A Phase 2b, Randomized, Double-blind, Placebo-controlled, Multi-center Study of the Effects of Psilocybin-assisted Psychotherapy on Psychiatric and Existential Distress in Advanced Cancer

Official Summary

The purpose of this research is to study the safety and effects of single-dose psilocybin 25mg versus an active placebo (single dose niacin 100mg) in the treatment of anxiety, depression, and existential distress (i.e., loss of meaning and hope; fear of death) in advanced cancer (i.e., stage 3 or 4). Study medications will be administered in conjunction with brief psychotherapy that is designed to treat anxiety, depression and existential distress in advanced cancer.

Eligibility Requirements

• Minimum Age: 21 Years
• Maximum Age: 100 Years

Study Design

• Study Type: INTERVENTIONAL
• Allocation: RANDOMIZED
• Model: PARALLEL
• Masking: DOUBLE
• Enrollment: 200 participants

Study Arms

• Participants receiving Study Drug (EXPERIMENTAL)
  Advanced cancer participants will receive experimental medication, psilocybin (25mg). In addition to the pharmacologic intervention, participants will receive a manualized psychotherapy platform. The combination of interventions is referred to as psilocybin-assisted psychotherapy (PAP).
• Participants receiving Placebo (ACTIVE_COMPARATOR)
  Advanced cancer participants will receive active placebo - single dose of niacin (100mg). In addition to the placebo, participants will receive the same manualized psychotherapy platform as the experimental arm.

Interventions

• DRUG: Psilocybin 25 mgs — One capsule containing 25mg of psilocybin will be administered with water orally. The appearance of psilocybin is Size 2 HPMC opaque.
• DRUG: Niacin 100mg — One capsule contains 100mg of niacin will be administered with water orally. The appearance of the active placebo is Size 2 HPMC opaque.
• BEHAVIORAL: Psychotherapy — The manualized psychotherapy platform will consist of 6 hours of preparatory psychotherapy (prior to the single medication session) and 8 hours of integration psychotherapy following the dosing session.

Primary Outcomes

• Change in Structured Interview Guide for the Hamilton Anxiety Scale (HAM-A): SIGH-A Score (Baseline, Week 8)

Secondary Outcomes

• Change in Structured Interview Guide for the Montgomery-Asberg Depression Rating Scale (MADRS): SIGMA Score (Baseline, Week 8)
• Change in Structured Interview Guide for the Montgomery-Asberg Depression Rating Scale (MADRS): SIGMA Score (Baseline, Week 12)
• Change in Structured Interview Guide for the Montgomery-Asberg Depression Rating Scale (MADRS): SIGMA Score (Baseline, Month 6)
• Change in Hospital Anxiety and Depression Scale (HADS) - Depression Subscale Score (Baseline, Week 8)
• Change in Hospital Anxiety and Depression Scale (HADS) - Depression Subscale Score (Baseline, Week 12)

Eligibility Criteria

Inclusion Criteria:

* Aged ≥ 21
* Diagnosis of Advanced Cancer defined as:

  * Solid tumors to include stage 3 or 4, metastatic illness, or recurrent illness
  * Hematologic malignancies to include, but not limited to, Stage 3 or 4 non-Hodgkins lymphoma, late-stage multiple myeloma or second-line therapy for multiple myeloma, and all forms of acute myeloid leukemia
* Functional Status defined as: Eastern Cooperative Oncology Group (ECOG) ≤2 and Palliative Performance Scale (PPS) ≥60%
* Clinically significant Anxiety defined as SIGH-A \>17 at Screening
* Have an identified support person: agree to be accompanied home (or to an otherwise safe destination) by the support person, or another responsible party, following dosing
* Participants of childbearing potential must agree to practice an effective means of birth control throughout the duration of the study. A person of childbearing potential is anyone assigned female or intersex at birth who has experienced menarche and who has not undergone surgical sterilization (e.g., hysterectomy, bilateral salpingectomy, bilateral oophorectomy) or has not completed menopause. Menopause is defined clinically as 12 months of amenorrhea in a person over age 45 in the absence of other biological, physiological, or pharmacological causes.

