Emerging Drugs of Abuse

Kavita Babu, MD, Edward W. Boyer, MD, PhD, Christina Hernon, MD, D. Eric Brush, MD
Patterns of recreational drug use undergo constant change. Health care providers must remain vigilant and informed regarding emerging drugs of abuse to care better for their patients. There is also a role for improved surveillance and characterization of novel drugs. This report reviews the clinical manifestations and toxicity of several new drugs of abuse, including dextromethorphan, hallucinogenic tryptamines (including bFoxy Methoxy Q), hallucinogenic amphetamines (including 2C-B and 2C-T-7), as well as the herbal hallucinogen, Salvia divinorum . Clin Ped Emerg Med 6:81-84 2005 Elsevier Inc. All rights reserved. KEYWORDS drugs of abuse, dextromethorphan, tryptamines, hallucinogenic amphetamines, Salvia divinorum

he decreased availability of lysergic acid diethylamide (LSD) in recent years has created a niche for novel hallucinogens that are rapidly gaining popularity among adolescents and young adults [1]. Their increased use reflects the intensity of neuropsychiatric effects, ease of procurement, decreased cost, presumed safety, and in some instances, perceived legality. Unfortunately, the emergence of these drugs, which include tryptamines, phenethylamines, and Salvia divinorum, has not been well recognized by the medical community [1]. Clinical identification of these new drugs of abuse can be difficult, if not impossible. Routine diagnostic testing may not identify these compounds or differentiate them from more common drugs of abuse. Thus, the medical literature contains few case reports of toxicity from these substances. Essentially, the only method of determining exposure to these hallucinogens may come from information provided by the patient. Increasing awareness of clinicians regarding these emerging drugs of abuse will enable better surveillance and further characterization of both the drugs and their users. All cases of toxicity from

recreational drug abuse should be managed in conjunction with a poison control center or toxicologist to facilitate management and improve national surveillance.

Dextromethorphan
Dextromethorphan (also called bDXMQ or bRoboQ) is one of a class of compounds known as dissociative agents that include phencyclidine (PCP, bangel dust Q) and ketamine (bSpecial K,Q bVitamin K Q). Striking increases in dextromethorphan abuse have been observed recently. Toxic Exposure Surveillance System data suggest that abuse or misuse of the drug by adolescents between the ages of 13 and 19 years has increased more than 300% over a 3-year period [2]. Interestingly, dextromethorphan abuse appears to follow a seasonal variation, with the peak exposures occurring between September and May. The abuse of dextromethorphan may be slightly more prevalent in women [3-5]. Younger adolescents may be at greater risk for dextromethorphan abuse [3,4,6,7]. In reports to poison control centers, the most common ages of children abusing the drug were ages 14 (23.1%), 16 (21.8%), 15 (15.4%), and 13 (10.3%) [7]. Dextromethorphan abuse has been reported in children as young as 11 years [5]. Despite the large number of over-the-counter products that contain dextromethorphan, 1 product line appears to be preferred for abuse; up to 87% of dextromethorphan abuse cases reported to poison control centers involved 81

Division of Medical Toxicology, Department of Emergency Medicine, University of Massachusetts Medical School, Worcester, MA 01655, USA. Reprint request and correspondence: Kavita Babu, MD, Division of Medical Toxicology, Department of Emergency Medicine, University of Massachusetts Medical School, Worcester, MA 01655.

1522-8401/$ - see front matter 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.cpem.2005.04.002

