Bird Et Al. 2021 PDF

International Review of Psychiatry
ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/iirp20
Psilocybin and MDMA for the treatment of

trauma-related psychopathology
Catherine I. V. Bird, Nadav L. Modlin & James J. H. Rucker
To cite this article: Catherine I. V. Bird, Nadav L. Modlin & James J. H. Rucker (2021) Psilocybin
and MDMA for the treatment of trauma-related psychopathology, International Review of
Psychiatry, 33:3, 229-249, DOI: 10.1080/09540261.2021.1919062
To link to this article: https://doi.org/10.1080/09540261.2021.1919062
© 2021 The Author(s). Published by Informa

UK Limited, trading as Taylor & Francis
Group.
Published online: 14 Jun 2021.
Submit your article to this journal
Article views: 15698
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at

https://www.tandfonline.com/action/journalInformation?journalCode=iirp20
INTERNATIONAL REVIEW OF PSYCHIATRY
2021, VOL. 33, NO. 3, 229–249
https://doi.org/10.1080/09540261.2021.1919062
REVIEW ARTICLE
Psilocybin and MDMA for the treatment of trauma-related psychopathology

Catherine I. V. Birda , Nadav L. Modlina and James J. H. Ruckera,b
a
The Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK; bSouth London and Maudsley NHS
Foundation Trust, London, UK
ABSTRACT ARTICLE HISTORY

