INTRODUCTION — Gamma hydroxybutyrate (GHB) is a medication and a drug of abuse used for its euphoric, anxiolytic, 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 have also been used as dietary "supplements" for purported health benefits, including bodybuilding and treatment of insomnia, anxiety, and alcohol dependence. Tolerance, psychologic and physical dependence, and withdrawal have been reported not only among individuals using GHB, GBL, and BD for recreational purposes and purported health benefits [1-12], but in medicinal use as well [13-15].
The clinical features and management of GHB withdrawal are reviewed here. Acute intoxication with GHB and its management are discussed separately, 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'.)
Assessment of the patient with substance use disorder is reviewed separately. (See "Clinical assessment of substance use disorders".)
EPIDEMIOLOGY — GHB products were first sold in the United States and Europe in the late 1980s as a sleep aid and for purported anabolic effects. GHB analogs, GBL and BD, were marketed in the late 1990s as "dietary supplements" and sold in health food stores, at gyms, and on the internet purportedly to help with sleep, weight loss, anxiety, depression, and other alleged health benefits. Regulation of GHB and its analogs resulted in the removal of products and a shift to illicit supplies. Pharmaceutical GHB is available (brand names include Xyrem, Alcover, and Somsanit). The chemical names and abbreviations for GHB are described below (see 'Pharmacology, cellular toxicology, and pathophysiology' below). The epidemiology of GHB abuse is discussed separately. (See "Gamma hydroxybutyrate (GHB) intoxication", section on 'Epidemiology'.)
The prevalence of chronic GHB abuse and dependence is not well known. From the 1990s to mid-2000s in the United States, there were reports of recreational use at nightclubs and dance parties and among bodybuilders and users of dietary supplements [1-5,16,17]. Surveillance in California and Texas reported relatively low numbers of GHB dependence cases from 1999 to 2015 [18,19]. Subsequent reports in the United States are limited to scattered case reports.
Cases of GHB dependence and withdrawal in European countries increased substantially in the mid to late 2000s and continue at significant rates, particularly in the United Kingdom and the Netherlands. Cases in the United Kingdom are predominately among nightclub and dance party attendees and men who have sex with men in urban areas of England and Ireland [20-29].
GHB dependence continues in the Netherlands among recreational drug users in both urban and rural areas [8,11,12,30-33]. Frequent relapse, high withdrawal severity, and repeat admissions for overdose, detoxification, and treatment continue to overburden Dutch treatment services.
The mean age of patients treated for GHB dependence has been reported as between 27 and 33 [11,21,22,30,34,35]. GHB-dependent patients are more frequently male, and often men who have sex with men, including those who practice "chemsex," for which GHB/GBL use is commonly reported [26-28,36,37]. Patients who use GHB often use other drugs concurrently, especially stimulants and alcohol [7,11,24,34,38,39].
GHB is associated with a high rate of admission for emergency (unplanned) detoxification; GHB dependence is difficult to treat [31,40]. Multisite research on more than 65,000 Dutch addiction patients found that GHB-dependent patients (n = 596) had the highest treatment intensity, comprised of the highest admission rates, most treatment contacts, longest treatment duration, and highest chance of readmission [9].
RISK FACTORS AND SIGNS OF DEPENDENCE — Studies suggest there is greater risk for abuse among people using GHB than those using alcohol [41]. Many factors contribute to this risk. The steep dose response, rapid onset of euphoric and anxiolytic effects, lack of hangover effects, cheap and easy access, trivialization of harms such as GHB coma (see below), and common perceptions of GHB as safe and life enhancing all may contribute to use and subsequent dependence [12,22,30,31,42]. Additional factors that may increase the risk of dependence include use for bodybuilding or self-medication of sleep problems [8,12,22,43] and psychiatric comorbidity, particularly anxiety and depression [8,21,44]. Past dependence and concurrent use or dependence on alcohol or drugs, particularly stimulants, is common among GHB users and may increase the risk and severity of dependence and withdrawal [1,2,4,7,8,11,12,16,21,45].
GHB-dependent users report frequent, sometimes daily, episodes of loss of consciousness (GHB coma) due to the steep dose response of GHB. Despite high rates of transport to emergency departments for overdose and associated trauma, users often perceive GHB comas as transient and harmless and tend to minimize risks associated with their use [27,30,31,42].
Warning signs of GHB/GBL dependence may include [25]:
●Weekday use when not partying, clubbing, or socializing
●Multiple use each day
●Waking for nighttime use
●Withdrawal symptoms when not using
●Use of other substances to prevent withdrawal symptoms at night
●Inability to skip a day without using
PHARMACOLOGY, CELLULAR TOXICOLOGY, AND PATHOPHYSIOLOGY — The pharmacology, cellular toxicology, and kinetics of GHB are discussed separately; aspects of these that are directly related to dependence and withdrawal are briefly discussed immediately below. (See "Gamma hydroxybutyrate (GHB) intoxication", section on 'Pharmacology and cellular toxicology' and "Gamma hydroxybutyrate (GHB) intoxication", section on 'Kinetics'.)
GHB acts primarily on GHB-specific receptors and on gamma aminobutyric acid (GABA)-B receptors. It may also exert effects on some subtypes of GABA-A receptors, although this has not been well established. Chronic use of GHB exerts multifaceted neurotransmitter and neuromodulatory effects on the GABA, dopamine, glutamate, serotonin, norepinephrine, and cholinergic systems; as well as on neurosteroidogenesis and oxytocin release.
Chronic GHB use is believed to lead to tolerance associated with downregulation of inhibitory GABA and GHB receptors. Abrupt cessation of GHB use results in a complex interaction of neurobiologic mechanisms, including decreased GABA- and GHB-mediated neuroinhibition, resulting in unopposed excitatory neurotransmission and the onset of a withdrawal syndrome. The complexity of the systems involved and diversity of the symptoms and signs manifested suggest that different medication combinations may be required for effective treatment [46].
