Gamma-hydroxybutyrate (GHB) is a short-chain fatty acid present endogenously in the brain and used therapeutically for the treatment of narcolepsy, as sodium oxybate, and for alcohol abuse/withdrawal. GHB is better known however as a drug of abuse and is commonly referred to as the “date–rape drug”; current use in popular culture includes recreational “chemsex,” due to its properties of euphoria, loss of inhibition, amnesia, and drowsiness. Due to the steep concentration–effect curve for GHB, overdoses occur commonly and symptoms include sedation, respiratory depression, coma, and death. GHB binds to both GHB and GABAB receptors in the brain, with pharmacological/toxicological effects mainly due to GABAB agonist effects. The pharmacokinetics of GHB are complex and include nonlinear absorption, metabolism, tissue uptake, and renal elimination processes. GHB is a substrate for monocarboxylate transporters, including both sodium-dependent transporters (SMCT1, 2; SLC5A8; SLC5A12) and proton-dependent transporters (MCT1–4; SLC16A1, 7, 8, and 3), which represent significant determinants of absorption, renal reabsorption, and brain and tissue uptake. This review will provide current information of the pharmacology, therapeutic effects, and pharmacokinetics/pharmacodynamics of GHB, as well as therapeutic strategies for the treatment of overdoses.
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White CM. Pharmacologic, pharmacokinetic, and clinical assessment of illicitly used gamma-hydroxybutyrate. J Clin Pharmacol. 2017;57(1):33–9.
Laborit H. Sodium 4-hydroxybutyrate. Int J Neuropharmacol. 1964;3:433–51.
Zhang Y, Huo M, Zhou J, Xie S. PKSolver: an add-in program for pharmacokinetic and pharmacodynamic data analysis in Microsoft Excel. Comput Methods Prog Biomed. 2010;99(3):306–14.
Carter LP, Pardi D, Gorsline J, Griffiths RR. Illicit gamma-hydroxybutyrate (GHB) and pharmaceutical sodium oxybate (Xyrem): differences in characteristics and misuse. Drug Alcohol Depend. 2009;104(1–2):1–10.
van den Brink W, Addolorato G, Aubin HJ, Benyamina A, Caputo F, Dematteis M, et al. Efficacy and safety of sodium oxybate in alcohol-dependent patients with a very high drinking risk level. Addict Biol. 2018;23(4):969–86.
Kim SY, Anderson IB, Dyer JE, Barker JC, Blanc PD. High-risk behaviors and hospitalizations among gamma hydroxybutyrate (GHB) users. Am J Drug Alcohol Abuse. 2007;33(3):429–38.
Liakoni E, Walther F, Nickel CH, Liechti ME. Presentations to an urban emergency department in Switzerland due to acute gamma-hydroxybutyrate toxicity. Scand J Trauma Resusc Emerg Med. 2016;24(1):107.
Britt GC, McCance-Katz EF. A brief overview of the clinical pharmacology of “club drugs”. Subst Use Misuse. 2005;40(9–10):1189–201.
WHO. Gamma-hydroxybutyric acid (GHB) critical review report. Hammamet, Tunisia; 2012.
Busardo FP, Gottardi M, Tini A, Minutillo A, Sirignano A, Marinelli E, et al. Replacing GHB with GBL in recreational settings: a new trend in chemsex. Curr Drug Metab. 2018;19(13):1080–5.
Griffiths RR, Johnson MW. Relative abuse liability of hypnotic drugs: a conceptual framework and algorithm for differentiating among compounds. J Clin Psychiatry. 2005;66(Suppl 9):31–41.
Corkery JM, Loi B, Claridge H, Goodair C, Schifano F. Deaths in the lesbian, gay, bisexual and transgender United Kingdom communities associated with GHB and precursors. Curr Drug Metab. 2018;19(13):1086–99.
Hockenhull J, Murphy KG, Paterson S. An observed rise in gamma-hydroxybutyrate-associated deaths in London: evidence to suggest a possible link with concomitant rise in chemsex. Forensic Sci Int. 2017;270:93–7.
Moresco M, Pizza F, Antelmi E, Plazzi G. Sodium oxybate treatment in pediatric type 1 narcolepsy. Curr Drug Metab. 2018;19:1073–9.
Hammoud MA, Bourne A, Maher L, Jin F, Haire B, Lea T, et al. Intensive sex partying with gamma-hydroxybutyrate: factors associated with using gamma-hydroxybutyrate for chemsex among Australian gay and bisexual men-results from the Flux Study. Sex Health. 2018;15(2):123–34.
