What are the long term effects of Adderall, Dexedrine, or Ritalin use?
14 Answers
Short summary: 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/Hyperac
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 signalling once they fully mature (see Performance enhancement at the cost of potential brain plasticity: neural ramifications of nootro... for more details).
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% d-amphetamine and 25% l-amphetamine, and Dexedrine is 100% 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: http://www.sciencedaily.c
Taking either of them could result in tolerance (see http://dx.doi.org/10.1016
[1] Link shows that both amphetamine and methylphenidate produce deficits in striatal dopamine markers after treatment, but that the markers recovered in methylphenidate-treated mice but not amphetamine-treated ones (indicating something reversible in methylphenidate but possibly not amphetamine). Although it didn't identify the mechanism and a 2-week waiting period may not be enough to extrapolate permanent effects
http://neurosciencenews.c
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 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 - which reduces the amount of dopamine in the synapse, and 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).
The mechanism of amphetamine (the chemical name for Adderall) is shown below
![]()
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 degradation by MAO enzymes + auto-oxidation.
![]()
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. The thing is, dopamine is a very reactive molecule when it isn't packaged by VMAT-2, 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: http://jpet.aspetjournals
Some of dopamine's neurotoxicity is caused by monoamine oxidase A (MAO) in the presynaptic terminal. When MAO catalyzes the degradation of dopamine, hydrogen peroxide (H2O2) is produced as a result, and this H2O2 can go on to damage the presynaptic terminal. Methylphenidate effectively reduces the amount of MAO degradation of dopamine in the presynaptic terminal by blocking dopamine reuptake - this reduces the amount of H2O2 released (but dopamine can still be degraded in the extracellular synapse and it's unclear if this also does damage).
Has amphetamine's neurotoxicity (relative to methylphenidate) been experimentally demonstrated?
Here's one of the papers (http://jpet.aspetjournal
Anyways, here's another very good thread discussing this theme:
http://www.longecity.org/
And a very comprehensive lit review article (discusses what I said here + more): http://www.ncbi.nlm.nih.g
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/methylphenida
http://jad.sagepub.com/co
And from the mentioned lit review (http://www.ncbi.nlm.nih.
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: http://www.sciencedaily.c
However... A recent paper (Methylphenidate Exposure Induces Dopamine Neuron Loss and Activation of Microglia in the Basal Ganglia of Mice ) 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.. See further discussion at Methylphenidate neurotoxic? - Brain Health, Methylphenidate Neurotoxicity?,and the comments at Methylphenidate Exposure Induces Dopamine Neuron Loss and Activation of Microglia in the Basal Ganglia of Mice
==
Some more reading:
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/Hyperac
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 signalling once they fully mature (see Performance enhancement at the cost of potential brain plasticity: neural ramifications of nootro... for more details).
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% d-amphetamine and 25% l-amphetamine, and Dexedrine is 100% 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: http://www.sciencedaily.c
Taking either of them could result in tolerance (see http://dx.doi.org/10.1016
[1] Link shows that both amphetamine and methylphenidate produce deficits in striatal dopamine markers after treatment, but that the markers recovered in methylphenidate-treated mice but not amphetamine-treated ones (indicating something reversible in methylphenidate but possibly not amphetamine). Although it didn't identify the mechanism and a 2-week waiting period may not be enough to extrapolate permanent effects
http://neurosciencenews.c
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 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 - which reduces the amount of dopamine in the synapse, and 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).
The mechanism of amphetamine (the chemical name for Adderall) is shown below
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 degradation by MAO enzymes + auto-oxidation.
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. The thing is, dopamine is a very reactive molecule when it isn't packaged by VMAT-2, 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: http://jpet.aspetjournals
Some of dopamine's neurotoxicity is caused by monoamine oxidase A (MAO) in the presynaptic terminal. When MAO catalyzes the degradation of dopamine, hydrogen peroxide (H2O2) is produced as a result, and this H2O2 can go on to damage the presynaptic terminal. Methylphenidate effectively reduces the amount of MAO degradation of dopamine in the presynaptic terminal by blocking dopamine reuptake - this reduces the amount of H2O2 released (but dopamine can still be degraded in the extracellular synapse and it's unclear if this also does damage).
Has amphetamine's neurotoxicity (relative to methylphenidate) been experimentally demonstrated?
Here's one of the papers (http://jpet.aspetjournal
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) (Gibb et al., 1994; McCann and Ricaurte, 2004). 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.
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.
Anyways, here's another very good thread discussing this theme:
http://www.longecity.org/
And a very comprehensive lit review article (discusses what I said here + more): http://www.ncbi.nlm.nih.g
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/methylphenida
http://jad.sagepub.com/co
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 (http://www.ncbi.nlm.nih.
