Variations In Effective Botanical Products

The Case for Diversity of Forms for Herbal Preparations as Supported by Scientific Studies

By Francis Brinker. N.D.

The recent designation of numerous botanical products as dietary supplements places them on a continuum from food to drugs that are used to benefit health. Human studies document the advantages of using herbal products from their whole fresh form to dried powders, teas, juices, tinctures, standardized extracts, essential oils, and isolated components. To best use plants for their health benefits, it is important to recognize the advantages and limitations in each of the product forms.

Introduction

For a number of years a debate has raged over the proper categorization of plant products having therapeutic value. When Congress passed the Kefauver-Harris Amendment in 1962 to establish FDA approval of drug efficacy and safety, traditional herbal remedies were no longer extensively employed. Most nonprescription plant medicines, with the exception of laxatives such as senna (Senna alexandrina P. Mill., Fabaceae) and cascara sagrada (Rhamnus purshiana DC., Rhamnaceae), and decongestants such as peppermint (Mentha x piperita L., Lamiaceae) oil and eucalyptus (Eucalyptus globulus Labill., Myrtaceae) oil, were bypassed in the Over the Counter (OTC) Review Panels that examined medicinal products from 1972 to the present. As a result, plants that were not certified as prescription or OTC drugs were classified as foods in the broad sense of this term. Dorland’s Medical Dictionary, 25^th edition, 1974, defined food as “anything which, when taken into the body, serves to nourish or build up the tissues or to supply body heat.”

Until fairly recently, “herbs and spices” was the phrase in commerce that described “nonnutrient” plant products used primarily in the diet as culinary flavoring agents or beverage teas. However, many plants had been employed and continue to be used by a growing portion of the populace for their health benefits. With passage in 1994 by the U.S. Congress of the Dietary Supplement Health and Education Act (DSHEA) a new classification, “dietary supplement,” was created for herbal products along with vitamins, minerals, amino acids, and other dietary ingredients. Dietary supplements are now a special subset of foods. It allows for product labels and advertising to make “statements of nutritional support,” frequently called “structure and function” claims. These claims must relate to the effect on the structure or a function of the body by a dietary ingredient. DSHEA prohibits dietary supplement products from making a therapeutic (drug) claim, i.e., claims relating to the diagnosis, treatment, cure, or prevention of any disease.

Since it is established that many drugs are derived from botanical sources, the realistic distinction between foods, dietary supplements, and drugs is often one of their intended use. Considering these factors, it is worthwhile to examine different botanical products shown to have beneficial effects in human studies to appreciate what forms are known to provide important healthcare support. Moving from food across the continuum toward drug products, from fresh plants to dried, from extracts to concentrates, from standardized extracts to isolated components, from oral to topical applications, several examples are given for each form described.

Whole Fresh and Dried Herbs as Prophylactic Foods

Cayenne

The consumption of fresh or dried herbal condiments in their whole, natural form in food can be advantageous. The ingestion of whole plants in the diet for their flavor has sometimes provided unforeseen health benefits. Cayenne pepper (Capsicum annuum var. frutescens (L.) Kuntze, Solanaceae) has been shown to have preventive value when consumed regularly. In 88 Thailand natives studied who regularly employed capsicum in their diet, plasma fibrinogen was lower while antithrombin III and fibrinolytic activity (anti-clotting factors) were significantly higher than for 55 white Americans residing in Thailand who consumed mostly American-style foods. The reduced coagulability of the blood of native Thais has led to a rarity of blood clots and strokes among this population.¹ A controlled study had 16 healthy medical students on one occasion consume two teaspoonfuls of ground fresh cayenne in noodles. The findings demonstrated that fibrinolysis was enhanced immediately afterward, though no change in fibrinogen levels was detected with this single exposure.² This acute test suggests the benefits of the Thai diet are at least partially attributable to its content of pungent cayenne pepper.

Garlic and Onions

Epidemiological evidence from 20 separate studies conducted worldwide (17 in the last decade) with over 150,000 subjects gives support to the consumption of garlic (Allium sativum L., Liliaceae) and onions (A. cepa L.) in the diet to help reduce the risk of cancers of the gastrointestinal tract. This influence seems to be due to allicin, diallyl sulfide, and other sulfur compounds that modulate gluthione S-transferase activity, act as nitrate scavengers, or have antibacterial activity.³

Whole Fresh or Powdered Dried Herbs as Remedies

Garlic

The ingestion of garlic (A. sativum) goes beyond its flavoring and food use to consumption intended to be therapeutic. A meta-analysis of 16 therapeutic trials involving nearly 1,000 patients showed beneficial effects from consuming daily 10 g fresh garlic (only dose tested), 18 mg garlic oil, or 600-900 mg dried garlic powder (equivalent to 1.8-2.7g fresh garlic or about one to one-and-a-half fresh cloves) daily. The loss of volatile compounds by drying with heat and by increasing surface area through powdering can reduce the potency and longevity of a product. Due to the potential loss of active volatile components over time in ordinary dried garlic, the powdered product (Kwai ®; Lichtwer Pharma, Berlin) in nine of the 16 studies contained a standardized allicin yield. When consumed daily both forms significantly lowered total serum cholesterol over a one- to three-month period, though the non-powdered garlic produced greater reductions (15 percent) than the dried powdered form (8 percent). Serum triglycerides were lowered an average of 13 percent in the eight studies where garlic (in powder form) was given daily. Aside from odor, side effects were rare.⁴

Ginger

Another familiar spice plant studied in connection with several health problems when used in its fresh or dried powdered form is ginger (Zingiber officinale Roscoe, Zingiberaceae) root (rhizome). Powdered dry ginger root demonstrated anti-inflammatory effects in 56 patients suffering from rheumatoid arthritis, osteoarthritis, or myositis (muscle inflammation) when taken in daily doses of one to two g on average. Pain was moderately to markedly relieved in over 75 percent of all three categories of patients.⁵ Five g of fresh ginger daily produced an equivalent effect in several cases of arthritis.⁶ Seven women consuming five g of raw ginger daily showed a dramatic reduction in pro-inflammatory thromboxane B2 after seven days.⁷

