Emerg Med Clin N Am 25 (2007) 499–525

Criminal Poisoning: Drug-Facilitated

Sexual Assault
Laura K. Bechtel, PhDa,
Christopher P. Holstege, MDb,*
a
Blue Ridge Poison Center, University of Virginia Health System,
P.O. Box 800744, Charlottesville, VA 22908-0774, USA
b
Division of Medical Toxicology, Department of Emergency Medicine,
University of Virginia, P.O. Box 800744, 1222 Jefferson Park Avenue,
4th Floor, Charlottesville, VA 22908-0774, USA

Sexual assault is defined as any undesired physical contact of a sexual

nature perpetrated against another person. Sexual assault is much broader
than the term rape, traditionally referred to as forced vaginal penetration
of a woman by a male assailant [1]. In 2003 to 2004 an average of
204,370 sexual assaults were reported to law-enforcement agencies in the
United States [2]. Because most sexual assaults are not reported, this na-
tional average is grossly underrepresented. The National Women’s Study
documented that 84% of women in their sample did not report their rapes
to the police [3]. Among United States college students, approximately 25%
of women reported experiencing completed or attempted rape [4]. In 2003,
approximately 9% of high school students reported having been forced to
have sexual intercourse [5]. Current estimates from available data indicate
that 1 in 6 women will be the victim of a sexual assault at least once in
her lifetime [6].
Drug-facilitated sexual assault (DFSA) is a complex and prevalent prob-
lem presenting to North American emergency departments (EDs) [7–10].
DFSA is defined as the use of a chemical agent to facilitate sexual assault.
The reported prevalence of DFSA varies. The US Department of Justice es-
timates 44% of sexual assaults are perceived to occur under the influence of
drugs or alcohol [2,11,12]. Often drugs and alcohol are used voluntarily by

* Corresponding author. Division of Medical Toxicology, Department of Emergency

Medicine, University of Virginia, P.O. Box 800744, 1222 Jefferson Park Avenue, 4th Floor,
Charlottesville, VA 22908-0774.
E-mail address: [email protected] (C.P. Holstege).

0733-8627/07/$ - see front matter Ó 2007 Elsevier Inc. All rights reserved.
doi:10.1016/j.emc.2007.02.008 emed.theclinics.com
500 BECHTEL & HOLSTEGE

the victim and offender [11]. One multicenter study estimates 4.3% of the
DFSAs examined were surreptitiously drugged victims and 35.4% of the
DFSAs involved voluntarily use of illicit drugs [10]. Because of the absence
of national scientific studies examining the prevalence of DFSAs in the
United States, the exact number of alcohol and illicit drug–related sexual
assaults is unknown. Yet an increasing number of independent testing pro-
grams are performing analyses on urine, blood, and hair samples collected
from individuals who claim to have been sexually assaulted and believe
that drugs were involved in the United Kingdom, France, and the United
States [8,10,13,14]. These reports are attributable to an increased awareness
of the problem and technological advances in rapid drug analyses.

Sexual assault victims and the emergency department

Identifying victims of DFSA and addressing specific medical and ulti-
mately legal issues are essential roles of the emergency health care provider.
When treating a victim of sexual assault, health care personnel have encoun-
tered numerous problems, such as not recognizing the urgency of medical
attention, not treating the patient as a victim, and failing to document all
available forensic evidence in a timely fashion. To help alleviate these prob-
lems, the Office for Victims of Crime (US Department of Justice) granted
funding for implementing Sexual Assault Nurse Examiner (SANE) pro-
grams. A SANE is a registered nurse who works closely with medical staff
and interacts with sexual assault crisis centers, law enforcement officers,
prosecutors, judges, forensic laboratory staff, and child protective services
workers to meet the multiple needs of victims and to hold offenders account-
able for their crimes [15,16].
Physicians may encounter unique circumstances when treating DFSA
victims because of potential delays when victims present for medical atten-
tion or not perceiving the patient as a sexual assault victim. The sedative-
hypnotic and amnesic properties of the drugs used to facilitate a sexual
assault can alter the victim’s behavior, increase the victim’s susceptibility
to sexual assault, and diminish recollection of events surrounding the sexual
assault. Often victims are reluctant to report incidents because of a sense of
embarrassment, guilt, perceived responsibility, or acquaintance to their
assaulter. Numerous reports have documented that the victims either do
not seek medical attention or delay seeking medical treatment for 3 to 7
days after the assault [17–23]. Extended delays in collecting specimens from
DFSAs may reduce the probability of detecting drugs potentially used to
facilitate a sexual assault. Most of the drugs typically used in the facilitation
of sexual assaults are rapidly absorbed and metabolized by the body, thereby
rendering them difficult to detect in routine urine and blood drug screenings.
The most commonly reported symptoms from victims of DFSA are con-
fusion, dizziness, drowsiness, impaired judgment, anterograde amnesia, lack
of muscle control, loss of consciousness, reduced inhibitions, nausea,
 CRIMINAL POISONING: DRUG-FACILITATED SEXUAL ASSAULT 501

Box 1. Common clinical effects reported by DFSA victims

Confusion
Dizziness
Anterograde amnesia
Impaired judgment
Reduced inhibitions
Drowsiness
Lack of muscle coordination
Loss of consciousness
Nausea
Vomiting
Hypotension
Bradycardia

hypotension, and bradycardia (Box 1). Victims of sexual assault may pres-
ent to the ED with physical injuries resulting from the assault or clinical ef-
fects of the drugs. For example, a victim may present to the ED with one or
a combination of the following: contusions, lacerations, broken bones,
altered metal status, or intoxication [24]. The health care team treats the
urgent injuries but may not inquire about the possibility of sexual assault.
They may mistake the clinical effects of the drug used on the victim for
self-induced substance abuse. Physicians should be aware that symptoms
mimicking alcohol toxicity may point to the possibility of a DFSA. SANEs
are trained in investigative interview techniques that may help a patient
recall specific events leading up to injuries caused by DFSA. Physicians
must recognize the need to provide prophylaxis against sexually transmitted
disease, assess female patients for pregnancy risk, or provide follow-up care
for medical and emotional needs. In addition, the emergency medical staff
must be aware of the necessity of collecting sensitive forensic evidence if
the victim decides to report the assault.

