Neuropharmacology of Selected Herbal Substances: A Learning Module for Patient-Physician Interaction and Interviewing Course

INTRODUCTION

Most medical education programs include a course in which one learning outcome goal is developing appropriate patient-physician interaction and interviewing skills. Included is the importance of obtaining an accurate medication history. To achieve this goal it is important to identify topics for discussion and illustration that will underscore the importance of developing communication skills, provide insights into patient behaviors that affect their health and provide relevant information about medical or public health issues that may not be adequately addressed elsewhere. One such topic is patient self-medication with “over the counter” preparations, “natural” products -including herbal substances, and dietary supplements.

A faculty facilitator leads student discussions on the issue of patient self-medication with herbal substances and physician responses to this behavior. The objectives of these discussions are as follows:
* Introduce students to the range of alternate therapies.
* Consider how patient safety can be assured and how the potential dangers in self-medication with herbal or other substances can be identified.
* Discuss physician resistance to the use of efficacious herbal therapies.
* Understand the dynamics of patient self-medication behaviors.
* Appreciate the significance of scientifically sound pharmacological and clinical data.
* Understand the necessity of assessing the safety and efficacy of a therapeutic regimen.

Introduction to the Learning Module

The learning module described here focuses on the issue of patient self-medication with herbal substances, specifically St. John’s Wort (SJW), Feverfew (FF), Ginkgo biloba (GB) and Valerian (VAL), four herbs commonly used for nervous system complaints.

Biochemistry and pharmacology courses usually provide little, if any, well-documented scientific or clinical information about herbal medications. Because herbal preparations are advertised as natural products and classified as dietary supplements by government regulatory agencies, most patients and many clinicians do not equate herbal preparations with conventional prescription drugs. Additionally, they assume that substances called “natural” are therefore safe. However, numerous studies document that herbal substances can evoke untoward side effects and important drug interactions. Patients frequently will not readily reveal their self-medication behaviors to interviewing physicians for fear of ridicule or because they do not consider herbal products as “medicine”.

Herbal medications have been used to treat neurological symptoms since ancient times and in recent years their use as self-medication preparations has greatly increased. Current research results indicate that some herbs contain specific, pharmacologically active compounds and can be appropriate treatments for selected patients with neurological complaints. Importantly, there is mounting evidence of significant dangerous side effects and drug interactions for some patients taking herbal medications (See references below). This learning module will introduce students to available evidence describing the efficacy, mechanisms of actions and safety of the active compounds in SJW, FF, GB and VAL in treating neurological complaints.

Many herbal medications are reported to alleviate neurological conditions by affecting cerebral blood flow while others may interact with neurotransmitter and neuropeptide receptor mechanisms. For example, the hypericin in SJW is effective in treating mild to moderate depression, the parthenolide in FF relieves migraine in some patients, the glycoside quercetin in GB has been shown to increase cerebral blood flow and augment cerebral function, and the valepotriates, valeric acid and sequiterpenes in VAL exert a sedative effect. Relevant references to pharmacological and clinical studies on the usefulness and safety of herbal medications are summarized below. Images and chemical formulae of the herbal medicines appear in the appendix.

Learning Module Discussion Points

GINKGO BILOBA
(Maidenhair tree, Kew tree)

Active ingredients
Quercetin & Quercitrin, Ginkgolides A and B and Bilobalide, a terpinoid.

Clinical use
Cerebrovascular insufficiency syndrome, ^{1, 2, 3, 4, 5}
Dementia and Alzheimer syndrome. ^{1, 4, 6, 7, 8, 9}

Significant pharmacological actions proven in human studies.
1)Increases cerebrovascular perfusion^{.1, 5, 6, 9, 10, 11}
2)Decreases blood viscosity. ^{5, 6, 10}
3)Platelet activating factor antagonist. ^{12, 13}
4) Decreases cytotoxicity produced by free radicals and oxidative stress.^{14, 15, 16, 17}

