Current Psychiatry Reports (2018) 20:118

https://doi.org/10.1007/s11920-018-0983-y

DISASTER PSYCHIATRY: TRAUMA, PTSD, AND RELATED DISORDERS (MJ FRIEDMAN, SECTION EDITOR)

A Review of the Neurobiological Basis of Trauma-Related Dissociation

and Its Relation to Cannabinoid- and Opioid-Mediated Stress Response:
a Transdiagnostic, Translational Approach
Ruth A. Lanius 1,2,3,4 & Jenna E. Boyd 4,5,6 & Margaret C. McKinnon 4,5,7 & Andrew A. Nicholson 1,2,3 & Paul Frewen 8 &
Eric Vermetten 9,10 & Rakesh Jetly 11 & David Spiegel 12

# Springer Science+Business Media, LLC, part of Springer Nature 2018

Abstract
Dissociative experiences have been associated with increased disease severity, chronicity, and, in some cases, reduced treatment
response across trauma-related and other psychiatric disorders. A better understanding of the neurobiological mechanisms
through which dissociative experiences occur may assist in identifying novel pharmacological and non-pharmacological treat-
ment approaches. Here, we review emerging work on the dissociative subtype of posttraumatic stress disorder (PTSD), and other
trauma-related disorders providing evidence for two related overarching neurobiological models of dissociation, the defense
cascade model of dissociation and Mobb’s threat detection model. In particular, we review neuroimaging studies highlighting
alterations in functional connectivity of key brain regions associated with these models, including connectivity between the
prefrontal cortex, the amygdala and its complexes, the insula, and the periaqueductal gray. Work implicating the kappa-opioid
and endocannabinoid systems in trauma-related dissociative experiences is also reviewed. Finally, we hypothesize mechanisms
by which pharmacological modulation of these neurochemical systems may serve as promising transdiagnostic treatment mo-
dalities for individuals experiencing clinically significant levels of dissociation. Specifically, whereas kappa-opioid receptor
antagonists may serve as a pharmacological vehicle for the selective targeting of dissociative symptoms and associated emotion
overmodulation in the dissociative subtype of posttraumatic stress disorder and transdiagnostically, modulation of the
endocannabinoid system may reduce symptoms associated with emotional undermodulation of the fight or flight components
of the defense cascade model.

Keywords PTSD . Dissociation . Stress response . Opioids . Endocannabinoids . Amygdala . Periaqueductal grey . Prefrontal
cortex

Ruth A. Lanius and Jenna E. Boyd contributed equally to this work.

This article is part of the Topical Collection on Disaster Psychiatry:
Trauma, PTSD, and Related Disorders

* Ruth A. Lanius 7
Department of Psychiatry and Behavioural Neuroscience, McMaster
Ruth.lanius@lhsc.on.ca University, Hamilton, ON, Canada
8
1
Department of Psychology, Western University, London, ON,
Department of Neuroscience, Western University, London, ON, Canada
Canada
9
2
Department of Psychiatry, Western University, London, ON, Canada Department of Psychiatry, Leiden University Medical Center,
3
Leiden, Netherlands
Lawson Health Research Institute, London, ON, Canada
4 10
Homewood Research Institute, Guelph, ON, Canada Military Mental Health Research, Ministry of Defense,
5 Utrecht, Netherlands
Mood Disorders Program, St. Joseph’s Healthcare, Hamilton, ON,
Canada 11
Canadian Forces, Health Services, Ottawa, ON, Canada
6
Department of Psychology, Neuroscience, and Behaviour, McMaster
12
University, Hamilton, ON, Canada Stanford University School of Medicine, Stanford, CA, USA
 118 Page 2 of 14
Introduction
Dissociative phenomena involve alterations in conscious-
ness underlying normal integration of thought, memory,
emotions, sense of self, body awareness, and perception
of the external environment [1]. Commonly experienced
symptoms of dissociation include disengagement (“spac-
ing out”), emotional constriction (reduced ability to expe-
rience emotions), memory disturbance (e.g., “blanks” in
memory), depersonalization (feeling outside of or as if
you do not belong to your own body), derealization (feel-
ing as though things around you are strange or unfamiliar),
and identity dissociation (e.g., feeling as though there is
more than one person inside of you) [2]. Although disso-
ciative phenomena occur across a wide range of psycho-
logical disorders and in healthy individuals [3, 4], patho-
logical dissociative symptoms typically develop following
chronic exposure to traumatic life events, particularly
those occurring early in development such as childhood
abuse and neglect [5]. Consistent with a traumatogenic
etiology, the neurobiological mechanisms of dissociation
have become increasingly understood through studies ex-
amining trauma-related disorders and the dissociative sub-
type of posttraumatic stress disorder (PTSD+DS). PTSD+
DS is a subtype diagnosed in approximately 15–30% of
individuals with PTSD [6, 7] and characterized by symp-
toms of depersonalization and derealization [1]. PTSD+DS
has been identified across individuals with differing trau-
ma etiologies, including military or combat trauma [6],
childhood abuse, and mixed civilian trauma [7].
Critically, however, dissociative symptoms are present
not only in PTSD but are also observed at clinically sig-
nificant levels in numerous other trauma-related disorders,
including borderline personality disorder (BPD) and dis-
sociative identity disorder (DID) [8], and in conditions less
classically associated with trauma exposure, such as major
depressive disorder (MDD) and depersonalization/
derealization disorder (DDD) [3]. Although DDD has not
been linked historically to traumatic experiences, some
evidence indicates that childhood interpersonal trauma is
predictive of a subsequent diagnosis of depersonalization
disorder [9]. Similarly, dissociative symptoms in MDD are
also linked to trauma exposure [10, 11]. For example, a
study by Sar and colleagues identified a subgroup of
women with MDD and comorbid dissociative disorders
who had higher rates of childhood abuse than women
with MDD and no dissociative disorder [11]. Taken to-
gether, these findings suggest strongly that dissociative
symptoms experienced transdiagnostically are often of a
traumatogenic nature.
Notably, dissociative symptoms, including those seen
in PTSD+DS, are associated with a longer duration of
illness (e.g., onset of PTSD in childhood), severe role
Curr Psychiatry Rep (2018) 20:118
impairment, and heightened suicidality [7]. Although
PTSD+DS has been identified across trauma types
(e.g., childhood abuse, military members, and veterans)
[6, 7], dissociative symptoms are often linked to chron-
ic, inescapable stress occurring within the context of
prolonged, repeated traumatic experiences (e.g., child-
hood neglect or abuse), where dissociation may serve
as a means of psychological escape from intense trauma
or suffering [12]. This recent meta-analysis reported
higher levels of dissociation among samples exposed to
childhood abuse or neglect than among non-abused or
neglected samples [12]. Moreover, a younger age of on-
set, a longer duration of abuse, and parental abuse were
associated with higher levels of dissociative symptoms
[12]. Hence, increased understanding of not only the
mechanisms through which dissociative symptoms
emerge, but also are maintained in trauma-exposed clin-
ical populations is likely to have wide-reaching implica-
tions. Given the association between dissociative symp-
toms and increased disease severity and comorbidity, the
identification of novel treatment modalities is crucial.
Accordingly, we review emerging evidence suggesting
the potential role of opioid- and endocannabinoid-
mediated stress responses in dissociative phenomena,
highlighting the implications of this literature for treat-
ment and pharmacotherapy.
The Neurobiology of Dissociation
Neurobiological Models of Dissociation
as Fronto-Limbic Inhibition
Recent neurobiological investigations of dissociative symp-
tomatology stem largely from the PTSD literature as well as
from studies investigating DID, BPD, and depersonalization/
derealization disorder (DDD) [13, 14]. Although dissociation
has been conceptualized broadly as including divisions within
one’s sense of self and has been considered relevant to cultural
phenomena such as possession [15], the majority of neurobi-
ological work to date has focused largely on symptoms con-
sistent with the aforementioned definition of dissociation as a
disturbance in integration of thought, memory, emotional feel-
ings, sense of self, body awareness, and perception of the
external environment, including symptoms of depersonaliza-
tion and derealization. Flashbacks in PTSD, for example com-
bine dissociation of future orientation (memory of surviving
the trauma) with intense reliving of the trauma. Despite this
limitation of our model, we are focusing on the aspects of
dissociation involving emotion overmodulation and associat-
ed emotional detachment.
Neuroimaging studies in PTSD support the existence
of a distinct dissociative subtype. Early work identified
Curr Psychiatry Rep (2018) 20:118
a neurobiological model reflecting emotion dysregula-
tion among individuals with PTSD+DS due to excessive
prefrontal inhibition of limbic regions, including the
amygdala [16]. This dysregulation is referred to as emo-
tional overmodulation and involves depersonalization
and derealization and associated emotional detachment
characteristic of individuals with PTSD+DS. Emotional
overmodulation seen in PTSD+DS contrasts sharply
with the more common presentation of PTSD involving
hyperemotionality, characterized by reduced prefrontal
activity and limbic over-activity, and often referred to
as emotional undermodulation [16]. Notably, whereas
PTSD is associated predominantly with emotional
undermodulation, individuals with PTSD+DS may cycle
between these two presentations, even though symp-
toms of emotional overmodulation often predominate
[16].
