Myrrh (Commiphora molmol) Clinical Summary

Traditional usage Myrrh is perhaps best known for its historical role in many religion traditions as an ingredient in anointing oils, incense and an embalming ointment. It was also used as a highly valued perfume. Myrrh has a long history of use as an antiseptic and astringent and used to treat problems of the mouth, gum and throat and digestive tonic. Myrrh was a common ingredient in toothpowders and for parasites. Actions Anti-inflammatory, antioxidant, antiseptic, anaesthetic, astringent, anticancer, antiparasitic hypocholesterolaemic, hypoglycaemic/insulinaemic, hepatoprotective, thyroid modulator Indications • Hypercholesterolaemia & dyslipidaemia • Cancer • Toxin exposure, oxidative stress & liver disorders • Diabetes & obesity • Hypothyroid • Parasitic infections • Bacterial infections including acne, gum disease, gingivitis • Neuralgia Toxicity HUMAN Transient skin rashes, headaches and gastrointestinal disorders have been reported in some patients during studies with Myrrh. One case of rhabdomyolysis with hemoglobinuria has been reported that resolved when Myrrh was discontinued. ANIMAL Toxicity studies revealed a significant increase in weight of reproductive organs as well as elevated levels of RBC and Hb in mice. High doses of 1 or 5 g plant resin/kg/d caused salivation, soft faeces, jaundice, dyspnoea, ataxia and eventually death in goats. Lower doses were safe. Use in pregnancy Contraindicated due to possible emmenagogic action Contraindications and cautions None documented. Drug interactions None documented. Administration and dosage Dried resin: 200mg – 600mg daily Liquid extract (resin) 1:5 90% alcohol: 1.0-2.5mL 3 times daily. A full monograph is available on: www.herbalextracts.com.au Description Myrrh is a reddish-brown resinous material obtained from the dried sap of the Commiphora species of trees. A range of related shrubs from the Burseraceae family can be used to obtain the resin. Different species are native to different regions, for example Commiphora myrrha is native to Yemen, Somalia and Ethiopia while Commiphora gileadensis is native to Jordan. The bushes yielding the resin do not grow more than 2-3 metres in height. They are sturdy bushes, with knotted branches, and branchlets that stand out at right-angles, ending in a sharp spine. The trifoliate leaves are scanty, small and very unequal, oval and entire.1 There are ducts in the bark, and large cavities can form inside which fill with a granular secretion. The secretions are freely discharged as ‘tear drops’ when natural fissures occur or when the bark is cut. Myrrh initially flows as a pale yellow liquid, but hardens to a reddish-brown mass. Commercially the dried resinous ‘tears’ can be found in many sizes but average the size of a walnut. The surface is rough and powdered, and the pieces are brittle, semi-transparent, oily, and often show whitish marks. High quality myrrh can be identified through the darkness and clarity of the resin. The scent of raw myrrh resin and its essential oil is sharp and pleasant though slightly bitter. When burned, it produces a smoke that is heavy with the scent of vanilla and bitter overtones.

Traditional usage Myrrh is perhaps best known for its historical role in many religion traditions. It was, and still is, a traditional ingredient in anointing oils in Christian, Jewish and Muslim religious ceremonies. Incense made from Myrrh was used in funerals and cremations. Myrrh has also been used historically in many cultures as a perfume and an embalming ointment and was highly valued - often worth more than its weight in gold. Hence, along with gold and frankincense, myrrh was one of the precious gifts that the three magi brought to Jesus. Myrrh has a long history of use as an antiseptic and astringent. In India as well as in the Middle East, Myrrh was traditionally used to treat problems of the mouth, gum and throat and was considered a tonic to the digestive system. Myrrh was a common ingredient in toothpowders and was considered excellent for ‘spongy gums’ and was also used to expel parasites. It was also used as a stimulating emmenagogue, an expectorant and mucous membrane stimulant in chronic respiratory and catarrhal states.

