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Review

Human Poisoning from Poisonous Higher Fungi: Focus on Analytical Toxicology and Case Reports in Forensic Toxicology

1
Laboratory LAT LUMTOX, 07800 La Voulte sur Rhône, France
2
Laboratory of Pharmacology and Toxicology, Lyon-Sud University Hospital–Hospices Civil de Lyon, 69002 Pierre Bénite, France
3
Department of Toxicology, Faculty of Pharmacy, University Claude Bernard, 69622 Lyon, France
4
Department of Toxicology and Genopathy, Lille University Hospital, 59000 Lille, France
*
Author to whom correspondence should be addressed.
Pharmaceuticals 2020, 13(12), 454; https://doi.org/10.3390/ph13120454
Submission received: 14 November 2020 / Revised: 3 December 2020 / Accepted: 9 December 2020 / Published: 11 December 2020
(This article belongs to the Special Issue Clinical and Forensic Toxicology: The Latest Updates)

Abstract

:
Several families of higher fungi contain mycotoxins that cause serious or even fatal poisoning when consumed by humans. The aim of this review is to inventory, from an analytical point of view, poisoning cases linked with certain significantly toxic mycotoxins: orellanine, α- and β-amanitin, muscarine, ibotenic acid and muscimol, and gyromitrin. Clinicians are calling for the cases to be documented by toxicological analysis. This document is therefore a review of poisoning cases involving these mycotoxins reported in the literature and carries out an inventory of the analytical techniques available for their identification and quantification. It seems indeed that these poisonings are only rarely documented by toxicological analysis, due mainly to a lack of analytical methods in biological matrices. There are many reasons for this issue: the numerous varieties of mushroom involved, mycotoxins with different chemical structures, a lack of knowledge about distribution and metabolism. To sum up, we are faced with (i) obstacles to the documentation and interpretation of fatal (or non-fatal) poisoning cases and (ii) a real need for analytical methods of identifying and quantifying these mycotoxins (and their metabolites) in biological matrices.

1. Introduction

There is an extremely diverse range of fungi about which little is known. One million five hundred thousand species were known in 2002, 5.1 million in 2005, and the figure reached 13.5 million species in 2018. In reality, the exact number of fungal species on Earth is as yet unknown, since we are only aware of a tiny proportion of this diversity, of which only 100,000 species have been described [1]. Among these, there are about 5000 species of so-called higher fungi [2], those where the sporophore (the reproductive organ in fungi) is visible to the naked eye. Of these, a few dozen species of mushroom [1] contain mycotoxins, which, when ingested, could cause poisoning of varying degrees of severity and may even result in death. These poisonings can be classified according to 14 specific syndromes, some more serious than others: acromelalgic, cerebellar, coprinic, digestive (and resinoid), encephalopathy, gyromitrin, muscarinic, orellanus, pantherina, paxillus, phalloidin, proximien, psilocybin (or narcotic), and rhabdomyolysis syndrome [3,4]. In 2019, White et al. proposed a new classification of mycotoxic syndromes based on the main clinical signs rather than toxins. The new classification is made up of six groups (1. cytotoxic damage, 2. neurological damage, 3. muscular damage, 4. metabolic damage, 5. gastrointestinal irritation, and 6. other signs) divided into several subgroups [5]. Several case reports have shown that poisonings are mostly seasonal, between August and November, the period when mushrooms grow given the favorable climate [6]. In France, an average of 1300 poisoning cases per year was reported between 2010 and 2017 [6]. These poisonings are almost never documented by toxicological analysis, the cause of poisoning is mainly based on clinical signs and case history [7,8,9], since there are so few analytical methods for identifying the toxins described in the biological matrices [10,11]. There are many reasons: the numerous varieties of mushroom involved, mycotoxins with different chemical structures, a lack of knowledge about distribution and metabolism. The lack of analytical methods for identifying and quantifying these mycotoxins and their metabolites in the biological matrices is therefore an obstacle to knowledge and interpretation of cases of fatal and non-fatal poisoning. The main mycotoxins suspected in the most serious cases are as follows: orellanine, α- and β-amanitin, muscarine, muscimol, ibotenic acid, and gyromitrin. The aim of this work is to carry out a review of the literature, from an analytical point of view, of reported poisoning cases that involve these compounds, and to establish an inventory of the analytical techniques available for identifying and quantifying these mycotoxins.

2. Method

We performed a systematic review of the medical literature in order to identify manuscripts of interest. As the research was restricted to the forensic interest, our search strategies used a combination of standardized terms related to forensic situations (e.g., postmortem, intoxication, and poisoning) and key words that were implemented in NCBI PubMed (1900–present) and Google Scholar (1900–present). In order to reduce the number of results, the word “mushroom” was used as constant keyword. The used keywords were (number of identified articles): “orellanine” (50), “amanitins” (288), “ibotenic acid” (33), “muscimol” (44), “muscarine” (35), “gyromitrin” (27), “poisoning” (1906), and “intoxication” (266). Publications that were not found in the literature search but cited in retrieved publications were also considered. Overall, 256 cases reports were identified for orellanine, 800 for amanitins, 82 for ibotenic acid/muscimol/muscarine and at least 950 cases for gyromitrin. Focusing on the analytical concern, as we were interested in articles on identification and/or quantification of these mycotoxins in fungi or in human or animal biological matrices: additional key words were used in this way (e.g., chromatography, identification, quantification, etc.). All in all, 15 technical publications were selected for orellanine, 33 for the amanitins, 15 for ibotenic acid/muscimol, 8 for muscarine, and 7 for gyromitrin. Every reported concentrations data have been converted to international system units.

3. Orellanine

3.1. Toxic Compounds

Orellanine (C10H8N2O6, M = 252.2) was first identified in 1957 by Grzymala after a mass poisoning in Poland resulting in 19 deaths [12]. It was isolated in 1962 [13]. Orellanine is a bipyridine N-oxide (2,2′-bipyridine-3,3′,4,4′-tetrahydroxy-1,1′-dioxide) [14]. It is very polar (logP = −1.19) [15] and stable in the mushroom. However, it is photosensitive: once extracted, it is reduced by mono-hydroxylation to orellinine (C10H8N2O5, M = 236.2), which has the same toxic properties as orellanine, then by bi-dehydroxylation to orelline (non-toxic) [16] (Figure 1). Orellanine is not thermosensitive: cooking the mushrooms does not reduce their toxicity [16]. To the best of our knowledge, no metabolism data regarding orellanine has been reported in any publication.

3.2. Toxic Mechanism and Toxicity in Humans and/or Animals

The toxicity of orellanine lies in its strong nephrotic properties leading to acute renal failure (group 1C in the White et al. classification [5]). Its toxic mechanism has not been precisely established yet. However, Richard and his team have shown that orellanine is responsible for the inhibition of proteins in the cytoplasm and mitochondria of renal cells after tests on Madin–Darby canine renal cells [17]. Other hypotheses have been advanced such as the inhibition of DNA and RNA in the renal cells, glutathione depletion, or inhibition of mitochondrial adenosine triphosphate production [16,18].
There is high variability in clinical outcomes in the case of poisoning: the evolution can be spontaneously favorable or can deteriorate into chronic renal failure, requiring a kidney transplant [19]. There is no antidote for orellanine; treatment is symptomatic (hemodialysis, N-acetylcysteine, and steroids) [7,19,20]. Several studies in mice show that the oral median lethal dose (LD50) is between 30 and 90 mg/kg [21,22]. However, humans have been shown to be far more sensitive than mice to this mycotoxin. In practice, the ingestion of 6 mushrooms can lead to acute renal failure requiring dialysis [23].

3.3. Toxic Species

Orellanine is the main toxin found in mushrooms of the genus Cortinarius of the family Cortinariaceae. The most frequently reported in poisoning cases are C. orellanus [24,25] (Figure 2) and C. speciosissimus [7,19]. Some cases also mention C. orellanosus [23], C. armillatus [26], and C. eartoxicus [27]. The toxicity of C. splendens [28] is still in doubt. These species are mainly found in Europe and North America. Some cases of poisoning in Australia have also been reported [27,29].

3.4. Description of the Syndrome

Orellanine causes orellanus syndrome, which is characterized by a long latency period: between 2–4 and 14 days after ingestion [16]. To date, there is no scientific explanation for this exceptionally long latency period. The fact remains that this sometimes makes it difficult to link the ingestion with the clinical phase of poisoning. The first symptoms to appear are usually nausea, vomiting, diarrhea, stomach pains, extreme thirst, headaches, anuria, or polyuria depending on the case (cf. Table 1). These symptoms are followed by renal impairment necessitating transplantation. If left untreated, the patient may die of acute renal failure.

3.5. Human Poisoning Cases Reported

Many cases of orellanine poisoning have been reported in the literature since 1957. A number of them are listed nonexhaustively in Table 1. These cases include 27 reported deaths and 17 kidney transplants in people aged 14 and 60. Most poisonings are unintentional, sometimes by confusion with hallucinogenic mushrooms [29,31]. One case reports voluntary consumption of Cortinarius orellanus by a psychiatric patient [24]. Due to its long latency period, many patients consume mushrooms several times, sometimes a few days after the first meal [7,32,33]. The majority of patients have a serum creatinine over the physiological range at the arrival to the hospital. Those with a higher level underwent a renal transplantation.

3.6. Analytical Aspect

Research began in the late 1970s to develop a quick, sensitive, and reliable analytical method for identifying and quantifying orellanine in mushrooms as a first step, then in biological matrices such as blood, urine, or organs (cf. Table 2). Many methods are based on the thin layer chromatography, only one is based on the gas chromatography. Most recent methods consist of a liquid chromatography coupled with tandem mass spectrometry.
Many poisoning cases in the biological matrices documented by research for orellanine have revealed the absence of orellanine in urine, plasma, and dialysis fluids between 2 and 25 days after the ingestion of mushrooms [41]. However, Rapior et al. using thin layer chromatography coupled with spectrofluorometry, reported a concentration of 6.12 mg/L in plasma 10 days after the ingestion of mushrooms [24]. Orellanine has also been quantified several times in renal biopsies with concentrations between 35 and 3000 mg/L up to 180 days after poisoning [24,41].

4. α- and β-Amanitin

4.1. Toxic Compounds

Since the 1790s (Paulet’s research into the toxins of Amanita phalloides, 1793–1808) [57], researchers have taken an interest in the compounds responsible for the toxicity of A. phalloides. After the identification of other compounds contained in these mushrooms (e.g., phalloidin), Wieland et al. first isolated an amanitin in 1941 (which they later named α-amanitin) then 8 other amatoxins were isolated and their structure described (β-amanitin, γ-amanitin, ε-amanitin, amanin, amanullin, amaninamide, amanullinic acid, and proamanullin) [57]. The main toxins of certain mushrooms in this family are α-amanitin and β-amanitin. α-amanitin (C39H54N10O14S, M = 918.9) and β-amanitin (C39H53N9O15S, M = 919.9) are bicyclic octapeptides (Figure 3).
The amatoxins are not thermosensitive, which means they cannot be destroyed by either cooking or freezing the mushrooms [58]. Moreover, they are gastroresistant [58] and their metabolism is currently unknown.

4.2. Toxic Mechanism and Toxicity in Humans and/or Animals

In the new classification, the amatoxins are classified in the cytotoxic group (1A) [5] as they are responsible for inhibiting RNA polymerase II and the transcription of DNA into RNA by interfering with messenger RNA. This brings about inhibition of protein synthesis, which leads to cell necrosis. The first cells to be affected are those with a high rate of protein synthesis such as enterocytes, hepatocytes and proximal renal cells [59]. Studies in mice show that renal lesions only occur in poisoning with low levels of amatoxins. In poisoning cases with high levels, the subject die due to acute liver failure or hypoglycemia before the renal lesions appear [60,61]. Amatoxins are mainly eliminated in the bile, but there is an enterohepatic cycle, which prolongs the hepatoxic action [62].
Several studies show that the LD50 of α-amanitin in humans is estimated to be 0.1 mg/kg per os [63]. Bearing in mind that a sporophore of Amanita phalloides (20–25 g) can contain 5–8 mg of amatoxins [64], the ingestion of one A. phalloides mushroom is theoretically a lethal dose for a 75 kg man. The same order of magnitude is found in mice in a study published by Wieland in 1959 [57] (LD50 = 0.1 mg/kg for α-amanitin and 0.4 mg/kg for β-amanitin by intraperitoneal injection). Finally, it has been shown that the concentration of amatoxins in the mushroom increases during the first stages of the mushroom’s development, then decreases during the mature stage [65].
As with orellanine, no specific antidote exists for the amanitins. Treatment is symptomatic (dialysis, activated charcoal hemoperfusion, glucose/saline perfusion, etc.) [66,67]. Only kidney or liver transplantation (depending on the symptoms) can save a patient with multiple organ failure [67,68]. Some authors propose treatments such as thioctic acid (alpha lipoic acid) [69,70], penicillin G [71], or silibinin [72,73], which may be capable of limiting, if not inhibiting, the amatoxins’ penetration into the liver cells and/or interrupting the enterohepatic cycle of the toxins [74]. However, these treatments have not really been clinically proven and there is no evidence to support the use of penicillin G or of thioctic acid. They are therefore not considered as part of the protocol for treatment of amanitin poisoning.
In view of all the cases of amanitin poisoning reported in the literature, it seems clear that infants and small children are more sensitive to these mycotoxins than adults, probably because of their lower body mass: the same dose of toxins ingested will be more toxic and the percentage of fatalities will be higher in young subjects.

4.3. Toxic Species

The amatoxins are the compounds responsible for the toxicity of Amanita phalloides [57] (Figure 4) also known as “death cap” in English-speaking countries [58], and without doubt the most well-known poisonous mushroom in the world. Probably all members of section Phalloideae contain potentially lethal levels of amanitins. These mycotoxins are also found in other species such as A. verna [75] and A. virosa [62], A. bisporigera [76], and A. ocreata [77]. Other genera contain amatoxins including Galerina (G. marginata and G. autumnalis) and Lepiota (L. brunneoincarnata and L. helveola) within the main species of concern [78].
Amatoxin-containing mushroom species have been worldwide identified (Northern, Central, and Western Europe, North and South America, South-East Asia, and Northern and Southern Africa) [58].
It should be noted that Amanita phalloides contains two other groups of toxins: phallotoxins and virotoxins [58]. These two families of cyclic peptides are only toxic by parenteral administration as they are hardly (or not at all) absorbed by the gastrointestinal tract [58]. They are therefore not usually taken into consideration in Amanita phalloides poisoning.

4.4. Description of the Syndrome

The amatoxins are responsible for phalloidin syndrome, which, like orellanus syndrome, is characterized by a long latency period (between 6 and 24 h) after ingestion of the mushroom [58]. First occurring symptoms are gastrointestinal (nausea, vomiting, diarrhea, and stomach pains) over a period of about 24 h. The second stage is a period of remission, usually lasting 24–36 h. During this period, the serum activity levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) rise progressively, showing liver damage. The third stage is characterized by renal and hepatic impairment, which could result in hepatic encephalopathy, convulsions, coma and death (4–7 days after ingestion of mushrooms) [74]. Death by amatoxin poisoning is most often caused by liver, or kidney failure, or sometimes both (cf. Table 3).

4.5. Human Poisoning Cases Reported

Given the large number of mushroom species containing amanitins throughout the world, a great number of amatoxin poisoning cases have been reported in the literature since the beginning of the last century (Table 3). Of these recorded poisonings, 72 deaths and 33 liver transplants are listed. Five of the deaths occurred up to several months after liver transplantation. This suggests persistent toxicity capable of damaging the graft. One case is unusual, the patient ate 2 caps of Amanita phalloides only in order to test the toxicity [114].
The result is fatal in 10–30% of cases [58], with the percentage tending to decrease mainly due to liver transplantation.

