Tetrodotoxin: Difference between revisions

{{short description|Neurotoxin}}

{{cs1 config|name-list-style=vanc}}

{{more science citations needed|date=February 2016}}

| Verifiedfields = changed

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| verifiedrevid = 456484184

| ImageFile=Tetrodotoxin.svg

| ImageSize=

| ImageFile2=Tetrodotoxin-based-on-xtal-1970-3D-balls.png

| IUPACName= (4''R'',4a''R'',5''R'',6''S'',7''S'',8''S'',8a''R'',10''S'',12''S'')-2-azaniumylidene-4,6,8,12-tetrahydroxy-6-(hydroxymethyl)-2,3,4,4a,5,6,7,8-octahydro-1''H''-8a,10-methano-5,7-(epoxymethanooxy)quinazolin-10-olate

| OtherNames=anhydrotetrodotoxin, 4-epitetrodotoxin, tetrodonic acid, TTX

|Section1={{Chembox Identifiers

| PubChem = 11174599

| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}}

| ChemSpiderID = 9349691

| SMILES = O1[C@@H]4[C@@](O)([C@@H]3O[C@@]1(O)[C@@H](O)[C@]2(N\C(N/[C@H](O)[C@H]23)=N)[C@@H]4O)CO

| SMILES1 = O1[C@@H]4[C@@](O)([C@@H]3O[C@@]1([O-])[C@@H](O)[C@]2(N\C(N/[C@H](O)[C@H]23)=[NH2+])[C@@H]4O)CO

| SMILES1_Comment = [[zwitterion]]

| InChI = 1/C11H17N3O8/c12-8-13-6(17)2-4-9(19,1-15)5-3(16)10(2,14-8)7(18)11(20,21-4)22-5/h2-7,15-20H,1H2,(H3,12,13,14)/t2-,3-,4-,5+,6-,7+,9+,10-,11+/m1/s1

| InChIKey = CFMYXEVWODSLAX-QOZOJKKEBM

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| StdInChI = 1S/C11H17N3O8/c12-8-13-6(17)2-4-9(19,1-15)5-3(16)10(2,14-8)7(18)11(20,21-4)22-5/h2-7,15-20H,1H2,(H3,12,13,14)/t2-,3-,4-,5+,6-,7+,9+,10-,11+/m1/s1

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| CASNo_Ref = {{cascite|correct|CAS}}

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| ChEBI_Ref = {{ebicite|changed|EBI}}

| ChEBI = 9506

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| IUPHAR_ligand = 2616

| ChEMBL = 507974

|Section2={{Chembox Properties

| C=11 | H=17 | N=3 | O=8

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|Section3={{Chembox Hazards

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}}

'''Tetrodotoxin''' ('''TTX''') is a potent [[neurotoxin]]. Its name derives from [[Tetraodontiformes]], an [[Order (biology)|order]] that includes [[Tetraodontidae|pufferfish]], [[porcupinefish]], [[ocean sunfish]], and [[triggerfish]]; several of these species carry the toxin. Although tetrodotoxin was discovered in these fish, it is found in several other animals (e.g., in [[blue-ringed octopus]]es, [[Taricha|rough-skinned newts]], and [[Naticidae|moon snails]]). It is also produced by certain infectious or [[symbiotic]] [[bacteria]] like ''[[Pseudoalteromonas tetraodonis|Pseudoalteromonas]]'', ''[[Pseudomonas]]'', and ''[[Vibrio]]'' as well as other species found in symbiotic relationships with animals and plants.<ref name="Chau_2011"/><ref name=Lago_2015/>

Although it produces thousands of intoxications annually and several deaths,<ref>{{cite journal |last1=Guardone |first1=Lisa |last2=Maneschi |first2=Andrea |last3=Meucci |first3=Valentina |last4=Gasperetti |first4=Laura |last5=Nucera |first5=Daniele |last6=Armani |first6=Andrea |date=2020-10-02 |title=A Global Retrospective Study on Human Cases of Tetrodotoxin (TTX) Poisoning after Seafood Consumption |url=https://www.tandfonline.com/doi/full/10.1080/87559129.2019.1669162 |journal=Food Reviews International |language=en |volume=36 |issue=7 |pages=645–667 |doi=10.1080/87559129.2019.1669162 |hdl=11568/1013333 |s2cid=204144112 |issn=8755-9129|hdl-access=free }}</ref> it has shown efficacy for the treatment of cancer-related pain in phase II and III clinical trials.<ref>{{cite journal |last1=Huerta |first1=Miguel Á |last2=de la Nava |first2=Javier |last3=Artacho-Cordón |first3=Antonia |last4=Nieto |first4=Francisco R. |date=May 2023 |title=Efficacy and Security of Tetrodotoxin in the Treatment of Cancer-Related Pain: Systematic Review and Meta-Analysis |journal=Marine Drugs |language=en |volume=21 |issue=5 |pages=316 |doi=10.3390/md21050316 |pmid=37233510 |pmc=10221257 |issn=1660-3397 |doi-access=free }}</ref>

Tetrodotoxin is a [[sodium channel blocker]]. It inhibits the firing of [[action potential]]s in neurons by binding to the [[voltage-gated sodium channels]] in [[Neuron|nerve cell]] [[Cell membrane|membranes]] and blocking the passage of sodium ions (responsible for the rising phase of an action potential) into the neuron. This prevents the nervous system from carrying messages and thus muscles from contracting in response to nervous stimulation.<ref name="Bane_2014">{{cite journal |vauthors=Bane V, Lehane M, Dikshit M, O'Riordan A, Furey A |title=Tetrodotoxin: Chemistry, Toxicity, Source, Distribution and Detection |journal=Toxins |volume=6 |issue=2 |pages=693–755 |date=February 2014 |pmid=24566728 |pmc=3942760 |doi=10.3390/toxins6020693 |doi-access=free}}</ref>

Its mechanism of action{{snd}}selective blocking of the sodium channel{{snd}}was shown definitively in 1964 by [[Toshio Narahashi]] and [[John Wilson Moore|John W. Moore]] at [[Duke University]], using the [[sucrose gap]] [[voltage clamp]] technique.<ref>{{cite journal |vauthors=Narahashi T, Moore JW, Scott WR |title=Tetrodotoxin blockage of sodium conductance increase in lobster giant axons |journal=The Journal of General Physiology |volume=47 |issue=5 |pages=965–974 |date=May 1964 |pmid=14155438 |pmc=2195365 |doi=10.1085/jgp.47.5.965}}</ref>

Apart from their [[bacteria]]l species of most likely ultimate biosynthetic origin (see below), tetrodotoxin has been isolated from widely differing animal species, including:<ref name="Chau_2011"/>

{{div col |colwidth=22em}}

* all octopuses and cuttlefish in small amounts, but specifically several species of the [[blue-ringed octopus]],<ref name="Chau_2011"/><ref name=Lago_2015/><ref name = Bane_2014/> including ''Hapalochlaena maculosa'' (where it was called "maculotoxin"),<ref name=Lago_2015/>

* various [[pufferfish]] species,<ref name="Chau_2011"/><ref name=Lago_2015/><ref name = Bane_2014/>

* certain [[Pomacanthidae|angelfish]],<ref>Sigma-Aldrich [https://www.sigmaaldrich.com/content/dam/sigma-aldrich/docs/Sigma/Product_Information_Sheet/1/t8024pis.pdf Tetrodotoxin (T8024) – Product Information Sheet.]</ref>

* species of ''[[Nassarius]]'' gastropods,<ref name="Chau_2011"/><ref name=Lago_2015/><ref name = Bane_2014/>

* species of [[Naticidae]] (moon snails),<ref name="Chau_2011"/><ref name="pmid1949060">{{cite journal | vauthors = Hwang DF, Tai KP, Chueh CH, Lin LC, Jeng SS | title = Tetrodotoxin and derivatives in several species of the gastropod Naticidae | journal = Toxicon | volume = 29 | issue = 8 | pages = 1019–24 | year = 1991 | pmid = 1949060 | doi = 10.1016/0041-0101(91)90084-5 }}</ref>

* several [[starfish]], including ''[[Astropecten]]'' species,<ref name="Chau_2011"/><ref name=Lago_2015/><ref name = Bane_2014/>

* several species of [[Xanthidae|xanthid crabs]].<ref name="Chau_2011"/><ref name=Lago_2015/>

* species of [[Chaetognatha]] (arrow worms),<ref name="Chau_2011"/><ref name = Bane_2014/>

* species of [[Nemertea]] (ribbon worms),<ref name="Chau_2011"/><ref name = Bane_2014/>

* a polyclad [[flatworm]],<ref name="Chau_2011"/>

* [[land planarian]]s of the genus ''[[Bipalium]]'',<ref name="Stokes_2014">{{cite journal | vauthors = Stokes AN, Ducey PK, Neuman-Lee L, Hanifin CT, French SS, Pfrender ME, Brodie ED, Brodie ED | title = Confirmation and distribution of tetrodotoxin for the first time in terrestrial invertebrates: two terrestrial flatworm species (Bipalium adventitium and Bipalium kewense) | journal = PLOS ONE | volume = 9 | issue = 6 | pages = e100718 | year = 2014 | pmid = 24963791 | pmc = 4070999 | doi = 10.1371/journal.pone.0100718 | bibcode = 2014PLoSO...9j0718S | doi-access = free }}</ref>

