Designer Drugs: Focus on Cathinones (Bath Salts) and Synthetic Cannabinoids (K2 or Spice)

Authors:

Timothy J. Wiegand, MD, Director of Medical Toxicology and Toxicology Consult Service, Associate Clinical Professor of Emergency Medicine, Department of Emergency Medicine, University of Rochester Medical Center and Strong Memorial Hospital, Rochester, NY.

Peer Reviewer:

Frank LoVecchio, DO, MPH, Vice Chair for Research, Medical Director, Samaritan Regional Poison Control Center, Emergency Medicine Department, Maricopa Medical Center, Phoenix, AZ.

Emergency physicians need to be able to treat a variety of clinical syndromes that occur in the setting of drug abuse. Over the past few years, synthetic designer drugs have become much more prevalent, with the number of new substances available to users increasing at a dizzying pace. Concomitant with increases in their availability have been dramatic increases in emergency department (ED) visits and hospitalizations from these substances.1,2 One of the more common ways of distributing these types of drugs has been as intentionally misrepresented products such as incense or bath salts.3 Despite warnings on the product labels that the items are "not for human consumption," users have perceived them as potentially safer drugs than their illicit counterparts. There is also an incredible amount of misinformation propagated about designer drugs. In the past few years, there have been media stories of people committing bizarre and violent acts while under the influence of designer drug products such as bath salts, and many sensational cases have initially been misattributed to designer drug intoxication.4,5 Emergency physicians need to be aware of the types of designer drugs available, how they work, as well as the potential toxicity they can cause in order to prevent life-threatening complications or even death in patients who present to the ED with intoxication due to these substances. This article will review the clinical presentation and management for several different designer drug classes, focusing primarily on the cathinones, which have been sold as psychoactive bath salts, and the synthetic cannabinoids, which were misrepresented as incense or "potpourri."

Introduction

Many designer drugs are analogues or derivatives of existing illicit drugs and are developed through subtle modifications of their chemical structure. Sometimes designer drugs are entirely different chemicals, albeit they produce similar effects to illegal drugs.6,7 The practice of misrepresenting designer drugs became increasingly prevalent in the United States starting in 2010, as bath salts, glass cleaner, incense, and potpourri products containing synthetic cathinones and synthetic cannabinoids were marketed out of smoke shops and gas stations. These items have included an increasingly broad array of chemicals and have been labeled in this way only to circumvent provisions of the Controlled Substances Act, which would have rendered the chemicals illegal had they been sold specifically for human consumption.8 Some of these same chemicals were sold as "legal highs" or "research chemicals" through the Internet and in countries such as the United Kingdom or other European Union states.

The most common designer drugs identified in the past few years have been the synthetic cannabinoids, which were first identified in an herbal marijuana replacement called Spice, and the designer stimulants, which have been primarily cathinones or beta-ketoamphetamines found in the bath salt products. Other designer drugs, including analogues of ketamine, PCP, and benzodiazepines, have also become more prevalent on the designer drug market.3,9 While the development of designer drugs may reflect ingenuity and adaptation to legislation, the deceptive marketing and distribution as innocuous products has been extremely dangerous and caused significant morbidity and mortality.8,10,11 There are no standards or quality controls for product development. Safety data and information about specific product toxicity are often non-existent. Many products containing designer drugs do not contain the same chemicals as indicated by their labels, contain more than one class of designer drug or multiple chemicals from the same class, or have widely varying doses and concentrations, sometimes with completely different chemicals within the same package.12-15 Dangerous doses of caffeine have been identified in some products.16,17

Background

The term "designer drugs" was first used in the 1980s as fentanyl analogues began appearing on the black market sold as "china white" or simply substituted as heroin.18,19 The practice of creating analogues of illicit substances in response to their restriction, however, dates back to the early 20th century when, during Prohibition, various ether products (i.e., diethyl ether) were sold as a replacement for ethanol.20 Another early example was the development of various esters of morphine (i.e., dibenzoylmorphine) in response to restrictions of heroin (diacetylmorphine) in the 1920s.21

In the 1960s and 1970s, designer amphetamines surfaced in parts of the United States.22 In the 1980s, fentanyl analogues were identified in heroin seizures.18 The 1990s saw the first cathinone, methcathinone, become available in the United States,23 and in the early 2000s, tryptamines, chemicals similar to psilocin and psilocybin, the active constituents in "magic mushrooms," were readily available through the Internet.24 In each of the last five decades, different designer drugs have been available, many limited to specific geographical or social niches, and usually a single drug or drug class was popular. Recent years, though, have seen a veritable explosion of many different designer drugs and drug classes widely available to the public across the globe. The 2010 European Monitoring Center for Drugs and Drug Addiction (EMCDDA) annual report identified 41 new chemicals that were classified as novel substances of abuse, the majority of which were synthetic designer drugs.3 In 2011, there was a similar number identified, with 42 additional new drugs confirmed.8,25,26 Several factors are responsible for the proliferation and interest in designer drugs. The Internet has become a prominent venue not only for the marketing and sale of designer drugs, but it has facilitated rapid dissemination of information about these substances. The practice of intentionally mislabeling designer drugs and marketing them directly to the public through places such as smoke shops, gas stations, and even convenience stores gives them a high degree of visibility and makes them increasingly available to a wide audience. The speed at which the designer drug market reacts to any perturbation is remarkable and unprecedented, as novel compounds appear quickly in response to restriction of specific chemicals.8,26

Availability and Regulation

The availability of designer drugs varies from country to country and even from state-to state in the United States, although throughout the world the Internet is an increasingly common source. While availability is influenced by the laws and regulations regarding specific substances and drug classes, the overall regulation of designer drugs has been difficult. The practice of regulating (scheduling) specific chemicals as they appear is time-consuming and currently not very effective.27 Scheduling entire classes of compounds can limit the legitimate use of specific drugs in research or as potential therapeutics. In fact, many of the designer drugs were first developed and studied to some extent (at least in vitro or in animal models) by medicinal chemists or others in drug development.7 This was particularly true for the synthetic cannabinoids and many of the designer stimulants. Despite this, human safety and toxicity data are virtually non-existent.28 There is significant difficulty in developing effective laws and regulations addressing synthetic designer drugs, and there can be undesirable effects of regulation as well.29 When a specific designer drug is scheduled, a broad array of replacements are often created, and many of them have more toxic effects than the chemical they replaced. When drugs are regulated in the United States and the European Union, the chemicals remain largely available through the Internet and from local drug distributors.8,16,27

Cathinones (a.k.a., "Bath Salts") and Other Designer Stimulants

Basics. Bath salts are not an actual drug of abuse, but the term refers to one of the more popular types of products used to misrepresent designer drugs. Other products are labeled as glass cleaner, pond cleaner, and insect repellant (as well as "attractant"). Selling a designer drug as a bath salt is not new; MDA and methamphetamine have been sold in this manner.3,30 Initially sold in smoke shops ("head shops") or over the Internet, bath salts typically contain analogues, or "chemical cousins," of existing drugs of abuse.31 These drugs are usually a white, off-white, or tan powder and sold in vials or ampules.31 Some specific bath salt products are called: Cloud 9, Ivory Wave, Vanilla Sky, White Rush, Freebase Bath Salt, Hurricane Charlie, Scarface, Ocean Snow, and "Charlie Sheen" bath salts.3,32,33 The designer drugs are sold "not for human consumption" in an effort to avoid existing legislation regarding drugs of abuse.

