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Efficacy of Psilocybin in OCD: a Double-Blind, Placebo-Controlled Study.

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT03356483
Recruitment Status : Recruiting
First Posted : November 29, 2017
Last Update Posted : November 15, 2018
Sponsor:
Collaborator:
Heffter Research Institute
Information provided by (Responsible Party):
Benjamin Kelmendi, MD, Yale University

Brief Summary:
This study aims to investigate the effects of oral psilocybin on OCD symptomatology and provide the first evidence of the neural mechanism that may mediate psilocybin's purported therapeutic effects on OCD.

Condition or disease Intervention/treatment Phase
Obsessive-Compulsive Disorder Drug: Psilocybin (0.25mg/kg) Drug: Niacin (250mg) Phase 1

Detailed Description:

Aim 1: To investigate the effects of psilocybin on OCD symptomatology. OCD symptom severity will be assessed before treatment and 24 and 48 hours after treatment, one week after treatment, two weeks, one month, three months, and six months after treatment. Hypothesis: We hypothesize that 0.25mg/kg of psilocybin will lead to greater symptom improvement than niacin (as the active-placebo-control agent) at all assessment points.

Aim 2: To explore the relationship between the psilocybin-induced brain connectivity changes and neuronal activation following symptom provocation in OCD. Resting-state brain connectivity will be assessed before and 48 hours after treatment. Neuronal activation induced by OCD-relevant provocative stimuli will be assessed 48 hours after the treatment. Hypothesis: We hypothesize that (i) psilocybin will normalize abnormal fronto-striatal functional connectivity in patients with OCD; (ii) psilocybin will decrease activation of anterior cingulate cortices, amygdala, and putamen in response to symptom-provoking stimuli, and normalization of one or more of these abnormalities will correlate with improvement in symptomatology after psilocybin treatment.

This study will pilot a single-center, randomized, active-placebo-controlled, double-blind design to examine the clinical and neural effects on OCD, of either 0.25mg/kg of psilocybin or active placebo-control agent (niacin 250mg), given along with non-drug preparatory and follow-up support appointments to 30 study participants.The duration of the randomized study phase is from consent until two weeks after drug administration. Participants will be followed for 24 weeks (3 months) post-study drug administration.

Eligible participants will be admitted as an inpatient for at least 3 nights / 4 days surrounding the initial drug administration (or more, at the option of the subject and the investigator). Participants will be randomized into active medication and active-placebo-control groups, and will be blinded as to their study condition. This admission 2 nights prior to the drug administration will allow the participant to adjust to sleeping on the unit and allow them to settle in to the research unit routine. A return for an fmri scan (48 hours after the administration session) will be scheduled. The participants who received active-placebo-control will be offered the option to receive open-label psilocybin.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: In the study, half of the participants will be randomized to receive psilocybin (n=15) or the active-placebo-control, niacin (n=15). Following the first treatment session of either the active agent or active-placebo-control, participants who were randomized to receive active-placebo-control will be offered the option to receive open-label psilocybin. The blind will be broken at 48-hours to make this determination.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Psilocybin Treatment in Obsessive-Compulsive Disorder: a Preliminary Efficacy Study and Exploratory Investigation of Neural Correlates.
Actual Study Start Date : November 13, 2018
Estimated Primary Completion Date : January 2022
Estimated Study Completion Date : July 2022

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Psilocybin
Psilocybin (0.25mg/kg)
Drug: Psilocybin (0.25mg/kg)
Psilocybin is a naturally occurring hallucinogenic ingredient found in some varieties of mushrooms that can be produced synthetically. It is considered to be a serotonergic psychedelic.
Other Name: "Magic Mushrooms"

Placebo Comparator: Niacin
Niacin (250mg)
Drug: Niacin (250mg)
A medication used to treat high cholesterol, triglyceride levels, and niacin deficiency.
Other Name: Nicotinic acid




Primary Outcome Measures :
  1. Changes in severity of OCD symptoms, which will be measured by The Yale-Brown Obsessive-Compulsive Scale (Y-BOCS). The Primary Outcome Measure will be collected at baseline and 48 hours, assessing change from baseline at 48 hours. [ Time Frame: Baseline, 48 hours post-drug, weeks: 1, 2, 4, 12, 24 post-drug ]
    Assesses severity and types of OCD symptoms over the past seven days. Consists of two parts: 1- symptom checklist, 2- symptom severity scale. The most prominent obsessions and compulsions are identified by the checklist and then rated by the symptom severity scale. The symptom severity scale consists of 11 items (3 items are not included in the total score) and uses a 0 to 4 severity scale. Total Y-BOCS scores range from 0 to 40, with higher scores indicating greater severity of OCD symptoms.


