new drugs of abuse

New Drugs of Abuse

Megan A. Rech,1,2* Elisabeth Donahey,1 Jacqueline M. Cappiello Dziedzic,2,3 Laura Oh,2,3 and

Elizabeth Greenhalgh1,4

1Department of Pharmacy Services, Loyola University Medical Center, Maywood, Illinois; 2Department of

Emergency Medicine, Loyola University Medical Center, Maywood, Illinois; 3Stritch School of Medicine, Loyola

University Chicago, Maywood, Illinois; 4Marcella Niehoff School of Nursing, Loyola University Chicago,

Maywood, Illinois

Drug abuse is a common problem and growing concern in the United States, and over the past decade,novel or atypical drugs have emerged and have become increasingly popular. Recognition and treat-ment of new drugs of abuse pose many challenges for health care providers due to lack of quantitativereporting and routine surveillance, and the difficulty of detection in routine blood and urine analyses.Furthermore, street manufacturers are able to rapidly adapt and develop new synthetic isolates of olderdrugs as soon as law enforcement agencies render them illegal. In this article, we describe the clinicaland adverse effects and purported pharmacology of several new classes of drugs of abuse includingsynthetic cannabinoids, synthetic cathinones, salvia, desomorphine, and kratom. Because many of thesesubstances can have severe or life-threatening adverse effects, knowledge of general toxicology is keyin recognizing acute intoxication and overdose; however, typical toxidromes (e.g., cholinergic, sympat-homimetic, opioid, etc.) are not precipitated by many of these agents. Medical management of patientswho abuse or overdose on these drugs largely consists of supportive care, although naloxone may beused as an antidote for desomorphine overdose. Symptoms of aggression and psychosis may be treatedwith sedation (benzodiazepines, propofol) and antipsychotics (haloperidol or atypical agents such asquetiapine or ziprasidone). Other facets of management to consider include treatment for withdrawalor addiction, nutrition support, and potential for transmission of infectious diseases.KEY WORDS synthetic cannabinoids, synthetic cathinones, salvia, desomorphine, kratom.(Pharmacotherapy 2014;**(**):**–**) doi: 10.1002/phar.1522

Drug abuse is a common problem and growingconcern in the United States, and over the past dec-ade, novel or atypical drugs have emerged andbecome increasingly popular. Staying current withthe new drugs of abuse can be challenging for healthcare practitioners due to lack of quantitative report-ing and surveillance, and the difficulty of detectionin routine blood and urine analyses. Furthermore,street manufacturers are able to rapidly adapt anddevelop new synthetic isolates of older drugs as soonas law enforcement agencies render them illegal.

“Legal highs” are widely advertised in headshops and gas stations, and through the Internet.These agents are marketed as legal alternatives thatproduce similar effects as illicit drugs; however,many of these substances can cause severe or life-threatening adverse effects.1 The Synthetic DrugAbuse Prevention Act of 2012 was enacted to com-bat this issue, banning several of the most commonisolates of synthetic cannabinoids and cathinones.2

Recognition and treatment of new drugs ofabuse pose many challenges for health care pro-viders. Knowledge of general toxicology is key inrecognizing acute intoxication and overdose;however, typical toxidromes are not precipitatedby many of these agents. Furthermore, toxicitymay be difficult to diagnose because most newdesigner drugs are not detected with conventional

*Address for correspondence: Megan A. Rech, Depart-ment of Pharmacy Services, Loyola University Medical Cen-ter, 2160 S 1st Avenue, Maywood, IL 60153; e-mail:[email protected].� 2014 Pharmacotherapy Publications, Inc.

R E V I E W O F T H E R A P E U T I C S

drug testing. Therefore, the purpose of this articleis to describe the pharmacology, clinical andadverse effects, and reported literature on severalnew classes of drugs of abuse.

