Stimulants of the Future III

[tweex]

I think he meant why an analogue of the pro-drug when they could have made a direct analogue of the drug of interest.

Cutting down on the abuse potential would certainly make sense.

 

[ebola?]

Vendors of clandestine drugs aren't attempting that.
...

Hm I daresay my definition is quite a lot narrower than that. DA/NE releaser.reuptake inhibitors, direct agonists at some DA receptor subtypes, some of the more stimulating opioids, adenosine receptor-medtated stimulants such as many xanthines, caffeine etc. And of course alkaloids such as brucine, strychnine and thebaine

This is a list of empirical examples. How do you define "stimulants"?

ebola

 

[Tryptamite]

Cutting down on the abuse potential would certainly make sense.

Makes sense for pharmaceutical companies coming under pressure from regulatory bodies re: their abusable medication.

Doesn't make sense for companies that are marketing the product for recreational or functional illicit use.

Perhaps substituting phendimetrazine like that bypasses the pro-drug aspect of the compound and becomes something that could be taken via all manner of ROAs and provide an immediate rush.

"Pro sexual stimulant" - phenmetrazine.

 

[tamarinds]

More pyrovalerones

 

[ebola?]

No thanks, I think we have plenty of those already, none of them particularly good.

ebola

 

[tweex]

Ampyzine
Not as much a stimulant of the future, as a poorly researched one of the past. Apparently exerts anti-aggressive effects in mice for up to 96 hours at high doses.

Weird structure.

Doesn't make sense for companies that are marketing the product for recreational or functional illicit use.

Still depends on the type of functional illicit use. I'll gladly take lisdexamfetamine over d-amphetamine if I'm going to be working on something for the next 14 hours. Hell, I'd take Adrafinil over Modafinil if my liver could withstand the massive doses required for decent stimulation. Of course the caveat always being that I'm not planning on sleeping for a while, but generally my mind is sharp enough on racetams if I'm not staying up over 18 hours.

 

[Lightning-Nl]

Personally, I'd like to see a TRI/TRA (Triple Reuptake Inhibitor/Triple Releasing Agent) appear on the prescription market. I think it would be 1000X's better at treating ADHD than the current non-serotonergic stimulants (such as Methylphenidate). This substance could also be used to treat Post-Traumatic Stress Disorder and it would probably be the best drug available for this indication since it's effects would be very similar (if not identical) to MDMA.

However, this sadly won't become reality. In reality, things like Amphetamine and Methylphenidate are going to go away (or at least fall out of favor with doctors in the same way Zolpidem has) because of Modafinil.

Modafinil (trade name Provigil) is a unique stimulant. It's main actions are on Orexin receptors. Modafinil is a potent agonist at both Orexin Receptor 1 and Orexin Receptor 2. Due to it's high binding affinity for these receptors, it causes immense downstream release of Dopamine and Norepinephrine (Which also means it probably modulates Cholinergic neurons through downstream activity as well). In addition to this, Modafinil is also a moderate/strong inhibitor of DAT and NET. It was also recently discover that Modafinil is a partial agonist od D2 dopamine with a Ki value of 16nM. They also believe that Modafinil acts as a positive allosteric modulator for glutaminergic neurons and through this same action, also inhibits GABAergic activity. It's also mentioned that Modafinil causes immense release of Histamine.

Modafinil will be used almost exclusively in the future, due to the fact that it's starting to become doctors "go-to" drug for ADHD and Narcolepsy (in my experience anyways). In fact, two psychiatrists I've been with now didn't want me on Adderall, and said that Modafinil would be a better option anyways. I would have tried it, but my insurance wouldn't cover it. So I got Adderall anyways.

If it's not Modafinil that's used, it will be one of it's derivatives. Laboratoire L. Lafon has already developed a couple derivatives of Modafinil and one of them is already on the market - Armodafinil (trade name; Nuvigil). They'll most likely increase it's affinity for DAT and NET.

 

[tweex]

I think JZAD-IV-22, a TRI might end up being the next modafinil: http://www.ncbi.nlm.nih.gov/pubmed/20864506

Armodafinil isn't precisely a modafinil derivate, but rather a single isomer of modafinil.

And Nefopam is a TRI that is currently on the market in some countries, but not a stimulant per se.

Amitifadine looks probable to be the second: https://www.ncbi.nlm.nih.gov/pubmed/21925682

Diclofensine looks like quite a good one recreationally, but won't be on the (above board) market.

IDK about serotonergic stims for ADHD though. I don't have ADHD, but I personally find them somewhat undesirable for studying/working. I prefer DA/NEergics, cholinergics, ampakines, etc I'd probably also be an inverse benzo fan, but haven't had the chance to try one yet. I'm all for serotonergics as party drugs and antidepressants though

 

[Lightning-Nl]

Tweex, alpha7 nicotinic agonism doesn't seem to have stimulant effects.

Memory enhancing, and focus-aiding, nootropic, yes, stimulant per se, not at all.

At least, not my experience with the cholinesterase inhibitor/alpha7 NAChR agonist galantamine. Wish I could afford to keep up with that stuff but its too expensive

An Alpha-7 nAChR agonist just got approved by the FDA as a treatment for Schizophrenia. It should hit the market soon. I don't remember how strong it's antipsychotic effects are, but it greatly improves cognitive functioning in people Schizoid Diseases. So I don't thing a7 agonists will be stimulants of the future perse, but they'll definitely be one of the many psychotic treatments of the future.

