The rise and fall of mandrake in medicine.

ETHNOPHARMACOLOGICAL RELEVANCE: Mandrake (Mandragora sp.) is one of the most famous medicinal plants. It has been in continuous medical use throughout written history and is still in use today in popular medicine. AIM OF THE STUDY: Mandrake derived drugs once played an important role in medicine and in magical practices. Today, the role of mandrake in popular medicine is marginal. However, natural products present in mandrake such as atropine and scopolamine, as well as their semi synthetic derivatives continue to hold and important role in medicine. Here we aim to trace the development of historical rationales and scientific events that led to the abandonment of mandrake as a medicine. MATERIALS AND METHODS: We review the medicinal uses of mandrake drugs since antiquity in an attempt to pinpoint use patterns that were popular in certain periods of time and others that are more general. We compare the uses from the native territories to those from regions where the plant got introduced and use literature reporting mandrake's chemistry and pharmacology in order to explain the diachronic changes of use patterns. RESULTS AND CONCLUSION: We found information about 88 different medicinal uses for mandrake, grouped into 39 conditions. According to the number of different medicinal uses, the most versatile period was the medieval (37), followed by the Renaissance (31), the classical (27), and the modern period (21). Considering the higher number of textual sources and use-records collected for the Renaissance period, the decrease of versatility in comparison to the medieval period appears robust. This seems to indicate a more consolidated use pattern, that might be conditioned by the reproduction of classic textual sources as well as by a less experimental approach and reduced popularity of mandrake in medicine. The introduction of the volatile anaesthetics with more reliable narcotic effects set the seal on using mandrake in surgery but opened the way for atropine being used as a prophylactic and antidote during surgical interventions.

Isolation, Identification and Pharmacological Effects of Mandragora autumnalis Fruit Flavonoids Fraction.

Since ancient times, Mandragora autumnalis has been used as a traditional medicinal plant for the treatment of numerous ailments. In light of this, the current study was designed to isolate and identify the chemical constituents of the flavonoids fraction from M. autumnalis ripe fruit (FFM), and evaluate its DPPH scavenging, anti-lipase, cytotoxicity, antimicrobial and antidiabetic effects. An ethyl acetate extract of M. autumnalis was subjected to a sequence of silica gel column chromatography using different eluents with various polarities. The chemical structures of the isolated compounds were identified using different spectral techniques, including 1H NMR and 13C NMR. FFM's anti-diabetic activity was assessed using a glucose transporter-4 (GLUT4) translocation assay, as well as an inhibition against α-amylase and α-glucosidase using standard biochemical assays. The FFM anti-lipase effect against porcine pancreatic lipase was also evaluated. Moreover, FFM free radical scavenging activity using the DPPH test and antimicrobial properties against eight microbial strains using the micro-dilution method were also assessed. Four flavonoid aglycones were separated from FFM and their chemical structures were identified. The structures of the isolated compounds were established as kaempferol 1, luteolin 2, myricetin 3 and (+)-taxifolin 4, based on NMR spectroscopic analyses. The cytotoxicity test results showed high cell viability (at least 90%) for up to 1 mg/mL concentration of FFM, which is considered to be safe. A dose-dependent increase in GLUT4 translocation was significantly shown (p < 0.05) when the muscle cells were treated with FFM up to 0.5 mg/mL. Moreover, FFM revealed potent α-amylase, α-glucosidase, DPPH scavenging and porcine pancreatic lipase inhibitory activities compared with the positive controls, with IC50 values of 72.44 ± 0.89, 39.81 ± 0.74, 5.37 ± 0.41 and 39.81 ± 1.23 µg/mL, respectively. In addition, FFM inhibited the growth of all of the tested bacterial and fungal strains and showed the greatest antibacterial activity against the K. pneumoniae strain with a MIC value of 0.135 µg/mL. The four flavonoid molecules that constitute the FFM have been shown to have medicinal promise. Further in vivo testing and formulation design are needed to corroborate these findings, which are integral to the pharmaceutical and food supplement industries.

In search of traces of the mandrake myth: the historical, and ethnobotanical roots of its vernacular names.

