Sublingual Cannabidiol for Anxiety
Phase: PHASE2
Conditions: Anxiety
Sponsor: Staci Gruber, Ph.D.

Official Title: Sublingual Cannabidiol for Anxiety 
 
Principal Investigator: Dr. Staci A. Gruber, Ph.D. 
 
NCT Number: NCT02548559 
 
Document Date: 01/21/2025 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

PARTNERS HUMAN RESEARCH COMMITTEE 
PROTOCOL SUMMARY 
Partners Human Subjects Research Application Form  
 
Filename: Protocol Summary 
Version Date: April 19, 2018 
 
  
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Answer all questions accurately and completely in order to provide the PHRC with the relevant 
information to assess the risk-benefit ratio for the study.  Do not leave sections blank. 
 
PRINCIPAL/OVERALL INVESTIGATOR 
Staci A. Gruber, Ph.D. 
 
PROTOCOL TITLE 
Sublingual Cannabidiol for Anxiety 
 
FUNDING 
Sundry Funds/Department 
 
VERSION DATE 
1/21/2025 
 
SPECIFIC AIMS 
Concisely state the objectives of the study and the hypothesis being tested. 
 
This investigation is designed to examine how the impact of the administration of 
sublingual high-cannabidiol (CBD) compounds on individuals with anxiety disorders. 
 
Specific Aim 1: To assess pre- and post-CBD treatment clinical state ratings of anxiety and 
quality-of-life ratings in individuals with anxiety disorders. 
 
Specific Aim 2: To assess pre- and post-CBD treatment performance on a range of 
neurocognitive measures designed to examine cognitive function. 
 
Specific Aim 3: In a subset of individuals, to examine structural and functional changes that may 
occur in the brain following treatment with CBD using magnetic resonance imaging (MRI). 
 
Exploratory Aim: In a subset of individuals, to examine the pharmacokinetics and 
pharmacodynamics (PK/PD) of this CBD tincture via continuous blood draw. 
 
Exploratory Aim: In a subset of individuals, to assess potential changes in circulating 
endocannabinoids pre- and post-CBD treatment. 
 
BACKGROUND AND SIGNIFICANCE 
Provide a brief paragraph summarizing prior experience important for understanding the 
proposed study and procedures. 
 
Cannabis has been used for medicinal purposes across many cultures for a range of disorders 
dating as far back as 4000 BC. The flowering plant has been used to treat a wide range of 
maladies due to its effects on both physical and psychological conditions. The plant is comprised 
of phytocannabinoids, terpenoids, flavonoids, steroids and enzymes, the concentrations of which 
vary depending on the strain; the phytocannabinoids are the most cannabis-specific of these 
components, and bind to receptors typically modulated by endogenous cannabinoids (Zhornitsky 

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& Potvin, 2012). These endocannabinoids act via G-protein-coupled cell membrane receptors in 
the central and peripheral nervous system, specifically CB1 and CB2 receptors. One 
phytocannabinoid in particular, delta-9 tetrahydrocannabinol (Δ9-THC), is the major 
psychoactive constituent of cannabis, and is a Schedule I substance in the United States. Δ9-THC 
exerts its effects acting as an agonist at CB1 receptors. Apart from Δ9-THC, there are many 
other phytocannabinoids present in cannabis, including cannabidiol (CBD), a non-psychoactive 
constituent of cannabis, which acts as a CB1 receptor antagonist; CBD does not have abuse 
potential, and thus does not appear on the DOJ’s scheduled substance list 
(http://www.deadiversion.usdoj.gov/schedules/). CBD, as well as other phytocannabinoids 
present in cannabis, contribute to the medicinal effects of cannabis. There is increasing evidence 
that CBD in particular may have significant medicinal properties and benefits; experimental 
studies in both animals and humans have demonstrated the CBD can act as an anticonvulsant, 
antipsychotic, and muscle relaxant. CBD has also been shown to be responsible for anxiolytic 
effects in animals and humans, although no clinical trials of CBD have been conducted to date in 
patients with anxiety. Additionally, a recent Canadian study reported that anxiety was the third 
most common symptom for which patients reported using medicinal cannabis (Walsh et al. 
2013). In contrast to THC, CBD is a CB1 receptor antagonist, and does not have abuse potential; 
thus, CBD is not a scheduled substance. 
 
