Journal of Analytical Toxicology, 2018;42:353–359

doi: 10.1093/jat/bky008
Advance Access Publication Date: 7 February 2018
Article

Article

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Modafinil in Forensic and Clinical Toxicology—
Case Reports, Analytics and Literature
Lars Radünz1,2,*, Hannah Reuter3, and Hilke Andresen-Streichert1,4
1
Department of Toxicology, Institute of Legal Medicine, University Medical Center Hamburg-Eppendorf, Butenfeld 34,
22529 Hamburg, Germany, 2Rudolf Boehm Institute of Pharmacology and Toxicology, Postgraduate Study
“Toxicology and Environmental Protection”, University of Leipzig, Germany, 3Catholic Marienkrankenhaus,
Department of Neurology, Hamburg, Germany, and 4Department of Toxicology, Institute of Legal Medicine,
University Medical Center, Cologne, Germany

*Author to whom correspondence should be addressed. Email: lars.raduenz@freenet.de

Abstract
Modafinil is used because of its wakefulness-promoting properties for treatment of diseases asso-
ciated with extreme sleepiness (i.e., narcolepsy). Additionally, it is misused as a “cognitive
enhancer” to increase alertness and to improve concentration. We present modafinil concentra-
tions in serum samples in five cases of our routine work measured by high-performance liquid
chromatography coupled with a photo diode array detector after solid-phase extraction. One sam-
ple was analyzed for clinical toxicology purposes. The other four were investigated for the police:
three cases of driving under the influence of drugs and one case of bodily harm. Sample prepara-
tion consisted of solid-phase extraction using Bond Elut® C18 columns. Papaverine was used as
internal standard. Chromatographic separation was carried out using a Polaris C18-A column in
an isocratic run. Wavelengths used for UV-detection were 220 nm for modafinil and 239 nm for the
internal standard, respectively. The method was validated with a reduced validation design for
rare analytes. A six-point-calibration from 0.5 to 5.0 mg/L, covering the therapeutic range
(0.9–3.3 mg/L), was used for quantification. Concentrations in serum were in the range of 1.3 to
~34 mg/L (median: 3.6 mg/L; mean: 9.0 mg/L). To our knowledge, there are only few publications
concerning the serum concentrations of modafinil in cases of (suspected) misuse, forensic cases
or intoxications. In our discussion, the serum concentrations we determined are compared with
the levels described in the literature so far.

Introduction marketed as armodafinil, has a half-life of ~15 h whereas the

The stimulant modafinil ((RS)-2-[(diphenylmethyl)sulfinyl]acet-
amide) is a wakefulness-promoting substance which is different in
structure (Figure 1) and effect when compared to amphetamine.
When considering the mode of action, multiple interactions with cat-
echolamine systems, e.g., inhibition of dopamine and noradrenaline
transporters in the brain and elevation of extracellular dopamine
and noradrenaline levels, are part of the neurochemical mechanisms,
but the complete mode of action is still unclear (1). Modafinil is a
racemic substance with the S- and R-isomer having equal pharma-
cologic activity but pharmacokinetic differences. The R-isomer,
S-isomer is eliminated faster with a half-life of 4–5 h. The racemate
and armodafinil have similar terminal half-lives (2). Modafinil is
metabolized to two pharmacologically inactive substances, modafinil
sulfone and modafinil acid (Figure 1) (3).
Modafinil is approved in Germany (brandname: Vigil®) for
treatment of excessive sleepiness associated with narcolepsy with or
without cataplexy in adults (4). Additionally, in the USA modafinil,
marketed as Provigil®, is prescribed to improve wakefulness in adult
patients with excessive sleepiness associated with obstructive sleep
apnea and shift work disorder (5). The usually recommended dose

