Pharmacological evaluation of aerosolized cannabinoids in mice

• Published in: European journal of pharmacology Vol. 399; no. 2; pp. 141 - 149
• Main Authors: Lichtman, Aron H, Peart, Joanne, Poklis, Justin L, Bridgen, D.Troy, Razdan, Raj K, Wilson, David M, Poklis, Alphonse, Meng, Yun, Byron, Peter R, Martin, Billy R
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 07.07.2000; Elsevier
• Subjects: Administration, Inhalation; Aerosol; Aerosols; Analgesics; Animals; Antinociception; Biological and medical sciences; Cannabinoid; Cannabinoids - antagonists & inhibitors; Cannabinoids - pharmacology; Dose-Response Relationship, Drug; Dronabinol - blood; Dronabinol - pharmacology; General pharmacology; Hallucinogens - pharmacology; Injections, Intravenous; Male; Marijuana; medical; Medical sciences; Mice; Mice, Inbred ICR; Nebulizer; Neuropharmacology; Pain - prevention & control; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; Piperidines - pharmacology; Pyrazoles - pharmacology; Rimonabant; SR 141716A; Δ 9-THC (Δ 9-tetrahydrocannabinol); Aerosol; Δ 9-THC (Δ 9-tetrahydrocannabinol); SR 141716A; Antinociception; Marijuana; Cannabinoid; Nebulizer; Blood; Blood plasma; Dose activity relation; Antagonist; Mechanism of action; Biological receptor; Nociception; Pharmaceutical technology; Rodentia; Intrapulmonary administration; Biological activity; Inhalation; Locomotion; Vertebrata; Particle size distribution; Mammalia; Analgesic; Mouse; Analog; Animal; Aerosols; Dosage form; Pharmacokinetics; Physicochemical properties
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/S0014-2999(00)00321-6

The reemergence on the debate of the use of marijuana for medicinal purposes has been the impetus for developing an acceptable delivery form of aerosolized cannabinoids. The goals of the present study were to: (1) develop and characterize the physical properties of an aerosolized form of Δ 9-tetrahydrocannabinol (Δ 9-THC), the major psychoactive constituent present in marijuana; and (2) assess the pharmacological effects of cannabinoid inhalation in mice. A Small Particle Aerosol Generator (SPAG) nebulizer, used to generate the aerosol, had an output of approximately 0.154 mg/l of aerosolized Δ 9-THC with a 2.0 μm mass median aerodynamic diameter and a 2.2 geometric standard deviation (GSD). Virtually all the particles were less than 5.0 μm in diameter suggesting that they were sufficiently small to penetrate deeply into the lungs. Inhalation exposure to aerosolized Δ 9-THC in mice elicited antinociceptive effects that were dependent on concentration and exposure time with an estimated Δ 9-THC dose of 1.8 mg/kg. On the other hand, inhalation exposure to Δ 9-THC failed to produce two other indices indicative of cannabinoid activity, hypothermia and decreases 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, inhalation exposure to a water soluble cannabinoid analog, 3-(5′-cyano-1′,1′dimethylheptyl)-1-(4- N-morpholinobutyrloxy)-Δ 8-tetrahydrocannabinol (O-1057), produced antinociception that was blocked by SR 141716A. These results demonstrate that the development of an aerosolized form of cannabinoids for human medicinal use is feasible.