Obsessive-compulsive disorder (OCD) is a neuropsychiatric disorder characterized by recurrent and distinctive obsessions and/or compulsions. The etiologies remain unclear. Recent findings have shown that oxidative stress, inflammation, and glutamatergic pathways play key roles in the causes of OCD. However, first-line therapies include cognitive-behavioral therapy but only 40% of the patients respond to this first-line therapy. Research for new treatment is mandatory. This review focuses on the potential effects of cannabidiol (CBD), as a potential therapeutic strategy, on OCD and some of the presumed mechanisms by which CBD provides its benefit properties. CBD medication downregulates GSK-3β, the main inhibitor of the WNT/β-catenin pathway. The activation of the WNT/β-catenin could be associated with the control of oxidative stress, inflammation, and glutamatergic pathway and circadian rhythms dysregulation in OCD. Future prospective clinical trials could focus on CBD and its different and multiple interactions in OCD.
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Mitochondrial modulators for obsessive–compulsive and related disorders: a systematic review and meta-analysis
Translational Psychiatry Open Access 28 June 2022
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Ruscio AM, Stein DJ, Chiu WT, Kessler RC. The epidemiology of obsessive-compulsive disorder in the National Comorbidity Survey Replication. Mol Psychiatry. 2010;15:53–63.
Bokor G, Anderson PD. Obsessive-compulsive disorder. J Pharm Pract. 2014;27:116–30.
Bloch MH, Bartley CA, Zipperer L, Jakubovski E, Landeros-Weisenberger A, Pittenger C, et al. Meta-analysis: hoarding symptoms associated with poor treatment outcome in obsessive-compulsive disorder. Mol Psychiatry. 2014;19:1025–30.
Alici D, Bulbul F, Virit O, Unal A, Altindag A, Alpak G, et al. Evaluation of oxidative metabolism and oxidative DNA damage in patients with obsessive-compulsive disorder. Psychiatry Clin Neurosci. 2016;70:109–15.
Attwells S, Setiawan E, Wilson AA, Rusjan PM, Mizrahi R, Miler L, et al. Inflammation in the neurocircuitry of obsessive-compulsive disorder. JAMA Psychiatry. 2017;74:833–40.
Grassi G, Pallanti S. Current and up-and-coming pharmacotherapy for obsessive-compulsive disorder in adults. Expert Opin Pharmacother. 2018;19:1541–50.
Fineberg NA, Reghunandanan S, Simpson HB, Phillips KA, Richter MA, Matthews K, et al. Obsessive-compulsive disorder (OCD): Practical strategies for pharmacological and somatic treatment in adults. Psychiatry Res. 2015;227:114–25.
Pallanti S, Grassi G, Cantisani A. Emerging drugs to treat obsessive-compulsive disorder. Expert Opin Emerg Drugs. 2014;19:67–77.
Apergis-Schoute AM, Gillan CM, Fineberg NA, Fernandez-Egea E, Sahakian BJ, Robbins TW. Neural basis of impaired safety signaling in obsessive compulsive disorder. Proc Natl Acad Sci USA. 2017;114:3216–21.
Rouhani N, Wimmer GE, Schneier FR, Fyer AJ, Shohamy D, Simpson HB. Impaired generalization of reward but not loss in obsessive-compulsive disorder. Depress Anxiety. 2019;36:121–9.
Dougherty DD, Brennan BP, Stewart SE, Wilhelm S, Widge AS, Rauch SL. Neuroscientifically informed formulation and treatment planning for patients with obsessive-compulsive disorder: a review. JAMA Psychiatry. 2018;75:1081–7.
Izzo AA, Borrelli F, Capasso R, Di Marzo V, Mechoulam R. Non-psychotropic plant cannabinoids: new therapeutic opportunities from an ancient herb. Trends Pharmacol Sci. 2009;30:515–27.
Campos AC, Moreira FA, Gomes FV, Del Bel EA, Guimarães FS. Multiple mechanisms involved in the large-spectrum therapeutic potential of cannabidiol in psychiatric disorders. Philos Trans R Soc Lond B Biol Sci. 2012;367:3364–78.
de Mello Schier AR, de Oliveira Ribeiro NP, de Oliveira e Silva AC, Hallak JEC, Crippa JAS, Nardi AE, et al. Cannabidiol, a Cannabis sativa constituent, as an anxiolytic drug. Rev Bras Psiquiatr Sao Paulo Braz 1999. 2012;34 Suppl 1:S104–10.
Micale V, Di Marzo V, Sulcova A, Wotjak CT, Drago F. Endocannabinoid system and mood disorders: priming a target for new therapies. Pharmacol Ther. 2013;138:18–37.
de Mello Schier AR, de Oliveira Ribeiro NP, Coutinho DS, Machado S, Arias-Carrión O, Crippa JA, et al. Antidepressant-like and anxiolytic-like effects of cannabidiol: a chemical compound of Cannabis sativa. CNS Neurol Disord Drug Targets. 2014;13:953–60.
Wilson RI, Nicoll RA. Endocannabinoid signaling in the brain. Science. 2002;296:678–82.
Castillo PE, Younts TJ, Chávez AE, Hashimotodani Y. Endocannabinoid signaling and synaptic function. Neuron. 2012;76:70–81.
Silvestri C, Di, Marzo V. The endocannabinoid system in energy homeostasis and the etiopathology of metabolic disorders. Cell Metab. 2013;17:475–90.
Kayser RR, Snorrason I, Haney M, Lee FS, Simpson HB. The endocannabinoid system: a new treatment target for obsessive compulsive disorder? Cannabis Cannabinoid Res. 2019;4:77–87.
Khan R, Naveed S, Mian N, Fida A, Raafey MA, Aedma KK. The therapeutic role of Cannabidiol in mental health: a systematic review. J Cannabis Res. 2020;2:2.
Allsop DJ, Copeland J, Lintzeris N, Dunlop AJ, Montebello M, Sadler C, et al. Nabiximols as an agonist replacement therapy during cannabis withdrawal: a randomized clinical trial. JAMA Psychiatry. 2014;71:281–91.
Crippa JaS, Hallak JEC, Machado-de-Sousa JP, Queiroz RHC, Bergamaschi M, Chagas MHN, et al. Cannabidiol for the treatment of cannabis withdrawal syndrome: a case report. J Clin Pharm Ther. 2013;38:162–4.
Trigo JM, Lagzdins D, Rehm J, Selby P, Gamaleddin I, Fischer B, et al. Effects of fixed or self-titrated dosages of Sativex on cannabis withdrawal and cravings. Drug Alcohol Depend. 2016;161:298–306.
Trigo JM, Soliman A, Quilty LC, Fischer B, Rehm J, Selby P, et al. Nabiximols combined with motivational enhancement/cognitive behavioral therapy for the treatment of cannabis dependence: a pilot randomized clinical trial. PloS ONE. 2018;13:e0190768.
Solowij N, Broyd SJ, Beale C, Prick J-A, Greenwood L-M, van Hell H, et al. Therapeutic effects of prolonged cannabidiol treatment on psychological symptoms and cognitive function in regular cannabis users: a pragmatic open-label clinical trial. Cannabis Cannabinoid Res. 2018;3:21–34.
Schindler F, Anghelescu I, Regen F, Jockers-Scherubl M. Improvement in refractory obsessive compulsive disorder with dronabinol. Am J Psychiatry. 2008;165:536–7.
Cooper JJ, Grant J. Refractory OCD due to thalamic infarct with response to dronabinol. J Neuropsychiatry Clin Neurosci. 2017;29:77–8.
Kayser RR, Raskin M, Snorrason I, Hezel DM, Haney M, Simpson HB. Cannabinoid augmentation of exposure-based psychotherapy for obsessive-compulsive disorder. J Clin Psychopharmacol. 2020;40:207–10.
Kayser RR, Haney M, Raskin M, Arout C, Simpson HB. Acute effects of cannabinoids on symptoms of obsessive-compulsive disorder: a human laboratory study. Depress Anxiety. 2020;37:801–11.
Duracková Z. Some current insights into oxidative stress. Physiol Res. 2010;59:459–69.
