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Published: 17 January 2025
Citation: Nowak, K.;
Chłopa´s-Konowałek, A.; Szpot, P.;
Zawadzki, M. The Issue of “Smart
Drugs” on the Example of Modafinil:
Toxicological Analysis of Evidences
and Biological Samples. J. Xenobiot.
2025,15, 15. https://doi.org/
10.3390/jox15010015
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Article
The Issue of “Smart Drugs” on the Example of Modafinil:
Toxicological Analysis of Evidences and Biological Samples
Karolina Nowak 1, † , Agnieszka Chłopa´s-Konowałek 2, †, Paweł Szpot 3and Marcin Zawadzki 4 ,5 ,*
1Department of Pharmacology, Faculty of Medicine, University of Opole, 48 Oleska Street,
45052 Opole, Poland; karolina.nowak@uni.opole.pl
2Department of Forensic Medicine, Division of Molecular Techniques, Wroclaw Medical University,
Sklodowskiej-Curie 52, 50369 Wroclaw, Poland; agnieszka.chlopas-konowalek@umw.edu.pl
3Department of Forensic Medicine, Faculty of Medicine, Wroclaw Medical University,
4 J. Mikulicza-Radeckiego Street, 50345 Wroclaw, Poland; pawel.szpot@umw.edu.pl
4Department of Social Sciences and Infectious Diseases, Faculty of Medicine, Wroclaw University of Science
and Technology, 27 Wybrzeze Wyspianskiego Street, 50370 Wroclaw, Poland
5Institute of Toxicology Research, 45 Kasztanowa Street, 55093 Borowa, Poland
*Correspondence: m.zawadzki@pwr.edu.pl
†These authors contributed equally to this work.
Abstract: Cognitive enhancement through stimulants such as modafinil is becoming in-
creasingly popular, with many individuals using prescription stimulants for non-medical
purposes to improve alertness, attention, and mood. The misuse of such substances has
raised concerns, particularly in forensic toxicology. The UHPLC-QqQ-MS/MS method
was developed to quantify modafinil in evidentiary samples and biological materials.
Additionally, the authors noted the presence of sodium adducts during the analysis of
samples with high concentrations of modafinil. The method was validated for accuracy,
precision, and linearity, with a concentration range of
0.1–10.0 µg/mL
for the evidences
and
1.0–100.0 ng/mL
for blood. The method successfully detected modafinil as the sole
substance in all evidences, with concentrations ranging from 90.7 to 120.8 mg, correspond-
ing to 45.5% to 80.5% of the labeled dose. The method was applied to real post-mortem
human cases, where, among others, the concentration of modafinil in blood was 110 ng/mL,
whereas, in another case, the concentration of modafinil in the putrefaction fluid exceeded
1000 ng/mL. The developed UHPLC-QqQ-MS/MS method is effective for the quantifica-
tion of modafinil in evidentiary samples and biological materials, offering a reliable tool
for forensic toxicology applications. This method can be used to evaluate modafinil use in
both legal and illicit contexts, including cases of overdose or misuse.
Keywords: modafinil; evidence; biological material; forensic toxicology; UHPLC-QqQ-MS/MS
1. Introduction
Some people attempt to enhance their cognitive functions, such as alertness, atten-
tion, concentration, and memory, as well as psychological functions, such as mood and
sleep
[1–3]
, through the use of stimulants [
4
,
5
]. This phenomenon is referred to as phar-
maceutical neuroprotective enhancement or cognitive enhancement (CE) [
1
,
6
]. Substances
used for CE include over-the-counter products, such as caffeine pills and energy drinks [
3
,
7
],
and prescription stimulants, like methylphenidate and modafinil, which, despite their
therapeutic effects [
1
], are also misused without medical discretion as so-called “smart
drugs” [8–12].
J. Xenobiot. 2025,15, 15 https://doi.org/10.3390/jox15010015
J. Xenobiot. 2025,15, 15 2 of 18
Approximately 0.5 million young people [
13
,
14
] and 4.8 million adults (including
2.5 million
young adults aged 18–25) [
15
–
17
] reported using stimulants for non-medical
purposes in 2015. Among American adults, approximately 6.6% used prescription stim-
ulants (for both therapeutic and “smart drug” uses), with 4.5% using them as prescribed
without misuse and 2.1% misusing prescription stimulants at least once [
9
]. Epidemi-
ological data indicate that 5–9% of primary and secondary school children and 5–35%
of college-aged individuals in the United States used stimulants, primarily for cognitive
enhancement but also to experience a “high” [
12
,
18
–
20
]. In the adult population (among
students and academic professionals) in the U.S., the most common reasons for non-medical
stimulant use include performance enhancement (e.g., increased alertness, concentration,
productivity, study aid, and motivation to complete tasks—reported by 78% of respondents).
Additionally, 15.5% cited experimentation or seeking a “high” as motivation for misusing
prescribed stimulants, while about 4% reported weight loss as the primary motivation for
non-medical stimulant use [9,21].
Among German students, 1.55% used prescribed stimulants, and 2.6% used illegal
stimulants to enhance cognitive performance [
11
]. In 2010, 34% of Swiss employees reported
experiencing chronic stress compared to only 7% of participants in a similar study in 2000
who reported frequent high levels of stress [
22
]. Approximately 6% of Swiss employees took
substances to enhance cognitive function, and 15% used substances to relax and unwind
after stressful workdays [
23
]. In a study among French medical students, 0.8% admitted
to using modafinil to improve academic performance, concentration, and alertness [
24
].
In an anonymous survey among surgeons, 2.2% of respondents (n= 957) reported using
modafinil [
25
]. Other subjective benefits of using cognitive-enhancing drugs include
increased mental endurance [
26
] and greater interest in work [
27
]. Reported reasons for
using cognitive enhancers include anxiety about academic failure, the need to meet high
professional demands, overcoming procrastination, and boosting motivation [28].
