New Drugs of Abuse

Megan A. Rech,1,2* Elisabeth Donahey,1 Jacqueline M. Cappiello Dziedzic,2,3 Laura Oh,2,3 and
Elizabeth Greenhalgh1,4
1

Department of Pharmacy Services, Loyola University Medical Center, Maywood, Illinois; 2Department of
Emergency Medicine, Loyola University Medical Center, Maywood, Illinois; 3Stritch School of Medicine, Loyola
University Chicago, Maywood, Illinois; 4Marcella Niehoff School of Nursing, Loyola University Chicago,
Maywood, Illinois

Drug abuse is a common problem and growing concern in the United States, and over the past decade,
novel or atypical drugs have emerged and have become increasingly popular. Recognition and treatment of new drugs of abuse pose many challenges for health care providers due to lack of quantitative
reporting and routine surveillance, and the difficulty of detection in routine blood and urine analyses.
Furthermore, street manufacturers are able to rapidly adapt and develop new synthetic isolates of older
drugs as soon as law enforcement agencies render them illegal. In this article, we describe the clinical
and adverse effects and purported pharmacology of several new classes of drugs of abuse including
synthetic cannabinoids, synthetic cathinones, salvia, desomorphine, and kratom. Because many of these
substances can have severe or life-threatening adverse effects, knowledge of general toxicology is key
in recognizing acute intoxication and overdose; however, typical toxidromes (e.g., cholinergic, sympathomimetic, opioid, etc.) are not precipitated by many of these agents. Medical management of patients
who abuse or overdose on these drugs largely consists of supportive care, although naloxone may be
used as an antidote for desomorphine overdose. Symptoms of aggression and psychosis may be treated
with sedation (benzodiazepines, propofol) and antipsychotics (haloperidol or atypical agents such as
quetiapine or ziprasidone). Other facets of management to consider include treatment for withdrawal
or addiction, nutrition support, and potential for transmission of infectious diseases.
KEY WORDS synthetic cannabinoids, synthetic cathinones, salvia, desomorphine, kratom.
(Pharmacotherapy 2015;35(2):189197) doi: 10.1002/phar.1522

Drug abuse is a common problem and growing

concern in the United States, and over the past decade, novel or atypical drugs have emerged and
become increasingly popular. Staying current with
the new drugs of abuse can be challenging for health
care practitioners due to lack of quantitative reporting and surveillance, and the difficulty of detection
in routine blood and urine analyses. Furthermore,
street manufacturers are able to rapidly adapt and
develop new synthetic isolates of older drugs as soon
as law enforcement agencies render them illegal.
*Address for correspondence: Megan A. Rech, Department of Pharmacy Services, Loyola University Medical Center, 2160 S 1st Avenue, Maywood, IL 60153; e-mail:
mrech@lumc.edu.
2014 Pharmacotherapy Publications, Inc.

Legal highs are widely advertised in head

shops and gas stations, and through the Internet.
These agents are marketed as legal alternatives that
produce similar effects as illicit drugs; however,
many of these substances can cause severe or lifethreatening adverse effects.1 The Synthetic Drug
Abuse Prevention Act of 2012 was enacted to combat this issue, banning several of the most common
isolates of synthetic cannabinoids and cathinones.2
Recognition and treatment of new drugs of
abuse pose many challenges for health care providers. Knowledge of general toxicology is key in
recognizing acute intoxication and overdose;
however, typical toxidromes are not precipitated
by many of these agents. Furthermore, toxicity
may be difficult to diagnose because most new
designer drugs are not detected with conventional

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drug testing. Therefore, the purpose of this article

is to describe the pharmacology, clinical and
adverse effects, and reported literature on several
new classes of drugs of abuse.