Jabs T. Reactive oxygen intermediates as mediators of programmed cell death in plants and animals. Biochem Pharmacol. 1999;57:231–45.
Vallée A, Lecarpentier Y. Crosstalk between peroxisome proliferator-activated receptor gamma and the canonical WNT/β-catenin pathway in chronic inflammation and oxidative stress during carcinogenesis. Front Immunol. 2018;9:745.
Weyemi U, Lagente-Chevallier O, Boufraqech M, Prenois F, Courtin F, Caillou B, et al. ROS-generating NADPH oxidase NOX4 is a critical mediator in oncogenic H-Ras-induced DNA damage and subsequent senescence. Oncogene. 2012;31:1117–29.
Behl A, Swami G, Sircar SS, Bhatia MS, Banerjee BD. Relationship of possible stress-related biochemical markers to oxidative/antioxidative status in obsessive-compulsive disorder. Neuropsychobiology. 2010;61:210–4.
Simon RH, Scoggin CH, Patterson D. Hydrogen peroxide causes the fatal injury to human fibroblasts exposed to oxygen radicals. J Biol Chem. 1981;256:7181–6.
Ursini F, Maiorino M, Brigelius-Flohé R, Aumann KD, Roveri A, Schomburg D, et al. Diversity of glutathione peroxidases. Methods Enzymol. 1995;252:38–53.
Rana SVS, Allen T, Singh R. Inevitable glutathione, then and now. Indian J Exp Biol. 2002;40:706–16.
Pellmar TC. Peroxide alters neuronal excitability in the CA1 region of guinea-pig hippocampus in vitro. Neuroscience. 1987;23:447–56.
Halliwell B. Oxidants and human disease: some new concepts. FASEB J. 1987;1:358–64.
Pellmar TC, Neel KL, Lee KH. Free radicals mediate peroxidative damage in guinea pig hippocampus in vitro. J Neurosci Res. 1989;24:437–44.
Paul LA, Fulton AM, Heppner GH. Reactive oxygen-mediated damage to murine mammary tumor cells. Mutat Res. 1989;215:223–34.
Graham DG. Oxidative pathways for catecholamines in the genesis of neuromelanin and cytotoxic quinones. Mol Pharmacol. 1978;14:633–43.
Yao JK, Reddy R, van Kammen DP. Reduced level of plasma antioxidant uric acid in schizophrenia. Psychiatry Res. 1998;80:29–39.
Kuloglu M, Atmaca M, Tezcan E, Gecici O, Tunckol H, Ustundag B. Antioxidant enzyme activities and malondialdehyde levels in patients with obsessive-compulsive disorder. Neuropsychobiology. 2002;46:27–32.
Beech H, Vaughan C. The behavioral treatment of obsessional states. London: Wiley; 1970.
Pigeolet E, Corbisier P, Houbion A, Lambert D, Michiels C, Raes M, et al. Glutathione peroxidase, superoxide dismutase, and catalase inactivation by peroxides and oxygen derived free radicals. Mech Ageing Dev. 1990;51:283–97.
Khandaker GM, Dantzer R, Jones PB. Immunopsychiatry: important facts. Psychol Med. 2017;47:2229–37.
Chiarello F, Spitoni S, Hollander E, Matucci Cerinic M, Pallanti S. An expert opinion on PANDAS/PANS: highlights and controversies. Int J Psychiatry Clin Pract. 2017;21:91–8.
Rodríguez N, Morer A, González-Navarro EA, Serra-Pages C, Boloc D, Torres T, et al. Inflammatory dysregulation of monocytes in pediatric patients with obsessive-compulsive disorder. J Neuroinflammation. 2017;14:261.
Mataix-Cols D, Frans E, Pérez-Vigil A, Kuja-Halkola R, Gromark C, Isomura K, et al. A total-population multigenerational family clustering study of autoimmune diseases in obsessive-compulsive disorder and Tourette’s/chronic tic disorders. Mol Psychiatry. 2018;23:1652–8.
Pearlman DM, Vora HS, Marquis BG, Najjar S, Dudley LA. Anti-basal ganglia antibodies in primary obsessive-compulsive disorder: systematic review and meta-analysis. Br J Psychiatry J Ment Sci. 2014;205:8–16.
Rao NP, Venkatasubramanian G, Ravi V, Kalmady S, Cherian A, Yc JR. Plasma cytokine abnormalities in drug-naïve, comorbidity-free obsessive-compulsive disorder. Psychiatry Res. 2015;229:949–52.
Wolf SA, Boddeke HWGM, Kettenmann H. Microglia in physiology and disease. Annu Rev Physiol. 2017;79:619–43.
Sierra A, Encinas JM, Deudero JJP, Chancey JH, Enikolopov G, Overstreet-Wadiche LS, et al. Microglia shape adult hippocampal neurogenesis through apoptosis-coupled phagocytosis. Cell Stem Cell. 2010;7:483–95.
Frick LR, Williams K, Pittenger C. Microglial dysregulation in psychiatric disease. Clin Dev Immunol. 2013;2013:608654.
Greer JM, Capecchi MR. Hoxb8 is required for normal grooming behavior in mice. Neuron. 2002;33:23–34.
Ting JT, Feng G. Neurobiology of obsessive-compulsive disorder: insights into neural circuitry dysfunction through mouse genetics. Curr Opin Neurobiol. 2011;21:842–8.
Marinova Z, Chuang D-M, Fineberg N. Glutamate-modulating drugs as a potential therapeutic strategy in obsessive-compulsive disorder. Curr Neuropharmacol. 2017;15:977–95.
Javitt DC, Schoepp D, Kalivas PW, Volkow ND, Zarate C, Merchant K, et al. Translating glutamate: from pathophysiology to treatment. Sci Transl Med. 2011;3:102mr2.
Sanacora G, Zarate CA, Krystal JH, Manji HK. Targeting the glutamatergic system to develop novel, improved therapeutics for mood disorders. Nat Rev Drug Discov. 2008;7:426–37.
Arnold PD, Sicard T, Burroughs E, Richter MA, Kennedy JL. Glutamate transporter gene SLC1A1 associated with obsessive-compulsive disorder. Arch Gen Psychiatry. 2006;63:769–76.
Daikhin Y, Yudkoff M. Compartmentation of brain glutamate metabolism in neurons and glia. J Nutr. 2000;130:1026S–31S.
Scimemi A, Tian H, Diamond JS. Neuronal transporters regulate glutamate clearance, NMDA receptor activation, and synaptic plasticity in the hippocampus. J Neurosci. 2009;29:14581–95.
Wu K, Hanna GL, Rosenberg DR, Arnold PD. The role of glutamate signaling in the pathogenesis and treatment of obsessive-compulsive disorder. Pharmacol Biochem Behav. 2012;100:726–35.
Kim M-S, Shutov LP, Gnanasekaran A, Lin Z, Rysted JE, Ulrich JD, et al. Nerve growth factor (NGF) regulates activity of nuclear factor of activated T-cells (NFAT) in neurons via the phosphatidylinositol 3-kinase (PI3K)-Akt-glycogen synthase kinase 3β (GSK3β) pathway. J Biol Chem. 2014;289:31349–60.
Ting JT, Feng G. Glutamatergic synaptic dysfunction and obsessive-compulsive disorder. Curr Chem Genom. 2008;2:62–75.
Chakrabarty K, Bhattacharyya S, Christopher R, Khanna S. Glutamatergic dysfunction in OCD. Neuropsychopharmacology. 2005;30:1735–40.
Starck G, Ljungberg M, Nilsson M, Jönsson L, Lundberg S, Ivarsson T, et al. A 1H magnetic resonance spectroscopy study in adults with obsessive compulsive disorder: relationship between metabolite concentrations and symptom severity. J Neural Transm Vienna Austria 1996. 2008;115:1051–62.
Pauls DL, Abramovitch A, Rauch SL, Geller DA. Obsessive-compulsive disorder: an integrative genetic and neurobiological perspective. Nat Rev Neurosci. 2014;15:410–24.
