Review: pharmacokinetics of illicit drugs in oral fluid

Review: Pharmacokinetics of illicit drugs in oral fluid

Olaf H. Drummer *

Victorian Institute of Forensic Medicine and Department of Forensic Medicine, Monash University,

57-83 Kavanagh Street, Southbank, Melbourne 3006, Australia

Received 4 November 2004; received in revised form 22 November 2004; accepted 22 November 2004

Available online 18 April 2005

www.elsevier.com/locate/forsciint

Forensic Science International 150 (2005) 133–142

Abstract

This article reviews studies that have measured drug concentrations in oral fluid following controlled dosing regimens. A

total of 23 studies have been identified over the last 15 years. These show that the amphetamines including designer

amphetamines, cocaine, cannabis and cocaine are quickly found in oral fluid following dosing and usually have similar

time-courses to that in plasma. Following common doses peak oral fluid concentrations exceed 0.1 mg/mL and often even 1 mg/

mL. The drug concentration will depend on whether a dilution step occurs with buffer as part of the sampling procedure. The

uses of collectors that stimulate oral fluid usually reduce the drug concentration compared to a non-stimulated manner. This

reduction will not disadvantage the recipient since it will potentially reduce the detectablity of drug in oral fluid compared to

non-stimulated collections. Only one recent study has been reported for a benzodiazepine. This showed nanogram per milliliter

concentrations for flunitrazepam. More studies are required for benzodiazepines and indeed for other drugs, particularly in

multiple drug situations and where disease may affect the pharmacokinetics of drugs.

# 2005 Elsevier Ireland Ltd. All rights reserved.

Keywords: Pharmacokinetics; Oral fluid; Drugs of abuse; Review

1. Introduction

The use of oral fluid (OF) to detect the presence of illicit

drugs has become increasingly popular as a non-invasive

specimen to detect drug-use [1].

A number of devices are now available to screen OF for

the presence of recreational drugs. The drugs of most interest

are amphetamines, ecstasy (MDMA), cocaine, opiates (mor-

phine, codeine), benzodiazepines and cannabis [1,2].

For the most part studies have shown that OF contains

predominately the parent drug. For example, cocaine is the

major species present in OF following the use of cocaine

[3–5], heroin and 6-acetylmorphine are dominant species

following use of heroin [6], while tetrahydrocannabinol

(THC) is the predominant species following smoking of

cannabis products [7,8].

* Tel.: +61 3 9684 4334; fax: +61 3 9682 7353.

E-mail address: [email protected].

0379-0738/$ – see front matter # 2005 Elsevier Ireland Ltd. All rights r

doi:10.1016/j.forsciint.2004.11.022

Schramm et al. [9] has provided an early review on

detection times and early studies pre 1990s. Other reviews

on the testing for drugs of abuse in OF also exist [10,11].

Pharmacokinetic studies provide an ability to determine

the concentration of target drugs following known doses, and

therefore provide an ability to assess the required sensitivity

of oral fluid drug-detecting devices. A number of these have

been conducted over the last 15 years.

This paper reviews published works that have measured

the concentration of recreational drugs in oral fluid follow-

ing a known dose of drug in volunteers.

2. Methods

Published peer-reviewed studies from 1990 were identi-

fied through references listed in known published studies.

Other studies were identified by using the public MedLine

database PubMed using the search string ‘‘pharmacokinetics

eserved.

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Summary of studies describing oral fluid concentrations

Reference Study detail Estimated dose Collection process and volume THC oral fluid data Comments

Cone [24] Two male subjects given single

IM doses of morphine or codeine

Morphine 10 and 20 mg or

codeine 60 and 120 mg

Stimulated with sour

candy (citric acid)

Morphine Cmax in OF 11

and 38 ng/mL at 0.5 h,

at 24 h near 0.6 ng/mL

for 10 and 20 mg doses.

