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Dr. Bob is Robert Hsiung, MD,
[email protected]Shown: posts 1 to 16 of 16. This is the beginning of the thread.
Posted by btnd on February 1, 2003, at 14:27:02
Ok I'm confused, most of the studies on pubmed show that amphetamine (or methamphetamine) is neurotoxic. So how can Adderall/Dexedrine or any other amphetamine-based drug be prescribed and used even by children? Is there a different action of amphetamine in small doses (up to 40 mg)? What about neurotoxicity? I'm mostly interested whether 50 mg amphetamine/daily is neurotoxic or not. I appreciate your input.
Posted by utopizen on February 1, 2003, at 16:15:49
In reply to Adderall - what is the action of amphetamines?, posted by btnd on February 1, 2003, at 14:27:02
> Ok I'm confused, most of the studies on pubmed show that amphetamine (or methamphetamine) is neurotoxic. So how can Adderall/Dexedrine or any other amphetamine-based drug be prescribed and used even by children? Is there a different action of amphetamine in small doses (up to 40 mg)? What about neurotoxicity? I'm mostly interested whether 50 mg amphetamine/daily is neurotoxic or not. I appreciate your input.
>>>>>>The term "neurotoxic" is both the most definitive and vague term in all neurology. How do you think they establish neurotoxicity? It's very difficult, and once it's done, there's still some doubts.
Besides, most of the "neurotoxicity" data on amphetamines comes from animals. Don't trust neurotoxicity data coming from an animal model. There's obviously a sketchy reason why they'd resort to an animal model to find out neurotoxicity, especially if it pertains to a widely use drug that has abuse potential.
And a lot of neurotoxic research is funded by federal funds. NIH, and particularly that drug abuse federal research bureau, can get more sketchy than a speed junky at a Etch-A-sKETCH contest when it comes to establishing neurotoxicity.
Peter Briggin loves citiing a trial where chimps given methamphetamine had holes in their brain.
Okay, this study should potentially concern you if you are a chimp. But otherwise, ignore these people. They get a lot of money, hundreds of thousands of dollars, from federal grants wishing to prove that amphetamines cause neurotoxicity.
Desoxyn (methamphetamine) is NOT neurotoxic in humans. It's never once been established as such. And if it ever had, it's probably IV methamphetamine, which is much different to a brain cell than methamphetamine that weans itself into your brain over a thirty minute period.
I've taken Desoxyn for a month, and I haven't been able to notice any holes in my head or sensed many drafts in the winter time. Yet if I did, I suppose this has its benefits. I'd be more open-minded, right?
Posted by stjames on February 1, 2003, at 17:21:56
In reply to Re: Adderall - what is the action of amphetamines?, posted by utopizen on February 1, 2003, at 16:15:49
> > Ok I'm confused, most of the studies on pubmed show that amphetamine (or methamphetamine) is neurotoxic. So how can Adderall/Dexedrine or any other amphetamine-based drug be prescribed and used even by children? Is there a different action of amphetamine in small doses (up to 40 mg)? What about neurotoxicity? I'm mostly interested whether 50 mg amphetamine/daily is neurotoxic or not. I appreciate your input.
At high levels almost everything is toxic. The tests that showed changes in neurology were at very high dose. Changes are not, per se, neurotoxicity. We have 90 years history of people taking amphetamines, so we would of seen neurotoxicity by this point, if it were there.Given how significant mental illness can be and the degree of change meds can bring, reporting changes to neurology because of these meds seems
a "well, duh". Since we are no where near being able to classify what most to the lifetime structure is of most parts of neurology, I think it is just as reasonable to infer the change in mental illness, while on meds, to the change in neurological structure. We do know some biochemical markers that are always assoc. with
neurotoxicity and they are not seen in amphetamine
use.
Posted by viridis on February 1, 2003, at 19:27:08
In reply to Adderall - what is the action of amphetamines?, posted by btnd on February 1, 2003, at 14:27:02
I don't know the specifics on amphetamines, but as StJames pointed out, just about everything is "neurotoxic" at high enough doses. Alcohol is, but no one worries about people who have a glass of wine with dinner. Nutmeg, dill, and various other herbs and spices can cause delirium and brain damage at high doses, yet obviously we don't worry about them. And, part of the action of a psychiatric med should be to change brain chemistry and functioning -- that's what we take them for. I'd have to check, but I think that "recreational" doses of amphetamines are way above what most people take for ADD etc.
As for the issue of animal models that Utopizen brought up -- you have to start somewhere, and although caution is certainly warranted in extrapolating results from animals to humans, this is a way to detect potentially unexpected dangers before the drugs are used on humans. And (sad as it may seem) chimps are about the best model there is -- they're the closest living relatives of humans and are extremely similar at the molecular and physiological levels.
