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Review Article

Role of natural products in mitigation of toxic effects of : 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 , Received in revised form: Nov 09, 2019 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 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 , 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

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.

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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 and has psychedelic properties . including METH (Bello et al., METH has a chemical formula of C10H15N 2011). derived from 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 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 , 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 , 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 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

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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 (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 and their therapeutic applications have been Results preserved in Iranian, Indian and Chinese Ginseng compendium(Taleb et Ginseng is a perennial plant with fleshy al., 2014). that belongs to the 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-, 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 such as Ginseng prevented the development of flavonoids, polyphenols, , alkaloids, 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-, -, and METH-induced craving and manage withdrawal syndrome RT (Tokuyama and Takahashi, 2001). In of drugs since ancient times (Lu et al., addition, ginseng reduced METH- and 2009). The effectiveness of herbal cocaine-induced hyperstimulation even medicines in the treatment of addiction to after 30 days of discontinuation (Tokuyama , , opiate, cocaine and et al., 1996). METH was evaluated in in-vitro, in-vivo In recent years, scientists have and clinical studies (Mantsch et al., 2007; investigated the ability of secondary Wang et al., 2010b; Wen et al., 2014; Yang metabolites from ginseng to ameliorate the et al., 2008) METH (Table 1). The aim of this review article is to explore and identify the role of herbal-based

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Table 1. Summarized effects of ginseng on methamphetamine adverse effects. All experiences were performed in mice.

Author [ref.] Evaluation Design Results Kim (Kim et al.) RT GTS (100 or 200 mg/kg, PrT) + METH (2 Reduced by 200 mg/kg GTS but not by mg/kg) other day 100 mg/Kg GTS DRS hypothermic 24 hours after RT received AP (1 mg/ kg) Inhibited by 200 mg/kg GTS, but not by response to AP repeated every 30 min (4 mg/kg) 100 mg/kg GTS Enhanced ambulatory Reduced by 200 mg/kg GTS but not by activity of AP 100 mg/Kg GTS Kim (Kim et al., 1996) MIH GTS (100 or 200 mg/kg, PrT) + METH (2 Reduced by 200 mg/kg GTS but not by mg/kg) 100 mg/Kg GTS CPP GTS (50 or 100 mg/kg, IP, PrT) + METH Reduced by 100 mg/kg GTS but not by (2 mg/kg) 50 mg/Kg GTS DRS 24 hours after CPP received AP (2 mg/kg, Reduced by 100 mg/kg GTS but not by SC) 50 mg/Kg GTS AP induced climbing GTS (50, 100, 200 mg/kg IP, PrT) + AP (2 Reduced by 200 and 100 mg/kg GTS but behavior mg/kg) not by 50 mg/Kg GTS Oh (Oh et al., 1997) Strial DA, DOPAC, GTS (50 and 100 mg/kg, IP, PrT, 2 times) Restored catecholamines depletion, 100 HVA + METH (10 mg/kg, 4 times) mg/kg was more potent than 50 mg/kg

Kim (Kim et al., 1998) MIH Rb1 or Rg1 (50, 100 and 200 mg/kg, IP, Reduced by 100 and 200 mg/kg; not by PrT) + METH (2 mg/kg IP) 50 mg/kg CPP Rb1 or Rg1 (50, 100 and 200 mg/kg, IP, Reduced by 100 mg/kg; not by lower PrT) + METH (2 mg/kg IP) doses DRS 24 hours after CPP received AP (2 mg/ kg) Reduced by 100 mg/kg ; not by lower doses

AP=apomorphine, CPP=conditional place performance, DA=dopamine, DOPAC=3, 4-dihydroxyphenylacetic acid, GTS=ginseng total , HVA=homovanillinic acid, METH=methamphetamine, MIH=methamphetamine-induced hyperactivity, PrT=pretreatment, and RT=reverence tolerance.

