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https://storify.com/fourminutemind/add-drugs-revealed-to-have-long-term-side-effects
Here is the whole article -- mainly reposting to save the links in case the link above ever goes down. Really important points about the potential for killing the dopamine in your brain the same way Ecstasy does -- and shows that they are both amphetamines.
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https://storify.com/fourminutemind/add-drugs-revealed-to-have-long-term-side-effects
Here is the whole article -- mainly reposting to save the links in case the link above ever goes down. Really important points about the potential for killing the dopamine in your brain the same way Ecstasy does -- and shows that they are both amphetamines.
ADD Drugs Revealed To Have Long-Term Side Effects
Adderall (ie, Dexedrine) can be neurotoxic in the long run by damaging dopamine neurons, while Ritalin has little to no neurotoxicity potential. This extended neurotoxicity leads to neurological disorders like Parkinson's Disease and Restless Leg Syndrome (RLS).
- Tolerance can happen with either, but tolerance is not neurotoxicity as it can be reversed by taking breaks.
Adderall Toxicity vs Tolerance: Many Causes
(I will use the word dexedrine interchangeably with Adderall, since they're mostly similar - Adderall is 75% d-amphetamine and 25% l-amphetamine, and Dexedrine is 100% D-amphetamine)
Having lived with ADD since I was young and having taken stimulants to help counteract their long term effects, I consider myself an authority on this subject.
With regards to heart health, this report shows that there is no increase in severe cardiovascular events for children. There is some research that suggests otherwise, but the article above seems to be the most rigorous.
However, taking either dexedrine or Adderall can lead to drug-tolerance. This means that you may need to get higher doses over time in order to achieve the same effect. However, numerous people with ADD are able to achieve a stable dose of either drug over time (but there is also a significant population that does get tolerant and that does need to titrate its dose over time). In any case, tolerance is reversible, and you can prevent it by taking breaks once in a while. 
Patients' Brains May Adapt to ADHD Medication
New research reveals how the brain appears to adapt to compensate for the effects of long-term ADHD medication, suggesting why ADHD medic...- The Neuroscience News report is a bit sobering - students who use Adderall long term will have significant depletion of dopamine when they try to quit the drug. This is yet another possible mechanism of tolerance (the brain's compensation of dopamine-loss by increasing the number of DAT transporters)
The effects BEYOND tolerance
Adderall is a dopamine release agent, whereas Ritalin is a dopamine reuptake inhibitor. Both of them increase dopamine signalling by increasing the amount of dopamine in the synapse (so more dopamine ends up binding to the dopamine receptors in the postsynaptic neuron).
The key difference is their action on the dopamine transporter, which generally moves a lot of the dopamine in the synapse back into the presynaptic neuron - effectively reducing the amount of dopamine in the synapse, and reducing dopamine signalling.
Ritalin increases dopamine signalling by effectively _blocking the dopamine transporter_. Meanwhile, Adderall does it by reversing the action of the dopamine transporter, which effectively forces even more dopamine into the synapse (where it can increase dopamine signalling even further).
There is another difference between the two: and that difference is related to the activity of the VMAT-2 transporter. This transporter effectively transports dopamine from the cellular cytosol into synaptic vesicles (pictured below), which effectively sequesters up the dopamine and prevents it from auto-oxidation. The VMAT-2 protein is well-documented as part of our pleasure-pain (reward/motivation) system: - Vesicular monoamine transporter 2 - Wikipedia, the free encyclopedia
VMAT2 is essential in the presynaptic neuron's ability to facilitate the release of neurotransmitters into the synaptic cleft.
The difference is this: Amphetamine effectively inhibits the activity of the VMAT-2 transporter, so it packages up less dopamine. Methylphenidate (the chemical name for Ritalin), on the other hand, enhances the activity of the transporter. And this difference is actually what makes amphetamine neurotoxic and methylphenidate comparatively benign.
