Acute Hydrocortisone Treatment Increases Anxiety but
Not Fear in Healthy Volunteers: A Fear-Potentiated
Christian Grillon, Randi Heller, Elizabeth Hirschhorn, Mitchel A. Kling, Daniel S. Pine, Jay Schulkin, and
Background: The debilitating effects of chronic glucocorticoids excess are well-known, but comparatively little is understood about the
role of acute cortisol. Indirect evidence in rodents suggests that acute cortisone could selectively increase some forms of long-duration
aversive states, such as “anxiety,” but not relatively similar, briefer aversive states, such as “fear.” However, no prior experimental studies in
humans consider the unique effects of cortisol on anxiety and fear, using well-validated methods for eliciting these two similar but
dissociable aversive states. The current study examines these effects, as instantiated with short- and long-duration threats.
Methods: Healthy volunteers (n ? 18) received placebo or a low (20 mg) or a high (60 mg) dose of hydrocortisone in a double-blind
crossover design. Subjects were exposed repeatedly to three 150-sec duration conditions: no shock; predictable shocks, in which shocks
were signaled by a short-duration threat cue; and unpredictable shocks. Aversive states were indexed by acoustic startle. Fear was
was operationally defined as the increase in baseline startle from the no shock to the two threat conditions (anxiety-potentiated startle).
Conclusions: These results suggest that hydrocortisone administration in humans selectively increases anxiety but not fear. Possible
corticotrophin-releasing hormones in the bed nucleus of the stria terminalis.
Key Words: Amygdala, anxiety, BNST, corticotropin-releasing hor-
mone (CRH), cortisol, fear, predictability, startle reflex
effects on brain function. Aversive and stressful events release cor-
tisol in humans (corticosterone in rodents) and evoke anxiety.
Acutely, cortisol restores homeostasis and enhances emotional
Less is known, however, about other psychological effects of corti-
sol in humans, specifically on aspects of emotional responding. A
key question is whether acute cortisol increases or decreases the
emotional response of humans to threat. This question is compli-
ally heterogeneous, reflecting involvement of distinct underlying
neural and psychopharmacology mechanisms. In the present
study, we argue for a functional differentiation between fear and
but not the former.
nderstanding the behavioral effects of glucocorticoids has
long been of paramount clinical importance, given their
role on the stress response and their potential debilitating
Prolonged exposure to glucocorticoids increases defensive re-
coids have been associated with both increased and decreased
exert differential, often poorly understood effects, on several brain
releasing hormone (CRH), which plays a pivotal role in stress and
anxiety. Glucocorticoids could relieve anxiety through negative
feedback on CRH released from the paraventricular nucleus of the
hypothalamus within the hypothalamic-pituitary-adrenal axis, re-
establishing homeostasis. Alternatively, glucocorticoids could af-
fect CRH in limbic areas (4,11,12), where CRH receptors affect anxi-
ety independently of hypothalamic-pituitary-adrenal axis (13). In
limbic structures, glucocorticoids sensitize rather than inhibit CRH
activity (reviewed in Schulkin et al. ). Glucocorticoid upregula-
tion of CRH messenger RNA expression has been documented in
the central nucleus of the amygdala (CeA) and bed nucleus of the
stria terminalis (BNST) (4,6,11,15,16), structures that have been as-
sociated with fear and anxiety, respectively (see following text). In
fact, not only chronic but also acute corticosterone can sensitize
aversive states in these structures (2,4,16), suggesting that gluco-
corticoids can enhance aversive states via action on limbic CRH.
and anxiety (operationally defined as aversive responses to short-
and long-duration threats, respectively) involve distinct brain re-
and BNST (17). Specifically, phasic fear-potentiated startle to a sig-
sustained forms of potentiated startle reflex (anxiety-potentiated
From the Mood and Anxiety Disorders Program (CG, RH, EH, DSP), National
land; Behavioral Health Service (MAK), Philadelphia Veterans Adminis-
roscience (JS), Georgetown University School of Medicine, Washington,
DC; and Psychological Health Strategic Operations (MV), Force Health
Protection and Readiness, Office of the Assistant Secretary of Defense,
Falls Church, Virginia.
