Psychopharmacology of Psilocybin in Cancer Patients

This research is being done to study the psychological effects of psilocybin in cancer
patients. Psilocybin is a naturally occurring substance found in some mushrooms that some
cultures have used for centuries in religious practices. Psilocybin has not been approved for
general medical use by the U.S. Food and Drug Administration (FDA). Its use in this study is
investigational. Psilocybin is a mood-altering drug with effects similar to other
hallucinogens like LSD and mescaline. Mescaline is the main psychoactive component of the
peyote cactus used in Native American religious practices. Such substances have been used for
centuries in some cultures as a way of inducing non-ordinary states of consciousness for
religious and spiritual purposes.

An earlier study that was done in our lab with healthy participants found that psilocybin,
given in a comfortable and supportive setting, can provide an experience that is personally
and spiritually meaningful for the participant. This study is being done to find out if
psilocybin can also produce personally and spiritually meaningful experiences in cancer
patients. This could be important because spirituality has been associated with increased
psychological coping and decreased depression in serious illness. People with a diagnosis of
cancer between the ages of 21 and 80 years old and who meet the medical requirements may
join. About 44 people are expected to take part in this study.

Inclusion criteria

Volunteers must:

- Have given written informed consent

- Have a high school level of education

- Be 21 to 80 years old

- Has or has had a cancer diagnosis that is potentially life-threatening. Patients with
an active cancer (e.g. stage III or IV with a poor prognosis) or disease progression
or recurrence are eligible. Patients who do not have an active cancer or disease
progression or disease recurrence are only eligible if at least 1 year has elapsed
since their diagnosis.

- Have an ECOG performance status of 0, 1, or 2.

- Have a DSM-IV psychiatric diagnosis, as determined by the SCID, of one or more of the
following Axis I psychiatric disorders that is either precipitated by or exacerbated
by the psychological stress of the cancer diagnosis: Generalized Anxiety Disorder;
Acute Stress Disorder; Post traumatic Stress Disorder; Major Depressive Disorder (mild
or moderate severity); Dysthymic Disorder; Adjustment Disorder with Anxiety;
Adjustment Disorder with Depressed Mood; Adjustment Disorder with Mixed Anxiety and
Depressed Mood; Adjustment Disorder with Disturbance of Conduct; Adjustment Disorder
with Disturbance of Emotions and Conduct. Psychiatric diagnosis will be determined by
BPRU staff.

- Patients receiving chemotherapy, hormonal therapy, radiation therapy, biologic
therapies may participate while receiving those therapies. Continuing hormonal
therapy, chemotherapy, or radiation treatment is acceptable if the patient is
tolerating the therapy or treatment in a sufficient fashion to allow administration of
oral psilocybin.

- Agree that for one week preceding each psilocybin session, he/she will refrain from
taking any nonprescription medication, nutritional supplement, or herbal supplement
except when approved by the research team. Exceptions will be evaluated by the
research team and will include acetaminophen, non-steroidal anti-inflammatory drugs,
and common doses of vitamins and minerals.

- Agree not to use nicotine for at least 2 hours before psilocybin administration, and
not again until questionnaires have been completed approximately 7 hours after
psilocybin administration.

- Agree to consume approximately the same amount of caffeine-containing beverage (e.g.,
coffee, tea) that he/she consumes on a usual morning, before arriving at the research
unit on the mornings of psilocybin session days. If the patient does not routinely
consume caffeinated beverages, he or she must agree not to do so on psilocybin session
days.

- Agree not to take any PRN medications on the mornings of psilocybin sessions, with the
exception of daily opioid pain medication. Non-routine PRN medications for treating
breakthrough pain that were taken in the 24 hours before the psilocybin session may
result in rescheduling the treatment session, with the decision at the discretion of
the investigators.

- Agree to refrain from using any psychoactive drugs, including alcoholic beverages,
within 24 hours of each psilocybin administration. As described elsewhere, exceptions
include daily use of caffeine, nicotine, and opioid pain medication.

Exclusion criteria

General Medical Exclusion Criteria

- Cancer with known CNS involvement, or other major CNS disease. In addition to
diagnostic results provided by the referring physician, patients will undergo a
neurological exam performed by our BPRU internist. Any patient with evidence of a
focal deficit will be excluded.

