![[dr. bob]](/dr-bob-sm.gif)
Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 1 to 25 of 25. This is the beginning of the thread.
Posted by france1000 on June 5, 2008, at 1:28:01
I am taking regularely Nac to protect my brain from Ritalin.
Recently i've began to take INDIUM SULPHATE in the Morning. (It is supposing to have many benefits for heath).
Knowing that Nac eliminats the metals from body - is possible that a Indium could be eliminated from body too ??? It means: no benifit from indium!?
Or i have only to make attention (2, 3 hours) between taking nac and indium?
Anyway someone knows if between this 3 drugs (nac, ritalin, indium) there are the interactions?
Posted by Molybdenum on June 5, 2008, at 4:31:26
In reply to Ritalin, NAC and Indium?, posted by france1000 on June 5, 2008, at 1:28:01
Hi,
Would you mind pointing me at an article expounding the neuroprotective action of Acetylcysteine in relation to Methylphenidate use?
I'm curious ;)
Thanks
Mr. M.
Posted by yxibow on June 5, 2008, at 4:47:06
In reply to Ritalin, NAC and Indium?, posted by france1000 on June 5, 2008, at 1:28:01
> I am taking regularely Nac to protect my brain from Ritalin.
>
> Recently i've began to take INDIUM SULPHATE in the Morning. (It is supposing to have many benefits for heath).
>
> Knowing that Nac eliminats the metals from body - is possible that a Indium could be eliminated from body too ??? It means: no benifit from indium!?
>
> Or i have only to make attention (2, 3 hours) between taking nac and indium?
>
> Anyway someone knows if between this 3 drugs (nac, ritalin, indium) there are the interactions?This would probably be best served in the alternative section.
Indium has no functionality or RDA in the human body despite advertising for it -- there are only so many elements that are actually utilized by the body, cobalt being a curious one having one molecule in Vitamin B-12. This could have an endless debate so I won't go further on it.
NAC has gone under some trials apparently for OCD or so posted on the web, again it is also a "dietary supplement"
I don't know about n-acetyl-cysteine but I can pretty sure say that Indium wouldn't interact as it is just a dust particle in the body if at all, and personally, just my opinion, so no ad hominem statements, is a waste of a $700/kg element used in LCDs and is becoming more scarce [soapbox off]
I think the main thing is to focus on your doctor and your treatment with Ritalin and to inform he or she of any supplements. With so many supplements out there, I mean I do take a few myself, so I'm not trying to have the pot and kettle thing, there is now are PDR editions for various dietary supplements.
I hope that helps and doesn't offend -- as I said I take tryptophan and 5HTP along with other prescription agents -- whether it helps sleep I really can't say, but I do inform my doctor.-- tidings
Jay
Posted by undopaminergic on June 5, 2008, at 4:59:27
In reply to Ritalin, NAC and Indium?, posted by france1000 on June 5, 2008, at 1:28:01
> I am taking regularely Nac to protect my brain from Ritalin.
>It is unlikely that Ritalin would increase your need for antioxidative therapy with N-acetylcysteine. Besides, there is some concern that high doses of NAC might give rise to toxic metabolites that may promote pulmonary hypertension, among other things.
Methylphenidate (Ritalin) and cocaine are actually neuroprotective against dopaminergic neurotoxicity from methamphetamine and MPTP, because they prevent the neurotoxins from entering dopamine (DA) neurons by means of the dopamine transporter (DAT) protein.
Posted by linkadge on June 5, 2008, at 8:26:08
In reply to Re: Ritalin, NAC and Indium?, posted by undopaminergic on June 5, 2008, at 4:59:27
There is no evidence I am aware of that suggests stimulants used at clincal doses for AD/HD are toxic to the brain.
Studies linking stimulants to neurotoxicity use doses that get people high. At these doses you are having major neurotransmitter release and are at risk of glutamatergic neurotoxicity and a correspoding increase in oxadative stress.
As mentioned DAT inhibitors can protect against the effecs of certain neurotoxins. This depends on deceased activity of the dopamine transporter. Chronic use can sometimes lead to compensatory dopamine transporter upregulation which may negate this effect.
Linkadge
Posted by france1000 on June 5, 2008, at 11:25:37
In reply to Ritalin, NAC and Indium?, posted by france1000 on June 5, 2008, at 1:28:01
Many of you have asked a link concerning the question: IF NAC PROTECTS THE BRAIN WHILE USING STIMULANTS ?
Here some "google - resultats":
Effect of antioxidant N-acetyl-l-cysteine on behavioral changes and neurotoxicity in rats after administration of methamphetamine.
Fukami G, Hashimoto K, Koike K, Okamura N, Shimizu E, Iyo M.
Department of Psychiatry, Chiba University, Graduate School of Medicine, 1-8-1 Inohana, Chuo, Chiba 260-8670, Japan.
Several lines of evidence suggest that oxidative stress may play a role in the behavioral changes and neurotoxicity in rats after administration of methamphetamine (MAP). N-acetyl-l-cysteine (NAC) is a precursor of glutathione, and it also exerts as an antioxidant. In this study, we investigated the effects of NAC on the behavioral changes (hyperlocomotion and development of sensitization) and neurotoxicity in male Wistar rats after administration of MAP. Pretreatment with NAC (30, 100 or 300 mg/kg, i.p.) attenuated significantly hyperlocomotion in rats induced by a single administration of MAP (2 mg/kg, i.p.), in a dose-dependent manner. Furthermore, pretreatment with NAC (100 mg/kg, i.p., 15 min before MAP injection, once daily for 5 consecutive days) blocked significantly the development of behavioral sensitization in rats after repeated administration of MAP (2 mg/kg, once daily for 5 consecutive days), whereas the behaviors in rats after repeated administration of NAC plus saline groups were not different from those of control (vehicle plus saline) groups. One week after administration of MAP (7.5 mg/kgx4, 2-h intervals), levels of dopamine (DA) in rat striatum were significantly decreased as compared with control groups. Pretreatment with NAC (1, 3, 10 or 30 mg/kg, i.p., 30 min before each MAP injection) attenuated significantly the MAP-induced reduction of DA in rat striatum, in a dose-dependent manner. These results suggest that NAC could prevent the behavioral changes (acute hyperlocomotion and development of behavioral sensitization) in rats and neurotoxicity in rat striatum after administration of MAP, and that NAC would be a useful drug for treatment of several symptoms associated with MAP abuse.
