It won't be long before they're banned as new studies show how neurotoxic they are, in particular to the dopaminergic system.
Edited by Isochroma, 07 January 2009 - 05:14 AM.
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Long-Term Effects Of Taking Modafinil and AHDH Drugs
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Rags847
, Feb 20 2008 07:24 AM
82 replies to this topic
#31 Guest_Isochroma_*
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Posted 07 January 2009 - 05:13 AM
I'm hearing a long series of excuses and apologetics for the tragedy of amphetamines and the now-proven permanent damage they cause even at small (ie. ADD-'treatment' level) doses. Damage to children, who often have no choice as they are dosed against their will with these neurolethal compounds. It is a sickening story.
It won't be long before they're banned as new studies show how neurotoxic they are, in particular to the dopaminergic system.
It won't be long before they're banned as new studies show how neurotoxic they are, in particular to the dopaminergic system.
#32 Guest_Isochroma_*
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Posted 07 January 2009 - 05:16 AM
Amphetamine brain damage measured
The brain damage caused by amphetamine use is still noticeable years later, say experts.
In fact, users undergo similar brain chemical changes to patients suffering from Alzheimer's Disease, stroke or brain tumours.
Methamphetamine, also known as "speed" is a stimulant which acts on the central nervous system and quickens the heartbeat.
Users report increased confidence, sociability and energy levels. The effects usually last for several hours with the user feeling particularly hyperactive, and very awake.
However, there can also be feelings of nervousness or irritability and depression as the effects of the drug wear off.
Neuron damage
But there is significant evidence that the drug can cause damage to the brain's neurons - the cells which are used for thinking.
Methamphetamine users have reduced concentrations of a chemical called N-acetyl-aspartate, which is a byproduct of the way neurons work.
Research carried out in Torrance, California, and reported in the journal "Neurology", compared the brains of 26 previous methamphetamine users with 24 non-users.
They found at least 5% lower concentrations of N-acetyl-aspartate in two key areas of the brain, the basal ganglia and frontal white matter.
Dr Thomas Ernst, who led the project, said: "Many brain diseases associated with brain cell or neuronal damage or loss, such as Alzheimer's disease and other dementias, epilepsy, multiple sclerosis, brain tumours, stroke and HIV brain diseases, consistently have shown decreased N-acetyl-aspartate.
"This, in the drug users' brains, suggests neuronal loss or damage as a result of long-term methamphetamine use."
Amphetamines work by releasing large quantities of the brain stimulating chemical dopamine.
Animal studies have shown brain abnormalities persisting four years after amphetamine use stops.
Groups such as the Institute for the Study of Drug Dependence say that amphetamine use is actually falling, despite its association with the club scene.
Amphetamine users can become dependant on the drug, and withdrawal symptoms can cause depression and lethargy.
Heavy, regular use can cause hallucinations, delusions and feelings of paranoia.
The brain damage caused by amphetamine use is still noticeable years later, say experts.
In fact, users undergo similar brain chemical changes to patients suffering from Alzheimer's Disease, stroke or brain tumours.
Methamphetamine, also known as "speed" is a stimulant which acts on the central nervous system and quickens the heartbeat.
Users report increased confidence, sociability and energy levels. The effects usually last for several hours with the user feeling particularly hyperactive, and very awake.
However, there can also be feelings of nervousness or irritability and depression as the effects of the drug wear off.
Neuron damage
But there is significant evidence that the drug can cause damage to the brain's neurons - the cells which are used for thinking.
Methamphetamine users have reduced concentrations of a chemical called N-acetyl-aspartate, which is a byproduct of the way neurons work.
Research carried out in Torrance, California, and reported in the journal "Neurology", compared the brains of 26 previous methamphetamine users with 24 non-users.
They found at least 5% lower concentrations of N-acetyl-aspartate in two key areas of the brain, the basal ganglia and frontal white matter.
Dr Thomas Ernst, who led the project, said: "Many brain diseases associated with brain cell or neuronal damage or loss, such as Alzheimer's disease and other dementias, epilepsy, multiple sclerosis, brain tumours, stroke and HIV brain diseases, consistently have shown decreased N-acetyl-aspartate.
"This, in the drug users' brains, suggests neuronal loss or damage as a result of long-term methamphetamine use."
Amphetamines work by releasing large quantities of the brain stimulating chemical dopamine.
Animal studies have shown brain abnormalities persisting four years after amphetamine use stops.
Groups such as the Institute for the Study of Drug Dependence say that amphetamine use is actually falling, despite its association with the club scene.
Amphetamine users can become dependant on the drug, and withdrawal symptoms can cause depression and lethargy.
Heavy, regular use can cause hallucinations, delusions and feelings of paranoia.
Edited by Isochroma, 07 January 2009 - 05:17 AM.
#33 Guest_Isochroma_*
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Posted 07 January 2009 - 05:20 AM
Amphetamine-Linked Free Radicals Damage the Brain
THURSDAY, April 13 (HealthDay News) -- Researchers say they've gained new insight into how amphetamines like ecstasy or "crystal meth" harm the brain.
In studies with mice, a team at the University of Toronto found that these drugs are converted in the brain into free radicals -- highly reactive molecules that cause neurodegenerative brain damage. The effects of this free radical damage can linger a long time after the amphetamine has left the body, the researchers say. Free radicals have been implicated in neurodegenerative diseases such as Alzheimer's and Parkinson's.
The Toronto team also believes that prostaglandin H synthase (PHS) -- an enzyme that synthesizes a range of hormones -- plays a critical role in the transformation of amphetamines into free radicals.
The findings appear in the April issue of the FASEB Journal, published by the Federation of American Societies for Experimental Biology.
Further study is required to determine if these findings apply to humans, the researchers said.
The findings about the role of PHS in converting amphetamines into free radicals in the brain may be relevant to neurodegenerative risks associated with aging, the researchers said.
"Preliminary results from other studies suggest that PHS may convert other compounds in our brains into free radicals, and there is some evidence in the clinical literature that suggests patients who take high does of PHS-inhibiting drugs such as aspirin may experience less neurodegeneration," study lead author Professor Peter Wells, of the Leslie Dan Faculty of Pharmacy, said in a prepared statement.
"The potential of substances like aspirin to prevent neurodegenerative damage merits more examination, particularly among people who take it chronically for pain," Wells said.
More information
The U.S. National Institute on Drug Abuse has more about methamphetamines.
THURSDAY, April 13 (HealthDay News) -- Researchers say they've gained new insight into how amphetamines like ecstasy or "crystal meth" harm the brain.
In studies with mice, a team at the University of Toronto found that these drugs are converted in the brain into free radicals -- highly reactive molecules that cause neurodegenerative brain damage. The effects of this free radical damage can linger a long time after the amphetamine has left the body, the researchers say. Free radicals have been implicated in neurodegenerative diseases such as Alzheimer's and Parkinson's.
The Toronto team also believes that prostaglandin H synthase (PHS) -- an enzyme that synthesizes a range of hormones -- plays a critical role in the transformation of amphetamines into free radicals.
The findings appear in the April issue of the FASEB Journal, published by the Federation of American Societies for Experimental Biology.
Further study is required to determine if these findings apply to humans, the researchers said.
The findings about the role of PHS in converting amphetamines into free radicals in the brain may be relevant to neurodegenerative risks associated with aging, the researchers said.
"Preliminary results from other studies suggest that PHS may convert other compounds in our brains into free radicals, and there is some evidence in the clinical literature that suggests patients who take high does of PHS-inhibiting drugs such as aspirin may experience less neurodegeneration," study lead author Professor Peter Wells, of the Leslie Dan Faculty of Pharmacy, said in a prepared statement.
"The potential of substances like aspirin to prevent neurodegenerative damage merits more examination, particularly among people who take it chronically for pain," Wells said.
More information
The U.S. National Institute on Drug Abuse has more about methamphetamines.
#34
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Posted 07 January 2009 - 08:56 AM
once again, you show nothing of value. its no news that amphetamine is bad for you...
you seem a bit ignorant when it comes to chemistry. Just because a molecule has a basic backbone, such as the benzene ring, or amphetamine, does not mean it exhibits the same toxicity as the parent compound...
I will give you an example, rather than mumble a study of no value like you did.
Selegeline consists of a methamphetamine backbone.. The effects of both compounds vary greatly.. Just because selegeline has a methamphetamine skeleton does not mean it exhibits the same properties as meth........
you seem a bit ignorant when it comes to chemistry. Just because a molecule has a basic backbone, such as the benzene ring, or amphetamine, does not mean it exhibits the same toxicity as the parent compound...
I will give you an example, rather than mumble a study of no value like you did.
Selegeline consists of a methamphetamine backbone.. The effects of both compounds vary greatly.. Just because selegeline has a methamphetamine skeleton does not mean it exhibits the same properties as meth........
#35 Guest_Isochroma_*
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Posted 08 January 2009 - 12:29 AM
On the contrary my useless acquantaince, you have shown your IGNORANCE quite well, and also your LAZINESS. You have shown NOTHING in your WORDS. I have provided proof; and furthermore proof RELEVANT to the TOPIC of this thread.
I TOOK THE TROUBLE to VALIDATE my words with actual studies. You even had the GALL to attack me for providing evidence of my assertions: "rather than mumble a study of no value like you did". Mumble? A study of "NO VALUE"???
How are those studies of "NO VALUE"? Tell me, my intelligent acquaintance, how those studies are of no value. Or maybe, get a grip! Your attack is simply revealing your agenda in the most obvious fashion.
So just give up and quit filling this thread with your stupid, unvalidated unproven personal opinion.
Leave the real discussion to those who know how to create and validate by evidence their propositions.
Oh and one more note on your carelessness, you double posted an identical copy of your 'response'. Embarrasing, eh?
I TOOK THE TROUBLE to VALIDATE my words with actual studies. You even had the GALL to attack me for providing evidence of my assertions: "rather than mumble a study of no value like you did". Mumble? A study of "NO VALUE"???
How are those studies of "NO VALUE"? Tell me, my intelligent acquaintance, how those studies are of no value. Or maybe, get a grip! Your attack is simply revealing your agenda in the most obvious fashion.
So just give up and quit filling this thread with your stupid, unvalidated unproven personal opinion.
Leave the real discussion to those who know how to create and validate by evidence their propositions.
Oh and one more note on your carelessness, you double posted an identical copy of your 'response'. Embarrasing, eh?
Edited by Isochroma, 08 January 2009 - 12:40 AM.
#36
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Posted 08 January 2009 - 12:39 AM
Meth is about ten times more powerful than regular amphetamine, and the doses used are pretty high. Enough so that they don't sleep for days or weeks on end. Which would require 300+ mg of regular amphetamine per day, and much more with tolerance. More than ten times the typical dose. Saying someone taking the equivalent of 300-500mg of amphetamines every day is analogous to someone taking 10-30mg every day is a pretty big stretch. To be honest only 5% lower concentrations is surprisingly better than I expected.
Pretty much every psych drug has some serious negative side effects in the long run, many of them very bad. Neuron death is a concern for amphetamines, but it's also a concern for caffeine and literally 90% of the US consumes caffeine on a daily basis.
Lower is lower, but the questions are how much lower does cognition become, especially with low doses? There's also neurogenesis, so nothing is really permanent. Not to mention neuroprotectants.
Ultimately, I can get many times more work done with amphetamines while on it because otherwise I am virtually useless without someone putting massive pressure on me or on the rare occasions I get hyperfocused on something actually useful. From everything I've seen for low doses if there's any impairment it's trivial, and the millions of people who have been taking it daily for decades are not walking zombies yet (except for a few who take way too much). I'm past the one year mark right now, and if anything I believe I am smarter than ever in my life, though I am not typical because I take a myriad of supplements including neuroprotectants and lithium (which can cause up to 3% brain growth in just 4 weeks!). One of my best friends has been on adderall for 15 years and she has the sharpest wit I've ever come across.
It's always good to see more research and I do have some concern, but the chances of a ban on amphetamines is about one in a million (aside from wonky countries like canada that even ban amino acids and choline sources). There's no doubt they have some bad effects (and potentially extremely bad if misused) but the good effects obviously outweigh them for a fairly large proportion of the population. Compared to antipsychotics, neuroleptics, MAOIs or benzos their side effects seem pretty mild. If I had to take antiphychotics or high dose lithium as a treatment instead I'd just go unmedicated unless it were a life and death matter.
Pretty much every psych drug has some serious negative side effects in the long run, many of them very bad. Neuron death is a concern for amphetamines, but it's also a concern for caffeine and literally 90% of the US consumes caffeine on a daily basis.
Lower is lower, but the questions are how much lower does cognition become, especially with low doses? There's also neurogenesis, so nothing is really permanent. Not to mention neuroprotectants.
Ultimately, I can get many times more work done with amphetamines while on it because otherwise I am virtually useless without someone putting massive pressure on me or on the rare occasions I get hyperfocused on something actually useful. From everything I've seen for low doses if there's any impairment it's trivial, and the millions of people who have been taking it daily for decades are not walking zombies yet (except for a few who take way too much). I'm past the one year mark right now, and if anything I believe I am smarter than ever in my life, though I am not typical because I take a myriad of supplements including neuroprotectants and lithium (which can cause up to 3% brain growth in just 4 weeks!). One of my best friends has been on adderall for 15 years and she has the sharpest wit I've ever come across.
It's always good to see more research and I do have some concern, but the chances of a ban on amphetamines is about one in a million (aside from wonky countries like canada that even ban amino acids and choline sources). There's no doubt they have some bad effects (and potentially extremely bad if misused) but the good effects obviously outweigh them for a fairly large proportion of the population. Compared to antipsychotics, neuroleptics, MAOIs or benzos their side effects seem pretty mild. If I had to take antiphychotics or high dose lithium as a treatment instead I'd just go unmedicated unless it were a life and death matter.
#37 Guest_Isochroma_*
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Posted 08 January 2009 - 12:43 AM
You're right on the unlikelyhood of a ban. The reason is that much of the system as it is constituted is quite dependant on drugging people so they can be slaves to the machine. Amphetamines are quite desireable to that end, and fit in with the capitalist system of working people ever longer hours for lower wages. The military makes great use of these agents as well.
And let us not forget the enormous multibillion dollar profits the pharmaceutical corporations make selling amphetamines to, among others, children.
All that matters is to extract as much as possible from people in the short-term, and if they are disabled later, well, that's just more money for the disease establishment.
The wildcard however, is that studies do eventually happen, and no matter how much pressure is applied eventually the truth gets out, and eventually after years or even decades, the government is forced to take action. By the pressure of agitators and victims, reality will eventually get pounded into the skulls of those who are responsible for regulation.
It takes patience, truth and never, never, never! giving up to force the world to change. It is like pushing against a glacier, grinding forward ever so slowly until at a certain moment, everything flows and power rotates into a new configuration which has a living future beyond the possibilities of the old.
And let us not forget the enormous multibillion dollar profits the pharmaceutical corporations make selling amphetamines to, among others, children.
All that matters is to extract as much as possible from people in the short-term, and if they are disabled later, well, that's just more money for the disease establishment.
The wildcard however, is that studies do eventually happen, and no matter how much pressure is applied eventually the truth gets out, and eventually after years or even decades, the government is forced to take action. By the pressure of agitators and victims, reality will eventually get pounded into the skulls of those who are responsible for regulation.
It takes patience, truth and never, never, never! giving up to force the world to change. It is like pushing against a glacier, grinding forward ever so slowly until at a certain moment, everything flows and power rotates into a new configuration which has a living future beyond the possibilities of the old.
Edited by Isochroma, 08 January 2009 - 12:49 AM.
#38
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Posted 08 January 2009 - 12:50 AM
On the contrary my useless acquantaince, you have shown your IGNORANCE quite well, and also your LAZINESS. You have shown NOTHING in your WORDS. I have provided proof; and furthermore proof RELEVANT to the TOPIC of this thread.
I TOOK THE TROUBLE to VALIDATE my words with actual studies. You even had the GALL to attack me for providing evidence of my assertions: "rather than mumble a study of no value like you did". Mumble? A study of "NO VALUE"???
How are those studies of "NO VALUE"? Tell me, my intelligent acquaintance, how those studies are of no value. Or maybe, get a grip! Your attack is simply revealing your agenda in the most obvious fashion.
So just give up and quit filling this thread with your stupid, unvalidated unproven personal opinion.
Leave the real discussion to those who know how to create and validate by evidence their propositions.
Oh and one more note on your carelessness, you double posted an identical copy of your 'response'. Embarrasing, eh?
Well, you have modafinil as the subject of this thread so I don't think you have a leg to stand on in the mistakes department. Modafinil isn't even a stimulant, really. It works on histamine receptors and is about as completely different from amphetamine as can be. And as I pointed out, there's a big difference between meth and amphetamines. Including the delivery method. Snorting is a much faster onset so the blood concentrations of even the same dose could be as much as ten times as high. Injection is even worse, and people who inject stimulants are almost invariably dead within a few months. Even in the study you cite originally they state there is no cause for undue alarm and you are obviously leaping to some dramatic conclusions. Banning amphetamines isn't going to happen, not in a million years. That's a fact. There's cause for concern and it does worry me and I am very cautious, but at the same time that doesn't mean people should throw out their pills, and for many people that's really not an option.
#39 Guest_Isochroma_*
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Posted 08 January 2009 - 12:54 AM
"Well, you have modafinil as the subject of this thread so I don't think you have a leg to stand on in the mistakes department."
Now now, don't be embarrasing yourself with half-truths. The title of this thread is:
"Long-Term Effects Of Taking Modafinil and AHDH Drugs (Adderall, Ritali, What do you think they are?"
I'm not talking about ALL the drugs in the title, obviously. Specifically, I'm talking about ADDERALL, ie.
1/4 dextroamphetamine saccharate
1/4 dextroamphetamine sulfate
1/4 (racemic dextro/levo-amphetamine) aspartate monohydrate
1/4 (racemic dextro/levo-amphetamine) sulfate
That is the formulation and thus ADDERALL is simply AMPHETAMINE under a different name. The name was chosen to hide the obviously negative connotations, and of course to provide the usual corporate branding and patent-protection.
However, your statement leads me to anticipate the topic of my next post, which might be the other drug quoted in the thread title. Do you really want me to start on that one too? Yay or Nay, it is your choice. Is it time yet to open that door?
Now now, don't be embarrasing yourself with half-truths. The title of this thread is:
"Long-Term Effects Of Taking Modafinil and AHDH Drugs (Adderall, Ritali, What do you think they are?"
I'm not talking about ALL the drugs in the title, obviously. Specifically, I'm talking about ADDERALL, ie.
1/4 dextroamphetamine saccharate
1/4 dextroamphetamine sulfate
1/4 (racemic dextro/levo-amphetamine) aspartate monohydrate
1/4 (racemic dextro/levo-amphetamine) sulfate
That is the formulation and thus ADDERALL is simply AMPHETAMINE under a different name. The name was chosen to hide the obviously negative connotations, and of course to provide the usual corporate branding and patent-protection.
However, your statement leads me to anticipate the topic of my next post, which might be the other drug quoted in the thread title. Do you really want me to start on that one too? Yay or Nay, it is your choice. Is it time yet to open that door?
Edited by Isochroma, 08 January 2009 - 12:56 AM.
#40 Guest_Isochroma_*
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Posted 08 January 2009 - 02:35 AM
It's time to examine another of the drugs mentioned in the thread's title, methylphenidate aka. Ritalin.
Abstract
Ritalin, or methylphenidate, is often used to treat attention deficit hyperactivity disorder (ADHD) and attention deficit disorder (ADD). Some of the many long-term effects of Ritalin use are reduced cerebral blood flow, increased energy consumption in many areas of the brain, permanent loss of brain tissue, life-long increased sensitivity to cocaine, and life-long increased rates of depression and anxiety.
Introduction
Ritalin, or methylphenidate, is commonly prescribed as treatment for attention deficit hyperactivity disorder (ADHD) and attention deficit disorder (ADD). It is estimated that 750,000 to 1 million school children are receiving 20 million prescriptions for stimulant medications and the figure is still growing (IMS Health 2002). Many of the long-term effects of Ritalin use stay with the patient for life. This is primarily because of the fact that Ritalin is most often used during childhood and adolescence while the brain is still developing.
Constricts Blood Flow to the Brain
Investigators from the Brookhaven National Laboratory used PET scans to study the effects of Ritalin on overall cerebral blood flow. They measured the effect of clinical doses of Ritalin on blood flow in normal volunteers. They found that Ritalin decreased the overall flow of blood into the brain. The loss was large: 23-30% in all areas of the brain, including the higher brain centers in the frontal lobes, as well as in the basal ganglia deeper in the brain. The changes were sufficiently dramatic to be grossly apparent in the before and after photos. The reduction in blood flow is most likely caused by construction of the blood vessels related to the drug’s impact on dopamine (Wang et al. 1994).
Increases the Brain’s Energy Consumption
The brain uses glucose to meet its energy needs. The affects of Ritalin occur throughout many parts of the brain and especially those affected by dopaminergic nerves. Scientists at the National Institute of Mental Health studied the effects of Ritalin in the brains of conscious rats. They found that there were significant dose dependent alterations in metabolic activity in numerous areas of the brain. Energy consumption was increased in areas of the brain that are central to both motor activity and mental function like the frontal cortex, mediodorsal thalamus, nucleus accumbens, and substantia negra (Porrino et al. 1987).