Schecke H, Lea T, Bohn A, Kohler T, Sander D, Scherbaum N, et al. Crystal methamphetamine use in sexual settings among German men who have sex with men. Front Psychiatry. 2019;10:886.
Bay T, Eghorn LF, Klein AB, Wellendorph P. GHB receptor targets in the CNS: focus on high-affinity binding sites. Biochem Pharmacol. 2014;87(2):220–8.
Absalom N, Eghorn LF, Villumsen IS, Karim N, Bay T, Olsen JV, et al. Alpha4betadelta GABA(A) receptors are high-affinity targets for gamma-hydroxybutyric acid (GHB). Proc Natl Acad Sci U S A. 2012;109(33):13404–9.
Carai MA, Colombo G, Brunetti G, Melis S, Serra S, Vacca G, et al. Role of GABA(B) receptors in the sedative/hypnotic effect of gamma-hydroxybutyric acid. Eur J Pharmacol. 2001;428(3):315–21.
Cash CD. Gamma-hydroxybutyrate: an overview of the pros and cons for it being a neurotransmitter and/or a useful therapeutic agent. Neurosci Biobehav Rev. 1994;18(2):291–304.
Maitre M, Klein C, Mensah-Nyagan AG. Mechanisms for the specific properties of gamma-hydroxybutyrate in brain. Med Res Rev. 2016;36(3):363–88.
Gobaille S, Hechler V, Andriamampandry C, Kemmel V, Maitre M. Gamma-hydroxybutyrate modulates synthesis and extracellular concentration of gamma-aminobutyric acid in discrete rat brain regions in vivo. J Pharmacol Exp Ther. 1999;290(1):303–9.
Castelli MP, Ferraro L, Mocci I, Carta F, Carai MA, Antonelli T, et al. Selective gamma-hydroxybutyric acid receptor ligands increase extracellular glutamate in the hippocampus, but fail to activate G protein and to produce the sedative/hypnotic effect of gamma-hydroxybutyric acid. J Neurochem. 2003;87(3):722–32.
Hechler V, Gobaille S, Bourguignon JJ, Maitre M. Extracellular events induced by gamma-hydroxybutyrate in striatum: a microdialysis study. J Neurochem. 1991;56(3):938–44.
Kaupmann K, Cryan JF, Wellendorph P, Mombereau C, Sansig G, Klebs K, et al. Specific gamma-hydroxybutyrate-binding sites but loss of pharmacological effects of gamma-hydroxybutyrate in GABA(B)(1)-deficient mice. Eur J Neurosci. 2003;18(10):2722–30.
Morse BL, Vijay N, Morris ME. Gamma-hydroxybutyrate (GHB)-induced respiratory depression: combined receptor-transporter inhibition therapy for treatment in GHB overdose. Mol Pharmacol. 2012;82(2):226–35.
Carai MA, Lobina C, Maccioni P, Cabras C, Colombo G, Gessa GL. Gamma-aminobutyric acidB (GABAB)-receptor mediation of different in vivo effects of gamma-butyrolactone. J Pharmacol Sci. 2008;106(2):199–207.
Dornbierer DA, Baur DM, Stucky B, Quednow BB, Kraemer T, Seifritz E, et al. Neurophysiological signature of gamma-hydroxybutyrate augmented sleep in male healthy volunteers may reflect biomimetic sleep enhancement: a randomized controlled trial. Neuropsychopharmacology. 2019;44(11):1985–93.
Ito Y, Ishige K, Zaitsu E, Anzai K, Fukuda H. Gamma-hydroxybutyric acid increases intracellular Ca2+ concentration and nuclear cyclic AMP-responsive element- and activator protein 1 DNA-binding activities through GABAB receptor in cultured cerebellar granule cells. J Neurochem. 1995;65(1):75–83.
Mathivet P, Bernasconi R, De Barry J, Marescaux C, Bittiger H. Binding characteristics of gamma-hydroxybutyric acid as a weak but selective GABAB receptor agonist. Eur J Pharmacol. 1997;321(1):67–75.
Ishige K, Aizawa M, Ito Y, Fukuda H. Gamma-butyrolactone-induced absence-like seizures increase nuclear CRE- and AP-1 DNA-binding activities in mouse brain. Neuropharmacology. 1996;35(1):45–55.
