Editing Aconitine

{{short description|Toxic plant alkaloid}}
<!--{{Distinguish|Aconitase}}: why would anyone confuse them?-->
{{chembox
| Verifiedfields = changed
| Watchedfields  = changed
| verifiedrevid  = 477240949
| Name           = 
| ImageFile      = Aconitine 2D Structure.png
| ImageSize      = 
| ImageFile1     = Aconitine-xtal-3D-sticks-skeletal.png
| ImageSize1     = 200px
| IUPACName      = 8-(acetyloxy)-20-ethyl-3α,13,15-trihydroxy-1α,6α,16β-trimethoxy-4-(methoxymethyl)aconitan-14α-yl benzoate
| OtherNames     = Acetylbenzoylaconine
| SystematicName = 
| Section1       = {{Chembox Identifiers
| IUPHAR_ligand = 2617
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 214292
| ChEMBL_Ref = {{ebicite|changed|EBI}}
| ChEMBL = 2103747 
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = X8YN71D5WC
| InChI1 = 1/C34H47NO11/c1-7-35-15-31(16-41-3)20(37)13-21(42-4)33-19-14-32(40)28(45-30(39)18-11-9-8-10-12-18)22(19)34(46-17(2)36,27(38)29(32)44-6)23(26(33)35)24(43-5)25(31)33/h8-12,19-29,37-38,40H,7,13-16H2,1-6H3/t19-,20-,21+,22-,23+,24+,25-,26?,27+,28-,29+,31+,32-,33+,34-/m1/s1
| InChIKey1 = XFSBVAOIAHNAPC-XTHSEXKGBF
| SMILES1 = O=C(O[C@H]5[C@]3(O)C[C@H]4[C@@]16C2N(CC)C[C@]([C@H]1[C@@H](OC)[C@@H]2[C@@](OC(=O)C)([C@@H](O)[C@@H]3OC)[C@H]45)(COC)[C@H](O)C[C@@H]6OC)c7ccccc7
| CASNo_Ref = {{cascite|correct|CAS}}
| CASNo=302-27-2
| PubChem=245005
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 2430
| KEGG = C06091
| 3DMet = 
| EC_number = 206-121-7
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C34H47NO11/c1-7-35-15-31(16-41-3)20(37)13-21(42-4)33-19-14-32(40)28(45-30(39)18-11-9-8-10-12-18)22(19)34(46-17(2)36,27(38)29(32)44-6)23(26(33)35)24(43-5)25(31)33/h8-12,19-29,37-38,40H,7,13-16H2,1-6H3/t19-,20-,21+,22-,23+,24+,25-,26?,27+,28-,29+,31+,32-,33+,34-/m1/s1
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = XFSBVAOIAHNAPC-XTHSEXKGSA-N
| SMILES=COC[C@]12CN(C)[C@@H]3[C@H]4[C@H](OC)C1[C@@]3([C@H](C[C@H]2O)OC)[C@@H]5C[C@]6(O)[C@@H](OC)[C@H](O)[C@@]4(OC(C)=O)[C@H]5C6OC(=O)c7ccccc7
  }}
| Section2       = {{Chembox Properties
|C =34|H=47|N=1|O=11
| MolarMass=645.73708
| Appearance=solid
| Density=
| MeltingPtC  = 203 to 204
| BoilingPt=
| Solubility=H<sub>2</sub>O: 0.3 mg/mL
ethanol: 35 mg/mL 
  }}
| Section3       = {{Chembox Hazards
| MainHazards=
| FlashPtC=
| AutoignitionPtC =
| GHSPictograms = {{GHS06}}
| GHSSignalWord = Danger
| HPhrases = {{H-phrases|300|330}}
| PPhrases = {{P-phrases|260|264|270|271|284|301+310|304+340|310|320|321|330|403+233|405|501}}
  }}
| Section4       = 
| Section5       = 
| Section6       = 
}}

'''Aconitine''' is an [[alkaloid]] toxin produced by various plant species belonging to the genus ''[[Aconitum]]'' (family [[Ranunculaceae]]), commonly known by the names '''wolfsbane''' and '''monkshood'''. Aconitine is notorious for its toxic properties.

==Structure and reactivity==
Biologically active isolates from ''[[Aconitum]]'' and ''[[Delphinium]]'' plants are classified as [[norditerpenoid]] [[alkaloid]]s,<ref>Biogenetically, aconitine is not a 'true' alkaloid, as it is not ultimately derived from amino acids.  Aconitine is ultimately derived from [[isoprene]], so it is technically a terpenoid and a ''pseudoalkaloid''.</ref> which are further subdivided based on the presence or absence of the C18 carbon.<ref>{{cite journal | vauthors = Shi Y, Wilmot JT, Nordstrøm LU, Tan DS, Gin DY | title = Total synthesis, relay synthesis, and structural confirmation of the C18-norditerpenoid alkaloid neofinaconitine | journal = Journal of the American Chemical Society | volume = 135 | issue = 38 | pages = 14313–20 | date = September 2013 | pmid = 24040959 | doi = 10.1021/ja4064958 | pmc = 3883312 | bibcode = 2013JAChS.13514313S }}</ref> Aconitine is a C19-norditerpenoid, based on its presence of this C18 carbon. It is barely soluble in [[water]], but very soluble in [[organic solvents]] such as chloroform or diethyl ether.<ref>{{ cite web | url = http://www.sigmaaldrich.com/catalog/product/sigma/a8001?lang=en | title = Aconitine | publisher = Sigma Aldrich |access-date=22 July 2016 }}</ref><ref>{{ cite web | url = http://datasheets.scbt.com/sc-202441.pdf | title = Aconitine sc-202441 Material Safety Data Sheet | publisher = Santa Cruz Biotechnology }}</ref> Aconitine is also soluble in mixtures of [[ethanol|alcohol]] and water if the concentration of alcohol is high enough.

