Worldwide poisoning potential of Brugmansia and Datura

Data of poison control centers from several countries reveal that a significant proportion of all poisonings is related to plant exposures [1‐4]. The most common causes of plant-related toxicity are accidental ingestion of poisonous plant materials, misuse of herbal products, suicide attempts and abuse of hallucinogenic plants. The most frequently abused psychoactive plants include representatives of the Solanaceae family, such as Brugmansia and Datura species.

Datura species, also called thornapple, devil’s apple, angel’s trumpet (in a broad sense) or devil’s trumpet, have their main center of origin in Mexico and the south-west United States (US) [5, 6]. Today, representatives of the genus Datura are considered as cosmopolitan and naturalized in many regions with tropical and temperate climate conditions [7], being widespread also in Africa, Asia and Europe, comprising noxious weeds or ornamentals. The genus includes annual herbs and perennial shrubs with erect and branched stems, alternate simple basal leaves and opposite leaves on terminal branches. The actinomorphic flowers are bisexual and pentamerous, with tubular corolla. The fruit is a spiny capsule with reniform seeds [8].

The genus Brugmansia was treated earlier as a subgenus or section of Datura. Today, arborescent species with pendulous flowers, native to South America are separated at the genus level, comprising B. arborea, B. aurea, B. candida, B. dolichocarpa, B. insignis, B. sanguinea, B. versicolor, and B. vulcanicola [9]. Most Brugmansia species had social and religious importance in ancient Andean cultures [10].

Both Brugmansia and Datura species are considered toxic, due to the presence of the tropane alkaloids atropine and scopolamine in each plant organ [11‐19]. Atropine is known for its anticholinergic activity, causing mydriasis, blurred vision, suppressed salivation, vasodilation, tachycardia and delirium [20]. Scopolamine, also called hyoscine, is an antimuscarinic agent and a smooth muscle relaxant. Anticholinergic agents can be used in various fields of medicine, such as ophthalmology diagnostics, as antispasmodics, pre- and postoperative medications, analgesics, narcotics, sedatives, and also in treatments of asthma, Parkinson’s disease and motion sickness [21‐24].

Several cases of intoxication by ingestion of various parts of Brugmansia and Datura species have been reported [25‐41]. Symptoms of intoxication include dilated pupils, confusion, hallucinations, dryness of skin and mucous membranes, increased blood pressure and heart rate, and increased body temperature [11, 36, 42‐44]. Administration of physostigmine is the preferred treatment for severe cases of Datura poisoning, but due to controversies regarding potential adverse effects of physostigmine, it is not routinely applied in less severe cases, when supportive care and observation is satisfactory [45, 46].

Due to the fact that both Brugmansia and Datura taxa are becoming widespread worldwide—partly as a result of their successful reproductive strategies, and partly because being cultivated for ornamental purposes, their toxicological significance is increasing not only in tropical, but also in temperate regions of the world.

The objective of this article was to characterize human plant exposures that involve Brugmansia and Datura taxa in their native (America) and non-native regions (Asia, Africa, and Europe), and discuss the poisoning potential of various plant parts. To assess the worldwide toxicological significance of these tropane alkaloid-containing plants, a large number of cases were reviewed, based on toxicological center reports and case studies from several countries. To demonstrate the importance of plant-related anticholinergic intoxications in a European country, where Brugmansia and Datura are not native, data provided by the Hungarian Toxicological Information Service (HTIS) were analyzed in detail. In addition, we wanted to highlight differences in the poisoning potential of various plant parts, by analyzing data related to alkaloid concentrations in various plant parts and secretions, focusing on plant organs that have received less attention so far, such as the flowers and their secretory products.

The 2005–2017 annual reports of the HTIS were reviewed to identify plant-related poisoning cases. Data were provided in a Microsoft Excel database by the HTIS. We analyzed a total of 2464 cases of human plant exposures and selected cases where the plant genera Brugmansia and Datura were involved. The data were analyzed to determine the frequency of poisonings, to identify the age and gender of those who were exposed, the reason for the exposure, and patient outcome. Descriptive statistics were used throughout the manuscript to characterize the data.

In addition, data of the HTIS were compared to similar data of other toxicology centers in the US [4], India [26], Taiwan [2], Switzerland [1] and Italy [3].

From the native American region of Brugmansia and Datura species, we have toxicology reports from Canada, the US and Mexico.

