Potential of Myristica fragrans and Phyllanthus acidus functional candies as antioxidant-based therapeutic agents for anxiety disorders: A comprehensive review
DOI:
https://doi.org/10.61511/bioculture.v3i1.2025.1798Keywords:
anxiety disorders, Myristica fragrans, neuroprotection, Phyllanthus acidus, serotonergic modulationAbstract
Background: Anxiety disorders represent a growing global mental health concern, affecting millions worldwide and significantly impacting quality of life. Conventional treatments, including Selective Serotonin Reuptake Inhibitors (SSRIs) and benzodiazepines, present challenges such as adverse effects, dependency risks, and limited accessibility. As a result, there is increasing interest in natural anxiolytic agents such as Myristica fragrans (nutmeg) and Phyllanthus acidus (otaheite gooseberry), which exhibit neuroprotective and antioxidant properties. Methods: This study employs a comprehensive literature review methodology, systematically analyzing experimental and clinical studies from Scopus, PubMed, and Google Scholar. Using the Critical Appraisal Skills Programme (CASP), studies were selected based on rigorous inclusion criteria, emphasizing pharmacological mechanisms, efficacy in anxiety management, and safety profiles. The primary focus was on the modulation of serotonergic, GABAergic, and hypothalamic-pituitary-adrenal (HPA) axis pathways by nutmeg and otaheite gooseberry extracts. Findings: The review identified eight key studies demonstrating that myristicin from Myristica fragrans enhances serotonin levels through monoamine oxidase inhibition while modulating GABAergic activity, resulting in significant reductions in anxiety-related behaviors (p < 0.05). Flavonoids and vitamin C in Phyllanthus acidus exhibited neuroprotective effects by reducing oxidative stress and lowering cortisol levels by approximately 20%. A synergistic combination of these extracts showed greater efficacy in reducing anxiety symptoms compared to individual extracts alone. Conclusion: Nutmeg and otaheite gooseberry extracts present a promising natural alternative for anxiety management, with evidence supporting their effectiveness in neurotransmitter modulation and oxidative stress reduction. However, concerns regarding high-dose toxicity, particularly the neurotoxic effects of myristicin and gastrointestinal risks of flavonoids, necessitate further large-scale clinical trials. Novelty/Originality of this Article: This study is the first to provide a systematic evaluation of the combined effects of Myristica fragrans and Phyllanthus acidus as a potential functional lozenge for anxiety relief. The findings contribute to advancing research on natural anxiolytic therapies with improved safety and efficacy.
References
Abba, S., Musa, S. A., Agbon, A., Oladele, S., Momoh, I. J., Ogbonna, E., & Omotosho, O. D. (2024). Oral administration of ethanol extract of Myristica fragrans elicited hyperactivity, anxiety and reduced dopamine level in rats: Ethanol seed extract of Myristica fragrans and anxiety. Babcock University Medical Journal, 7(2), 33–41. https://doi.org/10.38029/babcockuniv.med.j..v7i2.399
Alonso-Castro, A. J., Ruiz-Padilla, A. J., Ortiz-Cortes, M., Carranza, E., Ramírez-Morales, M. A., Escutia-Gutiérrez, R., ... & Zapata-Morales, J. R. (2021). Self-treatment and adverse reactions with herbal products for treating symptoms associated with anxiety and depression in adults from the central-western region of Mexico during the Covid-19 pandemic. Journal of ethnopharmacology, 272, 113952. https://doi.org/10.1016/j.jep.2021.113952
Azis Ikhsanudin, L. L., & Rais, D. D. (2021). Anti-inflammatory activity of Indonesian nutmeg seeds (Myristica fragrans Houtt): A topical gel formulation. Int. J. Public Health, 1(0), 3. https://doi.org/10.11591/ijphs.v10i3.20921
Aziz, L., & Treur, J. (2024). Higher-order adaptive dynamical system modelling of epigenetic mechanisms in infant temperament shaped by prenatal maternal stress. Cognitive Systems Research, 101315. https://doi.org/10.1016/j.cogsys.2024.101315
