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Gamma Butyrolactone (GBL) Withdrawal Syndromes

Received June 1, 2000; revised September 7, 2000; accepted October 3, 2000. From Psychiatry Service, James A. Haley Veterans' Hospital, Tampa, Florida; Department of Psychiatry and Behavioral Medicine, University of South Florida College of Medicine; University of South Florida College of Medicine, Tampa, Florida. Address correspondence and reprint requests to Dr. Catalano, University of South Florida Psychiatry Center, 3515 East Fletcher Avenue, Tampa, FL 33613; e-mail: gcatalan{at}hsc.usf.edu

Key Words: GBL • Withdrawal Syndromes • Drug Abuse

Abuse of gamma hydroxybutyrate (GHB) and gamma butyrolactone (GBL) has been increasing rapidly recently, and consultation-liaison psychiatrists are being called to evaluate and manage these cases in the emergency department (ED) and intensive care unit (ICU). GHB is a naturally occurring four-carbon molecule that rapidly depresses the central nervous system (CNS).¹ The drug was initially believed to be an anesthetic alternative because of its potent hypnotic and moderate amnestic effects.² However, the drug never received U.S. Food and Drug Administration (FDA) approval because of concerns over toxicity that arose in the clinical trials. GHB's precursor molecule, Dihydro-2(3H)-furanone, or GBL, was being manufactured by drug companies at the same time.³ GBL can be found in glue solvents, paint removers, textile aids, drilling oils, and nonacetone nail polish removers.⁴ GBL is rapidly metabolized into GHB in the body.⁵ GBL mimics GHB's physiologic effects, producing the same CNS and respiratory depression.^4,5

GHB was sold in the nonregulated marketplace as a popular performance-enhancing additive in bodybuilding formulas⁶ until 1990 when the FDA issued a GHB advisory warning.⁷ After the warning, GHB remained available through "underground" laboratories.⁸ It became a popular nightclub drug known as "GG," "G-Riffick," "Easy Lay," "Liquid X," "Scoop," "Grievous Bodily Harm," and "Somatomax."^8–10 GBL was also marketed as a dietary supplement because of its "fat burning" and "growth hormone releasing" properties. It is known as "RenewTrient," "Blue Nitro," "Revivarant," "Revivarant-G," "Blue Nitro Vitality," and "Bullet."^11–13 GBL was voluntarily pulled from shelves in early 1999 due to FDA-issued warnings. It remains available through the Internet and clandestine laboratories that sell GBL products and "kits" that are used to synthesize GHB from GBL.³

GHB crosses both the blood brain barrier and the placental barrier. In the brain GHB binds to GABA-B receptors in the basal ganglia, cortex, hippocampus, midbrain, and substantia nigra. At these and two other sites, GHB stimulates the release of opioid-like substances.² It also inhibits the release of noradrenaline. It has biphasic dopamine effects and therefore inhibits dopamine release at low doses and stimulates release at high levels.² In the case of GHB at high doses, a hypnotic state is achieved because of the release of opioid-like substances and dopamine.¹⁴ Other effects on the CNS include the following: initiating delta and REM wave sleep,¹⁴ decreasing cerebral glucose metabolism, inducing hypothermia, dilating cerebral vessels, and increasing cerebral blood flow.¹ Although GBL is rapidly metabolized into GHB, GBL is better absorbed giving it greater bioavailability.¹¹ GHB has a half-life of 27 min. and elimination occurs primarily through expiration of CO₂.¹⁵

In a review of the literature, there are few reports regarding the clinical sequelae of GBL ingestion.^4,11–13,16 At this time, there have been two deaths reported, both due to respiratory depression.¹² Symptoms associated with GBL ingestion include respiratory difficulty, vomiting, or aspiration.^4,11,13,16 All of the cases involved CNS depression^4,11–13,16 which increases the risk of aspiration. Amnesia and seizures were also frequently seen. Finally, alcohol use was present in the majority of cases and was present in both fatality cases.¹² In the cases with a nonfatal outcome, patients recovered from their symptoms rapidly, the longest duration being nine hours.⁴

There are other reports of GBL ingestions from poison control centers.^4,11 Rambourg-Schepens et al.⁴ reported a case series presented by Fogh et al. at the EAPCC 13th Congress in 1988. They described five cases of pediatric GBL ingestion. All of the children had episodes of vomiting and became unconscious. Respiratory depression and bradycardia were noted as well.⁴ A summary of cases from the Minnesota, New Mexico, and Texas Poison Control Centers reviewed multiple cases of GBL ingestion.¹¹ There were no fatalities. The most common symptoms reported were anxiety, confusion, obtundation, nausea/vomiting, bradycardia, prolonged unconsciousness, syncope, seizures, and respiratory depression.¹¹