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354
Figure 1. Chemical structure and metabolism of modafinil.
for adults is 200–400 mg (4, 5). Furthermore, modafinil is used off-
label (or without official approval), e.g., to treat fatigue syndrome in
patients with multiple sclerosis, cancer or depression. In an intensive
care unit the substance was used to improve and to accelerate the
rehabilitative process in patients who suffered fatigue, extreme day-
time sleepiness and/or depression during recovery from critical ill-
nesses (6). Modafinil also seems to be an option for treatment of
attention-deficit/hyperactivity disorder (ADHD) in children and
adults (7).
Besides being prescribed for medical reasons, modafinil is also
misused, without any medical indication, as a so-called “smart
drug” or “cognitive enhancer” to increase alertness and to improve
mental skills. In a study among French medical students, 0.8% of
the participants admitted modafinil use with the aim of increasing
academic performance, concentration and wakefulness (8). In an
anonymous survey among surgeons attending five international con-
ferences in 2011, 2.2% of the responders (n = 957) admitted to
modafinil intake (9).
According to the World Anti-Doping Agency (WADA) modafinil
is a substance prohibited during athletic competition (classified as a
“non-specified stimulant”) (10).
Adverse effects of modafinil therapy are mainly headache, nau-
sea, nervousness, rhinitis, back pain, diarrhea, anxiety, dizziness,
dyspepsia and insomnia (5). In a retrospective review of a Poison
Center chart, the most frequently reported clinical effects of a single
ingestion of modafinil were tachycardia, insomnia, agitation, dizzi-
ness, increased anxiety and nausea (11). Detailed reports on modafi-
nil intoxications are rare (12–14). To our knowledge, there is no
case of a lethal outcome after a modafinil monointoxication.
Several methods have been described for the detection of modafi-
nil and its two metabolites in plasma/serum and urine (15–20). The
method presented here is based on our routine method for general
unknown screening and consists of a basic solid-phase extraction
(SPE) and a fast high-performance liquid chromatography coupled
with a photo diode array detector method (HPLC-DAD) slightly
modified for separation and detection of modafinil. A six-point-
calibration was used for quantification. The method was validated
with a reduced validation design according to Peters et al. (21),
because in our laboratory modafinil is a rare analyte which has not
been present in many cases thus far .
Experimental
Chemicals and reagents
All chemicals and solvents were of analytical grade. Modafinil
was purchased from Cerilliant/Sigma Aldrich (Munich, Germany),
the internal standard papaverine from Sigma Aldrich (Munich,
Germany).
Radünz et al.
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Alkaline buffer was prepared by mixing a saturated dipotassium
phosphate solution with deionized water (1 + 3; v/v) resulting in a
pH value of ~9.5. Buffer for the mobile phase was prepared with
dipotassium phosphate, ortho-phosphoric acid (85%), a solution of
2.5 M sodium hydroxide and water (HPLC-grade).
Blank serum was received by the Institute of Transfusion
Medicine of the University Medical Center Hamburg-Eppendorf.
Analytical procedure
Sample preparation
Solid phase extraction (SPE) was carried out using Bond Elut® C18
columns (Agilent Technologies, Waldbronn, Germany) on a VacMaster®
extraction box (Biotage, Uppsala, Sweden). Before applying the sam-
ples the columns were conditioned with two times 1 mL methanol
and 1 mL deionized water each.
To 0.5 mL of the serum samples (calibrators, quality controls,
patient samples, blanks) 10 μL of the internal standard stock solu-
tion (0.1 mg/mL) were added. After short mixing 0.5 mL of alkaline
buffer were added to each sample and the samples were shaken for
5 min at 1,800 rpm. The samples were centrifuged at 14,650 rpm for
5 min and the supernatants were transferred to the SPE columns.
Subsequently, the columns were washed twice with 1 mL deionized
water. Immediately thereafter 40 μL of methanol were passed
through with vacuum to facilitate a better drying of the columns
before elution. The columns were dried with vacuum for ~2 min.
The samples were eluted with 750 μL of methanol into conic HPLC
sample vials, and the extracts were evaporated to dryness under a
stream of nitrogen at 40°C.
The residues were reconstituted in 60 μL of a mixture of acetoni-
trile (80% v/v) and ethanol (20% v/v). Finally, 60 μL of water
(HPLC-grade) were added.
Apparatus and chromatographic conditions