Epidemiology

An estimated 23.9 million Americans 12 yearsor older are current illicit drug users. TheNational Institute on Drug Abuse estimates thatoverall use of tobacco, alcohol, and illicit drugsresults in $600 billion annually in costs relatedto crime, health care, and lost work productiv-ity. Use of illicit drugs alone accounts for $193billion of the total. The illicit drugs routinelysurveyed include marijuana, hashish, cocaine,heroin, hallucinogens, inhalants, and prescrip-tion-type psychotherapeutics used nonmedically;many newer illicit drugs of abuse are not cur-rently tracked or reported, and thus it is difficultto capture the burden that new drugs of abuseplace on society.3

General Approach to Illicit Drug Users

Although intoxication with new drugs ofabuse may be difficult to diagnose and treat,treatment of these patients should beapproached similarly to that of other toxicologycases. General management should consist ofsupportive care combined with a detailed historyand physical examination that may be difficultto perform due to altered mental status. Themnemonic ABCDEFG can be used to guide clini-cians (Table 1). This approach combines basicemergency medical care (airway, breathing, andcirculation [ABC]) with specific toxicology man-agement, including decontamination (D) andenhanced elimination (E) methods, antidoteadministration (focused therapy [F]), and toxi-cologist or poison control center consultation(“get tox help” [G]).4 History should specificallyaddress type of ingestion, time of exposure,cumulative amount, and route of administration.Furthermore, evaluation of multiple drugs ofabuse, prescription opioid medications, andover-the-counter agents should be consideredbecause coingestion is common. Cliniciansshould be aware of the classic drug toxidromes(e.g., cholinergic, sympathomimetic, opioid) andtoxic vital signs (e.g., tachycardia, hyperthermia,hypotension) but should also realize the limita-tions due to confounding factors and atypicalpresentations with newer agents.4, 5 Many toxi-cologic ingestants can be treated with specific

antidotes. However, with the exception of theeffects of desomorphine and kratom potentiallybeing reversed by the l-opioid antagonist nalox-one, reversal agents have not been identified fornew drugs of abuse.Diagnosis of new drugs of abuse is also partic-

ularly challenging. Routine blood and urinescreening tests do not detect most of theseagents, although desomorphine is structurallysimilar to opioids and therefore may be detectedas such. Some new agents can be sent to labora-tories capable of mass spectrometry or gas orliquid chromatography for detection.6, 7 How-ever, clinical utility of these tests is limited dueto turnaround time and lack of a single test tocollectively detect all new drugs of abuse.8 Diag-nostic evaluation should include appropriate lab-oratory parameters including particular attentionto electrocardiogram and electrolyte abnormali-ties. An understanding of common drugs ofabuse in specific geographic locations may helpnarrow the differential diagnosis.

Synthetic Cathinones

Synthetic cathinones, commonly referred to as“bath salts,” are analogs of naturally occurringcathinones such as Catha edulis (khat). Khat isnative to Yemen and eastern Africa, where indig-enous people have been chewing the fresh leavesfor hundreds of years.9 Cathinone is the mainpsychoactive agent in khat, and it produces astimulant effect resulting in increased alertness,energy, and libido, and appetite suppression andeuphoria.10, 11 Although the World Health Orga-nization does not consider khat to be a seriouslyaddicting drug of abuse, chewing the agent hasbeen linked to peptic ulcers, myocardial infarc-tion, dilated cardiomyopathy, stroke, anddeath.7, 12

Synthetic cathinones were initially developedin the 1920s for therapeutic purposes, and inrecent years these agents have become drugs ofabuse.13 Widespread use began in Europe in theearly 1990s and then gained popularity in theUnited States, with at least 30 chemical com-pounds in existence and many street names(Table 2).7 Commercially available cathinonesinclude bupropion for smoking cessation anddepression, and diethylpropion for appetite sup-pression.7, 12 In 1993, cathinone was classifiedas a Schedule I controlled substance by the DrugEnforcement Agency (DEA).7 The SyntheticDrug Abuse Prevention Act of 2012 amendedthe Controlled Substances Act to make several

