Phytotherapy of opioid dependence and withdrawal syndrome: a review.

PHYTOTHERAPY RESEARCH Phytother. Res. (2013) Published online in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/ptr.5073

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 components 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. Nonetheless, 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

* Correspondence to: Hossein Hosseinzadeh, Pharmaceutical Research Center, Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran. E-mail: [email protected]

Copyright © 2013 John Wiley & Sons, Ltd.

has been implicated in the mechanisms of opioid tolerance. Repeated administration of opioids upregulates cyclic adenosine monophosphate (cAMP), proteinkinase 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 receptor-mediated activation of intracellular cascades may also be involved in the development of opioid tolerance and dependence. NMDA receptor antagonists 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-induced 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. Shortterm 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). Received 28 July 2013 Revised 18 September 2013 Accepted 22 September 2013

S. M. TABATABAI ET AL.

METHODS We searched SciVerse (ScienceDirect and Scopus), PubMed, Springerlink, ProQuest, Wiley Online Library, Google Scholar databases, and two Iranian scientific websites SID and IranMedex. We used keywords such as “plant” “phytotherapy”, “herbal”, “Complementary medicine”, and “tolerance” “dependence” “withdrawal syndrome”. All relevant data published from the year 2000 to present were included.

RESULTS Several plants (Table 1) and their active constituents (Table 2) have been shown to reduce opioid dependence and withdrawal syndrome in several animal and human studies. In the following section, these plants and their active constituents will be discussed.

PLANT EXTRACTS Areca catechu L. Areca nut (Areca catechu L.) belongs to the Arecaceae family. It is an ingredient of betel quid, a popular herbal masticatory in East Asia. It has psychoactive properties, and addiction may result from prolonged chewing. Consumption of this drug is associated with many adverse systemic conditions (Javed et al., 2010). The dichloromethane fraction (125 and 175 mg/kg) delayed the onset of withdrawal syndrome and decreased the total number of jumping in mice. The authors attributed these alleviating effects to the MAO-A inhibitory properties of this plant (Kumarnsit et al., 2005). Even though this fraction of the plant was effective in attenuating withdrawal expression in mice, associated adverse effects may limit its clinical applicability.

The striatal tissues of mice were analyzed for dopamine, serotonin, and their metabolites. The extract lowered locomotor activity in both morphine-treated and salinetreated mice but reduced DA and 5HT and their metabolites only in the morphine-treated group (Rauf et al., 2012). Benincasa hispida Cogn. Benincasa hispida Cogn. (Cucurbitaceae) is mentioned in the Ayurveda to be useful for nervous disorders. It contains triterpenes, sterols, and glycosides (Kirtikar and Basu, 1975). Grover et al. (2000) evaluated the fresh fruit pulp juice of this plant for its preventive and suppressive potential against morphine-withdrawal syndrome in morphine-dependent Swiss mice. In the first part, the mice treated with B. hispida juice did not show jumping episodes compared with untreated dependent mice, and this effect was statistically significant. In the second part of the study, the subgroup receiving the juice showed no jumping and markedly a lower number of stools. It was concluded that the juice of B. hispida could potentially prevent morphine-withdrawal problems or suppress these complications after their onset (Grover et al., 2000). No positive control was used in this experiment, and the method of induction of dependence was not clear. Different doses and different routes of administration were not examined. Caulis sinomenii Caulis sinomenii is the dried plant stems of Sinomenium acutum and S. acutum var. cinereum. The effect of this plant (10 g/kg) and its main active alkaloid, sinomenine, (60 mg/kg) on morphine conditioned place preference (CPP) was assessed in mice. Histamine levels were also measured in the mice brains. Treatment with both the extract and sinomenine reduced morphine place preference and lowered brain histamine levels (Mo et al., 2006).

Bacopa monneria

Coptis japonica

Bacopa monneria (BM) (Scrophulariaceae) is used in Ayurvedic medicine. The main component in BM is Bacopaside A, which has neuropharmacological activities. BM extract has Ca2+-channel blocking activity, which reduces morphine tolerance and modulates adenyl-cyclase activation by opioid receptors (Rauf et al., 2011). The effect of ethanolic extract of the whole parts of BM on withdrawal syndrome was assessed in vitro in guinea-pig ileum and showed inhibitory effects on withdrawal traces in the diagram in a dose-dependent manner. Authors suggested that the effect of BM alcoholic extract is probably associated with anticholinergic and Ca2+ channel antagonist activity of its components (Sumathi et al., 2002). The ethanolic extract of BM showed inhibitory effects on analgesic tolerance, withdrawal signs, and reversed tolerance to morphine (Sumathi and Veluchamy, 2007). In a study in 2012, the effects of the n-buthanolic BM extract on morphine-induced hyperactivity was studied.

Coptisine, an important ingredient in Coptis japonica, has been reported to inhibit MAO-A and is effective in the reduction of withdrawal syndrome signs (Kwon et al., 2008). Methanolic extract of C. japonica (MCJ) on morphineinduced CPP and p-CREB expression was assessed. Administrated 1 h before saline or morphine injection during the conditioning phase, the extract inhibited place preference. In the morphine-treated group, p-CREB expression was significantly increased in the dentate gyrus of mice showing CPP. In the MCJ pretreated group, p-CREB expression was not increased (Kwon et al., 2008). In another experiment, c-fos expression was investigated in different brain parts. An increase in the expression was seen in the morphine-induced CPP group (Lee et al., 2003). In conclusion, MCJ inhibits morphine-induced CPP through modulation of c-fos and p-CREB expression as well as mechanisms related to the dopaminergic system (Kwon et al., 2008; Lee et al., 2003).


Phytother. Res. (2013)


Alcoholic

Alcoholic

Bacopa monneria (Scrophulariaceae)


Aqueous and ethanolic extracts

Methanolic extract

Coptis japonica (Ranunculaceae)

Crocus sativus (Iridaceae)

Methanolic extract

–

Coptis japonica (Ranunculaceae)

Caulis sinomenii

Fruit juice

Benincasa hispida (Cucurbitaceae) Camellia sinensis (Theaceae)

( )-Epigallocatechin gallate

n-Buthanolic


–

N-buthanolic



Dichloromethane fraction

Type of extract

Areca catechu (Arecaceae)

Plant (family)

Naloxone-induced withdrawal

Naloxone-induced withdrawal, cAMP level evaluation Conditioned place preference. Measuring brain histamine levels Conditioned place preference c-fos expression in the cortex, striatum, nucleus accumbens, and hippocampus of mice Conditioned place preference. Measuring p-CREB expression

Clinical study, SGOT, SGPT, ALP, LDH, and gamma-GT, urea, creatinine, and uric acid. Histopathological study of kidney and liver Measuring DA, 5HT, and their metabolites in mice striata Morphine withdrawal

Tail-flick test, withdrawal signs, recording ambulatory activity Guinea-pig ileum

Hot-plate test

Naloxone-precipitated morphine withdrawal

Methods

Tested doses

–

Aqueous: 80, 160, and 320 mg/kg. Ethanolic: 200, 400, and 800 mg/kg

100 mg/kg orally

100 mg/kg

–

1 mL p.o. with each morphine injection –

(40 mg/kg)

100, 200, 500, and 1000 μg/mL

40 mg/kg

5, 10, and 15 mg/kg

75, 125, and 175 mg/kg

Table 1. Plants effective in reducing opiate dependence and withdrawal syndrome

Inhibition of increasing p-CREB expression during psychological dependence. Interaction with opioid system

Inhibition of increasing c-fos expression during psychological dependence

Lowering brain histamine levels

–

Crocin, safranal

Protoberberine alkaloids, coptisine

Sinomenine

( )-Epigallocatechin gallate

–

– Inhibition of cAMP increase

–

(Continues)

Hosseinzadeh and Jahanian (2010)

Kwon et al. (2008)

Lee et al. (2003)

Mo et al. (2006)

Oh et al. (2007)

Grover et al. (2000)

Rauf et al. (2012)

Sumathi et al. (2009)


–

–


Rauf et al. (2011)

Kumarnsit et al. (2005)

Author (year)

–

Bacopaside A, a mixture of Bacoside A3, Bacopaside II, and Bacosaponin C

–

Active ingredients

–

Anticholinergic and also calcium-channel antagonistic activity of its components –

Calcium-channel blocking activity, modulating the adenyl-cyclase activation by opioid receptors, effects against oxidative stress induced by nitric oxide (NO) –

