Version May 2024
INTRODUCTION — Gamma hydroxybutyrate (GHB) is a medication and a drug misused 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. GHB, GBL, and BD 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 [1-13], but in medicinal use as well [14-16].
The clinical features and management of GHB withdrawal and dependence are reviewed here. Throughout this review, we use the term "GHB" to refer to GHB and its analogs, GBL and BD, unless specifically noted. The following are discussed separately:
●The pharmacology of GHB and its analogs and the management of acute GHB intoxication (see "Gamma hydroxybutyrate (GHB) intoxication")
●The general management of the poisoned patient (see "General approach to drug poisoning in adults" and "Initial management of the critically ill adult with an unknown overdose")
●Assessment of the patient with substance use disorder (see "Substance use disorders: Clinical assessment")
EPIDEMIOLOGY — Gamma hydroxybutyrate (GHB) products were first sold in the United States (US) and Europe in the late 1980s as a sleep aid and for purported anabolic effects. GHB analogs, gamma butyrolactone (GBL) and 1,4 butanediol (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 [1-5]. As recreational use grew and reports of adverse effects increased, regulation of GHB and its analogs resulted in the removal of products and a shift to illicit supplies. Pharmaceutical GHB (sodium oxybate) is available (brand names include Xyrem, Xywav, Alcover, and Somsanit) for the treatment of narcolepsy. The epidemiology of GHB misuse is discussed separately. (See "Gamma hydroxybutyrate (GHB) intoxication", section on 'Epidemiology'.)
Prevalence — The prevalence of chronic GHB misuse and dependence is not well known and drawn largely from case reports, case series, and limited inclusion in some national surveillance systems. GHB use disorder is not recognized in the Diagnostic and Statistical Manual of Mental Illnesses (DSM-5), and there are no International Classification of Diseases – 10 edition (ICD-10) codes for GHB, thus limiting data collection.
Cases of GHB dependence and withdrawal internationally increased substantially in the mid to late 2000's and continue at rates higher than the US, particularly in the United Kingdom, Australia, and the Netherlands.
●In the US, the earliest cases of GHB dependence and withdrawal were reported in California and Minnesota in the early 2000's among bodybuilders, health supplement users, and recreational drug users [1,2,4,5]. National data collected by the US Substance Abuse and Mental Health Services on treatment services included GHB in 2016 and indicates that cases continue at a low level. Annually, the number of patients in treatment for GHB dependence increased from 225 in 2016 to 404 in 2021. The percentage of patients for whom GHB was identified as the primary drug of dependence also increased from 14 to 20 percent during this period [17,18].
●In the United Kingdom, cases are predominately among nightclub/dance party attendees and men who have sex with men [19-27]. Data from the National Drug Treatment Monitoring System (NDTMS) indicates that the number of patients in treatment for GHB/GBL dependence increased from 457 in 2016/2017 to 559 in 2022/2023, accounting for 2.5 percent of people in treatment for Club Drug dependence in that period [28,29].
●In Australia, the number of patients in treatment for GHB dependence increased from 164 in 2019, to 520 in 2020, and 479 in 2021 [30]. Case series have reported patients with GHB withdrawal in Sydney [31-34], where admissions in one health district quadrupled during the first 12 months after the coronavirus disease 2019 pandemic [33]. Co-use of methamphetamine is very common, ranging from 54 to 100 percent [31-34] and co-dependence of GHB with methamphetamine was 79 percent in one series [33]. While patients with GHB dependence are predominantly males, females account for 49 to 58 percent in these Australian case series [31-34]; approximately 60 percent of patients in treatment for GHB dependence from 2019 through 2021 were female [30].
●In the Netherlands, GHB misuse and dependence have had a significant health impact, requiring community level adaptations. Patients with GHB dependence accounted for 2 percent (956 total) of all patients receiving treatment in 2021 [35]. Dutch authorities have created a municipal approach to address GHB-related problems involving medical and addiction services, law enforcement, and municipal personnel, to break the recurring pattern of treatment and relapse [36]. Multisite research on more than 65,000 Dutch addiction patients found that patients with GHB dependence had the highest treatment intensity, comprised of the highest admission rates, most treatment contacts, longest treatment duration, and highest chance of readmission [8].
Demographics — The mean age of patients treated for GHB dependence is between 27 and 34 years [9,12,31,32,37-39]. Patients with GHB dependence 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 [9-12,25-27,32,33,37,40].
Patients who use GHB very frequently use other drugs concurrently, especially stimulants and alcohol.
