Journal of Pharmacy Practice http://jpp.sagepub.com/

Toxicology and Management of Novel Psychoactive Drugs Brian P. Kersten and Megan E. McLaughlin Journal of Pharmacy Practice published online 26 September 2014 DOI: 10.1177/0897190014544814 The online version of this article can be found at: http://jpp.sagepub.com/content/early/2014/09/25/0897190014544814

Published by: http://www.sagepublications.com

On behalf of:

New York State Council of Health-system Pharmacists

Additional services and information for Journal of Pharmacy Practice can be found at: Email Alerts: http://jpp.sagepub.com/cgi/alerts Subscriptions: http://jpp.sagepub.com/subscriptions Reprints: http://www.sagepub.com/journalsReprints.nav Permissions: http://www.sagepub.com/journalsPermissions.nav

>> OnlineFirst Version of Record - Sep 26, 2014 What is This?

Downloaded from jpp.sagepub.com at WRIGHT STATE UNIV on October 6, 2014

Continuing Education Article

Toxicology and Management of Novel Psychoactive Drugs

Journal of Pharmacy Practice 1-16 ª The Author(s) 2014 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0897190014544814 jpp.sagepub.com

Brian P. Kersten, PharmD, BCPS1, and Megan E. McLaughlin, PharmD, BCPS1

Abstract Health care providers are seeing an increased number of patients under the influence of several new psychoactive drug classes. Synthetic cannabinoids, cathinones, and piperazines are sought by users for their psychoactive effects, perceived safety profile, minimal legal regulations, and lack of detection on routine urine drug screening. However, these drugs are beginning to be recognized by the medical community for their toxic effects. The neuropsychiatric and cardiovascular toxicities are among the most common reasons for emergency medical treatment, which in some cases, can be severe and even life-threatening. Management strategies are often limited to supportive and symptomatic care due to the limited published data on alternative treatment approaches. The purpose of this article is to offer health care providers, emergency medical personnel in particular, an awareness and understanding of the dangers related to some of the new psychoactive drugs of abuse. The background, pharmacology, toxicity, management, detection, and legal status of each class will be discussed. Keywords synthetic cannabinoid, cathinone, piperazine, toxicity, drug abuse Goals 1. 2. 3.

Identify the classification of novel psychoactive drugs of abuse. Recognize the potential toxicity of each class of synthetic compound. Develop a management plan for toxicities related to the new designer drugs.

Continuing Education Learning objectives 1. 2. 3. 4. 5. 6. 7. 8.

Identify novel psychoactive substances of abuse. Describe reasons for the growing popularity of these agents. Explain the pharmacology and toxicology of each substance. Outline circumstances in which users may experience enhance effects. Compare the similarities and differences in common presenting symptoms of intoxication. Design treatment approaches for patients presenting with toxicity from the synthetic drugs. List current detection methods and the difficulties they present to clinicians. Describe the current legal status of the novel psychoactives and the challenges facing law enforcement.

Introduction Worldwide, there has been a dramatic surge in the demand and availability of novel psychoactive drugs. In the United States, synthetic cannabinoid (SCB), cathinone, and piperazine abuse is a growing concern among health care providers and public health officials.1,2 They have become highly sought after for their euphoric and stimulant effects. Unlike many traditional drugs of abuse, these new synthetic agents are relatively inexpensive, readily available to purchase through the Internet or head shops, typically legal to obtain and escape routine detection methods. Nevertheless, these synthetic substances can

produce a number of unwanted and sometimes dangerous side effects. Health care providers are faced with the task of managing acutely intoxicated patients with little understanding or guidance on the various toxicities. To complicate matters, in many

1

Pharmacy Department, Buffalo General Medical Center, Buffalo, NY, USA

Corresponding Author: Brian P. Kersten, Pharmacy Department, Buffalo General Medical Center, 100 High Street, Buffalo, NY 14203, USA. Email: [email protected]

Downloaded from jpp.sagepub.com at WRIGHT STATE UNIV on October 6, 2014

2

Journal of Pharmacy Practice

instances there exists little, if any, scientific data available to direct treatment decisions. The information provided in this article is intended to help clinicians in their management of intoxicated patients by reviewing essential topics related to the new synthetic drugs of abuse.

Methods We conducted an electronic search of the PubMed database (from 1966 to October 2013) and Google Scholar using the keywords cannabinoid, cathinone, piperazine, synthetic, designer drug, drug abuse, legal high, party pill, detection, kinetics, toxicity, adverse effects, treatment, and minor variations of these terms. In addition to each recognized drug classification, chemical compounds, slang words, or street names for the substances were used. Articles were limited to human reports and those available in English. We also screened each article as well as review articles for relevant references missed by the initial search. A final search of the electronic databases was conducted in December 2013.

Synthetic Cannabinoids Background The psychoactive effects of marijuana have been purportedly imitated by the emergence of SCBs in recent years. These compounds, deceptively marketed as ‘‘all natural’’ herbal blends and incense products, offer users an increasing number of options for achieving a subjectively pleasant and ‘‘legal high.’’1 Despite the perceptions that SCBs are harmless, there have been thousands of calls to Poison Control Centers and emergency department visits related to SCB toxicity.3,4 The SCBs were originally synthesized as a means to study the effects of marijuana on the cannabinoid (CB) receptors.5 Perhaps the most popular compound in this class is JWH-018. It was first developed by John W. Huffman in 1995, an organic chemist at Clemson University.5,6 Several other classes of synthetic compounds including the Alexandros Makriyannis (AM), cyclohexylphenol (CP), and Hebrew University (HU) series have also gained popularity.6 It is believed that the initial manufacturers of SCBs obtained documents of Huffman’s research to reproduce synthetic compounds for commercial enterprise. Table 1 provides a summary of the classification and various SCB compounds. After laboratory synthesis of SCBs, manufacturers dissolve such compounds in a solvent, such as acetone, and then spray the mixture on an assortment of dried plant leaves.7 The SCB-laced leaves are arranged in a thin layer under a fan to allow for the solvent to evaporate. They are then packaged as a loose leaf or rolled product and labeled ‘‘Not for human consumption.’’8 The product is sold commercially as ‘‘herbal incense,’’ ‘‘fragrance,’’ or ‘‘potpourri’’ under the better known proprietary names of K2 and Spice.1,9 Despite the warning, consumers know these products are meant to be smoked like marijuana by means of pipe, cigarette, blunt, or water bong.8 The graphic designs on K2 packaging further support

consumers are knowledgeable of the psychoactive effects. There are hundreds of different SCB-laced plant products available, but for the remainder of this review, they will be referred to as the popular US brand: K2. K2 became popular in Europe as early as 2004 when it began appearing in head shops and on the Internet.10 The SCB-laced plant product was not reported in the United States until December 2008 after being confiscated by the Customs and Boarder Patrol.11 With detection of cannabicyclohexanol, JWH-018 and JWH-073 in Japan in 2008, it has been confirmed that K2 products have reached many parts of the globe.12 It is thought that manufacturers in the United States obtain the SCBs from overseas to produce their signature brands to be packaged and sold.13 In the United States, K2 products remain available for purchase from head shops, convenience stores, gas stations, and on the Internet.8 A 3-g bag of K2 may cost roughly US$30 to US$50 but could vary considerably depending on where it is purchased.10,14-16 Users tend to be white males in their teens and 20s, although older individuals are not excluded.1,8,17 More than 80% of customers who have purchased K2 also report having used marijuana at least once during their lifetime.8

Pharmacology and Pharmacokinetics Little is known about the pharmacology and toxicology of SCB compounds. Much of the pharmacologic and toxic effects of SCBs are extrapolated from the main psychoactive CB of marijuana, D9-tetrahydrocannabinol (THC; Figures 1-3). CBs are abused for their effects on the CB receptors, which are located throughout the body. CB1 receptors (CB1R) are predominantly expressed in the brain, whereas CB2 receptors (CB2R) are primarily found on leukocytes and lymphocytes and are responsible for regulating immune function.18-20 THC is a partial agonist of the CB receptors and thus activation of CB1R produces the central nervous system (CNS) effects. The subjective, desirable psychoactive effects can include, but are not limited to increased energy, focus and creativity, euphoria, a dream-like state, relaxation or anxiolysis, sensory, perception and motor alterations, appetite stimulation, and uncontrollable laughter.8,10,20 However, undesirable properties such as anxiety, agitation, headache, depression, and paranoia are also observed in some cases.10,20 The SCBs, unlike THC, have demonstrated greater CB1R and CB2R affinity and function as full agonists.21-24 This greater efficacy and potency may, in part, explain the perceived severity of psychological and physiological reactions encountered by health care providers. Interestingly, THC is implicated to have mixed stimulatory– inhibitory effects on neurotransmitter release thus exhibiting both excitant and depressant properties.18 It is suspected that the interaction of SCBs at presynaptic CB1Rs antagonizes the release of several inhibitory and excitatory transmitters including acetylcholine, dopamine, glutamate, and g-aminobutyric acid (GABA).18,20 Onset and duration of effect are variable and may be dependent on the SCB product, amount ingested, and method of use.

