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Antidepressant-like effect of mitragynine isolated from Mitragyna speciosa Korth in mice model of depression.


Keywords: Mitragyna speciosa


Immobility time

Forced swimming test

Tail suspension test

Antidepressant-like activity

HPA axis



Mitragyna speciosa Keith, leaves have been used for decades as a traditional medicine to treat diarrhea, diabetes and to improve blood circulation by natives of Malaysia, Thailand and other regions of Southeast Asia. Mitragynine is the major active alkaloid in the plant. To date, the role of mitragynine in psychological disorders such as depression is not scientifically evaluated. Hence, the present investigation evaluates the antidepressant effect of mitragynine in the mouse forced swim test (FST) and tail suspension test (TST), two models predictive of antidepressant activity and the effect of mitragynine towards neuroendocrine system of hypothalamic-pituitary-adrenal (HPA) axis by measuring the corticosterone concentration of mice exposed to FST and TST. An open-field test (OFT) was used to detect any association of immobility in the FST and TST with changes in motor activity of mice treated with mitragynine. In the present study, mitragynine at dose of 10 mg/kg and 30 mg/kg i.p. injected significantly reduced the immobility time of mice in both FST and TST without any significant effect on locomotor activity in OFT. Moreover, mitragynine significantly reduced the released of corticosterone in mice exposed to FST and TST at dose of 10 mg/kg and 30 mg/kg. Overall, the present study clearly demonstrated that mitragynine exerts an antidepressant effect in animal behavioral model of depression (FST and TST) and the effect appears to be mediated by an interaction with neuroendocrine HPA axis systems.

[C] 2010 Elsevier GmbH. All rights reserved.


Mental disorder particularly major depression causes a significant burden on health worldwide. The main symptom of depression is characterized by a pervasive low mood, feeling of helplessness, loss of interest and loss of pleasure in most of the usual activities (Bhutani et al. 2009). Stressful environment, adverse life-event and lack of supporting relationship are some of the causal factor that contributes to development of depression in human.

Interactions between monoamine neurotransmitters system including 5-hydroxytryptamine (5-HT), noradrenaline (NA) and dopamine (DA) in the brain along with their specific reuptake and receptor protein has gain so much interest in the spectrum of antidepressant studies (Yi et al. 2008). As far, antidepressant drugs available in the market claimed to be effective in treatment of depression. However, the main significant drawbacks of that synthetic antidepressant are due to their high incidence of dangerous side effects and inadequate for number of individuals (Binfare et al. 2009). Therefore, other mechanism should be considered, as they might provide potential effective target with higher efficacy for treatment of depression, and perhaps with fewer drawbacks.

The hypothalamic-pituitary-adrenal (HPA) axis in the neuroendocrine system is one of the complicated neurobiological mechanisms which play important roles as similar as monoamine neurotransmitters system in the new antidepressant development. Dysfunction or hyperactivity of HPA axis system provides significant indicator of depression together in the response to stressors reflected by overproduction of glucocorticoid hormones mainly corticosterone in rodent and Cortisol in human (Xu et al. 2008). Hence, the normalization of the HPA axis system as another prime mechanism of antidepressant actions appears to be one of the special interest.

Recently, more herbal medicine has being used as alternative therapy for depression (Kessler et al. 2001). Due to its natural constituent and availability, natural herbs which obtained from natural sources are believed to provide less untoward effect profiles and provide greater effectiveness as compared to synthetic drug available over the market. Mitragyna speciosa Korth, is a tropical plant endemic to Southeast Asia particularly in northern peninsula of Malaysia, central and southern part of Thailand, and Indonesia (Jansen and Prast 1988; Mossadeq et al. 2009). It is popularly known by local as 'ketum' in Malaysia and 'kratom' in Thailand. The plant was classified under the coffee family of Rubiaceae. Mitragyna speciosa leaves have been used by natives for its opium-like effect and cocaine-like stimulant ability as anti-fatigue, anti-pain and as tonic to increase endurances or performances of work under hot sunlight (Reanmongkol et al. 2007). It is traditionally used by villagers as an alternative treatment for fever, malaria, cough, hypertension, diarrhea, to prolong sexual intercourse as well as substitution for treatment of opiate addiction such as morphine (Chan et al. 2005; Assanangkornchai et al. 2004).

