Category Archives: DIY antidepressants

Bacopa monnieri (Brahmi)

INTRODUCTION

Bacopa monnieri is a perennial creeping plant distributed in warm, marshy areas of South Asia, Africa, Australia, Europe, North and South America [1]. It is known as an important herb in Ayurvedic medicine, and has been used for a long time as a treatment for many health conditions [2]. It is said to possess adaptogenic, cognitive-enhancing, mood-brightening, anti-anxiety, anti-epileptic and sleep inducing properties [3]. It is widely available today as a supplement and is marketed primarily for its effects on brain health. It is sold in the form of herbal powder or extract prepared from the whole plant, known as “brahmi”. However, it should not be confused with another herb, Centella asiatica (Gotu kola), that is also called brahmi and used for the same purposes (and often combined with Bacopa monnieri) [3].

Pharmacological effects of the whole extract of Bacopa monnieri and its individual constituents have been investigated in animal and human studies, revealing many beneficial properties. Preclinical evidence supports use of Bacopa as an alternative antidepressant, nootropic and anxiolytic, although conclusive evidence for its effects on human emotional health is insufficient. Neuroprotective actions can be attributed to some alkaloids present in the herb, but mostly to its specific saponins, particularly bacosides, which are often used to standardize Bacopa extracts [3].

EFFECTS ON MOOD AND COGNITION

Animal studies

Standardized methanolic extract of Bacopa monnieri demonstrated a significant antidepressant effect on rats in a study using forced swim test (FST) and learned helplesness models, in the oral doses of 20 and 40 mg/kg daily, and was said to be comparable to that of imipramine [4]. Study on mice found antidepressant actions of brahmi (in the oral doses of 10, 20 and 30 mg/kg daily) to be greater than that of imipramine in FST and shock induced depression model (SID) after 7 days of treatment, but failed to detect any effects in the tail suspension test (TST) [5]. B. monnieri extract (BM) was evaluated for acute vs. chronic antidepressant effects in FST and TST in doses of 50 and 100 mg/kg. The effects were significant in mice treated with 50 mg/kg in chronic study (drug administration for 10 days), but not in acute study (drug given 1 hour before the procedure), while treatment with 100 mg/kg showed antidepressant properties comparable to imipramine in both the acute and chronic study [6]. Another study evaluated effects of BM on the expression of BDNF protein and mRNA in the hippocampus and frontal cortex of rats. BDNF is a signaling molecule critical for neuronal survival and growth. Reduction in BDNF levels has been correlated with stress induced changes in neural plasticity that accompany depressive-like behaviours, while successful antidepressant treatment typically upregulates BDNF and reverses dendritic atrophy in the brain areas involved in regulation of mood. Rats subjected to chronic unpredictable stress routine (CUS) for 28 consecutive days developed depression-like state, manifested in the form of anhedonia (indicated by reduced sucrose consumption), diminished exploratory activity and failures to escape from stressors. Feeding of BM in the doses of 80 and 120 mg/kg during the course of experiment counteracted the behavioral effects of stress and restored BDNF mRNA and protein levels in the hippocampus and frontal cortex [7]. A precise mechanism of BM action was not explored.

BM produced anxiolytic effects in rats at doses of 5, 10 and 20 mg/kg. Higher doses were reported to be comparable to lorazepam [8].

BM is capable of decreasing plasma corticosterone and attenuating the depletion of serotonin, norepinephrine and dopamine in the rat cortex and hippocampus after chronic stress [9]. Thus, its antidepressant and anxiolytic effects might be due to its actions on the monoaminergic system. BM constituents known as Bacopaside I and Bacoside A were shown to inhibit MAO-A and MAO-B enzymes in an in-vitro study [10]. Modulatory actions of BM on 5-HT2C receptor expression have been reported, including its down-regulation in the hippocampus [11]. 5-HT2C antagonists are known to produce rapid antidepressant effects by disinhibition of dopamine cells in the ventral tegmental area [12].

BM has inhibitory effect on acetylcholinesterase (AChE) enzyme [13], increases the levels of acetylcholine and the density of cholinergic neurons in the hippocampus [14]. AChE inhibitors are used to improve cognitive function and mood in the treatment of Alzheimer’s disease. BM was demonstrated to reverse the cortical reduction of GABA receptors in the model of epilepsy [15]. Activity on the GABAergic system might prove to be useful in the treatment of depression, since this illness has been associated with low cortical GABA [16]. In animal models, decreased GABA receptors have also been correlated with depressive-like behaviour [15].