Address correspondence to Christian Grillon, Ph.D., NIMH/MAP, 15K North
Drive, Building 15K, Room 203, MSC 2670, Bethesda, Maryland 20892-
2670; E-mail: Christian.firstname.lastname@example.org.
Received Aug 24, 2010; revised Dec 2, 2010; accepted Dec 4, 2010.
BIOL PSYCHIATRY 2011;xx:xxx
© 2011 Society of Biological Psychiatry
startle) to threatening contexts are mediated by projections from
the basolateral amygdala and lateral CeA to the BNST (17). Impor-
tantly, current models further indicate that CRH increases anxiety-
Indeed, infusion of CRH antagonist into the BNST blocks anxiety-
potentiated startle but leaves fear-potentiated startle unchanged,
in Davis ). These findings together with evidence of corticoste-
rone-mediated upregulation of CRH in the BNST (4,11,14,20) led us
to predict that cortisol would increase sustained anxiety states.
This hypothesis was tested in humans by studying the effect of
threat signals that predict a shock, whereas threatening contexts
refer to conditions where shocks are administered. In rodents, the
also be a long-duration unimodal stimulus (21). In humans, a con-
text can be a virtual space (22) or the sustained presentation of an
ambient light or screen color (23,24). Explicit threat cues evoke a
phasic fear response, because the associated threat is imminent
and of short-duration, whereas threatening contexts elicit sus-
in contexts associated with unpredictable compared with predict-
able shocks (22,25). We have developed a startle procedure to
examine short- and long-duration potentiated startle in response
are presented with three conditions, no shock (N), predictable
shocks (P), and unpredictable shocks (U). In P, shocks are signaled
time in U. A predictable shock evokes a robust increase in startle
reactivity during the explicit threat cue (fear-potentiated startle).
Both P and U elicit sustained levels of startle potentiation (anxiety-
potentiated startle), relative to N, with greater startle potentiation
during U compared with P (22,25). As a result, “baseline” startle
reactivity increases linearly from N to P to U (22,25). Clinical and
psychopharmacological studies relying on this procedure indicate
that fear-potentiated startle and anxiety-potentiated startle reflect
functionally distinct aversive states (27–29). Specifically, anxiety-
potentiated startle but not fear-potentiated startle is reduced by
anxiolytics (alprazolam and citalopram) (29,30) and is increased in
panic disorder and post-traumatic stress disorder (27,28). We ex-
pected hydrocortisone to enhance anxiety-potentiated startle but
not fear-potentiated startle, on the basis of the assumption that
tiated startle response.
Methods and Materials
Participants were paid healthy volunteers who gave written
informed consent approved by the National Institute of Mental
Health Human Investigation Review Board. Inclusion criteria in-
Clinical Interview for DSM-IV (31), 2) no history of a psychiatric
disorder in any first-degree relatives, 3) no medical condition that
interfered with the objectives of the study as established by a
as per history and confirmed by a negative urine screen. Partici-
pants met with a psychiatrist before providing consent. Twenty-
four subjects participated in the study, but 2 did not complete the
second session. The final group consisted of 22 subjects (15 male
subjects) with a mean age of 27.1 years (SD ? 4.3 years).
A double-blind crossover design was implemented, with each
subject being exposed to each treatment—placebo, 20 mg hydro-
ments were given as identical-appearing capsules 1 hour before
The procedure was similar to that of our previous psychophar-
macology studies examining responses to predictable and unpre-
dictable shocks (26–28). Subjects participated in three identical
testing sessions separated by 6–9 days. Subjects arrived at 8:30 AM
startle stimuli (habituation) were delivered every 18–25 sec to re-
duce initial startle reactivity. Afterward a shock workup procedure
hour later, the threat experiment was started. It consisted of three
150-sec conditions (Figure 1), a no shock condition (N), and two
conditions during which shocks were administered either predict-
ably (P) (i.e., only in the presence of a threat cue) or unpredictably
(U). In each condition, an 8-sec cue was presented four times. The
cues consisted of differently colored geometric shapes for the dif-
ferent conditions (e.g., blue square for N, red circle for P, green
had no signal value in the N and U conditions.
