Clinical trial NCT03891264
Conditions: Back Pain, Low
Sponsor: Massachusetts General Hospital
Start date: 2019-11-13; Completion date: 2020-11-23
Enrollment: 7 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
In this research, the study team will use brain imaging to evaluate the presence of neuroinflammation in the brains and spinal cords of patients with low back pain, and whether CBD effects levels of neuroinflammation. The efficacy of CBD use for low back pain treatment will also be evaluated by observing whether CBD administration will reduce neuroinflammation and low back pain symptoms.

Detailed description:
The goal of this research study is to test whether "glial cells" (the immune cells of the brain and spinal cord) that are active in patients with low back pain can be reduced with CBD. Previous studies have showed that patients with chronic low back pain demonstrated elevations in brain levels of the 18kDa translocator protein (TSPO), a marker of glial activation.

To test this hypothesis, the study team will image the brains and spinal cords of patients suffering from low back pain using integrated magnetic resonance- positron emission tomography (MR-PET), and a radiotracer called \[11C\]PBR28, which tracks levels of glial activation.

The efficacy of CBD as a treatment for chronic low back pain will be evaluated. The study team will observe whether 4 weeks of CBD treatment may reduce glial activation along with self-reported low back pain symptoms. To this end, patients will be evaluated clinically and/or re-scanned after completing the 4-week trial of minocycline.

This study will be enrolling individuals who have been suffering from chronic low back pain.

Arms: arm 1: Evaluation with Magnetic Resonance-Positron Emission Tomography Imaging and/or behavioral pain assessment before and after a 4-week trial of a liquid formulation of CBD.
Interventions: intervention 1: Cannabidiol
Intervention descriptions: intervention 1: Epidiolex, an agent within the anti-epileptic drug class, will be used. Epidiolex, Greenwich Biosciences Inc.'s CBD formulation, is a 100 mg/mL purified oral solution. The recommended starting dosage is 2.5mg/kg taken twice daily (5mg/kg/day). After one week, the dosage will be increased to a maintenance dosage of 10 mg/kg twice daily (20 mg/kg/day). At the end of the first week, the patient will increase the dose to 10 mg/kg twice daily for the following week.

Protocol documents:
Prot_SAP_000.pdf: 
 
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DETAILED PROTOCOL  
 
Investigation of Cannabidiol for Reduction of NeuroInflammation  
in Chronic Back Pain 
 
NCT # NCT03891264 
11/12/2020 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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DETAILED PROTOCOL: 
 
Investigation of Cannabidiol for Reduction of NeuroInflammation  
in Chronic Back Pain 
 
PI: Jodi Gilman, PhD 
Co-PI: Marco Loggia, PhD 
Co-I: A. Eden Evins, MD 
Co-I: Yi Zhang, MD 
Co-I: Jianren Mao, MD  
Co-I: Kristina Schnitzer, MD 
 
Date: 11/12/2020 
 
 
BACKGROUND AND SIGNIFICANCE 
 
Millions of individuals suffer from chronic pain  
Chronic pain is defined as pain without apparent biological value that has persisted 
beyond the normal tissue healing time (usually taken to be 3 or 6 months 1,2). Chronic 
pain is a widespread public health issue 3, and its prevalence is enormous. The weighted 
mean prevalence of chronic pain in the general population has been estimated by some at 
35.5%, or 105 million, in the United States 4. Not only does chronic pain affect both 
physical and mental functioning, thus compromising quality of life; it is also associated 
with astronomical costs. In addition to the direct costs of treating pain—including health 
care for diagnosis and treatment, drugs, therapies, and other medical expenses—chronic 
pain results in lost work time and reduced productivity 5,6. Past estimates of the annual 
cost of chronic pain in the United States, including healthcare expenses, lost income and 
productivity, were close to $100 billion 7.  
  
 
Treatment for chronic pain is unsatisfactory 
Despite the enormity of the phenomenon, clinical needs for chronic pain are largely 
unmet. The treatment of choice for the largest majority (as many as 90% 8) of patients 
seeking chronic pain management is based on opioid analgesics. However, the evidence 
supporting long-term effectiveness of opioid drugs in relieving pain and improving 
functional status is weak 9. For instance, despite the widespread use of opioids for 


 
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palliative care, more than half of all hospitalized patients experience pain in the last days 
of their lives, and 50-75% of cancer patients die in moderate to severe pain 10. 
 
The current opioid-based pharmacological approaches to treat chronic pain are not only 
ineffective, but they generally have multiple unpleasant side effects, including 
constipation, pruritus, respiratory depression, nausea, vomiting, hyperalgesia, dizziness, 
sedation 9, as well as abuse and dependence 8,11,12. Taken together, the unsatisfactory 
treatment efficacy and the occurrence of significant side effects, clearly stress the 
importance of achieving a deeper understanding of the pathophysiological mechanisms 
underlying chronic pain, in order to eventually identify viable treatment options 
alternative to ones currently available.  
 
 
Microglia and pain 
One of the reasons for the poor efficacy of the treatment options currently available for 
chronic pain might be that these are primarily aimed at suppressing neuronal activity 
within nociceptive pathways of the nervous system. However, it is now increasingly clear 
that neurons are far from being the only players that drive the establishment and/or 
maintenance of clinical pain symptoms. Rather, evidence from animal studies now 
suggests a central role of glial cells in the nervous system, including microglia 13,14.  
 
Microglia are a subpopulation of macrophages that rapidly activate in response to a 
variety of pathological conditions 15, including persistent pain 16-23. Microglial activation 
(MA) is characterized by a stereotypic pattern of cellular responses, including specific 
morphological changes, proliferation, increased or de-novo expression of cell surface 
markers or receptors, and migration to the site of injury 24. MA generally represents an 
adaptive homeostatic defense response which enables the destruction of invading micro-
organisms, the removal of potentially deleterious debris as well the promotion of tissue 
repair. However, animal studies have now showed that the uncontrolled activation of 
microglial cells under pathological pain conditions induces the release of substances that 
can sensitize pain pathways, such as proinflammatory cytokines, complement 
components, and others 25. While evidence of pain-related MA was originally observed in 
the spinal cord, more recently it was also discovered at the level of the brain, including in 
the rostral ventromedial medulla 20,26, the trigeminal nuclear complex 19,27, and the ventral 
posterolateral nucleus of the thalamus 28,29.  
 
While most of the evidence on the occurrence of pain-related glial responses in the 
central nervous system comes from animal studies, a few important observations indicate 
that similar phenomena should occur also in humans 13. First, immunohistochemical 
markers of microglial and astroglial activation have been detected in the spinal cord of a 
patient with chronic regional pain syndrome in a postmortem study 30. Furthermore, an 
increase in the concentration of the glial marker s-100β was reported in the cerebrospinal 
fluid of patients with lumbar disc herniation and in the serum of children with recurrent 
headaches 31,32. Finally, a positron emission tomography (PET) study has revealed that 


 
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human subjects with neuropathic pain secondary to peripheral nerve damage express 
increased thalamic binding for [11C](R)-PK11195 33, an in vivo marker of microglial cell 
activation 34,35. 
 
Recently, Co-PI Dr. Marco Loggia has also shown that patients with chronic low back 
pain (cLBP) have increased brain levels of the 18kDa translocator protein (TSPO), a 
marker of glial activation36. In addition, preliminary data collected from a different cohort 
of patients with cLBP and sciatica suggest an increase in spinal cord TSPO levels. 
Together, these results suggest that human chronic pain conditions are likely to be 
associated with a glial reaction, both in the spinal cord, as well as in the brain.  
 
 
Cannabidiol and pain 
There is a growing body of evidence to suggest that cannabinoids are beneficial for a 
range of clinical conditions, including pain, inflammation, epilepsy, and sleep disorders37. 
A large body of preclinical and clinical research indicates that the cannabinoid system 
modulates a broad range of physiological processes and behaviors including, but not 
limited to, pain, mood, appetite, neuronal activity, memory, immunity, and cell 
development. The endocannabinoid system’s contribution to the regulation of such a 
variety of processes makes phytocannabinoid pharmacological modulation a promising 
therapeutic strategy 38. 
 
The primary cannabinoids found in the cannabis plant include delta-9 -
tetrahydrocannabinol (THC), cannabidiol (CBD), and cannabinol (CBN), with THC 
being the primary psychoactive compound. The second most abundant compound in the 
plant is CBD, which is minimally psychoactive 39. Cannabinoid receptor type 1 (CB1) 
and type 2 (CB2) belong to a family of seven transmembrane Guanosine Binding Protein-
Coupled Receptors, and are widely expressed and distinguished by their specific 
functions, localization and signaling mechanisms. The psychotropic effects of cannabis 
are principally mediated by CB1, which is widely distributed throughout the brain, while 
CB2 is considered the peripheral cannabinoid receptor, found mainly in immune cells, as 
well as in chondrocytes, osteocytes and fibroblasts. Agonists targeting CB2 receptors 
have been proposed as therapies for the treatment or management of a range of painful 
conditions, including acute pain, chronic inflammatory pain, and neuropathic pain 40. In a 
preclinical model, researchers showed that stimulation of CB2 suppresses microglial 
activation 41.  
 
In the current study, we will test whether CBD is a glial inhibitor in patients with chronic 
lower back pain (cLBP). CBD was recently FDA-approved as a liquid formulation (see 
EPIDIOLEX package insert) for epilepsy for children ages 2 and up as well as adults, 
demonstrating significant reductions in total seizure frequency with minimal side effects. 
It is unclear whether cannabidiol reduces glial activation in humans. We will study 20 
patients with low back pain (pain duration > 6 months) longitudinally before and after 4 


 
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weeks of treatment with cannabidiol. Endpoints will be pain scores as well as brain levels 
of the 18kDa translocator protein (TSPO), a marker of glial activation36. 
 
 
SPECIFIC AIMS 
 
Primary Aim: Assess whether CBD reduces neuroinflammation in patients with 
cLBP. 
 
Hypothesis: Patients will demonstrate higher PET signal in the brain (thalamus, S1/M1 
representation of the lumbar spine) before CBD treatment in comparison to after CBD 
treatment. This within-subject comparison will allow us to evaluate short-term change 
over time in cLBP patients. 
 
SUBJECTS SELECTION 
 
We plan to identify 20 patients with chronic low back pain (cLBP; i.e., with a pain 
duration longer than 6 months), who will complete the study.  
 
We are not planning to enroll subjects from at-risk populations (e.g., children and minors, 
cognitively impaired persons, prisoners). Written informed consent form will be obtained 
in all cases.   
 
Inclusion Criteria:  
- 
age ≥ 18 and ≤ 75;  
- 
the ability to give written, informed consent;  
- 
ongoing pain that averaged at least 4, on a 0-10 scale of pain during a 
typical week, and present for at least 50% of days during a typical week; 
- 
on a stable pain treatment (pharmacological or otherwise) for the previous 
four weeks.  
- 
Chronic low back pain, ongoing for at least 6 months prior to enrollment.  
 
