Adverse Events Associated with Ingestion of Gamma-Butyrolactone Minnesota, New Mexico, and Texas, 1998-1999

Products containing gamma-butyrolactone (GBL) * are marketed for many claimed purposes, including to induce sleep, release growth hormone, enhance sexual activity and athletic performance, relieve depression, and prolong life. GBL is converted by the body into gamma-hydroxybutyrate (GHB), a drug banned outside of clinical trials approved by the Food and Drug Administration (FDA). Recognized manifestations of GHB toxicity include bradycardia, hypothermia, central nervous system depression, and uncontrolled movements (1). This report describes seven cases of GBL toxicity involving the product "Revivarant," which is labeled as containing 1.82 g of GBL per fluid ounce, reported from two hospital emergency departments (EDs) in Minnesota during October-December 1998 and summarizes an additional 34 cases of GBL toxicity reported to poison centers in New Mexico and Texas during October 1998-January 1999.

Minnesota

Patient 1. On November 26, 1998, a 24-year-old man vomited and had seizures shortly after drinking 3-4 oz of Revivarant. His behavior became unusual, and he alternated between extreme agitation and profound calm. Paramedics noted that his skin was warm, flushed, and profusely diaphoretic, and he had bradycardia (pulse as low as 45 beats per minute {bpm}). Systolic blood pressure was 110 mm Hg. Transcutaneous oxygen saturations (SpO2) were 96% on room air, and blood glucose by fingerstick was 90 mg/dL. During transport to an ED, he had periods of combativeness lasting 30 to 60 seconds followed by coma lasting 1-3 minutes. In the ED, he was unconscious with spontaneous eye opening, a positive withdrawal reflex, and no speech (Glasgow Coma Scale of 7); rectal temperature was 94.8 F (34.9 C). A urine toxicology screen and blood ethanol test were negative. He was intubated and admitted to the intensive-care unit (ICU) with a diagnosis of toxic encephalopathy. During the next 7 hours, his heart rate increased from 42 to 116 bpm and he became more alert. He had no recollection of events except for having ingested Revivarant. He was discharged with normal mental status.

Patient 2. On December 12, 1998, a 46-year-old woman had a seizure and lost consciousness after drinking approximately 2.7 oz of Revivarant in conjunction with ethanol. Paramedics found her unconscious and in severe respiratory depression with a pulse of 54 bpm. Oxygen was administered by mask; she had an SpO2 of 87%. On arrival in the ED, physical examination identified sinus bradycardia (54 bpm); temperature of 96.1 F (35.6 C); and miotic pupils. A serum ethanol level was 0.11%. She was admitted to the ICU, mechanically ventilated through the night, and awoke in improved condition the next morning; she was discharged with no memory of the events.

Patient 3. On November 8, 1998, a 31-year-old man drank approximately 1 oz of Revivarant, four beers, and a large sip of wine. Shortly thereafter, he gradually lost consciousness and subsequently fell. He regained consciousness but had involuntary muscle movements and episodes of confusion. Paramedics noted that he was ambulatory but confused. On physical examination in the ED, he was agitated, anxious, and unable to recall the preceding events. His shoulders twitched, and he had a small abrasion below his left eye. He had a pulse of 64 bpm and hypothermia (oral temperature of 95.2 F {35.1 C}). Breath ethanol level was 0.08%. He denied previous GBL use or illicit drug use. He recovered completely and was discharged.

Patients 4 and 5. On October 31, 1998, a 24-year-old man (patient 4) and a 26-year-old man (patient 5) each drank 10-13 oz of Revivarant while drinking alcohol at a bar. On leaving the bar, witnesses observed them fall and become unresponsive. On arrival at the ED, they alternated between somnolence and confusion. When awake, neither patient could consistently follow commands. Patient 4 had fecal incontinence. Vital signs for both patients were within normal limits. Breath ethanol levels were 0.09% (patient 4) and 0.15% (patient 5). Neither patient had a history of using medications or illicit drugs. After 2 hours of observation, the patients recovered but were unable to recall most of the evening's events.

