Comparison of acute oral toxicity of cannabinoids in rats, dogs and monkeys

For preclinical toxicologic evaluation, Δ ⁹-tetrahydrocannabinol ( Δ ⁹-THC), Δ ⁸-THC, and Cannabis extract were administered po to rats, dogs and monkeys as solutions in either absolute ethanol, sesame oil, or sesame oil with 2.5–9.0% ethanol. All three compounds were significantly more potent in female than in male Wistar-Lewis and Fischer rats. However, within the dosage range of 225–3600 mg/kg, Δ ⁹-THC and Δ ⁸-THC produced the same lethality, while both isomers were approximately twice as potent as the Cannabis extract. Death due to all three compounds consistently occurred between 36 and 72 hr after treatment regardless of the dose level or sex of the rats. Mortality in rats apparently resulted from severe hypothermia and other central effects. Toxicity was characterized by severe hypothermia, bradypnea, rapid weight loss, inactivity, wide stance, ataxia, muscle tremors, and prostration. Rats treated with equimolar amounts of tetrahydrocannabinol from the three compounds exhibited equivalent diversities and severities of clinical signs. In dogs and monkeys, single oral doses of Δ ⁹-THC and Δ ⁸-THC between 3000 and 9000/mg/kg were nonlethal. Predominant toxic signs in dogs included drowsiness, ataxia, prostration, anesthesia, tremors, mild hypothermia, salivation, emesis, and anorexia. Toxic signs in monkeys included hyperreactivity to stimuli, lethargy, drowsiness, characteristic huddled posture, slow movements, abnormal eating procedures and sedation. Histopathologic alterations did not occur in either dogs or monkeys.