Ben Lagha, O. M., Zakaria, M. P., Ismail, I. S., Nor-Khaizura, M. A. R., & Rukayadi, Y. (2020). Antibacterial activity of nutmeg (Myristica fragrans Houtt.) extract against foodborne pathogens on raw beef during chilled and frozen storage. Food Research, 4(2), 380-388. https://doi.org/10.26656/fr.2017.4(2).280
Bigalke, J. A., & Carter, J. R. (2022). Sympathetic neural control in humans with anxiety‐related disorders. Comprehensive Physiology, 12(1), 3085–3117. https://doi.org/10.1002/j.2040-4603.2022.tb00206.x
Cao, H., Wu, Y., Yin, H., Sun, Y., Yuan, H., & Tao, M. (2024). Global trends in the incidence of anxiety disorders from 1990 to 2019: Joinpoint and age-period-cohort analysis study. JMIR Public Health and Surveillance, 10(1), e49609. https://doi.org/ https://doi.org/10.2196/49609
Dai, W., Feng, K., Sun, X., Xu, L., Wu, S., Rahmand, K., ... & Han, T. (2022). Natural products for the treatment of stress-induced depression: Pharmacology, mechanism and traditional use. Journal of Ethnopharmacology, 285, 114692. https://doi.org/10.1016/j.jep.2021.114692
De Santa, F., Strimpakos, G., Marchetti, N., Gargari, G., Torcinaro, A., Arioli, S., ... & Farioli-Vecchioli, S. (2024). Effect of a multi-strain probiotic mixture consumption on anxiety and depression symptoms induced in adult mice by postnatal maternal separation. Microbiome, 12(1), 29. https://doi.org/10.1186/s40168-024-01752-w
Farooq, U., Khan, T., Shah, S. A., Hossain, M. S., Ali, Y., Ullah, R., ... & Capasso, R. (2021). Isolation, characterization and neuroprotective activity of folecitin: an in vivo study. Life, 11(8), 825. https://doi.org/10.3390/life11080825
Flückiger, C., Mahlke, F., John, G., Daus, P., Zinbarg, R. E., Allemand, M., & Schürmann-Vengels, J. (2025). How strongly are trait positive and negative affectivity associated with anxiety symptoms? A multilevel meta-analysis of cross-sectional studies in anxiety disorders. Journal of Anxiety Disorders, 109, 102956. https://doi.org/10.1016/j.janxdis.2024.102956
Grace, C., Heinrichs, M., Koval, P., Gorelik, A., von Dawans, B., Terrett, G., ... & Labuschagne, I. (2022). Concordance in salivary cortisol and subjective anxiety to the trier social stress test in social anxiety disorder. Biological psychology, 175, 108444. https://doi.org/10.1016/j.biopsycho.2022.108444
Hennekam, S., Richard, S. & Grima, F. (2020). Coping with mental health conditions at work and its impact on self-perceived job performance. Employee Relations, 42(3), 626-645. https://doi.org/10.1108/ER-05-2019-0211
Imran, M., Shah, A. H., Ullah, N., Alomar, S. Y., Rehman, A., Rehman, N. U., ... & Amin, A. (2024). Integrated computational analysis, in vitro, in vivo investigation on Myristica fragrans Houtt. essential oils for potential anti rheumatic activities. Journal of King Saud University-Science, 36(5), 103177. https://doi.org/10.1016/j.jksus.2024.103177
Iwata, N., Kobayashi, D., Kawashiri, T., Kubota, T., Kawano, K., Yamamuro, Y., Miyagi, A., Deguchi, Y., Chijimatsu, T., & Shimazoe, T. (2022). Mechanisms and safety of antidepressant-like effect of nutmeg in mice. Biological and Pharmaceutical Bulletin, 45(6), 738–742. Farooq, U., Khan, T., Shah, S. A., Hossain, M. S., Ali, Y., Ullah, R., ... & Capasso, R. (2021). Isolation, characterization and neuroprotective activity of folecitin: an in vivo study. Life, 11(8), 825. https://doi.org/10.3390/life11080825
Liu, M., Zhang, Z., Qin, C., Lv, B., Mo, S., Lan, T., & Gao, B. (2022). Effects of 4-week tangeretin supplementation on cortisol stress response induced by high-intensity resistance exercise: A randomized controlled trial. Frontiers in Physiology, 13, 886254. https://doi.org/10.3389/fphys.2022.886254
Kim, K. J., Cho, M. H., Lee, S., Ha, J. H., Chu, S. J., Chung, G., ... & No, K. T. (2025). Comparative analysis of antioxidant flavonoids in wild and cultivated soybean using integrated ion-filtering strategy-combined LC− HRMSn analysis. Food Bioscience, 105817. https://doi.org/10.1016/j.fbio.2024.105817
Kim, M., Kim, Y., Lee, H. W., Kim, K. M., Kim, S., & Oh, S. (2024). The Improvement in Sleep Quality by Zizyphi Semen in Rodent Models Through GABAergic Transmission Regulation. Nutrients, 16(24), 4266. https://doi.org/10.3390/nu16244266
