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It's exam time....Addy vs. Vyvanse

There isn't a single shred of evidence of neurotoxicity as a result of long-term amphetamine (the compound, not the class) use at therapeutic doses in humans and this is not due to a lack of research. E.g., Ricaurte tried to show this, but didn't publish negative results: https://projectreporter.nih.gov/project_info_description.cfm?aid=8429516&icde=0 - that's one of many instances of a study on amphetamine-induced neurotoxicity in humans. Based on 3 meta-analyses/med-reviews (too lazy to link them - see the 3 citations at the end of the first paragraph of this section), both structural and functional neuroimaging studies suggest that, relative to non-medicated controls, amphetamine and MPH induce persistent structural and functional improvements in a few output structures along DA/NE-ergic pathways when used for ADHD. No pathological effects on the brain were noted in those reviews. In a nutshell, current evidence in humans supports a lack of neurotoxicity from long-term amphetamine use at low doses (i.e., those used for treating ADHD).

Might be worth adding that the only positive findings of amphetamine-induced neurodegeneration in humans that I've seen is from 3 primary studies on recreational users. One study that had clear findings of neurodegeneration (IMO, probably neurotoxicity-related) involved participants who took minimum daily doses of 500 mg with an average of ~10 years of recreational use. A related paper and one other study found effects that were analogous to plasticity observed in drug addicts (e.g., borked reward processing and impaired D2 receptor signaling). So, the findings from the last 2 papers might simply be addiction-related neuroplasticity as opposed to a toxicity-related phenomenon.
 
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See, this is where things get sketchy. Amphetamine and MPH both cause neuroplastic changes in the function of some cognitive structures: depending on the study you'll often either see those labeled as positive adaptive changes or evidence of neurotoxicity.

I'm of the opinion that focusing on "per say" neurotoxicity is largely a waste of time. Yes, amphetamine can cause more oxidative stress on the cell--we can see this happen in a lab. But the extent to which this correlates with real-world changes in functional impairment is generally very low. The best evidence in that regard is the correlation between amphetamine use and Parkinsonism later in life. There's probably some real damage being done, in a dose-dependent manner, but the actual cellular damage is largely irrelevant to functional impairment except later in life when dopamine neurons are dying off in droves anyways--where any additional damage incurred throughout your lifespan as a result of amphetamine use (or more likely, as a result of negative lifestyle behaviors like chronic severe sleep deprivation and poor diet) are more likely to push you "over the edge" in terms of neuronal loss and promote Parkinsonian symptoms.
 
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It's unequivocal that sufficiently high doses of amphetamine will cause a neurotoxic effect in human DA neurons merely due to oxidative stress; that's been established as a consequence of excessive cytosolic/synaptic DA in general. I guess my point with the 2nd paragraph is that, unlike meth, amphetamine neurotoxicity is not readily apparent even in recreational users even though a mechanism of high-dose amph-induced neurotoxicity is well established. One notable difference between amph and meth (see diagram for reference) is that they appear to affect different EAATs, which results in a neurotoxic effect for meth via EAAT2 inhibition and a seemingly benign effect for amph (EAAT3 inhibition). A second ntox-related difference is that amph isn't a sigma-1 agonist like meth.

There's far too much interspecies variability in amph-induced neurotoxicity and amphetamine pharmacodynamics (e.g., the TAAR1 binding profile and monoamine receptor binding profile) for toxicity in a non-human animal to reflect on a human, so basically all primary studies involving amphetamine in non-human animals can't be generalized to humans. There's even more interspecies variability in amphetamine pharmacokinetics, but that's probably not relevant to neurotoxicity in any species.
 
I'd say pharmacokinetics could play a role in neurotoxicity. If you take an extreme analogy, imagine if you had a time release amphetamine which released 0.1mg a day over 10 years; taking that amount IR would have neurotoxic effects. What I'm trying to get at is that rate of absorption into the brain etc can have an effect on the pharmacodynamics of the drug.
 
PINKoPANaTHER said:
Yes, this is why I tried to qualify by saying "in therapeutic doses". I haven't read the studies on methamphetamine neurotoxicity, but I am very familiar with the studies that demonstrated sustained improvements in function with long term dextroamphetamine use, as I found it rather hard to believe at first (I don't routinely use amphetamines in any form because they cause way too many physical side effects for me). I think it would be very interesting if they actually performed a direct comparison study of groups of patients taking equivalent doses of Dextromethamphetamine and Dextroamphetamine to get a clearer picture of the damage either one can cause (also would be nice if they included high-dose abuse groups, but getting a study like that approved would be difficult).


I just saw the source request: I will look through my article archive and try to get a link posted here
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i would be very interested to read these studies that talk about sustained improvement after longterm amphetamine use, can you post some links ?

thanks !
 
Not to mention duration, lisdex > d-amp = the "good, euphoric, smoothly stimulating" part of amphetamine salts (Adderall/D,L-amp) without the jittery, anxiogenic L-isomer.
 
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