Studies in animals have revealed that acute treatment with CBD can exert anxiolytic effects in 
tests of experimentally-induced anxiety. Fogaca et al. (2014) infused CBD into the prelimbic 
medial prefrontal cortex in rats, resulting in anxiolysis during the contextual fear conditioning 
test and the elevated plus maze after rats submitted to a two-hour stressful event. Soares et al. 
(2010) and Campos et al. (2008) showed that both panic-like responses as well as anxiety 
induced by the elevated plus maze are reduced in male rats receiving CBD in the dorsal 
periaqueductal gray. Additionally, Resstel et al. (2009) concluded that CBD can attenuate acute 
autonomic responses to stress following restraint, as well as delayed emotional consequences. 
Chronic administration of CBD in animals is also associated with anxiolytic effects. Campos, de 
Paula Soares, et al. (2013) showed that repeated administration of CBD had a panicolytic effect 
in rats subjected to the elevated T-maze. Another study from Campos and Ortega (2013) 
determined that chronic CBD administration following daily unpredicatable stress reduced 
anxiety. 
 
While few human studies have been conducted to investigate CBD’s effects on anxiety, those 
that have been published confirmed the previous findings in animals that CBD can be anxiolytic. 
Fusar-Poli et al. (2009) demonstrated that 600 mg of CBD reduced anxiety in healthy subjects 
viewing fearful faces while undergoing functional magnetic resonance imaging (fMRI); the 
authors concluded that this effect was likely due to modulating the activation of limbic and 
paralimbic regions. This same group later reported that CBD alters subcortical prefrontal 
connectivity via the amygdala and anterior cingulate (Fusar-Poli et al. 2010). Additionally, in a 
model of experimentally induced anxiety in healthy subjects, Zuardi et al. (1993) found that 
300mg of CBD attenuated anxiety, as did the anxiolytic drugs diazepam and ipsapirone. To 
induce anxiety, the authors used the simulated public speaking test (SPST), which involves a 
subject speaking in front of a video camera for several minutes while physiological correlates of 
anxiety are measured (including heart rate and blood pressure), and self-report scales are 
administered to measure subjective anxiety. This model has also been used to induce anxiety in 
patients with social anxiety disorder (SAD); Bergamaschi et al. (2011) demonstrated that 
pretreatment with a single dose of CBD results in an anxiolytic effect for SAD patients. This 
single dose (600mg) was sufficient to reduce subjective anxiety, cognitive impairment, and 

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discomfort in SAD patients completing the SPST, compared to placebo, and reduced anxiety in 
the CBD-treated patients to a level similar to that of healthy controls. Crippa et al. (2011) 
confirmed CBD’s effects in SAD and further investigated the basis of CBD’s anxiolytic effect in 
SAD patients using neuroimaging. Relative to placebo, a single dose of CBD (400mg) was 
associated with significantly decreased subjective anxiety scores in SAD patients. 
 
Despite the recent interest in cannabinoid-based products, no published studies to date have 
conducted a clinical trial of products high in CBD in individuals who suffer from anxiety. 
Further, none have systematically evaluated baseline and follow-up clinical state and related 
quality of life measures in individuals taking CBD, or assessed measures of brain structure and 
function before and after treatment with CBD using neuropsychological measures or 
neuroimaging. As a growing number of states are legalizing medical marijuana and increasing 
evidence suggests that CBD may exert anxiolytic effects, there is a gap in the literature regarding 
the effects of CBD, often found in higher levels in medical marijuana than recreational 
marijuana, on anxiety. This investigation will be the first of its kind to conduct a double-blind 
clinical trial of high-CBD compounds (both full-spectrum and single-compound) in individuals 
with anxiety. The main outcome measures of the project will include a comprehensive 
assessment of anxiety using both self-report and administered scales pre- and post-treatment, as 
well as range of quality of life measures. In addition, this project will examine the impact of  
high CBD products relative to placebo on several cognitive domains using neuropsychological 
testing. Furthermore, a subset of eligible participants will complete a structural and functional 
MRI scanning to assess brain function and connectivity using a multimodal neuroimaging 
protocol prior to and following four weeks of treatment with high CBD compounds vs placebo.  
 
RESEARCH DESIGN AND METHODS 
Briefly describe study design and anticipated enrollment, i.e., number of subjects to be enrolled 
by researchers study-wide and by Partners researchers.  Provide a brief summary of the 
eligibility criteria (for example, age range, gender, medical condition).  Include any local site 
restrictions, for example, “Enrollment at Partners will be limited to adults although the sponsor’s 
protocol is open to both children and adults.”
 
This study is an investigation of 97 subjects who have expressed interest in using CBD for 
anxiety. Subjects will complete study visits at McLean Hospital. Following a preliminary phone 
screen and prior to any evaluation, all study subjects will be required to sign a McLean Hospital 
approved informed consent form that describes all study procedures. The phone screen includes 
questions related to medical history, substance use history, demographics, and screening 
questions from the OASIS (see below) to determine whether the subject has anxiety. 
 
