Gamma hydroxybutyrate (GHB) dependence and withdrawal
- Deborah L Zvosec, PhD
Deborah L Zvosec, PhD
- Research Associate, Department of Emergency Medicine
- Hennepin County Medical Center
- Stephen W Smith, MD
Stephen W Smith, MD
- Department of Emergency Medicine, Hennepin County Medical Center
- Associate Professor of Emergency Medicine
- University of Minnesota School of Medicine
- Section Editors
- Stephen J Traub, MD
Stephen J Traub, MD
- Section Editor — Toxicology
- Associate Professor of Emergency Medicine
- Mayo Medical School
- Michele M Burns, MD, MPH
Michele M Burns, MD, MPH
- Section Editor — Pediatric Toxicology
- Assistant Professor of Pediatrics and Emergency Medicine
- Harvard Medical School
Gamma hydroxybutyrate (GHB) is a drug of abuse that is used for its euphoric, stimulant, sedative, and sexual effects. Gamma butyrolactone (GBL) and 1,4 butanediol (BD) are analogs or precursors of GHB which, when ingested, are rapidly metabolized to GHB, with the same clinical effects. All three compounds, GHB, GBL and BD, are used as dietary “supplements” for purported health benefits, including bodybuilding and treatment of insomnia, anxiety, and alcohol dependence. Tolerance, psychological and physical dependence, and withdrawal have been reported among individuals using GHB, GBL, and BD for both recreational purposes and purported health benefits. [1-9].
GHB is also used as a therapeutic agent in the United States and Europe. In the US, GHB is available as Xyrem® (sodium oxybate), which has been approved by the Food and Drug Administration (FDA) for treatment of narcolepsy with cataplexy and/or excessive daytime sleepiness. In Europe, GHB is available as Xyrem®, as Alcover®, which has been studied for treatment of alcohol and drug dependence, and as Somsanit®, which has been approved as an anaesthetic. Craving, abuse, dependence, and withdrawal have been reported in therapeutic trials in which GHB/Alcover® was administered under close supervision [10-12], as well as among patients treated with Xyrem® [13,14].
The clinical features and management of GHB withdrawal are reviewed here. Acute intoxication with GHB and its management are discussed elsewhere, as is the general management of the poisoned patient. (See "Gamma hydroxybutyrate (GHB) intoxication" and "General approach to drug poisoning in adults".)
Throughout this review we use the term "GHB" to refer to GHB and its analogs, GBL and BD, unless specifically noted. The pharmacology of GHB and its analogs are discussed separately. (See "Gamma hydroxybutyrate (GHB) intoxication", section on 'Pharmacology and cellular toxicology'.)
Due to the absence of surveillance and systematic reporting mechanisms, little is known of the prevalence of chronic GHB abuse or dependence. Cases of GHB dependence and withdrawal have been reported in the United States (US), Canada, Europe, and Australia [1-8,15-21].
- Zvosec, DL, Smith, SW. Gamma hydroxybutyrate (GHB) addiction and withdrawal. From the GHB Addiction Study (Abstract). Ann Emerg Med 2004; 44:S91.
- Dyer JE, Roth B, Hyma BA. Gamma-hydroxybutyrate withdrawal syndrome. Ann Emerg Med 2001; 37:147.
- Slagel B, Kingstone E, Bhalerao S. Gamma hydroxybutyrate withdrawal in an orthopedic trauma patient. Can J Psychiatry 2003; 48:131.
- McDaniel CH, Miotto KA. Gamma hydroxybutyrate (GHB) and gamma butyrolactone (GBL) withdrawal: five case studies. J Psychoactive Drugs 2001; 33:143.
- Schneir AB, Ly BT, Clark RF. A case of withdrawal from the GHB precursors gamma-butyrolactone and 1,4-butanediol. J Emerg Med 2001; 21:31.
- Sivilotti ML, Burns MJ, Aaron CK, Greenberg MJ. Pentobarbital for severe gamma-butyrolactone withdrawal. Ann Emerg Med 2001; 38:660.
- Trendelenburg G, Heinz A, Ströhle A. Gamma-hydroxybutyrate dependence with social phobia. Am J Psychiatry 2004; 161:375.
- Mycyk MB, Wilemon C, Aks SE. Two cases of withdrawal from 1,4-Butanediol use. Ann Emerg Med 2001; 38:345.
- Zvosec DL, Smith SW, McCutcheon JR, et al. Adverse events, including death, associated with the use of 1,4-butanediol. N Engl J Med 2001; 344:87.