PMID: 15234256
Neuropsychopharmacology. 2004 Jun 16 [Epub ahead of print]Protective Effects of N-acetyl-L-cysteine on the Reduction of Dopamine Transporters in the Striatum of Monkeys Treated with Methamphetamine.
Hashimoto K, Tsukada H, Nishiyama S, Fukumoto D, Kakiuchi T, Shimizu E, Iyo M.
1Department of Psychiatry, Chiba University Graduate School of Medicine, Chiba, Japan.
Several lines of evidence suggest that oxidative stress might contribute to neurotoxicity in the dopaminergic nerve terminals after administration of methamphetamine (MAP). We undertook the present study to determine whether intravenous administration of N-acetyl-L-cysteine (NAC), a potent antioxidant drug, could attenuate the reduction of dopamine transporter (DAT) in the striatum of monkey brain after administration of MAP. Positron emission tomography studies demonstrated that repeated administration of MAP (2 mg/kg as a salt, four times at 2-h intervals) significantly decreased the accumulation of radioactivity in the striatum after intravenous administration of [(11)C]beta-CFT. In contrast, the binding of [(11)C]SCH 23390 to dopamine D(1) receptors in the monkey striatum was not altered after the administration of MAP. A bolus injection of NAC (150 mg/kg, i.v.) 30 min before MAP administration and a subsequent continuous infusion of NAC (12 mg/kg/h, i.v.) over 8.5 h significantly attenuated the reduction of DAT in the monkey striatum 3 weeks after the administration of MAP. These results suggest that NAC could attenuate the reduction of DAT in the monkey striatum after repeated administration of MAP. Therefore, it is likely that NAC would be a suitable drug for treatment of neurotoxicity in dopaminergic nerve terminals related to chronic use of MAP in humans.Neuropsychopharmacology advance online publication, 16 June 2004; doi:10.1038/sj.npp.1300512
PMID: 15199373
Posted by undopaminergic on June 5, 2008, at 15:03:00
In reply to NAC PROTECTS THE BRAIN WHILE USING STIMULANTS!!!, posted by france1000 on June 5, 2008, at 11:25:37
Experiments with NAC for protection against the neurotoxicity of large doses of methamphetamine are not relevant to the use of modest doses of Ritalin. In fact, Ritalin (methylphenidate) is even more effective than NAC in preventing methamphetamine neurotoxicity.
J Pharmacol Exp Ther. 2003 Mar;304(3):1181-7.Methylphenidate Alters Vesicular Monoamine Transport and Prevents Methamphetamine-Induced Dopaminergic Deficits
It has been hypothesized that high-dose methamphetamine treatment rapidly redistributes cytoplasmic dopamine within nerve terminals, leading to intraneuronal reactive oxygen species formation and well characterized persistent dopamine deficits. We and others have reported that in addition to this persistent damage, methamphetamine treatment rapidly decreases vesicular dopamine uptake, as assessed in purified vesicles prepared from treated rats; a phenomenon that may contribute to aberrant intraneuronal dopamine redistribution proposedly caused by the stimulant. Interestingly, post-treatment with dopamine transporter inhibitors protect against the persistent dopamine deficits caused by methamphetamine; however, mechanisms underlying this phenomenon have not been elucidated. Also of interest are findings that dopamine transporter inhibitors, including methylphenidate, rapidly increase 1) vesicular dopamine uptake, 2) vesicular monoamine transporter-2 (VMAT-2) ligand binding, and 3) VMAT-2 immunoreactivity in a vesicular subcellular fraction prepared from treated rats. Therefore, we hypothesized that methylphenidate post-treatment might protect against the persistent striatal dopamine deficits caused by methamphetamine by rapidly affecting VMAT-2 and vesicular dopamine content. Results reveal that methylphenidate post-treatment both prevents the persistent dopamine deficits and reverses the acute decreases in vesicular dopamine uptake and VMAT-2 ligand binding caused by methamphetamine treatment. In addition, methylphenidate post-treatment reverses the acute decreases in vesicular dopamine content caused by methamphetamine treatment. Taken together, these findings suggest that methylphenidate prevents persistent methamphetamine-induced dopamine deficits by redistributing vesicles and the associated VMAT-2 protein and presumably affecting dopamine sequestration. These findings not only provide insight into the neurotoxic effects of methamphetamine but also mechanisms underlying dopamine neurodegenerative disorders, including Parkinson's disease.
Full article available:
http://jpet.aspetjournals.org/cgi/content/full/304/3/1181
Posted by france1000 on June 5, 2008, at 15:16:40
In reply to Re: NAC PROTECTS THE BRAIN WHILE USING STIMULANTS!!!, posted by undopaminergic on June 5, 2008, at 15:03:00
QUESTION:
Ritalin (methylphenidate) taken alone is neuroprotective?
Posted by france1000 on June 5, 2008, at 15:21:24
In reply to A question!, posted by france1000 on June 5, 2008, at 15:16:40
I wanted to know too if:
Ritalin (methylphenidate)and Methamphetamine are both stimulants ?!
Posted by undopaminergic on June 5, 2008, at 15:25:49
In reply to Question nr. 2!, posted by france1000 on June 5, 2008, at 15:21:24
> QUESTION:
> Ritalin (methylphenidate) taken alone is neuroprotective?
>Yes, against some neurotoxins.
