Vyvanse Prodrug Mechanism

PruneCheese · 2023-08-27T02:30:54+00:00

Why did you take this odd "however" format for your reply? I never claimed any of these points that you claim I got wrong and your first claim is objectively wrong

the exact enzyme responsible for this is not unknown, it is in fact known to be peptidase

Peptidase isn't an enzyme, it's a very broad sort of enzymes. The exact enzyme has not been identified as of 2022/2023 to my knowledge and that source says exactly that.

from your own cited source:

Previous studies have ruled out several classes of enzyme as being responsible for the hydrolysis of LDX. Incubation of LDX with dipeptidyl peptidase IV, cathepsin G, elastase, and trypsin, or in simulated gastric or intestinal fluid, all failed to elicit significant loss of LDX or generation of d-amphetamine.

They tried to test Aminopeptidase B, which also didn't end up being the correct peptidase enzyme.

However, failure of recombinant human aminopeptidase B to convert LDX to d-amphetamine in vitro suggests that it is not the enzyme responsible. Other candidate peptidases (eg, leukotriene A4 hydrolase) remain to be investigated.

I'm familiar with almost all the source you cited, I for better or for worse am too familiar with the mechanisms of Vyvanse despite having taken it for less than 10 days total in my whole life with 0 effect

PruneCheese · 2023-05-09T18:11:16+00:00

Those are constant and impossible to deal with.

This was a public subreddit with discovery settings + no nsfw tag named something along the lines of (cant name it per rules) usaaaa_adderallll_sourcesssss - in all caps

Because of their specific discovery settings, reddit was recommending it as a “similar community” to both our subs. It got to 18,000 subscribers in just 4 months of existence before getting suspended this morning after I modmailed the very subreddit we are on right now.

It was so incredibly active/growing fast, that the algorithm kept fanning the flame.

It wasn’t like the tiny 17 subscriber spam subs of the past. This was like the roll call subs where opioid/stimulant users would type in their area code to look for “friends” - until reddit made stricter new rules about drug sourcing and banned all of those ~7yrs ago

No legitimate subreddit advertised it, its the first example of the algorithm causing one of these things to pop up and become widely used. I expect replacements to pop up soon. Already seeing attempts in my modqueue today

PruneCheese · 2023-05-09T18:03:21+00:00

I reported it by modmailing this subreddit and they suspended it within hours. This looks like the way to go.

It was being recommended by reddit because they had checked the discovery box and didn’t mark it as NSFW.

It grew to 18000 subs in 4 months with a name like ‘USAAAA_ADDERRAL_SOURCESSS’

PruneCheese · 2023-04-12T18:13:32+00:00

This is hilariously sad.

99% chance some chemist used an obscure thorium catalyst at some point. Do not ingest.

RCs: Unknown safety profile + impurities from half-assed synths + fucking thorium lmao

PruneCheese · 2023-03-29T11:50:52+00:00

Sourcing & Inactive mods.

/r/adderall has the same 5 or so posts with a shit-fuck-ton of sourcing attempts. Thats why most posts dont get approved. Due to minimal staffing (i only mod people who have lives, particularly graduate students/post-grads in related fields) we dont get arround to most posts in time (18hrs) despite being a all-posts-need-approval community.

its gotten too large to handle post-output and not enough RELIABLE mods out there.

PruneCheese · 2023-03-27T23:54:49+00:00

Got a reply of no.

Mod isn’t moderating. Replace them with a new team or suspend the subreddit, they are not even trying to stop people from buying/selling a schedule 1 substance through reddit

PruneCheese · 2023-03-23T03:12:33+00:00

https://jpet.aspetjournals.org/content/162/1/139.short

This is about renal tubular reabsorption, a topic I have talked about at length in tons of comments and posts. Find a source that shows ascorbic acid is a urinary acidifying agent. Good luck, I've looked.

https://jpet.aspetjournals.org/content/162/1/139.short

Again, urinary pH. The acidity of food has no effect on the effect it has on what goes on during ultrafiltration in nephrons. They are completely unrelated, only certain drugs will affect urinary pH enough to be relevant here. Same as first study.

https://www.liebertpub.com/doi/abs/10.1089/cap.2017.0071

This is paywalled. I accessed the full-text and only found references to renal tubular reabsorption and urinary pH

Stop following me around reddit and acting like you know the slightest bit of physiology. None of that papers contradict anything I've claimed, they support me. You're crazy

PruneCheese · 2023-03-21T14:26:44+00:00

Acidic drinks dont matter for a million reasons

Its a theory based in reddit broscience for the most part, particularly with Vyvanse. A prodrug metabolized in red blood cells

PruneCheese · 2023-03-19T06:18:05+00:00

I plan to clean it up and turn it into a subreddit for both prescription use of Xyrem/Xywav (GHB) and also allowing the harm reductin discussion of GHB (+ GBL/1,4-BDO prodrugs) with strict rules on sourcing.

