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MDMA, does it also hit any anxiety producing receptors or other negative stuff?

MeDieViL

MeDieViL

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Well, when i take really high doses of MDMA i suddenly get a very anxious and generally bad feeling, actually the opposite of a high while it seems to come up fine (feeling great and rolling great for a while then it hits me)

now my question is wheter MDMA is known to hit any receptors that could cause this and could basicly reverse the high?

its obvious that this is the result of abuse, needing too high doses and stuff, but just wonna know the sience behing it
 
I probably don't know enough to answer your question in much detail, but I'll just say that serotonin is a much more complex neurotransmitter than most people realise. Messing with your serotonin levels can be either anxiolytic or anxiogenic, and there is not by any means a linear correlation between the amount of serotonin in your brain and how good you feel, subjectively.

I think this is demonstrated quite well by the fact that both SSRIs and SSREs (well, the one SSRE, Tianeptine) can be used to treat the same psychological conditions in different people (depression, etc), even though they have effects on the serotonin system which are pretty much exact opposites of each other (one inhibits reuptake, the other enhances it).

Given this, if you abuse MDMA enough that your serotonin system begins to rewire itself, it's not surprising that the character of the effects begins to change.
 
of course mdma also releses norepinephrine, which can produce anxiety.
 
the serotonin inundation modulates out any likely tendency for almost anyone to experience an anxiogenic effect...your serotonergic system may be burnt

dopaminergicity is not typically anxiogenic though via conversion to NA it indeed can be, though i still would go with the former hypothesis
 
I very, very rarely use MDMA, and certainly haven't burnt out/lost my mojo with it, but I experience the same thing, all of a sudden the trip flips a switch and becomes tedious, tiresome, anxiogenic and I just want it over.
 
Could it theoretically be 5HT receptor "burn out" re-routing the neuron pathways that control SE modulated anxiety, much in the same way as D2 receptor burn out causes anxiety, paranoia etc?
dopaminergicity is not typically anxiogenic though via conversion to NA it indeed can be, though i still would go with the former hypothesis
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D2 burn out is the primary factor in stimulant binge mediated anxiety is it not?

Think of MDPV overdose, despite it having a 5:1 DA:NE transporter affinity.
 
Limpet_Chicken said:
I very, very rarely use MDMA, and certainly haven't burnt out/lost my mojo with it, but I experience the same thing, all of a sudden the trip flips a switch and becomes tedious, tiresome, anxiogenic and I just want it over.
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some ppl seem to have a problem with this while most other ppl dont, i wonder why, i dont think its just the serotonin receptors burnt out or something
 
I'l point out for thoroughness, that I am fairly atypical in my response to some drugs, I get to use valium as speed, only without the anxiety and cardio and nastiness, comedown etc for instance.

Got a few wierd quirks, possibly not relevant to this particular drug, but probably best not left out.

It sure as hell ain't burnout from frequent use, I don't think I've ever had a year where I've used MDMA more than 6-7 times, at the absolute most, my most frequent period of use ever, was a couple of years ago, doing a couple of pills a week, maybe another seshion doing 1-3 pills, and mashing it up on coke in the same week, but that didn't last long, my use of stimulants has in general, been very moderate, as I don't , on the whole, react well or pleasantly to them.
 
Yes. To the extent that MDMA agonizes the adrenergic system, it will be anxiogenic. Release of dopamine can also be anxiogenic (but delayed), in that it will cause downstream increases in NE and then epinephrine.

SSRIs, even the selective ones, can be anxiogenic for the first couple days. I'm not sure how this applies (or does not apply) to 5ht efflux.

ebola
 
Whoever came up with the idea that "D2 burn out is the primary factor in stimulant binge mediated anxiety" needs a kick in the perineum.

Your leading theories would have to be noradrenaline release causing anxiety, or 5-HT2C agonism causing anxiety. For the former to be true, you would have to get anxiety from methamphetamine.

But I think the second post has got to be the closest to being true. MDMA causes the release of a truck load of neurotransmitters, which then go on to effect the intrinsic excitability of pretty much every neuron in the brain. You'd be able to find an argument for nearly any hypothesis you want to run with.
 
Notice the term binge, the receptor desensitization and the subsequent re-routing of goal orientated reward mechanisms through new neuron pathways is implicated in the majority of paranoid/anxiolytic schizophrenia's, hence why antagonists are used to treat the condition.

MDMA won't cause primary noradrenaline release as it won't bind to the beta carbon electropositive site on the NEVMAT or reuptake site on the NET, it would be as a secondary function of it'a ability to antagonise both of these sites causing decreased reuptake and increased vesicle release akin to DA NEVMAT antagonism inspiring this mechanism.
 
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MDMA won't cause primary noradrenaline release as it won't bind to the beta carbon electropositive site on the NEVMAT or reuptake site on the NET, it would be as a secondary function of it'a ability to antagonise both of these sites causing decreased reuptake and increased vesicle release akin to DA NEVMAT antagonism inspiring this mechanism.
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NEVMAT? The beta carbon electropositive site?

None of this is true. Why? Because MDMA does directly release NE / Inhibit the reuptake thereof. Not only does it bind directly to NET, it has higher affinity there than at SERT.

Psychopharmacology (Berl). 2007 Jan;189(4):489-503. Epub 2005 Oct 12. Links
MDMA (Ecstasy) and human dopamine, norepinephrine, and serotonin transporters: implications for MDMA-induced neurotoxicity and treatment.Verrico CD, Miller GM, Madras BK.
Department of Psychiatry, Division of Neurochemistry, New England Primate Research Center, Harvard Medical School, 1 Pine Hill Drive, Southborough, MA 01772-9102, USA.