* toads of the genus ''[[Atelopus]]'',<ref name="Chau_2011"/>

* toads of the genus ''[[Brachycephalus]]'',<ref name=Pires2005>{{cite journal | author1=Pires, O.R. Jr. | author2=A. Sebben | author3=E.F. Schwartz | author4=R.A.V. Morales | author5=C. Bloch Jr. | author6=C.A. Schwartz | year=2005 | title=Further report of the occurrence of tetrodotoxin and new analogues in the Anuran family Brachycephalidae | journal=Toxicon | volume=45 | issue=1 | pages=73–79 | doi=10.1016/j.toxicon.2004.09.016 | pmid=15581685 }}</ref>

* the [[eastern newt]] (''Notophthalmus viridescens'')<ref>{{cite journal |last1=Marion |first1=Zachary |last2=Hay |first2=Mark |title=Chemical Defense of the Eastern Newt (Notophthalmus viridescens): Variation in Efficiency against Different Consumers and in Different Habitats |journal=PLOS ONE |date=2011 |volume=6 |issue=12 |doi=10.1371/journal.pone.0027581 |pages=e27581 |pmid=22164212 |pmc=3229496|bibcode=2011PLoSO...627581M |doi-access=free }}</ref>

* the western or [[Taricha|rough-skinned newts]] (''Taricha''; wherein it was originally termed "tarichatoxin"),<ref name="Chau_2011"/>

{{Div col end}}

Tarichatoxin was shown to be identical to TTX in 1964 by Mosher et al.,<ref>{{cite journal | vauthors = Scheuer PJ | title = Toxins from fish and other marine organisms | journal = Advances in Food Research | volume = 18 | pages = 141–61 | pmid = 4929140 | year=1970| doi = 10.1016/S0065-2628(08)60369-9 | isbn = 9780120164189 }}</ref><ref>{{cite journal | vauthors = Mosher HS, Fuhrman FA, Buchwald HD, Fischer HG | title = Tarichatoxin – tetrodotoxin: a potent neurotoxin | journal = Science | volume = 144 | issue = 3622 | pages = 1100–10 | date = May 1964 | pmid = 14148429 | doi = 10.1126/science.144.3622.1100 | bibcode = 1964Sci...144.1100M }}</ref> and the identity of maculotoxin and TTX was reported in ''Science'' in 1978,<ref>{{cite journal | vauthors = Sheumack DD, Howden ME, Spence I, Quinn RJ | title = Maculotoxin: a neurotoxin from the venom glands of the octopus Hapalochlaena maculosa identified as tetrodotoxin | journal = Science | volume = 199 | issue = 4325 | pages = 188–89 | date = Jan 1978 | pmid = 619451 | doi = 10.1126/science.619451| bibcode = 1978Sci...199..188S | quote = Maculotoxin, a potent neurotoxin isolated from the posterior salivary glands of the blue-ringed octopus. Hapalochlaena maculosa, has now been identified as tetrodotoxin. This is the first reported case in which tetrodotoxin has been found to occur in a venom. }}</ref> and the synonymity of these two toxins is supported in modern reports (e.g., at ''Pubchem''<ref>{{cite web | url = https://pubchem.ncbi.nlm.nih.gov/compound/20055121#section=Top | title = Tetrodotoxin | work = PubChem | publisher = National Center for Biotechnology Information (NCBI) }}</ref> and in modern toxicology textbooks<ref>{{cite book | vauthors = Stine KE, Brown TM | year = 2015 | title = Principles of Toxicology | edition = 3rd | pages = 196, 390 | location = Boca Raton, FL | publisher = CRC Press | isbn = 978-1466503434 | url = https://books.google.com/books?isbn=1466503432 }}</ref>) though historic monographs questioning this continue in reprint.<ref>{{cite book | last1 = Gage | first1 = Peter W. | last2 = Dulhunty | first2 = Angela F. | chapter = Effects of Toxin from the Blue-Ringed Octopus (''Hapalochlaena maculosa'') [Chapter III] | pages = 85–106 | title = Marine Pharmacognosy: Action of Marine Biotoxins at the Cellular Level | year = 2012 | orig-year = 1973 | editor-last1 = Martin | editor-first1 = D.F. | editor-last2= Padilla | editor-first2 = G.M. | url = https://books.google.com/books?isbn=032315560X | isbn = 978-0323155601 | location = Philadelphia, PA [New York, NY] | publisher = Elsevier [Academic Press] }}</ref>

The toxin is variously used by [[animal]]s as a defensive biotoxin to [[antipredator adaptation|ward off predation]], or as both a defensive and predatory venom (e.g., in octopuses, [[Chaetognatha|chaetognaths]], and [[ribbon worms]]).<ref>{{cite journal|last1=Spafford|first1=J.David|last2=Spencer|first2=Andrew N.|last3=Gallin|first3=Warren J.|date=27 March 1998|title=A Putative Voltage-Gated Sodium Channel α Subunit (PpSCN1) from the Hydrozoan Jellyfish, Polyorchis penicillatus: Structural Comparisons and Evolutionary Considerations|journal=Biochemical and Biophysical Research Communications|volume=244|issue=3|pages=772–80|doi=10.1006/bbrc.1998.8332|pmid=9535741}}</ref> Even though the toxin acts as a defense mechanism, some predators such as the [[common garter snake]] have developed insensitivity to TTX, which allows them to prey upon toxic [[newt]]s.<ref>{{cite journal | last1 = Brodie | first1 = Edmund D. III | last2 = Brodie | first2 = Edmund D. Jr | title = Tetrodotoxin Resistance in Garter Snakes: An Evolutionary Response of Predators to Dangerous Prey | journal = Evolution | date = May 1990 | volume = 44 | issue = 3 | pages = 651–659 | doi = 10.2307/2409442 | jstor = 2409442 | pmid = 28567972 }}</ref>

The association of TTX with consumed, infecting, or [[symbiotic bacteria]]l populations within the animal species from which it is isolated is relatively clear;<ref name="Chau_2011"/> presence of TTX-producing bacteria within an animal's microbiome is determined by culture methods, the presence of the toxin by chemical analysis, and the association of the bacteria with TTX production by toxicity assay of media in which suspected bacteria are grown.<ref name=Lago_2015/> As Lago et al. note, "there is good evidence that uptake of bacteria producing TTX is an important element of TTX toxicity in marine animals that present this toxin."<ref name=Lago_2015>{{cite journal | vauthors = Lago J, Rodríguez LP, Blanco L, Vieites JM, Cabado AG | title = Tetrodotoxin, an Extremely Potent Marine Neurotoxin: Distribution, Toxicity, Origin and Therapeutical Uses | journal = Marine Drugs | volume = 13 | issue = 10 | pages = 6384–406 | year = 2015 | pmid = 26492253 | pmc = 4626696 | doi = 10.3390/md13106384 | doi-access = free }}</ref> TTX-producing bacteria include ''[[Actinomyces]]'', ''[[Aeromonas]]'', ''[[Alteromonas]]'', ''[[Bacillus]]'', ''[[Pseudomonas]]'', and ''[[Vibrio]]'' species;<ref name=Lago_2015/> in the following animals, specific bacterial species have been implicated:{{efn|For a more comprehensive list of TTX-producing bacterial species associated with animals from which the toxin has been isolated or toxicity observed, and for a thorough discussion of the research literature regarding bacterial origins (and the remaining contrary perspectives, e.g., in newts), as well as for a thorough speculative discussion regarding biosynthesis, see<ref name="Chau_2011">{{cite journal | vauthors = Chau R, Kalaitzis JA, Neilan BA | title = On the origins and biosynthesis of tetrodotoxin | journal = Aquatic Toxicology | volume = 104 | issue = 1–2 | pages = 61–72 | date = Jul 2011 | pmid = 21543051 | doi = 10.1016/j.aquatox.2011.04.001 | bibcode = 2011AqTox.104...61C | url = http://charlie.ambra.unibo.it/didattica/docs/bioc-inq/Toxin/Marine_toxins/On%20the%20origins%20and%20biosynthesis%20of%20tetrodotoxin.pdf | access-date = 2016-02-29 | archive-url = https://web.archive.org/web/20160305152535/http://charlie.ambra.unibo.it/didattica/docs/bioc-inq/Toxin/Marine_toxins/On%20the%20origins%20and%20biosynthesis%20of%20tetrodotoxin.pdf | archive-date = 2016-03-05 | url-status = dead }}</ref>}}

{{hatnote|In the following table, [[open nomenclature]] terms "sp.", "spp.", "cf." are used; the non-italcized designation after a species name is the [[strain (biology)|strain]].}}

{|class="wikitable plainlist"

|+Association of animals with TTX-producing bacteria

|-

! Animal !! Bacteria !! Ref

|-

| ''[[Takifugu obscurus]]'', obscure pufferfish

|

* ''Aeromonas'' sp. Ne-1

* ''Bacillus'' sp. W-3

| <ref name=Lago_2015/><ref name = Bane_2014/><!-- actually 10.1016/j.toxicon.2010.03.019 cited by these two -->

|-

| ''[[Nassarius semiplicatus]]'', a gastropod

|

* ''Vibrio'' spp., including ''V. alginolyticus'', ''V.'' cf. ''shilonii'', and unassigned ones

* ''Marinomonas'' sp.

* ''Tenacibaculum'' cf. ''aestuarii''<!-- why cf.? because the 16S identity is not high enough (98.65%) to be the same species -->

| <ref name=Chau_2011/><!-- actually Wang 2008 cited by Chau -->

|-

| ''Hapalochlaena maculosa'', the [[Southern blue-ringed octopus]]

|

* ''Alteromonas'' spp.

