Cannabidiol Treatment in Patients With Early Psychosis
Phase: PHASE2
Conditions: Schizophrenia, Schizoaffective Disorder
Sponsor: Yale University

NCT02504151 
Cannabidiol Treatment in Patients With Early Psychosis 
 
Study Protocol and Statistical Analysis Plan 5/17/2017 

APPROVED BY THE YALE UNIVERSITY IRB 5/17/2017 VALID THROUGH 5/6/2018
APPROVED BY THE YALE UNIVERSITY IRB 5/17/2017 VALID THROUGH 5/6/2018
Page 1 of 40
DATE STAMPED-RECEIVED
PROTOCOL NUMBER
YALE UNIVERSITY
HUMAN INVESTIGATION COMMITTEE
Application to Involve Human Subjects in Biomedical Research 
100 FR1 (2013-1)
Please refer to the HIC website for application 
instructions and information required to complete 
this application. The Instructions are available at  
http://www.yale.edu/hrpp/forms-  
templates/biomedical.html
Submit the original application and one (1) copy 
of all materials including relevant sections of the 
grant which funds this project (if applicable) to 
the HIC.
HIC OFFICE USE ONLY
SECTION I: ADMINISTRATIVE INFORMATION
Title of Research Project:
Cannabidiol treatment in patients with Early Psychosis
Principal Investigator:
Mohini Ranganathan, MD
Yale Academic Appointment:
Assistant Professor
Department: Psychiatry
Campus Address:
Connecticut Mental Health Center, Clinical Neuroscience Research Unit, 34 Park St. New Haven, CT 06519
Campus Phone:
203-932-5711 x.2546
Fax:
203-937-4860
Pager:
203-867-7923
E-mail:
Mohini.Ranganathan@yale.edu
Protocol Correspondent Name & Address (if different than PI):
Madison Dykins
Campus Phone:
203-932-5711 x2526
Fax:
203-937-4860
E-mail:
 Madison.dykins@yale.edu
Yale Cancer Center CTO Protocol Correspondent Name & Address (if applicable): N/A
Campus Phone:
Fax:
E-mail:
Business Manager:
Campus Phone :
Fax :
E-mail
Faculty Advisor:(required if PI is a student, 
resident, fellow or other trainee)
NA
Yale Academic Appointment:

APPROVED BY THE YALE UNIVERSITY IRB 5/17/2017 VALID THROUGH 5/6/2018
APPROVED BY THE YALE UNIVERSITY IRB 5/17/2017 VALID THROUGH 5/6/2018
Page 2 of 40
Campus Address:

APPROVED BY THE YALE UNIVERSITY IRB 5/17/2017 VALID THROUGH 5/6/2018
APPROVED BY THE YALE UNIVERSITY IRB 5/17/2017 VALID THROUGH 5/6/2018
Page 3 of 40
Campus Phone:
Fax:
Pager:
E-mail:
Investigator Interests:
Does the principal investigator, or do any research personnel who are responsible for the design, 
conduct or reporting of this project or any of their family members (spouse or dependent child) 
have an incentive or interest, financial or otherwise, that may affect the protection of the human 
subjects involved in this project, the scientific objectivity of the research or its integrity? Note: 
The Principal Investigator (Project Director), upon consideration of the individual’s role and 
degree of independence in carrying out the work, will determine who is responsible for the 
design, conduct, or reporting of the research.
See Disclosures and Management of Personal Interests in Human Research  
http://www.yale.edu/hrpp/policies/index.html#COI
 Yes
X No
Do you or does anyone on the research team who is determined by you to be responsible for the 
design, conduct or reporting of this research have any patent (sole right to make, use or sell an 
invention) or copyright (exclusive rights to an original work) interests related to this research 
protocol?
 Yes
X No
If yes to either question above, list names of the investigator or responsible person:
The Yale University Principal Investigator, all Yale University co-investigators, and all Yale 
University individuals who are responsible for the design, conduct or reporting of research must 
have a current financial disclosure form on file with the University’s Conflict of Interest Office. 
Yale New Haven Hospital personnel who are listed as con-investigators on a protocol with a 
Yale University Principal Investigator must also have a current financial disclosure form on file 
with the University’s Conflict of Interest Office. If this has not been done, the individual(s) 
should follow this link to the COI Office Website to complete the
form:  http://www.yale.edu/coi/
NOTE: The requirement for maintaining a current disclosure form on file with the University’s 
Conflict of Interest Office extends primarily to Yale University and Yale-New Haven Hospital 
personnel.  Whether or not they are required to maintain a disclosure form with the 
University’s Conflict of Interest Office, all investigators and individuals deemed otherwise 
responsible by the PI who are listed on the protocol are required to disclose to the PI any 
interests that are specific to this protocol.
SECTION II: GENERAL INFORMATION
1. Performing Organizations:  Identify the hospital, in-patient or outpatient facility, school or 
other agency that will serve as the location of the research. Choose all that apply:
a. Internal Location[s] of the Study:
Magnetic Resonance Research Center
Yale University PET Center

APPROVED BY THE YALE UNIVERSITY IRB 5/17/2017 VALID THROUGH 5/6/2018
APPROVED BY THE YALE UNIVERSITY IRB 5/17/2017 VALID THROUGH 5/6/2018
Page 4 of 40
(MR-TAC)
YCCI/Church Street Research Unit (CSRU) 
Yale Cancer Center/Clinical Trials Office (CTO)
YCCI/Hospital Research Unit (HRU)
Yale Cancer Center/Smilow
YCCI/Keck Laboratories
Yale-New Haven Hospital
Yale-New Haven Hospital—Saint Raphael Campus 
Cancer Data Repository/Tumor Registry
Specify Other Yale Location:
b. External Location[s]:
APT Foundation, Inc.
Haskins Laboratories 
Connecticut Mental Health Center
John B. Pierce Laboratory, Inc.
Clinical Neuroscience Research Unit (CNRU)
Veterans Affairs Hospital, West Haven 
Other Locations, Specify: Institute of Living, Hartford Hospital
International Research Site
(Specify location(s)):
c. Additional Required Documents (check all that apply):
N/A
*YCCI-Scientific and Safety Committee (YCCI-SSC)
Approval Date:
*Pediatric Protocol Review Committee (PPRC)
Approval Date:
*YCC Protocol Review Committee (YRC-PRC)
Approval Date:
*Dept. of Veterans Affairs, West Haven VA HSS
Approval Date:
*Radioactive Drug Research Committee (RDRC)
Approval Date: 
YNHH-Radiation Safety Committee (YNHH-RSC)
Approval Date: 
Magnetic Resonance Research Center PRC (MRRC-PRC) Approval Date: 
YSM/YNHH Cancer Data Repository (CaDR)
Approval Date: 
Dept. of Lab Medicine request for services or specimens form
Imaging on YNHH Diagnostic Radiology equipment request form (YDRCTO request) found 
at http://radiology.yale.edu/research/ClinTrials.aspx)
*Approval from these committees is required before final HIC approval is granted. See instructions 
for documents required for initial submission and approval of the protocol. Allow sufficient time for 
these requests. Check with the oversight body for their time requirements.
2. Probable Duration of Project: State the expected duration of the project, including all 
follow-up and data analysis activities. 3 years
3. Research Type/Phase: (Check all that apply)
a. Study Type
Single Center Study 
Multi-Center Study
Does the Yale PI serve as the PI of the multi-site study? Yes
No 
Coordinating Center/Data Management
Other:
b. Study Phase
N/A
Pilot
Phase I
Phase II
Phase III
Phase IV

APPROVED BY THE YALE UNIVERSITY IRB 5/17/2017 VALID THROUGH 5/6/2018
APPROVED BY THE YALE UNIVERSITY IRB 5/17/2017 VALID THROUGH 5/6/2018
Page 5 of 40
Other (Specify)
4. Area of Research: (Check all that apply) Note that these are overlapping definitions and 
more than one category may apply to your research protocol. Definitions for the following 
can be found in the instructions section 4c:
Clinical Research: Patient-Oriented
Clinical Research: Outcomes and 
Clinical Research: Epidemiologic and Behavioral
Health Services 
Translational Research #1 (“Bench-to-Bedside”)
Interdisciplinary Research 
Translational Research #2 (“Bedside-to-Community”)
Community-Based Research
5. Is this study a clinical trial? Yes
No
NOTE the current ICMJE (International Committee of Medical Journal Editors) definition of a 
clinical trial: “any research study that prospectively assigns human participants or groups of humans 
to one or more health-related interventions to evaluate the effects on health outcomes.” Health-related 
interventions include any intervention used to modify a biomedical or health-related outcome (for 
example, drugs, surgical procedures, devices, behavioral treatments, dietary interventions, and 
process-of-care changes). Health outcomes include any biomedical or health-related measures 
obtained in patients or participants, including pharmacokinetic measures and adverse events”
If yes, where is it registered?
Clinical Trials.gov registry 
Other (Specify)
Registration of clinical trials at their initiation is required by the FDA, NIH and by the ICMJE.
If this study is registered on clinicaltrials.gov, there is new language in the consent form and compound 
authorization that should be used.
For more information on registering clinical trials, including whether your trial must be 
registered, see the YCCI webpage, http://ycci.yale.edu/researchers/ors/registerstudy.aspx or 
contact YCCI at 203.785.3482)
6. Does the Clinical Trials Agreement (CTA) require compliance with ICH GCP (E6)? 
Yes
No
7. Will this study have a billable service? A Billable Service is defined as a service or procedure 
that will be ordered, performed or result in charging in EPIC for individuals who are enrolled in 
a clinical research study, regardless if the charge is intended to be paid by the subject/their 
insurance or the research study.
Yes
No 
If you answered "yes", this study will need to be set up in OnCore Support  
http://medicine.yale.edu/ymg/systems/ppm/index.aspx

APPROVED BY THE YALE UNIVERSITY IRB 5/17/2017 VALID THROUGH 5/6/2018
APPROVED BY THE YALE UNIVERSITY IRB 5/17/2017 VALID THROUGH 5/6/2018
Page 6 of 40
8.. Are there any procedures involved in this protocol that will be performed at YNHH or 
one of its affiliated entities?  Yes No _X_  If Yes, please answer questions a through c 
and note instructions below.  If No, proceed to Section III.
a. Does your YNHH privilege delineation currently include the specific procedure that 
you will perform?
b. Will you be using any new equipment or equipment that you have not used in the 
past for this procedure?
c. Will a novel approach using existing equipment be applied?
If you answered “no” to question 7a, or "yes" to question 7b or c, please contact the YNHH 
Department of Physician Services (688-2615) for prior approval before commencing with 
your research protocol.

APPROVED BY THE YALE UNIVERSITY IRB 5/17/2017 VALID THROUGH 5/6/2018
APPROVED BY THE YALE UNIVERSITY IRB 5/17/2017 VALID THROUGH 5/6/2018
Page 7 of 40
SECTION IV:
PRINCIPAL INVESTIGATOR/FACULTY ADVISOR/ DEPARTMENT CHAIR 
AGREEMENT
As the principal investigator of this research project, I certify that:

The information provided in this application is complete and accurate.

I assume full responsibility for the protection of human subjects and the proper conduct of the 
research.

Subject safety will be of paramount concern, and every effort will be made to protect subjects’ 
rights and welfare.

The research will be performed according to ethical principles and in compliance with all federal, 
state and local laws, as well as institutional regulations and policies regarding the protection of 
human subjects.

All members of the research team will be kept apprised of research goals.

I will obtain approval for this research study and any subsequent revisions prior to my initiating the 
study or any change and I will obtain continuing approval of this study prior to the expiration date 
of any approval period.

I will report to the HIC any serious injuries and/or other unanticipated problems involving risk to 
participants.

I am in compliance with the requirements set by the University and qualify to serve as the 
principal investigator of this project or have acquired the appropriate approval from the 
Dean’s Office or Office of the Provost, or the Human Subject Protection Administrator at 
Yale-New Haven Hospital, or have a faculty advisor.

