γ-Hydroxybutyric acid (GHB), also known as 4-hydroxybutanoic acid, is a naturally occurring neurotransmitter and a depressant drug. It is a precursor to GABA, glutamate, and glycine in certain brain areas. It acts on the GHB receptor and is a weak agonist at the GABAB receptor. GHB has been used in medicine as a general anesthetic and as treatment for cataplexy, narcolepsy, and alcohol use disorder. It is also used illicitly for performance enhancement, date rape, and recreation.
It is commonly used in the form of a salt, with the conjugate base of GHB being called γ-hydroxybutyrate or oxybate. The sodium (NaGHB, sodium oxybate, or Xyrem) and potassium (KGHB, potassium oxybate) salts are common. GHB is produced as a result of fermentation, and is found in small quantities in some beers and wines, beef, and small citrus fruits.
Succinic semialdehyde dehydrogenase deficiency causes GHB to accumulate in the blood.
Medical uses
GHB is used in medicine in the treatment of narcolepsy and, more rarely, alcohol dependence, although its efficacy for that is uncertain. A 2010 Cochrane review concluded that "GHB appears better than NTX and disulfiram in maintaining abstinence and preventing craving in the medium term (3 to 12 months)". It is sometimes used off-label for the treatment of fibromyalgia. GHB is the active ingredient of the prescription medication sodium oxybate (Xyrem). Sodium oxybate is approved by the U.S. Food and Drug Administration for the treatment of cataplexy associated with narcolepsy and excessive daytime sleepiness (EDS) associated with narcolepsy.
GHB has been shown to reliably increase slow-wave sleep and decrease the tendency for REM sleep in modified multiple sleep latency tests.
The FDA-approved labeling for sodium oxybate suggests no evidence GHB has teratogenic, carcinogenic, or hepatotoxic properties. Its favorable safety profile relative to ethanol may explain why GHB continues to be investigated as a candidate for alcohol substitution.
The combination calcium oxybate/magnesium oxybate/potassium oxybate/sodium oxybate is also available as Xywav.
Adverse effects
Deaths One publication has investigated 226 deaths attributed to GHB. Of the 226 deaths included, 213 had a cardiorespiratory arrest and 13 had fatal accidents. Seventy-one of these deaths (34%) had no co-intoxicants. Postmortem blood GHB was 18–4400 mg/L (median=347) in deaths negative for co-intoxicants.
One report has suggested that sodium oxybate overdose might be fatal, based on deaths of three patients who had been prescribed the drug. However, for two of the three cases, post-mortem GHB concentrations were 141 and 110 mg/L, which is within the expected range of concentrations for GHB after death, and the third case was a patient with a history of intentional drug overdose. The toxicity of GHB has been an issue in criminal trials, as in the death of Felicia Tang, where the defense argued that death was due to GHB, not murder.
GHB is produced in the body in very small amounts, and blood levels may climb after death to levels in the range of 30–50 mg/L. Levels higher than this are found in GHB deaths. Levels lower than this may be due to GHB or to postmortem endogenous elevations.
Neurotoxicity In multiple studies, GHB has been found to impair spatial memory, working memory, learning and memory in rats with chronic administration. These effects are associated with decreased NMDA receptor expression in the cerebral cortex and possibly other areas as well. In addition, the neurotoxicity appears to be caused by oxidative stress.
Addiction Addiction occurs when repeated drug use disrupts the normal balance of brain circuits that control rewards, memory and cognition, ultimately leading to compulsive drug taking.Department of Health and Human Services, SAMHSA Office of Applied Studies 2005 National Survey on Drug Use and Health (ages 12 years and up); American Heart Association; Johns Hopkins University study, Principles of Addiction Medicine; Psychology Today; National Gambling Impact Commission Study; National Council on Problem Gambling; Illinois Institute for Addiction Recovery; Society for Advancement of Sexual Health; All Psych JournalAddiction and the Brain. Time
Rats forced to consume massive doses of GHB will intermittently prefer GHB solution to water.
Withdrawal
GHB has also been associated with a withdrawal syndrome of insomnia, anxiety, and tremor that usually resolves within three to twenty-one days. The withdrawal syndrome can be severe producing acute delirium and may require hospitalization in an intensive care unit for management. Management of GHB dependence involves considering the person's age, comorbidity and the pharmacological pathways of GHB. The mainstay of treatment for severe withdrawal is supportive care and benzodiazepines for control of acute delirium, but larger doses are often required compared to acute delirium of other causes (e.g. > 100 mg/d of diazepam). Baclofen has been suggested as an alternative or adjunct to benzodiazepines based on anecdotal evidence and some animal data. However, there is less experience with the use of baclofen for GHB withdrawal, and additional research in humans is needed. Baclofen was first suggested as an adjunct because benzodiazepines do not affect GABAB receptors and therefore have no cross-tolerance with GHB while baclofen, which works via GABAB receptors, is cross-tolerant with GHB and may be more effective in alleviating withdrawal effects of GHB.
GHB withdrawal is not widely discussed in textbooks and some psychiatrists, general practitioners, and even hospital emergency physicians may not be familiar with this withdrawal syndrome.
