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1242 SECTION 15: Toxicology nitroglycerin, nicardipine, or a sodium nitroprusside infusion (initial dose, 0.3 microgram/kg per minute). Blood pressure may be lowered aggressively if the patient does not have chronic hypertension. Treat ment for refractory hypertension is similar to that for hypertensive emergencies except that β-adrenergic blockers are not used (see Chapter 57, “Systemic Hypertension”).  BODY STUFFERS AND BODY PACKERS Cocaine and other drugs can be internally concealed. 63 Patients who swallow cocaine following police pursuit to conceal the evidence are termed “body stuffers. ” The swallowed packets are often poorly wrapped and can leak or perforate. 64 “Body packers” swallow a large number of well-sealed packets in order to smuggle drugs across international bor ders. Both methods can result in severe toxicity and death. 45,64 Management of an asymptomatic cocaine body packer brought in by police or customs officials is a treatment dilemma. 63 CT is the best imaging modality to identify the packets. 65-67 If the patient shows no signs of toxicity, give single-dose activated charcoal and institute whole-bowel irrigation with polyethylene glycol electrolyte solution to gently hasten packet elimination. 45,68 Continue whole-bowel irrigation until passage of the last packet, and then obtain a confirmatory CT to ensure that all containers have passed. For symptomatic patients, provide sedation and symptomatic care, and obtain immediate surgi cal consultation for operative removal of the packets. Do not consult for endoscopy or colonoscopy because endoscopic manipulation may rupture the packets. 63,64  DRUG INTERACTIONS Because cocaine is metabolized by plasma cholinesterase, coadminis tration of drugs such as succinylcholine and mivacurium that are also metabolized by plasma cholinesterase may lead to unpredictable rates of metabolism, leading to foreshortened or prolonged effects. Both lidocaine and cocaine are local anesthetics and act as sodium channel antagonists. It is thought that the neurotoxic effects of both occur by similar mechanisms. Despite theoretical risk in treating cocaine-induced dysrhythmias with lidocaine, it has been used safely in patients with cocaine-associated myocardial infarction. Monoamine oxidase inhibitors block the degradation of intracel lular catecholamines, increasing adrenergic neurotransmitters in the presynaptic terminals. Amphetamines are indirect-acting sympatho mimetic amines that induce the release of stored catecholamines and are also weak inhibitors of monoamine oxidase. Thus, patients taking monoamine oxidase inhibitors who subsequently use amphetamines or phenylpropanolamine (and to a lesser extent cocaine) may precipitate an acute syndrome of excessive catecholamine release that results in severe hypertension, tachycardia, hyperthermia, agitation, tremors, and pos sible severe neurotoxicity. DISPOSITION AND FOLLOW-UP Disposition depends on initial patient presentation, response to therapy, the nature of the stimulant involved, and expected duration of effect. Patients demonstrating resolution of toxicity and clear sensorium in the absence of focal complaints or end-organ damage should be advised of the medical risks of drug abuse and referred to appropriate detoxifica tion, counseling, and social support services.

of the stimulant involved, and expected duration of effect. Patients demonstrating resolution of toxicity and clear sensorium in the absence of focal complaints or end-organ damage should be advised of the medical risks of drug abuse and referred to appropriate detoxifica tion, counseling, and social support services. Patients who present with adrenergic excess following recent cocaine use and who respond to initial sedation may be expected to improve completely during a period of observation in the ED because of the relatively limited duration of cocaine effects. In contrast, amphetamines have a longer duration of effect and produce prolonged toxicity, which necessitates observation or hospitalization. WITHDRAWAL Cocaine withdrawal is characterized by irritability, paranoid ideation, and depression. 69 Although symptoms during cocaine withdrawal are generally milder than those during amphetamine withdrawal, psychological addiction may be particularly strong. Methamphetamine withdrawal is characterized by drowsiness, lethargy, hunger, tremor, and chills. There is considerable potential for long-term depression and suicide. Symptoms of withdrawal are strongest during the first 48 hours, but milder symptoms can last up to 2 weeks. Although pharmacologic adjuncts (e.g., antidepressants, adrenergic antagonists, dopaminergic agents) are sometimes used during cocaine or amphetamine withdrawal, there are no data confirming efficacy. 69-71 REFERENCES The complete reference list is available online at www.TintinalliEM.com. Hallucinogens Utsha Khatri David H. Jang INTRODUCTION The term hallucinogen is misleading. Hallucinogenic compounds rarely produce true hallucinations. Instead, users experience profound distor tions in body image, sensory perception, and time perception, in addi tion to rapid, intense alterations in mood, increased intensity of any emotions, and heightened suggestibility. Hallucinogen is sometimes used interchangeably with the term psychedelic. Hallucinogens are widely perceived as safe by the public and thus continue to be widely used. In fact, about 32 million Americans have used a psychedelic drug at least once in their lifetimes, or approximately 17% of all Americans between the ages of 21 and 64 years. 1 In addition, hallucinogens account for approximately 7% of U.S. ED visits involving illicit drugs. 2 However, these substances can cause dangerous physi ologic effects resulting in serious health consequences. 3-5 The identity, purity, and amount of hallucinogenic compound are usually uncertain, and individual response can be unpredictable. Hallucinogens in current use consist of both natural and synthetic compounds. 6 The proliferation of “designer drugs”—chemical analogs or derivatives of illicit drugs marketed to circumvent existing drug laws—is a growing problem. Manufacturers of designer drugs try to circumvent U.S. federal drug laws by stamping their product with advi sories such as “not intended for human consumption” or by identifying the products as plant food, bath salts, or potpourri. Prosecution through the Federal Analog Act, a section of the Controlled Substance Abuse Act, can occur only if the drug is “intended for human consumption. ” Because of this limitation in federal law, some states have moved to ban the sale of such agents. In the past decade, there has been a renewed interest in studying the potential therapeutic effects of hallucinogens. Clinical studies have demonstrated efficacy of hallucinogens such as psilocybin and lysergic acid diethylamide (LSD) in treating depression, anxiety, and substance addiction, but this area of research is in its infancy.