2 PHARMACOTHERAPY Volume **, Number **, 2014

cannabimimetic substances and hallucinogensSchedule I controlled substances.2 U.S. poisoncontrol centers began receiving calls related to“bath salts” in 2010, with a peak in volume inmid-2011.14 In 2011, 6137 exposures to syn-thetic cathinones were reported, followed by2691 exposures in 2012 and only 995 exposuresin 2013. This decrease should be interpretedwith caution because providers may havebecome more familiar with the treatment of syn-thetic cathinone abuse or overdose, and theymay be less likely to call poison control centersfor assistance.Low cost and inability to detect these agents

with conventional laboratory parameters makesthem particularly appealing to illicit drug users.Synthetic cathinones are sold in smoke shops,head shops, gas stations, and convenience stores,and on the Internet as bath salts, plant food,jewelry cleaner, research chemicals, and herbalextracts under many street names (Table 2).12

Chemically unrelated to Epsom salts or house-hold cleaning products, they are ambiguouslylabeled with the statement “not for human con-sumption.”1

Synthetic cathinones are available as white orlight brown powder, pills, or capsules.15 Dosesrange from a few milligrams to more than 1 g.12

The most common routes of administrationinclude nasal insufflation (“snorting”) and oralingestion; however, rectal, gingival, inhalation,

smoking, parenteral (intravenous and intramus-cular), “bombing” (wrapping powder in cigarettepaper and swallowing it), and “keying” (insuf-flating powder off the surface of a key) havebeen reported.7, 10, 12

The mechanism by which synthetic cathinonesexhibit an effect is similar to other stimulantsthrough functionally changing monoamine trans-porters through which the neurotransmittersserotonin, dopamine, and norepinephrine aretaken up from central synaptic clefts, resultingin increased postsynaptic neurotransmission.11

Each agent has variable effects and potency onserotonin, dopamine, and norepinephrine, andserum concentration does not predict toxicity.16

Advertised effects of synthetic cathinonesinclude euphoria, increased energy, openness,empathy, alertness, and increased libido.10 Dura-tion of action, dosing, and time of onset ofsymptoms vary with routes of administrationand purity of the product.7, 12 Users report theonset of psychoactive effects as between 10 and45 minutes and duration between 2 and4 hours, depending on route of administration.12

No published human data on the pharmacoki-netics and pharmacodynamics of the syntheticcathinones exist.10 Mephedrone is metabolizedvia phase I and II reactions involving varioushepatic cytochrome P450 (CYP) isoenzymesincluding CYP2C19, CYP2D6, and CYP1A2.6

The most common clinical findings reportedto poison centers include agitation, confusion,hallucinations, tachycardia, hypertension, mydri-asis, tremor, and fever. Additional serious effectsreported include rhabdomyolysis, electrolyteabnormalities, renal failure, seizures, anddeath.17 Exposure may precipitate a sympathom-imetic toxidrome including agitation, psychosis,hypertension, tachycardia, and seizures. Hyper-thermia, hyponatremia, and acute renal failurehave also been reported.12, 18 Aggressive violentbehavior, paranoia, and hallucinations are more

Table 1. General Management of Toxicology Cases

Pneumonic Management

A AirwayB BreathingC CirculationD DecontaminationE Enhanced eliminationF Focused therapy (antidote administration)G “Get tox help” (toxicologist or poison

control center consultation)

Table 2. Common Street Names and Active Compounds of New Drugs of Abuse

Drug of abuse Street names Active compounds

Syntheticcathinones9, 11

Khat, Bath salts, Meow meow, MCAT, Ivorywave Bubbles, Vanilla sky, Cloud 9,Explosion, White lightning

Methcathinone Ethylone, Mephedrone, MethedroneMethylenedioxypyrovalerone (MDPV)NaphyroneButylone 4-FluoromethcathinoneBrephedrone Pyrovalerone

Syntheticcannabinoids26

Spice (including variants such as Spice Gold,Spice Diamond, Spice Silver) K2, Krypton, AztecFire, Bombay Blue, Fake Weed, Yucatan Fire

