Clinical trial NCT02971605
Conditions: Healthy
Sponsor: Johns Hopkins University
Start date: 2017-07-01; Completion date: 2018-08-21
Enrollment: 13 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The proposed pilot study will assess whether ingestion of a classic hallucinogen (psilocybin) leads to changes in emotion processing and neural circuitry that may predict repeated self-administration of this drug and underlie an atypical mechanism of abuse liability, which may vitally contribute to the understanding of the potential for abuse and the underlying mechanisms supporting abuse of classic hallucinogens.

Detailed description:

Arms: arm 1: Participants will be administered a 25 mg/70 kg dose of psilocybin
Interventions: intervention 1: Psilocybin
Intervention descriptions: intervention 1: 25 mg/70 kg Psilocybin

Protocol documents:
Prot_SAP_000.pdf: 
 
 
Page 1 of 7 
 
Study Protocol with Statistical Analysis Plan 
 
 
 
 
Study Title:  
 
 
Persisting Effects of Psilocybin 
 
Clinical Trials ID (NCT number): NCT02971605 
 
Last Protocol Approval Date:  
April 24, 2017 
 


 
 
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This open-label, non-blinded study will involve 12 volunteers who will receive a high dose of psilocybin 
under supportive conditions. Assessments (questionnaires and emotional tasks) will be conducted during 
screening sessions, and 1 day before, 1 week after, and 1 month after the high-dose psilocybin session. 
Functional magnetic resonance imaging (fMRI) will also be conducted 1 day before, 1 week after, and 1 
month after the psilocybin session. 
 
Primary objectives: 
1. Assess the effects of psilocybin on the neural circuitry of emotion processing as measured by 
functional magnetic resonance imaging (fMRI) at 1 week and 1 month timepoints after psilocybin 
administration 
 
Secondary objectives: 
1. Assess the effects of psilocybin on emotional processing at 1 week and 1 month timepoints after 
psilocybin administration, well after acute subjective effects of the drug have subsided 
2. Assess the effects of psilocybin on personality at 1 week and 1 month timepoints after psilocybin 
administration 
 
Inclusion/Exclusion Criteria 
 
Overview of Screening Procedures: Participants will be screened via telephone to determine whether they 
meet major inclusion/exclusion criteria, and thus whether they are eligible for an in-person screening 
session. Participants who do not fail telephone screening will be invited to BPRU on the Johns Hopkins 
Bayview Campus for in-person screening. 
 
Consent will be obtained at the BPRU at a scheduled meeting after participants have passed telephone 
screening. Participants will be allowed to take as much time as necessary to decide whether or not to sign 
consent. Study staff will discuss the consent form with the participant after the participant has read the 
consent form. Study staff will ask questions to assess the individual’s understanding of the consent form. 
Participants may take the consent form home to review and return to sign consent if they wish. Participants 
who might be eligible for a future study will be asked to complete IRB-approved HIPAA-IRB Form 3 
“Authorization to contact you about future research studies”. Participants' files will be kept in a locked 
room and treated as confidential research material. All data will be collected using the unique identification 
code numbers assigned to each participant upon entry to the study. No individual identifiable information 
will be released without written authorization. These procedures have been used in the past to protect 
confidentiality of study data and no instance of loss of confidential information has occurred. 
 
Participants will be physically and psychologically healthy adult participants (approximately equal numbers 
of males and females) 18 to 45 years old. Non-English speakers and those with language or hearing 
impairments will not participate in the study. Participants will be recruited primarily from the 
Baltimore/Washington DC metro area. Participants will have used hallucinogens in the past, although 
preference will be given to those who have had minimal prior use (e.g. 1 to 2 prior uses) that was at least 3 
months ago. Potential participants will be carefully screened to eliminate those with significant medical or 
psychiatric illnesses (see below for specific inclusion/exclusion criteria). 
 
We expect to consent up to 100 volunteers at Johns Hopkins (some of whom will not pass the in-person 
screening), in order to achieve 12 participants who provide complete data. 
 
Screening evaluation will include a history and physical examination, ECG, a 30 cc blood draw for medical 
screening (e.g., complete blood count and Quest Test 18T Comprehensive metabolic panel with eGFR), a 
personal and family medical history questionnaire, psychiatric interview (SCID-5), and a urine drug test.  


