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DRUGS OF ABUSE II Robert H. Williams, PhD, DABCC, FACB, MT(ASCP) Timothy Erickson, MD, FACEP, FACMT Evaluating Hallucinogenic or Psychedelic Drug Intoxication in an Emergency Setting ABSTRACT Under certain conditions or in an overdose setting, several classes of drugs can induce illusions, hallucinations, or delusions. However, one of the hallmark features of hallucinogens or psychedelic agents is their ability to induce states of altered or distorted perception, thought, and mood. Many hallucinogens produce classic sympathomimetic effects; that is, hyperactivity, mydriasis (dilated pupils), hypertension, tachycardia, and hyperthermia. However, the effects vary considerably, depending upon the hallucinogen ingested. Qualitative confirmation by the laboratory that the patient is suffering from hallucinogen intoxication such as marijuana use can be helpful to the clinician. However, the common toxicologic drug screens used by most clinical laboratories do not detect many hallucinogenic agents (such as LSD [lysergic acid diethylamide]). Thus, diagnosis of hallucinogen ingestion and treatment is often based on history of use and physical examination. This is the second article in a 3-part series on clinical toxicology and drugs of abuse. On completion of this series, the reader will be able to correlate clinical findings from the poisoned patient with data provided by the clinical laboratory that leads to a diagnosis and describe the therapeutic interventions used by clinicians for patient management. From the Department of Pathology—Division of Clinical Pathology (Dr Williams), and the Department of Emergency Medicine—Division of Toxicology (Dr Erickson), University of Illinois at Chicago Medical Center, Chicago. Reprint requests to Dr Williams, Department of Pathology—Division of Clinical Pathology (M/C 750), University of Illinois at Chicago Medical Center, 840 S Wood St, 201G CSB, Chicago, IL 60612; or e-mail: [email protected] 394 L A B O R ATO RY M E D I C I N E VO L U M E 3 1 , N U M B E R 7 J U LY 2 0 0 0 Case Presentation History The patient was a 17-year-old high school student who was transported to the emergency department by paramedics after he was found “acting confused and wandering around the hallways at school.” The patient was combative and complained of “seeing lots of bright swirling colors.” In addition to his aggressive behavior, the patient had dilated pupils that were equal and reactive, his lungs were clear to auscultation, and his skin was normal color, but diaphoretic. His pulse was 100 beats per minute, respiration rate 28 breaths per minute, blood pressure 110/60 mm Hg, and temperature 37.8°C (100.0°F). The patient’s abdomen was soft and nontender with normal bowel sounds. An electrocardiogram revealed a sinus tachycardia with regular rate and rhythm. Otherwise, he appeared to be a normal healthy male, and based on discussions with his parents, he had been performing well in school. Suspecting hallucinogen ingestion, the physician ordered the tests in Table 1 and then gave the patient benzodiazepines for sedation. After a 6-hour observation period, the patient became more alert and cooperative. He admitted to doing “LSD (lysergic acid diethylamide) blotters” at school and “had a bad trip” for the first time. He also admitted to chronic use of marijuana for more than 3 months but denied using it recently or using other drugs of abuse or ethanol. His positive urine drug screen for cannabinoids supported his history. He was discharged home with reliable and concerned parents. Table 1. Laboratory Tests for Patient Suspected of Hallucinogenic (Psychedelic) Drug Ingestion Tests Patient Result Reference Range Electrolytes Sodium, mEq/L (mmol/L) 135 (135) 136-145 (136-145) Potassium, mEq/L (mmol/L) 3.9 (3.9) 3.5-5.0 (3.5-5.0) Chloride, mEq/L (mmol/L) 108 (108) 99-109 (99-109) Bicarbonate, mEq/L (mmol/L) 22 (22) 22-28 (22-28) Serum urea nitrogen, mg/dL (mmol/L) 20 (7.1) 10-20 (3.6-7.1) Creatinine, mg/dL (mmol/L) 0.8 (71) 0.6-1.2 (53-106) Glucose, mg/dL (mmol/L) 90 (5.0) 70-105 (3.9-5.8) 4.9 (4.9) 4.7-6.1 (4.7-6.1) 13,500 (13.5) 4,800-10,800 (4.8-10.8) 15 (150) 14-18 (140-180) 45 (0.45) 42-52 (0.42-0.52) 340 (340) 150-400 (150-400) < 5 (< 1.1) < 5 (< 1.1) Amphetamines None detected None detected Cannabinoids Positive None detected Cocaine metabolite None detected None detected Barbiturates None detected None detected Opiates None detected None detected Phencyclidine None detected None detected Complete blood count RBC count, 3 106/µL (3 1012/L) WBC count, /µL (3 109/L) Hemoglobin, g/dL (g/L) Hematocrit, % Platelet count, 3 103/µL Ethanol, mg/dL (mmol/L) (3 109/L) J U LY 2 0 0 0 VO L U M E 3 1 , N U M B E R 7 L A B O R ATO RY M E D I C I N E 4 rites and for neurologic and psychiatric diseases; Egyptian papyri document its use in childbirth, and its medicinal properties were recognized by the Chinese for 2,700 years. In Eastern Europe around the 16th century, morning glory seeds were known to cause hallucinations. Natural ergot (Claviceps purpurea) has also been associated with hallucinations and altered mental status. The synthetic hallucinogen, LSD, was formulated in 1938 by Albert Hofmann, a Swiss chemist at Sandoz, who several years later developed hallucinations after he accidentally became exposed to the compound. During the 1950s, psychiatrists used LSD as an adjunct for analytic psychotherapy4; around this time it also became popular as a recreational drug. LSD was banned by the federal government in 19665; it has been classified as an illicit substance (schedule I agent) with high abuse potential and no known medical use. Section Hallucinogens are a diverse group of drugs that alter and distort perception, thought, and mood. Synesthesias (sensory misperceptions such as hearing colors or seeing sounds) are common.1 Hallucinations are false perceptions that have no basis in external stimulation. Hallucinogens are sometimes described as being mind manifesting (psychedelic), generating a religious experience, and producing dreams.2 Several cultures have used naturally occurring hallucinogenic (psychedelic) compounds in ceremonial worship for centuries. The sacramental substance “soma,” described in the Hindu holy book, the Rig-Veda, as being godlike and intoxicating is thought to be derived from the juice of the hallucinogenic mushroom, Amanita muscaria.3 The Assyrians used cannabis during their religious Scientific Communications Urine drug screen 395 Although hallucinogen use diminished in the 1970s and early 1980s, recent statistics show that these substances are becoming more popular. In the United States, marijuana is the most commonly abused illicit psychedelic substance. It is estimated that more than 20 million people use it, with increased usage among teenagers.6 The most frequently abused substance is alcohol, followed by marijuana, then LSD.7 Approximately 14% of adolescents have used hallucinogens, with usage among high school students being about 10%.8 (found in the toad family, genus Bufo); the most significant phenylethylamines include mescaline and amphetamine derivatives such as MDMA (3,4-methylenedioxymethamphetamine); the major cannabinols are marijuana and hashish (contain delta-9-tetrahydrocannabinol). Amphetamines and the designer “hallucinogenic” amphetamines (ie, MDA, MDMA, and MDEA) are also sympathomimetic drugs, and thus will be discussed in the final article of this series. Although phencyclidine (PCP) and ketamine are considered anesthetics, they are primarily abused for their hallucinogenic properties. However, this Common Hallucinogenic or Psychedelic article is limited to the discussion of cannabinols, Substances LSD, and naturally occurring hallucinogenic and Table 2 lists some of the common hallucinogenic or psychedelic compounds. psychedelic agents. The major structural classes are the lysergamides, indolealkyamines, phenylethy- Lysergic Acid Diethylamide lamines, and cannabinols. The major lysergamides LSD, a potent hallucinogen, is the synthetic diethyinclude LSD and ololihqui (South American morn- lamide derivative of ergot alkaloids. It is water soling glory); the primary indolealkyamines are psilo- uble, colorless, tasteless, and odorless. LSD is cybin (found in certain mushrooms) and bufotenine commonly