eMedicine Specialties > Emergency Medicine > Toxicology

Toxicity, Mushroom - Disulfiramlike Toxins

C Crawford Mechem, MD, MS, FACEP, Associate Professor, Department of Emergency Medicine, University of Pennsylvania School of Medicine; Emergency Medical Services Medical Director, Philadelphia Fire Department

Updated: Jun 1, 2009

Introduction

Background

Edible wild mushrooms often are gathered by foragers and prized for their taste. Occasionally, toxic mushrooms are mistaken for edible species, and human poisoning occurs. In addition, some food aficionados around the globe will intentionally eat certain mushrooms, despite their content of known toxins. For example, Coprinus atramentarius contains the heat-stable toxin, coprine, which only causes toxicity when consumed with ethanol. Because victims of mushroom poisoning will most commonly seek initial medical care in emergency departments, it is important that emergency physicians be familiar with the diverse signs and symptoms of mushroom toxicity.

Coprinus atramentarius

C atramentarius, a member of Coprinaceae or inky cap family, is known familiarly as alcohol inky or inky cap. This mushroom is found particularly during autumn months in urban regions and along roadsides throughout the United States. Its cap is gray-brown, egg-shaped, smooth, and 2-3 inches in width. These mushrooms deliquesce, with gill tissue autodigesting to dark inky liquid after picking and with maturation.

Other coprine-containing mushrooms

Other Coprinus mushrooms that contain coprine include Coprinus insignis, Coprinus quadrifidus, and Coprinus variegatus. Some Coprinus mushrooms generally are not toxic, such as Coprinus comatus (ie, shaggy mane, lawyer's wig), which is sought for its asparagus-like qualities.

Clitocybe clavipes

C clavipes, of the family Tricholomataceae, is also associated with disulfiramlike reactions. However, coprine has not been identified in this species. C clavipes tends to grow in conifer trees or mixed woods and fruits in late autumn or winter. Its cap is gray-brown, mostly flat, and 1-3 inches in width. Gill extends down a stem that is club shaped and thickened near the base. C clavipes is commonly called fat-footed clitocybe or clubfoot funnel cap.

Pathophysiology

C atramentarius contains coprine (N5-1-hydroxycyclopropyl-L-glutamine), a protoxin without intrinsic toxicity. Coprine is metabolized to 1-aminocyclopropanol, which inhibits the enzyme aldehyde dehydrogenase (ALDH). ALDH catalyzes conversion of acetaldehyde to acetic acid.

Inhibition of ALDH produces a clinical syndrome similar to disulfiram (Antabuse) alcohol reaction. Disulfiram has been widely used in the manufacture of rubber since the 1800s. In 1937, an American chemical plant physician noted that employees exposed to disulfiram in the workplace developed a constellation of symptoms after drinking ethanol. These included flushing, headache, nausea, palpitations, and dyspnea, and the symptoms were severe enough to promote abstinence from ethanol. In later years, the basis for this effect, the disulfiram-mediated inhibition of ALDH, was discovered. Ethanol usually is metabolized by alcohol dehydrogenase to acetaldehyde, which is then metabolized by ALDH to acetate and carbon dioxide. Accumulation of acetaldehyde leads to the clinical manifestations of the disulfiram-ethanol interaction.

Disulfiram has been widely used in the treatment of alcohol dependence, although its benefits are the subject of controversy. It has also been used more recently in the management of cocaine dependence.^1,2  

After ingestion of coprine-containing mushrooms, ALDH is inhibited and consumption of ethanol results in acetaldehyde accumulation. This inhibition of ALDH takes at least 30 minutes, which is the time required to metabolize inactive coprine to active 1-aminocyclopropanol. Therefore, small volumes of ethanol ingested concomitantly with mushrooms may not cause toxicity. Enzyme inhibition generally persists for approximately 72 hours but may continue for 5 days. Ingestion of ethanol 3 days after mushroom ingestion may produce acetaldehyde toxicity.

Unlike disulfiram, coprine does not appear to inhibit dopamine beta-hydroxylase, the enzyme that hydroxylates dopamine to form norepinephrine within storage vesicles of presynaptic neurons. In experimental models, rats exposed to coprine are capable of eliciting a tachycardic response to ethanol challenge; those exposed to disulfiram are not capable of eliciting this response (presumably due to inhibition of dopamine beta-hydroxylase). Whether a similar response occurs in humans is unknown.