4.6. Analytical Aspect

Research began in the mid-1970s to develop a sensitive and reliable analytical method for identifying and quantifying α- and β-amanitin through radioimmunological techniques, thin layer chromatography or liquid chromatography-UV detection. Technological developments over the years have enabled researchers to reach better and better sensitivity levels using high-resolution mass detectors (cf. Table 4).
Testing for amanitins in various biological samples in a known case of amatoxin poisoning has revealed the elimination kinetics of these compounds. It is possible to find amanitins in blood (plasma or serum) up to 36–48 h after ingestion [61,90,151] in concentrations varying from 10 to 200 µg/L [91] and in urine up to 96 h after ingestion [89,151]. The urine concentrations range from 1 to 7100 µg/L, with a peak between 24 and 72 h [90,140,151].
Jaeger et al. have shown that it is also possible to find high concentrations of α- and β-amanitin in gastroduodenal fluid and feces (between 208 and 4950 µg/L in gastroduodenal fluid and between 23 and 14900 µg/L in feces) [90].
The amanitins have hepatic and renal tropism. As a consequence, it should be of interest to assay them in these matrices. Jaeger et al. reported concentrations of 10–3298 µg/L found in the liver and kidney samples (from autopsy or biopsy) of poisoned subjects [90].
There is an immunological technique for assaying alpha and gamma amanitins (but not beta amanitin) in urine available as a kit (BÜHLMANN ELISA kit). Its limit of detection is 0.22 µg/L with a limit of quantification of 1.5 µg/L [152].

5. Muscarine

5.1. Toxic Compounds

The first attempt to isolate muscarine, which was considered the main active substance in Amanita muscaria [153], dates back to the early 1810s with Braconnot and Schrader. At that time several researchers had tried in vain to isolate this psychoactive compound. It was not until 1869 that Schmiedeberg and Koppe believed they had isolated the substance and called it muscarine. The substance they isolated proved to be a mixture of muscarine and choline. Pure muscarine was actually isolated for the first time by King in 1922 [154]. The structure of muscarine was proposed in 1957 by Kögl et al. [155]: C9H20NO2+, M = 174.3 (Figure 5). Muscarine (tetrahydro-4-hydroxy-N,N,N-5-tetramethyl-2-furanmethanaminium) is a water-soluble thermostable alkaloid [154]. To the best of our knowledge, no studies or metabolism data have been published about this mycotoxin.

5.2. Toxic Mechanism and Toxicity in Humans and/or Animals

Muscarine is an agonist for the neurotransmitter acetylcholine; it activates muscarinic acetylcholine receptors and thereby activates the parasympathetic nervous system [155]. Due to its positively charged quaternary amine group, muscarine does not cross the blood–brain barrier and therefore does not reach the central nervous system. This mechanism of action puts it in group 2B of the White et al. classification [5] (neurotoxic molecules that do not reach the central nervous system). Unlike many mycotoxins, there is an antidote to muscarine: atropine. Administered intravenously, atropine counters the toxic cardiac effects of muscarine [156]. Muscarine poisoning must be proven (for example by identifying the mushroom species ingested) before administering atropine, since atropine can exacerbate some symptoms if administered in error (see ibotenic acid and muscimol, below).
The toxic effects of muscarine vary according to the amount ingested. Muscarine poisoning is rarely fatal; patients with pre-existing cardiac disorders will be more sensitive. The symptomatology usually resolves after a few hours. In cases where the patient is severely dehydrated, compensation for fluid and electrolyte loss should be considered [2].
Toxicity studies show the i.v. LD50 of muscarine in mice is 0.23 mg/kg [157,158]. No numerical data for humans have been published.
No mechanism or preferential route of elimination of muscarine from the organism has been described in the literature.

5.3. Toxic Species

Muscarine is actively present in several mushroom families: around 40 Inocybes of the family Inocybaceae (I. erubescens, I. subdestricta, I. fastigiata, I. geophilla, etc.), around 15 Clytocybes (Figure 6) of the family Tricholomataceae (C. cerussata, C. dealbata, C. rivulosa, C. phylophilla, etc.) [156]. It is also found in the genus Amanita (A. muscaria and A. pantherina) but in minute quantities [159], which makes its toxic action insignificant compared with these mushrooms’ other active compounds. Amanita muscaria takes its name from muscarine since, as explained above, muscarine was isolated from this species. However, the fly agaric only contains 0.0002–0.0003% of muscarine [153,159,160]. By comparison, I. subdestricta contains 0.43% and C. dealbata 0.15% [153].
Due to the great diversity of mushrooms containing muscarine, the toxin has been identified on every continent.

5.4. Description of the Syndrome

The syndrome associated with muscarine is called muscarinic syndrome. It has a short latency period (<6 h) as the first symptoms appear between 15 min and 2 h after ingestion [156]. The main clinical signs of muscarine poisoning are gastrointestinal distress (nausea, vomiting, diarrhea, and stomach pains), extreme sweating, bronchial, salivary and ocular hypersecretion, and blurred vision. Observed bradycardia, hypotension, and miosis are the direct consequences of acetylcholine receptors activation. In the most severe cases muscarine can cause myoclonus, convulsions, and loss of consciousness that may lead to coma and the death of the patient (cf. Table 5).

5.5. Human Poisoning Cases Reported

Case reports about muscarine poisoning are relatively rare. Table 5 shows published cases of muscarine poisoning. A fatal outcome was observed in three cases: an 11-year-old child [174], a 67-year-old woman presenting comorbidities (diabetes, arterial hypertension, and respiratory insufficiency) [172], and a 53-year-old woman with no particular medical history [170]. The other cases present a positive outcome.

5.6. Analytical Aspect

Since muscarine was isolated in 1922 [154], few analytical techniques have been published for identifying and quantifying the compound in different matrices. The first published techniques used thin layer chromatography or gas chromatography with mass detection for qualitative and/or quantitative analysis of muscarine in mushrooms. The technological advances of the early 21st century have enabled considerably greater sensitivity with liquid chromatography techniques coupled to tandem mass spectrometry. With these techniques it is now possible to quantify muscarine in biological matrices such as urine (Table 6).
To the best of our knowledge, no research on muscarine in blood or any other biological matrix has been published. Only one publication mentions a numerical value for muscarine in urine: 0.045 mg/L of muscarine was found in the urine of a 55-year-old suspected of having ingested A. muscaria [155].

6. Ibotenic Acid, Muscimol

6.1. Toxic Compounds

Ibotenic acid or α-amino-3-hydroxy-5-isoxazoleacetic acid (C5H6N2O4, M = 158.1) is an alkaloid, which is degraded by decarboxylation into muscimol (3-hydroxy-5-aminomethylisoxazole, C4H6N2O2, M = 114.1; Figure 7 and Figure 8). These compounds, isolated and described in the 1960s by a Japanese team, are thermostable [153] but the dehydration of ibotenic acid leads to the formation of muscimol by decarboxylation [183]. It would therefore be logical to consider the toxicity of cooked A. muscaria and A. pantherina mushrooms to be mainly attributable to muscimol. These two mycotoxins are the major factors in poisoning, but other toxins have also been identified in the mushrooms, including muscarine, in very low quantities, and muscazone, a structural isomer of ibotenic acid with less potent psychoactive properties than muscimol or ibotenic acid [153,183].
DeFeudis [160] states that muscimol is metabolized quickly after ingestion, and that consequently, its toxicity is shared with its psychoactive metabolites. However, no concrete metabolic study has been published about muscimol or ibotenic acid.

6.2. Toxic Mechanism and Toxicity in Humans and/or Animals

Ibotenic acid and muscimol are isoxazoles derived from glutamic acid and γ-aminobutyric acid (GABA) respectively [183]. Ibotenic acid and muscimol can cross the blood–brain barrier and thus act on the central nervous system [184], which puts them in group 2C of the White et al. classification [5] (neurotoxic molecules that reach the central nervous system). Ibotenic acid is a glutamate neurotransmitter agonist, a powerful neuronal excitant. It acts on the glutamic acid receptors associated with memory and learning. Muscimol is a γ-aminobutyric acid (GABA) agonist. It acts on the GABA receptors with a depressant effect and therefore causes related toxic effects such as visual distortions/hallucinations, loss of balance, slight muscle contractions, and altered sensory perceptions [153,183]. These two alkaloids are preferentially eliminated in urine [153,183]. Ibotenic acid and muscimol can be detected in urine one hour after mushroom ingestion [153].
Fatal poisoning by ibotenic acid and muscimol is very rare [153]. There is no antidote; the only treatment is symptomatic. Hospitalization for neurological surveillance is recommended [156]. In some cases it is necessary to sedate the patient to manage excessive agitation [9,162]. Atropine is to be avoided as it has a similar action to ibotenic acid and muscimol.
Ibotenic acid and muscimol are lethal in very high doses. The LD50 in rats is 129 mg/kg for ibotenic acid and 45 mg/kg for muscimol [158,185,186]. Stebelska [185] refers to a study of the toxicity of isoxazoles on mammals: the oral LD50 for muscimol is 10 mg/kg in rabbits and the oral LD50 for ibotenic acid is 38 mg/kg in mice. As with muscarine, no data for humans have yet been published.
A sporophore of Amanita muscaria can contain between 292 and 6570 µg/g of ibotenic acid and between 73 and 2440 µg/g of muscimol [187]. Given the average weight of 60 g and the minimal dose to produce psychotropic effects of 30–60 mg of ibotenic acid and around 6–10 mg of muscimol, a single mushroom is enough to experience hallucinogenic effects [185]. Some studies have shown that the intensity of the effects varies according to which part of the mushroom is consumed. Indeed, the cap of the mushroom has a higher concentration of psychoactive substances than the stem [188,189].

6.3. Toxic Species

Ibotenic acid and muscimol are mainly found in Amanita muscaria (Figure 9) and Amanita pantherina mushrooms, which belong to the genus Amanita of the family Amanitaceae. Virtually all mushrooms in genus Amanita contain high levels of muscimol and ibotenic acid. A. muscaria is undoubtedly the most iconic mushroom in the world, represented in illustrations, cartoons, etc., due to its bright colors and white spotted cap. These mushrooms have been identified in the United States, sub-Saharan Africa (South Africa, Zimbabwe) Japan, and Europe (cf. Table 5).
The possession, purchase, and sale of ibotenic acid and muscimol are not regulated in France. However, the possession, purchase, and sale of Amanita muscaria are illegal in the Netherlands [191], the state of Louisiana in the USA, the UK [192], and Romania [192]. In Thailand hallucinogenic mushrooms are classified as class V narcotics and are therefore illegal [193]. In Japan these two mushroom species are sold openly as dried mushrooms or dried mushroom “powder” on the internet and in “smoke shops” [186].

6.4. Description of the Syndrome

The syndrome produced by consuming mushrooms containing ibotenic acid and muscimol is called pantherina syndrome (or myco-atropine syndrome) [156]. The syndrome is characterized by a short latency period (30 min to 3 h) [156]. The first perceptible effects after ingestion are mainly nausea, vomiting, and diarrhea, followed by characteristic symptoms of central nervous system dysfunction (confusion, dizziness, myoclonus, visual and auditory hypersensitivity, and distortion of time and space) accompanied by mydriasis, fatigue, and drowsiness (cf. Table 5). The phenomenon of hallucinations has been discussed. After 2 h the subject presents altered states of consciousness lasting approximately 8 h [153].
Pantherina syndrome is sometimes confused with drunkenness.

6.5. Human Poisoning Cases Reported

The consumption of Amanita muscaria is connected with mysticism since the mushroom’s psychotropic properties have been known and prized for several thousand years. A. muscaria was traditionally used in religious, spiritual, or shamanic rituals by some tribes in Northern Europe and Northern Asia (Siberian shamans of tribes such as the Ostyak, Vogul, Kamchadal, Koryak, and Chukchi) [153]. The “Rig Veda”, the ancient Hindu text considered one of the world’s great religious works (composition estimated between 1500 and 900 BC) [194], advocates “Soma”. The term Soma has several meanings in Hindu mythology: a ritual drink, the plant (or the mushroom), and the god. Several hypotheses argue that Soma was extracted from Amanita muscaria [195,196]. In his book “Amanita muscaria; Herb of Immortality” Teeter considers the fly agaric to be at the centre of all religions and beliefs [197]. Theories about A. muscaria as soma have been very thoroughly debunked [198].
A. muscaria or A. pantherina poisonings can happen accidentally, through confusion with an edible mushroom species or ignorance of the fungi kingdom. However, a large proportion of these poisonings are from voluntary recreational consumption from those seeking psychotropic effects. Table 5 lists some examples. Only one case of death of a 55-year-old man attributed to an Amanita muscaria poisoning was reported [155]. Unfortunately, in this case, only muscarine in urine was quantified, neither ibotenic acid nor muscimol.

6.6. Analytical Aspect

Analytical techniques have been developed since the early 1980s with the aim of identifying and quantifying the principal mycotoxins responsible for pantherina syndrome. Liquid chromatography is the most widely used technique. It was not until the late 2000s that researchers considered the detection of isoxazoles in biological matrices (urine and serum; Table 7).
Some poisoning cases have been documented where patients’ biological samples were investigated for ibotenic acid and muscimol. Stříbrný et al. [176] reported varying concentrations of ibotenic acid between 32 and 55 mg/L, and of muscimol between 6 and 10 mg/L in urine (3–8 h after ingestion). Hasegawa et al. [177] reported concentrations of 96 µg/L of ibotenic acid and 101 µg/L of muscimol in the serum of a subject poisoned by A. ibotengutake (without specifying the period between ingestion and sampling).

7. Gyromitrin

7.1. Toxic Compounds

In 1885, Boehm and Külz isolated an oily substance from the false morel, which they believed to be the substance responsible for the mushroom’s toxicity. More advanced studies have shown that it is actually a mixture of non-toxic organic acids. Gyromitrin was finally isolated, synthesized and definitively identified in 1968 by List and Luft as acetaldehyde N-methyl-N-formylhydrazone or gyromitrin (C4H8N2O, M = 100.1) [206,207,208]. The hydrolytic cleavage of gyromitrin (Figure 10) leads to the formation of N-methyl-N-formylhydrazine and then methylhydrazine (or monomethylhydrazine, MMH) [209,210], which is used in astronautics as a rocket propellant [209]. Gyromitrin belongs to the hydrazine family and is volatile, thermosensitive, and very soluble in water [207]. This mycotoxin can be partially eliminated by drying or boiling the mushroom. Pyysalo [211] has shown that these measures can reduce the quantity of gyromitrin originally contained in the mushroom by up to 99–100%.

7.2. Toxic Mechanism and Toxicity in Humans and/or Animals

Gyromitrin is classed as a GABA-inhibiting mycotoxin, group 4A in the White et al. classification [5]. Its mechanism of toxic action is connected with the production of MMH. MMH interacts with pyridoxine dependent coenzymes, resulting in inhibition of glutamic acid decarboxylase and thus reduced GABA production, causing the neurological symptoms to occur. MMH can also cause methemoglobinemia [207,212]. In addition, MMH produces radical species that lead secondarily to hepatic cytolysis [207].
N-methyl-N-formylhydrazone and methylhydrazine are known to be hepatotoxic through the mechanism of producing radical species, but they are also known to be carcinogenic in animals [209,213].
Several studies have been conducted on animals to determine the lethal dose of 50% for gyromitrin and MMH. Patocka et al. [209] reported an oral LD50 for gyromitrin of 344 mg/kg in mice, 320 mg/kg in rats, 50–70 mg/kg in rabbits, and a resistance of over 400 mg/kg in chickens. In humans, the oral LD50 is estimated at 20–50 mg/kg in adults and 10–30 mg/kg in children [207]. Studies of the lethal dose of monomethylhydrazine have also been published, reporting a dose of 4.8–8 mg/kg in adults and 1.6–4.8 mg/kg in children [212]. Pyysalo et al. reported a concentration of 50 mg of gyromitrin/kg in fresh mushrooms (Finnish species).
There is considerable variation in individual responses to gyromitrin poisoning: ranging from simple stomach upset to the death of the patient (cf. Table 8). The outcome is fatal in approximately 10% of cases [207].
Treatment of gyromitrin poisoning is symptomatic. It may include administration of vitamin B6 (pyridoxine) to stop seizures and/or anticonvulsants such as clonazepam [207,212].

