The n e w e ng l a n d j o u r na l of
case records of the massachusetts general hospital
From the Departments of Emergency
Medicine (T.I.B.), Psychiatry (S.H.N.), and
Pathology (J.G.F.), Massachusetts General
Hospital; and the Departments of Medi-
cine (T.I.B.), Psychiatry (S.H.N.), and Pa-
thology (J.G.F.), Harvard Medical School
— both in Boston.
N Engl J Med 2013;369:2536-45.
DOI: 10.1056/NEJMcpc1304051
Copyright © 2013 Massachusetts Medical Society.
2536
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m e dic i n e
Founded by Richard C. Cabot
Eric S. Rosenberg, m.d., Editor Nancy Lee Harris, m.d., Editor
Jo-Anne O. Shepard, m.d., Associate Editor Alice M. Cort, m.d., Associate Editor
Sally H. Ebeling, Assistant Editor Emily K. McDonald, Assistant Editor
Case 40-2013: A 36-Year-Old Man
with Agitation and Paranoia
Theodore I. Benzer, M.D., Ph.D., Shamim H. Nejad, M.D., and James G. Flood, Ph.D.
Pr e sen tat ion of C a se
Dr. David P. Curley (Emergency Medicine): A 36-year-old man with a history of alcohol
and substance abuse was admitted to this hospital because of severe agitation and
paranoia.
The patient’s girlfriend reported that the patient had been sober for approxi-
mately 20 months, until he lost his job. Three days before admission, he began
drinking alcohol and taking “bath salts” (psychoactive drugs) intranasally after
having had no sleep and minimal oral intake. The night before admission, increas-
ing agitation developed and was associated with apparent auditory and visual hal-
lucinations that people were trying to harm him. On the morning of admission,
shortly after snorting more bath salts, he ran outside unclothed, shouting that
someone was trying to strangle him. His girlfriend called the police, who found
him running naked in the street. When emergency medical services personnel ar-
rived, they found him restrained by police officers, combative, and confused, with
nonsensical, paranoid, and rambling speech. The pulse was 157 beats per minute,
with bounding radial pulses, and the respiratory rate was 24 breaths per minute.
The pupils were 5 mm in diameter. The skin was flushed, warm, and diaphoretic.
A capillary glucose level was 268 mg per deciliter (14.9 mmol per liter). Soft re-
straints were applied, and oxygen was administered through a nonrebreather face
mask. The patient was transported to the emergency department at this hospital.
En route, he suddenly became quiet, and a seizure was suspected. The administration
of midazolam was attempted, but the patient pulled out the intravenous catheter.
On arrival, the patient was unable to communicate. His history was obtained
from his girlfriend. He had a history of depression, alcohol abuse, and drug abuse
(including heroin, cocaine, and prescription opiates). His only medication was flu­
ox­etine, which he reportedly had not taken for 2 weeks. He was allergic to shell-
fish and had no known allergies to medications. He smoked cigarettes. He lived
with his girlfriend and had recently lost his job at a service station. He had a fam-
ily history of hypertension, coronary artery disease, and diabetes mellitus.
On examination, the patient was agitated, flailing his arms and legs, jerking
his head, and making loud incomprehensible sounds. He was unable to cooper-
ate during the examination and required restraining by several security officers.
n engl j med 369;26 nejm.org december 26, 2013
The New England Journal of Medicine
 case records of the massachuset ts gener al hospital
The temperature was 37.0°C, the blood pressure
157/67 mm Hg, the pulse 173 beats per minute,
the respiratory rate 28 breaths per minute, and
the oxygen saturation 97% while he was breath-
ing ambient air. The skin was diaphoretic. The
pupils were equal and reactive to light; the gaze
was deviated upward, with slow, horizontal ocu-
lar movements. The patient’s speech was rapid
and mostly unintelligible, but he made references
to attacking and being attacked by animals,
people, and monsters. The remainder of the ex-
amination was normal. The prothrombin time,
prothrombin-time international normalized ratio,