Individuals will be assessed at baseline and weekly for four weeks of treatment with compounds 
administered as sublingual tinctures in a double-blind, randomized procedure: subjects will 
receive either a full-spectrum high CBD product, a single-compound CBD product, or matched 
placebo in a 3:1:1 randomization schedule. Each product will be analyzed and verified at an 
outside lab for safety and potency. Subjects will self-administer 1 ml (10mg/ml) of CBD or 
placebo sublingually three times daily. At each weekly visit, individuals will complete clinical 
scales and have a check-in with study staff. Neuropsychological testing will be performed at 
baseline and the final visit in order to assess cognitive performance. Buccal swabs will be 
collected for DNA analysis from all participants in the double-blind phase, and a subset of 

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individuals will complete blood draws at baseline and week 4 in order to assess levels of 
circulating endocannabinoids. Finally, a subset of individuals will receive an hour-long MRI 
scan at baseline and the final visit, with both resting state and task-related functional magnetic 
resonance imaging (fMRI) in each MRI session. In addition, a brief diffusion tensor imaging 
(DTI) sequence will also be acquired to examine white matter fiber tract integrity, and magnetic 
resonance spectroscopy (MRS) will be conducted to examine levels of certain metabolites in the 
brain. 
 
At the investigators’ discretion, in order to assess clinical state, participants may complete daily 
mood ratings either on paper or electronically via REDCap or StudyTrax. Additionally, subjects 
will be given the option to complete study drug diaries manually (pencil and paper) or via a 
secure web portal. 
 
In order to assess the efficacy of the dose chosen for the double-blind study, we will also conduct 
a small open-label phase I trial of the full-spectrum CBD tincture prior to initiating the double-
blind study. This open-label trial will enroll up to 22 participants who are interested in using 
CBD, and who have anxiety. This trial will determine whether patients derive clinical benefits at 
the current dosage proposed for the active treatment arm of the double-blind trial. This trial will 
examine all components of the originally proposed study. During the open-label phase, a subset 
of participants (up to n=16) will complete an extra visit that includes clinical rating scales and a 
2-hour continuous blood draw directly following administration of the tincture in order to assess 
plasma concentration of CBD over time and correlation with anxiety. 
 
Subjects will be recruited through IRB-approved advertisements and flyers in regions that have 
approved medical marijuana. Additionally, medical marijuana healthcare facilities throughout 
New England, including CannaCare, Integr8, MMJ Physician Practice, and others, may also 
refer interested patients to contact the study recruitment line for further screening. These 
healthcare groups provide their interested patients who meet for general inclusion criteria with 
study recruitment materials. The total sample size for the double-blind study is 75 (45 full-
spectrum CBD, 15 single-compound CBD, and 15 placebo); up to 15 of each group (45 total) 
will also complete the MRI scanning protocol. For the open-label trial, the total sample size is 
16 (we will enroll up to 22 to ensure 16 completers); up to 16 subjects will complete the MRI 
scanning protocol. 
 
Inclusion Criteria 
1) Subject has provided informed consent 
2) Subject is 18 or older 
3) Subject is a native English speaker or acquired English prior to age 5 
4) Subject scores a minimum of 16 on the Beck Anxiety Inventory (BAI) OR a minimum of 
11 on the Overall Anxiety Severity and Impairment Scale (OASIS) at the screening/baseline 
visit or at phone screening if within 2 weeks of the baseline visit 
 
Exclusion Criteria 
Subjects will be excluded if they report any of the following: 
1) Non-native English speakers 
2) Estimated IQ < 75 
3) Meets criteria for DSM-V classification of current substance abuse/dependence, a 
psychotic disorder, bipolar disorder, or an eating disorder 

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4) A history of head injury or loss of consciousness greater than 5 minutes 
5) Currently uses recreational marijuana more frequently than 1x/month 
6) Female subjects will be excluded if they have a positive urine pregnancy test 
7) Presence of a serious medical illness, including liver or kidney disease, or neurological          
 
disorder 
8) Allergy to coconut, as product is formulated in MCT (coconut) oil 
 
Additional Exclusions for Driving Simulator: 
1) Does not drive 
2) Endorses experiencing motion sickness 
 
Additional Exclusions for MR Component: 
1) Claustrophobia or metal implanted within the body, body piercings which are not 
removable  
2) Cardiac pacemakers, metal clips on blood vessels (also called stents), artificial heart 
valve, artificial arms, hands, legs, etc., brain stimulator devices, implanted drug pumps, 
ear implants, eye implants or known metal fragments in eyes, exposure to shrapnel or 
metal filings (wounded in military combat, sheetmetal workers, welders, and others), 
other metallic surgical hardware in vital area, certain tattoos with metallic ink, certain 
transdermal (skin) patches such as NicoDerm (nicotine for tobacco dependence), 
Transderm Scop (scopolamine for motion sickness), or Ortho Evra (birth control), certain 
intrauterine devices (IUDs) containing metal. 
3) Poor vision, as subjects must have normal or corrected-to normal vision for viewing of 
cognitive challenge paradigms during fMRI protocols 
 
Subjects who participate in the open-label phase of the study will not be eligible to also enroll in 
the double-blind study. 
 
