Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Low dose oral cannabinoid therapy reduces progression of atherosclerosis in mice

Nature volume 434, pages 782–786 (2005)Cite this article

A Corrigendum to this article was published on 26 May 2005

Abstract

Atherosclerosis is a chronic inflammatory disease, and is the primary cause of heart disease and stroke in Western countries1. Derivatives of cannabinoids such as delta-9-tetrahydrocannabinol (THC) modulate immune functions2 and therefore have potential for the treatment of inflammatory diseases. We investigated the effects of THC in a murine model of established atherosclerosis. Oral administration of THC (1 mg kg-1 per day) resulted in significant inhibition of disease progression. This effective dose is lower than the dose usually associated with psychotropic effects of THC. Furthermore, we detected the CB2 receptor (the main cannabinoid receptor expressed on immune cells2,3) in both human and mouse atherosclerotic plaques. Lymphoid cells isolated from THC-treated mice showed diminished proliferation capacity and decreased interferon-γ secretion. Macrophage chemotaxis, which is a crucial step for the development of atherosclerosis1, was also inhibited in vitro by THC. All these effects were completely blocked by a specific CB2 receptor antagonist4. Our data demonstrate that oral treatment with a low dose of THC inhibits atherosclerosis progression in the apolipoprotein E knockout mouse model, through pleiotropic immunomodulatory effects on lymphoid and myeloid cells. Thus, THC or cannabinoids with activity at the CB2 receptor may be valuable targets for treating atherosclerosis.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Figure 1: The cannabinoid receptor CB2 is expressed in human and mouse atherosclerotic plaques.
Figure 2: The cannabinoid receptor CB2 is expressed on macrophages and T lymphocytes within atherosclerotic plaques of ApoE-/- mice.
Figure 3: Reduced atherosclerotic plaque development and macrophage content in THC-treated ApoE-/- mice.
Figure 4: THC reduces proliferative responses and inhibits TH1 polarization.
Figure 5: THC reduces migration capacity and CCR2 expression in vitro.

References

  1. Libby, P. Inflammation in atherosclerosis. Nature 420, 868–874 (2002)

    Article  ADS  CAS  Google Scholar 

  2. Klein, T. W. et al. The cannabinoid system and immune modulation. J. Leukoc. Biol. 74, 486–496 (2003)

    Article  CAS  Google Scholar 

  3. Buckley, N. E. et al. Immunomodulation by cannabinoids is absent in mice deficient for the cannabinoid CB(2) receptor. Eur. J. Pharmacol. 396, 141–149 (2000)

    Article  CAS  Google Scholar 

  4. Rinaldi-Carmona, M. et al. SR144528, the first potent and selective antagonist of the CB2 cannabinoid receptor. J. Pharmacol. Exp. Ther. 284, 644–650 (1998)

    CAS  PubMed  Google Scholar 

  5. Libby, P., Ridker, P. M. & Maseri, A. Inflammation and atherosclerosis. Circulation 105, 1135–1143 (2002)

    Article  CAS  Google Scholar 

  6. Mach, F. Statins as immunomodulatory agents. Circulation 109 (suppl.), II15–II17 (2004)

    PubMed  Google Scholar 

  7. Srivastava, M. D., Srivastava, B. I. & Brouhard, B. Δ9 tetrahydrocannabinol and cannabidiol alter cytokine production by human immune cells. Immunopharmacology 40, 179–185 (1998)

    Article  CAS  Google Scholar 

  8. Zhu, L. X. et al. Δ-9-tetrahydrocannabinol inhibits antitumor immunity by a CB2 receptor-mediated, cytokine-dependent pathway. J. Immunol. 165, 373–380 (2000)

    Article  CAS  Google Scholar 

  9. Yuan, M. et al. Δ9-Tetrahydrocannabinol regulates Th1/Th2 cytokine balance in activated human T cells. J. Neuroimmunol. 133, 124–131 (2002)