Loss of Brain Tissue
A study at Ohio State University found that over 50 percent of the 24 young adults being studied had atrophy, or loss, of brain tissue. They were all treated with stimulants since childhood for hyperactivity. The researchers concluded that cortical atrophy may be a long term effect of taking stimulant medications (Nasrallah 1986).
Increased Sensitivity to Cocaine
A study at the Chicago Medical School examined how low doses of Ritalin affect dopamine cells in the brains of adolescent rats. Dopamine is a brain chemical that has been implicated in natural rewards, such as food and sex, as well as in drug abuse and addiction. The study showed that the rats experienced brain cell changes that subsequently made them more sensitive to the rewarding effects of cocaine (NIH 2003).
Another thirty year study at the University of California followed around 400 kids with ADHD that were treated with stimulant drugs during childhood. When those kids reached their mid to late 20s, researchers discovered they took up cigarette smoking earlier, smoked more heavily, and were more likely to abuse cocaine and other stimulants as adults (Lambert 1999).
This research also suggests a "sensitization hypothesis" based on animal studies showing that early exposure to amphetamine and methylphenidate predisposes rats to the reinforcing impact of cocaine. The same sensitization may occur in humans if exposure to stimulants such as methylphenidate predisposes children to the stimulating effects of tobacco, cocaine, and amphetamines (Lambert 1999).
Rates of Depression and Anxiety Increase
A study at the Harvard Medical School looked at how pre-adolescent exposure to methylphenidate affected certain behaviors in rats when they reached adulthood. They found that early exposure to twice-daily injections of methylphenidate increased behaviors that could indicate depression (NIH 2003).
Another study at the University of Texas Southwestern Medical Center assessed certain behaviors of adult rats that were given methylphenidate prior to adolescence. They found that compared to drug-naive rats, those chronically exposed to methylphenidate were less responsive to natural rewards, such as sugar and sex, and more sensitive to stressful situations. The animals that were exposed to methylphenidate also had increased anxiety-like behaviors and enhanced blood levels of stress hormones (NIH 2003).
Conclusion
Ritalin, or methylphenidate, is often used to treat attention deficit hyperactivity disorder (ADHD) and attention deficit disorder (ADD). Some of the many long-term effects of Ritalin use are reduced cerebral blood flow, increased energy consumption in many areas of the brain, permanent loss of brain tissue, increased sensitivity to cocaine, and life-long increased rates of depression and anxiety.
References
IMS Health. 2002. IMS Health Reports. http://www.imshealth.com
Lambert, N. 1999. Ritalin and its Cousins: Rx or Gateway Drugs? The Regents of the University of California. Vol. 27, No. 34.
Nasrallah, H., J. Loney, S. Olson, M. Mccalley-whitters, J. Kramer, C. Jacoby. 1986. Cortical atrophy in young adults with a history of hyperactivity in childhood. Psychiatry Research. 17: 241-246
NIH. 2003. http://www.nih.gov/n...003/nida-08.htm
Porrino, L.J., G. Lucignani. 1987. Different patterns of local brain energy metabolism associated with high and low doses of methylphenidate. Biological Psychiatry. 22: 126- 138
Wang, G.J., N.D. Volkow, J.S. Fowler, R. Ferrieri, D.J. Schyler, D. Alexoff, N. Pappas, J. Lieberman, P. King, D. Warner, C. Wong, R.J. Hitzemann, A.P. Wolf. 1994. Methylphenidate decreases regional cerebral blood flow in normal human subjects. Life Science. 54: PL143-PL146.
The Effects of Long-term Ritalin (Methylphenidate) Use
Krystle A. Cole
© 2007 NeuroSoup Trust. All Rights Reserved.
Abstract
Ritalin, or methylphenidate, is often used to treat attention deficit hyperactivity disorder (ADHD) and attention deficit disorder (ADD). Some of the many long-term effects of Ritalin use are reduced cerebral blood flow, increased energy consumption in many areas of the brain, permanent loss of brain tissue, life-long increased sensitivity to cocaine, and life-long increased rates of depression and anxiety.
Introduction
Ritalin, or methylphenidate, is commonly prescribed as treatment for attention deficit hyperactivity disorder (ADHD) and attention deficit disorder (ADD). It is estimated that 750,000 to 1 million school children are receiving 20 million prescriptions for stimulant medications and the figure is still growing (IMS Health 2002). Many of the long-term effects of Ritalin use stay with the patient for life. This is primarily because of the fact that Ritalin is most often used during childhood and adolescence while the brain is still developing.
Constricts Blood Flow to the Brain
Investigators from the Brookhaven National Laboratory used PET scans to study the effects of Ritalin on overall cerebral blood flow. They measured the effect of clinical doses of Ritalin on blood flow in normal volunteers. They found that Ritalin decreased the overall flow of blood into the brain. The loss was large: 23-30% in all areas of the brain, including the higher brain centers in the frontal lobes, as well as in the basal ganglia deeper in the brain. The changes were sufficiently dramatic to be grossly apparent in the before and after photos. The reduction in blood flow is most likely caused by construction of the blood vessels related to the drug’s impact on dopamine (Wang et al. 1994).
Increases the Brain’s Energy Consumption
The brain uses glucose to meet its energy needs. The affects of Ritalin occur throughout many parts of the brain and especially those affected by dopaminergic nerves. Scientists at the National Institute of Mental Health studied the effects of Ritalin in the brains of conscious rats. They found that there were significant dose dependent alterations in metabolic activity in numerous areas of the brain. Energy consumption was increased in areas of the brain that are central to both motor activity and mental function like the frontal cortex, mediodorsal thalamus, nucleus accumbens, and substantia negra (Porrino et al. 1987).
Loss of Brain Tissue
A study at Ohio State University found that over 50 percent of the 24 young adults being studied had atrophy, or loss, of brain tissue. They were all treated with stimulants since childhood for hyperactivity. The researchers concluded that cortical atrophy may be a long term effect of taking stimulant medications (Nasrallah 1986).
Increased Sensitivity to Cocaine
A study at the Chicago Medical School examined how low doses of Ritalin affect dopamine cells in the brains of adolescent rats. Dopamine is a brain chemical that has been implicated in natural rewards, such as food and sex, as well as in drug abuse and addiction. The study showed that the rats experienced brain cell changes that subsequently made them more sensitive to the rewarding effects of cocaine (NIH 2003).
Another thirty year study at the University of California followed around 400 kids with ADHD that were treated with stimulant drugs during childhood. When those kids reached their mid to late 20s, researchers discovered they took up cigarette smoking earlier, smoked more heavily, and were more likely to abuse cocaine and other stimulants as adults (Lambert 1999).
This research also suggests a "sensitization hypothesis" based on animal studies showing that early exposure to amphetamine and methylphenidate predisposes rats to the reinforcing impact of cocaine. The same sensitization may occur in humans if exposure to stimulants such as methylphenidate predisposes children to the stimulating effects of tobacco, cocaine, and amphetamines (Lambert 1999).
Rates of Depression and Anxiety Increase
A study at the Harvard Medical School looked at how pre-adolescent exposure to methylphenidate affected certain behaviors in rats when they reached adulthood. They found that early exposure to twice-daily injections of methylphenidate increased behaviors that could indicate depression (NIH 2003).
Another study at the University of Texas Southwestern Medical Center assessed certain behaviors of adult rats that were given methylphenidate prior to adolescence. They found that compared to drug-naive rats, those chronically exposed to methylphenidate were less responsive to natural rewards, such as sugar and sex, and more sensitive to stressful situations. The animals that were exposed to methylphenidate also had increased anxiety-like behaviors and enhanced blood levels of stress hormones (NIH 2003).
Conclusion
Ritalin, or methylphenidate, is often used to treat attention deficit hyperactivity disorder (ADHD) and attention deficit disorder (ADD). Some of the many long-term effects of Ritalin use are reduced cerebral blood flow, increased energy consumption in many areas of the brain, permanent loss of brain tissue, increased sensitivity to cocaine, and life-long increased rates of depression and anxiety.
References
IMS Health. 2002. IMS Health Reports. http://www.imshealth.com
Lambert, N. 1999. Ritalin and its Cousins: Rx or Gateway Drugs? The Regents of the University of California. Vol. 27, No. 34.
Nasrallah, H., J. Loney, S. Olson, M. Mccalley-whitters, J. Kramer, C. Jacoby. 1986. Cortical atrophy in young adults with a history of hyperactivity in childhood. Psychiatry Research. 17: 241-246
NIH. 2003. http://www.nih.gov/n...003/nida-08.htm
Porrino, L.J., G. Lucignani. 1987. Different patterns of local brain energy metabolism associated with high and low doses of methylphenidate. Biological Psychiatry. 22: 126- 138
Wang, G.J., N.D. Volkow, J.S. Fowler, R. Ferrieri, D.J. Schyler, D. Alexoff, N. Pappas, J. Lieberman, P. King, D. Warner, C. Wong, R.J. Hitzemann, A.P. Wolf. 1994. Methylphenidate decreases regional cerebral blood flow in normal human subjects. Life Science. 54: PL143-PL146.
Edited by Isochroma, 08 January 2009 - 03:22 AM.
#41 Guest_Isochroma_*
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Posted 08 January 2009 - 02:51 AM
New Study Shows Early Ritalin
May Cause
Long-term Effects On The Brain
San Juan, Puerto Rico, December 12, 2004 – A new study conducted in rats by the National Institutes of Health (NIH) and McLean Hospital/Harvard Medical School suggests that the misdiagnosis of attention-deficit hyperactivity disorder (ADHD) combined with prescription drug use in children may lead to a higher risk of developing depressive symptoms in adulthood.
This work, released at the annual American College of Neuropsychopharmacology (ACNP) conference in Puerto Rico, is among the first to examine the effects of early Ritalin exposure in rats on behavior and brain function during the later periods of life.
"Attention-deficit hyperactivity disorder can be a serious medical problem for children and their parents," says lead researcher William Carlezon, Ph.D., director of McLean Hospital's Behavioral Genetics Laboratory and associate professor of psychiatry at Harvard Medical School. "While Ritalin is an effective medication that improves the quality of life for many children with ADHD, accurately diagnosing and identifying the correct treatment regimen for the disorder is essential, especially when considering health effects that can last through adulthood."
Ritalin is a generic medication prescribed for children with attention-deficit hyperactivity disorder (ADHD), a condition that consists of a persistent pattern of abnormally high level of activity, impulsivity, and/or inattention. Usually diagnosed in children of preschool or elementary school age, ADHD has been estimated to affect 3 to 12 percent of children and is twice as common among boys. Children with ADHD are also likely to have other disorders, such as a learning disability, oppositional defiant disorder, conduct disorder, depression, or anxiety.
Because most children show some of these behaviors of inattention and hyperactivity at times, the diagnosis of ADHD is a complex process that should involve specialists. It is critical to determine whether a child's behavior is simply immature or exuberant, related to another issue such as a vision problem or learning disability, or is characteristic of a disorder such as ADHD.
In the work funded by the NIH, Dr. Carlezon and his chief collaborator, Dr. Susan Andersen, examined the effects of exposing rats to Ritalin during early development on behaviors later in life. They exposed normal rats to twice-daily doses of Ritalin during a period that is equivalent to approximately 4-12 years of age in humans. Examining the behavior during adulthood, Carlezon and Andersen conducted several types of tests that all showed that the animals had a reduced ability to experience pleasure and reward, particularly when it was measured by sensitivity to cocaine. In addition, they found that the animals exposed to Ritalin during pre-adolescence were more prone to express despair-like behaviors in stressful situations (such as swim tests) as adults. Overall, the animals showed more evidence of dysfunctional brain reward systems and depressive-like behaviors in adulthood.
These findings are critical because they suggest that Ritalin can have long-term consequences on normal-functioning brains. The study is particularly relevant when considering the difficulty in correctly diagnosing children with ADHD. In 1999, approximately 90 percent of children diagnosed with the disorder were taking Ritalin, with children beginning drug therapy at younger ages today, even during preschool in some instances. There is increasing evidence to suggest that correct diagnosis of ADHD is of the highest importance – children who are misidentified as having ADHD and subsequently placed on prescription drug therapy could face possible impaired brain performance as adults.
"Ritalin can be highly effective in the treatment of ADHD, but our work highlights the importance of getting a proper diagnosis", states Carlezon. "Although individuals such as teachers and coaches can assist in identifying children with the disorder, an experienced health care professional is best-trained to make the final assessment and recommend avenues of treatment."
ACNP, founded in 1961, is a professional organization of more than 700 leading scientists, including four Nobel Laureates. The mission of ACNP is to further research and education in neuropsychopharmacology and related fields in the following ways: promoting the interaction of a broad range of scientific disciplines of brain and behavior in order to advance the understanding of prevention and treatment of disease of the nervous system including psychiatric, neurological, behavioral and addictive disorders; encouraging scientists to enter research careers in fields related to these disorders and their treatment; and ensuring the dissemination of relevant scientific advances.
Edited by Isochroma, 08 January 2009 - 02:54 AM.
#42 Guest_Isochroma_*
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Posted 08 January 2009 - 03:08 AM
Ritalin may cause long-lasting changes in brain-cell function,
UB researchers find
SAN DIEGO -- Scientists at the University at Buffalo have shown that the drug methylphenidate, the generic form of Ritalin, which physicians have considered to have only short-term effects, appears to initiate changes in brain function that remain after the therapeutic effects have dissipated.
The changes appear to be similar to those that occur with other stimulant drugs such as amphetamine and cocaine, said Joan Baizer, Ph.D., UB professor of physiology and biophysics and senior author of the study. Results of the research were presented here today (Nov. 11, 2001) at the annual meeting of the Society for Neuroscience.
"Clinicians consider Ritalin to be short-acting," said Baizer. "When the active dose has worked its way through the system, they consider it 'all gone.' Our research with gene expression in an animal model suggests that it has the potential for causing long-lasting changes in brain cell structure and function." Ritalin is the drug of choice for the treatment of attention deficit disorder in children.
Baizer stated, however, that while the neuronal changes are similar to those seen with cocaine and other psychoactive drugs, it does not seem that methylphenidate in very low doses, as used therapeutically, produces much potential for drug abuse.
"Children have been given Ritalin daily for many years, and it is extremely effective and beneficial, but it's not quite as simple as a short-acting drug," Baizer said. "We need to look at it more closely." Baizer added: "Ritalin does appear to be safe when used properly, but it is still important to ask what it is doing in the brain."
Previous work in other laboratories has shown that high doses of amphetamine and cocaine switch on certain genes called "immediate early genes" in particular brain cells and that this action causes changes in some aspects of nerve cell function. One of those genes is called "c-fos." Amphetamine and cocaine both cause c-fos activity in the striatum, a brain structure important for both movement and motivation, and the presence of c-fos activity there has been implicated in the mechanism of addiction, Baizer said. The researchers wanted to see if methylphenidate caused c-fos activation in the same parts of the brain, and at the same levels, as the other drugs.
Using young rats as an animal model, they gave one group sweetened milk containing a relatively high dose of methylphenidate (20 mg/kg). Considering the differences in metabolism between rats and humans, this is comparable approximately to a dose on the high end of the range that is used therapeutically, Baizer said. They administered the drug at a time during the rat's 24-hour cycle that would simulate the timing of a child's dose. Another group received just sweetened milk. After 90 minutes, the optimal time for c-fos development in brain cells, the brains of both groups were analyzed for the presence of c-fos.
Results showed there were many more neurons with c-fos activity in the brains of rats given methylphenidate, particularly in the striatum, Baizer said, than in the brains of control rats. Rats receiving no treatment and sacrificed after a period of rest showed still less c-fos activity, suggesting that some of the c-fos activity is related to moving around in the home cage and not a pure drug effect.
"These data do suggest that there are effects of Ritalin on cell function that outlast the short term and we should sort that out," Baizer said. "There is no indication of tolerance, but we have no idea if there is adaptation to the effects."
One next step, she said, is to use microarray technology to see what other genes are turned on in response to short and long-term Ritalin use. Additional researchers on the study were Ashley Acheson, a graduate student in the UB Department of Psychology; Alexis Thompson, Ph.D., a research scientist at the UB Research Institute on Addictions, and Mark B. Kristal, Ph.D., UB professor of psychology.
Edited by Isochroma, 08 January 2009 - 03:10 AM.
#43 Guest_Isochroma_*
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Posted 08 January 2009 - 03:13 AM
Say hello to heart disease, Ritalin!
Henderson TA, Fischer VW . The American Journal of Cardiovascular Pathology. 1994;5:68-78.
"A number of adverse reactions have been associated with MPH therapy, particularly cardiovascular side effect, such as arrhythmia, tachycardia, and changes in blood pressure [1,2]. MPH is an amphetamine congener with a molecular structure resembling that of amphiphilic drugs. Administration of certain amphiphilic drugs has been shown to induce phospholipidoses by interfering with phospholipid catabolism in a variety of cell types, resulting in a lysosomal accumulation of abnormal amounts of membranes. Ultrastructurally, one striking alteration, among others, is the presence of lamellar bodies in a variety of tissues exposed to amphiphillic drugs."
"We have previously observed analogous lamellar membrane accumulations in myocardial cells of a patient on chronic therapy with MPH." "In order to determine if a causal relationship exists between MPH and ultrastructural myocardial changes previously described in the patient, we administered MPH to two rodent species.
Thirty male Swiss-Webster mice, weighing approximately 25-30 g each: Groups of 3 animals each were injected (intra-peritoneal) with 0.5 mg/kg, 2.5 mg/kg or 5.0 mg /kg of Ritalin. The injections were given three times a week for periods of 4 and 14 weeks prior to sacrifice.
Results: The myocardium of mice injected with 0.5 mg/kg MPH, regardless of treatment duration, showed little or no recognizable ultrasturctural changes…Incipient alterations were observed following treatment with 1.5 mg/kg MPH for 4 weeks; however administration of this dose for 14 weeks resulted in a variety of myocardial abnormalities similar to those seen with higher doses at all time points. Initially, foci of loose, unorganized aggregates of membranes and foci of distinctly circular membranous profiles with reduplication, suggesting the formation of lamellations, were observed. These abnormalities were reminiscent of a membrane folding back on itself and spiraling inward… "Pronounced lesions in our rodents were more evident with prolonged exposure and appeared to approach a stable level of incidence; however, lesions were highly focal and a wide range of alterations within individual animals was notices. These structural abnormalities persisted to a reduced degree, for a prolonged time after stopping the MPH injections.
"…it could be argued that our results do not directly apply to the clinical situation, because MPH was administered by injection. Yet, similar pathological changes were seen in the six mice that received MPH orally. The limited number of animals receiving MPH by this route dictates a cautious interpretation; nevertheless, we found no basis to expect a different pathological profile following oral administration."
"…it is difficult to draw conclusions concerning long-term accumulation or safe doses. Yet our observations definitively showed that lesions were present in animals treated with therapeutic doses and that these lesions persisted."
"this study, using laboratory animals under a controlled single drug regimen, corroborates and strengthens the previous supposition that MPH was a likely causal agent in the formation of similar ultrastructural alterations observed in a patient on chronic MPH therapy."
"Our treatment protocol revealed clearly the requirement of a minimal dose, in order to induce even incipient structural changes; however, these minimum dosages fell within the range of therapeutic dosage prescribed for patients with attention deficit disorders."
"Also noteworthy was the rapid development of pathological changes (i.e., within 3 weeks)."
"The rapid appearance of lamellar structures, coupled with the potential for irreversibility and the profound structural changes seen in a patient on long-term MPH therapy, suggests that these findings may have clinical consequences for drug interactions and long-term side effects of MPH of which clinicians should be aware."
Effects of Methylphenidate (Ritalin) on Mammalian Myocardial Ultrastructure
Henderson TA, Fischer VW . The American Journal of Cardiovascular Pathology. 1994;5:68-78.
"A number of adverse reactions have been associated with MPH therapy, particularly cardiovascular side effect, such as arrhythmia, tachycardia, and changes in blood pressure [1,2]. MPH is an amphetamine congener with a molecular structure resembling that of amphiphilic drugs. Administration of certain amphiphilic drugs has been shown to induce phospholipidoses by interfering with phospholipid catabolism in a variety of cell types, resulting in a lysosomal accumulation of abnormal amounts of membranes. Ultrastructurally, one striking alteration, among others, is the presence of lamellar bodies in a variety of tissues exposed to amphiphillic drugs."
"We have previously observed analogous lamellar membrane accumulations in myocardial cells of a patient on chronic therapy with MPH." "In order to determine if a causal relationship exists between MPH and ultrastructural myocardial changes previously described in the patient, we administered MPH to two rodent species.
Thirty male Swiss-Webster mice, weighing approximately 25-30 g each: Groups of 3 animals each were injected (intra-peritoneal) with 0.5 mg/kg, 2.5 mg/kg or 5.0 mg /kg of Ritalin. The injections were given three times a week for periods of 4 and 14 weeks prior to sacrifice.
Results: The myocardium of mice injected with 0.5 mg/kg MPH, regardless of treatment duration, showed little or no recognizable ultrasturctural changes…Incipient alterations were observed following treatment with 1.5 mg/kg MPH for 4 weeks; however administration of this dose for 14 weeks resulted in a variety of myocardial abnormalities similar to those seen with higher doses at all time points. Initially, foci of loose, unorganized aggregates of membranes and foci of distinctly circular membranous profiles with reduplication, suggesting the formation of lamellations, were observed. These abnormalities were reminiscent of a membrane folding back on itself and spiraling inward… "Pronounced lesions in our rodents were more evident with prolonged exposure and appeared to approach a stable level of incidence; however, lesions were highly focal and a wide range of alterations within individual animals was notices. These structural abnormalities persisted to a reduced degree, for a prolonged time after stopping the MPH injections.