Downloaded from jpp.sagepub.com at WRIGHT STATE UNIV on October 6, 2014

Kersten and McLaughlin

3

Table 1. Classification and Identification of Novel Psychoactive Drugs. Compound Synthetic cannabinoids18,63,151 Classical cannabinoids Nonclassical cannabinoids Naphthoylindoles

Benzoylindoles Phenylacetylindoles

Others

Cathinones63,70,151 Natural cathinones Methyl derivatives

Methylenedioxy derivatives Fluoro derivatives Pyrrolidine derivatives Other

Piperazines63,117,118,120,151 1-Benzylpiperazines (BZP) 1-Phenylpiperazines

Chemical and alternative names

Street names

D9-THCa HU-210 CP-47,497a CP-47,497-C8a AM-1220 AM-2201a JWH-015 JWH-018a JWH-019a JWH-073a JWH-081a JWH-122a JWH-200a JWH-398a AM-694a RCS-4a JWH-203a JWH-250a RCS-8a AB-001 AM-356 UR-144 XLR11

Aroma Aztec Thunder Bliss Bombay Blue Chill Zone Dark Matter Dream Everlast Exclusive Fake marijuana Fake weed Fusion Galaxy Herb Dream Herbal incense K2 K3 Magic Moon Rocks Red Magic Sence Skunk Smoke Space Spice Star Fire Yucatan Fire Zen

Cathinonea Cathine Methcathinone (ephedrine) Mephedronea (4-MMC, M-CAT) Butylone (bk-MBDB) Methedrone (bk-PMMA) Methylone (bk-MDMA) Ethylone (bk-MDEA) Flephedrone (4-FMC) 3-Fluoromethcathinone (3-FMC) 3,4-Methylenedioxypyrovaleronea (MDPV) Bupropion

Arctic Blast Bath salts Bubbles Chargeþ Cloud 9 Drone Hurricane Charlie Ivory Wave Ketones Khat Mef Meph Meow Meow Miaow Miaow MMC Hammer Plant feeder/food/fertilizer Rush White Lightening

BZPa 1-(3,4-Methylenedioxybenzyl)piperazine (MDBZP) 1-(3-Chlorophenyl)piperazine (mCPP) 1-(3-Trifluoromethylphenyl)piperazine (3-TFMPP)

A2 Bliss Bolts Charge ESP Euphoria Exodus Frenzy Good Stuff

1-(4-Methoxyphenyl)piperazine (pMeOPP) 1-(4-Fluorophenyl)piperazine (pFPP)

(continued)

Downloaded from jpp.sagepub.com at WRIGHT STATE UNIV on October 6, 2014

4

Journal of Pharmacy Practice

Table 1. (continued) Compound

Chemical and alternative names

Street names Herbal Ecstasy Jax Jump Legal E or Legal X Nemi Party pills PEP Rapture

a

Schedule I controlled substance.

Several reports suggest an onset within minutes; however, others indicate effects may take hours to manifest.16,25,26 The duration of action is fairly short (1-3 hours) making its use advantageous for active lifestyles.10,27 However, there is evidence describing effects lasting from several hours to greater than a day.25,28 There is also considerable interest in the metabolism and interactions due to the growing popularity of K2. THC undergoes hepatic metabolism mainly via oxidation by cytochrome P450 (CYP) enzyme CYP2C9, and then glucuronidation for urinary excretion.29 Similar to THC, it appears that SCB compounds like JWH-018 and JWH-073 are hydroxylated by CYP2C9 and CYP1A2 pathways.24,30 The SCB metabolites also demonstrate high affinity for CB1Rs, thus retaining their cannabimimetic effects.30,32 These compounds must then undergo glucuronic acid conjugation for urinary elimination.31 Drug–drug interactions may occur with K2 because these products often contain multiple SCBs rather than a single agent.33 An in vivo mouse experiment demonstrated synergistic, antagonistic, and additive THC-like effects depending on the end point examined.32 Collectively, these data may explain the greater potency regarding significant negative experiences and subjective psychoactive effects, particularly in comparison to THC.

Toxicology and Adverse Events The growing trend of K2 use has led to an increasing number of recognized adverse events, some of which can be severe and even fatal. Part of this can be explained by the pharmacokinetic and pharmacodynamics effects mentioned previously. However, other factors have been cited as potential reasons for the significant toxicities observed. For example, the number of different SCBs and their amounts may vary substantially when testing inter- and intrabatch concentrations.8,34,35 The intrabatch variability, sometimes referred to as ‘‘hot spots,’’ puts even the most experienced users at risk of overdose.35,36 Not only do these herbal mixtures contain unpredictable hot spots, they may be laced with other substances including the synthetic opioid O-desmethyltramadol, clenbuterol, a potent b2-agonist, and caffeine.35 Furthermore, unlike SCBs, cannabis is comprised of more than 50 other CBs and flavonoids including cannabidiol and cannabivarin. Cannabidiol is recognized to reduce

the anxiolytic and psychomimetic effect of THC, while cannabivarin has weak CB receptor antagonism.18,37 To our knowledge, there are no trials comparing THC and SCBs in humans and very limited prospective data on SCB use.25 The majority of evidence regarding adverse effects comes from Poison Control Center data, case reports, and Internet sources. Similarly, outbreak descriptions such as those from Denver, Colorado, and Brunswick, Georgia, in August and September 2013 provide valuable information and awareness for public health authorities, law enforcement, and health care providers.38,39 Not only do these reports describe epidemiologic patterns and adverse events, but they help to identify SCB brands like Crazy Clown and Black Mamba, which contain previously unrecognized CBs. In many instances, users describe the effects of K2 similar to those of THC with nearly 90% reporting a positive experience.8,16,36 However, a considerable number of users also experience unpleasant or negative effects following the use of K2.8,40 Such adverse effects include psychoactive reactions, as well as acute neurologic and cardiovascular events ranging from merely unpleasant to life-threatening. A list of adverse effects are reported in Table 2. The psychotic reactions associated with K2 include agitation, anxiety, illusions, auditory and visual disturbances and hallucinations, paranoia, and catatonia. Two surveys report a varying frequency of these common psychiatric effects.8,16 The reactions are often short lived and do not require medical attention.16,40 Occasionally, however, K2 users require emergency medical care often for psychoactive and cardiovascular adverse effects.17,40 Rarely, psychotic reactions can last for as long as several weeks or even months.28,41 The most common neurologic effect of K2 is cognitive impairment, but others may include dizziness, headaches, dysarthria, and ataxia.8,16,40,42 Seizure activity has been reported on several occasions.9,43-45 A national database identified that 3.8% of patients who require medical care for SCB intoxication present with seizures.40 Recently, there have been reports of acute ischemic stroke after smoking K2 with imaging, suggesting a possible embolic phenomenon.46,47 After psychoactive effects, tachycardia and palpitations are the most frequent reasons for seeking medical attention.16,17,40 The sympathomimetic effects of SCBs are well documented and may be associated with certain contaminants like

Downloaded from jpp.sagepub.com at WRIGHT STATE UNIV on October 6, 2014

Kersten and McLaughlin

5

Figure 2. Structures of methamphetamine, cathinone, and synthetic cathinone compounds.153

Figure 1. Structures of D9-tetrahydrocannabinol (THC) and synthetic cannabinoid compounds.152

clenbuterol and caffeine in the herbal mixtures rather than CB1R pharmacology alone.17,35,40 Although hypertension is often noted in this toxidrome, hypotension is observed as well.17,40 Users may also experience angina or

arrhythmias.8,40,42,45 In addition, K2 has been linked to STsegment elevation myocardial infarction in teenage patients.48 Various other adverse effects have been reported in the literature. Gastrointestinal effects such as nausea and vomiting are often noted.8,9,16,40,44 Similar to THC, CB hyperemesis syndrome has been recognized in habitual K2 users.49 Anticholinergic symptoms including mydriasis, xerostomia, and warm, dry skin are also fairly common.8,50,51 Acute kidney injury may be less common but can be particularly detrimental with several patients requiring hemodialysis.52,53 In rare circumstances, death has been linked to SCBs and K2 use.40,54-56 Suicidal ideation and intentional self-harm after ingestion has been implicated in some fatal cases.54,56,57

Downloaded from jpp.sagepub.com at WRIGHT STATE UNIV on October 6, 2014

6

Journal of Pharmacy Practice

Figure 3. Structures of 3,4-methylenedioxymethamphetamine (MDMA) and synthetic piperazine compounds.154

The abuse and dependence potential of K2 has been described in 1 survey study by several scenarios outlined in the Diagnostic and Statistical Manual of Mental Disorders (DSM). K2 users report attempting to get high in potentially hazardous situations such as operating a motor vehicle, the inability to reduce or stop K2 use, having tolerance symptoms, and using for longer than initially intended.8 A withdrawal or ‘‘hangover-like’’ effect, although fairly uncommon, may occur after K2 use, even a single ingestion.8,25,58 These symptoms may last a few days and can include headaches, insomnia, anxiety, restlessness, irritability, somatic pain, coughing, shortness of breath, and nausea.8,58

Management For patients presenting to the emergency department with suspicion of K2 exposure, initial management should include recording vital signs, initiating telemetry monitoring, and ensuring a protected airway.59,60 Laboratory testing is often warranted and may depend upon presenting complaints, physical examination, or clinical suspicion. Such testing may include a basic metabolic panel, complete blood count,

troponin, creatine kinase MB(CK-MB), creatine phosphokinase (CPK), and a blood gas.50,52,53,59-61 Clinicians may also consider ruling out potential coingestants depending on the history obtained.45,59 Treatment of SCB intoxication is supportive and symptomatic; there is no antidote. Intravenous (IV) fluid administration is reported as the most common intervention.40,59-61 Agitation, catatonia, and severe anxiety can be managed with IV or intramuscular (IM) benzodiazepines.40,50,60,61 Antiemetics17,40,60 and antipsychotics41,50,60 may be considered for nausea and vomiting and psychosis and hallucinations, respectively. Occasionally, patients are admitted for inpatient observation, and, rarely, require intubation and ventilatory support.9,17,50,60 Contacting the local Poison Control Center can also provide assistance in management, particularly when providers are unfamiliar with K2 intoxication.17,40

Detection and Legal Status Detection and identification of the SCBs has been a challenge to scientists, medical personnel, and law enforcement.