 
 
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As per standard BPRU screening procedures, screening physical examination and ECGs will be performed 
by BPRU medical staff (nurse, mid-level, or physician). ECGs will be interpreted by a cardiologist 
credentialed and privileged to read ECGs at Bayview Medical Center to determine if a significant 
abnormality exists. Participants will be requested to refrain from illicit drug use during the course of the 
study and a urine test will be conducted before the drug session (e.g., various opioids, stimulants and 
sedatives). Pregnant or nursing women are ineligible; female participants will receive a urine pregnancy 
test at intake and before the drug session, and must use effective methods of contraception during the study. 
With regard to psychiatric screening, clinical interviews and a structured psychiatric diagnostic interview 
(e.g., SCID) will be used to obtain baseline psychological data, including psychiatric history (including 
family history), psychoactive drug-use history, and information about employment status and current 
functioning (including mood and psychological and psychosomatic symptoms). Participants will be eligible 
if they are judged to be psychologically stable and do not meet any of the psychiatric exclusion criteria (as 
defined by DSM-V). Finally, participants will be required to meet standard inclusion/exclusion guidelines 
for brain imaging protocols (see below). All inclusion and exclusion criteria are described below: 
 
Inclusion criteria: 
• 18 to 45 years old 
• Have given written informed consent 
• Have at least a high-school level of education or equivalent (e.g. GED), and be fluent in English 
• Be healthy and psychologically stable as determined by screening for medical and psychiatric 
problems via a personal interview, a medical questionnaire, a physical examination, an 
electrocardiogram (ECG), and routine medical blood and urinalysis laboratory tests 
• 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 
morning of the drug session day. If the participant does not routinely consume caffeinated 
beverages, he/she must agree not to do so on the session day. 
• Agree to refrain from using any psychoactive drugs, including alcoholic beverages and nicotine, 
within 24 hours of each drug administration. The exception is caffeine. 
• Agree not to take any PRN medications on the mornings of drug sessions 
• Agree not to take sildenafil (Viagra®), tadalafil, or similar medications within 72 hours of each 
drug administration. 
• Agree that for one week before each drug session, he/she will refrain from taking any 
nonprescription medication, nutritional supplement, or herbal supplement except when approved 
by the study investigators. Exceptions will be evaluated by the study investigators and will 
include acetaminophen, non-steroidal anti-inflammatory drugs, and common doses of vitamins 
and minerals. 
• Have limited lifetime use of hallucinogens (at least one prior use of a hallucinogen, but 
preference will be given to those with the fewest number of prior exposures to a hallucinogen) 
• Last hallucinogen use was at least 3 months ago (but preference will be given to those with a 
greater duration of time since last hallucinogen use) 
 
General medical exclusion criteria: 
• Women who are pregnant (as indicated by a positive urine pregnancy test assessed at intake and 
before each drug session) or nursing; women who are of child-bearing potential and sexually 
active who are not practicing an effective means of birth control. 
• Cardiovascular conditions: coronary artery disease, stroke, angina, uncontrolled hypertension, a 
clinically significant ECG abnormality (e.g., atrial fibrilation), artificial heart valve, or TIA in 
the past year 
• Epilepsy with history of seizures  
• Insulin-dependent diabetes; if taking oral hypoglycemic agent, then no history of hypoglycemia 


 
 
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• Currently taking psychoactive prescription medication on a regular (e.g., daily) basis 
• Currently taking on a regular (e.g., daily) basis any medications having a primary centrally-
acting serotonergic effect, including MAOIs. For individuals who have intermittent or PRN use 
of such medications, psilocybin sessions will not be conducted until at least 5 half-lives of the 
agent have elapsed after the last dose. 
• More than 20% outside the upper or lower range of ideal body weight according to Metropolitan 
Life height and weight table 
 
Psychiatric Exclusion Criteria: 
• Current or past history of meeting DSM-5 criteria for schizophrenia spectrum or other psychotic 
disorders (except substance/medication-induced or due to another medical condition), or Bipolar 
I or II Disorder 
• Current or past history within the last 5 years of meeting DSM-5 criteria for a moderate or 
severe alcohol or drug use disorder (excluding caffeine and nicotine) 
• Have a first or second-degree relative with schizophrenia spectrum or other psychotic disorders 
(except substance/medication-induced or due to another medical condition), or Bipolar I or II 
Disorder 
• Has a psychiatric condition judged to be incompatible with establishment of rapport or safe 
exposure to psilocybin 
 
Additional MRI Exclusion Criteria: 
• Head trauma 
• Claustrophobia incompatible with scanning 
• Cardiac pacemaker 
• Implanted cardiac defibrillator 
• Aneurysm brain clip 
• Inner ear implant 
• Prior history as a metal worker and/or certain metallic objects in the body -- must complete MRI 
screening form (see eIRB Study Documents) and be approved by MRI technologist before each 
scan 
 
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. 
 