82 Coricidin HBP (67%) or another Coricidin product (21%) [3-5,8]. Dextromethorphan is well absorbed after ingestion, with maximum serum concentrations occurring at 2.5 hours [9]. The major metabolite of dextromethorphan, dextrorphan, is the agent responsible for all biologic activity. Dextrorphan reaches peak plasma concentrations at 1.6 to 1.7 hours after ingestion [10]. Dextromethorphan and its metabolites undergo renal elimination, with less than 0.1% of the drug being eliminated in the feces [11]. The half-life of the parent compound is approximately 2 to 4 hours in individuals with normal metabolism, but clinical effects from overdose may persist for a longer duration. The clinical presentation of dextromethorphan intoxication depends on the ingested dose. Minimally intoxicated persons may develop tachycardia, hypertension, vomiting, mydriasis, diaphoresis, nystagmus, euphoria, loss of motor coordination, and giggling or laughing [12]. In addition to the above findings, persons with moderate intoxication may demonstrate hallucinations and a distinctive plodding ataxic gait that has been compared with bzombielikeQ walking [13]. Severely intoxicated individuals in a dissociated state may be agitated or somnolent [3,4,12,14]. Extremely agitated patients may need to be physically restrained by prehospital personnel or police, actions that place patients at risk for hyperthermia, metabolic acidosis, and death. Experienced dextromethorphan users describe a rapidly developing and persistent tolerance to the drug [12]. Dependence on dextromethorphan is rarely described [15-17]. Although dextromethorphan is not thought to have addictive properties, susceptible individuals may develop cravings for and habitual use of the drug [4,18]. An abstinence syndrome, characterized by dysphoria and intense cravings, may be associated with cessation of dextromethorphan abuse [15,17,19,20]. Toxic psychosis and cognitive deterioration may arise from chronic use of the drug [15,19,20]. Toxicity in the setting of dextromethorphan abuse can arise from coingestants. In addition to dextromethorphan, over-the-counter cough formulations frequently contain other pharmaceutical agents such as chlorpheniramine, acetaminophen, or pseudoephedrine [21]. Chlorpheniramine is an H1-receptor antagonist. Consequently, individuals who have abused chlorpheniramine-containing dextromethorphan formulations may also exhibit anticholinergic signs and symptoms of tachycardia, dry mucosa, mydriasis, agitated delirium, urinary retention, gastrointestinal dysmotility, and warm flushed skin. Severe chlorpheniramine intoxication has also been associated with seizure activity, rhabdomyolysis, and hyperthermia [3]. Pseudoephedrine intoxication may mimic that of chlorpheniramine except that patients may exhibit diaphoresis. It is essential for clinicians to recognize that acetaminophen is a component of more

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than 100 cough and cold preparations. Accidental overdose may produce delayed hepatic injury and, potentially, death. Treatment of acute dextromethorphan intoxication is mainly supportive [3,14,22]. Basic life support measures, with rapid assessment of the airway and identification of abnormal vital signs, should be immediately performed. Patients with clinical evidence of dehydration or rhabdomyolysis should receive intravenous saline solution. Physical restraints may be required for severely agitated patients but should be replaced as rapidly as possible by chemical restraint. Agitation is best controlled with benzodiazepines. Hypertension and tachycardia may also respond well to sedating agents such as diazepam. Hyperthermia should be managed aggressively; if benzodiazepines and cooling blankets fail to produce an adequate response, paralysis and orotracheal intubation may be required to reduce muscular thermogenesis. Activated charcoal is indicated in cases of recent ingestion (eg, b1 hour after ingestion) but is of unclear benefit. Respiratory depression is rarely described in severe dextromethorphan intoxication but may respond to high-dose intravenous naloxone [17].

Tryptamines
Tryptamines are a class of natural and synthetic hallucinogenic chemicals [23]. Naturally occurring tryptamines include psilocin and psilocybin, the psychoactive components of Psilocybe mushrooms. Bufotenine is an indole alkaloid produced by Bufo and Rana species toads and has been used in the production of hallucinogenic snuff in South America. N,N-dimethyltryptamine (DMT) is an ingredient of a hallucinogenic mixture known as bayahuascaQ that is used in indigenous Amazonian religious ceremonies [24]. Many of the tryptamines currently used for recreational purposes were first synthesized in the laboratory of chemist Alexander Shulgin, PhD [23]. The synthetic methodology, dose, and clinical effects of many tryptamines were initially described in Dr Shulgins book, TIHKAL (bTryptamines I Have Known and LovedQ). The most noteworthy of the synthetic tryptamines are 5-MeoDiPT (bFoxy Methoxy Q), alpha-methyltryptamine (AMT, IT-290), and 5-MeO-DMT (5-methoxy-N,N-dimethyltryptamine) [24]. The pharmacology of tryptamines is poorly described. The route of administration, bioavailability, and duration of effect depends upon the chemical modification of the base structure, tryptamine. For example, 5-MeO-DiPT (Foxy Methoxy) may be administered by oral, intranasal, or intrapulmonary routes, but DMT must be smoked (due to extensive first-pass metabolism of the pure chemical). Clinical effects last for as little as 5 minutes with DMT or persist as long as 12 hours with 5-MeO-AMT. Each tryptamine appears to follow a dose-dependent

