Aconitum
By Frederick G. Strathmann, PhD, MBA, DABCC (CC, TC)
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Published in the September 2024 issue of Clinical & Forensic Toxicology News
Aconitum is a genus of over 250 species of herbaceous perennials of which most are extremely poisonous (1). The plants generally have lobed leaves and clusters of flowers with the characteristic upper hood giving it the common name of Monkshood and Helmet Flower. The showy flowers appear in summer and range in color from blues, purples, to white.
Aconitum is an ancient Greek name for the plant, used by the Greek physician and pharmacist Dioscorides, who lived around 40-90 A.D. and served as a botanist in Nero’s armies (2). In 1881, George Henry Lamson was convicted of using aconitine for the murder of his brother-in-law, Percy John, marking the first recorded homicide using aconitine. The trial details were published in 1913 as part of a series of Notable English Trials by William Hodge Company (3). One method used for poison analysis in this case was taste, which produced a “biting and numbing effect.”
Aconitum has also made notable appearances in recent fiction and popular culture:
In traditional medicine, aconite (dried tubers or root stocks of Aconitum plants) has long been used, particularly in Asia (India, China, and Japan) (4). In Ayurveda, the herb is detoxified according to the samskaras process and no longer possesses active toxicity. The carmichaeli and kusnezoffii species are used in traditional Chinese medicine for treating Yang deficiency, “coldness,” and general debilitation (5). In the 19th century, aconite was used in Western medicine to slow the pulse and as a sedative, although it has since been replaced by safer drugs (6). Finding its way into various foods and drinks, in 2018 a birthday party in China became a case study after 53 attendees ingested a homemade alcoholic drink (7). Although the risk of aconite toxicity is known, approximately 5000 cases of aconite poisoning incidents were reported in China, Germany, Japan, and other countries from 1993–2005; most cases of fatal poisoning occurred in China.
This genus of plants contains a series of alkaloids exemplified by aconitine. Over 14 have been identified, including mesaconitine, jesaconitine, hypaconitine, and deoxyaconitine (8). These alkaloids can be divided into three subgroups based on their chemical structure and effects on the body:
Marked symptoms of aconitine poisoning appear within minutes of administration. Initial signs include gastrointestinal distress, burning, tingling, and numbness in the mouth, followed by vomiting, motor weakness, and cutaneous sensations (9–11). Death typically occurs from asphyxia or ventricular arrhythmias (9). Treatment involves stomach evacuation and administration of atropine and digitalis or strophanthin. Protective effects against aconitine-induced cardiac symptoms can be achieved with barakol or tetrodotoxin. In the 2018 birthday party cited earlier, 15 of the individuals were reported to have numbness of tongue or limbs, vomiting, heart palpitations, or sudden death, with five of the individuals not surviving.
All parts of the Aconitum plant are poisonous, especially the roots, seeds, and flowers if ingested (4). Symptoms of poisoning include gastrointestinal distress, numbness, motor weakness, and cardiac issues. The toxin can also be absorbed through the skin, causing local and systemic effects.
The stomach is the primary site for the metabolism of aconitine, which undergoes transesterification and phase I metabolic pathways involving CYP2C9 and CYP2C8 enzymes (12). Post-oral administration, 14 metabolites and two ester hydrolysates of aconitine have been previously identified. Carboxylesterases (CEs) are instrumental in aconitine metabolism, predominantly located in the liver, intestine, and plasma. Specifically, CEs1A is most abundant in the liver and lung, while CEs2A is found in the liver, renal tubules, and gastrointestinal tract, facilitating differential hydrolysis across these tissues. Limited reports address the specific impacts of CEs1A and CEs2A on aconitine metabolism, though it's postulated that CEs2A plays a more significant role. Additionally, CEs in the gastric mucosa and intestine may catalyze ester hydrolysis of aconitine, with intestinal bacteria secreting enzymes contributing to this process. In the liver, aconitine metabolism involves phase I pathways with CYP3A4, CYP3A5, CYP1A1, and CYP1A2 isoenzymes with CYP2D6 demonstrated in human liver microsomes (13). Aconitine and its metabolites follow similar pathways, with phase I metabolites primarily found in urine and minor phase II metabolites present (14). Despite metabolic conversion, traces of aconitine remain in the blood postoral administration, implicating the potential toxicity or efficacy of aconitine and its metabolites.
The roots of Aconitum ferox supply the Nepalese poison called bikh, bish, or nabee, containing large quantities of pseudoaconitine. Several species of Aconitum have been used as arrow poisons in various cultures for hunting and warfare (15). In traditional Asian medicine, detoxified aconite is used in small doses to treat various conditions, although improper processing can result in toxicity.
