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A Phase 2 Study of Methylenedioxymethamphetamine‑Assisted Therapy in Young Adults (18‑25) with Chronic Treatment‑Resistant Major Depressive Disorder

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What is this study about?

The study focuses on young adults aged 18 to 25 who have chronic, treatment‑resistant Major Depressive Disorder, a condition where persistent low mood and loss of interest do not improve with standard antidepressant medicines. The investigational approach combines a short course of psychotherapy with a single oral dose of MDMA, a substance that can temporarily increase feelings of empathy, reduce fear, and improve mood when used under strict medical supervision.

The purpose of the trial is to determine whether this combined therapy is safe and practical for this age group. Participants first undergo screening and baseline assessments, then attend a series of therapy sessions during which the medication is taken in capsule form. After the treatment phase, they continue with follow‑up visits to monitor any side effects and to observe changes in mood and daily functioning, while a separate group receives the same therapy at a later time for comparison.

1 enrollment and consent

after joining the study you sign consent forms that explain the purpose and procedures of the trial

you confirm that you are aged 18 to 25 years and have chronic treatment‑resistant major depressive disorder

2 baseline assessments

you complete questionnaires that measure depression severity and functional impairment

you undergo a physical examination, laboratory tests, and safety screening required before any medication is given

3 randomization

you are randomly assigned to either the immediate‑treatment group or the delayed‑treatment control group

the group assignment determines when you will receive the study medication

4 preparatory therapy sessions

you attend a series of therapy meetings with a trained therapist to build rapport and learn what to expect during the medication session

these sessions help you become familiar with the therapeutic approach used in the trial

5 medication session

on the scheduled day you receive midomafetamine in a dose of 200 mg taken orally as capsules

the dose may be adjusted by the therapist according to individual response, following a flexible dosing plan

you remain in a comfortable, supervised setting for several hours while the medication takes effect, with therapist support throughout

6 integration sessions

over the weeks following the medication day you attend multiple integration meetings

these sessions help you process the experience and apply any insights to daily life

7 follow‑up assessments

at predetermined intervals (for example, 1 week, 4 weeks, and 8 weeks after the medication session) you repeat the depression and functional questionnaires

you also undergo safety checks to monitor any side effects or adverse events

8 final evaluation

at the end of the study period you complete a final assessment of depression severity and functional impairment

all adverse events are recorded and the overall safety of the trial is evaluated

Who Can Join the Study?

  • Be between 18 and 25 years old.
  • Be able to speak and read Norwegian fluently so you can understand the therapy and communicate with the study team.
  • Be able to swallow pills.
  • Provide a trusted contact person (such as a relative, spouse, close friend, or other support) who can be reached by the study team if you become suicidal or cannot be contacted.
  • Agree to tell the study team about any new medical conditions or procedures within 48 hours of learning about them.
  • If you are a woman who could become pregnant (women of childbearing potential), you must have a negative pregnancy test at the start of the study and before each dosing session, and you must use a highly effective form of birth control (such as hormonal implants, intrauterine devices, or sterilization) through 30 days after the last dosing session.
  • Agree to follow certain lifestyle changes, including fasting and not taking specific medications before dosing sessions, not taking part in any other interventional clinical trials during the study, having someone drive you home after each dosing session, and committing to the study’s medication dosing, therapy, and other procedures. You must also provide a contact who can complete study questionnaires.
  • At the screening visit, meet the diagnostic criteria for moderate to severe Major Depressive Disorder (MDD) without psychotic features (using the DSM‑5 guidelines and a score of 20 or higher on the MADRS rating scale). Your depression must have lasted at least 2 years (chronic) and you must have tried at least two different treatments that did not work, including both antidepressant medications (pharmacological treatment) and psychotherapy. At least one of the failed treatments must be a course of psychotherapy, and at least one failure must be related to your current depressive episode. All previous treatments must have been given at appropriate doses, frequencies, and durations and must have been tolerable.

Who Cannot Join the Study?

