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S.08.06 MDMA-assisted psychotherapy for PTSD: A promising novel experimental treatment moving into phase 3 trials with FDA breakthrough therapy designation



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1September 2019 | Volume 10 | Article 650
doi: 10.3389/fpsyt.2019.00650
published: 12 September 2019
Frontiers in Psychiatry |
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:, 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,
Reviewed by:
Tomislav Majic,
Charité–Universitätsmedizin Berlin,
Katrin H. Preller,
University of Zurich,
Lisa Jerome
Specialty section:
This article was submitted to
a section of the journal
Frontiers in Psychiatry
Received: 26 June 2019
Accepted: 13 August 2019
Published: 12 September 2019
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
Breakthrough for Trauma TreatmentFeduccia et al.
2September 2019 | Volume 10 | Article 650Frontiers in Psychiatry |
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). is application was among the 45% of applications
granted BTD status in 2017 (2). e 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
persons daily life, oen resulting in fractured relationships,
depression, decreased daily functioning, diminished cognitive
and psychosocial functioning, substance abuse, and high-cost
healthcare utilization ($34.9 billion in ination-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
(68). ese medications and trauma-focused psychotherapies
(e.g., eye movement desensitization, cognitive processing therapy,
prolonged exposure) are recommended as rst-line treatments
for PTSD (912). 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 eect size with respect to PTSD symptom reduction.
When compared to a control group, SSRIs either had insignicant
eects or small/moderate eects, while trauma-focused therapies
varied from small to large eects (12). e 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 (1720).
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 ecacy compared to the two approved SSRIs for treatment
of PTSD. e 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 eectiveness in reducing
PTSD symptoms, we have included an additional section in this
review comparing MDMA-assisted-psychotherapy with rst-line
psychological therapies.
MDMA-Assisted Psychotherapy
MDMA is a ring-substituted phenethylamine that is classied
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 eect 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
(2629). MDMA possesses a unique pharmacodynamic prole 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 (3034). Imaging studies found that MDMA
reduced activity in brain areas associated with anxiety, including
the amygdala, and increased activity in prefrontal cortex (3537).
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 eects that MDMA augments and enhances eectiveness
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. e psychotherapy during
MDMA-assisted sessions is relatively non-directive, supporting
the participants spontaneous experience, and designed to
Breakthrough for Trauma TreatmentFeduccia et al.
3September 2019 | Volume 10 | Article 650Frontiers in Psychiatry |
facilitate processing of challenging emotions in a safe and
controlled setting (4044). 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 aer 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, 4345), 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. ere was large between-group Cohen’s d eect 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. ese 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. e 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). e other 14 subjects were randomized to the control
group. e high response rate and large drops in CAPS-IV total
score in this subset suggests that MDMA therapy may be able
to eectively treat PTSD in individuals who do not adequately
respond to SSRIs.
Sertraline Phase 3 Trials for PTSD
Sertraline was investigated by Pzer for treatment of PTSD in
four studies of similar design with a 12-week exible 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 nd a
signicant dierence between the sertraline and placebo treated
groups on any of the primary ecacy outcomes. One study
(640, n = 208) reported ecacy 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 eect size was 0.31, with a 6.8 point mean
dierence between groups in CAPS-2 total score (LOCF). e
other study (671, n = 183) detected ecacy (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.
n = 17
n = 35
n = 12
Control group, mean
(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
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 sizeb1.5 0.6
Dropouts, n (%)c5 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.
Breakthrough for Trauma TreatmentFeduccia et al.
4September 2019 | Volume 10 | Article 650Frontiers in Psychiatry |
10 (p=0.04), and 12 (p = 0.016) on CAPS-2 but only in females
which was inuenced by mood improvement.
A combined analysis of the two positive studies found a
signicant dierence between sertraline and placebo groups only
in women but not in men. Results suggest much of the eect
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. e
report stated that there was insucient evidence to support any
ecacy 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 signicantly 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. e 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 signicantly 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). e dierence
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). e dierence
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 exible doses (20–50 mg) found paroxetine
to be signicantly better than placebo on CAPS-2 total score,
but not on CGI-I responders (dened 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 signicant). e
dierence between paroxetine and placebo groups on CAPS-2
total score was approximately 6 units for LOCF and OC
analysis. Analyses did not detect any dierences in gender on
e dierence 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 ecacy 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 ecacy evaluation of six MAPS-sponsored phase 2trials
on change from Baseline to Primary Endpoint in CAPS-IV
Total Severity indicated a signicant eect of MDMA over the
comparator group (p < 0.001), with a large between-group eect
size (0.9 Cohen’s d eect 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).
e fact that the control group in MDMA studies received the
same intensive psychotherapy as the active dose group adds to
the clinical signicance of these dierences. Results from MAPS-
sponsored MP-1 study detected signicant (p = 0.013) dierence
between MDMA (125 mg) and placebo groups on CAPS-IV total
scores 3–5 days aer the rst experimental session, demonstrating
a rapid clinical response aer 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–
Dropout % CAPS-2 (paroxetine–
Dropout % CAPS-IV (MDMA–
Dropout %
Study 1 −6.8
(effect size 0.31)
29.3% −14
(effect size 0.56)
35.5% −26.2
(effect size 0.9)
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.
