Toxicity Potential of Cyanogenic Glycosides in Edible Plants

*Kumbukani K. Nyirenda*

## **Abstract**

Cyanogenic glycosides are natural phytotoxins produced by over 2000 plant species, many of which are consumed by humans. The important food crops that contain cyanogenic glycosides include cassava (*Manihot esculenta*), sorghum (*Sorghum bicolor*), cocoyam (*Colocasia esculenta* L. and *Xanthosoma sagittifolium* L.), bamboo (*Bambusa vulgaris*), apple (*Malus domestica*), and apricot (*Prunus armeniaca*). Cyanogenic glycosides and their derivatives have amino acid-derived aglycones, which spontaneously degrade to release highly toxic hydrogen cyanide (HCN). Dietary cyanide exposure has been associated with several health challenges such as acute cyanide poisoning, growth retardation, and neurological disorders. This chapter will introduce general cyanogenesis principles, highlight major food plants with lethal cyanide levels, and provide epidemiological-based health conditions linked to cyanide intake. Furthermore, strategies for elimination of cyanogens from food crops, such as processing technologies, will be discussed. Finally, the chapter will analyze the role of cyanogenic plants in ensuring food security among resource-poor communities.

**Keywords:** cyanogenic glycosides, cyanogens, phytotoxins, detoxification, food safety

## **1. Introduction**

Many plant species that are grown for food contain phytotoxins in different parts of the plant. Natural toxins are usually secondary metabolites produced by plants for defensive purposes against threats such as bacteria, fungi, insects, and predators [1]. They may also occur in food plants because of natural selection and new breeding methods that enhance protective mechanisms of the crops [2]. The most common natural toxins found in food plants include lectins in beans, glycoalkaloids in potatoes, and cyanogenic glycosides in cassava, bitter apricot seed, bamboo shoots, and flaxseeds [3]. A review of several natural toxins in food plants commonly consumed in the world, including the toxicological effects associated with the ingestion of these toxins, shows that cyanogenic glycosides are the most important and extensively studied group of phytotoxins [4].

Cyanogenic glycosides are chemical compounds that release hydrogen cyanide (HCN) and are common in certain families such as the Fabaceae, Rosaceae, Leguminosae, Linaceae, and Compositae [2]. Approximately 25 cyanogenic glycosides, which are mostly found in the edible parts of plants, have been identified [4]. The potential toxicity of cyanogenic glycosides and their derivatives largely depends on their ability to release hydrogen cyanide. Dietary cyanide exposure

may result in acute poisoning and has also been associated with the etiology of several chronic diseases [5]. Therefore, the presence of cyanogenic glycosides in food and fodder presents a significant social and economic problem in many parts of the world, particularly in developing countries. In Africa, consumption of insufficiently processed cassava (*Manihot esculenta* Crantz) has been associated with cyanide poisoning, tropical ataxic neuropathy (TAN) disease, and konzo [6, 7]. In 1992, the death of three people in Nigeria was attributed to cyanide intake from cyanogenic glycosides of cassava [5], and a decade ago five Nigerians died of cyanide poison after reportedly eating a meal prepared with cassava flour.

Cyanogenic glycosides found in plants are not toxic on their own. However, when cell structures of plant are disrupted, cyanogenic glycoside will be brought together with the corresponding hydrolytic β-glucosidase enzyme. Subsequently, the glycoside degenerates to a sugar and a cyanohydrin that rapidly decomposes to hydrogen cyanide and an aldehyde or a ketone [8]. In bitter almonds and peach stones, cyanogenic glycoside, amygdalin, is converted to glucose, benzaldehyde, and toxic hydrogen cyanide. In edible plants, cyanide levels are reduced significantly during the processing to an accepted Food and Agricultural Organization (FAO)/World Health Organization (WHO) level of 10 mg HCN/kg dry weight [9]. However, when poorly processed lethal concentrations of the cyanogens may be obtained in the final edible products.

## **2. Cyanogenic glycosides in food plants**

Cyanogenic glycosides are a structurally diverse class of secondary metabolites that are mostly used by plants as a defense against various threats such as bacteria, fungi, insects, and predators [1]. The compounds consist of α-hydroxynitrile aglycones attached to a sugar moiety (Vetter, 2000) and are widely distributed in the plant kingdom [10]. Cyanogenic glycosides are common in certain families such as the Fabaceae, Rosaceae, Leguminosae, Linaceae, and Compositae, and their constituents provide a useful tool for taxonomic identification [2]. Several important food plants are known to synthesize cyanogenic glycosides; for example, linamarin in cassava and butter bean, dhurrin in sorghum and macadamia nut, and amygdalin in almond, peach, sweet cherry, and sour cherry [2, 11].

#### **2.1 Biosynthesis of cyanogenic glycosides**

In plants, cyanogenic glycosides are derivatives of five amino acids (valine, isoleucine, leucine, phenylalanine, and tyrosine) and the non-proteinogenic amino acid, cyclopentenyl glycine. Linamarin and lotaustralin are derived from valine, isoleucine, and leucine, while dhurrin is derived from tyrosine. Amygdalin and prunasin are derived from phenylalanine [12]. The biosynthesis of various cyanogenic glycosides in different plants has been described, and the most extensively reported are dhurrin in sorghum and linamarin in cassava [10]. The generic biosynthetic pathway for the production of cyanogenic glycosides from amino acids is shown in **Figure 1**.

The first two steps of biosynthetic production of cyanogenic glycoside are catalyzed by a cytochrome P450 enzyme through two successive N-hydroxylations of the amino group of the parent amino acid. The α-hydroxynitrile (cyanohydrin) is then generated following the decarboxylation and dehydration of aldoxime and nitrile, respectively [14]. The final step that produces cyanogenic glycoside involves glycosylation of the cyanohydrin moiety, and the process is catalyzed by UDPGglycosyltransferase [10].

**193**

**Figure 2.**

*Toxicity Potential of Cyanogenic Glycosides in Edible Plants*

which is widespread in cyanogenic plants [16].

*Enzymatic hydrolysis of cyanogenic compounds, linamarin, and dhurrin.*

Cyanogenesis is the ability of some plants to synthesize cyanogenic glycosides to form hydrogen cyanide via cyanohydrin intermediate [15, 16]. The hydrolysis of the cyanogenic glycosides is accomplished by the β-glucosidase enzymes, which facilitate the cleavage of the carbohydrate moiety of the cyanogenic glycoside to yield corresponding cyanohydrins which further decompose to release hydrogen cyanide and an aldehyde or ketone [17] as illustrated in **Figure 2**. The final step that produces the toxic compound, HCN, is catalyzed by hydroxynitrile lyase enzyme,

The cyanogenic glycosides linamarin (α-hydroxybutyronitrile-β-d-

*The biosynthetic pathway for cyanogenic glycosides from its precursor amino acid [13].*

glucopyranoside) and lotaustralin (ethyl linamarin) are distributed in cassava cell vacuoles, while the enzyme linamarase is found in the cell wall [18]. The hydrolysis of linamarin in cassava starts with the disruption of the root tissue during

*DOI: http://dx.doi.org/10.5772/intechopen.91408*

**2.2 Cyanogenesis**

**Figure 1.**

*Toxicity Potential of Cyanogenic Glycosides in Edible Plants DOI: http://dx.doi.org/10.5772/intechopen.91408*

**Figure 1.**

*Medical Toxicology*

obtained in the final edible products.

**2. Cyanogenic glycosides in food plants**

in almond, peach, sweet cherry, and sour cherry [2, 11].

**2.1 Biosynthesis of cyanogenic glycosides**

may result in acute poisoning and has also been associated with the etiology of several chronic diseases [5]. Therefore, the presence of cyanogenic glycosides in food and fodder presents a significant social and economic problem in many parts of the world, particularly in developing countries. In Africa, consumption of insufficiently processed cassava (*Manihot esculenta* Crantz) has been associated with cyanide poisoning, tropical ataxic neuropathy (TAN) disease, and konzo [6, 7]. In 1992, the death of three people in Nigeria was attributed to cyanide intake from cyanogenic glycosides of cassava [5], and a decade ago five Nigerians died of

cyanide poison after reportedly eating a meal prepared with cassava flour.

Cyanogenic glycosides found in plants are not toxic on their own. However, when cell structures of plant are disrupted, cyanogenic glycoside will be brought together with the corresponding hydrolytic β-glucosidase enzyme. Subsequently, the glycoside degenerates to a sugar and a cyanohydrin that rapidly decomposes to hydrogen cyanide and an aldehyde or a ketone [8]. In bitter almonds and peach stones, cyanogenic glycoside, amygdalin, is converted to glucose, benzaldehyde, and toxic hydrogen cyanide. In edible plants, cyanide levels are reduced significantly during the processing to an accepted Food and Agricultural Organization (FAO)/World Health Organization (WHO) level of 10 mg HCN/kg dry weight [9]. However, when poorly processed lethal concentrations of the cyanogens may be

Cyanogenic glycosides are a structurally diverse class of secondary metabolites that are mostly used by plants as a defense against various threats such as bacteria, fungi, insects, and predators [1]. The compounds consist of α-hydroxynitrile aglycones attached to a sugar moiety (Vetter, 2000) and are widely distributed in the plant kingdom [10]. Cyanogenic glycosides are common in certain families such as the Fabaceae, Rosaceae, Leguminosae, Linaceae, and Compositae, and their constituents provide a useful tool for taxonomic identification [2]. Several important food plants are known to synthesize cyanogenic glycosides; for example, linamarin in cassava and butter bean, dhurrin in sorghum and macadamia nut, and amygdalin

In plants, cyanogenic glycosides are derivatives of five amino acids (valine, isoleucine, leucine, phenylalanine, and tyrosine) and the non-proteinogenic amino acid, cyclopentenyl glycine. Linamarin and lotaustralin are derived from valine, isoleucine, and leucine, while dhurrin is derived from tyrosine. Amygdalin and prunasin are derived from phenylalanine [12]. The biosynthesis of various cyanogenic glycosides in different plants has been described, and the most extensively reported are dhurrin in sorghum and linamarin in cassava [10]. The generic biosynthetic pathway for the production of cyanogenic glycosides from amino acids is

The first two steps of biosynthetic production of cyanogenic glycoside are catalyzed by a cytochrome P450 enzyme through two successive N-hydroxylations of the amino group of the parent amino acid. The α-hydroxynitrile (cyanohydrin) is then generated following the decarboxylation and dehydration of aldoxime and nitrile, respectively [14]. The final step that produces cyanogenic glycoside involves glycosylation of the cyanohydrin moiety, and the process is catalyzed by UDPG-

**192**

shown in **Figure 1**.

glycosyltransferase [10].

*The biosynthetic pathway for cyanogenic glycosides from its precursor amino acid [13].*

#### **2.2 Cyanogenesis**

Cyanogenesis is the ability of some plants to synthesize cyanogenic glycosides to form hydrogen cyanide via cyanohydrin intermediate [15, 16]. The hydrolysis of the cyanogenic glycosides is accomplished by the β-glucosidase enzymes, which facilitate the cleavage of the carbohydrate moiety of the cyanogenic glycoside to yield corresponding cyanohydrins which further decompose to release hydrogen cyanide and an aldehyde or ketone [17] as illustrated in **Figure 2**. The final step that produces the toxic compound, HCN, is catalyzed by hydroxynitrile lyase enzyme, which is widespread in cyanogenic plants [16].

The cyanogenic glycosides linamarin (α-hydroxybutyronitrile-β-dglucopyranoside) and lotaustralin (ethyl linamarin) are distributed in cassava cell vacuoles, while the enzyme linamarase is found in the cell wall [18]. The hydrolysis of linamarin in cassava starts with the disruption of the root tissue during

**Figure 2.**

*Enzymatic hydrolysis of cyanogenic compounds, linamarin, and dhurrin.*

processing or chewing to release the endogenous enzyme (linamarase), which catalyzes the hydrolysis of linamarin to glucose and acetone cyanohydrins. During processing factors such as reduced moisture and increased temperature facilitate the spontaneous conversion of cyanohydrins to toxic hydrogen cyanide and the corresponding ketone, acetone [19].

In sorghum, the cyanogenic glycoside dhurrin (4-hydroxymandelonitrile-β-dglucopyranoside) and the enzyme β-glucosidase (dhurrinase) are stored in separate plant compartments. However, when the plant tissue is crushed, the enzyme and substrate dhurrin are brought in contact. The hydrolysis of dhurrin is then initiated by dhurrinase, which hydrolyzes the cyanogenic glycoside to form hydroxymandelonitrile and glucose. In acidic conditions or in the presence of hydroxynitrile lyase, the intermediate compound, hydroxymandelonitrile, further decomposes to generate hydrogen cyanide and hydroxybenzaldehyde [19] as shown in **Figure 2**. In food plants, cyanogenic glycosides are not toxic on their own. However, when cell structures of a plant are disrupted, cyanogenic glycosides will be brought together with the corresponding β-glucosidase enzyme to liberate a toxic compound, HCN.

## **3. Food plants with cyanogenic compounds**

Cyanogenic glycosides are present in over 100 families of flowering plants, and at least 2000 plant species are known to contain this class of natural toxins. In addition to high plants, they are also found in some species of ferns, fungi, and bacteria [16]. Cyanogenic glycosides are amino acid-derived constituents of plants produced as secondary metabolites and are used as a defensive mechanism against various threats such as bacteria, fungi, insects, and other predators. There are wide variations in the levels of cyanogenic glycosides in plants due to genetic and environmental factors such as location, season, and soil types [3]. **Table 1** shows the types of cyanogenic glycosides commonly found in major edible plants.

Approximately 25 cyanogenic glycosides have been reported in different cyanogenic food plants, and **Figure 3** shows structures of examples of cyanogenic glycosides commonly found in edible plants.

#### **3.1 Cassava**

Cassava (*Manihot esculenta* Crantz) is a perennial crop that originated from South America and was introduced in Africa by the Portuguese explorers during


**195**

**Table 2.**

Organization statistics [23].

*Major cassava-producing countries in the world.*

**Figure 3.**

*Toxicity Potential of Cyanogenic Glycosides in Edible Plants*

*Structures of cyanogenic glycosides found in major edible plants [20].*

the sixteenth and seventeenth centuries. The crop is a staple food in most African communities and has economic value in Africa, South America, and Southeast Asia. The crop is widely cultivated in the tropics, and a total area of over 18 million ha is grown to cassava [21], and over half a billion of the world's population depend on cassava as their major staple [22]. Africa is the largest producer of cassava in the world and accounts for over 53% of the global production [23]. According to the Food and Agriculture Organization, cassava is ranked third, after rice and corn, as the most important source of calories in the tropics [23]. The tuberous roots of the crop have high carbohydrate content, which makes cassava a good source of calorie for over half a billion people in the world. Additionally, cassava leaves are rich in proteins, vitamin C, vitamin A, and dietary fiber. Cassava is one of the world's most important tuberous food crops, with annual global production estimated at 252 million metric tons (MT) in 2011. **Table 2** shows the production trend among the top five producing countries in the world according to the Food and Agriculture

**Country Annual cassava production quantity (million metric tons)**

Nigeria 43.41 44.58 36.82 42.53 52.40 Brazil 26.54 26.70 24.40 24.50 25.45 Indonesia 19.99 21.59 22.04 23.92 24.01 Thailand 26.92 25.16 30.09 22.21 21.91 Ghana 10.22 11.35 12.23 13.50 14.24 Others 99.35 102.62 109.87 110.25 114.20 World 226.43 232.00 235.45 236.11 252.21

**2007 2008 2009 2010 2011**

*DOI: http://dx.doi.org/10.5772/intechopen.91408*

#### **Table 1.**

*Cyanogenic glycosides in major edible plants.*

*Toxicity Potential of Cyanogenic Glycosides in Edible Plants DOI: http://dx.doi.org/10.5772/intechopen.91408*

*Medical Toxicology*

corresponding ketone, acetone [19].