Most chemicals sold as bath salts are amphetamine analogues, in particular beta-ketoamphetamines, which are more formally called cathinones.3,8,31 The most common cathinones in the United States were initially mephedrone (4-methylmethcathinone) and MDPV (methylenedioxypyrovalerone), although a recent report by Prosser and Nelson in the Journal of Medical Toxicology identified 12 unique cathinones in bath salt products.8 Many more analogues are possible and are increasingly available as "research chemicals" over the Internet.8 In addition to cathinones, bath salts and other designer stimulant products contain pyrrolidines, aminoindanes, piperazines, and many other types of chemicals as active ingredients. Cathinones remain the most commonly identified chemicals, however.3,8,31,34

History. The simplest of the cathinones is called cathinone ((S)-2-amino-1-phenyl-1-propanone) and exists in nature in the leaves of the Khat (Catha edulis) plant.35 Chewing Khat leaves causes effects similar to amphetamines, including an increase in heart rate, blood pressure, and dilated pupils, along with alertness and euphoria.8 Khat chewing is common in the Middle East in Yemen and in east African countries such as Somalia. Synthetic versions of cathinone appeared early in the 20th century, with methcathinone (beta-keto-methamphetamine) and mephedrone (4-methylmethcathinone) synthesized in 1928 and 1929, respectively.8,35 Like their amphetamine cousins, some cathinones were useful as legitimate therapeutics. There is currently only one cathinone medically available. Bupropion (para-chloro-N-tert-butyl cathinone) is used for smoking cessation (Zyban™) as well as for the treatment of depression (Welbutrin™).35 Most other cathinones were abandoned for legitimate medical use due to intolerable side effects as well as their potential for abuse and dependence. Methcathinone was abused throughout the former Soviet Union and parts of the upper midwest United States in the 1980s and 1990s23,36 before waning in popularity as methamphetamine became widely available. Pyrovalerone, another type of cathinone that was used medicinally for chronic fatigue and as an anti-obesity agent, was identified as having a high potential for abuse, and there are reports of it becoming popular with injection drug users in the 1970s.37 An analogue of pyrovalerone, alpha-pyrovalerone (alpha-PVP), became a common "second generation" chemical sold in the bath salt replacements such as glass cleaners and other products, marketed "not for human consumption" after the sale of MDPV, mephedrone, and methylone was restricted in 2011.38,39

Prevalence. Data from the American Association of Poison Control Centers identified bath salt abuse in the United States as early as 2009; however, very few cases were reported. There was a dramatic increase in cathinone use as Poison Center calls increased from 303 in 2010 to 6072 in 2011.3,40 Data from other sources also confirmed this increase. The Toxicologic Investigators Consortium (ToxIC) Case Registry of poisoned patients seen by toxicologists in the United States also identified increasing hospitalizations related to cathinones or bath salt products from 2010 to 2011.41 Prior to 2009, the United Kingdom Poisons Information Service had no inquiries related to the designer cathinones; however, during a single year from 2009-2010, calls regarding these substances equaled the total number of calls received for both MDMA ("Ecstasy") and cocaine. After 2009 in the United Kingdom and across Europe, there was dramatic and rapid increase in availability, use, and hospitalization related to use of these drugs.42

Who Is Using These Drugs? Cathinone, or "psychoactive bath salt," users are more predominantly male, with most publications identifying males in well more than 50% of cases.43 A CDC Morbidity and Mortality Weekly Report from March 2011 described 35 patients ages 20-55 who presented to emergency departments across Michigan after use of products sold as bath salts; 54% of the subjects were male.44

Figure 1: Bath Salt Products
Figure 1 Bath Salt Products

Figure 2: Incense Products
Figure 2 Incense Products

Cathinones are often used concomitantly with many other intoxicating substances, including alcohol, marijuana, and other illegal drugs or prescription drugs.45 In an analysis of impaired or intoxicated drivers in Finland, the cathinone MDPV was detected in nearly 6% of cases, and benzodiazepines were a common co-intoxicant identified in these drivers.46 As with other designer drugs, including the synthetic cannabinoids (K2, Spice), certain populations, such as military personnel and athletes, may abuse these substances in particular because they are thought to be "legal" alternatives to drugs of abuse, or because they don't give a positive result on a standard urine drug screen.2,47,48

Cathinone use may vary by state or country as a function of specific scheduling laws and by the group and demographic surveyed. For example, in Europe mephedrone use is highest among those who attend bars and nightclubs, although use among the general population in groups such as college students is common.48 In one study of college students in the United Kingdom, previous use of mephedrone was identified in just over 20% (with daily use in 4.4%) of 1,000 college students surveyed.49 A 2010 survey identified 41.3% of over 2,000 U.K. clubbers ("nightclubs/raves") reporting mephedrone use on at least one occasion.48 In other countries, MDPV is more popular or more commonly detected during forensic analysis or in product samples. Cathinones, in addition to being the primary class of agents sold as bath salts in the United States, are increasingly identified as "ecstasy" or "Molly" substitutes or substituted as other stimulant drugs, including methamphetamine and cocaine.26,50 Designer drug use, in particular cathinones, MDPV, and mephedrone, is increasingly found in individuals monitored for drug use. In one study in Ireland, urine samples screened for specific "drugs of abuse" in 2010 found 13.9% were positive for mephedrone.48 In another study, using samples taken from patients at a drug treatment clinic, the prevalence of mephedrone was 37%.48

Route and Method of Use. Cathinones can be used through a variety of routes, including orally,51 insufflation,43 injection,52 or smoking.53 The IV route was the most common (63%) route of use in a CDC report of bath salt users in Michigan.44 Most mephedrone users at a rave or dance party using it as an "ecstasy" replacement ingested it orally (53%) or by insufflation (32%).48 Injection of bath salts can cause severe infections, and cases of necrotizing fasciitis are reported.52 The demographics and social setting of cathinone use influences the route of administration.

