Clinical Chemist’y 42:4

618-624 (1996)

Laboratory testing for recent alcohol

consumption: comparison of ethanol, methanol,
and 5-hydroxytryptophol
ANDERS HELANDER,l* OLOF BECK,2 and A. WAYNE JoNEs3

The ratio of 5-hydroxytryptophol to 5-hydroxyindole-3- amounts they consume [1, 2]. For this reason, underdiagnosis of
acetic acid (5HTOIJSHIAA) in urine was compared with alcohol misuse is not uncommon by these methods. Well-
concentrations of ethanol and methanol as a way to monitor controlled population surveys, for example, have accounted for
recent alcohol consumption. During detoxification of alco- only about half of the known consumption of alcohol [3]. To
hol-dependent subjects, ethanol persisted longer in urine help overcome this problem, a large number of biochemical and
than in breath or plasma. Blood and urinary methanol hematological tests have been developed to identify alcohol-
remained increased for 2-6 h after blood ethanol had dependent subjects or those engaged in hazardous drinking
returned to background concentrations, whereas 5HTOLI [4, 5]. However, when biochemical markers are evaluated in
5HIAA remained increased fir 6-15 h. In healthy volun- terms of diagnostic sensitivity and specificity, most studies still
teers who had ingested alcohol (range 3-98 g) the previous rely on self-reports as the “gold standard” for alcohol consump-
afternoon or evening, 87% (for men) and 59% (for women) tion, which creates a problem.
of all drinking occasions exceeding 7 g of alcohol were The limited reliability of interview data underscores the need
identified by an increased 5HTOIJ5HIAA in the first for more objective tests of recent alcohol consumption, permit-
morning urine void. This compares with 32% and 12%, ting frequent monitoring of individual drinking patterns. The
respectively, identified by analysis of ethanol (>200 xmol/ most obvious way to prove that a person has been drinking is by
L). No gender difference in the excretion pattern of demonstrating the presence of ethanol in blood, urine, saliva, or
SHTOIJSHLAA was seen. The results demonstrate that breath [6]. However, because ethanol is rapidly eliminated from
SHTOLJ5IJIAA provides a specific and more sensitive the body, this approach is practical only for consumption of
method to detect recent alcohol consumption than does alcohol within the past few hours. Increased concentrations of
ethanol or methanol. the metabolites of ethanol oxidation, acetaldehyde and acetic
acid, have been proposed as alternative indicators of recent
INDEXING mIt11s: alcoholism. 5-hydroxyindole-3-acetic acid. drinking. Acetaldehyde, however, is rapidly converted to acetic
alcohol metabolism serotonin
#{149} aldehyde
#{149} dehydrogenase acid by aldehyde dehydrogenase (ALDH), and the concentra-
alcohol dehydrogenase tion in peripheral blood is normally very low f7]4 Its use is
further hampered by problems associated with artifactual for-
A major problem in the early detection and treatment of alcohol mation after sampling the blood. The concentration of acetic
dependence is obtaining reliable information about a person’s acid, on the other hand, increases with the development of
drinking habits. Self-reports and diagnostic questionnaires are metabolic tolerance to alcohol, and might therefore be more
widely used for this purpose, but people with alcohol-related suitable as a marker of chronic alcoholism [8].
problems may deliberately deny or underreport the actual A metabolic interaction between ethanol and serotonin (5-
hydroxytryptamine) can be utilized for detection of recent
drinking [9-11]. 5-Hydroxytryptophol (5HTOL) is normally a
Karolinska Institute, Department of Clinical Neuroscience, Psychiatry Sec- minor metabolite of serotonin, but its formation increases
tion at St. Gorans Hospital, Stockholm, Sweden. dramatically after ingestion of ethanol, whereas 5-hydroxyin-
2 Department of Clinical Pharmacology, Karolinska Hospital, Stockholm,
dole-3-acetic acid (5HIAA), the major metabolite under normal
Sweden.
‘Department of Forensic Toxicology, University Hospital, Linkoping, Swe-

Address correspondence to this author at: Alcohol & Drug Dependence Unit,
St. Gorans Hospital, Box 12500, S-112 81 Stockholm, Sweden. Fax (+46) 8 Nonstandard abbreviations: ALDH, aldehyde dehydrogenase; 5HTOL,
6721994. 5-hydroxytryptophol; 5HIAA, 5-hydroxyindole-3-acetic acid; and ADH, alcohol
Received October 10, 1995; accepted January 24, 1996. dehydrogenase.

