CIGUATERA (or Ciguatera Poisoning, CP) is a foodborne illness due to the consumption of fish and marine invertebrate from tropical reefs, in perfect freshness and usually safe to eat, contaminated by neurotoxins (the ciguatoxins, CTXs) produced by a micro-algae, called Gambierdiscus.

Ciguatera throughout the centuries


Despite an apparent recent expansion of the ciguatera on a global scale, this phenomenon would probably exist since the creation of coral ecosystems. 

The first case of ciguatera-like poisoning ever described dates back to the year 650, according to the observations of a Chinese doctor and philosopher, CHAN TSANG CHI, to whom we owe the first report of a mortal case related to the consumption of a toxic fish (yellowtail jackfish).



In the16th century, with the first large-scale explorations, Pietro Martire d’Anghiera, a columnist for the Spanish court, reported the testimonies of Christopher Columbus, Vasco de Gama, Cortez and Magellan concerning several misfortunes, associated with consumption of toxic fish.



In 1675, during a stay in the Bahamas, the English physician and philosopher, John Locke, noticed that within the same fish species group, some specimens were toxic while others not. He also gave a very detailed description of ciguatera related syndrome and reported its chronic manifestations:


“…The fish, which are here, are many of them poisonous, bringing a great pain on their joints who eat them, and continue for some short time; and at last, with two or three days itching, the pain is rubbed off …Those of the same species, size, shape, colour, taste, are, one of them poison; the other not in the least hurtful …The distemper to men never proves mortal. Dogs and cats sometimes eat their last. Men, who have once had that disease, upon the eating of fish, though it be those which are wholesome, the poisonous ferment in their body is revived thereby, and their pain increased…”



It is to Fernandez de Queiros that we owe the first case report of Ciguatera in the Pacific, around 1606, after a massive poisoning with a fish from Lutjanus bohar family caught in the waters of the New Hebrides (Vanuatu).

Mention is made of "siguatados" fish, derived from "Sigua", the name given in Cuba to a gastropod mollusc Trochidae, Cittarium pica, responsible for a neurodigestive disorder.



In 1774, captain James Cook's crew was poisoned several times in the Vanuatu and New Caledonia by a Sparus pagrus.


In 1786, the Portuguese naturalist Antonio Parra, described an episode of fish poisoning in Havana, particularly evocative of the ciguatera syndrome as described today (short incubation time, combination of gastrointestinal, neurological symptoms, athralgia and myalgia, fatigue, dysgeusia, moving, breathing difficulties, dysesthesias in the extremities, etc.)



Concerning French Polynesia, James Morrison, 2nd boatswain on the “Bounty”, described the first cases of CP in 1792 in the Society Islands:


“….Among the fish there is a kind of conger eel of a brownish colour with a green border round the fins from head to tail. They are caught about the reefs and are of different sizes from one to six feet long; these fish are of a poisonous nature to some and if eaten gives the most excruciating pain while others who eat of it feel no effects nor do the natives know who will be affected by it, till they have eaten it. As they have a remedy for it they take no account of the matter and eat them at a venture. I partook of one of these fish without feeling the smallest effects from its poison, while another who eat of the same fish was almost raving mad, his body and limbs swelled to a very extraordinary degree and covered with red blotches and at the same time the hands and feet itching in such a manner as to be unsufferable and burning as if on fire, the eyes swelled and firey and to appearance fit to start from the sockets, this continued with short intermissions for eight days but in the course of a week more by the assistance of some of the priests who procured medicines he got quite well, but often found a great itching in the palms of the hands and hollow of the feet−These fish are called by the natives Puhi pirirauti and as they don’t know the good from the bad they are loth to throw them away and therefore eat them …”




It was only in 1976 that the origin of the phenomenon was elucidated by the scientists Takeshi Yasumoto and Raymond Bagnis, who made the link between episodes of poisonings among the inhabitants of the Gambier archipelago (French Polynesia) and the presence of blooms of the toxin-producing micro-algae Gambierdiscus.



Today, "ciguatera" refers to both the clinical symptoms and the complex underlying

the eco-toxicological phenomenon. 




Origin of Ciguatera


The true origin of ciguatera poisoning was elucidated in the mid 1970s and involves a benthic unicellular dinoflagellate, Gambierdiscus spp., whose populations preferentially grow on algal "turf" that cover damaged reef ecosystems. The genus Gambierdiscus is widely spread around the globe. To date, at least 18 species of Gambierdiscus are discribded worldwide: G. australes, G. balechii, G. belizeanus, G. caribaeus, G. carolinianus, G. carpenter, G. cheloniae, G. excentricus, G. holmesii, G. honu, G. jejuensis, G. lewisii, G. lapillus, G. pacificus, G. polynesiensis, G. scabrosus, G. silvae, G. toxicus.