Briefly describe study procedures.  Include any local site restrictions, for example, “Subjects 
enrolled at Partners will not participate in the pharmacokinetic portion of the study.”  Describe 
study endpoints.
 
Subjects will meet with the Principal Investigator, a Clinical Neuropsychologist, or a trained 
Research Assistant at McLean Hospital for five visits (baseline, and four weekly visits 
throughout the four-week treatment period). A subset of subjects in the open-label phase will 
also complete an optional 6th visit; this visit will occur after a >1 week washout period after the 
final (week 4) visit, where they will return to the lab to complete a 2-hour continuous blood draw 
after administration of the tincture. Subjects will review and sign the approved informed consent 
form prior to engaging in any study procedures. A structured clinical screening interview (SCID-
P or QuickSCID) will be administered, and demographic information, substance abuse/use, and 
medical histories will also be obtained. Study inclusion/exclusion criteria will be applied, and 
appropriate subjects will be enrolled and complete the rest of the study visit, which will consist 
of clinical ratings and quality of life scales, a neuropsychological assessment, a driving 
simulation task, and an hour-long MRI scan for a subset of eligible individuals. The imaging 
protocol will include structural and functional imaging techniques, as well as diffusion tensor 
imaging/diffusion kurtosis imaging and magnetic resonance spectroscopy. 
 

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For studies involving treatment or diagnosis, provide information about standard of care at 
Partners (e.g., BWH, MGH) and indicate how the study procedures differ from standard care.  
Provide information on available alternative treatments, procedures, or methods of diagnosis.
 
Standard of care for anxiety treatment includes medications, such as antidepressants, buspirone, 
and benzodiazepines, as well as psychotherapy. This study is an investigation of a plant-derived 
compound that has promise in the treatment of anxiety. Subjects will not be asked to change their 
current treatment regimen to participate in this study (i.e. discontinue other medications); this 
study will add CBD to their current regimen. 
 
Describe how risks to subjects are minimized, for example, by using procedures which are 
consistent with sound research design and which do not unnecessarily expose subjects to risk or 
by using procedures already being performed on the subject for diagnostic or treatment purposes.
 
Risks to subjects will be minimal throughout this study; please see below for detailed 
explanation of foreseeable risks and discomforts. The components of this study, including the 
clinical rating scales, neurocognitive tasks, and MR scanning have previously been used by the 
investigator in multiple studies. The administration of CBD will be low risk due to the add-on 
design of the study; patients will proceed with their treatment as usual, with CBD or placebo 
added to their medication regimen. See below for a detailed explanation of the risks of CBD 
administration in this population. 
 
Describe explicitly the methods for ensuring the safety of subjects.  Provide objective criteria for 
removing a subject from the study, for example, objective criteria for worsening disease/lack of 
improvement and/or unacceptable adverse events.  The inclusion of objective drop criteria is 
especially important in studies designed with placebo control groups.
 
The side-effect profile of CBD is extremely low, and adverse events are not anticipated. Subjects 
may withdraw from the study at any time and for any reason. A subject’s participation in the trial 
will end if they report adverse effects of CBD or placebo administration and wish to leave the 
study, or if study staff determine that study termination is appropriate due to adverse events.  
 
FORESEEABLE RISKS AND DISCOMFORTS 
Provide a brief description of any foreseeable risks and discomforts to subjects.  Include those 
related to drugs/devices/procedures being studied and/or administered/performed solely for 
research purposes.  In addition, include psychosocial risks, and risks related to privacy and 
confidentiality.  When applicable, describe risks to a developing fetus or nursing infant.
 
Risks Associated with Neuropsychological and Clinical Assessment/Rating Scales  
Although unlikely, it is possible that during the structured assessment or rating scales, subjects 
may become distressed when recalling periods of their lives or their current mood state. 
Subjects may also become frustrated during the neuropsychological testing. Subjects are 
informed that they can take a break and/or can choose to stop answering questions at any time. 
To mitigate any risks associated with the neurocognitive assessment or clinical ratings, clinical 
staff will be available to evaluate and advise the subject during study visits. 
 

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MR/fMRI/DTI/DKI/MRS 
Currently, there are no known risks associated with fMRI, MRI, DTI/DKI, or MRS scanning in 
the 3T scanner, however, there are some areas of concern that must be addressed.  First, 
participation in an MRI study requires subjects to be exposed to strong magnetic fields, the long-
term effects of which are unknown.  The magnetic fields also require caution given the risk of 
attraction of ferromagnetic metal objects by the high strength magnetic field.  Second, some 
subjects express discomfort by the relatively confined space within the bore of the MR scanner.  
Finally, some subjects find the scanning experience unpleasant because of the noise of the 
gradients during MRI image acquisition. Each of these risks is present for a clinical MR scan, 
which are not increased by the research project proposed in this application.  
 