Codeine Cmax in OF

184 and 308 ng/mL

at 0.5–0.75 h, at 24 h

levels 1–4 ng/mL for 60

and 120 mg doses

Analysis by GC–MS,

LOD 0.6 ng/mL

Menkes et

al. [8]

Thirteen male healthy volunteer

(age 22–36 years) cannabis users

(2–12 times per month) after

1 week abstinence

11 mg THC cigarette OF stimulated with

Wrigley’s chewing gum

Pre-dose THC in OF

0.4 ng/mL, OF concentrations

above 10 ng/mL for

first 6 h and showed

good correlation with

subjective intoxication

Analysis by GC–MS,

LOD 0.2 ng/mL

Cook et

al. [17]

Six male volunteers, age 19–32

years (weight 73.5 � 2.9 kg)

given oral (+)-methamphetamine

over 13 days

0.125 (9 mg) or 0.250

mg/kg (18 mg)

Mixed saliva OF concentrations 7.8 � 1.2

times plasma concentration,

correlation to plasma

concentration r2 0.50

(P < 0.0001). OF concentrations

ranged up to about

700 ng/mL, median about

250 ng/mL

GC–MS analysis,

LOD 1 ng/mL

Cook et

al. [18]

Six healthy males, age

26.7 � 1.7 years, received

(+)-methamphetamine

by smoking and iv

(a) 30 mg smoked

(22 mg inhaled)

and (b) 15 mg iv

Presumed spitting Bioavailability after smoking

90%, half-life 11 h, OF

concentrations several-fold

higher than plasma and

ranged from about 100 to

over 1000 up to 10 h

post-doses. No amphetamine

detected in OF

GC–NPD detection

Kato et al. [4] Six subjects given iv

doses cocaine

25 mg Spitting (unstimulated)

and stimulated using

citric acid

Cocaine readily detected

in OF within minutes.

Unstimulated concentrations

about five-fold higher

than stimulated OF. BE

and EME also detected

but in lower levels

Analysis by GC–MS

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Cone et al. [5] Male volunteers with a history

of cocaine abuse, given cocaine

by iv, intranasal, smoking

25 mg iv, 42 mg smoking Spitting with citric acid

stimulation

Readily detectable

concentrations on OF,

BE and EME also present

after all routes. S/P ratio

cocaine 3

Analysis by GC–MS,

citric acid stabilizes

cocaine loss with

NaF. LOD 1 ng/mL

Wang et al. [23] One subject received

intranasal heroin

12 mg heroin HCl Presumed spitting Heroin detected in OF

at 5 min, peak at 10 min

(308 ng/mL) and detectable

to about 1 h. 6-AM detected

at 5 min, peak concentration

at 10 min (59 ng/mL) and

detectable to about 6 h,

morphine detectable from

5 min to 4 h (peak

25 ng/mL at 1 h)

GC–MS, LOD

about 1 ng/mL

Jenkins et al. [6] Two subjects each received

smoked or iv doses of heroin

or cocaine in separate studies

Cocaine 44.8 mg iv or

40 mg smoked, heroin

5–20 mg iv or 2.6–12 mg

base smoked

Spitting with citric acid

stimulation 4 mL

Cmax heroin >3000 ng/mL

at 2–5 min after smoking,

and after iv Cmax was

6–20 ng/mL (3–12 mg

doses). Not detectable

after 5–30 min with lower

doses, but detectable to

24 h after 12 mg dose.

6-AM and morphine also

detected. Peak morphine

<16 ng/mL after iv. S/P

ratio for morphine about

1. Cmax cocaine 428–1927

at 5–30 min after iv doses.

BE also detected at lower

concentrations after iv

and smoked doses.

AEME detected after

smoking. Detection time

in OF about 8 h

Analysis by GC–

MS, LOD 1 ng/mL

for all analytes

Kintz [21] Single dose of MBDB to

one volunteer

100 mg MBDB No details provided Cmax 1083 ng/mL at 2 h.