and results of liver-function tests were normal,
as were blood levels of calcium, total protein, al-
bumin, and globulin; other test results are shown
in Table 1. Urinalysis revealed clear, yellow urine
with a specific gravity greater than 1.030, a pH
of 5.5, 2+ occult blood, 1+ albumin, and trace
ketones by dipstick. There were 3 to 5 red cells,
10 to 20 white cells, few squamous cells, and
very few renal tubular cells per high-power field
and few bacteria and 3 to 5 hyaline and granu-
lar casts per low-power field; mucin was pres-
ent. Urinalysis was otherwise normal. The urine
creatinine level was 3.50 mg per milliliter.
The patient was restrained, and midazolam
was administered intravenously, followed by lo-
razepam, but his condition did not improve.
Etomidate and rocuronium were administered,
the trachea was intubated, and mechanical venti-
lation was begun, followed by sedation with pro­
pofol. A urinary catheter and an esophagogastric
tube were inserted. A chest radiograph showed
low lung volumes and the correct placement of
the endotracheal and gastric tubes; changes con-
sistent with pulmonary edema or pneumothorax
were not observed. A computed tomographic scan
of the head, obtained without the administration
of contrast material, showed no acute intracra-
nial hemorrhage, infarction, or mass lesion.
An electrocardiogram showed sinus rhythm
at a rate of 113 beats per minute, with inverted
T waves in the inferior leads and nonspecific
T-wave abnormalities in the lateral leads.
Fomepizole, sodium thiosulfate, sodium bicar-
bonate, normal saline, and potassium chloride
were administered intravenously, and the patient
was admitted to the intensive care unit. The pulse
fell to 92 beats per minute, and 290 ml of urine
was excreted.
A diagnostic test result was received.
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INI T I A L M A NAGEMEN T A ND
Differ en t i a l Di agnosis
Dr. Theodore I. Benzer: All the speakers are aware of
the diagnosis in this case. This patient arrived in
the emergency department with agitation, deliri-
um, abnormal vital signs, and reports that he
had taken a toxic substance.
The first priority in the emergency department
is to ensure the safety of the patient and caregivers.
It was necessary to immediately restrain this pa-
tient and sedate him, because he was at risk of
harming himself and the staff. The initial evalu-
ation must include a search for any toxin on the
patient’s body and clothing or any exhaled or
excreted toxin that could harm the emergency
department staff. He did not have any visible
solid or liquid substances on his body or any un-
usual odors. Once the patient was restrained, the
clinical staff had the challenge, common in emer-
gency medicine, of making important therapeutic
decisions with very little clinical information.
Initial Management
Physical restraints on an agitated patient may
cause injury to the caregiver who is applying the
restraints, as well as skin injury and rhabdomy-
olysis in the patient.
In view of the tachycardia and hypertension
that were present on prehospital evaluation, it
was appropriate to sedate this patient with a
parenteral benzodiazepine, which usually has a
mild effect on the blood pressure; any decrease
in respiratory effort can usually be managed
with supplemental oxygen and bag-mask ventila-
tion. In addition, benzodiazepines are useful for
seizure control and for treatment of patients
who have taken sympathomimetic drugs or who
have ethanol withdrawal. If moderate doses of
a benzodiazepine do not control the agitation,
the airway should be secured through endo­
tracheal intubation, as was done in this case, to
allow for the administration of higher doses of
sedatives that could cause respiratory depres-
sion and the loss of protective mechanisms in
the airway.1
Differential Diagnosis
The initial history, as described by the patient’s
girlfriend, indicated that the patient had taken a
toxic substance, and this report is consistent
with his presentation with agitated delirium and
2537
 The n e w e ng l a n d j o u r na l of m e dic i n e