Secondary Outcome Measures :
  1. Acute Yale-Brown Obsessive-Compulsive Scale (A-YBOCS) [ Time Frame: 24 hours post-drug ]
    Examines specific participant OCD symptoms over prior 24 hours. The most prominent obsessions and compulsions that were previously identified by the checklist are rated by the symptom severity scale. The symptom severity scale consists of 11 items (3 items are not included in the total score) and uses a 0 to 4 severity scale. Total A-YBOCS scores range from 0 to 40, with higher scores indicating greater severity of OCD symptoms.

  2. Changes in brain connectivity, which will be measured with functional Magnetic Imaging Resonance (fMRI). [ Time Frame: Baseline & 48 hour post-drug ]
    Resting-state brain connectivity will be assessed before and 48 hours after treatment. Neuronal activation induced by OCD-relevant provocative stimuli will be assessed 48 hours after the treatment.

  3. Changes in depression symptoms, which will be measured by The Montgomery-Asberg Depression Scale (MADRS). [ Time Frame: Baseline, 2 days post-drug, weeks: 1, 2, 4, 12, 24 post-drug ]
    Assesses depression symptoms. Consists of 10 items and uses a 0 to 6 severity scale. Total scores range from 0 to 60, with higher scores indicating more severe depression.

  4. Changes in beliefs, which will be measured by The Brown Assessment of Beliefs Scale (BABS). [ Time Frame: Baseline, weeks: 2 & 24 post-drug ]
    Assesses the degree of conviction and insights participants have concerning their beliefs. Consists of 7 items and uses a 0 to 4 severity scale. The first six items are summed to create a total score that ranges from 0 to 24, with higher scores indicating poorer insight.

  5. Changes in depression symptoms, which will be measured by The Becks Depression Inventory (BDI). [ Time Frame: Baseline, 1 day post-drug, weeks: 2 & 24 post-drug ]
    Assesses depression symptoms. Consists of 21 items and uses a 0 to 3 severity scale. Total scores range from 0 to 63, with higher scores indicating more severe depression.

  6. Changes in dysfunctional beliefs, which will be measured by The Obsessive Beliefs Questionnaire (OBQ-44). [ Time Frame: Baseline & 2 weeks post-drug ]
    Measures dysfunctional beliefs in obsessive-compulsive disorder. Consists of 44 items that are rated on a seven-point Likert scale, ranging from 1 (disagree very much) to 7 (agree very much). It contains three subscales: overestimations of threat and responsibility for harm (RT subscale), importance and control of intrusive thoughts (ICT subscale), and perfectionism and the need for certainty (PC subscale), with higher scores indicating higher levels of each sub-scale.

  7. Changes in OCD symptoms, which will be measured by The Obsessive-Compulsive Inventory - Revised (OCI-R). [ Time Frame: Baseline & 2 weeks post-drug ]
    An inventory of OCD symptoms. Consist of 18 items that are rated on a 5-point Likert scale. Total scores range from 0 to 72, with higher scores indicating more severe OCD symptoms.

  8. Changes in OCD dimensions, which will be measured by The Obsessive-Compulsive Trait Core Dimensions Questionnaire (OC-TCDQ). [ Time Frame: Baseline & 2 weeks post-drug ]
    Measures different OCD dimensions. Consists of 20 items assessing two core dimensions of OCD: harm avoidance (10 items) and incompleteness (10 items). Each item is rated from 0: never applies to me to 4: always applies to me. Higher scores on questions assessing harm avoidance indicates greater levels of harm avoidance. Higher scores on questions assessing incompleteness indicates higher levels of incompleteness.