"…it could be argued that our results do not directly apply to the clinical situation, because MPH was administered by injection. Yet, similar pathological changes were seen in the six mice that received MPH orally. The limited number of animals receiving MPH by this route dictates a cautious interpretation; nevertheless, we found no basis to expect a different pathological profile following oral administration."
"…it is difficult to draw conclusions concerning long-term accumulation or safe doses. Yet our observations definitively showed that lesions were present in animals treated with therapeutic doses and that these lesions persisted."
"this study, using laboratory animals under a controlled single drug regimen, corroborates and strengthens the previous supposition that MPH was a likely causal agent in the formation of similar ultrastructural alterations observed in a patient on chronic MPH therapy."
"Our treatment protocol revealed clearly the requirement of a minimal dose, in order to induce even incipient structural changes; however, these minimum dosages fell within the range of therapeutic dosage prescribed for patients with attention deficit disorders."
"Also noteworthy was the rapid development of pathological changes (i.e., within 3 weeks)."
"The rapid appearance of lamellar structures, coupled with the potential for irreversibility and the profound structural changes seen in a patient on long-term MPH therapy, suggests that these findings may have clinical consequences for drug interactions and long-term side effects of MPH of which clinicians should be aware."
Edited by Isochroma, 08 January 2009 - 03:25 AM.
#44 Guest_Isochroma_*
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Posted 08 January 2009 - 04:30 AM
Ritalin was not the answer for Matthew
Followup to Associated Press Story of April 2000
By Shula Edelkind, August 15, 2000
Links updated April 2006
Last March, while skateboarding like any other 14-year-old American boy, Matthew Smith, of Berkley, Michigan, fell over and died. What happened? His death touched off a controversy as Medical Examiner Ljubisa Dragovic, in spite of pressure to "find some other explanation," announced that the boy's death was caused by heart damage from 8 years of Ritalin use.
What followed was an Associated Press article carried by multiple newspapers careful to include the quotes of two psychiatric professionals - and no cardiologists - claiming that side effects of Ritalin are "not significant and do not include death" and even that Dragovic's conclusions and diagnosis were "unfounded."
The immediate reaction of many parents whose children take Ritalin or other stimulants was to worry. The Feingold Association Help-Line reported numerous calls and e-mails from frantic parents whose children had been experiencing weakness, fast heartbeat, even heart murmurs. Some of those families opted to try diet therapy to replace drug therapy at that time. Not long after, however, at a local CHADD meeting in Atlanta, and presumably at other ADHD support groups across the country, it was whispered from sources unknown that the boy had been taking other prescription drugs as well, that he had an underlying pre-existing heart disorder, and that he had complained of symptoms but was ignored. Now that they could attribute Matthew's death to other medications, a freak medical condition, or parental neglect, people calmed down.
Nevertheless, questions remain -- how calm should we be? Is the grapevine accurate? How much should we worry? How many other children really are at risk? Do we know how to tell when they are in trouble before it is too late? Now that children are beginning to use Ritalin earlier, at age 2 and 3, and are expected to remain on it many years, or even their entire life, has this risk increased? How many years can a child safely take this medication before it becomes unsafe? If symptoms become "clinically significant," is it too late? Is it reversible? Why did none of the news articles quote a pediatric cardiologist? Or ANY cardiologist? What does a psychologist know about the "clinical significance" of a heart symptom? How can a psychiatrist, without ever looking at the child's heart muscle, decide that a Medical Examiner's decision is wrong?
The original news stories are no longer available, but for those of you who did not read the original Associated Press story, you can get more information at the following links:
Ritalin Prescription Takes Life Of 14 Year Old by the father of Matthew Smith
World Net Daily: Ritalin's long-term effects questioned
What actually killed Matthew?
According to Dr. Dragovic, upon autopsy Matthew's heart showed clear signs of small vessel damage -- the type caused by stimulant drugs such as amphetamines and cocaine. The boy did not have a pre-existing heart defect or disease. The boy had not been taking other drugs, prescription or illegal. The boy's complaints had not been ignored by his parents.
Dr. Dragovic describes his job as law enforcement. He is in the business, he says, of "calling a crow a crow, and an elephant an elephant. This is where the buck stops." He said that the type of damage he observed in Matthew's heart indicated small blood vessel changes that are caused by long term stimulant medication. He explained that this is nothing like the artery blockage in older men with high cholesterol and heart disease. This is a particular type of damage seen commonly in people who have abused cocaine or other stimulants. He explained that stimulant drugs affect every part of the body that has adrenergic receptors. Once the changes occur, you are left with a heart that cannot respond to sudden increases in functional demands. These changes seen in the blood vessels that supply the heart muscle are not reversible.
Current Recommendations (as of 2000)
The American Heart Association (AHA) recommends that before beginning treatment with any psychotropic drugs, children should be carefully evaluated for "long QT" and other heart rhythm abnormalities. The doctor should also take "a careful history ... with special attention to symptoms such as palpitations, syncope (fainting) or near-syncope." All other medications should also be known, because medications that affect the heart or inhibit the P450 system [the enzyme system dealing with toxins, medications, etc.] could cause problems. A careful history is important. But think -- Do you know whether your child has ever had palpitations or a feeling of weakness? Has anybody in your family ever had such an experience? How would you know if you have a long QT measurement without having an electrocardiogram to find out?
According to the AHA, tricyclic antidepressant (TCA) drugs such as imipramine and desipramine not only increase heart rate, but also prolong the various intervals of the heartbeat, as measured by EKG. These drugs include Tofranil, Anafranil, Elavil, Norpramin, Triavil ... Although they are often used together with Ritalin, and reported to be safe by studies such as the Findling study below, the AHA recommends frequent EKG monitoring of TCA, especially in combination with Ritalin, in spite of the fact that Ritalin itself is reported to increase heart rate and blood pressure only to an "insignificant degree." The AHA is specific that in the absence of symptoms or history of pre-existing heart disease or heart rhythm abnormalities, the use of Ritalin alone does not require an EKG prior to use, nor any later cardiovascular monitoring.
Dr. Rosenberg, a child psychiatrist with Children's Hospital of Michigan, when asked whether a child should be tested for any type of heart condition before prescribing Ritalin, responded that "it is far more important that the child have a psychiatric assessment by a trained mental health care professional and be prescribed appropriately." However, Dr. Rosenberg added that "if a child experiences racing heart beat or weakness, or any other symptoms, the parents should notify the person prescribing the medicine." Dr. Dragovic agreed, adding that unfortunately, some children have been under follow-up by pediatric cardiologists but nothing has surfaced because the detection of these changes is difficult. "Small vessel damage is insidious and much harder to see than problems with the large arteries that can be resolved by by-pass surgeries," he said. "More sophisticated stress tests are needed for a physicians to attempt to diagnose small vessel disease."
John Cantwell, MD, Director of Preventive Cardiology and Cardiac Rehabilitation at Piedmont Hospital in Atlanta, frequently deals with young adult athletes and runners. When Dr. Cantwell sees high school athletes with ADHD on stimulant medications that have any problem such as chest discomfort, palpitations or racing heart beat upon exercising, he tries to get them off the drugs. He agrees a parent should be concerned if there are any such symptoms. "In general," he said, "if a parent called and said her son is on Ritalin and playing ball but his heart is racing, I would try to do studies to see if the heart is normal or if it is working harder, if there are rhythm abnormalities." One approach, he said, is to do an EKG test while exercising. The doctor can also put the individual in a cardiac rehabilitation program for one day to monitor his heart. For complaints that are infrequent, it is possible to use an Event Recorder - the patient pushes a button when his or her heart beats fast and it is recorded and transmitted over the phone, or it is documented and transmitted later.
Dr. Cantwell also suggested that the physician can examine the heart to make sure it is not enlarged, that there is no heart murmur or other abnormalities. If there is any concern about symptoms or history, the patient or patient's parent can request a referral to a cardiologist. Unfortunately direct tests for small vessel disease would require complex catheterization, an invasive procedure not typically done on a child. If small vessel disease is detected, medical treatment -- for example, vasodilators like nitroglycerin -- might be recommended.
Dr. Dragovic pointed out, meanwhile, that there are five million children now using Ritalin or similar drugs in North America. While a few deaths may not be significant when talking about millions, they are 100% significant to their families. Saying that there would be no side effects from a drug "is as ridiculous as stating the earth is flat."
Research on the Safety of Ritalin
See the list of research studies
According to Dr. Rosenberg, the claim that the cardiac side effects of Ritalin are not significant has never been verified in any long-term studies, but only in short and 1-to-3 year studies.
One such study on the safety of both Ritalin and the combination of Ritalin with TCA is the study by Findling in 1996 on the use of Ritalin and TCA medications together and separately. While using only 22.5 mg of Ritalin alone, one of the 11 subjects, an adult, had a highly significant rise of 20 points in diastolic (the lower number) blood pressure. Depending on the original level, his blood pressure could have entered the "stroke zone." What would long term un-monitored use do to such a patient?
Findling concluded, however, that using these two medications together is safe, and said nothing in his abstract about the safety of Ritalin alone, even though it was clearly unsafe for that one person - and he was 10% of the sample.
Multiple studies since 1977 have shown that Ritalin affects the small blood vessels of the heart. Henderson & Fischer (1995) determined that lesions in the heart muscle seen in a patient on Ritalin could be caused dependably in rats and mice by administration of Ritalin. Dr. John Cantwell explained the connection -- when the small vessels cannot deliver appropriate amounts of oxygen to the myocardium (heart muscle cells), then those cells die. This forms the lesions that could be seen under the electron microscope. This effect is not reversible, according to the Henderson & Fischer study.
Apparently, moreover, not all children are equally affected. A study by Brown and Sexson (1989) concludes that "Because of the unexpected increase in diastolic blood pressure, careful monitoring of black adolescents who are receiving methylphenidate is recommended." This follows Brown's earlier study in 1984 which concluded that while the authors agreed that "cardiovascular functioning did not significantly increase as a function of methylphenidate" yet they caution that "due to the large intraindividual variability in cardiovascular response, careful monitoring of each patient's response is recommended." Translated, this means that while the effects are not significant averaged together, for some individual children they are indeed serious.
The American Heart Association's scientific advisors have been asked to comment about these studies, as well as whether they may know of any ongoing studies about unusual risk to African-American children. Jim Kiser, on behalf of their staff scientists, responded that the AHA has not yet taken a good look at the Brown and Sexson 1989 study, and therefore has no opinion on it. The scientists will be provided the study for future analysis. Kiser says that the AHA does fund research studies, and he agreed to pass on to the AHA scientific staff the specific request to consider funding scientific studies relating to the safety of Ritalin use in African-American children.
The American Heart Association does not discuss small vessel disease in connection with Ritalin, on their website. In fact, they specify that children on Ritalin do not need to be monitored. [editor note: since small vessel disease can only be accurately diagnosed by autopsy, perhaps they are right that such monitoring is not useful.] After our communication, it has been observed that the link to this page is no longer on their Home Page, and the information has also apparently been removed from their "Site Map."
While the stimulant drugs Ritalin, Adderall, etc. are ignored by the American Heart Association, however, they have several interesting articles on the connection of heart disease and the other stimulant drugs caffeine and cocaine: [The original links used in this article are no longer active, but following are updated search results of their website]
Caffeine ... "Whether high intakes of caffeine increases the risk of coronary heart disease is still under study." (What about studies on the risk of Ritalin and caffeine together? Should children using Ritalin be warned not to drink coffee or caffeinated sodas until such studies are completed?)
Cocaine & Heart Disease
Cocaine, Marijuana and Other Drugs
Cocaine Use and the Likelihood of Nonfatal Myocardial Infarction and Stroke 2001
Following are more articles on the risk of heart disease and stroke. Note that chronic high blood pressure is a major factor, yet the chronic elevated blood pressure in children or adults taking Ritalin - especially Black children - is not mentioned:
* Search results on risks of heart disease for African-Americans ... all risk factors discussed except Ritalin use.
* Stroke Risk Factors
* "High blood pressure - High blood pressure is defined in an adult as a systolic pressure of 140 mm Hg or higher and/or a diastolic pressure of 90 mm Hg or higher for an extended time. It's the most important risk factor for stroke."
* "Cigarette smoking - In recent years studies have shown cigarette smoking to be an important risk factor for stroke. The nicotine and carbon monoxide in cigarette smoke damage the cardiovascular system in many ways. Using birth control pills and smoking cigarettes greatly increases stroke risk." (How many young people taking Ritalin long term also smoke and / or use birth control? Are they adequately warned not to?)
* "Diabetes mellitus - Diabetes is an independent risk factor for stroke and is strongly correlated with high blood pressure. While diabetes is treatable, having it still increases a person's risk of stroke. People with diabetes often also have high cholesterol and are overweight, increasing their risk even more." (Are parents of children with diabetes and ADHD warned of this connection?)
* "Excessive alcohol intake - Excessive drinking (an average of more than one drink per day for women and more than two drinks per day for men) and binge drinking can lead to stroke. It can also raise blood pressure, contribute to obesity, high triglycerides, cancer and other diseases, and cause heart failure." (Are our children with ADHD adequately warned about this as they enter their late teens?)
* "Certain kinds of drug abuse - Intravenous drug abuse carries a high risk of stroke from a cerebral embolism . Cocaine use has been closely related to strokes, heart attacks and a variety of other cardiovascular complications. Some of them have been fatal even in first-time cocaine users." (Are our children with ADHD adequately warned that they may be even more at risk than their friends?)
Dr. Dragovic stressed (in our conversation held in 2000) that 5 million children in North America were being given Ritalin or similar drugs regularly. It is also known through Drug Enforcement Administration (DEA) reports that there has been a 9-fold increase in the abuse of Ritalin in the 10 years from 1990 to 2000, mostly by young people who crush it for snorting or injecting. What we are seeing in this area, he said, is "astonishing and brings up an awareness that there is an ocean-sized problem out there that needs to be looked at very carefully by multidisciplinary teams for careful reassessment of the use of this drug."
"In a balanced view," he continued, "one cannot neglect the reports and one cannot neglect the experimental studies that have shown clearly that there is a valid concern. If there is one death, we don't have to wait for 100,000 people to die before we conclude that it is dangerous. We have to have what we call intelligence."
"It is very logical that the more [Ritalin] people use, the greater are the chances for the development of these vessel changes and the greater the chances to experience serious health problems relative to the cardiovascular system and drug dependency."
Although Matthew and his family were healthy with no heart disease or other risk factors, and thus no way to predict this outcome, he did warn that in some cases there are risk factors to consider. Children with diabetes, for example, have a propensity to develop coronary problems. This could possibly mean that children with diabetes are more at risk than the general population.
Now that older children as well as adults are using Ritalin, there is an added problem of alcohol use. Dr. Dragovic discussed the combination of cocaine and alcohol, in which a chemical called cocaethylene is formed in the liver. This prolongs the half-life of cocaine, which is the length of time for half the cocaine to leave the body. The alcohol thus potentiates [makes stronger] the effect of the cocaine, causing possible overdose situations. Because both cocaine and Ritalin are stimulant drugs, while alcohol is a CNS (central nervous system) depressant, there may be the same situation with Ritalin, but he had not seen a case yet. (Remember, Medical Examiners only see cases that result in death.) There have been deaths, however, reported by Markowitz (1999) in which the combination of alcohol and Ritalin resulted in a chemical called ethylphenidate which was found in their blood and liver samples. A study by Markowitz (2000) suggests that even in non-overdose situations, "the metabolite ethylphenidate may contribute to drug effects." If your child on Ritalin insists on using alcohol, discuss with his physician whether continuing the Ritalin is wise.
Dr. Dragovic is concerned because there has been a substantial number of cardiovascular problems being reported about Ritalin. He is also aware of the cardiovascular effects of similar drugs. He appealed to those who are prescribing such medication, to weigh the risks and benefits, saying "My message will be that clinicians continue to treat their patients as individuals, not as diseases. Re-focus and look for potential side effects. And remember ... first do no harm."
References
1. Cardiovascular responses of hyperactive children to methylphenidate. Ballard JE et al., JAMA 1976 Dec 20;236(25):2870-4
2. A controlled trial of methylphenidate in black adolescents. Attentional, behavioral, and physiological effects. Brown RT, Sexson SB, Clin Pediatr (Phila) 1988 Feb;27(2):74-81
3. Effects of methylphenidate on cardiovascular responses in attention deficit hyperactivity disordered adolescents. Brown RT, Sexson SB, J Adolesc Health Care 1989 May;10(3):179-83
4. Attention deficit disorder and the effect of methylphenidate on attention, behavioral, and cardiovascular functioning. Brown RT, Wynne ME, Slimmer LW, J Clin Psychiatry 1984 Nov;45(11):473-6
5. Methylphenidate's effects on paired-associate learning and event-related potentials of young adults. Brumaghim JT, Klorman R, Psychophysiology 1998 Jan;35(1):73-85,
6. Effect of methylphenidate on young adult's vigilance and event-related potentials. Coons HW et al, Electroencephalogr Clin Neurophysiol 1981 Apr;51(4):373-87
7. Open-label treatment of comorbid depression and attentional disorders with co-administration of serotonin reuptake inhibitors and psychostimulants in children, adolescents, and adults: a case series. Findling RL, J Child Adolesc Psychopharmacol 1996 Fall;6(3):165-75
8. Atrioventricular nodal re-entrant tachycardia associated with stimulant treatment. Gracious BL, Journal of Child Adolescent Psychopharmacology 1999;9(2):125-8
9. Effects of methylphenidate (Ritalin) on mammalian myocardial ultrastructure. Henderson TA, Fischer VW, Am J Cardiovasc Pathol 1995;5(1):68-78
10. Biphasic inotropic effects of methamphetamine and methylphenidate on ferret papillary muscles. Ishiguro Y, Morgan JP, J Cardiovasc Pharmacol 1997 Dec;30(6):744-9
11. Attention deficit disorder and methylphenidate: a multi-step analysis of dose-response effects on children's cardiovascular functioning. Kelly KL, Rapport MD, DuPaul GJ, Int Clin Psychopharmacol 1988 Apr;3(2):167-81
12. Mechanisms of cardiac and vascular responses to cocaine. Knuepfer MM, Branch CA, Fischer VW, NIDA Res Monogr 1991;108:55-73
13. Cocaine-induced myocardial ultrastructural alterations and cardiac output responses in rats. Knuepfer MM, Branch CA, Gan Q, Fischer VW, Exp Mol Pathol 1993 Oct;59(2):155-68
14. Methylphenidate and nortriptyline in the treatment of poststroke depression: a retrospective comparison. Lazarus LW, Moberg PJ, Langsley PR, Lingam VR, Arch Phys Med Rehabil 1994 Apr;75(4):403-6
15. Effects of background anger, provocation, and methylphenidate on emotional arousal and aggressive responding in attention-deficit hyperactivity disordered boys with and without concurrent aggressiveness. Pelham WE, J Abnorm Child Psychol 1991 Aug;19(4):407-26
16. Methylphenidate and cocaine have a similar in vivo potency to block dopamine transporters in the human brain. Volkow ND et al, Life Sci 1999;65(1):PL7-12
17. Methylphenidate decreases regional cerebral blood flow in normal human subjects. Wang GJ, et al., Life Sci 1994;54(9):PL143-6
18. Absence of cardiovascular adverse effects of sertraline in children and adolescents. Wilens TE, Biederman J et al, J Am Acad Child Adolesc Psychiatry 1999 May;38(5):573-7
Edited by Isochroma, 08 January 2009 - 04:35 AM.
#45
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Posted 08 January 2009 - 05:00 PM
You show nothing new.. i like your last post with the picture though. Very touching. I cried reading it while listening to Chopins Nocturne in C sharp. About the myocardial structure, anything that raises blood pressure increasing the heart load will in the long term cause some sort of compensation. Any idiot would know that. Its like 1+1=2. Any stimulant will do the following, just so you can review your physiology and pharmacology:
1- constrict vessels
2-increase bp
3-increase heart rate
4-alter gut motility
and so on and so on.
You still have not shown that ritalins inherent activity at blocking dopamine reuptake is toxic in any way. You have just given me a nice review lecture on the activity of stimulants on the body. I can substitute the word coffee for everytime you have ritalin in your post and get away with it. As a matter of fact, I have provided a study, which shows that Ritalin actually prevents amphetamine induced dopamine deficits.. And your nice PET scan means nothing. I can put a someone having sex in there, on no drugs, and he will shine brighter than both your ritalin and cocaine user.
And just for your information, showing pictures and trying to throw sympathy cards in an argument is a very poor handling of an argument. I can do the same, by showing you a picture of some prisoner, and tell you, oh here is mathew the prisoner. Only if he was given ritalin, maybe he could have stayed home and done something constructive.
Here is something for you to read:
http://www.bnl.gov/b...nlpr092998.html
As you see, most of these studies with rats are done with ritalin given IV. If you know anything about pharmacology, which seems like you might not, and your scientists look like they are too busy fueling their scientology propaganda, than you know the bioavailibility, a word you can look up, is drastically changed depending on the route. There are studies since the 1933s, showing how effective ritalin is, and there are scanty studies showing any harm ritalin causes. As for the direct stimulant effects, that is a side effect you get with any thing that raises your blood pressure. It is a matter of balancing the doses and knowing the risk factors. That goes for anything.