Modafinil (MOD; 2-benzhydrylsulfinylacetamide) is considered the most commonly
used over-the-counter cognitive enhancer [
1
,
29
]. It is a centrally acting sympathomimetic
drug and a non-amphetamine stimulant, similar to methylphenidate and piracetam, exhibit-
ing a complex neurochemical profile that affects both online and offline processes. MOD is
currently used in the treatment of narcolepsy [
27
–
30
] and idiopathic hypersomnia, demon-
strating significant therapeutic benefits by promoting wakefulness and alertness in shift
work disorder [
1
,
31
] and obstructive sleep apnea [
30
,
32
–
34
]. It also showed potential in
treating neurodegenerative disorders (e.g., Alzheimer’s disease) and cognitive impairment
in schizophrenia [
35
]. MOD may enhance cognitive function in healthy individuals [
36
]
and was noted to improve symptoms in children and adults with ADHD [
37
]. Addition-
ally, modafinil has gained attention for its potential in treating cocaine addiction [
38
] and
methamphetamine addiction [39].
Modafinil was first introduced to the pharmaceutical market in France in the 1990s
as an eugeroic drug for narcolepsy. In 1998, the Food and Drug Administration (FDA) in
several countries (outside Europe) approved MOD for the treatment of narcolepsy, and in
2003, for shift work sleep disorder and obstructive sleep apnea [40].
The mechanism of action of MOD is complex and not fully understood [
41
]. Al-
though modafinil is classified as a psychostimulant, it operates along a neural pathway
distinct from that of amphetamine and cocaine [
33
]. It was shown to directly or indi-
rectly activate the dopaminergic [
42
,
43
], glutamatergic [
44
], noradrenergic [
30
,
42
], and
serotonergic [
42
] systems in various brain regions, including the prefrontal cortex, hip-
pocampus, hypothalamus, and striatum, while inhibiting GABAergic pathways in these
same regions [
1
,
8
,
21
,
30
,
36
,
41
,
44
–
46
]. However, Volkow et al. demonstrated the addictive
J. Xenobiot. 2025,15, 15 3 of 18
potential of modafinil through the inhibition of dopamine reuptake by DAT in the nucleus
accumbens [43].
After oral administration, MOD is rapidly absorbed from the gastrointestinal tract.
The therapeutic dose for adults ranges from 200 to 400 mg per day, administered in two
divided oral doses [
43
,
47
]. A 600 mg dose (administered orally) in humans did not produce
any patient-reported psychoactive effects (such as a high, rush, or stimulation) [
48
]. Even
the intake of modafinil by adults in doses several times higher than the recommended daily
doses does not cause life-threatening effects. Modafinil can be abused due to its stimulant
effects and can cause aggressive states or psychotic pathologies, which requires increased
monitoring. The uncontrolled consumption of this compound can also cause agitation,
insomnia, restlessness, irritability, aggression, confusion, nervousness, tremors, and palpita-
tions [
49
–
52
]. No life-threatening toxicity occurred, and to date, no fatal overdoses occurred
involving modafinil alone, but the simultaneous overdoses of multiple drugs, including
modafinil, have led to death [
53
]. The literature reported a case of a 15-year-old girl who
took 5000 mg (5 g) of modafinil at one time for suicidal purposes. Despite taking 60 times
the recommended dose of modafinil, this did not result in death [
51
]. Another case involved
a 17 year old who ingested 12 g of modafinil and required hospitalization due to altered
consciousness and encephalopathy caused by intoxication. Following discharge, the patient
exhibited persistent psychotic symptoms, including visual and auditory hallucinations [
50
].
The data on its use in toxic doses are also limited.
Following a single oral dose of 100 mg modafinil in 12 children, the average maxi-
mum plasma concentration was reached in approximately 2.1 h, averaging 2.2 mg/L. A
single
200 mg
oral dose administered to 24 adult patients reached a mean peak plasma
concentration of 4.8 mg/L in about 1.8 h [
54
]. The oral bioavailability of MOD is 40–60%.
Intravenous administration in humans was excluded due to its low solubility in water [
55
].
MOD is available in oral tablets [
47
]. It consists of R-(
−
) and S-(+) enantiomers and
was originally prescribed as a racemate under trade names such as Provigil
®
, Modasomil
®
,
Modavigil
®
, Modiodal
®
, Modalert
®
, and Vigil
®
[
56
]. The S- and R-isomers have equal
pharmacological activity but differ in pharmacokinetics. The R-isomer, marketed as ar-
modafinil, has a half-life of approximately 10–14 h, whereas the S-isomer is eliminated
more rapidly with a half-life of 3–5 h [
57
]. In individuals with liver or kidney impairment
and in older adults, the half-life may be prolonged. In patients with liver cirrhosis, the
elimination of modafinil decreases by approximately 60% [58].
Modafinil binds moderately to plasma proteins (approximately 60%), primarily to
albumin, which suggests a low risk of interactions with drugs that are strongly protein-
bound. The drug is metabolized in the liver through the cytochrome P450, primarily by
CYP3A4 and, to a lesser extent, by CYP2C9. Additionally, armodafinil is both a substrate
and an inhibitor of P-glycoprotein [
59
]. Moreover, MOD has the potential to inhibit
CYP2C19. Therefore, the co-administration of modafinil with drugs such as diazepam,
phenytoin, and propranolol may increase the blood levels caused by these medications. In
patients receiving these drugs, dose adjustments may also be necessary [
60
]. Approximately
10% of the administered dose is excreted as unchanged in the urine, while around 40–60%
undergoes conjugation to modafinilic acid, which, along with hydroxy-modafinil and
modafinil sulfone, is pharmacologically inactive [54,55].
The objective of this study was to develop and validate the UHPLC-QqQ-MS/MS
method for the simultaneous detection of modafinil in samples (tablets) and its quantifica-
tion in biological materials, such as peripheral blood, urine, vitreous humor, putrefaction
fluid, liver, kidney, and brain. The validated methods were applied to analyze five samples
in the form of tablets containing modafinil, purchased online, as well as for the determi-
J. Xenobiot. 2025,15, 15 4 of 18
nation of modafinil concentrations in post-mortem biological materials from three cases
(unrelated to modafinil intoxication).
2. Materials and Methods
2.1. Chemicals
Water (chemsolve
®
LC–MS), acetonitrile (chemsolve
®
LC–MS), and methanol (chemsolve
®
LC–MS) were purchased from WITKO (Łód´z, Poland); formic acid and ammonium formate
were purchased from Chem-Lab NV (Zedelgem, Belgium); modafinil was purchased from
Supelco (Roun Dock, TX, USA), internal standard methylphenidate-d
9
was purchased from
Ceriliant (Round Rock, TX, USA). Structures of modafinil and IS are presented in Figure S1
in Supplementary Materials.
