Epidiolex (CBD) in Patients With Biochemically Recurrent Prostate Cancer

Inclusion Criteria:

* Completion of localized therapy (prostatectomy or radiotherapy) for prostate adenocarcinoma (either histologically or cytologically confirmed)
* Biochemical (PSA) recurrence, defined as: \* PSA of \>= 0.2 ng/ml that has increased above nadir following radical prostatectomy OR \* PSA increase of 2.0 ng/ml above post-therapy nadir after radiotherapy NOTE: PSA measured at two consecutive time points (separated by 4 or more weeks) is required in order to demonstrate the requisite increase in PSA
* Eastern Cooperative Oncology Group (ECOG) performance status =\< 2
* Absolute neutrophil count \>= 1,500/microliters (at baseline \[pre-study\])
* Platelets \>= 80,000/microliters (at baseline \[pre-study\])
* Total bilirubin =\< institutional upper limit of normal (at baseline \[pre-study\])
* Aspartate aminotransferase (AST)(serum glutamic-oxaloacetic transaminase/alanine aminotransferase (ALT)(serum glutamate pyruvate transaminase) =\< institutional upper limit of normal (at baseline \[pre-study\])
* Glomerular filtration rate (GFR) \>= 30 mL/min/1.73 m\^2 using the Cockcroft-Gault formula (at baseline \[pre-study\])
* Patients with a prior or concurrent malignancy (non-prostate) whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen as determined by the treating physician are eligible
* Given that worsening of an underlying state of mental depression or suicidal ideation has been reported with Epidiolex, patients should be carefully screened for depression at baseline and if there are indications or a history of depression it is strongly recommended that these patients be closely followed together with behavioral health or psychiatric medical support. Patients with an established diagnosis of depression that, in the assessment of the investigator may make the administration of Epidiolex hazardous, should not be enrolled on this protocol
* Concurrent use of over-the-counter CBD oil, Marinol or marijuana is not permitted. Patients with a history of current over-the-counter CBD oil, Marinol or marijuana use for any reason are eligible only if they do the following: \* Complete a one-week washout period prior to study initiation \* Refrain from non-study related CBD oil, Marinol or marijuana use while on-study
* Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

* History of hypersensitivity to Epidiolex (cannabidiol) or sesame seeds (one of the inactive ingredients in Epidiolex)
* Any radiological evidence of metastatic disease (determined by standard of care computed tomography \[CT\] scans of abdomen. pelvis, chest, whole body bone scan or Axium positron emission tomography scan). Questionable lesions on bone scan will be confirmed by standard of care methods such as plain X-rays or Axium positron emission tomography scan, if not previously performed
* Receipt of prior cytotoxic chemotherapy for recurrent prostate cancer
* Use of androgen deprivation therapy (for example, bicalutamide, flutamide, nilutamide, or leuprolide acetate) concurrently or within the previous 3 months.
* Uncontrolled intercurrent illness such as active infections. Other illnesses will be evaluated and eligibility status determined at the discretion of the treating physician and the investigator
* Psychiatric illness/social situations that would limit compliance with study requirements
* Concomitant use of valproate or clobazam
* Concurrent use of over-the-counter CBD oil, Marinol or marijuana
* Epidiolex is a moderate inhibitor of CYP2C19 and a moderate/strong inhibitor of CYP3A4, therefore concurrent use of CYP2C19 substrates is not allowed