REVIEW
OF
THERAPEUTICS
New Drugs of Abuse Megan A. Rech,1,2* Elisabeth Donahey,1 Jacqueline M. Cappiello Dziedzic,2,3 Laura Oh,2,3 and Elizabeth Greenhalgh1,4 1
Department of Pharmacy Services, Loyola University Medical Center, Maywood, Illinois; 2Department of Emergency Medicine, Loyola University Medical Center, Maywood, Illinois; 3Stritch School of Medicine, Loyola University Chicago, Maywood, Illinois; 4Marcella Niehoff School of Nursing, Loyola University Chicago, Maywood, Illinois
Drug abuse is a common problem and growing concern in the United States, and over the past decade, novel or atypical drugs have emerged and have become increasingly popular. Recognition and treatment of new drugs of abuse pose many challenges for health care providers due to lack of quantitative reporting and routine surveillance, and the difficulty of detection in routine blood and urine analyses. Furthermore, street manufacturers are able to rapidly adapt and develop new synthetic isolates of older drugs as soon as law enforcement agencies render them illegal. In this article, we describe the clinical and adverse effects and purported pharmacology of several new classes of drugs of abuse including synthetic cannabinoids, synthetic cathinones, salvia, desomorphine, and kratom. Because many of these substances can have severe or life-threatening adverse effects, knowledge of general toxicology is key in recognizing acute intoxication and overdose; however, typical toxidromes (e.g., cholinergic, sympathomimetic, opioid, etc.) are not precipitated by many of these agents. Medical management of patients who abuse or overdose on these drugs largely consists of supportive care, although naloxone may be used as an antidote for desomorphine overdose. Symptoms of aggression and psychosis may be treated with sedation (benzodiazepines, propofol) and antipsychotics (haloperidol or atypical agents such as quetiapine or ziprasidone). Other facets of management to consider include treatment for withdrawal or addiction, nutrition support, and potential for transmission of infectious diseases. KEY WORDS synthetic cannabinoids, synthetic cathinones, salvia, desomorphine, kratom. (Pharmacotherapy 2014;**(**):**–**) doi: 10.1002/phar.1522
Drug abuse is a common problem and growing concern in the United States, and over the past decade, novel or atypical drugs have emerged and become increasingly popular. Staying current with the new drugs of abuse can be challenging for health care practitioners due to lack of quantitative reporting and surveillance, and the difficulty of detection in routine blood and urine analyses. Furthermore, street manufacturers are able to rapidly adapt and develop new synthetic isolates of older drugs as soon as law enforcement agencies render them illegal. *Address for correspondence: Megan A. Rech, Department of Pharmacy Services, Loyola University Medical Center, 2160 S 1st Avenue, Maywood, IL 60153; e-mail: [email protected]. Ó 2014 Pharmacotherapy Publications, Inc.
“Legal highs” are widely advertised in head shops and gas stations, and through the Internet. These agents are marketed as legal alternatives that produce similar effects as illicit drugs; however, many of these substances can cause severe or lifethreatening adverse effects.1 The Synthetic Drug Abuse Prevention Act of 2012 was enacted to combat this issue, banning several of the most common isolates of synthetic cannabinoids and cathinones.2 Recognition and treatment of new drugs of abuse pose many challenges for health care providers. Knowledge of general toxicology is key in recognizing acute intoxication and overdose; however, typical toxidromes are not precipitated by many of these agents. Furthermore, toxicity may be difficult to diagnose because most new designer drugs are not detected with conventional
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drug testing. Therefore, the purpose of this article is to describe the pharmacology, clinical and adverse effects, and reported literature on several new classes of drugs of abuse.
An estimated 23.9 million Americans 12 years or older are current illicit drug users. The National Institute on Drug Abuse estimates that overall use of tobacco, alcohol, and illicit drugs results in $600 billion annually in costs related to crime, health care, and lost work productivity. Use of illicit drugs alone accounts for $193 billion of the total. The illicit drugs routinely surveyed include marijuana, hashish, cocaine, heroin, hallucinogens, inhalants, and prescription-type psychotherapeutics used nonmedically; many newer illicit drugs of abuse are not currently tracked or reported, and thus it is difficult to capture the burden that new drugs of abuse place on society.3
antidotes. However, with the exception of the effects of desomorphine and kratom potentially being reversed by the l-opioid antagonist naloxone, reversal agents have not been identified for new drugs of abuse. Diagnosis of new drugs of abuse is also particularly challenging. Routine blood and urine screening tests do not detect most of these agents, although desomorphine is structurally similar to opioids and therefore may be detected as such. Some new agents can be sent to laboratories capable of mass spectrometry or gas or liquid chromatography for detection.6, 7 However, clinical utility of these tests is limited due to turnaround time and lack of a single test to collectively detect all new drugs of abuse.8 Diagnostic evaluation should include appropriate laboratory parameters including particular attention to electrocardiogram and electrolyte abnormalities. An understanding of common drugs of abuse in specific geographic locations may help narrow the differential diagnosis.
General Approach to Illicit Drug Users
Synthetic Cathinones
Although intoxication with new drugs of abuse may be difficult to diagnose and treat, treatment of these patients should be approached similarly to that of other toxicology cases. General management should consist of supportive care combined with a detailed history and physical examination that may be difficult to perform due to altered mental status. The mnemonic ABCDEFG can be used to guide clinicians (Table 1). This approach combines basic emergency medical care (airway, breathing, and circulation [ABC]) with specific toxicology management, including decontamination (D) and enhanced elimination (E) methods, antidote administration (focused therapy [F]), and toxicologist or poison control center consultation (“get tox help” [G]).4 History should specifically address type of ingestion, time of exposure, cumulative amount, and route of administration. Furthermore, evaluation of multiple drugs of abuse, prescription opioid medications, and over-the-counter agents should be considered because coingestion is common. Clinicians should be aware of the classic drug toxidromes (e.g., cholinergic, sympathomimetic, opioid) and toxic vital signs (e.g., tachycardia, hyperthermia, hypotension) but should also realize the limitations due to confounding factors and atypical presentations with newer agents.4, 5 Many toxicologic ingestants can be treated with specific
Synthetic cathinones, commonly referred to as “bath salts,” are analogs of naturally occurring cathinones such as Catha edulis (khat). Khat is native to Yemen and eastern Africa, where indigenous people have been chewing the fresh leaves for hundreds of years.9 Cathinone is the main psychoactive agent in khat, and it produces a stimulant effect resulting in increased alertness, energy, and libido, and appetite suppression and euphoria.10, 11 Although the World Health Organization does not consider khat to be a seriously addicting drug of abuse, chewing the agent has been linked to peptic ulcers, myocardial infarction, dilated cardiomyopathy, stroke, and death.7, 12 Synthetic cathinones were initially developed in the 1920s for therapeutic purposes, and in recent years these agents have become drugs of abuse.13 Widespread use began in Europe in the early 1990s and then gained popularity in the United States, with at least 30 chemical compounds in existence and many street names (Table 2).7 Commercially available cathinones include bupropion for smoking cessation and depression, and diethylpropion for appetite suppression.7, 12 In 1993, cathinone was classified as a Schedule I controlled substance by the Drug Enforcement Agency (DEA).7 The Synthetic Drug Abuse Prevention Act of 2012 amended the Controlled Substances Act to make several
Epidemiology
NEW DRUGS OF ABUSE Rech et al Table 1. General Management of Toxicology Cases Pneumonic
Management
A B C D E F G
Airway Breathing Circulation Decontamination Enhanced elimination Focused therapy (antidote administration) “Get tox help” (toxicologist or poison control center consultation)
cannabimimetic substances and hallucinogens Schedule I controlled substances.2 U.S. poison control centers began receiving calls related to “bath salts” in 2010, with a peak in volume in mid-2011.14 In 2011, 6137 exposures to synthetic cathinones were reported, followed by 2691 exposures in 2012 and only 995 exposures in 2013. This decrease should be interpreted with caution because providers may have become more familiar with the treatment of synthetic cathinone abuse or overdose, and they may be less likely to call poison control centers for assistance. Low cost and inability to detect these agents with conventional laboratory parameters makes them particularly appealing to illicit drug users. Synthetic cathinones are sold in smoke shops, head shops, gas stations, and convenience stores, and on the Internet as bath salts, plant food, jewelry cleaner, research chemicals, and herbal extracts under many street names (Table 2).12 Chemically unrelated to Epsom salts or household cleaning products, they are ambiguously labeled with the statement “not for human consumption.”1 Synthetic cathinones are available as white or light brown powder, pills, or capsules.15 Doses range from a few milligrams to more than 1 g.12 The most common routes of administration include nasal insufflation (“snorting”) and oral ingestion; however, rectal, gingival, inhalation,
3