Gamma butyrolactone (GBL) and 1,4 butanediol (BD) are GHB analogs that are rapidly metabolized to GHB after ingestion. GHB-dependent individuals may use the three compounds interchangeably. GHB tolerance, dependence, and withdrawal develop subsequent to chronic BD and GBL use and manifest with the same symptomatology as GHB dependence and withdrawal, although the shorter onset of action, greater potency, and longer duration of effect of GBL may increase the risk for dependence compared with GHB [8,11].
CLINICAL FEATURES OF WITHDRAWAL
Presentation and doses — GHB withdrawal is generally similar to alcohol or benzodiazepine withdrawal, commonly presenting with tremor, diaphoresis, anxiety, agitation, and confusion; but with a more rapid and abrupt onset and more prominent neuropsychiatric symptoms, such as delirium and psychosis [47]. However, the presentation of GHB withdrawal can be highly variable. Severe refractory withdrawal, often involving prolonged delirium and other complications, has been reported and may result in part from delayed, inadequate, or inappropriate treatment. Co-use and co-dependence on alcohol and other drugs, especially stimulants, is common and may be associated with a more severe clinical course [39]. (See "Alcohol withdrawal: Epidemiology, clinical manifestations, course, assessment, and diagnosis".)
GHB dosing patterns among dependent users prone to withdrawal vary significantly, from daily use among bodybuilders or nightly use among patients self-treating insomnia to binge use (as frequently as every 30 to 60 minutes over consecutive days) among "recreational" users for partying or extended chemsex [1,3,4,27,30]. Most GHB-dependent patients who develop withdrawal engage in frequent dosing (ie, every one to six hours) for a period of weeks to months or years [7,8,48]. However, severe withdrawal has occurred with use every two to three hours, around the clock, for 7 to 10 days [43,49,50].
Reported dose size among GHB-dependent patients is highly variable but typically ranges from 1 to 6 grams. Dutch data on 274 inpatient detoxifications among 229 patients reported a mean dose of 4 grams and a mean daily dose of 56 grams (range 10 to 312 grams) [10].
Patients withdrawing from GHB may present specifically for planned or acute, unplanned treatment of withdrawal symptoms, or may develop symptoms of withdrawal while in the emergency department, hospital, or intensive care unit. GHB withdrawal can also occur in patients admitted to psychiatric, detoxification, and correctional facilities.
Several inpatient studies involving a pharmaceutical GHB titration and taper protocol [8,10] and outpatient studies involving benzodiazepine and baclofen titration and taper protocols [22,24,51] report low rates of psychosis, delirium, and other complications, provided symptoms are treated rapidly and appropriate treatment is given. (See 'Management of acute withdrawal' below.)
Common symptoms, onset, and course — Symptoms of GHB withdrawal develop rapidly. Among frequent users, symptoms may begin as rapidly as 30 minutes after the last dose. Typically, symptom onset is within one to six hours of cessation or significantly decreased dosing. Patient presentation six hours or longer after their last dose and a history of withdrawal-related psychosis or delirium are potential risk factors for severe withdrawal [8].
Initial symptoms of GHB withdrawal most often include anxiety, agitation, tremor, diaphoresis, tachycardia, nausea, vomiting, and insomnia. Within 24 hours, symptoms may progress to severe withdrawal with refractory agitation, hallucinations, delusions, and delirium.
The symptom course is often unpredictable; apparent initial improvement may be followed by dramatic deterioration or the recurrence of symptoms including hallucinations, delirium, and non-neurologic complications such as rhabdomyolysis, acute kidney injury (ie, acute renal failure), and possibly death [5,6,8].
Profound insomnia is common and has been reported to play a key role in ongoing use, decision to seek treatment, withdrawal severity, and relapse [12,22,48]. Severe insomnia despite aggressive pharmacotherapy may exacerbate psychosis and delirium [2,3,52].
Variability in the presentation and treatment response may be due to GHB dose, total daily intake, and frequency of use. Delayed presentation for treatment is associated with more severe symptoms. Gamma butyrolactone (GBL) withdrawal may be associated with a more rapid onset of symptoms [48,53-55]. Patients who use both GHB and stimulants may experience increased agitation, restlessness, and tachycardia within the first five hours of GHB withdrawal [39].
Withdrawal duration ranges from 2 to 15 days, with longer presentations typically due to complications such as excited delirium, rhabdomyolysis, and acute kidney injury [8]. Treatment may require stays in the intensive care unit of up to 15 days and inpatient care for up to 32 days [56]. Patients with more frequent and higher dosing may experience more severe symptoms, higher rates of delirium, and more prolonged withdrawal [8,48].
Specific signs and symptoms
●Vital signs – Although tachycardia and hypertension have been reported [8,10,48], autonomic disturbances from GHB withdrawal may be mild to moderate, show only transient spikes, or be absent entirely despite profound delirium and a protracted hospital stay [1,57,58]. This stands in contrast to the severe autonomic instability seen with delirium tremens in alcohol withdrawal. (See "Management of moderate and severe alcohol withdrawal syndromes".)
●Central nervous system effects – Confusion, anxiety, paranoia, agitation, and combativeness are common in early or mild GHB withdrawal. Hallucinations (auditory, visual, tactile, or olfactory), disorientation, paranoid delusions, and delirium may develop quickly, often within the first 24 hours, and may persist for up to 14 days. Recurrent hallucinosis and delirium have been reported [8,57].
Tremor is an early and often persistent sign of GHB withdrawal [8,48,57]. Tonic-clonic seizures have been reported [6,8,13,59-62]. Nystagmus has been reported [6-8,63].