    Article  CAS  Google Scholar 

  10. Lyman, W. D., Sonett, J. R., Brosnan, C. F., Elkin, R. & Bornstein, M. B. Δ9-Tetrahydrocannabinol: a novel treatment for experimental autoimmune encephalomyelitis. J. Neuroimmunol. 23, 73–81 (1989)

    Article  CAS  Google Scholar 

  11. Malfait, A. M. et al. The nonpsychoactive cannabis constituent cannabidiol is an oral anti-arthritic therapeutic in murine collagen-induced arthritis. Proc. Natl Acad. Sci. USA 97, 9561–9566 (2000)

    Article  ADS  CAS  Google Scholar 

  12. Sulcova, E., Mechoulam, R. & Fride, E. Biphasic effects of anandamide. Pharmacol. Biochem. Behav. 59, 347–352 (1998)

    Article  CAS  Google Scholar 

  13. Brenneisen, R., Egli, A., Elsohly, M. A., Henn, V. & Spiess, Y. The effect of orally and rectally administered Δ9-tetrahydrocannabinol on spasticity: a pilot study with 2 patients. Int. J. Clin. Pharmacol. Ther. 34, 446–452 (1996)

    CAS  PubMed  Google Scholar 

  14. Chesher, G. B., Bird, K. D., Jackson, D. M., Perrignon, A. & Starmer, G. A. The effects of orally administered Δ9-tetrahydrocannabinol in man on mood and performance measures: a dose-response study. Pharmacol. Biochem. Behav. 35, 861–864 (1990)

    Article  CAS  Google Scholar 

  15. Lichtman, A. H., Poklis, J. L., Poklis, A., Wilson, D. M. & Martin, B. R. The pharmacological activity of inhalation exposure to marijuana smoke in mice. Drug Alcohol Depend. 63, 107–116 (2001)

    Article  CAS  Google Scholar 

  16. Varvel, S. A., Hamm, R. J., Martin, B. R. & Lichtman, A. H. Differential effects of Δ9-THC on spatial reference and working memory in mice. Psychopharmacology (Berl.) 157, 142–150 (2001)

    Article  CAS  Google Scholar 

  17. Nakashima, Y., Plump, A. S., Raines, E. W., Breslow, J. L. & Ross, R. ApoE-deficient mice develop lesions of all phases of atherosclerosis throughout the arterial tree. Arterioscler. Thromb. 14, 133–140 (1994)

    Article  CAS  Google Scholar 

  18. Reddick, R. L., Zhang, S. H. & Maeda, N. Atherosclerosis in mice lacking apo E. Evaluation of lesional development and progression. Arterioscler. Thromb. 14, 141–147 (1994)

    Article  CAS  Google Scholar 

  19. Tangirala, R. K., Rubin, E. M. & Palinski, W. Quantitation of atherosclerosis in murine models: correlation between lesions in the aortic origin and in the entire aorta, and differences in the extent of lesions between sexes in LDL receptor-deficient and apolipoprotein E-deficient mice. J. Lipid Res. 36, 2320–2328 (1995)

    CAS  PubMed  Google Scholar 

  20. Johnson, Z. et al. Interference with heparin binding and oligomerization creates a novel anti-inflammatory strategy targeting the chemokine system. J. Immunol. 173, 5776–5785 (2004)

    Article  CAS  Google Scholar 

  21. Daugherty, A. & Rateri, D. L. T lymphocytes in atherosclerosis: the yin-yang of Th1 and Th2 influence on lesion formation. Circ. Res. 90, 1039–1040 (2002)

    Article  CAS  Google Scholar 

  22. Moeller, F. & Nielsen, L. B. Aortic recruitment of blood lymphocytes is most pronounced in early stages of lesion formation in apolipoprotein-E-deficient mice. Atherosclerosis 168, 49–56 (2003)

    Article  CAS  Google Scholar 

  23. Song, L., Leung, C. & Schindler, C. Lymphocytes are important in early atherosclerosis. J. Clin. Invest. 108, 251–259 (2001)