Breakthrough for Trauma TreatmentFeduccia et al.
5September 2019 | Volume 10 | Article 650Frontiers in Psychiatry |
study of sertraline and one of paroxetine did not nd signicant
improvement until aer 12 weeks of daily drug administration.
e benecial eects of MDMA-assisted psychotherapy have
been shown to last for at least 12 months in many participants
(67.8% of n = 90 did not meet diagnostic criteria), while
paroxetine (12 weeks) and sertraline (3 weeks) drug labels
specify that long-term ecacy was not assessed. Sertraline was
only shown to statistically signicant in women and not men,
while MDMA has been eective for both males and females with
no dierence in response measured
Sertraline and paroxetine demonstrated superiority on the
CAPS-2 over placebo in two 12-week pivotal trials which led
to a new marketing label for the indication of PTSD. Both had
small to medium placebo-subtracted eect sizes (0.31–0.37 and
0.45–0.56, respectively) and require daily dosing for 12 weeks.
e dropout rate in active (75–125 mg blinded) MDMA-treated
subjects in MAPS-sponsored Phase 2 trials was 6.8% (5 of 74,
with 2 excluded for missing outcome data and 3 excluded for
early termination, with outcome data), considerably less than
SSRI trials where dropout rates were 11.7% in paroxetine-
treated and 28% in sertraline-treated subjects, indicating that
MDMA is better tolerated by a PTSD population than the two
SSRIs. Reduced drop-out rates in MAPS’ Phase 2 studies may
result from a strong therapeutic alliance, and commitment to
the course of psychotherapy, as well as the therapeutic eects
of MDMA. On the other hand, dropout rates (3 of 31, 9.7%)
were also low for the control group which could reect some
benet from the psychotherapy alone, or increased motivation
to remain in the study to receive active MDMA during the
open-label crossover segment.
In paroxetine trials, the most common adverse events (5% or
greater and at least 2× that of placebo) in the PTSD population
were: asthenia, sweating, nausea, dry mouth, diarrhea, decreased
appetite, somnolence, libido decreased, abnormal ejaculation,
female genital disorders, and impotence. Reported by 19% of
subjects, nausea was the most frequently experienced treatment-
emergent adverse event. For sertraline, the most common
eects were nausea, headache, insomnia, diarrhea, dry mouth,
ejaculation failure, somnolence, dizziness, and fatigue.
Administering MDMA in single doses spaced a month
apart in a controlled setting has several inherent benets
over chronic daily dosing of paroxetine or sertraline. Firstly,
compliance is not an issue in studies of MDMA, because all
dosing occurs in a clinic under supervision, whereas SSRIs
rely on patients self-administering daily doses which can be
a challenge due to cognitive and behavioral impairments that
can accompany PTSD (52).
Secondly, fewer side eects are reported aer MDMA due
to the limited number of administrations. Phase 2 safety data
showed that reactions were reported most frequently on the
day of MDMA administration and typically diminished in the
few days following. e most commonly reported reactions on
the day of the experimental session were anxiety, tight jaw/jaw
clenching, lack of appetite, headache, and fatigue (48). On the day
of blinded experimental sessions, reactions reported by the active
MDMA group by at least 2x of the frequency of the control group
were diarrhea, diculty concentrating, dizziness, heavy legs,
impaired gait/balance, jaw clenching/tight jaw, lack of appetite,
nausea, nystagmus, paresthesia, perspiration, sensitivity to cold,
thirst, and weakness. ese ndings are in line with clinical
trials in healthy controls (53, 54). On the other hand, patients
taking paroxetine and sertraline experience more prolonged
adverse reactions due to steady state drug plasma levels across
the 12-week treatment period.
Discontinuation of paroxetine and sertraline may be
accompanied by adverse effects (55), likely caused by
neuroadaptations of decreased levels of serotonin transporters in
neuronal membranes aer use of SSRIs (56). For discontinuation
of sertraline and paroxetine gradual tapering is recommended,
and patients should be monitored for discontinuation emergent
symptoms, which can be very troubling. Adverse events during
discontinuation (incidence of 2% or greater for paroxetine and
at least 2x that of placebo) were abnormal dreams, paresthesia,
and dizziness, and for sertraline, they were nausea, insomnia,
and diarrhea (18, 20). Post-marketing surveillance identied a
number of additional discontinuation emergent negative eects,
including sensory disturbances, agitation, anxiety, nausea,
and sweating; however causal relationship to drug hasn’t been
Single doses of MDMA have not produced discontinuation
symptoms. Some adverse reactions are reported during the 7
days following an MDMA dose, including anxiety, dizziness,
depressed mood, fatigue, headache, jaw clenching or tightness,
lack of appetite, nausea, and panic attack (48). By Day 5, the
only reactions reported in over 20% of active dose participants
were fatigue and anxiety. Both were reported by nearly equal
numbers of active and control dose participants. Symptoms were
mild to moderate in severity, and nearly all resolved within 7
days of dosing. Eight participants in the active dose group and
three in the control group, reported a reaction on the seventh
day of follow-up (not seven consecutive days of experiencing
the reaction) that was therefore recorded as an adverse event
(AE). Reactions tting AE criteria and reported by more than
two participants were anxiety and low mood, occurring in both
active and control groups. Both are prominent symptoms of
PTSD. Only three participants had the same reaction on day of
experimental session and 7 days following the session, which
included anxiety, low mood, and muscle tension.
