Perhaps someone can explain the exended release mechanism of vyvanse to me

[daveddd]

you guys are far out man

i just eat the things

[provoloney]

Originally Posted by KDLMaj

I just skimmed this, but the comparisons between Adderall and Vyvanse running around are a bit problematic.

People are focusing on the amount of amphetamine that is present in blood levels at any given moment and eliding it with the efficacy of the medication. However, the connection between the two is far more complicated.

There is an acute tolerance system that kicks in when the brain is exposed to methylphenidate or amphetamine (this is the reason why Ritalin LA was replaced with Concerta....Ritalin LA was created before we understood the acute tolerance system and thus didn't last nearly as long as expected). The method of delivery, the rate at which the drug increases in the system, and many other factors determine when and to what extent the brain ceases to respond to the medication. Looking at plasma concentrations of amphetamine is pointless- plasma concentrations of amphetamine continue to rise *after* peak effect has been reached- i.e. acute tolerance sets in before the drug has fully released into the bloodstream.

In sum: when it comes to amphetamine, Tmax is NOT the same as peak effectiveness. In short acting dexedrine (and spansules as well, is my understanding) Tmax is reached after benefits have begun to subside (this is why taking amphetamines can keep some folks from sleeping hours after the medication has supposedly "worn off")

What is interesting about Vyvanse (and I'm not sure they truly understand why this is the case just yet) is that its delivery system actually allows the user to garner benefits from the medication long after they would have had they used adderall XR. Users of Adderall XR cease to show clinically significant improvements in ADHD symptoms several hours earlier than users of Vyvanse.

So it i s true that this isn't an extended release medication, but focusing on Tmax comparisons between drugs misses the point entirely. Vyvanse was not, to my knowledge, initially anticipated to last as long as it does- Shire was trying to replace Adderall XR by adding some bells and whistles (a less abusable pro-drug....which was also a chance to get an ADHD stimulant medication that wasn't Schedule-II; though the FDA didn't end up biting on that one). The long acting version was a pleasant surprise, and it does make this medication far superior to Adderall XR for many folks.

And don't be fooled by Adderall's "Four different amphetamine salts"- 3 of them are just d-amphetamine and about 26% of the medication is l-amphetamine. Adderall is basically just d-amphetamine, and the half-lives of 3 of those salts are virtually the same. It lasts longer than methylphenidate simply because amphetamine naturally has a longer half-life. And Shire was forced to cease its claims that Adderall had a smoother onset and smoother withdrawal than methylphenidate- the FDA found no evidence to support the claim despite the fancy marketing about 4 different amphetamine salts. (Though many users have reported this to be the case- it may very well be because they were told this was the case before starting the medication. Shire's claim may not be in any official documentation any longer, but it's become part of the street wisdom of the medication)

Okay, going to bed. Apologies if I missed the point/repeated someone else's point!

This is a really fascinating post. My understanding of tachyphylaxis is that adhd meds typically work for a couple of hours after the medication reaches peak (i.e., the body keeps getting used to higher levels). This makes sense with every major medication we've had until now. Concerta and Adderall Peak at 7 hours, so the theory of acute tachyphylaxis says that these medications last 8-10. IR Dex tmax of 3 hour (i think) = 4-5 hours duration.

But Adderall is exactly the same medicine as vyvanse (- the l-amphetamine) and exactly the same medicine as immediate release dexedrine (though the vyvanse is distributing it slowly in the beginning). The more interesting question, then, is why vyvanse doesn't induce this acute tolerance phenomenon, but adderall and ir dex do. THat would be the key to its "extended release mechanism"

[KDLMaj]

the long-acting medications are often still in effect after Tmax is reached, but the effects are on the decline at that point.

Tmax for Concerta is a great case and point. Concerta is a three release medication- with each release being *greater* than the last. The original "long-acting" ritalin drug was Ritalin LA. It was a double release that was supposed to double duration, but it turned out that the second does wasn't nearly as effective as the first, and so the medication wasn't lasting very long. In order to maintain the same level of effect, the medication released the second time needed to be greater than the first- overcoming the acute tolerance mechanism (witnessed but not really understood). And since methylphenidate is so short-acting, Concerta actually needed 3 releases to maintain 12 hours of coverage.

Adderall XR gets by on two releases but only because amphetamine has a longer half-life and duration of action. Adderall XR lasts for approximately 8 hours for most users, but if you have two equal releases of Adderall (which lasts 4-6 hours- generally closer to 6 at medium to high doses), one imagines that there *should* be around 12 hours of coverage. It turns out, that's just not the case.

Vyvanse isn't adderall fyi, it's actually dexedrine. It turns into 100% d-amphetamine (Adderall is 74% d-amphetamine and 26% l-amphetamine). But the miraculous thing was that the drug releases so slowly in the system (it takes 4 hours to hit Tmax- which is bizarre for dexedrine) that acute tolerance doesn't seem to really kick in for much longer- hence getting 12-14 hours of coverage from the medication- several hours longer than taking equivalent dexedrine short release tablets.

[provoloney]

Originally Posted by KDLMaj

the long-acting medications are often still in effect after Tmax is reached, but the effects are on the decline at that point.

Tmax for Concerta is a great case and point. Concerta is a three release medication- with each release being *greater* than the last. The original "long-acting" ritalin drug was Ritalin LA. It was a double release that was supposed to double duration, but it turned out that the second does wasn't nearly as effective as the first, and so the medication wasn't lasting very long. In order to maintain the same level of effect, the medication released the second time needed to be greater than the first- overcoming the acute tolerance mechanism (witnessed but not really understood). And since methylphenidate is so short-acting, Concerta actually needed 3 releases to maintain 12 hours of coverage.