Like many other alkaloids, the basic [[nitrogen]] atom in one of the six-membered ring structure of aconitine can easily form salts and ions, giving it affinity for both [[chemical polarity|polar]] and [[lipophilicity|lipophilic]] structures (such as cell membranes and receptors) and making it possible for the molecule to pass the [[blood–brain barrier]].<ref>{{ cite book | author = Dewick PM | year = 2002 | title = Medicinal Natural Products. A Biosynthetic Approach | edition = 2nd | publisher = Wiley | isbn = 978-0-471-49640-3 }}</ref> The [[Acetoxy group|acetoxyl group]] at the c8 position can readily be replaced by a [[methoxy]] group, by heating aconitine in [[methanol]], to produce a 8-deacetyl-8-''O''-methyl derivatives.<ref>{{ cite journal |vauthors=Desai HK, Joshi BS, Ross SA, Pelletier SW | title = Methanolysis of the C-8 Acetoxyl Group in Aconitine-Type Alkaloids: A Partial Synthesis of Hokbusine A | journal = Journal of Natural Products | year = 1989 | volume = 52 | issue = 4 | pages = 720–725 | doi = 10.1021/np50064a009 | bibcode = 1989JNAtP..52..720D }}</ref> If aconitine is heated in its dry state, it undergoes a [[pyrolysis]] to form pyroaconitine ((1α,3α,6α,14α,16β)-20-ethyl-3,13-dihydroxy-1,6,16-trimethoxy-4-(methoxymethyl)-15-oxoaconitan-14-yl benzoate) with the chemical formula C<sub>32</sub>H<sub>43</sub>NO<sub>9</sub>.<ref>{{ cite book |veditors=Manske RH, Rodrigo R | chapter = Chapter 1 The Structure and Synthesis of C<sub>19</sub>-Diterpenoid Alkaloids |vauthors=Pelletier SW, Mody NV | title = The Alkaloids: Chemistry and Physiology | volume = 17 | year = 1979 | page = 4 | doi = 10.1016/S1876-0813(08)60296-1 | chapter-url = https://books.google.com/books?id=NTXlVrG0oIcC&pg=PA4 | isbn = 9780080865416 }}</ref><ref>{{ cite web | url = http://www.chemspider.com/Chemical-Structure.10211301.html | title = Pyroaconitine ChemSpider ID: 10211301 | publisher = Chemspider }}</ref>

==Mechanism of action==
Aconitine can interact with the voltage-dependent [[sodium channel|sodium-ion channels]], which are proteins in the cell membranes of excitable tissues, such as cardiac and skeletal muscles and [[neuron]]s. These proteins are highly selective for sodium ions. They open very quickly to [[depolarization|depolarize]] the cell membrane potential, causing the upstroke of an action potential. Normally, the sodium channels close very rapidly, but the depolarization of the membrane potential causes the opening (activation) of potassium channels and potassium efflux, which results in repolarization of the membrane potential.

Aconitine binds to the channel at the neurotoxin binding site&nbsp;2 on the alpha subunit (the same site bound by [[batrachotoxin]], [[veratridine]], and [[grayanotoxin]]).<ref>{{cite journal | vauthors = Gutser UT, Friese J, Heubach JF, Matthiesen T, Selve N, Wilffert B, Gleitz J | title = Mode of antinociceptive and toxic action of alkaloids of Aconitum spec | journal = Naunyn-Schmiedeberg's Archives of Pharmacology | volume = 357 | issue = 1 | pages = 39–48 | date = January 1998 | pmid = 9459571 | doi = 10.1007/pl00005136 | s2cid = 21509335 }}</ref> This binding results in a sodium-ion channel that stays open longer. Aconitine suppresses the conformational change in the sodium-ion channel from the active state to the inactive state. The membrane stays depolarized due to the constant sodium influx (which is 10–1000-fold greater than the potassium efflux). As a result, the membrane cannot be repolarized. The binding of aconitine to the channel also leads to the channel to change conformation from the inactive state to the active state at a more negative voltage.<ref>{{cite journal | vauthors = Benoit E | title = Mécanisme(s) d'action des neurotoxines agissant sur l'inactivation des canaux sodium activés par le potentiel de membrane |trans-title=Mechanism of action of neurotoxins acting on the inactivation of voltage-gated sodium channels | language = fr | journal = Comptes Rendus des Séances de la Société de Biologie et de Ses Filiales | volume = 192 | issue = 3 | pages = 409–436 | year = 1998 | pmid = 9759381 }}</ref> In neurons, aconitine increases the permeability of the membrane for sodium ions, resulting in a huge sodium influx in the axon terminal. As a result, the membrane depolarizes rapidly. Due to the strong depolarization, the [[Cell membrane#Permeability|permeability]] of the membrane for potassium ions increases rapidly, resulting in a potassium reflux to release the positive charge out of the cell. Not only the permeability for potassium ions but also the permeability for calcium ions increases as a result of the depolarization of the membrane. A calcium influx takes place. The increase of the calcium concentration in the cell stimulates the release of the [[Acetylcholine receptor|neurotransmitter acetylcholine]] into the [[Chemical synapse|synaptic cleft]]. [[Acetylcholine]] binds to acetylcholine receptors at the postsynaptic membrane to open the sodium-channels there, generating a new action potential.