Dopamine is a very reactive molecule, and when it autooxidizes in the presynaptic cytosol, it can actually damage the presynaptic terminal. Amphetamine accelerates this, and causes presynaptic terminal damage. Meanwhile, methylphenidate prevents it from happening.
Surprisingly enough, this produces interesting results, which led to this paper: Basically, that paper shows that methylphenidate actually attenuated the deficits associated with damage induced by methamphetamine (methamphetamine does all the damage of amphetamine , but adds A LOT to that damage). So surprisingly enough, methylphenidate actually can attenuate the neurotoxicity associated with amphetamine, if taken along with it.
Has amphetamine's neurotoxicity (relative to methylphenidate) been experimentally demonstrated? Here's one paper that addresses this question:
Amphetamine Treatment Similar to That Used in the Treatment of Adult Attention-Deficit/Hyperactivity Disorder Damages Dopaminergic Nerve Endings in the Striatum of Adult Nonhuman Primates
Department of Neurology (G.A.R., A.O.M., J.Y., G.H., T.X., A.H.M.) and Psychiatry (U.D.M.), The Johns Hopkins Medical Institutions, Balti...- As the use of amphetamine in the treatment of ADHD has increased, a large body of preclinical data has accrued indicating that amphetamine has the potential to damage brain dopamine-containing neurons in experimental animals.
In particular, animals treated with amphetamine develop lasting reductions in striatal dopamine, its major metabolite dihydroxyphenylacetic acid (DOPAC), its rate-limiting enzyme tyrosine hydroxylase, its membrane transporter (DAT), and its vesicular transporter (VMAT2) . Anatomic studies indicate that lasting dopaminergic deficits after amphetamine are due to damage of dopaminergic nerve endings in the striatum, with sparing of dopaminergic nerve cell bodies in the substantia nigra.
New Evidence Uncovers The Long Term Effects Of Adderall Use
Adderall is a popular stimulant treatment for ADHD and is used illicitly as a drug for its energy inducing effects. Its off-label use as ...- In particular, the results of the present study indicate that an oral regimen of amphetamine, modeled after dosing regimens used in patients with ADHD,engenders plasma amphetamine concentrations that result in toxicity to brain dopaminergic axon terminals in baboons and squirrel monkeys.
These results may have implications for the pathophysiology and treatment of ADHD and raise the question of whether or not plasma monitoring might be indicated in ADHD patients receiving higher, chronic doses of amphetamine.
Here's another very good thread discussing this theme: 
Amphetamine Neurotoxicity Reduction/Prevention - Brain Health
Page 1 of 5 - Amphetamine Neurotoxicity Reduction/Prevention - posted in Brain Health: I've noticed several threads on this forum dedicat...- And a very comprehensive lit review article (discusses what I've covered here and much more):
- Potential Adverse Effects of Amphetamine Treatment on Brain and Behavior: A Review
Abstract Rationale Amphetamine stimulants have been used medically since early in the twentieth century, but they have a high abuse poten... - That all being said, amphetamine's effects are not universally bad. It can increase neurogenesis, perhaps because many individuals with ADD are so distracted that their distraction effectively inhibits neural pathways from forming.
Amphetamine/methylphenidate can help promote the formation of these neural pathways by reducing this noise. See below:
- Literature Review: Update on Amphetamine Neurotoxicity and Its Relevance to the Treatment of ADHD
Abstract Objective: A review of amphetamine treatment for attention-deficit/hyperactivity disorder (ADHD) was conducted, to obtain inform... - In early studies, high doses of amphetamine, comparable to amounts used by addicts, were shown to damage dopaminergic pathways. More recent studies, using therapeutic regimens, appear contradictory. One paradigm shows significant decreases in striatal dopamine and transporter density after oral administration of “therapeutic” doses in primates.