  • Unable to give proper consent – you must be able to understand the study and agree to it.
  • Current or past psychotic disorder (such as schizophrenia) or bipolar disorder type 1 as identified by a clinical interview.
  • Diagnosis of autism spectrum disorder.
  • Having an active eating disorder that involves purging (self‑induced vomiting or misuse of laxatives) at the time of screening.
  • A medical condition that makes drugs that raise blood pressure and heart rate unsafe, such as a past heart attack (myocardial infarction), stroke (cerebrovascular accident), or aneurysm.
  • High blood pressure (≥140/90 mm Hg) measured on three separate occasions, known as essential hypertension.
  • History of serious heart rhythm problems called ventricular arrhythmia, except occasional harmless extra beats (premature ventricular contractions) without heart disease.
  • Having Wolff‑Parkinson‑White syndrome or any similar extra electrical pathway in the heart that has not been cured by a procedure called ablation.
  • Any significant heart rhythm disorder in the past year (such as atrial fibrillation, atrial tachycardia, atrial flutter, or paroxysmal supraventricular tachycardia) unless it was successfully treated by ablation and has been stable for at least one year without medication.
  • Abnormally long heart‑rate‑corrected QT interval (QTc) on an ECG – over 450 ms for men or over 460 ms for women – which can increase the risk of dangerous heart rhythms.
  • Other risk factors for a specific dangerous rhythm called Torsade de pointes, such as heart failure, low potassium (hypokalemia), or family history of Long QT Syndrome.
  • Significant ongoing dissociative symptoms (feelings of unreality or detachment).
  • Needing medicines that also lengthen the QT interval during the dosing sessions.
  • Current or past diagnosis of glaucoma unless cleared by an eye doctor.
  • Symptomatic liver disease or liver enzyme levels (AST/ALT) more than twice the normal upper limit.
  • Major depressive disorder that includes psychotic features.
  • History of very low sodium in the blood (hyponatremia) or very high body temperature (hyperthermia) that is clinically important.
  • Body weight less than 48 kg (about 106 lb).
  • Being pregnant or breastfeeding.
  • Having epilepsy (seizure disorder).
  • History of Hepatitis C virus infection unless it is inactive and has been evaluated and treated as needed.
  • Type 1 diabetes. Type 2 diabetes may be allowed only if heart disease is ruled out, the condition is stable, and a doctor approves.
  • Being a poor metabolizer of the enzyme CYP2D6, which affects how the study drug is processed.
  • Untreated or unstable hypothyroidism (underactive thyroid) unless you are on a stable dose of thyroid medication.
  • Moderate or severe alcohol or cannabis use disorder within the past year (meeting the clinical criteria for a disorder).
  • Any illicit drug use disorder (other than cannabis) or prescription drug misuse within the past year.
  • Current personality disorder of type A (paranoid, schizoid, schizotypal), type B (antisocial, borderline, histrionic, narcissistic), or type C (avoidant, dependent, obsessive‑compulsive) as assessed by a structured interview.
  • Serious risk of suicide, including recent frequent suicidal thoughts (score 4 or higher weekly) or any suicide attempt or preparatory behavior within the past six months.
  • Risk of harming others, as judged by the clinical interview and input from your treating psychiatrist.
  • Needing ongoing psychiatric medication (with some specific exceptions outlined in the study protocol).
  • Allergy or severe reaction to MDMA (midomafetamine) or any of its inactive ingredients (mannitol, magnesium stearate).
  • Use of monoamine oxidase inhibitors (MAOIs), a class of antidepressants that can interact dangerously with MDMA.
  • Being involved in a lawsuit where you could receive money for ongoing symptoms of depression or other psychiatric conditions.
  • Lack of sufficient personal resources, stable living situation, or ability to form a therapeutic relationship, as judged by the investigator.
  • Previous use of MDMA/ecstasy.
  • Any current problem that the investigator believes would interfere with participation in the study.
  • Previous treatment with electroconvulsive therapy (ECT) or ketamine.
  • Previous experience with psychedelic‑assisted therapy.

Where you can join this trial?

Verified and Recommended Sites

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Verified Sites

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Other Sites

Site Name City Country Status
Sykehuset Oestfold HF Kalnes Graalum Norway

Want to learn more about this study or check if you can participate? Contact us.

Trial status

Country Status Recruitment Start
Norway Norway
Not yet recruiting
01.01.2027

Trial locations

Midomafetamine is a medication that contains MDMA, a substance that can temporarily increase feelings of empathy, openness, and reduce fear. In the study participants take it by mouth in capsule form. It is being tested to see if, when combined with therapy, it can help young adults with severe depression that has not improved with other treatments. The trial checks whether it can be given safely and whether it might be useful.

The therapy used in the trial is a structured, manualized MDMA‑assisted psychotherapy. Participants meet with trained therapists in several sessions. The therapy is designed to help them talk about difficult feelings, learn new coping skills, and make sense of the experiences they have while the medication is active. This therapeutic approach works together with the medication to try to improve depression.

Investigated diseases:

Major Depressive Disorder – A mental health condition characterized by persistent feelings of sadness, loss of interest, and low energy. It often develops gradually and can last for weeks, months, or years if untreated. People may experience changes in sleep, appetite, and concentration as the condition continues. The symptoms tend to become more noticeable over time, affecting daily activities and relationships. Mood and motivation may fluctuate, but the overall pattern remains consistently low.

Trial ID:
2024-520319-42-01
Protocol code:
EMPATHY
Trial Phase:
Therapeutic exploratory (Phase II)

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