Δ9-Tetrahydrocannabinol-like discriminative stimulus effects of compounds commonly found in K2/Spice

Abstract

A number of cannabinoid compounds are being sold in the form of incense as “legal” alternatives to marijuana. The purpose of these experiments was to determine whether the most common of these compounds have discriminative stimulus effects similar to Δ9-tetrahydrocannabinol, the main active component in marijuana. Locomotor depressant effects of JWH-018, JWH-073, JWH-200, JWH-203, JWH-250, AM-2201 and CP 47,497-C8-homolog were tested in mice. The compounds were then tested for substitution in rats trained to discriminate Δ9-tetrahydrocannabinol (3 mg/kg, i.p.). The time course of the peak dose of each compound was also tested. Each of the synthetic cannabinoids dose-dependently decreased locomotor activity for one to two hours. Each of the compounds fully substituted for the discriminative stimulus effects of Δ9-tetrahydrocannabinol, mostly at doses that produced only marginal amounts of rate suppression. JWH-250 and CP 47,497-C8-homolog suppressed response rates at doses that fully substituted for Δ9-THC. The time courses varied markedly between compounds. Most of the compounds had a shorter onset than Δ9-THC, and three lasted substantially longer (JWH-073, JWH-250 and CP 47,497-C8-homolog). Several of the most commonly used synthetic cannabinoids produce behavioral effects comparable to those of Δ9-tetrahydrocannabinol, which suggests that these compounds may share the psychoactive effects of marijuana responsible for abuse liability. The extremely long time course of the discriminative stimulus effects and adverse effects of CP 47,497-C8-homolog suggest that CP 47,497-C8-homolog may be associated with increased hazards in humans.

Δ9-Tetrahydrocannabinol-like effects of novel synthetic cannabinoids found on the gray market

“…Rank order of potency for depression of locomotor activity was PB-22 = 5F-PB-22 > AB-FUBINACA = AKB-48 > UR-144 = XLR-11 = Δ 9 -THC. These findings confirm and extend previous findings that UR-144 and XLR-11 decrease locomotor activity in mice (Wiley et al, 2013), as well as those of earlier studies indicating that a range of synthetic cannabinoids depress locomotor activity (Wiley et al, 1998; Gatch and Forster, 2014). …”

AB-CHMINACA, AB-PINACA, and FUBIMINA: Affinity and Potency of Novel Synthetic Cannabinoids in Producing Δ9-Tetrahydrocannabinol–Like Effects in Mice

“…Similarly, the in vivo positive control D 9 -THC suppressed locomotor activity and showed hypothermic, antinociceptive, cataleptic, and D 9 -THC-like discriminative stimulus effects in mice. D 9 -THC-like discriminative stimulus effects were also observed with JWH-018, WIN55,212-2, and CP47,497, as has been shown previously with the former two compounds (Compton et al, 1992a;Wiley et al, 2014b) and with the C-8 homolog of CP47,497 (Gatch and Forster, 2014). Previous research has shown that these three compounds bind to the CB 1 receptor with high affinity and produce cannabimimetic effects in the tetrad battery (Compton et al, 1992a,b;Wiley et al, 1998).…”

Discriminative Stimulus Properties of Phytocannabinoids, Endocannabinoids, and Synthetic Cannabinoids

“…Further, substitution of JWH-018 and JWH-073 occurred following inhalation in mice trained to discriminate intraperitoneal Δ 9 -THC from vehicle [99]. For some naphthoylindoles, duration of their Δ 9 -THC-like discriminative stimulus effects appeared to differ from that of Δ 9 -THC itself [95,96].…”

“…Early studies demonstrated that JWH-018 and other indole-and pyrrole-derived synthetic cannabinoids exhibit orderly structure-activity relationships in binding assays and in a battery of pharmacological tests in mice, with good correlations between CB 1 receptor binding affinities and potencies for centrally mediated cannabinoid effects [90,93,94]. To the extent that these compounds were tested in discrimination procedures, they also were shown to dose-dependently substitute for psychoactive cannabinoids (Δ 9 -THC, CP55,940, or methanandamide) in rats and rhesus monkeys [54,90,[95][96][97][98], again with potencies that were consistent with their CB 1 receptor affinities. Further, substitution of JWH-018 and JWH-073 occurred following inhalation in mice trained to discriminate intraperitoneal Δ 9 -THC from vehicle [99].…”

“…For example, substitution of a phenylacetyl group for the naphthoyl substituent of JWH-018 resulted in a series of phenylacetylindoles [100,101]. Several of these compounds (JWH-203, JWH-204, JWH-205, JWH-250) have high CB 1 receptor affinity and were shown to substitute for Δ 9 -THC in rodents trained to discriminate Δ 9 -THC from vehicle [16,95]; however, another compound (JWH-202) that had low CB 1 receptor affinity did not substitute [16]. XLR-11 and UR-144 are two additional compounds that have appeared on the illicit market within the last few years [102].…”