7.3. Toxic Species

Gyromitrin is the main toxin in mushrooms of the genus Gyromitra of the family Discinaceae. The most common mushroom is Gyromitra esculenta (Figure 11), which is often confused with morel, hence its nickname: false morel [207] shares a subgroup with G. fastigiate [207] and G. ambigua [217]. There is no evidence that G. gigas contains gyromitrin. It would appear that a large proportion of the genus Gyromitra contains gyromitrin [209].
It should be noted that G. esculenta contains other toxins beside gyromitrin: pentanal N-methyl-N-formylhydrazone, 3-methylbutanal N-methyl-N-formylhydrazone, and hexanal N-methyl-N-formylhydrazone [210]. All these compounds lead to the formation of methylhydrazine by hydrolysis [209,210]. In addition, there is a small amount of N-methyl-N-formylhydrazine in the mushroom, formed by hydrolytic cleavage [209].
This fungi genus is found mainly in the northern hemisphere (Canada, United States, and Eastern Europe). Long considered edible, G. esculenta has been the cause of many deaths.

7.4. Description of the Syndrome

The syndrome resulting from gyromitrin poisoning is called gyromitra syndrome [156]. It is characterized by a long latency period (between 5 and 12 h) after consuming the mushrooms [207]. Like the majority of mushroom poisonings, the first perceptible symptoms are nausea, vomiting, stomach pains, and sometimes bloody diarrhea, resulting in dehydration and headaches. MMH being hepatotoxic, there is often jaundice, indicating liver damage. In severe cases of poisoning there are altered states of consciousness, lack of motor coordination, seizures, and coma, which may lead to the death of the patient (c.f. Table 8).
In most cases the symptoms disappear 2–6 h after ingesting the mushrooms [212].

7.5. Human Poisoning Cases Reported

The first cases of gyromitrin poisoning were reported in 1782, then towards the end of the 1800s [215,216]. Franke et al. [215] reported a large number of poisonings in Eastern Europe between 1782 and 1965. However, there are fewer cases of poisoning reported than for the other mycotoxins due to this toxin’s thermosensitivity (Table 8). Due to the long latency period, some patient ate mushrooms several times. Some of these patients died of liver failure [216].

7.6. Analytical Aspect

Very few quantitative analytical techniques regarding gyromitrin have been reported in the literature (Table 9). The majority report a quantification of MMH in mushrooms using gas chromatography. Only three publications have covered biological matrices in mice or humans. It should be noted that some authors measure methylhydrazine rather than gyromitrin because of its rapid metabolization in vivo. To our knowledge, no technique using liquid chromatography to identify and quantify gyromitrine or its metabolites was published.
No data have been published to date on the quantification of gyromitrin in human biological matrices following G. esculenta poisoning.

8. Conclusions

This review of the literature took an analytical perspective, and focused on highly toxic mycotoxins (orellanine, α- and β-amanitin, muscarine, ibotenic acid, muscimol, and gyromitrin). It identifies a set of knowledge gaps. There is indeed a lack of scientific data, particularly regarding the metabolism of mycotoxins in biological matrices, but there is also a lack of analytical tools. There is a real need for the development and validation of specialized analytical methods adapted for the analysis of these mycotoxins in various matrices. Their implementation in the context of a clinico-biological study comparing the results of biological samples analysis (identification and assay) with the case history and clinical signs of confirmed or suspected poisoning victims could strengthen our understanding and treatment of these poisonings.

Author Contributions

Conceptualization, E.F., J.G., J.-M.G., Y.G.; methodology, J.G., J.-M.G.; writing—original draft preparation, E.F.; supervision, J.G., J.-M.G., Y.G. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Conflicts of Interest

The authors declare no conflict of interest.

