Low doses of alcohol substantially decrease glucose metabolism in the
Nora D. Volkow,a,b,*Gene-Jack Wang,cDinko Franceschi,dJoanna S. Fowler,e
Panayotis (Peter) K. Thanos,cLaurence Maynard,fS. John Gatley,cChristopher Wong,c
Richard L. Veech,gGeorge Kunos,band Ting Kai Lib
aNational Institute on Drug Abuse, 6001 Executive Blvd., Room 5274, Bethesda, MD 20892, USA
bNational Institute on Alcohol Abuse and Alcoholism, Bethesda, MD 20892, USA
cMedical Department, Brookhaven National Laboratory, Upton, NY 11973, USA
dDepartment of Radiology, State University of New York at Stony Brook, Stony Brook, NY 11794, USA
eChemistry Department, Brookhaven National Laboratory, Upton, NY 11973, USA
fMiddlesettlement Family Practice, New Hartford, NY 13413, USA
gLaboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, Rockville, MD 20850, USA
Received 26 April 2005; revised 30 June 2005; accepted 4 July 2005
Available online 8 August 2005
Moderate doses of alcohol decrease glucose metabolism in the human
brain, which has been interpreted to reflect alcohol-induced decreases
in brain activity. Here, we measure the effects of two relatively low
doses of alcohol (0.25 g/kg and 0.5 g/kg, or 5 to 10 mM in total body
H2O) on glucose metabolism in the human brain. Twenty healthy
control subjects were tested using positron emission tomography (PET)
and FDG after placebo and after acute oral administration of either
0.25 g/kg, or 0.5 g/kg of alcohol, administered over 40 min. Both doses
of alcohol significantly decreased whole-brain glucose metabolism
(10% and 23% respectively). The responses differed between doses;
whereas the 0.25 g/kg dose predominantly reduced metabolism in
cortical regions, the 0.5 g/kg dose reduced metabolism in cortical as
well as subcortical regions (i.e. cerebellum, mesencephalon, basal
ganglia and thalamus). These doses of alcohol did not significantly
change the scores in cognitive performance, which contrasts with our
previous results showing that a 13% reduction in brain metabolism by
lorazepam was associated with significant impairment in performance
on the same battery of cognitive tests. This seemingly paradoxical
finding raises the possibility that the large brain metabolic decrements
during alcohol intoxication could reflect a shift in the substrate for
energy utilization, particularly in light of new evidence that blood-
borne acetate, which is markedly increased during intoxication, is a
substrate for energy production by the brain.
Published by Elsevier Inc.
Among substances of abuse, alcohol is the one most widely
consumed. It is estimated that 50% of Americans 12 years or older
consume alcohol at least once a month (SAMHSA, 2003). Though
6.8% are heavy drinkers (5 or more drinks on at least 5 different
days in the past 30 days), the majority of individuals use alcohol in
moderation. Brain imaging studies have shown that acute alcohol
administration results in decreased brain glucose utilization, which
has been interpreted to reflect decreases in brain activity during
intoxication. Most of the studies measuring effects of alcohol on
glucose metabolism have used moderate to high doses of alcohol
(0.5–1 g/kg administered over 15–45 min). Thus, the decrements
in brain glucose metabolism are likely to reflect the CNS
depressant effects of alcohol that occur at high doses (Pohorecky,
1977). However, in contrast to large doses, small doses of alcohol
are stimulatory (Pohorecky, 1977). This biphasic effect of alcohol
as a function of dose was corroborated for brain glucose
metabolism in an autoradiographic study in rodents showing that,
whereas a 1 g/kg dose of alcohol decreased metabolism, a 0.25 g/
kg dose increased it (Williams-Hemby and Porrino, 1994). The
extent to which a similar biphasic effect of alcohol on glucose
metabolism occurs in the human brain has not been investigated.
Here, we evaluate the effects of low to moderate doses of alcohol
(0.25 g/kg and 0.5 g/kg respectively) on brain glucose metabolism
and compare them to effects we had previously observed after
administration of a high dose (0.75 g/kg) to assess if we could
document the biphasic effects of alcohol on glucose metabolism in
the human brain.