Exclusion Criteria:  
- 
outpatient surgery within 2 months and inpatient surgery within 6 months 
from the time of scanning; 
-  
elevated baseline transaminase (ALT and AST) levels above 3 times the 
Upper Limit of Normal (ULN), accompanied by elevations in bilirubin 
above 2 times the ULN 
- 
any interventional pain procedures within 6 weeks prior to scanning 
procedure or at any point during study enrollment; 
- 
surgical intervention or introduction/change in opioid regimen at any point 
during study enrollment  
- 
contraindications to fMRI scanning and PET scanning (including presence 


 
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of a cardiac pacemaker or pacemaker wires, metallic particles in the body, 
vascular clips in the head or previous neurosurgery, prosthetic heart 
valves, claustrophobia);  
- 
current or past history within the last 5 years of major medical illness not 
affecting the central nervous system, other than chronic pain;  
-  
implanted spinal cord stimulator (SCS) for pain treatment; 
- 
any history of neurological illness or major medical illness affecting the 
central nervous system, unless clearly resolved without long-term 
consequences; 
- 
current or past history of major psychiatric illness;  
- 
PTSD, depression, and anxiety are exclusion criteria only if the 
conditions were so severe as to require hospitalization in the past  
year. 
- 
pregnancy or breast feeding; 
- 
history of head trauma requiring hospitalization;  
- 
major cardiac event within the past 10 years; 
- 
any use of recreational drugs in the past 3 months; 
- 
any marijuana use, medical or recreational, in the past 3 months; 
- 
an abnormal physical exam (e.g., peripheral edema); 
-  
use of immunosuppressive medications, such as prednisone, TNF 
medications within 2 weeks of the visit; 
- 
current bacterial or viral infection; 
-  
epilepsy or any prescription of an anti-epileptic drug  
-  
use of the medications valproate and clobazam, which may increase risk of 
hepatic AEs  
- 
use of medications with:  
-  
Strong and moderate CYP3A4 inhibitors including boceprevir, 
cobicistat, conivaptan, danoprevir, elvitegravir, ritonavir, indinavir, 
itraconazole, ketoconazole, lopinavir, paritaprevir and ombitasvir 
and/or dasabuvir, posaconazole, saquinavir and telaprevir, 
tipranavir, clarithromycin, diltiazem, idelalisib, nefazodone, 
nelfinavir, troleandomycin, voriconazole, aprepitant, cimetidine, 
ciprofloxacin, clotrimazole, crizotinib, cyclosporine, dronedarone, 
erythromycin, fluconazole, fluvoxamine, imatinib, tofisopam, 
disulfiram, and verapamil; 
-  
Strong and moderate inhibitors of CYP2C19 including fluoxetine 
and ticlopidine; 
- 
Sensitive and moderately sensitive substrates of CYP2C19 
including clobazam, lansoprazole, omeprazole, S-mephenytoin, 
and rabeprazole; 
-  
Sensitive and moderately sensitive substrates of CYP1A2 
including alosetron, duloxetine, melatonin, ramelteon, tasimelteon, 
theophylline, tizanidine, pirfenidone, and ramosetron; 


 
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-  
Sensitive and moderately sensitive substrates of CYP2B6 
including bupropion and efavirenz; 
-  
Sensitive and moderately sensitive substrates of CYP2C8 
including repaglinide, montelukast, pioglitazone, and rosiglitazone; 
-  
Sensitive and moderately sensitive substrates of CYP2C9 
including tolbutamide, celecoxib, glimepiride, and warfarin; 
-  
Sensitive and moderately sensitive substrates of UGT1A9 
including diflunisal, propofol, and fenofibrate; 
-  
Sensitive and moderately sensitive substrates of UGT2B7 
including, gemfibrozil, lamotrigine, and morphine; 
-  
The following CNS depressants including all antipsychotics, 
benzodiazepines (except for alprazolam, clonazepam, and lorazepam), and 
the non-benzodiazepine sleep aids including butabarbital sodium, 
eszopiclone, phenobarbital, ramelteon secobarbital sodium, suvorexant, 
zaleplon, and zolpidem; 
-  
regular use of opioids 
- 
actively suicidal, history of suicide attempt or an aborted attempt within 
the last 5 years, or engagement in non-suicidal self-injurious behavior 
within the last year 
- 
Any other contraindications to CBD administration noted by the study  
physician. 
 
SUBJECT ENROLLMENT  
 
Subjects will be recruited through advertising by flyers and printed announcements 
posted within as well as outside of our Partners community. In addition, email, web and 
bulletin board announcements posted in the community will be used. We will also use the 
Partners’ RSVP for Health system, Partners Clinical Trials, as well as ResearchMatch, a 
database of research volunteers developed by Vanderbilt University and approved for use 
by the PHRC. In addition, methods that advertise the study to the greater community will 
be used such as social media posts, posting flyers on community billboards in the greater 
Boston area, emails to physicians and family medicine centers, and advertisements in 
newspapers etc. will be adopted. Advertisements will briefly describe the study and invite 
subjects to call if they are interested. All subjects will undergo a telephone screening to 
attempt to distinguish potential subjects from those not meeting eligibility criteria. 
Informed consent will be obtained from all subjects before initiating any study 
procedures at study visit #1 (Behavioral visit). 
 
During screening, potential participants will be fully informed of the purpose and 
activities involved in the research study. Interested subjects will be scheduled for an in-
person visit where written informed consent will be immediately obtained, prior to 
initiating any of the study procedures. One copy of the signed consent form will be given 
to the patient and one will be kept in the study files for documentation. No time limits 


 
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will be imposed on the informed consent process. Participants will be permitted to take as 
much time as they desire to engage in the informed consent process; any and all of their 
questions will be answered. It is anticipated that obtaining written informed consent will 
take approximately 15-25 minutes, on average. Comprehension of the consent 
information will be assessed via solicitation of answers to questions throughout the 
process. If comprehension appears to be limited, participants will be actively queried to 
determine whether they need further explanation.  
 
A physician member of the staff will obtain informed consent, as in all other protocols 
involving [11C]PBR28 PET/MR scanning (e.g., 2011P002311). 
 
 
STUDY PROCEDURES 
 
After a behavioral visit aimed at determining eligibility, subjects will be scheduled for 
their first imaging visit, during which they will undergo a simultaneous MR-PET scan. At 
this visit, subjects will receive CBD. During the drug trial period, subjects will also be 
sent a daily survey to assess the treatment effect of the medication on their pain. As soon 
as possible after the end of the 4-week drug trial period, all subjects will be scanned 
again.  
 
Investigational Agent 
Epidiolex, an agent within the anti-epileptic drug class, will be used. Epidiolex, 
Greenwich Biosciences Inc.’s CBD formulation, is a 100 mg/mL purified oral solution, 
dissolved in the excipients sesame oil and anhydrous ethanol with added sweetener 
(sucralose) and strawberry flavoring. The drug is formulated from extracts prepared from 
Cannabis sativa L. plants that have a defined chemical profile and contain consistent 
levels of CBD as the principal phytocannabinoid. Extracts from these plants are 
processed to yield pure (>95%) CBD that typically contains less than 0.5% (w/w) THC. 
Cannabidiol is the active ingredient in Epidiolex; inactive ingredients include dehydrated 
alcohol, sesame seed oil, strawberry flavor, and sucralose. Of note, CBD has no 
psychoactive properties. The empirical formula of Epidiolex is C21H30O2 and its 
molecular weight is 314.46. The structure of CBD is provided in the figure below.  
 
 
Figure 1. Cannabidiol Structure 
 


 
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Dose and Exposure 
The recommended starting dosage is 2.5mg/kg taken twice daily (5mg/kg/day). 
Participants will follow a titration schedule, with 5 mg/kg/d in week 1, 10 mg/kg/d in 
week 2, 15 mg/kg/d in week 3, and 20 mg/kg/d in week 4. Subjects will increase to 20 
mg/kg/d on the first day of the final week of the study (week 4) and take Epidiolex at this 
dose for the remainder of this final week. If participants report AEs (tiredness, dizziness, 
not tolerating the medication well), the physician will decrease the dose by 5 mg/kg. 
Participants will be treated for 4 weeks in total. 
 
The 4-week duration of CBD administration is proposed because in the current study, we 
are investigating an endophenotype of pain- neuroinflammation- which may be detectable 
before verbal reports of pain reduction, which is notoriously noisy and susceptible to 
placebo effects. This pilot study will inform us of whether 4 weeks is enough to detect 
changes in TSPO binding that may precede verbal reports of pain reduction.   
 
Screening visit: Subjects eligible to participate will be recruited to participate in a 3-hour 
characterization session. In this session, we will obtain a signed consent form from the 
subjects, explain the procedures involved in the experiment, and administer some or all of 
the following validated assessments. We will also collect detailed contact information 
(address, social security number, medical record number) as well as collect a blood 
sample and a urine sample. Computer-based rating scales and questionnaires will be 
completed on a laptop. All assessments will be performed by fully trained study staff 
members such as post-doctoral research fellows and Clinical Research Coordinators, 
under the supervision of and periodic monitoring by the Principal Investigator (PI).  
 
Many of these assessments are already in use in one or more IRB approved protocols 
(e.g., 2011P002311). 
 
Hospital Anxiety and Depression Scale (HADS): The HADS is a 14-item self-report 
survey designed for populations with medical illness42. It does not include somatic 
symptoms, such as fatigue and sleeplessness, which may otherwise be attributable to 
pain. It asks patients to rate depression and anxiety symptom over the past week on a 4-
point Likert scale. It has been validated in several medical illness populations and has 
been used extensively in chronic pain patients. This scale will be repeated at Baseline 
scan, 2-week visit, and 4-week visit, and any significant increase will warrant clinical 
attention. If there is more than a 30% increase in symptoms of anxiety or depression, this 
will be immediately reported to the PI, who will consult with study clinicians. Clinicians 
will them determine, with the participant, whether it is in their best interest to continue 
the medication. 
 
The Pain Catastrophizing Scale (PCS): It is a 13-item self-report scale which measures 
pain-related Rumination, Magnification and Helplessness43. 
 


 
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PainDETECT44: The PainDETECT is a screening questionnaire used to estimate the 
likelihood of a neuropathic component in chronic pain. 
 
Social Provisions Scale (SPS): The social provisions scale measures the social support 
provided by the patient’s current relationships.45 
 
Snaith-Hamilton Pleasure Scale (SHAPS)46: The Snaith-Hamilton survey is a 14-item 
questionnaire designed to estimate the degree to which an individual is able to experience 
pleasure, or the anticipation of pleasure. The questionnaire assesses four domains of 
hedonic experience: interest/pastimes, social interaction, sensory experience, and 
food/drink. All items relate to daily experiences encountered by most people.  
 
Fibromyalgia Survey Questionnaire (FSQ)117: The Fibromyalgia Survey Questionnaire is 
a 5-item questionnaire that is aimed at assessing the presence of fibromyalgia, or pain 
centralization, subclinically in people who do not meet the fibromyalgia criteria. 
 
History and physical examination: an MD or NP will also collect medical history and 
perform a formal physical examination, including the recording of vital signs (heart rate, 
blood pressure, and body temperature). 
 
