Toxicological Profiles of African Medicinal Plants Used in Trypanosomiasis Therapy: Mechanisms, Safety, and Knowledge Gaps

African medicinal plants have long played a central role in the management of trypanosomiasis, a neglected tropical disease that continues to impose severe health and socioeconomic burdens across sub-Saharan Africa. Traditional therapies derived from roots, barks, leaves, and seeds are widely used due to their accessibility, affordability, and ethnopharmacological relevance, particularly in regions with limited access to conventional chemotherapeutics. While numerous plant species have demonstrated antitrypanosomal activity through mechanisms such as parasite membrane disruption, oxidative stress induction, and inhibition of key metabolic enzymes, far less attention has been devoted to their toxicological profiles and safety margins. Understanding toxicity is critical, as bioactive phytochemicals including alkaloids, flavonoids, terpenoids, and phenolic compounds can exert off-target effects on host tissues. Acute, subacute, and chronic toxicity studies have revealed variable effects ranging from hepatotoxicity, nephrotoxicity, and hematological alterations to neurobehavioral changes, depending on plant species, extraction methods, dosage, and duration of exposure. Additionally, mechanisms of toxicity often overlap with therapeutic pathways, complicating the risk–benefit balance of plant-based interventions. Interactions with conventional antitrypanosomal drugs further raise concerns regarding synergistic toxicity or metabolic interference. This article critically reviews the toxicological profiles of African medicinal plants used in trypanosomiasis therapy, emphasizing molecular and cellular mechanisms of toxicity, safety evaluation methodologies, and existing experimental evidence. It also identifies major knowledge gaps, including limited standardized toxicity assessments, insufficient long-term and reproductive toxicity data, and the lack of translational studies linking preclinical findings to human safety. Addressing these gaps is essential for integrating traditional remedies into evidence-based treatment frameworks and for guiding the development of safer, plant-derived antitrypanosomal agents that align with global health and regulatory standards.