Mitragyna speciosa contains abundant of indole alkaloids (Matsumoto et al. 2008). Mitragynine (Fig. 1) was found to be the primary active alkaloid compound of the entire plant which might hold the key for the effects of Mitragyna speciosa (Takayama 2004). it has a molecule formula of 9-methoxy-corynantheidine ([C.sub.23][H.sub.30] [N.sub.2] [O.sub.4]) with the molecular weight of 398.50 (Chee et al. 2008). Previously, in two different studies, alkaloid extract and aqueous extract of Mitragyna speciosa has been shown to have antidepressant-like effects in mouse models of behavioral despair tests (Kumarnsit et al. 2007a, 2007b). However, antidepressant mechanism of the plant in both studies is not clearly demonstrated. In consideration of previous findings, mitragynine could be a beneficial option in prevention and treatment for stress-induced disorder such as depression.


In the present study, we evaluated the antidepressant-like effect of mitragynine using two classical behavioral models of antidepressants screening known as forced swimming test (FST) and tail suspension test (TST) together with open-field test (OFT). In accordance to the tests, the effect of mitragynine on serum corticosterone concentrations (an index of HPA axis status) was also simultaneously investigated in the present study.

Materials and methods

Preparation of mitragynine from Mitragyna speciosa leaves

The fresh leaves of Mitragyna speciosa Korth. were collected from its natural sources around Peninsula Malaysia particularly in Perlis and Kedah. The plant was authenticated by botanist from Department of Botany, Faculty of Forestry, Universiti Putra Malaysia (UPM), Serdang, Malaysia, based on their microscopic and macroscopic characteristics. A voucher specimen (ATS 001) was deposited in the Herbarium of the Department of Botany, Faculty of Forestry, Universiti Putra Malaysia (UPM), Serdang, Malaysia. Mitragynine was purified from the fresh leaves of Mitragyna speciosa Korth according to the method described by previous study (Houghton and Ikram 1986; Ponglux et al. 1994; Reanmongkol et al. 2007).

The fresh leaves of Mitragyna speciosa (1 kg) were dried at 45-50 [degrees]C, powdered and macerated with absolute methanol for 72 hours. The extracts were mixed, filtered and evaporated using rotary evaporator (Eyela N-1000, Tokyo Rikakikai CO., LTD., Tokyo, Japan) to yield 14.5% (w/w) of crude methanol extract. The methanol extract was dissolved in 10% acetic acid solution, well shaken, left to stand for 24 hours and filtered to give acidic filtrate. The acidic filtrate was washed with petroleum ether, made into alkaline (pH 9) with 25% ammonia solution and extracted with chloroform. The combined chloroform extracts were washed with distilled water, dried over anhydrous sodium sulphate and evaporated to yield 0.73% (w/w) of crude alkaloid extract. The major alkaloid was isolated by silica gel column chromatography eluting with diethyl ether was identified as mitragynine with standard spectroscopic methods ([.sup.1]H NMR, [.sup.13]C NMR). Over all, the yield of mitragynine was approximately 0.087% (w/w) of the fresh leaves weight.

Reagent and chemicals

Mitragynine was dissolved in 20% (v/v) Tween-80 (polyoxyethylene sorbitan monooleate, Sigma-Aldrich Co.). Fluoxetine hydrochloride, amitriptyline hydrochloride and amphetamine hydrochloride were purchased from Sigma Chemical Co. (USA) and were used as reference drugs. All drugs were dissolved in physiological saline (NaCl 0.9%). All other reagents used in the study were of analytical grade.


Male mice from the ICR strain purchased from Northern RK Supplier, Sri Kembangan, Selangor, weighing 25-35g were used. Animals were placed at Animal house, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia Serdang, Selangor, Malaysia, housed 8 per cage under a normal 12-h/12-h light/dark schedule with the lights on at 07:00 a.m and had free access to water and food pellets. They were allowed at least 7 days to adapt to the laboratory prior to the administration. Experiments were carried out between 9:00 a.m. and 3:00 p.m. All studies were conducted in accordance with Animal Care Committee, Faculty of Medicines and Health Sciences, Universiti Putra Malaysia, Serdang. The minimum number of animals and duration of observations required to obtain consistent data were employed. All efforts were made to minimize animal suffering and to reduce the number of animal used.

