Cannabinoid facilitation of fear extinction memory recall in humans
Christine A. Rabinaka,*, Mike Angstadta, Chandra S. Sripadaa, James L. Abelsona, Israel Liberzona,b,
Mohammed R. Miladc, K. Luan Phana,b,d,e
aDepartment of Psychiatry, University of Michigan, Ann Arbor, MI, USA
bNeuroscience Program, University of Michigan, Ann Arbor, MI, USA
cDepartment of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
dDepartment of Psychiatry, University of Illinois at Chicago, Chicago, IL, USA
eMental Health Service Line, Jesse Brown VA Medical Center, Chicago, IL, USA
a r t i c l e i n f o
Received 29 March 2012
Received in revised form
27 June 2012
Accepted 28 June 2012
a b s t r a c t
A first-line approach to treat anxiety disorders is exposure-based therapy, which relies on extinction
processes such as repeatedly exposing the patient to stimuli (conditioned stimuli; CS) associated with
the traumatic, fear-related memory. However, a significant number of patients fail to maintain their
gains, partly attributed to the fact that this inhibitory learning and its maintenance is temporary and
conditioned fear responses can return. Animal studies have shown that activation of the cannabinoid
system during extinction learning enhances fear extinction and its retention. Specifically, CB1 receptor
agonists, such as D9-tetrahydrocannibinol (THC), can facilitate extinction recall by preventing recovery of
extinguished fear in rats. However, this phenomenon has not been investigated in humans. We con-
ducted a study using a randomized, double-blind, placebo-controlled, between-subjects design, coupling
a standard Pavlovian fear extinction paradigm and simultaneous skin conductance response (SCR)
recording with an acute pharmacological challenge with oral dronabinol (synthetic THC) or placebo
(PBO) 2 h prior to extinction learning in 29 healthy adult volunteers (THC ¼ 14; PBO ¼ 15) and tested
extinction retention 24 h after extinction learning. Compared to subjects that received PBO, subjects that
received THC showed low SCR to a previously extinguished CS when extinction memory recall was tested
24 h after extinction learning, suggesting that THC prevented the recovery of fear. These results provide
the first evidence that pharmacological enhancement of extinction learning is feasible in humans using
cannabinoid system modulators, which may thus warrant further development and clinical testing.
This article is part of a Special Issue entitled ‘Cognitive Enhancers’.
? 2012 Elsevier Ltd. All rights reserved.
The inability to suppress inappropriate fear responses is the
hallmark of anxiety disorders, such as post-traumatic stress (PTSD),
panic, and phobic disorders (Rauch et al., 2006; Rosenand Schulkin,
1998). A common, empirically-validated approach to treat these
disorders is Cognitive Behavioral Therapy (CBT) (Norton and Price,
2007), one componentof which involves repeated exposure to fear-
linked cues to produce “extinction” (clinically referred to as expo-
sure therapy leading to desensitization) of fear and avoidance
responses to these cues (Hofmann, 2008). After repeated presen-
tations, the patient learns that the previously feared stimulus does
notactually predict a negativeoutcome and anxiety is reduced. This
exposure-based learning can be modeled in the laboratory, in both
animals and humans, using Pavlovian fear conditioning models in
whichfear is first linked toa previouslyinnocuous cue (conditioned
stimulus; CS) and then decreased by presenting the CS alone
Unfortunately, a major limitation of extinction is that it is
a temporary phenomenon and extinguished fear can re-emerge
simplywith thepassage of
(Hermans et al., 2006; Myers and Davis, 2007; Robbins,1990). This
phenomenon demonstrates that original fear memory remains
within the brain and ready to re-emerge even after extinction,
suggesting that extinction is a new learning process that “over-
lays” the original fear memory (Bouton, 2002). The vulnerability
of fear memory to recovery creates significant limitations to the
durability and effectiveness of exposure-based therapies (Arch
and Craske, 2009; Craske et al., 2008), and this has become
a topic of intense translational science efforts to improve
* Corresponding author. Tel.: þ1 734 232 0415; fax: þ1 734 615 8739.