Pseudoginsenoside-F11 (PF11) is an Active compounds of ginseng have also ocotillol-type saponin found in shown similar effects. For example, it was quinquefolius (). The demonstrated that ginseng total saponin researchers showed that PF11 prevented (GTS) inhibited METH-induced and treated the METH-induced hyperlocomotion, CPP and RT, in rats and neurological disorders (Fu et al., 2016; Wu mice (Kim et al., 2005; Kim et al., 1996; et al., 2003). The orally administrated PF11 Tokuyama and Takahashi, 2001). However, greatly reduced the anxiety-like behaviors administration of GTS alone had no effect of mice and rats in the light–dark box task. on CPP (Tokuyama et al., 1996). As Oral administration of PF11 also shortened mentioned in the introduction, METH- the METH-induced prolonged immobility induced CPP is resulted by DRS. GTS time in the forced swimming task and inhibited development of DRS and increased latency in Morris water maze task exhibited antidopaminergic properties which implied that it decreased the (Kim et al., 1996). It was suggested that depression-like behavior and memory GTS modulated the dopaminergic system dysfunction (Wu et al., 2003). By activity by reducing the reuptake of measuring the neurotransmitters dopamine and raising its content in the rat concentrations, it was observed that PF11 brain (Figure 1) (Lacaille-Dubois and antagonized METH-induced decrease of Wagner, 1996). GTS also modulated the dopamine and other neurotransmitters (Wu action of serotonergic/adenosine A2A/δ- et al., 2003). Although, PF11 is not opioid receptor complex (Kim et al., 2005). produced by , it was Chronic use of METH was reported to documented that repeated pretreatment induce depletion of striatal dopamine and with P. ginseng extract inhibited its metabolites. Pretreatment of METH- development of RT and reappearance of intoxicated mice with GTS (100 mk/kg) for behavioral sensitization to METH and one-week, resulted in a marked reduction in cocaine, which are known as typical effects striatal dopamine, 3, 4- of psychostimulants (Kim et al., 2005). dihydroxyphenylacetic acid, and

AJP, Vol. 10, No. 4, Jul-Aug 2020 337 Moshiri et al. homovanillinic acid. However, treatment of SH-SY5Y neuroblastoma cells (Figure 1) mice with GTS alone did not change the (Nam et al., 2014; Shin et al., 2014). level of striatal dopamine and its Rb1 and Rg1 are the major metabolites. So, the researchers suggested components of GTS. Both single and that GTS might prevent METH-induced repeated administration (100 and 200 Parkinsonism (Oh et al., 1997). mg/kg) of these ginsenosides inhibited the Ginsenosides and panaxosides play an hyperlocomotion and CPP following important role in therapeutic effects of METH administration. These components ginseng. Ginsenosides attenuated the were also able to attenuate DRS. However, morphine-induced cAMP signaling lower doses of both compounds (50 mg/kg) pathway (Kim et al., 2005). Re were not effective against CPP, MIH, or is the main ginsenoside that is found in DRS in mice (Kim et al., 1998). ginseng leaf, and . The results of It was proposed that ginseng extract can in vitro and in vivo studies showed that be a useful alternative in prevention of ginsenoside Re significantly alleviated METH and cocaine addiction (Kim et al., METH-induced neurotoxic through 2005; Tokuyama et al., 1996). Ginseng can enhancement of the antioxidant capacity, also effectively attenuate prevention of mitochondrial oxidative psychostimulants-induced tolerance and damage, mitochondrial translocation of dependence and prevent their adverse protein kinase C, and apoptosis in the effects. However, clinical trials are dopaminergic system in mouse brain and essential to confirm these results (Table2).

Figure 1. A schematic illustration of therapeutic mechanisms of different natural compounds in the treatment of methamphetamine-induced neurotoxicity. , decrease and , increase following methamphetamine treatment.  means that both effects were reported in different studies. Yellow and blue abbreviations denote the related compounds in the right section of the Figure (ref).

