Aristolochia

The birthwort, also known as pipevine or Dutchman's Pipe vine, is a common name given to plants in the genus Aristolochia. Birthwort is notable for its use in Western herbal medicine, traditional Chinese medicine (TCM), Ayurvedic medicine, as well as many indigenous herbal traditions. This is despite causing cancer and kidney failure. Home run for evidence based medicine!

Against allopathy
Alternative medicine
Clinically unproven
v - t - e

Given the long and well-documented history of medical usage (since 300 BCE) and the extreme toxicity of birthwort, it could be argued that this is one of the best cases against the "appeal to tradition", and against the related "appeal to ancient wisdom", "appeal to nature" and "argument from authority" fallacies.

History

Ancient times

Aristolochia has been used for thousands of years in various cultures around the world as a panacea for numerous diseases. Birthwort was especially thought to be beneficial for women giving childbirth; the name Aristolochia derives from the Greek "άριστο λοχεία" for "noble birth" or "excellent birth". Aristolochia was commonly used in ancient Greek, Roman and Byzantine pharmaceutical recipes for a variety of conditions, including kidney ailments, peritonsillar abscess, bladder stones, edemas, gout, snakebite and uterine complaints.[1]

TheophrastusFile:Wikipedia's W.svg (c. 371–c. 287 BCE), a student of Aristotle, wrote the first botanic description and first report on the pharmaceutical properties of birthwort in c. 300 BCE:[1][2]

“”There are many uses of it for various purposes are enumerated; it is best for bruises on the head, good also for other wounds, against snake-bites, to produce sleep, for the womb as a pessary: for some purposes it is soaked with water and applied as a plaster, for others it is scraped into honey and olive-oil: against snake-bites it is drunk in sour wine and also sprinkled over the bite; to induce sleep it is given pounded up in black dry wine: in cases of prolapsus uteri it is used in water as a lotion. This plant then seems to have a surpassing variety of usefulness.

Other ancient writers who recommended birthwort for medical treatment included: Diocles of CarystusFile:Wikipedia's W.svg (c. 375–295 BCE), Philinus of CosFile:Wikipedia's W.svg (3rd century BCE), Heraclides of TarentumFile:Wikipedia's W.svg (c. 2nd–3rd century BCE), Aulus Cornelius CelsusFile:Wikipedia's W.svg (c. 25 BCE–c. 50 CE), Scribonius LargusFile:Wikipedia's W.svg (c. 1–c. 50 CE), Pedanius DioscoridesFile:Wikipedia's W.svg (c. 40–90 CE), and Pliny the Elder (23–79 CE).[1] Dioscorides wrote the first major book on herbal medicine between 50 and 100 CE, De Materia Medica,File:Wikipedia's W.svg which was highly influential for more than 1500 years.[3]

Medieval era

Aristolochia appeared in the Charaka SamhitaFile:Wikipedia's W.svg (c. 400 CE), which is the foundational text for Ayurvedic medicine.[4]:620

Saint Hildegard of BingenFile:Wikipedia's W.svg (1098-1179 CE), a medieval polymath, wrote several books, including the 9-volume Physica. Physica was written between 1151-1158 CE and includes a description of plants and their medical uses. A modern, English translation of the book includes this description of birthwort:[5]

“”Birthwort (byverwurtz) is hot, and a bit cold. Therefore, pulverize its root and leaves and add half as much feverfew powder and one-fourth as much cinnamon powder. Mix them together and eat it daily, either with bread or with warm wine, or in broth. You will have no great or lasting infirmity until the time you die. No one should shun powder prepared this way. If a healthy person eats this powder daily, he will not be lying sick in bed a long time. If he is sick and eats it, he will be well. In order to conserve this powder safely throughout the year, it should be placed in a new, earthenware vessel, enclosed in the earth. It will retain its powers.

Hildegard's Physica was the foundation of Hildegardian medicine, a now-minor field of quackery that is mostly practiced in Germany and Switzerland; it is not clear whether modern practitioners of Hildegardian medicine have prescribed birthwort.

