British Journal of Anaesthesia 115 (1): 68–75 (2015)

doi: 10.1093/bja/aev135
Advance Access Publication Date 16 May 2015
Clinical Practice

Effect of subanaesthetic ketamine on plasma

and saliva cortisol secretion

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N. Khalili-Mahani†, C. H. Martini, E. Olofsen, A. Dahan*, and M. Niesters
Department of Anesthesiology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands
*Corresponding author. E-mail: a.dahan@lumc.nl

Abstract
Background: The commonality between chronic conditions that are treated with low-dose ketamine, such as specific chronic
pain conditions, depression, and post-traumatic stress disorder, can be found in relation to the stress system, particularly the
hypothalamus–pituitary–adrenal axis. In this study we assess the effect of ketamine on the stress system by measuring plasma
and saliva cortisol production during and following exposure to low-dose ketamine.
Methods: In a double-blind, randomized, placebo-controlled study, the influence of subanaesthetic ketamine (0.29 mg kg−1 h−1
for 1 h, followed by 0.57 mg kg−1 h−1 for another hour) was studied with repeated plasma and saliva cortisol samples in 12
healthy male volunteers. A pharmacokinetic–pharmacodynamic model was used to describe the circadian rhythm–dependent
ketamine-induced production of cortisol.
Results: The endogenous mean baseline cortisol production was 7.9 ( 1.5) nM min−1. Consistent with the circadian rhythm,
cortisol production decayed by 1.25 nM min−1 h−1. Ketamine doubled the cortisol production at a concentration of 165 ( 35) ng
ml−1. The salivary cortisol concentration closely mirrored the plasma concentration and was exponentially related to the
plasma concentration with, at 100 ng ml−1 ketamine, a saliva:plasma ratio of 0.036 ( 0.006).
Conclusions: Ketamine has an appreciable effect on cortisol production. This may impact on critical physiological and
psychological functions.
Clinical trial registration: This study was registered in the Dutch Trial Register under number NTR2717 at www.trialregister.nl.

Key words: cortisol; HPA axis; ketamine; pharmacodynamics; pharmacokinetics; stress

Since its introduction into clinical practice in the early 1960s, the
use of ketamine has progressed from an anaesthetic induction
agent to a more versatile drug commonly used in the treatment
of acute and chronic pain, therapy-resistant major depression, mi-
graine, and post-traumatic stress disorder (PTSD).1–5 Antagonism
of the N-methyl-D-aspartate receptor (NMDA), an excitatory recep-
tor ubiquitously present in the central nervous system, is believed
to be ketamine’s major mechanism of action in the modulation of
chronic pain and associated disorders.1 An interesting observation
is that the commonality between chronic conditions that are trea-
ted with ketamine can be found in relation to the stress system,
more specifically the hypothalamus–pituitary–adrenal (HPA) axis,
which regulates the neuroendocrine system. HPA axis function is
primarily characterized by the synthesis and release of the steroid
hormone cortisol. Dysregulation of HPA axis function, marked by
abnormal (increased or decreased) cortisol responses to stress, is
demonstrated in various chronic pain conditions, as well as
depression and PTSD.6–8
Although the relation between ketamine and HPA axis func-
tion has been studied in animals and humans with often
ambiguous results (either finding an increased production or a
blunted cortisol response),9–14 less is known about the effect of

† Current affiliation: PERFORM Centre, Concordia University, Montreal, QC, Canada and Montreal Neurological Institute, McGill University, Montreal, QC,
Canada.
Accepted: April 3, 2015
© The Author 2015. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved.
For Permissions, please email: journals.permissions@oup.com

