PRESCRIBING INFORMATION

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Bitter tonic, gastric stimulant, sialagogue, cholagogue

Potential Indications

Based on appropriate evaluation of the patient, practitioners should consider prescribing gentian in formulations in the context of: • Stimulating gastric secretion, bile release from the gallbladder, bile production by the liver (4) • Loss of appetite,* dyspepsia,* asthenia, coated tongue, postprandial bloating, in combination with rhubarb (3) • Stimulating gastric secretion, constipation, flatulence, abdominal fullness,* itching of skin, in combination with rhubarb, cascara, and boldo (3) • Nausea, vomiting, heartburn, abdominal pain, constipation (4) • Stimulating pancreatic enzyme secretion (7)

Contraindications Gastric and duodenal ulcers,¹ hyperacidity,² gastric inflammation³ Warnings and Precautions None required. Interactions None known. Use in Pregnancy and Lactation No adverse effects expected. Side Effects

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Carminative, antiemetic, peripheral circulatory stimulant, spasmolytic, antiinflammatory, antiplatelet, diaphoretic, digestive stimulant, pungent

Potential Indications

Based on appropriate evaluation of the patient, practitioners should consider prescribing ginger in formulations in the context of: • Prophylaxis and treatment of nausea and vomiting from motion sickness (2,4) • Prophylaxis and treatment of postoperative nausea (2,4) • Morning sickness (2) • Drug-induced nausea (2) • Osteoarthritis (2) • Dyspepsia (4) • Digestive problems, nausea, vomiting, colic, flatulent dyspepsia, cramping (5) • Fever, the common cold (especially the fresh rhizome), conditions requiring expectoration (5) • Dysmenorrhea (5)

Contraindications According to the Commission E, using ginger is contraindicated in patients with gallstones, except under close supervision. In TCM, dried ginger is used cautiously during pregnancy. A daily dose of 2 g of dried ginger should not be exceeded in pregnancy. Warnings and Precautions The user should proceed with caution in cases of peptic ulceration, gastroesophageal reflux, or other gastric diseases. Interactions Ginger may increase the absorption of pharmaceutical drugs.   Although no problems have been reported in humans, ginger may increase the chance of bleeding. Daily doses of (dried) ginger in excess of 4 g should be prescribed with caution in patients who are already taking blood-thinning drugs such as warfarin or aspirin or who have increased risk of hemorrhage. Use in Pregnancy and Lactation No adverse effects are expected within the recommended dose (0.7 to 2.0 ml of 1:2 liquid extract). A daily dose of 2 g of dried ginger should not be exceeded in pregnancy. Ginger has been successfully used in clinical trials to treat pregnant women with nausea. Side Effects At doses approaching or greater than the maximum recommended dose, a blood-thinning effect and an increase in gastric secretory activity leading to heartburn is possible. Topical application of ginger may cause contact dermatitis in sensitive patients. Occupational allergic contact dermatitis from spices, including ginger, has been reported. Dosage Dose per day^* Dose per week^*   0.7-2.0 ml of 1:2 liquid extract 5-15 ml of 1:2 liquid extract

* This dose range is extrapolated from the British Pharmaceutical Codex 1934, the British Herbal Pharmacopoeia 1983, the British Pharmacopoeia 1975, and the author’s education and experience.

SUPPORTING INFORMATION

Traditional Prescribing

Traditional Western herbal medicine uses include: • Nausea, anorexia, colic, flatulent dyspepsia1,2 • Amenorrhea,3 dysmenorrhea;2 to improve circulation2 Uses and properties from TCM include: • For dried ginger:epigastric pain with cold feeling, vomiting and diarrhea with cold extremities, and faint pulse; dyspnea and cough with copious frothy expectoration4 • For fresh ginger:the common cold, vomiting caused by cold in the stomach, cough with thin white sputum4

Pharmacologic Research

Major constituents of ginger rhizome include an essential oil (1% to 3%, containing zingiberene and sesquiphellandrene) and pungent (hot) principles (1.0% to 2.5%, including gingerols and shogaols). • Several studies have examined the antiemetic and antinausea effects of ginger. The mechanism of action responsible for the antiemetic effect is still controversial, however, possibilities include a central effect via gastrointestinal serotonin antagonism, central and peripheral anticholinergic and antihistaminic effects, and a dampening of induced vestibular impulses to the autonomic centers of the central nervous system. • Oral administration of spraydried ginger extract significantly prevented ethanol-induced gastric mucosal damage. Ginger and 6-gingerol inhibited experimental gastric ulcers in vivo after oral administration. • Ginger and its pungent components exert an antiinflammatory effect by inhibiting both the cyclooxygenase and lipoxygenase enzymes belonging to the prostaglandin and leukotriene biosynthetic pathways, respectively. Oral intake of ginger extract inhibited carrageenan-induced paw swelling and was as active as aspirin in this model (although it was devoid of analgesic activity). Essential oil of ginger inhibited chronic adjuvant arthritis when given orally. • Fever reduction in an experimental model after oral doses of ginger extract was comparable to aspirin. • Several studies have demonstrated that ginger inhibits platelet aggregation in vitro. The inhibition of thromboxane formation appears to be the main cause of this antiplatelet action of ginger. • Oral doses of ginger and its constituents have been shown to: increase saliva production, gastric secretions, and activity and intestinal transit; decrease pepsin activity; inhibit gastric contraction and serotonin-induced diarrhea; and reverse the cisplatin-induced delay in gastric emptying. • Ginger and its components were thermogenic in perfused isolated tissues and significantly inhibited serotonin-induced hypothermia. • Pungent principles of ginger had antihepatotoxic effects in vitro, inhibited histamine release from mast cells in vitro, and exhibited antiallergic activity in vivo. Ginger, ginger extract, and its pungent principles have demonstrated antioxidant activity in vitro. • Ginger and its constituents have demonstrated antifungal activity, mild growth inhibition of gram-positive and gram-negative bacteria, antirhinoviral activity, and direct antiparasitic activity, all in vitro. • Ginger as a thromboxane synthetase inhibitor and prostacyclin agonist was postulated to have therapeutic potential in alcohol withdrawal and the complications of liver damage, recovery from serious burns, peptic ulceration, Kawasaki disease, preventing aging penile vascular changes and impotence, as an antidepressant, and as an analgesic in dysmenorrhea.

