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Is Cognitive Functioning Impaired in Methamphetamine Users? A Critical Review.

ebola? said:
Ah. Yes. I am not counting downregulation as damage, as this is the typical 'first pass' mechanism via which tolerance manifests, and one will easily observe tolerance 'even' with 10 mg / amphetamine / day. I operationalize "damage" as axon pruning or cellular death. 20-40 mg methamphetamine a day seems like a fairly forgiving upper limit, as even with solid tolerance, this would get me pretty solidly high. :P

ebola
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I guess I'm assuming the user isn't taking the whole daily dose in one sitting but spreading it out, but either way I seriously doubt cellular death will be a problem. The good thing with methamphetamine, unlike MDMA, is that from what we know so far, a massive amount of excess DA is being metabolized by MAO/COMT and auto-oxidized without any enzymes, then is overwhelming the anti-oxidants, causing damage to mitochondrial function, in very high doses meth induces hyperthermia which exacerbates all the damaging reactions, and can also cause ROS production via microglial activation, glutamate receptor-induced Ca2+ influx / NMDA receptor-mediated as well. None of these mechanisms should cause irreversible cellular damage at said dose, and if the latter is occurring to be on the safe side, the brain seems to be adapting very effectively to increase the anti-oxidant supply and block the damage. Researchers are having a hard time finding neurocognitive domains in which ex-meth abusers (defined sometimes as 150 - 15,000 mg per day) no longer perform within the normal range of their peers, although they have demonstrated lesser performance on some measures, which is quite expected considering abuse doses induce hyperthermia and are so much higher. MDMA on the other hand, seems to have some really nasty neurotoxic metabolites and also causes inhibition of tryptophan hydroxylase, greatly depleting SER and possibly causing DA to be taken up by SER receptors, which seem to be less resilient to NOS damage than their DA receptor counter-parts. Anyway, sounds like you should be safe getting solidly high at 10 mg d-meth :D
 
Amu said:
I guess I'm assuming the user isn't taking the whole daily dose in one sitting but spreading it out, but either way I seriously doubt cellular death will be a problem. The good thing with methamphetamine, unlike MDMA, is that from what we know so far, a massive amount of excess DA is being metabolized by MAO/COMT and auto-oxidized without any enzymes, then is overwhelming the anti-oxidants, causing damage to mitochondrial function, in very high doses meth induces hyperthermia which exacerbates all the damaging reactions, and can also cause ROS production via microglial activation, glutamate receptor-induced Ca2+ influx / NMDA receptor-mediated as well. None of these mechanisms should cause irreversible cellular damage at said dose, and if the latter is occurring to be on the safe side, the brain seems to be adapting very effectively to increase the anti-oxidant supply and block the damage. Researchers are having a hard time finding neurocognitive domains in which ex-meth abusers (defined sometimes as 150 - 15,000 mg per day) no longer perform within the normal range of their peers, although they have demonstrated lesser performance on some measures, which is quite expected considering abuse doses induce hyperthermia and are so much higher. MDMA on the other hand, seems to have some really nasty neurotoxic metabolites and also causes inhibition of tryptophan hydroxylase, greatly depleting SER and possibly causing DA to be taken up by SER receptors, which seem to be less resilient to NOS damage than their DA receptor counter-parts. Anyway, sounds like you should be safe getting solidly high at 10 mg d-meth :D
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Microglia activation can be partially stymied by NSAIDs. Perhaps ethanol would be neuroproctive via NMDA antagonism and GABA-A positive allosteric modulation reducing the Ca+ influx but this is only one variable of the combination. Cognitive deficits are certainly being found.

REF

http://www.ncbi.nlm.nih.gov/pubmed/11831502 [cognitive deficits]

http://neuro.psychiatryonline.org/article.aspx?articleID=101811 [Several studies listed finding mixed cognitive deficits]

"More recent studies have shown that long-term methamphetamine use is associated with impaired performance on a number of cognitive tasks.68—71 Volkow et al.71 tested a group of methamphetamine-dependent subjects and found that they exhibited performance deficits in both verbal memory and motor function. Simon et al.70 observed that the methamphetamine users in their study did not differ from controls on global Intelligence Quotient (IQ) measures, though they did perform significantly worse on tests of memory recall. The methamphetamine group in this same study had difficulty with tests that measured manipulation of information (i.e., Digit Span Task and Trail Making Part B), but had no problems on tasks that measured psychomotor speed separately (i.e., Trail Making Part A). The methamphetamine group also displayed deficits in abstract reasoning and task shifting strategies. In their study, Ornstein et al.72 reported that methamphetamine-dependent subjects displayed specific deficits in shifting categories on a computerized task shifting experiment when compared with chronic heroin users and nonsubstance using control subjects."