  9. Changes in anxiety, which will be measured by State-Trait Anxiety Inventory (STAI). [ Time Frame: Baseline, 2 days post-drug, weeks: 1, 2, 4, 12, 24 post-drug ]
    Measures state and trait anxiety. Consist of 40 items: 20 items measuring S-Anxiey and 20 items measuring T-Anxiety. State Anxiety Scale (S-Anxiety) evaluates the current state of anxiety. The Trait Anxiety Scale (T-Anxiety) evaluates relatively stable aspects of anxiety. The S-Anxiety scale assesses the intensity of current feelings "at this moment" from 1(not at all) to 4 (very much so). The T-Anxiety scale assesses the frequency of feelings "in general" from 1 (almost never) to 4 (almost always). The range of scores for each subtest is 20-80, with higher scores indicating greater anxiety.

  10. Changes in quality of life, which will be measured by The Quality of Life Enjoyment & Satisfaction Questionnaire (Q-LESQ-SF). [ Time Frame: Baseline, weeks: 2 & 24 post-drug ]
    Assesses quality of life and functionality. Consists of 16 items which are rated from 1 (very poor) to 5 (very good). Total score involves summing only the first 14 items to yield a raw total score. The raw total score ranges from 14 to 70. The raw total score is transformed into a percentage, with higher percentages indicating greater quality of life.

  11. Changes in experiential aspects of psilocybin, which will be measured by The Mystical Experience Questionnaire (MEQ). [ Time Frame: Day of drug administration, weeks: 2 & 24 post-drug ]
    Assesses different experiential aspects of psilocybin. Consists of 44 items which provides scale scores for each of seven domains of mystical experiences: Internal Unity (6 items); External Unity (6 items); Transcendence of Time and Space (8 items); Ineffability and Paradoxicality (5 items); Sense of Sacredness (7 items); Noetic Quality (4 items). Participants are asked to look back on the extended session that they have just experienced and to rate the degree of their experience of the following phenomena. Each item is rated from 0 (none; not at all) to 5 (extreme; more than ever before in my life and stronger than 4). Total scores are expressed as a proportion of the maximum possible score.

  12. Changes in subjects' behaviors and attitudes, which will be measured by The Community Observer Ratings of Changes in Subjects' Behavior and Attitudes (COM-R). [ Time Frame: 1 & 24 weeks post-drug ]
    Assesses the observations of close family members. Participants will be asked to designate 2 to 3 adults (spouse or other family members, friends, or co-workers) who can observe changes in the participants' behavior and attitude and report as part of the follow-up. They will rate the volunteer's behavior and attitudes using a 10 point scale (from 1=not at all, to 10=extremely) on eleven items: inner peace; patience; good-natured humor/playfulness; mental flexibility; optimism; anxiety; interpersonal perceptiveness and caring; negative expression of anger; compassion/social concern; expression of positive emotions; and self-confidence.

  13. Changes in meaning of life, which will be measured by The Schedule for Meaning in Life Evaluation (SMiLE). [ Time Frame: Baseline, weeks: 1 & 24 post-drug ]
    Assesses individual meaning in life. Participants are asked to name up to seven domains that they judge to be important to their individual meaning in life.Then they will rate their current level of satisfaction in each of these domains using a seven-point Likert scale (range, -3 to +3) and rate the importance of each of their chosen areas using a eight-point adjectival scale (range, 0 to 7). Higher total score indicate a greater meaning in life.

  14. Challenging Experience Questionnaire (CEQ) [ Time Frame: Day of drug administration ]
    Assesses difficult experiences induced by the interventions. Consists of 26 items that are rated from 0 (none; not at all) to 5 (extreme; more than ever before in my life). Participants are asked to rate the degree to which at any time during the previous session they experienced the following phenomena. Items are grouped into the following subscales: fear, grief, physical distress, insanity, isolation, death, and paranoia. Scores of each item are transformed into a percentage of the highest possible score. Subscale scores are calculated by averaging the transformed scores of the items in each subscale. The total score is the average of all the transformed item scores, with higher scores indicating more challenging experiences.

  15. 5-Dimension - Altered States of Consciousness (5D-ASC) [ Time Frame: Day of drug administration ]
    Assesses different mental states induced by the interventions. Consists of 94 items which are rated by placing marks on a horizontal visual analogue scale (100 millimeters in length). The scale ranges from no, not more than usual (on the left) to yes, very much more than usual (on the right). The items are scored by measuring the millimeters from the low end of the scale to the participant's mark (from 0 to 100).