IV route is very different to oral or even snorted. ASK any drug user, any fool in the street, or any doctor, and they will agree. Your rats were injected ritalin, and im sure you are aware with your scientology propaganda, ritalin is a stimulant. I consume caffeine o most days, but I can tell you, I would hate to fathom the idea of caffeine intravenously. Same with ephedrine. I have seen patients given ephedrine iv in the operation theatre to raise their BP, and the effects are dramatic, compared to oral dosing that athletes take.
About the cigarette smoking etc, with kids on ritalin, here you go again with your failures when it comes to causality and such. ADHD itself is known to cause pleasure seeking activity and such. ADHD patients are more likely to look for uninhibited sex, take drugs, drink alcohol, etc. So, in that sense, most kids with ADHD, are on ritalin, so yes, in some stupid way, you can agree that ritalin is somewhat connected to these pleasure seeking activities. It is like saying, most a study showed that caffeine increases the risk of cardiovascular disease, by studying people all around the world. You forget that coffee is not the cause, but rather the fact is, cigarrete smokers are more likely to drink caffeine, but that doesn't show a true link between caffeine and heart disease.
Your brain scans on the adults, done in 1986. I would like to see details of this study. if you have them of course. This reminds me of the study done by some 'scientist' showing brain scans and such of people on ecstasy, and had the scans in a journal and there was a massive hype over the scans. He was debunked only recently, showing that YOU CANNOT ACTUALLY ACCURATELY TELL IF THERE IS ATROPHY WITHOUT AN AUTOPSY. the most you can see is a change in grey to white matter distribution, or ventricular dilatation. Plus, 1986, thats the era where masive anti-drugs propagandists started fuelling the government with studies regarding many drugs. Puritans and such trying to prevent the degenerates from giving our children these bad bad drugs.
Dont exhaust your google function too much looking for more anti-ritalin articles. You wont have to anyways. There are many puritans like you around to distribute such false info. Like there are people telling cancer victims to take large doses of vitamin c to cure it.
1- constrict vessels
2-increase bp
3-increase heart rate
4-alter gut motility
and so on and so on.
You still have not shown that ritalins inherent activity at blocking dopamine reuptake is toxic in any way. You have just given me a nice review lecture on the activity of stimulants on the body. I can substitute the word coffee for everytime you have ritalin in your post and get away with it. As a matter of fact, I have provided a study, which shows that Ritalin actually prevents amphetamine induced dopamine deficits.. And your nice PET scan means nothing. I can put a someone having sex in there, on no drugs, and he will shine brighter than both your ritalin and cocaine user.
And just for your information, showing pictures and trying to throw sympathy cards in an argument is a very poor handling of an argument. I can do the same, by showing you a picture of some prisoner, and tell you, oh here is mathew the prisoner. Only if he was given ritalin, maybe he could have stayed home and done something constructive.
Here is something for you to read:
http://www.bnl.gov/b...nlpr092998.html
As you see, most of these studies with rats are done with ritalin given IV. If you know anything about pharmacology, which seems like you might not, and your scientists look like they are too busy fueling their scientology propaganda, than you know the bioavailibility, a word you can look up, is drastically changed depending on the route. There are studies since the 1933s, showing how effective ritalin is, and there are scanty studies showing any harm ritalin causes. As for the direct stimulant effects, that is a side effect you get with any thing that raises your blood pressure. It is a matter of balancing the doses and knowing the risk factors. That goes for anything.
IV route is very different to oral or even snorted. ASK any drug user, any fool in the street, or any doctor, and they will agree. Your rats were injected ritalin, and im sure you are aware with your scientology propaganda, ritalin is a stimulant. I consume caffeine o most days, but I can tell you, I would hate to fathom the idea of caffeine intravenously. Same with ephedrine. I have seen patients given ephedrine iv in the operation theatre to raise their BP, and the effects are dramatic, compared to oral dosing that athletes take.
About the cigarette smoking etc, with kids on ritalin, here you go again with your failures when it comes to causality and such. ADHD itself is known to cause pleasure seeking activity and such. ADHD patients are more likely to look for uninhibited sex, take drugs, drink alcohol, etc. So, in that sense, most kids with ADHD, are on ritalin, so yes, in some stupid way, you can agree that ritalin is somewhat connected to these pleasure seeking activities. It is like saying, most a study showed that caffeine increases the risk of cardiovascular disease, by studying people all around the world. You forget that coffee is not the cause, but rather the fact is, cigarrete smokers are more likely to drink caffeine, but that doesn't show a true link between caffeine and heart disease.
Your brain scans on the adults, done in 1986. I would like to see details of this study. if you have them of course. This reminds me of the study done by some 'scientist' showing brain scans and such of people on ecstasy, and had the scans in a journal and there was a massive hype over the scans. He was debunked only recently, showing that YOU CANNOT ACTUALLY ACCURATELY TELL IF THERE IS ATROPHY WITHOUT AN AUTOPSY. the most you can see is a change in grey to white matter distribution, or ventricular dilatation. Plus, 1986, thats the era where masive anti-drugs propagandists started fuelling the government with studies regarding many drugs. Puritans and such trying to prevent the degenerates from giving our children these bad bad drugs.
Dont exhaust your google function too much looking for more anti-ritalin articles. You wont have to anyways. There are many puritans like you around to distribute such false info. Like there are people telling cancer victims to take large doses of vitamin c to cure it.
Edited by medicineman, 08 January 2009 - 05:06 PM.
#46
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Posted 08 January 2009 - 06:07 PM
I read through my post, and I realize how dogmatic and insulting i sound. I apologize to isochrome. It would be better if we argue with no insults. I started it by calling you ignorant, and I apologize. It was I who was ignorant in being dogmatic about science. Your points will be taken into mind, and I will research what you had to say. I still hold back what I had to say in the previous post, without the insults. I was just in a bad state posting a reply. Ignore the insults, and once again I apologize for being childish.
#47
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Posted 09 January 2009 - 05:51 PM
After reading through the material and references in this thread, I still haven't found any compelling reasons to believe that ADHD medications or Modafinil should be avoided by those who need to take them. Unless, of course, you feel that you're at a particularly high risk of becoming a slave to the corporate machine and the pharmaceutical industry. In that case, I think different medications are appropriate.
In all seriousness, I don't think anyone would argue that Modafinil and ADHD drugs are completely harmless and without any neurological or even cardiac risks. For many people, myself included, the benefits of ADHD medications and Modafinil on quality of life will outweigh the known risks and downsides of these medications. Personally, I avoid Amphetamines because Modafinil and Methylphenidate are sufficient for me, and there is some legitimate reason to believe that amphetamines might be more neurotoxic than the other options. However, I have yet to see compelling evidence that any of these cause problems serious enough to outweigh the benefits.
Isochroma, you might be more successful if you were to argue against the overprescription and misuse of these medications rather than railing against them outright. EVERY medication has an upside and a downside. It is unreasonable and impossible to insist that these medications come without downsides. However, it is very important to balance the advantages of a medication with the risks and long term possible damage. And I would strongly suggest that you omit the appeals to emotion, anecdotes, and articles that portray the known possible side effects of these medications (anxiety in some, depression in others, aggravating heart conditions) as deep dark secrets of the pharmaceutical industries and reasons for all people to avoid these medications. Trust me, these side effects are well known among doctors, and doctors will watch for them. They are even more well known here among educated forum members, so these over dramatic appeals will only hurt your cause.
In all seriousness, I don't think anyone would argue that Modafinil and ADHD drugs are completely harmless and without any neurological or even cardiac risks. For many people, myself included, the benefits of ADHD medications and Modafinil on quality of life will outweigh the known risks and downsides of these medications. Personally, I avoid Amphetamines because Modafinil and Methylphenidate are sufficient for me, and there is some legitimate reason to believe that amphetamines might be more neurotoxic than the other options. However, I have yet to see compelling evidence that any of these cause problems serious enough to outweigh the benefits.
Isochroma, you might be more successful if you were to argue against the overprescription and misuse of these medications rather than railing against them outright. EVERY medication has an upside and a downside. It is unreasonable and impossible to insist that these medications come without downsides. However, it is very important to balance the advantages of a medication with the risks and long term possible damage. And I would strongly suggest that you omit the appeals to emotion, anecdotes, and articles that portray the known possible side effects of these medications (anxiety in some, depression in others, aggravating heart conditions) as deep dark secrets of the pharmaceutical industries and reasons for all people to avoid these medications. Trust me, these side effects are well known among doctors, and doctors will watch for them. They are even more well known here among educated forum members, so these over dramatic appeals will only hurt your cause.
#48
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Posted 09 January 2009 - 11:18 PM
Instead of just posting random studies why don't you refute the points I have made? If you have studies to back up your points, sure go ahead and use them but most of them are entirely irrelevant.
I have to think you are some kind of scientologist troll the way you keep on and on like this.
There are maybe a dozen cases a year of deaths that might be linked to stimulants out of the millions of people who use them, and in all these cases it's about the same story - obvious preexisting heart condition + heat stroke, and it's entirely avoidable and due to stupidity of the user/doctor/parents. Do you know how many people die from aspirin and tylenol each year? Thousands of them. Thousands every single year, and the beneficial effects of these OTC meds are really pretty negligible, just minor pain relief.
I have to think you are some kind of scientologist troll the way you keep on and on like this.
There are maybe a dozen cases a year of deaths that might be linked to stimulants out of the millions of people who use them, and in all these cases it's about the same story - obvious preexisting heart condition + heat stroke, and it's entirely avoidable and due to stupidity of the user/doctor/parents. Do you know how many people die from aspirin and tylenol each year? Thousands of them. Thousands every single year, and the beneficial effects of these OTC meds are really pretty negligible, just minor pain relief.
#49 Guest_Isochroma_*
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Posted 09 January 2009 - 11:53 PM
Construct & bgwithadd: Strange to hear these words. I'm only answering the thread's originator with studies.
How about I joggle your memories on the first poster's question, which is the topic of this thread?
In fact, he said that he is more concerned with 'ADHD drugs' than with Modafinil. So I decided to use the most popular ADHD drugs, which are Ritalin and Amphetamines as the topic of my posts. Still sounding logical?
So next time, Construct & bgwithadd, how about spending some more time finding some good research and less time attacking me? If you disagree with the research I present, then find counterpointing research. After all, that's what the guy wants, isn't it?
How about I joggle your memories on the first poster's question, which is the topic of this thread?
"Yet, I have more of a concern regarding ADHD drugs and long-term use, than I do with Modafinil.
Any good research out there on this topic?"
In fact, he said that he is more concerned with 'ADHD drugs' than with Modafinil. So I decided to use the most popular ADHD drugs, which are Ritalin and Amphetamines as the topic of my posts. Still sounding logical?
So next time, Construct & bgwithadd, how about spending some more time finding some good research and less time attacking me? If you disagree with the research I present, then find counterpointing research. After all, that's what the guy wants, isn't it?
Edited by Isochroma, 10 January 2009 - 12:09 AM.
#50 Guest_Isochroma_*
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Posted 10 January 2009 - 12:15 AM
And bgwithadd, what's with the insulting phrases? "scientologist troll"?
Are you so threatened by my posts that you can't attack me in a smarter way?
The majority of the words you've posted in this thread have been your own opinion, which the originator did NOT ask for.
The majority of my words in this thread have been studies, which the originator DID ask for.
Construct: "They are even more well known here among educated forum members, so these over dramatic appeals will only hurt your cause."
If you don't like reality you are not obligated to participate. I've quoted real studies and real cases; in fact the majority of the words I've posted in this thread are those precisely. Where is the matching quantity from you, Construct? What percent of your words addressed the originator's question, which was repeated in my previous post ("Any good research out there on this topic?")?
Both of these posters, it seems, are attempting despite reality to portray an inverse situation: one in which it is the poster who presents the majority of research (myself) - whose posts make real effort to answer the originator's question - as the one who is emotional, has a 'cause', etc. while they have resorted in the majority of their words to personal opinion, name-calling and other attacks, which the originator did NOT ask for.
Are you so threatened by my posts that you can't attack me in a smarter way?
The majority of the words you've posted in this thread have been your own opinion, which the originator did NOT ask for.
The majority of my words in this thread have been studies, which the originator DID ask for.
Construct: "They are even more well known here among educated forum members, so these over dramatic appeals will only hurt your cause."
If you don't like reality you are not obligated to participate. I've quoted real studies and real cases; in fact the majority of the words I've posted in this thread are those precisely. Where is the matching quantity from you, Construct? What percent of your words addressed the originator's question, which was repeated in my previous post ("Any good research out there on this topic?")?
Both of these posters, it seems, are attempting despite reality to portray an inverse situation: one in which it is the poster who presents the majority of research (myself) - whose posts make real effort to answer the originator's question - as the one who is emotional, has a 'cause', etc. while they have resorted in the majority of their words to personal opinion, name-calling and other attacks, which the originator did NOT ask for.
Edited by Isochroma, 10 January 2009 - 12:26 AM.
#51 Guest_Isochroma_*
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Posted 10 January 2009 - 01:53 AM
Stacy A Castner Ph.D and Patricia S Goldman-Rakic Ph.D
Yale University School of Medicine, Section of Neurobiology, New Haven, Connecticut USA
Correspondence: Dr Stacy A Castner, Yale University School of Medicine, Section of Neurobiology, 333 Cedar Street, New Haven, CT 06510
ABSTRACT
The dopamine hypothesis of schizophrenia posits that dopamine dysregulation plays a key role in the etiology of schizophrenia. In line with this hypothesis, repeated amphetamine (AMPH) exposure has been shown to alter dopamine systems and induce behaviors reminiscent of positive-like and negative-like symptoms in both human and nonhuman primates. The mechanisms by which AMPH produces disturbances in brain function and behavior are not fully understood. The present study has employed a novel AMPH regimen, 12 weeks of intermittent escalating low doses of AMPH, to produce a nonhuman primate model for the purpose of elucidating the behavioral and neural consequences of excessive dopamine exposure. Behavioral responses to acute AMPH challenge (0.4-0.46 mg/kg) were assessed prior to and following the chronic 12-week treatment regimen, and, at present monkeys have been followed out to 28 months post-treatment. After chronic treatment, enhanced behavioral responses to AMPH challenge were readily apparent at 5 days postwithdrawal, and, were still present at 28 months postwithdrawal. The enhanced behavioral responses to low-dose AMPH challenge that were observed in the present study resemble closely the behavioral profile that has been described for chronic high-dose AMPH treatment in monkeys; i.e., hallucinatory-like behaviors, static posturing, and fine-motor stereotypies were all exacerbated in response to AMPH injection. In some animals, acute challenges after chronic AMPH evoked aberrant behavioral responses that lasted for 4 days. AMPH-treated monkeys also exhibited a significant decrease in the incidence of motor stereotypies in the off-drug periods between challenges. The present results are the first to document persistent long-term behavioral effects of intermittent exposure to repeated low-dose AMPH treatment in nonhuman primates. These findings may lay the groundwork for the development of a primate mode of psychosis with possible positive-like and negative-like symptoms.
Repeated amphetamine (AMPH) use in humans can induce behaviors reminiscent of paranoid schizophrenia (e.g., Angrist 1994). Chronic AMPH treatment in nonhuman primates also induces a characteristic pattern of behavioral response that has been likened to paranoid schizophrenia in humans (e.g., Ellison 1994; Ellison et al. 1981; Ridley et al. 1982). Behaviors typically shown by monkeys undergoing chronic AMPH treatment include extreme vigilance, tracking of nonapparent stimuli, constant checking, startle responses in the absence of visible/audible stimuli, grasping in midair, and hyper-responsiveness to sensory stimuli (Ridley et al. 1982). This behavioral repertoire is reminiscent of positive-like symptoms in schizophrenic patients.
Negative-like symptoms of schizophrenia have also been observed during chronic AMPH treatment in monkeys. One hallmark negative symptom of schizophrenia is the psychomotor poverty syndrome (Liddle et al. 1992). In monkeys, Schlemmer et al. (1996) have shown that chronic AMPH treatment results in a significant decrease in motor stereotypies. Other studies have found that some monkeys treated with chronic AMPH exhibit catatonic-like states; for example, sitting frozen in one spot while staring off into space for extended periods of time (Ellison et al. 1981).
The aforementioned studies on the behavioral consequences of AMPH in monkeys were all conducted during chronic and/or high-dose AMPH exposure. One of the drawbacks of chronic AMPH animal models of psychosis is that they induce neurotoxicity of the nigrostriatal dopamine system (Ridley et al. 1983; Ellison and Ratan 1982; Ellison et al. 1978). In rodents, it has been shown that nigrostriatal neurotoxicity can be avoided if AMPH treatment consists of repeated, intermittent low-dose exposure to the drug. Compared to chronic and high-dose regimens, escalation of low doses permits neuronal adaptation and more closely models drug use in human AMPH addicts (Robinson and Becker 1986).
Taking our lead from the rodent literature, and in light of the fact that there is very little evidence of profound or long-lasting dopamine dysfunction resulting from repeated, intermittent AMPH use in humans, we have investigated the long-term behavioral consequences of a similar treatment regimen in rhesus monkeys (Wilson et al. 1996). Although there are data from positron emission tomography (PET) studies in nonhuman primates indicating that neuronal depression can occur in response to acute AMPH injections (Melega et al. 1997; Villemagne et al. 1998), the starting dose (0.1 mg/kg) of AMPH used in the chronic phase of the present experiment was 5 to 20 times lower than the doses used in the imaging studies. Nevertheless, it is our ultimate intention to examine the brains of the monkeys in the present study to determine whether neurotoxicity was produced by the intermittent treatment regimen.
The primary goal of the present manuscript is to determine the psychotomimetic consequences of chronic AMPH treatment both off drug and in response to acute, periodic low-dose AMPH challenge. If this regimen in nonhuman primates results in enhanced behavioral responses to subsequent AMPH challenge, and furthermore, these responses resemble those described above for chronic high-dose AMPH treatments in monkeys, then the escalating low-lose AMPH regimen used in the present study may produce a potentially valuable animal model of psychosis.
MATERIALS AND METHODS
Subjects
Subjects included five young adult male and five young adult female rhesus monkeys (Macaca mulatta) ranging in age from 4 to 8 years. Two of the females were used for histology (see below). Monkeys were maintained in single-unit housing (male cages: 35-in h ´ 26-in d ´ 49-in w; female cages 30-in h ´ 26-in d ´ 23.5-in w) on a 12:12 light dark cycle (lights on 7 A.M.-7 P.M.). Monkeys were provided with typical enrichment devices including: monkey-tested dog toys, logs, and plastic chains. New dog toys and chains were provided with cage rotation every 2 weeks. Logs, on the other hand, remained unchanged. Water was available ad libitum, and monkeys received 30 biscuits of standard high-fiber monkey chow, fruit, and peanuts each day. Food intake was monitored daily. Animals were taken care of in accordance with Yale Animal Use and Care Committee guidelines for nonhuman primates.
Drugs and Antibodies
S(+)-amphetamine sulfate was purchased from RBI (Natick, MA). For injections, amphetamine was dissolved in sterile saline solution. All injections were given IM AMPH doses referred to below are based on weight of salt and were administered to monkeys in mg/kg. Antibodies, a monoclonal mouse antityrosine hydroxylase (1:1000) and a monoclonal rat antidopamine transporter (1:10,000), were obtained from Chemicon (Temucula, CA).
Baseline Behavioral Observations
Monkeys were observed twice daily (Monday-Friday) in their home cage over a period of 3 to 6 months to establish a baseline behavioral profile for each monkey and document early day (10 A.M.-2 P.M.) and late day (5:30-8:00 P.M.) differences in behavior. On average, three to four monkeys were observed during a given session. Data were collected using a focal time-sampling procedure (2.5 min per monkey) on a Macintosh computer with a program, Monkey Watcher, designed especially for this purpose. For a given session, each monkey was observed for no less than 10 minutes. While manually operated, Monkey Watcher allows for documentation of the total duration, frequency, number of occurrences, and average duration of a given behavior. Twenty-four behaviors were assigned to keys on the keyboard; 23 keys were assigned specific behaviors (for a list of specific behaviors see left side of Table 1). The 23 behaviors assigned to specific keys on the keyboard were based on several weeks of observations of monkeys in their home cages prior to the start of data collection for the present study. The twenty-fourth key was designated "etcetera," and behaviors not assigned to one of the 23 specific keys were recorded by hand while the etcetera key was depressed. Many etcetera behaviors predominated only after AMPH administration and were unique to each monkey (note: some examples of etcetera behaviors relevant to the present manuscript are listed on the right side of Table 1). Behaviors from Table 1 are categorized in Table 2, and the eight behavioral categories defined in Table 2 are used throughout this manuscript. Two experimenters conducted observations during the first 8 months of the study. However, because of the extraordinary time demands of this project, only one observer was available on a daily basis for the latter stages of the experiment. From the baseline data, animals were assigned to either the experimental (n = 6) or control group (n = 2). An attempt was made to ensure that animals exhibiting high levels of stress behaviors under baseline conditions; for example, self-biting; self-grasping, and such motor stereotypies as pacing, circling, side-to-side, were distributed equally between groups (see Table 3).