An estimated 23.9 million Americans 12 years

or older are current illicit drug users. The
National Institute on Drug Abuse estimates that
overall use of tobacco, alcohol, and illicit drugs
results in $600 billion annually in costs related
to crime, health care, and lost work productivity. Use of illicit drugs alone accounts for $193
billion of the total. The illicit drugs routinely
surveyed include marijuana, hashish, cocaine,
heroin, hallucinogens, inhalants, and prescription-type psychotherapeutics used nonmedically;
many newer illicit drugs of abuse are not currently tracked or reported, and thus it is difficult
to capture the burden that new drugs of abuse
place on society.3

antidotes. However, with the exception of the

effects of desomorphine and kratom potentially
being reversed by the l-opioid antagonist naloxone, reversal agents have not been identified for
new drugs of abuse.
Diagnosis of new drugs of abuse is also particularly challenging. Routine blood and urine
screening tests do not detect most of these
agents, although desomorphine is structurally
similar to opioids and therefore may be detected
as such. Some new agents can be sent to laboratories capable of mass spectrometry or gas or
liquid chromatography for detection.6, 7 However, clinical utility of these tests is limited due
to turnaround time and lack of a single test to
collectively detect all new drugs of abuse.8 Diagnostic evaluation should include appropriate laboratory parameters including particular attention
to electrocardiogram and electrolyte abnormalities. An understanding of common drugs of
abuse in specific geographic locations may help
narrow the differential diagnosis.

General Approach to Illicit Drug Users

Synthetic Cathinones

Although intoxication with new drugs of

abuse may be difficult to diagnose and treat,
treatment of these patients should be
approached similarly to that of other toxicology
cases. General management should consist of
supportive care combined with a detailed history
and physical examination that may be difficult
to perform due to altered mental status. The
mnemonic ABCDEFG can be used to guide clinicians (Table 1). This approach combines basic
emergency medical care (airway, breathing, and
circulation [ABC]) with specific toxicology management, including decontamination (D) and
enhanced elimination (E) methods, antidote
administration (focused therapy [F]), and toxicologist or poison control center consultation
(get tox help [G]).4 History should specifically
address type of ingestion, time of exposure,
cumulative amount, and route of administration.
Furthermore, evaluation of multiple drugs of
abuse, prescription opioid medications, and
over-the-counter agents should be considered
because coingestion is common. Clinicians
should be aware of the classic drug toxidromes
(e.g., cholinergic, sympathomimetic, opioid) and
toxic vital signs (e.g., tachycardia, hyperthermia,
hypotension) but should also realize the limitations due to confounding factors and atypical
presentations with newer agents.4, 5 Many toxicologic ingestants can be treated with specific

Synthetic cathinones, commonly referred to as

bath salts, are analogs of naturally occurring
cathinones such as Catha edulis (khat). Khat is
native to Yemen and eastern Africa, where indigenous people have been chewing the fresh leaves
for hundreds of years.9 Cathinone is the main
psychoactive agent in khat, and it produces a
stimulant effect resulting in increased alertness,
energy, and libido, and appetite suppression and
euphoria.10, 11 Although the World Health Organization does not consider khat to be a seriously
addicting drug of abuse, chewing the agent has
been linked to peptic ulcers, myocardial infarction, dilated cardiomyopathy, stroke, and
death.7, 12
Synthetic cathinones were initially developed
in the 1920s for therapeutic purposes, and in
recent years these agents have become drugs of
abuse.13 Widespread use began in Europe in the
early 1990s and then gained popularity in the
United States, with at least 30 chemical compounds in existence and many street names
(Table 2).7 Commercially available cathinones
include bupropion for smoking cessation and
depression, and diethylpropion for appetite suppression.7, 12 In 1993, cathinone was classified
as a Schedule I controlled substance by the Drug
Enforcement Agency (DEA).7 The Synthetic
Drug Abuse Prevention Act of 2012 amended
the Controlled Substances Act to make several