McGuire PK, Bench CJ, Frith CD, Marks IM, Frackowiak RS, Dolan RJ. Functional anatomy of obsessive-compulsive phenomena. Br J Psychiatry. 1994;164:459–68.
van den Heuvel OA, van Wingen G, Soriano-Mas C, Alonso P, Chamberlain SR, Nakamae T, et al. Brain circuitry of compulsivity. Eur Neuropsychopharmacol. 2016;26:810–27.
Cohen K, Weizman A, Weinstein A. Modulatory effects of cannabinoids on brain neurotransmission. Eur J Neurosci. 2019;50:2322–45.
Covey DP, Mateo Y, Sulzer D, Cheer JF, Lovinger DM. Endocannabinoid modulation of dopamine neurotransmission. Neuropharmacology. 2017;124:52–61.
Mechoulam R, Hanuš LO, Pertwee R, Howlett AC. Early phytocannabinoid chemistry to endocannabinoids and beyond. Nat Rev Neurosci. 2014;15:757–64.
Rueda-Orozco PE, Montes-Rodriguez CJ, Soria-Gomez E, Méndez-Díaz M, Prospéro-García O. Impairment of endocannabinoids activity in the dorsolateral striatum delays extinction of behavior in a procedural memory task in rats. Neuropharmacology. 2008;55:55–62.
Lu H-C, Mackie K. An introduction to the endogenous cannabinoid system. Biol Psychiatry. 2016;79:516–25.
Blessing EM, Steenkamp MM, Manzanares J, Marmar CR. Cannabidiol as a potential treatment for anxiety disorders. Neurotherapeutics. 2015;12:825–36.
García-Gutiérrez MS, Navarrete F, Gasparyan A, Austrich-Olivares A, Sala F, Manzanares J. Cannabidiol: a potential new alternative for the treatment of anxiety, depression, and psychotic disorders. Biomolecules. 2020;10:1575.
Lutz B, Marsicano G, Maldonado R, Hillard CJ. The endocannabinoid system in guarding against fear, anxiety and stress. Nat Rev Neurosci. 2015;16:705–18.
Abrams DI. The therapeutic effects of Cannabis and cannabinoids: an update from the National Academies of Sciences, Engineering and Medicine report. Eur J Intern Med. 2018;49:7–11.
Meyer HC, Lee FS, Gee DG. The role of the endocannabinoid system and genetic variation in adolescent brain development. Neuropsychopharmacology. 2018;43:21–33.
García C, Palomo-Garo C, Gómez-Gálvez Y, Fernández-Ruiz J. Cannabinoid-dopamine interactions in the physiology and physiopathology of the basal ganglia. Br J Pharmacol. 2016;173:2069–79.
Szejko N, Fremer C, Müller-Vahl KR. Cannabis improves obsessive-compulsive disorder-case report and review of the literature. Front Psychiatry. 2020;11:681.
Pava MJ, Makriyannis A, Lovinger DM. Endocannabinoid signaling regulates sleep stability. PloS ONE. 2016;11:e0152473.
Lupica CR, Hu Y, Devinsky O, Hoffman AF. Cannabinoids as hippocampal network administrators. Neuropharmacology. 2017;124:25–37.
Russo E, Guy GW. A tale of two cannabinoids: the therapeutic rationale for combining tetrahydrocannabinol and cannabidiol. Med Hypotheses. 2006;66:234–46.
Pertwee RG. Endocannabinoids and their pharmacological actions. Handb Exp Pharmacol. 2015;231:1–37.
Bergamaschi MM, Queiroz RHC, Zuardi AW, Crippa JAS. Safety and side effects of cannabidiol, a cannabis sativa constituent. Curr Drug Saf. 2011;6:237–49.
Iffland K, Grotenhermen F. An update on safety and side effects of cannabidiol: a review of clinical data and relevant animal studies. Cannabis Cannabinoid Res. 2017;2:139–54.
Fernández-Ruiz J, Sagredo O, Pazos MR, García C, Pertwee R, Mechoulam R, et al. Cannabidiol for neurodegenerative disorders: important new clinical applications for this phytocannabinoid? Br J Clin Pharmacol. 2013;75:323–33.
Devinsky O, Cilio MR, Cross H, Fernandez-Ruiz J, French J, Hill C, et al. Cannabidiol: pharmacology and potential therapeutic role in epilepsy and other neuropsychiatric disorders. Epilepsia. 2014;55:791–802.
Ayati Z, Sarris J, Chang D, Emami SA, Rahimi R. Herbal medicines and phytochemicals for obsessive-compulsive disorder. Phytother Res PTR. 2020;34:1889–901.
Breuer A, Haj CG, Fogaça MV, Gomes FV, Silva NR, Pedrazzi JF, et al. Fluorinated cannabidiol derivatives: enhancement of activity in mice models predictive of anxiolytic, antidepressant and antipsychotic effects. PloS ONE. 2016;11:e0158779.
Casarotto PC, Gomes FV, Resstel LBM, Guimarães FS. Cannabidiol inhibitory effect on marble-burying behaviour: involvement of CB1 receptors. Behav Pharmacol. 2010;21:353–8.
Garakani A, Murrough JW, Freire RC, Thom RP, Larkin K, Buono FD, et al. Pharmacotherapy of anxiety disorders: current and emerging treatment options. Front Psychiatry. 2020;11:595584.
Bisogno T, Hanus L, De Petrocellis L, Tchilibon S, Ponde DE, Brandi I, et al. Molecular targets for cannabidiol and its synthetic analogues: effect on vanilloid VR1 receptors and on the cellular uptake and enzymatic hydrolysis of anandamide. Br J Pharmacol. 2001;134:845–52.
Leweke FM, Piomelli D, Pahlisch F, Muhl D, Gerth CW, Hoyer C, et al. Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia. Transl Psychiatry. 2012;2:e94.
Patel S, Hill MN, Cheer JF, Wotjak CT, Holmes A. The endocannabinoid system as a target for novel anxiolytic drugs. Neurosci Biobehav Rev. 2017;76:56–66.
Emamian ES. AKT/GSK3 signaling pathway and schizophrenia. Front Mol Neurosci. 2012;5:33.
Renard J, Norris C, Rushlow W, Laviolette SR. Neuronal and molecular effects of cannabidiol on the mesolimbic dopamine system: Implications for novel schizophrenia treatments. Neurosci Biobehav Rev. 2017;75:157–65.
Vallée A, Lecarpentier Y, Guillevin R, Vallée J-N. Effects of cannabidiol interactions with Wnt/β-catenin pathway and PPARγ on oxidative stress and neuroinflammation in Alzheimer’s disease. Acta Biochim Biophys Sin. 2017;49:853–66.
Appiah-Kusi E, Petros N, Wilson R, Colizzi M, Bossong MG, Valmaggia L, et al. Effects of short-term cannabidiol treatment on response to social stress in subjects at clinical high risk of developing psychosis. Psychopharmacology. 2020;237:1121–30.
Woelfl T, Rohleder C, Mueller JK, Lange B, Reuter A, Schmidt AM, et al. Effects of cannabidiol and Delta-9-tetrahydrocannabinol on emotion, cognition, and attention: a double-blind, placebo-controlled, randomized experimental trial in healthy volunteers. Front Psychiatry. 2020;11:576877.
Wilson R, Bossong MG, Appiah-Kusi E, Petros N, Brammer M, Perez J, et al. Cannabidiol attenuates insular dysfunction during motivational salience processing in subjects at clinical high risk for psychosis. Transl Psychiatry. 2019;9:203.
McGuire P, Robson P, Cubala WJ, Vasile D, Morrison PD, Barron R, et al. Cannabidiol (CBD) as an adjunctive therapy in schizophrenia: a multicenter randomized controlled trial. Am J Psychiatry. 2018;175:225–31.
Rodrigues da Silva N, Gomes FV, Sonego AB, Silva NR, da, Guimarães FS. Cannabidiol attenuates behavioral changes in a rodent model of schizophrenia through 5-HT1A, but not CB1 and CB2 receptors. Pharmacol Res. 2020;156:104749.
Silvestro S, Mammana S, Cavalli E, Bramanti P, Mazzon E. Use of cannabidiol in the treatment of epilepsy: efficacy and security in clinical trials. Molecules. 2019;24:1459.