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Garcinia kola animal study, the effects of ethanolic Garcinia kola, from Clusiaceae/ extract of C. inerme leaves on METH– Guttiferae family, is a well-known herb due induced changes in locomotion, motor to its wide range of therapeutic uses. In liver coordination, muscle power, and prepulse injury induced by METH, oral inhibition of acoustic startle response (PPI) administration of the aqueous extract of G. were evaluated in mice. The ethanolic kola for 6 weeks, attenuated the raised extract significantly inhibited serum levels of liver marker enzymes, hyperlocomotion and prevented the PPI alkaline phosphatase, aspartate disruptions induced by METH, however aminotransferase, and ,the extract did not affect motor aminotransferase, as well as total bilirubin. coordination and muscle tone (Chen et al., The pathological findings with a significant 2012a). Later, it was shown that the active reduction in hepatic vacuolated cells, constituent from the C. inerme ethanolic confirmed the biochemical laboratory test extract namely hispidulin also decreased results. None of METH-intoxicated animals METH-induced hyperlocomotion, pretreated by 200 mg/kg of aqueous extract nevertheless hispidulin neither impairs of G. kola (AEGK) died. Although, AEGK motor tone nor induces sedation in mice at doses of 100 and 0 (control group) mg/kg (Huang et al., 2015; Liao et al., 2016). respectively caused 30% and 50% death in Intracerebellar microinjection of hispidulin METH-intoxicated animals. Thus, it was also inhibited the METH-induced suggested that G. kola increased median hyperlocomotion through activation of lethal dose of METH (Oze et al., 2010). alpha6 subunit-containing GABAA Therefore, G. kola was proposed as a receptors (Figure 1) (Table 2) (Liao et al., hepatoprotective plant for the treatment of 2016). METH-induced liver toxicity (Oze et al., 2010). Silybum marianum It was also reported that kolaviron, a Silybum marianum (milk thistle) belongs biflavonoid complex from G. kola seeds, to the Asteraceae family has been can delay or even attenuate the onset of traditionally used in treatment of liver stereotypic behaviors in mice treated with a diseases (Gholami et al., 2015; Karimi et single dose of METH and inhibited the al., 2011). Silibinin (silybin) is the most negative effects of METH on learning and prevalent and active component isomer in memory (Ijomone et al., 2012). The brain silymarin. Silymarin flavonoid complex is histological findings revealed that pre- derived from the seeds and fruits and has treatment with kolaviron protected the many medical benefits (Gholami et al., hippocampal CA1 and CA2 regions against 2016; Gholami et al., 2015; Karimi et al., the METH-induced neurotoxicity (Ijomone 2011). In recent advances, silibinin showed et al., 2012). The researchers suggested that a preventive effect on METH-induced kolaviron restored the impaired cognitive recognition memory impairment in novel function induced by METH through object recognition test (NORT) in animal inhibition of acetylcholinesterase (Figure 1) (Lu et al., 2010). Silibinin significantly (Table 2) (Ijomone and Obi, 2013). increased the object recognition index in METH-injected mice. The neuroprotective Clerodendrum inerme L. effects of silibinin were associated with Clerodendrum inerme L. (Family: improvement of serotonin and dopamine Verbenaceae) has been traditionally used depletion in the hippocampus and the for the treatment of scrofulous, chronic prefrontal cortex, respectively (Figure 1) pyrexia, asthma, bronchitis, inflammation (Table 2) (Lu et al., 2010). and epilepsy (Shukla et al., 2014). In an

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Table 2. Summarized effects of herbs on methamphetamine (METH) intoxication and adverse effects.

Herb Compound Effective against METH adverse effect

C. siamea Lamk Barakol MIH Clerodendrum inerme L. Ethanolic extract MIH Prepulse inhibition of acoustic startle response hispidulin MIH Coffee Chlorogenic acid METH increased oxidative stress indexes METH–induced hepatotoxicity Corydalis ternata L-tetrahydropalmatine MICPP (all parameters) MIH Garcinia kola Aqueous extract METH induced hepatotoxicity METH lethal dose Kolaviron METH-impaired cognitive function biflavonoid METH-impaired learning and memory METH-induced hippocampal neurotoxicity METH stereotypic movement Citrus Limonene METH-increased dopamine concentration in NA MIH Ginseng Pseudoginsenoside-F11 Freezing time in the forced swimming task Latency in Morris water maze METH induced anxiety-like behavior ginseng total saponin DRS METH induced parkinsonism MICPP MIH RT Ginsenosides DRS METH-induced neurotoxicity MICPP MIH Glycyrrhizae uralensis Radix methanol extracts METH-increased dopamine concentration in NA MIH Grapes Resveratrol METH induced [3H] dopamine overflow MIH Saururus chinensis Sauchinone METH induced dopaminergic neurotoxicity METH-reduced Nitric Oxide production METH-increased gelial cells activation MICPP MIH Scutellariae baicalensis Georgi Baicalein Harm reduction of neutrophil in striatal METH-reduced dopamine transporter in striatal METH-reduced dopamine level in striatal METH-induced memory deficits METH-induced lipid peroxidation METH-reduced Nitric Oxide production Silybum marianum silibinin METH-impaired memory recognition METH-induced hippocampal and prefrontal cortex Stephania intermedia l-stepholidine METH self-administration behavior MIH l-Scoulerine METH induced anxiety like behavior MICPP DRS=dopamine receptor super sensitization; METH=Methamphetamine; MICPP=METH-induced conditioned place preference; MIH=METH-induced hyperactivity; NA=nucleus accumbens; RT=sensitization or reverse tolerance.