smoking, parenteral (intravenous and intramuscular), “bombing” (wrapping powder in cigarette paper and swallowing it), and “keying” (insufflating powder off the surface of a key) have been reported.7, 10, 12 The mechanism by which synthetic cathinones exhibit an effect is similar to other stimulants through functionally changing monoamine transporters through which the neurotransmitters serotonin, dopamine, and norepinephrine are taken up from central synaptic clefts, resulting in increased postsynaptic neurotransmission.11 Each agent has variable effects and potency on serotonin, dopamine, and norepinephrine, and serum concentration does not predict toxicity.16 Advertised effects of synthetic cathinones include euphoria, increased energy, openness, empathy, alertness, and increased libido.10 Duration of action, dosing, and time of onset of symptoms vary with routes of administration and purity of the product.7, 12 Users report the onset of psychoactive effects as between 10 and 45 minutes and duration between 2 and 4 hours, depending on route of administration.12 No published human data on the pharmacokinetics and pharmacodynamics of the synthetic cathinones exist.10 Mephedrone is metabolized via phase I and II reactions involving various hepatic cytochrome P450 (CYP) isoenzymes including CYP2C19, CYP2D6, and CYP1A2.6 The most common clinical findings reported to poison centers include agitation, confusion, hallucinations, tachycardia, hypertension, mydriasis, tremor, and fever. Additional serious effects reported include rhabdomyolysis, electrolyte abnormalities, renal failure, seizures, and death.17 Exposure may precipitate a sympathomimetic toxidrome including agitation, psychosis, hypertension, tachycardia, and seizures. Hyperthermia, hyponatremia, and acute renal failure have also been reported.12, 18 Aggressive violent behavior, paranoia, and hallucinations are more
Table 2. Common Street Names and Active Compounds of New Drugs of Abuse Drug of abuse Synthetic cathinones9,
Street names 11
Synthetic cannabinoids26 Salvia43 Kratom51 Krokodil67
Khat, Bath salts, Meow meow, MCAT, Ivory wave Bubbles, Vanilla sky, Cloud 9, Explosion, White lightning Spice (including variants such as Spice Gold, Spice Diamond, Spice Silver) K2, Krypton, Aztec Fire, Bombay Blue, Fake Weed, Yucatan Fire Diviner’s Sage, Mystic Sage, Sally D, Magic Mint Biak-biak, Ketum, Kahuam, Ithang, Thom Krokodil, Crocodile, Zoombie Drug
Active compounds Methcathinone Ethylone, Mephedrone, Methedrone Methylenedioxypyrovalerone (MDPV) NaphyroneButylone 4-Fluoromethcathinone Brephedrone Pyrovalerone JWH-015JWH-018JWH-073JWH-210CP-47,497CP-55, 490HU-210 Salvinorin A Mitragynine Desomorphine
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frequently reported compared with amphetamines.10 Multiple case reports describe an “excited delirium” after using synthetic cathinones.11, 15 Other case reports have shown compartment syndrome, suicide, and sudden cardiac death with synthetic cathinone use.19, 20 A physical withdrawal syndrome occurs in cyclic binge users about 4 hours after the last dose is taken. Users have reported short periods of sleepiness, irritability, depression, and anxiety followed by sleep lasting days, increased appetite, and insomnia lasting up to 2 weeks.21 Synthetic cathinones cannot be readily detected with routine testing, and no correlation of concentration with clinical effects has been reported.6 Exposure is a clinical diagnosis; therefore, history and physical examination findings are key.10 Synthetic cathinone intoxication should be suspected in a patient with acute onset altered mental status, excited delirium, renal failure, and sympathomimetic symptoms.22 The management of intoxication is symptomatic and supportive. Physical restraints should be used with caution.11 Parenteral benzodiazepines may be considered for treatment of agitation and may also be beneficial for prevention or treatment of seizures or concomitant alcohol withdrawal. Alternative sedatives include propofol or dexmedetomidine.11 Antipsychotics including haloperidol may be used in severe cases but may worsen hyperthermia.10 Hyperthermia can be treated with aggressive cooling techniques. Hypertonic saline and water restriction may be used for hyponatremia. Cardiac ischemia is treated as it would be by any other cause except that b-blockers should not be used.10 Synthetic Cannabinoids Synthetic cannabinoids, first produced in 1967, have been increasing in popularity over the past decade.7 Initially used as a drug of abuse in Europe in the mid-2000s, synthetic cannabinoids were identified in the United States in 2008.23 Similar to synthetic cathinones, these products are widely accessible. They are frequently marketed as incense in foil packets bearing the words “not for human consumption” and may be inhaled, ingested, and injected.1 They produce similar psychotropic effects to marijuana that contains the active component D9-tetrahydrocannabinol (THC).24 However, synthetic cannabinoids are structurally unrelated to THC and bind to cannabinoid receptors with an affinity of up to 100–800 times that of
THC.7, 24 As a class, these agents are multiplying in number, with hundreds of compounds and combinations already developed.7 The incidence of abuse of these novel compounds is increasing every year,25 with abuse increasing through 2011 but decreasing in 2013 in adolescents.26 As of February 2014, 22 synthetic cannabinoids have been placed under permanent or temporary Schedule I status.2 Table 2 lists common synthetic cannabinoid compounds and street names. Synthetic cannabinoids exhibit increased cannabinoid effects compared with THC due to increased binding affinity, full receptor agonism, and active metabolites.1 Cannabinoid-1 (CB1) receptors are located in the peripheral and central nervous systems, specifically in the dorsal root ganglion of the spine and cortical and subcortical regions of the brain.27 CB1 receptors modulate the neurotransmitters glutamate and c-aminobutyric acid.7 Cannabinoid-2 (CB2) receptors are expressed in immune tissue and the central nervous system, and they may affect pain and emesis.28 Both CB1 and CB2 receptors are affected by synthetic cannabinoids in varying ratios, with CB1 agonism producing a greater psychoactive effect. The paucity of information on the chemical content of these agents may lead to an unpredictable effect based on CB1:CB2 binding affinity. Similarly, little information exists regarding their pharmacokinetics and toxicokinetics. Onset and duration appear to be similar to marijuana but vary based on the product ingested.28 In one study, participants who had inhaled the cannabinoid receptor agonist JWH-018 had a detectable serum concentration within 5 minutes of exposure, which then decreased significantly over the next 3 hours.29 The participants subjectively reported the effects to last between 6 and 12 hours. JWH-018 is thought to undergo CYP oxidation, glucuronidation, and subsequent renal elimination. Metabolites vary in activity on the CB1 receptor in particular, potentially leading to unpredictable effects.1, 30 Synthetic cannabinoid consumers are frequently marijuana users and may be drawn to the reported similar psychotropic effects including euphoria and alteration in mood and sensorium.7, 32 Adverse effects include anxiety, paranoia, sedation, hallucinations, psychosis, and seizures that may be more intense due to full-receptor agonism and increased binding affinity.1, 31, 32 Of these, psychosis and anxiety tend to be the most reported. Cardiovascular
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30. 31.
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Drug Use 1975–2013. 2013 Overview. Key findings on adolescent drug use. Available from http://monitoringthefuture.org// pubs/monographs/mtf-overview2013.pdf. Accessed February 21, 2014. McCarberg BH, Barkin RL. The future of cannabinoids as analgesic agents: a pharmacologic, pharmacokinetic, and pharmacodynamic overview. Am J Ther 2007;14:475–83. Harris CR, Brown A. Synthetic cannabinoid intoxication: a case series and review. J Emerg Med 2013;44:360–6. Teske J, Weller JP, Fieguth A, Roth€amel T, Schulz Y, Tr€ oger HD. Sensitive and rapid quantification of the cannabinoid receptor agonist naphthalen-1-yl-(1-pentylindol-3-yl)methanone (JWH-018) in human serum by liquid chromatographytandem mass spectrometry. J Chromatogr B 2010;878:2659– 63. Hall W, Degenhardt L. Adverse health effects of non-medical cannabis use. Lancet 2009;374:1383–91. Seely KA, Lapoint J, Moran JH, Fattore L. Spice drugs are more than harmless herbal blends: a review of the pharmacology and toxicology of synthetic cannabinoids. Prog Neuropsychopharmacol Biol Psychiatry 2012;39:234–43. Brents LK, Gallus-Zawada A, Radominska-Pandya A, et al. Monohydroxylated metabolites of the K2 synthetic cannabinoid JWH-073 retain intermediate to high cannabinoid 1 receptor (CB1R) affinity and exhibit neutral antagonist to partial agonist activity. Biochem Pharmacol 2012;83:952–61. Schneir AB, Cullen J, Ly BT. “Spice” girls: synthetic cannabinoid intoxication. J Emerg Med 2011;40:296–9. The White House. Synthetic Drugs (a.k.a. K2, Spice, Bath Salts, etc.). Available from http://www.whitehouse.gov/ondcp/ ondcp-fact-sheets/synthetic-drugs-k2-spice-bath-salts. Accessed March 19, 2014. Papanti D, Schifano F, Botteon G, et al. “Spiceophrenia”: a systematic overview of “spice”-related psychopathological issues and a case report. Hum Psychopharmacol 2013;28:379– 89. Stefanis NC, Delespaul P, Henquet C, Bakoula C, van Os J. Early adolescent cannabis exposure and positive and negative dimensions of psychosis. Addiction 2004;99:1333–41. Zimmermann US, Winkelmann PR, Pilhatsch M, et al. Withdrawal phenomena and dependence syndrome after the consumption of “spice gold.” Dtsch Arztebl Int 2009;106:464–7. Forrester M, Kleinschmidt K, Schwarz E, Young A. Synthetic cannabinoid and marijuana exposures reported to poison centers. Hum Exp Toxicol 2012;31:1006–11. Castellanos D, Singh S, Thornton G, Avila M, Moreno A. Synthetic cannabinoid use: a case series of adolescents. J Adolesc Health 2011;49:347–9. Vohra R, Seefeld A, Cantrell FL, Clark RF. Salvia divinorum: exposures reported to a statewide poison control system over 10 years. J Emerg Med 2011;40:643–50. Braida D, Limonta V, Capurro V, et al. Involvement of j-opioid and endocannabinoid system on Salvinorin A-induced reward. Biol Psychiatry 2008;63:286–92. Tsujikawa K, Kuwayama K, Miyaguchi H, Kanamori T, Iwata YT, Inoue H. In vitro stability and metabolism of salvinorin A in rat plasma. Xenobiotica 2009;39:391–8. Kelly BC. Legally tripping: a qualitative profile of Salvia divinorum use among young adults. J Psychoactive Drugs 2011;43:46–54. Mowry M, Mosher M, Briner W. Acute physiologic and chronic histologic changes in rats and mice exposed to the unique hallucinogen salvinorin A. J Psychoactive Drugs 2003;35:379–82. Przekop P, Lee T. Persistent psychosis associated with salvia divinorum use. Am J Psychiatry 2009;166:832. Paulzen M, Gr€ under G. Toxic psychosis after intake of the hallucinogen salvinorin A. J Clin Psychiatry 2008;69:1501–2.
