Pharmacology and toxicology of new psychoactive substances

National Institute On Drug Abuse

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Abstract

Summary- Substantial progress was made on this project, with the publication of six research articles about opioid and stimulant NPS. Three publications describe the pharmacology of newly emerging opioids, whereas three others highlight the effects of synthetic stimulants. The US is experiencing an unprecedented drug overdose epidemic. Illicitly manufactured fentanyl is a major factor in the overdose crisis, but a number of opioid NPS have appeared in recreation drug markets worldwide. Isotonitazene is a non-fentanyl opioid NPS associated with many intoxications and fatalities. Recent studies show that isotonitazene is a potent mu-opioid receptor (MOR) agonist in vitro, but little information is available about its in vivo effects. To this end, we examined pharmacokinetics and pharmacodynamic effects of isotonitazene in rats. Male Sprague-Dawley rats with surgically implanted intravenous (i.v.) catheters and subcutaneous (s.c.) temperature transponders received isotonitazene (3 - 30 microgram/kg, s.c.) or its vehicle. Blood samples were drawn at various times for 4 h post-injection, and plasma was assayed using tandem mass spectrometry (MS/MS). Body temperature, catalepsy scores, and hot plate latencies were recorded at each blood draw. Plasma concentrations of isotonitazene rose in parallel with increasing dose (range 0.2-9.8 nanogram/mL), and half-life ranged from 30-60 min. The metabolites 4'-hydroxy nitazene and N-desethyl isotonitazene were detected, but plasma concentrations were below the limits of quantitation. Isotonitazene produced antinociception (ED50 = 4.22 microgram/kg), catalepsy-like symptoms (ED50 = 8.68 microgram/kg), and hypothermia (only at 30 microgram/kg) that were significantly correlated with concentrations of isotonitazene. The findings from our isotonitazene experiments demonstrate that the drug is a potent MOR agonist whose pharmacodynamic effects are related to circulating concentrations of the parent drug. The in vivo potency of isotonitazene to induce antinociception (ED50 = 4.22 microgram/kg) is greater than that of fentanyl (ED50 = 20 microgram/kg), and much greater than that of morphine (4.5 milligram/kg). The high potency of isotonitazene portends substantial risk to users who are exposed to the drug. Synthetic cathinones are a class of NPS that display psychomotor stimulant properties, and novel 4-chloro ring-substituted cathinones continue to emerge in illicit drug markets worldwide. We characterized the pharmacology of 4-chloro cathinone analogs, as compared to the effects of 4-methylmethcathinone (mephedrone). Synaptosomes were prepared from rat caudate for dopamine transporter (DAT) assays, or from whole brain minus caudate and cerebellum for norepinephrine transporter (NET) and serotonin transporter (SERT) assays. Findings from transporter uptake inhibition and release assays showed that mephedrone and 4-chloromethcathinone (4-CMC) function as substrates at DAT, NET, and SERT, with similar potency at all three transporters. By contrast, 4-chloro-alpha-pyrrolidinopropiophenone (4-C-alpha-PPP) was an uptake inhibitor at DAT and NET but had little activity at SERT. 4-Chloroethcathinone (4-CEC) was a low potency uptake inhibitor at DAT and NET but a substrate at SERT. In rats implanted with telemetry transmitters, mephedrone and 4-CMC increased blood pressure, heart rate, and locomotor activity to a similar extent. 4-CEC and 4-C-alpha-PPP were less potent at increasing blood pressure and had modest stimulatory effects on heart rate and activity. Our findings show that all three 4-chloro ring-substituted cathinones are biologically active, but only 4-CMC has potency comparable to mephedrone. Collectively, our results suggest that 4-CMC will have abuse potential and adverse effects in humans that are analogous to those associated with mephedrone.