Contents lists available at ScienceDirect Phytomedicine journal homepage: www.elsevier.com/locate/phymed Achillea millefolium is beneficial as an add-on therapy in patients with multiple sclerosis: A randomized placebo-controlled clinical trial Fatemeh Ayoobi a , Amir Moghadam-Ahmadi a,b , Houshang Amiri c,d , Alireza Vakilian a,b , Moslem Heidari a , Habib Farahmand e , Mahmood Sheikh Fathollahi f , Iman Fatemi g,h , Seyed Ali Shafiei i , Mohammad Alahtavakoli g,h , Ali Shamsizadeh g,h, ⁎ a Non-Communicable Diseases Research Center, Rafsanjan University of Medical Sciences, Rafsanjan, Iran b Department of Neurology, Medical School, Rafsanjan University of Medical Sciences, Rafsanjan, Iran c Neuroscience Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran d Department of Radiology and Nuclear Medicine, VU University Medical Center, Amsterdam, The Netherlands e Department of Radiology, Ali-Ebn Abitaleb Hospital, Rafsanjan University of Medical Sciences, Rafsanjan, Iran f Department of Epidemiology and Biostatistics and Member of Occupational Environment Research Center, Medical School, Rafsanjan University of Medical Sciences, Rafsanjan, Iran g Physiology-pharmacology Research Center, Rafsanjan University of Medical Sciences, Rafsanjan, Iran h Department of Physiology and Pharmacology, School of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran i Department of Physiology and Pharmacology, School of Medicine, Qom University of Medical Sciences, Qom, Iran ARTICLE INFO Keywords: Multiple sclerosis Achillea millefolium Add-on therapy MRI ABSTRACT Background: Multiple sclerosis (MS) is a neurological disease for which to date there is no cure and the existing disease-modifying drugs just slow down the disease progression. Purpose: In this clinical trial we evaluated the efficacy of Achillea millefolium (A. millefolium) aqueous extract in MS patients. Methods: A triple-blind randomized placebo-controlled parallel group trial was conducted on 75 MS patients. The patients were randomized into three groups including placebo and two groups receiving A. millefolium with two different doses, i.e. 250 mg/day and 500 mg/day, for 1 year. The primary outcome was the annualized relapse rate. Also, number and volume of lesions were obtained from magnetic resonance imaging (MRI) scans. Furthermore, we performed a comprehensive neurological and cognitive tests as follows: changes in the ex- panded disability status scale (EDSS), the multiple sclerosis functional composite (MSFC), fatigue severity scale (FSS), Ashworth spasticity assessment, Beck depression test, State-trait anxiety inventory (STAI), mini-mental status examination (MMSE), Wisconsin card sorting test (WCST), tower of London test (TOL), word-pair learning, paced auditory serial addition task (PASAT) and standard laboratory tests. Results: This study showed one year administration of A. millefolium (both doses) decreased the annual relapse rate in MS patients. The mean volume change of lesions significantly decreased in the 500 mg A. millefolium group. The add-on therapy also increased time to first relapse and the MSFC z-score; it decreased the EDSS score and improved performance in word-pair learning, PASAT, and WCST. Conclusion: We found beneficial effects of A. millefolium aqueous extract as an add-on therapy in MS patients. Introduction Multiple sclerosis (MS) is a neurological disease characterized by chronic progressive demyelinating lesions in the brain and the spinal cord (Rudick et al., 2002b). Its complications include motor and cog- nitive problems such as muscle weakness and deficits in attention and long-term memory (Polman et al., 2011). These deficits detrimentally affect many aspects of daily life, such as participating fully in the https://doi.org/10.1016/j.phymed.2018.06.017 Received 4 March 2018; Received in revised form 16 April 2018; Accepted 18 June 2018 Abbreviations: MS, multiple sclerosis; A millefolium, Achillea millefolium; EAE, experimental allergic encephalitis; RR-MS, relapsing-remitting MS; EDSS, expanded disability status scale; MRI, magnetic resonance imaging; FLAIR, fluid-attenuated inversion recovery; LPA, lesion prediction algorithm; FSS, fatigue severity scale; STAI, Spielberger state-trait: anxiety inventory; MMSE, mini-mental status examination; WCST, Wisconsin card sorting test; TOL, tower of London test; PASAT, paced auditory serial addition task; MSFC, multiple sclerosis functional composite ⁎ Corresponding author at: Physiology-pharmacology Research Center, Rafsanjan University of Medical Sciences, Rafsanjan, Iran. E-mail address: ashamsi@rums.ac.ir (A. Shamsizadeh). Phytomedicine 52 (2019) 89–97 0944-7113/ © 2018 Elsevier GmbH. All rights reserved. T