Sometimes it seems as if doses of supposed active constituents are too low to have an effect, and in the absence of clinical proof this has led sceptics to dismiss these medicines as mere placebos…. It is still routine to investigate and extract medicinal plants with a view to finding the single chemical entity responsible for the effect, and this may lead to inconclusive findings. If a combination of substances is needed for the effect, then the bioassay-led method of investigation, narrowing activity down firstly to a fraction and eventually a compound, is doomed to failure, and this has led to the suggestion that the plants are in fact devoid of activity…. When activity is thought to be lost through purification, synergy should be suspected.
—Dr. Elizabeth Williamson, “Synergy and Other Interactions in Phytomedicines” (Phytomedicine 8, no. 5 [2001])
All investigations have shown that most of the extracts and individual constituents thereof exert multivalent or pleiotropic pharmacological effects (this multivalance of pharmacological activities can generate additive or overadditive, potentiated synergistic effects)…. The synergistic effects that have been measured exceed the effects of single compounds, or mixtures of them at equivalent concentrations, by a factor of two to four, or more.
—Dr. Hildebert Wagner, “Natural Products Chemistry and Phytomedicine in the 21st Century” (Pure and Applied Chemistry 77, no. 1 [2005])
Synergy, in its simplest definition, means that the combination of two (or more) things produces outcomes greater than the sum of the individual parts and, additionally, that those outcomes cannot be predicted from a study of the individual parts themselves. Individual plants, because of their complex chemistry, are highly synergistic organisms by themselves. If plants are used in combination, the complexity, and resultant synergy, increases substantially.
Within older healing traditions such as traditional Chinese medicine (TCM) and Ayurveda, the inherent synergistic nature of plant medicinals and plant combinations is an integrated aspect of healing. Those systems, over millennia, developed their own language and understanding of plants as synergists. A similar understanding, using our own Western terminology and perspectives, has been lacking in our medical approaches—herbal or otherwise.
Medical technologists (usually from the younger generations) have slowly begun to move away from the dogma of monotherapy—that is, the use of a single compound to treat disease. It’s not that they inherently wanted to or that they innately understood that the system in which they were trained was flawed. Their change, as it is with most of us, was driven by events occurring in the outside world that they could no longer ignore; mainly, the emergence of multidrug-resistant microorganisms and AIDS.
AIDS (along with cancer), because of its spread, its disease dynamics, and its amazing adaptability, has forced a shift from a monotherapy frame to that of a multi-target paradigm of therapeutics. Multi-target therapies not only focus on killing the disease organism—which with AIDS and cancers are often futile—but also focus deeply on activating the natural defense, protective, and repair mechanisms in the body. In other words they also stimulate immune responses to disease and, as well, the body’s own highly elegant repair mechanisms.
The emergence of multidrug-resistant bacteria has also been a factor in challenging the monotherapy paradigm. As fast as new pharmaceuticals were developed for resistant organisms, new resistance emerged. Physicians learned, eventually, that if they combined therapies, for example if they used antimalarial drug combinations, the development of malarial resistance could be delayed. (Not stopped, mind you, just delayed.) But that recognition opened up the understanding that complex drug therapies were much more effective against the disease and, as well, could slow down and, presumably if they were elegant enough, stop resistance development altogether. The use of artemisinin combination therapy (ACT) is a product of that understanding. At a very crude, simplistic level these approaches by medical technologists are beginning to mimic the actions of plant medicines, as well as older systems of healing such as TCM.
Western herbalists have never been completely captured by the monotherapy paradigm, though they have often been strongly influenced, and sometimes fully seduced, by it. Medical (and naturopathic) herbalists, for example, since they often tend to mimic a medical reductionist model, generally lean much more strongly toward monotherapeutic thinking. They often lose sight of plant complexities in the search for “active” constituents and standardized herbs.
Community herbalists, like their counterparts in all third- (and some second-) world countries, tend to be more cognizant of plant complexities and subtleties, in part simply because they haven’t been trained to believe they know some ultimate truth about the nature of plant medicines or reality as a whole. Most of them consider plants to be an expression of the general intelligence and livingness of Nature. They never have felt plants to be insentient substances that can be analyzed and completely understood by science and then used however human beings wish.
All Western herbalists, no matter their orientation, do know that plants are much safer than pharmaceuticals, that they tend to produce more complex effects in the body than pharmaceuticals, and that they need to be part of a more complex treatment regimen, one that also includes immune regeneration and support for the body’s natural repair mechanisms. Herbalists just naturally tend to be more multi-target-therapy oriented than the majority of physicians. And most Western herbalists, not all, understand that whole-plant extracts are often more effective than isolated constituents and that plant combinations are often more effective than single-plant extracts.
In spite of this, Western herbalists as a group have nearly no understanding of synergy in plant medicines. Those few that do have some sense of it tend to speak of it in such vague terms that the concept is virtually useless. Part of the problem is simply that the concept hasn’t had any developed presence in the herbal literature. It is hard to think about something you have never heard about. Another very common problem is the fear of sounding too “New-Agey” or “airy-fairy”—translation: not “scientific” enough. Herbalists, like all other people on the planet, do want to be accepted by their culture; the pervasiveness of such a widespread reductionist paradigm has had the (often intended) effect of causing people to censor their own thoughts. Thus the long-term herbal mimicry of the monotherapy paradigm in both the United States and Europe that has had such a tenacious and negative influence on the field.
More deeply problematical, the majority of Western herbalists simply have not spent much time developing their own particular in-depth understanding of plant medicines, nor have they trusted themselves enough to support the modern development of their own unique system—a system that has very old roots in numerous indigenous cultures in the Americas, the older European cultures (Greek and Roman, for instance), and that of community herbalists nearly everywhere. Instead, most have mimicked older systems (TCM, for instance) or taken on the trappings of the newer system of technological medicine. They have spent decades trying to force their unique Western system, a system of which they have some sense every day of their lives, into those forms. (The American herbalist Michael Moore was a major exception to that trend.) Square peg into round hole living. It is time to own our own unique system, without embarrassment, without pretending or trying to be what we are not.
There are many aspects to our emerging Western herbal paradigm that need to be developed in depth; one of those is the understanding of plant synergy. This chapter is an early beginning, however brief or incomplete, in attempting to address it.
In the sense I am using the concept here, plant synergists act to increase the activity of other plants used for healing while affecting the body itself through a number of other, supportive actions. They do this through a wide range of mechanisms:
• They act to reduce toxic side effects of primary constituents.
• They increase depth and broadness of constituent penetration by among other things increasing intracellular transport.
• They enhance constituent activity by acting at different points of the same signaling cascade.
• They decrease the effective dose needed for cure.
Certain plant compounds alter the pharmacological actions of others, change their physicochemical properties, influencing biochemical parameters such as solubility, bioavailabilty, and activity. Some compounds enhance immune responses while others attack microbial organisms, weakening them and making them more susceptible to the heightened immune system. And still others specifically work to reduce viral and bacterial defenses to antimicrobial plant constituents so that the plant’s antibacterial and antiviral compounds are more effective.
Plants suffer bacterial and viral infection, just like we do. One of the things they do to deal with bacterial infections is produce antibacterial substances such as berberine in order to deal with them. Correspondingly, all bacteria, to differing degrees, have learned to deal with antimicrobial substances, most simply, to protect themselves from antimicrobial attack. One way they do this is to utilize multidrug-resistance pumps. MDRs act to pump antibacterial substances that get into a bacterial cell out again. In response, plants, over time, innovated chemical constituents that would deactivate MDRs.
Berberis fremontii (also known as Mahonia fremontii), one of the berberine-containing plants, for example, contains a compound, 5′-methoxyhydnocarpin (5′MHC), that is a potent MDR inhibitor of the efflux pump found in some Gram-positive bacteria, especially staphylococci. The plant then, when used medicinally, acts synergistically. One compound, 5′MHC, inactivates the MDR in the staph organisms, and another, berberine, kills the bacteria. (And yet another compound in the plant, porphyrin pheophorbide A, acts synergistically with both of them to kill MRSA organisms.) Sublethal doses of berberine, in numerous experiments, when combined with 5′MHC, become decidedly lethal. The compound 5′MHC itself has no antibacterial activity at all. Not surprisingly 5′MHC is common among the berberine-containing plants.
Because of the nature of this book, I am going to primarily explore plants that contain potent efflux inhibitors that deactivate those particular bacterial resistance mechanisms and, as well, plants that allow more effective penetration of plant compounds into the body. The field is still new; there isn’t a lot to work with yet, but I hope that this chapter will give you a good idea of the complexity that is possible when looking at synergists. I hope it will stimulate you to deepen the work yourself, for all of us are going to need to know these things.
