Help fill me in on drug tolerance please

[fake_blood96]

Hey everyone just trying to clear up some things regarding dopamine and serotonin releasing drugs and tolerance. So far it is my understanding that drugs like meth and cocaine cause the synapse to be flooded with more dopamine and obviously your brain doesn’t like this so it sets in motion downregulation of the dopamine receptors and increases the amount of enzymes that break down dopamine etc in order to keep the brain normal. So over time these dopamine releasing drugs will work less and less due to there being less dopamine in the brain from using the drugs and when there is dopamine there is also less receptors for it to bind to because of downregulation in order for us to get a good feeling from the drug.

Taking supplements like L-Tyrosine etc in order to replenish dopamine after a night out are good in that they help replenish the amount of dopamine in the brain to leave us feeling less like shit the following days after a big night out but continued use of l-tyrosine after a return to normalish levels of dopamine will not do anything to help with your tolerance to drugs like speed and cocaine because the brain will still be downregulating dopamine receptors due to excess dopamine produced from the l-tyrosine.

I’ve read that Seroquel will help in stopping tolerance because it blocks off dopamine receptors and your brain can try to upregulate again while you’re sleeping. Other drugs like Ketamine and MXE also can help with this?

All the above also applies to MDMA and the serotonin receptors in the same way I assume? Another thing being that serotonin replenishes at a much slower rate than dopamine but can be replenished much quicker with the help of 5-htp. I’m not sure if continued use of 5-htp will be beneficial in the upregulation of serotonin receptors to help decrease our tolerance to the drug like with l-tyrosine and dopamine receptors.

Please add to or correct me if I’m wrong on any of the above but also I have a few questions;

1: Is the amount of the dose or the frequency of use contributed with the downregulation of receptors, or is it both? Like I was thinking that ice being a potent and one of the most powerful drugs would definitely build up your tolerance to all other dopamine releasing drugs quicker than say your standard amphetamine sulphate would?

2: Also is it completely person dependant on how quickly your body becomes sensitive to these drugs again after abstinence?

3: Would sticking to GHB, Ketamine and Cannabis be ideal if I was to use drugs whilst giving my body time to resensitise itself to drugs like speed, cocaine and mdma as they don’t affect dopamine and serotonin?

Thanks for your help

 

[DeathDomokun]

It's not good to take an anti-psychotic (Seroquel) if you're not supposed to.
Dose and frequency (the amount you take) does affect/contribute to this.
Ketamine affects serotonin, it's an SRI.

I'll let someone more knowledgable address the rest of it. I saw your post in AusDD, one state down and there's no Ket to be found. You lucky fuck.

 

[sekio]

"Upregulation of dopamine receptors" seems mto be one of the greatest lures to get people to buy supplements/drugs. In reality you probably do not need to worry about the exact olevels of monoamines in your system, just make sure to eat a high-protien diet and get a ffair amount of excercise and your bodsy should have no problem maintaining homeostasis save for igf you choose to binge on meth.

You have the right idea for drug-induced tolerance. This tolerance seems to happen not only with dopamine receptors & serotonin receptors, but also e.g. opioid and cannabinoid receptors too. Everyone's body is different with regards to how sensitive their receptors are, and the different subtypes in different areas of the brain, etc, though so some may find that they "rebound" a lot faster than others after e.g. MDMA usage. Some may find that once tolerance develops it grows exponentially, some may find it simply plateaus, and some will be lucky t not experience tolerance in a major way.

Your body is a wonderful machine and is a lot "smarter" than a dish of cells used for affinity testing. Normally you do not need to "replenish" monoamines at all. To be totally honest I remember reading that neither tyrosine nor the tryptophan derivatives (5-HTP etc) have been shown to have an acute effect unless dosed rather high (multiple grams) or you've been on a serious releasing agent streak.

Also, it is incorrect to suggest that drugs like GHB, ketamine, cannabis have "no effect" on dopamine. Essentially every pleasurable drug will raise the amount of dopamine in the reward centres of the brain, directly or indirectly. Ketamine and MXE have activity at dopmaine receptors directly (as a partial agonist I belive) and also recent studies have shown that blocking the NMDA receptor increases the amount of dopamine released by other recreational substances. Activation of the GHB receptor is known to be a stimulant that releases DA too. Even cannabis elevates central dopamine concentrations.