Scutellariae baicalensis Georgi (Sowndhararajan et al., 2017). A recent Scutellariae baicalensis Georgi (or research showed that baicalein improved Huang Qin) is a Chinese plant that belongs METH-induced memory deficits in mice. to the Lamiaceae family and has a variety Repeated administration of baicalein of therapeutic applications. Baicalein, an resulted in attenuation of acute binge active component isolated from the roots METH-induced amnesia via dopamine D2 possesses free radical scavenging and anti- receptors in the passive avoidance test inflammatory effects. Several in vitro and (Figure 1). It also decreased lipid in vivo studies reported potent peroxidation and peroxynitrite production neuroprotective properties for baicalein in the hippocampus of mice (Wong et al.,

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2014). Pretreatment of METH-intoxicated Levo-tetrahydropalmatine mice with baicalein, attenuated the loss of Since last centuries, many species of dopamine transporter (Wu et al., 2006) and Corydalis have been used as traditional dopamine level (Liu et al., 2006) in the herbal medicines in Asia. Levo- striatum, dose-dependently. The authors tetrahydropalmatine (L-THP) is one of the suggested that the neuroprotective effect of most important active ingredients of baicalein in the mouse striatum is related to Corydalis ternata and it has analgesic reduction in neutrophil count and lipid (Wang et al., 2010a), sedative, hypnotic, peroxidation (Sowndhararajan et al., 2017; and neuroleptic properties (Ding, 1987; Wu et al., 2006). Baicalein also elevated Zhao et al., 2014a). It was approved by NO level in the brain and protected mice ministry of health of for medical uses brain from METH-induced reduction of NO and has been implemented into practice content (Liu et al., 2006). since 1977 (Gong et al., 2016; Su et al., 2013). L-THP is an antagonist of D1 and Sauchinone D2 dopamine receptors and modulates D3 Sauchinone is an active compound of receptors (Wang and Mantsch, 2012; Zhao Saururus chinensis (Asian lizard's tail) that et al., 2014a). Its affinity for D1 is 4-7 fold has been used for the treatment of hepatitis higher than for D2 receptor (Guo et al., and jaundice in Chinese traditional 1997). The rewarding properties of medicine (Kim et al., 2013a). Sauchinone, addictive drugs have been attributed to both which is a lignan structure, has D1 and D2 receptors (Bardo et al., 1993; hepatoprotective, antioxidant and anti- Park et al., 2014; Shippenberg and Herz, inflammatory effects. It can suppress NO 1987) (Figure 1). So, the therapeutic effects production in dorsal striatum of mouse of L-THP against different kinds of drug (Jang et al., 2012b; Lee et al., 2003). addiction such as nicotine (Faison et al., Regarding the effect of NO on METH- 2016), opiate (Liu et al., 2005; Liu et al., induced neurotoxicity, the potential 2009; Yue et al., 2012), cocaine (Mantsch protective effect of sauchinone against et al., 2007; Mantsch et al., 2010; Sushchyk METH adverse effects, was evaluated (Jang et al., 2016; Wang and Mantsch, 2012; Xi et al., 2012a). Sauchinone attenuated the et al., 2007) and ethanol (Kim et al., 2013b) METH-induced degeneration of have been evaluated. Additionally, L-THP dopaminergic nerve terminals. In addition, significantly ameliorated heroin craving pretreatment with sauchinone reduced the and increased the abstinence rate of heroin glial cell activation markers (glial fibrillary abusers in a double-blinded and placebo- acidic protein and CD11b antigens) and controlled clinical trial (Yang et al., 2008). inhibited the synthesis of NO (Figure 1) L-THP pretreatment attenuated the (Jang et al., 2012b). However, acquisition and expression of MICPP, administration of sauchinone alone did not facilitated the extinction of MICPP and show any significant changes in glial prevented the reinstatement of MICPP in markers or NO synthase activity (Jang et mice and rats (Gong et al., 2016; Su et al., al., 2012b). 2013) (Table 3). However, administration Kim and coworkers evaluated the effects of L-THP alone could not induce any of pretreatment with sauchinone on METH- conditioned place preference (Gong et al., induced hypertactivity (MIH) and CPP. 2016; Su et al., 2013). Yun et al. (2014) also Sauchinone induced a dose-dependent reported that L-THP suppressed the protective effect on MIH and suppressed serotonin-induced head twitch response the expression and acquisition of METH- (HTR) and climbing behavior through the induced CPP (MICPP) (Kim et al., 2013a). activation of dopaminergic system in mice The authors believed that these effects of (Yun, 2014a). sauchinone were related to inhibition of NO synthase (Table 2).