CBD Administration 
The administration of CBD is considered low-risk because of the add-on design of the study; in 
addition, previous studies of CBD administration have reported no signs of toxicity or serious 
side effects (Cunha et al. 1980; Consroe et al. 1991; Leweke et al. 2012; Zuardi et al. 2006 and 
2009). The safety of CBD administration in pregnant women and fetuses is currently unknown; 
thus, female participants capable of child-bearing will be screened for pregnancy prior to the 
study and at each study visit. Participants will be immediately disqualified and excluded from 
further participation in the study if they have a positive pregnancy test at any point during the 
study. 
 
Additionally, CBD is not a scheduled substance, and there is no risk of intoxication or addiction. 
The amount of THC included in the high CBD tincture is minimal, and will not exceed 0.3% by 
weight; therefore, the risk of significant side effects or psychoactive effects is extremely low. 
Sublingual tinctures are unlikely to be viewed by the public as analogous to recreational smoked 
marijuana, thus decreasing the risk that the subject will experience any potential negative 
appraisal arising from perceived notions associated with marijuana use. 
 
Blood Draw 
Subjects may have a bruise or pain from the site where the blood sample is acquired. There is 
also a small risk of feeling lightheaded, fainting, or infection. Clinical staff will be available to 
evaluate the subject if they experience any of these symptoms.  
 
DNA Collection 
The primary risk of collecting and examining genetic information is the remote possibility of 
future genetic discrimination.  It is possible that these data or the buccal swab samples from 
which they were derived could be stolen, analyzed, and used to reveal sensitive information that 
may in turn lead to insurance coverage or employment denial.  There is a very remote possibility 
that enough information could be stolen to help identify a person, exposing individuals to any 
risks that result as that identification.  Procedures described below minimize the possible breach 
of confidentiality. 
 
Protection of risks: To reduce the possible risk of a breach of confidentiality regarding genetic 
material, the informed consent will include a specific section addressing risks associated with 
collecting genetic material.  The consent form will have choices regarding the permissible uses 
of his/her DNA.  These range from “restriction to this study only” to “any future research use by 
the study investigators” (provided that any future study is approved by an IRB).  One of the 
choices must be initialed by the participant.   Participants will also be informed that they may 
have their DNA samples destroyed at any time, and will provide the necessary information on 
how to inform investigators to do this. 

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EXPECTED BENEFITS 
Describe both the expected benefits to individual subjects participating in the research and the 
importance of the knowledge that may reasonably be expected to result from the study.  Provide 
a brief, realistic summary of potential benefits to subjects, for example, “It is hoped that the 
treatment will result in a partial reduction in tumor size in at least 25% of the enrolled subjects.”  
Indicate how the results of the study will benefit future patients with the disease/condition being 
studied and/or society, e.g., through increased knowledge of human physiology or behavior, 
improved safety, or technological advances. 
 
There may be no direct benefits to the subjects; however, based on previous research, it is 
reasonable to expect that some subjects may experience an improvement in clinical state or 
quality of life related to a reduction in anxiety. 
 
It is reasonable to expect that this study will contribute to overall knowledge in this field and 
potentially provide benefits to society in general through improvements in treatment and 
management as a result of this increased level of understanding.  
 
Subjects are informed that there may be no direct benefit to them from participating in this 
study. Subjects may benefit from knowing that the results of this study may improve the 
future care of people prescribed medicinal marijuana, particularly those with anxiety. 
 
EQUITABLE SELECTION OF SUBJECTS 
The risks and benefits of the research must be fairly distributed among the populations that stand 
to benefit from it.  No group of persons, for example, men, women, pregnant women, children, 
and minorities, should be categorically excluded from the research without a good scientific or 
ethical reason to do so.  Please provide the basis for concluding that the study population is 
representative of the population that stands to potentially benefit from this research.
 
No subjects will be excluded on the basis of race, sex, ethnicity or sexual orientation.  
 
 
When people who do not speak English are excluded from participation in the research, provide 
the scientific rationale for doing so.  Individuals who do not speak English should not be denied 
participation in research simply because it is inconvenient to translate the consent form in 
different languages and to have an interpreter present.
 
All subjects must be native English speakers because several of the cognitive tasks require 
English as the native language in order to accurately assess cognitive state. 
 
For guidance, refer to the following Partners policy: 
          Obtaining and Documenting Informed Consent of Subjects who do not Speak English
          https://partnershealthcare-public.sharepoint.com/ClinicalResearch/Non-
English Speaking Subjects.1.10.pdf
 
 
 

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RECRUITMENT PROCEDURES 
Explain in detail the specific methodology that will be used to recruit subjects.  Specifically 
address how, when, where and by whom subjects will be identified and approached about 
participation.  Include any specific recruitment methods used to enhance recruitment of women 
and minorities.
 