Downloaded from jpp.sagepub.com at WRIGHT STATE UNIV on October 6, 2014

Kersten and McLaughlin

7

Table 2. Adverse Effects Associated With the Synthetic Cannabinoids, Cathinones, and Piperazines. Synthetic cannabinoids Cardiovascular

Cathinones

Piperazines

Angina,17,60 bradycardia,17,60 Angina,85,98 hypertension,85,92,98,99 17,40,44,50,51,60,61 hypertension, palpitations,91,93 tachycardia,85,92,98 hypotension,17,40,60 palpitations,8,27,42,45 tachycardia,16,17,25,40,44,50,51,60,61

ENT Xerostomia8,25,60 Hematologic – Gastrointestinal Appetite changes,8,17,42 nausea/ vomiting8,9,16,17,40,44,60 Musculoskeletal Rhabdomyolysis17,60

Epistaxis,93 sore mouth/throat93 Disseminated intravascular coagulation90 Abdominal pain,78 abnormal LFTs,78 anorexia,93,97 nausea/ vomiting84,85,91,93,99 Elevated creatine kinase,92 Involuntary movements131 92 rhabdomyolysis Amnesia,92 confusion,85,98 dizziness,2,78 Confusion,121,131,138,140,145,149 headache,84,91,99 insomnia,78,93,97 motor dizziness,121,124-126,130,140,145 2 98 91,99 automatism, seizure, tremor headache,121,131 insomnia,121,124126,131,140,145 seizure,121,124,131,138,141,145 121,131,138,140,141,145 syncope, tremor121,131

Ataxia16,17; amnesia and memory impairment8,40,42,60; coma17; confusion, attention disturbances, and concentration difficulties16,17,40,41,50,51,60,61; dizziness/ vertigo8,16,17,40,60; drowsiness/ lethargy8,17,40; dysarthria8,16,41; tremor44,51; headache8,16,17; stroke46,47; syncope9,17,60; seizures9,17,43,44 Renal Acute kidney injury52,53 Acute kidney injury,78 increased serum creatinine85 Ophthalmologic Mydriasis17,50,51,60 Abnormal vision,91,93 mydriasis92 Pulmonary Dyspnea17,60 Dyspnea,78 tachypnea85 Psychiatric Auditory and visual perception Agitation,92,97-99 aggression,91,92,94 changes,8,41,42 anxiety,91,97 depressed mood,99 9,17,40,42,44,50,51,61 agitation, hallucination/delusions,85,91,93,97-99 anxiety,8,16,27,42,44,61 depressed paranoia91,97,99 8,16,27 mood, hallucination/ delusions,8,9,16,17,40,41,44,60 catatonia,9 paranoia,8,16,27,42,61 suicidal ideation41,57 Other Anticholinergic symptoms,50,51,60 Bruxism,67,96 diaphoresis,84,91,99 electrolyte abnormalities,85 extremity hyperglycemia,61 pallor17,44,51 vasoconstriction,84,91,93,94,99 hyperthermia,92,93 metabolic acidosis,78 rash78 Neurological

Angina,121,124,125,131,145 hypertension,121,127,138,144 palpitations,121,124,125,131,140,145 QTc prolongation,121,131 tachycardia121,127,138,140-143 – – Abdominal pain,126,139 nausea/ vomiting121,125,126,131,140,143,145

Urinary retention121,126,131,145 Mydriasis138,141,143 – Agitation,121,124,126,131,140,141,143 anxiety,121,140,143,145,150 depressed mood,140 hallucinations,125,140 psychosis,125,140 dark/strange thoughts,140 mood disorders/swings,140 paranoia125,140 Bruxism,126,143,145 diaphoresis,131 hyponatremia,131 hyperthermia,124,138

Abbreviations: ENT, ear, nose, and throat; LFT, liver function test.

These compounds are not detected by routine urine or serum immunoassay drug screenings.25,55 Liquid chromatography– tandem mass spectrometry (LC–MS/MS) and gas chromatography–mass spectrometry (GC–MS) techniques have demonstrated the ability to identify SCB compounds and their metabolites.25,31,35,55 Unfortunately, these methods are highly specialized and most medical centers do not normally have access to such equipment. Even with access, the lengthy turnaround time for sample identification would not alter clinical decisions. The development of commercial testing is still in its infancy and is complicated by a rapidly changing composition of K2 products.55 Ever since K2 and similar products have been reported in the United States, there have been substantial efforts to curb their sales and abuse. Manufacturers can circumvent the Federal Analogue Act,62 which states ‘‘A controlled substance analogue shall, to the extent intended for human consumption, be

treated, for the purposes of any federal law as a controlled substance in schedule I’’ by placing ‘‘Not for human consumption’’ on the labeling. In March 2011, the first 5 SCBs (JWH-018, JWH-073, JWH-200, CP-47,497, and CP-47,497 C8 homologue) were made temporary schedule I substances by the Drug Enforcement Agency (DEA).11 At the time of writing, 15 SCB compounds are listed as schedule I agents under federal law, including the 5 drugs that were originally given temporary status.63,64

Cathinones Background The cathinones, commonly known in the United States as ‘‘bath salts’’ or in Europe as ‘‘plant food,’’ are another class of novel designer drugs.65,66 Although the use of cathinones is not

Downloaded from jpp.sagepub.com at WRIGHT STATE UNIV on October 6, 2014

8

Journal of Pharmacy Practice

Table 3. Common Means of Cathinone Abuse.65,67,83-86,91 Slang terminology

Means of use

– – Snorting Bombing Keying Eyeballing

Ingestion of capsules or tablets Diluting in water or juice Insufflation Powder wrapped in cigarette paper and swallowed Dipping a key into the powder and then insufflating Inserting into the eye

necessarily new, their use has risen dramatically in recent years. Synthetic cathinones have gained popularity mostly among younger individuals for their cocaine-like effects at low doses and amphetamine-like effects at higher doses. Poison Control Centers have reported an increasing volume of calls related to cathinone intoxication, with cases exceeding 6000 in 2011.67 A recent analysis of 1633 ‘‘bath salts’’ visits determined that the largest proportion of users were adult males between the ages of 18 and 29 years old.68 Cathinones have been synthesized and investigated for medical use since the 1920s. Presently, bupropion is the only cathinone derivative that is approved for medicinal use.69 While other cathinones have been investigated, none have been approved due to various adverse effects.70 The natural occurring cathinones, cathinone and cathine, are found in the khat plant, native to the Ethiopian region of Africa. Typically, 100 g of the raw khat plant, containing varying amounts of cathinone,71 is chewed for its amphetamine-like high.72-74 Desirable and undesirable effects of khat include stimulation, arousal, increased sensory perception, irritability, and anxiety.71,75-79 The synthetic cathinones, known as ‘‘legal highs,’’ are isolated from plant or fungal material and are the beta-keto analogs of the naturally occurring cathinones.72,80 The most common include mephedrone and methylenedioxypyrovalerone (MDPV), but several other derivatives are abused as well (see Table 1). Similar to the SCBs, the cathinones’ packages are labeled ‘‘Not for human consumption’’ and ‘‘Not tested for hazards or toxicity’’ allowing consumers to purchase them at head shops, convenience stores, gas stations, and on the Internet.65,69,70,75 The use of synthetic cathinones as recreational drugs seems to have gained popularity around 2007,70,79 likely due to decreased purity and availability of other common drugs of abuse. These compounds likely originate in China or India with a street price in the United States ranging from US$24 to US$35 for a half-gram package.65,81,82 The most common modes of cathinone consumption are insufflation (snorting), inhalation, and oral ingestion.65,67,70,78,79,83-85 Although not as widespread, sublingual, rectal, IM, intraocular, and IV modalities have been described65,67,69,78,79,83,85,86 (see Table 3). The most common routes of administration differ by age; younger users tend to avoid IV injection, whereas the older population is more likely to inject.68 All routes produce similar psychological and physiological effects, although onset and duration may differ.83

Table 4. Concomitant Drug Use to Modify Cathinone Effects.65,67,70,75,78,91-93 Desired effect

Suggested drugs

To enhance stimulant and entactogen effects

Cocaine, amphetamines, methamphetamines, caffeine, hallucinogens, kratom Alcohol, beta-blockers Gamma-hydroxybutyric acid (GHB), zopiclone Pregabalin, famotidine, omeprazole, domperidone Opiates Cannabis, benzodiazepines

To counteract tachycardia To produce visual hallucinations To counteract stomach pain

To produce speedball-like effects To counteract anxiety

Pharmacology and Pharmacokinetics Cathinone derivatives augment presynaptic concentrations of dopamine, norepinephrine, and serotonin by stimulating their release and antagonizing monoamine reuptake.74,87 Each compound has a varying affinity for the monoamine transporters. For example, mephedrone and methylone are relatively nonselective monoamine uptake inhibitors with affinity for dopamine and serotonin.87 Conversely, cathinone and methcathinone act as dopamine and norepinephrine uptake inhibitors and releasers.87 MDPV is a selective catecholamine uptake inhibitor without effect on monoamine release and its properties on dopamine reuptake are more potent than cocaine.65,87 Natural cathinone is rapidly metabolized and excreted as norepinephrine.72 The rate of absorption and metabolism is equal, thus limiting the amount of cathinone that enters the blood after chewing khat leaves.72 Synthetic cathinones appear to undergo significant phase I (demethylation and oxidation) and phase II (reduction) metabolism with only a relatively small amount of the drug excreted unchanged in the urine.75,88 The CYP enzymes CYP2B6, CYP2C19, CYP2D6, and CYP1A2 are reported to be involved in the metabolism.89,90 Studies examining half-life have not been conducted; however, users report an effect lasting approximately 2 to 4 hours with frequent redosing at 1- to 2-hour intervals.75,79,88 Clinical effects are similar to those of other stimulants and include euphoria, pleasurable sensations, mild sexual stimulation, alertness, psychomotor hyperactivity as well as tachycardia and hypertension.65,72 Users have reported cathinone ‘‘sessions’’ during which they consume up to 1 g in multiple doses over a period lasting approximately 4 to 10 hours.65,83,84 Usually, 25 to 75 mg of insufflated mephedrone results in rapid (within minutes), but short-lived effects (less than 60 minutes).65,69,86 Oral doses may range from 150 to 250 mg, with an onset of 45 minutes and effects lasting for 2 to 4 hours.65,83,84,91 Some users suggest using both oral and insufflation simultaneously to achieve rapid onset with longer lasting effects.65,67,70,75,78,84,92,93 Additionally, consumption of other drugs to augment the desired effects while diminishing the unwanted ones has been reported (see Table 4).

