GHB neurotoxiticy

[MeDieViL]

Neurotoxic effects induced by gammahydroxybutyric acid (GHB) in male rats.
Pedraza C, García FB, Navarro JF.

Department of Psychobiology, Faculty of Psychology, University of Málaga, Spain. [email protected]
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.

Any toughts on this study?

 

[Black]

interesting. especially that it appears to be especially toxic at low doses. looks like ghb's effects on gabaergic neurons somhow reverses the effects mediated by the ghb receptor. i'd like to see a study with focus on the dose dependency.

 

[MeDieViL]

interesting. especially that it appears to be especially toxic at low doses. looks like ghb's effects on gabaergic neurons somhow reverses the effects mediated by the ghb receptor. i'd like to see a study with focus on the dose dependency.

If ppl that take GHB indeed suffer from this kind of neurological damage wouldnt we have noticed? I mean i've taken GBL daily for weeks and i didnt notice any negative impact on my cognition unlike weed or MDMA, and i havent seen anyone report that their cognition was reduced after using GHB either.

I wonder if it could just by government propaganda? I'm not sure tough, thats why i posted it here.
If anyone that can acces the full paper can shed some light on this..

 

[Hammilton]

If ppl that take GHB indeed suffer from this kind of neurological damage wouldnt we have noticed? I mean i've taken GBL daily for weeks and i didnt notice any negative impact on my cognition unlike weed or MDMA, and i havent seen anyone report that their cognition was reduced after using GHB either.

I wonder if it could just by government propaganda? I'm not sure tough, thats why i posted it here.
If anyone that can acces the full paper can shed some light on this..

No, you probably wouldn't have noticed. Unless you were specifically looking for an impact, it's extremely unlikely that you would have noticed.

It doesn't look like government propaganda at all. Is the University of Malaga known to be a government stooge?

No.

Every time someone sees research they don't like they act like assholes and claim that it's propaganda. It's an extremely serious charge that you make like it's nothing just because you don't like the results.

 

[MeDieViL]

No, you probably wouldn't have noticed. Unless you were specifically looking for an impact, it's extremely unlikely that you would have noticed.

It doesn't look like government propaganda at all. Is the University of Malaga known to be a government stooge?

No.

Every time someone sees research they don't like they act like assholes and claim that it's propaganda. It's an extremely serious charge that you make like it's nothing just because you don't like the results.

I was just wondering about it because i've seen the 5meodalt study and here the concessus was that its bullshit. I wasnt trying to accuse them, just making sure its legit.

 

[El_Toro]

I abused G for 6 months and can tell you I suffer from cognitive problems. I knew of that study some time ago.

 

[MeDieViL]

http://www.drugs-forum.com/forum/showthread.php?t=84086

The full text can be found there.

 

[MeDieViL]

I abused G for 6 months and can tell you I suffer from cognitive problems. I knew of that study some time ago.

Interesting, this is the first time i've read about someone reporting cognitive problems.

There is a theory on drugs forum that its neurotoxiticy is caused by an increase in glutamate caused by the GHB receptors.

 

[Black]

If ppl that take GHB indeed suffer from this kind of neurological damage wouldnt we have noticed? I mean i've taken GBL daily for weeks and i didnt notice any negative impact on my cognition unlike weed or MDMA, and i havent seen anyone report that their cognition was reduced after using GHB either.

cognition deficits due to weed aren't mediated through neurotoxicity, and with mdma it's still controversial and could be caused by a number of reasons, neurotoxicity one of them.
you'd need a lot of neurotoxicity for it being noticed if not one small population of neurons is affected (don't really know how the distribution is here).
another point is that the neurotoxicity is reduced by taking larger doses (which everyone seems to be doing as the high from ghb comes from its gabaergic effects as opposed to those mediated by the ghb receptor).

still i wouldn't take it as a fact yet, that ghb is neurotoxic in practice. more research is definitely needed.

 

[bighooter]

When i was using g a few times a week for about a year i definately felt messed up in the head.

 

[MeDieViL]

Specific gamma-hydroxybutyrate-binding sites but loss of pharmacological effects of gamma-hydroxybutyrate in GABA(B)(1)-deficient mice.
Kaupmann K, Cryan JF, Wellendorph P, Mombereau C, Sansig G, Klebs K, Schmutz M, Froestl W, van der Putten H, Mosbacher J, Bräuner-Osborne H, Waldmeier P, Bettler B.