68

Editor’s key points
• Low-dose ketamine is commonly used to treat distressing
states such as pain and depression.
• It is unclear whether changes in stress hormone concentra-
tions are beneficial or harmful in pain and depression.
• This study found that even at low doses, ketamine doubles
cortisol production.
ketamine on the stress system at the low doses used for treat-
ment of depression, pain, and PTSD. We therefore developed
pharmacokinetic–pharmacodynamic (PKPD) models to estimate
the influence of low-dose ketamine on HPA axis function. Fur-
thermore, since less invasive sampling of cortisol from saliva
(compared with plasma cortisol) is a preferable method to test
the stress system, it was considered important to extend the
PKPD models using saliva cortisol sampling. This study is a first
step in quantifying the complex interaction of ketamine and
the increase in cortisol it causes on stress-related disorders (in-
cluding chronic pain).
Methods
−2
Twelve healthy male volunteers (ages 19–36 yr; BMI 21–27 kg m )
were recruited to participate in the study after approval of the
protocol was obtained from the Leiden University Medical Centre
ethics committee. Oral and written informed consent was ob-
tained from all participants. Exclusion criteria for enrolment in-
cluded medical disease (such as renal, liver, cardiac, or vascular
disease, including hypertension), presence or history of a neuro-
logic or psychiatric disease (e.g. increased cranial pressure, epi-
lepsy, psychosis), glaucoma, obesity (BMI >30 kg m−2), history of
chronic alcohol or drug abuse, or use of any centrally acting
medication. This study is part of a larger project on the effect of
ketamine on brain function and was registered in the Dutch Trial
Register (number NTR2717).15 In the current report we focus on
the cortisol response to low-dose ketamine administration. The
study was performed from May to July 2011.
Study design
In this single-blind, randomized, placebo-controlled crossover
study, subjects were examined on two occasions at least 1 week
apart. Subjects received S+-ketamine (Ketanest-S, Eurocept, An-
keveen, The Netherlands) on one occasion and placebo (NaCl
0.9%) on the other. No details regarding treatment effects were
given apart from the possibility of experiencing a drug ‘high’ dur-
ing treatment. To control for circadian effects, all subjects were
asked to arrive in the laboratory around 8:30 . Two intravenous
lines were inserted, one for blood sampling and one for adminis-
tration of ketamine. Drug infusion with either S+-ketamine or pla-
cebo was started at t=0 (at 10 ±10 min) at a low dose, 20 mg h−1
(70 kg)−1, for 1 h, followed by a high dose, 40 mg h−1 (70 kg)−1, for an-
other hour. These doses are based on the average S+-ketamine in-
fusion rates required to produce long-term relief of chronic pain.16
Ketamine and cortisol sampling
Venous blood was drawn to determine the plasma concentration
of ketamine (and its metabolite norketamine) and cortisol. Corti-
sol was measured from both saliva ( passive drool providing at
least 1 ml of saliva) and plasma in order to examine the sensitiv-
ity of each variable to our experimental condition. Cortisol
Ketamine’s effect on cortisol production | 69
samples were obtained before, during, and after ketamine infu-
sion. Plasma samples were obtained at t=0 (baseline), 15, 30, 60,
75, 90, 120, 130, 160, and 200 min following the start of ketamine
infusion; saliva samples were obtained at t=−30 (baseline 1), 0
(baseline 2), 60, 90, 120, 170, and 200 min.
All blood samples were centrifuged at 3500 rpm for 10 min
within 15 min of collection. Plasma was then stored at −25°C
for later analysis. Saliva was collected in 2 ml SaliCaps (IBL,
Hamburg, Germany) and centrifuged at 3000 rpm for 5 min,
which resulted in a clear supernatant of low viscosity, and was
stored at −25°C for later analysis. Plasma ketamine was measured
using high-performance liquid chromatography.17 The assay had
a coefficient of variation of 5.66% and 2.49% at concentrations
of 192 and 936 μM, respectively. Plasma cortisol was measured
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by electrochemiluminescence immunoassay (Roche Diagnostics,
Mannheim, Germany) using an Elecsys 2010 immunoanalyzer
(Roche Diagnostics).18 The assay had a coefficient of variation
of 1.3% and 1.1% at 208 and 1268 nM, respectively. Salivary con-
centrations were measured using a luminescence-enhanced en-
zyme immunoassay (IBL International, Hamburg, Germany).19
The intra- and interassay coefficients of variation were both <8%.
Data analysis
The PKPD model consisted of a ketamine PK component
coupled to a second part that describes the production and
elimination of cortisol (in which the endogenous production
of cortisol is made dependent on time to describe the circadian
effect on cortisol production) using the following indirect re-
sponse model20:
 
