Treating Chronic Pain With Pufferfish Poison

Pufferfish harbour a lethal toxin in their liver, skin and reproductive organs.

I was recently invited to visit a friend in Baja, Mexico. Although I’ve not yet been, I have unwittingly started making a list of all of the deadly creatures I might meet on my trip - one of which is the pufferfish.

Pufferfish contain a poison more lethal than cyanide, yet fugu, made from pufferfish flesh, is considered a delicacy in Japan and other Asian countries. Indeed, poisonings from fugu were once only reported in this region. Yet now, fugu poisonings are being observed in other parts of the Pacific Ocean, down the Pacific coast of North America to Baja, as well as in the Indian Ocean and Mediterranean Sea.

The toxin responsible is known as tetrodotoxin or TTX, and in pufferfish, TTX accumulates in the liver, skin and ovaries. The level of toxicity varies through the seasons, with females being more toxic than males. TTX is water soluble and heat stable - not only that, it becomes more toxic on cooking. It is for these reasons that chefs wishing to serve fugu must be properly trained and hold a license.

I’m unsure of the appeal of eating fugu. Some say it is tasteless, others say the trace amount of poison makes your mouth go all tingly, a pleasant sensation. It is possible in Japan at least, that the fugu served in restaurants is from a farmed, non-toxic variety of pufferfish. It’s not difficult to see the attraction of maximising supply and minimising the toxicity of pufferfish through farming, considering its popularity in Japan and the difficulties associated with cooking it.

TTX is a potent neurotoxin, a blocker of voltage-gated sodium channels along muscle cells and nerve fibres. These channels ordinarily pass messages about touch and other sensations from the skin and the rest of the body to the brain. High doses of TTX shut down these signals, resulting in the loss of feeling, and the paralysis of the muscles that control breathing, leading to respiratory arrest.

These voltage-gated sodium channels are required for the normal functioning of our bodies, yet they also report pain. A high dose of TTX might be lethal, but much lower doses have been found to ease chronic, life-altering, persistent pain.

Indeed, WEX Pharmaceuticals (owned by CK Life Sciences) are focussed on developing TTX as a non-opioid analgesic. Their lead product, Halneuron®, is in late stage clinical development for the treatment of moderate to severe chemotherapy-induced neuropathic pain, and cancer pain. Other studies are exploring TTX for the treatment of migraines and to reduce the negative effects associated with heroin withdrawal.

Although WEX are likely synthesizing TTX via chemical means in the lab, the actual source of pufferfish TTX has been hotly debated for years.

You see, there is no evidence to suggest that pufferfish make their own TTX. And although TTX was originally discovered in pufferfish, it has since been found in a huge number of different animals, both in those living in the sea as well as some on land - from octopus to crabs, from worms to newts. So where does TTX come from?

The now widely-accepted view is that pufferfish and other TTX-containing organisms accumulate the toxin from the food chain - the TTX is contained in the other organisms that they eat. Entering the food chain, TTX is first made by marine bacteria from diverse genera, including Vibrio, Aeromonas, Alteromonas, Bacillus, Pseudomonas, Actinomycetes, and Shewanella. Some sources suggest the TTX-producing bacteria colonise the affected organism and continue to produce it in situ. Others imply the TTX has already been made, is eaten and accumulates in the new host’s tissues.

Intriguingly, it is not currently known how the bacteria make TTX. At least 30 different forms of TTX have been found, each with differing potencies, implying that different pathways might have evolved in different bacteria. Although some bacterial strains responsible for making TTX have been found, it has not been easy to grow these in the lab and to study them.

When more is known about the pathways bacteria use to make TTX, it might be beneficial to transfer the process into a bacterium that does grow well in the lab, such as E. coli. TTX production could then be optimised for making pain medication. Until then, there are so many questions unanswered and a lot more work needs to be done. Large-scale genome sequencing efforts of TTX-producing bacteria from around the world and from different hosts could provide fascinating stories as to the evolution of TTX production and how it is migrating across the globe.

Further Reading

Wassel, M. A., Makabe-Kobayashi, Y., Iqbal, M. M. et al. (2024) The impact of tetrodotoxin (TTX) on the gut microbiome in juvenile tiger pufferfish, Takifugu rubripes Sci. Rep. 14:16684.

Zhang, H., Li, P., Wu, B., Hou, J., Ren, J., Zhu, Y., Xu, J., Si, F., Sun, Z., Liu, X. (2022) Transcriptomic analysis reveals the genes involved in tetrodotoxin (TTX) accumulation, translocation, and detoxification in the pufferfish Takifugu rubripes Chemosphere 303(1):134962.

About the Illustration

A narrow-lined pufferfish (Arothron manilensis) has been drawn with colours that indicate the amount of toxin in each part of the fish, with red being the highest, yellow the lowest, and green ‘not detected’. Watercolour and coloured charcoal pencil on paper, A3.