Amphetamine Neurotoxicity and Tolerance Reduction/Prevention III

[MocCozmiK]

I came across this article and thought it was pretty interesting.

http://journal.frontiersin.org/article/10.3389/fnsys.2014.00038/full

Basically explains how psychostimulants like methylphenidate, and amphetamine alter glutamate function, and may impair behavioral flexibility.
Healthy individuals run the risk of pushing themselves beyond optimal levels into hyperdopaminergic and hypernoradrenergic states, basically destroying the very behaviors they are striving to improve.

At optimal doses, dopamine binds to higher-affinity D1-like receptors, and norepinephrine binds to α2 receptors, leading to an increase in prefrontal cortical signal-to-noise ratio and enhancing the flow of information and strengthening neuronal communication.
When the levels of dopamine and norepinephrine rise beyond the optimal levels, they begin to activate dopamine D2-class receptors and noradrenergic α1 and β receptors, which leads to weakening of the signal-to-noise ratio via activation of neurons that may not be involved in the current

I have heard of people who take amphetamine/dex (adderall) with a very small dose of methylphenidate (ritalin) Because the ritalin is neuroprotective towards the amphetamine. Yeah, you are not going to get any euphoria, or recreation out of the Ritalin, it is primarily taken to protect the brain from amphetamines neurotoxicity.

Amphetamine competes with dopamine for a common binding site on the striatal Dopamine transporter So, both empirical calculation and experimental evidence may support the assumption that Methylphenidate, at least at low concentrations, may be actively transported by the DAT into dopaminergic neurons which may support the first possible mechanism of methylphenidate neuroprotection. These neuroprotective effects of Methylphenidate may be due, at least in part, to its ability to attenuate or prevent abnormal cytoplasmic dopamine accumulation in dopaminergic neurons by modulating the activity of the DAT and the VMAT-2 through several neuropharmacological mechanisms.

But good luck trying to talk a doctor into prescribing anyone a small dose of methylphenidate (Ritalin) with adderall/dex

 

[Razzic]

I came across this article and thought it was pretty interesting.

http://journal.frontiersin.org/article/10.3389/fnsys.2014.00038/full

Basically explains how psychostimulants like methylphenidate, and amphetamine alter glutamate function, and may impair behavioral flexibility.
Healthy individuals run the risk of pushing themselves beyond optimal levels into hyperdopaminergic and hypernoradrenergic states, basically destroying the very behaviors they are striving to improve.

At optimal doses, dopamine binds to higher-affinity D1-like receptors, and norepinephrine binds to α2 receptors, leading to an increase in prefrontal cortical signal-to-noise ratio and enhancing the flow of information and strengthening neuronal communication.
When the levels of dopamine and norepinephrine rise beyond the optimal levels, they begin to activate dopamine D2-class receptors and noradrenergic α1 and β receptors, which leads to weakening of the signal-to-noise ratio via activation of neurons that may not be involved in the current

I have heard of people who take amphetamine/dex (adderall) with a very small dose of methylphenidate (ritalin) Because the ritalin is neuroprotective towards the amphetamine. Yeah, you are not going to get any euphoria, or recreation out of the Ritalin, it is primarily taken to protect the brain from amphetamines neurotoxicity.

Amphetamine competes with dopamine for a common binding site on the striatal Dopamine transporter So, both empirical calculation and experimental evidence may support the assumption that Methylphenidate, at least at low concentrations, may be actively transported by the DAT into dopaminergic neurons which may support the first possible mechanism of methylphenidate neuroprotection. These neuroprotective effects of Methylphenidate may be due, at least in part, to its ability to attenuate or prevent abnormal cytoplasmic dopamine accumulation in dopaminergic neurons by modulating the activity of the DAT and the VMAT-2 through several neuropharmacological mechanisms.

But good luck trying to talk a doctor into prescribing anyone a small dose of methylphenidate (Ritalin) with adderall/dex

That is exactly the article I read. And mirrored exactly how others and myself are feeling after larger doses of dexamphetamine. At first (up to about 5mg twice daily and to a shorter extent 10mg twice daily short term till this problem occurred) this helped memory a lot and would explain the reaction with D1 Dopamine receptors. But afterwards activates D2-class receptors whilst turning off D1. So you get that wakeful feeling etc but without the great memory that I / we (other users) had at first. Also would explain why some users complain a lot about short term memory issues on higher doses of dex long term.

Really glad you found that article again. I read it and then couldn't find it again. I've read the same elsewhere also which kind of just reinforced the fact it was correct.

I do have access to Ritalin and Dexamphetamine, although my guy normally prescribes them at different times but taking low doses of both from what I read protects and gives you the benefit of both. Some say it is a bigger risk to the cardiovascular system, but I would have to disagree as if this works taking a low dosage for both then it would be the same or even BETTER than taking a high dosage of a single product.

The question would be at what dosage would ritalin be a protective to the negative dexamphetamine effects on the dopamine receptors. I would go so far as to say even half a tablet (5mg) but since the half life of ritalin is so much shorter than dex (average 3.5 hours, ranging from 1.3 to 7.7 in adults) and dex 8 - 11 hours maybe once the optimum dosage is found out to then switch to LA ritalin, although this may not be necessary for the pure protection aspect side of things (could just dose it twice the same as Dex)

Comments are very welcome on this.