Human studies

Many clinical studies have been performed on the effects of B. monnieri on various cognitive abilities and mood. Most of them were conducted on healthy adults, for the period of 12 weeks, using 300 mg of BM extract daily [17]. Improvements in learning rate, memory formation and retention, working memory, verbal skills, attention, energy and mood, as well as anxiety reductions were reported in the studies [3]. However, no research has been done on patients suffering from actual depression or anxiety disorder. A recent review of high quality studies on Bacopa concluded that there is some evidence that BM improves memory in free recall, but claims of enhancements in other aspects of cognitive functioning are not well supported [17]. It also noted that studies used very similar doses over similar time frames and focused primarily on memory, ignoring other cognitive domains. Therefore, more studies exploring higher doses, longer supplementation periods and different mental functions are required.

OTHER PROPERTIES

BM exhibited potent antioxidant effects in studies and was shown to increase the activity of antioxidant enzymes such as superoxide dismutase, catalase and peroxidase in the brain and other organs [19, 20, 21]. It also has anti-inflammatory properties [21], which are primarily attributed to its constituent betulinic acid [22], and has shown potential for the treatment of rheumatic conditions [23]. Various fractions of Bacopa extract demonstrated antibacterial and antifungal effects [24].

SAFETY

Bacopa monnieri is a safe and beneficial supplement. It has been used as medicine for a long time with no reports of toxicity or dangerous side-effects. However, a number of gastrointestinal side-effects such as diarrhea, nausea and abdominal cramping were found in some studies, using doses of 300 mg daily [25, 26]. Intestinal complaints were milder and less frequent in a study where BM was taken in escalating amounts [27]. Interaction of MB can occur with drugs phenobarbital and chlorpromazine, potentiating their sedative effects [2]. A new study reported inhibition of human cytochrome P450 enzymes (CYP1A2, CYP3A4, CYP2C9 and CYP2C19) by BM, which would occur mostly in the gut, less in the liver [28]. Therefore, caution is advised when taking Bacopa alonsgide other drugs metabolized by the same enzymes.

DOSAGE

Wide range of BM doses produced antidepressant effects in animal studies, with higher doses exhibiting more significant effects. Doses showing efficacy in both FST and TST models in mice (50-100 mg/kg) correspond to 243 – 486 mg daily for a 60 kg human (when converted to human equivalent dose, HED). Doses within this range (300-450 mg) are recommended by supplement manufacturers, and have been tested in most clinical studies for potential nootropic properties. In the rat study, the most effective BDNF-raising dose was found to be 80 mg/kg, corresponding to human 778 mg daily. More research is needed to show if such doses can be considered safe and tolerable.

CONCLUSION

There is a considerable amount of preclinical evidence for antidepressant and anti-stress properties of Bacopa monnieri extracts. Human studies have consistently found pro-cognitive effects of BM, but haven’t produced any good evidence of mood brightening effects. However, neither conventional antidepressants affect mood significantly in healthy individuals and often cause undesirable cognitive side-effects. BM’s antidepressant actions are most likely due to its MAO inhibiting, GABA-ergic, and possibly anti-inflammatory and antioxidant properties. As is the case with most antidepressants, it would need to be taken chronically, over a long period of time (several months or more), in order to notice any change. Due to potential unpleasant side-effects, it would be advisable to gradually increase the dose (for example, over several weeks) until the desired amount is reached.

REFERENCES:

[1] Bacopa monnieri. (2015, June 2). In Wikipedia, The Free Encyclopedia. Retrieved 12:17, June 2, 2015, from http://en.wikipedia.org/w/index.php?title=Bacopa_monnieri&oldid=665160273

[2] Gohil, Kashmira J., and Jagruti A. Patel. “A review on Bacopa monniera: Current research and future prospects.” International Journal of Green Pharmacy 4.1 (2010): 1.

[3] Abascal, Kathy. “Bacopa for the Brain.” ALTERNATIVE AND COMPLEMENTARY THERAPIES (2011).

[4] Sairam K. Antidepressant activity of standardized extract of Bacopa monniera in experimental models of depression in rats. Phytomedicine. 2002;9:207–211. doi: 10.1078/0944-7113-00116.