This review examines the role of trauma in psychiatric morbidity and analogous psychoneuro- Received 29 December 2020
biological changes. Trauma is a necessary criterion for Post-Traumatic Stress Disorder (PTSD), Accepted 13 April 2021
however, trauma history is highly correlated with a variety of psychiatric conditions. Some evi-
KEYWORDS
dence suggests that Major Depressive Disorder (MDD) is the most common psychiatric condition
Psilocybin; MDMA; trauma;
that arises following trauma. Approximately 50% of PTSD cases present with co-morbid MDD. depression; posttraumatic
Overlapping symptomatology and neurobiology between these conditions underlie the debate stress disorder; psychiatry;
over whether these phenomena result from problematic nosology or whether comorbid drug-assisted psychotherapy
MDD þ PTSD is a distinct phenotype of trauma-related psychopathology. Regardless, similar
treatment approaches have been employed historically, with varying success. The drug-assisted
psychotherapy treatment model, which combines pharmacological and psychotherapeutic
approaches, is currently being trialled as a novel treatment approach in psychiatry. Both psilo-
cybin- and 3,4-Methylenedioxymethamphetamine (MDMA)-assisted psychotherapy have received
Food and Drug Administration ‘breakthrough therapy’ designation for the treatment of resistant
MDD and PTSD, respectively. This paper reviews the therapeutic rationale of both psilocybin
and MDMA for treating both trauma-related MDD and PTSD.
Drug-assisted psychotherapy: psilocybin and in many respects, a recent review of the pre-1970s lit-
3,4-methylenedioxymethamphetamine (MDMA) erature concluded that they were likely to be safe when
Classical psychedelic drugs include phosphoryloxy- delivered in medically controlled settings and deserved
N,N-dimethyltryptamine (psilocybin), dimethyltrypt- further investigation with the benefit of modern para-
amine (DMT), d-lysergic acid diethylamide (LSD) and digms of trial design (Rucker et al., 2018).
mescaline. They are agonists at serotonin receptors, The Controlled Substance Act (CSA), 1970, in the
with the subjective psychoactive effects dependent on US (and the largely synonymous Misuse of Drugs
partial agonism of the type 2 A serotonin receptor Act, 1971, and associated regulations in the UK)
(Vollenweider & Kometer, 2010), which is predomin- severely restricted the use of psychedelics in research
antly expressed on layer V pyramidal neurons in the and prohibited all routine clinical use. However, in
prefrontal cortex (Hall et al., 2000; Saulin et al., 2012). 1992, the National Institute on Drug Abuse and the
Historical and present-day recreational, medicinal and FDA reached an agreement that facilitated the
religious use of plant-based psychedelics by different, resumption of clinical research with classical psyche-
geographically isolated human societies has been delics (Nichols, 2014).
observed (El-Seedi et al., 2005; Nichols, 2020; Tupper, Since then, modern pilot and feasibility trials have
2009). Some reports date this use extending back thou- demonstrated encouraging preliminary safety and effi-
sands of years, although this timeline is still debated. cacy data for psilocybin as a treatment for anxiety
Subsequent to the serendipitous discovery and market- and depression in end-of-life care (Griffiths et al.,
ing of LSD in the Western world, from 1950 to the 2016; Grob et al., 2011; Ross et al., 2016), OCD
early 1970s, more than 1,000 clinical papers were pub- (Moreno et al., 2006), alcohol dependence
lished about the treatment of thousands of patients (Bogenschutz et al., 2015), tobacco addiction (Johnson
with psychedelics. Whilst these trials were suboptimal et al., 2014), major depression (Carhart-Harris et al.,
CONTACT Catherine I. V. Bird [email protected] The Institute of Psychiatry, Psychology and Neuroscience, King’s College London,
London, UK
ß 2021 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits
unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
230 C. I. V. BIRD ET AL.
2021; Davis et al., 2020) and treatment-resistant and interpersonal trust (Feduccia & Mithoefer, 2018;
depression (Carhart-Harris et al., 2016, 2018). Johansen & Krebs, 2009). MDMA is often categorized
The drug development process with psilocybin is as an ‘entactogen’ (literally: ‘to produce touch within’)
now accelerating. More recently, a large randomized (Mithoefer et al., 2016). Since 2000, MDMA-assisted
placebo-controlled phase 1 trial compared the safety psychotherapy has been under clinical investigation
profile between a single dosing session of a placebo, for the treatment of PTSD (Mithoefer et al., 2019),
10 mg and 25 mg of psilocybin in 89 healthy volun- social anxiety in autistic adults (Danforth et al., 2018)
teers (Rucker et al., 2019). There were no serious and alcohol use disorder (Sessa et al., 2019). A pooled
adverse events recorded and no adverse events led to analysis of six randomized, double-blind controlled
withdrawal from the study. The adverse event profile clinical trials investigating MDMA-assisted psycho-
was of the expected ‘psychedelic’ nature, with the vast therapy for the treatment of PTSD found significantly
majority of ‘mood altered’ adverse events judged greater reductions in PTSD symptoms (measured by
(post-hoc) to be positive in nature (Rucker et al., The Clinician-Administered PTSD Scale for DSM-IV
2019). This trial concluded that psilocybin was safe (CAPS-IV)) (Mithoefer et al., 2019). Following two-
and well-tolerated when given to up to 6 healthy vol- drug treatment sessions with either active doses of
unteers, simultaneously, in a controlled setting. It MDMA (75–125 mg) or placebo/control doses
should be noted that the results from this trial have (0–40 mg), 54.2% of participants in the active group
yet to be published in a peer-reviewed journal. no longer met CAPS-IV diagnostic scores for PTSD
Numerous phase 2 multi-site clinical trials with in comparison to 22.6% in control groups (Mithoefer
psilocybin in the treatment of the major depressive et al., 2019).
disorder (MDD) and treatment-resistant depression There is no evidence from ongoing clinical trials
(TRD) are now ongoing (ClinicalTrials.gov Identifiers: with MDMA that suggest clinical neurotoxicity at the
NCT03775200; NCT04433858; NCT03866174). The doses used (Mithoefer et al., 2016). MDMA has been
most notable of these from a medical regulatory per- well-tolerated in modern clinical trials (Mithoefer
spective is a large multicentre randomized controlled et al., 2019). Acutely, the physical effects of MDMA
phase 2b trial of single doses of psilocybin given to include mildly increased heart rate and blood pres-
participants with treatment-resistant depression, tak- sure. A typical clinical ‘therapeutic’ dose is 125 mg,
ing place across Europe and North America. Results with effects lasting around 4–8 h (Johansen & Krebs,
are expected in 2022. 2009; Krediet et al., 2020). The majority of deaths fol-
MDMA was first synthesized by Merck in 1912 lowing recreational MDMA use have been linked
(Passie, 2018). Following the discovery of its psycho- either to polydrug use (Jones et al., 2011; Kaye et al.,
active properties, MDMA was used as an adjunct for 2009) or as a result of drug use plus risky behaviours
both individual and couples psychotherapy between and environment, for example of dehydration/over-
1977 and 1985 by an estimated 4000 psychiatrists and exertion at raves or due to brain oedemas following
psychologists (Eisner, 1989; Holland, 2001). Similar to over-hydration (Mithoefer et al., 2016). More granular
psilocybin and the other classical psychedelics, systematic reviews have reconfirmed these findings
MDMA became a controlled substance and was and further investigated adverse event data, conclud-
placed in Schedule 1 of the CSA in 1985 after becom- ing that MDMA at these doses is a relatively safe
ing popular for recreational use (‘ecstasy’). It remains treatment when given in a controlled environment
in this most restrictive category today. MDMA is an (Illingworth et al., 2020).
amphetamine derivative (Elliott & Beveridge, 2005) Treatment models of psilocybin- and MDMA-
and stimulates the release of monoamines (serotonin, assisted psychotherapy overlap (Krediet et al., 2020),
dopamine, norepinephrine), hormones (cortisol, oxy- with both drugs used to facilitate salutary psycho-
tocin) and downstream signalling molecules (includ- logical change within a safe, comfortable, trusting and
ing brain-derived neurotropic factor (BDNF)), which non-judgmental set and setting. Dosing sessions with
(amongst other things) may act to modulate neural MDMA and psilocybin take place in a comfortable,
circuitry implicated in the processing of traumatic quiet, neutrally furnished room, with relaxing music
memories (Dumont et al., 2009, Feduccia & and a supportive relationship with at least one therap-
Duvauchelle, 2008; Feduccia & Mithoefer, 2018; Nash ist, which is thought to ‘deepen’ the therapeutic pro-
& Brodkin, 1991). cess (Krediet et al., 2020; Mithoefer et al., 2016). The
MDMA elicits a wide range of subjective effects, psychotherapeutic approach to dosing is supportive
including increased feelings of empathy, affiliation but non-directive. ‘Preparation’ sessions are given
INTERNATIONAL REVIEW OF PSYCHIATRY 231
before and ‘integration’ sessions are given after drug- be the first psychiatric conditions to be treated with
dosing sessions. In MDMA-assisted sessions, both licenced MDMA or psilocybin outside of a research
inner focus and dialogue occur under the drug effect setting. In the present article, the role of trauma in
(Mithoefer et al., 2016). Inner focus and psychological psychiatric morbidity, and corresponding neurobio-
support are crucial to both approaches, but treatment logical changes in PTSD and MDD, are reviewed.
with psilocybin encourages sustained attention on Whilst PTSD and MDD are distinct disorders, they
internal processes with the aim to discuss the experi- often co-occur and demonstrate a significant degree
ence with the therapist after the drug session. of clinical overlap. Furthermore, trauma exposure is a
The limitations of clinical studies of MDMA or common driving factor underlying both conditions.
psilocybin-assisted psychotherapy are worth noting. Given the positions of psilocybin and MDMA in the
Whilst results from these trials are encouraging, large drug development process, the potential mechanisms
effect sizes need to be interpreted with caution. Early by which they may exert their therapeutic effects in
phase trials are mostly designed to demonstrate feasi- both trauma-related MDD and PTSD are discussed. A
bility and safety (not efficacy), have small sample sizes practical point of interest is whether psilocybin before
and/or are open-label. Larger, multi-site, placebo-con- MDMA or MDMA before psilocybin might be,
trolled RCTs are needed to further address questions respectively, better for MDD and PTSD subtypes of
of efficacy. Within a placebo-controlled RCT design, trauma-related mental health problems.
unblinding is a practical problem with psilocybin and
MDMA given the unique and profound subjective
Trauma & psychopathology
effects elicited by these substances. Some studies have
employed the use of an active control (e.g. niacin, Exposure to traumatic events, including serious acci-
methylphenidate or low dose psychedelics (Griffiths dents, physical or sexual abuse, war-related incidents
et al., 2016; Ross et al., 2016)). Despite this, a large and life-threatening illness (to oneself or loved ones),
proportion of clinicians and trial participants can dif- is a universal risk factor in the development of psy-
ferentiate between placebo and active doses (Garcia- chopathology (de Vries & Olff, 2009; Kessler et al.,
Romeu & Richards, 2018). Expectancy effects may be 2017). The World Health Organization’s World
exacerbated within research with psilocybin and Mental Health (WMH) Survey (n ¼ 68,894 in 24
MDMA as a result. The ever-growing ‘hype’ around countries) found 70.4% of responders had experienced
the therapeutic potential of these drugs may, too, con- lifetime traumas of the above description, with the
tribute to expectancy. An in-depth review of the limi- mean number of exposures reported at 4.6 (Kessler
tations of psychedelic research is out of the scope of et al., 2017). Reactions to traumatic events include
this review but see Barnby and Mehta (2018) and low mood, anxiety, exhaustion, dissociation, height-
Muthukumaraswamy (2021). ened physical arousal, agitation and numbness
Both psilocybin- and MDMA-assisted psychother- (Kessler et al., 2017), amongst others. Most can man-
apy have received ‘breakthrough therapy’ designation age this stress response to regain optimal functioning,
from the FDA, assigning priority in the regulatory and not all who experience a traumatic event will
drug development process. In 2017, MDMA was subsequently meet the criteria for a mental health
granted this designation for its use in psychotherapy condition (Atwoli et al., 2015; McQuaid et al., 2001).
for the treatment of PTSD. As of September 2020, The ‘Trauma- and Stressor-Related Disorders’ out-
The Multidisciplinary Association for Psychedelic lined in The Diagnostic and Statistical Manual of
Studies (MAPS) have completed one of two planned Mental Disorders, 5th Edition (DSM-5) include
phase 3 randomized, double-blind, placebo-controlled, Posttraumatic Stress Disorder (PTSD) and Acute
multi-site clinical trials to assess the safety and effi- Stress Disorder (ASD). Both cite trauma as a neces-
cacy of MDMA-assisted psychotherapy in participants sary diagnostic criterion (American Psychiatric
with PTSD (Mitchell et al., 2021; Multidisciplinary Association, 2013). As ASD requires symptoms to
Association for Psychedelic Research, 2020). resolve less than 1 month in the aftermath of the
Psilocybin therapy has been designated in the same trauma, PTSD is the diagnosis that is most likely to
‘breakthrough’ category for both the treatment of represent a chronic or lifelong condition (Howlett &
MDD and TRD (COMPASS Pathways, 2018; Feduccia Stein, 2016; Kessler, 2000) and a lifetime diagnosis
et al., 2019; Nichols, 2020). occurs in around 4% of the global population
Given the status of current research and drug (Koenen et al., 2017). PTSD is characterized by recur-
development efforts, PTSD and MDD seem likely to ring symptoms of depressive and negative thoughts
Figure 1. Overlapping symptomatology of MDD and PTSD.
and feelings (self-blame, isolation), hyperarousal (irrit- that of PTSD, defining distressing events that are usu-
ability, aggression, elevated startle response), re-expe- ally prolonged or repetitive in nature and where
riencing (intrusive upsetting memories, flashbacks, escape is difficult or impossible (prolonged domestic
nightmares) and avoidance of distressing memories, abuse, childhood sexual or physical abuse, discrimin-
feelings, thoughts or external reminders of the event. ation, torture, slavery) (World Health
DSM-5 includes a PTSD dissociative subtype that Organization, 2018).
includes experiences of depersonalization, derealisa- Trauma exposure has also been linked to the devel-
