{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,10]],"date-time":"2026-02-10T08:29:29Z","timestamp":1770712169498,"version":"3.49.0"},"reference-count":54,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2021,6,23]],"date-time":"2021-06-23T00:00:00Z","timestamp":1624406400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003711","name":"Ministry of Science and Technology","doi-asserted-by":"publisher","award":["MOST106-2314-B-039-016-MY3"],"award-info":[{"award-number":["MOST106-2314-B-039-016-MY3"]}],"id":[{"id":"10.13039\/501100003711","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JPM"],"abstract":"<jats:p>Areca nut (AN) was identified as carcinogenic to humans. Around 600 million people globally use AN in some form, yet no effective therapeutic drug is available to overcome AN addiction. This preclinical study examines the effects of antidepressants on AN use with animal models. We produced AN powder and dissolved it into drinking water, training 55 C57BL\/6 mice in free self-selection to drink AN water or normal water. Then, the mice were randomly divided into four groups. Selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), and tricyclic antidepressants (TCAs) were given as three treatment groups and one placebo group for four weeks. In the follow-up period, the preference and amount of free selection of AN and normal water, and oral pathological change were evaluated. There was a significant decrease in preference for AN drinking during the first four weeks, and the 36th week after drug withdrawal in the MAOI and SSRI groups (all p &lt; 0.05). The drug-reducing effect of AN water in the 1\u20134-week period was significant in the MAOI group (p &lt; 0.0001) and was also significant in the 3\u20134-week period in the SSRI group (p = 0.03). The TCA group did not show a decrease effect. At the endpoint (60 weeks), oral mucosal fibrosis (OSF) levels and risk in the SSRI (p = 0.0081) and MAOI (p = 0.01) groups were significantly lower than those in the control group. Antidepressant drugs MAOIs and SSRIs could reduce the amount of AN use and decrease the early stage of oral fibrosis in mice, but SSRIs may need to be boosted again.<\/jats:p>","DOI":"10.3390\/jpm11070591","type":"journal-article","created":{"date-parts":[[2021,6,23]],"date-time":"2021-06-23T03:22:00Z","timestamp":1624418520000},"page":"591","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Reduction in and Preventive Effects for Oral-Cancer Risk with Antidepressant Treatment"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1759-2279","authenticated-orcid":false,"given":"Chia-Min","family":"Chung","sequence":"first","affiliation":[{"name":"Center for Drug Abuse and Addiction, China Medical University Hospital, Taichung 40447, Taiwan"},{"name":"Graduate Institute of Biomedical Sciences, China Medical University, Taichung 40447, Taiwan"},{"name":"Environment-Omics-Diseases Research Centre, China Medical University Hospital, China Medical University, No. 2 Yude Road, Taichung 40447, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tzer-Min","family":"Kuo","sequence":"additional","affiliation":[{"name":"Environment-Omics-Diseases Research Centre, China Medical University Hospital, China Medical University, No. 2 Yude Road, Taichung 40447, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0665-8586","authenticated-orcid":false,"given":"Kun-Tu","family":"Yeh","sequence":"additional","affiliation":[{"name":"Department of Pathology, Changhua Christian Hospital, Changhua 50006, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0988-264X","authenticated-orcid":false,"given":"Chien-Hung","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Public Health, College of Health Science, Kaohsiung Medical University, Kaohsiung 80708, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7713-9487","authenticated-orcid":false,"given":"Ying-Chin","family":"Ko","sequence":"additional","affiliation":[{"name":"Environment-Omics-Diseases Research Centre, China Medical University Hospital, China Medical University, No. 2 Yude Road, Taichung 40447, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,6,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1080\/13556210120091464","article-title":"Metabolic effects of the consumption of Areca catechu","volume":"7","author":"Boucher","year":"2002","journal-title":"Addict. Biol."},{"key":"ref_2","first-page":"31","article-title":"Epidemiology of betel quid usage","volume":"33","author":"Gupta","year":"2004","journal-title":"Ann. Acad. Med."},{"key":"ref_3","unstructured":"IARC Working Group on the Evaluation of Carcinogenic Risks to Humans (2004). Betel-quid and areca-nut chewing and some areca-nut derived nitrosamines. IARC Monogr. Eval. Carcinog. Risks Hum., 85, 1\u2013334."