Constituents Chemical analysis of myrrh has shown that it is composed on round 8-10% volatile oil, 25-40% resin and around 50-60 % gum. Broad assessment reveals ash, salts, sulphates, benzoates, malates, acetates of potassium, formic acid, acetic acid, tannins and a lignan.2 A further breakdown of the resins reveals commiphoric acids, heeraboresene, heerabomyrrhols, commiferin, novel triterpenes, epimansumbinol, progesterone and steroids such as guggulsterone.3, 4 The gum exudates of Myrrh have been determined to have acidic polysaccharides with galactose, 4-O-methyl-glucuronicacid, and rabinose along with furanosesquiterpenoids, 5 lindestrene, curzerene, and germacrone.6 The essential oil of myrrh contains sesquiterpenoid hydrocarbons, elemol, furanodiene, furanodienone, isofuranogermacrene, curzerenone and lindestrene.7

Pharmacological activities Cholesterol Lowering Activity The plant sterol guggulsterone (guggulipid) obtained from Myrrh resin has been shown to lower LDL (low-density lipoprotein) cholesterol and triglyceride levels and raise serum high density lipoprotein levels in both animal and human studies. Guggulsterone may act in more than one way to lower cholesterol. It has been shown to act as an antagonist to the bile acid receptor (BAR),8 and through lowering the enzyme, human pancreatic IB phospholipase , which controls gastrointestinal absorption of fat and cholesterol.9 Guggulsterone also acts by antagonising the farnesoid X receptor (FXR), a hormone receptor that is activated by bile acids and responsible for a range of actions. Guggulsterone was shown to be a selective bile acid receptor modulator that regulates expression of a subset of FXR targets.10 Guggulsterone treatment decreased hepatic cholesterol in mice fed a high-cholesterol diet but was not effective in FXR-null mice. Thus, researchers suggested that inhibition of FXR activation is a basis for the cholesterol-lowering activity of guggulsterone.11 A study found that the decrease in serum cholesterol in rats treated with guggulsterone was associated with enhanced uptake of LDL by the liver through receptor mediated endocytosis. Membranes prepared from the liver of guggulsterone treated rats exhibited up to an 87% increase in binding sites for LDL. Significant decreases in lipid levels in both serum and liver membrane were observed.12 Human studies have found mostly favourable results for Myrrh. One RCT examined 43 patients, with moderately increased cholesterol, for the effect of guggul or placebo for 12 weeks. After 12 weeks, mean levels of total cholesterol and HDL in the active group were significantly reduced compared with the placebo group.13 Another double-blind, RCT examined the use of guggulipid in healthy adults with hypercholesterolemia compared with placebo. However, this 8 week study did not find favourable results. There were no significant changes in levels of total cholesterol, HDL-C, triglycerides, or VLDL-C in response to treatment with guggulipid. Though it was generally well tolerated, 6 participants treated with guggulipid developed a hypersensitivity rash compared with none in the placebo group.14 Another compared gugulipid therapy with clofibrate therapy. With gugulipid the average fall in cholesterol and triglycerides was 11 and 16.8% respectively and with clofibrate 10 and 21% respectively. HDL-cholesterol was increased in 60% cases who responded to gugulipid therapy. Clofibrate had no effect on HDL-cholesterol. A significant decrease in LDL-cholesterol was observed in the responders to both drugs.15 The effects of guggulipid or placebo for 24 weeks were compared as adjuncts to a fruit- and vegetable-enriched diet in hypercholesterolaemic patients. Guggulipid decreased the total cholesterol level by 11.7%, the LDL cholesterol by 12.5%, triglycerides by 12.0%, and the total cholesterol/HDL cholesterol ratio by 11.1% from the post-diet levels, whereas the levels were unchanged in the placebo group. The HDL cholesterol level showed no changes in the two groups. The lipid peroxides, indicating oxidative stress, declined 33.3% in the guggulipid group without any decrease in the placebo group. The combined effect of diet and guggulipid at 36 weeks was as great as the reported lipid-lowering effect of modern drugs. The changes in blood lipoproteins were reversed in the guggulipid group during the washout period without such changes in the placebo group. Side effects of guggulipid were headache and digestive complaints in a few patients.16 A combination of Myrrh and Inula was studied in 200 patients with ischemic heart disease. A 39% decrease in total cholesterol, 51% decrease in triglycerides, and 32% decrease in total blood lipids were reported. At the end of the six-month study period, 26% of the subjects had a complete restoration of normal ECG, 59 % showed improvement in the ECG, 25% had no chest pain, and patients experiencing dyspnoea fell to 80% at baseline to 32%. Of those still experiencing chest pain and dyspnoea, the subjective levels of pain also improved after treatment. 