tion and feeling detached (American Psychiatric opment and severity of various other psychiatric con-
Association, 2013). Severity can also be observed ditions including major depressive disorder (MDD),
through the degree of functional impairment as a dysthymia, bipolar disorder, substance abuse disorders
result of these symptoms, possibly contributing to an and anxiety disorders (Hammen et al., 1992; Koenen
increased risk of suicidality (Mauritz et al., 2013). The et al., 2008; Laugharne et al., 2010; Mueser et al.,
International Classification of Disease, 11th Revision 1998; Ompad et al., 2005), where trauma presents as
(ICD-11; World Health Organization, 2018) includes an external risk factor. MDD may be the most com-
complex posttraumatic stress disorder (CPTSD), mon condition following trauma (Center for
where all diagnostic requirements for PTSD must be Substance Abuse Treatment, 2014; Foa et al., 2006;
met along with additional problems including affect Laugharne et al., 2010) and there is an overlapping
regulation, beliefs about oneself (self-blame, worth- cluster of symptoms shared between MDD and PTSD
lessness) and difficulties in sustaining relationships diagnoses (see Figure 1). The relationship between
(World Health Organization, 2018). The trauma def- trauma exposure and MDD is complex and not well
inition under CPTSD is slightly less categorical than understood, where both depression and trauma
exposure are heritable traits (Coleman et al., 2020; participants with comorbid MDD-PTSD had signifi-
Kendler et al., 1999; Kendler & Karkowski-Shuman, cantly higher scores on PTSD symptoms scales (using
1997). However, robust correlations between child- the PTSD Checklist – Civilian Version (Weathers
hood adversity (e.g. physical and sexual abuse, family et al., 1994)) compared to those with MDD-only or
violence and neglect) and increased vulnerabilities to PTSD-only diagnoses (ts > 2.8; ps < 0.01).
adverse adult mental health outcomes, including MDD is a heterogeneous and aetiologically com-
PTSD, MDD and anxiety have been demonstrated plex condition with depressed mood and anhedonia
(Baldwin et al., 2019; Collishaw et al., 2007, Felitti being central to the condition. Anhedonia, concentra-
et al., 1998; McLaughlin et al., 2010). tion difficulties/memory impairment, sleep disturban-
The severity and impact of a stress reaction, and ces, guilt and distorted cognition are symptoms that
the lasting psychoneurobiological changes, represent overlap between PTSD and MDD (Flory & Yehuda,
risk factors contributing to adverse outcomes, includ- 2015) (see Figure 1). Comparable levels of PTSD
ing the subsequent development and/or diagnosis of a symptoms have been found in both participants with
psychiatric condition (Agorastos et al., 2019; Center MDD-only and PTSD-only, and more severe PTSD
for Substance Abuse Treatment, 2014). Underlying symptoms have been reported in participants with
genetic vulnerabilities affect outcomes following comorbid MDD and PTSD (Gros et al., 2010, 2012).
trauma exposure (Coleman et al., 2020; Daskalakis A history of MDD has shown to be predictive of
et al., 2018). Furthermore, there are a variety of fac- PTSD following exposure to trauma (Foa et al., 2006)
tors that influence outcomes following traumatic and PTSD has also been found to increase the risk
experiences (Grant et al., 2011). The nature and sever- for the first onset of MDD (Breslau et al., 1998).
ity of the trauma (e.g. assaultive vs. non-assaultive) Overall, PTSD and MDD in response to trauma may
can influence the occurrence and presentation of be best represented as two distinct, yet strongly
resulting psychopathology (McQuaid et al., 2001). related constructs (Post et al., 2016).
Gender, race, sexual orientation and previous expos- The high comorbidity rates between PTSD and
ure to trauma are some of the factors that can MDD may be due to imprecisions in the classification
increase the incidence of trauma exposure (Roberts of symptoms. An alternative explanation is that
et al., 2011; Van der Kolk, 2000; Wise et al., 2001). comorbid MDD and PTSD represent a trauma-related
phenotype that is separate from MDD, where comor-
bidity of these two conditions indicates an underlying
PTSD and MDD: comorbidity and treatment
degree of risk for psychopathology following trauma
It is estimated that 62–92% of PTSD cases demon- (Flory & Yehuda, 2015; Grant et al., 2008).
strate comorbidity (Gros et al., 2012; Keane et al., The conceptualization of co-morbidity between
2007; Perkonigg et al., 2000). MDD is the most com- PTSD and MDD has implications for treatment, spe-
mon co-morbid condition in those with a diagnosis cifically in determining whether treatments for PTSD
of PTSD (Center for Substance Abuse Treatment, can be effective in treating MDD and vice versa, or
2014), with co-occurring PTSD þ MDD present in for those who present with symptoms of
around half of those with PTSD (Elhai et al., 2005; both conditions.
Flory & Yehuda, 2015; Rojas et al., 2014). A US-based
report from 1997/8 showed that comorbid PTSD and
The neurobiology of the trauma response
depression was the most common psychiatric diagno-
sis (Macy, 1998 cit. Van der Kolk, 2000). The collection of symptoms and behaviours that are
Furthermore, the disorders share associated risk fac- captured within PTSD descriptions likely reflect
tors, symptoms and treatments (Carlson & Rosser- underlying changes in neurobiological and endocrine
Hogan, 1991; Grant et al., 2008; Gros et al., 2012; functions in response to stress. Dysregulation of brain
Levitan et al., 1998; Singer et al., 1995). circuitry involved in the stress response can lead to
The co-occurrence of PTSD and MDD is associ- alterations to the limbic system (which includes the
ated with increased burden, greater functional impair- amygdala, hypothalamus and hippocampus), the
ment and increased suicidal behaviours when hypothalamic-pituitary-adrenal (HPA) axis and key
compared to individuals with non-comorbid MDD monoamine neurotransmitter systems associated with
and PTSD (Center for Substance Abuse Treatment, traumatic experience(s) (Heim & Nemeroff, 2009;
2014; Frayne et al., 2004; Gros et al., 2012; Oquendo Van der Kolk, 2000; Weiss, 2007). Some structural
et al., 2003). Gros et al. (2012) demonstrated that and functional differences may represent more general
risk factors rather than changes resulting from trauma has also been observed in MDD (Drevets et al., 1992;
per se. Whilst not all depression involves a history of Siegle et al., 2002). Grant et al. (2011) demonstrated
childhood trauma, it has been suggested that there that the degree of heightened amygdala response in
may be biologically distinct subtypes of depression, depression may be a risk factor dependent on expos-
with a basis in the neurobiological changes associated ure to childhood trauma. Using fMRI, they found a
with severe childhood trauma (Heim et al., 2008). An strong positive correlation between childhood physical
in-depth description of neurobiological effects of abuse and amygdala response, where this relationship
trauma is out of the scope of this manuscript (see was much weaker in those with non-violent forms of
Heim & Nemeroff, 2009; Weiss, 2007), however a abuse like neglect, suggesting that depression is medi-
basic outline of these changes and how they relate to ated by heightened amygdala response, but differs by
behavioural symptoms of PTSD follows. Selected trauma type. Greater bilateral amygdala responses to
brain changes seen in MDD are also outlined. sad faces than happy faces were observed in depressed
patients using fMRI (Stuhrmann et al., 2013), where
healthy controls had greater amygdala responses to
The limbic system
happy than sad faces. In the depressed group, reduced
The limbic system receives sensory input via the thal- right amygdala response to happy faces was associated
amus, and its subcomponents (the amygdala, hypo- with increased physical anhedonia scores, which the
thalamus and the hippocampus) co-operate to authors suggest may result from ‘reduced salience
mediate balanced behavioural and affective responses attribution to positive information’ (Stuhrmann
to external stimuli. Those who are trauma-exposed et al., 2013).
may display impaired relay of information from the The hippocampus works to integrate control of
thalamus to the cortex under stressful conditions contextual aspects of fear conditions, fear condition-
(Kimble & Kaufman, 2004). ing and the control of stress response. Neuroimaging
The executive functions of the cortex filter out studies have shown decreased activation and lower
irrelevant information and inhibit responses to sen- levels of metabolism in the hippocampi of trauma-
sory stimuli, coordinating a complex, moderated exposed people, which may be associated with
response to any given situation. PTSD patients exhibit reduced hippocampal volume that, in turn, is relative
decreased volumes in cortical areas including the pre- to the length and severity of trauma experience
frontal cortex and the anterior cingulate cortex (Bremner et al., 1995, 1997; Gurvits et al., 1996; Heim
(Bremner, 2002; Heim & Nemeroff, 2009, Weiss, & Nemeroff, 2009; Stein et al., 1997). These changes
2007; Yamasue et al., 2003). Neglect and stress during in volume and activity may underlie the occurrence
childhood are associated with cortical atrophy, includ- of avoidance and numbing, memory loss of the
ing loss of neurons, dendrites and synaptic connec- trauma, as well as dissociation experiences (Weiss,
tions in these areas (Perry, 2002; Weiss, 2007). In 2007). Similarly, early life trauma in MDD patients
PTSD, these structural changes contribute to hypoac- (particularly childhood abuse), is associated with
tivation in these areas which, in turn, can impair reduced hippocampal volume (Vythilingam
extinction of fear responses and top-down mecha- et al., 2002).
nisms involved in inhibiting reactivity to emotional
stimuli (Etkin & Wager, 2007; Sherin & Nemeroff,
The HPA axis
2011; Yang et al., 2004).
The amygdala is a key limbic structure that is The HPA axis operates as the main neuroendocrine
involved in the mediation of fear responses and emo- stress response system (McEwen, 2004). Acute stress
tional processing (Heim & Nemeroff, 2009). The stimulates a hormonal cascade via this axis. The
amygdala generates an emotional valence that is sent hypothalamus is a part of the HPA axis, secreting cor-
to subcortical motor structures and the brain stem to ticotropin-releasing hormone (CRH) following trauma
determine an appropriate motor response or reflex and other stress. CRH stimulates the production and
(e.g. facial expression, startle reaction). In PTSD, the release of adrenocorticotropin (ACTH), which subse-
amygdala displays a heightened response to neutral quently stimulates the release of glucocorticoids (cor-
and emotional stimuli, contributing to irritability, tisol in humans) from the adrenal cortex (Heim &
aggression and overall hypervigilance (Sherin & Nemeroff, 2009). The hypothalamus receives emo-
Nemeroff, 2011; Shin et al., 2006). Increased amygdala tional information from the amygdala, and the HPA
activity, particularly in response to emotional faces axis is modulated by inhibitory activity from the PFC
and hippocampus. The release of cortisol from the combination model with psilocybin and MDMA is
adrenal cortex activates the sympathetic nervous sys- theoretically applicable and useful for the treatment of
tem and, normally, suppresses further CRH release. PTSD and/or trauma-related MDD.
Whilst uniform changes to cortisol levels in PTSD
have not been observed (see Yehuda (2006) for
MDD and PTSD: current treatments
review), decreased cortisol in response to chronic
stress is often observed in individuals with PTSD PTSD
leading to a dysregulation of the negative feedback In the UK, the only licenced drugs for the treatment of
loop between HPA axis and cortisol production. This PTSD are the antidepressant drugs sertraline and parox-
is hypothesized to lead to abnormal stress encoding etine (Hoskins et al., 2015; National Institute for Health
and fear processing (Sherin & Nemeroff, 2011). & Care Excellence, 2018). Both sertraline and paroxetine
A sustained, increased level of CRH as a result of are also the only antidepressants with FDA approval for
HPA dysregulation may contribute to hippocampal the treatment of PTSD in the United States (American
atrophy and a desensitized ACTH response to CRH Psychiatric Association, 2017). Other SSRIs and SNRIs
stimulation. including fluoxetine, venlafaxine and mirtazapine are
Hyperactivity of the HPA axis is observed in sometimes used off-label in the treatment of PTSD in
MDD, with increased cortisol levels observed in both countries (American Psychiatric Association, 2017;
patients experiencing a depressive episode (Posener Baldwin et al., 2014; National Institute for Health and
et al., 2000; Young et al., 2001). Care Excellence, 2018). A meta-analysis of 37 random-
The mechanisms discussed most probably influence ized placebo-controlled trials found that only paroxetine,
monoaminergic neurotransmitter turnover and subse- sertraline and venlafaxine were better at treating PTSD
quent neuromodulation. Current pharmacological symptoms than placebo (Ipser & Stein, 2012). While
treatments recommended for PTSD are all antidepres- approximately 60% of patients respond to SSRI treat-
sants (i.e. they were not developed to specifically ment, only 20–30% of patients achieve remission
address PTSD symptoms) that specifically target the (Alexander, 2012). The use of benzodiazepines can
serotonin transporter (SERT). The poor efficacy of negatively impact treatment outcomes in PTSD and are
treatments (such as sertraline) that influence SERT in not recommended as a first-line pharmacological treat-
PTSD suggests that pharmacologically targeting SERT ment (Van Minnen et al., 2002). Thus, pharmacological
is insufficient. In addition, revisiting traumatic memo- interventions for PTSD have been classified as ‘low
ries with the required emotional engagement via talk- effect’ treatments (Hamblen et al., 2019). Current UK
ing therapy alone is sufficiently challenging for some treatment guidelines recommend psychological interven-
patients that it introduces the risk of worsening the tions as the first-line therapy for the treatment of PTSD
condition (Feduccia et al., 2018). (National Institute for Health and Care Excellence,
It is in this context that promising results from 2018). Although it is worth noting that the comparative
MDMA-assisted psychotherapy for PTSD are interest- efficacy of pharmacological and psychological treatments
ing. MDMA, as well as being a SERT inhibitor, stimu- for PTSD is not yet established. The British Association
lates the release of serotonin into the synaptic cleft by for Psychopharmacology guidelines recommend
binding to vesicular transport proteins within the syn- pharmacological (paroxetine, sertraline or venlafaxine)
apse. This leads to an acute surge of extracellular or psychological (trauma focused CBT or EMDR) for
serotonin and a clinical state of interpersonal tender- the acute treatment of PTSD, highlighting that the com-
