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Unsustainable drugs

Lightning-Nl

Lightning-Nl

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Nov 11, 2012
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I got an interesting idea for a thread. I know what causes unsustainability is tolerance - the body adjusting itself to the presence of the drug in order to reach homeostasis. However, my question is; what about this adjustment makes using this drug "unsustainable" ?

For instance; tolerance to the euphoric effects of Amphetamine builds up very quickly. But the therapeutic effects can take years to build a tolerance to. But with MDMA; this is unsustainable, due to the fav that MDMA's effects on 5HT are so profound. Because 5HT upregulation is so significant, and occurs much faster than any of the other monoamines, using MDMA everyday would be very "unsustainable" in the long run.

Anyways, I'm curios what other drugs are unsustainable in a similar fashion. Can anyone name some more and why they're not sustainable for long term use?
 
(Nearly) all serotonergic psychedelics seem to classify as such.
 
In the long run probably only caffeine and weed are truly sustainable (and for some not even weed).
 
It depends on your definition of 'sustainable'. Everything is going to affect your body in some way, how detectable and what influence it has on your life can be subjective.
 
nAON said:
It depends on your definition of 'sustainable'. Everything is going to affect your body in some way, how detectable and what influence it has on your life can be subjective.
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Really. I'd say that most, if not all, substances have a sustainable effect on the user - but the range of effects changes with time and adjustation, often turning to neutral or negative / oppisite. So in my eyes, many psychiatric drugs - top most the serotonergic antidepressants - are not "sustainable" in terms of the wished effect, tolerance and adjustation (even genetic changes) build quickly and last for very long time.

On the other side, NMDA antagonists (also creating tolerance on their own, but at least in my own case, in low dosage tolerance builds up to some kind of plateau, where it lasts more or less. Even more if used in combination). Memantine works for months and months, after initial adjustation is done. A quite strange but nice thing is that low to moderate dosed opiates and/or dopaminergics, combined with NMDA antagonists, are quite sustainable... while on their own, they are some of the least sustainable ones...
 
Im not sure if this is what you'd count as "unsustainable", but its well known that Alcohol tolerance can develop to the point where some people can "easily" withstand doses that would be fatal to a naive user.

I don't think we really think about this as much with alcohol, as it is so easy/common to just increase the does the following day(or as soon as tolerance begins dulling the effects of the previous dose).


Im not entirely sure this is related to your original point though, as I believe the principal tolerance mechanism involved in alcohol tolerance can be attributed to the body increasing the speed at which it metabolizes. And if I'm not wrong, this change isn't really as a result of any changes in the brain, but more just a physical response.

Of course, everything Ive just said may just be irrelevant or incorrect.
But let me know
 
it depends on the person, i found tramadol to not produce proper tolerance for up to a year when used once daily.

no drug is sustainable forever in my experience

caffeine is a bad example because tolerance shoots up rapidly and it has a gut wrenching withdrawl that i find as bad as mild opiate withdrawl. i feel so shit when i cut out caffeine after a week of drinking it that nothing can make me happy and feel really depressed, bad headache constantly and nausea
 
pofacedhoe said:
it depends on the person, i found tramadol to not produce proper tolerance for up to a year when used once daily.



no drug is sustainable forever in my experience

caffeine is a bad example because tolerance shoots up rapidly and it has a gut wrenching withdrawl that i find as bad as mild opiate withdrawl. i feel so shit when i cut out caffeine after a week of drinking it that nothing can make me happy and feel really depressed, bad headache constantly and nausea
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I found tramadol tolerance to build quickly. Interesting. I wonder how much chemistry plays a part versus user expectation plays a part in such differences in individual experiences.
 
Im not entirely sure this is related to your original point though, as I believe the principal tolerance mechanism involved in alcohol tolerance can be attributed to the body increasing the speed at which it metabolizes. And if I'm not wrong, this change isn't really as a result of any changes in the brain, but more just a physical response.
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Both enzymatic induction in the liver and downregulation of GABA receptors in the brain account for alcohol tolerance.
...
Sustainability depends on what type of frequency of use is necessary to preclude increase of tolerance. I don't think that even daily use of caffeine or cannabis are sustainable in this way.

ebola
 
It might be better to ask what drugs are sustainable. I think partial agonist opioids probably are. Full agonists, especially the potent ones like fentanyl and those prone to tachyphlaxis are probably no good for long term use. Buprenorphine, even after seven years, will still get me high after all these years, but it sort of breaks the usual paradigm of using more and more. Using less and spacing the doses out is the key.

Something similar for stimulants is a huge area of interest right now. That's difficult, though. A partial agonist dopamine reuptake inhibitor is a bit of a impossibility. How do you have a ligand bound that only blocks part of the reuptake? Tough one. Somehow you want it to bind to the protein and reduce the affinity of dopamine for it. There has been work on so-called cocaine antagonists which bind to the transporter but in such a way that they're still able to bind to dopamine. I suspect that compounds like those probably do mildly inhibit the reuptake as well. That's an interesting area that deserves more research. Unfortunately I doubt that such a thing can be done for methamphetamine. It's simply too similar to dopamine, so there won't be much differentiation in binding site like with cocaine. I wonder about the possibility of dopamine reuptake enhancers to prevent the huge spike that releasers cause.
 