E-mail address: email@example.com (C.A. Rabinak).
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Neuropharmacology 64 (2013) 396e402
treatments for PTSD and other anxiety disorders (Graham and
Milad, 2011; Jovanovic and Ressler, 2010; Milad and Quirk,
2012). One approach to overcoming the limitations of exposure
therapy may be to enhance the strength of fear inhibitory learning
through understanding of its neural and neurochemical substrates
(Graham and Milad, 2011; Jovanovic and Ressler, 2010; Milad and
Exciting new evidence has shown that pharmacological agents
known as “cognitive enhancers” can increase fear extinction in
animals and facilitate exposure-based therapy in humans. Sup-
ported by animal evidence, clinical studies have shown that D-
cycloserine (DCS), a N-methyl-D-aspartic acid (NMDA) receptor
partial agonist, facilitates the retention (and maintenance when
tested months later) of extinction memory from CBT in a number of
anxiety disorders (Davis et al., 2006; Guastella et al., 2008;
Hofmann, 2007, 2008; Ledgerwood et al., 2003, 2004, 2005;
Norberg et al., 2008; Ressler et al., 2004; Walker et al., 2002). These
studies demonstrate the clinical impact of translational neurosci-
ence by coupling the basic science of fear extinction learning and
human neuropsychopharmacology. However, other studies have
failed to find any evidence that DCS facilitates fear extinction or
exposure therapy (Guastella et al., 2007a, 2007b; Norberg et al.,
2008; Parnas et al., 2005; Storch et al., 2007), so while DCS is
a promising cognitive enhancing agent for extinction and exposure
therapy there is a need to investigate additional pharmacological
Emerging studies in rodents suggest that activation of the
cannabinoid (CB) system within the brain may also regulate
extinction learning and retention, similar to the effects of DCS. For
example, activation of type 1 CB receptors, via agonists like D9-
tetrahydrocannabinol (THC), facilitates
whereas fear extinction does not occur when these receptors are
(Bitencourt et al., 2008; Chhatwal et al., 2005; de Oliveira Alvares
et al., 2008; Lafenetre et al., 2007; Lin et al., 2008, 2009; Lutz,
2007; Marsicano et al., 2002; Pamplona et al., 2008, 2006; Roche
et al., 2007). Pharmacologically enhancing endogenous cannabi-
noid (eCB) levels during extinction can enhance extinction reten-
tion and block return of extinguished fear in rats (Chhatwal et al.,
2005). These studies suggest that the efficacy of extinction
learning and retention can be enhanced via increasing activity of
In humans, however, the role of cannabinoids on fear extinction
learning remains unknown. The primary goal of this study was to
test the hypotheses that administration of an exogenous CB1
agonist would enhance the memory and maintenance of fear
extinction. In a randomized, double-blind, placebo-controlled,
between-subjects design, we coupled a standard Pavlovian fear
conditioning and extinction paradigm with an acute pharmaco-
logical challenge with oral dronabinol (synthetic THC) or placebo
2 h prior to extinction learning in healthy adult volunteers and
tested extinction retention 24 h after extinction learning.
2. Materials and methods
Twenty-nine healthy, right-handed volunteers (twelve males; aged 21e45
years; Caucasian ¼ 21; African American ¼ 4; Asian ¼ 2; More than one race ¼ 2)
participated in this studyand were randomlyassigned tothe THC (n ¼ 14) or placebo
(n ¼ 15) condition. Some participants (n ¼ 13) had a minimal history of marijuana
use (limited to <10 lifetime exposures; mean: 1.2 ? 0.44); none had history or signs
of neurological, psychiatric (including substance and alcohol abuse/dependence), or
medical illness as confirmed by medical examination and a modified Structured
Clinical Interview for DSM-IV (SCID-NP; (First et al., 2002)). All subjects had negative
urine toxicology and alcohol breathalyzer screens at time of study.