MDBD detected to 17 h

with LOD 2 ng/mL. BDB

also detected, Cmax

146 ng/mL at 2 h

Analysis by GC–

MS, LOD 2 ng/mL

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Table 1 (Continued )

Reference Study detail Estimated dose Collection process and volume THC oral fluid data Comments

Moolchan et

al. [22]

Self-reported recent users of

cocaine studied

0.1–2 g daily, median

1.0 g

Spitting with citric acid

stimulation

Admission OF cocaine

31 � 50 (range 5–171),

BE 54 � 45 (4–144),

EME 69 � 112 (5–337).

T1/2 7.9 h longer than

plasma at 3.8 h

Analysis by GC–MS

after SPE, LOD 1

ng/mL

O’Neal et al. [26] Five volunteers given codeine

and OF collected at various

times with different collectors

Single 30 mg liquid

codeine phosphate

Spitting, sugarless gum,

lemon drop

stimulation, Salivette,

Finger Collector and

Orasure device

Cmax of OF after spitting

was 3542 � 1625 ng/mL

at 0.25 h. At 6 h level was

38 � 11 ng/mL. Stimulated

collection gave lower OF

concentrations: �3.6

(acidic), �2.0 (non-acidic),

�1.3 (Salivette), X � 0.3

(finger collector)

Analysis by GC–MS,

LOD 1 ng/mL

Navarro et

al. [20]

Twelve prior users screened

as extensive metabolizers

given oral MDMA

100 mg MDMA Spitting Cmax OF 3375 � 1812 ng/mL at

1.5 h and detectable to

about 24 h, S/P ratio

variable, average about

7 in post-absorption phase

Analysis

by GC–MS, LOQ

50 ng/mL

Skopp et al. [30] Six Subjects on dihydrocodeine,

single dose 20 subjects with

repeat dosing

60 mg single or once

daily repeat dosing

Salivette At 2 h OF level mean

784 � 346 ng/mL, at 12 h

mean OF level was 176 � 268.

Saliva/plasma ratio 1.2–17.

Mean OF levels in chronic use

were 10.8 � 14.9 mg/mL

(range 0.1–66 mg/mL)

Analysis by HPLC,

LOD 5, LOQ

20 ng/mL

Niedbala et

al. [12]

Eighteen prior users of cannabis,

age 19–25 years smoked for

20–30 min, two control subjects

were tested for passive intake,

three subjects consumed one

brownie

2–25 mg per cigarette

(dose), 20–25 mg

per brownie

Intercept cotton fiber

with 0.8 mL diluent—

0.4 mL average

Cmax THC �70 ng/mL

THC in OF above 1 ng/mL

for at least 16 h, at 1 h

THC was �25 ng/mL.

Two control subjects

had no GC–MS positive

THC in OF. Oral marijuana

gave Cmax THC 4 ng/mL

at 1–2 h

Cannabinoids screened

by microplate EIA

with a 1.0-ng/mL

cut-off and confirmed

for THC by GCMS–MS

with a 0.5-ng/mL cut-off

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Kim et al. [27] Twelve males and seven female

healthy volunteers

(age 23–43 years) given codeine

sulfate orally

60 and 120 mg, three

doses each

Spitting with citric acid

stimulation

Cmax 639 � 64 ng/mL

(range 184–1288) and

1599 � 241 ng/mL

(range 620–3350) after

60 and 120 mg at 0.5–4 h.

S/P ratio 4. Detection

times were 7 and 21 h

after either dose using

cut-offs of 40 and 2.5

ng/mL. Some norcodeine

also detected.

Analysis by GC–MS

after SPE

Samyn et al. [19] Study 1: 12 healthy volunteers,

age 21–30 years given oral

MDMA. Study 2: users declare

amount of MDMA use before a

test drive

Study 1: 75 mg, Study 2:

25–95 mg initially and

from 0 to 4.5 additional

tablets

Spitting Study 1: Cmax 1215 � 944

ng/mL at 2 h. S/P ratios

ranged from 0.8 to 24. Study 2:

OF concentrations of MDMA

ranged from 55 to 3533 ng/mL

and up to 7077 ng/mL after

additional self-use

In study 1 showed

similar time-course

to plasma. Analysis

by LC–MS

Samyn et al. [31] Four subjects (age 30–40) tested with

single oral dose of flunitrazepam

1 mg Spitting Cmax FLU 0.57 and 2.4 ng/mL

at 2 and 4.5 h in two subjects,

corresponding 7-AF 0.58 and

0.94 ng/mL at 2 and 4.5 h.