618
 Clinical Chemistiy 42, No. 4, 1996 619

conditions, is concomitantly decreased. This metabolic shift can samples were collected from healthy volunteers (social drinkers
be monitored by analysis of blood or urine, and the excretion of without any history of previous excessive consumption of alco-
5HTOL will not normalize until several hours after blood and hol). Ethanol (160 g/L in orange juice) was administered at 0.8
urinary ethanol have reached background concentrations [11]. g/kg body weight to five women and five men (ages 23-39 years)
On the basis of this observation, increased urinary concentration after an overnight fast, and the drink was finished within 30 mm.
of 5HTOL was introduced as a sensitive biochemical marker of From all subjects participating in that experiment, the plasma
recent alcohol consumption [11, 12]. samples collected at the start of drinking and then at 2-h
An abnormally high concentration of methanol in body fluids intervals for a total of 10 h, and the urine samples collected at
or breath has also been suggested as an indicator of recent the start and then at every 2-3 h for 22 h, were also used for the
drinking [13]. Methanol accumulates in the body during the present study. All samples had since (for -30 months) been
metabolism of ethanol [14, 15], and, as for 5HTOL, the con- stored in l-mL portions at -80 #{176}C. The urinary 5HTOL/
centration remains increased for some time after ethanol is no 5HIAA ratio and the concentrations of plasma and urinary
longer detectable [16, 17]. Thus measurement of either 5HTOL ethanol and of urinary methanol (which was not analyzed in the
or methanol will provide a higher sensitivity than analysis of previous study) were determined as described above.
ethanol alone for the detection of recent alcohol consumption. In a new experiment on healthy volunteers, consecutive urine
The present study was carried out to evaluate further the samples were obtained daily from four women and four men
usefulness of 5HTOL as a marker of recent alcohol consump- (ages 24-49 years) over a period of 4-6 weeks. A lO-inL sample
tion, and to compare its sensitivity and specificity with those of of the first morning void was collected, and the subjects kept a
ethanol and methanol. record of the amount of alcoholic beverages, if any, consumed
the previous day throughout this period. The concentration of
Materials and Methods ethanol and the SHTOL/5HIAA ratio were determined.
DETERMINATION #{248}F
ETHANOL, METHANOL, AND ACETONE In an earlier study on the use of 5HTOL as a marker of
The concentrations of ethanol, methanol, and acetone in blood recent drinking [24], the possible interference by metabolic
and urine samples were determined by headspace gas chroma- acidosis in a subject with diabetes mellitus could not be ruled
tography essentially as described elsewhere [18]. To increase out. To examine this further, we assayed urine samples collected
sensitivity for determination of methanol, we used a salting-out from 20 diabetic patients (12 women and 8 men, ages 38-91
procedure, adding 1.2 g of sodium chloride to 0.5 mL of years) admitted to St. G#{246}rans Hospital for treatment of ketoac-