All female subjects completed study sessions about 1 week prior to menses
onset (based on self-reports of last period and cycle length), to insure that they were
studied while estrogen levels were low. This restriction was based on evidence that
high estradiol levels can facilitate fear extinction (Milad et al., 2010; Zeidan et al.,
2011). All participants gave written informed consent after explanation of the
experimental protocol, as approved by the University of Michigan Institutional
2.2. Fear conditioning, extinction, and testing procedures
Participants were studied over 3 consecutive days (see Fig. 1). On Day 1, all
participants underwent partial discrimination fear conditioning, inwhich they were
presented with two neutral visual conditioned stimuli on a computer screen (CS þ s;
e.g., blue and yellow squares) that co-terminated with an aversive white noise burst
US through a pair of headphones (500 ms, 100 dB; (Dunsmoor et al., 2008)) at
a partial reinforcement rate of 35%. Fear acquisition consisted of 15 non-reinforced
presentations of each of the CSs, intermixed with an additional 8 presentations of
each CSþ that co-terminated with the US. A third CS (e.g. red square) was presented
during fear conditioning but never paired with the US (CS?; adapted from Schiller
et al. (2010)).
The next day (Day 2) all participants underwent an extinction session in which
one of the CS þ s (e.g., blue square)wasextinguished (CS þ E) whereasthe other CSþ
(e.g., yellow square) was not (CS þ U). Approximately 120 min prior to initiation of
extinction training participants ingested an opaque gelatin capsule (size 00) with
dextrose filler that contained either synthetic THC (Marinol; 7.5 mg; Solvay
Fig. 1. Schematic of the experimental protocol.
C.A. Rabinak et al. / Neuropharmacology 64 (2013) 396e402
123.80 ? 3.19 min; THC, 119.36 ? 2.45 min]. The timing insured presence of peak
subjective effects and plasma levels of THC (Wachtel et al., 2002) during the
extinction training. The THC dose used is the lowest effective dose found to produce
behavioral and subjective effects (Kirk and de Wit,1999; Phan et al., 2008; Rabinak
et al., 2011; Wachtel et al., 2002). During extinction learning the CS þ E was pre-
sented in the absence of the US, whereas the CS þ U was not presented. There were
15 CS þ E and 15 CS? trials.
To assess extinction retention, we conducted an extinction memory recall test
approximately 24 h after the extinction learning session (Day 3). This consisted of 20
non-reinforced presentations of each of the CSs (CS þ E, CS þ U, and CS?). In each
experimental session (fear acquisition, extinction learning, and extinction recall
test) all CSs were presented for 4 s each and the mean inter-trial interval (ITI) was
12 s (range: 6e18 s). The designation of colored squares (blue, yellow, or red) as
CS þ E, CS þ U, or CS? was counterbalanced across the participants and the order
of trials was pseudo-randomized, such that no more than 2 presentations of the
same colored square (red, yellow, or blue) occurred in a row.
At the beginning of each sessionparticipants were told that they mayor may not
hear a loud noise burst and were instructed to pay attention to the computer screen
and try to figure out the relationship between the colored squares and the noise
burst. During each presentation of the colored square stimuli, participants were
asked to rate their expectancy that the US would occur on a 5-point scale (“Will you
hear a loud noise burst?”: 1 ¼ Definitely not; 3 ¼ Unsure; 5 ¼ Definitely). US
expectancy was scored as the first response within 3 s of CS onset (adapted from
(Dunsmoor et al., 2008)). Conditioned fear was indexed by changes in skin
conductance responses (SCRs) for each CS trial. Electrodes and headphones
remained in place during all sessions (removed only during breaks).
Marietta,GA)ordextrose alone(placebo; PBO)[PBO,
2.3. Psychophysiological measures and data analysis
SCRs were measured by two disposable carbon fiber electrodes attached
between the first and second phalanges of the second and third digits of the left
hand (EL509, BIOPAC Systems, Inc., Goleta, CA). The electrodes were connected to
a BIOPAC Systems skin conductance module (GSR100C) and skin conductance was
continuously sampled at a rate of 1000 samples per second, amplified, and stored on
a Dell laptop computerforoffline analysisusing AcqKnowledge4.1 software (BIOPAC
Systems, Inc.). The recorded waveforms were low pass filtered using a Blackman
window (cutoff frequency ¼ 125 Hz) and mean value smoothed over 100 adjacent
data points prior to scoring.
