ArticlePDF AvailableLiterature Review

The Current Status of Sweat Testing For Drugs of Abuse: A Review

Authors:
  • -Fondazione Policlinico Gemelli - Catholic University of the Sacred Heart

Abstract and Figures

Sweat is an alternative biological matrix useful to detect drugs of abuse intake. It is produced by eccrine and apocrine glands originating in the skin dermis and terminating in secretory canals that flow into the skin surface and hair follicles. Since many years it has been demonstrated that endogenous and exogenous chemicals are secreted in this biological sample hence its collection and analysis could show the past intake of xenobiotics. From the seventies the excretion of drugs of abuse has been investigated in human skin excretion; later in nineties forensic scientists began to experiment some techniques to trap sweat for analyses. Even if the use of skin excretions for drug testing has been restricted mainly by difficulties in sample recovery, the marketing of systems for the sample collection have allowed successful sweat testing for several drugs of abuse. In the recent years sweat testing developed a noninvasive monitoring of drug exposure in various context as criminal justice, employment and outpatient clinical settings. This paper provides an overview of literature data about sweat drug testing procedures for various xenobiotics especially cocaine metabolites, opiates, cannabis and amphetamines. Issues related to collection, analysis and interpretation of skin excretions as well as its advantages and disadvantages are discussed. Moreover the chance to apply the technique to some particular situation such as workplace drug testing, drivers, doping or prenatal diagnosis, the comparison between sweat and other non conventional matrices are also reviewed. According to literature data the analysis of sweat may be usefully alternative for verifying drug history and for monitoring compliance.
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The Current Status of Sweat Testing For Drugs of Abuse: A Review
N. De Giovanni* and N. Fucci
Institute of Legal Medicine, Catholic University of Sacred Heart, L.go Francesco Vito, 1 00168 Rome Italy
Abstract: Sweat is an alternative biological matrix useful to detect drugs of abuse intake. It is produced by eccrine and apocrine glands
originating in the skin dermis and terminating in secretory canals that flow into the skin surface and hair follicles. Since many years it has
been demonstrated that endogenous and exogenous chemicals are secreted in this biological sample hence its collection and analysis
could show the past intake of xenobiotics. From the seventies the excretion of drugs of abuse has been investigated in human skin excre-
tion; later in nineties forensic scientists began to experiment some techniques to trap sweat for analyses. Even if the use of skin excretions
for drug testing has been restricted mainly by difficulties in sample recovery, the marketing of systems for the sample collection has al-
lowed successful sweat testing for several drugs of abuse. In the recent years sweat testing developed a noninvasive monitoring of drug
exposure in various contexts as criminal justice, employment and outpatient clinical settings. This paper provides an o verview of litera-
ture data about sweat drug testing procedures for variou s xenobiotics especially cocaine metabolites, opiates, cannabis and ampheta-
mines. Issues related to collection, analysis and interpretation of skin excretions as well as its advantages and disadvantages are dis-
cussed. Moreover the chance to apply the technique to some particular situation such as workplace drug testing, drivers, doping or prena-
tal diagnosis, the comparison between sweat and other non conventional matrices are also reviewed. According to literature data the
analysis of sweat may be usefully alternative for verifying drug history and for monitoring compliance.
Keywords: Sweat testing, drugs of abuse, unconventional matrix.
1. INTRODUCTION
The diagnosis of acute intoxication by xenobiotics, together
with the determination of drug use/abuse is the target of forensic
toxicology. Analysis of biological fluids and tissues provides the
most objective method for documenting human drug exposure. The
choice of biological matrices is the crucial step for a correct inves-
tigation, because each biological specimen is unique and offers a
somewhat different pattern of information regarding drug use over
time. The toxicologist needs a deep knowing of various parameters
such as the purpose of the investigation, the kind of substances to
be identified, the time, way and modality of intake, the knowledge
of pharmacokinetic and pharmacodynamic of drugs [1].
Blood and urine are historically the biological matrices more
employed for testing of drugs of abuse both of cadavers and living
people. However, currently there is growing interest in the use of
alternative body fluids and tissues such as saliva, skin excretions
and hair for the diagnosis of drug use [2-7]. The purpose of these
studies was the exploration of less invasive collectors in order to
obtain more information regarding the use/abuse of psychotropic
drugs. Research may involve the detection of the parent compound
or metabolites and sensitivity, specificity, and reliability of drug
testing may vary depending on the drug [7]. Scientific international
literature developed analytical methodologies to detect xenobiotics
on sweat, matrix in which illicit compounds can be found with a
time window that allows peculiar information different from other
biological samples [8].
As referred by Kintz P. [9] since 1911 researchers established
that drugs are excreted by the body in sweat, but many analytical
and practical problems m ainly due to the difficulty in collecting
skin excretions, did not allow its application in forensic toxicology
until 1990s. In 1980 Phillips M. [10] devised an occlusive adhesive
patch that trapped solute and water components in sweat providing
a possible means to monitor patient compliance w ith therapeutic
regimens. The patch consisted of an absorbent pad impregnated
with sodium chloride crystals under a water-proof dressing. Later,
occlusive bandages, consisting of one to three layers of filter papers
or pieces of cotton, gauze, or towel were proposed to collect sweat
[9, 11]. Significant advances have been made in the past years to
*Address correspond ence to this author at the In stitute of Legal Medicine, Cath olic
University of Sacred Heart, L.go Francesco Vito, 1 00168 Rome Italy; Tel: 0039 6
35507031; Fax: 0039 6 3051168; E-mail: nadia.degiovanni@rm.un icatt.it
develop a sweat-patch technology. In fact a non occlusive sweat
collection device (patch) was developed by a commercial firm (Su-
dormed, Santa Ana, CA, USA) in 1990.
The variation between individuals in the amount of sweat they
excreted has caused difficulty for those attempting to construct a
universal sweat collection device. Earlier experiments to test for the
presence of specific substances in sweat have used patches that
occlude the skin causing numerous problems such as skin irritation,
alteration of both the steady-state, pH of the skin and the skin’s
colonizing bacteria [12]. Newer non occlusive patches use a trans-
parent film that allows oxygen, carbon dioxide and water vapor to
escape, while trapping the necessary traces of drug use excreted in
sweat [13]. Cone E.J. [8] found many benefits in using this type of
patch, including high subject acceptability, low incidence of aller-
gic reactions to the patch adhesive and ability to monitor drug in-
take for a period of several weeks with a single patch. Several stud-
ies have also found that the patch is resistant to inconspicuous tam-
pering [8, 12, 14]. Kintz P. et al. [12] also reported that no special
precautions were needed to wear the patches for several days except
to avoid excessive towel rubbing after bathing. Hence, success in
sweat testing for several drugs of abuse has been accomplished
because of substantial advances in sample collection and improved
accuracy of measurement methods. Consequently remarkable ad-
vances in sensitiv e analytical techniques have enabled the analysis
of drugs in unconventional samples such as skin excretions.
Some reviews regarding the employ of alternative biological
matrices were published in different periods. The first paper found
in literature [15] referred about the detection of drugs of abuse in
hair, nail, saliva and sweat. Preparation or pretreatment of samples,
analytical pro cedures, and the interpretation of analytical results are
discussed concomitantly.
A monographic report of NIDA was published in the year 1997
by Cone E.J. [8]. The usefulness of various biological fluids, in-
cluding sweat, together with the chemical and physical properties
was discussed. Research of sweat testing for drugs had been limited
because of the difficulty in collecting sweat samples and the author
suggests the employ of a sweat collection device that appeared to
offer promise for the collection of this sample. He refers about the
advantages of the sweat patch for drug monitoring that include the
high subject acceptability of wearing the patch, low incidence of
allergic reactions to the patch adhesive and ability to monitor drug
intake for a period of several weeks for the single patch.
2 Current Medicinal Chemistry, 2013, Vol. 20, No. 1 De Giovanni and Fucci
A review referring on the detection of marijuana, cocaine, opi-
ates, amphetamines, benzodiazepines, barbiturates, phencyclidine
and nicotine in sweat is reported with emphasis on forensic applica-
tions [16]. Sweat maybe applicable for use in driving while intoxi-
cated and surveying populations for illicit drug use. The review
refers about advantages and disadvantages of sweat testing com-
pared to saliva and urine.
Huestis MA et al. [11] in 1999 reviewed the detection of co-
caine, codeine and metabolites in sweat by GC/MS detailing results
from a new type of sweat collection device that allows rapid collec-
tion of sweat samples.
Various aspects concerning the practical application and foren-
sic interpretation of data obtained by drug monitoring from the skin
surface are discussed by Skopp G. et al. [17]. Basic information on
the composition of skin secretions and their particular transport
mechanisms, as far as known, are given. Drug molecules from
blood are considered to reach the skin surface by various routes
such as by sweat and sebum as well as by inter- and/or trans-
cellular diffusion. The role of the stratum corn eum as a temporary
drug reservoir exceeding positive drug findings in urine is outlined.
Cone E.J. in 2001 [18] provided an overview of global drug
trafficking patterns and drug use, and results from a survey of legal
statutes in twenty countries covering use of alternate matrices for
drug testing. He stated that advances have also been made in the use
of alternate biological matrices such as sweat for drug testing. Do-
lan K. et al. [19] published a brief overview providing qualitative
drug testing procedures using sweat; authors stated that sweat may
be useful in the detection of illicit drug use for developments in
patch technology which allows for a cumulative estimate of drug
exposure over several days. In the year 2010 Maurer H.H. [20]
published an important review on analytical toxicology describing
the procedures for screening, identification and quantification of
drugs, poisons and their metabolites in various matrices including
sweat. The paper focused on the selection of the most appropriate
bio-sample to be analyzed depending of the task to be fulfilled.
The authors of the present review believe useful to briefly refer
about the employ of sweat in clinical settings. Shearer D.S. et al. in
1998 [21] performed a drug testing of patients in a psychiatric out-
patient service allowing to identify patients who relap se into re-
newed use of drugs of abuse and in monitoring the effectiveness of
ongoing medical and psychological therapy. Moreover DuPont RL.
[22] proposed sweat for clinical settings and affirmed it could be
useful in schools and in-family based efforts to prevent drug use.
This review focuses the attention on skin excretions that may
provide an additional tool for monitoring drug use. Although the
use of sweat for drug testing has been hampered by difficulties in
sample collection and sensitivity of analytical methods, successful
sweat testing for several drugs of abuse has been accomplished
because of substantial advances facilitating sample collection and
improving the accuracy of diagnostic techniques [8].
For this purpose a computerized search of articles inserted in
“PUBMED” and ”SCOPUS” from 1992 to 2011 was performed.
100 papers were chosen including some reviews for their relevance
on sweat technology (Table 1). The articles reviewed were sched-
uled on the basis of the population studied and/or the referred appli-
cation (clinical setting, forensic application, workplace drug testing,
pregnancy, controlled administration, roadside testing, etc).
2. HUMAN SWEAT
Human sweat is a biological fluid and its secretion is an impor-
tant homeostatic mechanism for maintaining a constant core body
temperature to a narrow physiological range [11]. Randall W.C. in
1953 [23] stated that at temperatures above 31°C body heat is dissi-
pated by the release o f sweat on the skin surface resulting in evapo-
rative heat loss however a loss by sweating can also occur at other
temperatures. Eichna L.W. [24] asserted that the amount of sweat
secreted is highly variable and dependent upon daily activity, emo-
tional state and environmental temperature. Sweat is eliminated
from human body through the skin that consists of two layers; the
outer epidermis and the inner dermis. The epid ermis in turn is com -
posed of two main cell types, the pigmented melanocytes which
protect against damaging effects of sunlight, and keratocytes which
contain the filaments that provide the structural integrity of the skin.