The difference between the fresh and the dry powdered form of the root is in the relative water content and certain essential oil component yields.⁸ The fresh and dried ginger both contain active 6-gingerol and gingerdione along with other resinous pungent principles, extracted with n-hexane and methanol, that are responsible for the inhibition of inflammatory metabolite production by lipoxygenase and cyclooxygenase.^9,10 However, unlike nonsteroidal anti-inflammatory agents that can cause gastric mucosal irritation and ulceration,⁶ no adverse effects from ginger root occurred after three months to 2.5 years of use.⁵ The pungent 6-gingerol, 6-shogaol, and 6-gingesulfonic acid, and the aromatic zingiberene from an acetone extract of ginger, actually inhibited HCl/ethanol-induced gastric lesions in rats when administered orally^11,12 as effectively as the drug cetraxate.¹²

Dried powdered ginger root has also been studied for its ability to relieve nausea and vomiting from various causes. In randomized placebo-controlled, double-blind (PCDB) studies using a one-gram dose of the dried root, ginger was shown to be effective in reducing seasickness of 80 naval cadets;¹³ helped prevent nausea and emesis following anesthesia in major gynecological surgery with 60 women,¹⁴ and in day case surgery with 120 women as effectively as the drug metoclopramide;¹⁵ and relieved nausea and vomiting of early pregnancy with 30 women.¹⁶

Fresh Freeze-Dried versus Air-Dried Herbs

Nettles

The application of lyophilization (freeze-drying) technology to the preservation of active components found in living plants has enhanced the benefits derived from some familiar herbs. The fresh, freeze-dried leaves (Eclectic Institute, Inc., Sandy, Oregon) of the stinging nettle (Urtica dioica L., Urticaceae) were shown for the first time to provide effective symptomatic relief in allergic rhinitis based on global assessments in a randomized PCDB study with 69 patients.¹⁷ Active constituents identified in the stinging hairs of U. dioica include histamine, acetylcholine, and serotonin.¹⁸ Histamine in particular has been shown to function as an autacoid (organic substance carried in the circulation from certain cells to others on which it acts) in modulating the immune response in allergic patients and, potentially in so doing, ameliorating their condition.¹⁹ The activity due to histamine and the acetylcholine concentrated in nettle stinging hairs is lost after the leaves have been air-dried,²⁰ but freezing fresh nettle leaves is an effective means of preserving these components and serotonin.²¹ Rapid enzymatic breakdown of serotonin occurs in stinging nettle extract.¹⁸

Feverfew

Feverfew (Tanacetum parthenium (L.) Schultz-Bip., Asteraceae) is another plant that demonstrated therapeutic benefits following freeze-drying of the fresh leaves. To investigate its efficacy in 17 patients who had eaten fresh feverfew leaves daily for years to prevent migraine headaches, the freeze-dried form was used in a PCDB study lasting six months. Those given the placebo had a significant recurrence of migraine symptoms while the group receiving 50 mg daily of fresh freeze-dried feverfew showed no change compared to their use of fresh leaves.²² In a follow-up randomized PCDB crossover study, 60 volunteers each used one capsule of oven-dried feverfew leaves or placebo daily for four months. The feverfew capsules averaged 82 mg with 543 mg of the sesquiterpene lactone parthenolide per capsule. Use of this kind of feverfew reduced the number of migraines by 24 percent, alleviating their severity and causing no serious side effects.²³

A comparative study of fresh versus commercial dried feverfew leaves used chloroform extracts of each. The extract of fresh leaves contained sesquiterpene lactones, including parthenolide that inhibited arterial contractions in the same manner as pure parthenolide. The dried leaf extract induced arterial smooth muscle contractions although it had no parthenolide or other lactones, according to HPLC assay.²⁴ Analyses of many commercial feverfew products for their parthenolide content followed. While European feverfew in general yielded more parthenolide than American plants, some crude and commercial products contained little or no parthenolide at all. Parthenolide levels also fell during storage of the powdered leaf material. Variations among those products with sufficient parthenolide suggested a need to adjust the dosage based on its content.²⁵ However, a recent study using a dried alcoholic extract of feverfew leaves standardized to contain 0.5 mg of parthenolide was found to be ineffective at the indicated dosage as a prophylactic measure in treating migraine attacks.²⁶ It now appears that constituents in the whole leaf other than parthenolide are vital components for the beneficial effects of feverfew in migraine prevention.

Water Extracts versus Hydroalcoholic Extracts of Dried Herbs

Aside from consuming the fresh or dried plant, the most ancient form of herb use is by aqueous extraction. This could be described either as a soup, as in Chinese herbal medicine, or as a tea. Water acts well as a solvent for extracting carbohydrate, peptide, glycoside, and tannin constituents. Depending on the plant parts, the size of its fragments, their density, and the type of constituents, the effective portion may be infused (steeped—usually for leaves and flowers) or decocted (simmered—usually for roots and barks). However, water extracts are susceptible to fermentation due to their carbohydrate content. The discovery of distillation in Arabic medicine led to the use of concentrated alcohol in varying proportion with water as a solvent and preservative for medicinal extracts. The ethanol concentration in hydroalcoholic extracts made by macerating or percolating plant material is approximately 90 percent for resins, 60-70 percent for volatile oils, 45 percent for saponins, sterols, and most alkaloids, and 25 percent for components mostly soluble in water. However, ethanol precipitates proteins and high molecular weight polysaccharides out of solution, which are either removed by filtration or form sediment in storage bottles. Liquid extracts may be dried to form powder or solid extracts.

Valerian

Several clinical studies demonstrated the efficacy of an aqueous extract of valerian (Valeriana officinalis L., Valerianaceae) root in reducing sleep latency and improving its quality. The extract was prepared by grinding the air-dried root, infusing it in water, concentrating the extract, freeze-drying the concentrate, and encapsulating the powder. The weight of freeze-dried powder was about one third that of the dried root. Subjective evaluation by 128 people using 400 mg of this preparation indicated significant sleep enhancement, while those with sleep difficulties benefited the most.²⁷ Eight volunteers with mild insomnia used 450 mg or 900 mg of the aqueous extract in a double-blind study and responded with a significant decrease in sleep latency.²⁸ Valerian’s mild hypnotic effects were confirmed in a PCDB crossover study of 10 subjects having no sleep disturbances who were allowed to sleep at home for one night using 450 mg or 900 mg of the extract.²⁹

These findings were obtained even though potent sedative components in fresh valerian known as valepotriates are insoluble in water and were not detected in the extract.²⁹ Alcoholic extracts of valerian have shown sedative effects in animals. However, the instability of valepotriates in solution has led to a general disregard of their potential effects. Studies on valerian components including gamma-aminobutyric acid (GABA), alkaloids, the volatile oil constituents valeronone, valerenic acid, and valerenal derivatives have indicated that these all make seemingly minor contributions to the activity of the total extract. Aqueous and hydroalcoholic extracts act mostly at GABA-A receptor sites, whereas the lipophilic fraction and the major valepotriate, dihydrovaltrate, bind to barbiturate and peripheral benzodiazepine sites.³⁰ Uncertainty continues to exist regarding what components or combined activities are mostly responsible for valerian’s effects.