> I wanted to know too if:
>
> Ritalin (methylphenidate)and Methamphetamine are both stimulants ?!
>Yes, but their mechanisms of action are different.
Posted by france1000 on June 5, 2008, at 15:38:29
In reply to Re: Question nr. 2!, posted by undopaminergic on June 5, 2008, at 15:25:49
Thank you very much for your responses!!!
IN YOUR OPINION:
(And concerning my situation): You think that taking NAC during my Ritalin traitement - is not at all usefull ???
Posted by undopaminergic on June 5, 2008, at 17:00:04
In reply to Re: Question nr. 2!, posted by france1000 on June 5, 2008, at 15:38:29
> Thank you very much for your responses!!!
>
> IN YOUR OPINION:
> (And concerning my situation): You think that taking NAC during my Ritalin traitement - is not at all usefull ???
>NAC is probably good for your liver and kidneys, and it has some neuroprotective effects too, so it may be somewhat useful, but probably not greatly so.
Posted by linkadge on June 5, 2008, at 18:45:15
In reply to Re: Question nr. 2!, posted by undopaminergic on June 5, 2008, at 17:00:04
Its also a matter of dose too. The studies shown use somewhat higher doses of meth than what might be used for ADHD. This is an important destinction.
In some studies lower doses of amphetamines actually seem to promote axional regeneration in some models of brain injury.
I think its really about dose. I think too much ritalin like too much amphetamine will be neurotoxic. Whenever you take enough of the drug to promote the neurotransmitter release to get "high" you are probably risking neurotoxicity.
Also, when used in ADHD, stimulants tend to produce more of an inhibitory effect upon neurotransmission. When they are used at doses to produce a high, the main effect is likely excitory.
Linkadge
Posted by iforgotmypassword on June 6, 2008, at 2:36:06
In reply to NAC PROTECTS THE BRAIN WHILE USING STIMULANTS!!!, posted by france1000 on June 5, 2008, at 11:25:37
is it possible to take those amounts, or even the least amount mentioned, without danger? (these dosages were also given through injections it seems, and did not have to go through the stomach and liver first...)
i seem to remember that you should not go over a certain amount of NAC, but i could be wrong. my memory is not the greatest, and i could even be thinking of something else.
Posted by iforgotmypassword on June 6, 2008, at 2:37:52
In reply to NAC PROTECTS THE BRAIN WHILE USING STIMULANTS!!!, posted by france1000 on June 5, 2008, at 11:25:37
(sorry for duplicate, did not fill everything in)
is it possible to take those amounts, or even the least amount mentioned, without danger? (these dosages were also given through injections it seems, and did not have to go through the stomach and liver first...)
i seem to remember that you should not go over a certain amount of NAC, but i could be wrong. my memory is not the greatest, and i could even be thinking of something else.
Posted by undopaminergic on June 6, 2008, at 9:25:17
In reply to Re: Question nr. 2!, posted by linkadge on June 5, 2008, at 18:45:15
>
> I think its really about dose. I think too much ritalin like too much amphetamine will be neurotoxic. Whenever you take enough of the drug to promote the neurotransmitter release to get "high" you are probably risking neurotoxicity.
>Amphetamines and DAT-inhbitors produce some of the same neurobiological adaptions, such as downregulation of postsynaptic D2-receptors. However, the pattern of damage to presynaptic nerve terminals under discussion only occurs with amphetamines - at high doses - and not with cocaine or methylphenidate, even at massive doses, far beyond those used recreationally. In fact, the DAT-inhibitors protect against the toxic effects of high doses of amphetamines. High doses of DAT-inhibitors have the opposite effects of amphetamines in several respects - for instance, they produce increases in intracellular (vesicular) dopamine content, whereas amphetamines produce a depletion - including non-neurotoxic depletions at therapeutic doses, and this is one of the mechanisms underlying tolerance. It is not a matter of dose, but a matter of mechanisms of action.
For clarification, none of the above should be interpreted to mean that massive doses of cocaine or methylphenidate are harmless - they can be lethal in overdose, just like most other drugs. They can also produce tolerance and dependence, much like amphetamines do, but some of the mechanism are different and some of them are similar. It's also possible that they might promote certain types of neurotoxicity - but they are not capable of causing some of the types of damage seen with amphetamines.
Posted by linkadge on June 6, 2008, at 10:50:15
In reply to Re: NAC PROTECTS THE BRAIN WHILE USING STIMULANTS!, posted by iforgotmypassword on June 6, 2008, at 2:36:06
Yes this is like an injection of greater than 160mg of meth. That is going to give a sudden burst of neurotransmitter release. When you take the prescribed dose of like 25mg orally you are taking a lot less and less is getting to the brain in a longer frame of time.
Linkadge
Posted by linkadge on June 6, 2008, at 11:18:16
In reply to Re: Question nr. 2!, posted by undopaminergic on June 6, 2008, at 9:25:17
>Amphetamines and DAT-inhbitors produce some of >the same neurobiological adaptions, such as >downregulation of postsynaptic D2-receptors. >However, the pattern of damage to presynaptic >nerve terminals under discussion only occurs >with amphetamines - at high doses - and not with >cocaine or methylphenidate, even at massive >doses, far beyond those used recreationally.
Cocaine and methyphenidate do have neurotoxic potential. I havn't heard about what you are suggesting, but glutamatergic neurotoxicity is still a concern. Cocaine and ritalin also downregulate bcl-2 (among other antiapoptotic enzymes) in certain neural strucutres. These changes are generally dose dependant however.
http://www.freeradicalscience.com/showabstract.php?pmid=15681117
>In fact, the DAT-inhibitors protect against the >toxic effects of high doses of amphetamines. >High doses of DAT-inhibitors have the opposite >effects of amphetamines in several respects - >for instance, they produce increases in >intracellular (vesicular) dopamine content, >whereas amphetamines produce a depletion - >including non-neurotoxic depletions at >therapeutic doses, and this is one of the >mechanisms underlying tolerance.
