Skip to main content
SpringerLink
Log in

Single and multiple doses of rimonabant antagonize acute effects of smoked cannabis in male cannabis users

  • Original Investigation
  • Published:
Psychopharmacology Aims and scope Submit manuscript

Abstract

Rationale

A single 90-mg dose of the cannabinoid CB1 receptor antagonist rimonabant attenuates effects of smoked cannabis in humans.

Objectives

The objective of this study is to evaluate whether repeated daily 40-mg doses of rimonabant can attenuate effects of smoked cannabis to the same extent as a single higher (90 mg) dose.

Materials and methods

Forty-two male volunteers received one of three oral drug regimens in a randomized, double blind, parallel group design: (1) 40 mg rimonabant daily for 15 days, (2) placebo for 14 days, then 90 mg rimonabant on day 15, or (3) placebo for 15 days. All participants smoked an active or placebo cannabis cigarette 2 h after medication on days 8 and 15. Subjective effects were measured with visual analog scales and the marijuana-scale of the Addiction Research Center Inventory.

Results

Cannabis-induced tachycardia was significantly lower for the 40-mg group on day 8 and for the 40 and 90 mg rimonabant groups on day 15 as compared to placebo. The 40-mg dose significantly decreased peak subjective effects on day 8. Neither the 90-mg nor 40-mg doses significantly decreased peak subjective effects on day 15. Rimonabant treatment did not significantly affect Δ9-tetrahydrocannabinnol pharmacokinetics.

Conclusions

Repeated lower daily rimonabant doses (40 mg) attenuated the acute physiological effects of smoked cannabis to a similar degree as a single 90-mg dose; repeated 40-mg doses attenuated subjective effects after 8 but not 15 days.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  • Anggadiredja K, Nakamichi M, Hiranita T, Tanaka H, Shoyama Y, Watanabe S, Yamamoto T (2004) Endocannabinoid system modulates relapse to methamphetamine seeking: possible mediation by the arachidonic acid cascade. Neuropsychopharmacology 29:1470–1478

    Article  PubMed  CAS  Google Scholar 

  • Arnone M, Maruani J, Chaperon F, Thiebot MH, Poncelet M, Soubrie P, LeFur G (1997) Selective inhibition of sucrose and ethanol intake by SR 141716, an antagonist of central cannabinoid (CB1) receptors. Psychopharmacology 132:104–106

    Article  PubMed  CAS  Google Scholar 

  • Bensaid M, Gary-Bobo M, Esclangon A, Maffrand JP, Le Fur G, Oury-Donat F, Soubrie P (2003) The cannabinoid CB1 receptor antagonist SR141716 increases Acrp30 mRNA expression in adipose tissue of obese fa/fa rats and in cultured adipocyte cells. Mol Pharmacol 63:908–914

    Article  PubMed  CAS  Google Scholar 

  • Carai MA, Colombo G, Gessa GL (2004) Rapid tolerance to the intestinal prokinetic effect of cannabinoid CB1 receptor antagonist, SR 141716 (rimonabant). Eur J Pharmacol 494:221–224

    Article  PubMed  CAS  Google Scholar 

  • Chait LD, Fischman MW, Schuster CR (1985) Hangover effects the morning after marijuana smoking. Drug Alcohol Depend 15:229–238

    Article  PubMed  CAS  Google Scholar 

  • Chaperon F, Thiebot MH (1999) Behavioral effects of cannabinoid agents in animals. Crit Rev Neurobiol 13:243–281

    PubMed  CAS  Google Scholar 

  • Cippitelli A, Bilbao A, Hansson AC, del Arco I, Sommer W, Heilig M, Massi M, Bermudez-Silva FJ, Navarro M, Ciccocioppo R, de Fonseca FR (2005) Cannabinoid CB1 receptor antagonism reduces conditioned reinstatement of ethanol-seeking behavior in rats. Eur J Neurosci 21:2243–2251

    Article  PubMed  Google Scholar 

  • Cleland JG, Ghosh J, Freemantle N, Kaye GC, Nasir M, Clark AL, Coletta AP (2004) Clinical trials update and cumulative meta-analyses from the American College of Cardiology: WATCH, SCD-HeFT, DINAMIT, CASINO, INSPIRE, STRATUS-US, RIO-Lipids and cardiac resynchronisation therapy in heart failure. Eur J Heart Fail 6:501–508

    Article  PubMed  Google Scholar 

  • Cohen C, Perrault G, Voltz C, Steinberg R, Soubrie P (2002) SR141716, a central cannabinoid (CB1) receptor antagonist, blocks the motivational and dopamine-releasing effects of nicotine in rats. Behav Pharmacol 13:451–463

