Continuing Education: Review

MDMA-Assisted Psychotherapy for The Journal of Clinical Pharmacology

2022, 62(4) 463–471
Treatment of Posttraumatic Stress Disorder: © 2021, The American College of
Clinical Pharmacology
DOI: 10.1002/jcph.1995
A Systematic Review With Meta-Analysis

Kimberly W. Smith, PharmD1 , Dakota J. Sicignano1 , Adrian V. Hernandez, MD,

PhD1,2,3 , and C. Michael White, PharmD, FCP, FCCP1,2

Abstract
This article discusses current literature on the use of 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy in the treatment of
posttraumatic stress disorder (PTSD). MDMA, the intended active ingredient in illicit Ecstasy or Molly products, is a psychedelic that causes an
elevated mood, feeling of bonding, and increased energy. In MDMA-assisted psychotherapy, patients are subjected to 2 or 3 multihour sessions of
therapy with a team of psychiatrists. The dosing of MDMA is used to allow the therapist to probe the underlying trauma without causing emotional
distress. The use of MDMA-assisted psychotherapy treatment reduced patient’s Clinician-Administered PTSD Scale (CAPS) scores from baseline
more than control psychotherapy (–22.03; 95%CI, –38.53 to –5.52) but with high statistical heterogeneity. MDMA-assisted psychotherapy enhanced
the achievement of clinically significant reductions in CAPS scores (relative risk, 3.65; 95%CI, 2.39-5.57) and CAPS score reductions sufficient to no
longer meet the definition of PTSD (relative risk, 2.10; 95%CI, 1.37-3.21) with no detected statistical heterogeneity. While therapy was generally safe
and well tolerated, bruxism, anxiety, jitteriness, headache, and nausea are commonly reported. While MDMA-assisted psychotherapy has been shown
to be an effective therapy for patients with PTSD with a reasonable safety profile, use of unregulated MDMA or use in the absence of a strongly
controlled psychotherapeutic environment has considerable risks.

Keywords
clinical pharmacology, (CPH), drug abuse, drug development, psychiatry (PSY), psychopharmacology (PSP)

Posttraumatic stress disorder (PTSD) is a debilitating damage, elevated blood pressure and tachycardia with
mental health disorder characterized by avoidance, cardiovascular events including arrhythmias, a period
hypervigilance, and flashbacks where patients are re- of anhedonia after the elevated mood due to depletion
experiencing aspects of a traumatic event.1 It can be of serotonin, bruxism (jaw clenching) with tooth
further confounded by comorbid anxiety, depression, damage, and compromised objectivity with an elevated
substance abuse, and suicidal ideation and actions.1 risk of physical or sexual assault.3
PTSD affects nearly 7% of the population in the United The increases in energy, elevated mood, feelings of
States and causes those impacted to lose an average closeness with psychologists/psychiatrists, and the sur-
of 3.6 days of work per month. While there are sev- real aspect of the psychedelic effects that the MDMA
eral pharmacologic and nonpharmacologic treatment provides were proposed to enhance psychotherapy ses-
options available, many people with PTSD do not sions where patients with PTSD are reluctant or unable
adequately respond.2 to tap into the traumatic events due to acute panic
3,4-Methylenedioxymethamphetamine (MDMA)
can increase the feeling of energy via norepinephrine
1 University
release, elevate mood via serotonin release, increase of Connecticut School of Pharmacy, Storrs, Connecticut,
bonding with strangers via oxytocin release, and USA
2 Research Administration, Hartford Hospital, Hartford, Connecticut,
provide a psychedelic effect from its methylenedioxy
USA
molecular component.3 MDMA is a substance of 3 Unidad de Revisiones Sistemat́icas y Meta-anaĺisis (URSIGET), Vicerrec-
abuse and the active ingredient sought by purchasers torado de Investigacioń, Universidad San Ignacio de Loyola (USIL), Lima,
of Ecstasy and Molly, although many of these illicit Peru
products contain a variable amount of MDMA Submitted for publication 9 August 2021; accepted 25 October 2021.
and adulterants ranging from methamphetamine,
Corresponding Author:
lysergic acid, and synthetic cathinones that amplify C. Michael White, PharmD, FCP, FCCP, Distinguished Professor and Chair,
the adverse event potential. Users of illicit MDMA- Pharmacy Practice,UConn School of Pharmacy,69 N Eagleville Rd,Storrs,
containing products are at risk of hyperthermia and CT 06269-3092
hyponatremia with resultant rhabdomyolysis and renal Email: [email protected]
 15524604, 2022, 4, Downloaded from https://accp1.onlinelibrary.wiley.com/doi/10.1002/jcph.1995 by Universite Cote D'azur, Wiley Online Library on [29/12/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
464 The Journal of Clinical Pharmacology / Vol 62 No 4 2022