Patients 6 and 7. On December 12, 1998, a 19-year-old woman (patient 6) and a 22-year-old woman (patient 7) were brought to an ED by friends because of vomiting and decreased levels of consciousness. These symptoms followed ingestion of Revivarant (2 oz by patient 6 and an unknown amount by patient 7). Patient 6 had drank one beer; patient 7 had had no ethanol. Vital signs were normal except for respiratory depression. On physical examination, patient 6 was lethargic and disoriented. Patient 7 exhibited intermittent periods of extreme agitation, necessitating chemical treatment and physical restraint, punctuated by moments of calm during which her attention focused on minor details. Mental changes for both patients resolved, and they were discharged approximately 4 hours after arrival.

New Mexico

From October 3, 1998, through January 29, 1999, the New Mexico Poison Center identified 14 cases of adverse events resulting in an ED visit among persons who had ingested GBL-containing products. Ten (71%) of the cases were reported in January. Patients' ages ranged from 14 to 36 years; nine were male. Products used included "Firewater" (11 cases), "Blue Nitro Vitality" (two), and "RenewTrient" (one). The approximate amount ingested ranged from 1 to 10 oz (mean: 3 oz). Five (36%) persons also had ingested ethanol and/or other drugs. Most of the patients were discharged from the ED within 13 hours of arrival; three were hospitalized. The most common symptoms and signs were nausea/vomiting (10 {71%}), obtundation (nine {64%}), bradycardia (seven {50%}), prolonged unconsciousness (six {43%}), syncope (six {43%}), seizures (four {29%}), confusion (four {29%}), combativeness (four {29%}), respiratory depression (three {21%}), amnesia (two {14%}), and euphoria (two {14%}). One person had cardiac arrest, one had respiratory arrest, and one had a motor-vehicle crash associated with the effects resulting from use of a GBL-containing product. No deaths were reported.

Texas

From October 2, 1998, through January 24, 1999, Texas poison-control centers identified 20 adverse events resulting in ED visits among persons who had ingested GBL-containing products. Twelve (60%) of the cases were reported in January. Patients' ages ranged from 11 to 41 years; 13 were male. Products known to have been used included "RenewTrient" (six cases), "Revivarant" (four), "Revivarant-G" (two), and "Blue Nitro Vitality" (two). Ten persons also ingested ethanol and/or other drugs. Ten patients were admitted to the hospital from the ED. The most common symptoms and signs were obtundation (13 {65%}), prolonged unconsciousness (nine {45%}), respiratory depression (nine {45%}), anxiety/nervousness (seven {35%}), nausea/vomiting (six {30%}), confusion (six {30%}), tremors/twitching (four {20%}), tachycardia (three {15%}), and combativeness (three {15%}). One person had respiratory arrest; no deaths were reported.

Reported by: SW Smith, MD, AR Topliff, MD, M Danigelis, MD, DL Zvosec, PhD, LL Schrag, MD, SA Freiwald, MD, SR Gunn, MD, Dept of Emergency Medicine, Hennepin County Medical Center, Minneapolis; SC Setzer, Hennepin Regional Poison Center, Minneapolis; M Rock, MD, Methodist Hospital, St. Louis Park; MT Osterholm, PhD, State Epidemiologist, Minnesota Dept of Health. BE Benson, PharmD, New Mexico Poison Center, Albuquerque; J Padilla, MS, R Voorhees, MD, CM Sewell, DrPH, State Epidemiologist, New Mexico Dept of Health. L Williams, G Shepherd, North Texas Poison Center, Dallas; G Coody, PharmD, Div of Drugs and Medical Devices, Bur of Food and Drug Safety; DM Simpson, MD, State Epidemiologist, Texas Dept of Health. Center for Food Safety and Applied Nutrition, Food and Drug Administration. Environmental Hazards and Epidemiology Section, Health Studies Br, Div of Environmental Hazards and Health Effects, National Center for Environmental Health; Div of Applied Public Health Training, Epidemiology Program Office; and EIS officers, CDC.

