Stimulants without paranoia and tollerance

[MephedroneCandy]

So I came to the conclusion that stimulants like cocaine amphetamines etc... suck from a certain point of view, they basically have an inverted U response. This means that if you take a little you are stimulated euphoric etc... But as long as you take too much and the euphoria disappears, yes you are stimulated but it is a shitty experience and the euphoria disappears and also the locomotor hyperactivity.

In fact I remember when I took a little more speed or meth or isopropylphenidate than what was giving me euphoria, it was a shitty experience (a little as 20 mg more, first time not redosing). Virtually all the euphoria vanished. It also happened with mephedrone but in a lesser form.

That's why they created allosteric D1 receptor agonists. These here instead of directly agonizing it enhance it and tests on animates have shown that this shitty thing doesn't happen, in fact you can take as much as you want but then the effect doesn't change much avoiding becoming shitty. In addition, they have shown that they have VERY LITTLE TOLERANCE. If someone wants to try them he can request a custom synthesis. I think these are the best stimulants out there right now. No paranoia as D2 is not stimulated, very few side effects including improved instead of worsened cognitive performance and pure euphoria.

https://sci-hub.ru/10.1016/bs.apha.2019.06.001

 

[Skorpio]

I've always modeled stimulant euphoria as something more than dopaminergic signaling. Pure DRIs seen to be not very euphoric (though very compulsive), and it seems the most euphoric drugs have a fairly balanced release profile between DA:5HT:NE

 

[MephedroneCandy]

I've always modeled stimulant euphoria as something more than dopaminergic signaling. Pure DRIs seen to be not very euphoric (though very compulsive), and it seems the most euphoric drugs have a fairly balanced release profile between DA:5HT:NE

Amphetamine releases just noradrenaline too. Maybe by combining it with Strattera or similar we can get good effects. But first of all before making this speculations I need to try it... But if I really want to speculate the MUST would be MDMA+this allosteric thing. It would be like mephedrone.

 

[Skorpio]

Amphetamine releases just noradrenaline too. Maybe by combining it with Strattera or similar we can get good effects. But first of all before making this speculations I need to try it... But if I really want to speculate the MUST would be MDMA+this allosteric thing. It would be like mephedrone.

D-amphetamine releases enough serotonin to be used as a probe in PET studies.

Brain Serotonin Release Is Reduced in Patients With Depression: A [11C]Cimbi-36 Positron Emission Tomography Study With a d-Amphetamine Challenge

The serotonin hypothesis of depression proposes that diminished serotonergic (5-HT) neurotransmission is causal in the pathophysiology of the disorder. Although the hypothesis is over 50 years old, there is no firm in vivo evidence for diminished 5-HT neurotransmission. We recently demonstrated...

www.biologicalpsychiatryjournal.com

 

[MephedroneCandy]

D-amphetamine releases enough serotonin to be used as a probe in PET studies.

Brain Serotonin Release Is Reduced in Patients With Depression: A [11C]Cimbi-36 Positron Emission Tomography Study With a d-Amphetamine Challenge

The serotonin hypothesis of depression proposes that diminished serotonergic (5-HT) neurotransmission is causal in the pathophysiology of the disorder. Although the hypothesis is over 50 years old, there is no firm in vivo evidence for diminished 5-HT neurotransmission. We recently demonstrated...

www.biologicalpsychiatryjournal.com

Mdpv is pretty euphoric but it is just an NDRI.

 

[plumbus-nine]

I think a combined NDRI inverse agonist and NMDA antagonist would be a winner. I always loved combining low dose stim & dissociative for to get a clean, calm and slightly spaced out headspace with good ability to focus/do cognitive tasks. Much better than a stim alone, and able to cover the effects of sleep deprivation to some degree. Note that I don't recommend getting into sleep deprivation, I might have caught psychosis due to me over-stretching that. But we have opioids/NMDA antagonists combined so why not stims?

For tolerance this certainly does wonders. When using methylphenidate alone, I would start with an 18mg concerta which was almost too much without tolerance but after just a week required to even reach baseline. With MPH+DXM I was going for months with no noticeable tolerance, had to stop because of physical overstimulation, not loss of efficacy.

 

[negrogesic]

I think a combined NDRI inverse agonist and NMDA antagonist would be a winner. I always loved combining low dose stim & dissociative for to get a clean, calm and slightly spaced out headspace with good ability to focus/do cognitive tasks. Much better than a stim alone, and able to cover the effects of sleep deprivation to some degree. Note that I don't recommend getting into sleep deprivation, I might have caught psychosis due to me over-stretching that. But we have opioids/NMDA antagonists combined so why not stims?

For tolerance this certainly does wonders. When using methylphenidate alone, I would start with an 18mg concerta which was almost too much without tolerance but after just a week required to even reach baseline. With MPH+DXM I was going for months with no noticeable tolerance, had to stop because of physical overstimulation, not loss of efficacy.

