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Vapourization of cannabis has been explored as an alternative to smoking. The potential advantages of vapourization include the formation of a smaller quantity of toxic by-products such as carbon monoxide, polycyclic aromatic hydrocarbons, and tar, as well as a more efficient extraction of Δ9-THC (and CBD) from the cannabis materialReference 402Reference 411-Reference 414. The subjective effects and plasma concentrations of Δ9-THC obtained by vapourization of cannabis are comparable to those obtained by smoking cannabisReference 402. In addition, the study reported that vapourization was well tolerated with no reported adverse effects, and was preferred over smoking by the test subjectsReference 402. While vapourization has been reported to be amenable to self-titration (as has been claimed for smoking)Reference 402Reference 413, the proper use of the vapourizer for optimal administration of cannabis for therapeutic purposes needs to be established in more detailReference 414. The amount and type of cannabis placed in the vapourizer, the vapourizing temperature and duration of vapourization, and, in the case of balloon-type vapourizers, the balloon volume are some of the parameters that can affect the delivery of Δ9-THC and other phytocannabinoidsReference 413. Bioequivalence of vapourization compared to smoking has not been thoroughly established. Inhalation of vapourized cannabis (900 mg of 3.56% Δ9-THC; total available dose of 32 mg of Δ9-THC) in a group of patients taking stable doses of sustained-release morphine or oxycodone resulted in mean plasma Δ9-THC levels of 126.1 ng/mL within 3 min after starting cannabis inhalation, rapidly declining to 33.7 ng/mL Δ9-THC at 10 min, and reaching 6.4 ng/mL Δ9-THC at 60 minReference 280. Peak Δ9-THC concentration (Cmax) was achieved at 3 min in all study participantsReference 280. No statistically significant changes were reported for the AUC12 (12-hour area-under-the-curve) for either morphine or oxycodone, but there appeared to be a statistically significant decrease in the Cmax of morphine sulfate, and a delay in the time needed to reach Cmax for morphine during cannabis exposureReference 280. One clinical study reported that vapourizing 500 mg cannabis containing low-dose (2.9%) THC (14.5 mg THC), or high-dose (6.7%) THC (33.5 mg THC) was associated with median whole-blood Cmax values of 32.7 (low-dose) and 42.2 ng/mL (high-dose) THC, and median plasma Cmax values of 46.5 (low-dose) and 62.1 ng/mL (high-dose) THC at 10 min post-inhalation respectivelyReference 206. Median whole-blood Cmax values for 11-hydroxy-THC were 2.8 (low-dose) and 5.0 ng/mL (high-dose) and median plasma Cmax values were 4.1 (low-dose) and 7 ng/mL (high-dose) at 10 - 11 min post-inhalation respectively. Another clinical study reported that vapourizing cannabis with 11 - 12% THC content (administered dose of 300 µg/kg) was associated with mean plasma concentrations of 73.8 ng/mL THC and 6.9 ng/mL 11-hydroxy-THC 5 min post-vapourizationReference 415. A different clinical study showed that inhalation of 8 to 12 puffs of vapourized cannabis containing either 2.9% or 6.7% THC (400 mg each) was associated with a blood plasma Cmax of 68.5 ng/mL and 177.3 ng/mL respectively and median blood plasma concentration of 23 and 47 ng/mL respectivelyReference 416. Plasma Cmax of 11-hydroxy-THC was 5.6 and 12.8 ng/mL for the 2.9 and 6.7% doses, respectively.
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In humans, sex-dependent differences have been often observed in the biological and behavioural effects of substances of abuse, including cannabisReference 559. In male animals, higher densities of CB1 receptors have been observed in almost all cerebral regions analyzed whereas in females a more efficient coupling of the CB1 receptor to downstream G-protein signaling has been observedReference 560. In humans, sex differences in CB1 receptor density have also been reported, with men having higher receptor density compared to womenReference 561. Sex-dependent differences have also been noted with respect to cannabinoid metabolism. Pre-clinical studies in females report increased metabolism of THC to 11-hydroxy-THC compared to males where THC was also biotransformed to at least three different, less active metabolitesReference 562. There is also evidence to suggest that effects of cannabinoids vary as a function of fluctuations in reproductive hormonesReference 515Reference 563. Together, these findings suggest that the neurobiological mechanism underlying the sex-dependent effects of cannabinoids may arise from sexual dimorphism in the ECS and THC metabolism, but also from the effects of fluctuations in hormone levels on the ECSReference 515Reference 563.
A retrospective analysis that compared the analgesic, subjective, and physiological effects of smoked cannabis (3.56 or 5.60% THC, 800 mg cigarettes with 28 mg and 45 mg THC respectively) in 21 men and 21 women under double-blind, placebo-controlled conditions showed that among men, cannabis significantly decreased pain sensitivity in the cold pressor test compared to placebo, while in women active cannabis failed to decrease pain sensitivity relative to placeboReference 807. Active cannabis increased pain tolerance in both men and women immediately after smoking as well as increased subjective ratings associated with abuse liability ("take again", "liking", "good drug effect"), drug strength, and "high" relative to placebo. Ratings of "high" varied as a function of sex, with men exhibiting elevated ratings throughout the session relative to women. Men also exhibited greater increases in heart rate after smoking cannabis compared to women. Study subjects smoked cannabis daily or near-daily, and smoked on average 7 to 10 cannabis cigarettes/day.
Despite the evidence presented in these and other studies, there is some concern regarding the use of Δ9-THC in anti-tumoural strategies, especially if it is administered systemically because of its high hydrophobicity, relatively low agonist potency, and its well-known psychoactive propertiesReference 1303Reference 1339Reference 1340. Much also remains to be known about the expression levels of the cannabinoid receptors in different cancers, the effects of different cannabinoids on different cancer cell types, the identification of factors that confer resistance to cannabinoid treatment, as well as the most efficient approaches for enhancing cannabinoid anti-tumoural activity whether alone or in combination with other therapiesReference 1317Reference 1339. Lastly, the apparent biphasic effect of cannabinoids further highlights the need for more comprehensive dose-response studiesReference 1341.