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Lafourcade M, Larrieu T, Mato S, Duffaud A, Sepers M, Matias I, De Smedt-Peyrusse V, Labrousse VF, Bretillon L, Matute C, Rodríguez-Puertas R, Layé S, Manzoni OJ. Nutritional omega-3 deficiency abolishes endocannabinoid-mediated neuronal functions. Nat Neurosci. 2011 Mar ; 14(3):345-50. Pubmed Abstract

Comments on News and Primary Papers

Primary Papers: Nutritional omega-3 deficiency abolishes endocannabinoid-mediated neuronal functions.

Comment by:  Leonora LongCynthia Shannon Weickert (SRF Advisor)
Submitted 28 July 2011
Posted 28 July 2011

Omega-3 Fatty Acid Levels and Mental Health: Focus on Endocannabinoids and Schizophrenia
Deficiency in dietary omega-3 fatty acid intake appears to favor higher levels of omega-6 acids, which has implications for metabolites downstream of these two fatty acid precursors, including endogenous cannabinoids. While the excellent recent study in Nature Neuroscience (Lafourcade et al., 2011) did not find that increased omega-6 levels corresponded to altered levels of the two major endocannabinoids, 2-AG and anandamide, it did show that it led to a functional reduction of cannabinoid CB1R efficacy and decoupling of CB1R from its inhibitory G protein signaling. This is extremely interesting, given the evidence for changes in endocannabinoid function in schizophrenia (De Marchi et al., 2003; Eggan et al., 2008; Eggan et al., 2010; Dalton et al., 2011). While it is still not understood whether such changes are causal to the pathophysiology of schizophrenia, it is increasingly clear that modification of the endocannabinoid system could have implications for normal development (Bossong and Niesink, 2010; Malone et al., 2010), especially given the association of cannabis use with increased risk for schizophrenia (Moore et al., 2007).

Therefore, further investigation into this area would be welcome, since there are several unanswered questions on this subject. For example, Lafourcade et al. investigated the effect of modifying maternal dietary fatty acid intake on rodent behaviors relevant to symptoms of depression and anxiety, but it is not known whether such dietary modification, either pre- or postnatal, also detrimentally affects other rodent behaviors related to schizophrenia such as cognitive flexibility, response to pharmacological challenge with dopaminergic or glutamatergic agents, sensorimotor gating, and complex social behavior. In the context of human studies, is there a link between fatty acid and endocannabinoid levels in humans with differing dietary intake of omega-3 fatty acids, and if so, does such a link explain the occurrence of psychotic symptoms? Does omega-3 fatty acid treatment in animal models of schizophrenia or in human trials alter endocannabinoid ligands, receptors, and metabolic enzymes in the periphery and/or brain, and if so, how are these alterations related to improvement of or reversal of schizophrenia symptoms? Finally, while a reduced omega-3:omega-6 ratio appears detrimental to endocannabinoid function, would there be a limit to potential benefits of omega-3 supplementation; i.e., would it be harmful if the omega-3:omega-6 ratio was increased beyond a certain point, since overall increase in this ratio as a result of omega-3 supplementation may adversely impact on endocannabinoid levels in the opposite direction (Batetta et al., 2009; Wood et al., 2010)? The extent to which this has been tested, particularly during development, is not clear. In sum, the possible link between dietary fatty acids and brain cannabinoid system is an interesting area for schizophrenia researchers to consider, and is ripe for further investigation.


Batetta B, Griinari M, Carta G, Murru E, Ligresti A, Cordeddu L, Giordano E, Sanna F, Bisogno T, Uda S, Collu M, Bruheim I, Di Marzo V, Banni S. Endocannabinoids may mediate the ability of (n-3) fatty acids to reduce ectopic fat and inflammatory mediators in obese Zucker rats. J Nutr . 2009 Aug 1 ; 139(8):1495-501. Abstract

Bossong MG, Niesink RJ. Adolescent brain maturation, the endogenous cannabinoid system and the neurobiology of cannabis-induced schizophrenia. Prog Neurobiol . 2010 Nov 1 ; 92(3):370-85. Abstract

Dalton VS, Long LE, Weickert CS, Zavitsanou K. Paranoid Schizophrenia is Characterized by Increased CB(1) Receptor Binding in the Dorsolateral Prefrontal Cortex. Neuropsychopharmacology . 2011 Jul 1 ; 36(8):1620-30. Abstract

De Marchi N, De Petrocellis L, Orlando P, Daniele F, Fezza F, Di Marzo V. Endocannabinoid signalling in the blood of patients with schizophrenia. Lipids Health Dis . 2003 Aug 19 ; 2():5. Abstract

Eggan SM, Hashimoto T, Lewis DA. Reduced cortical cannabinoid 1 receptor messenger RNA and protein expression in schizophrenia. Arch Gen Psychiatry . 2008 Jul 1 ; 65(7):772-84. Abstract

Eggan SM, Stoyak SR, Verrico CD, Lewis DA. Cannabinoid CB1 receptor immunoreactivity in the prefrontal cortex: Comparison of schizophrenia and major depressive disorder. Neuropsychopharmacology . 2010 Sep 1 ; 35(10):2060-71. Abstract

Lafourcade M, Larrieu T, Mato S, Duffaud A, Sepers M, Matias I, De Smedt-Peyrusse V, Labrousse VF, Bretillon L, Matute C, Rodríguez-Puertas R, Layé S, Manzoni OJ. Nutritional omega-3 deficiency abolishes endocannabinoid-mediated neuronal functions. Nat Neurosci . 2011 Mar ; 14(3):345-50. Abstract

Malone DT, Hill MN, Rubino T. Adolescent cannabis use and psychosis: epidemiology and neurodevelopmental models. Br J Pharmacol . 2010 Jun 1 ; 160(3):511-22. Abstract

Moore TH, Zammit S, Lingford-Hughes A, Barnes TR, Jones PB, Burke M, Lewis G. Cannabis use and risk of psychotic or affective mental health outcomes: a systematic review. Lancet . 2007 Jul 28 ; 370(9584):319-28. Abstract

Wood JT, JS Williams, et al. Dietary docosahexaenoic acid supplementation alters select physiological endocannabinoid-system metabolites in brain and plasma. J Lipid Res. 2010;51(6):1416-1423. Abstract

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