Strychnine#Biosynthesis

File:StrychnineIII.svg

Strychnine is a terpene indole alkaloid belonging to the Strychnos family of Corynanthe alkaloids, and it is derived from tryptamine and secologanin.{{cite journal | vauthors = Bonjoch J, Solé D | title = Synthesis of Strychnine | journal = Chemical Reviews | volume = 100 | issue = 9 | pages = 3455–3482 | date = September 2000 | pmid = 11777429 | doi = 10.1021/cr9902547 | s2cid = 30921537}}{{cite book | vauthors = Dewick PM | title = Medicinal natural products: a biosynthetic approach | year = 2009 | publisher = A John Wiley & Sons | location = Chichester | isbn = 978-0-470-74167-2 | pages = 377–378 | edition = 3rd}} The biosynthesis of strychnine was solved in 2022.{{cite journal | doi = 10.1038/s41586-022-04950-4 | title = Biosynthesis of strychnine | journal = Nature | date = July 2022 | volume = 607 | issue = 7919 | pages = 617–622 | last1 = Hong | first1 = Benke | last2 = Grzech | first2 = Dagny | last3 = Caputi | first3 = Lorenzo | last4 = Sonawane | first4 = Prashant | last5 = López | first5 = Carlos E. Rodríguez | last6 = Kamileen | first6 = Mohamed Omar | last7 = Hernández Lozada | first7 = Néstor J. | last8 = Grabe | first8 = Veit | last9 = O'Connor | first9 = Sarah E. | pmid = 35794473 | pmc = 9300463 | s2cid = 250337382 | bibcode = 2022Natur.607..617H}} The enzyme, strictosidine synthase, catalyzes the condensation of tryptamine and secologanin, followed by a Pictet-Spengler reaction to form strictosidine.{{cite journal | vauthors = Treimer JF, Zenk MH | title = Purification and properties of strictosidine synthase, the key enzyme in indole alkaloid formation | journal = European Journal of Biochemistry | volume = 101 | issue = 1 | pages = 225–233 | date = November 1979 | pmid = 510306 | s2cid = 44588157 | doi = 10.1111/j.1432-1033.1979.tb04235.x | doi-access = free}} Many steps have been inferred by isolation of intermediates from Strychnos nux-vomica.{{cite journal | doi = 10.1039/C39730000217 | title = Biosynthesis of strychnine | journal = Journal of the Chemical Society, Chemical Communications | issue = 6 | pages = 217–218 | year = 1973 | vauthors = Heimberger SI, Scott AI | s2cid = 98685777}} The next step is hydrolysis of the acetal, which opens the ring by elimination of glucose (O-Glu) and provides a reactive aldehyde. The nascent aldehyde is then attacked by a secondary amine to afford geissoschizine, a common intermediate of many related compounds in the Strychnos family.

A reverse Pictet-Spengler reaction cleaves the C2–C3 bond, while subsequently forming the C3–C7 bond via a 1,2-alkyl migration, an oxidation from a Cytochrome P450 enzyme to a spiro-oxindole, nucleophilic attack from the enol at C16, and elimination of oxygen forms the C2–C16 bond to provide dehydropreakuammicine.{{cite journal | vauthors = Tatsis EC, Carqueijeiro I, Dugé de Bernonville T, Franke J, Dang TT, Oudin A, Lanoue A, Lafontaine F, Stavrinides AK, Clastre M, Courdavault V, O'Connor SE | title = A three enzyme system to generate the Strychnos alkaloid scaffold from a central biosynthetic intermediate | journal = Nature Communications | volume = 8 | issue = 1 | pages = 316 | date = August 2017 | pmid = 28827772 | pmc = 5566405 | doi = 10.1038/s41467-017-00154-x | doi-access = free | bibcode = 2017NatCo...8..316T | s2cid = 205542422}} Hydrolysis of the methyl ester and decarboxylation leads to norfluorocurarine. Stereospecific reduction of the endocyclic double bond by NADPH and hydroxylation provides the Wieland-Gumlich aldehyde, which was first isolated by Heimberger and Scott in 1973, although previously synthesized by Wieland and Gumlich in 1932.{{cite journal | doi = 10.1002/jlac.19324940116 | title = Über einige neue Reaktionen der Strychnos – Alkaloide. XI | trans-title = On some new reactions of the Strychnos alkaloids. XI | language = de | journal = Justus Liebig's Annalen der Chemie | volume = 494 | pages = 191–200 | year = 1932 | vauthors = Wieland H, Gumlich W | s2cid = 95378554}} To elongate the appendage by two carbons, acetyl-CoA is added to the aldehyde in an aldol reaction to afford prestrychnine. Strychnine is then formed by a facile addition of the amine with the carboxylic acid or its activated CoA thioester, followed by ring-closure via displacement of an activated alcohol.

