Strychnine: From Isolation to Total Synthesis – Part 1

Strychnine: From Isolation to Total Synthesis – Part 1

Author: Klaus Roth


For centuries, chemists fascinated by the extreme toxicity of certain plants have been interested in studying the various compounds they contain. Nux vomica (“poison nuts”, also known as “Quaker buttons”, from the species Strychnos nux vomica, and our primary source of strychnine) have proved to be particularly “hard nuts to crack”, and have given generations of chemists – including several Nobel Prize winners – a tough time in problems of isolation, structure determination, and finally total synthesis.

A Short Route to Strychnine

Here we look back with pride at some of the preeminent achievements in this regard, allowing ourselves perhaps to become infected with a bit of the enthusiasm synthetic organic chemists of our own day develop as they seek ever shorter and more elegant ways to prepare strychnine and other complex materials.


1. Natural-Product Chemistry

Medicinal herbs and poisonous plants have always exerted a magical fascination, leading physicians, naturalists, pharmacists, and chemists over the years to study them in an attempt to decipher more of the secrets of their mode of action. Even though it has been possible to isolate and investigate pure components from plants for almost 200 years, the field continues to be highly productive; indeed, new natural products are discovered, and have their structures established, on an almost daily basis. Many eventually become, either directly or with slight chemical modification, pharmaceutic agents or at least point the way toward potentially efficacious families of compounds [1,2].

True natural-product chemistry had its beginning in 1805 with isolation of morphine from the opium poppy (Papaver somniferum) by the German apothecary Friedrich Wilhelm Sertürner. The firm of E. Merck in Darmstadt, Germany, commercialized the isolation process, and began to market morphine as the first medicinal substance in the form of a pure, natural material in 1827. This also made it possible for the first time to offer precise dosages of a natural active agent: a milestone in medicinal therapy.

Spurred on by this achievement, additional highly effective plant-based active substances were soon isolated, a listing of which calls to mind a stroll through a pharmacist’s poison cabinet (Tab. 1). All of these materials would class as “natural”, even though many of them, as indicated, are more toxic than potassium cyanide.


Table 1. First active ingredients isolated from medicinal and poisonous plants [3,4].

 Year Active substance Plant source LD50*
  potassium cyanide   5 (rat)
1805 morphine opium poppy (Papaver somniferum) 335 (rat)
1817 narcotine opium poppy (Papaver somniferum) 853 (mouse)
1818 strychnine “poison nuts” (Strychnos nux vomica) 2 (mouse)
1818 veratrine** white hellebore (Veratrum album) 4 (rat)
1819 colchicine autumn crocus (Colchicum autumnale) 6 (mouse)
1820 caffeine Arabian coffee shrub (Coffea arabica) 192 (rat)
1820 quinine cinchona tree (Cinchona) 620 (rat)
1822 emetine ipecac (Caphaëlis ipecacuanha) 12 (rat)
1827 coniine poison hemlock (Conium maculatum) 5 (rat)
1828 nicotine tobacco plant (Nicotiana tabacum) 50 (rat)
1831 aconitine monk’s hood, wolfbane (Aconitum napellus) 2 (mouse)
1832 codeine opium poppy (Papaver somniferum) 427 (rat)
1833 atropine deadly nightshade (Atropa belladonna) 75 (mouse)
1833 thebaine Persian poppy (Papaver bracteatum) 54 (rat)

* The LD50-value in mg/(kg body weight) represents the amount of the substance in question that will cause half of the subject laboratory animals to die.
** “Veratrine” is a mixture of various veratrum alkaloids, in particular veratramine and cevadine.


From a scientific point of view, one such plant substance towers above all the others: strychnine. Since its isolation in 1818 by Pierre Joseph Pelletier and Joseph-Bienamé Caventou, no natural product has been studied so intensively. Despite the fact that its great chemical stability makes strychnine’s isolation from “poison nuts” a rather easy matter, determination of its structure proved extremely challenging. Before we delve into the structural studies and subsequent syntheses of strychnine, however, it is worth spending a bit of time looking more closely at the blessings and curses associated with the compound, and with its source, the common “strychnine tree”, Strychnos nux vomica.


2. Strychnos nux vomica, and its Poisonous Seeds

2.1. Nux vomica Seeds

In each of its yellow to orange fruits, the “strychnine tree” has two to four round, button-like seeds, which are called “poison nuts” or “quaker buttons” because of their characteristic form and character (see Fig. 1).