Table 1
Keyboard Behaviors
Table 2
Behavioral Categories
Table 3
Baseline Behavorial Profiles
Serum Dose Response
Prior to chronic AMPH administration, multiple serial blood draws were performed to examine possible group/sex/individual differences in AMPH metabolism. Specifically, monkeys in the experimental or AMPH group (n = 6) underwent three serial blood draw sessions. For the AMPH group, a dose-response curve was obtained (three doses of AMPH given at 1 month intervals to allow for recovery from phlebotomy). Animals first received 0.1 mg/kg AMPH IM, and serum samples were taken at timed intervals (5; 15; 30; 45; 60; 90; 120; 150; 180 min) postinjection. One month later, they received 0.8 mg/kg AMPH IM. AMPH concentrations in serum tended to peak at approximately 15 minutes postinjection coincident with peak elevation in heart rate in response to AMPH. The third midrange dose of AMPH varied (0.4-0.46 mg/kg; IM) based on the variability between individuals in serum concentrations of AMPH at the 15 minute (peak) time point for the two previous doses. To control for any untoward effects of ketamine restraint, isoflurane anesthesia, and phlebotomy, control animals were restrained once and subjected to the same procedure, but instead of receiving an AMPH injection they received saline. During blood draws, serum samples were also taken to look at possible effects of AMPH/sex on serum cortisol and prolactin (PRL) concentrations.
Prechronic Treatment Behavioral Dose Response
Following completion of the serum dose-response curve, behavioral baseline was re-established for each monkey. Next, behaviors were recorded as described above (see baseline behavioral observations) by means of a computer and on video for each animal at the same doses of AMPH that were administered in the serum analysis phase (saline; 0.1; 0.4-0.46; 0.8 mg/kg AMPH; IM). Focal time-sampling techniques were used to obtain behavioral observations for a minimum of 2 hours following each injection and at timed intervals thereafter, including: 6 to 8 hours postinjection; 24 hours post-injection, and as needed to allow for behavior to return to baseline. To achieve each curve, doses of AMPH were administered in ascending order, because there was the potential for behavioral enhancement with each subsequent injection of AMPH. During this phase, an adequate washout time, 2 weeks, was permitted between AMPH injections. AMPH animals were always paired with saline-treated controls. On challenge days, controls received an injection of the vehicle, 0.9% NaCl, by weight.
Chronic AMPH Treatment
Animals were subjected to an escalating intermittent low-dose binge regimen of AMPH modified from protocols that have been used to produce behavioral sensitization in rodents (e.g., Paulson et al. 1991). Monkeys received twice daily injections of AMPH or saline 5 days per week (weekends off) for 12 weeks. The dose of AMPH was increased by increments of 0.1 mg/kg at approximately regular intervals over the 12-week period (starting dose 0.1 mg/kg; ending dose 1.0 mg/kg AMPH). During chronic AMPH, the monkey's behaviors at each dose were recorded on computer and on videotape. With the exception of a 10 to 12 day period when the investigator was out of town, the monkeys were observed once or twice 5 days per week immediately following AMPH injection and once daily on the weekends during the 12 weeks of chronic AMPH treatment. The weekend observations were intended to document any signs of withdrawal.
Postchronic Treatment Behavioral Observations/Dose Response
Monkeys were observed once or twice daily in their home cage during the first 21 days postchronic AMPH treatment for signs of withdrawal, including psychomotor depression. Animals in the experimental group received AMPH challenges (0.4-0.46 mg/kg IM) on days 5, 11 (or 12, see Results section), and 21 of withdrawal. After this time, a behavioral dose-response curve was performed in the same manner as described above for the prechronic treatment phase. Animals also received discrete challenges of AMPH (0.4-0.46 mg/kg IM) at 6, 9, and 12 months postwithdrawal and periodically thereafter to monitor long-lasting behavioral consequences of treatment. For all AMPH challenges, behavioral responses were recorded on computer and on video. Additional AMPH challenges are ongoing as part of a longitudinal study. Following AMPH challenge, monkeys were observed at regular intervals until an animal's behavior returned to its prechallenge "baseline" level, referred to from here on as prechallenge behavior to distinguish it from prechronic treatment (baseline) behavior.
Four-Week AMPH Pilot Study
One female monkey was subjected to a 4-week escalating, intermittent, low-dose treatment regimen of AMPH. This monkey received the same doses of AMPH as the 12-week monkeys, but the doses were escalated more rapidly. The home cage behavior of this monkey was recorded before and after chronic treatment in response to 0.4 mg/kg AMPH challenge for signs of behavioral enhancement.
Immunocytochemistry
Three months after withdrawal and 1 week post-AMPH challenge, the 4-week AMPH-treated monkey was restrained with ketamine, subjected to an overdose of pentobarbital anesthesia, and then perfused transcardially with phosphate-buffered saline. During the saline flush, a frontal lobectomy was performed on one hemisphere to obtain fresh tissue for biochemical analysis. Next, perfusion was continued with a 4% paraformaldehyde solution with 0.2% glutaraldehyde and 15% picric acid. Tissue from an age-matched control (AMPH-naive) monkey was processed in the same manner. Immediately following the perfusions, the brains were removed, blocked, and sunk in 20% sucrose for several days. Tyrosine hydroxylase (TH) and dopamine transporter (DAT) immunocytochemistry were performed on cryostat obtained sections in accordance with previously published protocols from this laboratory (Krimer et al. 1997).
Serum Analysis
Serum AMPH and cortisol values were determined by National Psychopharmacology Laboratories (Knoxville, TX). Prolactin values were obtained from Metro Reference Labs (St. Louis, MO) in conjunction with National Psychopharmacology Laboratories.
Data Analysis
For serum data, two-way analysis of variance (ANOVA) with repeated measures was used where appropriate to identify sex differences and effects of time postinjection on serum concentrations. Factorial ANOVA was employed to identify sex differences in basal serum hormonal concentrations. Psychomotor depression data postchronic AMPH treatment for individual monkeys were analyzed by one-way factorial ANOVA.
RESULTS
Baseline Behavioral Observations
Table 3 shows the mean percentage time (± SEM) each of the six monkeys spent engaged in the eight behavioral categories across 30 to 40 baseline samples (four monkeys were later assigned to the AMPH group and two to the control group). Individual differences were particularly evident in motor stereotypies (Category I). For example, monkeys Jag, Vien, Flo, and Kram exhibited high levels of motor stereotypies (pacing or circling) before AMPH (or saline) treatment; whereas, the two other monkeys, Mad and Glas, rarely displayed these behaviors. In other behavioral categories, however, there was more uniformity across individuals. For example, all animals spent approximately 7 to 21% of their baseline time engaged in stimulus-driven responses (Category III, Tables 2 and 3), and none, on the other hand, exhibited responses "independent of stimuli" (Category IV). Submissive behaviors (Category VII, presenting and lipsmacking) were also displayed relatively infrequently. Similarly, static posturing (Category VI) was rarely observed during baseline for any monkey. Although intersubject variability was high for motor stereotypies, intrasubject variability in baseline behaviors was minimal across days/months for all monkeys (see Means ± SEM's for each monkey for each behavioral category in Table 3).
Serum Concentrations of Amphetamine
The challenge doses of AMPH used in this study (see below) were established by data from serum dose-response studies done before chronic AMPH administration. At the 0.1 mg/kg dose of AMPH, time following injection was highly significant (F[1,8] = 4.663; p = .0043; Figure 1A). There was a nonsignificant (F[1,8] = 2.292; p = .0752) trend for serum AMPH concentrations to peak earlier in females (15-90 min) than in males (120 min). For the second AMPH dose (0.8 mg/kg), AMPH concentrations in serum peaked at 30 and 45 min postinjection for females and males, respectively (F[1,8] = 3.15; p = .0242; see Figure 1A). Although females had higher AMPH serum concentrations across the 1st hour after injection as compared to males (F[1,2] = 30.876; p = .0309), the over-all pattern of the serum AMPH response across time did not differ for males and females (F[1,8] = 1.869; p = .1366). For the third part of the dose-response curve, the midrange dose, doses were adjusted between 0.4 and 0.46 mg/kg for each animal based on their responses to the 0.1 and 0.8 mg/kg AMPH challenges (see Methods section). Administration of 0.46 mg/kg AMPH did not produce higher serum AMPH concentrations that did administration of 0.4 mg/kg AMPH. For the adjusted midrange dose (see Figure 1A), the time postinjection was again significant as was the sex ´ time interaction (effect of time: F[1,5] = 7.52; p = .0036; sex ´ time: F[1,5] = 8.258; p = .0025), but there was no main effect of sex (F[1,2] = 0.379; p = .6009).
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Figure 1
Serum AMPH concentrations for males and females across time following injection of three different doses of AMPH (0.1, 0.4 to 0.46, 0.8 mg/kg). In response to 0.1 mg/kg AMPH, no sex differences were detected, but there was a significant effect of time postinjection on AMPH concentrations in serum (effect of sex: F[1,2] = 0.376; p = .6023; effect of time: F[1,8] = 4.663; p = .0043). Serum AMPH concentrations tended to peak slightly earlier in females than they did in males following 0.8 mg/kg AMPH, 30 and 45 minutes postinjection, respectively. Following the 0.4 to 0.46 mg/kg AMPH injections, there was a significant sex ´ time interaction. Although males tended to have lower serum AMPH concentrations during the first two samples postinjection, they had significantly higher serum AMPH concentrations during the 2nd and 3rd hours after injection as compared to the females (see text for statistics). Figure 1B shows that intact female rhesus monkeys had significantly high basal serum PRL concentrations than did intact males (F[1,4] = 15.85; p = .0164; * indicates significance at an alpha level of 0.05). The serum cortisol response for AMPH-treated and saline-treated monkeys across time under anesthesia are shown in Figure 1C. Both groups showed a significant increase in serum cortisol as the time postinduction of anesthesia increased (effect of time: F[1,7] = 4.853; p = .0059; * indicates significance at an alpha level of 0.05)
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Serum Concentrations of Prolactin and Cortisol
As shown in Figure 1B, females had significantly higher basal serum PRL concentrations than did males independent of stage of menstrual cycle (F[1,4] = 15.85; p = .0164). Both males and females, however, showed significant decreases in serum PRL concentrations in response to acute AMPH challenge (F[1,4] = 2.98; p = .0513). For example, in response to the 0.4 to 0.46 mg/kg AMPH injection, female serum PRL concentrations decreased from a mean of 64.333 ng/ml at baseline to 15 ng/ml at 180 min postinjection, and male concentrations decreased from 10.667 to 4.667 ng/ml across the same time period (data not shown).
Serum cortisol concentrations increased with time under anesthesia whether monkeys received AMPH or saline injections (see Figure 1C). There was a significant effect of time from anesthesia induction on cortisol concentrations (F[1,3] = 9.812, p = .0008). One of the controls had abnormally high serum cortisol concentrations (F[1,3] = 9.812, p = .0008). One of the controls had abnormally high serum cortisol concentrations at the start of the experiment, and therefore little change in serum cortisol across time.
Behavioral Responses to AMPH Challenge Pre- and Postchronic AMPH Treatment
The left side of Figures 2,3,4&5 present a sampling of behavioral responses to 0.4 to 0.46 mg/kg AMPH challenges for male monkeys, Jag and Glas, and female monkeys, Flo and Vien, both before and after AMPH treatment. Behavioral responses to each dose administration during the chronic phase are shown for all monkeys on the right side of Figures 2, 3, 4 & 5. Points on chronic graphs represent the responses given during the 1st hour following injection on the last early observation taken at each dose. Male monkey Jag spent significantly more time pacing during the 1st hour following AMPH challenge postchronic treatment than he did in response to the same challenge dose prior to treatment (Figure 2A). A much lower dose of AMPH was sufficient to elicit increased pacing in Jag after treatment than during the chronic treatment phase of the experiment (0.4 mg/kg vs. 0.9 mg/kg; see Figures 2A and 2B). As can be seen in Figure 2C, Jag also engaged in more fine-motor stereotypies in response to AMPH challenge after, as compared to before, chronic treatment. This behavior was not observed in response to pretreatment challenge (Figure 2C) and only periodically during the 1st hour postinjection during the chronic AMPH period (Figure 2D). Jag's fine-motor stereotypy characteristically involved an elaborate sequence of adept movements of the hands and fingers (some focused in midair, some focused on the cage bars), which looked like knitting and were referred to by the investigator as "fiddle with bars." This motor pattern became more elaborate as the number of AMPH experiences increased. Figure 2E shows that Jag made significantly more responses "independent of stimuli" during the post-treatment period than he did prior to treatment in response to a 0.4 mg/kg AMPH challenge. Again, during the chronic period (Figure 2F), only the higher AMPH doses elicited responses "independent of stimuli." These responses most often included checking, vigilance, and staring off into space. Similar to Jag, the other male monkey, Glas, showed a trend for increased motor stereotypies in response to AMPH challenge after, but not before, chronic AMPH treatment (Figure 3A). He rarely displayed this behavior during chronic AMPH treatment (Figure 3B). Following chronic AMPH treatment, monkey Glas also spent a greater percentage of time engaged in fine-motor stereotypies in response to AMPH challenge than he did before treatment (Figure 3C). Like Jag, Glas displayed fine-motor stereotypies variably during the 1st hour postinjection during the chronic phase (see Figure 3D). Fine-motor stereotypies shown by Glas encompassed a variety of behaviors including: toy rotation, "fiddle with squeeze mechanism," "pull squeeze mechanism," "fiddle with chain," "fiddle with fastener." Glas showed significantly more responses "independent of stimuli" in response to AMPH challenge after chronic AMPH treatment compared to his prechronic treatment challenge at the same dose (see Figure 3E). These behaviors were also increased following some of the higher AMPH doses (0.7-0.9 mg/kg) during the chronic phase (Figure 3F).
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Figure 2
Panels A to F indicate the percentage of the time observed in which Jag engaged in three behaviors (pacing, fine-motor stereotypy, responses "independent of stimuli") in response to AMPH injection before and after chronic AMPH treatment (A, C, E), and, across different doses during the chronic phase (B, D, F). Graphs reflect the percentage of time a given behavior was displayed during the 1st hour following AMPH injection. For most post-treatment challenges (panel A), Jag showed increased pacing relative to his pretreatment challenge. Pacing was also increased for Jag following the 0.9 mg/kg AMPH dose during the chronic phase of the experiment (panel B). Chronic phase data indicate the response by Jag to each dose on the morning of the last day at each AMPH dose. In response to post-treatment AMPH challenges (panel C), Jag showed fine-motor stereotypies that were not displayed in response to the same challenge dose pretreatment. He also tended to exhibit his fine-motor stereotypy, "fiddle with bars" variably following different doses during the chronic phase of the experiment (panel D). Notably, this behavior was shown by Jag for a significant percentage of time during the 1st hour following injection of 1.0 mg/kg. As seen in panel E, monkey Jag spent a significant percentage of his time engaged in responses "independent of stimuli" after chronic drug treatment as opposed to predrug treatment in response to an AMPH challenge (0.4 mg/kg). Responses "independent of stimuli" were also significantly augmented at the highest dose of AMPH (1.0 mg/kg) during the chronic phase for Jag (panel F). Note: The last two post-challenge days, 510 and 850, refer to an approximate day of challenge.
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Figure 3
Panels A, C, and E show the percentage of time observed that monkey Glas engaged in pacing, fine-motor stereotypy, and responses "independent of stimuli", respectively, in response to acute AMPH challenge prior to and following chronic AMPH treatment. Similar to his baseline behavioral profile (Table 3), Gals also spent little time pacing in response to acute challenge or during chronic AMPH treatment (A and B). However, like the other monkeys, panel A does show that there was a slight increase in Glas's pacing in response to AMPH challenge after as compared to prechronic treatment. Like Jag, Glas also spent a significantly greater percentage of his time engaging in fine-motor stereotypies in responses to post-treatment as opposed to pretreatment acute AMPH challenge (panel C). Again similar to Jag's response, Glas spent a variable percentage of time engaged in fine-motor stereotypies in response to different AMPH doses during the chronic phase (panel D). Responses "independent of stimuli" were elicited by lower AMPH challenge doses (0.45 mg/kg, panel E) than during chronic treatment (0.7 to 0.9 mg/kg, panel F)
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Figure 4
Figures 4A,4B,4C & 4D indicate the mean percentage time spent by female monkey Flo engaged in circling (A and B), static posturing (C and D), and responses "independent of stimuli" (E and F) during the 1st hour after AMPH injection. The left panels contain behavioral data for acute AMPH challenges (0.4 mg/kg) before and following chronic AMPH treatment. Data in the right panels pertain to the chronic phase of the experiment. Similar to monkey Jag, Flo showed a higher incidence of circling behavior in response to AMPH challenges post-treatment as compared to the same dose challenge prior to chronic AMPH treatment (A). As seen in panel B, circling was also displayed by Flo in response to the higher doses during the chronic phase of the experiment. Figure 4C shows that Flo spent a significantly greater percentage of her time engaged in static posturing in response to acute AMPH challenge following post-treatment challenges from day 49 on than she did prior to this time. Although it is not detectable in Figure 4D, static posturing was interjected by Flo for brief periods (10 to 15 s) during the chronic phase in response to 1.0 mg/kg AMPH. Panel E illustrates the significant increases in responses "independent of stimuli" for Flo in response to post-treatment as compared to pretreatment AMPH challenge. Responses "independent of stimuli" were displayed variably across doses during the chronic phase by Flo (F). Notably these behaviors were often displayed in conjunction with static posturing in response to post-treatment challenges.
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Figure 5
Figure 5 shows the percentage time spent by female monkey Vien engaged in pacing, static posturing, and responses "independent of stimuli" during the 1st hour following AMPH injection. Figures A, C, an E show these behaviors in response to acute AMPH challenge before and after chronic AMPH treatment, and Figures B, D, and F show the incidence of each behavior across doses during the chronic phase. As can be seen by comparing Figures A and B, pacing behavior was only displayed by monkey Vien in response to AMPH injection following chronic treatment. Vien spent significantly more time engaged in static posturing in response to 0.46 mg/kg AMPH after chronic treatment than she did prior to treatment ©. Figure D shows that this behavior was expressed for a longer duration in response to 0.9 mg/kg AMPH than it was in response to the other AMPH doses during chronic AMPH treatment. Like the other two behaviors, responses "independent of stimuli" were a prominent behavioral response exhibited by Vien in response to AMPH challenge only after chronic treatment. Vien also spent a significant percentage of time displaying these behaviors during the chronic phase of the experiment in response to the higher AMPH doses (0.5 to 1.0 mg/kg; see 5F)
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Figure 4A shows that monkey Flo exhibited enhanced circling behavior in response to a 0.4 mg/kg AMPH challenge after, but not before, chronic treatment. Circling behavior for monkey Flo was suppressed at the low doses and exacerbated at the high doses of AMPH during the chronic drug period (Figure 4B). After treatment, Flo also spent more time engaged in static posturing in response to post-treatment AMPH challenges (from day 49 on) than she did in response to her pretreatment AMPH challenge. The static posture assumed by monkey Flo after AMPH injection consisted of sitting at the front of her cage with her chest pressed flush against the bars and her arms extended toward the top of the cage with her head tilted while staring off into space. In this animal, static posturing became a predominant behavior in response to AMPH challenge after the chronic phase of the experiment. During the chronic phase (Figure 4D), her static posture, two arm stretch, was only displayed occasionally for very brief intervals in response to 1.0 mg/kg AMPH. As the postwithdrawal time increased, AMPH challenge induced Flo to spend a greater percentage of time engaged in responses "independent of stimuli" in response to acute AMPH challenge relative to her pretreatment challenge (Figure 4E). This behavior most often consisted of staring off into space. During the chronic phase of the experiment, responses "independent of stimuli" were increased in response to the midrange AMPH doses (0.4-0.6 mg/kg) and, to a slight extent, in response to the highest dose (1.0 mg/kg) (see Figure 4F). Notably, static posturing and responses "independent of stimuli," which were often exhibited simultaneously, became pronounced responses to acute AMPH challenge for the first time on day 49 of withdrawal from chronic treatment.
The other female monkey, Vien, also showed enhanced behavioral responses to AMPH challenge following chronic treatment. Like Flo and Jag, Vien exhibited increased motor stereotypy (pacing; Figure 5A) in response to acute challenge after, but not before, chronic treatment. On the other hand, she rarely paced in response to AMPH injection during the chronic phase (see Figure 5B). Vien, like the other female Flo, spent more time engaged in static posturing in response to acute AMPH challenge as the time postwithdrawal increased and as compared to her pretreatment response for this behavior (Figure 5C). Vien's static postures were sometimes similar to those exhibited by Flo; that is, she also sat for extended periods at the front of the cage with one arm extended over her head and her chest pressed against the cage bars. However, Vien also displayed a static posture that was more withdrawn and involved cowering in the back corner of her cage clinging to bars with two hands and one foot. Vien spent a greater percentage of time engaged in static posturing in response to 0.9 mg/kg AMPH than she did in response to the other doses during chronic treatment (see Figure 5D). Again, similar to the other AMPH-treated monkeys. Vien displayed significantly more responses "independent of stimuli" including checking, tracking nonapparent stimuli, and staring off into space to AMPH challenge after chronic treatment than she did prior to chronic treatment (Figure 5E). During chronic treatment, responses "independent of stimuli" were more often displayed by this monkey in response to higher, as compared to lower, doses of AMPH (see Figure 5F).