{{Main|Strychnine total synthesis}}

As early researchers noted, the strychnine molecular structure, with its specific array of rings, stereocenters, and nitrogen functional groups, is a complex synthetic target, and has stimulated interest for that reason and for interest in the structure–activity relationships underlying its pharmacologic activities.{{cite journal | vauthors = Nicolaou KC, Vourloumis D, Winssinger N, Baran PS | title = The Art and Science of Total Synthesis at the Dawn of the Twenty-First Century | journal = Angewandte Chemie | volume = 39 | issue = 1 | pages = 44–122 | date = January 2000 | pmid = 10649349 | doi = 10.1002/(SICI)1521-3773(20000103)39:1<44::AID-ANIE44>3.0.CO;2-L | s2cid = 20559096}} An early synthetic chemist targeting strychnine, Robert Burns Woodward, quoted the chemist who determined its structure through chemical decomposition and related physical studies as saying that "for its molecular size it is the most complex organic substance known" (attributed to Sir Robert Robinson).{{cite journal | vauthors = Robinson R | year = 1952 | title = Molecular structure of Strychnine, Brucine and Vomicine | journal = Progress in Organic Chemistry | volume = 1 | pages = 2}}{{cite journal | vauthors = Seeman JI, House MC | author-link1 = Jeffrey I. Seeman | year = 2022 | title = 'For Its Size, the Most Complex Natural Product Known.' Who Deserves Credit for Determining the Structure of Strychnine? | journal = ACS Central Science | volume = 8 | issue = 6 | pages = 672–681 | doi = 10.1021/acscentsci.1c01348 | pmc = 9228570 | pmid = 35756373 | quote = For its molecular size it is the most complex substance known.}} citing {{cite journal | vauthors = Woodward RB, Cava MP, Ollis WD, Hunger A, Daeniker HU, Schenker K | year = 1963 | title = The Total Synthesis of Strychnine | journal = Tetrahedron | volume = 19 | issue = 2 | pages = 247–288 | doi = 10.1016/S0040-4020(01)98529-1}}

File:Strychnine Star chemdraw.jpg

The first total synthesis of strychnine was reported by the research group of R. B. Woodward in 1954, and is considered a classic in this field.{{cite book | vauthors = Nicolaou KC, Sorensen EJ | date = 1996 | title = Classics in Total Synthesis: Targets, Strategies, Methods | publisher = Wiley | isbn = 978-3-527-29231-8}} {{page needed|date=June 2014}} The Woodward account published in 1954 was very brief (3 pages),{{cite journal | vauthors = Woodward RB, Cava MP, Ollis WD, Hunger A, Daeniker HU, Schenker K | title = The total synthesis of strychnine | journal = Journal of the American Chemical Society | volume = 76 | issue = 18 | pages = 4749–4751 | year = 1954 | doi = 10.1021/ja01647a088| bibcode = 1954JAChS..76.4749W }} but was followed by a 42-page report in 1963.{{cite journal | vauthors = Woodward RB | title = The total synthesis of strychnine | journal = Experientia | volume = 19 | issue = Suppl 2 | pages = 213–228 | year = 1963 | pmid = 13305562 | doi = 10.1016/S0040-4020(01)98529-1}} The molecule has since received continuing wide attention in the years since for the challenges to synthetic organic strategy and tactics presented by its complexity; its synthesis has been targeted and its stereocontrolled preparation independently achieved by more than a dozen research groups since the first success.{{cite journal | last1 = Eichberg | first1 = Michael J. | last2 = Dorta | first2 = Rosa L. | last3 = Lamottke | first3 = Kai | last4 = Vollhardt | first4 = K. Peter C. | year = 2000 | title = The Formal Total Synthesis of (±)-Strychnine via a Cobalt-Mediated [2 + 2 + 2]Cycloaddition | journal = Org. Lett. | volume = 2 | issue = 16| pages = 2479–2481 | doi = 10.1021/ol006131m | pmid = 10956526 }}{{cite journal | last1 = Eichberg | first1 = Michael J. | last2 = Dorta | first2 = Rosa L. | last3 = Grotjahn | first3 = Douglas B. | last4 = Lamottke | first4 = Kai | last5 = Schmidt | first5 = Martin | last6 = Vollhardt | first6 = K. Peter C. | year = 2001 | title = Approaches to the Synthesis of (±)-Strychnine via the Cobalt-Mediated [2 + 2 + 2] Cycloaddition: Rapid Assembly of a Classic Framework | journal = J. Am. Chem. Soc. | volume = 123 | issue = 38| pages = 9324–9337 | doi = 10.1021/ja016333t | pmid = 11562215 | bibcode = 2001JAChS.123.9324E }}

