Botanical Medicine—A Modern Perspective

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Chapter 33 Botanical Medicine—A Modern Perspective

Michael T. Murray, ND

Chapter Contents 33

Introduction

The Role of Herbs in Modern Pharmacy

Science Has Fueled the “Herbal Renaissance”, 
The Advantages of Herbal Medicines, 

The Study of Herbal Medicine

The History of Herbal Medicine, 
In the Beginning, 
Materia Medicas, 
Galen’s Influence, 
The Black Plague and Syphilis, 
Challenges to Galenical Medicine, 
The Thomsonian and Eclectic Movements, 
The Growth of the Pharmaceutic Industry, 

Final Comments

image Introduction

The term herb refers to a plant used for medicinal purposes. Are herbs effective medicinal agents or is their use merely a reflection of folklore, outdated theories, and myth? To the uninformed, herbs are generally thought of as ineffective medicines used before the advent of more effective synthetic drugs. To others, herbs are simply sources of compounds to isolate and then market as drugs. However, to some, herbs and crude plant extracts are effective medicines to be respected and appreciated.

For many people of the world, herbal medicines are the only therapeutic agents available. In the late 1990s, the World Health Organization estimated that about 80% of the world’s population relies on herbs for primary health care needs.1 This widespread use of herbal medicines is not restricted to developing countries, since it has been estimated that 70% of all medical doctors in France and Germany regularly prescribe herbal preparations.

Although herbal medicine has existed since the dawn of time, knowledge of how plants actually affect human physiology remains largely unexplored. Many individuals formulate their view of herbal medicine based on opinion, philosophy, and ideology. This chapter seeks to facilitate an informed view of herbal medicine. The past and future of herbal medicines are discussed. We believe that the continued evolution of the tradition of herbal medicine can only be accomplished within the context of continued scientific investigation.

Throughout the world, but especially in Europe, the United States, Canada, Australia, and Japan, a tremendous renaissance in the use and appreciation of herbal medicine occurred in the latter part of the twentieth century. For example, in the United States, the sale of herbal products skyrocketed from $200 million in 1988 to more than $3.5 billion in 1997 before leveling off in the $4 billion a year range (Table 33-1). Within the European Community annual sales exceeded $7 billion in 1997.2

TABLE 33-1 Total Estimated Herb Sales in the United States 1994-2005

YEAR $ TOTAL SALES (MILLIONS) % INCREASE (-DECREASE)
1994 2020  
1995 2470 22.3
1996 2990 21.1
1997 3557 19.0
1998 4002 12.5
1999 4110 2.7
2000 4260 3.7
2001 4397 3.2
2002 4276 −2.8
2003 4178 −2.3
2004 4320 3.4
2005 4410 2.1

Data from Ferrier GKL, Thwaites LA, Rea PR, et al. U.S. consumer herbal and herbal botanical supplement sales. Nutr Business J. 2006. http://www.nutritionbusiness.com.

The rebirth of herbal medicine, especially in developed countries, is largely based on a renewed interest by the public and scientific researchers. During the past 20 to 30 years, there has been a huge increase of scientific information concerning plants, crude plant extracts, and various substances from plants as medicinal agents. For example, a PubMed search of the term “herbal medicine” yielded over 1300 hits in 2010. However, the number of studies of botanical medicines is much higher. For example, there were 130 studies published on Ginkgo biloba alone in 2010.

image The Role of Herbs in Modern Pharmacy

Plants still play a major role in modern pharmacy. For the past 50 years, about 25% of all prescription drugs in the United States and other developed countries have contained active constituents obtained from plants. Digoxin, codeine, colchicine, morphine, vincristine, and yohimbine are some popular examples. Many over-the-counter (OTC) preparations are also composed of plant compounds. Pharmacognosy, the study of natural drugs and their constituents, plays a major role in current drug development. Unfortunately, the standard path of the approval of a drug is a process that typically takes 10 to 18 years at a total cost of roughly $250 million (Table 33-2).