**3. Food plants with cyanogenic compounds**

sides commonly found in edible plants.

Cocoyam (*Colocasia esculenta* and *Xanthosoma sagittifolium*)

*Cyanogenic glycosides in major edible plants.*

**3.1 Cassava**

processing or chewing to release the endogenous enzyme (linamarase), which catalyzes the hydrolysis of linamarin to glucose and acetone cyanohydrins. During processing factors such as reduced moisture and increased temperature facilitate the spontaneous conversion of cyanohydrins to toxic hydrogen cyanide and the

In sorghum, the cyanogenic glycoside dhurrin (4-hydroxymandelonitrile-β-dglucopyranoside) and the enzyme β-glucosidase (dhurrinase) are stored in separate plant compartments. However, when the plant tissue is crushed, the enzyme and substrate dhurrin are brought in contact. The hydrolysis of dhurrin is then initiated by dhurrinase, which hydrolyzes the cyanogenic glycoside to form hydroxymandelonitrile and glucose. In acidic conditions or in the presence of hydroxynitrile lyase, the intermediate compound, hydroxymandelonitrile, further decomposes to generate hydrogen cyanide and hydroxybenzaldehyde [19] as shown in **Figure 2**. In food plants, cyanogenic glycosides are not toxic on their own. However, when cell structures of a plant are disrupted, cyanogenic glycosides will be brought together with the corresponding β-glucosidase enzyme to liberate a toxic compound, HCN.

Cyanogenic glycosides are present in over 100 families of flowering plants, and at least 2000 plant species are known to contain this class of natural toxins. In addition to high plants, they are also found in some species of ferns, fungi, and bacteria [16]. Cyanogenic glycosides are amino acid-derived constituents of plants produced as secondary metabolites and are used as a defensive mechanism against various threats such as bacteria, fungi, insects, and other predators. There are wide variations in the levels of cyanogenic glycosides in plants due to genetic and environmental factors such as location, season, and soil types [3]. **Table 1** shows the

Approximately 25 cyanogenic glycosides have been reported in different cyanogenic food plants, and **Figure 3** shows structures of examples of cyanogenic glyco-

Cassava (*Manihot esculenta* Crantz) is a perennial crop that originated from South America and was introduced in Africa by the Portuguese explorers during

**Species Family Vegetative part Source of** 

Bamboo (*Bambusa vulgaris*) Poaceae Stem and sprouts Taxiphyllin Apple (*Malus domestica*) Rosaceae Seeds and fruits Amygdalin Apricot (*Prunus armeniaca*) Rosaceae Kernels Amygdalin

parenchyma

tips, and leaves

Araceae Leaves and roots Dhurrin

**HCN**

Linamarin Lotaustralin

Dhurrin

Prunasin

types of cyanogenic glycosides commonly found in major edible plants.

Cassava (*Manihot esculenta*) Euphorbiaceae Leaves, tuber peel, and

Sorghum (*Sorghum bicolor*) Poaceae Fruits (seeds), shoot

**194**

**Table 1.**

**Figure 3.** *Structures of cyanogenic glycosides found in major edible plants [20].*

the sixteenth and seventeenth centuries. The crop is a staple food in most African communities and has economic value in Africa, South America, and Southeast Asia. The crop is widely cultivated in the tropics, and a total area of over 18 million ha is grown to cassava [21], and over half a billion of the world's population depend on cassava as their major staple [22]. Africa is the largest producer of cassava in the world and accounts for over 53% of the global production [23]. According to the Food and Agriculture Organization, cassava is ranked third, after rice and corn, as the most important source of calories in the tropics [23]. The tuberous roots of the crop have high carbohydrate content, which makes cassava a good source of calorie for over half a billion people in the world. Additionally, cassava leaves are rich in proteins, vitamin C, vitamin A, and dietary fiber. Cassava is one of the world's most important tuberous food crops, with annual global production estimated at 252 million metric tons (MT) in 2011. **Table 2** shows the production trend among the top five producing countries in the world according to the Food and Agriculture Organization statistics [23].


#### **Table 2.**

*Major cassava-producing countries in the world.*

Despite the nutritional and economic benefits obtained from cassava, almost all parts of the plant contain cyanogenic glycosides, which limits the potential utilization of the plant as food for human and animal consumption. Each part of the cassava plant (leaves, stem, root) contains high levels of cyanogenic glycosides, mainly linamarin and lotaustralin with the former being the most predominant cyanogen at the ratio of 9:1 [17]. The biosynthesis of the major cyanogenic glucoside in cassava, linamarin, occurs in leaves and is then transported to the tuber [24]. Cassava leaves and the cortex or peel of the roots contain large quantities of cyanogenic glycosides (900–2000 mg HCN/kg dry matter) [8], while the tuberous parenchyma has approximately 20-fold lower levels. Studies have found that cassava roots contain a total cyanide content of 10–500 mg/kg of dry matter [25] although higher contents have also been reported, particularly in bitter cultivars. All cassava varieties are known to contain cyanogenic compounds, and cyanide levels depend on factors such as variety, plant age, soil condition, fertilizer application, and environmental conditions [25].

## **3.2 Cocoyam**

Cocoyam generally refers to two members of the Araceae family, namely, *Colocasia esculenta* (L.) Schott and *Xanthosoma sagittifolium* (L.) Schott. The plant is native to Central and South America where it has been cultivated and consumed for centuries but has since been naturalized in most tropical regions including sub-Saharan Africa [26]. Cocoyam is an important staple for most rural communities in many developing countries of Africa, Asia, and the Pacific. In sub-Saharan Africa, the most cultivated species, *Colocasia esculenta*, is extensively grown for livelihood by small-scale resource-poor farmers with minimal input.

For the last 3 decades, Africa's annual cocoyam output of about 10 MT has consistently been higher than other regions [9]. The continent's contribution to the global cocoyam output is presented in **Table 3**. The mean global production in the 2003–2012 decade was more than double the mean production obtained in the years between 1983 and 1992, which could principally be attributed to increased production in Africa. The major cocoyam-producing countries in Africa are Nigeria, Ghana, and Cameroon, which contributed about 68% of the global mean output between 2003 and 2012.

Edible cocoyam is a nutrient dense tuber crop that can be processed into flour and used to make mashed meal or porridge. The tubers can also be consumed baked or boiled. Cocoyam is rich in carbohydrates; as a result, it is an important source of


**197**

**3.5 Fruits and fruit kernels**

*3.5.1 Apple (Malus domestica)*

*Toxicity Potential of Cyanogenic Glycosides in Edible Plants*

calorie for millions of people in the tropical and subtropical regions [27]. In addition to carbohydrates, cocoyam contains other nutrients such as protein, vitamins, carotenoids, and minerals [28]. Apart from the nutrient composition of cocoyam tuber, antinutritional compounds such as cyanogenic glycosides have been reported in the crops albeit in lower concentrations (21.0–171.3 mg/kg dry matter) [29, 30]

Fresh immature bamboo shoots are consumed as vegetable in some Asian countries, and they contain appreciable quantities of vitamin C, carbohydrates, and protein [31]. Apart from the nutritive value, bamboo shoots contain lethal concentrations of cyanogenic glycosides. The cyanogenic glycoside present in bamboo shoot is taxiphyllin, which quickly decomposes when exposed to boiling water. Cyanide contents of 1000–8000 mg HCN/kg have been reported [32]. Although cyanide content of bamboo shoot is much higher than that of cassava root, the cyanide content in

bamboo shoots decreases substantially following harvesting and processing.

The plant sorghum [*Sorghum bicolor* (L.) Moench] belongs to the Poaceae family (tribe Andropogoneae) and is one of the most important crops in Africa, Asia, and Latin America. It is a very genetically diverse crop both in cultivated and wild species. About five sorghum's landraces are known, and the greatest variation within the sorghum genus is found in the Ethiopia-Sudan region, which is believed to be the origin of the plant. The most important global producers of sorghum are the United States of America, Nigeria, Sudan, Mexico, China, India, Ethiopia, Argentina, Burkina Faso, Brazil, and Australia [23]. Burkina Faso appears to be the world leader of sorghum production and consumption per inhabitant. There has been an increased demand for the crop in Africa over the last 50 years. Studies indicate that more than 35% of sorghum is grown directly for human consumption, while the rest is used primarily for animal feed, alcohol production, and industrial products [33]. Although sorghum is a widely grown cereal crop that resembles corn in general composition, it is an inferior crop due to the presence of cyanogenic glycosides, dhurrin and amygdalin, among other factors. The major cyanogenic glycoside in sorghum is dhurrin, and its content in shoot tips of seedlings is estimated at 30% dry weight. In young sorghum leaves, dhurrin and the enzymes responsible for its hydrolysis to hydrogen cyanide are localized in vacuoles and cytoplasm of plants, respectively. The compartmental separation of the enzyme and the substrate makes tissues free from cyanide in intact leaves. The levels of dhurrin decrease with plant age, and immature sorghum leaves contain higher concentrations of dhurrin than the mature ones [17].

Most fruits and fruit kernels contain the potentially toxic cyanogenic glycoside compound, amygdalin. The contents of amygdalin in fruit seeds vary significantly among varieties and environmental conditions [34]. The following sections will

Apple seeds contain appreciable amounts of amygdalin, a cyanogenic glycoside composed of cyanide and sugar. When metabolized in the digestive system, this

highlight two important sources of amygdalin: apple and apricot fruits.

*DOI: http://dx.doi.org/10.5772/intechopen.91408*

than other food plants.

**3.3 Bamboo shoot**

**3.4 Sorghum**

#### **Table 3.**

*Contributions of top producers to global cocoyam output in the last 3 decades [9].*

calorie for millions of people in the tropical and subtropical regions [27]. In addition to carbohydrates, cocoyam contains other nutrients such as protein, vitamins, carotenoids, and minerals [28]. Apart from the nutrient composition of cocoyam tuber, antinutritional compounds such as cyanogenic glycosides have been reported in the crops albeit in lower concentrations (21.0–171.3 mg/kg dry matter) [29, 30] than other food plants.

## **3.3 Bamboo shoot**

*Medical Toxicology*

conditions [25].

between 2003 and 2012.

*Mean production in million tons over 10 years.*

*Percentage of contribution to global mean.*

**3.2 Cocoyam**

Despite the nutritional and economic benefits obtained from cassava, almost all parts of the plant contain cyanogenic glycosides, which limits the potential utilization of the plant as food for human and animal consumption. Each part of the cassava plant (leaves, stem, root) contains high levels of cyanogenic glycosides, mainly linamarin and lotaustralin with the former being the most predominant cyanogen at the ratio of 9:1 [17]. The biosynthesis of the major cyanogenic glucoside in cassava, linamarin, occurs in leaves and is then transported to the tuber [24]. Cassava leaves and the cortex or peel of the roots contain large quantities of cyanogenic glycosides (900–2000 mg HCN/kg dry matter) [8], while the tuberous parenchyma has approximately 20-fold lower levels. Studies have found that cassava roots contain a total cyanide content of 10–500 mg/kg of dry matter [25] although higher contents have also been reported, particularly in bitter cultivars. All cassava varieties are known to contain cyanogenic compounds, and cyanide levels depend on factors such as variety, plant age, soil condition, fertilizer application, and environmental

Cocoyam generally refers to two members of the Araceae family, namely, *Colocasia esculenta* (L.) Schott and *Xanthosoma sagittifolium* (L.) Schott. The plant is native to Central and South America where it has been cultivated and consumed for centuries but has since been naturalized in most tropical regions including sub-Saharan Africa [26]. Cocoyam is an important staple for most rural communities in many developing countries of Africa, Asia, and the Pacific. In sub-Saharan Africa, the most cultivated species, *Colocasia esculenta*, is extensively grown for livelihood

For the last 3 decades, Africa's annual cocoyam output of about 10 MT has consistently been higher than other regions [9]. The continent's contribution to the global cocoyam output is presented in **Table 3**. The mean global production in the 2003–2012 decade was more than double the mean production obtained in the years between 1983 and 1992, which could principally be attributed to increased production in Africa. The major cocoyam-producing countries in Africa are Nigeria, Ghana, and Cameroon, which contributed about 68% of the global mean output

Edible cocoyam is a nutrient dense tuber crop that can be processed into flour and used to make mashed meal or porridge. The tubers can also be consumed baked or boiled. Cocoyam is rich in carbohydrates; as a result, it is an important source of

**Producer 1983–1992 1993–2002 2003–2012**

Africa 2.74 56.26 5.88 73.13 8.25 76.96 China 1.20 24.62 1.40 17.47 1.61 15.04 Cameroon 0.49 10.14 0.88 10.98 1.40 13.02 Ghana 1.01 20.64 1.53 19.04 1.57 14.62 Nigeria 0.52 10.61 2.60 32.36 4.28 39.91

World 4.88 8.04 10.72

*Contributions of top producers to global cocoyam output in the last 3 decades [9].*

**Meana %b Mean % Mean %**

by small-scale resource-poor farmers with minimal input.

**196**

*a*

*b*

**Table 3.**

Fresh immature bamboo shoots are consumed as vegetable in some Asian countries, and they contain appreciable quantities of vitamin C, carbohydrates, and protein [31]. Apart from the nutritive value, bamboo shoots contain lethal concentrations of cyanogenic glycosides. The cyanogenic glycoside present in bamboo shoot is taxiphyllin, which quickly decomposes when exposed to boiling water. Cyanide contents of 1000–8000 mg HCN/kg have been reported [32]. Although cyanide content of bamboo shoot is much higher than that of cassava root, the cyanide content in bamboo shoots decreases substantially following harvesting and processing.

## **3.4 Sorghum**

The plant sorghum [*Sorghum bicolor* (L.) Moench] belongs to the Poaceae family (tribe Andropogoneae) and is one of the most important crops in Africa, Asia, and Latin America. It is a very genetically diverse crop both in cultivated and wild species. About five sorghum's landraces are known, and the greatest variation within the sorghum genus is found in the Ethiopia-Sudan region, which is believed to be the origin of the plant. The most important global producers of sorghum are the United States of America, Nigeria, Sudan, Mexico, China, India, Ethiopia, Argentina, Burkina Faso, Brazil, and Australia [23]. Burkina Faso appears to be the world leader of sorghum production and consumption per inhabitant. There has been an increased demand for the crop in Africa over the last 50 years. Studies indicate that more than 35% of sorghum is grown directly for human consumption, while the rest is used primarily for animal feed, alcohol production, and industrial products [33]. Although sorghum is a widely grown cereal crop that resembles corn in general composition, it is an inferior crop due to the presence of cyanogenic glycosides, dhurrin and amygdalin, among other factors. The major cyanogenic glycoside in sorghum is dhurrin, and its content in shoot tips of seedlings is estimated at 30% dry weight. In young sorghum leaves, dhurrin and the enzymes responsible for its hydrolysis to hydrogen cyanide are localized in vacuoles and cytoplasm of plants, respectively. The compartmental separation of the enzyme and the substrate makes tissues free from cyanide in intact leaves. The levels of dhurrin decrease with plant age, and immature sorghum leaves contain higher concentrations of dhurrin than the mature ones [17].

## **3.5 Fruits and fruit kernels**

Most fruits and fruit kernels contain the potentially toxic cyanogenic glycoside compound, amygdalin. The contents of amygdalin in fruit seeds vary significantly among varieties and environmental conditions [34]. The following sections will highlight two important sources of amygdalin: apple and apricot fruits.

