5 ms·

Methylphenidate Exposure Induces Dopamine Neuron Loss in Mice

63 points by hoggle 12y ago

droopyEyelids 12y ago
Flagged for exaggerated headline, only demonstrated in mice now, which react differently to many stimulants.
- vixin 12y ago
  Maybe I've missed something but where is the exaggeration in the headline 'Methylphenidate Exposure Induces Dopamine Neuron Loss in Mice '? You mean it doesn't and they're wrong?
  - eatitraw 12y ago
    It could be that HN mods altered the headline by the time you saw it.
bayesianhorse 12y ago
So this article seems to point to a neurodegenerative effect of Methylphenidate. I would caution against drawing conclusions from this study as of yet. MP has been used for decades and there does not seem to be a clinically evident effect of this sort. In order to derive clinical recommendations (like "stop taking ritalin") the potential damage has to be higher than that of all the "side effects" of ADHD, for example violence, depression and social problems. Which currently does not seem to be the case...
- inmyunix 12y ago
  "Nevertheless, this work supports studies [51], [57], [58], [59] that demonstrate that drugs shown to increase the levels of dopamine in the synaptic cleft can contribute to degenerative changes in the basal ganglia."
- theonewolf 12y ago
  This type of degenerative side effect though might especially express itself later in life: making you much more likely to develop say dementia earlier than a normal human. It's not like it would be an immediate side effect. Often brain damage chronically over time is not immediately visible.
  - bayesianhorse 12y ago
    That effect should have been shown by now. I don't know of any studies specifically looking at this, but various global agencies require post-approval studies and monitoring which should have picked up on this. It's not like this drug is prescribed rarely or introduced very recently...
- xkcd-sucks 12y ago
  Traditional Parkinson's symptoms (problems w/ voluntary movement) only show up after 80-90% of dopaminergic neurons are gone. That's a whole lot of dead cells. Symptoms of pre-Parkinsonian dopaminergic neuron loss are (anhedonia, depression, psychiatric weirdness without movement disorder) are just beginning to be described, and it's very likely that stimulant use will be shown to cause pre-Parkinsonian symptoms in human populations once we know what to look for, and after somebody decides to spend tons of time and money investigating it. Maybe the appropriate clinical recommendation is to exercise caution with DAT ligands, and to use them as minimally as possible?
  - bayesianhorse 12y ago
    So the mice showed 80% loss after what? One or two years of chronic use? How come people have taken this for twenty years and more and we didn't notice the Parkinson epidemic?
    - xkcd-sucks 12y ago
      The mice showed a ~20% loss at high dose. At the low dose, the mice showed no significant loss but were vulnerable to a sub-threshold dose of a toxin and toxin+MPH mice showed a ~20% loss. This is in figure 1, and in the discussion. Exactly what behavioral effects result from a 20% loss of DA neurons is still an open question. So, the clinical implication is that people on methylphenidate might be vulnerable to things (rotenone, heavy metals, etc) which aren't toxic to "normal" people.
Snackchez 12y ago
Are there any similar types of research being done for Modafinil? I've recently been prescribed a "therapeutic" dose of Ritalin (I reacted severely to the lowest regular dose of Concerta) but have not started taking it. I'm wondering if this is as bad as it sounds as my technical reading comprehension skills are not that astute. I was using modafinil before with some success. The only problem was that my sleep patterns were all over the map and getting regular good sleep was becoming difficult.
- mietek 12y ago
  I'm also interested in long-term studies on modafinil. Please let me know if you find any. As for the sleep patterns, I've found sporadic use of melatonin to be quite helpful: http://www.gwern.net/Melatonin http://www.gwern.net/Melatonin
- mofreek 12y ago
  Concerta is a prolonged release version of Ritalin: https://en.wikipedia.org/wiki/Methylphenidate https://en.wikipedia.org/wiki/Methylphenidate
refurb 12y ago
A quick read of the abstract indicates that loss of neurons only occurred in mice at the higher dose (10 mg/kg). Typical doses of Ritalin in kids (6+ years old) is 5-10 mg per day in two doses.[1] 6 year old weigh about 20 kg (50th percentile) so each dose is ~0.25 mg/kg (5/20). Even if you double the dose, it's 0.50 mg/kg, below the 1 mg/kg where the study saw no neuron loss. To get to 10 mg/kg, kids would have to take 200 mg in a single dose. I'm pretty sure the side effects would be utterly intolerable even at half of that dose. It's probably worth following up, but I wouldn't be worried about this finding. [1] http://www.mayoclinic.org/drugs-supplements/methylphenidate-oral-route/proper-use/drg-20068297 http://www.mayoclinic.org/drugs-supplements/methylphenidate-...
- theonewolf 12y ago
  The problem is that children have developing brains, and this study doesn't take that into account. Could the drug "stunt" neurological development over the extent of a childhood? Even in low dosages? I wish we wouldn't medicate so much, especially in young children!
- bumeye 12y ago
  I think these results are fairly good. 'Just' some neuron loss at such doses. A lot of drugs can kill you if you take 20 times the recommended dose!
- troym 12y ago
  > I'm pretty sure the side effects would be utterly intolerable even at half of that dose. I'm absolutely sure. My son takes methylphenidate for traumatic narcolepsy and hyperphagia. At ~60 kg with a 30mg dose, he's got tremors, sweats, chattering teeth, etc. I can only assume that the researchers have reason to study using these higher doses in mice, but 1mg/kg and 10mg/kg was the first thing that caught my eye. Neurological degeneration seems entirely plausible when you're frying a brain with speed (so to speak).