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Table 3. Summarized of evaluation the effects of l-tetrahydropalmatine (L-THP) on methamphetamine (METH) adverse effects.

Reference Animal Evaluation Design Results

Yun (Yun, Mice Time spent in PrT l-THP 10 and 15 mg/kg, i.p.) + APO Inhibited climbing behavior 2014a) climbing behavior (2 mg/kg) HTR PrT l-THP 10 and 15 mg/kg, i.p.) + 5-HT Inhibited HRT (80 g/10 l/mouse, i.c.v.) Rats MIH l-THP (10 and 15 mg/kg) + METH (1 Inhibited MIH mg/kg ip) D3 receptor mRNA l-THP (15 mg/kg) + METH (1 mg/kg ip) Block the METH-induced expression in CPU decrease in D3 receptor mRNA (PCR) Gong (Gong Rats METH Self- METH addicted rats PrT l-THP (0, 1.25, Decreased the number of active et al., 2016) administration 2.5 and 5 mg/kg, i.p.) nose pokes Reinstatement test L-THP (0, 1.25, 2.5 and 5 mg/kg, i.p.) + Decreased the number of active METH (1 mg/kg) I.P. nose pokes MIH PrT l-THP (0, 1.25, 2.5 and 5 mg/kg, i.p.) 5 mg/kg reduced total distance + METH (1 mg/kg, i.p.). travel Su (Su et al., mice MICCP PrT L-THP (5, 10 and 20 mg/kg) + METH Attenuated by 10 and 20 mg/kg 2013) A) acquisition (1 mg/kg, i.p.) in conditioning phase B) expression PrT L-THP 5, 10 and 20 mg/kg) + METH Attenuated by 5 and 10 mg/kg in behavioral test C) extinction PrT METH (1 mg/kg i.p.) + L-THP (10 Facilitate the extinction of mg/kg) in the testing phase MICPP Reinstatement PrT L-THP (10.0 mg/kg.) + METH (1 inhibit the reinstatement mg/kg, i.p.). Chen (Chen mice Learning and METH (5 or 10 mg/kg) + L-THP (5 or 10 Resolved METH -elongation et al., 2012b) memory (Morris mg/kg) escape latencies and METH- water maze test) reduced platform site crossings Escape latencies Platform site crossings Expression of total METH (10 mg/kg) + L-THP (10 mg /kg ) Reversing METH- reduction ERK1/2 in the PFC ERK 1/2 expression (Western blotting)

Zhao (Zhao et mice MIH METH (2 mg /kg) + l-THP (5 and 10 l-THP attenuated MIH al., 2014a) mg/kg) Development and METH (2 mg /kg) + l-THP (5 and 10 l-THP attenuated the Expression of MILS mg/kg) Development and expression of MILS Activation of ERK PrT l-THP (5 and 10 mg/kg) + METH l-THP attenuated METH-induced (ERK1/2 in the NAc (2 mg/kg) Phosphorylation of ERK1/2 and CPU)

APO=apomorphine; CPU=caudate putamen; D=dopamine; ERK=extracellular-regulated kinase; HTR=5-HT- induced head twitch response; i.c.v.=Intracerebroventricular injection; i.p.=Intraperitoneal; l-THP=l- tetrahydropalmatine; METH=methamphetamine; MICPP=METH-induced conditioned place preference; MIH=methamphetamine induced hyperactivity; MILS=Meth-induced locomotor sensitization; NAC=nucleus accumbens; PFC=prefrontal cortex; PrT=Pretreatment with; Sch-23390=dopamine 1 antagonist .