e, there has been a renewed interest in studying the potential therapeutic effects of hallucinogens. Clinical studies have demonstrated efficacy of hallucinogens such as psilocybin and lysergic acid diethylamide (LSD) in treating depression, anxiety, and substance addiction, but this area of research is in its infancy. Conditions that mimic hallucinogen intoxication include sedativehypnotic withdrawal, anticholinergic poisoning, thyrotoxicosis, CNS infections, structural brain lesions, acute psychosis, hypoglycemia, and hypoxia. 8 Some prescription and nonprescription medications can cause hallucinations. The identity of street drugs is often misrepresented, and substitution or adulteration of product is common. 9,10 Drug-induced psychosis may be difficult to distinguish from primary psychotic disorders.11,12 A patient with substance-induced psychosis is more likely to have a diagnosis of dependence on any drug, report visual hallucinations, and have a history of parental drug abuse. CHAPTER Tintinalli_Sec15_p1187-1332.indd 1242 8/2/19 8:39 PM

psychosis may be difficult to distinguish from primary psychotic disorders.11,12 A patient with substance-induced psychosis is more likely to have a diagnosis of dependence on any drug, report visual hallucinations, and have a history of parental drug abuse. CHAPTER Tintinalli_Sec15_p1187-1332.indd 1242 8/2/19 8:39 PM CHAPTER 188: Hallucinogens 1243 can be discharged into the custody of family or friends if they are lucid and in medically stable condition after a period of observation. Patients with persistent psychotic symptoms or comorbid psychiatric illnesses require psychiatric evaluation. COMMON HALLUCINOGENS Common hallucinogens are listed in Table 188-1.  LYSERGIC ACID DIETHYLAMIDE LSD is a potent psychoactive drug. As little as 25 micrograms produces psychedelic effects. The hallucinogenic effects are believed to be medi ated through agonism at the serotonin type 2 (5-HT 2) receptor.16,17 LSD is a colorless, tasteless, odorless, water-soluble substance that is sold in various forms, but most commonly as small squares of dried blotter paper printed with colorful graphics and cartoons that have been perforated and soaked in liquid LSD solution. Each square typically delivers a dose of 20 to 80 micrograms. Other forms include “microdots” (tiny tablets), “windowpane” (gelatin sheets), impregnated sugar cubes or candy, and small bottles of “breath drops” (the drug in solution). The psychedelic effects begin within 30 minutes of ingestion, peak within 4 hours, and last between 8 and 12 hours. 18,19 Sympathomimetic stimulation with mydriasis and elevations of pulse, blood pressure, and temperature usually precede the psychedelic effects. 18,19 While severe symptoms are uncommon in recreational use, marked facial flushing, mild gastric distress, piloerection, increased muscle tension, and hyperreflexia may occur. In massive overdoses (approximately >400 micro grams), coagulopathy, hyperthermia, seizure, coma, and respiratory arrest have been reported. 20 Although very rare, vasospasm resulting in peripheral ischemia and strokes has also been reported. 21 The psychedelic effects of LSD depend on the user’s prevailing mood, expectations, and surrounding environment. Effects may be perceived as pleasurable or horrifying. Predominant effects induced by LSD include visual hallucinations, audiovisual synesthesia, and derealization and depersonalization phenomena. Subjective well-being, happiness, and closeness to others are increased by LSD. However, profound distortions in perception of sensory stimuli, time, emotions, and memories also occur and may cause users to experience paranoia, depression, extreme panic, or an acute psychotic reaction known as a dysphoric reaction or “bad trip, ” which can result in serious physical trauma or suicide. Prolonged and sometimes permanent psychosis, known as “flashbacks” or “hallucinogen-persisting perception disorder, ” can result. Diagnosis is based on history of use, the presence of sympathomi metic signs, and reported psychedelic effects. LSD can be detected in the urine for several days after ingestion using specific radioimmunoassay and enzyme immunoassay techniques. Reassurance and observation in a quiet, safe environment are generally the only interventions required to manage a dysphoric reaction. Oral or parenteral benzodiazepines are indicated for patients with extreme agitation or signs of excessive sym pathomimetic stimulation. Patients with paranoid or psychotic symp toms lasting longer than 8 to 12 hours may require hospital admission. Medical complications due to massive overdose are rare, and recovery is usually rapid and requires only supportive care.