SCR for each CS trial was calculated by subtracting the mean skin conductance
level during the 2 s before stimulus onset from the highest skin conductance level
that occurred in the 0.5e4.5 s latency window after stimulus onset. SCRs below
0.02 mS were scored as zero (LaBar et al., 1998; Schiller et al., 2010). Raw SCRs
were square root transformed to normalize the distributions and scaled according to
each subject’s mean square root transformed US response (LaBar et al., 1998; Milad
et al., 2005a; Orr et al., 2000; Schiller et al., 2010). To assess the level of conditioned
responding in anticipation of the aversive US separate from unconditioned
responses to the noise bursts, themselves, we included only non-reinforced trials of
the CS þ s in the analysis.
SCRs and US expectancy ratings were analyzed using analysis of variance
(ANOVA). Post-hoc comparisons between and within drug groups, using indepen-
dent and paired t tests, respectively, were performed after a significant F ratio was
obtained. We used a significance threshold of p < 0.05 (two-tailed), corrected for
multiple comparisons using Bonferroni correction. Unless otherwise stated all data
are presented as means ? SEM.
3.1. Fear acquisition
An ANOVA of SCR during fear acquisition revealed a significant
main effect of stimulus [F(1,27)¼ 16.12, p < 0.001], with greater SCR
responses to the CSþ [THC ¼ 0.38 ? 0.08; PBO ¼ 0.27 ? 0.08] than
to the CS? [THC ¼ 0.10 ? 0.07; PBO ¼ 0.18 ? 0.06] during the last
trial of fear acquisition. There were no significant differences in SCR
during fear acquisition between participants assigned to the THC
and PBO groups, as evidence by the absence of a significant main
effect of drug [F(1,27)¼ 0.05, p ¼ 0.82] or drug by stimulus inter-
action [F(1,27)¼ 4.11, p ¼ 0.53]. Similarly, participants rated the US as
more likely to occur during the CSþ [THC ¼ 3.39 ? 0.20;
PBO ¼ 3.40 ? 0.21] than the CS? [THC ¼ 1.29 ? 0.19;
PBO ¼ 1.47 ? 0.24] during the last trial of fear acquisition [main
effect of stimulus [F(1,27) ¼ 80.76, p < 0.001]]. There were no
significant differences in US expectancy ratings during fear
acquisition between participants assigned to the THC and PBO
groups [absence of main effect of drug: F(1,27)¼ 0.23, p ¼ 0.64; and
drug by stimulus interaction: F(1,27)¼ 0.15, p ¼ 0.70]. The two drug
groups responded similarly to the US and displayed high levels of
unconditioned SCRs [THC ¼ 1.16 ? 0.11; PBO ¼ 1.05 ? 0.10;
t(27)¼ 0.75, p ¼ 0.46].
3.2. Extinction learning
An ANOVA of SCR and of US expectancy ratings with three, two-
level factors e drug (THC, PBO), stimulus (CS þ E, CS?), and time
(early extinction [average first 4 trials], late extinction [average last
4 trials]) e revealed a significant main effect of time [SCR:
F(1,27)¼ 11.79, p ¼ 0.002; US Expectancy: F(1,27)¼ 26.82, p < 0.001],
main effect of stimulus [SCR: F(1,27)¼ 9.95, p ¼ 0.004; US Expec-
tancy: F(1,27)¼ 31.16, p < 0.001], and interaction between time and
stimulus [SCR: F(1,27) ¼ 17.67, p < 0.001; US Expectancy:
F(1,27)¼ 30.58, p < 0.001]. Both drug groups displayed significantly
greater SCRs and US expectancy ratings to the CS þ E during early
extinction [SCR: THC ¼ 0.34 ? 0.07; PBO ¼ 0.27 ? 0.05 (Fig. 2); US
Expectancy: THC ¼ 3.48 ? 0.23; PBO ¼ 3.13 ? 0.25 (not shown)]
PBO ¼ 0.13 ? 0.04 (Fig. 2); US Expectancy: THC ¼ 1.91 ? 0.33;
PBO¼ 1.90 ? 0.32 (notshown)]. Therewereno differences between
drug groups in SCRs or US expectancy ratings to the CS þ E [SCR:
Early Extinction: t(27)¼ 0.84, p ¼ 0.40; Late Extinction: t(27)¼ 0.06,
p ¼ 0.95; US Expectancy: Early Extinction: t(27)¼ 1.02, p ¼ 0.32;
Late Extinction: t(27)¼ 0.02, p ¼ 0.98].