Pharmacological actions demonstrated in laboratory.
1)Diminishes cytotoxic nitric oxide metabolites released from human endothelial cell cultures. ¹⁷
2)Attenuates neuronal apoptosis following oxidative stress in rat tissue in vitro. ^{16, 18}
3)Bilobalide is a potent inhibitor of NMDA (N-methyl-d-aspartate) receptor-induced phospholipase-?2 and associated degradation of brain phospholipid in rat hippocampus.¹⁹
4)There is dose-dependent excitation by Bilobalide of rat hippocampal CA1 neurons by disinhibition of GABAergic (gamma aminobutryic acid)transmission. ²⁰
5)Augmentation of GABA and glutamic acid has been demonstrated by Bilobalide in mouse cortex and hippocampus. ²¹
6)MAO (monoamine oxidase) inhibition has been reported in laboratory studies²² however, PET scan studies have not substantiated this effect in humans.²³

Favorable Clinical effects.
1)Improved vigilance and attention.^{1, 2, 3, 4, 5}
2)Slowing of cognitive function and memory decline in elderly patients.^{1, 2, 3, 4,5}
3)Slowing of decline of cognitive function in Alzheimer patients.^{6, 7, 8, 9}
4)Stabilization and improvement in social functions in Alzheimer patients.⁹
5)Potentiation of EEG ? waves.^{5, 24}
6)Diminished EEG ?, ? and ? waves.^{5, 24}

Warnings
1) Should not be combined with anticoagulant therapy or aspirin therapy.²⁴
2)Safety during pregnancy unknown.

FEVERFEW
(Tanacetum parthenium, Bachelor’s Button, Mutterkraut, Chamomile grande)

Active ingredients
Parthenolide (sesquiterpene lactone).
Parthenolide must be present in sufficient quantities (600
gm) to be effective.

Clinical use
Migraine prophylaxis.^{25, 26}

Significant pharmacological actions – proven in human studies.
1)Inhibits vasodilatation and other inflammatory responses by:
a) Inhibition of the Serotonin release from platelets.^{27, 28, 29}
b)Inhibition of leukocyte functions.^{28, 29, 30}
c)Inhibition of leukotriene synthesis.^{28, 29, 30}
d)Inhibition of prostaglandin synthesis. ^{28, 29, 31}

Favorable Clinical effects
1)Decreased frequency and severity of migraine attacks.^{25, 26, 32}
2)Decreased nausea associated with attacks.^{25, 26, 32}
3)No reported long-term (4-month) adverse effects.²⁶

Warnings
1) Not recommended for patients with a history of clotting disorder.^{26, 27, 28, 32}
2)May interact with non-steroidal anti-inflammatory drugs.³¹
3)”Post-Feverfew syndrome”, a condition which occurs in some patients when they abruptly terminate FF medication may occur, it includes mild anxiety, tension headache, insomnia and joint discomfort. ^{26, 32}
4)FF is an abortifactant. It is contraindicated for use in pregnant patients, may induce uterine contractions.³²
5)Not recommended for patients sensitive to plant products.³²
6)Patients may develop oral ulcers with extended use.^{25, 26}
7)Patients may develop gastric discomfort.²⁵
8)Its unpleasant taste may lead to noncompliance.^{26, 32}
9)No safety data available to support use in children.^{26, 32}
Note: Reports that FF mitigates symptoms of rheumatoid arthritis have not been substantiated.^{26, 27, 32}

ST. JOHN’S WORT
(Hypericum perforatum, Johanneskraut, Blutkraut, Herrgottsblut, Walpurgiskraut, Hexenkraut)

Active Ingredients³³
Hypericin, Pseudohypericin (naphthodianthrones), Hyperforin (phloroglycinol), Quercetin and Quercitrin (flavonoids).

Clinical use
1)Treatment of mild to moderate depression equivalent to TCA (tricyclic antidepressent) and SSRI (selective serotonin re-uptake inhibitor) drugs based on the Hamilton Depression score. SJW components appear to be free of the side effects associated with TCA or MAOI (MAO inhibitor)classes of drugs.^{34, 35, 37, 38, 39, 48, 49}
2)Treatment for seasonal affective disorder. ^{34, 38, 40}
Note: Hyperforin in Hypericum extract exerts the most prominent anti-depressant effect.^{38, 42, 43}

