Hostname: page-component-8448b6f56d-mp689 Total loading time: 0 Render date: 2024-04-23T17:21:24.466Z Has data issue: false hasContentIssue false
  • English
  • Français

Allostatic load and the cannabinoid system: implications for the treatment of physiological abnormalities in post-traumatic stress disorder (PTSD)

Published online by Cambridge University Press:  15 July 2019

James B. Lohr ,
Hang Chang ,
Michelle Sexton  and
Barton W. Palmer Open the ORCID record for Barton W. Palmer [Opens in a new window]
James B. Lohr*
Affiliation:
Center of Excellence for Stress & Mental Health, Veterans Affairs San Diego Healthcare System, San Diego, CA, USA Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA
Hang Chang
Affiliation:
Center of Excellence for Stress & Mental Health, Veterans Affairs San Diego Healthcare System, San Diego, CA, USA
Michelle Sexton
Affiliation:
Department of Anesthesiology, University of California, San Diego, La Jolla, CA, USA
Barton W. Palmer
Affiliation:
Center of Excellence for Stress & Mental Health, Veterans Affairs San Diego Healthcare System, San Diego, CA, USA Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA
*
*Address correspondence to: James B. Lohr, M.D., Professor of Neurosciences & Psychiatry, University of California, San Diego, 3350 La Jolla Village, Drive San Diego, CA 92161, USA. (Email: jlohr@ucsd.edu)
Get access Rights & Permissions [Opens in a new window]

Abstract

It is becoming clear that post-traumatic stress disorder (PTSD) is not simply a psychiatric disorder, but one that involves pervasive physiological impairments as well. These physiological disturbances deserve attention in any attempt at integrative treatment of PTSD that requires a focus beyond the PTSD symptoms themselves. The physiological disturbances in PTSD range over many systems, but a common thread thought to underlie them is that the chronic effects of PTSD involve problems with allostatic control mechanisms that result in an excess in what has been termed “allostatic load” (AL). A pharmacological approach to reducing AL would be valuable, but, because of the large range of physiological issues involved – including metabolic, inflammatory, and cardiovascular systems – it is unclear whether there exists a simple comprehensive way to address the AL landscape. In this paper, we propose that the cannabinoid system may offer just such an approach, and we outline evidence for the potential utility of cannabinoids in reducing many of the chronic physiological abnormalities seen in PTSD which are thought to be related to excess AL.

Keywords

Psychological traumaallostasisbiomarkersstress disorderstheoretical modelcomorbiditypharmacotherapyaugmentation
Type
Perspectives
Information
CNS Spectrums , Volume 25 , Issue 6 , December 2020 , pp. 743 - 749
Copyright
© Cambridge University Press 2019. This is a work of the U.S. Government and is not subject to copyright protection in the United States.

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 3rd ed. Washington, DC: Author; 1980.Google Scholar
Lohr, JB, Palmer, BW, Eidt, CA, et al. Is post-traumatic stress disorder associated with premature senescence? A review of the literature. Am J Geriatr Psychiatry. 2015; 23(7): 709–725.CrossRefGoogle ScholarPubMed
Wolf, EJ, Morrison, FG. Traumatic stress and accelerated cellular aging: From epigenetics to cardiometabolic disease. Curr Psychiatry Rep. 2017; 19(10): 75.CrossRefGoogle ScholarPubMed
McLeay, SC, Harvey, WM, Romaniuk, MN, et al. Physical comorbidities of post-traumatic stress disorder in Australian Vietnam War veterans. Med J Aust. 2017; 206(6): 251–257.CrossRefGoogle ScholarPubMed
McEwen, BS. Protective and damaging effects of stress mediators: Central role of the brain. Dialogues Clin Neurosci. 2006; 8(4): 367–381.Google ScholarPubMed