dCCp ðtÞ CKETðtÞ
¼ kIN  1  α  t þ  kOUT  CCp ðtÞ;
dt C100
where CKET is the ketamine concentration in plasma, CCp is the
cortisol concentration in plasma, C100 is the plasma ketamine
concentration that doubles kIN, kIN is the endogenous plasma
cortisol production rate at t=0 ( just before any ketamine/pla-
cebo infusion), and kOUT is the cortisol elimination rate. Cortisol
production in the body follows a periodic pattern consisting of
ultradian oscillations (20–120 min periods) and a circadian os-
cillation (with a period of 24 h) that can be described with com-
plex mathematical models.21–26 Such modelling approaches
depend on a sufficient rate of sampling over a longer period of
time. Our study took place over 3 h, with sparse sampling start-
ing 1 h after the start of infusion followed by half-hour (or long-
er) intervals. According to diurnal circulation patterns, the
highest level of cortisol is expected in the early morning, with
a significant increase at the time of awakening and gradual
decay starting a half-hour after awakening.27 Since we sampled
cortisol for 3 h, we modelled the cortisol decay with a linear
function (α·t).
The saliva cortisol concentration (CCs) was related to CCp using
an exponential function:
CCs ¼CCp  expðλþβ  CCp Þ
where λ and β are coefficients.
The population PK analysis was performed using the statistic-
al software package NONMEM (version 7.3.0; Icon Development
Solutions, Hanover, MD, USA).28 Plasma ketamine, plasma corti-
sol, and saliva cortisol were modelled simultaneously. For keta-
mine, one- and two-compartment models were tested; for
cortisol, a delay between plasma and saliva compartments was
70 | Khalili-Mahani et al.

tested as well as a linear function to describe the transition from Results

plasma to saliva. The concentration data were log transformed
All participants completed the study without major side effects.
and an additive model was used for residual error. The final
During exposure to ketamine, most subjects experienced feeling
model structure was based on the minimum objective function
a ‘drug high’, which increased in severity during the course of the
value with statistical significance set at P-values <0.01. All NON-
ketamine infusion. In Figure 1 the plasma ketamine concentra-
MEM output values are typical value ().
tion during and following infusion are given. The mean peak
plasma ketamine concentrations at the end of the first and se-
Standardized visual predictive check (SVPC) cond infusion hour were 74.9 ( 15.6) and 187.5 ( 32.8) ng
SVPCs were performed for ketamine, plasma cortisol, and saliva ml−1, respectively. The mean plasma and saliva cortisol levels
cortisol concentrations to evaluate the performance of the in placebo and ketamine sessions are given in Figure 1 and .
model. The SVPC gives the percentile of the observations of For both plasma and saliva cortisol concentrations, the change
each subject in the marginal distribution of the corresponding over time during and following placebo treatment is indicative
data simulations (ketamine or cortisol concentrations) as a func- of the circadian changes in cortisol production. The cortisol plas-

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tion of time.29 ma concentration peaked at the end of the ketamine infusion
(t=120 min), to 530 ( 145) nM, a concentration twice as high as

Ketamine concentration
A 200
Ketamine conc. (ng/mL)

150

100

50

0
–30 0 30 60 90 120 150 180 210
Time (min)

B Plasma cortisol concentration C Saliva cortisol concentration

400 P<0.0001 40 P<0.0001

DCortisol (nM)

DCortisol (nM)

200
20

0
0

600
Cortisol conc. (nM)

40
Cortisol conc. (nM)

30
400
20

10
200
0
–30 0 30 60 90 120 150 180 210 –30 0 30 60 90 120 150 180 210
Time (min) Time (min)

Fig 1 () Mean ketamine concentrations during and following i.v. infusion of 0.29 mg kg−1 h−1 for 1 h and 0.57 mg kg−1 h−1 for 1 h (green lines). () Mean plasma cortisol
concentrations in the ketamine (closed symbols) and placebo (open symbols) sessions and the difference in cortisol concentration between the ketamine and
placebo sessions (half open symbols). () Mean salivary cortisol concentrations in the ketamine (closed symbols) and placebo (open symbols) sessions and the
difference in cortisol concentration between the ketamine and placebo sessions (half open symbols).
 Ketamine’s effect on cortisol production | 71

Hypothalamus

CRH
Ketamine
infusion Anterior CCP CCS
pituitary

ACTH
V1 Adrenal plasma saliva
cortex kIN kOUT

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Cortisol

CL

Fig 2 Pharmacokinetic–pharmacodynamic model describing the production of plasma and salivary cortisol by ketamine. V1 is the volume of the single ketamine
compartment, CL is the ketamine clearance, kIN is the endogenous production of cortisol, which is under the influence of the circadian rhythm (clock) and ketamine,
CCp and CCs are the plasma and salivary cortisol concentrations, and kOUT is the cortisol elimination rate.