Participants received precise instructions with regard to risk of
shock in each condition, including the contingency between
shocks and cues in P and U. To minimize involvement of memory
ing the following information: “no shock” (N), “shock only during
shape” (P), or “shock at any time” (U). In each N, P, and U condition,
six acoustic startle stimuli were delivered: 1) three during intertrial
at 53–96 sec, and a third at 97–140 sec after the beginning of a
The threat experiment consisted of two series with a 5–10 min
rest between series. Each series started with the delivery of four
Table 1. Procedure: Timeline
Time (min) Events
Spielberger state anxiety 1
Salivary Sample 1
Salivary Sample 2
Nine startle (habituation)
Spielberger state anxiety 2
Retrospective anxiety rating 1
Spielberger state anxiety 3
Salivary sample 3
Retrospective anxiety rating 2
Spielberger state anxiety 4
Salivary sample 4
Salivary sample 5
2 BIOL PSYCHIATRY 2011;xx:xxx
C. Grillon et al.
N U. Each participant received both orders, with one-half of the
participants starting with P and the other one-half starting with U.
One shock was administered in each individual P and U condition
for a total of four shocks in P and four shocks in U. In each P, the
shock was randomly associated with one of the four threat cues,
being administered 7.5 sec after the onset of that cue. The shock
was given either 7 or 10 sec after the termination of a cue in the
unpredictable condition. No startle stimuli followed a shock by ?
The Spielberger state portion of the State–Trait Anxiety Inven-
tory questionnaire (32) was administered four times: 1) just after
arrival of the subjects (predrug), 2) before the first threat series
threat series. In addition, after each series, subjects retrospectively
rated their anxiety level in the presence and absence of the cue in
all anxious) to 10 (extremely anxious). Immediately after the last
of shock pain experienced during testing on an analogue scale
ranging from 0 (not at all painful) to 10 (extremely painful).
Five salivary samples were taken to assess cortisol changes dur-
3) just after the first threat period, 4) just after the second threat
period, and finally 5) 25 min later.
Stimuli and Physiological Responses
Stimulation and recording were controlled by a commercial
system (Contact Precision Instruments, London, England). The
presented through headphones. The eyeblink reflex was recorded
with electrodes placed under the left eye. The electromyographic
at a rate of 1000 Hz. The shock was administered on the left wrist.
Saliva was collected in non-coated Salivettes (Sarstedt, Nüm-
by a solid-phase radioimmunoassay with a commercially available
Coat-A Count Cortisol RIA kit (Siemens Medical Solutions Diagnos-
assay coefficients of variation were below 10%.
The electromyographic eyeblink was rectified and smoothed
reflex was determined in the 20–100-msec time frame after stimu-
lus onset relative to a 50-msec pre-stimulus baseline and averaged
within each condition, after which they were standardized into T
scores on the basis of data across sessions within each participant.
ITI to the threat cue in the P condition. Anxiety-potentiated startle
was defined as the increase in ITI startle reactivity from N to P and
Greenhouse-Geisser corrections (GG-?) were used for main effects
and interactions involving factors with more than two levels.
stimuli during startle habituation; the mean startle magnitude of
Figure 1. Schematic of the experiment. There were three conditions: no
shock (N), predictable shock (P), and unpredictable shock (U). Each subject
was presented with two series, each including three N, two P, and two U in
condition contained four 8-sec cues of different colors and geometric
shapes (for illustration purposes, the cues are squares in N, circles in P, and
triangles in U). In each P condition, a shock (indicated by Œ) was randomly
its onset. In each U condition, a shock was administered randomly in the
absence of the cues. In the N condition, no shock was administered. Startle
stimuli (indicated by 1) were delivered in the presence and in the absence
of the cue (i.e., during intertrial intervals).
