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Introduction: Cannabis products have been used in the management of headaches in adults and may play a role in pediatric chronic pain. Canadian pediatricians report increasing use of cannabis for the management of chronic headaches, despite no well-controlled studies to inform its dosing, safety, and effectiveness. The aim of our clinical trial is to determine the dosing and safety of a Cannabidiol (CBD)-enriched Cannabis Herbal Extract (CHE) for the treatment of chronic headaches in adolescents., Methods and Analysis: Youth, parents, and an expert steering committee co-designed this tolerability study. Twenty adolescents (aged 14 to 17 years), with a chronic migraine diagnosis for more than 6 months that has not responded to other therapies will be enrolled into an open label, dose escalation study across three Canadian sites. Study participants will receive escalating doses of a CBD-enriched CHE (MPL-001 with a THC:CBD of 1:25), starting at 0.2-0.4 mg/kg of CBD per day and escalating monthly up to 0.8-1.0 mg/kg of CBD per day. The primary objective of this study is to determine the safety and tolerability of CBD-enriched CHE in adolescents with chronic migraine. Secondary objectives of this study will inform the development of subsequent randomized controlled trials and include investigating the relationship between the dose escalation and change in the frequency of headache, impact and intensity of pain, changes in sleep, mood, function, and quality of life. Exploratory outcomes include investigating steady-state trough plasma levels of bioactive cannabinoids and investigating how pharmacogenetic profiles affect cannabinoid metabolism among adolescents receiving CBD-enriched CHE., Discussion: This protocol was co-designed with youth and describes a tolerability clinical trial of CBD-enriched CHE in adolescents with chronic headaches that have not responded to conventional therapies. This study is the first clinical trial on cannabis products in adolescents with chronic headaches and will inform the development of future comparative effectiveness clinical trials., Trial Registration: CAN-CHA trial is registered with ClinicalTrials.gov with a number of register NCT05337033., Competing Interests: Lauren E Kelly is the Scientific Director for The Canadian Collaborative for Childhood Cannabinoid Therapeutics (C4T) academic research team. She holds funding from the Canadian Institutes of Health Research, Canadian Cancer Society, Research Manitoba, the Sick Kids Foundation, the Children’s Hospital Research Institute of Manitoba, the University of Manitoba and a Mitacs Accelerate award in partnership with Canopy Growth. Dr. Kelly was a member of the Scientific Advisory Board for Health Products Containing Cannabis at Health Canada and is president elect for the Board of Directors of the Canadian Consortium for the Investigation of Cannabinoids (CCIC). Richard J. Huntsmanis a clinical lead for both the Cannabinoid Research Initiative of Saskatchewan and C4T. He was the co-chair of the Scientific Advisory Committee for Health Products Containing Cannabis at Health Canada. Katelynn E Boerner’s time is supported by a fellowship from the Canadian Child Health Clinician Scientist Program, and she currently holds unrelated funding from the Society of Pediatric Psychology, BC Children’s Hospital Research Institute, Canadian Institutes of Health Research, ZonMw: The Netherlands Organization for Health Research and Development, and the CHILD-BRIGHT Network. Evan C. Lewis has received speaking honoraria from Spectrum Therapeutics, Biome Grow, MedReleaf and Miravo Healthcare. He holds a non-salaried position as the Chief Medical Advisor for the JMCC Group. He was the Vice President of Neurology Services for Numinus, a psychedelic medicine treatment and research company. He is a member of the Expert Committee of the Medical Cannabis Clinicians Society (MCCS) in the United Kingdom and sits on the Advisory Councils for Cannabis Patient Advocacy & Support Services (CPASS) and MedCan. In the last 12 months, Samantha Lee Irwin has received honoraria for authoring a chapter for the Canadian Pharmacy Association (CPhA) and for doing an online lecture for NeuroDiem. She also receives compensation for scientific consulting (Impel NeuroPharma Inc, Biohaven Pharmaceuticals and Lundbeck A/S) and has had research support from the Duke Clinical Research Institute. Manik Chhabra has been granted the 2022 Research Manitoba-George & Fay Yee Centre for Healthcare Innovation in Health Research PhD Studentship Award. There are no patents, products in development or marketed products associated with this research to declare. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2024 Chhabra et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)