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The "magic" of MDMA

cannibalsnail

Bluelighter
Joined
Sep 18, 2011
Messages
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I have a theory about this "magic". Although I have never tried MDMA I have rolled a fair few times on RC combos. From my understanding the "magic" is that inexplicable feeling of love and compassion for every human in the world. Correct me if I'm wrong.

My theory is this: Aside from being a powerful monoamine releaser, MDMA also activates 5HT1A receptors. This triggers the release of Oxytocin and creates the whole "loved up" feeling. When I rolled on MDAI + 2-FMA I was euphoric, stimulated and a little bit empathogenic. When I threw in 5mg of 4-HO-MET (a 1A agonist as well as 2A) I felt so completely blissfully at peace with every human alive, I hugged everyone I could find etc. etc.

This would explain why non-phenethylamines are lacking in the magic and why MDA derivatives also lack it (6-APB). Methylone is said to have a hint of it but its lack of Serotonin release obviously diminishes the experience. Hence the unique structure of MDMA agonizes 5HT1A more selectively than other compounds as well as creating the euphoric push and this is the "magic".

Any input?
 
http://en.wikipedia.org/wiki/Norepinephrine

What about the effects on Norepinephrine?

I think that mdma primarily acts on Serotonin, Norepinephrine and partly Dopamine

so do cocaine and methamphetamine, its the psychedelic activity of mdma in combination with the potent release (and ratios of release) of monoamines that creates the magic. that and long term abstinence between dosing...
 
. that and long term abstinence between dosing...

Definitely that, i cant actually say that an mdma experience is anywhere near on the same level or depth when you dont wait long enough.
 
I've seen studies in various studies on 5-HT(1A) agonists causing elevated levels of oxytocin similar to MDMA. I've always thought about how a selective 5-HT(1a) agonist might potentiate the more "lacking" entactogens like 6-APB or Methylone, or even just plain stimulants to ease anxiety, especially in a social situation. The neuroprotective effects of 1a agnists is a nice bonus too.

Does anyone have any idea if the 5-HT(1B) would contribute to MDMA's entactogenic effects? I've Just read the abstracts for the papers below. pretty useful stuff in there about these two receptors, I'll see if I have access to any of these papers. The look like a good read. But now, bed!

http://www.ncbi.nlm.nih.gov/pubmed/16310183
5-HT1A and 5-HT1B receptor agonists and aggression: a pharmacological challenge of the serotonin deficiency hypothesis.

de Boer SF, Koolhaas JM.


Source

Department of Behavioral Physiology, Biological Center, University of Groningen, P.O. Box 14, 9750 AA Haren, The Netherlands. [email protected]


Abstract

More than any other brain neurotransmitter system, the indolamine serotonin (5-HT) has been linked to aggression in a wide and diverse range of species, including humans. The nature of this linkage, however, is not simple and it has proven difficult to unravel the precise role of this amine in the predisposition for and execution of aggressive behavior. The dogmatic view that 5-HT inhibits aggression has dominated both pharmacological research strategies to develop specific and effective novel drug treatments that reduce aggressive behavior and the pharmacological mechanistic interpretation of putative serenic drug effects. Our studies on brain serotonin and aggression in feral wild-type rats using the resident-intruder paradigm have challenged this so-called serotonin deficiency hypothesis of aggressive behavior. The well-known fact that certain 5-HT(1A/1B) receptor agonists potently and specifically reduce aggressive behavior without motor slowing and sedative effects is only consistent with this hypothesis under the assumption that the agonist mainly acts on the postsynaptic 5-HT(1A/1B) receptor sites. However, systemic injections of anti-aggressive doses of 5-HT(1A) and (1B) agonists robustly decrease brain 5-HT release due to their inhibitory actions at somatodendritic and terminal autoreceptors, respectively. The availability of the novel benzodioxopiperazine compound S-15535, which acts in vivo as a preferential agonist of the somatodendritic 5-HT(1A) auto-receptor and as an antagonist (weak partial agonist) at postsynaptic 5-HT(1A) receptors, allows for a pharmacological analysis of the exact site of action of this anti-aggressive effect. It was found that, similar to other prototypical full and partial 5-HT(1A) and/or 5-HT(1B) receptor agonists like repinotan, 8-OHDPAT, ipsapirone, buspirone, alnespirone, eltoprazine, CGS-12066B and CP-93129, also S-15535 very effectively reduced offensive aggressive behavior. Unlike the other ligands, however, a remarkable degree of behavioral specificity was observed after treatment with S-15535, in that the anti-aggressive effects were not accompanied by inhibiting (like other 5-HT(1A) receptor agonist with moderate to high efficacy at postsynaptic 5-HT(1A) receptors) or enhancing (like agonists with activity at 5-HT(1B) receptors and alnespirone) non-aggressive motor behaviors (e.g., social exploration, ambulation, rearing, and grooming) beyond the range of undrugged animals with corresponding levels of aggression. The involvement of 5-HT(1A) and/or 5-HT(1B) receptors in the anti-aggressive actions of these drugs was convincingly confirmed by showing that the selective 5-HT(1A) receptor antagonist WAY-100635 and/or the 5-HT(1B) receptor antagonist GR-127935, while inactive when given alone, effectively attenuated/prevented these actions. Furthermore, combined administration of S-15535 with either alnespirone or CGS-42066B elicited a clear additive effect, indicated by a left-ward shift in their dose-effect curves, providing further support for presynaptic sites of action (i.e., inhibitory somatodendritic 5-HT(1A) and terminal 5-HT(1B) autoreceptors). These findings strongly suggest that the specific anti-aggressive effects of 5-HT(1A) and 5-HT(1B) receptor agonists are predominantly based on reduction rather than enhancement of 5-HT neurotransmission during the combative social interaction. Apparently, normal display of offensive aggressive behavior is positively related to brief spikes in serotonergic activity, whereas an inverse relationship probably exists between tonic 5-HT activity and abnormal forms of aggression only.