Table 2. Mean Startle Magnitude Before and After Treatment at Baseline and During Cue and ITI
PosttreatmentITICue ITICueITI Cue
Hydrocortisone (20 mg)
Hydrocortisone (60 mg)
Hydrocortisone (20 mg)
Hydrocortisone (60 mg)
Mean (SEM) startle magnitude (?V). ITI, intertrial interval; Hab, habituation.
C. Grillon et al.
BIOL PSYCHIATRY 2011;xx:xxx 3
the four startle stimuli preceding the first threat block (prethreat
no-shock, predictable, and unpredictable conditions.
Baseline Startle. Data for one subject during startle habitua-
tion are not included in this analysis, due to technical difficulties.
Baseline startle (Table 2) was not affected by hydrocortisone. A
Drug (placebo, hydrocortisone/low, hydrocortisone/high) ? Time
magnitude scores revealed a Time effect [F(1,20) ? 4.4, p ? .05],
reflecting increased startle during prethreat (i.e., after treatment)
effect possibly reflected anticipatory anxiety before the threat ex-
significant (all p ? .1), suggesting that cortisol did not affect base-
Cued Fear-Potentiated Startle. To examine fear-potentiated
startle, startle magnitudes during ITI and during the cue in N and P
across treatments were analyzed with a Stimulus Type (cue, ITI) ?
Condition (N, P) ? Drug (3) ANOVA. As expected, there was a Stim-
ulus Type ? Condition interaction [F(1,21) ? 99.1, p ? .00009],
reflecting larger startle during the cue relative to ITI in P compared
with N. This interaction was not affected by hydrocortisone [non-
significant Stimulus Type ? Condition interaction ? Drug interac-
tion, F(2,42) ? 2.0, p ? ns, GG-? ? .98]. An analysis restricted to P
(Figure 2) confirmed the lack of effect of hydrocortisone on cued
fear-potentiated startle [Drug: F(2,42) ? .6, p ? ns, GG-? ? .95],
including when the analysis was restricted to the high hydrocorti-
sone dose [F(1,21) ? .3, p ? ns]. Similar results were obtained with
the raw scores (Supplement 1).
P, U) ANOVA. As expected (30), startle magnitude during ITI in-
3, Table 2), resulting in a condition linear trend [F(1,21) ? 87.0, p ?
.0001]. This increase was differentially affected by hydrocortisone
and placebo, as reflected by a significant Drug ? Condition linear
trend [F(1,21) ? 4.2, p ? .05]. To clarify this interaction, follow-up
tests compared each active treatment with placebo. The high
ns, GG-? ? .75] dose of hydrocortisone increased startle potentia-
tion. The high dose of hydrocortisone increased anxiety-potenti-
ated startle in both P [F(1,21) ? 6.1, p ? .02] and U [F(1,21) ? 4.2,
Anxiety over Time
Fear and anxiety were operationally defined by their duration
(i.e., short- vs. long-duration). However, what constitutes “short”
sec after the onset of threat cues in P. Was hydrocortisone also
and U conditions? We did not test anxiety-potentiated startle 4–7
(97–140 sec) in P and U (see Methods and Materials). In a post hoc
analysis, we investigated whether the high dose of hydrocortisone
enhanced anxiety to the same degree throughout P and U or
whether startle potentiation was insensitive to hydrocortisone ef-
fect at the earliest time. The placebo and high hydrocortisone data
were reanalyzed, taking into account the time of startle delivery
during each condition. To reduce the variability of startle magni-
tude and because there were no differences in the effect of hydro-
cortisone on anxiety in P and U, we averaged these two conditions
together. The data were then analyzed with a Drug (placebo, high
hydrocortisone) ? Condition (N, mean of P and U) ? Time (early,
middle, late) ANOVA. Figure 4 shows that the hydrocortisone-in-
duced enhancement of startle magnitude in P/U compared with N
did not differ across the three time points, suggesting that hydro-
cortisone increased potentiated startle as early as 15–50 sec after
the onset of N and U. This was confirmed statistically; the
Condition ? Drug interaction was significant [(F(1,21) ? 7.0, p ?