    Article  CAS  Google Scholar 

  24. Benagiano, M. et al. T helper type 1 lymphocytes drive inflammation in human atherosclerotic lesions. Proc. Natl Acad. Sci. USA 100, 6658–6663 (2003)

    Article  ADS  CAS  Google Scholar 

  25. Laurat, E. et al. In vivo downregulation of T helper cell 1 immune responses reduces atherogenesis in apolipoprotein E-knockout mice. Circulation 104, 197–202 (2001)

    Article  CAS  Google Scholar 

  26. Mulhaupt, F. et al. Statins (HMG-CoA reductase inhibitors) reduce CD40 expression in human vascular cells. Cardiovasc. Res. 59, 755–766 (2003)

    Article  CAS  Google Scholar 

  27. Kwak, B. R. et al. Reduced connexin43 expression inhibits atherosclerotic lesion formation in low-density lipoprotein receptor-deficient mice. Circulation 107, 1033–1039 (2003)

    Article  CAS  Google Scholar 

  28. Giroud, C. et al. Δ9-THC, 11-OH-Δ9-THC and Δ9-THCCOOH plasma or serum to whole blood concentrations distribution ratios in blood samples taken from living and dead people. Forensic Sci. Int. 123, 159–164 (2001)

    Article  CAS  Google Scholar 

  29. Hickey, M. J., Bullard, D. C., Issekutz, A. & James, W. G. Leukocyte-endothelial cell interactions are enhanced in dermal postcapillary venules of MRL/fas(lpr) (lupus-prone) mice: roles of P- and E-selectin. J. Immunol. 168, 4728–4736 (2002)

    Article  CAS  Google Scholar 

  30. Veillard, N. R., Steffens, S., Burger, F., Pelli, G. & Mach, F. Differential expression patterns of proinflammatory and antiinflammatory mediators during atherogenesis in mice. Arterioscler. Thromb. Vasc. Biol. 24, 2339–2344 (2004)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from the Swiss National Science Foundation to F.M. and J.-L.F., from the Ernst and Lucie Schmidheiny Foundation (Geneva) to F.M., and from the Foundation for Medical Research (France) to C.A. The authors of this manuscript belong to the European Vascular Genomics Network (http://www.evgn.org), a Network of Excellence supported by the European Community's sixth Framework Programme for Research, Priority 1. We would like to thank M. Kosco-Vilbois for helpful discussion in preparing the manuscript, and M.-L. Bochaton-Piallat (Pathology Department) for technical advice.

Author information

Author notes

  1. Niels R. Veillard and Claire Arnaud: These authors contributed equally to this work

Authors and Affiliations

  1. Division of Cardiology, Department of Medicine, Foundation for Medical Research, University Hospital, Faculty of Medicine, 1211, Geneva, Switzerland

    Sabine Steffens, Niels R. Veillard, Claire Arnaud, Graziano Pelli, Fabienne Burger & François Mach

  2. Division of Gastroenterology, University Hospital, Faculty of Medicine, 1211, Geneva, Switzerland

    Jean-Louis Frossard

  3. Institute of Legal Medicine, University Hospital, Faculty of Medicine, 1211, Geneva, Switzerland

    Christian Staub

  4. Laboratory for Molecular Neurobiology, Department of Psychiatry, University of Bonn, 53105, Bonn, Germany

    Andreas Zimmer

Authors
  1. Sabine Steffens
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Niels R. Veillard
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Claire Arnaud
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Graziano Pelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Fabienne Burger
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Christian Staub
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Andreas Zimmer
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jean-Louis Frossard
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. François Mach
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to François Mach.

Ethics declarations

Competing interests

The authors declare that they have no competing financial interests.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Steffens, S., Veillard, N., Arnaud, C. et al. Low dose oral cannabinoid therapy reduces progression of atherosclerosis in mice. Nature 434, 782–786 (2005). https://doi.org/10.1038/nature03389

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature03389

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing