A deep partial thickness burn model produced by applying cylindrical aluminum templates heated to 75°C for 5 sec to the depilated moistened skin in guinea pigs was described by Kaufman et al.80 Cylindrical aluminum templates (diameter, 3.76 cm; height, 3.78 cm; length of the handle, 24 cm; total weight, 500 g) were heated in a water bath for 2 h prior to the injury at a constant temperature of 75°C. The anesthetized guinea-pig was restrained and stretched on a metal meshed board and the midline corresponding to the spine was marked on the animal's back as well as the horizontal upper limits of both sacroiliac joints. The heated and moistened template was applied at right angles to the skin of the animals' back according to the pre-marked locations. Only minimal pressure was required to ensure a perfect contact between the template surface and the underlying dorsal skin.
The subjective and physiological effects after controlled administration of oro-mucosal nabiximols (Sativex®) or oral Δ9-THC have also been comparedReference 122. Increases in systolic blood pressure occurred with low (5 mg) and high (15 mg) oral doses of THC, as well as low (5.4 mg Δ9-THC and 5 mg CBD) and high (16.2 mg Δ9-THC and 15 mg CBD) oro-mucosal doses of nabiximols, with the effect peaking at around 3 h after administration. In contrast, diastolic blood pressure decreased between 4 and 8 h after dosing. Heart rate increased after all active treatments. A statistically significant increase in heart rate relative to placebo was observed after high-dose oral THC (15 mg Δ9-THC) and high-dose oro-mucosal nabiximols (16.2 mg Δ9-THC and 15 mg CBD), but the authors indicated that the increases appeared to be less clinically significant than those typically seen with smoked cannabis. High-dose oral THC (15 mg Δ9-THC) and high-dose oro-mucosal nabiximols (16.2 mg Δ9-THC and 15 mg CBD) were associated with significantly greater "good drug effects" compared to placebo, whereas low-dose oro-mucosal nabiximols (5.4 mg Δ9-THC and 5 mg CBD) was associated with significantly higher "good drug effects" compared to 5 mg THC. A subjective feeling of a "high" was reported to be significantly greater after 15 mg oral THC compared to placebo and to 5 mg oral THC. In contrast, neither the high nor the low doses of oro-mucosal nabiximols were reported to produce a statistically significant subjective "high" feeling. Study subjects reported being most "anxious" approximately 4 h after administration of 5 mg oral THC, 3 h after 15 mg oral THC, 5.5 h after low-dose nabiximols, and 4.5 h after high-dose oro-mucosal nabiximols. All active drug treatments induced significantly more anxiety compared to placebo. After 15 mg oral THC, the concentration of THC in plasma was observed to have a weak, but statistically significant, positive correlation with systolic and diastolic blood pressure, "good drug effect", and "high". After high-dose oro-mucosal nabiximols, positive correlations were also observed between plasma THC concentrations and "anxious", "good drug effect", "high", "stimulated", and M-scale (marijuana-scale) scores. Consistent with other studies, the authors of this study reported that linear correlations between plasma THC concentrations and physiological or subjective effects were weak. Lastly, although CBD did not appear to significantly modulate the effects of THC, the authors suggested it might have attenuated the degree of the subjective "high".
Tolerance to most of the effects of cannabis and cannabinoids can develop after a few doses, and it also disappears rapidly following cessation of administrationReference 140. Tolerance has been reported to develop to the effects of cannabis on perception, psychoactivity, euphoria, cognitive impairment, anxiety, cortisol increase, mood, intraocular pressure (IOP), electroencephalogram (EEG), psychomotor performance, and nausea; some have shown tolerance to cardiovascular effects while others have notReference 324Reference 332Reference 333. There is also some evidence to suggest that tolerance can develop to the effects of cannabis on sleep (reviewed inReference 209). As mentioned above, the dynamics of tolerance vary with respect to the effect studied; tolerance to some effects develops more readily and rapidly than to othersReference 330Reference 331. However, tolerance to some cannabinoid-mediated therapeutic effects (i.e. spasticity, analgesia) does not appear to develop, at least in some patientsReference 216Reference 325Reference 327. According to one paper, in the clinical setting, tolerance to the effects of cannabis or cannabinoids can potentially be minimized by combining lower doses of cannabis or cannabinoids along with one or more additional therapeutic drugsReference 502.