Strychnine is a neurotoxin which acts as an antagonist of glycine and acetylcholine receptors. It primarily affects the motor nerve fibers in the spinal cord which control muscle contraction. An impulse is triggered at one end of a nerve cell by the binding of neurotransmitters to the receptors. In the presence of an inhibitory neurotransmitter, such as glycine, a greater quantity of excitatory neurotransmitters must bind to receptors before an action potential is generated. Glycine acts primarily as an agonist of the glycine receptor, which is a ligand-gated chloride channel in neurons located in the spinal cord and in the brain. This chloride channel allows the negatively charged chloride ions into the neuron, causing a hyperpolarization which pushes the membrane potential further from threshold. Strychnine is an antagonist of glycine; it binds noncovalently to the same receptor, preventing the inhibitory effects of glycine on the postsynaptic neuron. Therefore, action potentials are triggered with lower levels of excitatory neurotransmitters. When the inhibitory signals are prevented, the motor neurons are more easily activated and the victim has spastic muscle contractions, resulting in death by asphyxiation.{{cite book | vauthors = Waring RH, Steventon GB, Mitchell SC | title = Molecules of death | publisher = Imperial College Press | date = 2007}} {{page needed|date=February 2017}} Strychnine binds the Aplysia californica acetylcholine binding protein (a homolog of nicotinic receptors) with high affinity but low specificity, and does so in multiple conformations.{{cite journal | vauthors = Brams M, Pandya A, Kuzmin D, van Elk R, Krijnen L, Yakel JL, Tsetlin V, Smit AB, Ulens C | title = A structural and mutagenic blueprint for molecular recognition of strychnine and d-tubocurarine by different cys-loop receptors | journal = PLOS Biology | volume = 9 | issue = 3 | pages = e1001034 | date = March 2011 | pmid = 21468359 | pmc = 3066128 | doi = 10.1371/journal.pbio.1001034 | doi-access = free | s2cid = 14123035}}

{{main|Strychnine poisoning}}

In high doses, strychnine is very toxic to humans (minimum lethal oral dose in adults is 30–120 mg) and many other animals (oral {{LD50}} = 16 mg/kg in rats, 2 mg/kg in mice),{{cite web | work = INCHEM: Chemical Safety Information from Intergovernmental Organizations | title = Strychnine | url = http://www.inchem.org/documents/pims/chemical/pim507.htm | access-date = 2010-12-14 | archive-date = 2015-01-03 | archive-url = https://web.archive.org/web/20150103231725/http://www.inchem.org/documents/pims/chemical/pim507.htm | url-status = live}} and poisoning by inhalation, swallowing, or absorption through eyes or mouth can be fatal. S. nux-vomica seeds are generally effective as a poison only when they are crushed or chewed before swallowing because the pericarp is quite hard and indigestible; poisoning symptoms may therefore not appear if the seeds are ingested whole.{{cite journal | vauthors = Koleva II, van Beek TA, Soffers AE, Dusemund B, Rietjens IM | title = Alkaloids in the human food chain--natural occurrence and possible adverse effects | journal = Molecular Nutrition & Food Research | volume = 56 | issue = 1 | pages = 30–52 | date = January 2012 | pmid = 21823220 | doi = 10.1002/mnfr.201100165 | s2cid = 9188046}}{{cite book | pmid = 29083795 | id = {{NCBIBook|NBK459306}} | title = Strychnine Toxicity | publisher = StatPearls | vauthors = Otter J, D'Orazio JL | date = August 7, 2023}}

File:Paolucci & lupi.jpg, Italy, 1924.]]

Strychnine poisoning in animals usually occurs from ingestion of baits designed for use against gophers, rats, squirrels, moles, chipmunks and coyotes. Strychnine is also used as a rodenticide, but is not specific to such unwanted pests and may kill other small animals.{{cite news |title=Sale of free strychnine, an outrageous abuse of the County's liberal policy |url=https://www.newspapers.com/image/565833577/?match=1&terms=strychnine%20abuse |access-date=5 June 2024 |publisher=The Weekly Spokesman-Review |date=23 August 1894}}{{cite web | title = CDC – The Emergency Response Safety and Health Database: Biotoxin: Strychnine – NIOSH | url = https://www.cdc.gov/niosh/ershdb/emergencyresponsecard_29750018.html | website = www.cdc.gov | access-date = 2016-01-02 | archive-date = 2015-12-21 | archive-url = https://web.archive.org/web/20151221180423/http://www.cdc.gov/niosh/ershdb/emergencyresponsecard_29750018.html | url-status = live}} In the United States, most baits containing strychnine have been replaced with zinc phosphide baits since 1990. In the European Union, rodenticides with strychnine have been forbidden since 2006. Some animals are immune to strychnine; usually these have evolved resistance to poisonous strychnos alkaloids in the fruit they eat, such as fruit bats. The drugstore beetle has a symbiotic gut yeast that allows it to digest pure strychnine.

Strychnine toxicity in rats is dependent on sex. It is more toxic to females than to males when administered via subcutaneous injection or intraperitoneal injection. Differences are due to higher rates of metabolism by male rat liver microsomes. Dogs and cats are more susceptible among domestic animals, pigs are believed to be as susceptible as dogs, and horses are able to tolerate relatively large amounts of strychnine. Birds affected by strychnine poisoning exhibit wing droop, salivation, tremors, muscle tenseness, and convulsions. Death occurs as a result of respiratory arrest. The clinical signs of strychnine poisoning relate to its effects on the central nervous system. The first clinical signs of poisoning include nervousness, restlessness, twitching of the muscles, and stiffness of the neck. As the poisoning progresses, the muscular twitching becomes more pronounced and convulsions suddenly appear in all the skeletal muscles. The limbs are extended and the neck is curved to opisthotonus. The pupils are widely dilated. As death approaches, the convulsions follow one another with increased rapidity, severity, and duration. Death results from asphyxia due to prolonged paralysis of the respiratory muscles. Following the ingestion of strychnine, symptoms of poisoning usually appear within 15 to 60 minutes.