This is actually very similar to cognitive tests given to MMDA users but still confounding variables couldn't be all controlled for in any of this cognitive studies.

Methamphetamine also causes inhibition of tryptophan hydroxylase [and certainly more] via free radical oxidation. But this is temporary which lasts and around a week.

"These observations suggest that the rapid decrease in central tryptophan hydroxylase activity induced by amphetamine analogs results from the reversible oxidation of a sulfhydryl site(s) within the enzyme molecule"

http://www.ncbi.nlm.nih.gov/pubmed/2714371?dopt=Abstract

Idk what you mean by this "...greatly depleting SER and possibly causing DA to be taken up by SER receptors, which seem to be less resilient to NOS damage than their DA receptor counter-parts."

but I would like to see a reference for that.
 
airsh0w said:
Microglia activation can be partially stymied by NSAIDs. Perhaps ethanol would be neuroproctive via NMDA antagonism and GABA-A positive allosteric modulation reducing the Ca+ influx but this is only one variable of the combination. Cognitive deficits are certainly being found.

REF

http://www.ncbi.nlm.nih.gov/pubmed/11831502 [cognitive deficits]

http://neuro.psychiatryonline.org/article.aspx?articleID=101811 [Several studies listed finding mixed cognitive deficits]

"More recent studies have shown that long-term methamphetamine use is associated with impaired performance on a number of cognitive tasks.68—71 Volkow et al.71 tested a group of methamphetamine-dependent subjects and found that they exhibited performance deficits in both verbal memory and motor function. Simon et al.70 observed that the methamphetamine users in their study did not differ from controls on global Intelligence Quotient (IQ) measures, though they did perform significantly worse on tests of memory recall. The methamphetamine group in this same study had difficulty with tests that measured manipulation of information (i.e., Digit Span Task and Trail Making Part B), but had no problems on tasks that measured psychomotor speed separately (i.e., Trail Making Part A). The methamphetamine group also displayed deficits in abstract reasoning and task shifting strategies. In their study, Ornstein et al.72 reported that methamphetamine-dependent subjects displayed specific deficits in shifting categories on a computerized task shifting experiment when compared with chronic heroin users and nonsubstance using control subjects."

This is actually very similar to cognitive tests given to MMDA users but still confounding variables couldn't be all controlled for in any of this cognitive studies.

Methamphetamine also causes inhibition of tryptophan hydroxylase [and certainly more] via free radical oxidation. But this is temporary which lasts and around a week.

"These observations suggest that the rapid decrease in central tryptophan hydroxylase activity induced by amphetamine analogs results from the reversible oxidation of a sulfhydryl site(s) within the enzyme molecule"

http://www.ncbi.nlm.nih.gov/pubmed/2714371?dopt=Abstract

Idk what you mean by this "...greatly depleting SER and possibly causing DA to be taken up by SER receptors, which seem to be less resilient to NOS damage than their DA receptor counter-parts."

but I would like to see a reference for that.
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Of course cognitive deficits are being found, the study says this clearly. The point is many of these deficits have not demonstrated a departure from the normal range, and most researchers were drawing conclusions that were not grounded in the study they performed. MDMA causes hyperthermia and serotonin release and subsequent depletion worse than d-meth does at threshold therapeutic and threshold euphoric doses, at least for serotonin systems, although in absurd doses d-meth will also cause similar deficits. As for why I stated SER receptors might cause worse NOS damage, that is because dopamine is not normally metabolized into pro-oxidant products at serotonin receptors unless there is a depletion of serotonin. What exactly do you want a reference for? Nothing is set in stone yet, but dopamine being taken up by sertonin transporters/receptors in the absence of serotonin is a well-known possible mechanism for MDMA neurotoxicity.

The big picture is a lot of people have bought into a certain level of disapproval for anything related to d-meth, while MDMA is accepted by much more people as a sane drug to take (ravers and what have you), and my response is d-meth is not as inherently neurotoxic compared to MDMA as someone laymen and even researchers believe, of course it matters what dose we're talking about, but while a therapeutic user of could get a full day of coverage with d-meth at 20 mg, as evidenced by numerous ADHD/TBI patients, the same is not the case for MDMA. What I want to instill in people via this thread is d-meth can be used in a reasonable fashion just like any other drug, and just because rat studies demonstrate neurotoxicity doesn't mean every single meth user is damned to eternal brain damage.
 