A Ketamine B Placebo
800 800
Plasma cortisol conc. (nM)

Plasma cortisol conc. (nM)

600 600

400 400

200 200

0 0
0 60 120 180 0 60 120 180
Time (min) Time (min)

C Ketamine D Placebo
60 60
Saliva cortisol conc. (nM)

Saliva cortisol conc. (nM)

40 40

20 20

0 0
0 60 120 180 0 60 120 180
Time (min) Time (min)

Fig 3 Individual plasma and salivary cortisol levels, individual (blue) and population data fits ( pink) for () plasma cortisol/ketamine treatment, () plasma
cortisol/placebo treatment, () salivary cortisol/ketamine treatment, and () salivary cortisol/placebo treatment.
72 | Khalili-Mahani et al.
that observed at the end of the placebo infusion [229 ( 135) nM].
Saliva cortisol peaked at t=170 min, 50 min after ending the keta-
mine infusion, to 35 ( 24) nM, about five times the concentra-
tion observed after placebo infusion at t=170 min.
The final PKPD model is presented in Figure 2 and consists of
one ketamine compartment and two cortisol compartments
( plasma and saliva), without any delay between the cortisol
compartments. Individual cortisol measurements, individual
data fits and population data fits are given in Figure 3 for both
plasma and saliva cortisol concentrations during and following
ketamine or placebo treatment; goodness of fit plots are shown
in Figure 4–. The estimated model parameters are collected
in Table 1. The endogenous cortisol production rate (i.e. without
the effect of ketamine; kIN) was estimated to be 7.88 nM min−1 at
t=0 (10  actual time) with an estimated baseline concentration
of 329 nM (kIN/kOUT). Due to the circadian effect, the cortisol pro-
duction decayed by 1.26 nM min−1 h−1 causing a decrease in cor-
tisol production to 4.11 nM min−1 at t=3 h (1 ).
Ketamine doubled the cortisol production at an effect-site
concentration of 165 ng ml−1. At that ketamine concentration,
the cortisol production increased to 15.8 nM min−1 at 10 .
Due to the circadian effect on cortisol release, the absolute keta-
mine effect will differ at other time points. For example, when the
subject is exposed to 165 ng ml−1 ketamine at 1  the cortisol
production will increase from 4.1 to 8.2 nM min−1.
The exponential function describing the relation between sal-
iva and plasma cortisol levels yielded significantly better data fits
compared with the tested linear function (P<0.01). Parameter es-
timates of the exponential function are given in Table 1. To get an
A Ketamine B Plasma cortisol
1000
Measured conc. (ng/mL)
Measured conc. (ng/mL)
100
100
10
10 100
Ind. predicted conc. (ng/mL) Ind. predicted conc. (ng/mL)
D SVPC Ketamine E SVPC cortisol
1.0
0.5
P
0.0
0 30 60 90 120 150 180 210
Time (min)
Fig 4 (–) Goodness of fit plots, measured vs individual predicted concentrations for () ketamine, () plasma cortisol, and () salivary cortisol. ( and ) Standardized
visual predictive checks for ketamine and cortisol ( plasma and saliva) concentrations. The broken lines represent the 2.5 and 97.5% confidence limits. For ketamine
and cortisol, 95% of the data lies within the 95% CIs. P is probability.
indication of the cortisol saliva:plasma ratio, we performed a
Monte Carlo simulation using equation 2 and the estimates of λ
and β with their s. The ratio is 0.036 ( 0.006) at 100 ng ml−1 ke-
tamine. This indicates that just a small but readily detectable
amount of cortisol is present in saliva that closely follows the
plasma concentration.
In Figure 4 and , the results of the SVPC are given. The accur-
acy of the PKPD model was acceptable with 95% of the ketamine
(Fig. 4), saliva cortisol, and plasma cortisol (Fig. 4) data points
within the 2.5 to 97.5 percentiles.
Discussion
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Cortisol is a stress biomarker that probably affects every system
in the human body (e.g. metabolism, immune response, brain
function). 30 Cortisol production displays a typical diurnal
rhythm (consisting of ultradian 20–120 min oscillations and a
circadian 24 h pattern), with a peak concentration in the morn-
ing hours (8–10 ; with peak plasma values ranging from 170
to 500 nM and peak saliva values <24 nM) and a valley in the
late afternoon/early evening (4–8 ; with peak plasma values
ranging from 60 to 300 nM and peak saliva values <12 nM). 27
Our study protocol standardized circadian effects by setting
the ketamine infusion time at 10 , giving the subjects 90
min to recover from early morning and potentially stress-
related variations upon arrival at 8:15–8:30 . We observed
cortisol values at baseline (t=−30 min) were in the range of
12–24 nM (saliva) and 315–407 nM ( plasma), in close agreement
with values reported in the literature.27
C Saliva cortisol
Measured conc. (ng/mL)
100
10
1
100 1000 1 10 100
Ind. predicted conc. (ng/mL)
1.0
Plasma cortisol Ketamine
Plasma cortisol Placebo
Saliva cortisol Ketamine
Saliva cortisol Placebo
0.5
0.0
–30 0 30 60 90 120 150 180 210
Time (min)
 Ketamine’s effect on cortisol production | 73