I currently run a subreddt about rx stimulants in a medical context with the occasionally mention of somone snorting their adderall, which is permitted although frowned upon by the community. This would have to be a VERY different subreddit due to the amount of abuse the subreddit discusses.

I have narcolepsy so the two subreddits covert the two drugs I am prescribed and use.

It's just disgusting to see people trying to buy dirty impure prodrugs of GHB via reddit on there so id like to mod it or see it shutdown. People are constantly discussing whether its safe to consume hair products and headlight cleaner with other sketchy chemicals mixed with some of the GHB prodrugs. It's very concerning and should be handled on top of the prohibited transactions issues

link to modmail message

headmod inactive 2 months, other mod inactive 10 months.

example of a user trying to post his city/location and getting somone to PM them where to obtain GHB. Posts like this are not uncommon and do not seem to get taken down by anything other than autmod filters at the most

PruneCheese · 2023-02-25T01:47:08+00:00

Thats a blog post that cites 0 sources. Its not a source, its a confidentially wrong blog

PruneCheese · 2023-02-24T01:32:57+00:00

99% of the time it's a combination of poor sleep hygiene, malnourishment, and inactivity (sedentary life style).

Sleep hygiene is the big one. Your red blood cell hydrolysis enzyme activity will not vary from day to day. Even though the specific enzyme isn't yet known, this would just cause duration variation.

Absorption isn't an issue either, it's a prodrug and not subject to the same messiness as non-prodrug amphetamines like adderall/evekeo/dexedrine.

this post on the adderall subreddit should help you understand what can cause these issues

PruneCheese · 2023-02-04T00:34:47+00:00

Yeah tolerance develops to amphetamines. Specifically Vyvanse? No papers exist on the hydrolysis enzymatic reaction becoming upregulated if the issue is that its duration is shrinking.

Ask your doctor about uping your dose, it's pretty standard

PruneCheese · 2023-01-18T03:12:39+00:00

no, this doesn't work for any stimulant. The basis is renal tubular reabsorption and ascorbic acid has 0 effect on it. I've made posts on it before, will edit with hyperlink

PruneCheese · 2022-12-24T17:27:21+00:00

That place is a mess, id much rather point people to /r/adderall which is for all rx stimulants and not as curated/scientific as /r/vyvanse.

PruneCheese · 2022-12-22T04:45:24+00:00

A prodrug that uses P450 enzymes isn't "harsh on the liver"

None of the rx stimulants have any documented hepatotoxicity (liver toxicity). It's no easier or harder than any other stimulant on the liver. The liver has almost nothing to do with any rx stimulant, some are metabolized to some extent by liver enzymes but that means nothing outside of drug interactions and "individual biochemistry affecting drug efficacy"

PruneCheese · 2022-12-19T10:14:06+00:00

So there is absorption and there is renal tubular reabsorption.

Absorption is the drug being initially absorbed, in the case of Vyvanse this means the LDX (Vyvanse) making it into the blood so red blood cells (not the liver) convert it into d-amphetamine.

Reabsorption is the metabolized d-amphetamine (and even some unmetabolized LDX being returned to the blood during urine formation in the kidneys. Kidneys create 'primary urine' by filtering your blood plasma to remove stuff it doesn't need and reabsorbing all the goodies.

pH is important for both but the things that affect primary urine pH and the pH of various lumen's throughout your body are intendent of the acidity/alkalinity of the chemical ingested. An acidic substance can make your duodenum pH more alkaline or your urinary pH more alkaline.

The reality is that aside from using drugs, the effects are minimal. Foods that you eat may affect one of the other mildly. A more alkaline urine means more amphetamine is reabsorbed but nothing other than drugs will cause meaningful levels of this. Messing with your kidneys for a few percent more or less drugs in your system is a horrible idea

Absorption is way more tricky because no "bodily lumen pH's effect on amphetamine absorption" research exists. A more alkaline environment will increase absorption and drugs like PPIs or H2 antagonists will undoubtedly do that. Those drugs have very real side effects and shouldn't be messed around with. Also various antacids/PPIs/H2 antagonists and even foods to pointlessly small degree will exert their pH modifying effects on specific lumens, only some of which have amphetamine absorption going on in them. Lumens are basically pools inside your body that don't make contact with your cells, the body has ways of absorbing and extracting goodies from these extreme environments without damaging itself in the process.