You can still obviously grow tollerant to methylphenidate or cocaine. The studies you are referring to are generally discussing the short term ability of ritalin to prevent some of the monoamine disturbances of high doses of amphetamines. Ritalin and cocaine do enhance the release of monoamines as well as block their reuptake. Longer term use of higher doses may also lead to monoamine depletion. Cocaine and ritalin also lead to dopamine transporter upregulation in certain limbic regions with long term us. Rats raised on ritalin show long term reward deficits and depressive behavior when they do not recieve the drug. This may be related to transporter upregulation.
Ritalin is also shows genotoxic potential. The long term effects of this are currenly not well established.
>It is not a matter of dose, but a matter of >mechanisms of action.
Are you arguing that euphoriant doses of ritalin or cocaine are in no ways neurotoxic? This is not true.
>It's also possible that they might >promote >certain types of neurotoxicity - but they are >not capable of causing some of the types of >damage seen with amphetamines.
I would argue that while amphetamines may produce a form of neurotoxicity not seen with cocaine, they likely have certain common mechanisms of toxicity. Euphoriant doses of stimulants place massive demands on the brain. The brain releases more glutamate. The cells are required to function harder and there is increased oxidative stress. The elevation of PKC can alter BCL-2 levels which can the cells more vulnerable to apoptosis. This coupled with excessive glutamate and insufficiant energy requirements can lead to cellular death. Excessive dopaminegic activity can also increase oxidative stress in certain cicumstances.
With cocaine abuse you still see things like cellular atrophy, loss of cortical grey matter, glial pathologies etc which are shared in meth abuse.
I think dose is important because any stimulant will put dose dependant demands on brain cells.
Linkadge
Posted by bleauberry on June 6, 2008, at 19:15:23
In reply to Ritalin, NAC and Indium?, posted by france1000 on June 5, 2008, at 1:28:01
NAC is not a strong chelator of metals. Yes it does help mobilize metals and encourage the process of eliminating them. It is a crucial part of the body's natural detox system for reducing normal everyday toxic exposure. But if you are talking about something powerful enough to sweep up all metals and escort them to the toilet, no, NAC does not have that power. NAC is actually harmful to many people at chelation forums because it has enough power to dislodge things like mercury and lead from storage, but not enough power to tightly hold onto them all the way to the toilet. Instead those metals get pulled from storage, stirred up in the blood, and redeposited in new places where they were not previously a concern, along with new symptoms and problems.
NAC at best might remove some of your current everyday toxic exposure, likely none of your previous exposure, and probably not much effect on metalic supplements.
Posted by SLS on June 10, 2008, at 6:35:48
In reply to Re: Question nr. 2!, posted by linkadge on June 6, 2008, at 11:18:16
Hi Linkadge.
Regardless of any agenda that *I* might have, I find your writing to be very well organized and cogent, and growing more so over time. Your knowledge is staggering. I hope you follow your passions in your continuing education - whatever they may be.
Sincerely,
Scott
Posted by SLS on June 10, 2008, at 6:44:57
In reply to Re: Ritalin, NAC and Indium?, posted by bleauberry on June 6, 2008, at 19:15:23
I don't know about chelation therapy, but NAC is a precursor to glutathione, a potent free-radical scavenger that reduces apoptopic processes within the cell.
- Scott
Posted by undopaminergic on June 10, 2008, at 12:21:57
In reply to Re: Question nr. 2!, posted by linkadge on June 6, 2008, at 11:18:16
> >Amphetamines and DAT-inhbitors produce some of >the same neurobiological adaptions, such as >downregulation of postsynaptic D2-receptors. >However, the pattern of damage to presynaptic >nerve terminals under discussion only occurs >with amphetamines - at high doses - and not with >cocaine or methylphenidate, even at massive >doses, far beyond those used recreationally.
>
> Cocaine and methyphenidate do have neurotoxic potential.
>Such a possibility cannot be ruled out, but an extensive - albeit not exhaustive - review of the available data suggests that any neurotoxic potential of cocaine - and probably methylphenidate - is subtle enough to routinely escape detection even after extreme conditions of exposure to massive mounts of cocaine. A notable exception is a couple of old reports from an author claiming to have found signs of cocaine-induced neurodegeneration in the "lateral habenula", but these are unconfirmed - and indeed contradicted - by other researchers. Furthermore, there are numerous reports confirming the lack of any detectable neurotoxicity from cocaine under various conditions - often following one or more of a variety of different experiments designed to provoke it.
However, the apparent lack of neurotoxicity should not be erroneously interpreted as a lack of other adverse effects, such as liver toxicity and cardiovascular complications. Heart attacks and strokes can easily have such consequences as severe brain damage and death.
> I havn't heard about what you are suggesting,
>That is remarkable, considering the amount of research on it published throughout the past few decades. I'll include a small subset of the relevant references below.
> You can still obviously grow tollerant to methylphenidate or cocaine.
>Since I already acknowledged that, I wonder why you deem it necessary repeat it.
> Ritalin and cocaine do enhance the release of monoamines as well as block their reuptake.
>Most of the studies suggesting such an effect of DAT inhibitors at the first glance no longer do upon closer investigation, but rather turn out merely to use sloppy and misleading language. The few reports on experiments actually designed to demonstrate a neurtransmitter-releasing effect of cocaine (I can't recall any on methylphenidate) only appear to succeed in the endevour under special experimental conditions that scarcely occur in nature. Under normal conditions, DAT inhibitors are more likely to reduce neurotransitter release due to increased stimulation of autoreceptors. Nevertheless, I'm open to the possibility that in certain situations, depending on a number of factors, reuptake inhibitors may have release-facilitating actions, but not through the same mechanisms - and almost certainly not to the same level - as the amphetamines.
> Longer term use of higher doses may also lead to monoamine depletion.
