Analgesic properties of the tetrahydrocannabinols, their metabolites, and analogs

Abstract

The tetrahydrocannabinols from marihuana were found to have moderate analgesic activity in mice by the hot-plate test (sc administration). Of the several metabolites of these two compounds tested, only the 11-hydroxy derivatives were more potent than the parent compounds. Analogs 1 and 2 (9-demethyl relatives which cannot be metabolized to 11-hydroxy compounds), both of which produce a pharmacological profile generally similar to that of delta8- and delta9-THC, were analgesically inert. This suggests that metabolism to 11-hydroxy congeners may be necessary for the mediation of analgesic activity in the mouse hot-plate test but not for other pharmacologic effects produced by these substances which we have examined.

Novel Δ9-tetrahydrocannabinol formulation Namisol® has beneficial pharmacokinetics and promising pharmacodynamic effects

“…Compared with intravenous administration and inhalation, the concentration of the 11-OH metabolite after oral THC administration from Namisol® was relatively high [14,29,32]. The ratio of 11-OH-THC : THC (based on peak plasma concentrations) was 1 : 30 for intravenous administration and 1 : 7 for inhalation, while this ratio was 1 : 0.6-0.8 for Namisol® [13,27,33].…”

“…Preclinical studies have found 11-OH-THC to be a highly potent CB1-agonist [14,15], and clinical studies also reported more rapid and larger effects after 11-OH-THC administration compared with THC [34][35][36]. In itself, this would have allowed us to predict the pharmacodynamic effects of higher doses in panel II, by reference to the results of other oral THC formulations in the literature which also produce high concentrations of 11-OH-THC.…”

“…The major metabolite of THC is 11-OH-THC [13]. This metabolite induces effects via CB1 receptors and has been described to be equally or up to seven times as potent as THC [14,15]. This could mean that the clinical effects of THC are related to the combined activities of THC and 11-OH-THC.…”

Cannabinoid receptor localization in brain.

“…A9-THC and other natural and synthetic cannabinoids produce characteristic motor, cognitive, and analgesic effects (4, 5). Early reports showing cannabinoid-like activity of 9f3-hydroxyhexahydrocannabinol (13-HHC) (6)(7)(8) inspired the synthesis of several distinct cannabinoids for studies of their potential use as analgesics (9) 55,940 was extracted, giving a radiochemical yield of 15% and a specific activity of 79 Ci/mmol (1 Ci = 37 GBq). Optimization and competition studies were carried out with slidemounted sections cut from unfixed frozen rat brains.…”

“…A9-THC and other natural and synthetic cannabinoids produce characteristic motor, cognitive, and analgesic effects (4,5). Early reports showing cannabinoid-like activity of 9f3-hydroxyhexahydrocannabinol (13-HHC) (6)(7)(8) inspired the synthesis of several distinct cannabinoids for studies of their potential use as analgesics (9). The synthetic cannabinoids share physicochemical properties with the natural cannabinoids and produce many behavioral and physiological effects characteristic of A9-THC but are 5-1000 times more potent and show high enantioselectivity.…”