2.2. Tested Samples
Five evidentiary samples (designated as D1–D5) were analyzed. The samples were
obtained from volunteers professionally engaged in emergency medical services, who
reported purchasing the products from websites. The products were originally claimed
to have originated from Asian countries. Each specimen was encased within a fragment
of a blister, as illustrated in Figure 1(D1—unknown name, D2—“Waklert
®
150”, D3—
“Modalert
®
200”, D4—“Modvigil
®
-200”, D5—“Modafresh-200”). The blister packs were
made of high-quality materials and, together with the printed labels, created the impres-
sion of authentic products. The individual blisters were enveloped in plastic bags, with
handwritten notes. Notably, each tablet exhibits a circular, convex shape and a lustrous,
snow-white appearance (Figure S2 in Supplementary Materials).
J. Xenobiot. 2025, 15, x FOR PEER REVIEW 4 of 18
determination of modafinil concentrations in post-mortem biological materials from three
cases (unrelated to modafinil intoxication).
2. Materials and Methods
2.1. Chemicals
Water (chemsolve® LC–MS), acetonitrile (chemsolve® LC–MS), and methanol (chem-
solve® LC–MS) were purchased from WITKO (Łódź, Poland); formic acid and ammonium
formate were purchased from Chem-Lab NV (Zedelgem, Belgium); modafinil was pur-
chased from Supelco (Roun Dock, TX, USA), internal standard methylphenidate-d9 was
purchased from Ceriliant (Round Rock, TX, USA). Structures of modafinil and IS are pre-
sented in Figure S1 in Supplementary Materials.
2.2. Tested Samples
Five evidentiary samples (designated as D1–D5) were analyzed. The samples were
obtained from volunteers professionally engaged in emergency medical services, who re-
ported purchasing the products from websites. The products were originally claimed to
have originated from Asian countries. Each specimen was encased within a fragment of a
blister, as illustrated in Figure 1 (D1—unknown name, D2—“Waklert® 150”, D3—
“Modalert® 200”, D4—“Modvigil®-200”, D5—“Modafresh-200”). The blister packs were
made of high-quality materials and, together with the printed labels, created the impres-
sion of authentic products. The individual blisters were enveloped in plastic bags, with
handwritten notes. Notably, each tablet exhibits a circular, convex shape and a lustrous,
snow-white appearance (Figure S2 in Supplementary Materials).
Figure 1. Cont.
J. Xenobiot. 2025,15, 15 5 of 18
J. Xenobiot. 2025, 15, x FOR PEER REVIEW 5 of 18
Figure 1. Fragments of blisters with tested samples. View from two sides of blisters.
2.2.1. Working Solutions, Calibration Curve, and Quality Control Samples
The standard solution (at concentration of 100 µg/mL) of modafinil was prepared in
acetonitrile, and the internal standard (IS) was prepared in methanol. The working solu-
tions of different concentrations were prepared by the dilution of the standard solution
with acetonitrile and were stored with stock solutions at −20 °C.
Evidentiary Samples
Calibration points (n = 9; 0.1, 0.2, 0.5, 0.8, 1.0, 2.0, 5.0, 8.0, and 10.0 µg/mL) and quality
control (QC) samples (n = 3) were prepared by spiking the appropriate working solution
into acetonitrile solutions.
Biological Materials
Calibration points (n = 7; 1, 2.5, 5, 10, 25, 50, and 100 ng/mL) and QC samples (n = 2)
were prepared as outlined above.
2.2.2. Procedure
Evidentiary Samples
Each tablet was weighted on an analytical scale (AS 220.R2, RADWAG, Radom, Po-
land) and then transferred into 10 mL plastic vials with 5 mL of methanol (LC-MS grade),
tightly closed, and sonificated for 30 min (Ultrasonic Cleaner USC300TH, VWR, Gdańsk,
Poland). Next, the samples were centrifuged at 2540× g at 4 °C for 10 min. The supernatant
was diluted with methanol by 10,000 folds. Then, 10 µL of the diluted sample was trans-
ferred into a 2 mL Eppendorf tube containing 10 µL of IS (methylphenidate-d9, 1 µg/mL)
and 80 µL of methanol. After mixing, the solution was transferred into inserts for au-
tosampler vials and analyzed by ultra-high performance liquid chromatography–triple
quadrupole tandem mass spectrometry (UHPLC-QqQ-MS/MS). The injection volume was
2 µL. All samples were prepared and analyzed in duplicates.
Figure 1. Fragments of blisters with tested samples. View from two sides of blisters.
2.2.1. Working Solutions, Calibration Curve, and Quality Control Samples
The standard solution (at concentration of 100
µ
g/mL) of modafinil was prepared
in acetonitrile, and the internal standard (IS) was prepared in methanol. The working
solutions of different concentrations were prepared by the dilution of the standard solution
with acetonitrile and were stored with stock solutions at −20 ◦C.
Evidentiary Samples
Calibration points (n= 9; 0.1, 0.2, 0.5, 0.8, 1.0, 2.0, 5.0, 8.0, and 10.0
µ
g/mL) and quality
control (QC) samples (n= 3) were prepared by spiking the appropriate working solution
into acetonitrile solutions.
Biological Materials
Calibration points (n= 7; 1, 2.5, 5, 10, 25, 50, and 100 ng/mL) and QC samples (n= 2)
were prepared as outlined above.
2.2.2. Procedure
Evidentiary Samples
Each tablet was weighted on an analytical scale (AS 220.R2, RADWAG, Radom, Poland)
and then transferred into 10 mL plastic vials with 5 mL of methanol (LC-MS grade), tightly
closed, and sonificated for 30 min (Ultrasonic Cleaner USC300TH, VWR, Gda´nsk, Poland).
Next, the samples were centrifuged at 2540
×
gat 4
◦
C for 10 min. The supernatant was
diluted with methanol by 10,000 folds. Then, 10
µ
L of the diluted sample was transferred
into a 2 mL Eppendorf tube containing 10
µ
L of IS (methylphenidate-d
9
, 1
µ
g/mL) and
80 µL
of methanol. After mixing, the solution was transferred into inserts for autosampler
vials and analyzed by ultra-high performance liquid chromatography–triple quadrupole
tandem mass spectrometry (UHPLC-QqQ-MS/MS). The injection volume was 2
µ
L. All
samples were prepared and analyzed in duplicates.