MAO-A inhibition

Possible mechanisms

PHYTOTHERAPY OF OPIOID DEPENDENCE



Aqueous root extract

Aqueous root extract

Delphinium denudatum (Ranunculaceae)

Delphinium denudatum (Ranunculaceae) Delphinium denudatum (Ranunculaceae) Ferula gummosa (Apiaceae)

Mentha longiflora (Lamiaceae)

Matricaria camomilla (Asteraceae)

Ethanolic and aqueous

Aqueous

–

Aqueous and hydroalcoholic

Marrubium vulgare Lamiaceae)

Matricaria camomilla (Asteraceae)

Aqueous

Methanol–chloroform (1:1) crude extract, various fractions Aqueous, ethanolic, and hydroethanolic

Hypericum perforatum (Hypericaceae)

Hypericum perforatum (Hypericaceae)

Fruit essential oil (FEO) of Cuminum cyminum

Cuminum cyminum (Apiaceae)

Alcoholic

Fruit essential oil (FEO) of Cuminum cyminum

–

Aqueous extract

Type of extract

Cuminum cyminum (Apiaceae)

Crocus sativus (Iridaceae) Crocus sativus (Iridaceae)

Plant (family)

Table 1. (Continued)

Naloxone-precipitated withdrawal. Locomotion tests

Naloxone-precipitated withdrawal. Inhibition of weight loss Naloxone-precipitated withdrawal.

Hot-plate test, naloxoneprecipitated withdrawal, locomotion tests

Naloxone-precipitated withdrawal


Naloxone-induced withdrawal Naloxone-induced withdrawal Naloxone-induced withdrawal

Tail-flick test, naloxone-induced withdrawal

Conditioned place preference

Tail-flick test, Naloxone-induced withdrawal

Conditioned place preference Conditioned place preference

Methods

10, 25, and 50 μg in paragigantocellularis nucleus 0.194, 0.776, and 1.358 g/kg i.p. (aqueous). 0.029, 0.12, and 0.2 g/kg (ethanolic)

25 mg/kg i.p. for 7 days

20 mg/kg p.o. (single dose or with each morphine injection) 0.4 and 1.2 (but not 0.8) mg/kg p.o. throughout dependence induction 0.1, 0.5, 1.5, or 2.5 g/kg i.p.

200, 400, 800, and 1600 mg/kg 700 mg/kg or 350 mg/kg (in different schedules) 0.42, 1.65, 3.0, and 4.2 g/kg i.p.

200, 400, 800, and 1600 mg/kg

0.001%, 0.01%, 0.5%, 0.1%, 1%, and 2%; 5 mL/kg

0.001%, 0.01%, 0.5%, 0.1%, 1%, and 2%; 5 mL/kg

200, 400, and 600 mg/kg

10, 50, and 100 mg/kg

Tested doses

Antinociception, partial opioid agonism, muscle relaxant

–

Increase in cAMP in CNS

Muscle relaxant, Opioid activity

Central serotonergic, nitric oxide synthase inhibitory effects –

Blockade of alpha7-type nicotinic receptor Opioid receptors, adenosine receptors

–

Alkaloids [flavon equamin (μ and κ agonist) isoquinoline alkaloids]. Flavonoids

–

(Continues)

Hosseinzadeh et al. (2011b)

Esmaeili et al. (2008)

Gomaa et al. (2003)

Hosseinzadeh et al. (2007)

Feily and Abbasi (2009)

–

Marrubiinic acid and uteolin (muscle relaxants), marrubiin (opioid activity) Apigenin (0.3%)

Sobhan et al. (2009)

Ramezani et al. (2001)

Rahman et al. (2002)

Zafari et al. (2002)

Zafari et al. (2001)

–

Tannins, saponins, terpenoids

–

Methyllycaconitine alkaloid (MLA), c-19 diterpenoid alkaloids –

Haghparast et al. (2008)

Linolool and β-D-glucopyranosides

Khatibi et al. (2008)

Imenshahidi et al. (2011)

Sahraei et al. (2007)

Author (year)

Crocin

–

– Interaction with dopaminergic system and GABAergic systems Linolool and β-D-glucopyranosides: inhibitory effects on NO. GABAergic system Involvement of GABAA and GABAB receptors, effect on locomotor activity is denied –

Active ingredients

Possible mechanisms




Oil

Nigella sativa (Ranunculaceae) Otostegia persica (Labiatae) Panax ginseng (Araliaceae) Panax ginseng (Araliaceae) Panax ginseng (Araliaceae)

Peganum harmala (Zygophylaceae)


Papaver rhoeas L. (Papaveraceae) Papaver rhoeas L. (Papaveraceae) Papaver rhoeas L. (Papaveraceae) Passiflora incarnata (Passifloraceae) Passiflora incarnate (Passifloraceae)

Crude seed oil

Nigella sativa (Ranunculaceae)

Harman and harmine

Norharman (β-carboline)

–

Methanol extract

–

–

Water–alcohol extract

Naloxone-precipitated (pharmacologic) and time-induced (physiologic) withdrawal scores Naloxone-precipitated withdrawal

Conditioned place preference Conditioned place preference Naloxone-precipitated withdrawal Naloxone-precipitated withdrawal Naloxone-precipitated withdrawal

Locomotor activity

–

Hydro-alcohol extract

Tail-flick response

Naloxone-precipitated withdrawal Naloxone-precipitated withdrawal Tail-flick response

Naloxone-precipitated withdrawal. Locomotion tests Physician assessment and self-report of signs and symptoms Hot-plate test

Conditioned place preference

Clinical assessment

Methods

–

Hydroalcoholic and hexane extracts Root extract

Ground seeds (oral)

Nigella sativa (Ranunculaceae)

–

Aqueous

Leaves (oral)

Type of extract

Nepeta glomerulosa (Lamiaceae)

Mythargyna speciosa (Rubiaceae)

Mythargyna speciosa (Rubiaceae)

Plant (family)


5 or 10 mg/kg i.p.

20 mg/kg i.p.

Pelleted with rat food

10, 50, and 100 mg/kg

60 drops

25, 50, and 100 mg/kg

25, 50, and 100 mg/kg

25, 50, and 100 mg/kg

100 and 200 mg/kg

500, 1000, and 1500 mg/kg 12.5, 50, 100, and 200 mg/kg 50, 100, and 200 mg/kg

2, 4, and 8 mL/kg

4 and 8 mL/kg p.o. after each morphine injection

500 mg TDS for 12 days

0.4, 1.2, 2.0, and 2.8 g/kg i.p.

1 and 2 mg/L

–

Tested doses

Opioid agonism, glutamate receptor antagonist Imidazoline receptor pathway

Opioid, monoaminergic, and cAMP pathways

–

c-Fos expression in nucleus accumbens and tyrosine hydroxylase expression Inhibition of opioid receptors and anti-dopaminergic activity Mild opioid, anti-dopaminergic, and anticholinergic effects Mild opioid, anti-dopaminergic, and anticholinergic effects –

–

Non-opioid mechanisms

–

NO synthesis inhibition, CNS oxidative stress attenuation –

Calcium-channel blockade

Through hypothalamus– pituitary–adrenal axis and the kappa opioid receptors GABAA enhancement

μ and κ agonism and other mechanisms

Possible mechanisms

Author (year)

Sahraei et al. (2006) Pourmotabbed et al. (2004) Akhondzadeh et al. (2002) Dhawan et al. (2002)

– – –

Norharman (β-carboline)

A tri-substituted benzoflavone moiety (BZF) Harmaline

–

(Continues)

Cappendijk et al. (1994)

Khalili et al. (2010)


–

–

Ramarao and Bhargava (1990) Bhargava and Bhargava (1990) Lee et al. (2011)

Abdel-Zaher et al. (2011)

–

–

Abdel-Zaher et al. (2010)

–

Hajhashemi et al. (2004)

Sangi et al. (2008)

–

–

Hosseinzadeh and Ziaee (2006)

–

Indole alkaloids Boyer et al. (2007) (mitargynine, 7-hydroxymitragynine etc.) – Khor et al. (2011)

Active ingredients



Nutshell extract

Pistacia vera (Anacardiaceae) Pistacia vera (Anacardiaceae)


Aqueous

Methanolic

Chloroform and aqueous-methanolic (1:3) fractions, chloroform MPLC fractions Leaf extract

Valeriana officinalis L. (Valerianaceae)

Aqueous, methanolic, and chloroform extracts of both aerial parts and rhizome

Trachyspermum copticum Aqueous extract (Apiaceae)