elevated heart rate and blood pressure. However, Infectious Causes

it is important not to dismiss other causes; at Central nervous system infections need to be
this point in the evaluation, infectious and psy- considered and treated urgently in the emergency
chiatric causes were still possible. department. Given this patient’s altered mental

Table 1. Laboratory Data.*

Reference Range, On
Variable Adults† Presentation
Hematocrit (%) 41.0–53.0 (men) 53.1
Hemoglobin (g/dl) 13.5–17.5 (men) 16.4
White-cell count (per mm3) 4500–11,000 24,100
Differential count (%)
Neutrophils 40–70 57
Lymphocytes 22–44 37
Monocytes 4–11 4
Eosinophils 0–8 1
Basophils 0–3 1
Platelet count (per mm3) 150,000–400,000 497,000
Sodium (mmol/liter) 135–145 143
Potassium (mmol/liter) 3.4–4.8 4.4
Chloride (mmol/liter) 100–108 99
Carbon dioxide (mmol/liter) 23.0–31.9 7.4
Plasma anion gap (mmol/liter) 3–15 37
Urea nitrogen (mg/dl) 8–25 19
Creatinine (mg/dl) 0.60–1.50 1.96
Estimated glomerular filtration rate (ml/min/1.73 m2)‡ ≥60 39
Glucose (mg/dl) 70–110 173
Phosphorus (mg/dl) 2.6–4.5 7.3
Magnesium (mmol/liter) 0.7–1.0 1.5
Lactic acid (mmol/liter) 0.5–2.2 24.4
Creatine kinase (U/liter) 60–400 (men) 825
Creatine kinase MB isoenzymes (ng/ml) 0.0–6.9 8.4
Troponin T (ng/ml) <0.03 <0.01
Arterial blood gases
Fraction of inspired oxygen Unspecified
pH 7.35–7.45 7.18
Partial pressure of carbon dioxide (mm Hg) 35–42 36
Partial pressure of oxygen (mm Hg) 80–100 221
Base excess (mmol/liter) −14.1

* To convert the values for urea nitrogen to millimoles per liter, multiply by 0.357. To convert the values for creatinine to
micromoles per liter, multiply by 88.4. To convert the values for glucose to millimoles per liter, multiply by 0.05551. To
convert the values for phosphorus to millimoles per liter, multiply by 0.3229. To convert the values for magnesium to
milligrams per deciliter, divide by 0.4114. To convert the values for lactic acid to milligrams per deciliter, divide by 0.1110.
† Reference values are affected by many variables, including the patient population and the laboratory methods used. The
ranges used at Massachusetts General Hospital are for adults who are not pregnant and do not have medical conditions
that could affect the results. They may therefore not be appropriate for all patients.
‡ If the patient is black, multiply the result by 1.21.

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 case records of the massachuset ts gener al hospital

status, we need to consider meningitis and en- tremens). This patient had many features of a
cephalitis. In a young, healthy patient, it is un- withdrawal-related toxidrome, but nothing in his
likely that pneumonia or pyelonephritis would be history suggested he had sedative or ethanol with-
manifested by altered mental status, but pulmonary drawal, and there were no marked tremors.
aspiration caused by a toxic ingestion and vomit-
ing would be a concern. In this case, urinalysis and Anticholinergic Agents
chest radiography revealed no evidence of infec- Anticholinergic agents (e.g., atropine and its con-
tion and the results of brain imaging were normal. geners and cyclic antidepressants) can cause
altered mental status, tachycardia, mydriasis, acute
Psychiatric Causes urinary retention, decreased bowel sounds, and
Many patients who present to the emergency de- fever but do not cause diaphoresis. Patients who
partment have a history of drug abuse, but many have taken an overdose of anticholinergic agents
also have a history of psychiatric disease. This are said to be “dry as a bone, blind as a bat, red as
patient’s agitated delirium was more likely to a beet, hot as an oven, and mad as a hatter.” This
have a toxic or metabolic cause than a psychiatric patient had altered mental status but did not show
one. However, the history, reported by the girl- the other signs of anticholinergic-drug abuse.
friend, of increasing paranoia and auditory and
visual hallucinations raises concern about under- The Serotonin Syndrome and the Neuroleptic
lying psychoses. Psychiatric assessments would Malignant Syndrome
need to wait until the delirium had resolved. Patients who have taken large doses of seroto-
nergic medications can present with agitated
Toxidromes delirium, autonomic dysfunction (fever, tachy-
It frequently takes hours or days for the results of cardia, hypertension, and diaphoresis), and neu-
toxicologic studies to become available, and thus romuscular hyperactivity. This clinical presenta-
emergency department clinicians must determine tion is known as the serotonin syndrome. The
the initial treatment on the basis of the early clin- neuroleptic malignant syndrome is character-
ical signs and symptoms that were observed after ized by fever, muscular rigidity, altered mental
a toxic substance was taken. Clinical signs and status, and autonomic instability in patients
symptoms are organized into toxidromes accord- who recently have begun taking a prescribed
ing to drug class.2 In evaluating this patient’s neuroleptic medication or have had a dosage in-
condition, I have tried to match his clinical pre- crease. This patient presented with many of the
sentation to the most likely toxidrome. characteristics of the serotonin syndrome and
the neuroleptic malignant syndrome, but he
Sympathomimetic Agents does not have a clear recent history of taking
Patients who have taken amphetamines or co- serotonergic or neuroleptic substances. How­
caine commonly present with tachycardia, hyper- ever, drugs obtained on the street frequently
tension, anxiety, psychomotor agitation, diapho- contain unexpected substances, and so these
resis, and mydriasis, and such patients may have diagnoses cannot be dismissed.
psychotic, self-destructive behavior. Seizures can
occur. This patient’s presentation is consistent Anion-Gap Acidosis
with the use of a sympathomimetic drug. This patient presented with severe anion-gap
acidosis, which can be caused by many sub-
Sedative or Ethanol Withdrawal stances. During the initial evaluation, the clini-
Sedative or ethanol withdrawal is characterized by cal staff focused on two toxic substances that
agitated delirium and features associated with the the patient may have taken, cyanide and toxic
use of sympathomimetic agents. Marked tremors alcohol (methanol or ethylene glycol). Since
are usually seen in patients with sedative or etha- there are effective antidotes for these substanc-
nol withdrawal, and seizures are common early in es, and since the patient’s history was unclear,
the withdrawal process. In patients who have taken the team decided to presumptively treat him for
benzodiazepines, seizures can be severe and result both substances. The team administered sodi-
in status epilepticus. Visual hallucinations are the um thiosulfate, which reacts with cyanide to
hallmark of severe ethanol withdrawal (delirium form the nontoxic thiocyanate, and fomepizole