In addition to their toxicity, the natural substances derived from Aconitum species have a potential range of positive biological effects on humans, such as analgesic, anti-inflammatory, and anti-cancer characteristics (16). Currently, over 71 phytochemical ingredients have been obtained and identified as the major bioactive constituents from different parts of the Aconitum plant, including alkaloids, flavonoids, steroids, and glycosides (8).
More than 70 traditional or modern processing methods are available for the detoxification of Aconitum, though the majority of alkaloids from Aconitum have been largely unexplored (12). Most of the Aconitum species naturally grow in low density and extensive extraction of most of the species in Asia has caused pressure on the wild population leading to concerns regarding extinction which further inhibits their study (1).
Historical methods included taste tests, as described in the 1881 Lamson case, where the alkaloid's effect on taste buds was used for identification. Contemporary methods have replaced such dangerous practices with safer, more reliable techniques. Like much of toxicology, mass spectrometry has become an invaluable tool to detect and quantify aconitine and other alkaloids in biological samples. In 2022, a simple and rapid method for quantifying aconitines and metabolites in whole blood for forensic investigation was published using QuEChERs (a solid phase extraction method) for sample preparation followed by LC-MS/MS for detection and identification (17). In comprehensive studies of Aconitum, even more sophisticated techniques such as two-dimensional chromatography and ion mobility have been used to systematically explore and identify the complex chemical composition in the hopes of better understanding and potentially harnessing the unique properties of the plant (18–20).
Frederick G. Strathmann, PhD, MBA, DABCC (CC, TC), is the SVP for global business at MOBILion Systems in Chadds Ford, PA and a CLIA lab director and clinical consultant for Smithers Biopharmaceutical Development Services at their Maryland and New Jersey facilities.
The author discloses salary/consultant fees from MOBILion Systems and board/committee membership/ advisory board role with Impact Proteomics.
No, no, go not to Lethe, neither twist Wolf's bane, tight-rooted, for its poisonous wine Nor suffer thy pale forehead to be kissed By nightshade, ruby grape of Proserpine…John Keats Ode on Melancholy
Monkshood is a distinctive looking wildflower borne on shoulder high erect and sturdy stems. The common name for this plant comes from the hood-like sepal on the flower. The hood is thought to look like an old fashioned cowl worn by monks.
All parts of monkshood are poisonous, especially the roots and seeds, and the flowers if eaten. In the past, wolves and criminals were poisoned with an extract from the European wolfsbane Acontium lycoctonum. This species was also supposedly used as a component in witches’ brew.
Aconitum is an ancient Greek name for the plant, used by the Greek physician and pharmacist Dioscorides. Dioscorides lived around 40-90 A.D. and served as a botanist in Nero’s armies. For an interesting discussion of Aconitum in literature and film click here.
George Henry Lamson in 1881 was convicted of using aconitine for the murder of his brother-in-law, Percy John. This was reported to be the first homicide using aconitine. The details of the trial were published in 1913[1] as part of a series of Notable English Trials by William Hodge company. One of the interesting facts of the case is the methods used for the analysis of the poison. One method was taste, “they applied some of the alkaloid obtained from the body to their tongues, which produced a “biting and numbing effect”; a precisely similar effect was produced by a similar application of aconitine.”. A word to the readers: WHAT DEDICATION! Stop complaining about your long hours and lack of instrumentation.
Kingdom: Plantae; Division: Magnoliophyta; Class: Magnoliopsida; Order:nbsp; Ranunculales; Family: Ranunculaceae; Genus: Aconitum; Species: napellus (the Common Monkshood). Over 100 species of Aconitum.
Aconitum, known as conite, monkshood, wolfsbane, leopard's bane, women's bane, Devil's helmet or blue rocket.
This genus of herbaceous perennial plants are chiefly natives of the mountainous parts of the northern hemisphere, growing in moisture retentive but well draining soils on mountain meadows. Their dark green leaves lack stipules. The plants are tall with the erect stem being crowned by racemes of large and eye-catching blue, purple, white, yellow or pink zygomorphic flowers with numerous stamens. They are distinguishable by having one of the five petaloid sepals (the posterior one), called the galea, in the form of a cylindrical helmet; hence the English name monkshood. There are 2–10 petals, in the form of nectaries. The two upper petals are large. They are placed under the hood of the calyx and are supported on long stalks. They have a hollow spur at their apex, containing the nectar. The other petals are small and scale like or non-forming. The 3–5 carpels are partially fused at the base.