- Hepatic dysfunction as indicated by the following values:

- GGT > 3 x ULN (upper limit of norm)

- AST > 3 x ULN

- ALT > 3 x ULN

- Tot Bili > 3.0 mg/dl

- Known paraneoplastic syndrome or "ectopic" hormone production by the primary tumor
such as the patient could have or be at risk for hypercalcemia, Cushing's syndrome,
hypoglycemia, syndrome of inappropriate antidiuretic hormone secretion, or carcinoid
syndrome

- Cardiovascular conditions: uncontrolled hypertension, angina, a clinically significant
ECG abnormality (e.g. atrial fibrillation), TIA in the last 6 months, stroke,
peripheral or pulmonary vascular disease (no active claudication)

- Blood pressure exceeding screening criteria described below

- Epilepsy with history of seizures

- Renal disease (creatinine clearance < 40 ml/min using the Cockcroft and Gault
equation)

- Insulin-dependent diabetes; if taking oral hypoglycemic agent, then no history of
hypoglycemia

- Females who are pregnant (positive pregnancy test) or nursing, or are not practicing
an effective means of birth control

- Currently taking on a regular (e.g., daily) basis: investigational agents,
psychoactive prescription medications (e.g., benzodiazepines), medications having a
primary pharmacological effect on serotonin neurons (e.g., ondansetron), or
medications that are MAO inhibitors. Long-acting opioid pain medications (e.g.
oxycodone sustained release, morphine sustained release -- which are usually taken at
12 hour intervals) will be allowed if the last dose occurred at least 6 hours before
psilocybin administration; such medication will not be taken again until at least 6
hours after psilocybin administration.

- For individuals who have intermittent or PRN use of investigational agents,
psychoactive prescription medications, medications having a primary pharmacological
effect on serotonin neurons, or medications that are MAO inhibitors, psilocybin
sessions will not be conducted until at least 5 half-lives of the agent have elapsed
after the last dose.

- In addition to the foregoing, patients will be excluded if they are currently using
any the following of potent metabolic inducers or inhibitors: Inducers - Rifamycin
(rifampin, rifabutin, rifapentine), anticonvulsants (carbamazepine, phenytoin,
Phenobarbital), Nevirapine, Efavirenz, Taxol, Dexamethasone), St Johns Wort;
Inhibitors - all HIV protease inhibitors, itraconazole, ketoconazole, erythromycin,
clarithromycin, troleandomycin.

- In addition to the foregoing, patients will be excluded if it is a medical requirement
that they receive any of the following drugs with low therapeutic index within 12
hours after receiving psilocybin: ergot alkaloids, pimozide, midazolam, triazolam,
lovastatin, simvastatin, fentanyl.

Psychiatric Exclusion Criteria

- Individuals with severity of depression or anxiety symptoms warranting immediate
treatment with antidepressant or daily anxiolytic medication (e.g., due to suicidal
ideation). We will interview patients to determine if referral (e.g., to Community
Psychiatry) is necessary. For all individuals who are consented and screened, we will
notify the referring physician as to: 1) whether the individual enrolled in the study
or not, and 2) if disqualified, why the individual was disqualified. If
disqualification was based on severe depression or anxiety (e.g., suicidal ideation),
this will be included in the information conveyed to the referring physician.
Permission for this contact will be obtained from the participant.

- Current or past history of meeting DSM-IV criteria for Schizophrenia, Psychotic
Disorder (unless substance-induced or due to a medical condition), or Bipolar I or II
Disorder

- Current or past history within the last 5 year of meeting DSM-IV criteria for alcohol
or drug dependence (excluding caffeine and nicotine).

- Have a first or second degree relative with schizophrenia, psychotic disorder (unless
substance induced or due to a medical condition), or bipolar I or II disorder.

- Currently meets DSM-IV criteria for Dissociative Disorder, Anorexia Nervosa, Bulimia
Nervosa, or other psychiatric conditions judged to be incompatible with establishment
of rapport or safe exposure to psilocybin.

Cardiovascular screening:

There will be at least four blood pressure assessment occasions over at least two separate
days. Within a day, assessment occasions will be separated by at least 15 minutes. Each
assessment occasion will involve two or more blood pressure readings. To qualify for the
study, the mean blood pressure (mm Hg) of the four or more assessment occasions will not
exceed 140 systolic and 90 diastolic.

Blood pressure will be taken while subjects are at rest and have been seated or supine for
at least 5 minutes. As recommended by the Joint National Committee on Prevention,
Detection, Evaluation and Treatment of High Blood Pressure, these assessments will involve
the average of 2 or more readings separated by two minutes. If the first 2 readings differ
by more than 5 mm Hg, additional readings will be obtained and averaged. On one or more of
the blood pressure measurement occasions, the volunteer will be acclimated to the automated
blood pressure monitoring equipment by repeatedly taking blood pressure (at least 3
readings) with the device. Because it has been our experience that time-to-time blood
pressure readings with the automated equipment can be variable due to measurement artifact,
any reading that initially exceeds our threshold value will be reassessed twice within 4
minutes to assure accuracy.