sold as liquid-impregnated blotter paper (Fig 1), microdots (tiny tablets), windowpanes (gelatin squares), liquid, powder, or tablets.7 Table 2. Hallucinogenic or Psychedelic Agents LSD is readily absorbed by the gastrointestinal tract, with ingestion being the most common route LSD (lysergic acid diethylamide) of exposure. Other routes of administration Morning glory seeds (Convolvulaceae) include intranasal, parenteral, sublingual, smokMushrooms ing, and conjunctival instillation. Typical street dose ranges from 50 to 300 mg; the minimum Amanita muscaria effective dose is 25 mg.9 LSD is about 80% protein Psilocybin (Psilocybe) bound and has an elimination half-life of 2.5 Mescaline/peyote hours. Onset of psychologic effects occurs within 30 to 60 minutes after ingestion, with peak effect at Phencyclidine (PCP), ketamine 3 to 5 hours. Metabolism by the liver leads to a Designer amphetamines pharmacologically inactive compound. 3,4-methylenedioxyamphetamine (MDA, “Love Drug”) Several naturally occurring plants contain lysergamides, such as morning glory (Riva 3,4-methylenedioxymethamphetamine (MDMA, “Ecstasy,” corymbosa) and Hawaiian baby woodrose (Ipo“XTC,” “Adam”) moea violacea). The lysergamides found in morn3,4-methylenedioxyethamphetamine (MDEA, “Eve”) ing glory have about one tenth the potency of Marijuana, hashish LSD; it takes 200 to 300 pulverized seeds to elicit a hallucinogenic effect.10 Belladonna alkaloids Jimson weed (Datura stramonium) Mandrake (Mandragora officinarum) Deadly nightshade (Atropa belladonna) 396 L A B O R ATO RY M E D I C I N E VO L U M E 3 1 , N U M B E R 7 J U LY 2 0 0 0 Indolealkyamines Psilocybin Psilocybin is found in 3 major genera of mushrooms: Psilocybe, Panaelous, and Conocybe.11 Mushrooms that contain psilocybin are found in the southern United States (Fig 2). The mushrooms can be recognized by their blue-green color after bruising. Psilocybin was first isolated by Albert Hofmann (of LSD fame). The effects are similar to LSD, but the duration of action is shorter (about 4 hours). Fig 1. LSD blotter papers. Bufotenine and Related Derivatives Toads of the genus Bufo have secretions that contain complex mixtures of cardiotoxins and neurotransmitters such as bufotenine, 5-methoxy, -N, N dimethyltryptamine (5-MeO-DMT), bufotenidine, and dehydrobufotenine. Ingestion of toad venom from this genus can cause severe reactions and death.12 The compound 5-MeO-DMT, which is present only in the toad Bufo alvarius, may be responsible for the hallucinogenic effect. It appears that smoking the compound is requisite to induce the hallucinogenic effect.13 Fig 2. Psilocybin mushrooms, “little brown shrooms.” N, N-dimethyltryptamine OH H 3C COOH C5H11 O THC OH CH2OH H 3C CH3 O 4 CH3 Phenylethylamines Peyote/Mescaline In the dry rocky slopes throughout the southwestern United States and northern Mexico grows the blue-green Peyote cactus, or Lophophora williamsii. The dried fleshy tips of the cactus are known as peyote buttons; ingestion of 6 to 12 buttons is necessary to produce a hallucinogenic effect.3 Mescaline is the active hallucinogenic alkaloid found in the peyote cactus. It is rapidly absorbed in the gastrointestinal tract. Mescaline pills contain either synthetic mescaline or ground peyote compressed Scientific Communications CH3 C5H11 Section In the Amazon basin grows a plant called the “yakee” (Virola calophylla). The bark of this plant contains the compound N, N-dimethyltryptamine (DMT), which is a potent short-acting hallucinogen. DMT has been used by the shamans as a hallucinogenic snuff.3 DMT is typically smoked, snorted, or injected, because it is not readily absorbed by the gastrointestinal tract. Maximum effect of the compound occurs rapidly (within 5 to 20 minutes); its duration is 30 to 60 minutes. OH THCCOOH H3 C CH3 C5H11 O 11-OH-THC Fig 3. Major metabolic route for THC [delta-9-tetrahydrocannabinol], including the primary active metabolite, 11-OH-THC, and the primary inactive metabolite, THCCOOH. SOURCE: Huestis MA. Marijuana. In: Levine BA, ed. Principles of Forensic Toxicology. Washington, DC: AACC Press; 1999:247. Used with permission. J U LY 2 0 0 0 VO L U M E 3 1 , N