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1038/s44159-022-00129-w

Review article Check for updates

Trauma-focused treatment for

comorbid post-traumatic stress
and substance use disorder
Alexander C. Kline1,2, Kaitlyn E. Panza1,2, Robert Lyons1,3, Shannon M. Kehle-Forbes4,5,6, Denise A. Hien7
& Sonya B. Norman    1,2,8,9 
Abstract Sections

Trauma-focused treatments — psychotherapies that focus on trauma Introduction

as a central component of treatment and use cognitive, emotional Treatment overview

or behavioural techniques to facilitate the processing of a traumatic Predictors of outcome
experience — are first-line interventions for post-traumatic stress
Improving treatment
disorder (PTSD). Although trauma-focused interventions are effective effectiveness
in treating PTSD and comorbid substance use disorder (SUD), these
Summary and future
treatments are underused. Further, this comorbidity remains difficult to directions
treat, with smaller treatment effect sizes and higher dropout rates than
for PTSD alone. In this narrative Review, we examine the literature from
clinical trials of trauma-focused treatment for patients with PTSD + SUD
that might elucidate the attenuated treatment response and high
rates of dropout. We first provide an overview of effective treatment
for PTSD + SUD with respect to PTSD and substance use outcomes.
We then review predictors of attendance and outcome in clinical
trials evaluating trauma-focused treatments for PTSD + SUD. Next, we
discuss possible strategies to improve response and reduce dropout in
treatment for PTSD + SUD. Altogether, this Review provides the basis for
recommendations for future research designed to improve treatment
attendance and response and to increase the availability and reach of
trauma-focused treatments for this population.
1
Mental Health Service, VA San Diego Healthcare System, San Diego, CA, USA. 2Department of Psychiatry,
University of California San Diego, San Diego, CA, USA. 3San Diego Joint Doctoral Program in Clinical Psychology,
San Diego State University and University of California, San Diego, CA, USA. 4Center for Care Delivery and
Outcomes Research, Minneapolis VA Healthcare System, Minneapolis, MN, USA. 5Department of Medicine,
University of Minnesota, Minneapolis, MN, USA. 6Women’s Health Sciences Division, National Center for PTSD,
Boston, MA, USA. 7Center of Alcohol & Substance Use Studies, Rutgers University, New Brunswick, NJ, USA.
8
Executive Division, National Center for PTSD, White River Junction, VT, USA. 9Center of Excellence for Stress and
Mental Health, VA San Diego, San Diego, CA, USA.  e-mail: snorman@health.ucsd.edu