Chromatography was performed on a Finnigan Surveyor HPLC
system by Thermo Fisher (Dreieich, Germany) consisting of Autosampler
Plus, LC Pump Plus and PDA Plus Detector. The injection volume
was 20 μL. The mobile phase consisted of acetonitrile (35% v/v) and
buffer solution (65% v/v).
Modafinil and the internal standard were separated on a Polaris
C18-A column (particle size: 5 μm; 250 mm × 4.0 mm I.D.; Agilent
Technologies, Waldbronn, Germany) with a flow rate of 1.0 mL/
min. Run time was 6 min, retention times of modafinil and papaver-
ine were ~3.1 and 4.3 min, respectively. Wavelengths were scanned
from 200 to 390 nm. Evaluations of the signals were done at
220 nm for modafinil and 239 nm for the internal standard, using
ChromQuest® software (Thermo Fisher, Dreieich, Germany).
Modafinil in Forensic and Clinical Toxicology
Quantification of modafinil
Quantification was based on signal area ratios of modafinil
(220 nm) and the internal standard (239 nm). A six-point-calibration
of modafinil spiked in blank serum was used (0.5, 1.0, 2.0, 3.0, 4.0
and 5.0 mg/L). The calibration points were chosen to cover the thera-
peutic range found in literature from 0.9 to 3.3 mg/L (22, 23).
Concentrations of the quality controls were 0.8 and 4.5 mg/L,
respectively.
Statistics
Valistat® software version 2.0 (Arvecon, Walldorf, Germany) was
used for determination of accuracy (bias), precision and repeatabil-
ity of the quality controls.
Case reports
All cases were analyzed according to our standard protocol for a
general unknown screening including immunological testing and a
GC–MS screening after basic solid-phase extraction according to the
extraction described above.
Four cases were analyzed for the police in 2015 including three
cases of “driving under the influence of drugs (DUID)”, and one
case of “bodily harm”. One sample was analyzed in 2013 for
another hospital as a suspected, and later confirmed, intoxication.
Case 1
In the first case, witnesses reported a car which accelerated, sud-
denly stopped and then crossed over driving into the oncoming traf-
fic. The driver turned the car back into the correct lane without
taking note of other cars, thereby nearly hitting one. He drove on in
a swerving manner and then ignored a red traffic light. The car was
stopped by the alarmed police. A blood sample was collected ~1.5 h
later. There was no information given about a modafinil intake
according to the police protocol.
Case 2
In the second case the police followed a car. The driver drove the
vehicle into the left-turn lane without signaling. The policemen
observed that he had not fastened his seat belt. The driver then com-
pleted the turn, thereby grazing the curb. The police stopped the car
and a blood sample was taken 1.5 h after that. As in the previous
case, there was no information for a modafinil intake according to
the police protocol.
Case 3
The third case started with a spontaneous traffic control by the
police at a petrol station. The driver exhibited various signs of drug
influence. He explained that he takes modafinil (“400–600 mg”)
and an antidepressant the nature of which was initially not further
specified. A blood sample was taken 2 h after the police’s arrival.
This sample was initially analyzed in a restricted analysis, because,
in Germany, DUID can be judged as an administrative offence only
when the most important illegal substances, like e.g., cannabis and
cocaine are involved, or as a criminal offence, e.g., in case of an acci-
dent under the influence of central nervous acting substances. In case
of a criminal offence, a larger spectrum of substances is analyzed
including various drugs and all kinds of narcotics.
In this case, modafinil and the (at this point) unknown antide-
pressant were not initially detected, because the case was an admin-
istrative offense where analysis does not cover these substances. In
355
the hearing at court, the accused reported he must take modafinil
because he was diagnosed about a year and a half prior with narco-
lepsy and cataplexy. He claimed that he had successfully proved his
driving ability in a sleep laboratory. Furthermore, he stated he had
to take imipramine. However, he expressed doubts that the blood
sample which was analyzed was really his. To settle this counter-
claim, a DNA test as well as an extended toxicological analysis
including modafinil and imipramine was ordered by the judge.
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Case 4
A man, walking up and down in front of a railway station, suddenly
hit another person in the face without provocation. The police were
alarmed and took the accused to the police station. The man told the