* ''Bacillus'' spp.

* ''Pseudomonas'' spp.

* ''Vibrio'' spp.

| <ref name="Chau_2011"/><ref name=Lago_2015/><ref name = Bane_2014/><ref name="Hwang_1989">{{cite journal | vauthors = Hwang DF, Arakawa O, Saito T, Noguchi T, Simidu U, Tsukamoto K, Shida Y, Hashimoto K | title = Tetrodotoxin-producing bacteria from the blue-ringed octopus ''Octopus maculosus'' [sic.] | journal = Marine Biology | volume = 100 | issue = 3 | pages = 327–32 | year =1988| doi = 10.1007/BF00391147 | s2cid = 84188968 }}</ref>

|-

| ''[[Astropecten polyacanthus]]'', a starfish

| ''[[Vibrio alginolyticus]]''

| <ref name=Lago_2015/><ref name = Bane_2014/>

|-

| ''[[Takifugu vermicularis]]'', a pufferfish

|

* ''Vibrio'' spp., including ''V. alginolyticus''

|<ref name="Chau_2011"/><ref name=Lago_2015/><ref name=Bane_2014/><ref>{{cite journal | title = Vibrio alginolyticus, a tetrodotoxin-producing bacterium, in the intestines of the fish Fugu vermicularis vermicularis | year = 1987 | journal = Marine Biology | pages = 625–30 | volume = 94 | issue = 4 | last1 = Noguchi | first1 = T. | last2 = Hwang | first2 = D.F. | last3 = Arakawa | first3 = O. | last4 = Sugita | first4 = H. | last5 = Deguchi | first5 = Y. | last6 = Shida | first6 = Y. | last7 = Hashimoto | first7 = K. | doi = 10.1007/BF00431409 | bibcode = 1987MarBi..94..625N | s2cid = 84437298 }}</ref>

|-

| Four species of [[Chaetognatha]] (arrow worms)

|

* ''V. alginolyticus''

| <ref name=Thuesen>{{cite journal | title = Bacterial production of tetrodotoxin in four species of Chaetognatha | vauthors = Thuesen EV, Kogure K | year = 1989 | journal = Biological Bulletin | pages = 191–94 | issue = 2 | volume = 176 | url =http://www.biolbull.org/content/176/2/191.full.pdf | doi = 10.2307/1541587 | jstor = 1541587 }}</ref>

|-

| Species of [[Nemertea]] (ribbon worms)

| ''Vibrio'' spp.

| <ref name="Chau_2011"/><ref>{{cite journal | title = The production of tetrodotoxin-like substances by nemertean worms in conjunction with bacteria | year = 2003 | journal = Journal of Experimental Marine Biology and Ecology | pages = 51–63 | volume = 288 | issue = 1 | last1 = Carroll | first1 = S. | last2 = McEvoy | first2 = E.G. | last3 = Gibson | first3 = R. | doi = 10.1016/S0022-0981(02)00595-6 | bibcode = 2003JEMBE.288...51C }}</ref>

|-

|}

The association of bacterial species with the production of the toxin is unequivocal – Lago and coworkers state, "[e]ndocellular symbiotic bacteria have been proposed as a possible source of eukaryotic TTX by means of an exogenous pathway",<ref name=Lago_2015/> and Chau and coworkers note that the "widespread occurrence of TTX in phylogenetically distinct organisms... strongly suggests that symbiotic bacteria play a role in TTX biosynthesis"<ref name="Chau_2011"/> – although the correlation has been extended to most but not all animals in which the toxin has been identified.<ref name="Chau_2011"/><ref name=Lago_2015/><ref name = Bane_2014/> To the contrary, there has been a failure in a single case, that of newts (''[[Taricha granulosa]]''), to detect TTX-producing bacteria in the tissues with highest toxin levels ([[skin]], [[Ovary|ovaries]], [[muscle]]), using [[polymerase chain reaction|PCR]] methods,<ref>{{cite journal |title=No evidence for an endosymbiotic bacterial origin of tetrodotoxin in the newt Taricha granulosa|journal=Toxicon |date=1 September 2004|volume=44|issue=3|pages=243–49|doi=10.1016/j.toxicon.2004.05.019|pmid=15302530 | vauthors = Lehman EM, Brodie ED, Brodie ED }}</ref> although technical concerns about the approach have been raised.<ref name="Chau_2011"/> Critically for the general argument, ''[[Takifugu rubripes]]'' puffers captured and raised in laboratory on controlled, TTX-free diets "lose toxicity over time", while cultured, TTX-free ''[[Takifugu niphobles]]'' puffers fed on TTX-containing diets saw TTX in the livers of the fishes increase to toxic levels.<ref name="Chau_2011"/> Hence, as bacterial species that produce TTX are broadly present in aquatic sediments, a strong case is made for ingestion of TTX and/or TTX-producing bacteria, with accumulation and possible subsequent colonization and production.<ref name="Chau_2011"/> Nevertheless, without clear biosynthetic pathways (not yet found in animals, but shown for bacteria),<ref>As Chau et al., op. cit., note, "Despite its long history and a thorough knowledge of its toxicity and pharmacology, neither the pathway to TTX nor even the biogenic origin of TTX is known. The debate into whether TTX is derived from bacteria or is endogenous to the host animals is on-going and the only published study into the substrates of TTX biosynthesis proved inconclusive."</ref> it remains uncertain whether it is simply via bacteria that each animal accumulates TTX; the question remains as to whether the quantities can be sufficiently explained by ingestion, ingestion plus colonization, or some other mechanism.<ref name="Chau_2011"/><ref name=Lago_2015/><ref name = Bane_2014/>

Tetrodotoxin binds to what is known as ''site 1'' of the fast [[voltage-gated sodium channel]].<ref name="Moczydlowski_2013">{{cite journal | vauthors = Moczydlowski EG | title = The molecular mystique of tetrodotoxin | journal = Toxicon | volume = 63 | pages = 165–83 | date = Mar 2013 | pmid = 23261990 | doi = 10.1016/j.toxicon.2012.11.026 }}</ref> Site 1 is located at the extracellular pore opening of the ion channel. Any molecule bound to this site will block sodium ions from going into the nerve cell through this channel (which is ultimately necessary for nerve conduction). [[Saxitoxin]], [[neosaxitoxin]], and several of the [[conotoxin]]s also bind the same site.<ref>{{cite journal |last1=Shen |first1=H |last2=Li |first2=Z |last3=Jiang |first3=Y |last4=Pan |first4=X |last5=Wu |first5=J |last6=Cristofori-Armstrong |first6=B |last7=Smith |first7=JJ |last8=Chin |first8=YKY |last9=Lei |first9=J |last10=Zhou |first10=Q |last11=King |first11=GF |last12=Yan |first12=N |title=Structural basis for the modulation of voltage-gated sodium channels by animal toxins. |journal=Science |date=19 October 2018 |volume=362 |issue=6412 |doi=10.1126/science.aau2596 |pmid=30049784 |doi-access=free}}</ref>

The use of this toxin as a biochemical probe has elucidated two distinct types of voltage-gated sodium channels (VGSCs) present in mammals: tetrodotoxin-sensitive voltage-gated sodium channels (TTX-s Na⁺ channels) and tetrodotoxin-resistant voltage-gated sodium channels (TTX-r Na⁺ channels). Tetrodotoxin inhibits TTX-s Na⁺ channels at concentrations of around 1–10 nM,<ref>{{cite web |title=Tetrodotoxin {{!}} Ligand page {{!}} IUPHAR/BPS Guide to Pharmacology |url=https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?tab=biology&ligandId=2616 |website=Guide to Pharmacology |publisher=International Union of Pharmacologists}}</ref> whereas micromolar concentrations of tetrodotoxin are required to inhibit TTX-r Na⁺ channels.<ref>{{cite journal |last1=Narahashi |first1=Toshio |title=Tetrodotoxin: A brief history. |journal=Proc Jpn Acad Ser B Phys Biol Sci |date=2008 |volume=84 |issue=5 |pages=147–54 |doi=10.2183/pjab.84.147 |pmid=18941294 |pmc=2858367}}</ref> Nerve cells containing TTX-r Na⁺ channels are located primarily in [[cardiac]] tissue, while nerve cells containing TTX-s Na⁺ channels dominate the rest of the body.

TTX and its analogs have historically been important agents for use as chemical tool compounds, for use in channel characterization and in fundamental studies of channel function.<ref name="Kao66" /><ref>{{cite journal | author = Blankenship, J.E. | year = 1976 | title = Tetrodotoxin: From Poison to Powerful Tool | journal = Perspectives in Biology and Medicine | volume = 19 | issue = 4, Summer | pages = 509–26 | doi = 10.1353/pbm.1976.0071 | pmid = 785373 | s2cid = 6117457 }}</ref> The prevalence of TTX-s Na⁺ channels in the [[central nervous system]] makes tetrodotoxin a valuable agent for the silencing of [[neurons|neural activity]] within a [[cell culture]].

