MDMA-Assisted Therapy for Severe PTSD: A Randomized, Double-Blind, Placebo-Controlled Phase 3 Study

Abstract

Post-traumatic stress disorder (PTSD) presents a major public health problem for which currently available treatments are modestly effective. We report the findings of a randomized, double-blind, placebo-controlled, multi-site phase 3 clinical trial (NCT03537014) to test the efficacy and safety of 3,4-methylenedioxymethamphetamine (MDMA)-assisted therapy for the treatment of patients with severe PTSD, including those with common comorbidities such as dissociation, depression, a history of alcohol and substance use disorders, and childhood trauma. After psychiatric medication washout, participants (n = 90) were randomized 1:1 to receive manualized therapy with MDMA or with placebo, combined with three preparatory and nine integrative therapy sessions. PTSD symptoms, measured with the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5, the primary endpoint), and functional impairment, measured with the Sheehan Disability Scale (SDS, the secondary endpoint) were assessed at baseline and at 2 months after the last experimental session. Adverse events and suicidality were tracked throughout the study. MDMA was found to induce significant and robust attenuation in CAPS-5 score compared with placebo (P < 0.0001, d = 0.91) and to significantly decrease the SDS total score (P = 0.0116, d = 0.43). The mean change in CAPS-5 scores in participants completing treatment was -24.4 (s.d. 11.6) in the MDMA group and -13.9 (s.d. 11.5) in the placebo group. MDMA did not induce adverse events of abuse potential, suicidality or QT prolongation. These data indicate that, compared with manualized therapy with inactive placebo, MDMA-assisted therapy is highly efficacious in individuals with severe PTSD, and treatment is safe and well-tolerated, even in those with comorbidities. We conclude that MDMA-assisted therapy represents a potential breakthrough treatment that merits expedited clinical evaluation. Appeared originally in Nat Med 2021; 27:1025-1033.

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Breakthrough for Trauma Treatment:
Safety and Eicacy of MDMA-
Assisted Psychotherapy Compared
to Paroxetine and Sertraline
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Public Full-text 1
]-E',F
1
September 2019 | Volume 10 | Article 650
REVIEW
doi: 10.3389/fpsyt.2019.00650
published: 12 September 2019
Frontiers in Psychiatry | www.frontiersin.org
Breakthrough for Trauma Treatment:
Safety and Efficacy of MDMA-
Assisted Psychotherapy Compared
to Paroxetine and Sertraline
Allison A. Feduccia 1, Lisa Jerome 1*, Berra Yazar-Klosinski 2, Amy Emerson 3,
Michael C. Mithoefer 4 and Rick Doblin 2
1 Department of Research Development and Regulatory Affairs, MAPS Public Benefit Corporation, Santa Cruz, CA, United
States, 2 Multidisciplinary Association for Psychedelic Studies, Santa Cruz, CA, United States, 3 MAPS Public Benefit
Corporation, Santa Cruz, CA, United States, 4 Department of Psychiatry and Behavioral Sciences, Medical University of
South Carolina, Charleston, SC, United States
Unsuccessfully treated posttraumatic stress disorder (PTSD) is a serious and life-
threatening
disorder.
Two
medications,
paroxetine
hydrochloride
and
sertraline
hydrochloride, are approved treatments for PTSD by the Food and Drug Administration
(FDA). Analyses of pharmacotherapies for PTSD found only small to moderate effects
when
compared
with
placebo.
The
Multidisciplinary
Association
for
Psychedelic
Studies (MAPS) obtained Breakthrough Therapy Designation (BTD) from the FDA for
3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for treatment
of PTSD on the basis of pooled analyses showing a large effect size for this treatment.
