Pulmonary pathologic changes in rats exposed to marihuana smoke for 1 year.

Exposure of rats to marihuana or placebo smoke for periods up to 365 days was performed with an automatic inhalator. Δ⁹-Tetrahydrocannabinol (Δ⁹-THC) concentrations in the marihuana smoke were similar to those inhaled by man and were presented to the rats in a 50-ml puff volume of 2-sec duration and a 30-sec exposure interval followed by a 30-sec period of fresh air each minute (1 puff/min). By varying the number of puffs from three simultaneously smoked marihuana cigarettes (0.9 to 1.2% Δ⁹-THC), 8 to 10 Fischer rats simultaneously received a single daily Δ⁹-THC dose of 0.4, 0.8 or 1.5 mg/kg, 6–7 days per week for 365 days. All treatment groups contained 30 males and 30 females except for the high-dose group which had 50 males and 50 females. At each of the lower doses $\text{2}\text{60}$ (3%) of the animals died while at the higher dose $\text{18}\text{108}$ (17%) died. Twenty-five percent ($\text{15}\text{60}$) of the placebo-smoked rats died primarily from carbon monoxide poisoning. No sham-smoked rats died. In deceased marihuana-smoked rats, organ congestion and focal petechial hemorrhages in the brain suggested circulatory failure. In contrast with an earlier 87-day inhalation study, pulmonary irritation progressed beyond a dose-related focal alveolitis or pneumonitis with the accumulation of yellow-brown alveolar macrophages admixed with a few neutrophils and mononuclear cells, to a spectrum of more pronounced inflammatory and focal proliferative changes. The development of focal granulomatous inflammation in the lung with giant cell forms of macrophages and cholesterol-like clefts were striking new developments in the marihuana-smoked rats, especially since these effects were dose related and nonreversible after a 30-day recovery period.