=== Biosynthesis ===

The biosynthetic route to TTX is only partially understood. It is long known that the molecule is related to [[saxitoxin]], and as of 2011 it is believed that there are separate routes for aquatic (bacterial) and terrestrial (newt) TTX.<ref>{{cite journal |last1=Chau |first1=R |last2=Kalaitzis |first2=JA |last3=Neilan |first3=BA |title=On the origins and biosynthesis of tetrodotoxin. |journal=Aquatic Toxicology (Amsterdam, Netherlands) |date=July 2011 |volume=104 |issue=1–2 |pages=61–72 |doi=10.1016/j.aquatox.2011.04.001 |pmid=21543051|bibcode=2011AqTox.104...61C }}</ref> In 2020, new intermediates found in newts suggest that the synthesis starts with geranyl guanidine in the amphibian; these intermediates were not found in aquatic TTX-containing animals, supporting the separate-route theory.<ref>{{cite journal |last1=Kudo |first1=Yuta |last2=Hanifin |first2=Charles T. |last3=Kotaki |first3=Yuichi |last4=Yotsu-Yamashita |first4=Mari |title=Structures of N-Hydroxy-Type Tetrodotoxin Analogues and Bicyclic Guanidinium Compounds Found in Toxic Newts |journal=Journal of Natural Products |date=25 September 2020 |volume=83 |issue=9 |pages=2706–17 |doi=10.1021/acs.jnatprod.0c00623 |pmid=32896120 |doi-access=free}}</ref> In 2021, the first genome of a TTX-producing bacterium was produced. This "''Bacillus'' sp. 1839" was identified as ''[[Cytobacillus]] gottheilii'' using its rRNA sequence. The researcher responsible for this study has not yet identified a coherent pathway but hopes to do so in the future.<ref>{{cite journal |last1=Melnikova |first1=DI |last2=Nijland |first2=R |last3=Magarlamov |first3=TY |title=The First Data on the Complete Genome of a Tetrodotoxin-Producing Bacterium. |journal=Toxins |date=9 June 2021 |volume=13 |issue=6 |page=410 |doi=10.3390/toxins13060410 |pmid=34207879 |pmc=8228330 |doi-access=free }}</ref>

=== Resistance ===

Animals that accumulate TTX as a defense mechanism as well as their predators must evolve to be resistant to the effects of TTX. Mutations in the VGSC genes, especially the genes for Na_v 1.4 (skeletal muscle VGSC, "TTX-s"<ref>{{cite journal |last1=Maruta |first1=Satoshi |last2=Yamaoka |first2=Kaoru |last3=Yotsu-Yamashita |first3=Mari |title=Two critical residues in p-loop regions of puffer fish Na+ channels on TTX sensitivity |journal=Toxicon |date=March 2008 |volume=51 |issue=3 |pages=381–387 |doi=10.1016/j.toxicon.2007.10.014|pmid=18067939 }}</ref>), are found in many such animals.<ref name="pmid35580905">{{cite journal |last1=van Thiel |first1=J |last2=Khan |first2=MA |last3=Wouters |first3=RM |last4=Harris |first4=RJ |last5=Casewell |first5=NR |last6=Fry |first6=BG |last7=Kini |first7=RM |last8=Mackessy |first8=SP |last9=Vonk |first9=FJ |last10=Wüster |first10=W |last11=Richardson |first11=MK |title=Convergent evolution of toxin resistance in animals. |journal=Biological Reviews of the Cambridge Philosophical Society |date=October 2022 |volume=97 |issue=5 |pages=1823–1843 |doi=10.1111/brv.12865 |pmid=35580905|pmc=9543476 }}</ref> These mutations have independently arisen several times, even multiple times in different populations of the same species as seen in the garter snake. They consist of different amino acid substitutions in similar positions, a weak example of [[convergent evolution]] caused by how TTX binds to the unmutated VGSC.<ref name="pmid35580905"/>

Another path to TTX resistance is toxin-binding proteins that hold onto TTX tightly enough to prevent it reaching the vulnerable VGSCs. Various proteins that bind TTX have been found in pufferfish, crabs, and gastropods. There are also proteins that bind [[saxitoxin]] (STX), a toxin with a similar mode of action.<ref name="pmid35580905"/>

== Chemical synthesis ==

In 1964, a team of scientists led by [[Robert B. Woodward]] elucidated the structure of tetrodotoxin.<ref name="Woodward_1964">{{cite journal | vauthors = Woodward RB | author-link = Robert B. Woodward | title = The Structure of Tetrodotoxin | journal = Pure Appl. Chem. | volume = 9 | issue = 1 | pages = 49–75 | year = 1964 | doi = 10.1351/pac196409010049 | s2cid = 98806870 | url = http://pac.iupac.org/publications/pac/pdf/1964/pdf/0901x0049.pdf | access-date = 2013-11-11 | archive-url = https://web.archive.org/web/20160304084234/http://pac.iupac.org/publications/pac/pdf/1964/pdf/0901x0049.pdf | archive-date = 2016-03-04 | url-status = dead }}</ref> The structure was confirmed by [[X-ray crystallography]] in 1970.<ref>{{ cite journal | first1 = Akio | last1 = Furusaki | first2 = Yujiro | last2 = Tomiie | first3 = Isamu | last3 = Nitta | title = The Crystal and Molecular Structure of Tetrodotoxin Hydrobromide | journal = [[Bulletin of the Chemical Society of Japan]] | volume = 43 | year = 1970 | issue = 11 | pages = 3332–41 | doi = 10.1246/bcsj.43.3332 | doi-access = }}</ref> [[Yoshito Kishi]] and coworkers reported the first [[total synthesis]] of [[racemic]] tetrodotoxin in 1972.<ref name="Kishi_1972a">{{cite journal | vauthors = Kishi Y, Aratani M, Fukuyama T, Nakatsubo F, Goto T | title = Synthetic studies on tetrodotoxin and related compounds. 3. A stereospecific synthesis of an equivalent of acetylated tetrodamine | journal = Journal of the American Chemical Society | volume = 94 | issue = 26 | pages = 9217–19 | date = Dec 1972 | pmid = 4642370 | doi = 10.1021/ja00781a038 }}</ref><ref name="Kishi_1972b">{{cite journal | vauthors = Kishi Y, Fukuyama T, Aratani M, Nakatsubo F, Goto T | title = Synthetic studies on tetrodotoxin and related compounds. IV. Stereospecific total syntheses of <small>DL</small>-tetrodotoxin | journal = Journal of the American Chemical Society | volume = 94 | issue = 26 | pages = 9219–21 | date = Dec 1972 | pmid = 4642371 | doi = 10.1021/ja00781a039 }}</ref> M. Isobe and coworkers<ref name="Taber_2005">{{cite web | url = https://www.organic-chemistry.org/Highlights/2005/02May.shtm | title = Synthesis of (-)-Tetrodotoxin | vauthors = Taber D | date = 2005-05-02 | work = Organic Chemistry Portal | publisher = organic-chemistry.org }}</ref><ref name="Isobe_2003">{{cite journal | vauthors = Ohyabu N, Nishikawa T, Isobe M | title = First asymmetric total synthesis of tetrodotoxin | journal = Journal of the American Chemical Society | volume = 125 | issue = 29 | pages = 8798–805 | date = Jul 2003 | pmid = 12862474 | doi = 10.1021/ja0342998 }}</ref><ref name="Isobe_2004">{{cite journal | vauthors = Nishikawa T, Urabe D, Isobe M | title = An efficient total synthesis of optically active tetrodotoxin | journal = Angewandte Chemie | volume = 43 | issue = 36 | pages = 4782–85 | date = Sep 2004 | pmid = 15366086 | doi = 10.1002/anie.200460293 }}</ref> and J. Du Bois reported the [[asymmetric synthesis|asymmetric]] total synthesis of tetrodotoxin in 2003.<ref name="Dubois_2003">{{cite journal | vauthors = Hinman A, Du Bois J | title = A stereoselective synthesis of (–)-tetrodotoxin | journal = Journal of the American Chemical Society | volume = 125 | issue = 38 | pages = 11510–11 | date = Sep 2003 | pmid = 13129349 | doi = 10.1021/ja0368305 | url = https://figshare.com/articles/journal_contribution/3654192 }}</ref> The two 2003 syntheses used very different strategies, with Isobe's route based on a [[Diels–Alder reaction|Diels-Alder approach]] and Du Bois's work using [[C–H bond activation]]. Since then, methods have rapidly advanced, with several new strategies for the synthesis of tetrodotoxin having been developed.<ref>{{cite journal | vauthors = Chau J, Ciufolini MA | title = The chemical synthesis of tetrodoxin: an ongoing quest | journal = Marine Drugs | volume = 9 | issue = 10 | pages = 2046–74 | date = 2011 | pmid = 22073009 | pmc = 3210618 | doi = 10.3390/md9102046 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Sato K, Akai S, Yoshimura J | title = Stereocontrolled total synthesis of tetrodotoxin from ''myo''-inositol and <small>D</small>-glucose by three routes: aspects for constructing complex multi-functionalized cyclitols with branched-chain structures | journal = Natural Product Communications | volume = 8 | issue = 7 | pages = 987–98 | date = Jul 2013 | doi = 10.1177/1934578X1300800726 | pmid = 23980434 | s2cid = 23840469 | doi-access = free }}</ref>