    PubMed  CAS  Google Scholar 

  • Compton DR, Aceto MD, Lowe J, Martin BR (1996) In vivo characterization of a specific cannabinoid receptor antagonist (SR141716A): inhibition of delta-9-tetrahydrocannabinol-induced responses and apparent agonist activity. J Pharmacol Exp Ther 277:586–594

    PubMed  CAS  Google Scholar 

  • de Fonseca FR, Del Arco I, Bermudez-Silva FJ, Bilbao A, Cippitelli A, Navarro M (2004) The endocannabinoid system: physiology and pharmacology. Alcohol Alcohol 40:2–14

    Google Scholar 

  • De Vries TJ, Shaham Y, Homberg JR, Crombag H, Schuurman K, Dieben J, Vanderschuren LJMJ, Schoffelmeer ANM (2001) A cannabinoid mechanism in relapse to cocaine seeking. Nat Med 7:1151–1154

    Article  PubMed  CAS  Google Scholar 

  • Derocq JM, Segui M, Marchand J, Le Fur G, Casellas P (1995) Cannabinoids enhance human B-cell growth at low nanomolar concentrations. FEBS Lett 369:177–182

    Article  PubMed  CAS  Google Scholar 

  • Despres JP, Golay A, Sjostrom L (2005) Effects of rimonabant on metabolic risk factors in overweight patients with dyslipidemia. N Engl J Med 353:2121–2134

    Article  PubMed  CAS  Google Scholar 

  • DiMarzo V, Goparaju SK, Wang L, Liu J, Batkai S, Jaral Z, Fezza F, Miura GI, Palmiter RD, Sugiura T, Kunos G (2001) Leptin-regulated endocannabinoids are involved in maintaining food intake. Nature 410:822–825

    Article  CAS  Google Scholar 

  • Folstein MF, Luria R (1973) Reliability, validity, and clinical application of the Visual Analogue Mood Scale. Psychol Med 3:479–486

    Article  PubMed  CAS  Google Scholar 

  • Fride E, Ginzburg Y, Breuer A, Bisogno T, Di Marzo V, Mechoulam R (2001) Critical role of the endogenous cannabinoid system in mouse pup suckling and growth. Eur J Pharmacol 419:207–214

    Article  PubMed  CAS  Google Scholar 

  • Galiegue S, Mary S, Marchand J, Dussossoy D, Carriere D, Carayon P, Bouaboula M, Shire D, Le Fur G, Casellas P (1995) Expression of central and peripheral cannabinoid receptors in human immune tissues and leukocyte subpopulations. Eur J Biochem 252:54–61

    Article  Google Scholar 

  • Gessa GL, Orru A, Lai P, Maccioni P, Lecca R, Lobina C, Carai MA, Colombo G (2006) Lack of tolerance to the suppressing effect of rimonabant on chocolate intake in rats. Psychopharmacology (Berl) 185:248–254

    Article  CAS  Google Scholar 

  • Gomez R, Navarro M, Ferrer B, Trigo JM, Bilbao A, Del Arco I, Cippitelli A, Nava F, Piomelli D, Rodriguez de Fonseca F (2002) A peripheral mechanism for CB1 cannabinoid receptor-dependent modulation of feeding. J Neurosci 22:9612–9617

    PubMed  CAS  Google Scholar 

  • Grotenhermen F (2004) Pharmacology of cannabinoids. Neuro Endocrinol Lett 25:14–23

    PubMed  CAS  Google Scholar 

  • Hilairet S, Bouaboula M, Carriere D, Le Fur G, Casellas P (2003) Hypersensitization of the Orexin 1 receptor by the CB1 receptor: evidence for cross-talk blocked by the specific CB1 antagonist, SR141716. J Biol Chem 278:23731–23737

    Article  PubMed  CAS  Google Scholar 

  • Howlett AC (1995) Pharmacology of cannabinoid receptors. Annu Rev Pharmacol Toxicol 35:607–634

    Article  PubMed  CAS  Google Scholar 

  • Huang W, Moody DE, Andrenyak DM, Smith EK, Foltz RL, Huestis MA, Newton JF (2001) Simultaneous determination of delta-9-tetrahydrocannabinol and 11-nor-9-carboxy-delta-9-tetrahydrocannabinol inhuman plasma by solid phase extraction and gas chromatography-negative ion chemical ionization-mass spectrometry. J Anal Toxicol 25:531–537

    PubMed  CAS  Google Scholar 

  • Huestis MA, Henningfield JE, Cone EJ (1992a) Blood cannabinoids. I. Absorption of THC and formation of 11-OH-THC and THCCOOH during and after smoking marijuana. J Anal Toxicol 16:276–282

