143 CASE REPORT Case report: gamma butzrolactone (GBL) withdrawal syndrome Copyright (c) 2023 Slovenian Medical Journal. This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License. Case report: gamma butzrolactone (GBL) withdrawal syndrome Odtegnitveni sindrom od gama-butirolaktona (GBL): prikaz primera Karla Makoter,1 Miha Krajnc2 Abstract Gama-butyrolactone (GBL) is an easily accessible and inexpensive recreational drug popular primarily in night clubs. GBL is a precursor of the endogenous neurotransmitter gamma-hydroxybutyrate (GHB), which acts as an agonist at the GABAB and GHB receptors in the central nervous system (CNS). Low doses inhibit dopamine release, resulting in euphoric effects and reduced central inhibition. Higher doses stimulate the secretion of opioid-like substances and rapidly depress CNS. Addiction develops after several weeks to months of everyday usage. The clinical features of withdrawal are in principle similar to those of ethanol and/or benzodiazepine withdrawal. This paper presents the case of GBL withdrawal syndrome, which was clinically manifested with developed delirium, confusion, hallucinations, and agitation. Therapeutic manage- ment include high doses of benzodiazepines and, if needed, barbiturates, anticonvulsive and antipsychotic drugs. Izvleček Gama-butirolakton (GBL) je zaradi lahke dostopnosti in nizke cene priljubljena rekreativna droga v nočnih klubih. Gre za prekurzor endogenega nevrotransmiterja, gama-hidroksibutirata (GHB), ki deluje kot agonist na receptorje GABAB in GHB v centralnem živčnem sistemu (CŽS). V nižjih odmerkih inhibira izločanje dopamina, povzroča evforične učinke in niža centralno inhibicijo. Višji odmerki spodbujajo izločanje opioidom podobnih substanc in povzročijo hitro depresijo CŽS. Odvisnost nastopi po nekaj tednih do mesecih vsakodnevne uporabe. Odtegnitev načeloma oponaša klinično sliko odtegnitve od alkohola in/ali benzodiazepinov. Predstavljamo primer odtegnitvenega sindroma od GBL, ki se je pokazal z razvojem delirija, zmedenostjo, halucinacijami in agitacijo. Zdravljenje vključuje visoke odmerke benzodiazepinov, po potrebi pa tudi barbiturate, antikonvulzive in antipsihotike. 1 Emergency center, University Medical Centre Maribor, Maribor, Slovenia 2 Unit for forensic psychiatry, Department of Psychiatry, University Medical Centre Maribor, Maribor, Slovenia Correspondence / Korespondenca: Karla Makoter, e: karla.makoter@gmail.com Key words: gamma-butyrolactone; GBL; withdrawal syndrome; dependence; acute toxicity Ključne besede: gama-butirolakton; GBL; odtegnitveni sindrom; odvisnost; akutna zastrupitev Received / Prispelo: 24. 11. 2021 | Accepted / Sprejeto: 3. 11. 2022 Cite as / Citirajte kot: Makoter K, Krajnc M. Case report: gamma butzrolactone (GBL) withdrawal syndrome. Zdrav Vestn. 2022;91(3– 4):143–8. DOI: https://doi.org/10.6016/ZdravVestn.3319 eng slo element en article-lang 10.6016/ZdravVestn.3319 doi 24.11.2021 date-received 3.11.2022 date-accepted Case report Klinični primer discipline Psychiatry, clinical psychology, psychosomat- ics Psihiatrija, klinična psihologija, psihosomatika article-type Case report: gamma butzrolactone (GBL) withdrawal syndrome Odtegnitveni sindrom od gama-butirolaktona (GBL): prikaz primera article-title Case report: gamma butzrolactone (GBL) withdrawal syndrome Odtegnitveni sindrom od gama-butirolaktona (GBL): prikaz primera alt-title gamma-butyrolactone, GBL, withdrawal syn- drome, dependence, acute toxicity gama-butirolakton, GBL, odtegnitveni sindrom, odvisnost, akutna zastrupitev kwd-group The authors declare that there are no conflicts of interest present. Avtorji so izjavili, da ne obstajajo nobeni konkurenčni interesi. conflict year volume first month last month first page last page 2023 92 3 4 1 6 name surname aff email Karla Makoter 1 karla.makoter@gmail.com name surname aff Miha Krajnc 2 eng slo aff-id Emergency center, University Medical Centre Maribor, Maribor, Slovenia Urgentni center, Urgentni klinični center Maribor, Maribor, Slovenija 1 Unit for forensic psychiatry, Department of Psychiatry, University Medical Centre Maribor, Maribor, Slovenia Enota za forenzično psihiatrijo, Oddelek za psihiatrijo, Univerzitetni klinični center Maribor, Maribor, Slovenija 2 Slovenian Medical Journallovenian Medical Journal 144 PSYCHIATRY, CLINICAL PSYCHOLOGY, PSYCHOSOMATICS Zdrav Vestn | March – April 2023 | Volume 92 | https://doi.org/10.6016/ZdravVestn.3319 1 Introduction 1.1 Presentation Gamma-hydroxybutyrate (GHB) and its precursor gamma-butyrolactone (GBL) are popular recreational drugs with strong hypnotic and amnestic effects (1,2,3). GBL was first synthesized in 1964 for use in anaesthesi- ology (4,5), while its clinical use was limited to the treat- ment of narcolepsy due to possible toxicity (6) (sodium oxybate, Xyrem®). GHB was classified as a controlled substance in 1990, which increased the trafficking of its precursors (GBL and 1,4-butanediol) (2,4,7). The use of GHB, GBL, and 1,4-butanediol has been prohibited in Slovenia since 2001 (7). They are still used in the chemical industry as a component of adhesives, solvents, paint, and nail pol- ish removers, as an intermediate factor in the synthesis of plastics, polymers, and pesticides, and as an additive in the textile industry. Production for recreational use, however, has moved to makeshift underground labora- tories and is estimated at around 200,000 tonnes annu- ally (8). 1.2 Pharmacology GHB is an endogenous substance structurally similar to the neurotransmitter gamma-aminobutyric acid (GA- BA), which acts as an agonist on GABAB and GHB re- ceptors in the central nervous system (CNS) (2,4). They are located in the basal ganglia, cerebral cortex, hippo- campus, midbrain and substantia nigra (4). GBL itself is a pharmacologically inactive precursor, but in vivo it is rapidly metabolized to GHB via serum lactonases in the liver, crosses the blood-brain barrier and the placenta, and causes rapid CNS depression (4,5). Being more li- pophilic than GHB, GBL is absorbed more quickly and takes effect within 20–30 minutes (2). One millilitre of pure GBL corresponds to approxi- mately 2.5 g of GHB (2). The effect is the same and with- out differences in toxicity (9). GBL and its analogues are sold in the form of liquid preparations for oral ad- ministration. GHB can form salts and is therefore also available as a powder, but there are no reports of nasal administration (4). Binding of endo- or exogenous GHB to receptors in the CNS stimulates the release of opioid-like substances in the prefrontal cortex (5,10). The effect is biphasic: at low doses it inhibits dopamine signalling, and at high doses it stimulates it (2,9). Lower (initial) doses cause a euphoric effect, relaxation, increase self-confidence and reduce inhibition, while higher doses have an inhibitory effect, similar to benzodiazepines (2). Other CNS effects of GHB/GBL include induction of delta waves and REM (rapid eye movement) sleep, decreased cerebral glucose metabolism, generalized hypothermia, cerebral vasodi- lation, increased cerebral blood flow (2,4), and increased secretion of prolactin and growth hormone via the neu- roendocrine system (4,5,11). The half-life of GHB/GBL is between 20 and 50 min- utes (2,4,5). Elimination is primarily via CO2 exhalation (5); only 1–5% of GHB is excreted in the urine (4,7). Due to rapid metabolism and elimination, the clinical pre- sentation can change from acute intoxication to with- drawal within 30 minutes (2,12). The excess concentration of GHB/GBL in the urine and blood is measurable a few hours after the last dose. Endogenous concentration of GHB in urine is usually 1 mg/L and slightly lower in plasma, and arbitrary excess values are above 10 mg/L in urine and above 5 mg/L in plasma (4,7). Gas chromatography is used to detect it in urine, blood and serum samples, which is carried out in Slovenia by the Institute of Forensic Medicine in Ljublja- na (7). 1.3 Acute poisoning and overdose Retrospective case studies (10,13) report that 53–83% of users had at least one overdose experience. In Slove- nia, the first case of GHB poisoning was found in 2002 at the University Medical Centre Ljubljana (UMCL) (7). Acute poisoning manifests with impaired consciousness and is accompanied by bradycardia, bradypnea, hypo- tension and hypothermia (4,7,9). The period of unre- sponsiveness is usually transient, with most patients re- covering within 2–3 hours of coma onset (4,16). During wakening, the patient may be aggressive and confused, and vomiting is also common (7). Reported deaths from GHB/GBL have generally re- sulted from respiratory depression or subsequent com- plications of aspiration due to vomiting (4,5). Death occurs more frequently when alcohol or illicit drugs are used together (5,9,14). Interactions between GHB/GBL and ethanol in animal models have shown that ethanol acts synergistically on sedative effects by competitively blocking the metabolism of GHB/GBL (4,15). In prac- tice, however, agitation is more common with concur- rent alcohol use (9). It can be assumed that ethanol at 145 CASE REPORT Case report: gamma butzrolactone (GBL) withdrawal syndrome lower doses of GHB/GBL promotes disinhibition and euphoria. Cocaine and ecstasy (3,4-methylenedioxy- methamphetamine, MDMA) in combination with GHB/GBL more frequently cause prolonged coma (9), since stimulant addicts generally require a higher dose of GHB/GBL for a sedative effect, which is manifested by deeper depression of consciousness. Acute poisoning treatment is supportive. There is no specific antidote. Preventive administration of naloxone is not recommended, as GHB/GBL’s mechanism of ac- tion is different from opioids (16). Gastric lavage is not effective, and only activated charcoal is recommended (7). Between 2000 and 2014, the UMCL treated 74 peo- ple for GHB poisoning, of which 80% of patients needed symptomatic treatment, 5% were treated in the inten- sive care unit, and 14% required mechanical ventilation (17). 