Amu said:
Of course cognitive deficits are being found, the study says this clearly. The point is many of these deficits have not demonstrated a departure from the normal range, and most researchers were drawing conclusions that were not grounded in the study they performed. MDMA causes hyperthermia and serotonin release and subsequent depletion worse than d-meth does at threshold therapeutic and threshold euphoric doses, at least for serotonin systems, although in absurd doses d-meth will also cause similar deficits. As for why I stated SER receptors might cause worse NOS damage, that is because dopamine is not normally metabolized into pro-oxidant products at serotonin receptors unless there is a depletion of serotonin. What exactly do you want a reference for? Nothing is set in stone yet, but dopamine being taken up by sertonin transporters/receptors in the absence of serotonin is a well-known possible mechanism for MDMA neurotoxicity.

The big picture is a lot of people have bought into a certain level of disapproval for anything related to d-meth, while MDMA is accepted by much more people as a sane drug to take (ravers and what have you), and my response is d-meth is not as inherently neurotoxic compared to MDMA as someone laymen and even researchers believe, of course it matters what dose we're talking about, but while a therapeutic user of could get a full day of coverage with d-meth at 20 mg, as evidenced by numerous ADHD/TBI patients, the same is not the case for MDMA. What I want to instill in people via this thread is d-meth can be used in a reasonable fashion just like any other drug, and just because rat studies demonstrate neurotoxicity doesn't mean every single meth user is damned to eternal brain damage.
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Well also Meth is physically addicting (has horrible withdrawls) and has had a more negative impact on society through its egotistic often aggressive like effects on many users. I understand that at low doses it could be efficacious for some uses with responsibility. Clearly all the data isn't in yet on the neurotoxicity of either of these drugs but it seems like neither are too horrible when they are not in excess and taken with good ambient temperatures and a healthy diet.
 
Pharmacologically, methamphetamine is extremely neuro-toxic. Disregarding pharmacology, methamphetamine will rot you to the core. http://www.youtube.com/watch?v=Qhng0fP8ZZ8

And MDMA is really no better physiologically, but it is better accepted than methamphetamine because there are mostly happy memories of it and a lack of violence of those under its effects. People generally like both these things. These things DO NOT necessarily make a drug good IMO.

Regarding low dose methamphetamine, it is still neuro-toxic at any dose because of the ratio of release of DA:SE and the fact that it does this unselectively, unlike reuptake inhibitors.
 
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Well also Meth is physically addicting (has horrible withdrawls) and has had a more negative impact on society through its egotistic often aggressive like effects on many users.
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What happens when one takes MDMA at dosages and with frequency similar to methamphetamine addicts? Anecdotally, very bad things indeed...

ebola
 
rollingstoned! said:
Pharmacologically, methamphetamine is extremely neuro-toxic. Disregarding pharmacology, methamphetamine will rot you to the core. http://www.youtube.com/watch?v=Qhng0fP8ZZ8

And MDMA is really no better physiologically, but it is better accepted than methamphetamine because there are mostly happy memories of it and a lack of violence of those under its effects. People generally like both these things. These things DO NOT necessarily make a drug good IMO.

Regarding low dose methamphetamine, it is still neuro-toxic at any dose because of the ratio of release of DA:SE and the fact that it does this unselectively, unlike reuptake inhibitors.
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Just curious what the DA:SE ratio has to do with it?
 
rollingstoned! said:
http://www.macalester.edu/academics/psychology/whathap/ubnrp/mdma/dopamine2.html
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The study listed from that link is.

http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&uid=7698172&cmd=showdetailview&indexed=google

It doesn't say dopamine gets taken up into the serotonic neurons. All that study said was

"The effects of the 5-HT2 receptor agonists 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) and 5-methoxy-N,N-dimethyltryptamine (5-MeODMT) on 3,4-methylenedioxymethamphetamine (MDMA)-induced dopamine release and 5-HT depletion in the striatum were studied. The MDMA-induced increase in the extracellular concentration of dopamine in the striatum was enhanced significantly in rats treated with either DOI (2 mg/kg, ip.) or 5-MeODMT (15 mg/kg, ip.), as assessed using in vivo microdialysis. Neither DOI nor 5-MeODMT alone altered the extracellular concentration of dopamine in the striatum. The striatal concentration of 5-HT was decreased, but not significantly, 7 days following a single administration of MDMA (10 mg/kg, sc.). However, 7 days following the concomitant treatment with DOI and MDMA the striatal concentration of 5-HT was significantly less than that in rats treated with MDMA alone or the vehicle-treated controls. It is concluded that activation of 5-HT2 receptors is an important determinant of the acute increase in extracellular dopamine and, consequently, the long-term depletion of brain 5-HT produced by MDMA."