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47. Forrester MB. Kratom exposures reported to Texas poison centers. J Addict Dis 2013;32:396–400. 48. Vicknasingam B, Narayanan S, Beng GT, Mansor SM. The informal use of ketum (Mitragyna speciosa) for opioid withdrawal in the northern states of peninsular Malaysia and implications for drug substitution therapy. Int J Drug Policy 2010;21:283–8. 49. Stolt A-C, Schroder H, Neurath H, et al. Behavioral and neurochemical characterization of kratom (Mitragyna speciosa) extract. Psychopharmacology 2014;231:13–25. 50. Boyer EW, Babu KM, Adkins JE, McCurdy CR, Halpern JH. Self-treatment of opioid withdrawal using kratom (Mitragynia speciosa korth). Addiction 2008;103:1048–50. 51. Prozialeck WC, Jivan JK, Andurkar SV. Pharmacology of kratom: an emerging botanical agent with stimulant, analgesic and opioid-like effects. J Am Osteopath Assoc 2012;112:792–9. 52. KRATOM (Mitragyna speciosa korth) (Street Names: Thang, Kakuam, Thom, Ketum, Biak). Available from http://www. deadiversion.usdoj.gov/drug_chem_info/kratom.pdf. Accessed February 4, 2014. 53. Nelsen JL, Lapoint J, Hodgman MJ, Aldous K. Seizure and coma following kratom (Mitragynina speciosa Korth) exposure. J Med Toxicol 2010;6:424–6. 54. Roche K, Hart K, Sangalli B. Kratom: a case of a legal high. Clin Toxicol 2008;46:598. 55. Kapp FG, Maurer HH, Auw€arter V, Winkelmann M, Hermanns-Clausen M. Intrahepatic cholestasis following abuse of powdered kratom (Mitragyna speciosa). J Med Toxicol 2011;7:227–31. 56. Sheleg SV, Collins GB. A coincidence of addiction to “Kratom” and severe primary hypothyroidism. J Addict Med 2011;5:300–1. 57. Arndt T, Claussen U, Gussregen B, et al. Kratom alkaloids and O-desmethyltramadol in urine of a “Krypton” herbal mixture consumer. Forensic Sci Int 2011;208:47–52. 58. Kronstrand R, Roman M, Thelander G, Eriksson A. Unintentional fatal intoxications with mitragynine and O-desmethyltramadol from the herbal blend Krypton. J Anal Toxicol 2011;35:242–7. 59. Holler JM, Vorce SP, McDonough-Bender PC, Magluilo J Jr, Solomon CJ, Levine B. A drug toxicity death involving propylhexedrine and mitragynine. J Anal Toxicol 2011;35:54–9. 60. Matsumoto K, Horie S, Takayama H, et al. Antinociception, tolerance and withdrawal symptoms induced by 7-hydroxymitragynine, an alkaloid from the Thai medicinal herb Mitragyna speciosa. Life Sci 2005;78:2–7. 61. McWhirter L, Morris S. A case report of inpatient detoxification after kratom (Mitragyna speciosa) dependence. Eur Addict Res 2010;16:229–31. 62. Takayama H. Chemistry and pharmacology of analgesic indole alkaloids from the rubiaceous plant, Mitragyna speciosa. Chem Pharm Bull (Tokyo) 2004;52:916–28. 63. Grund J-PC, Latypov A, Harris M. Breaking worse: the emergence of krokodil and excessive injuries among people who inject drugs in Eurasia. Int J Drug Policy 2013;24:265–74. 64. DESOMORPHINE (Dihydrodesoxymorphine; dihydrodesoxymorphine-D; Street Name: Krokodil, Crocodil). Available from http://www.deadiversion.usdoj.gov/drug_chem_info/desomorphine.pdf. Accessed February 27, 2014. 65. Thekkemuriyi DV, John SG, Pillai U. “Krokodil”—a designer drug from across the Atlantic, with serious consequences. Am J Med 2014;127:e1–2. 66. Eddy NB, Halbach H, Braenden OJ. Synthetic substances with morphine-like effect: clinical experience; potency, side-effects, addiction liability. Bull World Health Organ 1957;17:569–863. 67. Gahr M, Freudenmann RW, Hiemke C, et al. Desomorphine goes “crocodile.” J Addict Dis 2012;31:407–12.
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(43%) of the 37 cases reported concomitant exposures to other psychoactive agents. The most common symptoms recognized after isolated salvia use were confusion or disorientation, hallucinations, giddiness, dizziness, flushed sensation, and tachycardia. Vital sign abnormalities were present in only two patients (hypertension and tachycardia). Benzodiazepine administration for agitation was the most common therapeutic intervention reported. Several human case reports have reported acute psychosis secondary to salvia exposure,45, 46 which may allude to its ability to exacerbate, precipitate, or unveil psychiatric disorders. Clinicians should consider salvia exposure in cases of acute psychosis refractory to traditional medical care. Kratom Kratom is a tropical tree with opioid-like properties native to Thailand, Malaysia, Indonesia, Myanmar, and Papua New Guinea.47 Its bitter leaves are chewed to alleviate musculoskeletal pain and to increase energy, appetite, and sexual desire.47, 48 It has been used in the treatment of hypertension, diarrhea, and cough.49 Recently, it has gained increased recognition in Western countries as a “natural alternative” for those who self-treat chronic pain and as a remedy for opioid withdrawal; reports of its use as an opiate substitute date back to 1836.50 Kratom is a nonprescription herbal medication available on the Internet or in head shops. It is sold as leaves, powder, extract, capsule, pellet, or gum, and it can be smoked, chewed, or consumed as a tea.47 It has been suggested as a replacement for methadone because it is affordable, does not require physician supervision, and does not carry the stigma of methadone use.48 Many countries have banned or restricted kratom use.47 The DEA has listed kratom as a medication with no legitimate medical use; however, it has not been assigned Schedule I status.47, 51, 52 Reports of kratom use are rising; however, the number of kratom exposures remains small in the United States. It is difficult to establish the epidemiology because typical drug abuse metrics do not exist. In 2013 a retrospective study of the Texas Poison Control Network Database revealed no kratom exposures between 1998 and 2008, two exposures in 2009, one in 2010, four in 2012, and seven from January–September 2013.47 According to the System to Retrieve Information from Drug Evidence and the National Forensic
Laboratory Information System, mitragynine— the primary active alkaloid in kratom—was reported once in 2010, 44 times in 2011, and 81 times in the first 6 months of 2012.52 Kratom contains more than 40 alkaloids that interact with opioid and monoaminergic receptors but is structurally distinct from opioids.49 Mitragynine is likely responsible for its opioidlike effects. Mitragynine is an agonist of multiple receptors: the opioid receptors l, j, and D, as well as adenosine-2a, postsynaptic a-2, dopamine-2s, and serotonin receptors. Its action on a2-adrenergic agonists may mimic adjunctive therapies for opioid withdrawal such as clonidine.50 Onset of effect occurs 5–10 minutes after ingestion and duration is 2–5 hours. At low to moderate doses (1–5 g), mild stimulant effects include increased sociability, alertness, and energy; moderate to heavy usage (5–15 g) produces opioid-like effects.52, 53 Adverse effects are similar to opioids including nausea, vomiting, constipation, respiratory depression, itching, sweating, dry mouth, increased urination, anorexia, and palpitations. Neurologic effects include hallucinations, psychosis, seizures, and agitation.47 Serious toxicity is rare and usually involves relatively high doses (more than 15 g) or coingestants.50, 51 A 64-year-old man experienced multiple witnessed seizures requiring intubation 30 minutes after ingesting a tea made with kratom and Datura stramonium.53 Datura, commonly known as jimson weed, itself has rarely been associated with seizures. A 43-year-old man experienced a generalized tonic-clonic seizure lasting 5 minutes after he combined kratom with 100 mg of modafinil.50 This patient selftreated his opioid withdrawal with a tea made from kratom 4 times/day without significant adverse effects until he added modafinil in an attempt to improve alertness. Seizures and coma were reported in a 32-year-old man after kratom use, although coingestants were not reported.54 Cases of jaundice and pruritus after massive chronic exposure to kratom (14–21 g/day for 14 days)55 and severe primary hypothyroidism, potentially through reduction in the normal response of the thyroid gland to thyroid-stimulating hormone,56 have been reported. Fatalities typically involve coingestants. There are several case reports of death resulting from “Krypton,” a powder mixture containing mitragynine and O-desmethyltramadol, the active metabolite of tramadol and a l-receptor
