Repeated CP-55,940 Changed Liver Biotransformation Alongside Behavioral Tolerance in Rats
A rat study found behavioral tolerance to CP-55,940 alongside changes in liver biotransformation systems. The results suggest that repeated-exposure adaptation cannot be described solely by brain receptor changes, while not proving altered clearance caused the tolerance.
Acute and repeated metabolic responses differed
A single injected dose produced characteristic cannabinoid-related behaviors and increased mitochondrial respiration in brain and liver. Certain additional mitochondrial measures were unchanged. After eleven days of repeated administration, behavioral tolerance appeared and the initial increase in mitochondrial oxygen consumption disappeared.
Liver measurements also changed
Repeated exposure increased microsomal monooxygenase activities and cytochrome P450 content, with changes in some glutathione-related cytosolic enzyme measures. These are biotransformation-related observations. They do not by themselves establish the concentration-time course of CP-55,940 or quantify clearance of other drugs.
Metabolic adaptation and receptor adaptation can coexist
The authors noted prior receptor-downregulation explanations and reported concurrent biotransformation changes. The design does not isolate how much each process contributed to behavioral tolerance. It also does not establish a specific human drug interaction or show that THC and CP-55,940 induce the same enzymes.
The study's contribution is the combination of behavioral, mitochondrial and hepatic measurements after repeated synthetic-cannabinoid exposure. Applying it requires naming the compound and assay. An enzyme-activity change is not a substitute for a measured pharmacokinetic interaction, dose recommendation or individual impairment assessment.
Related: interpreting cannabis tolerance claims.
Research cited
Costa B; Parolaro D; Colleoni M. Chronic cannabinoid, CP-55,940, administration alters biotransformation in the rat. European journal of pharmacology (1996). doi:10.1016/0014-2999(96)00499-2. Findings discussed from the study abstract.