FLU detectable to at least 6 h.

Drug unstable, required 2%

NaF for stability

Analysis by negative

ion CI–GC–MS,

LOD FLU 0.05 ng/mL,

7-AF 0.1 ng/mL

Rohrig and

Moore [25]

Consumption of (a) three bagels

and (b) one bagel and ab lib

poppy seeds for 1 h

Unknown Epitope—1 mL (a) No morphine or codeine

detected at 1 h, LOD 3 ng per

device, (b) peak morphine at

15 min (130–205 ng/mL)

and was above 40 ng/mL

to about 1 h

Schepers et

al. [16]

Eight volunteers (four males age

26–40 years) received

(+)-methamphetamine sustained

release tablets

(a) 10 mg and (b) 20 mg Salivette cotton swab

with and without citric

acid

(a) Cmax MA 106 � 101

ng/mL (range 25–313) at 5 h,

Cmax AM 9 � 3 ng/mL, (b)

Cmax MA 192 � 121 ng/mL

(range 75–322) at 4.7 h,

Cmax AM 14 � 6 ng/mL.

Mean OF level was two

times plasma concentration,

95% range 2.3–4.3, neutral

collection gave 1.9 times

level than with citric acid

Analysis by SPE and

GC–MS, LOD

2.5 ng/mL

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Table 1 (Continued )

Reference Study detail Estimated dose Collection process and volume THC oral fluid data Comments

Barnes et al. [28] Nineteen volunteers given codeine

low or high dose

Codeine sulfate 60 or 120 mg Spitting with citric acid

stimulation,

Salivette with and without

stimulation

Codeine main species present

with some norcodeine. OF

concentrations ranged from

2.5 to 3961 ng/mL, norcodeine

2.6–191 ng/mL

Analysis by GC–MS,

LOQ 2.5 ng/mL

Huestis and

Cone [15]

Six healthy male volunteers with

previous history of

use smoked marijuana, two strengths or

placebo with random crossover design

1.75% (15.8 mg) and 3.55%

(33.8 mg) THC cigarettes

Spitting with citric acid

stimulation—5–10 mL

Cmax THC in OF 864 & 4167

ng/mL at 0.2 h following

1.55 and 3.55% cigarette (RIA).

Rapidly declined to well under

50 ng/mL within 1 h. Detection

times in OF 4–6 and 2–24 h

following two strengths using

1 ng/mL cut-off. Mean OF/P

ratio 1.2. Similar pharmacokinetics

profile to plasma obtained

Analyses by RIA

and by GC–MS

Kakinko et

al. [29]

Nineteen volunteers given

three initial oral doses of

codeine over a 7-day period,

and after 3-week break received

three high doses within 7 days

60 mg initially and

120 mg (high)

Salivette with and without

citric acid stimulation up

to 72 h post-dose

Study suggests 30 ng/mL

screening cut-off for RapiScan

and ELISA with a 15 ng/mL

confirmatory cut-off. Morphine

not detected in any OF

Analysis by Cozart

RapiScan, ELISA

(screen) and GC–MS

confirmation, LOD

2.5 ng/mL

Niedbala et

al. [14]

Five cannabis smokers,

age 21–25 years smoked in

sealed 36 m2 unventilated room and

four non-smoking volunteers,

age 37–49 years inhaled smoke

1.75% THC content

cigarette over 20 min

OF collected by Intercept All four passive smokers had

detectable THC in

OF—concentrations 7, 8,

12 and 26 ng/mL at 20 min.