Something to keep in mind: herbalism is and always will remain an art. Analytical knowledge, while important, has to be combined with a feeling for the craft, for the plants, for the people who come to us for help, and … for the bacterial organisms themselves. From this comes art … and the ability to truly reason while at the same time developing a genuine capacity to heal.
As I’ve said before, we need both feeling and thinking for this craft to flourish inside us, and behind it all, a deep and abiding love for the plants and the earth from which they, and we, come.
To begin I’ll just look briefly at a few of the synergists that have promise for the future, then I will get into several in more depth and explore how to use them for the treatment of resistant bacterial infections.
Most of the current synergy research taking place is looking at plants and plant compounds that can reverse drug resistance. Unfortunately, for my purposes anyway, most of the resistance-modifying studies that have taken place are looking at reducing the resistance of various forms of cancer to pharmaceuticals. I am not covering those here but am focusing solely on those that have been found to modify resistance in bacteria. MRSA is the bacteria upon which most study of medicinal plants’ ability to modify resistance has occurred.
In the list that follows, most of the plants were tested by using an antibiotic on a resistant organism, then adding the plant to the mix and seeing what happened. Once the herb, or its constituent(s), were combined with the antibiotic, the antibiotic either became effective or was so at much reduced levels, usually by a factor of four to eight, though in the case of thyme, the effectiveness threshold of tetracycline against MRSA went from 4 to 0.12 mg/L. Further tests were then conducted to find out just which bacterial efflux pumps were inactivated by the plant.
Dalea versicolor and Dalea spinosa both contain substances that are mildly antibacterial but others that specifically inhibit a particular efflux pump (NorA) in multidrug-resistant Staphylococcus aureus. They also inhibit the Bmr efflux pump found in Bacillus subtilis.
Ipomoea murucoides, Mexican morning glory, contains a number of compounds that are also potent inhibitors of the NorA efflux pump in resistant staph. These are, to date, the most potent inhibitors of NorA found, increasing the effectiveness of antibiotics 16-fold.
Geranium caespitosum also has a potent efflux inhibitor active against MRSA. It potentiates the activity of the plant antimicrobials berberine and rhein as well as the antibiotics ciprofloxacin and norfloxacin. Other geraniums act similarly; these plants are exceptionally good to combine with berberine in the treatment of GI tract infections such as E. coli and cholera.
Cymbopogon citratus, lemongrass, while having only mild antibacterial activity itself, is an exceptionally potent synergistic activator of antibiotics against MRSA.
Rauwolfia serpentina and R. vomitoria are active against the Bmr efflux pump in Bacillus subtilis, the NorA and Tet(K) pumps in MRSA, the PmrA pump in Streptococcus pneumoniae, and an ABC transporter that is associated with ciprofloxacin resistance.
Epicatechin gallate and epigallocatechin gallate, both in green tea (Camellia sinensis), have been found to be highly potent efflux inhibitors for both MRSA and Staphylococcus epidermidis. They inhibit both NorA and Tet(K) efflux pumps.
Rosmarinus officinalis (rosemary), Thymus vulgaris (thyme), and Lycopus europaeus (gypsywort, bugleweed) have been found effective against the Tet(K) efflux pump in E. coli and MRSA and the Msr(A) pump in MRSA.
Prosopis juliflora (and other Prosopis species—the mesquites), a very good medicinal tree and intense invasive, contains a number of potent piperidine alkaloids, one of which has been found to be a very potent inhibitor of the NorA pump in MRSA.
Extracts of myrrh gum (Commiphora), gotu kola (Centella asiatica), wild carrot (Daucus), licorice, and bitter orange (Citrus aurantium) are all effective in inhibiting the AcrAB-TolC efflux transporter that is present in a number of Gram-negative bacteria. (They are especially effective against multidrug-resistant Salmonella enterica var. typhimurium.) This efflux mechanism is a homologue of the MexAB-OprM efflux transporter that is widely present in resistant Gram-negative organisms. Both pumps affect a wide range of antibacterials. When used with pharmaceuticals, these plants reduced the MIC (minimum inhibiting concentration) by factors of 4 to 32.
Thymus vulgaris, thyme, inhibits the MexAB-OprM efflux pump and its gene expression. MexAB-OprM is heavily involved in the removal of tetracycline, beta-lactams, fluoroquinolones, chloramphenicol, novobiocin, macrolides, ethidium bromide, aromatic hydrocarbons, and homoserine lactones. Thyme essential oil, in tiny doses, one or two drops, when taken directly by mouth will enter the bloodstream immediately. If combined with herbs such as cryptolepis, it will potentiate their action against Gram-negative bacteria. Remember: Tiny doses.
The problem with most of these plants (gotu kola and licorice are exceptions) is that they are not highly systemic; that is, they are only moderately, if at all, present in any quantity in the blood. This makes their use as systemic synergists difficult—though of course they can be used topically and directly in the GI tract.
The next two are most likely systemic, though I don’t know them well enough to say, and the final one is systemic and could be used to a limited extent as a systemic synergist for some resistant bacteria.
Caesalpinia benthamiana (syn. Mezoneuron benthamianum) and Securinega virosa are two fairly important but relatively unknown (to Western herbalists) medicinal plants. The first has a wide activity against both Gram-negative and Gram-positive bacteria and is used to treat dysenteric diseases, and early indications are it may be systemic in nature. The second plant has some similar actions, especially in its wide use for dysenteric diseases. Both are efflux inhibitors. They definitely warrant further study.
Punica granatum (pomegranate), the final plant in this list, is synergistic with ampicillin, chloramphenicol, gentamicin, tetracycline, and oxacillin against 30 different MRSA and MSSA (methicillin-sensitive Staphylococcous aureus) strains. The plant extracts inhibit ethidium bromide efflux mechanisms in a number of different types of bacteria. There is also some evidence, not conclusive, that it is effective against the MexAB-OprM efflux pump in Gram-negative bacteria.
Pomegranate is systemic in that many of its constituents are circulated widely in the blood (peak in 1 hour, lasting about 4 hours), but how effective it would be to use it in practice, I don’t know. The plant has not been considered to be a synergist in any culture that uses it and really not much as an antibacterial in any of the healing systems I have looked at. It has been used for millennia in Ayurveda but primarily as an astringent (juice) somewhat like cranberry juice, or for intestinal worms (bark/root).
However, recent research is showing some interesting activity in the plant in the treatment of high blood pressure, the prevention of normal cellular degeneration that accompanies aging, reducing DNA damage, and reducing stress levels in the body.
I will now explore three synergistic plants in detail: licorice, ginger, and black pepper and its primary constituent, piperine.
Family: Leguminosae
Species Used: There are 18 or 20 or 30 species in the genus Glycyrrhiza (this gets tiresome—make up your minds). They are native to Europe, North Africa, Asia, Australia, and North and South America. All species have been used medicinally, but the two most common are Glycyrrhiza glabra (the European licorice) and Glycyrrhiza uralensis (the Chinese). Russian licorice, G. echinata, is often used in that region; the American licorice G. lepidota is rarely used these days in spite of its wide native range but was frequently used as a medicinal by the indigenous peoples in the Americas. (And, yeah, they used it just the same way.)
In this section I will refer to both the European and Chinese species herein as “the plant” or as “licorice,” sometimes as “it.” They are used pretty much interchangeably. If I talk about another species’ actions, I will list it by name.
Licorice is an unusual medicinal. It is potently antiviral, moderately antibacterial (but fairly strong against a few bacterial species such as Staphylococcus and Bacillus spp.), and moderately immune potentiating. But one of its real, and generally overlooked, strengths is that it is a very potent synergist. In fact, it should be considered one of the primary synergists in any herbal repertory.
The root, though the leaves do have similar but much milder actions.
Used as tea, in capsules, as tincture. Again: This herb is best used with other herbs in a combination formula.
Dried root, 1:5, 50 percent alcohol, 30–60 drops, up to 3x daily.
Add ½ to 1 tsp powdered root to 8 ounces water, simmer 15 minutes, strain. Drink up to 3 cups a day.
Take 2–8 “00” capsules per day.
Because of licorice’s many strengths, a lot of people overuse it, with sometimes serious side effects. This herb should rarely be used in isolation or in large doses or long term. Long-term use is especially discouraged. The side effects are many, specifically: edema, weak limbs (or loss of limb control entirely), spastic numbness, dizziness, headache, hypertension, and hypokalemia (severe potassium depletion)—especially in the elderly. Additional problems are decreases in plasma renin and aldosterone levels, and at very large doses decreased body and thymus weight and blood cell counts.