Downloaded from jpp.sagepub.com at WRIGHT STATE UNIV on October 6, 2014

Kersten and McLaughlin

9

Toxicology and Adverse Events Chewing natural khat has been associated with increased risk of myocardial infarction, dilated cardiomyopathy, oral cancer as well as duodenal ulcers.70,75 Overdose can occur after continuous daily consumption; symptoms of a mild overdose are trivial and include lethargy, mild depression, tremor, and nightmares. Significant overdose, however, can lead to psychological illness with symptoms of paranoid psychosis or delusional mania.71,77 There are no prospective studies examining cathinone use and toxicological effects similar to that of the SCBs. Data are limited to retrospective analyses, surveys, and case reports. The spectrum of toxicity is substantial and encompasses nearly all organ systems. In addition to the adverse events related to cathinone pharmacology, specific reactions are associated with IV administration. Injection site burning is common; blisters, venous thrombosis and scarring, abscess formation, and gangrene may occur with repeated administration.65,94 Compartment syndrome has also been reported in a number of cases.95 Despite use for its expected euphoria, roughly 20% of users report experiencing undesirable effects when using synthetic cathinones.70,83,93 The intoxicated patient often experiences vasoconstriction causing cold extremities and skin discoloration, skin rashes, and bruxism.67,96,97 Symptoms of acute toxicity can produce significant neurological, cardiovascular, and psychiatric symptoms (see Table 2). Most toxicities are relatively mild, although some users require medical observation and treatment for more severe reactions. Psychiatric manifestations account for a significant percentage of patients presenting for medical intervention. Overall, the most common adverse effect is agitation, ranging from mild to severe psychosis.70,92,97-99 This may occur in over 60% of patients.68 Other reported effects include anxiety, paranoia, delusions, dysphoria, depression, and suicidal ideation.72,84,85,91,93,94,96,98 Ninety-one percent of patients have neurological findings with altered mental status, confusion, and drowsiness being the most common.2 Other less frequently encountered effects include short-term memory loss, tremor, seizure, and coma.78,85,91-93,96,97 Repeated cathinone use, like methamphetamine, has shown to decrease dopaminergic transport, putting users at increased risk of parkinsonism-like symptoms and other neuropsychiatric disorders.94,100-103 In addition to the neuropsychiatric symptoms, patients often present with sympathomimetic toxicity. Tachycardia and hypertension are often encountered; however, dehydration and hyperthermia are seen with this toxidrome as well.68,92,98,99 Consistent with its pharmacologic effect, a number of cathinones have been associated with the development of serotonin syndrome, including a fatality.68,104 Chest pain and palpitations encompass the other common cardiovascular events.85,91,93,98 There are several articles describing death related to cathinone use. In some cases, other coingestants in addition to cathinone have been identified.68,105-111 One case describes the

development of excited delirium syndrome (ExDS), explained as a period of agitated delirium, hyperthermia, tachypnea, followed by a period of ‘‘giving up’’ and cardiac arrest.111,112 It is suspected that this most likely results from dysregulation of the dopaminergic pathways. In patients who survive the cardiac arrest from ExDS in other circumstances, hyperthermia is believed to play a role in subsequent coagulopathy, rhabdomyolysis, and multisystem organ failure.111,112 Chronic use may lead to additional effects such as anorexia, impaired memory, increased incidence of acute myocardial ischemia and coronary vasospasm, gastritis, oral keratonic lesions, and liver toxicity.65,113 There is little information about the addiction potential of synthetic cathinones. A survey of mephedrone users determined that 50% believed it to be addictive.70,83 Abusers report strong cravings and the urge to repeatedly use or increase their dose.70,83 It is thought that frequent consumption of high-dose cathinones can result in tolerance, dependence, and withdrawal symptoms including depression, anxiety, sleep disorders, tremors, paranoia, and cravings lasting several weeks.67

Management Similar to the SCBs, supportive measures should be initiated on presentation of suspected cathinone toxicity.68,95,109 Treatment of acute toxicity targets controlling agitation with benzodiazepines being the agents of choice.68,95 In controlling agitation, benzodiazepines may mitigate other toxicities such as hypertension and hyperthermia. The benzodiazepines often need frequent redosing to achieve adequate sedative effect, in which patients may ultimately require higher than normal doses.68 In rare cases where patients cannot be controlled with benzodiazepines alone, other sedatives such as propofol, barbiturates, and antipsychotics have been used.65,67,68,70 Clinicians should also keep in mind other substances (outlined in Table 4) may be contributing to toxic effects. Because some patients may present with signs and symptoms of sympathomimetic toxicity, hyperthermia and hypertension should be treated with cooling measures and antihyper tensives, respectively, if benzodiazepines are unsuccessful.65,67,70,98 IV fluids are required for dehydration and concern for rhabdomyolysis. Serotonin syndrome has been effectively managed using benzodiazepines and cyproheptadine.104 Occasionally severe intoxication requires inpatient admission and potentially intensive care.2

Detection and Legal Status Synthetic cathinones are not detected using standard drug tests, but often result in a false positive for methamphetamine.67 MDPV has also been reported to yield a false positive for phencyclidine (PCP). Serum and urine screening for cathinones can be detected via GC–MS and liquid chromatography–mass spectrometry (LC–MS) and possibly on human hair, but this technology is not readily available at most medical centers.67,114,115

Downloaded from jpp.sagepub.com at WRIGHT STATE UNIV on October 6, 2014

10

Journal of Pharmacy Practice

Internationally, cathinones are classified as a schedule I drug under the Convention on Psychotropic Substances, however, they remain legal in Israel, Yemen, and the horn of Africa.72,116 In the United States, mephedrone and MDVP are classified as schedule I controlled substances.63 All other cathinone derivatives are still legal for sale, possession, and use so long as they are labeled ‘‘Not for human consumption.’’

Piperazines Background Piperazine derivatives are rapidly becoming a popular class of designer drugs and are unique in the fact that they are entirely synthetic.117 They produce stimulant and hallucinogenic-like effects manifesting in euphoria, increased energy, and socialization.117-119 These compounds have been designed as phenylethylamine derivatives to mimic 3,4-methylenedioxymethamphetamine (MDMA) or Ecstasy. Recently referenced in pop culture, ‘‘Molly’’ is most likely a combination of these synthetic piperazines, having MDMA-like effects. Synthetic piperazines are derived from 2 main structural groups: 1-benzylpiperazine (BZP) and 1-phenylpiperazine. These compounds function as the basic configuration for various substitutions. In 1944, BZP was developed as an antihelminthic for livestock in the United Kingdom, but due to lower efficacy compared with piperazine and increased induction of seizures, it was never used for this indication.117,120,121 BZP was later studied as an antidepressant in the 1970s but not marketed due to its significant amphetamine-like effects. Ultimately, it was recommended that BZP should be under similar regulatory measures as amphetamines due to its abuse potential.120 Another piperazine compound, 1-(3-chlorophenyl)piperazine (mCPP), is the predominate metabolite of the antidepressants trazodone and nefazodone.117,122 Other prodrugs of BZP have been studied as antidepressants but have failed to reach market because of various amphetamine effects.117 The abuse of piperazines was kick-started in the late 1990s in the United States and Scandinavia, where they earned a reputation as rave or dance club drugs under the names ‘‘legal Ecstasy’’ or ‘‘party pills.’’120 At this time, BZP was the most popular and common active ingredient. Due to changes in legislation, active compounds have changed significantly. In 2004, mCPP was detected in street drugs in Sweden and the Netherlands, and a few years later, hundreds of thousands of mCPP tablets were confiscated in Europe.117,123 Young adults 14 to 25 years old124,125 are the typical users, with up to 18% reporting regular use.124 Nearly 90% report coingestion with other substances, including but not limited to alcohol, tobacco, CBs, Ecstasy, and hallucinogenic mushrooms.123,125 Piperazines are commonly promoted and sold on the Internet in capsule, pill, tablet, and powder form as ‘‘legal Ecstasy,’’ free bases and salts with prices ranging from

US$10 to US$60 per package.124,126 Although not as common, injection, smoking, and mixing into drinks have been reported.117,120,126 Hundreds of street names exist and may vary depending on product formulation (see Table 1).