Figure 1. The strychnine or “poison nut” tree’s seeds.


The typical strychnine tree, an evergreen native native to Sri Lanka, India, Tibet, southern China, Vietnam, and northern Australia, is now cultivated as well in western Africa and southeast Asia. The roughly apricot-size fruit contains 2–4 seeds with a diameter of 1–2 cm. They are regarded as very decorative and commonly utilized, either directly or after dyeing, in African or Indian jewelry. Referring to these seeds as a “nut” is in fact misleading, since despite its size their source is actually a berry; the designation “nux vomica” itself is also misleading, since consuming the seeds rarely causes one to vomit.

The highly poisonous nature of these seeds (their strychnine content can be as high as 3 %!) was recognized long ago, and soon exploited. Ground seeds have often been used in toxic bait intended for rats and other rodents, and also strewn about as a defense against rabid species. From early in the 17th century the poisonous powder was commonly available in pharmacies. Given human nature, it will hardly come as a surprise that such a readily accessible, highly effective poison would become subject to a great deal of misuse, so that the occasional disputed inheritance, dramatic case of jealousy, or similar tragedy might have become subject to sudden resolution in a more or less inconspicuous way [5,6].


2.2. Toxicity of Strychnine

Strychnine’s high toxicity is due to its interference in the function of neurons. Neuron excitation and deactivation is so closely managed through release of chemical signaling agents (neurotransmitters) that uncontrolled neuron activity is essentially ruled out. One of these neurotransmitters is the amino acid glycine, which attenuates neuron excitability through binding to the glycine receptors located on cell surfaces. Strychnine functions as an antagonist; that is, it displaces glycine from receptors without simultaneously triggering its dampening effect. Neurons thus become extremely readily – and uncontrollably – excitable.

In the case of strychnine poisoning, uncontrolled activity of spinal cord neurons results in simultaneous maximal contraction of the flexor and extensor muscles of a joint. Cataleptic attacks on the powerful musculature of the neck, back, and jaw are exceptionally painful. Muscles relax only after one to two minutes, only to contract again a few minutes later at the slightest stimulation. A victim remains fully conscious throughout such an episode; death ensues as a result of utter exhaustion, or cessation of breathing as a consequence of cramping of the respiratory musculature.


2.3. Medicinal Properties

It was Paracelsus who observed in 1585: “All things are poison, and nothing is without poison; only the dose causes something not to be poisonous.” Consistent with this observation, medicinal properties once were ascribed even to “poison nuts” and the strychnine they contained – in suitably small doses! Thus, in 1785, Joseph Jacob Plenk, the founder of modern dermatology, extolled “poison-nut powder” as a true miracle drug: a pain-reliever, restorative, called for in cases of dysentery and frenzy, for cobra bites, and against worms, plague, and the pains of colic. In 1803, Johann Friedrich Gmelin, physician and botanist, added to the list malaria, female hysteria, epilepsy, and general corruption of the bodily fluids.

These promises led to pulverized “poison nuts” – and strychnine itself after 1828 – becoming one of the most desired (and economically profitable) ingredients for the in those days universally popular “tonics”. Based on the notion that “the dosage is what matters”, the poisonous substance strychnine continued to be marketed as a tonic ingredient even into the 20th century.

Home remedies like this, sold by the bottle, must have tasted awful, because strychnine is one of the bitterest natural substances known – but that didn’t interfere with the success of such fortifying tinctures. On the contrary: extreme bitterness was apparently regarded as an indication of quality.


2.4. Doping Agent

Strychnine-containing tonics were popular well into the 20th century, and as early as 1900 they were also misused by aspiring athletes as legal doping agents. A bizarre example involved the legendary marathon at the 1904 Olympic Games in St. Louis, MO, USA. The ultimate winner, one Thomas Hicks, was so amply supplied during the race with “invigorating” brandy and strychnine that upon reaching the finish line he was in absolutely no condition to accept his gold medal, an occasion that had to be postponed for several hours.

Strychnine and Brandy in a Marathon Both of these “invigorating agents” are conspicuously useless for the purpose, besides which strychnine is extremely dangerous. Hicks suspected how lucky he had been to survive the race; he in fact never again participated in a marathon, though he lived to the formidable age of 89 [7-9].

