Pharmacological evaluation of aerosolized cannabinoids in mice

The reemergence on the debate of the use of marijuana for medicinal purpose s has been the impetus for developing an acceptable delivery form of aeroso lized cannabinoids. The goals of the present study were to: (1) develop and characterize the physical properties of an aerosolized form of ag-tetrahyd rocannabinol (Delta(9)-THC), the major psychoactive constituent present in marijuana; and (2) assess the pharmacological effects of cannabinoid inhala tion in mice. A Small Particle Aerosol Generator (SPAG) nebulizer, used to generate the aerosol, had an output of approximately 0.154 mg/l of aerosoli zed Delta(9)-THC with a 2.0 mu m mass median aerodynamic diameter and a 2.2 geometric standard deviation (GSD). Virtually all the particles were less than 5.0 mu m in diameter suggesting that they were sufficiently small to p enetrate deeply into the lungs. Inhalation exposure to aerosolized Delta(9) -THC in mice elicited antinociceptive effects that were dependent on concen tration and exposure time with an estimated Delta(9)-THC dose of 1.8 mg/kg. On the other hand, inhalation exposure to Delta(9)-THC failed to produce t wo other indices indicative of cannabinoid activity, hypothermia and decrea ses in spontaneous locomotor activity. The antinociceptive effects occurred within 5 min of exposure and lasted approximately 40 min in duration. The cannabinoid receptor antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2, 4-dichlorophenyl)-4-methyl-1 H-pyrazole-3-carboxamide HCl (SR 141716A), but not naloxone, blocked these antinociceptive effects (AD(50) = 0.09 mg/kg) indicating a cannabinoid receptor mechanism of action. Similarly, inhalatio n exposure to a water soluble cannabinoid analog, 3-(5'-cyano-1',1'dimethyl heptyl)-1-(4-N-butyrloxy)-Delta(8)-tetrahydrocannabinol (O-1057), produced antinociception that was blocked by SR 141716A. These results demonstrate t hat the development of an aerosolized form of cannabinoids for human medici nal use is feasible. (C) 2000 Elsevier Science B.V. All rights reserved.