File:Opisthotonus in a patient suffering from tetanus - Painting by Sir Charles Bell - 1809.jpg depicting opisthotonus caused by tetanus]]

After injection, inhalation, or ingestion, the first symptoms to appear are generalized muscle spasms. They appear very quickly after inhalation or injection – within as few as five minutes – and take somewhat longer to manifest after ingestion, typically approximately 15 minutes. With a very high dose, the onset of respiratory failure and brain death can occur in 15 to 30 minutes. If a lower dose is ingested, other symptoms begin to develop, including seizures, cramping, stiffness,{{cite journal | vauthors = Duverneuil C, de la Grandmaison GL, de Mazancourt P, Alvarez JC | title = Liquid chromatography/photodiode array detection for determination of strychnine in blood: a fatal case report | journal = Forensic Science International | volume = 141 | issue = 1 | pages = 17–21 | date = April 2004 | pmid = 15066709 | doi = 10.1016/j.forsciint.2003.12.010 | s2cid = 42860729}} hypervigilance, and agitation.{{cite journal | vauthors = Santhosh GJ, Joseph W, Thomas M | title = Strychnine poisoning | journal = The Journal of the Association of Physicians of India | volume = 51 | pages = 739–740 | date = July 2003 | pmid = 14621058}} Seizures caused by strychnine poisoning can start as early as 15 minutes after exposure and last 12–24 hours. They are often triggered by sights, sounds, or touch and can cause other adverse symptoms, including hyperthermia, rhabdomyolysis, myoglobinuric kidney failure, metabolic acidosis, and respiratory acidosis. During seizures, mydriasis (abnormal dilation), exophthalmos (protrusion of the eyes), and nystagmus (involuntary eye movements) may occur.

As strychnine poisoning progresses, tachycardia (rapid heart beat), hypertension (high blood pressure), tachypnea (rapid breathing), cyanosis (blue discoloration), diaphoresis (sweating), water-electrolyte imbalance, leukocytosis (high number of white blood cells), trismus (lockjaw), risus sardonicus (spasm of the facial muscles), and opisthotonus (dramatic spasm of the back muscles, causing arching of the back and neck) can occur. In rare cases, the affected person may experience nausea or vomiting.

The proximate cause of death in strychnine poisoning can be cardiac arrest, respiratory failure, multiple organ failure, or brain damage.

For occupational exposures to strychnine, the Occupational Safety and Health Administration and the National Institute for Occupational Safety and Health have set exposure limits at 0.15 mg/m³ over an 8-hour work day.{{cite web | title = Strychnine | url = https://www.cdc.gov/niosh/npg/npgd0570.html | work = CDC – NIOSH Pocket Guide to Chemical Hazards | access-date = 2017-09-15 | archive-date = 2017-05-11 | archive-url = https://web.archive.org/web/20170511071949/https://www.cdc.gov/niosh/npg/npgd0570.html | url-status = live}}

Because strychnine produces some of the most dramatic and painful symptoms of any known toxic reaction, strychnine poisoning is often portrayed in literature and film including authors Agatha Christie and Arthur Conan Doyle.{{cite web | title = Chemistry in its element – strychnine | url = http://www.rsc.org/chemistryworld/podcast/CIIEcompounds/transcripts/strychnine.asp | publisher = Royal Society of Chemistry | access-date = 18 May 2016 | archive-date = 23 June 2016 | archive-url = https://web.archive.org/web/20160623221712/http://www.rsc.org/chemistryworld/podcast/CIIEcompounds/transcripts/strychnine.asp | url-status = live}}

There is no antidote for strychnine poisoning.{{Cite web |date=2023-05-26 |title=Strychnine: Biotoxin {{!}} NIOSH {{!}} CDC |url=https://www.cdc.gov/niosh/ershdb/emergencyresponsecard_29750018.html |access-date=2024-08-12 |website=www.cdc.gov |language=en-us}} Strychnine poisoning demands aggressive management with early control of muscle spasms, intubation for loss of airway control, toxin removal (decontamination), intravenous hydration and potentially active cooling efforts in the context of hyperthermia as well as hemodialysis in kidney failure (strychnine has not been shown to be removed by hemodialysis).{{cite web |title=CDC – The Emergency Response Safety and Health Database: Biotoxin: Strychnine – NIOSH |url=https://www.cdc.gov/niosh/ershdb/emergencyresponsecard_29750018.html |url-status=live |archive-url=https://web.archive.org/web/20151221180423/http://www.cdc.gov/niosh/ershdb/emergencyresponsecard_29750018.html |archive-date=2015-12-21 |access-date=2016-01-02 |website=www.cdc.gov}} Treatment involves oral administration of activated charcoal, which adsorbs strychnine within the digestive tract; unabsorbed strychnine is removed from the stomach by gastric lavage, along with tannic acid or potassium permanganate solutions to oxidize strychnine.{{Cite journal |last=Patocka |first=Jiri |date=December 2015 |editor-last=Gupta |editor-first=Ramesh C. |title=Strychnine |url=https://www.researchgate.net/publication/282272675 |journal=Handbook of Toxicology of Chemical Warfare Agents |edition=2nd |publisher=Elsevier Inc. |pages=215–222 |doi=10.1016/B978-0-12-800159-2.00017-8 |isbn=978-0-12-800159-2 |via=ResearchGate}}

