• N&PD Moderators: Skorpio | thegreenhand

New versions of GHB

Mind-Expansion

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Joined
Jan 13, 2018
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21
Hey guys,

First of all I want to clarify that GHB was not meant to be abused as date rape drug or as a 24/7 intoxication. If used responsible, it does neither lead to tolerance nor withdrawals. The FDA actually approved GHB to treat narcolepsy. It's usually dosed twice at night at 4.5 grams. Compared to other depressants like benzodiazepines, GHB actually increases sleep quality.

Here are some studies:

There was a doubling of GH secretion, resulting from an increase of the amplitude and the duration of the first GH pulse after sleep onset. This stimulation of GH secretion was significantly correlated to a simultaneous increase in the amount of sleep stage IV. (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC508244/)

Unlike most synthetic hypnotics, GHB increased delta sleep and did not suppress REM sleep. It shortened the REM sleep latency and shifted REM sleep into the first third of the night. On one occasion it induced a sleep onset REM period which was experienced as an attack of sleep paralysis. Withdrawal was simple; there was no REM sleep rebound and sleep patterns immediately returned to their pre-drug form. Its major clinical drawback was its short duration of action: its hypnotic effect lasting only 2 to 3 hr. We suggest that GHB may serve as the prototype for a new class of hypnotic compounds derived from natural sources and capable of activating the neurological mechanisms of normal human sleep. (https://www.ncbi.nlm.nih.gov/pubmed/192353)

It's almost perfect except its short half life. But then I discovered the following:

It is possible, that, after entry into the cell, the compound ethyl 4-acetoxybutanoate of the invention slowly hydrolyses to form gammahydroxybutanoate or a similar compound in situ, to exercise the therapeutic effects thereof over a longer period of time. In any event, it has been found that ethyl 4-acetoxybutanoate has a much longer lasting effect, at equivalent dosage levels, than gammahydroxybutanoate. This makes it a far more effective treatment for narcolepsy than anything heretofore available. Indeed, the effect is so markedly longer lasting that ethyl 4-acetoxybutanoate shows potential for treatment of patients having conditions or disorders where gammahydroxybutanoate is of little or no use. In cases of chronic insomnia, for example, sufficient dosages of the present compound can be administered to maintain sleep throughout the night, without incurring the development of tolerance or withdrawal side effects. Currently available chemotherapeutic agents will not do this. (http://patents.com/us-4599355.html)

Unfortunately, I'm not a chemist. But this would be the ideal sleeping pill.
 
Here in the U.K ghb is prescribed for narcolepsy under the brand name xyrem. I've never heard of it been used for insomnia probably because of like you said it's short half life. So if the half life could be increased then I'd have to agree with you.....Sounds like the perfect cure for chronic insomnia.
 
GHB esters arent new, what I hate is the smell and taste are much more like drinking paint thinner (even more than GBL), also lingering. The effect is alot weaker by weight.
 
Here in the U.K ghb is prescribed for narcolepsy under the brand name xyrem. I've never heard of it been used for insomnia probably because of like you said it's short half life. So if the half life could be increased then I'd have to agree with you.....Sounds like the perfect cure for chronic insomnia.

The main reason it is not used for insomnia is the extremely narrow dose range, coupled with the high abuse potential (not to mention the whole ''date rape drug'' stigma)...

Even in a long-acting pro-drug form, it wouldn't be the treatment of choice for all but the most severe cases of insomnia.
 
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Ethyl 4-acetoxybutanoate would be a prodrug for GHB, the longer lasting effect must be from retarded hydrolysis. Similarly, isovaleric acid is available as its menthyl ester which is a prodrug. Isovaleric acid is a PAM for GABA-A receptors, same as benzodiazepines, interestingly it's an OTC anxiolytic in Poland and some former Soviet Union republics, and it's much more active than GHB on a weight basis, from my experience 100mg is roughly equivalent to 2-5mg of diazepam. It's mostly an anxiolytic with no hypnotic properties, it's subtle but definitely active and has worked for me for less severe anxiety or insomnia unlike many herbal OTC anxiolytics which are too dilute extracts, I suppose it could be compared to weak benzodiazepines like oxazepam. So I guess if you wanted a drug for light insomnia that isn't a benzodiazepine, menthyl isovalerate would be a more reasonable choice. But there are many hypnotics out there with short or long half-life to either specifically help you fall asleep fast or maintain sleep, active at the milligram level, so a GHB prodrug with a single dose being 4-5 grams could not possibly compete.
 
trans-4-Hydroxycrotonic acid is a conformally rigid GHB analogue so we can confirm one aspect of the QSAR. Pregabalin is chiral so we can conform a second conformal requirement and (1s,3s) 3-Hydroxycyclopent-1-enecarboxylic acid, ring-substituted derivatives and esters offer a way to explore the QSAR much, much further. This latter compound has a better LogP value so it will be more active than the x39 increase in affinity (a vague notion in some respects) suggests.

Just throw them all into Chemoffice and overlay them.

US Patent Application 20150196522 'Methods of using (1s,3s)-3-amino-4-difluoromethylenyl-1-cyclopentanoic acid' deals with it.
 
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Any known way to get rid of the GHB receptor affinity? At least for hypnotic purposes as it may help to reduce the rebound effect from its activity... for recreational purposes selectivity for the GHB receptor might be interesting. I would also be pretty curious about what is left of the withdrawal syndrome with just a GHB receptor agonist.

I don't think getting pregabalin into this applies per se. It may have weak GABAb agonism but it seems pretty controversial and I heard it is suspected that some of these compounds may target a specific GABAbR subtype. All in all maybe it is premature to use these structures to elucidate the GABAb pharmacophore? That pregabalin is chiral doesn't seem to prove anything anyway, or if it does .. care to clarify?

