Pharmacokinetics and –dynamics of pulmonal and intravenous ∆ 9 -tetrahydrocannabinol (thc) in humans

Cannabis is widely used in folk medicine to relieve pain. Analgesia could not be confirmed in our previous pain study with healthy subjects using oral THC (dronabinol, Marinol®). Extensive liver first pass metabolism and THC plasma peaks varying between 30 and 120 min were observed. The aim of the present study was to develop an inhalation solution of THC, to acquire pharmacokinetic profiles of pulmonal and intravenous (i.v.) THC, and to compare the analgesic effect of the inhalation solution vs. placebo. Eight healthy volunteers (4 female, 4 male) were included in the randomised, placebo controlled, double-blind, crossover study. Two aqueous, physiologically well tolerable formulations were prepared using a solubilisation technique. I.v. THC (0.053 mg/kg b.wt.), pulmonal THC (0.053 mg/kg b.wt.), or a placebo inhalation solution were administered as single doses. The inhalation solution was nebulised with a pressure-driven, commercially available nebuliser device. At defined time points blood samples were collected, somatic and psychotropic side effects (visual analog scales) and vital functions (blood pressure, heart rate, and oxygen saturation) monitored, and an ice water immersion test was performed to measure analgesic effects. Peak plasma levels of THC and its main metabolites 11-hydroxy-THC and 11-carboxy-THC after pulmonal administration were 22.62 ± 6.92 ng/mL (mean ± SEM), 1.83 ± 0.47 ng/mL, and 13.89 ± 2.94 ng/mL, respectively. The bioavailabilty of the pulmonal THC was 28.6 ± 8.2 %. The side effects observed in the inhalation session were coughing and slight irritation of the upper respiratory tract during the inhalation (reversible within 30 min, partly imparing inhalation efficiency), very mild psychotropic effects, and headache. The side effects after i.v. THC were much more prominent, also showing strong psychotropic symptoms, increased heart rate, and dry mouth. Neither pulmonal nor i.v. THC did significantly reduce pain in the ice water immersion test. In conclusion, this study shows that pulmonal THC produced peak plasma levels within minutes after inhalation. Due to reduced liver first pass metabolism the bioavailability was much higher compared to oral THC. However, the analgesic potency of THC in our pain model could not be increased by the better bioavailability of the pulmonal application form