I've seen it discussed elsewhere and even prescribed to a few people (although seldom) and always seems to be a low dose of Methylphenidate with a low to moderate dosage of dex.

*************Edit took my first dosage of Ritalin (split it 5mg then felt it but not really enough so took the other half of 5mg of total 10mg tablet) and I feel like a zombie, objects and lights seem to be the only thing I can really concentrate on for the past hour. Studying is beyond useless. So perhaps even 2.5mg as a protective agent (def no more than 5mg) for dex.

 

[Razzic]

I came across this article and thought it was pretty interesting.

http://journal.frontiersin.org/article/10.3389/fnsys.2014.00038/full

Basically explains how psychostimulants like methylphenidate, and amphetamine alter glutamate function, and may impair behavioral flexibility.
Healthy individuals run the risk of pushing themselves beyond optimal levels into hyperdopaminergic and hypernoradrenergic states, basically destroying the very behaviors they are striving to improve.

At optimal doses, dopamine binds to higher-affinity D1-like receptors, and norepinephrine binds to α2 receptors, leading to an increase in prefrontal cortical signal-to-noise ratio and enhancing the flow of information and strengthening neuronal communication.
When the levels of dopamine and norepinephrine rise beyond the optimal levels, they begin to activate dopamine D2-class receptors and noradrenergic α1 and β receptors, which leads to weakening of the signal-to-noise ratio via activation of neurons that may not be involved in the current

I have heard of people who take amphetamine/dex (adderall) with a very small dose of methylphenidate (ritalin) Because the ritalin is neuroprotective towards the amphetamine. Yeah, you are not going to get any euphoria, or recreation out of the Ritalin, it is primarily taken to protect the brain from amphetamines neurotoxicity.

Amphetamine competes with dopamine for a common binding site on the striatal Dopamine transporter So, both empirical calculation and experimental evidence may support the assumption that Methylphenidate, at least at low concentrations, may be actively transported by the DAT into dopaminergic neurons which may support the first possible mechanism of methylphenidate neuroprotection. These neuroprotective effects of Methylphenidate may be due, at least in part, to its ability to attenuate or prevent abnormal cytoplasmic dopamine accumulation in dopaminergic neurons by modulating the activity of the DAT and the VMAT-2 through several neuropharmacological mechanisms.

But good luck trying to talk a doctor into prescribing anyone a small dose of methylphenidate (Ritalin) with adderall/dex

My other post I didn't try the combination yet although I'm pretty confidence reading other peoples posts on various forums would do me no harm. Some are taking (apparently) 15mg of each, although they seem to get a different benefit out of each separately, where as I get zero from Ritalin apart from a slightly awake feeling (which could of been the coffee to be honest) of half a tab (so 5mg of the 10mg tab)

The biggest thing people have to say is how bad it would be for the cardiovascular system, which I could honestly not see a problem with, SPECIFICALLY if you take a lower does overall of dex due to the extremely small amount of ritalin you would need.

Found this also

http://jpet.aspetjournals.org/content/304/3/1181.abstract

Results reveal that methylphenidate post-treatment both prevents the persistent dopamine deficits and reverses the acute decreases in vesicular dopamine uptake and VMAT-2 ligand binding caused by methamphetamine treatment. In addition, methylphenidate post-treatment reverses the acute decreases in vesicular dopamine content caused by methamphetamine treatment. Taken together, these findings suggest that methylphenidate prevents persistent methamphetamine-induced dopamine deficits by redistributing vesicles and the associated VMAT-2 protein and presumably affecting dopamine sequestration. These findings not only provide insight into the neurotoxic effects of methamphetamine but also mechanisms underlying dopamine neurodegenerative disorders, including Parkinson's disease.

 

[Razzic]

This may be of interest:

Fish oil has been shown to be protective against amphetamine toxicity model Parkinsons disease:



Also, here's a good review article of amphetamine toxicity:

Aye cheers for that , I actually already take fish oil for the anti-inflammatory properties and anti-cancer properties, found that out AFTER I was trying to find out if it helps for ADD (it did but had to take pure EPA without DHA, which does not matter since EPA is readily transferred into DHA if needed but a LOT harder the other way around) plus helped with depressed, PLUS EPA was more anti-inflammatory which is great for us taking dex.

Just working on how to stop down regulation of D1 dopamine further and a2 norepinephrine receptors (if its not too late already) and perhaps reverse this. Or at LEAST find something that has a upregulation effect on these to help.

 

[MocCozmiK]

That is exactly the article I read. And mirrored exactly how others and myself are feeling after larger doses of dexamphetamine. At first (up to about 5mg twice daily and to a shorter extent 10mg twice daily short term till this problem occurred) this helped memory a lot and would explain the reaction with D1 Dopamine receptors. But afterwards activates D2-class receptors whilst turning off D1. So you get that wakeful feeling etc but without the great memory that I / we (other users) had at first. Also would explain why some users complain a lot about short term memory issues on higher doses of dex long term.