Emerging drugs of abuse

response in producing a variety of hallucinogenic experiences [23]. Patients who use tryptamines exhibit many findings seen in the serotonin syndrome. Vital sign abnormalities observed in tryptamine users include hypertension, tachycardia, tachypnea, and in severe intoxication, hyperthermia. Clinical effects of tryptamines include diaphoresis, mydriasis, sialorrhea, nausea, vomiting, diarrhea, and trismus. The neurological examination may be notable for tremor, hyperreflexia, clonus, and increased muscle tone. Neuropsychiatric effects include agitated delirium, confusion, and auditory and visual hallucinations. Patients using Foxy Methoxy experience disinhibition that may promote high-risk sexual activity [23]. The prevalence of tryptamine use is unknown; what is certain, however, is that adolescents and young adults are increasingly abusing tryptamines. Several factors have contributed to the increase in tryptamine popularity. First, excerpts from TIKHAL became widely available on the internet, leading to increased interest in this class of drug. Second, drug users recognized that the US Drug Enforcement Administration (DEA) has not yet scheduled many tryptamines as controlled substances. Third, the DEA has successfully disrupted the supply of LSD in recent months; drug users desiring a hallucinogenic experience have been forced to use other substances, many of which can be purchased via the internet [23]. Treatment of tryptamine intoxication may be similar to other sympathomimetic agonists. Patients should have vital signs aggressively corrected with a combination of supportive care and sedation. Activated charcoal may be useful after oral exposure but has limited utility for drugs that are insufflated or smoked. Benzodiazepines are the mainstay of treatment for agitation, hypertension, and hallucinations. Severely deranged vital signs may require treatment with b-adrenergic antagonists or nitroprusside [23].

83 product. Anecdotal reports of deaths after 2-CT7 use did not limit the drugs popularity, and in March 2004, 2-CT7 was classified as a Schedule I controlled substance [26]. Pharmacological data for hallucinogenic amphetamines are lacking. Although 2C-B and 2-CT7 may be administered via oral, intranasal, and intrarectal routes, the bioavailability, metabolism, and excretion of these drugs are poorly described. Both 2C-B and 2-CT7 exert their effects within 1 hour of use, and physiological and neuropsychiatric effects may persist for 6 to 10 hours. Low doses produce hypertension and tachycardia, whereas elevated doses are associated with shifts in color perception, enhanced auditory and visual stimulation, and even morbid hallucinations. Vomiting is a commonly described side effect of 2-CT7. It is uncertain if any of the 3 deaths after 2-CT7 use was associated with aspiration or seizure activity [25,26]. Management of toxicity from hallucinogenic amphetamines is similar to that for MDMA poisoning. Provision of supportive care, correction of vital signs, sedation with benzodiazepines, and evaluation for electrolyte abnormalities remain the hallmark of care. Clinicians should remain wary for signs of aspiration or seizure activity and treat these findings aggressively.

Salvia Divinorum (Salvia, Diviners Sage)

S divinorum is a perennial herb classified as a member of the mint family. While more than 500 species of Salvia exist, S divinorum is most recognized for its hallucinogenic properties. The active ingredient of S divinorum is Salvinorin A, a psychotropic diterpene that stimulates the opiate j receptor to produce hallucinations that mimic those of psilocybin [27]. Plants may be purchased from a variety of sources, including bheadQ shops, record stores, and online sources. Similarly, seeds may be purchased from internet vendors along with suggestions for successful cultivation [28]. The internet may have figured prominently in the expansion of this substances use. Because the DEA has not scheduled S divinorum and its active ingredients, many Web sites tout Salvinorin A as a blegalQ hallucinogen. Furthermore, online drug encyclopedias report that Salvia does not trigger any positive results on qualitative urine drug screens (btoxic screensQ). Salvias current popularity may be attributable to its marketing as a legal undetectable drug that can be safely purchased. So prevalent is the use of S divinorum among suburban adolescents that some Midwestern towns have adopted local legislation to render Salvinorin A illegal. The pharmacology of Salvia is poorly described, but Salvia may be chewed, smoked, or ingested as a decoction, an extract derived through boiling the leaves [29]. Interestingly, Salvinorin A is deactivated in the

Hallucinogenic Amphetamines
Hallucinogenic amphetamines are congeners of methylenedioxymethamphetamine (MDMA, bEcstasyQ). Alexander Shulgin initially described many members of this chemical class in his book, bPhenethylamines I Have Known and LovedQ (PIKHAL). As with tryptamines, many drug users have transitioned to hallucinogenic amphetamine use because of the declining availability of LSD. The manufacture of more than 300 amphetamines is described in PIKHAL. Of these, the most commonly used hallucinogenic amphetamines are 2C-B (bNexus,Q bBromo,Q bEros,Q Spectrum), and 2-CT7 (bBlue mysticQ) [25]. 2C-B gained popularity during the late 1980s as a legal substitute for Ecstasy, but it was permanently classified by the DEA as a Schedule I substance in 1995. When 2C-B was scheduled, 2-CT7 emerged as the next blegalQ Ecstasy