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Figure 1. Structure of orellanine and its decomposition products.
Figure 1. Structure of orellanine and its decomposition products.
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Figure 2. Cortinarius orellanus [30].
Figure 2. Cortinarius orellanus [30].
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Figure 3. Structure of amatoxins. R = NH2 for α-amanitin, R= OH for β-amanitin.
Figure 3. Structure of amatoxins. R = NH2 for α-amanitin, R= OH for β-amanitin.
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Figure 4. Amanita phalloides [79].
Figure 4. Amanita phalloides [79].
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Figure 5. Structure of muscarine.
Figure 5. Structure of muscarine.
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Figure 6. Clitocybe rivulosa (copyright ©Andgelo Mombert) [161].
Figure 6. Clitocybe rivulosa (copyright ©Andgelo Mombert) [161].
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Figure 7. Structure of ibotenic acid.
Figure 7. Structure of ibotenic acid.
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Figure 8. Structure of muscimol.
Figure 8. Structure of muscimol.
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Figure 9. Amanita muscaria [190].
Figure 9. Amanita muscaria [190].
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Figure 10. Structure of gyromitrin and its metabolites [209].
Figure 10. Structure of gyromitrin and its metabolites [209].
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Figure 11. Gyromitra esculenta [218].
Figure 11. Gyromitra esculenta [218].
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Table 1. Cases of orellanine poisoning.
Table 1. Cases of orellanine poisoning.
Ref.Date of IntoxicationCountryNSex/AgeOffset of Symptoms/Delay before HospitalizationSymptomsTreatmentNotesToxin QuantificationOutcomeMushroom Species
[12]1955–1957Poland144------25 deathsCortinarius orellanus
[34]-Finland9-- 6 hemodialysis--4 renal transplantationCortinarius speciosissimus
[34]NCSweden2M/24NC/NCNausea, vomiting, abdominal painGastric aspiration, hemoperfusion, hemodialysis--Renal function normalCortinarius speciosissimus
F/47NC/NCNausea, abdominal pain--Renal function normal
[19]August 1979Scotland3M/31H 36/D 10Nausea, vomiting, anorexia, muscle and abdominal pain, night sweats, headache, bilateral loin pain, severe burning thirst, oliguria, anuria, acute renal failurePeritoneal dialysis, hemodialysisPlasma creatinine: 2945 µmol/L at D 10; Plasma urea: 48 mmol/L at D 10; Percutaneous renal biopsy at W 3 and W 7 after admission-Renal transplantation at Mo 9Cortinarius speciosissimus
M/30NC/NCHemodialysisConsumption of the same mushroom on 2 consecutive days; Plasma creatinine: 1925 µmol/L at D 10; Plasma urea: 42 mmol/L at D 10; Percutaneous renal biopsy at W 21/2 and W 6 after admission-
F/25D 2/D 11-Consumption of the same mushroom on 2 occasions; Plasma creatinine: 91 µmol/L at D 11; Plasma urea: 4.5 mmol/L at D 11-Renal function normal
[35]1981France5------3 positive development; 1 death of intracerebral hematoma; 1 chronic renal failureCortinarius splendens
[36]September 1981Italy2M/38D 2/NCGastrointestinal disorder, acute renal failurePlasma exchange, dialysisRenal biopsy reveal tubulointerstitial necrosis + interstitial oedema-Positive developmentCortinarius speciosissimus
F/38Renal failure for 6 months
[37]NCGermany2------2 renal failureCortinarius speciosissimus
[32,33]1979–1993Sweden22M/41D 1/D 8Vomiting, severe burning thirst, polyuria, oliguriaHemoperfusion, hemodialysis, peritoneal dialysis3 meals during 2 weeks; Serum creatinine: 1600 µmol/L at D 8-Renal transplantation at Y 3Cortinarius speciosissimus
M/44D 2/D 10Nausea, vomiting, abdominal pain, oliguria, acute renal failurePeritoneal dialysis, hemodialysisSerum creatinine: 1500 µmol/L at D 10; Uremia: 37 mmol/L at D 10; Renal biopsy at Mo 2 reveal normal glomeruli and atrophic tubuli-Renal transplantation at Mo 9–10
F/47D 4/D 5Nausea, vomiting, abdominal and muscular pain, intense burning thirst, polyuria,Hemoperfusion, hemodialysisConsumption of 15 fruit bodies; Serum creatinine: 402 µmol/L at D 5, 780 µmol/L at D 12-Renal function normal
M/24D 4/D 5 after 1st mealNausea, abdominal and muscular pain, heavy thirstHemoperfusion, hemodialysisConsumption of 4–6 fruit bodies on 2 occasions; Serum creatinine: 158 µmol/L at D 5, 380 µmol/L at D 12-Renal function normal
F/60H 12/NCNausea, vomiting, hematuria, proteinuria, glycosuria, anuriaHemoperfusion, hemodialysisConsumption of 7 mushrooms; Serum creatinine: 154 µmol/L at D Renal transplantation at Mo 6
M/21D 3/NCPolyuria and then anuriaHemoperfusion, hemodialysisConsumption of 3 mushrooms-Renal transplantation at Mo 30; Renal biopsy on transplantation kidney at Y 7 reveal atrophic tubuli
M/14D 4/D 10Nausea, vomitingPeritoneal dialysisSerum creatinine: 1350 µmol/L at D 10; Uremia: 68 mmol/L at D 10 Renal transplantation at Mo 8
[38]NCSwitzerland1M/14NC/D 5Vomiting, anorexia, renal pain, leukocyturia, hematuriahemodialysis -Renal transplantation at Mo 14Cortinarius speciosissimus
[24]November 1987France1F/31D 8/D 10Nausea, vomiting, severe thirst, abdominal pain, renal failureHemodialysis, hemodialysis resin, plasmapheresis resin, furosemide, diltiazem, dopamine, vitamin C, amino acidPsychiatric patient; Deliberate ingestion of 2 fruit bodies (≈ 20 g); Serum creatinine: 1100 µmol/L at D 10; Renal biopsy at D 13 and 180 reveal chronic interstitial nephritisDetection by TLC; Plasma at D 10 = 6.12 mg/L; Renal biopsy at D 13 ≈ 280 mg/L, at D 180 = 3000 mg/LNCCortinarius orellanus
[25]September 1987France26M/between 21 and 28D 2–9/D 10–12Digestive disorders, asthenia, thirst, headache, chills, polyuria, lumbar pain, paresthesia, dysgeusia, skin rash, 12 acute tubulointerstitial nephritis with acute renal failure8 hemodialysis; 9 under corticosteroidsDuring a survival exercise; Serum creatinine: 172–2248 µmol/L-1 renal transplantation at Mo 10; 1 chronic hemodialysis; 2 persisting renal failure; 22 renal function normalCortinarius orellanus
[39]NCCanada1F/20H 8/D 5Nausea, vomiting, diarrhea, abdominal pain, proteinuria, pyuria, hematuriaSodium polystyrene sulfonateConfusion with hallucinogenic mushrooms; Serum creatinine: 356 µmol/L at D 5; Uremia: 10.1 mmol/L at D 5-Renal function normalNC
[40]NCGermany1M/27D 9/D 14Nausea, anorexia, oliguria, leukocyturia, acute renal failureHemodialysis, peritoneal dialysisSerum creatinine: 1450 µmol/L at D 14; Uremia: 59 mmol/L at D 14; Renal biopsy at D 14 reveal tubulointerstitial nephritis-Renal transplantation Cortinarius orellanus
[41]1994–1995Austria/Northern Italy8M/74D 2/NCNausea, abdominal and loin pain, uremiadialysis-TLC on fluids failed to detect orellaninNCCortinarius speciosissimus
F/33D 2/NCRenal biopsy at D 10Detection of orellanin in renal biopsy at D 10 by TLC ≈ 160 mg/L
F/34D 4/NC-TLC on fluids failed to detect orellanin
M/43D 4 /NC-
M/59D 5/NC-
F/52D 3/NC-
M/82D 5/NC-
M/54D 5/NC-
[41,42]August 1995Austria1M/23NC/D 14Nausea, abdominal and loin pain, acute anuriaHemodialysisConsumption of 5 raw fruit bodies confused with hallucinogenic mushrooms; Renal biopsy at D 180 reveal acute interstitial nephritisOrellanin not detected in the renal biopsyPeritoneal dialysis; Waiting for renal transplantation 6 months laterCortinarius speciosissimus
[41,43]NCAustria1M/28D 7/D 21Nausea, vomiting, lumbar pain, proteinuria, leukocyturia, erythocyturia, hyperphosphatemia, dehydration, anuriaHemodialysis, probucolConsumption of 2 raw fruit bodies confused with hallucinogenic mushrooms; Serum creatinine: 2033 µmol/L at D 16; Uremia: 28.3 mmol/L at D 16Detection of orellanin in renal biopsy at W 5 by TLC ≈ 35 mg/LHemodialysis 12 months later; Waiting for renal transplantationCortinarius speciosissimus
[44]NCAustria4M/37NC/NCNausea, vomiting, dizziness, oliguriahemodialysisSerum creatinine: 813 µmol/L at D 14; Uremia: 47 mmol/L at D 14-Positive development-
F/78D 7/D 11Nausea, vomiting, dizziness, malaise, arthralgia, severe metabolic acidosis, anuriaIsradipine, urapidil, clonidine, hemodialysis, steroidsSerum creatinine: 1768 µmol/L at D 11; Uremia: 80 mmol/L at D 11; Kidney biopsy reveal acute tubular necrosis, interstitial fibrosis-Chronic hemodialysis 10 months later
F/56D7/not admitted to the hospitalNausea, vomiting, malaiseNA-NARenal function normal
M/70NC/D 9Nausea, vomiting, anuria, malaise, arthralgiahemodialysisUnderwent partial gastrectomy in 1949; Serum creatinine: 1768 µmol/L at D 9; Uremia: 48.3 mmol/L at D 9-Chronic hemodialysis 10 months later
[31]NCSpain1M/32D 5/D 15Nausea, vomiting, anorexia, flanks and abdominal pain, acute renal failure, insomnia, anuria, dehydration, leukocytosis, glycosuria, proteinuriaHemodialysis, rehydrationPast of drug addict; Voluntary ingestion of 2 fruits bodies looking for hallucinogenic effects; Serum creatinine: 477 µmol/L at D 15; Uremia: 8.2 mmol/L at D 15; Renal biopsy at D 16 reveal acute tubulointerstitial nephritis-Positive developmentCortinarius orellanus
[45]October 1994Italy1M/53NC/H 18OliguriaActivated charcoal, intravenous fluids, plasmapheresis, hemodialysisSerum creatinine: 97.5 µmol/L at H 30; Percutaneous renal biopsy at D 8 reveal acute tubular necrosis with interstitial oedema-Renal allograft at Mo 17Cortinarius orellanus
[46]August 1997Ireland2F/66D5/D10Vomiting, colicky, diarrhea, abdominal pain, oliguria, hyponatremia, proteinuriaHemodialysis, prednisolone, intravenous N-acetylcysteinePast of left sided hydronephrosis; Serum creatinine: 1032 µmol/L at D 10; Uremia: 32.8 mmol/L at D 10-Renal function normalCortinarius orellanus
F/38NC/NCNCNCSerum creatinine: 376 µmol/L-NC
[29]NCAustralia3M/171–2 weeks/2–3 weekNausea, diarrhea, anuriaHemodialysis, methylprednisolone, prednisolonePast of drug addict; Voluntary ingestion looking for hallucinogenic effects; Serum creatinine: 1970 µmol/L; Uremia: 44.3 mmol/L; Renal biopsy reveal acute interstitial nephritis-Death of pulmonary oedema at Mo 5NC
M/26D 2/D 4Vomiting, epigastric, back and bilateral loin pain, acute renal failure, dehydration, oliguriaIntravenous fluids, intravenous frusemide, hemodialysisPast of polysubstance abuse; Voluntary ingestion of 12 uncooked mushrooms looking for hallucinogenic effects; Serum creatinine: 1050 at D 4; Uremia: 19.5 mmol/L at D 4; Renal biopsy at D 20 reveal edematous interstitial fibrosis-Peritoneal dialysis for 15 months
M/16D 4/D 8Vomiting, acute renal failure, oliguria, dehydrationIntravenous fluidsSerum creatinine: 760 at D8; Uremia: 15.6 mmol/L at D 8-Positive development; Patient failed to attend a scheduled outpatient appointment
[27]December 1985Australia, Tasmania2M/NCNC/D 7Kidney failureDialysis--Kidney transplantationCortinarius eartoxicus
NC/NCNCNC--Renal function normal
[7]NCGermany2M/30D 4/D 6Nausea, vomiting, back pain, proteinuriaIntravenous N-acetylcysteine, selenium, hemodialysisConsumption of remaining mushroom 3 days after the first; Serum creatinine: 459.7 µmol/L at D6, 928 µmol/L at D 7; Uremia: 12.9 mmol/L at D 6, 21.1 mmol/L at D 7-Renal function normalCortinarius speciosissimus
F/29NC/D 6Nausea, back pain, proteinuriaIntravenous N-acetylcysteine, seleniumConsumption of remaining mushroom 3 days after the first; Serum creatinine: 88.4 µmol/L at D 6; Uremia: 5.4 mmol/L at D 6-Renal function normal
[23]NCUnited States, Michigan1F/53D 3/D 9Vomiting, diarrhea, oliguriaIntravenous sodium bicarbonate, sodium polystyrene sulfonate, hemodialysisConsumption of 6 mushrooms; Serum creatinine: 1220 µmol/L at D 9; Uremia: 14.6 mmol/L at D 9; Renal biopsy at D 14 reveal acute tubular necrosis-Peritoneal dialysis 5 time a weekCortinarius orellanosus
[20]NCNorway84 M–4F/between 44 and 74D 2/D 7Gastrointestinal disorder, headache, myalgia, acute renal insufficiency, oliguria5 dialysis; 6 steroids + N-acetylcysteineSerum creatinine: 150–1627 µmol/L-3 chronic hemodialysis; 5 partial recoveryCortinarius orellanus
[47]NCAustria2F/62D 2/D 6Nausea, vomiting, epigastric pain acute renal failure, anemiaPrednisolone, intravenous N-acetylcysteineSerum creatinine: 587 µmol/L at D 6; Uremia: 28.2 mmol/L at D 6; Renal biopsy at D 8 reveal acute interstitial nephritisTLC on biopsy specimen failed to detect orellaninPrednisolone for 103 D; Renal function normalCortinarius speciosissimus
MD 2/D 6NauseaSerum creatinine: 890 µmol/L at D 6; Uremia: 36.8 mmol/L at D 6-
[48]NCWales1M/43D 4/D 14Nausea, vomiting, diarrhea, myalgia, fever, anuria, dehydration, hematuria, leukocyturia, acute kidney injuryHemodialysis, methylprednisolone, prednisoloneBlood creatinine: 2650 µmol/L at D 14; Uremia: 50 mmol/L at D 14; Kidney biopsy reveal severe interstitial nephritis at D 17-Kidney transplantation at Mo 20Cortinarius speciosissimus
N: number of patients; NC: not communicated; NA: not applicable; F: female; M: male; D: day; W: week; Mo: month; Y: year.
Table 2. Analytical methods for orellanine detection.
Table 2. Analytical methods for orellanine detection.
Ref.MatrixSeparationDetectionQualitative/QuantitativeLODLOQLinearityExtraction RecoveryAdditional Analytical Information
[14]MushroomsTLCUVQualitativeNANANANA-
[49]MushroomsTLCUV (254 nm)QualitativeNANANANA-
[50]Mushrooms, mouse serum and kidneyHPLCElectrochemistry
(Working electrode: glassy carbon TL-5A; Reference electrode: Ag/AgCl; Working potential: 900 mV)
Quantitative500 pgNC50–500 ng on columnAlleged to 100% on overloaded mouse serum and directly injected, 25% for mouse kidneyColumn: (200 mm × 4.6) 5 µm Nucleosil C18; Flow rate: 2 mL/min; Mobile phase: 0.05 citrate-phosphate buffer pH 4.5, 15.4% MeOH and PIC B6 1-hexane sulphonic acid 5 mM
[21]MushroomsTLCSpectrofluorometry
excitation = 396 nm; λemission = 447 nm)
