Psychopharmacology (2021) 238:581–588

https://doi.org/10.1007/s00213-020-05710-w

ORIGINAL INVESTIGATION

Discontinuation of medications classified as reuptake inhibitors

affects treatment response of MDMA-assisted psychotherapy
Allison A. Feduccia 1 & Lisa Jerome 2 & Michael C. Mithoefer 2,3 & Julie Holland 4

Received: 27 April 2020 / Accepted: 10 November 2020 / Published online: 21 November 2020
# The Author(s) 2020

Abstract
Rationale MDMA-assisted psychotherapy is under investigation as a novel treatment for posttraumatic stress disorder (PTSD).
The primary mechanism of action of MDMA involves the same reuptake transporters targeted by antidepressant medications
commonly prescribed for PTSD.
Objectives Data were pooled from four phase 2 trials of MDMA-assisted psychotherapy. To explore the effect of tapering
antidepressant medications, participants who had been randomized to receive active doses of MDMA (75–125 mg) were divided
into two groups (taper group (n = 16) or non-taper group (n = 34)).
Methods Between-group comparisons were made for PTSD and depression symptom severity at the baseline and the primary
endpoint, and for peak vital signs across two MDMA sessions.
Results Demographics, baseline PTSD, and depression severity were similar between the taper and non-taper groups. At the
primary endpoint, the non-taper group (mean = 45.7, SD = 27.17) had a significantly (p = 0.009) lower CAPS-IV total scores
compared to the taper group (mean = 70.3, SD = 33.60). More participants in the non-taper group (63.6%) no longer met PTSD
criteria at the primary endpoint than those in the taper group (25.0%). The non-taper group (mean = 12.7, SD = 10.17) had lower
depression symptom severity scores (p = 0.010) compared to the taper group (mean = 22.6, SD = 16.69). There were significant
differences between groups in peak systolic blood pressure (p = 0.043) and diastolic blood pressure (p = 0.032).
Conclusions Recent exposure to antidepressant drugs that target reuptake transporters may reduce treatment response to MDMA-
assisted psychotherapy.

Keywords MDMA . MDMA-assisted psychotherapy . SSRI . SNRI . Taper . Discontinuation syndrome . Psychedelics . PTSD

