The fourth in our series of 'in depth' interviews, with key people in the field, looking at their work and what it says about the future of applied neuroscience.

Among her many mantles, Harriet de Wit is a fellow of the American College of Neuropsychopharmacology, and professor at the Department of Psychiatry and Behavioral Neuroscience at the University of Chicago. Here she heads the Human Behavioural Pharmacology Laboratory, and has published widely in the human psychopharmacology of substance abuse and drug-associated conditioning and learning.
Her lab studies the behavioural effects of a number of psychoactive drugs on human volunteers, constructing a picture of the risk and resilience factors in the development of drug abuse, including genetics, stress, and environmental context.

At this year’s ECNP Congress, Professor de Wit will present some of this work, speaking in particular on the bidirectional relations between 3,4-Methylenedioxymethamphetamine (MDMA) and social context.

In conversation with ECNP, she described her reserach and the role MDMA could play in the future of psychotherapy.

Could you begin by introducing the therapeutic potential of MDMA: what do we already know and – importantly – what issues have you been exploring?
MDMA was widely used in the 1970’s as an adjunct in psychotherapy, purportedly because it decreased defensiveness and enhanced feelings of emotional closeness. That practice was stopped when the drug became illegal in the US. Since then, the drug has gained popularity as a ‘party drug’, used illegally in social contexts. Users claim that one of the main reasons for using it is its capacity to produce feelings of empathy and sociability.

In the last five years, a psychiatrist in Charleston, South Carolina named Michael Mithoefer has conducted controlled studies demonstrating the therapeutic value of MDMA in patients with post-traumatic stress disorder (PTSD). We've taken these promising findings another step by investigating, under laboratory conditions, the effects of single doses of the drug on emotional responses, cognition and social function, in healthy, non-patient participants.

We're trying to understand the basic psychological functions that the drug affects, which may shed light on its therapeutic value. We've sought psychological tasks and procedures that simulate mild emotional challenges, including both positive and negative emotional stimuli or events.

Are conditions such as PTSD a prime target, given MDMA’s putative potential in positively influencing autobiographical memory? And, while there certainly evidence in its favour, what do we actually know about how it achieves this?
We don't yet know how (i.e., by what psychological processes) MDMA helps in psychotherapy, especially for PTSD. It is possible that MDMA affects either positive or negative autobiographical memories, but we don’t know that yet for sure.

In our own studies, we've identified one possible psychological process that might help in psychotherapy: the drug seems to increase the threshold for detecting negative emotional expressions in others. When subjects are shown faces with angry expressions of varying intensity, they need to see a more intense version in order to identify the emotion as anger.

The drug does not affect happy expressions. We have also shown using brain imaging techniques that the drug reduces the brain’s signature response to negative expressions. It is possible that reduced sensitivity to judgement by others or negative expressions in others, could facilitate the psychotherapeutic process.

In your work, how do you go about study design, such that you can assess the positive and negative reception of the drug?
We try to use both images and real-life experiences to assess emotional reactivity to both positive and negative stimuli. To simulate negative social experiences we are currently using a public speaking task. We want to know whether MDMA dampens the stress of public speaking or social evaluation. To stimulate positive experiences we tested participants in a positive social setting to see whether the presence of others improved the experience. Using images, we have assessed participants’ reactions to positive and negative pictures (e.g., puppies, sunsets, bodily injuries), as well as to pictures of positive or negative emotions. We have also tested its effects on a simulated social rejection task (Cyberball). The outcome measures include subjective ratings, eye movements, smile or frown muscles, brain activation, and word usage in free speech.

How is recruitment managed? I can imagine in the early stages there a quite a few ‘willing’ volunteers that may have the wrong idea of what is to come…
We have an extensive recruitment and screening process, and only accept a small proportion of those who express interest in participating. Our rigorous inclusion/exclusion standards serve both safety and scientific purposes: we want to minimise any harm to participants, and we want to minimise variability from unknown sources in the participants’ responses.

Notably, at the time that subjects participate they do not know what drug they will receive, or even what class of drug it might be. We inform them of the possible side effects of MDMA. With respect to screening criteria for MDMA studies, we include only participants who have used the drug between four and 40 times in their lifetime, and they must be within a certain age range, weight range, have no medical problems, no psychiatric problems and no current drug use problems. With these precautions, we have not had any serious adverse reactions.

How far has our understanding come in terms of the mechanisms at play? You have written about the role of oxytocin, but you also note that there is only partial supporting evidence that oxytocin produces the prosocial effects of MDMA.
We don’t yet know how MDMA produces its effects and whether it is fully accounted for by oxytocin. MDMA does share a lot of effects with other prototypic stimulant drugs such as amphetamine (e.g., increased sociability, feelings of wellbeing) which don’t typically increase oxytocin, so at least some of its effects are probably related to its action on dopamine, norepinephrine and serotonin receptor systems.

Speaking more generally, are there any obstacles in securing funding and go-ahead for these types of research projects, or are we witnessing a shift in mind-set (particularly with respect to currently controlled substances)?
As with any drug that is not approved for medical purposes, there are lengthy regulatory processes to complete to get permission to use this drug. The process is time-consuming and we (the researchers) need to demonstrate that we are doing the research in a safe and responsible manner, and that the benefits outweigh the risks. Our research group is located in a hospital, with medical backup readily available should there be any adverse reactions. With regard to funding, if the work is safe, scientifically sound, and if it is relevant to public health, I do not see any serious obstacles to obtaining funding for research with MDMA or other similar drugs.

Recently science news have circulated a press release from scientists at the Multidisciplinary Association for Psychedelic Studies, who say that FDA approval of MDMA may come in as little as five years. Do you have any thoughts on this? And what will your lab be focusing on in the coming years?
I would say that research on therapeutic use should proceed with caution, and at least initially be conducted under close supervision in controlled settings. A rapid increase in availability or use in a broad range of clinical settings is likely to be associated with an increased incidence of adverse responses, which will set the field back again, in terms of public acceptance of drug-assisted psychotherapy.

Our group will continue to search for behavioural tasks that shed light on the psychological processes involved in the apparently unique effects of MDMA.

Harriet de Wit will speak at the 29th ECNP Congress in Vienna (17-20 September 2016) in session S.23 - Ecstasy, the love drug: acute effects of MDMA on psychosocial processes.