or anxiety reactions.3,4 MDMA appears to bilaterally baseline was –6.8 units greater in the sertraline than the
reduce activity in the amygdala, the brain structure that placebo group (P = .043), while the difference between
acquires and stores fearful memories.5 The reduction of groups in the second study (n = 183) was –9.8 units
amygdala activity with concomitant serotonin release (P = .016). Importantly, 29% of participants in trial
has been experimentally found to increase cognitive 1 and 28% in trial 2 withdrew during the study.14 A
flexibility, diminishing responses to negative stimuli combined analysis of 2 sertraline studies showed that
while enhancing responses to positive emotions that CAPS-II scores were –8.3 units lower in the sertraline
could be useful when working through the event(s) that group and placebo group but were only significantly
led to PTSD. improved in female subjects.14
The Drug Enforcement Agency designation as a Paroxetine was assessed in three 12-week phase III
Schedule I drug (no therapeutic uses, high abuse po- clinical trials in patients with PTSD with doses between
tential) made it very difficult to study MDMA-assisted 20 and 50 mg/day.14 In the first, second, and third
psychotherapy for many years. Early studies provided clinical trials, the differences in CAPS-II scores were –
enough promising safety and efficacy data on the 14 units (P < .001), –11 units (P < .001), and –6 units
controlled use of MDMA-assisted psychotherapy that (P = .047). No sex-based differences in efficacy was
in 2017, the Food and Drug Administration (FDA) found in these paroxetine trials. Similarly, 36%, 39%,
granted breakthrough therapy designation and the abil- and 33% of participants withdrew from the 3 trials,
ity to conduct more extensive clinical studies.6 Since respectively.14
then, there have been several clinical studies assessing Fluoxetine was assessed in 2 trials, 1 open prospec-
the efficacy and safety of MDMA-assisted PTSD psy- tive trial and 1 randomized double-blind placebo-
chotherapy including phase II clinical trials and a phase controlled trial, in patients with severe PTSD (CAPS
III clinical trial. scores >45 units) with daily doses between 20 and 80
There are 2 common outcome scales for PTSD. mg over 5 to 10 weeks and the change in CAPS score
The most common outcome measure is the Clinician- was the primary outcome.15,16 Both trials reported a
Administered PTSD Scale (CAPS), which was recently statistically significant decrease in CAPS scores. The
adapted as the Diagnostic and Statistical Manual of open prospective trial (n = 19) reported a decrease of
Mental Disorders (DSM) moved from the fourth edi- 21.8 units (P < .001) from baseline in CAPS-II scores
tion to the fifth edition.7–9 An aggregate CAPS score after 10 weeks of fluoxetine titrated up to 80 mg daily.15
≥50 units constitutes a severe case of PTSD.8 Another Similarly, the double-blind placebo-controlled trial (n =
outcome measure for PTSD symptoms is the Severity 47) reported a 12.59-unit (P = .0106) decrease in total
of Symptoms Scale for PTSD (SSSPTSD) but it is used CAPS scores relative to placebo after 5 weeks, with a
less often.10,11 An aggregate SSSPTSD score of ≥46 is max daily fluoxetine dose of 60 mg.16 Of note, 47%
considered severe PTSD. of participants in the open prospective trial and 27%
This article will provide an general overview of in the double-blind trial withdrew during the study.15,16
guideline-suggested pharmacologic options for PTSD Additionally, it was reported that 37% of participants
and then provide an in-depth assessment of the clinical did not benefit at all from fluoxetine in the prospective
trials assessing MDMA-assisted psychotherapy with its trial (37% had a good response and 26% had a partial
possible place in therapy. response).16
Venlafaxine extended release was assessed in 1 ran-
Current FDA- or Guideline-Recommended Pharmaco- domized double-blind, placebo-controlled trial (n =
logic Options 329) with a 24-week flexible daily dose between 37.5
Numerous medications have been assessed for use in to 300 mg also in patients with severe PTSD (17-
the treatment of PTSD, but sertraline and paroxetine item Clinician-Administered PTSD Scale [CAPS-SX17 ]
are the only 2 FDA-approved treatment options.12,13 score of at least 60).17 At study end, venlafaxine ex-
These agents and fluoxetine and venlafaxine are recom- tended release showed significantly greater reduction in
mended by the American Psychological Association’s the CAPS-SX17 score vs placebo, –51.7 units and –43.9
and the Veterans Administration Department of De- units, respectively (P = .006). A difference in CAPS-
fense PTSD guidelines.12,13 SX17 from baseline between groups was reported as –8.9
Sertraline was assessed in 4 phase III trials of similar (P = .006). This study reported no significant difference
design in patients with severe PTSD (CAPS-II scores in withdrawal rates between placebo and venlafaxine
>50 units) with a 12-week flexible daily dose between group, 33.3% vs 30.4%, respectively.17
50 and 200 mg.14 Two of the 4 studies failed to find
a significant difference between the sertraline- and MDMA-Assisted Psychotherapy Trial Selection and Anal-
placebo-treated groups for CAPS-II scores. Of the trials ysis Methods
that found significant benefits at 12 weeks, the first (n = We (K.S., D.S., C.W.) searched PubMed from incep-
208) reported that the change in CAPS-II scores from tion to September 20, 2021, using the search strategy:
 15524604, 2022, 4, Downloaded from https://accp1.onlinelibrary.wiley.com/doi/10.1002/jcph.1995 by Universite Cote D'azur, Wiley Online Library on [29/12/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Smith et al 465