Husnain M, Imran M, Ibrahim M, Assiri MA, Wattoo NZ, Irfan A. Pharmacological analysis of cannabis sativa: a potent herbal plant. Mini Rev Med Chem. 2020. https://doi.org/10.2174/1389557520666200628031644.
Loh KM, van Amerongen R, Nusse R. Generating cellular diversity and spatial form: wnt signaling and the evolution of multicellular animals. Dev Cell. 2016;38:643–55.
Oren O, Smith BD. Eliminating cancer stem cells by targeting embryonic signaling pathways. Stem Cell Rev. 2017;13:17–23.
Al-Harthi L. Wnt/β-catenin and its diverse physiological cell signaling pathways in neurodegenerative and neuropsychiatric disorders. J Neuroimmune Pharmacol. 2012;7:725–30.
Marchetti B, Pluchino S. Wnt your brain be inflamed? Yes, it Wnt! Trends Mol Med. 2013;19:144–56.
Vallée A, Lecarpentier Y, Guillevin R, Vallée J-N. Thermodynamics in neurodegenerative diseases: interplay between canonical WNT/beta-catenin pathway-PPAR gamma, energy metabolism and circadian rhythms. Neuromolecular Med. 2018;20:174–204.
Lecarpentier Y, Claes V, Duthoit G, Hébert J-L. Circadian rhythms, Wnt/beta-catenin pathway and PPAR alpha/gamma profiles in diseases with primary or secondary cardiac dysfunction. Front Physiol. 2014;5:429.
Lecarpentier Y, Vallée A. Opposite Interplay between PPAR gamma and canonical Wnt/beta-catenin pathway in amyotrophic lateral sclerosis. Front Neurol. 2016;7:100.
Vallée A, Lecarpentier Y. Alzheimer disease: crosstalk between the canonical Wnt/beta-catenin pathway and PPARs alpha and gamma. Front Neurosci. 2016;10:459.
He TC, Sparks AB, Rago C, Hermeking H, Zawel L, da Costa LT, et al. Identification of c-MYC as a target of the APC pathway. Science. 1998;281:1509–12.
Shtutman M, Zhurinsky J, Simcha I, Albanese C, D’Amico M, Pestell R, et al. The cyclin D1 gene is a target of the beta-catenin/LEF-1 pathway. Proc Natl Acad Sci USA. 1999;96:5522–7.
Angers S, Moon RT. Proximal events in Wnt signal transduction. Nat Rev Mol Cell Biol. 2009. https://doi.org/10.1038/nrm2717.
Sharma C, Pradeep A, Wong L, Rana A, Rana B. Peroxisome proliferator-activated receptor gamma activation can regulate beta-catenin levels via a proteasome-mediated and adenomatous polyposis coli-independent pathway. J Biol Chem. 2004;279:35583–94.
Rosi MC, Luccarini I, Grossi C, Fiorentini A, Spillantini MG, Prisco A, et al. Increased Dickkopf-1 expression in transgenic mouse models of neurodegenerative disease. J Neurochem. 2010;112:1539–51.
Clevers H, Nusse R. Wnt/β-catenin signaling and disease. Cell. 2012;149:1192–205.
Inestrosa NC, Montecinos-Oliva C, Fuenzalida M. Wnt signaling: role in Alzheimer disease and schizophrenia. J NeuroImmune Pharmacol. 2012;7:788–807.
Vallée A, Lecarpentier Y, Guillevin R, Vallée J-N. Interactions between TGF-β1, canonical WNT/β-catenin pathway and PPAR γ in radiation-induced fibrosis. Oncotarget. 2017;8:90579–604.
Vallée A, Lecarpentier Y, Vallée J-N. Hypothesis of opposite interplay between the canonical WNT/beta-catenin pathway and PPAR gamma in primary central nervous system lymphomas. Curr Issues Mol Biol. 2019;31:1–20.
Aberle H, Bauer A, Stappert J, Kispert A, Kemler R. β-catenin is a target for the ubiquitin–proteasome pathway. EMBO J. 1997;16:3797–804.
Wu D, Pan W. GSK3: a multifaceted kinase in Wnt signaling. Trends Biochem Sci. 2010;35:161–8.
Hur E-M, Zhou F-Q. GSK3 signalling in neural development. Nat Rev Neurosci. 2010;11:539–51.
Ambacher KK, Pitzul KB, Karajgikar M, Hamilton A, Ferguson SS, Cregan SP. The JNK- and AKT/GSK3β-signaling pathways converge to regulate puma induction and neuronal apoptosis induced by trophic factor deprivation. PLoS ONE. 2012;7:e46885.
Orellana AMM, Vasconcelos AR, Leite JA, de Sá Lima L, Andreotti DZ, Munhoz CD, et al. Age-related neuroinflammation and changes in AKT-GSK-3β and WNT/ β-CATENIN signaling in rat hippocampus. Aging. 2015;7:1094–111.
Karege F, Perret G, Bondolfi G, Schwald M, Bertschy G, Aubry J-M. Decreased serum brain-derived neurotrophic factor levels in major depressed patients. Psychiatry Res. 2002;109:143–8.
Motamedi S, Karimi I, Jafari F. The interrelationship of metabolic syndrome and neurodegenerative diseases with focus on brain-derived neurotrophic factor (BDNF): Kill two birds with one stone. Metab Brain Dis. 2017;32:651–65.
Colucci-D’Amato L, Speranza L, Volpicelli F. Neurotrophic factor BDNF, physiological functions and therapeutic potential in depression, neurodegeneration and brain cancer. Int J Mol Sci. 2020;21:7777.
Matsuda N, Lu H, Fukata Y, Noritake J, Gao H, Mukherjee S, et al. Differential activity-dependent secretion of brain-derived neurotrophic factor from axon and dendrite. J Neurosci. 2009;29:14185–98.
Yang J-W, Ru J, Ma W, Gao Y, Liang Z, Liu J, et al. BDNF promotes the growth of human neurons through crosstalk with the Wnt/β-catenin signaling pathway via GSK-3β. Neuropeptides. 2015;54:35–46.
Tayyab M, Shahi MH, Farheen S, Mariyath MPM, Khanam N, Castresana JS, et al. Sonic hedgehog, Wnt, and brain-derived neurotrophic factor cell signaling pathway crosstalk: potential therapy for depression. J Neurosci Res. 2018;96:53–62.
Hall D, Dhilla A, Charalambous A, Gogos JA, Karayiorgou M. Sequence variants of the brain-derived neurotrophic factor (BDNF) gene are strongly associated with obsessive-compulsive disorder. Am J Hum Genet. 2003;73:370–6.
Timpano KR, Schmidt NB, Wheaton MG, Wendland JR, Murphy DL. Consideration of the BDNF gene in relation to two phenotypes: hoarding and obesity. J Abnorm Psychol. 2011;120:700–7.
Wendland JR, Kruse MR, Cromer KR, Cromer KC, Murphy DL. A large case-control study of common functional SLC6A4 and BDNF variants in obsessive-compulsive disorder. Neuropsychopharmacology. 2007;32:2543–51.
Ren-Patterson RF, Cochran LW, Holmes A, Sherrill S, Huang S-J, Tolliver T, et al. Loss of brain-derived neurotrophic factor gene allele exacerbates brain monoamine deficiencies and increases stress abnormalities of serotonin transporter knockout mice. J Neurosci Res. 2005;79:756–71.
Dodman NH, Karlsson EK, Moon-Fanelli A, Galdzicka M, Perloski M, Shuster L, et al. A canine chromosome 7 locus confers compulsive disorder susceptibility. Mol Psychiatry. 2010;15:8–10.
Shapiro L, Weis WI. Structure and biochemistry of cadherins and catenins. Cold Spring Harb Perspect Biol. 2009;1:a003053.
Shapiro L, Love J, Colman DR. Adhesion molecules in the nervous system: structural insights into function and diversity. Annu Rev Neurosci. 2007;30:451–74.
Bozdagi O, Wang X, Nikitczuk JS, Anderson TR, Bloss EB, Radice GL, et al. Persistence of coordinated long-term potentiation and dendritic spine enlargement at mature hippocampal CA1 synapses requires N-cadherin. J Neurosci. 2010;30:9984–9.