The most common plant in this genus, Aconitum napellus (the Common Monkshood, European) was considered to be of therapeutic and toxicological importance. Its roots have occasionally been mistaken for horseradish. It has a short underground stem, from which dark-colored tapering roots descend. The crown or upper portion of the root gives rise to new plants. When touched to one's lip, the juice of the aconite root produces a feeling of numbness and tingling. This plant is used as a food plant by some Lepidoptera species including Dot Moth, The Engrailed, Mouse Moth, Wormwood Pug, and Yellow-tail.
The roots of Aconitum ferox supply the Nepalese poison called bikh, bish, or nabee. It contains large quantities of the alkaloid pseudoaconitine. Aconitum palmatum yields another of the bikh poisons. The root of Aconitum luridum, of the Himalaya, is said to be as virulent as that of A. ferox or A. napellus.
Several species of Aconitum have been used as arrow poisons. The Minaro in Ladakh use A. napellus on their arrows to hunt ibex, while the Ainus in Japan used a species of Aconitum to hunt bear. The Chinese also used Aconitum poisons both for hunting, and for warfare.
Many species of Aconitum are cultivated in gardens, having either blue or yellow flowers. Aconitum lycoctonum (Alpine wolfsbane), is a yellow-flowered species common in the Alps of Switzerland. As garden plants the aconites are very ornamental, hardy perennial plants. They thrive well in any ordinary garden soil, and will grow beneath the shade of trees. They are easily propagated by divisions of the root or by seeds. Aconitum Fischeri, Reichenbach, is found in the Rocky Mountain region of the United States; also in other sections of the world. There are many cultivars some with bicolor monkshood such as Aconitum x cammarum Eleanor which has white flowers outlined in blue-violet. For additional information on cultivated monkshood see the internet source.
Aconite (term for dried tubers or root stocks of aconitum plants) has long been used in the traditional medicine of Asia (India, China and Japan). In Ayurveda the herb is detoxified according to the samskaras process and studies show that it no longer possesses active toxicity. The carmichaeli species is used in traditional Chinese medicine as a treatment for Yang deficiency, "coldness", and general debilitation. The herb is one of the more toxic species equal to the European variety and is prepared in extremely small doses. More frequently ginger processed aconite, of lower toxicity, "fu zi" is used. Aconite is one ingredient of Tribhuvankirti, an Ayurvedic preparation for treating a "cold in the head" and fever. Aconite was mixed with patrinia and coix, in a famous treatment for appendicitis described in a formula from the Jingui Yaolue (ca. 220 A.D.) Aconite was also described in Greek and Roman medicine by Theophrastus, Dioscorides, and Pliny the Elder, who most likely prescribed the Alpine species Aconitum lycoctonum. The herb was cultivated widely in Europe, probably reaching England before the tenth century, where it was farmed with some difficulty, but came to be widely valued as an anodyne, diuretic, and diaphoretic. In the nineteenth century much aconite was imported from China, Japan, Fiji, and Tonga, with a number of species used to manufacture alkaloids of varying potency but generally similar effect, most often used externally and rarely internally. Effects of different preparations were standardized by testing on guinea pigs.
In Western medicine preparations of aconite were used until just after the middle of the 20th century, but it is no longer employed as it has been replaced by safer and more effective drugs and treatments. The 1911 British Pharmaceutical Codex regarded the medical uses and toxicity of aconite root or leaves to be virtually identical to that of purified aconitine. Aconite first stimulates and later paralyses the nerves of pain, touch, and temperature if applied to the skin or to a mucous membrane; the initial tingling therefore gives place to a long-continued anesthetic action. Great caution was required, as abraded skin could absorb a dangerous dose of the drug, and merely tasting some of the concentrated preparations available could be fatal. The local anesthesia of peripheral nerves can be attributed to at least eleven alkaloids with varying potency and stability. Internal uses were also pursued, to slow the pulse, as a sedative in pericarditis and heart palpitations, and well diluted as a mild diaphoretic, or to reduce feverishness in treatment of colds, pneumonia, quinsy, laryngitis, croup, and asthma due to exposure.
Both Chinese medicine and Ayurveda have methods of processing aconite to reduce its toxicity. In Chinese medicine, the traditional pao zhi or preparation of aconite is to steam it with ginger in a fairly elaborate procedure. Due to the variable levels of toxicity in any given sample of the dried herb, there are still issues with using it. Most but not all cases of aconite toxicity in Taiwan were due to the consumption of unprocessed aconite.