Mechanism and Effect. Cathinones and designer drugs sold as bath salts are stimulant drugs that have a mechanism of action similar to other common stimulant drugs such as amphetamines or cocaine.35,54,55 In-vitro studies as well as animal models comparing the effects of designer cathinones such as methylone and mephedrone to their amphetamine (or for MDPV, cocaine, or methylphenidate) counterparts confirm similarity in mechanism and effect.56,57 People use bath salts or cathinones for the same reason they use the amphetamines or cocaine — for alertness, euphoria, and increases in energy and in libido.8 Cathinones produce dose-dependent predictable clinical effects, including increased arousal, alertness, and attention at low doses, and agitation, delirium, hallucinations, seizures, and hyperthermia at higher doses.34,35,48 Some cathinones are structurally more similar to hallucinogenic amphetamines such as mescaline. These cathinones may also have more hallucinogenic effects, while others such as methylone function more like the empathogenic amphetamine MDMA ("ecstasy").58,59

MDPV, occasionally referred to as "super coke" by media or users, acts more like cocaine or methylphenidate, blocking reuptake of dopamine and norepinephrine. It has purely stimulant effects.55 MDPV is actually a more potent chemical than cocaine in terms of action and the dose required.55 These properties predicted that MDPV would have a high potential for abuse and dependence.55 Lower doses (i.e., 5-20 mg) of MDPV (as compared to other stimulants such as mephedrone) are required to obtain an effect.

Other cathinones such as mephedrone or methylone (which is beta-ketoMDMA) are more similar to MDMA ("ecstasy") or methamphetamine in their mechanism and effect. These have serotonergic activity in addition to increasing dopamine and norepinephrine levels through release of these neurotransmitters, rather than by blocking reuptake.57,60 In addition to in-vitro data, animal models and reports of intoxication confirm cathinone and bath salt products are similar to other stimulant drugs with regard to clinical effect and toxicity. Cathinone and "bath salt" user reports through Internet drug forums and chat rooms and surveys of drug use confirm that these substances are similar to other stimulants.61-63 The majority of users of mephedrone describe feeling similar to MDMA, although others report significant stimulant effects in addition to the feelings of warmth, openness, and empathy.49,63 Methylone has been frequently sold as MDMA or "Molly," which is not surprising given the similarity in structure and in response in animal models.

Clinical Presentation, Adverse Effects, and Toxicity. As cathinones are structurally similar to their amphetamine cousins, cathinone or bath salt intoxication produces similar clinical effects and toxicity. Sympathomimetic intoxication is seen clinically, although some of the cathinones are serotonergic and may cause serotonin syndrome.8,64-66 While there are differences in toxicity between specific cathinone or bath salt products, most of the effects will be dose-dependent and related to the amount and rapidity of the substance ingested as well as to underlying conditions and co-ingested substances.

Treatment relies on the history and physical exam and attention to clinical presentation rather than upon any laboratory result or report of a specific agent that was ingested. Regardless of the agent ingested, cardiovascular and neurologic symptoms predominate in most patients.10 Hypertension, tachycardia, agitation, and delirium, as well as elevations in temperature, are common with large ingestions or severe intoxications.35 The excited delirium syndrome has been reported with cathinone intoxication and in bath salt-related fatalities.34,67-70 Several different specific cathinones have been associated with fatality; however, methylone, MDPV, and mephedrone are the most common cathinones encountered in fatality reports in the literature.48,68,71-73 Patients with significant toxicity will require management for severe agitation, psychotic behavior, hallucinations, as well as treatment for elevations in heart rate, blood pressure, and temperature. Rhabdomyolysis, dehydration, and acidosis can develop in patients who are febrile or in those with excessive neuromuscular tone (i.e., rigidity or repetitive myoclonus), seizures, or who are struggling with restraints or fighting with police.45,72,74-76 Disseminated intravascular coagulation was reported in at least two cases that resulted in fatalities from bath salts.73 Acute kidney injury requiring hemodialysis has been reported.70 In the MMWR report describing bath salt intoxications in Michigan, symptoms included agitation (23 patients [66%]), tachycardia (22 [63%]), and delusions or hallucinations (14 [40%]).33

Specific toxicity and the need for hospitalization may be influenced by route of administration. Injection users of cathinones are reported to have severe tissue destruction, including necrotizing fasciitis and other tissue injury.77 Common features of cathinone intoxication included agitation (24%), tachycardia (22%), chest pain (13%), and confusion (14%).42 Depending upon the severity of their signs and symptoms, patients may require admission to the hospital or ICU. In a review of poison center calls related to bath salt intoxication involving 236 patients, nearly half were treated and released from the emergency department, 21% were admitted to the ICU, 12% were admitted to psychiatry, and 12% were lost to follow-up.10 In contrast to the synthetic cannabinoid intoxications, many patients hospitalized for cathinone intoxication have prolonged sympathomimetic symptoms; nearly half (45%) have symptoms > 24 hours, and nearly a third (30%) have symptoms > 48 hours. Care is primarily supportive and includes aggressive cooling, use of sedatives, and fluids. Management of specific toxicity and symptoms is discussed further below under the section on approach and management.

Synthetic Cannabinoids (a.k.a., K2 or Spice)

Background. Synthetic cannabinoids, often referred to as K2 or Spice, are some of the most common designer drugs seen in the ED. Although they represent a number of different chemicals from different chemical classes, the primary reason they are used is for their marijuana-like effect.78 They typically don't trigger a positive THC screen, so individuals can use these products to avoid detection.9,79 Individual synthetic cannabinoids are often many times more potent than THC, the active constituent of marijuana.80 Despite the fact that some of the synthetic cannabinoids were developed by medicinal chemists, there are virtually no human safety data available for this class of compounds.80,81 Synthetic cannabinoids do not typically identify the chemicals they contain. They are sold as herbal marijuana replacements across Europe and as incense and potpourri products in the United States, typically labeled "not for human consumption."82 A typical product contains several different innocuous plants such as bay bean, beach bean, blue lotus, dog rose/rosehip, lion's ear/tail, wild dagga, lousewort, Indian warrior, dwarf, skullcap, blue/sacred lotus, red clover, vanilla, and honey (among additional herbs/plants), along with a synthetic cannabinoid, which was usually simply dissolved in a solvent and sprayed onto the plant material.3 Many of these products contain mixtures of synthetic cannabinoids as well with varying amounts and concentrations of the drugs, even within a single packet.12,82,83

History. Synthetic cannabinoids became prominent designer drugs of abuse in 2004 when the herbal marijuana replacement product Spice was first sold in Europe.82 These products grew in popularity over the next several years, although it wasn't until 2008, after intense analysis, that synthetic cannabinoids were identified as the source of the "marijuana-like" effect.3,84,85