BACKGROUND: Mandrake (Mandragora spp.) is one of the most famous medicinal plant in western cultures since Biblical times and throughout written history. In many cultures, mandrake is related to magic and witchcraft, which is said to have a psychosomatic effect (especially when mandrake contains narcotic compounds) in addition to the pharmacological influence, as occurs with other narcotic magical plants. Due to its unique properties and related myths, it is not surprising that this plant has many names in many languages. METHODS: This paper presents an attempt to reconstruct the historical, ethnobotanical, and folkloristic roots of 292 vernacular names of Mandragora spp. in forty-one languages. We used the plant's morphological data, philology, myths and legends, medicinal properties and uses, as well as historical evidence and folkloric data, to explain meaning, origin, migration, and history of the plant's names. RESULTS: The names were classified into the following main categories: Derivatives of mandragora (19 languages), alraun (7) and of yabroukh (5). The salient groups of the plant's vernacular names are related to: Anthropomorphism (33 names in 13 languages); Similarity to other plants (28/9); Supernatural agents (28/9); Narcotic effects (21/8); Leaves, fruits, and seeds (21/8); Aphrodisiac properties (17/10); Use of a dog (15/9); Gallows (14/5); Black magic, sorcery, witchcraft (13/8), and Medicinal use (11/7). CONCLUSIONS: This frequency distribution of the mandrake's vernacular names reflects its widespread reputation as related to the doctrine of signatures, beliefs in its supernatural, natural, and mythic powers, and to a lesser extent, its uses in magic and medicine. A spatiotemporal analysis of the mandrake's names supports the old idea that the pulling ceremonies for this plant originated in the Near East and that various other myths related to this plant may have originated in different places and periods.

A Comprehensive Review on the Ethnopharmacology, Phytochemistry, Pharmacology, and Toxicology of the Mandragora Genus; from Folk Medicine to Modern Medicine.

The Mandragora genus (Solanaceae) is well known for its association with myths and has been used in herbal medicine since ancient times. This extensive literature review synthesizes the information currently available on the ethnobotany, Persian medicine (PM), traditional use, phytochemistry, pharmacology, and toxicity profile of Mandragora spp. The electronic search engines Scopus, Web of Science, PubMed, Google Scholar, and ScienceDirect were searched using keywords such as Mandragora, mandrake, phytochemistry, ethnopharmacology, Persian medicine, ethnobotany, and toxicity. Pertinent information was also extracted from books on PM, ethnomedicine, and dissertations. Mandragora species are found throughout the Mediterranean basin, Europe, Northern Africa, and the Himalayan regions. Traditionally, the species have been used to treat insomnia, dysuria, hemorrhoids, rheumatic pain, toothache, melancholia, and depression, among many others. In vitro studies have confirmed the biological properties of Mandragora spp. crude extracts, such as antioxidant, immunomodulatory, and enzyme-inhibiting effects. Various phytochemicals, such as alkaloids (e.g., atropine and scopolamine), coumarins (e.g., umbelliferone and scopoletin), withanolides (e.g., salpichrolide C), and lipid-like compounds (e.g., beta-sitosterol), have been isolated from Mandragora spp. Some of the pure compounds composing this plant are highlighted for their biologically active effects, including anticholinergic, antidepressant, antioxidant, and anti-inflammatory effects. Modern identifications of biological activities of the compounds isolated from Mandragora, especially alkaloids, support its traditional uses (e.g., for their narcotic effects). More in vivo studies are required to further understanding and most effectively utilize this genus, and extensive toxicological studies are required to validate its safety in clinical use.

Profiles of the Essential Oils and Headspace Analysis of Volatiles from Mandragora autumnalis Growing Wild in Tunisia.