For this purpose, we measured the regional brain metabolic
changes induced by a 0.25 g/kg and a 0.5 g/kg dose of alcohol
1053-8119/$ - see front matter. Published by Elsevier Inc.
* Corresponding author. National Institute on Drug Abuse, 6001
Executive Blvd., Room 5274, Bethesda, MD 20892, USA. Fax: +1 301
E-mail address: email@example.com (N.D. Volkow).
Available online on ScienceDirect (www.sciencedirect.com).
NeuroImage 29 (2006) 295 – 301
using PET and FDG. Twenty healthy controls were studied with
PET and FDG twice, once after placebo and once 40–50 min after
acute alcohol administration. We chose a 40–50 min delay since
this is the time when peak alcohol concentrations are reached in
brain after oral administration (Sammi et al., 2000). We selected
the 0.25 g/kg and 0.5 g/kg doses since these are typical doses
consumed by social drinkers (Stinson et al., 1998), roughly
equivalent to one and two drinks, respectively, for a 50 kg person.
In parallel, we also measured the behavioral and cognitive effects
of these low to moderate doses of alcohol. We hypothesized that, in
contrast to previous findings showing that high doses of alcohol
decreased brain glucose metabolism, low doses would increase
brain metabolic activity.
Material and methods
Twenty right-handed healthy subjects (37 T 9 years of age,
12M, 8F) who drank in moderation (not more than 5 drinks/week)
were selected. Each subject had a routine physical, psychiatric and
neurologic examination. Routine laboratory tests were performed,
as well as urine tests to exclude the use of psychoactive drugs.
Subjects were excluded if they had a present or past psychiatric
and/or neurological illness, if they had a present or past history of
substance abuse or dependence (except nicotine), if they had
medical illnesses and/or if they were taking any medication.
Subjects were also excluded if they expressed they would have
difficulty abstaining from drinking any alcohol for 1 week prior to
the study. Four of the subjects were current smokers. Subjects were
instructed to discontinue any over the counter medication 2 weeks
prior to the PET scan and were asked to abstain from alcohol for 1
week prior to the PET scans whether it was the placebo or the
alcohol scanning session. Self-reports were used to determine if
they had used any alcohol during the week prior to the study. The
study was approved by the Human Subjects Research Committee
of Brookhaven National Laboratory. After explaining the proce-
dure, written informed consent was obtained from each subject.
PET scans were acquired on a whole-body, high-resolution
positron emission tomograph (SiemensTI ECAT HR+; with 4.6 ?
4.6 ? 4.2 mm resolution at center of field of view and 63 slices) in
3D dynamic acquisition mode using FDG. Methods for positioning
of subjects, catheterizations, transmission scans and blood sam-
pling and analysis have been published (Wang et al., 1993).
Briefly, a 20 min emission scan was started 35 min after injection
of 4–6 mCi of FDG. Arterialized venous blood sampling was used
to measure FDG and glucose concentration in plasma.
Subjects were scanned on 2 different days with FDG within 1
week of each other. On one of the days, subjects drank a placebo
(100 ml of diet non-caffeinated soda) over a period of 40 min,
given 40–50 min prior to FDG (baseline-FDG scan) administra-
tion. On the other day, subjects drank a mixture of 95% ethanol
with diet soda added up to 100 ml over a period of 40 min, given
40–50 min prior to FDG (alcohol-FDG scan). The order was
randomized so that for half of the subjects the first scan was with
placebo, and for the other half, with alcohol. Thirteen subjects
received the 0.25 g/kg dose (8M, 5F) and 7 received the 0.5 g/kg
dose (4 M, 3 F). Subjects were blind to whether placebo or alcohol
was given. To avoid circadian variability (Bartlett et al., 1988), the
two scans for a given subject were done at the same time of day
(T1 h). Plasma alcohol concentration was measured prior to and
20, 40, 55, 80, 100, 140 and 160 min after the initiation of alcohol
administration using the enzymatic assay of Lloyd et al. (1978).