Frequency

United States

According to the 2007 Annual Report of the American Association of Poison Control Centers' National Poison Data System (NPDS), coprine-containing mushrooms account for a minority of reported mushroom exposures. Of 7733 mushroom exposures reported in 2007, only 16 cases were strongly suspected or confirmed to be related to coprine-containing mushrooms. Seven of these patients were treated in a health care facility. No deaths were reported.³

International

No adequate database exists to determine frequency of coprine exposure or toxicity internationally, although some sources suggest a 1-3% frequency of all reported mushroom poisonings.

Mortality/Morbidity

• With appropriate supportive care, morbidity associated with coprine-induced acetaldehyde toxicity is minimal and recovery is generally complete.
• Mortality and morbidity rates due to secondary effects, such as dehydration or cardiovascular collapse, are unknown. Esophageal rupture attributed to vomiting following co-ingestion of ethanol and coprine-containing mushrooms has been reported, but such cases appear to be infrequent. 

Age

Since ethanol ingestion precedes toxicity, children generally are not affected.

Clinical

History

History of mushroom ingestion is helpful. Raw and cooked mushrooms as well as the cooking water are capable of producing toxicity through ALDH inhibition. Symptoms begin within minutes of ethanol ingestion. Patients may relate symptoms to ethanol, not mushrooms. Ascertaining if other species of wild mushrooms were ingested concomitantly and the approximate elapsed time since ingestion is important. 

• Flushing or blotching red rash (face, neck, thorax)
• Sense of face and hand swelling
• Diaphoresis
• Palpitations/chest pain
• Dyspnea/hyperventilation
• Nausea/vomiting
• Metallic taste
• Headache
• Vertigo/dizziness
• Tingling paresthesias (perhaps due to hyperventilation)
• Apprehension/sense of impending doom
• Weakness

Physical

• Hypertension
• Hypotension
• Tachycardia (occasionally dysrhythmias)
• Flush, particularly of upper half of body (occasionally blotchy red rash of thorax and neck with facial erythema)
• Diaphoresis
• Confusion

Causes

An association with ethanol always exists, although ethanol use may be unintentional (eg, cough syrup).

Differential Diagnoses

Other Problems to Be Considered

Allergic reaction
Other disulfiramlike reactions (eg, metronidazole, oral hypoglycemic agents, carbon disulfide, thiram herbicides)
Atypical liver alcohol dehydrogenase enzymes (present in 85% of Japanese)

Workup

Laboratory Studies

• The extent of diagnostic testing is guided by the patient's clinical presentation. Appropriate laboratory studies may include the following: 
  
  
  • Electrolytes, BUN, creatinine levels (assess for dehydration and electrolyte abnormalities)
  • Serum ethanol levels (may be of value to determine if more acetaldehyde formation and progression of toxicity can be expected)
  • No clinical role for determination of acetaldehyde concentrations

Other Tests

• Obtaining an ECG in patients with chest pain would be prudent. A recent case report described a 22-year-old chronic alcoholic male on disulfiram who consumed alcohol and then developed anginal symptoms.⁴ ECG changes were consistent with an inferior wall myocardial infarction (MI). He underwent coronary angiography, which revealed clean vessels, and his MI was attributed to vasospasm. 
• Mycologist may positively identify mushroom species involved; however, unlike Amanita phalloides, positive identification of coprine-containing mushrooms rarely contributes to diagnosis or alters management.

Treatment

Prehospital Care

Supportive care and parenteral rehydration are essential.

Emergency Department Care

Symptomatic treatment (eg, antiemetics) and supportive maneuvers are mainstays of medical management.

• Provide intravenous fluids if GI effects have not abated.
• Hypotension generally responds to volume expansion with normal saline.
• Patients with severe hypotension may require vasopressor agents once volume restoration is ensured.
  
  
  • Direct-acting vasopressors (eg, norepinephrine) are preferred over indirect-acting agents (eg, dopamine).
  • Recommendation is an extension of known pharmacology of disulfiram, which inhibits dopamine beta-hydroxylase, thereby depleting presynaptic catecholamines.
• Activated charcoal may be beneficial if mushrooms were ingested recently.
• Fomepizole (4-methylpyrazole) could theoretically be of benefit by blocking alcohol dehydrogenase and formation of acetaldehyde. Its use in the treatment of methanol and ethylene glycol poisoning is well established. Fomepizole is currently very expensive, and its use is not established in this clinical setting.
• Histamine-2 blockers (cimetidine is best studied) reduce the severity of flush and hypotension in Asian patients who experience these effects following ethanol ingestion. The Asian flush is due in part to a relative deficiency of aldehyde dehydrogenase.
• Antiemetics with alpha-adrenergic blocking properties (eg, aliphatic and piperidine phenothiazines) should be avoided.