Because of licorice’s strong estrogenic activity, it will also cause breast growth in men, especially when combined with other estrogenic herbs. Luckily all these conditions tend to abate within 2 to 4 weeks after licorice intake ceases. Caution should be used, however, in length and strength of dosages.
A number of studies have found that large doses of licorice taken long term during pregnancy have detrimental effects on the unborn children. Low doses are apparently safe. Again, this plant should not be used in large doses or for lengthy periods of time especially if you are pregnant.
The herb is contraindicated in hypertension, hypokalemia, pregnancy, hypernatremia, and low testosterone levels. However, for short-term use (10 days or less), in low doses combined with other herbs, it is very safe.
The plant is highly synergistic. It is also additive. It should not be used along with estrogenic pharmaceuticals, hypertensive drugs, cardiac glycosides, corticosteroids, hydrocortisone, or diuretics such as thiazides, spironolactone, or amiloride.
The Glycyrrhiza genus is a member of the pea family with the usual pea-type leaves—a bunch of oval leaflets running along a central stem. The plants are perennials, can grow to 6 feet (2 m) in height, and bush out to 3 feet (1 m). The plants produce spikes of the usual pea-family flowers during the summer. They range in color from yellowish to blue to purple in the various species. The plant sends out both roots and rhizomes, the roots thick and fleshy, up to 4 inches in diameter, going as deep as 3 feet (1 m). The creeping rhizomes spread out from the primary root up to 26 feet (8 m) in length, often sending up shoots of new plants far from the original. The roots and rhizomes of the cultivated species are light in color, the wild species darker. The inside of most of the species is yellowish, and, in the European and Chinese species at least, quite sweet. The American species is not very sweet, though a lot of sources say it is (I have eaten it; still waiting for that sweet taste to emerge on my tongue). The American species, though low in sweetness, possesses many of the same medicinal actions as the more prominent medicinal species. I’ve not encountered any of the other less common species in practice.
The licorice flowers mature into clusters of spiky brown seed capsules each about the size of a grape (at least in the American species—the only one I have seen).
The genus ranges from semi-arid desert to lush, wet climes such as Yorkshire, England, and from sea level to 8,500 or so feet (2,500 m) in altitude. When wild, the plants often like growing along waterways in sandyish soil. The American species is endemic throughout Canada and most of the United States excluding the Southeast. The European species is cultivated many places in the Americas but has escaped and can be found here and there in California, Nevada, and Utah. I can’t find a record of any wild species in mid- to southern Africa (even though it is most likely grown there), but the genus seems to have spread pretty much everywhere else. If you look around you will probably find a licorice native in your eco-range someplace.
The plants grow fairly easily from root cuttings; the seeds are more demanding. The seeds need to be stratified for several weeks, then scarified and soaked for 2 hours in warm water before sowing if you want an easy germination. Treated seeds will germinate at about an 80 percent rate, and untreated at around 20 percent. Once started, the plants are pretty intent on remaining and spreading wherever they want to. Make sure you want it where you plant it—you won’t be able to get rid of it if you change your mind. A few places here and there consider it an invasive, because, well, it is.
Both the European and Chinese varieties warrant planting in the wild and letting them go; they are well able to look after themselves if released from captivity. As they are a major medicinal, the more they spread, the better off we will be.
The plants like a free-draining friable soil with a pH between 6 and 7, but they can take on a greater range than that and do quite well. They are drought tolerant and like the sun but do need a bit of water; they often grow wild along streambeds, where they are very tenacious.
It takes a few years for the plants to establish themselves (2 to 3 years is a good minimum period of time), but once they do, you will be able to harvest from them pretty much forever. You will rarely, if ever, be able to dig up the entire root system of an established plant, and it will continue to grow and spread from what is left. Commercial growers generally achieve somewhere between 15 and 50 tons per hectare of roots once the plants have matured. The older the plants and the deeper the dig, the bigger the yield. The plants produce a lot of root mass. You can get enough medicine for an entire family from just one established plant, pretty much forever.
The plant roots and rhizomes should be harvested in the fall or early spring and dried out of the sun. The larger roots should be cut into smaller sections before being dried.
There are hundreds of compounds in licorice, many of which have been intensively studied. The main one is glycyrrhizin, which makes up to 24 percent of the root by weight. Also: glabrin A and B, glycyrrhetol, glabrolide, isoglabrolide, scores of isoflavones, coumarins, triterpene sterols, saponins, and so on and on and on.
Actions
Adrenal cortex stimulant
Adrenal tonic
Analgesic
Antibacterial
Anticancer/tumor inhibitor
Antihyperglycemic
Anti-inflammatory
Antioxidative
Antispasmodic
Antistressor
Antitussive
Antiulcerative
Antiviral
Cardioprotective
Demulcent
Estrogenic
Expectorant
Gastric secretion inhibitor
Hepatoprotective
Immunomodulant
Immunostimulant
Laxative (gentle)
Mucoprotective
Prevents biofilm formation
Protects from effects of radiation exposure
Smooth muscle relaxant
Stimulates pancreatic secretions
Synergist (potent)
Thymus stimulant
Licorice is a fairly potent synergist (see page 217). It is specifically called for in treating resistant Gram-negative infections as it is most potent against that family of efflux mechanisms. In general, it increases the action of other herbs and pharmaceuticals, and if added to a mixture prior to tincturing it will enhance the extraction. It also acts as a detoxicant, and, most importantly, licorice is an inhibitor of one of the main efflux mechanisms in Gram-negative bacteria. As an antiviral, it prevents viral replication across a wide range of viruses, inhibits viral growth, inhibits neuraminidases in numerous influenza strains, inactivates virus particles, and inhibits RANTES secretion. As an immunostimulant, it stimulates interferon production, enhances antibody formation, and stimulates phagocytosis.
It takes about 4 hours for licorice’s glycyrrhizin to reach maximum serum concentration after oral ingestion; then it is slowly excreted, and eventually eliminated at 72 hours after ingestion. It stays in the body a long time.
Active Against
Arboviruses
Arthrinium sacchari
Bacillus coagulans
Bacillus megaterium
Bacillus stearothermophilus
Bacillus subtilis
Candida albicans
Chaetomium funicola
Clostridium sporogenes
Cytomegalovirus
Enterococcus faecalis
Enterotoxigenic Escherichia coli
Enterovirus 71
Epstein-Barr virus
Haemophilus influenzae
Helicobacter pylori
Hepatitis B and C
Herpes simplex
HIV-1
Influenza A (various strains, H1N1, H2N2, H9N2, novel H1N1 [WT], oseltamivir-resistant novel H1N1, and so on)
Japanese encephalitis virus
Klebsiella pneumoniae
Mycobacterium tuberculosis
Newcastle disease virus
Plasmodium spp.
Pseudorabies virus
Respiratory syncytial virus
Salmonella paratyphi
Salmonella typhi
Salmonella typhimurium
Sarcina lutea
SARS-related coronavirus (FFM1, FFM2)
Shigella boydii
Shigella dysentariae
Staphylococcus aureus
Streptococcus lactis
Streptococcus mutans
Streptococcus sobrinus
Toxocara canis
Trichophyton mentagrophytes
Trichophyton rubrum
Vaccinia virus
Varicella zoster virus
Vesicular stomatitis virus
Vibrio cholerae
Vibrio mimicus
Vibrio parahaemolyticus
Use to Treat
Use in cases of respiratory viral infections and oral bacterial problems (for gums and mucous membranes). Use as an adjunct for bacterial infections, especially of the GI tract and respiratory tract, especially if there is cramping or ulceration. But primarily, in the context of this book, use licorice as a synergist in systemic bacterial infections.
Note: Licorice should be used in combination rather than alone. See Side Effects and Contraindications (page 217). I would not recommend that this plant be used as a single medicinal.
Other Uses
As a sweetener. Glycyrrhiza glabra is also a potent plant remediator for reclaiming saline-heavy soils.
Licorice has been used as a food plant and medicinal for between four and five millennia. The genus name, Glycyrrhiza, is Greek in origin, glykys meaning “sweet” and rhiza “root.” The root’s main constituent, glycyrrhizin, is 50 times sweeter than sugar. All the species have been used in medicine in any geographical region they grew and by any culture that had access to them.
Variously known as mulethi, yasti-madhu, jasti-madhu, madhuka, mithiladki, and so on. The plant is considered cooling, tonic, demulcent, expectorant, diuretic, and a gentle laxative. It’s used for treating poisoning, ulcers, diseases of the liver, bladder, and lungs. Any inflammation in the mucous membranes anywhere in the body. For cough, sore throat, hoarseness, fever, and as a general tonic in debility from long-term disease conditions, especially those that are pulmonary or of the GI tract.