ness, empathy and warmth. It seems that these parative efficacy of psychological versus pharmacological
pharmacologically induced changes provide an oppor- treatment for PTSD has yet to be established (Baldwin
tunity to ‘engage’ with trauma-related material during et al., 2014).
psychotherapy in a way that is more likely to lead to NICE recommends trauma-focused, exposure-
positive reappraisal. Put another way, the effects of based psychotherapies for PTSD: cognitive processing
MDMA are sufficiently different to more classical therapy (CPT), cognitive therapy for PTSD (t-CBT),
SERT inhibitors that it may render the brain biologic- narrative exposure therapy (NET), prolonged expos-
ally ‘ready’ for psychological change, particularly ure therapy (PET), and Eye Movement
within a safe, supportive psychotherapeutic setting. Desensitisation and Reprocessing (EMDR). Trauma-
It seems there is an overlapping clinical and neuro- focused CBT and Eye Movement Desensitisation and
biological phenotype between depression and PTSD. Reprocessing (EMDR) therapy are favoured as evi-
This means that the pharmaco-/psycho-therapy dence-based therapies (Baldwin et al., 2014). Trauma-
focused psychotherapies aim to facilitate reductions in antidepressant and talking therapy may be more effi-
PTSD symptoms by encouraging re-exposure and re- cacious than either alone (Cleare et al., 2015).
processing of emotionally charged memories (Bradley Roughly 50–60% of people will see an improvement
et al., 2005; Kline et al., 2018). However, non- following antidepressant treatment, compared to
response to initial treatment with pharmacological 25–30% of those taking placebo (Anderson et al.,
and psychological treatments is high with PTSD 2008; Royal College of Psychiatrists, 2019).
(Baldwin et al., 2014). Around 40–60% of patients do Treatment-resistant depression (TRD), defined as
not achieve significant clinical improvement (Haagen those who do not improve despite (usually) at least
et al., 2015; Steenkamp et al., 2017; Watkins et al., two established treatments (Strawbridge et al., 2019),
2018). Those with dissociative symptoms, severe affect develops in approximately 1/3 of those with a diagno-
dysregulation, increased suicidal ideation and distur- sis of depression (Crown et al., 2002). Medical strat-
bances in learning, memory, attention, and concentra- egies for treatment-resistant depression include dose
tion may struggle to engage in trauma-focused increase, augmentation with a second antidepressant,
therapies (Bisson et al., 2013; Lanius et al., 2010; lithium or an antipsychotic (Cleare et al., 2015;
Raines et al., 2017). Psychosocial problems such as Taylor et al., 2018). In TRD, the risk of suicide
unemployment, homelessness and substance misuse increases, and patients are more likely to require hos-
may further undermine efforts at therapeutic engage- pitalization and less likely to respond to subsequent
ment (Davidson et al.,1991; Jakupcak et al., 2009; treatments (Bergfeld et al., 2018). People with TRD
Marshall et al., 2001; Sareen et al., 2007). Dropout are more likely to be economically inactive and psy-
rates between 25 and 30% have been reported and chosocially disabled, often leading to increased carer
one-third to one-half of patients completing treatment burden (Crown et al., 2002; Fava, 2003).
still report symptoms and ongoing impairment
(Bradley et al., 2005). Novel treatment approaches
Despite these treatment gaps, there has been little
Depression progress in pharmacological treatments for MDD or
Treatment approaches for MDD vary in intensity PTSD since the approval of SSRIs in the 1980s, with
depending on the severity of and the individual’s his- pharmaceutical companies reducing the focus on psy-
tory with depression. Psychological therapies are fav- chiatric drug treatments or ceasing this effort
oured for milder forms, with antidepressants and altogether (Hyman, 2013). However, more recently
combination treatments recommended for moderate esketamine, an N-methyl-D-aspartate (NMDA) recep-
to severe forms (Cleare et al., 2015; NICE; Maudsley tor antagonist, has been licenced as a treatment for
Prescribing Guidelines (Taylor et al., 2018)). The MDD given in combination with an SSRI, demon-
first-line treatment for moderate-severe depression is strating rapid and sustained antidepressant effects
a selective serotonin reuptake inhibitor (SSRI, for within hours of intranasal administration (Daly et al.,
example; sertraline, citalopram, fluoxetine, paroxe- 2019; Fedgchin et al., 2019; Murrough et al., 2013;
tine). Other pharmacological antidepressant treat- Ochs-Ross et al., 2018; Popova et al., 2019; Wilkinson
ments include serotonin-noradrenaline reuptake et al., 2018). The rapid action of esketamine high-
inhibitors (SNRIs; duloxetine, venlafaxine), noradren- lights the delayed therapeutic onset seen with SSRIs
aline and specific serotonergic antidepressants and other available pharmacotherapies. (R,S)ketamine,
(NASSAs; mirtazapine), tricyclic antidepressants as an adjunct to psychotherapy, has also been investi-
(TCAs; amitriptyline, clomipramine, imipramine) and gated for the treatment of PTSD, with encouraging
monoamine oxidase inhibitors (MAOIs; tranylcypro- preliminary results (Pradhan et al., 2017, 2018).
mine, phenelzine and isocarboxazid). Antidepressants The development of esketamine, whilst it reflects a
can be used in cases of mild depression, particularly new target mechanism of action, nonetheless is an old
when there is a history of moderate-severe recurrent drug with a new indication. Racemic ketamine was
depression, or the depression persists for 2–3 months developed as an anaesthetic to replace phencyclidine
(Cleare et al., 2015). Cognitive behavioural therapy in 1962, with its antidepressant properties not investi-
(CBT), behavioural activation and interpersonal psy- gated until the 1990s. Similarly, since the late 1990s,
chotherapy are some of the talking therapies recom- there has been a slow yet steady resurgence of
mended for mild-severe depression. Psychological research into the antidepressant and anxiolytic prop-
therapy alone is not recommended in severe cases of erties of psilocybin and methylenedioxymethamphet-
depression and combination therapy of an amine (MDMA). Although it should be noted that
the current model for the treatment of depression been observed in participants with TRD 1-day post
with ketamine does not involve an element of psycho- psilocybin session (Roseman et al., 2018), where the
therapy. The reasons for researchers ‘looking to his- authors hypothesized that psilocybin facilitated the
tory for inspiration’ are complex, but likely reflect a processing of negative memories/experiences acutely,
general failure to develop truly novel pharmacological allowing patients to ‘reconnect’ with their emotions
treatments in psychiatry and slow relaxation of the post drug effect. In the same sample of patients,
sociopolitical opprobrium that surrounded drugs such Mertens et al. (2020) observed decreased functional
as MDMA and psilocybin. connectivity between the ventromedial prefrontal cor-
The following section outlines the therapeutic util- tex and the amygdala post-treatment with psilocybin.
ity of treating trauma-related MDD and PTSD with It is worth noting that these scans were conducted
both psilocybin and MDMA. Based on existing evi- before psychological integration had occurred with
dence about their potential in eliciting salutary psy- the assigned therapists, which may be required to
chological change, potential mechanisms of action in achieve lasting benefits in the balanced processing of
MDD and PTSD symptom reduction are discussed. negative emotions (Vollenweider & Preller, 2020).
Further studies may elucidate the effects of psilocybin
on the amygdala and the relevance of these changes
MDMA and psilocybin-assisted psychotherapy:
to clinical outcomes. Kraehenmann et al. (2016) dem-
transdiagnostic uses
onstrated via fMRI connectivity analyses that psilo-
Mood effects and emotional processing cybin reduced threat-induced modulation of
Both psilocybin and MDMA can alter the processing connectivity from the amygdala to the primary visual
of affective information. In a randomized, double- cortex, suggesting a mechanism for decreased threat
blind study, comparing the effects of psilocybin, sensitivity following psilocybin. Furthermore, animal
ketanserin (a 5-HT2 receptor antagonist) or psilocy- studies have shown that psilocybin facilitates fear
bin þ ketanserin, Kometer et al. (2012) found that extinction in mice (Catlow et al., 2013) as well as pro-
psilocybin reduced recognition of negative facial moting functional and structural neural plasticity in
expression and enhanced positive mood. The ketan- the PFC in vivo and in vitro (Ly et al., 2018).
serin-only group displayed no effects on emotional Together, changes in neurogenesis, synaptogenesis
tasks but psilocybin-induced mood improvements and spinogenesis have been postulated to contribute
were obstructed and the recognition of negative emo- to antidepressant and anxiolytic effects of psilocybin
tional stimuli was attenuated, demonstrating the cen- (Ly et al., 2018).
tral role of the 5-HT2A receptor in these processes. The above findings suggest that the effects of psilo-
Correspondingly, Schmidt et al. (2013) observed that cybin on emotional processing may have therapeutic
psilocybin impaired the subjective discrimination utility in addressing negative cognitive and emotional
between fearful and neutral faces and reduced the biases seen in depression. It is possible that dampened
encoding of fearful faces. In TRD, improved emotion processing of emotional responses and increased
recognition was shown to persist 1-month post-treat- affinity to positive mood states occurring following
ment with psilocybin (Stroud et al., 2018) psilocybin is regulated by amygdala connectivity. In
As previously mentioned, hyperactivity of the PTSD, psilocybin may also inhibit fear responses dur-
amygdala and reduced pre-frontal control of the ing the revisiting of traumatic material. Depressive
region underlies a heightened fear response to emo- and negative thoughts are also present within PTSD
tional stimuli following trauma and has been observed diagnoses, and the potential for psilocybin to augment
in both MDD and PTSD populations. In fMRI studies positive mood states may also have therapeutic utility
in healthy volunteers, psilocybin attenuates amygdala in this population.
reactivity to negative and neutral stimuli There has been historic use of classical psyche-
(Kraehenmann et al., 2015). This was associated with delics, mainly LSD (and psilocybin and ketamine to a
observed increases in positive mood states following lesser extent), in the treatment of ‘concentration camp
psilocybin administration (Kraehenmann et al., 2015). syndrome’ (Bastiaans, 1983; Krediet et al., 2020). The
Reduced amygdala reactivity in response to affective therapy aimed to allow patients to re-experience trau-
stimuli and associated negative affect was decreased matic material within a supportive environment.
1-week post psilocybin administration in healthy vol- However, this treatment occurred prior to the add-
unteers (Barrett et al., 2020). However, in contrast, an ition of PTSD as a psychiatric diagnosis, and no clin-
increase in amygdala reactivity to fearful faces has ical research into the utility of psilocybin for the
treatment of PTSD has been conducted since. Acutely, MDMA induces a rapid, dose-dependent
Ayahuasca, which is a DMT-containing plant brew release of monoamines from pre-synaptic vesicles (5-
used in the Amazon basin for religious, medicinal HT). MDMA also competes with synaptic mono-
and spiritual uses, has been suggested as a possible amines for reuptake into the neuron. The net effect is
treatment for PTSD (Labate & Cavnar, 2013; Nielson an acute increase in monoamine concentration in the
& Megler, 2014). Observational research is currently synaptic cleft, however, MDMA has 10-fold more
being conducted on ayahuasca for the treatment of affinity for the 5-HT transporter in comparison to
PTSD (Krediet et al., 2020). It should be noted that either noradrenaline or dopamine, leading to a rela-
the ayahuasca brew contains various other psycho- tive surge in 5-HT concentration. Mice deficient in
active compounds including b-carboline alkaloids the serotonin transporter do not respond to MDMA
(Frecska et al., 2016). (Fox et al., 2007) and SSRIs act to attenuate the
Similar to psilocybin, neuroimaging studies with effects of MDMA, suggesting antagonistic competition
MDMA indicate reduced amygdala activity and to SERT in both animal and human models (Liechti
increased activity in the frontal cortex, modulating & Vollenweider, 2000; Schmidt & Taylor, 1987). This
circuitry that can become dysregulated following mechanism suggests MDMA may be a suitable candi-
trauma (Carhart-Harris et al., 2015; Gamma et al., date for antidepressant treatment under a similar
2000). In healthy volunteers using fMRI, Bedi et al. pharmacological rationale to the therapeutic use of
(2009), demonstrated an attenuated left amygdala SSRIs (Patel & Titheradge, 2015; White et al., 2008).
response to angry facial expressions following 1.5 mg/ Post-mortem brain tissue analysis, as well as measure-
kg of MDMA. Carhart-Harris et al. (2014) found that ments using cerebrospinal fluid in animal models,
following 100 mg of MDMA, perceptions of favourite have demonstrated 5-HT depletion following acute,
and worst autobiographical memories were changed MDMA-induced 5-HT release (Schmidt et al., 1986;
in healthy volunteers, where ‘worst’ memories were Taffe et al., 2003). However, the dosing regimens
interpreted less negatively post MDMA in comparison employed in these studies employed doses over 10
to a placebo group. These changes correlated with times the average recreational dose used, with mul-
lower blood-oxygen-level-dependent (BOLD) activa- tiple dosing sessions sometimes given in rapid succes-
tion of the left anterior temporal lobe and increased sion. This response is unlikely with the lower doses
activation of the superior frontal gyrus and mPFC. used in modern clinical research (Patel &
Favourite memories were perceived as being more Titheradge, 2015).
positive and more vivid and were associated with Given the current understanding of the role of the
increased activation of hippocampal regions, somato- 5-HT system in modulating mood in anxiety and
sensory cortex and bilateral fusiform gyrus than nega- depression, MDMA-assisted therapy may enhance
tive memories (Carhart-Harris et al., 2014). positive mood states and facilitate the therapeutic
These findings support the idea that systems processing of traumatic memories in PTSD (Feduccia
involved in emotional processing and memory are et al., 2018) and perhaps in trauma-related MDD.
modulated by MDMA (Feduccia et al., 2018). MDMA There is indirect evidence for the antidepressant
has also been demonstrated to reduce the identifica- effects of MDMA-assisted psychotherapy from sec-
tion of negative emotions (Bedi et al., 2010; Feduccia ondary outcomes in completed clinical trials. An