It sort of does exist, as a medication called "auvelity", containing something like 45mg of DXM and 100mg of bupropion. Looked it up out of curiosity and it costs nearly $600 a month. If I were a psychiatrist thinking about prescribing it to my patients, I'd just tell them to pop the equivalent amount of otc DXM (perhaps 10 cents worth) alongside their bupropion.

 

[Fertile]

How does one classify eugeroics? I think their are much more potent analogues of modafinil which is being explored as a treatment for cocaine dependence.

As I see the QSAR, it replaces an O with an S, has a 2 methylene spacer and then a nitrogen (not basic(. Someone evidently systematically discovered what parts of the scaffold are important for DAT transport and what is required for the 'wakefulness'. Benzylthio homologues of cocaine are known so I suspect that is where research began.

I have no idea if modafinil is of use in the treatment of cocaine dependence or if it's a guess. If their is good science, at least SOME of cocaines dependence liability isn't directly due to it's DAT transport effects.

A study comparing MDPV (or similar) to cocaine might uncover that. Who thought that an MD substitution would be more potent than the p-Me found in pyrovalerone (a medicine, don't forget).

I recall C6H6 making it and sending out samples. Someone else had found desoxypipradrol and MXE and so I got a nice letter containing samples of all 3 (legal back then). I did NOT like MDPV because it was like coke. desoxypipradrol was in desperate need of a a sacrificial moiety to lower T½ but MXE was perfect.

But nothing stands still. So we all look for the next big thing.

 

[fastandbulbous]

Low dose 3-methoxy PCE works pretty well as a stimulant at low doses (less than 10-15mg) and yes, it's a barrelload of fun!

 

[ecstacylover]

I've always modeled stimulant euphoria as something more than dopaminergic signaling.

It's an incredibly crude approximation to treat observable rodent behaviors as proxies for the internal states experienced by humans, but I think it's still worth pointing out that the degree to which rodents "like" a particular stimulus is completely unaffected by dopamine depletion (in contrast, it is a function of MOR activation).

 

[Fertile]

Oh so 3-OH PCP has appreciable MOR affinity? The data I have suggest that it's activity is 2 orders of magnitude lower than morphine (based on ED50 and displacement of other ligands. It seems to be a silent agonist more than anything.

I think the key things are reducing the locomotor stimulation, elimination time and most importantly, that seemingly sudden change from a stimulant to a psychosis inducing NMDA antagonist. If 3-OH PCP solves those issues, the O-acetyl derivative might be an appropriate prodrug i.e. it will lower MP significantly. Initially I wondered if the 3-MeO would be an appropriate prodrug, but it seems not.

As I mentioned before, it does seem that even in the 1970s many members of the US public, especially those living in urban areas had witnessed people under the influence of PCP doing strange and possibly dangerous and/or violent things. If someone has their executive function severely impaired, is stimulated, cannot feel pain and is delusional, I can see why it could be an issue. I wonder why so many thus delusional chose to wander about déshabillé if not nude? I am QUITE prepared to believe that the media gives the impression if it being more common that it seems.

 

[fastandbulbous]

Oh so 3-OH PCP has appreciable MOR affinity? The data I have suggest that it's activity is 2 orders of magnitude lower than morphine (based on ED50 and displacement of other ligands. It seems to be a silent agonist more than anything.

I think the key things are reducing the locomotor stimulation, elimination time and most importantly, that seemingly sudden change from a stimulant to a psychosis inducing NMDA antagonist. If 3-OH PCP solves those issues, the O-acetyl derivative might be an appropriate prodrug i.e. it will lower MP significantly. Initially I wondered if the 3-MeO would be an appropriate prodrug, but it seems not.

As I mentioned before, it does seem that even in the 1970s many members of the US public, especially those living in urban areas had witnessed people under the influence of PCP doing strange and possibly dangerous and/or violent things. If someone has their executive function severely impaired, is stimulated, cannot feel pain and is delusional, I can see why it could be an issue. I wonder why so many thus delusional chose to wander about déshabillé if not nude? I am QUITE prepared to believe that the media gives the impression if it being more common that it seems.

Well the hyperthermia PCP can induce probablyexplains the need to get naked...

 

[Fertile]

Maybe we have cracked it - a nudism drug?

 

[fastandbulbous]

Maybe we have cracked it - a nudism drug?

Nah, alcohol still wins out there!

 

[Fertile]

I don't think I've ever seen you consume ANY alcohol EVER. So now we know the reason why ;-)

 

[fastandbulbous]

I don't think I've ever seen you consume ANY alcohol EVER. So now we know the reason why ;-)

Might have something to do with thinking discarding clothing is a good idea, after a tiny amount of alcohol (in combination with stims, it can make me offencisely sarcastic!)