Activated charcoal is a substance that can bind to certain toxins in the digestive tract and prevent their absorption into the bloodstream.{{cite web |title=Charcoal, Activated (Oral Route) Proper Use - Mayo Clinic |url=https://www.mayoclinic.org/drugs-supplements/charcoal-activated-oral-route/proper-use/drg-20070087 |url-status=live |archive-url=https://web.archive.org/web/20240206023304/https://www.mayoclinic.org/drugs-supplements/charcoal-activated-oral-route/proper-use/drg-20070087 |archive-date=2024-02-06 |access-date=2024-02-06 |website=Mayo Clinic}} The effectiveness of this treatment, as well as how long it is effective after ingestion, are subject to debate.{{cite journal |vauthors=Shadnia S, Moiensadat M, Abdollahi M |date=April 2004 |title=A case of acute strychnine poisoning |journal=Veterinary and Human Toxicology |volume=46 |issue=2 |pages=76–9 |pmid=15080207 |s2cid=23272093}}{{cite book |title=Strychnine Toxicity |vauthors=Otter J, D'Orazio JL |date=August 7, 2023 |publisher=StatPearls |pmid=29083795 |id={{NCBIBook|NBK459306}}}}{{cite journal |vauthors=Cooney DO |date=August 1995 |title=Evaluation of the US pharmacopeia adsorption tests for activated charcoals and proposals for changes |journal=Veterinary and Human Toxicology |volume=37 |issue=4 |pages=371–7 |pmid=8540235 |s2cid=67975596}} According to one source, activated charcoal is only effective within one hour of poison being ingested, although the source does not regard strychnine specifically.{{cite journal |last=Lapus |first=Robert Michael |date=April 2007 |title=Activated charcoal for pediatric poisonings: the universal antidote? |url=https://emergency.med.ufl.edu/files/2013/02/Activated-charcoal.pdf |url-status=live |journal=Current Opinion in Pediatrics |volume=19 |issue=2 |pages=216–222 |doi=10.1097/MOP.0b013e32801da2a9 |pmid=17496769 |s2cid=6728477 |archive-url=https://web.archive.org/web/20240206022505/https://emergency.med.ufl.edu/files/2013/02/Activated-charcoal.pdf |archive-date=2024-02-06 |access-date=2024-02-06}} Other sources specific to strychnine state that activated charcoal may be used after one hour of ingestion, depending on dose and type of strychnine-containing product.{{cite journal |vauthors=Hayden JW, Comstock EG |date=1975 |title=Use of Activated Charcoal in Acute Poisoning |url=https://www.tandfonline.com/doi/pdf/10.3109/15563657508988096 |url-status=live |journal=Clinical Toxicology |volume=8 |issue=5 |pages=515–533 |doi=10.3109/15563657508988096 |pmid=770060 |s2cid=42542989 |archive-url=https://web.archive.org/web/20240308030358/https://www.tandfonline.com/doi/pdf/10.3109/15563657508988096 |archive-date=2024-03-08 |access-date=2024-02-06|url-access=subscription }} Therefore, other treatment options are generally favoured over activated charcoal.{{cite web |date=16 January 2020 |title=CDC Strychnine | Facts about Strychnine | Public Health Emergency Preparedness& Response |url=https://emergency.cdc.gov/agent/strychnine/basics/facts.asp |url-status=live |archive-url=https://web.archive.org/web/20240206022505/https://emergency.cdc.gov/agent/strychnine/basics/facts.asp |archive-date=6 February 2024 |access-date=6 February 2024}}

The use of activated charcoal is considered dangerous in patients with tenuous airways or altered mental states.{{cite journal |vauthors=Smith BA |year=1990 |title=Strychnine poisoning |journal=The Journal of Emergency Medicine |volume=8 |issue=3 |pages=321–325 |doi=10.1016/0736-4679(90)90013-L |pmid=2197324}}