Based on the annual reports of the American Association of Poison Control Centers (AAPCC) published for the years 1983–2009, the number of plant exposures reflected as a percentage of all exposures reported to US poison centers decreased from 8.9% in 1983 to 2.4% in 2009 [4]. Although Datura species were not among the 15 most common plant ingestions, hundreds of Datura intoxications occurred each year in the US. For example, in 1993, 318 Datura exposures were reported to the AAPCC; however, we can suspect that the true number of cases was even higher [47]. From the 45 fatalities recorded for a 26-year time period 1983–2009, Datura species were responsible for 20% of the fatal outcomes, being the leading cause of death attributed to plant exposures [4]. For the time period 1997–2001, an average of 1044 cases of anticholinergic plant exposures, including D. stramonium (jimson weed), was reported yearly in the US. Almost half (46%) of the cases were due to abuse ingestion; 53% of patients had to be treated in health care facilities, and six deaths were reported. The majority (77%) of cases occurred in individuals below 19 years of age [48]. According to the annual reports of the AAPCC, in the period of 2012–2017, neither Brugmansia nor Datura species were among the top 25 plant species involved in plant intoxications in the US [49‐54].

In the US and Canada, Datura poisoning has been reported primarily among adolescents who abuse the plant for its hallucinogenic effects (Table 1) [29, 32, 45, 48]. The most frequently reported Datura species is D. stramonium, which grows wildly throughout the US and the southern parts of Canada. Another common cause of intoxication can be gardening activity related to various Brugmansia taxa (angel’s trumpets in a narrow sense), which are frequently grown as ornamentals [36]. In case of children, playing around Brugmansia plants and getting in contact with certain plant parts, e.g., the flowers, can also lead to symptoms of intoxication (Table 1) [43].

In Mexico, the most widely distributed Datura species are D. discolor and D. stramonium. Here, the most frequent causes of intoxication include the use of Datura in traditional shamanic medicine, accidental ingestion by children, and abuse in adolescents and adults [7].

Poisoning cases with Datura have been frequently reported from Asia and Africa. In India, the total number of intoxication cases registered in a 3-year period (1999–2002) was 2720, out of which 1.5% was due to plant exposures. Children under the age of 18 years were involved in 15 cases related to toxic plants, out of which 10 cases (66%) were attributed to intoxication with various Datura species [26, 27]. Although the number of registered cases of plant intoxications seems to be very low for the country and population of this size—most probably due to underreporting—, the high ratio of Datura poisonings indicates by all means the significant poisoning potential of this plant genus in India. Accidental poisoning may occur when Datura seeds, resembling capsicum seeds, are mistakenly ingested. Consumption of wasp honey contaminated with Datura may also lead to poisoning [55]. Cases of accidental D. stramonium ingestion have been reported also from Saudi Arabia [56]. In Taiwan, 1414 plant-related poisoning cases were recorded in a 20-year period (1987–2006). Regarding the 389 cases of single-plant exposures, the most frequent type of intoxication, the anticholinergic toxidrome, was related to Brugmansia or Datura species. In adults, B. suaveolens (19%) and D. metel (16%) were the top two commonly ingested poisonous plants [2, 57]. Datura species may even cause intoxication when an otherwise edible plant is grafted on them, as in a case reported from Japan [30]. Mass poisoning was reported from Botswana, after consuming sorghum flour contaminated with Datura seeds [58] (Table 1).

In Ayurvedic medicine, in India, D. stramonium has been used to treat various health problems, such as inflammations, ulcers, wounds, rheumatism, gout, fever, asthma and bronchitis, and as a painkiller in headache or toothache. The external use, e.g., in the form of paste or solution to relieve local pain, may not have a deleterious effect; however, internal use may lead to severe anticholinergic symptoms [59]. In addition, some Chinese herbal medicines (CHM) contain anticholinergic agents. For example, “yangjinghua”, the dried flower of D. metel, has been used for treatment of bronchial asthma, bronchitis, pains and flu symptoms [31, 60]. In Malaysia, “kecubung” (Datura) is eaten as a traditional medicine to treat allergic rhinitis. In Africa, D. stramonium and D. ferox are frequently used in traditional medicine, mainly to relieve asthma and to reduce pain [61]. Inaccurate doses, improper use of traditional herbal medicines or contamination of CHM with atropine-like substances may lead to severe or even fatal anticholinergic toxidrome [33, 60] (Table 1).