Traditional Chinese medicine
See the main article on this topic: Traditional Chinese medicine

The Bencao GangmuFile:Wikipedia's W.svg (本草綱目) or Compendium of Materia Medica was first published in 1578 by Li ShizhenFile:Wikipedia's W.svg (李時珍). Aristolochia appears in the Bencao Gangmu as "馬兜鈴" (mǎ dōu líng).[6] Bernard Read's analysis of the Bencao Gangmu reported three species of Aristolochia (A. debilis, A. recurvilabra, and A. contorta),[7] but A. recurvilabra is now considered a synonym of A. debilis.[8]

G. A. Stuart reported that two species of Aristolochia were in use in China in 1911, A. kaempferi (馬兜鈴) and A. recurvilabra (A. debilis).[9] For A. kaempferi, Stuart stated:[9]

“”As the open, cellular structure of these fruits is considered by the Chinese to resemble the human lung, they are strongly recommended in all forms of pulmonary affections. They have very little taste or smell and are not poisonous [emphasis added]. Other diseases for which they are prescribed are hemorrhoids and ascites. One of the fruits burned over a lamp, and the charred remains taken with wine, is considered a sure cure for heartburn.

For A. debilis, Stuart stated:[9]

“”It is a highly valued remedy, being prescribed in combination with such drugs as ginseng and China root [Smilax china]. It is used in digestive disorders and chronic fluxes, especially those of women and children. It is regarded as being especially useful in summer diarrhoea and in chronic diarrhoea and dysentery… But in addition, this is regarded to be especially efficacious in expelling the 蠱 (Ku) poison. So highly is it valued for this purpose by the inhabitants of Lingnan that they have given it the name of 三百兩銀藥 (San-pai-liang-yin-yao) "three-hundred-taels-of-silver-drug." It is also considered to be a good remedy for snake-bite.

The Bencao Gangmu has remained in use continuously since its publication, and was replaced in China by the 10-volume Zhong Hua Ben Cao (中华本草, Encyclopedia of Chinese Materia Medica) in 1999, which includes 23 species of Aristolochia, with little mention of toxicity.[10] The species A. manshuriensis, A. fangchi, A. debilis, and A. contorta are included in the official Pharmacopoeia of the People's Republic of China.[11]

Western medicine
See the main article on this topic: Western medicine

In 1597, John GerardeFile:Wikipedia's W.svg wrote what became a very popular book, called The Herball, or Generall Historie of Plantes. The book cited three ancient authorities on the uses of "birthwoorte": Pedanius Dioscorides, GalenFile:Wikipedia's W.svg (129–c. 200/c. 216 CE) and Pliny the Elder.[12] The uses for "long birthwoorte" (A. longa) and "round birthwoorte" (A. rotunda) included:[12]

  • Dioscorides writeth, that a dram waight of long Birthwoort drunke with wine and also applied is good against serpents and deadly things: and that being drunk with myrrhe and pepper, it expelleth whatsoever is left in the matrix after the childe is delivered, the flowers also & dead children: and that being put up in a pessarie, it performeth the same.
  • Round Birthwoorte serveth for all these things, and also the rest of the other poisons: it is likewise available against the stuffing of the lungs, the hicket, the shakings or shiverings of agues, hardness of the milt or spleene, burstings, cramps and convolutions, paines of the sides, if it be drunk with water.
  • It plucketh out thornes, splinters, and shivers, and being mixed in plaisters, or pulteses, it draweth foorth scales or bones, removeth rottennesse and corruption, mundifieth and scoureth foule and filthie ulcers, and filleth them up with new flesh, if it be mixed with Ireos and honey.
  • Galen saith, that branched Birthwoort is of a more sweete and pleasant smell: it therefore is used in ointments; but it is weaker in operations than the former ones.
  • Birthwoort as Plinie writeth being drunk with water is a moste excellent remedie for crampes and convulsions, burses, and for such as have fallen from high places.
  • It is good for them that are short winded, and troubled with falling sickness.
  • The rounde Aristolochia doth beautifie, clense, and saften the teeth, if they be often frosted or rubbed with the powder thereof.

A. serpentaria is known to have been used medicinally by several Native American tribes (Koasati, Delaware, Osage, Choctaw, Náhuatl, Cherokee, Natchez, Alabama, Micmac, Mohegan, and Penobscot). Starting as early as the 1600s, European colonists, calling the plant "Virginia snakeroot", used it to treat snakebite.[13]

The 1931 book A Modern Herbal by Maud GrieveFile:Wikipedia's W.svg (1858–1941), reported the following on Aristolochia (note that no mention whatsoever is made of any possible side effects):[14]

“”Said to be useful as an aromatic stimulant in rheumatism and gout and for removing obstructions, etc., after childbirth. Dose, 1/2 to 1 drachm of the powdered root.