Research with mouse nerve-hemidiaphragm muscle preparation indicate that at low concentrations (<0.1&nbsp;μM) aconitine increases the electrically evoked acetylcholine release causing an induced muscle tension.<ref>{{cite journal | vauthors = Okazaki M, Kimura I, Kimura M | title = Aconitine-induced increase and decrease of acetylcholine release in the mouse phrenic nerve-hemidiaphragm muscle preparation | journal = Japanese Journal of Pharmacology | volume = 66 | issue = 4 | pages = 421–426 | date = December 1994 | pmid = 7723217 | doi = 10.1254/jjp.66.421 | url = http://www.jstage.jst.go.jp/article/jphs1951/66/4/66_4_421/_pdf | format = pdf | doi-access = free }}</ref> Action potentials are generated more often at this concentration. At higher concentration (0.3–3&nbsp;μM) aconitine decreases the electrically evoked acetylcholine release, resulting in a decrease in muscle tension. At high concentration (0.3–3&nbsp;μM), the sodium-ion channels are constantly activated, transmission of action potentials is suppressed, leading to non-excitable target cells or paralysis.

==Biosynthesis and total synthesis of related alkaloids==
Aconitine is biosynthesized by the [[monkshood]] plant via the [[terpenoid]] biosynthesis pathway (MEP chloroplast pathway).<ref>{{cite web | last1 = Viberti | first1 = Fabrizio | last2 = Raveggi | first2 = Elisa | name-list-style = vanc |title= Aconitine: How Poisonous, How Harmful? |url=http://flipper.diff.org/app/items/6692|website=flipper e nuvola|access-date=26 April 2017}}</ref> Approximately 700 naturally occurring C19-diterpenoid alkaloids have been isolated and identified, but the biosynthesis of only a few of these alkaloids are well understood.<ref name="pmid19275222">{{cite journal | vauthors = Zhao PJ, Gao S, Fan LM, Nie JL, He HP, Zeng Y, Shen YM, Hao XJ | title = Approach to the biosynthesis of atisine-type diterpenoid alkaloids | journal = Journal of Natural Products | volume = 72 | issue = 4 | pages = 645–9 | date = April 2009 | pmid = 19275222 | doi = 10.1021/np800657j | bibcode = 2009JNAtP..72..645Z }}</ref>

Likewise, only a few alkaloids of the aconitine family have been synthesized in the laboratory.  In particular, despite over one hundred years having elapsed since its isolation, the prototypical member of its family of norditerpenoid alkaloids, aconitine itself, represents a rare example of a well-known natural product that has yet to succumb to efforts towards its [[total synthesis]].  The challenge that aconitine poses to synthetic organic chemists is due to both the intricate interlocking hexacyclic ring system that makes up its core and the elaborate collection of oxygenated functional groups at its periphery.  A handful of simpler members of the aconitine alkaloids, however, have been prepared synthetically.  In 1971, the Weisner group discovered the [[total synthesis]] of talatisamine (a C19-norditerpenoid).<ref name="Wiesner_1974">{{cite journal | vauthors = Wiesner K, Tsai TY, Huber K, Bolton SE, Vlahov R | title=Total synthesis of talatisamine, a delphinine type alkaloid|journal=Journal of the American Chemical Society|date=July 1974|volume=96|issue=15|pages=4990–4992|doi=10.1021/ja00822a048| bibcode=1974JAChS..96.4990W}}</ref> In the subsequent years, they also discovered the [[Total synthesis|total syntheses]] of other C19-norditerpenoids, such as chasmanine,<ref name="Wiesner_1978">{{cite journal | vauthors = Wiesner K, Tsai TY, Nambiar KP |title=A new stereospecific total synthesis of chasmanine and 13-desoxydelphonine|journal=Canadian Journal of Chemistry|date=15 May 1978|volume=56|issue=10|pages=1451–1454|doi=10.1139/v78-237|doi-access=free}}</ref> and 13-deoxydelphonine.<ref name="Wiesner_1979">{{cite journal | vauthors = Wiesner K |title=Total synthesis of delphinine-type alkaloids by simple, fourth generation methods|journal=Pure and Applied Chemistry|date=1 January 1979|volume=51|issue=4|pages=689–703|doi=10.1351/pac197951040689|doi-access=free}}</ref>

