Negative vs positive energy (jaw clenching on MDMA)

[dopamimetic]

What makes the difference between that tension which you just want to go away and can even feel kinda heavy vs. the light headed stimulation that makes you dance through the night?

Guess it's a complexer puzzle involving multiple transmitters but is there a handy graph or something like around?

It seems to be not primarily serotonin related. Might be DA vs NE ratio or even brain regions, subtypes, peripheral vs central NE?

Too little NE is pro-depressive and tiring. But much of it isn't really fun either. Here it's more DA in moderation (like from memantine >50mg) which makes me chatty and dancey. Too much is destracting and leads to ADHD, too little to anhedonia and ADD. 5-HT is anxiolytic and makes me feel comfortable, too little is depressing. But NE is tricky. Seems like it can be perceived as either positive energy or negative tension and there is a complex metabolic interaction between NE and DA (why DA agonists are very different from releasers I guess).

Edit: There's more into norepinephrine than you (ok, at least I) thought. MDMA side effects appear to be primarily NErgenic. A nice example is reboxetine, once marketed as an antidepressant but now withdrawn from market because it was worse than placebo - no effect, just problems. I know that adrenaline rush feels nice and we need some NE for drive & focus but miss a piece. Maybe cortisol?

It appears to me that we need adrenaline for physical energy but it interferes with emotions and cognition. That all the positive things come out of central 5HT & DA, central NE basically mediates fear, aggressivity etc and peripheral (nor)epinephrine physical power and strength.

Dissociation blocks the feedback loops, you stop getting tachycardia from anxiety and you stop feeling the anxiety altogether. But it doesn't impair physical strength, at least not in me - I have more endurance and energy while dissociated, I don't feel pain, fear of pain so easy and my body doesn't overdrive but remains the natural autonomic regulation.

So I'd need a CNS-selective NE antagonist? Is it even possible for a drug to be CNS selective without relying on a peripheral inhibitor a la carbidopa?

 

[polymath]

The grinding of teeth and other repetitive behavior caused by amphetamine is because of the dopaminergic effect. For some reason the dopamine precursor l-dopa initially helps with nighttime bruxism but later makes it worse.

Bruxism: A Literature Review - PMC

Bruxism is a movement disorder characterized by grinding and clenching of teeth. Awake bruxism is found more in females as compared to males while sleep bruxism shows no such gender prevalence. Etiology of bruxism can be divided into three groups ...

www.ncbi.nlm.nih.gov

Recently it is derived that disturbances in central neurotransmitter system may be involved in the etiology of the bruxism [11, 12]. It is hypothesized that the direct and indirect pathways of the basal ganglion, a group of five subcortical nuclei that are involved in the coordination of movements is disturbed in bruxer. The direct output pathway goes directly from the stratum to the thalamus from where afferent signals project to the cerebral cortex. The indirect pathway on the other hand passes by several other nuclei before reaching it to the thalamus [13]. If there is imbalance between both the pathways, movement disorder results like Parkinson’s disease. The imbalance occurs with the disturbances in the dopamine mediated transmission of action potential. In case of bruxism there may be an imbalance in both the pathways. Acute use of dopamine precursors like L-dopa inhibits bruxism activity [11] and chronic long term use of l-dopa results in increased bruxism activity [11]. SSRTs (serotonin reuptake inhibitors) which exert an indirect influence on the dopaminergic system [14] may cause bruxism after long term use. Amphetamine [11] which increases the dopamine concentration by facilitating its release has been observed to increase bruxism. Nicotine stimulates central dopaminergic activities which might explain the finding that cigarette smokers report bruxism two times more than the non smokers [15].

 

[dopamimetic]

I happened to know a girl who got a whopping 150mg of d-amph scripted every day (guess she tricked the doc into this), and she was taking 20mg every few hours - if she missed a dose, she became very impulsive, angry and had increased muscle tonus together with hypertension. Against the latter she got propranolol (again, considered a malpractice by many but it helped).

So yeah there's something about initial dopamine effects vs. later stage and my hunch is that it will be related to the DA becoming metabolized into NE but I'm not sure.
At least dopamine agonists have a distinct profile, they don't cause any tension or teeth grinding. Low doses can even be sedating, medium ones are stimulating and motivating, high ones lead to manic and ADHD-esque behaviour.

5-MAPB was completely free of jaw clenching. 4,4'-dimethylaminorex too. The x-MMCs similar to amphetamine. 6-APB is pretty heavy but it is more pronounced in the later stages. So my feelings tell me norepinephrine which I read this morning in a paper too but maybe it was an old one or it's more complex.

Choline / nicotine indeed increase tension. SSRIs too, strangely SNRIs (venlafaxine, dextromethorphan) much less. NE tachyphylaxis?

 

[Rectify]

A big part of the MDMA high is the release of oxytocin, which promotes emotional bonding.

 

[dopamimetic]

I'm indeed curious about oxytocin, yet from reports it appears to be very unpredictable and not always positive but as my initial intent was to chemically replace missing intimacy and social bonding, it is a logical target ... Vasopressin seems to be somewhat involved too and I know very little about its effects.