Overdose Overdose of GHB can sometimes be difficult to treat because of its multiple effects on the body. GHB tends to cause rapid unconsciousness at doses above 3500 mg, with single doses over 7000 mg often causing life-threatening respiratory depression, and higher doses still inducing bradycardia and cardiac arrest. Other side-effects include convulsions (especially when combined with stimulants), and nausea/vomiting (especially when combined with alcohol).
The greatest threat to life due to GHB overdose (with or without other substances) is respiratory arrest. Other relatively common causes of death due to GHB ingestion include aspiration of vomitus, positional asphyxia, and trauma sustained while intoxicated (e.g., motor vehicle accidents while driving under the influence of GHB). The risk of aspiration pneumonia and positional asphyxia risk can be reduced by laying the patient down in the recovery position. People are most likely to vomit as they become unconscious, and as they wake up. It is important to keep the victim awake and moving; the victim must not be left alone due to the risk of death through vomiting. Frequently the victim will be in a good mood but this does not mean the victim is not in danger. GHB overdose is a medical emergency and immediate assessment in an emergency department is needed.
Convulsions from GHB can be treated with the benzodiazepines diazepam or lorazepam. Even though these benzodiazepines are also CNS depressants, they primarily modulate GABAA receptors whereas GHB is primarily a GABAB receptor agonist, and so do not worsen CNS depression as much as might be expected.
Because of the faster and more complete absorption of GBL relative to GHB, its dose-response curve is steeper, and overdoses of GBL tend to be more dangerous and problematic than overdoses involving only GHB or 1,4-B. Any GHB/GBL overdose is a medical emergency and should be cared for by appropriately trained personnel.
A newer synthetic drug, SCH-50911, which acts as a selective GABAB antagonist, quickly reverses GHB overdose in mice. However, this treatment has yet to be tried in humans, and it is unlikely that it will be researched for this purpose in humans due to the illegal nature of clinical trials of GHB and the lack of medical indemnity coverage inherent in using an untested treatment for a life-threatening overdose.
Detection of use GHB may be quantitated in blood or plasma to confirm a diagnosis of poisoning in hospitalized patients, to provide evidence in an impaired driving, or to assist in a medicolegal death investigation. Blood or plasma GHB concentrations are usually in a range of 50–250 mg/L in persons receiving the drug therapeutically (during general anesthesia), 30–100 mg/L in those arrested for impaired driving, 50–500 mg/L in acutely intoxicated patients and 100–1000 mg/L in victims of fatal overdosage. Urine is often the preferred specimen for routine drug abuse monitoring purposes. Both γ-butyrolactone (GBL) and 1,4-butanediol are converted to GHB in the body.R. Baselt, Disposition of Toxic Drugs and Chemicals in Man, 8th edition, Biomedical Publications, Foster City, CA, 2008, pp. 680–84.
A method of detecting GHB in saliva was developed in 2016.
Interactions
Combination with alcohol In humans, GHB has been shown to reduce the elimination rate (thus increasing the elimination ) of alcohol. This may explain the respiratory arrest that has been reported after ingestion of both drugs. A review of the details of 194 deaths attributed to or related to GHB over a ten-year period found that most were from respiratory depression caused by interaction with alcohol or other drugs.Zvosec et al. Proceedings of the American Academy of Forensic Science in Seattle, 2006. Web.archive.org (3 December 2007). Retrieved on 24 December 2011.
Endogenous production Cells produce GHB by reduction of succinic semialdehyde via succinic semialdehyde reductase (SSR). This enzyme appears to be induced by cAMP levels, meaning substances that elevate cAMP, such as forskolin and vinpocetine, may increase GHB synthesis and release. Conversely, endogeneous GHB production in those taking valproic acid will be inhibited via inhibition of the conversion from succinic acid semialdehyde to GHB. People with the disorder known as succinic semialdehyde dehydrogenase deficiency, also known as γ-hydroxybutyric aciduria, have elevated levels of GHB in their urine, blood plasma and cerebrospinal fluid.National Organization for Rare Disorders. Succinic Semialdehyde Dehydrogenase Deficiency . Retrieved 6 March 2010.
The precise function of GHB in the body is not clear. It is known, however, that the brain expresses a large number of receptors that are activated by GHB. These receptors are excitatory, however, and therefore not responsible for the sedative effects of GHB; they have been shown to elevate the principal excitatory neurotransmitter, glutamate. The benzamide antipsychotics—amisulpride, nemonapride, etc.—have been shown to bind to these GHB-activated receptors in vivo. Other antipsychotics were tested and were not found to have an affinity for this receptor.
GHB is a precursor to GABA, glutamate, and glycine in certain brain areas.
In spite of its demonstrated neurotoxicity, (see relevant section, above), GHB has neuroprotective properties, and has been found to protect cells from hypoxia.
Natural fermentation by-product GHB is also produced as a result of fermentation and so is found in small quantities in some beers and wines, in particular fruit wines. The amount found in wine is pharmacologically insignificant and not sufficient to produce psychoactive effects.
Pharmacology GHB is very similar to the important inhibitory neurotransmitter GABA, with an amino group of GABA being replaced by a hydroxy group. If taken orally, GABA does not effectively cross the blood–brain barrier while GHB does.