To ensure that the subjects would not fall asleep, they were
monitored throughout the procedure and were asked to keep their
eyes open. Subjects were scanned with their ears unplugged in a
dimly lit room with noise kept to a minimum. The only
intervention was the periodic assessment of the behavioral and
cognitive effects of alcohol or of placebo. For the females, the
studies were done in the mid-luteal phase (16–23 days after the
onset of menstruation).
Behavioral and cognitive evaluation
Before placebo or alcohol, and at 20, 40, 60, 80 and 135 min
after placebo or alcohol administration, subjects were asked to
evaluate on an analog scale (rated 0–10) their subjective sense of
intoxication, sleepiness, high and anxiety. To assess the cognitive
effects of alcohol, subjects were evaluated with the Stroop Test, the
Word Association Test (WA), Symbol Digit Modality Test (SDMT)
and arithmetic calculations (Lezak, 1995), which were obtained
prior to placebo or alcohol and 80 min (just prior to FDG injection)
and 140 min (end of PET scanning procedure) after initiation of
placebo or alcohol administration.
Regions were selected using a template of 423 non-overlapping
regions based on Talairach and Tournoux’s atlas (Talairach and
Tournoux, 1988). Values for the cortical, subcortical and cerebellar
regions were computed using the weighted average from the
different slices where the regions were obtained and grouped into
12 composite regions, which included frontal, parietal, temporal,
occipital cortices, insula, anterior cingulate gyrus, orbitofrontal
cortex, basal ganglia, thalamus, amygdala/hippocampus, mesen-
cephalon and cerebellum. An estimate of whole-brain metabolism
was obtained by averaging the values from all of the regions of
Differences in measures of regional brain glucose metabolism
during alcohol intoxication were evaluated using a factorial
repeated ANOVA with dose as the between factor (0.25 g/kg
versus 0.5 g/kg) and drug (placebo versus alcohol) and regions (12
different regions) as the repeated measures. For the behavioral
measures, we used a factorial repeated ANOVA with dose as the
between factor and drug and time as the repeated measures.
Pearson product moment correlations were used to quantify
the relationship between the changes in regional brain glucose
metabolism computed as percent change from placebo (placebo ?
alcohol / placebo ? 100) and the changes in the behavioral and
cognitive measures that were significantly affected by alcohol. To
compute the changes in self-reports of drug effects, we averaged the
scores obtained between 40 and 80 min after alcohol from those
obtained prior to alcohol administration. To compute the changes in
cognitive measures,we subtracted the scores collected prior to those
obtained 80 min after alcohol. In consideration of the ‘‘multiple’’
N.D. Volkow et al. / NeuroImage 29 (2006) 295–301
correlations, we set the level of significance to P ? 0.01, and values
of P < 0.05 are reported as trends.
Plasma alcohol concentration, behavioral and cognitive effects
Plasma alcohol concentrations differed across doses (F = 32,
P < 0.001) and time of measurement (F = 16, P < 0.001) (Table
1). Peak alcohol plasma concentrations were achieved around 40
min after administration and were 32 T 12 mg % for the 0.25 g/kg
dose and 71 T 18 mg % for the 0.5 g/kg dose. These values
correspond to peak blood alcohol concentrations (plasma alcohol/
1.16) of 27 mg % and 61 mg % respectively.
Peak behavioral effects for both doses of alcohol occurred
around 40 min after alcohol administration (Fig. 1). Both doses
increased self-reports for intoxication (df 5,85, F = 14, P <
0.0001), high (F = 18, P < 0.0001) and sleepiness (F = 2.6, P <
0.05) but did not change self-reports of anxiety. Though overall the
effects of the 0.5 g/kg dose tended to be greater than those for the
0.25 g/kg dose, the differences were only significant for self-
reports of high (F = 2.8, P < 0.01) (Fig. 1). Alcohol effects on
cognitive performance were minimal and were not significant
(Table 2). The cognitive effects did not differ between doses.