Kawauchi T, Sekine K, Shikanai M, Chihama K, Tomita K, Kubo K, et al. Rab GTPases-dependent endocytic pathways regulate neuronal migration and maturation through N-cadherin trafficking. Neuron. 2010;67:588–602.
Nuriya M, Huganir RL. Regulation of AMPA receptor trafficking by N-cadherin. J Neurochem. 2006;97:652–61.
Oyama T, Kanai Y, Ochiai A, Akimoto S, Oda T, Yanagihara K, et al. A truncated beta-catenin disrupts the interaction between E-cadherin and alpha-catenin: a cause of loss of intercellular adhesiveness in human cancer cell lines. Cancer Res. 1994;54:6282–7.
Huber O, Kemler R, Langosch D. Mutations affecting transmembrane segment interactions impair adhesiveness of E-cadherin. J Cell Sci. 1999;112:4415–23.
Moya PR, Dodman NH, Timpano KR, Rubenstein LM, Rana Z, Fried RL, et al. Rare missense neuronal cadherin gene (CDH2) variants in specific obsessive-compulsive disorder and Tourette disorder phenotypes. Eur J Hum Genet. 2013;21:850–4.
Schambony A, Kunz M, Gradl D. Cross-regulation of Wnt signaling and cell adhesion. Differ Res Biol Divers. 2004;72:307–18.
Bienz M. beta-Catenin: a pivot between cell adhesion and Wnt signalling. Curr Biol. 2005;15:R64–7.
Brembeck FH, Rosário M, Birchmeier W. Balancing cell adhesion and Wnt signaling, the key role of beta-catenin. Curr Opin Genet Dev. 2006;16:51–9.
Nagafuchi A. Molecular architecture of adherens junctions. Curr Opin Cell Biol. 2001;13:600–3.
Marie PJ, Haÿ E. Cadherins and Wnt signalling: a functional link controlling bone formation. BoneKEy Rep. 2013;2:330.
Thompson SL, Dulawa SC. Dissecting the roles of β-arrestin2 and GSK-3 signaling in 5-HT1BR-mediated perseverative behavior and prepulse inhibition deficits in mice. PloS ONE. 2019;14:e0211239.
Giese KP. GSK-3: a key player in neurodegeneration and memory. IUBMB Life. 2009;61:516–21.
Vallée A, Vallée J-N, Lecarpentier Y. PPARγ agonists: potential treatment for autism spectrum disorder by inhibiting the canonical WNT/β-catenin pathway. Mol Psychiatry. 2018. https://doi.org/10.1038/s41380-018-0131-4.
Vallée A, Lecarpentier Y, Vallée J-N. Targeting the canonical WNT/β-catenin pathway in cancer treatment using non-steroidal anti-inflammatory drugs. Cells. 2019;8:726.
Vallée A, Vallée J-N. Warburg effect hypothesis in autism spectrum disorders. Mol Brain. 2018;11:1.
Libro R, Bramanti P, Mazzon E. The role of the Wnt canonical signaling in neurodegenerative diseases. Life Sci. 2016;158:78–88.
Libro R, Diomede F, Scionti D, Piattelli A, Grassi G, Pollastro F, et al. Cannabidiol modulates the expression of Alzheimer’s disease-related genes in mesenchymal stem cells. Int J Mol Sci. 2016;18.
Giacoppo S, Pollastro F, Grassi G, Bramanti P, Mazzon E. Target regulation of PI3K/Akt/mTOR pathway by cannabidiol in treatment of experimental multiple sclerosis. Fitoterapia. 2017;116:77–84.
Hernández F, Gómez de Barreda E, Fuster-Matanzo A, Lucas JJ, Avila J. GSK3: a possible link between beta amyloid peptide and tau protein. Exp Neurol. 2010;223:322–5.
Ozaita A, Puighermanal E, Maldonado R. Regulation of PI3K/Akt/GSK-3 pathway by cannabinoids in the brain. J Neurochem. 2007;102:1105–14.
Trazzi S, Steger M, Mitrugno VM, Bartesaghi R, Ciani E. CB1 cannabinoid receptors increase neuronal precursor proliferation through AKT/glycogen synthase kinase-3beta/beta-catenin signaling. J Biol Chem. 2010;285:10098–109.
Barthel A, Schmoll D, Unterman TG. FoxO proteins in insulin action and metabolism. Trends Endocrinol Metab. 2005;16:183–9.
Almeida M, Ambrogini E, Han L, Manolagas SC, Jilka RL. Increased lipid oxidation causes oxidative stress, increased peroxisome proliferator-activated receptor-gamma expression, and diminished pro-osteogenic Wnt signaling in the skeleton. J Biol Chem. 2009;284:27438–48.
Essers MAG, de Vries-Smits LMM, Barker N, Polderman PE, Burgering BMT, Korswagen HC. Functional interaction between beta-catenin and FOXO in oxidative stress signaling. Science. 2005;308:1181–4.
Hoogeboom D, Essers MAG, Polderman PE, Voets E, Smits LMM, Burgering BMT. Interaction of FOXO with beta-catenin inhibits beta-catenin/T cell factor activity. J Biol Chem. 2008;283:9224–30.
Reif K, Burgering BM, Cantrell DA. Phosphatidylinositol 3-kinase links the interleukin-2 receptor to protein kinase B and p70 S6 kinase. J Biol Chem. 1997;272:14426–33.
Brunet A, Bonni A, Zigmond MJ, Lin MZ, Juo P, Hu LS, et al. Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell. 1999;96:857–68.
Stahl M, Dijkers PF, Kops GJPL, Lens SMA, Coffer PJ, Burgering BMT, et al. The forkhead transcription factor FoxO regulates transcription of p27Kip1 and Bim in response to IL-2. J Immunol. 2002;168:5024–31.
Schmidt M, Fernandez de Mattos S, van der Horst A, Klompmaker R, Kops GJPL, Lam EW-F, et al. Cell cycle inhibition by FoxO forkhead transcription factors involves downregulation of cyclin D. Mol Cell Biol. 2002;22:7842–52.
Fernández de Mattos S, Essafi A, Soeiro I, Pietersen AM, Birkenkamp KU, Edwards CS, et al. FoxO3a and BCR-ABL regulate cyclin D2 transcription through a STAT5/BCL6-dependent mechanism. Mol Cell Biol. 2004;24:10058–71.
Manolopoulos KN, Klotz L-O, Korsten P, Bornstein SR, Barthel A. Linking Alzheimer’s disease to insulin resistance: the FoxO response to oxidative stress. Mol Psychiatry. 2010;15:1046–52.
Shang YC, Chong ZZ, Hou J, Maiese K. Wnt1, FoxO3a, and NF-kappaB oversee microglial integrity and activation during oxidant stress. Cell Signal. 2010;22:1317–29.
Halleskog C, Mulder J, Dahlström J, Mackie K, Hortobágyi T, Tanila H, et al. WNT signaling in activated microglia is proinflammatory. Glia. 2011;59:119–31.
L’episcopo F, Serapide MF, Tirolo C, Testa N, Caniglia S, Morale MC, et al. A Wnt1 regulated Frizzled-1/β-Catenin signaling pathway as a candidate regulatory circuit controlling mesencephalic dopaminergic neuron-astrocyte crosstalk: Therapeutical relevance for neuron survival and neuroprotection. Mol Neurodegener. 2011;6:49.
Ma B, Hottiger MO. Crosstalk between Wnt/β-Catenin and NF-κB Signaling Pathway during Inflammation. Front Immunol. 2016;7:378.
Mitchell S, Vargas J, Hoffmann A. Signaling via the NFκB system. Wiley Interdiscip Rev Syst Biol Med. 2016;8:227–41.
Deng J, Miller SA, Wang H-Y, Xia W, Wen Y, Zhou BP, et al. beta-catenin interacts with and inhibits NF-kappa B in human colon and breast cancer. Cancer Cell. 2002;2:323–34.
Liu J, Liao Y, Ma K, Wang Y, Zhang G, Yang R, et al. PI3K is required for the physical interaction and functional inhibition of NF-κB by β-catenin in colorectal cancer cells. Biochem Biophys Res Commun. 2013;434:760–6.
