Full-Spectrum Cannabis Extract for Chronic Pain and Bone Health Biomarkers in Women

This is a randomized, triple-masked, placebo-controlled crossover clinical trial conducted in women aged 45 to 80 years with moderate to severe chronic pain that has persisted for at least 3 months and has not responded adequately to conventional pharmacological or non-pharmacological treatments. Participants will be randomlyallocated in permuted blocks to one of two treatments sequences. Sequence A will receive a full-spectrum medicinal cannabis extract with a cannabidiol to tetrahydrocannabinol ratio of 5:1 during the first treatment period, followed by a protocol-defined washout interval and matching placebo during the second treatment period. Sequence B will receive matching placebo during the first treatment period, followed by the washout interval and the full-spectrum medicinal cannabis extract during the second treatment period. The study product will be administered orally as softgel capsules. The target daily dose is 25 milligrams of cannabidiol and 5 milligrams of tetrahydrocannabinol. Dose titration during the first 2 weeks of each active treatment period will follow the final approved protocol.Participants, care providers, investigators, and outcome assessors will remain masked to treatment assignment as operationally applicable. Randomization will use a computer-generated sequence with permuted blocks of 4 and allocation concealment through opaque, sealed envelopes. The product and matching placebo will be supplied in indistinguishable presentations.Clinical evaluations will include pain intensity, quality of life, functional impact, sleep quality, concomitant medications, adherence, and adverse events. Laboratory assessments will include safety tests, selected bone metabolism biomarkers, inflammatory markers, and oxidative stress biomarkers. Bone mineral density and body composition will be assessed using dualenergy X-ray absorptiometry at protocol-defined baseline and final visits. Genetic analysis will evaluate CB and TRPV variants. Salivary anandamide, 2-arachidonoylglycerol, palmitoylethanolamide, and oleoylethanolamide will be quantified using liquid chromatography coupled with tandem mass spectrometry according to the final sample collection schedule.The primary efficacy analysis will compare pain outcomes across cannabis and placebo treatment periods while accounting for the crossover design. Secondary analyses will evaluate changes in patient-reported outcomes and biomarkers, treatment safety, and associations between genetic variants or salivary endocannabinoid profiles and treatment response.

Inclusion criteria

• Female sex, age 45 to 80 years
• Moderate to severe chronic pain, defined as a pain score of at least 4 on a 0 to 10 Visual Analog Scale, persisting for more than 3 months
• Documented inadequate response to at least 2 classes of analgesic treatments or non-pharmacological treatments
• Willingness to abstain from smoked cannabis and non-study cannabinoid products during the study
• Ability to understand the informed consent form and study questionnaires
• Willingness and ability to attend scheduled visits and biological sample collections during the study follow-up period

Exclusion criteria

• Cognitive impairment that precludes understanding of the informed consent form or study questionnaires
• Uncontrolled psychiatric condition, including uncontrolled psychotic disorder or bipolar disorder
• Pregnancy, breastfeeding, or intention to become pregnant during the study
• Current use of medicinal cannabis, smoked cannabis, or other cannabinoid products
• Known hypersensitivity to cannabinoids or formulation excipients
• Clinically significant hepatic impairment, defined as aspartate aminotransferase or alanine aminotransferase greater than 3 times the upper limit of normal, or severe heart failure classified as New York Heart Association class III or IV
• History of substance use disorder that, in the investigator's judgment, may interfere with study participation
• Use of medications that may interfere with bone metabolism, including bisphosphonates, systemic corticosteroids, or sex hormones, within 6 months before enrollment