police that he had taken “Modvigil” tablets obtained from India 3
days prior. He explained he was a courier and had to drive a lot, so
he took the tablets to remain awake constantly and do his job. The
man could not remember where he left his car. Later, he declared
himself to be addicted to “Modvigil” which contains modafinil.
Another person called the police and reported he had also been
attacked by an unknown man. It very soon became apparent that it
was the same man the police had arrested. The second incident had
happened subsequent to the first attack. The accused had stopped
the car of the second victim by stepping in front of the vehicle. The
driver thought the man wanted to tell him something and opened
the driver’s door. The accused talked to the victim in a foreign lan-
guage and suddenly kicked him and struck his shoulder with his fist.
He stopped the attack when two other men tried to help the driver.
When walking away from the car the accused smashed the right rear
light of the vehicle.
A blood sample was taken ~4.5 h after the first incident.
Before photos and fingerprints could be taken at the police sta-
tion, the man tried to escape and had to be captured by several offi-
cers. He kicked aggressively, tried to hit the policemen, and
screamed, so that he had to be put in handcuffs and shackles. After
this escape attempt the arrest procedure could proceed.
Case 5
An unconscious male patient with some blood at the corner of his
mouth passed out at a petrol station, and was taken to the emergency
room. In the hospital, an immunological drug test on his urine was
positive for benzodiazepines, and a blood alcohol level of 0.1‰ was
determined. No further conspicuous findings were initially noticed.
The patient was reported to have a psychiatric history. According to
the hospital in which the man was last treated for his mental disease,
the patient had a schizoaffective disorder and had not received benzo-
diazepines during his last stay there. A co-use of other substances as
well as consumption of alcohol was also unknown. The only known
medication was aripiprazole and folic acid.
A blood sample was taken for further toxicological analysis and
was sent by the admitting hospital to our laboratory.
The following day the man was awake and reorientated, but
reported a headache.
Results
Validation of the analytical method
Selectivity
Analysis of six different blank serum samples without internal stan-
dard showed no significant interacting signals at the retention times
of the internal standard and modafinil. Two samples from different
356
blank serums with internal standard were analyzed and did not
show any interferences either.
In addition, the chromatographic method was checked for inter-
ferences and co-elution with diphenhydramine (DPH), selected ben-
zodiazepines, antidepressants and neuroleptics. As has been
described before, DPH could be mistaken for modafinil in GC–MS
screening, because the spectra of modafinil and some of its metabo-
lites/artifacts are fairly similar to some DPH metabolites/artifacts
(12). The UV-spectra of both substances are also similar probably
due to the diphenyl-structure in both molecules. With the applied
HPLC conditions, modafinil and DPH could be chromatographi-
cally separated, so that misinterpretation of these two compounds
was excluded. Furthermore, analysis of different quality controls of
various benzodiazepines, antidepressants and neuroleptics revealed
no significant co-elution at the retention times of the internal stan-
dard and modafinil, respectively.
Calibration curve
Two calibration curves ranging from 0.5 to 5.0 mg/L were prepared
in blank serum. They were linear with r2 values of 0.999 and 0.998,
respectively.
Accuracy (bias), precision and repeatability
The quality controls (0.8 and 4.5 mg/L of modafinil spiked in blank
serum) were analyzed in duplicate on 5 different days. Bias was
9.5% for 0.8 mg/L and 2.8% for 4.5 mg/L. Precision showed RSDs
of 3.2 and 6.3%, respectively. RSDs of repeatability were 2.6 and
6.4%, respectively.
Limit of detection and lower limit of quantification
Limit of detection (LOD) and lower limit of quantification (LLOQ)
were determined with spiked blank serum samples by checking signal-
to-noise ratios of the modafinil peaks. LOD was 0.15 mg/L (signal-to-
noise >3), and LLOQ was 0.3 mg/L (signal-to-noise >10) (21).
Results of the samples
The quantitative results of modafinil and co-ingested substances along
with demographic data, type of the cases and reported symptoms are
shown in detail in Table I. Concentrations of modafinil in serum
ranged from 1.3 to ~34 mg/L (median: 3.6 mg/L, mean: 9.0 mg/L).