for patients with extreme agitation or signs of excessive sym pathomimetic stimulation. Patients with paranoid or psychotic symp toms lasting longer than 8 to 12 hours may require hospital admission. Medical complications due to massive overdose are rare, and recovery is usually rapid and requires only supportive care. 18-20 An important con sideration is that certain drugs may also be sold for use on blotting paper as LSD such as the 2C-series (2C-I) and N-2-methoxybenzylphenylethylamines (NBOMe). These agents are considered to be considerably more potent than LSD, and deaths have been reported.  PSILOCYBIN Psilocybin is a naturally occurring hallucinogenic compound found in at least six genera of mushrooms, but most notably the Psilocybe genus. Psilocybin is an indolealkylamine that is metabolized to the pharma cologically active compound psilocin. Both psilocybin and psilocin are believed to act as serotonin type 2 receptor agonists, similar to LSD. Psilocybin-containing mushrooms grow naturally in the southern United States and Europe but can also be grown from kits sold over the Internet. 24 Most species of psilocybin-containing mushrooms turn bluish when bruised, but this is not a definitive method of identification or determination of potency. Psilocybin-containing mushrooms may GENERAL APPROACH TO TREATMENT  ASSESSMENT The assessment of the hallucinogen-intoxicated patient should begin with assessment of vital signs and general clinical stability. Although severe vital sign abnormalities are rare with hallucinogens, the most common disturbances are hypertension and tachycardia resulting from sympathomimetic surge. A core temperature should also be obtained. While rare in isolated hallucinogen use, hyperthermia suggests severe poisoning and requires immediate intervention to avoid complications. Hypoxia and hypoglycemia, both alternative explanations for altered mental status, should be quickly identified and corrected. Serum chem istries, a venous blood gas, and a creatine phosphokinase should be considered, particularly if there is a concern for co-ingestions causing metabolic derangement or rhabdomyolysis. An ECG will be necessary to identify QRS or QT interval prolongation related to co-ingestants. Qualitative urine immunoassays are readily available for some of the described hallucinogens such as amphetamine analogs, but these tests are hampered by so many limitations (inaccuracy and inability to pin point remote versus recent hallucinogen use) that they rarely contrib ute to the management of acutely poisoned patients. The use of urine immunoassays should not guide clinical management of patients with suspected hallucinogen poisoning.  TREATMENT Supportive care is the mainstay of treatment in most situations. Creating a calm environment with few external stimuli and providing reassurance until the drug effects wear off are often sufficient in mild cases. Because most hallucinogens are rapidly absorbed and most patients with adverse events do not present until several hours after ingestion, gastric decontamination is rarely indicated. In moderate to severe cases, benzodiazepines are the preferred choice for chemical sedation because they possess no significant drug interactions, have no dystonic or anticholinergic adverse effects, do not prolong the QT interval or promote arrhythmias, and are reversible by flumazenil if oversedation occurs (although risk of inducing withdrawal in the benzodiazepine-tolerant individual should be a consideration). In the moderately to severely agitated patient in whom IV access has not been obtained, IM midazolam 2 to 5 milligrams should be given.

promote arrhythmias, and are reversible by flumazenil if oversedation occurs (although risk of inducing withdrawal in the benzodiazepine-tolerant individual should be a consideration). In the moderately to severely agitated patient in whom IV access has not been obtained, IM midazolam 2 to 5 milligrams should be given. In patients with IV access, starting doses of benzodiazepines are as follows: 1 to 2 milligrams IV of midazolam or lorazepam and 2 to 5 milligrams IV of diazepam. If the patient is severely agitated or hypertensive, doubling these doses is reasonable provided that continuous monitoring and fre quent reassessments are made. See Chapter 287, “ Acute Agitation, ” for detailed discussion of agitation. Antipsychotics such as haloperidol are frequently recommended as adjuncts for drug-induced delirium. Many antipsychotics (e.g., haloperidol) are potent dopamine receptor antagonists, which allows them to antagonize the psychiatric and psychomotor effects of select hallucinogens such as amphetamines. However, caution should be exercised when using antipsychotics because they can lower the seizure threshold, cause dystonia, precipitate dysrhythmias, and alter tempera ture regulation. Hypertension often responds to judicious use of sedation with a benzodiazepine, but in refractory cases, it can be treated with phentolamine or a calcium channel blocker. Provide active cooling for significant hyperthermia. Treatment of severe agitation, hyperthermia, or seizures may require neuromuscular paralysis, ice baths, and endotracheal intu bation. Seizures are treated with benzodiazepines or propofol. Patients with rhabdomyolysis require aggressive IV hydration to maintain urine output. Dantrolene is a potential treatment option for hallucinogeninduced hyperthermia, but evidence is limited.  DISPOSITION AND FOLLOW-UP Compared with other abused psychoactive agents, hallucinogens have some of the largest acute safety ratios when lethal doses are measured against the doses customarily used to produce the desired effects. 15 Most patients seen in the ED due to adverse reactions from hallucinogen use Tintinalli_Sec15_p1187-1332.indd 1243 8/2/19 8:39 PM