Introduction serotonin reuptake inhibitors (SSRI), sertraline and paroxetine,

PTSD is a relatively prevalent disorder, affecting 3 to 4% of the
global population (Hoge et al. 2004; Koenen et al. 2017). People
with PTSD can face reduced quality of life in multiple areas,
from workplace productivity to interpersonal relationships, and
are at increased risk for suicidal thoughts or behavior (Sareen
et al. 2007; Shea et al. 2010). Currently available treatments
include pharmacotherapies and psychotherapies. Two selective
* Allison A. Feduccia
afeduccia@gmail.com
1
Psychedelic.Support, Project New Day, Santa Cruz, CA, USA
2
MAPS Public Benefit Corporation, Santa Cruz, CA, USA
3
Medical University of South Carolina, Charleston, SC, USA
4
Private Practice, New York, NY, USA
are the only FDA-approved medications for PTSD, but other
adjunctive drugs are also commonly prescribed for sleep distur-
bances and anxiety associated with PTSD.
Six phase 2 randomized, double-blind placebo-controlled
clinical trials were conducted to investigate MDMA-assisted
psychotherapy for PTSD treatment (Mithoefer et al. 2019;
Mithoefer et al. 2018; Mithoefer et al. 2011; Oehen et al.
2013; Ot’alora et al. 2018). In these studies, participants
worked with a male and female co-therapy team who followed
a manualized format of MDMA-assisted psychotherapy. The
manualized treatment includes a course of preparatory psy-
chotherapy, two to three 8-hour long MDMA sessions, and
follow-up integrative psychotherapy. Symptom assessment
was conducted by a blinded independent rater who was not
present during therapy sessions. Encouraging findings have
been reported from an analysis of data pooled across these
six studies (Mithoefer et al. 2019). Compared to the placebo/
582
control group that received the same psychotherapy, partic-
ipants receiving active doses of MDMA (75–125 mg) had
significant reductions in symptoms, as measured via
Clinician-Administered PTSD Scale for DSM IV (CAPS-
IV). The between-group Cohen’s d effect size was 0.8, in-
dicating a large effect for active doses of MDMA as an
adjunct to psychotherapy. There was also a trend for active
dose participants to experience greater reductions in symp-
toms of depression.
MDMA increases synaptic concentrations of serotonin,
norepinephrine, and dopamine by reversing the flow of
neurotransmitter through membrane-bound transporter
proteins (SERT, NET, and DAT, respectively). Several
medications commonly prescribed for PTSD and depression
target one or more of these transporters, including selective
serotonin reuptake inhibitors (SSRIs), serotonin-
norepinephrine reuptake inhibitors (SNRIs), norepinephrine re-
uptake inhibitors (NRIs), and norepinephrine-dopamine reup-
take inhibitors (NDRIs). When MDMA is co-administered
with a reuptake inhibitor such as citalopram or fluoxetine, the
subjective and psychological effects are markedly attenuated
(Farre et al. 2007; Hysek and Liechti 2012; Liechti et al.
2000). For this reason, in order to investigate the effects of
MDMA-assisted psychotherapy on PTSD symptoms, partici-
pants in phase 2 studies tapered off psychiatric medications
prior to commencing MDMA sessions.
Reuptake inhibitors all modulate monoaminergic signaling
by blocking re-uptake of neurotransmitters back into termi-
nals, and the subsequent changes in neuronal discharge and
transmitter release. In addition, long-term administration of
SSRIs desensitizes and downregulates 5-HT1A autoreceptors,
leading to reduced negative feedback and ultimately more 5-
HT released into the synapse (Richelson 2001). Since the full
therapeutic effects of antidepressants are present only after
weeks of daily dosing, involvement of several mechanisms
has been posited, such as effects on downstream gene tran-
scription, synaptogenesis, inflammation, and the
hypothalamic-pituitary-adrenal axis (Malberg and Schechter
2005; Stahl 1998; Walker 2013). After chronic treatment
with sertraline or paroxetine, SERT is downregulated to
varying degrees in humans, depending on the brain re-
gion, with greater SERT radioligand occupancy occurring
in brain regions associated with depressive symptoms,
namely the subgenual cingulate, amygdala, and raphe nu-
clei (Baldinger et al. 2014). In SSRI-treated rats, SERT
binding was decreased by 80–90% in the CA3 region of
the hippocampus, and this reduction was not attributed to
decreased SERT gene transcription, suggesting that
chronic use of SSRIs decreases synaptic SERT protein
levels (Benmansour et al. 1999). Other neurotransmitters,
such as GABA, dopamine, glutamate, and noradrenaline,
are affected indirectly by SSRIs and may play a role in
the antidepressant effects (Olver et al. 1999).
Psychopharmacology (2021) 238:581–588
Cessation of antidepressants is associated with a variety of
psychological and physiological withdrawal symptoms, de-
scribed as a discontinuation syndrome in the DSM-5.
Tapering reuptake inhibitors is recommended for discontinu-
ation, with longer periods (months) of tapering resulting in
reduced frequency and severity of adverse effects compared
to abrupt cessation or short tapers (2–4 weeks) (Horowitz and
Taylor 2019). In order to understand whether or not having
recently tapered off a medication targeting the same primary
binding sites as MDMA would affect treatment response, we
pooled data from four phase 2 studies that included both the
CAPS-IV and the Beck Depression Inventory-II (BDI-II).
PTSD and depression symptom severity were compared, as
well as vital sign values during MDMA sessions, between
participants that tapered off reuptake inhibitors and those that
did not because they had not been taking them at the time of
initial study screening.
Methods
Setting
Four randomized, double-blind trials were conducted at dif-
ferent study sites in the USA (studies MP-8, MP-12), Canada
(study MP-4), and Israel (study MP-9). These four trials all
included the BDI-II, while the other two early phase 2 trials
(MP-1, MP-2) did not, and therefore are not included in this
analysis. Data were collected from December 2010 to
March 2017. Trials were approved by the Western-
