Coverdale Cook 2023 Mechanisms of Integration in Psychedelic Assisted Therapy

REVIEW
Mechanisms of integration in psychedelic-assisted therapy

Nicole S. Coverdalea and Douglas J. Cookb
ABSTRACT
Introduction: In recent clinical trials, psychedelic-assisted psychotherapy (PAP) led to symptomatic improvement
https://jmvfh.utpjournals.press/doi/pdf/10.3138/jmvfh-2023-0014 - Thursday, March 28, 2024 1:33:53 PM - IP Address:93.102.82.107
among people with several psychiatric conditions. PAP has three distinct phases: preparation, support during psyche
delic administration, and integration. The purpose of this scoping review was to identif y randomized controlled trials
that used PAP and synthesize the research base related to neuronal networks and neural function as measured with
neuroimaging during the integration period and to link these findings to psychological changes after PAP. Methods:
PubMed and ProQuest databases were searched using key words. Inclusion and exclusion criteria were used to deter
mine whether an article would be reviewed. The authors specifically focused on articles that used neuroimaging or
reported a psychological outcome one day or more after psychedelic administration. Results: Most articles used func
tional magnetic resonance imaging (f MRI) and, in particular, resting-state f MRI to assess functional connectivity.
Results generally reported changes in higher-order networks, although the direction of change in strength of connec
tivity was variable. Themes related to psychological findings were linked to increases in psychological and cognitive
flexibility, increased openness, and decreased neuroticism after psychedelic treatment. Discussion: In general, more
consistent methodolog y across the field should be applied to make progress in understanding network-based changes
underlying clinical improvements after PAP. Limited evidence suggests that changes in the executive control network,
and in its integration with other networks, may result in greater cognitive flexibility during the integration period.
Key words: cognitive, integration, military, neuroimaging , psychedelic-assisted psychotherapy, psychedelics, psychi
atric, Veterans
RÉSUMÉ
Introduction : Des essais cliniques récents montrent que la psychothérapie assistée par les psychotropes (PAP)
entraine une amélioration des symptômes chez les personnes atteintes de divers troubles psychiatriques. La PAP com
porte trois phases distinctes : la préparation, le soutien pendant l’administration des psychotropes et l’intégration.
Cette évaluation de la portée avait pour but, d’une part, d’isoler les essais cliniques randomisés utilisant la PAP et de
synthétiser les travaux fondamentaux sur les réseaux neuronaux et la fonction neuronale mesurée par neuro-imagerie
pendant la période d’intégration ; et, d’autre part, de lier ces résultats aux changements psychologiques obser vés après
la PAP. Méthodologie : Les bases de données PubMed et ProQuest ont été fouillées à l’aide de mots-clés. Des critères
d’inclusion et d’exclusion ont ser vi à déterminer si un article était retenu pour l’étude. Les auteur(e)s se sont concen
tré(e)s sur les articles qui rapportent l’emploi de la neuro-imagerie ou un résultat à caractère psychologique un jour
ou plus après l’administration des psychotropes. Résultats : La plupart des travaux relevés ont utilisé l’imagerie par
résonance magnétique fonctionnelle (IRMf ) et, en particulier, l’IRMf au repos pour évaluer la connectivité fonction
nelle. Les résultats ont généralement rapporté des changements dans les réseaux des fonctions supérieures, bien que
la direction du changement dans la force de la connectivité varie. Les thèmes des résultats à caractère psychologique
ont été associés à l’augmentation de la flexibilité psychologique et cognitive, à une ouverture accrue et à la diminution
du névrosisme après le traitement aux psychotropes. Discussion : En général, l’ensemble du domaine profiterait de
l’application d’une méthodologie plus cohérente pour mieux comprendre les changements dans les réseaux qui sous
tendent les améliorations cliniques post-PAP. Certaines données suggèrent que les changements dans le réseau de
contrôle des fonctions exécutives et dans son intégration avec d’autres réseaux peuvent entrainer davantage de flexibi
lité cognitive pendant la période d’intégration.
Mots-clés : cognition, intégration, militaire, neuro-imagerie, psychothérapie assistée par les psychotropes, psychédé
lique, psychiatrie, vétéran(e)s
a Centre for Neuroscience Studies, Queen’s University, Kingston, Ontario, Canada

b Department of Surgery, Kingston Health Sciences Centre, Kingston, Ontario, Canada
Correspondence should be addressed to Douglas J. Cook at Queen’s University — Surgery, 18 Stuart Street, Room 234, Kingston, Ontario,
Canada, K7L 3N6. Telephone: 613-549-6666 ext. 3696. Email: dj.cook@queensu.ca
38 Journal of Military, Veteran and Family Health

doi:10.3138/jmvfh-2023-0014 2023 9 ( 5 )
LAY SUMMARY
Psychedelic pharmacotherapies combined with structured psychotherapy have shown promise in the treatment of sev
eral psychological conditions. This type of therapy is known as psychedelic-assisted psychotherapy (PAP) and includes
three phases: preparation, in-session support, and integration. The purpose of this review was to identif y randomized
controlled trials (RCTs) that used psychedelics to treat a psychological condition and to summarize the literature on
changes that may be associated with clinical outcomes, as measured with MRI and various psychologically based tools.
Psychedelics were administered in 17 RCTs, and 16 of these did so within a PAP framework. A total of 19 studies were
identified that looked at MRI or psychological outcomes during the integration phase. Changes in brain networks
during integration were identified but were not consistent between studies because of small sample sizes and inconsis
tent methodolog y. Some evidence suggests that changes in the executive control network may occur after psychedelic
administration. Psychological changes after psychedelic administration were related to cognitive flexibility and person
ality traits such as openness and neuroticism. Overall, studies in this field should be repeated with a greater number of
participants and other MRI-based techniques.
INTRODUCTION integration in which the therapist undertakes a trad