#### *3.5.1 Apple (Malus domestica)*

Apple seeds contain appreciable amounts of amygdalin, a cyanogenic glycoside composed of cyanide and sugar. When metabolized in the digestive system, this

chemical degrades into highly poisonous hydrogen cyanide. Studies have reported that amygdalin content in apple seeds ranged from 1 to 4 mg/g, while that of apple juice was reported to be between 0.001 and 0.08 mg/ml [34].

## *3.5.2 Apricot fruits (Prunus armeniaca)*

Apricot fruits are widely cultivated in Central Asia, Africa, America, and Europe. There are two varieties of apricot kernels: bitter and sweet. Bitter apricot kernels contain a considerably high amount of the cyanogenic glycoside amygdalin and thus are unsafe for consumption. On the other hand, sweet varieties are safe for human consumption because of their low level of cyanogens [35]. The concentration of hydrogen cyanide in apricot kernels varies widely (49–4000 mg/kg), depending on whether the skin was included or not during cyanide determination. Ingestion of raw or improperly processed apricot kernels with high cyanide levels can cause serious acute problems that could lead to death [2].

## **4. Food processing technologies**

Incidences of health conditions associated with dietary intake of cyanogens can be prevented or reduced by effective removal of cyanogenic compounds in food plants prior to consumption. Food plants are traditionally processed using various methods that vary widely depending on geographical location and ethnicity of communities [36]. The main aims of the food processing techniques are to reduce toxicity and improve palatability and storability. The main processing techniques used worldwide for most food plants include drying, boiling/cooking, soaking/ wetting, fermentation, and/or a combination of the processes [8]. For example, processing techniques and stages used for production of snacks and main dishes from cassava roots are summarized in **Figure 4**.

**199**

*Toxicity Potential of Cyanogenic Glycosides in Edible Plants*

Drying is one of the most appropriate processing methods for removal of cyanogenic glycosides in food plants. This is a mass transfer process which removes water from the product by evaporation and keeps the product free from microorganisms. There are several drying methods that can be employed to reduce cyanogens from food products, and they include the use of sun, oven, freeze, and superheated steam. Studies have reported that in bamboo shoots around 80% cyanogenic glycoside reduction was obtained after vacuum freeze-drying for 24 hours at −50°C. On the other hand, superheated steam drying at 120–160°C afforded significant decomposition of taxiphyllin, which causes bitterness in bamboo shoots [37], while oven-drying after grating at 60°C for 8 hours led to very high reduction of cyanogen

In eastern and southern Africa, cassava is traditionally processed into flour by sun drying the peeled roots followed by pounding and sieving or heap fermentation. However, because this process does not allow enough contact between linamarase and linamarin, total cyanogen content of 59 ppm of HCN equivalents has been reported in processed products, which is higher than the WHO safe level of 10 ppm [39]. The high levels of residual cyanogens can be attributed to the drying process, which restricts the contact between the endogenous enzymes linamarase and cyanogenic glucoside and promotes the retention of cyanohydrin and free cyanide

The effectiveness of boiling/cooking on cyanogen removal from various plant food products shows that the method achieves different results depending on the processing duration and part of the plant species. Several studies have reported that cooking and boiling are among the most effective practices for reducing cyanogenic compounds from food plants. These processes appear to promote the rupture of cell walls, which allow translocation of cell contents including antinutrients and toxic substances [39]. A study on bamboo plant showed that cyanogenic glycoside in the shoots of *Bambusa vulgaris* were reduced by 67.84–76.92% after boiling for 10 minutes. Boiling the shoots for an additional 10 minutes further achieved up to 87% reduction in cyanogen content [37]. Similar studies in cassava reported that the efficacy of the boiling method for cyanogen reduction is substantially improved

when small-sized cassava pieces are boiled in a large volume of water [40].

However, some studies have reported that boiling can only reduce cyanogen content by 50%, and therefore, it is not an effective method for cyanide removal. The inefficiency of this processing method is attributed to the high temperatures. It is reported that at an elevated temperature of 100°C, linamarase, a heat-labile *β*-glycosidase, is denatured, and linamarin cannot then be hydrolyzed into cyanohydrin and subsequent HCN. A study by Cooke and Maduagwu [41] reported that bound glucosides were reduced to 45 to 50% after 25 min of boiling. Free cyanide and cyanohydrin in boiled cassava roots are found at very low concentrations.

Like most processing methods, soaking or wetting of harvested crops helps to improve the shelf life of the food products. Additionally, processing improves the safety and quality of the products. For example, a study reported that cassava flour and to a lesser extent *gari* stored under ambient conditions retained cyanogens over long periods [25]. However, if flour is mixed with water and the resultant wet

*DOI: http://dx.doi.org/10.5772/intechopen.91408*

**4.1 Drying**

content of up to 95% [38].

in dried cassava.

**4.2 Boiling/cooking**

**4.3 Soaking/wetting**

**Figure 4.**

*Common cassava processing methods used worldwide.*

*Toxicity Potential of Cyanogenic Glycosides in Edible Plants DOI: http://dx.doi.org/10.5772/intechopen.91408*

#### **4.1 Drying**

*Medical Toxicology*

chemical degrades into highly poisonous hydrogen cyanide. Studies have reported that amygdalin content in apple seeds ranged from 1 to 4 mg/g, while that of apple

Apricot fruits are widely cultivated in Central Asia, Africa, America, and Europe. There are two varieties of apricot kernels: bitter and sweet. Bitter apricot kernels contain a considerably high amount of the cyanogenic glycoside amygdalin and thus are unsafe for consumption. On the other hand, sweet varieties are safe for human consumption because of their low level of cyanogens [35]. The concentration of hydrogen cyanide in apricot kernels varies widely (49–4000 mg/kg), depending on whether the skin was included or not during cyanide determination. Ingestion of raw or improperly processed apricot kernels with high cyanide levels

Incidences of health conditions associated with dietary intake of cyanogens can be prevented or reduced by effective removal of cyanogenic compounds in food plants prior to consumption. Food plants are traditionally processed using various methods that vary widely depending on geographical location and ethnicity of communities [36]. The main aims of the food processing techniques are to reduce toxicity and improve palatability and storability. The main processing techniques used worldwide for most food plants include drying, boiling/cooking, soaking/ wetting, fermentation, and/or a combination of the processes [8]. For example, processing techniques and stages used for production of snacks and main dishes

juice was reported to be between 0.001 and 0.08 mg/ml [34].

can cause serious acute problems that could lead to death [2].

*3.5.2 Apricot fruits (Prunus armeniaca)*

**4. Food processing technologies**

from cassava roots are summarized in **Figure 4**.

**198**

**Figure 4.**

*Common cassava processing methods used worldwide.*

Drying is one of the most appropriate processing methods for removal of cyanogenic glycosides in food plants. This is a mass transfer process which removes water from the product by evaporation and keeps the product free from microorganisms. There are several drying methods that can be employed to reduce cyanogens from food products, and they include the use of sun, oven, freeze, and superheated steam. Studies have reported that in bamboo shoots around 80% cyanogenic glycoside reduction was obtained after vacuum freeze-drying for 24 hours at −50°C. On the other hand, superheated steam drying at 120–160°C afforded significant decomposition of taxiphyllin, which causes bitterness in bamboo shoots [37], while oven-drying after grating at 60°C for 8 hours led to very high reduction of cyanogen content of up to 95% [38].

In eastern and southern Africa, cassava is traditionally processed into flour by sun drying the peeled roots followed by pounding and sieving or heap fermentation. However, because this process does not allow enough contact between linamarase and linamarin, total cyanogen content of 59 ppm of HCN equivalents has been reported in processed products, which is higher than the WHO safe level of 10 ppm [39]. The high levels of residual cyanogens can be attributed to the drying process, which restricts the contact between the endogenous enzymes linamarase and cyanogenic glucoside and promotes the retention of cyanohydrin and free cyanide in dried cassava.

### **4.2 Boiling/cooking**

The effectiveness of boiling/cooking on cyanogen removal from various plant food products shows that the method achieves different results depending on the processing duration and part of the plant species. Several studies have reported that cooking and boiling are among the most effective practices for reducing cyanogenic compounds from food plants. These processes appear to promote the rupture of cell walls, which allow translocation of cell contents including antinutrients and toxic substances [39]. A study on bamboo plant showed that cyanogenic glycoside in the shoots of *Bambusa vulgaris* were reduced by 67.84–76.92% after boiling for 10 minutes. Boiling the shoots for an additional 10 minutes further achieved up to 87% reduction in cyanogen content [37]. Similar studies in cassava reported that the efficacy of the boiling method for cyanogen reduction is substantially improved when small-sized cassava pieces are boiled in a large volume of water [40].

However, some studies have reported that boiling can only reduce cyanogen content by 50%, and therefore, it is not an effective method for cyanide removal. The inefficiency of this processing method is attributed to the high temperatures. It is reported that at an elevated temperature of 100°C, linamarase, a heat-labile *β*-glycosidase, is denatured, and linamarin cannot then be hydrolyzed into cyanohydrin and subsequent HCN. A study by Cooke and Maduagwu [41] reported that bound glucosides were reduced to 45 to 50% after 25 min of boiling. Free cyanide and cyanohydrin in boiled cassava roots are found at very low concentrations.

#### **4.3 Soaking/wetting**

Like most processing methods, soaking or wetting of harvested crops helps to improve the shelf life of the food products. Additionally, processing improves the safety and quality of the products. For example, a study reported that cassava flour and to a lesser extent *gari* stored under ambient conditions retained cyanogens over long periods [25]. However, if flour is mixed with water and the resultant wet

flour left in the shade for 5 hours at about 30°C to allow HCN gas to escape, the total cyanide content is reduced three to sixfold. In Africa, the wetting method is commonly practiced in villages around Uvira in South Kivu Province of the Democratic Republic of Congo (DRC) where sporadic incidences of cyanide poisoning and Konzo have been reported [42]. An improved wetting study that reduced processing time to 2 hours was found to be equally effective in removing cyanogens. However, flour samples dried at temperatures above about 80°C lead to denaturing of linamarase, and the wetting method becomes ineffective.

In Malawi, soaking of cassava roots is mostly practiced in the lakeshore areas of northern Malawi and Nkhotakota in the central region, where cassava roots are soaked peeled or unpeeled [36]. A comparative study of the two soaking methods showed that soaking of peeled roots was more effective in reducing levels of cyanogens than soaking unpeeled roots [36]. In the former case, flours of negligible cyanogen contents were obtained, and the residual cyanogen contents were below the maximum FAO/WHO limit. Soaking of unpeeled cassava roots was found to be ineffective as its products gave values above the FAO/WHO recommended limit of 10 mg HCN eq./kg dry matter. The study showed that inclusion of the peel during processing led to high retention of cyanogens in the pulp.

#### **4.4 Fermentation**

Fermentation is one of the ancient methods of food preservation and became widely accepted in many cultures due to its nutritional value and variety of sensory attributes. Fermentation enhances the nutritive value of food through biosynthesis of vitamins and essential amino acids and degradation of antinutrients [39]. In the African region, fermentation by lactic acid bacteria is one of the most practiced processing methods. Fermentation is done with grated or soaked cassava roots, which could be peeled or unpeeled [36]. The process results in a decrease in pH of the food material during processing.

In western Africa and southern America, cassava parenchyma is ground, grated, or crushed into small pieces to disrupt many plant cells and allow good contact between linamarin and linamarase. The moist mash is then left to ferment for several days, the water-soluble cyanogens is squeezed out, and the residual HCN gas is removed by roasting. This process significantly reduced the cyanogen content of the product (*gari* or *farinha*) [39].

## **5. Health conditions associated with cyanide exposure**

Cyanide, one of the most rapidly acting poisons, exists in many forms. The most common are hydrogen cyanide and cyanide salts such as potassium cyanide, sodium cyanide, and calcium cyanide. Cyanide salts can react with acids and subsequently release HCN. In most developing countries, cyanide intake through food consumption is normally high since processed foods with residual levels of cyanogenic substances are a predominant diet among communities. However, cyanide toxicity appears to be a rare form of poisoning among the general population particularly in developed countries. Cyanide exposure occurs relatively frequently in individuals through a variety of modes including inhalation, ingestion, and dermal absorption. In food plants, ingestion of cyanogenic compounds is the most common form of cyanide exposure. The potential toxicity of cyanogenic plants is largely dependent on their ability to produce lethal concentrations of hydrogen cyanide when exposed to humans. The toxic compound, HCN, is formed following the hydrolysis of potentially toxic compounds, cyanogenic glycosides. The conversion process is initiated

**201**

*Toxicity Potential of Cyanogenic Glycosides in Edible Plants*

by the breakdown of the cyanogenic compounds upon disruption of the plant cells that occur during crushing of the edible plant material either during consumption or during processing of the food crop. The residual cyanogens in food products are the primary source of cyanide toxicity to humans when broken down in the gastrointestinal tract to form cyanide [43]. Generally, small quantities of cyanide are naturally detoxified by cellular enzymes and thiosulfates present in many tissues to

Human exposure to cyanide from consumption of food products with considerable amounts of cyanogenic glycosides is associated with health complications such as acute intoxications, chronic toxicity, neurological disorders, growth retardation, and goiter. The following sections will provide the epidemiological information, etiology, and prevalence of health conditions attributed to the toxic effects of

Acute cyanide poisoning occurs when the cyanide level exceeds the limit an individual can detoxify, and therefore the natural detoxification mechanisms are overwhelmed [44]. In humans, the cyanide ion (CN<sup>−</sup>) has a strong affinity to the trivalent iron (Fe3+) of the cytochrome oxidase and is readily absorbed from the intestinal and respiratory tracts [45]. A typical cherry red venous blood is seen in cases of acute cyanide poisoning because of the failure of the oxygen-saturated hemoglobin to release its oxygen at the tissues since the enzyme cytochrome oxidase is inhibited by the cyanide [44]. Thus, cyanide inhibits cytochrome oxidase preventing oxygen utilization leading to cytotoxic anoxia. This causes a decrease in the utilization of oxygen in the tissues. Additionally, increases in blood glucose and lactic acid levels and a decrease in the ATP/ADP ratio are observed, indicating a

Acute cyanide exposure mainly adversely affects the central nervous system (CNS) and the cardiovascular, endocrine, and respiratory systems. In humans, the clinical signs of acute cyanide intoxication can include rapid respiration, drop in blood pressure, dizziness, headache, stomach pains, vomiting, diarrhea, mental confusion, cyanosis with twitching, and convulsions followed by terminal coma and death. There is great variability of lethal doses reported in the literature. However, the mean lethal dose by mouth of cyanide in human adults is estimated to be in the range of 50 to 200 mg, and if untreated death is rarely delayed more than 1 hour [47].

Persistent and prolonged exposure to low levels of cyanide is known to produce

symptoms that are different from those observed in acute exposures described above. Chronic exposure to lower cyanide concentrations has been associated with several health conditions especially among cassava-eating populations. Health manifestations such as malnutrition, congenital malformations, neurological disorders, and myelopathy have been attributed to chronic cyanide toxicity [48]. Reports have also shown that goiter, the swelling of the thyroid glands, has occurred in communities where the levels of cyanogenic glycosides in cassava diets are greater

Although the entire human body is affected by dietary cyanide exposure, adverse effects on the central nervous system are the most prevalent because of

form relatively harmless thiocyanate, which is excreted in the urine [44].

*DOI: http://dx.doi.org/10.5772/intechopen.91408*

cyanogenic glycosides in edible plants.

shift from aerobic to anaerobic metabolism [46].

**5.1 Acute toxicity**

**5.2 Chronic toxicity**

than 10–50 mg/kg food [48].