Clinical Studies

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Antioxidant, antiplatelet activating factor (anti-PAF) activity, tissue perfusion enhancing, circulatory stimulant, cognition enhancing, neuroprotective

Potential Indications

Based on appropriate evaluation of the patient, practitioners should consider prescribing Ginkgo in formulations in the context of: • Cerebral insufficiency (restricted cerebral blood flow) and its related symptoms, such as memory and cognitive impairment, dizziness, tinnitus, acute cochlear deafness, headaches, anxiety and depression, and fatigue (1,4) • Early stages of primary degenerative dementia (Alzheimer’s-type) (1,4) • Multiinfarct (vascular) dementia (2,4) • Stroke of recent onset (2) • A tonic for older adults (2) • Vertigo or dizziness of vascular origin (2) • Tinnitus of vascular and involutional origin (4) • Peripheral arterial occlusive disease (Fontaine stage II [intermittent claudication] or stage III) (1,4) • Idiopathic sudden hearing loss (2) • Disorders resulting from reduced retinal blood flow, senile macular degeneration (3) • Enhancing cognitive function, including working and long-term memory, abstract reasoning, and processing speed in healthy individuals and particularly in older adults (2) • Improving attention in healthy young individuals (3) • Improving memory and cognitive performance in healthy individuals (2) • The effects of high altitude or hypoxia (2) • Antioxidant activity (3) • Congestive dysmenorrhea (3) • Anti-PAF activity (4a) • Asthma (4)

Contraindications None known. Warnings and Precautions Ginkgo should be used with caution in patients on anticoagulant or antiplatelet medication. Interactions Based on some case reports of possible interaction, caution should be exercised when prescribing Ginkgo with warfarin and aspirin. Use in Pregnancy and Lactation No adverse effects expected. Side Effects Dosage Dose per day^* Dose per week^*   3-4 ml of the standardized (2:1) liquid extract 21-28 ml of the standardized (2:1) liquid extract   Extracts providing standardized levels of ginkgo flavone glycosides are recommended. Ideally, aqueous ethanol extracts should contain 9.6 mg/ml of ginkgo flavone glycosides.   No restriction was found on the long-term use of Ginkgo. However, Ginkgo should be recommended for at least 6 weeks before any assessment of clinical benefit is made.

* This dose range is based on those used in clinical trials.

SUPPORTING INFORMATION

Traditional Prescribing

No information has been found for the traditional use of Ginkgo leaf. Ginkgo nuts were used in TCM.

Pharmacologic Research

Pharmacologic and clinical studies usually tested a special concentrated standardized extract of Ginkgo leaves, which is chemically complex, containing at least 26 identified components. The 50:1 concentrated extract is standardized to contain 22.5% to 25.0% flavonoid glycosides (ginkgo flavone glycosides) and 6% to 8% terpenoids (ginkgolides and bilobalide). • The ginkgolides are potent and specific PAF antagonists; the effects are long-lived and are rapidly established after oral doses. • Many experimental models have demonstrated the preventative and protective effects of standardized Ginkgo extract (high doses) and ginkgolides against hypoxia- or ischemia-induced damage of cerebral and cardiovascular tissues, both in vitro and in vivo after oral administration. • Standardized Ginkgo extracts have demonstrated potent antioxidant activity in many in vitro models. • Prior oral dosing with standardized Ginkgo extract enhanced the performance of a tested task, indicating improved retrieval of the learned response, in a well-controlled animal study. Oral administration of standardized Ginkgo extract to young and old rats facilitated behavioral adaptation despite adverse environmental influences. • Oral administration of standardized Ginkgo extract in conjunction with a high-fat diet reduced disturbances of lipid metabolism and the severity of plaque formation in an experimental model when compared with placebo and rutin. Ginkgo also affected metabolic processes in the liver and may modify lipid deposition in major arteries. • Chronic administration of standardized Ginkgo extract inhibited stress-induced corticosterone hyposecretion through a reduction in the number of adrenal peripheral benzodiazepine receptors. Ginkgo extract and ginkgolide B were also found to act at the hypothalamic level and were able to reduce corticotropin-releasing hormone expression and secretion. • Intragastric administration of a combined preparation of standardized extracts of Ginkgo and ginger demonstrated anxiolytic effects comparable to diazepam injection in vivo. • Ginkgo extract fractions relaxed penile corpus cavernosal tissues in vitro, an effect that may help maintain erection. • Topical application of standardized Ginkgo extract had antiinflammatory activity comparable to indomethacin in the croton oil test and promoted hair regrowth in shaved mice.

Clinical Studies

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Hepatoprotective, hepatic trophorestorative, choleretic, cholagogue, bitter tonic, hypocholesterolemic, antiemetic, diuretic, depurative

Potential Indications

Based on appropriate evaluation of the patient, practitioners should consider prescribing globe artichoke in formulations in the context of: • Hyperlipidemia (2,6) • Conditions requiring an increase in bile flow (2) • Dyspepsia and associated symptoms (e. g., constipation, abdominal pain, nausea, vomiting, flatulence, belching, fat intolerance) (4) • Non-ulcer dyspepsia, in combination with boldo and greater celandine (2) • Irritable bowel syndrome (4) • Biliary fistula (4) • Jaundice, gout (5) • Conditions requiring a depurative action (such as itchy skin) (5) • Long-term prevention and treatment of cardiovascular disease (7)

Contraindications Closure of the gallbladder Warnings and Precautions Globe artichoke should be used only with professional supervision in cholelithiasis (gallstones). The Commission E advises caution for patients with known allergy to globe artichoke and to other plants of the Compositae family. The likelihood of globe artichoke preparations causing an allergy is very low. Interactions None known. Use in Pregnancy and Lactation No adverse effects expected. Side Effects Clinical trials indicate that the safety and tolerability of globe artichoke is good. Contact with the fresh plant can cause contact dermatitis. No cases of allergic reaction after oral intake have been reported. Dosage Dose per day^* Dose per week^*   3-8 ml of 1:2 liquid extract 20-55 ml of 1:2 liquid extract

* This dose range is extrapolated from clinical trials.

