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All 50 posts   Subject: Therapeutic GHB does not cause withdrawal   Please login to post   Down

(Chief Bee)
05-27-03 03:29
No 435795
User Picture 
      Therapeutic GHB does not cause withdrawal     

This was really interesting, I can't find this journal online though... Can somebody help me verify if this is a paper-only journal or not?

The abrupt cessation of therapeutically administered sodium oxybate (GHB) does not cause withdrawal symptoms
J Toxicol Clin Toxicol 41(2), 131-5 (2003)
Medline (PMID=12733850)

Sodium oxybate (gamma-hydroxybutyrate; GHB) has demonstrated efficacy for the treatment of narcolepsy. However, there are reports of withdrawal following chronic abuse of illicit GHB which involve escalating both doses and dosing frequency. The present trial afforded an opportunity to test the hypothesis that chronic daily therapeutic dosing of sodium oxybate in narcoleptics does not cause withdrawal following abrupt cessation. Fifty-five narcoleptic patients, taking sodium oxybate (dose range 3-9 gm/night) for 7-44 months (mean 21 months), were randomized into a 2-week double-blind period: 29 patients received placebo and 26 continued to receive sodium oxybate.  During this 2-week trial period, the following symptoms were reported in patients receiving placebo (N): anxiety (2), dizziness (1), insomnia (1) and somnolence (1).  While these symptoms may represent possible symptoms of mild GHB withdrawal, they are also highly consistent with the returning symptoms of narcolepsy. We conclude there is minimal evidence of withdrawal symptoms following abrupt cessation of chronic sodium oxybate dosing in the therapeutic range.
(Hive Bee)
05-27-03 05:00
No 435809
User Picture 
      It is online
(Rated as: excellent)

It is available through
Edit DOI:10.1081/CLT-120019128

Narcolepsy is a debilitating, life-long disorder of the central nervous system (CNS). Typically beginning with excessive daytime sleepiness during the second and third decades of life, narcolepsy usually progresses to include sleep paralysis, hypnagogic hallucinations and cataplexy. These symptoms are believed to represent the abnormal activation of rapid eye movement (REM) sleep mechanisms during periods of wakefulness and non-REM sleep [1] . Narcolepsy is estimated to affect 140,000 patients in the United States [2] .

The primary cause of narcolepsy remains unknown, however recent studies suggest it involves deficits in CNS systems that depend on the neuropeptide hypocretin [3] . The cell bodies of hypocretin-containing neurons are found in the postero-medial hypothalamus where they project to various parts of the brain including nuclei believed to regulate sleep. Diminished concentrations of hypocretin in cerebrospinal fluid [4] and numbers of hypocretin-containing neurons [5] have been demonstrated in narcoleptic patients.

Regardless of the cause, the nightly administration of pharmacologic doses of sodium oxybate, which acts as an endogenous neurotransmitter or neuromodulator [6] , has been shown to improve the symptoms of narcolepsy. It appears to consolidate both REM and non-REM sleep, coinciding with significantly reduced daytime symptoms [7,8] . To date, many narcolepsy patients have participated in numerous clinical trials with this agent [8-10] . In all of these trials, sodium oxybate has shown great promise as a treatment for narcolepsy with no evidence of tolerance or dependence.

In contrast, reports have appeared in recent years which describe a severe withdrawal phenomenon following abrupt cessation of GHB, taken illicitly as a drug of abuse. Withdrawal has been associated with the chronic use of GHB, with dosing frequency ranging from every 30 minutes to 3 hours, dosing duration of 6 months to 4 years [11-13] and total daily doses ranging from 25 to 144 gm reported [11,14] . Following the last dose of GHB, symptoms of withdrawal have occurred from 30 minutes to 36 hours and lasted 5–15 days [11-13] . Mild withdrawal has been characterized as anxiety, tremor and insomnia while severe withdrawal has been described as autonomic instability, psychosis and delirium [13] . Reported symptoms of withdrawal have included nausea, vomiting, anxiety, confusion, tremor, insomnia, paranoia, agitation, amnesia, delirium, psychosis, auditory, visual and tactile hallucinations, tachycardia and hypertension [11-13,15] . Some of these cases involved polydrug abuse [13,15,16] .

Although neither dependence nor withdrawal have been reported during clinical trials with sodium oxybate in narcoleptic patients, the occurrence of withdrawal following chronic sodium oxybate therapy has never been formally studied [17] . The following randomized, placebo-controlled, long-term efficacy trial, in which patients were removed from long-term open label treatment with sodium oxybate, provided a model to test the hypothesis that daily dosing of therapeutic doses of sodium oxybate in narcoleptics does not cause the emergence of symptoms consistent with a withdrawal syndrome following abrupt cessation.

Fifty-five (55) narcoleptic patients (23 men and 32 women) participated. At the time of study entry, patients were participating in an open-label clinical trial where they were titrated to an optimal nightly dose (3, 4.5, 6, 7.5, or 9 g/night) of sodium oxybate for the treatment of their narcolepsy symptoms. The dose-dependent half-life of sodium oxybate is very short, ranging from 30–50 minutes at therapeutic doses in human volunteers [18] . Consequently, sodium oxybate is administered as two equally-divided doses with the first taken at bedtime and the second 2.5 hours later.

To participate in the trial, the patients were required to have been on long-term (i.e., greater than 6 months) sodium oxybate therapy. Since the primary endpoint for this study was the return of cataplexy following the discontinuation of treatment, providing evidence of long-term efficacy, patients could not be taking alternate medications for the treatment of cataplexy, such as tricyclic antidepressants and serotonin-selective reuptake inhibitors, for a period of 30 days prior to trial entry. In addition, patients were required to have a history of at least five cataplexy attacks per week prior to receiving any treatment for cataplexy.

This trial was conducted in accordance with the ethical principles that have their origins in the Declaration of Helsinki and comply with the U.S. Code of Federal Regulations, Title 21, Part 50.

Study Drug
The study drug was formulated as a pH-adjusted solution (pH range of 7.5–8.5) at a concentration of 500 mg/mL of sodium oxybate. The placebo was formulated as a sodium citrate solution equimolar to the sodium concentration in the 500 mg/mL sodium oxybate solution. Total nightly doses were 3, 4.5, 6, 7.5, or 9 g, taken orally as two equally-divided doses taken at bedtime and 2.5–4 hours later. Patients taking placebo dispensed a volume equivalent to their prescribed stable dose of sodium oxybate.

Study Design
The trial consisted of three phases (four clinic visits). During Phases I and II, patients continued taking sodium oxybate at the same dosage as they were taking in the open label trial. Phase I (screening) lasted three to five days (Visit 1 to Visit 2), during which patients were randomized. During Phase II (lead-in), patients received single-blind sodium oxybate for two weeks (Visit 2 to Visit 3). In Phase III (double-blind), half the patients received sodium oxybate at their established dosage, and half received placebo, for two weeks (Visit 3 to Visit 4). During Phases II and III, patients kept diaries to record the daily number of cataplexy attacks and adverse events.

Study Assessments
The primary efficacy variable was the change in the number of cataplexy attacks between baseline (two-week lead-in phase) and endpoint (two-week double-blind treatment phase).

Safety variables for this study included adverse events, changes in clinical laboratory results, vital signs, and physical examinations. The occurrence of narcolepsy symptoms and adverse events were recorded by each patient in daily diaries that were reviewed by the study investigators at the end of the trial. As this was an outpatient trial, no measurements of vital signs or clinical laboratory parameters were performed during the two-week double-blind period.

Statistical Analyses
The change in the number of cataplexy attacks was analyzed using a nonparametric analysis of covariance (ANCOVA). Specifically, the baseline number of cataplexy attacks and the change from baseline in the number of cataplexy attacks were replaced by their corresponding ranks. The rank changes from baseline in the number of cataplexy attacks were analyzed using ANCOVA, including the rank baseline number of cataplexy attacks, treatment group, and baseline-by-treatment group interaction.

A power analysis performed during the design of the trial indicated that 22 patients per treatment arm would have 80% power to detect a 40% difference in increase of cataplexy attacks between the treatment groups at a significance level of 0.05. Therefore, treatment groups consisting of 26 treatment patients (placebo-treated) and 29 control patients (sodium oxybate-treated) was deemed sufficient

Adverse events (AE) were summarized by body system and preferred term using the Coding Symbols for a Thesaurus of Adverse Reaction Terms (COSTART) dictionary. Adverse events were summarized by treatment group and by time period (prior to Phase I, Phase I, Phase II, and Phase III). The incidence of AEs was compared between the two treatment groups using Fisher's exact test. One-way analysis of variance (ANOVA) was used to compare the treatment groups. Within each treatment group, a paired t-test for each parameter was used to assess the significance of the mean change from baseline. The incidence of possible withdrawal symptoms reported was not treated in any statistical fashion.

Cataplexy Attacks
All 55 patients who received double-blind treatment completed the trial. There was no median change in the number of cataplexy attacks from baseline (two-week lead-in phase) to endpoint (two-week double-blind treatment phase) in the sodium oxybate group (median change 0.0), while cataplexy attacks increased by a median of 21.0 in the placebo group during the same two-week period. This difference was statistically significant (p<0.001).

Safety Assessments
A total of 17 patients (31%; 7 sodium oxybate patients and 10 placebo patients) experienced at least 1 AE during Phases I, II, or III of the trial. Of particular interest were the adverse events that occurred during Phase III, the two-week double-blind treatment period. During this phase, adverse events were reported by 22% (12/55) of patients in the trial, including 3 of 26 patients (12%) in the sodium oxybate group, and 9 of 29 patients (31%) in the placebo group. A comparison of the occurrence of adverse events between treatment groups was not significant (p=0.108). There was no statistically significant difference in the frequency of adverse events during any study period in this trial. There were no adverse events that were considered serious, and none led to patient discontinuation.

Analysis of AEs as they relate to literature reports of a possible withdrawal syndrome indicated that few patients experienced events that could be considered possible symptoms of a withdrawal phenomenon: two placebo patients reported anxiety and one each reported insomnia, dizziness, and somnolence. Although these symptoms may possibly be associated with a withdrawal syndrome, they are more consistent with the return of narcolepsy symptoms precipitated by the termination of sodium oxybate therapy.
The pharmacology of sodium oxybate is not well understood, and the mechanism of GHB addiction is unclear. The opiate antagonist naloxone has no clinical effect on the toxic effects of GHB, but interestingly, sodium oxybate substitutes for both opiates and ethanol in persons addicted to these drugs, suppressing withdrawal symptoms [19-22] and suggesting a common mechanism.

In contrast to reports of severe withdrawal phenomenon following chronic abuse of illicit GHB, 7–44 months of nightly sodium oxybate therapy at doses as high as 9 g/day was not associated with an abstinence syndrome in narcolepsy patients. A few patients did report mild symptoms of anxiety, somnolence, and sleeplessness. However, narcolepsy is a well-described sleep disorder, and the reported symptoms are entirely consistent with a return of the disease symptoms [1] . Indeed, excessive daytime sleepiness and fragmented nighttime sleep are among the most common of narcolepsy symptoms, and the reports of anxiety were temporally associated with worsening of the frequency and severity of cataplexy. In addition, no patients reported craving the discontinued sodium oxybate.

The dose-dependent half-life of sodium oxybate is very short. In trials conducted in human volunteers, the administration of sodium oxybate at doses of 4.5 or 9 g taken in equally divided doses 4 hours apart resulted in an elimination half-life of 35 and 50 minutes, respectively [18] . Thus, narcolepsy patients who are administered nocturnal doses of this medication therapeutically awaken with minimal or no measurable plasma oxybate and remain medication-free until their next nightly dose. This is in contrast to reports of GHB withdrawal that have been associated with increasing doses and increasing dose frequency, until some reported users were taking the drug around the clock [12] . Thus, there appears to be no likelihood of dependence or withdrawal even though the length of sodium oxybate exposure of patients in this study (7–44 months) is similar to cases of withdrawal reported following chronic GHB abuse (2–36 months) [12] .

Despite its reputation as GHB, a street drug of abuse, sodium oxybate appears to be a valuable treatment for narcolepsy. As with many controlled substances, intentionally escalating the dose and dosing frequency may lead to addiction and subsequent withdrawal; however, there is little evidence for withdrawal in patients taking chronic nightly therapeutic doses of sodium oxybate.

[the refs were too long for the 15000 character post length...]

Got democracy?
(Hive Addict)
05-27-03 21:48
No 435933
      I had always assumed that was true, and the...     

I had always assumed that was true, and the study reconfirms it. I think most people that experience severe withdrawal symptoms are dosing all day, every day. Even a mere 20 hour break between doses should significantly reduce the chances that you will have a bad withdrawal. It would be nice to see these results replicated in another similar study with a bigger sample size.

If you have the need to be high 24/7, at least try alternating with a drug that does not have a cross-tolerance to GHB. Although, I do not know of anything that does, except obviously its equivalents GBL and 1,4 Butanediol. I.E. Smoke pot or something else you like during the day, and only take GHB at night. It will save you trouble in the long run.
(Hive Bee)
05-28-03 16:19
No 436095
User Picture 
      1,4 Butanediol is habituating, it become a day     

1,4 Butanediol is habituating, it become a day to day habitude. But usually not withdrawal occur from less than two-three doses per day for a long period.(beside the insomnia and cold feeling from the dopamine rebound it produce when it wear off, but usually you dont feel it much with less than 3 doses, and it last only 2-3 hours.)(but it can fuck your night and force reboost to sleep, and the next day reboost to temper the dopamine rebound.)