Adderall XR gets by on two releases but only because amphetamine has a longer half-life and duration of action. Adderall XR lasts for approximately 8 hours for most users, but if you have two equal releases of Adderall (which lasts 4-6 hours- generally closer to 6 at medium to high doses), one imagines that there *should* be around 12 hours of coverage. It turns out, that's just not the case.

Vyvanse isn't adderall fyi, it's actually dexedrine. It turns into 100% d-amphetamine (Adderall is 74% d-amphetamine and 26% l-amphetamine). But the miraculous thing was that the drug releases so slowly in the system (it takes 4 hours to hit Tmax- which is bizarre for dexedrine) that acute tolerance doesn't seem to really kick in for much longer- hence getting 12-14 hours of coverage from the medication- several hours longer than taking equivalent dexedrine short release tablets.

That's really interesting that Vyvanse's slow rise is what reduces acute tolerance; are there any articles or anything you know of that talk about that? I'm just wondering why that happens with Vyvanse (since Vyvanse's tmax is only a couple of hours longer than it would be for regular dexedrine), but not for adderall, which has a 3 hour tmax, or adderall xr, that has a tmax of 6 hours or greater, which is longer than for vyvanse.

[empty]

Originally Posted by ADHD Ceilidh

Interesting point cpt. I wonder if those unsatisfied by absorption/effects are more likely to be vegetarian? That would be an interesting poll....

That's quite an interesting coincidence! Let me guess - if you're a vegitarian, you eat lots of soy products, right? As it turns out, uncooked soy beans (as in soy milk and similar foods and beverages) are one of the most potent trypsin inhibitors.

Trypsin is the enzyme responsible for metabolizing and activating Vyvanse (lisdexamfetamine), which is really just dextroamphetamine bonded to lysine (the amino acid). Why no one ever bothers to mention trypsin w.r.t. Vyvanse is beyond me - it's always these unspecified "enzymes" for some reason. (So much mystery surrounding such a simple drug!).

If you're eating uncooked soy products, it's no wonder Vyvanse stops cold after this, since all the trypsin your pancreas is secreting gets inactivated by the time it (and the Vyvanse molecules) reaches the liver, where most of the actual lysine cleavage (and the release of amphetamine) occurs (see below for more on this).

I've found that if I drink a glass of soymilk (or related foods) at any time during the 8 to 10 hours Vyvanse is normally effective, within a few hours, I'm having rebound ADHD symptoms. The Vyvanse then starts working again up to 8 hours later than it should (presumably when the inhibition of trypsin has declined).

It's really unfortunate Vyvanse and soy seem to interact this way (since I used to love soymilk). Shire never bothered to write about it in the prescribing information either, so I'm guessing millions of Vyvanse patients have no clue why their medication is so erratic because of a simple soybean (although in all fairness, any trypsin inhibitor will do this).

If you want more information, look up the Wikipedia pages for Trypsin and Trypsin Inhibitor.

Now for some more clarifications (and debunking of misinformation) on the chemistry that makes Vyvanse work:

The most recent studies indicate that your liver typically metabolizes ~80% of the Vyvanse dose after it leaves the digestive system and enters the bloodstream (or more accurately the hepatic portal system). The pancreas produces trypsin and sends it into the digestive tract, but eventually it ends up in the liver, waiting for molecules of Vyvanse to reach it. That's when and where the metabolism into dextroamphetamine occurs, and that's why it lasts so long, with such a slow multi-hour onset after ingesting it.

Unfortunately, earlier studies, including Shire's own FDA "New Drug Application" for NRP104 (the original code name for Vyvanse), claimed the intestines predominantly metabolized Vyvanse, but this turned out to be bogus after further investigation.

Think about this fact for a second - if Vyvanse was metabolized in the intestines, why would it still last 10+ hours even if you utilized the toilet (no, not for urine) several times during that period? Remember to count the 4 hour therapeutic life of d-AMP in the brain too, but either way, the math just doesn't add up.

That's why I don't understand why folks keep on spreading misinformation about Vyvanse being converted to d-AMP in the stomach, GI tract, etc. I realize the initial studies were very misleading about this, but it never made sense from a metabolic standpoint. The hepatic mechanism described above was always a much more logical explanation, and studies confirmed it.

[provoloney]

Empty -- that's true that most converts by the liver, but the studies have shown that almost all of the intact prodrug gets converted in the first couple of hours (i.e., by almost two hours, there is no intact prodrug in the bloodstream, and so basically all of it has converted). At that point, dextroamphetamine has a fairly long half-life, and the Shire d-amp graphs for vyvanse seem consistent with this. Am I missing something here? After the prodrug leaves the bloodstream, does it still remain unconverted somewhere?

[cillianred]

Originally Posted by empty

If you're eating uncooked soy products, it's no wonder Vyvanse stops cold after this, since all the trypsin your pancreas is secreting gets inactivated by the time it (and the Vyvanse molecules) reaches the liver, where most of the actual lysine cleavage (and the release of amphetamine) occurs (see below for more on this).

Fantastic! Now I know why my Vyvanse went kaput after breakfast this morning.

Darn you, Kashi cereal and your soy protein!

Back to scrambled eggs, I suppose. Thanks for the info.

[tenko]

Originally Posted by provoloney

Empty -- that's true that most converts by the liver, but the studies have shown that almost all of the intact prodrug gets converted in the first couple of hours (i.e., by almost two hours, there is no intact prodrug in the bloodstream, and so basically all of it has converted). At that point, dextroamphetamine has a fairly long half-life, and the Shire d-amp graphs for vyvanse seem consistent with this. Am I missing something here? After the prodrug leaves the bloodstream, does it still remain unconverted somewhere?

Does this mean avoiding soya past mid-morning is unnecessary?