J. Xenobiot. 2025,15, 15 6 of 18
Biological Materials
Post-mortem samples of various biological matrices were designated for routine toxi-
cological analysis: peripheral blood, urine, vitreous humor, putrefaction fluid, fragments
of liver, kidney, and brain. Samples of post-mortem biological fluids (0.2 mL each) and
homogenates of organs (0.2 g of each homogenate) were prepared according to the standard
procedure of our laboratory (liquid–liquid extraction (LLE) with 2 mL ethyl acetate, pH = 9
after the addition of 0.2 mL of ammonium carbonate and 0.02 mL of IS (methylphenidate-d
9
in concentration of 1
µ
g/mL), vortexed for 10 min, and centrifuged for 10 min at
2540×g
at 4
◦
C; the supernatant evaporated to dryness under the stream of N
2
, and, finally, the
dry residues diluted with 0.05 mL of methanol) [
61
–
65
]. This same procedure was used to
perform the calibration curve and method validation. Due to concentrations in biological
materials exceeding the ULOQ, additional measurements were performed following prior
dilution. The dilution effect was also assessed as part of the method validation.
2.2.3. Chromatographic and Spectrometric Conditions
Qualitative and quantitative toxicological analyses were performed using an ultra-high-
performance liquid chromatograph (Nexera X2, Shimadzu, Kyoto, Japan). The separation
was completed on Kinetex XB-C18 2.6
µ
m 2.1
×
150 mm column (Phenomenex, Torrance, CA,
USA). The thermostat was set at 40
◦
C. The mobile phase included (A)
10 mM
ammonium
formate in water with 0.1% formic acid and (B) acetonitrile with 0.1% formic acid. The gradient
elution was carried out at a constant flow of 0.4 mL/min. The applied gradient was as follows:
0 min, 5% B; 12 min, 98% B; 14 min, 98% B; and 15 min, 5% B; and those conditions were
carried out for 5 min. This mobile phase composition was employed for the quantitative
determination of modafinil in evidences (tablets) and biological materials.
In addition, in order to check the influence of the composition of the mobile phase on
the ability to monitor the modafinil precursor as 274 m/z([M + H]
+
), beyond the phase
used for the quantitative analysis, we performed two additional experiments. In the first
one, the phase composition was pure water (A) and pure acetonitrile (B), while, in the
second one, we used water with 0.1% formic acid and acetonitrile with 0.1% formic acid
(B). In both cases, the gradient elution remained the same.
A triple quadrupole mass spectrometer (LCMS-8050, Shimadzu, Kyoto, Japan)
equipped with an electrospray ionization (ESI) source was used for the detection of the
investigated compounds. Analyses were performed in two directions: the 1st was general
untargeted screening (scan mode, range of 50–1000 m/z) for checking for any impurities,
and the 2nd was the determination of the investigated substances in the multiple reaction
monitoring (MRM) positive mode.
The following MS parameters were fixed for both targeted (MRM) and untargeted analyses
(scan mode): nebulizing gas flow, 3 L/min; heating gas flow, 10 L/min; interface temperature,
250
◦
C; desolvation line (DL) temperature, 200
◦
C; heat block temperature, 350
◦
C; and drying
gas flow, 10 L/min. A summary of precursor and product ions, collision energies, dwell time,
Q1–Q3 pre-bias voltages, and retention time for modafinil and IS are presented in Table 1.
Table 1. MRM conditions used in the UHPLC/ESI-MS/MS analysis of modafinil and IS.
Compounds Precursor
Ion [m/z]
Product Ion
[m/z]
Dwell
(msec)
Q1 Pre-Bias
[V]
Collision
Energy [V]
Q3 Pre-Bias
[V]
Retention
Time [min]
Modafinil 166.9 152.1 *
115.2 2.0 −11
−11
−22
−40
−15
−19 5.57
Methylphenidate-d9242.9 93.1 *
61.1 1.0 −11
−15
−22
−49
−15
−10 4.42
* Ions selected for quantitative analysis.
J. Xenobiot. 2025,15, 15 7 of 18
2.2.4. Validation
Evidentiary Samples
The validation did not account for tablet morphology or the stability of the substance
in evidence samples. Validation included the determination of the following parameters:
limit of detection (LOD), lower limit of quantification (LLOQ), upper limit of quantification
(ULOQ), linearity, coefficient of determination (R
2
), intra- and inter-day precision, and
intra- and inter-day accuracy (n= 5; concentration: 0.2, 1.0, 8.0
µ
g/mL). Additionally, to
verify the selectivity of the method, samples in the form of tablets containing quetiapine
were prepared and analyzed using the presented method (applying the same dilutions for
the evidence samples).
The method validation was based on the recommendations outlined in the Guidance
for the Validation of Analytical Methodology and Calibration of Equipment used for Testing
of Illicit Drugs in Seized Materials and Biological Specimens (United Nations Office on
Drugs and Crime, UNODC) [66].
Biological Materials
Validation included: LOD, LOQ, ULOQ, R
2
, intra- and inter-day precision, intra- and
inter-day accuracy, recovery, and matrix effect (n= 5; concentration: 10 and
100 ng/mL
).
Method validation was performed in accordance with the Scientific Working Group for
Forensic Toxicology (SWGTOX) standard practices for method validation in forensic toxi-
cology [
67
]. To verify the selectivity of the method, blank samples of the analyzed matrices
were routinely tested. For matrices such as vitreous humor and organ fragments, biological
materials collected from deceased individuals were analyzed. These materials, previously
examined and designated for disposal per the experimenter’s decision, were used for
this purpose.
3. Results
3.1. Evidentiary Samples
Figure 2shows the characteristic precursor ions corresponding to modafinil or its
sodium adducts, observable in the positive Q3 scan mode of evidentiary samples (adducts
were observed for the analytical standard at high concentrations). Figure 3presents the
structures of two sodium adducts: [M + Na]
+
(296 m/z) and the dimer [2M + Na]
+
(
569 m/z
).
Figure S3 in the Supplementary Materials illustrates the proposed fragmentation of the
296 m/zion.