Detectable transiently

(20–65 min) from start of

smoking. Smokers had peak

OF concentrations of

150–390 ng/mL at 20–35 min

from start of smoking

GC–MS–MS, LOD

0.75 ng/mL in buffer

(three-fold dilution)

6-AM, 6-acetylmorphine; 7-AF, 7-amino flunitrazepam; AEME, anhydroecgonine methyl ester; AM, amphetamine; BE, benzoylecgonine; CI, chemical ionization; cTHC, 11-carboxy-THC; Cmax,

maximum concentration; EIA, enzyme immunoassay; EME, ecgonine methyl ester; FLU, flunitrazepam; GC–MS, gas chromatography–mass spectrometry; GC–MS–MS, gas chromatography

with tandem mass spectrometry; iv, intravenous; LOD, limit of detection; LOQ, limit of quantification; MA, methamphetamine; MDMA, 3,4-methylenedioxymethampetamine; MDB, 3,4-

methylenedioxy-2-butanamine; MDBD, N-methyl-1-(3,4-methylenedioxy)-2-butanamine; OF, oral fluid; SEM, standard error of mean; S/P ratio refers to saliva over plasma concentration ratio;

RIA, radioimmunoassay, SPE, solid phase extraction, THC, D9-tetrahydrocannabinol; T1/2, elimination half-life; Tmax, time to maximum concentration.

O.H. Drummer / Forensic Science International 150 (2005) 133–142 139

and drugs’’ in ‘‘oral fluid’’ or ‘‘saliva’’ for each of the

relevant drug types and through Science Direct (Elsevier).

For abbreviation for terms, see table legend of Table 1.

3. Results

A total of 23 peer-reviewed articles were found that

described the controlled administration of recreational drugs

to humans and measured, amongst other things, the con-

centration of drug in oral fluid. These are summarized in

Table 1. Table 2 describes the peak concentrations of drugs

in oral fluid following controlled doses.

3.1. Cannabis

There were four studies involving the use of cannabis.

These usually involved the administration of standard

research doses of THC (range 9–25 mg). Depending on

the cut-off or detection limit applied, the volume of oral

fluid collected and the dose of THC, the detection times

ranged up to about 30 h (LOD 0.5 ng/mL) [12]. The detec-

tion time was much longer than in other experiments, but the

subjects were not supervised and from the individual data

additional use during the observation period may have been

possible?

Following 2–25 mg of smoked cannabis, the Cmax in OF

was about 70 ng/mL and remained above 1 ng/mL for at

least 16 h. Subjects who had consumed 20–25 mg THC in

the form of brownies had much lower peak OF concentra-

tions of about 4 ng/mL at 1–2 h [13]. Smoking 1.75%

cigarettes over 20 min produced a peak THC in OF between

150 and 390 ng/mL shortly after cessation of smoking [14].

Table 2

Summary of reported peak oral fluid concentrations of drugs of abuse

Drugs Dose (mg)

Methamphetamine 9–18 (SM IV)

10 and 20 (PO ss)

MDMA 100 (PO)

75 (PO)

Codeine 30 (PO)

60 and 120 (PO)

60 and 120 (PO)

Dihydrocodeine 60

THC 2–25 (SM), 20–25 (PO)

16 and 34 (SM)

16 (SM)

Flunitrazepam 1

Cocaine �40 (IV, SM)

Heroin 12 (IN)

2.6–20 (IV, SM)

IN, intra-nasal; IV, intravenous; PO, oral; SM, smoking; ss, sustained rel

In both these studies, OF was collected with the Intercept1

device in which OF is diluted three-fold with buffer.

Oral fluid obtained by expectoration (spitting) gave

higher OF concentrations. The Cmax following 1.75%

(15.8 mg) and 3.55% (33.8 mg) cigarettes was 864 and

4167 ng/mL, respectively, at 0.2 h, but rapidly declined to

under 50 ng/mL within 1 h. There was a good relationship

between OF and plasma concentrations of THC. The average

ratio was 1.2 [15]. There was also a good relationship

between log [THC] and intoxication and heart rate in healthy

volunteers given 11 mg THC containing cigarette [8]. In this

study, OF concentrations were at or above 100 ng/mL for the

first 1 h and by 4 h were still about 10 ng/mL.