[[File:Wiesner Syntheses Schematic.jpg|thumb|Schematic for the Wiesner Syntheses of Napelline. Deoxydelphonine and Talatisamine]]

The total synthesis of napelline ('''Scheme a''') begins with [[aldehyde]] '''100'''.<ref name="Wiesner_1974"/> In a 7 step process, the A-ring of napelline is formed ('''104'''). It takes another 10 steps to form the [[lactone]] ring in the pentacyclic structure of napelline ('''106'''). An additional 9 steps creates the enone-aldehyde '''107'''. Heating in methanol with potassium hydroxide causes an [[aldol condensation]] to close the sixth and final ring in napelline ('''14'''). Oxidation then gives rise to diketone '''108''' which was converted to (±)-napelline ('''14''') in 10 steps.

A similar process is demonstrated in Wiesner's synthesis of 13-desoxydelphinone ('''Scheme c''').<ref name="Wiesner_1978"/> The first step of this synthesis is the generation of a conjugated [[enone|dienone]] '''112''' from '''111''' in 4 steps. This is followed by the addition of a benzyl vinyl ether to produce '''113'''. In 11 steps, this compound is converted to [[ketal]] 114. The addition of heat, DMSO and o-xylene rearranges this ketol ('''115'''), and after 5 more steps (±)-13-desoxydelphinone ('''15''') is formed.

Lastly, talatisamine ('''Scheme d''') is synthesized from diene '''116''' and nitrile '''117'''.<ref name="Wiesner_1979"/> The first step is to form tricycle '''118'''  in 16 steps. After another 6 steps, this compound is converted to [[enone]] '''120'''. Subsequently, this allene is added to produce [[Adduct|photoadduct]] '''121'''. This adduct group is cleaved and rearrangement gives rise to the compound '''122'''. In 7 steps, this compound forms '''123''', which is then rearranged, in a similar manner to compound '''114''', to form the aconitine-like skeleton in '''124'''. A racemic relay synthesis is completed to produce talatisamine ('''13''').

More recently, the laboratory of the late David Y. Gin completed the total syntheses of the aconitine alkaloids nominine<ref>{{cite journal | vauthors = Peese KM, Gin DY | title = Efficient synthetic access to the hetisine C20-diterpenoid alkaloids. A concise synthesis of nominine via oxidoisoquinolinium-1,3-dipolar and dienamine-Diels-Alder cycloadditions | journal = Journal of the American Chemical Society | volume = 128 | issue = 27 | pages = 8734–5 | date = July 2006 | pmid = 16819859 | pmc = 2610465 | doi = 10.1021/ja0625430 }}</ref> and neofinaconitine.<ref>{{cite journal | vauthors = Shi Y, Wilmot JT, Nordstrøm LU, Tan DS, Gin DY | title = Total synthesis, relay synthesis, and structural confirmation of the C18-norditerpenoid alkaloid neofinaconitine | language = EN | journal = Journal of the American Chemical Society | volume = 135 | issue = 38 | pages = 14313–20 | date = September 2013 | pmid = 24040959 | pmc = 3883312 | doi = 10.1021/ja4064958 | bibcode = 2013JAChS.13514313S }}</ref>

==Metabolism==
[[File:Aconine.svg|thumb|[[Aconine]]: an amorphous, bitter, non-poisonous alkaloid, derived from the decomposition of aconitine]]
Aconitine is metabolized by [[cytochrome P450]] isozymes (CYPs). There has been research in 2011 in China to investigate in-depth the CYPs involved in aconitine metabolism in human liver microsomes.<ref>{{cite journal | vauthors = Tang L, Ye L, Lv C, Zheng Z, Gong Y, Liu Z | title = Involvement of CYP3A4/5 and CYP2D6 in the metabolism of aconitine using human liver microsomes and recombinant CYP450 enzymes | journal = Toxicology Letters | volume = 202 | issue = 1 | pages = 47–54 | date = April 2011 | pmid = 21277363 | doi = 10.1016/j.toxlet.2011.01.019 }}</ref> It has been estimated that more than 90 percent  of currently available human drug metabolism can be attributed to eight main enzymes (CYP 1A2, 2C9, 2C8, 2C19, 2D6, 2E1, 3A4, 3A5).<ref>{{cite journal | vauthors = Bertilsson L, Lou YQ, Du YL, Liu Y, Kuang TY, Liao XM, Wang KY, Reviriego J, Iselius L, Sjöqvist F | title = Pronounced differences between native Chinese and Swedish populations in the polymorphic hydroxylations of debrisoquin and S-mephenytoin | journal = Clinical Pharmacology and Therapeutics | volume = 51 | issue = 4 | pages = 388–397 | date = April 1992 | pmid = 1345344 | doi = 10.1038/clpt.1992.38 | s2cid = 42831017 }}</ref> The researchers used [[Recombinant DNA|recombinants]] of these eight different CYPs and incubated it with aconitine. To initiate the metabolism pathway the presence of NADPH was needed. Six CYP-mediated metabolites (M1–M6) were found by [[Liquid chromatography–mass spectrometry|liquid chromatography]], these six metabolites were characterized by [[Liquid chromatography–mass spectrometry|mass-spectrometry]]. The six metabolites and the involved enzymes are summarized in the following table:
{| class="wikitable"
|-
! Metabolite!! Name !! Involved CYPs
|-
| M1 || O-Demethyl-aconitine || CYP3A4, CYP3A5, CYP2D6, CYP2C8
|-
| M2 || 16-O-Demethyl-aconitine || CYP3A4, CYP3A5, CYP2D6, CYP2C9
|-
| M3 || N-deethyl-aconitine || CYP3A4, CYP3A5, CYP2D6, CYP2C9
|-
| M4 || O-didemethyl-aconitine || CYP3A5, CYP2D6
|-
| M5 || 3-Dehydrogen-aconitine || CYP3A4, CYP3A5
|-
| M6 || Hydroxyl-aconitine || CYP3A5, CYP2D6
|}