Recent work has expanded significantly this conceptu-
alization in an effort to delineate further the subcortical
structures implicated in PTSD and PTSD+DS and to spec-
ify the directionality of connectivity between key regions
associated with emotional over- and undermodulation [17,
18, 19••, 20••]. In particular, subregions of the amygdala,
namely the centromedial amygdala (CMA) and basolateral
amygdala (BLA) complexes, and the periaqueductal gray
(PAG) have been tied uniquely to differential patterns of
brain connectivity among individuals with PTSD+DS
compared to PTSD [17, 18, 19••, 20••]. The CMA,
BLA, and PAG contribute differentially to fear process-
ing. Specifically, whereas the BLA is moderated by top-
down inhibition from the mPFC and is responsible for the
evaluation of sensory information and its subsequent cor-
tical processing via projections to the thalamus, striatum,
and PFC, the CMA is responsible for activation of
nociception and execution of fear responses via projec-
tions to the PAG and other subcortical brain regions
[21]. By contrast, the PAG and its subregions contribute
to autonomic responses associated with fear. Here, the
dorsolateral and lateral PAG (dl-PAG and l-PAG) are im-
plicated in activation of the sympathetic nervous system
in response to threat and subsequent activation of active
defense responses associated with emotional
undermodulation [22]. Conversely, the ventrolateral PAG
(vl-PAG) is thought to serve as a “brake” for the dl-PAG
and l-PAG, and is associated with passive defensive re-
sponses and activation of the parasympathetic nervous
system, thus its association in the literature is with emo-
tional overmodulation [22].
Dissociation and Response Inhibition
The connection between these brain regions and defensive
responding can be understood through a framework
Page 3 of 14 118
introduced by Mobbs et al. [23, 24] illustrating that threat
processing among healthy individuals is dependent on the
physical distance of the individual from an environmental
threat. Specifically, as threat approaches and is conse-
quently perceived as more imminent, defensive process-
ing at the neural level shifts from prefrontal brain regions
(e.g., orbitofrontal cortex, ventromedial PFC (vmPFC)) to
subcortical brain regions involved in primitive defensive
responses (e.g., amgydala and PAG) [23, 24]. For exam-
ple, Mobbs [23] found that among healthy control sub-
jects, anticipation of threat following initial detection
was associated with increased activity in forebrain struc-
tures, (e.g., vmPFC and hippocampus) as well as subcor-
tical structures including the hypothalamus and amygdala.
By contrast, when subjects perceived threat to be immi-
nent, midbrain and subcortical regions, including the PAG
and dorsal anterior cingulate cortex (dACC), were most
active [23]. Thus, among individuals with PTSD, bottom-
up processing of threat, with subcortical regions including
the PAG and amygdala driving these responses, is mir-
rored by imminent threat detection in healthy controls
and may lead to chronic hyperarousal and defensive pos-
turing towards perception of imminent threat. In particu-
lar, as reviewed above, emotional undermodulation in
PTSD is associated with reduced modulation of the amyg-
dala and dl-PAG by the mPFC leading to chronic activa-
tion of these brain regions and persistent hyperemotional-
ity and hyperarousal. By contrast, among individuals with
PTSD+DS, dominant top-down processing may indicate
over-regulation of defensive processing by PFC regions,
as seen in healthy controls during early detection of threat
(e.g., during a freeze or orienting response). Here, in
PTSD+DS, increased modulation of the amygdala and
PAG regions by the mPFC may be associated with passive
defensive responding and chronic emotional detachment
associated with symptoms of depersonalization and
derealization.
Dissociation and Defense Cascade
Mobbs et al.’s work [23, 24] is complemented by the defense
cascade model of dissociation [25, 26] (see Fig. 1), which
proposes that defensive responses to threat occur on a contin-
uum and are mediated by neural pathways involving the PAG,
hypothalamus, amygdala, and sympathetic and vagal nuclei.
While this model is based on the animal literature and has not
yet been explicitly examined in humans, several authors have
pointed to important relations between this established model
of defensive responding in animals and defensive responding
in humans [25, 26].
In this model, threat is met initially with an orienting
“freeze” response (analogous to early detection of threat as
described above) with threatening stimuli first processed
 118 Page 4 of 14
Defense Cascade Model
Dorsolateral PAG Mediated Ventrolateral PAG Mediated
Tonic
Hyperarousal Depersonalization
Immobility
& Hypervigilance
& Derealization
Defense Reaction
Responses Responses
Fight or Flight Unresponsive
Immobility
Response
Active Defense Passive Defense
Parasympathetic Dominance
Sympathetic Dominance
Endocannabinoids Kappa & Mu Opioids
Baseline Arousal
Dissociative Status
Fig. 1 Adapted with permission from Zeitschrift für Psychologie/Journal
of Psychology 2010; Vol. 218(2):109–127., p. 111 ©2010 Hogrefe
Publishing, www.hogrefe.com. The defense cascade model of
dissociation posits that defensive responses occur on a continuum,
mediated by pathways involving the periaqueductal gray (PAG),
hypothalamus, and amygdala. Here, threat is met initially with an
orienting freezing response via the superior colliculus and PAG,
followed by fight or flight (blue shaded area; mirrored in symptoms of
hyperarousal and hypervigilance) via activation of the sympathetic
nervous system and the dorsolateral PAG (lPAG) involved in activating
motor patterns of fight or flight, via the PAG, amygdala, and limbic
forebrain. Fight or flight is accompanied by release of
endocannabinoids, leading to analgesia. Fight or flight is followed by a
stage of tonic immobility (tonic immobility), with co-activation of both
the sympathetic and parasympathetic nervous systems. Critically, when
escape and/or chance of survival is low, a dissociative state follows
(yellow shaded area), referred to as unresponsive immobility/emotional
shutdown, mediated by the ventrolateral PAG (brake to the lateral PAG).
During unresponsive immobility (shutdown response), sensation,
perception, and motor abilities are significantly altered (mirrored by
symptoms of depersonalization and derealization) and vagal
parasympathetic activity dominates. Opioid-mediated analgesia
accompanies the shutdown response, and emerging work suggests that
perceptual and mood alterations (e.g., dysphoria) may be carried out by
the kappa-opioid (dynorphin) system (activated in response to chronic,
inescapable stress) ([2, 18, 19••])
by the superior colliculus (SC), a brain region closely tied
to the PAG, allowing the organism to determine the pres-
ence and location of threat in the environment at a subcor-
tical level. This is followed by fight or flight, via the sym-
pathetic nervous system with release of catecholamines
(e.g., noradrenaline) and activation of the l-PAG (and thus
motor patterns associated with fight or flight). In situations
where the chance of survival is deemed low and the stress-
or is inescapable, a state of tonic immobility followed by
unresponsive immobility/emotional shutdown ensues, also
referred to as a dissociative shutdown response, mediated
by activation of the ventrolateral PAG (vl-PAG) serving as
a break to the l-PAG and inhibition of fight or flight motor
patterns. These responses are mediated by activation of
Curr Psychiatry Rep (2018) 20:118
tactile, sensory, and proprioceptive afferent nerves, in com-
bination with fear, leading to activation of the vagal and
parabrachial sensory nuclei. This shutdown response is
thought to be associated with cortical-sensory deafferenta-
tion, where reduced integration of sensory stimuli via the
thalamus to the cortex allows the individual to reduce
responding to external stimuli [26]. During unresponsive
immobility, the individual exhibits reduced responsiveness
to sensory stimuli and pain acting as a means of shutting
down or modulating overwhelming sensory information.
Whereas in animals, tonic immobility (a form of death
feigning) may occur in order to prevent predation, in
humans a tonic immobility followed by unresponsive
immobility/emotional shutdown during inescapable stress
represents a psychological defense to trauma. Tonic immo-
bility and associated shutdown responses during inescap-
able stress can be considered analogous to dissociative
symptomatology, where reduced integration of environ-
mental sensory stimuli is associated with symptoms of dis-
engagement, depersonalization, and derealization, as well
as interrupted formation of memories and experiences of
emotion [26].
Although there is no direct evidence in humans that the
likelihood of survival increases in relation to the onset of
dissociative or shutdown responses, animal research indicates
that these responses are induced by cues that indicate immi-
nent threat, such as mechanical restraint, pointing towards
their role in enhancing survival [27]. Accordingly, future work
in humans should examine specifically whether chances of
survival increase and/or level of threat decreases in association
with tonic immobility or unresponsive immobility. Notably,
bodily reactions to threat consistent with tonic immobility
have been reported among healthy controls [28]. In particular,
when healthy individuals were shown a threatening
image indicating little chance of escape (gun pointing at
them), they exhibited reduced body sway and bradycardia
(indicative of tonic immobility). By contrast,
pictures consistent with an increased chance of escape (gun
pointing away from them) elicited increased body sway (e.g.,
preparation for active escape or flight) [28]. On balance, the
findings reviewed here suggest strongly that the defense cas-
cade model can be applied to humans.
The defense cascade model is complimented by Porges’
polyvagal theory [29], positing that the vagal complex of
the parasympathetic nervous system can be divided into
two systems, the dorsal vagal complex (DVC) and the ven-
tral vagal complex (VVC). The VVC is associated with
bonding, communication with others, and self-soothing,
acting as a brake for the sympathetic nervous system,
which is released under situations of threat allowing fight
or flight responses to occur [29]. Under the polyvagal the-
ory, immobilization and death feigning are thought to oc-
cur due to activation of the DVC and its inhibitory inputs
Curr Psychiatry Rep (2018) 20:118
to the heart, associated with immobilization, bradycardia,
and apnoea [29].