Time Course and Progression of Enhanced Behavioral Responses to AMPH Challenge
Table 4 highlights the time course of responses "independent of stimuli" in response to either acute AMPH challenge (Jag and Vien) or saline challenge (Mad and Kram). For each monkey, data shown indicate the percentage time displaying responses "independent of stimuli" in response to three acute injections; pretreatment, 21 days post-treatment, and 9 months post-treatment (Kram did not receive his post-treatment challenges at the same time as the other monkeys because of his relocation to another monkey room). Neither Jag nor Vien displayed significant responses "independent of stimuli" in response to acute AMPH challenge before chronic treatment. In contrast, following treatment, both monkeys showed a significant increase in the percentage of time engaged in this category of behavior in response to AMPH challenge. Remarkably, in response to AMPH challenge at 21 days and 9 months post-treatment, Jag and Vien showed persistence of responses "independent of stimuli" through 6 hours and, in most cases, through 72 hours postinjection. In contrast to the AMPH-treated monkeys, saline challenge almost never induced responses "independent of stimuli" in the two control monkeys, Mad and Kram.
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Table 4
Timecourse of Responses "Independent of Stimuli" After Acute AMPH or Saline Challenge
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Behavioral Changes Off-Drug After Chronic AMPH Treatment
In contrast to their enhanced responses to AMPH challenge after chronic treatment, most of the experimental monkeys showed significant decreases in the time spent engaged in motor stereotypies in the interim between challenges. For example, monkey Jag (Figure 6A) spent significantly less time pacing immediately following withdrawal from AMPH, between 3 and 9 months postwithdrawal, and, subsequently out to 15 months postwithdrawal as compared to his prechronic treatment baseline behavior (F[3,82] = 23.543; p = .0001). Monkey Vien also spent significantly less time pacing across all of her postchronic AMPH observations as compared to her pretreatment baseline samples (F[3,82] = 8.285; p = .0001; * indicates significant at 95% via Fischer PLSD and Scheffe F-test; Figure 6B). Flo showed a later onset of behavioral suppression after chronic AMPH treatment, exhibiting diminished circling only between 3 and 9 months postchronic AMPH treatment as compared to her baseline values (F[3,73] = 5.263; p = .0024; * indicates significant at 95% via Fischer PLSD and Scheffe F-test; Figure 6C). The other male monkey, Glas, (see Figure 6D) displayed only minimal motor stereotypies (pacing, one arm twirling, and somersaulting) before chronic AMPH administration, and, therefore, did not show a significant decrease in these behaviors in the months following withdrawal from AMPH (F[3,78] = 1.391; p = .2517).
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Figure 6
Figure 6 shows the mean (± SEM) percent time the four AMPH-treated monkeys displayed motor stereotypies off drug at different time points before and after chronic AMPH. Behavioral observations of motor stereotypies off drug were collected from four different time points: baseline (pretreatment), initial withdrawal from chronic AMPH, 3 to 9 months post-treatment, 9 to 15 months post-treatment. Monkey Jag, shown in panel A, spent significantly less time pacing immediately following withdrawal from AMPH, across 3 to 9 months postwithdrawal, and from 9 to 15 months postwithdrawal as compared to his baseline for this behavior prior to chronic AMPH (F[3,82] = 23.543; p = .0001). Monkey Vien (6B) also spent significantly less time pacing during all post-treatment time points tested compared to her baseline pacing behavior (F[3,82] = 8.285; p = .0001). In contrast, monkey Flo (6C) only showed a significant decrease in her circling behavior during the period between 3 to 9 months post-treatment (F[3,73] = 5.263; p = .0024). Monkey Glas (shown in 6D) showed the same general behavioral pattern as did the other AMPH-treated monkeys, but none of the comparisons of data across different time points for this monkey were significant (F[3,78] = 1.391; p = .2517). All single * indicates significance at 95% via Fischer PLSD and Scheffe F-test. Jag and Flo showed recovery of pacing and circling, respectively, during 9 and 15 months after chronic AMPH treatment ( ).
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Different from motor stereotypies, certain aberrant behaviors; for example, responses "independent of stimuli" continued to be expressed by some AMPH-treated monkeys even in the interim between drug challenges. For example, Vien showed high levels of responses "independent of stimuli" including: tracking nonapparent stimuli, cowering, and staring off into space. She often spent as much as 30% of her time observed engaging in such responses. The other AMPH-treated monkeys also showed an increased incidence of responses "independent of stimuli" after chronic drug treatment in the absence of additional drug challenges. In this study, after chronic AMPH administration, both male monkeys developed buccolingual dyskinesias, which were exacerbated by acute challenge and sometimes persisted for several days. One male, Jag, also displayed self-biting after chronic drug treatment.
The behavioral response of each monkey to the investigator was recorded on a daily basis. During chronic AMPH treatment, and in response to acute AMPH challenges postchronic treatment, normally aggressive monkeys (Jag and Vien) evidenced an increased incidence of submissive behaviors including presentation, lipsmacking, and reaching out to the investigator.
Saline-Treated Animals
There was very little variance in behaviors expressed by the two male control monkeys either during baseline observations or in response to saline challenge (see Tables 3 and 4). Neither of the control monkeys showed significant levels of any behaviors that were found to be enhanced in the AMPH-treated monkeys: for example, responses "independent of stimuli" (Table 4), fine-motor stereotypies, parasitotic-like grooming, static posturing, or buccolingual dyskinesias (data not shown).
Four-Week AMPH Pilot Study
The monkey subjected to the 4-week escalating low-dose AMPH regimen also displayed enhanced behavioral responses to low-dose AMPH challenge following chronic treatment as compared to her pretreatment challenge. Her enhanced behavioral responses were similar to those described above for the 12-week-treated monkeys. She continued to display enhanced responses to acute AMPH Challenge through her final challenge, which was given at approximately 3 months postchronic AMPH treatment and 1 week prior to sacrifice. TH and DAT immunoreactivity in the striatum did not reveal any apparent differences between the AMPH-treated monkey and age-matched control (Figures 7A, 7B, 7C & 7D).
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Figure 7
Markers of catecholamine synthesis and dopamine transport, TH (A and B) and DAT (C and D), immunoreactivities are shown for an age-matched control (A and C) and a 4-week AMPH-treated monkey (B and D). Figures on the left side are low-magnification (scale bar = 1 cm) and those on the right are high-magnification photomicrographs (scale bar = 10 m) of the caudate nucleus of the respective sections on the left side. No significant difference in TH immunoreactivity in the caudate nucleus of the control and AMPH-treated monkeys could be found (compare A [control] and B [AMPH-treated]). There were also no observable differences in the intensity of DAT immunoreactivity in the caudate of the control and AMPH-treated monkeys, C and D, respectively.
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DISCUSSION
The present study is the first to report on the behavioral consequences of repeated, intermittent, escalating low-dose AMPH exposure in the nonhuman primate and to determine the period of time over which these consequences last. The major findings of this longitudinal study on repeated low-dose AMPH exposure in rhesus monkeys are several fold. First, this chronic treatment regimen induces enhanced behavioral responses to acute AMPH challenge as long as 28 months postwithdrawal. Second, the behaviors elicited by acute low-dose AMPH challenge resembled behavioral responses that have previously been described only for chronic and/or high-dose AMPH treatment in monkeys. Third, aberrant behavioral responses induced by acute low-dose AMPH challenge tended to persist for several days following the challenge in monkeys pretreated with chronic AMPH. Fourth, chronically AMPH-treated monkeys showed aberrant behavioral responses in the absence of additional drug challenges. Finally, as extensively documented in rodents, our behavioral and serum data indicate that there may be sex differences in the biochemical as well as in the behavioral response to AMPH in rhesus monkeys.
Behavioral Consequences of Repeated AMPH Exposure in Rhesus Monkeys
Findings from the present study indicate that monkeys previously exposed to intermittent, repeated, escalating low-doses of AMPH display enhanced behavioral responses to subsequent acute low-dose AMPH challenges. Similar to findings from rodent studies, monkeys in the present study showed enhanced behavioral responses during chronic treatment and in response to acute low-dose AMPH challenges shortly after withdrawal as compared to their prechronic AMPH challenge, and these enhanced responses to acute AMPH challenge seemed to be relatively permanent (e.g., Bickerdike and Abercrombie 1997; Paulson et al. 1991).
The monkeys in this study also displayed behavioral depression following withdrawal from chronic AMPH treatment. Previous studies (e.g., Utera 1966) have shown that the behavioral depression evident following withdrawal tends to be transient in nature, with the length of the depression being positively correlated with the duration of chronic treatment. In contrast, although the present study in nonhuman primates is based on a small n, findings indicate considerable individual variability in recovery from behavioral depression, as is likely to be the case for humans. For example, while one monkey's (Flo) circling behavior returned to baseline by 9 months postchronic AMPH treatment, others (Jag and Vien) were still showing significantly less pacing behavior between 9 and 15 months post-treatment than they did before chronic AMPH treatment. One difference between rats and monkeys exposed to repeated AMPH is that rats show maximal behavior enhancement at 1 month postwithdrawal; whereas, behavioral responses to AMPH challenge in monkeys seem to become more "intense" as the time postwithdrawal increases.
One possible interpretation of our findings on repeated, intermittent low-dose AMPH exposure in monkeys is that they developed behavioral sensitization to AMPH. Behavioral sensitization refers to the enhanced behavioral response to an acute low-dose drug challenge shown by individuals having previous intermittent experiences with that drug or a similar agent (including stressors) as compared either to their own predrug baseline or to drug-naive controls (for reviews see Robinson and Becker 1986; Kalivas and Stewart 1991). The phenomenon of behavioral sensitization to psychomotor stimulants, such as AMPH and cocaine, has been extensively studied and well documented in rodents, but little is known about sensitization in nonhuman and human primates. The findings of enhanced behavioral responses to acute AMPH challenge out to 28 months post-treatment could be the first definitive evidence of long-lasting behavioral sensitization to AMPH in the nonhuman primate pending postmortem findings.
Another possible interpretation of the alterations in behavior observed after repeated, intermittent exposure to AMPH in rhesus monkeys might be neurotoxicity. At present, little data are available on the long-term neurochemical and biochemical consequences of repeated low-dose AMPH exposure in nonhuman primates or humans. Findings from one in vivo imaging study in humans suggests that neurotoxicity is not present in the striatum of repeated AMPH abusers (Wilson et al. 1996). Nevertheless, neurotoxicity cannot be ruled out as an explanation for some of the persistent behavioral abnormalities in the AMPH-treated monkeys, including the long-lasting behavioral depression that was observed in some of the monkeys. Several recent PET studies in nonhuman primates have found that a long-lasting reversible depression of the striatal dopamine system exists in both monkeys and baboons that have received several injections of AMPH at doses only slightly higher than those used in the present study (Melega et al. 1997; Villemagne et al. 1998). In fact, this type of neuronal depression, sometimes referred to as reversible neurotoxicity, might help to explain the persistent behavioral effects that were observed over several days following a low-dose challenge in the AMPH-treated monkeys in the present study.
However, other pieces of preliminary data from on-going studies in our laboratory indicate that striatal neurotoxicity, if it exists at all, may not be pronounced in our AMPH-treated animals and, therefore, not a full explanation of the behavioral consequences of repeated low-dose AMPH exposure in the present study. First, histological examination of TH and DAT immunoreactivity in the striatum has not so far revealed any significant differences between the 4-week AMPH-treated monkey and an age-matched control. Although there was evidence for increased dopamine turnover in the prefrontal cortex, the AMPH-treated monkey had normal tissue concentrations of dopamine in both the striatum and prefrontal cortex (unpublished observations, Castner et al.). Because several parameters of striatal and cortical dopamine function were not found to be compromised in the 4-week AMPH-treated monkey, and this monkey was subjected to the same doses of AMPH as the 12-week monkeys (albeit the AMPH doses were escalated more rapidly in the former), we suspect that the histological data obtained from the 4-week monkey implies that our intermittent low-dose AMPH treatment regimen may induce neural protection rather than degeneration of the dopamine system. Second, we have conducted a single-photon emission computed tomography (SPECT) imaging study to see if we could measure potentiation of AMPH-stimulated dopamine release by examining AMPH's ability to induce dopamine release and displace, iodine-123 iodobenzamide, [I123]-IBZM bound to striatal D2 dopamine receptors before and after 6 weeks of AMPH treatment (same AMPH doses used in the present experiment, but more rapid escalation). Results from four sensitized monkeys indicate that there are slight decreases in the percentage displacement at 1 month postchronic AMPH treatment as compared to pretreatment (Castner et al., in preparation). Taken together, these findings suggest that our escalating, intermittent, low-dose AMPH treatment regimen does not seem to result in frank striatal neurotoxicity. However, because we have not examined animals in the present study, striatal neurotoxicity or toxicity to other brain regions cannot be ruled out in this group of animals. However, it is important to point out that evidence of neural damage in these monkeys would not invalidate their potential value as animal models of psychosis, because our aim is to determine how closely their potential pathology resembles that which has already been described in postmortem studies of schizophrenic brains (Selemon et al. 1995, 1998; Benes et al. 1991). Indeed, the ultimate goal of this work is to produce an animal in whom cortical pathology is identical to that observed in schizophrenics.
Persistent Behavioral Responses in the Absence of Additional Drug Challenge
In some respects, the extent to which some monkeys show enhanced responses to AMPH challenge after chronic AMPH treatment was unexpected. Extrapolating from our serum data, the half-life of AMPH seems to be about 6 to 8 hours, similar to that in humans. AMPH's metabolic profile accounts for the finding that treated monkeys continued to exhibit significant drug-induced behaviors between 6 and 8 hours postinjection. However, it does not explain the persistence of symptomatology following a single 0.4 mg/kg AMPH challenge over a period of days, when it seems unlikely that any drug would remain in the system. Therefore, it may be the case, as mentioned above for either sensitization or neurotoxicity, that persistent behavioral abnormalities may reflect long-lasting changes in the system resulting from chronic, repeated AMPH administration. In addition, or conversely, it is possible that persistence of AMPH-induced behaviors after AMPH has already been metabolized in previously AMPH-treated animals could be explained by long-lasting system changes in response to an acute challenge, similar to those changes described in imaging studies in nonhuman primates (Melega et al. 1997; Villemagne et al. 1998). On the other hand, it could be the case that even extremely low concentrations of AMPH that might be present in the system in the days following the challenge are sufficient to produce the behavioral manifestations of the drug (e.g., Chuang et al. 1981). Another possible interpretation of the data is that the aberrant behaviors that manifest over a period of days after repeated AMPH treatment could reflect conditioned responses to the injection (Jodogne et al. 1994; Cabib et al. 1996; Antelman 1994; Antelman and Caggiula 1996). This statement does not imply that a single conditioned stimulus produces the behaviors, but that the entire context of the experimental days surrounding the injection contributes to the continued display of behaviors. In fact, there is considerable data in rodents that indicate that the conditions present during the induction of behavioral sensitization may affect expression of the sensitized response (Badiani et al. 1997; Badiani et al. 1995a; b; Post et al. 1992; Stewart 1992). In the present study, some AMPH-treated monkeys exhibited AMPH-like behaviors even in response to a saline challenge (personal observations). Further study is needed to explore these possibilities.
Putative Sex Differences in the Behavioral Consequences of Repeated AMPH Administration in Rhesus Monkeys
In rodents, it has been shown that intact females show a greater behavioral response to AMPH than do intact males (Beatty and Holzer 1978; Savageau and Beatty 1981; Robinson et al. 1982a; Becker et al. 1982; Robinson et al. 1982b). In the same vein, several observations in the present study are suggestive of sex differences in behavioral responses to AMPH in nonhuman primates. For example, one such difference that emerged in this study was static posturing. After chronic AMPH treatment, both females spent extended periods of time in static postures in response to AMPH challenges, whereas, neither of the males showed static posturing as a response to AMPH challenge. Conversely, AMPH-treated male monkeys in this study continued to engage in movement around the homecage as well as to show higher levels of fine-motor stereotypies in response to AMPH challenge than did females following chronic treatment. In response to AMPH treatment in the present study, both males and females showed increased submissive responses. However, the two sexes showed this increase differently; that is, males lipsmacked, the females presented. Based on data from this study, as well as data from other monkeys exposed to repeated AMPH in the lab, AMPH-induced appetite suppression seems to be more pronounced among young adult females, although some highly responsive males; for example, Jag, also showed significant appetite suppression both during chronic AMPH and in response to acute AMPH challenge post-treatment. In the rat, decreased ambulation and more focused stereotypy is considered a more "intense" response to AMPH than hyperlocomotion, based on dose-response studies (for discussion see Segal and Kuczenski, 1994). Thus, from the present findings, it might be tentatively concluded that females showed a more "intense" behavioral response to repeated AMPH treatment and subsequent AMPH challenge. However, this conclusion is highly preliminary, because one other male (in another 6-week AMPH study) has shown a response similar to that of the AMPH-treated females in this study (personal observations), and it is possible that sex differences in the behavioral response to AMPH of nonhuman primates may be masked by individual differences in AMPH responsivity. Individual differences may also help to explain the lack of pronounced sex differences in AMPH metabolism in the nonhuman primate. Recall that serum AMPH concentrations were obtained to determine if there were sex differences in AMPH metabolism in the nonhuman primate similar to those that have been described for rodents (e.g., Becker et al. 1982). Hepatic metabolism of AMPH is more rapid in male rats than it is in females. Thus, it is necessary to administer a slightly higher dose of AMPH to male rats in order to equate serum AMPH concentrations in male and female rats, and thereby, to ensure that behavioral differences reflect actual sex differences rather than metabolic differences. In the monkey, although there was a tendency for females to show higher peak serum concentrations of AMPH, no significant sex differences were observed in serum AMPH concentrations. In fact, at the midrange challenge dose, males tended to show higher serum concentrations than females during the 2nd and 3rd hours postinjection. Because the midrange dose was used for acute challenges, it is possible that this latter finding might help to explain the different behavioral profiles observed in the two sexes.
Repeated, Low-Dose AMPH Exposure in Rhesus Monkeys as a Model of Psychosis
The longitudinal model of repeated, low-dose AMPH exposure in rhesus monkeys developed here may provide insights into the etiology of schizophrenic psychoses. It has been suggested that any valid animal model of psychosis requires several key features (Liddle et al. 1992). First, it is necessary for such a model to induce what is classically defined as positive-like symptoms including hallucinatory-like behaviors. In the present study, 28 months after chronic AMPH treatment, monkeys responded to a low-dose AMPH challenge with myriad responses "independent of stimuli," including checking, tracking or swatting at nothing in the air, and staring off into space. Possibly even more revelant to the evaluation of repeated, low-dose AMPH exposure in monkeys as an animal model of psychosis is the fact that even at 20 months postdrug treatment, some monkeys continued to show aberrant behaviors in the absence of additional pharmacological challenge. Because some of the behavioral changes induced by repeated low-dose AMPH exposure appear to be "permanent," it is possible that some of the biochemical and anatomical changes found in our AMPH-treated monkeys' brains might be similar to those found in schizophrenics. Studies are currently in progress for comparing the cortex of amphetamine-treated monkeys and schizophrenics. Second, any potential animal model of schizophrenia should induce negative-like symptoms. In the repeated, low-dose AMPH exposure model presented here, some of the behaviors observed both during the latter stages of chronic AMPH treatment as well as in response to low-dose AMPH challenge in previously treated animals could be viewed as analogous to the increase in negative symptoms observed in schizophrenic patients over time (Dollfus and Petit 1995; Kulhara and Chandiramani 1990). For example, the static postures assumed by the females in response to AMPH challenge could be considered evidence of negative-like symptomatology stemming from repeated exposure to AMPH (Liddle et al. 1992). The persistent behavioral depression shown by some animals for up to 20 months after withdrawal, in the absence of drug, could be viewed as similar in nature to the psychomotor poverty syndrome that has been described in schizophrenic patients.
Because it is relatively easy to induce both positive-like and negative-like behavioral changes with pharmacological agents such as AMPH, it seems most important that any valid animal model simulate the third and most difficult-to-treat aspect of the schizophrenic syndrome, cognitive deficits. Preliminary results from a test of frontal lobe function in primates, the object retrieval task, suggest that repeated exposure to AMPH in monkeys impairs performance on this task (Castner and Goldman-Rakic, in preparation). The findings for AMPH-treated monkeys on the object retrieval task are similar to those that have been shown for subchronic PCP exposure in nonhuman primates on this task (Jentsch et al. 1997). Recently, we have shown that monkeys treated for 6 weeks with escalating, intermittent low-doses of AMPH show impairments on the object retrieval task up through 6 to 7 months postchronic treatment. Some of these 6-week treated monkeys are currently undergoing testing on varied spatial delayed response to see if the frontal lobe deficit suggested by the results from the object retrieval task extends to the realm of working memory. In sum, we have shown that repeated, intermittent exposure to escalating low-doses of AMPH produces monkeys that exhibit both negative-like and positive-like symptomatology in the presence and in the absence of drug. Although our AMPH treatment regimen cannot induce schizophrenia, it can establish a chronic condition that includes long-lasting neurochemical, biochemical, and behavioral changes. Therefore, repeated exposure to low-dose AMPH in rhesus monkeys may provide a powerful paradigm for studying the role of dopamine dysregulation in the induction of psychosis and a possible etiology of schizophrenia. Castner Al-Tikriti Baldwin Seibyl Goldman-Rakic Innis in preparation); Castner Goldman-Rakic in preparation)
Acknowledgements
The authors thank Tatyana Trakht and Heather Findlay for their expert technical assistance on this project. We also thank Dr. Robert Jakab for his help with photomicrography and Dr. Leonid Krimer, as well as Dr. Jakab, for their advice on immunocytochemistry. In addition, we thank Jonathon Traupman for creating the Monkey Watcher program. This work was supported by the Stanley Foundation and an NIMH grant MH44866 awarded to P. S. Goldman-Rakic.
