Therapeutics The Journal of Clinical Pharmacology 2016, 56(7) 845–851 C  2015, The American College of Clinical Pharmacology DOI: 10.1002/jcph.670 Long-Term Data of Effcacy, Safety, and Tolerability in a Real-Life Setting of THC/CBD Oromucosal Spray-Treated Multiple Sclerosis Patients Damiano Paolicelli, MD, Vita Direnzo, MD, Alessia Manni, MD, Mariangela D’Onghia, MD, Carla Tortorella, MD, Stefano Zoccolella, MD, Valentina Di Lecce, MD, Antonio Iaffaldano, MD, and Maria Trojano, MD Abstract Delta-9-tetrahydrocannabinol (THC)/cannabidiol (CBD) oromucosal spray was approved as add-on therapy for spasticity in patients with multiple sclerosis (MS).We show our 40-week postmarketing experience regarding effcacy and safety of THC/CBD spray in an Italian cohort of 102 MS patients. Patients were evaluated using the Expanded Disability Status Scale (EDSS) score, the Numerical Rating Scale (NRS) for spasticity, the Ambulation Index (AI), and Timed 25-Foot Walk (T25-FW) at the beginning of treatment and then every 3 months. After 4 weeks, if a clinically signifcant improvement in spasticity (at least 20% of baseline NRS score) was not seen, administration of the drug was stopped. In our cohort, patients received an average of 6.5 ± 1.6 sprays each day.The mean reduction to the NRS spasticity score was 2.5 ± 1.2 points (P < .0001). Thirty-seven patients (36.2%) discontinued the treatment. The incidence of adverse events (AEs) was 40.2%. Fifty-eight patients (56.9%) were also assessed using the NRS for pain, and 46 patients (45.1%) with bladder dysfunction were assessed for the IPSS (International Prostatic Symptoms Score) score, showing a signifcant improvement in these scales (P = .011 and P = .001, respectively). In conclusion, treatment with THC/CBD spray appears to be a valid answer to some of the unmet needs in MS patients, such as spasticity and other refractory-to-treatment symptoms. Keywords bladder dysfunction, multiple sclerosis, pain, spasticity, THC/CBD Multiple sclerosis (MS) is the most common chronic, nontraumatic neurological disorder among young adults. 1 MS currently affects around 2.3 million people in the world. 2,3 Depending on the site of damaged myelin, MS causes various symptoms, involving patient well-being and quality of life (QoL). Spasticity is a common and frequently disabling symptom of MS, and it is responsible for abnormal postures, pain, spasms, urinary dysfunction, and sleep disorders. 4 Its prevalence increases with disease dura- tion: after 9–10 years, approximately 50% of patients have greater than mild spasticity, and 30% have greater than moderate spasticity. 5 March 2011 saw the successful completion of the European Mutual Recognition Procedure for delta-9- tetrahydrocannabinol (THC)/cannabidiol (CBD) oro- mucosal spray as add-on therapy for patients with MS and moderate to severe spasticity, based on evidence of effcacy and safety from previous studies. 6–11 This oromucosal formulation contains a 1:1 fxed ratio of delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), from cloned Cannabis sativa L. plant. The main active substance, THC, acts as a partial agonist to human cannabinoid receptors (CB1 and CB2) and may modulate the effects of excitatory (glutamic acid, GLU) and inhibitory (γ -aminobutyric acid, GABA) neurotransmitters, leading to muscle relaxation with a consequent improvement of spasticity. 12 CBD is demonstrated to antagonize some unwanted effects of THC, including intoxication, sedation, tachycardia, anxiety, and other symptoms. 13 THC/CBD spray also showed some effect on the symptoms of overactive bladder in patients with MS, although a randomized controlled trial that aimed to assess the effcacy, tolerability, and safety of THC/CBD spray as an add-on therapy in ameliorating bladder symptoms 14 did not reach statistical signifcance. The Department of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari “Aldo Moro,” Bari,Italy Submitted for publication 2 September 2015; accepted 29 October 2015. Corresponding Author: Damiano Paolicelli, MD, Department of Basic Medical Sciences, Neuro- science and Sense Organs, University of Bari “Aldo Moro,” Policlinico, Piazza Giulio Cesare 11, 70124 Bari, Italy Email: damiano.paolicelli@uniba.it