Oral Medicinal Cannabis Does Not Alter Plasma Levels of Endocannabinoid-Related <i>N</i> -Acylethanolamines in Fibromyalgia Patients: Findings from a Randomized Placebo-Controlled Trial

Introduction: Fibromyalgia syndrome (FMS) involves central sensitization and possible endocannabinoid system dysfunction, with medicinal cannabis increasingly investigated as a treatment. We assessed whether chronic oral 1:1 THC:CBD alters plasma endocannabinoid-related N -acylethanolamines (NAEs)—palmitoylethanolamide (PEA), oleoylethanolamide (OEA), and stearoylethanolamide (SEA)—in FMS. Materials and Methods: In a single-center, randomized, double-blind, placebo-controlled pilot trial, 24 women with FMS were allocated to cannabis oil (10 mg/mL THC and CBD) or placebo. Plasma samples were collected at five timepoints between enrollment and week 12 (over 16 weeks), ∼10–14 h after evening dosing, under fasting conditions. NAEs were quantified by ultra-high-performance liquid chromatography mass spectrometer. Repeated-measures analysis of variance tested main effects of time and group, and their interaction; Greenhouse–Geisser corrections were applied as required. Effect sizes were reported as partial eta squared. Trial registration: ACTRN12623000345684. Results: Twenty-two participants completed the trial ( n = 11 per group). Plasma anandamide and 2-AG were below limits of detection and excluded from analyses. Mean plasma PEA, OEA, and SEA remained stable across all timepoints in both groups, with no significant effects of time, group, or time × group interaction (all p &gt; 0.05). Effect sizes were minimal (partial η 2 ≤ 0.06), indicating negligible influence of medicinal cannabis on peripheral NAEs. Discussion: Despite clinical benefits observed with this treatment, peripheral NAEs were unchanged, suggesting they may have limited utility as biomarkers for monitoring therapeutic response to this formulation in FMS. These preliminary findings support investigation of alternative mechanisms, likely driven by central rather than peripheral processes.