JWH-015JWH-018JWH-073JWH-210CP-47,497CP-55,490HU-210

Salvia43 Diviner’s Sage, Mystic Sage, Sally D, Magic Mint Salvinorin AKratom51 Biak-biak, Ketum, Kahuam, Ithang, Thom MitragynineKrokodil67 Krokodil, Crocodile, Zoombie Drug Desomorphine

NEW DRUGS OF ABUSE Rech et al 3

frequently reported compared with ampheta-mines.10 Multiple case reports describe an“excited delirium” after using synthetic cathi-nones.11, 15 Other case reports have shown com-partment syndrome, suicide, and sudden cardiacdeath with synthetic cathinone use.19, 20 A phys-ical withdrawal syndrome occurs in cyclic bingeusers about 4 hours after the last dose is taken.Users have reported short periods of sleepiness,irritability, depression, and anxiety followed bysleep lasting days, increased appetite, andinsomnia lasting up to 2 weeks.21

Synthetic cathinones cannot be readilydetected with routine testing, and no correlationof concentration with clinical effects has beenreported.6 Exposure is a clinical diagnosis; there-fore, history and physical examination findingsare key.10 Synthetic cathinone intoxicationshould be suspected in a patient with acuteonset altered mental status, excited delirium,renal failure, and sympathomimetic symptoms.22

The management of intoxication is symptom-atic and supportive. Physical restraints should beused with caution.11 Parenteral benzodiazepinesmay be considered for treatment of agitation andmay also be beneficial for prevention or treat-ment of seizures or concomitant alcohol with-drawal. Alternative sedatives include propofol ordexmedetomidine.11 Antipsychotics includinghaloperidol may be used in severe cases but mayworsen hyperthermia.10 Hyperthermia can betreated with aggressive cooling techniques.Hypertonic saline and water restriction may beused for hyponatremia. Cardiac ischemia is trea-ted as it would be by any other cause exceptthat b-blockers should not be used.10

Synthetic Cannabinoids

Synthetic cannabinoids, first produced in1967, have been increasing in popularity overthe past decade.7 Initially used as a drug ofabuse in Europe in the mid-2000s, syntheticcannabinoids were identified in the United Statesin 2008.23 Similar to synthetic cathinones, theseproducts are widely accessible. They are fre-quently marketed as incense in foil packets bear-ing the words “not for human consumption”and may be inhaled, ingested, and injected.1

They produce similar psychotropic effects tomarijuana that contains the active componentD9-tetrahydrocannabinol (THC).24 However,synthetic cannabinoids are structurally unrelatedto THC and bind to cannabinoid receptorswith an affinity of up to 100–800 times that of

THC.7, 24 As a class, these agents are multiply-ing in number, with hundreds of compoundsand combinations already developed.7 The inci-dence of abuse of these novel compounds isincreasing every year,25 with abuse increasingthrough 2011 but decreasing in 2013 in adoles-cents.26 As of February 2014, 22 synthetic cann-abinoids have been placed under permanent ortemporary Schedule I status.2 Table 2 lists com-mon synthetic cannabinoid compounds andstreet names.Synthetic cannabinoids exhibit increased can-

nabinoid effects compared with THC due toincreased binding affinity, full receptor agonism,and active metabolites.1 Cannabinoid-1 (CB1)receptors are located in the peripheral and cen-tral nervous systems, specifically in the dorsalroot ganglion of the spine and cortical and sub-cortical regions of the brain.27 CB1 receptorsmodulate the neurotransmitters glutamate andc-aminobutyric acid.7 Cannabinoid-2 (CB2) recep-tors are expressed in immune tissue and thecentral nervous system, and they may affect painand emesis.28 Both CB1 and CB2 receptors areaffected by synthetic cannabinoids in varyingratios, with CB1 agonism producing a greaterpsychoactive effect. The paucity of informationon the chemical content of these agents maylead to an unpredictable effect based on CB1:CB2binding affinity. Similarly, little informationexists regarding their pharmacokinetics and tox-icokinetics. Onset and duration appear to besimilar to marijuana but vary based on the prod-uct ingested.28 In one study, participants whohad inhaled the cannabinoid receptor agonistJWH-018 had a detectable serum concentrationwithin 5 minutes of exposure, which thendecreased significantly over the next 3 hours.29