I will identify a qualified successor should I cease my role as principal investigator and facilitate a 
smooth transfer of investigator responsibilities.
PI Name (PRINT) and Signature
Date
As the faculty advisor of this research project, I certify that:

The information provided in this application is complete and accurate.

This project has scientific value and merit and that the student or trainee investigator has the 
necessary resources to complete the project and achieve the aims.

I will train the student investigator in matters of appropriate research compliance, protection of 
human subjects and proper conduct of research.

The research will be performed according to ethical principles and in compliance with all federal, 
state and local laws, as well as institutional regulations and policies regarding the protection of 
human subjects.

The student investigator will obtain approval for this research study and any subsequent revisions 
Prior to initiating the study or revision and will obtain continuing approval prior to the expiration 
of any approval period.

The student investigator will report to the HIC any serious injuries and/or other unanticipated 
problems involving risk to participants.

I am in compliance with the requirements set forth by the University and qualify to serve as 
the faculty advisor of this project.
Date

APPROVED BY THE YALE UNIVERSITY IRB 5/17/2017 VALID THROUGH 5/6/2018
APPROVED BY THE YALE UNIVERSITY IRB 5/17/2017 VALID THROUGH 5/6/2018
Page 8 of 40
Department Chair’s Assurance Statement
Do you know of any real or apparent institutional conflict of interest (e.g., Yale ownership of a 
sponsoring company, patents, licensure) associated with this research project?
Yes (provide a description of that interest in a separate letter addressed to the HIC.) 
No
As Chair, do you have any real or apparent protocol-specific conflict of interest between yourself and 
the sponsor of the research project, or its competitor or any interest in any intervention and/or method 
tested in the project that might compromise this research project?
Yes (provide a description of that interest in a separate letter addressed to the HIC) 
No
I assure the HIC that the principal investigator and all members of the research team are qualified by 
education, training, licensure and/or experience to assume participation in the conduct of this research 
trial. I also assure that the principal investigator has departmental support and sufficient resources to 
conduct this trial appropriately.
Chair Name (PRINT) and Signature
Date
Department
YNHH Human Subjects Protection Administrator Assurance Statement
Required when the study is conducted solely at YNHH by YNHH health care providers.
As Human Subject Protection Administrator (HSPA) for YNHH, I certify that:

I have read a copy of the protocol and approve it being conducted at YNHH.

I agree to notify the IRB if I am aware of any real or apparent institutional conflict of interest.

The principal investigator of this study is qualified to serve as P.I. and has the support of the hospital 
for this research project.
YNHH HSPA Name (PRINT) and Signature
Date

APPROVED BY THE YALE UNIVERSITY IRB 5/17/2017 VALID THROUGH 5/6/2018
APPROVED BY THE YALE UNIVERSITY IRB 5/17/2017 VALID THROUGH 5/6/2018
Page 9 of 40
SECTION V: RESEARCH PLAN
1. Statement of Purpose: State the scientific aim(s) of the study, or the hypotheses to be tested.
This is a four week, randomized, placebo controlled, crossover trial comparing cannabidiol 
(CBD) to placebo in outpatients with psychotic disorder within their first five years of disease 
onset. We hypothesize that treatment with CBD will result in:
a. Primary Hypotheses:
i. Improvement evidenced by a reduction in scores on the Positive and Negative 
Syndrome Scale for Schizophrenia (PANSS).
ii. Improvement evidenced by a reduction in the Clinical Global Impression of Severity 
scale (CGI).
b. Secondary Hypothesis:
i. Greater improvement in functioning as measured on the “Patient Assessment of Own 
Functioning Inventory: (PAOFI) and the Quality of Life Scale (QLS)
ii. No worsening of depressive symptoms or suicidality as measured on the CDSS and 
CSSRS.
c. Exploratory Hypotheses:
i. Exploration of the effect of CBD on EEG recordings of MMN and P300 amplitude 
and latency, known endophenotypes/biomarkers of Schizophrenia
2. Background: Describe the background information that led to the plan for this project. 
Provide references to support the expectation of obtaining useful scientific data.
There is a need to develop anti-psychotic therapeutics with novel mechanisms of action and 
fewer side effects:
Current first and second generation anti-psychotics employ a common mechanism of dopamine 
receptor antagonism leading to varying degrees of motor side effects and QTc prolongation for 
the class as a whole. Second generation anti-psychotics have also been demonstrated to cause 
significant metabolic side effects including weight gain, dyslipidemia, and diabetes mellitus [1- 
3]. Specifically, the CATIE study found the prevalence of metabolic syndrome in schizophrenia 
to be 42% compared to 23% in the general population [4]. Given the significant morbidity and 
mortality associated with schizophrenia, even appropriate treatment with the currently available 
medications has the potential to add serious medical illness to an already poor prognosis [4, 5]. 
Thus, it is imperative that new antipsychotics with novel mechanisms of action be developed not 
only to find more tolerable therapies for this high risk group but also to address the significant 
portion of patients with incomplete response and potentially those with psychotic symptoms 
derived from neurodegenerative disease [6].
Cannabidiol, a component of herbal cannabis, may have antipsychotic effects via a novel 
mechanism of action:
Cannabidiol is a component of herbal cannabis, studied for a number of potential pharmaceutical 
indications since the 1970s given its purported hypnotic, anticonvulsant, neuroprotective and 
hormonal effects [7-10].  More recently, enthusiasm has mounted surrounding its potential as an 
anti-psychotic and anxiolytic. Initially thought to be a CB-1 antagonist, the mechanism of action

APPROVED BY THE YALE UNIVERSITY IRB 5/17/2017 VALID THROUGH 5/6/2018
APPROVED BY THE YALE UNIVERSITY IRB 5/17/2017 VALID THROUGH 5/6/2018
Page 10 of 40
of cannabidiol has more recently been thrown into question. Various alternative mechanisms 
have been suggested including modulation of the endocannabinoid system via FAAH inhibition 
leading to increased levels of the endogenous cannabinoid, anandamide, TRPV1 activation, 5- 
HT1A agonism, and NMDA receptor modulation [11-13]. Overall, the true mechanism of action 
remains unknown.  Studies have proposed that alterations in the endocannabinoid system, 
manifesting as significantly elevated levels of anandamide in the cerebrospinal fluid of 
schizophrenic patients, may suggest a protective role of this compound against psychosis, one 
that cannabidiol may modulate in therapeutically significant ways not yet fully understood. Brain 
imaging studies also demonstrate opposite effects of CBD and THC in particular brain regions 
thought to be associated with the development of psychosis.  Specifically, fMRI studies have 
demonstrated CBD’s augmentation of activity in the right posterior temporal gyrus, the left 
caudate and the hippocampus as well as attenuated activity in the right prefrontal area, all of 
which are the opposite of THC effects [14].  Despite the lack of clarity regarding its exact 
mechanism of action, clinical studies in both human and animal models have suggested 
antipsychotic effects as discussed below, with an extremely favorable side effect profile.
Cannabidiol has been shown to exhibit antipsychotic effects:
Within the last decade, animal models have demonstrated CBD’s ability to decrease 
hyperlocomotion induced by amphetamine and ketamine and to extinguish stereotyped behavior 
induced by apomorphine in rats [10, 15]. Human case studies also suggested antipsychotic 
effects of CBD in patients unable to tolerate or unresponsive to usual therapies. While the exact 
mechanism of action remains unknown, more recent clinical studies have demonstrated that pre- 
treatment with CBD inhibits the psychotomimetic effects of THC resulting in a significant 
decrease in self-reported paranoia and a non-statistically significant trend toward decreased 
PANSS scores [16]. Indeed, a high ratio of THC to CBD has been correlated with increased risk 
of psychotic symptoms further suggesting a protective role of CBD, at least among cannabis 
users [17, 18].
Perhaps most encouraging was a recent clinical trial by Leweke, et al. which showed similar 
reduction in PANSS scores in patients treated with CBD versus the D2/D3 antagonist 
amisulpride [11]. In this double blind parallel group randomized active controlled clinical trial, 
men and women aged 18-50 with acute exacerbation of schizophrenia or schizophreniform 
psychosis received four week courses of either cannabidiol or amisulpride with recording of 
baseline, day 14 and day 28 PANSS scores. Side effects were also measured using the 
Extrapyramidal Symptom Scale. Results revealed a similar reduction in PANSS scores in both 
groups, no difference in the percentage of responders and significantly fewer extrapyramidal side 
effects in the CBD group. This promising evidence for likely non-inferiority of CBD warrants 
replication as well as investigation of its use outside the acute stage and in the outpatient setting, 
which the proposed study intends to investigate.  Furthermore, the addition of objective outcome 
measurements including psychosocial, cognitive, mood, and biomarker data as well as the use of 
a wider range of cannabidiol dosages would contribute to the overall picture of CBD’s use as a 
novel anti-psychotic.
Cannabidiol has few side effects and is generally well tolerated:
Based on earlier studies of the 1970s, Cunha et al. demonstrated that 300-400mg daily doses of 
cannabidiol for 30 days in healthy subjects as well as 100-200mg daily for 4.5 months in subjects 
with epilepsy revealed no adverse effects beyond mild somnolence [19, 20]. High doses of the

APPROVED BY THE YALE UNIVERSITY IRB 5/17/2017 VALID THROUGH 5/6/2018
APPROVED BY THE YALE UNIVERSITY IRB 5/17/2017 VALID THROUGH 5/6/2018
Page 11 of 40
medication were also well tolerated in case studies of use in patients unable to tolerate or 
resistant to dopamine antagonists and in doses up to 10mg/kg (average of 700mg) daily for 6 
weeks in patients with Huntington’s Disease and in combination with alcohol [21-23].
Specifically, analysis of reported side effects in the latter study showed no significant difference 
between placebo and CBD [22]. Also, in the aforementioned trial comparing anti-psychotic 
effects of CBD and amisulpride, patients treated with cannabidiol had a significantly fewer 
extrapyramidal symptoms, less weight gain, and lower prolactin levels [11].
Individuals early in their course of illness may particularly benefit from treatment with a 
medication such as cannabidiol:
In treatment settings caring for patients with early psychosis, ~30% drop out of care within the 
first year which may be related to unwillingness to tolerate medication side effects associated 
with dopaminergic antipsychotic medications. As discussed above, CBD is very well tolerated 
and may thus be a suitable choice especially in early psychosis when patients are medication 
naïve and more sensitive to the side effects. Furthermore, these individuals typically have high 
rates of cannabis use (~30%) in this cohort, which is associated with worsening of symptoms, 
course and engagement with treatment. CBD, in laboratory studies has been shown to attenuate 
the effects of delta-9-tetrahydrocannabinol (THC), the main psychoactive component of cannabis 
and may potentially have benefits in this population. Furthermore, since CBD is known to be a 
component of cannabis, patients may have fewer reservations about accepting this as a treatment.
Thus, given some evidence supporting the antipsychotic potential of CBD, its effects on non- 
specific symptoms such as anxiety and insomnia and its favorable side effect profile, further 
study of CBD’s anti-psychotic effects may benefit from inclusion of more objective measures 
such as Event Related Potentials (ERPs).
ERPs are oscillatory brain responses seen on EEG triggered by particular stimuli. Numerous 
studies have demonstrated aberrations in event-related potentials in schizophrenia, specifically 
deficient mismatch negativity (MMN) and significantly decreased P300 amplitude and latency 
which are hypothesized to serve as indices of abnormal auditory sensory memory, information 
processing speed and allocation of attention ([24-26]. A recent study by Fisher, et al. 
demonstrated both a correlation between decreased MMN and increased PANSS scores as well 
as a correlation between decreased P300 amplitude and increased auditory hallucinations [25]. 
Attenuation of the MMN and decreased P300 measures have thus been suggested as 
endophenotypes of schizophrenia and potential biomarkers of disease [24, 27]. Studies assessing 
the effects of medications on the MMN and P300 are limited.  While clozapine use has been 
associated with increases in P300 amplitude, first generation anti-psychotics and olanzapine have 
not [28, 29]. However, further research on the use of biomarkers to assess medication effect is 
needed and collection of this data will shed light on the potential role of antipsychotics and CBD 
in particular on normalizing these processes.
Significance:
As outlined above, CBD has shown potential anti-psychotic effect via novel mechanisms of 
action as compared to the currently available drugs. CBD is likely to have an extremely 
favorable side effect profile. There is a need for novel anti-psychotics both to expand upon the 
currently available, effective battery of therapeutics and to limit the medical comorbidity 
associated with current therapies.