---Other Species---
Aristolochia cymbifera from Brazil and Mexico is said to have medicinal properties similar to the official species. Butte affirms it is a depressant to the sensory nerve centres and is useful in neuralgia and pruritis; it was formerly considered alexiteric, antiparalytic, antiperiodic and aphrodisiac.

A. argentina root is used in that republic as a diuretic and diaphoretic, especially for rheumatism.

A. indica is used as an emmenagogue, antiarthritic, stomachic, purgative and vermifuge, and in the East Indies is used for similar purposes as the American and European species.

A. sempervirens is said to be used by the Arabians as a remedy against the poisonous effects of snake-bite.

A. foetida in Mexico is used as a stimulant to foul ulcers.

A. serpentaria used in bilious, typhoid and typhus fevers, smallpox, pneumonia, amenorrhoea and fevers of a septicaemic type. It is often given in combination with Peruvian Bark [i.e., Cinchona spp.], rendering it more active and preventing ill effects on the stomach. It is also used in North America, as are several other varieties of the species, as an alexiteric and for the bites of mad dogs.

In 1881 the oldest skeptical organization in the world, Vereniging tegen de Kwakzalverij (VtdK, the Dutch Association Against Quackery), had already warned against pills with birthwort as a form of quackery, and described them as "pills made of nothing", but added that they "contain nothing harmful". Well, the VtdK was half-right…[15][16]

Discovery of toxicity

Early reports

William Cullen's Materia Medica reported in 1789 that an Aristolochia-containing substance called "Portland Powder",[note 1] was effective in treating gout but,[18]

“”Soon after finishing the course of their medicine, they became valetudinary [sickly] In different shapes; and particularly were much affected with dyspeptic, and what are called nervous complaints, with lowness of spirits.

…

In every one of them, before a year had passed after finishing the course of the powders, some hydropic symptoms appeared, which gradually increasing in the form of an ascites or hydrothorax, especially the latter joined with anasarca [swelling of the whole body], in less than two or at most three years proved fatal.

In 1815, Mathieu Orfila,File:Wikipedia's W.svg the father of modern toxicology, reported that Aristolochia was lethal to dogs.[1][19]

In 1888, a letter on the continuing usage of Portland Powder was published in The Peoria Medical Monthly, anecdotally stating that "every person treated by them died before the expiration of two years!"[20]

Modern research

As a result of scientific research conducted in the 20th century, it was discovered that birthwort can cause cancer and kidney failure because it contains aristolochic acid (AA), which is, in the amounts present in birthwort, a poison.[21] Aristolochic acid is one of the most potent carcinogens in the Carcinogenic Potency Database.[22][23]

In Belgium between 1990 and 1992, a weight-loss spa using TCM herbs thought that they were giving their clients Stephania tetrandraFile:Wikipedia's W.svg and Magnolia officinalisFile:Wikipedia's W.svg to help with weight loss. In reality the herbal supplements contained Aristolochia fangchi, and as a result, more than 100 out of its 1800 patients developed kidney failure. Several also developed urothelial and kidney cancers, and 39 had to undergo kidney transplants. Because TCM allows for the substitution of identically- or similarly-named plants, plants that are botanically unrelated may be substituted. In this case, the relatively safe Stephania tetrandra (漢防己, hàn fángjǐ) was intended for the clients, but the lethal Aristolochia fangchi (廣防己, guǎng fángjǐ) was given to the clients.[24][25] As epidemiologist Geoffrey Kabat noted:[26]

“”What is essential to realize is that the effects of Aristolochia [birthwort] were identified only thanks to the large cluster of cases of kidney failure occurring in young women who had attended the same spa. It is much more likely that isolated cases will go unnoticed, as happened with ephedra, and it could take years to identify a common cause.
People failed to recognize the nephrotoxic effects of Aristolochia in spite of its use in many cultures worldwide over thousands of years. In an interview, [Arthur P.] Grollman explained why: "The reason, of course, is quite simple. It's painless, and the damage happens much later, so you don't put together the fact that you took this medicine and four years later, you have kidney failure. It's been part of Ayurvedic, European, Chinese, and South American medicine for centuries. All of the great civilizations have used it. And not one reported its toxicity until the Belgians did 20 years ago. There are certain things that tradition can't tell you."

