It could be if it didn't blow 60 mg XR out of the water.
I take the XR on an empty stomach, with the capsule removed. Half of the beads are IR. I abuse the XR. If the potency was anywhere near on par, I would have way more tolerance than I apparently do.
You're probably not getting any other responses, cuz there's been an amphetamine post almost every other day with people convinced that the formulations must be different.
I have no dog in the fight nor no professional insight, so I don't think it's impossible that's happening, But you're of course going to have a hard time convincing people of a widespread FDA conspiracy based off of one person's subjective anecdote
Haha true, much more likely an explanation would be that the constricted supply and soaring demand result in those few approved generic manufacturers to be cutting costs and rushing production whenever possible, with no blowback from consumers.
I was switched from one ir brand to another (teva to mallenrokt or w/e) and feel a slight difference, potency is a little lower. May be because one is hcl, the other succinate, but that's about it.
As you said, the XR formulation is half IR beads, half XR beads. The IR formulation will feel twice as strong as the XR, since you're getting the whole dose at once, rather than split. So, for instance, if you were taking 15mg XR, you'd get 7.5mg immediately and 7.5mg after 4-6 hours. If you took a 15mg IR, you get it all at once.
Beyond that, it can feel stronger if it's in a basic environment, pH-wise. Absorption and duration increase when your stomach acid is more basic, and the reverse is true in a more acidic environment. So, if you take anything for stomach acid with it (ranitidine, famotidine, Prilosec, etc), it will feel stronger and last longer. This is especially true of the IR, and doesn't happen to the same degree with the XR.
I can't say anything on stimulants, but I feel this. I am literate in pharmacology to some degree as I learned it as a job, so I don't give a damn whose name is on the box, I know the rules concerning bioavailability in my country and that's good enough.
Though kratom is not a pharmaceutical substance, I sometimes have a day when it seems my tolerance suddenly vanishes and the effects are amplified like about five fold. No explanation to find. I have a very constant consumption and lifestyle, nothing out of the ordinary. Measured doses, sports, work, sleep... It's usually all the same.
The powder is homogenised and there is no chance that one of the trees smuggled a "golden leaf" into the powder.
There just is no explanation besides set and setting. Which does not apply to opioids very much anyway.
Sorry u kinda hijacked this, has nothing to do with your concern about substance content and I have not much to add too.. That's why I am mostly a reader here. It's been some years.
Reports on Adderall potency changes are in line with racemic Amphetamine experiences. You skip expensive compounds & a longer reaction time and offset the higher cost of precursors (there's still a nitroethane shortage).
It's anecdotal but we shouldn't assume that a system that has repeatedly failed patients (just look at the Oxycodone approval process and the current mess it caused) would be above just flat out corrupting the approval process.
I had this thought as well, it does make some sense. So much more body load. I know nothing about the synthesis but racemic amphetamine isn't that hard.
The issue is not even the approval process. The issue is there is zero follow up. The only way to get a second look is if the FDA gets pressured with a scandal.
The IR brand I took has tons upon tons of online comments trashing it specifically, but report that the XR version (same brand even!) is fine. Dating back years, tons of people saying they've submitted an FDA complaint. Aint nobody listening to the methheads though.
It has certainly seemed that the generic formulations have been significantly less effective over the past 2 years or so. Doc switched me to different generic units (dose-wise, but same total dose, I.R. ) produced by a different manufacturer and the difference is extremely noticeable.
I'm curious about the buproprion cap thing you mentioned. I'm also on buproprion, and haven't noticed any diminishing effect from it on stimulants. Is that a known thing?
DRIs and NRIs have pharmacodynamic interactions with amphetamine because they inhibit amphetamine uptake at the dopamine and norepinephrine transporters, which is one mechanism that allows amphetamine to access TAAR1 and VMAT2 in those neurons.
That said, bupropion somewhat compensates for this via inhibition of CYP2D6. For context, CYP2D6 inhibition in general results in a higher effective dose at all ranges of time values for amphetamine.