Licorice is considered a synergist, a specific additive to other herbal formulations.
Known as gancao in Chinese medicine, licorice has been used in China for three thousand years or so. The herb is considered sweet and mild, to regulate the function of the stomach, and to be qi tonifying, lung demulcent, expectorant, latent-heat cleansing, antipyretic, detoxicant, anti-inflammatory and spleen invigorative and is a synergist in many herbal formulations. The herb is used in pharyngolaryngitis, cough, palpitations, stomachache due to asthenia, peptic ulcer, pyogenic infection, and ulceration of the skin.
The ancient Egyptians used the plant as a major medicinal; the plant has often been found in their tombs. The Greek Theophrastus, in the third century BCE, noted the plant’s use for asthma, dry coughs, and respiratory problems. The Romans called the plant liquiritia, which eventually was corrupted to the word licorice. It was a primary medicine in ancient Rome for coughs. It was used throughout Europe as a primary medicinal and although harvested in the wild originally, it has been a main agricultural crop for over a thousand years.
The American Eclectics used it intensively, as did most medicinal practitioners in the Americas. The Eclectics used it for coughs, catarrhs, irritation of the urinary passages, diarrhea, and bronchial diseases. It was an early agricultural medicinal, grown by most people in their medicinal gardens. The indigenous tribes of the Americas used the indigenous species similarly; that is, for sore throat, chest pains, swellings, coughs; as an antidiarrheal; for stomachache, fevers, toothache, skin sores, spitting blood; and as a general tonic.
The medicinal species have been intensely studied for years. This look will be brief, as a full monograph would run to hundreds of pages.
As an immune stimulant: A double-blind, repeated (within subject), randomized trial with Echinacea purpurea, Astragalus membranaceus, and Glycyrrhiza glabra found that licorice significantly increased CD25 expression on T cells. It also increased CD69, CD4, and CD8 expression on T cells.
Postoperative sore throat: Forty adults about to undergo elective lumbar laminectomy were split into two groups. One received water, the other water with licorice. The use of licorice gargle performed 5 minutes before anesthesia was effective in reducing or eliminating the incidence and severity of postoperative sore throat in patients.
Tuberculosis: A randomized, double-blind, placebo-controlled study with 60 people with sputum-positive pulmonary tuberculosis was conducted. They were split into two groups, one taking placebo, the other licorice—in addition to their regular therapy. Sputum conversion was seen in 80 percent of the licorice group, and 70 percent in the placebo group. Fever was relieved in all in the licorice group, and 80 percent in the placebo group. Cough was relieved in 96 percent of the licorice group, and 81 percent of the placebo group. GI side effects were seen in 20 percent of the placebo group, and none of the licorice group. ALT and AST levels were raised in 6 percent of the licorice group, and 30 percent of the placebo group. Elevated uric acid in serum was observed in 3 percent of the licorice group, and 16 percent of the placebo group.
Hepatitis: A single compound, an interferon stimulator, from licorice was used to treat patients with subacute hepatic failure. The survival rate was 72 percent compared to 31 percent in those who received traditional therapies.
Atopic dermatitis: A licorice gel was used to successfully treat atopic dermatitis in a double-blind clinical trial, 30 people in each group. The gel significantly reduced erythema, edema, and itching over the 2-week trial.
Aphthous stomatitis: Bioadhesive patches containing licorice were used to control the pain and reduce healing time in recurrent aphthous ulcer. Licorice patches caused a significant reduction in the diameter of the inflammatory halo and necrotic center compared with placebo. (There have been three of these trials, all successful.)
Pharmaceutical side effects: In a comparative trial, licorice, when used along with spironolactone in the treatment of polycystic ovary syndrome, significantly reduced the side effects from spironolactone when used alone.
Peptic ulcer: Licorice was found in a trial with 100 people with peptic ulcer (86 of whom were unresponsive to conventional treatment) to be effective: 90 percent experienced good effects, 22 were cured, 28 were significantly improved.
Hepatitis A: In 13 cases of infectious hepatitis treated with licorice, the icterus index normalized in 13 days, urinary bile pigments were negative in 10 days, marked reduction of hepatomegaly took 9 days, pain over the liver disappeared in 8 days.
Hepatitis C: Glycyrrhizin has been used in Japan for more than 60 years in the treatment of hepatitis C. In several clinical trials it has been found to significantly lower AST, ALT, and GGT concentrations while reversing histologic evidence of necrosis and inflammatory lesions in the liver.
Lichen planus: In a clinical trial, 66 percent of people with lichen planus who took glycyrrhizin were cured.
Oral herpes: Glycyrrhizic acid cream, applied six times daily in people with acute oral herpetic infections (HSV1), resolved pain and dysphagia within 24 to 48 hours.
There have been a number of trials using licorice in combination with other herbs. It reduced risperidone-induced hyperprolactinemia in patients with schizophrenia. Reduced hyperuricemia in vegetarians. Was effective in the treatment of advanced pancreatic and other gastrointestinal malignancies. Was successful in the treatment of 138 cases of intestinal metaplasia and 104 of atypical hyperplasia of the gastric mucosa.
In vivo studies have found licorice to be potently antioxidant, to stimulant immune activity, to be anticonvulsant, to be potently anti-inflammatory on skin eruptions, to be hepatoprotective, to be cerebroprotective, to heal aspirin-induced ulcers, to be antispasmodic to the lower intestine, to be strongly antitussive, and to protect the mitochondria from damage.
Licorice is a fairly potent synergist through a number of avenues. Importantly, it is directly active against the efflux mechanism AcrAB-TolC in the Enterobacteriaceae family of bacteria, which are Gram-negative organisms. This efflux mechanism can extrude many diverse antibacterials including tetracyclines, fluoroquinolones, and chloramphenicol. Licorice, then, can effectively be added to formulations treating infections from that Gram-negative family, including, among others, Yersinia, Shigella, Serratia, Salmonella, Morganella, Klebsiella, Enterobacter, and Escherichia.
Licorice increases the potency of both herbs and pharmaceuticals when used with them. It has been found, for example, to enhance the action of anti-tuberculosis drugs, increasing positive outcomes in treatment; to increase the action of hydrocortisone; and to potentiate oseltamivir against resistant influenza strains. Chinese trials have shown that it increases the potency of other herbs in the treatment of rheumatoid arthritis and increases the anti-oxidant actions of other herbs such as astragalus and the isolated compound lycopene. Licorice enhances the anticancer activity of various herbs against prostate cancer cell lines; increases the effect of the neuromuscular blocking agent paeoniflorin; and significantly increases the immune-stimulating action of herbs such as Echinacea purpurea and Astragalus.
Licorice increases the strength of tincture formulations if added to the herbs prior to tincturing. For example, it enhances the solubility of compounds from other plants (e.g., the sapogenin isoliquiritigenin, the saikosaponins from ginseng) by a factor of up to 570.
Licorice also reduces toxicity in other plants; it prevents toxicity from aconite alkaloids and reduces the toxicity from a number of herbs used to treat rheumatoid arthritis in Chinese clinical trials.
Family: Zingiberaceae. There are about 1,400 members of the family, of which the genus Zingiber is usually referred to as the true gingers. The species in the Alpinia genus are probably the other most commonly used medicinals in the family.
Species Used: There are 85 or maybe 100 species of plants in the genus Zingiber. (Why have taxonomy anyway?) Z. officinale, the common food ginger, is the most famous and the one generally used for medicine. Many of the species in this family contain similar constituents and can be used medicinally, but their actions do differ. This short monograph looks only at the culinary ginger, Z. officinale.
The root. The root of ginger is really a rhizome, but nobody cares about the distinction but phytogrammarians, so I will just call it a root, as nearly all people who use language do.
The best form of the herb is the fresh juice of the root taken as a hot tea; it is most potent like this. Large quantities of the juice can be stabilized with alcohol (in an 80:20 juice-to-alcohol ratio) and then added to herbal combinations to blend the juice’s synergistic actions into the formula. If you are using the plant to treat resistant infections, this is the way to do it in tincture combinations. Fresh tincture of the root is nearly as good. Dried root is relatively useless.
The hot tea from the fresh juice is exceptionally potent in serious infection. It takes about 30 minutes after drinking the fresh juice hot tea for ginger’s compounds to enter the bloodstream; they reach peak concentration in about 60 minutes and then begin to decline. The fresh juice tea should be consumed every 2 to 3 hours in acute conditions to keep the constituents at high levels in the blood.
Juice one or more pieces of ginger, in total about the size of a medium to large carrot, or four pieces the size of your thumb. Save the plant matter that is left over (for making an infusion; see below).