84 gastrointestinal tract by an unknown mechanism, so pharmacological effect depends upon the amount of drug absorbed through the oral mucosa [29]. Hallucinations occur rapidly after exposure to the drug and are typically quite vivid [29]. One of the characteristic psychotropic effects is that of synesthesia, where users may report a confusion of the senses, such as hearing colors or smelling sounds [29]. Hallucinogenic effects are typically brief, lasting only 1 to 2 hours. Side effects are not described, but individuals may be susceptible to trauma, such as falls, through lack of insight [30]. In comparison to other hallucinogens, the physiological and neuropsychiatric effects produced by Salvia are relatively mild [30]. Symptoms severe enough to require treatment in the emergency department are uncommon but may include agitation and confusion. Gastrointestinal decontamination with activated charcoal may be considered if presentation is early after ingestion or if coingestants are suspected. Agitation may be managed through administration of benzodiazepines. To date, no significant cases of Salvia toxicity or deaths from overdose have been reported [30].

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10. Silvasti M, Karttunen P, Tukiannen H. Pharmacokinetics of dextromethorphan and dextrorphan: a single dose comparison of three preparations in human volunteers. Int J Clin Pharmacol Ther 1987;9:49327. 11. Baselt R, Cravey R, editors. Disposition of toxic drugs and chemicals in man. 3rd ed. Chicago (Ill): Yearbook Medical Publishers, Inc; 1989. 12. White W. The DXM Experience FAQ. Accessed May 2005. Available at http://www.erowid.org/chemicals/dxm/faq/dxm_experience.shtml#toc.5. 13. Anonymous. DXM Effects. Accessed May 2005. Available at http://www.erowid.org/chemicals/dxm/dxm_effects.shtml. 14. Graudins A, Ferm R. Acute dystonia in a child associated with therapeutic ingestion of a dextromethorphan-containing cough and cold syrup. J Toxicol Clin Toxicol 1996;34:35122. 15. Hinsberger A, Sharma V. Cognitive deterioration from long-term abuse of dextromethorphan: a case report. J Psychiatry Neurosci 1994;19:37527. 16. Fleming P. Dependence on dextromethorphan. BMJ 1986;293:597. 17. Wolfe T, Caravati E. Massive dextromethorphan ingestion and abuse. Am J Emerg Med 1995;13:17426. 18. Nicholson K, Hayes B, Balster R. Evaluation of the reinforcing properties and phencyclidine-like discriminative stimulus effects of dextromethorphan and dextrorphan in rates and rhesus monkeys. Psychopharmacology 1999;146:49259. 19. Dodds A. Toxic psychosis due to dextromethorphan. Med J Aust 1967;2:231. 20. Schadel M, Sellers E. Psychosis with Vicks Formula 44-D abuse. CMAJ 1992;147:84324. 21. Helfer J, Kim O. Psychoactive abuse potential of Robitussin-DM. Am J Psychiatry 1990;147:67223. 22. Henretig F, Cugini D, Dubin D. Dextromethorphan overdose in children. Vet Hum Toxicol 1988;3:364. 23. Brush D, Bird S, Boyer EW. Monoamine oxidase inhibitor poisoning resulting from internet misinformation on illicit substances. J Toxicol Clin Toxicol 2004;42:19125. 24. Smolinske S, Rastogi R, Schenkel S. Foxy Methoxy: a new drug of abuse. Internet J Med Toxicol 2004;7:3. 25. Drug Enforcement Administration. Club Drugs: An update. Accessed May 2005. Available at http://www.usdoj.gov/dea/pubs/ intel/01026_x.htm. 26. DeBoer D, Gizjels M, Maes R. Data about the new psychoactive drug 2C-B. J Anal Toxicol 1999;23:227. 27. Yan F, Roth BL, Salvinorin A. A novel and highly selective kappaopioid receptor agonist. Life Sci 2004;75:261529. 28. Drug Enforcement Administration. Salvia divinorum. Accessed May 2005. Available at http://www.deadiversion.usdoj.gov/ drugs_concern/Salvia_d/salvia_d.htm. 29. Siebert DJ. Salvia divinorum and salvinorin A: new pharmacologic findings. J Ethnopharmacol 1994;43:5326. 30. Halpern JH. Hallucinogens and dissociative agents naturally growing in the United States. Pharmacol Ther 2004;102:13128.

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