Selective [[enzyme inhibitor|inhibitors]] were used to determine the involved CYPs in the aconitine metabolism. The results indicate that aconitine was mainly metabolized by CYP3A4, 3A5 and 2D6. CYP2C8 and 2C9 had a minor role to the aconitine metabolism, whereas CYP1A2, 2E1 and 2C19 did not produce any aconitine metabolites at all. The proposed [[metabolic pathway]]s of aconitine in human liver microsomes and the CYPs involved to it are summarized in the table above.

==Uses==
Aconitine was previously used as an [[antipyretic]] and [[analgesic]] and still has some limited application in [[herbal medicine]], although the narrow [[therapeutic index]] makes calculating appropriate dosage difficult.<ref name="pmid19514874">{{cite journal | vauthors = Chan TY | title = Aconite poisoning | journal = Clinical Toxicology | volume = 47 | issue = 4 | pages = 279–285 | date = April 2009 | pmid = 19514874 | doi = 10.1080/15563650902904407 | s2cid = 2697673 }}</ref> Aconitine is also present in [[Yunnan Baiyao]], a proprietary [[traditional Chinese medicine]].<ref>{{cite web|title=Yunnan Baiyao finally discloses toxic ingredient|url=https://www.gokunming.com/en/blog/item/3202/yunnan_baiyao_finally_discloses_toxic_ingredient|website=GoKunming|date=2014-04-07}}</ref>

==Toxicity==
Consuming as little as 2 [[milligram]]s of pure aconitine or 1 gram of the plant itself may cause death by paralyzing [[Respiratory system|respiratory]] or heart functions. Toxicity may occur through the skin; even touching the flowers can [[Hypoesthesia|numb]] finger tips.<ref name=drugs/>

The toxic effects of aconitine have been tested in a variety of animals, including mammals (dog, cat, guinea pig, mouse, rat and rabbit), frogs and pigeons. Depending on the route of exposure, the observed toxic effects were [[local anesthetic]] effect, [[diarrhea]], [[convulsions]], [[Cardiac dysrhythmia|arrhythmias]] or death.<ref name="drugs">{{cite web |title=Aconite |url=https://www.drugs.com/npp/aconite.html |website=Drugs.com |access-date=23 June 2020 |date=9 August 2019}}</ref><ref name=rtecs>{{ cite web | title = RTECS | date = Oct 2011 | url = http://ccinfoweb2.ccohs.ca/rtecs/Action.lasso?-database=rtecs&-layout=Display&-response=detail.html&-op=eq&RTECS+NUMBER=AR5960000&-search }}</ref> According to a review of different reports of aconite poisoning in humans, the following clinical features were observed:<ref name="pmid19514874"/>

* Neurological: [[paresthesia]] and numbness of face, [[perioral]] area and four limbs; muscle weakness in four limbs
* Cardiovascular: [[hypotension]], [[palpitations]], chest pain, [[bradycardia]], [[sinus tachycardia]], ventricular ectopics and other arrhythmias, ventricular arrhythmias, and [[junctional rhythm]]
* Gastrointestinal: nausea, vomiting, abdominal pain, and diarrhea
* Others: dizziness, [[hyperventilation]], sweating, difficulty breathing, confusion, headache, and [[lacrimation]]

Progression of symptoms: the first symptoms of aconitine poisoning appear approximately 20 minutes to 2 hours after oral intake and include paresthesia, sweating and nausea. This leads to severe vomiting, colicky diarrhea, intense pain and then paralysis of the skeletal muscles. Following the onset of life-threatening arrhythmia, including [[ventricular tachycardia]] and ventricular fibrillation, death finally occurs as a result of respiratory paralysis or cardiac arrest.<ref name=Beike/>