Individuals who do not pass screening or choose not to participate will be asked whether they want us to 
keep their personal contact information. Identifiers for those individuals who do not want us to retain their 
information will be destroyed.  
 


 
 
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Drugs/ Substances/ Devices 
 
Psilocybin dose: The dose of psilocybin administered in this study will be a moderately high dose (25 
mg/70 kg). Psilocybin doses will be calculated based on body weight, which is consistent with our previous 
published studies  (Griffiths et al. 2006, Griffiths et al. 2011, Johnson et al. 2014) , controlled studies of 
psilocybin conducted in other research laboratories (Studerus et al. 2011) , and our ongoing protocols. 
Evidence from our psilocybin dose-effects study (Griffiths et al., 2011) and a study of psilocybin compared 
to an active control drug (Griffiths et al., 2006) suggests that similar doses (20 mg/70 kg to 30 mg/70 kg) 
are associated with strong psychoactive effects, mystical-type effects, and enduring positive effects on 
mood and emotions that last for at least 14 months (Griffiths et al., 2008; Griffiths et al., 2011). The 
proposed 25 mg/70 kg dose is less than the maximum dose that has been administered in our laboratory, 
and it is in the range of doses examined extensively in previous studies with hallucinogen-naïve individuals  
(Malitz et al. 1960, Metzner, Litwin & Weil 1965, Pahnke 1969, Pahnke et al. 1969, Leuner 1962) . The 
dose in the current study is considerably less than that (49 mg/70kg) administered safely under a previously 
authorized IND (Strassman 1992, 1998).  
 
Study Statistics 
 
Emotion processing tasks: Three well–established emotional processing tasks will be assessed in the fMRI 
scanner: an emotion recognition task, an emotional conflict Stroop task, and an emotional discrimination 
task. In the emotion recognition task (Gur et al. 2002, Moser et al. 2007, Gur et al. 2010) , participants 
identify positive and negative emotional facial expressions, with identification of the gender of actors as a 
control task. The primary outcome measures of this task are accuracy, response time, and average BOLD 
response to positive and negative facial expressions during emotion identification compared to gender 
identification. In the emotional conflict Stroop task  (Etkin et al. 2006, Egner et al. 2008) , participants 
identify the valence of emotional facial expressions (targets) with overlaid emotional words (distractors). 
Targets and distractors may have congruent or incongruent emotional valence. Primary outcome measures 
are response time, accuracy, and average BOLD response to incongruent compared to congruent trials, 
separated by the emotional valence of the distractor. The emotional discrimination task consists of selecting 
between neutral and negative facial expressions (Hariri et al. 2002, Hariri et al. 2003, Kraehenmann et al. 
2015) , with selection of geometric figures as a control task. The primary outcome measure is BOLD 
response in the amygdala to facial affect discrimination compared to the control task (psilocybin was not 
shown to acutely affect accuracy and response time) (Kraehenmann et al. 2015) . Participants will practice 
these tasks at each preparation meeting (Visits 3 and 4), before the baseline fMRI scan. 
 
Resting-State Scans: Blood-oxygen dependent level (BOLD) data will be collected for 12 minutes during a 
period of rest. The participant will be asked to simply rest with eyes opened and focused on a single point 
in the participant’s view. This scan will allow us to assess the long-term effects of psilocybin on resting-
state brain function, and it will also allow us to assess static and dynamic functional connectivity between 
brain regions and compare results to numerous other fMRI studies of resting-state brain activity. 
 
Longitudinal Emotion and Social Questionnaires: A battery of questionnaires will be completed one day 
before, one week after, and one month after psilocybin to assess emotional and social changes. This 
includes general [the Positive and Negative Affect Scale - X (Watson, Clark 1994)  and the Profile of Mood 
States (McNair, Lorr & Droppleman 1992) ] and emotion-specific [the Dispositional Positive Emotions 
Scale (Shiota, Keltner & John 2006) , the Depression Anxiety Stress Scale (Lovibond, Lovibond 1995) , 
and the State Trait Anxiety Inventory (Spielberger et al. 1983) ] measures, as well as a measure of social 
cognition [the Social Value Orientation test (Murphy, Ackermann, & Handgraaf, 2011)]. Outcome 
measures will consist of the validated scale scores for each questionnaire. 
 