Really glad you found that article again. I read it and then couldn't find it again. I've read the same elsewhere also which kind of just reinforced the fact it was correct.

I do have access to Ritalin and Dexamphetamine, although my guy normally prescribes them at different times but taking low doses of both from what I read protects and gives you the benefit of both. Some say it is a bigger risk to the cardiovascular system, but I would have to disagree as if this works taking a low dosage for both then it would be the same or even BETTER than taking a high dosage of a single product.

The question would be at what dosage would ritalin be a protective to the negative dexamphetamine effects on the dopamine receptors. I would go so far as to say even half a tablet (5mg) but since the half life of ritalin is so much shorter than dex (average 3.5 hours, ranging from 1.3 to 7.7 in adults) and dex 8 - 11 hours maybe once the optimum dosage is found out to then switch to LA ritalin, although this may not be necessary for the pure protection aspect side of things (could just dose it twice the same as Dex)

Comments are very welcome on this.

I've seen it discussed elsewhere and even prescribed to a few people (although seldom) and always seems to be a low dose of Methylphenidate with a low to moderate dosage of dex.

*************Edit took my first dosage of Ritalin (split it 5mg then felt it but not really enough so took the other half of 5mg of total 10mg tablet) and I feel like a zombie, objects and lights seem to be the only thing I can really concentrate on for the past hour. Studying is beyond useless. So perhaps even 2.5mg as a protective agent (def no more than 5mg) for dex.

I am currently prescribed 90mg of adderall IR daily, but only take 60mg daily, sometimes only 30mg. Just because I have taken adderall so long, I did some experimenting to find out if I even needed that much. There was no noticeable difference between 90 and 60mg, and some days even 30.
I only had access to about 2 months or so of Ritalin. And I only wanted to add Ritalin to the mix, because of the neuroprotective effects I read about. I started out with 5mg Ritalin, and felt no effects, which I didn't expect to feel anything, due to the fact that it was a small dose and I was taking it only as a neuroprotective aspects. But I upped the dose to 10mg of Ritalin, but taking only 5mg about 30 minutes before first dose of adderall. And same with second dose (on the second dose, using on 10mg)
So in total using 15mg per day of Ritalin. I did feel a slight bit more motivated on the 2nd dose. I contributed it a possible placebo effect though.
I am not sure that using this combo for such a short period of time is able to produce any neuroprotective qualities.

One thing I did notice concerning cardiovascular effects, is that my Fitbit showed my heart rate Bpm was slightly elevated, even at resting. I didn't feel any different. No physically noticeable signs of fast heart rate. About 2 days without the Ritalin, my heart rate went back to the normal resting Bpm.
The elevated heart rate Bpm was not hugely significant. But it was higher, when I threw Ritalin into the mix.
So I do think that is something to look at or to be considered.

 

[Razzic]

I am currently prescribed 90mg of adderall IR daily, but only take 60mg daily, sometimes only 30mg. Just because I have taken adderall so long, I did some experimenting to find out if I even needed that much. There was no noticeable difference between 90 and 60mg, and some days even 30.
I only had access to about 2 months or so of Ritalin. And I only wanted to add Ritalin to the mix, because of the neuroprotective effects I read about. I started out with 5mg Ritalin, and felt no effects, which I didn't expect to feel anything, due to the fact that it was a small dose and I was taking it only as a neuroprotective aspects. But I upped the dose to 10mg of Ritalin, but taking only 5mg about 30 minutes before first dose of adderall. And same with second dose (on the second dose, using on 10mg)
So in total using 15mg per day of Ritalin. I did feel a slight bit more motivated on the 2nd dose. I contributed it a possible placebo effect though.
I am not sure that using this combo for such a short period of time is able to produce any neuroprotective qualities.

One thing I did notice concerning cardiovascular effects, is that my Fitbit showed my heart rate Bpm was slightly elevated, even at resting. I didn't feel any different. No physically noticeable signs of fast heart rate. About 2 days without the Ritalin, my heart rate went back to the normal resting Bpm.
The elevated heart rate Bpm was not hugely significant. But it was higher, when I threw Ritalin into the mix.
So I do think that is something to look at or to be considered.

Great to hear from another person who has taken both

Yeah you wouldn't feel anything from Neuroprotective benefits same as people say you don't feel anything from Neurotoxicity, although I'm sure there would be some signs.

I feel the same way with dex most of the time, first dosage helps but second dosage helps more, I'm guessing this is because there is more in your system as the half life is so damn long (up to around 8 - 11 hours) Ritalin is around 3.5 on average, however I think it would stop most of the damage being done while it is being synthesized from dex as it is at peak levels and effectiveness around the 1 hour mark, which is around the same as Ritalin, wearing off around the same time (for peak effectiveness) 3 hour mark. http://jpet.aspetjournals.org/content/304/3/1181.abstract (from which I pasted a couple of posts back) verifies this also.