Pharmacology and Pharmacokinetics Unlike the SCBs and cathinones, there have been multiple studies of piperazines examining their effects in humans.121,126-131 Studies have evaluated the pharmacology of synthetic piperazines, finding them to centrally stimulate dopamine, serotonin, and norepinephrine release, as well as inhibit their reuptake.117,118,122 Effects are similar to amphetamine, but 10 times weaker.117,118,132 At low doses, piperazines produce stimulant effects, while higher doses often result in hallucinations.132,133 Hypertension, tachycardia, euphoria, increased sociability, and feelings of self-confidence are experienced after use.127,128 BZP inhibits dopamine reuptake and acts as a dopamine receptor agonist.134-136 It has a high affinity for alpha2adrenoreceptors, resulting in increased norepinephrine release. Additionally, BZP is a nonselective serotonin (5-HT2) receptor agonist explaining its hallucinogenic effects at higher doses. Contrary to BZP, the phenylpiperazine, 1-(3-trifluoromethylphenyl)piperazine (TFMPP) does not have the same dopaminergic or noradrenergic effects; rather it binds to central serotonin receptors and prevents serotonin reuptake.134-136 BZP and TFMPP are commonly coingested to mimic MDMA-like effects. Piperazines are rapidly absorbed through the gastrointestinal tract; however, due to complex multiphase distribution, peak serum concentrations do not occur until 75 to 90 minutes.123,129 BZP is not extensively metabolized, although some does undergo hydroxylation, and only a very small portion of BZP and its metabolites are recovered in the urine.123,129 The phenylpiperazines (mCPP and TFMPP) undergo significantly more metabolism, including hydroxylation, glucuronidation, and sulfation, and are mainly excreted as metabolites.123 CYP2D6 appears to be the main enzyme responsible for metabolism of the various piperazines, although CYP1A2 and CYP3A4 are also implicated.118 The difference in metabolism between individuals may be a common cause for the variability in desired effects and toxicity.123 The customary dose of BZP is 75 to 250 mg and TFMPP 5 to100 mg with an effect lasting 6 to 8 hours.117,133,137 Important to note, the onset of effect is not immediate and often users will take multiple doses before the effect begins to occur.133 In addition, as a way to hasten the effects, some use IV administration, although due to the alkaline nature of the BZP solution, this is quite painful.123,125

Toxicology and Adverse Events Although piperazines are marketed as natural ‘‘herbal’’ drugs, many recent experimental and epidemiological studies demonstrate the true risks associated with them.121,123,125,138,139 Adverse effects are typically mild including agitation,

Downloaded from jpp.sagepub.com at WRIGHT STATE UNIV on October 6, 2014

Kersten and McLaughlin

11

insomnia, headache, and nausea, and most users do not seek medical attention125 (see Table 2). Nevertheless, other effects can be quite severe. Common neuropsychiatric effects include anxiety, confusion, paranoia, short temper, and auditory hallucinations.125 Seizures can occur in as many as 1 in 5 patients presenting with piperazine toxicity.121,131 Cases of severe overdose may result in repetitive seizures and/or mixed metabolic and respiratory acidosis.121,131 There may be a relationship with increasing BZP serum concentrations and risk of seizure development.131 The seizing patient also has a higher potential for further injuries such as rhabdomyolysis, renal impairment, and multiorgan failure.138 The cardiovascular effects often seen and require medical intervention include hypertension, tachycardia, and chest pain.121,124,125,127,138,140-144 These symptoms are consistent with a sympathomimetic toxicity identified in acutely intoxicated patients. The toxidrome may include hyperthermia, diaphoresis, mydriasis, and tremors as well.124,125,128,131,140,143 Prolongation of the QT interval has also been reported.121,138 Other adverse effects encompass a variety of organ systems. There are reports of bruxism or general teeth and jaw problems during intoxication.126,143,145 Hyponatremia, serotonin syndrome, nephrotoxicity requiring dialysis, and disseminated intravascular coagulation although less common have been described as well.138,139 Users report an unpleasant ‘‘comedown’’ period, where they withdraw from social interactions and/or feel sluggish the following day.126 Fatalities are not common, but when they do occur are the result of severe organ system failure or suicide attempts.138,146

Management Diagnosis and management is determined by the history obtained and clinical presentation. The sympathomimetic toxidrome associated with piperazine toxicity is managed in much the same way as the cathinones. General supportive measures should be initiated along with electrocardiogram and electrolyte monitoring.96,121,134,139,143 Agitation and seizures should be treated with IV or IM benzodiazepines.134 Antipsychotics are not recommended for severe agitation as they may impede the natural thermoregulation, cause extrapyramidal side effects, and induce hypotension or arrhythmias.123 Cardiovascular effects such as tachycardia and hypertension may resolve by simply putting the patient in a calming environment. Severe hypertension has been successfully treated with IV antihypertensives and clonidine.134 Selective betablockers should be avoided as they can theoretically potentiate hypertensive episodes secondary to unopposed alpha-1 adrenergic receptor stimulation. In patients with refractory hypertension, labetalol can be considered for its mixed alpha- and beta-receptor antagonistic properties.134

Detection and Legal status Piperazines can be identified using GC–MS, LC–MS, thinlayered chromatography (TLC), or GC nitrogen phosphorus

detector (GC-NPD); however, these are not readily available at most institutions.134,146-148 Routine urine immunoassays will not detect piperazines; however, BZP may produce a false positive for amphetamines. Serum and urine drug concentrations are not routinely measured because they do not correlate closely with clinical toxicity and effects.134,146,147 Additionally, mCPP is a metabolite of trazodone, and therefore, may yield a false positive on the trazodone assay. Legislation against piperazines is challenging due to the numerous potential isomers and substitutions; thus, despite legal action, nearly all piperazine derivatives are currently legal to possess and use. In the United States, BZP and TFMPP were temporarily placed on the list of schedule I controlled substances in 2002. In March of 2004, BZP was permanently added while TFMPP was not, making it illegal to manufacture, distribute, or possess BZP in the United States.63 Individual states have passed legislation beyond BZP making certain piperazine derivatives illegal; however, in the majority of the country, there remains little to no legislation.

Conclusion The emergence of new psychoactive substances poses a significant challenge to government bodies, law enforcement officials, and the medical community as a whole. Users continue to seek innovative ways to achieve the appealing effects of psychoactive substances all while avoiding legal ramification. Although the sought after effects are deemed pleasurable, occasionally negative side effects require urgent medical care. Rarely, these adverse events may be life-threatening or fatal. New strategies aimed at deterring the high-risk populations are required to curb abuse and reduce the burden on health care providers. Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.

References 1. Hu X, Primack BA, Barnett TE, et al. College students and use of K2: an emerging drug of abuse in young persons. Subst Abuse Treat Prev Policy. 2011;6:16. 2. 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):624-625. 3. Synthetic Marijuana Data: October 31, 2013. American Association of Poison Control Centers. http://www.aapcc.org/alerts/synthetic-marijuana/. Accessed November 30, 2013. 4. Substance Abuse and Mental Health Services Administration, Center for Behavioral Health Statistics and Quality. The DAWN Report: Drug-Related Emergency Department Visits Involving

Downloaded from jpp.sagepub.com at WRIGHT STATE UNIV on October 6, 2014

12

5.

6. 7.

8.

9. 10.

11.

12.

13. 14.

15.

16. 17.

18.

19. 20. 21.

Journal of Pharmacy Practice Synthetic Cannabinoids. Rockville, MD: Center for Behavioral Health Statistics and Quality; 2012. http://www.samhsa.gov/ data/2k12/DAWN105/SR105-synthetic-marijuana.pdf. Accessed November 30, 2013. Comprehensive drug information on synthetic cannabinoids— ‘‘Spice’’ and ‘‘K2.’’ Hunterdon Drug Awareness Program; 2012. http://www.hdap.org/spice.html. Accessed December 7, 2013. Wells DL, Ott CA. The ‘‘new’’ marijuana. Ann Pharmacother. 2011;45(3):414-417. Vardakou I, Pistos C, Spiliopoulou C. Spice drugs as a new trend: mode of action, identification and legislation. Toxicol Lett. 2010; 197(3):157-162. Vandrey R, Dunn KE, Fry JA, et al. A survey study to characterize use of spice products (synthetic cannabinoids). Drug Alcohol Depend. 2012;120(1-3):238-241. Harris CR, Brown A. Synthetic cannabinoid intoxication: a case series and review. J Emerg Med. 2012;44(2):360-366. Deluca P, Shifano F, Davey Z, et al. Spice Report by the Psychonaut Web Mapping Research Project. London: Institute of Psychiatry, King’s College London; 2009. http://www. psychonautproject.eu/documents/reports/Spice.pdf. Accessed November 29, 2013. Department of Justice 21 CFR Part 1308. Schedules of Controlled Substances: Temporary Placement of Five Synthetic Cannabinoids Into Schedule I [Online]. Washington, DC: US Government Printing Office; 2011:11075-11078. http://www.gpo.gov/fdsys/ pkg/FR-2011-03-01/pdf/2011-4428.pdf. Accessed December 5, 2013. Uchiyama N, Kikura-Hanajiri R, Ogata J, et al. Chemical analysis of synthetic cannabinoids as designer drugs in herbal products. Forensic Sci Int. 2010;198(1-3):31-38. Piggee C. Investigating a not-so-natural high. Anal Chem. 2009; 81(9):3205-3207. Schifano F, Corazza O, Deluca P, et al. Psychoactive drug or mystical incense? Overview of the online available information on Spice products. Int J Cult Ment Health. 2009;2:137-144. Gunderson EW, Haughey HM, Ait-Daoud N, 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. Barratt MJ, Cakic V, Lenton S. Patterns of synthetic cannabinoid use in Australia. Drug Alcohol Rev. 2013;32(2):141-146. Forrester MB, Kleinschmidt K, Schwarz E, et al. Synthetic cannabinoid exposures reported to Texas poison centers. J Addict Dis. 2011;30(10):351-358. Pertwee RG. The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: D9-tetrahydrocannabinol, cannabidiol and D9-tetrahydrocannabivarin. Br J Pharmacol. 2008;153(2):199-215. Mackie K. Cannabinoid receptors as therapeutic targets. Annu Rev Pharmacol Toxicol. 2006;46:101-122. Mechoulam R, Parker LA. The endocannabinoid system and the brain. Annu Rev Psychol. 2013;64:21-47. Atwood BK, Huffman J, Straiker A, et al. JWH018, a common constituent of ‘Spice’ herbal blends, is a potent and efficacious

22.