Table 1 Pharmacokinetic–pharmacodynamic model parameter estimates. ω2 is the between-subjects variability (in the log domain); %CV is
the coefficient of variation; V1 is volume of the ketamine compartment; C100 is the concentration of ketamine causing a twofold increase in
kIN; kIN is the endogenous plasma cortisol production rate at t=0 ( just before any ketamine/placebo infusion); kOUT is the cortisol elimination
rat; α is slope of the linear function that describes the circadian release of cortisol over the short duration of the study; λ and β are coefficients
of the exponential relationship between plasma and salivary cortisol; σ2 is the variance of the residual error (in the log domain); IOC is the
interoccasion variability (i.e. between ketamine and placebo treatments), and CCp and CCs are the cortisol plasma and salivary
concentrations, respectively. *Not included in the statistical model.

Typical value () ω2 () [%CV]

Ketamine
V1 (litre) 196 (10) 0.02 (0.01) [12]
Clearance (litre min−1) 2.2 (0.1) *
C100 (ng ml−1) 165 (35) 0.46 (0.22) [68]
σ2 0.037 (0.006)

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Cortisol
kIN (nM min−1) 7.9 (1.5) 0.17 (0.07) [40]
kOUT (min−1) 0.024 (0.003) *
α (h−1) 0.16 (0.02) 0.09 (0.06) [31]
IOC variability on baseline CCp 0.06 (0.03) *
σ2 0.04 (0.005)
CCp→CCs
λ −3.4 (0.16) 0.14 (0.07) [38]
β 0.0012 (0.003) *
σ2 0.12 (0.01)

