September 22, 2023

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Identification of Gamma-Butyrolactone in JUUL Liquids

Abstract

Gamma-butyrolactone (GBL), a commonly used industrial solvent, is used recreationally as a central nervous system (CNS) depressant and, therefore, is a United States Drug Enforcement Agency List 1 gbl kaufen chemical of the Controlled Substances Act. GBL was identified presumptively in the liquid from JUUL Virginia Tobacco flavored pods during routine untargeted screening analysis of e-cigarette products by gas chromatography–mass spectrometry (GC–MS). Methods for the analysis of GBL were developed for GC–MS and liquid chromatography–tandem mass spectrometry (LC–MS-MS) in the liquids and the aerosol generated from the liquid. Three flavors of JUUL pods available at the time of analysis were obtained by direct purchase from the manufacturer, purchase from a local vape shop and submission from a third party. The only liquid flavor to contain GBL was Virginia Tobacco, with an average of 0.37 mg/mL of GBL, and it was detected in the aerosol. Studies evaluating the pharmacological effects of inhaling GBL do not exist; however, a case report of chronic oral GBL ingestion indicates acute lung injury. The identification of GBL in an e-cigarette product purportedly compliant with federal regulation continues to demonstrate public health and public safety concerns.

Introduction

Gamma-butyrolactone (GBL) is a small, lipophilic molecule that readily absorbs in the body when consumed orally. In vitro, GBL and gamma-hydroxybutyrate (GHB) are subject to interconversion depending on the pH (1). In vivo, GBL is a precursor to GHB, an endogenous chemical that is found in low concentrations in the body. GBL is rapidly metabolized to GHB by the enzyme lactonase, found in the blood and liver, with a mechanism of action similar to the gamma-aminobutyric acid (GABA) neurotransmitter (2–4). Evidence also suggests that it affects the balance of neurotransmitters of the GABA, cholinergic, dopaminergic and serotonergic systems (5). GHB increases the secretion of growth hormones and also causes changes in dopamine levels, affecting neurosteroids and possibly endogenous opioids (5). Some evidence exists of a G-protein coupled GHB-receptor (6). These proposed mechanisms suggest that administration of exogenous GBL/GHB has a widespread effect on various brain regions. When taken chronically, GBL can produce physical dependence and serious withdrawal symptoms (2–4, 7). Symptoms of dependence have been reported as occurring within a few weeks of initial use, and post-withdrawal symptoms have been reported as lasting sometimes months after cessation (4).

Pharmacokinetic and pharmacodynamic effects of the oral administration of GHB and GBL have been investigated (4, 5). The effects of GBL are produced by its rapid conversion to GHB, rather than from GBL itself. Because GBL is more lipophilic and absorbs more readily throughout the body than GHB, it has a faster onset. GBL is thought to have a higher abuse potential than GHB because GBL has a greater potency, faster onset of action and longer activity; 1 mL of pure GBL is reported as equivalent to ∼1.6–2.5 g of GHB (2–4, 7). The pharmacological effects of GHB last 1–4 hours, with complete elimination from urine typically occurring within 12 hours (5). Inhalation of GHB and GBL has not been investigated in humans, and little data for occupational exposure data exist. A respirator is indicated for safe handling (8), and a single case report describes significant acute lung injury (ALI) from a combination of ingestion and inhalation after self-dosing 2 mL of GBL every 2 hours orally for 3 months (9).

Oral dosages of GBL are generally in the single milliliter range (2, 3, 5, 7). Use of GBL, especially with alcohol and narcotics, has been linked to several serious side effects, including mental changes, respiratory depression, loss of consciousness, coma and death (3, 7, 10). With repeated use, symptoms of dependence can develop within days to a few weeks; physical dependence has been reported along with severe withdrawal symptoms that are similar to alcohol, heroin and other sedative-hypnotic drugs and can last more than 14 days (2–4, 7). Commonly reported symptoms of withdrawal are tremors, hallucinations, anxiety, delirium, seizures and insomnia (4). Post-withdrawal symptoms have also been reported, including depression, panic attacks, insomnia and withdrawal from social interactions, with a time course lasting from several weeks to months (4).

Epidemiology of GBL use is difficult to discern since it is linked to GHB, and neither chemical is part of routine drug screens. Reports generally agree that most users are in their teens to mid-30s, male and often identify as gay (2, 4). United States Substance Abuse and Mental Health Services collects data on GBL/GHB independently but reports them together (10), and the 2012 National Survey describes consistent recreational use (11). A survey to club patrons in South London identified trends gbl kaufen of GBL/GHB use in vaping devices as early as March of 2015 (12). GBL is often associated with poly-substance use. The most common reported drugs taken with GBL/GHB are alcohol (as a means of delivery), other “club drugs”, amphetamines and narcotics (3, 7, 14). Taking GBL in conjunction with other pharmacologically active chemicals can lead to serious side effects due to potentiation and drug–drug interactions.