Copernicus Institutional Review Board (Research Triangle
or Cary, NC; MP-8, MP-12), IRB Services/Chesapeake
(Aurora ON; MP-4), and Helsinki Committee of Beer
Yaakov Hospital (Israel; MP-9).
Participants and study design
Participant recruitment, inclusion/exclusion criteria, and study
designs were covered in detail in prior publications (Mithoefer
et al. 2019; Mithoefer et al. 2018; Ot’alora et al. 2018).
Briefly, studies enrolled male and female participants with
chronic PTSD (symptoms lasting greater than 6 months),
and Clinician-Administered PTSD Scale for DSM IV
(CAPS-IV) severity scores ≥50 (MP-8, MP-9, MP-12) or ≥
60 (MP-4). Psychiatric medications were tapered and
discontinued prior to commencing experimental sessions.
The protocols specified for medications to be tapered gradu-
ally over a period of weeks to minimize withdrawal symp-
toms, and for them to be discontinued at least five half-lives
of each drug prior to MDMA administration. Anxiolytics and
sedative hypnotics were used as needed between experimental
sessions. Participants taking gabapentin for pain management
could continue to do so throughout the course of the study.
Psychopharmacology (2021) 238:581–588
Participants taking stimulants to treat attention deficit disorder
were permitted to take them during the study, but had to dis-
continue use for five half-lives prior to each MDMA session
through ten days after each session. All participants gave writ-
ten informed consent.
Enrolled participants were randomized to receive either
active doses of MDMA (75–125 mg) or a control dose (0–
40 mg MDMA) during psychotherapy sessions with a
male/female co-therapy team. Since the aim of this paper
is to evaluate the effect of having recently tapered off
reuptake inhibitors on the treatment response, only data
from participants who received active MDMA doses in the
blinded study segment are included in this analysis (see sup-
plemental content for control group CAPS scores). Blinded
doses were administered during two 8-h psychotherapy ses-
sions spaced 3–5 weeks apart. Each initial dose was followed
approximately 1.5–2.5 h later by an optional supplemental
dose equal to half the initial dose. Each blinded experimental
session was followed by three non-drug 90-min integrative
sessions. The primary endpoint occurred 1–2 months (de-
pending on the study) after the second blinded session.
Blinded independent raters, who were not present during
any psychotherapy sessions, administered the primary out-
come measure (CAPS-IV). Participants self-reported depres-
sion symptoms on a secondary measure (BDI-II).
Assessments
The CAPS-IV is a semi-structured interview addressing PTSD
symptom clusters recognized by the DSM-IV (re-experiencing,
avoidance, and hyperarousal) (Blake et al. 1995; Nagy et al.
1993; Weathers et al. 2001). The CAPS-IV contains frequency
and intensity scores for each of the three symptom clusters that
are summed to produce a total severity score, the primary out-
come for these studies. The CAPS-IV has a dichotomous diag-
nostic score for meeting PTSD diagnostic criteria.
The Beck Depression Inventory–II (BDI-II) is an
established 21-item measure of self-reported depression
symptoms (Beck et al. 1996). Responses are made on a
four-point Likert scale and summed to produce an overall
score.
To monitor safety, vital signs were measured before, dur-
ing, and after the experimental sessions. Blood pressure and
heart rate were measured in intervals of 15 to 30 min, and
body temperature every 60 to 90 min during MDMA sessions.
Statistical analysis
Data were pooled across four studies that all used the CAPS-
IV and BDI-II. Only data from participants randomized to
receive active doses of MDMA (75 mg, 100 mg, and
125 mg) were included in the analyses. All available data at
each endpoint was used and missing data was not imputed.
583
Participants were divided into two groups for exploratory
analyses. The taper group consisted of participants who ta-
pered off medications classified as reuptake inhibitors (see
Table 1) at the time of screening or enrollment prior to com-
mencing blinded sessions. Medications classified as reuptake
inhibitors included selective serotonin reuptake inhibitors,
serotonin-norepinephrine reuptake inhibitors, norepinephrine
reuptake inhibitors, and norepinephrine-dopamine reuptake in-
hibitors. The non-taper group consisted of participants who did
not taper medications in this drug class, but could have tapered
medications from other drug classes (e.g., benzodiazepines).
The primary analysis of CAPS-IV total severity scores was a
repeated measures ANOVA with time (baseline and primary
endpoint) as the within-subject factor and group (taper vs. non-
taper) as the between-subject factor. If significant main effects
were detected, Bonferroni post hoc tests were used for between
group comparisons. BDI-II total scores were analyzed with the
same method. Independent-samples t tests compared peak vital
signs across the two experimental sessions. Pearson correlation
analyses were used to determine the relationship between time
of abstinence (antidepressant stop date to first MDMA session
date), the change in CAPS-IV scores (primary endpoint–base-
line), and the average peak vital signs in the MDMA sessions.
Group differences in baseline characteristics, demographics,
and PTSD diagnostic criteria (CAPS-IV) were evaluated with
Pearson’s chi-squared test or independent-samples t test.
Results
Sample
Table 1 displays the demographics and baseline characteristics
of the taper and non-taper groups. Of the 50 participants ran-
domized to active MDMA doses (75–125 mg), 16 met criteria
for the taper group, and the other 34 for the non-taper group
(Table 2). Most participants tapered off one drug (n = 12), but
Table 1 Demographics and baseline characteristics
Taper group Non-taper group p value
N = 16 N = 34
Sex, n (%) n.s.
Female 9 (56.3) 15 (44.1)
Male 7 (43.8) 19 (55.9)
Age, mean (SD) 40.7 (14.19) 39.8 (11.35) n.s.
Race/ethnicity, n (%) n.s.
White/Caucasian 15 (93.8) 28 (82.4)
Latino/Hispanic 1 (6.3) 1 (2.9)
Other 0 5 (14.7)
n.s., not significant
584 Psychopharmacology (2021) 238:581–588