U M B E R 7 L A B O R ATO RY M E D I C I N E 397 into a tablet. Use of mescaline often produces side Depending on the dose inhaled, the psychoactive effects, such as nausea, vomiting, and diaphoresis, effects of marijuana may last from 1 to 4 hours.22 before the user experiences a psychedelic effect. High doses can result in image distortion, a loss of personal identity, and fantasies and hallucinaCannabinols tions. Marijuana smoking can cause a 5-fold Marijuana, along with hashish, joint, pot, reefer, increase in the carboxyhemoglobin level comand Colombian ganga are common names given pared with tobacco.23 Also, in pregnant female to the psychoactive substance, delta-9-tetrahydro- smokers, studies have shown that a number of cannabinol (THC), obtained from the Indian neonatal neurobehavioral disturbances correlate hemp plant or Cannabis sativa. The primary active with marijuana usage. These problems appear to metabolite of THC is 11-hydroxy THC; the pri- disappear during infancy and reappear later in mary inactive metabolite is THC carboxylic acid early childhood.24 (Fig 3). Although the plant contains about 60 other resins called cannabinoids, these substances Diagnosis of have very little if any psychoactivity compared Hallucinogenic Toxic Effects with THC. In addition to the cannabinoids, the The differential diagnosis of hallucinogenic (psyplant also contains more than 200 chemical com- chedelic) drug use can be overwhelming, because pounds that may contribute to medical problems every drug class can induce hallucinations in difoften seen with marijuana use.10 Hashish and ferent patient populations. The diagnosis of halluhashish oil (hashish plus tobacco) are also derived cinogen use is often made on the basis of history from Cannabis sativa; they are smoked in pipes and physical examination. Drug-induced condiand contain higher concentrations of THC than tions associated with perceptual changes are generfound in marijuana. ally accompanied by physiologic abnormalities. With the hallucinogens, sympathomimetic effects Pharmacologic Actions of are common, occur shortly after ingestion, and LSD and Marijuana (THC) usually precede the hallucinogenic effects. DelirThe mechanism of action of most hallucinogenic ium or psychosis, however, is also observed with (psychedelic) drugs is poorly understood; how- other drugs that exhibit similar effects, such as ever, it is thought to involve neurotransmitters in PCP, amphetamines, cocaine, and anticholinerthe central nervous system.14 For example, LSD gics.10 Patients with amphetamine intoxication appears to alter thought and perception by its typically present with elaborate and paranoid deluactions on the serotonergic neurons.15,16 Sero- sion, as well as visual disturbances.10 Uncontroltonin (5-hydroxytryptamine or 5-HT) regulates platelet function and smooth muscle in the gasTable 3. Clinical Findings Associated trointestinal tract and cardiovascular system and With Hallucinogenic (Psychedelic) occurs as a neurotransmitter in the brain.17 Drug Intoxication Because LSD is structurally related to serotonin, it Visual hallucinations can serve as an agonist for several types of sero18 tonin receptors, such as 5-HT1 and 5-HT2. All Dilated pupils (mydriasis) the major classes of the hallucinogens appear to Tachycardia show a strong relationship between their interacHypertension tion with the 5-HT2 receptor and the production 19 of a hallucinogenic effect. Antagonists of this Tachypnea receptor appear to block many of the effects of Diaphoresis hallucinogenic drugs.20 Vomiting and diarrhea The effects of marijuana depend upon the route of administration and the concentration of Hyperthermia THC in the product. Although smoking usually Hyperactivity leads to immediate effects, the effects with oral Mental status changes ingestion are slow and often unpredictable owing 21 to the effects of acid pH of the stomach on THC. Coma 398 L A B O R ATO RY M E D I C I N E VO L U M E 3 1 , N U M B E R 7 J U LY 2 0 0 0 Laboratory Evaluation of Hallucinogen Toxic Effects 4 Common tests requested by clinicians for patients suspected of hallucinogen overdose include electrolytes, glucose, renal