Synthetic cannabinoids include a wide variety of agents from several different chemical classes. The first synthetic cannabinoid identified was JWH 018, synthesized in 1995 for the purpose of better understanding the human cannabinoid system.86 This chemical, along with several others that have been identified in the K2 or Spice products, were named after their creator John W. Huffman of Clemson University. Following JWH 018, a series of chemicals were identified, some similar to JWH 018 and others from completely different classes.84,85,87 By 2009, several synthetic cannabinoids from different chemical classes were identified across Europe.88 The products were just starting to be seen in the United States in 2009.89 Spice products increased in popularity in the United States during 2010, and the first synthetic cannabinoids, consisting of five specific chemicals, were banned in 2011.90 Additional chemicals as well as other classes of synthetic cannabinoids soon replaced the "banned chemicals" and the incense products remained widely available until recently. In July 2012, broader federal regulations targeting most of the synthetic cannabinoids known to date were implemented. As with other designer drugs, additional analogues continue to appear, however, along with entirely novel substances that, at least initially, are not subject to regulation. Most recently, chemicals that inhibit enzymes responsible for degrading endogenous cannabinoids have been discovered in Spice products.91

Prevalence and Demographics. Synthetic cannabinoids have been among the most common designer drugs encountered during the past several years.3 U.S. Poison Control Centers identified the first cases of hospitalized patients at the end of 2010, although the DEA detected synthetic cannabinoids in the United States in 2009.87,89 By 2011, use increased dramatically as media attention described the products as having marijuana-like effects. They were widely available through smoke shops, convenience stores, gas stations, and the Internet.89 In a survey of college students, 69 of 862 (8%) students had used synthetic cannabinoids. Use was more common in first- and second-year college students than in the third or fourth year. Similar to other designer drugs, males were more likely to have used K2.92 In the United States, a review of Poison Center National Poisons Data System information identified 1,898 synthetic cannabinoid exposures over a 10-month period in 2010. Just over 74% of the single-agent exposures were in males.93 Other surveys, focusing on individuals with previous use of synthetic cannabinoids, identified fairly high use with other recreational drugs in this population. A U.S. poison center review found 40% of synthetic cannabinoid users were younger than 19 years old (compared to more than 50% marijuana users).78 One study involving 29 hospitalized patients in Europe identified 25 males and 4 females ages 14-30 years (median 19) who were hospitalized related to synthetic cannabinoid use.94 Similar to other designer drugs, certain populations including military,47 athletes,95,96 and individuals on probation,97 as well as other individuals who are regularly tested for illicit drugs, had higher interest in synthetic cannabinoids. In one study of nearly 6,000 urine samples from athletes, nearly 5% of samples were positive for synthetic cannabinoids.95

Route and Method of Use. Synthetic cannabinoids are primarily smoked as part of a mixture of other plants and herbs.79 In one survey of college students, 88% had smoked these drugs in a "cigarette" and 26% had used a hookah. In addition to smoking, some users will orally ingest the products.98 The specific synthetic cannabinoids are also available as powdered chemicals in quantities that vary from milligrams to kilograms through Internet vendors.86 There are reports of severe toxicity following ingestion of these chemicals, and deaths are reported.86,93

Mechanism and Effect.The synthetic cannabinoids have varying, albeit relatively high, potencies at the CB1 and CB2 receptors when compared to delta-9-THC, the active constituent in marijuana.88 The CB1 receptor is primarily responsible for the psychoactive properties of cannabinoids, including euphoria, whereas the CB2 receptor is primarily found in the immune system (although it plays a minor role in the modulation of pain and mood).89 They also exert a full agonist effect compared to the partial agonism of marijuana, resulting in more intense psychoactive effects. In addition to the CB1 and CB2 action, some synthetic cannabinoids inhibit GABAergic transmission,99 enhance serotonergic transmission,100 as well as inhibit the enzyme monoamine oxidase.89,101 These effects can result in serotonergic-like effects or a "sympathomimetic" type picture with tachycardia, hypertension, agitation, and even seizures.98 In addition, multiple other chemical substances, including caffeine, synthetic stimulants such as those found in the psychoactive bath salts, designer benzodiazepines,15,102 and even beta-agonists,17 have been found as adulterants in K2.

Clinical Presentation, Adverse Effects, and Toxicity. Emergency physicians report a wide array of clinical signs and symptoms associated with synthetic cannabinoid product use, with the most common symptoms being acute anxiety,103 tachycardia,93,104 and psychosis.105 An early review of adverse effects seen in hospitalized patients identified these symptoms along with hypertension, tachypnea, hallucinations, racing thoughts, and seizures.89 Because most of the effects are short-lived, patients seen in the ED can usually be discharged after a period of observation.104 Some of the effects noted in hospitalized patients are similar to those seen with users of marijuana (i.e., anxiety, tachycardia, paranoia, and psychosis), but other effects such as seizures are not.94,106,107 In most reports, the acute severe effects such as seizure were rare, occurring in 3.8% in one large sample.93 Psychosis is also seen in individuals requiring hospitalization or psychiatric evaluation after synthetic cannabinoid use.105,108 The risk of precipitating psychosis with synthetic cannabinoid use is higher than for marijuana.108-110

Cardiac signs and symptoms are common during synthetic cannabinoid intoxication.93 In addition to chest pain and tachycardia,93 myocardial infarction111 and various cardiac arrhythmias, including bradycardia and conduction blocks, are reported.81 One patient developed refractory supraventricular tachycardia and recurrent seizures after ingesting a slurry of ethanol containing a synthetic cannabinoid.86

Addiction and dependence on the synthetic cannabinoids are reported,112,113 and a withdrawal syndrome is described, which consists of craving, sweating, nightmares, an increase in blood pressure and heart rate that is alleviated with the return to synthetic cannabinoid use.113

Other Designer Drugs

Designer drugs, in general, including many of the cathinones and other designer amphetamines such as MDMA (methylenedioxyamphetamine) or "Molly," remain common causes of hospitalization.41,114 Ultra-potent (400-600 microgram doses) hallucinogenic amphetamines such as 25i-NBOME, 25c-NBOME, and 25B-NBOME are now seen on the designer drug market. In addition to direct cannabinoid receptor agonists, chemicals that inhibit endogenous cannabinoid breakdown are appearing.91 Methoxetamine, a ketamine analogue, is a popular drug of abuse and available through a variety of venues. Designer benzodiazepines such as phenazepam are increasingly common.115,116

Approach to the Patient with Designer Drug Intoxication

Initial Exam and Laboratory Assessment. The management of patients presenting to the ED with intoxication from designer drugs is the same as the approach to other intoxicated or poisoned patients. Rapid assessment of airway, breathing, and circulatory status is critical. History, physical exam, and laboratory assessment should be thorough and efficient. Most designer drugs, including the cathinones and the synthetic cannabinoids, will not test positive on standard urine drugs of abuse screens.9,117,118 There are tests available for many of the agents from referral laboratories;119,120 however, the results will not be available in a clinically meaningful time frame. Management and treatment strategies need to be based upon the clinical presentation and features of intoxication rather than on any laboratory confirmation of the specific drug. Neurologic and cardiovascular systems are the most commonly impaired in hospitalized patients.121 Nausea and vomiting can be difficult to treat in certain patients. They occur in approximately 15% of patients.121 The skin should be checked for signs of redness and stigmata of drug use such as puncture marks or tracks. Intravenous use of designer drug products such as bath salts is associated with severe soft-tissue infection, including cellulitis, abscess, and even necrotizing fasciitis.77 Patients who have injected the designer drugs, or who have skin findings suggestive of infection or who remain febrile despite attenuation of agitation and muscle hyperactivity, should have blood cultures and receive empiric treatment with antibiotics.