J. Xenobiot. 2025, 15, x FOR PEER REVIEW 7 of 18
Methylphenidate-
d
9
242.9 93.1 *
61.1 1.0 −11
−15
−22
−49
−15
−10 4.42
* Ions selected for quantitative analysis.
2.2.4. Validation
Evidentiary Samples
The validation did not account for tablet morphology or the stability of the substance
in evidence samples. Validation included the determination of the following parameters:
limit of detection (LOD), lower limit of quantification (LLOQ), upper limit of quantifica-
tion (ULOQ), linearity, coefficient of determination (R
2
), intra- and inter-day precision,
and intra- and inter-day accuracy (n = 5; concentration: 0.2, 1.0, 8.0 µg/mL). Additionally,
to verify the selectivity of the method, samples in the form of tablets containing quetiapine
were prepared and analyzed using the presented method (applying the same dilutions
for the evidence samples).
The method validation was based on the recommendations outlined in the Guidance
for the Validation of Analytical Methodology and Calibration of Equipment used for Test-
ing of Illicit Drugs in Seized Materials and Biological Specimens (United Nations Office
on Drugs and Crime, UNODC) [66].
Biological Materials
Validation included: LOD, LOQ, ULOQ, R
2
, intra- and inter-day precision, intra- and
inter-day accuracy, recovery, and matrix effect (n = 5; concentration: 10 and 100 ng/mL).
Method validation was performed in accordance with the Scientific Working Group for
Forensic Toxicology (SWGTOX) standard practices for method validation in forensic tox-
icology [67]. To verify the selectivity of the method, blank samples of the analyzed matri-
ces were routinely tested. For matrices such as vitreous humor and organ fragments, bio-
logical materials collected from deceased individuals were analyzed. These materials, pre-
viously examined and designated for disposal per the experimenter’s decision, were used
for this purpose.
3. Results
3.1. Evidentiary Samples
Figure 2 shows the characteristic precursor ions corresponding to modafinil or its
sodium adducts, observable in the positive Q3 scan mode of evidentiary samples (adducts
were observed for the analytical standard at high concentrations). Figure 3 presents the
structures of two sodium adducts: [M + Na]
+
(296 m/z) and the dimer [2M + Na]
+
(569 m/z).
Figure S3 in the Supplementary Materials illustrates the proposed fragmentation of the
296 m/z ion.
Figure 2. Q3 scan of one of analyzed evidences.
Figure 2. Q3 scan of one of analyzed evidences.
J. Xenobiot. 2025,15, 15 8 of 18
J. Xenobiot. 2025, 15, x FOR PEER REVIEW 8 of 18
NH2
O
S
O
Na
+
N
O
S
O
H
H
NH2
O
S
O
Na+
[M + Na]+
[2M + Na]+
Figure 3. Structures of sodium adduct that can be observed in analyzed evidences.
Figure 4 shows product ion scan mass spectra of modafinil (precursor ion set to 167
m/z). Figure S4 (in Supplementary Materials) shows chromatograms with MRM transi-
tions typical for modafinil and IS.
Figure 4. Mass spectra of modafinil in product ion scan mode (CE: 10 (A), 20 (B), and 35 V (C)).
The linear concentration range was 0.1–10.0 µg/mL, LOD was 0.05 µg/mL, LLOQ was
0.1 µg/mL, ULOQ was 10.0 µg/mL, and R2 > 0.9999. Intra- and inter-day precision, as well
as intra- and inter-day accuracy, for all of three concentrations (low-QC, medium-QC,
high-QC; n = 5) were below 5% (detailed information in Table S1 in Supplementary Mate-
rials). The method was successfully applied to quantify modafinil in the evidence samples.
In all cases, modafinil was the only active substance detected (filling agents were not an-
alyzed). The modafinil content in individual samples ranged from 90.7 to 120.8 mg, cor-
responding to 45.5% to 80.5% of the stated dose, as indicated on the packaging. Detailed
results are presented in Table 2.
B
C
A
Figure 3. Structures of sodium adduct that can be observed in analyzed evidences.
Figure 4shows product ion scan mass spectra of modafinil (precursor ion set to
167 m/z
). Figure S4 (in Supplementary Materials) shows chromatograms with MRM
transitions typical for modafinil and IS.
J. Xenobiot. 2025, 15, x FOR PEER REVIEW 8 of 18
[M + Na]
+
[2M + Na]
+
Figure 3. Structures of sodium adduct that can be observed in analyzed evidences.
Figure 4 shows product ion scan mass spectra of modafinil (precursor ion set to 167
m/z). Figure S4 (in Supplementary Materials) shows chromatograms with MRM transi-
tions typical for modafinil and IS.
Figure 4. Mass spectra of modafinil in product ion scan mode (CE: 10 (A), 20 (B), and 35 V (C)).
The linear concentration range was 0.1–10.0 µg/mL, LOD was 0.05 µg/mL, LLOQ was
0.1 µg/mL, ULOQ was 10.0 µg/mL, and R
2
> 0.9999. Intra- and inter-day precision, as well
as intra- and inter-day accuracy, for all of three concentrations (low-QC, medium-QC,
high-QC; n = 5) were below 5% (detailed information in Table S1 in Supplementary Mate-
rials). The method was successfully applied to quantify modafinil in the evidence samples.
In all cases, modafinil was the only active substance detected (filling agents were not an-
alyzed). The modafinil content in individual samples ranged from 90.7 to 120.8 mg, cor-
responding to 45.5% to 80.5% of the stated dose, as indicated on the packaging. Detailed
results are presented in Table 2.
B
C
A
Figure 4. Mass spectra of modafinil in product ion scan mode (CE: 10 (A), 20 (B), and 35 V (C)).
The linear concentration range was 0.1–10.0
µ
g/mL, LOD was 0.05
µ
g/mL, LLOQ
was 0.1
µ
g/mL, ULOQ was 10.0
µ
g/mL, and R
2
> 0.9999. Intra- and inter-day precision,
as well as intra- and inter-day accuracy, for all of three concentrations (low-QC, medium-
QC, high-QC; n= 5) were below 5% (detailed information in Table S1 in Supplementary
Materials). The method was successfully applied to quantify modafinil in the evidence
samples. In all cases, modafinil was the only active substance detected (filling agents were
not analyzed). The modafinil content in individual samples ranged from 90.7 to 120.8 mg,
corresponding to 45.5% to 80.5% of the stated dose, as indicated on the packaging. Detailed
results are presented in Table 2.
