Since ancient times, humans have experimented with herbs and plants to induce pain relief for surgical procedures. One such plant, used for at least 15 centuries, is the mandragora, or mandrake. Its sedative effects are from the active ingredients scopolamine and atropine.1 In this article, we will trace the history of the use of this plant, from antiquity until the era immediately preceding the use of ether for surgical anesthesia, with an emphasis on the scientists, translators, and plagiarists who helped transfer knowledge from one civilization to the next.
The mandrake, or Mandragora officinarum (Fig. 1), belongs to the Solanaceae family, also known as the nightshade or potato family. It includes many poisons (mandrake, deadly nightshade, henbane) and foods (paprika, tobacco, eggplant, potato, tomato).2 The mandrake is a perennial herb, native to the eastern Mediterranean basin and has a short stem and large wrinkled leaves, with clustered bell-shaped flowers and berry-like orange fruit. The roots are forked into two, which with some imagination, may look like the lower half of a human body.3
Although it is not known when mandragora began to be used for sedation, it has been depicted in tablets and friezes since antiquity. The Ebers Papyrus (1500 before the common area [BCE]), an encyclopedic collection of older sources, lists >800 recipes and 700 drugs, including the mandrake, to treat a variety of ailments.4 The mandrake is sculpted on multiple tombs in Luxor-Thebes (Upper Egypt) dating from the 16th through the 14th century BCE. It is on a tablet from the 13th century BCE, thought to depict Princess Meritaten, daughter of King Amenhotep IV and Queen Nefertiti, offering a mandrake plant to her husband King Smenkhkare, who is holding a cane (Fig. 2). It is also on a frieze of a priest from the palace of the Assyrian King Sargon II of the eighth century BCE.5 All these suggest that the mandrake was used for medicinal benefits, but it is not clear that it was used for sedation until the time of Hannibal (247–182 BCE), who used it in war. He is said to have retreated in battle, leaving a feast with wine drugged with mandrake. The enemy drank, slept, and was ambushed when Hannibal’s troops returned.6 In his time, Hannibal was considered the best military strategist and his methods were copied by the Romans and others. A century later, Julius Caesar (100–44 BCE) used a similar trick to escape from Sicilian pirates.7 Celsus (c. 50 to c. 25 BCE), who wrote the encyclopedia De Medicina, said that toothaches and abscesses were “among the worst of tortures” and recommended that patients should drink a mixture containing mandrake for pain relief.8 The Romans used to give mandragora in wine to criminals before interrogations,9 and it may have been added to the wine offered to Jesus Christ on the cross.10
LEGENDS AND MYTHS
According to ancient legend, when the mandrake root is dug up, it screams and kills all who hear it. The Jewish historian Flavius Josephus (c. 37 to c. 100 of the common era [CE]) gives these instructions for uprooting the plant: “They dig a trench quite round about it, till the hidden part of the root be very small; they then tie a dog to it and when the dog tries hard to follow him that tied him, this root is easily plucked up, but the dog dies immediately as if it were instead of the man that would take the plant away.”11 Pliny the Elder (23–79 CE), in his book Naturalis Historia, warns that the person who pulls the plant must not have the wind blowing in their face.11 Such tales were repeated by Claudius Aelianus (c. 175 to c. 235 CE) in De Natura Animalium, repeated again in Byzantine times by the chronicler St. Theophanes the Confessor (758–818 CE), then found in Arab writings, and brought to Europe by the Crusaders.11 In medieval times, the herbalist Bartholomew Anglicus (c. 1203 to 1272 CE) summarized work transmitted through Arabian scholars and described the old legend.12 In the Grete Herball of 1526, we find the first writings of “disbelief in the supposed powers of the mandrake.”13 And in 1597, John Gerard disputed the legend, saying that he had “safely planted and replanted many mandrakes.”14
Another ancient legend surrounding the mandrake found its roots in the Old Testament. In Genesis 30:14–24, Rachel asks her sister Leah for the mandrakes that Leah’s son Reuben had harvested (Fig. 3). Leah exchanges this for a night of sleeping with their husband Jacob, and from that night her fifth son Issachar is conceived. Soon thereafter, Rachel, who had not borne any children, became pregnant with Joseph, the 11th of the 12 sons of Jacob. These births gave the mandrake a reputation among Christians of medieval Europe that it enhanced fertility.9 Its roots, because of their resemblance to the lower half of a human body, became prized possessions and were carved into talismans and worn around the neck as a love charm. Perhaps to increase their price, the old beliefs in the dangers of uprooting the plant were returned.11 The medieval Church, however, attached demonic qualities to the plant. Saint Hildegard (1098–1179 CE), in her book Physica, a text on the natural sciences, wrote that the plant can be used in the diabolical arts, that it “ministers to the Devil,” and cautioned that special baths must be taken to avoid its enchantment.11 Mandrake was used in an attempt to indict Joan of Arc for witchcraft. Among the 70 accusations levied on her, one was that she used to carry a mandrake as a talisman.15
