Clinical manifestations

Presentation and course

Two main toxidromes associated with hallucinogenic mushroom poisoning are related to the responsible toxin: the psilocybin toxidrome and the muscimol/ibotenic acid toxidrome.

Hallucinogenic mushroom poisoning (psilocybin toxidrome). Among the classifications of mushroom poisoning, this toxidrome corresponds to Group C of Barbato (01), Group 6 of Blackman (04), Group 2A of White (42), and Group 6 of the American Association of Poison Control Centers’ National Poison Data System (19).

At low doses, psilocybin produces perceptual distortions and alterations of thought or mood, with preserved awareness and minimal effects on memory and orientation. Alterations in perception and euphoria typically begin within 30 minutes of ingesting the psilocybin-containing mushrooms, though such manifestations may not develop for up to 2 hours. Symptoms generally last between 4 and 12 hours, depending on the amount ingested.

Various CNS manifestations have been reported, including euphoria, irritability, fear, agitation, depressed level of consciousness (ranging from lethargy to coma), confusion or delirium, incoherent babbling, misperceptions, hallucinations, delusions, dizziness, ataxia, myoclonus, seizures (mostly in young children), etc. Among the reported visual "hallucinations" is the perceived motion of stationary objects or surfaces, although this is, in fact, a perceptual disturbance of something that is actually seen and, hence, strictly speaking, a visual illusion rather than a hallucination. Other manifestations may include nausea, sympathomimetic activity (eg, mydriasis and tachycardia), hypotension, and hyperpyrexia (in children).

Hallucinogenic mushroom poisoning (muscimol/ibotenic acid toxidrome). Among classifications of mushroom poisoning, this toxidrome corresponds to Group D of Barbato (01), Group 5 of Blackman (04), Group 2C of White (42), and Group 3 of the American Association of Poison Control Centers’ National Poison Data System (19).

Several mushroom species (eg, Amanita muscaria, A pantherina, and apparently A aprica) contain ibotenic acid and muscimol and may cause both excitatory and sedating symptoms. Ingestion of muscimol/ibotenic acid–containing mushrooms often produces a syndrome with gastrointestinal upset, CNS depression, and CNS excitation, either alone or in combination. In a study of ingestions of ibotenic acid and muscimol-containing mushrooms reported to a U.S. regional poison center from 2002 to 2016 (31), 34 cases met the inclusion criteria: 23 cases of ingestion of Amanita muscaria, 10 of A pantherina, and one of A aprica. Reasons for ingestion included foraging (12), accidental (eg, in young children) (12), recreational (6), therapeutic (1), self-harm (1), and unknown (2). Twenty-five patients (74%) were symptomatic, and all but one developed symptoms within 6 hours. Six patients had symptoms for less than 6 hours, whereas 15 had symptoms lasting less than 24 hours. Ingestion of A pantherina was more likely to cause symptoms than ingestion of A muscaria in terms of gastrointestinal symptoms (80% vs. 35%), CNS depression (70% vs. 35%), and CNS excitation (70% vs. 35%). Five patients (ie, 20% of the symptomatic cases) were intubated. No deaths were reported.

Five frayed panther cap (A pantherina) fruiting bodies were eaten by mistake by two persons (27 and 47 years of age), resulting from a confusion of toxic mushrooms with edible species (37). Symptom onset occurred after 120 min, with CNS depression, variable obtundation, hallucinations, religious delusions, ataxia, and hyperkinetic behavior.

In another report, dried fly agaric (Amanita muscaria) fruiting bodies were eaten by five young persons (aged 18 to 21 years) at a party, producing the intended visual and auditory hallucinations in four of them, but instead producing unconsciousness resulting in hospitalization in the fifth person (36).

One study reported the clinical features and management of nine cases of mushroom poisoning in infants and children due to Amanita pantherina (eight cases) and Amanita muscaria (1 case) who were admitted to a children's hospital (02). Most ingestions were in toddlers, with boys more frequently involved. Symptom onset was between 30 and 180 minutes after ingestion, with the onset of CNS depression, variable obtundation, intermittent agitation, hallucinations, ataxia, or hyperkinetic behavior. Vomiting was rare. Seizures or myoclonic twitching occurred in four patients (44%) but was controlled with standard anticonvulsant therapy. Recovery was rapid and complete in all patients.