17 There is accumulating evidence that LDL oxidation is essential for atherogenesis, and antioxidants may either slow down or prevent atherogenesis. Myrrh and guggulsterone, were shown to effectively inhibit LDL oxidation mediated by a range of substances.18 Regulation of Blood Sugar and Adiposity Myrrh may also have a potential role in the prevention of diabetes. An extract of myrrh effectively increased glucose tolerance in both normal and diabetic rats.19 Other results suggest that activation of farnesoid X receptor (FXR) plays a critical role in regulating adipogenesis and insulin signaling. FXR is expressed in the adipose tissue and promotes adipocyte differentiation and lipid storage. FXR activation seems to lead to reduced synthesis of fatty acid in the liver and increased lipid storage in the adipose tissue. Guggulsterone antagonised the FXR and decreased the adipose cell size and lipid droplet accumulation.20 Guggulipid was shown to protect mice from diabetes and improved glucose tolerance in mice genetically at risk for obesity. Authors reported possible mechanisms for its metabolic effects, in particular those due to a newly identified component, commipheric acid. Both guggulipid and commipheric acid activated receptors that promoted the differentiation of preadipocytes cells to adipocytes. Commipheric acid lowered fasting blood glucose, plasma insulin, and plasma triglycerides without affecting food intake or body weight. These results suggest the possibility that guggulipid has anti-diabetic activity but the systemic bioavailability of orally dosed, pure commipheric acid appeared poor.21 Memory Enhancer A study explored the potential of gugulipid as cognitive enhancer. Gugulipid was investigated for its effect on learning and memory, parameters of oxidative stress and acetylcholinesterase (AChE) activity in streptozotocin STZ treated mice. Pre-treatment of gugulipid daily for 14 days started with the first dose of STZ significantly prevented STZ induced memory deficit. Post-treatment of gugulipid significantly decreased the latency time indicating anti-dementia activity. The study demonstrated that gugulipid has significant protective affect against streptozotocin-induced memory deficits model of dementia that can be attributed to anti-oxidant and anti-AChE activity of gugulipid. These observations suggest gugulipid as a potential anti-dementia drug.22 Thyroid Modulation Myrrh appears to have a role in modulating the thyroid. A study looked at the role of Myrrh in thyroid function of mice and to assess the involvement of lipid peroxidation (LPO), if any. While no marked change in the concentrations of thyroxine or T4 was observed, T3 concentration and T3/T4 ratio were enhanced following the administration of gugulu extract. A concomitant decrease in LPO was also noticed in liver, the principal site of T3 generation, suggesting that gugulu induced increase in T3 concentration is LPO mediated.23 The isolated ketosteroid from Myrrh showed a strong thyroid stimulatory action when administered to albino rats. It caused an increase in iodine-uptake by thyroid and enhanced activities of thyroid peroxidase and protease as well as oxygen consumption by muscle.24 The efficacy of guggulu in regulating hypothyroidism was evaluated in female mice. A range of parameters were assessed including thyroxine, T3, lipid-peroxidation (LPO) and anti-oxidative enzymes SOD and catalase. While the drug PTU induced hypothyroidism in mice the simultaneous administration of guggulu reversed this effect, indicating its potential to stimulate thyroid function. Although in PTU treated animals a marginal increase in hepatic LPO was observed, when simultaneously treated with guggulu, it was decreased. A parallel increase in the activity of endogenous antioxidants, SOD and CAT, in the latter group indicated the safe and antiperoxidative nature of the drug. These findings suggest the possible use of guggulu in the amelioration of hypothyroidism.25 Cytotoxic & Anticancer Activities Guggulsterone