Liam Davenport

September 27, 2016

VIENNA — MDMA (3,4-methylenedioxymethamphetamine), also known as ecstasy, may enhance psychological therapy in patients with posttraumatic stress disorder (PTSD) by reducing thoughts about the self and boosting positive emotions, new research shows.

H. Valerie Curran, PhD, Clinical Psychopharmacology Unit, University College London, United Kingdom, told delegates attending the 29th European College of Neuropsychopharmacology (ECNP) Congress that in comparison with placebo, MDMA reduced brain activation in response to self-referent processing substantially increased activation while patients recalled positive memories.

Previous studies have shown that MDMA acutely enhances emotional empathy and prosocial feelings and decreases feelings of social rejection. It also impairs recognition of angry and fearful expressions, which is reflected in reduced responses in the amygdala to angry faces, said Dr Curran.

The drug has also been shown to facilitate identification of positive mental states in other people and to impair the categorization of negative mental states. Furthermore, acute MDMA makes speech seem more friendly and empathic.

The drug has been tested in small-scale studies for use in the management of treatment-resistant PTSD. In one pilot study in which two 125-mg doses of MDMA or placebo were given in conjunction with psychological therapy, MDMA was associated with marked reductions in the number of participants meeting the diagnosis for PTSD. The effects persisted for almost 4 years following treatment.

Because memory is central to both the theory and therapy of PTSD, Dr Curran and colleagues examined the impact of MDMA on the self-referent encoding of positive and negative descriptors and subsequent memory.

In a double-blind, repeat-measures study, the investigators randomly allocated 22 individuals to receive 100 mg of MDMA hydrochloride or placebo. Sixty minutes after taking the drug or placebo, participants were given a self-referent encoding task and, 80 minutes after that, an autobiographical memory task. Two weeks later, the participants who had been given MDMA were switched to placebo, and vice versa. The two groups were then given the tasks they had performed earlier.

Brain Imaging Findings

For the self-referent task, the participants were asked, while undergoing MRI, to describe themselves by choosing from 108 positive and negative words and then, following a 5-second rest, describe another referent individual, in this case, the professional soccer player Wayne Rooney.

As a control for the test, participants were asked to indicate whether each word that was presented to them contained more than two syllables. They then performed a recognition task, in which they were required to identify the 108 previously seen adjectives after those words had been placed among 108 unseen adjectives.

The results showed that, in comparison with placebo, MDMA significantly reduced brain activation with respect to positive and negative self-referent processing in the medial prefrontal cortex and left insula. In addition, oxytocin levels were significantly higher 2 hours after MDMA administration than after administration of placebo (P = .026). There was also a significant increase in the subjective rating of feeling of closeness to others.

For the retrieval of emotional autobiographical memories, the patients were exposed to traumatic memories by being asked to identify their six most positive and six most negative memories.

While undergoing MRI, the participants were given cues to recall the memories, which were divided in terms of their emotional potency during the MDMA and placebo sessions. The memories were rated again after the MRI scanning was complete.

MDMA was associated with augmented responses to the most positive memories on blood oxygenation level dependent (BOLD) imaging in the bilateral fusiform gyrus and with reduced responses to the most negative memories on BOLD imaging in the left anterior temporal cortex.

In addition, MDMA was associated with significant improvements in the ratings of the most positive autobiographical memories with respect to their emotional content (P = .008), vividness (P = .0003), and positivity (P = .001). The drug had only a marginal impact on the rating of the most negative memories; there was only a marginally significant change in reduction of perceived negativity (P = .049).

"[A]cute MDMA reduces the BOLD response in the medial prefrontal cortex and the insula to words that are encoded in relation to oneself compared with control words," said Dr Curran. However, she noted, there was "no effect on memory per se in terms of word recognition.

"MDMA enhances the vividness, emotional intensity, and positivity of best autobiographical memories, whilst only modestly reducing the negativity of worst memories. These effects, combined with MDMA's prosocial effects, may mean MDMA enhances psychological treatment via emotional memory processing, as well as enhancement of the therapeutic alliance. What we now need is more research on the interaction of MDMA with evidence-based psychological therapies," she added.

New Treatment Option?

David Baldwin, MD, PhD, professor of psychiatry and academic lead for general adult psychiatry for clinical academic training at the University of Southampton, United Kingdom, who cochaired the session, commented that the studies that have been conducted so far in PTSD "provide useful data for the management of treatment-resistant PTSD.

"There's very little known about what to do next when patients don't respond to an SSRI [selective serotonin reuptake inhibitor] or to trauma-focused psychotherapy, and there are many patients that remain substantially disabled by symptoms," he told Medscape Medical News.

"Actually, there are three positive trials of MDMA in psychotherapy in PTSD, both in acute treatment and in follow-up, in keeping people well who have responded, and those kinds of studies are very encouraging.

"What we don't really know is whether they can enhance psychotherapy – that is, the more conventional psychotherapies, as, for example, might be delivered within the UK. Those kinds of studies haven't been done.

"There aren't large randomized controlled trials [RCTs]. The trials that have been done have been done with small samples, with slightly unusual psychotherapies, and I think what they do suggest is that there is a need for a larger RCT with more standardized psychotherapy, in which, on top of that, they use MDMA as an augmenting agent."

Possibly one of the biggest barriers to the use of MDMA in the treatment of PTSD is not in proving its efficacy but in overcoming legal and political hurdles.

"The data are the data. The studies of MDMA in posttraumatic stress disorder were included within the guidelines for anxiety disorders produced by the British Association of Psychopharmacology, so people are becoming aware of them," said Dr Baldwin.

"I think they're also aware of the limitations of the trials, but it does open up people's minds to the possibility that these sorts of more 'novel' interventions could be useful. So I think it should encourage further research."

The researchers and Dr Baldwin have disclosed no relevant financial relationships.

29th European College of Neuropsychopharmacology (ECNP) Congress. Abstract S.23.02. Presented September 19, 2016.

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