Combine ¼ cup fresh ginger juice with 12 ounces hot water, 1 tablespoon wildflower honey, the juice from ¼ lime (squeeze the juice into the cup, then drop in the rind), and ⅛ teaspoon cayenne.
Drink 4–6 cups per day. (If you don’t own a juicer, use infusion method two, below.)
In acute conditions: Drink 6 cups per day minimum.
Method One: The leftover plant matter from juicing ginger can be put into 1–2 cups hot water, depending on how much you have left, and allowed to steep for 4–8 hours, covered. Strain, and use the infused liquid as you would fresh ginger juice in making fresh ginger juice tea (above). It will be almost as useful as the fresh juice but not quite.
Method Two: Grate or chop gingerroot (a piece about the size of your thumb) as finely as you can. Steep in 8–12 ounces hot water for 2–3 hours, covered in order to preserve the essential oils in the tea. Drink 4–6 cups daily.
Ginger juice is exceptionally good (sometimes) in relieving the pain of burns and speeding up healing. Apply the fresh juice topically to the affected area with a cotton ball. It is also a good antibacterial and antifungal when applied to skin infections.
Fresh root, 1:2, 95 percent alcohol, 10–20 drops, up to 4x daily. (I do not prefer this approach, as the fresh juice is much, much better—nevertheless it is a million … well, okay, a billion … times better than using the dried root.)
In everything and anything, often.
Large doses should be avoided in pregnancy due to the plant’s emmenagogue effect, though the dried root can be used to help morning sickness in moderate doses. May aggravate gallstones, so caution is advised. Rarely: bloating, gas, heartburn, nausea—usually when using the dried, powdered root.
The root is synergistic with a number of antibiotics, especially the aminoglycosides, increasing their potency, especially against resistant organisms.
The exact geographical location of the original ginger plant is unknown—most likely someplace in Asia. It has been cultivated for four thousand or more years in China and India and reached the West around two thousand years ago. The genus name Zingiber is of ancient Hindu extraction; it means “horn-shaped.” (“They” say it’s from the shape of the root, but I don’t believe it; I’ve seen gingerroot roots.) The roots form dense clumps as they grow and that is what everyone harvests.
The plant is a perennial and likes warm, humid climates from sea level up to about 5,000 feet (1500 m) in altitude. It is rarely found wild; it’s a cultivated medicinal.
The plant grows 2 to 3 feet (up to 1 m) in height and looks like sort of a shortish bamboo with a thin central stalk. Zingiber plants look much alike and are often confused with the alpinias, another genus in the family.
Ginger is almost always cultivated from pieces of the living root, like potatoes. Simply allowing some gingerroot to begin budding, then cutting it into pieces, each with a bud, and planting them is usually how it is done. Most ginger plants on Earth are rootstock clones. And it is one of the most heavily cultivated plants on Earth. Everybody loves it. The plant is considered a perennial, but it generally depletes the soil in which it is grown so it’s usually rotated every other year. Unless it is in the exact right location it won’t last once the soil is depleted.
Ginger is a tropical plant. It likes sheltered locations, filtered sunlight, warmth, humidity, rich soil. It hates direct sun and so on; basically it wants to be pampered and protected from the elements. It can’t take freezing.
The root cuttings should be planted in late fall or early spring. No direct sun locations. Plant the cuttings 2 to 3 inches (5–10 cm) deep with the bud upward.
The plants need a lot of water, so don’t let the soil dry out. Mulch them thickly. They hate dry air. The leaves die back in 8 to 10 months, and that is when the roots should be harvested. The roots will last a long time before they dry out.
Several hundred constituents, including gingerols, zingiberol, zingiberene, shogaols, 3-dihydroshogaols, gingerdiols, mono- and diacetyl derivatives of gingerdiols, dihydrogingerdiones, labdadiene, and so on. The volatile oils such as the gingerols are very potent but much reduced in the dried roots. They are present at levels 6 to 15 times higher in fresh roots. Many constituents convert to shogaols as the root dries. The volatile constituents are the most antiviral.
Actions
Analgesic
Anthelmintic
Antiarthritic
Antibacterial
Antidiarrheal
Antiemetic
Antifungal
Anti-inflammatory
Antispasmodic
Antitussive
Antiviral
Carminative
Circulatory stimulant
Diaphoretic
Elastase inhibitor
Hypotensive
Immune stimulant
Synergist
Active Against
Acinetobacter baumannii
Angiostrongylus cantonensis
Anisakis simplex
Aspergillus niger
Bacillus subtilis
Campylobacter jejuni
Candida albicans
Candida glabrata
Coliform bacilli
Dirofilaria immitis
Escherichia coli
Fusarium moniliforme
Haemonchus contortus
Haemophilus influenzae
Helicobacter pylori (cagA+ strains)
Hepatitis C
HIV-1
Human cytomegalovirus
Influenza A
Klebsiella pneumoniae
Listeria spp.
Porphyromonas endodontalis
Porphyromonas gingivalis
Prevotella intermedia
Proteus vulgaris
Pseudomonas aeruginosa
Rhinovirus spp. (especially 1B)
Salmonella typhimurium
Shigella dysentariae
Shigella flexneri
Staphylococcus aureus
Staphylococcus epidermidis
Viridans streptococci
Use to Treat
Ginger is a synergist, increasing the actions of other herbs and boosting their effectiveness by relaxing blood vessels and increasing circulation, thus carrying the active constituents of the other herbs more efficiently throughout the body. It is an effective circulatory stimulant, calms nausea, reduces diarrhea and stomach cramping, reduces fever (by stimulating sweating), reduces cold chills, reduces inflammation in bronchial passageways, thins mucus and helps it move out of the system, reduces coughing (as much as codeine cough syrups), ameliorates anxiety, and provides analgesic relief equal to or better than ibuprofen.
The herb can also be used in some bacterial diarrheal conditions, especially where there is cramping (cholera, dysentery, E. coli, etc.), for reduced circulation with coldness in the extremities, for migraine headache if accompanied by cold hands or feet, and for a sluggish constitution.
It has been used every place it is grown as a medicine. Everyone not trapped in a technological culture uses it as a synergist for healing for colds and flu, nausea, poor circulation, and so on.
In Burma, fresh gingerroot is boiled in water (with palm sap as a sweetener) to get a hot infusion for treating colds and flu. In Congo, ginger is crushed and mixed with mango tree sap for colds and flu. In the Philippines fresh chopped ginger is boiled with water, and sugar added, to treat sore throat. It is used similarly in China and India. (There is a reason it is done this way.)
Ginger has a long historical tradition in warm climates as a food additive. Like many culinary spices it possesses strong antibacterial activity against a number of foodborne pathogens—especially against three of those now plaguing commercial foods: Shigella, E. coli, and Salmonella.
Two of the best ways to take ginger as food are the pickled ginger often served along with sushi in Japanese restaurants or candied gingerroot slices. Both make great snacks, can be eaten in large quantities, and are a healthy stimulant for the system.
Ginger has a very long history in Ayurveda, which calls it srangavera and about 50 other names depending on where you go. It is used for dyspepsia, flatulence, colic, vomiting, spasms of the stomach and bowels attended by fever, cold, cough, asthma, indigestion, lack of appetite, diarrhea, fever. The fresh juice (aha!), mixed with sugar and water, is a common form of preparation.
Fresh root: sheng jiang. (Dried root: gan jiang—a very different medicine.) Considered pungent and warm in traditional Chinese medicine (TCM), it is used as a diaphoretic, antiemetic, mucolytic, antitussive, detoxicant, anti-inflammatory. It is considered specific to warm the lungs, for pathogenic wind-cold conditions (i.e., severe intolerance to cold), slight fever, headache, general ache, nasal congestion, runny nose, cough, vomiting. It is usually prepared by decoction in water or pounded and the juice added to warm water. Ginger is generally combined with other herbs in TCM as it is considered to be a “guide” drug that carries the other herbs where they need to go. Ginger is also considered to be specific for ameliorating the toxic effects of other drugs or herbs. Estimates are that up to half of all Chinese herbal formulas contain it.
Everyone in the West has used ginger in much the same ways, though, historically, most of them tended to focus on its use for stomach and bowel complaints.
The research on ginger has been problematic in that distinctions haven’t been made (or looked for) between the actions of the fresh root and the dried root. (Common among scientists.) Nor has there been clarity about how the herb is prepared or what effect that might make on outcomes. (Common among scientists.) It is very rare that fresh preparations have been tested. (Ridiculous since that is the primary form of the medicine the world over.) Water extracts of the dried roots show very little antimicrobial activity—though they remain potently anti-inflammatory. If you don’t understand the problems inherent in the journal papers, the outcomes found—which vary all over the place—are hard to understand. Sigh. Plants possess very different medicinal actions depending on: when they are harvested, how they are harvested, if they are dried or fresh, how they are prepared as medicines, how often they are taken, how much is taken, and if they are taken in isolation or in combination. Scientists coming from a reductionist orientation have a hard time understanding all that; they don’t understand that herbal medicine really is rocket surgery.
