Post by Amtram on Feb 28, 2014 13:54:06 GMT -5
What are the long term effects of Adderall, Dexedrine, or Ritalin use?
Very interesting response from one of the commenters, Alex Chen, and I'm not sure if the link works, so I'm copying it here in all its glory.
If you visit the question, the links are active and there are some illustrations. I like it when people do so much homework on their conditions and treatments.
Very interesting response from one of the commenters, Alex Chen, and I'm not sure if the link works, so I'm copying it here in all its glory.
Short summary: Adderall/Dexedrine can be neurotoxic in the long run (by damaging dopamine neurons) while Ritalin has no neurotoxicity potential. Surprisingly, when Ritalin *and* Adderall are mixed together, Ritalin can actually help counteract Adderall's neurotoxicity potential.
Tolerance can happen with either, but tolerance is not neurotoxicity as it can be reversed by taking breaks.
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: www.sciencedaily.com/rele... 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 (see dx.doi.org/10.1016/S0006-... - discussed in [1]). 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.
[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
neurosciencenews.com/adhd... is a possible mechanism of tolerance (apparently, the brain compensates by increasing the number of DAT transporters)
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 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: jpet.aspetjournals.org/co.... 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.
Some of dopamine's neurotoxicity is actually 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.
Has amphetamine's neurotoxicity (relative to methylphenidate) been experimentally demonstrated?
Here's one of the papers (http://jpet.aspetjournals.org/co...
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:
www.longecity.org/forum/t...
And a very comprehensive lit review article (discusses what I said here + more): www.ncbi.nlm.nih.gov/pmc/...
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:
jad.sagepub.com/content/1...
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.gov/pmc/...
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: www.sciencedaily.com/rele.... 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.
==
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 www.sciencedaily.com/rele.... 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.
One study suggests a possible effect at ADD-related doses too (not too rigorous of a study, but it is suggestive):
www.sciencedaily.com/rele...
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.
Tolerance can happen with either, but tolerance is not neurotoxicity as it can be reversed by taking breaks.
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: www.sciencedaily.com/rele... 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 (see dx.doi.org/10.1016/S0006-... - discussed in [1]). 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.
[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
neurosciencenews.com/adhd... is a possible mechanism of tolerance (apparently, the brain compensates by increasing the number of DAT transporters)
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 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: jpet.aspetjournals.org/co.... 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.
Some of dopamine's neurotoxicity is actually 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.
Has amphetamine's neurotoxicity (relative to methylphenidate) been experimentally demonstrated?
Here's one of the papers (http://jpet.aspetjournals.org/co...
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:
www.longecity.org/forum/t...
And a very comprehensive lit review article (discusses what I said here + more): www.ncbi.nlm.nih.gov/pmc/...
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:
jad.sagepub.com/content/1...
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.gov/pmc/...
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: www.sciencedaily.com/rele.... 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.
==
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 www.sciencedaily.com/rele.... 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.
One study suggests a possible effect at ADD-related doses too (not too rigorous of a study, but it is suggestive):
www.sciencedaily.com/rele...
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.