Designer drug intoxication can cause derangements in cognition and mood ranging from mild anxiety to overt agitation and delirium, with excitatory or sympathomimetic features on physical exam.3,8 An EKG should be obtained in all patients presenting with designer drug intoxication. Myocardial infarction has been reported after synthetic cannabinoid intoxication.116 Multiple arrhythmias, including bradycardia and tachycardia as well as conduction blocks, have been reported with the synthetic cannabinoids.81

Patients with either synthetic cannabinoid or cathinone toxicity may have hallucinations and neuromuscular findings similar to other patients with serotonin syndrome.65 In these cases, intoxication may be similar to an overdose of the antidepressant bupropion.35 It is important to check a core temperature and assess the neuromuscular tone in these patients, as fever, rhabdomyolysis, and acidosis indicate more severe intoxication. The Excited Delirium Syndrome (ExDS) has been reported as a complication of the cathinone agents in particular (as it as for other stimulant drugs such as cocaine or methamphetamines).68,69,72

Acute kidney injury can occur due to myoglobinuria as a complication from rhabdomyolysis or hyperthermia, from direct drug-induced nephrotoxicity, or from vasospasm resulting in hypoperfusion.70 Intravenous fluids should be administered and dehydration corrected. If there is rhabdomyolysis, correct any metabolic abnormalities and hydrate to maintain good renal perfusion and urine output. The urine output goal for patients with rhabdomyolysis is 1-2 mL/kg/hour. Occasionally, dialysis is necessary for patients with severe acidosis or persistent renal failure with acidosis and electrolyte abnormalities, as in the case of severe sympathomimetic intoxication due to cathinone or bath salt ingestion.70

Caffeine is a common adulterant in many products. Ingestion of large amounts of caffeine will cause stimulation of beta-1 and beta-2 receptors and release of catecholamines. Signs and symptoms of toxicity include tachycardia, nausea, vomiting, anxiety, diaphoresis, chest pain, hypokalemia, and tremor. More severe intoxication due to caffeine can result in hypotension and even seizures.122

While most of the psychoactive bath salts and Spice product intoxications result in excitatory features on exam, other designer drugs can cause sedation. Coma can be a result from end-organ effects, including neurologic toxicity.

Deaths have been reported from cathinone intoxication, in particular, and aggressive supportive care in patients with severe agitation and sympathomimetic or serotonergic toxicity (serotonin syndrome) is critical.34,68,71 Benzodiazepines (or other GABAergic agents such as phenobarbital or propofol) are the mainstay of supportive care.67 Benzodiazepines are also used as the primary treatment for agitation, psychosis, or seizure during acute synthetic cannabinoid or Spice product intoxication. Doses of sedatives during treatment of designer drug intoxications are not based upon any specific total amount; the endpoint for dosing should be improved agitation and neuromuscular tone, and patients without stiffness, "twitching," or myoclonus or muscle spasm, and whose temperature has normalized. In some patients, more aggressive cooling measures such as intubation and paralysis in addition to the sedation, active cooling, and hydration will be required. Clonidine or dexmedetomidine may be used adjunctively to benzodiazepines, phenobarbital, or propofol. These drugs are used for agitated delirium, including severe alcohol withdrawal, bupropion overdose, or cocaine intoxication.123,124 Both of these agents act as sympatholytics and are used in both acute intoxication and withdrawal syndromes that result in excited delirium. In patients with persistent psychosis or hallucinations, consider low doses of potent antipsychotics such as risperidone or olanzapine.

Most patients with synthetic cannabinoid intoxication can be treated and discharged from the ED within several hours.93 Individuals with designer stimulant intoxication, such as from the bath salt products or cathinones, may require more intensive treatment and the intoxication lasts much longer. In both cases, psychosis can persist beyond the acute intoxication. In these patients, admission and assessment by a psychiatrist is crucial.

Summary

Designer drugs remain a common cause of hospitalization. There are a variety of products available that contain various types of designer drugs; however, the most common are designer stimulants such as the cathinones (misrepresented as bath salts and glass cleaners) and the synthetic cannabinoids or K2 and Spice products (which act similar to, albeit more intense than, marijuana). The ED physician must treat the clinical signs and symptoms the patient is exhibiting. Aggressive supportive care, including cooling, hydration, and judicious use of sedatives such as benzodiazepines, is important in preventing life-threatening toxicity or death. In addition to the acute toxicity, both the cathinones and the synthetic cannabinoids have been associated with addiction, dependence, and prolonged neuropsychiatric effects including psychosis. Regional Poison Control Centers and medical toxicologists are available and can be invaluable resources in helping with the management of patients with designer drug intoxication.

