The Effects of MDMA on Prefrontal and Amygdala Activation in PTSD.

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.

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.