===Toxicity===

TTX is extremely toxic. The [[Material safety data sheet|material safety data sheet]] for TTX lists the oral [[median lethal dose]] ([[LD50|LD₅₀]]) for mice as 334&nbsp;[[microgram|μg]] per kg.<ref>{{cite web | title = Material Safety Data Sheet Tetrodotoxin ACC# 01139 | url = https://fscimage.fishersci.com/msds/01139.htm | publisher = Acros Organics N.V. }}</ref> For comparison, the oral LD₅₀ of [[potassium cyanide]] for mice is 8,500&nbsp;μg per kg,<ref>{{IDLH|cyanides|Cyanides (as CN)}}</ref> demonstrating that even orally, TTX is more poisonous than [[cyanide]]. TTX is even more dangerous if administered intravenously; the amount needed to reach a lethal dose by injection is 8 μg per kg in mice.<ref>{{cite book | last1 = Gilman | first1 = Alfred Goodman | last2 = Goodman | first2 = Louis Sanford | last3 = Gilman | first3 = Alfred Zack | title = Goodman & Gilman's The pharmacological Basis of Therapeutics | date = 1980 | publisher = McGraw-Hill | location = New York | isbn = 0-07-146891-9 | page = 310 }}</ref>

The toxin can enter the body of a victim by [[ingestion]], injection, or [[inhalation]], or through abraded skin.<ref>{{cite journal | first1 = Jiri | last1 = Patockaa | first2 = Ladislav | last2 = Stredab | title = Brief Review of Natural Nonprotein Neurotoxins | journal=ASA Newsletter | date = April 23, 2002 | volume = 02-2 | issue = 89 | pages = 16–23 | url = http://www.asanltr.com/newsletter/02-2/articles/Neurotoxins.htm | access-date = 26 May 2012 | editor1-first = Richard | editor1-last = Price | publisher =Applied Science and Analysis inc. | issn = 1057-9419 }}</ref>

Poisoning occurring as a consequence of consumption of fish from the order [[Tetraodontiformes]] is extremely serious. The organs (e.g., liver) of the [[pufferfish]] can contain levels of tetrodotoxin sufficient to produce the described [[paralysis]] of the [[diaphragm (anatomy)|diaphragm]] and corresponding death due to [[respiratory failure]].<ref name=uhm>{{cite journal | vauthors = Clark RF, Williams SR, Nordt SP, Manoguerra AS | title = A review of selected seafood poisonings | journal = Undersea & Hyperbaric Medicine | volume = 26 | issue = 3 | pages = 175–84 | year = 1999 | pmid = 10485519 | url = http://archive.rubicon-foundation.org/2314 | archive-url = https://web.archive.org/web/20081007062742/http://archive.rubicon-foundation.org/2314 | url-status = usurped | archive-date = October 7, 2008 }}</ref> Toxicity varies between species and at different seasons and geographic localities, and the flesh of many pufferfish may not be dangerously toxic.<ref name=Bane_2014/>

The mechanism of toxicity is through the blockage of fast voltage-gated sodium channels, which are required for the normal transmission of signals between the body and brain.<ref>{{cite book | first1 = Humphrey | last1 = Rang | first2 = James | last2 = Ritter | first3 = Rod | last3 = Flower | first4 = Graeme | last4 = Henderson | title = Rang & Dale's Pharmacology | date = 2015 | publisher = Churchill Livingstone | isbn = 9780702053627 | edition = 8th }}</ref> As a result, TTX causes loss of sensation, and paralysis of voluntary muscles including the diaphragm and intercostal muscles, stopping breathing.<ref name=":0">{{cite web|title = CDC – The Emergency Response Safety and Health Database: Biotoxin: Tetrodotoxin – NIOSH|url = https://www.cdc.gov/niosh/ershdb/emergencyresponsecard_29750019.html|website = www.cdc.gov|access-date = 2016-01-03}}</ref>

[[File:Zh pharmacopoeia 1.JPG|thumbnail|upright|A Chinese pharmacopoeia, 1930.]]

The therapeutic uses of puffer fish ([[tetraodon]]) eggs were mentioned in the first Chinese pharmacopoeia [[Shénnóng Běn Cǎo Jīng|''Pen-T’so Ching'']] (The Book of Herbs, allegedly 2838–2698 BC by [[Shennong]]; but [[Chinese herbology#History|a later date is more likely]]), where they were classified as having "medium" toxicity, but could have a tonic effect when used at the correct dose. The principal use was "to arrest convulsive diseases".<ref name=Kao66>{{cite journal | vauthors = Kao CY | title = Tetrodotoxin, saxitoxin and their significance in the study of excitation phenomena | journal = Pharmacological Reviews | volume = 18 | issue = 2 | pages = 997–1049 | date = Jun 1966 | pmid = 5328391 }}</ref> In the [[Compendium of Materia Medica|''Pen-T’so Kang Mu'']] (Index Herbacea or The Great Herbal by Li Shih-Chen, 1596) some types of the fish Ho-Tun (the current Chinese name for [[tetraodon]]) were also recognized as both toxic yet, at the right dose, useful as part of a tonic. Increased toxicity in Ho-Tun was noted in fish caught at sea (rather than river) after the month of March. It was recognized that the most poisonous parts were the liver and eggs, but that toxicity could be reduced by soaking the eggs.<ref name=Kao66 /> (Tetrodotoxin is slightly water-soluble, and soluble at 1&nbsp;mg/ml in slightly acidic solutions.)<ref>{{cite web|title=T8024 Sigma Tetrodotoxin|url=http://www.sigmaaldrich.com/catalog/product/sigma/t8024?lang=en|website=Catalogue|publisher=Sigma-Aldrich|access-date=23 August 2015}}</ref>

The German physician [[Engelbert Kaempfer]], in his "A History of Japan" (translated and published in English in 1727), described how well known the toxic effects of the fish were, to the extent that it would be used for suicide and that the Emperor specifically decreed that soldiers were not permitted to eat it.<ref>{{cite book |last1=Kaempfer |first1=Engelbert |last2=Scheuchzer |first2=Johannes Caspar, trans. |title=The History of Japan … |series=Historia imperii Japonici |date=1727 |publisher=J.C. Scheuchzer (ed.) |location=London, England |volume=1 |pages=134–135 |url=https://babel.hathitrust.org/cgi/pt?id=gri.ark:/13960/t7zk6hz66;view=1up;seq=204}}</ref> There is also evidence from other sources that knowledge of such toxicity was widespread throughout southeast Asia and India.<ref name=Kao66 />

The first recorded cases of TTX poisoning affecting Westerners are from the logs of [[Captain (naval)|Captain]] [[James Cook]] from 7 September 1774.<ref name=uhm/> On that date Cook recorded his crew eating some local tropic fish (pufferfish), then feeding the remains to the pigs kept on board. The crew experienced numbness and shortness of breath, while the pigs were all found dead the next morning. In hindsight, it is clear that the crew survived a mild dose of tetrodotoxin, while the pigs ate the pufferfish body parts that contain most of the toxin, thus being fatally poisoned.

The toxin was first isolated and named in 1909 by Japanese scientist Dr. Yoshizumi Tahara.<ref name=Lago_2015/><ref>{{cite journal|last1=Suehiro|first1=M|title=[Historical review on chemical and medical studies of globefish toxin before World War II].|journal=Yakushigaku Zasshi|date=1994|volume=29|issue=3|pages=428–34|pmid=11613509}}</ref><ref name=uhm/> It was one of the agents studied by Japan's [[Unit 731]], which evaluated biological weapons on human subjects in the 1930s.<ref>{{cite book|url=https://books.google.com/books?id=ZzlNgS70OHAC&pg=PA295|title=Weapons of Mass Destruction: Chemical and biological weapons|editor1=Eric Croddy |editor2=James J. Wirtz |publisher=ABC-CLIO|date=2005|isbn=9781851094905}}</ref>

The diagnosis of pufferfish poisoning is based on the observed symptomatology and recent dietary history.<ref name="Harrisons98">{{cite book | last1 = Butterton | first1 = J.R. | last2 = Calderwell | first2 = S.B. | editor-first1 = Anthony S. | editor-last1 = Fauci | editor-first2 = Eugene | editor-last2 = Braunwald | editor-first3 = Kurt J. | editor-last3 = Isselbacher | editor-first4 = Jean D. | editor-last4 = Wilson | editor-first5 = Joseph B. | editor-last5 = Martin | editor-first6 = Dennis L. | editor-last6 = Kasper | editor-first7 = Stephen L. | editor-last7 = Hauser | editor-first8 = Dan L. | editor-last8 = Longo | chapter = Acute infectious diarrhoea disease and bacterial food poisoning | title = Harrison's principles of internal medicine | date = 1998 | publisher = McGraw-Hill, Health Professions Division | location = New York | isbn = 0070202915 | pages = [https://archive.org/details/harrisonsprincie14harr/page/796 796]–601 | edition = 14th | url-access = registration | url = https://archive.org/details/harrisonsprincie14harr }}</ref>

Symptoms typically develop within 30 minutes of ingestion, but may be delayed by up to four hours; however, if the dose is fatal, symptoms are usually present within 17 minutes of ingestion.<ref name=uhm/> [[Paresthesia|Having pins and needles]] of the lips and tongue is followed by developing it in the extremities, [[hypersalivation]], [[Perspiration|sweating]], headache, weakness, lethargy, [[ataxia|incoordination]], [[tremor]], paralysis, [[cyanosis|bluish skin]], [[aphonia|loss of voice]], [[dysphagia|difficulty swallowing]], and [[Epileptic seizure|seizures]]. The gastrointestinal symptoms are often severe and include [[nausea]], [[vomiting]], [[diarrhoea]], and [[abdominal pain]]; death is usually secondary to [[respiratory failure]].<ref name=":0" /><ref name="Harrisons98" /> There is increasing [[Shortness of breath|respiratory distress]], speech is affected, and the victim usually exhibits [[dyspnea|shortness of breath]], [[mydriasis|excess pupil dilation]], and [[hypotension|abnormally low blood pressure]]. Paralysis increases, and [[seizure|convulsions]], mental impairment, and [[cardiac arrhythmia|irregular heartbeats]] may occur. The victim, although completely paralysed, may be conscious and in some cases completely understandable until shortly before death, which generally occurs within 4 to 6 hours (range ~20 minutes to ~8 hours). However, some victims enter a [[coma]].<ref name=":0"/><ref name="Medscape_TTX">{{cite web | last1 = Benzer | first1 = Theodore | title = Tetrodotoxin Toxicity | url = http://emedicine.medscape.com/article/818763-overview|website=Medscape | access-date = 23 August 2015 }}</ref>