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 The n e w e ng l a n d j o u r na l of m e dic i n e

(4-methylpyrazole), an alcohol dehydrogenase as part of our routine screening for toxins; we

inhibitor that limits the toxic effects of metha- use liquid chromatography in combination with
nol and ethylene glycol. photodiode-array detection.4 This process uses
both chromatographic retention time and data
Bath Salts from various wavelengths in the ultraviolet spec-
The patient’s girlfriend indicated that the patient trum to identify unknown chromatographic peaks
had recently taken bath salts by nasal insuffla- in a patient’s blood sample. The conjugation of
tion. These bath salts are not sodium chloride the β-keto group with the phenyl moiety gives
bath salts or Epsom salts; rather, they are syn- cathinones a distinctly richer ultraviolet spectrum
thetic derivatives of cathinone, a sympathomi- than that of either methamphetamine or ephedrine
metic chemical found in the leaves of the khat (Fig. 1A). The addition or removal of alkyl groups
plant (Catha edulis). The use of bath salts is associ- at the carbon or nitrogen atoms of the propyl
ated with sympathomimetic activity and psychotic side chain does not substantially alter the ultra-
behavior (e.g., paranoia, hallucinations, and self- violet spectrum.5 However, the addition of alkyl
destructive and aggressive behavior). or alkoxy-type groups directly to the phenyl ring
The diagnostic test was screening of the blood notably changes the ultraviolet spectrum of the
and urine for toxins. resulting compound; such a change occurs in
MDMA and the designer cathinones methylone
and mephedrone (Fig. 1B). This patient’s blood
DR . THEOD OR E I. BENZER’S
DI AGNOSIS sample had a large chromatographic peak at
2.34 minutes, matching the retention time of au-
The use of a synthetic cathinone (bath salts), thentic standards of methcathinone and mephe­
causing a sympathomimetic toxidrome with psy- drone. The ultraviolet spectrum of the substance
chotic features, an acute lactic acidosis, and in the blood (Fig. 1D) matched that of methcathi-
rhabdomyolysis with renal failure. none but not that of mephedrone.
This patient’s most likely source of meth-
Pathol o gic a l Discussion cathinone was bath salts. An alternative source
results from the metabolism of N,N-dimethyl­
Dr. James G. Flood: The laboratory tests detected loraz- cathinone (Fig. 1C), another cathinone that is
epam, fluoxetine, norfluoxetine, and methcathi- known to be abused. We ruled out the latter
none in the patient’s blood. The blood tests were source because neither the blood sample nor the
negative for common stimulants, such as am- urine sample contained methylephedrine, the ma-
phetamine, methamphetamine, methylenedioxy­ jor metabolite of N,N-dimethylcathinone.6
methamphetamine (MDMA, or “ecstasy”), and co- It is possible that the laboratory misidentified
caine. Class-specific immunoassays of the urine as methcathinone another synthetic cathinone
were positive for amphetamines and benzodiaz- that did not undergo phenyl-ring substitution.
epines and negative for barbiturates, cocaine me- The addition of alkyl groups at the carbon or
tabolites, opiates, phencyclidine, and cannabinoids. nitrogen atoms of the propyl side chain (Fig. 1C)
The term “bath salts” refers to a diverse, ex- produces cathinones with an ultraviolet spectrum
panding group of synthetic designer drugs belong- very similar to that of methcathinone.5 If such a
ing to the cathinone class of sympatho­mimetic cathinone also had the same chromatographic
amines.3 Cathinones are closely related to other retention time as methcathinone, it would be
sympathomimetic amines, such as ampheta­mines easily misidentified as methcathinone. Of the
and ephedrine, differing only at the β-carbon of the 34 designer cathinones listed by Kelly,3 12 are
propyl side chain (Fig. 1A). At the β-carbon posi- likely to have ultraviolet spectra that would cause
tion, an absence of substitution is representative them to be mistaken for methcathinone. Tandem
of amphetamines, the presence of a ketone group mass spectrometry can differentiate between meth­
(known as β-keto) is characteristic of a cathinone, cathinone and methcathinone look-alikes but is
and the presence of a hydroxyl group is charac- not available 24 hours a day.
teristic of ephedrine. Methcathinone (ephedrone), The positive result on the urine test for am-
which was first synthesized in 1928, is the origi- phetamines is also directly attributable to the
nal designer drug derived from cathinone. use of methcathinone. When we assayed stan-
In our laboratory, methcathinone is detected dard d,l-methcathinone solutions using urinary