A series of articles have recently reported significant symptoms associated with GHB withdrawal.^14,17–21 The majority of cases involved coingestions with other substances of abuse,^14,17,18,20 but there were cases in which the only substance abused was GHB.^19,21 Symptoms of withdrawal ranged from mild to severe. Mild symptoms included increased anxiety, tremor, hypertension, insomnia, diaphoresis, nausea and tachycardia.^14,17–21 More severe symptoms included auditory and visual hallucinations, delirium, and paranoid delusions.^14,17,21 The duration of withdrawal symptoms ranged from approximately 48 hours to 12 days.¹⁸ The duration of GHB use by patients who went through withdrawal ranged from 4 months¹⁹ to 42 months.¹⁸ The median duration of GHB use was 24 months.^14,17–21 In fact, the three patients who experienced severe withdrawal symptoms had an average of 20 months of GHB abuse. Craig et al.²¹ noted the similarities between the reported cases of GHB withdrawal to be a prolonged use of GHB with a gradual increase in dose, drug cessation leading to anxiety and tremor and a history of previous unsuccessful GHB cessation attempts. At this time, there have been no reported cases of withdrawal from GBL.

We now present the case reports of three men who developed discrete withdrawal syndromes after abrupt discontinuation of GBL.

Case Report

Case 1. Mr. B. is a 35-year-old man who developed difficulties after he abruptly stopped using "RenewTrient" (GBL). He was a healthy man with no significant past medical or psychiatric history and no family psychiatric history. He denied alcohol use. He did admit to monthly marijuana use and an 11-year history of GBL use. He reported that he had been taking 30 ounces of GBL each day until 3 months ago, when he decreased his intake to 10 ounces/day. Mr. B. was a bodybuilder and was using GBL for its muscle building and fat burning properties.

Mr. B. took his last dose of GBL at bedtime one night and then completely discontinued use. The next day, in the early evening, he was shaking, and he developed chills and sweaty palms. That night, Mr. B. experienced significant insomnia as well, sleeping only 90 min. In the following days, Mr. B.'s symptoms progressed in severity. He developed frightening visual hallucinations of the "devil coming to kill me." His insomnia persisted, and the little sleep he had was interrupted by vivid nightmares. Mr. B.'s psychotic symptoms continued to worsen, with constant hallucinations of "the Devil throwing sand in my face" and his friends "trying to kill me with an axe." Mr. B. was very diaphoretic, agitated, and paranoid. He saw himself "tossed from heaven to hell" and heard his friends "plotting to take my family." Four days after he stopped using GBL, he used nalbuphine that had previously been prescribed to induce sleep. He slept well, but the symptoms continued over the next 3 days with no improvement. Mr. B. had fluctuations in consciousness during these episodes. He sought medical treatment eight days after he discontinued use GBL.

At the ED, Mr. B. did not inform anyone about his GBL use. His urine drug screen was negative. He was agitated to the point of requiring restraints. No medical reason was found to explain his psychiatric symptoms, thus, he was sent to a local mental health facility.

At the mental health facility, Mr. B.'s condition deteriorated further. He was given lorazepam (10 mg), haloperidol (10 mg), and diphenhydramine (50 mg) for agitation and restraints were required. Overnight, Mr. B.'s confusion worsened and his level of consciousness fluctuated. His blood pressure and pulse increased and he developed respiratory difficulty, so he was transported back to the ED.

At the ED, Mr. B. was somnolent and had a Glascow Coma Scale (GCS) of 6. He was afebrile, with a blood pressure of 172/102, a pulse of 104 bpm, a respiratory rate of 18 bpm and an oxygen saturation of 92%. His pupils were constricted (1 mm in diameter) and nonreactive. Mr. B. had a hypoactive gag reflex, was restless and easily agitated. He was placed on intravenous (IV) fluids, given naloxone (2 mg), thiamine (100 mg), and midazolam (5 mg), with no improvement in his condition. He was placed on oxygen by nasal cannula, and a work-up for organic causes was initiated. A CT scan of the head, chest radiograph and a cervical spine radiograph were normal. Blood gases, urinalysis, and complete blood count (CBC) were all within normal limits. Blood chemistries were all in the normal range, except for an elevated creatine phosphokinase (CPK) of 14,255 U/L that was likely because of Mr. B.'s constant struggling with his restraints. Cardiac enzymes were negative and there was no evidence of rhabdomyolysis. The urine drug screen (UDS) was positive for cannabinoids, opioids and benzodiazepines (even though his previous UDS was negative). His electrocardiogram (EKG) revealed tachycardia and possible LVH. While awaiting transfer to the ICU, Mr. B. became agitated and was given lorazepam (2 mg).