Chamomile

The water extract of another popular herb also shows some mild sedative and relaxing effects. A simple infusion made from two tea bags of chamomile flowers (Matricaria recutita L., Asteraceae, formerly M. chamomilla L.) in six ounces of hot water, when given to 12 cardiac patients to assess its cardiovascular effects, induced a deep sleep in 10 of the subjects.³¹ Isolated from an aqueous chamomile extract was the major flavone component apigenin that binds to central benzodiazepine receptors in vitro. Apigenin has shown an anxiolytic and mild sedative effect when injected intraperitoneally in mice.³² Similarly, certain fractions of a methanolic extract of chamomile bind to benzodiazepine sites, while those containing GABA show competitive binding at that receptor site as well.³³

Chamomile was also included in an herbal tea with vervain (Verbena officinalis L., Verbenaceae), licorice (Glycyrrhiza glabra L., Fabaceae), fennel (Foeniculum vulgare Mill., Apiaceae), and lemon balm (Melissa officinalis L., Lamiaceae) that significantly improved colic in a double-blind study with 68 infants.³⁴ Chamomile ethanolic extract has antispasmodic activity on intestinal muscle in vitro. This spasmolytic effect is likely due, at least in part, to essential oil constituents of chamomile.³⁵ Thus, alcoholic extracts of chamomile have activity similar to the traditional tea.

Juices as Nutriceuticals and Phytomedicines

When one considers plant juice extracts, the first thought is usually of the delicious liquids expressed from fruit and berries. Rapid consumption of relatively large amounts of these bottled juices, together with refrigeration and addition of antioxidants, allow for their effective short-term preservation. As a health aid, prune juice remains a favorite mild laxative for many, despite the fact that prunes lack FDA approval as an over-the-counter drug.

Tomato

Among vegetable juices, carrot (Daucus carota L., Apiaceae) juice is recognized as a rich source of beta-carotene, an important anticarcinogenic carotenoid. However, the succulent fruit of the tomato plant (Lycopersicum esculentum Mill., Solanaceae) provides the most familiar vegetable beverage. The extremely high content of the red carotenoid lycopene in tomatoes has brought renewed interest in their potential use as a preventive measure against cancer.³⁶ In a prospective cohort study of nearly 48,000 men the risk of prostate cancer was inversely associated with the consumption of tomatoes and their juice or sauce.³⁷ The separation of the juice from the fibrous pomace allows consumption of far greater amounts of the nutrients, or so-called nutriceuticals, found in food plants.

Cranberry

Cranberry (Vaccinium macrocarpum Aiton, Ericaceae) juice was long thought to be of benefit for some urinary tract calculi and infections due to lowering urine pH, but this effect was shown to be minor and transient.³⁸ However, consuming 16 ounces of cranberry juice daily for three weeks still completely relieved symptoms in over half of 60 patients diagnosed with acute infection of the urinary tract and provided moderate improvement for an additional 20 percent.³⁹

The explanation lay in the discovery that cranberry juice was a potent inhibitor of bacterial adherence in 15 of 22 subjects for up to three hours after drinking 15 ounces of cranberry cocktail.⁴⁰ This juice was most effective in strains of Escherichia coli that inhabit the urinary tract and have their greatest adherence to uroepithelial cells.⁴¹ Adhesion inhibitors in cranberry juice act on E. coli type P fimbriae that bind by lectins with specificity to uroepithelial cells.⁴² Such specific adhesion-binding anti-infective agents provide a potentially revolutionary adjunctive approach to treating infections.⁴³ The components in cranberry juice and other Vaccinium species that prevent this common urinary bacterial pathogen from adhering to the mucosa were recently identified as proanthocyanidins, a type of condensed tannin.⁴⁴

Laboratory evidence in a clinical trial with 28 patients from a long-term care facility suggests that cranberry juice may be even more effective as a preventive measure than as a treatment.⁴⁵ A randomized PCDB study with 153 elderly women consuming 300 ml cranberry juice per day found that it significantly reduced the incidence of bacteriuria with pyuria.⁴⁶

Comparing Different Extracts, Plant Parts, Species, and Markers

Echinacea

Clinical applications of alcoholic extracts of the root of Echinacea species for treating infections were developed in America by Eclectic physicians beginning over 100 years ago. Recent renewed interest in echinacea’s effects has led to a number of clinical studies and appreciation of the therapeutic potential of this plant and of the variations that occur with different preparations.⁴⁷ In Germany extensive research on the components and expressed juice of the aerial plant from the species known as purple coneflower (Echinacea purpurea (L.) Moench., Asteraceae) has been going on since the 1940s. However, a published scientific medical review addressing the safety and pharmacologic activity of this particular plant preparation (Echinacin®, Madaus & Co., Cologne) has only recently appeared in a journal in English.⁴⁸ The fresh juice extracted from the plant requires either removal of the water or the addition of 22 percent ethanol to the liquid or other preservation methods, i.e., heating or freezing, to prevent fermentation from occurring during long-term storage. Preservation alters the juice more or less, depending on the means used. For example, ethanol at higher concentrations precipitates some of echinacea’s high molecular weight polysaccharides.

A major potentially active component in pure, fresh E. purpurea herb juice is a 75,000 Dalton (D) acidic arabinogalactan polysaccharide that stimulates B-lymphocyte proliferation and b-interferon and tumor necrosis factor (TNF) a secretion by murine macrophages in vitro.⁴⁸ When E. purpurea roots were extracted with 30 percent ethanol, polymers of 10,000 D or greater were collected as ultrafiltration retentates. These polymeric compounds included high-molecular-weight arabinogalactans and arabinogalactan-containing glycoproteins. Their i.v. injection in mice caused a significant release of TNF-a and interleukin-1. In in vitro tests with mouse spleen cells the 40,000 D glycoprotein fractions induced interferon a, b release with secondary antiviral activity. A direct effect against herpes simplex virus 1 and influenza virus A was also shown by the fractions, as was mitogenic proliferation of spleen cells from mice and induction of the antibody IgM.^49,50 Fructan polymers from E. purpurea, polysaccharides that are soluble in ethanolic extracts up to certain degrees of polymerization, have shown other pharmacologic activity.⁵¹ The experimental effects of echinacea polymeric compounds would seem to be most pertinent to their administration by injection, since their absorption and activity with oral consumption remain to be established. However, oral administration of immunostimulants produced by the cellular breakdown of several types of bacteria has shown experimental success.⁴⁸ This is probably due to receptor binding of polymeric markers on mucosal- or gut-associated lymphoid tissue (MALT of GALT).