Bernasconi R, Lauber J, Marescaux C, Vergnes M, Martin P, Rubio V, et al. Experimental absence seizures: potential role of gamma-hydroxybutyric acid and GABAB receptors. J Neural Transm Suppl. 1992;35:155–77.
Jacobson LH, Vlachou S, Slattery DA, Li X, Cryan JF. The gamma-aminobutyric acid B receptor in depression and reward. Biol Psychiatry. 2018;83(11):963–76.
Bolser DC, Blythin DJ, Chapman RW, Egan RW, Hey JA, Rizzo C, et al. The pharmacology of SCH 50911: a novel, orally-active GABA-beta receptor antagonist. J Pharmacol Exp Ther. 1995;274(3):1393–8.
Lingenhoehl K, Brom R, Heid J, Beck P, Froestl W, Kaupmann K, et al. Gamma-hydroxybutyrate is a weak agonist at recombinant GABA(B) receptors. Neuropharmacology. 1999;38(11):1667–73.
Froestl W. Chemistry and pharmacology of GABAB receptor ligands. Adv Pharmacol. 2010;58:19–62.
Goodwin AK, Griffiths RR, Brown PR, Froestl W, Jakobs C, Gibson KM, et al. Chronic intragastric administration of gamma-butyrolactone produces physical dependence in baboons. Psychopharmacology. 2006;189(1):71–82.
Goodwin AK, Froestl W, Weerts EM. Involvement of gamma-hydroxybutyrate (GHB) and GABA-B receptors in the acute behavioral effects of GHB in baboons. Psychopharmacology. 2005;180(2):342–51.
Morse BL, Morris ME. Toxicokinetics/toxicodynamics of gamma-hydroxybutyrate-ethanol intoxication: evaluation of potential treatment strategies. J Pharmacol Exp Ther. 2013;346(3):504–13.
Hodor A, Palchykova S, Gao B, Bassetti CL. Baclofen and gamma-hydroxybutyrate differentially altered behavior, EEG activity and sleep in rats. Neuroscience. 2015;284:18–28.
Koek W, France CP. Cataleptic effects of gamma-hydroxybutyrate (GHB) and baclofen in mice: mediation by GABA(B) receptors, but differential enhancement by N-methyl-d-aspartate (NMDA) receptor antagonists. Psychopharmacology. 2008;199(2):191–8.
Koek W, Chen W, Mercer SL, Coop A, France CP. Discriminative stimulus effects of gamma-hydroxybutyrate: role of training dose. J Pharmacol Exp Ther. 2006;317(1):409–17.
Gold BI, Roth RH. Kinetics of in vivo conversion of gamma-[3H]aminobutyric acid to gamma-[3H]hydroxybutyric acid by rat brain. J Neurochem. 1977;28(5):1069–73.
Brenneisen R, Elsohly MA, Murphy TP, Passarelli J, Russmann S, Salamone SJ, et al. Pharmacokinetics and excretion of gamma-hydroxybutyrate (GHB) in healthy subjects. J Anal Toxicol. 2004;28(8):625–30.
Roth RH, Giarman NJ. Gamma-butyrolactone and gamma-hydroxybutyric acid I: distribution and metabolism. Biochem Pharmacol. 1966;15:1333–48.
Wong CG, Gibson KM, Snead OC 3rd. From the street to the brain: neurobiology of the recreational drug gamma-hydroxybutyric acid. Trends Pharmacol Sci. 2004;25(1):29–34.
Struys EA, Verhoeven NM, Jansen EE, Ten Brink HJ, Gupta M, Burlingame TG, et al. Metabolism of gamma-hydroxybutyrate to d-2-hydroxyglutarate in mammals: further evidence for d-2-hydroxyglutarate transhydrogenase. Metabolism. 2006;55(3):353–8.
Liakoni E, Gugelmann H, Dempsey DA, Wiegand TJ, Havel C, Jacob P, et al. Butanediol conversion to gamma-hydroxybutyrate markedly reduced by the alcohol dehydrogenase blocker fomepizole. Clin Pharmacol Ther. 2019;105(5):1196–203.
Vayer P, Mandel P, Maitre M. Conversion of gamma-hydroxybutyrate to gamma-aminobutyrate in vitro. J Neurochem. 1985;45(3):810–4.
Snead OC 3rd, Furner R, Liu CC. In vivo conversion of gamma-aminobutyric acid and 1,4-butanediol to gamma-hydroxybutyric acid in rat brain. Studies using stable isotopes. Biochem Pharmacol. 1989;38(24):4375–80.
