Review Article Role of natural products in mitigation of toxic effects of methamphetamine: A review of in vitro and in vivo studies Mohammad Moshiri1, 2, Ali Roohbakhsh3, 4, Mahdi Talebi5, Milad Iranshahy6, Leila Etemad3,* 1Medical Toxicology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran 2Department of Clinical Toxicology, Imam Reza Hospital, Mashhad University of Medical Sciences, Mashhad, Iran 3Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran 4Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran 5Department of community and Family Medicine, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran 6Department of Pharmacognosy, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran Article history: Abstract Received: Jul 24, 2019 Objective: Methamphetamine (METH) increases dopamine, Received in revised form: Nov 09, 2019 norepinephrine and serotonin concentrations in the synaptic cleft, Accepted: Dec 10, 2019 and induces hyperactivity. The current management of acute METH AJP, Vol. 10, No. 4, Jul-Aug poisoning relies on supportive care and no specific antidote is 2020, 334-351. available for treatment. The main objective of this review was to present the evidence for effectiveness of the herbal medicine in * Corresponding Author: alleviating the adverse effects of METH abuse. Tel: +98-513-7112611 Materials and Methods: Literature search was performed using Fax: +98-513-8823251 the following electronic databases: MEDLINE, Scopus, PubMed [email protected] and EMBASE. Results: Plant-derived natural products ginseng and sauchinone Keywords: Addiction reduced METH-induced hyperactivity, conditioned place Herbal preference and neurological disorder. Garcinia kola decreased Methamphetamine METH-induced hepatotoxicity, raised METH lethal dose, and Toxicity restored the METH-impaired cognitive function. Repeated administration of baicalein resulted in attenuation of acute binge METH-induced amnesia via dopamine receptors. Activation of extracellular-regulated kinase in the hypothalamus by levo- tetrahydropalmatine facilitated the extinction of METH-induced conditioned place preference and reduced the hyperactivity. Other herbal medicine from various parts of the world were also discussed including hispidulin, silymarin, limonene, resveratrol, chlorogenic acid and barakol. Conclusion: Based on the current study, some natural products such as ginseng and levo-tetrahydropalmatine are promising candidates to treat METH abuse and poisoning. However, clinical trials are needed to confirm these finding. Please cite this paper as: Moshiri M, Roohbakhsh A, Talebi M, Iranshahy M, Etemad L. Role of natural products in mitigation of toxic effects of methamphetamine: A review of based on in vitro and in vivo studies. Avicenna J Phytomed, 2020; 10(4): 334-351. AJP, Vol. 10, No. 4, Jul-Aug 2020 334 Herbal medicines for methamphetamine toxicity Introduction The enhanced neuronal dopaminergic Methamphetamine (METH), with transmission in mesolimbic tissue of the common street names "ice", "jib", "crystal" brain has a very important role in and "speed", is a potent neurotoxic behavioral changes due to different stimulant and has psychedelic properties . stimulants including METH (Bello et al., METH has a chemical formula of C10H15N 2011). derived from amphetamine and is available Conditioned place preference (CPP) as powder or crystals. Nagai Nagayoshi paradigm is an established method for firstly synthesized this compound from evaluating the potential reinforcing ephedrine in 1983 (Albertson et al., 1999; properties of drugs, and is a model for Lee, 2011). According to statistics, the assessing psychological dependence (Alavi number of METH consumers is increasing et al., 2016; Bahi et al., 2008; Duncan et al., every year. The number of METH 1983; Finlay et al., 1988; Kim et al., 1998; consumers has been estimated to be Wang et al., 2010b). CPP and behavioral approximately 37 million people, in 2015 sensitization of all drugs, specially (United Nations Office on Drugs and stimulants, are referred to elevated Crime, 2017). METH is generally used by dopamine concentration and DRS (Kim et oral ingestion, intravenous injection, nasal al., 1998). Following chronic consumption insufflations (snorting) or smoking. of METH or other amphetamine Depending on the routes of consumption, derivatives, depletion of dopamine in action its bioavailability varies between 60 and sites results in CPP (Duncan et al., 1983). 