function tests, and toxicology tests that help to confirm the presence of hallucinogens or compounds that may give rise to Scientific Communications Patient Management The basic approach for any patient with altered mental status who is suspected of taking a hallucinogenic drug should include consideration of administration of dextrose, thiamine, and naloxone as indicated (ie, patients who have hypoglycemia, Wernicke encephalopathy, or concurrent use of opiates, respectively) and a vigorous search for other etiologies.10 Table 4 lists the overall approach to managing a patient suspected of hallucinogen intoxication. The most common adverse effect is acute panic reactions, which present as frightening illusions, tremendous anxiety, apprehension, and terrifying loss of control.10 Thus, placing the patient in a quiet area may help to reduce his or her anxiety. The psychedelic agents rarely produce life-threatening problems. Sedation with benzodiazepines is usually sufficient to treat hypertension and tachycardia.10 Patients with hyperthermia, however, must be Test Your aggressively treated with hydration, active external Knowledge! coolants, and muscle relaxants ranging from ben- Look for the CE zodiazepines to paralytic agents, depending on the Update exam on Drugs of Abuse (005) degree of hyperthermia. Complications of hyper- in the September thermia, which include rhabdomyolysis, myoglo- issue of Laboratory binuric renal failure, hepatic necrosis, and Medicine. Participants disseminated intravascular coagulation, con- will earn 3 CMLE tribute to the morbidity and mortality found in credit hours. hallucinogenic drug intake. Table 4. Treatment of Patient With Hallucinogenic or Psychedelic Drug Intoxication Patient should be placed in a quiet room with close observation. Most patients generally require only supportive care. Support airway and administer oxygen, if comatose. Administer naloxone if concurrent opiate use suspected. If agitated, combative, or hyperactive, administer benzodiazepines—diazepam (Valium) or lorazepam (Ativan). If benzodiazepines ineffective, may give haloperidol (Haldol). Cool, if hyperthermic, and watch for rhabdomyolysis. Substance abuse/detoxification referral and counseling. J U LY 2 0 0 0 VO L U M E 3 1 , N U M B E R 7 L A B O R ATO RY M E D I C I N E 399 Section lable behavior or extreme agitation along with marked hyperthermia should suggest possible exposure to drugs such as cocaine or PCP. Table 3 lists the common clinical findings associated with hallucinogen ingestion. Other clinical findings observed include muscle weakness, ataxia, and hippus (spasmodic rhythmic pupillary dilation and constriction).25 The psychologic effects of LSD are dose related and effect changes in arousal, emotion, perception, thought processes, and self-image. The response to the drug is related to the person’s mindset, emotions, or expectations at the time and can be altered by the group or setting.26 Altered perceptions are common with synesthesias and loss of body image and alteration in visual perceptions, that is, distortion of people’s faces and bodies and undulation of objects. These effects usually last 6 to 12 hours.10 Hallucinogen persisting perception disorder, also called “flashbacks” (often induced by prolonged stress, illness, or exercise), can occur up to 18 months after ingestion.10 Special attention should be given to patients who ingest LSD and receive therapeutic doses of lithium or a selective serotonin-reuptake inhibitor, because they are at greater risk for seizures and flashbacks.27,28 The usual effects of marijuana use are fairly predictable and also include alterations in sensation, perception, cognition, and psychomotor functions. Physiologic effects are usually dose related; however, psychologic effects usually do not correlate with the amount taken. Increase in heart rate, urinary retention, mydriasis, and hypothermia are common clinical findings. Other effects with acute marijuana usage include decreased intraocular pressure and increased appetite (thus, its recommended use in the treatment of glaucoma and AIDS patients, respectively). Currently there is 1 prescription