272 Journal of Health Science, 51(3) 272–277 (2005)

— Minireview —

High-Performance Liquid Chromatographic

Analysis of Drugs of Abuse in Biologic
Samples
Kenichiro Nakashima*

Division of Analytical Research for Pharmacoinformatics, Department of Clinical Pharmacy, Course of Pharmaceutical Sciences,
Graduate School of Biomedical Sciences, Nagasaki University, 1–14 Bunkyo-machi, Nagasaki 852–8521, Japan

(Received December 16, 2004)

Recently, drug abuse has become a serious social problem world wide. In Japan, methamphetamine (MP) is the
most popular drug of abuse. In addition to MP, the use of 4,5-methylenedioxymethamphetamine (MDMA), called
ecstacy, is rapidly increasing, especially among young people. The development of simple and convenient analytical
methods for the analysis of these drugs of abuse is necessary for the prediction of and protection from human health
risks. Many useful methods have been developed for qualification and quantification of drugs of abuse. Among
these, gas chromatography with mass spectrometry (MS) and high-performance liquid chromatography with MS
(HPLC-MS or LC-MS) or fluorescence (HPLC-FL) detection are widely used. As highly sensitive methods, precolumn
or postcolumn derivatization methods are commonly utilized in HPLC. This review focuses on HPLC methods used
for the practical analysis of drugs of abuse, mainly for amphetamine derivatives and MDMAs in biologic samples
such as urine, blood, and hair.

Key words —–— analysis, drug abuse, high-performance liquid chromatography

INTRODUCTION thus can be easily taken orally, while MP that is

mainly taken by injection. For the prediction of and
Analyses of drugs of abuse are important for the protection from abuse of drugs, simple and sensi-
prediction of and protection from the risk to human tive methods for qualitative and quantitative analy-
health, especially for young people. The use of drugs ses are required. Many chromatographic methods
of abuse is increasing world wide and causing seri- such as thin-layer chromatography, gaschromatog-
ous social problems. In Japan, abuse of methamphet- raphy (GC), and high-performance liquid chroma-
amine (MP) is the most common and arrests for tography (HPLC) as well as immunoassays have
stimulant drug-related offences totaled 14624 in been developed. Among these, HPLC has been a
2003.1) Recently, the use of 4,5-methylenedioxy- secondary choice. However, HPLC essentially can
methamphetamine (MDMA), which is called ec- be applied to water-soluble compounds, and thus its
stacy, and 4,5-methylenedioxyamphetamine (MDA) use in the forensic and toxicologic fields is increas-
is increasing among the young. Although the arrests ing rapidly.
for MDMA-related offences numbered 256 in 2003,1) In this review, HPLC methods developed in the
which is very small compared with those for stimu- past 5 years and their use in the analyses of stimu-
lants, the increase in its use among teenagers is seri- lant- and MDMA-related compounds in biologic
ous. MDMA and MDA are used in tablet form, and samples are described.

*To whom correspondence should be addressed: Division of

Analytical Research for Pharmacoinformatics, Department of DRUGS OF ABUSE
Clinical Pharmacy, Course of Pharmaceutical Sciences, Gradu-
ate School of Biomedical Sciences, Nagasaki University, 1–14 Many types of drugs have been abused and
Bunkyo-machi, Nagasaki 852–8521, Japan. Tel. & Fax: +81- caused serious human health problems. Arrests for
95-819-2450; E-mail: [email protected] the possession and use of representative drugs of
 No. 3 273

abuse in Japan in 2003 are shown in Fig. 1. MP is

the most popular and the arrests of those less than
20 years old for stimulant-related offences totaled
524 in 2003.2) On the other hand, although the ille-
gal use of MDMA is less than that of MP, the num-
ber of confiscated tablets containing MDMA is rap-
idly increasing. The total number of MDMA tablets
confiscated in Japan was 393062 in 2003.1,2)