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1871","DOI":"10.1054\/bjoc.2000.1208","article-title":"Risk factors for leukoplakia and malignant transformation to oral carcinoma: A leukoplakia cohort in Taiwan","volume":"82","author":"Shiu","year":"2000","journal-title":"Br. J. Cancer"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1034\/j.1600-0714.2001.300404.x","article-title":"Epidemiological survey of oral submucous fibrosis and leukoplakia in aborigines of Taiwan","volume":"30","author":"Yang","year":"2001","journal-title":"J. Oral Pathol. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1192\/bjp.bp.111.107961","article-title":"Betel-quid dependence and oral potentially malignant disorders in six Asian countries","volume":"201","author":"Lee","year":"2012","journal-title":"Br. J. Psychiatry"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"E733","DOI":"10.1002\/ijc.27401","article-title":"The neoplastic impact of tobacco-free betel-quid on the histological type and the anatomical site of aerodigestive tract cancers","volume":"131","author":"Lee","year":"2012","journal-title":"Int. J. Cancer"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1111\/j.1600-0714.1995.tb01132.x","article-title":"Betel quid chewing, cigarette smoking and alcohol consumption related to oral cancer in Taiwan","volume":"24","author":"Ko","year":"1995","journal-title":"J. Oral Pathol. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1002\/ijc.20619","article-title":"Independent and combined effects of alcohol intake, tobacco smoking and betel quid chewing on the risk of esophageal cancer in Taiwan","volume":"113","author":"Lee","year":"2004","journal-title":"Int. J. Cancer"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"831","DOI":"10.1002\/ijc.21237","article-title":"Different impact from betel quid, alcohol and cigarette: Risk factors for pharyngeal and laryngeal cancer","volume":"117","author":"Lee","year":"2005","journal-title":"Int. J. Cancer"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"684","DOI":"10.1111\/j.1600-0714.2011.01022.x","article-title":"The use of tobacco-free betel-quid in conjunction with alcohol\/tobacco impacts early-onset age and carcinoma distribution for upper aerodigestive tract cancer","volume":"40","author":"Lee","year":"2011","journal-title":"J. Oral Pathol. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"3904098","DOI":"10.1155\/2017\/3904098","article-title":"Adverse Health Effects of Betel Quid and the Risk of Oral and Pharyngeal Cancers","volume":"2017","author":"Chen","year":"2017","journal-title":"BioMed Res. Int."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"370","DOI":"10.1016\/j.taap.2010.04.008","article-title":"Effects of arecoline on adipogenesis, lipolysis, and glucose uptake of adipocytes\u2014A possible role of betel-quid chewing in metabolic syndrome","volume":"245","author":"Hsu","year":"2010","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1016\/j.drugalcdep.2014.05.020","article-title":"Relationship between betel quid chewing and risks of cardiovascular disease in older adults: A cross-sectional study in Taiwan","volume":"141","author":"Lin","year":"2014","journal-title":"Drug Alcohol Depend."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1016\/j.drugalcdep.2008.01.003","article-title":"The effect of maternal betel quid exposure during pregnancy on adverse birth outcomes among aborigines in Taiwan","volume":"95","author":"Yang","year":"2008","journal-title":"Drug Alcohol Depend."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1080\/13556210050003766","article-title":"A dependency syndrome related to areca nut use: Some medical and psychological aspects among areca nut users in the Gujarat community in the UK","volume":"5","author":"Winstock","year":"2000","journal-title":"Addict. Biol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1080\/13556210120091455","article-title":"Chemical and analytical aspects of areca nut","volume":"7","author":"Lord","year":"2002","journal-title":"Addict. Biol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1007\/BF02256596","article-title":"Effects of Betel chewing on the central and autonomic nervous systems","volume":"8","author":"Chu","year":"2001","journal-title":"J. Biomed. Sci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1080\/13556210120091509","article-title":"Areca nut-abuse liability, dependence and public health","volume":"7","author":"Winstock","year":"2002","journal-title":"Addict. Biol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1303","DOI":"10.1111\/j.1360-0443.2010.02952.x","article-title":"Areca nut dependence among chewers in a South Indian community who do not also use tobacco","volume":"105","author":"Bhat","year":"2010","journal-title":"Addiction"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1194","DOI":"10.1111\/add.12530","article-title":"Betel-quid dependence domains and syndrome associated with betel-quid ingredients among chewers: An Asian multi-country evidence","volume":"109","author":"Lee","year":"2014","journal-title":"Addiction"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1001\/jamapsychiatry.2017.4307","article-title":"Association of DSM-5 Betel-Quid Use Disorder with Oral Potentially Malignant Disorder in 6 Betel-Quid Endemic Asian Populations","volume":"75","author":"Lee","year":"2018","journal-title":"JAMA Psychiatry"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1016\/j.canlet.2020.02.030","article-title":"Betel quid\u2013associated cancer: Prevention strategies and targeted treatment","volume":"477","author":"Ko","year":"2020","journal-title":"Cancer Lett."