Antidepressants May Scupper Efficacy of MDMA for PTSD

Megan Brooks

February 09, 2021

Recent use of selective serotonin reuptake inhibitors (SSRIs) may reduce the treatment response to 3,4-methylenedioxymethamphetamine (MDMA)–assisted psychotherapy for posttraumatic stress disorder (PTSD), even if patients are no longer taking SSRIs.

Pooled data from four phase 2 trials reveal that patients with recent SSRI exposure were significantly more likely to continue to meet PTSD diagnostic criteria after MDMA-assisted psychotherapy than their peers who had not recently taken SSRIs.

Although preliminary, the findings have implications for clinical practice if MDMA-assisted psychotherapy is approved by the US Food and Drug Administration, Allison Feduccia, PhD, study coauthor and founder of the education platform Psychedelic.Support, told Medscape Medical News.

"As psychedelic medicines become available, it's going to be important that we try to understand what factors impact the response rate and if there are ways that we can improve the treatment outcomes. Allowing for a longer period for tapering completely off SSRIs before initiating MDMA sessions might increase the effectiveness of MDMA," Feduccia said.

The study was published online November 20 in Psychopharmacology.

Reduced Response

The primary mechanism of action of MDMA involves the same reuptake transporters that are targeted by antidepressant medications commonly prescribed for PTSD. These medications include SSRIs, serotonin-norepinephrine reuptake inhibitors (SNRIs), norepinephrine reuptake inhibitors (NRIs), and norepinephrine-dopamine reuptake inhibitors (NDRIs).

Prior research shows that when MDMA is coadministered with a reuptake inhibitor, subjective and psychological effects of the therapy are attenuated.

The researchers sought to determine whether or not recent tapering off of an antidepressant that targets the same primary binding sites as MDMA would affect treatment response. They analyzed data on 50 adults who underwent two sessions of MDMA-assisted psychotherapy in phase 2 clinical trials.

For sixteen of these patients, SSRI therapy was tapered off prior to the MDMA sessions. For 34 patients, SSRI therapy was not tapered off, because the patients had not been taking the medication at the time of initial study screening (nontaper group).

The taper protocols specified that medications be tapered gradually over a period of weeks to minimize withdrawal symptoms and for them to be discontinued at least five half-lives of each drug prior to MDMA administration. Most participants were tapered off one drug, but some were tapered off multiple drugs.

Demographics, baseline PTSD, and depression severity were similar between the taper and the nontaper groups. Participants in the studies had chronic PTSD (symptoms lasting >6 months). Severity scores on the Clinician-Administered PTSD Scale for DSM IV (CAPS-IV) were ≥50.

After MDMA-assisted psychotherapy, the nontaper group had significantly lower (better) CAPS-IV total scores compared to the taper group (mean, 45.7 vs 70.3; P = .009).

About two thirds (63.6%) of the nontaper group no longer met PTSD criteria after MDMA-assisted therapy, compared with only 25% of those in the taper group.

The nontaper group also had lower depression symptom severity scores on the Beck Depression Inventory–II compared to the taper group (mean, 12.7 vs 22.6; P = .010).

"Another really interesting" observation, said Feduccia, is that the expected increases in systolic and diastolic blood pressure following MDMA administration were reduced in the taper group compared to the nontaper group.

"This suggests that MDMA didn't have the same physiological response in individuals who tapered SSRIs. This should be followed up," she said.

The investigators offer several potential mechanisms for the negative effect of recent SSRI use on MDMA-assisted psychotherapy for PTSD.

These include the downregulation of binding sites (serotonin, dopamine, and/or norepinephrine) related to SSRI use; reduced MDMA treatment-relevant increases in blood pressure in patients with recent SSRI use; and the possibility that withdrawal symptoms from SSRIs may reduce the effectiveness of MDMA psychotherapy.

Important Clinical Implications

Reached for comment, Steven R. Thorp, PhD, professor, California School of Professional Psychology, Alliant International University, San Diego, California, said the findings are "very interesting" and likely "not well known."

"There has been great interest in MDMA-assisted psychotherapy in recent years, and if this finding is replicated, it will have important implications for that research," Thorp said.

"Although psychotherapy is often preferred by clients with PTSD, compared to medications, and typically shows efficacy that is as strong or stronger (and longer lasting) than medications, many individuals with PTSD are provided with medication only," Thorp noted.

"This study suggests that, in addition to the other potential disadvantages of medications (eg, cost, side effects, potential for addiction), those who take SSRIs, SNRIs, NRIs, and NDRIs for PTSD may also benefit less from MDMA-assisted psychotherapy," Thorp added.

The four phase 2 studies used in the analysis were sponsored by the Multidisciplinary Association for Psychedelic Studies (MAPS), a nonprofit organization. Feduccia received salary support for fulltime employment with MAPS Public Benefit Corporation. Thorp has disclosed no relevant financial relationships.

Psychopharmacol. Published November 21, 2020. Full text

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