RISK FACTORS AND SIGNS OF DEPENDENCE — Studies suggest there is greater risk for dependence 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 chronic use, tolerance, and subsequent dependence [11,13,21,37,42-44]. Additional factors that may increase the risk of dependence include use for bodybuilding or self-medication of sleep problems [7,11-13,21,45] and psychiatric comorbidity, particularly anxiety and depression [7,12,20,46]. 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 [1,2,4,6,7,10,11,20,47].
Patients with GHB dependence report frequent, sometimes daily, episodes of loss of consciousness (GHB coma) due to the steep dose response of GHB [7,43]. Deaths of individuals with GHB dependence due to lethal overdoses have been reported [48,49]. Despite high rates of transport to emergency departments for overdose and associated trauma from falls and motor vehicle collisions, individuals often perceive GHB comas as transient and harmless and tend to minimize risks associated with use [26,37,42,43].
Warning signs of GHB/GBL dependence may include [24]:
●Weekday use when not partying, clubbing, or socializing
●Use multiple times 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 [50].
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 [7,10].
CLINICAL FEATURES OF WITHDRAWAL
Presentation and dosing patterns — 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 [51]. 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 [52]. (See "Alcohol withdrawal: Epidemiology, clinical manifestations, course, assessment, and diagnosis".)
Reported dose size among patients with GHB dependence 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) [9]. Other Dutch studies report that concentrations of GHB were approximately 650 mg/mL (since patients often report doses in milliliters without knowing concentration), although concentrations vary [53,54]. Daily doses of greater than 30 grams of GHB or 15 grams of GBL have been used to predict increased risk of severe withdrawal [55].
GHB dosing patterns among patients 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 [1,3,4,26,37]. Most patients with GHB dependence who develop withdrawal engage in frequent daily dosing (ie, every one to six hours) for a period of weeks to months or years. As physical dependence worsens, dosing may occur every 30 to 60 minutes, often with nocturnal/around-the-clock dosing to control withdrawal symptoms [1,6,7,39,55]. Patients with severe dependence often keep a bottle of GHB at hand to sip throughout the day as needed [7]. However, severe withdrawal has occurred with use every two to three hours, around the clock, for a duration as short as 7 to 10 days [45,56,57]. Dosing more than three times per day, particularly with nocturnal dosing, has been used to predict increased risk of severe withdrawal [32,39,55].
Patients with GHB withdrawal may present specifically for planned treatment or for acute, unplanned treatment of withdrawal symptoms, or may develop symptoms of withdrawal while hospitalized for GHB intoxication, trauma, or other medical conditions [58]. GHB withdrawal can also occur in patients admitted to psychiatric, detoxification, and correctional facilities.
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.
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 kidney failure), and possibly death [1,5,7,58,59].
Profound insomnia is common and has been reported to play a key role in ongoing use, decision to seek treatment, withdrawal severity, and relapse [11,21,55]. Severe insomnia despite aggressive pharmacotherapy may exacerbate psychosis and delirium [2,3,60].
Variability in the presentation and treatment response may be due to GHB dose, total daily intake, frequency of use, and use of co-intoxicants. Delayed presentation for treatment is associated with more severe symptoms. Gamma butyrolactone (GBL) withdrawal may be associated with a more rapid onset of symptoms [55,61,62]. Patients who use both GHB and stimulants may experience increased agitation, restlessness, and tachycardia within the first five hours of GHB withdrawal [52].
Patients with GHB dependence commonly self-treat withdrawal symptoms with alcohol, benzodiazepines, opioids, baclofen, or other drugs. They may attempt self-detoxification using regimens based on previous medical detoxifications or on information gathered from internet forums, chats, and recreational websites. This may delay presentation and affect withdrawal course [22,51,63,64].
Withdrawal duration ranges from 2 to 15 days, with longer presentations typically due to complications such as hyperactive delirium, rhabdomyolysis, and acute kidney injury [7]. Treatment may require stays in the intensive care unit of up to 15 days and hospitalization for up to 58 days [36]. Patients with more frequent and higher dosing may experience more severe symptoms, higher rates of delirium, and more prolonged withdrawal [7,55].
Specific signs and symptoms
●Vital signs – Although tachycardia and hypertension have been reported [7,9,55], 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 [1,65,66]. This stands in contrast to the severe autonomic instability seen with delirium tremens in alcohol withdrawal. In cases of severe GHB withdrawal, hyperthermia with a temperature up to 41.5⁰C has been reported [58,61]. (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 [7,65].
Tremor is an early and often persistent sign of GHB withdrawal [7,55,65]. Tonic-clonic seizures have been reported [7,14,33,63,67-70]. Nystagmus has been reported [6,7,48,67].
