Clinical trial NCT04286594
Conditions: Anxiety
Sponsor: Mclean Hospital
Start date: 2021-02-01; Completion date: 2023-08-24
Enrollment: 15 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This open-label to double-blind study evaluates the impact of cannabidiol (CBD) on anxiety in adults. Participants will use a custom-formulated sublingual (under-the-tongue) solution of whole plant, hemp-derived CBD twice daily for six weeks in addition to their normal treatment regimen. Participants' clinical state will be assessed weekly during the treatment period. Quality of life, sleep, general health, and cognitive function will also be assessed.

Detailed description:
This investigation will be the first of its kind to conduct a clinical trial of an industrial hemp-derived product in individuals with anxiety. Despite the recent interest in medical cannabis and cannabinoid-based products, the availability of hemp-derived products in all 50 states, and anecdotal evidence suggesting that hemp-derived products may have a profound anxiolytic effect, no studies have conducted a clinical trial of a hemp-derived product in individuals who suffer from anxiety.

This investigation is composed of two phases. Phase 1 is comprised of a six-week open-label clinical trial of the custom formulated hemp-derived high-CBD solution in individuals with anxiety (n=12). Participants will be pre-screened by phone in order to evaluate their eligibility for the study. If approved, participants will come to the hospital for a baseline/screening visit, and will complete a structured clinical interview, clinical and quality of life questionnaires, and cognitive assessments. Enrolled participants will be given study product to use for the duration of the study; participants will be instructed to self-administer the solution under the tongue twice daily for six weeks. Throughout the treatment period, participants will complete short in-person or phone visits on a weekly basis, where they will complete questionnaires about their mood and quality of life. Participants will also return to the hospital for a final visit after six weeks of treatment to complete additional questionnaires and cognitive assessments.

Phase 2 of the study is a double-blind clinical trial of this solution in patients with anxiety (n=40). This double-blind trial will begin after the open-label trial has been completed. In the same manner as the open-label trial, participants will be pre-screened by phone, and approved participants will come to the hospital for a baseline/screening visit to complete a structured clinical interview, questionnaires, and cognitive assessments. Eligible participants will also have the option to complete an hour-long MRI scan at the baseline and final visits. Enrolled participants will receive either CBD solution or placebo solution to self-administer throughout the six week treatment period, as described above. Participants will complete in-person visits and phone check-ins during the treatment period to complete questionnaires about their mood and quality of life. Participants in this phase of the study will also return for a final visit after six weeks of treatment to complete additional questionnaires, cognitive assessments, and an optional MRI scan. Note: Phase 2 was planned but study termination occurred prior to commencement.

Arms: arm 1: 0.5ml of sublingual CBD solution (30mg/ml) administered twice daily for six weeks.
Interventions: intervention 1: CBD
Intervention descriptions: intervention 1: Participants will receive CBD solution during the open-label phase of the trial.

Protocol documents:
Prot_SAP_000.pdf: 
PARTNERS HUMAN RESEARCH COMMITTEE 
PROTOCOL SUMMARY 
Partners Human Subjects Research Application Form  
 
Filename: Protocol Summary 
Version Date: April 19, 2018 
 
  
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Official Title: A Clinical Trial of a Hemp-Derived Cannabidiol Product for Anxiety 
 
Principal Investigator: Dr. Staci A. Gruber, Ph.D. 
 
NCT Number: NCT04286594 
 
Document Date: 05/12/2023 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Partners Human Subjects Research Application Form 
  
Filename: Protocol Summary 
Version Date:  June 1, 2005 
 
  
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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 
A Clinical Trial of a Hemp-Derived Cannabidiol Product for Anxiety 
 
FUNDING 
Sponsored by Charlotte’s Web (formerly known as Stanley Brothers Bio Tec) 
 
VERSION DATE 
5/12/2023 
 
SPECIFIC AIMS 
Concisely state the objectives of the study and the hypothesis being tested. 
 
The proposed investigation is designed to examine the impact of 6 weeks of treatment with a 
sublingual high-cannabidiol industrial hemp-derived compound on individuals with symptoms of 
anxiety. 
 
Specific Aim 1: To assess pre- and post-hemp treatment clinical state ratings of anxiety and 
quality-of-life ratings in individuals with symptoms of anxiety. 
 
