Effects of cannabidiol (CBD) oral solution in patients undergoing bilateral total knee arthroplasty: a randomized, controlled, parallel, triple blind, pilot study.

Sideris A.; Chan W.; Liu J.; Della Valle A.; Baaklini L.; Rodriguez J.; Kirksey M.; Chalmers B.; Mayman D.; Soffin E. et al. · The journal of pain · 2026

**Background & Methods** This was a randomized, controlled, triple-blind pilot study of 36 patients undergoing bilateral total knee arthroplasty (BTKA) who received four perioperative doses of placebo (n=12), 400mg CBD (n=12), or 800mg CBD (n=12) as an adjunct to standardized anesthesia and multimodal analgesia. The primary outcome was cumulative 72-hour opioid consumption measured in morphine milligram equivalents (MME), with secondary outcomes including pain scores, rescue analgesic use, inflammatory markers (IL-6), sleep quality, and mood assessment via HADS scale. **Key Findings** - The 400mg CBD dose demonstrated a potential opioid-sparing effect with post hoc analysis showing significantly lower opioid consumption compared to placebo (144 vs 209 MME, p=0.04), lower pain scores, and fewer rescue analgesic requirements, though this did not reach significance on primary Dunnett's test (p=0.10). - The 800mg CBD dose showed no opioid-sparing benefit (203.2 vs 209 MME, p=0.98) and was associated with greater adverse event burden without clinical advantage. - Both CBD groups reported improved subjective sleep domains; however, anxiety and depression scores were elevated, particularly in the 800mg group, and inflammatory marker IL-6 levels were higher in CBD-treated patients. **Dosage & Administration** Four perioperative doses of oral cannabidiol solution (Epidiolex®) at 400mg or 800mg total dosing regimens in the perioperative period. **Safety & Adverse Effects** The 800mg CBD dose demonstrated increased adverse event burden compared to placebo and lower doses. Both CBD groups showed elevated anxiety and depression scores on the HADS scale. Higher IL-6 inflammatory markers were observed in CBD-treated groups compared to placebo. The 400mg dose was described as remaining tolerable. **Evidence Quality** This is a small pilot RCT (n=36) with appropriate triple-blinding and randomization, representing early-phase evidence (Level II). Limitations include small sample size, pilot design, off-label drug use, lack of statistical significance on primary outcome analysis, substantial interindividual pharmacokinetic variability, and conflicting secondary outcomes (improved sleep but worse mood). Results suggest potential benefit at moderate dosing but require larger confirmatory trials to establish efficacy and optimal dosing.

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