Cannon, WB. Organization for physiological homeostasis. Physiol Rev. 1929; 9(3): 399–431.CrossRefGoogle Scholar
Wiener, N. Cybernetics; or, Control and Communication in the Animal and the Machine. New York: M.I.T. Press; 1961.Google Scholar
Sterling, P, Eyer, J. Allostasis: A new paradigm to explain arousal pathology. In: Fisher, S, Reason, J, eds. Handbook of Life Stress, Cognition and Health. New York, NY: J. Wiley & Sons; 1988:629–649.Google Scholar
McEwen, BS. Stress, adaptation, and disease. Allostasis and allostatic load. Ann N Y Acad Sci. 1998; 840: 33–44.CrossRefGoogle ScholarPubMed
McEwen, BS. The brain is the central organ of stress and adaptation. NeuroImage. 2009; 47(3): 911–913.CrossRefGoogle ScholarPubMed
McEwen, BS, Bowles, NP, Gray, JD, et al. Mechanisms of stress in the brain. Nat Neurosci. 2015; 18(10): 1353–1363.CrossRefGoogle Scholar
Selye, H. The Stress of Life. Rev. ed. New York: McGraw-Hill; 1976.Google Scholar
McEwen, BS, Stellar, E. Stress and the individual. Mechanisms leading to disease. Arch Intern Med. 1993; 153(18): 2093–2101.CrossRefGoogle ScholarPubMed
Sterling, P. Principles of allostasis: Optimal design, predictive regulation, pathophysiology and rational therapeutics. In: Schulkin, J, ed. Allostasis, Homeostasis, and the Costs of Adaptation. Cambridge, MA: MIT Press; 2003.Google Scholar
McFarlane, AC. The long-term costs of traumatic stress: Intertwined physical and psychological consequences. World Psychiatry. 2010; 9(1): 3–10.CrossRefGoogle ScholarPubMed
Mayer, EA. The neurobiology of stress and gastrointestinal disease. Gut. 2000; 47(6): 861–869.CrossRefGoogle Scholar
Seeman, TE, McEwen, BS, Rowe, JW, et al. Allostatic load as a marker of cumulative biological risk: MacArthur studies of successful aging. Proc Natl Acad Sci USA. 2001; 98(8): 4770–4775.CrossRefGoogle ScholarPubMed
Karlamangla, AS, Singer, BH, McEwen, BS, et al. Allostatic load as a predictor of functional decline: MacArthur studies of successful aging. J Clin Epidemiol. 2002; 55(7): 696–710.CrossRefGoogle ScholarPubMed
Glover, DA, Stuber, M, Poland, RE, et al. Allostatic load in women with and without PTSD symptoms. Psychiatry. 2006; 69(3): 191–203.CrossRefGoogle ScholarPubMed
Lee, EA, Bissett, JK, Carter, MA, et al. Preliminary findings of the relationship of lower heart rate variability with military sexual trauma and presumed posttraumatic stress disorder. J Trauma Stress. 2013; 26(2): 249–256.CrossRefGoogle ScholarPubMed
Vidovic, A, Gotovac, K, Vilibic, M, et al. Repeated assessments of endocrine- and immune-related changes in posttraumatic stress disorder. Neuroimmunomodulation. 2011; 18(4): 199–211.CrossRefGoogle ScholarPubMed
Maestripieri, D, Hoffman, CL. Chronic stress, allostatic load, and aging in nonhuman primates. Dev Psychopathol. 2011; 23(4): 1187–1195.CrossRefGoogle ScholarPubMed
Neigh, GN, Ali, FF. Co-morbidity of PTSD and immune system dysfunction: Opportunities for treatment. Curr Opin Pharmacol. 2016; 29: 104–110.CrossRefGoogle ScholarPubMed
Petrocellis, LD, Cascio, MG, Marzo, VD, et al. The endocannabinoid system: A general view and latest additions. Br J Pharmacol. 2004; 141(5): 765–774.CrossRefGoogle ScholarPubMed
Kendall, DA, Yudowski, GA. Cannabinoid receptors in the central nervous system: Their signaling and roles in disease. Front Cell Neurosci. 2017; 10: 294–294.CrossRefGoogle Scholar
Riedel, G, Davies, SN. Cannabinoid function in learning, memory and plasticity. Handb Exp Pharmacol. 2005; 168:445–477.CrossRefGoogle Scholar
Pertwee, RG. Handbook of Cannabis. Oxford, England: Oxford University Press; 2016.Google Scholar
Muniyappa, R, Sable, S, Ouwerkerk, R, et al. Metabolic effects of chronic cannabis smoking. Diabetes Care. 2013; 36(8): 2415–2422.CrossRefGoogle ScholarPubMed
Meier, MH, Pardini, D, Beardslee, J, et al. Associations between cannabis use and cardiometabolic risk factors: A longitudinal study of men. Psychosom Med. 2019; 81(3):281–288.CrossRefGoogle ScholarPubMed
