Advertisement

Psychopharmacology

, Volume 209, Issue 3, pp 245–253 | Cite as

Randomized, controlled, double-blind trial of taranabant for smoking cessation

  • Mary F. Morrison
  • Paulette Ceesay
  • Ira Gantz
  • Keith D. Kaufman
  • Christopher R. Lines
Original Investigation

Abstract

Rationale

It has been proposed that cannabinoid-1 receptor inverse agonists might be effective for smoking cessation. We evaluated this hypothesis with the cannabinoid-1 receptor inverse agonist taranabant.

Methods

Adults who smoked ≥10 cigarettes a day for >1 year and had an expired CO level of ≥10 ppm participated in a randomized, double-blind, 8-week, study of taranabant (N = 159) or placebo (N = 158). Taranabant was titrated from 2 mg once daily to 8 mg once daily. Patients received smoking cessation counseling. The primary efficacy endpoint was continuous abstinence, defined as no cigarettes assessed by daily patient self-report and verified by breath CO level (<10 ppm) and plasma cotinine test (<10 ng/ml), during the last 4 weeks of the 8-week treatment period.

Results

The percentage of patients achieving continuous abstinence was 7.5% for taranabant 2–8 mg and 6.3% for placebo (odds ratio = 1.2 [90% confidence interval (CI), 0.6, 2.5], P = 0.678). Change from baseline in body weight in the taranabant 2–8-mg group was −1.5 (90% CI, −1.8, −1.3) versus 0.6 kg (90% CI, 0.4, 0.9) in the placebo group. Compared to placebo, taranabant 2–8 mg was associated with an increased incidence of psychiatric-related adverse events (e.g., depression, 8.2% versus 2.5%, P = 0.048), gastrointestinal-related adverse events (e.g., nausea, 49.7% versus 19.0%, P < 0.001), and flushing/hot flash adverse events (10.7% versus 1.9%, P = 0.002).

Conclusions

Taranabant 2–8 mg did not improve smoking cessation and was associated with increased incidences of psychiatric-related, gastrointestinal-related, and flushing adverse events (ClinicalTrials.gov NCT00109135).

Keywords

Taranabant Cannabinoid-1 receptor inverse agonist Smoking cessation Randomized clinical trial 

Abbreviations

CB1

Cannabinoid-1

PHQ-9

Patient health questionnaire-9

ECGs

Electrocardiograms

APT

All patients treated

Notes

Acknowledgments

The following investigators participated in the study: CF Barish, Wake Research Associates, Raleigh, NC, USA; RJ Bielski, Summit Research Network, Okemos, MI, USA; CC Coleman, Mississippi Neuropsychiatric Clinic, Ridgeland, MS, USA; JM Ferguson, Radiant Research, Salt Lake City, UT, USA; LI Gilderman, University Clinical Research Associates, Inc., Pembroke Pines, FL, USA; JF Heiser, Pharmacology Research Institute, Los Alamitos, CA, USA; MB Jacobs, Radiant Research, Las Vegas, NV, USA; LR Lawson, Lovelace Scientific Resources, Inc., Albuquerque, NM, USA; PD Londborg, Summit Research Network, Seattle, WA, USA; LP Moldauer, Radiant Research, Denver, CO, USA; and MU Weerasinghe, Rochester Clinical Research, Inc., Rochester, NY, USA. The trial complied with the current laws of the country in which it was performed.

Funding support

This study was funded by Merck Research Laboratories. The funding organization was involved in the following: design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, and approval of the manuscript.

Disclosure

All authors are responsible for the work described in this paper. All authors were involved in at least one of the following: conception, design, acquisition, analysis, statistical analysis, interpretation of data, and drafting the manuscript and/or revising the manuscript for important intellectual content. All authors provided final approval of the version to be published. MF Morrison is a former employee of Merck, Astra Zeneca, and Shire and, in the past 2 years, has performed consultations for the following companies (no consultations were related to smoking cessation or CB1 receptor inverse agonists): Impax, BioAdvance, FemmePharma and Orexo. P Ceesay, I Gantz, KD Kaufman, and CR Lines are employees of Merck and own stock or stock options in Merck.