APPROVED BY THE YALE UNIVERSITY IRB 5/17/2017 VALID THROUGH 5/6/2018
APPROVED BY THE YALE UNIVERSITY IRB 5/17/2017 VALID THROUGH 5/6/2018
Page 12 of 40
Consent Procedures: Subjects who meet entry criteria will be invited to meet with the research 
staff, who will fully explain risks and procedures as outlined in the consent form. After 
reviewing this information and answering questions, informed consent will be obtained from all 
subjects. A copy of the consent form will be provided to all subjects.
Medical and Psychiatric Evaluation: Once written informed consent has been obtained, the 
diagnosis will be confirmed by a Structured Clinical Interview for DSM IV (SCID). A detailed 
medical and psychiatric history, physical examination (including vital signs, height, and weight), 
an electrocardiogram, and laboratory assessments (standard screening blood tests: CBC with 
differential and platelet count, electrolytes, creatinine, BUN, liver enzymes, T4, calcium, 
phosphate, TSH, and magnesium levels) will be performed. In addition, a full lipid profile, 
fasting glucose and insulin levels will be obtained. A pregnancy test will be done in all 
premenopausal women. A routine urinalysis and drug screen will be done as part of the 
screening process.
Subjects will be administered the PANSS and motor side effects scales (AIMS, Barnes akathisia 
scale, Simpson Angus scale). IQ will be measured at screening using the Wechsler Test of Adult 
Reading (WTAR). Subjects will also be asked to provide an informant who can be contacted to 
collect clinical and safety information relevant to the outcome measures on each visit. This could 
be a clinician or a family member/friend who sees the patient at least on a weekly basis.
Study Design: In this 2 period cross over design, subjects will be randomized in a 1:1 ratio to 
receive either: Order 1: CBD (Period 1) followed by placebo (Period 2) or Order 2: Placebo 
(Period 1) followed by CBD (Period 2) under double-blind conditions. The 2 study periods will 
be separated by a washout of at least 2 weeks. During each period subjects will receive study 
medications (CBD [total 800mg/day] or placebo) for a period of 4 weeks. This dose is within the 
dose range of doses that have been shown to be effective and safe. Randomization to the order of 
medication assignment will be stratified by baseline PANSS scores.
Study Visits:
Subjects will have the following visits during each period except for Visit I (screening), which 
will occur only at the beginning of their participation in the study:
Visit I: Screening (At least two visits: Visit Ia and Visit Ib.)
Visit II: Baseline: Will initiate treatment with study drug following baseline assessments. 
(Visits III, IV, V: Weekly clinical evaluation and study medication refill)
Visit III: (Week 1) 
Visit IV: (Week 2) 
Visit V: (Week 3)
Visit VI: (Week 4): End of treatment period visit 
Visit VII: Safety Follow up at week 5.
Visit VIII: One close-out visit will be conducted after Visit VII in Period 2 for lab review and 
safety follow up.
Note: Visits II-VI can be split into two visits, which must be completed within +/- 3 days of 
each other based on the subject’s availability.
Outpatient Medication Compliance: Medication compliance will be monitored throughout 
each study period by self-report and vial counts at study visits and using the Cellphone Assisted 

APPROVED BY THE YALE UNIVERSITY IRB 5/17/2017 VALID THROUGH 5/6/2018
APPROVED BY THE YALE UNIVERSITY IRB 5/17/2017 VALID THROUGH 5/6/2018
Page 13 of 40
Remote Observation of Medication Adherence (CAROMA). CAROMA may be used 1-2 times 
per day during the treatment period to confirm compliance. Flexible scheduling will be 
maintained regarding time and days of CAROMA depending on subject reliability, availability 
and frequency of in person visits. Subjects will be provided with a cellphone with the hardware, 
software and service necessary to transmit high quality video. Prior to randomization, the subject 
will be trained how to use the phone and also trained on the compliance protocol. For this, the 
subject will be placed in one clinic office with the phone. A research staff member will video call 
the subject from another location in the clinic and observe the subject consuming a syringe of 
water. Once successfully trained in the clinic, the subjects will be loaned the phone to take home 
for one trial CAROMA visit. This is to ensure that 1) the in-clinic training extends to the home, 
and 2) that the subject has adequate cellular service at home. Within a time period predetermined 
by agreement, subjects will be called on the cell phone and will be observed removing study 
medication from the packaging and swallowing the medication. The research assistant will log 
visual confirmation of compliance. Subjects will receive additional compensation for CAROMA 
visits as outlined in the “Economic Considerations” section below. Subjects who are not 
contactable will be assumed to be noncompliant for that visit and will not receive payment for the 
missed CAROMA visits.
Finally, compliance will also be confirmed by measuring CBD levels in plasma from blood 
sampled at regular intervals throughout the study.
Study Procedures:
Safety Assessment: during each visit. This will include assessment of psychiatric status, 
assessment of adverse events, vital signs, and safety labs (CBC, Chem 19, urinalysis, and urine 
toxicology).
Outcome measures:
1. Positive and Negative Syndrome Scale (PANSS) (Visits I-VI): The PANSS includes 3 
scales and 30 items: 7 items that make up the Positive Scale (eg, delusions, conceptual 
disorganization, hallucinatory behavior); 7 items that make up the Negative Scale (eg, 
blunted affect, emotional withdrawal, poor rapport, passive/apathetic social withdrawal); and 
16 items that make up the General Psychopathology Scale (eg, somatic concern, anxiety, 
guilt feelings, mannerisms and posturing, motor retardation, uncooperativeness, 
disorientation, poor impulse control, preoccupation). Individual items are scored with values 
ranging from 1 to 7.
2. Personal and Social Performance Scale (PSP) (Visits I-VI): The PSP scale is a validated 
clinician-related scale that measures personal and social functioning in the domains of: 
socially useful activities (eg, work and study), personal and social relationships, self-care, 
disturbing and aggressive behaviors. Information from the subject and the informant will be 
utilized in determining the rating. The interview with the informant may be conducted by 
phone once the initial in-person interview has occurred and informed consent has been 
obtained.
3. Clinical Global Impression (CGI) (Visits I-VI):
a.
Clinical Global Impression of Severity (CGI-S): The CGI-S consists of a single 7- 
point rating score of illness severity. Raters select one response based on the 
following question, “Considering your total clinical experience with this particular 
population, how mentally ill is your patient at this time?” Scores are: 1, Normal, not

APPROVED BY THE YALE UNIVERSITY IRB 5/17/2017 VALID THROUGH 5/6/2018
APPROVED BY THE YALE UNIVERSITY IRB 5/17/2017 VALID THROUGH 5/6/2018
Page 14 of 40
ill at all; 2, Borderline mentally ill; 3, Mildly ill; 4, Moderately ill; 5, Markedly ill; 6, 
Severely ill; or 7, Among the most severely ill subjects.
b.
Clinical Global Impression of Improvement (CGI-I): The CGI-I consists of a 
single 7-point rating score total improvement, regardless of whether or not the change 
it is due entirely to drug treatment. Raters select one response based on the following 
question, “Compared to your patient’s condition at the beginning of treatment, how 
much has your patient changed?” Scores are: 1, Very much improved; 2, Much 
improved; 3, Minimally improved; 4, No change; 5, Minimally worse; 6, Much 
worse; or 7, Very much worse. For the CGI-I Scale, the subject’s condition at the 
Day 1 (Baseline) visit will be the criterion for judging improvement at 
subsequent visits.
4.
Columbia Suicide Severity Rating Scale (CSSRS) (Visits I-VI): The CSSRS is an 
interview based rating scale to systematically assess suicidal ideation and suicidal behavior. 
Versions are available for Screening/Baseline and follow-up visits.
5.
Quality of Life Scale (QLS) (Visits II-VI): The QLS is a structured interview providing 
clinician ratings of function in key areas of everyday living.
6.
The Patient Assessment of Own Functioning Inventory: (PAOFI) (Visits II-VI): will be 
included as a subjective assessment of cognitive functioning. The PAOFI is a widely used 
self-report instrument that taps into the respondent’s own views and experiences regarding 
difficulty in everyday functioning.
7.
Motor side effect scales (Visits I-VI): Barnes Akathisia Scale, Simpson Angus Scale, and 
the AIMS; Further, the UKU side effects scale will be administered at weekly visits to 
assess for antipsychotic induced side effects.
8.
Metabolic parameters (Visits I, II, IV, VI): Appetite and food intake ratings (VAS) and 
three day dietary record (which have been shown to be predictors of energy intake and 
weight loss [30]), weight, fasting glucose and lipid profile.
9.
Smoking and Cannabis use (Visits I-VI): Past week Time Line Follow Back approach.
10. EEG testing: The main EEG outcome measures will be P50, P300 and ASSR as discussed 
above. Brain wave activity during tasks involved in the processing auditory and visual 
stimuli with different degrees of attentional and memory demands will be recorded. 
Auditory stimuli will include tones, white noise bursts, other digitized sounds (such as dog 
barks, rooster crows), or spoken words. Visual stimuli will include letters, numbers, words, 
geometric shapes, colored patterns, or photographic images. Some audiovisual stimuli may 
have emotive/emotionally salient or neutral content. Stimuli will be separated by intervals of
.5 to 30 seconds. Some stimuli will require a button-press response using a response pad. 
These may be target stimuli in target detection tasks, or recalled stimuli in memory tasks. 
The EEG session will last approximately 2 hours.

APPROVED BY THE YALE UNIVERSITY IRB 5/17/2017 VALID THROUGH 5/6/2018
APPROVED BY THE YALE UNIVERSITY IRB 5/17/2017 VALID THROUGH 5/6/2018
Page 15 of 40
On the testing days (Visit II and Visit VI), participants will be brought to the EEG testing 
booth. In the EEG recording, an elastic cloth cap with Ag/AgCl electrodes is worn by the 
subject. A conductive gel is then placed between the skin and the electrode prior to 
recording. The subject will then listen to sounds or view visual images produced by a 
computer. By varying the characteristics of the auditory and visual stimulation, different 
brain systems are activated. In some recordings, the subject will be asked to press a button 
to indicate what sort of stimulation he or she experienced. The EEG recordings will be 
obtained using a commercial psychophysiological system. The entire EEG procedure will 
take approximately 1.5 hours.
EEGs will be recorded at a sampling rate of 1024 Hz with on-line low-pass filter of 256Hz 
to prevent aliasing of high frequencies. A 64-channel electrode cap according to the 
extended 10-20 system will be utilized. Seven additional electrodes will be placed: two on 
the mastoid processes, two horizontal EOG channels lateral to the left and right eyes’ lateral 
canthi, two vertical EOG channels, one below (infraorbital) and one above (supraorbital) the 
right eye, and a channel on the tip of the nose. All electrodes will be referenced during 
recording to a common-mode signal (CMS) electrode between POz and PO3 and will be 
subsequently re-referenced digitally. A conductive gel will be placed between the skin and 
the electrodes prior to recording. The cap and all electrodes that come into contact with the 
skin will be cleaned and disinfected after each use in an antibacterial soap, which kills 
almost all vegetative microbial and viral life forms.
The main dependent measures of the EEG portion of the study will be traditional EEG 
waveform amplitude and latency. Secondary measures will be EEG spectral power, inter- 
electrode coherence, and inter-trial coherence.
11. CBD and Endocannabinoid Levels: Blood will be drawn at visit II-VI for plasma CBD 
and Anandamide levels. CBD levels will be assayed by our collaborator, Thomas Cooper, at 
Nathan Kline Institute. Serum Anandamide levels will be assayed by our collaborator, Alex 
Makriyannis, Director, Center for Drug discovery at Northeastern University.
12. Neuropsychological Testing (Visits I, II, and VI): A cognitive battery will be utilized to 
assess working memory, spatial working memory, episodic memory, and learning.
Drug Dose and Administration: CBD will be used under IND# 126731 and supplied by Insys 
Pharmaceuticals Ltd. with a shelf life of 1 year. The product will be stored in the Veterans 
Affairs Connecticut Healthcare System pharmacy in West Haven, CT as per package 
instructions. The investigators brochure from Insys Pharmaceuticals is submitted along with this 
application. Pharmacists will deliver medication vials to study staff for dispensing by study 
psychiatrists. The daily dose for this study is CBD 800mg in an oral solution. This dose has been 
previously shown to be well tolerated in healthy subjects as well as schizophrenia patients in a 
recent clinical trial of 42 patients who were treated with CBD 800 mg vs. Amisulpiride for 4 
weeks [11].
3. Genetic Testing   N/A