Specific Aim 2: To assess pre- and post-hemp 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 a high-CBD hemp product using multimodal magnetic 
resonance imaging (MRI) techniques. 
 
BACKGROUND AND SIGNIFICANCE 
Provide a brief paragraph summarizing prior experience important for understanding the 
proposed study and procedures. 
 
Cannabis sativa has been used medicinally for a range of disorders for thousands of years, 
including anxiety. Cannabis is comprised of more than 100 cannabinoids; D9-tetrahydrocannabinol 
(Δ9-THC) is the major psychoactive constituent, and cannabidiol (CBD) is the major non-
psychoactive constituent that has been touted to have a variety of potential medicinal benefits. 
Industrial hemp is a variety of the Cannabis sativa plant, which until recently was grown 
specifically for industrial uses, such as textiles. Hemp has much lower concentrations of THC than 
cannabis, defined as THC<0.3% by weight. In recent years, some hemp strains have been bred to 
produce particularly high concentrations of CBD with very low concentrations of THC, virtually 
eliminating the potential for intoxicating effects. Extracts from these hemp strains are 
manufactured into a variety of oils, capsules, sprays, etc., available in brick-and-mortar stores 
across the country as well as on the Internet. 


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Previous studies have demonstrated CBD’s acute anxiolytic potential in both animals and humans. 
Recently, our group began the first ever clinical trial of a high-CBD compound for anxiety. This 
trial, studied under IND #126898, examines the impact of a high-CBD, low-THC cannabis-derived 
sublingual solution on measures of anxiety, mood, quality of life, and cognition over a 4-week 
treatment period. Interim analyses completed on the first 5 subjects who completed the trial were 
extremely compelling; analyses indicate that patients reported a 68.29% reduction in anxiety 
symptoms on the primary outcome measure, the Beck Anxiety Inventory (BAI), from the baseline 
to final visit. The study product is very well-tolerated, with no serious adverse events occurring to 
date. 
        
 
The proposed investigation will be the first of its kind to conduct a clinical trial of an industrial 
hemp-derived product in individuals with anxiety. Despite the recent interest in MC and 
cannabinoid-based products, the availability of hemp-derived products in all 50 states, and 
anecdotal evidence suggesting that hemp-derived products may have a profound anxiolytic effect, 
no studies have conducted a clinical trial of a hemp-derived product 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 hemp-derived products, or assessed measures 
of cognition, brain structure and function before and after treatment using neuropsychological 
measures and neuroimaging. The recent passage of the Farm Bill of 2018 has resulted in the 
exclusion of industrial hemp-derived products (THC content <0.3% by weight) from the 
Controlled Substances Act (CSA). As such, it is now possible to conduct clinical trials on industrial 
hemp-derived CBD products, including those such as Charlotte’s Web (CW), which many 
thousands of consumers have purchased in recent years. As such, we will assess a proprietary 
hemp-derived formulation manufactured by CW that is a custom mixture of the “Extra Strength” 
and “Original” products that have been sold for several years; the custom formulation contains 
approximately 30mg/ml of CBD and 0.8 mg/ml THC. In addition to providing information 
regarding the potential efficacy of an industrial hemp-derived CBD product for anxiety, this study 
will allow the comparison of a NIDA-based product, studied in our other IND and which lacks 
ecological validity, to a product that many thousands of consumers have used. 
 
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 40 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 throughout 6 weeks of treatment with compounds 
administered as sublingual tinctures in a double-blind, randomized procedure: subjects will receive 
either a high CBD product or matched placebo. Each product will be analyzed and verified at an 


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outside lab for safety and potency. Subjects will self-administer 0.5 ml (15mg/ml) of CBD or 
placebo sublingually two 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. 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. Subjects will complete study drug diaries manually (pencil and 
paper) or electronically. 
 
In order to assess the efficacy of the dose chosen for the double-blind study, we will also conduct 
a small open-label trial of the CBD solution prior to initiating the double-blind study. This open-
label trial will enroll up to 12 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.  
 
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 40 (20 CBD, and 
20 placebo); up to 15 of each group (30 total) will also complete the MRI scanning protocol. For 
the open-label trial, the total sample size is 12. 
 