Estimating risk of long-term deleterious eects of discrete
doses of MDMA in a controlled setting compared to retrospective
studies in people reporting ecstasy use is inappropriate for several
reasons. Ecstasy can contain an unknown quantity of MDMA
and adulterants, or no MDMA at all, and most people ingesting
MDMA are polydrug users. Most studies are retrospective,
with only a single prospective study reported detecting signs of
a specic impairment in verbal memory in a sample of people
reporting nonmedical use, without detecting any functional or
structural changes in the brain (57, 58). Systematic reviews of the
literature found that most research enrolls people whose lifetime
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6September 2019 | Volume 10 | Article 650Frontiers in Psychiatry |
use far exceeds the average (5961). In contrast, cognitive
function in three trials of MDMA-assisted psychotherapy failed
to nd impairment aer any dose of MDMA (48). When asked
about ‘ecstasy’ use at 12-month follow-up aer participation in a
Phase 2 trial, eight participants, six of whom had taken ecstasy
prior to enrollment, reported having used it one to three times.
is indicates that MDMA given in the context of psychotherapy
does not have high abuse liability (41, 43, 44, 47, 62).
An additional risk of SSRIs is that t hey are contraindicated with
MAOIs and some other drugs due to inhibition of P450 enzymes.
Since these drugs are take-home medications, patients are at risk
of accidentally consuming a contraindicated medication that
could have serious adverse eects, including deat h. Accident al and
intentional overdoses have been reported with both SSRIs (63).
Since clinicians collect concomitant medication information at
each session before administering MDMA, the risk for accidental
use of a contraindicated medication is far reduced, and risk of
overdose is eliminated by dispensing only the recommended
dosage by a prescribing physician. B oth SSRI drug labels state that
alcohol is not recommended, but given that a signicant number
of people with PTSD also have comorbid alcohol use disorders,
refraining from alcohol may be particularly problematic for this
population and lead to negative eects (64, 65).
MDMA-assisted psychotherapy received BTD based on its
use in treating PTSD, a serious and life-threatening condition,
and on the basis of phase 2 clinical data that MDMA produced
substantial clinical improvement and greater compliance than
the two approved drugs for PTSD, paroxetine and sertraline.
Data from Phase 2 provides evidence that PTSD, independent
of cause, is treatable with 2 to 3 sessions of MDMA-assisted
psychotherapy, and oers a larger treatment eect, increased
compliance and lower risk of dropout, reduced possibility of
drug interactions compared to paroxetine and sertraline. ere
have been no deaths related to MDMA in controlled Phase
1 and 2 studies, and if it is approved for clinical use, MDMA
will be administered directly to patients, and only in licensed
MDMA clinics under controlled conditions similar to those in
clinical research. e single-dose regimen of MDMA produces
fewer, self-limiting, transient side eects and greater compliance
compared to daily dosing of paroxetine and sertraline.
In meta-analyses comparing efficacy of PTSD treatments
investigated in randomized controlled trials, trauma-focused
psychotherapies generally result in greater and more sustained
response than pharmacotherapies and other psychological
therapies (12, 66). Lee et al. report comparative eect sizes
from meta-analyses of randomized trials that included a control
condition, with controls for psychotherapy trials including
supportive psychotherapy, biofeedback, and relaxation training,
and excluding those with waitlist and treatment-as-usual
controls. Compared to control, aer 14–27 weeks of trauma-
focused therapies the eect size was −0.96. For all medications,
which included SSRIs, SNRIs, antiepileptics, antipsychotics, the
eect size was −0.44. e magnitude of eect (0.9) of MDMA-
assisted psychotherapy is in the range of rst-line trauma-focused
therapies. MDMA was compared to psychotherapy alone, or low
dose MDMA plus psychotherapy, as the control condition and
Phase 2 studies enrolled only participants who had previously
tried and failed to respond to or tolerate available treatments.
Beyond the quantifiable change of PTSD symptoms,
the degree to which MDMA supports the unfolding of a
healing experience through neurochemical changes should
be considered. Biochemically inducing a mental state more
receptive to engaging in deep therapeutic processing could
help to speed up symptom improvement or improve treatment
outcomes for those resistant to other therapies. ere is some
evidence from nonclinical experiments that MDMA may
increase neuroplasticity through BDNF-dependent mechanism
(67), and otherwise alter brain activity in key networks for
emotional-memory processing (30). Psychologically, MDMA
may ease the challenge of recalling traumatic memories and
feeling deeply into the associated emotions. Posttraumatic
growth measured by the Posttraumatic Growth Inventory
(PTGI), and personality shis measured by the NEO Personality
Prole have been observed aer MDMA-assisted psychotherapy
(43, 68). In addition, the importance of patient choice regarding
therapy for PTSD has been pointed out, and MDMA-assisted
psychotherapy may oer advantages in this area if it makes
processing trauma less arduous (69).