L-HTP did not affect locomotor activity synaptic plasticity and memory formation of animals, therefore, the HTR suppressing (Figure 1) (Thiels and Klann, 2001). The effect of L-THP was not related to motor reduction in ERK activation following impairments (Yue et al., 2012). METH administration was associated with In addition, L-THP attenuated the recognition memory impairment (Kamei et METH-induced hyperlocomotion and al., 2006). Zhao et al. showed that L-THP expression of the D3 receptor mRNA in the could activate the ERK signaling pathway striatum (Yun, 2014a). Zhao and coworkers in the nucleus accumbens (NAc) and also reported that co-administration of L- caudate putamen (CPu) (Zhao et al., THP and METH diminished METH- 2014a). Addictive drugs increase the induced locomotor sensitization and phosphorylation of ERK (Valjent et al., hyperactivity (Zhao et al., 2014a). 2006a). Amphetamine-induced locomotor Extracellular-regulated kinase (ERK) is sensitization and MICPP were attenuated an important protein that contributes to by inhibition of ERK phosphorylation

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(Valjent et al., 2006a; Valjent et al., 2006b). bioavailability and high production costs of It was also reported that single injection of 1-SPD are noted as the limitations in L-THP to alcohol naïve mice increased clinical researches (Sun et al., 2009). Mi et phosphorylation of ERK in the CPu but not al. evaluated the anti-addictive properties of in the NAc (Kim et al., 2013b). l-scoulerine (l-SLR), an analogue of l-SPD. In addition to inhibitory effects of L- l-SLR is a D2 receptor antagonist, D1 THP on dopamine receptors and ERK receptor agonist and a 5-HT1A receptor activation, L-HTP inhibited the partial agonist (Figure1) (Mi et al., 2016). l- amygdaloidal dopamine release (Lin et al., SLR attenuated the METH-induced 2002), facilitated the attachment of GABA anxiety-like behaviors in zebrafish. Indeed, to GABAA receptors (Halbsguth et al., pretreatment of mice with l-SLR attenuated 2003), antagonized the α1 adrenergic chronic METH-induced behavioral receptors (Ko et al., 1996), modulated sensitization and blocked the expression of serotonin receptors (Liu et al., 2009), METH-induced CPP. However, L-SLR inhibited voltage-sensitive Ca2+ channels failed to reduce acute MIH (Table 2) (Mi et (Henkes et al., 2011) and inhibited the al., 2016). expression of K⁺ channel (Kv1.5) (Li et al., 2017). All of these functions are involved Other herbal compounds in the development of addiction and There are more compounds from several dependence to drugs (Volkow and Morales, herbs that have been evaluated on METH- 2015). Therefore, it seems that L-THP is an induced adverse effects in independent appropriate compound for attenuation of researches or as a part of an experimental METH adverse effects. It also has potential method. Accordingly, barakol, the major to be used in the treatment of METH abuse. constituent of Cassia siamea Lamk, dose- However, more clinical trials are warranted dependently decreased the METH-induced to support its applications in clinical hyperlocomotion via inhibition of practice. dopaminergic receptors (Sukma et al., 2002). Stephania intermedia Chlorogenic acid is another important l-stepholidine (l-SPD) is an alkaloid polyphenol found in coffee, black , isolated from Stephania intermedia eggplants, peaches, prunes, green tea, and (Family: Menispermaceae). l-SPD several other foods (Rio et al., 2010). possesses dual pharmacological effects on Chlorogenic acid has anti-inflammatory, dopamine receptors. It acts as a partial antioxidant and hepatoprotective effects. agonist at D1 receptors and an antagonist at Pretreatments of rats with chlorogenic and D2 receptors (Natesan et al., 2008). It was caftaric acids resolved the METH–induced reported that l-SPD effectively antagonized hepatotoxicity and reversed METH- the D1 receptors in the presence of METH- increased oxidative stress indexes (Koriem induced dopamine release and attenuated and Soliman, 2014). METH self-administration behavior in rats Resveratrol (RES) is a polyphenolic (Yue et al., 2014). Yue and coworkers compound of grapes with antioxidant and assessed the effect of l-SPD on METH- anti-inflammatory properties that induced locomotor sensitization in mice. attenuated dopamine depletion in an animal They found that l-SPD prevented the model of Parkinson's disease induced by 6- hyperlocomotion and sensitized motor hydroxydopamine (Khan et al., 2010). behaviors induced by acute and chronic Although, pretreatment of mice with single METH administration (Ma et al., 2014). administration of RES did not reduce acute Their findings suggested that l-SPD may be MIH, repeated administration of RES (1–20 utilized therapeutically for the treatment of mg/kg) decreased MIH. Multiple-dose METH dependence. However, the poor administration of RES also attenuated