Suicidal Ideation. The Columbia-Suicide Severity Rating Scale (C-SSRS) (Posner et al., 
2010) will be used for prospective suicidality assessment. C-SSRS is a tool used to assess 
the lifetime suicidality of a participant and to track suicidal events through the treatment. The 
structured interview prompts recollection of suicidal ideation, including the intensity of the 
ideation, behavior and attempts with actual/potential lethality. The scale will be administered by 
study staff at the screening visit, baseline, two-week visit, and four-week visit. The C-SSRS 
“Screening/Baseline” will be collected at Screening and Baseline and the C-SSRS “since last 
visit” will be collected at subsequent visits. Participants who answer “yes” to any suicidal 
behavior questions or to suicidal ideation questions 4 or 5 on the C-SSRS during the study should 
be referred for appropriate psychiatric care. If there is more than a 30% increase in symptoms of 
anxiety or depression, this will be immediately reported to the PI, who will consult with study 
clinicians. Clinicians will then determine, with the participant, whether it is in their best interest 
to continue the medication. The decision to discontinue the participant from the study will be 
made by the PI in conjunction with clinical Co-Investigators.  
 
Safety monitoring: As participant suicidality and depression is monitored throughout the 
study with the C-SSRS and BDI questionnaires, any new or worsening expression of 
suicidal ideation or Answers of "Yes" to questions 4 or 5 on C-SSRS throughout the 
study will be evaluation by a licensed clinician member of study staff. The Standard 
Operation Procedure will be reviewed. To summarize, if any risk for self-harm or 
suicidality is identified at visit 1, visit 3, or visit 4, the research coordinators will 
immediately report this to study clinicians, who will determine whether a safety 
assessment is needed. If a clinician is needed to perform a safety assessment, study staff 
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in the Study Trax C-SSRS module. Following the initial suspicion or identification of 
self-harm and/or suicidality, a study clinician will follow up with the participant on the 
current nature of their situation, querying about any new ideation, intent, and/or plan 
since the last visit. These clinicians, along with the PI will then determine whether a 
participant can safely continue the study. If the clinicians determine that the participant 
cannot safely continue the study, the participant will be discontinued, and will be 
provided with a list of resources for follow-up care. 
 
Blood tests: a trained member of the study staff will draw venous blood (up to 10 ml) 
from all subjects in order to have them genotyped for the Ala147Thr TSPO 
polymorphism in the TSPO gene (rs6971) (unless this genotype information is already 
available), and to check liver enzyme values. Additionally, during screening for 
eligibility, we will conduct routine chemistry and LFT/GGT. We will obtain serum 
transaminases (ALT and AST) and total bilirubin levels in all patients prior to starting 
treatment with CBD.  
 
While [11C]PBR28 has the advantage of binding to the TSPO protein with a higher ratio 
of specific-to-nonspecific binding than [11C](R)PK1119547, it also presents a potential 
limitation, in that about 10% of human subjects show no binding to PBR2848 (whereas  
[11C](R)-PK11195 has never been associated with non-binding49). A recent study has 
demonstrated that the rs6971 polymorphism predicts PBR28 binding affinity in human 
platelets50. Since the low-affinity binder phenotype is consistent across all tissues within 
the same subject 49, testing for the Ala147Thr polymorphism has been suggested to 
predict low affinity for [11C]PBR28 in all organs, including the brain. High or Mixed 
affinity binders (Ala/Ala or Ala/Thr) will be considered eligible, whereas the Low 
affinity binders (Thr/Thr) will be considered ineligible for the research study. The MGH 
lab responsible for genotyping typically runs the genotyping assay only twice per month, 
requiring that we normally schedule screening and scanning visits approximately two 
weeks apart.  
 
An additional 10 mL of venous blood will be collected and stored for future 
investigations on the roles of genetic, molecular, and cellular factors in pain disorders. 
This will include the future possibility to generate induced pluripotent stem cells (iPSCs) 
from peripheral blood mononuclear cells51-53 to assess in-vitro alterations in patient-
derived neural or glial cells54,55.  
 
Urine drug test: We will also perform a urine test to screen for use of opioids and illicit 
drugs (including amphetamine, barbiturates, cocaine, marijuana, etc.). The urine drug 
screen will be performed during the screening visit. A rapid urine drug screening that 
utilizes monoclonal antibodies to detect elevated levels of specific drugs in urine, will be 
used for this purpose. Results will be read five minutes after the test was started.  
 
 


 
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MR-PET visits 
 
Participants eligible to continue into the study based on the screening visit and initial 
blood test will be asked to participate in a first MR-PET visit.  
 
Prior to each scan session, subjects will complete screening checklists for MRI and PET. 
These checklists will ask the patients whether they have any contraindications for MR or 
PET scanning. Female participants of childbearing age will be asked to have ~3mL of 
their blood drawn in order to perform a serum pregnancy test on the day of the scan 
(blood will be sent to the core lab for super stat testing). 
 
At the beginning of the scan session, an intravenous catheter will be placed in the 
participant’s antecubital vein of the left or right arm, prior to going to the scanning area. 
Up to 15mL of blood will be drawn to assess the levels of various substances in the 
blood, such as the proinflammatory cytokines IL-6 and TNF-alpha. Blood will be 
collected in various vials (e.g., purple top K3EDTA).  
 
Subjects will be instructed to remain still, with eyes open, for the total duration of the 
scans, except when prompted to express various ratings (e.g., pain intensity, 
unpleasantness, anxiety). The radioligand [11C]PBR28 will used to determine whether 
patients with chronic pain exhibit evidence of microglial activation.  
 
During the scan visit, subjects will be asked to complete the BPI, BDI and PROMIS-29 
assessments. 
 
Brief Pain Inventory (BPI): The BPI is a 15-item questionnaire assessing pain location, 
and 0–10 ratings of pain intensity, relief, quality, pain-related quality of life, and 
function. It has been validated in cancer and noncancer pain conditions56. 
 
Beck Depression Inventory (BDI): The 21-item BDI has shown good sensitivity and 
specificity for major depression in chronic pain patients. 
 
Patient Reported Outcomes Measurement Information System (PROMIS-29) 
questionnaire57: The PROMIS-29 is a 29-item self-report measure assessing physical, 
mental, and social health. 
 
The total duration of each scanning visit will be approximately 4 hours (and up to 6 
hours) (~45min for preparation, ~120 min for scanning procedures and ~60min for filling 
out questionnaires and observation, plus an additional ~90min to perform pregnancy test 
in women of childbearing age). In case of equipment failure (e.g., failure in 
radiosynthesis) delays of  > 2 hours may be possible. In this case, we will ask the 
participant if he or she feels comfortable with staying longer than anticipated, or will 
prefer reschedule to another date. 
 


 
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Depending on the patients’ level of discomfort and time constraints, we may occasionally 
shorten and simplify the scan visits. For instance, if the participant would feel too 
uncomfortable to lay down in the scanner for the full ~2:00 hours of scanning, we may 
administer the radioligand in the injection room and then scan the participant between 45 
and 90 minutes post-injection. 
 
The imaging visit, including all the procedures described above, will be repeated a 
second time after a 4-week trial of CBD.  
 
Drug Administration Protocol 
Following the behavioral visit, subjects will receive CBD. They will be instructed to take 
2.5mg/kg twice daily (5mg/kg/day). Participants will follow a titration schedule, with 5 
mg/kg/d in week 1, 10 mg/kg/d in week 2, 15 mg/kg/d in week 3, and 20 mg/kg/d in 
week 4. Subjects will increase to 20 mg/kg/d on the first day of the final week of the 
study (week 4) and take Epidiolex at this dose for the remainder of this final week. If 
participants report AEs (tiredness, dizziness, not tolerating the medication well), the 
physician will decrease the dose by 5 mg/kg. Participants will be treated for 4 weeks in 
total. Chronic CBD dosing up to 1500 mg/day has been reported to be tolerated well 
without AEs 58-61; minor AEs were reported after CBD use in children with epilepsy 
being treated with multiple other medications in doses up to 50 mg/kg/day62,63. 
Accordingly, we believe an upper limit of 20 mg/kg/day orally is reasonable and safe.  
 
Continuation of medication (e.g., NSAIDS) will be permitted on the condition that 
patients will be on a stable dose for at least 1 month before the baseline MR-PET scan.  
 
The Research Pharmacy at Massachusetts General Hospital will prepare the CBD. The 
study drug will be labeled as Epidiolex 100 mg/mL. It will be labeled with the name of 
the sponsor, lot number, trial subject identification number, storage conditions and the 
statement “for clinical trial use only.” Each container will be labeled with a unique 
number that will be recorded by study staff at the time of administration. As soon as 
possible after the 4-week CBD period, patients will be re-scanned and/or re-evaluated 
clinically to evaluate the hypothesis that CBD reduces glial activation and pain 
symptoms. Participants will be instructed to take CBD with food, rather than in a fasted 
state, and not to take CBD concurrently with alcohol. 
 
 
Follow-up Visits 
2-Week Visit. Patients will undergo a follow-up appointment at Week 2 with a study 
clinician, where health and adverse events will be assessed, and patients will complete 
questionnaires and will be reminded to increase medication dose. Participant may receive 
a ride to and from the study visit if requested.  
 


 
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4-Week Visit. Patients will undergo a second follow-up appointment immediately after 
the four-week treatment period with a study clinician, where we will assess back pain, 
general health, and adverse events. On the same day or as close as possible depending on 
scheduling, patients will be re-scanned, using identical protocols, to evaluate the 
hypothesis that CBD reduces glial activation. We will also repeat the questionnaires 
administered during the baseline visit to assess any changes in subjective pain. While this 
study is focused on mechanisms, and is not powered to detect a clinical effect, collecting 
pain scores will allow us to start evaluating the potential clinical significance of any 
reductions in neuroinflammation we will observe, and also provide important preliminary 
data for a subsequent clinical trial focused on efficacy. We will also take a small sample 
of blood for a follow-up liver function test. Participant may receive a ride to and from the 
study visit if requested. 
 
6-Week Call. We will conduct a follow-up call 2 weeks after the discontinuation of the 
study medication. In this call, we will assess back pain, general health and adverse 
events. 
 
 
 
DATA ACQUISITION AND ANALYSES 
 
MR-PET scanning will be performed at 3 Tesla, using Siemens TIM Trio whole-body 
MRI with head PET camera, and/or Siemens Verio whole-body MRI, whole-body PET 
camera (Biograph mMR).  
 
PET 
During each visit, [11C]PBR28 (up to 15 mCi, corresponding to ~3.7mSv) will be injected 
intravenously with a slow bolus over a 30-60s period64. This dose is compatible with a 
longitudinal study, because the total radiation of maximum ~7.4mSv received by the 
subjects participating in two scans will be significantly less than the maximum allowed 
annual whole-body dose set by the U.S. Food and Drug Administration at 5 REM, i.e., 
50mSv). The catheter will be flushed post-injection with 0.9% saline solution. Dynamic 
data will be collected over ~120 minutes in list mode, and framed post-collection. 
Regional uptake of the tracer will be estimated as SUV, SUVR, Vt and/or DVR.  
 
In addition, participants will be asked if they are willing to undergo spinal cord PET 
imaging, which will take ~20-30 minutes extra in the PET scanner at the end of the 90 
minutes post-injection. This will not add significant risk, as it will not require extra 
injection.  
 