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 case records of the massachuset ts gener al hospital

A B Alkyl analogues 2 β
N CH3
3
αH

6 CH3
CH3 5
2 β
Mephedrone β= –C=O
Absorbance Units

Absorbance Units
N CH3
3
αH 3,4-methylenedioxyl analogues
2 β
4 6 CH3 O N CH3
αH
5 CH2
Methamphetamine β= –CH2 6 CH3
O
5
Methcathinone β= –C=O MDMA β= –CH2
Ephedrine β= –CHOH Methylone β= –C=O

210 360 210 360

Wavelength (nm) Wavelength (nm)

C D
NH2 Authentic methcathinone
Cathinone α

N 2.339
N,N-dimethylcathinone α
0.008

Internal standard, 9.794

Norfluoxetine, 5.126
0.006
Absorbance Units

220 260 300 340 nm

Fluoxetine, 6.841
NH
N-ethylcathinone α 0.004
0.002 Patient’s blood sample
NH
α
2.817

5.936
0.000
Buphedrone
−0.002
NH
α
Pentedrone 2.00 3.00 4.00 5.00 6.00 7.00 8.00 9.00 10.00 220 260 300 340 nm
Minutes

Figure 1. Chemical Structures and Diagnostic Features of Amines.

Panel A shows the chemical structures and ultraviolet spectra of three classes of sympathomimetic amines. Panel B shows the effect
that phenyl-ring substitution in designer amphetamines and cathinones can have on the ultraviolet spectra. Panel C shows the side-
chain substitutions that create designer cathinones that have ultraviolet spectra similar to the ultraviolet spectrum of methcathinone.
Panel D shows a chromatogram of the patient’s blood. The chromatogram was obtained with liquid chromatography and photodiode-
array detection and shows a large, unknown chromatographic peak at 2.339 minutes. The peak was later attributed to methcathinone
because the retention time matched that of authentic methcathinone and because the ultraviolet spectrum of the substance in the blood
(inset) matched the ultraviolet spectrum of methcathinone. On the basis of the ultraviolet spectrum, methcathinone (maximum ultra-
violet absorbance, 248 to 250 nm) is easily differentiated from mephedrone (maximum ultraviolent absorbance, 260 to 262 nm). MDMA
denotes methylenedioxymethamphetamine.