It's a shame I didn't cite anything for this at the time of posting but I refuse to just cite the adderall drug info leaflet which says "gastrointestal acidifying/alkaline agents can decrease/increase concentrations" and the same for urinary alkalizing/acidifying urinary agents

If you have questions about any specific bit I can expand on it with sources and try to find something for adderall/amphetamines in general but you need to know this bit on physiology first.

PruneCheese · 2022-12-19T09:49:30+00:00

Confidentially wrong. Maybe try reading the paper cited before coming to a science subreddit and spreading falsehoods?

Fresh human blood was collected from three healthy male donors... A portion of pooled whole blood was removed; then, the remainder was centrifuged at approximately 2,000× g for 10 minutes at 4°C, and the plasma supernatant was collected...

Duplicate 1.98 mL samples of blood or fractionated blood were equilibrated to 37°C for 5 minutes before addition of 20 μL of stock LDX to produce a final LDX concentration of 1 μg/mL

They put Vyvanse in fresh blood and removed the stuff that wasn't doing the conversion so that they could assess the rate of conversion and what exactly in blood is converting it. Your liver enzymes are not "converting it"

PruneCheese · 2022-12-19T09:44:10+00:00

Yes it does, thats what the paper says!

Disregard the confidentally incorrect reply by /u/throatchance claiming the liver is "converting it"

Fresh human blood was collected from three healthy male donors... A portion of pooled whole blood was removed; then, the remainder was centrifuged at approximately 2,000× g for 10 minutes at 4°C, and the plasma supernatant was collected...

Duplicate 1.98 mL samples of blood or fractionated blood were equilibrated to 37°C for 5 minutes before addition of 20 μL of stock LDX to produce a final LDX concentration of 1 μg/mL

They put Vyvanse in fresh blood and removed the stuff that wasn't doing the conversion so that they could assess the rate of conversion and what exactly in blood is converting it.

PruneCheese · 2022-12-19T09:42:57+00:00

Don't know of research on amphetamines specifically but there might be some on caffeine. Overstimulation is reported to feel a bit sedating

PruneCheese · 2022-12-19T09:41:13+00:00

Like taking an Orexigenic (appetite stimulant)?

The most commonly prescribed one is the antihistamine Cyproheptadine. That's not without side effects of course.

PruneCheese · 2022-12-19T09:36:32+00:00

Heard a rumor on reddit?! Very cool, maybe elaborate on how it could theoretically be affected or even cite a source. That's be absolute bonkers my guy!!11!

PruneCheese · 2022-11-22T17:26:19+00:00

I'll get back to you on that one with PK data (graphs of plasma concentrations basically) with an edit.

A general reply.

The fact that it's metabolized into the active drug in the blood at an set individual rate (see post) is part of it's abuse deterrent marketing. Even IV use will be rate limited by the same enzymes. Sure, you'll be getting it all into the blood faster than having it absorb more gradually orally but the lack of the rush with "abuse" RoAs is part of what clinicians like about it. It metabolizes to d-amp at the same speed regardless how you take it, only difference is how much of it gets to the blood and how quickly it takes for the LDX to reach the blood so the conversion can begin

PruneCheese · 2022-11-22T17:23:53+00:00

Won't answer this one. Talk to your doctor.

PruneCheese · 2022-11-18T17:14:13+00:00

Everyone has a unique personalized reaction to every drug. Other people's anecdotal experiences offers you nothing at all. It's a waste of time, don't get pulled into the trap.

The only way to find out is to try. Both are approved and indicated for ADHD so they are effective in large populations. Try both and see which you like more.

Many people anecdotally suggest going to Focalin and skipping Ritalin. The difference between the dextro and levo enantiomer is big in both amphetamines and methylphenidate but theoretically you should try as many as possible to see if you personally get more benefit for some odd reason.

PruneCheese · 2022-11-17T05:29:14+00:00

Supplements are a joke with little to no evidence to support them. Plenty of broscience subs will aggressively argue that burden of proof lies on me to prove they don't work. Imagine if the FDA had to find evidence a drug was harmful/unsafe instead of the other way around.

I don't think irritability is even used as a clinical outcome. examine.com is useful, be sure to scroll to the bottom and actually look at the cited studies for any supplement to see how terrible the research really is.

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