Any performance-enhancing effect for strychnine would today be vigorously contested from a medical standpoint, but the compound nevertheless still appears on the World Anti-Doping Agency list of prohibited substances – presumably out of an abundance of caution [10]. A recent offender was the Russian long-distance runner Julia Smirnowa, found guilty of doping with strychnine and banned internationally from all further competition.

Since strychnine-containing home remedies were distributed in pharmacies in large bottles, inadvertent (or deliberate!) overdoses were common. From a current perspective it is remarkable to think how many people must have been poisoned, given the small difference between a dose that is modestly stimulating and one that is toxic. It is shocking to read, for example, of a prescription written for little “Baby Smith” by the Canadian physician Dr. C. F. Abraham for a tonic consisting of strychnine, belladonna, and Tolu balsam, with the notation “one teaspoonful every two hours” [11].

Administering strychnine-containing tonics to children was fairly common practice, however, well into the 20th century, and as late as 1976 it was considered necessary to warn doctors emphatically against this dangerous nonsense [12]. Strychnine was banned in 1978 from all official European pharmaceutical compilations [13], and was subsequently also no longer permitted in poisonous baits, so in essence it now plays no role in everyday life. But hold on a minute!


2.5. Homeopathy

Strychnine has perhaps not in fact completely disappeared, since for Samuel Hahnemann (1755–1843), the originator of homeopathic medicine, “poison nuts” were among the most important ingredients for homeopathic remedies. Strychnine-containing preparations were thought to act as curative agents for diseases of the central nervous system and the gastrointestinal tract, as well as in the liver and the musculoskeletal system. Moreover, they were recommended for patients with a harried and sedentary lifestyle, or suffering from “stomachache, heartburn, nausea, vomiting, a full feeling, gaseous colic, spastic constipation, gastritis, gastroenteritis, hemorrhoids, angina, cystitis, three-month cramps, diarrhea, fever, childbirth, flu, urinary retention, cough, colic, headaches, food poisoning! (exclamation point inserted by the author), gastrointestinal problems, menstrual concerns, muscular cramps, sinus infections, nervousness, operations, motion sickness, backache, sleeplessness, sniffles, pregnancy issues, morning sickness, dizziness, constipation generally, and poisoning!” (exclamation point again inserted by the author) [14].

With this impressive list of symptoms, a prize of over ten euros for a ten-pack of 1 mL ampules of Strychninum nitric D30 is certainly warranted [15]. One could easily prepare this D30 concoction on the basis of Samuel Hahnemann’s own instructions:

To begin with, for the “basic tincture”, for example, 25 g of strychnine (as the nitrate or sulfate) is dissolved in a liter of water. This liter of 0.06 molar strychnine “basic tincture” would contain 0.36·1023 strychnine molecules. To prepare from this a D1 potency solution, 100 mL (= 1/10) of basic tincture is diluted with water to a volume of one liter. This corresponds to a dilution of 1:10 (where “D” = deca). This liter at D1 potency would still contain 0.36·1022 molecules of strychnine. The same dilution procedure is then repeated 29 more times, so that a liter of the resulting D30 potency contains 0.36·10–7 molecules of strychnine. This is, of course, very little, and since we can assume that for Hahnemann and his disciples – just as for us – molecules would have been indivisible, the value can effectively be equated with zero. In other words, 100 mL of a D30 potency solution wouldn’t contain even a single molecule of strychnine.

Proponents of homeopathy are convinced that, despite the certainty that such a solution could not in fact contain more than at most one molecule of the purported “active ingredient”, it might still have a therapeutic effect. To be fair, one should point out that homeopathic practitioners do not technically practice “dilution”, but rather “succussion”, where the mixture must be vigorously shaken at each step. To be more precise – and strictly according to Hahnemann – each step requires “10 vigorous shakes with the hand, against a hard, but elastic object, such as a leather-bound book”. The process of “succussion” is thought to ensure that “the vital energy of the agent is activated”, with consecutive “succussions” increasing the potency of the remedy.