TABLE 33-2 Classic Examples of Drugs From Plants With a Correlation to Its Traditional Use

DRUG CLINICAL USE BOTANICAL SOURCE
Atropine Anticholinergic Atropa belladonna
Caffeine Central nervous system stimulant Cola nitida
Camphor Rubefacient Cinnamomum camphora
Cocaine Local anesthetic Erythroxylon coca
Codeine Analgesic/antitussive Papaver somniferum
Colchicine Antigout Colchicum autumnale
Digitoxin Cardiotonic Digitalis purpurea
Digoxin Cardiotonic Digitalis lanata
Emetine Amebicide/emetic Cephaelis ipecacuanha
Ephedrine Sympathomimetic Ephedra sinica
Gossypol Male contraceptive Gossypium spp.
Hyoscyamine Anticholinergic Hyoscyamus niger
Kawain Tranquilizer Piper methysticum
Methoxsalen Psoriasis/vitiligo Ammi majus
Morphine Analgesic Papaver somniferum
Noscapine Antitussive Papaver somniferum
Physostigmine Cholinesterase inhibitor Physostigma venenosum
Pilocarpine Parasympathomimetic Pilocarpus jaborandi
Podophyllotoxin Topical wart remedy Podophyllum peltatum
Quabain Cardiotonic Strophanthus gratus
Quinine Antimalarial Cinchona ledgeriana
Reserpine Antihypertensive Rauwolfia serpentine
Scopolamine Sedative Datura metel
Sennosides Laxative Cassia spp.
Theophylline Bronchodilator Camellia sinensis
Tubocurarine Muscle relaxant Chondrodendron tomentosum
Yohimbine Male erectile dysfunction Pausinystalia yohimbe

Data from De Smet PA. Drugs 1997;54:801-840.

Because a plant cannot be patented, plants are screened for biological activity and then the so-called “active” constituents (compounds) are isolated and typically chemically modified to produce unique substances. If the compound is powerful enough, the drug company begins the process to procure Food and Drug Administration (FDA) approval. Of 520 new drugs approved by the FDA or comparable entities in developed countries, 30 came directly from natural product sources and another 173 were either semisynthetic from a natural source or modeled after a naturally occurring compound.1

Because of the expense and lack of patent protection, few clinical evaluations were done before 1980 on whole plants or crude plant extracts as medicinal agents per se. A key factor in contributing to more research into herbal medicines after this time was the development in Europe of regulatory policies and practices that made it economically feasible for companies to do research. For example, in Germany, regulations allow herbal products to be marketed with drug claims if they are proven to be safe and effective.3 Whether the herbal product is available by prescription or OTC is based on its application and safety of use. Herbal products sold in pharmacies are reimbursed by insurance if they are prescribed by a physician.

The proof required by a manufacturer in Germany to illustrate safety and effectiveness for an herbal product is less (and more appropriate) than the proof required by the FDA for drugs in the United States. In Germany, a special commission (Commission E) developed a series of 400 monographs on herbal products similar to the OTC monographs in the United States. A herbal product is viewed as safe and effective if a manufacturer meets the quality requirements of the monograph or produces additional evidence of safety and effectiveness that can include data from existing literature, anecdotal information from practicing physicians, and limited clinical studies. In contrast, in the United States, extracts that are identical to those approved in Germany as drugs are available as “dietary supplements,” yet manufacturers are prohibited from making any therapeutic claims for their products. No medicinal claims are allowed for most herbal products in the United States because the FDA requires the same standard of absolute proof as required for new synthetic drugs. Thus far, the FDA has rejected the idea of establishing an independent “expert advisory panel” for the development of monographs similar to Germany’s Commission E monographs, as well as other ideas to create a suitable framework for the marketing of herbal products in the United States.

The monograph system in Germany allowed companies to market their products according to the guidelines of Commission E. With the ability to make appropriate claims, many companies achieved success with their products and were enabled to fund the necessary research to gain greater acceptance within mainstream, conventional medicine. The use of St. John’s wort extract in the treatment of depression is a perfect case in point to illustrate how Commission E monographs led to significant documentation of the efficacy of plants with a long history of folk use for depression.

When the Commission E monograph for St. John’s wort came out in 1984, it identified the constituent hypericin as the active constituent and permitted the medicinal use of the herb (in average doses of 2 to 4 g of herb, or 0.2 to 1 mg total hypericin) for depression, anxiety, or nervous excitement.