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 [71,72]. (See "Overview of the chronic neurologic complications of alcohol" and "Overview of the chronic neurologic complications of alcohol", section on 'Korsakoff syndrome'.)
●Cardiovascular effects – Although hypertension and tachycardia have been reported [7,9,36,55], autonomic instability tends to be mild to moderate [1,65], particularly when compared with alcohol withdrawal.
●Gastrointestinal effects – Gastrointestinal symptoms including nausea, vomiting, and diarrhea have been reported [7,55].
●Other effects – Diaphoresis is common in early or mild GHB withdrawal [7,55].
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 [1,4,7,34,38,39,68,73,74]. Rhabdomyolysis was reported in 7 to 16 percent of cases reviewed [7,58,75]. Acute kidney injury and failure necessitating dialysis have been reported in two cases of GBL withdrawal [76,77]. (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 [78]. Deaths due to opioid toxicity and from water intoxication with resultant hyponatremia have occurred in patients attempting self-treatment of GHB withdrawal [64].
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 use and discontinuation, the clinician must evaluate the patient for other, more common causes of delirium with hyperactive behavior 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 illicit drugs, 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, causes, and diagnosis" 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, which 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 individuals who use GHB, 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 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 — No randomized controlled studies of treatment for GHB withdrawal have been performed. The management approach described below is based on a review of retrospective and prospective case series documenting acute, unplanned emergency detoxification, planned inpatient and outpatient detoxification, and locally-initiated treatment protocols.
General approach — The treatment of GHB withdrawal is primarily supportive, including the prompt administration of sedatives to control symptoms and prevent progression to severe agitation, delirium, rhabdomyolysis, and seizures. Careful monitoring for respiratory depression and potential complications is critical. In general, we recommend inpatient treatment but recognize that this may not be possible or optimal in all clinical contexts. We assess the risk of severe withdrawal, whenever possible, to guide treatment. (See 'Assessing the risk of severe withdrawal' below.)
Early symptoms of anxiety, tremor, diaphoresis, insomnia, and tachycardia may develop very quickly following dose cessation and 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 "Substance use disorders: Determining appropriate level of care for treatment".)
Assessing the risk of severe withdrawal — We assess the risk of severe withdrawal to guide treatment in cases of acute unplanned and planned detoxification.
Whenever possible, gather information on the substance used (GHB, GBL [gamma butyrolactone], or BD [butanediol]), dose size, total daily dose, dosing pattern including nocturnal dosing or around-the-clock use, history of continuous daily use, regular use of other substances including use to self-treat withdrawal symptoms, time since last dose, and time and nature of withdrawal symptoms experienced previously, particularly psychosis and delirium.
The following suggest increased risk of developing severe withdrawal [6,27,55,79]:
●Daily doses of 30 grams or more of GHB or 15 grams of GBL
●Dosing three or more times per day
●Around the clock use, with nocturnal dosing for sleep or to control withdrawal symptoms
●Use of alcohol or drugs (benzodiazepines, opiates, baclofen) for sleep or self-treatment of withdrawal symptoms
●History of previous failed GHB detoxification
●History of previous severe GHB withdrawal with psychosis or delirium
●Significant medical or psychiatric co-morbid conditions including co-dependency on alcohol or drugs
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 hyperactive 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. In cases of planned detoxification, sedatives may be started before symptom onset, depending on the time since the last dose and risk of severe withdrawal [32]. 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. Diazepam may be administered orally for mild symptoms. Baclofen may also be used in addition to benzodiazepines. (See 'Benzodiazepines' below and 'Baclofen' 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 risk of respiratory depression than do benzodiazepines. Most patients treated with propofol, and some who receive a combination of a benzodiazepine and barbiturate, will 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 harm to the patient and caregivers, risk of complications (eg, delirium, 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. Barbiturates (eg, pentobarbital, phenobarbital) or propofol can also be used, particularly if there is benzodiazepine resistance, but pose a greater risk of respiratory depression compared with benzodiazepines. (See 'Benzodiazepines' below and 'Barbiturates' below and 'Propofol' 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 in adults for emergency medicine and critical care".)
Hyperthermia associated with severe GHB withdrawal has been reported, which is managed with control of neuromuscular hyperactivity and external cooling measures. 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 and should be administered as soon as symptoms are observed. 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 [80]. 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, or in cases of planned detoxification of patients at low risk for severe withdrawal, treatment with oral diazepam may suffice. For patients with GHB dependence taking less than 30 g of GHB per day and dosing less than three times per day, daily doses of diazepam ranging from 20 to 80 mg may be given [7,22,55,81].
