PEDIATRICS Vol. 106 No. 4 October 2000, pp. 829-830

EXPERIENCE AND REASON:
Verve and Jolt: Deadly New Internet Drugs

	ABSTRACT

Top Abstract Introduction Discussion References

As regulatory agencies have increased restrictions on the sale and marketing of -hydroxybutyrate (GHB), they have been frustrated by the appearance of precursor molecules such as -butyrolactone (GBL) that have become widely available over the Internet. These dangerous precursors are vigorously marketed to adolescents and young adults as dietary supplements that increase muscle mass and enhance sexual performance with seductive names such as Verve and Jolt, both easily recognizable teen icons. We present the case of an adolescent who ingested both of these GBL products 2 weeks apart, resulting in life-threatening respiratory depression and emergent intubation on both occasions. The GBL toxidrome, necessary acute interventions, and public health implications are reviewed. We urge all health care providers to report similar cases immediately to the FDA MedWatch system.-butyrolactone, -hydroxybutyrate, respiratory insufficiency, central nervous system depressants, substance abuse.

Gamma-hydroxybutyrate (GHB) ingestion can lead to rapid respiratory arrest, hypotension, bradycardia, and death. GHB has been linked to 58 deaths and >5700 recorded overdoses.¹ Street names for GHB include liquid ecstasy, liquid x, cherry meth, soap, and growth hormone booster.²

Outside of the United States, GHB is used for resuscitation, anesthesia, and addiction therapy, while in the United States use is restricted to tightly regulated clinical trials of treatment for narcolepsy.^3,4 The Food and Drug Administration (FDA) has prohibited the sale and manufacture of GHB because of the life-threatening toxic effects of illicit use.^5,6 Federal legislation has recently been passed that classifies GHB as a Schedule I substance, the most restrictive designation supported by the Drug Enforcement Agency.

Unfortunately, easy to produce precursors have kept individuals one step ahead of the regulatory process. Until February 2000, GHB precursor compounds were the legal way for adolescents and young adults to achieve effects physiologically equivalent to GHB. The precursor compound -butyrolactone (GBL), is easily synthesized and is being widely distributed in large quantities over the Internet. One of the enforcement problems the FDA faces is the inconsistent nomenclature for these various precursor products. GBL is also known by the chemical names 2,(3H)-furanone di-hydro, butyrolactone, 4-butyrolactone, dihydro-2(3H)-furanone, 4-butanolide, 2(3H)-furanone, dihydro, tetrahydro-2-furanone, and butyrolactone .⁷ In a casual Internet search conducted on March 29, 2000 (using the terms furanone, verve, -hydroxybutyrate, and then finding related sites), we counted >100 sites that sell this product in various forms. Though federal legislation has been signed that makes the GHB precursors controlled substances, the volume of product that has already been sold and distributed ensures that many individuals will still be affected. In addition, rapidly evolving naming and labeling practices enable the illegal sale of GHB precursors to continue despite the intervention of regulatory agencies.

We present a case of GBL ingestion in an adolescent that led to life-threatening respiratory depression.

	CASE PRESENTATION

An 18-year-old previously healthy female college freshman presented with GBL ingestion to our pediatric intensive care unit (PICU) paralyzed, intubated, and sedated after initial stabilization at an outside facility. She had a history of concomitant GBL and ethanol ingestion 2 weeks before admission causing respiratory arrest and requiring emergency intubation. The prior GBL product was a red liquid labeled Jolt. She rapidly recovered and was discharged from the hospital after 48 hours. She now presented 2 hours after a Verve ingestion at her boyfriend's house. She was found unresponsive by her friends, who called 911, Emergency Medical Services. On arrival, the Emergency Medical Technicians were given a 32-oz opened bottle of Verve 5.0 that her friends say she had ingested. The product, labeled 2,3(H)-furanone di-hydro, was obtained over the Internet. On initial examination she was unresponsive with a respiratory rate of 4. Two endotracheal intubation attempts failed in the field, but she was successfully bag-mask ventilated en route to the hospital. After arrival at the hospital, she was paralyzed with succinylcholine and successfully intubated with a 7.5-mm endotracheal tube. Postintubation arterial blood gas (fraction of inspired oxygen [FIO₂] = 1.0) showed pH 7.32, PCO₂ 35 mm Hg, and PO₂ 276 mm Hg. Vital signs were normal and she was well-perfused. She received 1 dose of charcoal and a 1200 mL normal saline bolus. Serum toxicological screen for acetaminophen, salicylates, ethanol, and tricyclics was negative. Urine screen for barbiturates, benzodiazepines, cannabis, cocaine, methadone, opiates, phencyclidines, and propoxyphenes was negative. She was transferred to our PICU by ambulance where she remained sedated and mechanically ventilated overnight. An electrocardiogram showed normal sinus rhythm at a rate of 90, normal axis, normal intervals, without evidence of hypertrophy, or ischemia. After extubation the following morning, she was observed for several hours and then agreed to be admitted to an inpatient drug treatment program.