- stinos 12y ago
  well, just an anecdote: back in 'the days' I used amphetamines (or whatever was supposed to be in the speed I bought from my dealer) for a couple of months, then quit it because it's disastrous for your body and switched to Ritalin for another couple of months because the amphetamine addiction was hard to cope with. And because Ritalin has very, very similar effects, including the side-effects like tremors and teeth grinding. So I was living the same sped up and fucked up life after all. Then I quit all of it which was followed by severe depression, while I never had such problems before that period of abuse. Depression, which afaik has been linked to dopamine functioning. Depression, which even years after the facts still sometimes wants to kick in. I'd almost say something is borken in my brain. Now I read an article saying use of MP might yield damage to dopamine neurons. Hey, sounds familiar. Now don't get me wrong, I'm not saying it's the same, but just using the fact that dosages in this study were way higher than what you normally use on your kids for instance means there's nothing to worry about seems a bit far fetched.
asciimo 12y ago
This is anecdotal, but rodents I know never have a hard time focusing or providing requisite attention. I think that ADHD is over-diagnosed in this population. OCD, on the other hand, is prevalent, but actually beneficial for the rodent lifestyle IMHO.
- tunap 12y ago
  Perhaps if you had finished with "sedentary lifestyle" or "consumption lifestyle" you wouldn't have been modded down so far? What do I know, I'm just another un-diagnosed aberrant.
  - Houshalter 12y ago
    I think he means the rats they did the study on.
may 12y ago
I think this is the money quote -- noting that these effects are noted on neurotypcial, and not on ADHD brains and therefore may or may not be generalizable: These results can only be interpreted in the context on normal brain structure and function, and thus would have direct implications for the illicit/neurocognitive use of MPH. Since the underlying anatomy and biochemistry of ADHD has not been definitively characterized, our findings may or may not be generalizable to the vast majority of humans who are properly diagnosed with ADHD and are prescribed methylphenidate. Nevertheless, this work supports studies [51], [57], [58], [59] that demonstrate that drugs shown to increase the levels of dopamine in the synaptic cleft can contribute to degenerative changes in the basal ganglia.
- jessaustin 12y ago
  ...the underlying anatomy and biochemistry of ADHD has not been definitively characterized... That's an understatement. The same could be said of any "disorder" or "syndrome" the study of which is motivated primarily by commerce in pharmaceuticals. If humanity survives long enough, future medicine will see "ADHD" as lying mostly within normal human psychological variety. Our clumsy efforts at treatment will be seen as prescribing 6" shoe risers to everyone, whether they're 5'1" or 6'3".
  - Houshalter 12y ago
    That sounds sort of dismissive to people who have ADHD. It is a real condition with real effects on people's lives, who get very real benefits from medication. It is not like prescribing 6" shoes to everyone. Of course the type of medication and dosage is adjusted to the patient.
narrator 12y ago
Methinks excess dopamine in the brain can get metabolized directly by MAO into DOPAL which, if ALDH2 is busy, can cause superoxide formation and cell death. "Both the accumulation of DOPAL and the enhancement of rotenone-induced toxicity were abrogated by inhibiting the formation of DOPAL with the MAO inhibitor, clorgyline. These observations suggest that the MAO-catalyzed formation of DOPAL and its accumulation by various mechanisms may be important processes that aggravate the neurotoxicity associated with mitochondrial dysfunction." http://pharmrev.aspetjournals.org/content/59/2/125.full http://pharmrev.aspetjournals.org/content/59/2/125.full So this is why MAO inhibitors are neuroprotective. They prevent this reaction.
paulwithap 12y ago
Does this come as a surprise to anyone?
apstls 12y ago
I wonder if Adderall, Vyvanse, and other ADD medications are chemically similar enough to Methylphenidate that they would exhibit a similar effect.
- Houshalter 12y ago
  Brand names are Concerta, Methylin, Ritalin, Equasym XL. I believe Adderall and other ADHD medications are similar in. I thought it was even in the title, but possibly the mods changed it. Watch it lose traction because no one knows what "Methylphenidate" means.
hoggle 12y ago
For anybody returning to this thread, here are some other discussions around this study I found on the web (thank you duckduckgo :) http://www.longecity.org/forum/topic/61161-methylphenidate-neurotoxic/ http://www.longecity.org/forum/topic/61161-methylphenidate-n... http://www.reddit.com/r/Nootropics/comments/1yd5bf/methylphenidate_neurotoxicity/ http://www.reddit.com/r/Nootropics/comments/1yd5bf/methylphe... http://www.plosone.org/annotation/listThread.action?root=53905 http://www.plosone.org/annotation/listThread.action?root=539... https://www.quora.com/What-are-the-long-term-effects-of-Adderall-Dexedrine-or-Ritalin-use https://www.quora.com/What-are-the-long-term-effects-of-Adde... --- And some studies suggesting other adverse neurodegenerative effects of MPH as well: "Methylphenidate treatment induces oxidative stress in young rat brain" http://www.sciencedirect.com/science/article/pii/S0006899306000606 http://www.sciencedirect.com/science/article/pii/S0006899306... "Methylphenidate induces lipid and protein damage in prefrontal cortex, but not in cerebellum, striatum and hippocampus of juvenile rats." http://www.ncbi.nlm.nih.gov/pubmed/22968482 http://www.ncbi.nlm.nih.gov/pubmed/22968482