Forensic laboratory analyses

All reported sexual assault cases are tested for the abuser’s DNA using
a ‘‘rape kit.’’ Care must be taken to ensure chain of custody. Semen, blood,
urine, vaginal secretions, saliva, vaginal epithelial cells, hair, and other bio-
logic evidence may be identified and genetically typed by a crime laboratory
[23,25]. The information derived from the analysis can often help determine
whether sexual contact occurred, provide information regarding the circum-
stances of the incident, and be compared with reference samples collected
from patients and suspects. The most common form of DNA analysis
used in crime labs for identification is called polymerase chain reaction
(PCR). PCR allows the analysis of evidence samples of limited quality
502 BECHTEL & HOLSTEGE

and quantity by making millions of copies of very small amounts of DNA.

Using an advanced form of PCR testing called short tandem repeats (STR),
the laboratory is able to generate a DNA profile that can be compared with
DNA from a suspect or a crime scene [25].
Sexual assault cases suspected of involving alcohol or drugs should have
samples sent to the state Department of Forensics for toxicology testing. In
addition to DNA testing, collection of urine and blood for forensic analysis
at a state laboratory is typically performed to identify drugs used to facili-
tate sexual assault. Hair samples removed from the scalp may be requested
for drug analysis when there is a significant delay in reporting a DFSA.
Analysis of drugs present in hair can offer several advantages over urine
and blood specimens in specific cases. The window of drug detection may
be extended from days to weeks and even months because of the stability
of the drug once it is deposited [26]. Analysis of sequential hair segments
can provide a chronicle of drug use. Because the mechanisms by which drugs
are deposited in hair are not well understood, prosecution of sexual abuse
offenders based solely on results obtained from hair analysis is controversial
[27]. Several factors are known to contribute to the deposition of drugs in
hair: rate of hair growth, anatomic location of hair, thickness and color
(melanin content) of hair, and environmental contamination. Drugs in
hair are usually present in low concentrations (pg/mg to ng/mg); therefore,
sensitive laboratory methods are required for detection [28–30].
Samples must be collected under strict chain-of-custody guidelines. A
three-tier chain of testing may be used to analyze drugs used to facilitated
sexual assault at many state forensic laboratories nationwide (Fig. 1). The
first tier of testing quantitatively screens for ethanol from blood specimens
using a gas chromatography with flame-ionization detection (GC-FID) or
a gas chromatography linked to mass spectrometry detection (GC-MS).
The second tier quantitates drugs of abuse, such as amphetamines, barbitu-
rates, benzodiazepines, cannabinoids, cocaine, lysergic acid diethylamide,
opioids, g-hydroxybutyrate (GHB), chloral hydrate, and dextromethor-
phan, using immunoassays and fluorescent polarization assays. Con-
firmation assays are performed using GC-MS or high-pressure liquid
chromatography linked to tandem mass spectroscopy (HPLC-MS/MS)
analyses. The third tier of testing, focusing on basic amine drugs (BAD),
uses an extremely sensitive and specific means of screening (HPLC-MS/
MS) for analysis of a broad array of 300 to 400 amine-containing com-
pounds, such as tricyclic antidepressants and benzodiazepines, that may
not be detected using tier two methodologies. In many states, victims per-
ceived to be under the influence of alcohol and having a blood alcohol con-
centration greater than 0.08 are not typically analyzed beyond the level of
first tier ethanol testing without specific medical documentation suspecting
symptoms of additional drug exposure. Many DFS cases (other than alco-
hol) may therefore be undetected under the current screening protocols per-
formed at some state forensic laboratories. Several published reports
 CRIMINAL POISONING: DRUG-FACILITATED SEXUAL ASSAULT 503

Alcohol
<80%

DOA
34-45%

BAD
<8%

Alcohol DOA BS
<80%% 34-45% <8%

Fig. 1. Three-tier chain of testing for drug-facilitated sexual assault at state forensic laborato-
ries. Recent publications indicate up to 80% of victims of sexual assaults are under the influence
of alcohol; 34% to 45% of sexual assaults are under the influence of drugs of abuse; and less
than 8% are under the influence of other basic amine drugs.

document 34% to 45% of victims of sexual assault are under the influence of
drugs of abuse (DOA); 8% are under the influence of drugs not typically de-
tected by standard DOA methods (eg, BAD) [7,8,10,21,31]. It is important
for physicians and SANE teams to document suspicions of drugs in the pa-
tient’s medical record, especially in cases of sexual assault. Documentation
of these suspicions justifies drug-specific analyses by the state forensic labo-
ratory. These analytic results are mandatory for the prosecution of sexual
predators.
The Drug-Induced Rape Prevention and Punishment Act of 1996 (Public
Law 104-305) modified 21 U.S.C. x 841 to provide penalties of up to 20
years’ imprisonment and fines for people who intend to commit a crime
of violence (including rape) by distributing a controlled substance to
another individual without that individual’s knowledge. This act provides
specific definitions of controlled substances and crimes of violence that assist
prosecutors in maximizing the penalties against sexual predators. Controlled
substances are categorized as schedule I to V drugs by the US Drug Enforce-
ment Administration (DEA) (Box 2). Extensive efforts have focused on doc-
umenting detection limits for common drugs used to facilitate sexual assault
to aid in prosecution of sexual predators [10]. Without the extensive efforts
of medical staff, forensic toxicologists, police, and judicial officials these
penalties against sexual assault offenders cannot be implemented.
504 BECHTEL & HOLSTEGE

Box 2. Classification of scheduled drugs in the United States

Schedule I drugs
The substance has a high potential for abuse.
The substance has no currently accepted medical use in
treatment in the United States.
There is a lack of accepted safety for use of the substance under
medical supervision.
The drugs are not available by prescription and are deemed to
have no medical use.
Schedule II drugs
The substance has a high potential for abuse.
The substance has a currently accepted medical use in treatment
in the United States or a currently accepted medical use with
severe restrictions.
Abuse of the substances may lead to severe psychologic or
physical dependence.
The drugs or other substances are only available by prescription,
and distribution is carefully controlled and monitored by the
DEA.
Schedule III drugs
The substance has less potential for abuse than the drugs or
other substances in schedules I/II.
The substance has a currently accepted medical use in treatment
in the United States.
Abuse of the substance may lead to moderate or low physical
dependence or high psychologic dependence.
The drugs or other substances are available only by prescription,
although control of wholesale distribution is somewhat less
stringent than schedule II drugs.
Schedule IV drugs
The drug or other substance has a low potential for abuse relative
to the drugs or other substances in schedule III.
The drug or other substance has a currently accepted medical
use in treatment in the United States.
Abuse of the drug or other substance may lead to limited
physical dependence or psychologic dependence relative to
the drugs or other substances in schedule III.
The drugs are available only by prescription, although control of
wholesale distribution is somewhat less stringent than
schedule III drugs.
 CRIMINAL POISONING: DRUG-FACILITATED SEXUAL ASSAULT 505

Schedule V drugs
The drug or other substance has a low potential for abuse relative
to the drugs or other substances in schedule IV.
The drug or other substance has a currently accepted medical
use in treatment in the United States.
Abuse of the drug or other substance may lead to limited
physical dependence or psychologic dependence relative to
the drugs or other substances in schedule IV.
Schedule V drugs are sometimes available without
a prescription.