By 2002, the International Agency for Research on Cancer (IARC) had concluded that herbal remedies containing Aristolochia are carcinogenic to humans. This conclusion was based upon sufficient evidence of carcinogenicity of AA in animals and sufficient evidence of carcinogenicity of herbal remedies containing Aristolochia in humans.[27] In 2012, IARC revised their evaluation to conclude that there was also sufficient evidence that AA itself is carcinogenic to humans. This conclusion was based on additional sufficient evidence showing that extracts of plants containing AA are carcinogenic to animals, as well as limited evidence that AA itself is carcinogenic to humans.[28]

European birthwort (A. clematitis), which has also used as a medicine, has been linked to Balkan endemic nephropathyFile:Wikipedia's W.svg (BEN), though this conclusion has taken decades to arrive at since the time that BEN was first diagnosed in the 1920s.[29][30] The source of BEN is likely wheat that is contaminated by seeds of A. clematitis[24] and/or bioaccumulation in grain from soil and water where A. clematitis has grown.[31][32] BEN has been found in northern Bosnia, eastern Croatia, Serbia, Kosovo, southwestern Romania and northwestern Bulgaria.[33] A 2016 study confirmed that AA-contaminated soil is a pathway to human exposure via bioaccumulation in food crops.[34] A 2018 study further confirmed that AAs are long-lived soil contaminants and that AA soil contamination in the Balkans was strongly correlated with BEN.[35]

The true number of cases of aristolochic acid nephropathy (AAN), which is usually fatal, is unknown and is probably underestimated.[24] "Approximately 5–10% of individuals exposed to AA develop renal insufficiency and/or cancer", and this suggests that there may be a genetic component to AA nephropathy.[36]

Additionally, it is suspected that AA exposure is associated with liver cancer (hepatocellular carcinoma, HCC), particularly for people exposed to hepatitis B virus.[37] A 2017 study found that large percentages of people with HCC were exposed to AA in some regions: 78% in Taiwan, 47% in mainland China, and 29% from southeast Asia.[38]

It is suspected that all species of Aristolochia contain some form of aristolochic acid (AA),[39] and dozens of species are known to contain either AA or AA analogs.[40]

Asarum

Asarum is a genus of plants used medicinally that are in the same family as the Aristolochia genus (Aristolochiaceae). Asarum species contain AA[41][40] and also contain AA analogs.[42][40] Asarum species are used in TCM (xixin, 细辛) and were also used traditionally by Native Americans.[42] As of 2017, it is unclear how safe Asarum species are,[42] and only 8 cases of AAN from Asarum ingestion have been reported in 45 years.[42][43]

Caterpillars love it, birds hate it

Many species of Aristolochia are food for the larvae (caterpillars) of species of swallowtail butterflies (family Papilionidae). It has been demonstrated that AA is sequestered in the caterpillars, and retained in the adult butterflies, making them unpalatable to most predators (mainly birds).[44][45]

Not all species of Aristolochia plants are palatable to all species of swallowtails. It has been found that introduced South American Aristolochia elegans in Queensland, Australia are lethal to the larvae of native swallowtails, the Richmond (Ornithoptera richmondia) and Cairns (Ornithoptera euphorion) birdwing butterflies.[46][47] This suggests that the swallowtails and Aristolochia have been engaged in an evolutionary arms race.File:Wikipedia's W.svg

Continuing usage

In 2003, two years after the US FDA issued warnings about herbal remedies containing AA, it was reported that 19 herbal products were available over the internet with Aristolochia as a stated ingredient, and 95 additional products were suspected to contain AA.[48] In 2018, it was reported that Aristolochia is still available for purchase on the internet.[49]

In 2010, the World Health Organization (WHO) was effectively encouraging the use of A. indica in a publication on Ayurvedic medicine.[50] In doing so, they were acting contrary to the information provided by one of their own agencies, IARC.[27][28] The WHO has continued to encourage the use of herbal medicine despite known problems with both efficacy and safety of herbal medicines.[4][51]

A 2009 literature review found that 99 species of Aristolochia have been used ethnobotanically, but only 24 of these species have been studied phytochemically.[52][22]

The English-language portion of the Internet regarding birthwort consists mainly of documents that describe the presence of aristolochic acid in birthwort and the plant's use in traditional medicine, as well as scientific studies of the plant's composition and toxicity. In other languages, however, there are many herbalist sites that actively recommend birthwort as a treament for all sorts of things.[53] Needless to say, such claims of efficacy are never accompanied by any actual statistical evidence.