SUPPORTING INFORMATION

Traditional Prescribing

Traditional Western herbal medicine uses include: • Jaundice,1,2 hypercholesterolemia, anorexia; as a liver tonic and antitoxic2 • Clearing the complexion,2 as a depurative for simple itch in children3 • Rheumatism, arthritis,2 gout, dropsies1 • Nephrosclerosis, urinary stones, oliguria, uremia3

Pharmacologic Research

Key constituents of globe artichoke leaves include caffeic acid derivatives, especially cynarin. • Studies from the 1930s indicate that globe artichoke increased bile flow from the liver, lowered cholesterol, and caused diuresis. More recently, globe artichoke extract demonstrated a marked choleretic effect in experimental models after intraperitoneal administration. Cynarin also increased bile secretion in vitro and in vivo after intraperitoneal administration. • Studies have demonstrated the hepatoprotective and hepatorestorative activity of globe artichoke extracts against liver toxins in vitro and in vivo by the oral route. • Globe artichoke extract exhibited strong antioxidant activity in vitro. • Globe artichoke extract and cynarin inhibited cholesterol synthesis in vitro and countered an increase in serum lipids in vivo after intraperitoneal and oral administration. • An antiatherosclerotic effect was demonstrated for globe artichoke extract in vivo after oral administration. • Oral administration of globe artichoke extract stimulated the movement of gastrointestinal contents along the small intestine in an acute experimental model.

Clinical Studies

PRESCRIBING INFORMATION

Actions	Hypoglycemic, antidiabetic, galactagogue
Potential Indications	Based on appropriate evaluation of the patient, practitioners should consider prescribing goat’s rue in formulations in the context of: • Non-insulin–dependent diabetes mellitus (4,5) • Improving lactation (4,5) • Possibly assisting weight loss (7)

Contraindications None known. Warnings and Precautions None required. Interactions None known. Use in Pregnancy and Lactation No adverse effects expected. Side Effects None expected if taken within the recommended dose range. Consumption of goat’s rue by sheep has caused poisoning.^1,2 (Toxic doses far exceeded those used therapeutically in humans.) Dosage Dose per day^* Dose per week^*   4.5-8.5 ml of 1:2 liquid extract 30-60 ml of 1:2 liquid extract

* This dose range is extrapolated from the British Herbal Pharmacopoeia 1983 and the author’s education and experience.

SUPPORTING INFORMATION

Traditional Prescribing	Traditional Western herbal medicine uses include: • Diabetes mellitus3 • As a galactagogue, vermifuge, nervous system stimulant, and diuretic4 • As a tonic in infectious diseases such as typhoid4
Pharmacologic Research	Key constituents of the aerial parts of goat’s rue include the alkaloid galegine, which is a guanidine derivative.5 In 1927, findings indicated that galegine possessed hypoglycemic properties, which led to the development of the related biguanide drugs. Biguanide drugs, such as metformin, increase the peripheral uptake of glucose by increasing the efficiency of available insulin; that is, they increase insulin sensitivity.6 • Dietary goat’s rue reduced serum glucose and body weight in both normal and genetically obese mice when compared with controls. Serum insulin was significantly reduced only in obese animals. Weight loss was associated with a persistent reduction in food intake by obese animals and an initial reduction in normal animals. However, weight loss in normal animals was then maintained, even with increased food intake above the control level.7 • Aqueous and ethanolic extracts of goat’s rue improved glucose tolerance in vivo after oral administration. Hypoglycemic activity was demonstrated for the fractions containing galegine.8 • Oral doses of goat’s rue extract and galegine both reduced blood glucose in an experimental model of diabetes.9 Another study found no hypoglycemic effect for oral goat’s rue extracts in normal or diabetic animals.10 • Goat’s rue had a regenerative effect on the insulin-producing cells (β cells) of the pancreas in vivo (route unknown).11 • A purified galegine-containing extract of goat’s rue dose-dependently inhibited the transport and uptake of glucose into human intestinal epithelial cells in vitro.12 • Aqueous extracts of goat’s rue inhibited platelet aggregation in vitro13–16 and in vivo by intravenous route.17
Clinical Studies	• Early clinical research demonstrated hypoglycemic activity for goat’s rue.18,19 Unlike the biguanide drugs, the herb did not have unpleasant side effects.19 • In an early controlled trial, nursing mothers receiving a preparation containing goat’s rue extract and mineral salts (dose undefined) produced a larger increase in colostrum volume (125%) between the third and fifth days after delivery than did women not receiving the preparation (75% increase). Volume of milk, but not percentage of milk solids, had increased by the fifth day in the treated group.20

PRESCRIBING INFORMATION

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Antiinflammatory, diaphoretic, diuretic, anticatarrhal

Potential Indications

Based on appropriate evaluation of the patient, practitioners should consider prescribing golden rod in formulations in the context of: • Upper respiratory tract catarrh or inflammation, especially of a chronic nature; influenza (5) • Rheumatoid arthritis and osteoarthritis, in combination with Fraxinus excelsior and Populus tremula (1) • Promoting diuresis (3) • Inflammation and infection of the urinary tract (4,5) • Prophylaxis and treatment of kidney or bladder stones (4,5)

Contraindications Warnings and Precautions Allergic reactions may occur in susceptible patients sensitized to plants from the Compositae family. Interactions None known. Use in Pregnancy and Lactation No adverse effects expected. Side Effects None expected if taken within the recommended dose range. Dosage Dose per day^* Dose per week^*   3-6 ml of 1:2 liquid extract 20-40 ml of 1:2 liquid extract

* This dose range is extrapolated from the British Herbal Pharmacopoeia 1983 and the author’s education and experience.