Effects on brain glucose metabolism
Alcohol significantly decreased whole-brain glucose metabo-
lism (ANOVA, Drug effect, df 1,18; F = 27, P < 0.0001) (Fig. 2).
The magnitude of the decrease in brain glucose metabolism
differed between the doses (ANOVA, drug by dose interaction
effect, df 1,18; F = 5.7, P < 0.03). Reductions in whole-brain
glucose metabolism were significantly smaller for the 0.25 g/kg
dose (10 T 13%) than for the 0.5 g/kg dose (23 T 11%). The smaller
decrements in whole-brain glucose metabolism for the 0.25 g/kg
dose than for the 0.5 g/kg dose were due to the fact that, while the
0.5 g/kg dose decreased whole-brain glucose metabolism in all
subjects, the 0.25 g/kg decreased metabolism in some subjects but
not in others (Fig. 3).
Alcohol-induced decrements in glucose metabolism were not
homogeneous throughout the brain but differed among the 12
regions analyzed (ANOVA, region effect, df 1,11; F = 2.1; P <
0.05). The regional changes also differed between the doses
(ANOVA, region by dose interaction effect, df 1,11; F = 2.5, P <
0.007) (Fig. 4). The regional differences between doses appeared to
be accounted for mostly by the significantly smaller decrements in
subcortical regions and cerebellum for the 0.25 g/kg than for the
0.5 g/kg dose. The largest differences between the 0.25 and the 0.5
g/kg dose were in thalamus (5% versus 26% respectively),
mesencephalon (4% versus 24%) and cerebellum (7% versus
24%) (Fig. 4).
Correlation with behavioral measures
Correlations between metabolism and self-reports of drug
effects showed a trend for significance (P < 0.05) between the
‘‘high’’ and changes in mesencephalon. Correlations with intox-
ication and sleepiness were not significant.
These results do not discern a biphasic response to the effects
of alcohol on glucose metabolism in the human brain as has been
reported in rodents. In contrast, we show that relatively low doses
of alcohol, just as had been reported for larger doses of alcohol
(Wang et al., 2003), significantly decreased glucose metabolism
in the human brain. Indeed, the 0.25 g/kg dose, which is
equivalent to one drink for a 50 kg person, induced a 10%
reduction, and the 0.5 g/kg dose, equivalent to two drinks,
induced a 23% reduction in whole-brain metabolism. These
marked reductions in whole-brain metabolism are consistent with
prior studies showing whole-brain metabolic reductions of 26%
by 0.75 g/kg of alcohol (Volkow et al., 2000), 25% by 40 g iv
(approximately 0.6 g/kg iv) (Schreckenberger et al., 2004) and
18% by 1 g/kg (Volkow et al., 1990). However, they are
considerably larger than the 2.8% decreases in brain glucose
metabolism reported with 0.5 g/kg alcohol (de Wit et al., 1990).
The reason for the discrepancy with the study by De Wit et al. is
unclear and may reflect differences in the times at which the FDG
measurements were made, experimental conditions, PET scanners
and/or subject characteristics.
The 0.5 g/kg dose had significantly greater effects on whole-
brain and regional brain metabolism than the 0.25 g/kg dose. The
differences appeared to be accounted for mostly by the fact that the
0.5 g/kg dose of alcohol decreased metabolism in all subjects,
while the 0.25 g/kg dose decreased whole-brain metabolism in
some subjects but not in others. This corroborates the intersubject
variability previously reported for the effects of alcohol on brain
metabolism as well as on its behavioral effects (de Wit et al., 1990).
Since there was not a correlation between alcohol plasma
concentration and the magnitude of the brain metabolic decre-
ments, this suggests that the variability cannot be accounted solely
by differences in blood alcohol concentration (BAC).