As keratocytes mature they lose their cell nucleus and move to the
outer portion of the skin; hence this layer (called stratum corneum)
consists entirely of keratocytes that have lost their nuclei. The un-
derlying dermis, which makes up the bulk of the skin is composed
of fibrous well vascularized connective tissue and it contains the
hair follicles, sweat and sebaceous glands [25]. Under the dermis
there is the adipose layer that consists of lobules of fat separated by
fibrous connective tissue. Blood vessels pass into and through this
layer. Sw eat is approximately 99% water with the most concen-
trated solute being sodium chloride. The rate of sweating is highly
dependent upon environmental temperatures and rates as high as 3
l/min have been recorded for short periods [2]. The m ajority of
sweat is produced by eccrine glands located in the transdermal layer
of most skin surfaces. Apocrine glands are an other type of sweat
gland located in specific regional areas like the skin of the axilla,
pubic region and around the nipples. Sweat glands often develop in
close association with hair follicles and sometimes empty directly
into hair follicles. Approximately 50% of the total volume of sw eat
is produced by the trunk, 25% by the legs and 25% by the head and
upper extremities [2]. Besides aqueous secretion, the skin is also
bathed with sebaceous secretions especially on the face and scalp.
The sebaceous secretions are primarily lipids that may transport and
adsorb many drugs [16].
Sweat and sebaceous glands are housed in the dermis and are
distributed through the body disproportionately. The highest con-
centration of sweat glands resides in the hands, while the forehead
contains the densest population of sebaceous glands [26]. Moisture
maybe lost from the skin by either insensible sweat likely caused by
diffusion through the skin and sensible sweat which is actively
excreted during stress and exercise [16]. Several reports have dem-
onstrated the sweat is suitable altern ative biological matrix for
monitoring recent drug use because a small but sufficient fraction
of the drug is excreted by the skin [8, 20, 25].
3. EXCRETION OF XENOBIOTICS INTO SWEAT
The excretion of drugs in sweat has important implications in
clinical and forensic toxicology as well as in preventative medicine.
Specific and sensitive detection or precise quantification of xenobi-
otics in bio-samples are great challenges in analytical toxicology.
Investigators have been studying the secretion of endogenous and
exogenous chemicals in sweat for many years. The sebaceous se-
cretion is primarily constituted by lipids th at may transport and
absorb many drugs. Different concentrations of drugs may be ex-
pected, depending upon the area of the body in which the sample is
taken, because fat-soluble drugs may be sequestered or secreted by
the skin. The mechanism by which drugs are incorporated into
sweat is not fully understood [27] and there are several potential
mechanisms by which drugs may be secreted in sweat including
passive diffusion from blood into sweat glands and transdermal
migration of drugs across the skin [2]. Non-ionized basic drugs
diffuse into sweat and become ionized as a result of the lower pH of
sweat as compared to blood [28]. The pH of sweat is generally in
the range of 4 to 6.8, with the average sweat pH from resting indi-
viduals considered to be 5.8. With the increased flow rate (follow-
ing exercise or above 31°C), sweat pH has been found to increase
to 6.8 [8, 28]. A low basal pH should favor concentration of basic
drugs in sweat thus producing a free-drug sweat/plasma (S/P) ratio
greater than 1. This assumption is supported by studies of the excre-
tion of ammonia in sweat. The observed S/P ratios for total ammo-
Sweat Testing for Dr ugs of Abuse Current Medicinal Chemistry, 2013, Vol. 20, No. 1 3
Table 1. Drugs of Abuse in Sweat: Crucial Aspects of Methodology
Reference Author Drugs and Metabolites Collection Device Mo dality and Time of
Wear
Analytical
Method Other Matrices Application
2 Cone EJ. et al. 1994 heroin and cocaine Sudormed/Band-
aid
Back, Abdomen / 0-3
Days GC/MS urine, hair Clinical setting
3 Smith FP. et al. 1996 cocaine Sweat wipes forehead skin swabs RIA-GC/MS hair, saliva, urine Drug users and
children
4 Kidwell DA. et al. 1997 cocaine Sweat wipes wiping forehead GC/MS/MS hair University popula-
tion
5 De Oliveira CDR. et al.
2007 GC/MS LC/MS saliva, hair, nails,
Review of chroma-
tographic proce-
dures
7 Vearrier D. et al. 2010 various Review of biologi-
cal matrices
8 Cone EJ. 1997 Monography
9 Kintz P. 1996
opiates, cocaine, can-
nabinoids, buprenor-
phine, metadone, nordi-
azepam
PharmChek back / 1 week GC/MS u rine, hair Clinical setting
11 Huestis M. et al. 1999 cocaine , codeine Sudormed/Fast
Patch palm, torso / 30 minutes GC/MS Review of sweat
testing
12 Kintz P. el al 1997 opiates PharmChek back /24 hours GC/MS no Clinical setting
13 Kidwell DA. et al. 2001 cocaine, metampheta-
mine, heroin PharmCheck arms GC/MS no
Environmental
contamination
14 Caplan YH. et al. 2001 hair, nail, blood ,
urine
Workplace drug
testing
15 Inoue T. el al 1992 Review of biologi-
cal matrices
16 Kidwell DA. et al. 1998 saliva Review - Forensic
17 Skopp G. et al. 1999 saliva Review- Road side
testing
18 Cone EJ. 2001 Review- Workplace
drug testing
19 Dolan K. et al. 2004 urine, hair, saliva Review- Forensic
20 Maurer HH. 2010
urine, blood, tissues,
hair, oral fluid,
nails, meconium
Review of analytical
toxicology
21 Shearer DS. et al. 1998 urine,saliv a, hair,
urine
Review of biologi-
cal matrices, Psy-
chiatric
22 DuPont RL. 2010 hair, saliva, urine General aspects,
Clinical setting
25 Levisky JA et al. 2000 cocaine, opiates Adipose tissue.
skin
skin collected during
autopsy GC/MS blood Autoptical data
26 Chawarski MC et al. 2007 opiates PharmCheck not specify GC/MS urine Clinical setting
27 Brunet BR et al. 2010 cocaine, opiates PharmCheck back. arm /1 week GC/MS no Pregnancy
28 Huestis MA etal 1998 alternative matrices Monography
30 Kacinko S.L. et al. 2005 cocaine PharmCheck back, abdomen / 4-15
hours GC/MS no Controlled
administration
31 Uemura N. et al. 2004 cocaine PharmCheck back, shoulder / 1-72
hours GC/MS no Controlled
administration
32 Schwilke EW.et al. 2006 opiates PharmCheck abdomen, back / 1
week, 1-15 hours GC/MS no Controlled
administration
34 Faergermann J. et al. 1993 terbinafine
stratum corneum,
dermis-epidermis,
sebum
hair, nails, plasma Controlled admini-
stration
35 Burns M. et al. 1995 cocaine Band-aid torso, biceps, back / 1
week urine Clinical setting
4 Current Medicinal Chemistry, 2013, Vol. 20, No. 1 De Giovanni and Fucci
(Table 1) contd…
Reference Author Drugs and Metabolites Collection Device Modalit y and Time of
Wear
Analytical
Method Other Matrices Application
36 Joseph RE. et al. 1998 cocaine, opiates Sebutape back, forehead /1-2
hours GC/MS plasma, sebum,
stratum corneum
Controlled admini-
stration
37 Liberty HJ. et al. 2004 cocaine PharmCheck biceps/ various time GC/MS urine Controlled admini-
stration
38 Kidwell DA. et al. 2003 cocaine Phar mChek-Skin
swabs arms /1-4 weeks
immunoassay
(CEDIA, Co-
zart,OraSure
ELISA) - GC/MS
urine Environmental
contamination
39 Pichini S. et al. 2003 MDMA PharmCheck-
Drugwipe 24 hours (back) immunoassay -
GC/MS urine Controlled admini-
stration
40 Balabanova S. et al. 1992 cocaine, morphine,
methadone
Pilocarpine
stimulation RIA Drugs users
42 Spiehler V. et al. 1996 cocaine PharmChek skin / 7 days Immunoassay-
GC/MS no
Drugs users, con-
trolled administra-
tion
43 Burns M. et al. 1995 cocaine PharmChek/Band-
aid up to 7 days RIA-GC/MS no Controlled admini-
stration
44 Skopp G. et al. 1996 theophylline, metha-
done, heroin , cocaine Sudormed
Controlled admini-
stration
45 Kintz P. et al. 1996 diazepam Sudormed 0-72 hours GC/MS no Controlled
administration
46 Kintz P. et al. 1996 codeine, phenobarbital Sudormed different sites / up to 7
days GC/MS Controlled
administration
47 Liberty HJ. Et al 2003 crack PharmChek,
Fastpatch
one per hand /15-30
minutes GC/MS urin e
Controlled admini-
stration
48 Fogerson R. et al. 1997 opiates PharmChek skin /1-10 day EIA-GC/MS urine
Controlled admini-
stration, adulteration
study
50 Moody DE. et al. 2001 cocaine, heroin PharmChek RIA /EIA no In vitro study
51 Moody DE. et al. 2004 cocaine PharmChek RIA/GC/MS Controlled admini-
stration
52 Mura P. et al. 1999 cannabinoids Drugwipe GC/MS urine,saliva,tears Drug users and drug
free
53 Samyn N. et al. 2000 amphetamines, cocaine,
opiates, cannabis Drugwipe GC/MS saliva, plasma, urine Drug users
54 Pacifici R. et al. 2001 MDMA Drugwipe GC/MS plasma, urine Controlled admini-
stration
55 Hazarika P. et al. 2010 cocaine, opiates Fingermark
immunoassay-
Fluorescence
microscopy
Drug users
57 Fay J. et al. 1996 metamphetamine PharmChek EIA-GC/MS Controlled admin-
istartion
58 Maurer HH. et al. 1997 xenobiotics GC/MS-LC/MS blood, urine, saliva,
hair
General aspects on
analytical toxicol-
ogy
59 Segura J. et al. 1998
General aspects on
analytical toxicol-
ogy
60 Kintz P. et al. 1998 nicotine PharmChek 72 hours GC/MS Cigarettes smokers
and nonsmokers
61 Preston KL. et al. 1999 cocaine sweat patches ELISA- GC/MS urine Clinical setting
62 Huestis M. et al. 2000 opiates PharmChek abdomen, back/ 1 week ELISA- GC/MS urine Clinical setting
63 Kintz P. et al. 2002
flunitrazepam, GHB,
cannabinoids, LSD,
ecstasy, ethanol
GC/MS/MS/NICI
Crime under the
influence
64 Samyn N. et al. 2002 cocaine, amphetamines,
cannabis Drugwipe GC/MS
blood, urine, oral
fluid Roadside testing
Sweat Testing for Dr ugs of Abuse Current Medicinal Chemistry, 2013, Vol. 20, No. 1 5
(Table 1) contd…
Reference Author Drugs and Metabolites Collection Device Mo dality and Time of
Wear
Analytical
Method Other Matrices Application
65 Saito T. et al. 2004 cannabinoids PharmChek skin /12 hours GC/MS-NICI no Method validation,
clinical setting
66 Follador MJ. et al. 2004 cocaine, cocaetilene PharmChek sweating part of the
body / 3-7 days GC/MS no Method validation
67 Pichini S.et al. 2005 salvia divinorum back / 2 hours GC/MS blood, urine, saliva Controlled study
68 Yang W. et al. 2006 metamphetamine, co-
caine, codeine
skin biopsy (glu-
teus maximus) GC/MS no
Clinical setting -
Method validation
69 Abanades S. et al. 2007 GHB PharmChek back/ 6 hours GC/MS plasma, oral fluid,
urine
Controlled admini-
stration- Pharma-
cokinetic
70 De Martinis BS. et al.2007 amphetamines analogs PharmChek GC/MS no
Method validation ,
in vitro study,
controlled admini-
stration
71 Brunet BR. et al. 2008 methadone, heroin,
cocaine PharmChek not specified / 7 days GC/MS Method validation,
pregnancy
72 Fucci N.et al. 2008 methadone PharmChek upper arms / 7 days GC/MS hair, urine Clinical setting
73 Barnes Aj. et al. 2009 MDMA PharmChek back, abdomen / 2 hours
- 7 days GC/MS no Controlled
administration
74 Barnes AJ. et al. 2010 methadone PharmChek back, arm / 2-24 days GC/MS no Controlled admini-
stration, pregnancy
75 Concheiro M. et al. 2011
buprenorphine, metha-
done, cocaine, opiates,
nicotine
Band-aid back, upper arm, lower
chest / 7 days LC/MS/MS no Method validation
76 Marchei E. et al. 2010 methylphenidate PharmChek back/ 24 hours LC/MS oral fluid, plasma Pilot study
77 Cirimele V. et al. 2000 clozapine LC/MS plasma, hair Schizophrenic
patients
78 Al-dirbashi OY. et al.2001 metamphetamine, am-
phetamine Abusers' clothes
HPLC/ UV -
fluorescence
detection
Method validation
79 Crouch DJ. et al. 2001
amphetamine, cannabi-
noids, cocaine, opiates,
PCP
Macroduct (pilo-
carpine stimula-
tion)
screening
LC/MS/MS urine Pilot study
80 Kintz P. et a l. 1998 methadone PharmCheck upper back (72 hours) LC/MS urine Clinical setting
81 Samyn N. et al. 2002 ecstasy SweatWipe wiping with cotton over