Salvia leriifolia (Lamiaceae) Salvia leriifolia (Lamiaceae) Stachys byzantine (Lamiaceae)

Rosmarinus officinali (Lamiaceae)

Alcohol and aqueous

–

Hydroalcoholic

Rhodiola rosea (Crassulaceae)

Rhodiola rosea (Crassulaceae) Rosmarinus officinalis (Lamiaceae)

Methanolic

Polygala telephioides

Hydroalcoholic

Essential oil

Type of extract

Pimpinella anisum (Apiaceae)


Plant (family)


100 to 1500 mg/kg

500 mg/kg

1.68 and 2.4 g/kg i.p. (aqueous). 0.96 g/kg (ethanolic) 0.96 and 1.68 g/kg i.p. (0.96 for MPLC fractions)

10, 15, or 20 mg/kg

300 mg/kg p.o. (single dose, not effective). 10, 100, and 300 mg/kg (after each morphine dose) 10, 15, and 20 mg/kg p.o. before each morphine dose or once before naloxone

0.25–2 g/kg

25, 50, 100 and 200 mg/kg

0.2, 0.25, and 0.3 (not 0.5) mL/kg i.p. before each morphine dose

Tested doses


Rhizome (1, 5, 25, and 50 mg/kg), aerial parts (1, 5, 25, 50, and 100 mg/kg)

Tail-flick method. 0.04, 0.16, 0.28, and Naloxone-precipitated 0.4 g/kg i.p. withdrawal. Locomotion test Naloxone-precipitated Different concentrations withdrawal (diluted 10, 100, and 1000 times)

Naloxone-precipitated withdrawal Hot-plate test

Conditioned place preference test Naloxone-precipitated withdrawal. Locomotion tests Naloxone-precipitated withdrawal. Locomotion tests

Naloxone-precipitated withdrawal, locomotion open field test, elevated plus maze, hot-plate test Naloxone-precipitated withdrawal, analgesic latency

Naloxone-precipitated withdrawal Hot-plate, writhing, and formalin tests

Naloxone-precipitated withdrawal. Locomotor activity tests Conditioned place preference test

Methods

Reduction of aspartate and glutamate, and inhibition of excitatory glutamatergic synaps –

Flavonoids may have been involved

Binding to GABA/benzodiazepine receptor Receptors

Inhibition of the cAMPdependent protein kinase. GABAergic enhancement, spasmolysis

Partial opioid agonist

Opioid receptors, inhibition of inflammatory mediators Cholinergic activity (memory impairment), acceleration of morphine clearance Increase in norepinephrine, dopamine, or 5HT, CRF antagonism, regulating heat-shock proteins –

GABAA enhancement, pharmacokinetic interaction with morphine, induction of conditioned aversion –

Possible mechanisms

Egashira et al. (2006)

–

–

Parvardeh et al. (2002)

–

–

–

Flavonoids, tannins

–

–

(Continues)

Sharifzadeh et al. (2006)

Jafari et al. (2007)


Hosseinzadeh and Lari(2000) Alemy et al. (2012)


Hosseinzadeh and Nourbakhsh (2003)

Mattioli et al. (2012b)

Mattioli and Perfumi (2011)

Haghparast et al. (2006)

–

Alkaloids, saponins, tannins, and flavonoids Oleanolic and ursolic acids (terpenoids)

Rosavin, salidroside


Aricioglu-Kartal et al. (2003)

Author (year)

–

Harman and harmine (β-carboline alkaloids)

Active ingredients



Darvishzadeh-Mahani et al. (2012) Hosseinzadeh et al. (2007) Linalool α-pinene Camphor and Borneol Crude aqueous and methanolic, hydroalcoholic (2:3 and 1:9), petroleum ether, chloroform fractions, MPLC chloroform fractions

–

Crocus sativus


cAMP, cyclic adenosine monophosphate; CREB, cAMP response element-binding protein; MPLC, medium pressure liquid chromatography.

50 and 100 mg/kg

0.28, 1.12, and 1.96 g/kg i.p., Benzodiazepine-like effects, 1.96 for chloroform, and cAMP pathway, muscle 0.28 for MPLC fractions relaxant (crude methanolic)

–

Kasture et al. (2009) –

Reduction of spine density in the nucleus accumbens shell – 100 mg/kg

Withania somnifera (Solanaceae) Withania somnifera (Solanaceae) Zingiber officinale (Zingiberaceae) Zhumeria majdae (Lamiaceae)

Withania somnifera (Solanaceae)

Commercial root extract

–

Tail-flick, morphinewithdrawal jumps Confocal laser scanning microscopy Tail-flick test, naloxoneprecipitated withdrawal Hot-plate test. Naloxoneprecipitated withdrawal. Locomotion tests

100 mg/kg

–

Glycowithanolides Ramarao et al. (1995) consisting of sitoindosides VII–X, withaferin-A – Kasture et al. (2009) – – –

100 mg/kg

Methods Type of extract Plant (family)


Tested doses

Possible mechanisms

Active ingredients

Author (year)


Saffron (Crocus sativus) is a member of the Iridaceae family. Crocin is a coloring pigment of saffron, which is responsible for anxiolytic-like effect, antidepressant and aphrodisiac activity, learning, and memory-improving properties. It also palliates physical signs of morphine withdrawal (Capasso et al., 1998). Saffron extract has many effects on CNS. It inhibits acquisition and expression of morphine-induced withdrawal and has interaction with the opioid system (Hosseinzadeh and Nassiri-Asl, 2013). The effects of aqueous and ethanolic extracts of saffron stigma and its constituents were evaluated on morphine-withdrawal syndrome in mice. Safranal was administrated at doses of 0.025 and 0.05 s.c. to nondependent mice. It was also injected at doses of 0.0085, 0.0175, 0.025, 0.05, and 0.15 mL/kg 30 min before morphine injection and at doses of 0.0045, 0.0085, 0.0175, 0.025, 0.05, and 0.15 mL/kg and doses of 0.0085, 0.0175, 0.025, 0.05, and 0.15 mL/kg 1 and 2 h, respectively, after morphine injection in morphine-dependent mice. Crocin and both the aqueous and ethanolic extracts decreased the number of jumping dose-dependently. Safranal induced seizure, irritability, wet dog shake, and death. At doses of 0.025 and 0.05 mL/kg, however, it did not have these effects on non-dependent mice. When safranal was injected instead of naloxone, it induced mild withdrawal syndrome dose-dependently. We can conclude that the aqueous and ethanolic extracts of C. sativus stigma and crocin can suppress morphine-withdrawal syndrome by interaction with the opioid system. However, safranal may exaggerate signs (Hosseinzadeh and Jahanian, 2010). In another study, the effects of the plant on CPP were evaluated. Morphine (at all doses) and the extract (at 50 mg/kg) induced significant CPP. The extract (at 50 and 100 mg/kg) before morphine administration (10 mg/kg) decreased the time spent in drug-paired side. In addition, injection of the extract (10 mg/kg) on the test day to the animals that received morphine on the conditioning days decreased the expression of morphine CPP. Findings of this study suggest that acquisition and expression of morphine-induced CPP could be inhibited by administration of plant extract, even though the extract could produce CPP by itself (Sahraei Hedayat et al., 2008). In another study, the effect of crocin on morphineinduced CPP and in the reinstatement of morphineinduced CPP with morphine primes was investigated. When crocin (600 mg/kg for 4 days i.p.) was administrated 30 min before the morphine injection, it decreased the acquisition of morphine CPP. In other groups, after extinction of morphine-induced CPP, a single dose of morphine (10 mg/kg) reinstated the place reference. Crocin at doses 400 and 600 mg/kg 30 min before this dose of morphine blocked morphine-induced reinstatement of place preference. These results showed that crocin can block morphineinduced CPP and the reinstatement of place preference following priming dose of morphine. Therefore, crocin could be used as a treatment for opioid addicts (Capasso et al., 1998). There is promising data indicating that saffron or its constituents crocin and safranal may be useful in the treatment of opioid dependence in human subjects. Phytother. Res. (2013)


Coptis japonica, Phellodendron amurense, and Berberis koreana Croton menthodorus (Euphorbiaceae) Aristeguietia discolor (Asteraceae) Croton menthodorus and Aristeguietia discolor

Berberine (an isoquinoline alkaloid)

Indole alkaloids

Flavonol glycosides

Flavonol glycosides

Flavonol glycosides




Coptis japonica, Phellodendron amurense, and Berberis koreana Coptis japonica, Phellodendron amurense, and Berberis koreana Coptis japonica, Phellodendron amurense, and Berberis koreana Coptis japonica, Phellodendron amurense, and Berberis koreana