The largest differences in metabolism between the doses were
in thalamus, mesencephalon and cerebellum, where the 0.25 g/kg
dose had no effect, whereas the 0.5 dose produced large
decrements in metabolism. The large decrements in metabolism
observed for the 0.5 g/kg dose (BAC 60 mg %) in thalamus, a brain
region in which drug-induced decrements in metabolism or
cerebral blood flow are associated with sedation (Volkow et al.,
1995; Fiset et al., 1999; Schlunzen et al., 2004), and in cerebellum,
a brain region involved with motor coordination (Miall et al.,
2001), could explain why the risks of being in a car crash for BAC
Plasma alcohol concentrations (mg %) for the subjects who received
0.25 g/kg and those that received 0.5 g/kg alcohol doses
Time (min) 0.25 g/kg Mean0.5 g/kg Mean
14 T 11
32 T 12
29 T 7
18 T 8
14 T 10
10 T 6
6 T 5
17 T 16
71 T 18
50 T 34
46 T 22
46 T 19
35 T 9
28 T 10
Values correspond to means and standard deviations.
N.D. Volkow et al. / NeuroImage 29 (2006) 295–301
in the 50–90 mg % range are so large, at least nine times greater
than for no alcohol in blood (Zador, 1991).
The reductions in whole-brain metabolism observed after
0.5 g/kg (23%) did not differ in magnitude from those we had
previously reported using the same experimental protocol and PET
instrument after 0.75 g/kg of alcohol (26%) (Volkow et al., 2000).
Furthermore, using a PET instrument with a much more limited
spatial resolution (PET VI camera) but the same experimental
protocol, we had reported that 1 g/kg reduced metabolism by 18%
(Volkow et al., 1990). These results would appear to indicate a
ceiling effect for the depressant effects of alcohol on glucose
metabolism in the human brain.
Our findings of decreases in metabolism after low, moderate
and high doses of alcohol differ from the results obtained by an
autoradiographic study in rodents (Williams-Hemby and Porrino,
1994), which reported regional increases in brain glucose
metabolism with 0.25 g/kg of alcohol, minimal effects with 0.5
g/kg and decreases with 1 g/kg. On the other hand, our findings in
humans are consistent with those of another autoradiographic study
done in low alcohol drinking (LAD) rats that reported decreases in
brain glucose metabolism both after a 0.25 g/kg and a 1 g/kg dose
of alcohol (Learn et al., 2003). However, in that study, the 0.25 g/
kg and 1 g/kg doses of alcohol had minimal effects in high alcohol
drinking (HAD) rats despite having equivalent BAC to those in
LAD. These discrepancies are therefore likely to reflect, in part,
differences in response to alcohol between strains. Other variables
known to influence the effects of alcohol on brain glucose
metabolism such as the timing of measurements after alcohol
(Lyons et al., 1998), past alcohol history of the animals (Porrino et
al., 1998), whether alcohol is self-administered versus given by the
investigator (Williams-Hemby et al., 1996) and dose and route of
administration (Williams-Hemby and Porrino, 1997) are also likely
to contribute to some of the discrepancies. In humans, imaging
studies have shown that alcohol-induced changes in brain glucose
metabolism are also sensitive to prior histories of chronic alcohol
use (Volkow et al., 1990) and to gender (Wang et al., 2003). In the
Fig. 1. Behavioral effects for the 0.25 g/kg and the 0.5 g/kg doses of alcohol. Measures correspond to mean and SE for the self-reports of drug effects,
which were scored from 0–10. The only difference between doses was for self-reports of ‘‘high’’, which were significantly higher for the 0.5 g/kg than for
the 0.25 g/kg alcohol dose (F = 2.8, P < 0.01).
Scores on neuropsychological tests obtained prior to and 80 and 140 min after initiation of alcohol intake
0.25 g/kg0.5 g/kg
Placebo ETOH 80 minETOH 140 minPlacebo ETOH 80 min ETOH 140 min
93 T 9
72 T 14
42 T 9
51 T 9
13 T 4
11 T 2
86 T 21
67 T 18
39 T 13
47 T 9
12 T 5
10 T 3
95 T 15
71 T 12
45 T 10
50 T 7
13 T 5
11 T 2
108 T 17
78 T 9
47 T 10
50 T 14
14 T 3
12 T 2
99 T 23
72 T 12
49 T 11
43 T 8
12 T 3
11 T 1
101 T 15
76 T 8
51 T 8
42 T 21
12 T 5
10 T 5
There were no differences in the scores before or after alcohol administration nor between subjects that received 0.25 g/kg and those that received 0.5 g/kg of
alcohol. Values correspond to means and standard deviations.