23.

24.

25.

26.

27.

28.

29.

30.

31.

32.

33.

34.

35.

36.

cannabinoid CB1 receptor agonist. Br J Pharmacol. 2010; 160(3):585-593. Atwood BK, Lee D, Straiker A, et al. CP47,497-C8 and JWH073, commonly found in ‘Spice’ herbal blends, are potent and efficacious CB1 cannabinoid receptor agonists. Eur J Pharmacol. 2011;659(2-3):139-145. Fantegrossi WE, Moran JH, Radominska-Pandya A, et al. Distinct pharmacology and metabolism of K2 synthetic cannabinoids compared to D9-THC: mechanism underlying greater toxicity. Life Sci. 2014;97(1):45-54. doi:10.1016/j.lfs.2013.09.017. Rajasekaran M, Brents LK, Franks LN, et al. Human metabolites of synthetic cannabinoids JWH-018 and JWH-073 bind with high affinity and act as potent agonists at cannabinoid type-2 receptors. Toxicol Appl Pharmacol. 2013;269(2):100-108. Auwarter V, Dresen S, Weinmann W, et al. ‘Spice’ and other herbal blends: harmless incense or cannabinoid designer drugs? J Mass Spectrom. 2009;44(5):832-837. Young AC, Medina G, Obafemi A, et al. Cardiotoxicity associated with the synthetic cannabinoid, K9, with laboratory confirmation. Am J Emerg Med. 2012;30(7):1320.e5-e7. Every-Palmer S. Synthetic cannabinoid JWH-018 and psychosis: an explorative study. Drug Alcohol Depend. 2011;117(2-3): 152-157. Berry-Caban CS, Kleinschmidt PE, Rao DS, et al. Synthetic cannabinoid and cathinone use among US soldiers. US Army Med Dep J. 2012:19-24. Maurer HH, Sauer C, Theobald DS. Toxicokinetics of drugs of abuse: current knowledge of the isoenzymes involved in the human metabolism of tetrahydrocannabinol, cocaine, heroin, morphine and codeine. Ther Drug Monit. 2006;28(3):447-453. Chimalakonda KC, Seely KA, Bratton SM, et al. Cytochrome P450-mediated oxidative metabolism of abused synthetic cannabinoids found in K2/Spice: identification of novel cannabinoid receptor ligands. Drug Metab Dispo. 2012;40(11): 2174-2184. Chimalakonda KC, Bratton SM, Le VH, et al. Conjugation of synthetic cannabinoids JWH-018 and JWH-073, metabolites by human UDP-glucuronosyltransferases. Drug Metab Dispos. 2011;39(10):1967-1976. Brents LK, Zimmerman SM, Saffell AR, et al. Differential drug– drug interactions of the synthetic cannabinoids JWH-018 and JWH-073: Implications for drug abuse liability and pain therapy. J Pharmacol Exp Ther. 2013;346(3):350-361. Seely KA, Prather PL, James LP, et al. Marijuana-based drugs: innovative therapeutics or designer drugs of abuse? Mol Interv. 2011;11(1):36-51. Perspectives on drugs: synthetic cannabinoids in Europe. European Monitoring Centre for Drugs and Drug Addiction; 2013. http://www.emcdda.europa.eu/topics/pods/synthetic-cannabinoids. Accessed December 21, 2013. Dresen S, Ferreiros N, Putz M, et al. Monitoring of herbal mixtures potentially containing synthetic cannabinoids as psychoactive compounds. J Mass Spectrom. 2010;45(10):1186-1194. Spaderna M, Addy PH, D’Souza DC. Spicing things up: synthetic cannabinoids. Psychopharmacol. 2013;228(4):525-540.

Downloaded from jpp.sagepub.com at WRIGHT STATE UNIV on October 6, 2014

Kersten and McLaughlin

13

37. Englund A, Morrison PD, Nottage J, et al. Cannabidiol inhibits THC-elicited paranoid symptoms and hippocampal-dependent memory impairment. J Psychopharmacol. 2013;27(1):19-27. 38. Centers for Disease Control and Prevention. Notes from the field: Severe illness associated with reported use of synthetic marijuana—Colorado August–September 2013. MMWR Morb Mortal Wkly Rep. 2013;62(49):1016-1017. 39. Centers for Disease Control and Prevention. Notes from the field: severe illness associated synthetic cannabinoid use—Brunswick, Georgia, 2013. MMWR Morb Mortal Wkly Rep. 2013;62(46):939. 40. Hoyte CO, Jacob J, Monte AA, 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. 41. Hurst D, Loeffler G, McLay R. Psychosis associated with synthetic cannabinoid agonists: a case series. Am J Psychiatry. 2011;168(10):1119. 42. Castellanos D, Singh S, Thornton G, et al. Synthetic cannabinoid use: a case series of adolescents. J Adolesc Heal. 2011;49(4): 347-349. 43. Schneir AB, Baumbacher T. Convulsion associated with the use of a synthetic cannabinoid product. J Med Toxicol. 2012;8(1):62-64. 44. Donnelly MT.Health advisory: K2 synthetic marijuana use among teenagers and young adults in Missouri. Jefferson, MO: Missouri Department of Health and Senior Services; 2010. http://health. mo.gov/emergencies/ert/alertsadvisories/pdf/HAd3-5-2010.pdf. Accessed December 5, 2013. 45. Lapoint J, James LP, Moran CL, et al. Severe toxicity following synthetic cannabinoid ingestion. Clin Toxicol. 2011;49(8):760-764. 46. Freeman MJ, Rose DZ, Myers MA, et al. Ischemic stroke after use of the synthetic marijuana ‘‘spice’’. Neurology. 2013;81(24): 2090-2093. 47. Korya D, Kapoor A, Labiner D. Ischemic stroke in a 28-year-old woman after smoking synthetic THC. Neurology. 2013;80(Meeting Abstracts 1):P06.250. 48. Mir A, Obafemi A, Young A, et al. Myocardial infarction associated with use of the synthetic cannabinoid K2. Pediatrics. 2011; 128(6):1622-1627. 49. Hopkins CY, Gilchrist BL. A case of cannabinoid hyperemesis syndrome caused by synthetic cannabinoids. J Emerg Med. 2013;45(4):544-546. 50. Simmons J, Cookman L, Kang C, et al. Three cases of ‘‘Spice’’ exposure. Clin Toxicol. 2011;49(5):431-433. 51. Banerji S, Deutsch CM, Bronstein AC. Spice ain’t so nice. Clin Toxicol. 2010;48:632 (abstract 137). 52. Centers for Disease Control and Prevention. Acute kidney injury associated with synthetic cannabinoid use—multiple states, 2012. MMWR Morb Mortal Wkly Rep. 2013;62(6):93-98. 53. Bhanushali GK, Jain G, Fatima H, et al. AKI associated with synthetic cannabinoids: a case series. Clin J Am Soc Nephrol. 2013; 8(4):1-4. 54. Shanks KG, Dahn T, Terrell AR. Detection of JWH-018 and JWH-073 by UPLC–MS–MS in postmortem whole blood casework. J Anal Toxicol. 2012;36(3):145-152. 55. Kronstrand R, Roman M, Andersson M, et al. Toxicological findings of synthetic cannabinoids in recreational users. J Anal Toxicol. 2013;37(8):534-541.

56. Patton AL, Chimalakonda KC, Moran CL, et al. K2 toxicity: fatal case of psychiatric complications following AM2201 exposure. J Forensic Sci. 2013;58(6):1676-1680. 57. Thomas S, Bliss S, Malik M. Suicidal ideation and self-harm following K2 use. J Okla State Med Assoc. 2012;105(11): 430-433. 58. Rominger A, Cumming P, Xiong G, et al. Effects of acute detoxification of the herbal blend ‘Spice Gold’ on dopamine D2/3 receptor availability: A [18F]fallypride PET study. Eur Neuropsychopharmacol. 2013;23(11):1606-1610. 59. Heath TS, Burroughs Z, Thompson AJ, et al. Acute intoxication caused by a synthetic cannabinoid in two adolescents. J Pediatr Pharmacol Ther. 2012;17(2):177-181. 60. Hermanns-Clausen M, Kneisel S, Szabo B, et al. Acute toxicity due to the confirmed consumption of synthetic cannabinoids: clinical and laboratory findings. Addiction. 2013;108(3):534-544. 61. Bebarta VS, Ramirez S, Varney SM. Spice: a new ‘‘legal’’ herbal mixture abused by young active duty military personnel. Subst Abuse. 2012;33(2):191-194. 62. United States 21 U.S.C. §813. Treatment of Controlled Substance Analogues [Online]. Washington, DC: US Government Printing Office; 1986:452. http://www.gpo.gov/fdsys/pkg/USCODE2008-title21/pdf/USCODE-2008-title21-chap13-subchapI-partBsec813.pdf. Accessed December 5, 2013. 63. United States 21 U.S.C. §812. Schedules of Controlled Substances: United States Code [Online]. Washington, DC: US Government Printing Office; 2010 522-526. http://www.gpo.gov/fdsys/pkg/ USCODE-2010-title21/pdf/USCODE-2010-title21-chap13-subchapI-partB-sec812.pdf. Accessed December 5, 2013. 64. Controlled Substances Act [Online]. Washington, DC: US Government Printing Office; 2012 579-584. http://www.gpo.gov/ fdsys/pkg/USCODE-2012-title21/pdf/USCODE-2012-title21chap13-subchapI-partB-sec812.pdf. Accessed December 9, 2013. 65. Zawilska JB, Wojcieszak J. Designer cathinones—an emerging class of novel recreational drugs. Forensic Sci Int. 2013; 231(1-3):42-53. 66. Corazza O, Demetrovics W, van den Brink W, et al. ‘Legal highs’ an inappropriate term for ‘novel psychoactive drugs’ in drug prevention and scientific debate. Int J Drug Policy. 2013; 24(1):82-83. 67. 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):144-149. 68. Warrick BJ, Hill M, Hekman K, et al. A 9-state analysis of designer stimulant, ‘‘Bath Salt,’’ hospital visits reported to Poison Control Centers. Ann Emerg Med. 2013;62(3):244-251. 69. Advisory council on the misuse of drugs. Consideration of the cathinones. https://www.gov.uk/government/uploads/system/ uploads/attachment_data/file/119173/acmd-cathinodes-report-2010. pdf. Accessed January 2, 2014. 70. Prosser JM, Nelson LS. The toxicology of bath salts: a review of synthetic cathinones. J Med Toxicol. 2012;8(1):33-42. 71. Bilinski P, Holownia P, Kapka-Skrzypczak, et al. Designer drug (DD) abuse in Poland: a review of the psychoactive and toxic properties of substances found from seizures of illegal drug