APPROVED BY THE YALE UNIVERSITY IRB 5/17/2017 VALID THROUGH 5/6/2018
APPROVED BY THE YALE UNIVERSITY IRB 5/17/2017 VALID THROUGH 5/6/2018
Page 16 of 40
A. Describe
i.
the types of future research to be conducted using the materials, specifying if 
immortalization of cell lines, whole exome or genome sequencing, genome wide 
association studies, or animal studies are planned
Depending on the future course of the project and the results of the work, 
genome wide (GWAS) genotyping, full exome sequencing, or full genome 
sequencing – or some intermediate stage between these – may be employed. 
Results from these subjects may be compared to other subjects that we or our 
collaborators have recruited or may recruit in the future in the course of this 
project or other projects; or other publicly-available data. We will consider any 
phenotypes about which information can be collected, concentrating, however, on 
psychiatric diagnoses, imaging measures, and response to treatment.
ii. the plan for the collection of material or the conditions under which material will 
be received
Samples will be drawn at the Connecticut Mental Health Center, the West Haven 
Va and the Institute of Living and transported to the West Haven VA for storage 
via Yale’s Intracampus Transport system.
iii. the types of information about the donor/individual contributors that will be 
entered into a database
No identifiers will be entered in the database.
iv. the methods to uphold confidentiality 
Discussed on pages 20 and 32-33.
B. What are the conditions or procedures for sharing of materials and/or distributing for 
future research projects?
N/A, as below.
C. Is widespread sharing of materials planned? 
No, there is not.
D. When and under what conditions will materials be stripped of all identifiers?
All biological materials studied in the DNA lab will have been stripped of any personal 
identifiers. Keys that can be used to match subject with genotype (and personal ID) will 
be retained indefinitely.

APPROVED BY THE YALE UNIVERSITY IRB 5/17/2017 VALID THROUGH 5/6/2018
APPROVED BY THE YALE UNIVERSITY IRB 5/17/2017 VALID THROUGH 5/6/2018
Page 17 of 40
E. Can donor-subjects withdraw their materials at any time, and/or withdraw the identifiers 
that connect them to their materials?
Yes, subjects are free to withdraw their identifiers at any time.
i.
How will requests to withdraw materials be handled (e.g., material no longer 
identified: that is, anonymized) or material destroyed)?
At subjects’ request, samples will be de-identified, however, we will continue to 
study genotype and phenotype data together.
F. Describe the provisions for protection of participant privacy
Bloods for genetic analysis will be collected at the screening visit and stored until 
analyzed.  The laboratory will receive no identifying information about the samples. A 
key linking the samples with identifying information will be stored in Dr. Ranganathan’s 
laboratory.
G. Describe the methods for the security of storage and sharing of materials
The genetic materials will be stored indefinitely for future study including genome-wide 
association studies.  There are no plans for sharing the samples. Participants can 
withdraw their identifiers at any time.
4. Subject Population: Provide a detailed description of the types of human subjects who will 
be recruited into this study.
Subjects with a diagnosis of Schizophrenia Spectrum Disorder will be recruited. The study aims 
to enroll patients with psychosis who do not currently require an inpatient hospitalization. We will 
attempt to enroll a significant portion of patients whose current treatment does not include anti- 
psychotic medication. Target sample size is 36. Expecting a screen failure rate of 50%, we will 
enroll up to 72 subjects to achieve the target sample.
5. Subject classification: Check off all classifications of subjects that will be specifically 
recruited for enrollment in the research project. Will subjects who may require additional 
safeguards or other considerations be enrolled in the study? If so, identify the population of 
subjects requiring special safeguards and provide a justification for their involvement.
Children
Healthy
Fetal material, placenta, or dead fetus 
Non-English Speaking
Prisoners
Economically disadvantaged persons 
Decisionally Impaired
Employees
Pregnant women and/or fetuses
Yale Students
Females of childbearing potential
NOTE: Is this research proposal designed to enroll children who are wards of the state as 
potential subjects?
Yes
No (If yes, see Instructions section VII #4 for further 
requirements)

APPROVED BY THE YALE UNIVERSITY IRB 5/17/2017 VALID THROUGH 5/6/2018
APPROVED BY THE YALE UNIVERSITY IRB 5/17/2017 VALID THROUGH 5/6/2018
Page 18 of 40
6. Inclusion/Exclusion Criteria: What are the criteria used to determine subject inclusion or 
exclusion?
Inclusion Criteria:
1. Primary psychotic disorder (Schizophrenia, Schizoaffective disorder, etc.)
2.   Age 18-65
3. Capable of providing informed consent
4. Within approximately five years of onset of psychosis/ presentation to treatment 
for psychosis
Exclusion Criteria:
1. Other current major psychiatric diagnoses that require pharmacological treatment 
(example: PTSD). Some diagnoses will be allowed at the PI discretion (example: 
Adjustment disorder)
2. Current substance dependence (other than nicotine or cannabis)
3. Serious medical or neurological illness or treatment for a medical disorder that 
could interfere with study participation as determined by principal investigator
4. History of significant head injury/trauma as determined by principal investigator
5. Women who are pregnant, nursing or unwilling to use appropriate birth control 
measures during study participation
6. Inability to complete neuropsychological tests
7. History of treatment resistance or current treatment with clozapine
8. Current treatment with investigational agents or participation in another clinical 
trial that may affect outcome measures
7. How will eligibility be determined, and by whom?
Subjects may first undergo a phone screen to initially determine eligibility. Information 
collected during the phone screen will only be used in the event that the subject continues to 
participate in the study.
After determining initial eligibility, research staff will provide a brief description of the 
research and the subject will present to the clinic for the screening procedures described 
above. Once all screening procedures have been collected, research staff as well as the 
principal investigator will review all relevant information and determine, based on the 
inclusion and exclusion criteria, if the subject will continue with the remaining study 
procedures. Subjects already on antipsychotics or other medications will continue use of the 
medications while participating in the current study.  Subjects will not be taken off their 
antipsychotic medications for participation in this study.
8. Risks: Participation in this study may be associated with risks related to:

APPROVED BY THE YALE UNIVERSITY IRB 5/17/2017 VALID THROUGH 5/6/2018
APPROVED BY THE YALE UNIVERSITY IRB 5/17/2017 VALID THROUGH 5/6/2018
Page 19 of 40
a. Psychiatric evaluation: Subjects will undergo a Structured Clinical Interview for 
DSM-IV conducted by a research assistant and a psychiatric and medical evaluation 
during screening. The diagnostic interviews may cover issues, which are stressful to a 
person, for example, questions regarding the experience of paranoid thoughts or social 
isolation. Thus, they may experience some distress during these interviews.
b. Loss of confidentiality: Participation in research may involve a loss of privacy and 
confidentiality. Therefore, extensive measures are in place to protect the 
confidentiality of subjects. (See below.)
c.
Study assessments: During the baseline and follow-up assessments, study participants 
may become tired or frustrated. If this occurs, they will be encouraged to take breaks. 
It is also possible that some individuals may experience discomfort during the 
interviews, when they are asked to talk about their psychiatric symptoms. Subjects 
may feel bored, tired, exhausted, discouraged or distressed by the questionnaires or 
EEG testing.
d. CBD administration: CBD is a naturally occurring component of cannabis that has 
been used recreationally and for medicinal purposes by large populations. As 
mentioned above, studies have shown good tolerance of cannabidiol even in high 
doses with relatively few side effects and no known severe events. Sedation and/or 
lightheadedness are likely to be the most common reported adverse reaction. Patient 
will be assessed weekly for the development of side effects.
e.
Worsening of psychosis: Participation in this study may be associated with worsening 
of psychosis especially in those individuals who are not on any other antipsychotics. 
Subjects will be evaluated on a weekly basis in face-to-face meeting with study staff. 
Psychotic symptoms, mood symptoms and suicidality will be assessed at each of these 
meetings. Further, subjects will be contacted approximately 5 times per week using 
CAROMA for the confirmation of compliance. During each of these visits, subjects 
will be asked if they have noticed any worsening of symptoms or any new side effects. 
If subjects report that they do notice a worsening of symptoms or side effects, this will 
be evaluated by an investigator on the team and subject will be asked to come into the 
clinic to be evaluated if clinically indicated. Subjects are well aware that in case of 
significant worsening of symptoms/ emergence of SI/HI, they may be escorted to the 
ER or admitted to an inpatient unit.
f.
Risk of blood draws: Blood will be drawn weekly during the study to monitor 
medication levels as well as safety labs. There are usually no serious medical problems 
with blood drawing, but there may be pain at the venipuncture site or bruising or 
infection may occur.
g. Risks of EEG: EEG is a non-invasive assessment. There are minimal risks associated 
with EEG/ERP recording. Traditionally, scalp abrasion has been used to improve

APPROVED BY THE YALE UNIVERSITY IRB 5/17/2017 VALID THROUGH 5/6/2018
APPROVED BY THE YALE UNIVERSITY IRB 5/17/2017 VALID THROUGH 5/6/2018
Page 20 of 40
signal impedance at the electrode site. The EEG/ERP system used in this laboratory is 
a high-impedance system and does not require scalp abrasion to obtain clean 
recording. A conductive gel is applied, which can be easily washed out of the subject’s 
hair with warm water. A shower facility for hair washing and sterile linens are 
available in the laboratory. Electrode caps and sensors will be washed and sterilized 
between subjects to minimize the risk of transmitting infection.
Potential benefits: Subjects will receive no direct benefit from this study.  Potential benefits 
may include improvement in psychotic and cognitive symptoms, decreased negative symptoms, 
avoidance of potential side effects from usual anti-psychotic medications themselves or from 
dose increases of such medications.  Overall, the development of novel anti-psychotics will 
provide benefit to the schizophrenia population as a whole.
Risk/Benefit ratio: As described above, the primary risks of this study are related to CBD 
administration and are low.  Extensive safety measures are in place to ensure that participants 
with worsening psychosis or mood symptoms are identified expeditiously. The overall risk- 
benefit ratio is therefore favorable.
9. Minimizing Risks: Describe the manner in which the above-mentioned risks will be 
minimized.
Loss of Confidentiality: There is a risk of loss of confidentiality in this study. All subject 
information will be kept confidential and only members of the investigative team with appropriate 
IRB/HIC and HIPAA training will have access to the study data. Data will be maintained and secured 
in locked file cabinets or password protected electronic media. A numbering code will be used to 
assign a unique identifier to each subject. The researchers will be applying for a certificate of 
confidentiality (COC).
For the Cellphone Assisted Remote Observation of Medication Adherence (CAROMA) 
procedures, subjects will be called and observed while taking study medications. The 
CAROMA procedure is not recorded, broadcast, nor will the likeness of the subjects be used 
for anything other than what has been specified. The potential for loss of confidentiality is if 
someone taps the phone while a call is being made, but this risk is no different from someone 
tapping into a phone (audio) conversation between the subject and the research team. The 
phones used for this practice will be encrypted by Yale University Information Technology 
Services (ITS) so that loss of confidentiality is minimized. CAROMA was set up with input 
from Yale ITS in order to conform to Yale’s policies.
Psychiatric Evaluation and Study Assessments: If subjects become tired, frustrated, or 
distressed during assessments or evaluations, they will be encouraged to take breaks.
CBD Administration: Patients will be assessed weekly for the development of side effects. 
Worsening of psychosis: Subjects will be evaluated on a weekly basis in face-to-face meeting 
with study staff. Psychotic symptoms, mood symptoms, and suicidality will be assessed at each 
of these meetings. Further, subjects will be contacted approximately 5 times per week using 
CAROMA for the confirmation of compliance. During each of these visits, subjects will be 
asked if they have noticed any worsening of symptoms or any new side effects. If subjects report