NEW DRUGS OF ABUSE Rech et al agonist.1,51, 57, 58 Autopsy examination revealed pulmonary edema in all cases, implying respiratory depression as cause of death. Furthermore, a fatality resulted from the combined use of kratom and propylhexedrine, an a-agonist and amphetamine-like stimulant found in nasal decongestant inhalers.59 Propylhexedrine, nicknamed “stovetop speed,” is similar to modafinil and primarily abused intravenously. Autopsy findings also showed pulmonary edema. Kratom has addiction potential; in animal models, both mitragynine and 7-a-hydroxymitragynine produced a state of dependence when given for 5 days.60 Similar to opioids, individuals build tolerance with heavy use. One user who initially gained 4 hours of euphoria with a single 4-g dose eventually built such a tolerance that he needed 40 g/day in divided doses to avoid symptoms of withdrawal.61 Withdrawal has been described as less intense but more protracted than with prescription opioids; symptoms may include abdominal pain, diarrhea, sweating, and irritability.50 Treatment parallels opioid withdrawal, and patients may respond to opioid replacement therapy.1 There are a few case reports of supervised detoxification. One describes the use of dihydrocodeine (an opioid agonist) 60 mg 4 times/day and lofexidine (an a-adrenergic antagonist) 0.2 mg twice/day, titrating downward over 4 days.61 Buprenorphine/naloxone has been used as an opioid replacement.50 Management of kratom overdose is similar to management of opioid overdose. Although animal literature provides conflicting results with respect to the utility of naloxone in reversing its effects, given its safety profile, naloxone should be considered if acute kratom overdose with respiratory depression is suspected.1, 62 Desomorphine Desomorphine, better known as krokodil for the skin lesions that plague its users, is an opioid analog that behaves pharmacologically similarly to heroin. First synthesized in the United States in 1932 as an alternative to morphine,63, 64 it has been used commercially in Switzerland under the brand name Permonid.64 Its popularity in Russia and other European countries as a less expensive alternative to heroin has been increasing since it was first reported in 2002.65 New reports of use in the United States including Missouri, Arizona, Utah, and Illinois have occurred.64
7
Desomorphine is a l-receptor agonist and synthetic derivative of morphine.63, 65 Analgesic effects are roughly 10 times that of morphine and therefore stronger than heroin.65 In an early comparison of desomorphine with morphine in patients with cancer, a 1:10 dosing ratio of desomorphine to morphine was used.66 At this dose, it was found to have a similar analgesic effect to morphine and similar occurrence of nausea and vomiting. Desomorphine has a more rapid onset of action (1–2 min) and shorter duration of action (1–2 hrs) than morphine, leading to increased potential for addiction, abuse, and withdrawal.65, 67 In 1936 the effects of desomorphine withdrawal were observed in six patients with terminal cancer.66 After 3 weeks of desomorphine use, the patients experienced withdrawal symptoms if the drug was withheld for as little as 4 hours. Short duration of action in drug abusers results in a perpetual cycle of acquiring supplies, preparing the drug, and administering the drug.63 Desomorphine is synthesized in at-home laboratories through a process similar to that of methamphetamine production. It involves chemicals that are low cost, readily available, and highly toxic. Minimal laboratory equipment is needed, and doses can be made in less than an hour.63 The adverse effects of desomorphine itself are typical of opioids.63 Due to variable chemical composition and the high degree of contamination of the final product, regular use results in near-immediate damage to vasculature, muscle, and bone, which may quickly progress to tissue necrosis and gangrene at the injection site.63 The severity of skin necrosis and muscle breakdown make way for a host of other systemic adverse effects including bacteremia, osteomyelitis, meningitis, speech and motor skill impairments, liver and kidney damage, venous ulcers, and skin eschars.63, 67 Due to these health concerns, average survival from first use of desomorphine is reported to be 2 years.67 Very limited data exist regarding treatment and management of patients who are addicted to or who acutely ingest large doses of desomorphine. The only published case report of desomorphine use in the United States is that of a 30-year-old man admitted with pain, swelling, and ulceration of the thigh after use for the past 6–7 months.65 He was noted to have painful necrotic ulcers on his thigh, and 2 months earlier, he had noticed swelling of his left little finger, which later turned black and autoamputated. The relationship between desomorphine
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use and the patient’s necrotic events was suspicious but could not be confirmed. Due to the lack of scientific data, treatment of desomorphine overdose and adverse effects largely consists of supportive care, opioid antagonism (naloxone administration), and precautions for opioid withdrawal. Although no published literature exists on withdrawal, mixed opiate agonists/antagonists such as buprenorphine/naloxone may be considered. Acute overdose should be approached similarly to heroin overdose and include naloxone for reversal of opioid agonism. Abusers should be screened for communicable diseases including human immunodeficiency virus and hepatitis. Additionally, patients often require intensive psychiatric care, thorough nutrition evaluations, and both physical and psychiatric rehabilitation.
4. 5. 6.
7. 8. 9. 10. 11.
Conclusion Abuse of new designer drugs is a national problem whose rate of development is outpacing that of legislation. Clinicians should familiarize themselves with management principles of these new agents. Medical management of patients who abuse or overdose on these drugs largely consists of supportive care, although naloxone may be used as an antidote for desomorphine overdose. Symptoms of aggression and psychosis may be treated with sedation (benzodiazepines, propofol) and antipsychotics (haloperidol or atypical agents such as quetiapine or ziprasidone). Other facets of management to consider include treatment for withdrawal or addiction, nutrition support, and potential for transmission of infectious diseases. Acknowledgment The authors would like to acknowledge Christina Hantsch Bardsley, MD, FACEP, FAACT, FACMT, for her help in developing the content of this article.
References 1. Rosenbaum CD, Carreiro SP, Babu KM. Here today, gone tomorrow . . . and back again? A review of herbal marijuana alternatives (K2, Spice), synthetic cathinones (bath salts), kratom, Salvia divinorum, methoxetamine, and piperazines. J Med Toxicol 2012;8:15–32. 2. Text of S. 3190 (112th): Synthetic Drug Abuse Prevention Act of 2012 (Introduced version). GovTrack.us. Available from https://www.govtrack.us/congress/bills/112/s3190/text. Accessed March 4, 2014. 3. U.S. Department of Health and Human Services, Substance Abuse and Mental Health Services Administration, & Center for Behavioral Health Statistics and Quality. Results from the 2012 National Survey on Drug Use and Health: Summary of
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National Findings. Illicit Drugs. Available from http:// www.samhsa.gov/data/NSDUH/2012SummNatFindDetTables/ NationalFindings/NSDUHresults2012.htm#ch2. Accessed March 4, 2014. Erickson TB, Thompson TM, Lu JJ. The approach to the patient with an unknown overdose [abstract vii]. Emerg Med Clin North Am 2007;25:249–81. Frithsen IL, Simpson WM Jr. Recognition and management of acute medication poisoning. Am Fam Physician 2010;81: 316–23. Meyer MR, Du P, Schuster F, Maurer HH. Studies on the metabolism of the a-pyrrolidinophenone designer drug methylenedioxy-pyrovalerone (MDPV) in rat and human urine and human liver microsomes using GC-MS and LC-high-resolution MS and its detectability in urine by GC-MS. J Mass Spectrom 2010;45:1426–42. Nelson ME, Bryant SM, Aks SE. Emerging drugs of abuse. Emerg Med Clin North Am 2014;32:1–28. Sutter ME, Chenoweth J, Albertson TE. Alternative drugs of abuse. Clin Rev Allergy Immunol 2014;46:3–18. Alles GA, Fairchild MD, Jensen M, Alles A. Chemical pharmacology of Catha edulis. J Med Chem 1960;3:323–52. Mas-Morey P, Visser MHM, Winkelmolen L, Touw DJ. Clinical toxicology and management of intoxications with synthetic cathinones (“bath salts”). J Pharm Pract 2013;26:353–7. Benzer TI, Nejad SH, Flood JG. Case records of the Massachusetts General Hospital. Case 40-2013. A 36-year-old man with agitation and paranoia. N Engl J Med 2013;369:2536–45. Prosser JM, Nelson LS. The toxicology of bath salts: a review of synthetic cathinones. J Med Toxicol 2011;8:33–42. Valente MJ, Guedes de Pinho P, Lourdes Bastos M, Carvalho F, Carvalho M. Khat and synthetic cathinones: a review. Arch Toxicol 2013;88:15–45. Bath Salts. Available from http://www.aapcc.org/alerts/bathsalts/. Accessed April 12, 2014. Kasick DP, McKnight CA, Klisovic E. “Bath salt” ingestion leading to severe intoxication delirium: two cases and a brief review of the emergence of mephedrone use. Am J Drug Alcohol Abuse 2012;38:176–80. Marinetti LJ, Antonides HM. Analysis of synthetic cathinones commonly found in bath salts in human performance and postmortem toxicology: method development, drug distribution and interpretation of results. J Anal Toxicol 2013;37:135– 46. Warrick BJ, Hill M, Hekman K. A 9-state analysis of designer stimulant, “bath salt,” hospital visits reported to poison control centers. Ann Emerg Med 2013;62:244–51. Adebamiro A, Perazella MA. Recurrent acute kidney injury following bath salts intoxication. Am J Kidney Dis 2012;59:273–5. Rojek S, Kłys M, Strona M, Maci ow M, Kula K. “Legal highs”—toxicity in the clinical and medico-legal aspect as exemplified by suicide with bk-MBDB administration. Forensic Sci Int 2012;222:e1–6. Carbone PN, Carbone DL, Carstairs SD, Luzi SA. Sudden cardiac death associated with methylone use. Am J Forensic Med Pathol 2013;34:26–8. Emerson TS, Cisek JE. Methcathinone: a Russian designer amphetamine infiltrates the rural Midwest. Ann Emerg Med 1993;22:1897–903. Banks ML, Worst TJ, Rusyniak DE, Sprague JE. Synthetic cathinones (“bath salts”). J Emerg Med 2014;46(5):632–42. doi: 10.1016/j.jemermed.2013.11.104. European Monitoring Centre for Drugs and Drug Addiction: EMCDDA 2009 Thematic paper—understanding the “Spice” phenomenon. Vardakou I, Pistos C, Spiliopoulou C. Spice drugs as a new trend: mode of action, identification and legislation. Toxicol Lett 2010;197:157–62. Gunderson EW. Synthetic cannabinoids: a new frontier of designer drugs. Ann Intern Med 2013;159:563–4. Johnston LD, O’Malley PM, Miech RA, Bachman JG, Schulenberg JE. Monitoring the Future National Survey Results on