.02], but the Condition ? Drug ? Time interaction was not
[(F(2,42) ? .6, p ? .5, GG-? ? .91].
Subjective Anxiety, State Anxiety, and Pain
the pain measures were not significantly affected by hydrocorti-
sone (Supplement 1).
Figure 2. Startle magnitude to the threat cue and during intertrial interval
(ITI) in the predictable shock condition. Fear-potentiated startle, the in-
creased startle magnitude from ITI to the threat cue, was not affected by
Figure 3. Startle magnitude during ITI in the N, P, and U conditions in each
treatment. Anxiety-potentiated startle in P and U is the increased startle
magnitude from the N to the P and from the N to the U condition, respec-
cortisone in the P and U conditions.*Significant (p ? .05) effect. Abbrevia-
tions as in Figures 1 and 2.
4 BIOL PSYCHIATRY 2011;xx:xxx
C. Grillon et al.
As expected, hydrocortisone increased cortisol levels dose-de-
? 86.7, p ? .0001, GG-? ? .34] and Time [F(4,84) ? 46.6, p ? .0001,
GG-? ? .34] as well as a Drug ? Time interaction [F(8,168) ? 35.0,
p ? .0001, GG-? ? .34]. The interaction reflected increased cortisol
levels after cortisol administration (high hydrocortisone ? low hy-
drocortisone ? placebo; all p ? .0009).
corticoids are anxiogenic in animals (2–5,14,16), much remains to
is whether cortisol sensitizes anxiety or is involved in its termina-
tion. The present results indicate that cortisol increases anxiety.
Specifically, we examined the effect of acute hydrocortisone treat-
ment on two types of potentiated startle responses, fear-potenti-
ated startle evoked by a short-duration threat cue and anxiety-
potentiated startle associated with longer-duration contextual
threat. Results showed that the high dose of hydrocortisone (60
mg) increased anxiety-potentiated startle without affecting fear-
sive states are consistent with the observation that increased en-
dogenous cortisol levels are associated with negative affect and
of cortisol on potentiated startle.
That glucocorticoids are anxiogenic is also in line with findings
that blockade of glucocorticoid synthesis reduces anxiety in hu-
mans. Indeed, the preclinical finding that inhibition of steroid syn-
thesis reduces both corticosterone levels and anxiety in rats ex-
humans. The effect of the cortisol synthesis inhibitor metyrapone
was evaluated in patients with panic disorders. In one study, me-
tyrapone nonsignificantly reduced anxiety symptoms in the
healthy comparison group (36). In another study, which used a
panicogenic carbon dioxide challenge, metyrapone modestly re-
duced anxiety during the period that preceded the panicogenic
challenge in the patients without affecting the panic symptoms to
the challenge itself, suggesting a differential effect of cortisol on
fear and generalized anxiety symptoms (37). These results are con-
sistent with the present findings that hydrocortisone increased
anxiety but not fear.
These findings point to an anxiogenic effect of hydrocortisone,
but contradictory results have been reported. Hydrocortisone de-
creases negative mood (38,39), but null effect (40,41) as well as
increased negative mood (7,42–44) have also been found. One
possibility is that hydrocortisone lessens negative mood during
(38,39). A relatively low dose of hydrocortisone (30 mg) affects fear
conditioning, decreasing it in male subjects and increasing it in
trend for a gender effect on anxiety responses. It is possible that
hydrocortisone did not affect the expression of fear per se in these
conditioning studies but influenced any of the multitudes of pro-
cesses involved in conditioning, such as attention, learning, and
memory. This latter interpretation is consistent with findings that
of post-traumatic stress disorder (9,48)—not by alleviating the ex-
pression of fear per se but by preventing the retrieval of “vivid and
fear and anxiety by interfering with emotional memory processes,
such a reduction would not be expected in our study because fear
and anxiety induction did not rely on memory. Indeed, the study
was explicitly designed to examine the expression of fear and anx-
iety as opposed to aversive learning and memory; each safe and
is thus possible that cortisol affects multiple emotional processes;
cortisol might both impair emotional memory retrieval and in-
at low doses, and the latter one being more likely at high doses.