If multiple reboosts are done for a short period (like 40*3ml doses for 3 days, amounting to an average 40g per day for 3 days) moist skin as well as jaundice occur, insomnia (multiple reboosting at night to sleep), changing humor, sex craving also occur. When the taking is abruptly stopped, after this short binge, jaundice/moist skin remain, but it is accompanied by itchs, by feeling of cold skin, by anxiety, panic attack, delirium, hallucinations, and vivid conscious dreams. Intense craving for benzos, and amnesia also occur. These symptoms last a couple of days, but itchs remained for 3-4 days.

I dont know if jaundice will occur with GBL or GHB, I think it is more an effect of aldehyde poisoning from the in vivo oxydation of 1,4B.

Otherwise it is a good drug.laugh Same kind of effects but way better than alcohol.

Also the euphoria temper with use, at the end its more a drugged feeling with no much more euphoria.
(Hive Addict)
05-28-03 20:46
No 436150
      search harder and you will find gbl     

That it what I am more curious about- how much and how often I can take it without the euphoria lessening to a large extent. I guess I will have to find that out for myself.
(Hive Addict)
05-29-03 17:30
No 436364
      previous post may have been in error     

I implied a few posts back that marijuana does not have a cross-tolerance with ghb. That may be incorrect. It was suggested in a book I read that marijuana and GHB overlap somewhat in their method of action. I am not sure whether this is true or not, as the evidence given in the book was shaky. Even if it is true, it is not to say that interleaving GHB and marijuana doses will produce bad withdrawal symptoms. What it would mean is that tolerance to the euphoria of GHB would be achieved just as quickly if you dosed GHB all day every day as it would taking ghb at night, then smoking weed all day, then taking ghb at night again. Again, the notion that weed and GHB overlap in their method of action is mostly speculation. Even if it isn't, your results may vary from the rule.

But I am beginning to believe that even drugs without a cross tolerance to GHB may work in the same way to create euphoric tolerance. For instance let's say you were to take meth one day, then opiates the next, ghb the day after, and weed the day after that. Would repeating this cycle over and over again cause you to have the same level of euphoria as you would taking one of the individual drugs ever four days? Or would you develop a "general tolerance" to euphoria?

This seems like something that would be common knowledge, but I do not remember reading about it.
(Hive Addict)
05-30-03 14:48
No 436591
      GHB abstinence     

Nowhere in the following atricles is any withdrawal symptoms mentioned:

Clinical efficacy of GHB in treatment of opiate withdrawal.
Eur Arch Psychiatry Clin Neurosci (1994) 244: 113-114
Two patients studied

GHB for tratment of opiate withdrawal syndrome.
Neuropsychopharmacology 1993, vol 9 no. 1
In a double-blind placebo controlled trial GHB (25mg/kg orally) suppressed most of the withdrawal symptomatology in 14 heroin addicts and 13 methadone-maintained subjects. The GHB effects was prompt (within 15 minutes) and persisted for between 2-3 hours. Subsequently the patients recieved GHB in an open study every 2-4 hours for the first two days and every 4-6 hours for the following 6 days. Most abstinence signs and symptoms remained suppressed and patients reported feeling well. Urine analysis failed to detect any opiate metabolites. No withdrawal symptomatology recurred after 8 days of treatment when GHB was suspended, and patients were challanged with an iv. injection of 0,4 mg Naloxone. The results indicate that GHB may be useful in the management of opiate withdrawal.

Pharmacokinetics of GHB in alcohol dependent patients after single and repeated oral doses
Be. J. clin. Pharmac. 1992, 34: 231-235

Treatment of Narcolepsy with GHB. A review of clinical and sleep laboratory findings.
Sleep 1986, 9(1): 285-289

Oral self-administration of GHB in the rat
European Journal of Pharmacology. 1995, 285: 103-107

(I'm Yust a Typo)
05-30-03 14:54
No 436593
      Yeah, but those patients got GHB only for a...     

Yeah, but those patients got GHB only for a week. If you are given a glass of whisky every 4-6 hours for a week then the chance that you're addicted to booze is very small. Getting into alcohol withdrawal after that study is also quite an achievement.

And that you can find journal articles which don't mention GHB addiction and/or withdrawal doesn't mean that such things don't exist.
(Synaptic Self-Mutilator)
05-31-03 14:27
No 436778

From what I understand, withdrawal like tolerance is a progressive condition... so yeah, for most they can't go into withdrawal after a week of regular dosing, but a user who has gone into withdrawal could easily get into that stage after a week of his regular dosing.

i.e. tolerance for a fresh brain develops slowly, for a "learned brain" it redevelops quickly... and same for withdrawal.
(President, Osmium Fan Club)
06-01-03 01:02
No 436878
      1-4 butandiol causing jaundice?     

I seriously doubt pure 2-4 butandiol causes jaundice. The conversion to GBL actually clears the liver of toxins...
II have used it for over 1 year at a time daily with few if any side effects. Yes the wiithdrall can last for a few days. Sleep returns after w few days...

beware metal contaminted 1-4 butandiol from China....

Dr Tom

DrWHO?TAOG=FreeRadicaLSonOB,Son 32nd MAsonG-O daughters of the AmericanRev1776-2003NeoRev!
(Hive Bee)
06-01-03 10:24
No 436953
User Picture 
      Yes jaundice     

Yes jaundice.

Along with flask moist skin.

Normally, when I took it at a daily basis lower than two/three doses per day, I did not have it, even after a few month.

But The two times I did a binge on it (boosting and reboosting every 1.5-2hours) and i got down like 100-120 mL in 3-4 days, I had jaundice. The two times. Along with moist skin. At those extreme i had vivid dreams in the withdrawal, otherwise not.
06-01-03 11:34
No 436961
User Picture 
      Lots of refs on GHB     

Post 403259 (pHarmacist: "Thruth About GHB! -DEA, Give Up, you Look Stupid!", General Discourse)

Accept No Imitations, There Can Only Bee One;
06-01-03 13:46
No 436974
      1,4Butanediol withdrawal not to be compared to GHB     

I do not believe 1,4 butanediol withdrawal should be discussed in the same thread as GHB withdrawal.  I would think that 1,4 butanediol withdrawal would have much more variability between patients due to the variability in the patients liver function profile.  I believe many of the negative effects associated with 1,4 butanediol use and withdrawal has little to due with GHB at all, but because of the fact that the patient is chronically ingesting a diol.  Thus 1,4 BD appears to have two types of pharmacologic actions, one attributable to its conversion to GHB and the other an inherent property of the diol itself. Poldrugo F, Snead OC 3rd Neuropharmacology. 1984;23:109-113

Yes jaundice. Along with flask moist skin.

I do not doubt this one bit.  Again nothing to due with the GHB, everything to due with the diol.
(Chief Bee)
06-07-03 06:07
No 438399
User Picture 
      Neuropharmacology. 1984;23:109-113     

Can someone fetch that Neuropharmacology. 1984;23:109-113 - it sounds VERY interesting!
(Hive Bee)
06-09-03 00:54
No 438718
      GHB Withdrawal     

On a personal note, I would like to say that SWIM told me that GHB/GBL/1,4-BDL is indeed _very_ addictive and from SWIM's own experiences it is probably just as bad as an opiate withdrawal - perhaps shorter-lasting.

SWIM also told me that using low doses of opiates to lower the effects of the GHB withdrawal can indeed be very effective, so I guess the effect is mutual.
(Chief Bee)
06-09-03 01:00
No 438720
User Picture 
      not the same thing     

Addictive, yes - but once-a-day use causes no withdrawal symptoms. So as long as you can limit yourself to that, then you'll be okay.
(Hive Bee)
06-14-03 01:45
No 439891
      On butanediol withdrawal
(Rated as: good read)

Can someone fetch that Neuropharmacology. 1984;23:109-113 - it sounds VERY interesting!

     I am currently in the process of obtaining numerous full text journal articles concerning the pharmacological differences of GHB and 1,4 Butanediol.  I will start a new thread when I get everything compiled.  Too many people have read TOX54 and somehow have come to the conclusion that GHB and 1,4 butanediol should be considered pharmacologically synonomous.  I hope to dispell that notion after I compile all of the needed information.  Until then here are two abstracts that point out that there are different pharmacological properties of 1,4B in comparison with GHB.

1,4 Butanediol, Gamma-Hydroxybutyric Acid and Ethanol: Relationships and Interactions
Poldrugo F, Snead OC 3rd
Neuropharmacology. 1984;23:109-113

We have investigated the interaction of 1,4 butanediol (1,4 BD) with ethanol and the involvement of the major metabolite of 1,4 BD, gamma-hydroxybutyric acid (GHB) in the ability of 1,4 BD to produce behavioral and EEG changes in rat as well as the toxic side effects of 1,4 BD. Behavioral, electrical, and biochemical studies in rats suggest that the effects of 1,4 BD are indeed mediated by GHB. Further, ethanol appears to block conversion of 1,4 BD to GHB. 1,4 BD however potentiates some of the behavioral effects of ethanol perhaps by a mechanism of action similar to that of other alcohols. Thus 1,4 BD appears to have two types of pharmacologic actions, one attributable to its conversion to GHB and the other an inherent property of the diol itself.

Effect of 1,4 butanediol on the ethanol withdrawal syndrome.
Poldrugo F
ALCOHOLISM (ZAGREB); 21 (2). 1985 (RECD. 1986). 124-127.

The effect of 1,4-butanediol (1,4 BD) and its metabolite, gamma-hydroxybutyric acid (GBH), on the ethanol (ETOH) withdrawal syndrome was ascertained. 1,4 BD significantly decreased and GBH increased ETOH withdrawal symptoms. These data indicate that the effect of 1,4 BD or ETOH withdrawal is due to 1,4 BD itself and not its metabolite.

     Unipolar Mania, Its good for life...laugh
06-21-03 07:08
No 441507
      those damned withdrawals...     

...are a combination of several things.  We are all familiar with the dopamine rebound, but remember that dopamine can convert to on, so if there is a very large build-up there is a rebound of more than one neurotransmitter to contend with.  Once the conversion is made and excessive epinephrine/norepinephrine appears you get the symptoms of panic, hallucinations, etc. 

Combine with this the issue of metabolic acidosis, which occurs with too frequent usage of GBL.  Keep in mind that people tend to dilute their GHB with water.  Is there a two way reaction we can anticipate if such a diluted mixture sits for too long?  I'm no chemist, I'm just asking.  In any event, the symptomology of metabolic acidosis is also consistent with that sited as GHB withdrawal syndrome. 

You probably already know that excessive epinephrine/norepinephrine can result in metabolic acidosis as well.

I have stayed on GHB for months, 24/7, without any problems at all quitting cold turkey (save the fact I couldn't sleep for shit for a week).  However, this was distilled at the highest point possible to even be a syrup, number one, so no GBL showing up.  Also, I take in four ounces of Green Kamut daily, which is an alkali forming food.  This is sufficient to prevent any acidosis issue.  As far as the dopamine build-up goes, rolling fires off a lot of my excess, and every three or four days I will take 24 hours off to let things clear.  Problem solved completely.

I once stayed on 24/7 without any days off at all for several weeks and when I quit I did feel a bit of angst, almost a mild buzz, really, for about a day.  I can't really say that it was an unpleasant feeling, but there was definitely some rebound thing going on.  However, I kept my doses consistent, both the amount and the intervals.  I waited until the dose finshed before redosing.

In a discussion about this on another board I talk about an experiment I tried with GBL.  I took SMALL doses every hour, on the hour, for two weeks.  Having stayed on GBL for longer than that with further spaced doses I anticipated no problems upon quitting.  However, when I sopped this schedule, even though I never even got high off the GBL, I had a terrible rebound that most certainly involved epinephrine.  It lasted about 12 hours or so before decreasing in severity.  pH was definitely acidic, although not alarmingly so.  I downed some wheatgrass, which relieved some of the issues in fairly short order, but it took the whole next day to feel normal again.

This made me understand just how severe this reaction could be for someone who stayed on for a few years before quitting cold.

These problems can be avoided as suggested above, by taking an entire day off every two or three days, and by maintaining a proper blood pH with alkaline forming foods.

I cannot ever believe that GHB is actually addictive.  Stopping this drug (food) is easy.  It has nothing in common with stopping coke or meth, which do not even involve physical withdrawals worth mentioning.  A person simply needs to be aware of what these symptoms are and take the necessary precautions...then GHB becomes the perfect drug.

Wish it was legal so I could do it again.
(Synaptic Self-Mutilator)
07-02-03 17:29
No 444020

Ghb is addictive and for those who get hooked on it, quitting is very difficult. Did anyone catch a recent dateline episode of a guy that had a taste for this stuff? From personal experience, I'll tell you it's hard to quit if you start abusing it...

I'd say it's perhaps a touch more addictive than alcohol. I suppose this post is really about withdrawal, I've found that the immediate withdrawal is not really the hard part to get through, it's the following weeks that are the toughest. If it doesn't produce physical withdrawal symptoms... that doesn't mean too much to me...
(Chief Bee)
07-02-03 17:39
No 444023
User Picture 
      Difference in usage pattern     

It is not addictive if only taken 1-2 times per 24 h, which is what the study suggests - but around the clock usage definitely is. In this case it's a big difference.
07-07-03 00:37
No 445035
      Not a universal effect?     

Difference in usage pattern always applies, I would think.  In the end, I can only speak from my own personal experience with GHB, and I never found it to be addictive.  Dosing more than say, three times in the day left me with a hazy, unpleasant feeling that made me cut back the next day.  Not only that, I never really developed a tolerance in the way that addicts report.  Perhaps this was due to the fact I came all the way off before redosing?  A typical day would be once upon waking (5:00 am) a dose at noon, then at four or five, then a few through the night to sleep. I chemically treated lawns during the summer in question, so physical exertion was the norm.  Maybe this played a role.