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METH-induced dopamine overflow in the sensitization of locomotor activity (Zhao et rat brain (Figure 1) (Miller et al., 2013). It al., 2012). also protected neuronal cell lines against Cinnamic Aldehyde (CA) or METH-induced apoptotic by caspase-3 cinnamaldehyde is a natural chemical dependent pathway (Kanthasamy et al., compound of tree, with a broad 2011). range of biological properties. In our Limonene a monoterpene from genus previous study, CA showed neuroprotective Citrus (Zhou et al., 2009) showed effects in METH-intoxicated animals and anxiolytic-like and antinociceptive enhanced learning and cognition. The properties and regulatory effects on author suggested that CA exerts its different neurotransmitters (De Almeida et protective effects through activation of the al., 2012; Do Amaral et al., 2007; Zhou et ERK pathway in the prefrontal cortex al., 2009). The HTR response was dose- (Saeed et al., 2018). dependently inhibited by intracerebroventricular injection of limonene in mice (Yun, 2014b). Conclusion Pretreatment of rats with limonene (200 and METH is a highly addictive substance 400 mg/kg), also reduced MIH in a dose- and induces many destructive effects in dependent manner (Yun, 2014b). The brain and causes psychological problems in protective effect of limonene on MIH may acute or chronic toxicity. Nowadays, herbal be related to increases in dopamine levels in products are very affordable, effective and the nucleus accumbens (Yun, 2014b) and available and are widely used for GABA levels in rat brain (Figure 1) (Zhou therapeutic purposes. Various herbal plants et al., 2009). have been suggested for alleviating METH The bioactive components from adverse effects and reducing tolerance and Glycyrrhizae uralensis radix with dependence to METH. Based on in vitro neuroprotective properties were able to and in vivo findings, only a few natural suppress cocaine-induced dopamine products such as ginseng and levo- release. Oral pretreatment of METH- tetrahydropalmatine have sufficient intoxicated rats with methanolic extract of documents and are promising candidates G. uralensis radix dose-dependently for treatment of METH abuse and toxicity. reversed MIH. Moreover, the methanolic However, clinical trials are needed to prove extract completely reversed the increased these finding. dopamine content in the brain tissues following METH treatment (Zhao et al., Acknowledgment 2014b). The authors are thankful to Mashhad Curcumin is a major natural phenolic University of Medical Sciences. component of Curcuma longa that has shown antidepressant effect. Conflicts of interest Neurochemical studies revealed that All authors declare no curcumin has the ability to modulate the financial/commercial conflicts of interest. serotonin pathway dependent function (Kulkarni et al., 2008). Curcumin also dose- dependently attenuated opioid tolerance References dependence through suppressing 2+ Alavi M S, Hosseinzadeh H, Shamsizadeh Ca /-dependent protein kinase A,Roohbakhsh A. 2016. The effect of II α activity (Hu et al., 2015). Pretreatment O-1602, an atypical cannabinoid, on with curcumin had no noteworthy effect on morphine-induced conditioned place acute MIH, however, its chronic preference and physical dependence. administration increased METH-induced Pharmacol Rep, 68: 592-597.

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