As described above, the PAG plays an important role in
carrying out motor patterns of fight or flight and is impli-
cated in the defense cascade model [25, 26] and in
Mobb’s threat processing model [23, 24]. Recent work
by Nicholson et al. identifies a pattern of predominant
top-down connectivity from the vmPFC to the amygdala
and PAG and from the amygdala to the PAG among indi-
viduals with PTSD+DS, consistent with overmodulation
of fear processing [19••]. Moreover, as compared to
PTSD, individuals with PTSD+DS exhibit greater func-
tional connectivity of both the CMA and the BLA with
frontal regions, supporting previous findings of increased
top-down inhibition and thus reduced defensive
responding via the CMA [17] (see Fig. 2).
Increased connectivity between the BLA and CMA has
also been found with regions involved in consciousness,
awareness, and proprioception, (e.g., superior parietal
lobe, precuneus, and cerebellar culmen) among individ-
uals with PTSD+DS [17], where this increased connectiv-
ity may be directly related to experiences of depersonali-
zation and derealization involving altered spatial percep-
tion, perspective taking, and understanding of oneself as a
part of one’s environment, particularly when confronted
with threat [17].
In a related pattern of contrast, among individuals with
PTSD and PTSD+DS, the amygdala shows differential
connectivity with insula subregions, a structure key to
monitoring of internal states and arousal [18]. Insular sub-
regions are thought to serve differential functions, with the
anterior, mid, and posterior insula associated with arousal
and interoceptive awareness, with awareness of body
movement and body ownership, and with processing and
perception of pain and sensorimotor function, respectively
[30]. Among individuals with PTSD+DS, increased insula-
BLA connectivity across insula subregions was reported in
a recent study when compared to patients with PTSD or
with controls [18]. In addition, dissociative symptoms of
depersonalization and derealization and PTSD symptom
severity predicted anterior insula-BLA connectivity among
PTSD+DS and PTSD patients [18]. These findings may be
related to altered arousal monitoring (e.g., due to the role
of the BLA in the evaluation of sensory information) [18].
Mid-insula-BLA and posterior insula-BLA connectivity,
respectively, may also be related to altered body perception
and reduced sensory integration seen in PTSD+DS [18].
Critically, the insula has been implicated in the defense
cascade model of dissociation, where it may partly mediate
tonic immobility experienced by individuals with PTSD,
leading to reduced responding to internal and external
cues, as well as reduced proprioceptive awareness [25]
(see Fig. 3 and Box 1).
Page 5 of 14 118
Box 1 Functional glossary: anatomical areas implicated in
PTSD, its dissociative subtype (PTSD+DS), dissociative dis-
orders, and borderline personality disorder
Emotion regulation
The Prefrontal Cortex (PFC) comprises distinct areas related to emotion
regulation, emotional processing, and executive functioning. Whereas
PTSD+DS is associated with excessive medial prefrontal inhibition
(mPFC) of limbic regions including the amygdala [16], the classical
presentation of PTSD is characterized by reduced prefrontal activity
and limbic over-activity, representing emotional undermodulation.
Lobule VI and crus I of the cerebellum are also involved in executive
functioning and in the regulation of emotional responses, further
supporting exacerbated top-down inhibition in the dissociative subtype
[31]. Finally, the hippocampus is associated with contextual responses
to traumatic memories [32••].
Emotion reactivity and response
The basolateral amygdala (BLA) aids in the evaluation of sensory infor-
mation and its subsequent cortical processing via projections to the
thalamus, striatum, and PFC. This subregion of the amygdala is mod-
erated by top-down inhibition from the mPFC [21]. By contrast, the
centromedial amygdala (CMA) is responsible for activation of
nociception and for the execution of fear responses via projections to
the PAG and other subcortical brain regions [21].
The periaqueductal gray (PAG) and its subregions contribute to auto-
nomic responses associated with fear. Here, the dorsolateral and lateral
PAG (dl-PAG and l-PAG) are implicated in activation of the sympa-
thetic nervous system in response to threat and active defense
responses, associated with emotional undermodulation [22].
Conversely, the ventrolateral PAG (vl-PAG) promotes emotional
overmodulation, serving as the “brake” for the dl-PAG and l-PAG, and
is associated with passive defensive responses and activation of the
parasympathetic nervous system [22]. The superior colliculus (SC) is
functionally tied to the PAG, allowing the organism to determine the
presence and location of threat in the environment at a subcortical
level. Finally, the hypothalamus is a key structure involved in regu-
lating stress hormones and the HPA axis [33].
Interoceptive awareness
The insular subregions have differential functions; the anterior insula is
associated with arousal and interoceptive awareness; the mid-insula is
related to awareness of body movement and body ownership; and the
posterior insula is associated with processing and perception of pain
and sensorimotor function.
Consciousness, awareness, and proprioception
The precuneus is involved in first-person perspective taking,
consciousness, and self-related mental representations during rest [34].
The superior parietal lobe has a wide range of functions, including
spatial orientation, motor imagery, monitoring of imagined limb
configuration, and proprioception [35]. Both the temporoparietal
junction (TPJ) and rolandic operculum (RO) have been previously
shown to be implicated in depersonalization responses [36–38]. The
dorsal posterior cingulate cortex (dPCC) is involved in consciousness,
awareness, and attention [39].
Fight or flight is associated with endocannabinoid-
mediated analgesia via the l-PAG [25], while tonic and un-
responsive immobility are associated with activation of the
parasympathetic nervous system and opioid-mediated anal-
gesia, leading to reduced awareness by the organism of
 118 Page 6 of 14
Directionality of Connectivity
PTSD
vmPFC
Bilateral
BLA
Bilateral
CMA
PAG
Fig. 2 Based on work by Nicholson and colleagues, the directionality of
connectivity of key brain regions implicated in emotional responding
among individuals with PTSD and PTSD+DS is elucidated. PTSD (left
side of image) is characterized by predominant bottom-up connectivity
from the peraqueductal gray (PAG) to the bilateral centromedial
amygdala (CMA) and from the BLA to the vmPFC suggesting
defensive responding driven by mibrain and limbic regions and chronic
sensory stimuli, including pain, and an effective temporary
“shut-down” of central nervous system activity hypothe-
sized to occur through functional cortical deafferentation
at the level of the thalamus [25, 26].
Importantly, Mobb’s threat detection model and the de-
fense cascade model complement one another, providing a
framework for understanding threat responding in the context
of key dimensions, including perceived imminence,
escapability, and proximity. In particular, both models posit
that when threat is perceived to be imminent, active defensive
responses are employed (e.g., fight or flight), which are driven
by subcortical brain structures (e.g., dACC, PAG) and associ-
ated with decreased prefrontal cortex activation.
Alternatively, increased prefrontal cortex activation is associ-
ated with reduced responding in subcortical regions (e.g.,
PAG and amygdala), driving passive defensive responses
when threat is deemed inescapable, characterized by tonic
immobility and increasing emotional detachment and emo-
tional shutdown if the stressor remains inescapable [23–25].
Taken together, the available evidence suggests that disso-
ciative responses in PTSD+DS are carried out by brain regions
involved in the defense cascade model of dissociation and also
mirror responses seen in Mobb’s threat detection model dur-
ing anticipation of threat. Subcortical regions, including the
amygdala, hypothalamus, and PAG are implicated, with the
PAG emerging as a key subcortical structure involved in mod-
ulation of both fight or flight and dissociative “shut-down”
responses via the dl-PAG/l-PAG and vl-PAG, respectively.
In particular, dissociative responses are thought to occur via
the vl-PAG indicating that the threat is too great for fight or
Curr Psychiatry Rep (2018) 20:118
Dissociative Subtype
vmPFC
Bilateral
BLA
Bilateral
CMA
PAG
fear responses. In contrast, PTSD+DS (right side of image) is
characterized by predominant top-down connectivity between the
bilateral CMA and PAG and vmPFC with the BLA, consistent with
chronic emotional overmodulation and detachment from emotional
responses associated with symptoms of depersonalization and
derealization
flight responses to be effective, leading to release of endoge-
nous opioids and a shutdown of sympathetic signaling and
increase in parasympathetic signaling, resulting in reduced
awareness of the environment and sensory integration.
Critically, the amygdala complexes also play important and
differential roles among individuals with PTSD+DS, with re-
duced activation of threat responses via the CMA and reduced
awareness of the external environment via the BLA due to
increased top-down inhibition [17, 19••] (also see Box 1).
Transdiagnostic Evidence for the Neurobiological
Model of Dissociation as Defensive Overmodulation
of Affective Arousal
The existing evidence among dissociative disorders, in-
cluding DID and depersonalization disorder also points
to aberrant reactivity and functional connectivity of key
regions associated with the defense cascade model of dis-
sociation and Mobb’s threat processing model and mirrors
findings of emotional overmodulation as seen in PTSD+
DS. Specifically, aberrant cortico-limbic functioning
among individuals with depersonalization disorder has
been reported, where increased activation in prefrontal
regions [e.g., mPFC, dlPFC and reduced activation of
limbic regions (e.g., the amygdala)] is seen in conjunction
with attenuated responding of the autonomic system [13].