APPROVED BY THE YALE UNIVERSITY IRB 5/17/2017 VALID THROUGH 5/6/2018
APPROVED BY THE YALE UNIVERSITY IRB 5/17/2017 VALID THROUGH 5/6/2018
Page 21 of 40
that they do notice a worsening of symptoms or side effects, this will be evaluated by an 
investigator on the team and subjects will be asked to come into the clinic to be evaluated if 
clinically indicated. Subjects are well aware that in case of significant worsening of symptoms/ 
emergence of SI/HI, they may be escorted to the ER or admitted to an inpatient unit.
Risks of Blood Draws: Due to the risks associated with phlebotomy procedures, subjects who 
have donated blood within eight weeks to the present study will be excluded. Subjects will be 
told that they should not give blood for at least eight weeks.
Risks of EEG: The risk of irritation during EEG set up will be minimized through careful 
application of electrodes and appropriate cleansing of the skin by trained technicians.
10. Data and Safety Monitoring Plan: Include an appropriate Data and Safety Monitoring Plan 
(DSMP) based on the investigator’s risk assessment stated below. (Note: the HIC will make 
the final determination of the risk to subjects.) For more information, see the Instructions, 
page 24.
a.
What is the investigator’s assessment of the overall risk level for subjects 
participating in this study?
Moderate risk
b.
If children are involved, what is the investigator’s assessment of the overall risk 
level for the children participating in this study?  No children will be enrolled.
c.
Copy, paste, and then tailor an appropriate Data and Safety Monitoring Plan 
from  http://www.yale.edu/hrpp/forms-templates/biomedical.html  for
i. Minimal risk
ii. Greater than minimal/moderate risk
iii. High risk
SAFETY: Subjects will be closely monitored for worsening of symptoms or side effects. They 
will be provided with a 24 hour access to study personnel to discuss any concerns. Subjects will 
be given a wallet card indicating they are taking experimental medication and directions for how 
to determine what they are taking in case of an emergency.
Adverse events will be reported to the HIC and any appropriate funding and regulatory agencies. 
The investigator will apprise fellow investigators and key study personnel of all serious and 
unanticipated adverse events that occur during the conduct of this research project. Adverse 
events will be graded as per HIC policy.
Data safety and monitoring plan: This is a moderate risk study, and no serious adverse events are 
expected.  If any should occur, however, the following grading system will be used to assess the 
seriousness of the adverse events:
0
No adverse event or within normal limits
1
Mild adverse event
2
Moderate adverse event
3
Severe adverse event resulting in hospitalization or prolongation of existing 
hospitalization, a persistent or significant disability/incapacity, or a congenital anomaly/birth 
defect.

APPROVED BY THE YALE UNIVERSITY IRB 5/17/2017 VALID THROUGH 5/6/2018
APPROVED BY THE YALE UNIVERSITY IRB 5/17/2017 VALID THROUGH 5/6/2018
Page 22 of 40
4
Life-threatening or disabling adverse event
5
Fatal adverse event
Serious unanticipated adverse events will be reported immediately to the VA Connecticut 
Healthcare System, Yale University School of Medicine, California Pacific Medical Center 
institutional review boards and any appropriate funding and regulatory agencies.  Serious 
anticipated adverse events will be reported immediately to the institutional review boards and 
others whenever their magnitude or frequency exceeds expectations.
The principal investigator will evaluate all adverse events and determine whether the adverse 
event affects the risk/benefit ratio of the study and whether modifications to the protocol or 
consent form are required. A summary of the adverse events will be reported to the institutional 
review boards periodically or, at minimum, when reapproval of the protocol is sought. The 
summary will include number of subjects enrolled and a summary of graded adverse events to 
date.  All adverse events will be graded using the following grading system:
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
Attribution
UNA 
TP
ATP
UN 
ATP
ATP
UN 
ATP
ATP
UN 
ATP
ATP
UN 
ATP
ATP
Unrelated
Unlikely
Possible
Probable
Definite
Totals
Total Subjects Enrolled to Date
The principal investigator will be responsible for monitoring the data and conducting 
performance of safety reviews at regular intervals, as indicated above.  The principal investigator 
will conduct a data and safety review at least quarterly and at any time a serious adverse event 
occurs. During the review process the principal investigator will evaluate whether the study 
should continue unchanged, require modification, continue or close to enrollment.
DSMB: A Data Safety Monitoring Board is being assembled for this study. Unblinded safety 
data will be provided to the committee for monitoring purposes, in a meeting that will be held 
approximately every 6 months. DSMB reports will be provided to the HIC. 
11. Statistical Considerations: 
General Strategy:
All outcomes will be summarized descriptively and assessed for normality prior to analysis using 
normal probability plots and Kolmogorov test statistics. Transformations or nonparametric 
analyses will be performed as necessary. All tests will be two-sided and considered statistically 
significant at alpha=.05. Post-hoc comparisons will be performed as appropriate and significance 
levels for secondary analyses will be adjusted for multiple tests using the Bonferroni correction. 
All analyses will be performed using SAS, version 9.3 (SAS Institute Inc., Cary, NC).

APPROVED BY THE YALE UNIVERSITY IRB 5/17/2017 VALID THROUGH 5/6/2018
APPROVED BY THE YALE UNIVERSITY IRB 5/17/2017 VALID THROUGH 5/6/2018
Page 23 of 40
Linear mixed models will be used assess symptom improvement as measured by the PANSS 
(primary hypothesis) and CGI. In these models group (CBD vs. placebo) and time (see study time 
points) will be modeled as within-subjects factor. Oder effects will also be tested. Least squares 
means and standard errors will be calculated in the mixed model and plotted to interpret significant 
effect. A significant group by time interaction explained by reduced symptoms over time due to 
CBD treatment will be supportive of our hypothesis. In the above models, the best fitting variance- 
covariance structure will be selected based on information criteria. The mixed effects approach is 
advantageous in that it is unaffected by randomly missing data and allows greater flexibility in 
modeling the correlation structure of repeated measures data [31]. Similar mixed models as 
described above will be employed to evaluate secondary outcomes (e.g., PAOFI, EEG parameters).
Power Analysis:
We will recruit 36 subjects and randomly assign 18 to receive either CBD followed by placebo 
(order 1) or placebo followed by CBD (order 2). Based on a within-subjects design and a two- 
tailed alpha=0.05, 36 subjects will provide 80% power to detect moderate treatment effects as 
small as d’=0.49. This compares favorably with the effects (d=0.7) observed by Leweke in their 
study comparing CBD to amisulpiride in schizophrenia patients.
SECTION VI: RESEARCH INVOLVING DRUGS, BIOLOGICS, RADIOTRACERS, PLACEBOS AND
DEVICES
If this section (or one of its parts, A or B) is not applicable, state N/A and delete the rest of the 
section.
A. DRUGS, BIOLOGICS and RADIOTRACERS
1. Identification of Drug, Biologic or Radiotracer: The investigational drug to be used in this study 
is Cannabidiol provided by Insys Pharmaceuticals. This study will be conducted under an IND# 
126731.
2. Background Information:
Cannabidiol (CBD) is a component of herbal cannabis that is present in varying concentrations in 
cannabis extracts. CBD has been shown to produce central effects including hypnotic, 
anticonvulsive, anxiolytic and neuroprotective effects [10]. Until recently, the mechanism of action 
of CBD was unclear. However, recently, CBD has been found to be a potent non-competitive 
inhibitor at CB-1 and CB-2 receptors [32] in addition to having effects at a third as of yet 
unidentified central cannabinoid G-protein coupled receptor.
CBD has also been used to treat patients with schizophrenia. Early case series suggested mixed 
results but good tolerability even at high doses [9]. Preliminary results from an SMRI funded 4- 
week, double-blind comparison of CBD vs. amisulpride in acute schizophrenic and 
schizophreniform psychosis have been promising. CBD significantly reduced acute psychotic 
symptoms after 2 and 4 weeks of treatment. CBD was equivalent to the amisulpride in efficacy and 
was also associated with fewer side effects [33].

APPROVED BY THE YALE UNIVERSITY IRB 5/17/2017 VALID THROUGH 5/6/2018
APPROVED BY THE YALE UNIVERSITY IRB 5/17/2017 VALID THROUGH 5/6/2018
Page 24 of 40
3. Source: a) Identify the source of the drug or biologic to be used.
b) Is the drug provided free of charge to subjects?
Yes
No 
If yes, by whom?  Insys
4. Storage, Preparation and Use: Describe the method of storage, preparation, stability information, 
and for parenteral products, method of sterilization and method of testing sterility and 
pyrogenicity.
Check applicable Investigational Drug Service utilized:
YNHH IDS
Yale Cancer Center
CMHC Pharmacy
West Haven VA
PET Center
None
Other:
Note: If the YNHH IDS (or comparable service at CMHC or WHVA) will not be utilized, explain in 
detail how the PI will oversee these aspects of drug accountability, storage, and preparation.
The material will be stored in the West Haven VA pharmacy as per package insert. Pharmacists 
will deliver medication vials to study staff for dispensing by study psychiatrists.
5. Use of Placebo:
Not applicable to this research project
If use of a placebo is planned, provide a justification which addresses the following:
a.
The study intervention include CBD or placebo. The inclusion of placebo is to permit 
comparison with CBD. However, we recognize that for an individual with a psychotic disorder 
the standard of care is treatment with first or second-generation antipsychotic medication. A 
large proportion of individuals with early psychosis discontinue or never initiate antipsychotic 
treatment due to a number of factors including fear of side effects, stigma etc. This study CBD 
versus Placebo will recruit all individuals. This study will not interfere with standard of care 
and will be in addition to treatment as usual. Due to the prevalent refusal of traditional 
antipsychotic treatment among individuals with early psychosis we anticipate that some 
subjects who will receive CBD/Placebo will be on no other medication. However, requiring 
treatment with traditional antipsychotics or proposing an active control instead of placebo will 
exclude this proportion of individuals and in fact result in data that is not generalizable to this, 
most vulnerable population. Safety assessments will be done in person weekly, and multiple 
times during the week over the phone. Furthermore, subjects will be encouraged to remain 
compliant with their regular treatment sessions and medications.
There is no alternative to CBD since its efficacy is unknown. The alternative is not to 
participate in this trial.
b. State the maximum total length of time a participant may receive placebo while on the study.
Four weeks
c.
Address the greatest potential harm that may come to a participant as a result of receiving

APPROVED BY THE YALE UNIVERSITY IRB 5/17/2017 VALID THROUGH 5/6/2018
APPROVED BY THE YALE UNIVERSITY IRB 5/17/2017 VALID THROUGH 5/6/2018
Page 25 of 40
placebo.
No improvement in psychotic symptoms or course of illness. Placebo by itself is not anticipated to 
worsen psychotic symptoms. However, if psychotic symptoms are worsening placebo will not 
prevent the decompensation.
d. Describe the procedures that are in place to safeguard participants receiving placebo.
Weekly follow up visits and safety assessments including PANSS assessments will be conducted 
to detect worsening of symptoms.
6. Use of Controlled Substances:
Will this research project involve the use of controlled substances in human subjects?
No
Yes  See HIC Application Instructions to view controlled substance listings.
If yes, is the use of the controlled substance considered:
Therapeutic: The use of the controlled substance, within the context of the research, has the 
potential to benefit the research participant.
Non-Therapeutic: Note, the use of a controlled substance in a non-therapeutic research study 
involving human subjects may require that the investigator obtain a Laboratory Research License. 
Examples include controlled substances used for basic imaging, observation or biochemical 
studies or other non-therapeutic purposes. See Instructions for further information.
7. Continuation of Drug Therapy After Study Closure
Not applicable to this project
Are subjects provided the opportunity to continue to receive the study drug(s) after the study has 
ended?
Yes   If yes, describe the conditions under which continued access to study drug(s) may apply 
as well as conditions for termination of such access.
No
The use of CBD is experimental. At this point there are no data supporting its use in the 
treatment of any illness.
B. DEVICES
1. Are there any investigational devices used or investigational procedures performed at YNHH, e.g., 
YNHH Operating Room or YNHH Heart and Vascular Center?  Yes
No
If Yes, please be aware of the following requirements:
a.
A YNHH New Product/Trial Request Form must be completed;
b. Your request must be reviewed and approved by a Hospital Committee before 
patients may be scheduled; and
c.
The notice of approval from YNHH must be submitted to the HIC for the protocol 
file.

