Circulating Oxytocin Changes in Response to MDMA vs. Placebo in Adult Patients With Autism Spectrum Disorder and Matched Healthy Controls

Circulating Oxytocin Changes in Response to MDMA vs. Placebo in Adult Patients With Autism Spectrum Disorder and Matched Healthy Controls

This study is to investigate the physiological mechanism of oxytocin system stimulation using 3,4-methylenedioxymethamphetamine (MDMA) as a physiological tool (acute oxytocin releases), not as a medication. This study seeks to test whether the oxytocin response after MDMA administration is different between individuals with autism spectrum disorder and matched healthy controls.

Oxytocin is a hypothalamic neuropeptide released both peripherally and centrally that modulates social behavior, emotional processing, and cognition through receptors in regions such as the amygdala, nucleus accumbens, and prefrontal cortex. Clinical, neurobiological, and genetic studies indicate altered oxytocin signaling in autism spectrum disorder (ASD): meta-analyses show lower peripheral oxytocin levels, reduced receptor binding in some brain areas (especially in females), and correlations between higher peripheral oxytocin receptor expression and better social functioning. Over the past two decades, oxytocin has been evaluated as a therapy for ASD, mainly to target social deficits. While exogenous oxytocin can transiently enhance social cognition and connectivity, long-term trials remain inconclusive. As with other hormone deficiencies, single basal oxytocin measurements are unreliable. An emerging alternative is the use of MDMA, which robustly increases circulating oxytocin concentrations in healthy individuals. Measuring oxytocin release after a standardized MDMA challenge could clarify whether ASD patients retain a functional oxytocinergic response, with a blunted release indicating pathway dysfunction.

The OxySPECTRUM study will address this by administering a single dose of MDMA to high- functioning ASD patients and matched neurotypical controls, comparing plasma neurophysin I (equimolar oxytocin surrogate marker) area under curve (AUC) responses.

Inclusion Criteria for patients:

• Adult patients with a confirmed diagnosis of autism spectrum disorder level 1 according to Diagnostic and Statistical Manual (DSM) V

Inclusion criteria for healthy controls:

• Adult healthy controls
• Matched for age, sex, BMI, and oestrogen replacement/menopause/hormonal contraceptives to patients
• No medication, except hormonal contraception
• A score of <32 in the Autism Spectrum Quotient

Exclusion Criteria:

• Participation in a trial with investigational drugs within 30 days
• Illicit substance use (except for cannabis) more than 10 times in lifetime or any time within the previous two months
• Consumption of alcoholic beverages >15 drinks/week
• Tobacco smoking >10 cigarettes/day
• Cardiovascular disease (coronary artery disease, heart failure, left ventricular ejection fraction (LVEF) <40%, stroke in the last 3 months, atrial fibrillation/flutter, Wolff-Parkinson-White (WPW)-Syndrome)
• Uncontrolled arterial hypertension (>140/90 mmHg) or hypotension (<85mmHg)
• Current or previous major psychiatric disorder (e.g., major depression, schizophrenia spectrum disorder)
• Psychotic disorder in first-degree relatives
• Pregnancy and breastfeeding
• Diagnosed CKD > grade III (GFR < 30ml/min)
• Diagnosed liver cirrhosis or alanine aminotransferase (ALAT) or aspartate aminotransferase (ASAT) levels 2.5 times above the normal range
• Confirmed epilepsy diagnosis
• Diagnosed autism spectrum disorder level 2 or 3 (according to DSM V criteria)