Of note, elevated SCRs and greater US expectancy ratings to the
CS þ E during early extinction learning were comparable to SCRs
and US expectancy ratings to the CS þ E during late fear acquisition
in both drug groups [SCR: THC: t(13) ¼ 0.44, p ¼ 0.67; PBO:
t(14)¼ 0.07, p ¼ 0.94; US Expectancy: THC: t(13)¼ ?0.41, p ¼ 0.69;
PBO: t(14)¼ 0.97, p ¼ 0.35], supporting successful acquisition and
next day retention of conditioned fear. In addition, there were no
significant differences in SCRs to the CS þ E and CS? between the
Fig. 2. Skin conductance responses (SCRs) to the CS þ E during extinction learning.
Mean SCRs to the CS þ E during early (average first four trials) and late (average last
four trials) extinction learning. PBO (green bars) and THC (red bars). (For interpretation
of the references to color in this figure legend, the reader is referred to the web version
of this article.)
C.A. Rabinak et al. / Neuropharmacology 64 (2013) 396e402
THC and PBO groups within or between earlyand late extinction, as
evidence by the absence of a significant main effect of drug [SCR:
F(1,27)¼ 0.04, p ¼ 0.85; US Expectancy: F(1,27)¼ 0.34, p ¼ 0.57], drug
by stimulus interaction [SCR: F(1,27)¼ 2.15, p ¼ 0.15; US Expectancy:
F(1,27)¼ 0.07, p ¼ 0.80], drug by time interaction [SCR: F(1,27)¼ 0.07,
p ¼ 0.80; US Expectancy: F(1,27)¼ 0.03, p ¼ 0.85 ], and drug by
stimulus by time interaction [SCR: F(1,27) ¼ 1.44, p ¼ 0.24; US
Expectancy: F(1,27)¼ 1.80, p ¼ 0.19].
3.3. Extinction memory recall test
An ANOVA of SCR during the extinction memory recall test (first
two CS þ E vs. first two CS þ U trials) revealed a significant drug by
stimulus interaction [F(1,27) ¼ 4.80, p < 0.05]. The THC group
exhibited smaller SCRs to the stimulus that had been previously
extinguished during the previous extinction learning phase
compared with the stimulus that had not been extinguished
[0.22 ? 0.08 for CS þ E vs. 0.35 ? 0.09 for CS þ U], whereas the PBO
group did not [0.37 ? 0.11 for the CS þ E vs. 0.23 ? 0.09 for the
CS þ U]. Moreover there was a significant difference in the mean
differential SCR to the CS þ E minus the CS þ U between the THC
and PBO groups during the extinction memory recall test [Fig. 3;
t(27)¼ ?2.29, p < 0.05]. Consistent with these findings the PBO
responses to the CS þ E during extinction recall, as evidenced by
significantlygreater SCRs tothe CS þ E during extinction recall than
duringlate extinction learning
0.13 ? 0.04 vs. Extinction Recall Test: 0.37 ? 0.11; t(14)¼ ?2.45,
p < 0.05], whereas THC during extinction learning prevented
spontaneous recovery of conditioned fear responding to the CS þ E
[Late Extinction learning: 0.13 ? 0.05 vs. Extinction Recall Test:
0.22 ? 0.08; t(13)¼ ?0.94, p ¼ 0.37].