[5] Kadali SRM, M.C. D, Rao A.S.R. S, Sri G K. Antidepressant Activity of Brahmi in Albino Mice. Journal of Clinical and Diagnostic Research : JCDR. 2014;8(3):35-37. doi:10.7860/JCDR/2014/7482.4098.

[6] Sindhu, Pabba, et al. “Evaluation of Antidepressant Activity of Bacopa Monnieri in Mice.” International Journal of Pharmacy 4.3 (2014): 144-148.

[7] Banerjee, Ritabrata, et al. “Chronic Administration of Bacopa Monniera Increases BDNF Protein and mRNA Expressions: A Study in Chronic Unpredictable Stress Induced Animal Model of Depression.” Psychiatry investigation 11.3 (2014): 297-306.

[8] Bhattacharya, S. K., and S. Ghosal. “Anxiolytic activity of a standardized extract of Bacopa monniera: an experimental study.” Phytomedicine 5.2 (1998): 77-82.

[9] Sheikh, Naila, et al. “Effect of Bacopa monniera on stress induced changes in plasma corticosterone and brain monoamines in rats.” Journal of ethnopharmacology 111.3 (2007): 671-676.

[10] Singh, Rajbir, et al. “In Vitro Evaluation of Bacopa monniera Extract and individual constituents on human recombinant monoamine oxidase enzymes.”Phytotherapy Research 28.9 (2014): 1419-1422.

[11] Krishnakumar, Amee, M. S. Nandhu, and C. S. Paulose. “Upregulation of 5-HT 2C receptors in hippocampus of pilocarpine-induced epileptic rats: Antagonism by Bacopa monnieri.” Epilepsy & Behavior 16.2 (2009): 225-230.

[12] Opal, M. D., et al. “Serotonin 2C receptor antagonists induce fast-onset antidepressant effects.” Molecular psychiatry (2013).

[13] Tembhre, Manju, et al. “Inhibitory Potential of Acephate and Ethanol Extract of Bacopa Monnieri on AChE in Rat Cortex and Hippocampus.” International Journal of Bioscience, Biochemistry and Bioinformatics 5.1 (2015): 45.

[14] Mathew, Jobin, et al. “Decreased GABA receptor in the cerebral cortex of epileptic rats: effect of Bacopa monnieri and Bacoside-A.” J Biomed Sci 19.25 (2012): 1-13.

[15] Sanacora G, Mason GF, Krystal JH: Impairment of GABAergic transmission in depression: new insights from neuroimaging studies. Critical Reviews in Neurobiology 2000, 14:23-45.

[16] Uabundit N, Wattanathorn J, Mucimapura S, Ingkaninan K. Cognitive enhancement and neuroprotective effects of Bacopa monnieri in Alzheimer’s disease model. J Ethnopharmacol 2010;127:26–31.

[17] Pase, Matthew P., et al. “The cognitive-enhancing effects of Bacopa monnieri: a systematic review of randomized, controlled human clinical trials.” The Journal of Alternative and Complementary Medicine 18.7 (2012): 647-652.

[18] Bhattacharya, S. K., et al. “Antioxidant activity of Bacopa monniera in rat frontal cortex, striatum and hippocampus.” Phytotherapy research 14.3 (2000): 174-179.

[19] Kapoor, Radhika, Saurabh Srivastava, and Poonam Kakkar. “Bacopa monnieri modulates antioxidant responses in brain and kidney of diabetic rats.”Environmental toxicology and pharmacology 27.1 (2009): 62-69.

[20] Ghosh, Tirtha, et al. “In vitro antioxidant and hepatoprotective activity of ethanolic extract of Bacopa monnieri Linn. aerial parts.” Iranian Journal of Pharmacology & Therapeutics 6.1 (2007): 77-85.

[21] Channa, Shabana, et al. “Anti-inflammatory activity of Bacopa monniera in rodents.” Journal of ethnopharmacology 104.1 (2006): 286-289.

[22] Viji, V., et al. “Betulinic acid isolated from Bacopa monniera (L.) Wettst suppresses lipopolysaccharide stimulated interleukin-6 production through modulation of nuclear factor-κB in peripheral blood mononuclear cells.”International immunopharmacology 10.8 (2010): 843-849.

[13] Viji, V., S. K. Kavitha, and A. Helen. “Bacopa monniera (L.) wettst inhibits type ii collagen‐induced arthritis in rats.” Phytotherapy Research 24.9 (2010): 1377-1383.