Let us here be tolerant, in the spirit of “chacun à son goût”, since homeopathic remedies at least would do no harm. The latter was experimentally demonstrated, incidentally, by 20 brave Swiss volunteers, each of whom on the 5th of February, 2011, at 10:23 (on the Paradeplatz/”Parade Ground” in Zurich) consumed an “overdose” of a strychnine-containing homeopathic remedy [16]. In this so-called “10:23 Challenge”, all the participants simultaneously swallowed an entire packet of Strychninum nitric D30. None of the participants subsequently showed any symptoms of either an overdose or a relevant side-effect. To date, no disciples of homeopathy appear to have offered a public reaction to the results.


2.6. Murder Weapon

Apart from senseless or at least questionable medical applications, strychnine has above all been a rich source of stimulus for the imaginations of mystery writers. From Agatha Christie to the latest TV dramas, plenty of fictional characters have been “finished off” with strychnine. In real life things are much different, though. To begin with, strychnine is today hard to come by. What’s more, almost every potential victim of strychnine-laced food would surely spit it out at once because of it being so horribly bitter. Furthermore, as will probably be obvious to the viewer of as few as two episodes of any TV series dealing with forensic medicine, strychnine poisoning is immediately recognizable from the hideously cramped posture of the corpse’s body, coupled with its distinctive sardonic smile. Furthermore, strychnine is exceptionally stable, so it is easily detectable in an exhumed body even years later. In other words, it is really not wise to consider using strychnine as a murder weapon.

Agatha Christie: The Chemistry of a (Nearly) Perfect MurderThis sobering insight should still not prevent us from marveling at the many clever, deceptive situations novelists have devised to keep an intended victim from noticing the presence of a horribly bitter substance in their food or drink. Agatha Christie served up an especially cleverly contrived murder in “The Mysterious Affair at Styles”, her very first murder mystery. This was set in Victorian England, and involved what was at the time a common strychnine-containing home remedy. The reader of mystery novels who in particular is also interested in chemistry will be amazed here not only by the author’s imagination, but also the extent of her chemical acumen (see Agatha Christie: The Chemistry of a (Nearly) Perfect Murder).



[1] D. J. Newman et al., Nat. Prod. Rep. 2000, 17, 215. DOI: 10.1039/A902202C

[2] M. S. Butler, Nat. Prod. Rep. 2008, 25, 475. DOI: 10.1039/B514294F

[3] R. H. Huxtable, S.K.W. Schwarz, Mol. Interv. 2001, 1, 189.

[4] S. McLaughlin, R. F. Margolskee, Am. Sci. 1994, 82, 538.

[5] J. Buckingham, Bitter Nemesis: The Intimate History of Strychnine, CRC Press, Boca Raton, 2007. ISBN 978-1-4200-5315-9

[6] R. Sedivy, Arsen, Strychnin & Co, Carl Ueberreuter, Vienna, Austria, 2008 (in German). ISBN: 978-3-8000-7390-0

[7] S. Pain, New Sci. 2004, 46.

[8] D. Martin, R. Gynn, The Olympic Marathon, Human Kinetics, Champaign, 2000. ISBN: 978-0-88011-969-6

[9] D. Dawson, K. Reid, Nature 1997, 388, 235.

[10] World Anti-Doping Agency, The 2015 Prohibited List, International Standard, 2014.

[11] R. C. McGarry, P. McGarry, Can. Med. Assoc. J. 1999, 161, 155.

[12] G. Jackson, G. Diggle, Brit. Med. J. 1973, 21, 176.

[13] F. Eiden, Kultur & Technik 2003, 27, 24 (in German).

[14] C. Hinspeter, Nux Vomica – eines der wichtigsten homöopathischen Mittel,, 2013 (in German).

[15] For current prizes see e.g. (in German)

[16] The 10:23 Campaign, The 10:23 Challenge,


The article has been published in German as:

and was translated by W. E. Russey.

Strychnine: From Isolation to Total Synthesis – Part 1

Just how toxic is strychnine, and why?

Strychnine: From Isolation to Total Synthesis – Part 2

Why did it take 130 years to determine the structure of strychnine?

Strychnine: From Isolation to Total Synthesis – Part 3

What can we learn from the total synthesis of strychnine?


All articles by Klaus Roth published in ChemistryViews

Strychnine: From Isolation to Total Synthesis – Interview

Christine Beemelmanns and Hans-Ulrich Reissig explain why the synthesis of strychnine is challenging till today


See all articles by Klaus Roth published in ChemViews Magazine

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