recovery ofconditioned fear
As expected the THC group reported low subjective US expec-
tancy ratings to the CS þ E during the extinction recall test
[2.07 ? 0.35] that were not significantly different from late
extinction learning [1.91 ? 0.33; t(13)¼ ?1.80, p ¼ 0.10], further
suggesting good retention of extinction memory. Interestingly, the
PBO group also reported low subjective US expectancy ratings to
the CS þ E during the extinction recall test [2.07 ? 0.32] that were
no different from the THC group [t(27)¼ ?0.48, p ¼ 0.64] or from
late extinction learning [1.90 ? 0.32; t(14)¼ ?0.68, p ¼ 0.51]. These
results suggest that the PBO group was able to maintain subjective
knowledge that the CS þ E no longer predicted the occurrence of
the US despite exhibiting a recovery of physiological fear
responding (SCR) to the CS þ E following extinction learning.
The present findings provide the first evidence that pre-
extinction administration of THC facilitates extinction of condi-
tioned fear in humans. In particular, participants that had received
PBO during extinction learning exhibited spontaneous recovery of
fear to a CSþ that was previously extinguished, whereas THC
attenuated spontaneous recovery of fear. Of note, THC did not affect
within-session extinction learning, but only influenced the ability
to successfully recall extinction memory when compared to PBO,
suggesting that THC affects the ability to maintain and/or
successfully retrieve extinction memory. These findings are
consistent with pre-clinical studies in rats in which cannabinoid
activation and/or enhancement can lead to facilitation of extinction
memory recall (Bitencourt et al., 2008; Chhatwal et al., 2005;
Lafenetre et al., 2007; Lin et al., 2009; Lutz, 2007; Pamplona et al.,
In rats, acute systemic administration of CB1 agonists, (e.g. WIN
55,212-2 and HU210) prior to extinction learning have been shown
to facilitate fear extinction (Lin et al., 2008, 2006, 2009; Pamplona
et al., 2008, 2006); but see (Chhatwal et al., 2005) and prevent
spontaneous recovery of extinguished conditioned fear responses
(Lin et al., 2006). In addition, cannabidiol, a non-psychoactive
phytocannabinoid, and pharmacological agents that enhance
levels of released eCBs, such as AM404, an eCB reuptake inhibitor,
and URB597, a fatty acid amide hydrolase (FAAH) inhibitor that
blocks hydrolysis of anandamide, have been shown to facilitate
within-session extinction learning (Bitencourt et al., 2008; Varvel
et al., 2007), enhance the retention of extinction (Bitencourt
et al., 2008; Chhatwal et al., 2005; de Oliveira Alvares et al., 2008;
Linet al., 2009; Varvel et al., 2007) and also decrease the recoveryof
conditioned fear responses in rats (Chhatwal et al., 2005) if given
prior to extinction learning. Conversely, co-administration of CB1
antagonists, such as AM251 and rimonabant [SR141716], block the
extinction enhancing effects of these CB1 agonists and reuptake/
metabolism inhibitors (Chhatwal et al., 2005; de Oliveira Alvares
et al., 2008; Varvel et al., 2007). When administered alone, CB1
antagonists lead to a profound disruption of extinction retention
when given either prior to extinction learning or immediately
following extinction learning, suggesting that CB1 receptor acti-
vation is necessary during extinction learning and for consolidation
of extinction memories in order to successfully retrieve these
memories at a later time (Chhatwal et al., 2005; de Oliveira Alvares
et al., 2008; Lin et al., 2009; Marsicano et al., 2002; Pamplona et al.,
2008, 2006; Suzuki et al., 2004). Consistent with these results are
findings thatextinction of fear is impaired in CB1 receptorknockout
mice when compared to wild-type mice (Kamprath et al., 2006;
Marsicano et al., 2002; Varvel et al., 2005).
