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Theories for no comedown

B

beyond-infinity

Bluelighter
Joined
Jul 24, 2003
Messages
560
I origionally started a thread similar to this on the ecstasy forum but most comments were anecdotal rather than theory based.

I'm curious as to the scientific reason i.e. with regard to brain chemistry, how it is that some people do not suffer from comedowns, or even feel in any way different to normal after having done large amounts of drugs (specifically ones that deplete brain chemicals). My girlfriend regularly takes high doses of MDMA. Anything up to around 12 strong pills in a night. She get's the full effects, strong euphoria, great buzz, but says she feels completely normal from the day after. She does get moody and irritated often within the 24 hour period after the session, but after that she's fine. I'm with her regularly and I don't see any changes in her either, anytime after then.

I recentley got chatting to a girl who said she has never experienced a comedown on anything and had been taking pills (e,speed) every weekend for the last 16 years.

Doing that many ecstasy pills must completely deplete you of serotonin. Surely without serotonin or severely lacking in it would cause you to feel different in some ways or other. I get strong comedowns i.e. depression, poor concentration, moodyness etc. after just a couple of good pills and I think it is very common to get some kind of a comedown, even if just poor concentration and laziness.

So is it just that a small percentage of people somehow have brains that are able to replenish their serotonin 10x faster than the rest of us (even without the aid of food - in my gf's case she sometimes doesn't eat for a day or two after), or are there any other credible theories as to why this happens?
 
that is interesting, I never knew of such things.
75mg of MDMA makes me feel like crap for 2-3 days after and even 150mg+ has MINIMAL positive effects during the experience.
on the other hand, small doses of amphetamine have zero negative impact the day after and are very effective for my purposes.
 
This isnt to scientific, but its interestring none the less. One time on a quest of idiocy i did about 14 pills in 3 days. it was a gram of pure mdma gel capped. Now this should have left me a horrible comedown right, oh i also did acid on the last day. Well no comedown, simply because i fell in love. I met a girl who had everything i ever looked for. i dont know maybe maybe the state of being in love produces serotonin but those days and the weeks that followed were some of the most magical ever. Also an important point is not only did i feel happy, my body felt fine, my mind was sharp, my words were clear. My thoughts are that you are ment to fall in love/reaffirm love on ecstasy and as long as you do that your ok. Pretty gay and plur i guess but hey results are results.
 
Wasn't there a shirt that said something like "Don't marry anyone you've met on Ecstasy untill 3 months later" or something? ;)
 
I think most of us have the ability to replenish our serotonin faster, there's just a matter of figuring out how to unlock that function in our brains. I've done more pills that I should have on a few nights, and sometimes I've paid for it in the morning with a harsh depression. More often than not though, especially if I'm in the right environment in the morning, perhaps warm in my own bed, with a beautiful sunrise peeking through my bedroom window, I'll feel just fine. After I have a small healthy snack, I'll usually feel fantastic with only minimal comedown symptoms.

Basically, what I'm saying is that the comedown can either be manageable or downright bad depending on many factors, mostly how I take care of my body during the experience (and after), but also my environment as well, and my mood going into the experience. I tend to be an optimistic, positive person on the whole, and I'm not prone to depression while sober. During depression, you tend to dwell on shortcomings and bad situations in your life. Well, deal with those shortcomings and bad situations before taking the drug, and understand that these things are manageable and not problems. After that, I don't see the comedown somehow convincing you otherwise.
 
There are genetic differences in how our body handles oxidative loads and the metabolism of other compounds. It's important to remember also that reductions in dopamine and serotonin in the brain do not cause depression in all people.

Usually I got through it okay because I reminded myself that any off-centered emotions were probably my brain coping and not actually me.
 
Probably boils down to lots of things. Firstly metabolic differences; so the people who don't get bad comedowns from 15 pills might actually metabolise MDMA more quickly than normal people, so the roll they get off 15 pills might be the same as a 3 pill roll for normal people.