>Most data indicate enhanced intracellular monoamine content following reuptake inhibition, in addition to the well known elevation of synaptic neurotransmitter concentrations - the very opposite of depletion. During withdrawal from long-term use - especially if abrupt - there is likely to be a relative or functional deficit of the affected neurotransmitters in the synapse, but to call this a depletion of monoamines would be very misleading.
> Cocaine and ritalin also lead to dopamine transporter upregulation in certain limbic regions with long term us.
>This is absolutely correct.
> Rats raised on ritalin show long term reward deficits and depressive behavior when they do not recieve the drug. This may be related to transporter upregulation.
>Yes, in addition to a variety of other adaptions, depending on the level of exposure to the drug in terms of dose and duration, as well as on other factors, including at least at which point in the life of the animal that treatment was started.
> Ritalin is also shows genotoxic potential. The long term effects of this are currenly not well established.
>I'm highly skeptical of that, although considering the endless genetic variety, there is a chance that Ritalin would be toxic to some subset thereof.
> >It is not a matter of dose, but a matter of >mechanisms of action.
>
> Are you arguing that euphoriant doses of ritalin or cocaine are in no ways neurotoxic? This is not true.
>I can only conclude that there is extremely little evidence of neurotoxicity of methylphenidate or cocaine at doses far exceeding those used for euphoria or other recreational purposes. However, it can never be absolutely guaranteed, for all time, that these drugs cannot possibly be neurotoxic under any circumstances - it only means that any neurotoxic effects are rare and elusive enough to have gone undetected through decades of research. It is almost certain, however, that other risks - aside from neurotoxicity - are much more significant and relevant in practice - these include, for instance, the consequences of drug induced behaviours, cardiovascular complications such as stroke and cardiac arrest, damage related to the routes of administration, toxic effects of contaminants accompanying the drug, heat stroke, seizures, and so on.
> I would argue that while amphetamines may produce a form of neurotoxicity not seen with cocaine, they likely have certain common mechanisms of toxicity. Euphoriant doses of stimulants place massive demands on the brain. The brain releases more glutamate. The cells are required to function harder and there is increased oxidative stress. The elevation of PKC can alter BCL-2 levels which can the cells more vulnerable to apoptosis. This coupled with excessive glutamate and insufficiant energy requirements can lead to cellular death. Excessive dopaminegic activity can also increase oxidative stress in certain cicumstances.
>While you are correct about much of the above, you seem to be overlooking several facts that are highly relevant to the outcome. First, the location of the elevated dopamine (DA): DAT-inibitors reduce cytosolic extravesicular DA, thus reducing intracellular oxidative stress from DA-[auto]oxidation (e.g. DA quinones), whereas amphetamines do the opposite. Second, the magnitude of DA elevation: only a relatively modest elevation of synaptic DA is possible by reuptake inhibition (by cocaine, etc.), whereas extensive synaptic release of neuronal stores of DA by amphetamines can produce DA concentrations that are several times higher. Third, you imply that the so-called euphoriant doses of stimulants are necessarily much higher than those used medically: this is actually somewhat true for amphetamines, especially following the development of tolerance, but the route of administartion is of great importance as to whether or not euphoria is felt. In contrast, therepeutic doses of methylphenidate generally produce levels of DAT-inhibition matching or exceeding those required - but not sufficient - to elicit feelings of euphoria if - and only if -the onset of DAT inhibition is rapid enough, which it rarely is following oral administration. On the other hand, experiments have demonstrated that comparable doses of intravenous methylphenidate are indistinguishable from cocaine even by experienced cocainists. The absolute level of DAT-inhibition - as long as it exceeds a critical point of about 50% - is of little significance to the induction and maintenance of a "rush", as opposed to the rapid rise and absence of decline in synaptic DA. Neither cocaine nor methylphenidate is potent and long-lasting enough to maintain synaptic DA levels at a sufficient level to satisfy the demanding abuser for long after peak levels of DAT-inhibition have been reached and the inevitable decline has begun, leading to binges, where new doses are administered before the effects of the previous ones have dissipated. The danger of such behaviour is not that it produces particularly harmful levels of DA, but other effects, such as hypertension from noradrenaline reuptake inhibition and - in the case of cocaine - possible cardiac arrythmias from interference with sodium channels.
> With cocaine abuse you still see things like cellular atrophy, loss of cortical grey matter, glial pathologies etc which are shared in meth abuse.
>Be careful not to erroneously attribute generalised, inspecific findings to particular causes - whether drug abuse or otherwise - without adequate supporting evidence in favour of such an interpretation.
> I think dose is important because any stimulant will put dose dependant demands on brain cells.
>So will many other substances as well - regardless of whether they are classified as stimulants or otherwise. The demands a substance puts on the brain (and body in general) depends on its properties, which determine how it interacts with the organism and therefore its potential to produce beneficial or detrimental effects. Amphetamines are capable of producing some neneficial effects in many cases where the other stimulants are not, but they are likewise capable of causing certain adverse consequences that the other stimulants cannot.
The references that I promised you above:
Life Sci. 1988;43(17):1403-9.
Cocaine, in contrast to D-amphetamine, does not cause axonal terminal degeneration in neostriatum and agranular frontal cortex of Long-Evans rats.
http://www.ncbi.nlm.nih.gov/pubmed/3185100Brain Res Bull. 1988 Aug;21(2):233-7.
Lack of long-term monoamine depletions following repeated or continuous exposure to cocaine.
http://www.ncbi.nlm.nih.gov/pubmed/2461246Brain Res. 1990 Apr 16;513(2):274-9.
Dopamine uptake inhibitors block long-term neurotoxic effects of methamphetamine upon dopaminergic neurons.
http://www.ncbi.nlm.nih.gov/pubmed/2140952Brain Res. 1990 Jun 4;518(1-2):67-77.