MRI 
MRI data will be acquired simultaneously to the PET data, and may include some or all 
of these standard sequences:  BOLD fMRI (e.g., for functional connectivity analyses, to 


 
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estimate motion parameters), Diffusion-Spectrum or Diffusion-Tensor Imaging volumes 
(DSI) (to perform tractography analyses); Chemical shift imaging (to estimate brain 
metabolites); a high resolution structural volume (for anatomical reference, cortical 
reconstruction, volumetric segmentation, and attenuation correction); in addition to 
various T1 and T2 weighted structural volumes.  
 
We may collect a 6-minute resting-state connectivity functional MRI scan. The additional 
MR sequences are only collected when all the core MRI data have been completed early, 
and the patient still needs to remain in the scanner to complete data acquisition. As 
mentioned before, this is an integrated PET/MR study, the MRI (including fMRI) data is 
collected throughout the PET data acquisition, and as such the participant needs to stay in 
the scanner for the 90 minutes to complete the brain scan. Therefore these additional MR 
sequences will not affect the duration of the scan. This additional data will be used for 
ancillary analyses.  
 
Behavioral measures 
Before, during and after the scans, subjects may be asked (either verbally, or using a 
button box connected to a computer) to express various behavioral ratings, including pain 
intensity, unpleasantness, and anxiety.  
 
 
BIOSTATISTICAL ANALYSES 
 
If time allows, we may collect resting-state fMRI scans. This will only be collected if  
core MRI data have been completed early, and the patient still needs to remain in the 
scanner to complete data acquisition. Therefore, the resting state fMRI will not affect the 
duration of the scan. All fMRI data will be stored on hard drive and storage clusters. 
Behavioral data will be recorded and stored in RedCap in preparation for statistical 
analyses.  
 
In order to address our aim (‘Assess the effect of CBD on glial activation and pain), we 
will perform paired t-tests in cLBP patients before vs after receiving CBD. We will also 
perform an ANOVA including age and sex as covariates of no interest. Additionally, 
secondary regression analyses will be performed in order to evaluate the association 
between imaging and behavioral data (e.g., questionnaire scores, pain duration, etc). For 
the exploratory assessment of the relationship between imaging and pain measures, we 
will use multiple regression analysis. We will use a thalamus-targeted region of interest 
analysis, in which mean SUVRs will be extracted from the voxels within the right and 
left thalamus labels of the Harvard-Oxford Subcortical Structural Atlas and will be 
correlated with differences in clinical pain scores from baseline to Week 4. To be 
consistent in our use of non-parametric methods, we will use a non-parametric regression 
method, Generalized Additive Models. We will compute residuals adjusting for the effect 
of genotype. The Ala147Thr polymorphism in the TSPO gene predicts binding affinity 


 
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for 11C-PBR28, with the Ala/Ala, Ala/Thr and Thr/Thr genotypes being associated with 
high, mixed and low affinity binding, respectively. For all analyses, we will adjust for the 
TSPO polymorphism. 
 
Since the analysis plan requires a pre- and post-scan, we will not include patients with 
only one scan in the analysis for this pilot study. If the pilot study warrants a larger trial, 
we will use likelihood based mixed models to produce unbiased estimates of effects in the 
presence of missing data.   
 
These analyses will be performed voxelwise for the brain data, using methods similar or 
identical to those we have previously used36, as well for spinal cord data using methods 
developed by Dr. Cohen-Adad65. In addition to these voxelwise analyses, for the spinal 
cord we will perform region-of-interest (ROI) analyses focused on the spinal cord 
segments contained in the T11-L1 vertebral levels (as these contain the lower 
lumbar/upper sacral spinal cord segments).  
 
All voxelwise analyses will be conducted using the FSL suite66 for the brain, and using 
the Spinal Cord Toolbox65 for the spinal cord. Group comparisons maps will be 
thresholded using threshold-free cluster enhancement67, and a corrected threshold of 
p=0.05. All behavioral, demographic and ROI data will be analyzed using Statistica 10.0 
(StatSoft Inc., USA), and an alpha level of 0.05.  
 
Consideration of sex as a biological variable 
 In addition to the aforementioned analyses, the effect of sex will be evaluated using 
ANOVAs, because animal research suggests the presence of a possible sexual 
dimorphism in the role of glia in pain (as pain hypersensitivity may be microglial-
dependent only in males68). The effect of menstrual cycle status will also be evaluated by 
comparing women in early follicular (day 2-7 after onset of menses) and midluteal (day 
20-25 after onset of menses), based on self-report69. 
 
 
POWER ANALYSIS 
 
The purpose of this pilot study is to collect data to adequately power a placebo-
controlled trial. The sample size proposed in this study, n = 20, is similar to other 
cohorts in the PET literature. Most similar to our study is a report in Brain by Loggia et 
al that showed significant reductions in TSPO binding between 10 chronic back pain 
patients and 9 healthy controls (Loggia, 2015). This is not a fully-powered trial. If we 
see a trend toward reduction in TSPO, this will warrant a fully-powered, placebo-
controlled trial, for which an adequate sample size will be calculated.  We will have 
dual criteria by which we will consider a trend-level effect to be worthy of 
consideration of applying for funding to support a larger placebo-controlled trial.  If we 
either (1) observe a TSPO reduction in binding of 5-10% on average from post to pre-


 
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CBD, or (2) observe a clear and consistent reduction in TSPO binding in those patients 
who also report pain reductions, we will consider this a trend worth pursuit. 
 
 
RISKS AND DISCOMFORTS 
 
All subjects will undergo a telephone or email screening to attempt to distinguish 
potential subjects from those not meeting eligibility criteria. Likely candidates will 
undergo a characterization and training session, which will include a clinical screening 
procedure. This procedure will involve answering questions about subjects’ medical 
history recording of medical history review and answering questions about their medical 
situation including liver disease, kidney disease, blood disorders, heart disease, alcohol 
and opioid use, high blood pressure, asthma and other respiratory disorders. 
 
PET/MR Procedure: The U.S. Food and Drug Administration (FDA) recently gave the 
first regulatory clearance of a hybrid PET/MRI scanner in the U.S. Additionally, FDA 
considers investigations of MRI software and hardware operating within FDA specific 
parameters as non-significant risk device studies. All studies will adhere to these FDA 
approved safety levels for the Siemens system. These safety parameters include static 
magnetic field, time varying magnetic fields (dB/dt), specific absorption rate (SAR), and 
acoustic noise levels. Subjects will be informed about minimal risks of routine high 
magnetic field and non-ionizing RF radiation involved in MR imaging.  
 
 
 
 
 
Subjects will also be informed about the PET procedure and the minor risks associated 
with exposure to radiation. Subjects will also be informed about small space within the 
magnet and noises made by switching gradients. Subjects will be informed that if they 
feel uncomfortable with the study, they can choose to terminate the study at any 
time.  They will be informed that their refusal to participate in the study or choosing to 
terminate it at some point will have no effect on care and treatment received by them at 
MGH now or in future.  The subjects will be informed that their personal information will 
be protected as per the HIPAA guidelines.  
 
Intravenous catheter: An intravenous catheter will be placed for this study. The subject 
will feel a slight pinprick, similar to a bee sting, and may feel some discomfort and have 
some bruising or bleeding at the site where the needle goes in. Depending on the length 
of time the catheter is in place, a bruise may last for a day or so. Rarely an infection may 
occur at this site.  If infection does occur, it will be treated. About 24 hours after the 
beginning of the imaging procedures, we will give the subject a phone call to determine 
whether he or she is experiencing study related issues. 
 
Radiation exposure: The radiation exposure in this study will be small and there is no 
evidence that it represents a major health risk.  If subjects have participated in other 
research studies in the past 12 months that have involved radiation exposure, they will be 


 
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asked to inform the investigators or study staff (by writing initials on the consent form 
verifying that they have not been exposed to other radiation in the past 12 months).  If it 
is determined that their prior radiation exposure exceeds our current guidelines, they may 
not be allowed to participate in this study.   
 
We will use [11C]PBR28 produced by the cyclotron/radiochemistry/radiopharmacy 
facility at the A. A. Martinos Center for Biomedical Imaging. The Martinos Center has 
studied several hundreds of people with this radioligand and have had no clinically 
detectable effects or side effects. Given the use of [11C]PBR28 in a small clinical trial, we 
are in the process of requesting an IND from the FDA. 
 
The IV injection will be administered by a licensed nuclear medicine technologist. 
Should there be an adverse event, Dr. Gilman will be responsible for communicating with 
the IRB within the stipulated time frame. 
 
Imaging will be stopped should any untoward reaction be observed during the imaging 
session or if the participant so requests for whatever reason. Some subjects find it 
unpleasant or feel anxious when confined in the enclosed space of the scanner. If this 
happens, the study will be aborted. Patients will be required to use earplugs to decrease 
the noise perceived while in the scanner. 
 
EPIDIOLEX (CBD): CBD is an FDA approved medication used to treat epilepsy. 
According to the FDA briefing document on Epidiolex, dated 04/19/2018, treatment-
emergent AEs in controlled trials for Lennox-Gastaut and Dravet syndromes included 
decreased appetite, diarrhea, irritability, somnolence, fatigue, aggression, pneumonia, 
rash, and hepatic symptoms, and in a very small number of patients, an increase in 
suicidal thoughts. Of note, AE related to hepatic function were likely due to the 
interaction between CBD and anti-epileptic drugs; prescription of an anti-epileptic drug is 
an exclusionary criterion for this proposed study. Further, CBD may produce 
pharmacokinetic interaction effects when taken with opioids (Benowitz et al., 1980; 
Kotlinska-Lemieszek et al., 2015). Any subjects who at baseline had elevated AST/ALT 
levels but still met the eligibility criteria for the study will undergo a follow-up liver 
function tests at 2 weeks. In addition, we will perform a liver function test in subjects 
who at any time point during the study develop clinical signs or symptoms suggestive of 
hepatic dysfunction. 
 
Given the use of EPIDIOLEX in a small clinical trial, we are in the process of requesting 
an IND (or an IND exemption) from the FDA. 
 
Questionnaires: Minimal risks associated with completing questionnaires are subject 
fatigue and the possibility of minor psychological distress associated with answering 
sensitive questions regarding psychological functioning. Subjects will be instructed to 
complete the questionnaires to the best of their ability, but will have the option to leave 


 
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any question(s) blank. In the unlikely event that evidence of physical or psychological 
disorder is found, with the individual's permission, the information will be shared with 
his or her primary care physician who can direct care as needed.  
 
Confidentiality: As detailed, the investigators are quite careful regarding the protection 
of confidentiality, and multiple procedures are in place to reduce the likelihood of a 
breach of confidentiality. However, there is a small risk that information about subjects 
could become known to people outside of this study, and this risk is identified in the 
informed consent form. 
 
The key investigators will meet quarterly to discuss any potential adverse event and side 
effects. We will involve the MGH Human Research Committee and Radiation Safety 
Committee if any additional potential risks arise. Adverse events and unanticipated 
problems involving risks to subjects or others will be reported to the PHRC in accordance 
with PHRC adverse event and unanticipated problems reporting guidelines, as well as 
FDA when appropriate. 
 
