Cannabidiol as a Treatment for Social Anxiety Disorder (R61)

Randomized Placebo-controlled Trial to Determine the Biological Signature of Cannabidiol as a Treatment for Social Anxiety Disorder (R61)

The R61 will include two CBD dose levels vs placebo (PBO) and examine potential engagement with two primary targets in a 3-week randomized controlled trial design. Willing and eligible subjects will be randomized to one of three randomized double-blind treatments (n = 20 each group): 1) CBD 800 mg (400 mg twice daily), 2) CBD 400 mg (200 mg twice daily), or 3) PBO twice daily for three weeks.

Participation is estimated at approximately 1 month from end of screening to endpoint for the primary R61 study period. This includes screening, baseline, week 2 stress task, Week 3 2-day imaging paradigm, and clinical safety assessments at weeks 2 and 3.

In the R61 trial, two doses of a Phase 3 trial suitable hemp-derived (legal) oral CBD formulation with enhanced bioavailability will be compared against placebo (PBO) in a 3-week double-blind randomized controlled trial. Participants will undergo a standardized stress task at week 2, and a standardized 2-day fear learning and extinction protocol at week 3, with functional MRI (fMRI) brain activation accompanying fear extinction recall and fearful faces tasks on the second day.

Inclusion Criteria:

1. Male or female outpatients aged 18 to 45 years of age
2. A primary mental health complaint (designated by the patient as the most important source of current distress and confirmed on Structured Clinical Interview for DSM-5 diagnoses by a certified clinical evaluator) of Social Anxiety Disorder (SAD), as defined by DSM-5 criteria
3. Overall social anxiety severity defined by a Liebowitz Social Anxiety Scale (LSAS) score of at least 60
4. Willingness and ability to participate in the informed consent process and comply with the requirements of the study protocol. Includes compliance with the requirements and restrictions listed in ICF and in the protocol (including consent to abstain from using marijuana, any cannabis-related products, or any tobacco products during the study).

Exclusion Criteria:

1. Known allergy or hypersensitivity to CBD or any of the excipients
2. A lifetime history of bipolar disorder, schizophrenia, psychosis, or delusional disorders; obsessive-compulsive disorder or an eating disorder in the past 12 months; neurocognitive disorders, intellectual disabilities, communication disorders or other cognitive dysfunction that could interfere with capacity to engage in therapy or complete study procedures; major depressive disorder, substance or alcohol use disorder (other than nicotine) in the last 6 months.
3. Positive urine toxicology for illicit drugs and/or cannabinoids, or self-reported use of CBD, THC or marijuana in the past 4 weeks prior to baseline
4. Patients with significant suicidal ideation (assessed by CSSRS SI score greater than 2) or who have enacted suicidal behaviors within 6 months prior to intake will be excluded from study participation and referred for appropriate clinical intervention.
5. Patients must be free of concurrent psychotropic medications including antipsychotics, anticonvulsants, benzodiazepines, and opioids, and medications that both have a narrow therapeutic index as determined by the study clinician, and are also substrates or moderate to strong inhibitors of CYP2C9, CYP2C19, CYP3A5, CYP3A7, UGT1A9, UGT2B7, CYP2C8, CYP1A2 or CYP2B6, or are strong inducers of CYP3A4 or CYP2C19, for at least 4 weeks prior to initiation of randomized treatment.
6. Inability to understand study procedures or informed consent process, or significant personality dysfunction likely to interfere with study participation (assessed during the clinical interview) or inability to comply with study procedures (such as planned extended travel) assessed on clinical interview.
7. Serious current unstable medical illness, or a condition for which hospitalization may be likely within the next year as assessed by medical history and physical exam. If any questions about medical safety emerge with screening procedures, consent will be formally obtained to contact patient's PCP in order to determine whether any medical concerns making participation unsafe or not feasible (such as need for extended inpatient care or medications with concern for significant drug interactions and/or safe utilization of CBD) are present.
8. Clinically significant abnormal physical examination, vital signs or 12 lead ECG at screening. Clinically significant abnormal values for hematology, clinical chemistry, or urinalysis at screening.
9. Pregnant women (to be ruled out by urine ß-HCG) and women of childbearing potential who are not using medically accepted forms of contraception (such as IUD, oral contraceptives, barrier devices, condoms and foam, or implanted progesterone rods stabilized for at least 3 months). Men must also be using at least one medically accepted form of contraception.
10. Any concurrent psychotherapy initiated within 3 months of baseline, or ongoing psychotherapy of any duration directed specifically toward treatment of SAD. Prohibited psychotherapy includes CBT, DBT, ACT, mindfulness-based approaches or psychodynamic therapy focusing on exploring specific, dynamic causes of the SAD symptomatology and providing management skills. General supportive therapy initiated greater than 3 months prior is acceptable.
11. Has received an investigational drug or used an invasive investigational medical device within 1 month or within a period less than 10 times the drug's half-life, whichever is longer, before Day 1
12. Patients with a history of head trauma causing loss of consciousness, seizure or ongoing cognitive impairment.
13. Contraindications for MRI including metal implants, surgical clips, probability of metal fragments, or braces that are prohibited due to severe risk of injury.
14. Left-handed
15. A prior history of a diagnosis of moderate to severe hepatic dysfunction or current bilirubin >=1.5X ULN and/or ALT or AST as 2X ULN, and/or if clinically significant signs and symptoms that are together suggestive of significant hepatic injury (i.e., nausea, vomiting, right upper quadrant pain, anorexia, fatigue, jaundice, dark urine).