Funny thing (I noticed anyway) is that it actually seems to work post-treatment to some degree also from that article. *Results reveal that methylphenidate post-treatment both prevents the persistent dopamine deficits and reverses the acute decreases in vesicular dopamine uptake and VMAT-2 ligand binding caused by methamphetamine treatment. In addition, methylphenidate post-treatment reverses the acute decreases in vesicular dopamine content caused by methamphetamine treatment.*

But then does go on to say prior treatment would be best, (of course stopping it from happening in the first place is better) but at least if something weird happened (as everyone is different) it would be possible to get benefits from post treatment also, the good thing about that being Ritalin / Methylphenidate has such a short half life it doesn't effect sleep quality like dex does.

I will talk to my doctor about this, he knows I study Neurobiology and biochem subjects of interest a lot (in my spare time and at uni, although only minor on the subjects not my topic of centration although this may change in the future) so is pretty confident in my medication taking abilities (due to our history together also) and adjusting my dosages, however has been iffy on mixing substances in the past. Maybe can convince him at very very low doses such as 2.5 mg - 5 mg max. I hated the feeling of 10 mg (for me) within a short space of time when I took x5 mg so maybe either more time needs to be between doses (at least 4 hours I'm thinking) or just once a day with one dex.

Did you notice your dex last longer also? Was thinking this might be possible as Ritalin blocks the reuptake along with the dex it could make the effective time dex works for you (without significantly increasing half life) longer, which would be fantastic since I seem to get 2 - 3 hours out of it even taking it with a urine alkaliser.

 

[MocCozmiK]

I didn't notice it lasting any longer. But I have been on adderall a long time 10+ years. So at this point I was mainly looking for any neuroprotective qualities.
I sure wish I would have known about the post treatment with methylphenidate. Let us know if you are able to try with the lower doses and how it goes.

 

[Razzic]

I didn't notice it lasting any longer. But I have been on adderall a long time 10+ years. So at this point I was mainly looking for any neuroprotective qualities.
I sure wish I would have known about the post treatment with methylphenidate. Let us know if you are able to try with the lower doses and how it goes.

Sorry I haven't been around, just an update.

Yesterday I had my dex (starting to get a bit of tolerance even after post holiday due to exams so upping the dose) went from 5mg and split the second tablet , so took 7.5mg. I was severely sick though (unrelated to dex) so had another half tab about 2 hours later as I thought most of it hadn't been digested. After that about an hour later I took 1/4 a tablet of Ritalin and was really really good.

My partner has noticed this difference more than a few times now. My memory goes off the chart. But importantly I think it is the timing I HAVE to get correct. Too late and I'm like a zombie as like I normally react to Ritalin. If I could describe it I kinda feel not all there at all. So using it I think around the hour mark (when dex has peaked and kicked in) makes it stay around for longer. Would make sense in how Ritalin acts. As mentioned previously I have tried it PRE dex and it it didn't work great at all. Again because of the mechanism of Ritalin I could see why, would stop most of the dex working.

Ultimately I barely slept last night so today was a bit different for me and I took the Ritalin too late so again I feel like a zombie. But the sleep was not due to the meds, mostly have a lot of my mind. (Lack of money, lack of solid place to live and questioning which uni campus I'm going to due to that and fighting some appeals etc) and on top of that exam time so its pretty shit.

At least I'm pretty confident I will pass the exam. Prior to the combo my memory is severely bad and seemed to be getting worse. Asked the Psychiatrist and he is kinda dumbfounded as to why. I've always had a pretty bad memory though unless I thoroughly enjoy what I'm doing or have a really bad event. So yeah 100% inattentive type.

 

[MocCozmiK]

Hope the exam went ok man..

 

[Pharmokinetictal]

So I think it's really important to understand that Dexedrine is not at all the same as methamphetamine. Meth is more potent and also affects 5HT to a much higher degree. Dex is actually fairly safe. Much safer than Ritalin...which acts more like cocaine than amphetamine. I wouldn't compare adderall or dex to meth in any further readings. Meth IS neurotoxic. Dex is not. Ritalin is more likely to be neurotoxic, especially combined with dex at the point in its pharmacokinetic profile where the DATs are finally being dephosphorylated and allowed to function properly (i.e. Recycle dopamine). It may help extend your effective half life, but it's really just adding another dopaminergic agent to the tail end of the one you're coming down from.

My suggestion would be to eat protein throughout the day, take your dex with TUMS to increase absorption and feed your body. I imagine that adding Ritalin would actually increase the chances of creating neurotoxicity simply through prolonging DAT inactivation and subsequent post synaptic Dopamine (and therefore NMDA-mediated glutamate) excitation. You're creating a constant EPSP downstream in your nigrostriatal reward pathway and likely increasing CREB induced modification of your D1/2 receptors.

Ritalin only mitigates methamphetamine induced apoptosis by sequestering DAT-mediated chaperoning of meth into the presynaptic neuron--where it wreaks havoc. Dex and adderall actually have Neuropore tive effects all on their own when not abused.

I know it sucks but maybe just cut back to 30mg for a few weeks and see what happens. Or switch to Ritalin completely and switch back in a month.