Kaufman EE, Nelson T. An overview of gamma-hydroxybutyrate catabolism: the role of the cytosolic NADP(+)-dependent oxidoreductase EC 18.104.22.168 and of a mitochondrial hydroxyacid-oxoacid transhydrogenase in the initial, rate-limiting step in this pathway. Neurochem Res. 1991;16(9):965–74.
Alzeer S, Ellis EM. Metabolism of gamma hydroxybutyrate in human hepatoma HepG2 cells by the aldo-keto reductase AKR1A1. Biochem Pharmacol. 2014;92(3):499–505.
Bhattacharya I, Boje KM. Feasibility of D-glucuronate to enhance gamma-hydroxybutyric acid metabolism during gamma-hydroxybutyric acid toxicity: pharmacokinetic and pharmacodynamic studies. Biopharm Drug Dispos. 2007;28(1):1–11.
Knerr I, Pearl PL, Bottiglieri T, Snead OC, Jakobs C, Gibson KM. Therapeutic concepts in succinate semialdehyde dehydrogenase (SSADH; ALDH5a1) deficiency (gamma-hydroxybutyric aciduria). Hypotheses evolved from 25 years of patient evaluation, studies in Aldh5a1-/- mice and characterization of gamma-hydroxybutyric acid pharmacology. J Inherit Metab Dis. 2007;30(3):279–94.
Gibson KM, Nyhan WL. Metabolism of [U-14C]-4-hydroxybutyric acid to intermediates of the tricarboxylic acid cycle in extracts of rat liver and kidney mitochondria. Eur J Drug Metab Pharmacokinet. 1989;14(1):61–70.
Pearl PL, Gibson KM, Cortez MA, Wu Y, Carter Snead O 3rd, Knerr I, et al. Succinic semialdehyde dehydrogenase deficiency: lessons from mice and men. J Inherit Metab Dis. 2009;32(3):343–52.
Hechler V, Ratomponirina C, Maitre M. Gamma-hydroxybutyrate conversion into GABA induces displacement of GABAB binding that is blocked by valproate and ethosuximide. J Pharmacol Exp Ther. 1997;281(2):753–60.
Snead OC 3rd, Bearden LJ, Pegram V. Effect of acute and chronic anticonvulsant administration on endogenous gamma-hydroxybutyrate in rat brain. Neuropharmacology. 1980;19(1):47–52.
Brown GK, Cromby CH, Manning NJ, Pollitt RJ. Urinary organic acids in succinic semialdehyde dehydrogenase deficiency: evidence of alpha-oxidation of 4-hydroxybutyric acid, interaction of succinic semialdehyde with pyruvate dehydrogenase and possible secondary inhibition of mitochondrial beta-oxidation. J Inherit Metab Dis. 1987;10(4):367–75.
Lee CR. Evidence for the beta-oxidation of orally administered 4-hydroxybutyrate in humans. Biochem Med. 1977;17(3):284–91.
Gibson KM, Goodman SI, Frerman FE, Glasgow AM. Succinic semialdehyde dehydrogenase deficiency associated with combined 4-hydroxybutyric and dicarboxylic acidurias: potential for clinical misdiagnosis based on urinary organic acid profiling. J Pediatr. 1989;114(4 Pt 1):607–10.
O'Connor T, Ireland LS, Harrison DJ, Hayes JD. Major differences exist in the function and tissue-specific expression of human aflatoxin B1 aldehyde reductase and the principal human aldo-keto reductase AKR1 family members. Biochem J. 1999;343(Pt 2):487–504.
Morris ME, Felmlee MA. Overview of the proton-coupled MCT (SLC16A) family of transporters: characterization, function and role in the transport of the drug of abuse gamma-hydroxybutyric acid. AAPS J. 2008;10(2):311–21.
Roiko SA, Vijay N, Felmlee MA, Morris ME. Brain extracellular gamma-hydroxybutyrate concentrations are decreased by L-lactate in rats: role in the treatment of overdoses. Pharm Res. 2013;30(5):1338–48.
Bhattacharya I, Boje KM. GHB (gamma-hydroxybutyrate) carrier-mediated transport across the blood-brain barrier. J Pharmacol Exp Ther. 2004;311(1):92–8.
Felmlee MA, Morse BL, Follman KE, Morris ME. The drug of abuse gamma-hydroxybutyric acid exhibits tissue-specific nonlinear distribution. AAPS J. 2017;20(1):21.