forehead GC/MS plasma, oral fluid,
urine
Controlled
administration
82 Gallardo 2009 Workplace drug
testing
83 Marchei E. et al. 2012 atomoxetine back / 6 hours LC/MS/MS blood, urine, oral
fluid Controlled study
84 Kintz P. 1996
opiates, cocaine, can-
nabinoids, benzodi-
azepine, amphetamine,
buprenorphine
PharmCheck 5 days GC/MS-LC/MS urine Drug users
85 Taylor JR. et al. 1998 methadone, cocaine,
opiates Pharm Check 5-10 days Im munoassay urine Clinical setting
86 Levisky JA. et al. 2001 cocaine, metampheta-
mine sweat patches 10 -14 days GC/MS urine Drug users
87 De la torre R. et al. 2004 amphetamines Review-
Pharmacokinetic
study
89 Barnes AJ. et al. 2008 metamphetamine, am-
phetamine PharmCheck back, abdomen / 1 week GC/MS no Controlled
administration
90 Kintz P. 1997 MBDB, BDB PharmCheck upper arm / up to 72
hours GC/MS urine Con trolled
administration
91 Kintz P. et a l. 1999 ecstasy Review biological
matrices
92 De Martinis BS. 2008 amphetamines Review of the
scientific literature
6 Current Medicinal Chemistry, 2013, Vol. 20, No. 1 De Giovanni and Fucci
(Table 1) contd…
Reference Author Drugs and Metabolites Collection Device Mo dality and Time of
Wear
Analytical
Method Other Matrices Application
93 De la torre R. et al. 2004 cannabinoids Review
95 Staub C. 1999 cannabinoids blood, saliva, hair,
meconium
Review of chroma-
tographic proce-
dures
96 Kintz P. et al. 2000 cannabinoids forehead wipes
(cosmetic pad) GC/MS
blood, urine, oral
fluid Roadside testing
97 Huestis M. et al. 2008 cannabinoids PharmChek Chest, abdomen /1-7
days GC/MS
Pharmacokinetic
study
98 Winhusen TM. et al. 2003 cocaine PharmCheck right arm, left arm / 7
days GC/MS urine Clinical setting
99 Kintz P. 1998 codeine Drugwipe-
PharmCheck
wiping forehead- upper
arm GC/MS saliva
Controlled admini-
stration
101 Concheiro M. et al. 2011 buprenorphine PharmCheck 12-24 hours GC/MS plasma, oral fluid
Controlled admini-
stration in preg-
nancy
102 Balabanova S. et al. 1995 nicotine pilocarpine
stimulation
sweat taken every hour
for 6 hours RIA/GC/MS Smokers and no
smokers subjects
104 Marchei E. et al. 2010 methylphenidate PharmChek up to 24 hours oral fluid
Pediatric subjects,
pharmacokinetic
study
105 Lankheet N.A. et al. 2011 sun itinib and metabo lites PharmChek upper arm /24 hours LC/MS/MS no Method validation -
Clinical setting
107 Samyn N. et al. 2000 amphetamines on-site testing urine, saliva Roadside testing
108 Kintz P. et al. 2000 Roadside testing-
General aspects
109 Walsh JM. et al. 2004 Roadside testing -
General aspects
110 Rivier L. 2000 Review- Alternative
biological samples
111 Rivier L. 2000 Doping- Alternative
biological samples
112 Huestis M.et al. 2002
Review- Pregnancy
, alternative biologi-
cal samples
113 Lozano J. et al. 2007
Review- Pregnancy
, alternative biologi-
cal samples
114 Gray T. et al. 2007
Review- Pregnancy
, alternative biologi-
cal samples
115 Daughton CG. 2011 Review- Forensic
nia have been reported to be 20-50 [2]. The stratum corneum con-
tains structures that may function as diffusion shunts, thus render-
ing three potentially distinct routes of penetration through the stra-
tum corneum: hair follicles, sweat ducts and the unbroken stratum
corneum. The study on steady state drug transport through the skin
support the contention that bulk diffusion pathway through the in-
tact stratum corneum predominates over diffusion shunts. Delivery
of high concentrations of the drug to the skin surface by sebum and
sweat could produce a deposition on the stratum corneum and allow
the skin to serve as a shallow drug depot [11, 29]. Many illicit drugs
may diffuse through the dermal and epidermal layers of the skin
[30]. Passive diffusion of drugs from capillaries in the skin into
perspiration seems to be the main pathway but excretion of sub-
stances via sebum and intercellular diffusion also contribute [2, 11].
The mechanism appears to be linked to the concentration gradient
in which only the free fraction of drug unbound to proteins, diffuses
through lipid membranes from plasma to sweat. Furthermore be-
cause under normal condition sweat with a mean pH of 6.3, is more
acidic than blood, basic drugs tend to accumulate in sweat [31].
Excretion into sweat depends upon a drug’s physical-chemical
properties such as molecular mass, pKa, protein binding and lipo-
philicity. Therefore parent drugs that more easily cross membranes
are expected to accumulate in sw eat in greater concen tration s than
polar hydrophilic metabolites [11, 19, 32]. The passage of lipid-
soluble compounds from blood to other fluids is also regulated by
the pH of the matrices considered. A modified version of the
Henderson-Hasselbalch equation, which uses the pKa and pH, al-
lows theoretical calculation of the fluid-to-plasma concentration
ratio [31]. There are other factors that appear not to have been con-
sidered for the transport of drugs into sweat. The rate at which
drugs move from subcutaneous tissues to the skin surface could be
significantly different from the rate at which drugs move from
sweat glands to the skin surface. If the transit time for drug to move
from subcutaneous tissue to sweat gland is considerably slower than
time for drug to move from sweat gland to skin surface, clearance
of the drug from the system would be significantly delayed. The
Sweat Testing for Dr ugs of Abuse Current Medicinal Chemistry, 2013, Vol. 20, No. 1 7
time to transport drug from adipose tissue to the skin surface could
be relatively short or extremely long, it depends on the rate of tran-
sition between layers, the transport mechanism, the degree of re-
versibility and the magnitude of the equilibrium constants [25].
Cone E.J. [8] stated that the mechanism for drug entry into
sweat was unclear, but most likely occurs by passive diffusion from
blood to the sweat glands. An alternate mechanism could involve
drug diffusion through the stratum corneum to the skin surface
where drug would be dissolved in sweat. Skopp G. et al. [17] ex-
plained the passag e of drug molecules from the skin capillaries into
perspiration as a passive diffusion process governed by the same
factors as the secretion into saliv a. The elimination of a substan ces
via sebum is delayed for many days as his the transcellular diffu-
sion and transport by the keratinocytes. Additionally, drug binding
to various skin fractions [33] and reabsorption of drugs from the
skin have been observed [34]. Therefore, a continued presence of
drugs on the skin surface results in the time period when blood or
urine levels are already undetectable [35]. Skopp G. et al. [17] con-
cluded th at the m aterial collected on the skin surface consists of
various constituents and originates from various sources. The main
analyte found on the skin surface is predominantly the parent drug.
The time interval between drug consumption and detection on the
skin surface depends on the nature of the particular drug and on the
sensitivity of the analytical method used. In chronic abusers drug
molecules are p ermanently present on the skin due to temporary
reservoir of the stratum corneum [17].
4. ANALYTICAL MET HODOLOGIES
The usefulness of a drug test resid es in its ability to accurately
detect the presence of parent drug or metabolites in biological fluids
or tissues following human drug administration [20]. This definition
reflects both chemical factors that influence test outcome such as
sensitivity, specificity and accuracy, and pharmacologic considera-
tion including dose, time and route of drug administration. Individ-
ual differences in rate of absorption, metabolism and excretion are
also pharmacologic variables that may influence test outcome [20].
In the following section analytical methodologies used to detect
drugs of abuse in sweat are reviewed; collection devices, immuno-
chemical screening tests validated for this purpose and confirma-
tory analy ses are also discu ssed.
a. Collection Devices
Two different approaches in testing for drugs in sweat can be
performed. The first method is aimed to detect recent use of drugs (
< 24 hours) and involves only collection of sweat at a point in time.
It is mainly oriented to identify individuals who are under the influ-
ence of drugs. This kind of collection device (Drugwipe) will be
discussed in the section of screening test. The second approach is
based on patch technology and allows monitoring of illicit drug use
for time windows wider than those provided by urine testing. This
is because the patches can be worn for up to one week or even four-
teen days. Drugs accumulate in the collection device, and little or
no drug degradation seems to occur during this time interval. Sys-
tematic collection of sweat specimens is difficult because of une-
qual distribution of sweat glands on different parts of the body.
Also there is irregular production of sweat volume which is highly
dependent upon an individual’s physical activity, emotional state,
and the temperature of the environment [28].
Sweating maybe induced by exercise and several milliliters of
sweat maybe collected in conjunction with an occlusive wrapping
or gloves. Drugs maybe caused to diffuse into the skin under an
electrical force but th is procedure has not been employ ed as a sam-
pling technique for diffusion of drugs out of the skin [16]. Small
amounts of sweat maybe produced by electrical diffusion of pilo-
carpine into the skin or by warming the area; some devices have
been developed using pilocarpine stimulation to increase sweat
production [11, 16, 40].
Several commercial devices are available for the collection of
sweat for drug analysis, however the most common application is
via the sweat patch. In recent years extraordinary advances in ana-
lytical techniques have enabled the detection of drugs and drug
metabolites in sweat. Early patch were made of absorbent cotton
pads sandwiched between a waterproof, polyurethane, outer layer
and a porous inner layer that is placed against the skin. A patch was
later developed that included a chemical binding layer in the ab-
sorbent pad to prevent external water and other molecules from
back diffusing into the absorptive pad [8].
(Table 1) summarizes some important characteristics, such as
the tipology of collection device, application site of the patch on
human body, time of wearing, that are discussed in the following
section.
In 1986 the use of a sample collection device (Macroduct) of
human sweat for anion analysis was reported [41]. Cole DE. et al.
[41] compared concentrations of chloride and sulfate in sweat ob-
tained by use of the Macroduct capillary-coil collection device with
results obtained by the conventional absorbent filter pad technique.
Samples obtained with the device weighed less than those obtained
conventionally, but sweat chloride concentrations were not signifi-
cantly different. Background contamination, a problem with the
filter pads, was negligible with the Macroduct collector [41]. Some
paper [2, 42] refer about the use of the patch Band-aid that consists
of an adhesive layer on a thin transparent film of surgical dressing
to which a rectangular absorbent pad is attached. Water, oxygen,
carbon dioxide and other gases pass freely through the polyurethane
adhesive “Tegaderm” covering of the patch but molecules larger
than vapor phase isopropanol are excluded by the molecular pore
structure of the plastic membrane. An application of Band-aid type
collection device [43] detected cocaine and its metabolites after
intranasal assumption, indicating that the patch technology can be
used to diagnose a single episode of cocaine use as far back as
seven days. A few individuals developed slight redness and irrita-
tion from the patches which were apparent upon removal.
