Poison Frogs: A Hidden Pharmacy

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Close-up of a poison frog at Mashpi Lodge, a symbol of Ecuador's unique biodiversity.

Thanks to a chance encounter in the 1970s, John Daly and his collaborators found in the secretion of skin of an Ecuadorian poison frog (Epipedobates anthonyi, the epibatidine nurse frog, or phantasmal poison frog) an alkaloid called epibatidine (Gillis, 2002). This is a toxic compound that works as a defence mechanism for poison frogs, and although its effects on ingestion vary from harmless to lethal, depending on the dose, in the majority of cases, their bitter taste alone is enough to generate an adverse effect in predators.

Uncovering the Secrets of Poison Frogs: The Discovery of Epibatidine

Evolutionary relationships among some poison frogs from the dendrobatidae family and other organisms
Figure 1.- Evolutionary relationships among some poison frogs from the dendrobatidae family and other organisms: The dark lines group together the dedrobatidae species, the yellow lines show the species that use alkaloids for defence, while the stars indicate in which species the presence of epibatidine has been detected. Taken and summarised from the article Tarvin et al. (2017). This chart also demonstrates that the toxic species (with the presence of alkaloids) are eye-catching and brightly coloured.

To complete their defence, as well as the alkaloids in their skin, poison frogs also are brightly and eye-catchingly coloured (see figure 1). This adaptation is known as aposematism. Both the chemical defence and bright colours evolved together to be able to send a clear message to predators: “Don’t eat me, I’m toxic!” But this defence mechanism would not have been possible if at the same time the poison frog hadn’t developed mechanisms to not intoxicate itself with its own venom.

While other organisms have opted to isolate these toxic compounds in different compartments or to detoxify themselves metabolically, poison frogs have become immune to their venom by desensitising the site that is the object of the toxin. That means that, in poison frogs, epibatidine, which affects the nervous system of its predators, blocking their pain receptors, does not affect them. For this not to happen, these frogs have managed to change the molecular objective of the toxin, developing replacement amino acids that prevent the toxin from uniting with the nervous receptors (Tarvin et al., 2017).

After many studies on the effects of epibatidine on the nervous system, it was found that this compound acts directly on the nicotine-acetylcholine receptors blocking the nervous impulse. For this reason, this alkaloid can act as a powerful painkiller, 200 times stronger than morphine and without causing adverse effects like addiction, because unlike morphine, it does not act on opioid receptors (Spande et al., 1992). Epibatidine has inspired innumerate innovations in the field of pharmacology, even though due to its toxicity its pharmaceutic development as a painkiller has been impossible (Tarvin, 2017).

A curious fact that emerged from the studies on toxins on poison frogs was that on collecting certain individuals for taking samples of their skin, it was found that despite belonging to the same species, they did not all have the same alkaloid in their skin. Thanks to this, it was deduced that these frogs acquire their toxicity from the food that they ingest, principally ants and other insects that live among the layer of dead leaves and in the case of the dedrobatidae, there are 800 different types of lipophilic alkaloids that come from their diet (Darst et al. 2005, Daly et al., 2005). Sadly, in the concrete case of epibatidine, the direct source of this alkaloid still has not been detected (Angerer 2011).

Epibatidine is found in some species of venomous frogs in the Neotropics, in the following types: Ameerega, Dendrobates (Oophaga) and Epipedobates belonging to the Dendrobatidae family (Tarvin, 2017). The latter is the type that interests us most, given that Epipedobates boulengeri (Boulenger’s poison frog) is the only member of this family that inhabits the forests of the lower part of the Mashpi Reserve (Figure 2).

Epipedobates frog

This is a very small frog of approximately 18 mm and, if observed carefully, its back is rather granular with a colouration that varies between red and dark brown. It inhabits the west of Ecuador and can be found in very varied ecosystems that range from dry forests to the cloud and rainforests of the Coast, and in Mashpi we can find it in the lower parts of the reserve, under 800 msnm. It prefers herbaceous and bushy vegetation that grows close to rivers, over the layer of dead leaves or stones.

Its other name, the “nurse frog” is due to the fact that it takes parental care and the males carry their spawn on their backs to move them or to protect them from predators. It is a diurnal species, and its diet is varied, including mites, coleopterans, dipterans, hemipterans and collembolans, although there is a high preference for ants (Lötters et al., 2007). Etymologically, the name Epipedobatae comes from two Greek terms: epipedos, which means ‘above the ground’, and bates, which means ‘to run’ and makes reference to the speed that they can move over the ground, something that I have witnessed, as they are very fast and slippery, which makes them difficult to trap. The specific title honours the Belgian naturalist George Boulenger, who at the beginning of the 20th century had described more than 2,500 species of amphibians, reptiles and fish.


Angerer, K. Frog tales – on poison dart frogs, epibatidine, and the sharing of biodiversity, Innovation. The European Journal of Social Science Research, 2011, 24:3, 353-369

Daly, J. W., Garraffo, H. M., Spande, T. F., Decker, M. W., Sullivan, J. P., Williams, M. (2000). Alkaloids from frog skin: the discovery of epibatidine and the potential for developing novel non-opioid analgesics. Natural Product Report. 17(2):131-5.

Darst, C. R., Menéndez‐Guerrero, P. A., Coloma, L. A., Cannatella, D. C. (2005). Evolution of Dietary Specialization and Chemical Defence  in Poison Frogs (Dendrobatidae): A Comparative Analysis. The American Naturalist, Vol. 165, No. 1, pp. 56-69.

Gillis, A.M. (2002). Serendipity and sweat in science. ‘‘Frog Man’’ Daly follows curiosity to ends of the Earth. The NIH record, 44(18). Available from: http://nihrecord.od.nih.gov/newsletters/09_03_2002/story01.htm [Accessed 2 October 2017].

Lötters, S., Miyata, K. y Proy, C. (2003). Another new riparian dendrobatid frog species from the upper Amazon basin of Peru. Journal of Herpetology 37:707-713.

Tarvin, R. D., Borghese C. M., Sachs, W., Harris R. A., Santos J. C., Zakon, H. H., Lu, Y., O’Connell, L. A., Cannatella, D. C. (2017). Interacting amino acid replacements allow poison frogs to evolve epibatidine resistance. Science 357 (6357), 1261-1266.

Spande, T.F., Garraffo, H. M., Edwards, M. W., Yeh, H. J. C., Panne, L., Daly, J. W. (1992). Epibatidine: A Novel (Chloropyridy1) azabicycloheptane with Potent Analgesic Activity from an Ecuadoran Poison Frog.  Journal of the American Chemical Society. 114, 3415-3418.

Tourists observing a yellow land iguana in its natural habitat at Finch Bay, Galapagos, included in Mashpi package tours.
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