 

[aced126]

So I think it's really important to understand that Dexedrine is not at all the same as methamphetamine. Meth is more potent and also affects 5HT to a much higher degree. Dex is actually fairly safe. Much safer than Ritalin...which acts more like cocaine than amphetamine. I wouldn't compare adderall or dex to meth in any further readings. Meth IS neurotoxic. Dex is not. Ritalin is more likely to be neurotoxic, especially combined with dex at the point in its pharmacokinetic profile where the DATs are finally being dephosphorylated and allowed to function properly (i.e. Recycle dopamine). It may help extend your effective half life, but it's really just adding another dopaminergic agent to the tail end of the one you're coming down from.

My suggestion would be to eat protein throughout the day, take your dex with TUMS to increase absorption and feed your body. I imagine that adding Ritalin would actually increase the chances of creating neurotoxicity simply through prolonging DAT inactivation and subsequent post synaptic Dopamine (and therefore NMDA-mediated glutamate) excitation. You're creating a constant EPSP downstream in your nigrostriatal reward pathway and likely increasing CREB induced modification of your D1/2 receptors.

Ritalin only mitigates methamphetamine induced apoptosis by sequestering DAT-mediated chaperoning of meth into the presynaptic neuron--where it wreaks havoc. Dex and adderall actually have Neuropore tive effects all on their own when not abused.

I know it sucks but maybe just cut back to 30mg for a few weeks and see what happens. Or switch to Ritalin completely and switch back in a month.

Do you have literature which suggests Ritalin and other DRIs are neurotoxic (to the same extent to releasing agents like methamphetamine and dexamphetamine)?

Also I wanted to raise a discussion when you pointed out that tums increase dexamphetamine absorption.

Stomach pH is very acidic (pH 1-2) and that means essentially more than 99% of dexamphetamine (pKa of protonated dexamphetamine ~ 10) molecules are protonated in the stomach and cannot be transported into the bloodstream from there. It is of my understanding that most of the amphetamine is actually absorbed from the ileum normally (pH ~ 7-7.5, much more reasonable).

Now, I did a little calculation to see to what extent taking a tablet of tums would raise the pH of the stomach to, and I found that (using typical values from this website: http://www.livestrong.com/article/476461-average-amount-of-stomach-acid-in-the-human-stomach/) depending on the what values you use, you could actually have the carbonate ions (1 Tums 500 tablet contains 5x10^-3 moles of carbonate ions) reacting with all​ the stomach acid. This is probably not what happens, and I'd think that the stomach will secrete more acid in response to this. I could not imagine the pH of the stomach going above 4 or so, as it is crucial that the stomach is acidic.

With that said, I would suggest that the amount of amphetamine (or any amine for that matter) absorbed from the stomach, with or without tums, is negligible to the amount absorbed in the ileum. Any thoughts or opinions on this matter are appreciated.

 

[Pharmokinetictal]

Do you have literature which suggests Ritalin and other DRIs are neurotoxic (to the same extent to releasing agents like methamphetamine and dexamphetamine)?

Also I wanted to raise a discussion when you pointed out that tums increase dexamphetamine absorption.

Stomach pH is very acidic (pH 1-2) and that means essentially more than 99% of dexamphetamine (pKa of protonated dexamphetamine ~ 10) molecules are protonated in the stomach and cannot be transported into the bloodstream from there. It is of my understanding that most of the amphetamine is actually absorbed from the ileum normally (pH ~ 7-7.5, much more reasonable). With that said, I would suggest that the amount of amphetamine (or any amine for that matter) absorbed from the stomach, with or without tums, is negligible to the amount absorbed in the ileum. Any thoughts or opinions on this matter are appreciated.

Nice response, dude. I like when people remain empathetically engaged in discussions about what drugs they put in their body. It's a fun learning process! So...

Firstly, it's really vital to recognize that the effects of AMPH and MPH are highly dependent on whether the drug is abused AND whether or not the user really has ADHD. ADHD patients tend to show much better tolerability of all psychostimulants compared to otherwise recreational users. Also, studies done on mice, rats, and even primates at does 40x higher than a human's is not a really good way to determine if AMPH or MPH is more toxic than the other. We'd literally need to look at your brain after it's been sliced, stained, milkshaked, and blotted for specific biomarkers. But I'm certain that experiment is more toxic to your brain than drinking bleech. So in the meantime, take any toxicology evaluation with a heavy grain of AMPH SALT. That said, regarding pH and absorption...

I just pulled this off wiki and I checked their sources; they're legit. I'm a parkinson's disease research scientist, so I usually will give you papers when I can. But trust me, taking 2-3 tums with dexedrine will definitely create a marked effect both in perceivable time of onset and also potency. Now it's not always the most comfortable thing. You're likely right that the stomach compensates by producing more HCl because I've experienced mild acid reflux doing this. But I tried it at my gf's behest and I was shocked at the results. So trust me there and read below:

"The oral bioavailability of amphetamine varies with gastrointestinal pH;[142-quoted below] it is well absorbed from the gut, and bioavailability is typically over 75% for dextroamphetamine.[2] Amphetamine is a weak base with a pKa of 9–10;[4] consequently, when the pH is basic, more of the drug is in its lipid soluble free base form, and more is absorbed through the lipid-rich cell membranes of the gut epithelium.[4][142] Conversely, an acidic pH means the drug is predominantly in a water-soluble cationic (salt) form, and less is absorbed.[4] Approximately 15–40% of amphetamine circulating in the bloodstream is bound to plasma proteins.[3]

