Come closer: a neurobiological analysis of the prosocial effects of MDMA

The neurobiological mechanism underlying prosocial behaviour (PSB) is yet not
known. Fundamental knowledge about this mechanism could lead to new input for
researchers seeking new insights into the biological mechanism of diseases in
which prosocial behaviour is lacking, such as autism spectrum disorder.
Additionally, knowledge about the mechanism underlying this positive kind of
behavior will also provide insights about why users proceed into repeated
(problematic) drug use.
In the current proposal the partydrug ecstasy (MDMA) will be used to induce a
prosocial state. The rationale for chosing MDMA is that MDMA differentiates
itself from other types of psychostimulants by its unique effects on social
behaviour. Acutely, it induces positive effects on social behaviour, referred
to as prosocial effects i.e. subjective feelings of closeness to, and openness
towards others, emotional warmth, enhanced well being, contentment, empathy and
euphoria. To date, these positive effects on social behaviour have almost
exclusively been assessed by means of self-reports or questionnaires. Besides
this lack of objective data, the mechanism underlying these effects is not
known.

In this study we will assess these prosocial effects in an objective way i.e.
by means of computer tasks and we will investigate the role of two potential
mediators and the role of a genotype variant in the mechanism underlying
prosocial behavior.

Main questions and hypotheses:
1) We would like to investigate the role of the hormone oxytocin in the
mechanism underlying MDMA-induced prosocial behavior. We hypothesize that
oxytocin will mimic MDMA-induced prosocial effects. This will be investigated
by comparing task performance after treatment with MDMA with that after
treatment with oxytocin and with placebo. Oxytocin concentrations after
treatments will also be assessed in the blood and correlated with performance
measures.

2) We would like to investigate the role of the 5-HT1a receptor in the
mechanism underlying MDMA-induced prosocial behavior. We hypothesize that the
5-HT1A receptor will block the occurence of prosocial effects after MDMA
intake. This will be investigated by comparing task performance after treatment
with MDMA alone with performance after treament with the MDMA-5-HT1a receptor
blocker combination and with placebo.

Minor question and hypothesis:
3) We would like to investigate the role of the serotonin transporter genotype
variants in the strength of MDMA-induced prosocial effects. We hypothesize that
MDMA users carrying the fast working SERT genotype variant (LaLa) will
experience more pronounced prosocial effects compared with the users carrying
the slow working variant. This will be investigated by including the genotype
variant as a dichotome variable (slow vs fast working variant) in the
statistical analysis.

Design:
The study will be conducted according to a double blind, placebo controlled,
crossover design with 4 treatment conditions on four occasions, separated each
by a minimum of 7 days washout.

Treatments:
Treatments will consist of MDMA (75mg) alone or in combination 5-HT1A receptor
blocker, oxytocin, and placebo . Treatment orders will be randomized by means
of a Latin Square. All treatments will have matching placebos.

MDMA (75mg) will be administered as a capsule. The 75mg-dose is based on
previous acute studies. Peak plasma levels are reached within 90 minutes.
Oxytocin (Syntocinon®) will be administered intranasally. This neuropeptide
crosses the blood-brain barrier reliably after intranasal administration. The
spray will be administered four times with a delay of 45s between
administrations + two additional administration in between testblocks. Each
administration will consist of one inhalation of the spray into each nostril.
Each inhalation will contain approximately 4 international units (IU) (total:
48 IU). Peak concentrations will be reached 45 minutes after administration.
The 5-HT1A receptor blocker (Pindolol; Visken® 20 mg) will be administered as a
capsule. Peak plasma levels are reached 60*post-administration; t1/2= 3 to 4
hours.

Administration of treatments (See study design) and collection of a blood
sample each test day to determine treament concentrations and oxytocin
concentrations in the blood.

The risks are confined to possible side effects of the treatments: MDMA,
Oxytocin (Syntocinon) and the 5-HT1a blocker (Visken). Subjects are MDMA users
and therefore familiar with possible side effects of MDMA.

Study burden in total: 18.5 hours, spread over minimally 5 weeks.