The burden of psychiatric conditions in the population itional psychotherapeutic approach over weeks to
is significant, with individual distress and impaired months to replace maladaptive behaviours or thought
function resulting in heavy socio-economic costs in processes with adaptive responses.
terms of health care expenditures and lost individual and Because the potential exists for a negative experi
family productivity.1,2 Despite the scale of the problem, ence with the use of psychedelics, therapeutic prepara
development of novel therapies for many conditions has tion sessions are vital to promote safety and maximize
largely stalled over the past two decades. However, in the probability of a positive outcome. The importance
recent years, after decades of limited access to psyche of set, which refers to the individual’s psychological
delics in Canada since the early 1970s,3 interest has been state and personality traits, has long been recognized as
renewed in the potential of psychedelic therapies to it relates to a person’s experience when using a psyche
address a variety of psychiatric conditions, particularly delic substance.18,19 For example, a meta-analysis of 14
those known to be treatment resistant, such as posttrau studies documented that individuals who have greater
matic stress disorder (PTSD) and anorexia nervosa.4-7 levels of absorption, openness, and acceptance were
Several randomized controlled trials (RCTs) of more likely to have positive experiences, whereas those
psychedelic pharmacotherapies, including the clas low in openness and surrender, or in preoccupied,
sical compounds lysergic acid diethylamine (LSD) and apprehensive, or confused psychological states, were
psilocybin and the non-classical compound 3,4-methyl more likely to experience acute negative reactions to the
enediox ymethamphetamien (MDM A; see McClure- experience.20 During preparation, development of a rela
Begley and Roth and Rudnick and Wall for discussion tionship between the patient and the therapist is vital
on the mechanism of action of each),8,9 showed bene because the strength of this relationship can influence
fit compared with placebo for conditions including the final treatment outcome.21 In this phase, an inten
depression and anxiety with life-threatening illness,10-12 tion for the psychedelic experience is also set, and how
chronic PTSD,4,5,13-15 and major depressive disorder to respond to feelings and memories that could arise (in
(MDD).16,17 Notably, the pharmacotherapies are deliv a non-directive way on the part of the therapist) is dis
ered in a framework known as psychedelic-assisted cussed. A thorough review of guidance for all aspects of
psychotherapy (PAP), in which a therapeutic relation therapeutic support during psychedelic use in a research
ship is developed between an individual and a practi setting has also been assembled by Johnson et al. and
tioner with training in psychedelic therapy. should be referred to for more details.22
In general, during drug administration, two ther
Phases of PAP apists or monitors are present, and music is used to
The practitioner, or psychedelic therapist, leads an indi encourage an immersive experience while also inten
vidual through defined stages of treatment, including sifying emotions and heightening mental imagery.23,24
preparation for the psychedelic experience, in-session Overall, participants are encouraged to turn their atten
support while the patient imbibes the pharmacotherapy tion inward, and this is supported using eyeshades and
and undergoes a psychedelic experience, followed by headphones. Similar to the concept of set, it is also well
Journal of Military, Veteran and Family Health 39

9 ( 5 ) 2023 doi:10.3138/jmvfh-2023-0014
Coverdale and Cook
recognized that the setting (environment) of a psyche fixed point. During a RS acquisition, BOLD time-series
delic experience can influence the therapeutic effects;19,25 data are collected, and brain regions with correlated
thus, care must be taken to ensure the room is relaxing time-series are assumed to form large-scale networks and
and comfortable.22 are said to be functionally connected.31,32 Alternatively,
Shortly after the psychedelic experience, the first of when f MRI is performed while the participant per
several integration sessions occurs in which therapeutic forms a task, the task is used to interrogate neural acti
rapport is maintained. In these sessions, there can be vation in regions of interest. The basic premise of f MRI
an accounting of what came up during the psychedelic is that a neural event triggers a local increase in blood
session and interpretation of the experiences and dis flow as a result of neurovascular coupling ,33 resulting in
cussion of their significance.22 In this phase, traditional an increased washout of deoxygenated hemoglobin and
psychotherapeutic approaches can be applied to identify an increase in the BOLD signal. Because of the tight
triggers, links to maladaptive behaviours, and strategies relationship between neural activity and the vascular
to manage triggers and create adaptive responses. Other response, the BOLD signal is influenced by cerebral
goals include dealing with any new psychosocial challen blood flow (CBF), the cerebral metabolic rate of oxygen
ges that arise after the experience and, importantly, incor consumption, and cerebral blood volume and is, thus, a
porating any insights or realizations into everyday life to surrogate measure of neural activation.34 Additionally,
encourage lasting positive changes. PAP practices related although the BOLD signal is influenced by CBF, CBF
to MDMA are particularly well developed, and a treat can also be examined directly with MRI using arterial
ment manual that summarizes the application of MDMA spin labelling (ASL).35
PAP for PTSD can be referenced for more details.26 The purposes of this review were to 1) to identify
Beyond the acute psychedelic experience, an after RCTs of psychedelic pharmacotherapies that evaluated
glow period, first noted decades ago, may last days to the effect on a clinical outcome, 2) to summarize how
weeks after the experience.27,28 It is characterized by an PAP is currently used in these trials, and 3) to review
elevated mood.27 Because it is in this period when integra and evaluate the literature related to the neurobiological
tion is typically performed, it is possible that the changes and psychological underpinnings of the integration
in mood resulting from PAP — combined with a large phase (labelled here as the subacute period). Specifically,
dose of psychotherapy — may facilitate lasting positive the authors reviewed the current state of the literature
changes. An important tool used in the quest to identify on the topic of how psychedelics modulate neurological
neurological changes that correlate with, or facilitate, networks and neuronal function as assessed with neu
these positive effects is neuroimaging, which can be roimaging and related these findings to documented
performed non-invasively and used to quantify many psychological changes. Of note, the authors did not
aspects of cerebral structure, function, and physiolog y. include literature related to the neurobiolog y of the per
iod during the psychedelic experience, because several
Neuroimaging primer reviews on this topic already exist (e.g., Kwan et al. and
The term neuroimaging usually includes any type of Vollenweider and Preller).36,37 For a review of RS f MR I
imaging used to assess the structure, function, or physi findings during and after psychedelic administration,
olog y of the brain or nervous system, such as computed see McCulloch et al.38
tomography or magnetic resonance imaging (MRI).
With MRI, beyond standard clinical sequences that METHODS
primarily examine structure, research-based techniques A scoping review to identify RCTs was performed using
that rely on blood-oxygen-level-dependent signal the PubMed and ProQuest databases using the Boolean
(BOLD) contrast — known as functional MRI (f MRI) operator (and) to combine the following search terms:
— have become popular. f MRI can be used at rest (rest clinical trial and psychedelic. Inclusion criteria were
ing state, or RS) while the participant is instructed to as follows: 1) primary research published in a peer-
stay awake and let their mind wander freely or during reviewed journal, 2) RCTs, and 3) assessed the effect of
a task.29,30 Recently, RS f MRI has been widely imple the psychedelic on a diagnosed psychiatric condition.
mented because it does not require active participant Studies examining the effects of cannabis or ketamine
engagement; rather, the participant is asked to let their were excluded, along with those that examined the effect
mind wander freely with either eyes shut or focused on a of micro-dosing psychedelics (i.e., frequent intake below