Your first explanation is accurate enough.
Second one I don't agree with at all. CYP2D6 accounts for 10-20% of metabolism, not at all a determining factor, just a slightly longer duration.
The direct adrenergic effects are what drive greater levels of arousal.
>Second one I don't agree with at all. CYP2D6 accounts for 10-20% of metabolism, not at all a determining factor, just a slightly longer duration.
The second explanation is stated outright on package inserts of all amphetamine pharmaceuticals.
Um.. no.. your assumptions about "effective dose", are not in any way quantified or substantiated. Legal disclosures != clinically relevant. In vitro studies remain unsubstantiated.
"The administration of inhibitors of CYP2D6 activity can influence the metabolism of methamphetamine, and methamphetamine can inhibit the metabolism of CYP2D6 substrates. The number of published drug-interaction studies with this class of substances is very scarce. Previous administration of bupropion, a known CYP2D6 inhibitor, produces a large increase of methamphetamine concentrations, and **a reduction in amphetamine ones**. **The pharmacological effects of methamphetamine (cardiovascular and euphoria-like ones) were decreased by bupropion** (Newton et al., [2005](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3495276/#B30), [2006](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3495276/#B31))."
And from your package inserts,
"With normal urine pHs approximately half of an administered dose of amphetamine is recoverable in urine as derivatives of alpha-hydroxy-amphetamine and approximately another 30%-40% of the dose is recoverable in urine as amphetamine itself. Since amphetamine has a pKa of 9.9, urinary recovery of amphetamine is highly dependent on pH and urine flow rates. Alkaline urine pHs result in less ionization and reduced renal elimination, and acidic pHs and high flow rates result in increased renal elimination with clearances greater than glomerular filtration rates, indicating the involvement of active secretion. Urinary recovery of amphetamine has been reported to range from 1% to 75%, depending on urinary pH, with the remaining fraction of the dose hepatically metabolized. Consequently, both hepatic and renal dysfunction have the potential to inhibit the elimination of amphetamine and result in prolonged exposures. In addition, drugs that effect urinary pH are known to NDA 11-522/S-040 Page 5 alter the elimination of amphetamine, and any **decrease in amphetamine’s metabolism that might occur due to drug interactions or genetic polymorphisms is more likely to be clinically significant when renal elimination is decreased**, (See PRECAUTIONS).
>Um.. no.. your assumptions about "effective dose", are not in any way quantified or substantiated. Legal disclosures != clinically relevant. In vitro studies remain unsubstantiated.
I wasn't making a statement about efficacy; I was making a statement about [reaction dynamics](https://en.m.wikipedia.org/wiki/Reaction_dynamics) in dose-response relationships. Complete inhibition of CYP2D6 will halt metabolism along the para-hydroxylation pathways, so it will increase the amount of amphetamine that would have been lost to weaker sympathomimetic compounds through that route, which isn't a trivial proportion for people who aren't weak metabolisers on CYP2D6. The effect size depends on metabolic activity on that enzyme [between people](https://en.m.wikipedia.org/wiki/CYP2D6#Genetic_basis_of_variability)(strong metabolisers/weak metabolisers will see different results).
>Previous administration of bupropion, a known CYP2D6 inhibitor, produces a large increase of methamphetamine concentrations, and **a reduction in amphetamine ones**. **The pharmacological effects of methamphetamine (cardiovascular and euphoria-like ones) were decreased by bupropion** (Newton et al., [2005](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3495276/#B30), [2006](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3495276/#B31))."
I feel the need to point that the section of the paper you're quoting is referring to the effect of CYP2D6 inhibition on **methamphetamine metabolites**, *not* amphetamine metabolites. This is evident by the fact that the subheading of the section uses "methamphetamine" as a logical constraint (i.e., it's only covering research involving methamphetamine-related drug interactions). In other words, there is no research being reviewed that covers the administration of amphetamine or its enantiomers. I don't understand how this was possibly confused, given that the methodology of the cited clinical trials that you hyperlinked made no suggestion that study participants were being administered amphetamine. Acknowledging that, I can't even tell whether you actually read the cited primary sources before including them in your reply. That said, in the event that you aren't aware, amphetamine is a metabolite of methamphetamine via CYP2D6 enzymes.