Medline + MAPS Site

outcomes were expressed as relative risk with its 95%CI,
Citations via Other
Search Non- Sources and on continuous outcomes as mean difference with
Duplicative Citations (n=0) its 95%CI. High heterogeneity of effects among studies
(n=133)
was defined as I2 >75%. All meta-analyses were per-
formed using the meta package from R 3.6.3 (R Foun-
Citations Screened by Citations Excluded dation for Statistical Computing, Vienna, Austria).
Title & Abstract (n=120) A 2-tailed P value <.05 was considered statistically
(n=133)
significant.
Results when patients were crossed over to alternate
therapy, adverse events, and long-term follow-up data
Full Texts Reviewed Full Texts Excluded were described narratively without statistical pooling
(n=13) 5 contained no new or
only duplicative data because the data were not deemed amenable for meta-
analysis.

Studies Included Demographic Overview of MDMA-Assisted Psychother-

6 unique studies
2 longer-term follow-up
apy Trials
assessments Table 1 provides methodological and demographic
information for all included trials.8,10,19–22 All trials
Legend: MAPS – Multidisciplinary Association for Psychedelic Studies
were randomized and double-blinded. Three studies
Figure 1. Preferred Reporting Items for Systematic Review and Meta- (Bouso et al, Mithoefer et al 2011, Mitchell et al)10,19,20
analyses diagram for 3,4-methylenedioxymethamphetamine search.
used placebo control, although given the psychedelic
effects associated with MDMA, the placebo was likely
inadequate for maintaining double blinding. Most of
([MDMA OR 3,4-methylenedioxymethamphetamine]
the trials were very small ranging from 6 (Buoso et al)
AND [PTSD OR posttraumatic stress disorder]) and
to 90 subjects (Mitchell et al) with the rest having 12
the website for the Multidisciplinary Association of
(Oehen et al)8 or 20 to 27 subjects (Mithoefer et al 2011,
Psychedelic Studies with backward citation tracking.18
Ot’alora et al, Mithoefer et al 2018).10,19–22
Citations were included if they represented unique
One trial (Bouso et al),10 used the SSSPTSD scale
studies of MDMA in patients with PTSD or if they
for their primary end point, while the others used the
provided information from the studies that were nondu-
more commonly used and better validated CAPS-IV
plicative of the published constitutive studies. Figure 1
(4 studies) or CAPS-V scales (1 study).8,19–22 The trial
is a Preferred Reporting Items for Systematic Review
by Bouso et al was pre–phase II, Mitchell was phase III,
and Meta-analyses diagram for the citations found to
and the rest were phase II trials.8,10,19–22
the final trials included. Data were dually extracted
All of the trials had specific safeguards to minimize
by 2 investigators (D.S., K.S.) with any discrepancies
the adverse effects of MDMA therapy.8,10,19–22 None
reconciled by a third investigator (C.W.).
of the trials used illicit sources of MDMA, which
We assessed the impact of MDMA vs control for the
could contain variable amounts of MDMA and may be
change in CAPS scores from baseline, the percentage of
contaminated or adulterated. Subjects taking MDMA
people in each group receiving a clinically significant
or placebo were kept in a supportive environment for
CAPS score reduction, and the percentage of people
an extended period (6-8 hours) in each experimental
no longer meeting the CAPS score criteria for PTSD
session so the pharmacologic effects of MDMA were
at the follow-up period using meta-analysis. For 3-arm
abolished before they left. Subjects were not allowed
trials, where there were 2 active MDMA dosing groups
to exercise to prevent amplifying the amphetamine-like
and 1 control (placebo or low-dose MDMA); means,
effects of the drugs. Subjects at high risk of cardiovas-
standard deviations, and numbers from the 2 active
cular events were excluded.8,10,19–22
MDMA dose arms were combined (A.H.) into 1 arm
using https://www.statstodo.com/CombineMeansSDs.
php. MDMA-Assisted Psychotherapy Efficacy
Random effects meta-analyses (A.H.) were used to The trial by Bouso et al10 was not amenable to
compare MDMA to control therapy, with the inverse meta-analysis. Bouso et al used moderate 50- to 75-
variance method. The restricted maximum likelihood mg MDMA doses, did not allow a second subse-
method was used to calculate between-study variance quent MDMA dose to be administered, and used the
tau,2 and the Hartung-Knapp method of adjustment SSSPTSD scale instead of the CAPS scale. While no
of 95%CIs was used. Effects of MDMA vs control statistical analyses were provided, the average scores on
(placebo or very low MDMA dose) on dichotomous the SSSPTSD were reduced 27% for MDMA-assisted
 466