Main plant source(s(


Bioactive compound

Guinea-pig ileum contraction Guinea-pig ileum contraction Using highly selective μ or κ agonists

6

10 , 10 , and 5 10 M 4 5 1.10 , 5.10 , 5 and 10

7

10–20 mg/kg

Through both μ and κ opioid receptors

Yoo et al. (2006)

1, 3, and 10 mg/kg

Locomotor activity, measuring dopamine receptors and transporters’ density in the caudate putamen of mice. NMDA receptor channel activity in Xenopus laevis oocytes Pentobarbitone sleep test

Downregulation and inhibition of dopamine (esp. D1) and NMDA receptors

Jang and Lee (2007)

1, 3, and 10 mg/kg

Hot-plate test

(Continues)

Capasso et al. (1998)

Capasso et al. (2000b)

Capasso et al. (1998)

Nassiri-Asl et al. (2007)

Jang and Lee (2007)

1 and 2 mg/kg

Jang and Lee (2007)

Author (year)

Recording locomotor activity

Possible mechanisms

1 or 2 mg/kg of berberine orally

Effective doses

Conditioned place preference test

Method

Table 2. Bioactive compounds effective in reducing opiate dependence and withdrawal syndrome




Methanolic extract of the plant and its pure components 6.25 and 18.5 mg/kg

1.10 , 5.10 5 and 10

4

,

5

Effective doses

Heroin seeking and self-administration in rats Conditioned 12.5 and place preference test 18.75 mg/kg Tail-flick test. 50, 75, and Naloxone-precipitated 100 mg/kg withdrawal 7 7 Guinea-pig ileum contraction10 , 5.10 , 6 and 10 M 7.5, 15, and Tail-flick test. Naloxone-precipitated 30 mg/kg withdrawal in mice

Guinea-pig ileum contraction

Argemone mexicana L. (Papaveraceae)

Chinese herbs of Corydalis and Stephania genera Chinese herbs of Corydalis and Stephania genera Cinnamomum tamala, Ocimum basilicum, and Artemisia vulgaris Brugmansia arborea (L.) Lagerheim (Solanaceae) Brugmansia arborea (L.) Lagerheim (Solanaceae)

Guinea-pig ileum contraction Guinea-pig ileum contraction

Method

Sickingia williamsii Standl (Rubiaceae) Aristolochia constricta (Aristolichiaceae)

Main plant source(s(

CREB, cAMP response element-binding protein.

Tropane alkaloids

Tropane alkaloids

Levo-tetrahydropalmatine (L-THP) Linalool

Levo-tetrahydropalmatine (L-THP)

Isoquinoline alkaloids (protopine alkaloids) Isoquinoline alkaloids (protopine and allocryptopin)

Bioactive compound


Inhibition of increased CREB and ERK phosphorylation Inhibition of NMDA receptors

Possible mechanisms

Capasso et al. (2003) Mattioli et al. (2012a)


Liu et al. (2009)

Yue et al. (2012)

Capasso et al. (1997b)

Capasso et al. (1997a) Capasso et al. (2000a)

Author (year)




Limited human trials have already established the safety of saffron, safranal, and crocin (unpublished data). Cuminum cyminum Some components of Cuminum cyminum (Apiaceae) include gamma-terpinene, 2-methyl-3phenyl-propanal, myrtenal, and glucopyranisides. Recent studies showed that fruit essential oil of C. cyminum has anticonvulsive effects through GABAA receptors (Haghparast et al., 2008; Khatibi et al., 2008). It is shown that the aqueous and ethanolic extracts as well as essential oil of C. cyminum L. seeds may be effective in petit mal and grand mal seizures (Hosseinzadeh et al., 2002). Khatibi et al. investigated the effect of C. cyminum essential oil on acquisition and expression of morphine conditional place preference in mice. Repeated administration 60 min before morphine injection conditioning phase (to evaluate acquisition) resulted in a significant decrease in CPP, but administration 60 min before the test in post-conditioning phase (to evaluate expression) showed a significant decrease in CPP scores only at higher doses. The oil did not cause CPP itself (Khatibi et al., 2008). Haghparast et al. (2008) showed that the effect of C. cyminum essential oil on expression of tolerance and dependence was more than acquisition, so it seems that it acts through short-term mechanisms for morphine tolerance and dependence. Some of the major components in C. cyminum seeds such as linolool and β-D-glucopyranosides have inhibitory effects on NO production. NO plays an important role in morphine tolerance and dependence induction (Haghparast et al., 2008). Delphinium denudatum Wall Both aqueous and alcoholic extracts of Delphinium denudatum Wall (Ranunculaceae) have anticonvulsant effects, as well as non-specific anti-stress effects, because of its adaptogenic activity. Analgesia and sedation are some other effects of D. denudatum in CNS (Nizami and Jafri, 2006). In 2001, a study was carried out to examine the effect of D. denudatum aqueous root extract against morphine tolerance and dependence in mice. Concomitant administration of the extract with morphine reduced naloxoneprecipitated jumping significantly and dose-dependently (Zafar et al., 2001). In another study, oral administration of aqueous root extract (200 to 1600 mg/kg) reduced withdrawal signs by 16.82% to 75.5% (Zafar et al., 2002). The extract seems to act centrally but not through opioid receptors. These effects may be the result of the main alkaloids in Delphinium genus such as methyllycaconitine alkaloid, which has a blocking function at alpha7-type nicotinic receptor, and c-19 diterpenoid alkaloids (Rahman et al., 2002). Ferula gummosa Boiss Ferula gummosa crude extract contains tannins and saponins but not alkaloids, flavonoids, or anthocyanins. Copyright © 2013 John Wiley & Sons, Ltd.

A chloroform fraction of the extract significantly decreased withdrawal jumps in mice with an effect comparable with diazepam. The extract had analgesic effects that were reversible by naloxone, suggesting opioid-like effects of the compounds (Ramezani et al., 2001). Hypericum perforatum Hypericum perforatum L. is a very well studied herb. Its efficacy profile in the treatment of mild to moderate depression has been demonstrated in many studies. Hyperforin, rather than hypericin, is thought to be responsible for the antidepressant activity (Barnes et al., 2001). It has also shown anticonvulsant effects (Hosseinzadeh et al., 2005). The extract is effective against ethanol and nicotine dependence and withdrawal in animal models (Uzbay, 2008). Acute treatment with hydroalcoholic H. perforatum extract significantly reduced withdrawal signs, but chronically treated rats showed only a reduction in diarrhea (Subhan et al., 2009). There were no positive control groups in the study, but the effects were attributed to the central serotonergic system and nitric oxide synthase inhibitory properties. In another study, H. perforatum extract was able to reduce withdrawal signs at 0.4 mL/200 g, but it was less effective than clonidine hydrochloride (0.2 mg/kg, i.p.) (Feily et al. and Abbasi, 2009). Put together, these results show that H. perforatum may be useful in the treatment of opioid dependence and withdrawal. However, if clinical trials are to be held in patients under methadone maintenance therapy, it should be taken into account that H. perforatum reduces plasma methadone levels, probably through induction of CYP3A4 enzyme and P-glycoprotein (Eich-Hochli et al., 2003). H. perforatum is already approved in the treatment of mild to moderate depression, and the data presented here clearly show its potential efficacy in morphine-dependent subjects. Marrubium vulgare L. Marrubiin, a furan labdane diterpene abundant in Marrubium vulgare L., has analgesic and muscle relaxant properties (Meyre-Silva and Cechinel-Filho, 2010). In one study, the aqueous or hydroalcoholic extracts reduced jumping episodes in morphine-dependent mice significantly and dose-dependently. This effect was partly attributed to muscle relaxant activity, because the extracts reduced motor activity and coordination. Marrubiinic acid and luteolin showed muscle relaxant activity in previous studies. Marrubiin may have also acted via opioid receptors (Hosseinzadeh et al., 2007c). Matricaria camomilla Matricaria camomilla L. (chamomile) is one of the most popular herbs with anxiolytic and anti-spasmodic effects. Bioactive ingredients include flavonoids apigenin, quercetin, patuletin, luteolin, and their glucosides. Its potential medical benefits include moderate antioxidant, antimicrobial, and antiplatelet activity. Animal model studies Phytother. Res. (2013)