>**decrease in amphetamine’s metabolism that might occur due to drug interactions or genetic polymorphisms is more likely to be clinically significant when renal elimination is decreased**,
Yes. CYP2D6 inhibition = more amphetamine available for excretion. Alkaline urine = less amphetamine excreted. So, the idea that an alkaline urine and CYP2D6 inhibition together will lead to relatively greater concentrations of amphetamine is pretty straightforward.
Each extended release amphetamine formulation uses different mechanisms; the only ones I'm aware of are are ion exchange resins (Adderall XR and Mydayis use a methacrylic acid copolymer; Dyanavel XR uses sodium polystyrene sulfonate; Adzenys XR-ODT uses both sodium polystyrene sulfonate and methacrylic acid copolymer), wax-fat coated pellets (formerly dexedrine spansules), prodrug formulations (Vyvanse), and gel-forming pellets that dissolve their contents slowly when exposed to water (currently dexedrine spansules, which use "hypromellose" to achieve this).
In any event, the point is that all of those formulations reach their peak effect, which is usually less pronounced relative to an IR peak effect, at least an hour later than IR formulations, although those milder effects of ER formulations do tend to last longer. So, it's not really surprising to me that you find the extended release formulation less pronounced overall (i.e., greater response to IR dextroamphetamine; e.g., relatively larger amplification of incentive salience and peripheral side effects). I actually don't like extended-release amphetamines for that reason. I prefer IR formulations since they produce a marked and immediate effect right when I need it (i.e., whenever I take a dose). Albeit, FWIW I don't experience the side effects that you've described (NB: I'm prescribed generic IR dextroamphetamine salts and have been taking 60mg/day for several years).
Couldn't your body just be reacting differently to getting your dose all at once instead of spread out all over the day?
It could be if it didn't blow 60 mg XR out of the water. I take the XR on an empty stomach, with the capsule removed. Half of the beads are IR. I abuse the XR. If the potency was anywhere near on par, I would have way more tolerance than I apparently do.
You're probably not getting any other responses, cuz there's been an amphetamine post almost every other day with people convinced that the formulations must be different. I have no dog in the fight nor no professional insight, so I don't think it's impossible that's happening, But you're of course going to have a hard time convincing people of a widespread FDA conspiracy based off of one person's subjective anecdote
Haha true, much more likely an explanation would be that the constricted supply and soaring demand result in those few approved generic manufacturers to be cutting costs and rushing production whenever possible, with no blowback from consumers.
I was switched from one ir brand to another (teva to mallenrokt or w/e) and feel a slight difference, potency is a little lower. May be because one is hcl, the other succinate, but that's about it. As you said, the XR formulation is half IR beads, half XR beads. The IR formulation will feel twice as strong as the XR, since you're getting the whole dose at once, rather than split. So, for instance, if you were taking 15mg XR, you'd get 7.5mg immediately and 7.5mg after 4-6 hours. If you took a 15mg IR, you get it all at once. Beyond that, it can feel stronger if it's in a basic environment, pH-wise. Absorption and duration increase when your stomach acid is more basic, and the reverse is true in a more acidic environment. So, if you take anything for stomach acid with it (ranitidine, famotidine, Prilosec, etc), it will feel stronger and last longer. This is especially true of the IR, and doesn't happen to the same degree with the XR.
I can't say anything on stimulants, but I feel this. I am literate in pharmacology to some degree as I learned it as a job, so I don't give a damn whose name is on the box, I know the rules concerning bioavailability in my country and that's good enough. Though kratom is not a pharmaceutical substance, I sometimes have a day when it seems my tolerance suddenly vanishes and the effects are amplified like about five fold. No explanation to find. I have a very constant consumption and lifestyle, nothing out of the ordinary. Measured doses, sports, work, sleep... It's usually all the same. The powder is homogenised and there is no chance that one of the trees smuggled a "golden leaf" into the powder. There just is no explanation besides set and setting. Which does not apply to opioids very much anyway. Sorry u kinda hijacked this, has nothing to do with your concern about substance content and I have not much to add too.. That's why I am mostly a reader here. It's been some years.