This link between the mandrake and demonic powers lasted for 4 centuries. Perhaps despite the church’s admonitions, the mandrake became a plant that piqued the imagination of writers. In 1518, Machiavelli wrote a play La Mandragola, wherein the plant is used as both an aphrodisiac and to restore fertility.16 Shakespeare mentions mandragora in many of his plays, primarily as a sedative: Othello (act III, scene iii), Antony and Cleopatra (act I, scene v), Romeo and Juliet (act IV, scene iii), King Henry IV part II (act I, scene ii; and act III, scene ii), and King Henry VI part II (act III, scene ii).17 In modern times, the mandrake is mentioned in Samuel Beckett’s Waiting for Godot (1954),18 and in Pokémon, a video game by Nintendo, Oddish is a weed-like character that shrieks when uprooted.19 More recently, the ancient legend is used by J. K. Rowling in her Harry Potter series, when Professor Sprout teaches the students at the Hogwarts School of Witchcraft and Wizardry about the mandrake, making sure they wear earmuffs when uprooting the plant.20
EARLY USE IN SURGERY
Two centuries after Hannibal used the mandrake for sedation, it was used for surgery, for which Celsus recommended it for pain relief.8 It is unclear why this recommendation was made, because scopolamine has only sedative and amnestic properties and it would not abolish pain or withdrawal from a painful stimulus. However, in combination with compounds that offer analgesia (e.g., opium), a true anesthetic state might be produced. Pliny the Elder (23–79 CE) wrote that it should be “given before operations to dull the sense.”9 During the reign of Nero (54–68 CE), mandrake was a soporific used during dental procedures.21 Pedanius Dioscorides (c. 40 to c. 90 CE) traveled with Nero’s army and described the medicinal value of hundreds of plants in his book De Materia Medica. He mentioned the superstitions regarding harvesting the mandrake plant and administered its root boiled in wine to his patients.22 In the section on mandragora, he states that the person who takes it “falls asleep in the position in which he was when he took it,” and that it can be used by physicians “when they intend to cut or burn.”11 It is said that the plant was given to Dioscorides by the Gods: in an old frieze, Heuresis, goddess of discovery, is shown handing a mandragora plant to Dioscorides, with a dog pulling the plant and dying.23 Throughout the writings of the Romans, the plant’s extract was used as a juice that the patient had to drink before surgical procedures and not in the form of inhalation.24 Because scopolamine and atropine have very low vapor pressures, inhalation would be ineffective and the mandrake juice had to be absorbed by mucous membranes.
Between the 7th and 15th centuries, the Islamic Empire expanded out of the Arabian Peninsula into the eastern Mediterranean, northern Africa, and eastern and western Europe. Through Constantinople, the Arabs were able to learn of the ancient sciences. Many of the original Arabian scientists were Christian and Jewish translators. Hunayn Ibn Ishaq (c. 809 to 873 CE), known as Joannitius, was the founder of the Arab Medical Renaissance. He worked in “the House of Wisdom,” an institution of learning, library, and translation bureau in the court of Caliph Al-Mamun in Baghdad. He is known to have translated many works by Galen, Hippocrates, Dioscorides, and others into Arabic.25
After this phase of translation from Latin into Arabic, science began to thrive. Arabian Medicine (Arabs, Persians, Spaniards, north Africans, and others, who were Jews, Christians, or Muslims, lived under Caliphate rule and wrote their scientific texts in Arabic) raised the medical profession from a menial position to that of a learned profession and began qualifying examinations for admission to medicine.26 Al-Razi (c. 865 to c. 925 CE), or Rhazes, worked near Tehran then in the court of the Caliph in Baghdad. He wrote a comprehensive book on medicine and conducted pharmacological experiments on animals. He spoke of Al Murquid, used to put patients to sleep for an operation by ingestion or rectal injection. This is thought to be a combination of opium, cannabis, henbane, and mandrake.27 Ibn al-Quff (1233–1286 CE) lived in what is now Jordan. In his book, Al-Omda Fi Sinaat Al-Jarrah (“The Mainstay in the Surgeon’s Craft”), he wrote that pain relief must be the responsibility of Al-Tabaaei (the physician), who should give Al-Murquid (the sleep medicine) so Al-Jaraaehi (the surgeon) can perform the surgery (Fig. 4). This is the first report suggesting a role for the anesthesiologist.28 Ibn Maymoon (1135–1204 CE), or Maimonides, lived in Cordoba, Fez, and Cairo. In addition to his numerous contributions to Judaism and philosophy, he wrote medical treatises, among them On Asthma, Poisons and Their Antidotes, where he mentioned the mandrake roots as sleeping pills and in the treatment of asthma.29 Mandrake may have been effective for such treatment because the active ingredient, scopolamine, has the capacity to diminish vagal activity.