Two of the most studied cognitive enhancers of extinction
learning are DCS and yohimbine, an alpha2-receptor antagonist
that promotes norepinephrine release (Kaplan and Moore, 2011).
Fig. 3. Skin conductance responses (SCRs) during the extinction memory recall test.
Mean differential SCRs during the first two trials of the CS þ E minus the first two trials
of the CS þ U during the extinction memory recall test. Difference scores greater than
zero reflect greater responding to the CS þ E, difference scores equal to zero reflect no
difference in responding between the CS þ E and CS þ U, and scores less than zero
reflect greater responding to the CS þ U (LaBar et al., 1998; LaBar et al., 1995). PBO
(green bars) and THC (red bars). (For interpretation of the references to color in this
figure legend, the reader is referred to the web version of this article.)
C.A. Rabinak et al. / Neuropharmacology 64 (2013) 396e402
As mentioned previously, DCS has been shown to enhance extinc-
tion learning in rats and humans and facilitate exposure therapy in
patients with anxiety (Davis et al., 2006; Hofmann, 2007, 2008;
Ledgerwood et al., 2003, 2004, 2005; Norberg et al., 2008; Ressler
et al., 2004; Walker et al., 2002). Moreover, DCS given immedi-
ately afterextinction learning
(Ledgerwood et al., 2004) and enhances extinction recall in rats,
suggesting that DCS also mediates consolidation of extinction
memories (Ledgerwood et al., 2003). Likewise, yohimbine also
enhances fear extinction in rats and humans (Holmes and Quirk,
2010) and has been shown to facilitate exposure therapy in
patients with claustrophobia (Powers et al., 2009). However, there
are concerns about the efficacy of these agents over repeated
sessions (i.e. with chronic use), which produces behavioral desen-
sitization (Parnas et al., 2005; Storch et al., 2007) and in preventing
relapse in translational applications (Kaplan and Moore, 2011).
In the brain, CB1 receptors are densely localized within brain
structures that are known to be critical for extinction learning,
retention and successful retrieval of extinction memories (ventro-
medial prefrontal cortex [vmPFC] and hippocampus [HPC]) (Bouton
et al., 2006; Corcoran et al., 2005; Kalisch et al., 2006; Mackie,
2005; Milad and Quirk, 2002; Milad et al., 2006, 2007; Myers and
Davis, 2007; Ochsner and Gross, 2005; Phelps et al., 2004; Quirk
and Beer, 2006; Quirk et al., 2006, 2003; Quirk and Mueller,
2008). In humans, vmPFC activation during extinction recall and
vmPFC thickness both correlate with magnitude of extinction
retention (Hartley et al., 2011; Milad et al., 2005b, 2007; Phelps
et al., 2004). In rats, cells within the infralimbic cortex (IL),
a homologous structure to the human vmPFC, display robust CS-
elicited activity during extinction recall which is inversely corre-
lated with spontaneous recovery of fear CRs (Milad and Quirk,
2002). Similarly, the hippocampus (HPC) is associated with
successful retrieval of extinction memory and is positively corre-
lated with vmPFC activation during extinction recall in humans
(Kalisch et al., 2006; Milad et al., 2007).
When eCBs are released from the postsynaptic cell they diffuse
in a retrograde fashion to activate presynaptic CB1 receptors, which
in turn inhibits presynaptic release of neurotransmitters (Chhatwal
and Ressler, 2007; Howlett, 2005; Lafenetre et al., 2007; Pertwee,
2005). In rodents it has been suggested that during extinction
learning activation of vmPFC CB1 receptors induces neuronal
plasticity, which subsequently increases inhibition on brain areas
involved in the expression of conditioned fear responses (e.g.
amygdala) (Lin et al., 2009) and HPC CB1 receptor activation
enhances glutamatergic neurotransmission, which may support
long-term extinction memory formation (consolidation) (de
Oliveira Alvares et al., 2008). We are currently investigating the
role of cannabinoids on the retention of extinction memory and its
effect on the underlying neural circuits in humans using a similar
Pavlovian fear conditioning-extinction paradigm coupled with
Anecdotal reports of recreational use of cannabis or psycho-
pharmacological studies of marijuana/THC suggests that CB1 acti-
vation decreases subjective anxiety (D’Souza et al., 2004; Sethi
et al., 1986; Wachtel et al., 2002). An early placebo-controlled
study showed that nabilone, a synthetic THC, dramatically
reduced anxiety in anxious patients (Fabre and McLendon, 1981).