Table 1. Method and Demographic Overview of MDMA-Assisted Psychotherapy Trials8,10,12-15

End Point
Assessment After
Study Predominant Primary Original + Supplemental Dose Last MDMA
Name/Year/Sample Size % Female Trauma Measure Regimen Experimental Sessions Baseline CAPS Scores Session

Placebo controlled trials

Bouso (2008) 100% Sexual Assault SSSPTSD MDMA 50–75 mg (n = 4) Placebo One 6-hour MDMA Moderate: N/A 1 mo (n = 4)
n = 6 R, DB, PC (n = 2) psychotherapy session Placebo: N/A 3 mo (n = 2)
6 mo (n = 1)
Mithoefer (2011) 85% Crime CAPS-IV MDMA 125 mg + 62.5 mg (n = 12) Two 8-h psychotherapy MDMA High: 79.2 ± 23.6 2 mo
n = 20 R, DB, PC Placebo (n = 8) sessions Placebo: 79.6 ± 22.0
Mitchell 2021 66% Developmental CAPS-V MDMA 80 mg + 40 mg (Session 1) Three 8-h psychotherapy MDMA Variable: 44.0 ± 6.0 2 mo
n = 90 R, DB, PC 80 mg + 40 or 120 mg + 60 mg sessions Placebo: 44.2 ± 6.2
(Sessions 2 and 3) (n = 46)
Placebo (n = 44)
Dose response trials
Oehen (2013) 83% Sexual assault CAPS-IV MDMA 125 mg + 62.5 mg (n = 8) Three 8-h psychotherapy MDMA High: 66.4 ± 13.6 3 wks
n = 12 R, DB, AC MDMA 25 mg + 12.5 mg (n = 4) sessions MDMA Low: 63.4 ± 7.9
Ot’alora (2018) 67% N/A CAPS-IV MDMA 125 mg + 62.5 mg (n = 12) Two 8-h psychotherapy MDMA High: 93.5 ± 20.2 1 mo
n = 27 R, DB, AC MDMA 100 mg + 50 mg (n = 9) sessions MDMA Moderate: 94.4 ± 20.2
MDMA 40 mg + 20 mg (n = 6) MDMA Low: 84.8 ± 8.0
Mithoefer (2018) 27% Occupational CAPS-IV MDMA 125 mg + 62.5 mg (n = 12) Two 8-h psychotherapy MDMA High: 89.7 ± 17.3 1 mo
n = 26 R, DB, AC (war/first MDMA 75 mg + 37.5 mg (n = 7) sessions MDMA Moderate: 82.4 ± 17.3
responders) MDMA 30 mg + 15 mg (n = 7) MDMA Low: 87.0 ± 14.1

CAPS, Clinician Administered PTSD Scale; DB, double blinded; MDMA, 3,4-methylenedioxymethamphetamine; N/A, not available; PC, placebo controlled; R, randomized; SSSPTSD, Severity of Symptoms Scale for Post-
Traumatic Stress Disorder.
MDMA high ≥125 mg; MDMA moderate = 50-100 mg; MDMA low = 30-49 mg; MDMA variable = loading and supplemental doses change between sessions.
The Journal of Clinical Pharmacology / Vol 62 No 4 2022

15524604, 2022, 4, Downloaded from https://accp1.onlinelibrary.wiley.com/doi/10.1002/jcph.1995 by Universite Cote D'azur, Wiley Online Library on [29/12/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
 15524604, 2022, 4, Downloaded from https://accp1.onlinelibrary.wiley.com/doi/10.1002/jcph.1995 by Universite Cote D'azur, Wiley Online Library on [29/12/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Smith et al 467

Figure 2. Pooled comparison of differences of CAPS scores from baseline for MDMA-assisted psychotherapy versus control. CAPS, Clinician-
Administered PTSD Scale; MD, mean difference; MDMA, 3,4-methylenedioxymethamphetamine.

Figure 3. Pooled comparison of the percentage of patients experiencing a clinically significant reduction in baseline CAPS scores for MDMA-assisted
psychotherapy vs control. CAPS, Clinician-Administered PTSD Scale; MDMA, 3,4-methylenedioxymethamphetamine; RR, relative risk.