Wernicke-Korsakoff syndrome has been reported in two patients who exhibited gait ataxia, cranial nerve VI palsy, and altered mental status (confusion, hallucinations, and delirium). Thiamine was administered to both patients, but symptoms persisted for 5 to 10 days [64,65]. (See "Overview of the chronic neurologic complications of alcohol" and "Overview of the chronic neurologic complications of alcohol", section on 'Korsakoff syndrome'.)
●Cardiovascular effects – Hypertension and tachycardia have been reported [8,10,48]. Generally, autonomic instability tends to be mild to moderate [1,57], particularly when compared with alcohol withdrawal.
●Gastrointestinal effects – Gastrointestinal symptoms including nausea, vomiting, and diarrhea have been reported [8,48].
●Other effects – Diaphoresis is common in early or mild GHB withdrawal [8,48].
Complications — Delirium is a relatively common complication of GHB withdrawal, and severe agitation and profound delirium refractory to benzodiazepines have been reported in cases of severe withdrawal [1,4,8,32,35,59,66]. Rhabdomyolysis was reported in 7 to 16 percent of cases reviewed [6,8]. Acute kidney injury and failure necessitating dialysis have been reported in two cases of GBL withdrawal [67,68]. (See "Rhabdomyolysis: Clinical manifestations and diagnosis".)
Lethality — Death can occur from GHB withdrawal. Death from cardiac arrest was reported in a patient whose hospital course was complicated by pneumonia, persistent hallucinosis, and recurrent delirium [1]. Another GHB-dependent male died while incarcerated; GHB withdrawal was untreated, resulting in severe rhabdomyolysis, hyperkalemia, and cardiac arrest [69]. Deaths due to hydrocodone toxicity and water intoxication with resultant hyponatremia have occurred in patients attempting self-treatment of GHB withdrawal [70].
DIFFERENTIAL DIAGNOSIS — GHB withdrawal is uncommon. The diagnosis is made clinically based upon the presence of typical symptoms in an individual with a known history of prolonged or habitual GHB use. Without obtaining a clear history of GHB abuse and discontinuation, the clinician must evaluate the patient for other, more common causes of agitated delirium for which the differential diagnosis is broad and reviewed in detail separately. (See "Diagnosis of delirium and confusional states" and "General approach to drug poisoning in adults".)
Of note, the autonomic disturbances associated with GHB withdrawal are typically mild when compared with withdrawal or acute intoxication syndromes associated with other sedative-hypnotic agents, alcohol, or sympathomimetic agents. Conversely, agitation and delirium are often prolonged with GHB withdrawal.
The differential diagnosis of GHB withdrawal includes other sedative-hypnotic or alcohol withdrawal syndromes, acute GHB intoxication, acute intoxication with sympathomimetics (including drugs of abuse, ephedrine, ma huang, pseudoephedrine), anticholinergic syndrome, hypoglycemia, seizure disorder, serotonin syndrome, thyroid storm, neuroleptic malignant syndrome, head injury, central nervous system infection (encephalitis, meningitis), and any of the medical etiologies of altered mental status, as well as functional psychosis. These subjects, including the following topics, are discussed separately. (See "Alcohol withdrawal: Epidemiology, clinical manifestations, course, assessment, and diagnosis" and "Gamma hydroxybutyrate (GHB) intoxication" and "Cocaine: Acute intoxication" and "Acute amphetamine and synthetic cathinone ("bath salt") intoxication" and "Methamphetamine: Acute intoxication" and "Anticholinergic poisoning" and "Hypoglycemia in adults without diabetes mellitus: Clinical manifestations, diagnosis, and causes" and "Serotonin syndrome (serotonin toxicity)" and "Thyroid storm" and "Neuroleptic malignant syndrome" and "Clinical features and diagnosis of acute bacterial meningitis in adults".)
LABORATORY EVALUATION
Specific testing for GHB — Gas chromatography or mass spectrometry is necessary to detect GHB. The results of such testing often require 7 to 10 days, precluding their use in acute management. Furthermore, the rapid disappearance of GHB in the blood (four to six hours) means that blood concentrations are likely to be negative unless the patient presents with acute intoxication and progresses directly to withdrawal. While confirmation of GHB in urine may confirm ingestion and support the diagnosis, it is unlikely to be positive if the urine specimen is collected longer than 6 to 12 hours after ingestion. Laboratory confirmation is unnecessary for the diagnosis of GHB withdrawal.
General evaluation — GHB withdrawal is a clinical diagnosis; no laboratory tests are necessary. Tests are obtained on the basis of the history and physical examination to investigate alternative diagnoses or complications. (See 'Differential diagnosis' above.)
Patients withdrawing from GHB may suffer from poor nutrition and may experience symptoms, such as vomiting, hyperthermia, diaphoresis, and agitation, that increase their risk for rhabdomyolysis, acute kidney injury, and other complications. In patients experiencing GHB withdrawal, we generally obtain the following studies:
●Basic electrolytes
●Blood urea nitrogen and creatinine
●Creatine kinase
●Complete blood count (see 'Complications' above)
Co-ingestants are common among GHB abusers, so it is reasonable to perform the basic studies done for all potentially poisoned patients, including:
●Fingerstick glucose
●Acetaminophen and salicylate concentrations
●Electrocardiogram, looking in particular for toxin-related interval abnormalities
●Qualitative pregnancy test in females of childbearing age
Additional studies are obtained as needed based upon the patient's presentation. (See "General approach to drug poisoning in adults", section on 'Toxicology screens (drug testing)' and "General approach to drug poisoning in adults", section on 'Other laboratory studies'.)
Testing for other drugs of abuse can identify the presence of alcohol, benzodiazepines, or opioids that may have been used for self-detoxification. Toxicologic screening may identify the presence of sympathomimetics, whose effects can mimic GHB withdrawal. (See "Testing for drugs of abuse (DOAs)".)
