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The Cannabinoid CB1 Receptor Antagonist Rimonabant Attenuates The Hypotensive Effect

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Background
Animal studies suggest that cannabinoid CB1 receptors play a role in regulating blood pressure (BP). In human studies, activation of CB1 receptors by cannabis or its active ingredient, Δ9-tetrahydrocannabinol (THC), has modest and inconsistent effects on BP.

Methods
We evaluated this phenomenon in 63 male cannabis smokers (mean [SD] age 27.7 ± 5.4 years, 70% African American, 10.3 ± 5.9 years of lifetime cannabis use) by administering escalating oral doses (1, 3, 10, 30, 90 mg) of the selective CB1 receptor antagonist rimonabant (or placebo) in a randomized, parallel-group, double-blind, placebo-controlled design. Subjects smoked an active (2.64% THC) or placebo marijuana cigarette 2 and 6 hours after rimonabant dosing. Blood pressure and symptoms were monitored for 90 minutes after smoking while subjects remained seated.

Results
Marijuana smoking alone (ie, after placebo rimonabant) had no consistent effect on BP, but 22% of subjects experienced symptomatic (dizziness, lightheadedness) hypotension, as did 20% to 33% of subjects who received pretreatment with rimonabant, 1, 3, or 10 mg. No subject receiving rimonabant, 30 or 90 mg, before marijuana smoking experienced symptomatic hypotension. The 7 subjects who experienced symptomatic hypotension had significantly higher mean (SD) peak plasma THC concentrations (181.6 ± 80.2) than did the 33 subjects who did not (109.0 ± 62.6). Rimonabant by itself had no effects on BP and did not alter THC pharmacokinetics.

Conclusions
These findings indicate that CB1 receptors play a role in mediating effects of cannabis smoking on BP in humans.

Studies in animals suggest that the cannabinoid CB1 receptor plays a role in regulating blood pressure (BP). Exogenous CB1 receptor agonists such as Δ9-tetrahydrocannabinol (THC, the primary psychoactive component in cannabis) and WIN 55212-2 and endogenous cannabinoids (endocannabinoids) such as anandamide decrease BP.1 This effect is blocked by CB1 receptor antagonists such as rimonabant (SR 141716)2, 3, 4and is absent in genetically engineered (knockout) mice lacking the CB1 receptor,5 suggesting that the reduction is mediated by CB1 receptor activation. Rimonabant also reduces hypotension in animal models of conditions associated with hypotension, including liver cirrhosis6, 7 hypovolemic shock,8 endotoxic shock,9 and cardiogenic shock.10

Clinical trials of oral synthetic THC (dronabinol) for the treatment of AIDS-related anorexia or chemotherapy-related nausea found a 0.3% to 1% incidence of hypotension.11 Experimental human studies show inconsistent effects of CB1 agonists on resting BP.1 Smoked cannabis and oral or intravenous (IV) THC have been reported to slightly increase,12, 13 slightly decrease,14 or have no effect15, 16, 17 on BP in supine or sitting subjects. More consistently reported are postural or orthostatic decreases in BP, often accompanied by lightheadedness, dizziness, or syncope. For example, a study of 8 healthy male cannabis users given oral THC (0.3 mg/kg) found that 7 experienced symptomatic hypotension when moved from a recumbent to 70° head-up position, which promptly resolved when they were reclined.18 A few studies have reported symptomatic decreases in BP even without changes in subjects' posture. A study of 10 healthy men given IV THC (0.022 or 0.044 mg/kg) reported significant decreases in systolic and diastolic BP, accompanied by dizziness or syncope in 3 subjects.19 A study of 18 patients with glaucoma who smoked a marijuana cigarette (2% THC) found that 5 experienced symptomatic hypotension, including lightheadedness, diaphoresis, and nausea.20

A study of rimonabant's ability to antagonize the psychological and physiological effects of smoked marijuana in experienced cannabis smokers21 afforded the opportunity to conduct a secondary analysis of the influence of rimonabant on cannabis-associated symptomatic hypotension. We report here the first human data showing that blockade of CB1 receptors by rimonabant significantly reduces the incidence of a BP effect (symptomatic hypotension) produced by smoked marijuana.

Methods
Subjects
Subjects were 63 physically and psychologically healthy men (mean [SD] age 27.7 ± 5.4 years, 70% African American) who had smoked cannabis for 10.3 ± 5.9 years and on 15.3 ± 10.2 of the 30 days preceding screening and had no other current substance dependence (except nicotine or caffeine). The study was approved by the institutional review board of the National Institute on Drug Abuse (NIDA). All subjects gave written informed consent and were paid for their participation.

Study design
The study used a randomized, placebo-controlled, double-blind, double-dummy design within each rimonabant dose block, with rimonabant doses given in ascending order. Sixty-three subjects were randomly assigned to 1 of 8 groups: placebo rimonabant/placebo marijuana (n = 10), placebo rimonabant/active marijuana (n = 10), active rimonabant (n = 2 from each dose for total n = 10)/placebo marijuana, and active rimonabant (1 mg [n = 8], 3 mg [n = 7], 10 mg [n = 6], 30 mg [n = 6], or 90 mg [n = 6])/active marijuana.