indicate potent antiinflammatory, anti-mutagenic, cholesterol-lowering, and gastroprotective effects (McKay and Blumberg, 2006). In one study, it was shown that co-administration of 25 mg/kg of M. camomilla (MC) extract (0.3% apigenin) with morphine on the course of induction of dependence (7 days of treatment with morphine) abolished withdrawal signs. A single-dose peritoneal administration of 25 mg/kg of the extract 30 min before naloxone challenge also inhibited these withdrawal signs significantly (p < 0.01). These results implied the ability of MC extract to inhibit the development of resistance in chronic treatment and attenuation of withdrawal syndrome in a single-dose treatment in dependent subjects. Seven days of MC treatment in rats showed a significant increase in plasma cAMP, suggesting a phosphodiesterase inhibitory effect of the extract. In the morphine-MC extract co-administered group, plasma cAMP concentration was significantly (p < 0.01) lower than the morphine-only group after naloxone challenge, whereas a single dose of MC extract did not lower cAMP levels in dependent rats after injection of naloxone. It was concluded that MC extract inhibited morphine dependence by a mechanism similar to phosphodiesterase inhibitors (such as rolipram), that is, by inhibition of cAMP upregulation pathway at transcriptional levels (Gomaa et al., 2003). In another study, central administration of the extract was shown to attenuate withdrawal signs (Esmaeili et al., 2008). The extracts used in these studies are standardized, and there is clinical evidence of its efficacy in generalized anxiety disorder (Amsterdam et al., 2009). Thus, it may be a good target for future studies.

In a novel study, zebrafish were used to evaluate the effects of mitragynine on morphine-induced CPP and withdrawal behavior. Exposure to mitragynine at concentrations of 1 and 2 mg/L for 20 min or 1 h before preference or withdrawal tests attenuated place preference and withdrawal-induced anxiety-like behavior in morphine-dependent fish. Mitragynine exposure reduced cortisol levels. It also suppressed the expression of CRF-R1 and CRF-R2 as well as pro-dynorphine genes caused by morphine treatment. It was proposed that mitragynine may act through the hypothalamus– pituitary–adrenal axis and the kappa opioid receptors (Khor et al., 2011). Different methods of study on the plant and its active components (particularly mitragynine) are carried out, and structure–activity relation data are available. Considering its popularity especially in Asia, it may play an important role in morphine detoxification if clinical and kinetic studies support its efficacy. Nepeta glomerulosa Boiss In 2006, the effect of this plant’s aerial parts extracts on morphine withdrawal was studied in male albino mice. The results showed a significant inhibition of withdrawal syndrome at all doses, and a maximum effect was observed at 2.8 g/kg of the extract. The extract also decreased markedly the incidence of rotarod and open field scores. These effects were similar to those of diazepam. It was then speculated that the extract exhibit its effects by acting on GABAA receptors (Hosseinzadeh and Ziaee, 2006), but no further tests were carried out to confirm this effect.

Mentha longiflora L. Nigella sativa Linn. The effects of the ethanolic and aqueous extracts of Mentha longiflora L. (Lamiaceae) leaves were investigated in white male mice. Phytochemical research confirmed the presence of alkaloids and flavonoids in both types of the extract. Both extracts diminished withdrawal syndrome at the administered doses (p < 0.001). However, the extracts were not as effective as diazepam. Mice treated with both extracts had decreased locomotion parameters (Hosseinzadeh et al., 2011b). Mitragyna speciosa Korth. Mitragyna speciosa Korth. (Rubiaceae) or kratom is abundant in Eastern Asia. It has been traditionally used for its opioum-like analgesic effects. This plant is increasingly purchased through Internet websites and forums as a self-treatment for opiate withdrawal (Boyer et al., 2007) The active compounds of this plant include several 9-methoxy-Corynanthe-type monoterpenoid indole alkaloids. Some synthetic congeners of these alkaloids have also been tested (Takayama, 2004). Mitragynine, the major constituent of the herb, is a partial μ and κ opioid receptor agonist. 7-hydroxymitragynine, a minor constituent of M. speciosa, was found to exhibit potent antinociceptive activity in mice. This alkaloid was shown to be more potent than morphine, and it was active through the oral route (Matsumoto et al., 2004). Copyright © 2013 John Wiley & Sons, Ltd.

Nigella sativa Linn. (Ranunculaceae) seeds have more than 30% fixed oil and 0.4–0.45% volatile oil. The fixed oil is rich in unsaturated fatty acids, while thymoquinone and carvacrol are the major active components of the volatile oil. Thymoquinone is considered the main active ingredient of N. sativa (Ali and Blunden, 2003). The effects of 500 mg ground N. sativa seeds after abrupt opioid discontinuation was assessed in heroin addicts without psychiatric problems or addiction to other types of substances. The results showed a consistent inhibition of withdrawal signs in the patients. The authors attributed this effect to the calcium-channel blocking property of N. sativa (Sangi et al., 2008). There was no control group in the study. Moreover, only patients with observed positive effects after the first administration were included in the analysis. Some patients used diazepam to enhance their sleeping. These methodology problems question the validity of the results. However, this investigation does show the effectiveness of N. sativa seeds on the subject patients. In an animal study, N. sativa oil administration significantly inhibited the development of tolerance to morphine at 4 mL/kg and nearly abolished tolerance to morphine with 8 mL/kg. N. sativa oil inhibited NO overproduction. NO synthase inhibitors enhanced the inhibitory effects of N. sativa on the development of tolerance and dependence, whereas these effects were antagonized by L-arginine. Phytother. Res. (2013)


It was concluded that N. sativa oil exerts these effects through inhibition of morphine-induced NO overproduction and oxidative stress and through maintenance of cellular antioxidant status (AbdelZaher et al. 2010). In another study, the effects of the oil on tramadolinduced tolerance and dependence were assessed. It was fed to mice before each tramadol injection (twice a day). Tolerance was inhibited by 4 and 8 but not 2 mL/kg. Withdrawal signs were attenuated at 4 mL/ kg. L-NAME, dizocilpine, and NAC enhanced, while L-arginine antagonized the oil’s effects (Abdel-Zaher et al., 2011). In another study, crude hydroalcoholic extract of N. sativa reduced expression but not acquisition of morphine-induced CPP in mice at 200 and 400 mg/kg. The extract itself caused preference at 400 mg/kg. It was concluded that the extract might have exerted its acute effects by its antioxidant activity, but on chronic administration, it may have shown opioidlike effects per se (Anvari et al. 2013). Although the human study has many shortcomings, convincing pharmacological studies ensure that this plant may be applicable in clinical trials.

Otostegia persica Otostegia persica (Lamiaceae) is used in Iranian folk medicine to alleviate opioid withdrawal syndrome. In a study, both oral and peritoneal administration of hydroalcoholic extract decreased jumping episodes and rearing reflexes dose-dependently. Clonidine and the hydroalcoholic extract suppressed diarrhea, piloerection, ptosis, and tremor. The hexane extract only inhibited diarrhea but did not show any effect on the other withdrawal signs. The authors suggest that flavonoids of hydroalcoholic extract have a role in alleviating withdrawal syndrome. Oral administration of extract was less effective possibly because of first pass effect or incomplete oral absorption (Hajhashemi et al., 2009).

Panax ginseng Panax ginseng (Araliaceae) saponines have effects on the CNS. The roots have an inhibitory effect on the development of tolerance and physical dependence of morphine (Ramarao and Bhargava, 1990). Analgesic activity and hypothermic effect have been seen in ginseng saponins. Long-term administration of ginseng extract (7 days) inhibited tolerance to the analgesic and hyperthermic effects of morphine (Bhargava and Ramarao, 1991). In another study, ginseng total saponins inhibited the development of morphine-induced tolerance and physical dependence and antagonized morphine-induced analgesia. The saponins inhibit morphine-6-dehydrogenase (an enzyme that catalyzes the synthesis of morphinone from morphine) and increases the level of hepatic glutathione. Both processes enhance the detoxification of morphine. These effects of total saponins may be related to complex pharmacological interactions between dopamine receptors and a serotonergic/adenosine A2A/δ-opioid receptor complex. Ginsenosides also modulate morphine-induced cAMP signaling pathway (Kim et al., 2005). Copyright © 2013 John Wiley & Sons, Ltd.