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 
8 on the Overall Anxiety Severity and Impairment Scale (OASIS) at the screening 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-IV classification of current substance abuse/dependence, psychotic 
disorder, bipolar disorder, or an eating disorder 
4) A first-degree relative with a psychotic disorder 
5) A history of head injury or loss of consciousness greater than 5 minutes 
6) Currently uses marijuana or cannabinoid-based products more frequently than 1x/month 
7) Female subjects will be excluded if they have a positive urine pregnancy test, or if they are 
currently breastfeeding 
8) Presence of a serious medical illness, including liver, kidney, or cardiovascular disease, or 
neurological disorder  
9) Allergy to coconut oil 


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10) Current use of valproate 
11) Currently enrolled in other research studies or clinical trials involving interventions 
 
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,  
3) Exposure to shrapnel or metal filings (wounded in military combat, sheet metal 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 
4) Poor vision, as subjects must have normal or corrected-to normal vision for viewing of 
cognitive challenge paradigms during fMRI protocols 
 
Concomitant medications will be allowed and will be assessed on a case-by-case basis with the 
study physician; participants may be excluded if they are taking strong inhibitors or inducers of 
CYP3A4 (e.g. fluconazole, fluoxetine, fluvoxamine, ticlopidine, St. John’s Wort, etc.), CYP2C19 
(e.g. ketoconazole, erythromycin, etc.), or CYP2D6 (e.g. paroxetine, buproprion, quinidine, 
ritonavir, glutethimide, etc.). Dosing schedules may be adjusted in order to offset CBD 
administration with concomitant medications to decrease the likelihood of any drug-drug 
interactions. Subjects must have been on stable medication/psychotherapy regimens for at least 3 
months prior to starting the study. 
 
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.
 
This study is designed to assess individuals who have expressed interest in using CBD for anxiety. 
Subjects will complete study visits at McLean Hospital.  
 
A total of 52 (12 in the open-label phase, and 40 in the double-blind phase) female and male 
participants with anxiety, of minimum age 18, will complete a baseline visit including clinical 
ratings, an assessment of conventional medication use, quality of life measures, a 
neuropsychological test battery, a buccal swab sample, and optional neuroimaging (in a subset of 
participants who are eligible). Participants will subsequently be treated for 6 weeks with the CW 
sublingual solution. All participants will self-administer 0.5 ml (15 mg of CBD) of solution twice 
daily (BID). Participants will return to the laboratory or complete remote visits each week to 
complete clinical ratings and check in with study staff. After 6 weeks of treatment, participants 
will complete final clinical scales and quality of life measures, a complementary 
neuropsychological battery, and a corresponding neuroimaging component (where applicable). 
The open-label phase of the study is expected to take approximately 12 months to complete, and 
will assess the efficacy of the dose chosen for the double-blind study. 
 


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40 female and male participants will be enrolled in the double-blind phase. Study procedures will 
remain the same as the open-label phase, however participants will receive CW solution or placebo 
solution in a double-blind, randomized fashion. All participants will self-administer 0.5ml of 
solution BID for 6 weeks. The double-blind phase of the study is expected to take 24 months to 
complete.  
 
Study Visits 
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 and reviewed with the study physician. Study inclusion/exclusion criteria will be 
applied, and appropriate subjects will be enrolled and complete the rest of the study visit.  
 
Open-Label Trial 
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. A structured clinical interview will be 
administered, and demographic information, substance abuse/use, and medical histories will also 
be obtained and reviewed with the study physician. Study inclusion/exclusion criteria will be 
applied, and appropriate subjects will be enrolled and complete the rest of the study visit. 
 
For the first stage of the study, 12 individuals will be assessed at baseline and weekly for 6 weeks 
of treatment with sublingual CW solution in an open-label fashion: all subjects will receive the 
CBD product. Subjects will self-administer 0.5 ml (15mg) of CBD sublingually two times daily, 
in the morning and the evening, for a daily total dose of 30 mg CBD; if no clinical benefit (>15% 
reduction in BAI ratings) is evident at the 2-week visit, patients will be given the option to add an 
additional dose in the middle of the day to bring the total daily dose to 45mg CBD. At the weekly 
visits throughout the treatment period, individuals will complete clinical scales and have a check-
in with study staff. In addition to clinical ratings and a check-in with study staff, 
neuropsychological testing will also be performed at baseline and week 6 in order to assess 
cognitive performance. A subset of individuals will receive an hour-long MRI scan at baseline and 
week 6, 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. Subjects will also 
provide a buccal swab sample for genetic analysis at the baseline visit; this will allow specification 
of genes related to degradative enzymes involved in the endocannabinoid system (e.g. FAAH, 
MAGL) and allow us to determine whether genetic profile can predict treatment response. 
 
