eMedicine Specialties > Pediatrics: Cardiac Disease and Critical Care Medicine > Toxicology

Toxicity, Mushrooms - Muscarine

Author: Martin I Herman, MD, FACEP, FAAP, Professor, Department of Pediatrics, Division of Critical Care and Emergency Medicine, University of Tennessee Health Sciences Center; President, Pediatric Emergency Services Specialists,PC; Assistant Medical Director of Emergency Services, LeBonheur Children's Medical Center
Coauthor(s): Peter Chyka, PharmD, FACCT, DABAT, Professor, Department of Clinical Pharmacy, University of Tennessee Health Science Center
Contributor Information and Disclosures

Updated: Feb 12, 2008

Introduction

Background

Muscarine was first extracted from Amanita muscaria (fly agaric) in 1869. It played an important part in delineating the role of acetylcholine (ACh) in neurohumoral physiology. In fact, since the late 1800s, pharmacologists have referred to the effects of stimulation of postganglionic choline receptors as the muscarinic effects of ACh.

An ironic note is that A muscaria provided the first source of muscarine (hence its name) but actually contains miniscule amounts of muscarine (0.005%). To produce a toxic effect, mushrooms must contain at least 0.01% of muscarine (as described in the Poisindex).¹ Mushrooms from the genera Inocybe and Clitocybe reliably contain sufficient amounts of this toxin. In fact, one species, Clitocybe dealbata, is so well known for its reliably high muscarine content that it is commonly referred to as the sweating mushroom. Mushrooms in the genera Boletus, Omphalotus, or Amanita may also contain some muscarine. Bear in mind that the muscarine content may vary from plant to plant, depending on where they are grown, on how they are prepared, or on how they are stored.

Mushrooms, which are classified as fungi, differ from other plants because they do not have chlorophyll. They have been a part of the human diet for years because they are a source of protein and essential amino acids. The edible varieties satisfy gustatory pleasures while providing nutritional value. They are generally low in calories and cholesterol and can improve the immune system and blood pressure. Because they are promoted for their nutrient values, many grocery stores now carry various commercially grown mushrooms, including shiitake, portabella, morels, chanterelle, oyster, and other mushrooms. The commercially grown, cultured mushrooms are the safest to enjoy.

Increased awareness and interest in the large variety of mushrooms found around the world has led to growing interest in foraging for wild mushrooms. Although finding mushroom delicacies in the wild may be satisfying, caution is required because many mushrooms contain deadly toxins. The challenge to all who forage for mushrooms is that they must be able to distinguish truffles (edible varieties) from toadstools (from the German todesstuhl, which means "death stool").

Mistaking a toxic mushroom for an edible one is the most common cause of poisoning. This problem might be especially important among immigrant populations if they mistake a toxic variety indigenous to their new country for a nontoxic variety they were used to eating in their homeland.

Fortunately, mushroom poisoning is rare. Of the roughly 5000 known mushroom species, approximately 200-300 are edible, and only 50-100 are poisonous. The odds are clearly favorable when one ingests an unidentified mushroom. However, approximately 7000 mushroom ingestions are reported every year to the American Association of Poison Control Centers (AAPCC) Poison Exposure Database.²

Children and adolescents younger than 19 years account for 78% of all reported ingestions. Many ingestions in children younger than 6 years are unintentional and consist of a child simply tasting a mushroom found growing in their yard or play area. This is not the case for ingestions in older children. Adolescents are most likely to engage in a misguided attempt to experience hallucinogenic effects of magic mushrooms or to intentionally ingest toxic mushrooms to commit suicide. Of note, poisonings can also occur when otherwise edible mushrooms are improperly stored, prepared, or cooked. Some unintentional ingestions might result from the purchase of misidentified or adulterated mushroom products through unregulated marketers on the Internet or other illicit sources.