MANAGEMENT OF ACUTE WITHDRAWAL
Background — No randomized controlled studies of treatment for GHB withdrawal have been performed. The management approach described below is based on a review of retrospective case series documenting acute, unplanned emergency detoxification and nonrandomized prospective studies of planned detoxification. In general, we recommend inpatient treatment but recognize that this may not be possible or optimal in all clinical contexts.
General approach — The treatment of GHB withdrawal is primarily supportive, including the administration of sedatives to control agitation, delirium, hyperthermia, and seizures; and careful monitoring for respiratory depression and potential complications.
Early symptoms of anxiety, tremor, diaphoresis, insomnia, and tachycardia may progress rapidly to severe withdrawal delirium, requiring intensive care. Aggressive efforts to control agitation and delirium may require tracheal intubation and mechanical ventilation. (See 'Severe withdrawal with delirium' below.)
Once severe withdrawal symptoms are under control, early involvement of psychiatric specialists is critical for ongoing evaluation and management of comorbid psychiatric illnesses that may contribute to relapse. Management of depression, anxiety, agitation, and insomnia is imperative prior to discharge, as well as facilitation of appropriate psychiatric follow-up and chemical dependence treatment. (See 'Chemical dependency treatment and relapse prevention' below and "Determining appropriate levels of care for treatment of substance use disorders".)
Dosing history — If the patient can provide reliable information, an approximation of dosing frequency, dose size, and total daily dose is helpful for managing withdrawal. The time of the patient's last GHB dose prior to presentation is useful.
Daily GHB doses of 10 grams or less have been reported in patients experiencing withdrawal [7,10,48]. Patients with more severe withdrawal tend to have a higher daily dose, usually >30 g GHB or >15 g gamma butyrolactone (GBL) per day, and more frequent dosing (often three times or more per day) [48].
Mild to moderate withdrawal without delirium — Patients who have anxiety, insomnia, and tremor but remain oriented and appropriately interactive (without delirium or hallucinations) are at less immediate risk for severe complications but may acutely progress to agitated delirium. We recommend inpatient detoxification for such patients.
To prevent acute decompensation, it is important to treat patients' symptoms (eg, anxiety, tremor, diaphoresis, insomnia) rapidly and aggressively with sedative-hypnotic agents. Diazepam is an excellent treatment choice. Intravenous (IV) diazepam can be titrated, but patients must be monitored closely for signs of respiratory depression and oversedation. (See 'Benzodiazepines' below.)
Barbiturates, such as pentobarbital and phenobarbital, can also be used. Propofol has been used successfully in cases of refractory withdrawal. Barbiturates and propofol pose a greater threat of respiratory depression than do benzodiazepines. The great majority of patients treated with propofol or a combination of a benzodiazepine and barbiturate require tracheal intubation and mechanical ventilation. (See 'Barbiturates' below and 'Propofol' below.)
Respiratory status should be closely monitored with pulse oximetry or capnography while sedatives are given. When possible, end-tidal carbon dioxide (EtCO2) monitoring is preferred, as patients may deteriorate rapidly and unpredictably. Frequent monitoring of mental status and vital signs (approximately every two hours) should be performed. (See "Carbon dioxide monitoring (capnography)".)
Although outpatient management of mild withdrawal is performed at some institutions, we believe it is safer to manage these patients in the hospital or in addiction treatment facilities with readily available transfer to hospitals when needed. (See 'Outpatient detoxification for acute withdrawal' below.)
Severe withdrawal with delirium — Severe withdrawal increases the risk of self-harm and complications (eg, hyperthermia, rhabdomyolysis, seizures) and requires treatment with large doses of sedatives. Therefore, close monitoring in an intensive care setting is needed. Benzodiazepines are the mainstay of treatment for severe GHB withdrawal. (See 'Benzodiazepines' below.)
Respiratory depression, due to the high doses of sedatives necessary to control refractory withdrawal, often necessitates tracheal intubation and mechanical ventilation. Rapid sequence intubation may be performed using standard induction and neuromuscular blocking medications. Continuous cardiac and pulse oximetry monitoring are needed. (See 'Complications' above and 'Benzodiazepines' below and "Rapid sequence intubation for adults outside the operating room".)
Although there are no published reports of hyperthermia associated with GHB withdrawal, standard external cooling methods should suffice for treatment should this occur. Rhabdomyolysis is a potential complication, and serum creatine kinase concentrations should be measured in patients with severe withdrawal. The diagnosis and management of rhabdomyolysis are reviewed separately. (See "Rhabdomyolysis: Clinical manifestations and diagnosis" and "Severe nonexertional hyperthermia (classic heat stroke) in adults", section on 'Management'.)
When IV sedatives are no longer necessary, agitation is well controlled, and delirium has resolved, the patient no longer requires intensive care unit-level care.
Medications used for sedation
Benzodiazepines — Benzodiazepines are the mainstay of treatment for GHB withdrawal. A long-acting benzodiazepine is recommended. Diazepam may be given in a dose of 10 mg IV every 5 to 10 minutes and titrated as necessary for adequate sedation [71]. Patients with extreme agitation may require more frequent and larger doses. Very large doses may be required and can be given, provided respiratory status is closely monitored and tracheal intubation can be performed immediately if necessary.
With less severe symptoms, treatment with oral diazepam may suffice. For GHB-dependent patients taking less than 30 to 32 g of GHB per day, daily doses of diazepam ranging from 20 to 80 mg may be given [8,23,48]. The Maudsley Guidelines found in the following reference provide extensive detail about GHB detoxification for inpatients undergoing acute unplanned withdrawal [72]. (See "Sedative-analgesic medications in critically ill adults: Properties, dose regimens, and adverse effects", section on 'Benzodiazepines'.)
