A Six-Person THC Study Found Pharmacokinetic Changes That Did Not Account for Observed Tolerance
A 1980 human study found changes in THC disposition during repeated oral administration, yet concluded that those changes could not account for the observed cardiovascular, psychological and skin-temperature tolerance. Detecting a pharmacokinetic change is different from demonstrating that it explains adaptation.
The challenge measured parent drug in plasma
Six subjects received repeated oral THC, with intravenous labeled THC challenges before and after that regimen. Pharmacokinetic evaluation used unchanged THC in plasma. This design separates the repeated exposure from the route used to characterize disposition.
Some parameters changed and others did not
Average clearance and an initial apparent distribution volume increased, while steady-state distribution volume and many model-dependent measures were unchanged. The pattern did not support treating every aspect of disposition as uniformly faster or larger after tolerance developed.
Urine represented only one elimination component
The fraction excreted in urine decreased, while total urine-plus-fecal elimination was not significantly changed. Total-metabolite observations also remained different from a selective parent-THC measurement. A change in one excretion pathway should not be labeled a change in total elimination without that comparison.
Interpreting the evidence
This small historical experiment illustrates the need to distinguish association from explanatory sufficiency. Its regimen and modeling cannot supply an individual's clearance rate or impairment timeline, and the authors' conclusion does not establish that pharmacokinetics never contributes to tolerance under other conditions.
Related reading: interpreting cannabis tolerance claims.
Research reference
Hunt CA; Jones RT (1980). Tolerance and disposition of tetrahydrocannabinol in man. The Journal of pharmacology and experimental therapeutics. PubMed research record.
This analysis draws on the supplied abstract.