Discussion
Regenthal et al. specified the therapeutic range of modafinil with
blood plasma concentrations ranging from 0.9 to 3.3 mg/L, and an
elimination half-life of 7–13 h was reported (22). Additionally, in a
single-dose pharmacokinetic study three different groups of partici-
pants (young males (ages 22–37), young females (ages 19–40) and
elderly males (ages 53–72)) received two 100 mg tablets of modafi-
nil. Blood samples for evaluation of pharmacokinetic parameters
were taken in intervals up to a maximum of 72 h post-dose. Maximum
blood plasma concentrations were 4.21 (±0.44) mg/L in young males
after 2.0 (±1.0) h, 5.20 (±0.83) mg/L in young females after 1.7
(±0.9) h and 4.81 (±0.89) mg/L in elderly males after 1.7 (±0.7) h (24).
This work group also examined the pharmacokinetic profiles of differ-
ent modafinil doses (200, 400, 600, 800 mg) in healthy male volun-
teers. The maximum blood plasma concentrations after a single
intake of 400, 600 and 800 mg modafinil were 8.7 (±1.3) mg/L after
Radünz et al.
2.3 (±0.5) h, 13.0 (±1.0) mg/L after 2.5 (±0.6) h and 15.0 (±1.0) mg/
L after 2.3 (±0.6) h, respectively (25).
In a case of an intoxication with escitalopram and modafinil a
fourteen year old girl ingested 20 tablets each containing 200 mg
modafinil and 10 tablets each containing 10 mg escitalopram. She
was tachycardic, anxious, diaphoretic and complained of a dry
mouth and diarrhea. Thirty three hours post ingestion, she still
remained tachycardic and hypervigilant, sleeping only 20 min at a
time. Modafinil concentration 24 h after ingestion was 18 mg/L (13).
In another case a 16-year-old girl was taken to the hospital with a
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fast heart rate, headache, “body tingling”, fleeting chest pain and
changes in behavior that included restlessness and visual hallucina-
tions. A serum sample was taken 18 h after initial presentation and
revealed a modafinil concentration of 13 mg/L. It was unclear
when and how much modafinil had been ingested (12). Another
15-year-old female adolescent took 5 g of modafinil in a suicide
attempt. She complained of severe headache, nausea and abdomi-
nal pain. Several hours later she developed dyskinesia which sub-
sided spontaneously. The patient did not sleep at all during the
first night in the hospital. The modafinil blood level was not deter-
mined in this case (14).
Case 1
The modafinil concentration of 2.1 mg/L is within the therapeutic
range. The reported uninhibited and nervous mood and the inces-
sant talking could be interpreted as results of the activating effects
of modafinil. The reddened, glazed eyes could result from THC,
which was found additionally in a rather low concentration. The
concentrations of diazepam and nordazepam are only at moderate
levels and most probably result from a diazepam intake some time
previously and not from an acute ingestion, but an impact by these
substances even in these rather low concentrations seems possible.
Cocaine was not detected in a blood sample which was taken in a
container stabilized with sodium fluoride, but its metabolites ecgoni-
nemethylester and benzoylecgonine were still present. The reported
sleepiness and the swerving and erratic driving could, therefore, be a
combined effect of a decreasing cocaine intoxication with minimal
concentrations of THC and low but effective concentrations of diaze-
pam and nordazepam. It should be noted, however, that the interpreta-
tion of these findings remains difficult, because some substances show
opposite effects, like modafinil and benzodiazepines. The observed driv-
ing mistakes and the descriptions by the police also show that modafinil
did not improve the man’s ability to drive or compensate the effects of
the other substances.
Case 2
The modafinil concentration of 3.8 mg/L is slightly above the reported
therapeutic range (22) and could, for instance, represent a peak con-
centration after the ingestion of 200 mg modafinil according to Wong
et al., where the accused fits in the group of the young males (ages
22–37). Most of the descriptions noted by the physician, such as the
man being excited, impolite, talkative, uninhibited and having a vary-
ing mood could stem from modafinil, the co-ingested alcohol and/or
from both. The swaying body motion is probably mainly the result of
the alcohol “co”-intoxication. Only a low concentration of 11-nor-9-
carboxy-THC was found, so that an influence by cannabis can be
excluded. Similar to case 1, modafinil does not seem to compensate
the negative effects of the co-ingested alcohol.
Modafinil in Forensic and Clinical Toxicology 357