Classes of mushroom toxins

Muscarine is one of the commonly accepted classes of mushroom toxins. Toxin groups include the following:

• Cyclopeptide (eg, Amanita phalloides) and cyclopeptide and/or orellanine (Cortinarius mushrooms)
• Ibotenic acid and/or muscimol (Amanita muscaria, Amanita pantherina)
• Gyromitrin or monomethylhydrazine (genus Gyromitra)
• Muscarine (Inocybe and Clitocybe mushrooms)
• Coprine (Coprinus atramentarius) (ie, inky cap)
• Psilocybin (Psilocybe and Paneolus mushrooms, magic mushrooms)
• GI irritants
• Miscellaneous

Distribution and recognition of mushrooms

Mushrooms that contain muscarine are commonly found in yards and public parks. Their prevalence and enticing appearance may pose a challenge to parents as they try to keep their children from sampling these potentially toxic plants. Clitocybe, Inocybe, and Amanita species are among those most commonly involved in muscarinic poisoning. Being able to recognizing these mushrooms and to educate parents and children about their dangers is important.

Clitocybe mushrooms are found as single specimens on lawns in the summer and fall. The mushrooms are whitish tan-to-gray and have 15- to 33-mm caps. Their stalks are hairless and are 1- to 5-cm long. Their gills are decurrent (running down the stalk), and the spores are white.

Inocybe mushrooms are typically found in or under hardwoods and conifers in the summer and fall. The mushrooms are small and brown and have conical caps as large as 6 cm in diameter. Stalks are 2-10 cm and have fine, brown-to-white hairs. The gills are notches, and the spores are brown.

A muscaria can occur singly or in groups, and it is found on the ground of forests, grassy areas, and lawns, especially under trees. The mushroom has a scarlet cap 5-30 cm in diameter, with warts. The stalk is white, frequently hollow, and often as long as 15-20 cm. A prominent cup (volva) is found at the bottom of the stalk with numerous rings extending superiorly. The gills are free and white. The spores are also white. The appearance varies depending on the geographic location. The scarlet red cap is found predominantly in western parts of North America. In eastern North America, the cap is orange to yellow-orange.

Classification systems

Because of the large numbers of mushroom species and difficulties in their identification, toxicologists have struggled with developing a system to facilitate the recognition of mushrooms and the treatment of mushroom ingestion.

In 1987, a group started in Germany proposed classifying mushroom poisonings on the basis of (1) a description of the mushroom, (2) toxicologic analysis, and (3) the patient's presenting signs and symptoms.

Because the lag time to toxicity appears to be an important factor, any system of classification should incorporate this lag. According to several observers, latent periods of >12 hours differentiate the lethal amatoxin poisonings from less serious, early-onset poisonings involving other toxins. People working with mushroom poisonings have known that notable mushroom toxicity can occur before 12 hours and suggest use of a lag time of >6 hours to separate the clinically significant ingestions of amanitin and gyromitrin from less toxic ingestions. Of course, serious ingestions may be neglected if they have a short onset time to GI irritation followed by serious problems, such as seizures, renal failure, liver failure, or hemolytic anemia.

To refine the current classification scheme, a toxin-directed system was developed. Mushroom ingestions may be classified on the basis of evidence of poisoning from the following toxins: amanitin, orellanine, gyromitrin, muscarine, pantherine, psilocybin, coprine, Paxillus toxin, and miscellaneous GI irritants. This system, which was originally proposed in Europe, was adapted for use in the United States. Table 1 below shows this toxin-based scheme.

US and European Classes of Mushroom Toxins

Open table in new window

An unfortunate feature is that all of the systems of nomenclature fail to recognize newly discovered toxic effects, such as those causing acute renal failure, delayed renal failure, rhabdomyolysis, and delayed CNS failure. To address these shortcomings, some have proposed simplifying the classification system by basing it on whether the toxins are hepatotoxic, nephrotoxic, neurotoxic, psychotropic, myotoxic, or gastroenteric.

Old taxonomy clearly fails to consider the lag times of various poisons. Although the 6-hour cutoff works well for amatoxin and gyromitrin toxicity, it causes some early onset toxicities to be missed and underestimates the need for the prolonged care needed in patients with delayed-onset toxicities.

When one combines the type of toxin and the onset of its effects, a new, time-to-onset–stratified, syndromic system emerges. This approach may enable early detection and enable application specific therapies, including transplantation.