Volunteers exposed passively to cannabis smoke in an

unventilated room (area 36 m2) from five smokers over

20 min gave detectable THC concentrations in OF ranging

from 7 to 26 ng/mL (mean 13 ng/mL). The concentrations

were only detectable in OF for about 30 min [14].

3.2. Methamphetamine and other amphetamines

The three studies involving methamphetamine collected

OF by either spitting into a cup or with use of a Salivette1

cotton bud collector. The use of citric acid to stimulate

production of OF almost halved the concentration of

methamphetamine [16]. The concentrations of methamphe-

tamine in OF was on average several-fold higher than plasma

in two studies [17,18], but only double in another [16], and

correlated strongly with the corresponding plasma concen-

tration [17]. Methamphetamine concentrations in OF peak

shortly after cessation of smoking and can reach about

700 ng/mL following standard oral doses of 10–20 mg.

Using Salivette1 Cmax was 106 and 313 ng/mL at 5 h

Peak concentration (mg/mL) References

Highest �1, median �0.25 [17,18]

0.1 and 0.2 [16]

3.4 [20]

1.2 [19]

3.5 [40]

0.6 and 1.6 [27]

�4 [28]

Acute 0.8, chronic 6.8 [30]

0.07 (SM), 0.004 (PO) [12]

0.9 and 4.2 [15]

0.15–0.39 [14]

0.006 [31]

0.4–1.9 [6]

0.3 [23]

>3 [6]

ease.

O.H. Drummer / Forensic Science International 150 (2005) 133–142140

following 10 and 20 mg doses of sustained release metham-

phetamine, respectively [16]. The half-life in OF was about

11 h on average [18].

Amphetamine was not always detected in OF following

administration of methamphetamine [16,18]. When present,

concentrations were about one-tenth that of methampheta-

mine [16].

There were three studies involving the administration of

designer amphetamines. Two MDMA studies showed OF

(direct expectoration) to plasma concentration ratios of

0.8–24 [19] with an average of about 7 in the post-absorption

phase [20]. Following 75 and 100 mg oral doses, Cmax was

about 1.2 and 3 mg/mL at 1–2 h [19,20]. Drug was detectable

to about 24 h using a cut-off of 50 ng/mL. When subjects were

allowed to freely use MDMA at a declared rate (25–95 mg)

OF concentrations ranged from 55 to over 3500 ng/mL, and

with additional recreational use to over 7 mg/mL. The time-

course to plasma concentration was very similar [19].

A single dose of MDBD to one volunteer gave a Cmax of

1 mg/mL at 2 h and was detectable to 17 h with a LOD of 2 ng/

mL. BDB was also detected in small concentrations [21].

3.3. Cocaine

Four studies investigated the formation and disappearance

of cocaine and metabolites in oral fluid. Cocaine was readily

detectable in OF, but concentrations were about five-fold

higher in unstimulated versus citric acid stimulated collection

[4]. Citric acid does stabilize cocaine from loss [5]. Both BE

and EME were detectable in OF after smoking or intravenous

administration [5]. The OF to plasma ratio is about 3 [5].

Self-reported users of cocaine (0.1–2 g daily) had OF

concentrations of cocaine, BE and EME of 31, 54 and 69 ng/

mL, respectively, at an average time of 17 h since last dose

and a longer terminal elimination half-life (7.9 h) than in

plasma [22]. Forty milligrams smoked cocaine gave Cmax

0.4–1.9 mg/mL within minutes of smoking. Detection time

in OF (citric acid stimulation) using a LOD 1 ng/mL was

about 8 h [6].