Mandragora autumnalis Bertol. (Solanaceae family), synonym of M. officinalis Mill., occurs in North Africa and grows natively in Northern and Central Tunisia, in humid to sub-arid climates. The ripe fruits of mandrake are odiferous with a particular, indescribable, specific odor, shared, to a lesser extent, by the leaves and roots. We carried out an investigation of the essential oils (EOs) and of the aromatic volatiles emitted by fresh leaves, roots and ripe fruits of M. autumnalis growing wild in Central Tunisia. The EOs were obtained from freshly collected plant material by hydrodistillation, while the volatile emissions from the powdered M. autumnalis tissues were sampled by headspace solid phase microextraction (HS-SPME); both types of samples were analyzed by gas chromatography-mass spectrometry (GC/MS). Fifty-one compounds representing 96.2-98.6 % of the total oil compositions were identified in the three tissues and belonged to different chemical classes specifically in 16 esters, 12 alcohols, 12 hydrocarbons, 6 ketones, 3 aldehydes and 3 acids. The main constituents were pentadecanoic acid (34.2 %) and hexadecanol (26.3 %). A total of 78 volatile compounds emanating from M. autumnalis tissues, representing 94.1-96.4 % of the total volatile compositions, were identified: 22 esters, 11 alcohols, 9 aldehydes, 14 ketones, 7 nitrogen, 10 hydrocarbons, 2 lactones, 1 sulfur and 2 ethers. Ethyl hexanoate (12.3 %) and 1,3-butanediol (12.3 %) were at the highest relative percentages. This study characterizes and distinguishes M. autumnalis from Tunisia and attributes the compounds responsible for the intoxicating and particular odor of fruits. Chemosystematic of Mandragora autumnalis based on the identification of essential oils and headspace volatiles of each of its organ can be used to characterize this species according to its geographic distribution.

Alkaloid chemodiversity in Mandragora spp. is associated with loss-of-functionality of MoH6H, a hyoscyamine 6ß-hydroxylase gene.

Mandrakes (Mandragora spp., Solanaceae) are known to contain tropane alkaloids and have been used since antiquity in traditional medicine. Tropane alkaloids such as scopolamine and hyoscyamine are used in modern medicine to treat pain, motion sickness, as eye pupil dilators and antidotes against organo-phosphate poisoning. Hyoscyamine is converted to 6ß-hydroxyhyoscyamine (anisodamine) and scopolamine by hyoscyamine 6ß-hydroxylase (H6H), a 2-oxoglutarate dependent dioxygenase. We describe here a marked chemo-diversity in the tropane alkaloid content in Mandragora spp. M. officinarum and M. turcomanica lack anisodamine and scopolamine but display up to 10 fold higher hyoscyamine levels as compared with M. autumnalis. Transcriptomic analyses revealed that H6H is highly conserved among scopolamine-producing Solanaceae. MoH6H present in M. officinarum differs in several amino acid residues including a homozygotic mutation in the substrate binding region of the protein and its prevalence among accessions was confirmed by Cleaved-Amplified-Polymorphic-Sequence analyses. Functional expression revealed that MaH6H, a gene isolated from M. autumnalis encodes an active H6H enzyme while the MoH6H sequence isolated from M. officinarum was functionally inactive. A single G to T mutation in nucleotide 663 of MoH6H is associated with the lack of anisodamine and scopolamine in M. officinalis.

Evolutionary history and biogeography of Mandragora L. (Solanaceae).

Mandragora L. (Solanaceae) is the only genus of the tribe Mandragoreae, one of the two tribes of the cosmopolitan nightshade family, which occur exclusively in Eurasia and northern Africa. The genus occurs discontinuously in the Mediterranean region, Turanian region, and on the Tibetan Plateau, representing a classical disjunction pattern in the biogeography of the Old World flora. In this study, we reconstructed the genus phylogeny using AFLP, eight plastid DNA regions and one nuclear (ITS) gene, and evaluated the taxonomic value of quantitative traits time to flowering, fruit and seed size. We also analyzed the evolutionary history of the genus based on a phylogenetic framework and dating inferred from a combined data set of seven plastid regions with one fossil calibration point. Our data suggest that Mandragora originated in the Eocene, apparently along the Tethyan coast in broadleaf deciduous mesophytic forests that covered most of the Mediterranean region at that time. The Mediterranean-Turanian clade diverged from the Tibetan Plateau clade about 20.5 million years ago (Ma) as a result of the plateau uplift which probably was enhanced by aridification in the interior of Eurasia. A second split within the genus occurred about 11.1 Ma and resulted in Western Mediterranean and Near East-Turanian clades. Mandragora turcomanica was found to have very closely related evolutionary history with plants from the Near East indicating a possible ancient human assisted migration from Israel to Persia in historic times. In the Tibetan Plateau area, the morphologically distinctive M. chinghaiensis is nested within the M. caulescens clade indicating a very recent diversification within this lineage.

