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The etiology of AD is multifactorial, involving a complex interplay of genetic, environmental, and physiological factors, including the aggregation of amyloid-\u03b2 (A\u03b2) and oxidative stress (OS). The role of OS in AD pathogenesis is of particular significance, given that an imbalance between oxidants and antioxidants promotes cellular damage, exacerbates A\u03b2 deposition, and leads to cognitive deterioration. Despite extensive research, current therapeutic strategies have largely failed, likely due to the use of single-target drugs unable to halt the multifactorial progression of the disease. In this study, we investigated the synergistic therapeutic effect of plant-derived bioactive compounds Withanone, Apigenin, Bacoside A, Baicalin, and Thymoquinone in combination with N,N-Dimethyltryptamine (NN-DMT), a psychedelic molecule. We used a transgenic Caenorhabditis elegans model to assess the behavioral and molecular outcomes following compound exposure. Motility assays, thioflavin S staining, and survival assays under oxidative stress were employed to evaluate the treatment efficacy. The results of the behavioral and molecular analyses indicated that the combination therapy exhibited a higher efficacy than the monotherapies, leading to a significant reduction in age-related motility defects in the AD model. Furthermore, the combination treatment substantially reduced A\u03b2 plaque burden, enhanced survival following OS insult, and demonstrated a synergistic effect in mitigating AD-related hallmarks. Taken together, these findings support the potential of combining NN-DMT with specific bioactive compounds as a promising multi-target therapeutic approach for AD.<\/jats:p>","DOI":"10.3390\/cells14120934","type":"journal-article","created":{"date-parts":[[2025,6,19]],"date-time":"2025-06-19T09:57:48Z","timestamp":1750327068000},"page":"934","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Investigating the Synergistic Neuroprotective Effects of Plant-Derived Antioxidants and the Psychedelic N,N-Dimethyltryptamine in Alzheimer\u2019s Disease Therapy"],"prefix":"10.3390","volume":"14","author":[{"given":"J\u00falia","family":"Jarne-Ferrer","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Therapeutic Chemistry, Institut de Neuroci\u00e8ncies, Universitat de Barcelona, Avda. Joan XXIII, 27, 08028 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3095-4254","authenticated-orcid":false,"given":"Merc\u00e8","family":"Pall\u00e0s","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Therapeutic Chemistry, Institut de Neuroci\u00e8ncies, Universitat de Barcelona, Avda. Joan XXIII, 27, 08028 Barcelona, Spain"},{"name":"Spanish Biomedical Research Center in Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5424-9130","authenticated-orcid":false,"given":"Christian","family":"Gri\u00f1\u00e1n-Ferr\u00e9","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Therapeutic Chemistry, Institut de Neuroci\u00e8ncies, Universitat de Barcelona, Avda. Joan XXIII, 27, 08028 Barcelona, Spain"},{"name":"Spanish Biomedical Research Center in Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9890-753X","authenticated-orcid":false,"given":"Aina","family":"Bellver-Sanchis","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Therapeutic Chemistry, Institut de Neuroci\u00e8ncies, Universitat de Barcelona, Avda. Joan XXIII, 27, 08028 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,6,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1016\/S0140-6736(15)01124-1","article-title":"Alzheimer\u2019s Disease","volume":"388","author":"Scheltens","year":"2016","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41572-021-00269-y","article-title":"Alzheimer Disease","volume":"7","author":"Knopman","year":"2021","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Breijyeh, Z., and Karaman, R. (2020). Comprehensive Review on Alzheimer\u2019s Disease: Causes and Treatment. 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