Besides accidental ingestion and wrongful use of traditional herbal medicines, intoxication with Datura extracts occurred most frequently when they were abused for hallucinogenic effects [20, 62], or due to crime-related poisoning [39, 40] (Table 1).

From the Datura genus, three species, D. ferox, D. innoxia and D. stramonium are widely distributed and naturalized in several European countries [63]. From Europe, we had access to data of national poison control centers in three countries, Hungary, Italy and Switzerland.

In Hungary, 2464 cases of contact with or ingestion of toxic plant material were registered in the period 2005–2017. During this interval, there has been an increasing tendency in the number of plant exposures (Fig. 1), in contrast to the decreasing tendency observed in the US [4]. Unlike in the US, but similarly to India and Taiwan, Brugmansia and Datura were among the species involved in the largest number of plant-related poisonings in Hungary. The top four plant taxa that regularly caused intoxications in Hungary were Brugmansia and Datura species, Convallaria majalis and Taxus baccata, accounting for 1–7%, 1–16%, 6–20%, and 8–19% of all plant-related intoxications, respectively, in the period 2005–2017 (Fig. 2). As shown in Table 2, the number of Brugmansia and Datura poisoning cases in Hungary was fluctuating from year to year, with no clear-cut tendency for the proportion of anticholinergic exposures. However, in the last five years of the study, the number of such poisoning cases was on the decrease. This could be due to several reasons: (1) Hungarian people became better informed regarding the risks of ingesting Brugmansia or Datura plant parts or extracts, and thus avoided exposure to these plants; (2) adolescents and young adults started to use other natural or synthetic drugs for their hallucinogenic properties; (3) not all cases were reported to the toxicological center, probably due to milder symptoms of intoxication, when the affected individuals did not seek medical attention. In contrast to the US, where Datura intoxications were responsible for one-fifth of plant-related fatalities, in Hungary there were no fatal intoxications related to Brugmansia or Datura for a 13-year time period, even though 12% of major outcomes were related to these species.

Between 2005 and 2017 in Hungary, Brugmansia and Datura taxa were responsible for 60% of all plant abuse cases, being the leading plants ingested for their hallucinogenic properties [64] (Tables 1, 2), while they accounted for a much lower proportion (18%) of suicide attempts. Considering all Brugmansia and Datura poisonings (167 cases), the percentage of abuse cases (60%) was double of accidental ingestions (30%), and only 10% was due to suicide attempts (Table 2). Intoxication with Brugmansia and Datura occurred mainly in the months August–October, which suggests that in most cases the fruits, and particularly the seeds are ingested. At this time of the year in temperate climate, the plants are still in bloom, but at the same time several fruits have already developed on these plants. In most cases, Brugmansia and Datura were taken without any co-ingestants, but in a number of cases, they were ingested together with alcohol and/or psychoactive drugs, such as benzodiazepines (Table 2).

With regard to gender, 75% of all Brugmansia and Datura ingestions in Hungary occurred in males and only 25% in females in the period of 2005–2017 (Table 2). This indicates that males are three times more likely to suffer anticholinergic intoxication by plant origin than females, in most cases by taking the risk of ingesting various plant parts or extracts of Brugmansia or Datura for their hallucinogenic properties.

Data on the types, frequency and severity of plant poisonings are available from Switzerland for a 29-year period (1966–1994). From a total of 24,950 registered cases of intoxication with plant material, severe plant poisonings were reported in 152 cases. Out of these, 17 cases (11%) were related to the ingestion of D. stramonium [1]. The Poison Control Center of Milan, the leading toxicological center in Italy, registered 4432 plant exposures for the time period 2001–2005. In the age group of 15–90 years, the second most frequent cause of plant-related intoxications was the recreational use of hallucinogenic species (41 cases, 7%), including D. stramonium (26 cases, 63%) [3].

In addition, we have several reports from other European countries about consuming Brugmansia or Datura for their hallucinogenic effect [28, 35, 38, 65]. Similarly, in Spain, Datura species are mainly used as recreational drugs, but recently the use for criminal purposes is increasing [7]. From the Netherlands, a series of scopolamine-facilitated robberies were reported, including some fatal cases [41] (Table 1).