her abused psychoactive agents, hallucinogens have some of the largest acute safety ratios when lethal doses are measured against the doses customarily used to produce the desired effects. 15 Most patients seen in the ED due to adverse reactions from hallucinogen use Tintinalli_Sec15_p1187-1332.indd 1243 8/2/19 8:39 PM 1244 SECTION 15: Toxicology TABLE 188-1 Common Hallucinogens Drug Typical Hallucinogenic Dose Duration of Action Clinical Features Complications Specific Treatment Lysergic acid diethylamide (LSD) 20–80 micrograms 8–12 h Mydriasis Tachycardia Anxiety Muscle tension Coma Hyperthermia Coagulopathy Persistent psychosis Hallucinogen persisting perception disorder Reassurance Benzodiazepines Psilocybin 5–100 mushrooms 4–6 milligrams of psilocybin 4–6 h Mydriasis Tachycardia Muscle tension Nausea and vomiting Seizures (rare) Hyperthermia (rare) Reassurance Hydration Benzodiazepines Mescaline 3–12 “buttons” 200–500 milligrams of mescaline 6–12 h Mydriasis Abdominal pain Nausea and vomiting Dizziness Nystagmus Ataxia Rare Supportive Benzodiazepines Methylenedioxymethamphetamine (MDMA, “ecstasy”) 50–200 milligrams 4–6 h Mydriasis Bruxism Jaw tension Ataxia Dry mouth Nausea Hyponatremia Hypertension Seizures Hyperthermia Arrhythmias Rhabdomyolysis Benzodiazepines Hydration Active cooling Dantrolene Specific serotonin antagonists Synthetic cathinone derivatives (“bath salts”) 50–300 milligrams of mephedrone 2–4 h Agitation Tachycardia Hypertension Diaphoresis Mydriasis Paranoia Panic reactions Hyperthermia Seizures Hyponatremia Rhabdomyolysis Benzodiazepines Hydration Active cooling Phencyclidine (PCP, “angel dust”) 1–9 milligrams 4–6 h Small or midsized pupils Nystagmus Muscle rigidity Hypersalivation Agitation Catatonia Coma Seizures Hyperthermia Rhabdomyolysis Hypertension Hypoglycemia Benzodiazepines Hydration Active cooling Marijuana (cannabis) 5–15 milligrams of tetrahydrocannabinol (THC) 2–4 h Tachycardia Conjunctival injection Acute psychosis (rare) Panic reactions (rare) Supportive Benzodiazepines Synthetic cannabinoids (“K2,” “spice”) 2–5 milligrams of JWH-018 * 3–4 h Tachycardia Conjunctival injection Acute psychosis Panic reactions Seizures (rare) Arrhythmias (rare) Supportive Benzodiazepines Bromo-benzodifuranylisopropylamine (Bromo-DragonFLY) 200–800 micrograms 10–14 h Agitation Hallucinations Seizures Vasoconstrictor with necrosis and gangrene Supportive Benzodiazepines *One of the first synthetic cannabinoids (1-pentyl-1H-indol-3-yl)-1-naphthalenyl-methanone, goes by the term JWH-018. be dried or cooked without losing potency. Hallucinogenic mushrooms sold on the street are often nonpsychoactive mushrooms that have been adulterated with LSD or phencyclidine (PCP). 9 Because of the variation in mushroom size and concentration of psychoactive compounds, there is little correlation between the number of mushrooms ingested and the hallucinogenic effects. A user may ingest as few as five or as many as 100 mushrooms for a single “dose, ” but the typical recreational dose is 10 to 50 milligrams, which corresponds to 20 to 30 grams of fresh mushrooms or 1 to 2 grams of dried mushroom powder. Hallucinogenic effects begin within 30 minutes of ingestion and last 4 to 6 hours. 25,26 The hallucinogenic effects are similar to, although less powerful than, those produced by LSD. Other common effects include mydriasis, tachycardia, nausea, and vomiting. Serious medical complications are extremely rare but include seizures, hyperthermia, rhabdomyolysis, and renal failure. 27 Mistaken identity and ingestion of highly toxic mushrooms are possible and can lead to serious outcomes.28 Management is supportive. There is no routinely available screening test for psilocybin or psilocin in the urine.

ations are extremely rare but include seizures, hyperthermia, rhabdomyolysis, and renal failure. 27 Mistaken identity and ingestion of highly toxic mushrooms are possible and can lead to serious outcomes.28 Management is supportive. There is no routinely available screening test for psilocybin or psilocin in the urine. If the patient’s symptoms are not consistent with psilocybin ingestion, consider the possibility that a toxic mushroom (see Chapter 220, “Mushroom Poisoning”) or other psychoactive substances were ingested.  MESCALINE AND PEYOTE Mescaline is found in many cacti, most notably the Mexican Peyote cactus (Lophophora williamsii ) and the Peruvian San Pedro cactus Tintinalli_Sec15_p1187-1332.indd 1244 8/2/19 8:39 PM

ty that a toxic mushroom (see Chapter 220, “Mushroom Poisoning”) or other psychoactive substances were ingested.  MESCALINE AND PEYOTE Mescaline is found in many cacti, most notably the Mexican Peyote cactus (Lophophora williamsii ) and the Peruvian San Pedro cactus Tintinalli_Sec15_p1187-1332.indd 1244 8/2/19 8:39 PM CHAPTER 188: Hallucinogens 1245 (Trichocereus pachanoi). Peyote is used in Native American religious ceremonies, and its legal use is restricted to the Native American Church. Mescaline is a phenylethylamine, structurally related to amphetamines, making it chemically distinct from LSD. 29 Mescaline is believed to act as a serotonin type 2 receptor agonist but is much less potent than LSD. Peyote is most commonly sold as raw cactus or “buttons, ” 2- to 3-cm disks sliced off of the top of the cactus. Each button contains approxi mately 45 milligrams of mescaline. A typical hallucinogenic dose is 200 to 500 milligrams. Pills or capsules sold on the street as “mescaline” are unlikely to be genuine and may instead contain LSD or PCP . 9 Peyote exposures reported to poison control centers are relatively rare com pared with other drugs of abuse. In 2007, for example, only 116 peyote or mescaline exposures were reported out of more than 2.4 million total drug exposures. Peyote is bitter tasting and within an hour of ingestion causes uncomfortable physical side effects—nausea, vomiting, abdominal discomfort, diaphoresis, dizziness, nystagmus, ataxia, and headache—that generally resolve after about 2 hours. Adrenergic stimulation causes mydriasis and mild elevations in pulse, blood pressure, and temperature. Hallu cinogenic effects begin several hours after ingestion and persist for 6 to 12 hours. Significant morbidity or mortality caused by the physiologic effects of mescaline has not been observed, but death can result from aberrant behavior while under the influence of the drug. 31 Mescalineintoxicated patients are managed supportively. Routine urine drug screens do not detect mescaline.  HALLUCINOGENIC AMPHETAMINES More than 50 “designer” amphetamines have been created for their hallucinogenic properties. Very briefly, many amphetamine analogs share a phenylethylamine backbone. Phenylethylamines are chemical structures with an ethyl group that has an aromatic group and a terminal amine. Additions and substitutions of select groups occur to modify the phar macologic properties and can help to predict toxicity from these substitutions. Best known is 3,4- methylenedioxymethamphetamine (MDMA), a synthetic phenylethylamine derivative structurally related to both amphetamines and mescaline and commonly known by the street names “ecstasy,” “E” , “ Adam, ” “XTC, ” “Molly, ” and “MDM. ” Other amphetamines similar to MDMA include 3,4-methylenedioxy- N-ethylamphetamine (MDEA or “Eve”) and methylenedioxyamphetamine (MDA or “love drug”). MDMA is known for both its psychedelic properties and unique effects on mood and intimacy, which have led to its reputation as a “love drug” popular in dance clubs. 32 MDMA has complex effects, interacting with dopamine, norepinephrine, acetylcholine, and β 2-adrenergic and serotonin type 2A receptors and affecting the release of several hormones, including prolactin, oxytocin, adrenocorticotrophic hormone, dehydroepiandrosterone, and antidiuretic hormone. MDMA is usually ingested as tablets in doses of 50 to 200 milligrams. The drug is colorless and tasteless—properties lending to its use as a date-rape drug. 34 Symptoms occur within 30 minutes of ingestion and last about 4 to 6 hours. These include feelings of euphoria, inner peace, enhanced sociability, verbosity, and heightened sexual interest.