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1016\/j.oooo.2016.04.003","article-title":"Oral submucous fibrosis: A historical perspective and a review on etiology and pathogenesis","volume":"122","author":"Tilakaratne","year":"2016","journal-title":"Oral Surg. Oral Med. Oral Pathol. Oral Radiol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1038\/sj.bjc.6600727","article-title":"The precancer risk of betel quid chewing, tobacco use and alcohol consumption in oral leukoplakia and oral submucous fibrosis in southern Taiwan","volume":"88","author":"Lee","year":"2003","journal-title":"Br. J. Cancer"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Wang, Y.Y., Tail, Y.H., Wang, W.C., Chen, C.Y., Kao, Y.H., Chen, Y.K., and Chen, C.H. (2014). Malignant transformation in 5071 southern Taiwanese patients with potentially malignant oral mucosal disorders. BMC Oral Health, 14.","DOI":"10.1186\/1472-6831-14-99"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Lin, C.-F., Wang, J.-D., Chen, P.-H., Chang, S.-J., Yang, Y.-H., and Ko, Y.-C. (2006). Predictors of betel quid chewing behavior and cessation patterns in Taiwan aborigines. BMC Public Health, 6.","DOI":"10.1186\/1471-2458-6-271"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Ghani, W.M.N., Razak, I., Yang, Y.-H., Talib, N., Ikeda, N., Axell, T., Gupta, P.C., Handa, Y., Abdullah, N., and Zain, R.B. (2011). Factors affecting commencement and cessation of betel quid chewing behaviour in Malaysian adults. BMC Public Health, 11.","DOI":"10.1186\/1471-2458-11-82"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"11687","DOI":"10.18632\/oncotarget.7049","article-title":"Antidepressants in association with reducing risk of oral cancer occurrence: A nationwide population-based cohort and nested case-control studies","volume":"7","author":"Chung","year":"2016","journal-title":"Oncotarget"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1016\/j.drugalcdep.2017.06.039","article-title":"Intoxication and substance use disorder to Areca catechu nut containing betel quid: A review of epidemiological evidence, pharmacological basis and social factors influencing quitting strategies","volume":"179","author":"Osborne","year":"2017","journal-title":"Drug Alcohol Depend."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"109982","DOI":"10.1016\/j.pnpbp.2020.109982","article-title":"Betel quid dependence mechanism and potential cessation therapy","volume":"103","author":"Ko","year":"2020","journal-title":"Prog. Neuro Psychopharmacol. Biol. Psychiatry"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1113","DOI":"10.3892\/etm.2013.925","article-title":"The antidepressant-like effects of paeoniflorin in mouse models","volume":"5","author":"Qiu","year":"2013","journal-title":"Exp. Ther. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.bbr.2016.04.011","article-title":"Variability in the effect of antide-pressants upon Wfs1-deficient mice is dependent on the drugs\u2019 mechanism of actions","volume":"308","author":"Reimets","year":"2016","journal-title":"Behav. Brain Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1016\/j.pnpbp.2014.06.008","article-title":"The depressogenic-like effect of acute and chronic treatment with dexamethasone and its influence on the activity of antidepressant drugs in the forced swim test in adult mice","volume":"54","author":"Serefko","year":"2014","journal-title":"Prog. Neuro Psychopharmacol. Biol. Psychiatry"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"597","DOI":"10.4103\/0973-1482.176177","article-title":"Oral submucous fibrosis: A clinico-histopathological correlational study","volume":"14","author":"Biradar","year":"2018","journal-title":"J. Cancer Res. Ther."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1186\/1758-3284-1-10","article-title":"Correlation of histopathological diagnosis with habits and clinical findings in oral submucous fibrosis","volume":"1","author":"Pandya","year":"2009","journal-title":"Head Neck Oncol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"786","DOI":"10.1111\/j.1369-1600.2011.00331.x","article-title":"Monoamine oxidase A variants are associated with heavy betel quid use","volume":"17","author":"Chen","year":"2011","journal-title":"Addict. Biol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0091-3057(99)00179-3","article-title":"Behavioral and biochemical studies of dichloromethane fraction from the Areca catechu nut","volume":"65","author":"Dar","year":"2000","journal-title":"Pharmacol. Biochem. Behav."