Table 2 Medications tapered

prior to experimental session 1 Taper group N = 16 Non-taper group N = 34

Tapered reuptake inhibitors, n (%)

Bupropion* 6 (37.5) 0
Citalopram 1 (6.3) 0
Desipramine 1 (6.3) 0
Desvenlafaxine 1 (6.3) 0
Duloxetine hydrochloride 1 (6.3) 0
Escitalopram** 2 (12.5) 0
Fluoxetine*** 2 (12.5) 0
Sertraline**** 5 (31.3) 0
Trazodone 2 (12.5) 0
Venlafaxine hydrochloride 1 (6.3) 0
Other tapered medications, n (%)
Anti-adrenergic drugs, peripherally acting 0 1 (2.9)
Antiepileptics 3 (18.8) 0
Anti-inflammatory and antirheumatic products 1 (6.3) 0
Antipsychotics 3 (18.8) 3 (8.8)
Anxiolytics 10 (62.5) 4 (11.8)
Beta-blocking agents 0 1 (2.9)
Hypnotics and sedatives 1 (6.3) 0
Psychostimulants 3 (18.8) 2 (5.9)
Opioids 1 (6.3) 2 (5.9)
Other analgesics and antipyretics 0 2 (5.9)
Nasal decongestant 0 1 (2.9)

n.s., not significant; NA, not applicable

*Includes bupropion hydrochloride
**Includes escitalopram oxalate
***Includes fluoxetine hydrochloride
****Includes sertraline hydrochloride

some participants tapered off two (n = 3) or three drugs (n =
1). Table 1 shows the number of participants that tapered
off each reuptake inhibitor. The average (SD) number of days
from when the medications were stopped to the first MDMA
session was 25.1 (17.7), range 4 to 70 days. The taper period
was required to be an appropriate length to avoid withdrawal
effects, but the start date for tapering period was not collected;
therefore the number of days for the taper period is unknown.
An interval of at least five times the particular drug and active
metabolites’ half-life plus 1 week for stabilization was needed
before the first MDMA session. One participant in the non-
taper group dropped out of the study prior to the primary
endpoint.
For the taper group, nine participants (56.3%) were female
with a mean (SD) age of 40.7 (14.19); for the non-taper group,
15 (44.1%) were female with a mean (SD) age of 39.8 (11.35).
The majority in both groups were White/Caucasian (non-taper
group: 82.4%; taper group: 93.8%). For these demographics,
there were no significant differences between groups.
Outcome measures–CAPS-IV and BDI-II
The mean (SD) change from baseline to the primary end-
point was −41.1 (19.86) for the non-taper group (n = 33)
and − 22.6 (33.80) for the taper group (n = 16). There was
a significant time × group interaction (F(1,47) = 5.86, p =
0.019) in the overall ANOVA for CAPS-IV scores. At
the end the primary endpoint (Table 3), the non-taper
group had significantly (p = 0.009) lower CAPS-IV total
scores (mean = 45.7, SD = 27.17) compared to the taper
group (mean = 70.25, SD = 33.60). More participants in
the non-taper group did not meet PTSD criteria at the
primary endpoint than those in the taper group (63.6%
vs. 25.0%), (X2(1) = 6.437, p = 0.011). There was no dif-
ference in CAPS-IV total scores at baseline between
groups. There was no significant correlation (r = 0.13,
p = 0.633) between the time of abstinence from the reup-
take inhibitor and the change in CAPS-IV total scores at
the primary endpoint.
Psychopharmacology (2021) 238:581–588 585