Once in the ICU, Mr. B.'s condition seemed to have stabilized. He was still afebrile, with improvement in his blood pressure. His pulse was 112 bpm and his GCS was still 6. His pupils were now 3 mm in diameter and were bilaterally reactive to light. Mr. B. was placed on continuous positive airway pressure (CPAP) because of previous respiratory difficulty. His oxygen saturation was 100%. He was given doses of lorazepam, as needed, for agitation.

Four hours after admission to the ICU, Mr. B. began having tonic-clonic seizure activity. He was placed on phenytoin and an electroencephalogram (EEG) was ordered. He was also placed on a continuous IV lorazepam drip (3 mg/hr).

The next day, 10 days after the discontinuation of GBL, Mr. B.'s clinical condition improved. He was alert and oriented in all spheres and was not experiencing any delusions or hallucinations at the time. It was at this time that Mr. B. informed the team about his recent discontinuation of GBL. His blood pressure and pulse normalized. His CPK decreased to 8800 U/ L. His lorazepam dose was decreased to 2 mg/hr, with good control of symptoms. The EEG was negative, and phenytoin was discontinued. Mr. B. was transferred to the general medicine floor the next day without incident. His CPK continued to decrease (2998 U/L on the day of discharge), and the lorazepam was tapered and discontinued without resumption of symptoms. The next day Mr. B. was fully oriented and without any evidence of psychosis.

Case 2. Mr. H. is a 49-year-old man brought to the ED by his family because of his "unusual behavior" and a 2-day history of severe agitation and irritability. He developed hyperreligious delusions and a belief that he had "special powers," which he refused to describe. Mr. H. had physically assaulted a stranger, telling him that "hellfire would rain down on him." He agreed to be admitted to the hospital.

Mr. H. was evaluated and collateral information was obtained from family and his outpatient psychiatrist. He reported a long history of substance abuse (alcohol, cocaine, and heroin) with abstinence from illicit substances for 2 years, which was confirmed by the collateral informants. In addition, in the past, Mr. H. had been diagnosed with a substance-induced mood disorder that was effectively treated with trazodone. He had no past psychotic symptoms, even during episodes of intoxication. His medical history was significant only for multiple orthopedic injuries secondary to a motor vehicle accident. There was no history of head injury. He had been evaluated in the past for chest pain and for substance withdrawal seizures. Family history was noncontributory.

Mr. H. admitted to the daily use of a supplement called "RenewTrient" (GBL) for the past 3 months. He had been using it to improve his sleep, "burn fat," and to "increase muscle mass." Mr. H. had been using four "droppers full" each night until 3 days before, when he decreased the supplement to 2 droppers full to last until his new supply arrived. He denied using any other medications within the past year.

Mr. H.'s mental status examination was significant for agitation and rapid speech. His mood was euphoric and he was very expansive. He was delusional, stating that he was "Jesus Christ" and that he could "heal all." Mr. H. was preoccupied with religious themes. He experienced auditory and visual hallucinations. He believed that his television was turning itself on and off and that he was receiving "messages from God through the television." Mr. H. was alert and fully oriented. His memory was intact and the remainder of his mental status examination was unremarkable.

Mr. H. was monitored for substance withdrawal. His vital signs remained stable throughout the hospital stay. His thyrotropin (TSH) was low initially, but normalized without treatment 1 week postdischarge. His rapid plasma reagin (RPR) was nonreactive, and his other lab results were unremarkable.

During Mr. H.'s first evening on the ward, he discussed his hyperreligious delusions. He became agitated twice, requiring two 5 mg doses of haloperidol and 30 mg of oxazepam for insomnia. His condition improved rapidly, with the delusions and rapid speech disappearing by 24 hours after admission. Mr. H. reported that his thinking had normalized; he was calmer and his speech was goal directed. His religious preoccupation had subsided. No other manic or psychotic symptoms were noted. After a period of observation, Mr. H. was discharged from the hospital. At follow-up, he was in stable condition and denied further GBL use.

Case 3. Mr. P. is a 34-year-old man with no past medical history, no family psychiatric history, and no history of any mood, anxiety, or psychotic symptoms. He had been using GBL on a daily basis for the past 18 months. Mr. P. had a 10-year history of intermittent cocaine use, currently using 2 times/ week. He had been using ecstasy 2 times/week for the past 18 months. Although Mr. P. admitted to using GBL and cocaine or ecstasy on the same day, he denied that he used them at the same time. He stated that his use of these substances was separated by a several hour time span. He also had been taking alprazolam (2 mg daily) for the past year.