Most other treatment options focus on controlling the convulsions that arise from strychnine poisoning. These treatments involve keeping the patient in a quiet and darkened room,{{Cite web |title=Drugs and Poisons Fact Sheet: Strychnine Permits - What you need to know |url=https://www.bulloo.qld.gov.au/downloads/file/978/9-strychnine-guide |access-date=12 August 2024 |publisher=Queensland Health}} anticonvulsants such as phenobarbital or diazepam, muscle relaxants such as dantrolene,{{Cite web |title=Final Diagnosis -- Case 550 |url=https://path.upmc.edu/cases/case550/dx.html |access-date=2024-08-12 |website=path.upmc.edu}} barbiturates and propofol,{{cite journal |vauthors=Lages A, Pinho J, Alves R, Capela C, Lourenço E, Lencastre L |date=16 May 2013 |title=Strychnine Intoxication: A Case Report |journal=Journal of Medical Cases |volume=4 |issue=6 |pages=385–388 |doi=10.4021/jmc1189w |s2cid=54707248 |doi-access=free}} and chloroform or heavy doses of chloral, bromide, urethane or amyl nitrite.{{cite book |title=Pharmacology and Therapeutics |vauthors=Cushny AR |date=January 1, 1940 |publisher=Lea & Febiger |edition=12 |asin=B000SNDA1U}}{{cite journal |vauthors=Buckley S |date=September 1873 |title=Case of Strychnine Poisoning Successfully Treated by Atropine |journal=Edinburgh Medical Journal |volume=19 |issue=3 |pages=211–213 |pmc=5315983 |pmid=29640880 |s2cid=4760315}}{{cite journal |date=1932 |title=The Treatment of Strychnine Poisoning |url=https://jamanetwork.com/journals/jama/article-abstract/280615 |url-status=live |journal=Journal of the American Medical Association |volume=98 |issue=23 |page=1992 |doi=10.1001/jama.1932.02730490038013 |archive-url=https://web.archive.org/web/20240206023304/https://jamanetwork.com/journals/jama/article-abstract/280615 |archive-date=2024-02-06 |access-date=2024-02-06|url-access=subscription }}{{cite web |date=8 September 2021 |title=Strychnine and Vomit: The Untold Story of Past US Addiction Treatments |url=https://filtermag.org/strychnine-addiction-treatments/ |url-status=live |archive-url=https://web.archive.org/web/20240206023305/https://filtermag.org/strychnine-addiction-treatments/ |archive-date=6 February 2024 |access-date=6 February 2024}} If a poisoned person is able to survive for 6 to 12 hours subsequent to initial dose, they have a good prognosis.

The sine qua non of strychnine toxicity is the "awake" seizure, in which tonic-clonic activity occurs but the patient is alert and oriented throughout and afterwards.{{cite journal |vauthors=Boyd RE, Brennan PT, Deng JF, Rochester DF, Spyker DA |date=March 1983 |title=Strychnine poisoning. Recovery from profound lactic acidosis, hyperthermia, and rhabdomyolysis |journal=The American Journal of Medicine |volume=74 |issue=3 |pages=507–512 |doi=10.1016/0002-9343(83)90999-3 |pmid=6829597 |s2cid=3222667}} Accordingly, George Harley (1829–1896) showed in 1850 that curare (wourali) was effective for the treatment of tetanus and strychnine poisoning.

Strychnine may be introduced into the body orally, by inhalation, or by injection. It is a potently bitter substance, and in humans has been shown to activate bitter taste receptors TAS2R10 and TAS2R46.{{cite journal | vauthors = Meyerhof W, Batram C, Kuhn C, Brockhoff A, Chudoba E, Bufe B, Appendino G, Behrens M | title = The molecular receptive ranges of human TAS2R bitter taste receptors | journal = Chemical Senses | volume = 35 | issue = 2 | pages = 157–170 | date = February 2010 | pmid = 20022913 | doi = 10.1093/chemse/bjp092 | doi-access = free | s2cid = 15537937}}{{cite journal | vauthors = Born S, Levit A, Niv MY, Meyerhof W, Behrens M | title = The human bitter taste receptor TAS2R10 is tailored to accommodate numerous diverse ligands | journal = The Journal of Neuroscience | volume = 33 | issue = 1 | pages = 201–213 | date = January 2013 | pmid = 23283334 | pmc = 6618634 | doi = 10.1523/JNEUROSCI.3248-12.2013 | s2cid = 17263291}}{{cite journal | vauthors = Meyerhof W, Born S, Brockhoff A, Behrens M | doi = 10.1002/ffj.2041 | title = Molecular biology of mammalian bitter taste receptors. A review | journal = Flavour and Fragrance Journal | volume = 26 | issue = 4 | pages = 260–268 | year = 2011 | s2cid = 82519304}} Strychnine is rapidly absorbed from the gastrointestinal tract.{{cite journal | vauthors = Lambert JR, Byrick RJ, Hammeke MD | title = Management of acute strychnine poisoning | journal = Canadian Medical Association Journal | volume = 124 | issue = 10 | pages = 1268–1270 | date = May 1981 | pmid = 7237316 | pmc = 1705440}}

Strychnine is transported by plasma and red blood cells. Due to slight protein binding, strychnine leaves the bloodstream quickly and distributes to bodily tissues. Approximately 50% of the ingested dose can enter the tissues in 5 minutes. Also within a few minutes of ingestion, strychnine can be detected in the urine. Little difference was noted between oral and intramuscular administration of strychnine in a 4 mg dose.{{cite book | title = Handbook of toxicology of chemical warfare agents | vauthors = Gupta RC | year = 2009 | publisher = Elsevier/Academic Press | isbn = 978-0-12-800159-2 | oclc = 433545336}} In persons killed by strychnine, the highest concentrations are found in the blood, liver, kidney and stomach wall. The usual fatal dose is 60–100 mg strychnine and is fatal after a period of 1–2 hours, though lethal doses vary depending on the individual.