http://www.ncbi.nlm.nih.gov/pubmed/16310769
5-HT1B receptors and aggression: a review.

Olivier B, van Oorschot R.


Source

Department of Psychopharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Sorbonnelaan 16, The Netherlands. [email protected]


Abstract

The serotonergic (5-HT) system in the brain is involved in the modulation of offensive aggressive behavior. The dogma that activity of the 5-HT system is inversely related to aggression is obsolete now. Research on the status of the 5-HT system before, during and after the execution of aggression is ongoing but has not yet led to a clear picture about the actual functional role of the 5-HT system, the more because state versus trait aggression seems to play a pivotal role in the outcome. Pharmacological challenges pinpoint 5-HT(1A) and 5-HT(1B) receptors as key players in the modulation of offensive aggression. This review emphasizes in particular the role of postsynaptic 5-HT(1B) (hetero) receptors as a premier site to modulate offensive aggression. Modulation of the firing and 5-HT release of the serotonergic neuron, via presynaptic 5-HT(1A) (auto) receptors, presynaptic 5-HT(1B) (auto) receptors and serotonergic transporters, may also have striking influences on aggression under certain conditions. Therefore, it is hypothesized that postsynaptic 5-HT(1B) (hetero) receptors directly influence the executive, consummatory phases of agonistic behavior, whereas presynaptic serotonergic feedback systems are particularly useful in the introductory (appetitive) phases of the agonistic behavioral complex.

http://www.ncbi.nlm.nih.gov/pubmed/16206880
Serotonergic mechanisms in aggression.

Olivier B.


Source

Department of Psychopharmacology, Utrecht Institute of Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.


Abstract

The serotonergic system in the CNS has complex interactions with many, if not all other neurotransmitter systems in the brain. Its localization, distribution and amazing receptor diversity makes it an appealing system for modulatory aspects in many basic behaviours, including food and water intake, sexual behaviour and aggression. Notwithstanding decades of research into the putative role of the serotonergic system in aggression, no clear picture about its specific role has emerged. It seems, dependent on state or trait, to be involved in either the performance or the termination of aggressive behaviours. The present technology appears not developed enough to give answers to these questions. Application of drugs and particular selective ligands for certain subtype receptors seems a more promising approach to unravelling the role of 5-HT in aggression. The (postsynaptic) 5-HT1B and to a lesser extent, the 5-HT1A receptor seems to play a prominent role, at least in rodents, in the modulation of (offensive) aggression.
 
I think the closest thing you'll see in regular usage is either one of the tryptamines, i think DPT has good action at 5ht1a - or Buspar, which is a partial agonist at 1a.
 
I think the closest thing you'll see in regular usage is either one of the tryptamines, i think DPT has good action at 5ht1a - or Buspar, which is a partial agonist at 1a.

If by DPT you mean "foxy" 5-MeO-DiPT then you're right that's probably the most used recreational substance with good 1a activity, which I would guess explains some of the more "lovey" effects of that drug, and probably some of the toxicity.
 