Mr. P. had been taking between 7–8 ounces of GBL (RenewTrient) on a daily basis since he started using it. He had never missed a dose (he was taking 2 ounces 4 times/day) until he abruptly stopped using GBL because he wanted to "get clean." The next day his head felt "cloudy and hazy," he was irritable and unable to sleep. The next evening, Mr. P. began having auditory, visual, and tactile hallucinations, all with a clear sensorium. He saw faces on the wall and felt that there were bugs on him. Later that night he became confused and disoriented. There were fluctuations in consciousness noted by his family, with Mr. P. spending little time in a lucid state. Three days after discontinuing the GBL, he became more confused and agitated. Mr. P. was taken to the ED by paramedics after he was found running naked through traffic and speaking unintelligibly. He was combative during transport and received lorazepam (2 mg).

While in the ED, Mr. P. had fluctuations in consciousness. He was restless, combative, and incoherent. He was attending to internal stimuli and was angered by his hallucinatory experiences. His agitation and combativeness necessitated that he be placed in restraints. Mr. P.'s blood alcohol level (BAL), acetaminophen level, and salicylate level were all zero. His metabolic panel was essentially within normal limits except for a slightly increased potassium level in this hemolyzed sample. His CBC was within normal limits, except for a slight increase in the percentage of granulocytes (81.9%). His UDS was positive for benzodiazepines and cocaine (as expected). Mr. P. was given haloperidol (15 mg) and lorazepam (4 mg) to control his agitation. He was then transferred to a local mental health facility.

Vital signs on admission revealed a blood pressure of 134/84, a temperature of 98.0°, a pulse of 87 bpm, and a respiratory rate of 20 bpm. Mr. P.'s condition did not improve. Episodes of lucidity alternated with periods of severe confusion and disorientation. He was unable to sleep and he indicated that he felt that people could read his mind and was very preoccupied with paranoid delusions. On a number of occasions, Mr. P. was noted to be responding to internal stimuli. During this stay, he was treated with lorazepam on both a standing dose (1 mg bid) on an as-needed basis in addition to his usual alprazolam dose. After 2 days of severe confusion and disorientation, Mr. P. was sent back to the ED for evaluation.

In the ED, Mr. P. was confused, agitated, and combative. This was six days after he had stopped taking GBL. He continued to experience both auditory and visual hallucinations. He was administered chlorpromazine (100 mg) and alprazolam (2 mg) in an attempt to control agitation. His blood pressure was 112/52, his temperature was 97.1°, his pulse was 123 bpm, and his respiratory rate was 20 bpm. Mr. P.'s physical examination was normal, with clear lung fields and good air exchange. He was incoherent and had slurred speech. His agitation and combativeness required doses of haloperidol (5 mg) and lorazepam (2 mg).

Mr. P. was admitted to the ICU. A CT scan of the head with contrast revealed no acute findings. Blood cultures were negative, and a UDS was positive for benzodiazepines only. His BAL was zero. The metabolic panel and CBC were both within normal limits. The vitamin B₁₂ level, folate level, TSH, and RPR were all within normal limits. Mr. P.'s oxygen saturation ranged from between 94% and 98% on room air. He remained agitated and was treated with lorazepam and haloperidol. While on his second day in the ICU, he continued to display agitation and severe thought disorganization, with some infrequent episodes of lucidity.

On the next day (eight days after the last dose of GBL), Mr. P. was alert and fully oriented. His agitation had disappeared, and he answered questions appropriately. No fluctuations in consciousness were noted. By the next day, Mr. P. was cooperative and completely aware of his situation. He denied all mood or anxiety symptoms. He denied any hallucinations and had no delusions. Mr. P. was subsequently discharged from the hospital in stable condition.

Discussion

We believe that each of our cases demonstrates withdrawal from GBL. In each case, there was a distinct temporal relationship between the onset of the patients' symptoms and their recent decrease in or discontinuation of GBL dose.

Our first patient, Mr. B., who initially presented with visual hallucinations, had no prior psychiatric or medical history. He admitted to an 11-year history of GBL use, with recent abrupt discontinuation. There was no drug use other than "monthly" marijuana abuse, which was confirmed by the family. He took no other medications except one dose of nalbuphine for sleep induction. His symptoms resolved eleven days after his last GBL dose. During the course of withdrawal he became delirious, suggesting an organic (rather than functional) explanation for his mental status changes and hallucinations. Mr. B. experienced somatic symptoms (such as tremor, diaphoresis, autonomic instability, respiratory difficulty and seizure activity) that are similar to those seen in patients undergoing alcohol or benzodiazepine withdrawal.