At the end of the baseline visit, eligible subjects will receive CBD solution. Subjects will be 
instructed on how to administer the compound in the morning and evening; they will be instructed 
how to draw 0.5 dropper of compound, deposit the amount in the dropper under the tongue, hold 
for 45-60 seconds, then swallow. 
 
Double-Blind Trial 
Individuals will be assessed in-person at baseline and weekly for 6 weeks of treatment with 
compounds administered as sublingual solutions in a double-blind, randomized procedure: 
subjects will receive either the CW solution or matched placebo. At the weekly visits throughout 
the treatment period, individuals will complete clinical scales and have a check-in with study staff. 


Partners Human Subjects Research Application Form 
  
Filename: Protocol Summary 
Version Date: April 19, 2018 
 
  
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In addition to clinical ratings and a check-in with study staff, neuropsychological testing will be 
performed at baseline and week 6 in order to assess cognitive performance. Finally, a subset of 
individuals will receive an hour-long MRI scan at baseline and week 6, 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. Subjects will also provide a buccal swab sample for genetic 
analysis at the baseline visit. 
 
At the end of the baseline visit, eligible subjects will be randomized to either CW solution or 
placebo using a standard alternating procedure in accordance with the McLean Pharmacy. Subjects 
will be instructed on how to administer the compound, as described above. 
 
For both the open-label and double-blind trials, the baseline and the final study visits are estimated 
to take approximately 3-4 hours, with the weekly visits in the interim estimated to take 
approximately 1 hour, and 15 minutes for phone check-ins, for a total of approximately 10-12 
hours required to complete all possible visits. Urine samples will be collected at every other visit 
(Visits 1, 3, 5, and 7) to measure THC via GCMS (Quest Diagnostics) and to monitor for the 
presence of other substances throughout the study. Female subjects will be informed that their 
sample will also be used to confirm negative pregnancy (HCG) status; if at any point their urine 
tests positive for HCG, they will be excluded from the study. We are currently in communication 
with several groups that may be able to assess for CBD in urine; we hope to utilize one of these 
groups to quantify CBD in urine throughout the study.  
 
Subjects will be given the option to complete daily study drug diaries manually (pencil and paper) 
or electronically. Adverse events and side effects will be assessed at weekly study visits and phone 
check-ins and all subjects will be advised to call study staff if they experience any adverse events. 
 
Clinical Ratings 
The Structured Clinical Interview for DSM-V Patient Version (SCID-P) and the SCID-P 
Substance Abuse/Dependence Module or the Quick Structured Clinical Interview for DSM-V 
Disorders (QuickSCID) will be administered to all study participants during visit 1 by the Principal 
Investigator, a Clinical Neuropsychologist or trained Clinical Research Assistant. Subjects will 
also complete clinical rating scales and questionnaires that have been shown to provide reliable 
estimates of current clinical state and are easily administered. They will also complete quality of 
life measures. All subjects will be given the following measures at the baseline and final visits that 
take approximately one hour to complete: Hamilton Anxiety Scale (HAM-A), Beck Anxiety 
Inventory (BAI), State-Trait Anxiety Inventory (STAI), Overall Anxiety Severity and Impairment 
Scale (OASIS), Barratt Impulsiveness Scale (BIS-11), Fagerström Test for Nicotine Dependence 
(FTND), Profile of Mood States (POMS), Alcohol Use Disorders Identification Test (AUDIT), 
Cannabis Use Disorders Identification Test-Revised (CUDIT-R – V1 only), Beck Depression 
Inventory (BDI), Positive and Negative Affect Scale (PANAS), the 36-Item Short-Form (SF36), 
the Pittsburgh Sleep Quality Index (PSQI), the Beck Hopelessness Scale (BHS), the Beck Scale 
for Suicide Ideation (BSS), the Marijuana Effect Expectancy Questionnaire - Brief (MEEQ-B, 
baseline only), Patient Global Impression of Change (PGIC) scale, a Treatment Expectancy 
questionnaire, a Motives questionnaire, the Arizona Sexual Experience Scale (ASEX), and a Side 
Effects Questionnaire (SEQ) developed by our group. In order to be consistent with a longitudinal, 
observational study in our group that subjects are often interested in joining, subjects interested in 
continuing into the other protocol will also complete the Rosenberg Self-Esteem scale, the 