63 points by hoggle 12y ago

droopyEyelids 12y ago

Flagged for exaggerated headline, only demonstrated in mice now, which react differently to many stimulants.

vixin 12y ago
Maybe I've missed something but where is the exaggeration in the headline 'Methylphenidate Exposure Induces Dopamine Neuron Loss in Mice '? You mean it doesn't and they're wrong?
- eatitraw 12y ago
  It could be that HN mods altered the headline by the time you saw it.

bayesianhorse 12y ago

So this article seems to point to a neurodegenerative effect of Methylphenidate. I would caution against drawing conclusions from this study as of yet. MP has been used for decades and there does not seem to be a clinically evident effect of this sort. In order to derive clinical recommendations (like "stop taking ritalin") the potential damage has to be higher than that of all the "side effects" of ADHD, for example violence, depression and social problems. Which currently does not seem to be the case...

inmyunix 12y ago
"Nevertheless, this work supports studies [51], [57], [58], [59] that demonstrate that drugs shown to increase the levels of dopamine in the synaptic cleft can contribute to degenerative changes in the basal ganglia."
theonewolf 12y ago
This type of degenerative side effect though might especially express itself later in life: making you much more likely to develop say dementia earlier than a normal human. It's not like it would be an immediate side effect. Often brain damage chronically over time is not immediately visible.
- bayesianhorse 12y ago
  That effect should have been shown by now. I don't know of any studies specifically looking at this, but various global agencies require post-approval studies and monitoring which should have picked up on this. It's not like this drug is prescribed rarely or introduced very recently...
xkcd-sucks 12y ago
Traditional Parkinson's symptoms (problems w/ voluntary movement) only show up after 80-90% of dopaminergic neurons are gone. That's a whole lot of dead cells. Symptoms of pre-Parkinsonian dopaminergic neuron loss are (anhedonia, depression, psychiatric weirdness without movement disorder) are just beginning to be described, and it's very likely that stimulant use will be shown to cause pre-Parkinsonian symptoms in human populations once we know what to look for, and after somebody decides to spend tons of time and money investigating it. Maybe the appropriate clinical recommendation is to exercise caution with DAT ligands, and to use them as minimally as possible?
- bayesianhorse 12y ago
  So the mice showed 80% loss after what? One or two years of chronic use? How come people have taken this for twenty years and more and we didn't notice the Parkinson epidemic?
  - xkcd-sucks 12y ago
    The mice showed a ~20% loss at high dose. At the low dose, the mice showed no significant loss but were vulnerable to a sub-threshold dose of a toxin and toxin+MPH mice showed a ~20% loss. This is in figure 1, and in the discussion. Exactly what behavioral effects result from a 20% loss of DA neurons is still an open question. So, the clinical implication is that people on methylphenidate might be vulnerable to things (rotenone, heavy metals, etc) which aren't toxic to "normal" people.

