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  #1  
Old 14-04-2009, 15:03
Systemdoll Systemdoll is offline
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GHB neurotoxicity

Please if someone may help swim on that publication :

Neurotoxic effects induced by gammahydroxybutyric acid (GHB) in male rats

Carmen Pedrazaa1 c1, Francisca Belén Garcíaa1 and José Francisco Navarroa1
a1 Department of Psychobiology, Faculty of Psychology, University of Málaga, Spain
Article author query
pedraza c
garcía fb
navarro jf
Abstract

Gammahydroxybutyric acid (GHB) is an endogenous constituent of the central nervous system that has acquired great social relevance for its use as a recreational ‘club drug’. GHB, popularly known as ‘liquid ecstasy’, is addictive when used continuously. Although the symptoms associated with acute intoxication are well known, the effects of prolonged use remain uncertain. We examined in male rats the effect of repeated administration of GHB (10 and 100 mg/kg) on various parameters: neurological damage, working memory and spatial memory, using neurological tests, the Morris water maze and the hole-board test. The results showed that repeated administration of GHB, especially at doses of 10 mg/kg, causes neurological damage, affecting the ‘grasping’ reflex, as well as alteration in spatial and working memories. Stereological quantification showed that this drug produces a drastic neuronal loss in the CA1 hippocampal region and in the prefrontal cortex, two areas clearly involved in cognitive and neurological functions. No effects were noted after quantification in the periaqueductal grey matter (PAG), a region lacking GHB receptors. Moreover, NCS-382, a putative antagonist of GHB receptor, prevented both neurological damage and working- memory impairment induced by GHB. This suggests that the effects of administration of this compound may be mediated, at least partly, by specific receptors in the nervous system. The results show for the first time that the repeated administration of GHB, especially at very low doses, produces neurotoxic effects. This is very relevant because its abuse, especially by young persons, could produce considerable neurological alterations after prolonged abuse.

Source :

http://journals.cambridge.org/action...ne&aid=5011108

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interesting study. didn't imagine ghb could be neurotoxic.
  #2  
Old 14-04-2009, 15:57
psyche psyche is offline
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Re: GHB neurotoxicity

That's interesting, since GHB has been found to to have neuroprotective effect too. The dose of 10 mg/kg isn't nowhere near applicable to humans.

Upload this to archive too, if you haven't already done so.
  #3  
Old 15-04-2009, 13:05
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Re: GHB neurotoxicity

It's always interesting to read up on more current research but please bear in mind that it refers to rats, not humans.

There is also no mention of the dosing strategy used, only that they studied "repeated administration". Whether this means that they tested the rats whilst they were under the effects of the GHB or not is unclear also.

It would be better if we could get clarification as to what constituted "brain damage" over, say, the altered brain state whilst under the effects of GHB which would return to baseline after an appropriate amount of time. Is said "brain damage" observable only under the effects of GHB administration or permanently?
  #4  
Old 15-04-2009, 16:40
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Re: GHB neurotoxicity

The full article has been uploaded here : Neurotoxic effects induced by gammahydroxybutyric acid (GHB) in male rats.
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Old 21-04-2009, 16:38
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Re: GHB neurotoxicity

10mg/kg is a sub-recreational dose in humans, so it would be expected that neurotoxicity would result with repeated doses that only stimulate the GHB receptor and leave GABA-BR alone.

This just confirms what I stated a year ago. Looking forward to reading the full article and getting any info on dosing pattern. I'll get my hands on the full article and anyone interested can PM me.
  #6  
Old 22-04-2009, 13:04
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Re: GHB neurotoxicity

Malsat, I would be very interested to hear your analysis of the full article.

Would it be possible for you to break down the findings in relation to your original thread on this topic?
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Old 22-04-2009, 19:20
malsat Gold member malsat is offline
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Re: GHB neurotoxicity

No problem MrG, might take a while though as I'm inundated with college work ATM.
  #8  
Old 23-04-2009, 17:23
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Re: GHB neurotoxicity

Swim has just read the whole article and now he feels sick. Swim has done doses of roughly 10mg/kg many times (Swim is ~70kg so this would be a dose of ~700mg, right?). In fact Swim has done doses lower than this also probably on about 20 occasions over the last month or so, dosing 2 or 3 times on each occasion (around 500mg per dose).
Swim did this because he finally synthesised some GHB but was then scared of overdosing so every time he took it he told himself he would just take a small dose and then take more after a while if he felt ok but he always ended up waiting to long so basically he was just taking loads of small doses