[24] Ghosh, T., et al. “Antimicrobial activity of various fractions of ethanol extract of Bacopa monnieri Linn. aerial parts.” Indian Journal of Pharmaceutical Sciences 69.2 (2007): 312.

[25] Morgan A, Stevens J. Does Bacopa monnieri improve memory performance in older persons? Results of a randomized, placebo-controlled, double-blind trial. J Altern Complement Med 2010;16:753–759.

[26] Stough C, Downey LA, Lloyd J, et al. Examining the nootropic effects of a special extract of Bacopa monniera [sic] on human cognitive functioning: 90 day double-blind placebo-controlled randomized trial. Phytother Res 2008;22:1629–1634.

[27] Pravina K, Ravindra KR, Goudar KS, et al. Safety evaluation of Baco- Mind in healthy volunteers: A phase I study [clinical report]. Phytomedicine 2007;14:301–309.

[28] Ramasamy, Seetha, Lik Voon Kiew, and Lip Yong Chung. “Inhibition of human cytochrome P450 enzymes by Bacopa monnieri standardized extract and constituents.” Molecules 19.2 (2014): 2588-2601.

Lycium barbarum fruits (Goji berries)

INTRODUCTION

Lycium barbarum is a deciduous shrub that grows 1-3 meters high and is widespread in warm climate regions, from Southeast Europe to China [1]. It is cultivated mostly for its edible berries, orange-to-red in color and 1-2 cm in length, known as wolfberries or Goji berries. Majority of Goji berries on the world market come from North China.

Lycium barbarum has been used in the traditional Chinese medicine for thousands of years [1]. Its berries (fruits) have been claimed to nourish liver, kidneys and lungs, to promote sexual health and fertility, cure vision problems, reduce fatigue and headache, and increase longevity [1, 2]. History of the traditional use has been taken as evidence of its extraordinary health benefits by various alternative medicine practitioners and commercial distributors, who have promoted Goji as a quasi-miraculous cure for medical conditions and an anti-aging product [1]. Goji berries have been heavily advertised recently and became a popular item on the health food market [1]. They are mostly sold as raw dried fruits, but also as juice, or in the form of powder or tablets. Some scientific studies have indeed found interesting and potentially useful pharmacological properties in the Lycium barbarum fruits, however, the conclusive evidence for their benefits to humans is still lacking.

Goji fruits are abundant in several classes of compounds. The most important are polysaccharides, carotenoids and flavonoids. They also contain essential fatty acids, free amino acids and vitamins B1, B2 and C [1]. The polysaccharide fraction is relatively characteristic for L. barbarum and has been investigated for potentially beneficial health effects.

ANTIDEPRESSANT AND NEUROPROTECTIVE EFFECTS

One study has shown that Lycium barbarum polysaccharides possess significant antidepressant properties [3]. Depressive-like behaviour was induced in rats by repeated injections of corticosterone (the main glucocorticoid hormone in rodents, equivalent to human cortisol). Increased glucocorticoid signaling has been identified in both animal and human studies as one of the most common physiological changes in depression and anxiety disorders, accompanying characteristic brain abnormalities and behavioral symptoms. As would be expected, corticosterone treatment resulted with dendritic atrophy of pyramidal cells and decreased levels of neurogenesis in subgranular zone of the hippocampus. Oral administration of Lycium barbarum polysaccharides (LBP) in doses from 1 mg/kg to 10 mg/kg for 14 consecutive days reversed this effects, increasing both neurogenesis and dendritic spine density. Important synaptic proteins (PSD-95 and synaptophysin) were also found to be upregulated. Moreover, LBP produced a significant antidepressant response in the forced swim test. However, further experiments showed that the increased synaptic plasticity alone, not the altered rate of neurogenesis, was responsible for the antidepressant effects of LBP. It was pointed out in the study that LBP treatment exerted a more potent effect than volontary physical exercise (wheel running) in the corticosterone model of depression, which was evaluated in the previous study by the same authors [4].