SUPPORTING INFORMATION

Traditional Prescribing	Traditional Western herbal medicine uses include: • Chronic upper respiratory tract catarrh or inflammation, influenza; flatulent dyspepsia;4 cystitis, urinary disorders4,5 • As a spray or gargle for nose and throat infection4 • Topically as a powder for hemorrhage5 Native Americans used the flowers or leaves of several species of golden rod as a tea for fevers and pain in the chest.6
Pharmacologic Research	• A proprietary herbal formula containing golden rod, Fraxinus excelsior and Populus tremula (1:1:3), demonstrated antiinflammatory, antipyretic, and analgesic activities in experimental models, including carrageenan-induced edema and adjuvant-induced arthritis (route unknown).7–9 In the case of the antiinflammatory models, each of the individual herbs also demonstrated activity.9 The antiinflammatory activity is the result, at least in part, of the antioxidant properties of the individual herbal extracts that have been established in several in vitro models.10 Similar to many NSAIDs, the combined extract and individual extracts inhibited dihydrofolate reductase in vitro.8 • Constituents of golden rod (3,5-O-caffeoylquinic acid and flavonoids) have inhibited leukocyte elastase (an enzyme involved in the progression of inflammation) in vitro. The ester saponins from golden rod induced the release of stored adrenocorticotropic hormone (ACTH) from pituitary corticotropic cells. The authors postulated that the release of ACTH might influence the release of glucocorticoids from the adrenal gland in vivo.11 • The flavonoid fraction of golden rod flowers demonstrated diuretic activity after oral administration in an experimental model.12 A low oral dose of an aqueous extract of golden rod containing 0.3% flavonoids produced diuresis and an increase in electrolyte excretion in an experimental model.13,14 • Golden rod extract demonstrated spasmolytic activity in acetylcholinepretreated isolated ileum.15 • An in vitro antifungal effect towards pathogenic species of Candida was demonstrated for triterpenoid saponins from golden rod.16,17 The whole plant did not possess broad-spectrum activity toward Candida spp. and dermatophytes in vitro.18 Essential oil of golden rod demonstrated antimicrobial activity against several bacteria, including Streptococcus faecalis and Escherichia coli, and exerted a strong fungicidal effect on dermatophyte strains in vitro.19 • Saponins from golden rod have displayed immunomodulatory and antitumoral effects in vitro.20
Clinical Studies	• A diuretic effect was observed in healthy volunteers after a single dose of golden rod tincture (100 drops, or approximately 4 ml) under double-blind, placebo-controlled conditions. In an uncontrolled trial, 70% of patients with urinary tract inflammation or symptomatic bacteriuria experienced complete disappearance of symptoms such as dysuria, frequency, and tenesmus when treated with the same preparation and dosage (duration of treatment not known). The fresh plant tincture (0.57 g/g) was made according to German Homoeopathic Pharmacopoeia (HAB).21 • Two reviews assessing a formulation containing golden rod, Fraxinus excelsior and Populus tremula, for treating rheumatic conditions, including arthritis, have been published. One review assessed that the randomized, double-blind, controlled trials were of medium methodological quality.22 The formulation demonstrated superior activity compared with placebo and was comparable to NSAID drugs but had a much lower incidence of adverse effects.7,23 The formulation consists of 60% Fraxinus excelsior, 20% golden rod, and 20% Populus tremula and is standardized for salicylates, flavonoids, and coumarins. • In a randomized, drug prospective study, treatment of ureteric calculi with either spasmoanalgesic drug therapy or an herbal preparation was compared. The preparation contained golden rod, dandelion root and leaf, Rubia tinctorum, Ammi visnaga, and a small amount of escin (a constituent of horsechestnut seed). Although no significant difference was observed with regard to transit times of the stones between the two groups, side effects and treatment costs were less in the herbal therapy group. The strength of the herbal extracts in these capsules was not defined.23 • In Germany, the Commission E supports using golden rod in conjunction with copious fluid intake to treat inflammatory diseases of the lower urinary tract, urinary calculi, and kidney gravel. Golden rod is also recommended as a prophylaxis for urinary calculi and kidney gravel.3 • ESCOP recommends golden rod for inflammatory conditions of the urinary tract, kidney gravel, and as an adjuvant therapy for bacterial infections of the urinary tract.24

PRESCRIBING INFORMATION

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Antihemorrhagic, anticatarrhal, mucous membrane trophorestorative, antimicrobial, antibacterial, bitter tonic, antiinflammatory, depurative, vulnerary, choleretic, reputed oxytocic

Potential Indications

Based on appropriate evaluation of the patient, practitioners should consider prescribing golden seal in formulations in the context of: • Catarrhal states of the mucous membranes when unaccompanied by acute inflammation (5) • Acute infectious diarrhea (4a, 5) • Giardiasis, hypertyraminemia (4a) • Gastritis, peptic ulcer (4a, 5) • Adjuvant therapy for non-insulin–dependent diabetes mellitus (4a) • Hepatic symptoms, skin disorders (5) • Disorders of the ear, nose, mouth, throat (5) • Uterine and pelvic hemorrhagic conditions, genitourinary tract discharges (5) • A tonic during convalescence (5)

Contraindications Berberine-containing plants are not recommended for use during pregnancy or for jaundiced neonates. Some reports suggest that golden seal is contraindicated in hypertensive conditions. Warnings and Precautions None required. Interactions Berberine may reinforce the effects of other drugs that displace the protein binding of bilirubin. Rather than possible uterine-contracting effects, this activity might explain the traditional contraindication for berberine-containing herbs in pregnancy. Use in Pregnancy and Lactation Contraindicated in pregnancy. Side Effects At daily doses higher than 0.5 g, berberine may cause dizziness, nose bleeds, dyspnea, skin and eye irritation, gastrointestinal irritation, nausea, diarrhea, nephritis, and urinary tract disorders. Such doses of berberine will not be reached using the recommended liquid doses outlined in this monograph. Dosage Dose per day^* Dose per week^*   2.0-4.5 ml of 1:3 tincture 15-30 ml of 1:3 tincture   Extracts providing quantified levels of hydrastine and berberine are recommended. Ideally, aqueous ethanol extracts should contain not less than 8 mg/ml of hydrastine and not less than 8 mg/ml of berberine.