Fig. 1. Number of Arrestees for Representative Drugs of Abuse

in Japan in 2003
HPLC DETECTION METHODS

HPLC is a very versatile method. The most com-

mon detection methods are ultraviolet (UV), elec- into the corresponding metabolite AP was signifi-
trochemical (EC), fluorescence (FL), and MS. For cantly higher than that of the R(–)-enantiomer.3) A
HPLC-UV and -FL methods, a derivatization pro- semi-microcolumn separation was applied to achiral
cedure is generally required to increase sensitivity. and chiral quantification of MP and AP using DIB-
LC-MS is a more versatile method for sensitive de- Cl as a label.4) The conventional RP-column was also
termination of many types of drugs including am- used for the detection of methamphetaimines in hu-
phetamines. As a conventional method, GC-MS is man urine. 5) AP and its metabolite, p-hydroxy-
well known and has generally been used in the fo- amphetamine, in rat urine were sensitively deter-
rensic and toxicologic fields. However, GC also re- mined after fluorescent labeling with dabsyl chlo-
quires derivatization to increase the volatility of tar- ride. The recoveries of AP and p-hydroxyampheta-
get compounds, and thus its use for water-soluble mine were 97 and 94%, respectively. The detection
compounds has been limited. On the other hand, LC- limits of the method were 10 ng for both com-
MS generally requires no derivatization of target pounds.6) Screening and quantification of MP were
compounds. This is an important advantage of ana- also achieved after dansyl chloride derivatization and
lytical procedure in terms of time reduction. As a solid-phase extraction with HPLC-FL detection and
result, LC-MS is becoming more commonly used GC-MS. A good correlation (r = 0.95) between
than GC-MS. HPLC and GC-MS was obtained for urinary MP.7)
Recently, the rapid emergency drug identifica- Automated HPLC-FL or -UV using a column-
tion high-sensitivity (REMEDi-HS) system utiliz- switching and on-column derivatization method for
ing HPLC has been used in emergency hospitals for AP was developed with o-phtaldialdehyde and N-
the detection of drugs of abuse as well as poison acetyl-L-cysteine as labeling reagents. The proposed
compounds. method is simple and rapid, with a total analytic time
of approximately 8 min. The limits of detection were
25 and 10 ng/ml with UV and FL detection, respec-
ANALYSIS OF BIOLOGIC SAMPLES tively.8) Direct determination of MP enantiomers
using HPLC-UV was performed with a strong cat-
Urine Sample ion-exchange precolumn (SCX) and phenyl-β -
For the determination of illegal compounds such cyclodextrin-bonded semi-microcolumn using the
as amphetamines and opiates, urine is the most com- column-switching method. The detection limit for
monly used sample. Many practical methods utiliz- both enantiomers was 0.1 µg/ml.9) N-Methylephe-
ing HPLC have been developed, as described be- drine, a tertiary AP, was determined using precolumn
low. derivatization with 9-fluorenylmethyl chloroformate.
Enantiomers of MP and its metabolite amphet- The limit of detection and quantification were 0.1
amine (AP) were sensitively determined using FL and 0.5 µg/ml, respectively.10) Simple and rapid de-
detection after derivatization with 4-(4,5-diphenyl- termination of APs and ephedrines with diode array
1H-imidazol-2-yl)benzoyl chloride (DIB-Cl). S(+)- detection was performed using solid-phase extrac-
and R(–)-enantiomers and p-hydroxymethamphet- tion. The recovery rates were at least 85%. Detec-
amine were detected in 19 Japanese abusers’ urine tion limits of APs and ephedrines were 0.2 and
samples. The degree of N-demethylation of S(+)-MP 0.5 mg/ml for human urine.11)
 274 Vol. 51 (2005)