Recruiting and enrollment will be the responsibility of the McLean study coordinators.  Subjects 
will be recruited from a number of sources, including IRB-approved flyers and post cards, as 
well as online postings (including the Partners Clinical Trials website), and through 
RPDR/RODY-Yes messaging.. Medical marijuana certification facilities may also refer 
interested patients to contact the study recruitment line for further screening. Potential subjects 
for this study must be capable of understanding the nature of this study as well as the 
discomforts and potential benefits. All subjects will be given as much time as they want to 
consider their participation in the study and ask any questions they may have before being 
asked to sign the consent form. 
 
 
Provide details of remuneration, when applicable.  Even when subjects may derive medical 
benefit from participation, it is often the case that extra hospital visits, meals at the hospital, 
parking fees or other inconveniences will result in additional out-of-pocket expenses related to 
study participation.  Investigators may wish to consider providing reimbursement for such 
expenses when funding is available
 
Subjects will be compensated for their time using a tiered payment system, with a payment of 
$75 for visits 1 (baseline visit) and 5 (final visit), and $50 for three weekly visits for a total of 
$300; if termination occurs during any point of the visit, subjects are compensated at a rate of 
$25 per hour. Subjects who participate in the scanning component of study will receive an 
additional $75 at visit 1 and visit 5 for a potential total of $450. Subjects will receive a 
completion bonus of $50 if they complete the study, for a total of $350 or $500, dependent on 
whether they receive MR scanning. Subjects in the open-label phase who complete the optional 
6th visit, which includes a blood draw, will receive an additional $150, for a total of $500 (if no 
MR scans are completed) or $650 (if MR scans are completed at Visits 1 and 5). Subjects in the 
double-blind phase who complete the optional blood-draws at Visits 1 and 5 will receive an 
additional $25/blood draw, for a total of $400 or $550 (if MR scans are completed). 
 
 
For guidance, refer to the following Partners policies: 
          Recruitment of Research Subjects 
          https://partnershealthcare-
public.sharepoint.com/ClinicalResearch/Recruitment Of Research Subjects.pdf
 
          Guidelines for Advertisements for Recruiting Subjects
          https://partnershealthcare-
public.sharepoint.com/ClinicalResearch/Guidelines For Advertisements.1.11.pdf
 
          Remuneration for Research Subjects
          https://partnershealthcare-
public.sharepoint.com/ClinicalResearch/Remuneration for Research Subjects.pdf

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CONSENT PROCEDURES 
Explain in detail how, when, where, and by whom consent is obtained, and the timing of consent 
(i.e., how long subjects will be given to consider participation).  For most studies involving more 
than minimal risk and all studies involving investigational drugs/devices, a licensed physician 
investigator must obtain informed consent.  When subjects are to be enrolled from among the 
investigators’ own patients, describe how the potential for coercion will be avoided.
 
Written, informed consent will be obtained from all participants following a screening interview 
to determine eligibility. All subjects will be required to give informed consent and must 
understand all procedures prior to their participation in the study. Consent will be obtained by the 
principal investigator, Dr. Staci Gruber, or a licensed physician investigator on the protocol, 
either Dr. David Olson, Dr. Franca Centorrino, or Dr. Gordana Vitaliano. If consent is obtained 
by Dr. Gruber, a licensed physician investigator will review and sign off on patient enrollment. A 
physician will also be available if the patient has any additional questions during the consent 
process. The consent form will include a description of the study, information about procedures, 
and assurances of confidentiality. A member of the research staff will explain the consenting 
procedure and be available for any questions that arise from the consent form. Prior to signing 
the informed consent, subjects will be asked if they have any questions regarding the conduct or 
design of the study. A copy of the signed consent form will be given to the study subject, and a 
copy placed in their research record. All subjects will be reminded that their participation is 
completely voluntary, and may withdraw or discontinue the neuropsychological evaluation at 
any time. The informed consent will be approved by the McLean Hospital Institutional Review 
Board, which monitors study progress, safety and outcome on a regular basis. All signed consent 
forms will be kept in the subject’s case report form in 
 
under lock and key. 
 
Remote Consenting Process  
We will remotely consent patients by one of the two following options. The first option will 
consist of consenting via REDCap. The second option is to send the participant the consent form 
ahead of time for their review, consent them over the phone, and have the participant physically 
sign or e-sign the consent form and either scan or take a photo of all pages, and send to us; this 
will be signed by the investigator. In-person written consent may also occur in rare 
circumstances. Each subject’s file will contain a note to file describing the procedure followed.  
 