From "Circe's Root" to "Spongia Soporifera": The Role of the Mandrake as True Anesthetic of Ancient Times.

Several ancient authors cited mandrake as a powerful and well-known narcotic drug: from Homer to Dioscorides, from Plato to Aristotle, passing from Hippocrates, Demosthenes, Theophrastus, Celsus, and Apuleius. Their detailed studies included the concrete appearance of the plant, the related recipes including mandrake as essential ingredient, the right dosages, how to administer the obtained medication, and the possible collateral effects. Even in the Middle Ages, the success of this root continued: Isidore of Seville, Theodoric of Cervia, Gilbertus Anglicus, and William from Varignana extensively reported their researches on sponges soaked with mandrake juice, which were used before surgical interventions as soporific tools. This article represents a travelogue among ancient ages to discover the anesthetic properties of the mandrake.

Topical treatment in pain medicine: from ancient remedies to modern usage.

Over several millennia, substances have been applied to the skin for treatment of pain. Some ingredients are in current use; others have been discontinued. Mechanisms of action include interactions with nociceptive neural networks and inflammatory processes. Substances must penetrate the stratum corneum barrier and vehicles that enhance penetration have been developed. Topical drugs with links to the past include menthol, capsaicin, some opioids, local anesthetic agents and NSAIDs. Mandragora is also described as an example of a herbal remedy that has been discontinued due to its toxicity. The future for topical drugs is promising, with the advent of new drugs tailored for specific pain mechanisms and the development of both penetration enhancers and sterile preparation methods.

The pharmacology of medieval sedatives: the "Great Rest" of the Antidotarium Nicolai.

ETHNOPHARMACOLOGICAL RELEVANCE: Past practices of compound drugs from different plant ingredients enjoyed remarkable longevity over centuries yet are largely dismissed by modern science as subtherapeutic, lethal or fanciful. AIM OF THE STUDY: To examine the phytochemical content of a popular medieval opiate drug called the "Great Rest" and gauge the bioavailability and combined effects of its alkaloid compounds (morphine, codeine, hyoscyamine, scopolamine) on the human body according to modern pharmacokinetic and pharmacodynamic parameters established for these compounds. CALCULATIONS AND THEORY: We reviewed the most recent studies on the pharmacodynamics of morphine, codeine, hyoscyamine and scopolamine to ascertain plasma concentrations required for different physiological effects and applied these findings to dosage of the Great Rest. RESULTS: Given the proportional quantities of the alkaloid rich plants, we calculate the optimal dose of Great Rest to be 3.1±0.1-5.3±0.76 g and reveal that the lethal dose of Great Rest is double the therapeutic concentration where all three alkaloid compounds are biologically active. CONCLUSION: This study helps establish the effective dose (ED50), toxic dose (TD50) and lethal dose (LD50) rates for the ingestion of raw opium, henbane and mandrake, and describes their probable combined effects, which may be applied to similar types of pre-modern pharmaceuticals to reveal the empirical logic behind past practices.

Special article: mandragora: anesthetic of the ancients.

Initial attempts at surgical anesthesia began many centuries ago, with the plants of antiquity. The mandragora, or mandrake, was used as a sedative and to induce pain relief for surgical procedures. It has been depicted in tablets and friezes since the 16th century before the common era (BCE) and used for its sedative effects by Hannibal (second century BCE) against his enemies. The Romans used the mandrake for surgery. The Arabs translated the scientific work of the Ancients and expanded on their knowledge. They developed the Spongia Somnifera, which contained the juice of the mandrake plant. After the fall of the Islamic cities of Europe to the Christians, scientific work was translated into Latin and the Spongia Somnifera was used in Europe until the discovery of the use of ether for surgical anesthesia.