Epidemiology

NEW DRUGS OF ABUSE Rech et al

Table 1. General Management of Toxicology Cases
Pneumonic

Management

A
B
C
D
E
F
G

Airway
Breathing
Circulation
Decontamination
Enhanced elimination
Focused therapy (antidote administration)
Get tox help (toxicologist or poison
control center consultation)

cannabimimetic substances and hallucinogens

Schedule I controlled substances.2 U.S. poison
control centers began receiving calls related to
bath salts in 2010, with a peak in volume in
mid-2011.14 In 2011, 6137 exposures to synthetic cathinones were reported, followed by
2691 exposures in 2012 and only 995 exposures
in 2013. This decrease should be interpreted
with caution because providers may have
become more familiar with the treatment of synthetic cathinone abuse or overdose, and they
may be less likely to call poison control centers
for assistance.
Low cost and inability to detect these agents
with conventional laboratory parameters makes
them particularly appealing to illicit drug users.
Synthetic cathinones are sold in smoke shops,
head shops, gas stations, and convenience stores,
and on the Internet as bath salts, plant food,
jewelry cleaner, research chemicals, and herbal
extracts under many street names (Table 2).12
Chemically unrelated to Epsom salts or household cleaning products, they are ambiguously
labeled with the statement not for human consumption.1
Synthetic cathinones are available as white or
light brown powder, pills, or capsules.15 Doses
range from a few milligrams to more than 1 g.12
The most common routes of administration
include nasal insufflation (snorting) and oral
ingestion; however, rectal, gingival, inhalation,

191

smoking, parenteral (intravenous and intramuscular), bombing (wrapping powder in cigarette

paper and swallowing it), and keying (insufflating powder off the surface of a key) have
been reported.7, 10, 12
The mechanism by which synthetic cathinones
exhibit an effect is similar to other stimulants
through functionally changing monoamine transporters through which the neurotransmitters
serotonin, dopamine, and norepinephrine are
taken up from central synaptic clefts, resulting
in increased postsynaptic neurotransmission.11
Each agent has variable effects and potency on
serotonin, dopamine, and norepinephrine, and
serum concentration does not predict toxicity.16
Advertised effects of synthetic cathinones
include euphoria, increased energy, openness,
empathy, alertness, and increased libido.10 Duration of action, dosing, and time of onset of
symptoms vary with routes of administration
and purity of the product.7, 12 Users report the
onset of psychoactive effects as between 10 and
45 minutes and duration between 2 and
4 hours, depending on route of administration.12
No published human data on the pharmacokinetics and pharmacodynamics of the synthetic
cathinones exist.10 Mephedrone is metabolized
via phase I and II reactions involving various
hepatic cytochrome P450 (CYP) isoenzymes
including CYP2C19, CYP2D6, and CYP1A2.6
The most common clinical findings reported
to poison centers include agitation, confusion,
hallucinations, tachycardia, hypertension, mydriasis, tremor, and fever. Additional serious effects
reported include rhabdomyolysis, electrolyte
abnormalities, renal failure, seizures, and
death.17 Exposure may precipitate a sympathomimetic toxidrome including agitation, psychosis,
hypertension, tachycardia, and seizures. Hyperthermia, hyponatremia, and acute renal failure
have also been reported.12, 18 Aggressive violent
behavior, paranoia, and hallucinations are more

Table 2. Common Street Names and Active Compounds of New Drugs of Abuse
Drug of abuse
Synthetic
cathinones9,

Street names
11

Synthetic
cannabinoids26
Salvia43
Kratom51
Krokodil67

Khat, Bath salts, Meow meow, MCAT, Ivory

wave Bubbles, Vanilla sky, Cloud 9,
Explosion, White lightning
Spice (including variants such as Spice Gold,
Spice Diamond, Spice Silver) K2, Krypton, Aztec
Fire, Bombay Blue, Fake Weed, Yucatan Fire
Diviners Sage, Mystic Sage, Sally D, Magic Mint
Biak-biak, Ketum, Kahuam, Ithang, Thom
Krokodil, Crocodile, Zoombie Drug

