Deadly neurotoxin may help de-stress pufferfish

Paper: Amano, M., Amiya, N., Takaoka, M., Sato, H., Takatani, T., Arakawa, O., & Sakakura, Y. (2019). Tetrodotoxin functions as a stress relieving substance in juvenile tiger puffer Takifugu rubripes. Toxicon, 171(2019), 54–61.


The blowfish, fugu, is considered a delicacy in many Asian nations. But unlike caviar or black truffles, fugu flesh contains a bit of an added thrill to consumers: if not prepared properly, a single, paper-thin piece of this fish (weighing just half an ounce) can kill you.

Fugu, along with 23 other types of pufferfishes, contains high levels of the extremely potent neurotoxin, tetrodotoxin (abbreviated TTX). TTX acts as a paralytic, meaning it stops muscles from working. At low doses, TTX causes tingling, numbness and vomiting. But ingesting enough will kill you as the muscles of the heart and respiratory systems stop functioning. TTX is one of the most potent neurotoxins known and is over 10,000 times more deadly than the equivalent weight of cyanide. You only need to eat 2 mg of the toxin (a dose that would fit on the head of a pin) to ingest a fatal dose. Worse yet, the toxin cannot be removed by cooking the fish and there is no known antidote.

Tetrodotoxin is widely found in marine and terrestrial animals

Fugu (Takifugu rubripes) is the most well-known species of pufferfish containing deadly the neurotoxin tetrodotoxin (TTX). Image from

Although TTX was first discovered in pufferfish (fishes in the family Tetraodontidae, lending to the toxin’s name), the toxin has been found in more than 140 animal species and numerous types of bacteria. Marine algae, worms, the blue ringed octopus, and poison dart frogs are just some of the species known to contain this powerful toxin. The wide-range of TTX bearing species has led scientists to speculate how so many different animals have come to harbor the exact same toxin and why they accumulate and retain such a toxic compound in their bodies.

Pufferfish can accumulate TTX through their food

As a prominent food fish, toxic pufferfish have served as a focal species for studying TTX. Scientists have long known that pufferfish accumulate TTX in various parts of their body, especially in their liver, ovaries, intestines, and skin. But, when toxic pufferfish are raised in aquariums with filtered water, TTX is no longer detected in their tissues. This finding led scientists to suspect that pufferfish do not create the TTX toxin themselves, but rather, accumulate the toxin from their environment. To test the theory that pufferfish obtain their deadly toxin exogenously (from the environment), scientists introduced TTX into the diet of non-toxic, hatchery-raised pufferfish. Sure enough, the fish that were fed TTX began accumulating the toxin in their tissues in the same way seen in wild-caught pufferfish.

The scientists noticed another change in the fish that had been given a TTX diet. When held in high densities in aquaria (as is often seen in pufferfish hatcheries), the fish become stressed and, as a result, will attack one another – chasing one another and nipping at other fishes’ fins. But the fish that were fed a diet containing TTX were noticeably less aggressive – they did not chase each other around the tanks or bite at other’s fins as frequently. Why would a neurotoxin alter the fishes’ behavior like this?

Can TTX reduce stress in pufferfish? 

In a follow up study, scientists decided to take a closer look at the stress pathway in pufferfish. When stressed, fish will produce a hormone (corticotropin-releasing hormone, or CRH for short) in their brain. This hormone triggers the production of other hormones that act in the body’s stress response. The bottom line: stress increases the amount of hormones like CRH in the body. So the scientists measured CRH and other stress hormones in hatchery-raised pufferfish that were fed a diet containing TTX and compared them to fish fed a regular, non-TTX containing diet.

Fugu is considered a delicacy but if not prepared properly, a single slice could prove fatal. Image from 

After a month, the pufferfish that had been fed the diet containing TTX had detectable levels of the neurotoxin in their body and brain tissues. Over the course of the study, the fish fed TTX grew at a faster rate, had noticeably fewer signs of aggression (i.e. their tails were still intact compared to the stressed out, tail-nipping fish on a regular diet), and had lower levels of stress hormones like CRH in their body.

Despite this finding, scientists still do not have a clear-cut answer to the question of why pufferfish accumulate TTX in their bodies. Since larval and juvenile pufferfish accumulate large amounts of the toxin on their skin, it is possible TTX serves as a defense against predators. In fact, many predatory fish appear to rapidly respond to TTX in pufferfish and will often spit out toxic individuals they have ingested. TTX may also serve as a secondary defense from predators, altering the behaviors of pufferfish in a way that makes them less likely to encounter predators in the first place. Pufferfish that have accumulated TTX in their brains act more cautiously than hatchery-raised fish lacking TTX in their tissues and ultimately have a higher survival rate in the wild than their non-toxic counterparts. The new finding that TTX reduces stress levels in pufferfish provides another possible explanation as to why pufferfish are so poisonous.


Additional Sources:

Largo et al., 2015. Tetrodotoxin, an extremely potent marine neurotoxin: Distribution, toxicity, origin, and therapeutical uses. Marine Drugs, 13(10): 6384-6406. doi: 10.3390/md13106384

Lorentz et al., 2016. Tetrodotoxin. Current Biology, 26 (R865-R881): R870-R872.

Carroll, Sean B. 21 Dec 2009. Whatever doesn’t kill some animals can make them deadly. The New York Times.

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