Accidental poisoning after ingestion of "aphrodisiac" berries: diagnosis by analytical toxicology.

BACKGROUND: A large number of plants, seeds, and berries have been used for medicinal, psychotropic, or aphrodisiac purposes for a thousand years. Mandragora officinarum belongs to the family of Solanaceae and is traditionally known as an aphrodisiac and is closely associated with witchcraft. OBJECTIVES: In this study we report a case of an accidental poisoning after ingestion of some "aphrodisiac" berries and the contribution of the toxicological analysis in the case investigation. CASE REPORT: A 35-year-old man was admitted to the hospital with clinical signs and symptoms of an anticholinergic syndrome. The diagnosis of the poisoning was made by the toxicological analysis of the patient's urine. The cause of the poisoning was revealed by his girlfriend's disclosure that the patient had intentionally consumed some "aphrodisiac" berries to enhance his sexual performance. Subsequently, berries similar to the ones consumed were sent to the laboratory. The analysis of the urine and the berries revealed the presence of hyoscyamine and scopolamine; the berries were identified as Mandragora officinarum berries. Decontamination and symptomatic treatment were proven effective for the control of this poisoning. The patient recovered completely after hospitalization for 4 days. CONCLUSION: This case report indicates the importance of analytical toxicology in diagnosis of intoxications after the consumption of unknown plants or plant products and presents the clinical aspects of Mandragora intoxication.

Tósigos y antídotos en la literatura cervantina: sobre los venenos en la España tardorrenacentista / “Tosigos” and antidotes in Cervantine literature: on the poisons in the late Renaissance Spain

Los textos cervantinos constituyen una interesante fuente para el estudio de la sociedad española tardorrenacentista. Nosotros hemos abordado las obras de Cervantes desde la óptica de la toxicología, analizando el uso de agentes tóxicos y venenosos, fundamentalmente alucinógenos y narcóticos en el ámbito de la práctica de la brujería y hechicería (ungüentos de brujas, filtros de amor, pócimas venenosas, etc.), así como las menciones a las hipotéticas sustancias dotadas de acción alexifármaca, como la verbena (Verbena officinalis), el cuerno de unicornio, las piedras bezoares o el castóreo. Las obras cervantinas en las que se hace referencia a estos preparados son las novelas El Quijote, La Galatea, Viaje del Parnaso y cuatro Novelas Ejemplares (La española inglesa, El licenciado Vidriera, El celoso extremeño y El coloquio de los perros), así como en las comedias Pedro de Urdemalas, La entretenida y El laberinto del amor. Entre los agentes tóxicos de origen herbal citados expresamente por Cervantes en el contexto analizado se encuentran el beleño (Hyoscyamus niger / albus), el tabaco (Nicotiana tabacum), la adelfa (Nerium oleander), el tártago (Euphorbia lathyris), el ruibarbo (Rheum officinale, Rumex alpinus) y, de forma enmascarada, el opio (Papaver somniferum). En relación con el resto de preparados dotados de actividad tóxica, Cervantes no identifica sus ingredientes, aunque, a tenor de la sintomatología descrita por el autor, podrían ser plantas de la familia de las solanáceas, como el beleño, el solano, la datura, la belladona o la mandrágora. Con respecto a los tóxicos minerales, únicamente hay referencias a los efectos del mercurio o azogue. El Dioscórides comentado por Andrés Laguna pudo ser la fuente técnica utilizada por Cervantes para documentarse en esta materia (AU)