Cells of the benthic dinoflagellate Gambierdiscus spp. (A): Optical microscope view ; B): Scanning electron microscope view.



Under the influence of environmental factors, generally related to natural events (hurricanes, tsunami…)  or anthropogenic activities (pollution, constructions...), populations of Gambierdiscus, already present in the environment, will proliferate.


For unclear reasons, only some strains of this dinoflagellate have the ability to produce ciguatoxins. In other terms, it is not the presence of high densities of Gambierdiscus that is responsible for ciguatera, but the strains present in the environment.



The massive colonization of the coral reef ecosystem by Gambierdiscus toxic strains constitutes the starting point of the reef’s food chain contamination. CTXs produced by the dinoflagellate are gradually accumulated in herbivorous fish when they graze on the microalgal turfs covering damaged or dead corals. The transfer of theses toxins to carnivorous fish occurs though predation, when carnivorous fish prey on contaminated herbivorous fish. Note that some invertebrates also bioaccumulate CTXs by filtration or grazing. The bioaccumulation of CTXs is associated to a biotransformation to more toxic compounds that lead to the poisoning in humans, which are at the top of the food chain.In total, about 400 fish species have been implicated in CP events.

Note that a new genus of ciguateric dinoflagellate, called Fukuyoa, has been identified. Do date, 3 species are known: F. yasumutoi, F. paulensis and F. ruetzeli.



 Global distribution of Gambierdiscus and Fukuyoa species.




Ciguatera Vectors


Ciguatera vectors are mainly from tropical and intertropical  ecosystems. Most of them are species that inhabit coral reefs. Note that some pelagic species, such as the Atlantic mackerel, can also transmit Ciguatera.

To date, about 400 fish species have been associated to CP events.







The species responsible for CP vary from a region to another, but some families are more at risk than others:


Access the research catalog of species involved in CP  cases recorded in French Polynesia and the South Pacific.




The genus Gambierdiscus can synthesize at least two major families of toxins: one lipid-soluble, the Ciguatoxins (CTXs) and another water-soluble, the Maitotoxins (MTXs). It is generally agreed that only CTXs are responsible for ciguatera fish poisoning, MTXs are usually not involved in human poisonings.

In humans, the average dose at which 50% of humans develop the symptoms, is estimated to be as low as 2 ng/kg of body weight, making CTXs one of the most potent natural substances known.

Other molecules such as gambieric acids, which exhibit antifungal activity, and gambierol have also been isolated from cultures of this micro-algae, but their role in ciguatera poisoning is still to be confirmed.

One might wonder about the ecological benefit for Gambierdiscus to produce these toxins. One hypothesis is that these metabolites provide an environmental benefit (e.g. defense mechanism) over potential competitors or predators.



Ciguatoxins (CTXs) are polycyclic polyether compounds, lipid-soluble, with a molecular weight between 1.023 and 1.159 Da. There are 3 main groups of CTXs throughout the main areas affected by ciguatera: Pacific ciguatoxins or P-CTXs, Caribbean ciguatoxins or C-CTXs and Indian Ocean ciguatoxins or I-CTXs. P-CTXs, composed of 13 ether rings, are described in two types, 1 and 2, the difference residing mainly in the E cycle. C-CTXs are composed of 14 cyclic ethers. To date, the structure of I-CTXs is yet to discover. In total, there are more than 40 different CTXs, which have been isolated primarily from Gambierdiscus cells and contaminated organisms.


The panel of CTXs in contaminated fish can vary significantly from one fish species to another. One single species may host several types of CTXs. So, one may talk about a “toxic profile” for a given trophic level.


Algal CTXs produced by Gambierdiscus undergo transformations from their accumulation in herbivorous fish until they pass through carnivorous fish. As a result, CTXs polarity as well as their toxicity increase. Thus, P-CTX-1B only found in carnivorous fish is 30 times more toxic than P-CTX-4B present in Gambierdiscus. This biotransformation phenomenon is responsible for the wide variability of the toxic profiles with respect to the fish and trophic level considered.


These understandings partly illustrate the complex mechanisms underlying the significant variation of ciguatera outbreaks severity from a geographical region to another.

Ciguatoxin P-CTX1B (extracted from carnivorous)




Impaired Nerve Conduction

A well-known consequence of the binding of CTXs to Nav channels, which they maintain in a permanent open state, is the appearance of spontaneous and/or repetitive discharges of action potentials. The marked increase of cellular excitability, generated by the binding of CTXs, in turn activates a sustained release of neurotransmitters (until exhaustion) at the level of the nerve endings, thus causing a modification of synaptic efficiency or even a deficiency in nerve messages transmission.