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47. Forrester MB. Kratom exposures reported to Texas poison centers. J Addict Dis 2013;32:396–400. 48. Vicknasingam B, Narayanan S, Beng GT, Mansor SM. The informal use of ketum (Mitragyna speciosa) for opioid withdrawal in the northern states of peninsular Malaysia and implications for drug substitution therapy. Int J Drug Policy 2010;21:283–8. 49. Stolt A-C, Schroder H, Neurath H, et al. Behavioral and neurochemical characterization of kratom (Mitragyna speciosa) extract. Psychopharmacology 2014;231:13–25. 50. Boyer EW, Babu KM, Adkins JE, McCurdy CR, Halpern JH. Self-treatment of opioid withdrawal using kratom (Mitragynia speciosa korth). Addiction 2008;103:1048–50. 51. Prozialeck WC, Jivan JK, Andurkar SV. Pharmacology of kratom: an emerging botanical agent with stimulant, analgesic and opioid-like effects. J Am Osteopath Assoc 2012;112:792–9. 52. KRATOM (Mitragyna speciosa korth) (Street Names: Thang, Kakuam, Thom, Ketum, Biak). Available from http://www. deadiversion.usdoj.gov/drug_chem_info/kratom.pdf. Accessed February 4, 2014. 53. Nelsen JL, Lapoint J, Hodgman MJ, Aldous K. Seizure and coma following kratom (Mitragynina speciosa Korth) exposure. J Med Toxicol 2010;6:424–6. 54. Roche K, Hart K, Sangalli B. Kratom: a case of a legal high. Clin Toxicol 2008;46:598. 55. Kapp FG, Maurer HH, Auw€arter V, Winkelmann M, Hermanns-Clausen M. Intrahepatic cholestasis following abuse of powdered kratom (Mitragyna speciosa). J Med Toxicol 2011;7:227–31. 56. Sheleg SV, Collins GB. A coincidence of addiction to “Kratom” and severe primary hypothyroidism. J Addict Med 2011;5:300–1. 57. Arndt T, Claussen U, Gussregen B, et al. Kratom alkaloids and O-desmethyltramadol in urine of a “Krypton” herbal mixture consumer. Forensic Sci Int 2011;208:47–52. 58. Kronstrand R, Roman M, Thelander G, Eriksson A. Unintentional fatal intoxications with mitragynine and O-desmethyltramadol from the herbal blend Krypton. J Anal Toxicol 2011;35:242–7. 59. Holler JM, Vorce SP, McDonough-Bender PC, Magluilo J Jr, Solomon CJ, Levine B. A drug toxicity death involving propylhexedrine and mitragynine. J Anal Toxicol 2011;35:54–9. 60. Matsumoto K, Horie S, Takayama H, et al. Antinociception, tolerance and withdrawal symptoms induced by 7-hydroxymitragynine, an alkaloid from the Thai medicinal herb Mitragyna speciosa. Life Sci 2005;78:2–7. 61. McWhirter L, Morris S. A case report of inpatient detoxification after kratom (Mitragyna speciosa) dependence. Eur Addict Res 2010;16:229–31. 62. Takayama H. Chemistry and pharmacology of analgesic indole alkaloids from the rubiaceous plant, Mitragyna speciosa. Chem Pharm Bull (Tokyo) 2004;52:916–28. 63. Grund J-PC, Latypov A, Harris M. Breaking worse: the emergence of krokodil and excessive injuries among people who inject drugs in Eurasia. Int J Drug Policy 2013;24:265–74. 64. DESOMORPHINE (Dihydrodesoxymorphine; dihydrodesoxymorphine-D; Street Name: Krokodil, Crocodil). Available from http://www.deadiversion.usdoj.gov/drug_chem_info/desomorphine.pdf. Accessed February 27, 2014. 65. Thekkemuriyi DV, John SG, Pillai U. “Krokodil”—a designer drug from across the Atlantic, with serious consequences. Am J Med 2014;127:e1–2. 66. Eddy NB, Halbach H, Braenden OJ. Synthetic substances with morphine-like effect: clinical experience; potency, side-effects, addiction liability. Bull World Health Organ 1957;17:569–863. 67. Gahr M, Freudenmann RW, Hiemke C, et al. Desomorphine goes “crocodile.” J Addict Dis 2012;31:407–12.
OF
THERAPEUTICS
New Drugs of Abuse Megan A. Rech,1,2* Elisabeth Donahey,1 Jacqueline M. Cappiello Dziedzic,2,3 Laura Oh,2,3 and Elizabeth Greenhalgh1,4 1
Department of Pharmacy Services, Loyola University Medical Center, Maywood, Illinois; 2Department of Emergency Medicine, Loyola University Medical Center, Maywood, Illinois; 3Stritch School of Medicine, Loyola University Chicago, Maywood, Illinois; 4Marcella Niehoff School of Nursing, Loyola University Chicago, Maywood, Illinois
Drug abuse is a common problem and growing concern in the United States, and over the past decade, novel or atypical drugs have emerged and have become increasingly popular. Recognition and treatment of new drugs of abuse pose many challenges for health care providers due to lack of quantitative reporting and routine surveillance, and the difficulty of detection in routine blood and urine analyses. Furthermore, street manufacturers are able to rapidly adapt and develop new synthetic isolates of older drugs as soon as law enforcement agencies render them illegal. In this article, we describe the clinical and adverse effects and purported pharmacology of several new classes of drugs of abuse including synthetic cannabinoids, synthetic cathinones, salvia, desomorphine, and kratom. Because many of these substances can have severe or life-threatening adverse effects, knowledge of general toxicology is key in recognizing acute intoxication and overdose; however, typical toxidromes (e.g., cholinergic, sympathomimetic, opioid, etc.) are not precipitated by many of these agents. Medical management of patients who abuse or overdose on these drugs largely consists of supportive care, although naloxone may be used as an antidote for desomorphine overdose. Symptoms of aggression and psychosis may be treated with sedation (benzodiazepines, propofol) and antipsychotics (haloperidol or atypical agents such as quetiapine or ziprasidone). Other facets of management to consider include treatment for withdrawal or addiction, nutrition support, and potential for transmission of infectious diseases. KEY WORDS synthetic cannabinoids, synthetic cathinones, salvia, desomorphine, kratom. (Pharmacotherapy 2014;**(**):**–**) doi: 10.1002/phar.1522
Drug abuse is a common problem and growing concern in the United States, and over the past decade, novel or atypical drugs have emerged and become increasingly popular. Staying current with the new drugs of abuse can be challenging for health care practitioners due to lack of quantitative reporting and surveillance, and the difficulty of detection in routine blood and urine analyses. Furthermore, street manufacturers are able to rapidly adapt and develop new synthetic isolates of older drugs as soon as law enforcement agencies render them illegal. *Address for correspondence: Megan A. Rech, Department of Pharmacy Services, Loyola University Medical Center, 2160 S 1st Avenue, Maywood, IL 60153; e-mail: [email protected]. Ó 2014 Pharmacotherapy Publications, Inc.
“Legal highs” are widely advertised in head shops and gas stations, and through the Internet. These agents are marketed as legal alternatives that produce similar effects as illicit drugs; however, many of these substances can cause severe or lifethreatening adverse effects.1 The Synthetic Drug Abuse Prevention Act of 2012 was enacted to combat this issue, banning several of the most common isolates of synthetic cannabinoids and cathinones.2 Recognition and treatment of new drugs of abuse pose many challenges for health care providers. Knowledge of general toxicology is key in recognizing acute intoxication and overdose; however, typical toxidromes are not precipitated by many of these agents. Furthermore, toxicity may be difficult to diagnose because most new designer drugs are not detected with conventional
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drug testing. Therefore, the purpose of this article is to describe the pharmacology, clinical and adverse effects, and reported literature on several new classes of drugs of abuse.
An estimated 23.9 million Americans 12 years or older are current illicit drug users. The National Institute on Drug Abuse estimates that overall use of tobacco, alcohol, and illicit drugs results in $600 billion annually in costs related to crime, health care, and lost work productivity. Use of illicit drugs alone accounts for $193 billion of the total. The illicit drugs routinely surveyed include marijuana, hashish, cocaine, heroin, hallucinogens, inhalants, and prescription-type psychotherapeutics used nonmedically; many newer illicit drugs of abuse are not currently tracked or reported, and thus it is difficult to capture the burden that new drugs of abuse place on society.3
antidotes. However, with the exception of the effects of desomorphine and kratom potentially being reversed by the l-opioid antagonist naloxone, reversal agents have not been identified for new drugs of abuse. Diagnosis of new drugs of abuse is also particularly challenging. Routine blood and urine screening tests do not detect most of these agents, although desomorphine is structurally similar to opioids and therefore may be detected as such. Some new agents can be sent to laboratories capable of mass spectrometry or gas or liquid chromatography for detection.6, 7 However, clinical utility of these tests is limited due to turnaround time and lack of a single test to collectively detect all new drugs of abuse.8 Diagnostic evaluation should include appropriate laboratory parameters including particular attention to electrocardiogram and electrolyte abnormalities. An understanding of common drugs of abuse in specific geographic locations may help narrow the differential diagnosis.