 
NOTE: When subjects are unable to give consent due to age (minors) or impaired decision-
making capacity, complete the forms for Research Involving Children as Subjects of Research 
and/or Research Involving Individuals with Impaired Decision-making Capacity, available on 
the New Submissions page on the PHRC website: 
      https://partnershealthcare.sharepoint.com/sites/phrmApply/aieipa/irb 
 
For guidance, refer to the following Partners policy: 
     Informed Consent of Research Subjects:
     https://partnershealthcare-
public.sharepoint.com/ClinicalResearch/Informed Consent of Research Subjects.pdf
 

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FMRI, DTI/DKI, and MRS data collected will be processed with software available in the 
Neuroimaging Center. Echo planar images will be analyzed off line using a semi-automated 
fMRI data analysis tool and a motion correction algorithm developed on-site at McLean.  
Measures of signal intensity will be derived by averaging the signal measured in all pixels in 
each region of interest (ROI) for each time point during the task activation period. 
 
 
Describe the plan to be followed by the Principal Investigator/study staff for review of adverse 
events experienced by subjects under his/her care, and when applicable, for review of sponsor 
safety reports and DSMB reports.  Describe the plan for reporting adverse events to the sponsor 
and the Partners’ IRB and, when applicable, for submitting sponsor safety reports and DSMB 
reports to the Partners’ IRBs.  When the investigator is also the sponsor of the IND/IDE, include 
the plan for reporting of adverse events to the FDA and, when applicable, to investigators at 
other sites.   
 
NOTE: In addition to the adverse event reporting requirements of the sponsor, the principal 
investigator must follow the Partners Human Research Committee guidelines for Adverse Event 
Reporting
 
In the unlikely event that an adverse event occurs, it will be reported by the primary investigator 
to the Institutional Review Board, and the IRB’s guidelines will be followed to ensure adequate 
reporting and response. All adverse events will be reported to the Partners Healthcare Internal 
Review Board for their records. 
 
MONITORING AND QUALITY ASSURANCE 
Describe the plan to be followed by the principal investigator/study staff to monitor and assure 
the validity and integrity of the data and adherence to the IRB-approved protocol.  Specify who 
will be responsible for monitoring, and the planned frequency of monitoring.  For example, 
specify who will review the accuracy and completeness of case report form entries, source 
documents, and informed consent.   
 
NOTE: Regardless of monitoring plans by the sponsor or others, the principal investigator is 
ultimately responsible for ensuring that the study is conducted at his/her investigative site in 
accordance with the IRB-approved protocol, and applicable regulations and requirements of the 
IRB.
 
Regulatory binders are kept for all studies at McLean Hospital in order to constantly 
monitor investigations and ensure that all data is collected safely. 
 
The principal investigator will be responsible for monitoring and ensuring the integrity of 
the data and adherence to the IRB-approved protocol. They will review any questions or 
concerns regarding data, and will review each signed consent form for the study. 
 
For guidance, refer to the following Partners policies: 
          Data and Safety Monitoring Plans and Quality Assurance
            https://partnershealthcare-
public.sharepoint.com/ClinicalResearch/DSMP in Human Subjects Research.pdf  
          

Partners Human Subjects Research Application Form 
  
Filename: Protocol Summary 
Version Date: April 19, 2018 
 
  
14 
 
          Reporting Unanticipated Problems (including Adverse Events)
          https://partnershealthcare-
public.sharepoint.com/ClinicalResearch/Reporting Unanticipated Problems including Adverse Events.pdf
 
 
 
PRIVACY AND CONFIDENTIALITY 
Describe methods used to protect the privacy of subjects and maintain confidentiality of data 
collected.  This typically includes such practices as substituting codes for names and/or medical 
record numbers; removing face sheets or other identifiers from completed 
surveys/questionnaires; proper disposal of printed computer data; limited access to study data; 
use of password-protected computer databases; training for research staff on the importance of 
confidentiality of data, and storing research records in a secure location.   
 
NOTE: Additional measures, such as obtaining a Certificate of Confidentiality, should be 
considered and are strongly encouraged when the research involves the collection of sensitive 
data, such as sexual, criminal or illegal behaviors.
 
Confidentiality of information collected will be maintained with the assignment of an 
identification number or code, which will be used in place of subject names in all data 
analyses and reports.  Computer systems are located in the Cognitive and Clinical 
Neuroimaging Core. Keys showing the assignment of identification numbers to subject 
names will be stored with subject files in room 204 of the Neuroimaging Building under lock 
and key.  All of the data that is collected will be kept for a minimum of seven years once the 
study has been completed.  Only the Principal Investigator, Dr. Staci Gruber, her research 
staff, and the study collaborators will have access to the data that is collected. 
 
All subjects will be required to give informed consent and must understand all procedures 
prior to their participation in the study. Subjects are informed of their confidentiality and 
privacy rights in the informed consent form. To ensure that subjects’ rights and safety are 
protected during the conduct of this research study, subjects consent to the inspection of their 
medical records by specifically authorized monitors. Such monitoring may be performed by 
the Human Research Protection Program of McLean Hospital, or by the FDA or other 
involved federal agency. 
 