 

[tweex]

An Alpha-7 nAChR agonist just got approved by the FDA as a treatment for Schizophrenia. It should hit the market soon. I don't remember how strong it's antipsychotic effects are, but it greatly improves cognitive functioning in people Schizoid Diseases. So I don't thing a7 agonists will be stimulants of the future perse, but they'll definitely be one of the many psychotic treatments of the future.

α7 receptors are a target for a lot more than schizophrenia, that is just apparently the first market. While they aren't locomotor stims, and really probably more fall in the category of nootropics/cognitive enhancers, I'd still classify them as "stimulants of the future" given we'll probably see them getting use in at least some roles traditional stims are currently used for.

And which medication is that? I couldn't find it with some quick google searching. I'd known GTS-21 was in trials, but I thought approval was a good ways off. Definitely sounds interesting.

 

[MagickalKat777]

Personally, I'd like to see a TRI/TRA (Triple Reuptake Inhibitor/Triple Releasing Agent) appear on the prescription market. I think it would be 1000X's better at treating ADHD than the current non-serotonergic stimulants (such as Methylphenidate). This substance could also be used to treat Post-Traumatic Stress Disorder and it would probably be the best drug available for this indication since it's effects would be very similar (if not identical) to MDMA.

They did have such a substance - AMT. And it is indeed quite an effective ADHD treatment as well as an effective antidepressant (probably the only antidepressant that has ever had a strong effect on me) and yes, it did have a roll quality to it but it has a LOT more effects than MDMA.

5-MeO-AMT is a much more toxic version but it is a TRI/TRA as well. I suspect that 5-MeO-AMT in a very low dose would lose much of its toxic edge - I never bothered with low doses of that one. This one would be an effective ADD/ADHD med but not so much for depression or PTSD.

Another thing to note is that neither of these substances ever really seemed to build much of a tolerance (at least not to a degree that you would see with, for example, daily amphetamine or opiate usage) although they are cross-tolerant with each other and other tryptamines.

α-Metyltryptamine (AMT), a tryptamine derivative, was one of the strongest re-uptake inhibitors and releasers of the three monoamines. The tryptamine derivative, 5-methoxy-α-methyltryptamine (5-MeO-AMT), also strongly inhibited re-uptake and increased the release of the three monoamines.

http://www.sciencedirect.com/science/article/pii/S0014299906013811

 

[lovepsychadelics]

I thought Modafinil was no longer approved by the FDA for the treatment of ADD/ADHD as of 2006 due to 2 cases of erythema multiforme or Stevens–Johnson syndrome amongst the 933 subjects receiving the medication. Mechcatie, E. (2006). FDA cites Stevens-Johnson in modafinil's ADHD rejection. Clinical Psychiatry News.

 

[ebola?]

Personally, I'd like to see a TRI/TRA (Triple Reuptake Inhibitor/Triple Releasing Agent) appear on the prescription market.

This sounds like a woefully unsustainable medication.

ebola

 

[MagickalKat777]

This sounds like a woefully unsustainable medication.

ebola

Just curious as to why you think this is the case. I can't find much on how successful Indopan was, just things about the recreational use that emerged in the 90s and studies relating to pharmacology but nothing about the clinical effectiveness.

 

[sekio]

Most TRAs in recent history (mephedrone, methylone, MDMA the APBs, subst. amphetamines) don't exactly have a steallar profile in chronic usage.

 

[MagickalKat777]

Do you think it possible to find more tryptamine TRI/TRAs like AMT? It might be an avenue worth exploring.

I agree with you about the ones you listed (I never had the APBs though) but I've used a lot of AMT without any real negatives in comparison with the rest. Surely if I was chronically dosing a sub-psychedelic dose it may well be an effective long term treatment for a number of conditions? I definitely noticed when I was doing it every other day that the chronic depression I struggled with was gone for up to a month after I took a break from usage. Medievil was using AMT daily in low doses and seemed to be doing quite well also.

Maybe the TRI activity is required in combination with the TRA activity to make chronic usage sustainable? AMT is a pretty balanced TRI and TRA.

 

[ebola?]

Maybe the TRI activity is required in combination with the TRA activity to make chronic usage sustainable?

Depending on binding affinities, the reuptake inhibition would block release. It would retain efficacy for slightly longer than a TRA but would still be quite unsustainable. I mean, cocaine is a pretty solid example of a TRI.

ebola

 

[simstimstar]

Depending on binding affinities, the reuptake inhibition would block release. It would retain efficacy for slightly longer than a TRA but would still be quite unsustainable. I mean, cocaine is a pretty solid example of a TRI.

ebola

And we all know how sustainable that one is!! haha. Another example would be naphyrone...yuck! I can't imagine daily dosing of that. There are some piperazines, too, but I don't want 'em.

Cheers,
SimStim

 

[sekio]

Any monoamine releaser that binds to a transporter protien is also a reuptake inhibitor.

I seem to recall that naphyrone, the actual chemical, is nicer than people give it credit for. There was a period in time where everything sold as naphyrone was really MDPV though.

 

[simstimstar]

Any monoamine releaser that binds to a transporter protien is also a reuptake inhibitor.

I seem to recall that naphyrone, the actual chemical, is nicer than people give it credit for. There was a period in time where everything sold as naphyrone was really MDPV though.

If you've ever had MDPV and you try Naphyrone you can definitely tell the difference... Naphyrone is quite unpleasant by comparison IMO.

Cheers,
-SimStim