Histological and ultrastructural evidence that D-amphetamine causes degeneration in neostriatum and frontal cortex of rats.
http://www.ncbi.nlm.nih.gov/pubmed/1975218Neurosci Lett. 1993 Apr 30;153(2):210-4.
Long-term cocaine administration is not neurotoxic to cultured fetal mesencephalic dopamine neurons.
http://www.ncbi.nlm.nih.gov/pubmed/8327196J Neurochem. 1993 Apr;60(4):1444-52.
Differing neurotoxic potencies of methamphetamine, mazindol, and cocaine in mesencephalic cultures.
http://www.ncbi.nlm.nih.gov/pubmed/8095976Brain Res. 1993 Jul 9;616(1-2):263-72.
Cocaine neurotoxicity and altered neuropeptide Y immunoreactivity in the rat hippocampus; a silver degeneration and immunocytochemical study.
http://www.ncbi.nlm.nih.gov/pubmed/8358618J Neurosci. 1994 Apr;14(4):2260-71.
Methamphetamine neurotoxicity involves vacuolation of endocytic organelles and dopamine-dependent intracellular oxidative stress.
http://www.ncbi.nlm.nih.gov/pubmed/8158268J Pharmacol Exp Ther. 1994 Dec;271(3):1320-6.
Protection against methamphetamine-induced neurotoxicity to neostriatal dopaminergic neurons by adenosine receptor activation.
http://www.ncbi.nlm.nih.gov/pubmed/7996441Brain Res. 1995 Apr 24;677(2):345-7.
Methamphetamine-induced serotonin neurotoxicity is mediated by superoxide radicals.
http://www.ncbi.nlm.nih.gov/pubmed/7552263J Pharmacol Exp Ther. 1998 Aug;286(2):1074-85.
Long-term effects of amphetamine neurotoxicity on tyrosine hydroxylase mRNA and protein in aged rats.
http://www.ncbi.nlm.nih.gov/pubmed/9694971Brain Res. 1999 Aug 7;837(1-2):15-21.
Methamphetamine generates peroxynitrite and produces dopaminergic neurotoxicity in mice: protective effects of peroxynitrite decomposition catalyst.
http://www.ncbi.nlm.nih.gov/pubmed/10433983Neurology. 2000 Mar 28;54(6):1344-9.
Evidence for long-term neurotoxicity associated with methamphetamine abuse: A 1H MRS study.
http://www.ncbi.nlm.nih.gov/pubmed/10746608J Pharmacol Exp Ther. 2002 Mar;300(3):1093-100.
Methylenedioxymethamphetamine decreases plasmalemmal and vesicular dopamine transport: mechanisms and implications for neurotoxicity.
http://www.ncbi.nlm.nih.gov/pubmed/11861820J Pharmacol Exp Ther. 2003 Mar;304(3):1181-7
Methylphenidate alters vesicular monoamine transport and prevents methamphetamine-induced dopaminergic deficits.
http://www.ncbi.nlm.nih.gov/pubmed/12604695Synapse. 2003 Aug;49(2):89-96.
Neurotoxic methamphetamine regimen severely impairs recognition memory in rats.
http://www.ncbi.nlm.nih.gov/pubmed/12740864Psychopharmacology (Berl). 2006 Apr;185(3):327-38. Epub 2006 Mar 3.
Cognitive function and nigrostriatal markers in abstinent methamphetamine abusers.
http://www.ncbi.nlm.nih.gov/pubmed/16518646J Neurochem. 2007 Nov;103(3):1219-27. Epub 2007 Aug 7.
A rapid oxidation and persistent decrease in the vesicular monoamine transporter 2 after methamphetamine.
http://www.ncbi.nlm.nih.gov/pubmed/17683483Synapse. 2008 Feb;62(2):91-100.
Persistent cognitive and dopamine transporter deficits in abstinent methamphetamine users.
http://www.ncbi.nlm.nih.gov/pubmed/17992686
Posted by linkadge on June 10, 2008, at 13:41:40
In reply to A Quick Accolade » linkadge, posted by SLS on June 10, 2008, at 6:35:48
Hey, thanks.
Linkadge
Posted by linkadge on June 10, 2008, at 19:08:04
In reply to Re: Question nr. 2!, posted by undopaminergic on June 10, 2008, at 12:21:57
>Such a possibility cannot be ruled out, but an >extensive - albeit not exhaustive - review of >the available data suggests that any neurotoxic >potential of cocaine - and probably >methylphenidate - is subtle enough to routinely >escape detection even after extreme conditions >of exposure to massive mounts of cocaine.
Cocaine is not necessarily directly neurotoxic to serotonergic and dopaminergic neurons in the way that amphetamines are, but this does not imply it is not neurotoxic. There are many studies demonstrating the ways in which cocaine is neurotoxic.
This study used clozapine in an animal model of cocaine neurotoxicity. They theorized that clozapine had some ability to reduce the cocaine induced glutamate release.
http://jpet.aspetjournals.org/cgi/content/full/312/1/297
Nextly cocaine has been shown to be neurotoxic to the medium spiny neurons in the neucleus accumbens (i.e. it directly damages the pleasure centres of the brain). This in conjunction with DAT transporter upregulation could be responsible for cocaine associated depression.
http://cocaine.org/reward/pleasure.html
The neurotoxic effects of cocaine are evident in regular users. The following study concluded that cocaine was directly neurotoxic to the frontal cortex as evidenced by glial activation and specific loss of choline, creatine and inositol containing compounds in the frontal cortex, in comparison to healthy control subjects.
http://cocaine.org/longterm/index.html
The next study examines the effects of cocaine and methamphetamine separately for their ability to deplete striatal dopamine concentrations. It concluded that cocaine and methamphetamine led to significant depletion of striatal dopamine as well as coenzyme q10. The study also found that q10 adminstration ameliorated the dopamine depletion. The study concluded that q10 administration appears to attentuate cocaine neurotoxicity.