Downloaded from jpp.sagepub.com at WRIGHT STATE UNIV on October 6, 2014

14

72.

73.

74.

75. 76. 77.

78.

79.

80.

81.

82.

83. 84. 85. 86. 87.

88.

89.

Journal of Pharmacy Practice products and the legal consequences thereof; part 1—cannabinoids and cathinones. Ann Agric Environ Med. 2012;19(4):857-870. Karila L, Reynaud M. GHB and synthetic cathinones: clinical effects and potential consequences. Drug Test Analysis. 2011; 3(9):552-559. Brenneisen R, Fisch HU, Koelbing U, et al. Amphetamine-like effects in humans of the khat alkaloid cathinone. Br J Clin Pharmacol. 1990;30(6):825-828. Widler P, Mathys K, Brenneisen R, et al. Pharmacodynamics and pharmacokinetics of khat: a controlled study. Clin Pharmacol Ther. 1994;55(5):556-562. Capriola M. Synthetic cathinone abuse. Clin Pharmacol. 2013;5: 109-115. Balint EE, Falkay G, Balint GA. Khat—a controversial plant. Wien Klin Wochenschr. 2009;121(19-20):604-614. Fayissa AM, Kelly JP. A review of the neuropharmacological properties of khat. Prog Neuropsychopharmacol Bio Psychiatry. 2008;32(5):1147-1166. James D, Adams RD, Spears R, et al. Clinical characteristics of mephedrone toxicity reported to the U.K. National poisons information service. Emerg Med J. 2011;28(8):686-689. Deluca P, Schifano F, Davey Z, et al; Psychonaut WebMapping Research Group. Mephedrone Report. London, United Kingdom: Institute of Psychiatry, King’s College London; 2010. http:// www.psychonautproject.eu/documents/reports/Mephedrone.pdf. Accessed December 29, 2013. Rikura-Hanajiri R, Uchiyama N, Goda Y. Survey of current trends in the abuse of psychotropic substances and plants in Japan. Leg Med (Tokyo). 2011;13(3):109-115. Adebamiro A, Perazella MA. Recurrent acute kidney injury following bath salts intoxication. Am J Kidney Dis. 2013;59(2): 273-275. Erickson T. ‘‘Bath Salt’’ abuse hits epidemic proportions. Emerg Phys Monthly; 2011. www.epmonthly.com/subspecialties/toxicology/bath-salt-abuse-hits-epidemic-proportions/. Accessed January 2, 2014. Carhart-Harris RL, King LA, Nutt DJ. A web-based survey on mephedrone. Drug Alcohol Depend. 2011;118(1):19-22. Winstock AR, Mitcheson LR, Deluca P, et al. Mephedrone: new kid for the chop? Addiction. 2010;106(1):154-161. Forrester MB. Synthetic cathinone exposures reported to Texas Poison Centers. Ann J Drug Alcohol Abuse. 2012;38(6):609-615. Info Sheet: MDPV. http://crew2000.org.uk. Accessed January 2, 2014. Simmler LD, Buser TA, Schramm Y, et al. Pharmacological characterization of designer cathinones in vitro. Br J Pharmacol. 2013;168(2):458-470. Kamata HT, Shima N, Zaitsu K, et al. Metabolism of the recently encountered designer drug, methylone, in humans and rats. Xenobiotica. 2006;36(8):709-723. Meyer MR, Du P, Schuster F, et al. Studies on the metabolism of the a-pyrrolidinophenone designer drug methylenedioxypyrovalerone (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(12):1426-1442.

90. Meyer MR, Vollmar C, Schwaninger AE, et al. New cathinonederived designer drugs 3-bromomethcathinone and 3fluoromethcathinone: studies on their metabolism in rat urine and human liver microsomes using GC–MS and LC–high-resolution MS and their detectability in urine. J Mass Spectrom. 2012; 47(2):253-262. 91. Winstock A, Mitcheson L, Ramsey J, et al. Mephedrone: use, subjective effects and health risks. Addiction. 2011;106(11): 1991-1996. 92. 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. 93. Dargan PI, Albert S, Wood DM. Mephedrone use and associated adverse effects in school and college/university students before the UK legislation change. Q J Med. 2010;103(11):875-879. 94. Van Hout MC, Bingham T. ‘‘A Costly Turn ON’’: patterns of use and perceived consequences of mephedrone based head shop products amongst Irish injectors. Int J Drug Policy. 2012;23(3): 188-197. 95. Levine M, Levitan R, Skoinik A. Compartment syndrome after bath salts. Ann Emerg Med. 2013;61(4):480-483. 96. Durham M. Ivory wave: the nextmephedrone? Emerg Med J. 2011;28(12):1059-1060. 97. Penders TM, Gestring R. Hallucinatory delirium following use of MDPV: ‘‘Bath Salts.’’ Gen Hosp Psychiatry. 2011;33(5): 525-526. 98. Spiller HA, Ryan ML, Weston RG, 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. 99. Mixmag’s Drug Survey: The results—2012. http://www.mixmag. net/drugssurvey. Accessed January 3, 2014. 100. McCann UD, Wong DF, Yokoi F, et al. Reduced striatal dopamine transporter density in abstinent methamphetamine and methcathinone users: evidence from positron emission tomography studies with [11C]WIN-35,428. J Neurosci. 1998;18(20):8417-8422. 101. De Bie RMA, Gladstone RM, Strafella AP, et al. Manganeseinduced parkinsonism associated with methcathinone (Ephedrine) abuse. Arch Neurol. 2007;64(6):886-889. 102. Stepens A, Logina I, Liguts V, et al. A parkinsonian syndrome in methcathinone users and the role of manganese. N Engl J Med. 2008;358(10):1009-1017. 103. Santosky Y, Lesyk R, Fedoryshyn L, et al. Manganic encephalopathy due to ‘‘ephedrone’’ abuse. Mov Disord. 2007;22(9):1337-1343. 104. Mugele J, Nanagas KA, Tormoehlen LM. Serotonin syndrome associated with MDPV use: a case report. Ann Emerg Med. 2012;60(1):100-102. 105. Lusthof KJ, Oosting R, Maes A, et al. A case of extreme agitation and death after the use of mephedrone in the Netherlands. Forensic Sci Int. 2011;206(1-3):e93-e95. 106. Aromatario M, Bottoni E, Santoni M, et al. New ‘‘Lethal highs’’: a case of deadly cocktail of GHB and mephedrone. Forensic Sci Int. 2012;223(1-3):e38-e41. 107. Dickson AJ, Vorce SP, Levine B, et al. Multiple-drug toxicity caused by the coadministration of 4-methylmethcathinone (mephedrone) and heroin. J Anal Toxicol. 2010;34(3):162-168.