The juice, or squeezed sap, of E. purpurea has been studied and used clinically in Germany orally as an alcohol-preserved liquid, a dehydrated lozenge, and a parenteral medication, all with distinct effects. However, the only clinical effects of the juice considered here will be from the oral administration of the alcohol-preserved liquid. In a randomized PCDB study with 109 subjects at risk for respiratory infections, 4 ml of echinacea juice consumed twice daily for eight weeks reduced the incidence and severity of the common cold while having similar tolerability as the placebo.^47,48 As an adjuvant therapy to local treatment with the drug econazole for vaginal candidiasis in a study with 203 patients, the group treated orally with echinacea juice in 30-drop doses three times daily for 10 weeks had a recurrence rate of 17 percent, compared to 60.5 percent when econazole was used alone.⁴⁸

The juice from fresh E. purpurea and the alcoholic extract of its roots shared a number of activities. They each enhanced resistance against viruses tested in mouse cell cultures: the root extract to influenza virus by 40 percent, the herb juice to herpes virus by 80 percent, and both to vesicular stomatitis virus by 50 percent.⁵² The inhibition of hyaluronidase, secreted by streptococci and other bacteria to enable penetration into tissue, has been demonstrated with echinacea plant juice.⁵³ Chicoric acid and caftaric acid, present in the roots and aerial parts of the dried E. purpurea plant in substantial quantities, have likewise shown antihyaluronidase activity.^54,55 Like the effect from the juice of the plant in vitro,⁴⁸ a 90 percent ethanol extract of E. purpurea dried, powdered root enhanced phagocytosis when administered orally to mice. This phagocytic enhancement is largely credited to its isobutylamide content,⁵⁶ which is greater in the root than in the aerial parts of the plant.⁵⁷ The isobutylamides in the roots also inhibit the proinflammatory metabolite production induced by lipoxygenase. Echinacea’s anti-inflammatory effect has also been attributed to its polysaccharides and aqueous extract.⁵⁸ The isobutylamides are responsible for the local tingling and anesthetic effects applied to relieve oral conditions such as toothaches and sore throats.⁵⁹

Ethanolic extracts of the root, popular in America, also show clinical activity comparable to the plant juice for colds and flu,⁴⁷ though they have definite differences in composition from the juice. In two PCDB studies with 24 subjects each, subjects consumed one capsule or 30 drops of ethanolic extracts of E. purpurea root orally three times daily. In the study using the liquid drops the phagocytic activity of neutrophils in consuming yeast particles was significantly enhanced.⁶⁰ A randomized PCDB study with 180 subjects using 90 or 180 drops daily of E. purpurea root hydro-ethanolic extract for treating flulike infections showed a significant reduction of symptoms at the higher dose compared to placebo.⁴⁷

The popular ethanolic extracts of the roots of other American species, E. angustifolia DC. and E. pallida (Nutt.) Nutt., have shown activities and efficacy similar to E. purpurea root extract.^{47,49,56,58,60} Like dried E. purpurea herb and root, they both contain the antihyaluronidase components chicoric acid and caftaric acid in their roots,^54,55 though other components vary in quantity (e.g., E. angustifolia root has more isobutylamides) and content (e.g., E. pallida root yields polyacetylenes, but not isobutylamides).^51,56,57,59 The concentration of isobutylamide components in E. purpurea and E. angustifolia ethanolic root extracts provides pain relief when applied locally in the mouth or for sore throats with inflamed lymphoid tissue. The most complete combination of active constituents found in echinacea species can probably best be obtained by ingesting the powdered roots of all three species together.

A recent randomized PCDB trial with 302 healthy volunteers using “standardized” extracts of E. purpurea and E. angustifolia for 12 weeks showed no objective advantage in preventing upper respiratory tract infections, though there was a significant consensus among participants that both “had a benefit.” However, the parts of the plants, the method of extraction, the solvent used, and the component and quantity to which the extract was standardized were not identified.⁶¹

Hawthorn

There are a number of other plant genera with effective medicinal preparations comprised of different species, plant parts, and proportions of active constituents. It is not unusual for different parts of closely related species to have similar applications and chemical makeup. A good example of this is hawthorn (Crataegus spp., Rosaceae). A review article states that Crataegus species have been clinically employed to treat angina pectoris, mild hypertension, cardiac arrhythmias, and to help treat congestive heart failure. Based on extensive supportive animal studies using a variety of proprietary extracts, concentrates, and isolates, the effectiveness of hawthorn extracts for these conditions is a result of complementary procyanidins, flavonoids, and other compounds found in varying proportions in several parts of different species.⁶² Comparable effects are obtained from seemingly dissimilar products.

Extensive use of hawthorn to treat coronary insufficiency led to a PCDB study using an orally administered solid form of a hydroalcoholic extract standardized to contain 5 percent oligomeric procyanidins made from the leaves, blossoms, and fruit of Crataegus laevigata (Poir.) DC. (formerly known as C. oxyacantha) and C. monogyna Jacq. Of the 80 ischemic or hypertensive cardiac patients in the study with coronary insufficiency stages II and III according to the New York Heart Association (NYHA), those given 180 mg of the hawthorn extract for six weeks showed significant improvement in the symptoms of difficult breathing, noticeably rapid heart beat, and water retention.⁶³ A freeze-dried aqueous fraction of Crataegus leaves and flowers with 3.3 percent oligomeric procyanidins improved recovery following ischemia [local anemia caused by mechanical obstruction of the blood supply] in an isolated rat heart when a 0.05 percent dilution of was used. Energy metabolism was accelerated and lactate levels were lowered.⁶⁴

Using the freeze-dried forms, the aqueous extract of Crataegus leaves and flowers demonstrated potent guinea-pig heart phosphodiesterase inhibition in vitro, more than the sap of the fruit, though not as great as the methanolic extract of the leaves alone or the comparative alkaloid theophylline. In addition to their procyanidins, the main Crataegus flavonoids, especially hyperoside found in C. monogyna, C. laevigata, and three other medicinal Crataegus species, strongly inhibited phosphodiesterase.⁶⁵ Crataegus flavonoids produced an increase in coronary flow and relaxation velocity, as well as slightly increased heart rate and contraction strength in isolated guinea-pig hearts.⁶⁶