An Australian protocol for planned detoxification in patients in whom mild withdrawal was predicted used a loading dose of diazepam (20 mg orally given every one to two hours, up to 60 mg or light sedation achieved) started as soon as possible after the last GHB dose and, ideally, prior to symptom onset. Maintenance dosing was diazepam 10 to 20 mg orally per hour, up to a maximum of 120 mg in 24 hours [32].
Diazepam has a rapid onset of action (maximum effect in five minutes with IV administration) 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 [65]. 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 [27].
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. (See "Sedative-analgesia in ventilated adults: Medication properties, dose regimens, and adverse effects", section on 'Benzodiazepines'.)
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) [22,27,52,53,69,74,82] 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. However, unlike alcohol withdrawal, hypertension and tachycardia may or may not occur with GHB withdrawal. 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 [22,24], 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 gamma aminobutyric acid (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 [7]. 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. Patients must be monitored closely for respiratory depression when barbiturates are administered with benzodiazepines, and many patients requiring concurrent benzodiazepine and barbiturate therapy will require tracheal intubation and mechanical ventilation. (See "Sedative-analgesia in ventilated adults: Medication properties, dose regimens, and adverse effects", section on 'Barbiturates'.)
Barbiturates are particularly useful in cases of GHB withdrawal resistant to benzodiazepines since they exert different effects on GABA-A receptors compared with benzodiazepines and also affect other receptors as well [3,32,34,73].
Depending on the amount of benzodiazepines already administered, an initial dose of phenobarbital 250 mg IV may be given 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 [65]. Most patients require approximately 500 mg for immediate symptom control [65]. Another approach is to administer phenobarbital 5 to 10 mg/kg IV boluses every two hours until sedation is achieved [32,34].
Orally administered phenobarbital may also be used. Australian case series describe a protocol for treatment of delirium refractory to diazepam (ie, patients who received >150 to 200 mg of diazepam in 24 hours) [32,34]. A loading dose of phenobarbital 30 mg orally, up to a maximum of 120 mg, was administered until light sedation was achieved, followed by additional 30 mg doses as needed, up to a total of 240 mg for patients on a general ward. Most patients also received baclofen orally. (See 'Baclofen' below.)
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 [7]. Tapered oral doses of phenobarbital may then be used over several weeks [65].
Alternatively, the patient can be transitioned to diazepam (oral or IV). 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, its therapeutic effect lasts for weeks. (See 'Benzodiazepines' above.)
Propofol — Propofol has been used to treat refractory agitation in severe GHB withdrawal [1,4,7,59]. Patients treated with propofol should be tracheally intubated and mechanically ventilated.
An initial IV infusion of 20 mcg/kg per minute (1.2 mg/kg per hour) may be given for 5 to 10 minutes and titrated up to 80 mcg/kg/minute until the patient is sedated. Sedation is maintained with infusion rates of 20 to 80 mcg/kg per minute. Doses up to 80 mcg/kg per minute may be necessary to control refractory agitation [83]. 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 [59,84-87]. 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 [86]. Doses up to 0.012 mcg/kg per minute (0.72 mcg/kg per hour) have been administered for GHB withdrawal [84]. 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 [88]. GHB acts mainly at GABA-B and GHB receptors, while benzodiazepines are mainly GABA-A agonists. Although it has not been studied in randomized trials, baclofen has been used off-label for pre-treatment of GHB withdrawal and for inpatient and outpatient detoxification [89]. (See 'Chemical dependency treatment and relapse prevention' below and 'Outpatient detoxification for acute withdrawal' below.)
Baclofen has been used as an adjunct therapy for inpatient treatment of severe cases refractory to benzodiazepine therapy [6,14,32,34,75,87]. The Maudsley Prescribing Guidelines recommend adding oral baclofen 10 mg three times daily to diazepam in cases of refractory symptoms [81]. An Australian protocol administered baclofen 10 to 25 mg three times daily in addition to diazepam in cases of suspected moderate or severe withdrawal [34]. Early administration of baclofen was associated with better treatment completion rates. Baclofen has been co-administered with either benzodiazepines or with phenobarbital in cases with refractory symptoms. In half of patients, baclofen was continued after discharge and weaned by taper over several weeks [32].
In a case report, baclofen monotherapy was used in a patient with previous presentations of GHB withdrawal that was refractory to both benzodiazepines and phenobarbital [69].
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 [5,7,55,58,61].
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 [22,47,71,72]. We recommend empiric treatment with thiamine, magnesium, and folate. Thiamine 100 to 500 mg may be given daily, with initial dose by injection, along with other vitamins as needed. (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, kidney 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) [7,9,54,68]. 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 [74].
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 [7,9,74].