Another recent meta-analysis paper, found no signicant
dierences in benets of pharmacological, psychotherapeutic,
or the combination at the end of treatment, except at the last
available endpoint during long-term follow-up, at which point
psychotherapeutic treatments were signicantly better than
medications. In this analysis, the combined treatments, which
included one MDMA-assisted psychotherapy trial, were slightly
but not signicantly more benecial than psychotherapeutic
treatments alone (66). Data from the other ve phase 2 MDMA
trials were not included, and the outcome from the MDMA trial
was analyzed along with other medication-therapy combinations
(e.g., SSRIs and CBT). Until MDMA-assisted psychotherapy
is compared to trauma-focused therapies in a randomized
trial, it is uncertain whether either approach is superior in
terms of ecacy or tolerance. ough it may potentially have
greater risks and increased likelihood of mild to moderate
adverse events compared with non-drug therapies, MDMA has
thus far demonstrated a favorable safety prole with limited
administrations in clinical settings. Patient experience of each
therapy, time to respond, and durability of response should be
evaluated. Future research could also explore whether MDMA
combined with existing manualized trauma-focused therapies
potentiates PTSD symptom reduction.
BTD is intended to expedite the development and approval of
promising treatments by allowing for more frequent interactions
Breakthrough for Trauma TreatmentFeduccia et al.
7September 2019 | Volume 10 | Article 650Frontiers in Psychiatry |
with the FDA, rolling review of documents, and the possibility
for priority review (6 months rather than the normal 10-month
review period) (1). BTD also receives an organizational
commitment from the FDA with more guidance and involvement
of FDA senior managers for ecient drug development.
Aer receiving BTD for this program, MAPS and the FDA also
reached agreement under the Special Protocol Assessment (SPA)
process for the design of two multi-site Phase 3 trials (MAPP1
and MAPP2) of MDMA-assisted psychotherapy for patients with
at least severe PTSD. ese two pivotal Phase 3 trials will enroll
approximately 200-300 participants at sites in the USA, Canada,
and Israel.
e pivotal Phase 3 trial started in November 2018. If Phase
3 trials produce signicant conrmatory results and satisfactory
safety prole, an application for marketing approval of MDMA-
assisted psychotherapy for PTSD will be led with the FDA.
Filing of a New Drug Application is projected for 2021, with
anticipated approval in 2022.
It is anticipated that MDMA, with its unique pharmacological
mechanisms combined with psychotherapy, has advantages
over existing medications used as rst-line PTSD treatments
in terms of safety and side eect proles, ecacy, and length
of remission. PTSD is a chronic condition that aicts a
substantial number of individuals who do not adequately
respond to available therapies and are at increased risk of
suicide, other mental health conditions, cardiovascular disease,
and cognitive impairment. Findings from both nonclinical and
clinical studies support a novel mechanism by which MDMA
amplies the therapeutic eects of psychotherapy by a dynamic
interaction of brain regions, and aliated neurochemicals
therein, known to be involved in fear extinction learning,
memory reconsolidation, emotional processing, and cognition
(30, 32, 39, 48, 70). With many apparent advantages over
existing medications, including ecacy, tolerability, and
duration of therapeutic eects, MDMA-assisted psychotherapy
has the potential to favorably impact the lives of thousands who
suer from PTSD world-wide.
Concept and review design: LJ, AF, AE, BY-K, RD, and MM.
Acquisition, analysis, or interpretation of data: LJ, AF, AE, BY-K,
RD, and MM. Draing of the manuscript: LJ, AF, AE, BY-K,
RD, and MM. Critical revision of the manuscript for important
intellectual content: LJ, AF, AE, BY-K, RD, and MM. Obtained
funding: RD.
The authors express great appreciation for the clinical
investigators responsible for conducting the studies of
MDMA-assisted psychotherapy, and MAPS and MAPS Public
Benet Corporation sta who helped support study sites,
data collection and analyses. By serving as the basis for the
Breakthrough erapy application, and through attention to
each study site, these teams made this report possible.
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Conict of Interest Statement: AF received salary support for full time
employment with MAPS PBC. LJ received salary support for full time employment
with MAPS PBC. BY-K received salary support for full time employment with
MAPS. AE received salary support for full time employment with MAPS PBC.
MM received salary support from MAPS PBC as a clinical investigator and
clinical trial medical monitor as well as for training and supervision of research
psychotherapists. RD received salary support for full time employment withMAPS.
e Multidisciplinary Association for Psychedelic Studies (MAPS), a 501(c)
(3) nonprot organization, provided the MDMA and fully funded this study.
MAPS Public Benet Corporation (MAPS PBC), a wholly owned subsidiary
of MAPS, was the trial organizer. MAPS and MAPS PBC assisted with study
design; monitoring of study data; analysis, management, and interpretation of
data; preparation, review, and approval of manuscript; and decision to submit the
manuscript for publication. e funder had no role in the collection of data or
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... Our search strategy identified 443 unique records from which 49 different studies, were identified as potentially relevant to this review (see Fig. 1). Five studies Ot'alora et al., 2018;Bouso et al., 2008;Mithoefer et al., 2019b;Oehen et al., 2013) with a total of 106 participants (69% female, mean age 47.8 years) with PTSD were ultimately included in the meta-analysis. Individual study characteristics are summarized in Table 1. ...
... Individual study characteristics are summarized in Table 1. One study (Mithoefer et al., 2013) was a follow-up study of another (Mithoefer et al., 2019b), and was therefore not treated as a separate report. ...