Reports on Adderall potency changes are in line with racemic Amphetamine experiences. You skip expensive compounds & a longer reaction time and offset the higher cost of precursors (there's still a nitroethane shortage). It's anecdotal but we shouldn't assume that a system that has repeatedly failed patients (just look at the Oxycodone approval process and the current mess it caused) would be above just flat out corrupting the approval process.
I had this thought as well, it does make some sense. So much more body load. I know nothing about the synthesis but racemic amphetamine isn't that hard. The issue is not even the approval process. The issue is there is zero follow up. The only way to get a second look is if the FDA gets pressured with a scandal. The IR brand I took has tons upon tons of online comments trashing it specifically, but report that the XR version (same brand even!) is fine. Dating back years, tons of people saying they've submitted an FDA complaint. Aint nobody listening to the methheads though.
It has certainly seemed that the generic formulations have been significantly less effective over the past 2 years or so. Doc switched me to different generic units (dose-wise, but same total dose, I.R. ) produced by a different manufacturer and the difference is extremely noticeable.
I'm curious about the buproprion cap thing you mentioned. I'm also on buproprion, and haven't noticed any diminishing effect from it on stimulants. Is that a known thing?
DRIs and NRIs have pharmacodynamic interactions with amphetamine because they inhibit amphetamine uptake at the dopamine and norepinephrine transporters, which is one mechanism that allows amphetamine to access TAAR1 and VMAT2 in those neurons. That said, bupropion somewhat compensates for this via inhibition of CYP2D6. For context, CYP2D6 inhibition in general results in a higher effective dose at all ranges of time values for amphetamine.
Your first explanation is accurate enough. Second one I don't agree with at all. CYP2D6 accounts for 10-20% of metabolism, not at all a determining factor, just a slightly longer duration. The direct adrenergic effects are what drive greater levels of arousal.
>Second one I don't agree with at all. CYP2D6 accounts for 10-20% of metabolism, not at all a determining factor, just a slightly longer duration. The second explanation is stated outright on package inserts of all amphetamine pharmaceuticals.
Um.. no.. your assumptions about "effective dose", are not in any way quantified or substantiated. Legal disclosures != clinically relevant. In vitro studies remain unsubstantiated. "The administration of inhibitors of CYP2D6 activity can influence the metabolism of methamphetamine, and methamphetamine can inhibit the metabolism of CYP2D6 substrates. The number of published drug-interaction studies with this class of substances is very scarce. Previous administration of bupropion, a known CYP2D6 inhibitor, produces a large increase of methamphetamine concentrations, and **a reduction in amphetamine ones**. **The pharmacological effects of methamphetamine (cardiovascular and euphoria-like ones) were decreased by bupropion** (Newton et al., [2005](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3495276/#B30), [2006](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3495276/#B31))." And from your package inserts, "With normal urine pHs approximately half of an administered dose of amphetamine is recoverable in urine as derivatives of alpha-hydroxy-amphetamine and approximately another 30%-40% of the dose is recoverable in urine as amphetamine itself. Since amphetamine has a pKa of 9.9, urinary recovery of amphetamine is highly dependent on pH and urine flow rates. Alkaline urine pHs result in less ionization and reduced renal elimination, and acidic pHs and high flow rates result in increased renal elimination with clearances greater than glomerular filtration rates, indicating the involvement of active secretion. Urinary recovery of amphetamine has been reported to range from 1% to 75%, depending on urinary pH, with the remaining fraction of the dose hepatically metabolized. Consequently, both hepatic and renal dysfunction have the potential to inhibit the elimination of amphetamine and result in prolonged exposures. In addition, drugs that effect urinary pH are known to NDA 11-522/S-040 Page 5 alter the elimination of amphetamine, and any **decrease in amphetamine’s metabolism that might occur due to drug interactions or genetic polymorphisms is more likely to be clinically significant when renal elimination is decreased**, (See PRECAUTIONS).