Figure 4. Pooled comparison of the percentage of patients no longer meeting CAPS score criteria for PTSD with MDMA-assisted psychotherapy
versus control. CAPS, Clinician-Administered PTSD Scale; MDMA, 3,4-methylenedioxymethamphetamine; RR, relative risk.

psychotherapy sessions compared to a 10% reduction follow-up in the MDMA-assisted psychotherapy group
in the placebo group.10 vs control.8,19–22 Statistical heterogeneity was not de-
Figure 2 provides the pooled change in CAPS score tected in either of these analyses.
results for MDMA-assisted psychotherapy vs control There were several possible sources of heterogeneity.
therapy.8,19–22 The reduction in CAPS scores from base- The average patient in Mitchell et al20 had a baseline
line were 22 points greater than that seen with control CAPS score of 44 units, just under the cutoff for severe
(mean difference, –22.03; 95%CI, –38.53 to –5.52). Even disease, while in all other trials, the average patient
though the direction of effect was consistent across all had average CAPS scores of ≈65 (Oehen et al8 ),
trials, the magnitude of effect varied substantially with ≈79 (Mithoefer et al19 ), ≈87 (Mithoefer et al22 ), and
high resulting statistical heterogeneity. ≈90 units (Ot’alora et al21 ). Among placebo controlled
Figure 3 shows that patients receiving MDMA- trials, Mitchell et al20 had a less robust reduction in
assisted psychotherapy were more likely to achieve CAPS score than Mithoefer19 with MDMA-assisted
clinically significant reductions in CAPS scores than psychotherapy (Figure 2). Among active controlled
control, while Figure 4 shows that more patients trials, Oehen et al8 has a less robust reduction in CAPS
no longer met the CAPS criteria for PTSD at scores from baseline with high dose MDMA-assisted
 15524604, 2022, 4, Downloaded from https://accp1.onlinelibrary.wiley.com/doi/10.1002/jcph.1995 by Universite Cote D'azur, Wiley Online Library on [29/12/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
468 The Journal of Clinical Pharmacology / Vol 62 No 4 2022

Figure 5. Impact of MDMA dose on CAPS response in active control trials. * P < .05 vs 25- to 40-mg doses of MDMA. CAPS, Clinician-Administered
PTSD Scale; MDMA, 3,4-methylenedioxymethamphetamine.

psychotherapy than the Mithoefer et al22 or Ot’alora et Oehen et al,8 Ot’alora et al,21 and Mithoefer et al22 ),
al21 trials (Figure 5). moderate (Ot’alora et al,21 Mithoefer et al22 ), and low
The time from the last experimental session to as- (Oehen et al,8 Ot’alora et al,21 and Mithoefer et al22 )
sessment of MDMA’s impact on the primary endpoint dose MDMA regimens received different supplemental
is not as likely a cause of heterogeneity.8,19–22 While doses of 60 to 62.5, 37.5 to 50, or 12.5 to 20 mg,
Oehen et al8 had 3 weeks of follow-up after the last respectively. These differences do not seem to explain
experimental session and less robust effects than other the statistical heterogeneity.
active control trials (Ot’alora et al,21 1 month; and Mithoefer et al 2018 was conducted primarily in
Mithoefer et al,19 2 months), Mitchell et al20 had 2 men while all the others were conducted primarily in
months of follow-up and less robust results vs placebo women.8,19–22 Sexual assault was the primary cause
than Mithoefer et al,22 which had 1 month of follow-up. of PTSD in 2 trials (Bouso et al,10 Oehen et al8 ),
The initial MDMA doses in placebo controlled trials veteran/first responder occupational trauma in 1 trial
varied from high 125 mg (Mithoefer et al19 ) to variable (Mithoefer et al22 ), crime-related trauma in 1 trial
(80 mg in session 1 and then 80 or 120 mg in sessions 2 (Mithoefer et al19 ), developmental trauma in one trial
or 3) (Mitchell et al20 ) in placebo-controlled trials. The (Mitchell20 ), and the cause was not broken out in 1 trial
other studies (Oehen et al,8 Ot’alora et al,21 Mithoefer (Ot’alora21 ). There were not enough data to assess these
et al22 ) assessed 2 or 3 different groups who all received factors as possible causes of statistical heterogeneity.
a different initial MDMA dose ranging from high Low-dose MDMA sessions in the active control
(>125 mg) or medium (50-100 mg) doses compared to trials did not reduce CAPS-IV scores more than the
low dose (30-49 mg) control therapy. However, there placebo sessions did in the placebo-controlled trials
were not major differences in CAPS score reductions suggesting the benefits are negligible.8,19–22 This was
in trials with moderate and high dose MDMA-assisted actually the intent of investigators, who were hoping
psychotherapy arms vs control (Figures 2 and 5).8,19–22 to have the low-dose MDMA comparator provide
All the placebo or active controlled trials allowed some MDMA-like effects to help maintain double-
a second subsequent MDMA or placebo dose to be blinding without providing much therapeutic benefit.
given part way through each assisted psychotherapy As such, this is not a likely explanation for the statistical
session to maintain the MDMA effects.8,19–22 Mithoefer heterogeneity.8,19–22
et al19 allowed a supplemental MDMA or placebo The size of the newest clinical trial by Mitchell et
dose but only if both the therapist and subject agreed. al20 allowed additional insight from subgroups within
Twenty-two of the 23 MDMA sessions where a supple- the PTSD population. Participants with the dissociative
mental dose was offered, it was accepted. However, it subtype of PTSD who received MDMA-assisted ther-
was never used in placebo sessions, raising questions apy had symptom reductions in CAPS-V scores versus
about the adequacy of blinding for the therapist and placebo (30.8 ± 9.0 vs 12.8 ± 12.8 points), which was
patient.19 High (Mithoefer et al,19 Mitchell et al,20 similar to those with nondissociative PTSD (23.6 ± 11.7
 15524604, 2022, 4, Downloaded from https://accp1.onlinelibrary.wiley.com/doi/10.1002/jcph.1995 by Universite Cote D'azur, Wiley Online Library on [29/12/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Smith et al 469