Hammilton said:
Something similar for stimulants is a huge area of interest right now. That's difficult, though. A partial agonist dopamine reuptake inhibitor is a bit of a impossibility. How do you have a ligand bound that only blocks part of the reuptake? Tough one. Somehow you want it to bind to the protein and reduce the affinity of dopamine for it. There has been work on so-called cocaine antagonists which bind to the transporter but in such a way that they're still able to bind to dopamine. I suspect that compounds like those probably do mildly inhibit the reuptake as well. That's an interesting area that deserves more research. Unfortunately I doubt that such a thing can be done for methamphetamine. It's simply too similar to dopamine, so there won't be much differentiation in binding site like with cocaine. I wonder about the possibility of dopamine reuptake enhancers to prevent the huge spike that releasers cause.
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My current "hack" for this is to take the MAOB-I Selegiline (which prevents the breakdown of dopamine) and the Dopamine Reuptake Inhibitor Armodafinil (which also reduces the dopamine releasing potency of amphetamines) along with (sometimes 2-fluoro-)(sometimes meth) amphetamine in greatly reduced doses, along with a lot of antioxidant/neuroprotective agents. Overall quite sustainable combo for me at least. There are also a bunch of Modafinil derivatives out there are really potent DRIs that are "devoid of cocaine-like behavior", you'll find them on pubmed/chem pretty easily. Hopefully some will hit the RC market soon.

Also Selegiline is a very sustainable drug (as long as you don't OD with stims on it...), in fact mice live something like 30% longer and in better health if they take it for life. Modafinil too, minus reported lifespan extension.
 
Uh....what about amphetamine? It blocks Dopamine reuptake, inhibits Monoamine Oxidase, and indirectly releases Dopamine. On top I that, it has D1 and D5 dopamine receptor affinity, and a1 adrenergic receptor affinity.

Granted, the receptor affinty is something like 8000 for D5 and 2000 for D1, but it exists none the less.
 
tweex said:
My current "hack" for this is to take the MAOB-I Selegiline (which prevents the breakdown of dopamine) and the Dopamine Reuptake Inhibitor Armodafinil (which also reduces the dopamine releasing potency of amphetamines) along with (sometimes 2-fluoro-)(sometimes meth) amphetamine in greatly reduced doses, along with a lot of antioxidant/neuroprotective agents.
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With personal bioassay, I still found this regimen unsustainable, in the sense that use of a classical stimulant more than once a week led to tolerance accrual. In fact, I seemed to be come tolerant somewhat specifically to the changes that selegiline conferred upon the amp high. I can't really explain this neurologically, particularly as selegiline's main effect seemed to persist (though I find it extremely subtle).

swampy said:
Uh....what about amphetamine?
Click to expand...

This is one of the least sustainable compounds when taken frequently. . .
 
I would say oxycodone for surebecause there is no real ceiling. After a while it takes such a ridiculous amount to achieve the same effects it gets rather expensive. IME it stopped working all together for pain and produced little to no effects after taking it for a long time.

MDMA seemed to stop working for me after doing it twice a week for 3 years or so. I do believe that is do to the natural serotonin levels running lower.
 
ebola? said:
With personal bioassay, I still found this regimen unsustainable, in the sense that use of a classical stimulant more than once a week led to tolerance accrual. In fact, I seemed to be come tolerant somewhat specifically to the changes that selegiline conferred upon the amp high. I can't really explain this neurologically, particularly as selegiline's main effect seemed to persist (though I find it extremely subtle).
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Interesting stuff, I guess we're all a bit different in chemical makeup (well, obviously...)
 
Well, it directly releases, I directly inhibits reuptake (by increasing phosphorylation of the transporter). It's affinity for dopamine receptors isn't relevant at doses that don't kill you.. it's not a partial agonist reuptake inhibitor. That would mean it binds to the transporter and only partially blocks reuptake. A drug that bound to an allosteric site on it that reduced dopamine's affinity would be the closest such thing.
 
Cannabis is one of the few substances that you can use daily for your entire life and still get high. The catch seems to be that you need to smoke different strains ( of extremeley high quality of course) from time to time so you it's wise to have a variety of connections. I cannot think of any other substance that is capable of this.
I'm a chronic pain suffer and an insomniac (and migraines) and I do use cannabis daily and have for many years and the effect is not like it was when I was 15 for the first time but decades later very high quality cannabis has all it's effects. It's only if I've been smoking the same thing forever that I notice diminished effects.
 
1-ethnyl-cyclohexanol has terribly high/quickly raising tolerance, more so than any substance i've ever tried. Using it for multiple days in a row is nearly impossible. Pregablin also seems to form tolerance very quickly as well, though long term abstaining isn't really needed to revive the effects.
 
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