Nature Reviews Psychology

Review article
Introduction
Exposure to traumatic events such as physical or sexual assault, military
combat, a natural disaster or a motor vehicle accident is common1.
Although most trauma survivors naturally recover, a subset develop
post-traumatic stress disorder (PTSD), a debilitating and typically
chronic psychiatric disorder. Symptoms of PTSD include trauma-
related intrusive thoughts and images, flashbacks and nightmares,
physical and/or emotional distress when reminded of the trauma, avoid-
ance of trauma-related cues, hypervigilance and negative changes in
mood and beliefs. Trauma exposure also heightens risk for substance
use disorder (SUD; alcohol and/or drug use disorders)2,3, which are
defined by problematic patterns of substance use that lead to clinically
meaningful impairment and distress4. PTSD and SUD are highly preva-
lent2,3,5–7, impairing8–10 and costly conditions11,12 that negatively influence
interpersonal relationships, occupational functioning, quality of life,
and physical and mental health3,5,6,8,13–15.
PTSD and SUD frequently co-occur. Epidemiological research
estimates that 46–58% of individuals diagnosed with PTSD also meet
criteria for alcohol use disorder or drug use disorder during their
lifetime7,16. Similarly, PTSD is often comorbid among individuals with
substance use difficulties. Lifetime alcohol use disorder5 and drug use
disorder6 (as defined by the Diagnostic and Statistical Manual of Mental
Disorders, Fifth Edition; DSM-5) increase the odds of meeting lifetime
criteria for PTSD by 30% and 50%, respectively. There are several viable
reasons why PTSD and SUD frequently co-occur17–19 (Fig. 1). According
to the high risk hypothesis, substance use might increase risk of trauma
exposure, owing to a greater likelihood of being in high-risk situations.
Alternatively, the susceptibility hypothesis suggests that substance use
might boost the risk of developing PTSD following trauma exposure,
possibly by worsening symptoms or interfering with natural recov-
ery20,21. Another hypothesis that has received substantive empirical
support18 is the self-medication hypothesis, which suggests that indi-
viduals with PTSD might use substances to cope with post-traumatic
stress symptoms and distress, ultimately leading to the development of
SUD. Finally, the shared vulnerability hypothesis stipulates that PTSD
Trauma exposure
SUD PTSD
Self-medication hypothesis
Shared vulnerability hypothesis
High risk hypothesis
Susceptibility hypothesis
Fig. 1 | Pathways for PTSD and SUD, and their co-occurrence. The high risk
hypothesis suggests that substance use disorder (SUD) increases the risk of post-
traumatic stress disorder (PTSD) by increasing the likelihood of trauma exposure
(yellow arrows). The self-medication hypothesis theorizes that PTSD increases
risk for SUD, as individuals might use substances to cope with symptoms of
PTSD, such as sleep difficulties, irritability or hypervigilance (purple arrow). The
susceptibility hypothesis posits that SUD increases risk for PTSD by negatively
affecting natural recovery after trauma exposure (grey arrow). The shared
vulnerability hypothesis suggests that PTSD and SUD have similar risk factors
(such as genetics, environmental risk factors or personality traits) and their
relationship is not causal (red arrows).
Nature Reviews Psychology
and SUD are not causally linked and that their co-occurrence is better
understood in terms of their shared risk factors, such as genetics or
personality traits. Any single or combination of these pathways can
result in co-occurring PTSD and SUD (referred to herein as PTSD + SUD).
The co-occurrence of PTSD and SUD is associated with height-
ened risk of a wide array of negative functional and health outcomes,
above having either disorder independently. Compared with either
disorder alone, individuals with PTSD + SUD report greater unem-
ployment; lower income; greater functional impairment; more severe
mental health symptoms; lower quality of life; greater risk of psychiatric
comorbidities, personality disorders and physical health problems;
greater service use and health-care costs; and higher rates of suicidal
ideation and attempts22–30. The immense impact of this comorbidity
on individuals and society (such as via health-care burden and costs)
indicates the crucial need for well-disseminated, effective treatments.
Several possible effective treatment options exist for PTSD + SUD.
Similar to PTSD alone, meta-analyses and reviews conclude that trauma-
focused treatments are highly effective for reducing PTSD symptoms
among patients with PTSD + SUD31–33. These treatments focus on trauma
as a central component of therapy and use cognitive, emotional or
behavioural techniques to facilitate the processing of a traumatic
experience. A 2021 meta-analysis of PTSD + SUD clinical trials indicated
that trauma-focused — but not non-trauma-focused — treatments
outperformed comparators on PTSD outcomes at post-treatment, but
did not outperform manualized SUD treatments at post-treatment or
follow-up33. For SUD outcomes, manualized SUD treatments showed
stronger outcomes compared with trauma-focused treatments at
post-treatment. Trauma-focused interventions are effective and do
not cause worsening symptoms or substance use34,35. Accordingly, the
US Veterans Affairs/Department of Defense clinical practice guide-
lines recommend that SUD should not be a contraindication for first-
line, trauma-focused therapies. However, it is extremely common for
patients with PTSD + SUD not to receive these effective treatments.
Further, even when implementing trauma-focused interventions, this
comorbidity remains difficult to treat31,32,36.
In this Review, we first provide a brief overview of effective treat-
ments for PTSD + SUD, highlighting both PTSD symptom and substance
use outcomes. Owing to strong evidence for its effectiveness, we centre
our discussion around trauma-focused treatment. We then review
predictors and correlates of treatment response and attendance in
individuals with PTSD + SUD, as well as possible strategies to improve
outcomes. Drawing from these, we conclude with recommendations
for future research to improve treatment access, attendance and
response for patients with PTSD + SUD.
Treatment overview
In the most updated systematic review and meta-analysis of randomized
controlled trials examining psychotherapies for PTSD, trauma-focused
treatments — particularly manualized therapy interventions such as
Prolonged Exposure37, Cognitive Processing Therapy38 and cognitive
therapy39 — were most effective in reducing symptoms of PTSD40. These
findings are consistent with prior meta-analyses and reviews of PTSD
interventions41–43 and support the universal status of trauma-focused
treatments as first-line interventions across the five major clinical
practice guidelines for PTSD44.
Despite evidence of their benefit, trauma-focused psychothera-
pies are underused as PTSD treatments45–50. For example, according to
one large study of medical records of more than 255,000 US veterans
from the Iraq and Afghanistan conflicts, only 20% of those diagnosed
Review article
with PTSD had received any Prolonged Exposure or Cognitive Pro-
cessing Therapy51, despite extensive dissemination efforts within the
Veterans Health Administration52. Standard SUD treatment typically
does not include treatment for PTSD, and it is even less likely to include
evidence-based, trauma-focused interventions40. In the instances in
which PTSD treatment has been provided alongside SUD treatment,
providers have often implemented non-trauma-focused interventions,
such as present-focused coping skills interventions or supportive
therapy53–55. Although these treatments are more broadly disseminated,
they have weaker recommendations than trauma-focused therapies
across clinical practice guidelines for PTSD treatment44.
Relative to PTSD-only clinical trials, which typically report large
effect sizes (standardized mean differences above 1.0)41,56 between
active intervention and control groups on PTSD outcomes, treatment
effects for trauma-focused interventions are typically smaller among
samples with PTSD + SUD, estimated at 0.41 in one review31. Within-
condition effect sizes adhere to a similar pattern, ranging from Hedges’
g of 1.38 for Prolonged Exposure and mixed cognitive and exposure
therapy conditions to 1.69 for Cognitive Processing Therapy among
patients with PTSD42, compared with 1.11 in trauma-focused treatment
for patients with PTSD + SUD33. Furthermore, a 2022 meta-analysis56 on
exposure therapy clinical trials for PTSD observed that SUD diagnosis
moderated PTSD outcome; trial effect sizes were larger in samples with
fewer patients diagnosed with SUD. Here, we provide a brief review
of outcomes of trauma-focused treatments for PTSD and comorbid
SUD, drawing principally from systematic reviews and randomized
controlled trials (Table 1).
Trauma-focused treatment for PTSD + SUD includes concurrent
or integrated therapies, which integrate PTSD and SUD treatments and
address both PTSD and substance use within one protocol, and non-
integrated interventions. The most commonly tested non-integrated,
trauma-focused therapy for PTSD + SUD is Prolonged Exposure. In Pro-
longed Exposure, patients revisit the trauma memory and associated
thoughts and feelings via imaginal exposure. Between sessions, patients
engage in in vivo exposure exercises, during which they gradually approach
trauma-related places, feelings and activities that are safe but that they
have been avoiding because they serve as distressing reminders of the
trauma. Across studies, this intervention is associated with significant
reductions in PTSD symptom severity, but generally does not outperform
substance use-only treatment on substance use outcomes31,33.
Less is known regarding the efficacy of other non-integrated
trauma-focused treatments, such as Eye Movement Desensitization
and Reprocessing, and Cognitive Processing Therapy for patients with
PTSD + SUD. In the former, patients process the trauma by holding
the memory and associated distress in their mind while engaging in
saccadic eye movements. In the latter, patients examine the meaning
and impact of the trauma and collaborate with therapists to identify and
reframe negative beliefs about the trauma that maintain symptoms
and dis­tress (such as, “the trauma is my fault” or “the world is a dan-
gerous place”). Preliminary results are promising for these two inter-
ventions and generally follow the findings reported on Prolonged
Exposure, where treatment is associated with strong PTSD outcomes.
Examples include a randomized pilot study of Eye Movement Desensiti-
zation and Reprocessing among women with PTSD + SUD57, as well as a
randomized trial of a culturally modified version of Cognitive Process-
ing Therapy among Native American women with full or subthreshold
PTSD and substance use58. Further, Cognitive Processing Therapy has
been effective among patients with PTSD + SUD in non-randomized
studies54,59, as well as in a randomized pilot study in which it was paired
Nature Reviews Psychology
with medication or placebo60. Principles of cognitive behavioural
therapy for SUD have also been integrated with Cognitive Processing
Therapy and piloted among patients with PTSD + SUD61. However,
future large-scale trials of Cognitive Processing Therapy and Eye Move-
ment Desensitization and Reprocessing for PTSD + SUD are crucial,
as these treatments are strongly recommended in clinical practice
guidelines for treatment of PTSD44.
In the past decade, integrated therapies have become more promi-
nent in treatment for PTSD + SUD. Integrated interventions are also
preferred by patients62. Many of the studies of integrated treatments
have examined present-focused, non-trauma-focused approaches
such as Seeking Safety63, which teach coping skills for PTSD + SUD but
do not include trauma processing or exposure to trauma reminders.
Clinical trials of integrated present-focused skills-based therapy have
generally found that the decrease in symptoms in PTSD and SUD is
comparable to that achieved with comparison treatment conditions,
such as SUD-specific therapies including relapse prevention or SUD
treatment as usual31,64–66. By contrast, there is stronger empirical sup-
port for integrated trauma-focused treatments, such as Concurrent
Treatment of PTSD and Substance Use Disorders Using Prolonged
Exposure (COPE)67, which combines traditional Prolonged Exposure
with relapse prevention strategies. These integrated trauma-focused
treatments have been associated with significantly lower PTSD symp-
toms and higher rates of PTSD diagnostic remission compared with
present-focused PTSD treatment or SUD-only treatment31,32,68,69. Sub-
stance use in these interventions tends to decrease comparably to that
in SUD and present-focused control conditions.
In sum, several effective treatment options for PTSD + SUD exist,
with clinical trials for PTSD + SUD indicating that trauma-focused
treatments show strong PTSD and SUD outcomes. Accordingly, clini-
cal practice guidelines recommend proceeding with these first-line
interventions for PTSD when SUD co-occurs44.
Predictors of outcome
Understanding predictors of outcome for trauma-focused treatment
for PTSD + SUD can improve the implementation and effectiveness of
these interventions, which are associated with smaller effect sizes com-
pared with PTSD alone. To add complexity to the picture, dropout in
treatment for PTSD + SUD is higher than for PTSD alone. Meta-analyses
have estimated dropout rates in trauma-focused psychotherapies
across randomized controlled trials for PTSD to be 18%70, slightly lower
than estimates for psychosocial treatments for SUD (30%) or alcohol
use (26%)71. These figures are substantially higher for PTSD + SUD, in
which dropout often ranges from 30% to more than 70%31,68,69,72–77.
In light of attenuated symptom reduction and high rates of dropout in
trauma-focused treatment for PTSD + SUD31–33, knowledge regarding
predictors and underlying processes could help to identify patients at
high risk of poor response and/or low attendance and inform tailored
strategies to improve outcomes.
Here, we review baseline and within-treatment predictors of PTSD
and SUD treatment response and attendance among patients with
PTSD + SUD (Table 2). We first review evidence for baseline psychoso-
cial patient characteristics and psychiatric characteristics, followed by
review of within-treatment predictors. We highlight trauma-focused
treatments, including non-integrated (for example, Prolonged Expo-
sure) and integrated (for example, COPE) interventions, focusing on
articles published with the following criteria: secondary analyses of
randomized clinical trials examining at least one trauma-focused
treatment; adult patients with PTSD + SUD; published between 2012
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Table 1 | Randomized clinical trials examining trauma-focused treatment for PTSD + SUD