References

  1. Wood DM, Greene SL, Dargan PI. Five-year trends in self-reported recreational drugs associated with presentation to a UK emergency department with suspected drug-related toxicity. Eur J Emerg Med 2012, July 30 [epub ahead of print].
  2. Jerry J, Collins G, Streem D. Synthetic legal intoxicating drugs: The emerging 'incense' and 'bath salt' phenomenon. Cleve Clin J Med 2012;79(4):258-264.
  3. 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(1):15-32.
  4. Zombie Attacker May Have Been Using Bath Salts. 2012. http://news.blogs.cnn.com/2012/05/29/reports-miami-zombie-attacker-may-have-been-using-bath-salts/. Accessed 12/9/12.
  5. Medical Examiner: Causeway Cannibal Not High on Bath Salts. 2012. http://miami.cbslocal.com/2012/06/27/medical-examiner-causeway-cannibal-not-high-on-bath-salts.
  6. Buchanan JF, Brown CR. 'Designer drugs.' A problem in clinical toxicology. Med Toxicol Adverse Drug Exp1988;3(1):1-17.
  7. Carroll FI, et al. Designer drugs: A medicinal chemistry perspective. Ann N Y Acad Sci 2012;1248:18-38.
  8. Prosser JM, Nelson LS. The toxicology of bath salts: A review of synthetic cathinones. J Med Toxicol 2012;8(1):33-42.
  9. Bebarta VS, Ramirez S, Varney SM. Spice: A new "legal" herbal mixture abused by young active duty military personnel. Subst Abus 2012;33(2):191-194.
  10. Spiller HA, et al. Clinical experience with and analytical confirmation of "bath salts" and "legal highs" (synthetic cathinones) in the United States. Clin Toxicol (Phila), 2011;49(6):499-505.
  11. Ross EA, Watson M, Goldberger B. "Bath salts" intoxication. N Engl J Med 2011;365(10):967-968.
  12. Zuba D, Byrska B, Maciow M. Comparison of "herbal highs" composition. Anal Bioanal Chem 2011;400(1):119-126.
  13. Davies S, et al. Purchasing 'legal highs' on the Internet — is there consistency in what you get? QJM 2010;103(7): 489-493.
  14. Wood DM, et al. Energy-1 ('NRG-1'): Don't believe what the newspapers say about it being legal. Emerg Med J 2011;28(12):1068-1070.
  15. Couch RA, Madhavaram H. Phenazepam and cannabinomimetics sold as herbal highs in New Zealand. Drug Test Anal 2012;4(6):409-414.
  16. Baron M, Elie M, Elie L. An analysis of legal highs: Do they contain what it says on the tin? Drug Test Anal 2011;3(9):576-81.
  17. Davies S, et al. Risk of caffeine toxicity associated with the use of 'legal highs' (novel psychoactive substances). Eur J Clin Pharmacol 2012;68(4):435-439.
  18. Ayres WA, Starsiak MJ, Sokolay P. The bogus drug: Three methyl & alpha methyl fentanyl sold as "China White." J Psychoactive Drugs 1981;13(1):91-93.
  19. Martin M, et al. China White epidemic: An eastern United States emergency department experience. Ann Emerg Med 1991;20(2):158-164.
  20. Brecher E. The Consumers Union Report on Licit and Illicit Drugs. Consumer Reports Magazine 1972.
  21. Esters of Morphine. UNODC Bulletin on Narcotics 1953:36-38.
  22. Ewald AH, Puetz M, Maurer HH. Designer drug 2,5-dimethoxy-4-methyl-amphetamine (DOM, STP): Involvement of the cytochrome P450 isoenzymes in formation of its main metabolite and detection of the latter in rat urine as proof of a drug intake using gas chromatography-mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 2008;862(1-2):252-256.
  23. Emerson TS, Cisek JE. Methcathinone: A Russian designer amphetamine infiltrates the rural midwest. Ann Emerg Med 1993;22(12):1897-1903.
  24. Long H, Nelson LS, Hoffman RS. Alpha-methyltryptamine revisited via easy Internet access. Vet Hum Toxicol 2003;45(3):149.
  25. Aceto MD, Scates SM, Martin BB. Spontaneous and precipitated withdrawal with a synthetic cannabinoid, WIN 55212-2. Eur J Pharmacol 2001;416(1-2):75-81.
  26. Addiction, E.M.C.f.D.a., European Monitoring Centre for Drugs and Addiction-Europol 2010 Annual Report on the implementation of Council Decision 2005/387/JHA. 2011.
  27. Kapka-Skrzypczak L, et al. Legal highs — legal aspects and legislative solutions. Ann Agric Environ Med 2011;18(2):304-309.
  28. Nichols D. Legal highs: The dark side of medicinal chemistry. Nature 2011;469(7328):7.
  29. Hammersley R. Dangers of banning spice and the synthetic cannabinoid agonists. Addiction 2010;105(2):373.
  30. Agency DE. "Cleopatras mini bath tablets passion" containing Dove logo MDA tablets and "Cleopatras exotic bath salt tablets" containing "Ice" methamphetamine from Vancouver, British Columbia. Microgram Bulletin 2004;37(4).
  31. Gerona RR, Wu AH. Bath salts. Clin Lab Med 2012;32(3):415-427.
  32. Caffery T, et al. Riding high on cloud 9. J La State Med Soc 2012;164(4):186-189.
  33. Centers for Disease Control and Prevention. Emergency department visits after use of a drug sold as "bath salts" — Michigan, November 13, 2010–March 31, 2011. MMWR Morb Mortal Wkly Rep 2011;60(19):624-627.
  34. 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(2):176-180.
  35. Coppola M, Mondola R. Synthetic cathinones: chemistry, pharmacology and toxicology of a new class of designer drugs of abuse marketed as "bath salts" or "plant food." Toxicol Lett 2012;211(2):44-49.
  36. Glennon RA. et al. Methcathinone: A new and potent amphetamine-like agent. Pharmacol Biochem Behav 1987;26(3):547-551.
  37. Deniker P, et al. [Abuse of pyrovalerone by drug addicts]. Ann Med Psychol (Paris), 1975;2(4):745-748.
  38. Sauer C, et al. New designer drug alpha-pyrrolidinovalerophenone (PVP): Studies on its metabolism and toxicological detection in rat urine using gas chromatographic/mass spectrometric techniques. J Mass Spectrom 2009;44(6):952-964.
  39. Kyle PB, Daley WP. Domestic abuse of the European rave drug prolintane. J Anal Toxicol 2007;31(7):415-418.
  40. Bronstein AC, et al. 2010 Annual Report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 28th Annual Report. Clin Toxicol (Phila), 2011;49(10):910-941.
  41. Wiegand TJ, Wax PM, Schwartz T, et al. The Toxicology Investigators Consortium Case Registry-The 2011 Experience. J Med Toxicol 2012;8:360-377.
  42. James D, et al. Clinical characteristics of mephedrone toxicity reported to the U.K. National Poisons Information Service. Emerg Med J 2011;28(8):686-689.
