Clinical trial NCT03752918: The Effects of MDMA on Prefrontal and Amygdala Activation in PTSD.
Official title: The Effects of MDMA on Prefrontal and Amygdala Activation in Posttraumatic Stress Disorder
Study type: INTERVENTIONAL
Overall status: WITHDRAWN
Phase: PHASE1
Conditions: Post Traumatic Stress Disorder
Keywords: MDMA
Lead sponsor: Yale University
Sponsor class: OTHER
First posted: 2018-11-26
Enrollment: 0
Sex: ALL
Minimum age (years): 21
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: This study will be a double-blind, placebo-controlled, within-subjects, crossover-dose neuroimaging study in which participants will initially receive either a single dose of MDMA 1.5mg/kg or a placebo (niacin 250mg), with a crossover dose to follow. Doses will be separated by 2 weeks.
Primary purpose: TREATMENT

Brief summary: This study aims to investigate the effects of MDMA on prefrontal and amygdala activation, and to explore the relationship between these MDMA-induced neural changes and the acute behavioral effects of the drug in patients with PTSD.

Detailed description: The investigators intend to utilize state-of-the-art validated Human Connectome Project (HCP) style approaches to determine the effects of MDMA on prefrontal and amygdala activation, and to explore the relationship between these MDMA-induced neural changes and the acute behavioral effects of the drug in patients with PTSD. In addition, the investigators will collect preliminary data on the MDMA effects on large-scale intrinsic functional connectivity using novel graph-based network analyses.

Specifically, the investigators will measure medial prefrontal cortex (mPFC) and amygdala activation in response to negative stimuli in patients with PTSD. The investigators hypothesize that MDMA will increase mPFC, but decrease amygdala, activation in response to negative stimuli.

The investigators will also explore the relationship between the MDMA-induced mPFC and amygdala activation, and performance on Ekman's Emotional Facial Expression task. This task is modulated by the mPFC and amygdala and as well as trauma severity in participants with PTSD. And finally, to explore the effects of MDMA on resting-state functional connectivity (rs-fcMRI) the investigators will use Coupled Intrinsic Connectivity Distribution (Coupled-ICD); an innovative, graph-based, fully data-driven approach that is particularly sensitive to paired rs-fcMRI data (e.g. pre/post-treatment).

Adult participants with PTSD will be recruited for a double-blind, placebo-controlled, within-subjects, crossover-dose neuroimaging study in which they will initially receive either a single dose of MDMA 1.5mg/kg or a placebo (niacin 250mg), with a crossover dose to follow. Doses will be separated by 2 weeks.

Eligibility criteria: Inclusion Criteria:

* Males or females between the ages of 21-55 years. Females will be included if they are not pregnant and agreed to utilize a medically (non-hormonal)\* accepted birth control method (to include implant birth control, condom, diaphragm with spermicide, intrauterine device, tubal ligation, abstinence, or partner with vasectomy) or if post-menopausal for at least 1 year, or surgically sterile.
* Able to provide written informed consent according to Yale HIC guidelines.
* Able to read and write English as a primary language.
* Diagnosis of PTSD, as determined by the Clinician Administered PTSD Scale (CAPS-5).
* Must have a score of 23 or higher on the Clinician-Administered PTSD Scale (CAPS-5) at screening.
* No more than mild TBI according to a modified version of the Brief TBI Screen.
* Must not have a medical/neurological problem or use medication that would render MDMA unsafe by history or medical evaluation.
* No prior exposure to MDMA.
* Are willing to remain overnight at the study site after each experimental session.
* Are willing to be driven home the day after the experimental sessions.
* Not currently taking any of the listed medications at the time of the study.
* Are willing to sign a medical release for the investigators to communicate directly with their therapist and doctors.
* Are willing to abstain from alcohol, street drugs, and tobacco products while in the study.

Exclusion Criteria:

* Patients with a diagnostic history of bipolar disorder, schizophrenia or schizoaffective disorder or currently exhibiting psychotic features as determined by the MINI 7.0 for the DSM-5.
* Serious suicide or homicide risk, as assessed by evaluating clinician.
* Substance abuse or dependence during the 6 months prior to screening; or a positive pre-study (screening) urine drug screen.
* Any significant history of serious medical or neurological illness.
* Any signs of major medical or neurological illness on examination or as a result of ECG screening or laboratory tests (e.g. positive urine tox, positive HIV/AIDS tests ).
* Abnormality on physical examination. A participant with a clinical abnormality may be included only if the study physician considers the abnormality will not introduce additional risk factors and will not interfere with the study procedure.
* Pregnant or lactating women or a positive urine pregnancy test for women of child-bearing potential at screening or prior to any imaging day.
* Any history indicating learning disability, mental retardation, or attention deficit disorder.
* Family history of cardiovascular diseases. History of hypertension with baseline blood pressure above 140 mmHg (systolic) and over 90 mmHg (diastolic). Any history of syncope and/or baseline blood pressure below 100mmHg (systolic).
* History of claustrophobia.
* BMI \> 30 kg/m2 or \>250 pounds.
* Anxiolytic, neuroleptic and SRI medications (off SRIs for 4 weeks, fluoxetine 5 weeks).
* Females taking hormonal contraceptives will not be able to participate in the study \*(Hormonal contraceptives are exclusionary because MDMA increases production of oxytocin which is heavily modulated by other hormones (e.g. estrogen). Therefore, women need to be naturally cycling/ovulating and not taking any hormonal medications to participate in this study).
* Any metal or electromagnetic implants, including: (Cardiac pacemaker, artificial heart valve, defibrillator, aneurysm clip, cochlear implants, shrapnel, neurostimulators, history of metal fragments in eyes or skin, significant hearing loss or other severe sensory impairment, a history of seizures or current use of anticonvulsants.