APPROVED BY THE YALE UNIVERSITY IRB 5/17/2017 VALID THROUGH 5/6/2018
APPROVED BY THE YALE UNIVERSITY IRB 5/17/2017 VALID THROUGH 5/6/2018
Page 26 of 40
Please contact Gina D’Agostino, gina.d’agostino@ynhh.org or 203-688-5052, to initiate the 
process.
2. What is the name of the device to be studied in this protocol? 
Has this device been FDA approved?
Yes
No
If yes, state for what indication.
3. Background Information: Provide a description of previous human use, known risks, and any 
other factors that might influence risks. If this is the first time this device is being used in humans, 
include relevant data on animal models.
4. Source:
a) Identify the source of the device to be used.
b) Is the device provided free of charge to subjects?
Yes
No
5.  What is the PI’s assessment of risk level (significant or non-significant) associated with the use of 
the device?
Significant Risk (SR) Device Study: A study of a device that presents a potential for serious 
risk to the health, safety, or welfare of a participant and 1) is intended as an implant; 2) is used in 
supporting or sustaining human life; or otherwise prevents impairment of human health; 3) is of 
substantial importance in diagnosing, curing, mitigating or treating disease, or otherwise prevents 
impairment of human health; or 4) otherwise presents a potential for serious risk to the health, 
safety, or welfare of a participant.
Significant Risk Devices require an Investigational Device Exemption (IDE) issued by the FDA. 
What is the IDE number assigned by the FDA?
Did the FDA approve this IDE as Category A (experimental/investigational) or as Category B
(non-experimental/investigational)? 
Who holds the IDE?
Non-Significant Risk (NSR) Device Study: A study of a device that does not meet the 
definition for a significant risk device and does not present a potential for serious risk to the health, 
safety, or welfare of participants.  Note that if the HIC concurs with this determination, an IDE is 
not required.

APPROVED BY THE YALE UNIVERSITY IRB 5/17/2017 VALID THROUGH 5/6/2018
APPROVED BY THE YALE UNIVERSITY IRB 5/17/2017 VALID THROUGH 5/6/2018
Page 27 of 40
6. Abbreviated IDE or Exempt IDE: There are abbreviated requirements for an IDE and there also 
are exemptions to the requirement for an IDE. See the criteria in the HIC Application Instructions, 
Section VI.B.4 at  
http://www.yale.edu/hrpp/resources/docs/100FR1aHICProtocol_Application_Instructions5-25-   
11.pdf to determine if these pertain to this study.
Abbreviated IDE or Exempt IDE – If criteria set forth in the HIC Application Instructions 
are met, copy and paste the completed relevant section from the Instructions into this application.
7.
Investigational device accountability:
a.
State how the PI, or named designee, ensures that an investigational device is 
used only in accordance with the research protocol approved by the HIC, and 
maintains control of the investigational device as follows:
b. Maintains appropriate records, including receipt of shipment, inventory at the site, 
dispensation or use by each participant, and final disposition and/or the return of 
the investigational device (or other disposal if applicable):
Documents pertinent information assigned to the investigational device (e.g., date, quantity, batch 
or serial number, expiration date if applicable, and unique code number):
Stores the investigational device according to the manufacturer's recommendations with respect to 
temperature, humidity, lighting, and other environmental considerations:
Ensures that the device is stored in a secure area with limited access in accordance with applicable 
regulatory requirements:
Distributes the investigational device to subjects enrolled in the IRB-approved protocol:
SECTION VII: RECRUITMENT/CONSENT AND ASSENT PROCEDURES
1. Targeted Enrollment: Give the number of subjects:
a.
targeted for enrollment at Yale for this protocol 
Approximately 70 to have 36 completers
b.
If this is a multi-site study, give the total number of subjects targeted across all 
sites_N/A 
2. Indicate recruitment methods below.  Attach copies of any recruitment materials that will be used.
Flyers
Internet/Web Postings
Radio
Posters
Mass E-mail Solicitation
Telephone
Letter
Departmental/Center Website
Television
Medical Record Review
Departmental/Center Newsletters
Departmental/Center Research Boards
Web-Based Clinical Trial Registries
Newspaper
YCCI Recruitment database
Clinicaltrials.gov Registry (do not send materials to HIC)
Other (describe):
3.
Recruitment Procedures:
a.Describe how potential subjects will be identified.

APPROVED BY THE YALE UNIVERSITY IRB 5/17/2017 VALID THROUGH 5/6/2018
APPROVED BY THE YALE UNIVERSITY IRB 5/17/2017 VALID THROUGH 5/6/2018
Page 28 of 40
Potential subjects will be identified through responses to the methods of advertisements listed 
above. An additional document with the language used for internet/web postings has been 
included. Furthermore, the research team will reach out to local mental health facilities 
(including the Connecticut Mental Health Center, the West Haven VA and the Institute of 
Living) through “lunch and learns”, etc. for patient referrals. A lunch and learn is a meeting 
that research staff schedule with clinicians and therapists at local mental health facilities where 
an overview of current research protocols are presented and discussed.
b. Describe how potential subjects are contacted.
Subjects will be asked to contact research staff through the advertisement methods listed above. 
In the event that a subject responds to an advertisement, they will be contacting study staff. In 
the event that subjects are referred from clinics or mental health facilities, research staff will 
require that the subjects’ clinician contacts the subject first and then refers the subject to the 
research clinic.
c.Who is recruiting potential subjects? 
Members of the research team.
4. Screening Procedures
a.
Will email or telephone correspondence be used to screen potential subjects for 
eligibility prior to the potential subject coming to the research office?      Yes       No
b. If yes, identify below all health information to be collected as part of screening and 
check off any of the following HIPAA identifiers to be collected and retained by the 
research team during this screening process.
HEALTH INFORMATION TO BE COLLECTED:
Please see attached phone screen
HIPAA identifiers:
Names
All geographic subdivisions smaller than a State, including: street address, city, county, precinct, zip codes and their 
equivalent geocodes, except for the initial three digits of a zip code if, according to the current publicly-available data from 
the Bureau of the Census: (1) the geographic unit formed by combining all zip codes with the same three initial digits contains 
more than 20,000 people, and (2) the initial three digits of a zip code for all such geographic units containing 20,000 or fewer 
people is changed to 000.
Telephone numbers 
Fax numbers
E-mail addresses
Social Security numbers 
Medical record numbers
Health plan beneficiary numbers 
Account numbers
All elements of dates (except year) for dates related to an individual, including: birth date, admission date, discharge 
date, date of death, all ages over 89 and all elements of dates (including year) indicative of such age, except that such ages 
and elements may be aggregated into a single category of age 90 or older
Certificate/license numbers
Vehicle identifiers and serial numbers, including license plate numbers 
Device identifiers and serial numbers
Web Universal Resource Locators (URLs) 
Internet Protocol (IP) address numbers
Biometric identifiers, including finger and voice prints  
Full face photographic images and any comparable images

APPROVED BY THE YALE UNIVERSITY IRB 5/17/2017 VALID THROUGH 5/6/2018
APPROVED BY THE YALE UNIVERSITY IRB 5/17/2017 VALID THROUGH 5/6/2018
Page 29 of 40
Any other unique identifying numbers, characteristics, or codes
5. Assessment of Current Health Provider Relationship for HIPAA Consideration:
Does the Investigator or any member of the research team have a direct existing clinical 
relationship with any potential subject?
Yes, all subjects
Yes, some of the subjects 
No
If yes, describe the nature of this relationship.
PI and some co-investigators may provide clinical care to some potential subjects and/or may work in 
the clinic where some potential subjects are treated.
6. Request for waiver of HIPAA authorization: (When requesting a waiver of HIPAA Authorization 
for either the entire study, or for recruitment purposes only. Note: if you are collecting PHI as part of 
a phone or email screen, you must request a HIPAA waiver for recruitment purposes.)
Choose one: For entire study:
For recruitment purposes only:
X
i. Describe why it would be impracticable to obtain the subject’s authorization for 
use/disclosure of this data;
NA
ii. If requesting a waiver of signed authorization, describe why it would be 
impracticable to obtain the subject’s signed authorization for use/disclosure of this 
data;
This data will serve to prescreen subjects who meet obvious exclusion criteria for the study. 
Thus it avoids subject and investigator burden related to screening of ineligible subjects.
Further, due to the stringent I/C criteria, the number of subjects screened who will need to go 
through exhaustive screening and be exposed to greater risk will increase if all potential 
subjects are to be brought in for a face to face screening.
iii.  Authorization will be obtained prior to subject participation in any research 
procedure. However, when the subject is initially contacted by phone when referred 
by a treater or in response to an ad, it would not be feasible to obtain a signed 
authorization over the phone. Subjects will be notified that all personal health 
information will remain confidential and will be given the option to be contacted for 
future research in the event that they are not eligible for the study. By signing this 
protocol application, the investigator assures that the protected health 
information for which a Waiver of Authorization has been requested will not be 
reused or disclosed to any person or entity other than those listed in this 
application, except as required by law, for authorized oversight of this research 
study, or as specifically approved for use in another study by an IRB.
Researchers are reminded that unauthorized disclosures of PHI to individuals outside of the Yale 
HIPAA-Covered entity must be accounted for in the “accounting for disclosures log”, by subject

APPROVED BY THE YALE UNIVERSITY IRB 5/17/2017 VALID THROUGH 5/6/2018
APPROVED BY THE YALE UNIVERSITY IRB 5/17/2017 VALID THROUGH 5/6/2018
Page 30 of 40
name, purpose, date, recipients, and a description of information provided.  Logs are to be 
forwarded to the Deputy HIPAA Privacy Officer.
7. Required HIPAA Authorization: If the research involves the creation, use or disclosure of 
protected health information (PHI), separate subject authorization is required under the 
HIPAA Privacy Rule. Indicate which of the following forms are being provided:
Compound Consent and Authorization form 
HIPAA Research Authorization Form
8. Consent Personnel: List the names of all members of the research team who will be obtaining 
consent/assent.
Mohini Ranganathan, M.D., Deepak C. D’Souza, M.D., Kim Bielen, B.S., Emma Deaso, B.A., Gina 
Creatura, B.A., Christina Luddy, B.S.,., Esra Sefik, B.S., Chloe Grond, B.A., Melissa Boucher, B.S., 
Madison Dykins, B.A., Mackenzie Griffin, B.S., and Ashley Sanders, B.A. 
9. Process of Consent/Assent: Describe the setting and conditions under which consent/assent will 
be obtained, including parental permission or surrogate permission and the steps taken to ensure 
subjects’ independent decision-making.
The consent process is a multistep process, whereby information about the risks and benefits of 
the study will be provided to potential subjects across several sessions. The number of sessions 
over which this information will be provided will depend on how well the subject understands 
and retains the information. The process begins with the subject initiating contact via telephone. 
The research staff will provide a brief description of the study following which the subject is 
screened by a member of the research team. Thereafter, potentially eligible candidates are 
scheduled for a face-to-face interview. The study procedures will be described as a research tool 
with potential to enhance our knowledge about the brain. Subjects will also be informed of all 
potential risks of participation. Subjects will be required to read the informed consent form and 
the investigator will additionally describe the risks and discomforts.
To ensure that the study subject understands the study, the subject will be asked questions about 
the study procedures and the risks associated with participation. If any concern arises that the 
study subject did not fully understand the study, the principal investigator (PI) may decide that 
the subject is not suitable for participation. This process generally takes about one hour. If the 
subject is still interested after all questions have been answered, the PI or staff member 
consenting, will ask the subject to sign the informed consent form. Any subject who appears 
incapable of providing informed consent will be excluded. Subjects will be informed that they 
can decline to participate in the study without penalty and given the opportunity to withdraw 
from the study prior to analysis of their data. Following the resolution of any questions, the 
subjects will be asked to sign the consent form if he/she agrees to participate.
10. Evaluation of Subject(s) Capacity to Provide Informed Consent/Assent: Indicate how the 
personnel obtaining consent will assess the potential subject’s ability and capacity to consent to the 
research being proposed.