Strychnine is rapidly metabolized by the liver microsomal enzyme system requiring NADPH and O₂. Strychnine competes with the inhibitory neurotransmitter glycine resulting in an excitatory state. However, the toxicokinetics after overdose have not been well described. In most severe cases of strychnine poisoning, the patient dies before reaching the hospital. The biological half-life of strychnine is about 10 hours.

A few minutes after ingestion, strychnine is excreted unchanged in the urine, and accounts for about 5 to 15% of a sublethal dose given over 6 hours. Approximately 10 to 20% of the dose will be excreted unchanged in the urine in the first 24 hours. The percentage excreted decreases with the increasing dose. Of the amount excreted by the kidneys, about 70% is excreted in the first 6 hours, and almost 90% in the first 24 hours. Excretion is virtually complete in 48 to 72 hours.

Strychnine was the first alkaloid to be identified in plants of the genus Strychnos, family Loganiaceae. Strychnos, named by Carl Linnaeus in 1753, is a genus of trees and climbing shrubs of the Gentianales order. The genus contains 196 various species and is distributed throughout the warm regions of Asia (58 species), America (64 species), and Africa (75 species). The seeds and bark of many plants in this genus contain strychnine.

The toxic and medicinal effects of Strychnos nux-vomica have been well known from the times of ancient India, although the chemical compound itself was not identified and characterized until the 19th century. The inhabitants of these countries had historical knowledge of the species Strychnos nux-vomica and Saint-Ignatius' bean (Strychnos ignatii). Strychnos nux-vomica is a tree native to the tropical forests on the Malabar Coast in Southern India, Sri Lanka and Indonesia, which attains a height of about {{convert|12|m}}. The tree has a crooked, short, thick trunk and the wood is close grained and very durable. The fruit has an orange color and is about the size of a large apple with a hard rind and contains five seeds, which are covered with a soft wool-like substance. The ripe seeds look like flattened disks, which are very hard. These seeds are the chief commercial source of strychnine and were first imported to and marketed in Europe as a poison to kill rodents and small predators. Strychnos ignatii is a woody climbing shrub of the Philippines. The fruit of the plant, known as Saint Ignatius' bean, contains as many as 25 seeds embedded in the pulp. The seeds contain more strychnine than other commercial alkaloids. The properties of S. nux-vomica and S. ignatii are substantially those of the alkaloid strychnine.

Strychnine was first discovered by French chemists Joseph Bienaimé Caventou and Pierre-Joseph Pelletier in 1818 in the Saint-Ignatius' bean.{{cite journal | vauthors = Pelletier PP, Caventou JB | author-link1 = Pierre-Joseph Pelletier | author-link2 = Joseph Bienaimé Caventou | year = 1818 | title = Note sur un nouvel alkalai | trans-title = Note on a new alkali | language = fr | url = https://books.google.com/books?id=-N43AAAAMAAJ&pg=PA323 | journal = Annales de Chimie et de Physique | volume = 8 | pages = 323–324 | access-date = 2016-10-06 | archive-date = 2024-03-08 | archive-url = https://web.archive.org/web/20240308030358/https://books.google.com/books?id=-N43AAAAMAAJ&pg=PA323#v=onepage&q&f=false | url-status = live}}{{cite journal | vauthors = Pelletier PP, Caventou JB | date = 1819 | url = https://books.google.com/books?id=sSE4AQAAIAAJ&pg=PA142 | title = Mémoire sur un nouvel alcali vegetal (la strychnine) trouvé dans la feve de Saint-Ignace, la noix vomique, etc. | trans-title = Memoir on a new vegetable alkali (strychnine) found in the St. Ignatius bean, the nux-vomica, etc) | language = fr | journal = Annales de Chimie et de Physique | volume = 10 | pages = 142–176 | access-date = 2016-10-06 | archive-date = 2024-03-08 | archive-url = https://web.archive.org/web/20240308030358/https://books.google.com/books?id=sSE4AQAAIAAJ&pg=PA142#v=onepage&q&f=false | url-status = live}} In some Strychnos plants a 9,10-dimethoxy derivative of strychnine, the alkaloid brucine, is also present. Brucine is not as poisonous as strychnine. Historic records indicate that preparations containing strychnine (presumably) had been used to kill dogs, cats, and birds in Europe as far back as 1640.{{cite book | vauthors = Gupta RC, Patocka J | date = 2009 | title = Handbook of Toxicology of Chemical Warfare Agents | url = https://books.google.com/books?id=OVpNT6Vpkx8C&q=1640 | location = London | publisher = Academic Press | page = 199 | isbn = 978-0-08-092273-7 | access-date = 2020-10-20 | archive-date = 2024-03-08 | archive-url = https://web.archive.org/web/20240308030358/https://books.google.com/books?id=OVpNT6Vpkx8C&q=1640#v=snippet&q=1640&f=false | url-status = live}} It was allegedly used by convicted murderer William Palmer to kill his final victim, John Cook.{{cite book | last = Hayhurst | first = Alan | title = Staffordshire MURDERS | year = 2008 | publisher = The History Press | location = Gloucestershire | isbn = 978-0-7509-4706-0 | pages = 15–36}} It was also used during World War II by Oskar Dirlewanger against civilians.{{cite book | vauthors = Grunberger R | title = The 12-Year Reich: A Social History of Nazi Germany, 1933–1945 | publisher = Holt, Rinehart and Winston | date = 1971 | page = 104}}