product called dronabinol (Marinol, Roxane Laboratories, Columbus, OH), that contains synthetic THC. In an attempt to promote the clinical usefulness of marijuana use, 5 states (CA, AZ, NH, MI, and MO) as of 1997 have passed nonbinding resolutions urging the federal government to make marijuana medically available. similar symptoms. Laboratory tests that can detect LSD exposure include immunoassays (radioimmunoassay, enzyme-multiplied immunoassy technique; enzyme-linked immunosorbent assay) and gas chromatography–mass spectrometry for the detection of LSD and its urinary metabolite, 2-oxyLSD.29,30 However, these assays are not routinely performed in most clinical laboratories. Also, some compounds, such as ergotamine, tricyclic antidepressants, verapamil, sertraline, and fentanyl can cross-react with LSD immunoassays.31 Although most laboratories do not analyze for the presence of LSD, most are capable of rapid immunoassay screening for other drugs that produce similar symptoms, that is, cocaine (as its metabolite, benzoylecgonine), amphetamines, PCP, and cannabinoids or marijuana (as its metabolite, THC). Nevertheless, it still is important to recognize that most standard screens for drugs of abuse do not include hallucinogens such as LSD.32 Testing for esoteric hallucinogens such as mescaline, psilocybin, and bufotenine, is generally performed by reference laboratories that specialize in toxicology. THC in marijuana is hydrophobic; thus, it accumulates in the lipid tissue; it also is highly protein bound and undergoes enterohepatic cycling. These combined properties of THC result in its slow elimination from the body. Immunoassays used to screen for THC contain antibodies directed toward delta-9-tetrahydrocannabinolcarboxylic acid (THCCOOH), the primary “inactive” metabolite, because little or no parent THC or 11-OH-THC “active” metabolite (Fig 3) is present in urine.33 However, the antibodies can crossreact with any of the metabolites (most of which lack psychoactivity), and their cross-reactivity varies considerably, depending upon the immunoassay method. They can also cross-react with other compounds such as ketoprofen, tolmetin, naproxen, ibuprofen, and acetylsalicylic acid, although such reactions do not appear to be a problem at the lowest level of sensitivity with immunoassays that are currently available.31 THC can be detected with immunoassays at a variety of sensitivity levels: 20, 400 L A B O R ATO RY M E D I C I N E VO L U M E 3 1 , N U M B E R 7 J U LY 2 0 0 0 50, and 100 ng/mL. Clinically it may be more important to use the lowest level. For federal workplace testing, the Substance Abuse Mental Health Services Administration of the Department of Health and Human Services, has established a screening cutoff of 50 ng/mL for cannabinoids.34 Unlike most clinical applications, federal workplace testing also requires confirmation of THCCOOH by gas chromatography–mass spectrometry at a cutoff of 15 ng/mL.35 It should be noted that passive exposure to marijuana smoke could give false-positive screening results, depending on the room concentration even after a single exposure.36 Studies have shown that THC can be detected for 1 to 3 days with single acute use and up to 4 weeks with daily (chronic) use.37 The detection of marijuana use depends on several factors, such as the lipid stores of the patient for THC, its frequency of use, and the sensitivity level used for its detection. The test result can be positive for more than 2 months.10 Although detection of marijuana in the urine can be rapidly determined using immunoassay methods, its presence rarely dictates the physician’s approach to patient management. There are no known cases of death associated with sole use of marijuana. The benefit of its detection, however, may be to rule out other potential hallucinogenic or psychoactive substances with similar signs and symptoms or to counsel a pregnant female on its possible side effects with fetal development. It is noteworthy that marijuana is often used in conjunction with other drugs such as opium, alcohol, cocaine, heroin, phencyclidine, and ketamine and, on rare occasions, with formaldehyde.38 