The half-life of amphetamine enantiomers differ and vary with urine pH.[4] At normal urine pH, the half-lives of dextroamphetamine and levoamphetamine are 9–11 hours and 11–14 hours, respectively.[4] An acidic diet will reduce the enantiomer half-lives to 8–11 hours; an alkaline diet will increase the range to 16–31 hours.[10][16] The immediate-release and extended release variants of salts of both isomers reach peak plasma concentrations at 3 hours and 7 hours post-dose respectively.[4] Amphetamine is eliminated via the kidneys, with 30–40% of the drug being excreted unchanged at normal urinary pH.[4] When the urinary pH is basic, amphetamine is in its free base form, so less is excreted.[4] When urine pH is abnormal, the urinary recovery of amphetamine may range from a low of 1% to a high of 75%, depending mostly upon whether urine is too basic or acidic, respectively.[4]"

I also gathered, from the FDA and Shire, Inc., this document on prescribing amphetamine. This is [142] from the above passages:
"Alkalinizing Agents
Gastrointestinal alkalinizing agents (e.g., sodium bicarbonate) increase absorption of amphetamines. Co-administration of ADDERALL XR and
gastrointestinal alkalinizing agents, such as antacids, should be avoided. Urinary alkalinizing agents (acetazolamide, some thiazides) increase the
concentration of the non-ionized species of the amphetamine molecule, thereby decreasing urinary excretion. Both groups of agents increase
blood levels and therefore potentiate the actions of amphetamines.

Acidifying Agents
Gastrointestinal acidifying agents (e.g., guanethidine, reserpine, glutamic acid HCl, ascorbic acid) lower absorption of amphetamines. Urinary
acidifying agents (e.g., ammonium chloride, sodium acid phosphate, methenamine salts) increase the concentration of the ionized species of the
amphetamine molecule, thereby increasing urinary excretion. Both groups of agents lower blood levels and efficacy of amphetamines."
-http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/021303s026lbl.pdf

Now getting to your great question regarding toxicity...

This paper is cited in the same wiki page: Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 15: Reinforcement and addictive disorders". In Sydor A, Brown RY. Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York, USA: McGraw-Hill Medical. p. 370. ISBN 9780071481274. Unlike cocaine and amphetamine, methamphetamine is directly toxic to midbrain dopamine neurons.

This is why it's so so so important to differentiate between methamphetamine and d-amphetamine. People often think the latter is a more legal, less stigmatized, 'diet' version of meth, but this is not the case at all. The only toxicity created via d-amph administration would be indirect because of its ability to enter dopamine vesicles through VMAT and expel them into the cellular cytosol. Dopamine will then diffuse out of the presynaptic cell via DAT reversal (though completely unprotected by vesicle exoctosis). This means that there is a greater chance of that dopamine being oxidized by reactive oxygen species into DOPAC and HVA before it enters the cleft. This is what occurs in diseases like Parkinson's, however; but I'm confident in saying that any oxidative stress caused via dopamine oxidation metabolites is negligible in a healthy individual who actually has ADHD and is not abusing psychostimulants. This is particular true with AMPH because it inhibits MAOs inside the presynaptic cell--preventing any dopamine metabolism created through any means other than auto/self-oxidation. It also releases dopamine completely independent of cell excitation, Ca2+ influx and glutamate release--all of which should help mitigate excitotoxic effects post-synapse. Based on AMPH and MPH pharmacology, I would expect the only way that AMPH-mediated neurotoxicity occurs by dopamine oxidation is through significant changes in its half-life OR the inactivation of DAT...which MPH is directly responsible for. So I wonder...if you take MPH after dAPMH, you might be subjecting your neuron to increases in dopamine release (via dAMPH) without any free DAT to push it out into the cleft (via MPH). That could lead to oxidative damage, possibly. But at this age, it's hard to tell what effect is being had and whether it is causing any real decrease in striatal dopamine.

Now I also recognize that article separated cocaine from METH, as well. So, too, should I be careful what I say about MPH. Nonetheless, what I said about blocking DAT at the tail-end of AMPHs decline might have negative effects on dopamine release or cause apoptosis through extended dopamine metabolite lifetimes.

- http://jad.sagepub.com/content/11/1/8.full.pdf+html (if you can't read that, sorry, it may be blocked to non academic readers)

Then again, I could be completely wrong about MPH. One paper suggests that "The availability of both dextroamphetamine and methylphenidate may contribute to minimize adverse events in a subsample of children in pediatric ADHD stimulant trials."
- https://www.ncbi.nlm.nih.gov/pubmed/24666268

After thoroughly reviewing dozens of articles on PubMed, I truly can't find anything that indicates AMPH or MPH are more toxic than the other--only that they are less toxic than METH and MDMA. Perhaps my distrust of MPH stemmed from the fact that it does not come in multiple salt forms, but rather as an HCl tablet. So it has one half-life, one crash, rather than AMPH which sometimes comes in multiple salt form--staggering the metabolism and crash. Eitherway! I have my theories regarding possible mechanisms of action when used in combination, but I can't definitely say anymore that MPH will cause neurotoxicity post adderall use.