In another study, after repeated administration of morphine, total saponins inhibited upregulation of cAMP pathway in the locus coeruleus. The saponins also decreased cAMP protein kinase A. The results of this study indicated that ginseng total saponins affect morphine dependence by modulating cAMP pathway (Seo et al., 2008). In a similar study, different extracts and saponins were evaluated. Ginseng total saponins, protopanaxadiol saponins, and protopanaxatriol saponins inhibit the development of morphine-induced tolerance and physical dependence, but the ether fraction only inhibited the development of morphine physical dependence (Kim et al., 1987). In 2011, a study was carried out to investigate the mechanism of wild ginseng on the behavioral effects of morphine in rats. The plant showed significant inhibition of morphine-induced locomotor activity, increase in c-Fos expression in nucleus accumbens, and tyrosine hydroxylase expression in ventral tegmental area (Lee et al., 2011). In conclusion, P. ginseng inhibits the development of tolerance and physical dependence on morphine. It has analgesic activity and hypothermic effect at high doses and antagonizes the acute pharmacological effects of morphine. There are many studies both on crude extract and ginseng saponins with significant results. Therefore, ginseng may be useful in the treatment of morphine-withdrawal syndrome. Papaver rhoeas In morphine-dependent guinea-pig ileum, contracture was prevented and reversed with papaverin treatment (Capasso and Loizzo, 2003). In one study, the expression of withdrawal signs was inhibited in mice by acute administration of P. rhoeas extract. The extract showed mild opioid and also anti-dopaminergic and anticholinergic activity (Pourmotabbed et al., 2004). In another study, it was shown that chronic administration of the extract in combination with morphine inhibited the acquisition of morphine CPP, but the expression of morphine-induced CPP could not be inhibited by acute administration (Sahraei et al., 2006). All of the results taken together suggest that the extract of P. rhoeas can reduce the withdrawal signs. Passiflora incarnata Passiflora incarnata (Passifloraceae) is used in the management of anxiety, insomnia, and epilepsy. A trisubstituted benzoflavone moiety has been derived from the bioactive methanol extract of this plant. The benzoflavone moiety has exhibited encouraging results in the reversal of tolerance and dependence of several addiction-prone psychotropic drugs, including nicotine, ethanol, diazepam, and delta-9-tetrahydrocannabinol. It also reduced naloxone-precipitated withdrawal jumps in morphine-dependent mice (Dhawan, 2003; Dhawan et al., 2002). In a clinical trial, Pssiflora extract plus clonidine tablet and clonidine tablet plus placebo drop were both effective in treating physical withdrawal symptoms. Phytother. Res. (2013)


However, the passiflora plus clonidine group was more effective than clonidine alone (Akhondzadeh et al., 2001).

dependently. However, high doses of this infusion are toxic (Haghparast et al., 2006). Polygala telephioides WILLD

Peganum harmala L. Peganum harmala L. (Syrian rue) is a wild-growing flowering plant of the Zygophylaceae family. Its seeds have hypothermic and hallucinogenic properties. Several properties of P. harmala such as antibacterial, antifungal, and MAO inhibition have been experimentally shown. It has also been known to interact with α2-adrenoceptor subtypes. The alkaloid extract of the seeds shows antinociceptive activity in the formalin test. Harmaline is the main active ingredient (Monsef et al., 2004) The effects of oral administration of seed powder reduced physiological withdrawal score significantly and to a level comparable with methadone in male rats. It was concluded that P. harmala may exert these effects via the opioid and monoaminergic systems and through signal transduction pathways such as cAMP (Khalili et al., 2010). The effects of harman, norharman, and harmine, three main alkaloids of this plant, are later discussed in this article.

Pimpinella anisum L. Pimpinella anisum L. (Apiaceae) essential oil contains eugenol and estragole, which have anesthetic, hypothermic, muscle relaxant, and anticonvulsant activities (Dallmeier and Carlini, 1981). Anethole has muscle relaxant effects (Albuquerque et al., 1995). Peritoneal injection of the essential oil induced conditioned place aversion in mice. The essential oil reduced morphine-induced CPP. The inhibitory effect of the essential oil was reversed by administration of bicuculline, a GABAA receptor antagonist (1.5 mg/kg i.p., 20 min before essential oil), but not by administration of GABAB receptor antagonist, CGP35348 (200 and 400 mg/kg i.p., 10 min before essential oil). These effects were attributed to GABA-potentiating properties of the essential oil, especially by enhancement of inhibitory GABA effects in the ventral tegmental area (Sahraei et al., 2002).

Pistacia vera Pistacia vera (Anacardiaceae) or pistachio, is a small tree originally from Persia (Iran). The gum extract has neuroprotective (Mansouri et al., 2005), muscle relaxant (Ziaei and Hosseinzadeh, 2010), hepatoprotective (Parvardeh et al., 2002b), and antiemetic effects (Hosseinzadeh et al., 2007c). In a study, antinociceptive activity of hydroalcoholic gum extract was determined. The extract (0.25–2 g/kg, i.p.) showed significant and dose-dependent antinociceptive activity in the hot-plate test, which was partially inhibited by naloxone. The antinociceptive effect may be mediated by opioid receptors, as well as inhibition of inflammatory mediators (Parvardeh et al., 2002a). In another study, an infusion of the red nutshell of pistachio reduced morphine-withdrawal syndrome doseCopyright © 2013 John Wiley & Sons, Ltd.

Chronic administration of P. telephioides with morphine reduced naloxone-induced jumping significantly and dose-dependently. In contrast, a single large dose did not suppress naloxone-induced jumping, indicating that it does not affect the expression of morphine-withdrawal syndrome. The most interesting finding of the study was that the extract reduced the plasma morphine concentration. It was finally concluded that PT may interfere with the kinetic of morphine, by accelerating morphine metabolism and excretion (Egashira et al., 2006). Rhodiola rosea L. Rhodiola rosea L. (Crassulaceae) contains organic acids, flavonoids, tannins, and phenolic compounds. The phenolic compounds rosavin, rhodioloside, and tyrosol are structurally related to catecholamines (Panossian et al., 2010). In one study, acute administration of R. rosea extract (3% total rosavins and 1% salidroside) 60 min before naloxone challenge inhibited the expression of tolerance dose-dependently. Nevertheless, pretreatment of mice 60 min before each morphine injection did not inhibit the development of tolerance to morphine analgesia at any administered dose. Acute administration of the extract 60 min prior to naloxone injection significantly decreased the frequency of withdrawal signs in a dose-dependent manner. R. rosea extract appears to increase brain content of neurotransmitters such as norepinephrine, dopamine, and serotonin, and this was speculated to be a possible underlying mechanism of action. CRF antagonists can reduce several signs of opiate withdrawal. It has been previously shown that the extract can reduce stress-induced and CRF-induced anorexia, probably by acting as a CRF antagonist. Therefore, it was hypothesized that the R. rosea extract prevents morphine dependence also by acting as a CRF antagonist. R. rosea may deter morphine dependence by regulating the stress-sensor heat-shock proteins. The extract had no effects on analgesic and withdrawal responses in morphine-naïve mice, so it may have the potential to attenuate these problems without affecting non-dependent subjects (Mattioli and Perfumi, 2011). Nonetheless, locomotion and exploratory activity of the mice were not assessed. No chemical drug was used as positive control. In another study, administration of the extract 1 h before morphine injection during the conditioning phase reduced morphine-induced CPP. A single dose of the extract 1 h before post-conditioning testing decreased the expression of CPP. Treatment with the extract did not produce CPP per se. Administration of the extract before each extinction session accelerated CPP extinction. The extinction phase was completed on day 12 in the control group, and on day 6 or 9 when treated at 15 and 20 mg/kg, respectively. Administration of the extract 1 h before priming morphine injection reduced reinstated CPP and completely abolished it at Phytother. Res. (2013)


20 mg/kg. Reinstatement induced by restrain stress was also inhibited by the extract when injected 1 h before the immobilization trial. All these effects were statistically significant and dose-dependent. The extract caused no motor impairment (Mattioli et al., 2012b). The methods and extracts used in these studies were standard, and the results were significant. This plant may be useful in the clinic. Rosmarinus officinalis L. Rosmarinus officinalis L. (Lamiaceae) has considerable amount of salicylates. It enhances memory and inhibits cognitive impairment in animal models (Hosseinzadeh et al., 2004). The aqueous extract was positive for alkaloids, saponins, tannins, and flavonoids, but the alcoholic extract lacked alkaloids. The aqueous and ethanolic extract reduced morphine-withdrawal syndrome in mice. Direct opioid-like activity, spasmolytic effects, and GABA enhancement were the attributed mechanisms of action for the aqueous extract (Hosseinzadeh and Nourbakhsh, 2003). In another study, the effects of different fractions were investigated in mice. A chloroform fraction was the most effective (Hosseinzadeh et al., 2007b).