Procedures
Subjects resided on the closed research ward of the NIDA Intramural Research Program for at least 1 day before dosing. Oral fluid intake was encouraged to facilitate elimination of cannabinoids from the body. Dosing did not occur until urine cannabinoid concentration was <20 ng/mL. After a light breakfast, subjects received a single oral dose of rimonabant or placebo at 9 am, then smoked an active or placebo marijuana cigarette starting 110 minutes later (the expected time of peak rimonabant plasma concentration). They smoked a second equivalent cigarette 6 hours later. Each cigarette was smoked for 8 puffs at 60-second intervals.

Blood pressure was measured via a standard automated arm cuff connected to a Passport NR Physiological Monitor (Datascope Corp, Paramus, NJ). Systolic and diastolic BPs were recorded 180 (1 hour before oral dosing), 90, 60, and 5 minutes before the start of smoking and 0, 5, 10, 15, 20, 25, 30, 45, 60, 75, and 90 minutes after the completion of smoking. Subjects remained seated in a padded armchair throughout the session. A nurse and physician were present to monitor subjects' condition. Subjects were asked to describe any symptoms that they experienced as they occurred. Symptomatic hypotension was defined as a BP decrease of >10 mm Hg accompanied by ≥1 symptoms typically associated with hypotension (eg, dizziness, lightheadedness, nausea).

Blood for THC (and rimonabant) assays was drawn from an indwelling venous catheter in the arm 10 minutes before rimonabant dosing, 5 minutes before the start of smoking, at the end of smoking, and 2, 5, 10, 15, 20, 40, 60, 80, and 100 minutes after smoking. Heparinized plasma was stored at −20°C until analysis. Δ9-Tetrahydrocannabinol was assayed by negative chemical ionization gas chromatography/mass spectrometry with a quantification limit of 0.5 ng/mL.22

Medication
Rimonabant and matching placebo capsules were supplied by Sanofi-Aventis, Inc, Malvern, PA. Each subject ingested 3 capsules containing 0, 1, 10, or 30 mg of rimonabant as needed to achieve the assigned rimonabant dose. Marijuana was supplied by the NIDA Research Technology Branch as machine-rolled cigarettes weighing an average of 764 mg. Active cigarettes contained 2.64% THC by weight, estimated to be about 20 mg of THC. Placebo cigarettes were identical in appearance and smell but had cannabinoids removed by solvent extraction.

Statistical analyses
The study enrolled 63 subjects; data from 3 subjects were not used: 2 subjects never smoked marijuana because of administrative issues (active marijuana/placebo rimonabant, active marijuana/rimonabant 3 mg) and 1 provided only 15 minutes of data after smoking (active marijuana/rimonabant 10 mg) because of behavioral factors. To control for intersubject variability in baseline BP, data were analyzed as peak absolute change from baseline. For evaluation of marijuana effects, baseline was the value recorded 5 minutes before the start of smoking; only values recorded in the 90 minutes after smoking were used in the analysis. For evaluation of effects of rimonabant by itself, baseline was the value recorded before rimonabant dosing (180 minutes before smoking); only values recorded before smoking were used in the analysis. This allowed inclusion of all subjects who received a particular rimonabant dose, not just those (2 at each dose level) who smoked placebo marijuana.

Group comparisons used the t test or 1-way analysis of variance for quantitative variables and likelihood ratio for categorical variables. Because of the relatively small sample sizes in each dose group and clinical experience suggesting that rimonabant doses <20 mg would have a weaker effect,23 the placebo and 3 lowest rimonabant dose groups (1, 3, 10 mg) were combined into a single group, as were the 2 highest dose groups (30 and 90 mg). This resulted in 2 dose groups for purposes of the categorical statistical analysis. The 2-tailed α for all statistical tests was set at .05. All analyses were done with SPSS version 12.0.0 (SPSS, Inc, Chicago, IL).

Results
Effects of marijuana and rimonabant alone
Rimonabant by itself had no significant effect on BP over the 2 hours after dosing (F = 1.41, P = .24 for peak change in systolic BP; F = 1.34, P = .26 for diastolic BP). The mean (SD) peak change in systolic BP was 2.8 ± 9.7 mm Hg after the highest rimonabant dose (90 mg) and −8.7 ± 10.6 mm Hg after placebo; peak change in diastolic BP was −2.4 ± 8.8 mm Hg after 90 mg rimonabant and 2.0 ± 13.8 mm Hg after placebo.

None of the 20 subjects receiving placebo marijuana (either with or without rimonabant pretreatment) experienced symptomatic hypotension.