doi:10.3138/jmvfh-2023-0014 2023 9 ( 5 )
the threshold for psychedelic effects). Ketamine stud focused on neuroimaging , and 9 focused on a psycho
ies were excluded because ketamine’s effects share some logical outcome (see Table 2).
properties with other psychedelics, but there are also To date, most studies performed have used f MRI.
notable differences.39 For the second review that identi Several subacute neuroimaging studies were performed
fied literature related to the integration phase of PAP, one day after psychedelic administration both in
the PubMed and ProQuest databases were used with healthy individuals and in those with treatment-resist
the Boolean operator (and) to combine the following ant depression (TR D). Among healthy adults without
search terms: neuroimaging , magnetic resonance imag psychiatric diagnoses, Pasquini et al. examined intra-
ing , psychological, outcome, and psychedelic. Retrieved and inter-network RSFC in the salience, default mode,
articles were included if they 1) were primary research visual, and sensorimotor networks. Compared with the
published in a peer-reviewed journal, 2) included an out placebo group, RSFC was decreased in the posterior
come measure completed at least one day after psyche cingulate cortex (PCC) of the default mode network
delic administration, 3) were longitudinal in nature and (DMN) one day after ayahuasca administration, and
included a baseline time point before psychedelic use, connectivity was increased between the salience net
4) used quantitative methods, and 5) included human work and the DMN.58 Other authors also reported
participants. Articles were excluded if participants changes in the DMN after psilocybin administration in
used psychedelics in a recreational setting or if the psy a group without a neuropsychiatric diagnosis, although
chedelic was used in a micro-dosing setting. Articles in the population included were experienced meditators,
which the administered psychedelic was ketamine were which likely alters RSFC in and of itself.66 Greater
excluded. In addition, because the focus of this portion scores on the Positive Persistent Effects scale were asso
of the review was not on clinical outcomes, articles that ciated with an increase in RSFC between the medial
reported only changes in clinical scores or diagnoses after prefrontal cortex and the PCC of the DMN.60,67,68
treatment without methodolog y to examine the under These findings are in line with those observed in a
lying mechanisms of these changes were not included. small open-label study of psilocybin with individuals
with TR D in which increased RSFC was documented
RESULTS between the subgenual anterior cingulate cortex
(ACC) and the PCC and precuneus one day after the
Use of PAP in RCTs
psychedelic experience. Increased connectivity was also
The literature search resulted in the identification of
observed between the ventromedial PFC (vmPFC) and
138 articles that were reviewed. A total of 17 RCTs (see
the bilateral inferior-lateral parietal cortex of the DMN.
Table 1) met the inclusion criteria. All but one, Palhano
This effect was predictive of treatment response at five
et al.,45 were carried out with a psychotherapeutic com
weeks.63 This study was also the first to examine CBF
ponent that included the three phases of PAP. In all
subacutely with ASL after psychedelic use and reported
studies reviewed that included PAP, preparation was
decreased CBF in the temporal lobe, where decreased
undertaken in two or more sessions before the psyche
CBF in the amygdala, in particular, was correlated
delic experience. Another commonality between stud
with a reduction in depression symptoms.63 Increased
ies that used PAP was that a mixed-gender therapist
dynamic functional connectivity between the ACC
team was present during the psychedelic sessions. One
to three experimental sessions were performed in the and PCC was also observed one week after psilocybin
studies, and, generally, dosing was consistent through in people with MDD,54 similar to the findings reported
out the sessions, although in some cases higher doses by Carhart-Harris et al.63
were used after the first session.5,16,42,46 Additionally, one Daws et al. reported on two trials: one open-label
to three sessions of integration were performed for every trial in which an MRI was performed one day after the
experimental session. second dose of psilocybin, and a double-blind RCT
in which participants had an MRI three weeks after a
Neuroimaging studies second psilocybin dose.51 In each, a community detec
Using the search strateg y for the second component tion algorithm was used to determine how brain regions
of the literature review, 191 studies were identified form communities that can then be used to provide an
that included either psychological or neuroimaging estimate of brain modularity, where this value indicates
outcomes; 19 of these met the inclusion criteria. Ten how segregated a network is from other networks in the

9 ( 5 ) 2023 doi:10.3138/jmvfh-2023-0014
Coverdale and Cook
brain.51 After psilocybin, global integration between the increased integration between the DMN and the execu
brain’s networks increased, and, in the open label trial, tive control network (ECN) and between the DMN and
change in modularity correlated with the six-month the salience network, which was not replicated in the
change in Beck Depression Inventory (BDI) score.69 A RCT. Finally, in the RCT, there was increased dynamic
community detection procedure, referred to as func functional connectivity of the ECN, which the authors
tional cartography, was used to examine interactions refer to as flexibility, which is indicative of how often
within, or between, different communities, which in a network changes its community allegiance over the
this case were between-network and within-network course of the scan. The change in ECN dynamic func
changes. In the open-label trial, after psilocybin, there tional connectivity correlated with the change in BDI
was a reduction in integration within the DMN and score in the psilocybin group.
Table 1. Summary of included RCT studies with a clinical outcome