Downloaded from jpp.sagepub.com at WRIGHT STATE UNIV on October 6, 2014

Kersten and McLaughlin

15

108. Maskell PD, De Paoli G, Seneviratne C, et al. Mephedrone (4methylmethcathinone)-related deaths. J Anal Toxicol. 2011; 35(3):188-191. 109. Imam SF, Patel H, Mahmoud M, et al. Bath salts intoxication: a case series. J Emerg Med. 2013;45(3):361-365. 110. Adamowicz P, Tokarczyk B, Stanaszek, et al. Fatal mephedrone intoxication—a case report. J Anal Toxicol. 2013;37(1):37-42. 111. Murray BL, Murphy CM, Beuhler MC. Death following recreational use of designer drug ‘‘Bath Salts’’ containing 3,4methylenedioxypyrovalerone (MDPV). J Med Toxicol. 2012; 8(1):69-75. 112. Otachbachi M, Cevik C, Bagdure S, et al. Excited delirium, restraints, and unexpected death. Am J Forensic Med Pathol. 2010;31(2):107-112. 113. Al Habori M. The potential adverse effects of habitual use of Catha edulis (khat). Expert Opin Drug Saf. 2005;4(6): 1145-1154. 114. Torrance H, Cooper G. The detection of mephedrone (4-methylmethcathinone) in 4 fatalities in Scotland. Forensic Sci Int. 2010;202(1-3):e62-e63. 115. Wikstrom M, Thelander G, Nystrom I, et al. Two fatal intoxications with the new designer drug methedrone (4-methoxymethcathinone). J Anal Toxicol. 2010;34(9):594-598. 116. Griffiths P, Lopez D, Sedefov R, et al. Khat use and monitoring drug use in Europe: the current situation and issues for the future. J Ethnopharmacol. 2010;132(3):578-583. 117. Elliott S. Current awareness of piperazines: pharmacology and toxicology. Drug Test Anal. 2011;3(7-8):430-438. 118. Mauer HH, Kraemer T, Springer D, et al. Chemistry, pharmacology, toxicology and hepatic metabolism of designer drugs of the amphetamine (Ecstasy), piperazine, and pyrrolidinophenone types. Ther Drug Monit. 2004;26:127-131. 119. Kalant H. The pharmacology and toxicology of ‘‘Ecstasy’’ (MDMA) and related drugs. CMAJ. 2001;165(7):917-928. 120. Sa Monteiro M, de Lourdes Vastos M, Guedes de Pinho P, et al. Update on 1-benzylpiperazine (BZP) party pills. Arch Toxicol. 2013;87(6):929-947. 121. Gee P, Richardson S, Woltersdorf W, et al. Toxic effect of BZP-based herbal party pills in humans: a prospective study in Christchurch, New Zealand. N Z Med J. 2005;118(1227): 1-10. 122. Fong MH, Garattini S, Caccia S. 1-m-Chlorophenylpiperazine is an active metabolite common to the psychotropic drugs trazodone, etoperidone and mepiprazole. J Pharm Pharmacol. 1982;34(10):674-675. 123. Arbo MD, Bastos ML, Carmo HF. Piperazine compounds as drugs of abuse. Drug Alcohol Depend. 2012;122(3):174-185. 124. Nicholson TC. Prevalence of use, epidemiology and toxicity of ‘herbal party pills’ among those presenting to the emergency department. Emerg Med Australas. 2006;18(2):180-184. 125. Wilkins C, Sweetsur P, Girling M. Patterns of benzylpiperazine/ trifluoromethylphenylpiperazine party pill use and adverse effects in a population sample of New Zealand. Drug Alcohol Rev. 2008;27(6):633-639. 126. Butler RA, Sheridan JL. Highs and lows: patterns of use, positive and negative effects of benzylpiperazine-containing party pills

127.

128.

129.

130.

131.

132.

133.

134.

135.

136.

137.

138.

139.

140.

(BZP-party pills) amongst young people in New Zealand. Harm Reduct J. 2007;4:18. Lin JC, Bangs N, Lee H, et al. Determining the subjective and physiological effects of BZP on human females. Psychopharmacology (Berl). 2009;207(3):439-446. Lin JC, Jan RK, Lee H, et al. Determining the subjective and physiological effects of BZP combined with TFMPP in human males. Psychopharmacology (Berl). 2011;214(3):761-768. Antia U, Lee HS, Kydd RR, et al. Pharmacokinetics of ‘party pill’ drug N-benzylpiperazine (BZP) in healthy human participants. Forensic Sci Int. 2009;186(1-3):63-67. Antia U, Tingle MD, Russel BR. In vivo interactions between BZP and TFMPP (party pill drugs). N Z Med J. 2009: 122(1303):29-38. Gee P, Gilbert M, Richardson S, et al. Toxicity from the recreational use of 1-benzylpiperazine. Clin Toxicol. 2008;46(9): 802-807. Bilinski P, Holownia P, Kapka-Skrzypczak, et al. Designer Drug (DD) abuse in Poland: a review of the psychoactive and toxic properties of substances found from seizures of illegal drug products and the legal consequences thereof: part II—piperazines/piperidines, phenylethylamines, tryptamines and miscellaneous ‘others’. Ann Agric Environm Med. 2012;19(4):871-882. 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. Schep LJ, Slaughter RJ, Vale JA, et al. The clinical toxicology of the designer ‘‘party pills’’ benzylpiperazine and trifluoromethylphenylpiperazine. Clin Toxicol (Phila). 2011; 49(3):131-141. Baumann MH, Clark RD, Budzynski AG, et al. Effects of ‘‘Legal X’’ piperazine analogs on dopamine and serotonin release in rat brain. Ann N Y Acad Sci. 2004;1025:189-197. Baumann MH, Clark RD, Budzynski AG, et al. Nsubstituted piperazines abused by humans mimic the molecular mechanism of 3,4-methylenedioxymethamphetamine (MDMA or ‘Ecstasy’). Neuropsychopharmacology. 2005; 30(3):550-560. Gijsman HK, Van Gerven J, Tieleman MC, et al. Pharmacokinetic and pharmacodynamic profile of oral and intravenous meta-chlorophenylpiperazine in healthy volunteers. J Clin Psychopharmacol. 1998;18(4):298-295. Gee P, Jerram T, Bowie D. Multiorgan failure from 1benzylpiperazine ingestion—legal high or lethal high? Clin Toxicol (Phila). 2010;48(3):230-233. Alansari M, Hamilton D. Nephrotoxicity of BZP-based herbal party pills: a New Zealand case report. N Z Med J. 2006; 119(1233):1-3. Theron L, Jansen K, Miles J. Benzylpiperazine-based party pills’ impact on the Auckland city hospital emergency department overdose database (2002–2004) compared with ecstasy (MDMA or methylenedioxymethamphetamine), gamma hydroxybutyrate (GHB), amphetamines, cocaine, and alcohol. N Z Med J. 2007; 120:U2416.

Downloaded from jpp.sagepub.com at WRIGHT STATE UNIV on October 6, 2014

16

Journal of Pharmacy Practice

141. Wood DM, Dargan PI, Button K, et al. Collapse, reported seizure—and an unexpected pill. Lancet. 2007;369(9571):1490. 142. Poon WT, Lai CF, Lui MC, et al. Piperazines: a new class of drug of abuse has landed in Hong Kong. Hong Kong Med J. 2010;16(1):76-77. 143. Wood DM, Button J, Lidder S, et al. Dissociative and sympathomimetic toxicity associated with recreational use of 1(-3-trifluoromethylphenyl) piperazine (TFMPP) and 1-benzylpi perazine (BZP). J Med Toxicol. 2008;4(4):254-257. 144. Vorce SP, Holler JM, Levine B, et al. Detection of 1-benzylpiperazine and 1-(3-trifluoromethylphenyl)-piperazine in urine analysis specimens using GC–MS and LC–ESI–MS. J Anal Toxicol. 2008;32(6):444-450. 145. Wilkins C, Girling M, Sweetsur P. The prevalence of use, dependency and harms of legal ‘party pills’ containing benzylpiperazine (BZP) and trifluorophenylmethylpiperazine (TFMPP) in New Zealand. J Subst Abuse. 2007;12:213-224. 146. Elliott S, Smith C. Investigation of the first deaths in the United Kingdom involving the detection and quantification of the piperazines BZP and 3-TFMPP. J Anal Toxicol. 2008; 32(2):172-177. 147. Dickson AJ, Vorce SP, Holler JM, et al. Detection of 1-benzylpiperazine, 1-(3-trifluoromethylphenyl)-piperazine and 1-(3chlorophenyl)-piperazine in 3,4-methylenedioxymethamphet

148.

149.

150. 151. 152.

153.

154.

amine-positive urine samples. J Anal Toxicol. 2010;34(8): 464-469. De Boer D, Bosman IJ, Hidvegi E, et al. Piperazine-like compounds: a new group of designer drugs-of-abuse on the European market. Forensic Sci Int. 2001;121(1-2):47-56. Jan RK, Lin JC, Lee H, et al. Determining the subjective effects of TFMPP in human males. Psychopharmacology. 2010;211(3): 347-353. Austin H, Monasterio E. Acute psychosis following ingestion of ‘Rapture’. Australas Psychiatry. 2004;12(4):406-408. Erowid. Documenting the complex relationship between humans & psychoactives. erowid.org. Accessed October 26, 2013. National Center for Biotechnology Information PubChem Compound. CID ¼ 16078, CID ¼ 10382701, CID ¼ 15942731, CID ¼ 9821569. http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid. Accessed January 2, 2014. National Center for Biotechnology Information PubChem Compound. CID ¼ 10836, CID ¼ 62258, CID ¼ 20111961, CID ¼ 45266826. http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid. Accessed January 3, 2014. National Center for Biotechnology Information PubChem Compound. CID ¼ 1615, CID ¼ 75994, CID ¼ 3084246. http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid. Accessed January 3, 2014.

Continuing Education Credit The New York State Council of Health-system Pharmacists (NYSCHP) is pleased to provide you with the opportunity to obtain continuing education credit for this article online at HealthSystemCE.org (http://www.healthsystemce.org); login using your email address and HSCE password; then click the ‘‘Journal CE’’ tab. There is no charge to NYSCHP members. If you are not a member of NYSCHP, call 1-518-456-8819 to pay the $15 fee to access the quiz and obtain the password necessary to access the Journal’s CE article. In lieu of this fee, a completed membership application with your dues may be submitted. A grade of 70% or above is required to earn the CE credit. Repeat examinations will be permitted once for a grade below 70%. The NYSCHP is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. Thisknowledge based program provides 1.4 contact hours (0.14 CEUs) of continuing education. Universal Activity Number is 01340000-14-147-H01-P. Submission of exam for CE credit expires 12/31/2017.

Downloaded from jpp.sagepub.com at WRIGHT STATE UNIV on October 6, 2014

Toxicology and management of novel psychoactive drugs.

Health care providers are seeing an increased number of patients under the influence of several new psychoactive drug classes. Synthetic cannabinoids,...
492KB Sizes 4 Downloads 7 Views