vs 14.3 ± 11.2 points). The beneficial impact MDMA Table 2. Common Adverse Events With MDMA or Placebo-Assisted
therapy on CAPS-V scores was similar, even in people Psychotherapy13,16
with a history of alcohol use disorder, substance use Placebo or Moderate or
disorder, or severe childhood trauma.20 Low-Dose High-Dose
Adverse Event MDMA, % MDMA, %
Efficacy of MDMA in Placebo or Low-Dose MDMA- Aggregate of phase II trials
Treated Patients Anxiety 48 72
In several trials, after the primary end point was as- Jaw clenching 19 64
sessed, participants in the placebo or low-dose MDMA Reduced appetite 23 49
Dizziness 19 40
groups were offered the ability to receive open la- Nausea 19 40
bel high-dose MDMA-assisted psychotherapy. These Depressed mood 3 8
results were not amenable to meta-analysis but are Irritability 0 6
discussed narratively. In Oehen et al,8 the 4 participants Panic attack 0 6
originally in the low-dose MDMA group responded Mitchell et al 2021 (phase III)
Muscle tightness 11 63
to open-label high-dose MDMA treatment, with a Reduced appetite 11 52
52% decrease in CAPS-IV score over the course of Nausea/Vomiting 11/0 30/9
treatment, and 50% of them no longer meeting criteria Excessive sweating 2 20
for PTSD diagnosis. In Mithoefer et al 2011,19 the open- Restlessness 0 15
label phase of the study included 7 of the 8 participants Jaw clenching 2 13
Dizziness 5 13
from the original placebo group. All subjects showed Jittery 0 11
clinically meaningful reductions in CAPS-IV score after Pyrexia 2 7
MDMA therapy was used, which averaged 48% lower Anxiety 0 7
than baseline. The eighth participant was satisfied with Blurred vision 2 9
the progress made during the placebo-controlled ther- MDMA, 3,4-methylenedioxymethamphetamine.
apy and chose not to join the open-label session.19 In
Ot’alora et al,21 the participants who originally received
low-dose MDMA were switched to open-label high- the last MDMA session, and this increased to 67.0%
dose MDMA therapy and achieved a 47% reduction of subjects at the end of 12 months after treatment.
in CAPS scores from the end of the blinded portion While the data from 2 of the trials are not published
of the study. In Mithoefer et al,22 the participants who and cannot be directly assessed, the pooled 1- to 2-
originally received low-dose MDMA were switched to month effects are aligned with those of the individual
open-label high-dose MDMA therapy and achieved a studies and shows that the benefits of MDMA-assisted
reduction in CAPS-IV score of 27 units, and 33% of psychotherapy are durable out to 12 months.23
6 participants no longer met PTSD diagnostic criteria.
Safety of MDMA-Assisted Psychotherapy
Durability of MDMA-Assisted Psychotherapy’s Impact In a pooled analysis by Mithoefer et al,6, using the
Jerome et al23 assessed the 4 aforementioned phase II same constituent trials as in Jerome et al,23 the safety of
studies, including 12-month posttreatment follow-up MDMA-assisted psychotherapy was assessed but not
analyses from these trials, along with 2 unpublished statistically analyzed. These events could have occurred
phase II studies to perform a pooled analysis of effi- from the time of enrollment through the 1- to 2-month
cacy and harm from MDMA-assisted psychotherapy. follow-up period after the last MDMA or placebo
Participants (n = 107) received 2 to 3 active sessions session.6 Table 2 provides the comparison of adverse
where moderate- or high-dose MDMA (75-125 mg) events occurring in >3 individuals in an experimental
was administered during the blinded or open-label group.6,20 The adverse events were predominantly mild
portions of the trials, and 91 participants had long-term to moderate in severity. Among rare but serious adverse
outcome data. The CAPS-IV scores were analyzed 1 to events, there was 1 patient receiving high-dose MDMA
2 months after the last active MDMA session, and at who experienced ventricular extrasystoles, and 1 person
least 12 months after the final MDMA session. There who received low-dose MDMA experienced suicidal
was a significant reduction in CAPS-IV scores from ideation. Patient attrition was 7.6% in these trials which
baseline to 1 to 2 months after the last MDMA assisted is comparably lower than the 17% to 36% rates in other
session (−44.8 units; standard error, 2.8; P < .0001). PTSD treatment trials, suggesting that patients felt the
CAPS-IV scores continued to decrease from the last benefits outweighed the risks.6
session out to 12 months of follow-up (−5.2 units; Mitchell et al20 was a phase III clinical trial and
standard error, 2.3; P < .05). Fifty-six percent of partic- not included in the pooled safety analysis by Mithoefer
ipants no longer met PTSD criteria 1 to 2 months after et al.6 Like the Mithoefer et al6 assessment, Mitchell
 15524604, 2022, 4, Downloaded from https://accp1.onlinelibrary.wiley.com/doi/10.1002/jcph.1995 by Universite Cote D'azur, Wiley Online Library on [29/12/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
470 The Journal of Clinical Pharmacology / Vol 62 No 4 2022