Prognosis and complications

Magic mushrooms continue to be fashionable among drug users, especially young drug users, in part because they are often believed to be relatively harmless compared to other hallucinogenic drugs (03). However, serious adverse outcomes have been reported, including myocardial infarction (05); psilocybin-induced takotsubo cardiomyopathy (25); severe rhabdomyolysis, acute renal failure, and posterior encephalopathy (03); psychosis and mania complicated by violent behavior and rhabdomyolysis (40); and protracted paranoid psychosis (07). Ingestion of magic mushrooms may result in horror trips combined with self-destructive and suicidal behavior, especially among people with mental or psychiatric disorders (33; 21).

Despite the potential for serious adverse outcomes, magic mushroom ingestion is relatively safe (24). Out of 9233 magic mushroom users, 19 (0.2%) reported having sought emergency medical treatment in the past year, with a per-event risk estimate of 0.06%. Young age was the only predictor associated with a higher risk of emergency medical presentations. The most common symptoms were psychological: anxiety/panic and paranoia/suspiciousness. All but one returned to baseline within 24 hours.

Although fatal A pantherina poisoning has been reported in the Pacific Northwest (37), human deaths related to muscimol/ibotenic acid–containing mushrooms are rare and mainly occur in young children, the elderly, or those with serious chronic illnesses.

The duration of clinical manifestations after Amanita muscaria (fly agaric or fly amanita) ingestion does not usually exceed 24 hours; however, paranoid psychosis with visual and auditory hallucinations can appear 18 hours after ingestion and can last for up to 5 days (07). A 48-year-old man with no previous medical history gathered and ate mushrooms he presumed to be A caesarea but which were instead A muscaria. Half an hour later he started to vomit. He was subsequently found unresponsive, having a seizure-like episode. He was comatose on admission 4 hours after ingestion. Laboratory results, including blood and urine toxicology analysis, and a brain CT scan were normal, except for an elevated creatine kinase level. Activated charcoal was administered. Ten hours after ingestion, he awoke and was fully orientated, but he became confused and uncooperative 8 hours later (18 hours after ingestion). Paranoid psychosis with visual and auditory hallucinations subsequently appeared and persisted until these manifestations gradually resolved on the sixth day. Follow-up 1 year later found no symptoms of psychiatric disease.

Serious and often permanent organ dysfunction or fatalities may result from accidentally ingesting a more toxic mushroom resembling one that is hallucinogenic. For example, some individuals who intend to harvest or procure "magic mushrooms" (ie, hallucinogenic mushrooms) obtain species that are more toxic instead, like some species of mushrooms of the genus Cortinarius, which are nephrotoxic (34).

A common feature among all species in the genus Cortinarius is that young specimens have a "cortina" (veil) between the cap and the stem, hence the name, which means “curtained.” The renal toxicity of these mushrooms can vary, presumably based on toxin dose and physical constitution, from mild, transient renal failure to irreversible total acute renal failure that necessitates continual dialysis (34). The nephrotoxicity of Cortinarius orellanus was first recognized in the 1950s, when this mushroom was identified as the cause of a mass poisoning of 135 people in Bydgoszcz, Poland, that resulted in 19 deaths (16). Affected individuals develop an acute tubulointerstitial nephritis (with severe interstitial nephritis, acute focal tubular damage, and interstitial fibrosis). The responsible toxin was identified to be orellanine, a bipyridine N-oxide compound. The onset of renal symptoms is typically delayed for 1 to 2 weeks after ingestion, although patients may have gastrointestinal discomfort in the latency period (16).

Biological basis

Etiology and pathogenesis

Mushrooms with significant psychoactive hallucinogenic effects fall into two main groups: (1) mushrooms containing psilocybin; and (2) mushrooms containing ibotenic acid and muscimol (isoxazoles). Both ibotenic acid and muscimol can cross the blood-brain barrier.

Hallucinogenic mushroom toxins produce their associated toxidromes by selectively affecting neurotransmission.

Psilocybin-containing mushrooms. Psilocybin mushrooms, commonly known as "magic mushrooms" or "shrooms," are a polyphyletic (ie, derived from more than one common evolutionary ancestor or ancestral group) group of fungi that contain the hallucinogenic neurotoxin, psilocybin. In fact, more than 50 species of fungi contain psilocybin (and its derivative psilocin); most of these are small brown or tan mushrooms. Biological genera containing psilocybin mushrooms include Psilocybe, as well as Gymnopilus, Inocybe, Panaeolus, Pholiotina, and Pluteus.