... Across studies, the duration of PTSD in participants was consistent with a chronic pattern of illness (7-22 years). Importantly, the severity of PTSD at baseline (as measured by the Clinician-Administered PTSD Scale [CAPS] Mithoefer et al., 2019b;Oehen et al., 2013;Mithoefer et al., 2013), or the Severity of Symptoms Scale for PTSD [SSSPTSD] (Bouso et al., 2008)) was similar between experimental and control group Table 1 Characteristics of included studies 265 (206) 248 (173) 220 (144) 85 (64) A. Bahji, et al. Progress in Neuropsychopharmacology & Biological Psychiatry 96 (2020) 109735 participants. ...
MDMA (3,4-methylenedioxymethamphetamine) is a amphetamine-type recreational drug that has recently re-emerged in clinical settings as a potential treatment for those with refractory PTSD.
... These effects seemingly target and address many of the fears of negative stimuli faced by PTSD patients. This led to the FDA recently granting a breakthrough therapy designation to MDMA, allowing for larger, well-controlled clinical trials to commence [40]. ...
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Post-traumatic stress disorder (PTSD) is an anxiety disorder that often presents after exposure to a traumatic, life-threatening event. Experiencing a traumatic event is not rare, with inciting incidents ranging from being burglarized to politically motivated genocide. While traditional psychopharmacology and psychotherapy are the mainstays of the treatment of PTSD currently, psychoactive drugs (otherwise known as psychedelics) are being explored for their novel role in the treatment of PTSD patients. Psychoactive drugs such as MDMA, ketamine, and psilocybin have been shown to specifically target and decrease fear and anxiety pathways in the brain. These unique properties hold the potential to be utilized in addressing symptoms of trauma in those with refractory or treatment-resistant PTSD. Historically, federal and state laws have restricted research into how psychoactive drugs can be used to treat mental illness due to the widespread belief that these drugs present more harm than benefit. However, the current shift in public opinion on psychedelics has propelled research to look into the benefits of these drugs for patients with mental illness. This article aims to discuss the mechanisms of how MDMA, ketamine, and psilocybin work in the PTSD brain, as well as their beneficial role in treatment.
... Although a growing body of clinical research suggests the efficacy of MDMA-assisted psychotherapy in individuals with treatment-refractory PTSD, MDMA has not yet been approved by regulatory agencies, which may explain why it is not being used widely (36). However, based on the promising results of previous trials, the FDA has recently granted Breakthrough Therapy designation in order to expedite the approval process (37). The first Phase 3 Study is now underway at 16 sites in the US, Canada and Israel, and applications are being submitted to the European Medicines Agency (EMA) for similar trials in Europe proposed to start later in 2019 (36). ...
BACKGROUND: Posttraumatic stress disorder (PTSD) is a common psychiatric condition that can develop following a traumatic experience. PTSD is associated with significant disability, a large economic burden, and despite the range of therapies to treat PTSD, response to antidepressants is limited. A growing body of clinical research suggests the efficacy of 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy in individuals with treatment-refractory PTSD. AIM: To assess the effectiveness and safety of MDMA-assisted psychotherapy for reducing symptoms of PTSD, a systematic review and meta-analysis was undertaken. METHODS: Six online databases were searched from inception to December 2018. Reference lists of relevant articles were manually searched as well as electronic sources of ongoing trials and conference proceedings. Researchers active in the subject were also contacted. Eligible studies included randomized and quasi-randomized clinical trials using MDMA-assisted psychotherapy for PTSD in comparison with other medications, placebo or no medication (supportive care). We used standard methodological procedures expected by the Cochrane Collaboration. Two authors assessed studies for inclusion and extracted data. Using random-effects meta-analysis with Cochrane's Review Manager 5.3, we obtained standardized mean differences [SMD] and rate ratios [RR] for reduction in PTSD symptomatology. RESULTS: A total of 5 trials met inclusion criteria, totaling 106 participants (average age: 35-40 years, 70% female). Studies were rated as moderate in quality. MDMA-assisted psychotherapy demonstrated a high rate of clinical response (RR = 3.47, 95% CI: 1.70, 7.06), remission (RR = 2.63, 95% CI: 1.37, 5.02), with a large effect size at reducing the symptoms of PTSD (SMD = 1.30, 95% CI: 0.66, 1.94). Available evidence indicates that MDMA was well-tolerated, with few serious adverse events reported across studies. CONCLUSIONS: MDMA-assisted psychotherapy appears to be a potentially safe, effective, and durable treatment for individuals with chronic, treatment-refractory PTSD. However, future studies involving larger samples and longer durations of treatment and follow-up are warranted-and underway.