This review covers data supporting BTD. In this treatment, MDMA is administered
with psychotherapy in up to three monthly 8-h sessions. Participants are prepared
for these sessions beforehand, and process material arising from the sessions in
follow-up integrative psychotherapy sessions. Comparing data used for the approval of
paroxetine and sertraline and pooled data from Phase 2 studies, MAPS demonstrated
that
MDMA-assisted
psychotherapy
constitutes
a
substantial
improvement
over
available pharmacotherapies in terms of safety and efficacy. Studies of MDMA-assisted
psychotherapy had lower dropout rates compared to sertraline and paroxetine trials. As
MDMA is only administered under direct observation during a limited number of sessions,
there is little chance of diversion, accidental or intentional overdose, or withdrawal
symptoms upon discontinuation. BTD status has expedited the development of MAPS
phase 3 trials occurring worldwide, leading up to a planned submission seeking FDA
approval in 2021.
Clinical
Trial Registration:
www.ClinicalTrials.gov,
identifiers
NCT00090064,
NCT00353938, NCT01958593, NCT01211405, NCT01689740, NCT01793610.
Keywords: methylenedioxymethamphetamine, posttraumatic stress disorder, breakthrough therapy, sertraline,
paroxetine, anxiety
Edited by:
Felix Müller,
University Psychiatric Clinic Basel,
Switzerland
Reviewed by:
Tomislav Majic,
Charité–Universitätsmedizin Berlin,
Germany
Katrin H. Preller,
University of Zurich,
Switzerland
*Correspondence:
Lisa Jerome
ilsa@mapsbcorp.com
Specialty section:
This article was submitted to
Psychopharmacology,
a section of the journal
Frontiers in Psychiatry
Received:
26 June 2019
Accepted:
13 August 2019
Published:
12 September 2019
Citation:
Feduccia!AA, Jerome!L,
Yazar-Klosinski!B, Emerson!A,
Mithoefer!MC and Doblin!R (2019)
Breakthrough for Trauma Treatment:
Safety and Efficacy of MDMA-
Assisted Psychotherapy Compared
to Paroxetine and Sertraline.
Front. Psychiatry 10:650.
doi: 10.3389/fpsyt.2019.00650
]-E',9
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Feduccia et al.
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September 2019 | Volume 10 | Article 650
Frontiers in Psychiatry | www.frontiersin.org
INTRODUCTION
Breakthrough therapy designation (BTD) is one of the Food
and Drug Administration’s (FDA) expedited drug development
pathways. To be eligible for BTD, a sponsor must demonstrate
that the investigational product is intended to treat a serious
and life-threatening condition, with preliminary evidence
supporting a substantial advantage at a clinically significant
endpoint over existing drugs (1). On August 16, 2017, the FDA
granted breakthrough therapy designation for MDMA-assisted
psychotherapy for the treatment of posttraumatic stress disorder
(PTSD). This application was among the 45% of applications
granted BTD status in 2017 ( 2). The aim of this review is to
summarize the data and rationale presented in the application
that led FDA to grant this designation.
PTSD is considered a serious and life-threatening disorder
and is associated with increased mortality, cardio-metabolic
morbidity,
and
suicide
risk.
PTSD
negatively
impacts
a
person’s daily life, often resulting in fractured relationships,
depression, decreased daily functioning, diminished cognitive
and psychosocial functioning, substance abuse, and high-cost
healthcare utilization ($34.9 billion in inflation-adjusted charges
for hospitalizations (2002–2011) ( 3). Approximately 7% of the
U.S. population, and 11.2–17.1% of veterans (4), will have PTSD
sometime in their life (5).
Only two drugs, the selective serotonin reuptake inhibitors
(SSRIs)
sertraline
hydrochloride
(Zoloft)
and
paroxetine
hydrochloride (Paxil), are approved oral medications for PTSD
(6–8). These medications and trauma-focused psychotherapies
(e.g., eye movement desensitization, cognitive processing therapy,
prolonged exposure) are recommended as first-line treatments
for PTSD ( 9–12). In a meta-analysis evaluating psychotherapy
versus
pharmacotherapy,
trauma-focused
psychotherapies
resulted
in
greater
and
longer
lasting
improvements
than
medications ( 12). Meta-analyses and network meta-analyses
found paroxetine, but not sertraline, performed better than
placebo ( 13, 14). Hoskins and colleagues reported that SSRIs
had a small effect size with respect to PTSD symptom reduction.