Rajavashisth, TB, Shaheen, M, Norris, KC, et al. Decreased prevalence of diabetes in marijuana users: Cross-sectional data from the National Health and Nutrition Examination Survey (NHANES) III. BMJ Open. 2012; 2: e000494.CrossRefGoogle ScholarPubMed
Penner, EA, Buettner, H, Mittleman, MA, et al. The impact of marijuana use on glucose, insulin, and insulin resistance among US adults. Am J Med. 2013; 126(7): 583–589.CrossRefGoogle ScholarPubMed
Sansone, RA, Sansone, LA. Marijuana and body weight. Innov Clin Neurosci. 2014; 11(7–8): 50–54.Google ScholarPubMed
Clark, TM, Jones, JM, Hall, AG, et al. Theoretical explanation for reduced body mass index and obesity rates in cannabis users. Cannabis Cannabinoid Res. 2018; 3(1): 259–271.CrossRefGoogle ScholarPubMed
Antel, J, Gregory, PC, Nordheim, U, et al. CB1 cannabinoid receptor antagonists for treatment of obesity and prevention of comorbid metabolic disorders. J Med Chem. 2006; 49(14): 4008–4016.CrossRefGoogle ScholarPubMed
Gary-Bobo, M, Elachouri, G, Gallas, JF, et al. Rimonabant reduces obesity-associated hepatic steatosis and features of metabolic syndrome in obese Zucker fa/fa rats. Hepatology. 2007; 46(1): 122–129.CrossRefGoogle ScholarPubMed
Alshaarawy, O, Anthony, JC. Are cannabis users less likely to gain weight? Results from a national 3-year prospective study. Int J Epidemiol. 2019. doi: 10.1093/ije/dyz044 CrossRefGoogle Scholar
Meier, MH, Pardini, D, Beardslee, J, et al. Associations between cannabis use and cardiometabolic risk factors: A longitudinal study of men. Psychosom Med. 2019; 81(3): 281–288.CrossRefGoogle ScholarPubMed
Ferguson, E, Ennis, N. The association between marijuana use and C-reactive protein: A longitudinal analysis. Paper presented at: 2018 Add Health Users Conference 2018; Bethesda, MD.Google Scholar
Alshaarawy, O, Anthony, JC. Cannabis smoking and serum C-reactive protein: A quantile regressions approach based on NHANES 2005–2010. Drug Alcohol Depend. 2015; 147: 203–207.CrossRefGoogle ScholarPubMed
Nagarkatti, P, Pandey, R, Rieder, SA, et al. Cannabinoids as novel anti-inflammatory drugs. Future Med Chem. 2009; 1(7): 1333–1349.CrossRefGoogle ScholarPubMed
Keen, L, Turner, AD. Differential effects of self-reported lifetime marijuana use on interleukin-1 alpha and tumor necrosis factor in African American adults. J Behav Med. 2015; 38(3): 527–534.CrossRefGoogle ScholarPubMed
Sexton, M, Cudaback, E, Abdullah, RA, et al. Cannabis use by individuals with multiple sclerosis: Effects on specific immune parameters. Inflammopharmacology. 2014; 22(5): 295–303.CrossRefGoogle ScholarPubMed
Parker, J, Atez, F, Rossetti, RG, et al. Suppression of human macrophage interleukin-6 by a nonpsychoactive cannabinoid acid. Rheumatol Int. 2008; 28(7): 631–635.CrossRefGoogle ScholarPubMed
Ho, WSV, Kelly, MEM. Cannabinoids in the cardiovascular system. Adv Pharmacol. 2017; 80: 329–366.CrossRefGoogle ScholarPubMed
Durst, R, Lotan, C. The potential for clinical use of cannabinoids in treatment of cardiovascular diseases. Cardiovasc Ther. 2011; 29(1): 17–22.CrossRefGoogle ScholarPubMed
Eid, BG. Cannabinoids for treating cardiovascular disorders: Putting together a complex puzzle. J Microsc Ultrastruct. 2018; 6(4): 171–176.Google ScholarPubMed
Von Der Haar, J, Talebi, S, Ghobadi, F, et al. Synthetic cannabinoids and their effects on the cardiovascular system. J Emerg Med. 2016; 50(2): 258–262.CrossRefGoogle ScholarPubMed
Schmid, K, Schonlebe, J, Drexler, H, et al. The effects of cannabis on heart rate variability and well-being in young men. Pharmacopsychiatry. 2010; 43(4): 147–150.CrossRefGoogle ScholarPubMed
Akirav, I. Cannabinoids and glucocorticoids modulate emotional memory after stress. Neurosci Biobehav Rev. 2013; 37(10, Part 2): 2554–2563.CrossRefGoogle ScholarPubMed