Consultations

Consultation with a regional PoisonControlCenter, toxicologist, or mycologist may be helpful.

Medication

The goals of pharmacotherapy are to reduce morbidity, to prevent complications, and to neutralize effects of the toxin.

GI decontaminant

These agents are empirically used to minimize systemic adsorption of the toxin.

Activated charcoal (Actidose-Aqua, Insta-Char, Liqui-Char)

Most useful if administered within 4 h of ingestion. Repeat doses may be used, especially with ingestion of sustained release agents. Limited outcome studies exist, especially when administration is more than 1 h after ingestion.
Administration of charcoal by itself (in aqueous solution), as opposed to coadministration with a cathartic, is becoming the current practice standard because no studies have shown benefit from cathartics and, while most drugs and toxins are adsorbed within 30-90 min, laxatives take hours to work. Dangerous fluid and electrolyte shifts have occurred when cathartics are used in small children.
When ingested dose is known, charcoal may be given at 10 times ingested dose of agent over 1 or 2 doses.

Dosing

Adult

1 g/kg PO/NG (50-75 g usual dose); may administer 0.5 g/kg PO/NG as repeat dose if desired
Cathartic: Not recommended

Pediatric

<2 years: Cathartic administration not recommended
1 g/kg PO/NG (12.5-25 g usual dose); may administer 0.5 g/kg PO/NG as repeat dose prn

Interactions

May inactivate ipecac syrup if used concomitantly; effectiveness of other medications decreases with coadministration; decreased levels occur when given with sherbet, milk, or ice cream

Contraindications

Documented hypersensitivity; poisoning or overdosage of mineral acids and alkalies; unprotected airway with absent gag reflex

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Protect airway prior to administration in patients with absent gag reflex or a depressed level of consciousness; when considering repeat dosing, monitor for active bowel sounds to minimize risk

Antiemetics

These agents are used to control nausea and vomiting.

Metoclopramide (Reglan)

Prokinetic agent that increases GI motility and accelerates gastric emptying. Works as antiemetic by blocking dopamine receptors in chemoreceptor trigger zone of CNS.

Dosing

Adult

10 mg IV q2-3h; not to exceed 1 mg/kg

Pediatric

<6 years: 0.1 mg/kg IV q2-3h
6-14 years: 2.5 mg IV q2-3h
>14 years: Administer as in adults

Interactions

May antagonize effects of metoclopramide; opiate analgesics may increase metoclopramide toxicity in CNS

Contraindications

Documented hypersensitivity; pheochromocytoma; GI hemorrhage, obstruction, or perforation; history of seizure disorders; parkinsonism; depression; psychosis; early post-GI surgery

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Caution in history of mental illness and Parkinson disease; may cause altered mental status and movement disorders (eg, extrapyramidal syndromes with dystonic reactions, tardive dyskinesia)

Prochlorperazine (Compazine)

May relieve nausea and vomiting by blocking postsynaptic mesolimbic dopamine receptors through anticholinergic effects and depressing reticular activating system.
In addition to antiemetic effects, it has the advantage of augmenting hypoxic ventilatory response, acting as a respiratory stimulant at high altitude.

Dosing

Adult

10 mg IV, slowly; may repeat once; not to exceed 40 mg/d
25 mg PR q12h

Pediatric

<20 lb: Not recommended
20-29 lb: 2.5 mg PR bid
30-39 lb: 2.5 mg PR tid
<12 years: 0.06 mg/lb IM

Interactions

Coadministration with other CNS depressants or anticonvulsants may cause additive effects; coadministration with epinephrine may cause hypotension

Contraindications

Documented hypersensitivity; bone marrow suppression; narrow-angle glaucoma; severe liver or cardiac disease; parkinsonism; depression

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Drug-induced Parkinson syndrome or pseudoparkinsonism occurs frequently; akathisia is most common extrapyramidal reaction in elderly persons; lowers seizure threshold; caution with history of seizures; may cause hypotension, altered mental status, and NMS

H2-receptor antagonists

H2-receptor antagonists are reversible competitive blockers of histamine at the H2 receptors, particularly those in the gastric parietal cells where they inhibit acid secretion. The H2-receptor antagonists are highly selective, do not affect the H1 receptors, and are not anticholinergic agents.

Ranitidine (Zantac)

H2-receptor antagonist that may be a useful adjunct in reducing emesis volume.