APPROVED BY THE YALE UNIVERSITY IRB 5/17/2017 VALID THROUGH 5/6/2018
APPROVED BY THE YALE UNIVERSITY IRB 5/17/2017 VALID THROUGH 5/6/2018
Page 31 of 40
Great care will be taken to ensure that the subject is able to give informed consent. If any 
concern arises that the study subject did not fully understand the study, the principal investigator 
may decide that the subject is not suitable for participation. This process will involve careful 
explanation of the consent form by a member of the research staff and a post- test to ensure 
understanding of the procedures and risks of the study. The subject will be required to get 75% 
of all questions and all the asterisked critical questions correct on a consent questionnaire in 
order to participate (see attached for details). Parents and family and non-research clinicians will 
be involved in the process when available. The patient’s primary clinician i.e. non-research 
clinician (if applicable) will be required to assent to patient’s participation. This is standard 
procedure for this clinic with all studies.
11. Documentation of Consent/Assent: Specify the documents that will be used during the 
consent/assent process. Copies of all documents should be appended to the protocol, in the same 
format that they will be given to subjects.
There will be consent forms for all participating subjects. The forms are attached to this 
application.
12. Non-English Speaking Subjects: Explain provisions in place to ensure comprehension for 
research involving non-English speaking subjects. Translated copies of all consent materials must 
be submitted for approval prior to use.
While we do not plan to actively seek out non-English speaking individuals, we may enroll 1 or 2 
Spanish speaking individuals to participate in this study. If the research staff recruits a Spanish 
speaking subject, an interpreter will be asked to go through the consent form thoroughly with the 
subject to make sure they have a complete understanding. If the subject is comfortable, they will then 
be asked to sign the Spanish short form consent form. We will have an interpreter present at all study 
visits to translate assessments and procedures. In addition, they will meet with a Spanish speaking 
medical doctor at all safety visits to assess for adverse events and side effects.
13. Consent Waiver: In certain circumstances, the HIC may grant a waiver of signed consent, or 
a full waiver of consent, depending on the study. If you will request either a waiver of consent, 
or a waiver of signed consent for this study, complete the appropriate section below.
Not Requesting a consent waiver 
Requesting a waiver of signed consent 
Requesting a full waiver of consent
A. Waiver of signed consent: (Verbal consent from subjects will be obtained. If PHI is 
collected, information in this section must match Section VII, Question 6)
Requesting a waiver of signed consent for Recruitment/Screening only
If requesting a waiver of signed consent, please address the following:
a. Would the signed consent form be the only record linking the subject and the research?
Yes
No
b. Does a breach of confidentiality constitute the principal risk to subjects? 
Yes
No
OR

APPROVED BY THE YALE UNIVERSITY IRB 5/17/2017 VALID THROUGH 5/6/2018
APPROVED BY THE YALE UNIVERSITY IRB 5/17/2017 VALID THROUGH 5/6/2018
Page 32 of 40
c. Does the research activity pose greater than minimal risk?
Yes If you answered yes, stop. A waiver cannot be granted. Please note: 
Recruitment/screening is generally a minimal risk research activity
No
AND
d. Does the research include any activities that would require signed consent in a non- 
research context?
Yes
No
Requesting a waiver of signed consent for the Entire Study (Note that an information 
sheet may be required.)
If requesting a waiver of signed consent, please address the following:
a. Would the signed consent form be the only record linking the subject and the research?
Yes
No
b. Does a breach of confidentiality constitute the principal risk to subjects? 
Yes
No
OR
c. Does the research pose greater than minimal risk?
Yes If you answered yes, stop. A 
waiver cannot be granted.
No
AND
d. Does the research include any activities that would require signed consent in a non- 
research context?
Yes
No
B. Full waiver of consent: (No consent from subjects will be obtained for the activity.)
Requesting a waiver of consent for Recruitment/Screening only
a. Does the research activity pose greater than minimal risk to subjects?
Yes If you answered yes, stop. A waiver cannot be granted. Please note: 
Recruitment/screening is generally a minimal risk research activity
No
b. Will the waiver adversely affect subjects’ rights and welfare?
Yes
No
c. Why would the research be impracticable to conduct without the waiver?
d. Where appropriate, how will pertinent information be returned to, or shared with 
subjects at a later date?
Requesting a full waiver of consent for the Entire Study (Note: If PHI is 
collected, information here must match Section VII, question 6.)
If requesting a full waiver of consent, please address the following:
a. Does the research pose greater than minimal risk to subjects? 
Yes If you answered yes, stop. A waiver cannot be granted.
No
b. Will the waiver adversely affect subjects’ rights and welfare?
Yes
No

APPROVED BY THE YALE UNIVERSITY IRB 5/17/2017 VALID THROUGH 5/6/2018
APPROVED BY THE YALE UNIVERSITY IRB 5/17/2017 VALID THROUGH 5/6/2018
Page 33 of 40
c. Why would the research be impracticable to conduct without the waiver?
d. Where appropriate, how will pertinent information be returned to, or shared with 
subjects at a later date?
SECTION VIII: PROTECTION OF RESEARCH SUBJECTS
Confidentiality & Security of Data:
a.
What protected health information (medical information along with the HIPAA identifiers) 
about subjects will be collected and used for the research?
Required private identifiable information about individuals will be collected by the research staff and 
be used for research purposes and charting after consent is obtained. This information includes the 
results from laboratory tests for both blood and urine, electrocardiogram (ECG) and physical 
examination results.
b.
How will the research data be collected, recorded and stored?
Yale University study team members will collect required research data through study procedures as 
outlined in this protocol and record it in confidential research records and protected computer files. 
Data will be stored at the Yale University or the VA in a manner that is compliant with IRB regulations 
at both institutions.
c.
How will the digital data be stored?
CD
DVD
Flash Drive
Portable Hard 
Drive
Secured Server
Laptop Computer
Desktop Computer
Other
d.
What methods and procedures will be used to safeguard the confidentiality and security of 
the identifiable study data and the storage media indicated above during and after the subject’s 
participation in the study?
All information obtained in this research study will be kept confidential and only be made 
available to the investigators. In all records of this research study, subjects will be identified by a 
unique identifier number code known only to researchers working directly on this protocol. These 
codes will not be derived from subjects PHI (e.g. name, date of birth etc.). A master list of subject 
names along with unique identifier number will be kept in a locked cabinet in the Principal 
Investigators office.
Do all portable devices contain encryption software?      Yes        No
If no, see http://hipaa.yale.edu/guidance/policy.html
e.
What will be done with the data when the research is completed? Are there plans to destroy 
the identifiable data? If yes, describe how, by whom and when identifiers will be destroyed. If 
no, describe how the data and/or identifiers will be secured.
Procedures to ensure confidentiality follow the regulations and policies of Yale School of 
Medicine. If the results of this research study are reported in any scientific meetings or literature, 
subjects will not be identified by name or photograph. Records will be maintained according to 
FDA Good Clinical Practice guidelines to ensure protection of confidentiality and security of

APPROVED BY THE YALE UNIVERSITY IRB 5/17/2017 VALID THROUGH 5/6/2018
APPROVED BY THE YALE UNIVERSITY IRB 5/17/2017 VALID THROUGH 5/6/2018
Page 34 of 40
records. Yale Human Investigations Committee (HIC), who approves the completion of this study 
at Yale, may inspect study records.
f. Who will have access to the protected health information (such as the research sponsor, the 
investigator, the research staff, all research monitors, FDA, Yale Cancer Center Data and Safety 
Monitoring Committee (DSMC), SSC, etc.)? (please distinguish between PHI and de-identified 
data)
All protected health information collected specifically for this research will be secured in the manner 
described above. The data will be stored in a secure location- we anticipate that the data will be 
stored for at least 10-15 years.
g. If appropriate, has a Certificate of Confidentiality been obtained? 
We have obtained a CoC from the Food and Drug Administration.
h.
Are any of the study procedures likely to yield information subject to mandatory reporting 
requirements? (e.g. HIV testing – reporting of communicable diseases; parent interview -incidents 
of child abuse, elderly abuse, etc.). Please verify to whom such instances will need to be reported.
If subjects report any threats of violence to a child or elderly person, this will be reported to the 
Department of Health and Human Services. Threats of violence to self or others will be assessed by 
the principal investigator who will determine appropriate reporting procedures. Furthermore, positive 
HIV, hepatitis B, or C results will be reportable to the Connecticut Department of Public Health.
SECTION IX: POTENTIAL BENEFITS
Potential Benefits:
Potential benefits: Subjects will receive no direct benefit from this study. Potential benefits may 
include improvement in psychotic symptoms, decreased negative symptoms, avoidance of 
potential side effects from usual anti-psychotic medications themselves or from dose increases of 
such medications.  Overall, the development of novel anti-psychotics will provide benefit to the 
schizophrenia population as a whole.
Risk/Benefit ratio: As described above, the primary risks of this study are related to CBD 
administration and are low.  Extensive safety measures are in place to ensure that participants 
with worsening psychosis or mood symptoms are identified expeditiously. The overall risk- 
benefit ratio is therefore favorable.
SECTION X: RESEARCH ALTERNATIVES AND ECONOMIC CONSIDERATIONS
1.
Alternatives: What other alternatives are available to the study subjects outside of the research? 
Alternatives include antipsychotics that are currently used to treat psychosis.