When compared to a control group, SSRIs either had insignificant
effects or small/moderate effects, while trauma-focused therapies
varied from small to large effects ( 12). The average dropout
rate for the 55 studies included in the meta-analysis was 29%
(0–79%) demonstrating that many individuals fail to tolerate or
respond to available treatments (12), including trauma-focused
psychotherapies, where the dropout can range from 28 to 68%
(15, 16). A network meta-analysis reported that dropout rate for
paroxetine and sertraline was greater than placebo (14).
The Multidisciplinary Association for Psychedelic Studies
(MAPS)
holds
an
Investigational
New
Drug
Application
(IND)
for
MDMA
as
an
adjunct
to
psychotherapy
for
treatment of PTSD. MAPS has sponsored six phase 2 trials
of MDMA-assisted psychotherapy for PTSD that lasted from
April 2004 to March 2017. The safety and efficacy results from
these trials were submitted to the FDA, along with a summary
of the sertraline and paroxetine data that supported the New
Drug Application (NDA) for approval of these drugs for
the indication of PTSD. Sertraline and paroxetine summary
data was extracted from documents found in the FDA drug
database, including the Review and Evaluation of Clinical
Data and the drug labels (17–20).
Here,
we
present
the
evidence
included
within
the
breakthrough therapy application showing that MDMA-assisted
psychotherapy was superior in phase 2 trials in terms of safety
and efficacy compared to the two approved SSRIs for treatment
of PTSD. The control groups in the MDMA trials also received
intensive psychotherapy (approximately 30 h), while SSRIs
pivotal trials used a placebo without any type of therapy for
comparison. Since the FDA does not regulate psychotherapy, the
BT application did not compare MDMA-assisted psychotherapy
to trauma-focused therapies. However, since trauma-focused
therapies have evidence for the greatest effectiveness in reducing
PTSD symptoms, we have included an additional section in this
review comparing MDMA-assisted-psychotherapy with first-line
psychological therapies.
EFFICACY AND DURABILITY OF
RESPONSE: MDMA VS. SSRIS
MDMA-Assisted Psychotherapy
MDMA is a ring-substituted phenethylamine that is classified
as an entactogen in the Merck Index ( 21) due to its properties
that can promote empathy and compassion for self and others.
MDMA stimulates release of serotonin, norepinephrine and
dopamine, and may act directly on some adrenergic, cholinergic,
and serotonergic receptors ( 22). MDMA elevates levels of the
neurohormone oxytocin, an effect likely mediated through direct
or indirect action on 5HT1A, 5HT2A, and 5HT4 receptors (23–
25), as well as elevating levels of prolactin, arginine vasopressin
(AVP), adrenocorticotrophic hormone (ACTH), and cortisol
(26–29). MDMA possesses a unique pharmacodynamic profile in
humans that includes increased emotional empathy, an increase
in feelings of interpersonal closeness, greater prosocial behavior,
and an increased ability to tolerate distressing memories, greater
reward from pleasant memories, and less distress in response to
social exclusion ( 30–34). Imaging studies found that MDMA
reduced activity in brain areas associated with anxiety, including
the amygdala, and increased activity in prefrontal cortex (35–37).
Hypotheses for MDMA’s therapeutic action include enhanced
fear extinction, memory reconsolidation, enhanced therapeutic
alliance, widening a window of tolerance for distressing thoughts
or experiences, and re-opening or enhancing a critical period
for experiencing social reward ( 25, 38, 39). It is likely through
these effects that MDMA augments and enhances effectiveness
of psychotherapy.
Investigators have developed standardized psychotherapeutic
methods for combining MDMA and psychotherapy that include
up to 3 sessions with MDMA and up to 12 non-drug sessions.
During preparatory sessions participants meet with the two
co-therapists, usually one male and one female, when they
discuss their goals, and concerns, and learn what to expect
during the MDMA-assisted session. The psychotherapy during
MDMA-assisted sessions is relatively non-directive, supporting
the
participants
spontaneous
experience,
and
designed
to
]-E',;
Breakthrough for Trauma Treatment
Feduccia et al.
