cannabinoids Anandamide and CBD have shown potential medical use against Malaria. Anandamide reduced parasitaemia and increased the survival rate of infected mice through the acceleration of eryptosis of infected erythrocytes (Bobbala et al., 2010).

 In a different study, CBD also increased the survival rate of infected mice compared to non-treated group (Campos et al., 2015). Regarding the neurological symptoms of Malaria, CBD combined with the anti-malarial drug Artesunate, prevents the long term cognitive deficits caused by the disease in mice (Campos et al., 2015). The mechanism underlying these effects are associated to neuroprotective and anti-inflammatory properties of CBD (Campos et al., 2015).

One study found that a minor cannabinoïd, 4-terpenyl cannabinolate, derived from cannabinol/CBN, is antimicrobial and shows antimalarial activity against the P. falciparum parasite with an IC50 of 2.7 μg/ml for clone D6 and 2.4 μg/ml for clone W2 (Sa et al., 2008).

Exposure of erythrocytes to 2.5 μM Anandamide induces erythrocytosis (Bentzen and Lang, 2007). Although plasma Anandamide concentrations are typically around 4 nM in healthy people, it is estimated that in diseased people Anandamide can locally rise up to 60 μM. Interestingly, erythocytosis was inhibited dose-dependently by N-acetylcystein/paracetamol, acetylsalicylic acid/aspirin and iboprofen suggesting reactive oxygen species are involved in the erythrocytic process.

In mice, 5 mg/kg subcutaneous Anandamide reduced parasitemia from ±37% to ±24% and increased 21-day survival from 0% to 67% of mice (Bobbala et al., 2010).

Interestingly, mice genetically deficient for the CB2 receptor show 50% survival and reduced clinical features in a 21-day experimental cerebral Malaria challenge, compared to 0% survival of wildtype mice (Alferink et al., 2016). Pharmacological blockade of CB2 also increased survival. Parasitemia was similar in both groups suggesting survival was not promoted through inhibition of parasitemia. Chemokine CCL17, however, was essential for enhanced survival (Alferink et al., 2016).

THC has a bi-phasic effect on inflammatory processes; in nanomolar concentrations (3 nM), THC inhibits pro-inflammatory cytokines like TNFα, IFNγ,  IL-6 and IL-8 and thus reduces inflammation. At micromolar concentrations (3 μM), THC is pro-inflammatory (Berdyshev et al., 1997; Svensson et al., 2010).

Dendritic cells are part of the innate immune system where they migrate from peripheral tissue to draining lymph nodes. 2AG promotes dendritic cell migration via CB2 and may therefore boost the innate immune response to plasmodial Malaria sporozoites (Svensson et al., 2010).

At the skin stage, a boost of the immune system could be beneficial whereas at the blood stage of Malaria, suppression of the immune system could be beneficial to suppress malarial fever. Theoretically, application of THC to the skin would lead to pro-inflammatory high skin concentrations and anti-inflammatory low systemic concentrations of THC, which should be optimal to treat Malaria.

Literature:

Alferink, J., Specht, S., Arends, H., Schumak, B., Schmidt, K., Ruland, C., Lundt, R., Kemter, A., Dlugos, A., Kuepper, J.M., et al. (2016). cannabinoid receptor 2 modulates susceptibility to experimental cerebral Malaria through a CCL17-dependent mechanism. J. Biol. Chem.

Bentzen, P.J., and Lang, F. (2007). Effect of Anandamide on erythrocyte survival. Cell. Physiol. Biochem. Int. J. Exp. Cell. Physiol. Biochem. Pharmacol. 20, 1033–1042.

Berdyshev, E.V., Boichot, E., Germain, N., Allain, N., Anger, J.P., and Lagente, V. (1997). Influence of fatty acid ethanolamides and delta9-tetrahydrocannabinol on cytokine and arachidonate release by mononuclear cells. Eur. J. Pharmacol. 330, 231–240.

Bobbala, D., Alesutan, I., Föller, M., Huber, S.M., and Lang, F. (2010). Effect of Anandamide in Plasmodium Berghei-infected mice. Cell. Physiol. Biochem. Int. J. Exp. Cell. Physiol. Biochem. Pharmacol. 26, 355–362.

Campos, A.C., Brant, F., Miranda, A.S., Machado, F.S., and Teixeira, A.L. (2015). Cannabidiol increases survival and promotes rescue of cognitive function in a murine model of cerebral Malaria. Neuroscience 289, 166–180.

Sa, A., Sa, R., D, S., Mm, R., F, Z., Rr, M., Yt, X., E, V., Rc, S., Vt, K., et al. (2008). cannabinoid ester constituents from high-potency Cannabis sativa., cannabinoid Ester Constituents from High-Potency Cannabis sativa. J. Nat. Prod. J. Nat. Prod. 71, 71, 536, 536–542.

Svensson, M., Chen, P., and Hammarfjord, O. (2010). Dendritic Cell Regulation by cannabinoid-Based Drugs. Pharmaceuticals 3, 2733–2750.