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Background Posttraumatic stress disorder is a prevalent mental health condition with substantial impact on daily functioning that lacks sufficient treatment options. Here we evaluate six phase 2 trials in a pooled analysis to determine the study design for phase 3 trials of MDMA-assisted psychotherapy for PTSD. Methods Six randomized, double-blind, controlled clinical trials at five study sites were conducted from April 2004 to February 2017. Active doses of MDMA (75–125 mg, n = 72) or placebo/control doses (0–40 mg, n = 31) were administered to individuals with PTSD during manualized psychotherapy sessions in two or three 8-h sessions spaced a month apart. Three non-drug 90-min therapy sessions preceded the first MDMA exposure, and three to four followed each experimental session. Results After two blinded experimental sessions, the active group had significantly greater reductions in CAPS-IV total scores from baseline than the control group [MMRM estimated mean difference (SE) between groups − 22.0 (5.17), P < 0.001]. The between-group Cohen’s d effect size was 0.8, indicating a large treatment effect. After two experimental sessions, more participants in the active group (54.2%) did not meet CAPS-IV PTSD diagnostic criteria than the control group (22.6%). Depression symptom improvement on the BDI-II was greatest for the active group compared to the control group, although only trended towards significant group differences [MMRM, estimated mean difference (SE) between groups − 6.0 (3.03), P = 0.053]. All doses of MDMA were well tolerated, with some expected reactions occurring at greater frequency for the active MDMA group during experimental sessions and the 7 days following. Conclusions MDMA-assisted psychotherapy was efficacious and well tolerated in a large sample of adults with PTSD. These studies supported expansion into phase 3 trials and led to FDA granting Breakthrough Therapy designation for this promising treatment. Trial registration Identifier: NCT00090064, NCT00353938, NCT01958593, NCT01211405, NCT01689740, NCT01793610.
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A critical period is a developmental epoch during which the nervous system is expressly sensitive to specific environmental stimuli that are required for proper circuit organization and learning. Mechanistic characterization of critical periods has revealed an important role for exuberant brain plasticity during early development, and for constraints that are imposed on these mechanisms as the brain matures¹. In disease states, closure of critical periods limits the ability of the brain to adapt even when optimal conditions are restored. Thus, identification of manipulations that reopen critical periods has been a priority for translational neuroscience². Here we provide evidence that developmental regulation of oxytocin-mediated synaptic plasticity (long-term depression) in the nucleus accumbens establishes a critical period for social reward learning. Furthermore, we show that a single dose of (+/−)-3,4-methylendioxymethamphetamine (MDMA) reopens the critical period for social reward learning and leads to a metaplastic upregulation of oxytocin-dependent long-term depression. MDMA-induced reopening of this critical period requires activation of oxytocin receptors in the nucleus accumbens, and is recapitulated by stimulation of oxytocin terminals in the nucleus accumbens. These findings have important implications for understanding the pathogenesis of neurodevelopmental diseases that are characterized by social impairments and of disorders that respond to social influence or are the result of social injury³.
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Numerous studies have suggested that MDMA can cause neurocognitive deficits. However, the available data can only suggest an association-rather than a causal relationship-between MDMA use and neurocognitive deficits. The reliability and robustness of this association was evaluated using Bradford Hill's criteria for determining causation in epidemiology research. Several limitations in the literature were found. Studies have recruited people who abuse ecstasy-an illicit drug that does not always contain MDMA. There is inherent risk in consuming impure or falsely identified substances; and using this as a source as for scientific opinion may introduce biases in our understanding the actuals risks associated with MDMA. Importantly, given that ecstasy research is predominately retrospective, baseline functioning cannot be established; which may be influenced by a variety of preexisting factors. Many studies introduce statistical errors by inconsistently dichotomizing and comparing light and heavy ecstasy users, making dose-response relationships inconclusive. When interpreting the ecstasy literature effect sizes are a more meaningful indicator of neurocognitive functioning rather than relying on p-values alone. Most meta-analyses have failed to find clinically relevant differences between ecstasy users and controls. There is also consistent evidence of publication bias in this field of research, which indicates that the literature is both biased and incomplete. Finally, suggestions for improving the ecstasy literature are provided.
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Background:: Posttraumatic stress disorder often does not resolve after conventional psychotherapies or pharmacotherapies. Pilot studies have reported that 3,4-methylenedioxymethamphetamine (MDMA) combined with psychotherapy reduces posttraumatic stress disorder symptoms. Aims:: This pilot dose response trial assessed efficacy and safety of MDMA-assisted psychotherapy across multiple therapy teams. Methods:: Twenty-eight people with chronic posttraumatic stress disorder were randomized in a double-blind dose response comparison of two active doses (100 and 125 mg) with a low dose (40 mg) of MDMA administered during eight-hour psychotherapy sessions. Change in the Clinician-Administered PTSD Scale total scores one month after two sessions of MDMA served as the primary outcome. Active dose groups had one additional open-label session; the low dose group crossed over for three open-label active dose sessions. A 12-month follow-up assessment occurred after the final MDMA session. Results:: In the intent-to-treat set, the active groups had the largest reduction in Clinician-Administered PTSD Scale total scores at the primary endpoint, with mean (standard deviation) changes of -26.3 (29.5) for 125 mg, -24.4 (24.2) for 100 mg, and -11.5 (21.2) for 40 mg, though statistical significance was reached only in the per protocol set ( p=0.03). Posttraumatic stress disorder symptoms remained lower than baseline at 12-month follow-up ( p<0.001) with 76% ( n=25) not meeting posttraumatic stress disorder criteria. There were no drug-related serious adverse events, and the treatment was well-tolerated. Conclusions:: Our findings support previous investigations of MDMA-assisted psychotherapy as an innovative, efficacious treatment for posttraumatic stress disorder.