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September 2019 | Volume 10 | Article 650
Frontiers in Psychiatry | www.frontiersin.org
facilitate processing of challenging emotions in a safe and
controlled setting (40–44). Participants may use eye shades, and
may listen to a program of music designed to support the therapy.
Periods of inner focus alternate with periods of talking to the
therapists. Vital signs are assessed periodically. Material arising
during MDMA-assisted psychotherapy sessions is integrated in
subsequent psychotherapy visits. Subsequently, participants are
encouraged to make time to explore and express their unfolding
experience using journaling or artwork. Participants in Phase 2
studies were contacted for 7 days after each experimental session.
More information concerning MDMA-assisted psychotherapy
can be found in publications and in the MDMA Treatment
Manual (42). Studies with a long term follow up demonstrate
durable improvement in PTSD ( 41, 43–45), social anxiety in
autistic adults ( 46), and anxiety associated with facing a life
threatening illness (22, 38).
Phase 2 Trials of MDMA-Assisted
Psychotherapy for PTSD Treatment
The six Phase 2 studies of MDMA-assisted psychotherapy
that
supported
the
breakthrough
application
followed
a
randomized,
double-blind,
placebo-controlled
design
with the Clinician-Administered PTSD Scale for DSM-IV
(CAPS-IV) as the primary efficacy measure ( 41, 44, 45,
47, 48). The CAPS-IV is an established measure of PTSD
symptoms (49, 50). To enroll, participants were required to
have a CAPS-IV total severity score of 50 or greater and to
have failed to respond to or tolerate at least one course of
treatment. The average duration of PTSD was 17.9 years.
The basic study design for the six studies included three
preparatory psychotherapy sessions, followed by 2–3 blinded,
8-h experimental psychotherapy sessions with MDMA (75–
125 mg) or comparator/placebo (0–40 mg MDMA), and three
90-min non-drug integrative psychotherapy visits following
each
experimental
session.
Experimental
sessions
were
scheduled approximately a month apart. Independent Raters
(not present during treatment, blinded to group assignment)
administered CAPS-IV at baseline, primary endpoint (3–8
weeks after two blinded sessions, or after three sessions in
one study), and secondary endpoints (time points during the
open-label crossover and at the 12-month follow-up).
Data was pooled across the six phase 2 studies (
Table 1
).
Results showed that the active dose group (MDMA 75–125 mg,
n = 72) was statistically superior to the control group (0–40 mg,
n = 31) at the primary endpoint (independent samples t-test,
p!<!0.001), with average (SD) drop in CAPS-IV total scores −37.8
(29.29) for the active group and −11.6 (17.93) for the control
group. There was large between-group Cohen’s
d
effect size (0.9).
Prior to enrollment in MAPS-sponsored Phase 2 trials, 17
and 35 subjects (of n = 105) had previously taken paroxetine and
sertraline, respectively (
Table 2
). Twelve participants had tried
both SSRIs. These individuals did not reach adequate symptom
reduction or failed to tolerate the SSRIs. From this subset,
20/38 (52.6%) subjects that received active doses of MDMA
(75–125! mg) no longer met criteria for PTSD at the primary
endpoint. The average drop in CAPS-IV total scores was −40.1
(25.66) for participants who had previously taken paroxetine and
−35.04 (27.5) in participants who had previously taken sertraline
(
Table 2
). The other 14 subjects were randomized to the control
group. The high response rate and large drops in CAPS-IV total
score in this subset suggests that MDMA therapy may be able
to effectively treat PTSD in individuals who do not adequately
respond to SSRIs.
Sertraline Phase 3 Trials for PTSD
Sertraline was investigated by Pfizer for treatment of PTSD in
four studies of similar design with a 12-week flexible dose (50,
100, 150, and 200 mg with 25 mg starting dose for titration)
(17, 20). Subjects who met DSM-III-R criteria with a CAPS-2
total score of 50 or greater were enrolled. Patients had a mean
duration of PTSD for 12 years and 44% of patients also had a
depressive disorder. Two of the four studies failed to find a
significant difference between the sertraline and placebo treated
groups on any of the primary efficacy outcomes. One study
(640, n = 208) reported efficacy on CAPS-2 total score at week
12 [last observation carried forward (LOCF) method, p = 0.043]
but not week 12 [observed case (OC)] or any earlier weeks.