References

  1. Addy C, Li S, Agrawal N, Stone J, Majumdar A, Zhong L et al (2008a) Safety, tolerability, pharmacokinetics, and pharmacodynamic properties of taranabant, a novel selective cannabinoid-1 receptor inverse agonist, for the treatment of obesity: results from a double-blind, placebo-controlled, single oral dose study in healthy volunteers. J Clin Pharmacol 48:418–427 [Epub 2008 Feb 7]CrossRefPubMedGoogle Scholar
  2. Addy C, Wright H, Van Laere K, Gantz I, Erondu N, Musser BJ et al (2008b) The acyclic CB1R inverse agonist taranabant mediates weight loss by increasing energy expenditure and decreasing caloric intake. Cell Metab 7:68–78CrossRefPubMedGoogle Scholar
  3. Akbas F, Gasteyger C, Sjödin A, Astrup A, Larsen TM (2009) A critical review of the cannabinoid receptor as a drug target for obesity management. Obes Rev 10:58–67 [Epub 2008 Aug 20]CrossRefPubMedGoogle Scholar
  4. Alberg AJ (2008) Cigarette smoking: health effects and control strategies. Drugs Today (Barc) 44:895–904CrossRefGoogle Scholar
  5. Cahill K, Ussher M (2007) Cannabinoid type 1 receptor antagonists (rimonabant) for smoking cessation. Cochrane Database Syst Rev (4):CD005353Google Scholar
  6. Christensen R, Kristensen PK, Bartels EM, Bliddal H, Astrup A (2007) Efficacy and safety of the weight-loss drug rimonabant: a meta-analysis of randomised trials. Lancet 370:1706–1713CrossRefPubMedGoogle Scholar
  7. Eisenberg MJ, Filion KB, Yavin D, Bélisle P, Mottillo S, Joseph L et al (2008) Pharmacotherapies for smoking cessation: a meta-analysis of randomized controlled trials. CMAJ 179:135–144PubMedGoogle Scholar
  8. European Medicines Agency (2006) Acomplia: scientific discussion. European Medicines Agency Web site. http://www.emea.europa.eu/humandocs/PDFs/ EPAR/acomplia/H-666-en6.pdf. Accessed 15 Oct 2009
  9. Filozof C, Fernández Pinilla MC, Fernández-Cruz A (2004) Smoking cessation and weight gain. Obes Rev 5:95–103CrossRefPubMedGoogle Scholar
  10. Forget B, Coen KM, Le Foll B (2009) Inhibition of fatty acid amide hydrolase reduces reinstatement of nicotine seeking but not break point for nicotine self-administration—comparison with CB(1) receptor blockade. Psychopharmacology 205:613–624CrossRefPubMedGoogle Scholar
  11. Gantz I, Erondu N, Suryawanshi A, Musser B, Nayee J, Johnson-Levonas AO et al (2008) A two-year study to assess the efficacy, safety, and tolerability of taranabant in obese patients: 52 week results. J Am Coll Cardiol 51(10 Suppl A):326 (Abstract 1021–220)Google Scholar
  12. Hughes JR, Keely J, Naud S (2004) Shape of the relapse curve and long-term abstinence among untreated smokers. Addiction 99:29–38CrossRefPubMedGoogle Scholar
  13. Izzo AA, Coutts AA (2005) Cannabinoids and the digestive tract. Handb Exp Pharmacol 168:573–598CrossRefPubMedGoogle Scholar
  14. Kroenke K, Spitzer RL, Williams JB (2001) The PHQ-9: validity of a brief depression severity measure. J Gen Intern Med 16:606–613CrossRefPubMedGoogle Scholar
  15. Lancaster T, Stead L, Cahill K (2008) An update on therapeutics for tobacco dependence. Expert Opin Pharmacother 9:15–22CrossRefPubMedGoogle Scholar