Morse BL, Vijay N, Morris ME. Mechanistic modeling of monocarboxylate transporter-mediated toxicokinetic/toxicodynamic interactions between gamma-hydroxybutyrate and L- lactate. AAPS J. 2014;16(4):756–70.
Wood DM, Greene SL, Dargan PI. Five-year trends in self-reported recreational drugs associated with presentation to a UK emergency department with suspected drug-related toxicity. Eur J Emerg Med : official journal of the European Society for Emergency Medicine. 2013;20(4):263–7.
Jackson VN, Halestrap AP. The kinetics, substrate, and inhibitor specificity of the monocarboxylate (lactate) transporter of rat liver cells determined using the fluorescent intracellular pH indicator, 2′,7′-bis(carboxyethyl)-5(6)-carboxyfluorescein. J Biol Chem. 1996;271(2):861–8.
Felmlee MA, Jones RS, Rodriguez-Cruz V, Follman KE, Morris ME. Monocarboxylate transporters (SLC16): function, regulation, and role in health and disease. Pharmacol Rev. 2020;72(2):466–85.
Morris ME, Rodriguez-Cruz V, Felmlee MA. SLC and ABC transporters: expression, localization, and species differences at the blood-brain and the blood-cerebrospinal fluid barriers. AAPS J. 2017;19:1317–31.
Wang Q, Darling IM, Morris ME. Transport of gamma-hydroxybutyrate in rat kidney membrane vesicles: role of monocarboxylate transporters. J Pharmacol Exp Ther. 2006;318(2):751–61.
Gerhart DZ, Enerson BE, Zhdankina OY, Leino RL, Drewes LR. Expression of monocarboxylate transporter MCT1 by brain endothelium and glia in adult and suckling rats. Am J Phys. 1997;273(1 Pt 1):E207–13.
Vijay N, Morris ME. Role of monocarboxylate transporters in drug delivery to the brain. Curr Pharm Des. 2013;20:1487–98.
Otsuka Y, Furihata T, Nakagawa K, Ohno Y, Reien Y, Ouchi M, et al. Sodium-coupled monocarboxylate transporter 1 interacts with the RING finger- and PDZ domain-containing protein PDZRN3. J Physiol Sci. 2019;69(4):635–42.
Gopal E, Miyauchi S, Martin PM, Ananth S, Roon P, Smith SB, et al. Transport of nicotinate and structurally related compounds by human SMCT1 (SLC5A8) and its relevance to drug transport in the mammalian intestinal tract. Pharm Res. 2007;24(3):575–84.
Martin PM, Dun Y, Mysona B, Ananth S, Roon P, Smith SB, et al. Expression of the sodium-coupled monocarboxylate transporters SMCT1 (SLC5A8) and SMCT2 (SLC5A12) in retina. Invest Ophthalmol Vis Sci. 2007;48(7):3356–63.
Martin PM, Gopal E, Ananth S, Zhuang L, Itagaki S, Prasad BM, et al. Identity of SMCT1 (SLC5A8) as a neuron-specific Na+-coupled transporter for active uptake of L-lactate and ketone bodies in the brain. J Neurochem. 2006;98(1):279–88.
Gopal E, Fei YJ, Sugawara M, Miyauchi S, Zhuang L, Martin P, et al. Expression of slc5a8 in kidney and its role in Na(+)-coupled transport of lactate. J Biol Chem. 2004;279(43):44522–32.
Rodriguez AM, Perron B, Lacroix L, Caillou B, Leblanc G, Schlumberger M, et al. Identification and characterization of a putative human iodide transporter located at the apical membrane of thyrocytes. J Clin Endocrinol Metab. 2002;87(7):3500–3.
Iwanaga T, Kishimoto A. Cellular distributions of monocarboxylate transporters: a review. Biomed Res. 2015;36(5):279–301.
Barac-Nieto M, Murer H, Kinne R. Lactate-sodium cotransport in rat renal brush border membranes. Am J Phys. 1980;239(5):F496–506.
Ganapathy V, Thangaraju M, Gopal E, Martin PM, Itagaki S, Miyauchi S, et al. Sodium-coupled monocarboxylate transporters in normal tissues and in cancer. AAPS J. 2008;10(1):193–9.
Cui D, Morris ME. The drug of abuse gamma-hydroxybutyrate is a substrate for sodium-coupled monocarboxylate transporter (SMCT) 1 (SLC5A8): characterization of SMCT-mediated uptake and inhibition. Drug Metab Dispos. 2009;37(7):1404–10.