Primary Psychedelic No. of Main finding
outcome and and session no. therapy (change in
Study Sample endpoint* N Study design and dose sessions† Control group scores)
Holze et al. 40
Anxiety STAI at week 42 Double-blind, LSD Unclear Placebo STAI: −14.9
with and 18 randomized, 1: 200 µg LSD and 1.3
without life- placebo- 2: 200 µg placebo
threatening controlled
illness cross-over
Von Rotz MDD Change in 52 Double-blind, PSIL 6 Placebo MADRS:−13.0
et al.41 MADRS and randomized 1: 0.215 mg/kg PSIL and −4.0
BDI from day placebo- placebo
−5 to day 14 controlled BDI: −13.2
PSIL and −5.0
placebo
Bogenschutz Alcohol use Percentage 93 Double-blind, PSIL 14 Diphenhydramine HDD: 9.7%
et al.42 disorder HDD weeks randomized 1: 25 mg/70 kg PSIL and
5-32 placebo- 2: 25-40 23.6% placebo
controlled mg/40 kg
Goodwin Treatment- Change in 233 Double-blind, PSIL 6 1 mg PSIL MADRS: −12.0
et al.17 resistant total score randomized 1: 25 mg, 10 25 mg, −7.9 10
MDD MADRS at placebo- mg, and 1 mg mg, and −5.4
week 3 controlled 1 mg
Carhart-Harris MDD Change in 59 Double-blind, PSIL 10 1 mg PSIL and QIDS-SR-16:
et al.43 QIDS-SR-16 randomized 1: 25 mg escitalopram −8.0 and −6.0
at week 6 controlled 2: 25 mg escitalopram
Davis et al.16 MDD Change in 24 Randomized PSIL 12-13 None Total group:
GRID-HAMD waiting-list 1: 20 mg/70 kg –14.1 at week 1
at weeks 1 controlled 2: 30 mg/70 kg and −13.9
and 4 (which
correspond
to weeks
5 and 8 for
delayed
treatment)
Mitchell et al.5 PTSD Change in 82 Double-blind, MDMA 15 Placebo CAPS-5: −24.4
CAPS-5 at randomized 1: 120 mg MDMA and
week 18 placebo- 2: 180 mg −13.9 placebo
controlled 3: 180 mg
Wolfson Anxiety and Change in 17 Double-blind, MDMA 11 Lactose STAI-T: −23.5
et al.44 distress; STAI-T at randomized 1: 125-167.5 mg MDMA and
life- week 6-8 placebo- 2: 125-167.5 mg −8.8 placebo
threatening controlled
illness
Palhano- Treatment- Change in 29 Double-blind, 1: 0.36 mg/kg None Liquid causing HAM-D: −14.4
Fontes et al.45 resistant HAM-D at randomized N,N-DMT gastric distress ayahuasca and
MDD day 7 placebo- matched for colour −2.81 placebo
controlled and taste
(Continued)

doi:10.3138/jmvfh-2023-0014 2023 9 ( 5 )
Table 1. (Continued)
Primary Psychedelic No. of Main finding
outcome and and session no. therapy (change in
Study Sample endpoint* N Study design and dose sessions† Control group scores)
Danforth Social Change in 11 Double-blind, MDMA 8 Placebo LSAS: −47.7
et al.46 anxiety in LSAS at randomized 1: 75-100 mg MDMA and
autistic week 8 placebo 2: 100-125 mg −23.3 placebo
adults controlled
Mithoefer PTSD Change in 26 Double-blind, MDMA 8 Low-dose MDMA CAPS-5: −11.4
et al.4 CAPS-5 at randomized 1: 75-112.5 mg (30-45 mg) low, −58.3
weeks 7-9 dose (medium), 125 medium, and
response 187.5 mg (high) −44.3 high

2: 75-112.5 mg,
125-187.5 mg
Ot’alora PTSD Change in 27 Double-blind, 1: 100-150 mg 11 Low-dose MDMA CAPS-5: −11.5
et al.15 CAPS-5 at randomized (medium), 125 (40-60 mg) low, −24.4
week 8 dose 187.5 mg (high) medium, −26.3
response 2: 100-150 mg, high
125-187.5 mg
Griffiths Depression Change in 50 Double-blind, PSIL 13 (on Low-dose PSIL (1 GRID-HAMD:

et al.11 and GRID-HAMD randomized 1: 30 or 22 mg/ average) or 3 mg/70 kg) −15.8 low dose
anxiety; and HAM-A cross-over 70 kg first, 16.3 high
late-stage at week 10 2: 1 or 3 mg/ dose first
cancer 70 kg (all HAM-A: −16.8
had two low dose first,
sessions with −18.2 high
randomization dose first
to receive high
or low dose first)
Ross et al.12 Anxiety; Numerous 29 Double blind, PSIL 8 Niacin Overall
late-stage outcomes randomized 1: 0.3 mg/kg reduction in
cancer and time cross-over 2: 250 mg niacin anxiety and
points (all had two depression with
sessions with PSIL
randomization
to receive niacin
or PSIL first)
Gasser Anxiety; Change in 12 Double-blind, LSD 5 Low-dose LSD STAI-S: −11.6
et al.10 life- STAI-S and randomized 1: 200 µg (20 µg) LSD and 4.0
threatening STAI-T at placebo 2: 200 µg placebo
illness week 8 controlled STAI-T: −8.0
LSD and 5.7
placebo
Oehen et al.14 PTSD Change 12 Double-blind, MDMA 15 Low-dose MDMA CAPS:−15.6
in CAPS- randomized 1: 187.5 mg (25-37.5 mg) MDMA and
5 week 3 placebo 2: 187.5 mg −3.2 placebo
after last controlled 3: 187.5 mg
psychedelic
session
Mithoefer PTSD Change in 20 Double-blind, MDMA 15 Lactose CAPS-5: −52.0
et al.13 CAPS-5 randomized 1: 125-187.5 mg MDMA and
at week 8 placebo 2: 125-187.5 mg −18.0 placebo
after last controlled
psychedelic
session
* Endpoint refers to the amount of time after the first psychedelic treatment session, unless otherwise stated.
†
The total number of sessions, including preparation, psychedelic experience, and integration.
STAI = State-Trait Anxiety Inventory, LSD = lysergic acid diethylamine, MDD = major depressive disorder, MADRS = Montgomery-
Åsberg Depression Rating scale, BDI = Beck Depression Inventory, PSIL = psilocybin, HDD = heavy drinking days, QIDS
SR-16 = 16-item Quick Inventory or Depressive Symptomatology-Self Report, GRID-HAMD = GRID-Hamilton Depression
Rating scale, PTSD = posttraumatic stress disorder, CAPS-5 = Clinician-Administered PTSD Scale for DSM-5, MDMA = 3,4
methylenedioxymethamphetamine, STAI-T = State-Trail Anxiety Inventory Trait scale, HAM-D = Hamilton Depression Rating
scale, N,N-DMT = N,N-dimethyltryptamine, LSAS = Leibowitz Social Anxiety Scale, HAM-A = Hamilton Anxiety Rating scale,
STAI-S = State-Trait Anxiety Inventory State scale.