tablets in doses of 50 to 200 milligrams. The drug is colorless and tasteless—properties lending to its use as a date-rape drug. 34 Symptoms occur within 30 minutes of ingestion and last about 4 to 6 hours. These include feelings of euphoria, inner peace, enhanced sociability, verbosity, and heightened sexual interest. The drug rarely causes actual hallucinations but can produce sensory effects such as alterations in the intensity of colors or sensation of textures. Other common effects include mydriasis, tachycardia, elevated blood pressure, nausea, jaw tension, bruxism, dry mouth, muscle aches, and ataxia. Current urinary amphetamine immunoassays incorporate a specific monoclonal antibody for MDMA and should routinely detect this drug. MDMA and related amphetamines can produce serious complications and death. 35-38 As with other amphetamines, large-quantity overdoses can cause severe hypertension, intracranial hemorrhage, and ischemia in the heart or brain. 35 Fatal arrhythmias and sudden cardiac death have been reported, even in the absence of underlying heart disease. 35,36 The most frequently cited causes of death are hyperthermia and hyponatremia.39-42 A syndrome of MDMA toxicity manifested by hyperthermia, seizures, disseminated intravascular coagulation, rhabdomyolysis, and hepato toxicity has been described. 43 This pattern shares many features of the serotonin syndrome, and combining MDMA with selective serotonin reuptake inhibitors (see Chapter 178, “ Atypical and Serotonergic Antidepressants”) or monoamine oxidase inhibitors (see Chapter 179, “Monoamine Oxidase Inhibitors”) can precipitate serotonin syn drome. 44 A purified or crystallized form of MDMA, known as Molly, is typically sold as a powder and is often taken orally. It is often viewed as a “safer form” of MDMA due to lack of adulterants, but it has been associated with adverse effects. Hyponatremia is predominantly due to excessive water consumption and inappropriate antidiuretic hormone secretion. 39,40 Excessive water drinking from thirst can occur if the drug is taken at hot and crowded club venues, with vigorous dancing and profuse sweating. 39,41 Chronic MDMA use results in permanent damage to serotonergic neurons. 46 Neuropsychiatric studies of habitual users demonstrate long-lasting cognitive impairment and mood dysfunction, including memory impair ment, diminished learning ability, and depression.47 GI decontamination with activated charcoal may be useful if the drug was ingested within 60 minutes of ED arrival. 48 Weigh benefits of charcoal against risk of vomiting and aspiration. Hypertension and tachycardia often respond to benzodiazepines. Severe hypertension is treated with IV phentolamine or nitroprusside. Rapid IV titration with high doses of benzodiazepines or propofol may be required to control symptoms in patients with refractory agitation or seizures. Arrhythmias are managed with standard therapy. Check serum electrolyte concentrations and anticipate and treat abnormalities, especially hyponatremia (see Chapter 17, “Fluids and Electrolytes”). Hyperthermia is managed with cooling measures and fluid resuscitation. 40,41 Patients with temperatures exceeding 40°C (104°F) have increased morbidity and mortality, so rapid cooling is important. 49 Due to the lack of supportive evidence from controlled studies and the potential harms of administration of dantrolene, including significant respiratory muscle weakness, expert opinion no longer supports use of dantrolene in amphetamine-induced hyperthermia. Cyproheptadine has been suggested for treatment of the serotonin syndrome. 50 See Chapter 178, “ Atypical and Serotonergic Antidepressants, ” for further discussion of serotonin syndrome.

ng significant respiratory muscle weakness, expert opinion no longer supports use of dantrolene in amphetamine-induced hyperthermia. Cyproheptadine has been suggested for treatment of the serotonin syndrome. 50 See Chapter 178, “ Atypical and Serotonergic Antidepressants, ” for further discussion of serotonin syndrome.  SYNTHETIC CATHINONE DERIVATIVES: “BATH SALTS” The abuse of cathinone is not new, as the young leaves and shoots of Catha edulis (khat) have been consumed for centuries in areas of Africa and the Arabian Peninsula in order to achieve stimulant effects. The use of synthetic cathinones, particularly in Europe and the United Kingdom, however, gained popularity in the late 2000s. Calls to U.S. poison control centers peaked in 2012, and use has slightly declined in the subsequent years, but this ingestant remains a public health concern, especially among “club-goers” and young adults. 51 Although cathinones were banned, manufacturers have frequently introduced new analogs; it has been estimated that nearly 250 such novel analogs are produced each year. 52 Cathinone and synthetic derivatives, including mephedrone, methylenedioxypyrovalerone, and methylone, are chemically similar to amphetamines. The synthetic cathinones differ structurally from other amphetamines by the addition of a ketone at the β position; this decreases penetration of the blood–brain barrier due to increased polarity. These drugs likely stimulate the release and inhibit the uptake of biogenic amines such as norepinephrine, dopamine, and serotonin. Synthetic cathinone derivatives are abused by individuals seeking a “legal” high with stimulatory effects similar to those of cocaine or methylenedioxymethamphetamine. To avoid legal complications, synthetic cathinones are described as “not for human consumption” and are often intentionally mislabeled as “bath salts,” “plant fertilizer, ” “research chemicals,” or “plant food . ” These drugs are given glamorous trade names such as “Bliss, ” “Ivory Wave, ” “Blue Silk, ” or “Vanilla Sky” and sell for approximately $25 to $35 per 500-milligram package. Synthetic cathinones are most commonly insufflated (“snorted”), ingested, or inhaled, and less commonly injected or absorbed. Duration of effects depends on method of use—1 to 2 hours with nasal insuffla tion and up to 4 hours if ingested. 53 Users seek the subjective effects of increased alertness, openness, empathy, and libido. However, the adverse clinical effects can be very dangerous and are most commonly cardiac, psychiatric, and neurologic in origin. Due to the similarity to amphetamines, patients may exhibit a sympathomimetic toxidrome including agitation, psychosis, tachycardia, hypertension, and seizures. Tintinalli_Sec15_p1187-1332.indd 1245 8/2/19 8:39 PM

