MDMA: looking beyond the conventional explanation

[Allylbenzene]

During investigations of phenethylamine SAR I learned that MDMA acts as an 2-adrenergic agonist. Likewise its cyclised counterpart MDTHIQ (TDIQ):

In radioligand binding studies TDIQ displays selective affinity for alpha(2)-adrenergic receptor subsites (i.e., alpha(2A)-, alpha(2B)-, and alpha(2C)-adrenergic receptors), and behavioral data suggest that it might exert an agonist (or partial agonist) effect at alpha(2)-adrenergic receptors or interact at alpha(2)-adrenergic heteroreceptors (source)

Shulgin reported using BP medication (imidazoline/α2-adrenergic agonists) in his experiments and notes entactogenic qualities reminiscent of MDMA.

Shulgin reports from this BL thread:

Rilmenidine:

8.0 mg 2C-B-fly and 2.0 mg of rilmenidine at 12:30 pm; cannabis vapor at 4:00: The result was spectacular. I got a +4 experience from a pure imidazoline blood pressure medication! It is probably the entactogenic core of MDMA.

I believe this capacity for calm contemplation and discussion of painful personal issues is a core feature of the entactogenic state of MDMA, and here I was experiencing it with blood pressure medication.... For me it’s really, astonishingly among the best psychedelic experiences I’ve ever had. Unbelievable. (Shulgin 2016) Pharm 2, p. 26-27

Clonidine:

0. 2 mg clonidine and 9.0 mg of 2C-B-fly at noon, cannabis at 3:00 pm: I felt it strongly by 30 minutes. By an hour I was pretty sure that it is more than 2C-B-fly.

I felt the rebirth of my love for my wife, no small thing. I have taken 2C-B-fly several times at various doses, and it was always relatively boring. This was completely different, much more than 2C-B-fly alone. It was spectacular that the primer/probe method worked. Clonidine (unlike 2C-B-fly) is a beautiful psychedelic.
...
I was very present, but not just in the moment. (Shulgin 2016) Pharm 2 , p. 25

Rilmenidine is an I1-imidazoline selective ligand and α2-adrenergic agonist, while Clonidine is an α2-adrenergic agonist. I think these receptors are too easily dismissed as unrelated or irrelevant to psychedelic & entactogenic effects, particularly α2-adrenergic which is also apart of LSD polypharmacology.

Shulgin introduced the "primer/probe method" which was noticed by this author:

Constructing the ecstasy of MDMA from its component mental organs: Proposing the primer/probe method
— 10.1016/j.mehy.2015.12.018

...the consensus is that the distinctive entactogenic effects [of MDMA] arise from the release of neurotransmitters, primarily serotonin. I propose an alternative hypothesis: The entactogenic mental state is due to the simultaneous direct activation of imidazoline-1 (I1) and serotonin-2 (5-HT2) receptors by MDMA.

I propose the "primer/probe" method to test these hypotheses. A "primer" is a drug that selectively activates 5-HT2 (e.g. DOB or MEM) or serotonin-1 (5-HT1) and 5-HT2 (e.g. DOET or 2C-B-fly). A "probe" is a drug that activates a receptor whose corresponding mental organ we wish to load into consciousness in order to understand its role in the mind.

This all seems relevant to the goal of recreating an MDMA style experience.

 

[Rectify]

Do A Little Research Into The Devilishly Named False Neurotransmitter Hypothesis. Visualize Their 3D Structures. Compare. Contrast. Opine.

 

[Rectify]

As Vecktor [Arrington] Put It, “MDMA Probably Acts As A Substrate” For Dopaminergic And Adrenalergic Receptors.