has been found to inhibit the proliferation of wide variety of human tumor cell types including leukemia, head and neck carcinoma, multiple myeloma, lung carcinoma, melanoma, breast carcinoma, and ovarian carcinoma. Guggulsterone also inhibited the proliferation of drug-resistant cancer cells.26 The genotoxic, cytotoxic and antitumor properties of Myrrh resin were studied in normal and Ehrlich ascites carcinoma cell-bearing mice. The cytotoxic and antitumor activity of Myrrh was found to be equivalent to those of the standard cytotoxic drug cyclophosphamide. The nonmutagenic, antioxidative and cytotoxic potential of Myrrh suggest a role in cancer therapy.27, 28 Guggulsterone has been shown to bind to the farnesoid X receptor and modulate expression of proteins with antiapoptotic, cell survival, cell proliferation, angiogenic, and metastatic activities in tumor cells. Guggulsterone mediates gene expression through regulation of various transcription factors, including NF-kappaB, and various steroid receptors such as androgen receptor and glucocorticoid receptors. Modulation of gene expression inhibits cell proliferation, induces apoptosis, suppresses invasion and abrogates angiogenesis. Evidence suggests that guggulsterone can suppress tumor initiation, promotion and metastasis.29 Guggulsterone has been shown to have a role in preventing bone resorption by suppressing receptor activity and tumor cell-induced osteoclastogenesis by suppressing the activation of NF-kappaB.30 Other constituents from Myrrh have also been shown to have moderate antiproliferative effects on human prostate cancer cell lines and can inhibit the expression of androgen receptor.31 A study examined the molecular mechanism of cell death (apoptosis) by guggulsterone, using PC-3 human prostate cancer cells as a model. The viability of PC-3 cells, but not a normal prostate epithelial cell line (PrEC), was reduced significantly on treatment with guggulsterone in a concentration-dependent manner. Guggulsterone was found to cause apoptosis.32 Another study found that Guggulsterone possesses antitumor-promoting effects in mouse skin cancer. Topical application of Guggulsterone prior to application of a tumor promotor (TPA) significantly inhibited skin oedema and hyperplasia as well as inhibiting a range of inflammatory mediators. These results provide evidence that Guggulsterone possesses anti-skin tumour-promoting effects in mice and could be useful for delaying tumour growth in humans.33 Guggulsterone, has also been shown to cause apoptosis in cancer cells through the activation of an enzyme involved with the expression of tumor necrosis factor as well as stimulating the overexpression of catalase and superoxide dismutase and modulating NK kappaB. Guggulsterone also inhibits promoter activity of androgen receptors.34, 35 Aside from inducing apoptosis, Guggulsterone has also been shown to also inhibit angiogenesis in vitro and in vivo. Researchers suggesting that further preclinical and clinical investigation of guggulsterone should be carried out for its efficacy against prostate cancer.36 Antioxidant, Hepatoprotective & Antiinflammatory Effects Myrrh was found to have hepatoprotective and antioxidant effects when mice were exposed to carbon tetrachloride and correlated with its antioxidant and free radical scavenger effects. It was thought to be comparable to Silymarin.37.38 Myrrh (Mirazid) was compared with the drug praziquantel to evaluate and compare hepatotoxic, genotoxic and carcinogenic effects in rats. Praziquantel was found to be a hepatotoxic, genotoxic and carcinogenic drug, while Mirazid seemed to be a safe and promising antiparasitic drug, free from hepatotoxic, genotoxic and carcinogenic effects.39 The anticlastogenic (radioprotective) effects of Commiphora molmol were studied in mice treated with cyclophosphamide (CP). The Myrrh treatment showed no mutagenicity but caused a highly significant and dose-dependent mitodepressant effect in the femoral cells and reduction of RNA levels in hepatic cells as compared with the control.40 Compounds isolated from the Myrrh resin were found to demonstrate antioxidant effects through significant inhibition of nitrous oxide formation in lipopolysaccharide (LPS)-activated murine macrophages.41 The impact of two types of antioxidant (butyl hydroxyl toluene from olive extract and the essential oil of Myrrh) on sebum squalene peroxidation by UV irradiation were studied. The results found the essential oil of Myrrh provides the best protection against squalene peroxidation. These results demonstrate that squalene peroxidation during solar exposure is mainly because of singlet oxygen and not free radical attack. This suggests that sun care cosmetics should make use not only of free radical scavengers but also of singlet oxygen quenchers such as Myrrh. 