    PubMed  CAS  Google Scholar 

  • Huestis MA, Sampson AH, Holicky BJ, Henningfield JE, Cone EJ (1992b) Characterization of the absorption phase of marijuana smoking. Clin Pharmacol Ther 52:31–41

    Article  PubMed  CAS  Google Scholar 

  • Huestis MA, Gorelick DA, Heishman SJ, Preston KL, Nelson RA, Moolchan ET, Frank RA (2001) Blockade of effects of smoked marijuana by the CB1-selective cannabinoid receptor antagonist SR141716. Arch Gen Psychiatry 58:322–330

    Article  PubMed  CAS  Google Scholar 

  • Jamshidi N, Taylor DA (2001) Anandamide administration into the ventromedial hypothalamus stimulates appetite in rats. Br J Pharmacol 134:1151–1154

    Article  PubMed  CAS  Google Scholar 

  • Kirkham TC (2003) Endogenous cannabinoids: a new target in the treatment of obesity. Am J Physiol Regul Integr Comp Physiol 284:R343–R344

    PubMed  CAS  Google Scholar 

  • Le Foll B, Goldberg SR (2004) Rimonabant, a CB1 antagonist, blocks nicotine-conditioned place preferences. Neuroreport 15:2139–2143

    Article  PubMed  Google Scholar 

  • Le Foll B, Goldberg SR (2005) Cannabinoid CB1 antagonists as promising new medications for drug dependence. J Pharmacol Exp Ther 312:875–883

    Article  PubMed  CAS  Google Scholar 

  • Matsuda LA, Lolait SJ, Brownstein MJ, Young AC, Bonner TI (1990) Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature 346:561–564

    Article  PubMed  CAS  Google Scholar 

  • McMahon LR (2006) Discriminative stimulus effects of the cannabinoid CB(1) antagonist SR 141716A in rhesus monkeys pretreated with Delta(9)-tetrahydrocannabinol. Psychopharmacology (Berl) 188:306–314

    Article  CAS  Google Scholar 

  • Mechoulam R, Gaoni Y (1965) A total synthesis of dl-delta-1-tetrahydrocannabinol, the active constituent of hashish. J Am Chem Soc 87:3273–3274

    Article  PubMed  CAS  Google Scholar 

  • Navarro M, Carrera MR, Del Arco I, Trigo JM, Koob GF, Rodriguez de Fonseca F (2004) Cannabinoid receptor antagonist reduces heroin self-administration only in dependent rats. Eur J Pharmacol 501:235–237

    Article  PubMed  CAS  Google Scholar 

  • Ohlsson A, Lindgren JE, Wahlen A, Agurell S, Hollister LE, Gillespie HK (1981) Plasma levels of delta-9-tetrahydrocannabinol after intravenous, oral and smoke administration. NIDA Res Monogr 34:250–256

    PubMed  CAS  Google Scholar 

  • Ohlsson A, Lindgren JE, Wahlen A, Agurell S, Hollister LE, Gillespie HK (1982) Single dose kinetics of deuterium labelled delta-1-tetrahydrocannabinol in heavy and light cannabis users. Biomed Environ Mass Spectrom 9:6–10

    Article  CAS  Google Scholar 

  • Pi-Sunyer FX, Aronne LJ, Heshmati HM, Devin J, Rosenstock J (2006) Effect of rimonabant, a cannabinoid-1 receptor blocker, on weight and cardiometabolic risk factors in overweight or obese patients: RIO-North America: a randomized controlled trial. JAMA 295:761–775

    Article  PubMed  CAS  Google Scholar 

  • Rao GK, Zhang W, Kaminski NE (2004) Cannabinoid receptor-mediated regulation of intracellular calcium by delta(9)-tetrahydrocannabinol in resting T cells. J Leukoc Biol 75:884–892

    Article  PubMed  CAS  Google Scholar 

  • Ravinet Trillou C, Arnone M, Delgorge C, Gonalons N, Keane P, Maffrand JP, Soubrie P (2003) Anti-obesity effect of SR141716, a CB1 receptor antagonist, in diet-induced obese mice. Am J Physiol Regul Integr Comp Physiol 284:R345–R353

    PubMed  Google Scholar 

  • Ravinet Trillou C, Delgorge C, Menet C, Arnone M, Soubrie P (2004) CB1 cannabinoid receptor knockout in mice leads to leanness, resistance to diet-induced obesity and enhanced leptin sensitivity. Int J Obes 28:640–648