THE SPONGIA SOMNIFERA
Perhaps the most important Arabian scientist was Ibn Sina (c. 980 to 1037 CE), or Avicenna. In his authoritative Canon of Medicine, he identified certain plants with pharmacological action, such as mandrake, opium, and henbane.30 He described the Spongia Somnifera: “Opium, juice of hyoscyamine, unripened berry of the blackberry, hog beans, lettuce seed, juice of hemlock, poppy, mandragora. Put these all together in a vessel and plunge therein a new sea-sponge, and put that in the sun during the dog-days until all the liquid is consumed. And when there is need, dip it a little in water and apply it to the nostrils of the patient, and he will quickly go to sleep.”31 It is this soporific sponge, with various compositions, that is seen in numerous writings through the next 8 centuries.32
Between the 11th and 15th centuries, as Arabian culture was declining because of the Crusades and internal dissension, Christian Europe was awakening from the Dark Ages. The flow of learning from the ancient Greeks and Romans, sustained and augmented by the Arabs, would now flow from them to Christian Europe.33 One of the first to accomplish the link was Constantine the African (c. 1018 to c. 1085 CE). An Arab Muslim by birth, he studied the medical sciences for 39 years and moved to the Benedictine monastery of Monte Cassino, taking his numerous writings with him. Despite the fact that these were verbatim translations of Arabic science, which also included works of Hippocrates and Galen, he claimed much of the discoveries for himself.34 His work was viewed as Arabicized contributions of Greek medicine, which was easily accepted in Monte Cassino and the remainder of southern Italy, as they had once been Greek colonies, and Greek traditions still lingered.31 Soon thereafter, with the fall of various European Arab cities to the Christians (Palermo in 1072 CE; Toledo in 1085 CE; Cordoba in 1212 CE; Granada in 1492 CE), their libraries became centers of translation.33 One of the most famous translators was Gerard of Cremona (1114–1187 CE), who worked in the library at Toledo between 1175 CE and his death, translating from Arabic into Latin the works of Aristotle, Ptolemy, Euclid, Archimedes, Galen, Avicenna, Rhazes, and many others.35 His translations were described as more scientific than those of Constantine the African. The Spongia Somnifera is found in his Latin translation of Avicenna’s work.36
The first medical school in Europe was founded late in the 11th century in Salerno, by Robert Guiscard, a Norman Crusader who had freed southern Italy from the Arabs.37,38 Salerno had been a health resort to the ancient Greeks, but because of its proximity to Monte Cassino (less than 5 miles), most writers associate it with the Benedictine monks and Constantine the African. It is considered the place where the decline of medicine in the Dark Ages was arrested, and for 200 years was the greatest medical center of Christian Europe.34 Injured Crusaders, including Robert, son of William the Conqueror, stopped there on their way home to seek medical treatment.38 By the merging of Greek, Latin, Hebrew, and Islamic influences, the medical school thrived and Salerno became known as the Hippocratic City.39 The Spongia Somnifera is mentioned in many writings by Salernitan physicians, such as the Bamberg Antidotarium of Nicholas of Salerno and the Monte Cassino Codex.40 Michael Scot (c. 1190 to c. 1250 CE), a graduate of Salerno, wrote: “Take of opium, mandragora and henbane equal parts, pound and mix them with water. When you want to saw or cut a man, dip a rag in this and put it to his nostrils. He will soon sleep so deep that you may do what you wish.”41
The second medical school of Christian Europe was founded at Montpellier, early in the 12th century, mainly by Jewish doctors who had been educators in the Moorish schools of Spain, but had fled Andalusia because of the various wars between Christians and Muslims.34 Guy de Chaulliac (1300–1367 CE), a French surgeon educated at that school, described in Chirurgica Magna the asphyxia, congestion, and death from the Spongia Somnifera, warning that the potency of plant extracts varied enormously, depending on climate and the method of extracting the juices.42
