Why does GBL act faster than GHB?

[Transform]

It's pretty well known that GBL hits a little faster than GHB, and is converted in the blood.
All I can seem to find online is that this is because it's more lipophilic, the same phrase from wikipedia copied everywhere.
What I want to know is why. It does seem to hit pretty fast, and some have suggested this is because it is absorbed in the stomach.
This does account somewhat, but I always thought that there aren't enough blood vessels here to be a significant part of any substances digestion.
Also, wouldn't GHB cyclise somewhat in the stomach making it noticeable at least, in the same time period as GBL, perhaps even fully active depending on how long the condensation takes?

I think the lipophilic property of GBL makes itself known at the BBB, where it is readily absorbed, and accumulates somewhat while being broken down both here and in the blood. (High partition coefficient means it has a high affinity for the brain, so most GBL passing through is absorbed, whereas GHB has just a normal coefficient?)

This would also explain the intense headache and miserable experience felt by some apparently lactonase deficient users their first time. I've seen headaches after an evening of steady medium-level GBL use for relatively novice users, and suspect this could be a property of GBL.
I've never seen the same with GHB, it seems to tend towards nausea instead.

 

[seusemgoose]

Its because the salt on the GHB takes more time to dissociate than it takes for GBL to convert to GHB and absorb

 

[Transform]

I was under the impression that the dissociation of the salt was what allowed it to dissolve, and certainly there would have been "time" for the salt to dissociate if GHB was stored in a solution?

 

[sekio]

GBL is less polar and more fat soluble, entering the body faster.

 

[vortex30]

GBL is less polar and more fat soluble, entering the body faster.

This. The basic idea here is that GBL is very quickly absorbed into the blood where it is then rapidly metabolized to GHB. GHB takes a much longer time to be absorbed by the stomach and enter the blood than GBL takes both to enter the blood, and get metabolized.

 

[Transform]

So it is absorbed in the stomach?

I suppose even if it was absorbed faster in the small intestine it would make a difference.

Any ideas about the headache in lactonase deficient users?

 

[Hyperthesis]

Allthough GBL rapidly converts to GHB in vivo, the lactone gave significantly more prolonged hypnotic effects than GHB when equimolar doses were compared both parenterally and orally in rats. Plasma drug concentrations were higher after GBL administration through both routes, consistent with the observed differences in the pharmacological activity of these two compounds. Oral GBL was absorbed much faster than oral GHB, with the dual effects of decreasing potential first-pass metabolism and elevating plasma drug concentrations to the region where capacity-limited elimination is operative. Parenteral GBL produced a slower initial drug plasma clearance than parenteral GHB. In spite of the rapid metabolism of GBL to GHB, the apparent tissue distribution of these two compounds may be different.

Res Commun Chem Pathol Pharmacol. 1978 Oct;22(1):107-18
PMID: 725311

 

[Transform]

What is capacity-limited elimination? Where there is so much so quickly that enzymes are saturated and can't break down something fast enough?

Thanks for the source

 

[Hyperthesis]

^The elimination (either by metabolic degradation or renal/hepatic elimination; but usually the latter one) is limited by saturating the responsible mechanisms, i.e. enzymes or transporters. In other words: There's simply too much substrate to be handled at once.

Edit: I found the following definition at a page from the university of Iowa (http://www.uiowa.edu/~c046138/tut-nonlin.htm), but it says more or less the same:

Capacity-limited metabolism: There are a finite number of drug metabolizing enzymes. As a consequence, if you increase the concentration of any substrate you will saturate the enzyme. This is theoretically possible with any drug that is metabolized. However, only a few compounds approach this concentration within the normal therapeutic range of the drug.

 

[MeDieViL]

All the problems with GBL seem to stem from one thing - it produces a much higher plasma level of GHB than the equivalent dose of GHB and causes it to happem in a shorter time span.

As for the GBL itself being toxic, it only has a plasma half life of 2-3 minutes, so that within 10-15 minutes of it getting into the blood, 98 % + has been converted into GHB. That sort of implies that any unpleasant effects seen after that 10-15minute window are due to the rapid increase and subsequent high peak plasma level of GHB, not the GBL. As far as I'm aware, the only thing that GBL does that GHB (& associated salts) doesn't is that it is an irritant to mucous membranes; once diluted to a 1 in 5 aqueous dilution (or less concentrated) it even loses that feature

http://www.bluelight.ru/vb/showpost.php?p=4106511&postcount=31

No it doesn't *sigh*, There are at least three threads out there where I've detailed that it doesn't take just an OH- ion, it also takes an H+ ion as well (in other words a whole molecule of water per molecule of GBL) This means that there is no ion imbalance caused by taking GBL. As for the mechanism, it's converted via plasma pseudoesterases which mean that for a given dose of GBL it's nearly all (90%+) converted to GHB within 10 mins. As GBL crosses the gut wall a hell of a lot faster, due to being a lot less polar than GHB and is then converted to GHB, This means that GBL produces higher peak plasma levels of GHB for a equal dose of both compounds (hence the faster onset, more side effects and more noticable withdrawl syndrome).

The acidosis is something that I had a lot of correspondance with raybeez about (he had a very large intake at one point) and it seems like acidosis does occur at very high dosage levels of GBL from there being more CO2 in the plasma (which is due to respiratory depression associated with very high doses). The thing is, if you were taking GHB at those doses you'd get acidosis as well from an identical respiratory depression.

Now there are some people out there who believe GHB is perfectly safe and GBL is highly toxic. That everything above has been explained in fine detail (with research to back it) seems to count for nothing and when pressed on they subject become very abusive; I hope one doesn't start that shit again here, but if so I'll collect together all the threads discussing it, which contain all the refs that both myself and raybeez have dug up. They always seem to keep refering back to one book, who's author's name I forget (a Dr somebody or other) saying 'he's a doctor so he must be right' - the fact that the research papers are written by doctors and professors seems to pass them by.