Table I. Background information and results of cases 1–5

Results

Sex Age Type of Reported symptoms/abnormalities Modafinil Co-ingested substances (mg/L)

(y) case (mg/L)

Case 1 m 33 DUID Observations by police: 2.1a THC ~0.0005

• driver’s mood: uninhibited and nervous OH-THC n.d.
• lack of concentration THC-COOH 0.041
• reddened, glazed eyes with dilated pupils slowly reacting to light Cocaine (NaF n.d.
• incessant talking stabilized) 0.033

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• sleepy Ecgoninemethylester 0.22
• immunological roadside drug test in urine was positive for Benzoylecgonine 0.18
tetrahydrocannabinol (THC) and cocaine Diazepam 0.14
Evaluation by physician: Nordazepam
• slightly reddened eyes
• not noticeably intoxicated
Case 2 m 28 DUID Observations by police: 3.8b THC n.d.
• smell of alcohol on the man’s breath OH-THC n.d.
• body swayed while standing THC-COOH 0.0074
• reddened eyes Blood alcohol 0.94‰
• known as a consumer of drugs of abuse concentration
Evaluation by physician:
• described him as excited, impolite, talkative, uninhibited and
emotionally labile
• glazed, strongly reddened eyes with small pupils
• smell of alcohol on the man’s breath
• mildly to moderately drunk / intoxicated
Case 3 m 30 DUID Observations by police: 3.6b THC 0.013
• immunological roadside drug test in urine was positive for OH-THC 0.0053
amphetamine THC-COOH 0.051
• driver’s mood: depressed, nervous, restless, showing Imipramine ~0.05
overconfidence and a lability
• dry mouth, frequently sucked his lips
• instructions had to be repeated several times showing a lack of
concentration
• disturbances of balance, problems getting out of the car
• glazed and reddened eyes with dilated pupils showing only a slight
reaction to light
• body was trembling
• goosebumps while inappropriately sweating.
Evaluation by physician:
• none (person did not want to cooperate)
Case 4 m 33 Bodily Observations by police: 1.3a THC n.d.
harm • very upset, gestured wildly, gazed, seemed confused OH-THC n.d.
• very exhilarated not being able to stand still THC-COOH 0.0042
• had to be handcuffed before the transport to the police station,
because he became more and more frantic and aggressive
• confused, absent
Evaluation by physician:
• person did not exactly know when he slept the last time and
admitted that he would “occasionally” take drugs
• moderately narrow pupils slowly reacting to light
• slightly slurred speech
• psychophysiological tests:
Walking on an imaginary line: hesitated before starting, pro-
blems with balance and raising his arms for supportfinger-fin-
ger-test: unsteadily. Romberg test: body swayed
• behavior: controlled with very clear signs of fatigue
• mildly intoxicated