18% of patients received benzodiazepines to alle- viate symptoms of agitation upon awakening, and 4% required atropine for bradycardia (17). 1.4 Chronic dependence and withdrawal Dependence typically develops after a few weeks to months of daily GHB/GBL use (4). It is assumed that the minimum duration of use is two to three months, at least three to four times a day (16). Withdrawal occurs rapidly (1–6 hours after the last dose), and symptoms last from 48 hours to 15 days, or an average of 9 days (2,4,5). Withdrawal symptoms may resemble the clinical pre- sentation of ethanol withdrawal and/or benzodiazepines and are therefore often difficult to distinguish from the latter (2,4,5,9,14,18). The most common milder with- drawal symptoms from GHB/GBL are tremors, hallu- cinations, tachycardia, insomnia, nausea, and vomiting. More severe symptoms such as delusions, psychosis, agitation, convulsions, and rhabdomyolysis occur less frequently (4,19). Delirium develops more frequently than with withdrawal from ethanol and/or benzodiaz- epines and within a shorter period since the last dose Figure 1: Algorithm for the treatment of gamma-butyrolactone (GBL). Adapted from Henderson DL, 2008 (19). WITHOUT DELIRIUM Outpatient/hospitalization 80–150 mg of diazepam for up to seven days Withdrawal symptoms from GBL / GHB FREQUENT USE at least three doses per 24 hours or > 30 mg GHB per 24 hours or > 15 mg GBL per 24 hours Outpatient treatment 20–40 mg of diazepam for up to seven days PRESENCE OF DELIRIUM Hospitalization High doses of diazepam (150–200 mg per 24 hours) Barbiturates if no response to benzodiazepines aer 24 hours LESS FREQUENT USE < three doses per 24 hours or < 30 mg GHB per 24 hours or < 15 mg GBL per 24 hours 146 PSYCHIATRY, CLINICAL PSYCHOLOGY, PSYCHOSOMATICS Zdrav Vestn | March – April 2023 | Volume 92 | https://doi.org/10.6016/ZdravVestn.3319 (4). Long-term effects such as more severe anxiety and depression, fear of leaving home and answering phone calls may persist for weeks to months after GHB/GBL use is stopped (2). In 2004, the GHB/GBL addiction and withdrawal treatment algorithm was published for the first time (16). It is based on the frequency of intake, daily dose of GHB/GBL, and the clinical presentation (Figure 1). In case of less frequent use, outpatient treatment with diazepam is recommended (2). The recommended initial daily dose of diazepam is 20–40 mg, divided in- to three doses, which is appropriately adjusted to the individual according to gender, age, comorbidities, and clinical deterioration. Similar to the treatment of alcohol withdrawal, other benzodiazepines may be used at diazepam-equivalent doses (16). Treatment of withdrawal with more frequent use of GHB/GBL (Figure 1) depends on clinical severity and presence of delirium. The main symptomatic treat- ment is sedation with high benzodiazepine doses for up to seven days (4). Guidelines recommend 75–200 mg of diazepam in the first 24 hours (2,16). In case of non-responsiveness to benzodiazepines or refractory symptoms, the drug of choice is baclofen, a receptor agonist, at a dose of 30 mg/day for the first five days (2,4). Baclofen is said to have beneficial effects on sub- sequent treatment, as patients reported better concen- tration and sleep and reduced desire for GBL (2). In the symptomatic treatment of advanced deliri- um and withdrawal, other barbiturates and propofol as well as antipsychotics have also proven to be effec- tive. In case of convulsions or seizures, it is reasonable to start treatment with anticonvulsants (4,8,13,20). Although cases of Wernicke-Korsakoff syndrome have been described, the routine use of vitamin B is not rec- ommended (4,21), but clinical judgment can still be used, depending on the patient’s history. 1.5 Purpose of the report In the case presentation, we will describe the course of treatment of a patient with GBL withdrawal syn- drome who progressed to delirium. Due to the simi- larity of the clinical presentation to other poisonings, the toxidrome is rarely clinically recognized, because despite the increasing frequency of use, healthcare workers are not yet well acquainted with the sub- stance. For the first time in the Slovenian literature, we present the latest guidelines for the treatment of GBL withdrawal. 