Another period of constant use for me lasted over a year, but I used MDMA every weekend at least for that year.  Someone has suggested that dopamine levels were kept reasonable becasue of that...I am not qualified to comment on that, so I guess its a question.

I wasn't claiming that GHB is not addictive, I was stating that I can't understand why it would be right from the beginning.

Of course, alcohol is not universally addictive, and I for one do not drink at all because I cannot stand the effect on my body.  I wonder if there is a correlation...
(Official Hive Translator)
07-07-03 09:35
No 445170
      2 Methyl_Ethyl:     

Can't wait to see your compilation! Very interesting!

(Active Asperger Archivist)
07-07-03 13:25
No 445207

When you complete your compilation, let me know, I will include it in my GBL/GHB Compilation digest.

Act quickly or not at all.
(Hive Bee)
07-07-03 16:22
No 445252
      Thanks for showing an interest...     

Rhodi, Antoncho, Aurelius, thank you for showing an interest in my project, unfortunately I have been on the downside of my usual manic existence, so as of late I have not been accomplishing, well anything...frown  Hopefully I will be back to my maniacal ways soon and will be able to find the time and motivation to finish it up, and perfect it.laugh

     Motivation and encouragement from such respectable bees as yourselves may have been the kick in the booty I was looking for....  Thanks... cool

Unipolar Mania, It's good for life...laugh
(Active Asperger Archivist)
07-07-03 20:45
No 445310
      Feeling down     

Don't worry about a lack of motivation, it is commonly experienced by many of us.  I could name a few, ahemrhodium, myself, barium

Don't worry, we'll be waiting anxiously until you get the kick you need.  Thanks for the help and good work attitude!

Act quickly or not at all.
(Hive Bee)
07-19-03 12:33
No 448421
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      Special issue of the journal Alcohol, on GHB ,
(Rated as: excellent)

Special issue of the journal Alcohol, on GHB, Alcohol, Volume 20, Issue 3, Pages 213-315 (April 2000)

Thomas R. Jerrells, p213

Preface to the Special Issue,
Gian Luigi Gessa, p215-216

Gamma-hydroxybutyric acid Efficacy, potential abuse, and dependence in the treatment of alcohol addiction,
Giovanni Addolorato, Fabio Caputo, Esmeralda Capristo, G. Francesco Stefanini and Giovanni Gasbarrini, p217-222

Safety and tolerability of gamma-hydroxybutyric acid in the treatment of alcohol-dependent patients,
Franco Beghè and Maria Teresa Carpanini, p223-225

Design and structure-activity relationship analysis of ligands of gamma-hydroxybutyric acid receptors,
Jean-Jacques Bourguignon, Martine Schmitt and Bruno Didier, p227-236

Characterization of the discriminative stimulus effects of gamma-hydroxybutyric acid as a means for unraveling the neurochemical basis of gamma-hydroxybutyric acid actions and its similarities to those of ethanol,
Giancarlo Colombo, Roberta Agabio, Mauro A. M. Carai, Carla Lobina, Marialaura Pani, Roberta Reali and Gian Luigi Gessa, p237-245

Gamma-hydroxybutyric acid An evaluation of its rewarding properties in rats and mice,
L. Fattore, M. C. Martellotta, G. Cossu and W. Fratta, p247-256

Gamma-hydroxybutyric acid in the treatment of alcohol and heroin dependence,
Luigi Gallimberti, Maurizio Raffaele Spella, Carlo Alberto Soncini and Gian Luigi Gessa, p257-262

Abuse and therapeutic potential of gamma-hydroxybutyric acid,
G. P. Galloway, S. L. Frederick-Osborne, Richard Seymour, Sarah E. Contini and David E. Smith, p263-269

Mechanism of the antialcohol effect of gamma-hydroxybutyric acid,
Gian Luigi Gessa, Roberta Agabio, Mauro A. M. Carai, Carla Lobina, Marialaura Pani, Roberta Reali and Giancarlo Colombo, p271-276

Gamma-hydroxybutyric acid as a signaling molecule in brain,
Michel Maitre, Christian Andriamampandry, Véronique Kemmel, Catherine Schmidt, Yann Hodé, Viviane Hechler and Serge Gobaille, p277-283

Gamma-hydroxybutyric acid and alcohol-related syndromes,
M. Moncini, E. Masini, F. Gambassi and P. F. Mannaioni, p285-291

Gamma-hydroxybutyric acid and growth hormone secretion Studies in rats and dogs,
Antonello E. Rigamonti and Eugenio E. Müller, p293-304


Full issue in Zip file:

Rename it as .zip!

Have fun! cool
(Chief Bee)
07-20-03 00:34
No 448528
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Wonderful collection, Chimimanie! I have backed up a copy of all the articles in a single 2MB PDF at my site:
(Chief Bee)
09-19-03 14:14
No 459955
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      GHB as an anti-cancer agent?     

-Hydroxybutyric acid and 5-fluorouracil, metabolites of UFT, inhibit the angiogenesis induced by vascular endothelial growth factor
Basaki Yuji, Chikahisa Lumi, Aoyagi Kumio, Miyadera Kazutaka, Yonekura Kazuhiko, Hashimoto Akihiro, Okabe Soko, Wierzba Konstanty, Yamada Yuji
Angiogenesis 4(3), 163-173 (2001) (


UFT, a drug composed of uracil and tegafur at the molar ratio of 4:1, is an orally active agent for the treatment of a wide variety of malignant tumours. Using a murine dorsal air sac (DAS) assay, we have previously shown that UFT and its metabolites, ?-hydroxybutyric acid (GHB) and 5-fluorouracil (5-FU), inhibited the angiogenesis induced by murine renal cell carcinoma. Here we report that UFT was more effective than other fluorinated pyrimidines such as 5-FU and doxifluridine (5'-DFUR) in blocking the angiogenic responses elicited by five human cancer cell lines which produced high levels of vascular endothelial growth factor (VEGF), but no detectable fibroblast growth factor-2 (FGF-2) in vitro. In contrast, UFT was unable to block the angiogenic response to one human gastric cancer cell line which produced both VEGF and FGF-2 in vitro. However, the production or secretion of VEGF by these cells was unaffected by GHB and 5-FU treatment. Interestingly, GHB suppressed the chemotactic migration and tube formation of human umbilical vein endothelial cells (HUVECs) stimulated by VEGF, without inhibiting their DNA synthesis. Since GHB did not affect the FGF-2-driven activities in HUVECs, its action appears to be VEGF-selective. On the other hand, 5-FU inhibited DNA synthesis and migration of HUVECs stimulated by both VEGF and FGF-2, and tube formation driven by VEGF, suggesting that 5-FU is cytotoxic to endothelial cells. The inhibitory effects of 5-FU, and especially those GHB, were reproduced under in vivo condition using the DAS assay. The VEGF-mediated angiogenesis was significantly inhibited by UFT, 5-FU, and especially by GHB. We propose that the selective inhibitory effects of GHB on VEGF-mediated responses of endothelial cells are involved in the anti-angiogenic activity of UFT.

UFT and Its Metabolites Inhibit the Angiogenesis Induced by Murine Renal Cell Carcinoma, as Determined by a Dorsal Air Sac Assay in Mice
Kazuhiko Yonekura, Yuji Basaki, Lumi Chikahisa, Soko Okabe, Akihiro Hashimoto, Kazutaka Miyadera, Konstanty Wierzba, Yuji Yamada
Clinical Cancer Research Vol. 5, 2185-2191 (1999) (


UFT, an anticancer agent that is composed of tegafur (FT) and uracil at a molar ratio of 1:4, is widely used in clinical practice in Japan to treat cancer patients requiring a long-term chemotherapy, and it is associated with few side effects, if any. In this study, we have evaluated the inhibitory effect of UFT against RENCA cell-induced angiogenesis by a dorsal air sac assay. Marked angiogenesis is induced by implantation of a chamber containing RENCA cells into mice. In this model, UFT showed a strong angiogenesis-inhibitory effect, whereas 5-fluorouracil (5-FU) and doxifluridine were less effective. Additional experiments revealed FT to be effective component of UFT; uracil remained ineffective in the inhibition of angiogenesis. Moreover, we have found that -hydroxybutyric acid and -butyrolactone, the metabolites of FT, possess a potent angiogenesis inhibitory effect that is amplified when the compounds are administered by a continuous infusion. This may reflect a transition in blood concentration of each metabolite resulting from the administration of UFT. Similar results were also obtained with respect to 5-FU. It was suggested that UFT has a stronger angiogenesis-inhibitory effect than did other fluorinated pyrimidines, partly due to its pharmacokinetic properties characterized by maintaining of higher and long-lasting blood levels of 5-FU and partly due the inhibitory effects derived from -hydroxybutyric acid and -butyrolactone, UFT-specific metabolites.
(Chief Bee)
11-15-03 20:52
No 471098
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      GHB Tolerance and Withdrawal in a Rat Model
(Rated as: excellent)

Gamma-hydroxybutyric Acid Tolerance and Withdrawal in a Rat Model
Bania, T. C.; Ashar, T.; Press, G.; Carey, P. M.
Academic Emergency Medicine Acad Emerg Med 10(7), 697-704 (2003) (
Medline (PMID=12837642)


Long-term daily use of gamma-hydroxybutyrate (GHB) and related compounds has recently been associated with a withdrawal syndrome. To the best of the authors' knowledge, there are currently no animal models of GHB withdrawal. Objectives: The authors studied and described the effect of chronic dosing of GHB (3-6 days) on tolerance and withdrawal in a rat model. Methods: Rats were administered GHB every three hours via intraperitoneal catheter. Groups of rats (2 per group) were dosed with GHB for either 3 (24 doses), 4 (32 doses), 5 (40 doses), or 6 (48 doses) days. The GHB dose was 0.25 g/kg for doses 1-8, 0.75 g/kg for doses 9-12, 1 g/kg for doses 13-16, 1.25 g/kg for doses 17-24, 1.5 g/kg for doses 25-32, 1.75 g/kg for doses 33-40, and 2 g/kg for doses 41-48. Following the last dose of GHB, the rats were scored using a 16-point ethanol intoxication-withdrawal scale rating spontaneous behaviors, response to handling, grooming, and neurological signs. Lower scores indicate intoxication, while higher scores indicate withdrawal. Scores were recorded at hours 0, 1, 2, 3, 4, 5, 6, 9, 12, and 24. Results: Tolerance: Rats dosed with GHB for more days were less intoxicated one hour after their last GHB dose despite receiving higher doses. Withdrawal: The scores for all rats dosed with GHB increased at hours 4 (p = 0.028), 5 (p = 0.037), 6 (p = 0.007), and 9 (p = 0.024) after the last dose, indicating withdrawal. The scores demonstrated a linear increase dependent upon the number of days of GHB dosing at hours 3 (p < 0.000), 4 (p = 0.004), 5 (p = 0.002), and 12 (p = 0.039) as well as prior to the last dose at hour 0 (p = 0.000). No rats developed seizures. Conclusions: Tolerance and mild withdrawal in rats can be induced by administering intraperitoneal GHB every three hours for 3-6 days. More prolonged dosing and higher doses of GHB may be necessary to induce severe withdrawal.
(Chief Bee)
01-29-04 17:13
No 485323
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      GHB Neurobiology & Tertiary alcohol analog
(Rated as: excellent)

From the street to the brain: neurobiology of the recreational drug gamma-hydroxybutyric acid
Wong CG, Gibson KM, Snead OC
Trends Pharmacol Sci. 25(1), 29-34 (2004) (
DOI:10.1016/ (PMID=14723976)

gamma-Hydroxybutyric acid (GHB) is a short-chain fatty acid that occurs naturally in the mammalian brain and is formed primarily from the precursor gamma-aminobutyric acid (GABA). The properties of GHB suggest that it has a neuromodulatory role in the brain and has the ability to induce several pharmacological and behavioral effects. GHB has been used clinically as an anesthetic and to treat alcoholism and narcolepsy. Furthermore, GHB has emerged recently as a major recreational drug of abuse. GHB appears to have dual mechanisms of action in the brain. Biochemical data suggest that the intrinsic neurobiological activity of GHB might be mediated through the GHB receptor, which is separate and distinct from the GABA(B) receptor. However, many of the pharmacological and clinical effects of exogenously administered GHB, including the properties of addiction, tolerance, withdrawal and intoxication, are probably mediated via the GABA(B) receptor, where GHB might act both directly as a partial agonist and indirectly through GHB-derived GABA.
____ ___ __ _

A tertiary alcohol analog of gamma-hydroxybutyric acid as a specific gamma-hydroxybutyric acid receptor ligand
Wu H, Zink N, Carter LP, Mehta AK, Hernandez RJ, Ticku MK, Lamb R, France CP, Coop A
J Pharmacol Exp Ther. 305(2), 675-9 (2003) (
DOI:10.1124/jpet.102.046797Medline (PMID=12606613)

gamma-Hydroxybutyric acid (GHB) shows great promise as a treatment for sleeping disorders but is also increasingly abused. The exact mechanism of action of GHB is yet to be delineated, but it is known to interact with specific GHB binding sites or receptors, to act as a weak agonist at GABA(B) receptors, and that GHB undergoes metabolism to GABA. In drug discrimination studies, GABA(B) agonists, and to a lesser extent GABA(A)-positive modulators, substitute for GHB. To delineate the relative contributions of each receptor system to the profile of GHB, tertiary alcohol analogs of GHB and its homolog, 5-hydroxypentanoic acid (UMB58), were prepared (UMB68 and UMB75, respectively), which cannot be metabolized to GABA-active compounds. Binding studies against [(3)H]NCS-382 [(2E)-(5-hydroxy-5,7,8,9-tetrahydro-6H-benzo[a][7]annulen-6-ylidene) ethanoic acid] showed that the tertiary alcohol analog of GHB (UMB68) has similar affinity to GHB, with the longer chain analogs possessing lower affinity. Against [(3)H]GABA, UMB68 showed no affinity (IC(50) >100 microM) at GABA(A) or GABA(B) receptors. In vivo studies showed that, at behaviorally active doses, rats trained to discriminate GHB did not recognize the novel ligands as GHB. Thus, UMB68 is a selective GHB receptor ligand in binding assays, will not undergo metabolism to GABA-active compounds, and does not show the same effects as GHB in vivo. These data suggest that, although UMB68 binds to the GHB receptor, it does not have the observed GABA receptor-mediated effects of GHB in vivo and could provide a novel tool for studying the pharmacology of the GHB receptor in the absence of complicating GABAergic effects.

