Common street names:

• Fantasy
• GBH
• GHB
• Grievous Bodily Harm
• Liquid Ecstasy

Precursors:

• Gamma butyrolactone (GBL)
• 1,4 butanediol (1,4BD)

This substance and the precursors are used as cleaning agents, but toxicologically they are most commonly seen as a substance of abuse, as a “Date rape” agent, or as an anabolic agent (although of unknown effectiveness, it is known to stimulate growth hormone (and prolactin) release). GHB is usually prepared as a sodium salt and is in the form of either a white crystalline powder or a colourless, odourless liquid with a salty taste. GBL and 1,4BD are generally only available in a liquid form (which will taste less salty than GHB) and also may be put into capsules or other mixtures.

There are some legitimate uses for these agents in the treatment of narcolepsy and as anaesthetic agents. The major effect is deep sedation with a rapid recovery of consciousness after a few hours. Supportive care is all that is required. Physostigmine has been used to reverse coma with some success but the risks and benefits of this antidote are poorly defined.

Gamma hydroxybutyrate (GHB) is an inhibitory neurotransmitter which predominantly acts through specific GHB receptors. GHB is also produced in small quantities in the central nervous system. In toxic amounts it may also have weak agonist effects on the GABAB receptor (similar to baclofen). Stimulation of GHB receptors leads to a range of effects on other neurotransmitters – in particular it has complex effects on dopaminergic neurones. It thereby acutely stimulates prolactin and growth hormone release (although there is no evidence for a long term anabolic effect as a consequence).(1)

The end result of high concentrations of GHB is a general anaesthetic effect, but it is presumed lesser degrees of intoxication are euphoric through dopaminergic mechanisms.

GHB is also formed from two precursors, gamma butyrolactone (GBL) and 1,4 butanediol (1,4BD). Conversion from GBL involves the enzymes alcohol and aldehyde dehydrogenase. Thus high concentrations of alcohol inhibit this conversion.(see figure) GBL may also act on GABAB receptors.(1)

GHB, GBL and 1,4BD are all absorbed orally, with peak concentrations and effect occurring within 1 to 2 hours. The onset of action is rapid and may be as early as 15 minutes after ingestion. GBL and 1,4BD are very rapidly converted to GHB and the onset of effect and time course is generally similar. GBL is more lipid soluble and may act more quickly and for slightly longer than GHB by virtue of its more rapid absorption and different tissue distribution.(2)

GHB, GBL and 1,4BD are not significantly bound to proteins and have a volume of distribution roughly equal to body water (0.6L/kg).

GHB is rapidly metabolised via the Krebs cycle to water and carbon dioxide.(see figure) A small amount is excreted unchanged in the urine where it may be detected for up to 4 to 6 hours. The elimination half-life of GHB is less than half an hour. This is consistent with the observation that most patients recover consciousness rapidly within 2 hours of presentation to hospital.

The dose ingested will obviously have a major influence on the clinical syndrome. Because this is usually taken as an illicit drug, the actual dose is unknown. However, the dose of GHB that is used to cause anaesthesia is 50mg/kg intravenously.(3) The oral doses used in narcolepsy and for other indications are of the order of 25-100 mg/kg/day (typically about 500mg every 4 hours in adults).(4;5)

A deep coma is characteristic of significant poisoning but generally short lived. In one series a GCS<8 was seen in half of the patients at the time of presentation and one quarter had a GCS of 3.(6) However, the median time to recovery of consciousness was one hour. The most deeply sedated patients still generally recover fully within 6 hours. Endo-tracheal intubation and ventilation may be necessary, and deaths have occurred with all three agents presumably as a result of respiratory arrest.(7;8) Patients may be briefly confused at the time of wakening.

Generalised tonic-clonic seizures, myoclonic jerks and absence seizures have all been reported but are not common.(6;9) Status epilepticus does not occur and supportive treatment is probably all that is required for short-lived seizure activity.

Similar to other causes of coma, mild bradycardia, hypotension or hypothermia may occur. Hypotension responds rapidly to IV fluids. Dyskinesia, dystonia, vomiting and hallucinations may occur occasionally – perhaps due to secondary effects on dopaminergic function.(6;9)

The majority of patients presenting to hospital have ingested other drugs – in particular alcohol and/or stimulants (e.g. amphetamines, MDMA, cocaine) seem to be common.(6) This may obviously lead to atypical presentations.

In patients with coma of unknown cause, an ECG, electrolytes, blood glucose, ABGs and paracetamol level will all be commonly done. No abnormalities are expected in any of these tests from GHB.