First Population Substance type Treatment Definition of PTSD measure and SUD measure and outcomes Sessions
author and setting condition (n) treatment outcomes attended, mean
(year) completion (s.d.)
(dropout rate)
Back69 US military Mixed SUD per COPE (54) Attendance of DSM-IV CAPS TLFB COPE: 8.8 (4.1)
(2019) veteran DSM-IV (63% AUD- RP (27) 12 sessions (COPE: PTSD symptoms Percentage of days using any RP: 7.4 (5.0)
outpatient only; 27% AUD and 46%; RP: 52%) decreased more in substance and percentage
sample drug use disorder; Attendance of COPE compared of days using alcohol
10% drug use ≥8 sessions (COPE: with RP at post- reduced in both conditions,
disorder only) 66.7%; RP: 55.6%) treatment (d = 1.4, with no between-treatment
P < 0.001) differences at post-treatment
for either outcome (substance
use: d = 0.0, P = 0.59;
alcohol use: d = 0.1, P = 0.95)
Coffey72 Mixed Alcohol mPE (45) Attendance of IES-R TLFB NR
(2016) sample from dependence per mPE + MET-PTSD ≥8 sessions PTSD symptoms Percentage days abstinent
residential DSM-IV (40) (mPE: 38%; decreased more from alcohol improved in all
SUD mPE + MET-PTSD: in mPE (d = 0.62) three conditions (P = 0.0001),
HLS (41)
treatment 40%; HLS: 12%). and mPE + MET- with no differences between
facility in PTSD (d = 0.36) HLS and mPE (d = 0.01) or HLS
USA than in HLS at and mPE + MET-PTSD (d = 0.21)
post-treatment at 3-month follow-up
Percentage days abstinent
from drug use improved in all
three conditions (P = 0.0001),
with no differences between
HLS and mPE (d = 0.02) or HLS
and mPE + MET-PTSD (d = 0.24)
at 3-month follow-up
Foa73 (2013) Mixed Alcohol PE + NAL (40) Percentage of PSS-I TLFB NR
treatment- dependence per PE + PBO (40) patients who PTSD symptoms Percentage of days
seeking DSM-IV ‘dropped out of decreased in all drinking reduced in all four
SC + NAL (42)
outpatient the study prior four conditions; conditions, with a significant
sample in SC + PBO (43) to the end of the main effect of main effect of naltrexone
USA treatment period’ PE, main effect (d = 0.42) at post-treatment
(PE + NAL: 35%; of naltrexone and The main effect of PE and the
PE + PBO: 38%; the PE–naltrexone PE–naltrexone interaction
SC + NAL: 31%; interaction all were both nonsignificant at
SC + PBO: 26%) nonsignificant at post-treatment (P values >0.51)
post-treatment
(P values >0.15)
Kehle- US military Mixed SUD per Phased MET + PE Attendance of PCL TLFB Phased MET + PE:
Forbes74 veteran DSM-IV (85% (88) 12 or more PE and PTSD symptoms Percentage of drug use or 9.2 (4.6)
(2019) outpatient met for alcohol Integrated MET sessions total, decreased in heavy drinking days reduced Integrated
sample dependence; MET + PE (95) which would entail both conditions in both conditions (P values MET + PE: 8.4
9% met for alcohol ≥8 PE sessions (P values <0.01), <0.01), with no difference (4.2)
abuse only; (phased MET + PE: with no difference between conditions at
18% met for drug 64%; integrated between conditions post-treatment (d = 0.27)
dependence; MET + PE: 77%) at post-treatment
6% drug depend- (d = 0.08)
ence only; 0% drug
abuse only)
Mills75 Mixed sample Mixed SUD COPE + TAU Attendance of all CAPS CIDI COPE + TAU
(2012) seeking per DSM-IV for substance 13 COPE sessions PTSD symptoms Number of drug classes used median: 5
outpatient (polysubstance dependence (55) (COPE + TAU decreased more and number of dependence TAU: NR
SUD use most common, TAU for substance for substance in COPE + TAU criteria met reduced in both
treatment with median = 4 dependence (48) dependence: 82%; compared with conditions (P values <0.001),
in Australia drug classes TAU for substance TAU at 9-month with no between-condition
in past month) dependence: NR) follow-up (P = 0.02) differences at 9-month
follow-up (P values >0.15)
Norman68 US military AUD per DSM-IV COPE (63) NR CAPS-5 TLFB COPE: 8.4 (4.6)
(2019) veteran SS (56) PTSD symptoms Percentage of heavy drinking SS: 11.4 (4.8)
outpatient decreased more in days improved in both
sample COPE compared conditions, with no between-
with SS through treatment difference through
6-month follow-up 6-month follow-up (d = 0.04,
(d = 0.41) P = 0.91)

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Table 1 (continued) | Randomized clinical trials examining trauma-focused treatment for PTSD + SUD
First Population Substance type Treatment Definition of PTSD measure and SUD measure and outcomes Sessions
author and setting condition (n) treatment outcomes attended, mean
(year) completion (s.d.)
(dropout rate)
Pearson58 Native Mixed SUD per Culturally Attendance of all 9 PSS-SR Drug use frequency Conditions
(2019) American DSM-IV (70% of adapted CPT (37) sessions (70%) PTSD symptoms Alcohol use frequency collapsed
women sample had SUD Waitlist control/ decreased more decreased more in culturally measuring
outpatient diagnosis) delayed in culturally adapted CPT group patients
sample intervention (36) adapted CPT compared with control group attending
in USA group compared (d = 0.77) at least one
Conditions
with control session: 6.1 (4.4)
collapsed
measuring group(d = 1.03)
patients
attending ≥1
session (n = 60)

Ruglass76 Mixed Mixed SUD COPE (39) NR CAPS ASI COPE: 6.1 (4.8)
(2017) outpatient per DSM-IV; RP (43) PTSD symptoms COPE and RP decreased RP: 7.2 (4.4)
sample also included decreased in both primary substance use in
Active monitoring Active
in USA subthreshold PTSD COPE and RP at past 30 days at 1-month and
(28) monitoring: 8.8
both 1-month and 3-month follow-ups (P values (3.8)
3-month follow- <0.001), with no differences
ups (P values between conditions
<0.001), with
no differences
between
conditions
(treatment–time
interaction P = 0.86)

Sannibale77 Mixed AUD per DSM-IV Integrated Attendance CAPS TLFB Integrated
(2013) outpatient trauma-focused of ≥9 sessions PTSD symptoms Percentage days abstinent trauma-focused
sample in CBT (33) (integrated decreased in improved in both groups CBT median: 11
Australia CBT for trauma-focused both conditions (P = 0.001), with no CBT for
AUD + supportive CBT: 39%; CBT for (P values 0.001), differences between AUD + supportive
counselling (29) AUD + supportive with no differences conditions (P = 0.053) counselling
counselling:38%) between median: 10
Drinks per drinking day
conditions over showed greater reductions
time (P = 0.977) with CBT for AUD + supportive
counselling at 5-month
follow-up (P = 0.048), but not
post-treatment (P = 0.735) or
9-month follow-up (P = 0.431)

Schacht106 Mixed Opioid use PE (30) Attendance of CAPS ASI PE: 1.8 (2.6)
(2017) outpatient disorder PE + monetary all 12 sessions or PTSD symptoms The main effect of time PE + monetary
sample incentive (28) ≥9 sessions with a decreased more and the time–condition incentive:
recruited 70% reduction in in PE + monetary interaction were 7.1 (4.1)
from PTSD symptoms incentive over nonsignificant on the ASI
outpatient (PE: 97%; time compared drug composite score
methadone PE + monetary with PE (P = 0.024)
maintenance incentive: 64%)
clinic in USA

van Dam144 Mixed Mixed substance Structured Attendance of PDS TLFB NR

(2013) sample abuse or writing at least 75% (≥7) PTSD symptoms Percentage of days abstinent
from SUD substance therapy + TAU (19) (structured writing decreased in increased in both conditions
residential dependence TAU (15) therapy + TAU: both conditions at follow-up (time main
or intensive per DSM-IV; 47%); Remaining (time main effect effect P < 0.001), with
outpatient also included in SUD outpatient P = 0.001), with no differences between
clinics in subthreshold PTSD programme (TAU: no differences conditions (treatment–time
Holland 27%) between interaction P = 0.62)
conditions
(treatment–time
interaction P = 0.13)
ASI, Addiction Severity Index; AUD, alcohol use disorder; CAPS-5, Clinician-Administered PTSD Scale for DSM-5; CBT, cognitive behaviour therapy; CIDI, Composite International Diagnostic
Interview version 3.0; COPE, Concurrent Treatment of PTSD and Substance Use Disorders using Prolonged Exposure; CPT, Cognitive Processing Therapy; DSM, Diagnostic and Statistical
Manual of Mental Disorders; EMDR, Eye Movement Desensitization and Reprocessing; HLS, healthy lifestyles sessions; IES-R, Impact of Event Scale — Revised; MET, motivational enhancement
therapy; MET-PTSD, motivational enhancement therapy for PTSD; mPE, modified Prolonged Exposure; NAL, naltrexone; NR, not reported; PBO, placebo; PCL, PTSD checklist for DSM-IV;
PE, Prolonged Exposure; PSS-I, PTSD Symptom Severity — Interview; PSS-SR, PTSD Symptom Scale Self-Report; PTSD, post-traumatic stress disorder; RP, relapse prevention; SC, supportive
counselling; s.d., standard deviation; SS, Seeking Safety; SUD, substance use disorder; TAU, treatment as usual; TLFB, timeline followback.