If the patient survives 24 hours, recovery without any aftereffects will usually occur over a few days.<ref name=Harrisons98/>

Therapy is supportive and based on symptoms, with aggressive early airway management.<ref name=uhm/> If consumed, treatment can consist of emptying the stomach, feeding the victim [[activated charcoal]] to bind the toxin, and taking standard life-support measures to keep the victim alive until the effect of the poison has worn off.<ref name=uhm/> [[Alpha-adrenergic agonist|Alpha adrenergic agonists]] are recommended in addition to intravenous fluids to increase the blood pressure; [[anticholinesterase]] agents "have been proposed as a treatment option but have not been tested adequately".<ref name="Medscape_TTX" />

No [[antidote]] has been developed and approved for human use, but a primary research report (preliminary result) indicates that a [[monoclonal antibody]] specific to tetrodotoxin is in development by [[USAMRIID]] that was effective, in the one study, for reducing toxin lethality in tests on mice.<ref>{{cite journal | vauthors = Rivera VR, Poli MA, Bignami GS | title = Prophylaxis and treatment with a monoclonal antibody of tetrodotoxin poisoning in mice | journal = Toxicon | volume = 33 | issue = 9 | pages = 1231–37 | date = Sep 1995 | pmid = 8585093 | doi = 10.1016/0041-0101(95)00060-Y }}{{closed access}}</ref>

=== Worldwide distribution of toxicity ===

Poisonings from tetrodotoxin have been almost exclusively associated with the consumption of pufferfish from waters of the Indo-Pacific Ocean regions, primarily because equally toxic pufferfishes from other regions are much less commonly eaten. Several reported cases of poisonings, including fatalities, nonetheless involved pufferfish from the Atlantic Ocean, [[Gulf of Mexico]], and [[Gulf of California]]. There have been no confirmed cases of tetrodotoxicity from the Atlantic pufferfish, ''[[Sphoeroides maculatus]]'', but three studies found extracts from fish of this species highly toxic in mice. Several recent intoxications from these fishes in Florida were due to [[saxitoxin]], which causes [[paralytic shellfish poisoning]] with very similar symptoms and signs. The trumpet shell ''[[Charonia|Charonia sauliae]]'' has been implicated in food poisonings, and evidence suggests it contains a tetrodotoxin derivative. There have been several reported poisonings from mislabelled pufferfish, and at least one report of a fatal episode in Oregon when an individual swallowed a rough-skinned newt ''[[Taricha granulosa]]'' on a dare.<ref>{{cite journal | vauthors = Bradley SG, Klika LJ | title = A fatal poisoning from the Oregon rough-skinned newt (Taricha granulosa) | journal = JAMA | volume = 246 | issue = 3 | pages = 247 | date = Jul 1981 | pmid = 7241765 | doi = 10.1001/jama.1981.03320030039026 }} {{closed access}}</ref>

In 2009, a major scare in the [[Auckland Region]] of [[New Zealand]] was sparked after several dogs died eating ''[[Pleurobranchaea maculata]]'' (grey side-gilled seaslug) on beaches.<ref>{{cite web | vauthors = McNabb P, Mackenzie L, Selwood A, Rhodes L, Taylor D, Cornelison C | date = 2009 | title = Review of tetrodotoxins in the sea slug ''Pleurobranchaea maculata'' and coincidence of dog deaths along Auckland Beaches. | publisher = Cawthron Institute for the Auckland Regional Council | work = Auckland Regional Council Technical Report 2009/108 | url = http://www.arc.govt.nz/albany/fms/main/Documents/Plans/Technical%20publications/Technical%20reports/2009%20100-150/TR2009108%20Review%20of%20toxins%20in%20the%20sea%20slug%20and%20coincidence%20of%20dog%20deaths%20along%20Auckland%20beaches.pdf | access-date = 2010-02-23 | archive-date = 2015-09-23 | archive-url = https://web.archive.org/web/20150923173109/http://www.arc.govt.nz/albany/fms/main/Documents/Plans/Technical%20publications/Technical%20reports/2009%20100-150/TR2009108%20Review%20of%20toxins%20in%20the%20sea%20slug%20and%20coincidence%20of%20dog%20deaths%20along%20Auckland%20beaches.pdf | url-status = dead }}</ref> Children and pet owners were asked to avoid beaches, and recreational fishing was also interrupted for a time. After exhaustive analysis, it was found that the sea slugs must have ingested tetrodotoxin.<ref name="NZ_Herald_10590940">{{cite news | url = http://www.nzherald.co.nz/auckland-region/news/article.cfm?l_id=117&objectid=10590940 | title = Puffer fish toxin blamed for deaths of two dogs | last = Gibson | first = Eloise | date = 15 August 2009 | work = [[The New Zealand Herald]] | access-date = 19 November 2011 }}</ref>

====Statistical factors====

Statistics from the Tokyo Bureau of Social Welfare and Public Health indicate 20–44 incidents of [[fugu]] poisoning per year between 1996 and 2006 in the entire country, leading to 34–64 hospitalizations and 0–6 deaths per year, for an average fatality rate of 6.8%.<ref name="tokyo">{{cite web |script-title = ja:危険がいっぱい ふぐの素人料理 | trans-title = Danger in fugu amateur cuisine | publisher = Tokyo Bureau of Social Welfare and Public Health | language = ja | url = http://www.mhlw.go.jp/topics/syokuchu/poison/animal_det_01.html | archive-url = https://web.archive.org/web/20100128100534/http://www.fukushihoken.metro.tokyo.jp/kenkou/anzen/anzen_info/shizendoku/hugu | archive-date = 28 January 2010 | url-status=dead }}</ref> Of the 23 incidents recorded within Tokyo between 1993 and 2006, only one took place in a restaurant, while the others all involved fishermen eating their catch.<ref name="tokyo"/> From 2006 through 2009 in Japan there were 119 incidents involving 183 people but only seven people died.<ref>{{cite web |script-title = ja: 自然毒のリスクプロファイル：魚類：フグ毒 | trans-title = Fish: fugu poison risk profile of natural poison | publisher = 厚生労働省 (Ministry of Health Labour and Welfare (Japan)) | language = ja | url = http://www.mhlw.go.jp/topics/syokuchu/poison/animal_det_01.html | archive-url = https://web.archive.org/web/20110927002233/http://www.mhlw.go.jp/topics/syokuchu/poison/animal_det_01.html | archive-date = 27 September 2011 | url-status=live }}</ref>

Only a few cases have been reported in the United States, and outbreaks in countries outside the Indo-Pacific area are rare. In Haiti, tetrodotoxin was thought to have been used in [[Haitian Vodou|voodoo]] preparations, in so-called [[zombie]] poisons. Subsequent careful analysis has however repeatedly called early studies into question on technical grounds, and failed to identify the toxin in any preparation.<ref name = Kao86>{{cite journal | vauthors = Yasumoto T, Kao CY | title = Tetrodotoxin and the Haitian zombie | journal = Toxicon | volume = 24 | issue = 8 | pages = 747–49 | pmid = 3775790 | doi=10.1016/0041-0101(86)90098-x | year=1986}}</ref><ref name = Kao90>{{cite journal | vauthors = Kao CY, Yasumoto T | title = Tetrodotoxin in "zombie powder" | journal = Toxicon | volume = 28 | issue = 2 | pages = 129–32 | pmid = 2339427 | doi=10.1016/0041-0101(90)90330-a | year=1990}}</ref><ref name="Hines">{{cite journal | title = Zombies and Tetrodotoxin | first = Terence | last = Hines | url = http://www.csicop.org/si/show/zombies_and_tetrodotoxin | journal = Skeptical Inquirer | volume = 32 | issue = 3 | date = May–June 2008 | pages = 60–62 | access-date = 2015-08-23 | archive-url = https://web.archive.org/web/20160709072251/http://www.csicop.org/si/show/zombies_and_tetrodotoxin | archive-date = 2016-07-09 | url-status = dead }}</ref> Discussion of the matter has therefore all but disappeared from the primary literature since the early 1990s. Kao and Yasumoto concluded in the first of their papers in 1986 that "the widely circulated claim in the lay press to the effect that tetrodotoxin is the causal agent in the initial zombification process is without factual foundation."<ref name = Kao86/>{{rp|748}}

Genetic background is not a factor in susceptibility to tetrodotoxin poisoning. This toxicosis may be avoided by not consuming animal species known to contain tetrodotoxin, principally pufferfish; other tetrodotoxic species are not usually consumed by humans.

====Fugu as a food====

Poisoning from tetrodotoxin is of particular public health concern in Japan, where ''[[fugu]]'' is a traditional delicacy. It is prepared and sold in special restaurants where trained and licensed [[chef]]s carefully remove the [[viscera]] to reduce the danger of poisoning.<ref>{{cite book|url=https://books.google.com/books?id=FvgNKPxb43IC&q=fugu+license&pg=PA390|title=Molecules of death |first1=Rosemary H. |last1=Warin|first2=Glyn B. |last2=Steventon|first3=Steve C. |last3=Mitchell|publisher= Imperial College Press|year=2007|page=390|isbn= 978-1-86094-814-5}}</ref> There is potential for misidentification and mislabelling, particularly of prepared, frozen fish products.