Thank you for challenging my on this! It was very interesting.

 

[aced126]

Nice response, dude. I like when people remain empathetically engaged in discussions about what drugs they put in their body. It's a fun learning process! So...

Firstly, it's really vital to recognize that the effects of AMPH and MPH are highly dependent on whether the drug is abused AND whether or not the user really has ADHD. ADHD patients tend to show much better tolerability of all psychostimulants compared to otherwise recreational users. Also, studies done on mice, rats, and even primates at does 40x higher than a human's is not a really good way to determine if AMPH or MPH is more toxic than the other. We'd literally need to look at your brain after it's been sliced, stained, milkshaked, and blotted for specific biomarkers. But I'm certain that experiment is more toxic to your brain than drinking bleech. So in the meantime, take any toxicology evaluation with a heavy grain of AMPH SALT. That said, regarding pH and absorption...

I just pulled this off wiki and I checked their sources; they're legit. I'm a parkinson's disease research scientist, so I usually will give you papers when I can. But trust me, taking 2-3 tums with dexedrine will definitely create a marked effect both in perceivable time of onset and also potency. Now it's not always the most comfortable thing. You're likely right that the stomach compensates by producing more HCl because I've experienced mild acid reflux doing this. But I tried it at my gf's behest and I was shocked at the results. So trust me there and read below:

"The oral bioavailability of amphetamine varies with gastrointestinal pH;[142-quoted below] it is well absorbed from the gut, and bioavailability is typically over 75% for dextroamphetamine.[2] Amphetamine is a weak base with a pKa of 9–10;[4] consequently, when the pH is basic, more of the drug is in its lipid soluble free base form, and more is absorbed through the lipid-rich cell membranes of the gut epithelium.[4][142] Conversely, an acidic pH means the drug is predominantly in a water-soluble cationic (salt) form, and less is absorbed.[4] Approximately 15–40% of amphetamine circulating in the bloodstream is bound to plasma proteins.[3]

The half-life of amphetamine enantiomers differ and vary with urine pH.[4] At normal urine pH, the half-lives of dextroamphetamine and levoamphetamine are 9–11 hours and 11–14 hours, respectively.[4] An acidic diet will reduce the enantiomer half-lives to 8–11 hours; an alkaline diet will increase the range to 16–31 hours.[10][16] The immediate-release and extended release variants of salts of both isomers reach peak plasma concentrations at 3 hours and 7 hours post-dose respectively.[4] Amphetamine is eliminated via the kidneys, with 30–40% of the drug being excreted unchanged at normal urinary pH.[4] When the urinary pH is basic, amphetamine is in its free base form, so less is excreted.[4] When urine pH is abnormal, the urinary recovery of amphetamine may range from a low of 1% to a high of 75%, depending mostly upon whether urine is too basic or acidic, respectively.[4]"

I also gathered, from the FDA and Shire, Inc., this document on prescribing amphetamine. This is [142] from the above passages:
"Alkalinizing Agents
Gastrointestinal alkalinizing agents (e.g., sodium bicarbonate) increase absorption of amphetamines. Co-administration of ADDERALL XR and
gastrointestinal alkalinizing agents, such as antacids, should be avoided. Urinary alkalinizing agents (acetazolamide, some thiazides) increase the
concentration of the non-ionized species of the amphetamine molecule, thereby decreasing urinary excretion. Both groups of agents increase
blood levels and therefore potentiate the actions of amphetamines.

Acidifying Agents
Gastrointestinal acidifying agents (e.g., guanethidine, reserpine, glutamic acid HCl, ascorbic acid) lower absorption of amphetamines. Urinary
acidifying agents (e.g., ammonium chloride, sodium acid phosphate, methenamine salts) increase the concentration of the ionized species of the
amphetamine molecule, thereby increasing urinary excretion. Both groups of agents lower blood levels and efficacy of amphetamines."
-http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/021303s026lbl.pdf

Now getting to your great question regarding toxicity...

This paper is cited in the same wiki page: Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 15: Reinforcement and addictive disorders". In Sydor A, Brown RY. Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York, USA: McGraw-Hill Medical. p. 370. ISBN 9780071481274. Unlike cocaine and amphetamine, methamphetamine is directly toxic to midbrain dopamine neurons.