 


 
 
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Longitudinal and Follow-Up Questionnaires: Participants will complete the Big Five Inventory (BFI)  
(John, Naumann & Soto 2008) , the Brief Affective Neuroscience Personality Scales (BANPS) (Barrett, 
Robins & Janata 2013) , the Tellegen Absorption Scale (Tellegen, Atkinson 1974) , and the Emotion 
Regulation Questionnaire (Gross, John 2003) which are validated measures of personality traits. These 
questionnaires will be administered during screening and at the 1-month post-psilocybin imaging session, 
in order to test the hypothesis that openness and positive emotional personality traits will increase, and 
negative emotional personality traits will decrease, after psilocybin administration. A prior study in our 
laboratory found changes in the domain of openness following psilocybin (MacLean, Johnson & Griffiths 
2011) . 
 
Statistical plan 
 
Assessing the effects of psilocybin on emotional processing. We hypothesize that psilocybin administration 
will lead to impaired recognition of negative emotional facial expressions, decreased emotional conflict to 
incongruent emotional stimuli during an emotional conflict processing task, decreased negative affect, and 
increased positive affect one week and one month after psilocybin administration, relative to baseline. 
Outcome measures of the emotion recognition task and emotional conflict Stroop task will be separately 
submitted to two-way repeated measures ANOVA, with assessment time-point (baseline, one week and one 
month post-psilocybin) and emotional valence of stimuli (positive vs negative) as within-subject factors. F-
tests will be used to assess whether there is a main effect of assessment time point and an effect of the 
interaction between assessment time point and emotional valence on each outcome measure. Planned 
comparisons will be used to test the hypothesis of impaired responding to negative emotional stimuli 
(confirmed by finding increased reaction time and decreased accuracy), and facilitated responding to 
positive emotional stimuli (confirmed by finding decreased reaction time and increased accuracy) at each 
post-psilocybin time point (one week, one month) compared to baseline. Outcome measures of the 
longitudinal questionnaires will be separately submitted to a one-way repeated measures ANOVA, with 
assessment time-point as a within-subject factor. An F-test will be used to assess whether there is a main 
effect of assessment time point on each outcome measure. 
 
Assessing the effects of psilocybin on the neural circuitry of emotion processing. We hypothesize that 
psilocybin administration will reduce amygdala BOLD response to negative emotional stimuli during 
emotion recognition and discrimination tasks, and ACC BOLD response during emotional conflict 
processing, one week and one month post-psilocybin. Whole-brain BOLD EPI data will undergo standard 
preprocessing (realignment/motion correction, co-registration across runs, normalization to the MNI 
template, smoothing, motion sensoring or “scrubbing” (Power et al. 2012) , physiological artifact correction 
(Behzadi et al. 2007) , 36-parameter confound regression and spike regression (Satterthwaite et al. 2013) ). 
Regions of interest (ROI) analysis will be performed, with ACC and amygdala as seed regions, to test the 
hypothesis of decreased BOLD response to negative stimuli and increased BOLD response to positive 
stimuli in these regions one week and one month post-psilocybin. The first eigenvector of the signal from 
all voxels in each region will be submitted to a mixed effects repeated measures ANOVA, with time point 
and the emotional valence of stimuli as within-subject main effects, and subject as a random effect. 
Subject-level contrasts will assess effects of task condition at each time point. Second-level t-tests will be 
used for planned comparisons to test the hypothesis of lower BOLD response to negative stimuli and higher 
BOLD response to positive stimuli post-psilocybin. We will repeat these analyses as whole-brain voxel-
wise analyses to evaluate change outside of hypothesized regions. Preprocessing and whole-brain statistical 
analysis will be conducted using Statistical Parametric Mapping (SPM; 
http://www.fil.ion.ucl.ac.uk/spm/software/spm12/) in MATLAB. ROI analysis will be conducted using 
MarsBaR (http://marsbar.sourceforge.net/). 
 
Secondary Outcome Questionnaire Measures: Repeated-measures ANOVA will be used when appropriate 
to assess change between groups and over time within groups in secondary outcome measures. Planned 


 
 
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comparisons will investigate change in questionnaire test scores between pre-session and post-session 
timepoints. 
 
Power Analysis: Assuming a one-way ANOVA with three levels (day before, one week and one month 
after) and 12 subjects, we have 75.8% power to observe significant connectivity change (p < 0.05) for a 
small observed effect size (r=0.25). The proposed study will provide data to directly estimate the effect of 
psilocybin on longer-term change in emotion and neural circuitry.