http://cocaine.org/coq10/index.html
The next article describes certain changes in the brains of cocaine users. It finds indication of presynaptic degeneration to dopamine neurons (page 4). It describes a neuroleptic malignant like syndrome as an indicator of extreme dopamine depletion. (page5) The article then extensivly describes long term cognitive deficits and cerebral atrophy in cocaine users (page 5). It also states (with reference to the ability of cocaine to deplete dopamine): "Although some investigators reported lack of long-term monoamine depletion following chronic treatment
of rats with cocaine (Kleven et al. 1987), the majority of studies point to the existence of DA deficiency (page 9). The article then gives reference to several studys describing the detrimental effects of cocaine on monoamine levels and synthesis.Additional reference to the neurotoxic effects of cocaine (page 12)
Recent findings of Ellison (1992; Ellison et al., this volume) clearly established that cocaine is also neurotoxic: Continuous exposure to cocaine for 3 to 5days (pellets releasing 103 milligrams (mg) of cocaine over 5 days), in a regimen that mimics bingeing in addicts, produced strik-ing axonal degeneration extending from lateral habenula along the fascic-ulus retroflexus toward the ventral tegmentum. In rats exposed to continuous cocaine, persistent changes in acetylcholine (ACh) and GABA receptors in the caudate were observed, implying damage to structures postsynaptic to DA neurons (Ellison et al., this volume). These neurodegenerative changes resembled effects of amphet-amine and were observed 30 days after removal of cocaine pellets, sugges-ting that they were long lasting or permanent. Neurochemical evidence of cocaine-induced neurodegeneration was also furnished by other investigators. Hurd and colleagues (1990)
showed that repeated cocaine self-administration produced decreased levels of extra-cellular ACh in rat caudate-putamen in addition to DA deficiency. Contin-uous administration of cocaine was also shown to produce a persistent reduction in binding of the muscarinic receptor ligand and an increase in binding of the central benzodiazepine receptor ligand in the caudate, NA, olfactory tubercle, dorsal hippocampus, amygdala, and cerebral cortex (Zeigler et al. 1991). The upregulation of benzodiazepine receptors (coupled to the GABAA receptors) could result from decreased GABA synthesis and may suggest degeneration of GABAergic neurons. The brain regions that degenerated after continuous cocaine exposure are very rich in ACh and are the crossroads for DA, GABA, and ACh inner-vations (Angevine and Cotman 1981); therefore their lesions are likely to cause impairment of neuronal functions mediated by these 12
neurotrans-mitters. Such effects were, in fact, observed behaviorally in rats in the forms of exaggerated fear, anxiety, and reduced exploratory behavior (Zeigler et al. 1991).
http://www.nida.nih.gov/pdf/monographs/Monograph163/Monograph163.pdf(I could go on, the above link is 344 pages)
>Furthermore, there are numerous reports >confirming the lack of any detectable >neurotoxicity from cocaine under various >conditions - often following one or more of a >variety of different experiments designed to >provoke it.I think I know the *study* you are referring to :)
>Under normal conditions, DAT inhibitors are more >likely to reduce neurotransitter release due to >increased stimulation of autoreceptors.
Yes, but cocaine is a monoamine releaser on its own right, so it will release dopamine in spite of messages from autoreceptors.
>Nevertheless, I'm open to the possibility that >in certain situations, depending on a number of >factors, reuptake inhibitors may have release->facilitating actions, but not through the same >mechanisms - and almost certainly not to the >same level - as the amphetamines.
Cocaine is a monoamine releaser, just like ritalin is.
>Most data indicate enhanced intracellular >monoamine content following reuptake inhibition, >in addition to the well known elevation of >synaptic neurotransmitter concentrations - the >very opposite of depletion.
Read the above and certainly request more if you want it. Like I said, ritalin is a norepinephrine/dopamine reuptake inhibitor with NE and DE releasing actions. Cocaine is a triple uptake inhibitor with monoamine releasing actions.
>I can only conclude that there is extremely >little evidence of neurotoxicity of >methylphenidate or cocaine at doses far >exceeding those used for euphoria or other >recreational purposes.
There is as much evidence as you are willing to consider.
>>
>> With cocaine abuse you still see things like >>cellular atrophy, loss of cortical grey matter, >>glial pathologies etc which are shared in meth >>abuse.
>>>Be careful not to erroneously attribute >generalised, inspecific findings to particular >causes - whether drug abuse or otherwise - >without adequate supporting evidence in favour >of such an interpretation.
That is refeneced above.
>Life Sci. 1988;43(17):1403-9.
>Cocaine, in contrast to D-amphetamine, does not >cause axonal terminal degeneration in >neostriatum and agranular frontal cortex of Long->Evans rats.
>http://www.ncbi.nlm.nih.gov/pubmed/3185100This was only a 3 day study.
>Brain Res Bull. 1988 Aug;21(2):233-7.
>Lack of long-term monoamine depletions following >repeated or continuous exposure to cocaine.
>http://www.ncbi.nlm.nih.gov/pubmed/2461246Ok, one study shows no monoamine depletion. There are starkly contrasting studies above. Also this is not evidence of lack of neurotoxicity.
>Brain Res. 1990 Jun 4;518(1-2):67-77.
>Histological and ultrastructural evidence that D->amphetamine causes degeneration in neostriatum >and frontal cortex of rats.
>http://www.ncbi.nlm.nih.gov/pubmed/1975218This study says absolutely nothing about cocaine or ritalin (?)
>Neurosci Lett. 1993 Apr 30;153(2):210-4.
>Long-term cocaine administration is not >neurotoxic to cultured fetal mesencephalic >dopamine neurons.
>http://www.ncbi.nlm.nih.gov/pubmed/8327196This is a very specific cell culture.
>J Neurochem. 1993 Apr;60(4):1444-52.