A classification of 14 syndromic categories of mushroom poisoning has been proposed. This classification system includes an improved definition of the miscellaneous category but has yet to be widely adopted.³ Muscarine is designated as an early-onset (<6 h) cholinergic neurotoxin in this new system.

• Early onset (<6 h)
  • Neurotoxic
    • Cholinergic (muscarine type, eg, from Clitocybe and Inocybe mushrooms)
    • Glutamatergic (isoxazoles, eg, muscimol, ibotenic acid from A muscaria or A pantherina)
    • Epileptogenic (monomethylhydrazines from Gyromitra species)
    • Hallucinogenic (eg, from Psilocybe mushrooms)
  • Allergic
    • Immunohemolytic (from Paxillus, or poison pax; not included in old taxonomy)
    • Pneumonic (puffballs, not included in old classifications)
  • GI
    • Disulfiram reaction (old coprine toxin group)
    • Miscellaneous toxins causing GI distress
• Late onset (6-24 h)
  • Hepatotoxic (with amatoxic [cyclopeptide] subgroup)
  • Nephrotoxic (previously unclassified)
  • Erythromelalgic (previously unclassified)
• Delayed (³ 24 h): Orellanine is now considered a late-onset nephrotoxin. Toxins derived from Tricholoma equestre (yellow Trich) and Russula subnigricans (blackening Russula) are the rhabdomyolytic late-onset toxins. The purple-dye toxin (from Hapalopilus rutilans) is a late-onset neurotoxin.
  • Nephrotoxic
  • Rhabdomyolytic
  • Neurotoxic

Perhaps clinicians will use this new syndromic classification system in the near future to quickly recognize possible mushroom poisonings and to make appropriate decisions regarding intervention, observation, and follow-up.

Pathophysiology

Mechanism of action

As noted above, muscarine is one of the 8 major mushroom toxins. It exerts its effects by means of the autonomic nervous system. The autonomic nervous system is composed of the sympathetic and parasympathetic systems and uses ACh as the chemical transmitter at both preganglionic and postganglionic synapses in the parasympathetic system. ACh is also the neurotransmitter at sympathetic preganglionic synapses, at some sympathetic postganglionic synapses, at the neuromuscular junction (somatic nervous system), and at some sites in the CNS. Nerve fibers that release ACh from their endings are described as cholinergic fibers.

ACh receptors are ligand-gated cation channels composed of 4 polypeptide subunits arranged in the form (a₂)(b)(g)(d). Two main classes of ACh receptors are recognized and are differentiated by their response to nicotine or muscarine.

When ACh stimulates preganglionic synapses, it produces sympathetic effects at various end organs of the autonomic system. These effects can be reproduced with the administration of nicotine as therefore are known as the nicotinic effects of ACh. ACh may also stimulate postganglionic receptors to produce effects such as salivation, lacrimation, defecation, micturition, sweating, miosis, bradycardia, and bronchospasm. Muscarine produces these effects, and hence they are referred to as muscarinic effects, and the postganglionic receptors are called muscarine receptors. Muscarinic receptors are the most diffuse receptors and are G-protein coupled. Two subgroups have been identified: M1 and M2. M1 receptors are excitatory, and M2 receptors are inhibitory. By convention, the muscarinic effects of various drugs are also referred to as cholinergic effects.

Muscarine is a quaternary trimethyl ammonium salt of 2-methyl-3-oxy-5-(amino)-tetrahydrofuran. It can stimulate both the M1 and M2 types of postganglionic cholinergic receptors (muscarinic receptors). When it does, it results in parasympathetic stimulation similar to that caused by the release of endogenous ACh. Because it is a quaternary salt, muscarine does not readily cross the blood-brain barrier. As a result, it causes few, if any, CNS symptoms. Muscarine is not metabolized by cholinesterase and therefore has a long biologic half-life.

Toxicity

The lethal dose is estimated to be 40-180 mg.

Frequency

United States

In 2005, 7146 mushroom ingestions were reported by US poison control centers.²  Nineteen (0.3%) were attributed to the muscarine-containing group of toadstools. Four (21%) of the 19 patients were children younger than 19 years of age. The 15 others (79%) were over 19 years.