BTW, I'm an animal lover with many rescued pets, but I have to acknowledge the value of animals in medical research, although I think the utmost care should be taken to minimize their use and suffering.
Posted by utopizen on February 2, 2003, at 0:47:41
In reply to Re: Adderall - what is the action of amphetamines?, posted by viridis on February 1, 2003, at 19:27:08
>
> BTW, I'm an animal lover with many rescued pets, but I have to acknowledge the value of animals in medical research, although I think the utmost care should be taken to minimize their use and suffering.>>
yeah, because if it weren't for chimps, I mean we might not have not cured AIDS...
Posted by utopizen on February 2, 2003, at 0:49:55
In reply to Re: Adderall - what is the action of amphetamines?, posted by viridis on February 1, 2003, at 19:27:08
Posted by viridis on February 2, 2003, at 1:41:05
In reply to Re: Adderall - what is the action of amphetamines?, posted by utopizen on February 2, 2003, at 0:47:41
Almost every artificial substance you ingest has been tested in animals first (and some you don't take have been rejected because of animal tests). So, unless you avoid all meds on these grounds, it's just an unfortunate but necessary part of the process.
Despite the hype to the contrary, there's no way to predict the possible effects on a complex system without animal testing.
But luckily, we're getting there. I don't like animal testing any more than you do -- I just don't see any way around it yet.
BTW, I'm a research biologist, although I don't do experiments on animals -- it would upset me too much.
Posted by utopizen on February 2, 2003, at 9:47:28
In reply to Re: Adderall - what is the action of amphetamines? » utopizen, posted by viridis on February 2, 2003, at 1:41:05
> Almost every artificial substance you ingest has been tested in animals first (and some you don't take have been rejected because of animal tests). So, unless you avoid all meds on these grounds, it's just an unfortunate but necessary part of the process.
>That's an absurd statement to make. I do not purify myself from animal research for the sake of myself. Doing so would not in any way contribute to the relief of animals from suffering. Such an assumption is based on the idea that cosmetics and pharmaceuticals share the same economic factors, which they don't. So it does not in any way invalidate my concern for animal testing. It also has nothing to do what I was saying.
But uh, how are those LD-50's going? Because actually, the alternatives the FDA allows for substituting LD-50's without animals is actually more accurate. It's tough to be any more vague than to simply herd a bunch of dogs in a room and dose them with a drug until half of them die.
It's still used because it IS vague, so when a pharma company gets sued, they can go, "hey, look, we couldn't have known, it didn't pose a problem in the LD-50's".
Posted by viridis on February 2, 2003, at 16:59:56
In reply to Re: Adderall - what is the action of amphetamines?, posted by utopizen on February 2, 2003, at 9:47:28
Hi Utopizen,
I don't want to get into a major argument about animal testing, and I agree that there's a big difference between pharmaceuticals and, say, cosmetics (I don't favor animal testing for frivolous products like that).
You can always find examples in which a particular species of animal reacts differently to a given substance than a human does -- I'm sure the LD-50s are quite different for many chemicals in dogs vs. humans, for example. But the problem is, what's the alternative? Some people propose computer models, cell cultures, etc. before bringing a drug to human trials. These approaches can be helpful, but we still don't have a way to model or approximate the complex interactions in a living organism without actually using an organism. So, do we go straight to humans? That seems awfully risky to me.
One case that comes to mind is Pregabalin, the successor to Neurontin. The company was getting all set to market it, when a study in mice showed a significantly higher incidence of tumors in the treatment vs. control group. Now, of course, that doesn't necessarily mean it will cause cancer in humans, but it sure raises a red flag, and points to the need for more study before it starts getting prescribed to people. In mice, which only live a few years, tumors show up quickly enough that they can be detected in an experiment. In humans, it could be 10 or 20 years down the road before users start developing cancer (if the drug is, in fact, a carcinogen in humans).
We could go back and forth, with you citing cases in which animals have proven to be poor substitutes for humans, and me giving examples of ways in which animal testing has contributed to drug development or alerted the pharm companies to unexpected dangers. I guess my view is that it's unfortunate that animal testing is necessary, and it's far from perfect, but it's the best approach we've got at this point.
Anyway, this is starting to move outside the realm of PB material, so probably we should get back to discussing what these drugs do in humans.
All the best,
Viridis
P.S. Good luck with your new pdoc!