>Differing neurotoxic potencies of >methamphetamine, mazindol, and cocaine in >mesencephalic cultures.
>http://www.ncbi.nlm.nih.gov/pubmed/8095976Again, a very specific cell culture. The study is incontrast to some of the above mentioned (in vivo) studies.
>J Neurosci. 1994 Apr;14(4):2260-71.
>Methamphetamine neurotoxicity involves >vacuolation of endocytic organelles and dopamine->dependent intracellular oxidative stress.
>http://www.ncbi.nlm.nih.gov/pubmed/8158268Again, this study says absolutely nothing about cocaine or ritalin.
>J Pharmacol Exp Ther. 1994 Dec;271(3):1320-6.
>Protection against methamphetamine-induced >neurotoxicity to neostriatal dopaminergic >neurons by adenosine receptor activation.
>http://www.ncbi.nlm.nih.gov/pubmed/7996441Again, this study says nothing about cocaine or ritalin.
>Brain Res. 1995 Apr 24;677(2):345-7.
>Methamphetamine-induced serotonin neurotoxicity >is mediated by superoxide radicals.
>http://www.ncbi.nlm.nih.gov/pubmed/7552263How does providing evidence that methamphetamine is neurotoxic support your argument that cocaine and ritalin are not neurotoxic??
>J Pharmacol Exp Ther. 1998 Aug;286(2):1074-85.
>Long-term effects of amphetamine neurotoxicity >on tyrosine hydroxylase mRNA and protein in aged >rats.
>http://www.ncbi.nlm.nih.gov/pubmed/9694971How does providing evidence that methamphetamine is neurotoxic support your argument that cocaine and ritalin are not neurotoxic??
>Brain Res. 1999 Aug 7;837(1-2):15-21.
>Methamphetamine generates peroxynitrite and >produces dopaminergic neurotoxicity in mice: >protective effects of peroxynitrite >decomposition catalyst.
>http://www.ncbi.nlm.nih.gov/pubmed/10433983How does providing evidence that methamphetamine is neurotoxic support your argument that cocaine and ritalin are not neurotoxic??
>Neurology. 2000 Mar 28;54(6):1344-9.
>Evidence for long-term neurotoxicity associated >with methamphetamine abuse: A 1H MRS study.
>http://www.ncbi.nlm.nih.gov/pubmed/10746608How does providing evidence that methamphetamine is neurotoxic support your argument that cocaine and ritalin are not neurotoxic??
>J Pharmacol Exp Ther. 2002 Mar;300(3):1093-100.
>Methylenedioxymethamphetamine decreases >plasmalemmal and vesicular dopamine transport: >mechanisms and implications for neurotoxicity.
>http://www.ncbi.nlm.nih.gov/pubmed/11861820How does providing evidence that methamphetamine is neurotoxic support your argument that cocaine and ritalin are not neurotoxic??
>J Pharmacol Exp Ther. 2003 Mar;304(3):1181-7
>Methylphenidate alters vesicular monoamine >transport and prevents methamphetamine-induced >dopaminergic deficits.
>http://www.ncbi.nlm.nih.gov/pubmed/12604695Ok. This point was made above. It does not show that ritalin is non neurotoxic. It does not mention the dose or the duration of treatment with ritalin.
>Synapse. 2003 Aug;49(2):89-96.
>Neurotoxic methamphetamine regimen severely >impairs recognition memory in rats.
>http://www.ncbi.nlm.nih.gov/pubmed/12740864How does providing evidence that methamphetamine is neurotoxic support your argument that cocaine and ritalin are not neurotoxic??
>Psychopharmacology (Berl). 2006 Apr;185(3):327->38. Epub 2006 Mar 3.
>Cognitive function and nigrostriatal markers in >abstinent methamphetamine abusers.
>http://www.ncbi.nlm.nih.gov/pubmed/16518646How does providing evidence that methamphetamine is neurotoxic support your argument that cocaine and ritalin are not neurotoxic??
>Neurochem. 2007 Nov;103(3):1219-27. Epub 2007 >Aug 7.
>A rapid oxidation and persistent decrease in the >vesicular monoamine transporter 2 after >methamphetamine.
>http://www.ncbi.nlm.nih.gov/pubmed/17683483How does providing evidence that methamphetamine is neurotoxic support your argument that cocaine and ritalin are not neurotoxic??
>Synapse. 2008 Feb;62(2):91-100.
>Persistent cognitive and dopamine transporter >deficits in abstinent methamphetamine users.
>http://www.ncbi.nlm.nih.gov/pubmed/17992686How does providing evidence that methamphetamine is neurotoxic support your argument that cocaine and ritalin are not neurotoxic??
Linkadge
Posted by undopaminergic on June 14, 2008, at 7:14:59
In reply to Re: Question nr. 2!, posted by linkadge on June 10, 2008, at 19:08:04
>
> Cocaine is not necessarily directly neurotoxic to serotonergic and dopaminergic neurons in the way that amphetamines are,
>Good, since that was my main point - at least until you expanded the scope of the discussion.
> but this does not imply it is not neurotoxic.
That's correct, and as I've noted, it's infeasible to prove that any substance lacks neurotoxic potential under all circumstances.
However, there is very little evidence to suggest that cocaine (or methylphenidate) has any significant neurotoxic potential, and much research that indicates a remarkable lack thereof. On the other hand, as I've previously explained, cocaine has other - more significant - properties that make it toxic in overdose - of particular relevance to this discussion is its cardiovascular effects, which may - among other things - cause cerebral ischaemia with consequent damage to neural tissues. Additionally, chronic cocaine administration can induce neurophysiological adaptions, which should not be confused with neurotoxicity.
The above is an attempt to summarise my current conclusions on this matter. You are of course entitled to take a different stance, and there is little for me to gain in trying to change it, whereas there is much time and effort to be lost in further argument. Therefore, this will be my final remark on this topic for this time.
This is the end of the thread.
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