In addition to providing immediate, prophylactic, and follow-up medical

care to the sexual assault victim, physicians need to implement resources
necessary to maintain the integrity of physical evidence, document the vic-
tim’s examination results/interpretation and interview history, and serve
as an expert opinion during judicial proceedings. Integration of all these
events is necessary to assist a victim of DFSA and support the prosecution
of the sexual predator [11,32].

What drugs are used to facilitate sexual assault?

Most sexual assaults have been linked to the abuse of alcohol
[7,9,31,33,34]. It is commonly accepted that there is a high degree of corre-
lation between alcohol intoxication and the risk for being sexually assaulted
[10]. In recent years, however, there has been increased attention in the lit-
erature to people using other drugs to render their victims unconscious or
lower their level of resistance with the intent to sexually assault them
[14,20,35,36]. In addition to alcohol, the drugs most often implicated in
DFSAs are GHB, flunitrazepam, and ketamine, although others, including
other benzodiazepines and sedative-hypnotics, are used also (Box 3). These
drugs share similar characteristics for producing sedation, hypnosis, and an-
terograde amnesia. These effects often rapidly incapacitate victims and the
effects can be intensified when they are willingly or involuntarily taken
with alcohol. Because of the sedative and amnesic properties of these drugs,
victims often have no memory of an assault, only an awareness or sense that
they were violated.

Ethanol
The most common drug associated with DFSA is alcohol [7]. Because
most sexual assault cases are not reported, the percent of alcohol-associated
sexual assault cases varies greatly (30%–75%). Because of the prevalence of
506 BECHTEL & HOLSTEGE

Box 3. Drugs used to facilitate sexual assault

Ethanol
Chloral hydrate
Benzodiazepines
Nonbenzodiazepine sedative-hypnotics
GHB
Ketamine
Opioids
Dextromethorphan
Barbiturates
Anticholinergics
Antihistamines

alcohol consumption by college students, numerous institutions across the

United States offer health information programs focused on increasing the
awareness of alcohol-associated sexual assaults [37,38]. These programs
heighten awareness that alcohol is a drug often used to facilitate sexual
assault and they assist victims in finding medical and legal aid.

Clinical effects
The clinical effects of alcohol are dose and time dependent. Ethanol me-
tabolism follows zero-order kinetics. Although the rate of metabolism varies
from person to person, because of phenotypic differences in alcohol dehy-
drogenase and metabolic tolerance in chronic drinkers, the reported average
rate of metabolism is found to be constant (about 15 mL/dL/h) [39,40]. The
clinical effects of ethanol intoxication include impaired judgment, incoordi-
nation, behavioral changes, ataxia, cognitive slowing, memory impairment,
nausea, vomiting, diplopia, and lethargy. Depending on a person’s pre-exist-
ing tolerance, respiratory depression, coma, and death may occur at levels of
300 to 400 mg/dL. It takes little volume to intoxicate a person. For example,
to achieve levels of intoxication of 200 mg/dL requires consumption of
about 100 mL of absolute ethanol in a 70 kg adult. Many liquors contain
40% to 50% ethanol; therefore six to seven shots (30 mL per shot) of liquor
in rapid succession may result in an ethanol level of 200 mg/dL [41]. Sig-
nificantly lower concentrations of ethanol are required to incapacitate
(or increase the susceptibility for sexual assault in) a smaller-framed victim
or a person who voluntarily or unwillingly coingests drugs with sedative or
psychotropic effects.

Laboratory monitoring
Analysis of ethanol levels from urine and blood specimens are commonly
evaluated in many clinical laboratories, private laboratories, and state
 CRIMINAL POISONING: DRUG-FACILITATED SEXUAL ASSAULT 507

laboratories. Blood alcohol is determined using enzymatic analyses. Blood

alcohol and urine analysis confirmation is performed using a GC-FID or
gas GC-MS [42,43]. Although most clinical laboratories set the limit of de-
tection at 10 mg/dL, published reports document the limits of detection for
ethanol using GC-FID and GC-MS as low as 1 and 0.02 mg/dL, respectively
[40,42]. These sensitive detection assays may therefore extend the time (12–
24 hours) required for submitting specimens from sexual assault cases and
enhance the possibility of prosecuting a perpetrator for a DFSA crime.
Back-tracking calculations (15 mg/dL/h and one half-life every 4 h) are of-
ten performed to estimate the blood alcohol level at a given time before the
actual time the blood sample was taken. Caution must be used with this
method of reverse extrapolation, because chronic alcohol abusers and heavy
drinkers metabolize alcohol faster than social or naı̈ve drinkers [40].

Choral hydrate ‘‘Mickey Finn’’

Anecdotal reports of combining drugs and alcohol to assault victims date
back to the early nineteenth and twentieth centuries. An infamous example
is Mickey Finn, the proprietor of Chicago’s Lone Star Saloon in the late
nineteenth and early twentieth centuries. He was alleged to have drugged
his customers with the addition of chloral hydrate to their ethanol-based
beverages and subsequently robbed them.
Chloral hydrate is classified as a nonbarbiturate hypnotic. It is an inex-
pensive transparent crystalline compound that can be easily dissolved in
beverages. It was first synthesized in 1832 and was one of the original de-
pressants developed for the specific purpose of inducing sleep. At therapeu-
tic single doses, chloral hydrate has a rapid onset (30 minutes), produces
minimal side effects, and is useful in alleviating sleeplessness caused by
pain or insomnia in a relatively short time. The abuse and misuse of this
drug and subsequent introduction of newer sedatives (barbiturates and
benzodiazepines) led to its decline for medicinal purposes.