Some people, either through diet or genetics have higher levels of antioxidants.

And then there will be lots of little differences that cumulate into differences in the way receptors regulate themselves.
 
My totally unscientific opinion on the matter is this: Some people have fried themselves so severely from drug use that they do not notice a comedown. This is because they are perpetually 'down' so to speak.

For example the people I grew up smoking cannabis with to this day report no comedown or burnout from getting high. This is probably because they never stoped smoking from when we were kids, I mean literally they have been stoned all day everyday for years. They forget what it means to be healthy and on top of their game. If you are pilling a few times a month it is easy to adapt to being etarded to a degree and never notice anything is abnormal until the eventual trainwreck.

Perhaps Le Junk can comment on this since he is the longest time user of MDMA on this board that I know of. I'm sure he has run into many people like that.
 
Interesting ideas.

I should have mentioned that by comedown I wasn't not referring to depression alone but the many adverse effects from low levels of neurochemicals. Depression can be avoided by the way you think about things, and your general outlook in life, as Indelibleface said. But poor concentration, a sense of dullness and low motivation can be harder to overcome. It depends on the individual. But it is surprising that some people notice no adverse effects from certain drugs without even trying to avoid/overcome them.

BilZ0r and nuke, you mention about oxidation/anitoxidants. How does this relate to brain chemistry with regard to comedowns?
Also, nuke, you say that reductions in dopamine and serotonin in the brain do not cause depression in all people. Is that possible with other effects usually associated with low levels of these chemicals?

Is it possible that people who don't notice any comedown actually have low levels of these chemcials as would be expected, but unlike the majority of people, this just netaurally wouldn't affect their thinking or behaviour in any way, almost like they naturally (without drugs) have far higher levels of neurochemicals than is actually required?
 
people who proclaim to suffer no comedowns or to have a viable 'cure' are either:

1. liars / in denial / dicksizing or brainfried aka nothing to worry about in re remaining wetware;

2. have only ingested real psychoactive drugs via google or fax form;

3. are in marketing for that new herbals zaibatsu or cheezweasly 'harm reduction alternative' promoters.

whatta goesa uppa musta cumma down, eh?

oh and oxidative stress damage is overrated, so is efficacy of antioxidants - FFS, there's not even a stadardised measure of their efficacy, just ask anyone who's ever ran an ORAC on an extractive complex that is both hydro and lypopophilic and contains 700 or so identified compounds?
 
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I mentioned antioxidants because MDMA is a known oxidant in humans, and oxidation plays a major role in MDMA induced neurotoxicity in rodents. The frank neurotoxicity seen in rodents may be evident in humans, or more likely, it is mirrored by a more subtle oxidative insult. Antioxidants could help protect against this. Also, come downs must, at least in part, have a physical side, and it's been shown that prolonged exercise induces oxidation, and antioxidants prevent this and at least to a degree, fight muscle fatigue.
 
BilZ0r said:
I mentioned antioxidants because MDMA is a known oxidant in humans, and oxidation plays a major role in MDMA induced neurotoxicity in rodents. The frank neurotoxicity seen in rodents may be evident in humans, or more likely, it is mirrored by a more subtle oxidative insult. Antioxidants could help protect against this. Also, come downs must, at least in part, have a physical side, and it's been shown that prolonged exercise induces oxidation, and antioxidants prevent this and at least to a degree, fight muscle fatigue.
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!!

The first time I ever see someone post something scientifically sound about the bad things that excersize can do to you! I officially love you now =D
 
^^lol, that is ironic and funny but oxidative stress just comes with the territory of how our bodies function, even under ideal conditions. And yes I also agree that oxidative stress is not the only or even main cause of MDMA neurotoxicity but considering how profound the positive change is when using antioxidants, it would be safe to say that it is one of the greater concerns with use.
 
beyond-infinity said:
BilZ0r and nuke, you mention about oxidation/anitoxidants. How does this relate to brain chemistry with regard to comedowns?
Also, nuke, you say that reductions in dopamine and serotonin in the brain do not cause depression in all people. Is that possible with other effects usually associated with low levels of these chemicals?
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Oxidative damage (excessive free radicals) is caused by the metabolism of MDMA and the elevated temperature from sertonergic and dopaminergic stimulation. This is what destroys axon terminals and tryptophan-hydroxylase, effectively diminishing both the amount of serotonin and number of places it can bind to, causing (maybe) depression, anxiety, etc.