Significant pharmacological actions proven in human studies.
Hypericum (SJW) extract often contains a mixture of several compounds which have different actions.³³
1)Hypericin, Pseudohypericin, Hyperforin:
a)Inhibit the re-uptake of serotonin in a dose-dependent manner.^{35, 41, 42}
b)Inhibit the re-uptake of dopamine, GABA and norepinephrine.^{41, 43}
c)Promote the release of serotonin and norepinephrine.⁴¹
d)Produce a weak inhibition of monoamine oxidase activity.^{44, 45, 46, 47}
e)Contribute to antiviral activity, including that of the HIV(Human Immunodeficiency Virus) through the inhibition of protein kinase-C by Hypericin.^{41, 44}
f)Induces hepatic cytochrome-P450 enzymes.⁴⁴ This action possesses a significant problem because it lowers the serum concentration of many commonly used medications.⁴⁷ For example: interferes with a cancer chemotherapy drug and with Idiniver, an important HIV drug. ⁴⁷

Pharmacological actions demonstrated in laboratory.
1)Induces the drug transporter P-glycoprotein in the gut.⁴⁸
2)Hyperforin augments ionic conductance in rat hippocampal neurons and GABA receptor-mediated responses.⁴⁸
3)Hyperforin is an NMDA receptor antagonist.⁴⁸
4)Quercetin and Quercitrin are reported to inhibit MAO.^{44, 46} Note:one study disputes the validity of MAO inhibition.³³
5)Interacts with GABA receptor.^{43, 45, 46}
6)Inhibits protein kinase-C activity.^{41, 44}

Warnings
The drug interactions and contraindications associated with St. John’s Wort are important and varied.
1)It is contraindicated with concomitant use of the following drugs: SSRI or MAOI drugs, lithium, ympathomimetic amines, anticholinergic drugs, barbiturates, non-prescription cold remedies and diet aids.^{34, 35, 36, 45, 46, 50}
2)Reduces plasma levels of:
a)Digoxin.⁵¹
b)Anti-rejection drugs (Ciclosporin, Cyclosporin).⁵³
c)Anti-AIDS drugs (Idiniver).⁵⁴
d)Warfarin (Coumadin).⁵⁵
e)Contraceptive steroids in humans,⁵⁵ probably by induction of hepatic cytochrome P450 enzymes ^{44, 51, 52, 53, 54, 55} and of drug transporter P-glycoprotein in the gut.^{49, 53, 55})
3)Drug interactions or ingestion of large amounts of St. John’s Wort extract may produce “serotonin syndrome”: severe myoclonus, hyperpyrexia, sweating, seizures and coma.^{45, 46}
4)Phototoxicity has been reported after long term use of large doses.^{34, 36}
5)Dry mouth, gastric distress and insomnia may occur.⁴⁴
6) The safety of SJW has not been demonstrated for pregnant and nursing mothers or for children.

Other important considerations
In contrast to most psychotropic medications there is no evidence that SJW will interact with ethanol.^{34, 36}

VALERIAN
(Valeriana officinalis, Katzenkraut, Baldrianwurzel)

Active ingredients
Valerenic acid, Valeranone, Homobaldrinal, Kessyl glycol (sesquiterpines, valepotriates), Borneol (monoterpene)
These components all hydrolyze readily, raising concern about the availability of active compounds in therapeutic preparations.⁵⁶

Clinical use
1) Relieves insomnia and sleep pattern
disturbances.^{56, 57, 58, 59, 60}
2)Relieves anxiety and produces mild sedation.^{59, 60}

Significant pharmacological actions proven in human studies.
1) Exerts a benzodiazepine-like effect.⁶²
2)Activates GABAA receptors.⁶³

Pharmacological actions demonstrated in laboratory.
1)Inhibition of GABA re-uptake.
2)Potentiation of potassium stimulated calcium dependent GABA release (rat tissue).^{61, 62}

Favorable Clinical effects.
1)Anxiolytic effect,^{57, 59} which is as effective as benzodiazepines.⁵⁸
2)Normal sleep patterns are restored.^{56, 57, 58, 59, 60, 64}
3)Sedative effect without “hangover”.^{60, 64}
4)Asian Valerian species contain kessyl glycol, which is more efficacious as a smooth muscle relaxant.⁵⁶

Pharmacological actions demonstrated in laboratory.
No carcinogenic effect in mice.

Warnings
1)Competes with benzodiazepines and barbiturates, but does not interact with ethanol.^{60, 64}
2)Clinical data following extended use are not available.
3)Safety for pregnant patients and children not available.
4)Patients are advised not to operate vehicles or machinery while using VAL
5) Some evidence of liver damage following extended use.⁶⁵

Utilization
The following are examples of scenarios that could be used to facilitate small group discussion. They can be easily adapted for Patient Based Learning modules. Alternatively, the scenarios can be provided to the students in advance to stimulate discussion in a larger classroom setting. The scenarios are designed to incorporate many other discussion issues regarding patient education, treatment and concerns.