A robust reduction of cortisol levels in the sham-placebo
session was observed, which is consistent with the expectation
of diurnal decay (Figs. 1 and 3). Because our study provides infor-
mation over a short part of the cortisol cycle, we described the
cortisol decay using a linear function (equation 1). Data analysis
of cortisol diurnal patterns using more complex models (expo-
nential, stochastic, sinusoidal) requires plasma or saliva sam-
pling over longer time periods.21–26 31 32 As alternatives to the
current approach, we modelled the cortisol decay using exponen-
tial and sinusoidal functions (data not shown). While the data
were well fitted by the alternative models, the more simple ap-
proach yielded the best fit in terms of the minimal objective func-
tion. The linear model correctly predicted a drop in plasma and
saliva cortisol release during the 3 h of our study (Fig. 3), which
is in agreement with values reported in the literature. Note that
prediction of cortisol concentrations from this model beyond
the time frame of the study may not be appropriate.
In our study, low-dose ketamine (dose range 0.29–0.57 mg
kg−1) produced a dose-dependent increase in cortisol production,
with a (relative) twofold increase at a concentration of 165 ng ml−1
(C100, Table 1). Since the ketamine effect was linked to kIN in the
PK model (equation 1), the absolute ketamine effect varies ac-
cording to the diurnal cortisol release pattern (with a reduction
in effect with a decaying cortisol production rate). While it is pos-
sible to link ketamine effect to other parameters of equation (1),
such as kOUT, our approach seems more intuitive (e.g. ketamine
influences cortisol secretion).20
In recent years, salivary cortisol measurement has become an
important biomarker in psychological and psychiatric assess-
ments. By repeatedly measuring both plasma and saliva cortisol
levels we demonstrated that these two variables were significant-
ly correlated, with saliva concentrations ∼4% of plasma concen-
trations (at 100 ng ml−1 ketamine). The relation between plasma
and saliva cortisol was best described by an exponential function.
Our PK model predicted that salivary cortisol closely mirrored
plasma cortisol concentrations, with a simultaneous peak con-
centration (occurring in-between sample times; Fig. 3 and ).
Although closely related, plasma and salivary cortisol are not
identical variables. In blood, >90% of cortisol is bound to proteins
(corticoid-binding globulin and albumin) and erythrocytes, and a
free unbound fraction that interacts its receptors.27,33 Salivary
cortisol reflects the portion of the biologically active fraction of
this steroid hormone (∼5%), which is unbound. We were unable
to observe a significant delay between salivary and cortisol plas-
ma concentration in the PK model (P>0.01). However, visual com-
parison of Figure 1 and  suggests a delay in reaching the peak of
plasma cortisol levels (appearing at min 120; 95% CI 245, 458 nM)
and saliva (appearing at min 170; 95% CI 7.8, 35.7 nM). The dis-
crepancy between the model and descriptive analyses may be re-
lated to the sparse sampling approach that we employed (with a
true peak in both saliva and plasma cortisol between 120 and 170
min). Alternatively, it may be related to the greater variability in
the saliva data. Comparing Figure 1 and , it can be seen that the
degree of between-subject variability is greater in salivary corti-
sol compared with plasma cortisol. Hypothetically, salivary corti-
sol may be related to a latent psychological modulation of the
neuroendocrine response measured from saliva, compared
with immediate endocrine effects that can be measured from
plasma.34
Our study has some limitations. Our results were obtained
from a group of healthy young male participants and thus are
not generalizable to women, the elderly, and children, or to any
clinical population. Our study was done over a short time interval
and the intersampling intervals were short (>30 min), therefore
we have been unable to model the circadian or ultradian cycles.
Considering that the stress response has a latency of 15–20 min,27
we may have missed response fluctuations between the low and
the higher dose range of our ketamine infusion. Also, our study
was timed strictly, thus we were unable to model ketamine–
cortisol interactions based on diurnal phases. Ketamine (but
not placebo) infusion comes with psychomimetic side effects
(most importantly ‘drug high’) that may have unblinded the
study.1 These psychomimetic effects may also have influenced
the subjective stress response of the participants, but we did
74 | Khalili-Mahani et al.
not collect enough psychometric data to incorporate such factors
in the PK model, and were unable to fully dissociate the pharma-
cological and psychological effects of ketamine on cortisol. Vena-
puncture often entails HPA axis activity and may have influenced
the study.35 However, the i.v. lines were inserted at least 90 min
prior to the first cortisol sample, so interference was unlikely.
The experimental context and the a priori states of anticipatory
stress may have had significant impact on the cortisol response.
We did not control for such effects in our study, but assume that
placebo and ketamine studies were similarly affected. Finally,
ketamine clearance of 2 litre min−1 is higher than previously
observed and higher than the expected liver blood flow.16 We
relate this to the characterization of the ketamine disposition
with a one-compartment model rather than two- or three-com-
partment models, as well as to the short time period of the
study with a relatively sparse sampling design.
In conclusion, we successfully performed a PKPD analysis to
describe the endogenous and time-varying production of cortisol
in plasma and saliva and quantified the effect of ketamine on
cortisol production.
Authors’ contributions
N.K.-M. was involved in the experimental design, performed part
of the experiments, and wrote parts of the manuscript; C.M.
performed the experiments; E.O. performed the data analysis;
A.D. wrote the protocol and the manuscript; M.N. had the initial
idea for the study, wrote the protocol, performed all experiments,
was involved in data analysis, and wrote the manuscript.
Funding
N.K.M. acknowledges research support from PERFORM Centre
(Concordia University, Montreal, QC, Canada) during completion
of this manuscript.
Declaration of interest
None declared.
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