Snackchez 12y ago

Are there any similar types of research being done for Modafinil? I've recently been prescribed a "therapeutic" dose of Ritalin (I reacted severely to the lowest regular dose of Concerta) but have not started taking it. I'm wondering if this is as bad as it sounds as my technical reading comprehension skills are not that astute. I was using modafinil before with some success. The only problem was that my sleep patterns were all over the map and getting regular good sleep was becoming difficult.

mietek 12y ago
I'm also interested in long-term studies on modafinil. Please let me know if you find any. As for the sleep patterns, I've found sporadic use of melatonin to be quite helpful: http://www.gwern.net/Melatonin http://www.gwern.net/Melatonin
mofreek 12y ago
Concerta is a prolonged release version of Ritalin: https://en.wikipedia.org/wiki/Methylphenidate https://en.wikipedia.org/wiki/Methylphenidate

refurb 12y ago

A quick read of the abstract indicates that loss of neurons only occurred in mice at the higher dose (10 mg/kg). Typical doses of Ritalin in kids (6+ years old) is 5-10 mg per day in two doses.[1] 6 year old weigh about 20 kg (50th percentile) so each dose is ~0.25 mg/kg (5/20). Even if you double the dose, it's 0.50 mg/kg, below the 1 mg/kg where the study saw no neuron loss. To get to 10 mg/kg, kids would have to take 200 mg in a single dose. I'm pretty sure the side effects would be utterly intolerable even at half of that dose. It's probably worth following up, but I wouldn't be worried about this finding. [1] http://www.mayoclinic.org/drugs-supplements/methylphenidate-oral-route/proper-use/drg-20068297 http://www.mayoclinic.org/drugs-supplements/methylphenidate-...

theonewolf 12y ago
The problem is that children have developing brains, and this study doesn't take that into account. Could the drug "stunt" neurological development over the extent of a childhood? Even in low dosages? I wish we wouldn't medicate so much, especially in young children!
bumeye 12y ago
I think these results are fairly good. 'Just' some neuron loss at such doses. A lot of drugs can kill you if you take 20 times the recommended dose!
troym 12y ago
> I'm pretty sure the side effects would be utterly intolerable even at half of that dose. I'm absolutely sure. My son takes methylphenidate for traumatic narcolepsy and hyperphagia. At ~60 kg with a 30mg dose, he's got tremors, sweats, chattering teeth, etc. I can only assume that the researchers have reason to study using these higher doses in mice, but 1mg/kg and 10mg/kg was the first thing that caught my eye. Neurological degeneration seems entirely plausible when you're frying a brain with speed (so to speak).
stinos 12y ago
well, just an anecdote: back in 'the days' I used amphetamines (or whatever was supposed to be in the speed I bought from my dealer) for a couple of months, then quit it because it's disastrous for your body and switched to Ritalin for another couple of months because the amphetamine addiction was hard to cope with. And because Ritalin has very, very similar effects, including the side-effects like tremors and teeth grinding. So I was living the same sped up and fucked up life after all. Then I quit all of it which was followed by severe depression, while I never had such problems before that period of abuse. Depression, which afaik has been linked to dopamine functioning. Depression, which even years after the facts still sometimes wants to kick in. I'd almost say something is borken in my brain. Now I read an article saying use of MP might yield damage to dopamine neurons. Hey, sounds familiar. Now don't get me wrong, I'm not saying it's the same, but just using the fact that dosages in this study were way higher than what you normally use on your kids for instance means there's nothing to worry about seems a bit far fetched.