Atsak, P, Roozendaal, B, Campolongo, P, et al. Role of the endocannabinoid system in regulating glucocorticoid effects on memory for emotional experiences. Neuroscience. 2012; 204: 104–116.CrossRefGoogle ScholarPubMed
Crosby, KM, Bains, JS. The intricate link between glucocorticoids and endocannabinoids at stress-relevant synapses in the hypothalamus. Neuroscience. 2012; 204: 31–37.CrossRefGoogle ScholarPubMed
Hill, MN, Tasker, JG. Endocannabinoid signaling, glucocorticoid-mediated negative feedback, and regulation of the hypothalamic-pituitary-adrenal axis. Neuroscience. 2012; 204: 5–16.CrossRefGoogle ScholarPubMed
Ramot, A, Akirav, I. Cannabinoid receptors activation and glucocorticoid receptors deactivation in the amygdala prevent the stress-induced enhancement of a negative learning experience. Neurobiol Learn Mem. 2012; 97(4): 393–401.CrossRefGoogle ScholarPubMed
Brotchie, JM. CB1 cannabinoid receptor signalling in Parkinson’s disease. Curr Opin Pharmacol. 2003; 3(1): 54–61.CrossRefGoogle ScholarPubMed
Morgese, MG, Cassano, T, Cuomo, V, et al. Anti-dyskinetic effects of cannabinoids in a rat model of Parkinson’s disease: Role of CB1 and TRPV1 receptors. Exp Neurol. 2007; 208(1): 110–119.CrossRefGoogle Scholar
Papa, SM. The cannabinoid system in Parkinson’s disease: Multiple targets to motor effects. Exp Neurol. 2008; 211(2): 334–338.CrossRefGoogle ScholarPubMed
Sinha, S, Umbreit, A, Sieberg, C, et al. 98 Dronabinol-induced hypomania: A case report and literature review. CNS Spectr. 2019; 24(1): 223–224.CrossRefGoogle Scholar
Tzavara, ET, Davis, RJ, Perry, KW, et al. The CB1 receptor antagonist SR141716A selectively increases monoaminergic neurotransmission in the medial prefrontal cortex: Implications for therapeutic actions. Br J Pharmacol. 2003; 138(4): 544–553.CrossRefGoogle ScholarPubMed
Tzavara, ET, Perry, KW, Rodriguez, DE, et al. The cannabinoid CB(1) receptor antagonist SR141716A increases norepinephrine outflow in the rat anterior hypothalamus. Eur J Pharmacol. 2001; 426(3): R3–4.CrossRefGoogle ScholarPubMed
Poddar, MK, Dewey, WL. Effects of cannabinoids on catecholamine uptake and release in hypothalamic and striatal synaptosomes. J Pharmacol Exp Ther. 1980; 214(1): 63–67.Google ScholarPubMed
Fitzgerald, PJ. Elevated norepinephrine may be a unifying etiological factor in the abuse of a broad range of substances: Alcohol, nicotine, marijuana, heroin, cocaine, and caffeine. Subst Abuse. 2013; 7: 171–183.Google ScholarPubMed
Reyes, BAS, Carvalho, AF, Szot, P, et al. Cortical adrenoceptor expression, function and adaptation under conditions of cannabinoid receptor deletion. Exp Neurol. 2017; 292: 179–192.CrossRefGoogle ScholarPubMed
Parker, L. Cannabinoids and the Brain. Cambridge, MA: MIT Press; 2017.CrossRefGoogle Scholar
Pertwee, RG. Pharmacology of cannabinoid CB1 and CB2 receptors. Pharmacol Therapeut. 1997; 74(2): 129–180.CrossRefGoogle ScholarPubMed
Pertwee, RG. Targeting the endocannabinoid system with cannabinoid receptor agonists: Pharmacological strategies and therapeutic possibilities. Philos Trans R Soc Lond B Biol Sci. 2012; 367(1607): 3353–3363.CrossRefGoogle ScholarPubMed
Reggio, PH. The Cannabinoid Receptors. New York: Humana; 2009.CrossRefGoogle Scholar
Scheen, AJ. The endocannabinoid system: A promising target for the management of type 2 diabetes. Curr Protein Pept Sci. 2009; 10(1): 56–74.CrossRefGoogle ScholarPubMed
Abood, ME, Sorensen, RG, Stella, N, et al. Endocannabinoids: Actions at Non-CB1/CB2 Cannabinoid Receptors. New York, NY: Springer; 2013.CrossRefGoogle Scholar
Reggio, PH. The Cannabinoid Receptors. New York, NY: Human Press; 2009.CrossRefGoogle Scholar
American Psychological Association. Clinical Practice Guideline for the Treatment of Posttraumatic Stress Disorder (PTSD) in Adults. Washington, DC: Author; 2017.Google Scholar