RATIONALE: 3,4-Methylenedioxymethamphetamine (MDMA, designated as "Ecstasy" if illicitly marketed in tablet form) induces significant decrements in neuronal serotonin (5-HT) markers in humans, nonhuman primates, and rats as a function of dosing and dosing regimen. In rats, MDMA-mediated effects are attributed, in part, to selective high-affinity transport of MDMA into 5-HT neurons by the 5-HT transporter (SERT), followed by extensive 5-HT release. OBJECTIVES: To clarify whether SERT-selective effects of MDMA at human monoamine transporters can account for the reported MDMA-induced selective toxicity of serotonin neurons in primate brain. METHODS: We investigated the interaction of [(3)H](+/-, RS)- (+, S)- and (-, R)-MDMA with the human SERT, dopamine (DA) transporter (DAT), and norepinephrine (NE) transporter (NET) in stably transfected human embryo kidney (HEK)-293 cells. RESULTS: The human DAT, NET, and SERT actively transported [(3)H]RS(+/-)-MDMA saturably, stereoselectively, and in a temperature-, concentration-, and transporter-dependent manner. MDMA exhibited the highest affinity for the NET>>SERT>or=DAT, the same rank order for MDMA inhibition of [(3)H]DA, [(3)H]NE, and [(3)H]5-HT transport and stimulated release of the [(3)H]monoamines, which differed from reports derived from rodent monoamine transporters. The extent of MDMA-induced release of 5-HT was higher compared with release of DA or NE. CONCLUSIONS: The affinity of MDMA for the human SERT in transfected cells does not clarify the apparent selective toxicity of MDMA for serotonin neurons, although conceivably, its higher efficacy for stimulating 5-HT release may be a distinguishing factor. The findings highlight the need to investigate MDMA effects in DAT-, SERT-, and NET-expressing neurons in the primate brain and the therapeutic potential of NET or DAT inhibitors, in addition to SERT-selective inhibitors, for alleviating the pharmacological effects of MDMA.

PMID: 16220332 [PubMed - indexed for MEDLINE]
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Although there seems to be relatively little research into the it's effect on NE related transporters prior to that paper, as recent as 2001 they were completely glossed over:

Which neuroreceptors mediate the subjective effects of MDMA in humans? A summary of mechanistic studies.Liechti ME, Vollenweider FX.
Clinical Research Unit, University Hospital of Psychiatry, Zurich, Switzerland.

In preclinical studies, 3,4-methylenedioxymethamphetamine (MDMA, 'Ecstasy') has been shown to release serotonin (5-HT), dopamine and norepinephrine. However, the role of these neurotransmitters and their corresponding receptor sites in mediating the subjective effects of MDMA has not yet been studied in humans. Therefore, we investigated the effects of three different neuroreceptor pretreatments on the subjective, cardiovascular and adverse effects of MDMA (1.5 mg/kg orally) in 44 healthy human volunteers. Pretreatments were: the selective serotonin reuptake inhibitor citalopram (40 mg intravenously) in 16 subjects, the 5-HT(2) antagonist ketanserin (50 mg orally) in 14 subjects, and the D(2) antagonist haloperidol (1.4 mg intravenously) in 14 subjects. Each of these studies used a double-blind placebo-controlled within-subject design and all subjects were examined under placebo, pretreatment, MDMA and pretreatment plus MDMA conditions. Citalopram markedly reduced most of the subjective effects of MDMA, including positive mood, increased extraversion and self-confidence. Cardiovascular and adverse effects of MDMA were also attenuated by citalopram. Haloperidol selectively reduced MDMA-induced positive mood but had no effect on other subjective effects of MDMA or the cardiovascular or adverse responses to MDMA. Ketanserin selectively reduced MDMA-induced perceptual changes and emotional excitation. These results indicate that the overall psychological effects of MDMA largely depend on carrier-mediated 5-HT release, while the more stimulant-like euphoric mood effects of MDMA appear to relate, at least in part, to dopamine D(2) receptor stimulation. The mild hallucinogen-like perceptual effects of MDMA appear to be due to serotonergic 5-HT(2) receptor stimulation. Copyright 2001 John Wiley & Sons, Ltd.
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Rationale means nothing if it isn't true.
 
Hammilton, interesting data. Thank you.

In me MDMA induces anxiety during onset, culminating just before the rush of euphoria and chemical love (or profound peace, or any other such description bordering to mystical experience). During this phase of anxiety pretty weird thoughts may arise, sometimes with paranoic aspects or tangible feelings of wrongness. It diminishes immediately when the sought MDMA-experience begins, and I have not had any bad aftereffects yet. I take MDMA in reasonable doses a few times a year, sometimes in the tail end of LSD.

I have not seen any reason to relieve this anxiety with benzodiazepines or such, because it goes away by itself. Thus it also seems unnecessary to me to take such substances with MDMA, MDMA itself makes me a bit stupid and sometimes confused which to also speaks against the addition of sedatives.

I have never experienced anxiety during the... trip, in lack of a better word due to lack in knowledge of english. It may happen that I get a bit anxious over my behaviour if I feel I have acted unethical during MDMA or ponder such acts whilst on the drug.
 
i also get anxiety when coming up but thats not the problem, when the drug starts working the anxiety is gone, but then somewhere during the high my high suddenly reverses with a bad feeling and anxiety ( when taken very high doses thinking everyone is fighting and stuff)
 
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