Originally, it was thought that hypericin acted as an inhibitor of the enzyme monoamine oxidase, thereby resulting in the increase of central nervous system monoamines such as serotonin and dopamine. However, it was later shown that St. John’s wort does not inhibit monoamine oxidase in vivo.4 The antidepressant activities appear to be related more to serotonin reuptake inhibition as occurs with the drugs Prozac, Paxil, and Zoloft; modulation of neuroendocrine function; downregulation of β-adrenergic receptors; and upregulation of serotonin receptors in the brain areas that are implicated in depression.4,5 In addition, it appears that although hypericin is an important marker, other compounds such as flavonoids are also thought to play a major role in the pharmacology of St. John’s wort. The key point here is that the further understanding and documentation of clinical effectiveness of St. John’s wort extract was largely the direct result of a commercial incentive created by the existence of Commission E.6

Science Has Fueled the “Herbal Renaissance”

Improvements in analytic techniques and modern pharmacology have given researchers the tools and understanding necessary to evaluate herbal medicines properly. Improvements in plant cultivation techniques and the quality of herbal extracts (quality control and standardization) have also led to the development of some effective plant medicines. These advances have created a renaissance in the appreciation and use of herbal medicine. It seems that science and medicine have finally advanced to a level where nature can be appreciated rather than discounted. The scientific investigation of plant medicines is replacing some of the mystery and romance of herbalism with a greater understanding of the ways in which herbs work. Thirty years ago it was impossible to determine exactly how herbs promoted their healing effects because analytic science had not advanced to a sufficient level of sophistication. This point is well illustrated by the fact that the main mechanism of action responsible for aspirin’s anti-inflammatory effect was not understood until the early 1970s, and its mechanism of action for pain relief has yet to be fully understood.

Because the mechanism of therapeutic action of a particular herb could not be fully elicited, many effective plant medicines were erroneously labeled as possessing no pharmacologic activity. Now, researchers equipped with greater understanding and more sophisticated technology are rediscovering the wonder of plants as medicinal agents. Much of the increased understanding is, interestingly, a result of synthetic drug research.

For example, one of the modern classes of drugs is calcium channel blockers. These agents block the entry of calcium into smooth muscle cells, thereby inhibiting contraction and promoting muscular relaxation. Calcium channel blocking drugs are currently being used in the treatment of high blood pressure, angina, asthma, and other conditions associated with smooth muscle contraction. They represent a highly evolved stage of modern drug pharmacy. After calcium channel drugs became better understood, it was discovered that many herbs contain components that possess calcium channel blocking activity. In most cases, the historical use of these herbs corresponded to their calcium channel blocking activity.

In addition to possessing currently understood pharmacologic activity, many herbs possess pharmacologic actions that are not consistent with modern pharmacologic understanding. For example, often an herb appears to affect homeostatic control mechanisms to aid normalization of many bodily processes. When there is a hyperstate, the herb has a lowering effect, and when there is a hypostate, it has a heightening effect. This action is totally baffling to orthodox pharmacologists, but not to experienced herbalists who have used terms such as alterative, amphoteric, adaptogen, or tonic to describe this effect.

The Advantages of Herbal Medicines

In general, herbal preparations are thought to have three major advantages: lower cost, fewer side effects, and medicinal effects that tend to normalize physiologic function. When used most effectively, the mechanism of action of an herb often corrects the underlying cause of a disorder. In contrast, a synthetic drug is often designed to alleviate the symptom or effect without addressing the underlying cause. Interestingly, research has often shown for many plants that the whole plant or crude extract is much more effective than isolated constituents. In many instances, multiple components produce multiple pharmacologic actions.

Herbal medicine will certainly play a major role in future medicine. As modern medicine gains more knowledge and understanding about health and disease, it is adopting therapies that are more natural and less toxic. Lifestyle modification, stress reduction, exercise, meditation, dietary changes, and many other traditional naturopathic therapies are becoming much more popular in standard medical circles. This illustrates the paradigm shift that is occurring in medicine.

With the continuing advancement in science and technology, there has been a great improvement in the quality of herbal medicines available and in the understanding of their optimal clinical use. Improvements in cultivation techniques coupled with improvements in quality control and standardization of potency will continue to increase the effectiveness of herbal medicines.

image The Study of Herbal Medicine

The study of herbal medicine spans the breadth of pharmacology, the study of the history, source, physical and chemical properties, mechanisms of action, absorption, distribution, biotransformation, excretion, and therapeutic uses of “drugs.” In many respects, the pharmacologic investigation of herbal medicine is just beginning. This textbook is replete with examples of herbs whose historical use is being justified by new investigations into its pharmacology.