American Psychiatric Association. Practice guideline for the Treatment of Patients with Acute Stress Disorder and Posttraumatic Stress Disorder. Washington, DC: Author; 2004.Google Scholar
Lancaster, CL, Teeters, JB, Gros, DF, et al. Posttraumatic stress disorder: Overview of evidence-based assessment and treatment. J Clin Med. 2016; 5(11): 105.CrossRefGoogle ScholarPubMed
McFarlane, AC. Post-traumatic stress disorder is a systemic illness, not a mental disorder: Is Cartesian dualism dead? Med J Aust. 2017; 206(6): 248–249.CrossRefGoogle Scholar
Von Kanel, R, Kraemer, B, Saner, H, et al. Posttraumatic stress disorder and dyslipidemia: Previous research and novel findings from patients with PTSD caused by myocardial infarction. World J Biol Psychiatry. 2010; 11(2): 141–147.CrossRefGoogle ScholarPubMed
Kibler, JL, Ma, M, Tursich, M, et al. Cardiovascular risks in relation to posttraumatic stress severity among young trauma-exposed women. J Affect Disord. 2018; 241: 147–153.CrossRefGoogle ScholarPubMed
Vries, GJ, Mocking, R, Assies, J, et al. Plasma lipoproteins in posttraumatic stress disorder patients compared to healthy controls and their associations with the HPA- and HPT-axis. Psychoneuroendocrinology. 2017; 86: 209–217.CrossRefGoogle ScholarPubMed
Slade, GD, Sanders, AE, By, K, et al. Role of allostatic load in sociodemographic patterns of pain prevalence in the U.S. population. J Pain. 2012; 13(7): 666–675.CrossRefGoogle ScholarPubMed
Blessing, EM, Reus, V, Mellon, SH, et al. Biological predictors of insulin resistance associated with posttraumatic stress disorder in young military veterans. Psychoneuroendocrinology. 2017; 82: 91–97.CrossRefGoogle ScholarPubMed
Dedert, EA, Becker, ME, Fuemmeler, BF, et al. Childhood traumatic stress and obesity in women: The intervening effects of PTSD and MDD. J Trauma Stress. 2010; 23(6): 785–763.CrossRefGoogle ScholarPubMed
Baumert, J, Lukaschek, K, Kruse, J, et al. No evidence for an association of posttraumatic stress disorder with circulating levels of CRP and IL-18 in a population-based study. Cytokine. 2013; 63(2): 201–208.CrossRefGoogle ScholarPubMed
Keen, L, Pereira, D, Latimer, W, et al. Self-reported lifetime marijuana use and interleukin-6 levels in middle-aged African Americans. Drug Alcohol Depend. 2014; 140: 156–160.CrossRefGoogle ScholarPubMed
Paulus, EJ, Argo, TR, Egge, JA, et al. The impact of posttraumatic stress disorder on blood pressure and heart rate in a veteran population. J Trauma Stress. 2013; 26(1): 169–172.CrossRefGoogle Scholar
Howard, JT, Sosnov, JA, Janak, JC, et al. Associations of initial injury severity and posttraumatic stress disorder diagnoses with long-term hypertension risk after combat injury. Hypertension. 2018; 71(5): 824–832.CrossRefGoogle ScholarPubMed
Alshaarawy, O, Elbaz, HA. Cannabis use and blood pressure levels: United States National Health and Nutrition Examination Survey, 2005–2012. J Hypertens. 2016; 34(8): 1507–1512.CrossRefGoogle ScholarPubMed
Gill, J, Vythilingam, M, Page, GG, et al. Low cortisol, high DHEA, and high levels of stimulated TNF-alpha, and IL-6 in women with PTSD. J Trauma Stress. 2008; 21(6): 530–539.CrossRefGoogle ScholarPubMed
Sherin, JE, Nemeroff, CB. Post-traumatic stress disorder: The neurobiological impact of psychological trauma. Dialogues Clin Neurosci. 2011; 13(3): 263–278.Google ScholarPubMed
Hauer, D, Kaufmann, I, Strewe, C, et al. The role of glucocorticoids, catecholamines and endocannabinoids in the development of traumatic memories and posttraumatic stress symptoms in survivors of critical illness. Neurobiol Learn Mem. 2014; 112: 68–74.CrossRefGoogle ScholarPubMed
Morilak, DA. Modulating the modulators: Interaction of brain norepinephrine and cannabinoids in stress. Exp Neurol. 2012; 238(2): 145–148.CrossRefGoogle ScholarPubMed