What are the potential mechanisms for the cortisol-induced
increase in anxiety-potentiated startle? The present study was
based on the premise (see introductory text) that: 1) anxiety is
mediated by activation of CRH receptors in the BNST (17), and 2)
cortisol increases extrahypothalamic CRH (16). Cortisol and CRH
might have worked together to enhance anxiety, cortisol potenti-
by findings that corticosterone administered in the BNST increases
anxiety-like behaviors in the rat (16). Accordingly, the failure of
late phase of each condition. Startle magnitude during the predictable and
unpredictable conditions were averaged together to reduce variability.
Table 3. Mean Cortisol Before and After Administration
Postdrug After 1st
Postdrug After 2nd
Hydrocortisone (20 mg)
Hydrocortisone (60 mg)
Mean (SEM) cortisol (ng/mL).
C. Grillon et al.
BIOL PSYCHIATRY 2011;xx:xxx 5
not affected by CRH (19).
An alternative possibility is that cortisol influenced brain areas
involved in the processing of contextual cues, as opposed to ex-
receptors and is essential for contextual processing, this structure
found a selective effect of corticosterone on cue and context con-
ditioning in rodents, possibly due to increased cortisol-induced
excitability of the hippocampus (49). A better comprehension of
this steroid hormone on various constituents of aversive states.
Little is known about the effect of cortisol on startle in humans.
Consistent with our results, past studies showed no significant
modulation of baseline startle of 4 days of prednisone treatment
(160 mg/day) (50) or acute treatment with cortisol (5 mg, 20 mg)
compared with placebo (40). These two studies also showed no
effect of cortisol on the modulation of startle by affective picture.
mildly aversive stimuli but increases the potentiation of startle to
more evocative and long-lasting threats.
The present results need to be interpreted in the context of its
strengths and limitations. The main strength of this study is its
reliance on a robust translational approach with a well-developed
and well-proven procedure. One limitation is the relatively small
sample size. However, this sample size is similar to or greater than
that of our previous psychopharmacological studies (29,30,51). In
addition, we used a within-subjects design, which improves statis-
tical power. Another limitation was that the effect of hydrocorti-
sone on potentiated startle was not found with the subjective anx-
iety data. Reports of dissociation between objective measures and
subjective reports are frequent in drug studies (51–53). The most
used to probe anxiety online, whereas the subjective anxiety mea-
sures were retrospective. Subtle differences in responding might
the design. Finally, it is highly likely that startle potentiation and
subjective reports reflect the influence of different structures, sub-
jective report being more cortically mediated than startle.
This study found that acute hydrocortisone increased anxiety
without affecting fear. These results raise concerns as to the use of
cortisol to treat anxiety (9,54). Cortisol might reduce fear by inter-
fering with retrieval of emotional memory (9), but it might also
animal studies that activation of CRH receptors in the BNST medi-
therefore be due to a potentiation of CRH activity in the BNST by
cortisol. This hypothesis, however, cannot be tested in humans. A
nature. Future studies in animals should examine the role of acute
glucocorticoids in sustained anxiety states and, more particularly,
whether any effect is dependent on CRH activity.
This research was supported by the Intramural Research Program
The author(s) declare that, except for income received from the
primary employer, no financial support or compensation has been
received from any individual or corporate entity over the past 3 years
interest. Dr. Pine has received compensation for activities related to
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