Diazepam has a rapid onset of action (maximum effect in five minutes) but a high volume of distribution, rapidly redistributing into adipose tissue, so its sedative effects may diminish rapidly, necessitating repeat doses until total body loading is achieved. Although loading doses (oral or IV) may not decrease the likelihood of withdrawal delirium, they reduce the severity of delirium and control agitation [57]. Once adequately loaded, patients generally need smaller additional amounts to control symptoms. Diazepam's high lipid solubility and slow metabolism and elimination create a long duration of action. Other benzodiazepines (eg, lorazepam, chlordiazepoxide) can be used to treat GHB withdrawal, although there is no advantage to these agents over diazepam.
Shortages of IV diazepam may necessitate other options. Oral diazepam is useful but does not have rapid onset. IV lorazepam is effective but lacks the long half-life and lipid solubility of diazepam. Nevertheless, if IV lorazepam is the only option, we recommend giving it in 2 mg increments every 10 to 15 minutes, titrating to effect. It is important to remember that lorazepam levels will drop substantially over 24 hours as will its therapeutic effect. Therefore, we recommend replacing IV lorazepam with oral diazepam as soon as possible.
Although symptom-triggered therapy protocols (similar to those used in the treatment of alcohol and benzodiazepine withdrawal) have not been validated specifically for GHB withdrawal, both objective and subjective scales (CIWA-Ar, OWS, SWS/OWS) [23,32,39,73,74] have been used. We believe they provide a sound management approach and concur with the concept of using rapidly escalating doses of a benzodiazepine until control of clinical symptoms such as agitation or delirium is achieved. The use of a validated alcohol or benzodiazepine withdrawal scale can aid in establishing a baseline and enabling ongoing assessment of the clinical course and the response to sedation. However, benzodiazepine dosing should be based on control of clinical symptoms rather than objective scoring [23,25], and clinicians must note that dosages may differ substantially when treating for GHB withdrawal; one must assess individual responses and dose accordingly (table 1). Use of this approach for alcohol withdrawal is reviewed separately. (See "Management of moderate and severe alcohol withdrawal syndromes", section on 'Management'.)
Resistance to benzodiazepine therapy occurs with some frequency among patients being treated for GHB withdrawal, particularly those taking high doses of GHB. Whereas GHB acts at GABA-B receptors (and GHB-specific receptors), benzodiazepines act at GABA-A receptors, which may account for the limited efficacy of benzodiazepines in some cases of severe acute GHB withdrawal [8]. In such cases, an adjunctive or alternative sedative should be used. We believe that if 100 mg of IV diazepam given over 60 minutes fails to achieve control of agitation, it is reasonable to add a barbiturate or propofol. (See 'Barbiturates' below and 'Propofol' below.)
Most, if not all, patients who require additional treatment with barbiturates and propofol will require tracheal intubation and mechanical ventilation.
Once acute withdrawal symptoms are controlled, benzodiazepine treatment may be continued over several weeks in severe cases, with the dose gradually tapered.
After the patient is stabilized on benzodiazepines, propofol, or barbiturates, the patient can be transitioned to oral or IV diazepam. If the patient remains stable on diazepam, then tapering can be fairly rapid, over five to seven days. Because of the long half-life and high lipid solubility of diazepam, serum concentrations decline slowly, and its therapeutic effect lasts for weeks.
Barbiturates — Phenobarbital and pentobarbital have been used successfully in several reported cases alone and in combination with benzodiazepines in the treatment of GHB withdrawal. Barbiturates are particularly useful in cases of GHB withdrawal resistant to benzodiazepines [3,66]. Patients must be monitored closely for respiratory depression when barbiturates are administered with benzodiazepines, and the great majority of patients requiring concurrent benzodiazepine and barbiturate therapy will require tracheal intubation and mechanical ventilation. (See "Sedative-analgesic medications in critically ill adults: Properties, dose regimens, and adverse effects", section on 'Barbiturates'.)
Phenobarbital has a longer half-life than pentobarbital and can be administered at an initial dose of 250 mg IV and then titrated for symptom control in increments of 125 to 250 mg IV every 15 to 30 minutes to achieve a serum concentration of 5 to 15 mcg/mL [57]. Most patients require approximately 500 mg for immediate symptom control [57]. Once the patient is stabilized for one week on a daily dose of phenobarbital, the dose may be decreased by 10 to 15 percent per week [8]. Alternatively, the patient can be transitioned to diazepam [8]. (See 'Benzodiazepines' above.)
Pentobarbital may be titrated for symptom control in 100 to 200 mg IV increments [57]. Some clinicians report administration of pentobarbital in accordance with their protocol for benzodiazepine-resistant ethanol withdrawal, giving 1 to 2 mg/kg IV doses every 30 to 60 minutes for symptom control [3].
Tapered oral doses of benzodiazepines and barbiturates may then be used over several weeks until the patient has stabilized [57].
Once stabilized, the patient can be transitioned to oral or IV diazepam. If the patient remains stable on diazepam, then tapering can be fairly rapid, over five to seven days. Because of the long half-life and high lipid solubility of diazepam, serum concentrations decline slowly, and its therapeutic effect lasts for weeks. (See 'Benzodiazepines' above.)
If phenobarbital is used for initial therapy, the outpatient detoxification protocol using phenobarbital described below may provide guidance for phenobarbital tapering. (See 'Detoxification for acute withdrawal using pharmaceutical GHB' below.)
Propofol — Propofol has been used to treat refractory agitation in severe GHB withdrawal [1,4,8]. Patients treated with propofol should be intubated and managed with mechanical ventilation. (See "Sedative-analgesic medications in critically ill adults: Properties, dose regimens, and adverse effects", section on 'Propofol'.)
An initial IV infusion of 5 mcg/kg per minute (0.3 mg/kg per hour) for 5 to 10 minutes until the patient is sedated to the desired level is the recommended dosage for withdrawal treatment. Sedation is maintained with infusion rates of 5 to 50 mcg/kg per minute, titrated to effect [75]. Doses up to 80 mcg/kg per minute may be necessary to control refractory agitation [76]. Dose must be titrated to symptom control with careful monitoring.