  16. Changes in different dimensions of emotional experience, which will be measured by The Positive and Negative Affect Schedule Expanded Form (PANAS-X). [ Time Frame: Baseline, 2 days post-drug, weeks: 1, 2, 4, 12, 24 post-drug ]
    Assesses different dimensions of the emotional experience. This scale consists of 60 words and phrases that describe different feelings and emotions. For each item participants rate to what extent they have felt this way during the past few weeks from 1 (very slightly or not at all) to 5 (extremely). The items are grouped into the following 4 subgroups and subscales; general dimension scales (negative affect, positive affect), basic negative emotion scales (fear, hostility, guilt, sadness), basic positive emotion scales (joviality, self-assurance, attentiveness), other affective states (shyness, fatigue, serenity, surprise). The items pertaining to each subscale are summed with higher scores indicating higher levels of each subscale.

  17. Changes of the effects of Psilocybin, which will be measured by The Persisting Effects Questionnaire (PEQ). [ Time Frame: 2 days post-drug, weeks: 4 & 24 post-drug ]
    Assesses effects of Psilocybin. Consists of 86 items that assess eight categories of possible change in attitudes, mood, social effects, and behavior: 1. positive attitudes about life and/or self (17 items); 2. negative attitudes about life and/or self (17 items); 3. positive mood changes (4 items); 4. negative mood changes (4 items); 5. altruistic/positive social effects (8 items); 6. antisocial/negative social effects (8 items); 7. positive behavior changes (1 item); and 8. negative behavior changes (1item). Each item is rated using a 6-point rating scale from 0 (none, not at all) to 5 (extreme). Higher scores of each subscale indicate greater changes in that category.

  18. Changes in connection to nature, which will be measured by The Nature Relatedness Scale (NRS). [ Time Frame: Baseline & 2 weeks post-drug ]
    Assesses the affective, cognitive, and experiential aspects of individuals' connection to nature. Consists of 21 items which are rated on a 7-point Likert scale. The total score is calculated by averaging all 21 items after the appropriate items are reversed scored. Higher score indicate a greater connection with nature.

  19. Changes in opinion towards pro-environmental behavior, which will be measured by The Pro-Environmental Behavior Scale (PEBS). [ Time Frame: Baseline & 2 weeks post-drug ]
    Assesses opinions towards the importance of pro-environmental behaviors. Consists of 17 items that are rated from 1(not at all important) to 7 (extremely important). Higher total scores indicate a greater level of importance of pro-environmental behaviors.

  20. Changes in anthropomorphism, which will be measured by The Individual Differences in Anthropomorphism Questionnaire (IDAQ). [ Time Frame: Baseline & 2 weeks post-drug ]
    Assesses individual differences in anthropomorphism. Consists of 15 items which are rated by a 10-point Likert scale. Higher total scores indicate a higher level of anthropomorphism.

  21. Changes in beliefs of mind-body dualism, which will be measured by The Mind-Body Dualism Scale. [ Time Frame: Baseline & 2 weeks post-drug ]
    Assesses beliefs of mind-body dualism. Consists of 11 items that are rated on a 7-point Likert scale. The total score is calculated after the appropriate items are reversed scored. Higher scores indicate a greater belief in mind-body dualism.

  22. Change in interpersonal connectedness, which will be measured by The Inclusion of Others in Self Scale (IOS). [ Time Frame: Baseline & 2 weeks post-drug ]
    Measures perceived interpersonal connectedness. A single-item, pictorial measure of closeness. Images range from the self and other as completely separate to the self and other almost completely overlapping.

  23. Change in moral relativism and idealism, which will be measured by The Ethical Positions Questionnaire (EPQ). [ Time Frame: Baseline & 2 weeks post-drug ]
    Assesses moral relativism and idealism. Consists of 20 items that are rated using a 9-point Likert scale (completely disagree to completely agree). Idealism scores are calculated by summing responses from items 1 to 10. Relativism scores are calculated by summing responses from items 11 to 20. Higher scores on items 1 to 10 indicate higher relativism and higher scores on items 11 to 20 higher idealism.


Other Outcome Measures:
  1. Changes in Immunological function. [ Time Frame: Baseline, 2 days post-drug, weeks: 2 & 24 post-drug ]
    Assesses changes in immunological profile by examining levels of cortisol, CRP, ACTH, IL-4, IL-6, IL-10, IL-12 INF-gamma, and TNF-alpha.