Table continues
358
Table I. Continued
Sex Age Type of Reported symptoms/abnormalities
(y) case
Case 5 m 35 Intoxication • difficult to wake patient up
• repeatedly fell asleep while the clinical staff was trying to talk to him
• in the course of the conservation became more wakeful
• denied any medication
• neurological symptoms: somnolent, disorientated and slowed
• at hospital admission: blood pressure 80/40 mm Hg; pulse 120/min
• known schizoaffective disorder
DUID, driving under the influence of drugs; THC, Δ9-Tetrahydrocannabinol; OH-THC, 11-hydroxy-THC; THC-COOH, 11-nor-9-carboxy-THC; n.d., not
detected.
a
Therapeutic.
b
Supratherapeutic.
c
Toxic.
d
No more material for confirmation, GC–MS screening provided no indications for benzodiazepines.
Case 3
The modafinil concentration of 3.6 mg/L is also above the therapeu-
tic range, but could result from a modafinil dose of 400–600 mg as
explained by the accused. The maximum concentrations after the
intake of 400 and 600 mg determined by Wong et al. (25) were even
higher, so that the last dose was probably some time before the inci-
dent. Modafinil could be the reason for the man’s nervousness, rest-
lessness, overconfidence and the trembling body during the police
control. However, the dry mouth, lack of concentration, distur-
bances of balance together with glazed and reddened eyes with
dilated pupils showing only a slight reaction to light more appropri-
ately fit an acute cannabis intoxication, which is also supported by
the measured cannabinoid concentrations (Table I).
The positive immunological test for amphetamine in urine con-
ducted by the police cannot be explained by modafinil because mod-
afinil shows no structural similarities to amphetamines which would
explain a cross-reactivity to the test. The blood sample tested immu-
nological negative for amphetamine as well as ecstasy.
Case 4
The therapeutic modafinil concentration of 1.3 mg/L was probably
higher during the crimes, because the elapsed time of 4.5 h from the
time of the first offence to the blood sampling is quite long. The
man was quite aggressive towards the police and his victims which,
along with the symptoms as described by the police like being very
upset, exhilarated, confused and gesturing wildly, fit well to the acti-
vating effects of modafinil. During the doctor’s examination the
man showed more symptoms of exhaustion rather than those of agi-
tation which could result from a decreasing effect of modafinil. The
physician noticed a slightly slurred speech, insecurities demonstrated
in the psychophysiological tests and very clear signs of fatigue. On
the other hand, with a rather low modafinil concentration in the
blood sample, both the aggressiveness as well as the tiredness could
also be withdrawal symptoms, as the man admitted to the police
that he had a modafinil addiction, and the time of the last modafinil
intake was unclear. It must be said however, that no reports con-
cerning modafinil addiction and possible withdrawal symptoms
could be found in literature to clearly support this theory.
The low concentration of 11-nor-9-carboxy-THC showed can-
nabis consumption some time previously, but no acute influence.
Radünz et al.
Results
Modafinil Co-ingested substances (mg/L)
(mg/L)
~34c Benzodiazepines
immunological weakly
positived
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Case 5
The last case presented a modafinil intoxication with a very high
modafinil concentration of ~34 mg/L. The symptoms do not fit the
previously mentioned side effects of modafinil. The few cases of
modafinil intoxications reported above also showed the more typical
adverse effects of anxiety, insomnia, tachycardia, restlessness or
nausea. This case is more contradictory: the patient lost conscious-
ness, was somnolent, disorientated and slowed. Headache, which
can be a side effect of modafinil, was reported the next day when he
was completely awake again. The attending physicians concluded
that epileptic seizures could have possibly occurred due to the intox-
ication leading to the loss of consciousness, or the intoxication itself
was the only trigger for the comatose state. The blood alcohol level
of 0.1‰ is negligible. The slightly positive result of the immunologi-
cal testing for benzodiazepines could not be confirmed with chro-
matographic methods due to too little material.
The reasons for the modafinil intake could not be clarified in
cases 1 and 2. The person in case 3 took modafinil for medical rea-
sons (narcolepsy with cataplexy), the man in case 4 told the police
he was addicted to modafinil, and case 5 was determined to be an
intoxication with modafinil.
The similarities in all cases were the sex and the approximate
age of the persons (male, aged between 28 and 35) and, except in
case 5, a co-use of cannabis.
Limitations
The two main metabolites modafinil sulfone and modafinil acid
were not analyzed, because they both do not contribute to the phar-
macologic effects and thus were not important for the interpretation
of the cases. Furthermore, an enantiomeric separation of the R- and
S-isomer was not done. However, as both enantiomers having equal
pharmacologic activity and all blood concentrations described in the
above mentioned literature refer to modafinil racemate, this is con-
sidered non-critical for a comparison of the concentrations in the lit-
erature with the concentrations we determined. In Germany the
approved medicine “Provigil”, as well as “Modvigil” as described in
case 4, contain racemic modafinil.
Papaverine was used as internal standard because it is the internal
standard of our established routine method. Although it is quite differ-
ent in structure as compared to modafinil, it proved to be well suited
Modafinil in Forensic and Clinical Toxicology
for the here presented method as demonstrated by the validation data
(calibration curve, accuracy (bias), precision and repeatability). Some
methods described in the literature use internal standards which are
structurally more closely related to modafinil, i.e., [bis-(4-fluoro-phenyl)-
methylsulfinyl]acetic acid or 3,3-diphenylpropylamine (17, 18).
Conclusion
There is scant literature on blood concentrations of modafinil in
cases of DUID, suspected misuse and/or intoxications. We have pre-
sented five cases from our routine work with different situations in
which a modafinil ingestion had been proven.
The police related cases were all sent to our laboratory within
the same year (2015), and the sample for the hospital was sent in
2013 showing that modafinil intake seems to be relatively rare in
forensic as well as clinical toxicology. Our laboratory investigates
~14,000 samples per year relating to clinical and forensic toxicol-
ogy. In 2016, no case of modafinil intake was found, so that, from
our point of view, the four cases falling into that 2015 period of time
did so only coincidentally, and do not hint at a “trend” towards ris-
ing consumption of modafinil in the area of Hamburg.
In summary, modafinil is a substance, although rare, has to keep
in mind in forensic and clinical toxicology, but which can be identi-
fied and quantified with simple chromatographic methods. Positive
samples could stem both from misuse of the substance as well as
from a prescribed medication.
Acknowledgments
Authors would like to thank the police officer Peter Kellerer of the police
department in Hamburg for his support concerning the background informa-
tions of the police cases and Marie Bösch for carefully reviewing this article
with regard to the English language.
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