Primary outcomes:
measure: Changes in activation of mPFC, amygdala, and nucleus accumbens upon presentation of emotional faces.
timeFrame: Initial Drug Dose, 2 weeks post drug dose (second drug dose).
Secondary outcomes:
measure: Changes in PTSD symptoms, which will be measured by The Clinician-Administered PTSD Scale 5 (CAPS-5).
timeFrame: Baseline, Initial Drug Dose and Second Drug Dose, 24 hours and 1 week after initial and second drug dose.
measure: Changes in depression symptoms, which will be measured by The Beck Depression Inventory II (BDI-II).
timeFrame: Baseline, Initial Drug Does and Second Drug Dose, 24 hours after initial and second drug dose, 3 and 5 days after initial and second drug dose (by phone), 1 week after initial and second drug dose, 15, 17, 19, and 21 days after second drug dose (phone).
measure: Changes in sleep patterns, which will be measured by The Pittsburgh Sleep Quality Index (PSQI).
timeFrame: Baseline, 24 hours after first and second drug dose, 1 week after initial and second drug dose.
measure: Changes in PTSD symptoms, which will be measured by The Posttraumatic Stress Disorder Checklist for the DSM-5 (PCL-5).
timeFrame: Baseline, 24 hours after initial and second drug dose, 3 and 5 days after initial and second drug dose (phone), 1 week after initial and second drug dose, 15, 17, 19, and 21 days after second drug dose (phone).
measure: Changes in personality traits, which will be measured by The NEO Personality Inventory - Revised (NEO PI-R).
timeFrame: Baseline, 1 week after initial and second drug dose.
measure: Changes in mental states, which will be measured The 5-Dimensional Altered States of Consciousness Scale (5D-ASC).
timeFrame: Initial and second drug dose.
measure: Changes in growth following a traumatic event, which will be measured by The Post traumatic Growth Inventory (PTGI).
timeFrame: Baseline, 24 hours after initial and second drug dose, 1 week after initial and second drug dose.
measure: Changes in well-being, which will be measured by The Well-Being Inventory (WBI).
timeFrame: Baseline, 1 week after initial and second drug dose.
measure: Changes in psychological inflexibility/experiential avoidance, which will be measured by The Acceptance and Action Questionnaire II (AAQ-II).
timeFrame: Baseline, 1 Week after initial and second drug dose.
measure: Changes in emotional regulation, which will be measured by The Emotion Regulation Questionnaire (ERQ).
timeFrame: Baseline, 1 week after initial and second drug dose.
measure: Changes in cognitive and emotional empathy, which will be measured by the Multifaceted Empathy Test (MET).
timeFrame: Baseline, Initial and Second Drug Dose, 24 hours after initial and second drug dose, 1 week after initial and second drug dose.
measure: Changes in the quality of specific relationships in terms of supportive and conflictual dynamics will be assessed with the Quality of Relationships Inventory (QRI)
timeFrame: Baseline, Initial and Second Drug Dose, 1 week after initial and second drug dose.
measure: Cognitive schemas about oneself and others, will be assessed by the Trauma and Attachment Beliefs Scale (TABS)
timeFrame: Baseline
measure: Brain injury will be assessed for with the CogState Neuropsychological Test
timeFrame: Baseline, 1 week after initial and second drug dose.
measure: Moral injury, or the sense of distress due to contradiction of deeply-held beliefs due to a traumatic event, will be measured by the Moral Injury Events Scale (MIES)
timeFrame: Baseline, Initial and Second Drug Dose, 24 hours after initial and second drug dose, 1 week after initial and second drug dose.
measure: Changes in concept and sense of existential meaning will be measured with the Purpose and Meaning scale (PIL)
timeFrame: Baseline, 1 week after second drug dose.
measure: Changes in depression symptoms, which will be measured Montgomery-Asberg Depression Rating Scale (MADRS).
timeFrame: Baseline, Initial and Second Drug Dose, 24 hours after initial and second drug dose, 1 week after initial and second administration.
Other outcomes:
Locations:
city: New Haven
country: United States
facility: Connecticut Mental Health Center
state: Connecticut
Study officials:
affiliation: Yale University
name: Benjamin Kelmendi, MD
role: PRINCIPAL_INVESTIGATOR
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