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Table 2 | Predictors of dropout and response in clinical trials of trauma-focused treatment for PTSD + SUD

Outcome Predictor category Time point

Baseline Within treatment

PTSD Psychosocial patient
characteristics
Psychiatric characteristics
Substance use characteristics
SUD Psychosocial patient
characteristics
Psychiatric characteristics
Substance use characteristics
Attendance Psychosocial patient
characteristics
Psychiatric characteristics
Substance use characteristics
PTSD, post-traumatic stress disorder; SUD, substance use disorder.
Ethnoracial group79,105; history of violent offending81; trauma
type (sexual assault or combat trauma)78; social support115
Anxiety sensitivity78; emotion dysregulation145; number
of traumas82; PTSD severity83; PTSD symptom severity78,82;
traumatic brain injury with loss of consciousness104
Duration of alcohol dependence78; substance use-related
impairment83; SUD diagnosis (single or multiple substances)146
Combat trauma type78; earlier trauma age80; ethnoracial
group78,105; religious affiliation79; social support115
Depressive symptom severity78; emotion dysregulation145
Alcohol use severity ; SUD diagnosis (single versus multiple
78
substances)146
Education99; employment status98; marital status69; trauma type
(accident or ‘other’ trauma)97
Anxiety sensitivity99; PTSD symptom severity77,100
Alcohol craving101; alcohol use severity101; drug use frequency77
None
Between-session changes in distress during
imaginal exposure85
Changes in alcohol use86; changes in
substance use89; between-session changes
in craving during imaginal exposure85
None
Changes in PTSD symptoms86
Between-session changes in substance
craving during imaginal exposure85
None
Changes in distress following imaginal
exposure103; changes in PTSD symptoms97,98
Changes in alcohol use102; changes in alcohol
craving following imaginal exposure103

(the publication date of the first PTSD + SUD trial to examine a trauma-
focused treatment75) and 2022; sample size ≥40; and aims targeting psy-
chosocial and clinical predictors of response (PTSD and SUD outcomes)
and attendance and/or dropout.
Predictors of treatment response
Non-psychiatric patient characteristics, such as demographic features,
have not emerged as consistent predictors of treatment response.
A secondary analysis of one PTSD + SUD clinical trial73 implicated
trauma type (sexual assault trauma or combat trauma) with worse
PTSD outcome at post-treatment, whereas combat trauma and racial
identification as white were associated with worse alcohol use out-
comes at post-treatment78. Secondary analyses of a trial that com-
pared integrated exposure therapy, relapse prevention and an active
monitoring control group76 examined patient characteristics such as
race and/or ethnicity and religious affiliation79, trauma characteristics
(trauma age and count)80 and history of violent offending81. However,
there is little indication that any single psychosocial patient charac-
teristic is reliably associated with PTSD or SUD treatment outcomes in
trauma-focused therapy.
There is greater evidence to link baseline psychiatric character-
istics with treatment response. Across conditions in one of the above
trials73, higher anxiety sensitivity was a predictor of worse PTSD out-
come, whereas higher baseline alcohol use severity was associated with
worse alcohol use outcomes at post-treatment78. Among patients
with higher pretreatment PTSD severity, Prolonged Exposure was supe-
rior to supportive counselling; baseline depressive symptom severity
also moderated alcohol-related outcome, such that Prolonged Exposure
was superior among patients endorsing higher symptoms of depres-
sion.78 Additional support for the possible link between baseline sever-
ity and treatment outcome in exposure therapy was derived from a
secondary analysis of integrated exposure therapy in another trial75;
greater baseline PTSD severity was positively associated with symptom
reduction through follow-up, and number of traumas was negatively
associated with PTSD symptom reduction82.
Multivariate, person-centred analytical approaches, such as latent
class analysis, have also been used to predict outcomes of PTSD + SUD
treatment83,84. A study of a trial of outpatient veterans randomized to
integrated exposure therapy or integrated coping skills therapy for
PTSD and alcohol use disorder68 used latent class analysis based on PTSD
symptoms and DSM-IV alcohol use disorder criteria to identify three
subgroups: moderate PTSD/low alcohol use disorder impairment (21%
of the sample); high PTSD/high alcohol use disorder impairment (48%);
and low PTSD/high alcohol use disorder impairment (31%)83. Although
drinking outcomes did not differ between treatments based on groups,
patients in both high alcohol use disorder impairment groups showed
superior PTSD outcomes in integrated exposure therapy. Overall, this
set of findings suggests that higher intensity (trauma-focused) and/or
combination treatments (simultaneous psychotherapy and pharma-
cotherapy) might be optimal for patients with more impairment and
more distress.
A smaller body of literature has examined within-treatment predic-
tors of PTSD and SUD response in trauma-focused therapies. In a second-
ary analysis of one trial69, patient-reported between-session changes in
distress and substance craving in COPE were predictive of outcome85.
Specifically, between-session habituation of distress and substance
craving predicted reductions in PTSD symptoms during treatment, and
between-session habituation in craving was modestly associated with
reductions in substance use during treatment. Researchers have also
studied the bidirectional effects of PTSD symptoms and substance use
during trauma-focused therapies. For instance, a secondary analysis of
one trial found that greater PTSD symptom severity during treatment
was associated with subsequent increases in alcohol use86, a pattern that
has also been observed in pharmacotherapy and non-trauma-focused