* This dose range is extrapolated from the British Pharmaceutical Codex 1934, the British Herbal Pharmacopoeia 1983, the British Herbal Compendium 1992, and the author’s education and experience.

SUPPORTING INFORMATION

Traditional Prescribing

Traditional Western herbal medicine uses include: • Golden seal was specifically indicated by Eclectic physicians for subacute or chronic inflammation of the mucous membranes, particularly when accompanied by discharge or catarrh. In general, golden seal was contraindicated in acute inflammation of the mucous membranes. However, in the case of otitis media, golden seal was indicated for both acute and chronic inflammation, especially when copious discharge was present.1 • Digestive disorders, gastritis, peptic ulceration, colitis, anorexia, atonic dyspepsia with hepatic symptoms2 • Upper respiratory catarrh; skin diseases, especially when dependent on gastric difficulties; as a tonic during convalescence1,2 • Menorrhagia, postpartum hemorrhage, submucosal myoma (fibroids), hemorrhagic endometriosis, dysmenorrhea1,2 • Topically for affections of the nose and throat, eczema, pruritus, otorrhea, catarrhal deafness and tinnitus, conjunctivitis1,2 Native Americans used golden seal for dropsy, skin diseases, indolent ulcers, gonorrhea, liver and stomach disorders, and as a tonic. Externally, the infusion was used as a remedy for sore eyes, and the root was chewed for sore mouth. Golden seal was official in the USP from 1831 to 1842 and 1863 to 1936 and in the NF from 1936 to 1960. Golden seal was used as a bitter tonic and an astringent to treat inflammation of the mucous membranes.3

Pharmacologic Research

Key constituents of golden seal include alkaloids of the isoquinoline group, particularly berberine and hydrastine. • In vitro and in vivo studies have demonstrated that berberine has antimicrobial activity against a wide variety of microorganisms, including bacteria, fungi, and parasites. Hydrastine has been found to produce 70% mortality in the tapeworm Echinococcus granulosus, both in vitro and in vivo. • Berberine combined with Geranium leaf extract (oral doses) significantly inhibited diarrhea. Oral berberine, given with Escherichia coli enterotoxin, significantly reduced intestinal fluid accumulation in vivo. • Intravenous berberine blocked arrhythmias and decreased the amplitude of delayed after-depolarizations in isolated ventricular muscles in vivo and in vitro. • Berberine increased thrombocytes, decreased factor XIII activity, inhibited platelet aggregation and adhesiveness, and inhibited clot retraction in experimental models (route unknown). • Berberine has demonstrated cytotoxic activity in several in vitro models. • Oral administration of berberine hydrochloride significantly increased bilirubin excretion in experimental hyperbilirubinemia without affecting the functional capacity of the liver. • Lipogenesis was suppressed in isolated sebaceous glands by berberine. • Berberine significantly decreased scopolamine-induced amnesia in an experimental model. • Treatment with berberine in an experimental model of diabetes led to healthier pancreatic tissue compared with controls. • Berberine had an immunosuppressive effect in an experimental model of renal autoimmune disease (route unknown).4 • Golden seal extract and its alkaloids demonstrated an antispasmodic action on isolated intestinal and uterine tissues. • Although golden seal extract produced a vasoconstrictive effect, it also inhibited epinephrine-(adrenaline), serotonin-, and histamine-induced contraction of isolated aorta. However, although isolated berberine or hydrastine did not show this vasoconstrictive effect, berberine demonstrated some inhibitory activity on aortic contraction induced by epinephrine. Hydrastine was inactive. The observed vasoconstrictive effect of golden seal extract may result from the presence of hydrastinine, a decomposition product of hydrastine. For more information on the pharmacology of berberine, the reader should review the barberry (Berberis vulgaris) and Indian barberry (Berberis aristata) monographs.

Clinical Studies

PRESCRIBING INFORMATION

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Vulnerary, antiinflammatory, depurative, adaptogenic, nervine tonic

Potential Indications

Based on appropriate evaluation of the patient, practitioners should consider prescribing gotu kola in formulations in the context of: • Improving the healing response of the skin and subcutaneous tissue (4a, 5) • Diabetic microangiopathy (4a) • Cellulitis;gastric or duodenal ulcer (4a) • Leg ulcers (4a, 5) • Leprosy (4,5) • Scleroderma (4a) • Venous insufficiency of the lower limbs (4a) • Varicose and postthrombotic syndromes (4a) • Keloids and hypertrophic scars (4a) • Hemorrhoids, in combination with bulking laxatives, if required (4a) • Mouth ulcers (6) • Chronic skin and rheumatic conditions (5) • Improving mental function (2,5) • Anxiety (4) • Improving adaptation to stressors (7) • Producing a rejuvenating tonic effect (4,5) • Chronic hepatic disorders (4a, 6) • Topical treatment for postthrombotic syndrome and varicose veins (4a) • Topical treatment for psoriasis, wounds (4,5) • Topical treatment for burns, leg ulcers, cellulitis (4) • Topical treatment for leprous ulcers, scar formation after surgery, eczema (5) • Topical treatment for stretch marks, in combination with α-tocopherol and collagen-elastin hydrolysates (4a)

Contraindications Known allergy. Warnings and Precautions None required. Interactions None known. Use in Pregnancy and Lactation No adverse effects expected. Side Effects Allergic contact dermatitis has been reported from using gotu kola, but it is a low risk treatment. Both the extract and the triterpene constituents are weak sensitizers.¹ Dosage Dose per day^* Dose per week^*   3-6 ml of 1:2 liquid extract 20-40 ml of 1:2 liquid extract   Many of the successful clinical trials used a triterpene fraction of gotu kola at higher doses (approximately equivalent to 2.5 to 7.0 g of leaf per day) than the previously outlined liquid doses. Hence these liquid doses may possibly need to be exceeded to achieve similar results. However, on the other hand, an advantage might exist from using the whole extract rather than an isolated fraction.