General Approach to Illicit Drug Users
Synthetic Cathinones
Although intoxication with new drugs of abuse may be difficult to diagnose and treat, treatment of these patients should be approached similarly to that of other toxicology cases. General management should consist of supportive care combined with a detailed history and physical examination that may be difficult to perform due to altered mental status. The mnemonic ABCDEFG can be used to guide clinicians (Table 1). This approach combines basic emergency medical care (airway, breathing, and circulation [ABC]) with specific toxicology management, including decontamination (D) and enhanced elimination (E) methods, antidote administration (focused therapy [F]), and toxicologist or poison control center consultation (“get tox help” [G]).4 History should specifically address type of ingestion, time of exposure, cumulative amount, and route of administration. Furthermore, evaluation of multiple drugs of abuse, prescription opioid medications, and over-the-counter agents should be considered because coingestion is common. Clinicians should be aware of the classic drug toxidromes (e.g., cholinergic, sympathomimetic, opioid) and toxic vital signs (e.g., tachycardia, hyperthermia, hypotension) but should also realize the limitations due to confounding factors and atypical presentations with newer agents.4, 5 Many toxicologic ingestants can be treated with specific
Synthetic cathinones, commonly referred to as “bath salts,” are analogs of naturally occurring cathinones such as Catha edulis (khat). Khat is native to Yemen and eastern Africa, where indigenous people have been chewing the fresh leaves for hundreds of years.9 Cathinone is the main psychoactive agent in khat, and it produces a stimulant effect resulting in increased alertness, energy, and libido, and appetite suppression and euphoria.10, 11 Although the World Health Organization does not consider khat to be a seriously addicting drug of abuse, chewing the agent has been linked to peptic ulcers, myocardial infarction, dilated cardiomyopathy, stroke, and death.7, 12 Synthetic cathinones were initially developed in the 1920s for therapeutic purposes, and in recent years these agents have become drugs of abuse.13 Widespread use began in Europe in the early 1990s and then gained popularity in the United States, with at least 30 chemical compounds in existence and many street names (Table 2).7 Commercially available cathinones include bupropion for smoking cessation and depression, and diethylpropion for appetite suppression.7, 12 In 1993, cathinone was classified as a Schedule I controlled substance by the Drug Enforcement Agency (DEA).7 The Synthetic Drug Abuse Prevention Act of 2012 amended the Controlled Substances Act to make several
Epidemiology
NEW DRUGS OF ABUSE Rech et al Table 1. General Management of Toxicology Cases Pneumonic
Management
A B C D E F G
Airway Breathing Circulation Decontamination Enhanced elimination Focused therapy (antidote administration) “Get tox help” (toxicologist or poison control center consultation)
cannabimimetic substances and hallucinogens Schedule I controlled substances.2 U.S. poison control centers began receiving calls related to “bath salts” in 2010, with a peak in volume in mid-2011.14 In 2011, 6137 exposures to synthetic cathinones were reported, followed by 2691 exposures in 2012 and only 995 exposures in 2013. This decrease should be interpreted with caution because providers may have become more familiar with the treatment of synthetic cathinone abuse or overdose, and they may be less likely to call poison control centers for assistance. Low cost and inability to detect these agents with conventional laboratory parameters makes them particularly appealing to illicit drug users. Synthetic cathinones are sold in smoke shops, head shops, gas stations, and convenience stores, and on the Internet as bath salts, plant food, jewelry cleaner, research chemicals, and herbal extracts under many street names (Table 2).12 Chemically unrelated to Epsom salts or household cleaning products, they are ambiguously labeled with the statement “not for human consumption.”1 Synthetic cathinones are available as white or light brown powder, pills, or capsules.15 Doses range from a few milligrams to more than 1 g.12 The most common routes of administration include nasal insufflation (“snorting”) and oral ingestion; however, rectal, gingival, inhalation,
3
smoking, parenteral (intravenous and intramuscular), “bombing” (wrapping powder in cigarette paper and swallowing it), and “keying” (insufflating powder off the surface of a key) have been reported.7, 10, 12 The mechanism by which synthetic cathinones exhibit an effect is similar to other stimulants through functionally changing monoamine transporters through which the neurotransmitters serotonin, dopamine, and norepinephrine are taken up from central synaptic clefts, resulting in increased postsynaptic neurotransmission.11 Each agent has variable effects and potency on serotonin, dopamine, and norepinephrine, and serum concentration does not predict toxicity.16 Advertised effects of synthetic cathinones include euphoria, increased energy, openness, empathy, alertness, and increased libido.10 Duration of action, dosing, and time of onset of symptoms vary with routes of administration and purity of the product.7, 12 Users report the onset of psychoactive effects as between 10 and 45 minutes and duration between 2 and 4 hours, depending on route of administration.12 No published human data on the pharmacokinetics and pharmacodynamics of the synthetic cathinones exist.10 Mephedrone is metabolized via phase I and II reactions involving various hepatic cytochrome P450 (CYP) isoenzymes including CYP2C19, CYP2D6, and CYP1A2.6 The most common clinical findings reported to poison centers include agitation, confusion, hallucinations, tachycardia, hypertension, mydriasis, tremor, and fever. Additional serious effects reported include rhabdomyolysis, electrolyte abnormalities, renal failure, seizures, and death.17 Exposure may precipitate a sympathomimetic toxidrome including agitation, psychosis, hypertension, tachycardia, and seizures. Hyperthermia, hyponatremia, and acute renal failure have also been reported.12, 18 Aggressive violent behavior, paranoia, and hallucinations are more
Table 2. Common Street Names and Active Compounds of New Drugs of Abuse Drug of abuse Synthetic cathinones9,
Street names 11
Synthetic cannabinoids26 Salvia43 Kratom51 Krokodil67
Khat, Bath salts, Meow meow, MCAT, Ivory wave Bubbles, Vanilla sky, Cloud 9, Explosion, White lightning Spice (including variants such as Spice Gold, Spice Diamond, Spice Silver) K2, Krypton, Aztec Fire, Bombay Blue, Fake Weed, Yucatan Fire Diviner’s Sage, Mystic Sage, Sally D, Magic Mint Biak-biak, Ketum, Kahuam, Ithang, Thom Krokodil, Crocodile, Zoombie Drug
Active compounds Methcathinone Ethylone, Mephedrone, Methedrone Methylenedioxypyrovalerone (MDPV) NaphyroneButylone 4-Fluoromethcathinone Brephedrone Pyrovalerone JWH-015JWH-018JWH-073JWH-210CP-47,497CP-55, 490HU-210 Salvinorin A Mitragynine Desomorphine
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frequently reported compared with amphetamines.10 Multiple case reports describe an “excited delirium” after using synthetic cathinones.11, 15 Other case reports have shown compartment syndrome, suicide, and sudden cardiac death with synthetic cathinone use.19, 20 A physical withdrawal syndrome occurs in cyclic binge users about 4 hours after the last dose is taken. Users have reported short periods of sleepiness, irritability, depression, and anxiety followed by sleep lasting days, increased appetite, and insomnia lasting up to 2 weeks.21 Synthetic cathinones cannot be readily detected with routine testing, and no correlation of concentration with clinical effects has been reported.6 Exposure is a clinical diagnosis; therefore, history and physical examination findings are key.10 Synthetic cathinone intoxication should be suspected in a patient with acute onset altered mental status, excited delirium, renal failure, and sympathomimetic symptoms.22 The management of intoxication is symptomatic and supportive. Physical restraints should be used with caution.11 Parenteral benzodiazepines may be considered for treatment of agitation and may also be beneficial for prevention or treatment of seizures or concomitant alcohol withdrawal. Alternative sedatives include propofol or dexmedetomidine.11 Antipsychotics including haloperidol may be used in severe cases but may worsen hyperthermia.10 Hyperthermia can be treated with aggressive cooling techniques. Hypertonic saline and water restriction may be used for hyponatremia. Cardiac ischemia is treated as it would be by any other cause except that b-blockers should not be used.10 Synthetic Cannabinoids Synthetic cannabinoids, first produced in 1967, have been increasing in popularity over the past decade.7 Initially used as a drug of abuse in Europe in the mid-2000s, synthetic cannabinoids were identified in the United States in 2008.23 Similar to synthetic cathinones, these products are widely accessible. They are frequently marketed as incense in foil packets bearing the words “not for human consumption” and may be inhaled, ingested, and injected.1 They produce similar psychotropic effects to marijuana that contains the active component D9-tetrahydrocannabinol (THC).24 However, synthetic cannabinoids are structurally unrelated to THC and bind to cannabinoid receptors with an affinity of up to 100–800 times that of
THC.7, 24 As a class, these agents are multiplying in number, with hundreds of compounds and combinations already developed.7 The incidence of abuse of these novel compounds is increasing every year,25 with abuse increasing through 2011 but decreasing in 2013 in adolescents.26 As of February 2014, 22 synthetic cannabinoids have been placed under permanent or temporary Schedule I status.2 Table 2 lists common synthetic cannabinoid compounds and street names. Synthetic cannabinoids exhibit increased cannabinoid effects compared with THC due to increased binding affinity, full receptor agonism, and active metabolites.1 Cannabinoid-1 (CB1) receptors are located in the peripheral and central nervous systems, specifically in the dorsal root ganglion of the spine and cortical and subcortical regions of the brain.27 CB1 receptors modulate the neurotransmitters glutamate and c-aminobutyric acid.7 Cannabinoid-2 (CB2) receptors are expressed in immune tissue and the central nervous system, and they may affect pain and emesis.28 Both CB1 and CB2 receptors are affected by synthetic cannabinoids in varying ratios, with CB1 agonism producing a greater psychoactive effect. The paucity of information on the chemical content of these agents may lead to an unpredictable effect based on CB1:CB2 binding affinity. Similarly, little information exists regarding their pharmacokinetics and toxicokinetics. Onset and duration appear to be similar to marijuana but vary based on the product ingested.28 In one study, participants who had inhaled the cannabinoid receptor agonist JWH-018 had a detectable serum concentration within 5 minutes of exposure, which then decreased significantly over the next 3 hours.29 The participants subjectively reported the effects to last between 6 and 12 hours. JWH-018 is thought to undergo CYP oxidation, glucuronidation, and subsequent renal elimination. Metabolites vary in activity on the CB1 receptor in particular, potentially leading to unpredictable effects.1, 30 Synthetic cannabinoid consumers are frequently marijuana users and may be drawn to the reported similar psychotropic effects including euphoria and alteration in mood and sensorium.7, 32 Adverse effects include anxiety, paranoia, sedation, hallucinations, psychosis, and seizures that may be more intense due to full-receptor agonism and increased binding affinity.1, 31, 32 Of these, psychosis and anxiety tend to be the most reported. Cardiovascular
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27. 28. 29.