A clinical study evaluated the development of tolerance to the effects of around-the-clock oral administration of THC (20 mg every 3.5 - 6 h) over six days, in 13 healthy male daily cannabis smokersReference 324. The morning THC dose increased intoxication ratings on day 2 but had less effects on days 4 (after administration of a cumulative 260 mg dose of THC) and 6, while THC lowered blood pressure and increased heart rate over the six-day period suggesting the development of tolerance to the subjective intoxicating effects of THC and the absence of tolerance to its cardiovascular effects. Tolerance to the subjective intoxicating effects of THC administered orally was manifested after a total exposure of 260 mg of THC over the course of four daysReference 324.
An early study by Hill of 26 healthy male cannabis smokers failed to demonstrate an analgesic effect of smoked cannabis (1.4% Δ9-THC, 12 mg Δ9-THC available in the cigarette) in response to transcutaneous electrical stimulationReference 812. The study did, however, report an increase in sensory and pain sensitivity to the applied stimulus. In contrast, Milstein showed that smoked cannabis (1.3% Δ9-THC, 7.5 mg Δ9-THC available in the cigarette) increased pain tolerance to a pressure stimulus in both healthy cannabis-naïve and cannabis-experienced subjects compared to placeboReference 813. Another study employing healthy cannabis smokers reported that smoking cannabis cigarettes (containing 3.55% Δ9-THC, or approximately 62 mg Δ9-THC available in the cigarette) was associated with a mild, dose-dependent, anti-nociceptive effect to a thermal heat stimulusReference 273. A more recent randomized, double-blind, placebo-controlled, crossover trial examined the effects of three different doses of smoked cannabis on intra-dermal capsaicin-induced pain and hyperalgesia in 15 healthy volunteersReference 268. Capsaicin was administered either 5 min or 45 min after smoking cannabis. Effects appeared to be dose- and time-dependent. No effect was observed 5 min after smoking, but analgesia was observed 45 min after smoking, and only with the medium dose of smoked cannabis (4% Δ9-THC); the low dose (2% Δ9-THC) had no effect whereas a high dose (8% Δ9-THC) was associated with significant hyperalgesia. This study identified a so-called "narrow therapeutic window"; a medium dose provided analgesic benefit, a high dose worsened the pain and was associated with additional adverse effects, and a low dose had no effect.
A randomized, placebo-controlled, double-blind, crossover study of 12 healthy cannabis-naïve volunteers administered a single oral dose of 20 mg Δ9-THC reported a lack of a significant analgesic effect following exposure to a multi-model pain test battery (pressure, heat, cold, and transcutaneous electrical stimulation)Reference 272. In addition, significant hyperalgesia was observed in the heat pain test. Psychotropic and somatic side effects were common and included anxiety, perceptual changes, hallucinations, strange thoughts, ideas and mood, confusion and disorientation, euphoria, nausea, headache, and dizziness.
A pre-clinical study in a rat model of RA reported that treatment with either THC or anandamide was associated with significant anti-nociception in the paw-pressure testReference 382. Another study in two different mouse models of RA (acute and chronic) reported that systemic administration (i.p.) of a range of doses of CBD (2.5 mg/kg, 5 mg/kg, 10 mg/kg, 20 mg/kg per day), after onset of acute arthritic symptoms, for a period of 10 days, was associated with the cessation of the progression of such symptomsReference 902. The daily 5 mg/kg i.p. dose was deemed to be the optimal dose for both acute (10 days) and chronic models (5-weeks) of arthritis. No obvious side effects were noted at any of the tested doses. Oral administration of 25 mg/kg of CBD for 10 days after onset of acute arthritic symptoms was associated with suppression of the progression of these symptoms, although the 50 mg/kg daily oral dose was almost equally effective. The 25 mg/kg daily oral dose was also effective in suppressing the progression of chronic arthritic symptoms when administered over a five-week period. Protective effects associated with exposure to CBD included the prevention of additional histological damage to arthritic hind-paw joints, suppression of TNF release from arthritic synovial cells, attenuation of lymph node cell proliferation, suppression of production of reactive oxygen intermediates and attenuation of lymphocyte proliferation.
The results from a study examining the anti-nociceptive effects of THC in a rat model of RA suggested that intraperitoneal administration of 4 mg/kg THC was associated with a significant decrease in the levels of spinal dynorphin, an increase in kappa-opioid receptor-mediated analgesia, and a decrease in NMDA-receptor-mediated hyperalgesiaReference 903. Another study by the same group and using the same animal model demonstrated that THC was equipotent and equiefficacious to morphine with regard to anti-nociception in the paw-pressure test, and that there was a synergistic anti-nociceptive interaction between THC and morphine in both arthritic and non-arthritic rats in the same paw-pressure testReference 384. A follow-up study again using the same animal model suggested an important role for the CB2 receptor in modulating the anti-nociceptive effects of THCReference 904. 2b1af7f3a8