Novartis Institutes for BioMedical Research, WKL-125.7.42, Novartis Pharma AG, CH-4002 Basel, Switzerland. [email protected]
gamma-Hydroxybutyrate (GHB), a metabolite of gamma-aminobutyric acid (GABA), is proposed to function as a neurotransmitter or neuromodulator. gamma-Hydroxybutyrate and its prodrug, gamma-butyrolactone (GBL), recently received increased public attention as they emerged as popular drugs of abuse. The actions of GHB/GBL are believed to be mediated by GABAB and/or specific GHB receptors, the latter corresponding to high-affinity [3H]GHB-binding sites coupled to G-proteins. To investigate the contribution of GABAB receptors to GHB actions we studied the effects of GHB in GABAB(1)-/- mice, which lack functional GABAB receptors. Autoradiography reveals a similar spatial distribution of [3H]GHB-binding sites in brains of GABAB(1)-/- and wild-type mice. The maximal number of binding sites and the KD values for the putative GHB antagonist [3H]6,7,8,9-tetrahydro-5-hydroxy-5H-benzocyclohept-6-ylidene acetic acid (NCS-382) appear unchanged in GABAB(1)-/- compared with wild-type mice, demonstrating that GHB- are distinct from GABAB-binding sites. In the presence of the GABAB receptor positive modulator 2,6-di-tert-butyl-4-(3-hydroxy-2,2-dimethyl-propyl)-phenol GHB induced functional GTPgamma[35S] responses in brain membrane preparations from wild-type but not GABAB(1)-/- mice. The GTPgamma[35S] responses in wild-type mice were blocked by the GABAB antagonist [3-[[1-(S)-(3,4dichlorophenyl)ethyl]amino]-2-(S)-hydroxy-propyl]-cyclohexylmethyl phosphinic acid hydrochloride (CGP54626) but not by NCS-382. Altogether, these findings suggest that the GHB-induced GTPgamma[35S] responses are mediated by GABAB receptors. Following GHB or GBL application, GABAB(1)-/- mice showed neither the hypolocomotion, hypothermia, increase in striatal dopamine synthesis nor electroencephalogram delta-wave induction seen in wild-type mice. It, therefore, appears that all studied GHB effects are GABAB receptor dependent. The molecular nature and the signalling properties of the specific [3H]GHB-binding sites remain elusive.

Looks like its correct that all effects from GHB are mediated by the GABAB receptors, this atleast means that ppl taking GHB have some protection against the neurotoxiticy.

Selective gamma-hydroxybutyric acid receptor ligands increase extracellular glutamate in the hippocampus, but fail to activate G protein and to produce the sedative/hypnotic effect of gamma-hydroxybutyric acid.
Castelli MP, Ferraro L, Mocci I, Carta F, Carai MA, Antonelli T, Tanganelli S, Cignarella G, Gessa GL.

Neuroscienze S.c.a r.l., Cagliari, Italy.
Two gamma-hydroxybutyric acid (GHB) analogues, trans-gamma-hydroxycrotonic acid (t-HCA) and gamma-(p-methoxybenzyl)-gamma-hydroxybutyric acid (NCS-435) displaced [3H]GHB from GHB receptors with the same affinity as GHB but, unlike GHB, failed to displace [3H]baclofen from GABAB receptors. The effect of the GHB analogues, GHB and baclofen, on G protein activity and hippocampal extracellular glutamate levels was compared. While GHB and baclofen stimulated 5'-O-(3-[35S]thiotriphospate) [35S]GTPgammaS binding both in cortex homogenate and cortical slices, t-HCA and NCS-435 were ineffective up to 1 mm concentration. GHB and baclofen effect was suppressed by the GABAB antagonist CGP 35348 but not by the GHB receptor antagonist NCS-382. Perfused into rat hippocampus, 500 nm and 1 mm GHB increased and decreased extracellular glutamate levels, respectively. GHB stimulation was suppressed by NCS-382, while GHB inhibition by CGP 35348. t-HCA and NCS-435 (0.1-1000 microm) locally perfused into hippocampus increased extracellular glutamate; this effect was inhibited by NCS-382 (10 microm) but not by CGP 35348 (500 microm). The results indicate that GHB-induced G protein activation and reduction of glutamate levels are GABAB-mediated effects, while the increase of glutamate levels is a GHB-mediated effect. Neither t-HCA nor NCS-435 reproduced GHB sedative/hypnotic effect in mice, confirming that this effect is GABAB-mediated. The GHB analogues constitute important tools for understanding the physiological role of endogenous GHB and its receptor.

gamma-Hydroxybutyrate modulation of glutamate levels in the hippocampus: an in vivo and in vitro study.
Ferraro L, Tanganelli S, O'Connor WT, Francesconi W, Loche A, Gessa GL, Antonelli T.

Department of Clinical and Experimental Medicine, Pharmacology Section, University of Ferrara, Ferrara, Italy.
The effect of gamma-hydroxybutyric acid on extracellular glutamate levels in the hippocampus was studied by microdialysis in freely moving rats and in isolated hippocampal synaptosomes. Intra-hippocampal (CA1) perfusion with gamma-hydroxybutyric acid (10 nM-1 mM) concentration-dependently influenced glutamate levels: gamma-hydroxybutyric acid (100 and 500 nM) increased glutamate levels; 100 and 300 microM concentrations were ineffective; whereas the highest 1 mM concentration reduced local glutamate levels. The stimulant effect of gamma-hydroxybutyric acid (100 nM) was suppressed by the locally co-perfused gamma-hydroxybutyric acid receptor antagonist NCS-382 (10 microM) but not by the GABA(B) receptor antagonist CGP-35348 (500 microM). Furthermore, the gamma-hydroxybutyric acid (1 mM)-induced reduction in CA1 glutamate levels was counteracted by NCS-382 (10 microM), and it was also reversed into an increase by CGP-35348. Given alone, neither NCS-382 nor CGP-35348 modified glutamate levels. In hippocampal synaptosomes, gamma-hydroxybutyric acid (50 and 100 nM) enhanced both the spontaneous and K(+)-evoked glutamate efflux, respectively, both effects being counteracted by NCS-382 (100 nM), but not by CGP-35348 (100 microM). These findings indicate that gamma-hydroxybutyric acid exerts a concentration-dependent regulation of hippocampal glutamate transmission via two opposing mechanisms, whereby a direct gamma-hydroxybutyric acid receptor mediated facilitation is observed at nanomolar gamma-hydroxybutyric acid concentrations, and an indirect GABA(B) receptor mediated inhibition predominates at millimolar concentrations.