30. 31.
32.
33. 34.
35.
36. 37. 38. 39. 40. 41. 42. 43. 44.
45. 46.
Drug Use 1975–2013. 2013 Overview. Key findings on adolescent drug use. Available from http://monitoringthefuture.org// pubs/monographs/mtf-overview2013.pdf. Accessed February 21, 2014. McCarberg BH, Barkin RL. The future of cannabinoids as analgesic agents: a pharmacologic, pharmacokinetic, and pharmacodynamic overview. Am J Ther 2007;14:475–83. Harris CR, Brown A. Synthetic cannabinoid intoxication: a case series and review. J Emerg Med 2013;44:360–6. Teske J, Weller JP, Fieguth A, Roth€amel T, Schulz Y, Tr€ oger HD. Sensitive and rapid quantification of the cannabinoid receptor agonist naphthalen-1-yl-(1-pentylindol-3-yl)methanone (JWH-018) in human serum by liquid chromatographytandem mass spectrometry. J Chromatogr B 2010;878:2659– 63. Hall W, Degenhardt L. Adverse health effects of non-medical cannabis use. Lancet 2009;374:1383–91. Seely KA, Lapoint J, Moran JH, Fattore L. Spice drugs are more than harmless herbal blends: a review of the pharmacology and toxicology of synthetic cannabinoids. Prog Neuropsychopharmacol Biol Psychiatry 2012;39:234–43. Brents LK, Gallus-Zawada A, Radominska-Pandya A, et al. Monohydroxylated metabolites of the K2 synthetic cannabinoid JWH-073 retain intermediate to high cannabinoid 1 receptor (CB1R) affinity and exhibit neutral antagonist to partial agonist activity. Biochem Pharmacol 2012;83:952–61. Schneir AB, Cullen J, Ly BT. “Spice” girls: synthetic cannabinoid intoxication. J Emerg Med 2011;40:296–9. The White House. Synthetic Drugs (a.k.a. K2, Spice, Bath Salts, etc.). Available from http://www.whitehouse.gov/ondcp/ ondcp-fact-sheets/synthetic-drugs-k2-spice-bath-salts. Accessed March 19, 2014. Papanti D, Schifano F, Botteon G, et al. “Spiceophrenia”: a systematic overview of “spice”-related psychopathological issues and a case report. Hum Psychopharmacol 2013;28:379– 89. Stefanis NC, Delespaul P, Henquet C, Bakoula C, van Os J. Early adolescent cannabis exposure and positive and negative dimensions of psychosis. Addiction 2004;99:1333–41. Zimmermann US, Winkelmann PR, Pilhatsch M, et al. Withdrawal phenomena and dependence syndrome after the consumption of “spice gold.” Dtsch Arztebl Int 2009;106:464–7. Forrester M, Kleinschmidt K, Schwarz E, Young A. Synthetic cannabinoid and marijuana exposures reported to poison centers. Hum Exp Toxicol 2012;31:1006–11. Castellanos D, Singh S, Thornton G, Avila M, Moreno A. Synthetic cannabinoid use: a case series of adolescents. J Adolesc Health 2011;49:347–9. Vohra R, Seefeld A, Cantrell FL, Clark RF. Salvia divinorum: exposures reported to a statewide poison control system over 10 years. J Emerg Med 2011;40:643–50. Braida D, Limonta V, Capurro V, et al. Involvement of j-opioid and endocannabinoid system on Salvinorin A-induced reward. Biol Psychiatry 2008;63:286–92. Tsujikawa K, Kuwayama K, Miyaguchi H, Kanamori T, Iwata YT, Inoue H. In vitro stability and metabolism of salvinorin A in rat plasma. Xenobiotica 2009;39:391–8. Kelly BC. Legally tripping: a qualitative profile of Salvia divinorum use among young adults. J Psychoactive Drugs 2011;43:46–54. Mowry M, Mosher M, Briner W. Acute physiologic and chronic histologic changes in rats and mice exposed to the unique hallucinogen salvinorin A. J Psychoactive Drugs 2003;35:379–82. Przekop P, Lee T. Persistent psychosis associated with salvia divinorum use. Am J Psychiatry 2009;166:832. Paulzen M, Gr€ under G. Toxic psychosis after intake of the hallucinogen salvinorin A. J Clin Psychiatry 2008;69:1501–2.
9
47. Forrester MB. Kratom exposures reported to Texas poison centers. J Addict Dis 2013;32:396–400. 48. Vicknasingam B, Narayanan S, Beng GT, Mansor SM. The informal use of ketum (Mitragyna speciosa) for opioid withdrawal in the northern states of peninsular Malaysia and implications for drug substitution therapy. Int J Drug Policy 2010;21:283–8. 49. Stolt A-C, Schroder H, Neurath H, et al. Behavioral and neurochemical characterization of kratom (Mitragyna speciosa) extract. Psychopharmacology 2014;231:13–25. 50. Boyer EW, Babu KM, Adkins JE, McCurdy CR, Halpern JH. Self-treatment of opioid withdrawal using kratom (Mitragynia speciosa korth). Addiction 2008;103:1048–50. 51. Prozialeck WC, Jivan JK, Andurkar SV. Pharmacology of kratom: an emerging botanical agent with stimulant, analgesic and opioid-like effects. J Am Osteopath Assoc 2012;112:792–9. 52. KRATOM (Mitragyna speciosa korth) (Street Names: Thang, Kakuam, Thom, Ketum, Biak). Available from http://www. deadiversion.usdoj.gov/drug_chem_info/kratom.pdf. Accessed February 4, 2014. 53. Nelsen JL, Lapoint J, Hodgman MJ, Aldous K. Seizure and coma following kratom (Mitragynina speciosa Korth) exposure. J Med Toxicol 2010;6:424–6. 54. Roche K, Hart K, Sangalli B. Kratom: a case of a legal high. Clin Toxicol 2008;46:598. 55. Kapp FG, Maurer HH, Auw€arter V, Winkelmann M, Hermanns-Clausen M. Intrahepatic cholestasis following abuse of powdered kratom (Mitragyna speciosa). J Med Toxicol 2011;7:227–31. 56. Sheleg SV, Collins GB. A coincidence of addiction to “Kratom” and severe primary hypothyroidism. J Addict Med 2011;5:300–1. 57. Arndt T, Claussen U, Gussregen B, et al. Kratom alkaloids and O-desmethyltramadol in urine of a “Krypton” herbal mixture consumer. Forensic Sci Int 2011;208:47–52. 58. Kronstrand R, Roman M, Thelander G, Eriksson A. Unintentional fatal intoxications with mitragynine and O-desmethyltramadol from the herbal blend Krypton. J Anal Toxicol 2011;35:242–7. 59. Holler JM, Vorce SP, McDonough-Bender PC, Magluilo J Jr, Solomon CJ, Levine B. A drug toxicity death involving propylhexedrine and mitragynine. J Anal Toxicol 2011;35:54–9. 60. Matsumoto K, Horie S, Takayama H, et al. Antinociception, tolerance and withdrawal symptoms induced by 7-hydroxymitragynine, an alkaloid from the Thai medicinal herb Mitragyna speciosa. Life Sci 2005;78:2–7. 61. McWhirter L, Morris S. A case report of inpatient detoxification after kratom (Mitragyna speciosa) dependence. Eur Addict Res 2010;16:229–31. 62. Takayama H. Chemistry and pharmacology of analgesic indole alkaloids from the rubiaceous plant, Mitragyna speciosa. Chem Pharm Bull (Tokyo) 2004;52:916–28. 63. Grund J-PC, Latypov A, Harris M. Breaking worse: the emergence of krokodil and excessive injuries among people who inject drugs in Eurasia. Int J Drug Policy 2013;24:265–74. 64. DESOMORPHINE (Dihydrodesoxymorphine; dihydrodesoxymorphine-D; Street Name: Krokodil, Crocodil). Available from http://www.deadiversion.usdoj.gov/drug_chem_info/desomorphine.pdf. Accessed February 27, 2014. 65. Thekkemuriyi DV, John SG, Pillai U. “Krokodil”—a designer drug from across the Atlantic, with serious consequences. Am J Med 2014;127:e1–2. 66. Eddy NB, Halbach H, Braenden OJ. Synthetic substances with morphine-like effect: clinical experience; potency, side-effects, addiction liability. Bull World Health Organ 1957;17:569–863. 67. Gahr M, Freudenmann RW, Hiemke C, et al. Desomorphine goes “crocodile.” J Addict Dis 2012;31:407–12.