A solid extract of the single species C. laevigata prepared from the leaves and flowers and standardized to 2.2 percent flavonoids called LI 132 (Lichtwer Pharma) was shown in isolated rat cardiomyocytes to have positive inotropic [affecting contraction of muscles, especially the heart muscle] effects with significantly more economical energetics than the drugs isoprenaline or ouabain. In addition, LI 132 prolonged the refractory period, a useful feature for the treatment of arrhythmias.⁶⁷ Pretreatment with LI 132 protects heart cell membranes, as shown by reduced LDH release from the isolated rat heart during reperfusion following ischemia.⁶⁸ In a PCDB study with 78 patients having functional class II chronic congestive heart failure (according to the New York Heart Association classification scheme), 600 mg of LI 132 were given daily for eight weeks. The working capacity of the hawthorn patients increased significantly. The systolic blood pressure, heart rate, and clinical symptoms scores improved significantly compared with placebo, and no severe side effects were observed.⁶⁹

A German symposium on Crataegus reported a number of important observations. One was that extract LI 132 improves the perfusion of all areas by reducing peripheral resistance, with efficacy dependent on dosage and duration. Arterial dilation occurs as a result of opening potassium channels in striated vascular muscle cells leading to membrane hyperpolarization and closure of calcium channels. This results in lower intracellular calcium, muscle cell relaxation, increased tissue perfusion, and decreased blood pressure. A comparative study showed the equivalence between LI 132 and the ACE-inhibitor captopril on stress tolerance. Quality of hawthorn products was determined to be due to flavonoids, including flavone glycosides, oligomeric procyanidins derived from catechin and epicatechin, and aromatic carboxylic acids.⁷⁰

These studies indicate that the therapeutic efficacy of hawthorn is not solely a result of one type of component or one plant part and is not restricted to a single species. Since the active constituents are multiple and vary in different plant parts, combining vegetative and reproductive plant parts for extraction helps assure the clinical results which are due to the totality of active components. Even though different constituent categories are used as markers for purposes of standardizing to a particular concentration, the activities of those marker substances do not describe the full influence of the total extract.

Standardization to Constituent Categories versus Single Marker

Ginkgo

Standardized extracts of ginkgo (Ginkgo biloba L., Ginkgoaceae) leaves have been extensively studied in vitro and in animal models and found to have a beneficial influence for neural and vascular functions. Human clinical trials have confirmed the usefulness of ginkgo in treating peripheral and cerebral circulation-deficient conditions. Like Crataegus spp., ginkgo leaves contain vaso-active flavonoids that contribute to improved arterial circulation. Three standardized, concentrated commercial products considered here are together identified as EGb 761® (developed by Schwabe, Karlsruhe, Germany) based on their content of several categories of active constituents. They have also demonstrated comparable effects in human studies. Initially, EGb 761 was standardized to a “flavone glycoside” content of 24 percent, based on the concentration of three flavonoid aglycones, quercetin, kaempferol, and isorhamnetin, hydrolyzed from over 20 glycosides (mostly derivatives of flavonol coumaroyl esters) present in the leaves. Later, EGb 761 content was further standardized to include six percent terpene lactones, a combination of five unique diterpenic ginkgolides and the sesquiterpene bilobalide. The presence of these flavonoid glycosides and terpenoids provides an array of activities that appear to account for standardized ginkgo’s therapeutic usefulness, though the proportions of specific flavonoids and terpene lactones remain variable.⁷¹

Early studies with EGb 761 focused on its use in peripheral arterial insufficiency. A randomized PCDB clinical trial with 79 patients suffering from arterial disease of the legs showed that 40 mg three times daily for six months significantly improved pain-free walking, maximum walking distances, and blood-flow recordings.⁷² Five controlled clinical trials all showed a highly significant improvement in walking distance for patients with peripheral arterial disease who used EGb 761.⁷³ A randomized PCDB parallel study of 20 patients with claudicating atherosclerotic arterial occlusive disease in stage II (intermittent claudication) used 160 mg EGb 761 twice daily for four weeks. The areas with deficient blood flow were decreased significantly for the ginkgo group compared to the placebo group.⁷⁴

To assess the effects of this G. biloba extract on mental performance, 40 mg three times daily were used in a PCDB study with 60 subjects. Those with the less favorable initial mental deterioration obtained the greatest benefit in improved mental performance indicative of enhanced vigilance.⁷⁵ In 120 geriatric patients with chronic cerebral insufficiency the use of 120 mg daily of the same G. biloba extract in an open one-year trial resulted in a statistically significant regression of vertigo, headache, tinnitus, mood disturbance short-term memory, and vigilance. No significant side effects or interactions with cardiac glycoside or antidiabetic medications were observed.⁷⁶ In two PCDB trials using the standardized extract with 54 and 31 elderly patients with idiopathic cognitive or memory impairment, respectively, 40 mg three times daily were used for 12 or 24 weeks. The ginkgo groups showed significant improvement. An increased interest in everyday activities accompanied improvement in cognitive function.^77,78

Tacrine, a drug approved in the U.S. for treatment of Alzheimer’s disease, was compared in single 40 mg doses with EGb 761 in single 240 mg doses in an open trial with 19 elderly subjects having memory problems. The ginkgo extract produced cognitive activator profiles in nine of these subjects versus only three for tacrine.⁷⁹ In 156 outpatients with mild to moderate Alzheimer’s or multi-infarct dementia a PCDB study using 240 mg EGb 761 daily for 24 weeks documented significant improvement in the ginkgo group for attention, memory, and behavior.⁸⁰ Alzheimer’s patients with mild to severe symptoms were similarly evaluated in a PCDB study with 120 mg daily of EGb 761 for 52 weeks. Ginkgo was both safe and effective in improving cognitive and social performance compared to placebo.⁸¹

A study of flavonoid glycosides in the leaves based on time of harvest showed high levels in the spring and much lower levels in the summer and fall. Leaves collected in spring maximize flavonoid content at about 1.7 percent.⁸² This percent yield provides about one-fourteenth the amount of an equivalent dose by weight of EGb 761. EGb 761 products have also been diluted by a factor of 25 to form liquid phytomedicines.⁷¹ These ginkgo phytomedicines have terpene lactone levels lower than those in French ginkgo leaves but 50 percent more than Chinese leaves and seven times more than German leaves.⁸³ To attain the flavonoid and terpenoid content of the concentrated (50:1) standardized extract, dosage for crude leaf products would need to be from 14-25 times the 120 mg daily dose used for EGb 761, or about 1.7-3 grams daily. Hydroalcoholic extracts would require a comparable dosage adjustment, depending on the ratio of herb weight to solvent volume. In either of these cases the proportion of flavonoids to ginkgolides would likely differ significantly from that of EGb 761. Therefore, duplication of research results obtained from the standardized extract cannot necessarily be assured with other forms. On the other hand, variation in proportions and activities of the individual flavonoid glycoside components and specific terpenoid ginkgolides occurs even in the context of standardization to these chemical categories.