  43. Fass JA, Fass AD, Garcia AS. Synthetic cathinones (bath salts): Legal status and patterns of abuse. Ann Pharmacother 2012;46(3):436-441.
  44. Emergency department visits after use of a drug sold as "bath salts" — Michigan, November 13, 2010–March 31, 2011. MMWR Morb Mortal Wkly Rep 2011;60(19):624-627.
  45. Thornton SL, Gerona RR, Tomaszewski CA. Psychosis from a bath salt product containing flephedrone and MDPV with serum, urine, and product quantification. J Med Toxicol 2012;8(3):310-313.
  46. Kriikku P, et al. New designer drug of abuse: 3,4-Methylenedioxypyrovalerone (MDPV). Findings from apprehended drivers in Finland. Forensic Sci Int 2011;210(1-3):195-200.
  47. Berry-Caban CS, et al. Synthetic cannabinoid and cathinone use among US soldiers. US Army Med Dep J 2012:19-24.
  48. Dargan PI, et al. The pharmacology and toxicology of the synthetic cathinone mephedrone (4-methylmethcathinone). Drug Test Anal 2011;3(7-8):454-463.
  49. Dargan PI, Albert S, Wood DM. Mephedrone use and associated adverse effects in school and college/university students before the UK legislation change. QJM 2010;103(11):875-879.
  50. DEA. Most "Molly" Seized in New York is 4-MEC. DEA New York Field Division: Intelligence Note, 2012.
  51. Penders TM, Gestring R. Hallucinatory delirium following use of MDPV: "Bath dalts." Gen Hosp Psychiatry 2011;33(5):525-526.
  52. Russo R, et al. Life-threatening necrotizing fasciitis due to 'bath salts' injection. Orthopedics 2012;35(1):e124-e127.
  53. Ross EA, et al. Psychoactive "bath salts" intoxication with methylenedioxypyrovalerone. Am J Med 2012;125(9):854-858.
  54. Coppola M, Mondola R. 3,4-methylenedioxypyrovalerone (MDPV): Chemistry, pharmacology and toxicology of a new designer drug of abuse marketed online. Toxicol Lett 2012;208(1):12-15.
  55. Baumann MH, Partilla JS, Lehner KR, et al. Powerful cocaine-like actions of 3,4-Methylenedioxypyrovalerone (MDPV), a principal constituent of psychoactive 'bath salts' products. Neuropsychopharmacology 2012, Oct. 17 [epub ahead of print].
  56. Baumann MH, Partilla JS, Lehner KR. Psychoactive "bath salts": Not so soothing. Eur J Pharmacol 2012, Nov. 23 [epub ahead of print].
  57. Baumann MH, et al. The designer methcathinone analogs, mephedrone and methylone, are substrates for monoamine transporters in brain tissue. Neuropsychopharmacology 2012;37(5):1192-203.
  58. Sogawa C, et al. Methylone and monoamine transporters: Correlation with toxicity. Curr Neuropharmacol 2011;9(1):58-62.
  59. Hill SL, Thomas SH. Clinical toxicology of newer recreational drugs. Clin Toxicol (Phila) 2011;49(8):705-719.
  60. Cozzi NV, et al. Inhibition of plasma membrane monoamine transporters by beta-ketoamphetamines. Eur J Pharmacol1999;381(1):63-69.
  61. Wood DM, Dargan PI. Novel psychoactive substances: How to understand the acute toxicity associated with the use of these substances. Ther Drug Monit 2012;34(4):363-367.
  62. Wood DM, Dargan PI. Understanding how data triangulation identifies acute toxicity of novel psychoactive drugs. J Med Toxicol 2012;8(3):300-303.
  63. Wood DM, Dargan PI. Mephedrone (4-methylmethcathinone): What is new in our understanding of its use and toxicity. Prog Neuropsychopharmacol Biol Psychiatry 2012;39(2):227-233.
  64. Warrick BJ, et al. Lethal serotonin syndrome after methylone and butylone ingestion. J Med Toxicol 2012; 8(1):65-68.
  65. Rasimas JJ. "Bath salts" and the return of serotonin syndrome. J Clin Psychiatry 2012;73(8):1126-1127.
  66. Joksovic P, et al. "Bath salts"-induced psychosis and serotonin toxicity. J Clin Psychiatry 2012;73(8):1125.
  67. Murphy CM, Dulaney AR, Beuhler MC, et al. "Bath salts" and "plant food" products: The experience of one regional US Poison Center. J Med Toxicol 2012, June 26 [epub ahead of print].
  68. Murray BL, Murphy CM, Beuhler MC. Death following recreational use of designer drug "bath salts" containing 3,4-Methylenedioxypyrovalerone (MDPV). J Med Toxicol 2012; 8(1):69-75.
  69. Penders TM, Gestring RE, Vilensky DA. Excited delirium following use of synthetic cathinones (bath salts). Gen Hosp Psychiatry 2012;34(6):647-650.
  70. Regunath H, et al. Bath salt intoxication causing acute kidney injury requiring hemodialysis. Hemodial Int 2012;16 Suppl 1:S47-S49.
  71. Cawrse BM, et al. Distribution of methylone in four postmortem cases. J Anal Toxicol 2012;36(6):434-439.
  72. Borek HA, Holstege CP. Hyperthermia and multiorgan failure after abuse of "bath salts" containing 3,4-methylenedioxypyrovalerone. Ann Emerg Med 2012;60(1):103-105.
  73. Young AC, Schwarz ES, Velez LI, et al. Two cases of disseminated intravascular coagulation due to "bath salts" resulting in fatalities, with laboratory confirmation. Am J Emerg Med 2012, Aug. 3 [epub ahead of print].
  74. Antonowicz JL, Metzger AK, Ramanujam SL. Paranoid psychosis induced by consumption of methylenedioxypyrovalerone: two cases. Gen Hosp Psychiatry 2011;33(6):640 e5-6.
  75. Penders TM, Gestring RE, Vilensky DA. Intoxication delirium following use of synthetic cathinone derivatives. Am J Drug Alcohol Abuse 2012;38(6):616-617.
  76. Penders TM. How to recognize a patient who's high on "bath salts." J Fam Pract 2012;61(4):210-212.
  77. Dorairaj JJ, et al. The untold truth about "bath salt" highs: A case series demonstrating local tissue injury. J Plast Reconstr Aesthet Surg 2012;65(2):e37-e41.
  78. Forrester M, et al. Synthetic cannabinoid and marijuana exposures reported to poison centers. Hum Exp Toxicol 2012;31(10):1006-1011.
  79. Vandrey R, et al. A survey study to characterize use of Spice products (synthetic cannabinoids). Drug Alcohol Depend 2012;120(1-3):238-241.
  80. Hudson S, Ramsey J. The emergence and analysis of synthetic cannabinoids. Drug Test Anal 2011;3(7-8):466-478.
  81. Young AC, et al. Cardiotoxicity associated with the synthetic cannabinoid, K9, with laboratory confirmation. Am J Emerg Med 2012;30(7):1320 e5-7.
  82. Seely KA, et al. Spice drugs are more than harmless herbal blends: A review of the pharmacology and toxicology of synthetic cannabinoids. Prog Neuropsychopharmacol Biol Psychiatry 2012;39(2):234-243.