β-caryophyllene, and n-tricosane (Khanavi et al., 2004; Morteza-Semnani et al., 2006). In one study, S. byzantina extract effectively reduced jumping episodes in a dose-independent manner. Clonidine was more effective than the extract. The extract did not reduce locomotion parameters at any dose. The extract did not show any analgesic effect even at the highest dose, but it did reduce morphine tolerance. The extract was shown to contain flavonoids and tannins but not saponins. The inhibitory effects on morphine dependence and withdrawal were attributed to the flavonoid components of the extract. Because the extract did not affect motor function, it was concluded that the plant extract had no depressant and sedative properties (Hosseinzadeh et al., 2008). Trachyspermum copticum A study was carried out to investigate the effects of Trachyspermum copticum microinjection into nucleus reticularis paragigantocellularis (PGi) on morphinewithdrawal syndrome. The results indicated T. copticum effectively reduces naloxone-induced withdrawal signs compared with the control group. One possible mechanism is the reduction of aspartate and glutamate in PGi and the inhibition of glutamate transmission in locus coeruleus (Jafari et al., 2005).

Salvia spp. Valeriana officinalis Salvia haematodes has CNS-depressant, antinociceptive, and anticonvulsant activities (Hosseinzadeh et al., 2003). Also, Salvia species are effective on inhibition of ethanol and morphine-withdrawal syndrome (Imanshahidi and Hosseinzadeh, 2006). Injection of Salvia leriifolia extract 0.5 h before and 0.5 h and 1 h after the last dose of morphine decreased the jumping episodes dose-dependently. Co-administration of aminophylline (20 mg/kg) and the ethanol extract significantly suppressed the expression of naloxone-precipitated jumping. Aminophylline, a non-selective adenosine receptor antagonist, blocked the effect of the extract. It may be possible that the extract decreased morphine dependence via an adenosine mechanism. It was also concluded that the extract may act via benzodiazepine-like pathways, because benzodiazepine binding sites have been introduced for some constituents of Salvia spp. (Hosseinzadeh and Lary, 2000). In another study, a single dose of Salvia limbata aerial parts methanolic extract before naloxone challenge decreased withdrawal escape jumps in morphine-dependent mice. The effects were significant at all doses (100 to 1500 mg/kg), but the best effect was observed at 1000 mg/kg. The extract showed intrinsic antinociceptive effects in the hot-plate test, so it was speculated that the extract might act through opioid receptors (Alemy et al., 2012). No study was carried out to confirm this. No positive control was used. Stachys byzantina C. Koch Stachys byzantina C. Koch (Lamiaceae) essential oil contains piperitenone, 6, 10, 14-trimethyl pentadecan2-one, sesquiterpenes such as α-copaene, spathulenol, Copyright © 2013 John Wiley & Sons, Ltd.

Valeriana officinalis L. (Valerianaceae) has anti-emetic (Hosseinzadeh et al., 2011a), sedative, and anxiolytic properties (Houghton, 1999). It may be effective on small seizure (Faraji and Motamedi, 2003). It has many active compounds such as valepotriates, baldrinals, valerenic acid, valerenal, and valeranone, and other constituents in the essential oils. These compounds affect the nervous system (Del Valle-Mojica et al., 2011; Sharma et al., 2010). Pretreatment with different doses (1, 5, 25, 50, and 100 mg/kg) of aqueous and methanolic extracts of aerial parts of V. officinalis L. 60 min before naloxone injection significantly decreased jumping in dependent mice. The aqueous and methanolic aqueous and methanolic extracts of the rhizome had similar effects at the same doses (Sharifzadeh et al., 2006). Withania somnifera Withania somnifera (Solanaceae) is an important herb in Ayurvedic medicine. W. somnifera has pharmacological activities such as immunomodulatory, hypolipidemic, antibacterial, and cardiovascular protection (Gupta and Rana, 2007). Chronic treatment with W. somnifera attenuated morphine-withdrawal syndrome. Also, the reduction of spine density in the nucleus accumbens shell was significantly prevented by chronic treatment with the extract in spontaneous and pharmacologically precipitated morphine withdrawal (Kasture et al., 2009). In another study, repeated administration of W. somnifera (100 mg/kg) for 9 days reduced the development of morphine tolerance. W. somnifera also Phytother. Res. (2013)


suppressed morphine-withdrawal jumps after naloxoneprecipitated withdrawal on day 10 of testing (Kulkarni and Ninan, 1997). Morphine-induced inhibition of gastrointestinal tract transit was reversed by pretreatment with glycowithanolides consisting of sitoindosides VII–X, in combination with withaferin-A. Also, the development of tolerance to morphine-induced analgesia was significantly inhibited by administration of glycowithanolides (100 mg/kg) i.p., o.d., for 10 days (Ramarao et al., 1995).

Zingiber officinale Roscoe In a study, the effect of ginger on morphine dependence and tolerance was investigated. The results indicated that ginger significantly prevents morphine tolerance and reduces symptoms of withdrawal (DarvishzadehMahani et al., 2012).

Zhumeria majdae Rech. f. & Wendelbo Crude methanolic extract of Z. majdae 30 min after the last morphine dose reduced withdrawal jumping episodes in mice compared with the control group. Petroleum ether aqueous-methanolic extracts also lowered jumping reflex dose-dependently. Three fractions obtained by the medium pressure liquid chromatography were administered at 0.28 g/kg, and all of them were effective in reducing the jumping reflexes. The crude methanolic extract grouped showed reduced locomotion, similar to the diazepam group. Because the analgesic effect of Z. majdae is antagonized by naloxone, it may be concluded that this plant may enhance the release of endogenous opioids or directly act on opiate receptors. Linalool, limonene, and α-pinene may reduce muscle tonicity via the cAMP system. Linalool (discussed later) also facilitates GABA transmission; thus, GABAergic inhibition of withdrawal syndrome is also a possible mechanism. Camphor and Borneol have inhibitory effects on cathecolamins by affecting cholinergic receptors. Furthermore, linalool blocks the effects of stimulatory amino acids such as glutamate. Linalool was responsible for the sedative and relaxant effects of the crude extract (Hosseinzadeh et al., 2007a).

and systems in the human body such as antimicrobial effects (Imanshahidi and Hosseinzadeh, 2008). A pharmaceutical composition containing protoberberine alkaloids has been proven to have an antidepressant effect in a Korean patent, no. 10-0281003. In another pharmaceutical invention, berberine was used for prevention and treatment of psychological dependence on morphine and analgesic tolerance to it. In this invention, the effect of berberine on psychological dependence on morphine was evaluated. Administration of 1 or 2 mg/kg of berberine orally 1 h before morphine decreased psychological dependence in down to a level equal to non-dependent mice. Administration of 1 or 2 mg/kg of berberine before morphine treatment decreased locomotor activity. Pretreatment with berberine did not affect analgesic effect of morphine. Pretreatment with 10 mg/kg of berberine inhibited morphine tolerance significantly in the hot-plate test (Jang and Lee, 2003; Jang and Lee, 2007). In another investigation, the effects of aqueous and ethanol extracts of Berberis vulgaris (barberry) fruit, as well as its active component, berberine, were studied on morphine dependence, hypnotic effects, muscle relaxant, and locomotor activity in mice. Berberine (10–20 mg/kg, i. p.) and both extracts of barberry reduced the number of jumping. Chronic administration of the extracts during the development of dependence also decreased the number of jumps significantly. Berberine (5–10 mg/kg), aqueous (100 mg/kg), and ethanol extracts (100–200 mg/kg) increased sleeping time and decreased latency significantly in the pentobarbitone sleep test. Berberine and the extracts reduced locomotion activity of animals. The extracts did not show muscle relaxant activity (Nassiri-Asl et al., 2007). Flavonol glycosides In a study in 1998, flavonol glycosides including quercetin3-O-(2-O-ß-apiofuranosyl)-rutinoside, rutin, kaempferol-3O-rutinoside, and kaempferol-3-O-(6-O-trans-p-couma royl)-ß-D-glucopyranoside taken from Croton menthodorus (Euphorbiaceae) alleviated morphine-withdrawal syndrome in vitro in guinea-pig ileum. The effect was dose-dependent (Capasso et al., 1998). In another study, flavonol glycosides isolated from Aristeguietia discolor (Asteraceae) reduced the contraction in a morphine-exposed segment of guinea-pig ileum after naloxone treating. Crude extract and flavonol glycosides reduced ileum contraction dose-dependently (Capasso et al., 2000b).