Table 3 Outcome measures and

vital signs Taper group Non-taper group p value
N = 16 N = 34a

CAPS-IV total scores, mean (SD)

Baseline 92.8 (13.47) 88.0 (19.37) n.s.
Primary endpoint 70.3 (33.60) 45.7 (27.17) 0.009
PTSD diagnostic criteria at primary endpoint, n (%) 0.016
Yes 12 (75.0) 12 (36.4)
No 4 (25.0) 21 (63.6)
BDI-II total scores, mean (SD)
Baseline 30.9 (11.18) 29.9 (11.89) n.s.
Primary endpoint* 22.6 (16.69) 12.4 (10.17) 0.010
Max vital signs**, mean (SD)
Systolic blood pressure 144.5 (18.54) 152.5 (17.60) 0.043
Diastolic blood pressure 87.8 (9.78) 93.1 (11.74) 0.032
Heart rate 103.8 (16.5) 101.3 (19.4) n.s.
Body temperature 37.2 (0.57) 37.2 (0.50) n.s.

CAPS-IV, Clinician-Administered PTSD Scale for DSM IV; BDI-II, Beck Depression Inventory-II; SD, standard
deviation
*At the primary endpoint n = 33 for the non-taper group
**Max vital signs during two blinded experimental sessions (MDMA 75–125 mg)