 
POTENTIAL BENEFITS: 
 
It is unlikely that individual subjects will benefit from taking part in this study. While this 
study is powered to possibly observe a statistically significant reduction in pain due to 
CBD, it is unclear whether the effect will be clinically meaningful. However, findings 
from these studies will help advance our understanding of the pathophysiology of pain 
disorders. In particular, this project will assess the role of microglia in the establishment 
and/or maintenance of chronic pain, and how this may be affected by CBD. 
 
 
REMUNERATION: 
 
Subjects will be paid by check at the completion of the study for their participation. 
 
We will pay up to $525. Payments will be as follows: 
 
- 
$75 for the initial behavioral session (Visit 1) 
- 
$50 for completing daily surveys 
- 
$200 for each MR-PET scanning visit 
 
If during the imaging visit(s) we cannot inject the subject with the radioligand (e.g., due 
to a failure in radiosynthesis, or to issues with the scanner) he/she will receive $50. 
 
If the subject will need to stop the scan early for any reason, he/she will still receive $50 
for his/her time. Additionally, parking fees will be covered as needed.  


 
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MONITORING AND QA 
 
The proposed study will be monitored for safety, with monthly staff meetings reviewing 
adverse events and treatment outcomes and directly reporting any adverse events. The PI 
will also routinely monitor and assure the validity and integrity of collected data and 
adherence to the IRB-approved protocol. The trained staff members who carry out the 
procedures will also carefully monitor the study throughout its duration. The team will 
evaluate the progress of the study, verify that the rights and well-being of the subjects are 
protected, verify that the reported study data are accurate, complete and verifiable from 
source documents, and the conduct of the study is in compliance with the approved 
protocol and amendments. Outcome monitoring and adverse events will all be reported 
through appropriate channels of the Human Studies Committee as well to the FDA when 
appropriate. 
 
If a patient develops clinical signs or symptoms suggestive of hepatic dysfunction (e.g., 
unexplained nausea, vomiting, right upper quadrant abdominal pain, fatigue, anorexia, or 
jaundice and/or dark urine), we will promptly measure serum transaminases and total 
bilirubin and interrupt or discontinue treatment with EPIDIOLEX, as appropriate. We 
will discontinue EPIDIOLEX in any patients with elevations of transaminase levels 
greater than 3 times the ULN and bilirubin levels greater than 2 times the ULN. Our 
physician monitoring group (Drs. Mao, Zhang, Schnitzer, and Evins) will consider 
stopping the study if back pain becomes significantly worse in 3 or more patients. If 
serum liver enzyme concentrations are significantly elevated (with elevations of 
transaminase levels greater than 3 times the ULN and bilirubin levels greater than 2 times 
the ULN) in 2 or more patients, which will be considered serious adverse events, the 
study will be stopped.  In addition, if two or more patients experience any serious adverse 
event, the study will be stopped. 
 
The Siemens MR-PET scanners have a built-in self-monitoring system that automatically 
shuts off if parameters exceed safe levels.  For backup protection NMR technicians 
constantly monitor the subjects’ physiological signs and the quality of the raw data. 
 
Quality assurance of the scanner’s performance is obtained by a daily quality assurance 
protocol.  More extensive quality assurance protocols are performed monthly under the 
commercial service contract with Siemens Medical Systems.  The daily quality assurance 
protocol consists of an image Signal-to-Noise measurement in a phantom and a stability 
run which checks the image-to-image variation in image intensity over 600 images using 
a standard echoplanar imaging sequence with a head-sized phantom.  The images are 
analyzed by the technologist to provide data on SNR (as an absolute, unitless number) 


 
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and stability expressed as the peak-to-peak variation in the mean of a 15x15 pixel region 
of interest (ROI) in the center of the phantom expressed as a percentage of the mean of 
the ROI.  Runs are performed at each of 3 TR values (300ms, 800ms, 1300ms).  The time 
course of the means is also reviewed to check for periodicities (the TR values are chosen 
so as not to be multiples of one another).  If the peak-to-peak variation is greater than 
0.5% of the mean value, the Siemens Medical System service engineer is called.   In 
addition to these daily quality assurance tests, the Siemens Medical System service 
engineer performs quality assurance tests once a month.  These tests include a SNR test, a 
small sample stability test, a gradient stability test, a gradient eddy current test, a shim 
test, an image uniformity test, and an RF stability test. 
 


 
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21-47, doi:10.1146/annurev-psych-113011-143739 (2013). 
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Ehrhart, J. et al. Stimulation of cannabinoid receptor 2 (CB2) suppresses microglial activation. J 
Neuroinflammation 2, 29, doi:10.1186/1742-2094-2-29 (2005). 
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Zigmond, A. S. & Snaith, R. P. The hospital anxiety and depression scale. Acta Psychiatr Scand 
67, 361-370 (1983). 
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Sullivan, M. J., Bishop, S. R. & Pivik, J. The Pain Catastrophizing Scale: Development and 
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Freynhagen, R., Baron, R., Gockel, U. & Tolle, T. R. painDETECT: a new screening 
questionnaire to identify neuropathic components in patients with back pain. Current medical 
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Cutrona, C. E. & Russell, D. W. The provisions of social relationships and adaptation to stress. 
Advances in personal relationships 1, 37-67 (1987). 
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Snaith, R. P. et al. A scale for the assessment of hedonic tone the Snaith-Hamilton Pleasure Scale. 
The British journal of psychiatry : the journal of mental science 167, 99-103 (1995). 
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Imaizumi, M. et al. Brain and whole-body imaging in nonhuman primates of [11C]PBR28, a 
promising PET radioligand for peripheral benzodiazepine receptors. Neuroimage 39, 1289-1298 
(2008). 
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Brown, A. K. et al. Radiation dosimetry and biodistribution in monkey and man of 11C-PBR28: a 
PET radioligand to image inflammation. J Nucl Med 48, 2072-2079, 
doi:10.2967/jnumed.107.044842 (2007). 
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Kreisl, W. C. et al. Comparison of [(11)C]-(R)-PK 11195 and [(11)C]PBR28, two radioligands for 
translocator protein (18 kDa) in human and monkey: Implications for positron emission 
tomographic imaging of this inflammation biomarker. Neuroimage 49, 2924-2932 (2010). 
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Owen, D. R. et al. An 18kDa Translocator Protein (TSPO) polymorphism explains differences in 
binding affinity of the PET radioligand PBR28. Journal of Cerebral Blood Flow and Metabolism 
(in press). 
51 
Lee, H. K., Morin, P. & Xia, W. Peripheral blood mononuclear cell-converted induced pluripotent 
stem cells (iPSCs) from an early onset Alzheimer's patient. Stem Cell Res 16, 213-215, 
doi:10.1016/j.scr.2015.12.050 (2016). 
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Agu, C. A. et al. Successful Generation of Human Induced Pluripotent Stem Cell Lines from 
Blood Samples Held at Room Temperature for up to 48 hr. Stem Cell Reports 5, 660-671, 
doi:10.1016/j.stemcr.2015.08.012 (2015). 
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Lee, H. K., Morin, P., Wells, J., Hanlon, E. B. & Xia, W. Induced pluripotent stem cells (iPSCs) 
derived from frontotemporal dementia patient's peripheral blood mononuclear cells. Stem Cell Res 
15, 325-327, doi:10.1016/j.scr.2015.07.004 (2015). 
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Wainger, B. J. et al. Modeling pain in vitro using nociceptor neurons reprogrammed from 
fibroblasts. Nat. Neurosci. 18, 17-24, doi:10.1038/nn.3886 (2015). 
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Wainger, B. J. et al. Intrinsic membrane hyperexcitability of amyotrophic lateral sclerosis patient-
derived motor neurons. Cell reports 7, 1-11, doi:10.1016/j.celrep.2014.03.019 (2014). 
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Tan, G., Jensen, M. P., Thornby, J. I. & Shanti, B. F. Validation of the Brief Pain Inventory for 
chronic nonmalignant pain. J Pain 5, 133-137, doi:10.1016/j.jpain.2003.12.005 (2004). 
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Hinchcliff, M. et al. Validity of two new patient-reported outcome measures in systemic sclerosis: 
Patient-Reported Outcomes Measurement Information System 29-item Health Profile and 
Functional Assessment of Chronic Illness Therapy-Dyspnea short form. Arthritis care & research 
63, 1620-1628, doi:10.1002/acr.20591 (2011). 
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Chiang, C. N. & Rapaka, R. S. Pharmacokinetics and disposition of cannabinoids. NIDA research 
monograph 79, 173-188 (1987). 
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Huestis, M. A. Pharmacokinetics and metabolism of the plant cannabinoids, delta9-
tetrahydrocannabinol, cannabidiol and cannabinol. Handbook of experimental pharmacology, 657-
690 (2005). 
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Deiana, S. et al. Plasma and brain pharmacokinetic profile of cannabidiol (CBD), cannabidivarine 
(CBDV), Delta(9)-tetrahydrocannabivarin (THCV) and cannabigerol (CBG) in rats and mice 
following oral and intraperitoneal administration and CBD action on obsessive-compulsive 
behaviour. Psychopharmacology 219, 859-873, doi:10.1007/s00213-011-2415-0 (2012). 
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Ujvary, I. & Hanus, L. Human metabolites of cannabidiol: A review on their formation, biological 
activity, and relevance in therapy. Cannabis and cannabinoid research 1, 90-101, 
doi:10.1089/can.2015.0012 (2016). 
62 
Devinsky, O. et al. Trial of cannabidiol for drug-resistant seizures in the Dravet syndrome. The 
New England journal of medicine 376, 2011-2020, doi:10.1056/NEJMoa1611618 (2017). 


 
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Devinsky, O. et al. Cannabidiol in patients with treatment-resistant epilepsy: an open-label 
interventional trial. The Lancet. Neurology 15, 270-278, doi:10.1016/s1474-4422(15)00379-8 
(2016). 
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Debruyne, J. C. et al. PET visualization of microglia in multiple sclerosis patients using 
[11C]PK11195. Eur J Neurol 10, 257-264 (2003). 
65 
Cohen-Adad, J. et al. in Proceedings of the 20th Annual Meeting of OHBM    3633 (Hamburg, 
Germany, 2014). 
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primer with examples. Hum. Brain Mapp. 15, 1-25 (2002). 
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Smith, S. M. & Nichols, T. E. Threshold-free cluster enhancement: addressing problems of 
smoothing, threshold dependence and localisation in cluster inference. Neuroimage 44, 83-98, 
doi:10.1016/j.neuroimage.2008.03.061 (2009). 
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Sorge, R. E. et al. Different immune cells mediate mechanical pain hypersensitivity in male and 
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Chung, K. C. et al. The Influence of Menstrual Cycle and Androstadienone on Female Stress 
Reactions: An fMRI Study. Front Hum Neurosci 10, 44, doi:10.3389/fnhum.2016.00044 (2016). 
 