The mouse bioassay developed for [[paralytic shellfish poisoning]] (PSP) can be used to monitor tetrodotoxin in pufferfish and is the current method of choice. An [[High-performance liquid chromatography|HPLC]] method with post-column reaction with alkali and fluorescence has been developed to determine tetrodotoxin and its associated toxins. The alkali degradation products can be confirmed as their [[trimethylsilyl]] derivatives by gas chromatography/mass spectrometry.{{citation needed|date=July 2019}}

Tetrodotoxin may be quantified in serum, whole blood or urine to confirm a diagnosis of poisoning in hospitalized patients or to assist in the forensic investigation of a case of fatal overdosage. Most analytical techniques involve mass spectrometric detection following gas or liquid chromatographic separation.<ref>{{cite book | last1 = Baselt | first1 = Randall C. | title = Disposition of toxic drugs and chemicals in man | date = 2008 | publisher = Biomedical Publications | location = Foster City, California | isbn = 978-0-9626523-7-0 | pages = 1521–22 | edition = 8th }}</ref>

== Modern therapeutic research ==

Tetrodotoxin has been investigated as a possible treatment for cancer-associated pain. Early clinical trials demonstrate significant pain relief in some patients.<ref>{{cite journal | vauthors = Hagen NA, Lapointe B, Ong-Lam M, Dubuc B, Walde D, Gagnon B, Love R, Goel R, Hawley P, Ngoc AH, du Souich P | title = A multicentre open-label safety and efficacy study of tetrodotoxin for cancer pain | journal = Current Oncology | volume = 18 | issue = 3 | pages = e109–16 | date = Jun 2011 | pmid = 21655148 | pmc = 3108870 | doi = 10.3747/co.v18i3.732 }}</ref><ref name="Hagen_2008">{{cite journal | vauthors = Hagen NA, du Souich P, Lapointe B, Ong-Lam M, Dubuc B, Walde D, Love R, Ngoc AH | title = Tetrodotoxin for moderate to severe cancer pain: a randomized, double blind, parallel design multicenter study | journal = Journal of Pain and Symptom Management | volume = 35 | issue = 4 | pages = 420–49 | date = Apr 2008 | pmid = 18243639 | doi = 10.1016/j.jpainsymman.2007.05.011 | doi-access = free }}</ref>

It has also been studied in relation to [[migraine]] headaches. Mutations in one particular TTX-sensitive Na⁺ channel are associated with some [[migraine]] headaches,<ref>{{cite journal | vauthors = Nieto FR, Cobos EJ, Tejada MÁ, Sánchez-Fernández C, González-Cano R, Cendán CM | title = Tetrodotoxin (TTX) as a therapeutic agent for pain | journal = Marine Drugs | volume = 10 | issue = 2 | pages = 281–305 | date = Feb 2012 | pmid = 22412801 | pmc = 3296997 | doi = 10.3390/md10020281 | doi-access = free }}</ref> although it is unclear as to whether this has any therapeutic relevance for most people with migraine.<ref name="isbn0-7890-0553-0">{{cite book | last = Stimmel | first = Barry | title = Alcoholism, drug addiction, and the road to recovery: life on the edge | publisher = Haworth Medical Press | location = New York | year = 2002 | chapter=12: Heroin Addiction | quote = Tetrodotoxin blocks the sodium currents and is believed to have potential as a potent analgesic and as an effective agent in detoxoification from heroin addiction without withdrawal symptoms and without producing physical dependence. | isbn = 0-7890-0553-0 }}</ref>

Tetrodotoxin has been used clinically to relieve negative affects associated with [[heroin withdrawal]].<ref>{{cite journal | vauthors = Song H, Li J, Lu CL, Kang L, Xie L, Zhang YY, Zhou XB, Zhong S | title = Tetrodotoxin alleviates acute heroin withdrawal syndrome: a multicentre, randomized, double-blind, placebo-controlled study | journal = Clinical and Experimental Pharmacology & Physiology | volume = 38 | issue = 8 | pages = 510–14 | date = Aug 2011 | pmid = 21575032 | doi = 10.1111/j.1440-1681.2011.05539.x | s2cid = 11221499 }}</ref>

{{Globalize|article|USA|2name=the United States|date=February 2017}}

In the U.S., tetrodotoxin appears on the [[select agent]]s list of the [[U.S. Department of Health and Human Services|Department of Health and Human Services]],<ref>{{cite web | title = HHS and USDA Select Agents and Toxins 7 CFR Part 331, 9 CFR Part 121, and 42 CFR Part 73. | url = https://www.cdc.gov/od/sap/docs/salist.pdf | access-date = 17 March 2013 | archive-url= https://web.archive.org/web/20090117165906/http://www.cdc.gov/od/sap/docs/salist.pdf | archive-date = 17 January 2009 | url-status=dead }}</ref> and scientists must register with HHS to use tetrodotoxin in their research. However, investigators possessing less than 500&nbsp;mg are exempt from regulation.<ref>{{cite web | url = https://www.selectagents.gov/PermissibleToxinAmounts.html | work = Federal Select Agent Program | title = Permissible Toxin Amounts | publisher = United States Centers for Disease Control and Prevention | access-date = 20 Feb 2017 }}</ref>

==Popular culture==

Tetrodotoxin serves as a plot device for characters to fake death, as in the films ''[[Hello Again (1987 film)|Hello Again]]'' (1987), ''[[The Serpent and the Rainbow (film)|The Serpent and the Rainbow]]'' (1988), ''[[The A-Team (film)|The A-Team]]'' (2010) and ''[[Captain America: The Winter Soldier]]'' (2014), [[War (2019 film)|War]] (2019), and in episodes of "[[Jane the Virgin]]", ''[[Miami Vice]]'' (1985),<ref>[https://www.imdb.com/title/tt0647033/?ref_=ttep_ep18 Miami Vice (1984–1990) Tale of the Goat]. IMDb</ref> ''[[Nikita (TV series)|Nikita]]'', ''[[MacGyver (1985 TV series)|MacGyver]]'' Season 7, Episode 6, where the antidote is ''[[Datura stramonium]]'' leaf, ''[[CSI: NY]]'' (Season 4, episode 9 "Boo") and ''[[Chuck (TV series)|Chuck]]''. In ''[[Law Abiding Citizen]]'' (2009) and ''[[Alex Cross (film)|Alex Cross]]'' (2012), its paralysis is presented as a method of assisting torture. The toxin was also referenced in "synthetic form" in the S1E2 of the series "[[FBI (TV series)|FBI]]". The toxin is used as a weapon in both the second season of ''[[Archer (2009 TV series)|Archer]]'', in ''[[Covert Affairs]]'' and in the ''[[Inside No. 9]]'' episode "[[The Riddle of the Sphinx (Inside No. 9)|The Riddle of the Sphinx]]".<ref>{{cite web | first = Kitin | last = Miranda | title = Covert Affairs Recap: Starlings of the Slipstream | work = Movie News Guide | date = 26 November 2014 | url = http://www.movienewsguide.com/covert-affairs-recap-starlings-of-the-slipstream/37969 | access-date = 25 July 2015 | archive-date = 6 August 2018 | archive-url = https://web.archive.org/web/20180806210742/https://www.movienewsguide.com/covert-affairs-recap-starlings-of-the-slipstream/37969 | url-status = dead }}</ref><ref>{{cite web | year = 2015 | title = Covert Affairs: Starlings of the Slipstream (season 5, episode 12, original air date 13 November 2014) | publisher = USA Networks | url = http://www.usanetwork.com/covertaffairs/episode-guide/season-5-episode-12-starlings-of-the-slipstream | access-date = 25 July 2015 }}</ref> In Columbo, Episode 2 of Season 7, fugu is used to kill the antagonists victim. [[Columbo (season 7)]] In ''[[The Apothecary Diaries]]'' light novel, as well as the respective manga<ref name="Manga1-Vol5-en">{{cite web|title=The Apothecary Diaries, Vol. 5, Chapter 25|url=https://squareenixmangaandbooks.square-enix-games.com/en-us/product/9781646090747|publisher=[[Square Enix]]|access-date=July 13, 2022|archive-date=June 16, 2023|archive-url=https://web.archive.org/web/20230616015227/https://squareenixmangaandbooks.square-enix-games.com/en-us/product/9781646090747|url-status=live }}</ref><ref name="Manga1-Vol7-en">{{cite web|title=The Apothecary Diaries, Vol. 7, Chapter 33|url=https://squareenixmangaandbooks.square-enix-games.com/en-us/product/9781646091201|publisher=[[Square Enix]]|access-date=November 19, 2022|archive-date=February 2, 2023|archive-url=https://web.archive.org/web/20230202021741/https://squareenixmangaandbooks.square-enix-games.com/en-us/product/9781646091201|url-status=live }}</ref> and anime<ref>{{cite web|last=Silverman|first=Rebecca|date=January 21, 2024|title=The Apothecary Diaries Episode 15|url=https://www.animenewsnetwork.com/review/the-apothecary-diaries/episode-15/.206695|access-date=2024-02-27|website=[[Anime News Network]]|archive-date=January 21, 2024|archive-url=https://web.archive.org/web/20240121185303/https://www.animenewsnetwork.com/review/the-apothecary-diaries/episode-15/.206695|url-status=live}}</ref><ref>{{cite web|last=Silverman|first=Rebecca|date=February 25, 2024|title=The Apothecary Diaries Episode 20|url=https://www.animenewsnetwork.com/review/the-apothecary-diaries/episode-20/.207960|access-date=2024-02-27|website=[[Anime News Network]]|archive-date=February 25, 2024|archive-url=https://web.archive.org/web/20240225142914/https://www.animenewsnetwork.com/review/the-apothecary-diaries/episode-20/.207960|url-status=live}}</ref> adaptations, fugu toxin is encountered across multiple mystery arcs.

