OTHER PROJECT INFORMATION - SECTION 7 - PROJECT SUMMARY/ABSTRACT 1 Increased abuse of designer cannabinoids, such as JWH-018 and AB-PINACA (sold as “Spice” or “K2”), 2 continues to be a severe public health concern despite Class I scheduling of these compounds by the DEA. 3 Preclinical studies of these compounds have repeatedly identified them as being THC-like, however 4 occurrences of emesis, hallucinations, seizures, and even death - effects not previously associated with THC 5 or other cannabis products - indicates that there are grave differences between synthetic and plant-derived 6 cannabinoids. We propose to systematically characterize the pharmacological differences among synthetic 7 cannabinoids (SCBs) based on their intrinsic activity in producing CB1 receptor-mediated effects as well as 8 their ability to modulate noncannabinoid effects. The overarching goals of this program are to determine 9 differences between drugs that predict their abuse-related effects and to use these differences to identify 10 useful strategies for acute management of the deleterious effects of designer cannabinoids. These goals will 11 be achieved by addressing three hypotheses: 1) SCBs vary in efficacy at CB1 receptors; 2) SCBs have 12 modulatory effects at other neurotransmitter systems; and 3) differences in the intrinsic activity of SCBs is 13 reflected in their deleterious and reinforcing effects. To address these aims, we propose to use a unique CB1 14 antagonist, AM6538, to temporarily inactivate a portion of CB1 receptors and then assess the ability of a range 15 of SCBs to produce antinociceptive effects or disrupt ongoing behavior. The fraction of receptors remaining for 16 each agonist following AM6538 treatment will vary directly with the intrinsic activity of the SCBs, providing a 17 quantifiable measure of their differences in vivo (apparent τ-value) The second aim of these studies is based 18 on the premise that the hallucinogenic effects of SCBs bear some similarities to the effects of other known 19 hallucinogens, namely LSD, salvinorin A, or ketamine, which are mediated by, respectively, 5-HT2, κ-opioid, or 20 glutamate receptors. To address this aim, drug discrimination procedures will be used to establish assays that 21 can determine the extent to which SCBs have subjective effects similar to those of other hallucinogens. The full 22 or partial substitution profile of the SCBs for the different training drugs is expected to be dependent on the 23 chemical structure of the SCBs or on their intrinsic activity. Lastly, we propose experiments to evaluate the 24 neurocognitive effects and reinforcing effects of SCBs in nonhuman primates in order to identify or clarify the 25 pharmacological relationship that exists between the abuse liability, the hallucinogenic-like profile, and the 26 intrinsic activity of designer cannabinoid drugs. The direct impact of these studies will be to elucidate the 27 relationship between CB1 efficacy and deleterious subjective effects of SCB products. This will aid in 28 characterizing novel drugs as they emerge in the `grey market', and, as well, begin to identify mechanisms by 29 which the effects of these SCBs differ from those of phytocannabiniods.

Increased abuse of designer cannabinoids (e.g., K2/Spice) continues to be a severe public health concern despite recent Class I scheduling of several compounds by the DEA. Preclinical studies of these compounds have repeatedly identified them as being THC-like, however occurrences of psychosis, seizures, and even death - effects not previously associated with THC or other cannabis products - indicates that there are grave differences between synthetic and plant-derived cannabinoids. We propose to systematically characterize the pharmacological differences among synthetic cannabinoids based on their intrinsic activity in producing CB1 receptor-mediated effects as well as their ability to modulate noncannabinoid effects. The overarching goals of this program are to: 1) determine differences between drugs that predict their abuse-related effects, and 2) identify useful strategies for acute management of their deleterious effects.