Screening and identification of AP, MP and their spheric pressure chemical ionization (APCI)-MS
derivatives were examined in the immunochemical using solid-phase extraction. Compounds examined
[Triage and fluorescence polarization immunoassay were AP, MP, illicit designer phenethylamines such
(FPIA)] and chromatographic (REMEDi) tech- as MDA, 4,5-methylenedioxyethylamphetamine
niques. REMEDi gave information on a single drug (MDEA), MDMA, N-methyl-1-(3,4-methylene-
and main metabolites in the samples with minimal dioxyphenyl)-2-butamanine (MBDB), and 4-bromo-
false-positive or false-negative results.12) 2,5-dimethoxyphenethylamine (BDMPEA), and
LC-electrospray ionization (ESI)-MS in the se- other phenetylamines such as benzyl-1-phenyl-
lected ion monitoring (SIM) mode was used for the ethylamine, cathinone, ephedrine, fenfluramine,
simultaneous determination of dimethylamphet- norfenfluramine, phentermine, 1-phenylethylamine,
amine, its main metabolite dimethylamphetamine- phenylpropanolamine, and propylhexedrine. The
N-oxide, and other metabolites MP and AP. A semi- detection limits ranged from 1 to 5 µg/l serum, and
micro SCX column was used with the detection lim- recovery rates ranged from 58 to 96%.20) The possi-
its of 5–50 ng/ml.13) Selegiline-N-oxide, a specific bility of creating a drug library with HPLC-AP-ESI
metabolite of selegiline, was examined as a new in- was examined for identification of toxicologically
dicator of selegiline administration in Perkinson’s relevant drugs in plasma. Forty different drugs were
disease treatment. For discrimination of selegiline extracted from spiked blank plasma and patient
use from MP use, analysis of the urinary metabo- samples. A search for significant peaks in the chro-
lites of selegiline is important. Selegiline-N-oxide matogram in the MS library was shown to result in
was first detected in urine, in addition to AP and more than 95% positive identifications.21) Para-
desmethylselegiline as metabolites.14) methoxyamphetamine and other amphetamine-re-
lated designer drugs such as MDMA, AP, and MDA
Blood Samples were determined using LC with sonic spray ioniza-
Blood samples are useful indetermining the tion MS. Weighted (1/x) quadratic calibration curves
short-term use of drugs of abuse. However, there were generated ranging from 10 to 1000 ng/ml
are some difficulties from the legal point of view in (blood and urine) or 20 to 2000 ng/g (tissue) with
obtaining abusers’ blood samples. correlation coefficients > 0.995.22) Selegiline and its
MP and AP in human plasma samples were de- three metabolites were sensitively assayed using a
termined with FL detection using DIB-Cl as a label- LC-APCI-MS/MS method. Lower limits of
ing reagent. The detection limit was less than quantitation were 0.1 ng/ml for selegiline and N-
0.87 ng/ml plasma. The method was used in two desmethylselegiline, and 0.2 ng/ml for MP and AP.
cases of illegally ingested MP.15) Simultaneous de- Extracted plasma samples retained quantitative ac-
termination of free-form AM in rat blood and brain curacy after storage for at least 7 days at –20°C or
was performed using in vivo microdialysis with up to 70 hr at room temperature.23)
dansyl chloride as a FL-label. Pharmacokinetic pa-
rameters of AP in rat blood and brain were reported.16) Hair Samples
The obesity drugs fenfluramine and phentermine in Hair yields useful samples in forensic and toxi-
rat brain and blood microdialyzates were determined cologic sciences, because it is very stable and easy
using HPLC-FL with DIB-Cl as a label.17) The to handle compared with other biologic samples and
method is very sensitive and detected < 23 fmol (S/N can indicate long-term intake of drugs of abuse. A
= 3) on the column for both compounds. history of abuse can also be clarified by segmental
Pholedrine (4′-hydroxymethamphetamine), a analysis of hair.
cardiovascular agent, was determined in A very sensitive HPLC-FL detection method for
amperometric detection using ion-pair extraction the determination of AP-related compounds such as
with bis(2-ethylhexyl)phosphoric acid as an ion-pair MDMA, MDA, AP, and MP was developed using
reagent.18) DIB-Cl as a label. Tentative chromatograms are
Pholedrine in a case of fatal intoxication was also shown in Fig. 2. The limits of detection for these
studied using LC-MS/MS. The method developed compounds range from 11 to 200 pg/mg hair. The
is very sensitive with a limit of detection of 0.8 ng/ml method was successfully used to determine MDMA
(S/N = 3) and lower limit of quantitation of 3 ng/ml and MDA in hair samples obtained from an MDMA
(S/N = 10).19) Analysis of underivatized APs and abuser and clarify the history of use, as shown in
phenethylamines was performed with LC-atmo- Fig. 3.24) The DIB-Cl derivatization method was also
 No. 3 275

Fig. 3. Concentrations of MDA and MDMA in MDMA Abusers’

Hair Strands Sectioned into 1-cm Segments
Reprinted from Ref. 24 with permission of Wiley & Sons Ltd.