9 ( 5 ) 2023 doi:10.3138/jmvfh-2023-0014
Table 2. Summary of psychedelic studies included during the integration period
44
Outcome measurements Psychedelic, session no. No. of therapy Control
Study Sample and time points N Study design and dose sessions† group Main finding
Goodwin MDD PANAS (affect), WSAS 233 Double-blind, PSIL 6 1 mg PSIL Improved function, quality of life,
et al.47 (function), EQ-5D-3LD randomized 1: 25 mg, 10 mg, and 1 mg and cognitive function at 3 weeks
(quality of life), and DSST placebo- with PSIL
Coverdale and Cook
(cognitive function) at controlled

weeks 3 and 12
Singleton PTSD RSFC and BOLD response 9 Open-label MDMA 15 for high- Low-dose Decreased cuneus activation
et al.48 to autobiographical recall trial 1: 30-45 mg (low), dose group, MDMA during recall of trauma
at 8 weeks after last dose 75-112.5 mg (medium), 23 for low- (30-45 mg)
125-187.5 mg (high) and medium
2: 30-45 mg, 75-112.5 mg, dose groups
125-187.5 mg
3: 30-45 mg, 75-112.5 mg,
125-187.5 mg
(after first two sessions, high-
doi:10.3138/jmvfh-2023-0014 2023 9 ( 5 )

dose group completed one more,
Journal of Military, Veteran and Family Health

and low- and medium-dose
groups completed three more
sessions at the highest dose)
Agin-Liebes Healthy adults AAQ (Psychological 261 Open-label Study centred on retreat Unclear None Increased psychological flexibility,
et al.49 and adults with flexibility), PANAS at trial participants who consumed decreased negative affect, and
self-reported month 3 ayahuasca up to four increased positive affect
PTSD, depression, times/week
or anxiety
Barba MDD RRS (rumination) Double-blind, PSIL 10 1 mg Reduced RRS and WBSI in PSIL,
et al.50 and WBSI (thought randomized 1: 25 mg PSIL and not escitalopram
suppression) at week 6 placebo- 2: 25 mg escitalopram
controlled
Daws MDD Brain modularity, Open- Open- PSIL 10 1 mg Decreased brain modularity,
et al.51 dynamic functional label: label and 1: 25 mg PSIL and increased dynamic functional
connectivity at week 6 19 double-blind 2: 25 mg escitalopram connectivity in executive control
RCT: randomized network with PSIL but not
59 placebo- escitalopram
controlled
McCulloch Healthy adults RSFC at week 1 and 10 Open-label PSIL None None Decreased RSFC in executive
et al.52 month 3 trial 1: 0.2-0.3 mg/kg control network
Rucker Healthy adults Cognitive function at 89 Double-blind, PSIL 3 Placebo PSIL: No change in cognitive
et al.53 days 8 and 29 randomized 1: 10 or 25 mg function in
placebo-
controlled
Doss et al.54 MDD RSFC and dynamic 24 Randomized PSIL 12-13 None Increased cognitive flexibility at
functional connectivity of waiting-list 1: 20 mg/70 kg week 3 and 6, decreased dynamic
ACC, PCC, PCET (cognitive controlled 2: 30 mg/70 kg functional connectivity between
flexibility) at week 6 ACC and PCC
Barrett Healthy adults BOLD response in 12 Open-label PSIL 4 None BOLD response to negative stimuli
et al.55 amygdala to negative stimuli 1: 25 mg/70 kg reduced at week 1 and back to
at week 1 and week 4 baseline at week 4
(Continued)
Table 2. (Continued)
Outcome measurements Psychedelic, session no. No. of therapy Control
Study Sample and time points N Study design and dose sessions† group Main finding
Mertens Healthy adults vmPFC and amygdala 19 Open-label PSIL 3 None Decreased FC between vmPFC
et al.56 connectivity during a face 1: 10 mg and right amygdala during fearful
processing task at day 1 2: 25 mg and negative face viewing
after last dose
Murphy- Healthy adults CFS, Stroop colour 48 Open label Ayahuasca Unclear None Increased CFS and more correct
Beiner and word task, WPCST responses on WPCST with
et al.57 (cognitive flexibility) at day 1 ayahuasca
Pasquini Healthy adults Inter- and intra-network 43 Randomized, Ayahuasca None Placebo Increased RSFC in salience
et al.58 RSFC at day 1 placebo- 1: mean = 0.36 (SD = 0.01) mg/ network, increased RSFC between
controlled mL of N,N-DMT, mean = 1.86 salience network and DMN, and
(SD = 0.11) mg/mL of harmine, decreased RSFC within DMN
mean 0.24 (SD = 0.03) mg/mL of
harmaline, and mean 1.20 (SD =
0.05) mg/mL of tetrahydroharmine
Netzband Healthy adults and NEO-PI-3 at month 6 48 Open-label Study centred on retreat Unclear None Reduced neuroticism with
et al.59 adults with self- participants who consumed ayahuasca
reported PTSD, ayahuasca up to six times/ week
depression, or anxiety
Smigielski Healthy experienced DMN RSFC at day 2 38
Double-blind, PSIL Performed at Lactose Increased RSFC between medial
et al.60 meditators randomized 1: 315 µg/kg a meditation prefrontal cortices and PCC of
placebo- retreat DMN in PSIL
controlled
Erritzoe Treatment-resistant NEO-PI-R at month 3 19 Open-label PSIL 5 None Decreased neuroticism and
et al.61 MDD 1: 10 mg increased extraversion and
2: 25 mg openness with PSIL
Roseman Treatment-resistant BOLD response in 19 Open-label PSIL Unclear None Increased BOLD response in
et al.62 MDD amygdala to emotional faces 1: 10 mg bilateral amydala with PSIL
at day one after last dose 2: 25 mg
Carhart- Treatment-resistant Change in cerebral blood 16 for Open-label PSIL None None Regions of decreased cerebral
Harris MDD flow and RSFC one day ASL 1: 10 mg blood flow and increased RSFC
et al.63 after dose 2 15 for 2: 25 mg within the DMN after PSIL
BOLD
Carhart- Healthy adults LOT-R and NEO-PI-R at 19 Placebo- LSD None Placebo Increased optimism and
Harris week 2 controlled 1: 75 µg openness with LSD
et al.64 cross-over
Maclean Healthy adults NEO-PI at month 1-2 and 52 Placebo- PSIL Unclear Placebo Greater openness at month 1-2
et al.65 month 14 controlled 1: 30 mg/kg with PSIL
* Endpoint refers to the amount of time after the first psychedelic treatment session, unless otherwise stated.
†
Total number of sessions includes preparation, psychedelic experience, and integration.
MDD = major depressive disorder; PANAS = Positive and Negative Affect Schedule, WSAS = Work and Social Adjustment Scale, EQ-5D-3LD = Euro-Qol-5-Dimensions 3-Levels, DSST = Digit
Symbol Substitution Test, PSIL = psilocybin, PTSD = posttraumatic stress disorder, RSFC = resting-state functional connectivity, BOLD = blood-oxygen-level dependent, MDMA = 3,4
methylenedioxymethamphetamine, AAQ = Acceptance and Action Questionnaire, RRS = Rumination Response Scale, WBSI = White Bear Suppression Inventory, RCT = randomized controlled trial,
9 ( 5 ) 2023 doi:10.3138/jmvfh-2023-0014