Additionally, I don't get why you would make a diester of GHB. Doesn't it make more sense to create a monoester and control the rate of hydrolysis by the bulkiness of the ester group as per usual? If it is a monoester you should still have a fair option to make a solid salt, perhaps even if it is on the gamma-hydroxy.
 
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Ethyl 4-acetoxybutanoate would be a prodrug for GHB, the longer lasting effect must be from retarded hydrolysis. Similarly, isovaleric acid is available as its menthyl ester which is a prodrug. Isovaleric acid is a PAM for GABA-A receptors, same as benzodiazepines, interestingly it's an OTC anxiolytic in Poland and some former Soviet Union republics, and it's much more active than GHB on a weight basis, from my experience 100mg is roughly equivalent to 2-5mg of diazepam. It's mostly an anxiolytic with no hypnotic properties, it's subtle but definitely active and has worked for me for less severe anxiety or insomnia unlike many herbal OTC anxiolytics which are too dilute extracts, I suppose it could be compared to weak benzodiazepines like oxazepam. So I guess if you wanted a drug for light insomnia that isn't a benzodiazepine, menthyl isovalerate would be a more reasonable choice. But there are many hypnotics out there with short or long half-life to either specifically help you fall asleep fast or maintain sleep, active at the milligram level, so a GHB prodrug with a single dose being 4-5 grams could not possibly compete.

Are there any studies about this drug? There are tons of hypnotics out there that help you fall asleep and maintain sleep, but not many that a) improve sleep quality and b) without incurring the development of tolerance and withdrawals. That's what I'm looking for.
 
Any known way to get rid of the GHB receptor affinity? At least for hypnotic purposes as it may help to reduce the rebound effect from its activity... for recreational purposes selectivity for the GHB receptor might be interesting. I would also be pretty curious about what is left of the withdrawal syndrome with just a GHB receptor agonist.

That would be indeed interesting.
 
Rhodium's GHB synthesis page has info on methyl 4-acetoxy butanoate and 1,4 butanediol diacetate among others, apparently they are not as euphoric as GHB, but because both are GHB prodrugs the only difference should be pharmacokinetics e.g. time to Cmax.
 
OP,
In my opinion mirtazapine would make a considerable addition to GHB in order to produce "the sleeping pill". The KOR agonism compounded with GHB's skeletal muscle relaxation could provide immediate sleep and comfort.
Love and welcome to bluelight,
Tez
 
OP,
The KOR agonism compounded with GHB's skeletal muscle relaxation
Are you referring to KOR agonism of Mirtazapine? I'm under the impression Mirtazapine doesn't have affinity for KOR, it certainly doesn't produce KOR agonist-like effects
 
I would also be pretty curious about what is left of the withdrawal syndrome with just a GHB receptor agonist.
IIRC, the sedative effects of GHB can be blocked with a GABA-B antagonist in animals, and I imagine then that a lot of withdrawals are therefore related to GABA-B agonism

On the pregablin note, the effects on GABA metabolism will be acting to increase signaling through both GABA-A and GABA-B systems and I'm curious what role the GABA-B system is playing, if its appreciable.

I'm wondering if Baclofen is a crappy GABA-B agonist or if there are PK problems with some people. Some people report zilch for psychoactive effects from Baclofen (myself being one of these people).

Maybe GHB and Baclofen are functionally selective/biased for a bit different pathways or have different affinity for GABA-B receptors containing different subunits?
 
Are there any studies about this drug? There are tons of hypnotics out there that help you fall asleep and maintain sleep, but not many that a) improve sleep quality and b) without incurring the development of tolerance and withdrawals. That's what I'm looking for.

Isovaleric acid is a prescribtion drug in France which will make arrticle searches easier unless you can read a language in cyrillic script.
 
Isovaleric acid also smells like toe jam/gym socks/overripe cheese. I'd stick to the esters.
 
Isovaleric acid also smells like toe jam/gym socks/overripe cheese. I'd stick to the esters.

Valerian alkaloids smell like athlete feet, I can second this. No amount of ginger beer made my valerian root caps go down any easier. In fact I puked the first one out :'D

Tez
 
Isovaleric acid also smells like toe jam/gym socks/overripe cheese. I'd stick to the esters.

So does n-valeric acid. The esters are prodrugs, are they not? I presume that (1S,3S) 3-Hydroxycyclopent-1-enecarboxylic acid would at least require tiny amounts. mono & diester of it are prodrugs. Hard to obtain but papers show 2 orders of magnitude less i.e. 1g->10mg so at least it is a solid at STP.
 
Gym socks?
Indeed! Its just not as “rancid sweaty” as butyric acid... but still... yuck
 
Isovaleric acid also smells like toe jam/gym socks/overripe cheese. I'd stick to the esters.

Me talking about nytol (which contains valerian root) in EADD about three weeks back.

But my god, this stuff is fucking minging. It smells and tastes like somebody has isolated some kind of toenail fungal infection and concentrated it into a single pill. They haven't even attempted to mask the taste (I am reminded here of when I decided ibuprofen had a nice taste so chewed one, before realising the nice flavour was actually a shell of sugar which was there with very good reason). Seriously you pick the pill up and swallow it and your fingers fucking stink, and then the taste nearly makes you gag.
 
One thing to keep in mind while reading patents,

It is not a research paper! It is an asset meant to be licensed, so the description includes some ‘advertising’ aspects to it.
Do not read every single text in patent and think it will be true. It needs to contain 1)Novelty 2)Inventive Step 3)Applicability to be patentable.

Plus, only legally effective part are only the CLAIMs part, not the lengthy descriptions in the earlier part of the patent.
 
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