	DISCUSSION

Top Abstract Introduction Discussion References

Although GHB has shown promise in the treatment of narcolepsy and potentially as a novel treatment to reduce the cellular effects of ischemic myocardial damage,³ the direct marketing of these agents and their precursors to adolescents as dietary supplements has led to serious public health concerns. The specific names Jolt and Verve are both recognizable teen iconsthe first is a popular soda; the second is a rock group. On the Internet, the marketing claims include sexual activity enhancer, all-natural party drug, fat-burning product, dietary supplement, and a Good Housecleaning Bargain product. The Verve product label shows a road going up into the clouds and states that 2,3(H) furanone di-hydro is for use as a solvent only. Internet marketing materials promote the product's blueberry flavor. Other GBL product names include Longevity, Revivarant, G.H. Revitalizer, Gamma G, Blue Nitro, Insom-X, Remforce, Firewater, and Invigorate.⁸ Another chemical related to GHB, 1,4 butanediol (BD), is being marketed as a sleep aid and has the same life-threatening effects as GBL. These product names include Revitalize Plus, Enliven, GHRE, SoatoPro, NRG#, Thunder Nectar, Weight Belt Cleaner, Cherry fX Bombs, Lemon fX Bombs, and Orange fX Bombs.⁹

A GHB-related ingestion should be considered in patients who have a suggestive history and who present with altered mental status, respiratory depression, coma, bradycardia, or uncontrolled movements.^10,11 Children who have ingested a GHB-related compound appear to have a similar toxidrome to adults. The increasing prevalence of GHB-related compounds left in the home has led to increasing accidental ingestions.¹²

GBL is rapidly metabolized to GHB once ingested. GHB is thought to be a weak partial agonist at the -aminobutyric acid receptor, with binding sites present in the cortex, hypothalamus, midbrain, basal ganglia, substantia nigra and the hippocampus.^13-15 The elimination half-life is 27 minutes.³ GHB and related compounds are not detected with common urine or serum screens. In cases where the unused portion of product cannot be recovered, GHB and related compounds can be detected using gas chromatography-mass spectrometry. If local testing is unavailable, a sample of serum, plasma, blood, or urine may be frozen and sent out later to a number of national laboratories that perform the gas chromatography-mass spectrometry testing.¹² Recently, a simple liquid-liquid extraction procedure for the analysis of GHB has been described.¹⁶

Currently, there is no definitive antidote for GHB-related products although neostigmine and physostigmine have shown promise as potential reversal agents.¹⁷ If supportive care is delivered in a timely manner, the patient will usually recover several hours postingestion. Rapid sequence intubation for treatment of hypoxia and for airway protection during charcoal administration has been recommended. A sedating agent may be withheld if the GHB sedation effect is sufficient.² If rescue therapy is delayed, incorrectly administered, or is not available, anoxic injury or death may result. Oftentimes, individuals who ingest GHB are not in locations where help is immediately available.

For simple GHB ingestion in a spontaneously breathing patient, intubation may not be necessary. In these uncomplicated cases, management will include positioning to reduce the risk of aspiration, oxygen supplementation, intravenous access, monitoring, stimulation, atropine for persistent bradycardia, and admission for observation.³

As the accessibility and use of GHB-related products increases, more cases of withdrawal attributable to chronic GHB abuse are being reported. Symptoms of GHB withdrawal include severe agitation, diaphoresis, tremors, mental status alterations, hypertension, and tachycardia.¹⁸ Withdrawal usually lasts from 3 to 12 days but may exceed these parameters in extreme cases of chronic use.¹⁹

We strongly encourage all health care providers to report any serious adverse events that occur with the illicit use of any products that contain GBL, GHB, or other GHB metabolites to the FDA's MedWatch Program by: phone (1-800-FDA-1088), fax (1-800-FDA-0178), via the MedWatch website at www.fda.gov/medwatch, or first-class mail, to MedWatch, HF-2, 5600 Fishers Lane, Rockville, MD 20852-9787. The more documented cases that are reported, the easier it will be for the FDA to take action against the makers and distributors of these harmful GHB precursors.