The Hive - Clandestine Chemists Without Borders
(Official Hive Translator)
01-30-04 03:28
No 485422

Thank you very much for providing these excellent articles!

Haven't read them yet, but:


Current ‘street’ names for GHB include ... grievous bodily harm, ... and nitro [5].

Absolutely hilarious!laugh


01-31-04 00:42
No 485597
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      GHB Withdrawal Syndrome
(Rated as: excellent)

Gamma-Hydroxybutyrate Withdrawal Syndrome
Jo Ellen Dyer PharmD, Brett Roth MD, Bruce A. Hyma MD.
ANNALS OF EMERGENCY MEDICINE February 2001;37:147-153. (


Study Objective: Gamma-hydroxybutyrate (GHB) withdrawal syndrome is increasingly encountered in emergency departments among patients presenting for health care after discontinuing frequent GHB use. This report describes the characteristics, course, and symptoms of this syndrome.

Methods: A retrospective review of poison center records identified 7 consecutive cases in which patients reporting excessive GHB use were admitted for symptoms consistent with a sedative withdrawal syndrome. One additional case identified by a medical examiner was brought to our attention. These medical records were reviewed extracting demographic information, reason for presentation and use, concurrent drug use, toxicology screenings, and the onset and duration of clinical signs and symptoms.

Results: Eight patients had a prolonged withdrawal course after discontinuing chronic use of GHB. All patients in this series were psychotic and severely agitated, requiring physical restraint and sedation. Cardiovascular effects included mild tachycardia and hypertension. Neurologic effects of prolonged delirium with auditory and visual hallucinations became episodic as the syndrome waned. Diaphoresis, nausea, and vomiting occurred less frequently. The onset of withdrawal symptoms in these patients was rapid (1 to 6 hours after the last dose) and symptoms were prolonged (5 to 15 days). One death occurred on hospital day 13 as withdrawal symptoms were resolving.

Conclusion: In our patients, severe GHB dependence followed frequent ingestion every 1 to 3 hours around-the-clock. The withdrawal syndrome was accompanied initially by symptoms of anxiety, insomnia, and tremor that developed soon after GHB discontinuation. These initial symptoms may progress to severe delirium with autonomic instability.

Dyer JE, Roth B, Hyma BA. Gamma-hydroxybutyrate withdrawal syndrome. Ann Emerg Med. February 2001;37:147-153.

     Unipolar Mania, It's good for life... laugh
(Hive Bee)
05-09-04 16:12
No 506013
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      More GHB ligands
(Rated as: excellent)

3-chloropropanoic acid (UMB66): a ligand for the gamma-hydroxybutyric acid receptor lacking a 4-hydroxyl group
Macias AT, Hernandez RJ, Mehta AK, MacKerell AD Jr, Ticku MK, Coop A.
Bioorg Med Chem. 2004 Apr 1;12(7):1643-7

Gamma-Hydroxybutyric acid (GHB) has gained in notoriety in recent years due to its association with sexual assaults. GHB is an endogenous ligand for GHB receptors, but its complete pharmacological mechanism of action in vivo remains unclear due to apparent GABAergic components. It has been proposed that the hydroxyl group in the 4-position acts as a hydrogen bond donor to the GHB receptor. Herein we show that 3-chloropropanoic acid possesses significant affinity for the GHB receptor, has no affinity for GABA receptors, and cannot undergo metabolism to GABAergic compounds. UMB66 is thus a selective agent for the study of GHB in vivo. These results, in combination with data from quantum mechanical calculations, suggest that the hydroxyl group of GHB actually acts as a hydrogen bond acceptor in contrast to the currently accepted model. This finding is anticipated to facilitate the rational design of novel agents with selectivity for GHB receptors that may be used to elucidate the mechanism of action of this common drug of abuse.

05-10-04 19:37
No 506266
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      GHB: Physical Dependence
(Rated as: good read)

Gamma-hydroxybutyrate: an emerging drug of abuse that causes physical dependence.
Galloway, Gantt P., Frederick, S. L., Staggers, Frank E., Gonzales, Marco, Stalcup, S. Alex & Smith, David E.
Addiction 1997 92 (1), 89-96.


Gamma-hydroxybutyrate (GHB) is a compound found in mammalian brain which meets many criteria of
a neurotransmitter. GHB has been investigated as a tool for inducing absence (petit mal) seizures, for use
as an anesthetic, and for treatment of narcolepsy, alcohol dependence and opiate dependence. Since 1990
GHB has been abused in the United States for euphoric, sedative and anabolic effects. Coma and seizures
have been reported following abuse of GHB, but dependence liability has received little attention. The
neuropharmacology, potential therapeutic uses and acute adverse effects of GHB are reviewed, followed by a
case series of eight people using GHB. Adverse effects of GHB may include prolonged abuse, seizure activity
and a withdrawal syndrome. This withdrawal syndrome include s insomnia, anxiety and tremor; withdrawal
symptoms resolve in 3± 12 days. GHB has the potential to cause a significant incidence of abuse and adverse
effects . Prolonged use of high doses may lead to a withdrawal syndrome, which resolves without sequelae.
Educational efforts should addres s the narrow therapeutic index, possible physical dependence and danger s of
combining GHB with other drugs of abuse.

     Unipolar Mania, It's good for life... laugh
(Hive Bee)
05-10-04 21:37
No 506290
      Yes, most people here probably could have...     

Yes, most people here probably could have found this anyways but its relevant and has a collection of 25+ articles about GHB from 1994-1999:
Some cool stuff on there, for example: Gamma hydroxybutyrate is not a GABA agonist (
(Chief Bee)
05-11-04 00:02
No 506321
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      GHB is a GABA-B agonist     

GHB is most definitely a GABAB receptor agonist, read this 2004 review: 
The Neuropharmacology of γ-hydroxybutyrate (GHB) (

Further reading:

The Discriminative Stimulus Effects of gamma-Hydroxybutyrate and Related Compounds in Rats Discriminating Baclofen or Diazepam: The Role of GABAB and GABAA Receptors
L. P. Carter, A. W. Unzeitig, H. Wu, W. Chen, A. Coop, W. Koek, and C. P. France, Journal of Pharmacology And Experimental Therapeutics 309, 540-547 (2004)

The discriminative stimulus effects of gamma-hydroxybutyrate (GHB) can be mimicked by GABAA receptor-positive modulators (e.g., diazepam) and GABAB receptor agonists (e.g., baclofen). The purposes of this study were to see whether stimulus control could be established with baclofen and to further characterize the role of GABAergic mechanisms in the behavioral actions of GHB by evaluating GHB and related compounds in rats discriminating either diazepam or baclofen. Training criteria were satisfied with baclofen and diazepam after 69 and 44 sessions, respectively. GHB and its precursors -butyrolactone and 1,4-butanediol occasioned >80% responding on the drug-associated lever in rats discriminating baclofen and <11% in rats discriminating diazepam. Diazepam and other GABAA receptor-positive modulators occasioned intermediate levels of responding on the baclofen lever, whereas baclofen occasioned less than 4% responding on the diazepam lever. The GABAB receptor antagonist CGP 35348 [(3-aminopropyl)(diethoxymethyl) phosphinic acid] partially antagonized the effects of baclofen as well as the baclofen-like effects of GHB, and flumazenil partially antagonized the effects of diazepam. This study established stimulus control with baclofen, and substitution data provided direct evidence for a role of GABAergic, especially GABAB, mechanisms in the discriminative stimulus effects of GHB. The lack of substitution by GHB or its metabolic precursors for diazepam indicates a comparatively smaller role of GABAA mechanisms in these effects of GHB. The inability of CGP 35348 to completely attenuate the effects of baclofen and GHB suggests that multiple receptors could be involved in the discriminative stimulus effects of GHB.

The Hive - Clandestine Chemists Without Borders
(Hive Bee)
05-11-04 23:53
No 506552
      One more link for this linkfest: ...     

One more link for this linkfest:
The first part is about Sam-E (which is also interesting) but there are a couple pages about GHB as well.  This includes the following 15 references:
1) Kam PC, Yoong FFY. Gamma-hydroxybutyric acid: an emerging recreational drug. Anaesthesia 1998;53: 1195-8.
2) Anon. FDA warns about GBL-related products. [WWW document] (1999). URL:
3) Montana Board of Pharmacy. National Pharmacy Compliance News 1999;20:2-3.
4) Anon. Important Message for Health Professionals. [WWW document] (1999). URL:
5) Lovecchio F, Curry SC, Bagnasco T. Butyrolactone-induced central nervous system depression after ingestion of Renewtrient, a "dietary supplement". N Engl J Med 1998;339:847-848.
6) Li J, Stokes SA, Woeckener A. A tale of novel intoxication: a review of the effects of gamma-hydroxybutyric acid with recommendations for management. Ann Emergency Med 1998;31:729-35.
7) Anon. Adverse events associated with ingestion of gamma-butyrolactone--Minnesota, New Mexico, and Texas, 1998-1999. MMWR 1999;48:137-40.
8) Chin R, Sporer K, Cullison B, Dyer JE, Wu T. Clinical course of gamma-hydroxybutyrate overdose. Ann Emergency Med 1998;31:716-22.
9) Li J, Stokes SA, Woeckener A. A tale of novel intoxication: seven cases of gamma-hydroxbutyric acid overdose. Ann Emergency Med 1998;31:723-8.
10) Friedman J, Westlake R, Furman M. "Grievous bodily harm:" gamma hydroxbutyrate abuse leading to a Wernicke-Korsakoff syndrome. Neurology 1996;46:469-71.
11) Louagie H, Verstraete AG, Soete CJ, Baetens DG, Calle PA. A sudden awakening from a near coma after combined intake of gamma-hydroxybutyric acid (GHB) and ethanol. J Toxicol Clin Tox 1997;35:591-4.
12) Palatini P, Tedeschi L, Frison G, Padrini R, Zordan R, Orlando R, et al. Dose-dependent absorption and elimination of gamma-hydroxbutyric acid in healthy volunteers. Eur J Clin Pharmacol 1993;45:353-6.
13) Tunnicliff G. Sites of action of gammahydroxybutyrate (GHB) - a neuroactive drug with abuse potential. J Toxicol Clin Tox 1997;35:581-90.
14) Scharf M, Hauck M, Stover R, McDannold M, Berkowitz D. Effect of gamma-hydroxybutyrate on pain, fatigue, and the alpha sleep anomaly in patients with fibromyalgia. Preliminary report. J Rheumatol 1998;25:1986-90.
15) Olson K, Dyer JE, Haller C. Central nervous system depression after ingestion of RenewTrient. N Engl J 1999;340:570.
05-12-04 03:19
No 506576
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      Case Studies: GHB 1,4B Withdrawal
(Rated as: good read)

Aaron B. Schneir, MD, Binh T. Ly, MD, and Richard F. Clark, MD
The Journal of Emergency Medicine, Vol. 21, No. 1, pp. 31–33, 2001


We describe a case of withdrawal from the
gamma hydroxybutyric acid (GHB) precursors gamma butyrolactone
and 1,4-butanediol. Symptoms included visual
hallucinations, tachycardia, tremor, nystagmus, and diaphoresis.
Administration of benzodiazepines and phenobarbital
successfully treated the withdrawal symptoms. As predicted
from the metabolism of gamma butyrolactone and
1,4-butanediol to GHB, the symptoms were nearly identical
to those reported from GHB withdrawal. Because GHB is
now illegal in the United States, individuals have begun
abusing the legal and easier to acquire GHB precursors.
More frequent cases of both abuse and withdrawal from
these GHB precursors can be expected.

Kathryn Craig, MD,* Hernan F. Gomez, MD,† John L. McManus, MD,* and Theodore C. Bania, MD
The Journal of Emergency Medicine, Vol. 18, No. 1, pp. 65–70, 2000


We report a case of gamma-hydroxybutyrate
(GHB) withdrawal resulting in severe agitation, mental
status changes, elevated blood pressure, and tachycardia
hours after stopping chronic use of GHB. The patient admitted
to substantial GHB abuse on a daily basis for 2.5
years. Previous attempts at cessation reportedly resulted in
diaphoresis, tremors, and agitation. The patient’s symptoms,
negative polypharmacy history, and negative urine
and blood toxicological analysis for alcohol, benzodiazepines,
sedative-hypnotics, or other substances suggested
the diagnosis of GHB withdrawal. Later analysis of a patient
drug sample confirmed the presence of GHB. The
patient required 507 mg of lorazepam and 120 mg of diazepam
over 90 h to control agitation. This is one of the few
reported cases of GHB withdrawal and one of the most
severe. Given the increasing use of GHB, more cases of
severe GHB withdrawal should be anticipated.