The structure of strychnine was first determined in 1946 by Sir Robert Robinson and in 1954 this alkaloid was synthesized in a laboratory by Robert B. Woodward. This is one of the most famous syntheses in the history of organic chemistry. Both chemists won the Nobel prize (Robinson in 1947 and Woodward in 1965).

Strychnine has been used as a plot device in the author Agatha Christie's murder mysteries.{{cite web | title = Killed by Agatha Christie: Strychnine and the detective novel | url = http://www.open.edu/openlearn/history-the-arts/culture/literature-and-creative-writing/literature/killed-agatha-christie-strychnine-and-the-detective-novel | website = www.open.edu | publisher = Open University | access-date = 27 July 2017 | archive-date = 20 August 2017 | archive-url = https://web.archive.org/web/20170820221016/http://www.open.edu/openlearn/history-the-arts/culture/literature-and-creative-writing/literature/killed-agatha-christie-strychnine-and-the-detective-novel | url-status = live}}

Strychnine was popularly used as an athletic performance enhancer and recreational stimulant in the late 19th century and early 20th century, due to its convulsant effects. One notorious instance of its use was during the 1904 Olympics marathon, when track-and-field athlete Thomas Hicks was unwittingly administered a concoction of egg whites and brandy laced with a small amount of strychnine by his assistants in an attempt to boost his stamina. Hicks won the race, but was hallucinating{{cite magazine | last1 = Abbott | first1 = Karen | author-link1 = Karen Abbott | date = August 7, 2012 | title = The 1904 Olympic Marathon May Have Been the Strangest Ever | magazine = Smithsonian Magazine | language = en | url = https://www.smithsonianmag.com/history/the-1904-olympic-marathon-may-have-been-the-strangest-ever-14910747/ | access-date = April 8, 2024 | quote = He began hallucinating, believing that the finish line was still 20 miles away.}} by the time he reached the finish line, and soon after collapsed.{{cite web | title = Thomas Hicks | url = https://www.olympedia.org/athletes/78551 | access-date = January 17, 2021 | work = Olympedia}}

Maximilian Theodor Buch proposed it as a cure for alcoholism around the same time. It was thought to be similar to coffee,{{cite web | url = http://io9.com/why-strychnine-was-an-early-performance-enhancing-drug-512532345 | title = Rat poison strychnine was an early performance-enhancing drug | vauthors = Inglis-Arkell E | date = 11 June 2013 | website = io9 | publisher = Gawker Media | access-date = 23 Nov 2015 | archive-date = 23 November 2015 | archive-url = https://web.archive.org/web/20151123151637/http://io9.com/why-strychnine-was-an-early-performance-enhancing-drug-512532345 | url-status = live}}{{cite web | url = http://www.spectroscopynow.com/details/ezine/sepspec12719ezine/Strictly-strychnine---medicines-to-be-avoided-by-athletes.html?tzcheck=1 | title = Strictly strychnine – medicines to be avoided by athletes | access-date = 2015-05-27 | archive-date = 2015-05-28 | archive-url = https://web.archive.org/web/20150528012115/http://www.spectroscopynow.com/details/ezine/sepspec12719ezine/Strictly-strychnine---medicines-to-be-avoided-by-athletes.html?tzcheck=1 | url-status = live}} and also has been used and abused recreationally.{{cite news |title=News Briefs |url=https://www.newspapers.com/image/436941471/?match=1&terms=Strychnine%20abuse |access-date=4 June 2024 |publisher=The Sioux City Journal |date=14 November 1908}}{{cite web |title=The Sonics - Strychnine lyrics |url=https://genius.com/The-sonics-strychnine-lyrics |website=Genius.com |access-date=4 June 2024}}

Its effects are well-described in H. G. Wells' novella The Invisible Man: the title character states "Strychnine is a grand tonic ... to take the flabbiness out of a man." Dr Kemp, an acquaintance, replies: "It's the devil. It's the palaeolithic in a bottle."{{cite wikisource | vauthors = Wells HG | author-link1 = H. G. Wells | title = The Invisible Man | wslink = The Invisible Man (1897) | chapter = Chapter 20 | date = 1897}}

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Category:Avicides

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Category:Strychnine poisoning