Another shows morphological evidence of “trophic” dendritic growth in the brains of adult and juvenile rats given systemic injections mimicking “therapeutic” treatment. Imaging studies of ADHD-diagnosed individuals show an increase in striatal dopamine transporter availability that may be reduced by methylphenidate treatment. And from the mentioned lit review:
- Potential Adverse Effects of Amphetamine Treatment on Brain and Behavior: A Review
Abstract Rationale Amphetamine stimulants have been used medically since early in the twentieth century, but they have a high abuse poten... - In contrast to concerns about potential adverse effects of amphetamine on the brain during aging, it is remarkable that the reduction of the heightened risk for substance abuse that is otherwise associated with ADHD by the initiation of stimulant treatment during childhood appears to be accompanied by a congruent reduction in structural brain pathology.
Unmedicated children with ADHD had smaller brain white matter volume than medicated children with ADHD (−8.9%, P<.001) or children without ADHD (−10.7%, P<.001), suggesting that early stimulant treatment may normalize brain white matter volume in ADHD 182.
The mentioned lit review also says that amphetamine appears to be less neurotoxic in younger primates, as compared to older primates. With that being said, there is one study that says that high doses of amphetamine in adolescence can impair adult working memory: 
Amphetamine Use In Adolescence May Impair Adult Working Memory
The declines in short-term or "working" memory are most pronounced when the rats are exposed during adolescence, rather than as adults, t...- Recent update (press release article after my original post): In fact, one end result of dopamine neurotoxicity is Parkinson's - the risk of which is increased among methamphetamine users - see:
- Increased risk of Parkinson's disease in methamphetamine users, study finds
The researchers examined almost 300,000 hospital records from California covering 16 years. Patients admitted to hospital for methampheta... - However, meth users destroy *far* more dopamine neurons than any person on Adderall could ever do (meth is far more neurotoxic than amphetamine, and the doses are usually far higher), so I don't think Adderall users need to fear a significantly higher risk of Parkinson's.
Possibly even in ADD-related doses too (not too rigorous of a study, but it is suggestive):
The study involved 66,348 people in northern California who had participated in the Multiphasic Health Checkup Cohort Exam between 1964 and 1973 and were evaluated again in 1995. The average age of the participants at the start of the study was 36 years old. Of the participants, 1,154 people had been diagnosed with Parkinson's disease by the end of the study.
Exposure to amphetamines was determined by two questions: one on the use of drugs for weight loss and a second question on whether people often used Benzedrine or Dexedrine. Amphetamines were among the drugs commonly used for weight loss when this information was collected.
According to the study, those people who reported using Benzedrine or Dexedrine were nearly 60 percent more likely to develop Parkinson's than those people who didn't take the drugs. There was no increased risk found for those people who used drugs for weight loss.
Amphetamine Abuse Can Ruin An Individual's Personality
However, despite being quite similar in function and structure, Adderall and Ritalin can indeed be taken without destroying your life.
Some of the subjective effects that are possibly of concern are effects on your personality and sense of self. It is hard to explain, but you can end up with a feeling that you are sort of just "observing" yourself live your life, you are not actually experiencing it. You can find yourself being extremely productive and doing everything right, but somehow it feels like someone else did it, you were just along for the ride. - It can be a good idea to take a break from the drugs from time to time to get your bearings and make sure you are in touch with yourself.
All These Side Effects And No Benefits
Furthermore, new research shows that Adderall has zero long term benefits. Dr Paolo Fusar-Poli and Professor Katya Rubia at King’s University led the research.
Patients' brains may adapt to ADHD medication
New research reveals how the brain appears to adapt to compensate for the effects of long-term ADHD medication, suggesting why ADHD medic...- Prof Rubia says:
‘There is currently no evidence for the long-term effectiveness of stimulant medication. In fact, there is evidence that the effect of medication diminishes over time and we know from clinicians that medication doses often need to be increased over time to be as effective as they were initially. Our findings could help explain why stimulants work very well in the short term but not so well long-term.’
The case for nootropics as safe, legal study drugs is being made without effort as the evidence against Adderall begins to mount.
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