I recently found a theory about why mdma's magic is unique. Mdma works on a wide variety of 5-ht subreceptors. I think it would also partially explain why some people hallucinate on high doses of mdma.
Not just visuals, but vivid hallucinations (a horse on the dance floor etc.). Mdma just activates them all or most of them together.
 
I recently found a theory about why mdma's magic is unique. Mdma works on a wide variety of 5-ht subreceptors. I think it would also partially explain why some people hallucinate on high doses of mdma.
Not just visuals, but vivid hallucinations (a horse on the dance floor etc.). Mdma just activates them all or most of them together.

I'm sorry but your pharmacological understanding is woefully lacking. MDMA exerts the majority of its effects by releasing/preventing the reuptake of Serotonin, Dopamine and Norepinephrine. Its less pronounced effect is to agonise 5HT1-x receptors. It also has non-relevant activity at several other receptor types.

5-HT receptors are not implicated in hallucination. D2/anticholinergic system are the relevant ones here.
 
5-HT receptors are not implicated in hallucination.

5-HT2a? I guess none of the serotonin receptors produce quite as drastic changes to the sensorium as anticholinergics do, but I thought it was pretty well established that 5-HT2a was the target of "classical" hallucinogens.

MDA, but not MDMA, seems to have notable activity in vivo at 5ht2a.
 
Yes but 2A agonists do not produce hallucinations. Anyone sane who has tried LSD will report that visual/colour distortions are its main effects and not full blown hallucinations a la Stim Psychosis or Datura.

That said some people seem to report hallucinations on classic psychedelics. Interestingly it is never scientific minded people, perhaps linking with research done on religious people, ghost believers etc. who have some gene linked with increased susceptibility. This or a lowered threshold to psychosis I believe explains how some individuals report seeing beings, talking to creatures and other hallucinations while others (myself included) see nothing more than colourful patterns even on breakthrough DMT doses.
 
5-HT2a? I guess none of the serotonin receptors produce quite as drastic changes to the sensorium as anticholinergics do, but I thought it was pretty well established that 5-HT2a was the target of "classical" hallucinogens.

I think he is making a distinction between 5HT2A-mediated sensory disturbances characteristic of "classical" hallucinogens (fractal imagery, breathing walls, wiggling patterns etc) and the full blown can't-tell-whats-real-and-whats-not psychotomimetic hallucinations of NMDA antagonists, anticholinergics and possibly stimulant psychosis.
 
Yes but 2A agonists do not produce hallucinations. Anyone sane who has tried LSD will report that visual/colour distortions are its main effects and not full blown hallucinations a la Stim Psychosis or Datura.

That said some people seem to report hallucinations on classic psychedelics. Interestingly it is never scientific minded people, perhaps linking with research done on religious people, ghost believers etc. who have some gene linked with increased susceptibility. This or a lowered threshold to psychosis I believe explains how some individuals report seeing beings, talking to creatures and other hallucinations while others (myself included) see nothing more than colourful patterns even on breakthrough DMT doses.

I have definitely seen more than just visual disturbances from 5-ht2a agonists and I am an atheist and definitely scientific minded. I'd want to be after 5 years of PhD. Low doses of 5-ht2a agonists usually just cause warping and colour changes but higher doses cause full blown hallucinations without going into delusions (believing the hallucinations are real).
 
I have definitely seen more than just visual disturbances from 5-ht2a agonists and I am an atheist and definitely scientific minded. I'd want to be after 5 years of PhD. Low doses of 5-ht2a agonists usually just cause warping and colour changes but higher doses cause full blown hallucinations without going into delusions (believing the hallucinations are real).

Agreed. I think the line gets drawn (per Cannibalsnail) at delusional (psychotomimetics; NMDA antags & antimuscarinics) or not delusional ("classical" hallucinogens; 5HT2a ags)
 
Agreed. I think the line gets drawn (per Cannibalsnail) at delusional (psychotomimetics; NMDA antags & antimuscarinics) or not delusional ("classical" hallucinogens; 5HT2a ags)

Agreed with your line, but if you push anything hard enough or are just stupidly sensitive it goes into delusional though *shudder* zopiclone *shudder*

Also to broaden our target search, does anyone have any good regs for MDMA's intercellular targets? I have a hunch VMAT2 plays a bigger role than we think...
 
Afaik, the ratio of 5-HT1a / 5-HT2a is even "better" for 5-MeO-DMT compared to DPT. That probably also explains the highly unusual psychedelia of 5-MeO-DMT.
 
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