Posted by utopizen on February 2, 2003, at 18:25:37
In reply to Re: Adderall - what is the action of amphetamines? » utopizen, posted by viridis on February 2, 2003, at 16:59:56
Yeah, I guess any more posts and Dr. Bob will be upset.
But the fact is, the FDA must approve alternative tests, so it's not like companies are doing their own thing and listening to lay people like me tell them what test is best!
And I've been following the Pregabalin thing. Who cares? It's cancer. I'll take it anyway. Neurontin was interesting, but it made me depressed sometimes. Hopefully that'll be tweaked out by Pregabalin. Do you let what drug you take get determined by some a few mice? Because I don't.
Posted by Shawn. T. on February 2, 2003, at 21:38:54
In reply to Adderall - what is the action of amphetamines?, posted by btnd on February 1, 2003, at 14:27:02
I'll choose to ignore the comments suggesting that amphetamines are not neurotoxic simply because all the research has been conducted on animals. Amphetamines cause the release of norepinephrine, dopamine, and serotonin from nerve terminals. The neurotoxicity of methamphetamine may be a result of its actions at the vesicular monoamine uptake transporter VMAT2. This theory states that methamphetamine prevents dopamine from being transferred to synaptic vesicles (basically storage compartments) due to its inhibitory actions at VMAT2. Free "unstored" dopamine in neuron terminals is then metabolized; this action results in the production of neurotoxic free radicals. I believe that this theory may also be applied to amphetamine, because it also inhibits VMAT2 activity.
An alternative theory is that methamphetamine and amphetamine produce neurotoxicity through the release of the excitatory neurotransmitter glutamate. When glutamate attaches to one type of glutamate receptor, NMDA receptors, it may produce neurotoxic effects. Think of this as a form of stress for neurons; too much excitatory activity causes damage. This damage may also be a result of the damaging properties of free radicals, but some researchers also argue that hyperthermia plays a role.
I don't believe that anyone is likely to know the difference between the effects of a 50mg/day and a 40mg/day dose of amphetamine on neurotoxicity, but I can make some suggestions related to diet. A reasonable piece of advice based on the research that I have described is to give children taking amphetamines a well balanced diet that provides them with adequate amounts of antioxidants. Another possibility is to give children omega-3 fatty acids (found in fish oil). Omega-3 fatty acids can increase the expression of VMAT2 in the brain; to some degree, this effect would counteract the effects of amphetamines at these transporters. You should also be aware of the fact that amphetamines affect children differently than they do adults. Young mice do not experience neurotoxic effects similar to those seen in older mice; naysayers will point out our lack of ability to translate this to humans, but it should offer some small bit of reassurance. Note that all those links are simply there as references to the points that I've made; you probably won't gain too much from reading them.
Shawn
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9648873&dopt=Abstract
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1436384&dopt=Abstract
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9871444&dopt=Abstract
Posted by utopizen on February 2, 2003, at 22:05:35
In reply to Re: Adderall - what is the action of amphetamines? » btnd, posted by Shawn. T. on February 2, 2003, at 21:38:54
Considering the widely abused rate of the amphetamines during the 60's and 70's, the rate of consquences stemming from such abuse would have been seen by now.
In one article written in '68 for the Atlantic, anecdotes of entire pill parties where it was commonplace to take 300mg-500mg of amphetamines at a time, often of the methamphetamine pharmaceutical Desoxyn combined with Nembutal, called Desbutal.
These people thought amphetamines had nearly made sleep obsolete, and would go days without it on a regular basis.
It's not just that rats have different neurochemistry. The biggest problem is trying to find equivelent dosing. Remember that for ritalin trials on pediatric uses, rat pups are required. And also remember that Ritalin and the amphetamines do not have weight coorelations to their dosing. An obsese adult may require less Ritalin than a 40 lb. 4 yr. old. So exactly how do you determine what a similar effect will occur from a dose given to a rat pup will be? The answer is you never will know, in the same reason that it remains impossible to extrapolate findings BETWEEN humans much less between entire species.
Posted by utopizen on February 2, 2003, at 22:06:16
In reply to Re: Adderall - what is the action of amphetamines? » btnd, posted by Shawn. T. on February 2, 2003, at 21:38:54
Posted by Shawn. T. on February 2, 2003, at 23:45:26
In reply to Re: Adderall - what is the action of amphetamines?, posted by utopizen on February 2, 2003, at 22:05:35
I should note that I didn't mention anything about Ritalin. There really isn't any evidence that Ritalin is neurotoxic. Another thing to note is that methamphetamine is known to be more neurotoxic than amphetamine. If you've ever heard of methamphetamine abusers that state that they no longer have the ability to feel pleasure, this is perhaps the best evidence available that the drug does cause neurotoxicity in humans. I agree that there really isn't any hard evidence to show that amphetamines cause neurotoxicity in humans. There also exists the possibility that the brain can recover from neurotoxicity. I don't believe that it is really possible to argue (based on hard evidence) one way or another on this issue. I'm certainly not arguing that amphetamines should not be made available for medicinal purposes. I do, however, believe that there are very serious consequences associated with methamphetamine abuse; you just cannot deny that. I really don't know the effects of amphetamine (not meth) abuse in adults; it's important to know that there is a risk involved, however. The real point that I was trying to make was that if amphetamine neurotoxicity does occur in humans over the relevant dosage range, then we have a basic knowledge of how to go about preventing it to some degree.