So nowhere did it say anything about toxicity. It just said that two serotonin agonists were adding to the depletion of serotonin perhaps through serotonic autoreceptor downregulation but dopamine was unaffected. I've never seen a single study showing such a feat was possible.
 
ebola? said:
Why would we disregard pharmacology?

ebola
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I would venture to guess that what is meant there is that the reinforcing effects always take one to beyond where the point in the old axiom is that 'the dose is the difference between medicine & poison' each and everytime with drugs such as that.
 
Even if this were true (responsible use of meth, while quite rare, appears to exist), the whole point of this forum is discussion of pharmacology, even if theoretical.

ebola
 
Has anyone mentioned MAO-B inhibitors to attenuate DA neuron death induced cognitive impairment? There are several studies (which I can dig up if anyone wants) that show that selegeline can help prevent METH induced DA neurotoxicity.
 
SNR said:
Has anyone mentioned MAO-B inhibitors to attenuate DA neuron death induced cognitive impairment? There are several studies (which I can dig up if anyone wants) that show that selegeline can help prevent METH induced DA neurotoxicity.
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Yeah I've seen those studies, I wonder if selegiline decreases therapeutic/recreational effects of stimulants though. Also, anti-oxidant supplements have the potential to turn pro-oxidant, and also have the potential to decrease the brain's endogenous supply of anti-oxidants, I wonder if selegiline would have any of these risks. It certainly does effect enzymes controlling such mechanisms (http://www.ncbi.nlm.nih.gov/pubmed/15959853). Certainly selegiline reduces locomotive and cardiovascular effects of methamphetamine, and we must also keep it in mind it has a host of actions besides being a MAO-B inhibitor, and has biphasic characteristics too, this is an excellent review of the pharmacology of selegiline: http://www.ncbi.nlm.nih.gov/pubmed/21971003. Another study (http://www.ncbi.nlm.nih.gov/pubmed/17651730) and (http://www.ncbi.nlm.nih.gov/pubmed/11358284) shows some of its interactions with meth.

Memantine also reduces meth neurotoxicity and it has been speculated that it also prevents stimulant-induced reversal of DAT/SERT. Do note that MAO-B inhibition will not block meth neurotoxicity completely because dopamine can auto-oxidize without enzymes and also uses COMT/MAO-A to metabolize into pro-oxidant by-products.
 
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ebola? said:
Even if this were true (responsible use of meth, while quite rare, appears to exist), the whole point of this forum is discussion of pharmacology, even if theoretical.

ebola
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I always use it responsibly anymore now that im out of my teens. When I was younger maybe 18 I would do a whole quarter grm of very potent shard and just be up for days. Take naps but not real sleep and use until I was in psychosis or really badly geeked. I can make a quarter last me a full week with just little bumps. The only drug I have so much love for but always feel bad after I use it. Shit tears your nose up....amongst other things. I wont even smoke unless its Really clear big nice shards just due to lung damage. Fuck that.

Bottom line there is a handful of people like me who may just have a few days of bumping for sexual purposes im sure, but theres not many. It really depends on our level of Attraction to certain drugs. I find sex a huge role in why I use every now and then but I also like the spacing out and thinking part of the drug. In my knowledge and Im hoping this makes sense the more attraction you have for a drug such as meth the more likely you are to go down the wrong road and not be an occasional user.

I hope it makes sense because attraction can play a huge role with how much a drugs used. Im 3 days in sorry if this is unreadable
 
I think the review is consistent with my experience with meth, that regardless of neurotoxicity, abuse may not cause cognitive impairment. I don't think it's that bad, but it definitely can make you go nuts while under it's influence.
 
Amu said:
Is Cognitive Functioning Impaired in Methamphetamine Users? A Critical Review.
http://www.ncbi.nlm.nih.gov/pubmed/22089317

I think the study does an excellent job of examining all the studies regarding ex-methamphetamine users' cognitive function and exposes some of the biases against methamphetamine even in scientific studies.
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Amu, is there any chance you have access to the full article? I've been searching all across my online sources and can't find it, and then this thread popped up on the 3rd to last page of Google results ;)

PLEASE let me know, really sounds like something I've been wanting to read, judging from the content of the abstract.

~ vaya

EDIT: While searching for the full-text online I stumbled across "The Neurocritic's Blog" where he/she conveys some pretty interesting insight, interesting enough that I thought I'd share the link with you all
 
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No problem, and thanks for the blog link. Guess I don't have much to worry about after a year of use.
 
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