Conclusion Patients who come to the emergency department with hallucinogen intoxication often have myriad signs and symptoms seen with other sympathomimetic drugs. The clinician often relies on history and physical examination, because most clinical laboratories cannot routinely rule in hallucinogen ingestions such as LSD and mescaline. The clinical laboratory, however, can be helpful in ruling out other drugs of abuse that may precipitate similar signs and symptoms. Most patients can be readily treated with sedation and by placing them in a quiet area for observation.l J U LY 2 0 0 0 VO L U M E 3 1 , N U M B E R 7 L A B O R ATO RY M E D I C I N E Scientific Communications 21. Ohlsson A, Lingren JE, Wahlen A, et al. Plasma delta-9tetrahydrocannabinol concentrations and clinical effects after oral and intravenous administration and smoking. Clin Pharmacol Ther. 1980;28:409-416. 22. Chait LD, Burke KA. Preference for high- versus lowpotency marijuana. Pharmacol Biochem Behav. 1994;49:643-647. 23. Wu TC, Tashkin DP, Djahed B, et al. Pulmonary hazards of smoking marijuana as compared with tobacco. N Engl J Med. 1988;318:347-351. 24. Richardson GA, Day NL, McGauhey PJ. The impact of prenatal marijuana and cocaine use on the infant and child. Clin Obstet Gynecol. 1993;36:302-318. 25. Leikin JB, Krantz AJ, Zell-Kanter M, et al. Clinical features and management of intoxication due to hallucinogenic drugs. Med Toxicol Adverse Drug Exp. 1989;4:324-350. 26. Bowers MB, Freedman DX. Psychedelic experiences in acute psychoses. Arch Gen Psychiatry. 1966;15:240-248. 27. Jackson TW, Hornfeldt CS. Seizures activity followed recreational LSD use in patients treated with lithium and fluoxetine [abstract]. Vet Hum Toxicol. 1991;33:387. 28. Markel H, Lee A, Holmes RD, et al. LSD flashback syndrome exacerbated by selective serotonin reuptake inhibitor antidepressants in adolescents. J Pediatr. 1994;125:817-819. 29. Jenkins AJ. Hallucinogens. In: Levine BA, ed. Principles of Forensic Toxicology. Washington, DC: AACC Press; 1999:286-308. 30. Fenton J. Lysergic acid diethylamide (LSD). In: Fenton J, ed. The Laboratory and the Poisoned Patient. A Guidebook for Interpreting Laboratory Data. Washington, DC: AACC Press; 1998;225-228. 31. Smith ML. Immunoassay. In: Levine BA, ed. Principles of Forensic Toxicology. Washington, DC: AACC Press; 1999:130-152. 32. Gold MS, Dackis CA. Role of the laboratory in the evaluation of suspected drug overdose. J Clin Psychiatry. 1986;47(suppl):17-23. 33. Huestis MA. Marijuana. In: Levine BA, ed. Principles of Forensic Toxicology. Washington, DC: AACC Press; 1999:246-263. 34. Department of Health and Human Services. Substance Abuse Mental Health Services Administration. Mandatory Guidelines for Federal Workplace Drug Testing Program Notice. Washington, DC. 59 Federal Register 29921 (1994). 35. Department of Health and Human Services, Substance Abuse Mental Health Services Administration: Mandatory Guidelines for Federal Workplace Drug Testing Program Notice. Washington, DC. 59 Federal Register 29922 (1994). 36. Cone EJ, Johnson RE, Darwin WD, et al. 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N Engl J Med. 1986; 314:1517-1518. 13. Weil AT, Davis W. Bufo alvarius: a potent hallucinogen of animal origin. J Ethnopharmacol. 1995;41:1-8. 14. Caldwell J, Sever PS. The biochemical pharmacology of abused drugs. Clin Pharmacol Ther. 1992;24:68-76. 15. Burris KD, Breeding M, Sanders-Bush E. (+) Lysergic acid diethylamide, but not its nonhallucinogenic congeners, is a potent serotonin 5HT1C receptor agonist. J Pharmacol Exp Ther. 1991;258:891-896. 16. Burris KD, Sanders-Bush E. Unsurmountable antagonism of brain 5-hydroxytryptamine-2 receptors by (+)-lysergic acid diethylamide and bromo-lysergic acid diethylamide. Mol Pharmacol. 1992;42:826-830. 17. Heym J, Jacobs BL. Serotonergic mechanisms of hallucinogenic drug effects. Monogr Neural Sci. 1987;13:55-81. 18. Pierce PA, Peroutka SJ. Hallucinogenic drug interactions with neurotransmitter receptor binding sites in human cortex. Neuropsychopharmacology. 1989;97:118-122. 19. Glennon RA, Titeler M, McKenney JD. 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