Journal of Military, Veteran and Family Health
ACC = anterior cingulate cortex, PCC = posterior cingulate cortex, PCET = Penn Conditional Exclusion Test, vmPFC = ventromedial prefrontal cortex, FC = functional connectivity, CFS = Cognitive
Flexibility Scale, WPCST = Wisconsin Picture Card Sorting Task, N,N-DMT = N,N-dimethyltryptamine, DMN = default mode network, NEO-PI-3 = Neuroticism, Extraversion, Openness Personality
Inventory-3, ASL = arterial spin labelling, LOT-R = Revised Life Orientation Test, NEO-PI-R = Neuroticism, Extraversion, Openness Personality Inventory-Revised, NEO-PI = Neuroticism, Extraversion,
45
Openness Personality Inventory.

Coverdale and Cook
The other two subacute studies of psilocybin in in the cuneus during recall of trauma that was no longer
TR D used f MR I to specifically examine the amyg present after MDMA PAP.
dala and prefrontal cortex. Roseman et al. used task-
based f MRI with an emotional faces task on the basis Psychology studies
of evidence that individuals with depression have In addition to the search for the neurobiological mech
increased activation in response to negative emotional anisms underlying the beneficial effects of psychedelic
stimuli.62 ,70,71 Despite an improvement in mood after pharmacotherapy, research has also focused on the
psilocybin, there was increased activation in the right identification of psychological changes that coincide
amygdala to negative faces, which was contrary to the with improvement in symptoms. In many cases, before
treatment, individuals developed maladaptive strategies
expected result.62 As a follow-up, functional connec

tivity was examined during the same task and was that perpetuated symptoms. This can occur across a
increased between the vmPFC and the bilateral amyg range of diagnoses. Psychological flexibility, defined
dala and between the vmPFC and the occipital-parietal as the process of staying in the present while adapt
cortices during face processing.56 ing behaviour in the face of challenging thoughts and
In addition to the studies previously described, emotions to remain in line with identified values,75 is a
a small number of studies examined various metrics construct linked to depression,72 obsessive-compulsive
with f MR I one week after the psychedelic experience, disorder (OCD),73 and PTSD;74 these conditions are
all using psilocybin.48,52 ,55 In a small sample of individ associated with a lack of flexibility. Increases in psych
uals with no neuropsychiatric diagnosis,55 emotional ological flexibility were reported that co-occurred with
response in the amygdala and ACC was examined with increased positive and decreased negative affect that
task-based MRI and RS f MRI before psilocybin admin persisted three months after ayahuasca.49 Related to the
istration, as well as one week and one month after. One concept of psychological flexibility, according to the
week after psilocybin, participants had reduced negative psychological model known as acceptance and commit
affect, although this returned to baseline at one month. ment therapy, a core component of psychological inflex
In contrast, increases in positive emotions measured ibility is experiential avoidance,76 which results when an
at one week persisted at one month. As well, on the individual does not remain in contact with an emotion,
emotion recognition task, where individuals identify thought, or memory and tries to change or prevent
the emotion on a face as happy, sad, fearful, angry, or such an event from occurring.77 Carhart-Harris et al.
neutral, there was a reduction in BOLD activation to reported a 10-point change on the Brief Experiential
all emotions in the bilateral amygdala, and this response Avoidance Questionnaire (BEAQ) in a psilocybin trial
returned to pre-psilocybin levels at one month.55 Non for MDD,78 whereas participants in the escitalopram
specific increases and decreases in RSFC were also group had a one-point reduction.43
reported; however, it seems likely that correction for Another concept used in neuropsycholog y that is
multiple comparisons in these data was not adequate. likely related to psychological flexibility is cognitive flex
In another study of 10 individuals, McCulloch ibility. Cognitive flexibility is an executive function used
et al. evaluated within- and between-network RSFC for the completion of goal-directed behaviour. It is typ
at one and three months after psilocybin administra ically measured as perseveration on a task that involves
tion. In this sample, connectivity within the ECN rule switching (for a review, see Uddin).79 Similar to
was decreased at one week but returned to baseline at psychological flexibility, impairments in cognitive flex
three months.52 Associations between these changes in ibility were identified in a range of neuropsychiatric con
the ECN were correlated with change in mindfulness ditions such as depression and OCD.80,81 In the subacute
scores between baseline and three months, but these period 24 hours after ayahuasca, participants without a
changes were primarily driven by two individuals in the neuropsychological diagnosis had increased cognitive
sample as a result of the small sample size. flexibility, based on self-report, and also made fewer
A single study used f MRI to examine FC at rest errors on a perseveration task, although practice effects
and during autobiographical recall of a neutral and may have influenced this result.57 As well, after treatment
traumatic memory of nine participants with PTSD with psilocybin, patients with MDD had reduced depres
before and two months after PAP with MDMA.48 sive symptoms and fewer perseverative errors at one and
Before treatment, participants had increased activation four weeks, indicative of greater cognitive flexibility.54

