GHB was discovered in 1960 while searching for an analog for γ-aminobutyric acid (GABA).31 Due to its central nervous system (CNS) depressive and amnestic properties, GHB was initially used as an anesthetic adjunct, especially in Europe but never gained favor in the United States for this indication. Outside the United States, GHB is still used for anesthesia or as an adjunct sedative for therapeutic hypothermia and wound care in children.434,3,53 During the 1970s, an investigational new drug protocol was submitted to the US Food and Drug Administration (FDA) to test the use of GHB as a treatment for sleep disturbances. In the 1980s and 1990s, body builders popularized GHB as an anabolic dietary supplement due to its release of growth hormone. Its euphoric effects were recognized at this time, and it rapidly gained favor as a “club drug.” Because it can cause coma and profound amnesia, GHB has been used in drug-facilitated sexual assault, and in 1990 the FDA banned all use of nonprescription GHB due to this concern.61
Following the FDA ban, the analogs GBL and 1,4-BD were quickly substituted for GHB in dietary supplements. After the Samantha Reid and Hillory J. Farias Date-Rape Prevention Act of 1999 was passed in 2000, the US Drug Enforcement Agency (DEA) classified GHB and its analogs as Schedule I substances claiming that GHB was a hazard to public safety.68 Also in 2000, a new drug application was submitted to the FDA for GHB—under the generic name sodium oxybate and the trade name Xyrem—to reduce the incidence of cataplexy and improve the symptoms of daytime sleepiness in patients with narcolepsy.29 This latter indication was approved in 2002 and given a Schedule III designation by the DEA,29 which was expanded in 2005 to include the treatment of excessive daytime sleepiness in patients with narcolepsy. It is now also used “off-label” for fibromyalgia, chronic fatigue syndrome, and depressive disorders.6,56,65 However, in 2010, the FDA declined to approve GHB for fibromyalgia.
In 2007, during an epidemic of toxicity from toy beads, marketed under the names Bindeez or Aquadots, 1,4-BD was identified in the sticky surface material that allowed the beads to reversibly adhere to one another. Multiple cases of toxicity were reported, largely in England and Australia.25,55
National statistics demonstrated a trend of escalating GHB abuse and poisoning throughout the 1990s. However, a decline has occurred in exposures reported to poison control centers and the Drug Abuse Warning Network in recent years. In 2002, there were 1386 exposures with GHB and its analogs and precursors reported to the American Association of Poison Control Centers (AAPCC)–Toxic Exposure Surveillance System, representing more than a twofold increase from approximately 600 GHB cases reported in 1996. Among these, 1181 exposures (85%) required treatment in a health care facility and resulted in 272 major outcomes and three deaths (Chap. 136).74 From the 2011 AAPCC NPDS report, 464 cases mentioned exposure to GHB, its analogs, and precursors. In 303 of those cases, GHB, its analogs, and precursors were the single xenobiotic of exposure. Of the reported cases, 224 were treated in a health care facility and 144 of those cases had moderate or major outcomes.8 The Drug Abuse Warning Network’s 2010 estimates revealed 1787 emergency department visits for GHB exposures, similar to the number of visits from 2004 to 2009, with a range of 1036 to 2207 visits to the emergency department.66 A recent retrospective review of deaths related to GHB, GBL, and 1,4-BD showed that men in their 20s were more likely to die from GHB poisoning. Thirty-four percent of these deaths were due to GHB alone.78
The apparent trend of decreased GHB exposures in the United States after 2000 contrasts with the increased use reported in some European countries and Australia.12,15,30 In Melbourne, Australia, a retrospective study showed a 4% increase per month in the number of ambulance calls related to GHB and its analogs from March 2001 to October 2005.12 In Spain, a study of 505 consecutive GHB-poisoned patients presenting to one hospital, from 2001 to 2007, revealed that these patients come to the hospital on the weekends, in the early morning hours, and will likely require more treatment if ethanol, amphetamines or their derivatives, and/or cocaine are concomitantly used.21