In 2016, it was estimated that ~100,000 people in the Balkans were at risk of BEN, and that ~25,000 people actually had BEN.[54]

A 2016 survey of plant food supplements of "botanicals of concern" (herbal medicines likely to contain AA) found that 3 of 18 samples (17%) contained AA, and that a literature survey found that 206 of 573 samples (36%) contained AA.[55]

A 2019 review found that AA was widespread in Chinese patent medicine.[40]

Algeria

A. longa is widely used in Algerian traditional medicine. It is used to treat cancer, skin infections, and diabetes.[56]

Bangladesh

As of 2013, A. indica was in use among herbalists in Bangladesh. Knowledge of toxicity among herbalists was limited and administered doses were often "very high".[57]

Brazil

A 2015 ethno-medicinal study of Paraná, Brazil in the vicinity of Parque Estadual da Cabeça do Cachorro found that A. triangularis was the second most frequently used herbal medicine.[58]

Bulgaria

A. clematitis is used in Bulgarian herbal medicine for several indications, including as a diuretic.[59]

Chile

A. chilensis is used in Chilean herbalism for various indications, including arthritis, hemorrhoids, gout, inflammation, weight loss, and overall health.[60][61] It is also used in teas.[60] According to researchers at Chile's Universidad de Santiago, consuming 1mg of the plant can cause harmful effects months after it was initially ingested.[61]

China

In Wenzhou, China, 102 patients were reported with end-stage nephropathy between the years 2004 and 2013. These patients had an astoundingly high incidence of cancer, 41%, which is typical in populations of patients with AAN.[62]

As of 2016, Chinese companies were still making A. debilis, A. manshuriensis, A. fangchi and A. bracteolata available for export for medicinal purposes.[63]

Colombia

A. anguicida was reported to be used in traditional medicine in the Atlantic Coast of Colombia. AA I was previously detected in A. anguicida.[64]

France

In 2016, it was reported that AA I and AA II were detected in a traditional medicine known as chiniy-trèf that is used in the French overseas region of Martinique. Chiniy-trèf is used for poisoning and hexes. It is prepared from caterpillars of the butterfly Battus polydamas, which feeds on the leaves of A. trilobata.[65]

India

A. indica, known as isvari, is used in Ayurvedic medicine. It is also found in Pakistan.[66]:37-38 According to Chandrakant Bhanushali, General Secretary of the Ayurvedic Drug Manufacturers Association, the doses typically used are much lower (100× less) than the toxic doses in Belgium.[67] This should not be particularly comforting since AA is sequestered by blood albumin, which also restricts excretion.[68] According to Bhanushali, A. indica is found in two medicines that are used internally: poogakhanda and gorochanadi vati, but usage of these medicines is negligible.[67] Also not particularly comforting is that the main ingredient of poogakhanda (or pooga khanda) is another human carcinogen, betelnut (Areca catechu),[69] and gorochanadi contains the toxic heavy metal lead as an ingredient.[70] Isvari was included in a list of Ayurvedic herbs without comment in a 2010 WHO report on training Ayurvedic medicine practitioners.[50]

A. bracteolata (syn. A. bracteata) is also used in Indian traditional medicine. It is used for treatment of parasitic worms, snakebite, inducing menstruation, and for childbirth.[66]:36-37

In 2019, Indian researchers reported an investigated on whether A. krisagathra or A. bracteolata might be useful for male contraception.[71]:305-324 The researchers acknowledged that the plants contain AA, but claimed that AA has many medicinal properties without acknowledging the danger of human use.[71]:308

Iran

In Iran, Aristolochia species are known as zaravand or chopoghak (A. longa and A. olivieri), and are still used in herbal medicine as of 2015.[72][73][74]