Swim thought he was doing his brain a favour by taking ghb instead of alcohol and other drugs. He has already half destroyed his brain with E and speed, now he discovers that when he thought he was being sensible and safe by taking small doses of GHB he was actually causing massive damage to his PFC and hippocampus

Can anybody reassure Swim in any way? He has actually noticed problems with his verbal fluency and articulacy as well spelling and general cognitive fuction. These problems are definitely not imagined and they have only manifested recently, Swim had attributed them to the fact that he is withdrawing from Zolpidem 20mg after a few months of nightly use.

Swim is just plain sickened by this he was full sure that GHB was completely non-toxic..... This is some fvcked up sh*t.
  #9  
Old 23-04-2009, 17:37
psyche psyche is offline
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Re: GHB neurotoxicity

No need to get hysteric, this is just one study not conducted on humans, and considering the history of ghb-science, I would be careful to draw too dramatic conclusions. Even if it was found to be true that GHB induces brain damage in humans, it wouldn't likely be more severe than alcohol or DXM.
  #10  
Old 23-04-2009, 17:46
lepetitchatorange lepetitchatorange is offline
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Re: GHB neurotoxicity

Thanks for your reply psyche but how could one not draw dramatic conclusions? In the study the rats recieved 10mg/kg once a day for 15 days, swim took less than 10mg/kg (smaller doses being more destructive it would seem) multiple times a day for 20 days out of the last 30!

There is no way of knowing wether swim suffered neurological damage and he will never know but really there is no reason why the results of this study with the rats would not be transferable to humans. It's not like studies with stimulants or something where they give the animals massive doses far in excess of human rec doses, in this case the smaller dose was more harmful!

As like I said Swim has definitely noticed problems with his congitive functions that he never had before, even now he is having problems typing and he used to be a 80wpm typer.
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Old 23-04-2009, 18:13
psyche psyche is offline
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Re: GHB neurotoxicity

The whole smalle doses are more destructible -concept seems very fishy. Have you heard of any drug that is more toxic in lower doses than higher? Surely during metabolism of regular dose the supposedly toxic lower plasma concentrations should be reached. This need further clarification, and I'd be interested in it too, but it just isn't realistic to assume that this is on completely different level of neurotoxicity than other drugs.

Edit: After going through it with care I'm not so sure what to think anymore. I knew there had been toxicological studies done on GHB before, but I guess never this comprehensive that analyse the brain combined with behavioral tests. Any analysis and comparision to other studies would be welcome. It would be very, very odd if small doses would be more detrimental. Is the methodology of this study ok? I found nothing wrong with it, but I don't completely understand it.

Last edited by psyche; 23-04-2009 at 19:09.
  #12  
Old 23-04-2009, 19:23
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Re: GHB neurotoxicity

It does seem counter-intuitive that a small dose would be more harmful than a large one. However like malsat said the low dose tends to act only on the GHB receptor and not on GABA-B.
The GHB receptor releases glutamate. Glutamate release is associated with neuron apoptosis (brain cell death). I
In higher doses the GABA-B activity would limit the release of excitatory glutamate.

I actually read about this release of glutamate after ghb receptor activation before and was concerned about the implications but then I was reassured after reading so many articles and forum posts about how benign and non-toxic GHB was. Now it seems my initial fears were justified. : (
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Old 23-04-2009, 20:52
psyche psyche is offline
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Re: GHB neurotoxicity

Quote:
It does seem counter-intuitive that a small dose would be more harmful than a large one. However like malsat said the low dose tends to act only on the GHB receptor and not on GABA-B.
The GHB receptor releases glutamate. Glutamate release is associated with neuron apoptosis (brain cell death). I
In higher doses the GABA-B activity would limit the release of excitatory glutamate.
Yes, seems very reasonable.

It would be nice to get some numbers. After all glutamate activity is highly pronounced in alcohol hangover, too, and is known to cause cell-damage. Acetaldehyde might have more to do with that, though.
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Old 23-04-2009, 21:15
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Re: GHB neurotoxicity

There is also this study

http://www.sciencedirect.com/science...9c3d4d0c150e9f

which mentions "SSADH deficiency disorder" where there is elevated levels of endogenous GHB. Symptoms include "mental retardation".