In the second case, Mr. H. developed an acute onset of psychiatric symptoms (delusions and hallucinations) without any change in sensorium, after a 50% decrease in his GBL intake. He developed no significant medical symptoms. He had no prior history of psychosis or mania. He denied any recent drug or alcohol use, which was confirmed by laboratory testing and collateral information. He was taking no outpatient medications. Mr. H. did initially receive haloperidol and oxazepam in the hospital. However, his symptoms resolved completely within 24 hours after admission, which would not be typical of a functional psychotic or manic episode. It is for these reasons that we feel the Mr. H.'s symptoms were induced by withdrawal from GBL.

In our third case, Mr. P. had been using GBL daily for the previous 18 months. His symptoms began within 24 hours of GBL discontinuation and remitted after 9 days, which is not suggestive of a functional etiology. He had no prior psychiatric or medical history. He admitted to a twice weekly use of ecstasy and cocaine, but he had been using these substances consistently without any previous problems. Although it is still possible that the use of ecstasy or cocaine could have caused some of Mr. P.'s symptoms, from a temporal standpoint, it makes more sense that withdrawal from GBL was the causative etiology. He was on alprazolam as an outpatient, which was continued throughout his hospital stays, so benzodiazepine withdrawal was not the etiology of his symptoms. Mr. P. experienced formication and delirium that were consistent with a withdrawal syndrome similar to that of alcohol or benzodiazepines. Other possible causes of delirium were ruled out. Even Mr. P.'s consistent use of alprazolam provided little protection from the GBL withdrawal.

Presently there are no reports on GBL withdrawal and little has been written in regards to the treatment of GHB withdrawal. In many of the cases of GHB withdrawal, sedative-hypnotic agents were used to control the symptoms.^{14,17–19,21} Benzodiazepines have worked well on multiple occasions.^17,19,21 In fact, one of the cases required treatment with an estimated 2,655 mg equivalents of diazepam.²¹ Addolorato et al.¹⁹ suggested that the use of benzodiazepines seemed to be sufficient to achieve regression of the GHB withdrawal syndrome. Craig et al.²¹ noted that the use of benzodiazepines in the treatment of GHB withdrawal appeared to be beneficial because GHB withdrawal and alcohol withdrawal are similar. Many similarities between alcohol and GHB have been noted.²² Columbo et al.²³ have demonstrated the development of cross-tolerance between alcohol and GHB in rats. There have been multiple reports of GHB being useful in suppressing alcohol withdrawal symptoms.^22,24 Craig et al. indicated that the evidence pointed towards a shared common mechanism of central action of GHB and alcohol.²¹ Because GBL is metabolized into GHB, one could assume that GBL withdrawal would be treated in a similar manner.

It is important that physicians be aware of the latest drugs that are being abused. In the case of GBL, its availability through the Internet guarantees widespread distribution, making it difficult to regulate manufacturers, even once federal laws and regulations are in place. The quality of GHB and GBL used is difficult to assess in the unregulated marketplace and to estimate the amount of GHB or GBL used is even more difficult when the majority of abusers quantify their use in "capsful" or "ounces."²¹ Concentrations of GHB and GBL vary considerably between suppliers and even between different batches from the same supplier, making quantification of ingested doses difficult. GHB and GBL are believed to be dangerous drugs not only because they can cause death,^12,25,26 but also because the rapid and uneventful recovery from intoxication often seen with these drugs can impart a false sense of security in their abuser.⁹

It is known that patients' previous exposure to GHB does not predict future response,²⁷ so continued recreational experimentation with these drugs may have a dire clinical outcome. It is certainly advisable to consider a GHB- or GBL-related intoxication in patients presenting in a coma or with a decreased level of consciousness, or a GHB-or GBL-withdrawal syndrome in cases of delirious or psychotic patients for which no other explanation can be found.^21,28 This is especially true if drug-related causes are suspected and the standard UDS is negative. However, it is equally important to note that a drug screen positive for other substances does not rule out GHB or GBL use or withdrawal because they are often consumed with alcohol and other illicit substances. In cases of GHB withdrawal, the use of benzodiazepines has been shown to be helpful in the control of symptoms ,^17,19,21 especially because GHB withdrawal syndromes closely resemble those of alcohol and benzodiazepine withdrawal.²¹ The cases that we have presented demonstrate that GBL withdrawal is similar to GHB, alcohol, and benzodiazepine withdrawal and that GBL withdrawal symptoms respond to the use of benzodiazepines. GBL withdrawal should be considered in the differential of patients presenting with the acute development of psychotic symptoms, with or without impairment of consciousness.

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