hair treatments might interfere with the detection of

Fig. 2. Chromatograms MP and AP in hair.28)
Chromatograms obtained from (A) spiked control human hair with Simultaneous determinations of eight
MDA and AP 1 ng/mg, MDMA 2 ng/mg and MP 1.1 ng/mg, (B) segment
5 of abuser’s hair containing MDA and MDMA 1.67 and 42.2 ng/mg,
underivatized APs, i.e., AP, ephedrine,
respectively. Detector sensitivity in (B) is four-fold lower than in A. methcathinone, p-methoxyamphetamine, MP, MDA,
Reprinted from Ref. 24 with permission of Wiley & Sons Ltd. MDMA, and MDEA, in hair was performed using
LC-APCI-MS. The analytes were digested in NaOH
1 M and extracted with 1-chlorobutane. The limits
applied to determine MP and AP in an abuser’s hair of detection ranged from 0.05 to 0.2 ng/g hair. The
samples, and very low amounts of both compounds method was applied to 93 authentic hair samples
were found.15) Enantiomer-specific FL detection was obtained from detoxification and methadone treat-
also developed for the determination of MPs in abus- ment patients.29) Polypyrrole-coated capillary in-tube
ers’ hair using DIB-Cl as a label. solid-phase microextraction was used for the simul-
Segment analysis of MP and AP was developed taneous assay of stimulants in spiked human hair
using FL detection with DIB-Cl as a label.25) Hair samples with ES/MS detection.30)
samples were segmentally analyzed based on 1-cm
long segments. In four samples, only the S(+)-enan- Other Samples
tiomers of MP and AP were detected.3) Furthermore, AP in rat brain was sensitively determined us-
chiral and achiral semi-microcolumn HPLC meth- ing in vivo microdialysis and ion-pairing LC with
ods with FL detection using DIB-Cl were applied to ES-MS/MS. Detection was performed with no
abusers’ single-hair analyses. S(+)-Enantiomers were postcolumn addition of an organic modifier. The
found in eight Japanese abusers’ hair samples. The detection limit was 0.001 µg/ml (5 nM) at S/N = 3.
achiral method was used to study the concentrations AP reached a maximum concentration of 0.086 ±
of these compounds in single black and white hair 0.017 µg/ml over 20–40 min after a single 3.0-mg/kg
strands of abusers.26) i.p. administration.31) AP, MP, and MDA derivatives
Fenfluramine and norfenfluramine in human hair in meconium were determined with LC-API-MS
as biomarker metabolites of N-nitrosofenfluramine using 3,4-methylenedioxypropylamphetamine as an
(N-Fen) were determined using HPLC-FL with DIB- internal standard. Separation was achieved with a
Cl as a label. The results obtained showed that the reverse-phase column using a linear gradient of
patients might have ingested N-Fen for a period of ammonium bicarbonate 10 nM (pH 9) and metha-
not less than five months.27) nol as mobile phases. The quantification limits were
The chemiluminescence detection method was 0.005 µg/g meconium for AP, MP, and 4-hydroxy-
used to study the effects of permanent wave, dye, 3-methoxymethamphetamine and 0.004 µg/g meco-
and decolorant treatments on MP and AP in abusers’ nium for MDA, MDMA, MDEA, and N-methyl-1-
hair. The concentrations of both compounds de- (3,4-methylenedioxyphenyl)-2-butanamine. The
creased in all cases. The results suggest that such method was used to analyze meconium in newborns
 276 Vol. 51 (2005)

to assess fetal exposure to AP derivatives.32) Detec- Oguri, K., Fukushima, S. and Ikeda-Wada, S. (2002)
tion of MP and AP in abusers’ clothing was per- Dansyl chloride derivatization of methamphetamine:
formed with FL and UV detection. The limits of a method with advantages for screening and analy-
detection were less than or equal to 37.3 pg for UV sis of methamphetamine in urine. J. Anal. Toxicol.,
and 0.4 pg for FL on column. MP and AP excreted 26, 17–22.
via sweat from the human body was also success- 8) Herraez-Hernandez, R., Campins-Falco, P. and Diaz-
fully determined.33) Oltra, S. (1999) Automated high-performance liq-
uid chromatographic determination of amphetamine
in biological fluids using column-switching and on-
column derivatization. Chromatographia, 49, 188–
CONCLUSION 196.
9) Makino, Y., Suzuki, A., Ogawa, T. and Shirota, O.
Recently developed HPLC methods for the de-
(1999) Direct determination of methamphetamine
termination of stimulant-related compounds in bio-
enantiomers in urine by liquid chromatography
logic samples are versatile and convenient, and thus with a strong cation-exchange precolumn and phe-
applicable to the analysis of many other drugs of nyl-β-cyclodextrin-bonded semi-microcolumn. J.
abuse. The author expects further development in Chromatogr. B, 729, 97–101.
HPLC methods, which will contribute to predicting 10) Herraez-Hernandez, R. and Campins-Falco, P.
and protecting human health from the risk of drug (2000) Derivatization of tertiary amphetamines with
abuse. 9-fluorenylmethyl chloroformate for liquid chroma-
tography: determination of N-methylephedrine.
Analyst (London), 125, 1071–1076.
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