St. John’s Wort

In contrast to ginkgo the standardization process applied to St. John’s wort (Hypericum perforatum L., Hypericaceae) has emphasized the presence of total hypericin content, though many compounds are now recognized as contributors to its activity. An early clinical study of its antidepressive effects used a hypericum extract standardized to hypericin in 15 women for four to six weeks. A quantitative improvement was shown for anxiety, dysphoric mood, loss of interest, hypersomnia, anorexia, morning depression, intractable constipation, and feelings of worthlessness. No side effects or changes in EEG, ECG, or laboratory parameters were noted.⁸⁴ In an animal study the hypericum standardized extract enhanced exploratory and water wheel activity, decreased aggressiveness in isolated males, and antagonized reserpine, indicators of antidepressant activity.⁸⁵ An in vitro study of an 80 percent hypericin extract from hypericum produced monoamine oxidase (MAO) type A inhibition.⁸⁶ Along with pseudohypericin, a similar polycyclic dione component, hypericin was then discovered to have potent antiretroviral activity.⁸⁷ As a result of these findings, hypericin became accepted as “the active constituent” of St. John’s wort.

Later in vitro tests of a hypericin-free hydroalcoholic Hypericum extract for MAO inhibition indicated that active fractions against type A inhibition contained xanthones⁸⁸ that had previously demonstrated potent activity of this type.⁸⁹ Flavonoids also have since been shown to contribute to this in vitro MAO-inhibiting effect,⁹⁰ while 95 percent pure hypericin is now known to be devoid of significant MAO inhibition.⁹¹ A crude hydroalcoholic extract of hypericum containing 0.1 percent hypericin has shown significant receptor affinity for GABA^A, GABA^B, and benzodiazepine, and inhibition of MAO A and B in vitro. However, the concentrations required for inhibition of these receptors to be individually significant are unlikely to be attained following oral administration, except for binding both types of GABA receptors. Purified hypericin has only shown affinity for the N-methyl-D-aspartate receptor, possibly contributing to its antiviral effects.⁹¹ Recently, a meta-analysis of 23 randomized trials with 1,757 outpatients suggested that hypericum extracts with variable hypericin content and daily doses from 0.4-2.7 mg total hypericin were more effective than placebo for treatment of mild to moderate depressive disorders.⁹²

Many studies have recently been published on the effects of a hypericum extract identified as LI 160 (Lichtwer Pharma) which is standardized to 0.31 percent total hypericin (the sum of its hypericin and pseudohypericin content). To test its reputed photosensitizing effects, exposure to ultraviolet radiation with the amount of hypericin consumed in normal therapeutic doses of this product (900 mg extract daily) was shown to be safe. Twice this dose produced only a slight increased photosensitivity after 15 days.⁹³ LI 160 (900 mg) is an effective therapy for patients with seasonal affective disorder⁹⁴ and compared favorably with amitryptyline in a six-week controlled clinical trial with 156 mild to moderately depressed outpatients.⁹⁵ LI 160 at doses of 1800 mg daily was equivalent to 150 mg of imipramine in a six-week, multicenter, randomized, controlled study with 209 severely depressed patients. The adverse effects for the hypericum extract were significantly less than for imipramine,⁹⁶ especially the influence on ECG effects which actually showed improved cardiac conduction for those using hypericum.⁹⁷

This methanolic LI 160 hypericum extract displayed no sensitization effect on the NMDA receptor channel and was a weak inhibitor of MAO in vitro, but it did inhibit serotonin, dopamine, and norepinephrine uptake by 50 percent concentrations from 0.85-6.2 mcg/ml.^98,99 Furthermore, while the density of beta-adrenoceptor in the frontal cortex was reduced by 16 percent, the 5-HT²-receptor density was increased there by 15 percent (in contrast to imipramine) when LI 160 was administered orally to rats at 240 mg/kg for 14 days.⁹⁹ In mice and rat studies LI 160 counteracted drugs that interfered with dopamine-mediated activity. The extract, its flavonoid fraction, and total hypericin fraction all reduced immobility in the rats undergoing a forced swimming test. Hyperforin, a potentially important component, was lost in the fractionation process and so was not tested.¹⁰⁰ Hyperforin modulates several neurotransmitter systems in vitro, and, though heat labile, one of its degradation products has sedative effects. Hypericum flavonoids have shown MAO inhibition and benzodiazepine binding, and its xanthones produce MAO inhibition. Oligomeric procyanidin components have demonstrated vasorelaxation effects, and the plant also contains the sedative amino acid transmitter GABA.¹⁰¹ The variety of bioactive compounds and their effects makes the quality of some products standardized to total hypericin of dubious value, especially at this time when pure hypericin is available for “reinforcing” the natural content of otherwise low-content products.

Essential Oils Internally and Topically

Arabic medicinal practitioners probably first extensively concentrated botanical distillation products over 1,000 years ago. The distillation of volatile oils provided pleasant fragrances to enhance the flavor of medicines and a more potent therapeutic influence from these active aromatic substances. A major limitation for the applications of these essential oils is their adverse effects on the liver and kidneys from excessive doses. The carefully regulated internal use of a few of the safer essential oils along with the inhalation or topical application of more toxic aromatics comprises the common therapeutic use of these substances. Some individuals trained in aromatherapy may use a larger number of such medications internally.