Hallucinogenic mushrooms resemble the common store mushroom Agaricus bisporus, although the flesh of Psilocybe mushrooms characteristically turns blue or green when bruised or cut. Because it is difficult to distinguish non-psilocybin species from the hallucinogenic ones by morphological observation in the wild, psilocybin-containing mushrooms may also be easily ingested unintentionally. Conversely, those seeking hallucinogenic species may inadvertently ingest those with greater toxicity.

Psilocybin-containing hallucinogenic mushrooms are frequently used as drugs of abuse, particularly in adolescents and young adults, and are available fresh, treated/preserved (eg, dried, cooked, frozen), or as dry powders or capsules (39; 05; 35; 36; 32).

Psilocybin toxicology. Psilocybin (4-phosphoryloxy-N,N-dimethyltryptamine) is a prodrug that is converted into the pharmacologically active form, psilocin, by dephosphorylation after ingestion. Psilocin itself is also present in the mushrooms in small amounts. Psilocybin and psilocin are both indolealkylamines that can be considered as derivatives of tryptamine and are structurally similar to the neurotransmitter serotonin (5-hydroxytryptamine) (43). Besides psilocybin and psilocin, two further tryptamines (baeocystin and norbaeocystin) are present in these mushrooms as minor components.

Muscimol/ibotenic acid–containing mushrooms. The fly agaric mushroom (Amanita muscaria) occurs in coniferous and deciduous woodlands of the Northern Hemisphere.

It has often been the model for mushrooms in artistic representations of fairies, gnomes, and elves. Amanita muscaria has been consumed in Asia as a hallucinogen for centuries and possibly millennia: its use in this capacity in the Kamchatka Peninsula and Siberia was recognized in the West by the mid-19th century (13). It may be confused with several edible species (Lycoperdon spp, Calvatia spp, Amanita caesarea) (30). The mushroom’s species name comes from the Latin word musca, for fly, because the mushroom was often used to attract and catch flies (hence, also its common name, “fly agaric”). Other mushrooms with these toxins are A pantherina (also called “panther” or “panther amanita”) and apparently A aprica as well.

Other Amanita species may contain muscimol and ibotenic acid in addition to muscarine (11). Inosperma species may variously contain muscimol and ibotenic acid as well as muscarine (28).

Muscimol/ibotenic acid toxicology. The name of the toxin muscarine derives from the Amanita muscaria mushroom from which it was first isolated by German chemists Oswald Schmiedeberg (1838-1921) and Richard Koppe at the University of Dorpat, who reported their findings in 1869 (38). However, although present, the concentration of muscarine in this mushroom is actually quite low, and the neurotoxicity of this particular mushroom is instead related to muscimol and ibotenic acid (30).

Muscimol, also known as agarin or pantherine, is chemically an isoxazole (ie, a type of azole or 5-membered heterocyclic compound containing a nitrogen atom and at least one other noncarbon atom, and specifically for an isoxazole, an azole with an oxygen atom next to the nitrogen).

Pharmacologically, muscimol is a potent, selective agonist for the GABA_A receptors, activating the receptor for the brain's principal inhibitory neurotransmitter and displaying sedative-hypnotic, depressant, and hallucinogenic activity (23). Muscimol binds to the same site on the GABA_A receptor complex as GABA itself, which is in contrast to other GABAergic drugs, such as barbiturates and benzodiazepines, which bind to separate regulatory sites.

The effects of muscimol begin 30 to 120 minutes after consumption and last for 5 to 10 hours. These include euphoria; dream-like states; out-of-body experiences; nausea and stomach discomfort; increased salivation; muscle twitching or tremors; and, in large doses, strong dissociation or delirium. About one third of the muscimol ingested is excreted unchanged, and the rest is conjugated or oxidized (30).

Ibotenic acid, or (S)-2-amino-2-(3-hydroxyisoxazol-5-yl)-acetic acid, is a psychoactive toxin that occurs naturally in Amanita muscaria and related species of mushrooms that are found in the temperate and boreal regions of the Northern Hemisphere. It is a conformationally restricted analogue of the neurotransmitter glutamate and acts as a particularly potent agonist of the NMDA receptor and multiple types of metabotropic glutamate receptors. Ibotenic acid also serves as a prodrug to muscimol when the mushroom is ingested, converting to muscimol in vivo via decarboxylation; apparently it acquires its psychoactive properties in this way. However, in humans, most of the ibotenic acid ingested is excreted unchanged in the urine, with only some of it being metabolized to muscimol (30).