If only these studies had been done a few months earlier I could have avoided taking G.
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Old 23-04-2009, 22:34
psyche psyche is offline
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Re: GHB neurotoxicity

I don't know of any other genetical disorders where a neurotransmitter is overexpressed, but would imagine that it would lead to serious problems with any neurotransmitter. But it doesn't mean that using a drug that releases any neurotransmitter would have anything to do with mental retardation.
Aside from developmental effect from having certain neurochemical imbalance from birth, the damage that would need to be done to cause mental retardation in already developed brain would have to be really huge. The brain is a very recovering and flexible organ; easty to disturb, but difficult to destroy permanently. The damage done by even the most dangerous drugs out there is usually reversible, and they do give heavy warning signs in the form of side-effects. This is not an alien chemical but a endogenous ligand, so it should be tolerated pretty well.

I also seriously doubt about little doses being more toxic. Keep in mind that GHB induced sleep is usually short, 3 to 4 hours, after which the user wakes up feeling very refreshed and alert because GABA-B receptors are not activated anymore, but only GHB receptors. With heavier doses too, there becames a period when only GHB receptors are activated. Also some board members here have pets that have used excessively as many as 8 years on end, so they would definately have been retarded seriously. GHB is also prescribed as Xyrem for narcolepsy, so the radical cognitive effects would've been noted by them too if they were so serious.

Here is a short yet comprehensive summary on GHB's neuropharmacology on erowid for those who want the big picture: http://www.erowid.org/chemicals/ghb/...acology1.shtml

All that being said, all drugs should be treated with caution. It could be interesting to see if there will be follow-up studies to this one, but I wouldn't worry about serious neurological damage based on this. It would be interesting to see what Malsat has to say about this matter.

Oh, and please read the rules. Self-incrimination is not allowed on this forum, so learn to use SWIM(someone who isn't me) or talk about your pets' drug experiences.

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Because it's reassuring to me.
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Old 23-04-2009, 23:21
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Re: GHB neurotoxicity

"If only these studies had been done a few months earlier I could have avoided taking G."

I should clarify, that was a quote from swims pet rat after reading the studies in the Scientific Rat Journal.
I personally never have taken GHB, thank god.
Sorry for the confusion, I will be more clear in future.

Anyway... thanks for the response swim is somewhat reassured now.
It was just that he had almost exclusively done only low doses and on many occasions while narcoleptics and those pets belonging to board members take much higher doses...
Also the fact that he thought GHB was completely benign and a safe alternative to low grade mdma and ketamine which he used to take.
He has learned his lesson now though and his is not going to experiment with chemicals any more.
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Old 24-04-2009, 00:33
psyche psyche is offline
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Re: GHB neurotoxicity

Glad to be able to help. It's good to see that SWIY respects and studys his drugs. It's better to be too cautious than too reckless.
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Old 24-04-2009, 20:13
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Re: GHB neurotoxicity

Here is another study showing a similar affect to spatial memory and learning after only five days of GHB administration.&nbsp; I must admit that this has me pretty concerned about the neurotoxic affects of GHB.&nbsp; I'm hopeful someone knowledgeable in neurology can share some insight on this topic. (Malsat?)&nbsp; <br><br><h2>Gamma-hydroxybutyric acid-induced cognitive deficits in the female adolescent rat.</h2>
<div class="authors"><!--AuthorList--><a href="http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&amp;Cmd=Search&amp;Term=%22Sircar %20R%22%5BAuthor%5D&amp;itool=EntrezSystem2.PEntre z.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel .Pubmed_RVAbstractPlus"><b>Sircar R</b></a>, <a href="http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&amp;Cmd=Search&amp;Term=%22Basak% 20A%22%5BAuthor%5D&amp;itool=EntrezSystem2.PEntrez .Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel. Pubmed_RVAbstractPlus"><b>Basak A</b></a>, <a href="http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&amp;Cmd=Search&amp;Term=%22Sircar %20D%22%5BAuthor%5D&amp;itool=EntrezSystem2.PEntre z.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel .Pubmed_RVAbstractPlus"><b>Sircar D</b></a>.</div>
<p class="affiliation">Departments
of Psychiatry and Behavioral Sciences, Neurology,and Pathology, Albert
Einstein College of Medicine, Bronx, New York, USA.</p>
<p class="abstract">gamma-hydroxybutyric
acid (GHB), a "club drug," is abused for its euphoric, sedative, and
anabolic effects. GHB use and abuse is most prevalent among adolescents
and young adults. Most GHB users report amnesia. In the present study,
we tested the hypothesis that GHB treatment in female adolescent rats
causes deficits in spatial learning and memory. Adolescent female rats
were treated daily with GHB (100 mg/kg) for 5 consecutive days. Control
rats received isovolumetric saline. Experimental and control rats were
tested in the hidden platform task (reference memory) of the Morris
water maze. GHB-treated adolescent female rats had significantly longer
latencies than saline-treated controls, and in the probe trial
drug-treated rats spent less time in the quadrant where the platform
was present prior to its removal than did control adolescent rats.
Together, these data indicate that GHB exposure in adolescent female
rats has a negative impact on spatial learning and memory.</p><br>
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Old 26-04-2009, 20:45
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Re: GHB neurotoxicity