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Satisfaction with Life (SLS) scale, and pain scales (Visual Analog Scale (VAS), Numerical Rating 
Scale (NRS), Pain Distress Scale (PDS), Pain Disability Index (PDI), Neuropathic Pain Scale 
(NPS), and Pain Catastrophizing Scale (PCS)) and PTSD scales (PTSD Checklist – Civilian (PCL-
C) and the UCLA PTSD Reaction Index), where applicable, retrospectively at the final visit. 
Subjects will also complete a subset of these measures, specifically the anxiety and mood-related 
measures (BAI, BDI, STAI, OASIS, POMS, HAM-A, and PANAS), along with the SEQ, at each 
weekly visit. An Abuse Liability Rating Scale (ALR) will be completed at V3 and V7. 
 
Please note that if suicidality is endorsed spontaneously, on any of the clinical scales, or during 
the SCID or weekly check-ins with study staff, the patient will be immediately assessed for 
suicidality risk. Please see “Suicidality SOP” attachment for further information. 
 
Neuropsychological Assessment 
In addition to the clinical rating scales, the proposed investigation also includes a brief battery of 
neuropsychological tests to examine the potential effects of CBD on cognition in subjects with 
anxiety. Individuals will complete neuropsychological assessments at two time points; at baseline 
at after 6 weeks of treatment. The neurocognitive battery is primarily designed to evaluate frontal, 
executive, and memory functions as well as general intellectual capacity. The neuropsychological 
measures will be administered by a trained psychometrician and were chosen because they are 
standard, well-known measures that can be administered and scored reliably. Measures to be 
administered at baseline and both follow-up visits include the Rey Auditory Verbal Learning Test 
(RAVLT); Benton Visual Retention Test (BVRT); Letter-Number Sequencing of the Wechsler 
Adult Intelligence Scale (WAIS-R); Stroop Color-Word Test; Trail Making Test A & B; the 
Controlled Oral Word Association (FAS) Test; and the Multi Source Interference Task (MSIT). In 
addition, the 2 factor Wechsler Abbreviated Scale of Intelligence – II (WASI-II) will be 
administered at baseline to obtain IQ estimates from subjects. The neurocognitive assessment 
battery will take approximately 1.5 hours to complete. Many of these tests, including the RAVLT, 
BVRT, DSST, Trail Making Test, and the COWAT have alternate versions to use at the follow-
up visit, in order to reduce the likelihood that subjects remember portions of the assessments from 
baseline. 
 
Buccal Swab 
Buccal swab samples will be collected at the baseline visit using Endo-DNA kits and used for 
genotyping.  
 
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. 
 


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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. The daily 
dose is the same as another protocol using a cannabis-derived sublingual solution (2015P000959), 
and no serious adverse events have been reported in that study. 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. Additional termination 
criteria include: subject does not use solution as directed; subject sustains a significant head injury; 
any study exclusions are met (i.e. change in medical status, pregnancy, etc.) 
  
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. 
 
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.  


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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 
CBD has been shown to have an extremely low side effect profile and since the total amount of 
THC will not exceed 0.3% by weight, we do not expect significant side effects or psychoactive 
effects. CBD is not a scheduled substance, and there is no risk of intoxication or addiction to CBD. 
As with any clinical trial, there are risks of experiencing side effects from the administration of 
CBD or placebo; these side effects are very rare. Cunha et al. (1980) reported no signs of toxicity 
or serious side effects; in this two-part, placebo-controlled, double blind study, healthy volunteers 
were given 3 mg/kg of CBD or placebo per day for 30 days, and patients with epilepsy were given 
200-300mg CBD or placebo per day for 4.5 months. The total dose of CBD per day for the current 
study will be 30mg – thus, we expect no significant side effects. Other studies have reported no 
adverse effects of CBD in patients with Huntington’s disease, schizophrenia, and Parkinson’s 
disease after repeated administration (Consroe et al. 1991; Leweke et al. 2012; Zuardi et al. 2006 
and 2009). Subjects will have the opportunity to report adverse effects at their weekly check-in 
visits via direct contact with the PI and study staff. This weekly reporting will reduce the likelihood 
that subjects experience significant negative side effects for any significant period of time, and the 
PI as well as they study physician will be reachable by page 24 hours a day 7 days a week.  
 