Moreover, reduced responsivity of the insula has been
noted among individuals with depersonalization disorder
in response to aversive or sad images [13, 14], a finding
that may be related to experiences of tonic immobility and
Curr Psychiatry Rep (2018) 20:118
Paerns of Increased Connecvity
in the Dissociave Subtype versus PTSD
Superior Parietal Lobe,
Dorsal Posterior Post.
Cingulate Cortex, Insula
Precuneus
Temporoparietal Juncon
Consciousness, Awareness
vlPAG
of Bodily Self &
Propriocepon
Cerebellum
Superior Parietal Lobe
Dorsal Posterior Cingulate
Cortex
Precuneus
Temporoparietal Juncon
Fig. 3 Increased patterns of resting-state functional connectivity in the
dissociative subtype as compared to PTSD without the subtype. Here,
brain regions with an asterisk indicate seed regions from insula,
amygdala, and periaqueductal gray functional connectivity studies
comparing patients with the dissociative subtype of PTSD with PTSD
patients [17, 18, 20••]. Regions in green correspond to brain areas
implicated in emotion regulation, including the prefrontal cortex and
lobule VI/crus I of the cerebellum. Areas in yellow correspond to areas
implicated in emotion reactivity and response, including the amygdala
complexes (bilateral basolateral amygdala and centromedial amygdala)
and the ventrolateral periaqueductal gray. Critically, the left amygdala is
associated with detailed and elaborate emotional response evaluation,
while the right amygdala is more involved in rapid and automatic
detection of emotional stimuli [21]. Brain areas in red correspond to
subregions of the insula related to interoceptive awareness. Finally,
brain areas in blue are related to the processing of awareness,
reduced responding to internal and external cues [25] and
that is consistent with findings of reduced insula-BLA
connectivity in PTSD+DS [18].
In addition to findings in depersonalization disorder, indi-
viduals with DID also demonstrate aberrant neural reactivity
consistent with excessive top-down inhibition of limbic re-
gions, depending on their identity state [13, 14]. In particular,
when individuals with DID were in a “traumatic identity state”
(a state with access to trauma memories), these patients
showed increased activity in limbic regions, as well as de-
creased activity in prefrontal regions, and increased perfusion
in the thalamus in comparison to when they were in their
“normal functioning identity state” (a state where dissociative
amnesia is present) [13, 14]. Findings of increased thalamic
perfusion in the trauma vs. dissociative identity state are crit-
ical given the role of the thalamus in sensory integration and in
the defense cascade model of dissociation [3, 25]. Moreover,
Sar and colleagues reported reduced perfusion in the
orbitofrontal cortex of individuals with DID while in their
Page 7 of 14 118
Interocepve Awareness
Anterior Insula*
Mid Insula*
Posterior Insula*
Mid Ant.
Insula Insula Emoon Regulaon
PFC
PFC
Le Cerebellum (Lobule VI/Crus I)
BLA
Le
CMA Right
BLA
Right
CMA
Emoon Reacvity & Response
Le Basolateral Amygdala*
Right Basolateral Amygdala*
Le Centromedial Amygdala*
Right Centromedial Amygdala*
Ventrolateral Periaqueductal Gray*
consciousness, and proprioception, including the superior parietal lobe,
dorsal posterior cingulate cortex, precuneus, and the temporoparietal
junction. Importantly, among patients with the dissociative subtype of
PTSD, increased connectivity between emotion regulation regions
(regions in green) and emotion reactivity regions (regions in yellow) is
thought to contribute to a characteristic pattern of emotion
overmodulation associated with symptoms such as depersonalization
and derealization and emotional detachment. Additionally, increased
connectivity between emotion reactivity regions (regions in yellow) and
regions relating to interoceptive awareness, perception of self, and bodily
self-awareness (regions in blue) may provide an explanation for
symptoms such as an altered sense of self and altered perception of the
environment associated with symptoms of depersonalization and
derealization. Abbreviations: PFC, prefrontal cortex; BLA, basolateral
amygdala; CMA, centromedial amygdala; vlPAG, ventrolateral
periaqueductal gray; post, posterior; ant, anterior
“normal identity state” [40], suggesting that during the normal
identity state individuals with DID may experience emotional
undermodulation. Importantly, in Mobb’s threat processing
model, the OFC is activated as threat becomes more distant,
suggesting it is involved in signaling safety [24].
Finally, among BPD samples, whereas trait dissociation
was associated with increased amygdala-dlPFC connectivity,
acute dissociative experiences correlated to reduced amygdala
reactivity to negative stimuli [13], again mimicking findings
among individuals with PTSD+DS [41]. Furthermore, among
individuals with BPD, increased prefrontal activity and re-
duced amygdala responding in response to painful stimuli
has been reported in conjunction with reduced pain sensitivity
[13, 14].
In sum, the available literature investigating dissociation
transdiagnostically among PTSD+DS, depersonalization dis-
order, DID, and BPD supports a model of emotional
overmodulation underlying dissociative experiences.
Moreover, these findings converge with the defense cascade
 118 Page 8 of 14
model of dissociation highlighting aberrant reactivity of lim-
bic regions, including the amygdala and insula [25] seen in
dissociative disorders and BPD [13, 14].
Opioid- and Endocannabinoid-Mediated
Contributions to Dissociation and Stress
Responses
Opioid-Mediated Contributions
Recent work elucidating the neurochemical components of the
defense cascade model of dissociation provides opportunities
for the identification of specific, targeted treatment approaches
for dissociative symptoms transdiagnostically. As mentioned
briefly above, opioid-mediated contributions play a critical role
in defensive responding. Moreover, not only are opioids in-
volved in the analgesic aspects of defensive responses, but they
also play important roles in their enactment. Specifically, opi-
oids are implicated in immobility, suppressed vocal responses,
and downregulation of the sympathetic nervous system [3].
Furthermore, opioid receptors are found in high volumes in
the thalamus and claustrum and may be related to reduced
somatosensory integration and disruptions in consciousness as-
sociated with shutdown defensive responses [3, 42].
The endogenous opioid system has long been associated
with combine paragraphs PTSD. Here, seminal work by van
der Kolk utilizing an animal model of PTSD, inescapable
shock, provided a key demonstration of the relation between
endogenous opioids and stress-induced analgesia [43], with
later work identifying further an association between chronic
PTSD symptomatology and heroin abuse in Vietnam veterans
[44]. The inescapable shock model has been suggested to
mimic closely chronic, inescapable trauma experienced by
victims of childhood abuse. Inescapable shock is also associ-
ated with altered responding of the endogenous opioid system,
particularly, initial upregulation followed by chronic down-
regulation of opioid signaling [43]. It was hypothesized that
these processes become conditioned responses, replicable at
the time of exposure to trauma cues or subsequent stress [43].
This hypothesis was supported in work identifying secretion
of endogenous opioids following exposure to trauma-related
stimuli [45] and increased β-endorphin levels in the cerebro-
spinal fluid of veterans with PTSD compared to those without
PTSD, as well as correlations between PTSD intrusion and
avoidant symptoms and β-endorphin levels [46].
Notably, it has been further suggested that this chronic
downregulation of the endogenous opioid system and upreg-
ulation of opioid release in response to stress may lead trau-
matized individuals to engage in subsequent self-destructive
behavior (e.g., self-harm, involvement in future abusive rela-
tionships) [47]. Additional research suggests that the release
of opioids at the time of trauma may be protective, where
Curr Psychiatry Rep (2018) 20:118
among juvenile burn victims, levels of PTSD symptomatolo-
gy were correlated with the dose of morphine received
posttrauma, such that those who received higher doses of
morphine reported fewer PTSD symptoms 6 months
posttrauma [48]. Similarly, individuals given morphine during
initial treatment of physical trauma were less likely to develop
PTSD (OR 0.47, p < .001) [49]. Taken together, these findings
suggest that mu-opioid receptors play an important role in
posttrauma reactions and increased opioid signaling following
trauma may be protective.
Indeed, upregulation of opioid responding appears to per-
sist among individuals with PTSD. For example, Pitman and
colleagues reported findings of naloxone (opioid receptor an-
tagonist) reversible stress-induced analgesia among veterans
with PTSD in comparison to those without PTSD, suggesting
upregulation of the opioid response following exposure to
trauma cues [50]. In addition, altered mu-opioid receptor bind-
ing has been reported among combat-exposed individuals
with PTSD and those without PTSD in comparison to non-
trauma-exposed controls, where reduced binding was reported
in subcortical regions, including the amygdala and thalamus,
and cortical regions, including the insula, mPFC, and dorsal
ACC [51]. By contrast, increased binding was reported in the
orbitofrontal cortex among the PTSD group compared with
the trauma-exposed controls and healthy controls [51]. Here,
the authors posit that inhibitory action of mu-opioid receptors
in the OFC may lead to impaired regulation of subcortical
structures involved in emotional responding [51], i.e., emotion
undermodulation.
Opioids also play a central role in attachment processes,
where social isolation is associated with reduced opioid levels
and reduced availability of endogenous opioids leads to in-
creased motivation to seek social contact [52]. Here, van der
Kolk linked profound disruptions in attachment that occur as a
result of prolonged childhood abuse with alterations in the en-
dogenous opioid system [43], as mirrored in findings of altered
endogenous opioid levels and receptor availability among indi-
viduals with PTSD [45, 46, 51]. The relation between attach-
ment processes and alterations in the endogenous opioid system
are of particular importance given the strong relation between
attachment trauma and dissociative symptomatology [53, 54].