Placebo-subtracted effect size was 0.31, with a 6.8 point mean
difference between groups in CAPS-2 total score (LOCF). The
other study (671, n = 183) detected efficacy (OC) of sertraline at
weeks 2 (p!=!0.041), 4 (p = 0.0002), 6 (p = 0.011), 8 (p = 0.006),
TABLE 2 |
Mean change from baseline to the primary endpoint in CAPS-IV
total scores in MAPS-sponsored phase 2 subjects who had previously taken
sertraline, paroxetine, or both.
Paroxetine
n = 17
Sertraline
n = 35
Paroxetine/
sertraline
n = 12
Control group, mean
(SD)
(MDMA 0–40 mg)
−21.0 (24.01)
n = 4
−15.9 (16.87)
n = 10
−30.3 (18.50)
n = 3
Active group
(MDMA 75–125 mg)
−40.1 (25.66)
n = 13
−35.04 (27.5)
n = 25
−38.2
(29.90)
n = 9
TABLE 1 |
Pooled CAPS-IV data from six phase 2 MAPS-sponsored studies of
MDMA-assisted psychotherapy.
Active group
(MDMA 75–125 mg)
N = 72
Control group
(MDMA 0–40 mg)
N = 31
Change in CAPS-IV total scores a,
mean (SD)
−37.8 (29.29)
−11.6 (17.93)
Cohen’s
d
effect sizeb
1.5
0.6
Dropouts, n (%)c
5 of 74 (6.8%)
3 of 31 (9.7%)
aChange in CAPS-IV scores from baseline to the primary endpoint (1–2 months post
2–3 MDMA sessions).
bWithin-group Cohen’s d effect size calculated by dividing the change from baseline to
primary endpoint by the standard deviation.
cFor the active group, 3 terminated early but completed an endpoint assessment and
2 terminated early with no endpoint assessments. For the control group, 3 terminated
early but completed an endpoint assessment.
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Breakthrough for Trauma Treatment
Feduccia et al.
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September 2019 | Volume 10 | Article 650
Frontiers in Psychiatry | www.frontiersin.org
10 (p!=!0.04), and 12 (p = 0.016) on CAPS-2 but only in females
which was influenced by mood improvement.
A combined analysis of the two positive studies found a
significant difference between sertraline and placebo groups only
in women but not in men. Results suggest much of the effect
on PTSD scales correlated with improvement in the HAM-D,
therefore it is unclear whether sertraline treats PTSD or comorbid
depression, an indication the drug was already approved for. The
report stated that there was insufficient evidence to support any
efficacy claim beyond 3 weeks of treatment. However, a longer-
term study that randomized responders (n = 96) in a 24-week
open-label continuation trial of sertraline (50–200 mg/day), or
switched to placebo for 28 weeks, found significantly reduced
relapse rates for the sertraline group, in both males and females.
Paroxetine Phase 3 Trials for PTSD
Paroxetine
(20–50
mg/day)
demonstrated
superiority
over
placebo on change from baseline for the CAPS-2 total score
in two multicenter, placebo-controlled studies in adults who
met DSM-IV criteria for PTSD. The trials were sponsored by
GlaxoSmithKline ( 18, 51). In these studies, 858 patients had
PTSD symptoms with duration on average of 13 years. Major
depressive disorder was present in 41% of patients and non-
PTSD anxiety disorder was reported for 40% of patients. Primary
outcomes were change from baseline to endpoint on CAPS-2
total score and the proportion of responders assessed by the
Clinical Global Impression-Global Improvement Scale (CGI-I),
a 3-item observer-rated scale.
