9-THC delta is converted through microsomal hydroxylation to 11-hydroxy-delta 9-THC (11-OH-delta 9-THC), which is a key intermediate for increased metabolism in 11-nor-delta 9-THC-9-carboxylic acid (11-noracid) by hepatic alcohol-dehydrogenase enzymes and a potent psychoactive metabolite. Since there is a notable discrepancy between many of the beneficial and adverse effects of THC that have been documented in rodent studies using injection-based approaches compared to human studies in which cannabis users were examined, it should be noted that the THC injection-based approach has limitations for translational research. This hypothermic difference based on the route of administration is not surprising, since inhaled THC rapidly enters the bloodstream and is absorbed by the brain, while injected THC is metabolized in the liver before reaching the systemic circulation. Alternatively, injected THC produces lower initial concentrations of THC in the brain than those inhaled, and levels build up over time until maximum THC levels are reached after 90 minutes, comparable to those inhaled.
In preclinical studies, the dosage of THC is usually determined based on whether it produces blood THC concentrations within the desired range observed in humans after cannabis use. Studies in rodents using THC injections allow for control of both dose and timing; however, maximum plasma concentrations of THC are found a little later after injection than inhalation4,25,26,27. Men in general had higher levels of THC, while women had higher levels of metabolites, which supports previous findings of strong sex differences in the pharmacokinetics of THC. Although the maximum plasma THC concentrations were similar, inhalation produced higher THC concentrations in the brain at 15, 30 and 60 minutes compared to injection. In fact, given the enormous accumulation of 11-OH-THC in the brain after injection, as well as its significant potency in the CB1R, it seems reasonable to hypothesize that the injection of THC produces a much stronger and more sustained activation of the cerebral CB1R than THC administered by inhalation.
The THC chromatogram illustrates THC (black line) and THC-D3 (gray line) with an overlapping peak at 2.7 minutes (fig. These sex differences in THC metabolism may also have implications for human consumption of THC, especially when consumed orally, since enterohepatic metabolism will affect THC metabolism. Therefore, it is not clear if THC injections that produce levels of THC in the blood similar to those observed after inhalation are truly comparable in terms of their impact on the activation of the central cannabinoid system.