ICF_001.pdf: 
Informed Consent  
 
Investigation of Cannabidiol for Reduction of NeuroInflammation  
in Chronic Back Pain 
 
NCT # NCT03891264 
11/12/2020 
  
 


Partners HealthCare System 
Research Consent Form 
 
 
 
Certificate of Confidentiality Template 
Version Date: January 2019 
 
 
 
Page 1 of 19 
 
 
Subject Identification 
 
Protocol Title: Investigation of Cannabidiol for Reduction of 
NeuroInflammation in Chronic Back Pain 
 
Principal Investigator: Jodi Gilman, PhD 
 
Site Principal Investigator:       
 
Description of Subject Population: Adults with Chronic Low Back Pain  
 
 
About this consent form 
 
Please read this form carefully.  It tells you important information about a research study.  A 
member of our research team will also talk to you about taking part in this research study.  
People who agree to take part in research studies are called “subjects.”  This term will be used 
throughout this consent form.  
 
Partners HealthCare System is made up of Partners hospitals, health care providers, and 
researchers.  In the rest of this consent form, we refer to the Partners system simply as 
“Partners.” 
 
If you decide to take part in this research study, you must sign this form to show that you want to 
take part.  We will give you a signed copy of this form to keep.
 
 
Key Information 
 
Taking part in this research study is up to you.  You can decide not to take part.  If you decide to 
take part now, you can change your mind and drop out later.  Your decision won’t change the 
medical care you get within Partners now or in the future.   
 
The following key information is to help you decide whether or not to take part in this research 
study.  We have included more details about the research in the Detailed Information section that 
follows the key information.  
 
 
 


Partners HealthCare System 
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Version Date: January 2019 
 
 
 
 
Page 2 of 19 
Subject Identification 
Why is this research study being done? 
 
The goal of this research study is to identify whether cannabidiol (CBD) reduces activation of 
glial cells, which are the immune cells of the nervous system. Cannabidiol is a naturally 
occurring compound found in cannabis plant, and is considered to be a safe, non-addictive 
substance. We are also looking to find out whether CBD may reduce symptoms of low back 
pain. This is not a treatment study.  
 
How long will you take part in this research study? 
 
If you decide to join this research study, it will take you about 4-6 weeks to complete the study. 
During this time, we will ask you to make 2 imaging visits to MGH Charlestown Navy Yard 
campus and 2 office visits to 101 Merrimac Street. 
 
What will happen if you take part in this research study? 
 
If you choose to take part in this study, you will come to MGH for a 3-hour screening visit, 
which will include a blood test, a urine test, and a physical exam. Depending on the results of the 
initial screening visit, you might be eligible to participate in up to 2 imaging visits. As part of the 
study, we are using a machine which combines Magnetic Resonance Imaging (MRI) and 
Positron Emission Tomography (PET) into one device. The MRI part of it uses a powerful 
magnet to make a picture of the body, while the PET part of it makes pictures by using special 
dyes with a small dose of radioactivity attached to them that “light up” inside the body. 
 
To study the effect of CBD, you will be asked to take a medication called EPIDIOLEX for 4 
weeks after the first imaging visit. EPIDIOLEX is a liquid formaulation of CBD. A doctor will 
talk to you about how much to take. You will be treated with CBD for 4 weeks in total. You will 
have 1 imaging visit before taking CBD, and a second after taking CBD for 4 weeks, so we can 
compare glial cell activation. 
 
Why might you choose to take part in this study? 
 
We cannot promise any benefits to you from taking part in this research study. However, 
possible benefits may include a reduction in pain while taking the drug.  Others with chronic 
back pain may benefit in the future from what we learn in this study. 
 
Why might you choose NOT to take part in this study? 
 
Taking part in this research study has some risks and requirements that you should consider 
carefully.   


Partners HealthCare System 
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Subject Identification 
 
Important risks and possible discomforts from CBD include sleepiness, decreased appetite, 
diarrhea, lack of energy), and risks of PET/MRI scans (radiation exposure). CBD may cause an 
increase in suicidal thoughts or actions in a very small number of people. It is possible that 
patients taking EPIDIOLEX may test positive on a cannabis drug screen. 
 
A detailed description of side effects, risks, and possible discomforts can be found later in this 
consent form in the section called “What are the risks and possible discomforts from being in this 
research study?” 
 
Other things to consider are the time commitment of 4 visits, and requirements to travel to MGH.  
 
What other treatments or procedures are available for your condition? 
 
Other treatments or procedures that are available to treat chronic low back pain include: 
• Medications (e.g., non-steroidal anti-inflammatory drugs, opiates, muscle relaxants) 
• Transcutaneous electrical nerve stimulation 
• Physical exercise and stretching 
• Epidural steroid injection 
• Physical therapy 
• Back surgeries 
• Acupuncture 
 
If you have questions or concerns about this research study, whom can 
you call? 
 
You can call us with your questions or concerns.  Our telephone numbers are listed below.  Ask 
questions as often as you want.  
 
Jodi Gilman, PhD is the person in charge of this research study.  You can call her at 617-643-
7293 Monday-Friday from 9am to 5pm with questions about this research study. If you have any 
medical questions related to the study you can call Dr. Kristina Schnitzer at 617-726-2000, and 
ask for pager #27399 (24/7, for emergencies). 
 
If you have questions about the scheduling of appointments or study visits, call our study staff: 
Grace Wheeler: 
(617) 643-4692  
gwheeler@mgh.harvard.edu 
 
If you want to speak with someone not directly involved in this research study, please contact 
the Partners Human Research Committee office.  You can call them at 857-282-1900. 
 


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Subject Identification 
You can talk to them about: 
 Your rights as a research subject 
 Your concerns about the research 
 A complaint about the research 
 Any pressure to take part in, or to continue in the research study 
 
Detailed Information 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law.  This Web site will not include information that can identify you.  At most, the 
Web site will include a summary of the results.  You can search this Web site at any time. 
 
Why is this research study being done? 
 
The goal of this research study is to identify whether cannabidiol (CBD) reduces activation of 
glial cells, which are the immune cells of the nervous system. We are also looking to find out 
whether CBD may reduce symptoms of low back pain. This is not a treatment study, but rather a 
study to discover when CBD reduces neuroinflammation.  
 
CBD (in the form of EPIDIOLEX) is a prescription medicine that is used to treat seizures 
associated with Lennox-Gastaut syndrome or Dravet syndrome (rare forms of childhood 
epilepsy) in people 2 years of age and older. It is not known whether CBD is effective for 
chronic back pain. We are asking you to take part in this study because you have chronic low 
back pain lasting at least 6 months. 
 
Who will take part in this research? 
 
We are asking you to take part in this research study because you are an adult with chronic lower 
pack pain. About 20 people will take part in this research study at Massachusetts General 
Hospital. The National Institutes of Health is paying for this research study to be done. 
 
What will happen in this research study? 
 
If you choose to take part in this study, we will ask you to sign this consent form before we do 
any study procedures. 
 
A screening visit will evaluate your eligibility for the study. If you are eligible, you will be asked 
to participate in an initial brain imaging visit.  
 


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Subject Identification 
During the study, you will receive a bottle containing CBD. You will take CBD for 4 weeks in 
total, and your dose will increase each week. When you start the medication, we will ask you to 
take 2.5mg/kg twice daily (5mg/kg/day). Each week, a member of the study team will remind 
you to increase the dose by 5mg/kg/day for the following week (week 2 dose = 10mg/kg/day; 
week 3 dose = 15mg/kg/day; week 4 final dose = 20mg/kg/day). At the end of the second week, 
a study physician will meet with you (by phone or in person) to assess tolerability. If you are not 
tolerating the medication well, the physician will decrease your dose to 5 mg/kg twice daily (10 
mg/kg/day). The study physician may discontinue the medication if you do not tolerate it well. 
 
Magnetic Resonance Imaging (MRI) and Positron Emission Tomography (PET) are tests that 
allow us to take images of your brain and spinal cord. MRI uses a powerful magnet to make 
images of the body, while PET uses something called a radiotracer, that binds to the specific 
cells we are interested in viewing, and causes them to “light up” so the scanner can detect them. 
 
Screening Visit 
 
This visit will take up to 3 hours, during which you will complete some tests and procedures to 
see if you will be eligible to further participate in this study.  
 
During the visit, we may: 
 
•    Ask you questions about your health (past and present), including mental and 
emotional health.   
•    Ask you to fill out questionnaires about your pain 
• Do a physical examination.  
• Draw about 2 tablespoons of blood to assess radiotracer binding affinity. Low affinity 
for [11C]PBR28 disqualifies the subject for the research study. 
• Collect a urine sample to test for certain drugs 
 
MR-PET visits  
 
All the eligible participants will complete two MR-PET scan visits. Each MR-PET visit will last 
approximately 4 hours (and up to 6 hours). We will ask you to avoid strenuous exercise for 24 
hours before the MR-PET scan. 
 
Before the MR-PET scan, we will:  
 
• Ask you some questions about your recent health and have you fill out some 
questionnaires to make sure it is safe for you to have an MR-PET scan. 


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Subject Identification 
• Draw about 1 teaspoon of blood to test for pregnancy if you are a female who is 
able to become pregnant. Pregnant women cannot take part in this research study.  
• Measure your weight 
 
If you still qualify, we will ask you to take off anything that contains metal and change into 
hospital approved clothing. Then we will: 
 
• Place an IV catheter (a thin, flexible plastic tube with a needle attached) into a vein 
in your arm.  The IV catheter will be used to inject the radiotracer known as 
[11C]PBR28 into your body, as well as draw about 2 tablespoons of blood to assess 
the function of various organs, body systems, cells, molecules, and genes in pain 
disorders. 
 
The MR-PET Scans 
 
You will lie still in the MR-PET scanner for about 2 hours. The scanner is a tunnel.  You will lie 
on your back on a narrow table that will slide you into the tunnel. In order to help hold your head 
still, we may place foam pillows under and around your head.  
 
The top and sides of the tunnel will be close to your face and body, which can make some people 
uncomfortable. If you have ever experienced a fear of enclosed spaces (claustrophobia), please 
tell the study staff.   
 
The scanner makes loud banging and beeping noises taking images, so we will give you earplugs 
to protect your ears.  
 
First, we will take some pictures of your brain and/or whole body. Then we will inject the 
radiotracer into the IV catheter in your vein and take more images. You will not feel the radio-
tracer in your body and it will quickly leave your body through your urine. The Martinos Center 
has completed hundreds of MR-PET scans in a number of patient populations and healthy 
volunteers using [11C]PBR28. There have been no side effects associated with the administration 
of this radiotracer. This dye will travel through your blood stream, so the MR-PET scanner can 
see how the different parts of your brain and/or whole body are working.   
 
Before, during and after the scans, you may be asked to express various behavioral ratings, 
including pain intensity, unpleasantness and anxiety. 
 
After the brain scan is complete, we may collect additional 20 minutes of data from your spinal 
cord. This spinal cord imaging is optional, and will only be done if you are still comfortable in 
the scanner. After the scan is complete, you will sit up slowly and we will remove your catheter.  


Partners HealthCare System 
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Subject Identification 
 
Somebody from the study staff will call you the day following each scan to check on you. Of 
course, you can contact us at any time if you have questions (see contact information under “If I 
have questions or concerns about this research study, whom can I call?”). 
 