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"14065","DOI":"10.1073\/pnas.93.24.14065","article-title":"Brain monoamine oxidase A inhibition in cigarette smokers","volume":"93","author":"Fowler","year":"1996","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_40","first-page":"493","article-title":"Inhibitory effect of acetylcholine on monoamine oxidase A and B activity in different parts of rat brain","volume":"58","author":"Osman","year":"2008","journal-title":"Arzneim. Forsch."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1037\/0022-006X.75.1.85","article-title":"Fluoxetine, smoking, and history of major depression: A randomized controlled trial","volume":"75","author":"Spring","year":"2007","journal-title":"J. Consult. Clin. Psychol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1016\/S0091-3057(01)00715-8","article-title":"Nicotinic\u2013serotonergic interactions in brain and behaviour","volume":"71","author":"Seth","year":"2002","journal-title":"Pharmacol. Biochem. Behav."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1378\/chest.122.2.403","article-title":"Stopping smoking: A prospective, randomized, double-blind study comparing nortriptyline to placebo","volume":"122","author":"Younes","year":"2002","journal-title":"Chest"},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Hughes, J.R., Stead, L.F., Hartmann-Boyce, J., Cahill, K., and Lancaster, T. (2014). Antidepressants for smoking cessation. Cochrane Database Syst. Rev., CD000031.","DOI":"10.1002\/14651858.CD000031.pub4"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"406","DOI":"10.1111\/jop.12581","article-title":"Oral submucous fibrosis: An update on current theories of pathogenesis","volume":"46","author":"Arakeri","year":"2017","journal-title":"J. Oral Pathol. Med."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1111\/j.1600-0714.2007.00579.x","article-title":"Natural history of potentially malignant oral lesions and conditions: An overview of the literature","volume":"37","author":"Napier","year":"2008","journal-title":"J. Oral Pathol. Med."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"e18672","DOI":"10.1097\/MD.0000000000018672","article-title":"Antidepressant-induced reduction in betel-quid use in patients with depression: A pioneer clinical study","volume":"99","author":"Hung","year":"2020","journal-title":"Medicine"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"e125","DOI":"10.1017\/S2045796020000384","article-title":"Effect of antidepressants for cessation therapy in betel-quid use disorder: A randomised, double-blind, placebo-controlled trial","volume":"29","author":"Hung","year":"2020","journal-title":"Epidemiol. Psychiatr. Sci."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"514","DOI":"10.1016\/S0140-6736(64)92907-1","article-title":"Release of a Kinin Peptide in the Carcinoid Syndrome","volume":"1","author":"Oates","year":"1964","journal-title":"Lancet"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"961","DOI":"10.1084\/jem.20101629","article-title":"Platelet-derived serotonin links vascular disease and tissue fibrosis","volume":"208","author":"Dees","year":"2011","journal-title":"J. Exp. Med."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"2836","DOI":"10.1161\/01.CIR.102.23.2836","article-title":"Evidence for Possible Involvement of 5-HT 2B Receptors in the Cardiac Valvulopathy Associated with Fenfluramine and Other Serotonergic Medications","volume":"102","author":"Rothman","year":"2000","journal-title":"Circulation"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1316","DOI":"10.1056\/NEJM199804303381816","article-title":"Endocardial Fibrosis Associated with Fenfluramine\u2013Phentermine","volume":"338","author":"Fowles","year":"1998","journal-title":"N. Engl. J. Med."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"826","DOI":"10.1016\/S1474-4422(07)70218-1","article-title":"Fibrotic heart-valve reactions to dopamine-agonist treatment in Parkinson\u2019s disease","volume":"6","author":"Antonini","year":"2007","journal-title":"Lancet Neurol."},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Alsamman, S., Christenson, S.A., Yu, A., Ayad, N.M.E., Mooring, M.S., Segal, J.M., Hu, J.K., Schaub, J.R., Ho, S.S., and Rao, V. (2020). Targeting acid ceramidase inhibits YAP\/TAZ signaling to reduce fibrosis in mice. Sci. Transl. Med., 12.","DOI":"10.1126\/scitranslmed.aay8798"}],"container-title":["Journal of Personalized Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-4426\/11\/7\/591\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:21:38Z","timestamp":1760163698000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-4426\/11\/7\/591"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,6,23]]},"references-count":54,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2021,7]]}},"alternative-id":["jpm11070591"],"URL":"https:\/\/doi.org\/10.3390\/jpm11070591","relation":{},"ISSN":["2075-4426"],"issn-type":[{"value":"2075-4426","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,6,23]]}}}