Methylphenidate Exposure Induces Dopamine Neuron Loss in Mice | Hacker News Reader

Methylphenidate Exposure Induces Dopamine Neuron Loss in Mice

plosone.org

63 pointshoggle54 comments

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-...

You cannot directly convert mouse to human doses. For this, you need to calculate HED[1] (Human Equivalent Dosage). Using your numbers:

HED (mg/kg) = Animal Dose (mg/kg) x [Animal Km / Human Km]

We use 3 for mice and 25 for human (child)

HED = 10 x ( 3 / 25) = 1,2 mg/kg

In a 20kg kid we have a dose of 24 mg, which is only slightly higher than a normal dose.

[1] http://www.fasebj.org/content/22/3/659.full.pdf

That's a fair comment. One can't assume that an equal dose per kg will translate reliabily from an animal to a human.

My only reply is that the BSA method of dose conversation has issues of it's own (referred to in your paper) with regards to drug metabolism.

Also, the focus of the paper is on dose translations from animal to human studies. One would obviously want to be conservative in that regard.

You are right. Drug metabolism is key here; that´s why I am not too worried about the results of this study.

I have a child (24kg) with - properly diagnosed - severe ADHD on 20mg daily and the benefits clearly outweigh the potential risks; as with everything in life, nothing has zero risk.

Adult here who has taken Methylphenidate for 28 years. I would strongly suggest that weekends and holidays are also days off the medication.

Thanks for the hint. Our neuro suggested to halve the dose during weekends and holidays to avoid potential withdrawal symptoms

Out of curiosity why do you recommend this?

As someone who's taken (and continues to take) various stimulants to manage ADD:

Because you build up a tolerance over time, which requires larger doses, and because untreated ADD/ADHD is also linked to increased creativity and some degree of impulsiveness (which can be a good thing, vs. indecisiveness).

If I were doing more creative work, I would probably go without during creative phases and with while producing (for example, as a journalist, go without to come up with ideas for stories, then back on to burn through the associated research, production, refining, etc.).

At higher doses, I'm able to fixate on one task to the exclusion of all else (e.g. distractions, music, hunger, illness); at moderate doses, I tend to flit between interesting topics until I find something I can easily focus on (or perhaps until the medication kicks in at full strength).

Methylphenidate was inducing psychosis in me: delusions and hallucinations, which gradually got worse over time. This is a known side effect of amphetamine and similar drugs (like methylphenidate) when taken for long periods of time. When I started going off it on weekends, the psychosis stopped, and I was able to take it for several more years before I finally stopped taking it altogether. I took it ages 6 to 12 or so.

Withdrawing every weekend was uncomfortable, but better than psychosis.

As every one else said, but I will add a couple of notes.

ADD is part of who I am its just not very compatible with current work environments. I don't like to feel drugged all the time and I know that i'm ok with out being medicated.

I have developed sufficient coping skills as an adult to enable me to choose when I need to be medicated and when I don't.

I just wanted to thank you for still answering on this thread. Your sharing of your experiences is very much welcome, I've only been on Ritalin for over a month and already feel exactly as you describe it. Still, I'm asking myself if you couldn't also harm your wiring by having this on/off thing going on (I'm currently on 30mg Ritalin LA which presumably is a rather high dosage). I've always been more interested into computers so this brain thing is kind of new to me - a blacker kind of box than it already is so to say :)

I would have been kicked out of school with out ritalin so there wasn't much option when I started taking it at 9. You have to judge for yourself as an adult if the costs out weight the risks.

Because Ritalin exists to medicate children into submission so they can sit at a desk for 8 hours a day like good little workers, and it's less important to comply with this constraint on weekends and holidays, when the parents, not the school system, have to deal with the child's desire to not sit at a desk for 8 hours a day like a good little worker.

That's the difficulty with animal studies. There are general rules that can be used to guide interpretation of results, but every drug is unique and there are a lot of exceptions to any rule.

And that's ignoring individual variation in response.

It shouldn't surprise anyone that so many drugs in development fail.

Thank you for posting this. I do not personally work with animals, but I knew there must be a way to convert doses between mice and humans given how often my colleagues test drugs on rats and mice.

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.