Consistent with this and evidence from rodents, studies in humans
using functional magnetic resonance imaging (fMRI) have found
that oral THC (vs. PBO) attenuates amygdala reactivity to aversive/
fear stimuli using a social-threat paradigm (Phan et al., 2008) and
that the level of amygdala reactivity is inversely related to the level
of cannabis use (Cornelius et al., 2010), consistent with the notion
that THC and other cannabinoids may have an anxiolytic role via
central fear mechanisms. The anxiolytic effects of eCB enhancers in
rodents and humans have sparked interest in CB1 receptors as
a pharmacological target for treating anxiety disorders (Gaetani
et al., 2003, 2009; Hill and Gorzalka, 2009; Witkin et al., 2005).
However, some important issues need to be addressed if CB1
agonists are to be used as a treatment for anxiety disorders. For
instance, the subjective effects of THC tend to be biphasic; low
doses generally promote anxiolytic-like effects, whereas higher
doses may induce anxiogenic-like effects (D’Souza et al., 2004;
Genn et al., 2004; Viveros et al., 2005). Moreover, we found THC
administration facilitates extinction of conditioned fear in partici-
pants with minimal or no previous history of marijuana usage;
however we cannot generalize these findings to chronic marijuana
users. In fact, chronic heavy marijuana smokers experience
a disruption or alteration in frontal-limbic network, in the absence
of intoxication, which in turn could affect the efficacy of THC on
extinction learning (Cornelius et al., 2010; Gruber et al., 2009). Also,
because some 13 of the 29 participants had minimal prior exposure
to marijuana (mean: 1.2 times over lifetime), these findings also
requirereplication in a THC-naïve cohort. Futurestudies areneeded
to address these important issues.
Anxiety disorders, such as PTSD, are difficult to treat because
many patients only partially respond to CBTs (Cloitre, 2009; Foa,
2000; van Minnen et al., 2002) and even fewer respond to first-
line pharmacological treatments, such as selective serotonin
reuptake inhibitors (SSRIs) (Stein et al., 2009, 2006). Interestingly,
poor extinction retention and vmPFC-HPC dysfunction have been
implicated in anxiety disorders such as PTSD and could under-
mine the maintenance of the therapeutic effects of exposure
(Charney and Deutch, 1996; Foa, 2000; Milad et al., 2009; Orr
et al., 2000; Pitman et al., 2001; van Minnen and Hagenaars,
2002). Given that enhancing cannabinoid transmission, via CB1
agonists, helps extinction recall, the cannabinoid system is
a promising target for improving the learning that goes on in
psychotherapy and improving the likelihood of success and its
maintenance in patients with PTSD, and other difficult-to-treat
anxiety disorders. Moreover, proof-of-concept studies such as
this will provide the necessary bioassay of THC’s putative anxio-
lytic effects and enhance the pace of drug development of
cannabinoid modulators (agonists such as THC, or FAAH inhibitors
such as URB597). The present study is a critical translational first
step towards the development of cannabinoid modulators as an
adjunctive strategy to exposure-based therapies to augment
extinction learning and prevent the return of fear memories in
people suffering from anxiety disorders.
This work was supported bya grant from the National Center for
Research Resources (UL1RR024986) to C.A.R. and K.L.P. The content
is solely the responsibility of the authors and does not necessarily
represent the official views of the National Center for Research
Resources or the National Institutes of Health. The authors would
like to thank Shoko Mori, Maryssa, Lyons, Christina Harrison, and
Daanish Chawala for their assistance in recruitment, participant
screening, data collection and analyses.
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