Δ9-Tetrahydrocannabinol-like effects of novel synthetic cannabinoids in mice and rats

Abstract

Rationale Novel cannabinoid compounds continue to be marketed as "legal" marijuana substitutes, even though little is known about their molecular and behavioral effects. Objectives Six of these compounds (ADBICA, ADB-PINACA, THJ-2201, RCS-4, JWH-122, JWH-210) were tested for in vitro and in vivo cannabinoid-like effects to determine their abuse liability. Methods Binding to and functional activity at CB1 cannabinoid receptors was tested. Locomotor activity in mice was tested to screen for behavioral activity and to identify behaviorally active dose ranges and times of peak effect. Discriminative stimulus effects of the six compounds were tested in rats trained to discriminate Δ9-tetrahydrocannabinol (Δ9-THC). Results ADBICA, ADB-PINACA, THJ-2201, RCS-4, JWH-122, JWH-210 showed high affinity binding at the CB1 receptor at nanomolar affinities (0.59 nM to 22.5 nM) and all acted as full agonists with nanomolar potencies (0.024 to 111 nM) when compared to the CB1 receptor full agonist CP 55,940. All compounds depressed locomotor activity below 50% of vehicle responding, with depressant effects lasting 1.5 to nearly 4 h. All compounds fully substituted (<80% Δ9-THC-appropriate responding) for the discriminative stimulus effects of Δ9-THC. 3,4-Methylenedioxy-methamphetamine (MDMA) was tested as a negative control and did not substitute for Δ9-THC (11% Δ9-THC-appropriate responding). Conclusions All six of the compounds acted at the CB1 receptor and produced behavioral effects common to abused cannabinoid compounds, which suggest that these compounds have substantial abuse liability common to controlled synthetic cannabinoid compounds.

Behavioral and Pharmacokinetic Profile of Indole-Derived Synthetic Cannabinoids JWH-073 and JWH-210 as Compared to the Phytocannabinoid Δ9-THC in Rats

“…However, treatment with JWH-210 (0.1–5 mg/kg) did not result in locomotor activity change. Our results are not consistent with those previously described showing that treatment with JWH-210 (0.5–5 mg/kg; Gatch and Forster, 2016 ) or JWH-073 (3–30 mg/kg; Marshell et al, 2014 ) elicited a dose-dependent reduced locomotor activity. These discrepancies could be due to the species (rat vs .…”

“…Control animals were treated with the corresponding amounts of sunflower oil as vehicle. The doses of the SCs were selected according to the reports from users on the internet and according to the potency of similar compounds that have been tested in preclinical experiments (Cha et al, 2015 ; Gatch and Forster, 2016 ; Ossato et al, 2016 ). The doses of Δ 9 -THC were selected based on our previous results focusing on its behavioral and pharmacokinetic effects induced by different routes of administration (Micale et al, 2013a ; Hlozek et al, 2017 ).…”

Synthetic Pot: Not Your Grandfather’s Marijuana

“…Consistent with the higher in vitro efficacy of SCBs as compared to Δ 9 -THC, multiple laboratories reliably report that hypothermic effects obtained with SCBs are greater in magnitude than those observed after administration of maximally effective doses of Δ 9 -THC in mice [109, 146, 147]. In contrast, multiple research groups consistently demonstrate that Δ 9 -THC elicits a similar degree of locomotor suppression as higher efficacy SCBs [109, 148] [135]. No consistent efficacy-dependent results are obtained with the cannabinoid tetrad endpoints of analgesia and catalepsy, presumably due to numerous methodological variables associated with data collection across laboratories.…”

The chemistry and pharmacology of synthetic cannabinoid SDB‐006 and its regioisomeric fluorinated and methoxylated analogs

“…21,22 Analogs of JWH-018 containing a fluorine substituent (JWH-412, 3) or a methoxy group (JWH-081, 4) on the naphthalene ring have been identified in SC products from the marketplace or authentic SC user specimens. 31,32 The benzylic indole-3-carboxamide SDB-006 (6) was seized in Finland in December 2013, 33 and has since been reported elsewhere. 31,32 The benzylic indole-3-carboxamide SDB-006 (6) was seized in Finland in December 2013, 33 and has since been reported elsewhere.…”

“…[23][24][25][26][27][28] These modifications are not restricted to 3-naphthoylindoles, and several regioisomers and homologues of methoxybenzoylindole SC RCS-4 (5) have also been reported 29,30 despite no precedent in the scientific literature, with position of methoxy substituent affecting cannabinoid potency in vitro. 31,32 The benzylic indole-3-carboxamide SDB-006 (6) was seized in Finland in December 2013, 33 and has since been reported elsewhere. 34,35 Although this compound was unprecedented in the scientific literature at the time of its discovery, other benzylic indole-3-carboxamides had been reported as potent, water-soluble CB 1 receptor agonists.…”