J. Xenobiot. 2025,15, 15 9 of 18
Table 2. Results of toxicological analyzes of evidentiary samples.
No. Determined
Substance
Tablet
Weight [mg]
Amount of
Substance in the
Sample [mg]
Percentage of
the Total Weight
of the Tablet [%]
Probable Dose
(Data from the
Bister) [mg]
Percentage
of the Dose
[%]
Presence of
Impurity
D.1 Modafinil 401.0 90.7 22.5 200 * 45.5 No
D.2 Modafinil 269.2 120.8 44.9 150 80.5 No
D.3 Modafinil 318.4 92.0 28.9 200 46.0 No
D.4 Modafinil 333.0 109.7 32.9 200 54.8 No
D.5 Modafinil 341.1 105.3 30.8 200 52.6 No
* Information from handwritten inscription on the plastic bag.
3.2. Biological Materials
The linear concentration range was 1.0–100 ng/mL, LOD was 0.5 ng/mL, LLOQ was
1.0 ng/mL, ULOQ was 100 ng/mL, and R2> 0.9999. The remaining results of the method
validation is shown in Table 3.
Table 3. Results of biological material method’s validation; n= 5.
Validation Results
Intra-day precision [%] 10 ng/mL 2.3
100 ng/mL 14.9
Intra-day accuracy [%] 10 ng/mL 8.6
100 ng/mL 5.8
Iner-day precision [%] 10 ng/mL 2.9
100 ng/mL 10.0
Inter-day accuracy [%] 10 ng/mL 13.0
100 ng/mL 6.3
Recovery [%] 10 ng/mL 111.1
100 ng/mL 110.8
Matrix effect [%] 10 ng/mL 105.8
100 ng/mL 110.2
Similarly to the evidentiary samples, the method was successfully applied to determine
the MOD in biological materials. Table 4shows the concentrations of MOD in three post-
mortem cases. Additionally, in case 1, modafinil sulfone was qualitatively detected in all
tested samples.
Table 4. Modafinil concentrations in authentic forensic cases (biological fluids and tissues).
Concentrations of Modafinil [ng/mL aor ng/g b]
Case Number/Sex
Biological Material
Blood Urine Vitreous Humor Putrefaction Fluid Liver Kidney Brain
Case 1/Male 110 >3000 30 (−) 250 210 410
Case 2/Male (−) (−) (−) >1000 (−) (−) (−)
Case 3/Male 0 14 (−) (−) (−) (−) (−)
(−) material was not collected, aconcentration for biological fluids, bconcentration for solid tissues.
J. Xenobiot. 2025,15, 15 10 of 18
4. Discussion
Modafinil, in addition to its approved use for treating excessive sleepiness—classified
as a “smart drug”—is frequently misused by healthy individuals, including night-shift
workers, students, and healthcare professionals [
8
–
12
]. These individuals use modafinil to
combat fatigue and drowsiness, enhance concentration and alertness, improve memory
and cognitive abilities, and cope with stress and anxiety; some also misuse it to experience
a euphoric “high” [12,18–20].
Although the long-term effects of modafinil use in healthy individuals remain un-
known, the drug is easily accessible online, often with limited information about its use
and potential harmful effects [
68
,
69
]. Other acquisition options include online shops, retail
outlets, pharmacies (with or without a prescription), and sources such as colleagues, friends,
or family [
68
]. The core issue lies in the uncertainty regarding whether the purchased prod-
uct is an authentic medicinal product, with its qualitative and quantitative composition
matching the approved characteristics, or if it deviates from the manufacturer’s guaranteed
standards. Products purchased from the black market, which often closely mimic the
appearance of legitimate pharmaceutical products, may pose serious risks to the health and
safety of users. This could inspire trust among users unaware of the potential risks, leading
them to mistakenly believe they are dealing with a product of controlled quality. These
risks particularly arise from discrepancies in the actual content of the active substance in
such products.
In cases of high modafinil concentrations in evidentiary samples, both precursor ions
and sodium adducts, such as [M + Na]
+
and the dimer [2M + Na]
+
, can be observed. In our
study, these adducts formed independently of the mobile phase compositions we tested.
Pan [
70
] suggested that dimer formation can be concentration-dependent, indicating a
non-covalent association, with the abundance of dimer ions correlating with the expected
number of hydrogen bonds within the molecules. Additionally, Grocholska et al. [
71
] noted
that the greatest challenge in forming non-covalent complexes in the ESI-MS mode un-
equivocally proved that the binding is specific. Mass spectrometry often detects nonspecific
complexes, influenced by ionization source parameters and analyte concentrations.
In biological samples, the 274 m/zion is typically not observed, with only diphenyl-
methylium being detected. The absence of the [M + H]
+
ion is attributed to its low stability
in the ion source, which promotes the formation of diphenylmethylium via a charge-
directed mechanism [72].
Table S2 in the Supplementary Materials presents the selected parameters for modafinil
detection methods using liquid chromatography coupled with an MS/MS detector in
biological samples. To date, LC-MS/MS techniques were not used for the quantitative
analysis of modafinil in evidentiary samples. Our developed method was applied to both
the samples and biological materials.
For the samples we analyzed, modafinil was the only detected substance. Its concen-
tration in the individual evidentiary samples ranged from 90.7 to 120.8 mg, corresponding
to 45.5 to 80.5% of the labeled dose (based on blister pack information). Assi et al. [
73
]
analyzed eight tablets purchased from four different websites, with labeled doses of 100
and 200 mg of modafinil. The modafinil content in these tablets ranged from 57.6 to 72.7%.