inical effects can be very dangerous and are most commonly cardiac, psychiatric, and neurologic in origin. Due to the similarity to amphetamines, patients may exhibit a sympathomimetic toxidrome including agitation, psychosis, tachycardia, hypertension, and seizures. Tintinalli_Sec15_p1187-1332.indd 1245 8/2/19 8:39 PM 1246 SECTION 15: Toxicology Hyperthermia and hyponatremia may also be present. Other reported symptoms include sweating, nausea, headache, chest pain, palpitations, tremor, memory loss, and suicidal ideation. Repeated use in some can lead to the development of “excited delirium, ” a syndrome with symp toms of extreme agitation and violent behavior, which can rarely lead to cardiac arrest. 54 Synthetic cathinones are not detected on routine urine toxicology screens. Treatment is primarily supportive and includes cardiovascular monitoring as well as the general approach outlined earlier. Admission to a monitored or intensive care unit setting is appropriate for patients with severe and persistent symptoms. In September 2011, the U.S. Drug Enforcement Administration issued an emergency order to place three synthetic cathinones (mephedrone, methylenedioxypyrovalerone, and methylone) temporarily into Schedule I under the Controlled Substances Act. This rendered illegal the manufacture, sale, or possession of these agents; this administrative action subsequently became law. In subsequent years, additional synthetic cathinones have been similarly assigned Schedule I status.  PHENCYCLIDINE PCP is a synthetic piperidine derivative that is structurally related to ketamine. PCP does not fit easily into a single classification, as the drug combines features of hallucinogens, depressants, and stimulants. Unlike classic hallucinogens, PCP causes a clouding of the sensorium rather than heightened sensory awareness. The primary pharmacologic action is blockade of N-methyl-d-aspartate receptor channels. At high concentrations, PCP also interacts with other receptors and channels, including the opioid and acetylcholine receptors and voltage-gated electrolyte channels. PCP exhibits sympathomimetic effects by blocking reuptake of norepinephrine and dopamine. PCP is easily and inexpensively synthesized. Powdered (“angel dust”) or liquid (“dippers”) drug is often combined with tobacco, marijuana, or other leafy materials and is usually smoked. PCP can also be ingested orally, snorted, or intravenously injected. 56 PCP may be unknowingly ingested, due to its being sold as another drug or used as an adulterant in another illicit drug product. 24 The onset of action depends on the mode of administration. With smoking, a rapid initial peak in plasma concentrations occurs in 5 minutes, with a second peak (likely due to absorption from the lungs) at about 20 minutes; effects generally last 4 to 6 hours. With large doses, effects can persist for days due to the drug’s lipid solubility and accumulation in fat stores. 57,58 Patients may experience CNS stimulation or depression, with clinical presentations ranging from physical violence to catatonic or comatose states. 56,59 A combination of cholinergic, anticholinergic, and sympa thomimetic effects causes a confusing clinical toxidrome. PCP is often coadministered with other drugs such as crack cocaine (“beam me up”), marijuana (“crystal supergrass”), or ethanol, which also complicates the clinical picture. 57 The most common findings in PCP-intoxicated patients are altered mental status, hallucinations, multidirectional nys tagmus, retrograde amnesia, hypertension (generally mild), and agita tion.57 Feelings of detachment (dissociation) from the environment and self may give the user feelings of strength, power, and invulnerability.