Daily Surveys 
 
You will be asked to fill out a daily survey for 7 days before you start taking CBD and for 4 
weeks while you are taking CBD. You will be sent a survey to complete by the end of each day. 
This survey will be sent to you via email and you will have until 11:59pm each night to complete 
the survey. The survey will take about 5 minutes to complete and will ask you about your low 
back pain symptoms.  
 
Please let the study staff know if you do not have internet access and we can arrange to call you 
to administer the survey. 
 
Follow-up Visits 
 
2-Week Visit. You will have a follow-up appointment Week 2 with a study clinician, where we 
will check on your health, remind you to increase your medication dose, and ask you to complete 
some questionnaires. We may also take a small sample of blood for a follow-up liver function 
test. As you will be taking Epidiolex daily at the time of this visit, we will ask you whether you 
can drive to the visit; if you cannot because the medication makes you drowsy, we will arrange 
transportation. 
 
4-Week Visit. You will have a second follow-up appointment immediately after the four-week 
treatment period, where we will assess back pain, general health, and adverse events. On the 
same day or as close as possible depending on scheduling, you will be re-scanned. We will also 
repeat the questionnaires administered during the baseline visit to assess any changes in 
subjective pain. We will also take a small sample of blood for a follow-up liver function test. 
Again, we will ask you whether you can drive to the visit; if you cannot because the medication 
makes you drowsy, we will arrange transportation. 
 
 
6-Week Call. You will have a follow-up phone call 2 weeks after the discontinuation of the 
study medication. In this call, we will assess back pain, general health and adverse events. 
 
Study Information Included in Your Electronic Medical Record 
 


Partners HealthCare System 
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Subject Identification 
A notation that you are taking part in this research study will be made in your electronic medical 
record. Information obtained from research related questionnaires and MR-PET scans will not be 
included in your medical record, however research results that relate to your general medical 
care may be included in your record (for example, list of allergies, results of standard blood tests 
done at the hospital labs). 
 
Whom can I contact if I want to stop taking the study drug? 
 
If you wish to stop taking the study drug, you should tell the principal investigator of this study, 
Dr. Jodi Gilman. Occasionally, Dr. Gilman and her study team may decide to have you stop 
taking the study drug or terminate your participation in the study, without your permission. This 
may happen if they think that you cannot follow the study plan or if your health is in question. 
One reason you may be asked to stop is if you are experiencing side effects from the study drug.  
 
What happens if I stop the study early? 
 
If you decide to stop participating in the study before the planned end of the study, we will ask 
that you continue to follow the schedule of visits. If you are unable or unwilling to return to the 
MGH Charlestown Navy Yard campus for visits, we will ask if we can call you for phone 
interviews instead of study visits. 
 
For what type of research will my samples be used? 
 
Your blood samples and information will be used to understand pain disorders. They will be 
coded with a study identification number that can NOT be directly traced back to you. The long-
term goal of research with your blood samples is to better understand, prevent, diagnose, and 
treat chronic pain. However, it is not possible to list every future research project that could be 
performed with these samples. Since we cannot predict all of the research questions that will be 
relevant in the future. As we learn more about the human body and the underlying mechanisms 
leading to chronic pain, there may be new types of research that can be done and new research 
questions. 
 
We may also perform limited genetic research on the deoxyribonucleic acid (DNA) from your 
samples or cell lines. DNA is the material that makes up your genes. DNA provides the 
instructions that tell our cells how to grow and function. Ribonucleic acid (RNA) is made from 
DNA, and is used to encode for proteins, the building blocks of cells. We may also perform 
genetic research by analyzing proteins that are present in differing amounts in people with pain 
disorders and thereby identifying patterns of RNA and DNA that may affect or predict the onset 
of chronic pain. Although genetic information may be analyzed, no genetic information will be 
given to you or placed in your medical records. 
 


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Subject Identification 
Do you agree to let us store your samples and health information for future genetic and cellular 
research related to chronic pain disorders? 
 
 
 Yes           
 No 
Initials___________ 
 
What researchers can use my samples and what information about me 
can they have? 
 
Your de-identified samples or cell lines may be made available broadly to researchers at 
academic institutions, and shared with for-profit companies and non-profit organizations. These 
academic institutions, companies, and organizations may be located nationally or internationally, 
and they may perform any of the research described in the previous section. Your samples will 
not be sold to anyone for profit. Blood samples may be sent to a separate location for generation 
of the iPSC lines to produce neurons and glial cells. 
 
 
How long will my samples, cell lines, and information be kept? 
 
There is no scheduled date on which your samples, cell lines and information will be destroyed.  
Your samples will be used to create living tissue samples and cell lines, which may be stored and 
used for research indefinitely. The code linking your samples and cell lines to your medical 
record may be kept indefinitely so that your samples and updated health information may be 
used for research in the future.   
 
Can I stop allowing my samples and information to be stored and used 
for research? 
 
Yes. You have a right to withdraw your permission at any time. If you do, your samples and 
information will be destroyed. However, it will not be possible to destroy samples and 
information that have already been given to researchers. If you decide to withdraw your 
permission, you should contact Dr. Gilman in writing. 
 
In order to allow researchers to share test results, the National Institutes of Health (NIH) and 
other central repositories have developed special data (information) banks that analyze data and 
collect the results of whole genome studies.  These banks may also analyze and store DNA 
samples, as well.  These central banks will store your genetic information and samples and give 
them to other researchers to do more studies.  We do not think that there will be further risks to 
your privacy and confidentiality by sharing your samples and whole genome information with 
these banks.  However, we cannot predict how genetic information will be used in the future.  
The samples and data will be sent with only your code number attached.  Your name or other 


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Subject Identification 
directly identifiable information will not be given to central banks.  There are many safeguards in 
place to protect your information and samples while they are stored in repositories and used for 
research.  
 
How may we use and share your samples and health information for 
other research?
 
The samples and information we collect in this study may help advance other research.  If you 
join this study, we may remove all information that identifies you (for example your name, 
medical record number, and date of birth) and use these de-identified samples and data in other 
research.  It won’t be possible to link the information or samples back to you.  Information 
and/or samples may be shared with investigators at our hospitals, at other academic institutions 
or at for-profit, commercial entities.  You will not be asked to provide additional informed 
consent for these uses. 
 
Will you get the results of this research study? 
 
You and your doctor should not expect to get information about the results of the research study 
or the results of your individual participation in the research study.  The researchers involved in 
this study will study samples and information from many people.  It could take many years 
before anyone knows whether the results have any meaning.  There is a small chance that 
researchers could find out something from the study that might be important to your health.  If 
this happens, we may contact you to find out if you would like to learn more.  However, even if 
we find something important to your health, we cannot guarantee that you will be contacted. 
 
What are the risks and possible discomforts from being in this research 
study? 
 
EPIDIOLEX: EPIDIOLEX is an FDA approved medication used to treat two forms of epilepsy. 
 
Common side effects: 
 
1. EPIDIOLEX may cause liver problems. As part of the study, we will collect blood to 
check your liver before you start taking EPIDIOLEX and after one month of treatment. In 
some cases, EPIDIOLEX treatment may need to be stopped. Any subjects who at 
baseline had elevated AST/ALT levels but still met the eligibility criteria for the study 
will undergo a follow-up liver function tests at 2 weeks. In addition, we will perform a 
liver function test in subjects who at any time point during the study develop clinical 
signs or symptoms suggestive of hepatic dysfunction. 


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2. EPIDIOLEX may cause you to feel sleepy, which may get better over time. Do not drive, 
operate heavy machinery, or do other dangerous activities until you know how 
EPIDIOLEX affects you.  
3. EPIDIOLEX may cause suicidal thoughts or actions in a very small number of people, 
about 1 in 500. Call a healthcare provider right away if you have any of these symptoms, 
especially if they are new, worse, or worry you: thoughts about suicide or dying, attempt 
to commit suicide, new or worse depression, new or worse anxiety, feeling agitated or 
restless, panic attacks, trouble sleeping, new or worse irritability, acting aggressive, being 
angry, or violent, acting on dangerous impulses, an extreme increase in activity and 
talking (mania), other unusual changes in behavior or mood. 
4. Other adverse reactions are: sleepiness, decreased appetite, diarrhea, lack of energy, rash, 
insomnia, poor quality sleep, and infections. 
 
Treatment with Epidiolex is contraindicated for individuals taking medications that impact 
specific CYP450 enzymes, including some CNS depressants, including all antipsychotics, 
benzodiazepines (except for alprazolam, clonazepam, and lorazepam), and non-benzodiazepine 
sleep aids including butabarbital sodium, eszopiclone, phenobarbital, ramelteon secobarbital 
sodium, suvorexant, zaleplon, and zolpidem. All medications, including but not limited to those 
mentioned, must be discussed with the study physician.  
 
It is possible that patients taking EPIDIOLEX may test positive on a cannabis drug screen. There 
may be other risks of CBD that are currently unknown at this time.  
 
Until you know how this drug affects you, please don’t drive or operate hazardous machinery, as 
this drug may cause sleepiness. Other medicines (e.g., clobazam) or alcohol may increase 
sleepiness. 
 
Epidiolex should be taken consistently with respect to meals, and should not be taken in a fasted 
state. In addition, Epidiolex should not be taken with concurrent alcohol use.  
 
We will assess suicidality, depression and anxiety throughout the study. If you report any new or 
worsening expression of suicidal ideation and or/emergent depression, you may be asked to 
speak with a licensed clinician. These clinicians, along with the PI will then determine whether a 
you can safely continue the study. If the clinicians determine that the you cannot safely continue 
the study, your participation in the study will be discontinued, and you will be provided with a 
list of resources for follow-up care. 
 
MRI: MRIs use powerful magnets to make images. There are no known radiation risks 
associated with MRI. However, persons with certain medical metal implants, such as surgical 
clips, or pacemakers should not have an MRI. All credit cards and other items with magnetic 


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strips should also be kept out of the MRI room. People who feel uncomfortable in confined 
spaces (claustrophobia) may feel uncomfortable in the narrow tube. The MRI makes loud 
banging noises as it takes images. Earplugs can be used to reduce the noises. The MRI can be 
stopped at any time at your request. If you are or suspect you are pregnant, you should not 
participate in this study. The MRI has the potential, during normal routine use, to cause localized 
warming of your skin and the underlying tissues. You should immediately inform us if you 
experience discomfort due to warming and the procedure will be stopped. 
 
Radiation Exposure: As a result of your participation in this study, you will be exposed to 
radiation from two PET scans of your brain. Please note that this radiation is not necessary 
for your medical care and is for research purposes only.  The maximum amount of radiation to 
which you could be exposed to in this study is approximately 7.4 milliSieverts (mSv).  A mSv 
is a unit of radiation dose. This amount of radiation is about the same as you would 
normally get in 2.4 years from natural background sources from the earth and the sky.  
 
Scientists disagree on whether radiation doses at these low levels are harmful. A possible effect 
that could occur at doses associated with this study is a slight increase in the risk of developing 
cancer later in life.  
 
Since the effects of radiation can add up over time, it is important that you tell the study doctors 
about your past clinical imaging and research-related radiation exposure.  If you have taken part 
in other research studies in the past 12 months that have involved radiation exposure, please tell 
us. If it appears that your earlier radiation exposure is more than our current guidelines, it is 
possible that you will not be allowed to take part in this study. 
 
Have you participated in other research studies (not including this study) involving radiation 
exposure within the last 12 months? 
 
 Yes           
 No 
Initials___________ 
 
Genetic Testing: Genetic information that results from this study does not have medical or 
treatment importance at this time. However, there is a risk that information about taking part in a 
genetic study may influence insurance companies of employers regarding your health. To further 
safeguard your privacy, genetic information obtained in this study will not be placed in your 
medical record. Taking part in a genetic study may also have a negative impact on family or 
other relationships. If you do not share information about taking part in this study, you will 
reduce this risk. We may perform Genome wide association studies (GWAS) with this data. 
GWAS are hypothesis free methods to identify associations between genetic regions (loci) and 
traits (including diseases). 
 


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Risks to an Embryo or Fetus: Radiation exposure or the use of CBD may be harmful to an 
embryo or fetus (developing baby still in the womb) or to a nursing infant. Because of these 
risks, women cannot take part in this study if they are pregnant or breastfeeding.    
 
If you are a menopausal woman and have not had a period for the past 12 months or more, you 
will not need to have a pregnancy test. Also, you will not need to have a pregnancy test if you 
have had a hysterectomy (surgical removal of your uterus and/or ovaries). All other female 
subjects must have a negative pregnancy test before having the MR-PET scan.   
 
There may be other risks and side effects of the MR-PET scan that are not known at this time. 
 
Incidental Findings: We are doing the MR-PET scan in this study to answer research questions, 
not as part of your medical care. The information from this study will not usually become part of 
your hospital record. This MR-PET scan is not the same as the one that your doctor would order.  
It may or may not show problems that would be found on a standard MRI or PET scan. This type 
of scan is considered experimental.   
 
If we do see something that looks like a medical problem, we will ask a radiologist (a doctor who 
specializes in test results of this sort) to review the results. If the radiologist thinks that you may 
have a medical problem, we will tell you and help you get follow-up care. 
If the radiologist thinks that you may have a medical problem, but it turns out that you don’t, we 
may have caused you to worry needlessly about your health.   
 
IV Catheter and Blood Draw: Drawing blood or placing the IV catheter into a vein in your arm 
may cause some pain, discomfort, bruising, bleeding, swelling, and redness in the area where we 
take blood samples from or place the IV catheter. You may have a bruise or feel painful or 
uncomfortable for 2-3 days after. Rarely, an infection may occur, which can be treated.   
 
Questionnaires: We will ask you questions about your emotional or mental health 
(psychological questions). Some of these questions may make you uncomfortable. You are 
allowed to skip any question you do not want to answer, but it could mean being excluded by the 
study (depending on how necessary the particular answer is).  
 
Medical Information: We will make a notation in your medical record that you are a part of this 
study. There is a small risk that your confidential medical information could be revealed or 
discovered by mistake. The results of this research study won’t be placed in your medical 
records. In addition, your samples and information will be coded and the key to the code will be 
kept in a separate, locked file. We won’t share or publish any information that will identify you. 
 
What are the possible benefits from being in this research study? 


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You may not directly benefit from taking part in this study, though it is possible that you will 
experience some reductions in pain. We hope the information obtained from this study will help 
scientists discover a potential mechanism of action for CBD. 
 
What other treatments or procedures are available for my condition? 
 
You do not have to take part in this study to be treated for low back pain. Other treatments or 
procedures that are available to treat low back pain include: 
 
• Medications (e.g., non-steroidal anti-inflammatory drugs, opiates, muscle relaxants) 
• Transcutaneous electrical nerve stimulation 
• Physical exercise and stretching 
• Epidural steroid injection 
• Physical therapy 
• Back surgeries 
• Acupuncture
 
 
Can you still get medical care within Partners if you don’t take part in 
this research study, or if you stop taking part? 
 
Yes.  Your decision won’t change the medical care you get within Partners now or in the future.  
There will be no penalty, and you won’t lose any benefits you receive now or have a right to 
receive. 
 
We will tell you if we learn new information that could make you change your mind about taking 
part in this research study. 
 
 
What should you do if you want to stop taking part in the study? 
 
If you take part in this research study, and want to drop out, you should tell us.  We will make 
sure that you stop the study safely.  We will also talk to you about follow-up care, if needed. 
 
Also, it is possible that we will have to ask you to drop out of the study before you finish it.  If 
this happens, we will tell you why.  We will also help arrange other care for you, if needed. 
 


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Will you be paid to take part in this research study?
 
We will pay you up to $525 for the following: 
• $75 for the initial screening visit  
• $50 for completing daily surveys  
• $200 for each MR-PET scanning session 
 
If, for some reason, we cannot inject you with the dye during the imaging visit(s), you will 
receive $50. If you have to stop the scan early for any reason, we will pay you $50 for the 
imaging visit(s). We will also reimburse you for your parking in the hospital garage during study 
visits. 
 
We may use your study information and test results to develop a new product or medical test to 
be sold. The hospital and researchers may benefit if this happens. There are no plans to pay you 
if your samples are used for this purpose. 
 
What will you have to pay for if you take part in this research study? 
 
Study funds will pay for certain study-related items and services. We may bill your health insurer 
for, among other things, routine medical care you would receive even if you did not take part in 
this research. You will be responsible for payment of any deductibles and co-payments required 
by your insurer for this routine care or other billed care. If you have any questions about costs to 
you that may result from taking part in the research, please speak with the study doctors and 
study staff. If necessary, we will arrange for you to speak with someone in Patient Financial 
Services about these costs. You will also be responsible for paying for transportation to and from 
study visits, although we will validate parking in the hospital garage during study visits. It is 
important to note that if you do receive any benefit from the CBD treatment, and decide to 
continue treatment from CBD after your study participation is over, you and your insurance 
company will be responsible for the cost of the CBD. 
 
What happens if you are injured as a result of taking part in this 
research study?
 
We will offer you the care needed to treat any injury that directly results from taking part in this 
research study.  We reserve the right to bill your insurance company or other third parties, if 
appropriate, for the care you get for the injury.  We will try to have these costs paid for, but you 
may be responsible for some of them.  For example, if the care is billed to your insurer, you will 
be responsible for payment of any deductibles and co-payments required by your insurer. 


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Subject Identification 
 
Injuries sometimes happen in research even when no one is at fault.  There are no plans to pay 
you or give you other compensation for an injury, should one occur.  However, you are not 
giving up any of your legal rights by signing this form. 
 
If you think you have been injured or have experienced a medical problem as a result of taking 
part in this research study, tell the person in charge of this study as soon as possible.  The 
researcher's name and phone number are listed in the beginning of this consent form. 
 
 
If you take part in this research study, how will we protect your privacy? 
 
Federal law requires Partners to protect the privacy of health information and related information 
that identifies you.  We refer to this information as “identifiable information.” 
 
In this study, we may collect identifiable information about you from: 
• Past, present, and future medical records 
• Research procedures, including research office visits, tests, interviews, and 
questionnaires 
 
Who may see, use, and share your identifiable information and why: 
• Partners researchers and staff involved in this study 
• The sponsor(s) of the study, and people or groups it hires to help perform this research or 
to audit the research 
• Other researchers and medical centers that are part of this study 
• The Partners ethics board or an ethics board outside Partners that oversees the research 
• A group that oversees the data (study information) and safety of this study 
• Non-research staff within Partners who need identifiable information to do their jobs, 
such as for treatment, payment (billing), or hospital operations (such as assessing the 
quality of care or research) 
• People or groups that we hire to do certain work for us, such as data storage companies, 
accreditors, insurers, and lawyers 
• Federal agencies (such as the U.S. Department of Health and Human Services (DHHS) 
and agencies within DHHS like the Food and Drug Administration, the National 
Institutes of Health, and the Office for Human Research Protections), state agencies, and 


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foreign government bodies that oversee, evaluate, and audit research, which may include 
inspection of your records 
• Public health and safety authorities,  if we learn information that could mean harm to you 
or others (such as to make required reports about communicable diseases or about child 
or elder abuse) 
• Other researchers within or outside Partners, for use in other research as allowed by law. 
 
Certificate of Confidentiality 
 
A federal Certificate of Confidentiality (Certificate) has been issued for this research to add 
special protection for information and specimens that may identify you.  With a Certificate, 
unless you give permission (such as in this form) and except as described above, the researchers 
are not allowed to share your identifiable information or identifiable specimens, including for a 
court order or subpoena.  
 
Certain information from the research will be put into your medical record and will not be 
covered by the Certificate.  This includes records of medical tests or procedures done at the 
hospitals and clinics, and information that treating health care providers may need to care for 
you.  Please ask your study doctor if you have any questions about what information will be 
included in your medical record.  Other researchers receiving your identifiable information or 
specimens are expected to comply with the privacy protections of the Certificate.  The Certificate 
does not stop you from voluntarily releasing information about yourself or your participation in 
this study. 
 
Even with these measures to protect your privacy, once your identifiable information is shared 
outside Partners, we cannot control all the ways that others use or share it and cannot promise 
that it will remain completely private.  
 
Because research is an ongoing process, we cannot give you an exact date when we will either 
destroy or stop using or sharing your identifiable information.  Your permission to use and share 
your identifiable information does not expire.   
 
The results of this research may be published in a medical book or journal, or used to teach 
others.  However, your name or other identifiable information will not be used for these 
purposes without your specific permission. 
 
Your Privacy Rights 
 
You have the right not to sign this form that allows us to use and share your identifiable 
information for research; however, if you don’t sign it, you can’t take part in this research study. 


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You have the right to withdraw your permission for us to use or share your identifiable 
information for this research study.  If you want to withdraw your permission, you must notify 
the person in charge of this research study in writing.  Once permission is withdrawn, you cannot 
continue to take part in the study. 
 
If you withdraw your permission, we will not be able to take back information that has already 
been used or shared with others, and such information may continue to be used for certain 
purposes, such as to comply with the law or maintain the reliability of the study. 
 
You have the right to see and get a copy of your identifiable information that is used or shared 
for treatment or for payment.  To ask for this information, please contact the person in charge of 
this research study.  You may only get such information after the research is finished. 
 
 
Informed Consent and Authorization 
 
Statement of Person Giving Informed Consent and Authorization 
 
 I have read this consent form. 
 This research study has been explained to me, including risks and possible benefits (if 
any), other possible treatments or procedures, and other important things about the study. 
 I have had the opportunity to ask questions. 
 I understand the information given to me. 
 
Signature of Subject: 
 
I give my consent to take part in this research study and agree to allow my identifiable 
information to be used and shared as described above. 
 
 
 
 
 
 
 
 
Subject 
Date 
Time 
 
Statement of Study Doctor or Person Obtaining Consent 
 
 I have explained the research to the study subject. 
 I have answered all questions about this research study to the best of my ability. 


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Signature of Study Doctor or Person Obtaining Consent: 
 
 
 
 
 
 
 
 
Study Doctor or Person Obtaining Consent 
Date 
Time
 
Consent Form Version Date:  11/12/2020