42, 43 Turmeric and myrrh were found to be useful for controlling oxidative damages and genotoxicity induced by lead acetate intoxication.44 The Jerusalem Balsam a historical herbal formula containing four plants: Boswellia spp., Commiphora spp., Aloe spp and Mistacia lentiscus was found to have anti-inflammatory, anti-oxidative and anti-septic properties.45 Guggulsterone has been found to potently inhibit the activation of nuclear factor-kappaB (NF-kappaB), a critical regulator of inflammatory responses. This is thought to be the mechanism behind the antiinflammatory effect of guggulsterone.46 The anti-inflammatory effect of Myrrh was due to down regulation of inflammatory mediators such TNF-alpha and some interleukins and inhibition of MAPK activation.47 Antiparasitic Activity A proprietary formula containing Myrrh, Mirazid, has been extensively studied for its role in the treatment of parasitic and bacterial infections. It has been found to be effective against human Hymenolepiosis, Schistosoma, Fascioliasis, Strongyloides stercoralis and Dicrocoeliasis dendriticum. One study found parasitologic cure rate was between 95-100% for Hymenolepiosis nana & H. diminuta one week post-treatment. Two participants who initially did not respond, were cured by another Mirazid course.48 A small trial treated children with fascioliasis or schistosoma with Myrrh (Mirazid) for 3-7 days. Parasitologic cure was 90.9% in fascioliasis and 100% in schistosomiasis at 4 weeks post treatment. After a second dose Fasciola patients who remained positive were cured.49 The parasitological cure rate for fasciola with Mirazid in other studies was found to be 88- 94% without any side-effects. The cases not completely responding to a single course of treatment showed a marked reduction of the egg intensity. It was concluded that Mirazid is safe and effective in the treatment of human fascioliasis under the field conditions.50,51 Patients infected with schistosoma were treated with Myrrh (Mirazid) for six days and resulted in a parasitological cure rate after three months was around 97% without any side-effects. Patients not completely responded to a single course of treatment showed marked reduction of egg intensity. It is concluded that Mirazid proved to be safe and very effective in treatment of Schistosoma infections.52 Another study found similar results after three days with a cure rate of 91.7%. Re-treatment of cases who did not respond for a further six days gave a cure rate of 76.5%, increasing the overall cure rate to 98.09%. The drug was well tolerated, and side effects were mild and transient.53 Two other trials have compared the anti-schistosomal activity of mirazid in comparison with that of the drug praziquantel. However, in these trials Mirazid showed only low cure rates of between 9-15% compared with cure rates of 60-80% with praziquantel. 54,55 While these trials do not suggest a positive role between Mirazid and schistosoma, they may have been limited by the length of the trial, as other successful trials were conducted over at least 6 days. Strongyloidiasis caused by Strongyloides stercoralis, is considered difficult to treat. All cases in a trial were cured by Mirazid given for one month except three resistant cases. Only one case responded to repeated course of Mirazid, while the other two cases still had larvae in their stool.56 Myrrh extract (Mirazid) was shown to be successful and safe in the treatment of Dicrocoeliasis dendriticum infection in both humans and animals with a 100% cure rate.57 ,58 A study examined the effects on mice livers infected with Schistosoma mansoni before and after treatment with Mirazid or extract of Citrus reticulata root. Treatment with C. reticulata or Mirazid improved liver enzyme activities with a noticeable reduction in ova count and worm burden.59 Mirazid has been compared with azithromycin and praziquantel but was not found to be effective against Cryptosporidium. 