**5.3 Neurological effects**

#### *Toxicity Potential of Cyanogenic Glycosides in Edible Plants DOI: http://dx.doi.org/10.5772/intechopen.91408*

by the breakdown of the cyanogenic compounds upon disruption of the plant cells that occur during crushing of the edible plant material either during consumption or during processing of the food crop. The residual cyanogens in food products are the primary source of cyanide toxicity to humans when broken down in the gastrointestinal tract to form cyanide [43]. Generally, small quantities of cyanide are naturally detoxified by cellular enzymes and thiosulfates present in many tissues to form relatively harmless thiocyanate, which is excreted in the urine [44].

Human exposure to cyanide from consumption of food products with considerable amounts of cyanogenic glycosides is associated with health complications such as acute intoxications, chronic toxicity, neurological disorders, growth retardation, and goiter. The following sections will provide the epidemiological information, etiology, and prevalence of health conditions attributed to the toxic effects of cyanogenic glycosides in edible plants.

### **5.1 Acute toxicity**

*Medical Toxicology*

**4.4 Fermentation**

the food material during processing.

of the product (*gari* or *farinha*) [39].

flour left in the shade for 5 hours at about 30°C to allow HCN gas to escape, the total cyanide content is reduced three to sixfold. In Africa, the wetting method is commonly practiced in villages around Uvira in South Kivu Province of the Democratic Republic of Congo (DRC) where sporadic incidences of cyanide poisoning and Konzo have been reported [42]. An improved wetting study that reduced processing time to 2 hours was found to be equally effective in removing cyanogens. However, flour samples dried at temperatures above about 80°C lead to denaturing of linama-

In Malawi, soaking of cassava roots is mostly practiced in the lakeshore areas of northern Malawi and Nkhotakota in the central region, where cassava roots are soaked peeled or unpeeled [36]. A comparative study of the two soaking methods showed that soaking of peeled roots was more effective in reducing levels of cyanogens than soaking unpeeled roots [36]. In the former case, flours of negligible cyanogen contents were obtained, and the residual cyanogen contents were below the maximum FAO/WHO limit. Soaking of unpeeled cassava roots was found to be ineffective as its products gave values above the FAO/WHO recommended limit of 10 mg HCN eq./kg dry matter. The study showed that inclusion of the peel during

Fermentation is one of the ancient methods of food preservation and became widely accepted in many cultures due to its nutritional value and variety of sensory attributes. Fermentation enhances the nutritive value of food through biosynthesis of vitamins and essential amino acids and degradation of antinutrients [39]. In the African region, fermentation by lactic acid bacteria is one of the most practiced processing methods. Fermentation is done with grated or soaked cassava roots, which could be peeled or unpeeled [36]. The process results in a decrease in pH of

In western Africa and southern America, cassava parenchyma is ground, grated,

Cyanide, one of the most rapidly acting poisons, exists in many forms. The most common are hydrogen cyanide and cyanide salts such as potassium cyanide, sodium cyanide, and calcium cyanide. Cyanide salts can react with acids and subsequently release HCN. In most developing countries, cyanide intake through food consumption is normally high since processed foods with residual levels of cyanogenic substances are a predominant diet among communities. However, cyanide toxicity appears to be a rare form of poisoning among the general population particularly in developed countries. Cyanide exposure occurs relatively frequently in individuals through a variety of modes including inhalation, ingestion, and dermal absorption. In food plants, ingestion of cyanogenic compounds is the most common form of cyanide exposure. The potential toxicity of cyanogenic plants is largely dependent on their ability to produce lethal concentrations of hydrogen cyanide when exposed to humans. The toxic compound, HCN, is formed following the hydrolysis of potentially toxic compounds, cyanogenic glycosides. The conversion process is initiated

or crushed into small pieces to disrupt many plant cells and allow good contact between linamarin and linamarase. The moist mash is then left to ferment for several days, the water-soluble cyanogens is squeezed out, and the residual HCN gas is removed by roasting. This process significantly reduced the cyanogen content

**5. Health conditions associated with cyanide exposure**

rase, and the wetting method becomes ineffective.

processing led to high retention of cyanogens in the pulp.

**200**

Acute cyanide poisoning occurs when the cyanide level exceeds the limit an individual can detoxify, and therefore the natural detoxification mechanisms are overwhelmed [44]. In humans, the cyanide ion (CN<sup>−</sup>) has a strong affinity to the trivalent iron (Fe3+) of the cytochrome oxidase and is readily absorbed from the intestinal and respiratory tracts [45]. A typical cherry red venous blood is seen in cases of acute cyanide poisoning because of the failure of the oxygen-saturated hemoglobin to release its oxygen at the tissues since the enzyme cytochrome oxidase is inhibited by the cyanide [44]. Thus, cyanide inhibits cytochrome oxidase preventing oxygen utilization leading to cytotoxic anoxia. This causes a decrease in the utilization of oxygen in the tissues. Additionally, increases in blood glucose and lactic acid levels and a decrease in the ATP/ADP ratio are observed, indicating a shift from aerobic to anaerobic metabolism [46].

Acute cyanide exposure mainly adversely affects the central nervous system (CNS) and the cardiovascular, endocrine, and respiratory systems. In humans, the clinical signs of acute cyanide intoxication can include rapid respiration, drop in blood pressure, dizziness, headache, stomach pains, vomiting, diarrhea, mental confusion, cyanosis with twitching, and convulsions followed by terminal coma and death. There is great variability of lethal doses reported in the literature. However, the mean lethal dose by mouth of cyanide in human adults is estimated to be in the range of 50 to 200 mg, and if untreated death is rarely delayed more than 1 hour [47].

#### **5.2 Chronic toxicity**

Persistent and prolonged exposure to low levels of cyanide is known to produce symptoms that are different from those observed in acute exposures described above. Chronic exposure to lower cyanide concentrations has been associated with several health conditions especially among cassava-eating populations. Health manifestations such as malnutrition, congenital malformations, neurological disorders, and myelopathy have been attributed to chronic cyanide toxicity [48]. Reports have also shown that goiter, the swelling of the thyroid glands, has occurred in communities where the levels of cyanogenic glycosides in cassava diets are greater than 10–50 mg/kg food [48].

#### **5.3 Neurological effects**

Although the entire human body is affected by dietary cyanide exposure, adverse effects on the central nervous system are the most prevalent because of the high metabolic demand for oxygen in neurons and its control of respiratory function. Thus, the stimulation of carotid and aortic bodies contributes to the poor functions of the central nervous system and respiratory system.

Chronic human exposure to cyanide has been studied in African regions where populations consume large amounts of cyanide-containing cassava root. Neurological findings among the affected individuals include symmetrical hyperreflexia of the upper limbs, symmetrical spastic paraparesis of the lower limbs, spastic dysarthria, diminished visual acuity, peripheral neuropathy, cerebellar signs, and deafness [6]. Cyanide intake from a cassava-dominated diet is a contributing factor in two forms of nutritional neuropathies, tropical ataxic neuropathy described from Nigeria, and epidemic spastic paraparesis described from Mozambique, Tanzania, and Zaire [49, 50].

### *5.3.1 Tropical ataxic neuropathy*

The term tropical ataxic neuropathy refers to several neurological disorders caused by many factors including toxiconutritional agents. The syndrome, first reported in Jamaica in 1897 and named tropical ataxic neuropathy in 1959, describes several neurological symptoms effecting the mouth, eyesight, hearing, or gait. In the African population, TAN is predominantly prevalent among the elderly population of mostly older males and females. TAN is mostly attributed to cyanide intake due to constant consumption of foods derived from cassava with high levels of cyanogenic compounds [48]. Studies conducted in West Africa particularly Nigeria, Tanzania, Uganda, Kenya, the West Indies, and tropical Asia have reported that cases of TAN generally occur in older people who have consumed a monotonous cassava diet over the years.

## *5.3.2 Konzo*

Konzo, which means "bound legs" in Yaka language of Kwango region in the Democratic Republic of Congo, was first described in 1938 by an Italian missionary doctor. It is a distinct neurological disease with selective upper motor neuron damage and is characterized by an abrupt onset of an irreversible, non-progressive and symmetrical spastic paraparesis [50]. The disease is mostly associated with high dietary cyanogen consumption from poorly processed roots of bitter cassava combined with a protein-deficient diet low in sulfur amino acids [43]. Studies have found that cassava processing methods that involve shortcuts, as practiced during times of war and famine, exacerbate the health condition among the communities. Since its first description in the DRC, Konzo epidemics have been reported from many cassava-consuming areas in rural Africa. The disease has extended beyond DRC borders, and it remains a serious health problem among African communities that subsist on cassava [48]. In sub-Saharan Africa, at least seven countries have reported the outbreaks of Konzo, and they include the Democratic Republic of Congo, Mozambique, Tanzania, Central African Republic, Angola, Cameroon, and Zambia. In most of the affected countries, the epidemics were preceded by food shortages and several weeks of exclusive consumption of poorly processed bitter cassava roots, resulting in high dietary cyanide exposure, which was confirmed by high levels of thiocyanate in serum and urine [50].

#### **5.4 Goiter and cretinism**

Goiter and cretinism are common diseases in most developing countries because of low intake of iodine (<100 μg/day) among communities. Populations that exclusively depend on cassava as a staple food have shown high incidences of endemic goiter and cretinism. Several studies have reported that populations with very low

**203**

**Figure 5.**

*Cyanide metabolism in the body [54].*

*Toxicity Potential of Cyanogenic Glycosides in Edible Plants*

iodine intake and correspondingly high thiocyanate levels showed severe endemic goiter. The endocrine effect may be due to formation of thiocyanate, a lesser toxic metabolite of cyanide. Thiocyanate is known to block iodine uptake in the body and compete with iodide ion (I<sup>−</sup>) as a substrate for the thyroid peroxidase, thereby decreasing the iodination of tyrosine to form iodotyrosine by the thyroid gland. Consumption of food products with residual cyanogenic glycosides even at a very

In humans, low birth weights among children are a common health problem especially in developing countries. Chronic exposure to cyanogenic glycosides has been reported as a major contributing factor to this health problem. Growth retardation is particularly a serious problem in populations consuming foods with inadequate proteins especially diets that are low in sulfur-containing amino acids such as methionine and cysteine. Cyanide detoxification in the human body requires sulfur donors from sulfur-containing amino acids [43], and thus, dietary exposure to cyanide has been identified as one of the contributing factors to growth retardation among children [51].

Hydrogen cyanide whether ingested directly or released from cyanogens is readily absorbed in the blood by binding to iron in hemoglobin and quickly distributed to organs such as the liver, kidney, brain, and blood tissue. However, about 80

low concentration can cause iodine deficiency leading to goiter [43].

*DOI: http://dx.doi.org/10.5772/intechopen.91408*

**5.5 Growth retardation**

**6. Cyanide detoxification**

*Toxicity Potential of Cyanogenic Glycosides in Edible Plants DOI: http://dx.doi.org/10.5772/intechopen.91408*

iodine intake and correspondingly high thiocyanate levels showed severe endemic goiter. The endocrine effect may be due to formation of thiocyanate, a lesser toxic metabolite of cyanide. Thiocyanate is known to block iodine uptake in the body and compete with iodide ion (I<sup>−</sup>) as a substrate for the thyroid peroxidase, thereby decreasing the iodination of tyrosine to form iodotyrosine by the thyroid gland. Consumption of food products with residual cyanogenic glycosides even at a very low concentration can cause iodine deficiency leading to goiter [43].

#### **5.5 Growth retardation**

*Medical Toxicology*

*5.3.1 Tropical ataxic neuropathy*

*5.3.2 Konzo*

the high metabolic demand for oxygen in neurons and its control of respiratory function. Thus, the stimulation of carotid and aortic bodies contributes to the poor

Chronic human exposure to cyanide has been studied in African regions where populations consume large amounts of cyanide-containing cassava root. Neurological findings among the affected individuals include symmetrical hyperreflexia of the upper limbs, symmetrical spastic paraparesis of the lower limbs, spastic dysarthria, diminished visual acuity, peripheral neuropathy, cerebellar signs, and deafness [6]. Cyanide intake from a cassava-dominated diet is a contributing factor in two forms of nutritional neuropathies, tropical ataxic neuropathy described from Nigeria, and epidemic spastic paraparesis described from Mozambique, Tanzania, and Zaire [49, 50].

The term tropical ataxic neuropathy refers to several neurological disorders caused

by many factors including toxiconutritional agents. The syndrome, first reported in Jamaica in 1897 and named tropical ataxic neuropathy in 1959, describes several neurological symptoms effecting the mouth, eyesight, hearing, or gait. In the African population, TAN is predominantly prevalent among the elderly population of mostly older males and females. TAN is mostly attributed to cyanide intake due to constant consumption of foods derived from cassava with high levels of cyanogenic compounds [48]. Studies conducted in West Africa particularly Nigeria, Tanzania, Uganda, Kenya, the West Indies, and tropical Asia have reported that cases of TAN generally occur in

older people who have consumed a monotonous cassava diet over the years.

high levels of thiocyanate in serum and urine [50].

**5.4 Goiter and cretinism**

Konzo, which means "bound legs" in Yaka language of Kwango region in the Democratic Republic of Congo, was first described in 1938 by an Italian missionary doctor. It is a distinct neurological disease with selective upper motor neuron damage and is characterized by an abrupt onset of an irreversible, non-progressive and symmetrical spastic paraparesis [50]. The disease is mostly associated with high dietary cyanogen consumption from poorly processed roots of bitter cassava combined with a protein-deficient diet low in sulfur amino acids [43]. Studies have found that cassava processing methods that involve shortcuts, as practiced during times of war and famine, exacerbate the health condition among the communities. Since its first description in the DRC, Konzo epidemics have been reported from many cassava-consuming areas in rural Africa. The disease has extended beyond DRC borders, and it remains a serious health problem among African communities that subsist on cassava [48]. In sub-Saharan Africa, at least seven countries have reported the outbreaks of Konzo, and they include the Democratic Republic of Congo, Mozambique, Tanzania, Central African Republic, Angola, Cameroon, and Zambia. In most of the affected countries, the epidemics were preceded by food shortages and several weeks of exclusive consumption of poorly processed bitter cassava roots, resulting in high dietary cyanide exposure, which was confirmed by

Goiter and cretinism are common diseases in most developing countries because of low intake of iodine (<100 μg/day) among communities. Populations that exclusively depend on cassava as a staple food have shown high incidences of endemic goiter and cretinism. Several studies have reported that populations with very low

functions of the central nervous system and respiratory system.

**202**

In humans, low birth weights among children are a common health problem especially in developing countries. Chronic exposure to cyanogenic glycosides has been reported as a major contributing factor to this health problem. Growth retardation is particularly a serious problem in populations consuming foods with inadequate proteins especially diets that are low in sulfur-containing amino acids such as methionine and cysteine. Cyanide detoxification in the human body requires sulfur donors from sulfur-containing amino acids [43], and thus, dietary exposure to cyanide has been identified as one of the contributing factors to growth retardation among children [51].

## **6. Cyanide detoxification**

Hydrogen cyanide whether ingested directly or released from cyanogens is readily absorbed in the blood by binding to iron in hemoglobin and quickly distributed to organs such as the liver, kidney, brain, and blood tissue. However, about 80

**Figure 5.** *Cyanide metabolism in the body [54].*

percent of the absorbed cyanide is detoxified in the liver mainly by the mitochondrial enzyme rhodanese, which catalyzes the transfer of sulfur from a sulfate donor to cyanide, forming a less toxic metabolite, thiocyanate. There are two primary detoxification mechanisms of ingested cyanide in the body. The minor one involves methemoglobin in the red blood cells, which temporarily neutralize cyanide by reversible reaction [52]. The major pathway proceeds by the conversion of cyanide to a less toxic thiocyanate (SCN). This process is catalyzed by the enzyme rhodanese present in most tissues, by a reaction with sulfur [43], as shown in **Figure 5**. The two amino acids, cysteine and methionine, are the common source of sulfur [53]. The generated SCN is then slowly excreted through urine and sweat.