This may explain why betrayal trauma, assault by one expected
to love and protect, is particularly likely to trigger immobiliza-
tion, since it imposes not only the current assault but diminishes
the prospect of future escape [55].
Whereas most studies have investigated the mu-opioid sys-
tem (activated by neurochemical endorphins) in trauma-
exposed persons, the kappa-opioid system is also a candidate
mechanism for mediating negative emotional experiences
such as depression and dysphoria to chronic inescapable stress
[56]. Recent evidence for the dysphoric components of the
kappa-opioid system comes from a study demonstrating that
the dissociogenic drug ketamine’s antidepressant effect is
Curr Psychiatry Rep (2018) 20:118
completely blocked by the opiate antagonist naloxone [57].
Furthermore, recent work has tied the kappa-opioid system
(dynorphins) to disruptions in consciousness [42, 58•]. Here,
studies reveal that individuals who ingested Salvia divinorum
(SD), a kappa-opioid receptor agonist, described alterations in
consciousness, including abrupt shifts in normal waking con-
sciousness and disorientation, marked changes in sensory pro-
cessing and perceptual integration (including auditory, visual,
and interoceptive perception), visual distortions, tactile, or
kinaesthetic hallucinations, change in affect (both negative
and positive), and altered reality monitoring [42, 58•].
Notably, these individuals also reported experiences of deper-
sonalization, or a feeling as though they do not belong to their
own body, similar to those described as altered states of con-
sciousness associated with PTSD+DS [59]. Although these
experiences may not be precisely equivalent to dissociative
experiences of individuals with PTSD+DS or other trauma-
related disorders, we hypothesize that the kappa-opioid sys-
tem may play a contributing role in experiences of dissocia-
tion in trauma-related disorders (see Fig. 2). In particular,
opioid-mediated analgesia is thought to be a key component
of defensive “shut-down,” and may also play a critical role in
the experience of disrupted consciousness, as seen during dis-
sociative states [25].
The claustrum has been implicated as a key structure in-
volved in kappa-opioid mediated disruptions in conscious-
ness, and potentially, dissociative experiences [42, 60]. In par-
ticular, the claustrum is thought to be in part responsible for
consciousness given its anatomical location and reciprocal
connections with multiple cortical regions [60]. More recently,
it has been suggested that the endogenous kappa-opioid sys-
tem may play a key role in this function, given high volumes
of kappa-opioid receptors (KOR) in the claustrum and afore-
mentioned alterations in experiences of consciousness de-
scribed by subjects who have ingested SD [42]. Importantly,
the claustrum has also been implicated in defensive
responding among individuals with PTSD [61]. Along with
the insula, the claustrum is considered a component of the
salience network (SN), a brain network integral in orienting
individuals to salient internal and external stimuli. Recent in-
vestigations have revealed decreased integration of the claus-
trum with the SN during subliminal threat processing among
individuals with PTSD [61]. Although not investigated in
PTSD+DS specifically, this finding may indicate a reduced
ability to integrate conscious experience during salience de-
tection (in this case, threat detection) among individuals with
PTSD. Critically, given the claustrum’s role in the integration
of perceptual stimuli into consciousness, aberrant functioning
of the claustrum could lead to disrupted threat processing ob-
served in both PTSD and its dissociative subtype.
In line with these findings, emerging work using positron
emission tomography (PET) neuroimaging has identified al-
terations in KOR receptor availability among trauma-exposed
Page 9 of 14 118
individuals in relation to trauma-related symptomatology.
Specifically, lower levels of KOR availability in the
amygdala-anterior cingulate cortex-ventral striatal neural cir-
cuit, and in the insula, caudate, and frontal cortex were asso-
ciated with increased severity of a composite symptom score,
including symptoms of emotional numbing, anhedonia, de-
tachment, and reduced range of affect [62]. Here, reduced
availability of KORs may be related to increased circulating
opioids following trauma. The aforementioned symptoms
converge with symptoms such as emotional numbing and de-
tachment. Furthermore, these regions are implicated in both
Mobb’s threat processing model and the defense cascade
models of dissociation.
Finally, emerging work has identified increased functional
connectivity of the claustrum with the bed nucleus of the stria
terminalis (BNST) among individuals with PTSD+DS as
compared to those with PTSD and to healthy controls [63].
The BNST is a subcortical brain structure considered an ex-
tension of the amygdala that has been implicated consistently
in the anticipation of threat and worry about the future (as
compared to the amygdala, involved in evaluation and re-
sponse to immediate threat) [63]. Critically, as the BNST also
contains KORs, the authors posit that increased connectivity
between the BNST and the claustrum in PTSD+DS may be
related to increased activation of the kappa-opioid system in
response to chronic inescapable stress, leading to dissociative
symptoms and secondary dysphoria.
Thus, while alterations in the mu-opioid system first
emerged in the PTSD literature, in association with symptoms
including intrusions and avoidance and increased analgesia [3,
45, 46], the kappa-opioid system has emerged as a candidate
neurochemical system mediating alterations in consciousness.
In particular, while both the mu- and kappa-opioid system
may be involved in dissociative reactions and the defense
cascade, the mu-opioid system may be related to analgesic
effects, while the kappa-opioid system is responsible for alter-
ations in consciousness and dysphoria. Here, we posit that the
kappa-opioid system and claustrum play key roles in dissocia-
tive symptoms and dysphoria. In particular, this hypothesis is
supported by findings of increased endogenous opioids
among individuals with PTSD [45, 46] and evidence of aber-
rant functional connectivity of the claustrum in PTSD+DS
[63], coupled with the role of the claustrum in experiences
of consciousness as mediated by the kappa-opioid system
[42]. Furthermore, when considering the role of opioid during
defensive shutdown under conditions of inescapable stress (as
in defense cascade model of dissociation), it is likely that the
release of opioids during this shift in defensive responding
plays a role in experiences of disrupted consciousness. In par-
ticular, given findings reviewed above indicating an associa-
tion between the kappa-opioid system and experiences of al-
tered consciousness in healthy individuals [42, 58•] and the
dissociative quality of defensive shutdown responses, it is
 118 Page 10 of 14
possible that the release of endogenous opioids during this
phase of the defense cascade underlies experiences of
disrupted consciousness.
Endocannabinoid-Mediated Contributions
The endogenous cannabinoid (endocannabinoid) system has
also been characterized as a key component of the defense
cascade model (see Fig. 1). In particular, endocannabinoid
signaling, emanating from the lateral PAG [2], is responsible
for analgesia during the fight or flight response [25]. In addi-
tion, endocannabinoids are important regulators of the stress
response and are involved in adaption of the neuroendocrine
system following repeated stress [64]. Endocannabinoids play
a neuromodulatory role associated with inhibition of neuro-
transmitter release from both excitatory and inhibitory neu-
rons and have been shown to influence the behavioral com-
ponents of the fight or flight stage of the defense cascade [64].
For example, cannabis use has been associated with reduced
neuronal firing in the amygdala and increased reactivity of the
vmPFC of humans in response to emotional stimuli [64].
Importantly, among individuals with PTSD, increased avail-
ability of cannabinoid receptor type 1 (CB1 receptors) in the
amygdala (associated with reduced bioavailability of
endocannabinoids) was associated with increased attentional
bias to threat, which mediated the relation between CB1 re-
ceptor availability and threat-related symptomatology (e.g.,
re-experiencing, hyperarousal) [65]. These data suggest that
reduced levels of endocannabinoids may be related to in-
creased threat sensitivity and related symptoms in individuals
with PTSD.
Given these findings, among others, Hill et al. [64] sug-
gest an endocannabinoid deficiency hypothesis of PTSD,
where exposure to stress reduces endocannabinoid signal-
ing, resulting in hyperactivity of the amygdala, hypoactivity
of the mPFC, and impaired regulation of the stress response.
This may be particularly relevant for individuals who expe-
rience predominantly emotion undermodulation. By con-
trast, the effects of cannabinoids on other brain structures
implicated in Mobb’s fear processing model and the defense
cascade model may diverge from these findings.
Specifically, injection of cannabinoid receptor agonists into
the dl-PAG of rats was associated with increased sympathet-
ic activity, blood pressure, and limb movements [66], sug-
gesting that they may be important in carrying out motor
and sympathetic responses of fight or flight. Paradoxically,
exposure to stressful stimuli has been associated with in-
creased levels of endocannabinoids in the PAG of rats and
injection of CB1 agonists into the PAG has also been asso-
ciated with anxiolytic effects in rats [67]. Importantly, these
aberrant findings may be understood through findings of a
bell-shaped dose response curve, whereby low doses of
Curr Psychiatry Rep (2018) 20:118
cannabinoids are associated with anxiolytic effects and high
doses are associated with anxiogenic effects [68].
Given the role of endocannabinoids in mediating fight or
flight in the defense cascade, their neuromodulatory role and
impact on emotional responses via signaling in the amygdala
and vmPFC, and their role in modulating activity of the PAG,
modulation of the endocannabinoid system may provide an
opportunity to treat emotion undermodulation, including
hyperarousal/fight or flight symptoms associated with the de-
fense cascade. Importantly, however, cannabinoids are known
to have paradoxical effects at high doses, where increased
fight or flight and panic-like symptoms are observed.