  83. Simolka K, et al. Analysis of synthetic cannabinoids in "spice-like" herbal highs: Snapshot of the German market in summer 2011. Anal Bioanal Chem 2012;404(1):157-171.
  84. Schlatter J, Chiadmi F, Chariot P. [The spice in France: Mixed herbs containing synthetic cannabinoids]. Ann Biol Clin (Paris), 2012;70(4):413-422.
  85. (EMCDDA), E.M.C.f.D.a.D.A., Understanding the 'Spice' Phenomenon. EMCDDA publication series 2009:25.
  86. Lapoint J, et al. Severe toxicity following synthetic cannabinoid ingestion. Clin Toxicol (Phila) 2011;49(8):760-764.
  87. Seely KA, et al. Marijuana-based drugs: Innovative therapeutics or designer drugs of abuse? Mol Interv 2011;11(1):36-51.
  88. EMCDDA, Synthetic cannabinoids and 'Spice.' 2011.
  89. Wells DL, Ot CA. The "new" marijuana. Ann Pharmacother 2011;45(3):414-417.
  90. Shank, KG, et al. Analysis of first and second generation legal highs for synthetic cannabinoids and synthetic stimulants by ultra-performance liquid chromatography and time of flight mass spectrometry. J Anal Toxicol 2012;36(6):360-371.
  91. Uchiyama N, Kawamura M, Kikura-Hanajiri R, et al. URB-754: A new class of designer drug and 12 synthetic cannabinoids detected in illegal products. Forensic Sci Int 2012, Oct. 9 [epub ahead of print].
  92. Hu X, et al. College students and use of K2: An emerging drug of abuse in young persons. Subst Abuse Treat Prev Policy 2011;6:16.
  93. Hoyte CO, et al. A characterization of synthetic cannabinoid exposures reported to the national poison data system in 2010. Ann Emerg Med 2012;60(4):435-438.
  94. Hermanns-Clausen M, Kneisel S, Szabo B, et al. Acute toxicity due to the confirmed consumption of synthetic cannabinoids: Clinical and laboratory findings. Addiction 2012, Sept. 13 [epub ahead of print].
  95. Heltsley R, et al. Prevalence of synthetic cannabinoids in U.S. athletes: Initial findings. J Anal Toxicol 2012;36(8):588-593.
  96. Moller I, et al. Screening for the synthetic cannabinoid JWH-018 and its major metabolites in human doping controls. Drug Test Anal 2011;3(9):609-620.
  97. Bryan S. Synthetic marijuana trips up man on probation. Sun Sentinel (online newspaper) 2012.
  98. Cohen J, et al. Clinical presentation of intoxication due to synthetic cannabinoids. Pediatrics 2012;129(4):e1064-e1067.
  99. Ando RD, et al. The inhibitory action of exo- and endocannabinoids on [(3)H]GABA release are mediated by both CB(1)and CB(2)receptors in the mouse hippocampus. Neurochem Int 2012;60(2):145-152.
  100. Velenovska M, Fisar Z. Effect of cannabinoids on platelet serotonin uptake. Addict Biol 2007;12(2):158-166.
  101. Fisar Z. Inhibition of monoamine oxidase activity by cannabinoids. Naunyn Schmiedebergs Arch Pharmacol 2010;381(6):563-572.
  102. Georgianova EK, et al. [An experimental model of benzodiazepine intoxication]. Eksp Klin Farmakol 1997;60(5):61-64.
  103. Schneir AB, Cullen J, Ly BT. "Spice" girls: Synthetic cannabinoid intoxication. J Emerg Med 2011;40(3):296-299.
  104. Harris CR, Brown A. Synthetic cannabinoid intoxication: A case series and review. J Emerg Med 2012, Sept. 15 [epub ahead of print].
  105. Hurst D, Loeffler G, McLay R. Psychosis associated with synthetic cannabinoid agonists: A case series. Am J Psychiatry 2011;168(10):1119.
  106. Pant S, et al. Spicy seizure. Am J Med Sci 2012;344(1):67-68.
  107. Schneir AB, Baumbacher T. Convulsions associated with the use of a synthetic cannabinoid product. J Med Toxicol 2012;8(1):62-64.
  108. Every-Palmer S. Synthetic cannabinoid JWH-018 and psychosis: An explorative study. Drug Alcohol Depend 2011;117(2-3):152-157.
  109. Johnson LA, Johnson RL, Alfonzo C. Spice: A legal marijuana equivalent. Mil Med 2011;176(6):718-720.
  110. Castellanos D, Thornton G. Synthetic cannabinoid use: Recognition and management. J Psychiatr Pract 2012;18(2):86-93.
  111. Mir A, et al. Myocardial infarction associated with use of the synthetic cannabinoid K2. Pediatrics2011;128(6):e1622-e1627.
  112. Castellanos D, et al. Synthetic cannabinoid use: A case series of adolescents. J Adolesc Health 2011;49(4):347-349.
  113. Gunderson EW, et al. "Spice" and "K2" herbal highs: A case series and systematic review of the clinical effects and biopsychosocial implications of synthetic cannabinoid use in humans. Am J Addict 2012;21(4):320-326.
  114. Gibbons S, 'Legal highs' — novel and emerging psychoactive drugs: A chemical overview for the toxicologist. Clin Toxicol(Phila) 2012;50(1):15-24.
  115. Boland DM, et al. Fatality due to acute alpha-methyltryptamine intoxication. J Anal Toxicol 2005;29(5):394-397.
  116. Brush DE, Bird SB, Boyer EW. Monoamine oxidase inhibitor poisoning resulting from Internet misinformation on illicit substances. J Toxicol Clin Toxicol 2004;42(2):191-195.
  117. Kadaria D, Sinclair SE. A case of acute agitation with a negative urine drug screen: A new wave of "legal" drugs of abuse. Tenn Med 2012;105(9):31-32.
  118. Macher AM, Penders TM. False-positive phencyclidine immunoassay results caused by 3,4-methylenedioxypyrovalerone (MDPV). Drug Test Anal 2012, May 20 [epub ahead of print].
  119. Kneisel S, Auwarter V, Kempf J. Analysis of 30 synthetic cannabinoids in oral fluid using liquid chromatography-electrospray ionization tandem mass spectrometry. Drug Test Anal 2012, Oct. 18 [epub ahead of print].
  120. Sobolevsky T, Prasolov I, Rodchenkov G. Detection of urinary metabolites of AM-2201 and UR-144, two novel synthetic cannabinoids. Drug Test Anal 2012, Oct. 5 [epub ahead of print].
  121. Forrester MB, et al. Synthetic cannabinoid exposures reported to Texas poison centers. J Addict Dis 2011;30(4):351-358.
  122. Haller C. Caffeine. In: Olson MK, ed. Poisoning and Drug Overdose. McGraw Hill: United States; 2007:142-143.
  123. Salomone A, et al. Simultaneous analysis of several synthetic cannabinoids, THC, CBD and CBN, in hair by ultra-high performance liquid chromatography tandem mass spectrometry. Method validation and application to real samples. J Mass Spectrom 2012;47(5):604-610.
  124. Brents LK, et al. Phase I hydroxylated metabolites of the K2 synthetic cannabinoid JWH-018 retain in vitro and in vivo cannabinoid 1 receptor affinity and activity. PLoS One 2011;6(7):e21917.