Epidemiology

Intentional intoxication with hallucinogenic mushrooms continues to be a significant problem in the United States and in parts of Europe. Among 174 adolescents already identified as substance abusers, a quarter (26%) reported having used hallucinogenic mushrooms, frequently in conjunction with alcohol or other drugs, typically producing intoxication for 5 to 6 hours (39). Among undergraduate college students, psilocybin users were significantly more likely than nonusers of psilocybin to use other drugs (eg, cocaine, ecstasy, opiates, nonprescribed prescription drugs, and LSD) (20).

From data collected between September 2008 and December 2009, the Youth Risk Behavior Surveillance System of the U.S. Centers for Disease Control and Prevention reported that 8% of high school students had used a hallucinogenic drug (eg, LSD, phencyclidine [PCP; "angel dust"], mescaline, or hallucinogenic mushrooms) at least once in their life (17). Hallucinogen use was more common among males (10.2%) than among females (5.5%) and more common among Caucasians (9.0%) than among Hispanics (7.9%) or African Americans (3.3%).

Although seizures of hallucinogenic mushrooms are not consistently monitored in Europe, 19 countries reported 950 seizures of hallucinogenic mushrooms in 2019, amounting to 55 kilograms (18). Among young adults (aged 15 to 34), the most recent national surveys report prevalence estimates for hallucinogenic mushroom use equal to or less than 1%, except for Finland (2.0% in 2018), Estonia (1.6% in 2018), and the Netherlands (1.1% in 2019).

In the 2019 Annual Report of the American Association of Poison Control Centers’ National Poison Data System, there were 5799 reports of single-substance exposures to mushrooms; the type of mushroom was unknown or unidentified in 76% (19). Categories of potentially neurotoxic exposures with substantial numbers of individuals affected were (using their classification system): 33 cases of Group 2 (muscimol/ibotenic acid); 49 cases of Group 3 (monomethylhydrazine); 18 cases of Group 4 (muscarine/histamine); 10 cases of Group 5 (coprine); and 590 cases of Group 6 (psilocybin/psilocin). Thus, the vast majority with potentially neurotoxic exposures were for hallucinogenic mushrooms (Groups 2 and 6).

The largest category of identified mushroom exposures reported to poison control centers in the United States was represented by psilocybin/psilocin-containing hallucinogenic mushrooms (19). Of 590 case mentions, there were 387 single exposures, meaning that many of these exposures involved multiple individuals simultaneously. Of the 387 exposures, 144 involved individuals aged 13 to 19, 188 involved individuals aged 20 years and older, and 55 involved adults of unknown age; 331 (96%) of these 346 exposures in adolescents and adults were acknowledged to have been intentional.

In 2019, there were no fatalities in these categories of potentially neurotoxic mushroom exposures reported to poison control centers in the United States (19). However, 354 individuals were treated in a healthcare facility, and of these, 112 (32%) suffered a minor adverse outcome, 176 (50%) suffered a moderate adverse outcome, and eight (2%) suffered a major adverse outcome.

Occasional fatalities following Amanita muscaria ingestion have been reported (29).

Prevention

Prevention is optimally achieved by eating only non-hallucinogenic mushrooms that are commercially cultivated for human consumption. If used, illicit recreational hallucinogenic mushrooms should be kept out of reach from children. Mushroom foragers should eat only one type of wild mushroom and save a sample in a dry paper bag for later identification, if this proves necessary.

Differential diagnosis

Confusing conditions

If ingestion or poisoning is suspected, various toxins need to be considered (depending on the particular presenting symptoms), including alcohol, cannabis, other hallucinogens (LSD, PCP, etc.), glue sniffing, nitrous oxide, anticholinergics, opiates, sympathomimetics (eg, methamphetamine, cocaine), etc. When considering hallucinogenic mushroom toxicity, it is important to keep in mind that (1) recreational exposures are often multiple; (2) mushrooms obtained by foraging are frequently misidentified; and (3) mushrooms obtained illicitly may also be misidentified and may contain adulterants.

Diagnostic workup

The diagnosis of mushroom poisoning should be based on the presenting syndrome, and supported, if possible, by the description and toxicological analysis of the mushroom (14; 15). Unfortunately, according to data from the American Association of Poison Control Centers, the exact mushroom species in cases of hallucinogenic mushroom poisoning often go unidentified (14; 15; 19). Ideally, a sample of the mushrooms ingested should be obtained so identification can be confirmed by a mycologist. In most cases, the mushroom in question has already been digested, but collecting the patient’s gastric contents by means of gastric lavage or after emesis might yield identifiable spores.