{{LD50}} values for mice are 1&nbsp;mg/kg orally, 0.100&nbsp;mg/kg intravenously, 0.270&nbsp;mg/kg intraperitoneally and 0.270&nbsp;mg/kg subcutaneously. The [[lowest published lethal dose]] (LDLo) for mice is 1&nbsp;mg/kg orally and 0.100&nbsp;mg/kg intraperitoneally. The [[lowest published toxic dose]] (TDLo) for mice is 0.0549&nbsp;mg/kg subcutaneously. LD50 value for rats is 0.064&nbsp;mg/kg intravenously. The LDLo for rats is 0.040&nbsp;mg/kg intravenously and 0.250&nbsp;mg/kg intraperitoneally. The TDLo for rats is 0.040&nbsp;mg/kg parenterally. For an overview of more test animal results (LD50, LDLo and TDLo) see the following table.<ref name=rtecs/>

{| class="wikitable"
|-
! Species observed !! Type of test !! Route of exposure !! Dose data (mg/kg) !! Toxic effects
|-
| Human || LDLo || Oral || 0.028 || Behavioral: excitement
Gastrointestinal: hypermotility, diarrhea
Gastrointestinal: other changes 
|-
| Human || LDLo || Oral || 0.029 || Details of toxic effects not reported other than lethal dose value
|-
| Cat || LD<sub>50</sub> || Intravenous || 0.080 || Behavioral: convulsions or effect on seizure threshold 
|-
| Cat || LDLo|| Subcutaneous || 0.100 || Details of toxic effects not reported other than lethal dose value 
|-
| Guinea pig || LD<sub>50</sub> || Intravenous || 0.060|| Behavioral: convulsions or effect on seizure threshold 
|-
| Guinea pig || LDLo || Subcutaneous || 0.050 || Details of toxic effects not reported other than lethal dose value 
|-
| Guinea pig || LDLo || Intravenous || 0.025 || Cardiac: arrhythmias (including changes in conduction) 
|-
| Mouse || LD<sub>50</sub> || Intraperitoneal || 0.270 || Details of toxic effects not reported other than lethal dose value 
|-
| Mouse || LD<sub>50</sub> || Intravenous || 0.100 || Sense Organs and Special Senses (Eye): lacrimation
Behavioral: convulsions or effect on seizure threshold
Lungs, Thorax, or Respiration: dyspnea 
|-
| Mouse || LD<sub>50</sub> || Oral || 1 || Details of toxic effects not reported other than lethal dose value
|-
| Mouse || LD<sub>50</sub> || Subcutaneous || 0.270 ||Details of toxic effects not reported other than lethal dose value 
|-
| Mouse || LDLo || Intraperitoneal || 0.100 || Details of toxic effects not reported other than lethal dose value 
|-
| Mouse || LDLo || Oral || 1 || Behavioral: convulsions or effect on seizure threshold
Cardiac: arrhythmias (including changes in conduction)
Gastrointestinal: hypermotility, diarrhea 
|-
| Mouse || TDLo || Subcutaneous || 0.0549 || Peripheral Nerve and Sensation: local anesthetic
Behavioral: analgesia
|-
| Rabbit || LDLo || Subcutaneous || 0.131 || Details of toxic effects not reported other than lethal dose value 
|-
| Rat || LD<sub>50</sub> || Intravenous || 0.080 || Behavioral: convulsions or effect on seizure threshold 
|-
| Rat || LD<sub>50</sub> || Intravenous || 0.064 || Details of toxic effects not reported other than lethal dose value 
|-
| Rat || LDLo || Intraperitoneal || 0.250 || Cardiac: other changes
Lungs, Thorax, or Respiration: dyspnea 
|-
| Rat || LDLo || Intravenous || 0.040 || Cardiac: arrhythmias (including changes in conduction) 
|-
| Rat || TDLo || Parenteral || 0.040 || Cardiac: arrhythmias (including changes in conduction) 
|-
| Frog || LDLo || Subcutaneous || 0.586 || Details of toxic effects not reported other than lethal dose value 
|-
| Pigeon || LDLo || Subcutaneous || 0.066 || Details of toxic effects not reported other than lethal dose value 
|}
* Note that LD<sub>50</sub> means lethal dose, 50 percent kill; LDLo means lowest published lethal dose; TDLo means lowest published toxic dose

For humans the lowest published oral lethal dose of 28 μg/kg was reported in 1969.