The participants subjectively reported the effectsto last between 6 and 12 hours. JWH-018 isthought to undergo CYP oxidation, glucuronida-tion, and subsequent renal elimination. Metabo-lites vary in activity on the CB1 receptor inparticular, potentially leading to unpredictableeffects.1, 30

Synthetic cannabinoid consumers are fre-quently marijuana users and may be drawn tothe reported similar psychotropic effectsincluding euphoria and alteration in mood andsensorium.7, 32 Adverse effects include anxiety,paranoia, sedation, hallucinations, psychosis,and seizures that may be more intense due tofull-receptor agonism and increased bindingaffinity.1, 31, 32 Of these, psychosis and anxietytend to be the most reported. Cardiovascular


symptoms may include tachycardia and hyper-tension, and, rarely, arrhythmias and myocardialinfarction.1, 7, 31, 33 Other adverse effectsinclude nausea, vomiting, and acute kidneyinjury.7, 33, 34 As such, synthetic cannabinoidsdo not fit a classically defined toxidrome.Long-term effects, addiction, and withdrawal

potential are difficult to characterize; however,parallels may be drawn from data on long-termmarijuana use. Long-term users may be atincreased risk for new-onset and relapse of psy-chosis and reduced brain volume and emotionalprocessing.23, 30 Furthermore, cognitive deficitsincluding decreased attention, verbal learning,and memory were reported with chronic mari-juana use.30, 36 In a review of 41 studies, anassociation was found between synthetic cannab-inoid use and the triggering of a psychotic eventin vulnerable patients.35 One case reportdescribed an apparent instance of withdrawal ina patient who inhaled the product “Spice Gold”daily over 8 months.37 The patient hadattempted abstinence previously and experiencedsweating, unrest, tremor, and gastrointestinalsymptoms. During admission to a hospital fordetoxification, the patient experienced drugcraving, nightmares, unrest, sweating, hyperten-sion, and headache. For treatment of thesesymptoms, the patient received clonidine, thehypnotic zopiclone, and promethazine.The largest age group of exposures to syn-

thetic cannabinoid occurs in adolescents, withup to 40% of users 19 years or younger.38 Acase series characterized adolescent users asmostly male (91%) with an average age of17.3 years.39 In this group of 11 youths at a hos-pital addiction treatment center, all reportedsubjective feelings of euphoria while intoxicated,with 9 (82%) reporting negative mood changes.All patients described memory impairment. Nolong-term effects of synthetic cannabinoids werereported.Care of the synthetic cannabinoids–intoxi-

cated patient is largely supportive.7, 28, 33, 39 Incases where a large quantity of ingestion is sus-pected, gastrointestinal decontamination may beconsidered. Benzodiazepines may play a role inthe treatment of seizures and psychomotor agita-tion; antipsychotics may alternatively be usedfor agitation.35, 39

Salvia

Salvia is a hallucinogen derived from the plantSalvia divornorum Lamiaceae, a member of the

mint family, native to Mexico, which has beenused in Mazatecan culture for centuries.7, 40 Inrecent years, increased use has been observed inthe United States. Touted as a legal alternativeto marijuana, the DEA is considering giving sal-via Schedule I classification, thus rendering itillegal.2 At least 20 states have implemented leg-islation placing regulatory controls on salvia.Common street names are listed in Table 2.Recently, salvia has become more readily

available to consumers due to distributionthrough head shops and the Internet. The Sub-stance Abuse and Mental Health Services Admin-istration annual survey of drug use in the UnitedStates showed that the overall rate of current illi-cit drug use in 2012 among persons aged12 years or older was 23.9 million (9.2% of theU.S. population). However, hallucinogens onlyaccounted for about 1 million (0.4%) of the pop-ulation.3