2 Case report In February 2020, the emergency clinic of the De- partment of Psychiatry of the University Medical Centre Maribor treated a 34-year-old detainee with a referral di- agnosis of unspecified delirium. The judicial officers said that he “has been behaving strangely for several days”, and on the day of admission he was said to be “purely in his own world”, “confused and aggressive”. He had never been hospitalized or seen by a psychiatrist before. At the first examination, he was unable to establish meaningful contact, his reality control was greatly reduced, and delir- ium was observed. We observed disturbances in percep- tion; he acted under the influence of visual and auditory hallucinations, and his behaviour was disorganized. The somatic and neurological examinations were difficult to perform due to agitation and suspected psychosis, al- though they were grossly without abnormalities. There were wounds on both wrists from resisting handcuffing. The patient was involuntarily admitted to the Foren- sic Psychiatry Unit for observation and diagnosis. In the prison infirmary he received 2 mg of lorazepam (2 mg intramuscularly); on the ward, he received zolpidem (5 mg daily for seven days), diazepam (initially 10 mg three times a day for three days, followed by 5 + 5 + 10 mg dai- ly for two days, followed by 5 + 0 + 5 mg daily for three days, and before discontinuation another 5 mg in the evenings for three days) and quetiapine (25–50 mg in the evening when he stabilized). Physical restraint with belts was required. Laboratory results showed marked leucocytosis (K-leukocytes: 26.14 * 109/L; normal val- ues: 4.00–10.00 x 109/L) with low C-reactive protein (S-CRP: 9 mg/L; normal values: < 5 mg/L) and elevated ammonia concentrations (plasma ammonia: 57 μmol/L; normal values: < 50 μmol/L). A computed tomography (CT) scan of the brain was performed (unremarkable), along with an abdominal ultrasound, which showed mild liver injury. Hepatitis markers were negative. Due to subfebrile body tempera- ture (body temperature: 37.4°C), chest radiography was performed, which did not show evidence of a bacterial or viral respiratory infection. Infectious disease special- ists performed a lumbar puncture (unremarkable find- ings) and started empiric antibiotic treatment with levo- floxacin 500 mg/12h. On the third day of hospitalization, the patient’s men- tal condition improved and was able to have a mean- ingful conversation. Physical restraints were no longer necessary. The patient denied the abuse of alcohol and illegal drugs. His condition continued to improve daily. 147 CASE REPORT Case report: gamma butzrolactone (GBL) withdrawal syndrome Occasional psychomotor agitation was still present, but his behaviour was completely normal. After 10 days of hospitalization, the patient admitted to having abused GBL for many years. He bought it on- line for €100/L. Initially it had a euphoric effect, but later he took it to sleep better. Doses were “depending on the day”, one to five times a day, about three to five drops. We were unable to obtain information about what substance and in what quantities the patient used to dilute GBL. On the 17th day of hospitalization, the patient was transferred back to custody. Upon discharge, his con- sciousness was not impaired; he was generally well-ori- ented, formally and substantively organized in his think- ing, adequate in contact, without obvious productive psychopathological symptoms. His cardiorespiratory system was without abnormalities. 3 Discussion GHB/GBL is a “club drug” (20) or “date rape drug” (8), popular in nightclubs and known under the names “Ruffles”, “Roofies”, “GG”, “G-Riffick”, “Easy Lay”, “Liquid X” or “Liquid ecstasy” (5,22), etc. Until the 1990s, GHB/ GBL was sold over the counter in the United States as a performance enhancer, in bodybuilding formulas, and in dietary supplements (4), purported to burn fat and in- crease muscle mass, slow aging, and boost libido (2,5). It was supposed to have a favourable effect on the indi- vidual’s communicativeness, relaxation, and openness, similar to alcohol, but without side effects such as smell on the breath, hangover and the possibility of detection in urine samples or police breathalysers (20). Because of these properties, the substance initially attracted individ- uals who were not (yet) aware of its side effects and the high possibility of developing dependence. Compared to