According to Malsat's theory the neurotoxicity occurs at low doses of GHB due to activation of the GHB receptor, which is excititatory, without activation of the GABAb receptor which is inhibitory. The GHB receptor causes excess glutamate formation which leads to excitotoxicity (neuron death). Since alcohol acts as a neurotransmitter inhibitor and stimulates the GABA system would it make sense to have a couple of alcoholic drinks while coming down from G to limit the potential for neurotoxicity due to excitotoxicity?

Malsat can you please comment?
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Old 27-04-2009, 21:09
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Re: GHB neurotoxicity

The best thing would be to take a high dose antioxidant, eg. N-acetyl-cysteine or something.
Taking alcohol afterwards is probably to little to late, in fact it would probably just increase the damage done.


The above is the opinion of swims pet rat who has absolutely no expertise on this subject (or any other) and who has about 8 brain cells left after his own chemical misadventures.
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Old 27-04-2009, 21:34
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Re: GHB neurotoxicity

Why would taking an antioxidant help? Excitotoxicity is caused by over exposure of brain neurons to glutamate. I don't believe oxidative damage plays a role here. Please correct me if I am wrong.
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Old 27-04-2009, 21:42
psyche psyche is offline
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Re: GHB neurotoxicity

Please keep in mind that comedown from alcohol also increases glutamate levels.
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Old 27-04-2009, 22:00
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Re: GHB neurotoxicity

Psyche do you have a reference for that information? I'd be interested in reading it. So what causes Glutamate levels to decrease? Is there a glutamate antagonist?

After a little research on google it appears that Taurine and Theanine can help modulate glutamate levels and reduce excitoxicity.
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Old 28-04-2009, 00:10
psyche psyche is offline
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Re: GHB neurotoxicity

Well, alcohol hangover doesn't exactly give rise to glutamate levels, but it temporarily increases the number of glutamate receptors and decreases the number of GABA receptors. From erowid:

Quote:
The mechanism for the acute withdrawal symptoms is currently believed to be the short-term down regulation of GABA receptors and up-regulation of glutamate receptors as the body counterbalances the sedative effects of the alcohol. As alcohol levels in the bloodstream fall, it takes time for the GABA and glutamate systems to return to normal.
http://www.erowid.org/chemicals/alco...hangover.shtml

Attached is also a study about possible alcohol hangover mechanisms.

I would imagine this GHB study would have followers since it's a patented medicine we are talking about, right?
Attached Files
File Type: pdf Alcohol Hangover Mechanisms and Mediators, Swift 1998.pdf (114.3 KB, 10 views)
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Old 28-04-2009, 00:38
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Re: GHB neurotoxicity

BBer, if you look at the studies that are linked above you will see that oxidative damage is involved.
Malsat never actually said that it was excitoxicity that was involved, that was my (wholly uninformed) theory.
It seemed to make sense since activation of the GHB receptor causes the release of glutamate, but those studies don't even mention glutamate either.
Anyway other neurotoxic drugs, eg. MDMA, cause damage through oxidation and taking antioxidants has been shown to reduce or even eliminate the damage done, you can never have to many antioxidants anyway...
The reason I said N-acetyl-cysteine is because it also reduces glutamate activity as well as being an antioxidant.
Theanine increases dopamine and GABA synthesis so it could change the effects of GHB as well.

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