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Edited by Isochroma, 10 January 2009 - 02:00 AM.
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Her younger sister, Jennie, had ADHD too, and was on Ritalin. But she stopped Ritalin the day 'Steph' died and the whole family stopped believing in ADHD.
If you saw CBS' Hard Copy, June 24, 1998, you saw Stephanie Hall.
You learned that Stephanie, like millions of other children in the US, had attention deficit hyperactivity disorder-ADHD (sometimes referred to as ADD or attention deficit disorder) and was on Ritalin.
You saw a picture of Stephanie a lovely, healthy, normal girl. Next, in what was a brief segment that hardly told her story, you saw Stephanie's gravestone.
Born January 11, 1984. Died January 5, 1996. Her parents, Michael and Janet, were shown at the grave "where (they) visit 'Steph' now."
Stephanie's Mom Janet, remembers the school days:
In 1st grade Stephanie was a quite shy girl. She had a great love of books, she just loved school… she made new friends easily. Then…it was about the 2nd or 3rd week of 1st grade, her teacher told me, 'Stephanie had a hard time staying on task and that she was making noises.' But she didn't make noises at home. Anyhow the teacher suggested that Stephanie be tested for ADD and that she could be seen by the school psychologist at no cost to us…We took her to another doctor instead. He said she was easily distracted but could read just fine and had normal intelligence...Aside from ear infections as a preschooler Steph was healthy as could be, [but despite all that she was] diagnosed ADD and prescribed Ritalin. It was then that her headaches began…every day, except on weekends, when she didn't take [Ritalin]."
When Stephanie's teacher continued to complain about her behavior, the psychologist suggested "Stephanie needs a behavior modification approach to deal with some residual effects and strong-willed ness," those not taken care of by the Ritalin.
Yet what seemed to be most modified was Stephanie's Ritalin dosage.
So began a series of Ritalin adjustments over the next five years--beginning with 5mg morning and noon--and eventually increasing to 40mg a day.
While her behavior and school performance seemed to improve, some disturbing symptoms also surfaced. Besides the headaches during the school week corresponding with the times she was on medication she also complained of nausea and stomach aches. She displayed mood swings and bizarre behavior. Her neurologist noticed in coordination during his exams.
In the 4th grade Janet recalls:
"Stephanie took off running from the child care center she went to after school. [Daycare workers] chased her but couldn't catch her. She yelled 'I'm 10 ½ now.' She took off across a busy 5-lane road, bought her grandmother a paper and took it all the way downtown where she worked. The day-care workers were screaming at her to come to them. Her DARE officer couldn't believe she acted like that.
They called me at work. I never worked after school hours again."
One day the following summer when Stephanie was off medication she suddenly "zoned out," according to her mother, and seemed "disconnected." Stephanie told her she loved her. They always told each other this, so Janet thought nothing of it. But then Stephanie said it again and she had this empty stare on her face.
"Steph, what's the matter?," said Janet. "I see her again," said Stephanie. "Who?" "The angel--she looks mad."
Then Stephanie snapped out of it. She said the angel had white and red all around her. Some of the angels were blue. And they all had 4 wings.
"It reminds me of when she was first put on Ritalin back in the 1st and 2nd grade," said Janet. "and told me of seeing angels then."
Janet recalls the 6th grade beginning with promise:
"Stephanie made friends easily. Her teachers thought she was the greatest. She wanted to be a paramedic and help people. She had a boy she liked. She was doing OK until the day in October when the vice-principal called and said she was swearing--totally out of character. She was always a good girl. I had never heard her swear. Some girl tried to take her lunch money. A few weeks later I caught her swearing at a boy after school let out. I was shocked, I grounded her. Then, her grades started going down…mostly D's."
By the end of the year Stephanie's mother became so concerned that she asked to have her medication increased. The pediatrician agreed to increase the dose to 25mg in the morning and 15mg at noon beginning after Christmas.
"Steph returned to school and took the increase that morning. She seemed real weird, out of it. I kept asking 'Steph are you OK?'" "She kept saying 'I'm OK Mom,' 'I'm OK.'"
But when Janet picked her up after school she seemed OK, not spaced out like she had been in the morning. The rest of the day went smoothly and as Stephanie went to bed, she was obviously in a playful mood.
"She went on upstairs jumping around with her littlest sister, asking for a dollar." Janet said. "'It's 9:00 'Steph,' get to bed,' I said. 'OK Mom, I love you.' 'I love you too,' I said."
The following morning when Stephanie's dad went to wake her for school, she didn't respond. "We called paramedics and the police. Some of them were about to cry. Stephanie was so cold. I kept saying to them 'She is supposed to bury me, not me bury her'… No other family should know the agony of burying their child."
Nothing unusual was found at autopsy. The coroner ruled death by natural causes. Cause of death--cardiac arrhythmia.
A NEUROLOGIST’S OPINION
Was Stephanie's death a "natural death" as the coroner concluded? Her parents, didn't think so, and asked me to review the case. True, sudden deaths, even in children, and especially those with a negative autopsy, are likely due to an abnormal heart rhythm—cardiac arrhythmia. To conclude, as the coroner did, that this was a "natural death" means that all known diseases or abnormalities that could possibly contribute to such a death have been ruled out. How often do normal, disease- and drug-free, 12 year olds develop a cardiac arrhythmia and die suddenly? In 1989, the National Center for Health Statistics reported a total of 149 sudden deaths due to unknown causes in the age groups 5-14 years, or 4.2 deaths per million children per year. This is rare.
ADHD—THE DISEASE?
Stephanie was diagnosed with ADHD in the first grade. Does it kill? Does it cause heart problems? Does it cause inattention, Impulsiveness, Hyperactivity, Failing grades? Is it a real disease as claimed by psychiatry? I submit that not only did ADHD not kill Stephanie Hall, but that ADHD is not even a disease.
A multitude of forces--US psychiatry, child psychiatry, education, Novartis (the manufacturer of Ritalin, formerly Ciba-Geigy) and Children & Adults with Attention Deficit Disorders (CHADD--financed and controlled by Novartis, just as psychiatry is financed and controlled by the pharmaceutical industry)--have conspired to convince people like Stephanie's parents that ADHD is a real brain "disease"—a "chemical imbalance." Further, they tell us ADHD must be treated with Ritalin—to balance the "chemical imbalance." Ritalin is to ADHD as insulin is to diabetes, and as penicillin is to pneumonia, they would have us believe. The not-so-subtle difference is that diabetes and pneumonia are real diseases needing real treatments, while ADHD is an "invention"--a total, complete, fraud! When there is no disease, there is no need for "treatment." Without the "disease" designation, there is no insurance reimbursement. What we have, therefore, are millions of entirely normal children, just like Stephanie Hall, fraudulently diagnosed, then drugged for profit under the guise of "treatment."
Like most psychiatric disorders/diseases, ADHD was never discovered or validated by finding a 'diagnostic,' (confirmatory) physical or chemical abnormality upon physical exam, laboratory test, x-ray, scan or biopsy.
Rather, it was invented at the American Psychiatric Association in 1980 and has been revised, by vote or show of hands, on two occasions since, in 1987 and 1994. The names have changed throughout the years from "hyperactivity," and "hyperactive child syndrome" in the 50's and 60's; minimal brain dysfunction"—"MBD" in the 70's;"attention deficit disorder"—"ADD" in the 80's; to the current conceptualization of ADHD in 1987. No matter the name, each invented "disease" became the object of millions of dollars worth of biologic research, fraudulent on the face of it, because there was never a disease. Not surprisingly, nothing was proven, scientifically or medically, and yet they continue to implant the illusion in the public consciousness of a "disease" needing "treatment" and thus spread a ever-wider marketplace net, victimizing normal children by the millions.
Lest there be any doubt, consider the remarks of James M. Swanson, Ph.D., ADHD researcher and a member of CHADD's Professional Advisory Board, at the March, 5-8, 1998 meeting of the American Society for Adolescent Psychiatry:
"I would like to have an objective diagnosis for the disorder (ADHD). Right now psychiatric diagnosis is completely subjective…We would like to have biological tests--a dream of psychiatry for many years."
In a letter to me dated May 13, 1998, F. Xavier Castellanos, MD, of the National Institute of Mental Health reiterates Swanson's admission:
"…I have noted your critiques of the diagnostic validity of ADHD. I agree that we have not yet met the burden of demonstrating the specific pathophysiology (abnormality) that we believe underlies this condition."
Lawrence Diller, MD, of the University of California, San Francisco, characterizes ADHD research thusly: "The reason why you have been unable to obtain any articles or studies presenting clear and confirming evidence of a physical or chemical abnormality associated with ADHD is that there are none…the search for a biological marker is doomed from the outset because of the contradictions and ambiguities of the diagnostic construct of ADHD as defined by the DSM. I liken efforts to discover a marker (abnormality) to the search for the Holy Grail."
STEPHANIE'S ENCEPHALOPATHY (BRAIN DYSFUNCTIONS)
Does ADHD cause confusion, disorientation ("spacey," "out of it, weird"), hallucinations (4-winged, red and blue angels from the 1st grade on) dissociative states, organic psychosis (bolting from day-care, running across a busy highway, not responding normally until she was miles away), Tourette's syndrome (the emergence of wholly-out-of-character swearing), clumsiness, incoordination (denotes generalized or diffuse brain dysfunction) headaches, nausea and vomiting (side effects of Ritalin) in an otherwise normal 12-year old girl? Stephanie had none of these things before "coming down" with ADHD and taking Ritalin. Nor was any abnormality--on physical exam or diagnostic testing--noted in her medical record prior to Ritalin treatment.
We can agree now that none of Stephanie's encephalopathic symptoms (descriptions obtained by history--subjective) or signs (abnormalities seen and documented by examiners—objective) were due to ADHD.
Her only brain disease, it appears, was Ritalin poisoning--Ritalin "encephalo-pathy" (encephalon—brain, apathy--disease), verified by knowing she had Ritalin in her system, verifiable had any examiner sought to look for Ritalin in the body and body fluids (e.g., urine, blood and cerebro-spinal fluid).
RITALIN, PSYCHIATRIC DRUGS & THE HEART
What of Ritalin's toxicity for the heart? Did the coroner consider that Ritalin might have caused Stephanie's sudden death, her cardiac arrhythmia? Did he look at the extensive literature on Ritalin and other drugs in the amphetamine family and their commonplace cardiovascular effect?
THE RITALIN INSERT
The Ritalin manufacturer's insert describes it as a "mild" central nervous system stimulant. It fails to tell you that Ritalin is dangerous and addictive—a drug of abuse, or that it is an "amphetamine." Like other amphetamines (e.g.,Dexedrine), like prescription versions of "meth," methamphetamine (e.g., Desoxyn and Gradumet), like cocaine, morphine and Demerol--Ritalin is classified by the Drug
Enforcement Administration (DEA) and by the International Narcotics Control Board (INCB) as a "controlled," Schedule II drug.
The insert also explains that for children 6 years and over—Stephanie's age when she started-- the average dose of Ritalin is 20-30 mg daily with some requiring as much as 40-60 mg daily. The recommended, or target dose, for children, is said to be 0.3-0.6 mg/kg, that for adults 0.1-0.3 mg/kg. Stephanie's dose was almost always in the in the vicinity of 1.0-1.6 mg/kg range—excessive. It was increased the day before she died.
Of 2,993 adverse reaction (AR) reports concerning Ritalin or methylphenidate listed by the FDA's Division of Pharmacovigilance and Epidemiology (DPE), from 1990 to 1997, there were 160 deaths and 569 hospitalizations--36 of them life-threatening.
Ritalin is known to cause cardiac arrhythmia, tachycardia and hypertension. Ritalin and other amphetamines can interfere with the bodies phospholipids (complex fat) chemistry causing the accumulation of abnormal membranes visible with an electron microscope. In 1972, Fisher identified such abnormalities in a heart muscle biopsy from an adult who had been on Ritalin for 4½ years.
In 1994, Henderson & Fischer next exposed experimental mice and rats Ritalin, and found identical membrane proliferation to that in the patient described by Fischer in 1972. Moreover, they found that "The MP (Ritalin) doses used in the experimental rodents fell within the range of therapeutic dosage prescribed for patients with attention deficit disorders (ADD/ADHD)."
Even alternative drugs to Ritalin--such as the commonly used tricyclic antidepressants [e.g., Norpramin (desipramine)] cause severe side effects (16 sudden, cardiac deaths linked to tricyclic antidepressants, most of them in normal children said by school teachers to have ADHD).
As of May, 1996, there were 13 cases of liver failure leading to death or liver transplant from Cylert (pemoline), touted to be the "safest," of the stimulants prescribed for ADHD.
Other similar molecules include fenfluramine (Pondimin)—the "fen" of "fen-phen"—the weight reduction compound found to cause heart valve defects, leading to its being withdrawn from the market.
In The Pathology of Drug Abuse, Karch writes: "Amphetamine's adverse effects on the heart are well established …[sharing] common mechanisms with cocaine toxicity…cardiomyopathy seems to be a complication of amphetamine abuse more often than cocaine abuse…The clinical history in most of these cases is consistent with arrhythmic sudden death [as in Stephanie Hall]. Reports of amphetamine related sudden death were first published shortly after amphetamine became commercially available." [late 1930's, about the same time Bradley discovered the paradoxical, calming effect of amphetamines that has lead to today's Ritalin epidemic]
NOT A NATURAL DEATH AT ALL
Stephanie's death was called a "natural death," by the coroner. It was not! Although entirely normal, Stephanie was said to have a "disease"—ADHD. She never had a symptom or sign of a real, actual disease until the day Ritalin was begun.
By design, Stephanie and her parents never understood the true risk /benefit equation of "treating" ADHD with Ritalin. As in virtually every case across the nation with ADHD portrayed as a "disease," the informed consent rights of Stephanie and her parents were trampled.
In a perversion of the Hippocratic-medical mission so complete as to be unthinkable, the ADHD "industry" have invented--contrived a "disease" to have something for which to give a drug—all of it for profit.
See the picture of Stephanie—pretty, a young woman in bloom, normal, healthy, bright-with-promise, best reader in her class, loved, embodiment of the hopes and dreams of her parents. From the first day of Ritalin on she was no longer physically normal, subject to the chemical assault on her brain and body in the name of "treatment." Then she was dead…not a "natural death" at all.
Thank God that the outcome isn't this tragic in most cases. Thank God most survive the "disease" and the "treatment." But, it is past time for the parents of the nation to wake up to this unimaginable-unspeakable thing that is being done to 5 million entirely normal, if troubled, children in the US daily.
How many deaths, we will never know, because the reporting system the federal government has in place is entirely voluntary and greatly to the liking of the ADHD "industry" not wanting to be found out, not wanting the public afraid of their products, not wanting them withdrawn from the market.
Who killed Stephanie Hall? Let us name them. Let us subpoena them. Will Stephanie get her day in court? Will any of the millions, deceived and damaged every day?
PS. On page 3, lines 10-13, of the Statement of the National Institutes of Health, Consensus Conference on ADHD, November 16-18, 1998, is a "confession" that ADHD has never been validated as a disease and that children said to have it are, therefore, normal:
"… we do not have an independent, valid test for ADHD, and there are no data to indicate that ADHD is due to a brain malfunction."
Call the NIH. The director’s name is Dr. Harold Varmus ( 301-496-4891). You ask him why Stephanie Hall died from treatment for a disease that doesn’t exist—never has. You ask him why an end to the ADHD "epidemic" has not been announced. You ask him why they haven’t told the parents of the 5 million children said to have it, to tear off the "label" (ADHD) and throw the Ritalin in the toilet. I testified a the NIH. I accused them of fraud. They didn’t deny it—they can’t. It appears (1/6/99) that it is business as usual in the multibillion dollar psycho-pharmaceutical, ADHD industry.
Written by: Dr. Fred Baughman and Stephanie's Mom Janet.
Edited by Isochroma, 10 January 2009 - 05:31 AM.
#53 Guest_Isochroma_*
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Posted 10 January 2009 - 07:46 AM
Onwards to the darker lands!
Blackness tempts us tread down darkened halls,
watched by the breathing walls.
Under every rock, slimy nasties writhe and wriggle.
Parkinson's disease (also known as Parkinson disease or PD) is a degenerative disorder of the central nervous system that often impairs the sufferer's motor skills, speech, and other functions.[1]
Parkinson's disease belongs to a group of conditions called movement disorders. It is characterized by muscle rigidity, tremor, a slowing of physical movement (bradykinesia) and, in extreme cases, a loss of physical movement (akinesia). The primary symptoms are the results of decreased stimulation of the motor cortex by the basal ganglia, normally caused by the insufficient formation and action of dopamine, which is produced in the dopaminergic neurons of the brain.
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Treatment of mice with methamphetamine produces cell loss in the substantia nigra
Studies were conducted to determine if treatment of mice with methamphetamine (METH) would produce a loss of dopaminergic cells in the substantia nigra. The number of TH+/Nissl-stained was significantly decreased in both Swiss-Webster (S-W) and C57bl mice (approx. cell loss of 40% and 45%, respectively) 5-8 days after treatment with METH. In these same mice there was a corresponding decrease in neostriatal dopamine (DA) content (90% and 92%, respectively). In parallel studies, treatment with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) produced similar neuropathological effects. The finding that nigral cell loss occurs after METH treatment indicates that the METH-treated mouse may be a very relevant model of Parkinson's disease (PD).
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Elisabeth R. Garwooda(a), Wosen Bekeleb(b), Charles E. McCullochc(c) and Chadwick W. Christined(d),
(a)Pennsylvania State University School of Medicine, United States
(b)University of California, San Francisco, School of Medicine, United States
©Department of Epidemiology and Biostatistics, University of California, San Francisco, United States
(d)Department of Neurology, University of California, 505 Parnassus Avenue Box 0114, San Francisco, CA 94143, United States
Received 13 September 2005; accepted 17 March 2006. Available online 28 March 2006.
Abstract
Background
Since the 1930's, amphetamine drugs have been used therapeutically and recreationally. High doses are associated with acute injury to axon terminals of dopaminergic neurons. It is unknown whether low dose exposure to amphetamine over a prolonged time period is associated with the development of Parkinson's disease (PD).
Methods
A telephone survey of drug and chemical exposure was administered to patients from three faculty practice clinics at UCSF. Patients were asked to participate if they had been diagnosed with peripheral neuropathy (PN), amyotrophic lateral sclerosis (ALS), or PD between the ages of 40 and 64. Spouses or caregivers were also asked to participate. “Amphetamine exposure” was defined as a prior use of amphetamine, methamphetamine or dextroamphetamine. “Prolonged exposure” was defined as amphetamine use that occurred more than twice a week for ≥3 months or weekly usage for ≥1 year and had to occur before diagnosis of the neurological condition.
Results
Prolonged exposure to either prescribed or non-prescribed amphetamine was common, occurring in 15% with PN (11/76), 13% with ALS (9/72), and 11% with PD (17/158). Prolonged amphetamine exposure was more frequent in diseased patients compared to spouses when all diseases were combined (adjusted OR = 3.15, 95% CI 1.42–7.00, p = 0.005). When tested alone, only the Parkinson's disease group retained statistical significance (adjusted OR = 8.04, 95% CI 1.56–41.4, p = 0.013). For most individuals, exposure occurred long before diagnosis (averages: PN 25 years, ALS 28 years, and PD 27 years).
Conclusions
The elevated rate of prolonged amphetamine exposure in PD is intriguing and bears further investigation.
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The persistent, sustained increase in the sensitivity to the psychosis-inducing properties of stimulants suggests that chronic consumption of central stimulants induces a permanent alteration in the functional organization of the central nervous system, especially dopaminergic systems. This hypothesis has been presented in reference to amphetamines (111, 117) and indeed similar considerations have been raised for cocaine (167, 205). Arguments for the DA nature of these chronic effects come from studies on L-dopa treatment, which is more easily studied clinically in a prospective manner. In general, psychomotor disturbances are rare in the early phases of L-dopa treatment of Parkinsonism but become increasingly frequent as treatment is continued (117). After two years of treatment, the incidence of such side effects rises to nearly 70% (118). It has also been noted that these side effects (relative to individual doses of L-dopa) tend to increase with chronic administration, such that lower doses are required to elicit psychosis and dyskinesia (117). Thus, a long-lasting hypersensitivity appears to develop, not only to central stimulants but also to L-dopa, such that previously well tolerated doses may later come to induce toxic symptoms.
Edited by Isochroma, 10 January 2009 - 08:23 AM.
#54 Guest_Isochroma_*
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Posted 10 January 2009 - 08:33 AM
Further treading deeper dreading
Methylphenidate is widely and effectively used for the treatment of attention deficit hyperactivity disorder during early childhood and adolescence, but until now possible effects of this treatment on brain development and the maturation of monoaminergic systems have not been investigated systematically. This experimental animal study describes the effects of methylphenidate administration (2 mg/kg/day) for 2 weeks to very young (prepubertal) and somewhat older (postpubertal) rats on the densities of dopamine, serotonin, and norepinephrine transporters in the striatum and in the midbrain. As shown by ligand-binding-assays, the K(D) values of all three transporters were unaffected by this treatment. No alterations were found for the Bmax values of [3H]-paroxetine and [3H]-nisoxetine binding, but the density of dopamine transporters (Bmax values of [3H]-GBR binding) in the striatum (but not in the midbrain) was significantly reduced after early methylphenidate administration (by 25% at day 45), and this decline reached almost 50% at adulthood (day 70), that is, long after termination of the treatment. This is the first empirical demonstration of long-lasting changes in the development of the central dopaminergic system caused by the administration of methylphenidate during early juvenile life.