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Rationale Standard therapeutic approaches to reduce social anxiety in autistic adults have limited effectiveness. Since 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy shows promise as a treatment for other anxiety disorders, a blinded, placebo-controlled pilot study was conducted. Objectives To explore feasibility and safety of MDMA-assisted psychotherapy for reduction of social fear and avoidance that are common in the autistic population. Methods Autistic adults with marked to very severe social anxiety were randomized to receive MDMA (75 to 125 mg, n = 8) or inactive placebo (0 mg, n = 4) during two 8-h psychotherapy sessions (experimental sessions) in a controlled clinical setting. Double-blinded experimental sessions were spaced approximately 1 month apart with 3 non-drug psychotherapy sessions following each. The primary outcome was change in Leibowitz Social Anxiety Scale (LSAS) Total scores from Baseline to one month after the second experimental session. Outcomes were measured again six months after the last experimental session. Results Improvement in LSAS scores from baseline to the primary endpoint was significantly greater for MDMA group compared to the placebo group (P = 0.037), and placebo-subtracted Cohen’s d effect size was very large (d = 1.4, CI − 0.074, 2.874). Change in LSAS scores from baseline to 6-month follow-up showed similar positive results (P = 0.036), with a Cohen’s d effect size of 1.1 (CI − 0.307, 2.527). Social anxiety remained the same or continued to improve slightly for most participants in the MDMA group after completing the active treatment phase. Conclusions This pilot trial demonstrated rapid and durable improvement in social anxiety symptoms in autistic adults following MDMA-assisted psychotherapy. Initial safety and efficacy outcomes support expansion of research into larger samples to further investigate this novel treatment for social anxiety. Trial registration identifier, NCT00302744
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Atrophy of neurons in the prefrontal cortex (PFC) plays a key role in the pathophysiology of depression and related disorders. The ability to promote both structural and functional plasticity in the PFC has been hypothesized to underlie the fast-acting antidepressant properties of the dissociative anesthetic ketamine. Here, we report that, like ketamine, serotonergic psychedelics are capable of robustly increasing neuritogenesis and/or spinogenesis both in vitro and in vivo. These changes in neuronal structure are accompanied by increased synapse number and function, as measured by fluorescence microscopy and electrophysiology. The structural changes induced by psychedelics appear to result from stimulation of the TrkB, mTOR, and 5-HT2A signaling pathways and could possibly explain the clinical effectiveness of these compounds. Our results underscore the therapeutic potential of psychedelics and, importantly, identify several lead scaffolds for medicinal chemistry efforts focused on developing plasticity-promoting compounds as safe, effective, and fast-acting treatments for depression and related disorders.
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Background: Post-traumatic stress disorder (PTSD) is prevalent in military personnel and first responders, many of whom do not respond to currently available treatments. This study aimed to assess the efficacy and safety of 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for treating chronic PTSD in this population. Methods: We did a randomised, double-blind, dose-response, phase 2 trial at an outpatient psychiatric clinic in the USA. We included service personnel who were 18 years or older, with chronic PTSD duration of 6 months or more, and who had a Clinician-Administered PTSD Scale (CAPS-IV) total score of 50 or greater. Using a web-based randomisation system, we randomly assigned participants (1:1:2) to three different dose groups of MDMA plus psychotherapy: 30 mg (active control), 75 mg, or 125 mg. We masked investigators, independent outcome raters, and participants until after the primary endpoint. MDMA was administered orally in two 8-h sessions with concomitant manualised psychotherapy. The primary outcome was mean change in CAPS-IV total score from baseline to 1 month after the second experimental session. Participants in the 30 mg and 75 mg groups subsequently underwent three 100-125 mg MDMA-assisted psychotherapy sessions in an open-label crossover, and all participants were assessed 12 months after the last MDMA session. Safety was monitored through adverse events, spontaneously reported expected reactions, vital signs, and suicidal ideation and behaviour. This study is registered with, number NCT01211405. Findings: Between Nov 10, 2010, and Jan 29, 2015, 26 veterans and first responders met eligibility criteria and were randomly assigned to receive 30 mg (n=7), 75 mg (n=7), or 125 mg (n=12) of MDMA plus psychotherapy. At the primary endpoint, the 75 mg and 125 mg groups had significantly greater decreases in PTSD symptom severity (mean change CAPS-IV total scores of -58·3 [SD 9·8] and -44·3 [28·7]; p=0·001) than the 30 mg group (-11·4 [12·7]). Compared with the 30 mg group, Cohen's d effect sizes were large: 2·8 (95% CI 1·19-4·39) for the 75 mg group and 1·1 (0·04-2·08) for the 125 mg group. In the open-label crossover with full-dose MDMA (100-125 mg), PTSD symptom severity significantly decreased in the group that had previously received 30 mg (p=0·01), whereas no further significant decreases were observed in the group that previously achieved a large response after 75 mg doses in the blinded segment (p=0·81). PTSD symptoms were significantly reduced at the 12-month follow-up compared with baseline after all groups had full-dose MDMA (mean CAPS-IV total score of 38·8 [SD 28·1] vs 87·1 [16·1]; p<0·0001). 85 adverse events were reported by 20 participants. Of these adverse events, four (5%) were serious: three were deemed unrelated and one possibly related to study drug treatment. Interpretation: Active doses (75 mg and 125 mg) of MDMA with adjunctive psychotherapy in a controlled setting were effective and well tolerated in reducing PTSD symptoms in veterans and first responders. Funding: Multidisciplinary Association for Psychedelic Studies.