No particular diagnostic procedures are available or needed for most patients with hallucinogenic mushroom toxicity, although identification of the mushroom by a mycologist is still desirable. The regional poison control center may be contacted for consultation, referral, and assistance in mushroom identification. In the United States, a nationwide telephone number automatically directs calls to the nearest poison control center (1-800-222-1222). A mycologist can also be contacted through the North American Mycological Association, a local university, or sometimes a botanical garden.

The following blood studies are recommended for most patients with possible mushroom toxicity evaluated on an emergency basis: complete blood count, basic serum metabolic profile, baseline liver and renal function studies, and creatine kinase. Urine drug testing should also be considered, especially if the patient exhibits alterations of behavior or mental status, or if substance abuse, suicidal intent, or foul play is suspected.

Management

Gastrointestinal decontamination. There is a very limited and somewhat controversial role for gastrointestinal decontamination in cases of mushroom poisoning, with some advocating the use of activated charcoal in the first hour and others discounting this as lacking evidence of efficacy. Furthermore, the CNS manifestations of hallucinogenic mushroom toxicity develop rapidly after ingestion, with absorption before activated charcoal is usually considered. A reasonable approach is to consider activated charcoal administration in patients who are alert and who present for care within 1 hour of hallucinogenic mushroom ingestion. Patients admitted to the hospital are typically given activated charcoal to stop the absorption of toxic compounds and to prevent further intoxication, even though adsorption to activated charcoal has not been demonstrated for these fungal toxins. Supportive evidence for the efficacy of activated charcoal administration in this setting is largely indirect, from animal studies and from analogy with other toxic ingestions. Because of the potential for further volume depletion, the combination of a cathartic (eg, sorbitol) and activated charcoal is not generally recommended.

Syrup of ipecac administration in remote locations soon after pediatric ingestion of toxic mushrooms may prevent or minimize toxicity, but unsupervised children typically only try exploratory nibbles of mushrooms in their local environments and, thus, rarely have serious consequences. Because most serious mushroom poisonings are only detected hours after ingestion, gastric emptying by gastric lavage or syrup of ipecac in the emergency department is not likely to be beneficial. If treatment occurs within the first hour of ingestion, gastric lavage may be considered; however, this recommendation also lacks strong empiric evidence. Nasogastric aspiration in alert patients to obtain a sample for spore analysis can be considered if no other mushroom sample of what was ingested is available and gastric contents might still contain partially digested mushrooms.

Hallucinogenic mushroom toxicity. In hallucinogenic mushroom toxicity, the most frequent form of neurotoxic mushroom poisoning, care is primarily supportive. Most patients can be treated without medications. Toxicity usually lasts between 6 and 8 hours, but some symptoms may take several days to subside.

CNS excitation with agitation and "panic attacks" may occur with hallucinations after ingestion of psilocybin-containing mushrooms. Patients with these findings should initially be placed in a quiet room. With severe agitation, benzodiazepines (eg, midazolam or lorazepam) may prove helpful.

Seizures are uncommon with hallucinogenic mushroom poisoning, except in young children. Seizures may occur in children, particularly after ingestion of mushrooms that contain muscimol and ibotenic acid. Initial management includes oxygenation, support of the airway and breathing, and administration of anticonvulsants (eg, lorazepam). Various anticonvulsants have been used to treat seizures in such patients, but respiratory depression may occur when some of these agents (eg, benzodiazepines) are administered intravenously.

Special attention should be given to monitoring breathing, airway control, and circulation. Intravenous fluids may be necessary to correct volume loss from vomiting. In rare cases, anticholinergic drugs, such as atropine, may be needed. With A muscaria poisoning, anticholinergic drugs (eg, atropine) are rarely, if ever, needed; the species name was applied because muscarine was first identified from preparations of this mushroom, even though few muscarinic effects are observed following ingestion of these mushrooms.

In the absence of a clinically evident infection, it is unnecessary to treat low-grade fever with antipyretics in an agitated or hyperactive patient with hallucinogenic mushroom ingestion.

If symptoms such as vomiting, diarrhea, and abdominal pain begin 5 to 6 hours or more after ingestion, mushrooms that can cause potentially life-threatening or severe toxicity (eg, A phalloides or Cortinarius spp) should be considered.

Outcomes

The vast majority of poisoned individuals recover without serious permanent morbidity. Neurologic presentations of hallucinogenic mushroom poisoning are rarely fatal. Factors that increase the risk of a fatal outcome include age (eg, young children or the elderly) and amount ingested. Uncommon fatalities and serious adverse outcomes do occur, however, and include suicide, protracted psychosis, and myocardial infarction.