According to an article by the Indian scientists Thorat and Dahanukar, "Crude aconite is an extremely lethal substance. However, the science of Ayurveda looks upon aconite as a therapeutic entity. Crude aconite is always processed i.e. it undergoes 'samskaras' before being utilized in the Ayurvedic formulations. This study was undertaken in mice, to ascertain whether 'processed' aconite is less toxic as compared to the crude or unprocessed one. It was seen that crude aconite was significantly toxic to mice (100% mortality at a dose of 2.6 mg/mouse) whereas the fully processed aconite was absolutely non-toxic (no mortality at a dose even 8 times as high as that of crude aconite). Further, all the steps in the processing were essential for complete detoxification".
This genus of plants contains a series of alkaloids exemplified by aconitine. Over 14 have been identified including: mesaconitine, jesaconitine, hypaconitine and deoxyaconitine.
A more detailed description of the alklaloid structure can be found in the 2006 Journal of Analytical Toxicology article. The aconitum alkaloids may be divided into three subgroups.nbsp; The first contain 2 ester bonds on the diterpene structure. This group activates voltage-dependent sodium channels and inhibit noradrenaline reuptake. Activation of the sodium channels with excessive depolarization result in suppression of pain transmission. The second group is monoesters which block the voltage-dependent sodium channel and have strong antiarrhythmic properties. The second group seems to be competitive antagonists of the first group. The third group does not have an ester side chain and are less toxic than either of the first two groups.
Marked symptoms appear within a few minutes of the administration of a poisonous dose of aconite. The initial signs are gastrointestinal. There is a sensation of burning, tingling, and numbness in the mouth, and of burning in the abdomen. Usually death ensues before a numbing effect on the intestine can be observed. After about an hour, there is severe vomiting. Pronounced motor weakness and cutaneous sensations similar to those above described soon follow. The pulse and respiration steadily fail until death occurs from asphyxia. There are some discrepancies in the literature on this point as some of the recent cases indicate that death may be from ventricular arrhythmias. The treatment is to empty the stomach by tube or by a non-depressant emetic. The physiological antidotes are atropine and digitalis or strophanthin, which should be injected subcutaneously in maximal doses. The historic antidotes of alcohol, strychnine, and warmth were employed, although with limited or no success.
The above description of poisoning is characteristic of an oral administration. However, poisoning may occur simply by picking the leaves without wearing gloves; the aconitine toxin is absorbed easily through the skin. From practical experience, the sap oozing from eleven picked leaves will cause cardiac symptoms for a couple of hours. In this event, there will be no gastrointestinal effects. Tingling will start at the point of absorption and extend up the arm to the shoulder, after which the heart will start to be affected.
Aconitine is a potent neurotoxin that blocks tetrodotoxin-sensitive sodium channels. Pretreatment with barakol 10 mg/kg IV reduces the incidence of aconitine-induced ventricular fibrillation and ventricular tachycardia, as well as mortality. Five μg/kg IV of tetrodotoxin has the same effect. The protective effects of barakol are probably due to the prevention of intracellular sodium ion accumulation.
Canadian actor, Andre Noble died on July 30, 2004 after a camping trip where he was thought to have accidentally consumed aconite from Monkshood. Although there is little detail about this case, the American Academy of Forensic Sciences in 2008 [11] reported a case of accidental poisoning by A. napellus caused by eating a few of the flowers. Within 4 hours the victim collapsed and died. An LC/MS/MS method was developed for the analysis of acontine and found concentrations of the poison in the blood and urine from autopsy. The manner of death suggests that ventricular arrhythmias precipitated by the plant material resulted in cardiac death. A case thought to be suicide was reported [6] in 2000 with identification and quantitation of 6 of the aconitine alkaloids.
In a report in 2004 [7] the authors reviewed the aconitine poisonings in Taiwan from 1990-1999 and found 17 reported cases. All of these patients survived with supportive care with no long term sequelae. In these cases life threatening ventricular tachyarrhythmias was the most common consequence of ingestion of the aconite roots. Charcoal hemoperfusion was the suggested mode of treatment in these patients. In laboratory studies the class 1 antiarrhythmics, particularly flecanide and beta blockers were the best drugs for inhibiting mortality; while the calcium antagonists or amiodarone showed no effect.
An interesting case from France was reported in 2005 [5] where the hospital laboratory was able to use LC/MS/MS to quantitate aconitine plasma levels after an intentional sub-lethal dose of a home preparation of dried aconitum napellus root. The plasma half-life of aconitine was approximately 4 hours in this case.
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