asciimo 12y ago

This is anecdotal, but rodents I know never have a hard time focusing or providing requisite attention. I think that ADHD is over-diagnosed in this population. OCD, on the other hand, is prevalent, but actually beneficial for the rodent lifestyle IMHO.

tunap 12y ago
Perhaps if you had finished with "sedentary lifestyle" or "consumption lifestyle" you wouldn't have been modded down so far? What do I know, I'm just another un-diagnosed aberrant.
- Houshalter 12y ago
  I think he means the rats they did the study on.

may 12y ago

I think this is the money quote -- noting that these effects are noted on neurotypcial, and not on ADHD brains and therefore may or may not be generalizable: These results can only be interpreted in the context on normal brain structure and function, and thus would have direct implications for the illicit/neurocognitive use of MPH. Since the underlying anatomy and biochemistry of ADHD has not been definitively characterized, our findings may or may not be generalizable to the vast majority of humans who are properly diagnosed with ADHD and are prescribed methylphenidate. Nevertheless, this work supports studies [51], [57], [58], [59] that demonstrate that drugs shown to increase the levels of dopamine in the synaptic cleft can contribute to degenerative changes in the basal ganglia.

jessaustin 12y ago
...the underlying anatomy and biochemistry of ADHD has not been definitively characterized... That's an understatement. The same could be said of any "disorder" or "syndrome" the study of which is motivated primarily by commerce in pharmaceuticals. If humanity survives long enough, future medicine will see "ADHD" as lying mostly within normal human psychological variety. Our clumsy efforts at treatment will be seen as prescribing 6" shoe risers to everyone, whether they're 5'1" or 6'3".
- Houshalter 12y ago
  That sounds sort of dismissive to people who have ADHD. It is a real condition with real effects on people's lives, who get very real benefits from medication. It is not like prescribing 6" shoes to everyone. Of course the type of medication and dosage is adjusted to the patient.

narrator 12y ago

Methinks excess dopamine in the brain can get metabolized directly by MAO into DOPAL which, if ALDH2 is busy, can cause superoxide formation and cell death. "Both the accumulation of DOPAL and the enhancement of rotenone-induced toxicity were abrogated by inhibiting the formation of DOPAL with the MAO inhibitor, clorgyline. These observations suggest that the MAO-catalyzed formation of DOPAL and its accumulation by various mechanisms may be important processes that aggravate the neurotoxicity associated with mitochondrial dysfunction." http://pharmrev.aspetjournals.org/content/59/2/125.full http://pharmrev.aspetjournals.org/content/59/2/125.full So this is why MAO inhibitors are neuroprotective. They prevent this reaction.

paulwithap 12y ago

Does this come as a surprise to anyone?

apstls 12y ago

I wonder if Adderall, Vyvanse, and other ADD medications are chemically similar enough to Methylphenidate that they would exhibit a similar effect.

Houshalter 12y ago
Brand names are Concerta, Methylin, Ritalin, Equasym XL. I believe Adderall and other ADHD medications are similar in. I thought it was even in the title, but possibly the mods changed it. Watch it lose traction because no one knows what "Methylphenidate" means.

hoggle 12y ago

For anybody returning to this thread, here are some other discussions around this study I found on the web (thank you duckduckgo :) http://www.longecity.org/forum/topic/61161-methylphenidate-neurotoxic/ http://www.longecity.org/forum/topic/61161-methylphenidate-n... http://www.reddit.com/r/Nootropics/comments/1yd5bf/methylphenidate_neurotoxicity/ http://www.reddit.com/r/Nootropics/comments/1yd5bf/methylphe... http://www.plosone.org/annotation/listThread.action?root=53905 http://www.plosone.org/annotation/listThread.action?root=539... https://www.quora.com/What-are-the-long-term-effects-of-Adderall-Dexedrine-or-Ritalin-use https://www.quora.com/What-are-the-long-term-effects-of-Adde... --- And some studies suggesting other adverse neurodegenerative effects of MPH as well: "Methylphenidate treatment induces oxidative stress in young rat brain" http://www.sciencedirect.com/science/article/pii/S0006899306000606 http://www.sciencedirect.com/science/article/pii/S0006899306... "Methylphenidate induces lipid and protein damage in prefrontal cortex, but not in cerebellum, striatum and hippocampus of juvenile rats." http://www.ncbi.nlm.nih.gov/pubmed/22968482 http://www.ncbi.nlm.nih.gov/pubmed/22968482