Trihexyphenidyl Alters Its Host’s Metabolism, Neurobehavioral Patterns, and Gut Microbiome Feedback Loop—The Modulating Role of Anacyclus pyrethrum

Trihexyphenidyl (THP)—a synthetic anticholinergic medication used to manage parkinsonism and extrapyramidal symptoms—has gained significant clinical recognition. However, there is a critical gap in understanding its withdrawal effects. This study investigates the intricate interplay between gut microbiota and oxidative stress during THP withdrawal. Furthermore, it explores the therapeutic potential of Anacyclus pyrethrum (AEAP) for alleviating the associated adverse effects. This comprehensive research combines behavioral tests, biochemical analysis, gut microbiome assessment utilizing matrix-assisted laser desorption ionization–time of flight mass spectrometry (MALDI-TOF MS), and oxidative stress measures. The results reveal that the chronic administration of THP leads to severe withdrawal syndrome, marked by heightened anxiety, depressive-like behaviors, increased cortisol levels, elevated oxidative stress, and gut dysbiosis. However, the administration of AEAP alongside THP shows a significant capacity to mitigate these deleterious effects. Co-treatment and post-treatment with AEAP increased bacterial density and diversity, promoting the proliferation of beneficial bacteria associated with improved gut health. Furthermore, AEAP administration reduced cortisol levels and exhibited potent antioxidant properties, effectively countering the THP-induced oxidative damage. This study highlights the withdrawal effects of THP and underscores the therapeutic potential of AEAP for managing these symptoms. The findings reveal its promising effects in alleviating behavioral and biochemical impairments, reducing oxidative stress, and restoring gut microbiota, which could significantly impact the clinical management of THP withdrawal and potentially extend to other substance withdrawal scenarios.