Based on the presumption that tetrodotoxin is not always fatal, but at near-lethal doses can leave a person extremely unwell with the person remaining conscious,<ref name=Harrisons98 /> tetrodotoxin has been alleged to result in [[zombie]]ism, and has been suggested as an ingredient in [[Haitian Vodou]] preparations.<ref name=Davis85 /> This idea first appeared in the 1938 non-fiction book ''Tell My Horse'' by [[Zora Neale Hurston]] in which there were multiple accounts of purported tetrodotoxin poisoning in Haiti by a voodoo sorcerer called the [[bokor]].<ref>{{cite book | last1 = Hurston | first1 = Zora Neale | editor-first1 = Ishmael | editor-last1 = Reed | editor-first2 = Henry | editor-last2 = Louis | title = Tell my horse: Voodoo and life in Haiti and Jamaica | date = 2009 | pages=336| publisher = Harper Perennial | location = New York | isbn = 978-0061695131 | edition = 1st Harper Perennial Modern Classics}}</ref> These stories were later popularized by [[Harvard]]-trained [[ethnobotanist]] [[Wade Davis (anthropologist)|Wade Davis]]<ref name="Davis85">{{cite book | last1 = Davis | first1 = Wade | title = 'The Serpent and the Rainbow | date = 1985 | publisher = Simon and Schuster | location = New York | isbn = 978-0671502478 | edition = 1st Touchstone | title-link = The Serpent and the Rainbow (book) }}</ref> in his 1985 [[The Serpent and the Rainbow (book)|book]] and [[Wes Craven]]'s 1988 film, both titled ''[[The Serpent and the Rainbow (film)|The Serpent and the Rainbow]]''. James Ellroy includes "blowfish toxin" as an ingredient in [[Haitian Vodou]] preparations to produce zombieism and poisoning deaths in his dark, disturbing, violent novel ''[[Blood's a Rover]]''. But this theory has been questioned by the scientific community since the 1990s based on [[analytical chemistry]]-based tests of multiple preparations and review of earlier reports (see above).<ref name = Kao86/><ref name = Kao90/><ref name="Hines"/>

* [[Clairvius Narcisse]], Haitian man allegedly buried alive under the effect of TTX

* [[Tetrodocain]], North Korean medical injection derived from tetrodotoxin

* [[4-Aminopyridine]]

* [[Brevetoxin]]

* [[Ciguatoxin]]

* [[Domoic acid]]

* [[Neosaxitoxin]]

* [[Okadaic acid]]

{{notelist}}

{{Reflist}}

== Further reading ==

{{refbegin|33em}}

* {{cite journal | vauthors = Bane V, Lehane M, Dikshit M, O'Riordan A, Furey A | title = Tetrodotoxin: chemistry, toxicity, source, distribution and detection | journal = Toxins | volume = 6 | issue = 2 | pages = 693–755 | year = 2014 | pmid = 24566728 | pmc = 3942760 | doi = 10.3390/toxins6020693 | doi-access = free }}

* {{cite journal | vauthors = Lago J, Rodríguez LP, Blanco L, Vieites JM, Cabado AG | title = Tetrodotoxin, an Extremely Potent Marine Neurotoxin: Distribution, Toxicity, Origin and Therapeutical Uses | journal = [[Marine Drugs]] | volume = 13 | issue = 10 | pages = 6384–406 | year = 2015 | pmid = 26492253 | pmc = 4626696 | doi = 10.3390/md13106384 | doi-access = free }}

* {{cite journal | vauthors = Moczydlowski EG | title = The molecular mystique of tetrodotoxin | journal = Toxicon | volume = 63 | pages = 165–83 | year = 2013 | pmid = 23261990 | doi = 10.1016/j.toxicon.2012.11.026 }}

* {{cite journal | vauthors = Lange WR | title = Puffer fish poisoning | journal = American Family Physician | volume = 42 | issue = 4 | pages = 1029–33 | year = 1990 | pmid = 2220511 }}

* {{cite journal | vauthors = Nagashima Y, Matsumoto T, Kadoyama K, Ishizaki S, Taniyama S, Takatani T, Arakawa O, Terayama M | title = Tetrodotoxin poisoning due to smooth-backed blowfish, ''Lagocephalus inermis'' and the toxicity of ''L. inermis'' caught off the Kyushu coast, Japan | journal = Shokuhin Eiseigaku Zasshi. Journal of the Food Hygienic Society of Japan | volume = 53 | issue = 2 | pages = 85–90 | year = 2012 | pmid = 22688023 | doi = 10.3358/shokueishi.53.85| doi-access = free }}

* {{cite journal | vauthors = Padera RF, Tse JY, Bellas E, Kohane DS | title = Tetrodotoxin for prolonged local anesthesia with minimal myotoxicity | journal = Muscle & Nerve | volume = 34 | issue = 6 | pages = 747–53 | year = 2006 | pmid = 16897761 | doi = 10.1002/mus.20618 | s2cid = 22726109 }}

* {{cite journal | title = Tetrodotoxin poisoning associated with eating puffer fish transported from Japan – California, 1996 | journal = Morbidity and Mortality Weekly Report | volume = 45 | issue = 19 | pages = 389–91 | year = 1996 | pmid = 8609880 | author1 = Centers for Disease Control Prevention (CDC) }}

* {{cite journal | vauthors = Cole JB, Heegaard WG, Deeds JR, McGrath SC, Handy SM | title = Tetrodotoxin poisoning outbreak from imported dried puffer fish – Minneapolis, Minnesota, 2014 | journal = Morbidity and Mortality Weekly Report | volume = 63 | issue = 51 | pages = 1222–25 | year = 2015 | pmid = 25551594 }}

* {{cite journal | vauthors = Liu SH, Tseng CY, Lin CC | title = Is neostigmine effective in severe pufferfish-associated tetrodotoxin poisoning? | journal = Clinical Toxicology | volume = 53 | issue = 1 | pages = 13–21 | year = 2015 | pmid = 25410493 | doi = 10.3109/15563650.2014.980581 | s2cid = 23055817 }}

* {{cite journal | vauthors = Rivera VR, Poli MA, Bignami GS | title = Prophylaxis and treatment with a monoclonal antibody of tetrodotoxin poisoning in mice | journal = Toxicon | volume = 33 | issue = 9 | pages = 1231–37 | year = 1995 | pmid = 8585093 | doi = 10.1016/0041-0101(95)00060-y}}

* {{cite journal | vauthors = Chang FC, Spriggs DL, Benton BJ, Keller SA, Capacio BR | title = 4-Aminopyridine reverses saxitoxin (STX)- and tetrodotoxin (TTX)-induced cardiorespiratory depression in chronically instrumented guinea pigs | journal = Fundamental and Applied Toxicology | volume = 38 | issue = 1 | pages = 75–88 | year = 1997 | pmid = 9268607 | doi = 10.1006/faat.1997.2328| s2cid = 17185707 }}

* {{cite journal | vauthors = Ahasan HA, Mamun AA, Karim SR, Bakar MA, Gazi EA, Bala CS | title = Paralytic complications of puffer fish (tetrodotoxin) poisoning | journal = Singapore Medical Journal | volume = 45 | issue = 2 | pages = 73–74 | year = 2004 | pmid = 14985845 }}

* {{cite journal | vauthors = How CK, Chern CH, Huang YC, Wang LM, Lee CH | title = Tetrodotoxin poisoning | journal = The American Journal of Emergency Medicine | volume = 21 | issue = 1 | pages = 51–54 | year = 2003 | pmid = 12563582 | doi = 10.1053/ajem.2003.50008 }}

{{refend}}

* [https://web.archive.org/web/20030618223848/http://www.cbwinfo.com/Biological/Toxins/TTX.html Tetrodotoxin: essential data] (1999)

* [https://www.fda.gov/Food/FoodSafety/FoodborneIllness/FoodborneIllnessFoodbornePathogensNaturalToxins/BadBugBook/ucm070842.htm Tetrodotoxin] from the [[Bad Bug Book]] at the U.S. [[Food and Drug Administration]] website

* [https://www.nytimes.com/2009/12/22/science/22creature.html New York Times, "Whatever Doesn't Kill Some Animals Can Make Them Deadly"]

{{Chemical agents}}

{{Authority control}}

[[Category:Marine neurotoxins]]

[[Category:Guanidine alkaloids]]

[[Category:Ichthyotoxins]]

[[Category:Sodium channel blockers]]

[[Category:Orthoesters]]

[[Category:Adamantane-like molecules]]

[[Category:Secondary metabolites]]

[[Category:Analgesics]]

[[Category:Non-protein ion channel toxins]]

[[Category:Zwitterions]]

[[Category:Voltage-gated sodium channel blockers]]

[[Category:Octopus toxins]]

[[Category:Amphibian toxins]]