As an overview: There have been some 30 clinical trials with 2,300 people using gingerroot. Following is just a sampling of a few of those and of a few in vivo and in vitro studies.
Anti-inflammatory action: Gingerol and its related compounds are potent inhibitors of lipopolysaccharide-induced PGE2 production in vitro. Inhibit both COX-1 and COX-2 in vitro through inhibiting several genes involved in the inflammatory response (acting on cytokines, chemokines, 5-lipoxygenase, and COX-2). Of 56 people (28 with rheumatoid arthritis, 18 with osteoarthritis, 10 with muscular discomfort) who took dried ginger, 75 percent reported relief from pain and swelling. In a doubleblind, randomized, placebo-controlled clinical trial with 102 people with osteoarthritis, ginger was found to be as effective as ibuprofen in relieving pain and swelling. Numerous other in vivo studies have shown that ginger-root has both anti-inflammatory and analgesic actions; some used the essential oil massaged into the affected area—it works really well.
Antiemetic/antinausea: Various clinical studies have found that gingerroot is especially effective for treating severe morning sickness in pregnant women. The dried root was used, of course, and was found more effective in severe cases. (The fresh root is better for nausea.)
Antiadhesion: In vivo, gingerroot interferes with the adhesion of enterobacterial disease organisms to the intestinal wall. This, in essence, reduces entero-infection of the GI tract, short-circuiting the disease process. Ginger is also an elastase inhibitor. Many bacteria use elastase to break down cellular tissue, helping their penetration of the body. (Ginger also reduces spasms in the intestinal tract, relaxing the intestinal wall at the same time.)
Antidiarrheal: Gingerroot interferes with the colonization of cells by enterogenic bacteria, thus reducing diarrhea, and reducing bacterial load. The root alters bacterial and host cell metabolism through a unique-to-ginger mechanism.
Cerebroprotective: In vivo studies found that gingerroot protects rats from brain damage and memory impairment.
Immunostimulant: In vivo studies with gingerroot have found that it increases immune markers across the board, pre- and post-infection.
Detoxification: In vivo rat studies found that ginger reduces cadmium levels and toxicity in rats, acting as a heavy metal detoxifier. And gingerroot in vivo reduces the effects of organophosphate insecticides.
Anthelmintic: Ginger was found to be effective in the treatment of endoparasites and stomach problems in ethnoveterinary practice in Pakistan, killing all red stomach worms (Haemonchus contortus) in test animals. It has been found active against a number of other endoparasites in other trials.
Other studies have found antiulcerative, antitumor, gastric antisecretory, antifungal, antispasmodic, anticonvulsant, and antiallergenic actions in the plant.
Ginger increases the potency of herbs and pharmaceuticals if added to a protocol, inhibits bacterial resistance mechanisms in pathogens, stimulates circulation, and reduces the toxicity of endotoxins and pollutants. It dilates blood vessels and increases circulation, helping the blood, and the constituents in the blood from other herbs, to achieve faster and more effective distribution in the body.
Ginger is highly effective in reducing the ability of bacteria to extrude antibacterials out of their cells. (In consequence it increases the potency of a number of pharmaceuticals.)
Ginger potentiates the activity of aminoglycoside antibiotics (arbekacin, gentamicin, tobramycin, streptomycin) and other antibiotics such as bacitracin and polymyxin B, against vancomycin-resistant enterococci (which are Gram-positive)—essentially by increasing the permeability of the cell membrane; ginger is a strong p-glycoprotein inhibitor, as strong as the pharmaceutical verapamil. It also increases the effectiveness of daunomycin (used in the treatment of cancer), increasing the accumulation of the pharmaceutical three-fold and significantly reducing the P-gp-mediated efflux of the drug. This is common in P-gp inhibitors since cancer cells tend to use P-gp efflux mechanisms to get rid of pharmaceuticals.
Sublethal levels of tetracycline become lethal against staph organisms when ginger is added; compounds from ginger modify bacterial resistance in Acinetobacter baumanii; ginger potentiates the action of nifedipine on antiplatelet aggregation in normal human volunteers and the hypertensive; ginger potentiates the effectiveness of clarithromycin against Helicobacter pylori independent of whether the bacterial strain was susceptible to the pharmaceutical or not prior to the addition of ginger.
Ginger also has direct synergistic actions with other herbs. It potentiates their activity, increasing it substantially. For example, constituents in magnolia, but not in ginger, enhance sucrose intake in rats and reduce immobility time in swimming tests. But when ginger volatile oils are added to the mix, sucrose intake is increased exponentially; reduction time for immobility was also increased.
In other studies, when ginger oils are added to magnolia, they combine to produce a tremendously synergistic outcome in the treatment of depression. Serotonin in the brain and noradrenaline levels in the prefrontal cortex increase substantially after ginger is added to subclinical (inactive) doses of magnolia.
Ginger is also considered to be specific for ameliorating the toxic effects of other drugs or herbs used in TCM. In vivo studies found that ginger reduces cadmium levels and toxicity in rats, acting as a heavy metal detoxifier. It also reduces the effects of organophosphate insecticides in vivo.
Species Used: Piperine is a potent alkaloid found in two different peppers, black pepper (Piper nigrum) and long pepper (Piper longum). It is the primary constituent responsible (along with an isomer of piperine—chavicine) for the spicy pungency of pepper.
Piperine is the most common constituent in black pepper, running from 5 percent to 9 percent. Long pepper has much less, from 1 percent to 2 percent.
The pepper plant itself can be used as a synergist if you are so inclined; for a number of reasons I prefer the isolated constituent as a synergist, however. I will talk about both approaches in this section and the reasons why I am suggesting the constituent in this case.
Because this book is concentrating on the treatment of resistant bacterial organisms, many of which can have severe impacts if not treated effectively, it makes sense to me to use the isolated constituent piperine rather than the whole herb in this instance. The herb itself can be used; it is, however, about one-fifteenth as strong as piperine. Since piperine is, at this point, relatively easy to find, I would suggest having some on hand, just in case. If you don’t have it or it becomes no longer available (see Finding Black Pepper and Piperine on opposite page) you can indeed use the pepper itself.
Both Piper nigrum and Piper longum are prepared as tinctures, 1:5, 65 percent alcohol. Dosage: 5–15 drops as needed. Piperine is not very water soluble; you need an alcohol tincture to extract it from the peppercorns. I would highly recommend using whole peppercorns, freshly ground, for making the tinctures. Previously ground pepper is much weaker.
Actions
Analgesic
Antibacterial
Anticonvulsant
Antidiarrheal
Antidysphagic (essential oil)
Antihyperlipidemic (reduces lipid levels in the blood)
Anti-inflammatory
Antimutagenic
Antioxidant
Antispasmodic
Antitumor inhibitor
CYP3A4 inhibitor
Free radical scavenger (potent)
Hepatoprotector
Immunostimulant
Increases oxygen uptake by red blood cells
Intestinal mucosa modulator
Melanocyte stimulant
Modulates thyroid hormone levels in the blood
Neural protector/stimulant
P-glycoprotein inhibitor
Reduces blood glucose levels
Reduces erythrocyte fragility
Stimulates production and release of pancreatic enzymes, bile acids, and gastric acids
Stimulates the pituitary/adrenal axis
Synergist
Testosterone antagonist
Vasodilator
You can also, if you wish, make trikatu, the traditional Ayurvedic combination that is added to herbs as a formulation synergist. It is prepared using Piper nigrum and P. longum and gingerroot in a ratio of 1:1:1; that is, equal parts of each herb or their tinctures. I prefer the tinctures. Use a tincture of fresh gingerroot, or, more preferably, the alcohol-stabilized fresh juice (as described in the ginger monograph) and tinctures of the two peppers as outlined above. Combine them in equal parts and then add that combined tincture to whatever formulation you are making. If you are making 4 ounces of an influenza formulation, then add an extra ounce of trikatu to make a total of 5 ounces. In other words, add 25 percent to any formulation you are making. It is going to be spicy.
If you wish to use pure piperine, you will need to buy it, as it is a manufactured product. It is relatively inexpensive. Normal dosing, for instance to enhance the uptake of nutrients from food, is 20 mg daily.
Note: I would not use piperine as a regular supplement; in my opinion, it is indicated only for medical conditions that necessitate its use. If you have a systemic infection, especially if it is Gram-negative, piperine is a highly effective synergist for the herbs you will use to treat it and should be considered as a part of the treatment approach.