The researchers employed the following methods to determine the content of MOD: Fourier
transform-infrared (FTIR), near-infrared (NIR), and Raman spectroscopy. Harvanová and
Gondová [
74
] conducted enantioseparation studies on R- and S-modafinil in five sam-
ples: three were commercial pharmaceutical preparations of modafinil and armodafinil
purchased from a pharmacy and an online pharmacy, while the other two were illegal
modafinil powders bought online from China. The relative standard deviation (RSD) for
the three pharmacy-obtained samples ranged from 0.3 to 0.7%, while the modafinil content
J. Xenobiot. 2025,15, 15 11 of 18
in the illegal powders was 99.5% and 96.9%, respectively (the sum of S- and R-MOD). The
authors analyzed, among others, Modvigil™ (200 mg) and Waklert
®
(150 mg), obtained
from a local drug store in Ukraine and an online pharmacy (also in Ukraine). The content of
R,S-MOD in Modvigil™ was 198.4
±
0.5 mg (out of the declared 200 mg), while the content
of R-MOD in the Waklert
®
product was 150.8
±
0.5 mg (out of the declared
150 mg
). In
contrast, in our study, products with the same names contained MOD at levels of 80.5%
(Waklert
®
) and 54.8% (Modvigil
®
), respectively. The samples we examined most likely
came from the black market. In addition, we did not know the expiration date, which is
also crucial in the case of an active substance content. This is a clear example demonstrat-
ing that counterfeit products, mimicking pharmaceutical-grade items, fall outside quality
control standards and have compositions (and contents) that differ from those declared
on the packaging. The authors [
74
] employed an HPLC-UV method for the determination
(calibration curves in a range of 5–150
µ
g/mL; R
2
> 0.999; LOD: 15 (R-MOD) and 20 ng/mL
(S-MOD); LLOQ: 45 (R-MOD) and 60 ng/mL (S-MOD); recoveries: 100.5–102.3% (SD from
0.4 to 1.0% for both enantiomers)).
Among the methods developed to date for the determination of modafinil in biologi-
cal samples, and in pharmaceutical formulations, it is worth mentioning those utilizing
e.g., high-performance liquid chromatography with ultraviolet detection (HPLC-UV) [
75
],
mass spectrometry (MS) [
76
], gas chromatography coupled with mass spectrometry (GC-
MS) [
77
], and capillary electrophoresis with PDA detection (CE-PDA) [
78
,
79
] methods
were developed.
Table S2 in the Supplementary Materials presents selected parameters of LC-MS/MS
methods for the determination of modafinil in biological materials. The extraction methods
include LLE, solid-phase extraction (SPE), and protein precipitation (PP). All methods
listed in Table S2 utilized a C18 column, a commonly used type of column for analyses
in clinical and forensic toxicology. The composition of the mobile phase in most methods
was a mixture of water and acetonitrile, with or without additives such as acetic acid and
ammonium formate. Similarly, both our method and the majority of methods listed in
Table S2 for modafinil determination employed a gradient program for the mobile phase.
In our method, the injection volume was among the smallest, and some methods
used non-deuterated analytical standards as internal standards, which would render such
methods unsuitable for forensic toxicology. The LLOQ in our method was 1 ng/mL,
comparable to other methods for determining modafinil in plasma samples. For urine
samples, LC-MS/MS methods typically have higher LOD and LLOQ values, in the range
of 100–300 ng/mL. The recovery rates, both in our method and in other methods described
in Table S2, were satisfactory.
Modafinil is available by prescription and is characterized by low potency, requiring
high doses to achieve significant stimulant effects [
80
]. Its onset of action is slow, typically
occurring 60–100 min after administration [81].
Overdoses of modafinil are sporadic but can result in life-threatening toxicity [
68
,
69
].
One reported case involved a healthy 32-year-old man who was found unconscious, face
down on the bathroom floor, with evidence of vomiting. An empty blister pack of modafinil
and equipment for insufflation were discovered nearby. The patient was admitted to the
emergency department, where he was intubated while sedated and then transferred to the
intensive care unit (ICU). Upon regaining lucidity, the patient confirmed having insufflated
an estimate of over 600 mg and ingesting a methylphenidate (less than 200 mg). Clinicians
attributed his condition to severe hyponatremia and subsequent cerebral edema caused by
the modafinil overdose [53].
In general, modafinil overdose symptoms are mild and include headaches, dizziness,
nausea, tachycardia, insomnia, nervousness, diarrhea, anxiety, and abdominal pain [
58
].
J. Xenobiot. 2025,15, 15 12 of 18
Clinical studies showed that doses up to 1200 mg/day for 7–21 days or a single dose
as high as 4500 mg do not typically result in life-threatening effects. However, other
adverse effects were observed, including anxiety, irritability, aggression, confusion, tremors,
palpitations, chest pain, and sleep disturbances. Doses exceeding 1000 mg were associated
with dyskinesia, likely due to dopaminergic activity [51].
Accidental poisonings involving modafinil were also reported in children. The high-
est reported accidental ingestion involved a 3-year-old boy who consumed 800–1000 mg
(
50–63 mg/kg
) of modafinil but remained in a stable condition [
51
]. In two cases involv-
ing teenage girls, symptoms included tachycardia, insomnia, agitation, dizziness, and
anxiety, with serum modafinil concentrations of 13–18 mg/L measured 18–24 h post-
hospitalization [54].
In another instance, a 14-year-old girl ingested 20 tablets containing 200 mg modafinil
each and 10 tablets containing 10 mg escitalopram each [
82
]. Her symptoms were similar to
those previously described [
58
], and her serum modafinil concentration was measured at
18 mg/L 24 h after hospital admission [
82
]. A separate case involved a 16-year-old girl who
presented with rapid heartbeat, headache, “tingling sensations”, transient chest pain, and
behavioral changes, including anxiety and visual hallucinations. A serum sample taken
18 h
post-admission revealed a modafinil concentration of 13 mg/L, although the timing
and amount of modafinil ingested were unclear [83].
Modafinil is often regarded as having a very low potential for abuse and dependence.
Many believe it is not addictive because it does not directly target the brain’s reward
circuitry [
84
]. However, several cases of modafinil addiction were reported. Four case
reports documented modafinil dependence syndrome [
85
], involving individuals with
pre-existing psychiatric disorders, such as schizoaffective disorder [
52
,
85
] and bipolar
disorder [
86
], as well as a history of methamphetamine dependence [
87
]. Notably, no
cases of abuse or dependence were reported in patients taking modafinil for approved
medical conditions.
Modafinil should be used with caution in patients with a history of psychiatric disor-
ders, such as psychosis, depression, manic excitation, major anxiety disorders, psychomotor
agitation, insomnia, and substance abuse [47].
Furthermore, there is limited literature on blood concentrations of modafinil in cases in-
volving DUID (driving under the influence of drugs), suspected misuse, and/or intoxications.