Looks like glutamate is the problem here.

 

[RacerAtom]

Interesting that the neurotoxicity is more pronounced at lower dosages, the minimum dosage used recreationally is about 15mg/kg which is much greater than 100mg/kg in rats.

It wouldn't be the first time that glutamate excitotoxicity has been an issue in rats either, NMDA antagonists like ketamine have been shown to induce excitotoxicity in rats but not humans at equivilent dosages because they have a much higher metabolism, so the mechanism by which GHB induces neurotoxicity may not exist in humans.

Strangely rats given the GHB pro-drug GBL actually tend to live longer than those given placebo.

It's also important to remember that GHB and GBL are found in meat and wine at those kind of dosages, and no studies to my knowledge have shown that beef causes neurotoxicity. Also people with narcolepsy take 6-8g every night and their brains haven't been destroyed by it.

Studies need to take a look at the effect it has over time, many drugs will cause temporary cognitive impairment or changes in the brain after repeated use, but after a period of abstinence this often reverses itself.

 

[chaoticc]

If ppl that take GHB indeed suffer from this kind of neurological damage wouldnt we have noticed? I mean i've taken GBL daily for weeks and i didnt notice any negative impact on my cognition unlike weed or MDMA, and i havent seen anyone report that their cognition was reduced after using GHB either.

I wonder if it could just by government propaganda? I'm not sure tough, thats why i posted it here.
If anyone that can acces the full paper can shed some light on this..

thats a good point there, i've never noticed anything negative from ghb on my brain at all. You'd find that information ironic, considering GHB is rumored to having its 'life-preserving' properties..

 

[MeDieViL]

The presence of gamma-hydroxybutyric acid (GHB)
and gamma-butyrolactone (GBL) in
alcoholic and non-alcoholic beverages
by
Elliott S, Burgess V.
Regional Laboratory for Toxicology,
Sandwell and West Birmingham Hospitals NHS Trust,
City Hospital,
Dudley Road,
Birmingham B187QH, UK.
[email protected]
Forensic Sci Int. 2005 Jul 16;151(2-3):289-92.

ABSTRACT

Gamma-hydroxybutyric acid (GHB) and its precursor gamma-butyrolactone (GBL) are regularly implicated in instances of surreptitious drug administration, particularly in beverages (so-called "spiked drinks"). In order to assist in the interpretation of cases where analysis of the actual beverage is required, over 50 beverages purchased in the UK were analysed for the presence of GHB and GBL. It was found that naturally occurring GHB and GBL were detected in those beverages involving the fermentation of white and particularly red grapes. No GHB or GBL was detected in other drinks such as beer, juice, spirits or liqueurs. GHB/GBL was detected in red wine vermouth (8.2 mg/L), sherry (9.7 mg/L), port (GBL), red wine (4.1-21.4 mg/L) and white wine (-9.6 mg/L). The presence of GHB/GBL did not appear to be influenced by the alcohol content or the pH of the beverage. In addition, the concentration in wines did not appear to be related to the geographical origin of the grape type. This is believed to be the first published data concerning the endogenous presence of GHB and GBL in the beverages described.

Looks like you can consume toxic doses with wine, or i must be missing something here.

 

[seep]

^Molarity roughly 0.0001

Which vintner bottles the 21.4 mg/L red?

 

[Black]

Looks like you can consume toxic doses with wine, or i must be missing something here.

you are. it's mg and not g.
even if you drink 10l (>14 bottles) of the most potent red wine you wouldn't feel the 0.2g of ghb. with 140 bottles you'd have a decent dose

 

[seep]

^That's 10-15 liters of ethanol, which you're also likely to feel.

 

[MeDieViL]

I see i was completely miscalculating, i was thinking that 10 mg/kg would be 80mg for me, but its actually 800mg, so those severely toxic doses cant be taken with wine.

 

[clay404]

so what is the toxic dose in this study? is it anywhere near a recreational dose (1-2.5 grams??) or is it much lower or even lower than the ghb found in wine? I'm confused and inept at math and science .\\

 

[MeDieViL]

10mg/kg is the very toxic dose and 100mg/kg is the dose that is less toxic. But i dont know how many ml GHB is how many grams, and i dont know wheter you could just translate the doses to humans like that, i hope anyone else can answer your question.