specimen [19]. The limits of detection for analysis of ethanol and idosis or coma. Thereafter, we assayed additional samples
methanol were 200 j.molIL and 15 /.Lmol/L, respectively. The collected at 1-week intervals for a total of 3-5 weeks, having
concentration of ethanol in breath was determined with a asked the patients not to consume any alcohol during this
hand-held analyzer (Alcolmeter S-D2; Lion Labs., Barry, UK) period. The concentrations of ethanol and acetone and the
and the result reported as presumed blood alcohol concentra- 5HTOL/5HIAA ratio were determined.
tion. All blood samples were collected from an antecubital vein
into Vacutainer Tubes containing EDTA (Becton Dickinson,
DETERMINATION OF 5HTOL AND 5HIAA Meylan Cedex, France) for preparation of plasma by centrifu-
The concentration of 5HTOL in urine is expressed as a ratio to gation. The urine samples were collected into plastic tubes
the concentration of 5HIAA, because ingestion of foods rich in without preservative. Before analysis, the plasma and urine
serotonin (such as banana, pineapple, kiwifruit, and walnuts) can samples were stored at -80 #{176}C. Samples were thawed overnight
otherwise cause false-positive results [20]. 5HTOL and 5HIAA at 4 #{176}C.
The study was approved by the local Ethical Committee
were determined with sensitive gas chromatographic-mass spec- (VSO/SSO) in Stockholm.
trometric and HPLC methods [10, 12, 2/]. The reference limit
used to indicate an increased urinary 5HTOL/5HIAA ratio was Results
set at 15 pmol/nmol [12, 22, 23]. Figure 1 shows the time course of concentrations of ethanol in
breath, plasma, and urine, and of methanol in plasma and urine,
CLINICAL PROCEDURES as well as the 5HTOL/5HIAA ratio in urine, for each of the 10
Male alcohol-dependent patients (ages 40-62 years) were re- alcohol-dependent subjects during detoxification. Ethanol was
cruited from the detoxification unit at St. G#{246}rans
Hospital. usually detectable longer in urine than in breath or plasma. The
Blood and urine samples (10 mL each) for determination of concentration of methanol was markedly increased in the first
ethanol, methanol, and the 5HTOL/51-IIAA ratio were col- sample [mean 0.57 ± 0.15 (SD) mmol/L in plasma and 0.62 ±
lected from 10 subjects with a blood alcohol concentration of 0.17 mmol/L in urine] and did not start to fall until the blood
23.7-57.5 mmollL (mean 43.6) on admission to the hospital. ethanol had returned to background concentration. Thereafter,
Thereafter, the breath ethanol concentration was measured methanol remained increased for a further 2-6 h (mean 3.5 h).
every 4-6 h, and blood and urine samples were also collected. The urinary SHTOL/51-HAA ratio in the first sample ranged
When breath measurements indicated zero ethanol concentra- between 331 and 1081 pmol/nmol (mean 684 ± 259 pmol/
tion, sampling of blood and urine was continued at 3-h intervals nmol), and remained above the cutoff for 6-15 h (mean 10 h)
for another 12-15 h. after ethanol was no longer detectable in blood samples.
In a previous experimental protocol [11], blood and urine Figure 2 shows the time course of concentrations of ethanol
620 Helander et al.: Lab testing for alcohol consumption