QuantitativeNCNCNCNC-
HPLCMSQualitativeNANANANA
-NMRQualitativeNANANANA
[22]Mushrooms-Polarography
(Working electrode: dropping mercury; Reference electrode: saturated calomel)
QualitativeNANANANA-
[51]MushroomsHPLCUV (260, 290 nm)Quantitative40–50 pg on columnNC5–500 ng on columnNCColumns: (150 mm × 4.6) 5 µM Rosil CN and (150 mm × 3.9) 5 µM µBondapak C18; Flow rate: 0.5 mL/min and 0.8 mL/min; Mobile phase: H3PO4 pH 1 and H3PO4 pH/ACN (94/6 v/v); 1-octane-sulphonic acid 2.5 Mm; RT: 4.43 min and 6.58
[24]Biological fluids and renal biopsyTLCSpectrofluorometry in 2D
excitation = 399 nm; λemission = 447 nm)
Quantitative10 ngNCNCNC-
[28]MushroomsTLCSpectrofluorometry
excitation = 400 nm; λemission = 450 nm)
Quantitative15 ng depositNCNCNC-
ElectrophoresisSpectrofluorometry
excitation = 400 nm; λemission = 450 nm)
Quantitative25 ng depositNCNCNC
-ESRQuantitative5000 ngNCNCNC
[41]Urine, blood and renal biopsyTLCUV (366 nm)Semi quantitative≈ 10 ngNCNCNC-
[52]MushroomsTLCUV (365 nm)Semi quantitative≈ 50 ng depositNCNCNC-
HPLCPhotodiode (288 nm)QuantitativeNCNCNCNCPreparative column: (115 mm × 13 mm) C18; Flow rate: 1 mL/min; Mobile phase: ACN/H2O (5/95 v/v) pH 1 1% TFA; RT: 6.5 min
HPLCESI-MSQuantitativeNCNCNCNCFlow rate: 10 µL/min direct MS source
[10]Mushrooms and rat plasmaHPLCESI-MS/MS (triple Q)
(253 to 191; 253 to 219; 253 to 163 m/z)
Quantitative4.9 µg/LNC4.9–5000 µg/L≈ 91% mushrooms
≈ 60% plasma
Column: (50 mm × 2.1 mm) 1.8 µm Eclipse Plus C18 RRHD; Flow rate: 0.2 mL/min; Mobile phase: 4 mM ammonium formate pH 2.5 (A), MeOH 0.2% HCOOH (B)
ESI-MS/MS (QTOF)Quantitative4.9 µg/LNC4.9–5000 µg/LFlow rate: 0.2 mL/min; Mobile phase: 5 mM ammonium formate/MeOH (90/10; v/v) 0.02% HCOOH (A), 5 mM ammonium formate in MeOH 0.02% HCOOH (B)
[53]Rat gastric contentHPLC(−) ESI-MS/MS (triple Q)
(Scan range: 120–600 m/z)
QuantitativeNCNCNCNCColumn: (50 mm × 2.1 mm) 2 µm Ascentis Express C18; Flow rate: 0.25 mL/min; Mobile phase: H2O 0.1 N HCOOH (A), ACN (B)
[54]Rat gastric contentGCMS with Supersonic Molecular BeamQualitativeNCNANANAColumn: (4 m × 0.25 mm ID), 0.1 µm VF-5HT; Flow rate: 8 mL/min; T injector: 200 °C; GC oven: 120–300 °C at 30 °C/min
[26]MushroomsHPLCUV–visible (295 nm)Quantitative17000 ng/gNC17000–680000 ng/g78.3%Column: (150 mm × 4.6 mm) 3 µm PLRP-S C18; Flow rate: 0.3 mL/min; Mobile phase: 4 mM ammonium acetate (A), MeOH (B)
ESI-MS/MS (triple Q)
(253 to 163; 253 to 191; 253 to 219; 253 to 236 m/z)
Quantitative30 ng/gNC6800–13600 ng/g85.0%Column: (250 mm × 4.1 mm) 10 µm Hamilton PRP-1; Flow rate: 0.4 mL/min; Mobile phase: H2O 1% HCOOH (A), ACN (B)
[55]Mice kidneyHPLCUV–visibleQuantitativeNC10 µg/g of tissue15–50 µg/g of tissueNC-
HPLCESI-MS/MS (triple Q)
(235 to 236 m/z)
Quantitative20 ng/gNCNC91%
[56]Standard solution-PSI-HR-MS/MS
(253.0468 to 219.0404 m/z)
QualitativeNANANANA-
NA: not applicable; LOD: limit of detection; LOQ: limit of quantification; NC: not communicated.
Table 3. Cases of amatoxines poisoning.
Table 3. Cases of amatoxines poisoning.
Ref.Date of IntoxicationCountryNSex/AgeOffset of Symptoms/Delay before HospitalizationSymptomsTreatmentNotesToxin QuantificationOutcomeMushroom Specie
[80]9 October 1944Great Britain4F/26H 6/H 18Vomiting, diarrhea, comaGastric lavage, glucose, atropine, insulinUremia: 25 mmol/L at D 3-Death at H 111 of gastric hemorrhages, kidney and liver failureAmanita phalloides
9 October 1944F/38H 6/H 18Vomiting, diarrhea, cyanosisGastric lavage, atropine, magnesium sulfate, insulin, glucose, nikethamide, percortoneUremia: 23.3 mmol/L at D 3-Death at H 76 of gastric hemorrhages, kidney and liver failure
25 September 1944F/57H 8/D 1Vomiting, diarrhea, abdominal pain, comaCastor oil, intravenous plasma--Death at H 126 of kidney and liver failure
18 August 1945F/6NC/D 3Vomiting, diarrhea, cyanosisGastric lavage, atropine--Death at H 60 of kidney and liver failure
[81]1943Great Britain3F/≈ 25NCJaundice, hallucinationsNC--Positive developmentAmanita phalloides
F/NCNC/D 2Vomiting, diarrhea, abdominal pain, severe muscular cramps, constipation, anorexiaNC--Positive development
F/5NC/D 2Vomiting, diarrhea, delirium, comaNC--Death at D 2 of liver degeneration
[82]September 1961United States, Washington DC1M/8NCVomiting, lethargy, inability to see, irrational response, cerebral oedemaNCVisit to the hospital because of head trauma after a bike fallAmatoxins identification in the liver by TLCDeath on the hospital D 4NC
[83]13 November 1962United States, California2M/43H 5/NCNausea, vomiting, diarrhea, oliguria, renal failure, dehydration, distention of the abdomen, hyperventilation, disorientation, hallucinations, coma, cyanosis, apneaPeritoneal dialysis, intravenous plasma, antibioticsPast of alcoholism; Serum creatinine: 1202 µmol/L at D 3; Uremia: 33 mmol/L at D 3; Septicemia complication-Death at D 12 of kidney and liver failure, central nervous system complicationPossible Amanita phalloides
4 October 1962F/43H 2/D 4Vomiting, slight lacrimation, acute renal failure, anuria, pruritus, dyspnea, confusion, hyponatremia, pulmonary oedema,Atropine, peritoneal dialysisUremia: 10 mmol/L at D 4; Renal biopsy at D 43 reveal renal tubular necrosis-Positive development
[84]NCUnited States, California5M/77H 6/D 1Vomiting, diarrhea, abdominal pain, severe cramping, hypotension, rapid supraventricular tachycardia, anuria, muscular hyperactivity, coma, hypoglycemiaAtropine intramuscularly, intravenous fluids, digitalis, sodium bicarbonate, dextrose, Amanita phalloides antitoxin, peritoneal dialysis--Death at D7 of kidney and liver failureAmanita verna
1 M and 3 F/20, 60, 62, 63H 10–15/NCGastrointestinal disorders, oliguria, dehydration, neutropeniaNC--Positive developmentAmanita verna, Amanita phalloides
[70]Between 1968 and 1974United States, California28NC/Between 14 months and 87 years oldNCNausea, vomiting, diarrhea, abdominal painSupportive care, 14 thioctic acid-Amatoxins identification in mushrooms by TLC8 deaths; 20 Positive developmentA. phalloides, A. virosa, A. verna et G. autumnalis
[66]NCSwitzerland84 H–4 F/between 16 and 55NC/H 16Severe gastrointestinal disordersDialysis, hemoperfusion, penicillin, vitamin CALT peak at 1920 IU/L at D 3 for one patient-Positive developmentAmanita phalloides
[85]Fall 1981United States, California10M/45H 8/H 12Nausea, abdominal cramping, diarrhea, dehydration, oliguria, encephalopathy, respiratory arrest, seizures, hepatic comaRehydration, vitamin K, thioctic acid, diazepam, phenytoinConsumption of 2 or 3 mushrooms; AST at D 6: 4220 U/L; ALT at D 6: 7272 U/L; Serum creatinine at D 11: 336 µmol/L-Death at D 12 of kidney and liver failure, cerebral oedemaNC
M/80D 1/H 48Nausea, vomiting, diarrhea, dehydration, confusion, hypotension, supraventricular tachycardia, oliguria, encephalopathy, comaRehydration, dextroseSerum creatinine at D 2: 380 µmol/L; Uremia: 8.7 mmol/L; AST at D 4: 2410 U/L; ALT at D 4: 2500 U/L; Septicemia developed on D 7Amatoxins identification positive on the mealDeath at D 9
M/39H 12/D 4Vomiting, diarrhea, dehydration, hematemesis, cardiopulmonary arrestRehydrationAST at D 4: 4860 U/L; AST at D 5: 2820 U/L; ALT at D 5: 3220 U/L; Serum creatinine at D 5: 513 µmol/L-Death at D 6 of multiorgan failure
M/18H 8–10/NCNausea, vomiting, abdominal cramps, diarrhea, dehydration, bradycardia, hypotensionRehydration, dextrose, dexamethasone, vitamin K, temporary transvenous pacemakerConsumption of 10 mushrooms; AST at D 3: 5280 U/L; ALT at D 3: 5100 U/L-Positive developmentAmanita phalloides
3 M–3 F/21–37H 8–12/NCNausea, vomiting, abdominal cramps, diarrheaSupportive care, activated charcoalLaotian refugees; AST peak between 617 and 2565 U/L; ALT peak between 648 and 5870 U/L-Positive developmentAmanita species
[86]November 1981Italy1F/21H 10/NCNausea, vomiting, abdominal pain, diarrheaPlasmapheresis, forced diuresis8 months of pregnancyα-amanitin = 18.5 ng/mL in the serum by HPLC; No amatoxins in amniotic fluidPositive developmentAmanita phalloides
[87]28 February 1983United States, California1F/3H 8/D 2Nausea, vomiting, abdominal pain, diarrhea, hypotension, oliguria, hematuria, encephalopathy grade III, comaRehydration, charcoal slurry, lactulose, dopamine and dobutamine hydrochloride, antibiotics, methylprednisolone, charcoal hemoperfusionConsumption of 2 tablespoons of mushrooms; AST at D 2: 16,648 U/L; ALT at D 2: 9844 U/L; Left hepatic lobectomy on the transplant liver because of necrosis at D 9-Orthotopic liver transplantation at D 5 + neurological deficitsAmanita ocreata
[88]1982–1983United States, California2110 M–11 F/5–82H 6–29/D 1–12Nausea, vomiting, abdominal cramps, diarrheaSupportive care, activated charcoal, 5 dexamethasoneAST peak: 77–11674 U/L; ALT peak: 72–9233 U/LAmatoxins identification positive in serum of 3 patients by RIA2 deaths; 19 Positive developmentA. phalloides, A. ocreata, L. clypeolaria
[67]NCUnited States, California2F/19H 9/NCNausea, vomiting, diarrhea, abdominal pain, hepatic encephalopathyRehydration, gastric lavage, charcoal, dialysisConsumption of 6 ounces of mushrooms; AST: 1608 U/L; ALT: 2600 U/L-Orthotopic liver transplantationAmanita phalloides
M/45H 7/NCNausea, vomiting, diarrhea, oliguria, encephalopathy grade IIIRehydration, gastric lavage, charcoal, hemodialysisConsumption of ≈ 250 g of mushrooms; AST: 3800 U/L; ALT: 5600 U/L-Orthotopic liver transplantation
[89]22 October 1988United States, Oregon52 M–3 F/33–52H 7–11/<H 24Nausea, vomiting, diarrhea, abdominal cramps, dehydration, hypophosphatemia, 2 encephalopathy grade I and 2 encephalopathy grade IIRehydration, silymarin, penicillinConsumption of 60–100 mushrooms; 1 diabetic had undergone previous cholecystectomy and pelvic surgery; 1 pulmonary tuberculosis-4 liver transplantation at D 5–7; 1 deathAmanita phalloides
[90]1984–1989France4522 M–23 F/2–81H 6–24/NCGastrointestinal disorders; 43 hepatic injury; 6 functional renal failureSupportive care, penicillin G, silibinin; 1 hemodialysis; 2 gastric lavageAST peak: 380–17000 U/L; ALT peak: 520–16,000 U/LAmatoxins identification in biological matrix by HPLC-UV2 liver transplantation at D 5; 8 deaths; 35 positive developmentAmanita phalloides
[91]NCUnited States, New York4F/90H 12/H 30Nausea, vomiting, diarrhea, weakness, hypotension, hepatic failureRehydration, penicillin, cimetidine, activated charcoal, vitamin KPast of hypertension, permanent pacemaker; Serum creatinine at D 2: 124 µmol/L; Uremia at d2: 16.1 mmol/L; AST at D 7: 4099 U/L; ALT at D 7: 5394 U/LAmatoxins identification positive in admission and post-mortem serumDeath at D 7 of hepatic failureAmanita/Lepiota species
M/64H 12/H 30Nausea, vomiting, abdominal crampsRehydration, penicillin, cimetidine, activated charcoal, vitamin KSerum creatinine at D 2: 159 µmol/L; Uremia at D2: 11.8 mmol/L; AST at D 5: 5620 U/L; ALT at D 5: 8620 U/L-Hepatitis
F/40
M/42
H 3/H 18Nausea, vomiting, diarrhearehydration, prochlorperazine, charcoal, penicillin, charcoal hemoperfusion, heparinConsumption of 4–6 mushrooms-Positive developmentLepiota chlorophyllum
[68]1991–1992France4F/27H 10/NCNausea, vomiting, abdominal pain, diarrhea, encephalopathy grade I, anemia, leukopeniarehydration, silibinin, ceftazidime, hemodialysisConsumption of 300 g of mushrooms; AST at D2: 2990 U/L; ALT at D2: 2730 U/L-Liver transplantation, chronic renal failure, myocardiopathyLepiota helveola
M/35H 12/NCVomiting, diarrhea, abdominal pain, hepatitisNCConsumption of alcohol during the meal-Positive developmentLepiota brunneolilacea
F/33H 12/NCVomiting, diarrhea, abdominal pain, dehydration, hepatic cytolysis, disorientation, asterixisNCAST at D 2: 5800 U/L; ALT at D 2: 2700 U/L-Liver transplantation at D 4
F/8H 12/NCVomiting, diarrhea, abdominal pain, dehydration, encephalopathy grade IIIrehydration, albuminAST at D 2: 1416 U/L; ALT at D 2: 1560 U/L; ALT at D 3: 5082 U/L-Orthotopic liver transplantation at D 5
[92] Turkey 33 M/9, 11, 14H 12/H 30Nausea, vomiting, abdominal pain, diarrhea, dehydrationGastric lavage, charcoal hemoperfusion, rehydration, lactulose, penicillin, streptomycin, forced diuresis, dexamethasone, vitamins, hemodialysisConsumptions of ≈ 80 g of mushrooms; AST peak: 276–1760 U/L; ALT peak: 388–3450 U/Lα-amanitin identification positive in serum by TLCPositive developmentAmanita phalloides
[93]27 December 1996 to 5 January 1997United States, California109 M–1 F/ 12/68H 8–26/D 2–8Nausea, vomiting, diarrhea, abdominal cramps, weakness,rehydration, H2-blockers, activated charcoal, penicillin, N-acetylcysteine, vitamin K, hemodialysisAST peak 594–6998 U/L; ALT peak: 930–7120 U/L-2 deaths at D 7 and D 9 of multiorgan failureAmanita phalloides
[94]1995Australia2M/46NC/D 1Vomiting, diarrhea, hepatic and renal failurerehydration, penicillin, N-acetylcysteineConsumption of 8 mushrooms; ALT at D 3: >10,000 U/L; Serum creatinine at D 3: 535 µmol/L-Death at D 6 of hepatic failure waiting for a liver transplantationAmanita phalloides
1998M/39H 18/H 36Nausea, vomiting, diarrhea, dehydration,rehydration, penicillin, N-acetylcysteineConsumption of 3 mushrooms; ALT peak at D 3: 8199 U/L; Serum creatinine at D 2: 102 µmol/L-Positive development
1988–199753 M–2 F/7–45D 1–2/NCVomiting, diarrhearehydration, activated charcoal, penicillin1 patient ALT peak: 2938 U/L-Positive development
[95]NCThailand5F/36H 12/NCNausea, vomiting, diarrhea, jaundice, acute liver failure, hepatic encephalopathySupportive care, vitamin K, neomycin, lactuloseSerum creatinine: 132.6 µmol/L; Uremia: 2.2 mmol/L; AST: 3400 U/L; ALT: 3930 U/L-Death at D 6Amanita virosa
M/8H 12/NCNausea, vomiting, diarrhea, jaundice, hepatic encephalopathy, convulsions, gastrointestinal bleeding, hypoglycemiarehydrationSerum creatinine at D 4: 35.4 µmol/L; Uremia at D 4: 0.8 mmol/L; ALT at D 4: 1738 U/L-Death at D 5