Peppermint

One of the safest essential oils used as a flavoring agent is oil of peppermint (Mentha x piperita L., Lamiaceae). Its smooth muscle relaxing effects were shown in a study with 27 subjects. Relaxation of the lower esophageal sphincter was demonstrated, but gastric reflux was an undesirable result of this effect.¹⁰² A PCDB crossover study applying this spasmolytic property to irritable bowel syndrome used 0.2 ml of peppermint oil in 18 patients. One or two doses three times daily were consumed in enteric-coated capsules to avoid gastric reflux and to prevent absorption proximal to the problem. This form of peppermint oil was significantly better than placebo in relieving abdominal symptoms and helping the patients feel better.¹⁰³

A study with six healthy and six ileostomy subjects compared the kinetics of peppermint oil in enteric-coated capsules versus soft gelatin capsules. From monitoring urinary levels of menthol following consumption, peak menthol excretion was shown to be lower and delayed in the healthy subjects using enteric-coated capsules, while the ileostomy patients using this form had incomplete absorption and reduced urinary excretion. These results verified the delayed-release effect of these special capsules.¹⁰⁴ However, a later randomized, PCDB crossover study with 33 patients using the same dosage as above indicated no superiority over placebo for irritable bowel syndrome. Six patients even experienced heartburn while using the peppermint oil, in spite of the enteric-coated capsules.¹⁰⁵ A PCDB multicenter study with 39 patients suffering from idiopathic [non-ulcerous] dyspepsia with moderate to severe pain used enteric-coated capsules with a combination of 90 mg peppermint oil and 50 mg caraway oil (Carum carvi L., Apiaceae). After four weeks the results for the medicated patients were significantly superior to placebo with 63 percent without pain and 90 percent showing improvement.¹⁰⁶

Based on in vitro tests using isolated guinea pig large intestine and rabbit jejunum [part of the intestine], the mechanism by which peppermint oil relaxes gastrointestinal smooth muscle appears to be by reducing calcium influx in these cells.¹⁰⁷ Peppermint oil has been applied locally to help reduce spasm during colonoscopic exams. By injecting a diluted suspension of the oil along the path of the sigmoidoscope, it was found to relieve spasm within 30 seconds in all 20 cases.¹⁰⁸ In a PCDB study with 141 patents receiving barium enemas, the group using the peppermint oil mixed with the barium had less colonic spasm during examination and a significantly higher proportion of these patients (60 percent) had no residual spasm compared to those in the placebo group (35 percent).¹⁰⁹ In an experimental study the amount of peppermint oil in a 1:3.5 (31 percent w/w) alcoholic extract of M. x piperita was sufficient to produce an antispasmodic effect in isolated guinea-pig ileum using acetylcholine and histamine as spasmogens.³⁵ Peppermint oil is an effective analgesic even when applied topically on the skin. In a randomized PCDB crossover study with 32 subjects a 10 percent peppermint oil in 90 percent alcohol solution had a significant analgesic effect in reducing sensitivity to headache when applied to large areas of the forehead and temples.¹¹⁰ Thus, the local effect of peppermint oil relieving spasm or pain is applicable internally and topically.

Tea Tree

Noteworthy in many essential oils is their antimicrobial effect. The essential oils often inhibit both gram positive and gram negative bacteria in addition to yeast.¹¹¹ One essential oil product popular for its antibacterial, antifungal, and antiprotozoal effects is tea tree oil (Melaleuca alternifolia Cook, Myrtaceae). An early study of its use in 96 cases of vaginitis caused by Trichomonas vaginalis used an emulsified solution of 40 percent tea tree oil in 13 percent isopropyl alcohol applied locally on a saturated tampon for 24 hours. This was followed by daily vaginal douches in which the solution was diluted in water to 1.0 percent (0.4 percent oil). The average treatment required to effect a clinical cure was six office treatments and 42 vaginal douches. The results compared favorably with treatment by standard antitrichomonal suppositories. Several cases involving Candida albicans infections were also resolved.¹¹²

Compared with twice-daily topical application of a 1.0 percent clotrimazole solution in a randomized, double-blind, multicenter trial with 117 patients, pure tea tree oil was comparable in resolving chronic toenail onychomycosis caused mostly (96 percent) by Trichophyton species. After six months of treatment the culture and clinical results for both groups were similar, and three months later both groups were equivalent in sustaining improvement or resolution.¹¹³ Another comparative randomized clinical trial used 5 percent tea tree oil or 5 percent benzoyl peroxide in water-based gel or lotion, respectively, for treating mild to moderate acne in 124 patients for three months. Both treatments had a significant effect in reducing the number of lesions, although the onset of action was slower for tea tree oil. However, the tea tree oil caused fewer irritating side effects.¹¹⁴

Of particular significance are the results of in vitro antibacterial effects of tea tree oil against antibiotic-resistant strains of Staphylococcus aureus. All 60 methicillin-resistant isolates of S. aureus were susceptible to inhibition by tea tree oil with a minimum inhibitory concentration of 0.25 percent and minimum bactericidal concentration of 0.5 percent. Of these bacterial isolates 29 were also resistant to the antibiotic mupirocin. Tea tree oil was also effective against the S. aureus isolates that were susceptible to these two antibiotics. This tea tree oil complied with the Australian Standard by containing less than 15 percent 1,8-cineole and more than 30 percent terpinen-4-ol.¹¹⁵ However, the Australian Standard, established for commercial purposes, does not confirm which components are active antimicrobials. Though the terpinen-4-ol inhibited all 12 gram positive, gram negative, and acid-fast bacteria and yeast test organisms, the major essential oil components linalool, terpinolene, and alpha-terpineol were also active against all organisms except Pseudomonas aeruginosa, while even 1,8-cineole inhibited seven of the 12. Based upon the minimum inhibitory concentrations, the linalool, terpinolene, and alpha-terpineol were the most potent.¹¹⁶ Once again, product standardization does not necessarily reflect the presence of some of the major components that contribute to desired activity.

Isolated Components Internally and Topically

Isolation of the most potent active constituent responsible for a particular effect of a plant extract has been the modus operandi of pharmaceutical chemists and pharmacognosists for the last two centuries. This has proven useful as a means of both reducing and simplifying dosage based on the small amount and exact content of the final product. However, in purifying a single component of an extract the total effect obtained from the extract is inevitably altered.