et al., 2018; Hysek et al., 2012, 2014; Schmid open-label, proof of concept, phase 1 trial investigat-
et al., 2014). ing MDMA-assisted psychotherapy for alcohol use
MDMA has been theorized to have antidepressant disorder (AUD) (Sessa et al., 2019, 2021) demon-
properties (Holland, 2001; Sessa & Nutt, 2007), but strated significant decreases in depressive symptoms
currently, no human trials have directly investigated as measured by the Patient Health Questionnaire-9
the use of MDMA for the treatment of MDD and (PHQ-9). Improvements in self-compassion, mindful-
existing literature on the antidepressant effects of ness and quality of life were also observed, although
MDMA is limited. Majumder et al. (2011) demon- the final results for these measures have yet to be
strated antidepressant-like effects in an animal model published. A randomized, double-blind, dose-response
of depression, and an observational study by the same phase II trial investigating MDMA-assisted psycho-
group suggested that direct, rapid-onset antidepres- therapy for chronic PTSD, where participants were
sant action following MDMA ingestion (in a variety randomized to receive 30 mg (active control), 75 mg
of settings) occurred in subjects with a predisposition or 125 mg over two sessions, employed the Beck
to depression (Majumder et al., 2012). Depression Inventory-II (BDI-II) as a secondary
outcome. Depressive symptoms were significantly Increased emotional empathy (Kuypers et al.,
reduced in the 125 mg group compared with the 2017), subjective ratings of closeness to others and
30 mg group (mean change of BDI-II score of 24.6 increased feelings of trust (Schmid et al., 2014) have
vs 4.6; p ¼ 0.0003) at 1 month follow up. been seen following MDMA. Increased feelings of
Comparisons between the 75 mg and 30 mg groups openness and closeness towards others have also been
were non-significant, although the 75 mg group dem- reported (Schmid et al., 2014). Oxytocin levels
onstrated a larger average drop from baseline increase as a result of 5-HT efflux, following MDMA,
(Mithoefer et al., 2019). A pooled analysis of four which has been hypothesised to contribute to subject-
phase 2 RCTs investigating MDMA for PTSD ive increases in feelings of trust (Hysek et al., 2014;
(Mithoefer et al., 2019), including the above study Vizeli & Liechti, 2018). Thompson et al. (2007) sug-
demonstrated that improvement in depression symp- gest MDMA-stimulated oxytocin may be central to
toms (as measured by the BDI-II) only trended prosocial effects of MDMA. However, the exact role
towards significant group differences but was greatest of oxytocin released following MDMA is still unclear.
for the active group compared to the control group Oxytocin modulates neural circuitry related to the
(Mithoefer et al., 2019). The therapy delivered in neurobiological response to trauma, including the
these trials followed a manual specifically designed for amygdala and the PFC, and has been shown to reduce
the treatment of PTSD (Mithoefer et al., 2016). A activity in the amygdala (Eckstein et al., 2015) This is
meta-analysis of four RCTs investigating MDMA- a potential underlying mechanism of the attenuation
assisted psychotherapy for treatment of PTSD of amygdala activity observed (Carhart-Harris et al.,
observed a significant decrease in BDI scores in the 2015; Feduccia et al., 2018; Gamma et al., 2000).
75 mg group only, in comparison to placebo Furthermore, the use of oxytocin as an adjunct to
(Illingworth et al., 2020). Although the persistence psychotherapy has been investigated due to its pur-
and/or emergence of depressive symptoms may be ported ability to enhance prosocial behaviour
part of the therapeutic process involved in the proc- (MacDonald et al., 2013). However, the apparent
essing of previously avoided traumatic memories relatedness of improved emotional empathy following
(Illingworth et al., 2020). Alternatively, it may be that MDMA, and peripheral oxytocin levels, has not been
(subtle) changes in depressive symptomatology are observed consistently (Kuypers et al., 2014, 2017).
not well captured by operationalised measures Psilocybin has been shown to increase emotional
designed to quantify. Qualitative analyses may be use- empathy, without affecting cognitive empathy
ful in capturing these characteristic changes in quality. (Pokorny et al., 2017), as well as decrease feelings of
However, it is worth noting that in Mithoefer et al.’s social exclusion and rejection processing in the anter-
MDMA for PTSD trials, changes in depressive symp- ior cingulate cortex (Preller et al., 2016) These effects
toms were a secondary outcome measure. The self- may contribute to improved patient-therapist relation-
report BDI scale, the outcome measure used in these ships and reduce social withdrawal (Vollenweider &
trials, is not a blinded outcome measure thus expect- Preller, 2020). In depression, participants reported
ancy effects are more likely to have contributed to increased feelings of connection (from self, others and
findings. A recent, phase 3 RCT investigating MDMA the world) and reduced feelings of avoidance follow-
therapy for PTSD by the same group demonstrated ing psilocybin-assisted psychotherapy (Watts et al.,
MDMA therapy was effective in reducing depressive 2017). Qualitative analysis of participant accounts in a
mood symptoms (as measured by the BDI-II) pilot trial investigating the use of psilocybin for smok-
(Mitchell et al., 2021). ing cessation, participants reported feelings of recon-
nection of their environment, as well as increased
Social cognition prosocial behaviour and altruism (Noorani et al.,
Impaired social cognition and empathic abilities con- 2018). Charuvastra and Cloitre (2008) found that
tribute to negative social interactions and impact the positive outcomes in PTSD therapy show a firm rela-
ability to perceive and process socially relevant infor- tionship with the strength of the therapeutic alliance.
mation (Weightman et al., 2014). Improved thera- Empathy as an essential component of the therapeutic
peutic alliance and emotional empathy are outcomes alliance across psychotherapeutic modalities has been
central to the hypothesized social processing improve- suggested (Feller & Cottone, 2003). Psilocybin may
ments following both MDMA and psilocybin- help in reducing treatment drop-out rates and
assisted therapy. improve psychotherapeutic efficacy by supporting the
development of a strong therapeutic alliance via the with Professor Allan Young at King’s College London.
promotion of empathy in PTSD. King’s College London receives grant funding from
COMPASS Pathways PLC to undertake phase 1 and phase
2 trials with psilocybin. COMPASS Pathways PLC has paid
Conclusion for James Rucker and Liam Modlin to attend trial-related
meetings and conferences to present the results of research
Existing evidence that may support the use of psilo- using psilocybin. James Rucker asserts that COMPASS
cybin-assisted psychotherapy for the treatment of Pathways had no influence over the content of this article.
trauma-related symptomatology, and MDMA-assisted James Rucker has undertaken paid consultancy work for
Beckley PsyTech and Clerkenwell Health. Payments for
psychotherapy for the treatment of depressive symp-
consultancy work are received and managed by King’s
tomatology, has been outlined above. Whilst depres- College London. James Rucker does not benefit personally.
sion is a complex psychosocial condition with a James Rucker has no shareholdings in pharmaceut-
multitude of triggers, there is robust evidence to sug- ical companies.
gest that it can arise as a result of traumatic experien-
ces, particularly in early life. When comorbid with
ORCID
PTSD, a multifaceted approach to treatment is
required. The combination of psychotherapy and Catherine I. V. Bird http://orcid.org/0000-0002-
pharmacology as is presented in drug-assisted psycho- 8656-6931
therapy models seems to be a valuable approach in
treating both depression and PTSD, especially in References
those who have not responded to available treatments.
Agorastos, A., Pervanidou, P., Chrousos, G. P., & Baker,
The occasional persistence of depressive symptoms D. G. (2019). Developmental trajectories of early life
following MDMA may be an artefact or a key mech- stress and trauma: A narrative review on neurobiological
anism in the processing of traumatic memories. A aspects beyond stress system dysregulation. Frontiers in
potential treatment course could be to administer Psychiatry, 10, 118. https://doi.org/10.3389/fpsyt.2019.
MDMA-assisted psychotherapy in the first instance 00118
Alexander, W. (2012). Pharmacotherapy for post-traumatic
and then offer psilocybin-assisted psychotherapy in
stress disorder in combat veterans: Focus on antidepres-
those for whom depressive symptoms still persist. It sants and atypical antipsychotic agents. P & T, 37(1), 32.
has been suggested that this course may allow the American Psychiatric Association. (2013). Diagnostic and
patient to be more accustomed to the heightened statistical manual of mental disorders (5th ed.). APA.
arousal experienced under psilocybin after experienc- American Psychiatric Association. (2017). Clinical practice
ing more ‘present’ altered states of consciousness guideline for the treatment of Posttraumatic Stress
Disorder (PTSD) in adults. https://www.apa.org/ptsd-
under MDMA (Krediet et al., 2020). The ‘trust guideline/ptsd.pdf
enhancing’ qualities of MDMA may prove useful in Anderson, I. M., Ferrier, I. N., Baldwin, R. C., Cowen, P. J.,
strengthening therapeutic alliance in the first instance Howard, L., Lewis, G., Matthews, K., McAllister-
to allow for a ‘deeper’ subsequent acute psilocybin Williams, R. H., Peveler, R. C., Scott, J., & Tylee, A.
experience. Proof of concept studies is required in (2008). Evidence-based guidelines for treating depressive
disorders with antidepressants: A revision of the 2000
order to directly investigate the potential transdiag-
British Association for Psychopharmacology guidelines.
nostic uses of psilocybin- and MDMA-assisted psy- Journal of Psychopharmacology, 22(4), 343–396. https://
chotherapy for comorbid and non-comorbid PTSD doi.org/10.1177/0269881107088441
and depression. Atwoli, L., Stein, D. J., Koenen, K. C., & McLaughlin, K. A.
(2015). Epidemiology of posttraumatic stress disorder:
Prevalence, correlates and consequences. Current Opinion
Disclosure statement in Psychiatry, 28(4), 307–311. https://doi.org/10.1097/
YCO.0000000000000167
James Rucker is an honorary consultant psychiatrist at The
Baldwin, D. S., Anderson, I. M., Nutt, D. J., Allgulander,
South London & Maudsley NHS Foundation Trust, a con-
C., Bandelow, B., den Boer, J. A., Christmas, D. M.,
sultant psychiatrist at Sapphire Medical Clinics and an
Davies, S., Fineberg, N., Lidbetter, N., Malizia, A.,
NIHR Clinician Scientist Fellow at the Centre for Affective
McCrone, P., Nabarro, D., O’Neill, C., Scott, J., van der
Disorders at King’s College London.
Wee, N., & Wittchen, H.-U. (2014). Evidence-based
pharmacological treatment of anxiety disorders, post-
Funding traumatic stress disorder and obsessive-compulsive dis-
order: A revision of the 2005 guidelines from the British
James Rucker’s salary is funded by a fellowship (CS-2017- Association for Psychopharmacology. Journal of
17-007) from the National Institute for Health Research Psychopharmacology, 28(5), 403–439. https://doi.org/10.
(NIHR). James Rucker leads the Psychedelic Trials Group 1177/0269881114525674
Baldwin, J. R., Reuben, A., Newbury, J. B., & Danese, A. Biological Psychiatry, 41(1), 23–32. https://doi.org/10.
(2019). Agreement between prospective and retrospective 1016/S0006-3223(96)00162-X
measures of childhood maltreatment: A systematic review Breslau, N., Kessler, R. C., Chilcoat, H. D., Schultz, L. R.,
and meta-analysis. JAMA Psychiatry, 76(6), 584–593. Davis, G. C., & Andreski, P. (1998). Trauma and post-
https://doi.org/10.1001/jamapsychiatry.2019.0097 traumatic stress disorder in the community: The 1996
Barnby, J. M., & Mehta, M. A. (2018). Psilocybin and men- Detroit Area Survey of Trauma. Archives of General
tal health–don’t lose control. Frontiers in Psychiatry, 9, Psychiatry, 55(7), 626–632. https://doi.org/10.1001/arch-
293. https://doi.org/10.3389/fpsyt.2018.00293 psyc.55.7.626
Barrett, F. S., Doss, M. K., Sepeda, N. D., Pekar, J. J., & Carhart-Harris, R. L., Bolstridge, M., Day, C. M. J., Rucker,
Griffiths, R. R. (2020). Emotions and brain function are J., Watts, R., Erritzoe, D. E., Kaelen, M., Giribaldi, B.,
altered up to one month after a single high dose of psilo- Bloomfield, M., Pilling, S., Rickard, J. A., Forbes, B.,
cybin. Scientific Reports, 10(1), 1–14. https://doi.org/10. Feilding, A., Taylor, D., Curran, H. V., & Nutt, D. J.
1038/s41598-020-59282-y (2018). Psilocybin with psychological support for treat-
Bastiaans, J. (1983). Mental liberation facilitated by the use ment-resistant depression: Six-month follow-up.
of hallucinogenic drugs. In L. Grinspoon, & B. B. Psychopharmacology, 235(2), 399–408. https://doi.org/10.
Bakalar (Eds.), Psychedelic reflections (pp 143–152). 1007/s00213-017-4771-x
Human Science Press. Carhart-Harris, R. L., Bolstridge, M., Rucker, J., Day,
Bedi, G., Hyman, D., & de Wit, H. (2010). Is ecstasy an C. M. J., Erritzoe, D., Kaelen, M., Bloomfield, M.,
“empathogen”? Effects of ± 3, 4-methylenedioxymetham- Rickard, J. A., Forbes, B., Feilding, A., Taylor, D., Pilling,
phetamine on prosocial feelings and identification of S., Curran, V. H., & Nutt, D. J. (2016). Psilocybin with
emotional states in others. Biological Psychiatry, 68(12), psychological support for treatment-resistant depression:
1134–1140. https://doi.org/10.1016/j.biopsych.2010.08.003 An open-label feasibility study. The Lancet. Psychiatry,
Bedi, G., Phan, K. L., Angstadt, M., & De Wit, H. (2009). 3(7), 619–627. https://doi.org/10.1016/S2215-
Effects of MDMA on sociability and neural response to 0366(16)30065-7
social threat and social reward. Psychopharmacology, Carhart-Harris, R., Giribaldi, B., Watts, R., Baker-Jones, M.,
207(1), 73–83. https://doi.org/10.1007/s00213-009-1635-z Murphy-Beiner, A., Murphy, R., Martell, J., Blemings, A.,
Bergfeld, I. O., Mantione, M., Figee, M., Schuurman, P. R., Erritzoe, D. & Nutt, D. J. (2021). Trial of Psilocybin ver-
Lok, A., & Denys, D. (2018). Treatment-resistant depres- sus Escitalopram for depression. New England Journal of
sion and suicidality. Journal of Affective Disorders, 235, Medicine, 384(15), 1402–1411. https://doi.org/10.1056/
362–367. https://doi.org/10.1016/j.jad.2018.04.016 NEJMoa2032994
Bisson, J. I., Roberts, N. P., Andrew, M., Cooper, R., & Carhart-Harris, R. L., Murphy, K., Leech, R., Erritzoe, D.,
Lewis, C. (2013). Psychological therapies for chronic Wall, M. B., Ferguson, B., Williams, L. T. J., Roseman,
post-traumatic stress disorder (PTSD) in adults. L., Brugger, S., De Meer, I., Tanner, M., Tyacke, R.,
Cochrane Database of Systematic Reviews, 2013(12), Wolff, K., Sethi, A., Bloomfield, M. A. P., Williams,
CD003388. https://doi.org/10.1002/14651858.CD003388. T. M., Bolstridge, M., Stewart, L., Morgan, C., … Nutt,
pub4 D. J. (2015). The effects of acutely administered 3,4-