Dexmedetomidine — A few case reports describe the use of dexmedetomidine as an adjunct therapy for severe GHB withdrawal delirium [77-79]. Dexmedetomidine is a short-acting alpha-2 adrenoreceptor agonist that produces relatively little respiratory depression. As dexmedetomidine involves a distinct mechanism of sedation from benzodiazepines, patients are more interactive and better able to communicate their needs. A typical adult dose of dexmedetomidine given in the intensive care unit setting for sedation is 0.2 to 1.5 mcg/kg per hour [79]. Doses up to 0.012 mcg/kg per minute (0.72 mcg/kg per hour) have been administered for GHB withdrawal [77]. In the absence of controlled studies, we recommend that dexmedetomidine be used only as an adjunct treatment pending further study.
Baclofen — Baclofen is a high-affinity GABA-B agonist that has been used to reduce the severity of withdrawal symptoms and improve abstinence in substance use disorders [80]. GHB acts mainly at GABA-B and GHB receptors, while benzodiazepines are mainly GABA-A agonists.
Baclofen has been used as an adjunct therapy for inpatient treatment of severe cases refractory to benzodiazepine therapy [7,13,81], in both inpatient and outpatient detoxification protocols along with benzodiazepine tapers [21,22,51,72,82], and as a sole prospective detoxification treatment in a patient with multiple previous GHB detoxification attempts resistant to benzodiazepine therapy [60]. Baclofen has also been administered to patients after GHB detoxification to reduce craving and prevent relapse [77,83]. (See 'Chemical dependency treatment and relapse prevention' below.)
Baclofen administered in 10 mg doses three times daily has been reported to decrease craving and enable patients to decrease their GHB or GBL doses during the two days prior to planned detoxification (so-called "pre-loading"), which may allow for lower starting doses of benzodiazepine for detoxification, improve symptom control, and shorten the overall course of detoxification [24,82].
Although no adverse effects related to baclofen use for GHB dependence have been reported in supervised outpatient clinical settings, respiratory depression due to a concurrent baclofen and GHB abuse has been reported in other settings [84]. Baclofen withdrawal is an additional potential adverse effect, but this has not been described in relation to GHB dependence therapy. Randomized controlled trials of baclofen for treatment of GHB withdrawal are needed.
Antipsychotic medications — Haloperidol and other neuroleptic agents are not routinely recommended for the treatment of GHB withdrawal. These agents are ineffective for the control of withdrawal symptoms and may have adverse effects, including dystonic reactions, anticholinergic effects, lowered seizure threshold, cardiac dysrhythmia, neuroleptic malignant syndrome, and hyperthermia [5,8,48,53].
Management of seizures — A small number of cases of seizure associated with GHB withdrawal have been reported, and additional reports document twitching and tonic-clonic movements. Benzodiazepines are used to treat seizures associated with GHB withdrawal. (See 'Benzodiazepines' above.)
IV fluids and vitamin repletion — Wernicke-Korsakoff syndrome has been reported in patients experiencing GHB withdrawal, abusing both GHB and alcohol, or using GHB to reduce alcohol intake [23,45,64,65]. We recommend empiric treatment with thiamine, magnesium, and folate. Thiamine 100 mg may be given daily, with initial dose by injection, along with other vitamins as needed [75]. (See "Wernicke encephalopathy".)
Poor nutrition and withdrawal symptoms (eg, vomiting, diaphoresis, agitation) may contribute to fluid, glucose, and electrolyte imbalances, placing patients at increased risk for rhabdomyolysis, acute kidney injury, and arrhythmias. Glucose, electrolytes, renal function studies, creatine kinase, and fluid status should be monitored and corrected as needed. (See 'Laboratory evaluation' above.)
Restraints — Physical restraints may be necessary initially to control severe agitation and prevent injury to the patient and staff. Sedation is much preferred, and physical restraints should be removed as soon as sedation is achieved. Appropriate monitoring is crucial, particularly while physical restraints are in place. (See "Assessment and emergency management of the acutely agitated or violent adult", section on 'Physical restraints'.)
Antihypertensive medications — Hypertension can occur with GHB withdrawal as a result of central sympathetic stimulation, in which case, it is best treated by controlling such stimulation with sedatives (eg, diazepam).
Only pre-existing primary hypertension should be managed using antihypertensive medications. We believe that beta blocking medications are contraindicated in GHB withdrawal. They are ineffective in treating or preventing withdrawal delirium and may worsen hypertension and coronary ischemia.
Detoxification for acute withdrawal using pharmaceutical GHB — Due to a relatively large number of cases of GHB withdrawal that were refractory to treatment with benzodiazepines, Dutch specialists developed an inpatient detoxification treatment protocol using titration and tapering (DeTiTap) of pharmaceutical GHB (which is often sodium-GHB) [8,10,59]. Although long-acting medications are generally preferred for withdrawal treatment, and GHB has a short duration of action, the DeTiTap protocol has been successful. Large studies (total n = 450) report that GHB withdrawal symptoms were significantly reduced, and successful detoxification was achieved in 85 percent of cases [32].
Using this protocol, patients are admitted and administered a dose of pharmaceutical GHB within 2.5 hours of the last self-administered dose to prevent withdrawal symptoms. The initial dose is calculated per protocol and titrated up or down over the course of one to two days to identify the dose at which the patient is stable and experiences neither withdrawal nor sedation. Once this dose is found, subsequent doses are tapered over 7 to 14 days (mean 11 days). The protocol has been incorporated into national Dutch treatment guidelines as standard GHB detoxification [8,10,32].