Berberine

Such is the case with the antiseptic alkaloid berberine, found in plants in conjunction with similar components that also have antimicrobial activity. Berberine is found in a relatively high concentration (2-10 percent) in alcoholic extracts of the root/rhizome of goldenseal (Hydrastis canadensis L., Ranunculaceae) along with a significant amount of hydrastine (2-5 percent) and a smaller quantity of canadine.^117,118 Both hydrastine and its oxidation product hydrastinine have been shown to be antibacterial in vitro against both gram-positive and gram-negative species.¹¹⁹ Berberine also is found in several barberry (Berberis spp., Berberidaceae) and Oregon grape (Mahonia spp., Berberidaceae) species, together with palmatine, jatrorrhizine, and other alkaloids.^120,121 Palmatine and jatrorrhizine have also shown potent antimicrobial activity in vitro.¹²²

Berberine sulfate has demonstrated a broad spectrum antimicrobial effect in vitro against several strains of gram positive, gram negative, and acid-fast bacterial test organisms, as well as some yeast, fungus, and protozoa.¹²³ Its clinical efficacy has been demonstrated with its use in eye drops for the treatment of Chlamydia trachomatis infections. Trachoma is a major cause of blindness and impaired vision through the world. Twenty patients with stage I or II active trachoma lesions were cured with a 0.2 percent solution of berberine chloride, using two drops in the eye three times daily for three weeks. Post-treatment conjunctival scrapings were negative for C. trachomatis after using berberine, whereas patients “effectively” treated with 20 percent sulphacetamide still had positive scrapings for Chlamydia after treatment.¹²⁴ Another clinical trial demonstrated its usefulness internally in 42 children with giardiasis taking 10 mg/kg/day of berberine orally. After 10 days comparable results were obtained with 108 children using furazolidone, 88 using metronidazole, or 46 taking quinacrine hydrochloride.¹²⁵

In a controlled study of diarrhea due to gastroenteritis, 100 children were treated with antibiotics or 25 mg berberine tannate orally four times daily. Both groups had equivalent success and recovery rates.¹²⁶ Similar results were obtained in treating severe diarrhea in a comparative study using 250 mg chloramphenicol four to six times daily for two days and then three times daily (264 cases) or 50 mg berberine hydrochloride orally three times daily for two days and then twice daily (356 cases). However, in choleraic diarrhea, berberine was found superior to chloramphenicol in reducing mortality in cases where Vibrio cholerae could not be detected, but the two were equivalent in cases where this organism was identified. Berberine produced no side effects, but it also showed no vibriocidal activity.¹²⁷ In a randomized controlled trial of 165 adult patients using 400 mg of berberine sulfate in a single oral dose, measurement of stool volumes showed that berberine was safe and effective for acute diarrhea caused by toxins secreted by E. coli. In this single dose method its activity against Vibrio cholerae diarrhea was slight.¹²⁸

Berberine’s efficacy for infections caused by organisms that it does not destroy deserves attention. In an in vitro study of berberine sulfate against E. coli, the berberine showed no effect on the bacterial growth. However, it blocked adhesion of the bacteria to epithelial cells due to a reduction in the synthesis and assembly of the bacterial fimbria which attach.¹²⁹ Besides its in vitro bacteriostatic effects on Streptococcus pyogenes, berberine sulfate also has been shown to block adherence of this organism to epithelial cells. Berberine caused release of the adhesin lipoteichoic acid from the bacteria. It also prevented the lipoteichoic acid retained by the streptococci from complexing with the fibronectin of the host cells or dissolved this complex once it formed.¹³⁰ An earlier study had shown berberine hydrochloride could induce bactericidal effects of penicillin and chloromycetin in enteric organisms previously immune to the effects of berberine or these antibiotics.¹³¹ Thus, the effects of berberine in some infectious conditions are due to more than a bactericidal activity, and its combination with complementary antimicrobials suggests therapeutic advantages.

Capsaicin

The use of cayenne pepper (Capsicum annuum var. frutescens (L.) Kuntze, Solanaceae) as a pungent spice was discussed at the beginning of this article for its beneficial internal effect of enhancing fibrinolysis in humans. The pungent component of this spice, capsaicin, is known for the burning sensation that it causes locally. The effect of capsaicin on pain-conducting sensory nerves from the skin and mucous membranes results in initial stimulation and then blockage of the release of the neurotransmitter substance P. For chronic pain conditions this results in an analgesic effect when applied regularly to the skin.

Capsaicin’s efficacy against pain was first demonstrated in 23 patients with chronic post-herpetic neuralgia uncontrolled by other medication. The subjects were treated in an open-label study with a topical application of 0.025 percent capsaicin in a cream base four times daily over the painful area. After four weeks 56 percent achieved good or excellent results, and 78 percent noted improvement in their pain.¹³² These results were confirmed in a PCDB study with 32 elderly patients having post-herpetic neuralgia for over a year. The capsaicin cream was applied topically three to four times daily for six weeks. The placebo group used the cream base topically. By the fourth and sixth weeks 77 percent of the capsaicin group had reduced pain, while only 31 percent of the placebo group experienced improvement.¹³³

A study of 14 patients with post-mastectomy pain syndrome unresponsive to other methods also used the topical 0.025 percent capsaicin cream locally. After four weeks 12 subjects showed improvement and eight had good to excellent responses. Six months later 50 percent still had good pain relief.¹³⁴ A PCDB study with 197 patients with pruritic psoriasis likewise used a 0.025 percent capsaicin cream topically four times daily for six weeks for symptomatic relief. Patients who used the capsaicin cream had significantly greater relief and reduced severity of psoriasis after four and six weeks.¹³⁵ The most common side effect with the 0.025 percent cream was a transient burning, stinging, or erythema [reddening of the skin] at the site of application.^132-135

Several case reports that were unresponsive to other treatments described effective treatment of painful diabetic neuropathy with 0.025 percent capsaicin .¹³⁶ A stronger, 0.075 percent capsaicin cream was used in an eight-week controlled study of 22 randomly assigned subjects with chronic and severely painful diabetic neuropathy. Capsaicin proved significantly better than placebo in improving pain status. In a follow-up open-label study, about 50 percent of the subjects reported complete or improved pain control.¹³⁷ An eight-week multicenter PCDB study with 277 subjects suffering from painful diabetic neuropathy confirmed the results with the stronger capsaicin cream. Significant improvement in pain status, walking, working, sleeping, and recreational participation were found with the capsaicin cream versus placebo.¹³⁸ Another PCDB study with 58 diabetic patients with painful symmetrical polyneuropathy used 0.075 percent capsaicin cream on painful areas four times daily for four weeks. By this study’s parameters improvement was described in 67-71 percent of capsaicin patients and 41-50 percent in the placebo group, but the results reached statistical significance in only one of the four measures of pain or pain relief.¹³⁹

In an open trial 23 HIV patients having painful sensory neuropathy received topical treatment with the more potent capsaicin cream and obtained benefits th