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researchers discover immune system mechanism behind methamphetamine tolerance

I'm sorry for being a no-post user bumping an ancient thread, but this is so interessting. Anything came from it more recently?

I did MDMA a few times many years ago, and quickly lost the magic. This was a real shock to me, and very depressing as I really loved MDMA and thought I did everything to do it safely; few times a year, reasonable dose, no redosing, antioxidants, no other drugs, etc. Eventually I came to terms with the fact that I had "used up my times" of MDMA, but I'm still curious about how MDMA works and what causes the loss of magic.

The whole serotonin thing never seemed all that believable to me. The magic simply can't be caused by serotonin release, since other serotonin releasers don't cause MDMA magic, but tend to cause similar dizziness and other side effects that MDMA does. I know about the serotonin->oxytocin cascade theory, and it is very interessting, but still, I can't shake the thought that some completely different neurochemical process, possible still unknown, must be involved. Learning about the trace amine signalling also opens up the possibility, at least to my pretty ignorant mind, that chemical interference in other signalling systems have a much bigger impact on your feelings than the regular suspects dopamine and serotonin. Perhaps the only reason we are looking at those transporters is that they were easier to identify because they use more of the neurotransmitter? Or perhaps they are just the vessel for the simple emotional systems of lower organisms (no offense, squids!) that we have inherited, but their use today is only a biological backdrop or a scaffold on which our thinking and emotional brain is built with completely different, more specialized and delicate neurotransmitters that we have yet to discover? Their receptors would have evolved from the usual suspects, such as the serotonin and dopamine receptors, and the evolutionary pressure would have been to make them ignore serotonin and dopamine, but perhaps they would still be completely unprotected against "analogs" like MDMA?

That the immune system would cause loss of magic, now this could certainly explain a lot of the observed phenomena. Some metabolite or perhaps a protein modified by MDMA during metabolism would be the cause of the magic, and there would be antibodies formed against it with repeated use. Perhaps this modified protein or metabolite is involved in the actual signalling cascade for your regular, household, love! Perhaps the immune system itself is a part of the biological mechanism behind love; killing off neural connections to imprint a feeling of love towards certain identified objects (like friends).

Perhaps part of our immune system isn't involved in killing off germs at all, but has been adapted to be used as an ad-hoc homeostasis device. It would be running around watching for those modified proteins, allowing us to eat certain fruits containing poisonous alkaloids instead of just leaving the task completely to the cytochromes and other enzymes.

I'm no biologist or chemist, so there's a high chance I'm just rambling nonsense, and I'm aware of this risk. Still, this is so interessting I couldn't keep quiet.
 
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the loss of magic with mdma is simply loss of novelty. wait two years and it will come back though you need to up the dose
 
pofacedhoe: sorry, it is simply not :( Abstinence has little effect on mdma "tolerance". It will get you back the speedy effects and even the mongyness, but not the magic. There has been some anecdotal reports of St Johns wort extracts and piracetam being used to get the magic back, but it's not clear if it really works. It is also hard to see how it would work pharmacologically.
 
I'm with pofacedhoe, I think it's state-related associative learning combined with abuse of dopamine-releasing drugs (which MDMA does). Similar to other amphetamine tolerance, your brain starts to 'learn' that amphetamine release causes tons of dopamine release & the rain acts to modulate that, resulting in much less 'magic'. Usually after 10-100 doses. Some people seem much more predisposed to it.

The whole 'MDMA loses magic, you can't do anything about it, & nobody knows why' doesn't stand for me. Seems like a cop out. Drugs don't just suddenly stop providing pleasure while producing stimulatory effects for no reason.

I would imagine much of the direct agonist action & NE release stays the same, explaining the heart rate/stimulation remaining relatively constant.
 
I'm with pofacedhoe, I think it's state-related associative learning combined with abuse of dopamine-releasing drugs (which MDMA does). Similar to other amphetamine tolerance, your brain starts to 'learn' that amphetamine release causes tons of dopamine release & the rain acts to modulate that, resulting in much less 'magic'. Usually after 10-100 doses. Some people seem much more predisposed to it.

The whole 'MDMA loses magic, you can't do anything about it, & nobody knows why' doesn't stand for me. Seems like a cop out. Drugs don't just suddenly stop providing pleasure while producing stimulatory effects for no reason.

I would imagine much of the direct agonist action & NE release stays the same, explaining the heart rate/stimulation remaining relatively constant.