For BDI-II total scores, there was a significant time × group
interaction (F(1,47) = 4.88, p = 0.032) in the overall ANOVA.
The non-taper group (mean = 12.4, SD = 10.17) had lower
depression symptom severity (p = 0.010) at the primary end-
point compared to the taper group (mean = 22.6, SD = 16.69).
The mean (SD) change from baseline to the primary endpoint
was −17.2 (11.48) for the non-taper group and − 8.3 (16.70)
for the taper group. Baseline BDI-II scores were equivalent
between groups.
Vital signs
For vital sign values across the two blinded sessions, there
were significant differences between taper groups for peak
(maximum elevation) values during the session for systolic
(p = 0.043) and diastolic (p = 0.032) blood pressure. The
non-taper group had higher maximum blood pressure values
(systolic mean = 152.5, SD = 17.60; diastolic mean = 93.1,
SD = 11.74) than the taper group (systolic mean = 144.5,
SD = 18.54; diastolic mean = 87.8, SD = 9.78). No significant
between-group differences were detected for body tempera-
ture or heart rate, and no differences were found between
groups at the pre-dose measurement or the session endpoint
for any vital signs. The number of days abstinent from reup-
take inhibitors prior to the first MDMA positively correlated
with average maximum body temperature (r = 0.381, p =
0.032) during the MDMA sessions. Systolic (r = 0.326, p =
0.069) and diastolic blood pressure (r = 0.307, p = 0.088)
trended in the same direction, with longer periods of absti-
nence associated with higher max blood pressure readings.
Discussion
MDMA-assisted psychotherapy reduces PTSD symptom se-
verity. Recent prior use and tapering of medications that tar-
get monoamine reuptake transporters resulted in blunted
therapeutic and physiological responses to MDMA in phase
2 trials. Participants who tapered reuptake inhibitors at the
time of study enrollment had significantly higher CAPS
scores at the primary endpoint compared to participants
who had not recently taken medications in these drug clas-
ses. More participants still met PTSD diagnostic criteria in
the taper group (75%) compared to the non-taper group
(36.4%) at the primary endpoint. Moreover, expected in-
creases in systolic and diastolic blood pressure following
MDMA administration were reduced in the taper group
compared to the non-taper group.
There are a few possible explanations for these results.
The binding sites (SERT, NET, DAT) for MDMA may
have still been downregulated in individuals who tapered
reuptake inhibitor medications at the time of study enroll-
ment. In studies with knockout mice strains, SERT and
DAT were necessary for MDMA-stimulated efflux of se-
rotonin and dopamine in the striatum and prefrontal cor-
tex (Hagino et al. 2011). Transporter receptor occupancy
studies in humans have found that SSRI treatment at
586
minimum therapeutic doses resulted in a mean SERT oc-
cupancy of 76–85% (percent reduction in binding potential)
(Meyer et al. 2004), and in rats treated with SSRIs, receptor
densities are reduced to a similar extent (Wamsley et al.
1987). Because of these neuroadaptations, gradual tapering
is recommended for discontinuation of drugs in this class to
minimize withdrawal symptoms. The time required to re-
cover normal function remains uncertain, but patients can
experience withdrawal symptoms for weeks to months, and
sometimes even years after cessation of reuptake inhibitors
(Davies et al. 2018; Horowitz and Taylor 2019). The sever-
ity of withdrawal symptoms appears to be related to the
drug, dose, duration of taking the medication, taper dura-
tion, and step-down dosing patterns.
In addition to SERT, other serotonin receptors important
for modulating the effects of MDMA could have been func-
tioning differently after chronic use of these medications. For
example, rats were dosed daily with fluoxetine for 14 days and
subsequently challenged with a 5-HT1A agonist at various
time points after discontinuation. Two days post-treatment,
5-HT1A mediated release of ACTH and oxytocin was reduced
by 68–74% compared to placebo controls, and 60 days post-
discontinuation, oxytocin response was reduced by 26%
(Raap et al. 1999). MDMA enhances release of both oxy-
tocin and ACTH (Dumont et al. 2009; Grob et al. 1996;
Hysek et al. 2012). Increased oxytocin may partially medi-
ate the prosocial effects of MDMA and the processing of
negative emotional stimuli (Hysek et al. 2014; Kirkpatrick
et al. 2015), and both oxytocin and ACTH could be in-
volved in the therapeutic effects observed in MDMA-
assisted psychotherapy trials. Alterations in function of oth-
er serotonin receptors could also impact the subjective ef-
fects of MDMA. Prior studies have found less sensitivity of
5-HT2A and 5-HT4 receptors in humans after administration
of SSRIs (Haahr et al. 2014; Meyer et al. 2001). In the
MDMA-assisted psychotherapy trials, participants were re-
quired to have completed tapering off psychiatric medica-
tions at least five drug half-lives prior to starting the blinded
sessions. In this sample, there was a large range in the num-
ber of days of abstinence from the reuptake inhibitors but
there was no significant relationship between days of absti-
nence and PTSD symptom severity at the primary endpoint.
However, the small sample size and different types of med-
ications tapered may have occluded information about ab-
stinence duration and the treatment effect. A greater maxi-
mum body temperature during MDMA sessions was asso-
ciated with longer periods of abstinence, suggesting a larger
pharmacological effect of MDMA. The short taper duration
and minimal period of abstinence (average 25 days) may
not have been sufficient for neurotransmitter systems to
reach homeostatic equilibrium.
MDMA-induced elevations of vital signs are dependent
on enhanced monoamine release, which occurs through
Psychopharmacology (2021) 238:581–588