100% (Harris et al., 2003). METH Low to moderate doses of METH may metabolism in the liver produces less active cause nausea, vomiting, headache, tremor, metabolites, such as amphetamine, 4- irritability, euphoria, positive mood, hydroxymethamphetamin and increased temperature, reduced appetite, norephedrine. Approximately 50% of confusion, hallucinations, behavioral METH is excreted unchanged in the urine disinhibition and short-term improvement (Cruickshank and Dyer, 2009). of cognition and formication (Moshiri et al., METH indirectly affects serotoninergic, 2019; Vahabzadeh and Ghassemi Toussi, dopaminergic and adrenergic systems. Due 2016). Sever toxicity may be associated to similar molecular structure, METH with renal failure, seizure and coma. inhibits dopamine, norepinephrine and Serotonin syndrome may occur in a small serotonin transporters reuptake and proportion of users (Kiyatkin and Sharma, increases their concentrations in the 2009). Chronic exposure to METH can lead synapses and indirectly stimulates to paranoid psychosis, hallucinations, and monoamine receptors (Courtney and Ray, cardiomyopathy and increases the risk of 2014; Moshiri et al., 2018). METH-induced hemorrhagic and ischemic stroke hyperactivity (MIH) is resulted from (Cruickshank and Dyer, 2009). release and inhibition of the reuptake of The current management of acute METH dopamine (Kim et al., 1998). Repeated poisoning relies on supportive care and no administration of METH causes an specific antidote is available for treatment. enhancement in the METH accelerated Benzodiazepines are used to control motor effects. This phenomenon is named delirium, agitation, and seizures. In patients sensitization or reverse tolerance (RT) who do not respond to benzodiazepines, (Kim et al., 1996; Tsang et al., 1985). It was haloperidol or other antipsychotic drugs reported that treatment of animals with may be considered (Tien et al., 2010). It METH increases sensitivity to was suggested that compounds which apomorphine, a dopamine receptor agonist, decrease the availability of monoamines in and induces dopamine receptor super presynaptic regions, block the monoamine sensitization (DRS) (Tsang et al., 1985). receptors or suppress the monoamines post AJP, Vol. 10, No. 4, Jul-Aug 2020 335 Moshiri et al. receptor signaling, are not able to attenuate medicines in the treatment of METH abuse the METH-induced reinforcement and and toxicity. adverse effects (Ghadiri et al., 2017; Pickens et al., 1968). The main mechanisms proposed for Materials and Methods METH-induced neurotoxicity are oxidative We performed a non-systematic stress, monoamines and ionic homeostasis literature review from several databases dysregulation and hyperthermia. Oxidative including Scopus, PubMed and EMBASE. stress is mediated by two distinct oxygen We searched the literature without time and nitric oxide (NO)-based pathways. So, restriction. Searches were conducted using the antioxidant compounds and NO the keywords “Addiction”, “Herb”, synthase (NOS) inhibitors have shown “Methamphetamine”, “Toxicity”, poison”, protective effects on METH-induced “natural” and “extract”. More than 300 neurotoxicity (Jang et al., 2012b). articles were found and 42 related articles Herbs have been used in traditional were added. No human studies such as case medicine to cure a broad spectrum of reports or clinical trials, were found. illnesses over the past 1000 years. Information about medicinal plants and their therapeutic applications have been Results preserved in Iranian, Indian and Chinese Ginseng traditional medicine compendium(Taleb et Ginseng is a perennial plant with fleshy al., 2014). roots that belongs to the Araliaceae family. Plants produce a wide range of This popular herb grows widely in America metabolites in their roots, leaves, flowers, and more tropical areas, especially, east of or seeds that are frequently used in the Asia and oriental countries. Over many pharmaceutical field. Plant-based years, in traditional medicine, ginseng roots medicines are more affordable and have been used as anti-diabetes, anti- available than modern medicines and have inflammatory, antianxiety, anti-fatigue, various pharmacological properties anti-depressant, and memory enhancer, and including anti-inflammatory, antimicrobial, for improvement of physical and sexual antifibrotic, anticancer, and neuroprotective activities (Lacaille-Dubois and Wagner, effects. These health benefits are attributed 1996). to several classes of phytochemicals such as Ginseng prevented the development of flavonoids, polyphenols, tannins, alkaloids, morphine tolerance and dependence in and monoterpenes (Umesha et al., 2013). rodents (Kim et al., 2005; Tokuyama and Herbal medicines have been used to Takahashi, 2001). It also reduced reduce the adverse effects, dependency and morphine-, cocaine-, and METH-induced craving and manage withdrawal syndrome RT