It's been said that the duration of action of a prescription amphetamine stimulant has little to do with the half-life. For example, dexedrine ir has a 10-16 hour half-life I think but duration is said to be only 4-6 hours, because of acute tachyphylaxis. Adderall XR peaks at 6 hours fasted and has a 10-12 hour duration, which I can understand. What I don't get, is how Vyvanse shows a 12-14 hour duration in studies. the d-amphetamine in Vyvanse peaks at less than only 4 hours, and then just enough is released to smooth out the descent a little, so how does Vyvanse have such a long duration? The prodrug mechanism wouldn't explain it (as everyone says), b/c the d-amphetamine peak tmax still is earlier than adderall xr. I'm thinking it has to do with either: (1) the effect of l-amphetamine in adderall. Somehow it would alter the duration... or (2) vyvanse's release somehow keeps tachyphylaxis from occuring. But why would it?
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N&PD Moderators: Skorpio
what is the actual pharmacological principle behind amphetamine duration?
- Thread starter dalt123
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/navarone/
Bluelighter
IIRC its mostly due to its rate of metabolism, and that can depend from person to person.
BTW half-life is not exactly the duration of the drug but rather the time it takes for the drug to reach 50% blood concentration compared to the initial concentration.
Vyvanse (Lisdexamfetamine) is actually a prodrug of amphetamine (amphetamine bondedn to an amino acid which makes it inactive but the metabolic process breaks up the bond releasing pure amphetamine.
In a way you can consider it as a extended release form of amphetamine since it obviously wont get split all at the same time.
Tachyphylaxis occurs when a heavy dose is repeated over a short period of time, in the case oy Vyvanse if taken not taken in excesive doses, it gives time for the body to, how to say, heal up from the neurotransmitter overload cause by amphetamine.Thanks navarone, this is helpful. the only thing that's confusing me, though, is that I thought that in addition to tachylaxis over the long term, with stimulants there is a form of acute tachyphylaxis that lasts during the day also. I may be confused, but I remember reading somewhere that stimulants like concerta, etc., were designed to have an ascending pharmacokinetic profile during the day, as it was found to work better than a steady profile. in theory, a stimulant is only good for a few hours after it reaches Cmax. all of the metabolic prodrug stuff seems to be completed within a few hours with Vyvanse, and it peaks earlier than any other long acting stimulant (according to the package insert I think it's like 4 hours fasted). It made me wonder if there is something unique about d-amphetamine compared to partially racemic forms like adderall.it is partly how the drug works : even thou MethAmphetamine has a long half life, and is throwing out as much Dopamine as it can, eventually your Dopamine will run low, even if the Amphetamine is still there in your brain trying to work, so you will not feel much effect from it.
Interestingly, Dopamine seems to run out alot quicker than norAdrenaline, and that is why after many hours on Amphetamines, you are getting that bad adrenaline feeling at the end. At that point, it is really good to take about 2 Ritalin. It protects the brain, and makes the good feelings come back- it seems to put the dopamine back up, and reduces the amphetamine releasing any more norAdrenaline.
I have done this many times, and it works really well.Last edited:Sure, it's still somewhat mysterious exactly why amphetamine's typical duration of perceived central effects doesn't quite square with the amount of time it should be circulating through the bloodstream. And one theory that I personally think has a lot to it is exactly as you say: various 'curves' of effect that arise from acute tachyphylaxis.
High seas of theory ahead, sorry. After all I'm one of the people who started talking about memantine a lot in recent years:
Dopamine "depletion" per se doesn't occur at anywhere near therapeutic doses of amphetamine, or even the more reasonable range of recreational doses ... it seems to take a lot for this to happen.
More to the point in terms of both short-term and long-term sensitivity/tolerance is acute receptor re-regulation, triggered responses of desensitization and sensitization.
We already understand, I think, that the sleep state where amphetamine is withdrawn (relatively) is pretty relevant in the way the response develops. To an extent these acute changes are reversed during a sleep phase, although perhaps a dominating trend (of tolerance or sensitization to any particular effects) begins to linger and take precedence and this is the development of what is perceived as more long-term tolerance or sensitivity.
Practically speaking, I find that on amphetamine, if I take my jumpy, reward-primed neurons and go do something like jerk off or play a video-game, something essentially low challenge with easy rewards, then the stuff feels like it wears off a hell of a lot faster than if I were to -- relaxedly, because high stress burns out the effect too -- work on something challenging yet interesting during the day, like my artistic pursuits/career. Hmm. Acutely and over time.
Opting for sleep deprivation, again IME, is also a way to create an ephemeral quality in the effects. By the way, to a significant extent my experience of "tolerance" in general is largely of the stuff (say a Vyvanse) working, but only for like two hours. That and adrenergic effects becoming prominent as a higher dose is needed to achieve the desired effects, which for me include a stimulation of motivation and joie de vivre as much or moreso than focus. I take memantine and use behavioral strategies and healthy living, with much success taking the same therapeutic amphetamine dose 6 out of 7 days for almost two years now. YMMV.hamhurricane
Bluelighter
there is quite a lot going on in a formulation like adderall which i do not completely understand. there is a great study which compares the DA releasing potency/duration of d-AMPH, d,l-AMPH, and the proprietary blend of salts and approx 76:24 ratio of d:l isomers that is adderall. this study challenges the idea that l-AMPH is inactive, at the very least it would seem to have a potent effect in modulating d-AMPH if not possessing an intrinsic stimulant effect of its own. Adderall releases over 25% more DA at its peak than racemic AMPH or d-AMPH, it also hits faster and lasts quite a bit longer than both. i find that amazing.Last edited:hamhurricane
Bluelighter
^^^
since seep did not comment in this thread i will assume you are asking me?
keeponkeepnon
Bluelighter
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Grue/ Dr. Beat any explanation as to why an unchanging daily dose of adderall (20 mg) is pleasant and beneficial for the first 2 - 3 days then progressively becomes more unpleasant (ie moodiness, NE feelings galore, anger, etc) as the days goes on. The only solution being a 4-5 day break. How is anyone able to use amphetamine therapeutically and not hate their life as a result ?
Perhaps not AD discussion but this thread has been more useful than 85% of em out there.Grue/ Dr. Beat any explanation as to why an unchanging daily dose of adderall (20 mg) is pleasant and beneficial for the first 2 - 3 days then progressively becomes more unpleasant (ie moodiness, NE feelings galore, anger, etc) as the days goes on. The only solution being a 4-5 day break. How is anyone able to use amphetamine therapeutically and not hate their life as a result ? Perhaps not AD discussion but this thread has been more useful than 85% of em out there.
Memantine has been used succesfully for this purpose, grue also mentioned it in hes post, its no magic antidote however and taking a 1 or 2 day break a week is still advised.