     Unipolar Mania, It's good for life... laugh
(Chief Bee)
05-12-04 20:19
No 506711
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      Short notes about rodents on GHB
(Rated as: good read)

Abstracts Of The 10Th Biennial Ebps Meeting (#P111)
A Comparison of the Discriminative Stimulus Effects of Gamma-Hydroxybutyrate and Gamma-Butyrolactone in Rats
L. E. Baker, T. J. Van Tilburg, A. E. Brandt and A. D. Poling
Behavioural Pharmacology, Vol 14 Suppl. 1, S65 (2003)

Gamma-hydroxybutyrate (GHB) and its precursor gamma-butyrolactone (GBL) produce sedative and intoxicating effects in humans. Media attention has recently focused on the rampant recreational use of GHB and its notorious involvement in numerous drug-facilitated sexual assaults. The GHB precursors, GBL and 1,4-BD are found in some industrial solvents and also present a potential health hazard because their supply is not easily controlled. Relatively little is known about the neurobehavioral effects of GHB and its precursors. The aim of the present investigation was to characterize the discriminative stimulus effects of GHB and GBL. Sixteen male Sprague-Dawley rats were trained to discriminate GHB (300 mg/kg, IG) from vehicle. Another eight rats were trained to discriminate GBL (150 mg/kg, IP) from vehicle. Several compounds were examined for stimulus generalization to each training drug. GHB (75–300 mg/kg) and GBL (37.5–150 mg/ kg) exhibited cross generalization. Another GHB precursor, 1,4-butanediol (100 -400 mg/kg) produced dose-dependent increases in drug-appropriate responding and fully substituted for both GHB and GBL. The benzodiazepines, alprazolam (0.5–2.0mg/kg) and diazepam (2.5-10 mg/kg) did not substitute for either  training drug, nor did the anxiolytic, buspirone (1–10mg/kg). These results support previous findings that GHB's discriminative stimulus effects are not related to anxiolytic  effects and they do not appear to be mediated by GABAA receptor actions. Rather, GHB and GBL appear to have unique discriminative stimulus properties that may be mediated by GHB receptors. Further testing of selective GHB antagonists and GABAB antagonists are planned to further evaluate the mechanisms underlying the discriminative stimulus properties of these substances.
____ ___ __ _

Acute and repeated administration of gammahydroxybutyrate (GBH) produces neurobehavioral and neurochemical alterations in mice
S. F. Ali and Y. Itzhak
Journal of Neurochemistry, Vol 87 (Suppl. 1), 69 (2003)

The GHB is a metabolite of gamma-aminobutyric acid (GABA). Recently, the recreational use of GHB had markedly increased in many major cities in the US, particularly in the "rave" parties. In the present study we investigated the behavioral and neurochemical outcome of repeated administration of GHB to mice. Acute administration of 100, 200 and 300 mg/kg GHB produced dose-dependent hypolocomotion. Animals treated with GHB (200 mg/kg/day) for 14 days developed a significant tolerance to the sedative effect of GHB as determined on days 6 and 14. The administration of 300 mg/kg GHB to naive animals caused marked catalepsy which was absent in the GHB pretreated mice. These findings indicate that repeated administration of GHB produced tolerance to both the sedative and the cataleptic effect of GHB. The content of striatal dopamine (DA) and its metabolites DOPAC and HVA were determined 72 h after the repeated administration of GHB. The level of DA and HVA in tissue from GHB treated mice was significantly higher than control. The rewarding effect of GHB was investigated in the CPP paradigm. The pairing of GHB (250 mg/ kg) with one compartment of the CPP cage, in alternate days for 7 days, and with saline injections in the other compartment for 7 days induced significant place preference. Taken together, the present study indicates that repeated administration of GHB produces tolerance to the behavioral effects and support the abuse potential of GHB. The elevation of striatal DA concentration observed may be associated with GHB-induced decrease in DA release during the course of repeated exposure to the drug.

The Hive - Clandestine Chemists Without Borders
05-13-04 03:50
No 506775
User Picture 
      Role of GHB and GABA-B Receptors
(Rated as: good read)

Effects of gamma-Hydroxybutyrate (GHB) on Schedule-Controlled Responding in Rats: Role of GHB and GABA-B Receptors
Lawrence P. Carter, Huifang Wu, Weibin Chen, Christopher M. Cruz, R. J. Lamb, Wouter Koek, Andy Coop, and Charles P. France
Medline (PMID=14569056)

gamma-Hydroxybutyrate (GHB), a metabolite of -aminobutyric acid
(GABA), is an increasingly popular drug of abuse and was
recently approved for the treatment of narcolepsy (Xyrem).
GHB and GABA receptors have been implicated in mediating
effects of GHB; however, the relative importance of each of
these receptors is unclear. This study evaluated the effects of
selective antagonists in combination with GHB and related
compounds on schedule-controlled responding. Eight male
Sprague-Dawley rats responded under a fixed-ratio schedule
of food presentation. Cumulative dose-effect curves were generated
and ED50 values calculated to evaluate the relative potency
at decreasing responding. The rank-order potency was
as follows: diazepam  baclofen  -butyrolactone (GBL)
1,4-butanediol (1,4-BDL)  GHB. All compounds decreased
responding 20 min after administration. The duration of action.
of diazepam, GHB, and GBL was shorter than that of 1,4-BDL
and baclofen. p-3-Aminopropyl-p-diethoxymethyl phosphinic
acid (CGP 35348) antagonized the rate-decreasing effects of baclofen
and not GHB; flumazenil antagonized the effects of diazepam
and not GHB. The GHB receptor antagonist (2E)-(5-hydroxy-
5,7,8,9-tetrahydro-6H-benzo[a][7]annulen-6-ylidene ethanoic acid
(NCS-382) did not attenuate the rate-decreasing effects of GHB,
baclofen, or diazepam; larger doses of NCS-382 further decreased
rate of responding when given in combination with each
of these compounds. These studies show that GBL, 1,4-BDL, and
GHB differ significantly in potency and duration of action. The
ability of CGP 35348 to antagonize the rate-decreasing effects of
baclofen may be limited by the involvement of multiple GABAB
receptor subtypes and the lack of antagonism of GHB by NCS-
382 may be due to its own GHB-like effects.

     Unipolar Mania, It's good for life... laugh
(Chief Bee)
05-16-04 22:29
No 507559
User Picture 
      H. Laborit GHB Review & GHB Absorption Studies
(Rated as: excellent)

Sodium 4-Hydroxybutyrate
H. Laborit
Int. J. Neuropharmacol. 3, 433-452 (1964) (

The author presents a general review of the pharmacology of sodium 4-hydroxybutyrate, the principal elements of which are:
(a) very low toxicity, and metabolic application;
(b) the hypnotic activity, which does not cause a decrease in the intensity of oxidative processes;
(c) the potentiating action on anaesthetics and neuroplegics, and the antagonizing action against certain convulsants;
(d) the absence of ventilatory depression;
(e) the facilitating action on hypothermia.
The EEG study and the stereotaxic study of the cerebral evoked potentials, as well as the cardiovascular and antishock activity are described. The author insists on the strong potassium and cholesterol lowering effects of the drug, and on its protein sparing action. The mechanism of action is discussed. Numerous data permit to assume that this mechanism is essentially characterized by an activation of the pentose pathway. Finally, a brief summary is presented of its applications in anaesthesiology, obstetrics, psychiatry and in internal medicine.
[5 tables, 9 figs., 42 refs.]
____ ___ __ _

Dose-dependent absorption and elimination of gamma-hydroxybutyric acid in healthy volunteers
P. Palatini L. Tedeschi, G. Frison, R. Padrini, R. Zordan, R. Orlando, L. Gallimberti, G. L. Gessa, and S. D. Ferrara
Eur. J. Clin. Pharmacol. 45, 353-356 (1993) (

Gamma-hydroxybutyric acid (GHB) is effective in treatment of the alcohol and opiate withdrawal syndromes. Its absorption and disposition kinetics have been studied in 8 healthy male volunteers following oral administration of single doses of 12.5, 25 and 50 mg/kg. The AUC increased disproportionately with the dose and so the apparent oral clearance decreased significantly as the dose was increased, whereas the terminal half-life and mean residence time increased. The peak plasma concentration normalised to the lowest dose fell significantly with increasing doses, whilst the corresponding peak times increased. These findings suggest that both the oral absorption and the elimination of GHB are capacity-limited processes. GHB did not bind to significant extent to plasma proteins over the therapeutic concentration range. The pharmacokinetic parameters in healthy volunteers were not significantly different from those previously observed in alcohol-dependent patients with compensated alcoholic liver disease.
____ ___ __ _

Absorption of Sodium γ-Hydroxybutyrate and Its Prodrug γ-Butyrolactone: Relationship between In Vitro Transport and In Vivo Absorption
C. Arena and Ho-Leung Fung
Journal of Pharmaceutical Sciences 69(3), 356-358 (1980) (

A qualitative relationship between in vitro transport and of absorption of sodium γ-hydroxybutyrate and γ-butyrolactone as demonstrated. As with other short-chain acids, sodium γ-hydroxybutyrate showed capacity-limited transport in vitro, consistent with the previous observation that this drug exhibited slower in vivo absorption with increasing dose. The prodrug lactone, on the other hand, showed a higher intestinal flux than the acid in the everted gut, and in vivo absorption also was more rapid. Capacity-limited transport and absorption of the lactone appeared less evident. Thus, the increased oral hypnotic activity of the lactone over that of the acid most likely is a result of its more favorable intestinal transport characteristics.
____ ___ __ _

A Sudden Awakening from a Near Coma After Combined Intake of Gamma-Hydroxybutyric Acid (GHB) and Ethanol
Henk K. Louagie; Alain G. Verstraete; Christophe J. De Soete; Dimitri G. Baetens; Paul A. Calle
Clinical Toxicology, 35(6), 591-594 (1997) (

Objective: A case of a sudden awakening from a near coma after combined intake of gamma-hydroxybutyric acid (GHB) (125 µg/mL), ethanol (134 mg/dL), and cannabinoids is described. Methods: GHB was determined by gas chromatography-mass spectrometry after acetonitrile precipitation and derivation with N-methyl-N-trimethylsilyltrifluoroacetamide, using valproic acid as the internal standard. Conclusion: The described case illustrates the consequences of GHB overdose. GHB overdose should be considered in every case of unexplained sudden coma, i.e., without any evidence of head injury, intake of coma-inducing drugs, or increasing intracranial pressure. GHB overdose will be missed by routine toxicological screening.

The Hive - Clandestine Chemists Without Borders
(Chief Bee)
05-19-04 23:43
No 508290
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      GHB Receptor Function, 1,4-BD/GBL difference etc.
(Rated as: excellent)

Chronic 1,4-butanediol treatment in rats: cross-tolerance to γ-hydroxybutyrate and (±)-baclofen
Kary A. Eckermann, Wouter Koek and Charles P. France
European Journal of Pharmacology 484(2-3), 259-262 (2004) (

The effects of 1,4-butanediol, γ-hydroxybutyrate (GHB), and (±)-baclofen on food-maintained responding in rats were assessed before, during, and after chronic treatment with 1,4-butanediol. Six weeks of treatment with 1,4-butanediol (twice daily, 320 mg/kg for 3 weeks followed by 560 mg/kg for 3 weeks) decreased sensitivity to the rate-decreasing effects of (±)-baclofen and GHB without changing sensitivity to 1,4-butanediol. Sensitivity to (±)-baclofen and GHB returned to control values 2–3 weeks after discontinuation of treatment. These data suggest that tolerance to the effects of GHB or its precursors might result from changes in GABAB mechanisms.
____ ___ __ _

gamma-hydroxybutyrate serum levels and clinical syndrome after severe overdose
Sporer KA, Chin RL, Dyer JE, Lamb R
Annals of Emergency Medicine 42(1), 3-8 (2003) (

Study objective: We discuss a prospective case series of patients who present with a severe gamma-hydroxybutyrate intoxication with confirmatory serum and urine gamma-hydroxybutyrate levels. Methods: Patients with a clinical suspicion of gamma-hydroxybutyrate-like drug overdoses and a Glasgow Coma Scale score of 8 or lower were identified from July 1998 through January 1999. Serial serum specimens and a single urine specimen were collected. The levels of gamma-hydroxybutyrate were performed by gas chromatography-mass spectrometry. Results: All 16 suspected severe gamma-hydroxybutyrate overdose patients had significant serum or urine levels of gamma-hydroxybutyrate. Serum levels ranged from 45 to 295 mg/L, with a median of 180 mg/L (interquartile range [IQR] 235 to 118 mg/L). Patients who developed a Glasgow Coma Scale score of 3 had serum levels that ranged from 72 to 300 mg/L, with a median of 193 mg/L (IQR 242 to 124 mg/L). The time of awakening ranged from 30 minutes to 190 minutes, with a median of 120 minutes (IQR 150 to 83 minutes). Quantitative serum gamma-hydroxybutyrate levels did not correlate with the degree of coma or the time to awakening. Urine levels ranged from 432 to 2,407 mg/L, with a median of 1,263 mg/L (IQR 1,550 to 796 mg/L). Mild transitory hypoventilation occurred in 5 of the 16 patients. Conclusion: All of our patients with clinically suspected severe gamma-hydroxybutyrate overdose were confirmed to have significant serum and urine levels of exogenous gamma-hydroxybutyrate. They presented with severe coma that lasted 1 to 2 hours. Transient hypoventilation occurred in one third of these patients.
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Effects of sustained gamma-hydroxybutyrate treatments on spontaneous and evoked firing activity of locus coeruleus norepinephrine neurons
Steven T. Szabo, Mark S. Gold, Bruce A. Goldberger and Pierre Blier
Biological Psychiatry 55(9), 934-939 (2004) (

