Concentration-effect relationship of delta-9-tetrahydrocannabiol and prediction of psychotropic effects after smoking marijuana.

Harder S, Rietbrock S

Department Clinical Pharmacology, University Hospital Frankfurt/Main, Germany.

On the basis of a publication by Cochetto et al. [1981] we performed simulations of the effect-time course (high-rating) after smoking marijuana. The intention was to characterize the concentration-effect relationship of THC and to provide information on how long psychotropic effects (and therefore impairment of cognitive or motoric functions) last after intake of a cannabinoid product. The parameter estimates (+/-SD) of the pharmacokinetic disposition and the pharmacodynamic model (sigmoidal Emax model) after smoking 1 marijuana cigarette containing 9 mg THC were as follows: T/2 alpha = 5 minutes (+/-1.2), T/2 beta = 75 minutes (+/-23), Teq (equilibrium half-life with the effect site) = 29 minutes. (+/-2), ECe50 = 7.2 ng/ml THC (+/-0.5), E0 (baseline high rating) = 18% (+/-2.0), Emax (amplitude of the high rating) = 23% (+/-2.5), Hill coefficient = 9.0 (+/-3.0). On the basis of this curve fit, the effect-time course after repeated smoking (5 joints) in different intervals (120, 60, and 30 minutes) and for different dose strengths 9 mg (standard joint), 3 mg (weak joint) and 1 mg (agricultural hemp) were simulated. The duration of the effect after 1 dose of 9 mg is about 45 minutes. After the last cigarette, recovery (decline < 50% Emax) will last about 100 minutes. A dosing interval of 1 h leads to a continuous "high", and recovery will last about 150 minutes after the last joint. Smoking the weak dose strength (3 mg) every hour will result in a short plateau of the maximal effect (about 20 minutes) and a decline after the last joint within 1 h. Only repeated smoking every 30 minutes will lead to a prolonged plateau phase with a recovery time of about 80 minutes. Using hemp with a low THC content (1 mg), dosing intervals of 2 h and 1 h will not provoke a psychotropic response due to THC. Smoking every 30 minutes will probably lead to a short-term moderate response. In conclusion, our simulations show that dose and dosing interval are determinants of the duration of the psychotropic effects of THC. These simulations may be beneficial for the interpretation of THC levels, e.g. associated with accidents or traffic violations. Furthermore, misuse of natural hemp with a low THC content seems unlikely.