3.4. Opiates

Limited studies are available for heroin. Heroin is

detected within minutes in OF following nasal insufflation

(snorting). In an early experiment on one volunteer, a 12 mg

dose gave a peak heroin concentration of 0.3 mg/mL and was

detectable for about 1 h at a 1 ng/mL LOD. 6-AM and

morphine were rapidly found in OF peaking at about 60

and 25 ng/mL at 10 and 60 min, respectively [23]. Two

subjects given 2.6–10.5 mg smoked gave Cmax of heroin

greater than 3 mg/mL, but was less than 10 ng/mL beyond

60–120 min. Intravenous heroin gave lower Cmax up to

30 ng/mL after 3–12 mg doses. Mean OF:plasma ratio

was about 1 [6].

Intramuscular (IM) morphine sulfate at doses of 10 and

20 mg gave a Cmax of 11 and 38 ng/mL in two subjects,

respectively, using a stimulated collection process [24]. At

24 h concentrations were barely detectable.

Consumption of poppy seeds from bagels either gave no

detectable morphine or it was up to about 0.2 mg/mL for a

short time (�1 h). Morphine concentrations were about

40 ng/mL at 1 h. [25].

Codeine presence in OF has been studied in five studies.

The administration of 30 mg liquid codeine phosphate to five

volunteers gave a Cmax of 3.5 mg/mL at 0.25 h. At 6 h

concentration had rapidly declined to 38 ng/mL. The con-

centration was dependent on the manner of collection;

stimulated OF reduced concentrations by up to a factor of

three [26].

IM administration of 60 and 120 mg codeine phosphate

produced a maximum OF concentration of 184 and 308 ng/

mL in two subjects, respectively, using a stimulated collec-

tion process. [24]. By 24 h, OF concentrations were detect-

able but were quite low.

Similarly, oral administration of 60 and 120 mg codeine

sulfate gave Cmax 0.6 and 1.6 mg/mL, respectively, at

between 1/2 and 4 h. The average OF:plasma ratio was 4

[27]. Similarly, 60 and 120 mg codeine sulfate produced OF

concentrations ranging up to 4 mg/mL. Norcodeine was also

detected in small amounts in OF [28]. Screening and con-

firmation cut-off of 30 and 15 ng/mL have been proposed

based on another study on volunteers given 60 and 120 mg

codeine [29].

Dihydrocodeine 60 mg single dose gave a peak OF

concentration of 0.8 mg/mL at 2 h and a OF:plasma con-

centration ratio of 1.3–17 [30]. Following chronic use of 0.4

to 2.6 g daily OF concentrations in 20 subjects ranged up to

66 mg/mL (mean: 10.8 � 14.9 mg/mL). Dihydrocodeine

was detectable until about 24 h after last use using a limit

of detection of 5 ng/mL. Two subjects gave no detectable

dihydrocodeine in OF and plasma suggesting non-compli-

ance [30].

3.5. Benzodiazepines

Only one study has examined the presence of benzodia-

zepines in OF. This involved administration of 1 mg fluni-

trazepam to four subjects. Cmax of flunitrazepam and 7-

aminometabolite ranged from 0.6 to 4 ng/mL and from 0.9 to

2 ng/mL at 1–4.5 h. NaF preservative was required to reduce

conversion to the 7-amino metabolite [31]. Several other

studies were performed earlier and are discussed in the

review by Kidwell et al. [10].

4. Discussion

A review of the literature over the last 15 years has shown

a number of pharmacokinetic studies aimed at examining the

presence of drugs of abuse in oral fluid. Most of these studies

have been aimed at the amphetamines, cannabis, cocaine and

the opiate class of drugs.

O.H. Drummer / Forensic Science International 150 (2005) 133–142 141

Collectively they show that with the possible exception

of benzodiazepines, these drugs of abuse are readily detect-

able in oral fluid and can show similar pharmacokinetics to

plasma. This relationship to plasma is important if oral fluid

is to be used as a surrogate to plasma, particularly in

situations, where invasive collection procedures are too

difficult, i.e. at the roadside for drug-using drivers. This

relationship is perhaps not surprising since there is a known

relationship between OF and plasma concentrations depend-

ing on the pH of the two specimens, the degree of protein

binding in plasma and the pKa of the drug [32]. For basic

drugs such as the amphetamines OF concentrations are much

higher than the corresponding plasma concentration

[16,17,19,20]. This increases the detectability of this class

of drugs. In contrast, there is very little partitioning of THC

between plasma and OF due to the high lipophilicity of the

drug, yet similarity in time profiles occurs. This is due

possibly to reserves of THC deposited in the oral mucosa

that is leached out with time [8,15].