Implications for Treatment and Future Pharmacotherapies
Increased identification of the roles of the kappa-opioid and
endocannabinoid systems in the defense cascade model pro-
vides a unique opportunity for identification of targeted novel
pharmacotherapeutic interventions for individuals with PTSD
and PTSD+DS, and for those experiencing clinically signifi-
cant dissociative symptoms more broadly (see Table 1). This
is particularly critical given the only modest efficacy of cur-
rent pharmacotherapy approaches for individuals with PTSD
[69] and findings that individuals with PTSD often retain their
diagnosis or continue to experience clinically significant
symptoms following treatment with first-line psychotherapies
[70, 71]. Furthermore, pharmacological and non-
pharmacological treatment approaches to dissociative symp-
toms in PTSD+DS and transdiagnostically have not been ad-
equately explored.
Both endocannabinoids and opioids are released in re-
sponse to stress and play differential and important roles in
the defensive cascade model, modulating fight or flight and
dissociative shutdown responses, respectively. Thus, modula-
tion of these neurochemicals provides the opportunity to in-
tervene differentially for patients exhibiting predominantly
emotion undermodulation/fight or flight symptomatology
(PTSD) and those who present with emotion
overmodulation/passive defensive responses associated with
dissociative symptoms (PTSD+DS). Pharmacological inter-
ventions that target these neurochemical systems may be of
significant benefit as these patterns of defensive responding
are re-enacted among individuals with trauma-related pathol-
ogy. Evidence of disrupted endocannabinoid and opioid sig-
naling among individuals with PTSD and other trauma-related
pathology provides further evidence for their potential utility.
Indeed, emerging evidence points to the use of naloxone and
naltrexone, nonspecific opioid receptor antagonists targeting
both mu- and kappa-opioid receptors, in the treatment of dis-
sociative symptoms among individuals with depersonaliza-
tion disorder [72] and BPD [51; but see 52].
The kappa-opioid system has been linked further to dys-
phoric components of the opioid response, including reduced
Curr Psychiatry Rep (2018) 20:118
Table 1 Hypothesized mechanisms and target symptoms of proposed
pharmacological interventions
Proposed Symptom targeted Hypothesized
pharmacological mechanism
treatment and evidence
Opioid-receptor • Dissociative symptoms, Reduced signaling at
antagonists including KORs
depersonalization, • KORs linked to
derealization, dysphoric components
emotional numbing, of opioid response
and dysphoria
• Reduced KOR
availability in amygdala
and anterior cingulate
cortex associated with
dysphoric symptoms
among trauma-exposed
individuals
• Use of KOR agonists
associated with
experiences of altered
consciousness,
disorientation, and
perceptual disturbances,
including
depersonalization and
derealization
Cannabinoid • Hyperarousal, Increased activation of
receptor re-experiencing CB1 receptors
agonists symptoms • Increased availability of
CB1 receptors (due to
reduced bioavailability
of endocannabinoids) in
amygdala of individuals
with PTSD associated
with increased
attentional bias to threat
and hyperarousal
• Treatment with nabilone
(synthetic cannabinoid)
or THC associated with
reduced nightmares and
hyperarousal in
individuals with PTSD
(small uncontrolled
trial)
KOR, kappa-opioid receptor; CB1, cannabinoid receptor type 1
motivation, and has been associated with depressive states
[73]. KOR antagonists have also been found to have antide-
pressant effects among rodents [74]. Furthermore, recent work
highlights that among trauma-exposed individuals, KOR
availability in several key regions associated with Mobb’s
defense model and the defense cascade model, including the
amygdala and anterior cingulate cortex, are associated with
dysphoric symptoms [62]. Thus, these findings provide pro-
vocative evidence that opioid receptor antagonists, and in par-
ticular KOR antagonists, may be effective both in disrupting
re-enactment of emotional shutdown and in reducing
Page 11 of 14 118
dissociative symptoms of depersonalization and derealiza-
tion and negative mood states associated with PTSD+DS.
Importantly, given the transdiagnostic nature of dissocia-
tive symptoms [8], KOR antagonists may prove to be
useful in their treatment across disorders where dissocia-
tive symptoms predominate.
Whereas the kappa-opioid system exerts its influence dur-
ing the unresponsive immobility/emotional shutdown phase
of the defense cascade model, endocannabinoids have
emerged as important regulators of fight or flight responses.
Emerging work also highlights the potential utility of canna-
binoid receptor agonists in the treatment of PTSD. In particu-
lar, uncontrolled trials of nabilone, a synthetic form of Δ9-
tetrahydocannbinol (THC, the psychoactive component of
cannabis), have reported reductions in nightmares and re-
duced PTSD symptom severity among individuals with
PTSD [75, 76]. In addition, a recent randomized-controlled
trial reported a reduction in distressing nightmares in a small
sample of individuals with PTSD [77]. Specifically, a sample
of 10 males with PTSD stemming from operational trauma
(i.e., combat) who reported distressing dreams at baseline ex-
perienced a significant reduction on the Clinician
Administered PTSD Scale (CAPS) recurrent and distressing
dreams item (− 3.6 points, where the maximum score is 8 and
higher scores indicate greater frequency and intensity of
symptoms) after receiving treatment with nabilone for a peri-
od of 7 weeks [77]. Similarly, the addition of THC to the drug
regimen of individuals with PTSD was associated with re-
duced nightmares and hyperarsoual [78]. Thus, there is emerg-
ing evidence that treatment with THC or nabilone reduces
nightmares among individuals with PTSD and may be asso-
ciated with reduced hyperarousal.
Although treatment with both kappa-opioid antagonists
and cannabinoids appears to hold promise for the treatment
of dysregulation in the dissociative and fight or flight compo-
nents of the defense cascade among individuals with PTSD
and PTSD+DS, respectively, a lack of rigorous randomized-
controlled trials precludes definitive conclusions about their
efficacy. Furthermore, given findings of bell-shaped dose re-
sponse curve for the use of cannabis [68], careful dosing and
investigation of the therapeutic effects of different doses will
be important. Similarly, KOR antagonists have been found to
have long durations of action [74], and thus careful investiga-
tion of dosing and effects of the drug over the period that it is
active will be necessary. Moreover, the utility of these inter-
ventions may differ for individuals with PTSD+DS and those
with PTSD. Specifically, individuals with PTSD+DS do not
experience only static symptoms of depersonalization and de-
realization, but rather vacillate between symptoms of emotion
under- and overmodulation (although emotion overmodulation
predominates). By contrast, individuals with PTSD without the
dissociative subtype do not usually experience symptoms of
depersonalization and derealization [16]. It is therefore
 118 Page 12 of 14
important to treat both symptoms of emotion under- and
overmodulation experienced in PTSD+DS, and thus treatment
with endocannabinoids may be appropriate not only for indi-
viduals with PTSD but may also be potentially combinable with
KOR antagonists in those with PTSD+DS. Importantly, the
longitudinal course of PTSD and PTSD+DS remain unknown
(e.g., an individual may meet criteria for PTSD and PTSD+DS
at different times), rendering it necessary for clinicians to close-
ly monitor patient’s symptoms in order to ensure appropriate
treatment.
Conclusions
We have reviewed emerging neurobiological models of disso-
ciative symptomatology often experienced by individuals
with trauma-related disorders, including the dissociative sub-
type of PTSD, BPD, and DID as well as other psychiatric
disorders. In particular, the defense cascade model of dissoci-
ation and Mobb’s threat processing model complement one
another to provide an elegant description of neurobiological
responses to threat and, consequently, dissociative symptom-
atology [23–25]. These models describe differential responses
to threat depending on perceived imminence, escapability, and
proximity. Here, individuals utilize active defensive responses
(e.g., fight or flight) driven by subcortical brain structures
(e.g., PAG, amygdala) and associated decreased prefrontal
cortex activation when threat is perceived to be imminent
(e.g., fight or flight). By contrast, when threat is deemed ines-
capable, reduced activation of subcortical regions (e.g., PAG
and amygdala) associated with increased prefrontal cortex
activation drive passive defensive responses characterized by
emotional detachment and dissociative shutdown, including
reduced responding to environmental stimuli, a response char-
acteristic of dissociative symptoms, including depersonaliza-
tion and derealization [23–25]. A growing body of evidence
reviewed here suggests key alterations in structures implicated
in these models among individuals with PTSD+DS, BPD and
DID, including most notably, the amygdala, PAG, claustrum,
and prefrontal cortical regions [13, 14, 17, 18, 19••, 20••, 63].
Indeed, emerging work has identified aberrant reactivity and
connectivity of subcortical regions involved in the defense
cascade, including the PAG, amygdala, and claustrum among
individuals with PTSD+DS, as well as findings of predomi-
nant top-down connectivity between forebrain and subcortical
regions consistent with early findings of emotional
overmodulation [17, 18, 19••, 20••, 63].
Our understanding of these neurobiological mechanisms
allows for the opportunity to discover novel pharmacological
interventions. We reviewed an emerging body of evidence
implicating the kappa-opioid system in experiences of altered
consciousness, carried out by regions implicated in PTSD+
DS, including the BNST and claustrum [42, 56, 58•, 60, 63].