PLANT BIOACTIVE COMPONENTS Some active ingredients of plants have also been studied for their effects on opioid tolerance and withdrawal syndrome.

Berberine Berberine is an isoquinoline alkaloid. It is the major component in some plants such as C. japonica, Phellodendron amurense, Berberis koreana, and Berberis vulgaris (Jang and Lee, 2003; Jang and Lee, 2007). B. vulgaris and its most important component, berberine, showed therapeutic effects on many organs Copyright © 2013 John Wiley & Sons, Ltd.

Indole alkaloids Indole alkaloids isolated from Sickingia williamsii Standl (Rubiaceae) showed an inhibitory effect on withdrawal-induced contractions in guinea-pig ileum in a dose-dependent manner (Capasso et al., 1997a). Ibogaine is an indole alkaloid usually derived from Tabernanthe iboga. It has shown various effects on different neurotransmitter systems. In one study, intracreberal administration of ibogaine attenuated some of naloxone-induced withdrawal signs in rats (Dzoljic et al., 1988). In another study, it failed to attenuate morphine-induced CPP in mice (Luxton et al., 1996). In a study on heroin-dependent humans, drugPhytother. Res. (2013)


seeking behavior and withdrawal complaints were diminished in 76% (25) of the subjects after a singledose treatment with ibogaine (Alper et al., 2000). There are many studies in the literature about the effects of iboga alkaloids, some with conflicting results (Popik et al., 1995). Ibogaine, however, remains an important component of the drug culture worldwide (Alper et al., 2008). Isoquinoline alkaloids The effect of isoquinoline alkaloids from Argemone mexicana L. (Papaveraceae) on withdrawal syndrome was investigated using guinea-pig ileum contraction method. The methanolic extract of the plant and its pure components reduced withdrawal-induced contractions. The major components in A. mexicana are protopine and allocryptopin, so this effect can be associated with these isoquinoline alkaloids (Capasso et al., 1997b). Also in 2000, four new protopine alkaloids were isolated from Aristolochia constricta (Aristolichiaceae) and showed anti-addictive effect in vitro in guinea-pig ileum dose-dependently (Capasso et al., 2000a).

only one dose for each was used, and the effects were not compared with a chemical as positive control, the effects of these two alkaloids could not be compared. Two beta-carboline alkaloids, harman and harmine, have pharmacological effects including convulsive or anticonvulsive actions, binding to benzodiazepine receptors, tremoregenesis, and MAO inhibition. Two morphine pellets were implanted in the rats’ scapular area, and harmane (5 or 10 mg/kg), harmine (5 or 10 mg/kg), and saline were injected i.p. to the groups (n = 12 for each), 72 h after morphine implantation. After 45 min, withdrawal syndrome was precipitated by naloxone, and withdrawal signs were observed for 15 min. At both doses, harmine attenuated all signs significantly except for jumping. Harman intensified jumping reflexes but ameliorated wet dog shakes, writhing, defecation, tremor, and ptosis. The effect of harman on jumping reflexes was similar to clonidine. At the doses administered, neither reduced animal locomotor activity in naïve or morphine-dependent rats. Imidazoline receptors were also speculated to be involved (Aricioglu-Kartal et al., 2003). No positive control was applied. Linalool

Tropane alkaloids Tropane alkaloids isolated from Brugmansia arborea (L.) Lagerheim (Solanaceae) reduced opioid withdrawal in vitro significantly and dose-dependently (Capasso and de Feo, 2003). In another study, the effects of Brugmansia arborea extract, its chromatographic fractions and pure alkaloids on the expression, and the acquisition of morphine tolerance and dependence were evaluated. B. arborea extract had an inhibitory effect on the expression of morphine tolerance but no effect on its acquisition. However, B. arborea extract, its fractions, and pure alkaloids reduced significantly both acquisition and expression of morphine dependence (Mattioli et al., 2012a).

In one study, linalool (50, 75, and 100 mg/kg), clonidine, an alpha-2 receptor agonist and memantine, an NMDA receptor antagonist, and saline were injected to mice concomitantly with morphine injection to evaluate their effect on the acquisition of dependence and tolerance. A single dose of the agents on the test day was used in other groups to evaluate the expression of dependence and tolerance. Linalool, clonidine, and memantine reduced the acquisition and expression phases of dependence and tolerance as shown by naloxone-challenge and tail-flick tests, respectively. The effect of linalool was 48% at a dose of 75 mg/kg and 95.6% at 100 mg/ kg. It was concluded that linalool has a significant effect on morphine tolerance, and dependence may be mediated through the inhibition of NMDA receptors (Hosseinzadeh et al., 2012).

Catechins ( )-Epigallocatechin gallate, one of the main tannins of green tea, attenuated withdrawal signs in rats dosedependently. It also inhibited morphine-induced increased cAMP concentrations in the locus coeruleus at 100 mg/kg. It also inhibited D-2 dopamine receptor signaling (Oh et al., 2007) Norharman (β-carboline) Norharman is a harmala alkaloid also found endogenously in human and rat tissue. It is elevated in alcoholics and opiate addicts and has psychogenic and hallucinogenic effects. Its effects on morphine abstinence were compared with ibogaine (an indole alkaloid) in male rats. Involvement of these alkaloids as opioid agonists and their action as glutamate receptor antagonists were concluded to be a possible underlying mechanism for these alkaloids (Cappendijk et al., 1994). At the doses administered, norharman was generally more effective than ibogaine. However, because Copyright © 2013 John Wiley & Sons, Ltd.

Levo-tetrahydropalmatine Levo-tetrahydropalmatine (L-THP) is an alkaloid present in plenty of Chinese herbal preparations. It is obtained from Chinese herbs of Corydalis and Stephania genera. It is a dopamine antagonist with more affinity to D2 than D1. It has also an antagonistic effect on D3. In a study on morphine-abstinent rats, it showed inhibitory effects on heroin self-administration in a fixed ratio at different doses. However, it decreased heroin-seeking behavior induced by heroine in a dose-dependent manner (Yue et al., 2012). In another study, the inhibitory effect of L-THP on psychological dependence and locomotor stimulation induced by oxycodone was shown by the CPP method in rats and mice. In this study, it also inhibited the increase of CREB and ERK phosphorylation in nucleus accumbens and hippocampus, which may be the underlying mechanism in inhibition of oxycodone-induced CPP (Liu et al., 2009). Phytother. Res. (2013)


CONCLUSION Opioid dependence and withdrawal syndrome are still the leading problems associated with licit and illicit opioid uses. According to the results, we can claim that plants and their active ingredients are good choices to ameliorate opioid-induced pharmacological changes such as tolerance, physical and psychological dependence, and withdrawal syndrome. Some plant orders and families showed great involvement in our data and contained a large number of plants with mentioned effects. One of the most important order is Lamiales (specially Lamiaceae and Scrophulariaceae families). The others are Ranunculales (specially Ranunculaceae, Menispermaceae, and Papaveraceae families) and Apiales (specially Apiaceae and Araliaceae families). Solanaceae from solanales and Asteraceae from Asterales orders have great involvement. In some studies, mechanisms of action of the plants were investigated. Plants offer a great variety of actions including symptomatic improvement (i.e. spasmolytic and sedative), opioid partial agonism (similar to replacement medications), neurotransmitter (cholinergic, adrenergic, dopaminergic, glutamergic, and GABAergic) modulation, and interfering with signaling pathway such as the cAMP and NO pathways. Oxidative stress has been suggested

to play a role in the process of dependence and withdrawal (Xu et al., 2006). Although most of the literature in this issue is confined to animal studies, the results seem to be promising. Clinical studies, however, are needed to confirm the safety and efficacy of these herbal extracts and preparations. They could be used experimentally in detoxification centers along with standard pharmacological and psychological therapy. Although traditional compound herbal formulae have been effective in a holistic approach (Doosti et al., 2013), certain classes of compounds such as alkaloids have been demonstrated to be effective, as well as flavonoids and flavonol glycosides. Thus, screening for other potentially effective plants and natural products in these classes should be continued, and further research should be carried out to identify specific fractions and active components of the plants already tested. The studies tend to speculate underlying mechanisms of action rather than confirming them by reliable pharmacological studies. The pharmacological profile of some the herbs, however, may contribute to our knowledge of opioid dependence.

Conflict of Interest The authors have declared that there is no conflict of interest.

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