Drugs administration

The animals were randomly assigned into control and six experimental groups (8 mice per group) as follows: vehicle-treated; mitragynine 5mg/kg; mitragynine 10 mg/kg; mitragynine 30mg/kg; fluoxetine 20 mg/kg; amitriptyline 10 mg/kg and amphetamine (1 mg/kg). Mitragynine and all drugs were intraperitoneally (i.p.) administered once. Mitragynine was dissolved in 20% Tween-80 and diluted to the desired concentration on the day of testing while fluoxetine, amitriptyline and amphetamine were dissolved in normal saline (0.9% NaCl). Vehicle and mitragynine were injected i.p., 30 min before testing. Fluoxetine was administered i.p., 60 min before testing, amitriptyline was administered i.p., 30 min before testing and amphetamine was administered i.p., 15 min before undertaking the test.

Forced swimming test (FST)

The test was conducted according to the reported methodology originally described by Porsolt with minor modification (Porsolt et al. 1977). Briefly, mice were individually forced to swim in an open cylindrical container (diameter 14 cm, height 20 cm), with a depth of 15 cm of water at 25 [+ or -] 1 [degrees]C. The immobility time, defined as the absence of escape-oriented behaviors, such as swimming, was scored during 6 min with the help of stop-watch, as described previously by (Eckeli et al. 2000; Zomkowsi et al. 2004; Kaster et al. 2007). Each mouse was judge to be immobile when it ceased struggling and remained floating motionless in the water, making only those movements necessary to keep its head above water. The parameter obtained was the number of seconds spent immobile. The water in the containers was changed after each trial.

Tail suspension test (TST)

The total duration of immobility induced by tail suspension test was measured according to the method described by Steru et al. (1985). Mice both acoustically and visually isolated were suspended 50 cm above the floor by adhesive tape placed approximately 1 cm from the tip of the tail. The total immobility period was scored manually during 6 minutes test session with the help of stop-watch. Immobility was defined as the absence of any limb or body movements, except for those caused by respiration or when they hung passively and completely motionless. The parameter obtained was the number of seconds spent immobile. Parameter used was the number of seconds spent immobile.

Open-field test (OFT)

In order to rule out any unspecific locomotor effect of mitragynine on antidepressant-like effect of these compounds, mice were administered with the same regimen as in the FST or TST. Their locomotor activities (crossing activity) were evaluated in the open-field paradigm. Before each test, animals were kept in the test room at least 1 hour before the open-field test (OFT) for habituation. The ambulatory behavior was assessed in open-field test described by Rodrigues et al. (1996) and Peng et al. (2007) with slight modifications. The main apparatus consisted of square arena (50 cm x 50 cm x 40 cm) high with grey surface covering every wall. The floor of the arena was divided equally into twenty-five squares (10 cm x 10 cm) marked by black lines. All animals were used only once in this test. These animals were different from those used in the FST and TST. Each mouse was placed individually into the center of the arena and allowed to explore freely. The number of squares crossed with all paws (crossing) were observed and counted in 60 minutes. During the test session, the locomotor or crossing activity of mice was recorded and saved using video camera for permanent record (Moklas et al. 2008). The square arena was cleaned with a solution of 10% alcohol between tests and dried after occupancy by each mouse in order to hide animal clues and to prevent each mouse from being influenced by the odors present in the urine and feces of the previous mouse.

Corticosterone assay

Blood from each mouse was withdrawn immediately after exposure to force swim test (FST) and tail suspension test (TST) respectively. In order to avoid fluctuations on hormone levels due to circadian rhythm, mice were bled at 12:00 p.m. to 13:00 p.m. on the day of sacrifice. Blood was collected through cardiac puncture and sampled into plain tubes and was kept in room temperature. It was centrifuged at 3000 rpm for 10 minutes to separate the serum and red blood cells. The serum was kept frozen at -20 [degrees]C freezer and stored it until assayed was performed. Serum corticosterone concentrations were determined using a commercially available enzyme immunoassay kits (corticosterone ELISA, IBL International GMBH, Hamburgh Germany) used for the quantitative determinants of corticosterone in serum or plasma followingthe manufacturer's instructions. The sensitivity of the assay was <1.631 nmol/1. Intra-assay and inter-assay coefficients of variations were less than 4.09% and 6.36% respectively. Data were expressed as nmol/1.

Statistical analysis

Data were expressed as the mean [+ or -] standard error of mean (S.E.M.). Comparisons between experimental and control groups were performed by one-way analysis of variance (ANOVA) followed by Tukey's HSD test when appropriate. P < 0.05 was considered significant.