amphetamine reagents, we found that methcath-
inone concentrations of 80,000 ng per milliliter
and higher caused a positive test result for am-
phetamines (a methamphetamine solution at a
concentration of 1000 ng per milliliter is used to
calibrate the assay). This cross-reactivity is under-
standable given the similarity in structure of meth-
cathinone and methamphetamine (Fig. 1A), the
target analyte in the urine test for amphetamines.
The methcathinone metabolite ephedrine probably
also contributed to the observation of immuno-
reactive amphetamines in the patient’s urine.
We concluded that methcathinone is the major
finding in the patient’s blood sample that is in-
dicative of the use of bath salts. We also con-
cluded that methcathinone cross-reacted in this
hospital’s KIMS (kinetic interaction of micropar-
ticles in solution) urine immunoassay for amphet-
amines, contributing to a false positive result.
Discussion of M a nagemen t
Dr. Shamim H. Nejad: When this patient presented
to the emergency department, he showed marked
confusion, paranoia, agitation, and autonomic
dysfunction and required restraining by security
officers, physical restraints, the administration of
benzodiazepines, and eventually intubation with
mechanical ventilation. The incidence of cathinone
intoxication is unknown; however, in patients with

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 The n e w e ng l a n d j o u r na l
cathinone intoxication who have presented to
emergency departments, severe agitation, violent
behavior, hypertensive crisis, hyperthermia, sei-
zures, and death have all been observed.
Diagnosis of Cathinone-Induced Delirium
The diagnosis of cathinone-induced delirium can
be a challenge because most patients are unable
to provide a reliable history at the time of presen-
tation, and the routine drug screens that are per-
formed in most hospitals with the use of immu-
noassays do not readily detect these compounds.
If an acquaintance of the patient provides a pa-
tient history of recent bath salt use, as in this
case, specific testing can be requested, but the
results may not be received in time to inform im-
mediate treatment. As in this case, the use of
synthetic cathinones often leads to a false posi-
tive screening for amphetamines. Gas or liquid
chromatography with mass spectrometry is the
standard method for the detection of cathinones,
but this method is of limited clinical value be-
cause results can be delayed, and thus it is neces-
sary for caregivers to recognize the clinical toxi-
drome and manage it appropriately.
The clinical presentation of patients with cathi-
none-induced delirium is similar to the presenta-
tion of patients who have taken sympathomimetic
agents and consists of the acute onset of altered
mental status, agitated behavior, and autonomic
dysfunction, as well as severely violent behavior
(similar to the behavior observed with phencycli-
dine-induced or methamphetamine-induced psy-
chosis). In this patient, increasingly erratic behavior
developed along with paranoia (including delusions
of persecution), aggressive and violent psychomo-
tor activity requiring physical restraints, tachycar-
dia, and increased blood pressure. The core triad
of symptoms (sudden development of altered
mental status, agitated behavior, and autonomic
dysfunction) was first described by Bell in 1849 in
a study of psychiatric patients.7 Over the years, the
syndrome consisting of these three symptoms has
been referred to by many other names (e.g., Bell’s
mania, acute exhaustive mania, delirious mania,
lethal catatonia, agitated delirium, and excited
delirium), but it is most accurately categorized as
a subset of excitable malignant catatonia.7,8
Management of Cathinone-Induced Delirium
Once the diagnosis of cathinone-induced deliri-
um has been made or is suspected, the focus
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of m e dic i n e
should quickly turn to controlling the patient’s
agitated behavior in order to reduce the need for
physical struggle with security personnel or
physical restraints that may exacerbate injury,
hyperthermia, and metabolic acidosis. In patients
with cathinone-induced delirium, as in those
with malignant catatonia, initial sedation should
be achieved with the use of γ-aminobutyric acid
type A (GABAA) agonists such as benzodiazepines
or propofol. To minimize or prevent the worsen-
ing pyrexia and autonomic instability that occurs
with the use of dopamine antagonists in such pa-
tients, an agent such as intravenous haloperidol
should be administered judiciously and only after
therapy with GABAA agonists is initiated. Mono-
therapy with dopamine antagonists should be
avoided because it may exacerbate the catechol-
amine surge and hyperthermia that often occur
in patients with cathinone-induced delirium and
thus cause the development of the malignant
catatonia that is characteristic of the neuroleptic
malignant syndrome. On presentation, this pa-
tient was given midazolam and lorazepam and
had a limited response, and he was subsequently
intubated and sedated with propofol for the pur-
pose of further diagnostic evaluation and man-
agement.
After the patient’s agitation is under control,
attention is turned to minimizing or addressing
such medical complications as metabolic acidosis,
rhabdomyolysis, hyperthermia, and multisystem
failure. This patient received aggressive supportive
care, including the administration of intravenous
fluids, sodium thiosulfate for possible cyanide
poisoning, fomepizole for the possible ingestion of
ethylene glycol or methanol, and sodium bicarbon-
ate (by continuous infusion) for metabolic acidosis.
Once medical stability has been achieved, then
the focus should be on reversing the neurotrans-
mitter dysregulation induced by synthetic cathi-
nones. One of the challenges in treating cathi-
none-induced delirium is that there are multiple
synthetic cathinones available and each one has a
different receptor profile on the serotonergic,
dopaminergic, and noradrenergic systems (Fig. 2).
Methcathinone, the substance present in this case,
has particularly strong effects on the dopaminer-
gic and noradrenergic systems, as does metham-
phetamine; however, methcathinone has a much
weaker effect on the serotonergic system than
does methamphetamine.3
The treatment strategy after the patient was
 case records of the massachuset ts gener al hospital