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Posted 10 January 2009 - 10:37 PM
Isochroma, are you even reading these studies or are you just collecting documents and text that look like they might support your point? We all appreciate good, scientific studies and this is what we're looking for, but the sensational news articles about isolated incidents are not helpful at all. Furthermore, those news articles contain incorrect information (i.e. the claim that Ritalin is an amphetamine) and are clearly written by a journalist and not someone with proper knowledge of the subject.
The other studies seem to tell the same stories that we all know very well already: Stimulants cause behavioral alterations, stimulants have withdrawal effects, stimulant abuse, especially methamphetamine, is very bad for you. I did gather some useful information from your a handful of your studies, though. This portion was particularly enlightening:
It would be very helpful if you did the following with your studies in the future:
1. Provide a short summary of the study and the relevant conclusions from the study
2. Provide a link to the text of the entire study, so that we can read more if we're interested.
The other studies seem to tell the same stories that we all know very well already: Stimulants cause behavioral alterations, stimulants have withdrawal effects, stimulant abuse, especially methamphetamine, is very bad for you. I did gather some useful information from your a handful of your studies, though. This portion was particularly enlightening:
At present, little data are available on the long-term neurochemical and biochemical consequences of repeated low-dose AMPH exposure in nonhuman primates or humans. Findings from one in vivo imaging study in humans suggests that neurotoxicity is not present in the striatum of repeated AMPH abusers (Wilson et al. 1996).
It would be very helpful if you did the following with your studies in the future:
1. Provide a short summary of the study and the relevant conclusions from the study
2. Provide a link to the text of the entire study, so that we can read more if we're interested.
#56
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Posted 10 January 2009 - 10:43 PM
but the density of dopamine transporters (Bmax values of [3H]-GBR binding) in the striatum (but not in the midbrain) was significantly reduced after early methylphenidate administration (by 25% at day 45), and this decline reached almost 50% at adulthood (day 70), that is, long after termination of the treatment. This is the first empirical demonstration of long-lasting changes in the development of the central dopaminergic system caused by the administration of methylphenidate during early juvenile life.
This is an interesting study. Could anyone with some more knowledge on the subject shed some light on whether or not 2mg/kg/day for a mouse is equivalent to a human ADHD treatment dose or is it more like a dose that one would use to abuse Methylphenidate? I'm also particularly curious as to the effects of reduced concentrations of dopamine transporters.
#57
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Posted 10 January 2009 - 10:51 PM
but the density of dopamine transporters (Bmax values of [3H]-GBR binding) in the striatum (but not in the midbrain) was significantly reduced after early methylphenidate administration (by 25% at day 45), and this decline reached almost 50% at adulthood (day 70), that is, long after termination of the treatment. This is the first empirical demonstration of long-lasting changes in the development of the central dopaminergic system caused by the administration of methylphenidate during early juvenile life.
This is an interesting study. Could anyone with some more knowledge on the subject shed some light on whether or not 2mg/kg/day for a mouse is equivalent to a human ADHD treatment dose or is it more like a dose that one would use to abuse Methylphenidate? I'm also particularly curious as to the effects of reduced concentrations of dopamine transporters.
Here is a somewhat related study:
ET demonstrates reduced dopamine transporter expression in PD with dyskinesias.
Troiano AR, de la Fuente-Fernandez R, Sossi V, Schulzer M, Mak E, Ruth TJ, Stoessl AJ. From the Pacific Parkinson's Research Centre (A.R.T., R.d.l.F.-F., M.S., E.M., T.J.R., A.J.S.), Department of Physics and Astronomy (V.S.), and TRIUMF (V.S.), UBC, Vancouver, BC, Canada.
OBJECTIVE: Dyskinesias are common in Parkinson disease (PD). Prior investigations suggest that dopamine (DA) terminals compensate for abnormal DA transmission. We verified whether similar adaptations could be related to the development of treatment-related complications. METHODS: Thirty-six patients with PD with motor fluctuations were assessed with PET using [(11)C]-d-threo-methylphenidate (MP) and [(11)C]-(+/-) dihydrotetrabenazine (DTBZ). The expression of DA transporter relative to DA nerve terminal density was estimated by determining the MP/DTBZ ratio. Age, treatment, and disease severity were also taken into account in the evaluation of our data. RESULTS: Twenty-seven of the 36 patients had dyskinesias. Nine individuals had motor fluctuations without dyskinesia. The two patient groups were comparable in terms of age, disease duration and severity, medication, and striatal MP and DTBZ binding potentials. The MP/DTBZ ratio in the caudate was not different between groups (nondyskinesia 1.54 +/- 0.36, dyskinesia 1.39 +/- 0.28; mean +/- SD, p = 0.23). Putaminal MP/DTBZ was decreased in individuals with dyskinesia (1.18 +/- 0.24), compared to those who had motor fluctuations without dyskinesia (1.52 +/- 0.24, p = 0.019). The relationship between putaminal MP/DTBZ ratio and the presence of dyskinesias was not altered after correcting for age, treatment, and measures of disease severity. CONCLUSIONS: This investigation supports the role of presynaptic alterations in the appearance of dyskinesias. Dopamine (DA) transporter downregulation may minimize symptoms by contributing to increased synaptic DA levels in early Parkinson disease, but at the expense of leading to increased extracellular DA catabolism and oscillating levels of DA. Such oscillations might ultimately facilitate the appearance of dyskinesias.
PMID: 19020294 [PubMed - as supplied by publisher]
This is very interesting! Although the interactions are vastly more complex than we can explore from these studies, it would be very interesting if Methylphenidate lowered DA transporter densities over time, resulting in higher synaptic DA levels! After all, methylphenidate's mode of action is to block the DA transporter, resulting in higher concentrations of DA in the synaptic cleft. Of course, it might be equally likely that the reduced DA transporter concentration is merely a reaction to a reduced level of available dopamine due to higher catabolism, but wouldn't the net effect still be a damping of DA neuron firing? Can anyone find any studies in this vein?
Edited by Construct, 10 January 2009 - 10:54 PM.
#58
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Posted 14 January 2009 - 10:54 AM
In a sense, everything DOES cause neuronal death. Even neurotransmitters themselves do. The question is how severe and at what doses. Is it linear to dose or exponential?
Unfortunately they can't find real answers to this without cutting up the brains of people who do and don't use amphetamine at various doses and ages and measuring how many neurons they have, though some primate studies at lower (and perhaps higher) doses might give us some idea.
Also, all death is permanent, but new receptors should grow. I guess that's why neuroprotectants and neurogenesis are the most important thing I worry about lately. Things like lithium, piracetam, theanine and tuarine will hopefully keep the damage down a bit - and they do seem to help me somewhat from developing tolerance as I had hoped they would.
what do neuroprotectants do? whats neurogenesis? do they help with brainfog or neurotoxity?
#59
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Posted 15 January 2009 - 08:37 AM
In a sense, everything DOES cause neuronal death. Even neurotransmitters themselves do. The question is how severe and at what doses. Is it linear to dose or exponential?
Unfortunately they can't find real answers to this without cutting up the brains of people who do and don't use amphetamine at various doses and ages and measuring how many neurons they have, though some primate studies at lower (and perhaps higher) doses might give us some idea.
Also, all death is permanent, but new receptors should grow. I guess that's why neuroprotectants and neurogenesis are the most important thing I worry about lately. Things like lithium, piracetam, theanine and tuarine will hopefully keep the damage down a bit - and they do seem to help me somewhat from developing tolerance as I had hoped they would.
what do neuroprotectants do? whats neurogenesis? do they help with brainfog or neurotoxity?
Neuroprotectants stop neuron death, basically. Not completely, but they help. Of course a certain amount of neuron death is normal anyway, and nothing is going to completely stop it or probably even come close.
Neurogenesis is creation of new neurons. It occurs naturally but usually not enough to even replace the dead ones. Some substances, like lithium, can increase this to the point that your brain actually grows. For lithium it can grow up to 3% in a matter of weeks. It seems to be likely that a lot of mental diseases are actually neurodegenerative diseases, so this is a good thing.
#60
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Posted 16 January 2009 - 10:31 AM
Can Memantine at least partially protect from neurotoxicity from the 'ADHD drugs'?...
1: Neurotoxicology. 2008 Jan;29(1):179-83. Epub 2007 Sep 22. Links
Memantine prevents MDMA-induced neurotoxicity.
Chipana C, Camarasa J, Pubill D, Escubedo E.
Unitat de Farmacologia i Farmacognòsia, Facultat de Farmàcia, Nucli Universitari de Pedralbes, Universitat de Barcelona, Av. Joan XXIII s/n, 08028 Barcelona, Spain.
MDMA (ecstasy) is an illicit drug causing long-term neurotoxicity. Previous studies demonstrated the interaction of MDMA with alpha-7 nicotinic acetylcholine receptor (nAChR) in mouse brain membranes and the involvement of alpha-7 nicotinic acetylcholine receptors (nAChR) in dopaminergic neurotoxicity induced by MDMA in mice. The aim of the present study was to investigate the utility of memantine (MEM), an alpha-7 nAChR antagonist used for treatment of Alzheimer's disease patients, to prevent neurotoxicity induced by MDMA in rats and the oxidative effect of this amphetamine derivative in mice striatal synaptosomes. In isolated mouse striatal synaptosomes (an in vitro model of MDMA neurotoxicity of dopaminergic origin), MDMA (50 microM)-induced reactive oxygen species (ROS) production that was fully inhibited by MEM (0.3 microM). This effect of MEM was fully prevented by PNU 282987 (0.5 microM), a specific agonist of alpha-7 nAChR. The preventive effect of MEM on this oxidative effect can be attributed to a direct antagonism between MDMA (acting probably as agonist) and MEM (acting as antagonist) at the alpha-7 nAChR. In Dark Agouti rats (an in vivo model of MDMA neurotoxicity of serotonergic origin), a single dose of MDMA (18 mg/kg) induced persistent hyperthermia, which was not affected by MEM pre-treatment. [(3)H]Paroxetine binding (a marker of serotonergic injury) was measured in the hippocampus of animals killed at 24h and 7 days after treatment. MDMA induced a significant reduction in [(3)H]paroxetine binding sites at both times of sacrifice that was fully prevented by pre-treatment with MEM. Since previous studies demonstrate that increased glutamate activity is not involved in the neurotoxic action of MDMA, it can be concluded that the effectiveness of MEM against MDMA-induced neurotoxicity would be the result of blockade of alpha-7 nAChR, although an indirect mechanism based on the interplay among the various neurotransmission systems leading to an increase in basal acetylcholine release should also be taken into account.
PMID: 17980434 [PubMed - indexed for MEDLINE]
1: Neuropharmacology. 2008 Jun;54(8):1254-63. Epub 2008 Apr 9. Links
Memantine protects against amphetamine derivatives-induced neurotoxic damage in rodents.
Chipana C, Torres I, Camarasa J, Pubill D, Escubedo E.
Unitat de Farmacologia i Farmacognòsia, Facultat de Farmàcia, Universitat de Barcelona, Avda Joan XXIII s/n, Zona Universitaria Pedralbes, 08028 Barcelona, Spain.
We hypothesize that 3,4-methylenedioxymethamphetamine (MDMA) and methamphetamine (METH) interact with alpha-7 nicotinic receptors (nAChR). Here we examine whether memantine (MEM), an antagonist of NMDAR and alpha-7 nAChR, prevents MDMA and METH neurotoxicity. MEM prevented both serotonergic injury induced by MDMA in rat and dopaminergic lesion by METH in mice. MEM has a better protective effect in front of MDMA- and METH-induced neurotoxicity than methyllycaconitine (MLA), a specific alpha-7 nAChR antagonist. The double antagonism that MEM exerts on NMDA receptor and on alpha-7 nAChR, probably contributes to its effectiveness. MEM inhibited reactive oxygen species production induced by MDMA or METH in synaptosomes. This effect was not modified by NMDA receptor antagonists, but reversed by alpha-7 nAChR agonist (PNU 282987), demonstrating a preventive effect of MEM as a result of it blocking alpha-7 nAChR. In synaptosomes, MDMA decreased 5-HT uptake by about 40%. This decrease was prevented by MEM and by MLA but enhanced by PNU 282987. A similar pattern was observed when we measured the dopamine transport inhibited by METH. The inhibition of both transporters by amphetamine derivatives seems to be regulated by the calcium incorporation after activation of alpha-7 nAChR. MDMA competitively displaces [(3)H]MLA from rat brain membranes. MEM and METH also displace [(3)H]MLA with non-competitive displacement profiles that fit a two-site model. We conclude that MEM prevents MDMA and METH effects in rodents. MEM may offer neuroprotection against neurotoxicity induced by MDMA and METH by preventing the deleterious effects of these amphetamine derivatives on their respective transporters.
PMID: 18455739 [PubMed - indexed for MEDLINE]
1: Eur J Pharmacol. 2008 Jul 28;589(1-3):132-9. Epub 2008 May 20. Links
Memantine prevents the cognitive impairment induced by 3,4-methylenedioxymethamphetamine in rats.
Camarasa J, Marimón JM, Rodrigo T, Escubedo E, Pubill D.
Laboratory of Pharmacology and Pharmacognosy, Faculty of Pharmacy, University of Barcelona, Barcelona, Spain. jcamarasa@ub.edu <jcamarasa@ub.edu>
Amphetamine abuse is an important risk factor for the development of cognitive impairment involving learning and memory. Since in previous studies we have demonstrated the effectiveness of alpha-7 nicotinic receptor antagonists in preventing the neurotoxicity induced by amphetamine derivatives, the present paper seeks to determine whether pre-treatment with memantine (MEM) (an antagonist of both nicotinic and NMDA receptors) counteracts the memory impairment induced by 3,4-methylenedioxymethamphetamine (MDMA or ecstasy) administration in male Long Evans rats. In mice, MDMA and MEM induced a locomotor stimulant response but with a different profile. Moreover, MEM inhibited the rearing and thygmotaxis behaviour induced by MDMA. Non-spatial memory was tested in the object recognition test and the spatial learning and memory was tested in the Morris water maze. In our experimental conditions, rats receiving MEM pre-treatment recovered the ability to discriminate between the familiar and the novel object that had been abolished by MDMA treatment. Animals treated with MDMA showed impaired learning in the Morris water maze. Results of the probe trial demonstrated that MDMA-treated rats did not remember the location of the platform, but this memory impairment was also prevented by the MEM pre-treatment. Moreover, MEM alone improved the learning task. No differences were observed between the different groups as regards swim speed. In conclusion, MEM significantly improved the learning and memory impairment induced by MDMA and constitutes the first approach to the treatment of the long-term cognitive deficits found in ecstasy users.
PMID: 18582864 [PubMed - in process]
1: Neurotoxicology. 2008 Jan;29(1):179-83. Epub 2007 Sep 22. Links
Memantine prevents MDMA-induced neurotoxicity.
Chipana C, Camarasa J, Pubill D, Escubedo E.
Unitat de Farmacologia i Farmacognòsia, Facultat de Farmàcia, Nucli Universitari de Pedralbes, Universitat de Barcelona, Av. Joan XXIII s/n, 08028 Barcelona, Spain.
MDMA (ecstasy) is an illicit drug causing long-term neurotoxicity. Previous studies demonstrated the interaction of MDMA with alpha-7 nicotinic acetylcholine receptor (nAChR) in mouse brain membranes and the involvement of alpha-7 nicotinic acetylcholine receptors (nAChR) in dopaminergic neurotoxicity induced by MDMA in mice. The aim of the present study was to investigate the utility of memantine (MEM), an alpha-7 nAChR antagonist used for treatment of Alzheimer's disease patients, to prevent neurotoxicity induced by MDMA in rats and the oxidative effect of this amphetamine derivative in mice striatal synaptosomes. In isolated mouse striatal synaptosomes (an in vitro model of MDMA neurotoxicity of dopaminergic origin), MDMA (50 microM)-induced reactive oxygen species (ROS) production that was fully inhibited by MEM (0.3 microM). This effect of MEM was fully prevented by PNU 282987 (0.5 microM), a specific agonist of alpha-7 nAChR. The preventive effect of MEM on this oxidative effect can be attributed to a direct antagonism between MDMA (acting probably as agonist) and MEM (acting as antagonist) at the alpha-7 nAChR. In Dark Agouti rats (an in vivo model of MDMA neurotoxicity of serotonergic origin), a single dose of MDMA (18 mg/kg) induced persistent hyperthermia, which was not affected by MEM pre-treatment. [(3)H]Paroxetine binding (a marker of serotonergic injury) was measured in the hippocampus of animals killed at 24h and 7 days after treatment. MDMA induced a significant reduction in [(3)H]paroxetine binding sites at both times of sacrifice that was fully prevented by pre-treatment with MEM. Since previous studies demonstrate that increased glutamate activity is not involved in the neurotoxic action of MDMA, it can be concluded that the effectiveness of MEM against MDMA-induced neurotoxicity would be the result of blockade of alpha-7 nAChR, although an indirect mechanism based on the interplay among the various neurotransmission systems leading to an increase in basal acetylcholine release should also be taken into account.
PMID: 17980434 [PubMed - indexed for MEDLINE]
1: Neuropharmacology. 2008 Jun;54(8):1254-63. Epub 2008 Apr 9. Links
Memantine protects against amphetamine derivatives-induced neurotoxic damage in rodents.
Chipana C, Torres I, Camarasa J, Pubill D, Escubedo E.
Unitat de Farmacologia i Farmacognòsia, Facultat de Farmàcia, Universitat de Barcelona, Avda Joan XXIII s/n, Zona Universitaria Pedralbes, 08028 Barcelona, Spain.
We hypothesize that 3,4-methylenedioxymethamphetamine (MDMA) and methamphetamine (METH) interact with alpha-7 nicotinic receptors (nAChR). Here we examine whether memantine (MEM), an antagonist of NMDAR and alpha-7 nAChR, prevents MDMA and METH neurotoxicity. MEM prevented both serotonergic injury induced by MDMA in rat and dopaminergic lesion by METH in mice. MEM has a better protective effect in front of MDMA- and METH-induced neurotoxicity than methyllycaconitine (MLA), a specific alpha-7 nAChR antagonist. The double antagonism that MEM exerts on NMDA receptor and on alpha-7 nAChR, probably contributes to its effectiveness. MEM inhibited reactive oxygen species production induced by MDMA or METH in synaptosomes. This effect was not modified by NMDA receptor antagonists, but reversed by alpha-7 nAChR agonist (PNU 282987), demonstrating a preventive effect of MEM as a result of it blocking alpha-7 nAChR. In synaptosomes, MDMA decreased 5-HT uptake by about 40%. This decrease was prevented by MEM and by MLA but enhanced by PNU 282987. A similar pattern was observed when we measured the dopamine transport inhibited by METH. The inhibition of both transporters by amphetamine derivatives seems to be regulated by the calcium incorporation after activation of alpha-7 nAChR. MDMA competitively displaces [(3)H]MLA from rat brain membranes. MEM and METH also displace [(3)H]MLA with non-competitive displacement profiles that fit a two-site model. We conclude that MEM prevents MDMA and METH effects in rodents. MEM may offer neuroprotection against neurotoxicity induced by MDMA and METH by preventing the deleterious effects of these amphetamine derivatives on their respective transporters.
PMID: 18455739 [PubMed - indexed for MEDLINE]
1: Eur J Pharmacol. 2008 Jul 28;589(1-3):132-9. Epub 2008 May 20. Links
Memantine prevents the cognitive impairment induced by 3,4-methylenedioxymethamphetamine in rats.
Camarasa J, Marimón JM, Rodrigo T, Escubedo E, Pubill D.
Laboratory of Pharmacology and Pharmacognosy, Faculty of Pharmacy, University of Barcelona, Barcelona, Spain. jcamarasa@ub.edu <jcamarasa@ub.edu>
Amphetamine abuse is an important risk factor for the development of cognitive impairment involving learning and memory. Since in previous studies we have demonstrated the effectiveness of alpha-7 nicotinic receptor antagonists in preventing the neurotoxicity induced by amphetamine derivatives, the present paper seeks to determine whether pre-treatment with memantine (MEM) (an antagonist of both nicotinic and NMDA receptors) counteracts the memory impairment induced by 3,4-methylenedioxymethamphetamine (MDMA or ecstasy) administration in male Long Evans rats. In mice, MDMA and MEM induced a locomotor stimulant response but with a different profile. Moreover, MEM inhibited the rearing and thygmotaxis behaviour induced by MDMA. Non-spatial memory was tested in the object recognition test and the spatial learning and memory was tested in the Morris water maze. In our experimental conditions, rats receiving MEM pre-treatment recovered the ability to discriminate between the familiar and the novel object that had been abolished by MDMA treatment. Animals treated with MDMA showed impaired learning in the Morris water maze. Results of the probe trial demonstrated that MDMA-treated rats did not remember the location of the platform, but this memory impairment was also prevented by the MEM pre-treatment. Moreover, MEM alone improved the learning task. No differences were observed between the different groups as regards swim speed. In conclusion, MEM significantly improved the learning and memory impairment induced by MDMA and constitutes the first approach to the treatment of the long-term cognitive deficits found in ecstasy users.
PMID: 18582864 [PubMed - in process]
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