Other detoxification mechanisms exist and include the binding of hydroxocobalamin (vitamin B12) to cyanide to form cyanocobalamin. Small quantities of cyanide along with CO2 are eliminated through this pathway.

## **7. Conclusion**

Cyanogenic glycosides are widely distributed in edible plants, and they play a major role in plant protection against herbivores, pathogens, and competitors. The presence of the potentially toxic compounds in food plants has also contributed to food security, particularly in the sub-Saharan African region. Most of the cyanogenic plants, such as cassava, have several agricultural advantages over other crops due to their outstanding ecological adaptation, low labor requirement, and high tolerance to extreme stress conditions such as drought and poor soils. Additionally, the cyanogenic compounds act as a deterrent against thieves and pests. However, several health disorders and diseases have been associated with consumption of food products with high quantities of residual cyanogens. Consequently, it is recommended that consumers should prepare foods properly before consumption in order to prevent adverse effects of cyanogenic glycosides in food plants. There are various traditional processing techniques that are relatively effective in removing cyanide from food plants, especially those involving grating and crushing. Generally, the efficiency of the technique largely depends on the duration of the process, material size, moisture, and temperature. In order to improve food safety, researchers have extensively studied mechanisms that accelerate cyanogenesis and cyanide volatilization during processing, which is a strategic step in detoxification of food plants. Therefore, effective processing technologies should be promoted among communities to enhance safety and organoleptic properties of products derived from cyanogenic food plants.

**205**

**Author details**

Kumbukani K. Nyirenda

Plant and Soil Sciences Department, University of Pretoria, Pretoria, South Africa

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

\*Address all correspondence to: knyirenda@medcol.mw

provided the original work is properly cited.

*Toxicity Potential of Cyanogenic Glycosides in Edible Plants*

*DOI: http://dx.doi.org/10.5772/intechopen.91408*

## **Conflict of interest**

The author declares that there is no conflict of interest.

*Toxicity Potential of Cyanogenic Glycosides in Edible Plants DOI: http://dx.doi.org/10.5772/intechopen.91408*

*Medical Toxicology*

**7. Conclusion**

derived from cyanogenic food plants.

The author declares that there is no conflict of interest.

**Conflict of interest**

percent of the absorbed cyanide is detoxified in the liver mainly by the mitochondrial enzyme rhodanese, which catalyzes the transfer of sulfur from a sulfate donor to cyanide, forming a less toxic metabolite, thiocyanate. There are two primary detoxification mechanisms of ingested cyanide in the body. The minor one involves methemoglobin in the red blood cells, which temporarily neutralize cyanide by reversible reaction [52]. The major pathway proceeds by the conversion of cyanide to a less toxic thiocyanate (SCN). This process is catalyzed by the enzyme rhodanese present in most tissues, by a reaction with sulfur [43], as shown in **Figure 5**. The two amino acids, cysteine and methionine, are the common source of sulfur [53].

Other detoxification mechanisms exist and include the binding of hydroxocobalamin (vitamin B12) to cyanide to form cyanocobalamin. Small quantities of

Cyanogenic glycosides are widely distributed in edible plants, and they play a major role in plant protection against herbivores, pathogens, and competitors. The presence of the potentially toxic compounds in food plants has also contributed to food security, particularly in the sub-Saharan African region. Most of the cyanogenic plants, such as cassava, have several agricultural advantages over other crops due to their outstanding ecological adaptation, low labor requirement, and high tolerance to extreme stress conditions such as drought and poor soils. Additionally, the cyanogenic compounds act as a deterrent against thieves and pests. However, several health disorders and diseases have been associated with consumption of food products with high quantities of residual cyanogens. Consequently, it is recommended that consumers should prepare foods properly before consumption in order to prevent adverse effects of cyanogenic glycosides in food plants. There are various traditional processing techniques that are relatively effective in removing cyanide from food plants, especially those involving grating and crushing. Generally, the efficiency of the technique largely depends on the duration of the process, material size, moisture, and temperature. In order to improve food safety, researchers have extensively studied mechanisms that accelerate cyanogenesis and cyanide volatilization during processing, which is a strategic step in detoxification of food plants. Therefore, effective processing technologies should be promoted among communities to enhance safety and organoleptic properties of products

The generated SCN is then slowly excreted through urine and sweat.

cyanide along with CO2 are eliminated through this pathway.

**204**

## **Author details**

Kumbukani K. Nyirenda Plant and Soil Sciences Department, University of Pretoria, Pretoria, South Africa

\*Address all correspondence to: knyirenda@medcol.mw

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

## **References**

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[2] Vetter J. Plant cyanogenic glycosides. Toxicon [Internet]. 2000;**38**(1):11-36. DOI: 10.1016/S0041-0101(99)00128-2

[3] Onojah PK, Odin EM. Cyanogenic glycoside in food plants. The International Journal of Innovation in Science and Mathematics [Internet]. 2015;**3**(4):2347-9051. Available from: https://www.ijism.org/administrator/ components/com\_jresearch/files/ publications/IJISM\_402\_Final.pdf

[4] Bolarinwa IF, Oke MO, Olaniyan SA, Ajala AS. A review of cyanogenic glycosides in edible plants. In: Soloneski S, Larramendy ML, editors. Toxicology—New Aspects to This Scientific Conundrum. Rijeka, Croatia: Intech; 2016

[5] Monago CC, Akhidue V. Cyanide poisoning. Journal of Applied Sciences and Environmental Management. 2002;**6**(1):22-25

[6] Tylleskär T, Rosling H, Banea M, Bikangi N, Cooke RD, Poulter NH. Cassava cyanogens and konzo, an upper motor neuron disease found in Africa. Lancet. 1992;**339**(8787):208-211

[7] Mlingi N, Poulter NH, Rosling H. An outbreak of acute intoxications from consumption of insufficiently processed cassava in Tanzania. Nutrition Research. 1992;**12**(6):677-687

[8] Cardoso A, Mirone E, Ernest M, Massza F, Cliff J, Haque R, et al. Modification of nutritional quality of cassava through plant nutrition. Journal of Food Composition and Analysis. 2005;**18**:451-461

[9] FAO/WHO. WHO Food Additive Series: 65. Safety evaluation of certain food additives and contaminants. Prepared by the 74th Meeting of the Joint FAO/WHO Expert Committee on Food Additives (JECFA). Geneva; 2012

[10] Jones PR, Møller BL, Høj PB. The UDP-glucose:p-hydroxymandelonitrile-O-glucosyltransferase that catalyzes the last step in synthesis of the cyanogenic glucoside dhurrin in Sorghum bicolor. Isolation, cloning, heterologous expression, and substrate specificity. The Journal of Biological Chemistry. 1999;**274**(50):35483-35491

[11] Jones DA. Why are so many food plants cyanogenic? Phytochemistry. 1998;**47**(2):155-162

[12] Francisco IA, Pinotti MHP. Cyanogenic glycosides in plants. Brazilian Archives of Biology and Technology. 2000;**43**(5):487-492

[13] Ganjewala D, Kumar S, Devi SA, Ambika K. Advances in cyanogenic glycosides biosynthesis and analyses in plants: A review. Acta Biologica Szegediensis. 2010;**54**(1):1-14

[14] Bak S, Kahn RA, Nielsen HL, Møller BL, Halkier BA. Cloning of three A-type cytochromes P450, CYP71E1, CYP98, and CYP99 from *Sorghum bicolor* (L.) Moench by a PCR approach and identification by expression in Escherichia coli of CYP71E1 as a multifunctional cytochrome P450 in the biosynthesis of the cyanogen. Plant Molecular Biology. 1998;**36**(3):393-405

[15] Harborne JB. Recent advances in chemical ecology. Natural Product Reports. 1986;**3**:323-344

[16] Harborne JB. Plant toxins and their effects on animals. In: Introduction to Ecological Biochemistry. London: Academic Press; 1993. pp. 71-103

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*Toxicity Potential of Cyanogenic Glycosides in Edible Plants*

potential (HCNp) and appearance of cassava flours from South-Eastern African region. The International Food Research Journal [Internet]. 2015;**22**(3):973-980. Available from:

[26] Onwueme IC. Tropical Root and Tuber Crops—Production, Perspectives and Future Prospects. Rome: FAO; 1994.

[28] FAO. Roots, Tubers, Plantain and Bananas in Human Nutrition. Rome: FAO; 1991. ISBN: 92-5-103138-X

[29] Olajide R, Akinsoyinu AO, Babayemi OJ, Omojola AB, Abu AO, Afolabi KD. Effect of processing on energy values, nutrient and antinutrient components of wild cocoyam [*Colocasia esculenta* (L.) Schott] corm. Pakistan Journal of Nutrition.

[30] Igbadul BD, Amoye J, Twadue I. Effect of fermentation on the proximate composition , antinutritional factors and functional properties of cocoyam (*Colocasia esculenta*) flour. African Journal of. Microbiology Research [Internet]. 2014;**8**(3):67-74. Available from: 10.1016/j.

foodchem.2013.01.059%5Cnhttp://

abstract/07E643346419%5Cnhttp:// academicjournals.org/journal/AJMR/

www.davidpublishing. com/davidpublishing/Upf ile/12/1/2014/2014120172701049. pdf%5Cnhttp://academicjournals.

org/journal/AJMR/article-

[31] Bhargava A, Kumbhare V, Srivastava A, Sahai A. Bamboo parts and seeds for additional source of nutrition. Journal of Food Science and Technology. 1996;**33**(2):145-146

2011;**10**(1):29-34

[27] Nail H. Understanding the production of the major tropical/ subtropical root crops: cassava, potatoes, yams and cocoyams. In: Technical Paper, China; 2010. pp. 17-35

www.ifrj.upm.edu.my

ISBN: 92-5-103461-3

*DOI: http://dx.doi.org/10.5772/intechopen.91408*

[17] Poulton JE. Cyanogenesis in plants. Plant Physiology. 1990;**94**(2):401-405

[18] Gruhnert C, Biehl B, Selmar D. Compartmentation of cyanogenic glucosides and their degrading enzymes.

Planta. 1994;**195**(1):36-42

731-741

30). Geneva; 1993

2008;**3**(7):439-445

site/339/default.aspx

[19] McMahon JM, White WLB, Sayre RT. Cyanogenesis in cassava (*Manihot esculenta* Crantz). Journal of Experimental Botany. 2005;**46**(288):

[20] JECFA. Cyanogenic glycosides. In: Toxicological evaluation of certain food additives and naturally occurring toxicants. 39th Meeting of the Joint FAO/WHO Expert Committee on Food Additive (WHO Food Additives Series

[21] Baguma Y, Sun C, Borén M,

Olsson H, Rosenqvist S, Mutisya J, et al. Sugar-mediated semidian oscillation of gene expression in the cassava storage root regulates starch

synthesis. Plant Signaling & Behavior.

[22] Aryee FNA, Oduro I, Ellis WO, Afuakwa JJ. The physicochemical properties of flour samples from the roots of 31 varieties of cassava. Food Control. 2006;**17**(11):916-922

[23] FAO. FAOSTAT [Internet]. Rome; 2015. Available from: faostat.fao.org/

[24] Wheatley C, Chuzel G. Cassava: The nature of the tuber and use as a raw material. In: Macrae R, Robinson RK, Sadler M, editors. Encyclopedia of Food Science, Food Technology and Nutrition. San Diego, California: Academic Press; 1993. pp. 964-970

[25] Chiwona-Karltun L, Afoakwa EO, Nyirenda D, Mwansa CN, Kongor EJ, Brimer L. Varietal diversity and processing effects on the biochemical composition, cyanogenic glucoside

*Toxicity Potential of Cyanogenic Glycosides in Edible Plants DOI: http://dx.doi.org/10.5772/intechopen.91408*

[17] Poulton JE. Cyanogenesis in plants. Plant Physiology. 1990;**94**(2):401-405

[18] Gruhnert C, Biehl B, Selmar D. Compartmentation of cyanogenic glucosides and their degrading enzymes. Planta. 1994;**195**(1):36-42

[19] McMahon JM, White WLB, Sayre RT. Cyanogenesis in cassava (*Manihot esculenta* Crantz). Journal of Experimental Botany. 2005;**46**(288): 731-741

[20] JECFA. Cyanogenic glycosides. In: Toxicological evaluation of certain food additives and naturally occurring toxicants. 39th Meeting of the Joint FAO/WHO Expert Committee on Food Additive (WHO Food Additives Series 30). Geneva; 1993

[21] Baguma Y, Sun C, Borén M, Olsson H, Rosenqvist S, Mutisya J, et al. Sugar-mediated semidian oscillation of gene expression in the cassava storage root regulates starch synthesis. Plant Signaling & Behavior. 2008;**3**(7):439-445

[22] Aryee FNA, Oduro I, Ellis WO, Afuakwa JJ. The physicochemical properties of flour samples from the roots of 31 varieties of cassava. Food Control. 2006;**17**(11):916-922

[23] FAO. FAOSTAT [Internet]. Rome; 2015. Available from: faostat.fao.org/ site/339/default.aspx

[24] Wheatley C, Chuzel G. Cassava: The nature of the tuber and use as a raw material. In: Macrae R, Robinson RK, Sadler M, editors. Encyclopedia of Food Science, Food Technology and Nutrition. San Diego, California: Academic Press; 1993. pp. 964-970

[25] Chiwona-Karltun L, Afoakwa EO, Nyirenda D, Mwansa CN, Kongor EJ, Brimer L. Varietal diversity and processing effects on the biochemical composition, cyanogenic glucoside

potential (HCNp) and appearance of cassava flours from South-Eastern African region. The International Food Research Journal [Internet]. 2015;**22**(3):973-980. Available from: www.ifrj.upm.edu.my

[26] Onwueme IC. Tropical Root and Tuber Crops—Production, Perspectives and Future Prospects. Rome: FAO; 1994. ISBN: 92-5-103461-3

[27] Nail H. Understanding the production of the major tropical/ subtropical root crops: cassava, potatoes, yams and cocoyams. In: Technical Paper, China; 2010. pp. 17-35

[28] FAO. Roots, Tubers, Plantain and Bananas in Human Nutrition. Rome: FAO; 1991. ISBN: 92-5-103138-X

[29] Olajide R, Akinsoyinu AO, Babayemi OJ, Omojola AB, Abu AO, Afolabi KD. Effect of processing on energy values, nutrient and antinutrient components of wild cocoyam [*Colocasia esculenta* (L.) Schott] corm. Pakistan Journal of Nutrition. 2011;**10**(1):29-34

[30] Igbadul BD, Amoye J, Twadue I. Effect of fermentation on the proximate composition , antinutritional factors and functional properties of cocoyam (*Colocasia esculenta*) flour. African Journal of. Microbiology Research [Internet]. 2014;**8**(3):67-74. Available from: 10.1016/j. foodchem.2013.01.059%5Cnhttp:// www.davidpublishing. com/davidpublishing/Upf ile/12/1/2014/2014120172701049. pdf%5Cnhttp://academicjournals. org/journal/AJMR/articleabstract/07E643346419%5Cnhttp:// academicjournals.org/journal/AJMR/

[31] Bhargava A, Kumbhare V, Srivastava A, Sahai A. Bamboo parts and seeds for additional source of nutrition. Journal of Food Science and Technology. 1996;**33**(2):145-146

**206**

*Medical Toxicology*

**References**

1988;**75**(2):225-233

[1] Wink M. Plant breeding importance of secondary metabolites for production against pathogens and herbivores. Theoretical and Applied Genetics.