Bogenschutz, M. P., Forcehimes, A. A., Pommy, J. A., methylenedioxymethamphetamine on spontaneous brain
Wilcox, C. E., Barbosa, P. C. R., & Strassman, R. J. function in healthy volunteers measured with arterial
(2015). Psilocybin-assisted treatment for alcohol depend- spin labeling and blood oxygen level–dependent resting
ence: A proof-of-concept study. Journal of state functional connectivity. Biological Psychiatry, 78(8),
Psychopharmacology, 29(3), 289–299. https://doi.org/10. 554–562. https://doi.org/10.1016/j.biopsych.2013.12.015
1177/0269881114565144 Carhart-Harris, R. L., Wall, M. B., Erritzoe, D., Kaelen, M.,
Bradley, R., Greene, J., Russ, E., Dutra, L., & Westen, D. Ferguson, B., De Meer, I., Tanner, M., Bloomfield, M.,
(2005). A multidimensional meta-analysis of psychother- Williams, T. M., Bolstridge, M., Stewart, L., Morgan,
apy for PTSD. American Journal of Psychiatry, 162(2), C. J., Newbould, R. D., Feilding, A., Crown, W. H.,
214–227. https://doi.org/10.1176/appi.ajp.162.2.214 Finkelstein, S., Berndt, E. R., Ling, D., Poret, A. W.,
Bremner, J. D. (2002). Neuroimaging of childhood trauma. Rush, A. J., & Russell, J. M. (2014). The effect of acutely
Seminars in Clinical Neuropsychiatry, 7(2), 104–112. administered MDMA on subjective and BOLD-fMRI
https://doi.org/10.1053/scnp.2002.31787 responses to favourite and worst autobiographical memo-
Bremner, J. D., Randall, P., Scott, T. M., Bronen, R. A., ries. The International Journal of
Seibyl, J. P., Southwick, S. M., Delaney, R. C., McCarthy, Neuropsychopharmacology, 17(04), 527–540. https://doi.
G., Charney, D. S., & Innis, R. B. (1995). MRI-based org/10.1017/S1461145713001405
measurement of hippocampal volume in patients with Carlson, E. B., & Rosser-Hogan, R. (1991). Trauma experi-
combat-related posttraumatic stress disorder. The ences, posttraumatic stress, dissociation, and depression
American Journal of Psychiatry, 152(7), 973–981. https:// in Cambodian refugees. The American Journal of
doi.org/10.1176/ajp.152.7.973 Psychiatry, 148(11), 1548–1551. https://doi.org/10.1176/
Bremner, J. D., Randall, P., Vermetten, E., Staib, L., ajp.148.11.1548
Bronen, R. A., Mazure, C., Capelli, S., McCarthy, G., Catlow, B. J., Song, S., Paredes, D. A., Kirstein, C. L., &
Innis, R. B., & Charney, D. S. (1997). Magnetic reson- Sanchez-Ramos, J. (2013). Effects of psilocybin on hippo-
ance imaging-based measurement of hippocampal vol- campal neurogenesis and extinction of trace fear condi-
ume in posttraumatic stress disorder related to childhood tioning. Experimental Brain Research, 228(4), 481–491.
physical and sexual abuse—a preliminary report. https://doi.org/10.1007/s00221-013-3579-0
Center for Substance Abuse Treatment. (2014). Trauma- approaches to PTSD. Current Psychiatry Reports, 20(5),
informed care in behavioral health services. Substance 30. https://doi.org/10.1007/s11920-018-0898-7
Abuse and Mental Health Services Administration. Davidson, J. R., Hughes, D., Blazer, D. G., & George, L. K.
Charuvastra, A., & Cloitre, M. (2008). Social bonds and (1991). Post-traumatic stress disorder in the community:
posttraumatic stress disorder. Annual Review of An epidemiological study. Psychological Medicine, 21(3),
Psychology, 59, 301–328. https://doi.org/10.1146/annurev. 713–721. https://doi.org/10.1017/s0033291700022352
psych.58.110405.085650 Davis, A. K., Barrett, F. S., May, D. G., Cosimano, M. P.,
Cleare, A., Pariante, C., Young, A., Anderson, I., Christmas, Sepeda, N. D., Johnson, M. W., Finan, P. H., & Griffiths,
D., Cowen, P., Dickens, C., Ferrier, I., Geddes, J., R. R. (2020). Effects of psilocybin-assisted therapy on
Gilbody, S., Haddad, P., Katona, C., Lewis, G., Malizia, major depressive disorder: A randomized clinical trial.
A., McAllister-Williams, R., Ramchandani, P., Scott, J., JAMA Psychiatry. Advance online publication. https://
Taylor, D., & Uher, R. (2015). Evidence-based guidelines doi.10.1001/jamapsychiatry.2020.3285
for treating depressive disorders with antidepressants: A de Vries, G. J., & Olff, M. (2009). The lifetime prevalence
revision of the 2008 British Association for of traumatic events and posttraumatic stress disorder in
Psychopharmacology guidelines. Journal of the Netherlands. Journal of Traumatic Stress, 22(4),
Psychopharmacology, 29(5), 459–525. https://doi.org/10. 259–267. https://doi.org/10.1002/jts.20429
1177/0269881115581093 Drevets, W. C., Videen, T. O., Price, J. L., Preskorn, S. H.,
Coleman, J. R. I., Peyrot, W. J., Purves, K. L., Davis, Carmichael, S. T., & Raichle, M. E. (1992). A functional
K. A. S., Rayner, C., Choi, S. W., H€ ubel, C., Gaspar, anatomical study of unipolar depression. The Journal of
H. A., Kan, C., Van der Auwera, S., Adams, M. J., Lyall, Neuroscience, 12(9), 3628–3641. https://doi.org/10.1016/
D. M., Choi, K. W., Dunn, E. C., Vassos, E., Danese, A., S0091-3057(01)00687-6
Maughan, B., Grabe, H. J., Lewis, C. M., … Breen, G. Dumont, G. J., Sweep, F. C. G. J., Van der Steen, R.,
(2020). Genome-wide gene-environment analyses of Hermsen, R., Donders, A. R. T., Touw, D. J., van
major depressive disorder and reported lifetime trau- Gerven, J. M. A., Buitelaar, J. K., & Verkes, R. J. (2009).
matic experiences in UK Biobank. Molecular Psychiatry, Increased oxytocin concentrations and prosocial feelings
25(7), 1430–1446. https://doi.org/10.1038/s41380-019- in humans after ecstasy (3,4-methylenedioxymethamphet-
0546-6 amine) administration. Social Neuroscience, 4(4),
Collishaw, S., Pickles, A., Messer, J., Rutter, M., Shearer, C., 359–366. https://doi.org/10.1080/17470910802649470
& Maughan, B. (2007). Resilience to adult psychopath- Eckstein, M., Becker, B., Scheele, D., Scholz, C., Preckel, K.,
ology following childhood maltreatment: Evidence from Schlaepfer, T. E., Keith, V. G., Kendrick, M., Maier, W.,
a community sample. Child Abuse & Neglect, 31(3), & Hurlemann, R. (2015). Oxytocin facilitates the extinc-
211–229. https://doi.org/10.1016/j.chiabu.2007.02.004 tion of conditioned fear in humans. Biological Psychiatry,
COMPASS Pathways. (2018). Compass pathways receives 78(3), 194–202. https://doi.org/10.1016/j.biopsych.2014.
FDA breakthrough therapy designation for psilocybin ther- 10.015
apy for treatment-resistant depression. https://compass- Eisner, B. (1989). Ecstasy: The MDMA story. Ronin
pathways.com/compass-pathways-receives-fda-break- Publishing.
through-therapy-designation-for-psilocybin-therapy-for- Elhai, J. D., North, T. C., & Frueh, B. C. (2005). Health ser-
treatment-resistant-depression/ vice use predictors among trauma survivors: A critical
Crown, W. H., Finkelstein, S., Berndt, E. R., Ling, D., review. Psychological Services, 2(1), 3–19. https://doi.org/
Poret, A. W., Rush, A. J., & Russell, J. M. (2002). The 10.1037/1541-1559.2.1.3
impact of treatment-resistant depression on health care Elliott, J. M., & Beveridge, T. J. (2005). Psychostimulants
utilization and costs. The Journal of Clinical Psychiatry, and monoamine transporters: Upsetting the balance.
63(11), 963–971. https://doi.org/10.4088/JCP.v63n1102 Current Opinion in Pharmacology, 5(1), 94–100. https://
Daly, E. J., Trivedi, M. H., Janik, A., Li, H., Zhang, Y., Li, doi.org/10.1016/j.coph.2004.09.005
X., Lane, R., Lim, P., Duca, A. R., Hough, D., Thase, El-Seedi, H. R., De Smet, P. A., Beck, O., Possnert, G., &
M. E., Zajecka, J., Winokur, A., Divacka, I., Fagiolini, A., Bruhn, J. G. (2005). Prehistoric peyote use: Alkaloid ana-
Cubala, W. J., Bitter, I., Blier, P., Shelton, R. C., … lysis and radiocarbon dating of archaeological specimens
Singh, J. B. (2019). Efficacy of esketamine nasal spray of Lophophora from Texas. Journal of
plus oral antidepressant treatment for relapse prevention Ethnopharmacology, 101(1–3), 238–242. https://doi.org/
in patients with treatment-resistant depression: A 10.1016/j.jep.2005.04.022
randomized clinical trial. JAMA Psychiatry, 76(9), Etkin, A., & Wager, T. D. (2007). Functional neuroimaging
893–903. https://doi.org/10.1001/jamapsychiatry.2019. of anxiety: A meta-analysis of emotional processing in
1189 PTSD, social anxiety disorder, and specific phobia.
Danforth, A. L., Grob, C. S., Struble, C., Feduccia, A. A., American Journal of Psychiatry, 164(10), 1476–1488.
Walker, N., Jerome, L., Yazar-Klosinski, B., & Emerson, https://doi.org/10.1176/appi.ajp.2007.07030504
A. (2018). Reduction in social anxiety after MDMA- Fava, M. (2003). Diagnosis and definition of treatment-
assisted psychotherapy with autistic adults: A random- resistant depression. Biological Psychiatry, 53(8),
ized, double-blind, placebo-controlled pilot study. 649–659. https://doi.org/10.1016/S0006-3223(03)00231-2
Psychopharmacology, 235(11), 3137–3148. https://doi.org/ Fedgchin, M., Trivedi, M., Daly, E. J., Melkote, R., Lane, R.,
10.1007/s00213-018-5010-9 Lim, P., Vitagliano, D., Blier, P., Fava, M., Liebowitz, M.,
Daskalakis, N. P., Rijal, C. M., King, C., Huckins, L. M., & Ravindran, A., Gaillard, R., Van Den Ameele, H.,
Ressler, K. J. (2018). Recent genetics and epigenetics Preskorn, S., Manji, H., Hough, D., Drevets, W. C., &
Singh, J. B. (2019). Efficacy and safety of fixed-dose Frecska, E., Bokor, P., & Winkelman, M. (2016). The thera-
esketamine nasal spray combined with a new oral anti- peutic potentials of ayahuasca: Possible effects against
depressant in treatment-resistant depression: Results of a various diseases of civilization. Frontiers in
randomized, double-blind, active-controlled study Pharmacology, 7, 35. https://doi.org/10.3389/fphar.2016.
(TRANSFORM-1). International Journal of 00035
Neuropsychopharmacology, 22(10), 616–630. https://doi. Gamma, A., Buck, A., Berthold, T., Hell, D., &
org/10.1093/ijnp/pyz039 Vollenweider, F. X. (2000). 3, 4-
Feduccia, A. A., & Duvauchelle, C. L. (2008). Auditory Methylenedioxymethamphetamine (MDMA) modulates
stimuli enhance MDMA-conditioned reward and cortical and limbic brain activity as measured by
MDMA-induced nucleus accumbens dopamine, sero- [H215O]-PET in healthy humans.
tonin and locomotor responses. Brain Research Bulletin, Neuropsychopharmacology, 23(4), 388–395. https://doi.
77(4), 189–196. https://doi.org/10.1080/ org/10.1016/S0893-133X(00)00130-5
17470910802649470 Garcia-Romeu, A., & Richards, W. A. (2018). Current per-
Feduccia, A. A., & Mithoefer, M. C. (2018). MDMA- spectives on psychedelic therapy: Use of serotonergic hal-
assisted psychotherapy for PTSD: Are memory reconsoli- lucinogens in clinical interventions. International Review
dation and fear extinction underlying mechanisms? of Psychiatry, 30(4), 291–316. https://doi.org/10.1080/
Progress in Neuro-Psychopharmacology & Biological 09540261.2018.1486289
Psychiatry, 84(A), 221–228. https://doi.org/10.1016/j. Grant, D. M., Beck, J. G., Marques, L., Palyo, S. A., &
pnpbp.2018.03.003 Clapp, J. D. (2008). The structure of distress following
Feduccia, A. A., Holland, J., & Mithoefer, M. C. (2018). trauma: Posttraumatic stress disorder, major depressive
Progress and promise for the MDMA drug development disorder, and generalized anxiety disorder. Journal of
program. Psychopharmacology, 235(2), 561–571. https:// Abnormal Psychology, 117(3), 662–672. https://doi.org/10.
doi.org/10.1007/s00213-017-4779-2 1037/a0012591
Feduccia, A. A., Jerome, L., Klosinski, B., Emerson, A., Grant, M. M., Cannistraci, C., Hollon, S. D., Gore, J., &
Mithoefer, M. C., & Doblin, R. (2019). Breakthrough for Shelton, R. (2011). Childhood trauma history differenti-
trauma treatment: Safety and efficacy of MDMA-assisted ates amygdala response to sad faces within MDD.
Journal of Psychiatric Research, 45(7), 886–895. https://
psychotherapy compared to paroxetine and sertraline.
doi.org/10.1016/j.jpsychires.2010.12.004
Frontiers in Psychiatry, 10, 650. https://doi.org/10.3389/
Griffiths, R. R., Johnson, M. W., Carducci, M. A.,
fpsyt.2019.00650
Umbricht, A., Richards, W. A., Richards, B. D.,
Felitti, V. J., Anda, R. F., Nordenberg, D., Williamson,
Cosimano, M. P., & Klinedinst, M. A. (2016). Psilocybin
D. F., Spitz, A. M., Edwards, V., Koss, M. P., & Marks,
produces substantial and sustained decreases in depres-
J. S. (1998). Relationship of childhood abuse and house-
sion and anxiety in patients with life-threatening cancer:
hold dysfunction to many of the leading causes of death
A randomized double-blind trial. Journal of
in adults: The Adverse Childhood Experiences (ACE)
Psychopharmacology, 30(12), 1181–1197. https://doi.org/
Study. American Journal of Preventive Medicine, 14(4), 10.1177/0269881116675513
245–258. https://doi.org/10.1016/S0749-3797(98)00017-8 Grob, C. S., Danforth, A. L., Chopra, G. S., Hagerty, M.,
Feller, C. P., & Cottone, R. R. (2003). The importance of McKay, C. R., Halberstadt, A. L., & Greer, G. R. (2011).
empathy in the therapeutic alliance. The Journal of Pilot study of psilocybin treatment for anxiety in patients
Humanistic Counseling, Education and Development, with advanced-stage cancer. Archives of General
42(1), 53–61. https://doi.org/10.1002/j.2164-490X.2003. Psychiatry, 68(1), 71–78. https://doi.org/10.1001/archgen-
tb00168.x psychiatry.2010.116
Flory, J. D., & Yehuda, R. (2015). Comorbidity between Gros, D. F., Price, M., Magruder, K. M., & Frueh, B. C.
post-traumatic stress disorder and major depressive dis- (2012). Symptom overlap in posttraumatic stress disorder
order: Alternative explanations and treatment considera- and major depression. Psychiatry Research, 196(2–3),
tions. Dialogues in Clinical Neuroscience, 17(2), 141–150. 267–270. https://doi.org/10.1016/j.psychres.2011.10.022
https://doi.org/10.31887/DCNS.2015.17.2/jflory Gros, D. F., Simms, L. J., & Acierno, R. (2010). Specificity
Foa, E. B., Stein, D. J., & McFarlane, A. C. (2006). of posttraumatic stress disorder symptoms: An investiga-
Symptomatology and psychopathology of mental health tion of comorbidity between posttraumatic stress dis-
problems after disaster. Journal of Clinical Psychiatry, order symptoms and depression in treatment-seeking
67(2), 15–25. veterans. Journal of Nervous & Mental Disease, 198(12),
Fox, M. A., Andrews, A. M., Wendland, J. R., Lesch, K. P., 885–890. https://doi.org/10.1097/NMD.0b013e3181fe7410
Holmes, A., & Murphy, D. L. (2007). A pharmacological Gurvits, T. V., Shenton, M. E., Hokama, H., Ohta, H.,
analysis of mice with a targeted disruption of the sero- Lasko, N. B., Gilbertson, M. W., Orr, S. P., Kikinis, R.,
tonin transporter. Psychopharmacology, 195(2), 147–166. Jolesz, F. A., McCarley, R. W., & Pitman, R. K. (1996).
https://doi.org/10.1007/s00213-007-0910-0 Magnetic resonance imaging study of hippocampal vol-
Frayne, S. M., Seaver, M. R., Loveland, S., Christiansen, ume in chronic, combat-related posttraumatic stress dis-
C. L., Spiro, A., III, Parker, V. A., & Skinner, K. M. order. Biological Psychiatry, 40(11), 1091–1099. https://
(2004). Burden of medical illness in women with depres- doi.org/10.1016/S0006-3223(96)00229-6
sion and posttraumatic stress disorder. Archives of Haagen, J. F., Smid, G. E., Knipscheer, J. W., & Kleber,
Internal Medicine, 164(12), 1306–1312. https://doi.org/10. R. J. (2015). The efficacy of recommended treatments for
1001/archinte.164.12.1306 veterans with PTSD: A metaregression analysis. Clinical
Psychology Review, 40, 184–194. https://doi.org/10.1016/ International Journal of Neuropsychopharmacology,