In 1996 a noninvasive and non-occlusive skin patch (Su-
dormed) was investigated for the systematic collection of drugs of
abuse over a period of several days [44]. First, the applicability an d
user friendliness were tested by volunteers. A single dose experi-
ment using theophylline as a mod el compound showed that there
was a delay in time before the substance could be determined in the
pad. The so-called sweat patch appears to be a valuable tool in
clinical and forensic toxicology, as it offers a longer and prospec-
tive surveillance period compared with blood and urine testing [44].
In the same year benzodiazepines and metabolites [45], codeine and
phenobarbital [46] were analyzed from sweat collected by means of
Sudormed. Patches were removed at specified times over one week
and drug content was determined by gas chromatography/mass
spectrometry. Drugs were detectable in the 2-4 hours period follow-
ing the administration.
Huestis M.A. et al. in 1999 [11] referred about the evaluation of
two “Fastpatch” devices in a controlled clinical trial for the disposi-
tion of cocaine, codeine and their metabolites. These patches re-
quire only 30 minutes for sweat collection because they employ
heat-induced sweat stimulation and a larger cellulose pad for in-
creased drug collection. Through mild heating and a slightly large
collection, “Fastpatch” [47] shows the promise of shorter required
wear periods than other sweat patches, and possibly longer time
periods of detected use. There were no significant differences in
detection rates between 15, 20 and 30 minutes wear periods.
In 1990 a device called “PharmCheck” sweat patch [11] was
marketed as a non occlusive sweat collection, consisting of a medi-
cal-grade cellulose blotted paper collection pad covered by a thin
layer of polyurethane and acrylate adhesives. The absorption pad
8 Current Medicinal Chemistry, 2013, Vol. 20, No. 1 De Giovanni and Fucci
consists of inert cellulose that retains the non volatile components
of sweat collected from the surface of the sk in. The release liner
allows removal of the collection pad from the adhesive layer after
patch use. Many advantages of the patch were observed, first of all
it didn’t alter the transport properties of the skin and water was not
trapped against the skin minimizing the skin irritation. Mo reover
the patch is relatively impervious to environmental contamination
[37] and appears to be relatively tamper-proof, in fact the patch
adhesive is specially formulated so that it can only be applied once
and cannot be removed and successfully reapplied to the skin sur-
face [8]. The disadvantages include high inter-subject variability,
the possibility o f environmental contamination of the patch before
the application or after removal, and the risk of accidental removal
during a monitoring period.
The recommended procedure is to clean the skin with 70% iso-
propanol swabbing before application of the patch [48]. Each patch
has unique nine-digit-number printed underneath the polyurethane
layer that is visible through a window while that patch is being
worn, useful in maintaining the chain of custody. The w ater com-
ponent of sweat, vaporized by body heat, passes through the polyu-
rethane; solids, salts and drugs excreted in the sweat or that p ass
through the skin are trapped on the collection pad. Although an
other research [4] showed that drugs can remain on the skin for
several days after application of the patch, the 70% isopropanol is
not the most effective solvent in removal of drugs. Drugs deposited
on the skin of drug free volunteers several days prior the application
of the sweat patch were not completely removed by normal hygiene
or the cleaning procedures recommended before application of the
sweat patch [13]. The key component of the “PharmCheck” sweat
patch, th e membrane, has been tested for the passage of externally
applied materials. Drugs in the uncharged state rapidly penetrated
the membrane, but charged species were greatly slowed [13]. In
basic media detectable concentrations of cocaine, methampheta-
mine and heroin were observed at the earliest collection time after
drugs were placed on the outside of the membrane.
In conclusion numerous devices have been developed for col-
lection of sweat specimens. The most common device in current use
is the “PharmCheck” sweat patch which usually is worn by an indi-
vidual for five to ten days. This device has been utilized in several
field trials comparing sweat test results to conventional urinalysis
and the results have been favorable.
b. Time Window
It was not established the optimal time of wearing sweat
patches, although many scientists performed many studies for dif-
ferent illicit drugs. In 1998 Joseph R.E. et al. [36] established that
after dosing some illicit drugs appeared in sebum within 1-2 hours
and were detected for 1-2 days. A study [37] examining minimum
length of wear necessary to detect recent or concurrent cocaine use
in a convenience sample of active cocaine users established that the
minimum duration that patches must be worn to detect recent or
concurrent cocaine use is more than two hours and less than or
equal to one day. Analyte concentrations increase significantly with
increasing lengths of wear. The relative detection time of sweat
respect to other specimens was suggested by Caplan Y.H. et al.
[14]. Sweat provides a cumulative measure of drug use and could
be applied to the monitoring of individuals in drug rehabilitation
programs because it provides a prospective, rather than retrospec-
tive approach.
Time window depends in part on drug use pattern [38]; in fact
three different patterns (chronic, occasional and no-use) are readily
identified by daily urinalysis, while patch identifies only some of
the occasional cocaine use episodes and virtually all of the frequent
chronic users. Some studies [31, 39] suggest that there is a time
dependent loss of drug during patch wearing over time. One of the
most likely mechanism involved in drug loss is re-absorption back
into the skin. Results on 3,4-methylenedioxymethamphetamine
(MDMA) in sweat [39] showed an inflection in the kinetic at ten
hours post-administration. This observation revealed the possibility
that MDMA already incorporated in patches could be reabsorbed by
the skin. According to this notice, the re-absorption (back transfer),
degradation or hydrolysis, and loss of cocaine to the environment
that may account for substantial loss of cocaine from skin sweat
collection patches during patch wear, was studied [31].
c. Screening Tests
Sweat patch analysis requires extraction and sensitive ch roma-
tographic methods in combination with mass spectrometry to
achieve an effective limit of quantification. Even though, immuno-
assays commonly used to screen samples prior to confirmation by
gas chromatography/mass spectrometry (GC/MS), and mainly
commercialized for urine samples, were also applied to alternative
specimens such as sweat ( Table 1).
The first immunochemical detection of drugs in apocrine sweat
collected the samples from the axillary perspiration [49]. The de-
termination of the drugs (sum of parent drug and metabolites) was
performed by radioimmunoassay (RIA). Measurable drug concen-
trations of cannabinoids, benzodiazepines, cocaine, barbiturates,
morphine, methadone and cotinine were found in all samples. Bala-
banova S. et al. [40] investigated the presence of cocaine, morphine
and methadone in sweat samples obtained after stimulation of the
eccrine sweat glands.
A different system [42] for the analysis of co caine in sweat em-
ployed a solid-phase enzyme immunoassay (EIA) involving modi-
fied microtiter plates after extraction of pad with acetate bu ffer and
methanol; this procedure showed to have cross-reactivity for co-
caine and benzoylecgonine with higher concentration of parent
drug.
In 2001 [50] two types of immunoassays (RIA and microplate
enzyme immunoassay), were compared to detect and quantitate
cocaine, heroin and metabolites in extracts of sweat patches. Assays
were first evaluated for sensitivity in detection of the different con-
centrations of analytes known to be excreted in sweat. Various
cross-reactivities were evaluated for both devices. In 2004 Moody
D.E.et al. [51] reported a comparative an alysis of sweat patches for
cocaine and metabolites by RIA and gas chromatography-positive
ion chemical ionization mass spectrometry. Sweat patches worn by
subjects receiving treatmen t for cocaine dependence to compare the
procedures were analyzed. Patches were extracted with acetate
buffer pH5 directly analyzed. Time expended on performing RIA
analysis of all th e samples was cost-effective when the results were
used to exclude negatives from and predict dilutions required for
GC-MS analysis. RIA offers a sensitive and specific alternative
initial test for cocaine d etermination in extracts of sweat patches
[51].
Although the initial research in the area of alternative speci-
mens utilized RIA, newer non isotopic commercial immunoassays
are widely available for screening of drugs and drug metabolites.
Techniques such as Enzyme-Linked Immunosorbent Assay
(ELISA), have been adapted for detection of analytes in sw eat
patches [14]. Kidwell D.A. et al. [38] compared three different
immunoassays to screen specimens for cocaine on matrices not
commonly tested: a modified manual Microgenics CEDIA, Cozart
ELISA and OraSure ELISA. Before the immunochemical test dried
skin swabs or patches were extracted with two portion of 0,1M of
chloride acid. Both the Cozart and OraSure cocaine immunoassays
performed similarly and showed a reasonably strong correlation
with each other. In contrast, although the modified Microgenics
assay showed the requisite sensitivity for the matrices examined, it
had poor precision when run in a manual mode.
Sweat Testing for Dr ugs of Abuse Current Medicinal Chemistry, 2013, Vol. 20, No. 1 9
A rapid onsite test called “DrugWipe” immunochemical strip
test, was also assessed; the device is a pen size, immunochemical-
based test strip used for the detection of drugs of abuse on surface.
The wiping part enables the user to sample drug particles from any
kind of surface such as the sk in; it is simple to u se and results can
be obtained after two minutes. In 1999 Mura P. et al. [52] evaluated
the results of tests when applied to sweat. Regular users of cannabis
and persons who denied consuming it were studied. The results
obtained with DrugWipe in sweat were compared with anamnesis
data. The Authors observed that DrugWipe may be useful for
screening cannabis in sweat when the intake took place less than
two hours before. Potential drug users participated voluntarily in a
study [53] to evaluate the usefulness of the DrugWipe for the
screening of cocaine, opiates, amphetamine and cannabinoids refer-
ring about advantages and disadvantages of the test. DrugWipe for
the analyses of drugs of abuse in sweat [54] have also been applied
to healthy volunteers familiar with the effects of MDMA after sin-
gle oral dose. MDMA consumption could be detected at two hours
and for as long as twelve hours after drug administration. Pichini S.
et al. [39] found the onsite test positive at 1.5 hours but few false-
negative results appeared in the first six hours after administration.
A particular application [55] regarding an immunoassay based
technique was recently used for the detection of psychoactive sub-
stances in the sweat deposited within fingermarks of a narcotic drug
user using white light and/or a fluorescence light source. In particu-
lar Hazarika P. et al. [55] showed that morphine can be detected in
the sweat deposited within a latent fingermark, concluding that
fingermarks images can provide information on drug usage of an
individual.
d. Confirmatory Analytical Techniques
Immunochemical screening always needs confirmatory analysis
to be performed by chromatographic techniques. When alternative
matrices are used the employ of confirmatory analytical techniques
is mandatory. Advances in sensitive methodologies have enabled
the analysis of drugs in unconventional biological materials such as
sweat. Scientific literature refers about the detection of drugs of
abuse in sweat employing both gas and liquid chromatographic
methods.
Many papers were published about the detection of xenobiotics
in sweat ( Table 1) by gas chromatography mainly coupled with
mass spectrometry [11, 12, 25, 27, 30-32, 36, 39, 42, 45-48, 51, 53,
56-74]. Some of them discuss sweat combined with other biological
matrices. In this section we discuss some representative papers
referring about the analytical procedure applied to many com-
pounds. Kintz P. et al. [12] in 1997 conducted a study on sweat
patches applied to some subjects during heroin maintenance pro-
gram. The target drugs were extracted in acetonitrile solution and
the residues were analyzed by gas chromatography-mass spec-
trometry in electron impact mode directly and after silylation. Her-
oin was the major drug present in sweat, followed by 6-
acetylmorphine and morphine. No correlation between the doses of
heroin administered and the concentrations of heroin measured in
sweat, was observed. Sweat testing for cocaine, codeine and me-
tabolites by EIA and GC/MS was performed [11] on voluntary
people administered with cocaine and codeine. Sweat patches were
eluted by sodium acetate buffer successively extracted by Solid
Phase Extraction (SPE) and derivatized to obtain silyl-derivatives
analyzed by GC/MS in selected ion monitoring mode. The authors
concluded that the combination of EIA and GC/MS analysis was
sensitive enough to detect cocaine in sweat after minimal abuse.