In Study 1 (20 and 40 mg) and Study 2 (20 and 50 mg),
paroxetine
was
significantly
superior
to
placebo
on
both
outcome measures. In Study 1 (n = 551), paroxetine was better
than placebo (p < 0.001) at 4, 8, and 12-week time points for
the LOCF and OC analyses. 71% of 40 mg paroxetine and 76%
of 20 mg paroxetine treated patients met response criteria on
CGI-I compared to 48% of placebo (p < 0.001). The difference
between paroxetine and placebo groups on CAPS-2 total score
was approximately 14 units for LOCF and OC analyses for both
dose groups. In Study 2 (n = 307), paroxetine was better than
placebo (p < 0.001) at 12-week time point for the LOCF and OC
analyses. 76% of paroxetine treated patients met response criteria
on CGI-I compared to 50% of placebo (p < 0.001). The difference
between paroxetine and placebo groups on CAPS-2 total score
was approximately 11 units for LOCF and 14 units for OC.
A third study with flexible doses (20–50 mg) found paroxetine
to be significantly better than placebo on CAPS-2 total score,
but not on CGI-I responders (defined as patients having a
score of! 1 “very much improved” or 2 “much improved”). In
Study 3 (n!=!322), CAPS-2 total score was statically superior in
paroxetine group compared to placebo for LOCF (p = 0.047) but
not OC analysis (p = 0.071) at the 12-week time point. On the
CGI-I, 60% of paroxetine treated subjects met response criteria
compared to 52% of placebo (not statistically significant). The
difference between paroxetine and placebo groups on CAPS-2
total score was approximately 6 units for LOCF and OC
analysis. Analyses did not detect any differences in gender on
treatment!outcomes.
The difference in CAPS-2 total scores between paroxetine and
placebo in mean change from baseline at 12 weeks was roughly
6-14 units across the three studies. According to the drug label,
the efficacy of paroxetine to treat PTSD beyond 12 weeks had
not been investigated in controlled clinical trials, yet PTSD is a
chronic condition.
Comparison: SSRIs vs. MDMA
Primary efficacy evaluation of six MAPS-sponsored phase 2!trials
on change from Baseline to Primary Endpoint in CAPS-IV
Total Severity indicated a significant effect of MDMA over the
comparator group (p < 0.001), with a large between-group effect
size (0.9 Cohen’s
d
effect size) that was approximately double that
of paroxetine (0.45–0.56) and triple that of sertraline (0.31–0.37).
In comparison of mean change in CAPS total scores, placebo
subtracted scores for sertraline ranged from 6.8–9.8 units, for
paroxetine 6–14 units, and for MDMA 26.2 units (
Table 3
).
The fact that the control group in MDMA studies received the
same intensive psychotherapy as the active dose group adds to
the clinical significance of these differences. Results from MAPS-
sponsored MP-1 study detected significant (p = 0.013) difference
between MDMA (125 mg) and placebo groups on CAPS-IV total
scores 3–5 days after the first experimental session, demonstrating
a rapid clinical response after a single MDMA dose. SSRIs require
at least 2 weeks of daily dosing with dose titrations to produce
any detectable PTSD symptom improvements, and one pivotal
TABLE 3 |
Comparison of sertraline, paroxetine, and MDMA mean CAPS reduction LOCF, intent-to-treat.
Sertraline
Paroxetine
MDMA
CAPS-2 (sertraline–
placebo)a
Dropout %
CAPS-2 (paroxetine–
placebo)a
Dropout %
CAPS-IV (MDMA–
control)b
Dropout %
Study 1
−6.8
(effect size 0.31)
29.3%
−14
(effect size 0.56)
35.5%
−26.2
(effect size 0.9)
7.6%
Study 2
−9.8
(effect size 0.37)
28.4%
−11
(effect size 0.45)
39.0%
—
Study 3
—
−6
(effect size 0.09)
33.0%
—
aEffect sizes were not reported in FDA statistical package for paroxetine. Placebo subtracted effect. Size were determined from CAPS scores by calculating the change from baseline
divided by the standard deviation.
bPrimary endpoint was 1–2 months after 2–3 blinded experimental sessions.
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