Active compounds
Methcathinone Ethylone, Mephedrone, Methedrone
Methylenedioxypyrovalerone (MDPV)
NaphyroneButylone 4-Fluoromethcathinone
Brephedrone Pyrovalerone
JWH-015JWH-018JWH-073JWH-210CP-47,497CP-55,
490HU-210
Salvinorin A
Mitragynine
Desomorphine

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frequently reported compared with amphetamines.10 Multiple case reports describe an

excited delirium after using synthetic cathinones.11, 15 Other case reports have shown compartment syndrome, suicide, and sudden cardiac
death with synthetic cathinone use.19, 20 A physical withdrawal syndrome occurs in cyclic binge
users about 4 hours after the last dose is taken.
Users have reported short periods of sleepiness,
irritability, depression, and anxiety followed by
sleep lasting days, increased appetite, and
insomnia lasting up to 2 weeks.21
Synthetic cathinones cannot be readily
detected with routine testing, and no correlation
of concentration with clinical effects has been
reported.6 Exposure is a clinical diagnosis; therefore, history and physical examination findings
are key.10 Synthetic cathinone intoxication
should be suspected in a patient with acute
onset altered mental status, excited delirium,
renal failure, and sympathomimetic symptoms.22
The management of intoxication is symptomatic and supportive. Physical restraints should be
used with caution.11 Parenteral benzodiazepines
may be considered for treatment of agitation and
may also be beneficial for prevention or treatment of seizures or concomitant alcohol withdrawal. Alternative sedatives include propofol or
dexmedetomidine.11 Antipsychotics including
haloperidol may be used in severe cases but may
worsen hyperthermia.10 Hyperthermia can be
treated with aggressive cooling techniques.
Hypertonic saline and water restriction may be
used for hyponatremia. Cardiac ischemia is treated as it would be by any other cause except
that b-blockers should not be used.10
Synthetic Cannabinoids
Synthetic cannabinoids, first produced in
1967, have been increasing in popularity over
the past decade.7 Initially used as a drug of
abuse in Europe in the mid-2000s, synthetic
cannabinoids were identified in the United States
in 2008.23 Similar to synthetic cathinones, these
products are widely accessible. They are frequently marketed as incense in foil packets bearing the words not for human consumption
and may be inhaled, ingested, and injected.1
They produce similar psychotropic effects to
marijuana that contains the active component
D9-tetrahydrocannabinol (THC).24 However,
synthetic cannabinoids are structurally unrelated
to THC and bind to cannabinoid receptors
with an affinity of up to 100800 times that of

THC.7, 24 As a class, these agents are multiplying in number, with hundreds of compounds
and combinations already developed.7 The incidence of abuse of these novel compounds is
increasing every year,25 with abuse increasing
through 2011 but decreasing in 2013 in adolescents.26 As of February 2014, 22 synthetic cannabinoids have been placed under permanent or
temporary Schedule I status.2 Table 2 lists common synthetic cannabinoid compounds and
street names.
Synthetic cannabinoids exhibit increased cannabinoid effects compared with THC due to
increased binding affinity, full receptor agonism,
and active metabolites.1 Cannabinoid-1 (CB1)
receptors are located in the peripheral and central nervous systems, specifically in the dorsal
root ganglion of the spine and cortical and subcortical regions of the brain.27 CB1 receptors
modulate the neurotransmitters glutamate and
c-aminobutyric acid.7 Cannabinoid-2 (CB2) receptors are expressed in immune tissue and the
central nervous system, and they may affect pain
and emesis.28 Both CB1 and CB2 receptors are
affected by synthetic cannabinoids in varying
ratios, with CB1 agonism producing a greater
psychoactive effect. The paucity of information
on the chemical content of these agents may
lead to an unpredictable effect based on CB1:CB2
binding affinity. Similarly, little information
exists regarding their pharmacokinetics and toxicokinetics. Onset and duration appear to be
similar to marijuana but vary based on the product ingested.28 In one study, participants who
had inhaled the cannabinoid receptor agonist
JWH-018 had a detectable serum concentration
within 5 minutes of exposure, which then
decreased significantly over the next 3 hours.29
The participants subjectively reported the effects
to last between 6 and 12 hours. JWH-018 is
thought to undergo CYP oxidation, glucuronidation, and subsequent renal elimination. Metabolites vary in activity on the CB1 receptor in
particular, potentially leading to unpredictable
effects.1, 30
Synthetic cannabinoid consumers are frequently marijuana users and may be drawn to
the reported similar psychotropic effects
including euphoria and alteration in mood and
sensorium.7, 32 Adverse effects include anxiety,
paranoia, sedation, hallucinations, psychosis,
and seizures that may be more intense due to
full-receptor agonism and increased binding
affinity.1, 31, 32 Of these, psychosis and anxiety
tend to be the most reported. Cardiovascular