I believe that any "loss of magic" is analogous to that phase in marriage when both spouses are still quite happy, but the honeymoon is over.
 
Well I for one know my MDMA tolerance has nothing to do with novelty or getting used to it. I don't call it magic loss because its really more near complete immunity to it (funnily enough given the thread topic). A dose of 100-125mg MDMA used to put me on the floor for four hours feeling like my whole body is orgasming barely able to stand up. After taking maybe 12-16 pills in the space of three months (no more than one session per week) it just stopped working. Its been 7 years now with 6-12 month breaks between tries and still 190mg of really good MDMA that 100-125mg smashes everyone else who tries it does less than a cup of coffee. In fact if someone slipped 150mg of MDMa in my coffee without me knowing I doubt I'd even notice. I've tried SJW, piracetam, NMDA antagonists, and 5-htp and none of them really made a difference.

I think with psychedelics novelty is involved with tolerance over the years because with them although they still hit me hard and it is fun, it still doesn't have to same wow factor it used to. Definitely no uncontrollable laughter.

Anything came from it more recently?

There have been a few studies on attaching drug molecules to highly immune reactive proteins like influenza proteins which results in the body reacting to the drug as a pathogen and preventing it from making it to the brain/receptors. Thereby effectively creating a vaccine to particular drugs.
 
I'm with pofacedhoe, I think it's state-related associative learning combined with abuse of dopamine-releasing drugs (which MDMA does). Similar to other amphetamine tolerance, your brain starts to 'learn' that amphetamine release causes tons of dopamine release & the rain acts to modulate that, resulting in much less 'magic'. Usually after 10-100 doses. Some people seem much more predisposed to it.

The whole 'MDMA loses magic, you can't do anything about it, & nobody knows why' doesn't stand for me. Seems like a cop out. Drugs don't just suddenly stop providing pleasure while producing stimulatory effects for no reason.

I would imagine much of the direct agonist action & NE release stays the same, explaining the heart rate/stimulation remaining relatively constant.

my experience with both mdma and amphetamine is that abstinence brings back the magic, BUT you will still need a much bigger initial dose to reach that magic point. when i started taking mdma 100mg would floor me, now i need 250mg min BUT it still is amazing, yet i am aware of what to expect so its not quite as shockingly magical, though still an amazing high that blows my mind and fills me with love for everythiing and everyone. mdma also makes me way hornier now that it did in the past. anyway i no longer smoke tobacco and i swear for me tobacco has always ruined the magic of mdma. makes me feel great for five minutes then i feel way more sober and a bit bored, same with speed and cocaine hence i no longer smoke tobacco.

anyway i still find amphetamine has magic i just need a fat strong line and i'm going like a jackhammer though i rarely partake due to the awful comedown from most types of amphetamine style monoamine releasers for me
 
That the immune system would cause loss of magic, now this could certainly explain a lot of the observed phenomena. Some metabolite or perhaps a protein modified by MDMA during metabolism would be the cause of the magic, and there would be antibodies formed against it with repeated use. Perhaps this modified protein or metabolite is involved in the actual signalling cascade for your regular, household, love! Perhaps the immune system itself is a part of the biological mechanism behind love; killing off neural connections to imprint a feeling of love towards certain identified objects (like friends).

Perhaps part of our immune system isn't involved in killing off germs at all, but has been adapted to be used as an ad-hoc homeostasis device. It would be running around watching for those modified proteins, allowing us to eat certain fruits containing poisonous alkaloids instead of just leaving the task completely to the cytochromes and other enzymes.

I see a lot of people dismissing this idea out of hand without providing any evidence, so lets see what the science says. Janda's first study linked in the OP's post didn't do much to show whether this mechanism contributes to tolerance or even whether these adducts form in vivo, however his followup study does just that:

Self-vaccination by methamphetamine glycation products chemically links chronic drug abuse and cardiovascular disease.
http://www.ncbi.nlm.nih.gov/pubmed/17592122


Basically the study shows these meth-glycoprotein adducts are formed in vivo, and levels of these antibodies are correlated with the amount of meth self administration. Now there's a big jump from that finding to saying that these antibodies are contributing to tolerance, but I don't think there's any evidence against the idea either. When you consider the way "vaccines" are made against small molecule drugs, is it really out of the question to say that the body might have a natural mechanism to recognize and remove drugs like meth or MDMA in a similar way? Unfortunately it doesn't look like Janda's group has gone any further with these studies, and I haven't been able to find any other paper's on the topic.
 
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