Cervantine texts are an interesting source for the study of Spanish late Renaissance society. We have studied the works of Cervantes from the toxicology viewpoint, analyzing the use of toxic and poisonous substances, essentially hallucinogenic and narcotic agents in the field of witchcraft and sorcery practice (witches ointments, love filters, poisonous potions, etc.), as well as references to hypothetical substances endowed with alexipharmic action, as the vervain (Verbena officinalis), unicorn horn, bezoar stones or castoreum. Cervantine works which refers to these preparations are the novels Don Quixote, The Galatea, Voyage to Parnassus and four Exemplary Novels (The Spanish-English Lady, The Licentiate of Glass, The Jealous Extremaduran and The Colloquy of the Dogs), as well as the comedies Pedro de Urdemalas, The Amusing Woman and The Labyrinth of Love. Toxic agents of herbal origin mentioned explicitly by Cervantes in the analyzed context include the henbane (Hyoscyamus niger / albus), tobacco (Nicotiana tabacum), oleander (Nerium oleander), spurge (Euphorbia lathyris), rhubarb (Rheum officinale, Rumex alpinus), and masked way, opium (Papaver somniferum). In relation to the rest of preparations endowed with toxic activity, Cervantes does not identify its ingredients, though, within the meaning of the symptoms described by the author, they could be plants of the Solanaceae family, as the henbane, nightshade, jimsonweed, belladonna or mandrake. Concerning toxic minerals, only there are references to the effects of mercury (“azogue”). The Dioscorides commented by Andrés Laguna could be the technical font used by Cervantes to document in this matter (AU)

New withanolides from Mandragora officinarum: first report of withanolides from the Genus Mandragora.

Two new withanolides named mandragorolide A (1) and mandragorolide B (2) were isolated from the MeOH extract of the whole plant of Mandragora officinarum of Jordanian origin, along with five known withanolides namely larnaxolide A (3), withanolide B (4), datura lactone 2 (5), withanicandrin (6) and salpichrolide C (7). Compound 3 has been reported only once before, from the leaves of Larnax glabra. This is the first report of withanolides of different biogenetic types from the genus Mandragora. Isolation of known fatty compounds, coumarins, sterols and tropane alkaloids was also achieved in this study.

Breve historia del dolor y de la analgesia / Brief history of pain and analgesia

El dolor ha acompañado al ser humano desde el mismo momento en que éste apareció sobre la tierra. Desde entonces, y a lo largo de toda su historia, el hombre ha tratado no sólo de buscar la razón del mismo, sino también de encontrar remedios para su alivio(AU)

Pain has accompanied human beings since the moment this species appeared on Earth. From that moment on, and throughout his long history, mankind has tried not only to look for the causes of pain but also to find remedies to relieve pain(AU)

Mandrake--an ancient herbal discovered.

I recently purchased the pharmacy container (illustrated) from an antique dealer friend who had kept three of these tins for 20 years intending to convert them into lamp bases. Fortunately I persuaded him to sell them to me rather than being hacked up. The other two are labeled 'BETT. RT PUL' 'LUNGWORT'. (All three are similarly painted, lidded tins and all stand 13 inches high, with a diameter of seven inches.) The label 'MANDRAKERT' immediately conjured up two impressions, firstly my boyhood reading of Mandrake the magician comics, and secondly a strong interest to research the story behind this 19th century tin's mystical contents.

Anticholinergic syndrome due to 'Devil's herb': when risks come from the ancient time.

We describe a case of Mandragora autumnalis poisoning which occurred in a 72-year-old female patient who had eaten the venenous M. Autumnalis, picked near her home, mistaking it for the edible Borago Officinalis. M. Autumnalis is a solanaceous plant, common in the Sicilian countryside, which contains a variable concentration of solanum alkaloids, causing gastrointestinal irritation, and tropane alkaloids, with anticholinergic properties. Unluckily, M. Autumnalis is often mistaken for the edible B. Officinalis, likewise widespread in Sicilian countryside. The diagnosis of Mandragora poisoning was made on the basis of clinical symptoms and signs of anticholinergic syndrome associated with a history of vegetable meal of uncontrolled origin, moreover analysing the vegetable obtained from gastric lavage. Decontamination and symptomatic treatment were useful in our patient to control acute poisoning.

Substances isolated from Mandragora species.

The present state of knowledge in the chemistry of mandragora plant is reviewed. Isolations and identifications of the compounds were done from all parts of this plant. Up-to-date more than 80 substances were identified in different species of the genus Mandragora.