Background: Gamma-hydroxybutyrate is currently used to promote nighttime sleep in the treatment of narcolepsy; however, it is also a drug of abuse ("Liquid Ecstacy") associated with a withdrawal syndrome with anxiety features. Of interest, the activity of locus coeruleus neurons is a reflective index of these above mentioned behavioral states.
Methods: Using in vivo extracellular unitary recordings, sustained administration of gamma-hydroxybutyrate (40 mg/kg/day via minipump implanted subcutaneously) on the spontaneous and sensory-evoked burst firing of locus coeruleus norepinephrine neurons was assessed in rats.
Results: A 2-day and 10-day gamma-hydroxybutyrate administration decreased the spontaneous firing activity of locus coeruleus neurons by 52% and 54%, respectively, when compared with controls. A similar degree of attenuation on evoked burst firing of norepinephrine neurons also occurred in these rats (2-day gamma-hydroxybutyrate: 47% and 10-day gamma-hydroxybutyrate: 58%), when compared with controls. In contrast, rats treated with gamma-hydroxybutyrate for 10 days followed by removal of the minipump for 36 hours resulted in a 33% augmentation in spontaneous locus coeruleus activity as compared with controls. Furthermore, a robust 79% increase in burst firing in response to paw-pinch was exhibited in theses rats.
Conclusions: Chronic gamma-hydroxybutyrate treatment inhibits the spontaneous and sensory-evoked burst firing of locus coeruleus norepinephrine neurons, whereas these indices are enhanced during drug withdrawal. The alteration in norepinephrine activity during chronic gamma-hydroxybutyrate administration may contribute to the ability of this agent to induce sleep and regulate narcoleptic episodes. Enhanced norepinephrine activity during withdrawal may be related to symptoms of anxiety on rapid termination of this drug in abusers.
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Gamma-hydroxybutyrate receptor function determined by stimulation of rubidium and calcium movements from NCB-20 neurons
Kemmel V, Taleb O, Andriamampandry C, Aunis D, Maitre M
Neuroscience 116(4), 1021-31 (2003) (

Gamma-Hydroxybutyrate is derived from GABA in brain and plays specific functional roles in the CNS. It is thought to exert a tonic inhibitory control on dopamine and GABA release in certain brain areas, through specific gamma-hydroxybutyrate receptors. Apart from modifying certain calcium currents, the specific transduction mechanism induced by stimulation of gamma-hydroxybutyrate receptors remains largely unknown. We investigated the possible contribution of K(+) channels to the hyperpolarization phenomena generally induced by gamma-hydroxybutyrate in brain, by monitoring (86)Rb(+) movements in a neuronal cell line (NCB-20 cells), which expresses gamma-hydroxybutyrate receptors. Physiological concentrations of gamma-hydroxybutyrate (5-25 microM) induce a slow efflux of (86)Rb(+), which peaks at 5-15 min and returns to baseline levels 20 min later after constant stimulation. This effect can be reproduced by the gamma-hydroxybutyrate receptor agonist NCS-356 and blocked by the gamma-hydroxybutyrate receptor antagonist 6,7,8,9-tetrahydro-5-[H]-benzocycloheptene-5-ol-4-ylidene. The GABA(B) receptor antagonist CGP 55845 has no effect on gamma-hydroxybutyrate-induced (86)Rb(+) efflux. The pharmacology of this gamma-hydroxybutyrate-dependent efflux of (86)Rb(+) is in favor of the involvement of tetraethylammonium and charybdotoxin insensitive, apamin sensitive Ca(2+) activated K(+) channels, identifying them as small conductance calcium activated channels. We demonstrated a gamma-hydroxybutyrate dose-dependent entry of calcium ions into NCB-20 neuroblastoma cells at resting potential. Electrophysiological data showed that this Ca(2+) entry corresponded mainly to a left-hand shift of the current/voltage relation of the T-type calcium channel. This process must at least partially trigger small conductance calcium activated channel activation leading to gamma-hydroxybutyrate-induced hyperpolarization.
____ ___ __ _

Cloning and characterization of a rat brain receptor that binds the endogenous neuromodulator γ-hydroxybutyrate
Christian Andriamampandry, Omar Taleb, Sandrine Viry, Claude Muller, Jean Paul Humbert, Serge Gobaille, Dominique Aunis, and Michel Maitre
The FASEB Journal express article (2003) (

γ-Hydroxybutyrate (GHB) is an endogenous neuromodulator with therapeutical applications in anesthesia, sleep disorders, and drug addiction. We report the cloning of a GHB receptor from a rat hippocampal cDNA library. This receptor has a molecular mass of 56 kDa and belongs to the seven-transmembrane receptor family. The peptidic sequence has no significant homology with any known receptor, including GABAB receptors. Its mRNA is restricted to the brain and is particularly abundant in the hippocampus, cortex, striatum, thalamus, olfactory bulbs, and cerebellum, matching the distribution of GHB binding sites in rat brain. Southern blot revealed the presence of homologous sequences in several species including the human. Binding assays on transfected CHO cells showed a dissociation constant (Kd) of 426 nM for GHB and no affinity for GABA, baclofen, or glutamate. In patch-clamp experiments, transfected CHO cells revealed a functional G-protein-coupled receptor as demonstrated by GTP-?-S-induced irreversible activation. Application of 0.1-15 µM GHB specifically induced an inward current at negative membrane potentials that was not reproduced by application of baclofen (10 µM). CGP-55845, a GABAB receptor antagonist, did not inhibit the GHB-induced response nor did the GHB receptor antagonist NCS-382, suggesting that the GHB receptor system includes several subtypes.
____ ___ __ _

Comparison of the actions of γ-butyrolactone and 1,4-butanediol in Swiss–Webster mice
Christopher M. de Fiebre, Nancy Ellen C. de Fiebre, Scott L. Coleman and Michael J. Forster
Pharmacology Biochemistry and Behavior 77(4), 705-710 (2004) (

The abuse of γ-hydroxybutyrate (GHB) and two of its precursors, γ-butyrolactone (GBL) and 1,4-butanediol (1,4-BD) are recognized as a public health concern. Here, we report dose–response and time-course analyses for effects of GBL and 1,4-BD on locomotor activity and body temperature in Swiss–Webster mice. Locomotor activity was measured for 2 h following a single injection of one of four doses of each agent plus a saline vehicle control. At 50 mg/kg, GBL produced an initial depression of locomotor activity which was followed by stimulation of locomotor activity. In contrast, 1,4-BD at 50 mg/kg stimulated locomotor activity without producing any depression of activity. At higher doses, GBL produced primarily a dose-dependent decrease in locomotor activity that returned to baseline within 50 min. In contrast, 1,4-BD produced an initial depression which was followed by stimulation of activity. Body temperature was measured rectally across a 2.5-h time course following injection with either agent. Both drugs produced hypothermia with peak effects occurring at 20 and 30 min for both drugs for the lower and higher dose, respectively. At 150 mg/kg, GBL produced a greater hypothermic response; however, no differences in hypothermic response were observed at 100 mg/kg. These studies demonstrate that the precursor drugs to GHB have some differential actions from each other.

The Hive - Clandestine Chemists Without Borders
(Hive Bee)
06-13-04 17:12
No 513170
User Picture 
      Novel GHB ligand     

4-Hydroxy-trans-2-nonenoic acid is a gamma-hydroxybutyrate receptor ligand in the cerebral cortex and hippocampus.
Murphy TC, Poppe C, Porter JE, Montine TJ, Picklo Sr MJ.
J Neurochem. 2004 Jun;89(6):1462-70.

Abstract Elevated production of 4-hydroxy-trans-2-nonenal (HNE) occurs in numerous neurological disorders involving oxidative damage. HNE is metabolized to the non-toxic 4-hydroxy-trans-2-nonenoic acid (HNEAcid) by aldehyde dehydrogenases in the rat cerebral cortex. Based upon the structural similarity of HNEAcid to ligands of the gamma-hydroxybutyrate (GHB) receptor, we hypothesized that HNEAcid is an endogenous ligand for the GHB receptor. HNEAcid displaced the specific binding of the GHB receptor ligand (3)H-NCS382 (30 nm) in membrane preparations of human frontal cerebral cortex and whole rat cerebral cortex with IC(50s) of 3.9 +/- 1.1 and 5.6 +/- 1.2 micro m, respectively. Inhibition was attenuated when the carboxyl group of HNEAcid was replaced with an aldehyde or an alcohol. HNEAcid (300 micro m) did not displace the binding of beta-adrenergic receptor and GABA(B) receptor antagonists, demonstrating the selectivity of HNEAcid for the GHB receptor. HNEAcid is formed in homogenates of human frontal cortical gray matter in an NAD(+)-dependent (V(Max), 0.71 nmol/min/mg) and NADP(+)-dependent (V(Max), 0.12 nmol/min/mg) manner. Lastly, (3)H-NCS382 binding is elevated 2.7-fold with age in the cerebral cortex of rats. Our data demonstrate that an HNE metabolite, formed in rat and human brain, is a signaling molecule analogous to other bioactive lipid peroxidation products.

Can someone post full text?
(Hive Bee)
06-13-04 17:48
No 513176
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      GHB analogs - J med chem
(Rated as: excellent)

Weird that this didn't seem to bee posted before, although it is referenced in here:

Analogues of gamma-hydroxybutyric acid. Synthesis and binding studies.
Bourguignon JJ, Schoenfelder A, Schmitt M, Wermuth CG, Hechler V, Charlier B, Maitre M.
J Med Chem. 1988 May;31(5):893-7.

Substituted 4-hydroxybutyric (GHB) or trans-4-hydroxycrotonic acids (T-HCA) and structurally related compounds were synthesized and submitted to [3H]GHB binding. Structure-activity relationships studies highlighted for [3H]GHB binding (a) the necessity of a nonlactonic, relatively extended conformation of the gamma-hydroxybutyric chain, (b) the existence of some bulk tolerance in the vicinity of the hydroxyl group, and (c) the high sensitivity toward isosteric replacements of the carboxyl or the hydroxyl groups. T-HCA has been recently identified as a naturally occurring substance in the central nervous system (CNS) and shows a better affinity than GHB. Our findings are in favor of the presence in the CNS of specific GHB binding sites, which are different from the GABA and the picrotoxin binding sites, and for which T-HCA may be an endogenous ligand.
(Hive Bee)
06-13-04 19:36
No 513188
      Fulltext: Novel GHB receptor ligand
(Rated as: excellent)

Here's the full article for you 7is:

4-Hydroxy-trans-2-nonenoic acid is a gamma-hydroxybutyrate receptor ligand in the cerebral cortex and hippocampus.
Murphy TC, Poppe C, Porter JE, Montine TJ, Picklo Sr MJ.
Journal of Neurochemistry
2004, 89 (6), 1462-1470

Elevated production of 4-hydroxy-trans-2-nonenal (HNE) occurs in numerous neurological disorders involving oxidative damage. HNE is metabolized to the non-toxic 4-hydroxy-trans-2-nonenoic acid (HNEAcid) by aldehyde dehydrogenases in the rat cerebral cortex. Based upon the structural similarity of HNEAcid to ligands of the gamma-hydroxybutyrate (GHB) receptor, we hypothesized that HNEAcid is an endogenous ligand for the GHB receptor. HNEAcid displaced the specific binding of the GHB receptor ligand (3)H-NCS382 (30 nm) in membrane preparations of human frontal cerebral cortex and whole rat cerebral cortex with IC(50s) of 3.9 +/- 1.1 and 5.6 +/- 1.2 micro m, respectively. Inhibition was attenuated when the carboxyl group of HNEAcid was replaced with an aldehyde or an alcohol. HNEAcid (300 micro m) did not displace the binding of beta-adrenergic receptor and GABA(B) receptor antagonists, demonstrating the selectivity of HNEAcid for the GHB receptor. HNEAcid is formed in homogenates of human frontal cortical gray matter in an NAD(+)-dependent (V(Max), 0.71 nmol/min/mg) and NADP(+)-dependent (V(Max), 0.12 nmol/min/mg) manner. Lastly, (3)H-NCS382 binding is elevated 2.7-fold with age in the cerebral cortex of rats. Our data demonstrate that an HNE metabolite, formed in rat and human brain, is a signaling molecule analogous to other bioactive lipid peroxidation products.
(Chief Bee)
06-14-04 01:27
No 513230
User Picture 
      GHB: GABA-B and Glutamatergic Mechanisms
(Rated as: excellent)

Role of GABAB receptors in the sedative/hypnotic effect of γ-hydroxybutyric acid
Mauro A. M. Caraia, Giancarlo Colombo, Giuliana Brunettia, Samuele Melis, Salvatore Serra, Giovanni Vacca, Sarah Mastinu, Angelo Maria Pistuddi, Costantino Solinas, Giorgio Cignarella, Giovanna Minardi and Gian Luigi Gessa
European Journal of Pharmacology, 428(3), 315-321 (2001) (

The present study was aimed at identifying the receptor systems involved in the mediation of the sedative/hypnotic effect of γ-hydroxybutyric acid (GHB) in DBA mice. Administration of the putative antagonist of the GHB binding site, 6,7,8,9-tetrahydro-5-hydroxy-5H-benzocyclohept-6-ylideneacetic acid (NCS-382; 50–500 mg/kg, i.p.), significantly increased the duration of loss of righting reflex induced by GHB (1000 mg/kg, i.p.). In contrast, the GABAB receptor antagonists, (2S)(+)-5,5-dimethyl-2-morpholineacetic acid (SCH 50911; 25–100 mg/kg, i.p.) and (3-aminopropyl)(cyclohexylmethyl)phosphinic acid (CGP 46381; 12.5–150 mg/kg, i.p.), completely prevented the sedative/hypnotic effect of GHB. SCH 50911 (100 and 300 mg/kg, i.p.) was also capable to readily reverse the sedative/hypnotic effect of GHB (1000 mg/kg, i.p.) in mice that had lost the righting reflex. SCH 50911 (100 mg/kg, i.p.) also completely abolished the sedative/hypnotic effect of the GABAB receptor agonist, baclofen. These results indicate that the sedative/hypnotic effect of GHB is mediated by the stimulation of GABAB receptors and add further support to the hypothesis that the GABAB receptor constitutes a central site of action of GHB.
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γ-Hydroxybutyrate modulation of glutamate levels in the hippocampus: an in vivo and in vitro study
Luca Ferraro, Sergio Tanganelli, William Thomas O'Connor, Walter Francesconi, Antonella Loche, Gian Luigi Gessa, Tiziana Antonelli
Journal of Neurochemistry 78(5), 929-939 (2001) (http:///

The effect of γ-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 γ-hydroxybutyric acid (10nM-1mM) concentration-dependently influenced glutamate levels: γ-hydroxybutyric acid (100 and 500nM) increased glutamate levels; 100 and 300µM concentrations were ineffective; whereas the highest 1mM concentration reduced local glutamate levels. The stimulant effect of γ-hydroxybutyric acid (100nM) was suppressed by the locally co-perfused γ-hydroxybutyric acid receptor antagonist NCS-382 (10µM) but not by the GABAB receptor antagonist CGP-35348 (500µM). Furthermore, the γ-hydroxybutyric acid(1mM)-induced reduction in CA1 glutamate levels was counteracted by NCS-382 (10µM), 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 100nM) enhanced both the spontaneous and K+-evoked glutamate efflux, respectively, both effects being counteracted by NCS-382 (100nM), but not by CGP-35348 (100µM). These findings indicate that γ-hydroxybutyric acid exerts a concentration-dependent regulation of hippocampal glutamate transmission via two opposing mechanisms, whereby a direct γ-hydroxybutyric acid receptor mediated facilitation is observed at nanomolar γ-hydroxybutyric acid concentrations, and an indirect GABAB receptor mediated inhibition predominates at millimolar concentrations.