0 Breath Ethanol D Urinary Ethanol U Urinary Methanol

Plasma Ethanol A Plasma Methanol * Urinary 5HTOL/5HIAA

80 1.0 80 1.0 #{149} E

#{182}000
100
:; 0.8
60 0.8 0
60
E
o
E E
E06 0.6 50 -

40 40 40
#{149}6 0A 0.4
C #{149} 30
#{149} -
20 20 0.2 20
Ui
10
=
0 0 0 0 - U,
12 16 20 24

80 1.0 80 1.0 #{149} 6

#{182}000
#{149}I00
= 60
0.8
60 0.8 0
o E a
E E0.6 0.6 so -

40 - 40 40
0.4
0.4
= _ 30
#{149} .=
20 o.z 20 02 20 3
Ui

0 - . .,. .T1TTT7 0 0 0
10
u,

80 80 1.0 - #{182}000
1000
-100
100 0.8
-J
60 80 0
..
0 a
0.
E 50 0.6
40 40
40
0 0.4 =
C 30 U)
20 20 20 -j
Ui 02 0
l0 I-
0 0 A U)
0

80 1.0 - 1000 80 1.0 - 1000 a

- 100 tOO
0.8
60 60 0.8 0
o E a
E E0’6 50 0.6 50
.4Q -
40
40 40
0.4
30 0.4
= C 30
#{149} .c U,
20 20 20 0.2 20
uj 0.2
to #{149}I0
0 0 0 0 0 0 ii,
0 4 8 12 16 20 24 28

80 80 1.0 #{149}
iooo

;:I
-J
80 60 0.8
0 0
a E
a 0.6
40 40 40

_
0
0 C 0.4
= 30 =
U,
20 20 02 20
UJ 0
to
0 0 0 0 v,
0 4 8 12 #{182}620 24 28

Tim. (hI Tim. (hI

Ag. 1. Time course of concentrations of ethanol in breath, plasma, and urine, and of methanol in plasma and urine, as well as the ratio of
5HTOL/5HIAA in urine, in samples collected from 10 male alcohol-dependent subjects (A-fl during detoxification.
The dashed line represents the cutoff limit used to indicate an abnormal 5HTOL/51-IIM ratio (>15 pmol/nmol).

in plasma and urine, and of methanol in urine, as well as the drinking. The 5HTOL/5HIAA ratio was increased >100-fold
5HTOL/5HIAA ratio in urine, for the five female and five male in the 6-h sample and did not return to baseline until after
social drinkers after administration of ethanol at 0.8 g/kg body 14-16 h. No significant gender differences in ethanol elimina-
weight. The concentration of methanol was highest in the 6-h tion rate or in the urinary excretion patterns of methanol and
sample (-5 times baseline) and decreased again to the baseline 5HTOL/5HIAA were seen.
concentration (<0.04 mmollL) 10-12 h after the start of In the experiment involving analysis of consecutive morning
 Clinical Chemistry 42, No. 4, 1996 621

0 P-ethanol 0 U-ethanol U-methanol U-5HTOL/5HIAA

U P-ethanol 9 #{149}
U-ethanol 9 A U-methanol 9 #{149}
U-5HTOL/5HIAA g

0.20- 25 1000

#{149}000E
-J 20
‘..-. 0.15 - -J
0
0

E 15
E
- 0.10 - Ag. 2. Concentration-time profiles of ethanol in plasma
0 (P) and urine (U), methanol in urine, and the ratio of
iO C 10
30 5HTOL/5HIAA in Urine, in samples collected from healthy
Ui 20 social-drinking volunteers (five women and five men, ages
0.05
5 I- 23-39 years) after oral administration of ethanol at 0.8
10 g/kg body weight.
The drink was finished within 30 mm in the morning after an
0 0 overnight fast. Data represent mean values ± SD for the 5HTOL/
0 2 6 10 14 18 22 5HIAA ratio, but, for clarity, SOs have been omitted for the other
variables. The dashed line represents the cutoff limit used to
Time (h) indicate an abnormal 5HTOL/5HIAA ratio (>15 pmol/nmol(.

urine samples, an average of 29 g of alcohol (range 3-98 g/day) both ethanol and 5HTOL/5HIAA in all subjects except one.
had been consumed the previous day on 155 of a total of 261 This male subject showed one slightly increased metabolite ratio
sampling days, according to the self-reported drinking proto- (21 pmol/nmol), although no alcohol consumption was reported
cols. Usually, drinking occurred in the evening or late after- the previous evening. We observed a significant correlation
noon. Analysis of the urinary 5HTOL/5HIAA ratio in the first between the amount of alcohol consumed and the urinary
morning void identified on the average 73% (sensitivity) of all 5HTOL/5HIAA ratio in the first morning void the next day
drinking occasions exceeding 7 g of alcohol, as compared with (Fig. 4).
22% by analysis of ethanol (>200 mol/L) (Table 1). On some In the urine samples collected from 20 diabetic patients
occasions when relatively large amounts of alcohol had been with metabolic ketoacidosis or admitted to hospital in diabetic
consumed, the second and, in one case, even the third void of coma, the highest concentration of acetone was 4.4 mmol/L.
urine the next day confirmed that the 5HTOL/5HIAA ratio The 5HTOL/5HIAA ratios were 6.5 ± 3.4 pmol/nmol (mean
remained increased for considerably longer than ethanol could ± SD, n = 85), and all samples except one showed ratios
be detected (Fig. 3). The mean sensitivity for analysis of ethanol below the cutoff limit of 15 pmol/nmol. This single value was
and the 5HTOL marker was somewhat less for women than for only slightly increased (17 pmol/nmol) and was present in the
men (Table 1). However, two women reported that they occa- urine sample collected immediately upon admission to the
sionally voided during the night. The specificity was 100% for hospital.

