Oral Δ9-tetrahydrocannabinol Toxicity in Rats Treated for Periods Up to Six Months

The chronic toxicity of Δ9-tetrahydrocannabinol (Δ9-THC) given orally 28, 90, and 180 days to Fischer rats at doses of 2, 10, and 50 mg/kg was investigated. Some 180-day treated animals were monitored after a 30-day recovery interval. The lower doses used corresponded to the Δ9-THC content of marihuana or hashish. In the first 10 days CNS-depression, incoordination, ataxia and passivity, poikilothermia, and hypopnea occurred to which tolerance developed. During days 10–20, irritability, hypersensitivity, hyperactivity, and aggression predominated. Fighting occurred between days 20–100. Tremors and clonic convulsions appeared after day 70 in 50% of the animals at 50 mg/kg and 12% at 10 mg/kg. Tolerance developed to CNS-stimulation, fighting and neurotoxicity and lethal cumulative toxicity was seen although the cause of death was not established. Growth rate of both sexes was inhibited despite an elevation in food consumption after a transient anorexia No morphological changes could be ascribed to Δ9-THC. Except for a rise of 28–45% in SGOT and 46–69% in SGPT in males at higher doses and a belated hyperglycemia in both sexes, clinical chemistry, hematological, and urinalysis parameters were within normal ranges. The greatest changes were seen in ratios of organ/FBW at 50 mg/kg: 10–20% increase in brain, lungs, kidneys, heart, and liver; 45% increase in adrenals; 96% increase in male pancreas and 13–25% increase in testis and prostate. The present investigation implicated reasonable doses of Δ9-THC in undesirable behavioral changes highlighted by fighting aggression, convulsive activity, and lethal cumulative toxicity. The absence of morphological changes despite changes in growth rate and organ weights indicated a functional impairment that was not an immediate threat to the life of the organism because of initiation of as yet unknown protective mechanisms.