Effect of a traditional syrup from Citrus medica L. fruit juice on migraine headache: A randomized double blind placebo controlled clinical trial Mehrnaz Jafarpour a , Gholamhossein Yousefi b,c,n , Azadeh Hamedi d,e,nn , Abdolhamid Shariat f , Alireza Salehi g , Mojtaba Heydari g a Department of Phytopharmaceuticals (Traditional Pharmacy), School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran b Department of Pharmaceutics, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran c Center for Nanotechnology in Drug Delivery, Shiraz University of Medical Sciences, Shiraz, Iran d Department of Pharmacognosy, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran e Medicinal Plants Processing Research Center, Shiraz University of Medical Sciences, Shiraz, Iran f Department of Neurology, Shiraz Neurosciences Research Center and Clinical Neurology Research Center, Shiraz University, Medical Sciences, Shiraz, Iran g Department of Traditional Medicine, Research Center for Traditional Medicine and History of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran article info Article history: Received 27 June 2015 Received in revised form 13 November 2015 Accepted 21 December 2015 Available online 22 December 2015 Keywords: Citron Citrus medica Migraine headache Juice syrup Persian Traditional Medicine Clinical trial abstract Ethnopharmacological relevance: In Persian ethnomedicine several herbal remedies and functional foods have been used to treat migraine headache which are mostly summarized in Qarabadin-e-kabir (Aghili- Shirazi MH, 1773). One of them is Citron syrup (Sharbat-e-Balang) containing edible Citrus medica L. fruit juice and sugar. The present study was designed to assess the efficacy and safety of Citron syrup on patients with migraine headache. Materials and methods: Citron syrup was prepared as described in Qarabadin-e-kabir. In this double blind randomized placebo-controlled clinical trial, ninety patients with migraine headache were allocated to three parallel groups (Citron syrup, propranolol or placebo). Patients received 15 ml of Citron syrup, placebo syrup or 20 mg of propranolol tablet three times daily after a meal for 4 weeks. Primary out- comes were obtained from three measures: the frequency (per month), mean duration (hour) and mean intensity (visual analogue scale “VAS” 0–10 score) of headache attacks evaluated prior to and following 4 weeks of the intervention. Results: Citron syrup was superior to placebo in reduction of headache attacks intensity (P o0.01) and duration (p o0.0001) and as effective as propranolol in patients with migraine headache (P 40.05). However, unlike propranolol, Citron syrup could not significantly reduce the frequency of attacks com- pared to placebo. No indication of any serious side effects from Citron syrup was observed. Conclusion: According to obtained results, Citron syrup as a traditional Persian remedy can be suggested as an effective treatment for decreasing pain intensity and duration of attacks in migraine headache and the effectiveness is comparable to propranolol. However, the syrup did not show significant effect on frequency of attacks. & 2015 Elsevier Ireland Ltd. All rights reserved. 1. Introduction Headache is a very common disorder with lifetime prevalence of about 96% in general population. The point prevalence of headache is 11% in men and 22% in women (Rasmussen et al., 1991). Migraine is among the most common types of headache which affects up to 12% of the general population (Lipton et al., 2001) It is more frequent in women with 1-year prevalence of 15– 18% of women and 6% of men (Mathers et al., 2003). Multiple therapeutic modalities are recommended in patients with mi- graine headache including pharmacologic and non-pharmacologic treatments for prevention and treatment of migraine attacks. Pharmacologic preventive treatments include beta blockers, anti- depressants and anticonvulsants though there is insufficient re- sponse to these drugs. Scientific evidences show that only two thirds of the patients who received these treatments will have a 50% reduction in the frequency of headaches. On the other hand, Contents lists available at ScienceDirect journal homepage: www.elsevier.com/locate/jep Journal of Ethnopharmacology http://dx.doi.org/10.1016/j.jep.2015.12.040 0378-8741/& 2015 Elsevier Ireland Ltd. All rights reserved. n Corresponding author at: Department of Pharmaceutics, Center for Nano- technology in Drug Delivery Shiraz University of Medical Sciences, Shiraz, Iran. nn Corresponding author at: Department of Pharmacognosy, School of Pharmacy, Medicinal Plants Processing Research Center, Shiraz University of Medical Sciences, Shiraz, Iran. E-mail addresses: ghyousefi@sums.ac.ir (G. Yousefi), hamediaz@sums.ac.ir (A. Hamedi). Journal of Ethnopharmacology 179 (2016) 170–176