MDMA for severe chronic neuropathic pain

Ecstasy to Alleviate SEvere Chronic Neuropathic Pain (EASE Pain) Trial: A Randomized Controlled Pilot Trial

This will try a single oral dose of MDMA combined with psychotherapy to see if it reduces pain and improves function in adults with moderate-to-severe chronic neuropathic pain that hasn't responded to standard medications.

Quick facts

• Phase: PHASE2
• Study type: Interventional
• Enrollment: 40 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: Unity Health Toronto (other)
• Locations: 1 site (Toronto, Ontario)
• Trial ID: NCT07301632 on ClinicalTrials.gov

What this trial studies

This is a randomized, triple-blind, two-arm pilot in which participants receive preparatory psychotherapy, a single oral 120 mg dose of MDMA (with an optional 40 mg supplemental dose at 2 hours) plus psychotherapy or an active placebo, followed by integrative psychotherapy and online home modules. The primary feasibility outcomes include recruitment, data completion, blinding integrity, and drug-related safety, with the primary clinical endpoint measured at 16 weeks and total subject participation lasting 16 weeks. Secondary clinical measures include change in pain interference (PROMIS-PI), physical function, activity, emotional function, global improvement ratings, and adverse events. All data are entered into REDCap and the study is conducted under Health Canada regulation at a single site.

Who should consider this trial

Good fit: Adults aged 18 and over with clinician-confirmed chronic neuropathic pain for more than 3 months, moderate-to-severe symptoms (PROMIS-PI ≥ 60 and average pain ≥ 5/10), and inadequate response to at least two guideline-recommended medications are the intended participants.

Not a fit: People with mild or non-neuropathic pain, those who cannot participate in required psychotherapy sessions or home modules, or those with contraindications to MDMA or relevant medical/psychiatric exclusions are unlikely to benefit or be eligible.

Why it matters

Potential benefit: If successful, this approach could offer a new single-dose MDMA-plus-psychotherapy option that meaningfully lowers pain interference and improves function for people with treatment-refractory neuropathic pain.

How similar studies have performed: MDMA-assisted psychotherapy has shown substantial benefits in randomized trials for PTSD, but its use for chronic neuropathic pain is novel and largely untested in large clinical trials.

Eligibility criteria

Inclusion Criteria:

* Consenting adults 18 years and older.
* Diagnosis of chronic neuropathic pain (greater than 3 months in duration) by a clinician with specialized training in chronic pain, confirmed with the standardized Leeds Assessment of Neuropathic Symptoms and Signs questionnaire.
* Suffering from moderate-to-severe pain as defined by
* Baseline Patient Reported Outcomes Measurement System - Pain Interference (PROMIS-PI) score of greater than or equal to 60
* An average pain intensity of greater than or equal to 5 on a 0-10 numeric rating scale,43
* Treatment-refractory pain as defined by a failure of ≥2 medications recommended in the Canadian consensus guidelines on the management of CNP to generate self-reported meaningful improvement in symptoms.
* For participants of childbearing potential, use of a highly effective or double-barrier methods of contraception. Abstinence is acceptable if it is the preferred and usual lifestyle of the participant.
* Sufficient English skills to participate in psychotherapy.

Exclusion Criteria:

* Past or current history of a psychotic disorder, mania, hypomania, bipolarity, current suicidal ideation, stimulant use disorder (i.e., cocaine, amphetamine, methamphetamine, MDMA, methylphenidate (Ritalin), etc , and any other substance use disorder within the past 12 months assessed by history and confirmed the Mini-International Neuropsychiatric Interview \[MINI\]. Other secondary psychiatric comorbidities (e.g., anxiety disorders, trauma related disorders, other personality disorders. etc.) will not be excluded
* Participants with a history of suicide attempts are not excluded unless a significant risk of suicidal behavior is present at the time of screening as determined by the CRSS (Columbia suicide rating scale)
* History of prior MDMA use (excluded to maintain blinding integrity)
* Long QT syndrome, measured by an ECG with a QTc more than 450 ms for males, and 470 ms for females.
* Presence of a relative or absolute contraindication to MDMA or Methylphenidate:
* Pre-existing cardiovascular disorders evidenced in clinical records or disclosed on patient self-report, such as: uncontrolled hypertension (sustained blood pressure ≥160/100 mmHg), angina (ongoing angina at rest, recent hospitalization for acute coronary syndrome within the past 3 months, or a history of revascularization (e.g., stenting or bypass surgery) within the past 6 months), arterial occlusive disease; heart failure, hemodynamically significant congenital heart disease, cardiomyopathies, myocardial infarction (within the past 6 months), potentially life-threatening arrhythmias (new-onset within the last 3 months), arrhythmias causing hemodynamic instability (SBP \< 90 mm Hg), or requiring urgent intervention (e.g., atrial fibrillation with rapid ventricular response or ventricular tachycardia), channelopathies, aneurysmal vascular disease (e.g., thoracic and/or abdominal aorta, intracranial, and peripheral arterial vessels), advanced arteriosclerosis
* Cerebrovascular conditions: acute stroke or recent history of intracerebral hemorrhage (ischemic or hemorrhagic stroke occurring within the past 6 months)
* Conditions at risk of elevation of blood pressure and increase heart rate, such as glaucoma, tension, agitation, thyrotoxicosis, pheochromocytoma
* Motor tics and/or family history or diagnosis of Tourette's syndrome
* Moderate to severe chronic kidney disease or kidney failure, such as requiring dialysis, significant treatment adjustments for kidney function, or regular nephrologist follow-up)
* Moderate to severe liver disease, such as cirrhosis, a history of significant jaundice unrelated to temporary illness, or any liver condition requiring regular monitoring by a specialist).
* Current treatment with selective serotonin reuptake inhibitors (SSRI's) and serotonin-norepinephrine reuptake inhibitors (SNRI's), tricyclic antidepressants, serotonin 5-HT1 receptor agonists (triptans) and 5-HT3 receptor antagonist antiemetics (risk of Serotonin Syndrome)
* Hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption (methylphenidate contains lactose)
* Seizure disorders
* Pregnancy, or breastfeeding
* Known hypersensitivity to study drugs or any study drug excipients
* Medications that interact with study drugs including:
* Any lifetime history use of any stimulant medication (e.g., Adderall, Vyvanse, Ritalin)
* Caffeine intake within 24 hours
* Monoamine oxidase inhibitors (MAOI) within 14 days (e.g. phenelzine, moclobemide, isoniazid, linezolid, phenelzine, harmine) due to risk of hypertensive crisis
* CYP2D6 substrates and modifiers (such as: buproprion, fluoxetine, paroxetine, duloxetine, mirabegron).
* Adrenergic agents (e.g. clonidine) risk of sudden death
* Vasopressor agents (ephedrine pseudoephedrine)
* Coumarin anticoagulants (e.g., warfarin),
* Anticonvulsants (e.g., phenobarbital, diphenylhydantoin, primidone)
* Anti-psychotics and inhibitors of dopamine uptake (e.g. haloperidol, DOPA, tricyclic antidepressants)
* Concomitant medication that could prolong ECG QT interval (e.g. ondansetron, risperidone, methadone)
* Selective Serotonin Reuptake Inhibitors (citalopram, sertraline, fluvoxamine, escitalopram)
* Selective Norepinephrine Uptake Inhibitors (e.g. venlafaxine, duloxetine); Serotonergic Drugs (e.g. dextromethorphan, fentanyl, St. John's Wort, tramadol, 5-hydroxytryptophan); serotonin 5-HT1 receptor agonists (triptans) and 5-HT3 receptor antagonist antiemetics due risk of Serotonin Syndrome which is a potentially life- threatening condition
* Currently engaged in psychotherapy for CNP (other psychotherapy for non-CNP is allowed).
* Any other clinically significant medical illness that, in the opinion of the investigator, may interfere with the interpretation of the study results or constitute a health risk for the participant if they take part in the study.

Where this trial is running

Toronto, Ontario

• St. Michael's Hospital — Toronto, Ontario, Canada (RECRUITING)

Study contacts

• Principal investigator: Akash Goel, MD,MPH,FRCPC — Unity Health Toronto
• Study coordinator: Akash Goel, MD,MPH,FRCPC

Conditions: Chronic Neuropathic Pain, 3, 4-methylenedioxymethamphetamine hydrochloride