* This dose range is extrapolated from the British Herbal Pharmacopoeia 1983. Higher relative doses of the triterpene fraction have been used in most clinical trials.

SUPPORTING INFORMATION

Traditional Prescribing	Traditional Western herbal medicine uses include: • Skin and rheumatic conditions, including chronic eczema, chronic rheumatism, leprosy, ulcers2,3 • Topically for poorly healing wounds, leprous ulcers, scar formation after surgery2 Traditional Ayurvedic uses include: • As a depurative and tonic4 • As a rasayana (rejuvenating) remedy, hence it is used to improve memory and prolong life span5 • Topically for eczema, leprosy, secondary syphilitic ulcers, psoriasis4,5
	Gotu kola has been traditionally used in many countries. In Thailand, the whole plant has been used as a depurative, particularly to treat skin diseases and as a diuretic and antidiarrheal remedy.6 In Indonesia, gotu kola has been used for mouth ulcers and oral thrush.7 In Fijian traditional herbal medicine, gotu kola was employed as a tonic for wasting diseases, such as tuberculosis, stomach problems, and rheumatic swelling and pain. Gotu kola was used both internally and topically to relieve pain.8 In TCM, gotu kola is used for traumatic injuries, boils, urinary stones, and to counteract toxicity and reduce swelling.9 In Hong Kong, gotu kola is also used for hepatitis, measles, the common cold, tonsillitis, bronchitis, and to treat poisoning. External uses include treatment of snakebite and bleeding wounds.10 In South Africa, gotu kola has been employed to treat wounds, cancer, leprosy, fever, and syphilis.11
Pharmacologic Research	The aerial parts of gotu kola contain pentacyclic triterpene ester saponins,12 the most abundant of which is asiaticoside. The triterpenoid content of good quality gotu kola dried herb is commonly 2% to 3% when analyzed by high-performance liquid chromatography (HPLC).13 • Gotu kola and asiaticoside demonstrated activity against herpes simplex virus-1 (HSV-1) and HSV-2 in vitro.14 • The triterpene fraction of gotu kola has demonstrated wound-healing activity in many experimental models (by injection, oral, and topical administration). The mechanism of action includes the stimulation of maturation of scar tissue by the increased production of type I collagen (and hence collagen synthesis) and a decrease in the inflammatory reaction and myofibroblast production.15 The constituents also stimulated glycosaminoglycan synthesis16 and acted specifically to shorten the immediate phase of healing.17 Aqueous extract of gotu kola, particularly as a gel formulation, promoted healing in experimental open wounds.18 Oral and topical administration of gotu kola extract produced faster epithelialization and a higher rate of wound contraction in vivo compared with controls.19 • Asiaticoside demonstrated activity in models of both normal and delayed wound healing after both topical and oral administration. Angiogenesis was promoted in isolated tissue.20 Topical asiaticoside enhanced the induction of antioxidants at the initial stage of healing.21 • Oral administration of gotu kola extract inhibited gastric ulceration in cold- and restraint-induced stress models. Brain GABA levels were increased.22 Complete mucosal cytoprotection was observed in an experimental model (by oral route).23 • The antiulcer activity may be related to a protective effect on stress. Gotu kola extract also prevented the experimental rise in plasma corticosterone levels following immobilization stress.24 In other studies, oral gotu kola extract demonstrated normalizing effects against a variety of stressors.25 • The triterpene fraction of gotu kola reduced experimentally induced acute radiation dermatitis via its antiinflammatory activity (after topical application).26 • Oral administration of gotu kola and the partially purified triterpenoid fraction retarded the development of solid and ascites tumors and increased life span in an experimental model.27 • An antianxiety effect was demonstrated in several experimental models for an aqueous extract of gotu kola (by injection28 and orally29). Sedative and antidepressant activity has also been demonstrated.30 Oral administration of an aqueous extract of gotu kola caused a decrease in the turnover of central monoamines and improved learning and memory in experimental models.31
Clinical Studies	Most of the clinical trials listed here used the triterpene fraction of gotu kola (TFGK), with doses ranging from 60 to 180 mg per day (approximately 2.5 to 7.0 g of dried herb equivalent). The majority of these preparations contained 40% asiaticosides, 30% madecassic acid, and 30% asiatic acid. • Oral administration of TFGK for 60 days demonstrated efficacy in a double-blind, placebo-controlled trial in patients with venous hypertensive microangiopathy.32 In an uncontrolled trial33 and in a randomized, single-blind, placebo-controlled trial,34 TFGK improved symptoms, microcirculation, and capillary permeability in patients with venous hypertension. In another trial, symptoms and ankle edema were improved in patients with venous hypertension after TFGK treatment, with no significant change observed in the placebo group.35 TFGK treatment (120 mg/day) for 6 months was beneficial for diabetic microangiopathy by improving microcirculation and decreasing capillary permeability. This trial was of prospective, randomized, placebo-controlled design.36 • TFGK treatment produced significant improvement in symptoms of heaviness in the lower limbs and edema in a randomized, doubleblind, multicenter, placebo-controlled trial involving patients with venous insufficiency of the lower limbs. Two oral doses were trialled (60 mg/day or 120 mg/day) for 8 weeks.37 Benefit was also demonstrated for TFGK treatment of patients with chronic venous insufficiency in an open study.38 In a randomized, double-blind, comparative trial, TFGK demonstrated superior efficacy over hydroxyethylrutoside in treating venous insufficiency.39 In an open trial, TFGK treatment provided an increase in venous return and improvement of symptoms in patients with varicose and postthrombotic syndromes.40 In a controlled, crossover study involving patients with postphlebitic syndrome and venous insufficiency, oral treatment with TFGK provided better results in microcirculatory measurements than treatment with the flavonoids diosmin or hydroxyethylrutoside.41 • Oral treatment with TFGK produced a decrease in the elevated mucopolysaccharide turnover observed in patients with varicose veins.42 • Treatment with TFGK caused a significant reduction of circulating endothelial cells in patients with postphlebitic syndrome compared with baseline values.43 Oral administration of TFGK and bulking laxatives (when required) produced a beneficial effect in patients with first- and second-degree hemorrhoids in an uncontrolled trial.44 • Positive results have been recorded in uncontrolled trials for treating gastric and duodenal ulcers (TFGK, oral),45,46 gastritis (asiaticoside, oral),47 and bladder lesions caused by bilharzial infection (TFGK, injection).48 No benefit was observed for the healing of leg ulcers in patients treated with asiaticoside (by injection) compared with placebo.49 However, positive results were obtained for oral use of TFGK taken for 3 to 8 weeks in 50 patients with leg ulcers.50 • Oral treatment with TFGK for an average of 55 days was successful in treating patients with cellulitis.51 After 3 months’ oral TFGK treatment, reduced tendency to sclerosis in cellulitic tissue was observed in a double-blind, placebo-controlled study.52 • Oral administration of TFGK has been successfully used to treat keloids and hypertrophic scars. In a study involving 227 patients, treatment with TFGK for a period of 2 to 18 months had therapeutic value in both preventing (together with surgical revision) and reducing keloids. A subset of the patients involved in the curative study confirmed the activity of TFGK in a double-blind, placebo-controlled trial.53 • In a preliminary trial, TFGK taken for 3 to 24 months improved histology in 5 of 12 patients with chronic hepatic disorders, including alcoholic cirrhosis and cirrhosis of undetermined origin.54 • Gotu kola dried herb (0.5 g/day for 3 months) increased the intelligence quotient, general mental ability, and behavior in mentally disabled children in a randomized, placebo-controlled, clinical trial in India.55 • In an uncontrolled trial, gotu kola relieved the symptoms of patients with anxiety and improved mental functioning.56 • In a double-blind trial, gotu kola tended to increase the mean level of red blood cells, blood sugar, serum cholesterol, vital capacity, and total protein in normal volunteers. An increase in hemoglobin was statistically significant. This finding was thought to be indicative of a corticosteroid-like activity.57,58 • Gotu kola has been used to treat leprosy patients from very early times and in recent years in both uncontrolled trials59–61 and a controlled trial (gotu kola powder or asiaticoside compared with diamino-diphenylsulfone over a period of 1 year).62 • Asiaticoside was not successful in treating scleroderma in children.63 However, TFGK demonstrated symptomatic relief in a small group of patients with systemic scleroderma. The 13 patients received TFGK by intramuscular injection ranging from 11/2 months to 11/2 years. Two patients received TFGK orally for a portion of their treatment.64 In another small, uncontrolled trial, oral doses of TFGK improved arthralgia and finger joint movement in scleroderma patients.65 • A systematic review published in 2000 concluded that, compared with placebo, treatment with a cream containing gotu kola extract, α-tocopherol, and collagen-elastin hydrolysates is associated with fewer women developing stretch marks. This result occurred only for women who had previously encountered stretch marks during pregnancy.66 • Topical application of gotu kola or TFGK has been successfully used to treat: • Postthrombotic syndrome and varicose veins (double-blind, placebo-controlled trial; TFGK)67 • Chronic venous insufficiency (single-blind, controlled trial of TFGK against oral administration of the drug tribenoside)68 • Psoriasis (uncontrolled trial; water and oil extract of gotu kola)69 • Leg ulcers (uncontrolled trial;70 placebo-controlled trial, TFGK by injection or topical71) • Soiled wounds resistant to other treatments (standardized gotu kola extract combined with essential oils; uncontrolled trial)72 • Burns (topical, injection, or both; uncontrolled trials with TFGK or gotu kola extract)73,74 • Cellulitis (uncontrolled trial; standardized gotu kola extract)75

