Mania is a serious neuropsychiatric condition associated with significant morbidity and mortality. Previous studies have suggested that environmental exposures can contribute to mania pathogenesis. We measured dietary exposures in a cohort of individuals with mania and other psychiatric disorders as well as in control individuals without a psychiatric disorder. We found that a history of eating nitrated dry cured meat but not other meat or fish products was strongly and independently associated with current mania (adjusted odds ratio 3.49, 95% confidence interval (CI) 2.24–5.45, p < 8.97 × 10−8). Lower odds of association were found between eating nitrated dry cured meat and other psychiatric disorders. We further found that the feeding of meat preparations with added nitrate to rats resulted in hyperactivity reminiscent of human mania, alterations in brain pathways that have been implicated in human bipolar disorder, and changes in intestinal microbiota. These findings may lead to new methods for preventing mania and for developing novel therapeutic interventions.
This is a preview of subscription content
Subscribe to Journal
Get full journal access for 1 year
only $9.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Get time limited or full article access on ReadCube.
All prices are NET prices.
Uher R. Gene-environment interactions in severe mental illness. Front Psychiatry. 2014;5:48.
Reyes TM. Diet, inflammation and the brain: commentary on the 2014 named series. Brain Behav Immun. 2014;42:6–9.
Jacka FN, Pasco JA, Mykletun A, Williams LJ, Nicholson GC, Kotowicz MA, et al. Diet quality in bipolar disorder in a population-based sample of women. J Affect Disord. 2011;129:332–7.
Rios AC, Maurya PK, Pedrini M, Zeni-Graiff M, Asevedo E, Mansur RB, et al. Microbiota abnormalities and the therapeutic potential of probiotics in the treatment of mood disorders. Rev Neurosci. 2017;28:739–49.
Dickerson F, Stallings C, Origoni A, Vaughan C, Khushalani S, Yolken R. Markers of gluten sensitivity in acute mania: a longitudinal study. Psychiatry Res. 2012;196:68–71.
Saunders EF, Ramsden CE, Sherazy MS, Gelenberg AJ, Davis JM, Rapoport SI. Reconsidering dietary polyunsaturated fatty acids in bipolar disorder: a translational picture. J Clin Psychiatry. 2016;77:e1342–7.
Gonzalez-Estecha M, Trasobares EM, Tajima K, Cano S, Fernandez C, Lopez JL, et al. Trace elements in bipolar disorder. J Trace Elem Med Biol. 2011;25(Suppl 1):S78–83.
Anderson G, Maes M. Bipolar disorder: role of immune-inflammatory cytokines, oxidative and nitrosative stress and tryptophan catabolites. Curr Psychiatry Rep. 2015;17:8.
Severance EG, Tveiten D, Lindstrom LH, Yolken RH, Reichelt KL. The gut microbiota and the emergence of autoimmunity: relevance to major psychiatric disorders. Curr Pharm Des. 2016;22:6076–86.
Brown NC, Andreazza AC, Young LT. An updated meta-analysis of oxidative stress markers in bipolar disorder. Psychiatry Res. 2014;218:61–8.
Severance EG, Lin J, Sampson HA, Gimenez G, Dickerson FB, Halling M, et al. Dietary antigens, epitope recognition, and immune complex formation in recent onset psychosis and long-term schizophrenia. Schizophr Res. 2011;126:43–50.
Johnson IT. The cancer risk related to meat and meat products. Br Med Bull. 2017;121:73–81.
Li Z, Rava M, Bedard A, Dumas O, Garcia-Aymerich J, Leynaert B, et al. Cured meat intake is associated with worsening asthma symptoms. Thorax. 2017;72:206–12.
Dickerson F, Stallings C, Origoni A, Vaughan C, Katsafanas E, Khushalani S, et al. A combined marker of inflammation in individuals with mania. PLoS ONE. 2013;8:e73520.
Dickerson F, Katsafanas E, Schweinfurth LA, Savage CL, Stallings C, Origoni A, et al. Immune alterations in acute bipolar depression. Acta Psychiatr Scand. 2015;132:204–10.
Dickerson FB, Boronow JJ, Stallings C, Origoni AE, Ruslanova I, Yolken RH. Association of serum antibodies to herpes simplex virus 1 with cognitive deficits in individuals with schizophrenia. Arch Gen Psychiatry. 2003;60:466–72.
Spitzer RL, Williams JB, Gibbon M, First MB. The Structured Clinical Interview for DSM-III-R (SCID). I: history, rationale, and description. Arch Gen Psychiatry. 1992;49:624–9.
Mesuere B, Debyser G, Aerts M, Devreese B, Vandamme P, Dawyndt P. The Unipept metaproteomics analysis pipeline. Proteomics. 2015;15:1437–42.
Dickerson F, Stallings C, Sullens A, Origoni A, Leister F, Krivogorsky B, et al. Association between cognitive functioning, exposure to Herpes Simplex Virus type 1, and the COMT Val158Met genetic polymorphism in adults without a psychiatric disorder. Brain Behav Immun. 2008;22:1103–7.
