While cannabinoids are lipophilic and anecdotal evidence suggests that cannabinoids dissolve better in fats and oils, the influence of various fats on cannabinoid absorption in vivo has been poorly studied. A pre-clinical study examined the effect of dietary fats on THC and CBD absorption in in ratsReference 427. A dose of 12 mg/kg of THC or CBD in either lipid-free formulation or lipid long-chain triglycerides (LCT)-based formulation (sesame oil) was administered to rats by oral gavage. The absolute bioavailability of THC was 2.5 times higher in the lipid-based (Cmax = 172 ng/mL; AUC = 1050 h.ng/mL) versus lipid-free formulation (Cmax = 65 ng/mL; AUC = 414 h.ng/mL). The absolute bioavailability of CBD was three times higher in the lipid-based (Cmax = 308 ng/mL; AUC = 932 h.ng/mL) versus lipid-free formulation (Cmax = 87 ng/mL; AUC = 327 h.ng/mL). Furthermore, an in vitro lipolysis model was used to assess the mechanism by which lipids could enhance the bioavailability of THC and CBD. Results showed that 30% of THC and CBD was solubilized in the micellar layer and therefore was readily available. Incubation studies suggested that cannabinoids have a 70 to 80% association range with natural chylomicrons from rat and human. Chylomicrons act as carriers in the intestine and potentially transfer THC and CBD to the systemic circulation via the intestinal lymphatic system and therefore avoid hepatic first-pass metabolism, which would explain the increased bioavailability with the lipid-based formulation. The authors concluded that administration of cannabinoids with a fatty meal or in the form of a lipid-rich cannabis-containing cookie may increase systemic exposure and therefore change the efficacy of the drug by turning a barely effective dose into a highly effective one, or even, a therapeutic dose into a toxic one.
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Target Δ9-THC plasma concentrations have been derived based on the subjective "high" response that may or may not be related to the potential therapeutic applications. Various pharmacodynamic models provide blood plasma concentration estimates in the range of 7 to 29 ng/mL Δ9-THC necessary for the production of a 50% maximal subjective "high" effectReference 490. Other studies suggest that Δ9-THC plasma concentrations associated with 50% of the maximum "high" effect range between 2 and 250 ng/mL Δ9-THC (median of 19 ng/mL; mean of 43 ng/mL Δ9-THC) for the smoked or intravenous routes, while for the oral route the values range between 1 and 8 ng/mL Δ9-THC (median and mean of 5 ng/mL Δ9-THC)Reference 137Reference 493. Notably, impairment of driving performance is seen with plasma concentrations between 7 and 10 ng/mL (whole blood, approximately 3 - 5 ng/mL) and this blood THC concentration has been compared to a blood-alcohol concentration (BAC) of 0.05% which itself is associated with driver impairmentReference 154.
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