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: http://www.sciencedaily.c
However... A recent paper (Methylphenidate Exposure Induces Dopamine Neuron Loss and Activation of Microglia in the Basal Ganglia of Mice ) 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.. See further discussion at Methylphenidate neurotoxic? - Brain Health, Methylphenidate Neurotoxicity?,and the comments at Methylphenidate Exposure Induces Dopamine Neuron Loss and Activation of Microglia in the Basal Ganglia of Mice
==
Some more reading:
- A review of the relevant neurotoxic effects
- Is the treatment with psychostimulants in children and adolescents with attention deficit hyperactivity disorder harmful for the dopaminergic system?
- http://www.sciencedaily.c
om/rele.... (meth increases Parkinson's risk, though this probably shouldn't concern people on Adderall too much) - http://www.sciencedaily.c
om/rele... (possibly increased risk of Parkinson's for Dexedrine...)
The good news is that ADHD meds are usually safe for the long haul. They have been prescribed for over 40 years now. It is not ideal for research into long term effects as outlined in this summary. But they are generally safe and well tolerated.
There are some health conditions which can be affected negatively and these need to be kept in mind if you are thinking of taking these meds for the rest of your life.
Side effects such as problems with appetite, mood disturbances and sleeping have all been documented but it is interesting to note that these may well be short term and/or that patients manage to adjust. In one survey, only 20% of the patients mentioned thsee side effects to their doctor.
There is also the issue that ADHD exists alongside many co-morbid disorders and the interactions of anti-depressants and stimulants is not so easy to assess.
It would be unwise to hide any previous mental illness when talking to your doctor about getting a prescription for these meds.
Hereare some facts you may be unaware of when you have to cope with ADHD with your kids
Dexadrine, Adderall and Ritalin are all stimulant drugs which will certainly increase your heart rate and also blood pressure. If you have problems with these conditions, then you might want to have more careful monitoring which your doctor can advise you on. You might have to take a lower dose in the long run. This is the view of the American College of Cardiology which you can see in their article here on the risks for people with cardiac issues.
As regards kids (there is no mention of your age in the question), there has been a lot of controversy about whether these drugs can slow down growth. The good news is that over a period of 10 years, kids on these meds did not show reduced growth at all compared to kids who were not being medicated. There were earlier studies that showed in the short term and in certain periods of the child's life, there seemed to be some stunted growth but the long term results show that normal growth and weight are maintained.
Thyroid, allergies and glaucoma should all be mentioned if they are relevant because they can also impact on the negative side effects of these drugs. In fact it is always wise to make sure you do not have any of the conditions which mimic in many ways ADHD, as recommended in this article here:-
This is taken from my nine year and counting experience of taking Adderall for my ADHD.
These are all I can think of right now, and they're all not medical effects, just my own anecdotal effects.
- Tolerance: Even after a month or two off it, I don't feel the effects of the drug nearly as much as I did when I went on it back in 5th grade. I can take 20 mg instant release and fall asleep an hour later. I fall asleep just as it's kicking in. It used to have a stimulant-like effect on me while simultaneously calming me and helping me focus, but I feel the stimulant aspect very little these days. Despite the tolerance though, I focus better with it than without it, though I'm not sure if it's because the drug is actually working or if I merely think it's helping.
- Mild psychological dependence: Occasionally, I start to feel like I need Adderall just to function and deal with life. When this happens, I stop taking it for a few days to reassess.
- Fear of dependence: Sometimes I fear that I'll become an addict, that one day I'll lose control. When that happens, I stop taking Adderall and I think about how I've been on Adderall for almost a decade, and have not yet developed a crippling addiction.
- People finding out: I let slip once that I take Adderall, and one of my classmates asked me if he could have some. I gave him some, but that was the first and only time I ever gave out my Adderall to anyone.
- Better appetite and weight control: I'm not in any way advocating Adderall as a weight-loss tactic, but before Adderall, I was overweight. I ate McDonald's for dinner almost every night, and wasn't in the best shape. When I went on Adderall, I lost a substantial amount of weight, and had more energy since I wasn't distracted by my ADHD anymore. I lost weight and got in better shape. I've been able to maintain a healthy weight and relationship with food ever since. The appetite suppressant aspect of Adderall showed me that I didn't have to eat nearly as much as I was, and made me appreciate food much more, as a source of nutrition and pleasure. In fact, I lost so much weight that my pediatrician put me on a "see-food" diet; if I saw it, I ate it (it being food of course). Even when I'm on Adderall and don't feel my appetite suppressed, my resting metabolism is elevated beyond what it would usually be.
- Looking forward to more Adderall: A new Adderall prescription is like Christmas on my birthday, in all honesty.
These are all I can think of right now, and they're all not medical effects, just my own anecdotal effects.