common findings in PCP-intoxicated patients are altered mental status, hallucinations, multidirectional nys tagmus, retrograde amnesia, hypertension (generally mild), and agita tion.57 Feelings of detachment (dissociation) from the environment and self may give the user feelings of strength, power, and invulnerability. Violent actions, agitation, bizarre and unpredictable behavior, and hal lucinations or delusions are frequent. Diaphoresis, tachycardia, muscle rigidity, dystonic reactions, ataxia, and a decreased response to painful stimuli can occur. About 10% of patients are described as comatose. Pupil size is variable; it is noteworthy that widely dilated pupils (which may be expected due to sympathomimesis) are uncommon with PCP toxicity. Medical complications from PCP toxicity are frequent. 55,59,60 Seizures occur in about 3% of patients, and up to 70% of cases exhibit rhabdo myolysis (occasionally producing acute renal failure). 58 Hypoglycemia, hypertension causing intracerebral hemorrhage, hyperthermia causing hepatic necrosis, and multiorgan failure can occur. 57,58,60,61 Violent behavior can result in self-injury. Evaluate patients with suspected PCP toxicity for occult injury, hypoglycemia, and rhabdomyolysis.55,56,59 PCP can be detected by com mercially available urine drug screens up to 8 days after single use and up to several weeks after long-term use. 62 Cough and cold medications (dextromethorphan, diphenhydramine, and doxylamine), analgesics (ibuprofen, meperidine, and tramadol), and psychotropics (imipramine, mesoridazine, thioridazine, and venlafaxine) cross-react with the drug screen and produce false-positive results. Sedation and physical restraints are frequently required to control violent and aggressive behavior. Parenteral benzodiazepines are pref erable to physical restraints because fighting against restraints may contribute to rhabdomyolysis. Treatment is generally supportive and follows the general outline provided earlier. Patients exhibiting only minor clinical features of PCP intoxication and no medical complications can be discharged when behavior normalizes. 55,56,58,59 In a case series of 184 patients, 84% went home, 8% were admitted, and the rest were trans ferred to a crisis center.  MARIJUANA OR CANNABIS Marijuana or cannabis consists of the dried leaves and flowers of the hemp plant Cannabis sativa. Hashish is prepared from the dried resin from the flower tops of this plant. The psychoactive ingredient in mari juana is tetrahydrocannabinol (THC). Marijuana is most often smoked64 but can also be ingested. Symptoms persist for 2 to 4 hours after smoking, or longer if ingested. Clinical effects include drowsiness, euphoria, heightened sensory awareness, paranoia, and distortions of time and space. Hallucinations do not usually occur at usual doses. Common physiologic effects of marijuana are mild tachycardia, injected conjunctiva, bronchodilation, orthostatic hypotension, and impaired motor coordination. 65 Medical complications, which are rare, include panic reactions, brief toxic psychoses, pneumomediasti num, and pneumothorax. Reporting of acute cardiac events associated with marijuana use 66,67 is possibly the result of aging in the population of marijuana users and the increasing availability of medical marijuana. As of November 2017, 29 U.S. states, the District of Columbia, Puerto Rico, and Guam have authorized the medical use of marijuana, and as of January 2019, nine states and the District of Columbia have authorized its recreational use. Early studies in locations that have legalized marijuana have demonstrated increases in hospital admissions, ED visits, and calls to poison centers.

Puerto Rico, and Guam have authorized the medical use of marijuana, and as of January 2019, nine states and the District of Columbia have authorized its recreational use. Early studies in locations that have legalized marijuana have demonstrated increases in hospital admissions, ED visits, and calls to poison centers. 68 An unintentional and concerning consequence in states that have adopted legalization has also been a significant increase in the number of pediatric exposures and ingestions. Marijuana is used for treatment of medical conditions such as glau coma and chemotherapy-related nausea and to promote weight gain in patients with human immunodeficiency virus infection and acquired immunodeficiency syndrome. Chronic cannabis use is associated with psychiatric, respiratory, cardiovascular, and bone effects. 70 Cyclic vomiting syndrome, also called cannabinoid hyperemesis syndrome, is increasingly recognized as an entity associated with cannabinoid over use; it is characterized by cyclical vomiting, diffuse abdominal pain, and relief with hot showers. 71-73 Symptoms are often misdiagnosed as gastroparesis or opiate withdrawal, and patients often undergo extensive laboratory testing and advanced imaging. Expert consensus recommends that treatment should focus on education on the need for cannabis cessation. Capsaicin as a topical preparation is reasonable as a first-line treatment. 74 Antipsychotics, including haloperidol and olanzapine, have been found to provide symptom relief in limited case studies.75 Acute psychiatric symptoms due to marijuana use can generally be managed with reassurance alone, but benzodiazepines can be used for severe symptoms. Standard urine drug screens are unreliable indicators of acute marijuana intoxication. High lipid solubility results in extensive deposition within body fat and slow excretion in the urine. After a single use, THC is detected by commercially available urine screens for up to 3 days. With long-term use, cannabinoids can be detected up to a month or longer after abstinence. 76 False-positive urine cannabinoid screening can occur due to use of ibuprofen, naproxen, pantoprazole, or efavirenz (a nonnucleoside reverse transcriptase inhibitor used to treat human immunodeficiency virus infection).  SYNTHETIC CANNABINOIDS Around the world, there has been a dramatic increase in the demand, availability, and abuse of novel psychoactive drugs. This class includes synthetic cannabinoids, cathinone, and piperazine. Unlike THC, Tintinalli_Sec15_p1187-1332.indd 1246 8/2/19 8:39 PM

