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Adderall Uses And Effects On The Brain: How ADHD Medication Impacts Neural Connections Over Time

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What are the long term effects of Adderall, Dexedrine, or Ritalin use?

This question originally appeared on Quora. Answer by Alex K. Chen, Atmospheric and Pathology expert. 

Short Answer: 

Adderall/Dexedrine can be neurotoxic in the long run (by damaging dopamine neurons) while Ritalin does not have as much neurotoxicity potential. Surprisingly, when Ritalin and Adderall are mixed together, Ritalin can actually help counteract Adderall's neurotoxicity potential. 

Whether or not Adderall's neurotoxicity applies to those who take doses relevant to ADD is unclear. Most of the studies use amphetamine does higher than those used for treating ADHD, but 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 uses doses similar to those used for treating ADHD (though I'm not sure if this paper shows neurotoxicity as opposed to mere down regulation).

Tolerance can happen with either, but tolerance is not neurotoxicity as it can be reversed by taking breaks. When one takes either of these drugs when young, there can be subtle developmental effects too. They could lead to neurons "believing" that there is more dopamine than there actually is, which could lead to mature circuits with reduced dopamine signaling once they fully mature

So in short - there are three effects: tolerance, neurotoxicity, and developmental. Tolerance is reversible, while neurotoxicity is not. Developmental effects are the most complicated, and still difficult to adequately summarize.

Long Answer:

It depends on many factors:

(I will use the word dexedrine interchangeably with Adderall, since they're mostly similar - Adderall is 75 percent d-amphetamine and 25 percent l-amphetamine, and Dexedrine is 100 percent d-amphetamine). As someone with ADD who has been concerned about their long term effects, I have done a huge amount of research into this. I'll update this post with time.

First of all, regarding the cardiovascular risks: this study shows that there is no increase in severe cardiovascular events for children with no pre-existing heart abnormalities. This could be different for older adults who may be more vulnerable to getting heart attacks, however. Most young people shouldn't worry about the cardiovascular effects.

Taking either of them could result in 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. In any case, tolerance is reversible, and you can prevent it by taking breaks once in a while.

Now to discuss the possible effects beyond tolerance:

There is a real difference between the two, however. Adderall is a dopamine release agent, whereas Ritalin is a dopamine re-uptake inhibitor. Both of them increase dopamine signaling 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 - which reduces the amount of dopamine in the synapse, and dopamine signaling. Ritalin increases dopamine signaling by effectively blocking the dopamine transporter. 

Meanwhile, amphetamine (the chemical name for 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 signaling even further). 

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 harmless. Amphetamine accelerates this damage, and causes damage to certain neurons in the brain. 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. Keep in mind, though, that methylphenidate has a shorter half-life than amphetamine.

Has amphetamine's neurotoxicity (relative to methylphenidate) been experimentally demonstrated? Here's one of the papers. 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, 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.

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. In early studies, high doses of amphetamine, comparable to amounts used by addicts, were shown to damage dopaminergic pathways.

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 or children without ADHD, suggesting that early stimulant treatment may normalize brain white matter volume in ADHD.

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 studythat says that high doses of amphetamine in adolescence can impair adult working memory: With that said, the study was done in rats that didn't even have ADD, so it may not be that applicable. But it is still something that may merit consideration.

However, a recent paper suggests that methylphenidate exposure can increase inflammation and dopamine neuron loss in the basal ganglia, and that extracellular dopamine can auto-oxidized and get degraded too. So methylphenidate may not be as innocuous as once believed (though I would not be too concerned yet). There will definitely be a need of more research on this.

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