A B

Figure 2. The Effects of Selected Drug Classes on the Neurotransmission of Monoamines.

The vesicular monoamine transporter 2 (VMAT2) is a membrane protein responsible for the sequestration of cytoplasmic monoamines
in synaptic vesicles. Monoamine transporters are integral plasma-membrane proteins that regulate the extracellular level of monoamine
neurotransmitters. Three major classes of monoamine transporters (serotonergic, dopaminergic, and noradrenergic) are responsible for the
COLOR FIGURE
reuptake of their associated neurotransmitters. Panel A shows the release of these neurotransmitters from vesicles and normal reuptake.
A neural
Draft impulse
3 leads to the fusion of vesicles with the neuronal membrane, thereby causing the release of monoamines into the syn-
12/05/13
aptic cleft
Author and resulting in the binding of monoamines to postsynaptic receptors. Extracellular monoamines are then moved by mono-
Benzer
Figamine
# transporters
2 back into the presynaptic terminal. Panel B shows the effects of such drugs as cocaine, amphetamines, methylphenidate,
and cathinones on the neurotransmission of monoamines. These drugs cause changes in the functional activity of monoamine transporters
Title
MEand VMAT2, generally resulting in an increased amount of monoamines in the cytosol and the synaptic cleft, which leads to increased
DEpostsynaptic activity. Different cathinone compounds have different affinities for monoamine classes and varying effects on VMAT2 activity
Artist SBL
that ultimately cause heterogeneous clinical symptoms, depending on the types of cathinone compounds present in the drug.
AUTHOR PLEASE NOTE:
Figure has been redrawn and type has been reset
Please check carefully

Issue date
transferred to the intensive care unit took into ac-
count the pathophysiology of cathinone-induced
delirium. The administration of midazolam and
propofol was quickly stopped, and dexmedeto-
midine, an α2-adrenergic agonist that can ame-
liorate excess noradrenergic activity, was begun.9
Low-dose haloperidol administered as a continu-
ous infusion to treat excess mesolimbic dopami-
nergic transmission was also initiated.10 To avoid
administering a dopamine antagonist alone after
dexmedetomidine had been discontinued, pheno­
barbital was administered because it targets
GABAA, α-amino-3-hydroxy-5-methyl-4-isoxazole
propionic acid (AMPA), and kainate receptors
and ultimately reduces neuroexcitability. The
administration of levocarnitine, which facilitates
the transport of long-chain free fatty acids across
the mitochondrial membrane and thus enhances
antioxidative protection, was also initiated.11
Dr. Eric S. Rosenberg (Pathology): Dr. Briant,