NEW DRUGS OF ABUSE Rech et al

symptoms may include tachycardia and hypertension, and, rarely, arrhythmias and myocardial
infarction.1, 7, 31, 33 Other adverse effects
include nausea, vomiting, and acute kidney
injury.7, 33, 34 As such, synthetic cannabinoids
do 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-term
marijuana use. Long-term users may be at
increased risk for new-onset and relapse of psychosis and reduced brain volume and emotional
processing.23, 30 Furthermore, cognitive deficits
including decreased attention, verbal learning,
and memory were reported with chronic marijuana use.30, 36 In a review of 41 studies, an
association was found between synthetic cannabinoid use and the triggering of a psychotic event
in vulnerable patients.35 One case report
described an apparent instance of withdrawal in
a patient who inhaled the product Spice Gold
daily over 8 months.37 The patient had
attempted abstinence previously and experienced
sweating, unrest, tremor, and gastrointestinal
symptoms. During admission to a hospital for
detoxification, the patient experienced drug
craving, nightmares, unrest, sweating, hypertension, and headache. For treatment of these
symptoms, the patient received clonidine, the
hypnotic zopiclone, and promethazine.
The largest age group of exposures to synthetic cannabinoid occurs in adolescents, with
up to 40% of users 19 years or younger.38 A
case series characterized adolescent users as
mostly male (91%) with an average age of
17.3 years.39 In this group of 11 youths at a hospital addiction treatment center, all reported
subjective feelings of euphoria while intoxicated,
with 9 (82%) reporting negative mood changes.
All patients described memory impairment. No
long-term effects of synthetic cannabinoids were
reported.
Care of the synthetic cannabinoidsintoxicated patient is largely supportive.7, 28, 33, 39 In
cases where a large quantity of ingestion is suspected, gastrointestinal decontamination may be
considered. Benzodiazepines may play a role in
the treatment of seizures and psychomotor agitation; antipsychotics may alternatively be used
for agitation.35, 39
Salvia
Salvia is a hallucinogen derived from the plant
Salvia divornorum Lamiaceae, a member of the

