Pooled analysis of four phase 2 trials found that participants who had not recently tapered off reuptake‑inhibiting antidepressants showed significantly greater reductions in PTSD and depression symptoms and were more likely to no longer meet PTSD criteria after MDMA‑assisted psychotherapy than those who had tapered. The findings suggest recent exposure to reuptake‑targeting antidepressants may blunt MDMA’s therapeutic effects and alter cardiovascular responses.
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.
Feduccia and colleagues frame the study within ongoing investigations of MDMA-assisted psychotherapy as a treatment for post-traumatic stress disorder (PTSD). Earlier phase 2 trials demonstrated large between-group reductions in CAPS‑IV PTSD severity for participants receiving active MDMA (75–125 mg) plus manualised psychotherapy compared to control doses, and MDMA is known to increase synaptic serotonin, norepinephrine, and dopamine via reversal of transporter proteins (SERT, NET, DAT). Because many commonly prescribed antidepressant medications for PTSD (SSRIs, SNRIs, NRIs, NDRIs) act on the same reuptake transporters, prior studies have shown that co-administration or recent use of such drugs can attenuate MDMA's subjective and physiological effects, and participants in the phase 2 trials were required to taper off psychiatric medications before MDMA sessions to minimise interactions and withdrawal effects. This paper pools data from four phase 2 randomized, double-blind trials to explore whether recent tapering off medications classified as reuptake inhibitors affected clinical and physiological responses to active MDMA-assisted psychotherapy. The investigators compared PTSD severity (CAPS‑IV), depression symptoms (BDI‑II), and peak vital signs during MDMA sessions between participants who had tapered off reuptake inhibitors prior to blinded sessions (taper group) and those who had not been taking such medications at screening (non-taper group). The intent was to assess whether recent exposure to reuptake inhibitors blunts treatment response to MDMA-assisted psychotherapy and to characterise any related physiological differences.
Using pooled data from four randomized, double-blind Phase II trials conducted in the USA, Canada, and Israel between December 2010 and March 2017, the study analysed only participants who were randomised to receive active doses of MDMA (75 mg, 100 mg, or 125 mg) during the blinded segment. The trials shared a manualised psychotherapy format that included preparatory sessions, two 8‑hour blinded MDMA-assisted psychotherapy sessions spaced 3–5 weeks apart (each with an optional supplemental half-dose 1.5–2.5 hours after the initial dose), and three non-drug integrative sessions afterwards. The primary outcome assessment occurred 1–2 months after the second blinded session and was administered by independent blinded raters. Participants were adults with chronic PTSD (symptoms >6 months) meeting CAPS‑IV severity thresholds (≥50 in most studies, ≥60 in one study). Psychiatric medications were tapered and discontinued prior to experimental sessions according to protocol guidance (medications to be discontinued at least five half-lives before MDMA), though the extracted text notes that exact taper start dates and taper durations were not collected. The investigators divided the analytic sample into a taper group (participants who had tapered off medications classified as reuptake inhibitors prior to the blinded sessions) and a non-taper group (participants who had not been taking reuptake inhibitors at screening; they may have tapered other drug classes). Primary analyses consisted of 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 for CAPS‑IV total scores and BDI‑II total scores; Bonferroni post hoc tests were applied when main effects were detected. Independent-samples t tests compared peak (maximum) vital signs across the two MDMA sessions between groups. Pearson correlations explored relationships between days abstinent from reuptake inhibitors (stop date to first MDMA session), change in CAPS‑IV scores, and average peak vital signs. Baseline group comparisons used chi-squared tests or independent t tests as appropriate. All available data at each endpoint were used and missing data were not imputed.