Clinical effects
The diagnosis of chloral hydrate can be difficult to differentiate from
alcohol, benzodiazepine, and barbiturate intoxication, because all share sim-
ilar clinical effects. Although the exact mechanism of action of chloral
hydrate has not been determined, it is a general central nervous system
(CNS) depressant having sedative effects with minimal analgesic effects
when administered independently. At low doses (!20 mg/kg) symptoms
may include relaxation, dizziness, slurred speech, confusion, disorientation,
euphoria, irritability, and hypersensitivity rash. At higher doses (O50 mg/
kg) chloral hydrate can cause hypotension, hypothermia, hypoventilation,
tachydysrhythmia, nausea, vomiting, diarrhea, headache, and amnesia
[44]. The elimination half-life (t1/2) of chloral hydrate is 4 to 12 hours
508 BECHTEL & HOLSTEGE

[44,45]. If coingested with alcohol, chloral hydrate metabolism may be seri-

ously impaired. Because ethanol and chloral hydrate are both metabolized
by CYP2E1 and alcohol dehydrogenase, coingestion may not only exacer-
bate their clinical effects but also prolong their duration of action [45,46].

Laboratory monitoring
Chloral hydrate is not detected on routine, commercially available drug
screens. Quantification of chloral hydrate and its metabolites trichloroethanol
(TCE), TCE-glucuronide, and trichloroacetic acid can be detected in less than
1 mL plasma using HPLC-MS/MS and capillary gas chromatography with
electron-capture detection (GC/ECD) [47–49]. Limit of detection for chloral
hydrate is 5 ng/mL and 10 ng/mL for its metabolites using GC/ECD [49].

Benzodiazepines
Benzodiazepines are a large class of drugs that bind to specific receptor
sites on g-aminobutyric acid (GABA)-mediated receptor synapses in the
brain. Benzodiazepines are believed to increase GABA-mediated chloride
conduction into the postsynaptic neuron, prolonging hyperpolarization of
the cell and diminishing synaptic transmission, thereby producing its seda-
tive properties. Drugs within this class vary in their affinity and efficacy at
their receptor. This variation results in differences in the degree of clinical
effects, time of onset, and rate of metabolism. Ultimately, with a faster
rate of onset there tends to be greater abuse potential [50]. Although na-
tional statistics are not available to estimate the prevalence of benzodiaze-
pines used to facilitate sexual assault, recent publications estimate
approximately 8% of sexual assault cases are positive for benzodiazepines
[7,8,10,28]. Flunitrazepam (Rohypnol) is the most frequently reported
(4% of sexual assault cases) date rape drug belonging to the benzodiazepine
class [7]. The high incidence of flunitrazepam in DFSA is partially attribut-
able to the development and implementation of specific toxicologic tests in
response to increased public awareness resulting in a testing bias
[7,9,32,51,52]. Other benzodiazepines that have been reported in sexual as-
sault victims are diazepam, triazolam, temazepam, tetrazepam, and clonaze-
pam [13,19,28,53,54].
Flunitrazepam is a fast-acting sedative-hypnotic and is categorized as
a schedule I drug in the United States. Because it is still licensed for use
in Europe, Asia, and Latin America for sedation and treatment of insomnia,
sexual predators can acquire this drug through illegal trafficking [55]. On the
street, flunitrazepam is known as Roofies, Forget pill, Rubies, Ruffies,
Rope, Roopies, Ropies, Rib, R-2, Roaches, Papas, Mexican Valium and
Circles. Sexual assault predators use flunitrazepam because it can be easily
dissolved into a beverage, it is relatively tasteless and odorless, it quickly in-
capacitates victims, and routine drug screens do not detect its presence.
 CRIMINAL POISONING: DRUG-FACILITATED SEXUAL ASSAULT 509

Clinical effects
Flunitrazepam is more potent than diazepam owing to its slower dissoci-
ation from the GABA receptor [56–58]. It is rapidly absorbed and distributed
into tissues on oral administration. The onset of its sedative, amnesic,
hypnotic, and disinhibitory effects can occur within 20 to 30 minutes [56].
Although the effects of flunitrazepam occur rapidly when used alone, it is
often coingested with alcohol, which amplifies its effects [59,60]. Initial
symptoms may consist of dizziness, disorientation, lack of coordination,
and slurred speech, which mimic alcohol intoxication. Other unique effects
are anterograde amnesia as early as 15 minutes after oral administration
[20]. Rapid alternation of hot and cold flashes may precipitously be followed
by loss of consciousness. Large doses (O2 g) have produced aspiration, mus-
cular hypotonia, hypotension, bradycardia, coma, and death [13,21,54,61].
The clinical diagnosis of flunitrazepam can be difficult to differentiate from
alcohol intoxication.

Laboratory monitoring
Patients who have a complaint of sexual assault who seem intoxicated or
have anterograde amnesia should be suspected of unknowingly ingesting
a benzodiazepine. Commonly marketed drug screens turn positive for
most benzodiazepines, but not all (ie, flunitrazepam; other benzodiazepines
marketed outside the United States). Point of care testing is available for
benzodiazepines in the ED, but clinical samples must be confirmed and
documented under strict chain-of-custody procedures [62]. In addition to
adhering to standard rape protocols, a urine or hair specimen should be an-
alyzed for benzodiazepine and their metabolites by a state forensic labora-
tory using GC-MS or HPLC-MS/MS [30,61,63–65]. Flunitrazepam
metabolites can be detected up to 60 hours in the urine using an automated
immunoassay system (EMIT II), categorized as a general toxicologic screen
that is available in many hospital laboratories. Flunitrazepam metabolites
can be detected and as early as 7 days in hair samples (HPLC-MS/MS) [54].