60 Antibacterial actions The crude extract of Myrrh and particular constituents were examined for the effects on several bacteria. Potentiation was reported by Myrrh with concurrent ciprofloxacin and tetracycline against Staph. aureus, several Salmonella and two K. pneumoniae strains. The antibacterial activity of terpenes from Myrrh were favourable against multidrug-resistant strains of Staph aureus.61 Different species and plant parts of Myrrh were investigated for anti-oxidant, antimicrobial, anti-inflammatory, anticancer and cytotoxic effects. Mild antioxidant activities were noted for some species and the antimicrobial activity was best for Gram-positive bacteria and the yeasts compared with Gram-negative bacteria. All concentrations exhibited antibacterial activity, with complete bactericidal effect achieved by the 24th hour. Anticancer activities were also reported for leaf and stem of a number of different species.62 The essential oil, chloroform extract and seven sesquiterpenoids compounds isolated from the oleo-gum-resin of Myrrh showed a wide range of inhibiting activity against both Gram (+) and Gram (-) bacteria.63 Sesquiterpene fractions from Myrrh were found to display antibacterial and antifungal activity against standard pathogenic strains of Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa and Candida albicans. These compounds also had local anaesthetic activity.64 A study determined myrrh oil cytotoxicity to human gingival fibroblasts and epithelial cells and its effect, on interleukin production. Cell viability and cytotoxicity were determined and found that concentrations less than 0.001% had little effect on fibroblast and epithelial cell viability after 24 hours. However increasing concentrations of Myrrh oil and increased exposure time, increased cytotoxicity and decreased cell viability.65 Different extracts of Myrrh were found to be moderately active against Staphylococcus aureus, Pseudomonas aeruginosa, and Plasmodium falciparum and other extracts inhibited COX-2. The compound syringic acid showed moderate antimalarial, anticandidal, and antimycobacterial activity; while mearnsetin and quercetin exhibited antioxidant activity comparable to ascorbic acid and trolox.66 Tetracycline was compared to Guggulipid for nodular cystic acne over 3 months. Both treatments produced a progressive reduction in the lesions in the majority of patients. With tetracycline, the percentage reduction in the inflammatory lesions was 65% as compared to 68% with gugulipid.67 Actions Anti-inflammatory, antioxidant, antiseptic, anaesthetic, astringent, anticancer, antiparasitic hypocholesterolaemic, hypoglycaemic/insulinaemic, hepatoprotective, thyroid modulator Indications • Hypercholesterolaemia & dyslipidaemia • Cancer • Toxin exposure, oxidative stress & liver disorders • Diabetes & obesity • Hypothyroid • Parasitic infections • Bacterial infections including acne, gum disease, gingivitis • Neuralgia Toxicity HUMAN • Transient skin rashes, headaches and gastrointestinal disorders (nausea, abdominal discomfort) have been reported during studies with Myrrh. In most cases they did not result in discontinuing treatment. 68 • One case of rhabdomyolysis with haemoglobinuria in a 55 year old man taking Myrrh has been reported. The disorders occurred after two weeks of treatment and then resolved when Myrrh was discontinued.69 • No other significant adverse effects in human studies have been documented. ANIMAL • Toxicity studies on Myrrh have been carried out in mice. Dosages in acute study were 0.5, 1.0 and 3 g/kg, while in chronic study dosage was 100 mg/kg per day. There was no significant difference in mortality in acute or chronic treatment compared to controls. There was a significant increase in weight of testes, caudae epididymides and seminal vesicles in the Myrrh group. Biochemical studies revealed no differences in treated animals, however, haematological studies revealed a significant increase in RBC and haemoglobin levels compared to the control group. Myrrh failed to show any spermatotoxic effects.70 • Another study examined goat kids for toxicity of Myrrh. The very high doses of 1 or 5 g plant resin/kg/d caused grinding of teeth, salivation, soft faeces, jaundice, dyspnoea, ataxia and recumbency. Death occurred between 5 and 16 d. Anaemia, leucopaenia, increases in bilirubin, cholesterol, triglycerides and creatinine, and decreases in total protein and albumin were reported. The oral dose of 0.25 g plant resin/kg/d was not toxic.71 Use in pregnancy Contraindicated due to possible emmenagogic action Contraindications and cautions None documented. Drug-interaction None documented. Administration and dosage Dried resin: 200mg – 600mg daily Liquid extract (resin) 1:5 90% alcohol: 1.0-2.5mL 3 times daily.

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