Randolph C, Tierney MC, Mohr E, Chase TN. The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS): preliminary clinical validity. J Clin Exp Neuropsychol. 1998;20:310–9.
Dickerson FB, Boronow JJ, Stallings CR, Origoni AE, Cole S, Yolken RH. Association between cognitive functioning and employment status of persons with bipolar disorder. Psychiatr Serv. 2004;55:54–8.
Tsikas D, Fuchs I, Gutzki FM, Frolich JC. Measurement of nitrite and nitrate in plasma, serum and urine of humans by high-performance liquid chromatography, the Griess assay, chemiluminescence and gas chromatography-mass spectrometry: interferences by biogenic amines and N(G)-nitro-L-arginine analogs. J Chromatogr B Biomed Sci Appl. 1998;715:441–4. discussion 445-8.
Dailey MJ, Stingl KC, Moran TH. Disassociation between preprandial gut peptide release and food-anticipatory activity. Endocrinology. 2012;153:132–42.
Malkoff-Schwartz S, Frank E, Anderson BP, Hlastala SA, Luther JF, Sherrill JT, et al. Social rhythm disruption and stressful life events in the onset of bipolar and unipolar episodes. Psychol Med. 2000;30:1005–16.
Sylvia LG, Alloy LB, Hafner JA, Gauger MC, Verdon K, Abramson LY. Life events and social rhythms in bipolar spectrum disorders: a prospective study. Behav Ther. 2009;40:131–41.
Curing and smoking meats for home food preservation literature review and critical preservation points. http://nchfp.uga.edu/publications/nchfp/lit_rev/cure_smoke_rev.html 2002.
Ellenbroek B, Youn J. Rodent models in neuroscience research: is it a rat race? Dis Model Mech. 2016;9:1079–87.
Meijer MK, Sommer R, Spruijt BM, van Zutphen LF, Baumans V. Influence of environmental enrichment and handling on the acute stress response in individually housed mice. Lab Anim. 2007;41:161–73.
Kant AK, Graubard BI. 40-year trends in meal and snack eating behaviors of American adults. J Acad Nutr Diet. 2015;115:50–63.
Walker R. Nitrates, nitrites and N-nitrosocompounds: a review of the occurrence in food and diet and the toxicological implications. Food Addit Contam. 1990;7:717–68.
Zhu S, Cordner ZA, Xiong J, Chiu CT, Artola A, Zuo Y, et al. Genetic disruption of ankyrin-G in adult mouse forebrain causes cortical synapse alteration and behavior reminiscent of bipolar disorder. Proc Natl Acad Sci USA. 2017;114:10479–84.
Young JW, Henry BL, Geyer MA. Predictive animal models of mania: hits, misses and future directions. Br J Pharmacol. 2011;164:1263–84.
Scott J, Murray G, Henry C, Morken G, Scott E, Angst J, et al. Activation in bipolar disorders: a systematic review. JAMA Psychiatry. 2017;74:189–96.
Cheniaux E, Filgueiras A, Silva Rde A, Silveira LA, Nunes AL, Landeira-Fernandez J. Increased energy/activity, not mood changes, is the core feature of mania. J Affect Disord. 2014;152-4:256–61.
Kirshenbaum GS, Clapcote SJ, Duffy S, Burgess CR, Petersen J, Jarowek KJ, et al. Mania-like behavior induced by genetic dysfunction of the neuron-specific Na+,K+-ATPase alpha3 sodium pump. Proc Natl Acad Sci USA. 2011;108:18144–9.
Abulseoud OA, Camsari UM, Ruby CL, Mohamed K, Abdel Gawad NM, Kasasbeh A, et al. Lateral hypothalamic kindling induces manic-like behavior in rats: a novel animal model. Int J Bipolar Disord. 2014;2:7.
Nowland MH, Hugunin KM, Rogers KL. Effects of short-term fasting in male Sprague-Dawley rats. Comp Med. 2011;61:138–44.
Henry BL, Minassian A, Young JW, Paulus MP, Geyer MA, Perry W. Cross-species assessments of motor and exploratory behavior related to bipolar disorder. Neurosci Biobehav Rev. 2010;34:1296–306.
Perry W, Minassian A, Henry B, Kincaid M, Young JW, Geyer MA. Quantifying over-activity in bipolar and schizophrenia patients in a human open field paradigm. Psychiatry Res. 2010;178:84–91.
Logan RW, McClung CA. Animal models of bipolar mania: the past, present and future. Neuroscience. 2016;321:163–88.
Oliveira J, Busson M, Etain B, Jamain S, Hamdani N, Boukouaci W, et al. Polymorphism of Toll-like receptor 4 gene in bipolar disorder. J Affect Disord. 2014;152:395–402.
Bueno BG, Caso JR, Madrigal JLM, Leza JC. Innate immune receptor Toll-like receptor 4 signalling in neuropsychiatric diseases. Neurosci Biobehav Rev. 2016;64:134–47.
Elhaik E, Zandi P. Dysregulation of the NF-kappa B pathway as a potential inducer of bipolar disorder. J Psychiatr Res. 2015;70:18–27.