Martin M, Rehani K, Jope RS, Michalek SM. Toll-like receptor-mediated cytokine production is differentially regulated by glycogen synthase kinase 3. Nat Immunol. 2005;6:777–84.
Manicassamy S, Reizis B, Ravindran R, Nakaya H, Salazar-Gonzalez RM, Wang Y-C, et al. Activation of beta-catenin in dendritic cells regulates immunity versus tolerance in the intestine. Science. 2010;329:849–53.
Cho HH, Song JS, Yu JM, Yu SS, Choi SJ, Kim DH, et al. Differential effect of NF-kappaB activity on beta-catenin/Tcf pathway in various cancer cells. FEBS Lett. 2008;582:616–22.
Fliniaux I, Mikkola ML, Lefebvre S, Thesleff I. Identification of dkk4 as a target of Eda-A1/Edar pathway reveals an unexpected role of ectodysplasin as inhibitor of Wnt signalling in ectodermal placodes. Dev Biol. 2008;320:60–71.
Hoeflich KP, Luo J, Rubie EA, Tsao MS, Jin O, Woodgett JR. Requirement for glycogen synthase kinase-3beta in cell survival and NF-kappaB activation. Nature. 2000;406:86–90.
Beurel E, Michalek SM, Jope RS. Innate and adaptive immune responses regulated by glycogen synthase kinase-3 (GSK3). Trends Immunol. 2010;31:24–31.
Lutgen V, Narasipura SD, Sharma A, Min S, Al-Harthi L. β-Catenin signaling positively regulates glutamate uptake and metabolism in astrocytes. J Neuroinflammation. 2016;13:242.
Narasipura SD, Henderson LJ, Fu SW, Chen L, Kashanchi F, Al-Harthi L. Role of β-catenin and TCF/LEF family members in transcriptional activity of HIV in astrocytes. J Virol. 2012;86:1911–21.
Lecarpentier Y, Schussler O, Hébert J-L, Vallée A. Molecular Mechanisms Underlying the Circadian Rhythm of Blood Pressure in Normotensive Subjects. Curr Hypertens Rep. 2020;22:50.
Atalay S, Jarocka-Karpowicz I, Skrzydlewska E. Antioxidative and anti-inflammatory properties of cannabidiol. Antioxidants. 2019;9:21.
Borges RS, Batista J, Viana RB, Baetas AC, Orestes E, Andrade MA, et al. Understanding the molecular aspects of tetrahydrocannabinol and cannabidiol as antioxidants. Molecules. 2013;18:12663–74.
Rajesh M, Mukhopadhyay P, Bátkai S, Haskó G, Liaudet L, Drel VR, et al. Cannabidiol attenuates high glucose-induced endothelial cell inflammatory response and barrier disruption. Am J Physiol Heart Circ Physiol. 2007;293:H610–9.
Pan H, Mukhopadhyay P, Rajesh M, Patel V, Mukhopadhyay B, Gao B, et al. Cannabidiol attenuates cisplatin-induced nephrotoxicity by decreasing oxidative/nitrosative stress, inflammation, and cell death. J Pharmacol Exp Ther. 2009;328:708–14.
Fouad AA, Albuali WH, Al-Mulhim AS, Jresat I. Cardioprotective effect of cannabidiol in rats exposed to doxorubicin toxicity. Environ Toxicol Pharmacol. 2013;36:347–57.
Hamelink C, Hampson A, Wink DA, Eiden LE, Eskay RL. Comparison of cannabidiol, antioxidants, and diuretics in reversing binge ethanol-induced neurotoxicity. J Pharmacol Exp Ther. 2005;314:780–8.
Campos AC, Fogaça MV, Sonego AB, Guimarães FSCannabidiol. neuroprotection and neuropsychiatric disorders. Pharmacol Res. 2016;112:119–27.
da Silva VK, de Freitas BS, Garcia RCL, Monteiro RT, Hallak JE, Zuardi AW, et al. Antiapoptotic effects of cannabidiol in an experimental model of cognitive decline induced by brain iron overload. Transl Psychiatry. 2018;8:176.
Vomund S, Schäfer A, Parnham MJ, Brüne B, von Knethen A. Nrf2, the master regulator of anti-oxidative responses. Int J Mol Sci. 2017;18:2772.
Rajesh M, Mukhopadhyay P, Bátkai S, Patel V, Saito K, Matsumoto S, et al. Cannabidiol attenuates cardiac dysfunction, oxidative stress, fibrosis, and inflammatory and cell death signaling pathways in diabetic cardiomyopathy. J Am Coll Cardiol. 2010;56:2115–25.
Costa B, Trovato AE, Comelli F, Giagnoni G, Colleoni M. The non-psychoactive cannabis constituent cannabidiol is an orally effective therapeutic agent in rat chronic inflammatory and neuropathic pain. Eur J Pharmacol. 2007;556:75–83.
Wu H-Y, Jan T-R. Cannabidiol hydroxyquinone-induced apoptosis of splenocytes is mediated predominantly by thiol depletion. Toxicol Lett. 2010;195:68–74.
Gęgotek A, Ambrożewicz E, Jastrząb A, Jarocka-Karpowicz I, Skrzydlewska E. Rutin and ascorbic acid cooperation in antioxidant and antiapoptotic effect on human skin keratinocytes and fibroblasts exposed to UVA and UVB radiation. Arch Dermatol Res. 2019;311:203–19.
Pertwee RG. The pharmacology of cannabinoid receptors and their ligands: an overview. Int J Obes. 2006;30 Suppl 1:S13–8.
Gómez Del Pulgar T, De Ceballos ML, Guzmán M, Velasco G. Cannabinoids protect astrocytes from ceramide-induced apoptosis through the phosphatidylinositol 3-kinase/protein kinase B pathway. J Biol Chem. 2002;277:36527–33.
Molina-Holgado E, Vela JM, Arévalo-Martín A, Almazán G, Molina-Holgado F, Borrell J, et al. Cannabinoids promote oligodendrocyte progenitor survival: involvement of cannabinoid receptors and phosphatidylinositol-3 kinase/Akt signaling. J Neurosci. 2002;22:9742–53.
Wang S, Xu Q, Shu G, Wang L, Gao P, Xi Q, et al. N-Oleoyl glycine, a lipoamino acid, stimulates adipogenesis associated with activation of CB1 receptor and Akt signaling pathway in 3T3-L1 adipocyte. Biochem Biophys Res Commun. 2015;466:438–43.
Wang Y, Mukhopadhyay P, Cao Z, Wang H, Feng D, Haskó G, et al. Cannabidiol attenuates alcohol-induced liver steatosis, metabolic dysregulation, inflammation and neutrophil-mediated injury. Sci Rep. 2017;7:12064.
Hou Y, Moreau F, Chadee K. PPARγ is an E3 ligase that induces the degradation of NFκB/p65. Nat Commun. 2012;3:1300.
Lee C-H, Olson P, Evans RM. Minireview: lipid metabolism, metabolic diseases, and peroxisome proliferator-activated receptors. Endocrinology. 2003;144:2201–7.
Marx N, Duez H, Fruchart J-C, Staels B. Peroxisome proliferator-activated receptors and atherogenesis: regulators of gene expression in vascular cells. Circ Res. 2004;94:1168–78.
Cunard R, Ricote M, DiCampli D, Archer DC, Kahn DA, Glass CK, et al. Regulation of cytokine expression by ligands of peroxisome proliferator activated receptors. J Immunol. 2002;168:2795–802.
Ricote M, Li AC, Willson TM, Kelly CJ, Glass CK. The peroxisome proliferator-activated receptor-gamma is a negative regulator of macrophage activation. Nature. 1998;391:79–82.
Giannini S, Serio M, Galli A. Pleiotropic effects of thiazolidinediones: taking a look beyond antidiabetic activity. J Endocrinol Investig. 2004;27:982–91.
Vallée A, Lecarpentier Y, Guillevin R, Vallée J-N. Thermodynamics in gliomas: interactions between the canonical WNT/Beta-catenin pathway and PPAR gamma. Front Physiol. 2017;8:352.