Anyway, if anybody is interested they can try searching this forum and OD and find those threads, but no doubt one of the aforementioned GHB zealots had chance to start, so I'll end up having to give links to those threads anyway!

http://www.bluelight.ru/vb/showpost.php?p=3861154&postcount=4

^ I'll be honest and say that I don't know what the mechanism of this observation could be, but it is from a study in dogs - dogs do not have the exact same biochemistry as humans (all mammals have slightly different biochemisty, meaning that they respond differently to the same drug). It's possible that dogs do not possess significant amounts of plasma pseudoesterase to metabolize the GBL to GHB.

My reason for the above comment is based on the following study

Journal of Toxicology: : Volume 39, Number 6 / 2001 Pages: 653 - 654 DOI: 10.1081/CLT-100108502

"During GHB poisoning, acidosis can be due to respiratory acidosis (1), metabolic acidosis has also been reported (2)..."

The above was from an article about GHB intoxication in people admitted to emergency rooms. GBL was also stated to produce metabolic acidosis in large doses, so unlike in dogs (which was also using intravenous infusion of the drugs) both GHB and GBL have been found to produce acidosis in humans (so GBL isn't inherently more dangerous in humans than GHB).

This observation (that both produce acidosis in humans as well as 1,4-BDO) is also confirmed in the following:

Gamma-hydroxybutyrate, gamma-butyrolactone, and 1,4-butanediol: A case report and review of the literature.
Pediatric Emergency Care. 16(6):435-440, December 2000.

This leads to the conclusion that it must be GHB that is responsible for the acidosis as the only metabolite that GBL & 1,4-BDO have in common is GHB. As to how GHB causes the acidosis, that's still up for discussion as far as I know, but I'm still putting money on endocrine effects until all the evidence is in.

Incidentally, 1,4-BDO is much more toxic than either GHB or GBL as it requires the liver to convert it to GHB via alcohol dehydrogenase in a manner analogous to the metabolism of ethanol to acetic acid, thereby putting a 'load' on the liver in the same way alcohol does (and we all know the damage large doses of alcohol can have on the liver). It also appears to be similar to other polyhydric alcohols in irritating the lining of the GI tract


With regard to you & your g/f's admission to hospital, was she on any meds that you were not (I'm including the contraceptive pill)? This can alter the bone density for women (which is why women are many times more likely to suffer from oesteoporosis after the menopause), leading to easier fracturing of bones. Such conditions can also occur due to things like mineral/vitamin deficiency from poor diet (a common cause of ill health in persons dependant upon drugs of abuse) and inhertited risk factors.

I did a search for other threads re GBL/GHB and found this comment that you posted a while ago

Quote:
Note how acidic compounds (which GBL is) in the human diet causes acidosis.
GBL isn't an acidic compound as it does not alter the concn of hydrogen ions in solution. While I agree with the statement in your post that consuming acidic compounds can lead to Ca++ depletion because of reduction of plasma pH (consequently solublizing Ca++ ions from bone), I don't think you can make the logical jump to GBL causes Ca++ depletion because it's acidic because of the fact that GBL isn't acidic, nor does it 'leave behind' an excess of H+ during conversion to GHB as the hydrolysis of GBL to GHB consumes a H+ and an OH- ion therefore leaving the concn of H+ ions unaltered.
Last edited by fastandbulbous; 27-11-2005 at 23:22..

http://www.bluelight.ru/vb/showpost.php?p=3665098&postcount=34

 

[Solipsis]

it is an irritant to mucous membranes; once diluted to a 1 in 5 aqueous dilution (or less concentrated) it even loses that feature

Can you give a foundation for the lost of this feature and/or how you come about that number of 1 in 5?
What I am interested in is the effect of GHB and GBL on stomach lining, with chronic use to really note the effects. I know about the harmlessness of moderate use

I stopped using either a little over a year ago by the way but I would like to know if there is any reason to suspect that GHB solutions or 1 in 5 GBL aqueous solutions can contribute to a 'weak stomach' with consequences of things like inflammation, irritation, ulcers, etc.

Perhaps chronically it could have an effect on stomach acidity? Buffer your acid?

 

[C0MPAQ]

GBL is rapidly converted into GHB by lactonase enzymes found in the blood [less than a second]. GBL ismore lipophilic (fat soluble) than GHB, and so it is absorbed faster and has higherbioavailability; the paradox is that this can mean that GBL has a faster onset of effectsthan GHB itself, even though it is a prodrug 33. The levels of lactonase enzyme can varybetween individuals, and GBL is not active in its own right, so people who have nevertried GBL before may have delayed or fewer effects than expected; however, oncesomeone has taken GBL a few times, the production of lactonase enzymes is increasedand he/she will feel the effects as normal 34. It has been suggested that muscle tissuemay sequester a large part of the initial GBL dose, thereby delaying conversion to GHBand prolonging the duration of action 35.Likely because of these pharmacokinetic features, GBL tends to be more potent, fasteractingand of a longer duration of activity than GHB 33.

http://www.who.int/medicines/areas/quality_safety/4_3_Review.pdf

The levels of lactonase enzyme can vary between individuals, meaning that first-time users can show unpredictable results, even from small doses. In many this manifests as slow onset of effects, followed by headaches, semi-consciousness which is distinct from GBL sleep in normal users. If the user decides to try again at a later date, they appear to be able to enjoy the effects normally.

https://en.wikipedia.org/wiki/Gamma-Butyrolactone