Fifty participants randomised to active MDMA doses comprised the analytic sample, of whom 16 were classified in the taper group and 34 in the non-taper group; one participant in the non-taper group dropped out before the primary endpoint. The extracted text does not clearly report mean ages for each group. Most participants tapered one reuptake inhibitor (n = 12), with a few tapering two (n = 3) or three (n = 1) drugs. The average number of days from medication cessation to the first MDMA session was 25.1 (SD 17.7), range 4–70 days; taper start dates and taper durations were not recorded. For the primary outcome, CAPS‑IV total severity, there was a significant time × group interaction (F(1,47) = 5.86, p = 0.019). The mean change from baseline to primary endpoint was −41.1 (SD 19.86) for the non-taper group (n = 33 at endpoint) and −22.6 (SD 33.80) for the taper group (n = 16). At the primary endpoint, the non-taper group had significantly lower CAPS‑IV scores (mean 45.7, SD 27.17) than the taper group (mean 70.25, SD 33.60), p = 0.009. A greater proportion of participants in the non-taper group no longer met PTSD diagnostic criteria at the primary endpoint (63.6%) compared to the taper group (25.0%); chi-squared X2(1) = 6.437, p = 0.011. There was no significant correlation between days abstinent from reuptake inhibitors and change in CAPS‑IV scores (r = 0.13, p = 0.633). Depression symptoms measured by BDI‑II also showed a significant time × group interaction (F(1,47) = 4.88, p = 0.032). The non-taper group had lower BDI‑II scores at the primary endpoint (mean 12.4, SD 10.17) than the taper group (mean 22.6, SD 16.69), p = 0.010. Mean changes from baseline to endpoint were −17.2 (SD 11.48) for non-taper and −8.3 (SD 16.70) for taper. Regarding physiological responses during MDMA sessions, the non-taper group exhibited higher peak blood pressure values: systolic mean 152.5 (SD 17.60) versus 144.5 (SD 18.54) in the taper group (p = 0.043), and diastolic mean 93.1 (SD 11.74) versus 87.8 (SD 9.78) (p = 0.032). No significant between-group differences were found for peak heart rate or body temperature, nor were there differences at pre-dose or session endpoint measurements. Days abstinent prior to the first MDMA session positively correlated with average maximum body temperature during sessions (r = 0.381, p = 0.032); correlations with systolic (r = 0.326, p = 0.069) and diastolic blood pressure (r = 0.307, p = 0.088) trended in the same direction but did not reach conventional significance.
Feduccia and colleagues interpret the pooled results as evidence that recent prior use and tapering of medications targeting monoamine reuptake transporters was associated with attenuated clinical and physiological responses to MDMA-assisted psychotherapy in these Phase II samples. Participants who had tapered reuptake inhibitors showed smaller reductions in PTSD severity and depression scores and were less likely to no longer meet PTSD diagnostic criteria at the primary endpoint, while also demonstrating smaller MDMA-induced rises in systolic and diastolic blood pressure compared with participants who had not recently taken such medications. The authors propose biological explanations centred on transporter and receptor adaptations induced by chronic reuptake inhibitor treatment. Long-term SSRI use can downregulate SERT expression and alter other serotonin receptor function (for example, diminished 5-HT1A-mediated hormonal responses and reduced sensitivity of 5-HT2A/5-HT4 receptors), which could blunt MDMA-stimulated efflux of monoamines and downstream release of oxytocin and ACTH—mechanisms thought to contribute to MDMA's subjective and therapeutic effects. Reduced extracellular monoamine increases after MDMA would also be consistent with the smaller blood pressure elevations seen in the taper group. The authors note, however, that body temperature and heart rate did not differ between groups, and that precise contribution of each monoamine to physiological effects remains uncertain. Withdrawal or discontinuation syndrome is offered as an alternative or complementary explanation. Participants in the taper group often discontinued multiple medications and may have experienced withdrawal symptoms that either interfered with therapeutic engagement during MDMA sessions or overlapped with PTSD and depression measures. Nonetheless, baseline CAPS‑IV and BDI‑II scores were equivalent between groups, and the placebo/control psychotherapy arm (reported in supplemental material) did not show taper-related differences, which the authors interpret as evidence that discontinuation effects alone do not fully account for the observed differences in MDMA response. The lack of a relationship between days abstinent and PTSD outcome is acknowledged, with the authors suggesting that the small sample size, heterogeneity of medications tapered, and variable abstinence intervals (average 25 days, range 4–70) may have obscured any temporal effects. Key limitations are highlighted: small and unequal group sizes (taper n = 16, non-taper n = 34), pooling across multiple sites, heterogeneity in the specific medications and number of drugs tapered, and absence of recorded taper durations or start dates. The taper group also discontinued other psychiatric medications which could have influenced outcomes, and the possibility that the taper group represented a more severe clinical burden is acknowledged though not evident in baseline measures. The authors conclude that these preliminary findings warrant attention in ongoing and future trials, and that phase 3 data with larger samples will be needed to characterise effects of discontinuation of specific medications more precisely. Finally, the investigators suggest a practical implication: if confirmed, allowing substantially longer tapering and abstinence periods off reuptake inhibitors prior to MDMA-assisted psychotherapy might increase treatment efficacy, a consideration for clinical practice should MDMA-assisted psychotherapy gain regulatory approval.
