Factors affecting psychoactive effects of stimulants/entactogens?

[cannibalsnail]

Are there any neuropharmacological factors that affect the subjective effects between different stimulants other than monoamine release/reuptake values?

This may sound like a "what should I take" thread but I assure you it isn't. What I am trying to understand is this: Would a mix of for example fluoroamphetamines to perfectly mimic the DA/NE release/reuptake profile of amphetamine would the subjective effects be identical? I don't want to know this mix, just the science behind the mechanism of stimulants.

Do different chemicals induce different release levels in different parts of the brain? Does binding in the CNS impact effects? Receptor binding on/off times? What makes different stimulants feel different?

 

[Epsilon Alpha]

Its not even close to that simple. There's a lot of other dirty poorly understood pharmacology going on with pretty much every drug of abuse than "it causes xyz ratios of NE/DA/5HT efflux". While you are right regarding on/off times, binding sites (look at cocaine vs modafinil at the DAT), affinity for slightly different versions of a protein, additional receptor binding, membrane changes/penetration, genomic effects, mindset/goal of taking said compound, and even plain old boring kinetics play a massive role in subjective responses. Crazy thing is that's not even an exhaustive list!

The possibilities for dirty receptor(more broadly "target") binding is also just nuts with small molecule drugs, while they may not play a large role in CNS/subjective effects the fact that we know what less than 1/2 (last time I checked) the human GPCR's do leaves so many options open.

Sorry, you've got me ranting about target identification haha. Tend to get a bit lost in the details with that topic!
But, you might make a compound/combination that closely mimics another drug in the short term with some sort of combo by matching its major pharmacological actions but I believe that there will still be some small difference people can identify with enough time.

 

[cannibalsnail]

Do you mind going into more detail about the topic? I'm very curious.

 

[atrollappears]

What EA said. If you look at 4-FA's 5-HT/DA/NE EC50s/IC50s, its effects don't really make sense. Very very little SERT action, yet full MDMA-like effects in some... direct agonism? TAAR? 5-HT2A/B? Who knows...

 

[Epsilon Alpha]

Ok, well the whole "transport reversal" theory is kind of bunk as a total explaination for releasing agent's mechanisms of action, yes the transporter is reversed but there is also certain other targets aside from the transporter to be bound to induce release. Its partly why MDAI upset the RC crowd that thought it would be the next MDMA, and why people rage at how "special" ketamine/DXM/LSD are. Yes there are classes of drugs that bind to one common target, but there is much more each one could bind to as well.

Hope that helped