et al found increases in anxiety, dizziness, jaw clench- MDMA is being used in patients with PTSD who
ing, lack of appetite, and nausea (Table 2). In their were not sufficiently responsive to unenhanced trauma-
hemodynamic assessment, systolic (146 ± 19 vs 118 focused psychotherapy and would likely be tried be-
± 16 mm Hg), diastolic blood pressure (87 ± 10 vs fore patients would be offered SSRI or venlafaxine
76 ± 10 mm Hg), and pulse (92 vs 66 beats per therapy.13 An advantage of trying MDMA-enhanced
minute) were elevated in the MDMA session vs the psychotherapy before moving to other pharmacother-
placebo session 3 with similar comparative changes apeutic options is that the MDMA benefits are long
after experimental sessions 1 and 2.20 Since patients lasting, but MDMA exposure is only intermittent and is
with hypertension, advanced age, or those at high risk ingested in the presence of health professionals.8,10,19–23
of cardiovascular events can have muted baroreceptor The need for chronic use of SSRIs or venlafaxine
buffering capacity, they could experience accentuated may be a contributing factor in the high patient with-
blood pressure increases and adverse cardiovascular drawal rate from the available studies.15–17 There is no
events over what was seen in these clinical trials.24 Over- evidence that the use of MDMA in the absence of
all, 37% of MDMA participants and 32% of placebo trauma-focused psychotherapy would provide benefits
participants reported suicidal ideation at baseline.20 and would not be a monotherapeutic option like the
The prevalence of suicidal ideation during the study SSRIs or venlafaxine.
never exceeded baseline and was not exacerbated in While the trials assessing MDMA-assisted psy-
the MDMA group.20 While some of these adverse chotherapy yielded consistent directions of effect that
events were likely directly related to MDMA use (jaw were superior to that of psychotherapy alone, the
clenching), the others could have occurred in part due sample sizes of these trials were small and statistical
to discussing the traumatic PTSD-causing events.3 heterogeneity was high for the comparison of the
Jerome et al23 reported on the results of a question- difference in CAPS scores between groups. However,
naire sent to the participants in the constituent phase there were other limitations as well.8,10,19–22 One of the
II trials 12 months after their last MDMA session. limitations with the trials assessing MDMA-assisted
On a 5-point scale, with 1 being slight and 5 being psychotherapy is that the psychotherapy provided in
large or severe, 86% of participants said their benefits both groups was structured to fit what would likely
were a 4 or 5, and no one said they received a benefit work best for those receiving MDMA. Future studies
of 1. Conversely, no one reported experiencing a 5, comparing MDMA-assisted psychotherapy vs proven
2% of participants reported a 4, 3% reported a 3, 2% trauma-focused psychotherapy regimens would have
reported a 2, and 5% reported a 1 for adverse events, much better applicability to the clinical situation even
so most people did not report adverse events from though it would eliminate the ability to blind the
MDMA-assisted psychotherapy. Participants receiving patients and investigators. As it is, there is evidence that
MDMA-assisted psychotherapy reported the following the psychotherapists and patients in the current trials
benefits: 84% had improved feelings of well-being, 72% were able to determine who was receiving MDMA,
had less excess vigilance, 71% had fewer nightmares, taking away some of the internal validity benefits
69% had less avoidance, 69% had less anxiety, and of blinding.19 Another limitation is that when world
66% had improved sleep. Only 1.2% of participants experts in an area pioneer a treatment modality, the
reported feeling worse or having worse sleep, while benefits and the risks in those studies may not reflect
2.4% of participants reported increased nightmares, what is seen when the therapy is widely available and
avoidance, excessive vigilance, and anxiety.23 The short- being conducted by frontline practitioners. Future stud-
term adverse events from MDMA therapy need to be ies in which MDMA-assisted psychotherapy is assessed
weighed against these long-term benefits after the few vs other modalities by frontline practitioners will be
MDMA-assisted psychotherapy sessions have ended. important. A final limitation is that the patients in the
available trials had more severe PTSD as evidenced by
their high baseline CAPS scores.8,10,19–22 Future studies
MDMA’s Place in Therapy and Future Directions assessing MDMA in patients with less severe PTSD is
The Veterans Administration Department of Defense needed.
guidelines for systematic review specifies that trauma-
focused psychotherapy is preferable to pharmacother-
apy if it is available and the patient is able to access Conclusion
this care and is amenable to this treatment modality.13 Current pharmacologic therapies for PTSD must be
Pharmacotherapy, preferably with selective serotonin taken daily and have modest efficacy. MDMA-assisted
reuptake inhibitors (SSRIs) or venlafaxine, is an option psychotherapy is a novel experimental therapy that is
for those without access to trauma-focused psychother- only given in 2 or 3 sessions. The reductions in CAPS-
apy or those unwilling to engage in it.13 IV or CAPS-V scores are pronounced, the benefits
 15524604, 2022, 4, Downloaded from https://accp1.onlinelibrary.wiley.com/doi/10.1002/jcph.1995 by Universite Cote D'azur, Wiley Online Library on [29/12/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Smith et al 471