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Review article
treatments for PTSD + SUD87,88. Similarly, increases in alcohol use in
this trial68 predicted subsequent greater PTSD symptoms, though at a
smaller effect size. Consistent with these findings, another secondary
analysis of a PTSD + SUD trial76 indicated that higher substance use dur-
ing COPE and relapse prevention treatment was associated with greater
PTSD symptom severity at post-treatment89. By contrast, a second-
ary analysis of a trial comparing COPE and relapse prevention among
military veterans69 did not adhere to this pattern of findings: changes in
PTSD symptoms did not predict the likelihood of next-session substance
use, or vice versa, in either treatment condition90.
Overall, the bidirectional relationships within treatment between
PTSD symptoms and substance use warrant future study, as monitoring
these changes in therapy might be a prognostic marker of outcome. It
is also possible that providers could track and attend to these features
during therapy to inform in-session strategies to improve response.
These findings also highlight that patients with PTSD + SUD should
not be required to abstain from substances before engaging in trauma-
focused therapy. Reductions in use are likely to occur during PTSD
therapy for many patients, and requiring a period of abstinence before
trauma-focused treatments will preclude patients from getting effec-
tive treatment. Further, evidence suggests that even in the context
of continued substance use, trauma-focused treatments still lead to
significant reductions in PTSD symptoms68,89.
Predictors of attendance
Treatment dropout has received considerable attention in the PTSD
literature owing to the robust, positive association between attend-
ance and response82,91–93, as well as the high dropout rates observed in
PTSD + SUD treatment. There is no uniform benchmark for dropout
across the literature. Definitions vary, ranging from stringent thresh-
olds of any attendance less than a full treatment protocol75 to failure to
complete an a priori specified subset of sessions (for example, attend-
ance of ≥8 sessions of a 12-session treatment protocol)72. The relation-
ship between attendance and outcome is complex. Some patients
respond to treatment more quickly than others, so greater session
attendance is not universally better94,95. It is also likely that a subset
of patients who do not attend a full treatment protocol and ‘drop out’
experience meaningful symptom reduction, meet their treatment goals
and appropriately decide to discontinue treatment96. These considera-
tions notwithstanding, greater treatment attendance in most cases
substantially raises the likelihood of optimal treatment response82,91–93.
Dependable predictors of dropout among patients with
PTSD + SUD in trauma-focused treatments have failed to emerge,
with only a subset of patient characteristics inconsistently linked to
attendance in individual studies. Preliminary analyses in one trial
indicated that married patients were less likely to complete therapy69.
In secondary studies of several trials72,73,76, despite exploratory analyses
that examined a large number of potential predictor variables, only
trauma type, employment and education were linked to attendance97–99.
By contrast, similar to evidence suggesting links between base-
line severity and treatment response, greater psychiatric distress
and PTSD and SUD severity might be linked to worse attendance in
trauma-focused treatments. Among outpatients randomized to inte-
grated exposure-based therapy or cognitive behavioural therapy in
a clinical trial for PTSD and alcohol use disorder, drinks per drinking
day at baseline and PTSD severity were each negatively associated with
attendance77. Similarly, in a trial of outpatient veterans with PTSD + SUD
randomized to receive integrated exposure therapy or relapse preven-
tion69, there was a statistical trend for greater PTSD symptom severity
Nature Reviews Psychology
to be associated with higher dropout (the weak relationship might have
been due to the small sample size)100. SUD severity at the start of treat-
ment has also been linked to attendance. In one trial68 that compared
integrated exposure therapy or integrated coping skills therapy for
PTSD and alcohol use disorder, a greater percentage of heavy drinking
days in the 3-month interval before treatment and greater alcohol use
disorder severity (per DSM-IV criteria) were associated with lower ses-
sion attendance in both treatments101. Finally, in a secondary analysis
of Prolonged Exposure in another trial72, greater anxiety sensitivity was
associated with higher dropout, and there was a statistical trend for
greater number of drug use days at baseline linked to higher dropout99.
A promising, complementary avenue for identifying signals of
dropout risk is to examine variables during therapy. For example,
increases in alcohol use between sessions among patients randomized
to integrated exposure therapy has been associated with higher drop-
out risk102. Early treatment satisfaction was also linked to attendance
in this trial68, with eventual completers reporting higher treatment
satisfaction early in therapy relative to dropouts. Changes in craving
and distress after imaginal exposure among veterans randomized
to integrated exposure therapy for PTSD + SUD have also been linked to
attendance, with increases in these variables from prior sessions raising
the odds of dropping out at the next session103. Another clinical trial73
observed that changes in alcohol use and PTSD symptoms during
therapy were associated with attendance in nuanced ways, moder-
ated by treatment97. Faster reductions in alcohol use were linked to
higher dropout among patients receiving Prolonged Exposure, with a
curvilinear relationship between the slope of changes in PTSD symp-
toms and dropout; among patients with low baseline PTSD severity,
dropout rates were high for patients who improved quickly and low
for patients who improved slowly. A machine learning analysis using
data from another trial76 indicated that within-treatment improvement
of PTSD symptoms was linked to attendance, moderated by age, such
that faster PTSD symptom improvement predicted worse attendance
among younger patients and better attendance among older patients98.
Overall, there is minimal evidence thus far to suggest that psy-
chosocial patient characteristics — which are frequently static and
unmodifiable — indicate dropout risk in trauma-focused therapy for
PTSD + SUD. However, within-treatment variables — which are more
proximal to dropout and more likely to be modifiable — show prom-
ise. For example, increases in substance use, distress and cravings
have been associated with worse attendance. Further examination of
changes in salient markers during therapy and how these might influ-
ence patient engagement in treatment is an important future direction
in research. Such work could inform strategies to improve attendance
and ultimately treatment outcome.
Considerations and limitations
The literature on predictors of effectiveness and attendance in trauma-
focused treatments for PTSD + SUD (Table 3) should be interpreted in
the context of several considerations. Findings are often inconsistent
across studies, which might be due to a combination of factors. First,
patient characteristics (such as employment or education) are not
always operationalized uniformly, which can influence study results.
Furthermore, although several studies examined a large number of
potential predictors, most of these variables were not significantly
related to attendance or treatment response. A few studies explored
a dozen or more variables, with the vast majority showing no link to
outcomes78,82,97,99,100. Thus, few predictors were identified even when
taking a lenient approach and broadly exploring a wide array of potential
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Table 3 | Characteristics of secondary analysis studies of clinical trials for PTSD + SUD

Primary trial Secondary Hypotheses Variables tested Outcomes Sample Analyses

analysis size

Back et al. Badour et al. Exploratory Within-session and between-session habituation PTSD and SUD 54 Multilevel models and
(2019)69 (2017)85 and a priori of distress; within-session and between-session generalized linear models
habituation of craving
Badour et al. Exploratory Changes in PTSD symptoms and substance use Changes in PTSD 81 Lagged multilevel models
(2021)90 and a priori during treatment and substance
use during
treatment
Brown et al. Exploratory Ethnoracial group Attendance; 79 Piecewise linear mixed
(2020)105 PTSD, SUD, effects models
depression,
and anxiety
Gros et al. A priori TBI with loss of consciousness versus no TBI/TBI Attendance; 51 ANOVA and ANCOVA with
(2017)104 without loss of consciousness PTSD, depression last observation carried
and SUD forward for missing data
Jarnecke Exploratory Changes in cravings and distress during treatment Attendance; 46 Multilevel models and
et al. (2019)103 changes in PTSD survival analysis
and substance
use during
treatment
Jarnecke A priori Social support PTSD and SUD 81 Piecewise linear mixed
et al. (2022)115 effects models
Jeffirs et al. A priori Single SUD versus poly-SUD Attendance; 54 Multilevel models
(2019)146 PTSD and SUD
Szafranski A priori Age; gender; race; education level; income; Attendance 51 Survival analysis
et al. (2017)100 relationship status; employment status; military
rank; PTSD symptom severity; depressive symptom
severity; total drug use days at baseline; total alcohol
use days at baseline
Coffey et al. Belleau et al. Exploratory Age; gender; race; education; income; employment; Attendance 85 Logistic regression using
(2016)72 (2017)99 number of current additional anxiety/depressive the Fournier approach147
disorders; depressive symptom severity; PTSD
symptom severity; baseline number of drinking days;
baseline number of drug use days; alcohol craving;
anxiety sensitivity; emotion regulation
Foa et al. McLean, Exploratory Order of onset of PTSD and AUD Attendance; 154 Multilevel models
(2013)73 Su & Foa PTSD and
(2014)148 alcohol use
Zandberg Exploratory Age; gender; race; co-habitation status; employment PTSD and SUD 165 Multilevel models using
et al. (2016)78 status; education level; income; number of comorbid the Fournier approach147
Axis I disorders; presence versus absence of
additional substance use disorder; presence versus
absence of personality disorder; depressive symptom
severity; index trauma type; number of traumatic
events; baseline clinician-rated PTSD severity; age
of trauma onset; PTSD duration; anxiety sensitivity;
baseline percentage days heaving drinking; craving;
age of alcohol dependence onset; duration of
alcohol dependence
Zandberg Exploratory Age; gender; race; co-habitation status; employment Attendance 165 Logistic regression using
et al. (2016)97 status; education level; income; number of comorbid the Fournier approach147
Axis I disorders; presence versus absence of
additional substance use disorder; presence versus
absence of personality disorder; depressive symptom
severity; index trauma type; number of traumatic
events; baseline clinician-rated PTSD severity; age
of trauma onset; PTSD duration; anxiety sensitivity;
baseline percentage days heaving drinking; craving;
age of alcohol dependence onset; duration of
alcohol dependence; PTSD symptom improvement
slope; alcohol use improvement slope; PTSD
symptom improvement slope squared; alcohol use
improvement slope squared; interaction between
baseline PTSD severity and slopes of improvement

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Table 3 (continued) | Characteristics of secondary analysis studies of clinical trials for PTSD + SUD