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 The n e w e ng l a n d j o u r na l
would you tell us about this patient’s hospital
course?
Dr. Judith A. Briant (Medicine): On arrival at the
intensive care unit, the patient was given propo-
fol and midazolam to maintain adequate seda-
tion. On the second day, he was transitioned
from propofol and midazolam to dexmedetomi-
dine and haloperidol administered intravenously
by continuous infusion. On the third day, he was
extubated but became agitated and had copious
oral secretions that necessitated reintubation
and resedation with intravenous propofol and
haloperidol by continuous infusion. On the
fourth day, the administration of phenobarbital
was begun. The patient was weaned off halo-
peridol and propofol, and on the seventh day, he
was successfully extubated. By the ninth day, he
was completely weaned off phenobarbital and
had returned to his baseline mental status.
The lactic acidosis resolved by the second day.
Acute renal failure developed owing to a combi-
nation of acute tubular necrosis and rhabdomy-
olysis; the peak creatine kinase level was 14,965 U
per liter, on the third day. The plasma creatinine
level peaked at 6.0 mg per deciliter (530 μmol per
liter) on the third day, but the patient maintained
sufficient urine output that renal-replacement
therapy was not required. The rhabdomyolysis
was treated with fluids. Acute liver injury also
developed; aspartate aminotransferase and ala-
nine aminotransferase levels peaked on the
third day at 1937 U per liter and 2309 U per liter,
respectively, but these levels returned to normal
with supportive care.
A ventilator-associated pneumonia due to
methicillin-sensitive Staphylococcus aureus devel-
oped and was treated with vancomycin and ce-
fepime for 8 days. On the seventh day, hyperten-
sion developed and required treatment with
intravenous nitroglycerin. The blood pressure
was controlled with oral labetalol, nifedipine,
and clonidine. On discharge, the patient was
referred to a new primary care physician, and he
agreed to see a mental health provider about his
substance abuse. He has not followed up with
caregivers at this hospital.
Dr. Benzer: Dr. Flood, how did you acquire au-
thentic methcathinone for your test standards?
Dr. Flood: The laboratory acquired authentic
methcathinone from Sigma-Aldrich in 1993, be-
fore it became a Schedule I drug (defined by the
2544 n engl j med 369;26 nejm.org december 26, 2013
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of m e dic i n e
Controlled Substances Act as a drug with a high
potential for abuse and a lack of medical value).
We acquired several more authentic standards in
2011 (including the most popular ones at the time,
which were mephedrone, 4-methylethcathinone
[4-MEC], methylone, and methylenedioxypyro­
valerone [MDPV]), but even with these authentic
standards, the laboratory can identify only 5 of
the 34 designer cathinones listed by Kelly.3
A Physician: One of the challenges the Drug
Enforcement Administration has faced in the
regulation of synthetic drugs is that the drugs are
always changing, and it is tough to stay informed
about the chemical structures of the drugs that
are being made. Is the entire class of cathinones
currently banned, or just methcathinone?
Dr. Flood: As of November 28, 2012, a total of
43 states and Puerto Rico had legislatively
banned substituted cathinones.12 With rare ex-
ceptions (e.g., bupropion), the entire cathinone
class is targeted for banning in the United States
and Europe.
Dr. Rosenberg: Dr. Flood, when were the results
of toxicologic testing available to the clinical
team?
Dr. Flood: The samples were collected just be-
fore 9 a.m. The results of the urine tests were
reported at 10:50 a.m., and the results of the
blood tests were reported at 1:25 p.m.
Dr. Nancy Lee Harris (Pathology): Where did the
term “bath salts” come from?
Dr. Curley: The name originated in the United
Kingdom. The drugs went from France to the
United Kingdom, and while they were being
used recreationally in the United Kingdom, they
became illegal. In order to get around the law,
dealers started marketing the drugs under a va-
riety of names, one of which was bath salts be-
cause the crystalline drugs resemble sodium
chloride bath salts.
PATHOL O GIC A L DI AGNOSIS
Methcathinone (bath salts) intoxication.
This case was discussed at the Medical Case Conference.
Dr. Benzer reports receiving payment for expert testimony on
behalf of physicians regarding alleged malpractice in delivering
emergency department care to patients. No other potential con-
flict of interest relevant to this article was reported.
Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.
We thank Dr. Andrew Lundquist (Medicine) for assistance in
organizing the conference.
 case records of the massachuset ts gener al hospital

References
1. Kao L, Moore GP, Jackimczyk K. The
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(http://www.justice.gov/dea/pr/microgram
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10. Young R, Glennon RA. Discriminative
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11. Alves E, Binienda Z, Carvalho F, et al.
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brain. Neuroscience 2009;158:514-23.
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tures. Substituted cathinones (a.k.a.
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justice/substituted-cathinones-enactments
.aspx).
Copyright © 2013 Massachusetts Medical Society.

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