Sublingual solutions are unlikely to be viewed by the public as analogous to recreational smoked 
marijuana, thus decreasing the risk of the subject experiencing any potential negative appraisal 
arising from perceived notions associated with marijuana use while partaking in this study.  
 
The safety of CBD administration in pregnant women and fetuses is unknown. Female participants 
capable of child-bearing will be asked to provide a sample of urine before the study is begun and 
at each subsequent study visit in order to screen for pregnancy. If the pregnancy test is positive at 
any point during the study, the subject will be immediately disqualified and participation in the 
study will cease. Participation requires that the participant uses contraception methods (such as 
abstinence, diaphragm, condom, or an intrauterine device) to prevent pregnancy for the duration 
of the study. The participant will be asked to notify study staff immediately if she misses a period 
or thinks she might be pregnant. In this case, the participant may have to withdraw from the study. 
 
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. 


Partners Human Subjects Research Application Form 
  
Filename: Protocol Summary 
Version Date: April 19, 2018 
 
  
11 
 
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
 
 
 


Partners Human Subjects Research Application Form 
  
Filename: Protocol Summary 
Version Date: April 19, 2018 
 
  
12 
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 Rally) and via RPDR messaging. Medical marijuana 
certification facilities and anxiety clinics 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
 
A tiered payment system will be used for a payment of $75 at visit 1, $30 each at visits 2, 3, 4, 
5, and 6, and $75 at visit 7 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 7 for a total of 
$450. Subjects will receive a completion bonus of $50 if they complete the study, for a total of 
$350 or $500, depending on whether they receive MR scanning. Subjects may withdraw from 
the study at any point; and will still receive payment for the portion of the study they completed 
at a rate of $25/hr.  
 
 
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
 
 


Partners Human Subjects Research Application Form 
  
Filename: Protocol Summary 
Version Date: April 19, 2018 
 
  
13 
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 the licensed physician investigator on the protocol, Dr. David 
Olson. 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 room 204 
of the Neuroimaging Center 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 using the MGB consent template. 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, and a copy will be provided to the 
participant. 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
 
 
 


Partners Human Subjects Research Application Form 
  
Filename: Protocol Summary 
Version Date: April 19, 2018 
 
  
14 
DATA AND SAFETY MONITORING 
Describe the plan for monitoring the data to ensure the safety of subjects.  The plan should 
include a brief description of (1) the safety and/or efficacy data that will be reviewed; (2) the 
planned frequency of review; and (3) who will be responsible for this review and for determining 
whether the research should be altered or stopped.  Include a brief description of any stopping 
rules for the study, when appropriate.  Depending upon the risk, size and complexity of the 
study, the investigator, an expert group, an independent Data and Safety Monitoring Board 
(DSMB) or others might be assigned primary responsibility for this monitoring activity.        
 
NOTE: Regardless of data and safety monitoring plans by the sponsor or others, the principal 
investigator is ultimately responsible for protecting the rights, safety, and welfare of subjects 
under his/her care. 
 
Data analyses will be conducted on the open-label phase of the study prior to initiating the double-
blind phase in order to ensure that patients derive clinical benefit from the dose selected. 
Specifically, in conjunction with Dr. Olson, we will assess clinical response after the first 5 patients 
have completed their 6 week trial. If we do not see clinical improvement based on a review of 
clinical scales, subjective reports and performance, we will consider increasing the dose to 1 
droppers two times a day for a total of 60 mg CBD per day. Clinical improvement will be defined 
as a 15% reduction in BAI scores from baseline. Findings will be used to inform the double blind 
phase of the study, which would not begin until adequate dose/response is achieved. An 
amendment would be submitted to the IRB for approval prior to adjusting the dose of CBD. 
 
In the unlikely event that an adverse event occurs, it will be reported to the primary investigator 
and the Institutional Review Board’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. There are currently no plans to utilize a Data Safety Monitoring Board (DSMB) due 
to the extremely low side-effect profile of CBD, but if the IRB deems that an independent DSMB 
is necessary, the investigators would be happy to suggest individuals who are appropriate or to 
consider outside suggestions from IRB members. 
 