    Article  CAS  Google Scholar 

  • Rinaldi-Carmona MR, Barth F, Heaulme M, Shire D, Calandra B, Congy C, Martinez S, Maruani J, Neliat G, Caput D, Ferrara P, Soubrie P, Breliere JC, Le Fur GL (1994) SR141716, a potent and selective antagonist of the brain cannabinoid receptor. FEBS Lett 350:240–244

    Article  PubMed  CAS  Google Scholar 

  • Simiand J, Keane M, Keane PE, Soubrie P (1998) SR 141716, a CB1 cannabinoid receptor antagonist, selectively reduces sweet food intake in marmoset. Behav Pharmacol 9:179–181

    PubMed  CAS  Google Scholar 

  • Tomasini MC, Ferraro L, Bebe BW, Tanganelli S, Cassano T, Cuomo V, Antonelli T (2002) Delta(9)-tetrahydrocannabinol increases endogenous extracellular glutamate levels in primary cultures of rat cerebral cortex neurons: involvement of CB(1) receptors. J Neurosci Res 68:449–453

    Article  PubMed  CAS  Google Scholar 

  • Tseng AH, Craft RM (2004) CB(1) receptor mediation of cannabinoid behavioral effects in male and female rats. Psychopharmacology (Berlin) 172:25–30

    Article  CAS  Google Scholar 

  • Turpault S, Kanamaluru V, Lockwood GF, Bonnet D, Newton J (2006) Rimonabant pharmacokinetics in healthy and obese subjects. Clin Pharmacol Ther 79:P50

    Article  Google Scholar 

  • Van Gaal LF, Rissanen AM, Scheen AJ, Ziegler O, Rossner S (2005) Effects of the cannabinoid-1 receptor blocker rimonabant on weight reduction and cardiovascular risk factors in overweight patients: 1-year experience from the RIO-Europe study. Lancet 365:1389–1397

    Article  PubMed  CAS  Google Scholar 

  • Walker JM, Huang SM (2002) Cannabinoid analgesia. Pharmacol Ther 95:127–135

    Article  PubMed  CAS  Google Scholar 

  • Wang L, Liu J, Harvey-White J, Zimmer A, Kunos G (2003) Endocannabinoid signaling via cannabinoid receptor 1 is involved in ethanol preference and its age-dependent decline in mice. Proc Natl Acad Sci U S A 100:1393–1398

    Article  PubMed  CAS  Google Scholar 

  • Westlake TM, Howlett AC, Bonner TI, Matsuda LA, Herkenham M (1994) Cannabinoid receptor binding and messenger RNA expression in human brain: an in vitro receptor autoradiography and in situ hybridization histochemistry study of normal aged and Alzheimer’s brains. Neuroscience 63:637–652

    Article  PubMed  CAS  Google Scholar 

  • Williams CM, Kirkham TC (1999) Anandamide induces overeating: mediation by central cannabinoid (BC1) receptors. Psychopharmacology 143:315–317

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

We thank Dr. Jennifer Schroeder for help with the statistical analysis. This work was supported by the Intramural Research Program of the National Institutes of Health, National Institute on Drug Abuse, and Sanofi-Aventis and conducted under a Cooperative Research and Development Agreement (CRADA) between the National Institutes of Health and Sanofi-Aventis. Drs. Bonnet and Le Fur work for the study sponsor, Sanofi-Aventis. The other authors are National Institute on Drug Abuse (NIDA) scientists and have no conflicts to declare. The investigators and sponsor contributed to study design and data management and analysis. The NIDA investigators collected all data and prepared the manuscript. The sponsor controlled the allocation schedule and reviewed the manuscript.

Author information

Author notes

  1. Susan J. Boyd

    Present address: Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, 21201, USA

Authors and Affiliations

  1. Clinical Pharmacology and Therapeutics Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, 21224, USA

    Marilyn A. Huestis, Susan J. Boyd, Stephen J. Heishman, Kenzie L. Preston & David A. Gorelick

  2. Sanofi-Aventis Inc., Montpellier, 34184, France

    Denis Bonnet & Gerard Le Fur

Authors
  1. Marilyn A. Huestis
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Susan J. Boyd
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Stephen J. Heishman
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kenzie L. Preston
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Denis Bonnet
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Gerard Le Fur
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. David A. Gorelick
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Marilyn A. Huestis.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Huestis, M.A., Boyd, S.J., Heishman, S.J. et al. Single and multiple doses of rimonabant antagonize acute effects of smoked cannabis in male cannabis users. Psychopharmacology 194, 505–515 (2007). https://doi.org/10.1007/s00213-007-0861-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-007-0861-5

Keywords

Search

Navigation