More recently a sensitive gas chromatography-negative ion chemi-
cal ionization mass spectrometry (GC/MS-NICI) method [65] was
developed and validated for the measurement of Delta(9)-
tetrahydrocannabinol (THC) in human sweat patches. Patches were
extracted with methanol-sodium acetate buffer pH 5.0 for 30 min-
utes. Extracted solution was diluted with sodium acetate buffer (pH
4.5) and extracted by solid-phase extraction columns (CleanScreen;
United Chemical Technologies). Dried extracts were derivatized
with trifluoroacetic acid and analyzed by gas chromatograph inter-
faced with an mass selective detector operated in NICI-selected ion-
monitoring mode. The same paper studied various potential inter-
fering compounds added to low quality-control samples founding to
not influence THC quantification. Saito T. et al. [65] stated that
GC/MS-NICI assay for THC in human sweat provides adequate
sensitivity and performance characteristics for analyzing THC in
sweat patches and meets the requirements of the proposed Sub-
stance Abuse and Mental Health Services Administration's guide-
lines (SAMHSA) for sweat testing [6 ].
A semi-quantitative gas chromatographic/mass spectrometric
method [66] was developed to simultaneously detect cocaine and
cocaethylene in sweat samples collected by PharmChek, eluted with
sodium acetate buffer (pH 5.0) and extracted by solid-phase micro-
extraction (SPME). The method showed to be very simple, rapid
and sensitive. A positive chemical ionization gas chromatogra-
phy/mass spectrometric method was validated to simultaneously
quantify drugs and metabolites in skin collected after controlled
administration of methamphetamine, cocaine and codeine [68].
Amphetamines were eluted from PharmChek sweat patches [70]
with sodium acetate buffer, extracted with disk solid phase extrac-
tion and analyzed using GC/MS-Electron Impact mode with a fully
validated procedure that permitted the simultaneous analysis of
multiple amphetamine analogs in human sweat. Another application
for amphetamine detection in sweat patches following controlled
MDMA administration was performed by Barnes AJ. et al. [73]. A
sensitive, specific and validated GC/MS method (electron impact
ionization and selected ion monitoring) was presented to simultane-
ously quantify methadone, heroin, cocaine and metabolites in sweat
[71].
The successful interface of liquid chromatography with mass
spectrometry (LC-MS) has brought a new light into bioanalytical
and forensic sciences as it allows the detection of drugs and me-
tabolites at concentrations that are difficult to analyze using the
more commonly adopted GC/MS based techniques [75-83]. Liquid
chromatography allows the separation of enantiomeric mixtures of
xenobiotics employing chiral stationary phases [80]. In 1998 [80]
an enantioselective separation of methadone was obtained using an
alpha-1-acid glycoprotein column and liquid chromatography/Ion
Spray Mass Spectrometry. The separation of R- and S-methadone
can be used to document some physiologic mechanisms of excre-
tion and incorporation into sweat. The combination of LC-MS with
innovative instrumentation such as triple quadrupoles, ion traps and
time-of-flight mass spectrometers has been focused [82]. Methyl
phenidate and ritanilic acid [76], buprenorphine, methadone, co-
caine, heroin, nicotine and their main metabolites [75] were deter-
mined in patches using previously validated liquid chromatography-
electrospray ionization mass spectrometric methods. A procedure
based on LC-MS/MS was described [83] for the determination of
atomoxetine and its metabolites in sweat and other matrices. Ana-
lytes were extracted from sweat patch with tert-butyl methyl ether
and the organic layer was evaporated and redissolved in mobile
phase. Separated analytes were identified and quantified by positive
electrospray ionization tandem mass spectrometry and in multiple
reaction monitoring acquisition mode. Kintz P. et al. [84] applied
sweat patches to known heroin abusers coming from a detoxifica-
tion center; target drugs (opiates, cocaine, cannabinoids, benzodi-
azepines, amphetamines and buprenorphine ) were analyzed either
by GC/MS or LC-MS depending on the target compound. de
Oliveira C.D.R. et al. [5] published a review of chromatographic
procedures for determination of amphetamines, cannabinoids, opi-
ates, nicotine, cocaine and alcohol in alternative biological matri-
ces. Gas chromatographic and liquid chromatographic procedures
with different detectors and sample preparation techniques such as
liquid/liquid, SPE and SPME extraction were discussed.
10 Current Medicinal Chemistry, 2013, Vol. 20, No. 1 De Giovanni and Fucci
5. SWEAT VERSUS OTHER MATRICES
The selection of the specimens for drugs analysis is influenced
by a variety of factors, principally ease of specimens collection,
analytical and testing considerations and interpretation of results.
Moreover each specimen gives different information respect to the
detection window. Many papers simultaneously studied different
biological matrices, including sweat, for the detection of drugs of
abuse, but some of them focused on the direct comparison between
the different specimens. The new matrices demonstrate some dis-
tinct advantages over urinalysis, e.g. less invasive procedures, dif-
ferent time course of drug detection [18]. A comparison [9] be-
tween urine, sweat and hair was performed to identify the best ma-
trix in drug testing. In contrast with urine, hair analysis has a wide
window of detection, ranging from months to years. Testing indi-
viduals for illicit drugs with sweat patches worn continually would
provide effective coverage for a week.
Smith FB. et al. [3] compared the concentrations of cocaine and
benzoylecgonine in the hair, saliva, skin secretions and urine sam-
ples of cocaine – using mothers, their children, and other adults
living in the same environment. Most of the skin swabs from the
adult subjects and most of their children were positive for cocaine.
The presence of co caine in swabs could indicate that it originated
from sweat. However negative child urine and saliv a results contra-
dict this hypothesis and imply recent surface contact.
Joseph R.E. et al. [36] examining the disposition of cocaine,
codeine, and metabolites in stratum corneum, sebum and plasma
collected from African-American males after administrations of
cocaine and codeine compared the results with the distribution in
sweat. Stratum corneum consists of 15-20 layers of keratinized cells
that are similar to hair with the exception that fewer disulfide bonds
are present in stratum corneum compared with hair. Sebum is an
oily substance composed primarily of wax ester fatty acids pro-
duced in cells of sebaceous glands. No relationship was observed
between drug concentrations in sebum and stratum corneum com-
pared with dose. Interpretation of drug distribution and elimination
in sebum and stratum corneum was complicated by possible con-
tamination of specimens with drugs from sweat.
The analysis of urine and patch test for methadone, opiates and
cocaine metabolites was performed on patients with a diagnosis of
opiate addiction prescribed methadone [85]. There was good
agreement between sweat patches and urine tests for methadone and
opiates, but only moderate agreement for benzoylecgonine probably
due to urine tests only detecting use over the last 2-3- days. Sweat
patches may be more sensitive and detecting illicit drug use as they
provide a longer period of collection. A comparison between urine
and sweat patches results obtained from a woman with a history of
chronic methamphetamine and cocaine abuse [86] was reported.
The results of the study rise further questions about the preferential
use of the sweat patch in detecting new episodes of drug use in
formerly chronic drug users. Advances analytical techniques have
enabled the detection of drugs in alternative biological specimens
for the purposes of workplace testing. Caplan YH. et al. [14] evalu-
ated some of these specimens (oral fluid, hair and sweat) in order to
determine their utility in Federally Regulated programs focusing the
attention on advantages and disadvantages of the matrices consid-
ered.
To compare the efficacy of sweat testing versus urine testing for
detecting drug use [62] paired sweat patches were applied and re-
moved quickly and compared to 3-5 consecutive urine specimens
from patients in a methadone maintenance treatment program. The
identification of heroin and / or 6-acetylmorphine in sweat patches
confirmed the use of heroin in 78% of th e positive cases and differ-
entiated illicit heroin use from possible ingestion of codeine or
opiate-containing foods.
Kidwell DA. et al. [38] highlighted advantages and disadvan-
tages of daily u rine and sw eat patches to establish the pattern o f the
drug use among cocaine abusers. The patch identified some of the
occasional cocaine use episodes and all of the frequent chronic
users. A comparison [72] between hair and sweat was performed on
heroin abusers in methadone treatment calculating the ratio between
methadone and its metabolite in both biological matrices; these
ratio appeared to be comparable.
In conclusion each biological matrix shows peculiarities that
could be used in different context hence the role of the forensic
toxicologist is also the choice of the most suitable sample. Sweat
samples provide cumulative measure of drug exposure, they are
able to monitor drug intake for a period of days to weeks, they de-
tect parent drugs and metabolites, the collection is non invasive and
the devices are relatively tamper proof. However the large variation
in sweat production, the volume unknown and the high Intersubject
variability are some of the major disadvantag es.
6. MONOGRAPHIC STUDIES
In this section we summarized papers regarding the most com-
mon substances of abuse in sweat found in the international litera-
ture.
a. Amphetamines
Amphetamines are powerful psychostimulants, producing in-
creased alertn ess, wakefulness, insomnia, energy and self-
confidence in association with decreased fatigue and appetite as
well as enhanced mood, well-being and euphoria [87]. Hepatic
metabolism is extensive in most cases, but a significant percentage
of the drug always remains unaltered. Amphetamine and related
compounds are weak bases with a relatively low molecular weight
[87]. These characteristics allow amphetamine-type stimulants to
diffuse easily across cell membranes and lipid layers and to those
tissues or biological substrates with a more acidic pH than blood,
facilitating their detection in alternative matrices [87].
Already in the years ’80 a method for the detection of metham-
phetamine and its major metabolite in sweat from habitual users by
mass fragmentography has been developed [88]. Sweat samples
were extracted with meth anol and after trifluoroacetyl derivatiza-
tion, analyzed by mass fragmentography. Later in 1996 [57] sweat
was collected with the “PharmChek TM” sweat patch and drugs
were eluted from the collection pad of the patch. A solid phase,
enzyme immunoassay using microtiter plates was modified for
analysis of methamphetamine. The results were confirmed by
GC/MS. Barnes A.J. et al. [89] confirmed these results studying the
excretion of MAMP and AMP after controlled MAMP administra-
tion. A procedure based on GC/MS [90] for the simultaneous iden-
tification of N-methyl-1-(3,4-methylenedioxyphenyl)-2-butanamine
(MBDB) and its desmethylated metabolite 3,4-(methylene dioxy-
phenyl)-2-butanamine (BDB) in sweat specimens were presented.
Sweat specimens, which were collected by a sweat patch, were
tested after methanolic elution. MBDB was present in higher con-
centrations than its metabolite. A review [91] of the procedures for
the determination of MDMA derivatives, methylendioxyampheta-
mine (MDA), MDMA, methylendioxyethylamphetamine (MDEA),
MBDB in saliva, sweat and hair was reported. The parent drug was
found to be always in higher concentrations than metabolites. The
development and validation of a method for the simultaneous quan-
tification of some amphetamines related drugs in sweat was also
reported [70].
A brief review [92] for the detection of AMP and methylendi-
oxy-derivatives in sweat was reported. According to guidelines for
drug monitoring using sweat as alternative specimens proposed by
SAMHS A requirements for a positive sweat test include ampheta-
mines screen test with higher than 25 nanograms/patch and a con-
Sweat Testing for Dr ugs of Abuse Current Medicinal Chemistry, 2013, Vol. 20, No. 1 11
firmation cut off of 25 nanograms/patch for amphetamines and
methylenedioxy-derivatives. De Martinis BS [92] reviewed the
indexed literature founding limits of detection and quantification
ranging from 0.72 ng/patch to 5 ng/patch and from 1.4 ng/patch to 5
ng/patch for all analytes respectively.
Pharmacokinetic studies [81, 39] were performed after the oral
administration of MDMA to healthy volunteers known to be recrea-
tional MDMA-users. Sw eat wipes were collected after administra-
tion and the MDMA levels averaged 25 nanograms/wipe [81], also
demonstrating large intersubject variability with peak MDMA con-
centrations for the same dose varied in magnitude 30-fold [39].