Cases of accidental intoxication were reported from Italy and Turkey, when D. stramonium flowers were mistaken for the similarly trumpet-shaped pumpkin (Cucurbita sp.) flowers [34, 66], or B. suaveolens flowers were unintentionally ingested [44] (Table 1).

The concentrations of tropane alkaloids vary depending on the Brugmansia or Datura species, seasons of the year and the plant parts involved in the exposure [16, 17, 19, 46]. The ratio of scopolamine and atropine in various plant organs was found to be species dependent, e.g., in D. innoxia, scopolamine was found to be predominant in all plant organs, while atropine levels were found to be higher as compared to scopolamine in leaf samples of D. metel [17]. Alkaloid levels may even differ in two varieties of the same species, the purple-flowered variety of D. stramonium (var. tatula) contained significantly higher alkaloid concentrations in all plant parts, except the stem, as compared to the white-flowered variety (var. stramonium) [17].

The alkaloid content is influenced also by whether the plant is in the juvenile or the reproductive stage, being the highest when the plant is flowering [46]. A study on four Datura taxa revealed that the alkaloid content of the stem and the leaf significantly decreased with plant aging, i.e., during transition from summer to autumn [17].

The alkaloid content is generally the greatest in the flowers and the seeds of various Datura species (e.g., up to 0.61 and 0.66% in D. stramonium [67]; 0.1–0.8 and 0.2–0.5% in the flowers and seeds of D. metel, respectively) [68], but in the case of D. metel similarly high alkaloid concentrations were reported for the leaves, as well (0.5%) [67, 68].

The atropine and scopolamine concentration of D. stramonium seeds was determined as 1283 and 678 μg/g, respectively [69]. The seeds of D. metel were reported to contain 2788 and 2020 μg/g; D. metel leaves 69.87 and 840.4 μg/g; while B. pittieri leaves contained 64.67 and 448.2 μg/g of atropine and scopolamine, respectively [70]. Calculating with average alkaloid content data, 1 g Datura seed would contain 2.9 mg atropine and 0.5 mg scopolamine, which is already in the toxic range. Bioavailability depends on whether the seeds were chewed, ground or swallowed as a whole, and also whether some kind of extract was prepared from various plant parts or dried plant parts were smoked [46].

Scopolamine and atropine were detected also in the floral nectar of Brugmansia and Datura species. From five Datura species studied, only D. tatula was characterized by the dominance of atropine, while the nectar of D. innoxia, D. metel, D. meteloides and D. stramonium, and also that of B. suaveolens contained higher ratio of scopolamine than atropine [16, 71]. Nectar alkaloid concentrations in D. innoxia, D. metel and D. meteloides ranged from 58 to 400, 85–132 and 120–190 μg/mL scopolamine, and 2–37, 3–4 and 0.19–0.42 μg/mL atropine, respectively [16]. Consumption of Brugmansia or Datura flowers [34, 44, 65, 66] and/or their secretory product, the nectar, may also cause severe anticholinergic symptoms. Nectar volumes in small-flowered species, such as D. quercifolia and D. stramonium are typically around 25 μL/flower, whereas large-flowered species, e.g., B. suaveolens, D. innoxia and D. metel can produce substantial amounts, up to 150 μL nectar per flower [71, 72]. Knowing that the toxic doses of atropine and scopolamine range between 2.0 and 6.5 mg in case of oral administration [20], the ingestion of the nectar of 50–100 flowers can induce severe anticholinergic intoxication, if we calculate with an average nectar volume of 100 μL/flower in large-flowered species [72] and an average nectar alkaloid concentration of 215 μg/mL [16]. Nectars containing tropane alkaloids may also be processed into toxic honeys, which may cause intoxication when ingested [73, 74].

Data of poison information centers from all over the world indicate that most exposures to Brugmansia and Datura are related to abuse, in connection with their hallucinogenic property, mostly in the age group of adolescents. Accidental ingestion is less frequent, but has been reported in small children, and also in adults who have mistaken various plant parts of the toxic species for their edible counterparts. Anticholinergic intoxication may also result from the improper use of traditional herbal medicines containing Datura. More recently, the use of Brugmansia and Datura as incapacitating drug in sexual crimes and robberies has caught the attention of authorities. The highest toxicological significance can be attributed to the flowers and seeds of Brugmansia and Datura, but exposure to the leaves and floral nectar can also cause intoxication.