j.cpr.2017.10.009 15(06), 825–840. https://doi.org/10.1017/
Hall, H., Farde, L., Halldin, C., Lundkvist, C., & Sedvall, G. S1461145711001209
(2000). Autoradiographic localization of 5-HT2A recep- Jakupcak, M., Cook, J., Imel, Z., Fontana, A., Rosenheck,
tors in the human brain using [3H] M100907 and [11C] R., & McFall, M. (2009). Posttraumatic stress disorder as
M100907. Synapse, 38(4), 421–431. https://doi.org/10. a risk factor for suicidal ideation in Iraq and Afghanistan
1002/1098-2396(20001215)38:4<421::AID-SYN7>3.0. war veterans. Journal of Traumatic Stress, 22(4), 303–306.
CO;2-X https://doi.org/10.1002/jts.20423
Hamblen, J. L., Norman, S. B., Sonis, J. H., Phelps, A. J., Johansen, P. Ø., & Krebs, T. S. (2009). How could MDMA
Bisson, J. I., Nunes, V. D., Megnin-Viggars, O., Forbes, (ecstasy) help anxiety disorders? A neurobiological
D., Riggs, D. S., & Schnurr, P. P. (2019). A guide to rationale. Journal of Psychopharmacology, 23(4), 389–391.
guidelines for the treatment of posttraumatic stress dis- https://doi.org/10.1177/0269881109102787
order in adults: An update. Psychotherapy, 56(3), Johnson, M. W., Garcia-Romeu, A., Cosimano, M. P., &
359–373. https://doi.org/10.1037/pst0000231 Griffiths, R. R. (2014). Pilot study of the 5-HT2AR agon-
Hammen, C., Davila, J., Brown, G., Ellicott, A., & Gitlin, ist psilocybin in the treatment of tobacco addiction.
M. (1992). Psychiatric history and stress: Predictors of Journal of Psychopharmacology, 28(11), 983–992. https://
severity of unipolar depression. Journal of Abnormal doi.org/10.1177/0269881114548296
Psychology, 101(1), 45–52. https://doi.org/10.1037/0021- Jones, L., Bates, G., Bellis, M., Beynon, C., Duffy, P.,
843X.101.1.45 Evans–Brown, M., & McVeigh, J. (2011). A summary of
Heim, C., & Nemeroff, C. B. (2009). Neurobiology of post- the health harms of drugs (Technical document).
traumatic stress disorder. CNS Spectrums, 14(1), 13–24. Department of Health.
Heim, C., Newport, D. J., Mletzko, T., Miller, A. H., & Kaye, S., Darke, S., & Duflou, J. (2009).
Nemeroff, C. B. (2008). The link between childhood Methylenedioxymethamphetamine (MDMA)-related
trauma and depression: Insights from HPA axis studies fatalities in Australia: Demographics, circumstances, toxi-
in humans. Psychoneuroendocrinology, 33(6), 693–710. cology and major organ pathology. Drug and Alcohol
https://doi.org/10.1016/j.psyneuen.2008.03.008 Dependence, 104(3), 254–261. https://doi.org/10.1016/j.
Holland, J. (Ed.). (2001). Ecstasy: The complete guide: A drugalcdep.2009.05.016
comprehensive look at the risks and benefits of MDMA. Keane, T. M., Brief, D. J., Pratt, E. M., & Miller, M. W.
Park Street Press. (2007). Assessment of PTSD and its comorbidities in
Hoskins, M., Pearce, J., Bethell, A., Dankova, L., Barbui, C., adults. In M. J. Friedman, T. M. Keane, & P. A. Resick,
Tol, W. A., van Ommeren, M., de Jong, J., Seedat, S., (Eds.), Handbook of PTSD: Science and practice (pp.
Chen, H., & Bisson, J. I. (2015). Pharmacotherapy for 279–305). Guilford.
post-traumatic stress disorder: Systematic review and Kendler, K. S., & Karkowski-Shuman, L. (1997). Stressful
meta-analysis. British Journal of Psychiatry, 206(2), life events and genetic liability to major depression:
93–100. https://doi.org/10.1192/bjp.bp.114.148551 Genetic control of exposure to the environment?
Howlett, J. R., & Stein, M. B. (2016). Prevention of trauma Psychological Medicine, 27(3), 539–547. https://doi.org/10.
and stressor-related disorders: A review. 1017/s0033291797004716
Neuropsychopharmacology : Neuropsychopharmacology, Kendler, K. S., Karkowski, L. M., & Prescott, C. A. (1999).
41(1), 357–369. https://doi.org/10.1038/npp.2015.261 Causal relationship between stressful life events and the
Hyman, S. E. (2013). Psychiatric drug development: onset of major depression. American Journal of
Diagnosing a crisis. In Cerebrum: The Dana forum on Psychiatry, 156(6), 837–841. https://doi.org/10.1176/ajp.
brain science (Vol. 2013). Dana Foundation. 156.6.837
Hysek, C. M., Domes, G., & Liechti, M. E. (2012). MDMA Kessler, R. C. (2000). Posttraumatic stress disorder: The
enhances “mind reading” of positive emotions and burden to the individual and to society. The Journal of
impairs “mind reading” of negative emotions. Clinical Psychiatry, 61(5), 4–12.
Psychopharmacology, 222(2), 293–302. https://doi.org/10. Kessler, R. C., Aguilar-Gaxiola, S., Alonso, J., Benjet, C.,
1007/s00213-012-2645-9 Bromet, E. J., Cardoso, G., Degenhardt, L., de Girolamo,
Hysek, C. M., Schmid, Y., Simmler, L. D., Domes, G., G., Dinolova, R. V., Ferry, F., Florescu, S., Gureje, O.,
Heinrichs, M., Eisenegger, C., Preller, K. H., Quednow, Haro, J. M., Huang, Y., Karam, E. G., Kawakami, N.,
B. B., & Liechti, M. E. (2014). MDMA enhances emo- Lee, S., Lepine, J.-P., Levinson, D., … Koenen, K. C.
tional empathy and prosocial behavior. Social Cognitive (2017). Trauma and PTSD in the WHO world mental
and Affective Neuroscience, 9(11), 1645–1652. https://doi. health surveys. European Journal of Psychotraumatology,
org/10.1093/scan/nst161 8(5), 1353383. https://doi.org/10.1080/20008198.2017.
Illingworth, B. J. G., Lewis, D. J., Lambarth, A. T., Stocking, 1353383
K., Duffy, J. M. N., Jelen, L. A., & Rucker, J. J. (2020). A Kimble, M., & Kaufman, M. (2004). Clinical correlates of
comparison of MDMA-assisted psychotherapy to non- neuro- logical change in posttraumatic stress disorder:
assisted psychotherapy in treatment-resistant PTSD: A An overview of critical systems. Psychiatric Clinics of
systematic review and meta-analysis. Journal of North America, 27(1), 49–65. https://doi.org/10.1016/
Psychopharmacology. Advance online publication. https:// S0193-953X(03)00108-4
doi.org/10.1177/0269881120965915 Kline, A. C., Cooper, A. A., Rytwinksi, N. K., & Feeny,
Ipser, J. C., & Stein, D. J. (2012). Evidence-based pharma- N. C. (2018). Long-term efficacy of psychotherapy for
cotherapy of post-traumatic stress disorder (PTSD). The posttraumatic stress disorder: A meta-analysis of
randomized controlled trials. Clinical Psychology Review, Laugharne, J., Lillee, A., & Janca, A. (2010). Role of psycho-
59, 30–40. https://doi.org/10.1016/j.cpr.2017.10.009 logical trauma in the cause and treatment of anxiety and
Koenen, K. C., Ratanatharathorn, A., Ng, L., McLaughlin, depressive disorders. Current Opinion in Psychiatry,
K. A., Bromet, E. J., Stein, D. J., Karam, E. G., Meron 23(1), 25–29. https://doi.org/10.1097/YCO.
Ruscio, A., Benjet, C., Scott, K., Atwoli, L., Petukhova, 0b013e3283345dc5
M., Lim, C. C. W., Aguilar-Gaxiola, S., Al-Hamzawi, A., Levitan, R. D., Parikh, S. V., Lesage, A. D., Hegadoren,
Alonso, J., Bunting, B., Ciutan, M., de Girolamo, G., … K. M., Adams, M., Kennedy, S. H., & Goering, P. N.
Kessler, R. C. (2017). Posttraumatic stress disorder in the (1998). Major depression in individuals with a history of
world mental health surveys. Psychological Medicine, childhood physical or sexual abuse: Relationship to neu-
47(13), 2260–2274. https://doi.org/10.1017/ rovegetative features, mania, and gender. The American
S0033291717000708 Journal of Psychiatry, 155(12), 1746–1752. https://doi.org/
Koenen, K. C., Stellman, S. D., Sommer, J. F., Jr., & 10.1176/ajp.155.12.1746
Stellman, J. M. (2008). Persisting posttraumatic stress Liechti, M. E., & Vollenweider, F. X. (2000). The serotonin
disorder symptoms and their relationship to functioning uptake inhibitor citalopram reduces acute cardiovascular
in Vietnam veterans: A 14-year follow-up. Journal of and vegetative effects of 3, 4-methylenedioxymetham-
Traumatic Stress, 21(1), 49–57. https://doi.org/10.1002/jts. phetamine (‘Ecstasy’) in healthy volunteers. Journal of
20304 Psychopharmacology, 14(3), 269–274. https://doi.org/10.
Kometer, M., Schmidt, A., Bachmann, R., Studerus, E., 1177/026988110001400313
Seifritz, E., & Vollenweider, F. X. (2012). Psilocybin Ly, C., Greb, A. C., Cameron, L. P., Wong, J. M., Barragan,
biases facial recognition, goal-directed behavior, and E. V., Wilson, P. C., Burbach, K. F., Soltanzadeh
mood state toward positive relative to negative emotions Zarandi, S., Sood, A., Paddy, M. R., Duim, W. C.,
through different serotonergic subreceptors. Biological Dennis, M. Y., McAllister, A. K., Ori-McKenney, K. M.,
Psychiatry, 72(11), 898–906. https://doi.org/10.1016/j. Gray, J. A., & Olson, D. E. (2018). Psychedelics promote
biopsych.2012.04.005 structural and functional neural plasticity. Cell Reports,
Kraehenmann, R., Preller, K. H., Scheidegger, M., Pokorny, 23(11), 3170–3182. https://doi.org/10.1016/j.celrep.2018.
T., Bosch, O. G., Seifritz, E., & Vollenweider, F. X. 05.022
MacDonald, K., MacDonald, T. M., Br€ une, M., Lamb, K.,
(2015). Psilocybin-induced decrease in amygdala reactiv-
Wilson, M. P., Golshan, S., & Feifel, D. (2013). Oxytocin
ity correlates with enhanced positive mood in healthy
and psychotherapy: A pilot study of its physiological,
volunteers. Biological Psychiatry, 78(8), 572–581. https://
behavioral and subjective effects in males with depres-
doi.org/10.1016/j.biopsych.2014.04.010
sion. Psychoneuroendocrinology, 38(12), 2831–2843.
Kraehenmann, R., Schmidt, A., Friston, K., Preller, K. H.,
https://doi.org/10.1016/j.psyneuen.2013.05.014
Seifritz, E., & Vollenweider, F. X. (2016). The mixed
Macy, R. D. (1998). Prevalence rates for PTSD and utiliza-
serotonin receptor agonist psilocybin reduces threat-
tion rates of behavioral health services for an adult
induced modulation of amygdala connectivity.
Medicaid population [Unpublished doctoral dissertation].
NeuroImage: Clinical, 11, 53–60. https://doi.org/10.1016/j. Majumder, I., White, J. M., & Irvine, R. J. (2011).
nicl.2015.08.009 Antidepressant-like effects of 3, 4-methylenedioxyme-
Krediet, E., Bostoen, T., Breeksema, J., van Schagen, A., thamphetamine in an animal model of depression.
Passie, T., & Vermetten, E. (2020). Reviewing the Behavioural Pharmacology, 22(8), 758–765. https://doi.
Potential of Psychedelics for the Treatment of PTSD. org/10.1097/FBP.0b013e32834d0f05
International Journal of Neuropsychopharmacology, 23(6), Majumder, I., White, J. M., & Irvine, R. J. (2012).
385–400. https://doi.org/10.1093/ijnp/pyaa018 Antidepressant-like effects of ecstasy in subjects with a
Kuypers, K. P., de la Torre, R., Farre, M., Yubero-Lahoz, S., predisposition to depression. Addictive Behaviors, 37(10),
Dziobek, I., Van den Bos, W., & Ramaekers, J. G. (2014). 1189–1192. https://doi.org/10.1016/j.addbeh.2012.05.022
No evidence that MDMA-induced enhancement of emo- Marshall, R. D., Olfson, M., Hellman, F., Blanco, C.,
tional empathy is related to peripheral oxytocin levels or Guardino, M., & Struening, E. L. (2001). Comorbidity,
5-HT 1a receptor activation. PLoS One, 9(6), e100719. impairment, and suicidality in subthreshold PTSD.
https://doi.org/10.1371/journal.pone.0100719 American Journal of Psychiatry, 158(9), 1467–1473.
Kuypers, K. P., Dolder, P. C., Ramaekers, J. G., & Liechti, https://doi.org/10.1176/appi.ajp.158.9.1467
M. E. (2017). Multifaceted empathy of healthy volunteers Mauritz, M. W., Goossens, P. J., Draijer, N., & Van
after single doses of MDMA: A pooled sample of pla- Achterberg, T. (2013). Prevalence of interpersonal trauma
cebo-controlled studies. Journal of Psychopharmacology, exposure and trauma-related disorders in severe mental
31(5), 589–598. https://doi.org/10.1177/ illness. European Journal of Psychotraumatology, 4(1),
0269881117699617 19985. https://doi.org/10.3402/ejpt.v4i0.19985
Labate, B. C., & Cavnar, C. (Eds.). (2013). The therapeutic McEwen, B. S. (2004). Protection and damage from acute
use of ayahuasca. Springer Science & Business Media. and chronic stress: Allostasis and allostatic overload and
Lanius, R. A., Vermetten, E., Loewenstein, R. J., Brand, B., relevance to the pathophysiology of psychiatric disorders.
Schmahl, C., Bremner, J. D., & Spiegel, D. (2010). Annals of the New York Academy of Sciences, 1032(1),
Emotion modulation in PTSD: Clinical and neurobio- 1–7. https://doi.org/10.1196/annals.1314.001
logical evidence for a dissociative subtype. American McLaughlin, K. A., Conron, K. J., Koenen, K. C., &
Journal of Psychiatry, 167(6), 640–647. https://doi.org/10. Gilman, S. E. (2010). Childhood adversity, adult stressful
1176/appi.ajp.2009.09081168 life events, and risk of past-year psychiatric disorder: A
test of the stress sensitization hypothesis in a population- controlled trial. American Journal of Psychiatry, 170(10),
based sample of adults. Psychological Medicine, 40(10), 1134–1142. https://doi.org/10.1176/appi.ajp.2013.
1647–1658. https://doi.org/10.1017/S0033291709992121 13030392
McQuaid, J. R., Pedrelli, P., McCahill, M. E., & Stein, M. B. Muthukumaraswamy, S. (2021, March 8). Blinding and
(2001). Reported trauma, post-traumatic stress disorder expectancy confounds in psychedelic randomised controlled
and major depression among primary care patients. trials. PsyArXiv. https://doi.org/10.31234/osf.io/q2hzm
Psychological Medicine, 31(7), 1249–1257. https://doi.org/ Nash, J. F., & Brodkin, J. E. S. S. E. (1991). Microdialysis
10.1017/S0033291701004202 studies on 3,4-methylenedioxymethamphetamine-induced
Mertens, L. J., Wall, M. B., Roseman, L., Demetriou, L., dopamine release: Effect of dopamine uptake inhibitors.
Nutt, D. J., & Carhart-Harris, R. L. (2020). Therapeutic Journal of Pharmacology and Experimental Therapeutics,
mechanisms of psilocybin: Changes in amygdala and pre- 259(2), 820–825.
frontal functional connectivity during emotional process- National Institute for Health and Care Excellence. (2018).
ing after psilocybin for treatment-resistant depression. Post-traumatic stress disorder [NICE guideline no. 116].
Journal of Psychopharmacology, 34(2), 167–180. https:// https://www.nice.org.uk/guidance/ng116/resources/post-
doi.org/10.1177/0269881119895520 traumatic-stress-disorder-pdf-66141601777861
Mitchell, J. M., Bogenschutz, M., Lilienstein, A., Harrison, Nemeroff, C. B. (2007). Prevalence and management of
C., Kleiman, S., Parker-Guilbert, K., Ot’alora, M., Garas, treatment-resistant depression. Journal of Clinical
W., Paleos, C., Gorman, I., Nicholas, C., Mithoefer, M., Psychiatry, 68(8), 17.
Carlin, S., Poulter, B., Mithoefer, A., Quevedo, S., Wells, Nichols, D. E. (2014). The Heffter Research Institute: Past
G., Klaire, S. S., van der Kolk, B., Tzarfaty, K., Amiaz, R., and hopeful future. Journal of Psychoactive Drugs, 46(1),
Worthy, R., Shannon, S., Woolley, J. D., Marta, C., 20–26. https://doi.org/10.1080/02791072.2014.873688
Gelfand, Y., Hapke, E., Amar, S., Wallach, Y., Brown, R., Nichols, D. E. (2020). Psilocybin: From ancient magic to
Hamilton, S., Wang, J. B., Coker, A., Matthews, R., de modern medicine. The Journal of Antibiotics, 73(10), 679.
Boer, A., Yazar- Klosinski, B., Emerson, A. & Doblin, R. https://doi.org/10.1038/s41429-020-0311-8
(2021). MDMA-assisted therapy for severe PTSD: a Nielson, J. L., & Megler, J. D. (2014). Ayahuasca as a candi-
randomized, double-blind, placebo-controlled phase 3 date therapy for PTSD. In B. C. Labate & C. Cavnar,
study. Nature Medicine, 1-9. https://doi.org/10.1038/ (Eds.), The therapeutic use of ayahuasca (pp. 41–58).
s41591-021-01336-3 Springer.
Mithoefer, M. C., Feduccia, A. A., Jerome, L., Mithoefer, Noorani, T., Garcia-Romeu, A., Swift, T. C., Griffiths, R. R.,
A., Wagner, M., Walsh, Z., Hamilton, S., Yazar- & Johnson, M. W. (2018). Psychedelic therapy for smok-
Klosinski, B., Emerson, A., & Doblin, R. (2019). MDMA- ing cessation: Qualitative analysis of participant accounts.
assisted psychotherapy for treatment of PTSD: Study Journal of Psychopharmacology, 32(7), 756–769. https://
design and rationale for phase 3 trials based on pooled doi.org/10.1177/0269881118780612
analysis of six phase 2 randomized controlled trials. Ochs-Ross, R., Daly, E. J., Zhang, Y., Lane, R., Lim, P.,
Psychopharmacology, 236(9), 2735–2745. https://doi.org/ Foster, K., Hough, D., Manji, H., Drevets, W. C.,
10.1007/s00213-019-05249-5 Sanacora, G., Adler, C., McShane, R., Gaillard, R., &
Mithoefer, M. C., Grob, C. S., & Brewerton, T. D. (2016). Singh, J. B. (2018). S114. Efficacy and safety of intranasal
Novel psychopharmacological therapies for psychiatric esketamine plus an oral antidepressant in elderly patients
disorders: Psilocybin and MDMA. The Lancet. with treatment-resistant depression. Biological Psychiatry,
Psychiatry, 3(5), 481–488. https://doi.org/10.1016/S2215- 83(9), S391. https://doi.org/10.1016/j.biopsych.2018.02.
0366(15)00576-3 1005
Moreno, F. A., Wiegand, C. B., Taitano, E. K., & Delgado, Ompad, D. C., Ikeda, R. M., Shah, N., Fuller, C. M., Bailey,
P. L. (2006). Safety, tolerability, and efficacy of psilocybin S., Morse, E., Kerndt, P., Maslow, C., Wu, Y., Vlahov,
in 9 patients with obsessive-compulsive disorder. The D., Garfein, R., & Strathdee, S. A. (2005). Childhood sex-
Journal of Clinical Psychiatry, 67(11), 1735–1740. https:// ual abuse and age at initiation of injection drug use.
doi.org/10.4088/JCP.v67n1110 American Journal of Public Health, 95(4), 703–709.
Mueser, K. T., Goodman, L. B., Trumbetta, S. L., https://doi.org/10.2105/AJPH.2003.019372
Rosenberg, S. D., Osher, F. C., Vidaver, R., Auciello, P., Oquendo, M. A., Friend, J. M., Halberstam, B., Brodsky,
& Foy, D. W. (1998). Trauma and posttraumatic stress B. S., Burke, A. K., Grunebaum, M. F., Malone, K. M., &
disorder in severe mental illness. Journal of Consulting Mann, J. J. (2003). Association of comorbid posttrau-
and Clinical Psychology, 66(3), 493–499. https://doi.org/ matic stress disorder and major depression with greater
10.1037/0022-006X.66.3.493 risk for suicidal behavior. American Journal of Psychiatry,
Multidisciplinary Association for Psychedelic Research. 160(3), 580–582. https://doi.org/10.1176/appi.ajp.160.3.
(2020). From the desk of Rick Doblin, Ph.D. -Autumn 580
2020. https://maps.org/news/bulletin/articles/479-bulletin- Passie, T. (2018). The early use of MDMA (‘Ecstasy’) in