The process of collection of oral fluid can lead to

alterations in the drug concentration. All studies that have

compared collection processes have shown that stimulated

saliva (citric acid) reduces the concentration of drug

[4,16,26]. Deceases can amount to two to three-fold for

codeine [26], methamphetamine [16] or even five-fold for

cocaine [4]. These changes are due to a dilution effect by the

increased output of oral fluids as well as a possible pH effect.

This suggests that collecting oral fluid from drivers unable to

provide a quick specimen may not disadvantage them in

terms of increasing the detectability of drug in this specimen.

With the exception of flunitrazepam, peak concentrations

of drugs in OF easily exceed 100 ng/mL, and many are

above 1 mg/mL (codeine, dihydrocodeine, heroin, cocaine,

MDMA). The longer half-life amphetamines will remain

high for some period due to their slow elimination from the

body, whereas THC, cocaine and heroin remain at relatively

high concentrations for a short period of time (see Tables 1

and 2). Chronic use will lead to an accumulation of drug in

OF. This is typified by dihydrocodeine in which OF con-

centrations rise over 10-fold with repeated use [30].

In uncontrolled situations OF concentrations tend to be

similar to or higher than the controlled dose studies. Drug-

users observed to be impaired have shown amphetamine

concentrations in OF range up to12 mg/mL (median 2.7,

n = 12). MDMA was also detected in nine volunteers, six of

whom were also positive for amphetamine. The MDMA

concentration range in OF was 0.4–6.3 mg/mL (median

1.8 mg/mL). There were 11 cases positive to THC in OF

with a concentration range of 1.4–42 ng/mL (median 10 ng/

mL). There were five cases positive to morphine in OF. The

concentration range was 0.09–8 mg/mL (median 0.9 mg/mL)

[33].

Oral fluid taken from impaired drivers gave median THC

concentrations of 6.4 ng/mL (n = 91, greater than 2 ng/mL

cut-off). Amphetamines were detected in 74 drivers at

concentrations greater than the cut-off (50 ng/mL). The

median MDMA and MDEA concentrations were 97 and

315 ng/mL, respectively. Benzoylecgonine was detected in

21 cases greater than the applied cut-off giving a median

concentration of 148 ng/mL. Twenty cases had morphine

detected at greater than the applied cut-off with a median of

32 ng/mL [34].

In OF specimens collected in workplaces using the

Intercept1 collector drugs of abuse were detected in

5.06%. THC prevalence was 3.2% (cut-off 1.5 ng/mL),

cocaine 1.1% (6 ng/mL as BE), opiates 0.23% (30 ng/mL)

and methamphetamine/amphetamine 0.47% (120 ng/mL).

The THC positives were predominately (61%) in the �4–

49.9 ng/mL, although 8.8% were over 50 ng/mL. Ninety-

three percent of the methamphetamine positives were

�160 ng/mL [35,36].

A number of factors may affect the clearance of drugs in

plasma. This includes diseases of the heart, renal and liver

disease, obesity, etc. [37,38]. Similarly, concomitant drug-

use can affect clearance through a competition of binding

sites or through metabolic pathways, or even in persons with

a high degree of fitness [39]. How these factors will affect

drug concentration in OF will need to be established as well

as methods designed to adulterate or change the concentra-

tion of drug in OF.

This review shows that there are a number of studies that

have examined the concentration of selected drugs of abuse

in OF. While this provides much useful information more

studies are required, particularly for some of the other

abused drugs and in situations, where the pharmacokinetics

may be altered by either concomitant drug-use or disease

states.

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