REVIEW Phytotherapy of Opioid Dependence and Withdrawal Syndrome: A Review Seyed Meghdad Tabatabai, Saeedeh Dashti, Fatemeh Doosti and Hossein Hosseinzadeh * Pharmaceutical Research Center, Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran Development of tolerance and dependence is a major problem associated with opioid treatment. Withdrawal syndrome is common between medical and illicit users of these agents. Phytomedicine has shown promise in the treatment of this complicated psychosomatic condition. In this study, the effects of plant extracts and active compo- nents on morphine dependence and withdrawal syndrome are discussed. Proper keywords were used to search through PubMed, Google Scholar, and SciVerse, as well as two local scientific databases, www.iranmedex.com and www.SID.com. All relevant results (original articles, meeting abstracts, patents, etc.) published from 2000 to 2013 were chosen for final review. A total of 35 plant species were studied on this subject. Plants from Lamiaceae, Ranunculaceae, and Apiaceae families were especially effective. A few studies were carried out on human subjects and the rest in animal models. Opioid dependence and withdrawal syndrome remain an intimidating challenge. None- theless, plants and their derivatives are suitable sources for their treatment. Although there are several plants shown to be effective in animal models, few clinical studies are available. Copyright © 2013 John Wiley & Sons, Ltd. Keywords: opioid dependence; withdrawal syndrome; tolerance; morphine; herbal remedy; phytotherapy. INTRODUCTION The emergence of tolerance and withdrawal symptoms is common when opioid analgesics and other illicit opiates are used. Treatment of illicit drug users is confined to opiate replacement therapy and symptomatic treatment of withdrawal signs. Herbal therapy may be a reasonable option for the treatment of opioid dependence and withdrawal (Doosti et al., 2013). So far, many herbs and their active components have shown attenuating effects on opioid dependence and withdrawal syndrome in several animal and human studies. This paper aims to review these studies. OPIOID TOLERANCE, DEPENDENCE, AND WITHDRAWAL Tolerance is characterized by the decreased effect of a drug after repeated exposure, requiring higher doses to achieve the same effects. Withdrawal syndrome is a series of physical, emotional, and behavioral changes after discontinuing a drug (Blasig et al., 1973). Three subtypes of opioid receptors (μ, δ, and κ) belong to G-protein-coupled receptor family. Uncoupling between opioid receptors and G-protein signaling has been implicated in the mechanisms of opioid toler- ance. Repeated administration of opioids upregulates cyclic adenosine monophosphate (cAMP), protein- kinase A system, and several phosphoproteins like cAMP response element-binding protein (CREB) (Sadock et al., 2007). Within pain signaling, excitatory amino acids such as L-glutamate and L-aspartate and neuropeptides are released by presynaptic neurons. NMDA recep- tor-mediated activation of intracellular cascades may also be involved in the development of opioid tolerance and dependence. NMDA receptor antago- nists are shown to alleviate morphine tolerance and physical dependence in mice (Gonzalez et al., 1997). Some findings suggest that nitric oxide (NO) has an important role in the expression of morphine-in- duced withdrawal syndrome (Zarrindast et al., 2003). Free radicals produced in this pathway play an important role in the expression of physical dependence on morphine. The antioxidant effect of many natural compounds may therefore ameliorate withdrawal signs. Opioids have noticeable effects on dopaminergic and adrenergic systems. Activation of dopaminergic neurons of the tegmental area mediates reward pathway and addiction. Prolonged exposure to opioids leads to change in number and sensitivity of receptors. Short- term use of opioids reduces the activity of adrenergic neurons in locus coeruleus and rostral ventrolateral medulla (Baraban et al., 1995). Prolonged use activates a moderating compensation mechanism in neurons. Therefore, cessation leads to rebound hyperactivity (Sadock et al., 2007). * Correspondence to: Hossein Hosseinzadeh, Pharmaceutical Research Center, Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran. E-mail: hosseinzadehh@mums.ac.ir PHYTOTHERAPY RESEARCH Phytother. Res. (2013) Published online in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/ptr.5073 Copyright © 2013 John Wiley & Sons, Ltd. Received 28 July 2013 Revised 18 September 2013 Accepted 22 September 2013