doi:10.3138/jmvfh-2023-0014 2023 9 ( 5 )
Cognitive inflexibility has also been linked to rumin alters CBF, the results must be interpreted with caution.
ation,82 which involves repetitively and passively focus For instance, studies that artificially increased CBF and
ing on one’s distress and the causes and consequences then looked at BOLD activation have documented less
of the distress,83 and one study documented reduced activation when CBF is higher.87,88 On the basis of this
rumination and thought suppression after psilocybin.50 work, if the reduced CBF observed in the amygdala after
Other studies looked at more general markers of cogni psilocybin in Carhart-Harris et al. is a replicable find
tive function with the Cambridge Neuropsychological ing , then this may have contributed to the unexpected
Test Automated Battery (CANTAB) and the Digit increased level of activation to negative stimuli among
Symbol Substitution Test (DSST) after psilocybin.84,85 individuals with TRD.56,62,63 Because of this limitation
After psilocybin, there were no differences compared of f MRI, it is important that findings be replicated with
with baseline on the CANTAB assessment,53 whereas other techniques that more directly measure neuronal
improvements were observed on the DSST.47 activity, such as magnetoencephalography. Alterna
Additionally, changes in personality dimensions tively, an assessment of CBF, cerebral metabolic rate
were also reported after psychedelic therapy. These of oxygen consumption, and cerebrovascular reactivity
studies typically used the Neuroticism, Extraversion, after psychedelic treatment could be used to verify that
Openness Personality Inventory-Revised to assess what these parameters have not changed. If this is the case,
are known as the Big Five personality factors: agreeable then f MRI could be used.
ness, neuroticism, extraversion, conscientiousness, and Additionally, characterizing patterns of RSFC with
openness.86 Among individuals without a neuropsych gradients analysis, rather than strength of connections,
iatric diagnosis, increased openness was documented may provide information about brain architecture that
at two months after psilocybin, and this persisted at is independent of vascular effects that may result from
14 months.65 Increased openness was also observed in the psychedelic. The typical methodolog y for examining
healthy individuals two weeks after LSD.64 As well, RSFC strength involves creating a correlation matrix in
among participants with TR D, three months after which the correlation is between the BOLD time course
psilocybin therapy, openness and extraversion were of different brain regions of interest or of the whole brain
increased, and neuroticism was decreased.61 Finally, where an atlas is used to define sometimes hundreds of
at an ayahuasca retreat where approximately half the areas. The resulting matrix represents how each cortical
sample of 24 participants had a current or historical area is connected to every other area, and this high dimen
diagnosis of depression, anxiety, or PTSD and the other sionality makes interpretation and replication difficult.
half had no diagnosis, agreeableness was increased, and Consequently, recent efforts in the field have focused
neuroticism decreased, on the day after the retreat. This on identifying summary metrics using dimensionality
change was maintained at six months compared with a reduction approaches. These approaches have identified
control group.59 a set of connectivity gradients, in which each gradient
explains a majority of the variance in the data.89-91
DISCUSSION As well, most psychedelic studies published to date
Over the past several years, promising trials of psyche have used RSFC estimates from f MRI with little dis
delic treatment, combined with psychotherapy, have cussion of the limitations of these techniques, the main
been completed with several different pharmacothera one being that the repeatability of RSFC is low.92 A
pies for a range of conditions. Overall, the neuroimaging solution that should be used in future studies is to col
literature examining subacute changes after treatment is lect data over a greater number of sessions before and
lacking because of small sample sizes and inconsistent after treatment.92 Finally, although estimates of RSFC
methodologies, particularly in the use of RS f MRI. It are commonly performed, analysis strategies can vary
is noteworthy that all the studies to date have relied widely and can include evaluations of seed-based con
on f MRI as a surrogate to quantify neural activity. The nectivity to the rest of the brain, network connectivity
BOLD signal fundamentally relies on the concentra — which can be atlas based or data driven on the basis
tion of deoxygenated hemoglobin, which is influenced of an independent component analysis — or between
by CBF, cerebral blood volume, and the cerebral meta specific regions of interest. So far, the literature includes
bolic rate of oxygen consumption.34 Therefore, when studies that use all these approaches, making compari
f MRI is used in the context of an intervention that also son among them difficult.51,52 ,54,55,58,63,93

