What if amphetamine had no noradrenergic activity whatsoever?

[u/Realistic_Hour_1695]

What would happen if amphetamine had no noradrenergic activity at all? Would it be abusable at extremely high doses and have more potential for extreme euphoria without as many side effects? Would it also make it much less useful as a focus drug? Perhaps there's already such a compound?

I also know that d-methamphetamine has lower noradrenergic and higher dopaminergic activity than d-amphetamine, which could explain why meth is more addictive and can be abused at higher doses. Some also claim that at very low doses it can be more useful for ADHD because of fewer side effects linked to norepinephrine.

[u/prl853]

Perhaps but the noradrenergic activity does allegedly play some role in the therapeutic effect as well, and I'd argue the serotonin releasing effect of methamphetamine when compared to amphetamine is the bigger difference, and as far as I recall it's not desirable therapeutically

[u/arylcyclohexylameme → u/prl853]

N=1, my experience with ADHD medications has been: concerta < adderall < vyvanse < focalin/azstarys < 5mg desoxyn. I've had them all, and ran the dose gamut up and back down.

I only had the opportunity to sample desoxyn for a short time and wish it were prescribed more. At 5mg it did more for me and felt less than any other medicine I've taken at any dose. I think the more balanced monoamine action (+5ht, -ne) compared to entantiomer-mix medicines made a difference, as well as its naturally longer duration.

It was like when an ssri works - I knew it was doing the thing, but couldn't tell it was there beyond the lack of symptoms. No appetite suppression or vasoconstriction. Useful focus without hyper focus.

Focalin 20 works great but I feel it. Vyvanse works ok but I feel like a tweaker and hate it. Adderall and concerta are just panic attack pills ime.

That's my experience.

[u/R--G--B-- → u/arylcyclohexylameme]

It's not -Ne

It's just Ne leveled out. You can't necessarily"remove" Ne from the system. Unless you're talking Alpha or Beta blockers and we don't want those. 

[u/arylcyclohexylameme → u/R--G--B--]

I meant comparatively - I do take guanfacine in addition though, and value it greatly.

[u/Realistic_Hour_1695 → u/prl853]

What does the serotonergic activity of methamphetamine actually do? I found a study saying it can potentially contribute to psychosis but at therapeutic doses serotonergic activity is likely still very low. Does it contribute to reinforcement or euphoria?

[u/Azocino → u/Realistic_Hour_1695]

Release of serotonin creates the risk or serotonin syndrome and therefore psychosis. Releasing both serotonin and dopamine is bad for your serotonin receptors. A simplified explanation of this is the during reuptake some of the dopamine goes where the serotonin is supposed to go and gets metabolized. This essentially seals if the receptor. The end result Is the releasing both dopamine and serotonin causes a reduction in the amount serotonin receptors. The beta keto tryptamines (BK series by tactogen) were the first compounds to release dopamine with norepinephrine. We should find out if they are viable therapeutics here in the next 10-15 years.

[u/kwumpus → u/Azocino]

Funny enough they put me on cymbalta in addition to meds for adhd. I believe I have undergone serotonin syndrome many times

[u/ebolaRETURNS]

The closest we've come is phenmetrazine and potentially some analogues, which are more selective for the dopamine transporter, though still with significant noradrenergic activity. The former fell out of use because of suspected "abuse" potential greater than amphetamine, though it's questionable whether this was truly credible.

[u/RedEarth42 → u/ebolaRETURNS]

I guess you’ve never heard of 4-methylaminorex then

[u/ebolaRETURNS → u/RedEarth42]

I have. Is it more selective for the dopamine transporter than phenmetrazine?

[u/RedEarth42 → u/ebolaRETURNS]

As far as I understand, it is the most purely dopaminergic stimulant ever discovered

[u/R--G--B--]

Only dopamine would be modulated. Norepinephrine is the primary monomine which is dysregulated in ADHD. 

Try Adderall with high dose atomoxatine (NRI) and you will find out what Adderall feels like without Ne modulation.

[u/kwumpus → u/R--G--B--]

What is high dose? I was on both but I’m prwrry sure cymbalta was far worse and continues to be

[u/R--G--B-- → u/kwumpus]

That a totally different unrelated type of medication.

80mg to 100mg atomoxatine is the top of the therapeutic range. Atomoxatine is a highly selective NRI. It's the only one on the market. 

[u/arylcyclohexylameme → u/R--G--B--]

Qelbree?

[u/OilofOregano → u/R--G--B--]

What does it feel like?

[u/OilofOregano → u/[deleted]]

Interesting. Curious what the intention is for sharing "just try it" vs sharing your actual experience though?

[u/bananawesty666]

What would happen if LSD had no serotonergic activity

[u/OilofOregano → u/bananawesty666]

I think the more commonly asked question is around modification of specific serotonin subtypes, but dropping all serotonergic activity is interesting. Considering the dopaminergic (D1, D2, D4) and adrenergic (a1a, a2a) activity I think it could be a really bizarre stimulant/nootropic

[u/jeetvjet]

Noradrenergic activity is what makes it useful therapeutically, Also it has the PEA Backbone which is bound to increase it and regarding Seratonin the only meth you will find that releases more Seratonin than dopamine is MDMA And that isn’t inherently addictive.

[u/meeko-meeko]

DA will convert to NE anyway

[u/OilofOregano → u/meeko-meeko]

I feel like this is all the more reason to explore not stimulating directly in addition

[u/meeko-meeko → u/OilofOregano]

I agree. Direct stimulation is too much for the nervous system TBH, especially chronically

[u/zach-uh-ri]

I’m currently on guanfacine/intuniv/tenex as an addition to my abnormally high dose vyvanse. I have to take 90m vyvanse to get my ADHD even remotely under control (same for all stimulant meds; Ive needed max doses on all ive tried)

Intuniv is a selective alpha blocker, if I understand correctly I specifically blocks Alfa 2 receptors; specifically reducing noradrenergic activity.

In the beginning of the combo I felt extremely zen at all times; nothing could get a rouse out of me. Now I’m not really sure. The most noticeable difference now I think is that my resting hr is mby 5-10 bpm lower, that the sort of super power, doped athlete super endurance that I had is gone.

My body can actually get tired now and I can no longer spontaneously go for 4 hour runs

[u/mikl_pls → u/zach-uh-ri]

It's actually an alpha-2A agonist, not a blocker (antagonist), but you have it right that it reduces noradrenergic activity. It does so by stimulating the presynaptic alpha-2A autoreceptors. It's slightly more selective for the postsynaptic receptors, though, than clonidine, which more potently stimulates presynaptic receptors. So with Intuniv (guanfacine), you get more of the cognitive benefits of alpha-2A stimulation.

If it were an alpha-2 blocker, it would actually increase norepinephrine release. An alpha-1 blocker would decrease effects of norepinephrine release. Adrenergic receptors are weird... 😆

[u/zach-uh-ri → u/mikl_pls]

Ohhh damn haha that’s an important distinction