This is why it's so so so important to differentiate between methamphetamine and d-amphetamine. People often think the latter is a more legal, less stigmatized, 'diet' version of meth, but this is not the case at all. The only toxicity created via d-amph administration would be indirect because of its ability to enter dopamine vesicles through VMAT and expel them into the cellular cytosol. Dopamine will then diffuse out of the presynaptic cell via DAT reversal (though completely unprotected by vesicle exoctosis). This means that there is a greater chance of that dopamine being oxidized by reactive oxygen species into DOPAC and HVA before it enters the cleft. This is what occurs in diseases like Parkinson's, however; but I'm confident in saying that any oxidative stress caused via dopamine oxidation metabolites is negligible in a healthy individual who actually has ADHD and is not abusing psychostimulants. This is particular true with AMPH because it inhibits MAOs inside the presynaptic cell--preventing any dopamine metabolism created through any means other than auto/self-oxidation. It also releases dopamine completely independent of cell excitation, Ca2+ influx and glutamate release--all of which should help mitigate excitotoxic effects post-synapse. Based on AMPH and MPH pharmacology, I would expect the only way that AMPH-mediated neurotoxicity occurs by dopamine oxidation is through significant changes in its half-life OR the inactivation of DAT...which MPH is directly responsible for. So I wonder...if you take MPH after dAPMH, you might be subjecting your neuron to increases in dopamine release (via dAMPH) without any free DAT to push it out into the cleft (via MPH). That could lead to oxidative damage, possibly. But at this age, it's hard to tell what effect is being had and whether it is causing any real decrease in striatal dopamine.

Now I also recognize that article separated cocaine from METH, as well. So, too, should I be careful what I say about MPH. Nonetheless, what I said about blocking DAT at the tail-end of AMPHs decline might have negative effects on dopamine release or cause apoptosis through extended dopamine metabolite lifetimes.

- http://jad.sagepub.com/content/11/1/8.full.pdf+html (if you can't read that, sorry, it may be blocked to non academic readers)

Then again, I could be completely wrong about MPH. One paper suggests that "The availability of both dextroamphetamine and methylphenidate may contribute to minimize adverse events in a subsample of children in pediatric ADHD stimulant trials."
- https://www.ncbi.nlm.nih.gov/pubmed/24666268

After thoroughly reviewing dozens of articles on PubMed, I truly can't find anything that indicates AMPH or MPH are more toxic than the other--only that they are less toxic than METH and MDMA. Perhaps my distrust of MPH stemmed from the fact that it does not come in multiple salt forms, but rather as an HCl tablet. So it has one half-life, one crash, rather than AMPH which sometimes comes in multiple salt form--staggering the metabolism and crash. Eitherway! I have my theories regarding possible mechanisms of action when used in combination, but I can't definitely say anymore that MPH will cause neurotoxicity post adderall use.

Thank you for challenging my on this! It was very interesting.

Thanks for giving a thorough response as well!

It would be of great if you had any papers containing pharmacokinetic data evaluating how much does tums increase absorption, or something similar. I searched around the net to no avail, and I even asked here previously but did not get any responses. I'm quite surprised that I haven't been able to find anything on this phenomenon and to what extent it occurs depending on stomach pH.

 

[coco0410]

I by accident took 440 mg of vyvanse, I have a headache right now.
​

 

[Ozle]

So I think it's really important to understand that Dexedrine is not at all the same as methamphetamine. Meth is more potent and also affects 5HT to a much higher degree. Dex is actually fairly safe. Much safer than Ritalin...which acts more like cocaine than amphetamine. I wouldn't compare adderall or dex to meth in any further readings. Meth IS neurotoxic. Dex is not. Ritalin is more likely to be neurotoxic

Through what mechanism is meth specifically neurotoxic compared to d-amp? Is it purely down to potency, or is the 5-HT release a significant factor? If it's the latter, then I'm confused about your second statement w.r.t. Ritalin's potential neurotoxicity. AFAIK the major difference in action (and abuse potential) between Ritalin and cocaine is that cocaine significantly inhibits the reuptake of 5-HT in addition to DA and NE, which would seem to essentially make it the reuptake inhibitor analogue of meth, and Ritalin the reuptake inhibitor analogue of plain amphetamine. If this is indeed the case, then the difference in neurotoxicity for cocaine vs. Ritalin should be quite significant (comparable to meth vs. d-amp).

 

[Madrus]

If I'm understanding this correctly, don't take clonodine with methampetamine?
https://www.ncbi.nlm.nih.gov/pubmed/9668674

But it may be saying that clonodine + MA = more toxicity only after they had produced lesions using DSP-4, that selective NE neurotoxin
?\_(ツ)_/?

 

[Ozle]

I've only read the abstract, but to me it sounds like they were trying to model a very specific subset of symptoms seen in Parkinson's disease. It shouldn't really come as a surprise to learn that the dopamine depletion caused by substances like meth or amphetamine is exacerbated by Parkinson's (which is characterised by dopamine depletion). From what I understood, that study was just one of many attempts to pin down the exact mechanisms of some of the various symptoms of Parkinson's.

 

[Seppi]

Through what mechanism is meth specifically neurotoxic compared to d-amp?

Sigma receptor 1 agonism.

Just to be clear, the biomolecular targets in humans that methamphetamine and amphetamine do not share as common targets are the alpha-2 adrenergic receptors (meth is an agonist, amph is not a ligand), both sigma receptors (meth is an agonist, amph is not a ligand), and the 5-HT1A receptor (amph is a ligand - presumably an agonist, meth is not a ligand).

 

[ydrone]

anyone in this thread have insight or sources on reduced efficacy of amps when administered after high intensity interval type training? Obviously there is all kind of research around working while on amps, but i cant find anything about post exertion administration.

Anecdotally i notice reduced effects and duration. IM in good shape, recover quickly, but have noticed this affect after recently being started on adderall.