Urine & Blood drug screens
Most quick urine screens (immunoassays) do not detect GHB. Specific assays with HPLC are usually required. Only GHB is usually detected in the urine, but all may be detected in the blood. To screen for toxicity only an assay for GHB is required. If GHB is found specific assays for GBL and 1,4BD may identify the presence of the precursor.(7)

GHB will appear in the urine and blood in significant quantities for a short period of time only. Significant poisonings will generally result in positive screens if these are performed while the patient is unconscious. Delayed urine drug screens (e.g. the following day) will be negative.(6) This is for two reasons. First the half-life is short and there are no measurable metabolites. Second, small amounts of GHB and GBL are produced naturally so cut-off points for reporting positive results are set high. (There is also a small amount of post-mortem production of GHB).

GHB, GBL and 1,4BD all present with a very similar clinical picture, and do not differ to a meaningful degree in their toxicity on a weight or molar basis.

Supportive care is usually all that is required. Patients should be nursed on their sides to help maintain their airway. Intubation and sometimes a short period of ventilation may be necessary

Patients may be discharged after they become asymptomatic as long as at least 3 to 4 hours have elapsed since ingestion.

No GI decontamination is warranted due to the rapid absorption, good prognosis and rapid recovery with supportive care alone.

Physostigmine significantly shortens the period of sedation,(3) and has been used to avoid the need for ventilation.(10) The standard dose is 1-2 mg IV given as a slow push over 5 to 10 minutes. The risks and benefits of physostigmine in this situation are poorly defined and would require evaluation in a randomised trial before it could be recommended. Physostigmine may cause adverse effects such as bradycardia and seizures. Patients should have ECG monitoring while it is administered, bradycardia should respond to atropine. The response to physostigmine is typically delayed by 2 to 10 minutes meaning that even in responders there is a period of time in which they may aspirate while awaiting the response. Physostigmine has also been reported to cause sudden fatal deteriorations in tricyclic antidepressant overdose – it should not be administered to comatose patients who have an abnormal ECG (heart block, QRS widening).

Is not indicated due to the very short half-life.

An uneventful recovery is the usual course and no follow up is required. A withdrawal syndrome (clinically similar to alcohol withdrawal) has been reported in regular heavy users.(11)

1. Tunnicliff G. Sites of action of gamma-hydroxybutyrate (GHB)–a neuroactive drug with abuse potential. J Toxicol Clin Toxicol 1997; 35(6):581-590.
2. Arena C, Fung HL. Absorption of sodium gamma-hydroxybutyrate and its prodrug gamma-butyrolactone: relationship between in vitro transport and in vivo absorption. J Pharm Sci 1980; 69(3):356-358.
3. Henderson RS, Holmes CM. Reversal of the anaesthetic action of sodium gamma-hydroxybutyrate. Anaesth Intensive Care 1976; 4(4):351-354.
4. Mamelak M, Scharf MB, Woods M. Treatment of narcolepsy with gamma-hydroxybutyrate. A review of clinical and sleep laboratory findings. Sleep 1986; 9(1 Pt 2):285-289.
5. Maremmani I, Lamanna F, Tagliamonte A. Long-term therapy using GHB (sodium gamma hydroxybutyrate) for treatment-resistant chronic alcoholics. J Psychoactive Drugs 2001; 33(2):135-142.
6. Miro O, Nogue S, Espinosa G, To-Figueras J, Sanchez M. Trends in illicit drug emergencies: the emerging role of gamma-hydroxybutyrate. J Toxicol Clin Toxicol 2002; 40(2):129-135.
7. Zvosec DL, Smith SW, McCutcheon JR, Spillane J, Hall BJ, Peacock EA. Adverse Events, Including Death, Associated with the Use of 1,4-Butanediol. The New England Journal of Medicine 2001; 344(2):87.
8. Mason PE, Kerns WP. Gamma hydroxybutyric acid (GHB) intoxication. Acad Emerg Med 2002; 9(7):730-739.
9. Sporer KA, Chin RL, Dyer JE, Lamb R. Gamma-hydroxybutyrate serum levels and clinical syndrome after severe overdose. Ann Emerg Med 2003; 42(1):3-8. 10. Caldicott DG, Kuhn M. Gamma-hydroxybutyrate overdose and physostigmine: Teaching new tricks to an old drug? Ann Emerg Med 2001; 37:(1):99-102.
11. McDaniel CH, Miotto KA. Gamma hydroxybutyrate (GHB) and gamma butyrolactone (GBL) withdrawal: five case studies. J Psychoactive Drugs 2001; 33(2):143-149.

FDA warning on GBL containing products
www.fda.gov/bbs/topics/ANSWERS/ANS00953.html
H&S information on 1,4 butanediol
http://ntp-support.niehs.nih.gov/NTP_Reports/NTP_Chem_HS_HTML/NTP_Chem1/Radian110-63-4.html
NTP review of 1,4 butanediol
ehp.niehs.nih.gov/ntp/members/tox54/tx54full.pdf