N.D. Volkow et al. / NeuroImage 29 (2006) 295–301
current study, we did not have a large enough sample to assess the
gender effects on the responses to alcohol.
Comparison with effects of sedative drugs and with anesthetics
by low doses of alcohol contrasts with its relatively mild behavioral
contrasts with the much smaller decrements in brain glucose
metabolism that we had previously reported in healthy controls
induced by the benzodiazepine drug lorazepam at doses that had
more pronounced behavioral and cognitive effects. Lorazepam (30
Ag/kg iv) decreased whole-brain glucose metabolism 13% and
induced marked sedation and disruption in the neuropsychological
measures for which alcohol, at the doses given in this study, did not
induce impairment (Volkow et al., 1993). However, despite the
modest decreases in cortical metabolism, lorazepam induced
relatively large decreases in thalamus (25% T 9), which were
associated with its sedative effects (Volkow et al., 1995).
On the other hand, the anesthetic agents, when given at doses
that produce anesthesia, induce larger whole-brain metabolic
decrements than those reported here for alcohol. The magnitude
of the decrements varies for the various anesthetics. At doses
titrated to induce participant unresponsiveness, halothane reduced
whole-brain glucose metabolism by 40% (Alkire et al., 1999),
isoflurane by 46% (Alkire et al., 1997) and propofol by 55%
(Alkire et al., 1995). Decrements in glucose metabolism by
halothane and isoflurane tend to be uniform throughout the brain,
whereas propofol appears to affect cortical metabolism to a greater
extent than subcortical metabolism.
Effects of alcohol on energy utilization
We were surprised by the large decrements in whole-brain
glucose metabolism, particularly with the 0.5 g/kg dose, which
induced muchlarger decrementsthanthose inducedbylorazepam at
a dose thatproduced greater sedation and cognitive impairment than
this dose of alcohol (Volkow et al., 1995). Moreover, in two of the
subjects in the current study, whole-brain glucose metabolism was
anesthetics that induce unconsciousness. Yet, these subjects were
alert and only moderately intoxicated. This leads us to question the
possibility that, during acute alcohol intoxication, there could be a
shift in substrate utilization by the brain. In fact, it has been
suggested that acetate, which serves as an energy substrate for
astrocytes (Cruz et al., 2005), could become available as an energy
Fig. 3. Individual values for percent changes in whole-brain glucose
metabolism after 0.25 g/kg and after 0.5 g/kg alcohol. Notice that while the
0.5 g/kg alcohol doses decreased metabolism in all subjects the response to
0.25 g/kg alcohol was quite variable.
Fig. 4. Regional changes in brain glucose metabolism expressed as percent
change from placebo. *Significant differences between doses. Values
correspond to means and SE.
Fig. 2. Images of brain glucose metabolism for a subject tested at baseline (placebo) and after 0.25 g/kg alcohol and for a subject tested at baseline and after
0.5 g/kg alcohol. Axial planes shown are at the thalamic and cerebellar levels.
N.D. Volkow et al. / NeuroImage 29 (2006) 295–301
substrate after alcohol administration (Waniewski and Martin,
1998). Acetate is readily taken up into the brain, crossing the
blood–brain barrier via the monocarboxylate transporter. Although
acetate concentration in blood is constitutively low (about 0.2 to 0.3
mM), it rises significantly during alcohol intoxication (Waniewski
and Martin, 1998). A single intravenous dose of 0.5 g/kg alcohol in
human results in acetate plasma levels of up to 1 mM (Orrego et al.,
1988). The use of acetate by the brain is reportedly limited by its
availability. Plasma acetate levels during intoxication (around 1
around 10–20% of total brain metabolic rate. This would require a
high Km for acetate utilization. Indeed, at least one paper
(Waniewski and Martin, 1998) reports a Km of 9 mM for acetate
transport by astrocytes that is consistent with this view.