Adverse events using this protocol are uncommon; delirium was reported in only 2 percent of patients [32]. Two cases of hypernatremia in patients treated with pharmaceutical sodium-GHB have been reported. In both cases, excessive doses of GHB were administered in addition to infusions of sodium chloride solution (NaCl). When high doses of sodium-GHB are being given, serum sodium concentrations should be monitored daily [85].
A matched-subject, multicenter observational study compared a subset of Dutch patients detoxified using the pharmaceutical GHB taper (n = 42) with a historical sample of GHB-dependent Belgian patients detoxified using a benzodiazepine taper (n = 42) [32]. The Belgian patients experienced more severe withdrawal, a higher rate of delirium (21 versus 5 percent), more adverse events (21 versus 5 percent), and more transfers to critical care for treatment (2 versus 0 patients). A similar pharmaceutical GHB detoxification protocol has been developed in Denmark [86].
Outpatient detoxification for acute withdrawal — Treatment of GHB withdrawal and detoxification from GHB dependence should be performed in an inpatient setting whenever possible, as the risks entailed by outpatient treatment are high, particularly in cases of acute unplanned detoxification. The clinical course of GHB withdrawal is variable and unpredictable, can entail prolonged delirium, and is potentially lethal. However, in some cases, outpatient treatment may be necessary. Some patients may be unable to pay for inpatient treatment, while others are unwilling to be inpatients. Supervised outpatient treatment is safer than unsupervised self-treatment, which has proven fatal in some instances.
Several studies suggest that closely monitored detoxification for GHB withdrawal in ambulatory settings can be safe and successful when delivered by a specialist team with ready access to acute medical treatment if needed, particularly for patients who ingest lower cumulative daily doses. Outpatient clinics and treatment services in London [22,24], Dublin [28,38,51], and Melbourne [7] report successful outpatient detoxification using symptom-guided diazepam titration and tapers and baclofen, with close follow-up for monitoring and ongoing psychiatric and social support. The Maudsley Guidelines protocol in the following reference provides more detailed guidance about planned GHB/GBL detoxification in ambulatory settings [72].
Closely monitored outpatient detoxification for GHB withdrawal may be acceptable if the following conditions are met:
●GHB dependence is mild, involving less than three regular doses of GHB per day and a total daily dose of less than 30 grams of GHB (or less than 15 grams of GBL)
●No history of previous GHB detoxification or treatment failures
●No comorbid alcohol or drug dependence, especially benzodiazepines
●Adequate social support is present, and a family member or friend is at home to supervise daily diazepam dosing
●No symptoms or signs of active withdrawal are detected
●Treatment center has an established protocol for planned outpatient GHB detoxification, including the following:
•Detailed intake performed, including GHB use history (individual dose size, frequency, and total daily dose of GHB, GBL, and/or BD)
•Carefully planned and closely monitored initial diazepam titration on day one, with direct observation of several diazepam doses over four to six hours
•Daily monitoring following initial treatment dose and observation period
•Psychiatric treatment and social counseling provided
•Capacity for seamless hospital admission for acute medical care as needed
•Follow-up with close monitoring over two to four weeks to check for tachycardia, insomnia, anxiety, or other medical deterioration and to provide ongoing counseling and post-detoxification psychiatric treatment of depression, anxiety, insomnia, or other complications (see 'Chemical dependency treatment and relapse prevention' below)
One other outpatient protocol has been reported for the treatment of patients with mild GHB withdrawal (ie, no psychotic symptoms; vital signs normalized rapidly with treatment) [8]. This approach used phenobarbital as part of a symptom-driven substitution-taper protocol originally developed for sedative-hypnotic drug detoxification. Patients were stabilized using benzodiazepines initially and then switched to an equivalent dose of phenobarbital divided over four to six doses daily, or were started on fixed-dose phenobarbital 60 mg every two hours until symptoms subsided. Patients were continued on this dose for one week and then tapered by 10 to 15 percent of the starting dose each week. Additional elements of the outpatient treatment protocol included relapse prevention training, counseling, medical and psychiatric services, and screening for drug use.
CHRONIC SEQUELAE FOLLOWING DETOXIFICATION — Few data exist on the long-term effects of chronic GHB use. Problems reported following GHB detoxification include the following [9,22]:
●Impaired memory
●Impaired learning and cognition
●Depression and anxiety
●Tremor
●Insomnia
Cognitive problems experienced by chronic GHB users following detoxification and impairment of learning and memory in animals following GHB administration have been reported [87]. These associations suggest potential neurotoxicity, either through direct effects or from hypoxia-induced brain injury due to multiple overdoses resulting in coma.
Some dependent GHB users report frequent, even daily, episodes of coma related to use [27,30], and Dutch studies document high rates of admission to emergency departments for such comas [9]. Dutch research involving functional magnetic resonance imaging (MRI), verbal and spatial memory testing, and questionnaires assessing negative affect (depression, anxiety, stress) has been conducted comparing GHB users reporting four or more GHB-related comas with GHB users without comas and polydrug users with no GHB use. Findings suggest that multiple GHB comas are associated with impaired memory and affect, and with alterations of brain structures involved in memory and affect [88,89].
Potential pre-existing cognitive impairment in GHB-dependent users and the effects of polydrug use complicate research on the long-term cognitive effects of chronic GHB use. Nevertheless, the high prevalence and severity of cognitive impairment in this relatively young cohort (average age 28 years) suggest that GHB use generally and the high number of GHB-induced comas among some users have adverse long-term effects on cognition [40].
Permanent cerebellar dysfunction has been attributed to chronic GHB use in one case [90].
CHEMICAL DEPENDENCY TREATMENT AND RELAPSE PREVENTION — Relapse is common among GHB-dependent patients, on the order of 70 percent, with the greatest risk during the first week [10,28]. General management of substance misuse is discussed separately; specific issues pertaining to GHB are discussed here. (See "Clinical assessment of substance use disorders".)