PRESCRIBING INFORMATION

Actions

Choleretic, cholagogue, spasmolytic, mild laxative, antiinflammatory, antiviral (topically), vulnerary (topically)

Potential Indications

Based on appropriate evaluation of the patient, practitioners should consider prescribing greater celandine in formulations in the context of: • Biliary dyskinesia, in combination with turmeric (2) • Increasing bile flow and pancreatic secretion, in combination with milk thistle and turmeric (3) • Cholangitis, gallstones, cholecystitis without stones (3,5) • Cramping pain of the gastrointestinal tract and gall ducts (4,5) • Liver disease, jaundice, bilious dyspepsia, bilious headache, migraine, supraorbital neuralgia, skin conditions, especially psoriasis (5) • Chronic bronchitis, whooping cough (4) • An enema for colonic polyposis (4) • Topical treatment for warts (4,5)

Contraindications None known. Warnings and Precautions Given the nature of the alkaloid content of this herb and the reported cases of hepatotoxicity (see the “Side Effects” section in this monograph), long-term use of higher doses (except topical) is not recommended. Interactions None known. Use in Pregnancy and Lactation No adverse effects expected. Side Effects

PRESCRIBING INFORMATION

Actions	Expectorant, spasmolytic, bronchospasmolytic
Potential Indications	Based on appropriate evaluation of the patient, practitioners should consider prescribing Grindelia in formulations in the context of respiratory conditions marked by spasm, asthma, whooping cough, bronchitis, dry and irritable cough, and upper respiratory catarrh. (5)
Contraindications	None known.
Warnings and Precautions	None required.
Interactions	None known.
Use in Pregnancy and Lactation	No adverse effects expected.
Side Effects	None expected if taken within the recommended dose range. The British Herbal Pharmacopoeia 1983 notes that large doses are reported to cause renal irritation.1 This warning may be the result of the presence of saponins.
Dosage	Dose per day*	Dose per week*
	1.5-3.0 ml of 1:2 liquid extract	10-20 ml of 1:2 liquid extract

* This dose range is extrapolated from the British Herbal Pharmacopoeia 1983 and the author’s education and experience.