Table 1. Sensitivity and specIficity of urinary (U) ethanol and 5HTOL/5HIAA ratio to detect recent alcohol consumption in
healthy social drinkers.
Increased U-ethanol Normal U-ethanol
No. of days 5lITOL/5HIAA >200 amoi/L 5HIOL/5HIAAb <200 gemol/L
No. of
Age, Total With >7 g Alcohol intake No. No. alcohol- No. No.
years study ethanol range, g (mean) days Sens., % days Sen.., % free days days Spec., % days Spec., %
Men
32 43 23 9-98 (29.8) 20 87 5 22 20 20 100 20 100
39 38 21 8-48 (24.5) 14 67 7 33 12 12 100 12 100
40 27 21 8-74 (27.8) 20 95 4 19 6 6 100 6 100
49 35 30 14-83 (45.0) 29 97 16 53 5 4 80 5 100
Mean 87 32 95 100
Women
24 30 9 8-50 (27.1) 3 33 1 11 19 19 100 19 100
30 32 15 8-71 (27.1) 11 73 2 13 16 16 100 16 100
38 28 18 8-60 (21.4) 14 78 1 6 10 10 100 10 100
41 28 18 9-64 (24.0) 9 50 3 17 10 10 100 10 100
Mean 59 12 100 100
>15 pmol/nmol.
‘<i pmol/nmol.
622 Flelander et al.: Lab testing for alcohol consumption

40

0 30 o lot void
A-
#{149}
2nd void
0
20 e 3rd void
E
=
to 0

H 11
“4
“4

‘!I
=
U)
‘4- -J
‘4 to 0
I-
00 U,
too

1000
0 20 40 60 80 100
Fig. 3. Urinary ethanol concentrations and 5HTOL/5HIAA ratios in the
first, second, and, in one case, third morning voids collected on 16 Amount of alcohol (g)
days from three of the social drinkers. Fig. 4. Correlation between the urinary 5HTOL/5HIAA ratio in the first
The clashed line represents the cutoff limit used to indicate an abnormal morning void and the amount of alcohol consumed (range 3-98 g) on
5HT0L/5HlA ratio (>15 pmol/nmol). the day before sampling in eight social-drinking female and male
subjects.
Accordingto the self-report protocols, drinking usually occurred in the evening or
Discussion late afternoon. The dashed line represents the cutoff limit used to indicate an
Hitherto, the determination of ethanol in body fluids or breath abnormal 5HTOL/5HIAA ratio (>15 pmol/nmol).