autumn-2020/8663-from-the-desk-of-rick-doblin-ph-d- psychotherapy (1977–1985). Drug Science, Policy and
autumn-2020 Law, 4, 205032451876744. https://doi.org/10.1177/
Murrough, J. W., Iosifescu, D. V., Chang, L. C., Al Jurdi, 2050324518767442
R. K., Green, C. E., Perez, A. M., Iqbal, S., Pillemer, S., Patel, R., & Titheradge, D. (2015). MDMA for the treat-
Foulkes, A., Shah, A., Charney, D. S., & Mathew, S. J. ment of mood disorder: All talk no substance?
(2013). Antidepressant efficacy of ketamine in treatment- Therapeutic Advances in Psychopharmacology, 5(3),
resistant major depression: A two-site randomized 179–188. https://doi.org/10.1177/2045125315583786
Perkonigg, A., Kessler, R. C., Storz, S., & Wittchen, H. U. Psychological Trauma: theory, Research, Practice, and
(2000). Traumatic events and posttraumatic stress dis- Policy, 9(6), 746–749. https://doi.org/10.1037/tra0000239
order in the community: Prevalence, risk factors and Roberts, A. L., Gilman, S. E., Breslau, J., Breslau, N., &
comorbidity. Acta Psychiatrica Scandinavica, 101(1), Koenen, K. C. (2011). Race/ethnic differences in expos-
46–59. https://doi.org/10.1034/j.1600-0447.2000. ure to traumatic events, development of post-traumatic
101001046.x stress disorder, and treatment-seeking for post-traumatic
Perry, B. (2002). Childhood experience and the expression stress disorder in the United States. Psychological
of genetic potential: What childhood neglect tells us Medicine, 41(1), 71–83. https://doi.org/10.1017/
about nature and nurture. Brain and Mind, 3(1), 79–100. S0033291710000401
https://doi.org/10.1023/A:1016557824657 Rojas, S. M., Bujarski, S., Babson, K. A., Dutton, C. E., &
Pokorny, T., Preller, K. H., Kometer, M., Dziobek, I., & Feldner, M. T. (2014). Understanding PTSD comorbidity
Vollenweider, F. X. (2017). Effect of psilocybin on and suicidal behavior: Associations among histories of
empathy and moral decision-making. International alcohol dependence, major depressive disorder, and sui-
Journal of Neuropsychopharmacology, 20(9), 747–757. cidal ideation and attempts. Journal of Anxiety Disorders,
https://doi.org/10.1093/ijnp/pyx047 28(3), 318–325. https://doi.org/10.1016/j.janxdis.2014.02.
Popova, V., Daly, E. J., Trivedi, M., Cooper, K., Lane, R., 004
Lim, P., Mazzucco, C., Hough, D., Thase, M. E., Shelton, Roseman, L., Demetriou, L., Wall, M. B., Nutt, D. J., &
R. C., Molero, P., Vieta, E., Bajbouj, M., Manji, H., Carhart-Harris, R. L. (2018). Increased amygdala
Drevets, W. C., & Singh, J. B. (2019). Efficacy and safety responses to emotional faces after psilocybin for treat-
of flexibly dosed esketamine nasal spray combined with a ment-resistant depression. Neuropharmacology, 142,
newly initiated oral antidepressant in treatment-resistant 263–269. https://doi.org/10.1016/j.neuropharm.2017.12.
depression: A randomized double-blind active-controlled 041
study. American Journal of Psychiatry, 176(6), 428–438. Ross, S., Bossis, A., Guss, J., Agin-Liebes, G., Malone, T.,
https://doi.org/10.1176/appi.ajp.2019.19020172 Cohen, B., Mennenga, S. E., Belser, A., Kalliontzi, K.,
Posener, J. A., DeBattista, C., Williams, G. H., Kraemer, Babb, J., Su, Z., Corby, P., & Schmidt, B. L. (2016).
H. C., Kalehzan, B. M., & Schatzberg, A. F. (2000). 24- Rapid and sustained symptom reduction following psilo-
Hour monitoring of cortisol and corticotropin secretion
cybin treatment for anxiety and depression in patients
in psychotic and nonpsychotic major depression.
with life-threatening cancer: A randomized controlled
Archives of General Psychiatry, 57(8), 755–760. https://
trial. Journal of Psychopharmacology, 30(12), 1165–1180.
doi.org/10.1001/archpsyc.57.8.755
https://doi.org/10.1177/0269881116675512
Post, L. M., Feeny, N. C., Zoellner, L. A., & Connell, A. M.
Royal College of Psychiatrists. (2019). Position statement on
(2016). Post-traumatic stress disorder and depression co-
antidepressants and depression. https://www.rcpsych.ac.
occurrence: Structural relations among disorder con-
uk/docs/default-source/improving-care/better-mh-policy/
structs and trait and symptom dimensions. Psychology
position-statements/ps04_19–-antidepressants-and-
and Psychotherapy: Theory, Research and Practice, 89(4),
418–434. https://doi.org/10.1111/papt.12087 depression.pdf?sfvrsn=ddea9473_5
Pradhan, B. K., Wainer, I. W., Moaddel, R., Torjman, Rucker, J. J., Iliff, J., & Nutt, D. J. (2018). Psychiatry & the
M. C., Goldberg, M., Sabia, M., Parikh, T., & Pumariega, psychedelic drugs. Past, present & future.
A. J. (2017). Trauma Interventions using Mindfulness Neuropharmacology, 142, 200–218. https://doi.org/10.
Based Extinction and Reconsolidation (TIMBER) psycho- 1016/j.neuropharm.2017.12.040
therapy prolong the therapeutic effects of single ketamine Rucker, J., Young, A., Bird, C., Daniel, A., Lennard-Jones,
infusion on post-traumatic stress disorder and comorbid M., Marwood, L., Posadas, K. G., Reinholdt, F., Saldarini,
depression: A pilot randomized, placebo-controlled, F., Stansfield, S., Williams, S., Weston, N., Eriksson, H.,
crossover clinical trial. Asia Pacific Journal of Clinical & Malievskaia, E. (2019). Psilocybin administration to
Trials: Nervous System Diseases, 2(3), 80. https://doi.org/ healthy participants: Safety and feasibility in a placebo-
10.4103/2542-3932.211589 controlled study. ACNP 2019. http://www.compasspath-
Pradhan, B., Mitrev, L., Moaddell, R., & Wainer, I. W. ways-posters.com/ACNP2019_Rucker_poster.pdf
(2018). d-Serine is a potential biomarker for clinical Sareen, J., Cox, B. J., Stein, M. B., Afifi, T. O., Fleet, C., &
response in treatment of post-traumatic stress disorder Asmundson, G. J. (2007). Physical and mental comorbid-
using (R, S)-ketamine infusion and TIMBER psychother- ity, disability, and suicidal behavior associated with post-
apy: A pilot study. Biochimica et Biophysica Acta, traumatic stress disorder in a large community sample.
1866(7), 831–839. https://doi.org/10.1016/j.bbapap.2018. Psychosomatic Medicine, 69(3), 242–248. https://doi.org/
03.006 10.1097/PSY.0b013e31803146d8
Preller, K. H., Pokorny, T., Hock, A., Kraehenmann, R., Saulin, A., Savli, M., & Lanzenberger, R. (2012). Serotonin
St€ampfli, P., Seifritz, E., Scheidegger, E. S. M., & and molecular neuroimaging in humans using PET.
Vollenweider, F. X. (2016). Effects of serotonin 2A/1A Amino Acids, 42(6), 2039–2057. https://doi.org/10.1007/
receptor stimulation on social exclusion processing. s00726-011-1078-9
Proceedings of the National Academy of Sciences, 113(18), Schmid, Y., Hysek, C. M., Simmler, L. D., Crockett, M. J.,
5119–5124. https://doi.org/10.1073/pnas.1524187113 Quednow, B. B., & Liechti, M. E. (2014). Differential
Raines, A. M., Currier, J., McManus, E. S., Walton, J. L., effects of MDMA and methylphenidate on social cogni-
Uddo, M., & Franklin, C. L. (2017). Spiritual struggles tion. Journal of Psychopharmacology, 28(9), 847–856.
and suicide in veterans seeking PTSD treatment. https://doi.org/10.1177/0269881114542454
Schmidt, A., Kometer, M., Bachmann, R., Seifritz, E., & Stein, M. B., Koverola, C., Hanna, C., Torchia, M. G., &
Vollenweider, F. (2013). The NMDA antagonist ketamine McClarty, B. (1997). Hippocampal volume in women vic-
and the 5-HT agonist psilocybin produce dissociable timized by childhood sexual abuse. Psychological
effects on structural encoding of emotional face expres- Medicine, 27(4), 951–959. https://doi.org/10.1017/
sions. Psychopharmacology, 225(1), 227–239. https://doi. S0033291797005242
org/10.1007/s00213-012-2811-0 Strawbridge, R., Carter, B., Marwood, L., Bandelow, B.,
Schmidt, C. J., & Taylor, V. L. (1987). Depression of rat Tsapekos, D., Nikolova, V., Taylor, R., Mantingh, T., de
brain tryptophan hydroxylase activity following the acute Angel, V., Patrick, F., Cleare, A. J., & Young, A. (2019).
administration of methylenedioxymethamphetamine. Augmentation therapies for treatment-resistant depres-
Biochemical Pharmacology, 36(23), 4095–4102. https:// sion: Systematic review and meta-analysis. British Journal
doi.org/10.1016/0006-2952(87)90566-1 of Psychiatry, 214(1), 42–51. https://doi.org/10.1192/bjp.
Schmidt, C. J., Wu, L., & Lovenberg, W. (1986). 2018.233
Methylenedioxymethamphetamine: A potentially neuro- Stroud, J. B., Freeman, T. P., Leech, R., Hindocha, C.,
toxic amphetamine analogue. European Journal of Lawn, W., Nutt, D. J., Curran, H. V., & Carhart-Harris,
Pharmacology, 124(1–2), 175–178. https://doi.org/10. R. L. (2018). Psilocybin with psychological support
1016/0014-2999(86)90140-8 improves emotional face recognition in treatment-resist-
Sessa, B., Higbed, L., O’Brien, S., Durant, C., Sakal, C., ant depression. Psychopharmacology, 235(2), 459–466.
Titheradge, D., Williams, T. M., Rose-Morris, A., Brew- https://doi.org/10.1007/s00213-017-4754-y
Girard, E., Burrows, S., Wiseman, C., Wilson, S., Stuhrmann, A., Dohm, K., Kugel, H., Zwanzger, P.,
Rickard, J., & Nutt, D. J. (2021). First study of safety and Redlich, R., Grotegerd, D., Rauch, A. V., Arolt, V.,
tolerability of 3,4-methylenedioxymethamphetamine- Heindel, W., Suslow, T., Zwitserlood, P., & Dannlowski,
assisted psychotherapy in patients with alcohol use dis- U. (2013). Mood-congruent amygdala responses to sub-
order. Journal of Psychopharmacology, 35(4), 375–383. liminally presented facial expressions in major depres-
https://doi.org/10.1177/0269881121991792 sion: Associations with anhedonia. Journal of Psychiatry
Sessa, B., & Nutt, D. J. (2007). MDMA, politics and medical & Neuroscience, 38(4), 249–258. https://doi.org/10.1503/
research: Have we thrown the baby out with the bath- jpn.120060
Taffe, M. A., Huitron-Resendiz, S., Schroeder, R., Parsons,
water? Journal of Psychopharmacology, 21(8), 787–791.
L. H., Henriksen, S. J., & Gold, L. H. (2003). MDMA
https://doi.org/10.1177/0269881107084738
exposure alters cognitive and electrophysiological sensi-
Sessa, B., Sakal, C., O’Brien, S., & Nutt, D. (2019). First
tivity to rapid tryptophan depletion in rhesus monkeys.
study of safety and tolerability of 3, 4-methylenedioxy-
Pharmacology Biochemistry and Behavior, 76(1), 141–152.
methamphetamine (MDMA)-assisted psychotherapy in
https://doi.org/10.1016/S0091-3057(03)00217-X
patients with alcohol use disorder: Preliminary data on
Taylor, D., Barnes, T. R. E., & Young, A. H. (2018). The
the first four participants. BMJ Case Reports CP, 12(7),
Maudsley prescribing guidelines (13th Ed.). Wiley
1–4. https://doi.org/10.1136/bcr-2019-230109
Blackwell.
Sherin, J. E., & Nemeroff, C. B. (2011). Post-traumatic
Thompson, M. R., Callaghan, P. D., Hunt, G. E., Cornish,
stress disorder: The neurobiological impact of psycho- J. L., & McGregor, I. S. (2007). A role for oxytocin and
logical trauma. Dialogues in Clinical Neuroscience, 13(3), 5-HT(1A) receptors in the prosocial effects of 3,4 meth-
263–278. ylenedioxymethamphetamine (“ecstasy”). Neuroscience,
Shin, L. M., Rauch, S. L., & Pitman, R. K. (2006). 146(2), 509–514. https://doi.org/10.1097/JCP.
Amygdala, medial prefrontal cortex, and hippocampal 0b013e3182979d32
function in PTSD. Annals of the New York Academy of Tupper, K. W. (2009). Ayahuasca healing beyond the
Sciences, 1071(1), 67–79. https://doi.org/10.1196/annals. Amazon: The globalization of a traditional indigenous
1364.007 entheogenic practice. Global Networks, 9(1), 117–136.
Siegle, G. J., Steinhauer, S. R., Thase, M. E., Stenger, V. A., https://doi.org/10.1111/j.1471-0374.2009.00245.x
& Carter, C. S. (2002). Can’t shake that feeling: Event- Van der Kolk, B. A. (2000). Posttraumatic stress disorder
related fMRI assessment of sustained amygdala activity and the nature of trauma. Dialogues in Clinical
in response to emotional information in depressed indi- Neuroscience, 2(1), 7–22.
viduals. Biological Psychiatry, 51(9), 693–707. https://doi. Van Minnen, A., Arntz, A., & Keijsers, G. P. J. (2002).
org/10.1016/S0006-3223(02)01314-8 Prolonged exposure in patients with chronic PTSD:
Singer, M. I., Anglin, T. M., Song, L. Y., & Lunghofer, L. Predictors of treatment outcome and dropout. Behaviour
(1995). Adolescents’ exposure to violence and associated Research and Therapy, 40(4), 439–457. https://doi.org/10.
symptoms of psychological trauma. JAMA, 273(6), 1016/S0005-7967(01)00024-9
477–482. https://doi.org/10.1001/jama.1995. Vizeli, P., & Liechti, M. E. (2018). Oxytocin receptor gene
03520300051036 variations and socio-emotional effects of MDMA: A
Steenkamp, M. M., Schlenger, W. E., Corry, N., Henn- pooled analysis of controlled studies in healthy subjects.
Haase, C., Qian, M., Li, M., Horesh, D., Karstoft, K. I., PLoS One, 13(6), e0199384. https://doi.org/10.1371/jour-
Williams, C., Ho, C. L., Shalev, A., Kulka, R., & Marmar, nal.pone.0199384
C. (2017). Predictors of PTSD 40 years after combat: Vollenweider, F. X., & Kometer, M. (2010). The neurobiol-
Findings from the National Vietnam Veterans longitu- ogy of psychedelic drugs: Implications for the treatment
dinal study. Depression and Anxiety, 34(8), 711–722. of mood disorders. Nature Reviews. Neuroscience, 11(9),
https://doi.org/10.1002/da.22628 642–651. https://doi.org/10.1038/nrn2884
Vollenweider, F. X., & Preller, K. H. (2020). Psychedelic Zarate, C. A., & Sanacora, G. (2018). The effect of a sin-
drugs: Neurobiology and potential for treatment of psy- gle dose of intravenous ketamine on suicidal ideation: A
chiatric disorders. Nature Reviews. Neuroscience, 21(11), systematic review and individual participant data meta-
611–624. https://doi.org/10.1038/s41583-020-0367-2 analysis. American Journal of Psychiatry, 175(2), 150–158.
Vythilingam, M., Heim, C., Newport, J., Miller, A. H., https://doi.org/10.1176/appi.ajp.2017.17040472
Anderson, E., Bronen, R., Brummer, M., Staib, L., Wise, L. A., Zierler, S., Krieger, N., & Harlow, B. L. (2001).
Vermetten, E., Charney, D. S., Nemeroff, C. B., & Adult onset of major depressive disorder in relation to
Bremner, J. D. (2002). Childhood trauma associated with early life violent victimisation: A case-control study. The
smaller hippocampal volume in women with major
Lancet, 358(9285), 881–887. https://doi.org/10.1016/
depression. American Journal of Psychiatry, 159(12),
2072–2080. https://doi.org/10.1176/appi.ajp.159.12.2072 S0140-6736(01)06072-X
Watkins, L. E., Sprang, K. R., & Rothbaum, B. O. (2018). World Health Organization. (2018). International classifica-
Treating PTSD: A review of evidence-based psychother- tion of diseases for mortality and morbidity statistics (11th
apy interventions. Frontiers in Behavioral Neuroscience, Revision). https://icd.who.int/browse11/l-m/en
12, 258. https://doi.org/10.3389/fnbeh.2018.00258 Yamasue, H., Kasai, K., Iwanami, A., Ohtani, T., Yamada,
Watts, R., Day, C., Krzanowski, J., Nutt, D., & Carhart- H., Abe, O., Kuroki, N., Fukuda, R., Tochigi, M.,
Harris, R. (2017). Patients’ accounts of increased Furukawa, S., Sadamatsu, M., Sasaki, T., Aoki, S.,
“connectedness” and “acceptance” after psilocybin for Ohtomo, K., Asukai, N., & Kato, N. (2003). Voxel-based
treatment-resistant depression. Journal of Humanistic analysis of MRI reveals anterior cingulate gray-matter
Psychology, 57(5), 520–564. https://doi.org/10.1177/ volume reduction in posttraumatic stress disorder due to
0022167817709585 terrorism. Proceedings of the National Academy of
Weathers, F. W., Litz, B. T., Herman, D., Huska, J., & Sciences, 100(15), 9039–9043. https://doi.org/10.1073/
Keane, T. (1994). The PTSD checklist-civilian version pnas.1530467100
(PCL-C). National Center for PTSD. Yang, P., Wu, M. T., Hsu, C. C., & Ker, J. H. (2004).
Weightman, M. J., Air, T. M., & Baune, B. T. (2014). A Evidence of early neurobiological alternations in adoles-
review of the role of social cognition in major depressive cents with posttraumatic stress disorder: A functional
disorder. Frontiers in Psychiatry, 5, 179. https://doi.org/
MRI study. Neuroscience Letters, 370(1), 13–18. https://
10.3389/fpsyt.2014.00179
Weiss, S. J. (2007). Neurobiological alterations associated doi.org/10.1016/j.neulet.2004.07.033
with traumatic stress. Perspectives in Psychiatric Care, Yehuda, R. (2006). Advances in understanding neuroendo-
43(3), 114–122. https://doi.org/10.1111/j.1744-6163.2007. crine alterations in PTSD and their therapeutic implica-
00120.x tions. Annals of the New York Academy of Sciences, 1071,
White, K. J., Walline, C. C., & Barker, E. L. (2008). Serotonin 137–166. https://doi.org/10.1196/annals.1364.012
transporters: Implications for antidepressant drug develop- Young, E. A., Carlson, N. E., & Brown, M. B. (2001).
ment. In Drug addiction (pp. 193–215). Springer. Twenty-four-hour ACTH and cortisol pulsatility in
Wilkinson, S. T., Ballard, E. D., Bloch, M. H., Mathew, depressed women. Neuropsychopharmacology, 25(2),
S. J., Murrough, J. W., Feder, A., Sos, P., Wang, G., 267–276. https://doi.org/10.1016/S0893-133X(00)00236-0

Bird Et Al. 2021 PDF

Uploaded by

Copyright:

Available Formats

Bird Et Al. 2021 PDF

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Bird Et Al. 2021 PDF

Uploaded by

Copyright:

Available Formats

International Review of Psychiatry

ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/iirp20

Psilocybin and MDMA for the treatment of

Catherine I. V. Bird, Nadav L. Modlin & James J. H. Rucker

To link to this article: https://doi.org/10.1080/09540261.2021.1919062

© 2021 The Author(s). Published by Informa

Published online: 14 Jun 2021.

Submit your article to this journal

Article views: 15698

View related articles

View Crossmark data

Full Terms & Conditions of access and use can be found at

Psilocybin and MDMA for the treatment of trauma-related psychopathology

ABSTRACT ARTICLE HISTORY

Figure 1. Overlapping symptomatology of MDD and PTSD.

Psychology Review, 40, 184–194. https://doi.org/10.1016/ International Journal of Neuropsychopharmacology,

You might also like