Dosage in acute conditions: Piperine should be taken prior to the herbal formulation you are using so that the intestinal wall has already been altered by the time your herbs get to the GI tract. Take 20 mg piperine 15–30 minutes prior to your herbs and then again 4–6 hours later, 30 minutes before taking your herbs again. Piperine will stay strongly present in the body for about 6 hours.
So … take piperine twice daily, 20 mg each time, in acute conditions to a max of 40 mg daily. Generally, not to exceed 7 days. If you are taking your herbs six times daily, you still only need to take piperine twice, once before the first dose, and then again 4–6 hours later.
Black pepper can exacerbate gastric reflux problems, but its major side effects occur on the reproductive system. In traditional medicine it is considered a mild contraceptive. The whole herb, however, is generally pretty safe along these lines unless taken in huge doses for extended periods of time. Studies on piperine, on the other hand, have found that it does interfere with egg implantation if taken long term in high doses.
However, the impacts on the male reproductive system are more severe. When taken as a supplement continued oral intake of piperine decreases the weight of the testes, lowers sperm production, decreases intracellular testosterone, and decreases the fertilizing capacity of sperm. Constant piperine intake has deleterious effects on the Leydig cells, epididymis, and seminiferous tubes even at doses of 1 mg/kg of body weight (that is, roughly, 70 to 80 mg daily for an adult male).
Piperine should primarily be used for short-term treatment of acute conditions. Women who are trying to become pregnant should not use it. Men with low testosterone levels should be very cautious in its use and not use it for longer than 2 weeks.
Piperine will increase the bioavailability of scores of drugs. (It will decrease the bioavailability of a few others such as diclofenac sodium.) If you are taking pharmaceuticals, you should check for synergy (the list is too long for this book) or simply not take them together. It is highly likely that the supplement will increase bioavailability and thus the impacts of the pharmaceutical.
Piper nigrum contains at least 200 identified constituents with more being discovered all the time. The most important is considered to be the alkaloid piperine, which is present at levels of up to 9 percent of the dried peppercorns in black pepper. It is the primary substance responsible for the peppery taste of the spice.
Other major compounds are chavicine, coumaperine, piperidine, numerous piperidine amides, piperettine, piperanine, piperolein A, B, and C, piperonal, and so on.
Piper nigrum is native to southern India, where it is extensively cultivated. The plant is a flowering vine that produces grape-like clusters of dark red berries, at the center of which is a large white seed. The seed, as is sometimes the case, comprises most of the berry; the pulp surrounding it is fairly thin, with the usual thinnish outer rind of the fruit covering that. Basically, it is not a very exciting berry.
The black peppercorns that we use for a spice, however, are produced from the green, unripe berries. The berries are harvested and briefly immersed in hot water, thus slightly cooking them. This ruptures the cell walls in the berry and activates a number of enzymes that will cause the outer pulp and rind that surround the white seed to blacken during drying. The fruits are then spread in the sun to dry for several days. The outer pulp and rind wrinkle and turn black. Once dried the fruits are usually sold whole to preserve the strength of the corns, then ground into the powder that we call black pepper just before use.
White pepper is simply the pepper seeds themselves absent the pulp and rind. In this case the ripe berries are soaked in water for a week until the outer rind and pulp soften and slough off the inner seed. The seed is then dried, sold, and ground into a fine powder.
Black pepper has been used in India for at least four thousand years as both spice and medicine. It is probably the most common spice in the world after salt.
Black pepper has a primary place in Ayurveda, often combined with long pepper (Piper longum) and ginger to form a compound called trikatu or the three acrids. This combination has been a primary element of Ayurvedic compounding since at least 600 BCE; most Ayurvedic formulations contain it.
Trikatu is considered specific for correcting imbalances in the three doshas, psychospiritual aspects of the human body that when out of balance lead to disease expressing itself physically. This formulation is (as are the three herbs individually) considered specific for “activating” the potency of the plants with which it is combined. This has been its main use for millennia.
As a single herb, black pepper (and long pepper) has been used for a variety of conditions (constipation, diarrhea, earache, gangrene, heart disease, hernia, hoarseness, indigestion, insect bites, insomnia, joint pain, liver problems, lung disease, oral abscesses, sunburn, tooth decay, and toothaches), but its main uses have been, internally, for disease conditions accompanied by fever and/or diarrhea, dysentery, GI tract disorders, and urinary problems, and externally for rheumatism and neuralgia.
Black pepper was incorporated into the Chinese materia medica during the Middle Ages. It is considered specific for warming the middle, dispersing cold, dispelling phlegm, for wind-cold, and for diarrhea, usually for conditions accompanied by vomiting, diarrhea, and abdominal pain. It is also considered specific for epilepsy. The synergistic actions of the plant are apparently unknown in this system.
I am splitting this section into two parts: 1) nonsynergist actions and 2) synergist actions. Most of the studies have been on the isolated constituent piperine. (There are several hundred studies on piperine; this is just a sampling; most of the studies have been in these areas.)
Black pepper does have some antibacterial activity itself. In vitro studies of a number of its constituents (not piperine) found them active against Bacillus subtilis, Bacillus sphaericus, Staphylococcus aureus, Klebsiella aerogenes, and Chromobacterium violaceum. The essential oil of black pepper is effective against Bacillus subtilis, Pseudomonas aeruginosa, Candida albicans, Trichoderma spp., and Aspergillus niger. An aqueous solution of black pepper was tested against 12 genera of oral bacteria isolated from 200 individuals and was found to be effective against 75 percent of them (unfortunately the abstract does not list the bacteria; the full paper is regrettably elusive). Piperine itself is active against Leishmania spp. and Trypanosoma cruzi.
Here is a look at some of the studies.
In vitro: Black pepper is a strong antioxidant, more potent than alpha-tocopherol when used at similar concentrations. One of pepper’s constituents is as potent as the synthetic antioxidants BHA and BHT.
In vitro: Black pepper inhibits cholesterol esterification in HepG2 cells; it potently inhibits binding between slCAM-1 and LFA-1 of THP-1 cells, dose dependently.
In vivo, guinea pig and rabbits: Crude extracts of black pepper, at low doses, have a mild laxative effect in constipation. However, in larger doses they are antispasmodic, reducing contractions in the intestine, and are antisecretory and antidiarrheal. Piperine, at lower doses than the pepper extract, acts identically.
In vivo, diarrhea, mice: Piperine inhibits castor oil and arachidonic acid–induced diarrhea.
In vivo, inflammation, mice: 1) Piperine reduces inflammation in both chronic and acute models; 2) inhibits monosodium urate crystal– induced inflammation (specific for gouty arthritis); 3) significantly reduces inflammation around joints in arthritic mice studies. It produces anti-inflammatory, antinociceptive, and antiarthritic actions. It inhibits expression of IL6 and MMP13 and production of PGE2.
In vivo, cancer, animal models: Numerous studies have found that piperine protects animals from induced cancer, reduces tumor incidence in others, and increases life span in terminal cases.
In vivo, neuroprotection, mice/rats: 1) Piperine significantly improves memory and protects the hippocampus from neurodegeneration; 2) blocks convulsions induced by intracerebroventricular injection of kainate; 3) inhibits synchronized oscillation of intracellular calcium in rat hippocampal networks, represses spontaneous synaptic activities, and protects hippocampal neurons from apoptosis.
Human clinical trial, epilepsy in children: Clinical trials (randomized, crossover, placebo-controlled, double-blind) with a piperine derivative in China in the treatment of epilepsy found that it reduced the number of seizures in a majority of the children who used it.
Human clinical trial, dysphagia in elderly: Inhalation of black pepper essential oil by elderly persons suffering from difficulty or inability to swallow (dysphagia) showed remarkable effects in restoring swallowing ability.
The synergistic actions of black pepper and piperine are primarily generated by three things: 1) the circulatory actions of the plant or its isolated constituent; 2) their effects on P-gp and CYP3A4; 3) their impacts on efflux pumps in bacteria.
Pepper and piperine expand blood vessel diameter and increase circulation. Piperine is strongly present in the blood (it binds to albumin for transport) and easily crosses internal organism barriers (organs and systems both: blood-brain barrier and so on). It reaches every part of the body.
Piperine and pepper have specific effects on blood constituents. In my opinion the actions of the plant and its constituent on red blood cells (reducing their fragility and increasing their oxygen uptake) play an important part in their synergistic actions. Pepper and piperine also appear to have specific actions on white blood cells. They do have some immune-stimulating actions, but more importantly they seem to be highly protective of white blood cells, being active against leishmanial and tryposomal parasites of the macrophages. They seem to produce the same effects on white blood cells as they do on red, that is, reducing their fragility and enhancing their normal actions. Although no one has tested for this, it seems as if piperine may play a particular role as a hematoprotector and hematoregenerator not only of red blood cells but also white, though differently than the other plants I have discussed so far.