Modification of Cells Morphology

As a consequence of a massive influx of Na+ ions into the cells, following the binding of CTXs, a significant increase in the volume of the nodes of Ranvier of myelinated nerve fibers and synaptic terminals is observed, resulting from a call of compensatory water molecules, from the extracellular compartment to the intracellular compartment.

All of the modifications induced by CTXs (depolarization and hyper-excitability, increase in intracellular Na+ and Ca2+, anarchic release of neuromediators, swelling linked to the influx of water, etc.), associated with the very broad distribution of their biological targets within the organism, is at the origin of the diversity of the clinical signs observed in the CP-affected persons.

Thus, at neurological level, the multitude of symptoms encountered in CP such as motor, sensory, cerebellar, psychiatric impairments, is a direct consequence of the alteration of the fibers of the peripheral, central and autonomic nervous system. At digestive level, it is the high level of intracellular Ca2+ that would be the cause of profuse diarrhea. At the cardiac level, the action of CTXs takes place via the autonomic nervous system, with bradycardia and hypotension being linked to parasympathetic hyperstimulation and low sympathetic tone. Finally, at muscle level, the intracellular increase in Ca2+ generates an increase in the frequency and intensity of muscle contractions, while the discharges of spontaneous and repetitive action potentials induce disordered muscle contractions. These effects are all the more important when they concern the heart muscle since it is both the nerves supplying the heart and the heart muscle that are affected.

Sites and modes of action of ciguatoxins. (A) In motor and sensory neurons ciguatoxins cause persistent activation of Nav channels (1) and block Kv channels (2). This causes both membrane depolarisation (3) and leads to spontaneous and repetitive action potential firing (4). The resultant Na+ loading causes swelling of axons, nerve terminals and perisynaptic Schwann cells (5). (B) At synapses, ciguatoxins elevate the intracellular Ca2+ concentration via InsP3-mediated Ca2+ release from internal stores (6) or via activation of Cav channels due to terminal depolarisation (8). Also intracellular concentrations of Ca2+ increase due to an alteration in the Na+ gradient driving the Na+-Ca2+ exchanger (7), an effect that also occurs in cardiac myocytes. The tonic action potential firing initiated in axons induces repetitive, synchronous and asynchronous neurotransmitter release at synapses and the neuromuscular junction (9), to produce transient increases and decreases in the quantal content of synaptic responses. This results in spontaneous and tetanic muscle contractions (10). In addition, ciguatoxins also impair synaptic vesicle recycling that exhausts the pool of neurotransmitter vesicle available for release. By Nicholson et Lewis, 2006




After their ingestion, CTXs circulate into the blood stream for a few hours/days while a part of them are directly excreted in urine and feces.

Due to their high lipophilic properties, the un-excreted CTXs  diffuse and strongly fix in different organs and tissues, such as the liver, muscles, fat and brain.

Even if the process of  “detoxification” in humans remains unknown, toxicokinetic experiences conducted on marine organisms have shown that the complete elimination of the toxins was long but possible (several months or years).

To date, no treatment has shown the capability to improve CTXs elimination yet.


Ciguatoxins Detection Tests


CTXs detection represents a significant technical challenge, due to their chemical nature, the multiplicity of congeners and the low levels of toxins present in contaminated organisms. However, even if several detection tests are now available, currently there is no standard test duly validated by the scientific community, that could enable public authorities to establish a seafood security regulation at an international level. To date, the only reliable methods to detect CTXs are laboratory tests based on toxins mode of action (functional tests), or chemical properties.


In vivo Tests

Biological test on mouse or “Mouse bio-assay” (MBA) was the first CTXs detection test used. It is based on the symptoms and mice survival time observed after a 24h-48h period, following an intraperitoneal (ip) or intravenous (iv) injection of fish extract to be analyzed. Several animal species other than mice have been used: cats, chicken or mongooses that have a better CTXs sensitivity but require large amount of extracts or, methods using invertebrates, such as mosquitoes, crayfish, fly larvae or shrimps. These tests were gradually replaced by other methods following the 3R rule: “Reduce, Refine, Replace”, based on CTXs chemical, pharmacological and immunological properties.