The Hive - Clandestine Chemists Without Borders
(Chief Bee)
07-09-04 16:35
No 518398
User Picture 
      Reviews on GHB Withdrawal & Analogs
(Rated as: excellent)

gamma-Hydrobutyric acid (GHB) and its chemical modifications: A review of the GHBergic system
Waszkielewicz A, Bojarski J.
Pol J Pharmacol. 56(1), 43-9 (2004) (

gamma-Hydroxybutyric acid (GHB) is a naturally occurring substance with function of an inhibitory neurotransmitter in the central nervous system in mammals. GHB can be used as a medicine in narcolepsy (Xyrem) and for general anesthesia (sodium oxybate). It is also a popular drug of abuse, causing coma, addiction and severe withdrawal syndrome, and, therefore, demanding thorough studies on the GHBergic system and expanded research on toxicology of this compound. The aim of this review is to present the proved and some suggested mechanisms of its action from pharmacological point of view, which may help to properly treat intoxication or other pathological states caused by GHB ingestion. Some new GHB derivatives studied for analogous action and their present use are also described.
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Clinical features and management of gamma-hydroxybutyrate (GHB) withdrawal: a review
McDonough M, Kennedy N, Glasper A, Bearn J
Drug Alcohol Depend. 75(1), 3-9 (2004) (

Aim: To examine the clinical course of gamma-hydroxybutyrate (GHB) withdrawal and generate management guidelines. Design: Review and analysis of all published reports of GHB or GHB precursor withdrawal identified from electronic searches. Findings: In total, 38 cases of GHB or GHB precursor withdrawal were identified, 36 of which were from the US. A rapidly deteriorating course into delirium (53% of cases) was typical for heavily dependent users. Symptoms were broadly similar to alcohol withdrawal but often occurred earlier in usage with delirium being associated with severe dependence as determined by more frequent ingestion. High dose benzodiazepines were effective in pharmacological management of GHB withdrawal. In benzodiazepine refractory cases withdrawal responded to other sedative agents, mainly pentobarbital or chloral hydrate. No withdrawal seizures but one death was recorded.  Conclusions: GHB withdrawal is potentially life threatening and requires vigorous clinical management, preferably as an inpatient for severe cases. A management algorithm is proposed.

The Hive - Clandestine Chemists Without Borders
(Chief Bee)
07-14-04 22:12
No 519445
User Picture 
      Acute Toxicity From Home-Brewed GHB
(Rated as: good read)

Acute Toxicity From Home-Brewed Gamma Hydroxybutyrate
Barbara Hodges, MD, James Everett, MD, PhD
J Am Board Fam Pract 11(2), 154-157 (1998)


Gamma hydroxybutyrate (GHB) has become an increasingly dangerous, illicitly marketed substance with numerous potential health hazards.[1-8] GHB was originally developed as an anesthetic but was withdrawn as a result of unwanted side effects.[4] Marketed for the treatment of narcolepsy and alcohol withdrawal, it was used illicitly as a growth hormone and fat-burning drug by body builders. It has also been used as a date-rape drug.[1,2,9,10] In 1990 the Food and Drug Administration banned the sale of GHB in the United States.

Common street names for gamma hydroxybutyrate include GHB, Liquid E, Liquid X, and Scoop. It is also referred to as gamma hydroxy, 4-hydroxybutyrate, gamma hydroxybutyrate sodium, and sodium oxybate. This drug, reported to stimulate growth hormone release, body building, and weight loss, as well as act as a sleeping potion,[1-5] is also associated with a number of serious neurologic, cardiovascular, respiratory, and gastrointestinal side effects.[10-15] We describe a case of GHB abuse from a home-brewed preparation resulting in toxicity, withdrawal symptoms, and rhabdomyolysis. The withdrawal symptoms included insomnia, anxiety, and tremors, which resolved within 9 days.[13,16] This case is the first reported describing GHB overdose associated with withdrawal symptoms and rhabdomyolysis.

GHB became popular as a drug to help assault women.[1,2,10] Several properties of this drug account for its popularity as an tool in sexual assault. First, although no longer legally accessible, GHB is easily and cheaply manufactured in the home. Second, the drug is colorless, tasteless, and odorless, and it mixes well with all liquid and foods; as a result, it is easy for an unaware person to consume this drug. Third, shortly after consumption of GHB, sedation is rapid, and amnesia is complete.[1] The sedated person will not recall any events that occurred shortly before or during the period of sedation, including rape, physical abuse, or even the person they were with shortly before becoming unconscious. These effects make GHB an ideal agent of assault. A rapist could sexually assault a woman, and the victim would not recall the details of the experience. As a result of the victim's amnesia, the rape might not be reported.

GHB is also popular among body builders. Its popularity increased after GHB was reported to enhance muscle mass.[1] Although the muscle-building properties of GHB have never been proven, GHB remains popular among body builders as an aid to increasing muscle mass.[1,3]

GHB became popular as an aid for weight loss after it was advertised as the active ingredient in Love Potion #8 1/2. This substance was sold in nutrition stores and to the public by mail order under the generic name of GHB. Among the most falsely advertised properties of Love Potion #8 1/2 was that GHB could help a person lose weight by suppressing appetite. Although there is no reported evidence that this claim is true, GHB continues to be used as an appetite suppressant.[4,17]

Case Report

A 27-year-old white man was brought to the emergency department with altered mental status, agitation, hallucinations, and seizures. He became more obtunded but responded to deep pain. Physicians were unable to obtain a history from the patient or his family. The emergency department physician accomplished endotracheal intubation. The patient was given oxygen and intravenous fluids, and cardiac monitoring and pulse oximetry were started. A urinary catheter was inserted, and urine and blood samples were sent for analysis. A total of 4 mg of naloxone hydrochloride and 50 percent dextrose was administered intravenously without effect. The patient's pupils were decreased in size to 3 mm but remained equal and reactive, and he was hypertensive (blood pressure 180/100 mmHg). An electrocardiogram showed sinus tachycardia with a rate of 115 beats per minute. The respiratory rate was 16/min with somewhat shallow respirations.

A nasogastric tube was then inserted for gastric lavage followed by oral administration of 50 g of activated charcoal. One hour after arrival the patient became only moderately alert but continued to be severely agitated and have hallucinations and seizure activity. He attempted to remove his endotracheal tube. Information obtained from the immediate family and spouse described the patient as a weight builder who had been using home-brewed GHB for 7 years. His wife stated that her husband consumed 1 tablespoon of GHB four times a day. He had had numerous episodes of impaired psychomotor skills while operating a motor vehicle.

Results of the serum and urine drug screening tests were negative. No serum ethanol was reported. A prominent hilum, without evidence of acute disease, was seen on the portable chest radiograph. Computed tomographic scans of his head with and without contrast were negative. An electrocardiogram showed sinus tachycardia with a heart rate of 113 beats per minute and nonspecific ST segment elevation in precordial leads V1 and V2. Arterial blood gas measurements were pH 7.33, pCO2 26 mmHg, and bicarbonate 22 mEq/L. Serum electrolytes were sodium 142 mEq/L, potassium 4.0 mEq/L, chloride 99 mEq/L, urea nitrogen 52 mg/dL, creatinine 2.0 mg/dL, and serum glucose 71 mg/dL. The anion gap was 26.4 mmol/L. Calculated serum osmolality was 275 mOsm/kg H2O and measured 297 mOsm/kg H2O. The white cell count was 14,000 /µL with a normal differential. Hemoglobin was 17.6 mg/dL. Total creatine kinase was 34,500 mg/dL, lactic dehydrogenase 559 U/L, fibrinogen 305 mg/dL, and aspartate aminotransferase 190 U/L. Prothrombin time was 11.2 sec with an international normalized ratio of 0.83. Lumbar puncture was performed, and results were negative. Viral cultures of lumbar puncture grew no organisms.

Approximately 3 hours after arrival, the patient became more alert but continued to be belligerent, severely agitated, and confused. He was admitted to the intensive care unit, sedated, paralyzed, and subsequently intubated secondary to rhabdomyolysis. He continued to be combative, agitated, and uncooperative throughout his stay in the intensive care unit and after extubation on the 5th day. His creatine kinase level decreased to 1300 mg/dL with vigorous intravenous hydration, and by day 7 his temperature, blood pressure, and heart rate remained stable, and results of a physical examination were unremarkable. During his hospitalization he was examined by a consulting psychiatrist, nephrologist, and neurologist. Recommendations were followed. The psychiatrist diagnosed the patient's condition as Axis I (acute brain disorder with delirium secondary to illicit drug use). Axis II was GHB withdrawal.

Arrangements were made to transfer the patient from the intensive care unit to a hospital for addiction management and detoxification. The patient had a good support system at home. His mother was instrumental in making arrangements to assist in placing him in an addiction center for inpatient therapy.


GHB is an illegal drug in the United States.[10] It is falsely promoted for strength training, muscle building, weight loss, and inducing sleep. GHB is produced as a white powder, but it is more commonly encountered as an odorless, clear liquid. It has a salty taste that is masked when mixed with a drink. GHB will remain in a person's blood for approximately 4 hours and will remain detectable in the urine until it has been excreted.[4,6,9,13]

Illicit use of GHB often involves oral doses of 1/4 teaspoon to 4 tablespoons. It has been associated with numerous central nervous system effects, and reported complications include convulsions, confusion, seizure-like activity, shortness of breath, and combative and self-injurious behavior followed by coma. Less severe effects include drowsiness, dizziness, hypomania, hallucinations, headache, confusion, nausea, vomiting, diarrhea, uncontrollable shaking, transient amnesia, and incontinence. In all reported cases, symptoms resolved rapidly with drug discontinuation. Acute symptoms usually resolve within 8 hours. Body builders usually ingest 1 to 2 teaspoons (2.5 to 5.0 g) per day.[8,10,17-19]

Because GHB is an illegal drug in the United States, much of the drug sold on the street is home-brewed and laced with accidental contaminants, the most common and dangerous of which is lye. No antidote to GHB exists. To date there have been no reported deaths in the medical literature directly attributed to GHB. Physical dependence was reported in one source.[15] Gamma hydroxybutyrate is known to act synergistically with alcohol, benzodiazepines, narcotics, and other neuroleptic medications to produce central nervous system and respiratory depression.[6,7] This case is the first report of chronic high-dose abuse with withdrawal syndrome.

In our case, the patient took GHB to increase his muscle mass, and his use of GHB resulted in an acute episode of seizures, rhabdomyolysis, and a profound coma with respiratory depression. Rhabdomyolysis most likely was secondary to his seizure activity. The diagnosis of GHB abuse was supported by the patient's history of ingestion of GHB as reported by his family. The patient also admitted to taking increasing amounts of GHB to achieve euphoria. Comprehensive urine drug testing did not identify other central nervous system depressants.

With supportive treatment, the symptoms of acute GHB toxicity resolved within 8 hours. The patient began to experience withdrawal symptoms within 24 hours, however, and subsequent rhabdomyolysis required sedation with ventilatory support. During the withdrawal period, he experienced tremors, shakes, insomnia, and anxiety and was stabilized by day 7 of intensive care hospitalization.

