Co-exposure to gamma-hydroxybutyrate is associated with attenuated neuropsychiatric and stimulant effects of metamfetamine
Creators: name: Greene, Shaun Lawrence
name: Syrjanen, Rebekka
name: Hodgson, Sarah Ellen
name: Abouchedid, Rachelle
name: Schumann, Jennifer
Publisher: name: Taylor & Francis
Year: 2024
Subjects: subject: Medicine
subject: Microbiology
subject: FOS: Biological sciences
subject: Physiology
subject: Pharmacology
subject: Biotechnology
subject: Immunology
subject: FOS: Clinical medicine
subject: Marine Biology
subject: Science Policy
subject: Mental Health
subject: Hematology

description: Acute metamfetamine toxicity is characterized by stimulant effects and neuropsychiatric disturbance, which is attenuated by gamma-aminobutyric acid type A receptor agonists including benzodiazepines. We utilized clinical registry data to examine the effect of co-exposure to a gamma-aminobutyric acid type B receptor agonist (gamma-hydroxybutyrate) in illicit drug cases with analytically confirmed exposure to metamfetamine. The Emerging Drugs Network of Australia Victoria is an ethics board-approved prospective registry collecting clinical and analytical data (utilising blood samples) on emergency department illicit drug presentations. Comparison groups were defined by analytically confirmed exposure: lone metamfetamine, metamfetamine plus gamma-hydroxybutyrate, metamfetamine plus benzodiazepine, metamfetamine plus gamma-hydroxybutyrate plus benzodiazepine. Cases with co-exposure to other stimulants or sedatives were excluded. Median metamfetamine blood concentrations were significantly greater in metamfetamine plus gamma-hydroxybutyrate (<i>n</i> = 153, median = 0.20 mg/L, interquartile range: 0.10–0.32 mg/L, 95 per cent confidence interval: 0.20–0.23 mg/L) and metamfetamine plus gamma-hydroxybutyrate plus benzodiazepine (<i>n</i> = 160, median = 0.20 mg/L, interquartile range: 0.10–0.30 mg/L, 95 per cent confidence interval: 0.20–0.30 mg/L) positive groups compared to gamma-hydroxybutyrate negative groups including metamfetamine (<i>n</i> = 81, median = 0.10 mg/L, interquartile range: 0.05–0.21 mg/L, 95 per cent confidence interval: 0.09–0.18 mg/L) and metamfetamine plus benzodiazepine (<i>n</i> = 73, median = 0.10 mg/L, interquartile range: 0.06–0.20 mg/L, 95 per cent confidence interval: 0.09–0.20 mg/L) groups (<i>P</i> &lt; 0.0004). Presenting heart rate in metamfetamine plus gamma-hydroxybutyrate cases (<i>n</i> = 153, median = 72 beats per minute, interquartile range: 63–86 beats per minute, 95 per cent confidence interval: 70–78 beats per minute) was significantly lower than metamfetamine plus benzodiazepine cases (<i>n</i> = 73, median = 84 beats per minute, interquartile range: 73–98 beats per minute, 95 per cent confidence interval: 80–90 beats per minute, <i>P</i> &lt; 0.0001), and lone metamfetamine cases (<i>n</i> = 81, median = 110 beats per minute, interquartile range: 87–131 beats per minute, 95 per cent confidence interval: 93–120 beats per minute, <i>P</i> &lt; 0.0001). Presenting temperature in metamfetamine plus gamma-hydroxybutyrate cases (median = 35.8 °C, interquartile range: 35.0–36.2 °C, 95 per cent confidence interval 35.6–35.9 °C) was significantly lower than metamfetamine plus benzodiazepine cases (median 36.2 °C, interquartile range 35.7–36.6 °C, 95 per cent confidence interval, 36.0–36.4 °C, <i>P</i> = 0.017), and lone metamfetamine cases (median = 36.5 °C, interquartile range: 35.8–37.1 °C, 95 per cent confidence interval: 36.2–36.7 °C, <i>P</i> &lt; 0.0001). Median presenting systolic blood pressure was significantly (<i>P</i> ≤ 0.001) lower in benzodiazepine positive groups (metamfetamine plus benzodiazepine median = 120 mmHg, interquartile range: 109–132 mmHg, 95 per cent confidence interval: 116–124 mmHg and metamfetamine plus benzodiazepine plus gamma-hydroxybutyrate median = 124 mmHg, interquartile range: 110–137 mmHg, 95 per cent confidence interval: 120–129 mmHg). Incidence of sedation (Glasgow Coma Scale less than 9) was significantly greater in metamfetamine plus gamma-hydroxybutyrate cases (63 per cent) compared to metamfetamine plus benzodiazepine cases (27 per cent, <i>P</i> &lt; 0.0001) and lone metamfetamine cases (15 per cent, <i>P</i> &lt; 0.0001). Incidence of agitation was significantly lower in metamfetamine plus gamma-hydroxybutyrate plus benzodiazepine cases (17 per cent, <i>P</i> &lt; 0.0001) and metamfetamine plus gamma-hydroxybutyrate cases (34 per cent, <i>P</i> = 0.0004) compared to lone metamfetamine cases (58 per cent). Differences in gamma-aminobutyric acid type A and B receptor physiology may offer a gamma-aminobutyric acid type B agonist-facilitated alternative pharmacodynamic mechanism able to attenuate metamfetamine stimulant and neuropsychiatric toxicity. Metamfetamine intoxicated patients with analytically confirmed co-exposure to gamma-hydroxybutyrate had significantly reduced heart rate, body temperature and incidence of agitation compared to patients with lone metamfetamine exposure. Metamfetamine intoxicated patients with analytically confirmed co-exposure to a benzodiazepine had significantly reduced systolic blood pressure compared to patients with lone metamfetamine exposure. We hypothesize that gamma-aminobutyric acid type B receptor agonists may be beneficial in the management of acute metamfetamine toxicity.