The mechanism through which Salvinorin A,the active plant component of salvia, causes hal-lucinations and altered sense of self differs fromother hallucinogens (lysergic acid diethylamide[LSD] and psilocybin [“magic mushrooms”])that are serotonin agonists. Salvia stimulatesj-opioid receptors, with little effect on l-opioidreceptors.41 One study exploring the dose-dependent effects of salvia demonstrated that therewarding effect was antagonized by pretreat-ment with a CB1 receptor antagonist and j-opi-oid antagonist, suggesting that salvia alsomodulates the endocannabinoid system.41

Salvinorin A can be absorbed buccally throughmanual chewing of salvia, or the leaves can becrushed to extract a liquid that can be ingestedor smoked. Oral ingestion, however, is limiteddue to first-pass metabolism and enzymatic deg-radation.42 A self-reported survey of 500 partici-pants showed that the preferred route ofadministration was smoking or vaporization(92.6%); the mean � SD duration of action wasreported to be 14.1 � 12.8 minutes.43 Aninhaled dose of only 200–500 lg produces anonset of effect within 30 seconds, and the degreeof hallucination was frequently described as“intense” by respondents.The potential harm and degree of dependence

from recreational salvia use is unclear. Chronicingestion in rats and mice did not demonstratecardiac abnormalities or histologic changes inseveral vital organs, suggesting the toxicity is rel-atively low.44 A retrospective review of 10 yearsof poison control data revealed only 37 cases ofsalvia use, all of which were intentional.40 Sixteen


(43%) of the 37 cases reported concomitant expo-sures to other psychoactive agents. The mostcommon symptoms recognized after isolated sal-via use were confusion or disorientation, halluci-nations, giddiness, dizziness, flushed sensation,and tachycardia. Vital sign abnormalities werepresent in only two patients (hypertension andtachycardia). Benzodiazepine administration foragitation was the most common therapeutic inter-vention reported. Several human case reportshave reported acute psychosis secondary to salviaexposure,45, 46 which may allude to its ability toexacerbate, precipitate, or unveil psychiatric dis-orders. Clinicians should consider salvia expo-sure in cases of acute psychosis refractory totraditional medical care.

Kratom

Kratom is a tropical tree with opioid-likeproperties native to Thailand, Malaysia, Indone-sia, Myanmar, and Papua New Guinea.47 Its bit-ter leaves are chewed to alleviatemusculoskeletal pain and to increase energy,appetite, and sexual desire.47, 48 It has been usedin the treatment of hypertension, diarrhea, andcough.49 Recently, it has gained increased recog-nition in Western countries as a “natural alterna-tive” for those who self-treat chronic pain and asa remedy for opioid withdrawal; reports of itsuse as an opiate substitute date back to 1836.50

Kratom is a nonprescription herbal medicationavailable on the Internet or in head shops. It issold as leaves, powder, extract, capsule, pellet,or gum, and it can be smoked, chewed, or con-sumed as a tea.47 It has been suggested as areplacement for methadone because it is afford-able, does not require physician supervision, anddoes not carry the stigma of methadone use.48

Many countries have banned or restrictedkratom use.47 The DEA has listed kratom as amedication with no legitimate medical use;however, it has not been assigned Schedule Istatus.47, 51, 52

Reports of kratom use are rising; however, thenumber of kratom exposures remains small inthe United States. It is difficult to establish theepidemiology because typical drug abuse metricsdo not exist. In 2013 a retrospective study of theTexas Poison Control Network Database revealedno kratom exposures between 1998 and 2008,two exposures in 2009, one in 2010, four in2012, and seven from January–September 2013.47

According to the System to Retrieve Informationfrom Drug Evidence and the National Forensic

Laboratory Information System, mitragynine—the primary active alkaloid in kratom—wasreported once in 2010, 44 times in 2011, and 81times in the first 6 months of 2012.52

Kratom contains more than 40 alkaloids thatinteract with opioid and monoaminergic recep-tors but is structurally distinct from opioids.49