The History of Herbal Medicine

The history of the use of plants as medicines is full of interesting stories and fascinating facts. The evolution that occurred in herbal medicine over the centuries is only beginning to be recognized as more natural medicines gain acceptance. Interestingly, this acceptance is largely a result of increased scientific investigation.

A trend exists toward using natural substances, including compounds found in the human body, such as interferon, interleukin, insulin, and human growth hormone, as well as foods, food components, herbs, and herbal compounds. More and more researchers are discovering the tremendous healing properties of these natural compounds and their advantages over synthetic medicines and surgery in the treatment of many health conditions. Through these scientific investigations, a trend toward natural medicine is emerging. To better appreciate this evolutionary trend, this section presents some of the historical aspects of herbal medicine. Much of the following is derived from Barbara Griggs’ Green Pharmacy: A History of Herbal Medicine.7

In the Beginning

Plants have been used as medicines since the dawn of animal life. The initial use of plants as medicines by humans is thought to have been a result of “instinctive” dowsing. Animals in the wild still provide evidence that this phenomena occurs. Animals, with a few notable exceptions, eat plants that heal them and avoid plants that do them harm. Presumably humans also possessed this instinct at one time.

As civilizations developed, medicine men and women were responsible for transmitting the information on herbs to their successors. Before the advent of written language, this information was handed down by verbal and experiential means.

Besides instinctive dowsing, it was commonly believed that plants had been signed by the “creator” with some visible or other clue that would indicate its therapeutic use. This concept is commonly referred to as “the doctrine of signatures.” Common examples of this doctrine are the following:

• Panax ginseng (ginseng): its roots bear a strong resemblance to a human figure, and its general use is as a tonic.

• Caulophyllum thalictroides (blue cohosh): its branches are arranged like limbs in spasm, indicating its usefulness in the treatment of muscular spasm.

• Sanguinaria canadensis (bloodroot): its roots and sap are a beautiful blood color, corresponding to its traditional use as a “blood purifier.”

• Lobelia inflata (lobelia): its flowers are shaped like a stomach, corresponding to its emetic qualities.

• Hydrastis canadensis (goldenseal): its yellow-green root signifies its use in jaundice as well as infectious processes.

All of these uses have been confirmed by recent research.

Materia Medicas

With the development of written language, materia medicas (books containing prescribing information on herbs) became the vehicle of passing information about the medicinal use of herbs to future herbalists. Materia medicas were recorded in ancient China, Babylon, Egypt, India, Greece, and other parts of the world. From these materia medicas, it is quite obvious that herbal medicines were highly respected therapies in ancient times.

Galen’s Influence

No system, rules, or classification of Western herbal materia medicas existed until the first century AD, when Galen, the Greek physician who founded experimental physiology, established his system of rules and classification. Galen’s classification was based on Hippocratic medicine (i.e., balance of the four humors: blood, yellow and black bile, and phlegm) and a profound belief in a beneficent nature. Although his system is considered seriously flawed in the light of modern medical knowledge, Galen is historically considered to be the founder of scientific herbalism.

Galen evaluated and classified each plant according to its relation to Hippocratic medical theory. Although based initially in Hippocratic principles, Galen constructed his own elaborate, and rigid, system of medicine. Galen’s work also signified the beginning of a clear division between the professional physician and the traditional healer. As only the well educated could understand Galen’s system, and even with the best schooling it remained a mystery to many, all challenges to the professional physician were effectively squelched by dogma.

Galen’s system dominated European medical thinking for 1500 years. Perhaps if the Roman Empire had continued to flourish, others would have surfaced to develop alternative theories. Instead, Galenical medicine reigned unchallenged throughout the Middle Ages. By the nineteenth century, the “professional” physician, confident in his supposedly superior knowledge, took Galenical philosophy to an extreme probably never imagined by Galen, by the adoption of bloodletting, purging, and administering exotic medicines. This was in direct contrast to the traditional healer’s patient use of traditional herbs and tremendous faith in the healing power of nature.

The Black Plague and Syphilis

Although Galenical medicine dominated the Middle Ages, herbal medicine was still deeply entrenched in European culture. The Black Plague of 1348 may have been the beginning of change in medical thought, since conventional medicine was totally useless. As nearly one third of Europeans died during this plague, the public began to lose faith in Galenical medicine. Nearly 150 years later another blow was dealt to Galenical medicine, when syphilis became the major medical problem. Unlike the Black Death, patients with syphilis tended to survive longer, giving physicians more time to experiment with treatments. At this time, perhaps the greatest hoax in the history of medicine began. Mercury became the standard medical treatment for syphilis despite the fact that even Galen thought mercury too poisonous to use.