Neurogenesis enhancing properties of LBP were also found in another study that examined its effects on sexual behaviour in male rats [2]. Corticosterone administration was used to induce defects in sexual motivation and performance, and was shown to decrease neurogenesis in the hippocampus and the subventricular zone of the olfactory system (SVZ), as well as suppress testosterone levels. LPB treatment was found to reverse this, rescuing neurogenesis in both regions, increasing testosterone and restoring normal sexual behaviour. LBP was also capable of enhancing sexual performance in healthy male rats not treated with corticosterone. Neurogenesis was shown to be essential for both normal sexual functioning and the beneficial, pro-sexual effect of LBP.

Several other studies confirmed LBP’s pro-neurogenic effects. Treatment of rats with LBP before and after subjecting them to severe trauma reduced cognitive and behavioral defects attributed to hippocampal cell death (apoptosis) and impaired neurogenesis. LBP alleviated those cellular changes and restored the hippocampal volume [5]. Similar observations were made in the study of hypoxia-induced injury to the hippocampus; LBP showed neuroprotective effects against oxidative damage, suppressed inflammation and apoptotic signaling, improved neurogenesis and reduced deficits in spatial memory [6]. Its protective effects in ischemia and reperfusion injury were also reported in several studies [7, 8].

Possible beneficial effects of wolfberry on subjective states and neurological functioning have also been investigated in clinical studies. Daily consumption of Goji fruit extract was reported to increase the quality of sleep, decrease fatigue, dizziness, chest distress and anorexia in elderly subjects [9]. In another study, a commercial Goji juice was found to improve the subjective well-being, neurological performance and gastrointestinal functioning in young healthy adults [10].

OTHER BENEFITS

Antioxidant properties of Goji fruit extracts or purified polysaccharides have been in the focus of many studies. Protective effects of LBP against oxidative stress in animal cells and tissues have been demonstrated both in vivo and in vitro [11, 12, 13]. In the single clinical study, consumption of Goji juice increased serum antioxidant markers in healthy participants [14]. Animal studies have shown that LBP can improve insulin sensitivity and exert hypolipidemic effects (lowering cholesterol and triglycerides) [15]. A lot of research has focused on its immunostimulatory and antitumor properties [16, 17], including one clinical study on cancer patients where LBP in combination with immunotherapy resulted with increased remission rates [18].

TOXICITY

Goji berries can be regarded as safe, even when consumed in large quantities. They have been used for a long time as food and folk medicine, with no reports of adverse effects [1]. Recently, there have been only a few cases of allergic reactions, and adverse interactions have been documented in patients taking warfarin [19].

VALIDITY OF RESEARCH

It should be noted that almost all research on pharmacological properties of wolfberry was done by Chinese scientists. Clinical studies have been conducted exclusively in China, and have not been of highest quality [1]. Typically, studies were limited by small size, lack of statistical analysis and poor controls. Some were conducted by scientists either affiliated with or directly sponsored by the company selling Goji products. Independent research is needed.

CONCLUSION

Preclinical evidence suggests that Goji products (berries, extracts or juice) might be beneficial in the treatment of depression and other neurodegenerative disorders. Clinical evidence is still insufficient, proper studies are yet to be conducted. Regular consumption of wolfberry might potentially bring some improvement in the hedonic function, in combination with other strategies and substances. Since the fruit is not toxic, one could freely experiment with different dosages to find if it could produce a mood enhancing effect, while enjoying many other health benefits.

REFERENCES:

[1] Potterat O. Goji (Lycium barbarum and L. chinense): phytochemistry, pharmacology and safety in the perspective of traditional uses and recent popularity. Planta Med. 2010;76:7–19. doi: 10.1055/s-0029-1186218.

[2] Lau BW-M, Lee JC-D, Li Y, et al. Polysaccharides from Wolfberry Prevents Corticosterone-Induced Inhibition of Sexual Behavior and Increases Neurogenesis. Borlongan CV, ed. PLoS ONE. 2012;7(4):e33374. doi:10.1371/journal.pone.0033374.

[3] Zhang E, Yau SY, Lau BW, Ma H, Lee TM, Chang RC, et al. Synaptic plasticity, but not hippocampal neurogenesis, mediated the counteractive effect of wolfberry on depression in rats (1) Cell Transplant.2012;21:2635–49.

 [4] Yau S. Y.; Lau B. W.; Tong J. B.; Wong R.; Ching Y. P.; Qiu G.; Tang S. W.; Lee T. M.; So K. F. Hippocampal neurogenesis and dendritic plasticity support running-improved spatial learning and depression-like behaviour in stressed rats. PLoS One 6(9):e24263; 2011.