And, yes, things like anxiety, circadian disruption, decreased impulsitivity, and many other side effects, affect people differently/variably in a dopamine/serotonin reduced environment. One of my friends who was a lifelong meth user says he tried a serotonin reuptake enhancer for a while and it didn't make him that depressed at all.
 
nuke said:
Oxidative damage (excessive free radicals) is caused by the metabolism of MDMA and the elevated temperature from sertonergic and dopaminergic stimulation. This is what destroys axon terminals and tryptophan-hydroxylase, effectively diminishing both the amount of serotonin and number of places it can bind to, causing (maybe) depression, anxiety, etc.

And, yes, things like anxiety, circadian disruption, decreased impulsitivity, and many other side effects, affect people differently/variably in a dopamine/serotonin reduced environment. One of my friends who was a lifelong meth user says he tried a serotonin reuptake enhancer for a while and it didn't make him that depressed at all.
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I assume you refer to Tianeptine?

You've probably read enough of my posts to know I am one of those panic-struck melancholics. Tianeptine is actually one medication that did something positive for me - the depression lifted, and, more importatntly, there was even some slight motivation! SSRIs, on the other hand, make me feel poisoned, and as you may have read, MDx-like substances cause me to crash insanely.

I have reason to believe that whatever role serotonin plays in depression, it is the availability of presynaptic serotonin that seems to be more important than its post synaptic flooding.
 
It may have been tianeptine, I can't recall now, it was a couple years back.

As an adjunct to the goodness of l-theanine, I used to experience a lot of depression and anxiety nastiness that's been gradually clearing up as time goes by, and I think a lot of it has to do with my diet, I rarely eat meat anymore and eat tons of cocoa powder and green tea (maybe the MDMA and mild amphetamine abuse and psychedelics use did something positive, too). SSRIs didn't do shit for me.
 
To my knowledge, Tianeptine is the only Serotonin uptake enhancer available commercially.

Short of ULD Ketamine, Tianeptine is one drug I'd be happy to take daily. Too bad it has such a short halflife, making it necessary to dose at least 2 times a day for best effectiveness (3 ideally).

As with many other promising drugs though, Tianeptine is unavailable in Canada :(
 
I don't know how much variation there is in any given population for the metabolic breakdown of MDMA/MDA, but one of the metabolic routes results in the production of alphamethyldopamine. Now this compound is reuptaken just like dopamine and effectively is a false neurotransmitter. The trouble comes from the fact that alphamethyldopamine has only a fraction of dopamine's activity, so results in underactivity of the dopaminergic system. That combined with it's resistance to breakdown by MAO due to the alpha methyl group means thast it's a significant factor.

Now if someone's genetics means that they convert more of a dose of MDMA to alphamethyldopamine than most of the population then I'd imagine they're more likely to suffer from effects like depression etc (alphamethyldopamine is the active compound formed from alphamethylDOPA, which is used clinically to treat high blood pressure under the name Aldomet - it has a notoriously high incedence of side effects that read just like those of a comedown from MDMA)
 
^ Is this a cytochrome pathway, by any chance?

That would make sense for me since I don't seem to get much out of the -codone opiates DXM, or alprazolam. I find the MDA crash infinitely more destructive than the amphetamine crash.
 
Don't know - at a stretch (a very long stretch) it could be a reverse process of COMT (catechol O-methyl transferase), but most likely is a P450 mediated metabolic pathway. If anybody else wants to look tonight, please report your findings as I'm a bit scattered at the moment.
 
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