Thus, we suggest that treatment with kappa-opioid antagonists
Curr Psychiatry Rep (2018) 20:118
may be a promising approach to the treatment of emotion
overmodulation, including symptoms of depersonalization
and derealization [79]. In contrast, the endocannabinoid sys-
tem has been implicated in downregulation of fight or flight
responses of the defense cascade, suggesting that treatment
with cannabinoids may target emotion undermodulation,
which importantly, is experienced by individuals with
PTSD+DS and often precede symptoms of emotion
overmodulation, including symptoms of depersonalization
and derealization. Future work will be critical to understand
the efficacy of these putative pharmacological interventions,
particularly in order to determine when and at what doses
therapeutic effectiveness can be achieved.
References
Papers of particular interest, published recently, have been
highlighted as:
• Of importance
•• Of major importance
1. American Psychiatric Association. Diagnostic and statistical man-
ual of mental disorders. 5th ed. Arlington: American Psychiatric
Publishing; 2013.
2. Briere J, Weathers FW, Runtz M. Is dissociation a multidimensional
construct? Data from the multiscale dissociation inventory. J
Trauma Stress. 2005;18(3):221–31.
3. McKinnon MC, Boyd JE, Frewen PA, Lanius UF, Jetly R,
Richardson JD, et al. A review of the relation between dissociation,
memory, executive functioning and social cognition in military
members and civilians with neuropsychiatric conditions.
Neuropsychologia. 2016;90:210–34.
4. Spiegel D, Lewis-Fernández R, Lanius R, Vermetten E, Simeon D,
Friedman M. Dissociative disorders in DSM-5. Annu Rev Clin
Psychol. 2013;9:299–326.
5. Dalenberg CJ, Brand BL, Gleaves DH, Dorahy MJ, Loewenstein
RJ, Cardeña E, et al. Evaluation of the evidence for the trauma and
fantasy models of dissociation. Psychol Bull. 2012;138(3):550–88.
6. Wolf EJ, Lunney CA, Miller MW, Resick PA, Friedman MJ,
Schnurr PP. The dissociative subtype of PTSD: a replication and
extension. Depress Anxiety. 2012;29:679–88.
7. Stein DJ, Koenen KC, Friedman MJ, Hill E, McLaughlin KA,
Petukhova M, et al. Dissociation in posttraumatic stress disorder:
evidence from the world mental health surveys. Biol Psychiatry.
2013;73(4):302–12.
8. Lyssenko L, Schmahl C, Bockhacker L, Vonderlin R, Bohus M,
Kleindienst N. Dissociation in psychiatric disorders: a meta-
analysis of studies using the dissociative experiences scale. Am J
Psychiatry. 2017;175:37–46.
9. Simeon D, Guralnik O, Schmeidler J, Sirof B, Knutelska M. The
role of childhood interpersonal trauma in depersonalisation disor-
der. Am J Psychiatry. 2001;158(9):1027–33.
10. Parlar M, Frewen PA, Oremus C, Lanius RA, Mckinnon MC.
Dissociative symptoms are associated with reduced neuropsycho-
logical performance in patients with recurrent depression and a
history of trauma exposure. Eur J Psychotraumatol. 2016;7:29061.
Curr Psychiatry Rep (2018) 20:118
11. Sar V, Akyüz G, Oztürk E, Alioğlu F. Dissociative depression
among women in the community. J Trauma Dissociation.
2013;14:423–38.
12. Vonderlin R, Kleindienst N, Alpers GW, Bohus M, Lyssenko L,
Schmahl C. Dissociation in victims of childhood abuse or neglect:
a meta-analytic review. Psychol Med. 2018.
13. Krause-Utz A, Frost R, Winter D, Elzinga BM. Dissociation and
alterations in brain function and structure: implications for border-
line personality disorder. Curr Psychiatry Rep. 2017;19:6.
14. Brand BL, Lanius R, Vermetten E, Loewenstein RJ, Spiegel D.
Where are we going? An update on assessment, treatment, and
neurobiological research in dissociative disorders as we move to-
ward the DSM-5. J Trauma Dissociation. 2012;13:9–31.
15. Sar V, Alioǧlu F, Akyüz G. Experiences of possession and paranor-
mal phenomena among women in the general population: are they
related to traumatic stress and dissociation? J Trauma Dissociation.
2014;15(3):303–18.
16. Lanius RA, Vermetten E, Loewenstein RJ, Brand B, Christian S,
Bremner JD, et al. Emotion modulation in PTSD: clinical and neu-
robiological evidence for a dissociative subtype. Am J Psychiatry.
2010;167(6):640–7.
17. Nicholson AA, Densmore M, Frewen PA, Théberge J, Neufeld RW,
McKinnon MC, et al. The dissociative subtype of posttraumatic
stress disorder: unique resting-state functional connectivity of
basolateral and centromedial amygdala complexes.
Neuropsychopharmacology. 2015;40(10):2317–26.
18. Nicholson AA, Sapru I, Densmore M, Frewen PA, Neufeld RWJ,
Theberge J, et al. Unique insula subregion resting-state functional
connectivity with amygdala complexes in posttraumatic stress dis-
order and its dissociative subtype. Psychiatry Res Neuroimaging.
2016;250:61–72.
19.•• Nicholson AA, Friston KJ, Zeidman P, Harricharan S, McKinnon MC,
Densmore M, et al. Dynamic causal modeling in PTSD and its disso-
ciative subtype: bottom-up versus top-down processing within fear and
emotion regulation circuitry. Hum Brain Mapp. 2017;38(11):5551–61.
This recent study utilizes dynamic causal modeling to elucidate the
directionality of connectivity between key brain regions implicated
in PTSD and its dissociative subtype.
20.•• Harricharan S, Rabellino D, Frewen P, Densmore M, Theberge J,
McKinnon M, et al. fMRI functional connectivity of the
periaqueductal gray in PTSD and its dissociative subtype. Brain
Behav. 2016;6:e00579. This study highlights novel work indicat-
ing an important role of the periaqueductal gray in the neuro-
biology of PTSD and its dissociative subtype.
21. Duvarci S, Pare D. Amygdala microcircuits controlling learned fear.
Neuron. 2014;82:966–80.
22. Bandler R, Keay KA, Floyd N, Price J. Central circuits mediating
patterned autonomic activity during active vs. passive emotional
coping. Brain Res Bull. 2000;53(1):95–104.
23. Mobbs D, Marchant JL, Hassabis D, Seymour B, Tan G, Gray M,
et al. From threat to fear: the neural organization of defensive fear
systems in humans. J Neurosci. 2009;29(39):12236–43.
24. Mobbs D, Yu R, Rowe JB, Eich H, FeldmanHall O, Dalgleish T.
Neural activity associated with monitoring the oscillating threat
value of a tarantula. Proc Natl Acad Sci U S A. 2010;107(47):
20582–6.
25. Kozlowska K, Walker P, McLean L, Carrive P. Fear and the defense
cascade. Harv Rev Psychiatry. 2015;23(4):263–87.
26. Schauer M, Elbert T. Dissociation following traumatic stress.
Zeitschrift Psychol / J Psychol. 2010;218(2):109–27.
27. Gallup GG, Rager DR. Tonic immobility as a model of extreme
states of behavioural inhibition. In: Sanberg PR, Ossenkopp KP,
Kavaliers M, editors. Motor activity and movement disorders.
New York: Springer Science+Business Media; 1996.
28. Volchan E, Rocha-Rego V, Bastos AF, Oliveira JM, Franklin C,
Gleiser S, et al. Immobility reactions under threat: a contribution
Page 13 of 14 118
to human defensive cascade and PTSD. Neurosci Biobehav Rev.
2017;76:29–38.
29. Porges SW. The polyvagal theory: neurophysiological foundations
of emotions, attachment, communication, and self-regulation. New
York: Norton; 2011.
30. Craig AD. How do you feel—now? The anterior insula and human
awareness. Nat Rev Neurosci. 2009;10(1):59–70.
31. Stoodley C, Schmahmann J. Evidence for a topographic organiza-
tion in the cerebellum of motor control versus cognitive and affec-
tive processing. Cortex. 2010;46:831–44.
32.•• Fenster RJ, Lebois LAM, Ressler KJ, Suh J. Brain circuit dysfunc-
tion in post-traumatic stress disorder: from mouse to man. Nat Rev
Neurosci. 2018;19:535–51. A recent review describing alter-
ations in brain function and connectivity and symptom do-
mains of PTSD.
33. Ulrich-Lai YM, Herman JP. Neural regulation of endocrine and
autonomic stress responses. Nat Rev Neurosci. 2009;10:397–409.
34. Cavanna AE, Trimble MR. The precuneus: a review of its function-
al anatomy and behavioural correlates. Brain. 2006;129:564–83.
35. Wolbers T, Weiller C, Büchel C. Contralateral coding of imagined
body parts in the superior parietal lobe. Cereb Cortex. 2003;13:
392–9.
36. Zaytseva Y, Szymanski C, Gutyrchik E, Pechenkova E, Vlasova R,
Wittmann M. A disembodied man: a case of somatopsychic deper-
sonalization in schizotypal disorder. Psych J. 2015;4:186–98.
37. Murray RJ, Debbané M, Fox PT, Bzdok D, Eickhoff SB. Functional
connectivity mapping of regions associated with self- and other-
processing. Hum Brain Mapp. 2015;36:1304–24.