Morocco

In Morocco, A. baetica and A. longa were reported to be in use among herbalists as of 2015, often substituted by the differently toxic and unrelated Bryonia dioica under the common name "bereztem".[75]

Pakistan

A 2017 article on Pakistani folk medicine reported on four plant species that are widely used in folk medicine, including A. indica.[76] The article analyzed the antimicrobial, antioxidant, cytotoxic and anti-inflammatory potential of the plants and concluded two of the non-Aristolochia species had the strongest effects.[76] The authors did not study safety or mention the hazardousness of Aristolochia. Nonetheless, NaturalNews and its affiliate site 'Science.News' reported on this article, distorting its results and touting A. indica.[77][78]

Papua New Guinea

A. indica is used for malaria, abortion, and uterine inflammation in parts of Papua New Guinea.[79]

Paraguay

A. triangularis was reported to be widely used in combination with yerba maté (Ilex paraguariensis) in Paraguayan folk medicine.[80]

Peru

It was reported in 2007 that A. ruiziana (known locally as bejuco de contra-aire) is used traditionally in the Amazonian part of Peru for "untangling a person who is confused or having trouble progressing in life."[81]

Romania

A. clematitis is recommended by many herbalists in Romania, being used in tinctures, infusions, and creams, and used topically for a wide variety of diseases, including burns, varicose veins, eczema, psoriasis, acne, urticaria, hemorrhoids, skin cancer, genital herpes, and boils, among other things.[82][83] It is also claimed that, in low doses, birthwort taken internally is not carcinogenic, but is in fact an effective treatment for several forms of cancer and many other diseases, and that birthwort "is one of the most powerful medicinal plants we have. It has so many possible applications that it would take entire tomes to describe them. It would not be amiss to say that the potency of birthwort's beneficial effects could be compared to that of an atomic bomb."[82][84]

South Korea

A study of Aristolochia in traditional Korean medicine‎‎ found that AA is found in some Korean herbal remedies, that South Koreans have experienced AAN, and that there is a possibility that AAN is under-diagnosed in South Korea.[85]

Sri Lanka

A. indica is used traditionally as a tonic, a stimulaent, an emenagogue (increasing pelvic blood flow), an emetic. and for fevers.[86]:56

Taiwan

It has been estimated that about a third of Taiwan's herbal medicine prescriptions contain AA, and birthwort is considered to be a significant cause of kidney failure and upper urinary tract cancer in Taiwan.[21] In Taiwan, 76% of clear cell renal cell carcinoma (ccRCC) cases had been exposed to AA based on examination of DNA adducts.[87] A case-control study found that cumulative consumption of 250 mg of AA increased the risk of ccRCC by odds ratio (OR)=1.25.[87]

United States

A limited (i.e., non-random) 2014 survey of 30 dietary supplements marked in the United States found 20% of samples contained AA I and 7% contained AA II.[88] Presumably the sample was of supplements that were suspected of containing AA.

One of the more popular herbal medicine books, The Herb Book by John Lust,[89] was reprinted in 2014, and has not been revised since its initial publication in 1974. Though there is a warning on usage of A. clematitis in the book, it is far from sufficient, particularly because the full danger was not known in 1974 and because instruction for usage is still given. The warning states:

“”CAUTION: Birthwort contains a substance that acts similar to the poisonous alkaloid colchicine.[note 2] Use with care, preferably under medical direction.
—John Lust[89]

If you manage to find a medical professional to supervise your consumption of A. clematitis, you're in more trouble than you think.

Since 2017, Hawaii Pharm has been selling a tincture containing A. clematitis, including on Amazon.com, that is intended for internal consumption.[90][91]

Zimbabwe

A. albida was reported to be used by traditional healers for treatment of malaria in Zimbabwe.[92]

gollark: For what purpose?
gollark: QuickJS?
gollark: The allocator parameters remind me of Zig.
gollark: Hmm. Actually, if I remember that one random detail of the spec correctly, this might be fine.
gollark: Denied.

See also

Notes
  1. Portland Powder contained "equal parts of roots of round birthwort [A. rotunda] and gentian [Gentiana spp.], of the leaves of germander [Teucrium spp.] and ground pine, and of the tops of the lesser centaury [Centaurium pulchellum]…"[17]
  2. As an aside, colchicine (extracted from plants of the genus Colchicum, "autumn crocus") is also a renal (kidney) toxin, but its mechanism of action is different than that of aristolochic acid. Lust was a naturopath and not a toxicologist, so his understanding of toxicology was superficial.