Vallée A, Lecarpentier Y, Guillevin R, Vallée J-N. Demyelination in multiple sclerosis: reprogramming energy metabolism and potential PPARγ agonist treatment approaches. Int J Mol Sci. 2018;19:1212.
Park KS, Lee RD, Kang S-K, Han SY, Park KL, Yang KH, et al. Neuronal differentiation of embryonic midbrain cells by upregulation of peroxisome proliferator-activated receptor-gamma via the JNK-dependent pathway. Exp Cell Res. 2004;297:424–33.
Vallée A, Lecarpentier Y, Vallée J-N. Thermodynamic aspects and reprogramming cellular energy metabolism during the fibrosis process. Int J Mol Sci. 2017;18:2537.
Vallée A, Lecarpentier Y, Guillevin R, Vallée J-N. Reprogramming energetic metabolism in Alzheimer’s disease. Life Sci. 2018;193:141–52.
Grimes CA, Jope RS. The multifaceted roles of glycogen synthase kinase 3beta in cellular signaling. Prog Neurobiol. 2001;65:391–426.
Jeon M, Rahman N, Kim Y-S. Wnt/β-catenin signaling plays a distinct role in methyl gallate-mediated inhibition of adipogenesis. Biochem Biophys Res Commun. 2016;479:22–7.
Gustafson B, Eliasson B, Smith U. Thiazolidinediones increase the wingless-type MMTV integration site family (WNT) inhibitor Dickkopf-1 in adipocytes: a link with osteogenesis. Diabetologia. 2010;53:536–40.
Osborne AL, Solowij N, Babic I, Lum JS, Newell KA, Huang X-F, et al. Effect of cannabidiol on endocannabinoid, glutamatergic and GABAergic signalling markers in male offspring of a maternal immune activation (poly I:C) model relevant to schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry. 2019;95:109666.
Piomelli D. The molecular logic of endocannabinoid signalling. Nat Rev Neurosci. 2003;4:873–84.
Campos AC, Fogaça MV, Scarante FF, Joca SRL, Sales AJ, Gomes FV, et al. Plastic and neuroprotective mechanisms involved in the therapeutic effects of cannabidiol in psychiatric disorders. Front Pharmacol. 2017;8:269.
Viveros MP, Llorente R, Suarez J, Llorente-Berzal A, López-Gallardo M, de Fonseca FR. The endocannabinoid system in critical neurodevelopmental periods: sex differences and neuropsychiatric implications. J Psychopharmacol. 2012;26:164–76.
McPartland JM, Duncan M, Di Marzo V, Pertwee RG. Are cannabidiol and Δ(9) -tetrahydrocannabivarin negative modulators of the endocannabinoid system? A systematic review. Br J Pharmacol. 2015;172:737–53.
Laprairie RB, Bagher AM, Kelly MEM, Denovan-Wright EM. Cannabidiol is a negative allosteric modulator of the cannabinoid CB1 receptor. Br J Pharmacol. 2015;172:4790–805.
Mackey SR, Golden SS, Ditty JL. The itty-bitty time machine genetics of the cyanobacterial circadian clock. Adv Genet. 2011;74:13–53.
Dunlap JC. Molecular bases for circadian clocks. Cell. 1999;96:271–90.
Reppert SM, Weaver DR. Coordination of circadian timing in mammals. Nature. 2002;418:935–41.
Hastings MH, Maywood ES, Brancaccio M. The mammalian circadian timing system and the suprachiasmatic nucleus as its pacemaker. Biology. 2019;8:13.
Atger F, Mauvoisin D, Weger B, Gobet C, Gachon F. Regulation of mammalian physiology by interconnected circadian and feeding rhythms. Front Endocrinol. 2017;8:42.
Johnson CH, Elliott JA, Foster R. Entrainment of circadian programs. Chronobiol Int. 2003;20:741–74.
Carneiro BTS, Araujo JF. Food entrainment: major and recent findings. Front Behav Neurosci. 2012;6:83.
Bloch G, Herzog ED, Levine JD, Schwartz WJ. Socially synchronized circadian oscillators. Proc Biol Sci. 2013;280:20130035.
Bell-Pedersen D, Cassone VM, Earnest DJ, Golden SS, Hardin PE, Thomas TL, et al. Circadian rhythms from multiple oscillators: lessons from diverse organisms. Nat Rev Genet. 2005;6:544–56.
Mohawk JA, Green CB, Takahashi JS. Central and peripheral circadian clocks in mammals. Annu Rev Neurosci. 2012;35:445–62.
Dibner C, Schibler U, Albrecht U. The mammalian circadian timing system: organization and coordination of central and peripheral clocks. Annu Rev Physiol. 2010;72:517–49.
Wirz-Justice A, Terman M. Chronotherapeutics (light and wake therapy) as a class of interventions for affective disorders. Handb Clin Neurol. 2012;106:697–713.
Wulff K, Gatti S, Wettstein JG, Foster RG. Sleep and circadian rhythm disruption in psychiatric and neurodegenerative disease. Nat Rev Neurosci. 2010;11:589–99.
Hogenesch JB, Gu YZ, Jain S, Bradfield CA. The basic-helix-loop-helix-PAS orphan MOP3 forms transcriptionally active complexes with circadian and hypoxia factors. Proc Natl Acad Sci USA. 1998;95:5474–9.
Gekakis N, Staknis D, Nguyen HB, Davis FC, Wilsbacher LD, King DP, et al. Role of the CLOCK protein in the mammalian circadian mechanism. Science. 1998;280:1564–9.
Goldbeter A. A model for circadian oscillations in the drosophila period protein (PER). Proc Biol Sci. 1995;261:319–24.
Schibler U, Sassone-Corsi P. A web of circadian pacemakers. Cell. 2002;111:919–22.
Ko CH, Takahashi JS. Molecular components of the mammalian circadian clock. Hum Mol Genet. 2006;15 Spec No 2:R271–7.
Roenneberg T, Merrow M. The circadian clock and human health. Curr Biol. 2016;26:R432–43.
Taylor BJ, Hasler BP. Chronotype and mental health: recent advances. Curr Psychiatry Rep. 2018;20:59.
McClung CA. How might circadian rhythms control mood? Let me count the ways. Biol Psychiatry. 2013;74:242–9.
Nota JA, Sharkey KM, Coles ME. Sleep, arousal, and circadian rhythms in adults with obsessive-compulsive disorder: a meta-analysis. Neurosci Biobehav Rev. 2015;51:100–7.
Cox RC, Olatunji BO. Circadian rhythms in obsessive-compulsive disorder: recent findings and recommendations for future research. Curr Psychiatry Rep. 2019;21:54.
Schubert JR, Coles ME. Obsessive-compulsive symptoms and characteristics in individuals with delayed sleep phase disorder. J Nerv Ment Dis. 2013;201:877–84.
Kluge M, Schüssler P, Künzel HE, Dresler M, Yassouridis A, Steiger A. Increased nocturnal secretion of ACTH and cortisol in obsessive compulsive disorder. J Psychiatr Res. 2007;41:928–33.
Cox RC, Olatunji BO. A systematic review of sleep disturbance in anxiety and related disorders. J Anxiety Disord. 2016;37:104–29.
Alvaro PK, Roberts RM, Harris JK. The independent relationships between insomnia, depression, subtypes of anxiety, and chronotype during adolescence. Sleep Med. 2014;15:934–41.
Cox RC, Tuck B, Olatunji BO. The role of eveningness in obsessive-compulsive symptoms: cross-sectional and prospective approaches. J Affect Disord. 2018;235:448–55.
Nota JA, Gibb BE, Coles ME. Obsessions and time of day: a self-monitoring study in individuals with obsessive-compulsive disorder. J Cogn Psychother. 2014;28:134–44.
Kenardy J, Fried L, Kraemer HC, Taylor CB. Psychological precursors of panic attacks. Br J Psychiatry. 1992;160:668–73.
Willis TA, O’Connor DB, Smith L. The influence of morningness-eveningness on anxiety and cardiovascular responses to stress. Physiol Behav. 2005;85:125–33.
English T, Carstensen LL. Emotional experience in the mornings and the evenings: consideration of age differences in specific emotions by time of day. Front Psychol. 2014;5:185.