A shift from glucose to acetate as an energy substrate during
alcohol intoxication could provide a potential explanation for our
previously reported, seemingly paradoxical finding showing greater
alcoholic subjects when compared with controls, despite not having
reduced behavioral, cognitive and motoric responses (Volkow et al.,
1990). Alcoholics have significantly higher blood acetate concen-
trations after acute alcohol than controls, which is an effect that
appears to reflect increased ethanol elimination (Nuutinen et al.,
1985). We reported a similar, though opposite, dissociation in
brain glucose metabolism after alcohol than males despite demon-
strating much greater levels of intoxication (Wang et al., 2003). This
would also be consistent with the significantly lower concentrations
of blood acetate after acute alcohol administration reported for
females when compared with males (Hannak et al., 1985).
If indeed there is an increase in brain acetate utilization as an
energy source during alcohol intoxication, this could also provide
an explanation of why alcohol increases cerebral blood flow even
though it decreases brain glucose metabolism (Newlin et al., 1982;
Mathew and Wilson, 1986; Volkow et al., 1988; Sano et al., 1993;
Schwartz et al., 1993; Tiihonen et al., 1994). Similarly, the
variability in the effects of alcohol on brain glucose metabolism
among strains of rodents and between human subjects could
reflect, in part, differences in the rate of metabolism of alcohol to
acetate or, alternatively, differences in the ability to utilize acetate
as a substrate for energy in brain. However, future studies are
required to determine if indeed there is an increase in brain acetate
metabolism as an energy source during alcohol intoxication.
This study evaluated the two alcohol doses in different groups
of subjects, so the dose effects are confounded by the variability in
responses to alcohol between subjects. Despite the intersubject
variability, significant dose effects, mostly in subcortical structures,
were revealed. However, studies done in the same subjects are
required to properly address dose effects.
Measures of brain metabolism were made mostly during the
influx phase of alcohol, but PET FDG studies have shown that the
regional metabolic effects differ between the influx and elimination
phases (Schreckenberger et al., 2004). Thus, these findings may
differ for the clearance phase.
Because of technical constraints imposed by the PET proce-
dure, the cognitive tests were only done at 80 min after initiation of
alcohol (just prior or FDG injection) and at 140 min (end of PET
scanning). Thus, while we cannot rule out the possibility that there
may have been some cognitive disruption during the early
ascending curve of the alcohol phase, the point is that at the time
when we observed the large brain metabolic decrements there was
no evidence of significant cognitive disruption.
Though we are speculating that the large decreases in whole-
brain metabolism could reflect metabolism of acetate as an
alternative energy source, we did not measure acetate concentration
in plasma, which could have allowed us to assess if indeed there
was an association with alcohol-induced decrements in brain
Furthermore, we do not have a detailed description of the
drinking histories from the subjects, and thus we could not
ascertain if the amount of alcohol intake affected the brain
metabolic decrements induced by alcohol.
metabolism in the human brain but instead showed decreases in
metabolism after low and moderated doses of alcohol. The apparent
paradoxical results between the large decrements in brain glucose
metabolism induced by alcohol at doses that induced minimal
cognitive impairment have led us to hypothesize that the large
decrements may reflect changes in substrate utilization by the brain
during alcohol intoxication (i.e. acetate). This possibility is relevant,
but also for the basic understanding of brain metabolism.
The authors gratefully acknowledge support from Department
of Energy (Office of Health and Environmental Research, contract
DE-AC01-76CH00016) and National Institutes of Health, NIAAA
(AA 09481). This research was also supported in part by the
Intramural Research Program of the NIH, National Institute on
Alcohol Abuse and Alcoholism. The authors also thank Karen
Apelskog, Cheryl Kassed, Payton King, Noelwah Netusil, Jean
Logan, David Schlyer, Colleen Shea and Donald Warner for advice
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