MDMA-assisted psychotherapy for treatment of anxiety and other psychological distress related to life-threatening illnesses: a randomized pilot study

This double-blind, placebo-controlled study (n=18) with MDMA (125mg, 2-3 sessions) in combination with psychotherapy found no significant difference in anxiety in a population with life-threatening illnesses. Though no significant group difference was found (p=.056), the study showed a large effect size (g=1.03) and a larger sample size might find a significant difference (favouring MDMA).

Abstract

“The success of modern medicine creates a growing population of those suffering from life-threatening illnesses (LTI) who often experience anxiety, depression, and existential distress. We present a novel approach; investigating MDMA-assisted psychotherapy for the treatment of anxiety in people with an LTI. Participants with anxiety from an LTI were randomized in a double-blind study to receive MDMA (125 mg, n = 13) or placebo (n = 5) in combination with two 8-h psychotherapy sessions. The primary outcome was change in State-Trait Anxiety Inventory (STAI) Trait scores from baseline to one month post the second experimental session. After unblinding, participants in the MDMA group had one open-label MDMA session and placebo participants crossed over to receive three open-label MDMA sessions. Additional follow-up assessments occurred six and twelve months after a participant’s last experimental session. At the primary endpoint, the MDMA group had a greater mean (SD) reduction in STAI-Trait scores, – 23.5 (13.2), indicating less anxiety, compared to placebo group, – 8.8 (14.7); results did not reach a significant group difference (p = .056). Hedges’ g between-group effect size was 1.03 (95% CI: – 5.25, 7.31). Overall, MDMA was well-tolerated in this sample. These preliminary findings can inform development of larger clinical trials to further examine MDMA-assisted psychotherapy as a novel approach to treat individuals with LTI-related anxiety.“

Authors: Philip E. Wolfson, Julane Andries, Allison A. Feduccia, Lisa Jerome, Julie B. Wang, Emily Williams, Shannon C. Carlin, Evan Sola, Scott Hamilton, Berra Yazar-Klosinski, Amy Emerson, Michael C. Mithoefer & Rick Doblin

Summary

Individuals facing a life-threatening illness often contend with anxiety, depression, anger, and despair. These feelings can exacerbate the distress already caused by the illness itself, and can affect recovery.

Early investigations with psychedelic compounds such as LSD suggested that psychoactive substances held promise in addressing distress, pain, and anxiety in people with LTIs. Results from studies suggest that psychedelics are an efficacious modality for the treatment of depression, anxiety, and psycho-existential distress among those with LTIs.

MDMA stimulates release of monoamines, elevates levels of oxytocin, reduces activity in the amygdala and right insular region in response to negative emotional stimuli, increases superior frontal cortex activity, and increases connectivity between the amygdala and hippocampus. This study examined the effects of MDMA-assisted psychotherapy on people with LTI-related anxiety.

Results

Ninety-two of 110 participants failed to meet eligibility criteria and were excluded from the study. Three participants were excluded after enrollment and prior to randomization. The overall sample had a mean age of 54.9 years, was mostly female and White/Caucasian, and had a history of anxiety, major depression, PTSD, or insomnia. Many participants were taking opioid medications, and several discontinued them before, during, or within 24 h after an experimental session.

The primary outcome was change in STAI-Trait anxiety scores35 from baseline to one-month post second blinded experimental session. The MDMA group had a greater mean (SD) change in STAI-Trait anxiety score compared to the placebo group, but these group differences were not statistically significant.

Results showed that the MDMA group significantly benefited vs. the placebo group for post-traumatic growth and mindfulness, but failed to reach statistically significant between-group differences on state anxiety, depression, sleep quality, and global functioning.

After three MDMA-assisted psychotherapy sessions, mean STAI-Trait anxiety scores decreased nearly 4 points from their last blinded session. Nearly all outcome scores improved from baseline to treatment exit and long-term follow-ups. In the overall ANOVAs, participants reported statistically significant improvements in PSQI sleep quality, GAF global functioning, FACIT physical well-being, FACIT social and family well-being, FACIT emotional well-being, FACIT functional well-being, and DAP subscales fear of death and neutral acceptance.

Participants showed significant increases in PTGI posttraumatic growth, SCS self-compassion, and FFMQ mindfulness after a traumatic event.

MDMA was well-tolerated, with the most commonly reported reactions being thirst, jaw clenching/tight jaw, dry mouth, headache, and perspiration. Most other TEAEs were likely associated with participants’ life-threatening illnesses, and one participant discontinued treatment after the primary endpoint.

Two participants reported two SAEs related to cancer progression during the follow-up period. Elevations in vital signs did not require any medical intervention and approached pre-drug values by session end.

At the end of each blinded session, participants and co-therapy team members were asked to guess whether MDMA or placebo had been administered. The investigators guessed correctly 32 of 36 sessions and incorrectly 4 of 36 sessions.

Discussion

In this study, participants who received MDMA-assisted psychotherapy had greater reductions in anxiety, although group differences did not reach statistical significance. The study was likely biased by one potential outlier and by participant belief in the MDMA group.

In the blinded portion of the study, individuals who took MDMA experienced improvements in depression, sleep quality, STAI-State anxiety, and global functioning. These results warrant larger clinical trials to examine MDMA-assisted psychotherapy as a novel approach to treat LTI-related anxiety.

After three MDMA sessions, participants had improved anxiety, depression, sleep, global functioning, wellbeing, self-compassion, mindfulness, and attitudes regarding death. These improvements were stable and above baseline levels at the 6- and 12-month follow-up visits, suggesting that MDMA-assisted psychotherapy might have the potential to provide long-term benefits.