Recently the disposition of MDMA and metabolites in human sweat
following controlled MDMA administration was also reported by
Barnes A.J. et al. [73]. MDMA was the primary analyte detected
with concentrations up to 3007 nanograms/patch. MDA was de-
tected at much lower concentrations, whereas no HMMA or HMA
was detected. The variability in sweat excretion suggests that re-
sults should be interpreted qualitatively rather than quantitatively.
b. Cannabis
The use of marijuana and hashish (derived from cannabis Sa-
tiva) mostly by smoking, produces sedation, euphoria, hallucina-
tions or temporal distortion. The main psychoactive compound is
THC which is first biotransformed to an active metabolite, 11-
hidroxy-THC which in turn is rapidly converted to an inactive me-
tabolite, 11-nor-9-carboxy-THC [8]. In contrast to the majority of
drugs of abuse which are weak base and tend to concentrate in bio-
logical matrices more acidic than plasma, THC is a n eutral mole-
cule and its diffusion is expected to be slower [93]. Not surprisingly
lipophilic drugs can be detected in skin and adipose tissue. Johans-
son E. [94] demonstrated that in heavy marijuana users, THC re-
mained in adipose tissue up to 28 days after smoking. Only a few
papers were found in literature referring about the detection of can-
nabis in sweat. Early paper detecting THC in sweat [49] found the
parent drug to be the primary analyte. In a study conducted in a
detoxification center, sweat patches were applied to 20 known her-
oin abusers. Target drugs analyzed either by GC-MS or LC-MS
included delta9-tetrahydrocannabinol, identified in nine cases (4-38
ng/patch) [84]. In 1999 Staub C. [95] found THC in low amount
and the principal acidic urinary metabolite (11-nor-9-carboxy-THC)
has been never detected in sweat. An editorial discussion on the
usefulness of sweat testing of the detection of cannabis smoke has
been reported in 2004 [93]. In order to demonstrate an intake of
cannabis Mura P. et al. [52] evaluated the results of DrugWipe.
Regular users of cannabis and persons who denied consuming it
were studied. The results obtained were compared with anamnesis
data and indicated that DrugWipe could be useful for screening
cannabis in sweat when the intake took place less than two hours
before. The non-instrumental immunoassay Drugwipe was also
used in a Belgian study for the screening of cocaine, opiates, am-
phetamine and cannabinoids in saliva and sweat [53]. Procedures
using GC/MS to test for THC in forehead wipes were developed
and validated [96, 65]. Injured drivers were tested, some of them
were positive for THC, but metabolites were never detected [96].
Saito T. et al. [65] developed an assay with adequate sensitivity and
performance ch aracteristics for analy zing THC in sweat p atches
meeting the requirements of the proposed SAMHSA’s guidelines
for sweat testing [6]. Huestis MA . et al. [97] evaluated THC excre-
tion in daily cannabis users after cessation of drug use. Moreover
some subjects were administered oral doses of THC for five con-
secutive days; the results demonstrated that THC does not readily
enter sweat following oral ingestion.
c. Coca ine
Cocaine is a powerful addictive stimulant drug extracted from
“Erythroxylon coca” leaves that can be administered intranasally, or
by intravenous or intramuscular injection. It can also be taken
orally, sublingually, vaginally or rectally or it can be smoked. The
human metabolism transforms cocaine into two major metabolites
(benzoylecgonine and ecgonine methylester) and some other minor
metabolites [8]. In recent years cocaine is becoming the most popu-
lar drug of abuse and many studies on its detection in sweat have
been published.
A clinical study [43] examined a skin patch method of monitor-
ing drug use after two different treatment doses. Analysis of the
patch content yielded cocaine lev els from the cocaine subjects that
accurately reflected usage. Mean levels were significantly different
for the two treatment doses. The data do indicate that the patch
technology can be used to diagnose a single episode of cocaine use
as far back as seven days.
The use of a sweat patch for detecting cocain e abuse in cocaine-
dependent patients participating in a clinical trial was studied [98].
The reliability and validity of quantitative sweat patch results, the
possible degradation of cocaine to benzoylecgonine as a function of
the length of time that a patch is worn and the relative costs associ-
ated with sweat patch were also ev aluated. The results revealed n o
significant degradation of cocaine to benzoylecgonine associated
with wearing th e patch . The excretion of cocaine in sweat o f volun-
teers receiving low and high doses, was again evaluated in 2005
[30]. Pharm-Chek sweat patches were collected before the admini-
stration, during and after controlled dose. Cocaine was the primary
analyte detected and frequently the only one.
Some contamination studies were performed on different popu-
lation. An application of sweat test was performed on cocaine-using
mothers and their children [3]. To distinguish actual drug use from
passive exposure to the drug a comparison between forehead swabs
and other biological materials were performed. In a second trial a
random population of adults at a major United States University [4]
was studied. Sweat was obtained by wiping the forehead with a
cosmetic puff containing isopropanol. Moderate amounts of cocaine
and benzoylecgonine are slowly lost when placed on the skin possi-
bly due to absorption. To test the persistence of larger amounts of
cocaine and benzoylecgonine on the skin through removal by nor-
mal hygiene and absorption by the body, two sets of experiments
were carried out. After three days of normal hygiene and three re-
moval steps the drugs were undetectable.
More recently Kidwell D.A. et al. [38] made a comparison of
daily urine, sweat and skin swabs among cocaine users. Large
quantities of cocaine were found on the skin of individuals with
urine positivity and an evaluation of drug contamination on the
external patch membrane was performed. Immunoassays were stud-
ied and validated in various papers using different techniques. A
solid-phase enzyme immunoassay [42] involving microtiter plates
was modified for the analysis of cocain e in sweat, collected with
the PharmChek patch that contained primarily parent cocaine, and
the method was validated for qualitative detection.
The monitoring of cocaine use was performed in substance-
abuse-treatment patients by sweat testing [61]. Sweat and urine
specimens were collected from methadone-maintenance patients to
evaluate the use of sweat testing to monitor cocaine use through
ELISA test. Immunoassays were also evaluated by Moody D.E. et
al. [50] for their ability in the detection of cocaine and metabolites
discussing the cross reactivity. Later a RIA method [51] using
sweat patches worn by subjects receiving treatment for cocaine
dependence was developed.
Various methodologies were proposed to identify and quantitate
cocaine and its metabolites. A semi-quantitative method (SPME
followed by GC/MS) was elaborated to simultaneously detect co-
caine and cocaethylene in sweat [66]. GC/MS [68, 71] and LC-MS
methods [75] for many substances including cocaine and its me-
tabolites in sweat were developed and comprehensively validated.
These methods permit fast and simultaneous quantification of many
12 Current Medicinal Chemistry, 2013, Vol. 20, No. 1 De Giovanni and Fucci
drugs and metabolites in sweat patches, with good selectivity and
sensitivity.
The minimum length of wear necessary to detect recent or con-
current cocaine use in a convenience sample of active cocaine users
was examined [37]. Differences in analyte concentrations with in-
creasing longer-term wear were observed. Some studies compared
different sites of application of the patches to establish the best
collection point. Huestis M.A. et al. [11] reviewed sweat testing for
cocaine discussing that diversifying the site of collection change
drug disposition in sweat. Generally concentration of cocaine are
higher in sweat specimens collected on the hand respect to the
torso. This observation is likely to be due to differences in the anat-
omy and physiology of the skin on the palm of the hand compared
to the torso skin. Uemura N. et al. in 2004 [31] also investigated the
effect of sweat patch location (back and shoulder) on cocaine levels
after controlled intravenous cocaine exposure in different subjects.
The analysis showed cocaine and metabolites levels in sweat eight-
fold higher on the back than those on the shoulders.
A continuing social problem is presented by the large number
of individuals who smoke crack; crack is a mixture of cocaine hy-
drochloride and sodium hydrogen carbonate which liberates the
cocaine base from the hydrochloride with some cracking noise.
Liberty HJ et al. [47] have identified unique pyrolysis products of
crack or burned cocaine as anhydroecgonine methylester and
ecgonidine through GC/MS that allow for the detection of crack use
distinct from other cocaine use.
d. Opiates
Opium is a natural product containing morphine as the principal
alkaloid. Illicit market synthesizes heroin adding two acetyl groups
to morphine in order to obtain a stronger drug. Following intake,
heroin is rapidly deacetylated to 6-acetylmorphine which is then
further hydrolyzed to morphine at a slower rate [8].
Many papers refer that opiates are excreted in sweat, and the
parent drug is the predominate analyte found. Heroin and its me-
tabolites [2] were investigated in sweat patches in order to evalu ate
the possible use of alternative matrices. The data suggested that
sweat patches could serve as a useful monitoring device in surveil-
lance of individuals in treatment and probation programs. In a study
conducted in a detoxification center [84], sweat patches were ap-
plied to known heroin abusers, to detect heroin, 6-acetylmorphine,
morphine and codeine. When detected, heroin was always present
in lower concentrations than 6-acetylmorphine, which was the ma-
jor analyte found in sweat. It is noteworthy that sweat is one of the
few matrices in which heroin is readily detected. After opiate (co-
deine, or heroin or poppy seeds) administration [48] patch perform-
ances were evaluated. Heroin and 6-acetylmorphine or codeine but
little morphine were found in sweat after heroin or codeine admini-
stration as contrasted to the metabolite profile found in urine or
blood. Heroin and 6-acetylmorphine or codeine appear in sweat
within 24 hours of administration of opiates in controlled studies
and peak within the first three days. An other study [12] conducted
during an heroin maintenance program applied sweat patches to
subjects that received intravenously two or three doses of heroin
hydrochloride ranging from 80 to 1000 mg/day. The sweat patch
was applied ten minutes before the first dosage and removed ap-
proximately 24 hours later, minutes before the next dosage. Except
in one case, heroin was the major drug present in sweat, followed
by 6-acetylmorphine and morphine. No correlation between the
doses of heroin administered and the concentrations of heroin
measured in sweat were observed.
The time course, the cumu lative excretion, the intra-subject
variability, the influence of site application, and the concentrations
of codeine in sweat following administration of a single dose of the
drug, was also performed [46]. Codeine was detectable at one hour
following the administration, and a plateau concentration was ob-
served on the third day. The peak codeine concentration was deter-
mined during the 12-24 hours period. Morphine was never detected
in sweat and inter-subject variability was enormous, but Kintz P. et
al. [46] suggest that the sweat patch technology can be useful for
documenting drug use over a one week period of surveillance. Co-
deine phosphate was orally administered to six subjects testing
sweat immediately with the Drugwipe and applying the sweat patch
at the same time [99]. Codeine was quantified in the patch by
GC/MS. In all subjects except one, the Drugwipe tested positive for
opiates. After controlled oral codeine administration [32, 68] sig-
nificant variability in concentrations was observed in patches ap-
plied to various locations in the upper body. Codeine was detected
within one hour and peaked within 24 hours and no metabolites
were detected. The study comprehensively evaluated hourly and
weekly sweat patches to ch aracterize the duration, accumulation,
reproducibility, time of first appearance and dose concentration
relationship of codeine excretion in sweat.
Methadone is a opioid pain reliever, similar to morphine. It re-
duces withdrawal symptoms in people addicted to heroin or other
narcotic drugs without causing the "high" associated with the drug
addiction. It is used in detoxification and maintenance programs for
the management of physical dependence of narcotics [1]. Some
studies were found in literature about its possible detection on
sweat samp les. Henderson G.L. et al. [56] already in 1973 referred
about the excretion of methadone and metabolites in human sweat.
Later [44, 80, 85, 100] the presence of methadone was again inves-
tigated in 24 hours perspiration samples obtained from patients
receiving daily maintenance doses of the drug. No correlation be-
tween the dose methadone administered and the concentrations of
methadone in sweat was observed but sweat patches were reliable
giving valid results for patient on maintenance methadone.