Nonbenzodiazepine hypnotics
Zopiclone, eszopiclone, zolpidem, and zaleplon belong to a new genera-
tion of sedative-hypnotics that are structurally different from benzodiaze-
pines (Fig. 2). Like benzodiazepines, these drugs modulate the GABAA
receptor chloride channel by binding to the benzodiazepine (BZ) receptors,
otherwise known as the omega (u1) receptors, in the brain [66] without bind-
ing to peripheral BZ receptors [67,68]. These drugs therefore have fewer
muscle-relaxant properties [68]. The rapid-onset and amnesic properties of
this class of drugs can result in disinhibition, passivity, and retrograde am-
nesia, making it a favored DFSA drug. These drugs require only a low dose
510 BECHTEL & HOLSTEGE

Non-benzodiazepine hypnotics:

Zolpidem (Ambien) Eszopiclone (Lunesta) Zaleplon (Sonata)

Benzodiazepine structure:
N C A = benzene ring
A B
C B = 7-membered diazepine ring
R7 C N

C = 5-aryl substituent ring

C
R2’

Fig. 2. Structural similarities between benzodiazepine and nonbenzodiazepine sedative-hyp-

notics. The nonbenzodiazepine hypnotics share a common pyrimidine ring (boxed) structure
containing various chemical side groups. Members of the benzodiazepine class share common
structural features: (A) benzene ring; (B) 7-membered diazepine ring; (C) 5-aryl substituent ring.

to cause an effect and are rapidly metabolized. Because of the amnesic prop-
erties of these drugs, victims are often confused following the event and may
be delayed in reporting the sexual assault [7]. Commonly used drug screens
do not test for these substances; therefore, suspected amnestic drug use must
be documented to justify more elaborate drug testing by state agencies. All
these characteristics make these drugs potential agents in DFSA.
Recognition of these new-generation sleep aids as potential agents used in
facilitating sexual assault has only recently been reported in the United
States, United Kingdom, and France [7,8,21,69,70]. Few published reports
in the United States tested sexual assault victims for the presence of zolpi-
dem, and unfortunately those that tested did not report its prevalence rate
[61,71]. Because of the increased prevalence of short-acting nonbarbiturate
use on college campuses and across the United States and minimal data es-
timating the prevalence of these drugs used in sexual assault, there is a strong
demand for national systematic studies to estimate the prevalence of non-
barbiturate sleep aids in DFSA.
Most of the nonbenzodiazepine sleep aids are available through a pre-
scription as a schedule IV drug and are readily available in North American
social circles (ie, college campuses). These highly prescribed insomnia drugs
are available in a tablet form that may be crushed and dissolved into
 CRIMINAL POISONING: DRUG-FACILITATED SEXUAL ASSAULT 511

a beverage or food of an unsuspecting victim. All may produce additive

CNS-depressant effects when coadministered with other psychotropic med-
ications, such as anticonvulsants, antihistamines, ethanol, and other drugs
that themselves produce CNS depression.

Clinical effects and drug characteristics

Zolpidem
Zolpidem is available as an immediate- or extended-release tablet. An
average oral dose of 10 to 15 mg has a rapid onset of clinical symptoms
between 10 and 30 minutes. Clinical effects peak at approximately 1.5 hours
for immediate release, duration lasts for about 6 to 8 hours for both imme-
diate- and extended-release preparations, and the t1/2 is approximately 2.5
hours [72]. Clinical effects may include dizziness, psychomotor, confusion,
nervousness, amnesia, and hallucinations. There is evidence of minimal re-
spiratory depression when used as a single agent, but zolpidem may produce
additive CNS-depressive effects and death when coadministered with other
sedatives [73].

Zaleplon
Zaleplon is available as an immediate-release tablet or capsule. An aver-
age oral dose of 10 to 15 mg has a rapid onset of clinical symptoms of ap-
proximately 10 to 30 minutes. Although the t1/2 for zaleplon is about 1 hour,
the duration of clinical effects may persist for greater than 6 hours. This per-
sistence may be because of the higher affinity of zaleplon for specific a2 and
a3 subunits of the GABA receptor, unlike zolpidem or zopiclone [74]. Clin-
ical effects may include somnolence, dizziness, psychomotor, confusion, ner-
vousness, rebound amnesia, and hallucinations. Higher doses (O40–60 mg)
may cause increased CNS effects and impaired motor skills [44].

Eszopiclone
The precise mechanism of action of eszopiclone is unknown, but its effect
is believed to result from its interaction with GABA-receptor complexes at
binding domains located close to or allosterically coupled to benzodiazepine
receptors. An average dose of 2 to 3 mg has a rapid onset of clinical
symptoms occurring in approximately 30 minutes. Both immediate and
extended-release forms are available. Clinical effects may include dizziness,
psychomotor dysfunction, confusion, nervousness, amnesia, and halluci-
nations. Nausea, vomiting, and anticholinergic effects have been reported
in less than 10% of patients [75]. By itself, eszopiclone has not been reported
to cause respiratory depression, but it may produce additive CNS-depres-
sant effects when coadministered with other sedatives. The clinical effects
of eszopiclone are longer in duration compared with zopiclone or zolpidem,
with a t1/2 of 6 hours [67].
512 BECHTEL & HOLSTEGE

Zopiclone
Zopiclone is not currently available in the United States. It is the racemic
mixture of two stereoisomers; the active stereoisomer is eszopiclone. Clinical
effects therefore are similar to eszopiclone.

Laboratory analysis
Because of the amnesic properties of these drugs, victims often may not
report the sexual assault for several days. Sensitive analytic techniques are
necessary to detect these drugs and their metabolites in urine or hair samples
after a single dose. Unfortunately, the drug screens found in most hospital
laboratories do not detect the new generation short-acting class of sleep aids
called nonbenzodiazepine hypnotics. Although numerous private facilities
are now capable of detecting nonbenzodiazepine drugs, most state forensic
laboratories integrate these HPLC-MS/MS amine-detection tests into their
repertoire of available toxicologic screens. Because testing of nonbenzodia-
zepine drugs is a third tier of testing in many state forensic laboratories, only
cases containing documentation suspecting drugs other than alcohol or
common drugs of abuse may be analyzed in this manner.

g-hydroxybutyrate, 1,4-butanediol, and g-butyrolactone

Since March 2000, GHB and the synthetic precursor compounds, 1,4-bu-
tanediol (1,4-BD) or g-butyrolactone (GBL), have been schedule I agents in
the United States. The availability of GHB has been restricted in numerous
countries, such as Australia, Brunei, Canada, Finland, France, Italy, Japan,
New Zealand, Norway, the United States, South Africa, Sweden, Switzer-
land, and the United Kingdom. GHB can be illegally purchased as an odor-
less and colorless liquid form or an off-white powder that easily dissolves in
liquids. GHB is sold on the street under various names, including Liquid
ecstasy, Liquid X, Liquid E, Gib, Natural sleep-500, Somatomax, Georgia
home boy, Grievous bodily harm, Soap, Scoop, Easy lay, Salty water, G-rif-
fick, Cherry menth, and Organic Quaalude.
Sexual assault perpetrators have used GHB as a fast and effective means
of intoxication for their victims. Although national statistics are not avail-
able to estimate the prevalence of GHB used to facilitate sexual assault, re-
cent publications estimate approximately 4% of alleged sexual assault cases
in the United States are positive for GHB [7,9,21,76]. Numerous GHB-
related DFSA cases have also been published in the United Kingdom and
France [21,70,77,78]. Sexual assault cases report victims have either
voluntarily or unwillingly ingested GHB on a date, at social parties, or in
‘‘rave’’ dance party settings.
GHB is a naturally occurring substance produced in the brain. GHB is
reversibly metabolized to GABA through multiple endogenous enzymes
(Fig. 3) [79–81]. Illicit consumption of GHB, or the synthetic GHB
 CRIMINAL POISONING: DRUG-FACILITATED SEXUAL ASSAULT 513