has represented the only generally available objective method to

prove recent consumption of alcohol. However, because ethanol social drinkers after the ingestion of ethanol at 0.8 g/kg body
is rapidly eliminated from the body, this approach will only weight. Accordingly, an increased methanol concentration is not
detect very recent drinking, even though ethanol can be de- specific for recent alcohol consumption, but may be useful for
tected for some hours longer in urine than in blood or breath, detection of chronic drinking [27, 28].
owing to retention of urine in the bladder. The use of even more The results of the present study demonstrate that the urinary
sensitive analytical assays may increase diagnostic sensitivity, but 5HTOL/5HJAA ratio provides a more sensitive method to
also the risk of false-positive results, because several microor- detect recent alcohol consumption compared with analysis of
ganisms occasionally found in humans are capable of producing ethanol or methanol in blood, breath, or urine. The specificity
ethanol by metabolic conversion of glucose or other endogenous for detecting alcohol was also very high with the 5HTOL/
substrates /25]. 5HIAA ratio [29]. A dose-dependent increase in the urinary
An increased concentration of methanol in body fluids or excretion of 5HTOL is seen after each drink, owing to compet-
breath has been suggested as an alternative indicator of recent itive inhibition of ALDH by ethanol-derived acetaldehyde and
drinking [13]. The concentration of methanol increases during a (or) the change in hepatic redox state [30]. In contrast to
drinking spree owing to competitive inhibition of alcohol dehy- methanol, the baseline value for 5HTOL/5HIAA is not in-
drogenase (ADH). The methanol might originate from endog- creased after prolonged misuse and can therefore be used to
enous sources, but it is also present as a congener in alcoholic identify recent drinking in both social drinkers and chronic
beverages and can be derived from various foodstuffs (e.g., fruits consumers. The major advantage of 5HTOL/5HIAA compared
and fruit juices) [26]. In the present experiments, methanol with ethanol and methanol is that the serotonin metabolite ratio
remained increased even after the blood ethanol concentration stays increased for several hours longer than ethanol and
had returned to background concentrations in both alcohol- methanol, thereby increasing diagnostic sensitivity. However,
dependent subjects and healthy volunteers. This time lag be- the exact time available for detection of acute alcohol consump-
tween ethanol and methanol clearance agrees with previous tion by analysis of urine depends not only on the dose and time
reports [14-17] and implies that methanol is more sensitive than since the last drink, but also on voiding between the time of
ethanol as indicator of recent drinking. However, an abnormally drinking and sampling.
high concentration of methanol in blood or urine could reflect To enhance the specificity of the marker, 5HTOL is ex-
recent as well as long-term continuous drinking. After acute pressed as a ratio with 5HIAA rather than creatinine, because
intake of alcohol by healthy volunteers, the concentration of dietary serotonin might otherwise cause false-positive results
methanol increased to -0.14 mmol/L on average before return- owing to a general increase in the urinary output of serotonin
ing to baseline values after 10-12 h. During chronic drinking, metabolites [20]. To discriminate between normal and increased
methanol accumulates gradually to reach much higher concen- values of the urinary 5HTOL/5HIAA ratio, the cutoff limit was
trations, and complete clearance after termination of drinking originally set at 20 pmollnmol [12]. However, after careful study
might require several days [14]. This was further confirmed in of a large number of abstinent subjects of both Caucasian and
the alcohol-dependent subjects during detoxification, where Oriental origin [22/, a lower limit of 15 pmollnmol was intro-
methanol leveled out within the concentration range reached in duced into clinical practice. Actually, all those subjects had ratios
 Clinical Chemistry 42, No. 4, 1996 623

<10 pmol/nmol, but we used a higher cutoff to reduce the risk 5. Conigrave KM, Saunders JB, Whitfield JB. Diagnostic tests for
of reporting false positives. The ratio is stable both within day alcohol consumption. Alcohol Alcohol 1995:30:12-26.
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tion, and diminished performance. Clin Chem 1993;39:1837-44.
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indicate that gender and diabetic ketoacidosis do not markedly Clin Exp Res 1985;9:468-71.
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the alcohol-sensitizing drugs disulfiram (Antabuse#{174};Dumex, metabolism to 5-hydroxyttyptophol by ethanol ingestion in man. J
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Wayne, NJ), both potent inhibitors of ALDH, represent the
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T. Time
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This new biochemical marker can be useful for investigating
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thank Ulla Lindstr#{246}mfor the collection of samples, and Tina Determination of urinary 5-hydroxyindole-3-acetic acid by high-
Bur#{233}nius,
Gun Jacobsson, and Catharina L#{246}wenmofor skillful performance liquid chromatography with electrochemical detec-
tion and direct sample injection. Anal Biochem 1991:196:170-3.
technical assistance.
22. Helander A, Walzer C, Beck 0, Balant L, Borg S, von Warthurg J-P.
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