Subjects are required to have a structural MRI scan of clinical quality at least once per year at 
McLean Hospital that is reviewed by a board-certified radiologist or neurologist and a clinical 
report is generated usually within 2-4 days. If the subject has not received a structural clinical scan 
in the past year, one will be obtained for the present study. Subjects will not receive more than one 
structural clinical MRI within a given 12-month period unless a follow-up scan is recommended 
by the radiologist who reads the scan. Abnormal reports are reviewed by the Clinical Director of 
the McLean Imaging Center (MIC), Dr. David Olson and forwarded to the Principal Investigator, 
in this case, Dr. Gruber, and the designated study physician. If an abnormality is present, the study 
physician and PI will coordinate the process of contacting the subject so that an appointment can 
be made to discuss the findings. The MIC Clinical Director may also assist with this process when 
requested and appropriate. If a follow-up scan is recommended by the radiologist, we will offer 
the subject a cost-free repeat scan (with contrast if indicated). In all cases we offer a copy both of 
the clinical report and the MRI scan (on film or cd) to subjects to take to their primary care or other 
consulting physicians, at no cost. 
 
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 


Partners Human Subjects Research Application Form 
  
Filename: Protocol Summary 
Version Date: April 19, 2018 
 
  
15 
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  
          
          Reporting Unanticipated Problems (including Adverse Events)
          https://partnershealthcare-
public.sharepoint.com/ClinicalResearch/Reporting_Unanticipated_Problems_including_Adverse_Events.pdf


Partners Human Subjects Research Application Form 
  
Filename: Protocol Summary 
Version Date: April 19, 2018 
 
  
16 
 
 
 
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. 
 
SENDING SPECIMENS/DATA TO RESEARCH COLLABORATORS OUTSIDE 
PARTNERS 
Specimens or data collected by Partners investigators will be sent to research collaborators 
outside Partners, indicate to whom specimens/data will be sent, what information will be sent, 
and whether the specimens/data will contain identifiers that could be used by the outside 
collaborators to link the specimens/data to individual subjects.


Partners Human Subjects Research Application Form 
  
Filename: Protocol Summary 
Version Date: April 19, 2018 
 
  
17 
 
In some cases, urine samples may be sent to Quest Diagnostics to assess recent substance use. 
The samples will be labeled with the subject’s initials, date of birth, and study ID.  
 
Data collected during the study may be sent to Dr. Yuval Zolotov (a recognized public health 
expert in Israel) in order to provide public health context to our research findings. A Data Sharing 
Plan is on file detailing the method of sharing, security provisions, etc. 
 
Specifically address whether specimens/data will be stored at collaborating sites outside 
Partners for future use not described in the protocol.  Include whether subjects can withdraw 
their specimens/data, and how they would do so.  When appropriate, submit documentation of 
IRB approval from the recipient institution.
 
Specimens will not be stored off-site for future use not described in the protocol. 
 
RECEIVING SPECIMENS/DATA FROM RESEARCH COLLABORATORS OUTSIDE 
PARTNERS 
When specimens or data collected by research collaborators outside Partners will be sent to 
Partners investigators, indicate from where the specimens/data will be obtained and whether the 
specimens/data will contain identifiers that could be used by Partners investigators to link the 
specimens/data to individual subjects.  When appropriate, submit documentation of IRB 
approval and a copy of the IRB-approved consent form from the institution where the 
specimens/data were collected.
 
N/A 
 
 
STATISTICAL APPROACHES 
All statistical analyses will be conducted using IBM SPSS Statistics (version 28).  Data will be 
screened for outliers and any data points more than 2 standard deviations from the group means 
will be excluded. Additionally, data will be screened for skew, kurtosis, non-normality, and 
homogeneity of variance. If the assumptions of parametric inferential analyses are not met, the 
appropriate non-parametric analyses (e.g. Wilcoxon-Signed Rank Test) will be performed. 
Descriptive statistics will be used to characterize the demographic data. Baseline clinical and 
neuropsychological data will be assessed using 2-tailed paired t-tests to compare follow-up 
timepoints to baseline values. When needed, Bonferroni corrections for multiple comparisons 
will be utilized.