Wang Q, Lu Y, Morris ME. Monocarboxylate transporter (MCT) mediates the transport of gamma-hydroxybutyrate in human kidney HK-2 cells. Pharm Res. 2007;24(6):1067–78.
Lam WK, Felmlee MA, Morris ME. Monocarboxylate transporter-mediated transport of gamma-hydroxybutyric acid in human intestinal Caco-2 cells. Drug Metab Dispos. 2010;38(3):441–7.
Morse BL, Felmlee MA, Morris ME. Gamma-hydroxybutyrate blood/plasma partitioning: effect of physiologic pH on transport by monocarboxylate transporters. Drug Metab Dispos. 2012;40(1):64–9.
Smith JP, Drewes LR. Modulation of monocarboxylic acid transporter-1 kinetic function by the cAMP signaling pathway in rat brain endothelial cells. J Biol Chem. 2006;281(4):2053–60.
Carl SM, Lindley DJ, Das D, Couraud PO, Weksler BB, Romero I, et al. ABC and SLC transporter expression and proton oligopeptide transporter (POT) mediated permeation across the human blood--brain barrier cell line, hCMEC/D3 [corrected]. Mol Pharm. 2010;7(4):1057–68.
Roiko SA, Felmlee MA, Morris ME. Brain uptake of the drug of abuse gamma-hydroxybutyric acid in rats. Drug Metab Dispos. 2012;40(1):212–8.
Scharf MB, Lai AA, Branigan B, Stover R, Berkowitz DB. Pharmacokinetics of gammahydroxybutyrate (GHB) in narcoleptic patients. Sleep. 1998;21(5):507–14.
Palatini P, Tedeschi L, Frison G, Padrini R, Zordan R, Orlando R, et al. Dose-dependent absorption and elimination of gamma-hydroxybutyric acid in healthy volunteers. Eur J Clin Pharmacol. 1993;45(4):353–6.
Ferrara SD, Zotti S, Tedeschi L, Frison G, Castagna F, Gallimberti L, et al. Pharmacokinetics of gamma-hydroxybutyric acid in alcohol dependent patients after single and repeated oral doses. Br J Clin Pharmacol. 1992;34(3):231–5.
Morris ME, Hu K, Wang Q. Renal clearance of gamma-hydroxybutyric acid in rats: increasing renal elimination as a detoxification strategy. J Pharmacol Exp Ther. 2005;313(3):1194–202.
Vijay N, Morse BL, Morris ME. A novel monocarboxylate transporter inhibitor as a potential treatment strategy for gamma-hydroxybutyric acid overdose. Pharm Res. 2015;32(6):1894–906.
Lettieri JT, Fung HL. Dose-dependent pharmacokinetics and hypnotic effects of sodium gamma-hydroxybutyrate in the rat. J Pharmacol Exp Ther. 1979;208(1):7–11.
Arena C, Fung HL. Absorption of sodium gamma-hydroxybutyrate and its prodrug gamma-butyrolactone: relationship between in vitro transport and in vivo absorption. J Pharm Sci. 1980;69(3):356–8.
Morse BL, Morris ME. Effects of monocarboxylate transporter inhibition on the oral toxicokinetics/toxicodynamics of gamma-hydroxybutyrate and gamma-butyrolactone. J Pharmacol Exp Ther. 2013;345(1):102–10.
Morris ME, Morse BL, Baciewicz GJ, Tessena MM, Acquisto NM, Hutchinson DJ, et al. Monocarboxylate transporter inhibition with osmotic diuresis increases gamma-hydroxybutyrate renal elimination in humans: a proof-of-concept study. J Clin Toxicol. 2011;1(2):1000105.
Docherty JR, Green AR. The role of monoamines in the changes in body temperature induced by 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) and its derivatives. Br J Pharmacol. 2010;160(5):1029–44.
Felmlee MA, Roiko SA, Morse BL, Morris ME. Concentration-effect relationships for the drug of abuse gamma-hydroxybutyric acid. J Pharmacol Exp Ther. 2010;333(3):764–71.
FDA Xyrem Label 2020 [Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/021196s033s034lbl.pdf. Accessed Sept 2020
Felmlee MA, Wang Q, Cui D, Roiko SA, Morris ME. Mechanistic toxicokinetic model for gamma-hydroxybutyric acid: inhibition of active renal reabsorption as a potential therapeutic strategy. AAPS J. 2010;12(3):407–16.