Syphilis did, however, open the door for the use of some new herbs from the Americas. A French physician, Nicholas Monardes, published a comprehensive account of sarsaparilla and several other “new” drugs in the treatment of syphilis in 1574. Many Europeans at the time believed that syphilis had come to Europe from the West Indies with Columbus’s sailors, and because there was a general belief that whatever disease was native to a country might be cured by the medicinal herbs growing in that region, it was only natural for sarsaparilla to become a popular remedy. Because the standard treatment of syphilis was the use of mercury, which often resulted in greater morbidity than did syphilis, sarsaparilla was a welcome alternative. Despite initial excitement, Monardes’ sarsaparilla cure eventually lost favor, probably due to other components in the cure; specifically, patients were confined to a warm room for 30 days and for the following 40 days were required to abstain from both wine and sexual intercourse.

Although the public popularity of sarsaparilla waned, it continued to be used in the treatment of syphilis. During military operations in Portugal in 1812, a British Inspector General of Hospitals noted that the Portuguese soldiers suffering from syphilis who used sarsaparilla recovered much faster and more completely than their British counterparts who were treated with mercury.

Sarsaparilla was also used by the Chinese in the treatment of syphilis. Later clinical observations in China would demonstrate, through the use of blood tests, that sarsaparilla is effective in about 90% of cases of acute syphilis and 50% of cases of chronic syphilis.

Although sarsaparilla was clearly more beneficial than mercury in the treatment of syphilis, mercury was the standard medical treatment of choice for more than four and a half centuries. Some historians have stated that “the use of mercury in the treatment of syphilis may have been the most colossal hoax ever perpetrated” in the history of medicine. Mercury represented a new kind of medicine, one formulated and prepared in a laboratory using the new techniques of chemistry. It helped to prepare the way for future synthetic and mineral drugs at the expense of herbal medicines.

Challenges to Galenical Medicine

The 1500s also saw a strong challenge to Galenical medicine from within the traditional circles. Specifically, Paracelsus, an alchemist who believed strongly in the doctrine of signatures, was responsible for founding modern pharmaceutic medicine. Paracelsus is probably most remembered for the development of laudanum (tincture of opium). After Paracelsus, Galenical preparations and treatments fell greatly out of favor.

In public circles, herbal medicine was regaining some respect as well. In the early 1600s, Culpepper, an English pharmacist, published his book The English Physician. Instead of requiring patients to purchase expensive exotic or imported drugs, Culpepper recommended the herbs his clients and readers had growing in their own backyards. Although Culpepper’s herbal philosophy is based on astrologic rationalizations, it reinforced a strong English tradition of domestic herbal medicine. This came at a time when professional physicians were beginning to become contemptuous of herbal medicine.

Meanwhile, in the Americas during the 1600 and 1700s, herbs used traditionally by Native Americans were becoming quite popular, especially in the treatment of malaria and scurvy. Herbal medicine continued to gain even greater respect in the late 1700s, as exemplified by English physician Withering’s classic description of digitalis. However, mercury, bleeding, and purging were still the “standard” medical treatments, epitomized by George Washington’s death from complications incurred during treatment of a sore throat (i.e., he was bled to death).

The Thomsonian and Eclectic Movements

During the early 1800s, standard medicine may have been ready to reconsider traditional herbal remedies, but then came the Thomsonian movement. Samuel Thomson (1769-1843) patented a system of herbal medicine that, in 1839, claimed more than 3 million faithful followers. Although Thomson brought back to medicine the vitalistic Hippocratic idea of vis medicatrix naturae and gained widespread public support for the use of herbal medicine, the Thomsonian movement was probably detrimental to medical reform.

Thomsonians became locked in prejudice and dogma and insisted that all medical knowledge was complete and could be found in Thomson’s works. These and other claims roused scorn, indignation, rage, and resentment in the average North American doctor. Frequently based on purging through the use of herbal emetics, Thomson’s treatments were often as harsh as the standard treatments of the times (for further discussion, see Chapter 4).

During the 1800s, the eclectic movement attempted to bridge the gaps between standard medical thought, Thomsonianism, and traditional herbal medicines. Rather than attack the existing medical system, the eclectic movement sought to bring about reform by educating physicians about the use of herbal medicines. Several eclectic medical colleges were established and, for a while, it appeared that the eclectic movement was making headway in its attempt to reform the medical system from within.