Another famous medical school was in Bologna, where Hugh of Lucca (1160–1257 CE) was a surgeon. He had accompanied the army in the Fifth Crusade during the 3-year siege of Damietta on the Nile River and witnessed Arabian surgery after using the Spongia Somnifera.43 His son Theodoric (1210–1298 CE) wrote of using the sponge in Cyrurgia Theodorici, prepared by soaking it in a mixture of mandrake, poppy, henbane, and other herbs, and patients were allowed to chew on the sponge.44 The herbalist Bartholomew Anglicus (c. 1203 to 1272 CE) refers to the anesthetic-like properties of the mandrake: “the rind thereof melded with wine ... shall be cut in their body, for they should slepe and not fele the sore knitting.”12 William Turner (c. 1508 to 1568 CE), a graduate of the medical school at Bologna, wrote about the mandrake in his A New Herball: “It is given to those who must be burned or cutting.… If they drynk thys drynke they shall fele no payne, but they shall fall into a forgetfull and slepishe drowsiness.”45 Gabriel Fallopius (1523–1562 CE) wrote that “if soporifics are weak, they do not help; if they are strong, they are exceedingly dangerous.” There was no attempt at purification or precise dosing and people often died.42
DECREASE IN USE OF THE MANDRAKE
For the next 200 years, there is very little mention of the mandrake or the Spongia Somnifera.32,46 Juvin and Desmonts32 examined this period and listed possible explanations, including a combination of religious, social, and surgical changes: The sponge was being used by showmen and magicians, but the political climate forbade dabbling in the occult; over the centuries, patients began expecting deeper sedation than the Spongia Somnifera could offer; earlier operations had been shorter in duration and on more superficial tissues; and alterations of texts by copying errors resulted in weaker plant compositions of the sponge.32
The Spongia Somnifera appears again in 1847, soon after the first use of ether for surgical anesthesia. The Lancet published an abstract of a French paper written by Dauriol, a physician describing using the sponge for general anesthesia on 5 patients. His composition did not include mandrake, but he described using the juice of various plants then drying the sponge in the sun until it is needed for surgery. He recommended this as a substitute for ether.47 (The reference in The Lancet was incorrect, in that it said this manuscript was in the wrong French journal. Thanks to another publication,48 we were able to retrieve the original French article49 from a medical journal that had stopped publishing soon after the Dauriol article.)
The last scientific work on the mandrake is provided by the eminent British anesthetist Sir Benjamin Ward Richardson (1828–1896 CE), famous for editing Dr. John Snow’s On Chloroform and Other Anaesthetics and publishing it after his friend’s death. He tried to recreate the mixture of Dioscorides, experimenting on pigeons, rabbits, and himself. Based on the actions of the juice of the mandrake plant, he wrote that it must contain an alkaloid that is one of the most active anesthetics.48 That chemical is scopolamine.
To date, the ethers have been used for surgical anesthesia for about one and a half centuries. Mandrake was used for surgical anesthesia for 15 centuries. Students of the history of anesthesia may have noticed that, although ether had been used for nonsurgical purposes (e.g., asthma; showmanship) for about 30 years (c. 1818 to 1846 CE) before a physician started using it during surgery,50 the gap for the mandrake between its use for sedation and surgery was about 250 years (c. 200 BCE to c. 50 CE).
In conclusion, the history of surgical anesthesia began many centuries ago, using the plants of antiquity. The use of the mandrake can be traced from the ancient Egyptian and Assyrian civilizations to that of the Greeks and Romans, on to the Arabs, then to Europe. In 1946 CE, in a book entitled Victory Over Pain: A History of Anesthesia, dedicated to Drs. Arthur E. Guedel and Ralph M. Waters, Victor Robinson wrote: “In the vast brotherhood of pain, there is neither East nor West: with opium and mandrake and hashish and henbane, the Oriental healer, like his Occidental colleague, sought to bring to his operative patients the balm of merciful sleep.”51
Name: Elie J. Chidiac, MD.
Contribution: This author helped analyze the data and write the manuscript.
Attestation: Elie J. Chidiac approved the final manuscript.
Name: Romeo N. Kaddoum, MD.
Contribution: This author helped analyze the data and write the manuscript.
Attestation: Romeo N. Kaddoum approved the final manuscript.
Name: Samir F. Fuleihan, MD.
Contribution: This author helped analyze the data and write the manuscript.
Attestation: Samir F. Fuleihan approved the final manuscript.
This manuscript was handled by: Steven L. Shafer, MD.
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