Functional Tests

The radioligand-receptor test or “Receptor binding-assay” (RBA) is a neuropharmacological test based on the specific affinity of CTXs and brevetoxins (PbTxs) to the site 5 of voltage sensitive calcium channels (VSSCs) alpha subunits found on excitables cells membranes. Concerning CTXs detection, RBA measures the binding of a radiolabelled toxin, tritiated PbTx ([3H]PbTx-3), to this receptor, which compete with unradiolabled CTXs contained within the extract to be analyzed. Well adapted to CTXs detection from complex and varied biological matrices, RBA offers a high sensitivity (10-10M detection limit) and allows the use of untreated or partially purified extracts. It is economically more viable than the mouse bioassay, as it is easily automated to allow maximum processing capacity, making it an ideal tool for large-scale ciguatera risk monitoring programs. However, due to the regulatory constraints imposed by radioelements storing and handling, it appears difficult to generalize this test. However, recent labeling of brevetoxin with a fluorescent element gives hope for a greater applicability of this test.

Cell toxicity test or “Cell based-assay” (CBA) is another functional test allowing to measure the “overall toxicity” of a sample, by measuring the viability of a cultured cells line exposed to toxic extracts. This test is commonly used for the detection of a wide range of marine toxins: e.g. those active on VSSCs (saxitoxins, tetrodotoxins, brevetoxins and ciguatoxins), those active on Na+/K+ ATPases pumps (palytoxins), maitotoxins acting on VSCCs, okadaic acid which inhibits serine / threonine protein phosphatases, or pectenotoxins and dinophysistoxins…Besides its capacity to detect a wide range of marine biotoxins, CBA is also very sensitive (10-12M) and replicable, making it an excellent CTXs standard detection test candidate.



Immunological Tests

Various immunological assays have been developed for CTXs screening: the radioimmunoassay (RIA) or the “sandwich” test or enzyme-linked immunosorbent assay (ELISA). These tests are based on the principle of a highly specific recognition between an antibody (CTXs anti-antibody) and its antigen (CTXs). Theoretically, this approach seems to be the most promising one for the implementation of a fast, reliable, sensitive (up to 5×10-12M) and cheaper screening test. Its operating principle could also enable high-throughput screening of marine samples, and, most of all, its direct use on the field by fishermen and the general population. Two trials of developing such a test have been attempted: the CIGUATECT ™ and Cigua-Check ® (ToxiTec Inc. / Oceanit). But, these test kits have been withdrawn from the market, partly due to high false positives and false negatives reactions.

The CTXs’ complexity and chemical diversity; their low natural immunogenicity related to their polycyclic polyether nature; as well as the limited availability of pure standards of CTXs, partially explains the apparent difficulties to develop a reliable test.


Analytical Tests

Analytical tests (e.g. HPLC, LC-MS / MS) are based on high performance liquid chromatography techniques coupled with detection of each toxins families using Ultra-violet (UV), fluorescence, or tandem mass spectrometry. With a great sensitivity, these tests allow distinction and quantification of the different CTXs congeners within the same toxic family, but they require, as a prerequisite, to have the corresponding pure standards of the toxins. Therefore, the main limitations of this technique are that it does not detect new toxic families and, unlike the so-called functional tests, it doesn’t provide indication on the fish sample “whole toxicity”. Also, this type of methodology appears difficult to adapt to a CTXs high-throughput screening due to the several preliminary purification steps of the biological matrices. Therefore, these tests are most of the time used as confirmatory testing.


Traditional Tests

As contaminated organisms cannot be identified by their appearance, odor, color or taste, island populations (which are highly exposed  to CP risk), have gradually developed a wide range of traditional tests in attempt to detect ciguatoxic specimens. Across south pacific territories, several detection methods coming form popular beliefs or long ancestral practices are used. These traditional tests consist in 1/ giving a piece of flesh or liver of the suspicious fish to an animal or insect and observing its reaction; 2/ observing the oxydation of a silver coin or some matches in contact with the flesh; or 3/ observing the appearance of the whole fish or some of its organs.

A study has verified the effectiveness of two traditional detection tests used in French Polynesia (the rigor mortis method and hemorrhagic test). The ciguatoxic status of fisf samples, based on the use of the two tests by local fishermen, was  compared to toxicity analysis, of the same samples, by Receptor Binding Assay (RBA). Despite a predictability rate not exceeding 70%, the use of these tests combined with the population knowledge on suspicious toxic species and fishing areas, may help to significantly reduce the risk of CP within fish dependent communities, at the condition that the test users are accustomed to these tests. The opportunity for island populations of remote archipelagos to use on site and cost-effective validated traditional tests may therefore represent a day to day valuable asset in ciguatera risk management.


Examples of traditional tests used by French Polynesia’s fishermen to differentiate toxic fish over healthy fish.


 Learn more about CTXs detection tests:

Pasinszki T, Lako J, Dennis TE. Advances in Detecting Ciguatoxins in Fish. Toxins (Basel). 2020 Jul 31;12(8):494. doi: 10.3390/toxins12080494. PMID: 32752046; PMCID: PMC7472146.






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