In one study of 65,474 patients with drug and behavioral conditions, GHB-dependent patients had the highest admission and re-admission rates, greatest number of treatment contacts, and longest average duration of treatment [9]. Re-admission rates for GHB-dependent patients were two to five times higher than those of alcohol-dependent and other drug-dependent patients. Several studies describe GHB dependence as particularly disruptive to users [9,31,40], with frequent dosing (up to hourly around the clock) and frequent overdose contributing to difficult living conditions [31].
Early and intensive involvement of psychiatric specialists is critical for post-detoxification management of comorbid conditions such as depression, anxiety, and sleep disturbances (insomnia is a significant factor in relapse) [22,40].
Baclofen has been used successfully to reduce craving and prevent relapse after detoxification. Patients report that baclofen reduces craving and anxiety and aids sleep and concentration [22,77]. In an open-label, non-randomized trial, baclofen (45 to 60 mg/day) in addition to cognitive behavioral therapy was superior to cognitive behavioral therapy alone [83]. Patients given baclofen had higher treatment completion rates at three months (95 versus 69 percent), lower relapse rates (15 versus 50 percent), and limited side effects. An earlier, smaller study of GHB-dependent patients treated with 30 to 60 mg baclofen per day for three months reported similar results [91].
As early as possible during inpatient treatment, clinicians should discuss ongoing, intensive outpatient management of chemical dependency with the patient and family members. Coordinated care following discharge may entail counselling (eg, cognitive behavioral therapy), lifestyle training, and interventions to assist with housing, debt management, and other needs that are important for preventing relapse [31,38,40].
PITFALLS IN MANAGEMENT — Multiple drug dependencies have been reported among GHB users, and clinicians treating patients with GHB withdrawal should be aware of this possibility. Co-dependencies may result from concurrent recreational use of GHB and other drugs, or from use of benzodiazepines, alcohol, or opiates for self-treatment of GHB withdrawal. Conversely, GHB may be used as an alcohol or drug substitute, or for self-treatment of alcohol or drug dependence/withdrawal.
ADDITIONAL RESOURCES
Regional poison control centers — Regional poison control centers in the United States are available at all times for consultation on patients with known or suspected poisoning, and who may be critically ill, require admission, or have clinical pictures that are unclear (1-800-222-1222). In addition, some hospitals have medical toxicologists available for bedside consultation. Whenever available, these are invaluable resources to help in the diagnosis and management of ingestions or overdoses. Contact information for poison centers around the world is provided separately. (See "Society guideline links: Regional poison control centers".)
Society guideline links — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Treatment of acute poisoning caused by recreational drug or alcohol use" and "Society guideline links: Poisoning prevention".)
SUMMARY AND RECOMMENDATIONS
●Epidemiology – Illicit use of gamma hydroxybutyrate (GHB) occurs for recreation and for a number of alleged health benefits, including bodybuilding and treatment of insomnia, generalized and social anxiety, and alcohol dependence. GHB use can lead to severe dependence. Cessation can lead to withdrawal, which may be lethal. (See 'Epidemiology' above.)
●Clinical features – Onset of GHB withdrawal symptoms occurs rapidly, typically within one to six hours of cessation or decrease. Initial symptoms include anxiety, tremor, agitation, diaphoresis, tachycardia, vomiting, and insomnia. Insomnia can be profound. Within 24 hours, symptoms may progress to severe withdrawal, with refractory agitation, hallucinations, delusions, and delirium. Delirium may develop rapidly and persist as long as 14 days. Symptom course often progresses unpredictably. Autonomic instability, if present, is usually mild to moderate. (See 'Clinical features of withdrawal' above.)
Severe and refractory agitation increases the risk of hyperthermia, rhabdomyolysis, and disseminated intravascular coagulation. (See 'Complications' above.)
●Diagnosis – The diagnosis of GHB withdrawal is made clinically based on the presence of typical symptoms in an individual with a known history of prolonged or habitual GHB use. Without such a history, the clinician must evaluate the patient for other, more common causes of agitated delirium, for which the differential diagnosis is broad. (See 'Differential diagnosis' above and "Diagnosis of delirium and confusional states" and "General approach to drug poisoning in adults".)
●Laboratory studies – No laboratory tests are necessary to diagnosis GHB withdrawal. Tests are obtained on the basis of the history and examination to investigate alternative diagnoses or complications. In patients experiencing GHB withdrawal, we generally obtain the following studies: basic electrolytes, blood urea nitrogen and creatinine, creatine kinase, and a complete blood count. Co-ingestants are common among GHB abusers, so it is reasonable to perform the basic studies for poisoned patients, including fingerstick glucose, acetaminophen and salicylate levels, electrocardiogram, and a pregnancy test in females of childbearing age. (See 'Laboratory evaluation' above.)
●Treatment – Treatment of GHB withdrawal is primarily supportive, with administration of sedatives to control agitation, delirium, hyperthermia, and seizures; and careful monitoring for respiratory depression and potential complications. We suggest clinicians use long-acting benzodiazepines for the control of symptoms due to GHB withdrawal (Grade 2C). We give diazepam 10 mg intravenously (IV) every 5 to 10 minutes; titrate to restfulness. Patients with extreme agitation may require more frequent and larger doses. Very large doses may be administered, provided respiratory status is closely monitored and tracheal intubation can be performed immediately if necessary. Alternative and adjunctive treatments include barbiturates, propofol, and dexmedetomidine. (See 'Management of acute withdrawal' above and 'Benzodiazepines' above.)
●Withdrawal – The clinical course of withdrawal is unpredictable, even with optimal treatment. For this reason, we recommend that patients with mild withdrawal be treated in an inpatient setting or in a closely monitored outpatient setting using a GHB detoxification protocol and with ready access to acute medical care. Patients with severe withdrawal require admission to an intensive care unit. Management of withdrawal and dependency is reviewed in the text. (See 'Management of acute withdrawal' above.)