Effects of mitragynine on immobility time of FST

After 30 minutes of treatment, mitragynine significantly reduced (P < 0.05) the duration of immobility time at 10 mg/kg and 30 mg/kg respectively as compared to control. Antidepressant drug of selective serotonin reuptake inhibitor, fluoxetine at 20 mg/kg and tricyclic antidepressant drug amitriptyline at 10 mg/kg that used as positive control, administered by i.p. route caused significant reduction (P < 0.05) in the immobility time of mice forced swim test (FST) as compared with control (Fig. 2).


Effects of mitragynine on immobility time of TST

Mitragynine at 10 mg/kg and 30 mg/kg significantly reduced (P < 0.05) immobility time of mice in tail suspension test (TST) as compared to the control (vehicle). The clinically effective antidepressant fluoxetine at 20 mg/kg and amitriptyline at 10 mg/kg that used as positive control produced a marked significant reduction (P < 0.05) in the duration of immobility time as compared with control (Fig. 3).


Effects of mitragnine on locomotor activity of OFT

Treatment with mitragynine at 10 mg/kg and mitragynine at 30 mg/kg which significantly reduced duration of immobility time in FST and TST produced no significant difference in number of crossing activity of mice in OFT. The clinically effective antidepressant fluoxetine at 20 mg/kg and amitriptyline at 10 mg/kg which significantly reduced the duration of immobility time of mice FST and TST produced no significant difference in number of crossingactivity as compared to control. However, psychostimulant drug, amphetamine hydrochloride at 1 mg/kg which served as reference drug in open-field test (OFT) significantly increased (P < 0.05) the number of crossing activity of mice as compared with control (Fig. 4).


Effects of mitragynine on serum corticosterone levels in mice exposed to FST

Swim stress procedure evoked a significant increased (P < 0.05) in serum corticosterone levels of control mice as compared to other treatment. Mitragynine elicited a significant reduction (P < 0.05) in increased serum corticosterone levels induced by forced swim test (FST). Mitragynine treatment of 5 mg/kg, 10 mg/kg and 30 mg/kg significantly reduced (P < 0.05) the serum corticosterone levels in mice as compared with control. Amitriptyline at 10 mg/kg and fluoxetine at 20 mg/kg decreased the serum corticosterone levels (P < 0.05) significantly as compared to control Fig. 5).


Effects of mitragynine on serum corticosterone levels in mice exposed to TST

A significant increased (P < 0.05) in serum corticosterone concentrations were observed in mice exposed to TST of control vehicle-treated mice. Mitragynine at 10 mg/kg and 30 mg/kg significantly reduced (P < 0.05) the serum corticosterone levels in mice as compared with control. Treatment of mice with fluoxetine at 20 mg/kg and amitriptyline at 10 mg/kg significantly reduced (P < 0.05) the serum corticosterone in TST as compared with control Fig. 6).



Behavioral studies have been shown to play an important part in the evaluation and development of antidepressant drugs (Xu et al. 2008). Forced swimming test (FST) and tail suspension test (TST) are among behavioral models that widely and routinely used for screening new antidepressant compound (Cryan et al. 2005). In the present study, statistically significant results were obtained in FST with treatment of mitragynine at 10 mg/kg and 30 mg/kg (33% and 48% reduction respectively). Positive control antidepressant drugs fluoxetine and amitriptyline produced significant result on immobility time (57% and 76% reduction respectively) similar with previous study (Reneric and Lucki 1998). The highest dose of mitragynine shows comparable effect as fluoxetine and amitriptyline in terms of its antidepressant actions revealing mitragynine might share some pharmacological mechanisms with established antidepressant drugs in this investigation.

Similar outcome were obtained in TST as mitragynine extract at doses 10 mg/kg and 30 mg/kg significantly reduced the immobility time (47% and 58% reduction respectively). Fluoxetine at 10 mg/kg and amitriptyline at 20 mg/kg decreased the immobility time (75% and 76% reduction respectively). These results indicate that mitragynine extract has a dose-dependent antidepressant-like effect that is comparable to established antidepressant drugs. Hence, the antidepressant action of mitragynine could possibly through one of the mechanisms precipitated by established antidepressant agents that manage to be detected in TST.