Mitragynine is likely responsible for its opioid-like effects. Mitragynine is an agonist of multiplereceptors: the opioid receptors l, j, and D, aswell as adenosine-2a, postsynaptic a-2, dopa-mine-2s, and serotonin receptors. Its actionon a2-adrenergic agonists may mimic adjunc-tive therapies for opioid withdrawal such asclonidine.50

Onset of effect occurs 5–10 minutes afteringestion and duration is 2–5 hours. At low tomoderate doses (1–5 g), mild stimulant effectsinclude increased sociability, alertness, andenergy; moderate to heavy usage (5–15 g) pro-duces opioid-like effects.52, 53 Adverse effectsare similar to opioids including nausea, vomit-ing, constipation, respiratory depression, itching,sweating, dry mouth, increased urination, anor-exia, and palpitations. Neurologic effects includehallucinations, psychosis, seizures, and agita-tion.47

Serious toxicity is rare and usually involvesrelatively high doses (more than 15 g) or coin-gestants.50, 51 A 64-year-old man experiencedmultiple witnessed seizures requiring intubation30 minutes after ingesting a tea made with kra-tom and Datura stramonium.53 Datura, com-monly known as jimson weed, itself has rarelybeen associated with seizures. A 43-year-oldman experienced a generalized tonic-clonic sei-zure lasting 5 minutes after he combined kratomwith 100 mg of modafinil.50 This patient self-treated his opioid withdrawal with a tea madefrom kratom 4 times/day without significantadverse effects until he added modafinil in anattempt to improve alertness. Seizures and comawere reported in a 32-year-old man after kratomuse, although coingestants were not reported.54

Cases of jaundice and pruritus after massivechronic exposure to kratom (14–21 g/day for14 days)55 and severe primary hypothyroidism,potentially through reduction in the normalresponse of the thyroid gland to thyroid-stimu-lating hormone,56 have been reported.Fatalities typically involve coingestants. There

are several case reports of death resultingfrom “Krypton,” a powder mixture contain-ing mitragynine and O-desmethyltramadol, theactive metabolite of tramadol and a l-receptor


agonist.1,51, 57, 58 Autopsy examination revealedpulmonary edema in all cases, implying respira-tory depression as cause of death. Furthermore,a fatality resulted from the combined use of kra-tom and propylhexedrine, an a-agonist andamphetamine-like stimulant found in nasaldecongestant inhalers.59 Propylhexedrine, nick-named “stovetop speed,” is similar to modafiniland primarily abused intravenously. Autopsyfindings also showed pulmonary edema.Kratom has addiction potential; in animal

models, both mitragynine and 7-a-hydroxymi-tragynine produced a state of dependence whengiven for 5 days.60 Similar to opioids, individu-als build tolerance with heavy use. One userwho initially gained 4 hours of euphoria with asingle 4-g dose eventually built such a tolerancethat he needed 40 g/day in divided doses toavoid symptoms of withdrawal.61 Withdrawalhas been described as less intense but more pro-tracted than with prescription opioids; symp-toms may include abdominal pain, diarrhea,sweating, and irritability.50 Treatment parallelsopioid withdrawal, and patients may respond toopioid replacement therapy.1 There are a fewcase reports of supervised detoxification. Onedescribes the use of dihydrocodeine (an opioidagonist) 60 mg 4 times/day and lofexidine (ana-adrenergic antagonist) 0.2 mg twice/day, titrat-ing downward over 4 days.61 Buprenorphine/nal-oxone has been used as an opioidreplacement.50

Management of kratom overdose is similar tomanagement of opioid overdose. Although ani-mal literature provides conflicting results withrespect to the utility of naloxone in reversing itseffects, given its safety profile, naloxone shouldbe considered if acute kratom overdose withrespiratory depression is suspected.1, 62

Desomorphine

Desomorphine, better known as krokodil forthe skin lesions that plague its users, is an opi-oid analog that behaves pharmacologically simi-larly to heroin. First synthesized in the UnitedStates in 1932 as an alternative to mor-phine,63, 64 it has been used commercially inSwitzerland under the brand name Permonid.64