==Diagnosis and treatment==
For the analysis of the ''Aconitum'' alkaloids in biological specimens such as blood, serum and urine, several [[GC-MS]] methods have been described. These employ a variety of extraction procedures followed by derivatisation to their trimethylsilyl derivatives. New sensitive [[Liquid chromatography–mass spectrometry|HPLC-MS]] methods have been developed as well, usually preceded by SPE purification of the sample.<ref name=Beike>{{cite journal | vauthors = Beike J, Frommherz L, Wood M, Brinkmann B, Köhler H | title = Determination of aconitine in body fluids by LC-MS-MS | journal = International Journal of Legal Medicine | volume = 118 | issue = 5 | pages = 289–93 | date = October 2004 | pmid = 15674996 | doi = 10.1007/s00414-004-0463-2 | s2cid = 2490984 }}</ref> The antiarrhythmic drug [[lidocaine]] has been reported to be an effective treatment of aconitine poisoning of a patient. Considering the fact that aconitine acts as an agonist of the [[sodium channel]] receptor, antiarrhythmic agents which block the sodium channel (Vaughan-Williams' classification I) might be the first choice for the therapy of aconitine induced arrhythmias.<ref>{{cite journal | vauthors = Tsukada K, Akizuki S, Matsuoka Y, Irimajiri S | title = [A case of aconitine poisoning accompanied by bidirectional ventricular tachycardia treated with lidocaine] | language = ja | journal = Kokyu to Junkan. Respiration & Circulation | volume = 40 | issue = 10 | pages = 1003–6 | date = October 1992 | pmid = 1439251 }}</ref> Animal experiments have shown that the mortality of aconitine is lowered by [[tetrodotoxin]]. The toxic effects of aconitine were attenuated by tetrodotoxin, probably due to their mutual antagonistic effect on excitable membranes.<ref>{{cite journal | vauthors = Ohno Y, Chiba S, Uchigasaki S, Uchima E, Nagamori H, Mizugaki M, Ohyama Y, Kimura K, Suzuki Y | title = The influence of tetrodotoxin on the toxic effects of aconitine in vivo | journal = The Tohoku Journal of Experimental Medicine | volume = 167 | issue = 2 | pages = 155–8 | date = June 1992 | pmid = 1475787 | doi = 10.1620/tjem.167.155 | url = http://www.jstage.jst.go.jp/article/tjem1920/167/2/167_2_155/_pdf | format = pdf | doi-access = free }}</ref> Also [[paeoniflorin]] seems to have a detoxifying effect on the acute toxicity of aconitine in test animals. This may result from alternations of pharmacokinetic behavior of aconitine in the animals due to the pharmacokinetic interaction between aconitine and paeoniflorin.<ref>{{cite journal | vauthors = Fan YF, Xie Y, Liu L, Ho HM, Wong YF, Liu ZQ, Zhou H | title = Paeoniflorin reduced acute toxicity of aconitine in rats is associated with the pharmacokinetic alteration of aconitine | journal = Journal of Ethnopharmacology | volume = 141 | issue = 2 | pages = 701–8 | date = June 2012 | pmid = 21930193 | doi = 10.1016/j.jep.2011.09.005 }}</ref> In addition, in emergencies, one can wash the stomach using either tannic acid or powdered charcoal. Heart stimulants such as strong coffee or caffeine may also help until professional help is available.<ref>{{cite book | first = Sax N. | last = Irving | name-list-style = vanc | title = Dangerous Properties of Industrial Materials | edition = Fifth | location = New York | publisher = Van Nostrand Reinhold Company Inc. | isbn = 978-0-442-27373-6 | lccn = 78-20812 | year = 1979 }}</ref>

==Famous poisonings==
During the [[Indian Rebellion of 1857]], a British detachment was the target of attempted poisoning with aconitine by the Indian regimental cooks. The plot was thwarted by [[John Nicholson (East India Company officer)|John Nicholson]] who, having detected the plot, interrupted the British officers just as they were about to consume the poisoned meal. The chefs refused to taste their own preparation, whereupon it was force-fed to a monkey who "expired on the spot". The cooks were hanged.

Aconitine was the poison used by [[George Henry Lamson]] in 1881 to murder his brother-in-law in order to secure an inheritance. Lamson had learned about aconitine as a medical student from professor [[Robert Christison]], who had taught that it was undetectable—but forensic science had improved since Lamson's student days.<ref>{{cite book | last = Macinnis | first = Peter | name-list-style = vanc | title = It's True! You Eat Poison Every Day | publisher = Allen & Unwin | year = 2006 | isbn = 9781741146264 | pages = [https://archive.org/details/itstrueyoueatpoi0000mcin/page/80 80–81] | url = https://archive.org/details/itstrueyoueatpoi0000mcin/page/80 }}</ref><ref>{{cite book | last = Macinnis | first = Peter | name-list-style = vanc | title = Poisons: From Hemlock to Botox and the Killer Bean of Calabar | publisher = Arcade Publishing | year = 2005 | isbn = 978-1-55970-761-9 | pages = [https://archive.org/details/poisonsfromhemlo00maci/page/25 25–26] | url = https://archive.org/details/poisonsfromhemlo00maci/page/25 }}</ref><ref>{{ cite book | title = Some Famous Medical Trials | vauthors = Parry LA, Wright WH | publisher = Beard Books | year = 2000 | isbn = 978-1-58798-031-2 | page = 103 }}</ref>

[[Rufus T. Bush]], American industrialist and yachtsman, died on September 15, 1890, after accidentally taking a fatal dose of aconite.

In 1953 aconitine was used by a Soviet biochemist and poison developer, [[Grigory Mairanovsky]], in experiments with prisoners in the secret [[NKVD]] laboratory in Moscow. He admitted killing around 10 people using the poison.<ref>{{cite news|url=http://www.novayagazeta.ru/data/2010/gulag06/00.html |script-title=ru:Лаборатория Икс |trans-title=Laboratory X |newspaper=Novaya Gazeta |date=2010-05-06 |language=ru |url-status=dead |access-date=2013-04-08 |archive-url=https://web.archive.org/web/20100530064919/http://www.novayagazeta.ru/data/2010/gulag06/00.html |archive-date=2010-05-30 }}</ref>

In 2004 Canadian actor [[Andre Noble]] died from aconitine poisoning. He accidentally ate some monkshood while he was on a hike with his aunt in Newfoundland.