Boland EM, Ross RJ. Recent advances in the study of sleep in the anxiety disorders, obsessive-compulsive disorder, and posttraumatic stress disorder. Psychiatr Clin North Am. 2015;38:761–76.
Roenneberg T, Kuehnle T, Juda M, Kantermann T, Allebrandt K, Gordijn M, et al. Epidemiology of the human circadian clock. Sleep Med Rev. 2007;11:429–38.
Coles ME, Wirshba CJ, Nota J, Schubert J, Grunthal BA. Obsessive compulsive disorder prevalence increases with latitude. J Obsessive Compuls Relat Disord. 2018;18:25–30.
Beaver LM, Klichko VI, Chow ES, Kotwica-Rolinska J, Williamson M, Orr WC, et al. Circadian regulation of glutathione levels and biosynthesis in drosophila melanogaster. PloS ONE. 2012;7:e50454.
Krishnan N, Davis AJ, Giebultowicz JM. Circadian regulation of response to oxidative stress in Drosophila melanogaster. Biochem Biophys Res Commun. 2008;374:299–303.
Krishnan N, Kretzschmar D, Rakshit K, Chow E, Giebultowicz JM. The circadian clock gene period extends healthspan in aging drosophila melanogaster. Aging. 2009;1:937–48.
Musiek ES. Circadian clock disruption in neurodegenerative diseases: cause and effect? Front Pharmacol. 2015;6:29.
Segal JP, Tresidder KA, Bhatt C, Gilron I, Ghasemlou N. Circadian control of pain and neuroinflammation. J Neurosci Res. 2018;96:1002–20.
Spengler ML, Kuropatwinski KK, Comas M, Gasparian AV, Fedtsova N, Gleiberman AS, et al. Core circadian protein CLOCK is a positive regulator of NF-κB-mediated transcription. Proc Natl Acad Sci USA. 2012;109:E2457–65.
Narasimamurthy R, Hatori M, Nayak SK, Liu F, Panda S, Verma IM. Circadian clock protein cryptochrome regulates the expression of proinflammatory cytokines. Proc Natl Acad Sci USA. 2012;109:12662–7.
Biello SM, Bonsall DR, Atkinson LA, Molyneux PC, Harrington ME, Lall GS. Alterations in glutamatergic signaling contribute to the decline of circadian photoentrainment in aged mice. Neurobiol Aging. 2018;66:75–84.
Colwell CS, Ralph MR, Menaker M. Do NMDA receptors mediate the effects of light on circadian behavior? Brain Res. 1990;523:117–20.
Brancaccio M, Edwards MD, Patton AP, Smyllie NJ, Chesham JE, Maywood ES, et al. Cell-autonomous clock of astrocytes drives circadian behavior in mammals. Science. 2019;363:187–92.
Brancaccio M, Patton AP, Chesham JE, Maywood ES, Hastings MH. Astrocytes control circadian timekeeping in the suprachiasmatic nucleus via glutamatergic signaling. Neuron. 2017;93:1420–35.e5.
Chen TL. Inhibition of growth and differentiation of osteoprogenitors in mouse bone marrow stromal cell cultures by increased donor age and glucocorticoid treatment. Bone. 2004;35:83–95.
Soták M, Sumová A, Pácha J. Cross-talk between the circadian clock and the cell cycle in cancer. Ann Med. 2014;46:221–32.
Matsu-Ura T, Moore SR, Hong CI. WNT takes two to tango: molecular links between the circadian clock and the cell cycle in adult stem cells. J Biol Rhythms. 2018;33:5–14.
Guo B, Chatterjee S, Li L, Kim JM, Lee J, Yechoor VK, et al. The clock gene, brain and muscle Arnt-like 1, regulates adipogenesis via Wnt signaling pathway. FASEB J Publ Fed Am Soc Exp Biol. 2012;26:3453–63.
Yasuniwa Y, Izumi H, Wang K-Y, Shimajiri S, Sasaguri Y, Kawai K, et al. Circadian disruption accelerates tumor growth and angio/stromagenesis through a Wnt signaling pathway. PloS ONE. 2010;5:e15330.
Janich P, Pascual G, Merlos-Suárez A, Batlle E, Ripperger J, Albrecht U, et al. The circadian molecular clock creates epidermal stem cell heterogeneity. Nature 2011;480:209–14.
Lin F, Chen Y, Li X, Zhao Q, Tan Z. Over-expression of circadian clock gene Bmal1 affects proliferation and the canonical Wnt pathway in NIH-3T3 cells. Cell Biochem Funct. 2013;31:166–72.
Sahar S, Sassone-Corsi P. Metabolism and cancer: the circadian clock connection. Nat Rev Cancer. 2009;9:886–96.
Yang X, Wood PA, Ansell CM, Ohmori M, Oh E-Y, Xiong Y, et al. Beta-catenin induces beta-TrCP-mediated PER2 degradation altering circadian clock gene expression in intestinal mucosa of ApcMin/+ mice. J Biochem. 2009;145:289–97.
Duffield GE, Best JD, Meurers BH, Bittner A, Loros JJ, Dunlap JC. Circadian programs of transcriptional activation, signaling, and protein turnover revealed by microarray analysis of mammalian cells. Curr Biol. 2002;12:551–7.
Sancar A, Lindsey-Boltz LA, Unsal-Kaçmaz K, Linn S. Molecular mechanisms of mammalian DNA repair and the DNA damage checkpoints. Annu Rev Biochem. 2004;73:39–85.
Chen L, Yang G. PPARs integrate the mammalian clock and energy metabolism. PPAR Res. 2014;2014:653017.
Yang X, Downes M, Yu RT, Bookout AL, He W, Straume M, et al. Nuclear receptor expression links the circadian clock to metabolism. Cell. 2006;126:801–10.
Wang N, Yang G, Jia Z, Zhang H, Aoyagi T, Soodvilai S, et al. Vascular PPARgamma controls circadian variation in blood pressure and heart rate through Bmal1. Cell Metab. 2008;8:482–91.
Yang G, Jia Z, Aoyagi T, McClain D, Mortensen RM, Yang T. Systemic PPARγ deletion impairs circadian rhythms of behavior and metabolism. PloS ONE. 2012;7:e38117.
Wang H-M, Zhao Y-X, Zhang S, Liu G-D, Kang W-Y, Tang H-D, et al. PPARgamma agonist curcumin reduces the amyloid-beta-stimulated inflammatory responses in primary astrocytes. J Alzheimers Dis. 2010;20:1189–99.
Fontaine C, Dubois G, Duguay Y, Helledie T, Vu-Dac N, Gervois P, et al. The orphan nuclear receptor Rev-Erbalpha is a peroxisome proliferator-activated receptor (PPAR) gamma target gene and promotes PPARgamma-induced adipocyte differentiation. J Biol Chem. 2003;278:37672–80.
Green CB, Douris N, Kojima S, Strayer CA, Fogerty J, Lourim D, et al. Loss of Nocturnin, a circadian deadenylase, confers resistance to hepatic steatosis and diet-induced obesity. Proc Natl Acad Sci USA. 2007;104:9888–93.
Murillo-Rodríguez E, Budde H, Veras AB, Rocha NB, Telles-Correia D, Monteiro D, et al. The endocannabinoid system may modulate sleep disorders in aging. Curr Neuropharmacol. 2020;18:97–108.
Santucci V, Storme JJ, Soubrié P, Le Fur G. Arousal-enhancing properties of the CB1 cannabinoid receptor antagonist SR 141716A in rats as assessed by electroencephalographic spectral and sleep-waking cycle analysis. Life Sci. 1996;58:PL103–10.
Lafaye G, Desterke C, Marulaz L, Benyamina A. Cannabidiol affects circadian clock core complex and its regulation in microglia cells. Addict Biol. 2019;24:921–34.
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Vallée, A., Lecarpentier, Y. & Vallée, JN. Possible actions of cannabidiol in obsessive-compulsive disorder by targeting the WNT/β-catenin pathway. Mol Psychiatry 27, 230–248 (2022). https://doi.org/10.1038/s41380-021-01086-1
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