- Gallimberti L, Spella MR, Soncini CA, Gessa GL. Gamma-hydroxybutyric acid in the treatment of alcohol and heroin dependence. Alcohol 2000; 20:257.
- Addolorato G, Castelli E, Stefanini GF, et al. An open multicentric study evaluating 4-hydroxybutyric acid sodium salt in the medium-term treatment of 179 alcohol dependent subjects. GHB Study Group. Alcohol Alcohol 1996; 31:341.
- Addolorato G, Caputo F, Capristo E, et al. Gamma-hydroxybutyric acid efficacy, potential abuse, and dependence in the treatment of alcohol addiction. Alcohol 2000; 20:217.
- LeTourneau JL, Hagg DS, Smith SM. Baclofen and gamma-hydroxybutyrate withdrawal. Neurocrit Care 2008; 8:430.
- Wang YG, Swick TJ, Carter LP, et al. Safety overview of postmarketing and clinical experience of sodium oxybate (Xyrem): abuse, misuse, dependence, and diversion. J Clin Sleep Med 2009; 5:365.
- Miotto K, Darakjian J, Basch J, et al. Gamma-hydroxybutyric acid: patterns of use, effects and withdrawal. Am J Addict 2001; 10:232.
- Bell J, Collins R. Gamma-butyrolactone (GBL) dependence and withdrawal. Addiction 2011; 106:442.
- Stijnenbosch PJ, Zuketto C, Beijaert PJ, Maat A. [GHB withdrawal delirium]. Ned Tijdschr Geneeskd 2010; 154:A1086.
- Addolorato G, Caputo F, Capristo E, Gasbarrini G. Diazepam in the treatment of GHB dependence. Br J Psychiatry 2001; 178:183.
- Degenhardt L, Copeland J, Dillon P. Recent trends in the use of "club drugs": an Australian review. Subst Use Misuse 2005; 40:1241.
- O'Toole JG, Kristian MR, Devereux L, Kurien R. Gamma-hydroxybutyrate dependence in a rural setting in Wales. J Subst Abuse 2009; 14:70.
- Wojtowicz JM, Yarema MC, Wax PM. Withdrawal from gamma-hydroxybutyrate, 1,4-butanediol and gamma-butyrolactone: a case report and systematic review. CJEM 2008; 10:69.
- Maxwell JC. Substance Abuse Trends in Texas: June 2010: Addiction Research Institute, Gulf Coast Addiction Technology Transfer Center and U.T. Center for Social and Behavioral Research 2010.
- Anderson IB, Blanc PD, Kim SY, et al. Reports of gamma hydroxybutyrate (and precursor) dependence and withdrawal: A five-year review of Poison Control Center Data [abstract]. Clin Toxicol 2005; 43:525.
- McDonough M, Kennedy N, Glasper A, Bearn J. Clinical features and management of gamma-hydroxybutyrate (GHB) withdrawal: a review. Drug Alcohol Depend 2004; 75:3.
- Snead OC 3rd, Gibson KM. Gamma-hydroxybutyric acid. N Engl J Med 2005; 352:2721.
- Gianutsos G, Suzdak PD. Evidence for down-regulation of GABA receptors following long-term gamma-butyrolactone. Naunyn Schmiedebergs Arch Pharmacol 1984; 328:62.
- Miotto K, Roth B. GHB withdrawal syndrome. Texas Commission on Alcohol and Drug Abuse. Austin, TX 2001. Available online at: http://www.dshs.state.tx.us/WorkArea/DownloadAsset.aspx?id=10417.
- Van Sassenbroeck DK, De Paepe P, Belpaire FM, et al. Tolerance to the hypnotic and electroencephalographic effect of gamma-hydroxybutyrate in the rat: pharmacokinetic and pharmacodynamic aspects. J Pharm Pharmacol 2003; 55:609.
- Catalano MC, Glass JM, Catalano G, et al. Gamma butyrolactone (GBL) withdrawal syndromes. Psychosomatics 2001; 42:83.
- Zvosec, DL, Smith, SW. Acute complications of Gamma hydroxybutyrate addiction. (Abstract). Acad Emerg Med 2005; 12:S13.
- Bennett WR, Wilson LG, Roy-Byrne PP. Gamma-hydroxybutyric acid (GHB) withdrawal: a case report. J Psychoactive Drugs 2007; 39:293.