Exclusion Criteria:

* Unstable medical conditions or serious abnormalities of complete blood count, chemistries, or ECG that in the opinion of the study physician would preclude safe participation in the trial. Some examples include:

  * Congestive heart failure
  * Clinically significant arrhythmias (e.g., ventricular fibrillation, torsades) or clinically significant ECG abnormality (i.e., QTC interval \> 450)
  * Recent acute myocardial infarction or evidence of ischemia
  * Malignant hypertension
  * Congenital long QT syndrome
  * Acute renal failure
  * Severe hepatic impairment
  * Respiratory failure
* Risk for hypertensive crisis defined as Screening, Baseline, and Medication Session (prior to dosing) Blood Pressure \>140/90 mmHg.
* Significant central nervous system (CNS) pathology. Some examples include:

  * Primary or secondary cerebral neoplasm
  * Epilepsy
  * History of stroke
  * Cerebral aneurysm
  * Dementia
  * Delirium
* Primary psychotic or affective psychotic disorders. Some examples include current or past DSM-5 criteria for:

  * Schizophrenia spectrum disorders
  * Schizoaffective disorder
  * Bipolar I with psychotic features
  * Major Depressive Disorder with psychotic features
* Family history of first-degree relative with psychotic or serious bipolar spectrum illness. Examples include first-degree relative with:

  * Schizophrenia spectrum disorders
  * Schizoaffective disorder
  * Bipolar I with psychotic features
* High risk of adverse emotional or behavioral reaction based on investigator's clinical evaluation. Examples include:

  * Agitation
  * Violent behavior
* Active substance use disorders (SUDs) defined as: DSM-5 criteria for alcohol or drug use disorder (excluding caffeine and nicotine) within the past year
* Extensive use of serotonergic hallucinogens (e.g., LSD, psilocybin) defined as:

  * Any use in the last 12 months
  * \>25 lifetime uses
* Clinically significant suicidality or high risk of completed suicide defined as:

  * Active suicidal behavior (interrupted or aborted attempt; preparatory acts) as assessed by Baseline Version of C-SSRS. If C-SSRS items are 4 or 5, participant is ineligible
  * History of suicide attempt(s) within the past year
  * Have any suicidal ideation or thoughts, in the opinion of the study physician or PI, that presents a serious risk of suicidal or self-injurious behavior
* History of hallucinogen persisting perception disorder (HPPD)
* Cognitive impairment as defined by: Montreal Cognitive Assessment Test (MoCA) \< 23
* Concurrent Medications

  * Antidepressants
  * Centrally-acting serotonergic agents (e.g., MAO inhibitors)
  * Antipsychotics (e.g., first and second generation)
  * Mood stabilizers (e.g., lithium, valproic acid)
  * Aldehyde dehydrogenase inhibitors (e.g., disulfiram)
  * Significant inhibitors of UGT 1A0 or UGT 1A10
  * Niacin. Note: If taking any supplement containing niacin, agrees to suspend use for at least five days prior to dosing and for the duration of the study
* Have a positive urine drug test including Amphetamines, Barbiturates, Buprenorphine, Benzodiazepines, Cocaine, Cannabis, Methamphetamine, MDMA, Methadone, Opiates (Morphine, Oxycodone), Phencyclidine (PCP), and Tetrahydrocannabinol (THC).

  * Note: Prescribed opiate medications (e.g., cancer-related pain) will be allowed to continue through the study period for participants who have been on a stable dose of such medicine for at least 1 month prior to Screening, as determined during review of concomitant medications.
  * Note: Prescribed benzodiazepine medications and non-benzodiazepine sleeping medications will be allowed to continue through the study period for partic

Trial Locations

• University of Colorado Anschutz Medical campus (CU AMC), Aurora, Colorado, United States
• NYU Langone Health, New York, New York, United States

Contact Information

• Sydney Weiner, MA — CONTACT
  Phone: 212-263-6283
  Email: sydney.weiner@nyulangone.org
• Stephen Ross, MD — CONTACT
  Phone: 212-263-6289
  Email: stephen.ross@nyulangone.org

Study Officials

• Stephen Ross, MD — PRINCIPAL_INVESTIGATOR
  NYU Langone Medical Center

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