MDMA in Subjects With Moderate Hepatic Impairment and Subjects With Normal Hepatic Function

PTSD is a serious debilitating disorder that negatively impacts a person's daily life.
3,4-methylenedioxymethamphetamine (MDMA) is a ring-substituted phenylisopropylamine
derivative that releases serotonin, norepinephrine and dopamine. MDMA has been shown to
reduce defenses and fear of emotional injury, enhance communication, and increase empathy,
creating productive psychological state that enhances the therapeutic process for the
treatment of PTSD and other anxiety disorders. This is supported by data from an
international series of Phase 2 pilot studies of MDMA-assisted psychotherapy conducted by the
sponsor that provide preliminary evidence that chronic PTSD, independent of cause, is
treatable with two to three sessions of MDMA-assisted psychotherapy and associated non-drug
preparatory and integrative psychotherapy. The results from multiple independent studies in
Phase 2 efficacy analyses demonstrate superiority of MDMA-assisted psychotherapy over
psychotherapy with placebo and low dose MDMA.

This protocol is for a Phase 1, open-label study with a primary purpose of evaluating the
effect of moderate hepatic impairment in the pharmacokinetics of MDMA and its active
metabolite, 3,4-methylene-dioxyamphetamine (MDA), and determining whether an adjustment to
the dosage would be indicated in this group of patients in comparison to patients with normal
liver function. Because people with moderate hepatic impairment may experience greater
exposure to drug than people without it, the secondary purpose of this study is to evaluate
the effect of moderate hepatic impairment on the safety and tolerability of oral MDMA, with
special attention to ECG data. The study will enroll eight participants, ages 18 to 65 years
old, with moderate hepatic impairment, and eight healthy controls with normal hepatic
function who are matched with participants with moderate impaired hepatic function on the
basis of age, weight and gender.

Participants who give their written informed consent will be screened for study participation
that will include a physical examination, assessing current and prior medical and physical
health, and a baseline electrocardiogram (ECG) reading. If applicable, they may begin
tapering off any contraindicated psychiatric medication. Participants who meet study criteria
will receive a single dose of 80 mg MDMA on the first day of a three-day stay at the study
site. Blood will be collected periodically in order to calculate pharmacokinetics of MDMA and
its active metabolite methylenedioxyamphetamine (MDA). Blood will be collected ten times on
Day 1 (-5 min, 0 hours (drug administration), 0.5 h, 1, 2, 4, 6, 7, 10 and 12 hours),
starting five minutes before drug administration. Subjective effects of MDMA will be assessed
through 15 visual analog scales at similar time points to blood collection, at 0.5, 1, 2, 4,
6 and 7 hours post-drug. There will be six 12-lead ECG measurements on Day 1. Participants
will remain at the study site for two more days. Drug safety will be assessed by measuring
blood pressure, heart rate and body temperature after MDMA administrations, collecting
adverse events throughout the study and measuring suicidal thoughts or behaviors with the
Columbia Suicide Severity Rating Scale (C-SSRS). Blood will be collected 24 and 36 hours
after drug administration, and ECG will be performed on Day 2, and a single ECG and blood
draw will occur on Day 3, 4 and 5. Participants will return for eight and 15 days after drug
administration. They will have a single blood draw on each day. The study ends 15 days after
drug administration, approximately one month after screening.

The primary outcome measure will be area under the curve from dosing to last dose (AUC) of
MDMA and MDA. AUC will be computed from plasma collected multiple times after a single dose
of MDMA, twice on the day following the day of drug administration, and once daily for three
more days. Other pharmacokinetic measures will be maximal values of MDMA and MDA (Cmax), and
time to reach maximum MDMA and MDA levels (Tmax). Safety measures will also include a
comparison of subjective effects across groups, ECG readings, number of adverse events, and
suicidal ideation or behavior as measured via C-SSRS during the study.

Inclusion Criteria:

- Participants with moderate hepatic impairment (class B according to Child- Pugh's
criteria).

- Participants with normal hepatic function: no clinically significant findings from
medical history, physical examination, laboratory values within protocol defined
parameters.

- Age 18 to 65 years.

- Weight > 45 kg

- Negative Carbohydrate Deficient Transferrin blood test at Screening and negative
breathalyzer alcohol test prior to trial drug administration.

- Negative urine test for drugs of abuse at Screening and prior to trial drug
administration.

- Able to comprehend and willing to sign an informed consent form.

Exclusion Criteria:

- Have a current psychiatric diagnosis.

- Are pregnant or nursing, or are women of child bearing potential who are not
practicing an effective means of birth control.

- Have acute or exacerbating hepatitis, fluctuating or rapidly deteriorating hepatic
function as indicated by widely varying or worsening of clinical and/or laboratory
signs of hepatic impairment within 2 weeks.

- Have autoimmune liver disease; esophageal variceal bleeding within 6 months prior to
screening, unless successfully treated with banding, or gastric varices.

- Have spontaneous bacterial peritonitis within 3 months prior to screening.

- Have a portosystemic shunt, organ transplant, Wilson's disease, cholestatic liver
disease (e g, primary biliary cirrhosis or primary sclerosing cholangitis)

- Evidence or history of significant hematological, endocrine, cerebrovascular,
cardiovascular (including controlled hyper-tension), coronary, pulmonary, renal,
gastrointestinal, immunocompromising, or neurological disease, including seizure
disorder, or any other medical disorder judged by the investigator to significantly
increase the risk of MDMA administration.

- For moderate hepatic impairment participants: have clinically significant laboratory
findings except as related to hepatic impairment.

- For control participants only: have clinically significant laboratory results outside
the normal limits, including AST >48 U/L, ALT > 55 U/L, GGT > 48 U/L, bilirubin > 1.2
mg/dL or hemoglobin < 12 g/dL.

- Have a history of any illness that, in the opinion of the Investigator, might confound
the results of the trial or pose risk in administering the trial drug to the subject.

- Have any positive test for drugs of abuse and /or alcohol at screening.

- Have a history or presence of clinically significant abnormal 12-lead ECG or an ECG
with QTc by Bazett's correction of > 450 ms in men, > 470 ms in women on the screening
ECG.

- Have a PR interval > 240 ms, QRS > 110 ms or a history of prolongation of QT interval.

- Have mental incapacity, unwillingness or language barriers precluding adequate
understanding or subject co-operation.

- Are unwilling to stay in the clinical unit for the required duration as per the
protocol.

- Have a history of multiple and/or severe allergies to drugs or foods or a history of
severe anaphylactic reaction.

- Have a known or suspected allergy to trial product or related products.