Primary trial Secondary Hypotheses Variables tested Outcomes Sample Analyses

analysis size

Mills et al. Mills et al. Exploratory Age; sex; born in Australia; years of school PTSD 55 Linear regression models
(2012)75 (2016)82 completed; unemployed; history of imprisonment; with backward stepwise
age of first intoxication; history of injecting drug use; removal
past-month number of drug classes used; main drug
of concern alcohol; age of first trauma exposure;
age of worst trauma exposure; childhood trauma;
trauma type (nine types tested); number of trauma
types experienced; number of traumas experienced;
trauma exposure preceded age of first intoxication;
PTSD symptom duration; PTSD symptom severity;
depression severity; state anxiety; trait anxiety;
positive screen for borderline personality disorder;
history of SUD treatment; history of PTSD treatment;
engaged in current PTSD treatment; engaged in
current SUD treatment; current antidepressant
use; therapist; started COPE; sessions attended;
proportion of time spent in SUD treatment during
follow-up; antidepressant use during follow-up;
trauma exposure during follow-up
Norman et al. Kline et al. A priori Percentage of heavy drinking days; percentage of Attendance 119 Regression models
(2019)68 (2021)101 days abstinent; percentage of drug use days; alcohol
craving; duration of AUD; number of AUD criteria
Kline et al. A priori Changes in PTSD symptom severity, alcohol use Attendance 110 Cox proportional hazard
(2021)102 and patient satisfaction during treatment models
Panza et al. Exploratory Latent class membership based on symptoms PTSD and SUD 119 Latent class analysis
(2021)83 of PTSD and AUD and linear mixed effects
models
Tripp et al. Exploratory Changes in PTSD symptom severity and alcohol use PTSD and SUD 107 Lagged multilevel models
(2020)86 and a priori during treatment
Ruglass et al. Hien et al. A priori Emotional dysregulation PTSD and SUD 110 Generalized linear mixed
(2017)76 (2017)145 models
Hien et al. A priori Changes in substance use during treatment PTSD 82 Lagged multilevel models
(2018)89
Fitzpatrick A priori Trauma age; trauma count PTSD and SUD 82 Generalized estimating
et al. (2020)80 equations
Lopez- Exploratory History of violent offending Attendance; 80 Piecewise mixed effects
Castro et al. PTSD and SUD models
(2019)81
Lopez- Exploratory Age; race; gender; PTSD symptom change; marital Attendance 70 Iterative Random Forest
Castro et al. status; education; years since trauma; full versus algorithm and Poisson
(2021)98 subthreshold PTSD; baseline self-report PTSD regression models
severity; baseline clinician-rated PTSD severity;
baseline major depressive disorder diagnosis; age
of earliest trauma; more than one traumatic event;
number of traumatic events; trauma before age
18; sexual assault; physical assault; other trauma;
accident; SUD versus AUD; substance use change;
employment; emotion regulation; baseline past 7
days substance use; baseline past 30 days substance
use; problem substance; intervention; baseline past
30 days polysubstance use
Ruglass & Exploratory Race/ethnicity; religious affiliation PTSD and SUD 107 Generalized linear mixed
Yali (2019)79 models
AUD, alcohol use disorder; COPE, Concurrent Treatment of PTSD and Substance Use Disorders using Prolonged Exposure; PTSD, post-traumatic stress disorder; SUD, substance use disorder;
TBI, traumatic brain injury.

predictors. At the other end of the spectrum, some studies focused on
a small number of patient characteristics or even just one79–81,104,105. It
is also likely that many of the studies were devised post-hoc after the
conclusion of the clinical trial and were exploratory in nature, suggesting
that this literature would benefit from theory-driven models to inform
future hypothesis-driven studies.
There is also heterogeneity across studies with regard to outcome
measures, analytical methods and definitions of response and dropout.
Statistical approaches ranged from basic baseline comparisons between
patients (for example, comparisons between treatment completers and
dropouts on demographic variables or symptom severity) to machine
learning approaches98. Additionally, sample sizes were often modest,

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which limits the power to detect small effects. Finally, the data in these
studies came from clinical trials and therefore the findings might have
limited generalizability to clinic settings given that features of trials and
clinics can often differ (for example, clinical trials often have financial
incentives for patients to complete treatment and assessments, greater
flexibility regarding scheduling, incentives for researchers to collect
data, and/or smaller caseloads for clinicians compared with routine
clinical settings). All of these factors could affect study findings and hold
implications for future research. These limitations notwithstanding,
evidence to date indicates that patients’ baseline severity might be a
prognostic marker of treatment response and attendance. Additionally,
a small yet promising body of research examining within-treatment
predictors suggests that modifiable markers during therapy might
signal the outcome. Additional work in this area is warranted.
Improving treatment effectiveness
Given smaller effect sizes and high dropout rates, there is considerable
interest in developing and evaluating strategies to improve response
and attendance in trauma-focused interventions for PTSD + SUD. In this
section, we review potential paths to improve response and attendance,
primarily from pilot studies and clinical trials. We first review strate-
gies that have been evaluated for patients with PTSD + SUD, and then
discuss strategies showing initial effectiveness in PTSD that could be
applied to PTSD + SUD (Table 4).
A small body of literature has examined treatment augmentations
with the goal of improving response and attendance, including contin-
gency management (using incentives to reinforce positive behaviour
change) and motivational enhancement (facilitating behaviour change
by exploring and resolving ambivalence to change), both strategies
initially developed to treat SUD. In a clinical trial for PTSD and comorbid
opioid use disorder, patients randomized to receive Prolonged Expo-
sure with financial incentives attended substantially more sessions
and demonstrated significantly greater PTSD symptom reduction
compared with patients in Prolonged Exposure without incentives106.
Regarding motivational enhancement, in one clinical trial, Prolonged
Exposure augmented with motivational enhancement therapy was
not more beneficial than Prolonged Exposure alone with regard to
attendance or PTSD and SUD outcomes72.
Pilot research suggests that implementing trauma-focused ther-
apy with patients in residential SUD treatment shows considerable
promise for improving attendance and outcome. Prolonged Exposure
with nine residential SUD patients with PTSD in one study reduced PTSD
symptoms at post-treatment through 3-month follow-up compared
with treatment as usual (which did not include trauma-focused PTSD
therapy)107. Furthermore, all patients in Prolonged Exposure completed
the entire treatment protocol. The study authors speculated that the
structure and supports inherent to residential treatment helped
patients who might otherwise have dropped out of outpatient care
to complete trauma-focused treatment. However, in addition to the
small sample size of this study, patients were not randomly assigned
to receive Prolonged Exposure or treatment as usual, meaning that
factors other than treatment condition, such as self-selection of pre-
ferred treatment, might have had an impact on the results. Although
integrating trauma-focused therapy into residential SUD treatment
holds significant potential to increase the likelihood of completing
and therefore benefiting from these interventions, studies with larger
samples using a randomized design are needed.
Strategies designed to improve outcomes and attendance in PTSD
treatment might be relevant to PTSD + SUD treatment as well. One
Nature Reviews Psychology
possible strategy is ‘flexing’ the length of therapy (providing addi-
tional sessions and/or offering additional ‘stressor’ sessions when indi-
cated), which might help patients to fully benefit from trauma-focused
therapy108. The trajectories and timing of patient response in trauma-
focused treatments are variable109,110, supporting this flexible approach.
Also consistent with the idea of flexible treatment length, baseline
severity of PTSD and SUD was associated with treatment response and
attendance in several studies77,78,82,83,100,101. Further, baseline comorbidi-
ties influence outcome in PTSD treatment. For example, meta-analysis
of clinical trials for PTSD indicates that greater concurrent depres-
sion severity at the start of treatment is associated with attenuated
response to trauma-focused psychotherapy111. Similarly, in alcohol use
treatment, baseline alcohol consumption and dependence severity
are strong predictors of response, and more severe psychopathology
is associated with worse outcome112. Although trauma-focused treat-
ment protocols typically prescribe 10–12 sessions, a greater number
of sessions — a higher ‘dose’ — might be needed for optimal response
among patients with PTSD + SUD, who typically present with greater
distress, severity, stressors and impairment than patients with PTSD
alone. This flexibility is provided in manualized, trauma-focused treat-
ments. Importantly, although additional sessions might provide one
method to improve outcomes, increasing attendance is required to
leverage this strategy.
Better understanding of patient preferences is another potential
avenue to improve attendance and outcome in PTSD + SUD treat-
ment. In a clinical trial that compared Prolonged Exposure and ser-
traline (an antidepressant medication that is also often effective in
reducing PTSD symptoms) among 200 patients with PTSD, patients
who received the treatment they preferred were more likely to com-
plete treatment and showed better response on PTSD, depression
and anxiety outcomes compared with patients who received their
non-preferred treatment option113. In another study, a 30 min shared
decision-making intervention at the start of treatment was associated
with greater likelihood of preferring trauma-focused treatment and
completion of adequate treatment dose (≥9 sessions) among veterans
with PTSD114. Although patients in the study were randomized to either
the shared decision-making intervention or usual care condition, the
sample of this pilot study was small (n = 27), necessitating replication
in larger samples.
Leveraging social support and close relationships might be another
path to enhance treatment outcomes. In a trial comparing COPE and
relapse prevention69, social support moderated PTSD and SUD out-
comes in both interventions during treatment115. Similarly, there is
preliminary evidence that family involvement in PTSD treatment can
improve attendance. Consistent with this idea, efforts by loved ones
to encourage patients to participate in treatment and face distress
are strongly associated with better attendance in trauma-focused
therapy116. A brief family intervention117 — providing psychoeducation
about PTSD and treatment, generating family member support for
treatment and reducing family symptom accommodation — delivered
as an adjunct to trauma-focused therapy was associated with reduced
dropout rates in a small (20 veteran–partner dyads) pilot randomized
trial118. A full randomized clinical trial for veterans with PTSD evaluat-
ing Prolonged Exposure enhanced through family inclusion compared
with standard Prolonged Exposure is underway (ClinicalTrials.gov
NCT03256227)119.
Another promising strategy to reduce dropout in PTSD treat-
ment is for clinicians to systematically check in with patients about
their intent to continue therapy and problem-solve on the basis of
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Table 4 | Potential strategies to improve treatment outcome