M/36NCNausea, vomiting, diarrhea, acute liver failure, hepatic encephalopathyNC--Death at D 4–6
M/11
F/6
[62]NCUnited States, Ohio4F/53H 10/NCNausea, vomiting, abdominal cramps, diarrhea, hypokalemia, anemia, hepatic encephalopathy grade IIICharcoal hemoperfusion, penicillin G, thioctic acid, vitamin C, dexamethasone, PepcidConsumption of ≈ 900 g of mushrooms; Past of breast cancer, left mastectomy; AST peak: 1494 U/L; ALT peak: 1277 U/L-Orthotopic liver transplantation at D 4 + mild renal insufficiencyAmanita virosa
M/25NC/H11Vomiting, abdominal cramps, diarrheaCharcoal hemoperfusion, forced diuresis, hydration, vitamin K, decadron, penicillin G, vitamin C, cimetidineConsumption of 40–50 g of mushrooms-Positive development
M/35H 10½/NCNausea, vomiting, diarrhea, abdominal painCharcoal hemoperfusion, fluid and electrolyte repletion, penicillin G, dexamethasoneConsumption of 40–50 g of mushrooms; AST peak: 761 U/L; ALT peak: 531 U/L-Positive development
M/47 Nausea, vomiting, diarrhea, abdominal painCharcoal hemoperfusion rehydration, electrolyte repletion, penicillin G, dexamethasone, vitaminsAST peak: 154 U/L; ALT peak: 122 U/L-Positive development
[96]NCJapan1M/6H 6–10/H 36Nausea, vomiting, diarrhea, abdominal pain, dehydration, hepatic insufficiency, mild proteinuria, glycosuria, hematuriarehydration, plasma exchange, hemodiafiltration, activated charcoalAST peak at H62: 18450 U/L; ALT peak at H62: 13,554 U/LAmatoxins identification negative in urine and blood at H80; Amatoxins identification positive in mushrooms by HPLCPositive developmentPossible Galerina fasciculata
[97]NCFrance1F/22H 2/H 13Nausea, vomiting, diarrhea, abdominal painrehydration, silymarin, activated charcoal, N-acetylcysteine, vitamins, antibiotics, fungizone2 months of pregnancy; AST peak at H53: 3200 U/L; ALT peak at H67: 4127 U/L-Positive developmentAmanita phalloides
[98]NCSwitzerland1F/61H 12–16/H 36Nausea, vomiting, diarrhea, dehydration, hypoglycemia,rehydration, vitamin K, penicillin G, silibinin, N-acetylcysteineDried and frozen mushrooms during 7–8 months; Serum creatinine at H 48: 270 µmol/L; AST at H 48: 1424 U/L; ALT at H 48: 2326 U/LAmatoxins identification positive in urine at D 4: 37.3 µg/LDeath at D4 of liver and renal failure (patient declined the liver transplantation)Amanita phalloides
[99]NCTurkey2M/44H 8/NCNausea, diarrhea, abdominal pain, encephalopathy grade III, hepatitisNCTransplanted liver necrosis; AST at D 10 postoperative: 10,270 U/L; ALT at D 10 postoperative: 5670 U/L-Death at D 10 after an orthotopic liver transplantation Amanita phalloides
F/20NC/D 2Nausea, vomiting, diarrhea, confusion, lethargy, agitation, hepatic encephalopathy grade II, hepatitisNC--Orthotopic liver transplantation
[100]NCGermany1F/64NCHepatic encephalopathy grade IIINCObesity, hypertension, chronic heart failure-Hepatocyte transplantationAmanita phalloides
[101]NCTurkey1M/11H 24/NCNausea, vomiting, abdominal cramps, diarrhea, metabolic acidosis, fever, jaundice, unconsciousness, hypotonia, hepatic encephalopathy grade IIIGastric lavage, activated charcoal, vitamin K, penicillin G, bicarbonate, ampicillin, lactulose, vitamin C, plasmapheresisAST peak: 774 U/L; ALT peak: 200 U/L-Orthotopic liver transplantationAmanita phalloides
[102]NCFrance5M/NCH 9/NCVomiting, diarrhea, abdominal pain, dehydrationPenicillin G, silimarinAST at H 48: 150 U/L; ALT at H48: 270 U/LAmatoxins identification positive by RIA in urine at H 24: 5.99 µg/LPositive developmentAmanita phalloides
F/NCH 11/NCVomiting, diarrheaNC-Amatoxins identification positive in urine at H 27: 14.3 µg/L; Negative in serum by RIA
M/NCH 14/NCAmatoxins identification positive in urine at H 27: 11.6 µg/L; Negative in serum by RIA
M/NCD 1/D 1Diarrhea, liver and renal insufficiencyN-acetylcysteineAST at H 60: 1014 U/L; ALT at H 60: 2645 U/LAmatoxins identification negative in serum, urine and feces at H72 < 1.5 µg/L
3NCNCNCNCNCAmatoxins identification in urine at H > 36; 1.5 < X < 5 µg/LNCNC
[103]1988–2002Italy11157 M–54 F/18–94H ≈ 12/H 30–45Nausea, vomiting, diarrhearehydration, glucose, electrolyte repletion, vitamin K, activated charcoal, dexamethasone, penicillin GAST peak: 4330 U/L; ALT peak: 5428 U/LAmatoxins identification positive in urine in 62 patients2 deaths at D 11 and D 29Amatoxins-containing species
[104]2000–2004Czech Republic3417 M–17 F/1–73H 1–24/H 1–168Vomiting, diarrhea, abdominal cramps, weakness, hepatic failure, coagulopathy, encephalopathy, renal failureGastric lavage, activated charcoal, penicillin G, thioctic acid, hemoperfusion, hemodialysis, N-acetylcysteine, silymarin, forced diuresis5 intentional ingestion (suicide); 5 alcohol abuse-3 deaths at D 5 of cardiac arrest, D 5 during liver transplantation and M 19 of renal damage; 14 persistent hepatic or renal damageAmanita phalloides
[105]NCTurkey1F/16H 7/D 3Nausea, vomiting, abdominal pain, diarrhea, lethargy, liver failureSupportive care, silibinin, oral charcoal, plasmapheresis--Liver transplantation at D 7Amanita phalloides
[106]NCTunisia4F/6H 7/NCVomiting, diarrhea, abdominal pain,---Death at D 1 before arriving at emergencies of liver failureLepiota brunneoincarnata
M/15NC/H 7Vomiting, diarrhea, fever, hypovolemia, hepatic cytolysis, hematemesis,rehydrationAST peak at D 3: 5400 U/L; ALT peak at D 3: 5500 U/L-Death at D 3 of liver failure with brain oedema
F/12NC/H 12Vomiting, diarrhea, abdominal pain, coma, brain oedema, hepatic cytolysisNCAST peak at D 3 > 10000 U/L; ALT peak at D 3 > 10,000 U/L-Brain death at D 3; Death at D 11 of multiorgan failure
M/3H 7/NCVomiting, diarrhea, abdominal pain, hepatic cytolysis, acute renal failure, metabolic acidosisrehydration, vitamin KAST peak at D 3 > 10,000 U/L; ALT peak at D 3 > 10,000 U/L-Death at D 4 of multiorgan failure
[72]January 2000 to October 2010Germany79NCMedial H 14.5/Medial H 29.4Nausea, vomiting, diarrhea, abdominal pain, coagulopathy9 activated charcoal, laxative, 10 silibinin, 3 penicillin, 6 N-acetylcysteineAST medial peak: 3242 U/L; ALT medial peak: 3907 U/L10 amatoxins identification positive in urine by ELISA: 15.3–125 µg/L (4 after H 48)10 positive developmentNC
[107]March 1992 to November 2009Portugal104 M–6 F/16–75H 7–12/<H 48Vomiting, diarrhea, abdominal pain, encephalopathy grade I, acute liver failureSupportive care, silibinin, penicillin G, N-acetylcysteine, hemodialysis, hemodiafiltrationAST medial peak: 5295 U/L; ALT medial peak: 6919 U/L-4 deaths (3 liver transplantation); 3 liver transplantation alive; 3 positive developmentAmanita phalloides
[108,109]January 1995 to December 2009Switzerland3220 M–12 F/1, 4–74H 1, 25–6/NCNausea, vomiting, diarrhea, dehydration, acute liver failure, encephalopathy grade IActivated charcoal, silibinin, gastric lavage, forced diuresis, laxatives, penicillin G, N-acetylcysteine2 intentional ingestionsAmatoxins identification positive in urines by ELISA; 1.6 < X < 118 µg/L5 deaths at D 3–9 of liver failure; 27 positive developmentAmanita phalloides, Amanita virosa
[110]NCTurkey1M/63H 7–8/H 36Nausea, vomiting, diarrhea, weakness, dehydrationGastric lavage, activated charcoal, hemodialysis, rehydration, silibinin, N-acetylcysteine, penicillin G, multivitaminChemotherapy + surgery for a colon carcinoma 2 months before; Liver transplantation refused because of colon carcinoma; AST peak at H 90: 3570 U/L; ALT peak at H 90: 3282 U/L-Death at H 134 of cardiac arrestAmanita phalloides
[77]NCUnited States, Massachusetts2F/72H 28 (after the 1st meal)/D 2Vomiting, diarrhea, abdominal painActivated charcoal, N-acetylcysteine, penicillin G, silibinin, cimetidinePast of hypertension; Consumption of the same mushroom on 2 consecutive days; AST peak at H 64: 9640 U/L; ALT peak at H 64: 9360 U/L-positive developmentAmanita ocreata
M/45H 14/ D 1Past of hypertension; AST peak at H 60: 2868 U/L; ALT peak at H 60: 4212U/L-
[8]NCAustralia1F/58H 9/D 1Vomiting, diarrhea, coagulopathy liver failure, encephalopathySilibinin, penicillin G, N-acetylcysteineConsumption of 6 mushrooms; AST peak at H 96: 1842 U/L; ALT peak at H 96: 2143 U/L-Death at D 5 of fulminant liver failureAmanita phalloides
[111]November 2011France3M/8NC/H 9Vomiting, diarrhea, abdominal cramps, asthenia, fever, confusion, dehydration,Activated charcoal, penicillin G, silibinin, N-acetylcysteineAST at D 4: 1018 UI/L; ALT at D 4: 3205 UI/L-positive developmentLepiota brunneoincarnata
F/11NC/H 9Vomiting, abdominal cramps-
[112]January 2002 to December 2012Italy242NC/Medial 53NCGastrointestinal disordersN-acetylcysteine, forced diuresis, activated charcoalα-amanitin identification positive in urine: medial: 39.21 µg/L 5 Deaths; 5 Liver transplantation; 232 positive developmentAmatoxins-containing species
[76]NCUnited States, New York1M/65H 14/NCVomiting, diarrhea,rehydration, antiemetics, N-acetylcysteine, silimarin, biliary drainage, octreotideAST peak: 5102 U/L; ALT peak: 2546 U/L-positive developmentAmanita bisporigera
[75]NCRepublic of Macedonia8M/54H 24/NCNausea, vomiting, diarrhea, weakness, fatigue, confusion, neurological reaction depression, liver encephalopathy grade III, renal failureActivated charcoal, N-acetylcysteine, vitamins, penicillin G, H2 blocker, ornicetil, hemoperfusion, plasma exchange, plasmapheresisConsumption of the same mushroom on 2 occasions; AST peak: 4714 U/L; LT peak: 5824 U/L; Serum creatinine peak: 180,000 µmol/L; Uremia: 13.3 mmol/L-Death at hospitalization D 5 of hepatorenal failure
M/30NC/NCNausea, vomiting, diarrhea, weakness, fatigue, confusion, neurological reaction depression, liver encephalopathy grade III, renal failureConsumption of the same mushroom on 2 occasions; AST peak: 3600 U/L; ALT peak: 6025 U/L; Serum creatinine peak: 230000 µmol/L; Uremia: 1.9 mmol/LDeath at hospitalization D 5 of hepatorenal failureAmanita verna
F/75H 10/NCNausea, vomiting, diarrhea, weakness, fatigue, abdominal painAST peak: 307 U/L; ALT peak: 321 U/Lpositive development
F/54NC/D 1Nausea, vomiting, diarrhea, abdominal painConsumption of ≈ 300 g of mushrooms
F/31NC/D 1Nausea, vomiting, diarrhea, weakness, fatigueConsumption of ≈ 300 g of mushrooms; Cholecystectomy in the past; AST peak: 306 U/L; ALT peak: 293 U/L
M/34H 10/NCNausea, vomiting, diarrhea, weakness, fatigueConsumption of ≈ 300 g of mushrooms
M/23
F/32
NC/NCNausea, abdominal painActivated charcoal, N-acetylcysteine, vitamins, penicillin G, H2 blocker, hemoperfusion, -
[113]August 2014Sweden6NCNCNausea, vomiting, diarrhea, liver impairmentSilibinin, N-acetylcysteineSyrians refugeeAmatoxins identification positive in urinepositive developmentAmanita virosa
[114]NCTurkey1M/61H 8–9/H 24Nausea, vomiting, diarrhea, abdominal pain, fatigue, dehydrationrehydration activated charcoal, penicillin GVoluntary ingestion of 2 caps in order to test the toxicity ≈ 21.3 mg amatoxins AST peak at H 72: 1777 U/L; ALT peak at H 72: 2496 U/Lα-amanitin in urine at D 4: 2.7 µgL; β-amanitin in urine on D 4: 1.25 µg/Lpositive developmentAmanita phalloides
[115]October 18 2013Turkey1M/39NC/H 12Nausea, vomiting, diarrhea, abdominal pain, dehydration, jaundiceGastric lavage, activated charcoal, rehydration, N-acetylcysteine, antihistamine, vitamins, corticosteroidConsumption of 5 mushrooms ≈ 19.93 mg amatoxins; ALT peak at H 90: 5124 U/L-positive developmentLepiota brunneoincarnata
[73]1999–2015Slovenia32NCNCNC29 silibinin, rehydration8 PSS1; 8 PSS2; 3 PSS3; Serum creatinine PSS3 group: 185.6 ± 40.7 µmol/L-1 death; 1 liver transplantation; 30 positive developmentAmanita phalloides
[116]April 2013Hong Kong7M/48H 12/NCVomiting, diarrheaN-acetylcysteine, silibinin, penicillin G, activated charcoalSerum creatinine at H 30: 229 µmol/L; ALT peak at H 48: 4856 U/LAmatoxins identification positive in urinepositive developmentAmanita farinosa
F/47H 12/NCVomiting, diarrhea, feverN-acetylcysteine, silibinin, penicillin G, vitamin K, activated charcoalALT peak at H 72: 5132 U/LAmatoxins identification positive in urineLiver transplantation at D 5
March 2015M/29H 12/D 4Vomiting, diarrhea, jaundice, confusion, hepatic encephalopathyN-acetylcysteine, penicillin G, vitamin K, silibininSerum creatinine at D 4: 241 µmol/L; ALT peak at D 4: 9390 U/LAmatoxins identification negative in urineLiver transplantation at D 6NC
NCSouth AfricaF/43H 12/D 5Vomiting, diarrhea, jaundice, confusion, tachycardia, hypotension, metabolic acidosisSupportive care--Death at D 6
M/44H 12/Vomiting, diarrheaN-acetylcysteine, activated charcoal-Amatoxins identification negative in urinepositive development
Hong KongM/74H 9/D 1Vomiting, diarrheaN-acetylcysteine, silibinin, penicillin G, activated charcoal-Amatoxins identification positive in urinepositive development
ChinaF/40H 8/D 4Vomiting, diarrhea, dehydrationN-acetylcysteine, silibinin, penicillin G, activated charcoal--positive development
[117]July 2007 to August 2016Czech Republic2312 M–11 F/7–78H 2–48/H 8–60Nausea, vomiting, diarrhea, abdominal pain, 5 hepatic encephalopathy grade I and II, 3 hepatic encephalopathy grade III and IVActivated charcoal, rehydration, N-acetylcysteine, silibinin, hemoperfusion, plasmapheresisAST: 0.5–95 U/L-2 deaths (1 at Mo 2 after liver transplantation); 5 liver transplantation; 16 positive developmentAmanita phalloides
[118]28 November 2013China1313 M/19–56H 9–21/NCNausea, vomiting, diarrhea, abdominal pain, fatigue, weakness, anorexia, palpitation, chest tightness, eye pain, blurred vision, leg cramps, oliguria, tachycardiaRehydration, antiemetics, silibinin, Shenshuaining, hemodialysisConsumption of ≈ 10–120 g of mushrooms; AST peak: 2600 U/L; ALT peak: 3581 U/L-positive developmentGalerina sulciceps
