A Randomized, Triple-Masked, Placebo-Controlled Crossover Trial of Full-Spectrum Cannabis Extract for Chronic Pain and Bone Health Biomarkers in Women

EVALUATION OF BONE TURNOVER BIOMARKERS, CB2 AND TRPV1 POLYMORPHISMS AS POTENTIAL PREVENTIVE DATA IN OSTEOPOROSIS AND PERCEPTION OF IMPROVEMENT IN QUALITY OF LIFE IN WOMEN WITH CHRONIC PAIN TREATED WITH MEDICINAL CANNABIS

Chronic pain disproportionately affects women and may coexist with impaired bone health, particularly during midlife and after menopause. The endocannabinoid system is involved in pain modulation and bone homeostasis; however, clinical studies that integrate pain outcomes, bone-related biomarkers, genetic variants, and salivary endocannabinoids remain limited.This randomized, triple-masked, placebo-controlled crossover trial will evaluate the effects of a full-spectrum medicinal cannabis extract with a cannabidiol to tetrahydrocannabinol ratio of 5:1 on chronic pain in women aged 45 to 80 years with chronic pain refractory to conventional treatment. Eighty participants will be randomly assigned to one of two treatment sequences: full-spectrum cannabis extract followed by matching placebo, or matching placebo followed by full-spectrum cannabis extract. The treatment periods, washout interval, and visit schedule will follow the final approved protocol.The primary outcome is change in chronic pain intensity measured using the Visual Analog Scale. Secondary outcomes include quality of life, sleep quality, functional impact, bone health biomarkers, bone mineral density measured by dualenergy X-ray absorptiometry, salivary endocannabinoids, the association of CB and TRPV genetic variants with treatment response, and adverse events. The study aims to generate evidence on the clinical effects and biological correlates of medicinal cannabis therapy in women with chronic pain.

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