- Couper FJ, Logan BK. Addicted to driving under the influence--a GHB/GBL case report. J Anal Toxicol 2004; 28:512.
- Rosenberg MH, Deerfield LJ, Baruch EM. Two cases of severe gamma-hydroxybutyrate withdrawal delirium on a psychiatric unit: recommendations for management. Am J Drug Alcohol Abuse 2003; 29:487.
- Herold AH, Sneed KB. Treatment of a young adult taking gamma-butyrolactone (GBL) in a primary care clinic. J Am Board Fam Pract 2002; 15:161.
- Galloway GP, Frederick SL, Staggers FE Jr, et al. Gamma-hydroxybutyrate: an emerging drug of abuse that causes physical dependence. Addiction 1997; 92:89.
- Perez E, Chu J, Bania T. Seven days of gamma-hydroxybutyrate (GHB) use produces severe withdrawal. Ann Emerg Med 2006; 48:219.
- Hoffman, RJ, Hoffman, RS, Nelson, L. Cross tolerance of gamma-butyrolactone (GBL) and benzodiazepines. J Tox Clin Toxicol 2000; 38:227.
- Zvosec DL, Smith SW, Hall BJ. Three deaths associated with use of Xyrem. Sleep Med 2009; 10:490.
- The abrupt cessation of therapeutically administered sodium oxybate (GHB) does not cause withdrawal symptoms. J Toxicol Clin Toxicol 2003; 41:131.
- Zvosec DL, Smith SW. Comment on "The abrupt cessation of therapeutically administered sodium oxybate (GHB) may cause withdrawal symptoms". J Toxicol Clin Toxicol 2004; 42:121.
- Hornfeldt, CS. The abrupt cessation of therapeutically administered sodium oxybate (GHB) does not produce withdrawal symptoms (Abstract). J Tox Clin Toxicol 2001; 39:516.
- Xyrem® (sodium oxybate) oral solution. Available online at: jazzph.isat-tech.com/media/PI.pdf (Accessed on March 19, 2011).
- Wiegand, TJ, Zvosec, DL, Smith, SW. Use of propofol for severe GHB withdrawal: Two cases (Abstract). J Tox Clin Tox 2005; 43:665.
- Greene, T, Dougherty, T, Rodi, A. Gamma butyrolactone (GBL) withdrawal presenting as acute psychosis (Abstract). J Tox Clin Toxicol 1999; 37:651.
- Reeves, J, Duda, R. GHB/GBL intoxication and withdrawal: A review and case presentation. Addictive Disorders and their Treatment 2003; 2:25.
- Hutto B, Fairchild A, Bright R. gamma-Hydroxybutyrate withdrawal and chloral hydrate. Am J Psychiatry 2000; 157:1706.
- Stein LA, Lebeau R, Clair M, et al. A web-based study of gamma hydroxybutyrate (GHB): patterns, experiences, and functions of use. Am J Addict 2011; 20:30.
- Glasper A, McDonough M, Bearn J. Within-patient variability in clinical presentation of gamma-hydroxybutyrate withdrawal: a case report. Eur Addict Res 2005; 11:152.
- Bialer PA. Designer drugs in the general hospital. Psychiatr Clin North Am 2002; 25:231.
- Zvosec, D, Smith, S, Ladmer, D. Gamma Hydroxybutyrate withdrawal syndrome in the Emergency Department: Clinical course and autonomic instability (Abstract). Ann Emerg Med 2006; 48:S100.
- Mahr G, Bishop CL, Orringer DJ. Prolonged withdrawal from extreme gamma-hydroxybutyrate (GHB) abuse. Psychosomatics 2001; 42:439.
- Bowles TM, Sommi RW, Amiri M. Successful management of prolonged gamma-hydroxybutyrate and alcohol withdrawal. Pharmacotherapy 2001; 21:254.
- Chew G, Fernando A 3rd. Epileptic seizure in GHB withdrawal. Australas Psychiatry 2004; 12:410.
- Friedman J, Westlake R, Furman M. "Grievous bodily harm:" gamma hydroxybutyrate abuse leading to a Wernicke-Korsakoff syndrome. Neurology 1996; 46:469.
- Jacobs, K, Bain, B. Delirium with Wernicke's disease after abrupt cessation of 1,4 butanediol. Med Psychiatry 1999:41.
- Craig K, Gomez HF, McManus JL, Bania TC. Severe gamma-hydroxybutyrate withdrawal: a case report and literature review. J Emerg Med 2000; 18:65.