  2. Neuropsychological - Cognitive Assessment [ Time Frame: 2 days post-drug ]
    Assesses changes in OCD relevant neuropsychological function using a probabilistic reversal-learning task.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   21 Years to 55 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. DSM-5 diagnosis of OCD established by a trained clinician interview and confirmed by Mini International Neuropsychiatric Interview MINI (edition 7).
  2. YBOCS score of 18 or greater at evaluation.
  3. Patients must have failed at least one medication and/or therapy trial of standard care treatment for OCD.
  4. English speaking - able to understand the process of consent and the risk and benefits associated with the study, and able to give written informed consent.
  5. Must sign a medical release for the investigators to communicate directly with their therapist and doctors to confirm a medication and/or medical history.
  6. Are willing to be driven home the morning after the experimental sessions, after the 48-hour post session assessments either by a driver arranged by the subject or by the site personnel or taxi.
  7. Has been off selective serotonin inhibitors for five half-lives of the drug plus 2 weeks.
  8. Must avoid starting a new psychiatric medication during the study. Should participant's doctor recommend starting a new psychiatric medication, participant will be required to notify the study team.
  9. Must provide a contact (relative, spouse, close friend or other caregiver) who is willing and able to be reached by the Clinical Investigators in the event of a participant becoming suicidal.
  10. Are willing to refrain from taking any psychiatric medications during the study period.
  11. Must have a negative pregnancy test at study entry and prior to each experimental session if able to bear children, and must agree to use adequate birth control.
  12. Are willing to commit to medication dosing, experimental sessions, follow-up sessions, to complete evaluation instruments and commit to be contacted for all necessary telephone contacts.

Exclusion Criteria:

  1. Personal or immediate family history of schizophrenia, bipolar affective disorder, delusion disorder, paranoid disorder, or schizoaffective disorder.
  2. Active suicidal intent
  3. Unremitted Tourette syndrome
  4. Pervasive developmental disability
  5. Current substance abuse disorder
  6. Anxiolytic, neuroleptic, and SRI medications
  7. Unstable neurological or medical condition; history of seizure, chronic/severe headaches.
  8. Any contraindications to undergoing an MRI scan, including having metal implants or metal fragments in the body. With participants who may have been exposed to metal fragments and who wish to participate in the MRS scans, a plain film X-ray may be order to clarify their eligibility status. Women of childbearing potential who elected not to have the pregnancy test, will be excluded from MRI.
  9. Any history of head injury with loss of consciousness for more than 30 minutes.
  10. Positive urine pregnancy test at the time of screening
  11. Any unstable medical condition that my render study procedures unsafe.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03356483


Contacts
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Contact: Benjamin Kelmendi, MD 203-974-7752 ben.kelmendi@yale.edu
Contact: Giuliana DePalmer, MA 203-974-7680 giuliana.depalmer@yale.edu

Locations
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United States, Connecticut
Connecticut Mental Health Center Recruiting
New Haven, Connecticut, United States, 06519
Contact: Ben Kelmendi, MD    203-974-7752    ben.kelmendi@yale.edu   
Sponsors and Collaborators
Yale University
Heffter Research Institute
Investigators
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Principal Investigator: Benjamin Kelmendi, MD Yale University
Study Director: Christopher Pittenger, MD, PhD Yale University

Publications:
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Responsible Party: Benjamin Kelmendi, MD, Associate Research Scientist, Yale University
ClinicalTrials.gov Identifier: NCT03356483     History of Changes
Other Study ID Numbers: 2000020355
First Posted: November 29, 2017    Key Record Dates
Last Update Posted: November 15, 2018
Last Verified: November 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Benjamin Kelmendi, MD, Yale University:
Psilocybin

Additional relevant MeSH terms:
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Compulsive Personality Disorder
Obsessive-Compulsive Disorder
Personality Disorders
Mental Disorders
Anxiety Disorders
Niacin
Niacinamide
Nicotinic Acids
Psilocybin
Hypolipidemic Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Lipid Regulating Agents
Vasodilator Agents
Vitamin B Complex
Vitamins
Micronutrients
Nutrients
Growth Substances
Physiological Effects of Drugs
Hallucinogens
Psychotropic Drugs