Jonathan P. Winickoff, MD^*,
Constance S. Houck, MD^{*, §}
Ellen L. Rothman, MD^*,
Howard Bauchner, MD^*
* Department of Pediatrics
Boston Medical Center and Boston University Medical School
 Departments of Medicine and ^§ Anesthesia
Children's Hospital Boston and Harvard Medical School
Boston, MA 02115

	FOOTNOTES

Received for publication Apr 17, 2000; accepted Jun 7, 2000.

Reprint requests to (J.P.W.) Clinical Effectiveness Program, Children's Hospital, 300 Longwood Ave, Boston MA 02115. E-mail: jwinickoff{at}yahoo.com

	ABBREVIATIONS

GHB, -hydroxybutyrate; FDA, Food and Drug Administration; GBL, -butyrolactone; PICU, pediatric intensive care unit.

	REFERENCES

Top Abstract Introduction Discussion References

1. "Date-rape" drug curbs become law. Statistics from Drug Enforcement Agency as reported in the Washington Post/Associated Press. February 19, 2000:A02
2. Li J, Stokes SA, Woeckener A A tale of novel intoxication: seven cases of gamma-hydroxybutyric acid overdose. Ann Emerg Med. 1998; 31:723-728 [CrossRef][Medline]
3. 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; 31:729-736 [CrossRef][Medline]
4. Kam PC, Yoong FF Gamma-hydroxybutyric acid: an emerging recreational drug. Anaesthesia. 1998; 53:1195-1198 [CrossRef][Medline]
5. Food and Drug Administration. GHB warning. FDA News. 1990(Nov 8):P90-53:1-2
6. Food and Drug Administration Updates: injuries, deaths linked again to GHB abuse. FDA Consumer. 1997; 31:2
7. FDA warns about products containing gamma butyrolactone or GBL and asks companies to issue a recall. Food and Drug Administration Talk Paper. April 13, 1999
8. Report serious adverse events associated with dietary supplements containing GBL, GHB, or BD. US FDA Medwatch. August 25, 1999
9. FDA warns about GBL-related Products. FDA Talk Paper. May 11, 1999
10. Adverse events associated with ingestion of gamma-butyrolactoneMinnesota, New Mexico, and Texas, 1998-1999. MMWR Morb Mortal Wkly Rep. 1999;48:137-140
11. Ryan JM, Stell I Gamma hydroxybutyratea coma-inducing recreational drug. J Accid Emerg Med. 1997; 14:259-261 [Abstract]
12. Li J, Gamma-hydroxybutyrate intoxication and overdose. Ann Emerg Med. (Correspondence) 1999;33
13. Lingenhoehl K, Brom R, Heid J, Gamma-hydroxybutyrate is a weak agonist at recombinant GABA(B) receptors. Neuropharmacology. 1999; 38:1667-1673 [CrossRef][Medline]
14. Snead OC III, Liu CC Gamma-hydroxybutyric acid binding sites in rat and human brain synaptosomal membranes. Biochem Pharmacol. 1984; 33:2587-2590 [CrossRef][Medline]
15. Hechler V, Gobaille S, Maitre M Localization studies of gamma-hydroxybutyrate receptors in rat striatum and hippocampus. Brain Res Bull. 1989; 23:129-135 [Medline]
16. Couper FJ, Logan BK Determination of gamma-hydroxybutyrate (GHB) in biological specimens by gas chromatography-mass spectrometry. J Anal Toxicol. 2000; 24:1-7 [Medline]
17. Viera AJ, Yates SW Toxic ingestion of gamma-hydroxybutyric acid. South Med J. 1999; 92:404-405 [Medline]
18. Craig K, Gomez HF, McManus JL, Bania TC Severe gamma-hydroxybutyrate withdrawal: a case report and literature review. J Emerg Med. 2000; 18:65-70 [CrossRef][Medline]
19. Galloway GP, Frederick SL, Staggers FE Jr, Gamma-hydroxybutyrate: an emerging drug of abuse that causes physical dependence. Addiction. 1997; 92:89-96 [CrossRef][Medline]