other stimulants (cocaine, amphetamines), GHB/GBL is also relatively cheap and easily ordered through online platforms based in countries where the substance is still legal (8). In a retrospective study (2), GHB/GBL abusers cited the three most common reasons for use: to gain confi- dence in social interactions, to increase sexual activity, and to improve sleep. Consumption usually began for the first two reasons, followed by higher doses that induced sedation and sleep. This establishes a “circular pattern” of taking smaller stimulant doses in the morning and during the day and larger doses before bed (20). Addicts reported that they “liked the person they became when on GHB/ GBL” (2). However, the initial effect of euphoria, satis- faction and relaxation gradually wore off, and consump- tion of higher doses transformed them into introverted “zombies” lacking motivation, who were often unable to maintain a normal social life and daily functioning, such as going to school, college, or service (2). Our patient ordered GBL online at a relatively low price and reported no problems with procurement or shipment delivery. In the initial period, he reported in- creased self-confidence and better physical performance. Soon he needed higher doses, which no longer achieved the initial stimulating effects. The main purpose of con- tinued consumption was to sleep better. Long-term use of the substance numbed the patient, induced psychomotor retardation, and gradually pushed him into isolation. Af- ter his unexpected arrest, he abruptly stopped using the substance after several years of continued use; the clinical presentation of withdrawal manifested on the first day in detention and escalated until he was hospitalized. After appropriate treatment, the symptoms disappeared com- pletely within a few days. We did not know about the substance abuse at the be- ginning of treatment. The patient had no history of alcohol or illicit drug use. During diagnosis, organic pathology, toxic encephalopathy, CNS infection and hepatitis were excluded. Toxicology tests were negative. The presence of GHB/GBL in urine or blood is not routinely determined in our laboratory, but in any case, the window of possible detection had already expired by the time of admission. The patient received treatment with benzodiazepines and an antipsychotic, which resulted in improvement. The cause of delirium was unclear until the patient’s impair- ment of consciousness subsided, and he admitted that he had consumed GBL. Treatment was not suboptimal de- spite not knowing the cause of the delirium. We conclude from the case that the patient was not fully aware of the severity of his addiction, did not expect withdrawal symptoms, and did not initially associate them with stopping GBL consumption. Patients addicted to GHB/GBL are frequently not rec- ognized. Many describe difficulties in seeking treatment due to a lack of familiarity with the substance on the part of healthcare workers or the inaccessibility of detoxi- fication facilities (2). Before seeking proper help, many GHB/GBL addicts attempt to self-medicate with benzo- diazepines and alcohol (4). 4 Conclusions Based on the clinical case of treatment of a patient with GBL withdrawal, we confirmed that it is a cheap and easily accessible recreational drug that causes severe addiction. 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Long-term use, dosing several times a day, and com- bining with ethanol or other drugs are predictive crite- ria for risky consumption that may cause acute intoxi- cation and/or more severe withdrawal symptoms. The clinical presentation of withdrawal can vary from mild symptoms to advanced delirium. Diagnosing can be dif- ficult due to the rapid metabolism and elimination of the substance from the body, as well as the non-specificity of the toxidrome, which can mimic intoxication with other central nervous system depressants (ethanol, ben- zodiazepines), or the clinical features of the toxidrome are masked by substances with opposite effects (cocaine) (4). Acute poisoning is frequently unrecognized since the detection of the substance in blood or urine is not routinely performed. GHB/GBL addicts frequently abuse more than one substance, or they try to alleviate with- drawal symptoms empirically with other illegal substanc- es or prescription drugs. Our patient was most likely not even aware of the depth of his problems and would have hypothetically continued his substance abuse if he had not been arrested. Conflict of interest None declared. Inform consent of the patient The patient has given his written consent for the pub- lication of the paper, which is kept at UMC Maribor.