may be seen within a few weeks of the last session, 2002: 1-60. https://www.ptsd.va.gov/professional/assessment/
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10. Bouso JC, Doblin R, Farré M, et al. MDMA-assisted psy-
are completed. Long-term improvements in sleep,
chotherapy using low doses in a small sample of women with
nightmares, and general well-being were commonly chronic posttraumatic stress disorder. J Psychoactive Drugs.
reported. When MDMA was cautiously used in these 2008;40:225-236.
clinical trials, they were generally well tolerated, but 11. Foa E B, McLean C P, Zang Y, et al. Psychometric properties of
anxiety, nausea, vomiting, and jaw clenching are the posttraumatic stress disorder symptoms scale interview for
DSM-5 (PSSI-5). Psychol Assess. 2016;28:1159-1165.
commonly reported. The literature base is hampered
12. Guideline Development Panel for the Treatment of PTSD in
by small sample sizes within the clinical trials and a Adults, American Psychological Association: summary of the
lack of direct comparison to other drugs in treatment clinical practice guideline for the treatment of posttraumatic
of PTSD. Blood pressure is transiently increased stress disorder (PTSD) in adults. Am Psychologist. 2019;74:596-
during MDMA sessions, so the risk-benefit balance 607.
13. Veterans Affairs and Department of Defense. VA/DOD
is not as clear for those with underlying hypertension
Clinical Practice Guidleline for the Management of
or cardiovascular disease. Additionally, illicit MDMA Posttraumatic Stress Disorder. 2017; Version 3.0. https:
sources have not been studied and may have additional //www.healthquality.va.gov/guidelines/MH/ptsd/VADoDP
risks due to adulteration and contamination and TSDCPGClinicianSummaryFinal.pdf. Accessed September
these sessions used many safeguards to reduce risks 30, 2021.
14. Feduccia AA, Jerome L, Yazar-Klosinski B, Emerson A,
from both MDMA and reliving the traumatic event
Mithoefer MC, Doblin R. Breakthrough for trauma treat-
that must be in place before this therapy is tried in a ment: safety and efficacy of MDMA-assisted psychother-
patient. apy compared to paroxetine and sertraline. Front Psychiatry.
2019;10:650.
Conflicts of Interest 15. Nagy LM, Morgan CA, South SM, Charney DS. Open prospec-
tive trial of fluoxetine for posttraumatic stress disorder. J Clin
The authors declare that they have no conflicts of interest to Psychopharmacol. 1993;13:107-113.
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in posttraumatic stress disorder. J Clin Psychiatry. 1994;55:517-
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