I have tried Ritalin and Concerta. After talking with other ADHD people, their effects and side effects are a bit of a crap shoot; roughly half of those I spoke with had minimal-to-no side effects. For me, they were only marginally effective and the Ritalin caused a long-term neural side effect that comes and goes despite ceasing the drug many months ago.
Overall, if they help but have side effects, you have to carefully weigh the potential long-term negatives and closely monitor your symptoms. Most all are cataloged in the drug interaction and warning sheets given with the drugs; it is advisable to also research them on the web.
There are two alternatives that I am aware of that are non-amphetamine medications; Intuniv and Strattera. Intuniv was marginally helpful to me and it was obvious that a dose capable of being sufficiently efficacious to help me was going to be more than I could handle due to side effects. Strattera was a wonder drug for me, but my prostate enlarged drastically, and I consider that a very cruel outcome.
Any of the meds that can cause brain function changes significant enough to quell ADHD symptoms (depending on the severity of your symptoms) are indeed profound medications and need to be carefully monitored. The long-term use of any amphetamine-based product has shown to be somewhat-to-very deleterious over the life of the user. As someone once said, "You might see old junkies, but you never see an old speed freak."
Beyond that, the psychoactve and behvioral changes these drugs bring on are more insidious than the physical ones and, in some cases, can become permanent — a small percentage, granted, but who knows who it will be? As with anything in life, those changes that you can effect without introducing foreign substances into your body have the best chance of making real changes vs. the temporary effects afforded by a drug. Learning to meditate (which is a huge accomplishment for most with ADD/ADHD) is major, as are learning organizational methods, dietary changes, exercise and other things. Yes, a pill is easier, but only in one sense in that the effects are temporary and the side effects can be permanent.
ADHD is a bitch, pure and simple, otherwise it wouldn't be listed as a covered condition in the Americans with Disabilities Act. Still, as with any disability, there are myriad coping and conditioning methods that should be attempted in earnest, and pills should be the last resort.
Thanks to Alex Chen for his thorough article. Excellent work.
Overall, if they help but have side effects, you have to carefully weigh the potential long-term negatives and closely monitor your symptoms. Most all are cataloged in the drug interaction and warning sheets given with the drugs; it is advisable to also research them on the web.
There are two alternatives that I am aware of that are non-amphetamine medications; Intuniv and Strattera. Intuniv was marginally helpful to me and it was obvious that a dose capable of being sufficiently efficacious to help me was going to be more than I could handle due to side effects. Strattera was a wonder drug for me, but my prostate enlarged drastically, and I consider that a very cruel outcome.
Any of the meds that can cause brain function changes significant enough to quell ADHD symptoms (depending on the severity of your symptoms) are indeed profound medications and need to be carefully monitored. The long-term use of any amphetamine-based product has shown to be somewhat-to-very deleterious over the life of the user. As someone once said, "You might see old junkies, but you never see an old speed freak."
Beyond that, the psychoactve and behvioral changes these drugs bring on are more insidious than the physical ones and, in some cases, can become permanent — a small percentage, granted, but who knows who it will be? As with anything in life, those changes that you can effect without introducing foreign substances into your body have the best chance of making real changes vs. the temporary effects afforded by a drug. Learning to meditate (which is a huge accomplishment for most with ADD/ADHD) is major, as are learning organizational methods, dietary changes, exercise and other things. Yes, a pill is easier, but only in one sense in that the effects are temporary and the side effects can be permanent.
ADHD is a bitch, pure and simple, otherwise it wouldn't be listed as a covered condition in the Americans with Disabilities Act. Still, as with any disability, there are myriad coping and conditioning methods that should be attempted in earnest, and pills should be the last resort.
Thanks to Alex Chen for his thorough article. Excellent work.
There are a few long term affects with amphetamines, but not too many, see here: Adderal vs Ritalin . ADHD drugs review It's not always going to be neurotoxic, but we've been prescribing it for over 50 years now; there are lots of minor and larger effects if you use it long term. Most common effects only show up when it’s abused. Assuming you don't abuse amphetamines, some of the more common long term effects are likely to be along the lines of depression, paranoia and growth being inhibited in children.
The good news is such severe side-effects rarely show up (only about 15% of patients have reported any), and most of the people with these affects have had these problems short-term and have then gotten over it. So there are some upsides to this story! The downside is that many of the effects cannot be properly researched, so there may be some more effects that are not listed my doctors, as they can be disguised by other disorders.
Make sure you tell your doctor everything, as especially with drugs like these, it's important that you list everything, as one little detail can make all the difference. Addiction is also possible in the long run; even the most cautious people can become addicted. While this is also not guaranteed, it is still possible. Most studies with medicines like this are inconclusive due to wrong study methods, so it's difficult to get a read on them, but the general thing is that the long term effects don't show up very commonly, and if it does, it's usually going to be short term, and you will probably be able to get over them. Always notify your doctor if harmful effects show up, they will give you advice and can help you further.