 

[fake_blood96]

Yeh i reckon my brain really likes homeostasis or just doesn't replenish the chemicals as quick as others because i've never totally abused drugs to the point of charlie sheen (in which case i'd understand them not doing much anymore) and sure i've had small benders every now and then but friends who have done the same continue to get good effects while i won't if i do them every weekend or even every few weekends, i'm having a few months off completely give myself a chance to resensitise myself but i know the same thing will happen once i start to do drugs on the weekend again my tolerance always builds extremely quickly.

so by high protein diet that includes protein shakes too or only from meats? And also what did you mean by tyrosine or 5-htp don't have an acute effect?

And so how does ketamine have an indirect effect on dopamine and apparently serotonin too? it obviously doesn't cause a massive release of it but does it just stop your reuptake of it so there is more in the synapse?

and you're saying that GHB receptor activation causes a stimulant effect that releases dopamine too?

thanks

 

[sekio]

does [ketamine] just stop your reuptake of it so there is more in the synapse?

and you're saying that GHB receptor activation causes a stimulant effect that releases dopamine too?

Right on both counts. Ketamine/MXE have the same dopamine-boosting effects as methylphenidate does.

once i start to do drugs on the weekend again my tolerance always builds extremely quickly.

This is probably a sign that you should limit your usage.

As for the protien-in-the-diet thing all the research I have seen suggests that small doses of amino acids (under a gram) are basically placebo. And humans naturally derive their amino acids from a balanced diet of protien. So just make sure to get some diversity, don't just stick to protien shakes or beans and rice, mix it up daily and you'll feel good & eat well too.

 

[fake_blood96]

ah k, yeh i definitely feel that tyosine and 5-htp eliminate comedowns for me.

Also why is meth so neurotoxic? say compared to standard amphetamine or mdma, is it just because it is so strong and potent or is it something in the chemical makeup that is so bad for our head and will destroy it a lot quicker than other drugs.

 

[sekio]

Metahmphetamine releases incredibly large amounts of monoamines and also raises metabolic rate by a large amount, causing overheating and brain damage with long-term usage.

 

[fake_blood96]

so does the overheating actually kill brain cells because of the unnatural prolonged heat forced upon them? would the same then apply if you were stuck out in a desert? haha

 

[fake_blood96]

and how is it that 4-MAR which is equal to in effects of meth and also duration, apparently considered to be as about as neurotoxic as only standard amphetamine and also has a smoother comedown etc?

 

[adder]

4-MAR long-term usage doesn't cause as much depletion of dopamine and serotonin as methamphetamine does. Concerning "smoother comedown", recovery of processes leading to synthesis of aforementioned monoamines is also much faster.

 

[Epsilon Alpha]

and how is it that 4-MAR which is equal to in effects of meth and also duration, apparently considered to be as about as neurotoxic as only standard amphetamine and also has a smoother comedown etc?

Well a portion of the neurotoxicity observed in humans is due to several small factors adding up to cumulative damage. But, from the reading I've done its likely the following:

1)4-MAR and its related compounds lack a reactive metabolite
2)Possess reduced affinity for secondary targets associated with neurotoxicity such as NAChR, TAAR, and likely various mGluR's
3)Something in their mechanism of action may prevent them from activating a pro-apoptosis pathway or long term downregulation pathway

Its a shame these compounds are likely horrific for your cardiovascular system, they'd make excellent lead design compounds if their toxicity hadn't scared every legitimate researcher away.

But, adding to the tolerance talk: there is a lot of info suggesting that there are 2 main "varieties" of tolerance. Firstly there is the standard downregulation/upregualtion of various genes and proteins that everyone talks about. But, and perhaps more importantly for long term tolerance, changes in the wiring of the brain's drug/reward response pathways independent of gross protein/receptor changes. Things like mRNA transcription rates, connections to other neurons, and long term changes in the regulation responses of various proteins all factor into it.

That's partly why acute tolerance seems to build so much faster in users who have been abstinent for so long, the brain has learned how to better respond to whatever change the drug is trying to induce.