38. Blanke O, Arzy S. The out-of-body experience: disturbed self-
processing at the temporo-parietal junction. Neuroscientist.
2005;11:16–24.
39. Leech R, Sharp DJ. The role of the posterior cingulate cortex in
cognition and disease. Brain. 2014;137:12–32.
40. Sar V, Unal SN, Ozturk E. Frontal and occipital perfusion changes
in dissociative identity disorder. Psychiatry Res Neuroimaging.
2007;156(3):217–23.
41. Lanius RA, Brand B, Vermetten E, Frewen PA, Spiegel D. The
dissociative subtype of posttraumatic stress disorder: rationale, clin-
ical and neurobiological evidence, and implications. Depress
Anxiety. 2012;29(8):701–8.
42. Stiefel KM, Merrifield A, Holcombe AO. The claustrum’s pro-
posed role in consciousness is supported by the effect and target
localization of Salvia divinorum. Front Integr Neurosci. 2014;8:20.
43. van der Kolk BA. The trauma spectrum: the interaction of biolog-
ical and social events in the genesis of the trauma response. J
Trauma Stress. 1988;1(3):273–90.
44. Bremner JD, Southwick SM, Darnell A, Charney DS. Chronic
course ptsd in Vietnam combat veterans: course of illness and sub-
stance abuse. Am J Psychiatry. 1996;153(3):369–75.
45. Van der Kolk BA. The psychobiology and psychopharmacology of
PTSD. Hum Psychopharmacol. 2001;16:S49–64.
46. Baker DG, West SA, Orth DN, Hill KK, Nicholson WE, Ekhator NN,
et al. Cerebrospinal fluid and plasma β-endorphin in combat veterans
with post-traumatic stress disorder. Psychoneuroendocrinology.
1997;22(7):517–29.
47. van der Kolk BA. The compulsion to repeat the trauma: re-enact-
ment, revictimization, and masochism. Psychiatr Clin N Am.
1989;12:389–411.
48. Saxe G, Stoddard F, Courtney D, Cunningham K, Chawla N,
Sheridan R, et al. Relationship between acute morphine and the
course of PTSD in children with burns. J Am Acad Child
Adolesc Psychiatry. 2001;40(8):915–21.
49. Holbrook TL, Galarneau MR, Dye JL, Quinn K, Dougherty AL.
Morphine use after combat injury in Iraq and post-traumatic stress
disorder. N Engl J Med. 2010;362(2):110–7.
 118 Page 14 of 14
50. Pitman RK, van der Kolk BA, Orr SP, Greenberg MS. Naloxone-
reversible analgesic response to combat-related stimuli in posttraumatic
stress disorder: a pilot study. Arch Gen Psychiatry. 1990;47:541–4.
51. Liberzon I, Taylor SF, Phan KL, Britton JC, Fig LM, Bueller JA,
et al. Altered central μ-opioid receptor binding after psychological
trauma. Biol Psychiatry. 2007;61(9):1030–8.
52. Panksepp J. Affective neuroscience: the foundation of human and
animal emotions. New York: Oxford University Press; 1998.
53. Schore AN. Dysregulation of the right brain: a fundamental mech-
anism of traumatic attachment and the psychopathogenesis of post-
traumatic stress disorder. Aust N Z J Psychiatry. 2002;36:9–30.
54. Schore AN. Attachment trauma and the developing right brain:
origins of pathological dissociation. In: Dell PF, O’Neil JA, editors.
Dissociation and the dissociative disorders: DSM-V and beyond.
New York: Routledge; 2011.
55. Gobin RL, Freyd J. Do participants detect sexual abuse depicted in
a drawing? Investigating the impact of betrayal trauma exposure on
state dissociation and betrayal awareness. J Child Sex Abus.
2017;26(3):233–45.
56. Land BB, Bruchas MR, Lemos JC, Xu M, Melief EJ, Chavkin C.
The dysphoric component of stress is encoded by activation of the
dynorphin-opioid system. J Neurosci. 2008;28(2):407–14.
57. Williams NR, Heifets B, Sudheimer K, Pannu J, Pankow H,
Hawkins J, et al. Opioid receptor antagonism attenuates antidepres-
sant effects of ketamine. Am J Psychiatry.
58.• Addy PH, Garcia-Romeu A, Metzger M, Wade J. The subjective
experience of acute, experimentally-induced Salvia divinorum in-
ebriation. J Psychopharmacol. 2015;29(4):426–35. This study
highlights the role of the kappa-opioid receptor agonist, Salvia
divinorum, in experiences of altered consciousness consistent
with depersonalization and derealisation experiences.
59. Frewen PA, Lanius RA. Trauma-related altered states of conscious-
ness: exploring the 4-d model. J Trauma Dissociation. 2014;15(4):
436–56.
60. Crick FC, Koch C. What is the function of the claustrum? Philos
Trans R Soc Lond Ser B Biol Sci. 2005;360:1271–9.
61. Rabellino D, Tursich M, Frewen PA, Daniels JK, Densmore M,
Theberge J, et al. Intrinsic connectivity networks in post-traumatic
stress disorder during sub- and supraliminal processing of threat-
related stimuli. Acta Psychiatr Scand. 2015;132(5):365–78.
62. Pietrzak RH, Naganawa M, Huang Y, Corsi-Travali S, Zheng M-Q,
Stein MB, et al. Association of in vivo κ-opioid receptor availability
and the transdiagnostic dimensional expression of trauma-related
psychopathology. JAMA Psychiatry. 2014;71(11):1262–70.
63. Rabellino D, Densmore M, Harricharan S, Jean T, McKinnon MC,
Lanius RA. Resting-state functional connectivity of the bed nucleus
of the stria terminalis in post-traumatic stress disorder and its dis-
sociative subtype. Hum Brain Mapp. 2017;39:1367–79.
64. Hill MN, Campolongo P, Yehuda R, Patel S. Integrating
endocannabinoid signaling and cannabinoids into the biology and
Curr Psychiatry Rep (2018) 20:118
t r e a t m e n t o f p o s t t r a u m a t i c s t r e s s d i s o r d e r.
Neuropsychopharmacology. 2018;43(1):80–102.
65. Pietrzak RH, Huang Y, Corsi-Travali S, Zheng M-Q, Lin S, Henry
S, et al. Cannabinoid type 1 receptor availability in the amygdala
mediates threat processing in trauma survivors.
Neuropsychopharmacology. 2014;39(11):2519–28.
66. Dean C. Endocannabinoid modulation of sympathetic and cardio-
vascular responses to acute stress in the periaqueductal gray of the
rat. Am J Phys Regul Integr Comp Phys. 2011;300(3):R771–9.
67. Moreira FA, Aguiar AC, Campos AC, Lisboa SF, Terzian AL,
Resstel LB, et al. Antiaversive effects of cannabinoids: is the
periaqueductal gray involved? Neural Plast. 2009;625469.
68. Moreira FA, Wotjak CT. Cannabinoids and anxiety. Curr Top
Behav Neurosci. 2010;2:429–50.
69. Hoskins M, Pearce J, Bethell A, Dankova L, Barbui C, Tol WA,
et al. Pharmacotherapy for post-traumatic stress disorder: systemat-
ic review and meta-analysis. Brit J Psychiatry. 2015;206:93–100.
70. Steenkamp MM, Litz BT, Hoge CW, Marmar CR. Psychotherapy
for military-related PTSD. JAMA. 2015;314(5):489–500.
71. Bradley R, Greene J, Russ E, Dutra L, Westen D. A multidimen-
sional meta-analysis of psychotherapy for PTSD. Am J Psychiatry.
2005;162(2):214–27.
72. Simeon D, Knutelska M. An open trial of naltrexone in the treat-
ment of depersonalization disorder. J Clin Psychopharmacol.
2005;25(3):267–70.
73. Lalanne L, Ayranci G, Kieffer BL, Lutz PE. The kappa opioid
receptor: from addiction to depression, and back. Front
Psychiatry. 2014;5:170.
74. Chavkin C. The therapeutic potential of κ-opioids for treatment of
pain and addiction. Neuropsychopharmacology. 2011;36(1):369–70.
75. Fraser GA. The use of a synthetic cannabinoid in the management
of treatment-resistant nightmares in posttraumatic stress disorder.
CNS Neurosci Ther. 2009;15(1):84–8.
76. Cameron C, Watson D, Robinson J. Use of a synthetic cannabinoid
in a correctional population for posttraumatic stress disorder–relat-
ed insomnia and nightmares, chronic pain, harm reduction, and
other indications. J Clin Psychopharmacol. 2014;34(5):559–64.
77. Jetly R, Heber A, Fraser G, Boisvert D. The efficacy of nabilone, a
synthetic cannabinoid, in the treatment of PTSD-associated night-
mares: a preliminary randomized, double-blind, placebo-controlled
cross-over design study. Psychoneuroendocrinology. 2015;51:585–8.
78. Roitman P, Mechoulam R, Cooper-Kazaz R, Shalev A. Preliminary,
open-label, pilot study of add-on oral Delta9-tetrahydrocannabinol
in chronic post-traumatic stress disorder. Clin Drug Investig.
2014;34(8):587–91.
79. Lanius, UF, Paulsen, SL, Corrigan, FM, Neurobiology and
Treatment of Traumatic Dissociation: Toward an Embodied Self,
Springer Piblishing Company, 2014.