N: number of patients; NC: not communicated; F: female; M: male; H: hour; D: day; Mo: month; AST: aspartate aminotransferase; ALT: alanine aminotransferase.
Table 4. Analytical methods for amatoxins detection.
Table 4. Analytical methods for amatoxins detection.
Ref.MatrixSeparationDetectionQualitative/QuantitativeLODLOQLinearityExtraction RecoveryAdditional Analytical Information
[119]Rabbit serum-RIAQualitativeα-: 50 pgNANANA-
[70]Pure substancesTLC-Qualitativeα-: 50 µgNANANA-
[120]MushroomsHPTLCSpectrophotometryQuantitative50 ng depositNCNCNC-
[121]Serum, urine, duodenal fluid, gastric juice, mushrooms-RIAQuantitative3 µg/LNC3.3–100 µg/LNC-
[122]Serum, urine, stomach washingsHPLCUV (280 nm)Quantitative10 µg/LNC20–500 µg/L110%Column: (250 mm × 4.6 mm) 5 µm Ultrasphere ODS C18; Flow rate: 1 mL/min; Mobile phase: 0.02 M ammonium acetate/ACN (88/12; v/v) pH 5; RT α-: 12.1 min, β-: 7.4 min
[123]Serum, urine, mushroomsHPLCUV (302 nm)Quantitative10 ngNC0.5–20 mg/Lα-: 81.1–98.1%
β-: 80.6–97.3%
Column: (125 mm × 4.0 mm) 5 µm Lichrosorb RP-18; Flow rate: 1 mL/min; Mobile phase: ACN (A), 0.01 M acetic acid-ammonium acetate buffer pH 5 (B); RT α-: 14.9 min, β-: 9.1 min
[124]Plasma, urine-RIAQuantitative0.1 µg/L plasma
1 µg/L urines
NC0.1–20 µg/L plasma; 1–100 µg/L urines101.3% plasma
110% urine
-
[125]Serum, urineHPLCAmperometry
(Reference electrode: Ag/AgCl; Working potential: 600 mV)
Quantitative in serum; Qualitative in urineα-: 40 pg on column
β-: 80 pg on column
NC1–1000 µg/Lα-: 53–65%
β-: 36%
Column: (250 mm × 4.6 mm) 5 µm Spherisorb ODS2 - (250 mm × 4.6 mm) 5 µm Hypersil WP300 Butyl; Flow rate: 1 mL/min; Mobile phase: 0.02 M ammonium acetate/ACN (92:8; v/v) 0.5 mM EDTA pH 5; RT α-: 16.5 min, β-: 12.0 min
[126]PlasmaHPLCUV (303 nm)Quantitative for α-amanitin9.74 µg/L10 µg/L10–100 µg/L67.3–105.56%-
[127]PlasmaHPLCAmperometry/EC
(Reference electrode: Ag/AgCl; Working potential: 350 mV)
Quantitative for α-amanitin2 µg/LNC3–200 µg/L80–82.5%Column: (150 mm × 4.6 mm) 5 µm PLRP-S 100 Å; Flow rate: 0.5 mL/min; Mobile phase: 0.05 M phosphate buffer—ACN (91/9; v/v) pH 9.5
[128,129]MushroomsHPLCUV (214, 295 nm)Quantitative10 µg/L = 0.5 ng/g mushroomsNCNCNCColumn: (250 mm × 4.6 mm) 5 µm Ultrasphere ODS; Flow rate: 1 mL/min; Mobile phase: 0.02 M aqueous ammonium acetate/ACN (90/10; v/v A) (76/24; v/v B)
[63]Urine, mushroomsElectrophoresisDAD: 190–350 nmQuantitative1000 µg/LNC1–1000 mg/LNCCapillary length: 36 cm (50 µm); T separation: 25°C; Buffer: 100 mM phosphate (pH 2.4)
[130]UrineHPLCCoulometry
(Full scale range 50 µA until 12.5 min, 20 µA up to 20 min)
Quantitative for α-amanitin2 µg/L10 µg/L10–200 µg/L77–80.4%Column: (250 mm × 4.6 mm) Supelcosil LC 18; Flow rate: 1 mL/min; Mobile phase: 0.005 M bisodic phosphate aqueous solution pH 7.2 and ACN (90/10; v/v); Electrode: graphite
[131]Plasma, urineHPLCESI-UV-MS
(UV: 302 nm)
(SIM mode (+): α- 919, 920, 921 m/z; β- 920, 921, 922 m/z)
Quantitative2.5 µg/L5.0 µg/L5–75 µg/Lα-: 49.1–62.5%
β-: 52.1–57.5%
Column: (100 mm × 2.1 mm) 3 µm HP ODS Hypersil RP-18; Flow rate: gradient; Mobile phase: MeOH-0.01 M ammonium acetate pH 5 (10/90; v/v A) (70/30 v/v B)
[132]Serum, urineELISA-Quantitative for β-amanitin0.08 µg/LNC0.080–2 µg/LNC-
[133]MushroomsHPLCHILIC-ESI-MS/MS (ion trap)
(scan range: 600–930 m/z)
Quantitative20 ng/gα-: 26.8 ng/g
β-: 33.3 ng/g
20–500 µg/L63–75%Column: (250 mm × 2.0 mm) 5 µm 80 Å TSK-Gel Amide 80; Flow rate: 0.2 mL/min; Mobile phase: 2 mM ammonium formate + 5mM HCOOH (A), ACN (B), MeOH (C); RT: α- ≈ 7.18 min, β- ≈ 8.94 min
[134]Serum, liverHPLCESI-MS/MS/MS (ion trap)
(α- 941 to 746 (CE 40%) m/z; Full-scan of product ions of m/z 746 (CE 25%))
Quantitative for α-amanitin0.26 ng/g (serum)
0.5 ng/g (liver)
NC1–50 µg/L95% (serum)
98% (liver)
Column: (100 mm × 4.6 mm) Synergi RP-Polar; Flow rate: 0.5 mL/min; Mobile phase: 0.01 M ammonium acetate in H2O 0.1% HCOOH (A), 0.01 M ammonium acetate in MeOH 0.1% HCOOH (B); RT: α-: 4.5 min
[135]UrineElectrophoresisDAD (214 nm)Quantitative2.5 µg/L5 µg/L5 - 100 µg/LNCCapillary length: 48 cm (75 µm); T separation: 25 °C
[136]PlasmaHPLCESI-MS/MS (ion trap)
(SIM mode: α- 919–921 m/z; β- 920–922 m/z)
Quantitative0.5 µg/LNC10–500 µg/L77–79%Column: (150 mm × 2.0 mm) Capcell Pak C18 UG120; Flow rate: 0.2 mL/min; Mobile phase: H2O 0.1% HCOOH (A), ACN 0.1% HCOOH (B); RT: α-: 19.0 min, β-: 20.1 min
[137]MushroomsHPLCESI-TOF-MS
(Full-scan: 100–1000 m/z)
Quantitative30 ng/gNC100–1000 ng/g53.1–69.6%Column: (150 mm × 2.0 mm) 3 µm TSK-gel Amide-80; Flow rate: 1 mL/min; Mobile phase: ACN (A), 15% MeOH in 10 mM ammonium acetate (B)
[11]Serum, urineUPLCESI-MS/MS (triple Q)
(α- 919.6 to 919.6 (20 eV) m/z; β-: 920.6 to 920.6 (20 eV) m/z)
Quantitative0.5–1.5 µg/LNC2–420 µg/L91.3–110%Column: (100 mm × 2.1 mm) 1.7 µm ACQUITY BEH Shield RP18; Flow rate: 0.4 mL/min; Mobile phase: H2O 0.1% HCOOH (A), MeOH (B); RT: α-: 2.23 min, β-: 2.49 min
[138]UrineMALDIESI-TOF-MS-MSQuantitative0.5 µg/LNC10–500 µg/L60–80%-
[139]Urine, liverUPLCESI-MS/MS (triple Q)
(α-: 919.48 to 259.13 (44 eV)/919.48 to 901.53 (28 eV) m/z; β-: 920.48 to 259.13 (42 eV)/920.48 to 902.44 (26 eV) m/z)
Quantitative0.20 µg/L (urine)
10 ng/g (liver)
0.46–0.57 µg/L (urine)
12.3–14.7 ng/g (liver)
10–200 µg/L (et ng/g)90.4–105.0% (urine)
90.2– 12.9% (liver)
Column: (100 mm × 2.1 mm) 1.8 µm ACQUITY HSS T3; Flow rate: 0.5 mL/min; Mobile phase: 0.02 M ammonium acetate pH 5 (A), ACN (B); RT: α-: 5.73 min, β-: 5.27 min
[140]UrineUPLC(-) ESI-HR/MS/MS (orbitrap)
(SIM mode: α-: 917.3458 m/z; β-: 918.3298 m/z)
Quantitative for α-amanitin1 µg/L1 µg/L1–100 µg/L64–102%Column: (150 mm × 2.1 mm) 2.6 µm TF Accucore PhenylHexyl; Mobile phase: 10 mM ammonium acetate in H2O 0.01% HCOOH pH 5 (A), ACN 0.1% HCOOH (B), 2-propanol/ACN (1:1; v/v) (C); RT: α-: 8.23 min, β-: 7.61 min
[141]UrineUPLCHR/MS/MS (orbitrap)
(SIM mode: α-: 919.3614 m/z; β-: 920.3455 m/z)
Quantitativeα-: 0.25 µg/L
β-: 0.5 µg/L
α-: 0.5 µg/L
β-: 0.75 µg/L
1–100 µg/L88.4–93.4%Column: (100 mm × 2.1 mm) 2.6 µm Accucore C18; Flow rate: 0.4 mL/min; Mobile phase: 10 mM ammonium acetate buffer 0.1% HCOOH (A), ACN 0.1% HCOOH (B); RT: α-: 1.9 min, β-: 1.7 min
[142]MushroomsHPLCDAD (303 nm)Quantitative2 ng/gNCNCNCColumn: (150 mm × 4.6 mm) 5 µm C18; Flow rate: 1 mL/min; Mobile phase: 0.05 M ammonium acetate pH 5.5 with HCOOH/ACN (90:10; v/v)
[143]UrineUPLCESI-TOF/MS
(Full-scan 50–1000 m/z)
Quantitative1 µg/LNC1–1000 µg/L86–98%Column: (100 mm × 2.1 mm) 2.2 µm Acclaim RS 120, C18; Flow rate: 0.2 mL/min; Mobile phase: H2O/ACN (99/1; v/v) 2mM ammonium formate, 0.1% HCOOH (A), ACN/H2O (99/1; v/v) 2mM ammonium formate, 0.1% HCOOH (B); RT: α-: 6.05 min, β-: 6.08 min
[144]Rat liver and kidney
Serum
HPLCDAD-EC
(UV: 305 nm)
Quantitative for α-amanitinUV: 110 ng/g (liver)
160 ng/g (kidney)
EC: 70 ng/g (liver)
40 ng/g (kidney)
UV: 330 ng/g (liver)
500 ng/g (kidney)
EC: 210 ng/g (liver)
110 ng/g (kidney)
UV: 330–10000 µg/L (liver)
500–10000 µg/L (kidney)
EC: 210–10000 µg/L (liver)
110–10000 µg/L (kidney)
UV: 99.4% (liver)
100% (kidney)
EC: 98.8% (liver)
99.7% (kidney)
Column: (250 mm × 4.6 mm) 5 µm Spherisorb RP-18 ODS2; Flow rate: 1 mL/min; Mobile phase: 20% MeOH in 50 mM citric acid, 0.46 mM octanessulfonic acid pH 5.5 with 10 M NaOH
[145]Serum, urineUPLCESI-MS/MS (triple Q)
(α-: 919.5 to 259.1 (42 eV)/919.5 to 86.0 (68 eV) m/z; β-: 920.5 to 259.1 (42 eV)/920.5 to 86.0 (71 eV) m/z)
Quantitative0.5–1 ng/g1–2.5 ng/g1–100 µg/L80.7–88.6%Column: (100 mm × 2.1) 1.6 µm; Flow rate: 0.2 mL/min; Mobile phase: 0.2% HCOOH in H2O (A), 0.2% HCOOH in MeOH (B); RT α-: 4.72 min, β-: 4.96 min
[146]Food with mushroomsHPLC(-) ESI-MS/MS (triple Q)
(α-: 917.4 to 205.1/917.4 to 257.1 m/z; β-: 918.4 to 205.1/918.4 to 257.1 m/z)
Quantitative5 ng/g10 ng/g10–2000 ng/g77.6–90.4%Column: (150 mm × 3.0 mm) 2.5 µm XBridge™ BEH C18; Flow rate: 0.3 mL/min; Mobile phase: MeOH (A), 0.03% ammonia solution in H2O pH 10.5 (B)
[147]Rat plasmaHPLC(+) ESI-MS/MS (triple Q)
(MRM: 919.45 to 259.20 (47 eV); 919.45 to 901.45 (26 eV); 919.45 to 86.15 (50 eV) m/z)
Quantitative for α-amanitin3.0 µg/L8.5 µg/L10–1500 µg/L85–115%Column: (100 mm × 2.1 mm) 5 µm Hypersil GOLD C18; Flow rate: 0.2 mL/min; Mobile phase: 0.02 mol/L ammonium acetate, 0.1% HCOOH (A), ACN (B); RT: 4.86 min
[148]Rat plasma and urineHPLCPDA-MS/MS/MS (IT-TOF)
(PDA scan: 190–400 nm; Full-scan: 700–1000 m/z; Multiple stage fragmentation: 100–900 m/z for MS2, 50–900 m/z for MS3)
QualitativeNCNANANAColumn: (100 mm × 2.1 mm) 3µm Inertsil ODS-3; Flow rate: 0.2 mL/min; Mobile Phase: 20 mM ammonium acetate, 0.1% HCOOH (A), ACN (B); RT α-: 11.05 min, β-: 10.20 min
[149]UrineHPLCESI-MS/MS (triple Q)
(α-: 919.3 to 338.9 m/z; 15N10- α-: 929.3 to 911.4 m/z, β-: 920.3 to 644.3 m/z)
Quantitative with 15N10-α-amanitinα-: 0.458 µg/L
β-: 0.930 µg/L
NCα-:1–200 µg/L
β-: 2.5–200 µg/L
α-: 97.8%
β-: 71.1%
Column: (50 mm × 2.1 mm) 1.7 µm Acquity BEH HILIC; Flow rate: gradient; Mobile phase: 10 mM ammonium formate in ACN (25/75; v/v) 1% HCOOH (A), 10 mM ammonium formate in ACN (10/90; v/v) 0.2% HCOOH (B)
[56]Standard solution-PSI-HR-MS/MS
(α-: 919.3610 to 86.0606 m/z; β-: 920.3405 to 86.0606 m/z)
QualitativeNANANANA-
[150]Mushrooms-LFIAQualitativeα-: 10 µg/L
β-: 2000 µg/L
γ-: 10 µg/L
NANANA-
NA: not applicable; LOD: limit of detection; LOQ: limit of quantification; NC: not communicated; RT: retention time; DAD: diode array detection; EC: electrochemical.
Table 5. Cases of ibotenic acid, muscimol, and muscarine poisoning.
Table 5. Cases of ibotenic acid, muscimol, and muscarine poisoning.
Ref.Date of IntoxicationCountryNSex/AgeOffset of Symptoms/Delay before HospitalizationSymptomsTreatmentNotesToxin QuantificationOutcomeMushroom Specie
[162]NCSouth Africa4M/62H 0.5/H1.5Dizziness, tiredness, clouding vision, vomiting, disorders of the state of consciousness, miosis, salivation, twitching, agitation, visual hallucinationsAtropine, diuresis, gastric lavage, rehydration, antibiotic, sedative, analgesicConsumption of 2 tablespoonful-Positive development with mental deficit for 6 weeksAmanita pantherina
F/51Dizziness, tiredness, nausea, miosisGastric lavage, atropine, rehydration, antibiotic, sedative, analgesic
M/16Dizziness, tiredness, clouding vision, nausea, vomiting, salivation, twitchingGastric lavage, atropine, rehydration, sedative, analgesic
M/23H 1/NCTwitching, tiredness, visual problem, disorders of the state of consciousness, salivation, severe respiratory embarrassmentGastric lavage, atropine, rehydration, analeptics, antibiotic, tracheostomy, sedative, analgesic
[163]20 July 1964United States, Massachusetts1M/58H 2/H 4Nausea, vomiting, diarrhea, salivation, blurred vision, twitching, disorientation, disorders of the state of consciousnessGastric lavage, glucose, atropineObesity, concomitant consumption of alcohol-Positive developmentAmanita crenulata
[164]NCFinland3F/27H 2/NCNausea, vomiting, vertigo, twitching, hallucinations, loss of consciousness, salivation, hypothermiaGastric lavage, activated charcoal, glucoseConfusion with Macrolepiota procera; Consumption of fried mushrooms-Positive developmentAmanita regalis
M/55H 2/H 4Nausea, vomiting, disorientation, hallucinations, sudation, hypothermiaActivated charcoalPast of inferior myocardial infarction, renal insufficiency, glaucoma; Consumption of about 2 cooked mushrooms, confusion with Macrolepiota procera
F/53H 1/H 3VomitingActivated charcoalConfusion with Macrolepiota procera, consumption of cooked mushrooms
[165]17 December 1980Zimbabwe2M/10NC/NCNausea, vomiting, dizziness, disorders of the state of consciousness, twitching, mydriasisGlucoseConsumption of a handful of mushrooms-Positive developmentAmanita pantherina
F/20H 0.33/NCNausea, epigastric discomfort, blurred vision, drowsiness, confusion, twitchingDextrose, diuretic, atropineConsumption of cooked mushrooms
[166]27 September 1981United states, New York1M/58H 1.5/H 2.25Nausea, vomiting, diarrhea, sudation, confusion, agitation, disorientation, visual hallucinationsRehydration, gastric lavage, activated charcoalConsumption of cooked mushrooms-Positive developmentAmanita muscaria
[167]NCUnited States, Missouri54 M, 1F/NCH 1/NCVomiting, diarrhea, abdominal cramps, salivation, diaphoresis, tiredness, weakness, mydriasis, blurred vision, bradycardiaAtropine--Positive developmentAmanita muscaria suspected
[168]1979–1989;
Between 6 April 6 and 23 May
United States, Washington118 M, 3 F/11 months to 20 YONCVomiting, incoherent babbling, confusion, irritability, hysteria, hallucinations, myoclonic jerking, lethargy, ataxia, bradycardia, mydriasisSyrup of Ipecac, gastric lavage, charcoal, anticonvulsants, atropine1 voluntary consumption seeking hallucinogenic experience; 1 autistic male-Positive developmentAmanita pantherina, Amanita muscaria
[169]NCPoland5F/18H 0.33/H 5Auditory and visual hallucinations, tiredness, gastric pain, loss of consciousnessActivated charcoal, antidiarrheal, potassium chlorideVoluntary consumption seeking hallucinogenic experience, concomitant consumption of alcohol-Positive developmentAmanita muscaria
[170]NCAustralia1F/53H1/H3Headache, chest and abdominal pain, vomiting, diarrhea, sweating, confusion, hypotension, bradycardia, metabolic and respiratory acidosisIntubation, rehydration, atropine, adrenaline, noradrenaline, metaraminol, glucagon, activated charcoal, dialysisConsumption of 2 mushrooms Death at H10Rubinoboletus sensu lato pro tempe
[171]NCPoland2F/47H2/NCNausea, abdominal pain, vomiting, diarrhea, agitation, vertigo, paresthesia of left arm, mystical experiences, speech disorderNCConfusion with Macrolepiota procera; Consumption of 5 mushrooms-Positive developmentAmanita pantherina
F/27H2/H3Nausea, abdominal pain, vomiting, diarrhea, dizziness, anxiety, humming in headActivated charcoal, laxatives, infusions, electrolytes supplementation