Subjects are informed that all the information obtained in this study will be used for research 
investigational purposes only.  Name of subjects will never be publicly disclosed at any 
time. Subjects will not be identifiable in any publication that may arise from this research. 
 
Subjects will receive a copy of the consent document to keep as well as a copy of the 
“Partners Healthcare Notice for Use and Sharing of Protected Health Information.”  Subjects 
will be informed that this research will be conducted and administered in compliance with 
all state and federal laws. 
 

Partners Human Subjects Research Application Form 
  
Filename: Protocol Summary 
Version Date: April 19, 2018 
 
  
16 
 
Campos, A.C. et al. (2008). Involvement of 5HT1A receptors in the anxiolytic-like effects of 
cannabidiol injected into the dorsolateral periaqueductal gray of rats. Journal of 
Psychopharmacology 199(2), 223-230 
 
Campos, A.C., de Paula Soares, V., Carvalho, M.C., Ferreira, F.R., et al. (2013). Involvement of 
serotonin-mediated neurotransmission in the dorsal periaqueductal gray matter on cannabidiol 
chronic effects in panic-like responses in rats. Psychopharmacology 226, 13-24 
 
Campos, A.C., Ortega, Z., Palazuelos, J., Fogaca, M.V., et al. (2013). The anxiolytic effect of 
cannabidiol on chronically stressed mice depends on hippocampal neurogenesis: the involvement 
of the endocannabinoid system. Int J Neuropsychopharmacol. 16(6), 1407-1419 
 
Consroe, P., Laguna, J., Allender, J., Snider, S., et al. (1991). Controlled clinical trial of 
cannabidiol in Huntington’s disease. Pharmacol. Biochem. Behav. 40, 701–708 
 
Crippa, J.A.S. et al. (2011). Neural basis of anxiolytic effects of cannabidiol (CBD) in 
generalized social anxiety disorder: a preliminary report. Journal of Psychopharmacology, 25, 
121-130 
 
Cunha, J.M., Carlini, E.A., Pereira, A.E., Ramos, O.L., Pimentel, C., Gagliardi, R., et al. (1980). 
Chronic administration of cannabidiol to healthy volunteers and epileptic patients. 
Pharmacology 21(3), 175-185  
 
Fogaca, M.V. et al. (2014). Effects of intra-prelimbic prefrontal cortex injection of cannabidiol 
on anxiety-like behavior: involvement of 5HT1A receptors and previous stressful experience. 
European Journal of Neuropsychopharmacology 24(3), 410-419 
 
Fusar-Poli, P., Crippa, J.A., Bhattacharyya, S., Borgwardt, S.J., et al. (2009). Distinct effects of 
{delta}9-tetrahydrocannabinol and cannabidiol on neural activation during emotional processing. 
Arch Gen Psychiatry 66(1), 95-105 
 
Fusar-Poli, P., Allen, P., Bhattacharyya, S., Crippa, J.A., et al. (2010). Modulation of effective 
connectivity during emotional processing by Delta(9)-tetrahydrocannabinol and cannabidiol. Int 
J Neuropsychopharmacol. 13(4), 421-32 
 
Leweke, F.M. et al. (2012). Cannabidiol enhances anandamide signaling and alleviates psychotic 
symptoms of schizophrenia. Translational Psychiatry, 2, e94 
 
Resstel, L.B.M. et al. (2009). 5-HT1A receptors are involved in the cannabidiol-induced 
attenuation of behavioural and cardiovascular responses to acute restraint in rats. British Journal 
of Pharmacology 156, 181-188 
 
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panic-like response by activating 5-HT1A receptors. Behavioral Brain Research 213(2), 225-229 
 
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Pharmaceuticals 5, 529-552 
 
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Statistical Approaches 
All statistical analyses will be conducted using IBM SPSS Statistics (version 25).  Data will be 
screened for outliers (defined as outside 1.5x the interquartile range), skew, kurtosis, non-
normality, and homogeneity of variance. If the assumptions of parametric inferential analyses 
are not met, the appropriate non-parametric analyses will be performed. Baseline demographic, 
clinical, and neuropsychological data will be assessed using 2-tailed analyses of variance 
(ANOVAs). Treatment effects over the course of the study will be assessed using mixed model 
ANOVAs with Scheffe post hoc tests utilized to assess between-group differences and Least 
Significant Difference (LSD) post hoc tests utilized to assess change over time (repeated-
measures). Independent t-tests will be conducting for each individual treatment arm to assess 
post hoc differences between baseline data relative to post-treatment data. In order to observe 
small-to-medium effect interaction effect sizes (f=.20) with 85% statistical power with alpha set 
at .05, it is estimated that the sample size should be at least 45 participants.