Adverse events using this protocol are uncommon; delirium was reported in only 2 percent of patients [74]. 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 [90]. No association between severity of symptoms and pulse and blood pressure were found using this detoxification method, suggesting that relative stability of vital signs may not be suitable for monitoring of withdrawal [54].
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) [74]. 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 [79].
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 planned 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 and are not at risk for severe withdrawal. Outpatient clinics and treatment services in London [21,23], Dublin [91], and Melbourne [6] report successful planned 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 and the Camden and Islington National Health Service (NHS) Foundation Trust in England describe a carefully monitored outpatient detoxification protocol for patients at very low risk for severe withdrawal and in settings where rapid transfer for acute hospital treatment is available [81,92]. The regimen involves "pre-loading" with oral baclofen for a week prior to detoxification treatment, with attempted reduction of GHB/GBL doses. On the first day of detoxification, the patient is administered diazepam and baclofen orally and observed for four hours in the clinic. The patient is continuously monitored at home by a non-drug using adult, who supervises administration of diazepam and baclofen. The patient must return daily to the clinic for observation and titration of medications. When symptoms have resolved and diazepam has been tapered completely, the patient may continue with baclofen for up to four to six weeks.
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 misuse has been reported in other settings [93]. Baclofen withdrawal is an additional potential adverse effect, but this has not been described in relation to GHB dependence therapy. (See "GABA-B agonist (baclofen, phenibut) poisoning and withdrawal", section on 'Baclofen'.)
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 use or dependence, especially benzodiazepines
●Adequate social support is present, and a family member or friend is at home for 24-hour monitoring and 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 (with or without baclofen) 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 and patient commitment to a detailed treatment plan
•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)
An outpatient protocol with phenobarbital has been reported for the treatment of patients with dependence who ingest less than 30 grams of GHB per day and are at low risk of severe withdrawal [7]. This protocol was 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 (ie, 10 to 15 mg diazepam to 30 mg of phenobarbital) [94] 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 [7].
CHRONIC SEQUELAE FOLLOWING DETOXIFICATION — Few data exist on the long-term effects of chronic GHB use. Problems reported following GHB detoxification include the following [8,21]:
●Impaired memory
●Impaired learning and cognition
●Depression and anxiety
●Tremor
●Insomnia
Psychoactive substances are known to change brain function and structure, causing cognitive and behavioral deficits that may persist after detoxification and affect treatment outcomes, including relapse. Cognitive problems experienced by chronic GHB users following detoxification and impairment of learning and memory in animals following GHB administration have been reported [95]. A Dutch study of 103 patients with GHB dependence found cognitive impairment in 56 percent of patients pre-detoxification and in 31 percent post-detoxification. Memory effects were most prominent and were predictive of relapse [96]. These associations suggest potential neurotoxicity, either through direct effects or from hypoxia-induced brain injury due to multiple overdoses resulting in coma.
Many patients with GHB dependence report frequent, even daily, episodes of coma related to use [26,37], and Dutch studies document high rates of admission to emergency departments for such comas [8]. 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 of some studies suggest that multiple GHB comas are associated with impaired memory and affect, and with alterations of brain structures involved in memory and affect [97,98], with microstructural alterations in white matter, and higher self-reported impulsivity [99]. However, another study reported that, while cognitive impairment, particularly of memory functions, was found pre- and post-detoxification, it was not associated with the severity of GHB use disorder, or the number of GHB-induced comas [96].
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 may have adverse long-term effects on cognition [100].
Permanent cerebellar dysfunction has been attributed to chronic GHB use in one case [101].
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 [9,32,102]. General management of substance misuse is discussed separately; specific issues pertaining to GHB are discussed here. (See "Substance use disorders: Clinical assessment".)
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 [8]. 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 [8,42,100], with frequent dosing (up to hourly around the clock) and frequent overdose contributing to difficult living conditions [42].
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) [21,100].
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 [21,84]. 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 [103]. 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 [104].
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 [42,100].
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 delirium with hyperactive behavior, 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 individuals who use GHB, 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.)
●Management – Management 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. (See 'Management of acute withdrawal' above and 'Benzodiazepines' above.)
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, baclofen, propofol, and dexmedetomidine. (See 'Severe withdrawal with delirium' above and 'Barbiturates' above and 'Propofol' above and 'Baclofen' above.)
●Treatment site – 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. Closely monitored detoxification for planned GHB withdrawal in ambulatory settings may be safe for patients who ingest lower cumulative daily doses and are not at risk for severe withdrawal. (See 'Management of acute withdrawal' above and 'Outpatient detoxification for acute withdrawal' above.)
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