Khairan, K., Faradilla, M., & Ginting, B. (2024). Isolation of Nutmeg Essential Oil (Myristica fragrans houtt) From Aceh Indonesia and Their Antioxidant and Antibacterial Activities. Indonesian Journal of Pharmacy, 35(3), 425–436. https://doi.org/10.22146/ijp.8399
Liu, X., Yang, F., Huang, N., Zhang, S., & Guo, J. (2024). Thirty-year trends of anxiety disorders among adolescents based on the 2019 Global Burden of Disease Study. General Psychiatry, 37(2), e101288. https://doi.org/10.1136/gpsych-2023-101288
Nguyen, L. T. H., Nguyen, N. P. K., Tran, K. N., Shin, H. M., & Yang, I. J. (2024). Intranasal administration of the essential oil from Perillae Folium ameliorates social defeat stress-induced behavioral impairments in mice. Journal of Ethnopharmacology, 324, 117775. https://doi.org/10.1016/j.jep.2024.117775
Okiki, P. A., Nwobi, C. P., Akpor, O. B., Adewole, E., & Agbana, R. D. (2023). Assessment of nutritional and medicinal properties of nutmeg. Scientific African, 19, e01548. https://doi.org/10.1016/j.sciaf.2023.e01548
Prottay, A. A. S., Ripu, T. R., Sarwar, M. N., Rahman, T., Ahmmed, M. S., Bappi, M. H., ... & Islam, M. T. (2025). Anxiogenic-like effects of coumarin, possibly through the GABAkine interaction pathway: Animal studies with in silico approaches. Behavioural Brain Research, 480, 115392. https://doi.org/10.1016/j.bbr.2024.115392
Rodríguez-Landa, J. F., German-Ponciano, L. J., Puga-Olguín, A., & Olmos-Vázquez, O. J. (2022). Pharmacological, neurochemical, and behavioral mechanisms underlying the anxiolytic- and antidepressant-like effects of flavonoid chrysin. Molecules, 27(11), 3551. https://doi.org/10.3390/molecules27113551
Saeed A, et al. (2022). Effects of curcumin on anxiety: A systematic review and meta-analysis. Phytother Res, 36(5):2100-2112. https://doi.org/10.1002/ptr.7480
Sah, A., & Singewald, N. (2025). The (neuro) inflammatory system in anxiety disorders and PTSD: Potential treatment targets. Pharmacology & Therapeutics, 108825. https://doi.org/10.1016/j.pharmthera.2025.108825
Silva dos Santos, J., Goncalves Cirino, J. P., de Oliveira Carvalho, P., & Ortega, M. M. (2021). The pharmacological action of kaempferol in central nervous system diseases: A review. Frontiers in Pharmacology, 11, 565700. https://doi.org/10.3389/fphar.2020.565700
Seneme, E. F., dos Santos, D. C., Silva, E. M. R., Franco, Y. E. M., & Longato, G. B. (2021). Pharmacological and Therapeutic Potential of Myristicin: A Literature Review. Molecules, 26(19), 5914. https://doi.org/10.3390/molecules26195914
Shafi, Z., Pandey, V. K., Habiba, U., Singh, R., Shahid, M., Rustagi, S., ... & Shaikh, A. M. (2025). Exploring the food safety and preservation landscape of Myristica fragrans (L.) against foodborne pathogen: A review of current knowledge. Journal of Agriculture and Food Research, 101639. https://doi.org/10.1016/j.jafr.2025.101639
Taheri, Y., Suleria, H. A. R., Martins, N., Sytar, O., Beyatli, A., Yeskaliyeva, B., ... & Sharifi-Rad, J. (2020). Myricetin bioactive effects: Moving from preclinical evidence to potential clinical applications. BMC Complementary Medicine and Therapies, 20, 1–14. https://doi.org/10.1186/s12906-020-03033-z
Tan, S. P., Tan, E. N. Y., Lim, Q. Y., & Nafiah, M. A. (2020). Phyllanthus acidus (L.) Skeels: A review of its traditional uses, phytochemistry, and pharmacological properties. Journal of Ethnopharmacology, 253, 112610. https://doi.org/10.1016/j.jep.2020.112610
Takeichi, M., & Sato, T. (1999). Studies on the psychosomatic functioning of ill-health according to eastern and Western medicine 3. Two treatment methods using kampo medication for stress-related and lifestyle disease. The American journal of Chinese medicine, 27(03n04), 315-329. https://doi.org/10.1142/s0192415x99000367
Wang, D., Liu, Y., Tang, K., He, N., & Özcan, M. M. (2024). Antioxidant effect and acaricidal potential against camel tick, Hyalomma dromedarii of the essential oil hydrodistilled from Myristica fragrans Houtt.(Nutmeg). Veterinary Parasitology, 332, 110339. https://doi.org/10.1016/j.vetpar.2024.110339
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Copyright (c) 2025 Anindita Azkia Fauzana, Efada Aini Ayu Maheswari, Jennifer Angeline, Azizah Bonitha Zahrah Santoso, Reny I’tishom
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