The authors of the present review didn’t find papers referring
the detection of methadone in sweat in the scientific literature in the
period 1998 – 2007. Successively [72] a comparison between hair
and sweat samples from patients in long term maintenance therapy
was performed. Fucci N. et al. [72] referred about their experience
with sweat applied to supervise methadone therapy of heroin abus-
ers. Some advantages respect to hair were found such the time win-
dow of sweat shorter than hair that allows the doctor easily to check
the therapeutic program of abusers. A good agreement between
patients, when the application of the patch was proposed instead of
the daily collection of urine or hair cut, was underlined. The devel-
opment of an analytical method for the simultaneous quantification
of methadone and other xenobiotics in sweat is reported by Brunet
B.R. et al. [71]. The excretion of methadone in sweat of pregnant
women after controlled methadone administration was also studied
[74]. Methadone was present in all weekly patches, correlation
between patch concentrations and total amount of drug adminis-
tered and concentrations and duration of patch wear were both
weak.
Buprenorphine is a strong opioid painkiller which is used to
treat moderate to severe pain; it is currently under investigation as a
pharmacotherapy to treat abusers for opioid dependence [1]. Some
papers [26, 101] evaluated the utility of sweat testing for monitor-
ing of drug use in outpatient clinical settings and opioid dependent
pregnant women. Chawarski M.C. et al. [26] comp ared sweat toxi-
cology with urine toxicology and self report drug use during a ran-
domized clinical trial of the efficacy of buprenorphine for treatment
of opioid dependence in primary care settings. The other research
[101] evaluated buprenorphine and its metabolites pharmacokinet-
ics after sublingual administration to pregnant women, suggesting
that, like methadone, upward dose adjustments may be needed with
advancing gestation.
e. Other Substances
Other substances were investigated in human sweat, such as
nicotine, the object of some scientific studies before the year 2000.
Sweat Testing for Dr ugs of Abuse Current Medicinal Chemistry, 2013, Vol. 20, No. 1 13
In 1990 [49] specimens of apocrine and eccrine sweat collected
without and after pilocarpine stimulation from smokers and non-
smokers exposed to tobacco smoke were investigated. The concen-
trations were determined by RIA, so that the values obtained repre-
sent the concentrations of nicotine plus its metabolites, e.g. cotin-
ine. The levels measured in apocrine sweat were higher than those
in eccrin e sweat. Th e presence o f nicotine in sweat obtained from
smokers and non-smoker exposed to tobacco smoke after four hours
to eight days of nicotine-free time was investigated [102]. The sum
of nicotine and its metabolites were determined by RIA. The pres-
ence of unchanged nicotine was revealed by GC/MS. In a study
conducted with cigarettes smokers and nonsmokers [60], Pharm-
Chek sweat patches were applied to subjects for 72 hours. Nicotine
was determined using GC/MS, and it was not detected in non-
exposed nonsmokers, while it was found in passive and active
smokers.
Not only narcotics and stimulants, but also many alkaloids and
barbiturates are excreted in the sw eat and detected quantitatively by
the same principles [46, 103]. To determine the time course, the
cumulative excretion, the intra-subject variability, the influence of
site application, and the concentrations of phenobarbital in sweat
following administration of a single dose of the drug a clinical
study was performed [46]. Phenobarbital was first observed three
hours after administration, and cumulative excretion was continual
throughout the week. Intersubject variability was enormous with the
concentrations in the range of 0.5 - 33 nanograms/patch. These data
suggest that the sweat patch technology can be useful for docu-
menting drug use over a one-week period of surveillance.
Benzodiazepines were also studied [45] to determin e the cumu-
lative excretion, the time course, the dose-concentration relation-
ship, and concentrations of diazepam and its metabolites in sweat
following oral administration of single dose of the drug. Irrespec-
tive of the time of collection, diazepam and nordiazepam were pre-
sent, but oxazepam was never detected. Drugs were detectable in
the two to four hours period following the administration. Concen-
trations were in the range 0.1 to 6.0 nanograms/patch for both
drugs.
The determination of clozapine in sweat was performed using a
liquid chromatographic method [77]. The correlation between clo-
zapine levels in hair and sweat and the daily dose was also studied.
The main active ingredient of the hallucinogenic mint Salvia Divi-
norum (Salvinorin A) was also investigated in sweat but never de-
tected from consumers [67]. After controlled administration of
gamma-hydroxybutyric acid (GHB) sweat and other biological
fluids were analyzed by GC/MS [69]. GHB was detected in sweat
at low concentrations, hence this biological matrix appears not to be
suitable for monitoring GHB consumption. Methylphenidate, a
prescription amphetamine derivative used in the treatment of atten-
tion-deficit hyperactivity disorder, has been amply described in
conventional biological matrices. Recently, the excretion of meth-
ylphenidate and its principal metabolite (ritalinic acid ) in sweat has
been studied [76, 104]. Atomoxetine, a drug approved for the
treatment of attention–deficit hyperactivity disorder, was recently
detected by a LC-MS/MS procedure in conventional and non-
conventional biological matrices from individuals in drug treatment
[83]. Sunitinib, used to treat tumors such as gastrointestinal, renal
cell carcinoma, pancreatic neuroendocrine tumors, was detected in
sweat collected from a patient th erapeutically treated with the drug
[105].
7. FORENSIC APPLICATIONS
Sweat testing received particular attention by scientists for its
possible application on roadside and workplace drug testing that
would be the object of the following sections.
a. Roadside Drug Testing
To establish driver’s impairment sweat samples are obtained by
wiping the forehead. Some studies were found in literature referring
experien ces in this context.
An interesting European study called “ROSITA” (ROadSIde
Testing Assessment) was born to evaluate devices for the analysis
of sweat and other matrices in order to control drivers under the
influence of drugs (www.rosita.org). The objective of the ROSITA
study is “to identify the requirements for road side testing equip-
ment, and to make an international comparative assessment of ex-
isting equipment or prototypes. The assessment will address road
side testing result validity, equipment reliability, usability and us-
age costs.
The first results published [106, 107] referred about the evalua-
tion of various analytical devices to test sweat. Eight nations were
enrolled and about 3000 drivers were tested to evaluate the role
played by the drugs of abuse in the drive performances. The useful-
ness of sweat was demonstrated, it was best accepted respect to
other matrices by drivers, but the need to more investigation was
underlined [17].
Prospective analytical studies [96, 108] were performed in large
population of drivers implicated in non-fatal traffic accidents to
determine the significance of drug levels observed in blood, urine,
saliva and sweat. The samples were tested for pharm aceuticals an d
drugs of abuse by hyphenated chromatographic methods. The
authors observed that a lim itation in the use of the sweat for road-
side testing is the absence of a suitable immunoassay to detect the
parent compound. Sweat samples by wiping the forehead were
obtained from drivers who failed the field sobriety tests at police
roadblocks [64]. The positive predictive value of sweat wipe analy-
sis by GC/MS was over 90% for cocaine and amphetamines and
80% for cannabis.
A global overview [109] on the issue of drugs and driving dis-
cussing the utility of alternative specimens including sweat was
presented by Walsh J.M. et al. in the year 2004. A special attention
for the effects of medicinal and illegal drugs on driving perform-
ance was reported and Walsh J.M. et al. drew conclusion regarding
the risk of the drug to traffic safety.
b. Workplace Drug Testing
Workplace drug testing is a well-established application of fo-
rensic toxicology and it aims to reduce workplace accidents caused
by affected workers. Several classes of abused substances may be
involved, such as alcohol, amphetamines, cannabis, cocaine, opiates
and also prescription drugs, such as benzodiazepines. Since the
1970’s, urine drug testing has been the most common technique for
detecting drug use in the workplace.
National laws of each country provide the underpinnings of
drug-testing programs, but most countries have not addressed use of
these alternate matrices. In 2001 [18] Cone EJ. reviewed national
and local laws of many countries providing the employ of drug-
testing programs, discussing that only a few countries have statutes
that specifically mention the use of alternate biological matrices. In
our knowledge only very few advances have been made in the last
ten years. Caplan Y.H. et al. [14] discussed about the use of alterna-
tive specimens for workplace drug testing suggesting that oral fluid,
hair and sweat appear to sufficiently meet the requirements to be
added. No other paper were found in the recent literature. On 13th
April 2004 the U.S. Department of Health and human services
(www.samhsa.gov) published a notice in the Federal Register pro-
posing to establish also scientific and technical guidelines for the
testing o f alternative matrices (like sweat) in addition to urine
specimens [6].
14 Current Medicinal Chemistry, 2013, Vol. 20, No. 1 De Giovanni and Fucci
c. Other Forensic Applications
Forensic toxicology can be involved in several situations to
document impairment, such as: crime under influence, date rape,
psychiatric disorders, determination of the cause of death. In some
particular situations, it can be very cautious to investigate exposure
to psycho-active drugs, due to late sampling of biological speci-
mens.
In the context of the “crime under the influence” many biologi-
cal specimens h ave been tested to verify the u se of drugs after sex-
ual assaults such as drugs spiked in food. Only a paper was found
[63] exploiting the use of sweat to detect drugs administered during
sexual assault.
The use of sweat in doping context was referred [59] to detect
anabolic steroids, diuretics and corticosteroids. Two papers regard-
ing the possible application of sweat in sport doping were published
[110, 111] that discussed sampling, analytical procedures and inter-
pretation of the results.
Being the skin constantly exposed to sweat and sebum, drugs
may be sequestered in this tissue. Moreover there is evidence that
after chronic exposure lipophilic drugs may be stored in adipose
tissue creating a drug depot. Hence in this section we consider some
paper describing the analysis of drugs in these matrices. Yang W. et
al. [68] described the analysis of 55 skin biopsies collected from 15
volunteers after controlled administration of methamphetamine,
cocaine and codeine. Levisky J.A. [25] considered the adipose tis-
sue and skin in illicit drug related deaths for qualitative and quanti-
tative analyses removing the tissues from the abdominal region
during the autopsy.
Particular applications detected methamphetamine in garments
belonging to known-abusers [78] extracting the drugs from the
textile using a mixture of organic solvents and morphine in the
sweat deposited within fingermarks of a narcotic drug user [55].
8. DRUG USE DURING PREGNANCY
The maternal abuse is often underestimated due to the stigma of
drug use during pregnancy and the accompanying legal, ethical and
economic issues. In utero drug exposure can have a severe impact
not only on the development of the fetus, but also on the child dur-
ing later stages of life. Accurate identification of in utero drug ex-
posure has important implications for the care of the mother and
child, but can raise difficult legal issues. Detection of in utero drug
exposure has traditionally been accomplished through urine testing;
however, the window of detection is short, reflecting drug use for
only a few days before delivery, hence other biological matrices
such as sweat can be used [112]. Maternal drug use during preg-
nancy can be monitored with alternative matrices such as sw eat
testing that offers a longer window of detection of about one week
and decreases the likelihood of missing recent use.
Some reviews regarding various biological matrices [113] and
bioanalytical methods [114] useful for the detection of exposure
from different gestational periods in pregnancy to drugs of abuse
were found in literature. Drug detection in maternal blood, oral
fluid, and sweat accounts only for acute consumption that occurred
in the hours previous to collection and gives poor information con-
cerning fetal exposure [113].
Some characteristics of sweat such as the easy and noninvasive
collection, the detection window of a few days before a patch appli-
cation and the difficult to quantify the amount of sweat secreted
allow this matrix to be considered for qualitative purposes [114].
Sweat specimens from pregnant opioid – dependent women (treated
with methadone) were examined to detect methadone, cocaine and
heroin metabolites [27, 74]. Correlation between patch concentra-
tions and total amount of methadone administered and concentra-
tions and duration of patch wear were both weak. Although there
were large intra- and inter-subject variations in sweat drug concen-
trations, sweat testing was an effective alternative technique to
qualitatively monitor illicit drug use and simultaneously document
methadone medication-assisted treatment [27]. An opioid-depen
dent buprenorphine-maintained pregnant woman [75] was submit-
ted to weekly sweat patches application detecting buprenorphine,
cocaine, opiates, methadone and tobacco biomarkers with good
selectivity and sensitivity. 75.0% of sweat patch es were positive for
buprenorphine, 93.8% for cocaine, 37.5% for opiates, 6.3% for
methadone and all for tobacco biomarkers. The pharmacokinetics of
buprenorphine was studied [101] after high-dose sublingual tablet
administration in three opioid-dependent pregnant women detecting
buprenorphine and its metabolite in only four of 25 specimens in
low concentrations (less than 2.4 ng/patch).
