different opinion because they act like little doctors who know everything about their drug of choice. but even the smartest forum member can only guess, for example what kind of longterms effects a great drug like mdma will have for user in about 40 years. may be we simply can not explain the comedown too. all i want to say is our brain is a VERY difficult lil thingy.
 
ld 100 said:
for me there are huge differences between comedowns. with meth they can be almost non-existent or nightmares which last for days. i always think this is a sign that drugs like meth or xtc effect our brain in a way we do not completely understand. a lot of people in drug forums have a different opinion because they act like little doctors who know everything about their drug of choice. but even the smartest forum member can only guess, for example what kind of longterms effects a great drug like mdma will have for user in about 40 years. may be we simply can not explain the comedown too. all i want to say is our brain is a VERY difficult lil thingy.
Click to expand...

Although I don't disagree with you, I can't resist but interject with your "little doctors" comment and say that many people who post here do know MUCH more about the drugs they are using than their doctors ;).
 
i'm defnitely sure a shitload of people on here would know a lot more than i do, that's why i'm on BL reading a shitload of articles and threads so that i know as much of a drug as i can before i try them :)

where they're bs-ing or not is up to my brain to filter that all out :\
 
As someone once suggested that the actual aspect of MDMA "comedown" was, although physical in some ways , mainly due to the release of the strong emotions bringing with them negative ones ! The chemical rush pushing these negatives to the back of the mind but nevertheless releasing them from their normal residence .Then after the effects have worn off , and the loved upness has died away, the released negativity, maybe not accessed as actual events , just "bad feelings" Whether this has any validity I do not know but it doesn't seem impossible given MDMAs ability to allow massive inhibition loss to occur!
So in brief, a physical and psychological combination with the psychological factor being very prevalent with some individuals . How one could actually measure such a theory doesn't leap straight to the mind , but interesting observation I feel.
 
^gee, well, to measure, one would first try the basic bat of cog tests commonly avail at a psych facility /lab near you - or to anyone w/internet access and then..ah, doggone it i've gone all asoftcock, tis the rainbow remnants of elven bush serpents, damn hippies and their sunrise psych sets that last 4 days...
 
just a thought, but despite the reported neurotoxicity of the mix- amphetamines make some people feel great after using them and a lot of pills are mixed with them?
 
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fastandbulbous said:
^ Another attack of the brain weevils, Nano? started off easily enough but rapidly got to the point where I need a translator (& babelfish doesn't cover it!)
Click to expand...
I am still trying to figure out what the verb (?) "gone asoftcock" means ;)
 
nanobrain said:
^gee, well, to measure, one would first try the basic bat of cog tests commonly avail at a psych facility /lab near you - or to anyone w/internet access and then..ah, doggone it i've gone all asoftcock, tis the rainbow remnants of elven bush serpents, damn hippies and their sunrise psych sets that last 4 days...
Click to expand...

Translation (maybe):
Well, to measure, one would first try the basic battery of cognitive tests commonly available at a psychiatric facility or laboratory. Maybe even on the internet. Confound, my giganic [internet?] phallus grows flaccid and I cannot maintain my regular measure of wit; copious amount of psychedelics have unnerved me! God forsake the modern hippies and their festivals of rapid electronic music lasting for days.
 
^ and nuke goes where babelfish fears to tread (if a fish can tread anywhere in the first place =D )

Dondante said:
^^True.

And from looking at it, it seems that alpha-MeDA is actually a very minor metabolite of alpha-methylDOPA. I didn't see anything about alpha-MeDA being the principally active metabolite.
Click to expand...

Is it? I'd been working under the impression for years that decarboxylation to a weaker 'false' neurotransmitter was the principal mechanism of action as a hypotensive agent (and why things like depression were such a common & serious side effect). What set me off was years ago my grandad had them prescribed for his blood pressure and he hated the drug because of the depression (he eventually had to be put on an ACE inhibitor & some other drug, purely due to the development of symptoms of severe clinical depression).


Right - update apparently the active metabolite is alpha methylnoradrenaline, but as the metabolic pathway would be

Alphamethyl DOPA ----> alphamethyldopamine ---->alphamethylnoradrenaline

via the same enzymes that are responsible for dopamine & noradrenaline biosynthesis (DOPA decarboxylase & dopamine hydroxylase).

As an intermediate metabolite for the active end drug, you can't really call alphamethyldopamine a very minor metabolite of alphamethylDOPA as it's conversion to the intermediate metabolite is essential for the final drug action.

This also means that any alphamethyldopamine produced from the metabolism of MDA/MDMA is going to largely end up as alphamethylnoradrenaline. Looking at the SPC sheet for aldomet, theres a striking resemblance of the side effects to those of a pills comedown.

If anybody can find how long it takes to clear the false neurotransmitter from being used at the synapses in place of noradrenaline, that might account for the length of time that the 'Tuiesday blues' last for.


Link to an online version of SPC sheet here
 
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beyond-infinity said:
Depression can be avoided by the way you think about things, and your general outlook in life, as Indelibleface said.
Click to expand...
Not 'clinical' depression. It basically dictates the way you think about things and your general outlook on life. If you can 'avoid it' then by definition you aren't depressed and there's nothing to avoid. If not, there's still nothing to avoid.
 
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