MDMA-assisted psychotherapy reduced anxiety and other symptoms in people with chronic illnesses undergoing treatment. This effect was attributed to MDMA’s effect of decreasing amygdala activity, during presentation of negative stimuli, and increasing frontal lobe activity.

Outcome measures included STAI, BDI-II, PSQI, PTGI, MADRS, GAF, SCS, FFMQ, DAP, and FACIT at baseline, treatment exit, 6-month follow-up, and 12-month follow-up. Participants were randomized to receive MDMA or placebo.

Participants with PTSD were more likely to use MDMA, which stimulates mindfulness, introspection, and empathy toward oneself and others. MDMA may reduce anxiety through reducing attention and concern over the bodily experience of anxiety.

MDMA-assisted psychotherapy has demonstrated sustained reductions in PTSD symptoms in individuals who had failed to respond adequately to existing pharmacologic or psychotherapeutic treatments. This treatment may help people with life-threatening injuries by reducing fears of disease recurrence or death, and embracing compassion for self, others, and one’s situation.

During two MDMA sessions, subjects reported treatment emergent adverse events and expected reactions. The durability of improvement several months after treatment sessions demonstrates benefits might extend beyond the acute treatment effects.

MDMA was well-tolerated by individuals with life-threatening illnesses, and no participants discontinued treatment due to adverse effects related to MDMA. Psychiatric adverse events were infrequent, and MDMA was not associated with serious suicidal ideation or behavior.

The study was exploratory, small, and might have been influenced by a placebo effect. However, after three MDMA sessions, all participants showed significant improvements in outcomes at treatment exit, 6-month, and 12-month endpoints.

Conclusions

These findings provide preliminary evidence that MDMA-assisted psychotherapy may be a safe and feasible treatment for those with LTIs for anxiety reduction and relief of other psychiatric symptoms.

A Phase 2 clinical trial was conducted using a double-blinded, randomized, placebo-controlled design with an open-label crossover. Participants received 125 mg of MDMA over two to four weeks, with an optional supplemental dose of 62.5 mg 90 – 150 min after the initial dose.

A study was conducted in an outpatient psychiatric clinic in San Anselmo, CA, on people with life-threatening cancer or non-dementing neurological illnesses. The participants had scores on the State Trait Anxiety Inventory Trait subscale of 45 (of 80), indicating moderate to severe anxiety.

Methods

Participants with serious medical conditions were excluded, including those who were receiving primary treatment for their illness, had uncontrolled hypertension, had a history of significant cerebrovascular or cardiovascular disease, or had diabetes type I or II.

Participants were randomized to receive either MDMA or lactose in an approximate 1:3 ratio using a web-based randomization system with unique container numbers. The blind was broken after completion of all study assessments at the primary endpoint.

Participants prepared for blinded sessions with a male and female co-therapy team in three 60 to 90-min non-drug sessions. The first of two blinded experimental sessions occurred within five weeks of study enrollment, and participants received either 125 mg of MDMA or the placebo during each experimental session.

Participants were provided with eyeshades and headphones to support reflecting on internal thoughts and emotions, and were encouraged to “go within” their experience. Physiological measures were taken every half hour for the first four hours, and hourly for the remainder of the experimental session. The participants and co-therapy team members guessed which condition they had received, and the researchers recorded any potential biases that might have been introduced due to perceived group assignments inducing a placebo effect.

Participants received two integrative nondrug therapy sessions and one open-label MDMA psychotherapy session after each experimental session. They were assessed for anxiety, depression, and subjective sleep quality one month after the second experimental session and six and 12 months after the final experimental session.

The STAI is a well-established and stable measure of cross-situational and current mood anxiety. Other measures of anxiety, depression, and related symptoms included the Montgomery-sberg Depression Rating Scale and Beck Depression Inventory-II, as well as the Global Assessment of Functioning and the Functional Assessment of Chronic Illness Therapy Scale.

Adverse events were collected during the experimental sessions and for seven consecutive days following. The Columbia Suicide Severity Rating Scale was used to monitor suicidal ideation and behavior.

This was a feasibility study that was not powered to detect statistical significance. It included all participants at a given time point and used an intent-to-treat analysis for safety and efficacy measures.

The primary outcome measure was the change in STAI-Trait scores for measure of anxiety from baseline to one month after the second blinded experimental session.

Due to the small number of participants, data was pooled from each stage and analyzed using a one-way (time) repeated measures ANOVA. Within-subject Tukey’s pairwise tests were used to compare outcome scores at baseline, 6-month follow-up, and 12-month follow-up.

Acknowledgements

We express our gratitude to the eighteen individuals who participated in the study, the therapists who supported them, the study coordinator, the study data manager, the study media manager, the night attendants, and the family members who inspired, encouraged, and supported the study.

Author contributions

The study was designed by P.W., J.A., L.J., A.F., A.E., B.Y.K, R.D., M.M., and A.F., L.J., J.W., E.S., S.C, E.W, A.E., B.Y.K, R.D., M.M.

Funding

The Multidisciplinary Association for Psychedelic Studies provided the MDMA and funded this study. MAPS PBC organized the trial and MAPS PBC assisted with study design, monitoring, analysis, management and interpretation of data.

Competing interests

Philip Wolfson received contractual support from MAPS to serve as the study’s principal investigator, Julane Andries received compensation for her work as a therapist in the study from MAPS, Allison Feduccia received salary support for full time employment with MAPS, Lisa Jerome received salary support for full time employment with MAPS.

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