In 2009 [[Lakhvir Singh]] of [[Feltham]], west London, used aconitine to poison the food of her ex-lover [[Lakhvinder Cheema]] (who died as a result of the poisoning) and his current fiancée Gurjeet Choongh. Singh received a life sentence with a 23-year minimum for the murder on February 10, 2010.<ref>{{ cite news | url = http://news.bbc.co.uk/1/hi/england/london/8492936.stm | title = Poisoning in west London in 2009 | date = 2010-02-10 | newspaper = BBC TV News }}</ref>

In 2022, twelve diners at a restaurant in [[Regional Municipality of York|York Region]] became acutely ill following a meal. All twelve became seriously ill and four of them were admitted to the intensive care unit after the suspected poisoning.<ref>{{ cite news | url = https://www.medpagetoday.com/special-reports/features/100462| title = 12 People Poisoned at Toronto-Area Restaurant| date = 30 August 2022}}</ref>

==In popular culture==
Aconitine was a favorite poison in the ancient world. The poet [[Ovid]], referring to the proverbial dislike of stepmothers for their step-children, writes:

<blockquote><poem>''Lurida terribiles miscent aconita novercae''.<ref>Ovid, Metamorphoses, 1.147</ref>

Fearsome stepmothers mix lurid aconites.</poem> </blockquote>

Aconitine was also made famous by its use in [[Oscar Wilde]]'s 1891 story "[[Lord Arthur Savile's Crime (short story)|Lord Arthur Savile's Crime]]".  Aconite also plays a prominent role in James Joyce's ''[[Ulysses (novel)|Ulysses]]'', in which the father to protagonist Leopold Bloom used [[pastilles]] of the chemical to commit suicide.  Aconitine poisoning plays a key role in the murder mystery ''Breakdown'' by [[Jonathan Kellerman]] (2016). In [[Twin Peaks (season 3)|''Twin Peaks'' season 3]] part 13, aconitine is suggested as a means to poison the main character.<ref>{{cite magazine |url=https://ew.com/recap/twin-peaks-season-3-episode-13 |title=Twin Peaks recap: 'The Return: Part 13' |last=Jensen |first=Jeff |date=7 August 2017 |magazine=Entertainment Weekly |publisher=Meredith Corporation |access-date=4 May 2020 |quote="Clark offered to sell him Aconitine, a toxin with a rich literary history."}}</ref>

''Monk's Hood'' is the name of the third Cadfael novel written in 1980 by [[Ellis Peters]]. The novel was made into an episode of the television series ''[[Cadfael]]'' starring [[Derek Jacobi]].

In the third season of the Netflix series ''[[You (TV series)|You]]'', two of the main characters poison each other with aconitine. One survives (due to a lower dose and an antidote), and the other is killed. 

Hannah McKay ([[Yvonne Strahovski]]), a serial killer in the Showtime series ''[[Dexter (TV series)|Dexter]]'' uses aconite on at least three occasions to poison her victims.

In season 2 episode 16 of the series ''[[Person of Interest (TV series)|Person Of Interest]]'', aconitine is shown in a syringe stuck to the character Shaw ([[Sarah Shahi]]) nearly being injected and causing her death, until she is rescued by Reese ([[Jim Caviezel]]).

In a 2017 episode of ''[[The Doctor Blake Mysteries]]'', fight manager Gus Jansons ([[Steve Adams (actor)|Steve Adams]]) murdered his boxer, Mickey Ellis (Trey Coward), during a match by applying aconitine he had put in petroleum jelly and applying it to a cut over the boxer’s eye. He feared being [[blackmail]]ed over a murder he helped cover up. He had made the poison from [[Aconitum|wolfsbane]] he had seen in a local garden.<ref>December Media Pty. “A Lethal Combination.” The Doctor Blake Mysteries, Season 5, Episode 1. Australian Broadcasting Corporation, 17 September 2017.</ref> 

Aconitine poisoning is used by Villanelle to kill the Ukrainian gangster, Rinat Yevtukh in ''Killing Eve: No Tomorrow'' by [[Luke Jennings]] (2018).

== See also ==
* [[Pseudaconitine]]
* [[Tetrodotoxin]], a sodium channel blocker

== References ==
{{Reflist|32em}}

==External links==
*{{Commons category-inline}}

{{Chemical agents}}
{{Neurotoxins}}
{{Ancient anaesthesia-footer}}

[[Category:Diterpene alkaloids]]
[[Category:Ion channel toxins]]
[[Category:Non-protein ion channel toxins]]
[[Category:Neurotoxins]]
[[Category:Acetate esters]]
[[Category:Benzoate esters]]
[[Category:Secondary alcohols]]
[[Category:Tertiary alcohols]]
[[Category:Nitrogen heterocycles]]
[[Category:Sodium channel openers]]
[[Category:Plant toxins]]
[[Category:Heterocyclic compounds with 6 rings]]
[[Category:Methoxy compounds]]