193

mint family, native to Mexico, which has been

used in Mazatecan culture for centuries.7, 40 In
recent years, increased use has been observed in
the United States. Touted as a legal alternative
to marijuana, the DEA is considering giving salvia Schedule I classification, thus rendering it
illegal.2 At least 20 states have implemented legislation placing regulatory controls on salvia.
Common street names are listed in Table 2.
Recently, salvia has become more readily
available to consumers due to distribution
through head shops and the Internet. The Substance Abuse and Mental Health Services Administration annual survey of drug use in the United
States showed that the overall rate of current illicit drug use in 2012 among persons aged
12 years or older was 23.9 million (9.2% of the
U.S. population). However, hallucinogens only
accounted for about 1 million (0.4%) of the population.3
The mechanism through which Salvinorin A,
the active plant component of salvia, causes hallucinations and altered sense of self differs from
other hallucinogens (lysergic acid diethylamide
[LSD] and psilocybin [magic mushrooms])
that are serotonin agonists. Salvia stimulates
j-opioid receptors, with little effect on l-opioid
receptors.41 One study exploring the dosedependent effects of salvia demonstrated that the
rewarding effect was antagonized by pretreatment with a CB1 receptor antagonist and j-opioid antagonist, suggesting that salvia also
modulates the endocannabinoid system.41
Salvinorin A can be absorbed buccally through
manual chewing of salvia, or the leaves can be
crushed to extract a liquid that can be ingested
or smoked. Oral ingestion, however, is limited
due to first-pass metabolism and enzymatic degradation.42 A self-reported survey of 500 participants showed that the preferred route of
administration was smoking or vaporization
(92.6%); the mean  SD duration of action was
reported to be 14.1  12.8 minutes.43 An
inhaled dose of only 200500 lg produces an
onset of effect within 30 seconds, and the degree
of hallucination was frequently described as
intense by respondents.
The potential harm and degree of dependence
from recreational salvia use is unclear. Chronic
ingestion in rats and mice did not demonstrate
cardiac abnormalities or histologic changes in
several vital organs, suggesting the toxicity is relatively low.44 A retrospective review of 10 years
of poison control data revealed only 37 cases of
salvia use, all of which were intentional.40 Sixteen

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PHARMACOTHERAPY Volume 35, Number 2, 2015

(43%) of the 37 cases reported concomitant exposures to other psychoactive agents. The most
common symptoms recognized after isolated salvia use were confusion or disorientation, hallucinations, giddiness, dizziness, flushed sensation,
and tachycardia. Vital sign abnormalities were
present in only two patients (hypertension and
tachycardia). Benzodiazepine administration for
agitation was the most common therapeutic intervention reported. Several human case reports
have reported acute psychosis secondary to salvia
exposure,45, 46 which may allude to its ability to
exacerbate, precipitate, or unveil psychiatric disorders. Clinicians should consider salvia exposure in cases of acute psychosis refractory to
traditional medical care.
Kratom
Kratom is a tropical tree with opioid-like
properties native to Thailand, Malaysia, Indonesia, Myanmar, and Papua New Guinea.47 Its bitter
leaves
are
chewed
to
alleviate
musculoskeletal pain and to increase energy,
appetite, and sexual desire.47, 48 It has been used
in the treatment of hypertension, diarrhea, and
cough.49 Recently, it has gained increased recognition in Western countries as a natural alternative for those who self-treat chronic pain and as
a remedy for opioid withdrawal; reports of its
use as an opiate substitute date back to 1836.50
Kratom is a nonprescription herbal medication
available on the Internet or in head shops. It is
sold as leaves, powder, extract, capsule, pellet,
or gum, and it can be smoked, chewed, or consumed as a tea.47 It has been suggested as a
replacement for methadone because it is affordable, does not require physician supervision, and
does not carry the stigma of methadone use.48
Many countries have banned or restricted
kratom use.47 The DEA has listed kratom as a
medication with no legitimate medical use;
however, it has not been assigned Schedule I
status.47, 51, 52
Reports of kratom use are rising; however, the
number of kratom exposures remains small in
the United States. It is difficult to establish the
epidemiology because typical drug abuse metrics
do not exist. In 2013 a retrospective study of the
Texas Poison Control Network Database revealed
no kratom exposures between 1998 and 2008,
two exposures in 2009, one in 2010, four in
2012, and seven from JanuarySeptember 2013.47
According to the System to Retrieve Information
from Drug Evidence and the National Forensic