Agents that able to enhance locomotor activity in OFT including stimulants, convulsants and anticholinergic tend to produce a false positive result in FST and TST (Bourin et al. 2001; Butterweck et al. 2003). In fact, hyperkinesia also causes false positive effect in FST and TST by shortening the immobility time in both tests (Takahashi et al. 2008). Therefore, OFT was used to exclude these false effects that could be associated with hyperkinesia (Kwon et al. 2009). The main difference between antidepressants and psycho-stimulant is that antidepressants would not cause general increased in motor activity (Borsini and Meli 1988). As a classical stimulant agent, amphetamine produces effects via elevation of mood and energy (hyperactivity) (Rothman and Baumann 2003). Mitragynine seems unable to produce acute toxicity or psycho-stimulant side effect related with hyperkinesia in the brain. In addition, the finding suggested that reduction of immobility time elicited by mitragynine in FST as well as in TST was specifically arises via its antidepressant mechanism. This outcome is similar with previous study which reported alkaloid and methanol extract of Mitragyna speciosa leaves produced no significance effect over locomotor activity and on pentobarbital-induced sleep in mice (Reanmongkol et al. 2007).

Forced swimming in FST induced alterations in the HPA axis, thereby increase the Cortisol level of mice (Shalam et al. 2007). Reduction of HPA axis hyperactivity by antidepressants is crucial in defining its therapeutic effects. In the present study, we observed that mitragynine significantly reduced the corticosterone concentration in mice exposed to FST and TST, in a way similar to previous outcomes obtained using different antidepressant compounds (Yi et al. 2007). Indeed, the present study shows mitragynine reduced the corticosterone level of mice similar to classical antidepressant drugs, amitriptyline and fluoxetine. These results are somewhat similar to clinical studies that revealed amitriptyline caused significant decreased of salivary Cortisol in depressed patient (Deuschle et al. 2003) while fluoxetine produced the initial recovery of HPA axis in depression (Inder et al. 2001).

Previous study also demonstrated that antinociceptive effect of mitragynine is mediated through descending noradrenergic and serotonergic systems receptors suggesting that mitragynine might be able to stimulate the release of endogenous noradrenaline (NA) and serotonin (5-HT) from nerve terminals of descending monoaminergic neuron (Matsumoto et al. 1996). In fact, numerous studies have reported that most classical antidepressants produce antinociceptive actions (Casas et al. 1995; Rodrigues-Filho and Takahashi 1999). Taken together those findings, we suggest that the antidepressant-like action of mitragynine might be through the restoration of monoamine neurotransmitter levels including serotonin, noradrenaline and dopamine in mice. However, based on our behavioral approach, we could not make definitive conclusions on the detailed mechanism of mitragynine on monoamine levels. Thus, further studies should be taken to confirm this particular issue.

In conclusion, our results obviously show that administration of mitragynine is able to produce an antidepressant-like effect in FST and TST, which not due to effect of psycho-stimulant or hyperkinesia. Besides, we provide convincing evidence that the effect is due to interaction with neuroendocrine HPA axis systems. Taken together, our findings are somewhat in accordance with clinical results, further suggesting that mitragynine may exert a role in the modulation of depression and has psychotherapeutic value in management of depression disorder. However, some consideration should be taking into account that FST and TST is not the only model of depression by which the results obtained using this model should be considered and interpreted with caution due to some differences among experimental animals and clinical studies in human. Hence, further investigations are necessary to evaluate the effect of mitragynine in other animal's behavioral model including relevant antidepressant doses of mitragynine on its safety and efficacy level.


This study was supported by Fundamental Research Grants Scheme, Universiti Putra Malaysia. UPM Serdang, Selangor, Malaysia.


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N. Farah Idayu (a), M. Tauflk Hidayat (a), (b), *, MAM. Moklas (a), F. Sharida (a), A.R. Nurul Raudzah (a), A.R. Shamima (a), Evhy Apryani (a)

(a) Human Anatomy Laboratory, Department of Human Anatomy, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, 43400 Selangor. Malaysia (b) Laboratory of Physical Performance and Skills Analysis, Sports Academy, Universal Putra Malaysia, Serdang, 41400, Selangor, Malaysia

* Corresponding author. Tel: +603 89472356.

E-mail address: (M. Taufik Hidayat).

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Title Annotation:Short communication
Author:Idayu, N. Farah; Hidayat, M. Tauflk; Moklas, M.A.M.; Sharida, F.; Raudzah, A.R. Nurul; Shamima, A.R.
Publication:Phytomedicine: International Journal of Phytotherapy & Phytopharmacology
Article Type:Report
Geographic Code:9MALA
Date:Mar 15, 2011
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