O O O
H2N
OH 5
OH OH
H2N
Glutamate GABA

7 Succinic
Succinic acid
KREB cycle semialdehyde

3 4
Potential Drugs of Abuse

O
O
1
GBL O
HO
OH
GHB
2
HO
OH
1,4-BD

Fig. 3. GHB metabolism. In the brain, g-hydroxybutyrate (GHB) is reversibly metabolized into
g-aminobutyric acid (GABA) using the endogenous enzyme GABA transaminase. Illicit con-
sumption of 1,4-butanediol (1,4-BD) or g-butyrolactone (GBL) may also be metabolized into
GABA by way of multiple endogenous enzyme systems. The endogenous metabolic enzymes
involved are (1) lactonase, or nonenzymatic ester hydrolysis; (2) alcohol dehydrogenase or
aldehyde dehydrogenase; (3) GHB dehydrogenase; (4) succinic semialdehyde reductase or
NADPH-dependent aldehyde reductase; (5) glutamic acid decarboxylase; (6) GABA transami-
nase; (7) succinic semialdehyde dehydrogenase. Potential drugs of abuse are boxed and in bold.

precursor compounds 1,4-BD or GBL, promotes GABA activity [81]. In ad-

dition to increased metabolism to GABA, GHB has direct effects on the
CNS by binding GHB-specific receptors. Animal studies support the exis-
tence of distinct GHB receptors in the CNS, because GHB can still act as
a neuromodulator even in the presence of the GABAB-specific inhibitor ba-
clofen and in GABAB receptor knockout mice [82–84]. GHB is suggested to
increase dopamine levels in the substantia nigra, potentiate the endogenous
opioid system, and mediate GABA transmission [81].
GHB, 1,4-BD, and GBL are frequently sold on the street and at rave
dance parties in liquid form and are colorless and tasteless. These drugs
can be easily masked in drinks and consumed by willing or unwilling victims
of sexual assault.

Clinical effects
Onset of GHB effects occurs in approximately 15 to 30 minutes, depend-
ing on the dose (average 1–5 g) and chemical purity. Clinical effects are
514 BECHTEL & HOLSTEGE

augmented in the presence of coadministered drugs, such as alcohol and

other sedative drugs [85]. The clinical effects are dose dependent and typi-
cally last 3 to 6 hours. Initial symptoms include drowsiness, disorientation,
and dizziness. Low dose (!1 g) produces mild symptoms, such as CNS de-
pression, amnesia, hypotonia, and reduced inhibitions (similar to alcohol).
Larger doses, 1 to 2 g, cause increased somnolence, drowsiness, dizziness,
bradycardia, and bradypnea. High doses (O2 g) often interfere with motor
coordination and balance, induce significant respiratory depression and bra-
dypnea, Cheyne-Stokes respiration, nausea, vomiting, diminished cardiac
output, coma, and death [73,86,87].

Laboratory monitoring
GHB is metabolized quickly (t1/2w30 minutes) and is not detected on
most routine urine and serum toxicology screens. Several state and private
laboratories have the ability to perform analyses on blood, urine, and hair
samples using GC-FID or GC-MS [30,76,88]. Testing sensitivity is not the
primary issue with GHB; timely collection of sample collection is. Because
of its rapid metabolism, plasma samples should be collected less than 6 to
8 hours after ingestion and urine samples collected in less than 10 to 12
hours. Urine and plasma may exhibit endogenous levels of GHB within 8
to 12 hours after ingestion (!1 mg/dL in urine, !4 mg/L in blood/plasma)
[89]. Samples reaching endogenous levels make it difficult to legally prove
GHB doping in sexual assault cases. Exogenous levels of GHB have been
detected in hair samples at 7 days postintoxication [70]. The timely presen-
tation of the patient for medical attention and physician recognition of
GHB symptoms presented by sexually assaulted victims are essential for
prosecution of sexual offenders.

Ketamine
Ketamine (ketamine hydrochloride) is an analgesic and general anesthetic
that produces a rapid-acting dissociative effect. It was first synthesized
in1962 as a medical anesthetic for humans and animals. Today ketamine
is approved for use in emergency medicine, critical care, and veterinary med-
icine. The prosecution of a ketamine-facilitated sexual assault perpetrator in
1993 and the increase in its illicit use prompted the DEA to restrict ketamine
as a schedule III drug in August 1999. Ketamine is outlawed in the United
Kingdom and classified as a schedule I narcotic in Canada. Ketamine is
available by prescription as a tablet or a parenteral solution. On the street,
ketamine is sold under various names, including K, Ket, Special K, Super
acid, Super C, Spesh, Vitamin K, Smack K, Kit-kat, Keller, Barry Keddle,
HOSS, The Hoos, Hossalar, Kurdamin, Kiddie, Wonk, Regreta, and
Tranq. Ketamine generally is sold illegally as either a colorless, odorless liq-
uid or as a white or off-white powder. Liquid ketamine can be rapidly
 CRIMINAL POISONING: DRUG-FACILITATED SEXUAL ASSAULT 515

injected intramuscularly. Either liquid or powder form can be easily dis-

guised in a victim’s beverage. Ketamine powder can even be sprinkled
onto marijuana or tobacco and smoked.