Laboratory Information System, mitragynine

the primary active alkaloid in kratomwas
reported once in 2010, 44 times in 2011, and 81
times in the first 6 months of 2012.52
Kratom contains more than 40 alkaloids that
interact with opioid and monoaminergic receptors but is structurally distinct from opioids.49
Mitragynine is likely responsible for its opioidlike effects. Mitragynine is an agonist of multiple
receptors: the opioid receptors l, j, and D, as
well as adenosine-2a, postsynaptic a-2, dopamine-2s, and serotonin receptors. Its action
on a2-adrenergic agonists may mimic adjunctive therapies for opioid withdrawal such as
clonidine.50
Onset of effect occurs 510 minutes after
ingestion and duration is 25 hours. At low to
moderate doses (15 g), mild stimulant effects
include increased sociability, alertness, and
energy; moderate to heavy usage (515 g) produces opioid-like effects.52, 53 Adverse effects
are similar to opioids including nausea, vomiting, constipation, respiratory depression, itching,
sweating, dry mouth, increased urination, anorexia, and palpitations. Neurologic effects include
hallucinations, psychosis, seizures, and agitation.47
Serious toxicity is rare and usually involves
relatively high doses (more than 15 g) or coingestants.50, 51 A 64-year-old man experienced
multiple witnessed seizures requiring intubation
30 minutes after ingesting a tea made with kratom and Datura stramonium.53 Datura, commonly known as jimson weed, itself has rarely
been associated with seizures. A 43-year-old
man experienced a generalized tonic-clonic seizure lasting 5 minutes after he combined kratom
with 100 mg of modafinil.50 This patient selftreated his opioid withdrawal with a tea made
from kratom 4 times/day without significant
adverse effects until he added modafinil in an
attempt to improve alertness. Seizures and coma
were reported in a 32-year-old man after kratom
use, although coingestants were not reported.54
Cases of jaundice and pruritus after massive
chronic exposure to kratom (1421 g/day for
14 days)55 and severe primary hypothyroidism,
potentially through reduction in the normal
response of the thyroid gland to thyroid-stimulating hormone,56 have been reported.
Fatalities typically involve coingestants. There
are several case reports of death resulting
from Krypton, a powder mixture containing mitragynine and O-desmethyltramadol, the
active metabolite of tramadol and a l-receptor

NEW DRUGS OF ABUSE Rech et al

agonist.1,51, 57, 58 Autopsy examination revealed
pulmonary edema in all cases, implying respiratory depression as cause of death. Furthermore,
a fatality resulted from the combined use of kratom and propylhexedrine, an a-agonist and
amphetamine-like stimulant found in nasal
decongestant inhalers.59 Propylhexedrine, nicknamed stovetop speed, is similar to modafinil
and primarily abused intravenously. Autopsy
findings also showed pulmonary edema.
Kratom has addiction potential; in animal
models, both mitragynine and 7-a-hydroxymitragynine produced a state of dependence when
given for 5 days.60 Similar to opioids, individuals build tolerance with heavy use. One user
who initially gained 4 hours of euphoria with a
single 4-g dose eventually built such a tolerance
that he needed 40 g/day in divided doses to
avoid symptoms of withdrawal.61 Withdrawal
has been described as less intense but more protracted than with prescription opioids; symptoms may include abdominal pain, diarrhea,
sweating, and irritability.50 Treatment parallels
opioid withdrawal, and patients may respond to
opioid replacement therapy.1 There are a few
case reports of supervised detoxification. One
describes the use of dihydrocodeine (an opioid
agonist) 60 mg 4 times/day and lofexidine (an
a-adrenergic antagonist) 0.2 mg twice/day, titrating downward over 4 days.61 Buprenorphine/naloxone has been used as an opioid
replacement.50
Management of kratom overdose is similar to
management of opioid overdose. Although animal literature provides conflicting results with
respect to the utility of naloxone in reversing its
effects, given its safety profile, naloxone should
be considered if acute kratom overdose with
respiratory depression is suspected.1, 62
Desomorphine
Desomorphine, better known as krokodil for
the skin lesions that plague its users, is an opioid analog that behaves pharmacologically similarly to heroin. First synthesized in the United
States in 1932 as an alternative to morphine,63, 64 it has been used commercially in
Switzerland under the brand name Permonid.64
Its popularity in Russia and other European
countries as a less expensive alternative to heroin has been increasing since it was first
reported in 2002.65 New reports of use in the
United States including Missouri, Arizona, Utah,
and Illinois have occurred.64

