To the best of our knowledge, this is the first systematic review to summarise the evidence and assess the quality of the studies on the activity or toxicity of cannabis against Plasmodium sp. The findings suggest that cannabis and its derivatives exhibit activity against P. falciparum in vitro, with THC demonstrating high activity and CBD showing mild activity, indicating a potential antimalarial effect. Additionally, they have shown efficacy in reducing parasitemia and improving disease tolerance in animal models infected with P. berghei or P. falciparum. However, the toxicity of these compounds has not been thoroughly investigated. Moreover, most studies present an unknown or unclear risk of bias due to insufficient methodological details. Therefore, further well‐designed research is needed to confirm these findings.

This review identified a greater number of in vitro studies, which was expected, as these studies are less complex, more cost‐effective and easier to conduct than in vivo studies [28]. Future perspectives include the need to increase the number of in vivo studies to validate the promising results of the in vitro studies. Additionally, the development of more advanced experimental models, such as organoids and 3D culture systems, could help reduce the reliance on animal models [29].

Almost all in vitro studies were conducted in North America, specifically in the United States. All studies were funded by national research centers and drug abuse agencies, and the availability of research resources and infrastructure may help explain this. On the other hand, in vivo studies were mainly conducted in Africa and South America, where malaria is endemic [30, 31], which may explain the emphasis on animal models for testing antimalarial interventions. Conducting research in these regions is essential to ensuring that the findings apply to the populations most affected by the infection, particularly as they progress to human studies.

The cannabis plant comprises multiple species, with the three primary ones being C. sativa , C. indica and C. ruderalis [32]. Additionally, it contains various active compounds that can be classified as cannabinoids (e.g., THC and CBD) and non‐cannabinoids (e.g., terpenes and flavonoids) [32]. In the explored studies on malaria, C. sativa and their isolated cannabinoid compounds were the most studied. Although this review focused on cannabis‐derived compounds, other plant‐derived compounds exhibit antimalarial activity, such as machaeriol B isolated from Machaerium multiflorum, which demonstrated in vitro antimalarial activity against the P. falciparum W2 clone [33].

Studies demonstrated that THC [22, 23] presents high activity against P. falciparum and THC's mechanism of action does not appear to involve hemozoin formation inhibition, as it does for chloroquine [22]. Additionally, the included studies in this review reported the potential antimalarial effects of cannabis‐derived compounds through various mechanisms, primarily by modulating the immune response and directly inhibiting parasite growth. A previous study indicated a reduction of pro‐inflammatory cytokines by more than 90% in animal model tests [34]. Moreover, another study that performed a molecular docking analysis revealed that cannabis compounds effectively bind to Plasmodium sp. proteins, disrupting essential cellular functions [13]. The potential of cannabis‐derived compounds as antimalarial agents warrants further investigation to fully understand their mechanisms of action and therapeutic applicability.

There is a lack of further data on the toxicity of cannabis‐derived compounds in the included studies. Despite their therapeutic effects, their use may be associated with toxicities, particularly due to THC, including psychological events (anxiety, paranoia and psychosis), as well as neurological, gastrointestinal and cardiovascular disorders [35].

The assessment of the methodological quality of the studies revealed that, generally, the in vitro studies had an unknown risk of bias. Exceptions, such as temperature control and the absence of industry sponsorship, were classified as moderate and low risk, respectively. Industry funding of biomedical research can lead to biased study outcomes [36], making the absence of funding in these studies further strengthen the reliability of their results. On the other hand, the in vivo studies showed variability in risk of bias, with selective reporting of outcomes classified as high risk, and randomization, blinding of investigators and handling of incomplete data classified as unclear risk across all studies. These methodological limitations highlight the need for more rigorous standards in the planning of future studies to ensure the reliability and validity of the results.

This systematic review has several strengths, including the use of four databases and grey literature, which underscores the robustness of the comprehensive search. Moreover, the methodological quality of the studies ensured a thorough and rigorous reporting assessment of the reviewed literature. However, some limitations should be acknowledged. Articles were missed because they were not indexed in the databases searched or written in non‐Roman characters. Finally, the studies included in this review exhibited meaningful heterogeneity, which prevented a meta‐analysis.

Future research should prioritize well‐designed preclinical studies to clarify the mechanisms of action of cannabis‐derived compounds against Plasmodium sp. In addition, standardized methods for evaluating efficacy and toxicity are urgently needed, as current evidence remains limited and heterogeneous. Expanding investigations into diverse compound formulations, dosage regimens and their pharmacokinetic, pharmacodynamic and pharmacogenomic profiles may provide critical insights into therapeutic potential. Ultimately, rigorous studies addressing safety and long‐term effects are needed before these compounds can be considered as candidates for antimalarial therapy.