Elsevier

American Heart Journal

Volume 151, Issue 3, March 2006, Pages 754.e1-754.e5
American Heart Journal

Clinical Investigations
Prevention and Rehabilitation
The cannabinoid CB1 receptor antagonist rimonabant attenuates the hypotensive effect of smoked marijuana in male smokers

https://doi.org/10.1016/j.ahj.2005.11.006Get rights and content

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.

Section snippets

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

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

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

References (23)

  • C. Ledent et al.

    Unresponsiveness to cannabinoids and reduced addictive effects of opiates in CB1 receptor knockout mice

    Science

    (1999)
  • Cited by (60)

    • Cardiovascular Effects of Medical Marijuana: A Systematic Review

      2021, American Journal of Medicine
      Citation Excerpt :

      Cannabinoid receptor 1 is responsible for heart rate and blood pressure responses via heart regulatory centers and the peripheral autonomic system.41 Gorelick et al suspect that THC levels in the blood lead to acute hypotension secondarily to activation of cannabinoid receptors in the arterial wall causing vasodilatation.46 Vasodilatation may result in hypotension, leading to the perception of dizziness and further progression to presyncope or syncope.

    • Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of ASP3652, a Reversible Fatty Acid Amide Hydrolase Inhibitor, in Healthy, Nonelderly, Japanese Men and Elderly, Japanese Men and Women: A Randomized, Double-blind, Placebo-controlled, Single and Multiple Oral Dose, Phase I Study

      2020, Clinical Therapeutics
      Citation Excerpt :

      To further confirm the potential of off–target activities, investigation of activity-based protein profiling, as conducted for BIA 10-2474, would be important.15 Activation of CB1 receptors by cannabis reportedly causes symptomatic hypotensive effects.16 To evaluate the symptomatic hypotensive effect of ASP3652 in detail, further evaluation of heart rate and blood pressure is needed in future studies.

    • Mechanisms contributing to cognitive deficits in cannabis users

      2017, Neuropharmacology
      Citation Excerpt :

      However, very few studies have been designed to directly assess the role of CB1 receptors in mediating the effects of Δ9-THC on human brain function, or more broadly the role of CB1 receptors in cognition (Colizzi et al., 2016). In humans, Δ9-THC-induced subjective effects were blocked by a high dose of the CB1 receptor antagonist AVE1625 (Zuurman et al., 2010), whereas the subjective effects of smoked cannabis were only partially blocked by the CB1 receptor antagonists rimonabant and surinabant (Huestis et al., 2001; Gorelick et al., 2006). Existing data linking CB1 receptors to cognition are largely limited clinical trials of rimonabant that were halted upon its withdrawal from the market in 2008.

    • Cannabinoids in the Cardiovascular System

      2017, Advances in Pharmacology
      Citation Excerpt :

      Smoking or ingestion of cannabis has long been known to induce tachycardia with variable effects on blood pressure, although chronic users often experience bradycardia and prolonged reduction in blood pressure (Gorelick et al., 2006; Jones, 2002). This is due to a dose-dependent effects of the phytocannabinoid, THC, and modulation of the autonomic nervous system, at least partly via CB1R activation (Benowitz, Rosenberg, Rogers, Bachman, & Jones, 1979; Fant, Heishman, Bunker, & Pickworth, 1998; Gorelick et al., 2006). Since the identification of eCBs, extensive investigations have been carried out to examine their hemodynamic effects.

    View all citing articles on Scopus

    This research was supported by the Intramural Research Program of the National Institutes of Health, NIDA, and by Sanofi-Aventis, Inc. The study sponsor participated in the design of the primary study and reviewed the manuscript but had no role in the data analysis or drafting of the manuscript.

    View full text