SUPPORTING INFORMATION

Traditional Prescribing	Traditional Western herbal medicine uses include: • Bronchitis, asthma, upper respiratory catarrh, whooping cough; harsh and dry cough, difficult breathing resulting from heart disease1,2 • Cystitis1,2 Native Americans used Grindelia species for a variety of therapeutic purposes, including coughs, the common cold, tuberculosis, skin infections, and colic in children. The dried leaf and flowering tops of Grindelia were official in the USP from 1882 to 1926 and the NF from 1926 to 1960. Several species have been official under this name and have been used as sedatives, antispasmodics, expectorants, and as remedies for poison ivy, a liquid extract being used in the last case.3
Pharmacologic Research	The aerial parts of Grindelia contain resin and saponins. An antimicrobial activity has been demonstrated in vitro, which is not the result of the saponins but is at least partially caused by the resin fraction.4
Clinical Studies	No clinical studies using Grindelia have been found.

PRESCRIBING INFORMATION

Actions	Antidiabetic, hypoglycemic, hypocholesterolemic, weight reducing
Potential Indications	Based on appropriate evaluation of the patient, practitioners should consider prescribing Gymnema in formulations in the context of: • Diabetes mellitus (both insulin-dependent and non-insulin– dependent) (3,5) • Reducing the sense of taste for sweet foods (3,5) • Reducing appetite and calorie intake (3,5)

Contraindications None known. Warnings and Precautions None required. Interactions None known. Use in Pregnancy and Lactation No adverse effects expected. Side Effects As with all saponin-containing herbs, oral use may cause irritation of the gastric mucous membranes and reflux. Dosage Dose per day^*∧ Dose per week^*   3.5-11.0 ml of 1:1 liquid extract 25-75 ml of 1:1 liquid extract   One to two ml per day is all that is necessary for reducing sweet-craving and the sweet taste. In the latter case, the extract should be applied directly to the tongue, rinsed off, and swallowed after 1 minute. This procedure can be done at 2- to 3-hour intervals.

* This dose range is extrapolated from traditional Ayurvedic medicine^1,3 and the author’s education and experience.

∧ Less may be needed if combined with other antidiabetic herbs. Some cases of diabetes will respond quickly, but best results come after 6 to 12 months of continuous use.

SUPPORTING INFORMATION

Traditional Prescribing	Traditional Ayurvedic uses include: • Glycosuria, diabetes (known as the “sugar destroyer”)1,2 • Urinary disorders, fever, cough3 Ayurvedic texts note that chewing Gymnema leaf removes the ability to taste sweet or bitter substances.2
Pharmacologic Research	Key constituents of Gymnema leaves include saponins, which are present as both nonacylated glycosides known as gymnemasaponins and the acylated gymnemic acids.4 Gymnemic acid referred to in the literature is often not defined and most likely refers to the crude saponin fraction or to a mixture of gymnemic acids. • The antisweet principles of Gymnema include the gymnemic acids,5 gymnemasaponins,6 and gurmarin (a peptide).7 Gymnemic acid suppressed the sweet taste of sweeteners in chimpanzees. Gymnemic acid had no effect on the responses to bitter, salty, or sour compounds.8,9 • Oral administration of Gymnema demonstrated hypoglycemic activity in experimental models of diabetes. Gymnema treatment: • Regulated blood sugar and increased the activity of the enzymes that facilitate the use of glucose by insulin-dependent pathways10 • Increased the uptake of glucose into glycogen and protein in liver, kidney, and muscle10 • Corrected hyperglycemia in mild diabetic models and significantly prolonged life span in models of severe diabetes (with completely destroyed pancreatic tissue)11 • Reduced postprandial serum glucose and improved glucose tolerance. (Pancreas weight and content of insulin were not changed.)12 • Returned fasting blood glucose levels to normal after 20 days. (A rise in insulin and pancreatic islet regeneration occurred to some extent.)13 • Produced hypoglycemic activity in a slow and steady manner, with 12 to 24 weeks of treatment required in mild diabetes14 • Lowered blood sugar levels in normal and diabetic models but was six times less potent than tolbutamide in diabetic animals15 • The mechanism of action may also include inhibition of glucose absorption in the intestine.16 • Feeding with Gymnema aqueous extract decreased body weight in fat and lean rats compared with those consuming only the test diet. In addition to lowering blood glucose levels, Gymnema also improved hypertriglyceridemia but not hypercholesterolemia.17 In another study, oral administration of Gymnema extract fractions decreased body weight gain and food intake and increased fecal excretion of cholesterol, total neutral steroids, total bile acids, and cholic acid–derived bile acid.18 Gymnema ingestion produced a significant lowering of cholesterol in a hypertension model.19
Clinical Studies	• Several clinical studies verify that pretreatment with Gymnema extract, Gymnema infusion, and gymnemic acid solution reduced the sweet taste of sweeteners.20–23 A period of at least 30 seconds was required after tasting the Gymnema infusion for the full sweet-suppression effect to appear.23 • Gymnema powder (10 g/day for 7 days) demonstrated a hypoglycemic effect in mild diabetic models in an uncontrolled trial. Serum triglycerides, free fatty acid and cholesterol levels, and creatinine excretion, were also decreased.24 • A controlled study involving patients with insulin-dependent diabetes found that Gymnema extract reduced insulin requirements, fasting blood glucose, glycosylated hemoglobin, and glycosylated plasma protein levels compared with patients receiving insulin therapy alone. Cholesterol, triglycerides, free fatty acids, and serum amylase were also lowered. Some suggestion of enhancing endogenous insulin production, possibly by pancreatic regeneration, was demonstrated. Gymnema extract (400 mg/day, equivalent to 10 to 13 g/day of dried leaf) was administered for 6 to 30 months.25 • A second study by the same research group found that the same Gymnema extract (400 mg/day for 18 to 20 months) produced similar results for patients with non-insulin–dependent diabetes with a reduction of similar biochemical parameters and hypoglycemic drug requirements. Fasting and postprandial serum insulin levels were elevated in the Gymnema group compared with controls taking only conventional drugs. Administering Gymnema to healthy volunteers did not produce any acute reduction in fasting blood glucose levels.26 • Clinical research under double-blind, placebo-controlled conditions found that a concentrated Gymnema extract (gymnemic acid content not defined) considerably diminished the sweet taste and significantly decreased appetite and the amount of calories consumed for up to 90 minutes after the sweet-numbing effect.27