Highway to hell or magic smoke? The dose-dependence of Δ⁹-THC in place conditioning paradigms

Abstract

The prerequisites for responsible cannabis use are at the heart of current inquiries into cannabis decriminalization by policy makers as well as academic and nonacademic stakeholders at a global scale. Δ-tetrahydrocannabinol (Δ-THC), the prime psychoactive compound of the , as well as cannabimimetics that resemble the pharmacological properties and psychological effects of Δ-THC, lend themselves handsomely to the preclinical scrutiny of reward-related behavior because they carry marked translational value. Although a functional dichotomy of the psychological effects of Δ-THC (rewarding versus aversive) has been abundantly reported in place conditioning (PC) paradigms, and might be best attributed to a dose-dependence of Δ-THC, most PC studies with Δ-THC feature no significant effects at all. Therefore, after decades of rigorous research, it still remains undetermined whether Δ-THC generally exerts rewarding or aversive effects in rodents. Here, we set out to extrapolate the commonly alleged dose-dependence of the rewarding and aversive effects of Δ-THC from the existing literature, at the behavioral pharmacological level of analysis. Specifically, our meta-analysis investigated: (i) the alleged bidirectional effects and dose-dependence of Δ-THC in the PC test; (ii) methodological inconsistencies between PC studies; and (iii) other pharmacological studies on cannabinoids (i.e., dopamine release, anxiety, stress, conditioned taste aversion, catalepsy) to substantiate the validity of PC findings. Our findings suggest that: (i) Δ-THC dose-dependently generates rewarding (1 mg/kg) and aversive (5 mg/kg) effects in PC; (ii) an inconsistent use of priming injections hampers a clear establishment of the rewarding effects of Δ-THC in PC tests and might explain the seemingly contradictory plethora of nonsignificant THC studies in the PC test; and (iii) other pharmacological studies on Δ-THC substantiate the dose-dependent biphasic effects of Δ-THC in PC. A standardized experimental design would advance evidence-based practice in future PC studies with Δ-THC and facilitate the pointed establishment of rewarding and aversive effects of the substance.

Effects of ∆9-tetrahydrocannabinol on aversive memories and anxiety: a review from human studies

“…Furthermore, Bedse et al [147] demonstrated in mice that the 2-AG depletion-induced anxiety-like behavior after stress exposure was counteracted by the administration of 0.25 mg/kg THC. Overall, these findings confirm the bidirectional effects of THC on anxiety, despite the varying dose range associated with anxiolytic and anxiogenic effects [148]. Of note, at doses ranging from 3.0 to 10 mg/kg in rats, and from 10 to 20 mg/kg in mice, THC also produced sedative-like effects [143].…”

Early-life stress exacerbates the effects of WIN55,212-2 and modulates the cannabinoid receptor type 1 expression

“…Indeed, there are contradictory results, because i.p. Δ 9 -THC administration could promote either conditioning place preference (CPP) or even aversion in a dose-dependent manner (Kubilius et al, 2018;Manwell et al, 2014;Murray and Bevins, 2010). By contrast, more consistent results have been reported using WIN55,212-2, since it induced CPP (Castañé et al, 2004;Manzanedo et al, 2010) probably due to its higher affinity for CB1 and CB2 receptors than Δ 9 -THC (Thomas et al, 1998).…”

“…In rodents, some studies have achieved the self-administration of cannabinoids, using intravenous Δ 9 -THC (Spencer et al, 2018), vaporized Δ 9 -THC (Freels et al, 2020), or intravenous R-(+)-[2,3-Dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1napthalenylmethanone mesylate (WIN55,212-2), a synthetic cannabinoid receptor agonist (Kirschmann et al, 2017;Mendizábal et al, 2006). The low reliability of the cannabinoids self-administration could be due to the low rewarding effects of Δ 9 -THC observed in the conditioning place preference paradigm (Kubilius et al, 2018). Indeed, there are contradictory results, because i.p.…”

An Interdisciplinary Framework for Islamic Cognitive Theories

“…Studying the dose‐dependent nature of cannabinoids’ reward‐related psychological effects can not only bear implications for explaining and treating motivational disorders, but also for cannabis decriminalization (Kubilius et al. ). Leaving aside that the Islamic permissibility of cannabis use can be debated in and of itself, such research potentially conflicts with Islamic legal maxims and precepts if its rationale is to simply push cannabis decriminalization policies for recreational cannabis use.…”