[5] Gao J, Chen C, Liu Y, Li Y, Long Z, Wang H, Zhang Y, Sui J, Wu Y, Liu L, Yang C. Lycium barbarum polysaccharide improves traumatic cognition via reversing imbalance of apoptosis/regeneration in hippocampal neurons after stress. Life Sci. 2015 Jan 15;121:124-34.

[6] Lam C-S, Tipoe GL, So K-F, Fung M-L. Neuroprotective Mechanism of Lycium barbarum Polysaccharides against Hippocampal-Dependent Spatial Memory Deficits in a Rat Model of Obstructive Sleep Apnea. Ma D, ed. PLoS ONE. 2015;10(2):e0117990. doi:10.1371/journal.pone.0117990.

[7] Li S-Y, Yang D, Yeung C-M, et al. Lycium Barbarum Polysaccharides Reduce Neuronal Damage, Blood-Retinal Barrier Disruption and Oxidative Stress in Retinal Ischemia/Reperfusion Injury. Ko B, ed. PLoS ONE. 2011;6(1):e16380. doi:10.1371/journal.pone.0016380.

[8] He M, Pan H, Chang RC-C, So K-F, Brecha NC, Pu M. Activation of the Nrf2/HO-1 Antioxidant Pathway Contributes to the Protective Effects of Lycium Barbarum Polysaccharides in the Rodent Retina after Ischemia-Reperfusion-Induced Damage. Gallyas Jr. F, ed. PLoS ONE. 2014;9(1):e84800. doi:10.1371/journal.pone.0084800.

[9] Li DY, Yuan XL, Xia HF, Ma L, Guo ZY, Shen YY, Rong QZ. Preliminary clinical observations for effects of Ning Xia wolfberry extract on old peoples. Chin Tradit Herb Drugs 1989; 20: 26–28

[10] Amagase H, Nance DM. A randomized, double-blind, placebo-controlled, clinical study of the general effects of a standardized Lycium barbarum (Goji) juice, GoChi™. J Altern Compl Med 2008; 14: 403–412

[11] Shan X, Zhou J, Ma T, Chai Q. Lycium barbarum Polysaccharides Reduce Exercise-Induced Oxidative Stress. International Journal of Molecular Sciences. 2011;12(2):1081-1088. doi:10.3390/ijms12021081.

[12] Liu L, Lao W, Ji Q-S, Yang Z-H, Yu G-C, Zhong J-X. Lycium barbarum polysaccharides protected human retinal pigment epithelial cells against oxidative stress-induced apoptosis. International Journal of Ophthalmology. 2015;8(1):11-16. doi:10.3980/j.issn.2222-3959.2015.01.02.

[13] Zhang L, Gu J, Chen Y, Zhang L. A Study on Four Antioxidation Effects ofLycium Barbarum Polysaccharides In Vitro. African Journal of Traditional, Complementary, and Alternative Medicines. 2013;10(6):494-498.

[14] Amagase H, Sun B, Borek C. Lycium barbarum (goji) juice improves in vivo antioxidant biomarkers in serum of healthy adults. Nutr Res 2009; 29: 19–25

[15] Ming M, Guanhua L, Zhanhai Y, Guang C, Xuan Z. Effect of the Lycium barbarum polysaccharides administration on blood lipid metabolism and oxidative stress ofmice fed high-fat diet in vivo. Food Chem 2009;113: 872–877

[16] Chen Z, Tan BKH, Chan SH. Activation of T lymphocytes by polysaccharide-protein complex from Lycium barbarum L. Int Immunopharmacol 2008; 8: 1663–1671

[17] Gan L, Zhang SH, Yang XL, Xu HB. Immunomodulation and antitumor activity by a polysaccharide-protein complex from Lycium barbarum. Int Immunopharmacol 2004; 1: 563–569

[18] Cao GW, Yang WG, Du P. Observation of the effects of LAK/IL-2 therapy combining with Lycium barbarum polysaccharides in the treatment of 75 cancer patients. Zhonghua Zhong Liu Za Zhi (Chin J Oncol) 1994;16: 428–431

[19] Ge B, Zhang Z, Zuo Z. Updates on the Clinical Evidenced Herb-Warfarin Interactions. Evidence-based Complementary and Alternative Medicine : eCAM. 2014;2014:957362. doi:10.1155/2014/957362.