Its popularity in Russia and other Europeancountries as a less expensive alternative to her-oin has been increasing since it was firstreported in 2002.65 New reports of use in theUnited States including Missouri, Arizona, Utah,and Illinois have occurred.64

Desomorphine is a l-receptor agonist andsynthetic derivative of morphine.63, 65 Analge-sic effects are roughly 10 times that of morphineand therefore stronger than heroin.65 In an earlycomparison of desomorphine with morphine inpatients with cancer, a 1:10 dosing ratio of deso-morphine to morphine was used.66 At this dose,it was found to have a similar analgesic effect tomorphine and similar occurrence of nausea andvomiting. Desomorphine has a more rapid onsetof action (1–2 min) and shorter duration ofaction (1–2 hrs) than morphine, leading toincreased potential for addiction, abuse, andwithdrawal.65, 67 In 1936 the effects of desomor-phine withdrawal were observed in six patientswith terminal cancer.66 After 3 weeks of deso-morphine use, the patients experienced with-drawal symptoms if the drug was withheld for aslittle as 4 hours. Short duration of action indrug abusers results in a perpetual cycle ofacquiring supplies, preparing the drug, andadministering the drug.63 Desomorphine is syn-thesized in at-home laboratories through a pro-cess similar to that of methamphetamineproduction. It involves chemicals that are lowcost, readily available, and highly toxic. Minimallaboratory equipment is needed, and doses canbe made in less than an hour.63

The adverse effects of desomorphine itself aretypical of opioids.63 Due to variable chemicalcomposition and the high degree of contamina-tion of the final product, regular use results innear-immediate damage to vasculature, muscle,and bone, which may quickly progress to tissuenecrosis and gangrene at the injection site.63

The severity of skin necrosis and muscle break-down make way for a host of other systemicadverse effects including bacteremia, osteomyeli-tis, meningitis, speech and motor skill impair-ments, liver and kidney damage, venous ulcers,and skin eschars.63, 67 Due to these health con-cerns, average survival from first use of deso-morphine is reported to be 2 years.67

Very limited data exist regarding treatmentand management of patients who are addicted toor who acutely ingest large doses of desomor-phine. The only published case report of deso-morphine use in the United States is that of a30-year-old man admitted with pain, swelling,and ulceration of the thigh after use for the past6–7 months.65 He was noted to have painfulnecrotic ulcers on his thigh, and 2 monthsearlier, he had noticed swelling of his left littlefinger, which later turned black and autoampu-tated. The relationship between desomorphine


use and the patient’s necrotic events was suspi-cious but could not be confirmed.Due to the lack of scientific data, treatment of

desomorphine overdose and adverse effects lar-gely consists of supportive care, opioid antago-nism (naloxone administration), and precautionsfor opioid withdrawal. Although no publishedliterature exists on withdrawal, mixed opiate ag-onists/antagonists such as buprenorphine/nalox-one may be considered. Acute overdose shouldbe approached similarly to heroin overdose andinclude naloxone for reversal of opioid agonism.Abusers should be screened for communicablediseases including human immunodeficiencyvirus and hepatitis. Additionally, patients oftenrequire intensive psychiatric care, thoroughnutrition evaluations, and both physical and psy-chiatric rehabilitation.

Conclusion

Abuse of new designer drugs is a nationalproblem whose rate of development is outpacingthat of legislation. Clinicians should familiarizethemselves with management principles of thesenew agents. Medical management of patientswho abuse or overdose on these drugs largelyconsists of supportive care, although naloxonemay be used as an antidote for desomorphineoverdose. Symptoms of aggression and psychosismay be treated with sedation (benzodiazepines,propofol) and antipsychotics (haloperidol oratypical agents such as quetiapine or ziprasi-done). Other facets of management to considerinclude treatment for withdrawal or addiction,nutrition support, and potential for transmissionof infectious diseases.

Acknowledgment

The authors would like to acknowledge ChristinaHantsch Bardsley, MD, FACEP, FAACT, FACMT, forher help in developing the content of this article.

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