195

Desomorphine is a l-receptor agonist and

synthetic derivative of morphine.63, 65 Analgesic effects are roughly 10 times that of morphine
and therefore stronger than heroin.65 In an early
comparison of desomorphine with morphine in
patients with cancer, a 1:10 dosing ratio of desomorphine to morphine was used.66 At this dose,
it was found to have a similar analgesic effect to
morphine and similar occurrence of nausea and
vomiting. Desomorphine has a more rapid onset
of action (12 min) and shorter duration of
action (12 hrs) than morphine, leading to
increased potential for addiction, abuse, and
withdrawal.65, 67 In 1936 the effects of desomorphine withdrawal were observed in six patients
with terminal cancer.66 After 3 weeks of desomorphine use, the patients experienced withdrawal symptoms if the drug was withheld for as
little as 4 hours. Short duration of action in
drug abusers results in a perpetual cycle of
acquiring supplies, preparing the drug, and
administering the drug.63 Desomorphine is synthesized in at-home laboratories through a process similar to that of methamphetamine
production. It involves chemicals that are low
cost, readily available, and highly toxic. Minimal
laboratory equipment is needed, and doses can
be made in less than an hour.63
The adverse effects of desomorphine itself are
typical of opioids.63 Due to variable chemical
composition and the high degree of contamination of the final product, regular use results in
near-immediate damage to vasculature, muscle,
and bone, which may quickly progress to tissue
necrosis and gangrene at the injection site.63
The severity of skin necrosis and muscle breakdown make way for a host of other systemic
adverse effects including bacteremia, osteomyelitis, meningitis, speech and motor skill impairments, liver and kidney damage, venous ulcers,
and skin eschars.63, 67 Due to these health concerns, average survival from first use of desomorphine is reported to be 2 years.67
Very limited data exist regarding treatment
and management of patients who are addicted to
or who acutely ingest large doses of desomorphine. The only published case report of desomorphine use in the United States is that of a
30-year-old man admitted with pain, swelling,
and ulceration of the thigh after use for the past
67 months.65 He was noted to have painful
necrotic ulcers on his thigh, and 2 months
earlier, he had noticed swelling of his left little
finger, which later turned black and autoamputated. The relationship between desomorphine

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PHARMACOTHERAPY Volume 35, Number 2, 2015

use and the patients necrotic events was suspicious but could not be confirmed.
Due to the lack of scientific data, treatment of
desomorphine overdose and adverse effects largely consists of supportive care, opioid antagonism (naloxone administration), and precautions
for opioid withdrawal. Although no published
literature exists on withdrawal, mixed opiate agonists/antagonists such as buprenorphine/naloxone may be considered. Acute overdose should
be approached similarly to heroin overdose and
include naloxone for reversal of opioid agonism.
Abusers should be screened for communicable
diseases including human immunodeficiency
virus and hepatitis. Additionally, patients often
require intensive psychiatric care, thorough
nutrition evaluations, and both physical and psychiatric rehabilitation.

4.
5.
6.

7.
8.
9.
10.
11.

Conclusion
Abuse of new designer drugs is a national
problem whose rate of development is outpacing
that of legislation. Clinicians should familiarize
themselves with management principles of these
new agents. Medical management of patients
who abuse or overdose on these drugs largely
consists of supportive care, although naloxone
may be used as an antidote for desomorphine
overdose. Symptoms of aggression and psychosis
may be treated with sedation (benzodiazepines,
propofol) and antipsychotics (haloperidol or
atypical agents such as quetiapine or ziprasidone). Other facets of management to consider
include treatment for withdrawal or addiction,
nutrition support, and potential for transmission
of infectious diseases.
Acknowledgment
The authors would like to acknowledge Christina
Hantsch Bardsley, MD, FACEP, FAACT, FACMT, for
her help in developing the content of this article.

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