Ecstasy to Alleviate SEvere Chronic Neuropathic Pain Trial

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.