One study presented five cases encountered during routine work, highlighting various
scenarios where modafinil ingestion was confirmed [
47
]. These included three cases of
DUID (2.1–3.8 mg/L of modafinil in blood), one case of bodily harm (1.3 mg/L), and one
case later confirmed as intoxication (approx. 34 mg/L of modafinil). The patient in the final
case experienced loss of consciousness, somnolence, disorientation, and slowed responses.
A headache, a known side effect of modafinil, was reported the following day when the
patient regained full consciousness.
According to Baselt, the therapeutic range of modafinil concentrations in plasma
is 2–9 mg/L [
54
], while Regenthal et al. reported a narrower therapeutic range of
0.9–3.3 mg/L [88]
. In the cases described, the modafinil concentrations measured were
below therapeutic levels and did not contribute to the individual’s death. For example, the
blood concentration reported in case 1 of this study (110.0 ng/mL) was significantly lower
than the concentrations observed in other cases [
47
]. This difference may be attributed to
the fact that none of the reported cases involved intentional self-harm using modafinil. It
may also be related to the use of black-market modafinil, which, as demonstrated in our
research, may contain a lower dose of the drug than stated on the packaging. Moreover, it
is difficult to interpret concentrations in cases where modafinil is detected in putrefaction
fluids or solid tissues (e.g., our case 2). In addition, modafinil was not the only substance
J. Xenobiot. 2025,15, 15 13 of 18
identified in all three cases. Among the substances detected were THC with metabolites,
CBD, cocaine with metabolites, amphetamine, methamphetamine, MDMA, MDA, ketamine
with metabolite, 2C-B, 4-chloromethcathinone (4-CMC), mephedrone, tadalafil, mianserine
with metabolite, levamisole, sildenafil with metabolites, aripiprazole with metabolite, and
several substances from the benzodiazepine class.
Modafinil intake appears to be relatively uncommon in both forensic and clinical
toxicology. According to literature data [
47
], police-related cases were all submitted to the
laboratory in 2015, while the hospital sample was sent in 2013. The statistics indicate that
approximately 14,000 clinical and forensic toxicology analyses were conducted annually.
In 2016, no cases of modafinil intake were reported [
47
]. From the authors’ experience,
after analyzing over 1,000 forensic toxicology samples annually, modafinil was detected
in only three cases (two in 2023 and one in 2024). These findings should be interpreted as
incidental and do not suggest an increasing trend in modafinil consumption.
It remains unclear whether this low number of reported abuse cases is due to the
limited availability of the drug, or if it reflects the drug’s lower abuse potential. Another
possible explanation is that patients abusing modafinil may not seek medical assistance or
contact poison centers for consultation.
Additionally, forensic toxicology laboratories do not receive samples from all autopsies,
as forensic pathologists often confirm causes of death unrelated to xenobiotic poisoning.
Another important consideration is that routine diagnostic testing typically focuses on
detecting ethanol, highly toxic drugs, and substances like benzodiazepines, barbiturates,
and opioids. Standard toxicology screening panels often do not detect “smart drugs”,
including modafinil.
5. Conclusions
The developed UHPLC-QqQ-MS/MS method was successfully applied for the quanti-
tative analysis of modafinil in the evidentiary samples and biological matrices, making it
suitable for use in forensic toxicology. The method was validated for accuracy, precision,
and linearity, with a concentration range of 0.1–10.0
µ
g/mL for evidentiary samples and
1.0–100.0 ng/mL for blood. For the evidentiary samples, intra- and inter-day precision,
as well as intra- and inter-day accuracy, for all of three checked QC concentrations were
below 5%. For biological materials, intra- and inter-day precision, as well as intra- and
inter-day accuracy, for both QC levels were below 15%, recovery was 111.1% for low QC
and 110.8% for high QC, and the matrix effect was 105.8% for low QC and 110.2% for high
QC samples. In the examined evidentiary samples, modafinil was the only detected active
substance; however, its content was lower than the amount declared on the packaging,
in some cases, by over 50%. Although modafinil was not the cause of death in the cases
studied and was present at low concentrations (case 1: 110 ng/mL in blood,
>3000 ng/mL
in urine, 30 ng/mL in vitreous humor, 250 ng/g in liver, 210 ng/g in kidney, 410 ng/g
in brain; case 2: >1000 ng/mL in putrefaction fluid; case 3: 14 ng/mL in urine), its pres-
ence indicates that “smart drugs” such as modafinil should be routinely monitored in
toxicological investigations.
Supplementary Materials: The following supporting information can be downloaded at: https:
//www.mdpi.com/article/10.3390/jox15010015/s1. Figure S1: Structures of modafinil and IS
(methylphenidate-d
9
). Figure S2: Tablets after removal from blisters. Figure S3: Proposed fragmen-
tation of sodium adduct of modafinil (296 m/z). Figure S4: MRM of modafinil in blank methanolic
solution sample (A), and stock solutions: 0.05
µ
g/mL (LOD) (B), 0.1
µ
g/mL (LLOQ) (C), 1.0
µ
g/mL
(D), and 10.0
µ
g/mL (ULOQ) (E); MRM of IS methylphenidate-d
9
in 1.0
µ
g/mL (F). Table S1: Results
of evidentiary sample method’s validation; n= 5. Table S2: Comparison of selected parameters
J. Xenobiot. 2025,15, 15 14 of 18
of methods for determining modafinil in biological matrices with the liquid chromatography with
MS/MS detection system [89–98].
Author Contributions: Conceptualization, K.N. and A.C.-K.; methodology, K.N. and A.C.-K.; valida-
tion, K.N. and A.C.-K.; formal analysis, K.N. and A.C.-K.; investigation, K.N. and A.C.-K.; resources,
K.N. and A.C.-K.; data curation, K.N. and A.C.-K.; writing—original draft preparation, K.N. and
A.C.-K.; writing—review and editing, K.N., A.C.-K., P.S. and M.Z.; visualization, K.N.; supervision,
P.S. and M.Z. All authors have read and agreed to the published version of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: The use of the forensic case samples collected from cadavers
was approved by the ethics committee of Wroclaw Medical University (No. 184/2023), approved on
16 February 2023.
Informed Consent Statement: Not applicable.
Data Availability Statement: The data that supports the findings in this study are available from the
corresponding authors upon reasonable request.
Conflicts of Interest: The authors declare no conflicts of interest.
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