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. Participants were divided into two groups for exploratory analyses. The taper group consisted of participants who tapered off medications classified as reuptake inhibitors (see Table) at the time of screening or enrollment prior to commencing blinded sessions. Medications classified as reuptake inhibitors included selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, norepinephrine reuptake inhibitors, and norepinephrine-dopamine reuptake inhibitors. 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. nontaper) 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-baseline), 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.
MDMA-assisted psychotherapy reduces PTSD symptom severity. Recent prior use and tapering of medications that target 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 classes. 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 increases 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 enrollment. In studies with knockout mice strains, SERT and DAT were necessary for MDMA-stimulated efflux of serotonin and dopamine in the striatum and prefrontal cortex. Transporter receptor occupancy studies in humans have found that SSRI treatment at minimum therapeutic doses resulted in a mean SERT occupancy of 76-85% (percent reduction in binding potential), and in rats treated with SSRIs, receptor densities are reduced to a similar extent. Because of these neuroadaptations, gradual tapering is recommended for discontinuation of drugs in this class to minimize withdrawal symptoms. The time required to recover normal function remains uncertain, but patients can experience withdrawal symptoms for weeks to months, and sometimes even years after cessation of reuptake inhibitors. The severity of withdrawal symptoms appears to be related to the drug, dose, duration of taking the medication, taper duration, and step-down dosing patterns. In addition to SERT, other serotonin receptors important for modulating the effects of MDMA could have been functioning differently after chronic use of these medications. For example, rats were dosed daily with fluoxetine for 14 days and subsequently challenged with a 5-HT 1A agonist at various time points after discontinuation. Two days post-treatment, 5-HT 1A mediated release of ACTH and oxytocin was reduced by 68-74% compared to placebo controls, and 60 days postdiscontinuation, oxytocin response was reduced by 26%. MDMA enhances release of both oxytocin and ACTH. Increased oxytocin may partially mediate the prosocial effects of MDMA and the processing of negative emotional stimuli, and both oxytocin and ACTH could be involved in the therapeutic effects observed in MDMAassisted psychotherapy trials. Alterations in function of other serotonin receptors could also impact the subjective effects of MDMA. Prior studies have found less sensitivity of 5-HT 2A and 5-HT 4 receptors in humans after administration of SSRIs). In the MDMA-assisted psychotherapy trials, participants were required to have completed tapering off psychiatric medications at least five drug half-lives prior to starting the blinded sessions. In this sample, there was a large range in the number of days of abstinence from the reuptake inhibitors but there was no significant relationship between days of abstinence and PTSD symptom severity at the primary endpoint. However, the small sample size and different types of medications tapered may have occluded information about abstinence duration and the treatment effect. A greater maximum body temperature during MDMA sessions was associated 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 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 demonstrated that pre-treatment with the SSRI citalopram reduced MDMA-induced increases in systolic and diastolic blood pressure and heart rate, but not body temperature. MDMA-stimulated elevations in body temperature are partially dependent on norepinephrine and possibly serotonin, 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 participants were experiencing withdrawal symptoms and discontinuation syndrome after cessation of medications. A g r e a t e r n u m b e r o f i n d i v i d u a l s i n t h e t a p e r 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 psychological and somatic symptoms after stopping reuptake inhibitors 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 withdrawal 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 severity 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 placebo 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, one participant 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 administered, 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 tapering could be involved, but it is worth noting that a lack of response to MDMA was observed in a different population under investigation.
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Randomised, triple-blind, placebo-controlled Phase II trial (n=14) of MDMA-assisted psychotherapy for PTSD comparing full dose (125 mg + optional 62.5 mg booster) versus low active placebo (25 mg + optional 12.5 mg booster) across three 8-hour therapy sessions.
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