Therapeutic Drug Monitoring of Cannabinoids: Therapeutic Reference Ranges for Delta-9-tetrahydrocannabinol in Medical Cannabis, Nabiximols, Dronabinol and Nabilone
Friederike Amann 1 2 3, Gudrun Hefner 3 4, Peter Cremer-Schaeffer 5, Gerhard Gründer 1 2 3, Winfried Häuser 6, Xenia M Hart 1 3 7, Frank Petzke 8, Gerald Zernig 3 9 10, Ursula Havemann-Reinecke 3 11
- 1Central Institute of Mental Health, Department of Molecular Neuroimaging, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
- 2German Center for Mental Health (DZPG)-partner site Mannheim-Heidelberg-Ulm, Mannheim, Germany.
- 3Society for Neuropsychopharmacology and Pharmacopsychiatry (AGNP), Mannheim, Germany.
- 4Psychiatric Hospital, Vitos Clinic for Forensic Psychiatry, Eltville, Germany.
- 5Bundesopiumstelle, Bundesinstitut für Arzneimittel und Medizinprodukte, Bonn, Germany.
- 6Medical Center Pain Medicine and Mental Health Saarbruecken, Saarbruecken, Germany.
- 7Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan.
- 8Department of Pain Medicine, University Medical Center Göttingen (UMG), Göttingen, Germany.
- 9Private Practice for Psychotherapy and Court-Certified Expert Witness, Hall in Tirol, Austria.
- 10Department of Pharmacology, Medizinische Universität Innsbruck, Innsbruck, Austria.
- 11Department of Psychiatry and Psychotherapy, University Medical Center Göttingen (UMG), Göttingen, Germany.
Affiliationer
Medical cannabis, nabiximols, dronabinol and nabilone are used for various medical conditions. Despite their pronounced pharmacokinetic variability and complex concentration-effect relationships, therapeutic drug monitoring recommendations are lacking. We aimed to identify therapeutic reference ranges based on blood concentration-clinical effect relationships. Studies reporting blood concentrations and clinical effects/adverse effects or assessing cannabinoid receptors 1 and 2 occupancy were selected through a systematic literature search in the MEDLINE database via PubMed. Twenty-three articles were selected for vaporized/smoked medical cannabis, three for nabiximols, nine for dronabinol and one for nabilone. No article was identified for delta-9-tetrahydrocannabinol-dominant cannabis extracts. For vaporized/smoked medical cannabis, an orienting therapeutic reference range of 15-30 ng/mL delta-9-tetrahydrocannabinol was identified for pain reduction in diabetic peripheral neuropathy, while concentrations of <20 ng/mL delta-9-tetrahydrocannabinol were significantly correlated with intraocular pressure reduction and 7.5-10 ng/mL with improvement of tic symptoms. Half-maximum effective concentrations of 7-29 ng/mL delta-9-tetrahydrocannabinol were reported for “high” effects. For nabiximols, a preliminary therapeutic reference range of 1-10 ng/mL delta-9-tetrahydrocannabinol was determined for treating neuropathic pain and spasticity in adults with multiple sclerosis. For chemotherapy-induced nausea and vomiting, a preliminary therapeutic reference range of 1-5 ng/mL for nabilone and 5-15 ng/mL delta-9-tetrahydrocannabinol for dronabinol was assessed. In conclusion, relatively low concentrations may be sufficient to achieve therapeutic effects across all substances studied, with medical cannabis demonstrating these effects at lower concentrations than typically observed in recreational use. Nevertheless, adverse effects at therapeutic reference ranges cannot be excluded.