man immunodeficiency virus infection).  SYNTHETIC CANNABINOIDS Around the world, there has been a dramatic increase in the demand, availability, and abuse of novel psychoactive drugs. This class includes synthetic cannabinoids, cathinone, and piperazine. Unlike THC, Tintinalli_Sec15_p1187-1332.indd 1246 8/2/19 8:39 PM CHAPTER 188: Hallucinogens 1247 synthetic cannabinoids (variably known as “K2, ” “spice, ” or “fake marijuana”) are extremely potent. These synthetic agents are full agonists of the cannabinoid receptors, and as compared to THC, they cause more severe physiologic and psychological effects. One of the first synthetic cannabinoids, (1-pentyl-1H-indol-3-yl)-1-naphthalenyl-methanone, goes by the term JWH-018 for the initials of J.W . Huffman, who devel oped this compound to investigate drug–receptor interactions. After being produced in the laboratory, synthetic cannabinoids are dissolved in a solvent and then sprayed on an assortment of dried plant leaves (often with other preservatives and additives such as synthetic opioids and caffeine). 78 They are sold in shops and on the Internet and labeled as “incense” and “not for human consumption. ” The appeal of such products is driven by the desire for a legal “high” that is not detectable by current urine drug assays. The product is usually rolled in paper and smoked in a manner similar to marijuana. Effects begin within minutes and may last for several hours, generally disappearing within 4 hours. 79 Most users will not seek or require medical attention, but some have experienced adverse reactions, with anxiety and tachycardia being the most common. 80 Other reported adverse effects include hypertension, diaphoresis, tremulousness, and agitation. 80,81 In 2018, there was an outbreak of unexplained and severe (including fatal) bleeding that was postulated to be due to contamination of synthetic cannabinoids with brodifacoum (a vitamin K antagonist). In severe cases, patients may present in a semi-catatonic state and can be at risk for bradycardia, hypotension, renal failure, or secondary trauma. Synthetic cannabinoids can precipitate psychosis in patients with prior mental illness. 83 Symptoms are usually self-limited and short lived, and treatment is supportive. Tachycardia, agitation, and anxiety can be treated with benzodiazepines titrated to effect. Patients with severe psychosis may be treated with antipsychotics if deemed necessary. Patients with severe and persistent symptoms may require admission, but the vast majority can be discharged once they are awake and have normal vital signs. In 2012, the enactment of the Synthetic Drug Abuse Prevention Act permanently placed 26 types of synthetic cannabinoids and stimulants into Schedule I (most restrictive) of the Controlled Substances Act. However, effective regulation is difficult because new products (with unpredictable chemical formulas) are rapidly proliferating.  DESIGNER ALKALOIDS Bromo-benzodifuranyl-isopropylamine, or Bromo-DragonFLY, is another phenylethylamine analog. 84 Bromo-DragonFLY stimulates serotonin receptors in the brain, similar to LSD. Bromo-DragonFLY was developed as a research chemical to study the relationship between molecular structure and psychedelic activity. The name comes from its chemical structure—two furanyl rings with double bonds and a side amphetamine arm—which gives it the appearance of a dragonfly. In 2005, Bromo-DragonFLY became available in human experimental markets and was soon diverted to hallucinogenic use. Bromo-DragonFLY is sold as a white to pink powder that can be snorted, smoked, or injected. Bromo-DragonFLY may also be sold on blotter paper, similar to LSD, which has led to confusion in users seeking LSD and mistakenly consuming Bromo-DragonFLY instead.

perimental markets and was soon diverted to hallucinogenic use. Bromo-DragonFLY is sold as a white to pink powder that can be snorted, smoked, or injected. Bromo-DragonFLY may also be sold on blotter paper, similar to LSD, which has led to confusion in users seeking LSD and mistakenly consuming Bromo-DragonFLY instead. Bromo-DragonFly is often used in combination with other drugs in an effort to enhance or prolong effects. The hallucinogenic dose of Bromo- DragonFLY ranges from 200 to 800 micrograms, with the onset of action within 20 to 90 minutes and a typical duration of hallucinogenic effects up to 10 to 14 hours. However, accounts of experiences lasting 2 to 3 days after consumption of a single dose have been reported. Toxicity includes agitation, hallucinations, and tonic-clonic seizures that may be delayed in onset. 86 Bromo-DragonFLY acts as a long-acting vasoconstrictor that can cause necrosis and gangrene several weeks after use. Bromo-DragonFLY has been associated with fatalities in several countries. 87 Two similar compounds, 2C-B-FLY and 3C-B-FLY , are also abused as hallucinogens. Benzylpiperazine and trifluoromethylphenylpiperazine are synthetic phenylpiperazine analogs used as substitutes for amphetamine-derived designer drugs. 79,88 These two compounds are usually combined and sold as “Legal X” in attempt to mimic the effects of MDMA. These drugs are legally available in many countries. Clinical findings include sympathomimetic effects such as palpitations, agitation, anxiety, confusion, dizziness, headache, tremor, mydriasis, insomnia, urinary reten tion, vomiting, and seizures. 79,89 Across Europe and the United States, Bromo-DragonFLY has been associated with deaths and delayed complications due to severe periph eral vasoconstriction and limb ischemia. Such complications are likely due to the agent’s potent serotonergic properties. LESS COMMONLY ABUSED HALLUCINOGENS Other drugs with hallucinogenic properties ( Table 188-2) are enjoy ing increasing popularity due to Internet promotion of these “natural” psychoactive agents. 79,90 TABLE 188-2 Less Commonly Abused Hallucinogens Hallucinogen Typical Route of Use Onset of Action Duration of Action Additional Features of Acute Toxicity Salvia divinorum: salvinorin A Smoking of dried leaves 20–60 s (smoking) 20–30 min (smoking) Headache Chewed leaves held in sublingual (SL) or buccal location 10–20 min (SL or buccal) 30–90 min (SL or buccal) Toad venom or eggs: bufotoxins

of Use Onset of Action Duration of Action Additional Features of Acute Toxicity Salvia divinorum: salvinorin A Smoking of dried leaves 20–60 s (smoking) 20–30 min (smoking) Headache Chewed leaves held in sublingual (SL) or buccal location 10–20 min (SL or buccal) 30–90 min (SL or buccal) Toad venom or eggs: bufotoxins Ingestion of toad venom extract or food made with toad eggs 30–60 min (nausea and vomiting) 1–3 d (untreated) Abdominal pain, vomiting Sympathomimetic effects Features similar to cardiac glycoside toxicity Ipomoea species (morning glory): lysergic acid amide Ingestion of seeds 1–2 h 6–10 h None Nutmeg: myristicin Ingestion of seeds or ground spice 3–6 h 6–24 h Some features resemble anticholinergic toxicity Datura species (Jimson weed and angel’s trumpet): scopolamine, atropine, and hyoscyamine Ingestion of seeds Smoking dried plant parts 1–3 h (ingestion) 5 min (smoking) 24–48 h Anticholinergic effects Ketamine Snorting dried powder or smoking of powder admixed with marijuana or tobacco 5–15 min (nasal insufflation) 1–3 min (smoking) 45–60 min (nasal insufflation) 30–45 min (smoking) Sympathomimetic effects Dextromethorphan Ingestion of liquid Nasal insufflation of powder 20–60 min (ingestion) 4–6 h (ingestion) Nausea, vomiting, and diarrhea Tintinalli_Sec15_p1187-1332.indd 1247 8/2/19 8:39 PM