Smoking a marijuana cigarette after placebo rimonabant had no consistent effect on BP compared with smoking a placebo cigarette (Table I) either in group means (t = 0.29 and P = .78 for systolic and t = 0.56 and P = .58 for diastolic BP in morning session, t = 0.88 and P = .40 for systolic and t = 1.56 and P = .14 for diastolic BP in afternoon session) or proportion of subjects showing a change of >10 mm Hg (likelihood ratio = 0.46 and P = .50 for systolic and likelihood ratio = 0.60 and P = .74 for diastolic BP in morning session, likelihood ratio = 3.37 and P = .19 for systolic and likelihood ratio = 3.94 and P = .14 for diastolic BP in afternoon session). Marijuana smoking after placebo rimonabant produced episodes of symptomatic hypotension in 2 (22%) of 9 subjects (Table II).

Effects of marijuana after rimonabant pretreatment
Marijuana smoking after lower doses of active rimonabant (1, 3, or 10 mg), as after placebo, produced episodes of symptomatic hypotension in 20% to 33% of subjects (Table II). All subjects recovered promptly and completely after being placed in reclining or Trendelenburg position. The first 3 subjects who experienced symptomatic hypotension were also given isotonic sodium chloride solution IV. Because these 3 subjects had substantially recovered before receiving a significant volume of fluid, fluid administration was not used in the remaining subjects (Table II). No subject lost consciousness or required further treatment.

Marijuana smoking after higher doses of active rimonabant (30 or 90 mg) produced no episodes of symptomatic hypotension. There was a significant difference in proportion of subjects experiencing symptomatic hypotension at the 2 highest rimonabant doses (0%, 0/12) versus at the 3 lower doses and placebo (25%, 7/28) (P = .02).

Characteristics associated with symptomatic hypotension
In 5 subjects (2 who received placebo, 1 who received 1 mg of rimonabant, and 2 who received 3 mg of rimonabant), symptomatic hypotension was accompanied by substantial increases in heart rate (27-44 beat/min), resulting in heart rates of 89 to 131 beat/min. In the remaining 2 subjects (who received 1 and 10 mg of rimonabant), heart rate decreased (by 17 and 39 beat/min, respectively) along with BP. There were no apparent differences in subject characteristics between those experiencing an increase versus decrease in heart rate (data not shown).

Among the 40 subjects who smoked active marijuana, there were no significant differences in sociodemographic and cannabis-use variables between those who did or did not experience symptomatic hypotension, except for race/ethnicity (Table III). The 7 subjects who experienced symptomatic hypotension had significantly higher mean (SD) peak plasma THC concentrations after smoking (181.6 ± 80.2) than did the 33 subjects who did not (109.0 ± 62.6) (Table III). The peak concentration for all subjects occurred within 2 minutes of the end of smoking.

Discussion
In this study of adult male experienced cannabis smokers, smoking a single marijuana cigarette (2.64% THC) while seated had no consistent group effect on BP (Table I). This absence of a robust consistent BP effect from marijuana is consistent with numerous prior studies using smoked marijuana or oral or IV THC.1, 14 About 25% of subjects experienced symptomatic hypotension, typically lightheadedness or dizziness. This pattern is also consistent with several prior studies, which have reported symptomatic hypotension in 28% to 30% of subjects receiving marijuana or IV THC, even without changes in posture.19, 20 Individual differences in food intake or hydration are unlikely to explain the occurrence of hypotension because all subjects were well hydrated and ate a light breakfast the morning of the study session. Subjects who experienced symptomatic hypotension had about two-thirds higher peak plasma THC concentrations than those who did not (Table III), consistent with this phenomenon being a pharmacologic effect of THC, rather than a nonspecific response to the experimental situation.

The CB1 receptor antagonist rimonabant produced a dose-dependent attenuation of this symptomatic hypotensive response to marijuana. No such episodes occurred in subjects receiving the 2 highest doses, 30 and 90 mg. Subjects receiving lower doses (1, 3, or 10 mg) experienced the same rate (20%-33%) as those receiving placebo rimonabant. The blocking effect of rimonabant was not due to alterations in THC pharmacokinetics. There was no significant difference in mean peak plasma THC concentration or in THC area under the curve (0-1.8 hours after smoking) between subjects receiving placebo rimonabant and those receiving 90 mg.21 Rimonabant by itself had no significant effect on BP, demonstrating that the blocking effect was not due to a physiologically opposing rimonabant effect canceling out the marijuana effect.

Five subjects who experienced symptomatic hypotension had an accompanying substantial increase in heart rate, presumably because of expected compensatory cardiovascular mechanisms. It is not clear why 2 subjects did not have such tachycardia. This absence is probably not due to attenuation of the tachycardic response by rimonabant. These 2 subjects were pretreated with 1 and 10 mg, and rimonabant produced no significant attenuation of marijuana-induced tachycardia at doses <90 mg.21

Taken together, our results indicate that the symptomatic hypotensive effect of cannabis is mediated by action at CB1 receptors. This extends to humans previous findings in animals that CB1 receptors play a role in the regulation of BP. In animal models, CB1 receptor blockade significantly reduces the hypotension associated with liver cirrhosis,6, 7 hypovolemic shock,8 endotoxic shock,9 and cardiogenic shock.10 Our results suggest that it might be worthwhile to explore the usefulness of CB1 receptor blockade in these human illnesses.

Source, Graphs and Figures: Elsevier
 
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