Clinical effects
The onset of action after oral ingestion can be as little as 20 minutes [90].
Hallucinatory effects may be short-acting (!1 hour) but so intense that the
victim may have trouble discerning reality [77]. Ketamine produces effects
similar to phencyclidine and dextromethorphan. The onset of clinical effects
is rapid and depends on route of administration. Anesthesia effects by way
of intramuscular injection take as little 20 to 30 seconds, oral ingestion
about 30 minutes, and nasal insufflation approximately 10 minutes
[44,91,92]. The t1/2 for ketamine is 2 to 3 hours [93]. Duration of anesthetic
effects is dose dependent (usually !1 hour) and effects on the senses, judg-
ment, and coordination can have a longer duration (w6–24 hours). Ket-
amine can cause delirium, amnesia, dissociative anesthesia hallucinations,
hypersalivation, nystagmus, impaired motor function, hypertension, and
potentially fatal respiratory problems. Effects on blood pressure and respi-
ratory depression can be significantly enhanced when coingested with
alcohol.

Laboratory monitoring
No immunoassays are available to detect ketamine at this time. Ketamine
and its active metabolites norketamine and dehydronorketamine can be
detected in urine samples using GC-MS or LC-MS analyses. The limit of
detection is 1 ng/mL [94,95].

Barbiturates
Barbiturates can produce a wide range of CNS depression, ranging from
mild sedation to general anesthesia. They are categorized based on their ul-
trashort-acting, short-acting, medium-acting, or long-acting duration of
clinical effects (Table 1). Barbiturates are classified as schedule II to IV
drugs based on their rapid time of onset and duration and their abuse po-
tential. They can inhibit excitatory or enhance inhibitory synaptic transmis-
sion. Barbiturates inhibit excitatory synaptic transmission by reducing
glutamate-induced depolarizations [96]. Barbiturates enhance the effective-
ness of GABA transmission by directly activating chloride channels and de-
pressing synaptic transmission at virtually all synapses. Barbiturates effect
the duration, not frequency, of GABA channel opening, thereby hyperpola-
rizing and decreasing the firing rate of neurons [97].
The estimated prevalence of barbiturates used to facilitate sexual assault
is only about 1%, because of limited availability in recent years [7]. The
516 BECHTEL & HOLSTEGE

Table 1
Characterization of barbiturates
Chemical name Duration DEA scheduled classification
Thiamylal Ultrashort Schedule III
Thiopental (‘‘truth serum’’) Ultrashort Schedule III
Methohexital Ultrashort Schedule IV
Amobarbital Short Schedule II
Aprobarbital Short Schedule II
Butabarbital Short Schedule II
Pentobarbital Short Schedule II
Secobarbital Short Schedule II
Butalbital Medium Schedule II
Cyclobarbital Medium Schedule III
Talbutal Medium Schedule II
Methylphenobarbital Long Schedule IV
Mephobarbital Long Schedule IV
Phenobarbital Long Schedule IV

ultrashort-acting barbiturate thiopental was recently reportedly used to fa-

cilitate a sexual assault in Italy [98]. The slang terms for these drugs are
barbs, barbies, sleepers, blue bullets, nembies, pink ladies, and red devils.

Clinical effects
Onset of clinical symptoms varies (15–40 minutes) and the degree of
symptoms is dose and drug dependent. Clinical effects may consist of
CNS and respiratory depression, hypothermia, bullous skin lesions, aspira-
tion pneumonia, nystagmus, dysarthria, ataxia, drowsiness hypothermia, re-
nal failure, muscle necrosis, hypotension, hypoglycemia, coma, and death
[44]. Coingestion with alcohol or other CNS depressants enhances toxic ef-
fects. Duration of effects depends on the dose and the specific drug itself.

Laboratory monitoring
Detection periods for barbiturates vary greatly depending on the specific
barbiturate being used. Each barbiturate has a different half-life in the body.
Ultrashort- and short-acting barbiturates (thiopental, secobarbital) may
only be detected in the urine for 1 to 4 days, whereas longer-duration bar-
biturates (phenobarbital) can be detected for 2 to 3 weeks. Many larger hos-
pital facilities can detect most barbiturates from urine samples with an
extensive toxicology screen using competitive fluorescence polarization im-
munoassays [99]. Detection depends on the dose and half-life of the specific
drug being tested. State forensic laboratories have extremely sensitive as-
says, such as HPLC-MS/MS and GC/MS-MS, capable of detecting very
low concentrations of barbiturates from urine and hair samples that can
greatly expand the window of detection [98].
 CRIMINAL POISONING: DRUG-FACILITATED SEXUAL ASSAULT 517

Opioids
Several opioid drugs are included in the analysis for date-rape drugs.
Although these drugs are highly regulated or only available by prescription,
illicit use of these drugs is still common nationwide. Opiates are the naturally
derived narcotics, such as heroin, morphine, and codeine. These are isolated
from the poppy plant Papaver somniferum. Heroin is the only opiate cur-
rently listed as a schedule I drug, primarily owing to the rapid onset of action,
clinical effects (euphoria and sedation), and its high abuse potential. Metab-
olism of codeine to morphine is required for its analgesic effects (Fig. 4).
Opioids include the semisynthetic compounds, such as hydrocodone, hydro-
morphone, oxycodone, and fentanyl. These drugs all have potent analgesic
and sedative properties but different pharmacokinetic properties. These
drugs are available in powder or tablet forms having a slightly bitter taste.
Either form can be hidden in a beverage, smoked, or inhaled. These drugs
can easily be used to incapacitate a sexual assault victim.

Clinical effects
The major clinical effects of opioids are analgesia, sedation, pinpoint
pupils (miosis), euphoria, and respiratory depression [44]. Pinpoint pupils
may not always be seen in all and should not be solely relied on for the di-
agnosis. The onset of clinical symptoms varies with the drug and the method
of administration. Onset of effects for oral ingestion of opioids varies, but
most are within 30 to 60 minutes; inhalation or injection is more rapid
(within 5 minutes). Duration of clinical effects depends on the specific opioid
drug. Naloxone reversal of sedation may clue the health care team to the
presence of opioids.

Codeine Heroin

norcodine 6-acetyl morphine

Morphine

Morphine-3-glucuronide Morphine-6-glucuronide

Fig. 4. The opiate metabolites detected by immunoassay and GC-MS. A small percentage of
codeine is converted to active metabolites by CYP2D6 to norcodeine (w10%), morphine
(w10%), and hydrocodone (!2%). Heroin is rapidly metabolized to 6-acetyl morphine and
then hydrolyzed to morphine; both are active metabolites. Morphine is conjugated to inactive
metabolite morphine-3-glucuronide and the potent metabolite morphine-6-glucuronide.
518 BECHTEL & HOLSTEGE

Laboratory monitoring
In the hospital setting commercial immunoassays are designed to detect
naturally occurring opiates (morphine and codeine). Specific GC-MS anal-
ysis protocols are available for confirming natural, synthetic, and semisyn-
thetic opioid compounds from urine specimens. In addition, specific
immunoassays and GC-MS protocols are available for detection of metha-
done and propoxyphene. Documentation of suspected opioid-related clini-
cal symptoms assists state laboratories in detecting and confirming
a diverse array of opioid compounds potentially used to incapacitate a victim
of sexual assault.

