BACKGROUND: Alpha-synuclein (α-syn) aggregation products may cause neural injury and several neurodegenerative disorders (NDs) known as α-synucleinopathies. Alkaloids are secondary metabolites present in a variety of plant species and may positively affect human health, particularly α-synucleinopathy-associated NDs. AIM: To summarize the latest scientific data on the inhibitory properties of alkaloids in α- synucleinopathies, especially in Parkinson's disease. METHODS: Literature search was performed using web-based databases including Web of Science, PubMed, and Scopus up to January 2024, in the English language. RESULTS: Harmala alkaloids, caffein, lycorine, piperin, acetylcorynoline, berberin, papaverine, squalamine, trodusquemine and nicotin have been found to be the most active natural alkaloids against synucleinopathy. The underlying mechanisms that contribute to this effect would be the inhibition of α-syn aggregation
elimination of formed aggregates
improvement in autophagy activation
promotion of the activity and expression of antioxidative enzymes
and prevention of oxidative injury and apoptosis in dopaminergic neurons. CONCLUSION: The findings of the present study highlight the inhibitory activities of alkaloids against synucleinopathy. However, no clinical data supports the reported activities in humans, which calls attention to the need for conducting clinical trials to elucidate the efficacy, safety, proper dosage, unwanted effects and pharmacokinetics aspects of alkaloids in humans.