Shawn
Posted by viridis on February 3, 2003, at 1:51:33
In reply to Re: Adderall - what is the action of amphetamines?, posted by utopizen on February 2, 2003, at 18:25:37
"And I've been following the Pregabalin thing. Who cares? It's cancer. I'll take it anyway".
Funny how attitudes change with age. If I thought something I took had a good chance of causing cancer, I'd avoid it no matter what. And yet, I smoked for years when I was younger.
BTW, I'm especially sensitive about this right now -- a good friend is having a mastectomy tomorrow, and it seems likely that the cancer has already spread. She's in her 30s and will have to undergo extensive chemo- and radiation therapy. So, this really is serious, once you have to face it.
Posted by uchiha itachi on August 21, 2004, at 4:28:51
In reply to Re: Adderall - what is the action of amphetamines?, posted by utopizen on February 1, 2003, at 16:15:49
>> The term "neurotoxic" is both the most definitive and vague
>> term in all neurology. How do you think they establish
>> neurotoxicity? It's very difficult, and once it's done,
>> there's still some doubts.
To be able to make such a statement with absolution, you'd
have to be a doctor. But after reading your post, the term
impossible comes to mind.
Neurotoxic is not in any way vague. It can be used loosely,
however, since the terminology doesn't require a neurotoxin
to be present. The only difficulty that comes into factor with
the use of that term is when the observed damage is nothing
but a mere deficit caused by a substance.>> Besides, most of the "neurotoxicity" data on amphetamines
>> comes from animals. Don't trust neurotoxicity data coming
>> from an animal model. There's obviously a sketchy reason
>> why they'd resort to an animal model to find out neurotoxicity,
>> especially if it pertains to a widely use drug that has
>> abuse potential."
No, what would be sketchy is if they started using human models to
support their findings. In order to get any conclusive data, you'd
have to have a preserved brain to start with. To get that, first,
you perfuse the test subject's body fully with warm then cold
saline solution (otherwise the brain would turn into putty);
then you decapitate them and extract their brain; and finally,
you take the brain slices and examine them under a microscope.
That's quite possible. But then you'd have to find someone
willing to take the drugs and is on the verge of dying. Makes
it a lot more difficult, but not impossible. And lastly, you'd
have to find someone who's dying from something that's not
related to their heart, brain, kidney, or liver. Otherwise chances
are that they'll die from the drugs.>> And a lot of neurotoxic research is funded by federal funds.
>> NIH, and particularly that drug abuse federal research bureau,
>> can get more sketchy than a speed junky at a Etch-A-sKETCH
>> contest when it comes to establishing neurotoxicity."
Where'd you get that from? From what I've seen NIDA's
(NIH's drug abuse subsidary) funding for neurotoxicity has
been almost entirely for drugs like MDMA.>> Desoxyn (methamphetamine) is NOT neurotoxic in humans. It's never
>> once been established as such. And if it ever had, it's probably
>> IV methamphetamine, which is much different to a brain cell than
>> methamphetamine that weans itself into your brain over a thirty
>> minute period.
Prove it. If it doesn't cause a build-up of neurotoxins, then
you must have concrete proof.
Also, it's foolish to think that IV methamphetamine is
any different then the solidified form. The crystal form has
a specific oral availability that's used in equating how much
of the drug will be absorbed into your blood stream. The pill
that you pop would roughly give you the same concentration
of the drug as if you took it IV.
>> I've taken Desoxyn for a month, and I haven't been able to
>> notice any holes in my head or sensed many drafts in the winter
>> time. Yet if I did, I suppose this has its benefits. I'd be
>> more open-minded, right?"
If you could see a hole in your head, it would be because
somebody shot you.
You've only taken it a month. That doesn't mean shit. If you take
it for years and you still don't notice any cognitive deficits,
then I'll believe you.And damn.. I just realized that this topic is from a year ago.
Arg.. and I wasted all this time writing it too.
This is the end of the thread.
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