[9] FAO/WHO. WHO Food Additive Series: 65. Safety evaluation of certain food additives and contaminants. Prepared by the 74th Meeting of the Joint FAO/WHO Expert Committee on Food Additives (JECFA). Geneva;

[10] Jones PR, Møller BL, Høj PB. The UDP-glucose:p-hydroxymandelonitrile-O-glucosyltransferase that catalyzes the last step in synthesis of the cyanogenic glucoside dhurrin in Sorghum bicolor. Isolation, cloning, heterologous expression, and substrate specificity. The Journal of Biological Chemistry.

[11] Jones DA. Why are so many food plants cyanogenic? Phytochemistry.

[13] Ganjewala D, Kumar S, Devi SA, Ambika K. Advances in cyanogenic glycosides biosynthesis and analyses in plants: A review. Acta Biologica Szegediensis. 2010;**54**(1):1-14

[14] Bak S, Kahn RA, Nielsen HL, Møller BL, Halkier BA. Cloning of three A-type cytochromes P450, CYP71E1, CYP98, and CYP99 from *Sorghum bicolor* (L.) Moench by a PCR approach and identification by expression in Escherichia coli of CYP71E1 as a multifunctional cytochrome P450 in the biosynthesis of the cyanogen. Plant Molecular Biology. 1998;**36**(3):393-405

[15] Harborne JB. Recent advances in chemical ecology. Natural Product

[16] Harborne JB. Plant toxins and their effects on animals. In: Introduction to Ecological Biochemistry. London: Academic Press; 1993. pp. 71-103

Reports. 1986;**3**:323-344

[12] Francisco IA, Pinotti MHP. Cyanogenic glycosides in plants. Brazilian Archives of Biology and Technology. 2000;**43**(5):487-492

1999;**274**(50):35483-35491

1998;**47**(2):155-162

2012

[2] Vetter J. Plant cyanogenic glycosides. Toxicon [Internet]. 2000;**38**(1):11-36. DOI: 10.1016/S0041-0101(99)00128-2

[3] Onojah PK, Odin EM. Cyanogenic

International Journal of Innovation in Science and Mathematics [Internet]. 2015;**3**(4):2347-9051. Available from: https://www.ijism.org/administrator/ components/com\_jresearch/files/ publications/IJISM\_402\_Final.pdf

[4] Bolarinwa IF, Oke MO, Olaniyan SA, Ajala AS. A review of cyanogenic glycosides in edible plants. In:

Soloneski S, Larramendy ML, editors. Toxicology—New Aspects to This Scientific Conundrum. Rijeka, Croatia:

[5] Monago CC, Akhidue V. Cyanide poisoning. Journal of Applied Sciences and Environmental Management.

[6] Tylleskär T, Rosling H, Banea M, Bikangi N, Cooke RD, Poulter NH. Cassava cyanogens and konzo, an upper motor neuron disease found in Africa. Lancet.

[7] Mlingi N, Poulter NH, Rosling H. An outbreak of acute intoxications from consumption of insufficiently processed cassava in Tanzania. Nutrition Research.

[8] Cardoso A, Mirone E, Ernest M, Massza F, Cliff J, Haque R, et al. Modification of nutritional quality of cassava through plant nutrition. Journal of Food Composition and Analysis.

Intech; 2016

2002;**6**(1):22-25

1992;**339**(8787):208-211

1992;**12**(6):677-687

2005;**18**:451-461

glycoside in food plants. The

[32] Ferreira VL, Yotsuyanagi K, Carvalho CR. Elimination of cyanogenic compounds from bamboo shoots *Dendrocalamus giganteus* Munro. Tropical Science. 1995;**35**(4):342-346

[33] Awika JM, Rooney LW. Sorghum phytochemicals and their potential impact on human health. Methods in Molecular Biology. 1931;**2019**:121-140

[34] Bolarinwa IF, Orfila C, Morgan MRA. Amygdalin content of seeds, kernels and food products commercially-available in the UK. Food Chemistry. 2014;**152**:133-139

[35] Bolarinwa IF, Orfila C, Morgan MRA. Determination of amygdalin in apple seeds, fresh apples and processed apple juices. Food Chemistry. 2015;**170**:437-442

[36] Kalenga Saka JD, Nyirenda KK. Effect of two ethnic processing technologies on reduction and composition of total and non-glucosidic cyanogens in cassava. Food Chemistry. 2012;**130**(3):605-609

[37] Rawat K, Nirmala C, Bisht MS. Processing techniques for reduction of cyanogenic glycosides from bamboo shoots. In: 10th World Bamboo Congress, Korea 2015. 2015

[38] Lambri M, Fumi MD. Food technologies and developing countries: A processing method for making edible the highly toxic cassava roots. Italian Journal of Agronomy. 2014;**9**(2):79-83

[39] Montagnac JA, Davis CR, Tanumihardjo SA. Nutritional value of cassava for use as a staple food and recent advances for improvement. Comprehensive Reviews in Food Science and Food Safety. 2009;**8**(3):181-194

[40] Oke OL. Eliminating Cyanogens from cassava through processing: Technology and tradition. Acta Horticulturae. 1994;**375**(375):163-174 [41] Cooke RD, Maduagwu EN. The effects of simple processing on the cyanide content of cassava chips. International Journal of Food Science and Technology. 1978;**13**(4):299-306

[42] Bradbury JH. Simple wetting method to reduce cyanogen content of cassava flour. Journal of Food Composition and Analysis. 2006;**19**(4):388-393

[43] Rosling H. Measuring effects in humans of dietary cyanide exposure from cassava. Acta Horticulturae. 1994;**375**(375):271-284

[44] Salkowski AA, Penney DG. Cyanide poisoning in animals and humans: A review. Veterinary and Human Toxicology. 1994;**36**(5):455-466

[45] Way JL. Cyanide intoxication and its mechanism of antagonism. Annual Review of Pharmacology and Toxicology. 1984;**24**(1):451-481

[46] WHO. Toxicological evaluation of certain food additives and naturally occurring toxicants. WHO Food Additive Series: 30. Geneva, Switzerland: World Health Organization; 1993

[47] Gosselin R, Hodge H, Smith R, Gleason MN. Clinical Toxicology of Commercial Products, Annals of Internal Medicine. 4th ed. Vol. 85. Baltimore: Williams and Wilkins; 1976. 554 p

[48] FSANZ. Final assessment report proposal P257. Advice on the preparation of cassava and bamboo shoots. Canberra; 2004

[49] Osuntokun BO. Cassava diet, chronic cyanide intoxication and neuropathy in the Nigerian Africans. World Review of Nutrition and Dietetics. 1981;**36**:141-173

[50] Tylleskar T, Banea M, Bikangi N, Fresco L, Persson LA, Rosling H. Epidemiological evidence from Zaire

**209**

*Toxicity Potential of Cyanogenic Glycosides in Edible Plants*

*DOI: http://dx.doi.org/10.5772/intechopen.91408*

for a dietary etiology of konzo, an upper motor neuron disease. Bulletin of the World Health Organization.

[51] Banea-Mayambu JP, Tylleskär T, Tylleskär K, Gebre-Medhin M, Rosling H. Dietary cyanide from insufficiently processed cassava and growth retardation in children in the Democratic Republic of Congo (formerly Zaire). Annals of Tropical Paediatrics. 2000;**20**(1):34-40

[52] Lundquist P, Rosling H, Sorbo B. Determination of cyanide in whole blood, erythrocytes, and plasma. Clinical Chemistry. 1985;**31**(4):591-595

[53] Diasolua D, Kuo Y, Lambein F. Cassava cyanogens and free amino acids in raw and cooked leaves. Food and Chemical Toxicology.

[54] Omaye ST. Food and Nutritional Toxicology. Boca Raton, USA: CRC Press

2003;**41**(8):1193-1197

LLC; 2004

1991;**69**(5):581-589

*Toxicity Potential of Cyanogenic Glycosides in Edible Plants DOI: http://dx.doi.org/10.5772/intechopen.91408*

for a dietary etiology of konzo, an upper motor neuron disease. Bulletin of the World Health Organization. 1991;**69**(5):581-589

*Medical Toxicology*

[32] Ferreira VL, Yotsuyanagi K,

compounds from bamboo shoots *Dendrocalamus giganteus* Munro. Tropical Science. 1995;**35**(4):342-346

[33] Awika JM, Rooney LW. Sorghum phytochemicals and their potential impact on human health. Methods in Molecular Biology. 1931;**2019**:121-140

[34] Bolarinwa IF, Orfila C, Morgan MRA. Amygdalin content of seeds, kernels and food products commercially-available in the UK. Food

Chemistry. 2014;**152**:133-139

[35] Bolarinwa IF, Orfila C, Morgan MRA. Determination of amygdalin in apple seeds, fresh apples and processed apple juices. Food Chemistry. 2015;**170**:437-442

2012;**130**(3):605-609

[36] Kalenga Saka JD, Nyirenda KK. Effect of two ethnic processing technologies on reduction and

[37] Rawat K, Nirmala C, Bisht MS. Processing techniques for reduction of cyanogenic glycosides from bamboo shoots. In: 10th World Bamboo Congress, Korea 2015. 2015

[38] Lambri M, Fumi MD. Food

[39] Montagnac JA, Davis CR, Tanumihardjo SA. Nutritional value of cassava for use as a staple food and recent advances for improvement. Comprehensive Reviews in Food Science and Food Safety. 2009;**8**(3):181-194

[40] Oke OL. Eliminating Cyanogens from cassava through processing: Technology and tradition. Acta Horticulturae. 1994;**375**(375):163-174

technologies and developing countries: A processing method for making edible the highly toxic cassava roots. Italian Journal of Agronomy. 2014;**9**(2):79-83

composition of total and non-glucosidic cyanogens in cassava. Food Chemistry.

Carvalho CR. Elimination of cyanogenic

[41] Cooke RD, Maduagwu EN. The effects of simple processing on the cyanide content of cassava chips. International Journal of Food Science and Technology. 1978;**13**(4):299-306

[42] Bradbury JH. Simple wetting method to reduce cyanogen content of cassava flour. Journal of Food Composition and Analysis.

[43] Rosling H. Measuring effects in humans of dietary cyanide exposure from cassava. Acta Horticulturae.

[44] Salkowski AA, Penney DG. Cyanide poisoning in animals and humans: A review. Veterinary and Human Toxicology. 1994;**36**(5):455-466

[45] Way JL. Cyanide intoxication and its mechanism of antagonism. Annual Review of Pharmacology and Toxicology. 1984;**24**(1):451-481

[46] WHO. Toxicological evaluation of certain food additives and naturally occurring toxicants. WHO Food Additive Series: 30. Geneva, Switzerland: World Health

[47] Gosselin R, Hodge H, Smith R, Gleason MN. Clinical Toxicology of Commercial Products, Annals of Internal Medicine. 4th ed. Vol. 85. Baltimore: Williams and Wilkins; 1976. 554 p

[48] FSANZ. Final assessment report proposal P257. Advice on the preparation of cassava and bamboo

[49] Osuntokun BO. Cassava diet, chronic cyanide intoxication and neuropathy in the Nigerian Africans. World Review of Nutrition and Dietetics. 1981;**36**:141-173

[50] Tylleskar T, Banea M, Bikangi N, Fresco L, Persson LA, Rosling H. Epidemiological evidence from Zaire

shoots. Canberra; 2004

2006;**19**(4):388-393

1994;**375**(375):271-284

Organization; 1993

**208**

[51] Banea-Mayambu JP, Tylleskär T, Tylleskär K, Gebre-Medhin M, Rosling H. Dietary cyanide from insufficiently processed cassava and growth retardation in children in the Democratic Republic of Congo (formerly Zaire). Annals of Tropical Paediatrics. 2000;**20**(1):34-40

[52] Lundquist P, Rosling H, Sorbo B. Determination of cyanide in whole blood, erythrocytes, and plasma. Clinical Chemistry. 1985;**31**(4):591-595

[53] Diasolua D, Kuo Y, Lambein F. Cassava cyanogens and free amino acids in raw and cooked leaves. Food and Chemical Toxicology. 2003;**41**(8):1193-1197

[54] Omaye ST. Food and Nutritional Toxicology. Boca Raton, USA: CRC Press LLC; 2004

**211**

**Chapter 11**

**Abstract**

hypotension.

**1. Introduction**

places.

accidents.

intoxications in humans and animals.

*Djafer Rachid*

Intoxication by Harmel

Herbal medicine has taken a prominent place in the North African skincare

system because of the increased installation of herbalists and healers, but unfortunately most of these do not have the required level to practice this medicine. The Harmel (*Peganum harmala* L.) belongs to the family Zygophyllaceae, which has 24 genera and 240 species. It is a herbaceous plant, perennial, glabrous, and bushy, from a height of 30–100 cm, with a thick rhizome, its strong, unpleasant odor reminiscent of that of the Rue (*Ruta graveolens*). The Harmel is a toxic plant widespread in North Africa which has an important place in traditional medicine in several indications. It is used as a sedative, antitussive, antipyretic, antirheumatic, and antihelminthic, and to treat some skin diseases. Harmel is ingested with a glass of water or mixed with honey or pounded with olive oil. The intoxications are mainly due to overdose; the absorption of a quantity of seed greater than a teaspoon causes hallucinations and vomiting. In France, Harmel as well as its compounds (Harmine, Harmaline, Harmol, and harmalol) have been classified among the astonishing substances. The clinical manifestations described in the literature include: digestive disorders, bradycardia; neurological disorders paralysis, central nervous system depression; renal disorders; and in severe cases, dyspnoea and hypothermia and

**Keywords:** intoxication, Harmel, toxic plant, botanical study, toxicological analysis

North Africa has one of the oldest and richest traditions associated with the use of medicinal plants where they are very important to people in many

In recent years, there has been a significant increase in phytotherapy, which

The aim of our work is to make a complete toxicological study of Harmel, which is a plant widely used in traditional medicine in the Maghreb countries, but given its richness in toxic alkaloids of type β-carboline, it causes many accidents and

has led to several studies on traditional herbal treatments that have identified problems of toxicity or interaction that may cause therapeutic failures or

## **Chapter 11** Intoxication by Harmel

*Djafer Rachid*

## **Abstract**

Herbal medicine has taken a prominent place in the North African skincare system because of the increased installation of herbalists and healers, but unfortunately most of these do not have the required level to practice this medicine. The Harmel (*Peganum harmala* L.) belongs to the family Zygophyllaceae, which has 24 genera and 240 species. It is a herbaceous plant, perennial, glabrous, and bushy, from a height of 30–100 cm, with a thick rhizome, its strong, unpleasant odor reminiscent of that of the Rue (*Ruta graveolens*). The Harmel is a toxic plant widespread in North Africa which has an important place in traditional medicine in several indications. It is used as a sedative, antitussive, antipyretic, antirheumatic, and antihelminthic, and to treat some skin diseases. Harmel is ingested with a glass of water or mixed with honey or pounded with olive oil. The intoxications are mainly due to overdose; the absorption of a quantity of seed greater than a teaspoon causes hallucinations and vomiting. In France, Harmel as well as its compounds (Harmine, Harmaline, Harmol, and harmalol) have been classified among the astonishing substances. The clinical manifestations described in the literature include: digestive disorders, bradycardia; neurological disorders paralysis, central nervous system depression; renal disorders; and in severe cases, dyspnoea and hypothermia and hypotension.

**Keywords:** intoxication, Harmel, toxic plant, botanical study, toxicological analysis

## **1. Introduction**

North Africa has one of the oldest and richest traditions associated with the use of medicinal plants where they are very important to people in many places.