Strategy Description Context studied

Patient-targeted strategies
Contingent monetary
incentives
Adjunctive family
intervention
Shared decision-making
Routine monitoring of
intent to continue therapy
Providing additional
sessions of trauma-focused
therapy
Treatment delivery strategies
Brief exposure-based
treatment models
Trauma-focused therapy in
residential SUD treatment
settings
Massed treatment models
Telehealth
PTSD, post-traumatic stress disorder; SUD, substance use disorder; VA, Veterans Affairs.
In a clinical trial for PTSD and comorbid opioid use disorder, patients randomized Outpatient civilian sample with PTSD and
to trauma-focused therapy with contingent monetary incentives attended more comorbid opioid use disorder (n = 58)106
sessions and reported greater PTSD symptom reduction than those without monetary
incentives
Two-session brief intervention as an adjunct to trauma-focused therapy that included 20 outpatient veterans with PTSD and family
psychoeducation about PTSD and treatment, generating family member support member dyads (n = 40)103
for treatment, and reducing family symptom accommodation was associated with
reduced dropout. This strategy has yet to be tested among patients with PTSD + SUD
In a pilot study, a 30 min shared decision-making intervention at the start of therapy Outpatient veterans with PTSD (n = 27)114
was associated with greater preference for evidence-based treatment and greater
likelihood of attending at least nine sessions of treatment. This strategy has yet to be
tested among patients with PTSD + SUD
Although the data are observational, implementing an intent-to-attend item at the Outpatient active duty service members
end of each session was associated with significantly reduced dropout rate. This with PTSD (n = 108)120
strategy has yet to be tested among patients with PTSD + SUD
In a randomized, controlled, repeated measures, semi-crossover design, 34% of Individuals in outpatient setting with PTSD
patients reached end-state criteria after 12 sessions of modified Cognitive Processing (n = 100)108
Therapy. This strategy has yet to be tested among patients with PTSD + SUD
Written Exposure Therapy, a five-session protocol associated with significantly Systematic review and meta-analysis149;
reduced dropout was more effective than waitlist control in one clinical trial with veterans with PTSD at VA clinics (n = 277)150;
civilians and noninferior to Cognitive Processing Therapy in another clinical trial with veterans (n = 126)151 and civilians (n = 46)152
veterans. This strategy has yet to be tested among patients with PTSD + SUD with PTSD in clinical trials
Provides access to trauma-focused therapy for high-risk patients with SUD in need Veterans with PTSD and SUD in a residential
of residential treatment. Prolonged Exposure, for example, was implemented with SUD treatment programme (n = 30)107
veterans in a residential SUD programme, who attended three sessions per week and
reported significant symptom reduction and high attendance
Data from both clinical trials and effectiveness research show promise in improving Civilians (n = 121)153 and military personnel
response and attendance and maintain strong outcomes when sessions of a (n = 370)154 with PTSD in clinical trials;
treatment protocol were delivered within a shorter time frame (for example, 2 weeks review155
compared with 3–4 months). This strategy has yet to be tested among patients with
PTSD + SUD
Telehealth with trauma-focused treatments has shown strong outcomes that are Veterans with PTSD in clinical trials
comparable to those of traditional, in-person therapy. This strategy has yet to be ((n = 132)156, (n = 207)157, (n = 125)158); female
tested among patients with PTSD + SUD veterans and civilians in a clinical trial
(n = 126)159; review160

patients’ concerns120. In a trial of active duty soldiers receiving trauma-
focused PTSD therapy121, a subset of patients were asked to rate their
likelihood of attending the next session at the end of each session. If a
patient reported low intent, the clinician initiated a problem-solving
discussion with the patient to prevent dropout120. Patients’ intent to
return was predictive of therapy attendance, an effect that has been
observed in treatment studies for other psychiatric disorders122,123,
and patients whose therapists asked about their intent to continue
treatment were half as likely to drop out as those who were not que-
ried. Although it shows preliminary potential in reducing dropout,
this study was observational; a sufficiently powered trial with ran-
dom assignment of patients is needed to ascertain the efficacy of this
approach.
Overall, many of these strategies to improve attendance and out-
come in PTSD treatment have been conducted with small sample sizes,
open trial or observational data designs, and/or have yet to be evalu-
ated among patients with PTSD + SUD. Other novel treatment delivery
models that show preliminary effectiveness in treatment for PTSD
(Box 1) have yet to be tested in populations with comorbid substance
use. Although the discussed strategies show initial promise, adequately
powered studies and random assignment of patients with PTSD + SUD
are needed to evaluate their effectiveness.
Summary and future directions
Despite the effectiveness of trauma-focused interventions for many
patients with PTSD + SUD, these therapies are underused, and this comor-
bidity remains challenging to treat. Psychosocial patient characteristics
do not predict response or attendance consistently across studies, and
patients’ baseline PTSD and SUD severity might be linked to treatment
outcome in nuanced ways (Table 2). Patients who present with more
severe symptoms, greater substance use and greater impairment might
show strong response to trauma-focused treatment78,82,83, yet greater
severity might be associated with worse attendance77,99–101. Evaluation
and dissemination of evidence-based strategies to improve attendance
for these patients — who are likely to be experiencing significant distress
and impairment — are crucial.

