There were no significant differences between the effects seen with the low (2.9%) and the high (6.7%) dose of cannabis. Vapourized cannabis significantly increased measures of "stoned" and "sedated" immediately post-dose and lasted 3.3 h (or 4.3 h with the addition of alcohol). Feelings of "anxious" showed significant cannabis-dose effects through 1.4 h. Undesirable effects, including "feeling thirsty" and "dry mouth/throat", increased for the first 3.3 h post-dose.
However, adverse events were slightly more frequent and more severe during the active treatment period. Self-titrated doses were lower and showed limited efficacy compared to high fixed doses and subjects typically reported significantly lower ratings of "high" and shorter duration of "high" with nabiximols and placebo compared to smoking cannabis. Significantly higher scores were reported by occasional than frequent smokers for "difficulty concentrating", "altered sense of time", "feeling hungry", "feeling thirsty", "shakiness/tremulousness", and "dry mouth or throat".
In contrast, CBD reduced the anti-convulsant potencies of chlordiazepoxide, clonazepam, trimethadione, and ethosuximide used for minor seizuresReference 263Reference 745. ED50 doses for CBD in rats ranged from as low as 12 mg/kg (p.o.) to as high as 380 mg/kg (i.p.) in miceReference 263Reference 745Reference 746. Another study reported that CBD attenuated epileptiform activity in vitro in hippocampal slices and displayed anti-convulsant activity in vivo (100 mg/kg) in one rat model of epilepsy, attenuating seizure severity, tonic-clonic seizures and mortalityReference 735.
Many study subjects had had previous experience with cannabis; a significant number of those who withdrew from the study upon starting treatment with the cannabis extract did not have previous experience with cannabis. While there were no statistically significant differences between active treatment with the cannabis extract and placebo, trends in favour of active treatment were observed for mobility, self-reported spasm frequency, and ability in getting to sleep. The cannabis extract was generally well tolerated with no serious adverse events during the study period.
THC dose-dependently elevated heart rate, and systolic blood pressure dropped at the lower dose (i.e. 30 mg) but increased at higher doses (i.e. 75 mg and 90 mg). With regard to subjective responses, "any drug effect" and "thirsty"’ ratings increased as a function of dose, however for effects such as "good drug effects", "high", "tired/sedated", "stoned", "forgetful" and "confused/difficulty concentrating" doses larger than 30 mg were not consistently associated with higher ratings. 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 min post-inhalation. Subjective effects were then measured at several time points and effects were correlated with concentrations of cannabinoids in oral fluid and blood. Blood THC was positively associated with "high", "good drug effect", "stimulated", "stoned", "anxious", and "restless" and with feelings of altered time, "slowed/slurred speech", "dizziness", and "dry mouth/throat".
CBD was also reported to have some minor negative effects on motor function at a dose of 100 mg/kg, which was paradoxically attenuated when the dose was doubled (200 mg/kg)Reference 733. However, despite the evidence from animal studies and anecdotal claims, limited clinical information exists regarding the use of cannabis and cannabinoids to treat symptoms associated with SCI such as pain, spasticity, muscle spasms, urinary incontinence, and difficulties sleeping. Double-blind, crossover, placebo-controlled studies of oral Δ9-THC and/or nabiximols suggested modest CBD hemp oil improvements in pain, spasticity, muscle spasms, and sleep quality in patients with SCIReference 642Reference 715Reference 716. Slightly more than half of the study subjects had a maintenance dose of 20 mg/day of THC or more (maximum of 30 mg THC/day).
A follow-up study by this same group examined the anti-convulsive effects of CBD in two other rat models of temporal lobe and partial epilepsyReference 733. CBD at doses of 1, 10, and 100 mg/kg significantly attenuated the percentage of animals displaying seizure events (temporal lobe epilepsy); however, there was no significant effect upon the mean number of seizure occurrences per animal or on seizure severity. In the model of partial seizure, CBD (1, 10, 100 mg/kg) decreased the percentage of animals that developed tonic-clonic seizures and was associated with decreased mortality rate (at 10 and 100 mg/kg), but had no effect on overall seizure severity.
Compared with frequent smokers, occasional smokers had significantly increased heart rates relative to baseline and higher systolic and diastolic blood pressure just after dosing. These findings suggest that frequent cannabis users can develop some tolerance to some psychomotor impairments despite higher blood concentrations of THC. Occasional smokers also reported significantly longer and more intense subjective effects compared with frequent smokers who had higher THC concentrations suggesting tolerance can develop to the subjective effects. A dose run-up clinical study looking at the pharmacokinetic and pharmacodynamic profile of supratherapeutic oral doses of THC (i.e. 15 mg, 30 mg, 45 mg, 60 mg, 75 mg, 90 mg) in seven cannabis users reported that Cmax generally increased as a function of dose but varied considerably across subjects, especially at higher dosesReference 496. There was also substantial variability for Tmax both within and between subjects with an overall median of 3.3 h for both THC and 11-hydroxy-THC.