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PHARMACOTHERAPY Volume **, Number **, 2014
(43%) of the 37 cases reported concomitant exposures to other psychoactive agents. The most common symptoms recognized after isolated salvia use were confusion or disorientation, hallucinations, giddiness, dizziness, flushed sensation, and tachycardia. Vital sign abnormalities were present in only two patients (hypertension and tachycardia). Benzodiazepine administration for agitation was the most common therapeutic intervention reported. Several human case reports have reported acute psychosis secondary to salvia exposure,45, 46 which may allude to its ability to exacerbate, precipitate, or unveil psychiatric disorders. Clinicians should consider salvia exposure in cases of acute psychosis refractory to traditional medical care. Kratom Kratom is a tropical tree with opioid-like properties native to Thailand, Malaysia, Indonesia, Myanmar, and Papua New Guinea.47 Its bitter leaves are chewed to alleviate musculoskeletal pain and to increase energy, appetite, and sexual desire.47, 48 It has been used in the treatment of hypertension, diarrhea, and cough.49 Recently, it has gained increased recognition in Western countries as a “natural alternative” for those who self-treat chronic pain and as a remedy for opioid withdrawal; reports of its use as an opiate substitute date back to 1836.50 Kratom is a nonprescription herbal medication available on the Internet or in head shops. It is sold as leaves, powder, extract, capsule, pellet, or gum, and it can be smoked, chewed, or consumed as a tea.47 It has been suggested as a replacement for methadone because it is affordable, does not require physician supervision, and does not carry the stigma of methadone use.48 Many countries have banned or restricted kratom use.47 The DEA has listed kratom as a medication with no legitimate medical use; however, it has not been assigned Schedule I status.47, 51, 52 Reports of kratom use are rising; however, the number of kratom exposures remains small in the United States. It is difficult to establish the epidemiology because typical drug abuse metrics do not exist. In 2013 a retrospective study of the Texas Poison Control Network Database revealed no kratom exposures between 1998 and 2008, two exposures in 2009, one in 2010, four in 2012, and seven from January–September 2013.47 According to the System to Retrieve Information from Drug Evidence and the National Forensic
Laboratory Information System, mitragynine— the primary active alkaloid in kratom—was reported once in 2010, 44 times in 2011, and 81 times in the first 6 months of 2012.52 Kratom contains more than 40 alkaloids that interact with opioid and monoaminergic receptors but is structurally distinct from opioids.49 Mitragynine is likely responsible for its opioidlike effects. Mitragynine is an agonist of multiple receptors: the opioid receptors l, j, and D, as well as adenosine-2a, postsynaptic a-2, dopamine-2s, and serotonin receptors. Its action on a2-adrenergic agonists may mimic adjunctive therapies for opioid withdrawal such as clonidine.50 Onset of effect occurs 5–10 minutes after ingestion and duration is 2–5 hours. At low to moderate doses (1–5 g), mild stimulant effects include increased sociability, alertness, and energy; moderate to heavy usage (5–15 g) produces opioid-like effects.52, 53 Adverse effects are similar to opioids including nausea, vomiting, constipation, respiratory depression, itching, sweating, dry mouth, increased urination, anorexia, and palpitations. Neurologic effects include hallucinations, psychosis, seizures, and agitation.47 Serious toxicity is rare and usually involves relatively high doses (more than 15 g) or coingestants.50, 51 A 64-year-old man experienced multiple witnessed seizures requiring intubation 30 minutes after ingesting a tea made with kratom and Datura stramonium.53 Datura, commonly known as jimson weed, itself has rarely been associated with seizures. A 43-year-old man experienced a generalized tonic-clonic seizure lasting 5 minutes after he combined kratom with 100 mg of modafinil.50 This patient selftreated his opioid withdrawal with a tea made from kratom 4 times/day without significant adverse effects until he added modafinil in an attempt to improve alertness. Seizures and coma were reported in a 32-year-old man after kratom use, although coingestants were not reported.54 Cases of jaundice and pruritus after massive chronic exposure to kratom (14–21 g/day for 14 days)55 and severe primary hypothyroidism, potentially through reduction in the normal response of the thyroid gland to thyroid-stimulating hormone,56 have been reported. Fatalities typically involve coingestants. There are several case reports of death resulting from “Krypton,” a powder mixture containing mitragynine and O-desmethyltramadol, the active metabolite of tramadol and a l-receptor
NEW DRUGS OF ABUSE Rech et al agonist.1,51, 57, 58 Autopsy examination revealed pulmonary edema in all cases, implying respiratory depression as cause of death. Furthermore, a fatality resulted from the combined use of kratom and propylhexedrine, an a-agonist and amphetamine-like stimulant found in nasal decongestant inhalers.59 Propylhexedrine, nicknamed “stovetop speed,” is similar to modafinil and primarily abused intravenously. Autopsy findings also showed pulmonary edema. Kratom has addiction potential; in animal models, both mitragynine and 7-a-hydroxymitragynine produced a state of dependence when given for 5 days.60 Similar to opioids, individuals build tolerance with heavy use. One user who initially gained 4 hours of euphoria with a single 4-g dose eventually built such a tolerance that he needed 40 g/day in divided doses to avoid symptoms of withdrawal.61 Withdrawal has been described as less intense but more protracted than with prescription opioids; symptoms may include abdominal pain, diarrhea, sweating, and irritability.50 Treatment parallels opioid withdrawal, and patients may respond to opioid replacement therapy.1 There are a few case reports of supervised detoxification. One describes the use of dihydrocodeine (an opioid agonist) 60 mg 4 times/day and lofexidine (an a-adrenergic antagonist) 0.2 mg twice/day, titrating downward over 4 days.61 Buprenorphine/naloxone has been used as an opioid replacement.50 Management of kratom overdose is similar to management of opioid overdose. Although animal literature provides conflicting results with respect to the utility of naloxone in reversing its effects, given its safety profile, naloxone should be considered if acute kratom overdose with respiratory depression is suspected.1, 62 Desomorphine Desomorphine, better known as krokodil for the skin lesions that plague its users, is an opioid analog that behaves pharmacologically similarly to heroin. First synthesized in the United States in 1932 as an alternative to morphine,63, 64 it has been used commercially in Switzerland under the brand name Permonid.64 Its popularity in Russia and other European countries as a less expensive alternative to heroin has been increasing since it was first reported in 2002.65 New reports of use in the United States including Missouri, Arizona, Utah, and Illinois have occurred.64
7
Desomorphine is a l-receptor agonist and synthetic derivative of morphine.63, 65 Analgesic effects are roughly 10 times that of morphine and therefore stronger than heroin.65 In an early comparison of desomorphine with morphine in patients with cancer, a 1:10 dosing ratio of desomorphine to morphine was used.66 At this dose, it was found to have a similar analgesic effect to morphine and similar occurrence of nausea and vomiting. Desomorphine has a more rapid onset of action (1–2 min) and shorter duration of action (1–2 hrs) than morphine, leading to increased potential for addiction, abuse, and withdrawal.65, 67 In 1936 the effects of desomorphine withdrawal were observed in six patients with terminal cancer.66 After 3 weeks of desomorphine use, the patients experienced withdrawal symptoms if the drug was withheld for as little as 4 hours. Short duration of action in drug abusers results in a perpetual cycle of acquiring supplies, preparing the drug, and administering the drug.63 Desomorphine is synthesized in at-home laboratories through a process similar to that of methamphetamine production. It involves chemicals that are low cost, readily available, and highly toxic. Minimal laboratory equipment is needed, and doses can be made in less than an hour.63 The adverse effects of desomorphine itself are typical of opioids.63 Due to variable chemical composition and the high degree of contamination of the final product, regular use results in near-immediate damage to vasculature, muscle, and bone, which may quickly progress to tissue necrosis and gangrene at the injection site.63 The severity of skin necrosis and muscle breakdown make way for a host of other systemic adverse effects including bacteremia, osteomyelitis, meningitis, speech and motor skill impairments, liver and kidney damage, venous ulcers, and skin eschars.63, 67 Due to these health concerns, average survival from first use of desomorphine is reported to be 2 years.67 Very limited data exist regarding treatment and management of patients who are addicted to or who acutely ingest large doses of desomorphine. The only published case report of desomorphine use in the United States is that of a 30-year-old man admitted with pain, swelling, and ulceration of the thigh after use for the past 6–7 months.65 He was noted to have painful necrotic ulcers on his thigh, and 2 months earlier, he had noticed swelling of his left little finger, which later turned black and autoamputated. The relationship between desomorphine
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PHARMACOTHERAPY Volume **, Number **, 2014
use and the patient’s necrotic events was suspicious but could not be confirmed. Due to the lack of scientific data, treatment of desomorphine overdose and adverse effects largely consists of supportive care, opioid antagonism (naloxone administration), and precautions for opioid withdrawal. Although no published literature exists on withdrawal, mixed opiate agonists/antagonists such as buprenorphine/naloxone may be considered. Acute overdose should be approached similarly to heroin overdose and include naloxone for reversal of opioid agonism. Abusers should be screened for communicable diseases including human immunodeficiency virus and hepatitis. Additionally, patients often require intensive psychiatric care, thorough nutrition evaluations, and both physical and psychiatric rehabilitation.
4. 5. 6.
7. 8. 9. 10. 11.
Conclusion Abuse of new designer drugs is a national problem whose rate of development is outpacing that of legislation. Clinicians should familiarize themselves with management principles of these new agents. Medical management of patients who abuse or overdose on these drugs largely consists of supportive care, although naloxone may be used as an antidote for desomorphine overdose. Symptoms of aggression and psychosis may be treated with sedation (benzodiazepines, propofol) and antipsychotics (haloperidol or atypical agents such as quetiapine or ziprasidone). Other facets of management to consider include treatment for withdrawal or addiction, nutrition support, and potential for transmission of infectious diseases. Acknowledgment The authors would like to acknowledge Christina Hantsch Bardsley, MD, FACEP, FAACT, FACMT, for her help in developing the content of this article.
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