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Although relationships between psychosocial patient character-
istics and treatment outcome have not been found, race and cultural
factors should not be ignored. For example, secondary analysis of
a trial that compared COPE and relapse prevention69 indicated that
PTSD and SUD outcomes differed on the basis of ethnoracial group105.
Long-standing disparities in rates of trauma exposure, access to care,
quality of care and representation in clinical trials among individuals
from ethnic and racial minority groups are well documented (Box 2).
These issues reflect a clear imperative to examine factors, particularly
systemic factors, that contribute to treatment outcomes and treatment
completion in underserved individuals.
Another important future direction for research is continued inves-
tigation of within-treatment factors. Variables that are modifiable —
including patient attitudes and beliefs, barriers, motivation, substance
use or avoidant coping strategies124 — are particularly important for
future study. Research on modifiable, within-treatment variables
might help to illuminate the factors that negatively affect treatment
Box 1
Novel interventions and
delivery models
Novel treatments and delivery methods are potential pathways to
improving response and attendance. Briefer treatment interventions
might be optimal for patients at high risk of dropout. For instance,
Written Exposure Therapy is a brief, effective exposure-based
treatment for post-traumatic stress disorder (PTSD) that has
not yet been formally evaluated among patients with PTSD
co-occurring with substance use disorder (PTSD + SUD)151,152. Dropout
is lower in Written Exposure Therapy than in other trauma-focused
treatments151,152 and therefore highly relevant for PTSD + SUD given
high dropout rates in this population. Notably, a similar expressive
writing paradigm was associated with strong adherence and
significant reductions in PTSD symptoms among women with PTSD
in a residential SUD treatment facility161.
Another delivery model yet to be formally tested among
patients with PTSD + SUD is massed trauma-focused treatment,
which typically consists of daily treatment sessions over the
span of 2 weeks, in contrast to typical weekly therapy. Massed
treatment has been associated with substantially reduced dropout.
Massed Prolonged Exposure was evaluated to be noninferior to
weekly Prolonged Exposure on PTSD outcomes, with a lower dropout
rate154. Massed treatment that drastically shortens treatment
duration might be especially relevant and effective among
patients with PTSD + SUD, who often experience considerable
stressors outside of treatment.
Finally, telehealth is comparable in effectiveness to standard,
face-to-face treatment for PTSD156–158,160 and SUD162, but has not
been sufficiently evaluated among patients with PTSD + SUD. Virtual
treatment for patients with PTSD + SUD presents unique challenges
(for example, time and privacy concerns for patients at residential
settings; decreased capacity to gauge patient sobriety), but holds
immense promise to increase access to trauma-focused therapy for
patients with PTSD + SUD.
Nature Reviews Psychology
processes and engagement. Greater precision in identifying modifiable
factors and processes during therapy will provide the potential for
clinicians to promptly identify patients at risk of poor response and
dropout and intervene to prevent these outcomes.
Several additional avenues of future research hold promise in
answering further questions related to prediction and change mecha-
nisms, as well as ultimately improving treatment outcomes. Much of
the research on prediction of outcome in PTSD + SUD treatment has
used models that evaluate single key predictors. However, it is unlikely
that any single variable in isolation will reliably explain individual
differences in treatment outcomes in a clinically meaningful way125.
Models that leverage multiple variables simultaneously might improve
prediction of patient adherence and response to intervention. Taking
advantage of multivariable prediction models — which are likely to
provide more powerful estimates of treatment effects for different
patients — will require larger datasets126. This approach might include
patient-level meta-analysis to provide the statistical power and patient
heterogeneity to evaluate effectiveness between treatments, media-
tors of treatment effects and patient-level moderators of outcome.
To this end, Project Harmony is a study that is currently aggregating
and analysing data from more than 40 independent treatment studies
for PTSD + SUD, including psychotherapy, medication and their com-
bination127. Future research should also leverage large observational
datasets from health-care systems to emulate randomized trials128,129
and compare effectiveness between treatments in real-world settings130
among patients with PTSD + SUD.
Future study of trauma-focused treatments for PTSD + SUD should
also investigate their impact on other markers of recovery, such as
psychosocial functioning. The lack of data on psychosocial functioning
outcomes is concerning because PTSD + SUD is associated with dif-
ferential and often worse baseline functioning than single disorders22
and impairment in psychosocial functioning is an important diagnostic
element. Furthermore, trauma-focused therapy tends to yield smaller
effects for functioning and quality of life outcomes than symptom-
focused measures131. Evaluating functional outcomes in PTSD + SUD
provides a crucial pathway to more comprehensively understand the
real-world impact of treatments on the daily lives of patients.
Clinical trials that evaluate other trauma-focused interventions
for patients with PTSD + SUD are also needed. Prolonged Exposure
and COPE have been the most commonly studied trauma-focused
treatments in clinical trials, whereas less is known about other options,
such as Eye Movement Desensitization and Reprocessing, Cognitive
Processing Therapy, Imagery Rescripting or Written Exposure Therapy.
A randomized clinical trial is underway to compare Eye Movement
Desensitization and Reprocessing, Prolonged Exposure and Imagery
Rescripting in conjunction with SUD treatment among patients with
PTSD + SUD (Netherlands Trial Register, identifier: NL7885)132. Another
need is large comparative effectiveness trials in real-world clinical set-
tings that provide the power to detect subgroup differences. One such
randomized trial is underway, comparing trauma-focused therapy
or non-trauma-focused therapy (present-centred therapy) among
patients with PTSD + SUD receiving concurrent SUD treatment (Clini-
calTrials.gov NCT04581434). Data from these studies will also help
to inform the use of second-line interventions (non-trauma-focused
treatments). There are no current evidence-based recommendations
for treatment following non-response to first-line treatments.
Although evidence regarding pharmacological interventions for
PTSD + SUD is outside the scope of this Review, future clinical trials
should evaluate combination treatments that provide SUD-focused
Review article
Box 2
Treatment challenges in
underserved populations
Little is known regarding post-traumatic stress disorder plus
substance use disorder (PTSD + SUD) treatment attendance and
response among patients from minority racial and/or ethnic
backgrounds and other marginalized identities. These individuals
have been under-represented in clinical trials, with white and male
participants making up most PTSD and PTSD + SUD treatment study
samples33,163–165. Furthermore, small sample sizes and high rates
of attrition mean that individual PTSD + SUD treatment studies are
often underpowered to examine potential differences in treatment
outcome across demographic variables. Systematic reviews of
PTSD + SUD treatment have also been unable to elucidate the ethnic,
racial or gender identity breakdown of participants across studies to
examine whether effectiveness of PTSD + SUD interventions differs
between these groups31,32.
Treatment access and outcomes might differ across race,
ethnicity, sexual orientation and gender identity. For example,
individuals from ethnic and racial minority groups experience
higher rates of trauma and PTSD166–168, yet are less likely to receive
PTSD treatment168–171. For SUD treatment specifically, there are also
disparities in access, treatment completion and quality of care172,173.
Very little is known about PTSD + SUD outcomes in individuals with
intersectional identities, such as women who are also from racial
minority groups.
The lack of knowledge about PTSD + SUD treatment attendance
and outcomes across diverse populations is a crucial gap for future
research. Future research should evaluate when, how and under
what conditions effective treatments should be adapted from
standardized implementation among patients from marginalized
groups to improve outcome174. Ascertaining possible differences in
access, preferences and outcome of existing treatments is crucial
to improving the reach and effectiveness of these interventions for
patients from underserved groups.
133
medication concurrently with trauma-focused therapy . Impor-
tantly, medications are recommended in SUD treatment134, yet remain
underused and understudied in the context of comorbid PTSD135.
Our final recommendation is research with the goal of increasing
the availability and reach of trauma-focused treatments. Given that
trauma-focused interventions for PTSD remain underused45–50, it is
extremely likely that even fewer patients with PTSD + SUD are offered
these treatments in clinical practice. A crucial first step is to gain a more
precise understanding of how often patients in various settings with
PTSD + SUD receive trauma-focused treatments. Although some clini-
cal practice guidelines now recommend trauma-focused treatments for
PTSD + SUD, there is limited knowledge of whether these recommenda-
tions have increased uptake. Second, we strongly recommend research
to identify the patient-level, provider-level and organization-level
barriers (for example, provider beliefs, patient knowledge regarding
evidence-based interventions or provider training opportunities)
Nature Reviews Psychology
specific to treatment of PTSD + SUD that might limit the availability
of trauma-focused treatments.
Patients with PTSD and co-occurring substance use should not
be turned away from first-line, trauma-focused treatments for PTSD,
despite long-standing concerns that processing the trauma would lead
to clinical worsening such as relapse or symptom exacerbation55,136–143.
The relationship between PTSD symptoms and substance use is often
bidirectional and mutually reinforcing, meaning that for many patients,
reducing substance use without PTSD treatment is difficult. Together
with data showing that trauma-focused treatments are safe and effec-
tive for patients with SUD, these findings have fundamentally changed
best practice treatment for patients with PTSD + SUD. Despite the
immense progress to date, crucial work lies ahead to improve the ability
to treat people with comorbid PTSD + SUD.
Published online: xx xx xxxx
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Acknowledgements
The authors thank A. Klein and P. Hitchcock for comments on earlier versions of this
manuscript.
Author contributions
A.C.K. and S.B.N. developed the idea and outline for the manuscript. K.E.P. and R.L. researched
data for the manuscript. All authors contributed substantially to discussion of the content.
All authors wrote the article. All authors reviewed and/or edited the manuscript before
submission.
Competing interests
The authors declare no competing interests.
Additional information
Correspondence should be addressed to Sonya B. Norman.
Peer review information Nature Reviews Psychology thanks Tracy Simpson, Marleen de Waal
and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
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