9. INTERPRETATION OF THE ANALYTICAL RESULTS
Duration of patch wear, variability in sweat production, and
stability of drugs on the patch are some of the complex factors in-
volved in interpretation of drug concentrations in this specimen. A
major limitation of sweat patch testing [79] is that the production of
liquid perspiration varies with ambient temperature and physical
activity. Therefore the volume of perspiration collected by the patch
worn during the week, is unknown. This precludes meaningful
quantitative analysis of drugs detected on the patch and limits the
interpretative value of a sweat patch drug test result. Moreover
being the volume of sweat limited, preserving part of the specimen
for an independent retest is difficult.
Despite of this consideration, SAMHSA issued mandatory
guidelines [6] for the federal workplace drug testing programs for
sweat testing. After chronic exposure lipophilic drugs may be
stored in adipose tissue hence they do accumulate in fat falsely
suggesting new episodes of drug intake. Interpretation of drug dis-
tribution and elimination in sebum and stratum corneum is compli-
cated by possible contamination of specimens with drugs from
sweat [2, 36], particularly because parent drug is often detected as
the major analy te in the sw eat patch.
Cone EJ. et al. [2] refer that during the course of the cocaine
experiments, sweat patches were challenged in passive drug con-
tamination studies (transdermal and cocaine vapor). The exterior
environment during exposure was ruled out as an alternate explana-
tion because the same subject showed negative results in other ex-
periments. The authors concluded that environmental contamination
of the sweat patch had most likely occurred during the removal and
the storage process resulting in positive tests for cocaine. Obviously
careful procedures must be employed in removal and handling of
the sweat patches to prevent the production of false positive drug
test results.
False positive interpretations may arise from prior presence of
drugs on the exterior of the skin which are not removed by the
cleaning process. Skin contamination experiments is distinct from
drugs permeating the skin, entering the blood stream and being re-
excreted by the sweat into the patch [13]. The presence of contami-
nants in the environment and hence the importance of the correct
forensic interpretation was recently underlined by Daughton C.G. in
2011 [115]. Many drugs, especially illicit drugs, are readily ex-
creted via sweat glands, including those on the fingers. This has the
potential to result in contamination of samples during their collec-
tion or during various steps in analysis. Contamination of samples
by analysts who are using prescribed or illicit drugs is an under-
investigated potential source of erroneous data.
The presence of metabolites in sweat is thought to distinguish
passive exposure from active use. The finding in skin wipes of
unique metabolites of drugs that are not present in the environment
would indicate use rather than exposure. The presence of heroin, 6-
acetylmorphine, acetylcodeine allows unequivocal differentiation
Sweat Testing for Dr ugs of Abuse Current Medicinal Chemistry, 2013, Vol. 20, No. 1 15
between licit opiate u se and heroin abuse [27]. The presence of
cocaethylene or ecgonine methylester is thought to indicate the use
of cocaine rather than exposure to it [16]. This unique metabolites
are present in minor amounts requiring very sensitive techniques for
detecting use versus exposure. Kidwell DA. et al. [16] stated that
the benzoylecgonine/cocaine ratio varies widely. They also ob-
served that some subjects showed a very high ratio, they speculated
the presence of active enzymes on th eir skin or different excretory
pathways for cocaine and its metabolites. However they performed
experiments that showed cocaine stable in contact with the skin.
This implies that the enzymes are not sufficiently active for sub-
stantial cocaine hydrolysis [16].
Kidwell DA. et al. [38] found positive results for an unknown
period after cocaine cessation. In a legal setting the issue of when
drug use occurs is crucial. For example, judges require drug absti-
nence as a standard condition of probationary release. Prior drug
use may be irrelevant to meeting this condition. If the sweat patch is
used as a stand-alone test for determining drug use status during the
period that the sweat patch is worn, then it is essential that the patch
does not falsely report previous drug use as “current drug use”. For
chronic users it is not clear whether a cocaine appearing in the
patches came from current drug ingestion, previous drug ingestion,
previous drug contamination, current drug contamination, or a
combination of the above.
CONCLUSIONS
Forensic scientists have long detected the presence of drugs in
biological materials using body fluids such as urine, blood, and/or
tissues. In recent years, remarkable advances in sensitive analytical
techniques have prompted the analysis of drugs in unconventional
biological samples more easily collectable.
Patch technology allows the monitoring of illicit drug use for
time windows wider than those provided by urine testing. Because
the patches can be worn for up to one week, drugs tend to accumu-
late in the collection device, and no drug degradation appears to
occur during this time interval. A series of clinical studies were
designed to determine the identity, concentration, time course, dose
dependency, and variability of drug and metabolite excretion in
sweat following administration of single dose of illicit drugs to
human subjects.
Although there are large intra- and inter-subject variations in
sweat drug concentrations, sweat testing was found to be an effec-
tive alternative technique to qualitatively monitor illicit drug use
and simultaneously document medication-assisted treatment.
Advantages of sweat analysis using sweat patches include: con-
tinuous drug testing can be undertaken over a longer period (up to
7-14 days) than urine or saliva, the process of specimens collection
is less invasive than urine collection, the patches appear to be rela-
tively tamper resistant and tamper evident, and the patch can be
applied and removed quickly and little training is required for the
sanitary. Moreover sweat patches are readily accepted by subjects
limiting the number of required monitoring visits.
Disadvantages of sweat analysis using sweat patches limited
routine use of this biological matrix. Concentrations of drugs in the
patch are much lower than urine, making repeated testing (confir-
mation retesting) a potential problem. Possibility of environmental
contamination of patch before application or after removal must be
taken into account. Moreover there is the risk of accidental or de-
liberate removal of patch during monitoring period. The effects of
vigorous or prolonged exercise on the transfer of drugs into sweat
and / or the deposition of these drugs onto the patch are unknown
and there is evidence that outward transdermal migration of some
accumulated drugs may lead to an incorrect interpretation of new
drug use. Finally the possibility of time-dependent drug loss from
the patch by drug degradation on skin is also possible together with
re-absorption into the skin and consequent volatile losses through
the covering membrane of the patch.
Sweat patches provide a convenient alternative that avoids
some of the problems with drug testing such as violations of pri-
vacy in observed urination, possibility of disease transmission, and
transport of noxious fluids. This technology benefits from low inva-
siveness and pose fewer ethical problems for sample collection than
does blood or urine testing. Nevertheless it would be premature to
replace urine toxicology testing with sweat patch in both research
and clinical settings. Continuing improvements in sweat collection
and testing methods may result in the availability of a substantially
improved sweat device in the near future.
CONFLICT OF INTEREST
The author(s) confirm that this article content has no conflicts
of interest.
ACKNOWLEDGEMENTS
Declared none.
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Supplementary resource (1)

... Sweat is an aqueous solution that contains a great variety of compounds, such as NaCl, lactate [1], nitrogenous compounds (ammonia, urea and amino acids [2,3]), metal ions (e.g., zinc and iron [4,5]), heavy metals (e.g., arsenic, cadmium, lead and mercury [6]), immune biomarkers (e.g., IgG, IgD and interleukin-1α [7]), cortisol and stress biomarkers [8], lactoferrin [9] and xenobiotics (e.g., drugs of abuse [10] and ethanol [11,12]). The main function of sweat is thermoregulation, leading to heat dissipation by water evaporation [1] in response to an increase in body core temperature. ...
... Different images of the alginate beads were taken during the experiments at 1, 2, 3, 4, 5, 6,7,8,9,10,13,16,19,25,30,35 and 50 min, using a 20 MP (megapixel) + 2 MP dual camera with an f/1.8 aperture (Huawei, Shenzhen, China) placed 25 cm over the sample. The same light conditions and camera settings were kept during all experiments using a photography chamber (MVpower Kit Photography Illumination Studio, Cube 80 × 80 × 80 cm 3 , 3× softbox 50 × 70 cm 2 , 3× light sources 135 W and 4× background colours, black, white, blue and red, Kissta). ...
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Lactate is present in sweat at high concentrations, being a metabolite of high interest in sport science and medicine. Therefore, the potential to determine lactate concentrations in physiological fluids, at the point of need with minimal invasiveness, is very valuable. In this work, the synthesis and performance of an alginate bead biosystem was investigated. Artificial sweat with different lactate concentrations was used as a proof of concept. The lactate detection was based on a colorimetric assay and an image analysis method using lactate oxidase, horseradish peroxidase and tetramethyl benzidine as the reaction mix. Lactate in artificial sweat was detected with a R² = 0.9907 in a linear range from 10 mM to 100 mM, with a limit of detection of 6.4 mM and a limit of quantification of 21.2 mM. Real sweat samples were used as a proof of concept to test the performance of the biosystem, obtaining a lactate concentration of 48 ± 3 mM. This novel sensing configuration, using alginate beads, gives a fast and reliable method for lactate sensing, which could be integrated into more complex analytical systems.
... Studies have adopted varying methods to collect sweat for composition analyses [14][15][16], including the direct collection of sweat from the skin using glass jars or tubes and sweat collection using made-to-measure apparatuses (e.g., sweat pouches, glass pipettes, and arm bags) and commercial products. However, pH alteration, skin irritation, barrier property disturbance, and variations in the body region for sweating and the aim of examination have resulted in difficulty in designing a universal apparatus to fit all test conditions [17]. ...
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... Their advantage is non-invasiveness, painless collection compared to blood collection, but due to the smaller number of published data, especially in terms of assessing the effects of physiological and psychological status, they still remain only alternative matrices in practice [42,45]. In the case of sweat and hair, the preference lies in the possibility of detecting certain drugs and medicines even after a longer period of time, in contrast to blood [46,47]. On the other hand, there are limitations, including intra and intervariability among individuals, as well as a lack of data about the possible contamination [48]. ...
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Ahyahuasca is a term commonly used to describe a decoction prepared by cooking the bark or crushed stems of the liana Banisteriopsis caapi (contains β-carbolines) alone or in combination with other plants, most commonly leaves of the shrub Psychotria viridis (contains N,N-dimethyltryptamine-DMT). More than 100 different plants can serve as sources of β-carbolines and DMT, which are the active alkaloids of this decoction, and therefore it is important to know the most accurate composition of the decoction, especially when studying the pharmacology of this plant. The aim was to summarize the latest sensitive methods used in the analysis of the composition of the beverage itself and the analysis of various biological matrices. We compared pharmacokinetic parameters in all of the studies where decoction of ayahuasca was administered and where its composition was known, whereby minimal adverse effects were observed. The therapeutic benefit of this plant is still unclear in the scientific literature, and side effects occur probably on the basis of pre-existing psychiatric disorder. We also described toxicological risks and clinical benefits of ayahuasca intake, which meant that the concentrations of active alkaloids in the decoction or in the organism, often not determined in publications, were required for sufficient evaluation of its effect on the organism. We did not find any post-mortem study, in which the toxicological examination of biological materials together with the autopsy findings would suggest potential lethality of this plant.
... At present, the dried blood sample method is promising because of its economical and athlete-friendly characteristics (Lange et al., 2020;Thevis et al., 2020). Other potential matrices include hair (Kintz, 2003;Shah et al., 2014), saliva (Thieme, 2012), sweat (De Giovanni et al., 2013) and exhaled breath (Garzinsky et al., 2021;Miller et al., 2019). Next-generation "omics" from blood samples have long been proposed as robust markers of hormonal doping that are less prone to biological and technical bias (e.g., Narduzzi et al., 2019;Pitsiladis et al., 2016;Reichel, 2011). ...
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