A smaller role in the plant’s synergism is played by the general medicinal actions of the plant—that is, it is to some extent antibacterial, which will give additive effects (at the least) to the antibacterial actions of the other herbs used with it; it is analgesic, helping with pain; it is anti-inflammatory; if you are treating inflammatory infections, its specific actions there will help immensely; and if you are treating CNS problems, it will, in addition to helping other herbs get to the affected area, add its own neuroprotective actions to the mix.
Black pepper and piperine also possess a number of efflux inhibition actions. Piperine inhibits the NorA efflux pump in Staphylococcus aureus. It also inhibits ethidium bromide efflux. Ethidium bromide is a substrate for all the efflux pumps in Staphylococcus aureus (except NorC). Ethidium bromide is also a substrate in a number of efflux pumps in some Gram-negative bacteria—those that possess the SMR efflux pumps, and in Mycobacterium spp. Specifically, piperine has been found to be an inhibitor of the RV1258c efflux pump in Mycobacterium tuberculosis.
But perhaps the major strength of the plant and its constituent piperine is the effects they have on permeability glycoprotein (P-glycoprotein or P-gp) and CYP3A4. Black pepper and piperine are potent inhibitors of both.
All living organisms have to deal with one primary survival reality: determining what is me and not me and then identifying whether or not the “not-me” is going to be harmful to the “me.” There are a great many mechanisms that all organisms have to do this and they have a lot of options available for dealing with unsafe substances that “not-mes” can generate. Basically, they control access to their cells. In general, they all have four mechanisms for this: 1) assisted exclusion; 2) metabolic conversion; 3) solubilizer attachment; 4) reduction in assisted absorption. What this means in practical terms is this: When a substance is taken into the body and touches the GI tract membrane, an immediate identification process occurs. What is this thing? And is it safe? If the intestinal wall identifies it as harmful, then it can:
Exclude it; that is, use what is called an efflux pump or an efflux transporter to move the thing out, making sure it does not affect the cell/organism.
Metabolize it; that is, chemically turn it into something else that is not harmful, which is then either used or excreted from the cell/organism. The chemical substances that are thus created are called metabolites.
Attach it; that is, link the substance chemically to a highly water-soluble substance, often glucuronic acid. This creates a new compound that is unable to diffuse through cell membranes. It is then excreted in either urine or feces.
Reduce assisted absorption; that is, inhibit influx transporters. Assisted absorption involves the use of transporter proteins, a.k.a. influx transporters, in the lining of the intestinal wall. These proteins transfer useful substances into the cells of the intestinal wall and from there they are transported to the blood. Influx transporters are strongly active in moving such things as amino acids across the intestinal membrane. One of the most potent is gamma-glutamyltransferase (GGT). It is present in the cell membranes of the intestines, kidneys, bile duct, liver, spleen, heart, brain, and seminal vesicles.
All these responses make it harder for substances to get into the body and affect it. Many pharmaceuticals are considered to be foreign substances and, when these actions take place, up to 85 percent of a pharmaceutical may be inactivated, which is part of the reason doses are so high with some drugs.
Piperine affects all four of those mechanisms that control access to cells. It has particularly strong effects on efflux pumping, metabolization, glucuronic acid attachment, and GGT.
There are a number of efflux transporters. P-gp, or permeability glycoprotein, is one of the more prominent. P-gp is found mainly in the intestinal wall, kidneys, liver, brain, testes, adrenal gland, and uterus. It is also common in cancer cells and a few bacteria. You can visualize P-gp as a barrier lining the intestinal wall and choosing which substances to let into the body and, if so, how much (it also does this at the blood-brain barrier). Piperine significantly reduces the ability of P-gp to block incoming substances. As a result, if you take piperine or black pepper (or the traditional Ayurvedic blend trikatu), more of the medicinal will pass through the intestinal wall and into the bloodstream. Sometimes, the amount getting into the blood is substantially higher, up to 32 times its levels without piperine. This is why particular care needs to be taken if you are using piperine and are also taking pharmaceuticals. It is also why you should never take piperine with severe infections of the intestinal wall such as E. coli and cholera. Piperine would allow the bacteria to more easily infiltrate the intestinal wall and get deeper into your system.
CYP3A4 is one of the more important metabolizers in the human body. It affects the broadest range of substances (or substrates as they are called) of any of the CYP family of enzymes, affecting thousands if not hundreds of thousands of substances. It is a main metabolizer in the intestinal wall and liver. Generally, it does one of two things: converts a substance to another that has lower biological activity or makes substances more water soluble, which reduces their ability to move into cells. Inhibition of CYP3A4 means that the substance is left in its original, highly bioactive form when it gets into the body. Piperine strongly inhibits CYP3A4. (It has also been found to inhibit CYP1A2, CYP1A1, and CYP2D6.)
Piperine/black pepper also inhibits AHH or aryl hydrocarbon hydroxylase, which metabolizes aromatic hydrocarbons. (This makes piperine useful for enhancing the impact of herbs like juniper berry, which is high in aromatic hydrocarbons, in the treatment of UTI.)
Piperine/black pepper also strongly inhibits UDP-glucuronyl-transferase (a.k.a. UGT). UGT is the enzyme that attaches glucuronic acid to xenobiotics to facilitate their removal from the body. This action by piperine increases the time that foreign substances, e.g., herbs or pharmaceuticals, remain in the body/bloodstream prior to elimination, from 2 to 4 hours longer.
Piperine/black pepper also significantly stimulates the activity of the influx transporter GGT, increasing the movement of substances across the intestinal membrane.
Piperine, and black pepper, thus increase the amount of any substance going into the body, keep it in its most potent form (unmetabolized), and keep it in the body longer. Piperine/black pepper also, for similar reasons, facilitates the movement of substances into the brain and CNS, uterus, testes, adrenals, kidneys, and liver. If any of those systems are being treated for disease, for example, bacterial meningitis or hepatitis C, piperine will increase the amount of herb getting to the meninges or the liver.
At the same time piperine/black pepper stimulates circulation and increases blood vessel size so that the substances are widely circulated throughout the body very rapidly.
A number of studies have looked at the actions of black pepper and piperine along these lines. Most studies have occurred with piperine. However, there has been some work with trikatu, the traditional Ayurvedic blend of the two peppers and gingerroot.
In vivo, goats, pharmaceuticals: If trikatu was preadministered to mountain goats before their treatment with pefloxacin (a fluoroquinolone antibiotic used in India in veterinary practice), the drug levels in the body and its penetration into various parts of the body were substantially increased. Other studies have found that trikatu increases the bioavail-ability of vasicine and indomethacin.
Human clinical study, pharmaceuticals: Trikatu increased the concentrations of vasicine by over 200 percent and sparteine by over 100 percent in the blood plasma of human volunteers.
In vivo, mice/rats, pharmaceuticals: Piperine increased the effects of pentobarbital-induced hypnosis in mice. Blood and brain pentobarbital levels were higher in treated animals; piperine also prolonged hexobarbital sleeping time and zoxazolamine paralysis; enhanced the bioavailability of aflatoxin B1; enhanced the bioavailability of etoposide; increased the bioavailability of nimesulide, thus allowing the use of reduced, and safer, doses; and delayed elimination of phenytoin.
In vivo, mice/rats, herbs: Piperine increases the movement of radio-labeled L-leucine, L-isoleucine, and L-valine across the intestinal wall, enhancing uptake; increases the uptake of curcumin and its presence in serum; and increases plasma levels of epigallocatechin gallate from green tea.
Human clinical study/trial, pharmaceuticals: A single oral dose of propranolol (40 mg) or theophylline (150 mg) alone or in combination with piperine (20 mg) was given each day for 7 days. Increased oral bioavailability was found in the piperine group. A single dose of piperine (20 mg) administered with phenytoin significantly increased the mean plasma concentration of phenytoin; a crossover, placebo-controlled study found that piperine increased the bioavailability of nevirapine, increased its mean plasma concentrations, and reduced its elimination from the body; another study found it increased the bioavailability of vasicine and sparteine.
Human clinical trial/study, herbs: A crossover study with volunteers given 2 grams curcumin found that its serum levels were either undetectable or very low. When piperine was administered with the curcumin, serum levels were 2,000 percent higher. Piperine enhanced bioavailability, serum concentration, and extent of absorption; a double-blind study found that piperine (5 mg) increased plasma concentrations of CoQ10 by 30 percent.