binding of MDMA to transporter proteins. Reduced peak
systolic and diastolic blood pressure in the taper group is
consistent with the hypothesized lower concentrations of
extracellular monoamines after MDMA administration in
this group. However, this is not concordant with findings
of no significant differences detected between groups for
peak heart rate or body temperature. It has been demonstrat-
ed that pre-treatment with the SSRI citalopram reduced
MDMA-induced increases in systolic and diastolic blood
pressure and heart rate, but not body temperature (Liechti
and Vollenweider 2001). MDMA-stimulated elevations in
body temperature are partially dependent on norepineph-
rine and possibly serotonin (Liechti 2014), although the
exact contribution of each transmitter remains unclear.
Taken together, this evidence suggests that the reduced rise
in blood pressure for the taper group in our sample may
have resulted from blunted efflux of serotonin after
MDMA administration.
The other possible explanation for the reduced response to
MDMA-assisted psychotherapy in the taper group is that par-
ticipants were experiencing withdrawal symptoms and dis-
continuation syndrome after cessation of medications. A
greater number of individuals in the taper
group discontinued anxiolytics and psychostimulants prior to
the first experimental session, which may have also elicited
negative effects. This could have influenced the results in one
of two ways. If participants were having bothersome psycho-
logical and somatic symptoms after stopping reuptake inhibi-
tors or other medications, they may not have been able to fully
engage in the therapeutic processing of traumatic memories
during MDMA sessions. Alternatively, some of the withdraw-
al symptoms could have overlapped with symptoms of PTSD
or depression, and therefore influenced the results of the
CAPS-IV or the BDI-II. However, baseline depression and
PTSD severity scores were equivalent between the taper and
non-taper groups, suggesting that withdrawal symptom sever-
ity was not responsible for the differences in outcome between
groups. In addition, withdrawal symptoms would not be likely
to cause a differential in blood pressure elevations. The place-
bo group showed a similar response across the taper/non-taper
groups to psychotherapy alone suggesting that discontinuation
of reuptake inhibitors did not interfere with psychotherapeutic
processing.
In a study of MDMA-assisted psychotherapy for social
anxiety in autistic adults (Danforth et al. 2018), one partic-
ipant failed to exhibit expected changes in vital signs and
reported no changes in subjective effects during the blinded
sessions. The co-therapy team and the participant both
guessed with high certainty that placebo had been adminis-
tered, but an analysis of a plasma sample taken during the
experimental session confirmed that MDMA had been
ingested. This person had tapered off an SSRI at the time
of study enrollment. Other factors besides medication
Psychopharmacology (2021) 238:581–588
tapering could be involved, but it is worth noting that a lack
of response to MDMA was observed in a different popula-
tion under investigation.
Limitations
There are limitations that should be noted in interpreting the
findings presented here. The sample sizes were small, with an
unequal number of participants in each group (taper group n =
16 vs. non-taper group n = 34), and data were pooled across
four similar studies at different sites. In the taper group, the
number and duration of medications tapered varied between
participants, and sample sizes were too small to determine
how these factors affected treatment responses. In addition,
the length of each medication taper was not available; there-
fore, we could not include this information in the analyses.
The taper group also discontinued other psychiatric medica-
tions which could have impacted outcomes. Given the number
of medications they were on at study enrollment, it is possible
that the taper group may have represented a more severe bur-
den of PTSD that was not reflected in the outcome measures.
Data from ongoing phase 3 trials will provide a larger sample
to further characterize the effects of discontinuation of specific
medications.
Conclusions
Discontinuation of antidepressant medications classified as
reuptake inhibitors reduced the positive outcomes of
MDMA-assisted psychotherapy compared to participants
who had not recently taken these medications. These prelim-
inary findings have implications for clinical practice if
MDMA-assisted psychotherapy becomes an FDA-approved
treatment after phase 3 trials are completed. Adjustments to
taper procedures, specifically allowing for a significantly lon-
ger period for tapering completely off reuptake inhibitors prior
to initiating MDMA sessions, could potentially increase the
effectiveness of MDMA when used as an adjunct to therapy.
Supplementary Information The online version contains supplementary
material available at https://doi.org/10.1007/s00213-020-05710-w.
Acknowledgments The authors thank the staff at MAPS and MAPS
PBC, the therapists and individuals who participated in these trials, and
the study site personnel.
Funding These four phase 2 studies were sponsored by the
Multidisciplinary Association for Psychedelic Studies (MAPS), a
501(c)(3) non-profit organization. MAPS provided the MDMA and fully
funded this study from private donations. MAPS Public Benefit
Corporation (MAPS PBC), wholly owned by MAPS, organized the trials.
Allison Feduccia received salary support for full time employment with
MAPS PBC. Lisa Jerome received salary support for full time employ-
ment with MAPS PBC. Michael Mithoefer received salary support for
587
work with MAPS PBC. Julie Holland received compensation from
MAPS PBC for her work as medical monitor.
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