In recent years, there has been a significant increase in phytotherapy, which has led to several studies on traditional herbal treatments that have identified problems of toxicity or interaction that may cause therapeutic failures or accidents.

The aim of our work is to make a complete toxicological study of Harmel, which is a plant widely used in traditional medicine in the Maghreb countries, but given its richness in toxic alkaloids of type β-carboline, it causes many accidents and intoxications in humans and animals.

## **2. Botanical study**

## **2.1 Botanical description**

*Peganum harmala* L. belongs to the Zygophyllaceae family, which has 24 genera and 240 species. It is a herbaceous plant, which is perennial, hairless, bushy, and from a height 30–100 cm tall, with thick rhizome, and it has a strong, unpleasant smell reminiscent of that of the Rue and its bitter taste repels the animals [1–3].

The erect, very rowing stems disappear in winter. They have alternate leaves, divided into narrow strips that remain green for part of the dry season.

The solitary flowers with five elliptic, solitary petals are large (25–30 mm) and yellowish-white green (**Figure 1**). They are formed by small white flowers at the axils of the branches and a globose fruit containing several flattened seeds [3, 4].

The fruits are small spherical capsules with three chambers from 6 to 10 mm in diameter that stand straight on its stem and depressed at the top. Capsules contain more than 50 small triangular seeds [5].

The seeds, dark brown in color, are small and angular and have a diameter of 3–4 mm × 2 mm (**Figure 2**) [1].

The outer seed coats are cross-linked and have a bitter taste, with a particular smell, because they contain a red pigment called "Turkey red" and a

**Figure 1.** *Harmel flower [4].*

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in alkaloids [6].

**2.2 Botanical classification**

**Genre:** *Peganum*

**Arabic name:** Harmel

**3. Geographic distribution**

Turkestan to Tibet, and Siberia [7].

**4. Chemical composition**

**2.3 Appellations**

**Branch:** Spermatophytes **Sub-branch:** Angiosperms **Class:** Dicotyledonous **Subclass:** Rosidae **Order:** Sapindales **Family:** Zygophyllaceae

**Species:** *Peganum harmala* L. [3]

**Spanich name:** armalà, harmagà

**English name:** Harmel, syrian rue, African rue, wild rue **French name:** Harmel, rue syrienne, rue africaine

Harmel contains the following chemical compounds:

• Flavonoids: coumarin, tannins, sterols.

Roots contain 2% harmine and 1.4% harmol.

• Amino acids: phenylalanine, valine, histidine, glutamic acid

plant (3–4%): the leaf (0.52%) and the root or the stem (0.36%).

• Alkaloids (toxic principles): Harmane, harmine, harmaline, harmol [8, 9].

Their content increases in summer due to the maturity of the seed [10].

The alkaloids are more concentrated in the seeds than in the other parts of the

• Harmalin or Harmidine (3,4-dihydroharmine) or (7-methoxy-1-methyl-4,9 dihydro-3H-β-carboline) is of a general formula C13H14N2O. It is the main alkaloid of *Peganum harmala* and the first that was isolated by Göbel from seeds and roots. This compound is slightly soluble in water and alcohol, and quite soluble in hot alcohol and dilute acids. Harmalin is almost twice more toxic than harmine. It forms the 2/3 total toxic alkaloids of the seed [8].

*DOI: http://dx.doi.org/10.5772/intechopen.92936*

fluorescent compound. The harvest is done in summer because the seeds are rich

Harmel is a plant that grows spontaneously throughout the world, generally in the Mediterranean area, especially in the quite dry areas in Europe (Spain, Russia, and Hungary); in North Africa in the steppe and semi-arid regions (Eastern Morocco, Northern Sahara and Algerian highlands, Tunisia, Libya steppes, and deserts of Egypt); and in Asia, it is widespread in the steppes of Iran, Pakistan,

**Figure 2.** *Harmel seeds [4].*

fluorescent compound. The harvest is done in summer because the seeds are rich in alkaloids [6].

## **2.2 Botanical classification**

*Medical Toxicology*

**2. Botanical study**

**2.1 Botanical description**

more than 50 small triangular seeds [5].

3–4 mm × 2 mm (**Figure 2**) [1].

*Peganum harmala* L. belongs to the Zygophyllaceae family, which has 24 genera and 240 species. It is a herbaceous plant, which is perennial, hairless, bushy, and from a height 30–100 cm tall, with thick rhizome, and it has a strong, unpleasant smell reminiscent of that of the Rue and its bitter taste repels the animals [1–3]. The erect, very rowing stems disappear in winter. They have alternate leaves,

The solitary flowers with five elliptic, solitary petals are large (25–30 mm) and yellowish-white green (**Figure 1**). They are formed by small white flowers at the axils of the branches and a globose fruit containing several flattened seeds [3, 4]. The fruits are small spherical capsules with three chambers from 6 to 10 mm in diameter that stand straight on its stem and depressed at the top. Capsules contain

The seeds, dark brown in color, are small and angular and have a diameter of

The outer seed coats are cross-linked and have a bitter taste, with a particular smell, because they contain a red pigment called "Turkey red" and a

divided into narrow strips that remain green for part of the dry season.

**212**

**Figure 2.** *Harmel seeds [4].*

**Figure 1.** *Harmel flower [4].* **Branch:** Spermatophytes **Sub-branch:** Angiosperms **Class:** Dicotyledonous **Subclass:** Rosidae **Order:** Sapindales **Family:** Zygophyllaceae **Genre:** *Peganum* **Species:** *Peganum harmala* L. [3]

## **2.3 Appellations**

**Arabic name:** Harmel **English name:** Harmel, syrian rue, African rue, wild rue **French name:** Harmel, rue syrienne, rue africaine **Spanich name:** armalà, harmagà

## **3. Geographic distribution**

Harmel is a plant that grows spontaneously throughout the world, generally in the Mediterranean area, especially in the quite dry areas in Europe (Spain, Russia, and Hungary); in North Africa in the steppe and semi-arid regions (Eastern Morocco, Northern Sahara and Algerian highlands, Tunisia, Libya steppes, and deserts of Egypt); and in Asia, it is widespread in the steppes of Iran, Pakistan, Turkestan to Tibet, and Siberia [7].

## **4. Chemical composition**

Harmel contains the following chemical compounds:


The alkaloids are more concentrated in the seeds than in the other parts of the plant (3–4%): the leaf (0.52%) and the root or the stem (0.36%).

Their content increases in summer due to the maturity of the seed [10]. Roots contain 2% harmine and 1.4% harmol.

• Harmalin or Harmidine (3,4-dihydroharmine) or (7-methoxy-1-methyl-4,9 dihydro-3H-β-carboline) is of a general formula C13H14N2O. It is the main alkaloid of *Peganum harmala* and the first that was isolated by Göbel from seeds and roots. This compound is slightly soluble in water and alcohol, and quite soluble in hot alcohol and dilute acids. Harmalin is almost twice more toxic than harmine. It forms the 2/3 total toxic alkaloids of the seed [8].

• Harmane (1-methyl-9-pyrido [3,4-b]indole) is of a general formula C12H10N2. This alkaloid is crystallized in several organic solvents as colorless prisms. It is readily soluble in methanol, acetone, chloroform, or ether, but moderately soluble in hot water [8].

• Harmine or Banisterin (7-methoxy-1-methyl-9-pyrido[3,4-b]indole) is of a general formula C13H12N2O. It is slightly soluble in water, alcohol or ether.

Harmalol (1-methyl-4,9-dihydro-3H-β-carbolin-7-ol) is of a general formula

• C12H12N2O. It is an unstable alkaloid when exposed to air. It is crystallized in water as tri-hydrate. It is soluble in hot water, acetone, or chloroform, but poorly soluble in benzene [8].

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*DOI: http://dx.doi.org/10.5772/intechopen.92936*

**5. Traditional use of the plant**

blepharitis, and alopecia.

and rheumatism [11, 14].

and insomnia in children) [7].

mumps.

children [7].

traditional medicine to treat several disorders.

• Digestive disorders: colic and hemorrhoids.

Harmalicidine and tetrahydroharmine.

• Other β-carbolines isolated from the plant *Peganum harmala* are:

*Peganum harmala* L. is considered one of the most famous medicinal plants in

• Skin disorders: antiseptic and healing, dermatosis (eczema) and burning and

• General disorders: hypnotic, antipyretic, analgesic, and antitussive.

• Gynecologic disorders: emmenagogue and abortifacient agent [11, 12].

• Infectious disorders: neonatal tetanus, anthelmintic, antimalarial, and

• To treat certain nervous system disorders such as Parkinson's disease [13], in psychiatric conditions such as nervousness and insomnia in adults and

• Other diseases such as diabetes, high blood pressure, poisoning, snake venom,

• External use: the fresh plant either chopped and used in poultices, or after extraction of the juice for the composition of a liniment based on sheep fat, or use the dry plant or the seeds in the form of fumigations (to treat depression

*Medical Toxicology*

soluble in hot water [8].

• Harmane (1-methyl-9-pyrido [3,4-b]indole) is of a general formula C12H10N2. This alkaloid is crystallized in several organic solvents as colorless prisms. It is readily soluble in methanol, acetone, chloroform, or ether, but moderately

• Harmine or Banisterin (7-methoxy-1-methyl-9-pyrido[3,4-b]indole) is of a general formula C13H12N2O. It is slightly soluble in water, alcohol or ether.

Harmalol (1-methyl-4,9-dihydro-3H-β-carbolin-7-ol) is of a general formula C12H12N2O. It is an unstable alkaloid when exposed to air. It is crystallized in water as tri-hydrate. It is soluble in hot water, acetone, or chloroform, but

**214**

•

poorly soluble in benzene [8].

• Other β-carbolines isolated from the plant *Peganum harmala* are: Harmalicidine and tetrahydroharmine.

## **5. Traditional use of the plant**

*Peganum harmala* L. is considered one of the most famous medicinal plants in traditional medicine to treat several disorders.


Seed oils obtained by decoction of the seeds in olive oil are very effective (rheumatic diseases). The dried plants, or the seeds, are sprayed and sieved to give the powder of the Harmel and also the decoction of roots.

• Internal use: seeds—a tea spoon, about 2.5 g, swallowed directly with a glass of water or mixed with honey or crushed with olive oil, fresh plant chopped and boiled in oil, or dry leaves in decoction.

## **6. Pharmacodynamics**

## **6.1 Cardiovascular effects**

In vivo studies have shown that different extracts of *Peganum harmala* where its main active alkaloids, harmine, harmalin, harman, and harmalol, have different cardiovascular effects, such as bradycardia, decreased blood pressure, peak aortic flow and contractile strength of the heart and vasodilator, and antigenic inhibitory effects [15].

## **6.2 Effects on the nervous system**

Many in vitro and in vivo studies have indicated that alkaloids of *Peganum harmala* act on both the central and peripheral nervous system by inducing effects such as analgesia, hallucination, excitation, and antidepressant effect [16]. In addition, *Peganum harmala* β-carbolines have been shown to interact with dopamine, GABA, 5-hydroxytryptamine, benzodiazepines, and imidazoline at the level of their receptors present in the nervous system and in this way inducing their numerous psychotic pharmacological effects [17, 18].

## **6.3 Antibacterial, antifungal, insecticide, and antiparasitic**

Different studies have shown different pharmacological effects such as antiparasitic effect, antifungal, antibacterial [18], and insecticides effects [19] of alkaloids derived from *Peganum harmala* seeds.

## **6.4 Effects on the immune system**

*Peganum harmala* β-carbolines have been shown to have immunomodulatory effects in several studies [20]. Extracts of this plant have a significant anti-inflammatory effect via the inhibition of prostaglandin (mediator of inflammation).

## **6.5 Antidiabetic effects**

Harmine is the main alkaloid of *Peganum harmala* that is involved in the antidiabetic effect. One study showed that this compound regulates the expression of the receptor Peroxysomes Gamma Proliferator-Activated (PPARγ), the main regulator of adipogenesis and the molecular target of antidiabetic drugs, by inhibition of the signaling pathway [21]. Studies have indicated that harmel extract has no activity on insulin secretion, as this hypoglycemic activity is associated with the pancreas. It affects the use and/or absorption of glucose [22].

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*Intoxication by Harmel*

**6.6 Anticancer effects**

and in vivo [23].

**7. Toxicokinetic**

**7.1 Absorption**

**7.2 Distribution**

**7.3 Metabolism**

*DOI: http://dx.doi.org/10.5772/intechopen.92936*

based on seeds or all parts of the plant.

giving harmol and harmalol.

sulfoconjugation processes.

**8. Mechanism of toxic action**

account only about 0.6% of a dose [25].

the therapeutic or prophylaxis of magic [14, 24].

In vitro studies have demonstrated a decrease in cell viability of cancer cells from various brain, colon, breast, lung, liver, esophagus, and stomach tissues following harmine treatment. Several researchers have shown the cytotoxicity of different *Peganum harmala* extracts in tumor cell lines in vitro

The main way of administration is the oral way by ingestion of preparation

oil which will increase the penetration of alkaloids by the skin.

distribute throughout the body (heart, liver, kidneys, and lungs).

After ingestion, the alkaloids are well absorbed by the gastrointestinal tract. The dermal way is used as a poultice and ointments where the seeds are mixed with olive

Inhalation of alkaloids by fumigation is possible because this practice is used for

Alkaloids cross the blood-brain barrier to the central nervous system. They

• Phase I: alkaloids undergo hepatic O-demethylation by cytochrome P450 2D6,

• Phase II: the metabolites of the oxidation phase will undergo glycuro- and

• Phase III: β-carbolines alkaloids are excreted by bile and urine in conjugated form (glucuronates and sulfates); excretion of unchanged harmine should

Harmine reversibly inhibits monoamine oxidase A (MAO-A) and thus increases the central levels of amines such as noradrenaline (NA) and serotonin (5-HT) at the

brain level which may explain the antidepressant effect of the plant.

## **6.6 Anticancer effects**

*Medical Toxicology*

**6. Pharmacodynamics**

**6.1 Cardiovascular effects**

**6.2 Effects on the nervous system**

psychotic pharmacological effects [17, 18].

derived from *Peganum harmala* seeds.

**6.4 Effects on the immune system**

affects the use and/or absorption of glucose [22].

inflammation).

**6.5 Antidiabetic effects**

**6.3 Antibacterial, antifungal, insecticide, and antiparasitic**

effects [15].

Seed oils obtained by decoction of the seeds in olive oil are very effective (rheumatic diseases). The dried plants, or the seeds, are sprayed and sieved to give the

• Internal use: seeds—a tea spoon, about 2.5 g, swallowed directly with a glass of water or mixed with honey or crushed with olive oil, fresh plant chopped and

In vivo studies have shown that different extracts of *Peganum harmala* where its main active alkaloids, harmine, harmalin, harman, and harmalol, have different cardiovascular effects, such as bradycardia, decreased blood pressure, peak aortic flow and contractile strength of the heart and vasodilator, and antigenic inhibitory

Many in vitro and in vivo studies have indicated that alkaloids of *Peganum harmala* act on both the central and peripheral nervous system by inducing effects such as analgesia, hallucination, excitation, and antidepressant effect [16]. In addition, *Peganum harmala* β-carbolines have been shown to interact with dopamine, GABA, 5-hydroxytryptamine, benzodiazepines, and imidazoline at the level of their receptors present in the nervous system and in this way inducing their numerous

Different studies have shown different pharmacological effects such as antiparasitic effect, antifungal, antibacterial [18], and insecticides effects [19] of alkaloids

*Peganum harmala* β-carbolines have been shown to have immunomodulatory effects in several studies [20]. Extracts of this plant have a significant anti-inflammatory effect via the inhibition of prostaglandin (mediator of

Harmine is the main alkaloid of *Peganum harmala* that is involved in the antidiabetic effect. One study showed that this compound regulates the expression of the receptor Peroxysomes Gamma Proliferator-Activated (PPARγ), the main regulator of adipogenesis and the molecular target of antidiabetic drugs, by inhibition of the signaling pathway [21]. Studies have indicated that harmel extract has no activity on insulin secretion, as this hypoglycemic activity is associated with the pancreas. It

powder of the Harmel and also the decoction of roots.

boiled in oil, or dry leaves in decoction.