Over-the-counter medications
Several medications that may be used to facilitate sexual assault are
legally available without a prescription. Although these medications are di-
verse in class, their clinical effects may be used to incapacitate a sexual as-
sault victim. Sexual predators may use these drugs because their effects
are exacerbated with alcohol and can easily be used to adulterate a victim’s
drink.

Dextromethorphan
Dextromethorphan is sold over the counter as an antitussive agent alone
or in combination with other cough aids (pseudoephedrine, acetaminophen,
chlorpheniramine). It is the d-isomer of the potent opiate analgesic 3-me-
thoxy-N-methylmorphine (levorphanol). Although dextromethorphan is
structurally related to opioids, it is devoid of analgesic or sedative effects
at therapeutic doses. Dextromethorphan is metabolized by CYP2D6 to
a more potent metabolite, dextrorphan [100,101]. Dextrorphan is a stronger
noncompetitive antagonist than dextromethorphan for the N-methyl-D-as-
partate glutamate receptor [102]. These properties promote its use in treat-
ment of neuropathic and postoperative pain management [102–106].
Even though dextromethorphan has a strong safety profile at therapeutic
concentrations, it is highly abused for its sedative, hallucinogenic, short-
term memory loss, dissociative, and euphoric properties at high doses. Al-
though no cases have been published using dextromethorphan in DFSA,
large doses can impair a victim’s sensory and motor skills making it a poten-
tial drug for use in DFSA. Dextromethorphan is widely available over the
counter in liquid, tablet, and gel capsule formulations, or over the internet
in a white power form [107]. Although liquid dextromethorphan has
a bad taste, crystallized and powder forms can easily be disguised in drinks
and consumed by an unknowing victim. Street names for dextromethorphan
are Dex, DXM, Tuss, Robo, Skittles, Triple-C, and Syrup.
Despite the safety of dextromethorphan when used at the recommended
dosage (!120 mg/day), higher doses can result in nausea, vomiting, seizure,
 CRIMINAL POISONING: DRUG-FACILITATED SEXUAL ASSAULT 519

loss of consciousness, irregular heartbeat, and death [108,109]. Serotonin

syndrome may develop in patients on other serotoninergic drugs because
of additive inhibition of serotonin reuptake by dextromethorphan [110].
Patients who have genetic variations in CYP2D6 causing rapid metabolism
of dextromethorphan may present with greater clinical effects [111–113].

Anticholinergics
Scopolamine and atropine are anticholinergic agents of the belladonna al-
kaloid family. Scopolamine is used for motion sickness and as an adjunct to
anesthesia to produce sedation and amnesia. Scopolamine produces a higher
degree of sedation than atropine because of the higher degree of penetration
into the CNS. The high potency, rapid onset, and amnestic effects of scopol-
amine have lead to its being included on testing for DFSA cases [114].
The major clinical effects of scopolamine are classic anticholinergic symp-
toms, such as dilated pupils (mydriasis), dry mouth, hallucinations, and
slurred speech. Other clinical effects are tachycardia, vomiting, confusion,
and amnesia. Large doses can result in coma, seizures, and death. The onset
of clinical symptoms is fast (within 15–30 minutes) and duration of effects
may last up to 2 to 3 days.

Antihistamines
Antihistamines are typically used in the treatment of allergies or insomnia.
First-generation antihistamines (diphenhydramine, chlorpheniramine) read-
ily cross the blood-brain barrier, producing greater CNS effects than second-
generation antihistamines (fexofenadine). First-generation antihistamines hit
central and peripheral histamine (H1 and H2) receptors, but are still widely
used because they are effective and inexpensive [115]. Few cases have docu-
mented the use of diphenhydramine in DFSA [32], yet the anticholinergic
proprieties of antihistamines make this a class of drugs feasible for DFSA.
First-generation antihistamines can cause CNS depression and anticho-
linergic symptoms, such as sedation, hallucinations, confusion, agitation,
and psychosis. Onset of action is 15 to 60 minutes and clinical symptoms
typically last 4 to 6 hours [116]. Large doses can exacerbate these effects
and can even result in cardiotoxicity, coma, and seizures [117]. Coingestion
with alcohol or other sedative-hypnotic drugs may increase some or all of
these clinical symptoms. Victims may have difficulty distinguishing events
of a sexual assault because of the anticholinergic effects of the drugs. A vic-
tim may not present for hours or days after a sexual assault, therefore,
because of the clinical effects of the drugs themselves.

Laboratory monitoring
Analysis of blood or urine antihistamine levels is not typically performed
in the health care setting. Because these nonprescription drugs are
520 BECHTEL & HOLSTEGE

commonly used by the general public, interpretation of a positive test result

is problematic. Dextromethorphan cross-reacts with most immunoassays
for opioid compounds. Confirmation protocols for dextromethorphan are
available using GC-MS. Most anticholinergics are detected using GC-MS.
Urine specimens are sufficient for the highly specific GC-MS and HPLC-
MS/MS analyses [47,118]. When a victim of sexual assault reports or pres-
ents with specific signs and symptoms, it is imperative that the medical staff
document these findings and relay this information to the laboratory on col-
lecting the necessary biologic samples. Without such documentation, state
forensic laboratories may overlook the need to specifically analyze biologic
specimens for these agents.

Summary
DFSA is a complex and ever-prevalent problem presenting to North
American emergency departments. Emergency personnel should consider
DFSA in patients who are amnestic to the specific details of the event fol-
lowing a reported sexual assault. The presence of ethanol or a positive rou-
tine drug screen in a sexual assault victim does not exclude the potential for
another drug being present. In addition, a negative routine drug screen does
not exclude all potential agents that are used in DFSA. It is imperative for
emergency personnel to clearly document the history and the presenting
signs and symptoms to assist laboratory personnel to hone in and detect
the agent used in a DFSA.

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