[9]NCSlovenia1M/48H1.5/H4Nausea, vomiting, somnolence, disturbance of consciousness, myoclonus, hypothermia, tachycardia, confusion, visual and auditory hallucinations and paranoia at H18Activated charcoal, midazolam, olanzapineConfusion with Amanita caesarea-paranoid psychosis with auditory and visual hallucinations for 5 daysAmanita muscaria
[172]05 October 2005France2M/67H 2/H 15Vomiting, abdominal pain, diarrhea, sudation, miosis Rehydration, activated charcoal, laxative, atropineMedical history of arterial hypertension, dyslipidemia, renal colic-Positive developmentInocybe patouillardii
F/67H 2/H 15Vomiting, abdominal pain, diarrhea, sudation, miosis, disturbance of consciousness, cardiac arrest, hypothermia, tachycardiaIntubation, adrenaline, atropine, antibiotic, anticonvulsantMedical history of diabetes, arterial hypertension, dyslipidemia, hypothyroidism, restrictive respiratory failure secondary to obesity-Death of postanoxic encephalopathy at J 7
[173]November 2006 to January 2008Israel148–60H 0.25–2/NCNausea, vomiting, abdominal pain, diarrhea, diaphoresis, salivation, lacrimation, tachycardia, blurred vision, miosisRehydration, antiemetic, atropineConfusion with Suillus granulatus and Tricholoma terreum; Consumption of cooked mushrooms-Positive developmentInocybe fastigiata, I. geophylla, I. patouillardii
[174]Autumn 2006Turkey1M/11H 2/NCVomiting, abdominal pain, diarrhea, salivationNCConfusion with Russula sp.; Consumption of cooked mushrooms-Death at D 4Inocybe rimosa
[175]2010France23M/59H 1/NCNausea, vomiting, abdominal pain, sweating, motor and sensory deficit in the lower limbs, bradycardia, miosis, hypothermia, dehydration, functional renal failure, occlusive thrombosisAtropine, surgery for the occlusive thrombosisMedical history of bi-femoral bypass surgery in 1989-Positive developmentNC
F/76H 0.5/NCVomiting, diarrhea, sweating, bradycardia, cardiovascular collapse, miosis, hypothermia, dehydration, functional renal failureAtropineMedical history of lower limb arteriopathy obliterans
[155]NCCzech Republic1M/55NC/NCNCNC-In urine: muscarine: 0.045 mg/LDeathAmanita muscaria
[176]NCCzech Republic4F/28H 1.5/NCVomiting, hallucinationsGastric lavage, activated charcoal, intubation-In urine: IBO at H 4: 47.7 mg/L; MUS at H 4: 9.9 mg/LPositive developmentAmanita pantherina
M/66NC/NCdizzinessGastric lavage, activated charcoalConfusion with Amanita rubescensIn urine: IBO at H 8: 32.2 mg/L; MUS at H 4: 6.0 mg/L
M/62NC/H 6Diarrhea, agitation, incoherenceNC-In urine: IBO at H 6: 55.2 mg/L; MUS at H 6: 7.4 mg/L
F/62NC/H 2.5Nausea, vomiting, hallucinationsActivated charcoal, laxative, diuresis-In urine: IBO at H 3: 37.3 mg/L; MUS at H 3: 7.6 mg/L
[177]NCJapan1M/59NC/NCNCNC-In serum: IBO: 95.9 µg/L; MUS: 105 µg/LPositive developmentAmanita ibotengutake
[178]SpringtimePoland1M/21NC/NCUnconscious, seizure, mydriasis, salivation, hyperthermiaIntubation, gastric lavage, rehydrationVoluntary consumption seeking hallucinogenic experience; Stop his treatment for depression; Consumption of marijuana-Positive developmentAmanita muscaria
N: number of patients; NC: Not communicated; F: female; M: male; H: hour; D: day; IBO: ibotenic acid; MUS: muscimol.
Table 6. Analytical methods for muscarine detection.
Table 6. Analytical methods for muscarine detection.
Ref.MatrixSeparationDetectionQualitative/QuantitativeLODLOQLinearityExtraction RecoveryAdditional Analytical Information
[179]MushroomsTLCReactant of Thies and ReutherQuantitative6 µgNCNCNC-
[180]MushroomsTLCSIMS-MSQualitative10 µg depositNANANA-
HPLCUV (254 nm)QualitativeNCNANANAColumn: (250 mm × 4.6 mm) 10 µm Lichrosorb RP-8; Mobile phase: H2O 1% glacial acetic acid (A), ACN (B)
HPLCMS/MS (triple Q)QualitativeNCNANANA-
[133]MushroomsUPLC-HILICESI-MS/MS (ion trap)
(Scan range: 90–180 m/z)
Quantitative5 ng/g5.1 ng/g5–50 µg/L84–94%Column: (250 mm × 2.0 mm) 5 µm 80 Å TSK-Gel Amide 80; Flow rate: 0.2 mL/min; Mobile phase: 2 mM ammonium formate + 5 mM HCOOH (A), ACN (B), MeOH (C); RT: ≈ 9.5 min
[158]UrineHPLCESI-MS
(Full-scan mode)
Qualitative3 µg/LNCNC90%Column: (150 mm × 2.0) 5 µm Gemini C18; Flow rate: 0.2 mL/min; Mobile phase: 8 mmol/L heptafluorobutyric acid in H2O; RT: 14.2 min
[155]UrineHPLCESI-MSQuantitative0.09 µg/L0.3 µg/L0.3–2000 µg/L95–96%Column: (150 mm × 2.0 mm) 5 µm Gemini C18; Flow rate: 0.2 mL/min; Mobile phase: 8 mmol/L heptafluorobutyric acid in H2O (A), ACN (B); RT: 10.0 min
[181]MushroomsHPLCESI-MS/MS (triple Q)
(SRM mode: 174 to 57;174 to 115; 174 to 60;174 to 97 m/z)
QuantitativeNCNCNCNCColumn: (150 mm × 2.0 mm) 5 µm 110 Å Gemini C18; Flow rate: 0.15 mL/min; Mobile phase: H2O (A), ACN (B); RT: 1.8 min
[182]UrineElectrophoresisESI-MS/MS (triple Q)
(SIM and MRM mode)
Quantitative0.73 µg/LNC0.1–10.00 mg/L92.6–95.4%Capillary length: 100 cm (50 µm); Sheath liquid: H2O/MeOH/CH3COOH (20/79.65/0.35 v/v/v/); Flow rate: 0.4 mL/min
[143]UrineUPLCESI-TOF/MS
(Full-scan 50–1000 m/z)
Quantitative0.09 µg/LNC0.1–100 µg/L97%Column: (100 mm × 2.1 mm) 2.2 µm Acclaim RS 120, C18; Flow rate: 0.2 mL/min; Mobile phase: H2O/ACN (99/1; v/v) 2 mM ammonium formate, 0.1% HCOOH (A), ACN/H2O (99/1; v/v) 2 mM ammonium formate, 0.1% HCOOH (B); RT: 2.05 min
[56]Standard solution-PSI-HR-MS/MS
(α-: 174.1486 to 174.1486 m/z)
QualitativeNANANANA-
NA: not applicable; LOD: limit of detection; LOQ: limit of quantification; NC: not communicated; RT: retention time.
Table 7. Analytical methods for ibotenic acid and muscimol detection.
Table 7. Analytical methods for ibotenic acid and muscimol detection.
Ref.MatrixSeparationDetectionQualitative/QuantitativeLODLOQLinearityExtraction RecoveryAdditional Analytical Information
[199]MushroomsGCMSQuantitativeNCNCNCNCColumns: (0.75 m × 2.8 mm) OV-101 and (1.2 m × 2.8 mm) SE-30; Helium flow rate: 20 mL/min; T transfer line: 175 °C
[200]MushroomsHPLCUV (440, 570 nm)Quantitative30 ngNCNCNCColumn: (350 mm × 2.7 mm); RT IBO: 11 min, MUS: 83 min
[188]MushroomsHPLCUV (210 nm)Quantitative1 ppmNCNC<98%Column: (25 mm × 4.0 mm) IRICA RP-18T; Flow rate: 0.6 mL/min; Mobile phase: H2O/ACN/MeOH (65:20:15; v/v/v) with 2.1 mM sodium dodecyl sulfate + 4 mM H3PO4, isocratic mode
[201]MushroomsHPLCUV (230, 254 nm)Quantitative18 µg/L IBO
0 µg/L MUS
NC50–1000 µg/L IBO
100–3000 µg/L MUS
NCColumn: (250 mm × 4.6 mm) 5 µm Spherisorb S5 ODS-2; Flow rate: 0.1 mL/min; Mobile phase: 5 mM octylammonium o-phosphate
[202]MushroomsHPLCPDAQuantitative just of IBONCNCNCNCPreparative column IBO: (115 mm × 13 mm) C18; Flow rate IBO: 0.5 mL/min; RT IBO: 8.2 min; Column MUS: (150 mm × 4.6) Zorbax SB-Aq; Flow rate MUS: 1.0 mL/min; RT MUS: 12.8 min; Mobile phase: H2O/ACN/MeOH (65:20:15; v/v/v) with 2.1 mM sodium dodecyl sulfate + 4 mM H3PO4, isocratic mode
HPLCUV-MS
(UV: 254 nm)
Column: (100 mm × 2.1 mm) 5 µm XTerraTM MS C18; Flow rate: 0.5 mL/min; Mobile phase: H2O/MeOH (19:1; v/v) to ACN/H2O/MeOH (18:1:1; v/v/v)
[203]MushroomsHPLCESI-MS/MS (triple Q)
(IBO: 159 to 113.1;159 to 42.3 m/z; MUS: 115.1 to 98.1; 115.1 to 67.2; 115.1 to 39.4 m/z)
QuantitativeNCNCNCNCColumn: (150 mm × 2.1 mm) 5 µm Uptisphère ODB C18; Flow rate: 0.2 mL/min; Mobile phase: 2mM ammonium formiate buffer pH 3 (A), ACN (B)
[189]MushroomsGCMS
(SIM: IBO: 257 m/z, MUS: 243 m/z)
Quantitative IBO/MUSNCNC10–400 ppm IBO
25–2000 ppm MUS
NCColumn: (30 m × 0.25 mm) 0.25 µm DB-5 ms; Helium flow rate: 53 mL/min; T injector: 250 °C; Toven: 100 °C
[204]MushroomsHPLCUV (256 nm)Quantitative7.8 ppm IBO
1.4 ppm MUS
25.9 ppm IBO
4.6 ppm MUS
40–2500 ppm IBO
25–2500 ppm MUS
95.4–101.1%Column: (150 mm × 2.1 mm) 3.5 µm Symmetry C18; Flow rate: 0.2 mL/min; Mobile phase: 10 mM ammonium acetate (A), ACN (B); RT IBO: 25.92 min, MUS: 24.65 min
LCESI-MS/MS (ion trap)
(IBO: 419 to 355; 419 to 235; 419 to 183 m/z; MUS: 347 to 317; 347 to 276; 347 to 226; 347 to 183 m/z)
Qualitative25 ppmNANANA
[158]UrineHPLCESI-MS
(Full-scan mode)
Qualitative50 µg/L IBO
40 µg/L MUS
NCNC15% IBO
22% MUS
Column: (150 mm × 2.0 mm) 5 µm Gemini C18; Flow rate: 0.2 mL/min; Mobile phase: 8 mmol/L heptafluorobutyric acid in H2O; RT: IBO 2.6 min, MUS 4.6 min
[176]UrineGCMS
(Full Scan: 40–400 m/z and SIM: MUS: 113 m/z; IBO: 257 m/z)
Quantitative1 mg/LNC1–15 mg/L74% IBO
80% MUS
Column: (15 m × 0.25 mm) 0.25 µm HP-5MS; Helium flow rate: 1.5 mL/min; T injector: 220 °C; T transfer line: 250 °C
[186]MushroomsLC-HILICESI-MS/MS (triple Q)
(IBO: 159 to 113.1 m/z; MUS: 115 to 98.1 m/z)
Quantitative<10 µg/gNC10–500 µg/g84.6–107%Column: (150 mm × 2.0 mm) 3 µm TSK-GEL Amide-80; Flow rate: 0.5 mL/min; Mobile phase: H2O 0.5% HCOOH (A), ACN 0.5% HCOOH (B)
[177]SerumLC-HILICESI-MS/MS (triple Q)
(IBO: 159 to 113.1 m/z; MUS: 115 to 98.1 m/z)
Quantitative1 µg/L IBO
2.5 µg/L MUS
NC10–1000 µg/L87.9–103%Column: (150 mm × 2.0 mm) 3 µm TSK-GEL Amide-80; Flow rate: 0.5 mL/min; Mobile phase: H2O 0.5% HCOOH (A), ACN 0.5% HCOOH (B)
[187]MushroomsElectrophoresisPDA (214 nm)Quantitative1.5 µg/g IBO
1.8 µg/g MUS
4.6 µg/g IBO
5.4 µg/g MUS
2.5–7000 mg/L87–95%Capillary length: 57 cm (75 µm); Running buffer: 25 mM sodium phosphate pH 3 (5:95; v/v)
[182]UrineElectrophoresisESI-MS/MS (triple Q)
(SIM and MRM mode)
Quantitative0.15 µg/L IBO
0.05 µg/L MUS
NC10–1000 µg/L92.6–95.4%Capillary length: 100 cm (50 µm); Flow rate: 0.4 mL/min; Sheath liquid: H2O/MeOH/CH3COOH (20/79.65/0.35; v/v/v)
[205]UrineNMR-Quantitative30 mg/L IBO
3 mg/L MUS
NC2–417 mg/L IBO
3–278 mg/L MUS
NC-
[56]Standard solution-PSI-HR-MS/MS
(IBO: 159.0397 to 113.0348 m/z MUS: 115.0504 to 98.0241 m/z)
QualitativeNANANANA-
NA: not applicable; LOD: limit of detection; LOQ: limit of quantification; NC: not communicated; RT: retention time; IBO: ibotenic acid; MUS: muscimol.
Table 8. Cases of gyromitrine poisoning.
Table 8. Cases of gyromitrine poisoning.
Ref.Date of intoxicationCountryNSex/AgeOffset of symptoms/Delay before hospitalizationSymptomsTreatmentNotesToxin QuantificationOutcomeMushroom specie
[214]11 May 1935United States, Michigan7F/69NC/D 1Vomiting, severe chest and legs pain, fever, tachycardia, convulsions, comaMorphine, atropine, stomach wash, caffeine, sodium benzoateConsumption of dried mushrooms after having been parboiled-Death at D 5Gyromitra esculenta
[215]Between 1782 and 1965Eastern EuropeMinimum of 654--Gastrointestinal disordersNC--At least 114 deathGyromitra esculenta
[216]9 June 1962France1F/8D 3/NCVomiting, agitation, delirium, bilateral mydriasis, coma, muscular hypertonia, arterial hypertensionNCConsumption on 2 occasions-Death of liver failureGyromitra esculenta
April 19643F/7H 12/NCVomiting, subictus, delirium, agitation, coma, oliguria, fever, respiratory collapse, liver failureTracheotomy, artificial ventilationConsumption several times over 3 weeks-Death of liver failure at H 102
F/4Vomiting, liver failureNCPositive development
F/NCVomiting, asthenia, subictus, liver failurePositive development
Between 1817 and 1965NC282NC/NCNC/NCVomitingNC-21 death
[206]NCItaly1F/53D 1/D 1Vomiting, diarrhea, jaundice, hypotension, anuria, severe enlargement of the liver, right hemiplegia, comaPlasma infusion, corticosteroidsAutopsy: liver necrosis, brain oedema, TLC on intestine extractDeath at D 3Gyromitra esculenta
[212]SpringtimeCanada2F/49H 2/D 1Nausea, vomiting, abdominal pain, hot and cold chills, fatigue, anorexia, jaundiceRehydration, analgesic, antiemetic, Vitamin B6, antacid, antihistamineAST on D 5: 431 U/L; ALT on D 5: 472 U/L-Positive developmentGyromitra esculenta
M/56NC/D 1Nausea, vomiting, abdominal pain, jaundice, headacheAST on D 4: 116 U/L-
N: number of patients; NC: not communicated; F: female; M: male; H: hour; D: day; AST: aspartate aminotransferase; ALT: alanine aminotransferase.
Table 9. Analytical methods for gyromitrine detection.
Table 9. Analytical methods for gyromitrine detection.
Ref.MatrixSeparationDetectionQualitative/QuantitativeLODLOQLinearityExtraction RecoveryAdditional Analytical Information
[206]VisceraTLCUV (254–277 nm)
IR (NC)
Qualitative and quantitativeNCNC0.1–0.5 g/LNC-
[219]Mice gastric content GCUV and IRQuantitativeNCNCNCNCColumn: (2 mm × 2 mm) Chromosorb 103; T column: 160 °C; Helium flow rate: 20 mL/min; RT: GYRO: 17 min, MFH: 15.7 min
[220]MushroomsGCMSQuantitativeNCNCNCNCColumn: 50 m FFAP
[221]Mice peritoneal fluidsGCMSQuantitative (MH)NCNCNCNC-
[222]MushroomsTLCSpectrofluorimetry
excitation = 340 nm; λemission = 610 nm)
QuantitativeNCNC0.43–2.17 ngNC-
[223]MushroomsGCFIDQuantitativeNCNCNC30–74% GYRO
96–124% MH
Column: (25 mm × 0.31 mm) SE-54; Helium flow rate: 1 mL/min; RT: 7.3 min
[224]MushroomsGCEI-MS
(Full-scan 35–650 m/z)
QuantitativeMH: 12 µg/L = 0.3 µg/g of gyromitrinNCNC–1.2 mg/L36–55%Column: (30 mm × 0.25 mm) 0.25 µm HP5-MS
[56]Standard solution-PSI-HR-MS/MS
(101.0713 to 73.0764 m/z)
QualitativeNANANANA-
NA: not applicable; LOD: limit of detection; LOQ: limit of quantification; NC: not communicated; GYRO: gyromitrin; MFH: N-methyl-N-formylhydrazine; MH: methylhydrazine.
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MDPI and ACS Style

Flament, E.; Guitton, J.; Gaulier, J.-M.; Gaillard, Y. Human Poisoning from Poisonous Higher Fungi: Focus on Analytical Toxicology and Case Reports in Forensic Toxicology. Pharmaceuticals 2020, 13, 454. https://doi.org/10.3390/ph13120454

AMA Style

Flament E, Guitton J, Gaulier J-M, Gaillard Y. Human Poisoning from Poisonous Higher Fungi: Focus on Analytical Toxicology and Case Reports in Forensic Toxicology. Pharmaceuticals. 2020; 13(12):454. https://doi.org/10.3390/ph13120454

Chicago/Turabian Style

Flament, Estelle, Jérôme Guitton, Jean-Michel Gaulier, and Yvan Gaillard. 2020. "Human Poisoning from Poisonous Higher Fungi: Focus on Analytical Toxicology and Case Reports in Forensic Toxicology" Pharmaceuticals 13, no. 12: 454. https://doi.org/10.3390/ph13120454

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