The mechanism by which GHB produces its clinical effects remains unknown despite extensive investigation. GHB is undetectable by routine toxicology testing and does not appear to alter routine laboratory studies drastically. The lack of rapid distinctive diagnostic markers mean that all other causes of acute unresponsiveness must be ruled out even when a history of GHB is known.[13,19]

Diagnosis of GHB is made after detecting toxic levels of GHB in either serum or urine of a patient suspected to have ingested toxic levels of GHB. The diagnosis is not made based on clinical signs and symptoms, but the clinical signs and symptoms and the history should alert the physician to the possibility of GHB toxicity, for which a drug-specific screening test should be ordered. Treatment of GHB overdose is symptomatic and supportive care. Special interventions include continuous observation, cardiac and pulse oximetry monitoring, airway maintenance, and ventilatory support as needed. Temperature regulation might also be indicated if hypothermia develops. Intravenous access should be maintained. Standard treatment of polysubstance overdose, such as gastric lavage and the administration of activated charcoal, is indicated. If GHB toxicity is strongly suspected, then induction of vomiting should be avoided, because the patient can suddenly experience decreased alertness, which would increase the risk of aspiration. Naloxone hydrochloride, flumazenil (Romazicon), or both should be considered because of possible multiple drug abuse. On recovery the patient's mental status should be assessed and substance abuse counseling arranged. Cases should be reported to local poison control centers so that accurate statistical data can be collected regarding the incidence of GHB toxicity.[7]


GHB is a dangerous drug with potential for abuse among all segments of the population. Its use can be associated with coma and seizure-like activity. Abuse can become more widespread as reports of euphoric effects increase. Although further sale of this drug is prohibited, new cases with acute symptoms continue to be reported.[1,2] Family physicians should be alerted to the potent effects of GHB. Family physicians should also educate their patients about the true dangers of this unusual recreational drug and ask their patients who they suspect or know to be body builders about their use of any dietary or muscle-building supplements. Additionally, they should ask patients about the use of any other substances they might be using to increase muscle mass and warn them about the dangers associated with using GHB.


1. Marwick C. Coma-inducing drug GHB may be reclassified. JAMA 1997;277:1505-6.
2. Gamma hydroxy butyrate use - New York and Texas, 1995-1996. MMWR Morbid Mortal Wkly Rep 1997;46:281-3.
3. Friedman J, Westlake R, Furman M. "Grievous bodily harm:" GHB abuse leading to a Wernicke-Korsakoff syndrome. Neurology 1996; 46:469-71.
4. Steele MT, Watson WA. Acute poisoning from gamma hydroxybutyrate (GHB). Mo Med 1995;92:354-7.
5. Einspruch BC, Clark SM. Near fatality results from health food store sleeping potion. Tex Med 1992; 88:10.
6. Ross TM. Gamma hydroxybutyrate overdose: two cases illustrate the unique aspects of this dangerous recreational drug. J Emerg Nurs 1995;21:374-6.
7. Poisindex information system. Atlanta: Microdex, Inc, 1974-1997: vol 91.
8. Stephens BG, Baselt RC. Driving under the influence of GHB? J Anal Toxicol 1994;18:357-8.
9. Chin MY, Kreutzer RA, Dyer JE. Acute poisoning from gamma-hydroxybutyrate in California. West J Med 1992;156:380-4.
10. McKenna M. CDC issues warning on date rape drug. The Atlanta Journal-Constitution, 1997 April 4:A3.
11. Multistate outbreak of poisonings associated with illicit use of gamma hydroxybutyrate. MMWR Morbid Mortal Wkly Rep 1990;39:861-3.
12. Stehlin D. Georgia man arrested in GHB seizure (gamma hydroxybutyrate). FDA Consumer 1994; 28:30-2.
13. Dyer JE. Gamma hydroxybutyrate: a health-food product producing comma and seizure-like activity. Am J Emerg Med 1991;9:321-4.
14. Hoffman RS. Gamma hydroxybutyrate. Emergency Med 1992; 9: 92.
15. Ferrara SD, Tedeschi L, Frison G, Rossi A. Fatality due to gamma-hydroxybutyric acid (GHB) and heroin intoxication. J Forensic Sci 1995;40:501-4.
16. Galloway GP, Frederick SL, Staggers F Jr. Physical dependence on sodium oxybate. Lancet 1994;343:57.
17. Mack RB. Love potion number 81/2. Gamma-hydroxybutyrate poisoning. N C Med J 1993;54:232-3.
18. Luby S, Jones J, Zalewski A. GHB use in South Carolina. Am J Public Health 1992;82:128.
19. Palatini P, Tedeschi L, Frison G, Padrini R, Zordan R, Orlando R, et al. Dose-dependent absorption and elimination of GHB in healthy volunteers. Eur J Clin Pharmacol 1993;45:353-6.

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07-14-04 22:51
No 519448
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      Forensic Science Update: gamma-Hydroxybutyrate
(Rated as: good read)

Forensic Science Update: Gamma-Hydroxybutyrate (GHB)
Carl S. Hornfeldt, Kevin Lothridge, J. C. Upshaw Downs
Forensic Science Communications, Vol. 4, No. 1 (2002) (

The past decade has seen a dramatic increase in the use of gamma-hydroxybutyrate (GHB) and related substances. Because of their current popularity as recreational compounds of abuse and their unfortunate effectiveness as "drug-facilitated sexual assault" agents, forensic scientists are being called upon to determine the role of these compounds in overdose and sexual assault cases with increasing frequency. The objective of this paper is to provide an update on the history, mechanism, clinical effects, legal status, legitimate use, and laboratory analysis of these compounds.

The Hive - Clandestine Chemists Without Borders
(Chief Bee)
11-13-04 16:08
No 541385
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      Symposium on γ-hydroxybutyrate (GHB)
(Rated as: excellent)

Symposium on γ-hydroxybutyrate (GHB)
The Clinical Toxicology of GHB – an Introduction

Jeffrey Brent, MD, PhD, Toxicological Reviews, 23(1), 1 (2004)

First synthesised in 1960 by Laborit as a y-aminobutyric acid (GABA) analogue that would traverse the blood-brain barrier, γ-hydroxybutyrate (GHB) has become a molecule of great toxicological and medical importance. In the decades after its synthesis, GHB found medical application as an induction agent for general anaesthesia. Although not widely utilised for this purpose any more, it is presently being used worldwide as a therapeutic agent in the treatment of cataplexy and ethanol withdrawal and dependence.

Toxicological interest in GHB quickly followed its introduction into clinical medicine. Starting in the late 1970s GHB was promoted as a supplement for muscle building. The rationale for this was the attempt to promote a spike of growth hormone secretion associated with the induction of sleep. It was felt that GHB might thus boost endogenous levels of this hormone. As its use and availability became widespread, and knowledge of its effects diffused over the Internet, GHB evolved as a club drug and agent of date rape. Attempts to restrict the availability of GHB led to the realisation that its physiological precursors y-butyrolactone (GBL) and 1,4-butanediol (1,4-BD) could be ingested and thus act as prodrugs.

In this issue of Toxicological Reviews, we present a state-of-the-art print symposium on GHB and its analogues. Each of the papers presented represent the most detailed publications in their respective areas ever published. The symposium begins with a comprehensive overview of the neurobiology and neuropharmacology of GHB by Wong et al. In this paper, they review GHB metabolism and the neuropharmacology of GHB and GABA-B receptors, showing them to be two distinct physiological entities. Despite the presence of a distinct GHB receptor, Wong et al. demonstrate that it is the interaction of this agent with the GABA-B receptor that appears to be the mechanism for the multiple neurophysiological effects of GHB as an endogenous neuroactive molecule, medication and drug of abuse.

The paper by Palmer provides an in-depth analysis of the toxicology of GBL and 1,4-BD. In this paper, Palmer describes the physiological conversion of these precursors to GHB as well as the process of ex vivo synthesis of GBH from GBL. Also provided is a detailed discussion of the US regulatory and legislative history of GHB and its analogues leading to GHB’s unique designation by the US FDA as a so-called schedule I drug (high potential for abuse preparation without justifying medical utility) and as a pharmaceutical preparation a schedule III drug (lower potential for abuse than schedule I or II drugs and with accepted medical use). Palmer further offers an erudite review of the clinical presentation of toxicological effects of GHB, GBL and 1,4-BD.

The article by Morris-Kukoski addresses the ‘analytical-gap’ between the numerous yet complex choices for quantitative determination of GHB and the very limited options for simple qualitative, but potentially clinically more useful, assays. To facilitate an understanding of GHB detection techniques, this article reviews the fundamental concepts of gas chromatography and mass spectrometry and the application of these techniques to quantitative confirmatory GHB analyses. Yet, the goal of a clinically useful rapid GHB screening assay has been elusive. Morris-Kukoski describes the simple colorimetric assays and the more complex analyses that although developed, have not found widespread clinical utility. Also included in this paper is a discussion of sample storage considerations and methods for accounting for endogenous GHB.

With widespread use of GHB and its prodrugs, reports of tolerance to its effects, and a withdrawal syndrome provoked by its discontinuation, have begun appearing in the medical literature. The paper by Tarabar and Nelson describes the clinical features of GHB (and GBL) tolerance and withdrawal, concluding with a neuropharmacologically based discussion of the treatment of this potentially life-threatening withdrawal syndrome.

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γ-Hydroxybutyric Acid: Neurobiology and Toxicology of a Recreational Drug
C. Guin Ting Wong; Katherine F.Y. Chan; K. Michael Gibson; O. Carter Snead III
Toxicological Reviews, 23(1), 3-20 (2004) (

γ-Hydroxybutyric acid (GHB) is a short-chain fatty acid that occurs naturally in mammalian brain where it is derived metabolically from ?-aminobutyric acid (GABA), the primary inhibitory neurotransmitter in the brain. GHB was synthesised over 40 years ago and its presence in the brain and a number of aspects of its biological, pharmacological and toxicological properties have been elucidated over the last 20–30 years. However, widespread interest in this compound has arisen only in the past 5–10 years, primarily as a result of the emergence of GHB as a major recreational drug and public health problem in the US. There is considerable evidence that GHB may be a neuromodulator in the brain. GHB has multiple neuronal mechanisms including activation of both the ?-aminobutyric acid type B (GABAB) receptor, and a separate GHB-specific receptor. This complex GHB-GABAB receptor interaction is probably responsible for the protean pharmacological, electroencephalographic, behavioural and toxicological effects of GHB, as well as the perturbations of learning and memory associated with supra-physiological concentrations of GHB in the brain that result from the exogenous administration of this drug in the clinical context of GHB abuse, addiction and withdrawal. Investigation of the inborn error of metabolism succinic semialdehyde deficiency (SSADH) and the murine model of this disorder (SSADH knockout mice), in which GHB plays a major role, may help dissect out GHB- and GABAB receptor-mediated mechanisms. In particular, the mechanisms that are operative in the molecular pathogenesis of GHB addiction and withdrawal as well as the absence seizures observed in the GHB-treated animals.
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γ-Butyrolactone and 1,4-Butanediol: Abused Analogues of γ-Hydroxybutyrate
Robert B. Palmer,
Toxicological Reviews, 23(1), 21-31 (2004) (

γ-Hydroxybutyrate (GHB) is a GABA-active CNS depressant, commonly used as a drug of abuse. In the early 1990s, the US Drug Enforcement Administration (DEA) warned against the use of GHB and restricted its sale. This diminished availability of GHB caused a shift toward GHB analogues such as ?-butyrolactone (GBL) and 1,4-butanediol (1,4-BD) as precursors and surrogates. Both GBL and 1,4-BD are metabolically converted to GHB. Furthermore, GBL is commonly used as a starting material for chemical conversion to GHB. As such, the clinical presentation and management of GBL and 1,4-BD intoxication shares a great deal of common ground with that for GHB. This similarity exists not only for acute intoxication but also for withdrawal in those patients with a history of extended high-dose abuse. This review examines the history of GHB analogue abuse as well as the clinical presentation and management of acute intoxication and withdrawal associated with abuse of these compounds.
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γ-Hydroxybutyrate: Bridging the Clinical-Analytical Gap
Cynthia L. Morris-Kukoski,
Toxicological Reviews, 23(1), 33-43 (2004) (

Laboratory detection of γ-Hydroxybutyrate (GHB) has been published as early as the 1960s. However, wide-scale use of GHB during the 1990s has led to the development of current analytic methods to test for GHB and related compounds. Detection of GHB and related compounds can be clinically useful in confirming the cause of coma in an overdose patient, determining its potential role in a postmortem victim, as well as evaluating its use in a drug-facilitated sexual assault victim. Analytical method sensitivity must be known in order to determine the usefulness and clinical application. Most laboratory cut-off levels are based on instrument sensitivity and will not establish endogenous versus exogenous GHB levels. Interpretation of GHB levels must include a knowledge base of endogenous GHB, metabolism of GHB and related compounds, as well as postmortem generation. Due to potential analytical limitations in various GHB methods, it is clinically relevant to specifically request for GHB as well as related GHB compounds if they are also in question. Various storage conditions (collection time, types of containers, use of preservatives, storage temperature) can also affect the analysis and interpretation of GHB and related compounds.
____ ___ __ _

The γ-Hydroxybutyrate Withdrawal Syndrome
Asim F. Tarabar; Lewis S. Nelson
Toxicological Reviews, 23(1), 45-49 (2004) (

γ-Hydroxybutyrate (GHB) is an endogenous inhibitory transmitter that, when administered in pharmacological doses, has sedative-hypnotic properties. It is used in anaesthesia for the treatment of narcolepsy/catalepsy and in alcohol/opioid detoxification treatment regimens. Based on its purported anabolic effects, GHB use became established among bodybuilders. As the euphorigenic effects of GHB became publicised, attendees at dance clubs and rave parties began to use it alone or in combination with other psychoactive drugs. Following the ban of GHB in 1990, several precursor products (e.g. ?-butyrolactone, butanediol) became widely used as replacement drugs until their ultimate proscription from lawful use in 2000. GHB and its precursors, like most sedative-hypnotic agents, can induce tolerance and produce dependence. Although many GHB users will experience a mild withdrawal syndrome upon drug discontinuation, those with chronic heavy GHB use can experience severe withdrawal. This syndrome clinically resembles the withdrawal syndrome noted from alcohol and other sedative-hypnotic drugs (e.g. benzodiazepines). Distinct clinical features of GHB withdrawal are its relatively mild and brief autonomic instability with prolonged psychotic symptoms. Patients with fulminant GHB withdrawal require aggressive treatment with cross-tolerant sedative hypnotics, such as benzodiazepines.

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