What dose of Ritalin did you take to have such side effects?

Something like 50mg/day IIRC

There may be pharmacokinetic reasons for using these higher doses in mice. The rate at which drugs absorb through the blood brain barrier, are metabolized by the liver, and are eliminated by the kidneys are all factors one must consider. Not to mention the does response for MPD in mice may in fact be different. The goal of this study was not to simulate therapeutic dosing of MPD, but of chronic (short term, high dose) application of the drug. You are correct in noting that this study does not directly translate to humans taking the typical therapeutic dose, but it certainly does raise questions.

I agree. I would love to see what plasma concentrations were achieved in the mice at each dose and compare that to what is typically seen in humans.

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!

Exactly. Dosage relative to weight matters when drawing conclusions.

Its easy to read articles/papers like the OP link and be alarmed, but the three biggest risk factors with Ritalin (and similar drugs) is that the dose is appropriate for weight, the dosage is scheduled properly and sleep.

If the dosage schedule is above the half life of the medication, and blood level is still high at +12 hours later then neurons will get "burned" and lost.

Don't sleep for the required hours and schedule, neurons get "burned" as well.

This is also why recreational crystal meth [1] is very bad for the brain. Crystal meth overloads the neurons and definitely not equivalent to Rx Ritalin as intelligently prescribed.

[1] http://www.drugabuse.gov/publications/drugfacts/methamphetam...

> This is also why recreational crystal meth [1] is very bad for the brain. Crystal meth overloads the neurons and definitely not equivalent to Rx Ritalin as intelligently prescribed.

"Crystal meth" isn't equivalent to Ritalin (methylphenidate), but it is equivalent to Desoxyn (brand name for methamphetamine), and more or less equivalent to Adderall (d-amphetamine, with a bit of l-amphetamine).

All three drugs are prescribed for a variety of conditions and, in appropriate doses, are safe[0]. The main difference between Desoxyn and Adderall is that the extra methyl group attached to the amphetamine makes it cross the blood-brain barrier more easily, which means that the equivalent doses are smaller (by weight). The metabolic processes and the effects on the brain are virtually identical, though, so it's misleading to draw a line between them and label one as "good" and the other "bad".

The real reason that people think of crystal meth as "bad" is because it's taken in far higher doses recreationally than would ever be prescribed medically, and because it's smoked (not that this is inherently bad, but changing the means of ingestion changes the onset, duration of effects, etc.[1])

[0] At least, to the extent that we can say that any pharmaceutical is "safe"

[1] This is why nicotine gum is frustrating to many smokers, because it takes much longer to absorb.

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!

> 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).

Maybe I read the abstract differently or don't fully understand it but its conclusion doesn't seem to align with yours, right?

"Collectively, our results suggest that chronic MPH usage in mice at doses spanning the therapeutic range in humans, especially at prolonged higher doses, has long-term neurodegenerative consequences."

I was on about 60mg/day (across three doses) when I was 8 or 9. Not sure how typical that kind of dosing is.

Very high. How much time were you on that dosage ? Any bad side effect ?

I was on high doses like that for at least a couple years, but I don't remember what the exact doses I was on when. It's hard to say what was a side effect of the Ritalin and what wasn't, but I suspect the following:

* Stunted height - I'm several inches shorter than my father, grandfathers and uncles (all in the 6'2" to 6'4" range).

* Very short temper and aggressive tendencies (went away entirely in my teens when I was on significantly lower doses)

I also remember having serious withdrawal symptoms if I missed doses.

if you want to read about 0.25 mg kg^-1, see: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2988577/

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.

...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".

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.

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...

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?

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?

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.

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.

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...

"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."

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

So this is why MAO inhibitors are neuroprotective. They prevent this reaction.

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.

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

Concerta is a prolonged release version of Ritalin: https://en.wikipedia.org/wiki/Methylphenidate

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-n...

http://www.reddit.com/r/Nootropics/comments/1yd5bf/methylphe...

http://www.plosone.org/annotation/listThread.action?root=539...

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/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

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.

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.

I think he means the rats they did the study on.

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

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.

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

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?

It could be that HN mods altered the headline by the time you saw it.

Does this come as a surprise to anyone?

Reply on news.ycombinator.com