Editorial Note

Editorial Note: GBL is metabolized to GHB in the body, but because of better absorption GBL has greater bioavailability than GHB on an equimolar basis (2). Clinical effects of GHB appear to be dose-related and include reports of vomiting, hypotonia, tremors, seizures, aggression, impairment of judgment, coma, respiratory depression, hypothermia, and bradycardia (1). GHB mixed with ethanol acts synergistically to produce central nervous system and respiratory depression (3). Symptoms usually resolve with supportive care within 2-96 hours (4). Death occurring when GHB was the sole intoxicant also has been reported (5). Toxic effects of GBL would be expected to be similar or identical to those of GHB, but previous clinical experience is limited (6,7). There is no antidote for GHB; treatment consists of supportive therapy until symptoms of toxicity subside. A withdrawal syndrome, which can include insomnia, tremor, and anxiety, has been reported following discontinuance of GHB in chronic, high-dose users (8).

GBL is an industrial and household solvent of acrylate polymers, and unintentional poisonings have been reported (6,9). It also is marketed as a dietary supplement at health food stores and on the World-Wide Web under several trade names. Although labeled as dietary supplements, GBL-containing products are illegally marketed, unapproved new drugs that have been involved in at least 55 reports of adverse events, including one death (10). On January 21, 1999, FDA asked manufacturers to recall their GBL-containing products and warned consumers through press releases to avoid taking these products (10). Public education efforts should inform consumers that FDA review procedures for drugs are different than those used for dietary supplements. Consumers should be alert to the potential dangers of these products and understand that terms such as "natural" do not necessarily imply safety. Physicians should counsel patients about these products and be prepared to recognize and treat the toxic reactions that some might produce. Chronic GBL users should be monitored for withdrawal symptoms when discontinuing use of the product. Depending on the severity of the withdrawal symptoms, medical intervention may be required. Physicians are encouraged to report serious adverse events associated with these products to FDA's MedWatch program, telephone (800) 332-1088.

References

1. Li J, Stokes SA, Woeckener A. A tale of novel intoxication: a review of the effects of gamma-hydroxybutyric acid with recommendations for management. Ann Emerg Med 1998;31:729-36.

2. Lettieri J, Fung HL. Improved pharmacological activity via pro-drug modification: comparative pharmacokinetics of sodium gamma-hydroxybutyrate and gamma-butyrolactone. Res Commun Chem Pathol Pharmacol 1978;22:107-18.

3. Mamelak M. Gammahydroxybutyrate: an endogenous regulator of energy metabolism. Neurosci Biobehav Rev 1989;13:187-98.

4. CDC. Multistate outbreak of poisonings associated with illicit use of gamma hydroxy butyrate. MMWR 1990;39:861-3.

5. CDC. Gamma hydroxy butyrate use -- New York and Texas 1995-1996. MMWR 1997;46:281-3.

6. Rambourg-Schepens MO, Buffet M, Durak C, Mathieu-Nolf M. Gamma butyrolactone poisoning and its similarities to gamma hydroxybutyric acid: two case reports. Vet Hum Toxicol 1997;39:234-5.

7. LoVecchio F, Curry SC, Bagnasco T. Butyrolactone-induced central nervous system depression after ingestion of RenewTrient, a "dietary supplement" {Letter}. N Engl J Med 1998;339:847-8.

8. Galloway GP, Frederick SL, Staggers FE, Gonzales M, Stalcup SA, Smith DE. Gamma-hydroxybutyrate: an emerging drug of abuse that causes physical dependence. Addiction 1997;92:89-96.

9. Higgins TF, Borron SW. Coma and respiratory arrest after exposure to butyrolactone. J Emerg Med 1996;14:435-7.

10. Food and Drug Administration. FDA warns about products containing gamma butyrolactone or GBL and asks companies to issue a recall. Rockville, Maryland: US Department of Health and Human Services, Public Health Service, Food and Drug Administration, 1999. (Talk paper T99-5). Available at: . Accessed February 24, 1999.

Also is known as dihydro-2(3H)-furanone; 4-butanolide; 2(3H)-furanone, dihydro; tetrahydro-2-furanone; and butyrolactone gamma.

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