9 ( 5 ) 2023 doi:10.3138/jmvfh-2023-0014
Coverdale and Cook
From the review of the neuroimaging studies, it is these trials have been done within the framework of
apparent that results are somewhat inconsistent across PAP, which was the case in all studies reviewed here
studies. That said, the network, or regions within net except for one. To date, no study has examined the
works, in which changes were most often observed effect of PAP versus psychedelic administration with
included the DMN and the ECN.51,52 ,54,63 Changes out concurrent therapeutic support (although admin
in DMN connectivity during a psychedelic experi istering a psychedelic without some preparation and
ence have often been implicated in positive effects on in-session support is likely unethical). Some work does
mood and other symptomatolog y observed after the support a reduction in symptoms of depression and anx
experience.94,95 Indeed, Daws et al. found reduced with- iety even when psychedelic administration is done in a
in-DMN community recruitment and increased recruit naturalistic setting without psychological support,101
ment between DMN and ECN and between DMN and which suggests some benefit may be derived without the
the salience network one day after psilocybin.51 Changes addition of psychotherapy. Additionally, the majority
in the DMN have been related to the concept of ego of RCTs discussed previously used PAP, and therefore
dissolution and the positive effects of psychedelic phar psychotherapy likely plays a role in its efficacy. However,
macotherapies.94,96 This concept has yet to be evaluated many studies that attempted to identify more long-term
during the integration phase and requires further study. neurobiological or psychological changes have not used
As mentioned earlier, changes in the ECN were psychotherapy as part of the intervention (or at least it is
documented after psychedelic administration. As unclear what psychotherapy was performed), which was
reviewed by Uddin,79 several neuroimaging studies the case for 7 of 19 articles included in the second liter
revealed an association between the ECN (also known ature review. There is some evidence that psychotherapy
as the lateral frontoparietal network) and behavioural alone can change RSFC in depression.101,103 Therefore,
indices of cognitive flexibility and executive function. when attempting to gain an understanding of the mech
In terms of psychological changes after psychedelic anistic changes with PAP, it is important to include
treatment, it should be noted that there is some uncer both psychedelic and psychotherapy components in the
tainty regarding the concept of psychological flexibility, intervention unless there is a clear rationale for includ
because a recent review identified problems with con ing just the psychedelic treatment.
sistency in applying the definition, with a wide variety Beyond the limitations to current studies with
of terminolog y used and problems with the applica respect to design (small sample sizes, methodologies
tion of the most commonly used measurement tools used, validity of the constructs being measured), another
(the Acceptance and Action Questionnaire [A AQ ], limitation, as with much of science, is a lack of inclusion
A AQ-II, and the BEAQ ).97-100 of marginalized communities. In a review of psychedelic
Overall, definitions and construct validity need to studies from 1993 to 2017, 82.3% of participants were
be further validated for flexibility, particularly psych non-Hispanic white.104 Rates of trauma and mental ill
ological flexibility.97 In terms of cognitive flexibility, ness are higher among members of racialized commun
when thought of as a component of executive func ities,105,106 low-income individuals,107,108 and members of
tion,79 the limited neuroimaging evidence that does the LGBTQIA+ community.109,110 As a result, individ
exist supports the notion the ECN may be implicated in uals in these groups have both greater distress and more
the positive changes observed with psychedelic pharma use for novel therapies such as PAP but, at the same
cotherapy,51,52 particularly in terms of increased integra time, likely have less access to such treatments. There
tion with other networks.51 Although speculative, it is fore, moving forward, equitable inclusion in trials must
feasible that, after psychedelic administration, the com become a priority, and PAP must not be solely available
bination of increased psychological flexibility, cognitive to those of higher socio-economic statuses.
flexibility, or both, combined with reduced experiential
avoidance, rumination, and thought suppression, is Use of PAP with military members
what allows progress to be made in psychotherapy that and Veterans
would not otherwise be possible. Active military personnel and Veterans experience men
Although the excitement over the published RCTs tal illness,111 including PTSD,112,113 at rates higher than
to date has centred primarily on psychedelics as a treat the general population because of exposure to traumatic
ment, much less focus has been placed on the fact that events during duty. In particular, effective treatment

doi:10.3138/jmvfh-2023-0014 2023 9 ( 5 )
options for PTSD are limited,114 and individuals with Investigation: NS Coverdale
PTSD do not respond to first-line treatment — select Data Curation: NS Coverdale
ive serotonin reuptake inhibitors — in 40%-60% of
Writing — Original Draft: NS Coverdale
cases.115 A number of studies reviewed using MDMA-
assisted psychotherapy have resulted in positive out Writing — Review & Editing : NS Coverdale and DJ Cook
comes;4,5,13-15 however, several factors are unaccounted Super vision: DJ Cook
for in current studies that are relevant to current or
former military personnel. The most significant of these ETHICS APPROVAL
include co-occurring traumatic brain injury and higher Ethics approval was not required for this article.
rates of psychiatric comorbidity than the general popu

lation.115,116 Limited research has been done specifically INFORMED CONSENT
with military personnel and Veterans,4,117 and future N/A
work should directly target this group to confirm that
PAP is both safe and efficacious for this population. REGISTRY AND REGISTRATION NO.
OF THE STUDY/TRIAL
Conclusion N/A
Despite mounting evidence that PAP improves clini
cal outcomes for people with several neuropsychiatric ANIMAL STUDIES
conditions, the question of how these changes occur N/A
remains largely unanswered. With this review, the auth
ors have put forth the current hypotheses as to what FUNDING
occurs during the integration phase. Uncovering these No funding was received for this article.
mechanisms is an important step so that treatments
can be further refined on the basis of condition, type of PEER REVIEW
psychedelic, and type of psychotherapy to better ser ve This article has been peer reviewed.
those with neuropsychiatric conditions.
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Mechanisms of integration in psychedelic-assisted therapy

a Centre for Neuroscience Studies, Queen’s University, Kingston, Ontario, Canada

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INTRODUCTION integration in which the therapist undertakes a trad­

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Table 1. Summary of included RCT studies with a clinical outcome

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response 187.5 mg (high) −44.3 high

Griffiths Depression Change in 50 Double-blind, PSIL 13 (on Low-dose PSIL (1 GRID-HAMD:

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Table 2. Summary of psychedelic studies included during the integration period

(cognitive function) at controlled

doi:10.3138/jmvfh-2023-0014 2023 9 ( 5 )

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9 ( 5 ) 2023 doi:10.3138/jmvfh-2023-0014

Openness Personality Inventory.

expected result.62 As a follow-up, functional connec­

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rates of psychiatric comorbidity than the general popu­

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as a treatment for anorexia ner vosa : a pilot study.” Front

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25. Carhart-Harris RL, Roseman L, Haijen E, Erritzoe D, 1997;10(4-5):237-49. https://doi.org/10.1002/

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Walker N, Jerome L, et al. Reduction in social anxiety

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https://doi.org/10.1016/j.neuropharm.2017.12.041. learned helplessness and depression symptomatolog y : a

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INTRODUCTION integration in which the therapist undertakes a trad

expected result.62 As a follow-up, functional connec

rates of psychiatric comorbidity than the general popu