Dosing

Adult

50 mg IV q8h

Pediatric

1 mg/kg IV q6-8h

Interactions

May decrease effects of ketoconazole and itraconazole; may alter serum levels of ferrous sulfate, diazepam, nondepolarizing muscle relaxants, and oxaprozin

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Caution in renal or liver impairment; consider adjusting dose or discontinuing treatment if changes in renal function occur during therapy

Antiemetic, Serotonin Antagonist

These agents are used to treat vomiting and symptomatic nausea resulting from radiation therapy and/or chemotherapy, for postoperative nausea and vomiting, and for general symptomatic relief.

Ondansetron (Zofran)

Selective 5-HT3-receptor antagonist that blocks serotonin both peripherally and centrally. Indicated for nausea and vomiting due to radiation and/or chemotherapy, for postoperative nausea and vomiting, and for general symptomatic relief. While historically an expensive medication, recent availability of a generic form has removed cost as a consideration.

Dosing

Adult

Nausea and vomiting secondary to gastric irritation: 4-8 mg PO q8h; 4-8 mg IV q4h up to 3 doses

While not studied specifically in setting of poisoning by mushrooms containing disulfiramlike toxins, dosing similar to other indications seems appropriate

Pediatric

Nausea and vomiting secondary to gastric irritation: 4 mg PO q8h; 0.1-0.15 mg/kg IV q4h up to 3 doses

While not studied specifically in setting of poisoning by mushrooms containing disulfiramlike toxins, dosing similar to other indications seems appropriate

Interactions

Although potential for cytochrome P-450 inducers (barbiturates, rifampin, carbamazepine, and phenytoin) to change half-life and clearance of ondansetron, dosage adjustment is not usually required

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

May cause headache

Follow-up

Further Inpatient Care

• Continue supportive care.

Complications

• Complications from prolonged emesis
  • Mallory-Weiss esophageal tears (upper GI bleeding)
  • Esophageal rupture (mediastinitis)
  • Volume depletion

Prognosis

• The prognosis is excellent.

Patient Education

• Educate patients about the risks of eating unidentified wild mushrooms.
• If toxic mushrooms were intentionally eaten, educate patients about coprine toxicity with ethanol ingestion.
• For excellent patient education resources, visit eMedicine's Poisoning Center and Poisoning - First Aid and Emergency Center. Also, see eMedicine's patient education articles Food Poisoning and Activated Charcoal.

Miscellaneous

Medicolegal Pitfalls

• Failure to recognize co-ingestion of other toxic mushrooms, such as Amanita phalloides
• Failure to recognize an esophageal injury associated with vomiting
• Failure to recognize ethanol ingestion (eg, cough syrup ingestion)

References

1. Malcolm R, Olive MF, Lechner W. The safety of disulfiram for the treatment of alcohol and cocaine dependence in randomized clinical trials: guidance for clinical practice. Expert Opin Drug Saf. Jul 2008;7(4):459-72. [Medline].

2. Garbutt JC. The state of pharmacotherapy for the treatment of alcohol dependence. J Subst Abuse Treat. Jan 2009;36(1):S15-23; quiz S24-5. [Medline].

3. Bronstein AC, Spyker DA, Cantilena LR Jr, Green JL, Rumack BH, Heard SE. 2007 Annual Report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 25th Annual Report. Clin Toxicol (Phila). Dec 2008;46(10):927-1057. [Medline].

4. Tayyareci Y, Acarel E. Acute myocardial infarction associated with disulfiram-alcohol interaction in a young man with normal coronary arteries. Turk Kardiyol Dern Ars. 2009;37(1):48-50. [Medline].

5. Banys P. The clinical use of disulfiram (Antabuse): a review. J Psychoactive Drugs. Jul-Sep 1988;20(3):243-61. [Medline].

6. Berger KJ, Guss DA. Mycotoxins revisited: Part II. J Emerg Med. Feb 2005;28(2):175-83. [Medline].

7. Brent J, McMartin K, Phillips S, Aaron C, Kulig K; Methylpyrazole for Toxic Alcohols Study Group. Fomepizole for the treatment of methanol poisoning. N Engl J Med. Feb 2001;344(6):424-9. [Medline].

8. Carlsson A, Henning M, Lindberg P, Martinson P, Trolin G, Waldeck B, et al. On the disulfiram-like effect of coprine, the pharmacologically active principle of Coprinus atramentarius. Acta Pharmacol Toxicol (Copenh). Apr 1978;42(4):292-7. [Medline].