**216**

In vitro studies have demonstrated a decrease in cell viability of cancer cells from various brain, colon, breast, lung, liver, esophagus, and stomach tissues following harmine treatment. Several researchers have shown the cytotoxicity of different *Peganum harmala* extracts in tumor cell lines in vitro and in vivo [23].

## **7. Toxicokinetic**

## **7.1 Absorption**

The main way of administration is the oral way by ingestion of preparation based on seeds or all parts of the plant.

After ingestion, the alkaloids are well absorbed by the gastrointestinal tract. The dermal way is used as a poultice and ointments where the seeds are mixed with olive oil which will increase the penetration of alkaloids by the skin.

Inhalation of alkaloids by fumigation is possible because this practice is used for the therapeutic or prophylaxis of magic [14, 24].

## **7.2 Distribution**

Alkaloids cross the blood-brain barrier to the central nervous system. They distribute throughout the body (heart, liver, kidneys, and lungs).

## **7.3 Metabolism**

• Phase I: alkaloids undergo hepatic O-demethylation by cytochrome P450 2D6, giving harmol and harmalol.


## **8. Mechanism of toxic action**

Harmine reversibly inhibits monoamine oxidase A (MAO-A) and thus increases the central levels of amines such as noradrenaline (NA) and serotonin (5-HT) at the brain level which may explain the antidepressant effect of the plant.

Harmine is neurotoxic in vivo. Indeed, it has been shown that this injection is accompanied by tetany, convulsion movements or tremors, and these effects fade several minutes after injection [26].

All β-carbolines have in common an indole nucleus with a structural analogy to the serotonin molecule known for its important role in the functioning of the central nervous system. Harmalin and harmine are serotonin antagonists. It is likely that the hallucinogenic and behavioral modifying activity of these substances is related to this indolic structure [15].

Harmine and harmalin would exert a central anticholinergic action but at high doses can cause seizures and digestive manifestations, while harmane exerts an inhibitory action of the central dopaminergic system, inducing high-dose sedation and REM sleep disturbances [27–29].

The use of this plant for abortive purposes or to activate the term work is known. This abortive activity of harmel is due to these derivatives of quinazoline, which cause the contraction of the uterine muscle via induction of prostaglandin secretion [29].

## **9. Plants toxicity**

## **9.1 In animals**

Intoxication in animals is expressed by excitability, trembling, muscular rigidity, staggering gait, and jerky breathing. The animal is in an interrupted narcotic state with a short period of excitement. After a few hours, there is onset of dyspnea and mydriasis, hypothermia, and urinary disorders with abortion in case of gestation [24, 30].

• The aqueous seed extract has a myorelaxant effect on smooth rabbit and guinea pig muscles in vitro. These studies suggest that this extract has antispasmodic, antihistamine, and anti-adrenergic effects.

The laboratory animal studies have shown the following results [8]:


#### **9.2 In humans**

Clinical observations of acute intoxications by Harmel showed that Harmalin, at a dose of 4 mg/kg, would produce psycho-mimetic effects in humans [16].

Ingestion: 10–30 min after the ingestion of a teaspoon of seeds (2.5 g) appears the following clinical signs:


**219**

*Intoxication by Harmel*

• Obnubilation.

• Intense asthenia.

blood pressure occur.

hallucinations.

and hallucinations.

identification.

• Diffuse abdominal pain.

• Persistence of headaches.

*DOI: http://dx.doi.org/10.5772/intechopen.92936*

Seven hours after absorption, we note:

• Sharp and symmetrical osteotendinous reflexes.

These phases can change favorably in a few hours.

**10. Diagnosis of acute harmel intoxication**

by searching for debris and alkaloids.

**10.1 Botanical identification**

**10.2 Toxicological analysis**

• Harmane 0.70.

• Harmane 234, 287 and 347 nm.

• Harmine 241, 301 and 336 nm.

• Harmaline 218, 260 and 376 nm.

developer reagent, and calculate alkaloid Rfs:

In severe cases, paralysis, CNS depression, dyspnea and hypothermia, and low

Inhalation: 5 min after fumigation inhalation appears intoxication and visual

The diagnosis is based on the history and/or the appearance of nausea, vomiting,

Vomiting, spontaneous or induced, and gastric washing fluids are kept in clean pots that must be kept and sent to the laboratory to identify the plant with certainty

From gastric washing and/or from vomiting, recover debris (leaves, seeds, etc.).

Extract by chloroform in an alkaline medium to extract the alkaloids after drying under nitrogen, collect the residue by methanol and pass to the ultraviolet spectro-

Perform thin-layer chromatography with GF254 Silica Gel as stationary phase and elute with the mobile phase (ammonia 1.5 and methanol 100), use iodoplatinate

Send plant leaf, fruit, and seed samples used in the laboratory for plant

See the botanical description section and extract to search for alkaloids.

photometer [31] the maximum absorption in methanol:

Then, abdominal pain is accompanied by bilious vomiting. Four hours after ingestion the patient presents:

*Intoxication by Harmel DOI: http://dx.doi.org/10.5772/intechopen.92936*

• Obnubilation.

*Medical Toxicology*

several minutes after injection [26].

related to this indolic structure [15].

and REM sleep disturbances [27–29].

antihistamine, and anti-adrenergic effects.

**9. Plants toxicity**

**9.1 In animals**

**9.2 In humans**

the following clinical signs:

(flame vision).

Harmine is neurotoxic in vivo. Indeed, it has been shown that this injection is accompanied by tetany, convulsion movements or tremors, and these effects fade

All β-carbolines have in common an indole nucleus with a structural analogy to the serotonin molecule known for its important role in the functioning of the central nervous system. Harmalin and harmine are serotonin antagonists. It is likely that the hallucinogenic and behavioral modifying activity of these substances is

Harmine and harmalin would exert a central anticholinergic action but at high doses can cause seizures and digestive manifestations, while harmane exerts an inhibitory action of the central dopaminergic system, inducing high-dose sedation

The use of this plant for abortive purposes or to activate the term work is known. This abortive activity of harmel is due to these derivatives of quinazoline, which cause the contraction of the uterine muscle via induction of prostaglandin secretion [29].

Intoxication in animals is expressed by excitability, trembling, muscular rigidity, staggering gait, and jerky breathing. The animal is in an interrupted narcotic state with a short period of excitement. After a few hours, there is onset of dyspnea and mydriasis, hypothermia, and urinary disorders with abortion in case of gestation [24, 30].

• The aqueous seed extract has a myorelaxant effect on smooth rabbit and guinea pig muscles in vitro. These studies suggest that this extract has antispasmodic,

Clinical observations of acute intoxications by Harmel showed that Harmalin, at

Ingestion: 10–30 min after the ingestion of a teaspoon of seeds (2.5 g) appears

• Hypoacusia and amaurosis neurosensory disorders and visual hallucinations

The laboratory animal studies have shown the following results [8]:

a dose of 4 mg/kg, would produce psycho-mimetic effects in humans [16].

• Euphoria or intoxication, violent headache, and tingling extremities.

• Harmane: DL 50 in mice is 50 mg/kg intraperitoneally.

• Harmalin: lethal dose in rats is 120 mg/kg subcutaneously.

Then, abdominal pain is accompanied by bilious vomiting.

Four hours after ingestion the patient presents:

• Harmine: DL 50 in mice is 38 mg/kg intravenously.

**218**

• Sharp and symmetrical osteotendinous reflexes.

Seven hours after absorption, we note:


These phases can change favorably in a few hours.

In severe cases, paralysis, CNS depression, dyspnea and hypothermia, and low blood pressure occur.

Inhalation: 5 min after fumigation inhalation appears intoxication and visual hallucinations.

## **10. Diagnosis of acute harmel intoxication**

The diagnosis is based on the history and/or the appearance of nausea, vomiting, and hallucinations.

Vomiting, spontaneous or induced, and gastric washing fluids are kept in clean pots that must be kept and sent to the laboratory to identify the plant with certainty by searching for debris and alkaloids.

Send plant leaf, fruit, and seed samples used in the laboratory for plant identification.

## **10.1 Botanical identification**

From gastric washing and/or from vomiting, recover debris (leaves, seeds, etc.). See the botanical description section and extract to search for alkaloids.

#### **10.2 Toxicological analysis**

Extract by chloroform in an alkaline medium to extract the alkaloids after drying under nitrogen, collect the residue by methanol and pass to the ultraviolet spectrophotometer [31] the maximum absorption in methanol:


Perform thin-layer chromatography with GF254 Silica Gel as stationary phase and elute with the mobile phase (ammonia 1.5 and methanol 100), use iodoplatinate developer reagent, and calculate alkaloid Rfs:

• Harmane 0.70.


## **11. Treatment of acute intoxication**

There is no antidotic treatment for Harmel intoxication. In the event of a coma, the symptomatic treatment must be instituted as a matter of urgency in order to maintain the vital functions [32].

## **11.1 Evacuator and scrubber treatment**

Emergency gastric washing is used to remove parts of the plant that are not yet absorbed, and administration of activated charcoal is used to trap the rest of the plant. Induce osmotic diuresis is used in order to increase the renal elimination of alkaloids by perfusing hypertonic fluids (10% mannitol, 10% glucose serum). We need to monitor hemodynamic parameters.

## **11.2 Symptomatic treatment**

Hospitalization in intensive care of the intoxicated provides an early respiratory resuscitation by tracheal intubation and mechanical ventilation in case of coma. Cautious warming in case of hypothermia (cover the patient and then give him a hot drink) and administration of diazepam are performed to treat seizures.

## **12. Conclusion**

The injudicious taking of *Peganum harmala* causes clinical manifestations of intoxication; digestive disorders—bradycardia; neurological disorders—euphoria, hallucinations, generalized tremors, and even convulsive seizures; kidney disorders—uremia and anuria; and in severe cases, paralysis, central nervous system depression, dyspnea, as well as arterial hypotension.

Cases of poisoning by medicinal plants are very frequent and poorly known by the health services because the majority of victims do not come to the hospital for consultation. Today, African legislation is needed to regulate this profession of herbalists and herbalists.

## **Author details**

Djafer Rachid Department of Toxicology, Faculty of Medicine, University of Annaba, Algeria

\*Address all correspondence to: djafertox@yahoo.fr

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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2004:312-322

ISSN: 2153 733X

*DOI: http://dx.doi.org/10.5772/intechopen.92936*

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[17] Pennes HH, Hoch PH.

Psychiatry. 1957;**113**:887-892

Fitoterapia. 2010;**81**:779-782

[18] Nenaah G. Antibacterial and antifungal activities of (beta)-carboline alkaloids of *Peganum harmala* (L.) seeds and their combination effects.

[15] Aarons DH, Victor Rossi G,

[16] Frison G, Favretto D,

FAO; 2002. pp. 114-115

2009;**5**(31)

[2] Quezel P, Santa S. Nouvelle flore de l'Algérie et des régions désertiques méridionales. CNRS. 1963;**2**:59

[3] Ozenda P. Flore du Sahara. CNRS.

[4] Weckesser W. First record of *Peganum harmala* (Zygophyllaceae) in Val Verde County, Texas, and subsequent eradication treatment. Phytoneuron. 27 September 2013;**71**:1-5.

[5] Moloudizargari M, Mikaili P, Aghajanshakeri S, Asghari MH, Shayegh J. Pharmacological and therapeutic effects of *Peganum harmala* and its main alkaloids. Pharmacognosy

[6] Yahya M. A phytochemical studies of the plants used in traditional medicine of Saudi Arabia. Fitoterapia.

[7] Hammiche V, Merad R, Azzouz M. Plantes toxiques à usage médicinal du partour méditerranéen. Saint Etienne:

[8] Mahmoudian M, Jalipour H, Dardashti PS. Toxicity of *Peganum harmala*: Review and a case report. Iranian Journal of Pharmacology and

Therapeutics. 2002;**1**:1-4

[9] Lamchouri F, Settaf A,

2002;**60**:123-129

Cherrah Y, El Hamidi M, Tligui N, Lyoussi B, et al. Experimental toxicity of *Peganum harmala* seeds. Annales Pharmaceutiques Françaises.

[10] Ben Salah N, Amamou M, Jerbi Z, Ben Salah F, Yacoub M. One case of

Reviews. 2013;**7**(14):199

1986;**3**(52):179-182

Springer; 2013

## **References**

*Medical Toxicology*

• Harmine 0.68.

• Harmaline 0.38.

**11. Treatment of acute intoxication**

**11.1 Evacuator and scrubber treatment**

need to monitor hemodynamic parameters.

maintain the vital functions [32].

**11.2 Symptomatic treatment**

**220**

**Author details**

herbalists and herbalists.

**12. Conclusion**

Department of Toxicology, Faculty of Medicine, University of Annaba, Algeria

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

There is no antidotic treatment for Harmel intoxication. In the event of a coma, the symptomatic treatment must be instituted as a matter of urgency in order to

Emergency gastric washing is used to remove parts of the plant that are not yet absorbed, and administration of activated charcoal is used to trap the rest of the plant. Induce osmotic diuresis is used in order to increase the renal elimination of alkaloids by perfusing hypertonic fluids (10% mannitol, 10% glucose serum). We

Hospitalization in intensive care of the intoxicated provides an early respiratory resuscitation by tracheal intubation and mechanical ventilation in case of coma. Cautious warming in case of hypothermia (cover the patient and then give him a hot

The injudicious taking of *Peganum harmala* causes clinical manifestations of intoxication; digestive disorders—bradycardia; neurological disorders—euphoria, hallucinations, generalized tremors, and even convulsive seizures; kidney disorders—uremia and anuria; and in severe cases, paralysis, central nervous system

Cases of poisoning by medicinal plants are very frequent and poorly known by the health services because the majority of victims do not come to the hospital for consultation. Today, African legislation is needed to regulate this profession of

drink) and administration of diazepam are performed to treat seizures.

\*Address all correspondence to: djafertox@yahoo.fr

provided the original work is properly cited.

depression, dyspnea, as well as arterial hypotension.

Djafer Rachid

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[3] Ozenda P. Flore du Sahara. CNRS. 2004:312-322

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[5] Moloudizargari M, Mikaili P, Aghajanshakeri S, Asghari MH, Shayegh J. Pharmacological and therapeutic effects of *Peganum harmala* and its main alkaloids. Pharmacognosy Reviews. 2013;**7**(14):199

[6] Yahya M. A phytochemical studies of the plants used in traditional medicine of Saudi Arabia. Fitoterapia. 1986;**3**(52):179-182

[7] Hammiche V, Merad R, Azzouz M. Plantes toxiques à usage médicinal du partour méditerranéen. Saint Etienne: Springer; 2013

[8] Mahmoudian M, Jalipour H, Dardashti PS. Toxicity of *Peganum harmala*: Review and a case report. Iranian Journal of Pharmacology and Therapeutics. 2002;**1**:1-4

[9] Lamchouri F, Settaf A, Cherrah Y, El Hamidi M, Tligui N, Lyoussi B, et al. Experimental toxicity of *Peganum harmala* seeds. Annales Pharmaceutiques Françaises. 2002;**60**:123-129

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**223**

Section 4

Interaction in Clinics

Section 4