Wang Q, Morris ME. Flavonoids modulate monocarboxylate transporter-1-mediated transport of gamma-hydroxybutyrate in vitro and in vivo. Drug Metab Dispos. 2007;35(2):201–8.
Raybon JJ, Boje KM. Pharmacokinetics and pharmacodynamics of gamma-hydroxybutyric acid during tolerance in rats: effects on extracellular dopamine. J Pharmacol Exp Ther. 2007;320(3):1252–60.
Lettieri J, Fung HL. Absorption and first-pass metabolism of 14C-gamma-hydroxybutyric acid. Res Commun Chem Pathol Pharmacol. 1976;13(3):425–37.
Wang Q, Wang X, Morris ME. Effects of L-lactate and D-mannitol on gamma-hydroxybutyrate toxicokinetics and toxicodynamics in rats. Drug Metab Dispos. 2008;36(11):2244–51.
Giarman NJ, Roth RH. Differential estimation of gamma-butyrolactone and gamma-hydroxybutyric acid in rat blood and brain. Science. 1964;145(3632):583–4.
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(1):107–18.
Carter LP, Koek W, France CP. Lack of effects of GHB precursors GBL and 1,4-BD following i.c.v. administration in rats. Eur J Neurosci. 2006;24(9):2595–600.
Fung HL, Tsou PS, Bulitta JB, Tran DC, Page NA, Soda D, et al. Pharmacokinetics of 1,4-butanediol in rats: bioactivation to gamma-hydroxybutyric acid, interaction with ethanol, and oral bioavailability. AAPS J. 2008;10(1):56–69.
Goodwin AK, Brown PR, Jansen EE, Jakobs C, Gibson KM, Weerts EM. Behavioral effects and pharmacokinetics of gamma-hydroxybutyrate (GHB) precursors gamma-butyrolactone (GBL) and 1,4-butanediol (1,4-BD) in baboons. Psychopharmacology. 2009;204(3):465–76.
Thai D, Dyer JE, Benowitz NL, Haller CA. Gamma-hydroxybutyrate and ethanol effects and interactions in humans. J Clin Psychopharmacol. 2006;26(5):524–9.
Okun MS, Boothby LA, Bartfield RB, Doering PL. GHB: an important pharmacologic and clinical update. J Pharm Pharm Sci : a publication of the Canadian Society for Pharmaceutical Sciences, Societe canadienne des sciences pharmaceutiques. 2001;4(2):167–75.
Mason PE, Kerns WP 2nd. Gamma hydroxybutyric acid (GHB) intoxication. Acad Emerg Med Off J Soc Acad Emerg Med. 2002;9(7):730–9.
Bania TC, Chu J. Physostigmine does not effect arousal but produces toxicity in an animal model of severe gamma-hydroxybutyrate intoxication. Acad Emerg Med Off J Soc Acad Emerg Med. 2005;12(3):185–9.
Zvosec DL, Smith SW, Porrata T, Strobl AQ, Dyer JE. Case series of 226 gamma-hydroxybutyrate-associated deaths: lethal toxicity and trauma. Am J Emerg Med. 2011;29(3):319–32.
Berling I, Whyte IM, Isbister GK. Oxycodone overdose causes naloxone responsive coma and QT prolongation. QJM. 2013;106(1):35–41.
Fox LM, Hoffman RS, Vlahov D, Manini AF. Risk factors for severe respiratory depression from prescription opioid overdose. Addiction. 2018;113(1):59–66.
Marinetti LJ, Ehlers BJ. A series of forensic toxicology and drug seizure cases involving illicit fentanyl alone and in combination with heroin, cocaine or heroin and cocaine. J Anal Toxicol. 2014;38(8):592–8.
Pahlman C, Qi Z, Murray CM, Ferguson D, Bundick RV, Donald DK, et al. Immunosuppressive properties of a series of novel inhibitors of the monocarboxylate transporter MCT-1. Transpl Int. 2013;26(1):22–9.
Curtis NJ, Mooney L, Hopcroft L, Michopoulos F, Whalley N, Zhong H, et al. Pre-clinical pharmacology of AZD3965, a selective inhibitor of MCT1: DLBCL, NHL and Burkitt’s lymphoma anti-tumor activity. Oncotarget. 2017;8(41):69219–36.
Ovens MJ, Davies AJ, Wilson MC, Murray CM, Halestrap AP. AR-C155858 is a potent inhibitor of monocarboxylate transporters MCT1 and MCT2 that binds to an intracellular site involving transmembrane helices 7-10. Biochem J. 2010;425(3):523–30.
