Chula Mad J Vol. 48 No.7 July 2004 Gamma-Hydroxybutyrate (GHB) and its derivatives: A new and novel neuroactive drug of abuse Krisda Sirampuj* Sirampuj K. Gamma-Hydroxybutyrate (GHB) and its derivatives: A new and novel neuroactive drug of abuse. Chula Med J 2004 Jul; 48(7): 491 - 502 There has been increasing attention in the abuse of gamma-hydroxybutyrate (GHB) , with some evidence in other parts of the world especially the United States. In vitro and animal research models show that, while GHB shares certain properties with some depressant drugs abusive to central nervous system, it also has unique aspects of its pharmacology including actions at a specific neural receptor which probably mediates many of its effects. So far, the assessment of the abusive potential of GHB with standard animal models has not yielded a picture of a highly abusive substance, and little testing of the drug in human has been done. Vel}' little systematic data exist on the tolerance and dependence of GHB, but both have been seen in human users. Quantitative data on the prevalence of GHB abuse is incomplete, but various qualitative measures indicate that a mini-epidemic of GHB abuse began in the late 1980s and continues to the present. GHB is often included with the group of the so-called 'club drugs', which can be used as an intoxicant. It also has been used as a growth promoter and sleep-aid agent, also implicated in cases of 'date rape', usually in combination with alcohol. Undoubtedly the easy availability of GHB and some of its precursors has contributed to its popularity. With as yet unknown consequences for the scope of the public health problem, recent changes in the control status of GHB in the US may reduce its availability. Experts on drug abuse need to familiarize themselves with GHB since it has a potentiality to be a new type of problem of drug abuse with some unique properties. Keywords: Gamma-hydroxybutyrate, GHB, Gamma-butyrolactone, GBL, Novel neuroactive drug, New type of drug abuse. Reprint request: Sirampuj K. Faculty of Liberal Arts, Thammasat University, Khong Luang, Prathum Thani 12121, Thailand. E-mail: [email protected] Received for publication: May 15, 2004. Objective: This review highlights the biochemistry, neuropharmacology, and toxicology of the naturally­ occurring fatty acid derivative, gamma-hydroxybutyrate (GHB). GHB is derived from gamma­ aminobutyric acid (GABA) and is proposed to function as an inhibitory chemical transmitter in the central nervous system. 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As the dose of these drugs is increased, a initially developed as anesthetic agents and was sold sharp increase in adverse effects may occur. in the US in health food store as a performance Overdoses with these drugs can result in life­ enhancing additive in bodybuilding formulas. However threatening symptoms of CNS depression, coma, in 1990, the US Food and Drug administration (FDA) respiratory depression, apnea, bradycardia, banned its distribution due to its widespread reports hypotension, and seizures.(3) According to the Drug of poisoning and adverse reactions. In 2000, GHB Abuse Warning Network (DAWN), GHB emergency was placed into schedule I of the Federal Controlled department mentions have increased from 56 in 1994 Substance Act.(1) to 3,340 in 2001. Since 1990, the US Drug Enforcement Administration (DEA) has documented more than Abusive use of GHB 15,600 overdoses and law enforcement encounters Despite being banned by the FDA, GHB is and 72 deaths related to GHB. The FDA has released still widely available in the underground drug market. reports and warning conveying the adverse health There are analogs of GHB; Gammabutyrolactone consequences of GHB, GBL, and 1,4-butanediol. (GBL) and 1,4-butanediol which are marketed as Ingestion of the products containing these substances dietary supplements in health food stores, sport have been linked to at least 122 serious illnesses and nutrition stores and on the internet. GBL is converted three deaths. (2) The FDA has issued warnings for both into GHB in an alkaline environment such as in the GBL and 1,4-butanediol, stating that the drugs presence of sodium or potassium hydroxide and the have a potential for abuse and are a public health reaction is complete in under an hour. Additionally, danger.(1) once digested these analogs of GHB are rapidly metabolized to GHB in vivo by a rapidly acting Situation in Thailand lactonase found in the blood and liver. 1,4-butanediol In 2003, the Food and Drug Administration of is converted to GHB by alcohol dehydrogenase and Thailand reported death of a woman and seven cases aldehyde dehydrogenase. Due to the efficient of serious illness resulted from drinking wine that conversion of both GBL and 1,4-butanediol, their contains GBL, tetrahydrofuran (THF), and acetonitrile toxicological profiles are essentially analogous to that or methyl cyanide.(4.5) The wine was in a lot of 144 of GHB.(2) bottles which two foreigners had been hired to mail Factors that seem to contribute to the the bottles to the US but the company was unable to addictive potential of GHB and its metabolic send it. (4) precursors include its purported anabolic effects, 494 Chula Med J Biotransformation of GHB and THF effects such as behavioral sedation and narcosis in Comparing the structures of GBL with 1, mammals, gastrointestinal tract like nausea, vomiting 4-butanediol and THF, itwas found that each of these and diarrhea and may cause respiratory depression, compounds share the same 4-carbon backbone and coma, and death. Overdose of GHB can cause life­ the differences between them are due to the different threatening effects similar to acute THF toxicity, such functional groups at the C-1 and C-4. Hydrolysis of as respiratory depression, apnea, hypotension, coma GBL opens the 5-membered ring of the 4-carbon and death. Currently there are no antidotes to treat backbone, forming GHB. Conversions of these GHB overdose or THF toxicity. Knowledge about the structure are as follows: the conversion of 1, biotransformation of THF to GHB could be useful in 4-butanediol to THF can be accomplished by designing pharmacological interventions.