- Su, M, Traub, S, Hussain, E, et al. 1,4-Butanediol withdrawal complicated by urinary retention. (Abstract). J Tox Clin Toxicol 2001; 39:542.
- Benjamin DM. Gamma-hydroxybutyrate (GHB) - Withdrawal with severe rhabdomyolysis, hyperkalemia, and cardiac arrest. (Abstract K4), Proceedings of the American Academy of Forensic Sciences, San Antonio, TX, February 2007. Vol. XIII.
- Zvosec DL, Smith SW. GHB withdrawal fatalities: two cases. 2011 (in press).
- Dyer, JE, Haller, CA. Gamma hydroxybutyrate and the comatose patient. Pulmonary and Critical Care Update, Chest Online 2001, Lesson 22. Available online at: www.chestnet.org/education/online/pccu/vol14/index.php (Accessed on August 22, 2007).
- Tarabar AF, Nelson LS. The gamma-hydroxybutyrate withdrawal syndrome. Toxicol Rev 2004; 23:45.
- Anderson IB, Dyer JD. Withdrawl: Central nervous system depressants. In: Medical Toxicology, 3rd, Dart RC. (Ed), Lippincott, Williams, & Wilkins, Philadelphia 2004. p.135.
- Dill C, Shin S. High-dose intravenous benzodiazepine. Acad Emerg Med 2000; 7:308.
- Daeppen JB, Gache P, Landry U, et al. Symptom-triggered vs fixed-schedule doses of benzodiazepine for alcohol withdrawal: a randomized treatment trial. Arch Intern Med 2002; 162:1117.
- Busto UE, Sykora K, Sellers EM. A clinical scale to assess benzodiazepine withdrawal. J Clin Psychopharmacol 1989; 9:412.
- Saitz R, Mayo-Smith MF, Roberts MS, et al. Individualized treatment for alcohol withdrawal. A randomized double-blind controlled trial. JAMA 1994; 272:519.
- Gonzalez A, Nutt DJ. Gamma hydroxy butyrate abuse and dependency. J Psychopharmacol 2005; 19:195.
- Coomes TR, Smith SW. Successful use of propofol in refractory delirium tremens. Ann Emerg Med 1997; 30:825.
- Olmedo, RE, Nelson, L, Howland, M, Hoffman, RS. Propofol safely controls delirium tremens (Abstract). J Tox Clin Tox 2000; 38:537.
- Sharma, AN, Nelson, L, Hoffman, RS. Refractory sedative-hypnotic withdrawal treated with propofol (Abstract). J Tox Clin Tox 2000; 38:537.
- Glisson JK, Norton J. Self-medication with gamma-hydroxybutyrate to reduce alcohol intake. South Med J 2002; 95:926.
- Stalcup, SA, Stalcup, J. GHB addiction and outpatient treatment of GHB withdrawal. Presentation at the 2003 National GHB Conference, "Spotlight on GHB," Orlando, Florida, 2003.
- Hayner G, Galloway G, Wiehl WO. Haight Ashbury free clinics' drug detoxification protocols--Part 3: Benzodiazepines and other sedative-hypnotics. J Psychoactive Drugs 1993; 25:331.
- Stalcup SA, Christian D, Stalcup J, et al. A treatment model for craving identification and management. J Psychoactive Drugs 2006; 38:189.
- Barth KS, Hines S, Albanese RP. Permanent neurologic damage from chronic gamma hydroxybutyrate abuse. Am J Addict 2006; 15:483.
- PHARMACOLOGY, CELLULAR TOXICOLOGY, AND PATHOPHYSIOLOGY
- CLINICAL FEATURES OF WITHDRAWAL
- Risk factors for development of GHB dependence
- Dosing patterns
- Common symptoms, onset, and course
- Specific signs and symptoms
- DIFFERENTIAL DIAGNOSIS
- LABORATORY EVALUATION
- Specific testing
- General testing
- General approach
- - Mild to moderate withdrawal, without delirium
- - Severe withdrawal, with delirium
- - Benzodiazepines
- - Barbiturates
- - Propofol
- - Anticonvulsants
- - Baclofen
- - Antihypertensives
- - Antipsychotics
- Vitamins and fluids
- Outpatient detoxification
- Persistent symptoms post-detoxification
- CHEMICAL DEPENDENCY TREATMENT AND RELAPSE PREVENTION
- PITFALLS IN MANAGEMENT
- ADDITIONAL RESOURCES
- SUMMARY AND RECOMMENDATIONS