Bola BM, Chadwick AL, Michopoulos F, Blount KG, Telfer BA, Williams KJ, et al. Inhibition of monocarboxylate transporter-1 (MCT1) by AZD3965 enhances radiosensitivity by reducing lactate transport. Mol Cancer Ther. 2014;13(12):2805–16.
Follman KE, Morris ME. Treatment of gamma-hydroxybutyric acid and gamma-butyrolactone overdose with two potent monocarboxylate transporter 1 inhibitors, AZD3965 and AR-C155858. J Pharmacol Exp Ther. 2019;370(1):84–91.
Lobina C, Agabio R, Reali R, Gessa GL, Colombo G. Contribution of GABA(A) and GABA(B) receptors to the discriminative stimulus produced by gamma-hydroxybutyric acid. Pharmacol Biochem Behav. 1999;64(2):363–5.
Baker LE, Van Tilburg TJ, Brandt AE, Poling A. Discriminative stimulus effects of gamma-hydroxybutyrate (GHB) and its metabolic precursor, gamma-butyrolactone (GBL) in rats. Psychopharmacology. 2005;181(3):458–66.
Baker LE, Searcy GD, Pynnonen DM, Poling A. Differentiating the discriminative stimulus effects of gamma-hydroxybutyrate and ethanol in a three-choice drug discrimination procedure in rats. Pharmacol Biochem Behav. 2008;89(4):598–607.
Lobina C, Colombo G, Gessa GL, Carai MA. Different sensitivity to the motor incoordinating effects of gamma-hydroxybutyric acid (GHB) and baclofen in GHB-sensitive and GHB-resistant rats. Brain Res. 2005;1033(1):109–12.
Carai MA, Quang LS, Atzeri S, Lobina C, Maccioni P, Orru A, et al. Withdrawal syndrome from gamma-hydroxybutyric acid (GHB) and 1,4-butanediol (1,4-BD) in Sardinian alcohol-preferring rats. Brain Res Brain Res Protoc. 2005;15(2):75–8.
Quang LS, Colombo G, Lobina C, Maccioni P, Orru A, Gessa GL, et al. Evaluation for the withdrawal syndrome from gamma-hydroxybutyric acid (GHB), gamma-butyrolactone (GBL), and 1,4-butanediol (1,4-BD) in different rat lines. Ann N Y Acad Sci. 2006;1074:545–58.
Goodwin AK, Gibson KM, Weerts EM. Physical dependence on gamma-hydroxybutrate (GHB) prodrug 1,4-butanediol (1,4-BD): time course and severity of withdrawal in baboons. Drug Alcohol Depend. 2013;132(3):427–33.
Goodwin AK, Kaminski BJ, Weerts EM. Self-administration of gamma-hydroxybutyric acid (GHB) precursors gamma-butyrolactone (GBL) and 1,4-butanediol (1,4-BD) in baboons. Psychopharmacology. 2013;225(3):637–46.
Weerts EM, Goodwin AK, Griffiths RR, Brown PR, Froestl W, Jakobs C, et al. Spontaneous and precipitated withdrawal after chronic intragastric administration of gamma-hydroxybutyrate (GHB) in baboons. Psychopharmacology. 2005;179(3):678–87.
Brunt TM, van Amsterdam JG, van den Brink W. GHB, GBL and 1,4-BD addiction. Curr Pharm Des. 2014;20(25):4076–85.
McDonough M, Kennedy N, Glasper A, Bearn J. Clinical features and management of gamma-hydroxybutyrate (GHB) withdrawal: a review. Drug Alcohol Depend. 2004;75(1):3–9.
van Noorden MS, Mol T, Wisselink J, Kuijpers W, Dijkstra BAG. Treatment consumption and treatment re-enrollment in GHB-dependent patients in The Netherlands. Drug Alcohol Depend. 2017;176:96–101.
The studies from the Morris laboratory were supported in part by NIH grant R01DA023223. MAF is supported in part by NIH grant SC1 DA-052150.
Conflict of Interest
The authors declare that they have no conflict of interest.
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Felmlee, M.A., Morse, B.L. & Morris, M.E. γ-Hydroxybutyric Acid: Pharmacokinetics, Pharmacodynamics, and Toxicology. AAPS J 23, 22 (2021). https://doi.org/10.1208/s12248-020-00543-z