  16. Le Foll B, Goldberg SR (2005) Cannabinoid CB1 receptor antagonists as promising new medications for drug dependence. J Pharmacol Exp Ther 312:875–883 [Epub 2004 Nov 3]CrossRefPubMedGoogle Scholar
  17. Le Foll B, Forget B, Aubin HJ, Goldberg SR (2008) Blocking cannabinoid CB1 receptors for the treatment of nicotine dependence: insights from pre-clinical and clinical studies. Addict Biol 13:239–252CrossRefPubMedGoogle Scholar
  18. Le Foll B, Gorelick DA, Goldberg SR (2009) The future of endocannabinoid-oriented clinical research after CB(1) antagonists. Psychopharmacology (Berl) 205:171–174 [Epub 2009 Mar 20]CrossRefGoogle Scholar
  19. Leite CE, Mocelin CA, Petersen GO, Leal MB, Thiesen FV (2009) Rimonabant: an antagonist drug of the endocannabinoid system for the treatment of obesity. Pharmacol Rep 61:217–224PubMedGoogle Scholar
  20. Lin LS, Lanza TJ Jr, Jewell JP, Liu P, Shah SK, Qi H et al (2006) Discovery of N-[(1 S, 2 S)-3-(4-Chlorophenyl)-2- (3-cyanophenyl)-1-methylpropyl]-2-methyl-2- {[5-(trifluoromethyl)pyridin-2-yl]oxy}propanamide (MK-0364), a novel, acyclic cannabinoid-1 receptor inverse agonist for the treatment of obesity. J Med Chem 49:7584–7587CrossRefPubMedGoogle Scholar
  21. Nides M (2008) Update on pharmacologic options for smoking cessation treatment. Am J Med 121(4 Suppl 1):S20–S31CrossRefPubMedGoogle Scholar
  22. Rucker D, Padwal R, Li SK, Curioni C, Lau DC (2007) Long term pharmacotherapy for obesity and overweight: updated meta-analysis. BMJ 335:1194–1199CrossRefPubMedGoogle Scholar
  23. Shiffman S, Elash CA, Paton SM, Gwaltney CJ, Paty JA, Clark DB, Liu KS, Di Marino ME (2000) Comparative efficacy of 24-hour and 16-hour transdermal nicotine patches for relief of morning craving. Addiction 95(8):1185–1195CrossRefPubMedGoogle Scholar
  24. Shiffman S, Shadel WG, Niaura R, Khayrallah MA, Jorenby DE, Ryan CF, Ferguson CL (2003) Efficacy of acute administration of nicotine gum in relief of cue-provoked cigarette craving. Psychoparmacology 166:343–350Google Scholar
  25. Spitzer RL, Kroenke K, Williams JB (1999) Validation and utility of a self-report version of PRIME-MD: the PHQ primary care study. Primary care evaluation of mental disorders. Patient health questionnaire. JAMA 282:1737–1744CrossRefPubMedGoogle Scholar
  26. Ständer S, Schmelz M, Metze D, Luger T, Rukwied R (2005) Distribution of cannabinoid receptor 1 (CB1) and 2 (CB2) on sensory nerve fibers and adnexal structures in human skin. J Dermatol Sci 38:177–188CrossRefPubMedGoogle Scholar
  27. Tanda G, Goldberg SR (2003) Cannabinoids: reward, dependence, and underlying neurochemical mechanisms—a review of recent preclinical data. Psychopharmacology (Berl) 169:115–134 [Epub 2003 Jun 24]CrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Mary F. Morrison
    • 1
    • 2
  • Paulette Ceesay
    • 1
  • Ira Gantz
    • 3
  • Keith D. Kaufman
    • 3
  • Christopher R. Lines
    • 1
    • 4
  1. 1.Merck Research LaboratoriesUpper GwyneddUSA
  2. 2.Temple UniversityPhiladelphiaUSA
  3. 3.Merck Research LaboratoriesRahwayUSA
  4. 4.Merck Research LaboratoriesNorth WalesUSA

Personalised recommendations