International

In Europe, the incidence of all types of toxic mushroom ingestions is higher than that of the United States. An average of 70 cases per year occurs in Japan. Other countries, such as China and South Africa, also report mushroom toxicities. Whether these toxicities are due to mushrooms containing muscarine is not known.

Mortality/Morbidity

Fatalities from mushroom poisoning are rare but do occur.

• In Japan, 3-4 fatal cases due to mushrooms are reported per year, but whether muscarine is involved is unknown.
• Deaths due to Inocybe patouillardii have been reported in Europe.
• In 2005, 6 deaths were reported to US poison control centers, but none were due to muscarine-containing mushrooms.² No deaths in the United States have been attributed to muscarine toxicity in the last 20 years.

Age

• Adults often forage for morels or truffles. Because toxin-containing mushrooms may appear similar to edible mushrooms and because they grow in the same areas because of their similar nutrient requirements, erroneous identification and ingestion may occur. Immigrant groups unfortunately mistake toxic, mushrooms in their new countries for edible mushrooms that grow in their native countries.
• Children are primarily poisoned by sampling wild mushrooms on their own or when an adult feeds them a poison mushroom, intentionally or not.
• Teens may ingest toxic mushrooms in a quest for a drug-toxin induced hallucinogenic experience. Lay information and misinformation are certainly factors with the widespread growth of Internet sites that promote the ingestion of wild mushrooms for their effects.

Clinical

History

Assess the following:

• Quantity of mushrooms ingested
• Preparation of the mushroom
• Time of the ingestion
• Symptoms
• Timing of symptom onset
• Treatment before the patient's arrival
• Other medications, coingestants
• Past medical history
  • Heart block
  • Asthma
  • Prostate hypertrophy
  • Gastric disorders
  • Gastric outlet obstruction
• Possibility of adulterants, such as pesticides

Physical

Signs and symptoms related to the ingestion of a muscarine-containing mushroom typically appear after 0.5-2 hours and may last 6-24 hours. Muscarinic effects, such as sweating, salivation, lacrimation, urination, defecation, gastric cramping, miosis, emesis, bronchospasm, and bradycardia are seen. Profuse sweating is a prominent feature and should alert the provider to the possibility of a cholinergic poisoning.

The acronyms SLUDGE (salivation, urination, diarrhea, gastric upset, and emesis) and DUMBBELS (diarrhea, urination, miosis, bradycardia, bronchospasm, emesis, lacrimation, and salivation) may be useful memory aids.

• Vital signs
  • Pulse - Reflex tachycardia or bradycardia
  • Respiration - Unaffected to labored with bronchospasm
  • Blood pressure - Hypotension
• Integumentary findings
  • Flushing
  • Sweating
• Head, ears, eyes, nose, and throat findings
  • Pupillary constriction
  • Blurred vision
  • Copious secretions
  • Watery eyes
  • Tearing
• Cardiovascular symptoms
  • Reflex tachycardia
  • Bradycardia (more commonly)
• Respiratory signs
  • Copious bronchial secretion
  • Wheezing
  • Shortness of breath
• GI symptoms
  • Cramping
  • Vomiting
  • Increased bowel activity
  • Diarrhea
• Urinary tract symptoms
  • Bladder spasms
  • Ureteral spasms
  • Increased urination
• Neurologic signs
  • Headache
  • Ataxia
  • Seizures (uncommon)

Causes

• Erroneous identification and ingestion of a wild mushroom containing the muscarine toxin is one cause.
• Reliance on various urban myths regarding the ability to detect a poisonous mushroom from an edible one is another cause. Myths include the following:
  • Staining of silver is an indicator or lack of safety.
  • The person can peel the mushroom cap or rely on the presence of bugs and slugs. These are unreliable safety markers.
  • The person can evaluate the particular habitat where a mushroom grows to predict the safety of the plant. This thought is erroneous.
• Children fed mushrooms that were incorrectly identified.
• Children may sample or taste toxic mushrooms they find in yards or picnic areas.
• Inadvertent poisoning can occur after a person ingests dried mushrooms purchased on the Internet or from other sources where the composition of the mushroom may be unreliable or where the mushrooms may be contaminated with unknown toxic compounds.

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