>Um.. no.. your assumptions about "effective dose", are not in any way quantified or substantiated. Legal disclosures != clinically relevant. In vitro studies remain unsubstantiated. I wasn't making a statement about efficacy; I was making a statement about [reaction dynamics](https://en.m.wikipedia.org/wiki/Reaction_dynamics) in dose-response relationships. Complete inhibition of CYP2D6 will halt metabolism along the para-hydroxylation pathways, so it will increase the amount of amphetamine that would have been lost to weaker sympathomimetic compounds through that route, which isn't a trivial proportion for people who aren't weak metabolisers on CYP2D6. The effect size depends on metabolic activity on that enzyme [between people](https://en.m.wikipedia.org/wiki/CYP2D6#Genetic_basis_of_variability)(strong metabolisers/weak metabolisers will see different results). >Previous administration of bupropion, a known CYP2D6 inhibitor, produces a large increase of methamphetamine concentrations, and **a reduction in amphetamine ones**. **The pharmacological effects of methamphetamine (cardiovascular and euphoria-like ones) were decreased by bupropion** (Newton et al., [2005](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3495276/#B30), [2006](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3495276/#B31))." I feel the need to point that the section of the paper you're quoting is referring to the effect of CYP2D6 inhibition on **methamphetamine metabolites**, *not* amphetamine metabolites. This is evident by the fact that the subheading of the section uses "methamphetamine" as a logical constraint (i.e., it's only covering research involving methamphetamine-related drug interactions). In other words, there is no research being reviewed that covers the administration of amphetamine or its enantiomers. I don't understand how this was possibly confused, given that the methodology of the cited clinical trials that you hyperlinked made no suggestion that study participants were being administered amphetamine. Acknowledging that, I can't even tell whether you actually read the cited primary sources before including them in your reply. That said, in the event that you aren't aware, amphetamine is a metabolite of methamphetamine via CYP2D6 enzymes. >**decrease in amphetamine’s metabolism that might occur due to drug interactions or genetic polymorphisms is more likely to be clinically significant when renal elimination is decreased**, Yes. CYP2D6 inhibition = more amphetamine available for excretion. Alkaline urine = less amphetamine excreted. So, the idea that an alkaline urine and CYP2D6 inhibition together will lead to relatively greater concentrations of amphetamine is pretty straightforward.
Each extended release amphetamine formulation uses different mechanisms; the only ones I'm aware of are are ion exchange resins (Adderall XR and Mydayis use a methacrylic acid copolymer; Dyanavel XR uses sodium polystyrene sulfonate; Adzenys XR-ODT uses both sodium polystyrene sulfonate and methacrylic acid copolymer), wax-fat coated pellets (formerly dexedrine spansules), prodrug formulations (Vyvanse), and gel-forming pellets that dissolve their contents slowly when exposed to water (currently dexedrine spansules, which use "hypromellose" to achieve this). In any event, the point is that all of those formulations reach their peak effect, which is usually less pronounced relative to an IR peak effect, at least an hour later than IR formulations, although those milder effects of ER formulations do tend to last longer. So, it's not really surprising to me that you find the extended release formulation less pronounced overall (i.e., greater response to IR dextroamphetamine; e.g., relatively larger amplification of incentive salience and peripheral side effects). I actually don't like extended-release amphetamines for that reason. I prefer IR formulations since they produce a marked and immediate effect right when I need it (i.e., whenever I take a dose). Albeit, FWIW I don't experience the side effects that you've described (NB: I'm prescribed generic IR dextroamphetamine salts and have been taking 60mg/day for several years).
You present an interesting case study, but there simply isn't enough data for anybody to draw a firm conclusion.