Letters to the Editor  |   October 2006
Nitric Oxide and Anandamide in OMT Research
Author Affiliations
  • George B. Stefano, PhD
    Neuroscience Research Institute State University of New York College at Old Westbury, Vice Chairman, State University of New York Research Foundation Old Westbury
  • Elliott J. Salamon, IV, OMS
    Neuroscience Research Institute State University of New York College at Old Westbury
    Associate Research Scientist
Article Information
Osteopathic Manipulative Treatment / OMT in the Laboratory
Letters to the Editor   |   October 2006
Nitric Oxide and Anandamide in OMT Research
The Journal of the American Osteopathic Association, October 2006, Vol. 106, 588-589. doi:
The Journal of the American Osteopathic Association, October 2006, Vol. 106, 588-589. doi:
To the Editor: We are writing in response to the June 2005 original contribution by John M. McPartland, DO, and coauthors.1 We are pleased to have data from our laboratory cited as a means of demonstrating a relationship between endothelial anandamide (AEA) release and constitutive nitric oxide synthase to potentially describe the therapeutic effects of osteopathic manipulative treatment.2 
We would like to take a moment to briefly clarify and expand on our laboratory's findings. In short, we propose that therapeutic manual manipulations aid in circulation and provide increased blood flow to peripheral vascular tissue, and that these effects are mediated by nitric oxide. These assertions are based on experimental data obtained from our laboratory demonstrating that mechanical perturbance of excised neural and vascular tissue stimulate release of nitric oxide. These findings, when combined with numerous analogous findings,36 support our hypothesis that physical manipulations increase the concentration of nitric oxide in the blood, allowing the recipient to experience the numerous beneficial effects of increased nitric oxide concentrations within the vasculature. These effects are in addition to and in conjunction with the classic vasodilation induced by nitric oxide. Such effects include antiviral, antibacterial, and antioxidant protection in addition to mediating a key signaling molecule in the stress-and-relaxation response.7 Thus, from our perspective, it is no wonder that, after undergoing osteopathic manipulative treatment (OMT), patients often report feeling “better.” 
In addition to our findings related to the release of nitric oxide by mammalian and invertebrate tissue—and in further corroboration with the findings of McPartland and colleagues1—we demonstrate the presence of numerous other signaling molecules within the blood, notably the endocannabinoids AEA and 2-arachidonylglycerol. These are naturally occurring constitutive nitric oxide synthase–derived, nitric oxide–stimulating signaling molecules that are also constitutively expressed by nervous tissue, which can further initiate profound physiologic effects when stimulated.7 
The molecule of particular note is AEA, an endogenous endocannabinoid, which can also cause nitric oxide release from human immune cells, neural tissues, and human vascular endothelial cells.7 Anandamide can also initiate invertebrate immune cell constitutive nitric oxide synthase–derived nitric oxide. These findings lend further credence to and strongly support the findings reported by McPartland and his coinvestigators.1 In addition, these results open new doors for the osteopathic physician's use of OMT as an immune system regulator. 
As an aside, it is interesting that a new theoretical paradigm is beginning to emerge in the realm of osteopathic medical research—one that has united researchers from the laboratory as well as the clinic in an effort to explore this unique and exciting area of medicine. We look forward to future collaborations. 
McPartland JM, Giuffrida A, King J, Skinner E, Scotter J, Musty RE. Cannabimimetic effects of osteopathic manipulative treatment. J Am Osteopath Assoc. 2005; 105:283–291. Available at: Accessed September 27, 2006.
Salamon E, Zhu W, Stefano GB. Nitric oxide as a possible mechanism for understanding the therapeutic effects of osteopathic manipulative medicine [review]. Int J Mol Med. 2004;14:443 –449.
Stefano GB. Autoimmunovascular regulation: morphine and anandamide and ancondamide stimulated nitric oxide release [review]. J Neuroimmunol. 1998;83:70 –76.
Stefano GB, Goumon Y, Bilfinger TV, Welters I, Cadet P. Basal nitric oxide limits immune, nervous and cardiovascular excitation: human endothelia express a mu opiate receptor [review]. Prog Neurobiol. 2000;60:513 –530.
Cadet P, Zhu W, Mantione K, Rymer M, Dardik I, Reisman S, et al. Cyclic exercise induces anti-inflammatory signal molecule increases in the plasma of Parkinson's patients. Int J Mol Med. 2003;12:485 –492.
Stefano GB, Prevot V, Cadet P, Dardik I. Vascular pulsations stimulating nitric oxide release during cyclic exercise may benefit health: a molecular approach [review]. Int J Mol Med. 2001;7:119 –129.
Stefano GB, Esch T, Cadet P, Zhu W, Mantione K, Benson H. Endocannabinoids as autoregulatory signaling molecules: coupling to nitric oxide and a possible association with the relaxation response [review]. Med Sci Monit. 2003;9:RA63–RA75. Available at: Accessed September 27, 2006.