Cannabinoid Interactions With Central and Peripheral Pain Mechanisms in Osteoarthritis of the Knee

Inclusion Criteria:

• Ability to read and speak English to allow for written informed consent,phenotyping, and patient-reported outcomes measures

• Willingness to participate in a drug intervention trial

• Diagnosis of osteoarthritis (OA) of the knee by a medical provider (confirmed bychecking medical records)

• Chronic knee pain, defined as moderate to severe knee pain for ≥ 6-month duration

• No use of cannabis or CBD in the past in the month prior to study enrollment as perself-report

• Fibromyalgia (FM) Survey Criteria score available. The questionnaire will beassessed by the research team for scoring. We will recruit enough patients tosatisfy the spectrum of FM scores in four quartiles based on our previously existingdata. Once a quartile is filled (approximately 40 patients enrolled), then we willnot include more people from that quartile.

• Self-reported normal visual acuity or correctable (with corrective lenses- glassesor contacts) to at least 20/40 for reading instructions in the MRI and visualsensitivity testing

• No contraindications to magnetic resonance imaging (MRI) (for example (e.g.), metalimplants)

• Able to lie still on their back for 1-1.5 hours during MRI

• Willingness to refrain from pain medications such as non-steroidal anti-inflammatorydrugs (NSAIDs) and acetaminophen for 12 hours prior to neuroimaging and QuantitativeSensory Testing (QST)

• Willingness to refrain from alcohol and nicotine before QST and neuroimaging (alcohol and nicotine consumption is allowed after testing is completed)

• Willingness to refrain from physical activity or exercise that would causesignificant muscle and/or joint soreness for 48 hours prior to testing (routineexercise or activity that does not lead to soreness is acceptable)

• Willingness to maintain a stable treatment regimen for chronic knee OA pain duringthe clinical trial (e.g., not initiating a new course of physical therapy)

• No use of adjunctive pain medications or stable chronic daily use of adjunctive painmedications (excluding opioids)

• Willingness to avoid grapefruit juice or food products for the duration of thestudy;

• Females of reproductive potential must agree to use acceptable birth control fromthe screening visit and until the completion study drug administration. Sexuallyactive male participants and/or their female partners must agree to use effectivecontraception during study drug treatment of the male participant. Male participantsmay also agree not to donate sperm during study drug treatment

Exclusion Criteria:

• Individuals who are actively applying for or in litigation for compensation ordisability and other aspects associated with potential secondary gain perself-report

• Inability to provide written informed consent

• Previous total knee arthroplasty

• Planned total knee arthroplasty within the time frame of the study

• Severe physical impairment (e.g., blindness, deafness, paraplegia)

• Co-morbid medical conditions that may significantly impair physical functionalstatus (e.g., history of non-skin malignancy, or autoimmune disorder)

• Use of cannabis or CBD in the past month per self-report and/or drug screen

• Current opioid use (excepting tramadol) per self-report and/or drug screen

• Current valproate, clobazam, or warfarin use per self-report or medical records

• Current use of moderate or strong inhibitors of cytochrome p450 (CYP) enzymes CYP3A4and CYP2C19, strong inducers of CYP3A4 or CYP2C19, moderate or stronginhibitors/inducers of CYP2C9, and narrow therapeutic index drugs (e.g.,cyclosporine, amphotericin B). Participants will also not be allowed to start usingthese drugs during the study period if they wish to stay in the study

• Self-reported allergies to sesame oil or cannabis/cannabinoids

• Self-reported medical or psychiatric conditions that in the judgment of studypersonnel would preclude participation in this study (e.g., schizophrenia,malignancy, psychosis, suicidal ideation, history of substance abuse; note thatstable anxiety and depression are not exclusions)

• Pregnant or nursing

• Liver failure

• Self-reported liver cirrhosis

• Active diagnosis or current symptoms of hepatitis by self-report

• Self-reported uncontrolled diabetes

• Blood pressure at screening above 180 systolic and/or 120 diastolic

• Resting heart rate at screening less than 50 beats per minute (bpm) or greater than 100 bpm;

• Elevated liver enzymes and bilirubin (measured via blood test at screening):

• Serum total bilirubin ≥ 2.5 milligrams per deciliter (mg/dL); or,

• Alanine Aminotransferase (ALT) or Aspartate Aminotransferase (AST) ≥ 3x upperlimit normal (ULN); or,

• Alkaline phosphatase ≥ 2 times ULN

• Severe cardiovascular disease (examples: history of myocardial infarction, unstableangina, severe coronary artery disease, congestive heart failure, or severe valvularabnormalities) that is self-reported by patient or by medical record

• Severe claustrophobia precluding MRI

• Unable to fit in or lie comfortably in MRI

• Diagnosed peripheral neuropathy

• Diagnosed or self-reported epilepsy or history of seizures

• Current head injury or history of head injury (e.g., traumatic brain injury)

• Any impairment, activity, behavior, or situation that in the judgment of the studyteam would prevent satisfactory completion of the study protocol