References
  1. Ancient Medicinal Use of Aristolochia: Birthwort's Tradition and Toxicity by John Scarborough, Pharmacy in History, Vol. 53, No. 1, 2011.
  2. Enquiry into Plants, Book 6 by Theophrastus, Arthur F. Hort (Translator). Harvard University Press (1916). ISBN 0674990889.
  3. De Materia Medica by Dioscorides Pedanius, translated by T. A. Osbaldeston & R. P. A. Wood (2000) IBIDIS. ISBN 0620234350. Aristolochia appears on pp. 368-371 of the translation.
  4. Global hazards of herbal remedies: lessons from Aristolochia: The lesson from the health hazards of Aristolochia should lead to more research into the safety and efficacy of medicinal plants by Arthur P. Grollman & Donald M. Marcus (2016) EMBO Reports 17(5):619-25. doi: 10.15252/embr.201642375.
  5. Hildegard von Bingen's Physica: The Complete English Translation of Her Classic Work on Health and Healing, translated by Priscilla Throop (1998). Healing Arts Press. ISBN 0892816619.
  6. 本草綱目/草之七 Wikisource (Compendium of Materia Medica / Grass, Seven)
  7. Chinese Medicinal Plants from the Pen Tsʻao Kang Mu 本草綱目 A.D. 1596 by Bernard E. Read (1936). Peking Natural History Bulletin, 3rd ed.
  8. Aristolochia recurvilabra Hance The Plant List: A Working List of All Plant Species.
  9. Chinese Materia Medica. 1. Vegetable Kingdom by G. A. Stuart (1911). Presbyterian Mission Press, revised from F. Porter Smith.
  10. Health Department and National Chinese Medicine Management Office (ed.). Zhong Hua Ben Cao, 3–460–509. Shanghai Science Technology Publication. 1999. ISBN 7532351068.
  11. Pharmacopoeia of the People's Republic of China (2005). Chemical Industry Press, 2 volumes: ISBN 7502520627 and ISBN 7502520635.
  12. The Herball, or Generall Historie of Plantes] by John Gerarde (1597). John Gerard]
  13. Florida Ethnobotany by Daniel F. Austin (2004) CRC Press, pp. 109-110. ISBN 0849323320.
  14. Birthwort, A Modern Herbal by M. Grieve.
  15. Reconfortatief of gezondheids en zeer versterkende pillen (Maandblad 15 juli 1881, jaargang 1, nummer 7) (9 jan 2009 | Van de Webredactie | Laatste wijziging: 10 jun 2009) Kwakzalverij
  16. Reconfortatief of gezondheids en zeer versterkende pillen (15 juli 1881) Nederlands Tijdschrift tegen de Kwakzalverij 1(7).
  17. The Modern Practice of Physic etc. etc. by Robert Thomas (1828) 9th ed., page 219
  18. A Treatise of the Materia Medica by William Cullen (1789) Volume 2, page 54
  19. De l'Aristoloche (aristolochia clematitis) In Traité des poisons tiré des régnes minéral, vétal et animal; ou, Toxicologie génerale, considére sous les rapports de la physiologie de la pathologie et de la médécine légale by M. P. Orfila (1815) 3rd ed., volume 2, pp. 276-279.
  20. Beware of Nostrums (1888) The Peoria Medical Monthly volume 8, page 128.
  21. Chung-Hsin Chena, et al. "Aristolochic acid-associated urothelial cancer in Taiwan." Proceedings of the National Academy of Sciences. 2012 April 9.
  22. Research and Publications on Herbal Products Known or Suspected to Contain Aristolochic Acid, a Human Carcinogen (archived from April 27, 2017).
  23. Aristolochic acid, sodium salt: Cancer Test Summary (archived from April28, 2017).
  24. Aristolochic acid nephropathy: A worldwide problem by Frédéric D. Debelle et al. (2008) Kidney International 74:158–169; doi:10.1038/ki.2008.129.
  25. Urothelial carcinoma associated with the use of a Chinese herb (Aristolochia fangchi) by J. L. Nortier et al. N. Engl. J. Med. 2000 Jun 8;342(23):1686-92.
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