The movement eventually failed, however. Several factors were probably responsible for this: a split in the ranks, which diluted the movement; harsh measures like mercury, calomel, and bloodletting were finally discarded by the conventional professional physician, due to a decrease in infectious disease as a result of improved sanitation and hygiene; and, perhaps most important, the failure to establish and sustain quality medical schools.

The Flexner report on medical education in 1910 spelled doom for the eclectics; by 1920, seven of the eight schools that had existed before the report closed, with the last school closing in 1938. Meanwhile, the standard medical schools, aided by the Rockefeller Foundation, flourished, promoting the growth of the modern pharmaceutic industry and the current near-monopoly of the medical profession.

The Growth of the Pharmaceutic Industry

Because a plant cannot be patented, little research was done before the latter part of the twentieth century. Instead, pharmaceutic firms and researchers screened plants for biological activity and then the so-called active constituents were isolated and chemically modified to produce unique, patentable compounds. Much to the dismay of the researchers was the discovery that in many instances the isolated constituents were less biologically active than the crude herb. Because the crude herb provided no economic reward to the American pharmaceutic firm, the crude herb or extract never reached the marketplace. In contrast, European policies on herbal medicines made it economically feasible for companies to research and develop phytopharmaceutics. The policies in the United States contributed to the tremendous growth of the pharmaceutic industry and loss of appreciation and respect for herbal medicine.

The herbal industry further compounded the problem by failing to provide quality herbal products or take advantage of technologic advances that allowed for standardization of chemical constituents. The herb that best exemplifies the failure to adopt standardization techniques is digitalis. One batch of crude digitalis might have a low level of active constituents, making the crude herb ineffective, whereas the next batch might be unusually high in active constituents, resulting in toxicity or even death, when standard amounts are used. The lack of standardization made it easier for U.S. pharmaceutic firms to rationalize their economic need to isolate, purify, and chemically modify the active constituents of digitalis so they could market these compounds as drugs. The problem with using the pure active constituent is that the safe dosage range is smaller: digitalis toxicity and death have increased dramatically as a result of purification. Toxicity was less of a factor when using the crude herb because overconsumption of potentially toxic doses resulted in vomiting or diarrhea, thus avoiding the severe heart disturbance and death that now occur with pure digitalis cardiac glycoside drugs.

Fortunately, several European and Asian pharmaceutic firms began specializing in phytopharmaceutics in the latter half of the twentieth century. These companies have played a prominent role in researching, developing, and promoting herbal medicines.

Research is demonstrating that crude extracts often have greater therapeutic benefit than the isolated “active” constituent. This has been long known in other parts of the world, but in this country, isolated plant drugs are still thought of as having the greatest therapeutic effect. This myth is gradually being eroded as our knowledge of herbal medicines increases.

If current standardization techniques had been available earlier in this century, it is possible that many current prescription drugs would be herbal extracts instead of isolated and modified active constituents or synthetic chemicals.

image Final Comments

Although the future looks extremely promising for herbal medicine, ultimately its growth and continued success will be determined by the following:

• Continued scientific investigation and clinical research

• Adoption by manufacturers of recognized standards of quality

• Governmental regulations that allow meaningful therapeutic claims

References

1. De Smet P.A. The role of plant-derived drugs and herbal medicines in healthcare. Drugs. 1997;54:801–840.

2. Mahady G.B. Global harmonization of herbal health claims. J Nutr. 2001;131(suppl 3):1120S–1123S.

3. Keller K. Legal requirements for the use of phytopharmaceutical drugs in the Federal Republic of Germany. J Ethnopharmacol. 1991;32:225–229.

4. Thiede H.M., Walper A. Inhibition of MAO and COMT by hypericum extracts and hypericin. J Geriatr Psychiatry Neurol. 1994;7:S54–S56.

5. Perovic S., Muller W.E.G. Pharmacological profile of hypericum extract. Effect of serotonin uptake by postsynaptic receptors. Arzneim Forsch. 1995;45:1145–1148.

6. Butterweck V. Mechanism of action of St. John’s wort in depression: what is known? CNS Drugs. 2003;17:539–562.

7. Griggs B. Green pharmacy. A history of herbal medicine. London: Robert Hale; 1981.

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