9. Christensen JK, Moller IW, Ronsted P, Angelo HR, Johansson B. Dose-effect relationship of disulfiram in human volunteers. I: Clinical studies. Pharmacol Toxicol. Mar 1991;68(3):163-5. [Medline].

10. Hender E, May T, Beulke S. Poisoning due to eating fungi in Victoria. Aust Fam Physician. Oct 2000;29(10):1000-4. [Medline].

11. Ho MP, Yo CH, Liu CM, Chen CL, Lee CC. Refractive hypotension in a patient with disulfiram-ethanol reaction. Am J Med Sci. Jan 2007;333(1):53-5. [Medline].

12. Kunkel DB, Connor DA. Coprine-containing mushrooms. In: Spoerke DG, Rumack BH. Handbook of Mushroom Poisoning: Diagnosis and Treatment. CRC Press, LLC; 1994:303-7.

13. Meyer JH, Herlocher JE, Parisian J. Esophageal rupture after mushroom-alcohol ingestion. N Engl J Med. Dec 2 1971;285(23):1323. [Medline].

14. Michelot D. Poisoning by Coprinus atramentarius. Nat Toxins. 1992;1(2):73-80. [Medline].

15. Miller NS, Goodwin DW, Jones FC, Gabrielli WF, Pardo MP, Anand MM, et al. Antihistamine blockade of alcohol-induced flushing in orientals. J Stud Alcohol. Jan 1988;49(1):16-20. [Medline].

16. Suh JJ, Pettinati HM, Kampman KM, O'Brien CP. The status of disulfiram: a half of a century later. J Clin Psychopharmacol. Jun 2006;26(3):290-302. [Medline].

17. Wright C, Moore RD. Disulfiram treatment of alcoholism. Am J Med. Jun 1990;88(6):647-55. [Medline].

18. Yilmaz A, Gursoy S, Varol O, Nur N, Ozyilkan E. Emergency room cases of mushroom poisoning. Saudi Med J. Jun 2006;27(6):858-61. [Medline].

Keywords

mushroom toxicity, mushroom poisoning, disulfiram-like toxins, toxic mushrooms, coprine, coprine-containing mushroom toxicity, Coprinus atramentarius, C atramentarius, alcohol inky, inky cap, Clitocybe clavipes, C clavipes, fat-footed clitocybe, clubfoot funnel cap, disulfiram, Antabuse

Contributor Information and Disclosures

Author

C Crawford Mechem, MD, MS, FACEP, Associate Professor, Department of Emergency Medicine, University of Pennsylvania School of Medicine; Emergency Medical Services Medical Director, Philadelphia Fire Department
C Crawford Mechem, MD, MS, FACEP is a member of the following medical societies: American College of Emergency Physicians, National Association of EMS Physicians, and Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.

Medical Editor

B Zane Horowitz, MD, FACMT, Professor, Fellowship Director, Department of Emergency Medicine, Oregon Health and Sciences University; Medical Director, Oregon Poison Center; Medical Director, Alaska Poison Control System
B Zane Horowitz, MD, FACMT is a member of the following medical societies: American Academy of Clinical Toxicology and American College of Medical Toxicology
Disclosure: Nothing to disclose.

Pharmacy Editor

John T VanDeVoort, PharmD, Regional Director of Pharmacy, Sacred Heart & St. Joseph's Hospitals
John T VanDeVoort, PharmD is a member of the following medical societies: American Society of Health-System Pharmacists
Disclosure: Nothing to disclose.

Managing Editor

Michael Hodgman, MD, Assistant Clinical Professor of Medicine, Department of Emergency Medicine, Bassett Healthcare
Michael Hodgman, MD is a member of the following medical societies: American College of Medical Toxicology, American College of Physicians, Medical Society of the State of New York, and Wilderness Medical Society
Disclosure: Nothing to disclose.

CME Editor

John D Halamka, MD, MS, Associate Professor of Medicine, Harvard Medical School, Beth Israel Deaconess Medical Center; Chief Information Officer, CareGroup Healthcare System and Harvard Medical School; Attending Physician, Division of Emergency Medicine, Beth Israel Deaconess Medical Center
John D Halamka, MD, MS is a member of the following medical societies: American College of Emergency Physicians, American Medical Informatics Association, Phi Beta Kappa, and Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.

Chief Editor

Asim Tarabar, MD, Assistant Professor, Department of Surgery, Section of Emergency Medicine, Yale University School of Medicine; Consulting Staff, Department of Emergency Medicine, Yale-New Haven Hospital
Disclosure: Nothing to disclose.

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