APPROVED BY THE YALE UNIVERSITY IRB 5/17/2017 VALID THROUGH 5/6/2018
APPROVED BY THE YALE UNIVERSITY IRB 5/17/2017 VALID THROUGH 5/6/2018
Page 35 of 40
2.
Payments for Participation (Economic Considerations): Describe any 
payments that will be made to subjects, the amount and schedule of payments, 
and the conditions for receiving this compensation.
Subjects will be paid as below. Subjects will be paid only for the visits that they 
participate in. Visit payments can be split if procedures for that visit occurred on two 
separate days, without changing the total payment for that particular visit. 
Subjects may be compensated up to $25 for unscheduled visits.
Table 1: Payment schedule
Purpose
Visit
Payment per visit in 
Period I
Payment per visit in 
Period II
Screening
Ia and Ib
$25/visit up to $50
N/A
Baseline
II
$75
$75
Week
III
$50
$50
Week
IV
$50
$50
Week
V
$50
$50
Week
VI
$75
$75
Follow up
VII
$25
$25
Compliance
CAROMA
$5/ day up to $80
$5/ day up to $80
Return of phone
$20
$20
Study close out visit
N/A
$25
Total per period
Up to $475
Up to $450
Total for both periods:
Up to $ 925
3.
Costs for Participation (Economic Considerations): Clearly describe the 
subject’s costs associated with participation in the research, and the interventions 
or procedures of the study that will be provided at no cost to subjects.
Subjects will not be charged for any aspects of this study.
4.
In Case of Injury: This section is required for any research involving more than 
minimal risk.
a.
Will medical treatment be available if research-related injury occurs? Yes
b.
Where and from whom may treatment be obtained? Treatment may be 
provided by the Yale-New Haven Hospital or any health care provider 
chosen by the study subjects.
c.
Are there any limits to the treatment being provided? Only emergency care 

APPROVED BY THE YALE UNIVERSITY IRB 5/17/2017 VALID THROUGH 5/6/2018
APPROVED BY THE YALE UNIVERSITY IRB 5/17/2017 VALID THROUGH 5/6/2018
Page 36 of 40
will be provided. Limits to treatment may be imposed by the insurance carrier of the 
study subjects.
d.
Who will pay for this treatment?
How will the medical treatment be accessed by subjects? The study team will provide 
assistance to the study subjects in accessing medical treatment through referrals, or the study 
subject may choose to access treatment on their own. Furthermore, the study team will be in 
contact with the subject’s non-research clinicians who will also aid the subject in getting 
appropriate treatment.

APPROVED BY THE YALE UNIVERSITY IRB 5/17/2017 VALID THROUGH 5/6/2018
APPROVED BY THE YALE UNIVERSITY IRB 5/17/2017 VALID THROUGH 5/6/2018
Page 37 of 40
Consent Questionnaire
This is a questionnaire to help us to test your understanding of the study protocol. For you to 
qualify for this study, you will need to pass this test. To pass this test, you will need to score 
at least a 75% and also get all three questions underlined.
You will have only 2 chances to take this test. Incorrect answers on your first attempt will 
tell us those parts of the study you did not understand well, so that we can go over the 
consent form again with you. If you answer more than 5 questions wrong at your first 
attempt, you will not be considered for this study.
1. Will you need to stop taking your antipsychotic medication as part of this study?
Yes
No
Maybe
I can decide
2. What medications might you receive?
Cannabidiol
Haldol
Placebo
Paxil
Ativan
3. Will you be able to choose what medication that you may receive in this study?
Yes
No
Maybe
Don’t know
4. During the study, will you or the study doctor or the research team know exactly which 
study medication you are on?
Yes
No
Maybe
Don’t know
5. Could your schizophrenia symptoms get worse during this study?
Yes
No
Maybe
Don’t know
6. Will blood be drawn for this study?
Yes
No
Maybe
Don’t know
7. Can the study medication have side effects?
Yes
No
Maybe
Don’t know
8. Name at least 2 side effects of the study medication.
9. Once you start the study, are you free to stop at any time?

APPROVED BY THE YALE UNIVERSITY IRB 5/17/2017 VALID THROUGH 5/6/2018
APPROVED BY THE YALE UNIVERSITY IRB 5/17/2017 VALID THROUGH 5/6/2018
Page 38 of 40
Yes
No
Maybe
Don’t know
10. What would happen to your regular treatment if you dropped out of the study?
a. Treatment with regular clinician will end
b. Treatment with regular clinician will continue
c. Don’t know
11. Will you be hospitalized for this study?
Yes
No
Maybe
Don’t know
12. Will you get paid for taking part in this study?
Yes
No
Maybe
Don’t know
 
/  
Signature
Date

APPROVED BY THE YALE UNIVERSITY IRB 5/17/2017 VALID THROUGH 5/6/2018
APPROVED BY THE YALE UNIVERSITY IRB 5/17/2017 VALID THROUGH 5/6/2018
Page 39 of 40
WALLET CARD (CBD)
IMPORTANT
The holder of this card is participating in a clinical study with an investigational drug called 
cannabidiol, as a treatment for schizophrenia. There is a 1/2 chance this person can be on 
placebo.
Treatment Period:
From:  
To:
 
EMERGENCY CONTACT
If this subject presents to you for treatment, please contact the research clinic below:
Doctor:
Mohini Ranganathan, M.D.
.
HIC# 1412015000
Phone:
203-932-5711 x 2546
.
CBD Study
Doctor:
Deepak Cyril D’Souza, M.D.
.
HIC# 1412015000
Phone:
203-932-5711 x 2594
.
CBD Study
24 Hour Emergency:
203-974-7540
.
Dial 0 for the operator and ask that the on call research psychiatrist be paged.

APPROVED BY THE YALE UNIVERSITY IRB 5/17/2017 VALID THROUGH 5/6/2018
APPROVED BY THE YALE UNIVERSITY IRB 5/17/2017 VALID THROUGH 5/6/2018
Page 40 of 40
References
1.
Stahl, S.M., L. Mignon, and J.M. Meyer, Which comes first: atypical antipsychotic treatment or 
cardiometabolic risk? Acta Psychiatr Scand, 2009. 119(3): p. 171-9.
2.
Meyer, J.M., et al., Change in metabolic syndrome parameters with antipsychotic treatment in 
the CATIE Schizophrenia Trial: prospective data from phase 1. Schizophr Res, 2008. 101(1-3): 
p. 273-86.
3.
Newcomer, J.W., Metabolic considerations in the use of antipsychotic medications: a review of 
recent evidence. J Clin Psychiatry, 2007. 68 Suppl 1: p. 20-7.
4.
McEvoy, J.P., et al., Prevalence of the metabolic syndrome in patients with schizophrenia: 
baseline results from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) 
schizophrenia trial and comparison with national estimates from NHANES III. Schizophr Res, 
2005. 80(1): p. 19-32.
5.
Nasrallah, H.A., et al., Low rates of treatment for hypertension, dyslipidemia and diabetes in 
schizophrenia: data from the CATIE schizophrenia trial sample at baseline. Schizophr Res, 
2006. 86(1-3): p. 15-22.
6.
Conley, R.R. and D.L. Kelly, Management of treatment resistance in schizophrenia. Biol 
Psychiatry, 2001. 50(11): p. 898-911.
7.
Zuardi, A.W., et al., Action of cannabidiol on the anxiety and other effects produced by delta 9- 
THC in normal subjects. Psychopharmacology, 1982. 76(3): p. 245-50.
8.
Zuardi, A.W., J.A. Rodrigues, and J.M. Cunha, Effects of cannabidiol in animal models 
predictive of antipsychotic activity. Psychopharmacology, 1991. 104(2): p. 260-4.
9.
Zuardi, A.W., et al., Cannabidiol monotherapy for treatment-resistant schizophrenia. J 
Psychopharmacol, 2006.
10.
Zuardi, A.W., et al., Cannabidiol, a Cannabis sativa constituent, as an antipsychotic drug. Braz 
J Med Biol Res, 2006. 39(4): p. 421-9.
11.
Leweke, F.M., et al., Cannabidiol enhances anandamide signaling and alleviates psychotic 
symptoms of schizophrenia. Translational psychiatry, 2012. 2: p. e94.
12.
Campos, A.C., et al., Multiple mechanisms involved in the large-spectrum therapeutic potential 
of cannabidiol in psychiatric disorders. Philos Trans R Soc Lond B Biol Sci, 2012. 367(1607): p. 
3364-78.
13.
Gururajan, A., D.A. Taylor, and D.T. Malone, Cannabidiol and clozapine reverse MK-801- 
induced deficits in social interaction and hyperactivity in Sprague-Dawley rats. J 
Psychopharmacol, 2012. 26(10): p. 1317-32.
14.
Bhattacharyya, S., et al., Opposite effects of delta-9-tetrahydrocannabinol and cannabidiol on 
human brain function and psychopathology. Neuropsychopharmacology. 35(3): p. 764-74.
15.
Moreira, F.A. and F.S. Guimaraes, Cannabidiol inhibits the hyperlocomotion induced by 
psychotomimetic drugs in mice. Eur J Pharmacol, 2005. 512(2-3): p. 199-205.
16.
Englund, A., et al., Cannabidiol inhibits THC-elicited paranoid symptoms and hippocampal- 
dependent memory impairment. Journal of Psychopharmacology, 2013. 27(1): p. 19-27.
17.
Morgan, C.J. and H.V. Curran, Effects of cannabidiol on schizophrenia-like symptoms in people 
who use cannabis. Br J Psychiatry, 2008. 192(4): p. 306-7.
18.
Schubart, C.D., et al., Cannabis with high cannabidiol content is associated with fewer psychotic 
experiences. Schizophr Res, 2011. 130(1-3): p. 216-21.
19.
Cunha, J.M., et al., Chronic administration of cannabidiol to healthy volunteers and epileptic 
patients. Pharmacology, 1980. 21(3): p. 175-85.

APPROVED BY THE YALE UNIVERSITY IRB 5/17/2017 VALID THROUGH 5/6/2018
APPROVED BY THE YALE UNIVERSITY IRB 5/17/2017 VALID THROUGH 5/6/2018
Page 41 of 40
20.
Carlini, E.A. and J.M. Cunha, Hypnotic and antiepileptic effects of cannabidiol. Journal of 
Clinical Pharmacology, 1981. 21(8-9 Suppl): p. 417S-427S.
21.
Consroe, P., R. Sandyk, and S.R. Snider, Open label evaluation of cannabidiol in dystonic 
movement disorders. International Journal of Neuroscience, 1986. 30(4): p. 277-82.
22.
Consroe, P., et al., Controlled clinical trial of cannabidiol in Huntington's disease.
Pharmacology, Biochemistry & Behavior, 1991. 40(3): p. 701-8.
23.
Consroe, P., et al., Interaction of cannabidiol and alcohol in humans. Psychopharmacology, 
1979. 66(1): p. 45-50.
24.
Umbricht, D. and S. Krljes, Mismatch negativity in schizophrenia: a meta-analysis. Schizophr 
Res, 2005. 76(1): p. 1-23.
25.
Fisher, D.J., et al., Attenuation of mismatch negativity (MMN) and novelty P300 in schizophrenia 
patients with auditory hallucinations experiencing acute exacerbation of illness. Biol Psychol, 
2014. 100: p. 43-9.
26.
Bramon, E., et al., Meta-analysis of the P300 and P50 waveforms in schizophrenia. Schizophr 
Res, 2004. 70(2-3): p. 315-29.
27.
Naatanen, R. and S. Kahkonen, Central auditory dysfunction in schizophrenia as revealed by the 
mismatch negativity (MMN) and its magnetic equivalent MMNm: a review. Int J 
Neuropsychopharmacol, 2009. 12(1): p. 125-35.
28.
Umbricht, D., et al., Effects of clozapine on auditory event-related potentials in schizophrenia.
Biol Psychiatry, 1998. 44(8): p. 716-25.
29.
Korostenskaja, M., et al., Effects of olanzapine on auditory P300 and mismatch negativity 
(MMN) in schizophrenia spectrum disorders. Prog Neuropsychopharmacol Biol Psychiatry, 
2005. 29(4): p. 543-8.
30.
Drapeau, V., et al., Appetite sensations and satiety quotient: Predictors of energy intake and 
weight loss. Appetite, 2007. 48(2): p. 159-66.
31.
Gueorguieva R, Krystal JH. Move over ANOVA. Progress in analyzing repeated-measure data 
and its reflection in papers published in the Archives of General Psychiatry. Arch Gen 
Psychiatry. 2004; 61: 310–317.
32.
Thomas, A., et al., Cannabidiol displays unexpectedly high potency as an antagonist of CB(1) 
and CB(2) receptor agonists in vitro. Br J Pharmacol, 2007.
33.
Leweke FM, K.D., Gerth CW. Cannabidiol as an antipsychotic: a double-blind, controlled 
clinical trial on cannabidiol vs. amisulpride in acute schizophrenics. in Symposium on the 
Cannabinoids, International Cannabinoid Research Society. 2005. Burlington, Vermont.