Frye MA, McElroy SL, Prieto ML, Harper KL, Walker DL, Kung S, et al. Clinical risk factors and serotonin transporter gene variants associated with antidepressant-induced mania. J Clin Psychiatry. 2015;76:174–80.
Xu W, Cohen-Woods S, Chen Q, Noor A, Knight J, Hosang G, et al. Genome-wide association study of bipolar disorder in Canadian and UK populations corroborates disease loci including SYNE1 and CSMD1. BMC Med Genet. 2014;15:2.
Bondonno CP, Croft KD, Ward N, Considine MJ, Hodgson JM. Dietary flavonoids and nitrate: effects on nitric oxide and vascular function. Nutr Rev. 2015;73:216–35.
Andreazza AC, Kauer-Sant’anna M, Frey BN, Bond DJ, Kapczinski F, Young LT, et al. Oxidative stress markers in bipolar disorder: a meta-analysis. J Affect Disord. 2008;111:135–44.
Moreira FA, Guimaraes FS. Role of serotonin receptors in panic-like behavior induced by nitric oxide in the rat dorsolateral periaqueductal gray: effects of chronic clomipramine treatment. Life Sci. 2005;77:1972–82.
Ukil A, Biswas A, Das T, Das PK. 18 Beta-glycyrrhetinic acid triggers curative Th1 response and nitric oxide up-regulation in experimental visceral leishmaniasis associated with the activation of NF-kappa B. J Immunol. 2005;175:1161–9.
Abdul-Cader MS, Amarasinghe A, Abdul-Careem MF. Activation of toll-like receptor signaling pathways leading to nitric oxide-mediated antiviral responses. Arch Virol. 2016;161:2075–86.
Schmitz EI, Potteck H, Schuppel M, Manggau M, Wahydin E, Kleuser B. Sphingosine 1-phosphate protects primary human keratinocytes from apoptosis via nitric oxide formation through the receptor subtype S1P(3). Mol Cell Biochem. 2012;371:165–76.
Evans SJ, Bassis CM, Hein R, Assari S, Flowers SA, Kelly MB, et al. The gut microbiome composition associates with bipolar disorder and illness severity. J Psychiatr Res. 2017;87:23–9.
Schwarz E, Maukonen J, Hyytiainen T, Kieseppa T, Oresic M, Sabunciyan S, et al. Analysis of microbiota in first episode psychosis identifies preliminary associations with symptom severity and treatment response. Schizophr Res. 2017;92:398–403.
Dickerson F, Severance E, Yolken R. The microbiome, immunity, and schizophrenia and bipolar disorder. Brain Behav Immun. 2017;62:46–52.
Guida F, Turco F, Iannotta M, De Gregorio D, Palumbo I, Sarnelli G, et al. Antibiotic-induced microbiota perturbation causes gut endocannabinoidome changes, hippocampal neuroglial reorganization and depression in mice. Brain Behav Immun. 2017;67:230–45.
Gacias M, Gaspari S, Santos PM, Tamburini S, Andrade M, Zhang F, et al. Microbiota-driven transcriptional changes in prefrontal cortex override genetic differences in social behavior. eLife. 2016;5:e13442.
Magnusson KR, Hauck L, Jeffrey BM, Elias V, Humphrey A, Nath R, et al. Relationships between diet-related changes in the gut microbiome and cognitive flexibility. Neuroscience. 2015;300:128–40.
Gomez-Arango LF, Barrett HL, McIntyre HD, Callaway LK, Morrison M, Dekker Nitert M, et al. Connections between the gut microbiome and metabolic hormones in early pregnancy in overweight and obese women. Diabetes. 2016;65:2214–23.
Cooper DN, Kable ME, Marco ML, De Leon A, Rust B, Baker JE, et al. The effects of moderate whole grain consumption on fasting glucose and lipids, gastrointestinal symptoms, and microbiota. Nutrients. 2017;9:E173.
Pereira C, Ferreira NR, Rocha BS, Barbosa RM, Laranjinha J. The redox interplay between nitrite and nitric oxide: from the gut to the brain. Redox Biol. 2013;1:276–84.
Rohrmann S, Linseisen J. Processed meat: the real villain? Proc Nutr Soc. 2016;75:233–41.
This work was supported by a NIMH P50 Silvio O. Conte Center at Johns Hopkins (grant# MH-94268), the American Academy of Neurology Medical Student Research Award, the William C. Walker fund of the Johns Hopkins Department of Psychiatry and Behavioral Science, and by the Stanley Medical Research Institute.
Conflict of interest
The authors declare that they have no conflict of interest.
Electronic supplementary material
About this article
Cite this article
Khambadkone, S.G., Cordner, Z.A., Dickerson, F. et al. Nitrated meat products are associated with mania in humans and altered behavior and brain gene expression in rats. Mol Psychiatry 25, 560–571 (2020). https://doi.org/10.1038/s41380-018-0105-6
Molecular Psychiatry (2022)
Molecular Psychiatry (2020)