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MDMA-assisted psychotherapy for treatment of PTSD has recently progressed to Phase 3 clinical trials and received Breakthrough Therapy designation by the FDA. MDMA used as an adjunct during psychotherapy sessions has demonstrated effectiveness and acceptable safety in reducing PTSD symptoms in Phase 2 trials, with durable remission of PTSD diagnosis in 68% of participants. The underlying psychological and neurological mechanisms for the robust effects in mitigating PTSD are being investigated in animal models and in studies of healthy volunteers. This review explores the potential role of memory reconsolidation and fear extinction during MDMA-assisted psychotherapy. MDMA enhances release of monoamines (serotonin, norepinephrine, dopamine), hormones (oxytocin, cortisol), and other downstream signaling molecules (BDNF) to dynamically modulate emotional memory circuits. By reducing activation in brain regions implicated in the expression of fear- and anxiety-related behaviors, namely the amygdala and insula, and increasing connectivity between the amygdala and hippocampus, MDMA may allow for reprocessing of traumatic memories and emotional engagement with therapeutic processes. Based on the pharmacology of MDMA and the available translational literature of memory reconsolidation, fear learning, and PTSD, this review suggests a neurobiological rationale to explain, at least in part, the large effect sizes demonstrated for MDMA in treating PTSD.
Importance Posttraumatic stress disorder (PTSD) is a prevalent mental disorder, with a high risk of chronicity, comorbidity, and functional impairment; PTSD is complicated to treat, and the debate on the best treatment approach is ongoing. Objective To examine comparative outcomes and acceptability of psychotherapeutic and pharmacological treatments and their combinations in adults with PTSD. Data Sources Embase, MEDLINE, PsycINFO, Cochrane Controlled Trials Register, and PSYNDEX were searched for studies published from January 1, 1980, to February 28, 2018. Reference lists of included studies and of previously published guidelines and systematic reviews were also searched. Study Selection Of 11 417 records identified, 12 published randomized clinical trials (RCTs) comprising 922 participants, contributing 23 direct comparisons between psychotherapeutic and pharmacological treatments or their combinations were included. Data Extraction and Synthesis Standardized mean differences (SMDs) and odds ratios were aggregated using random-effects network and pairwise meta-analyses. Risk of bias and indirectness was rated for each study, and network confidence was rated using the Confidence in Network Meta-Analysis framework. Main Outcomes and Measures The primary outcome was the comparative benefit between 2 treatment approaches to PTSD symptom improvement, and secondary outcome was the comparative acceptability of the treatment approaches, as indicated by patient dropout rates before treatment termination. Results No treatment approach was found to be superior at the end of treatment (for all, 95% CI included 0). At the last follow-up, psychotherapeutic treatments showed greater benefit than pharmacological treatments in both network (SMD, −0.83; 95% CI, −1.59 to −0.07) and pairwise (SMD, −0.63; 95% CI, −1.18 to −0.09, 3 RCTs) meta-analyses. No difference was found between combined treatments and psychotherapeutic treatments at long-term follow-up, and combined treatments were associated with better outcomes than pharmacological treatments in the network meta-analysis (SMD, −0.96; 95% CI, −1.87 to −0.04), but not in the pairwise meta-analysis, which included 2 RCTs (SMD, −1.02; 95% CI, −2.77 to 0.72). No evidence was found for differential acceptability of the 3 treatment approaches. Conclusions and Relevance These results suggest superiority of psychotherapeutic treatments over pharmacological treatments; network, but not pairwise, meta-analyses suggest superiority of combined treatments over pharmacological treatments in improving PTSD symptom severity in the long term. The scarcity of reported long-term findings hampers definite conclusions and demonstrates the need for robust evidence from large-scaled comparative trials providing long-term follow-up data.
Background: Neuroimaging studies imply that the regular use of ±3,4-methylenedioxymethamphetamine (MDMA), the major constituent of ecstasy pills, alters the brain's serotonergic system in a dose-dependent manner. However, the relevance of these findings remains unclear due to limited knowledge about the ecstasy/MDMA use pattern of real-life users. Aims: We examined the representativeness of ecstasy users enrolled in neuroimaging studies by comparing their ecstasy use habits with the use patterns of a large, international sample. Methods: A systematic literature search revealed 10 imaging studies that compare serotonin transporter levels in recreational ecstasy users to matched controls. To characterize the ecstasy use patterns we relied on the Global Drug Survey, the world's largest self-report database on drug use. The basis of the dose comparison were the Usual Amount (pills/session), Use Frequency (sessions/month) and Dose Intensity (pills/year) variables. Results: Both the average Usual Amount (pills/session) and Use Frequency (sessions/month) of neuroimaging study participants corresponded to the top 5-10% of the Global Drug Survey sample and imaging participants, on average, consumed 720% more pills over a year than the Global Drug Survey participants. Conclusions: Our findings suggest that the serotonin brain imaging literature has focused on unusually heavy ecstasy use and therefore the conclusions from these studies are likely to overestimate the extent of serotonergic alterations experienced by the majority of people who use ecstays.