The first class session should consist of the faculty facilitator briefly introducing the topic of alternative and complementary medicine. This emphasizes the fact that patients are using many herbs and dietary supplements and that they are frequently hesitant to discuss these treatments with their physician.

The students are asked to take an anonymous written poll to disclose what alternative and/or complementary medications they or close family members are currently using. Collecting this information in class and tabulating the results will emphasize the widespread use of these products. The results of the poll are discussed, including voluntary disclosure of how they became aware of the products or who recommended them. Subsequently, the facilitator introduces the objectives of the learning module. The rationale for selecting St. John??bf?s Wort, Feverfew, Valerian, and Ginkgo Biloba as self-medication examples is described in the introduction to the learning module.

A brief presentation of the chemical and trade names for these four herbal compounds, their active chemical ingredients and their purported effects are described (See “Introduction to the Learning Module”). This can include a discussion by the class of the information on the labels of the products, as well as why they continue to be considered dietary supplements and are not regulated by the Federal Food and Drug Administration (See “Learning Model Discussion Points”).

Subsequently, subgroups or individual students are assigned key references describing pharmacological actions, favorable clinical effects and warnings regarding safety for each herbal remedy. Students are instructed to summarize assigned articles for presentation and group discussion in subsequent classes paying particular attention to the adequacy of the reported data, side effects and cost of recommended dosages/month. (See “Learning Model Discussion Points”)

Following the class reports described above students are given copies of the four clinical presentations below. Each history is read aloud. The facilitator guides the discussion of the clinical use and safety of the herbal substances given in the history provided by the patient or family. Students decide what advice should be conveyed to the patient and family. Students are asked to explain the rationale for their advice based on their understanding of the pharmacological effects and hazards of self-medication and information obtained from the summaries of relevant references.

A discussion of the physician’s attitudes regarding these substances follows. It is important that the physician become knowledgeable about these medications and equally important that they build trust in their patient-physician relationship to assure that patients disclose all pharmacologically active substances they are consuming.

FEVERFEW

A 21-year-old college student presents to the student health services because she tested positive on two home pregnancy tests during the past week. Her menses are overdue by 14 days. She is sexually active and is not currently taking contraceptives. She states that she uses contraceptive foam “most of the time”. She is a good historian and provides a long history of severe migraine headaches. She reveals that on the advice of a friend who works in a health food store she has been taking Feverfew daily for the past two years. The duration, intensity and frequency of her headaches have been significantly reduced over that time. She is unsure about continuing this pregnancy and asks your advice.

GINKGO BILOBA

A 72-year-old male is brought to the Emergency Department with a complaint of melena. Approximately three years ago he was diagnosed with mitral stenosis. Following a thrombotic CVA he was placed on Coumadin. He has been stable on 5 mgm of Coumadin for the past year. Until recently he had clotting studies checked on a routine basis. His recovery from the CVA has been complete and he has no discernible residual difficulties.

Because his children were concerned about him living alone in a fairly distant city they convince him to move in with one of his children. He has been with his oldest son and daughter-in-law for about three weeks.

The patient is a good historian and is able to give a very complete history of his prescriptions. When asked about over the counter medications he denies taking aspirin or NSAIDS but indicates that the daughter-in-law has been giving him “some vitamins”.

Questioning of the daughter-in-law yields the information that she has supplemented his medication regimen with Vitamin C and Vitamin E. She tells the doctor that she knows those will help her father-in-law ward off disease and “think better”. The doctor asks her if she is giving him any other supplements and she replies, “Yes, my husband and I take ginkgo tablets every day so we don’t get senile and we give Dad some too.”

ST. JOHN’S WORT

A 17-year-old female is brought to your office by her grandmother. Her history includes amenorrhea, weight loss and complaints of exhaustion. Her grandmother states that she cries a lot and rarely leaves the house. She has done everything she can think of but the child will not “get over it”. Further questioning reveals that the girl’s boyfriend was killed in an automobile accident after graduation this spring. She has been at the grandmother’s house in Pikeville, KY for three months. Because of her profound sorrow immediately after the boy’s funeral and her loss of interest in taking care of her personal needs, eating or socializing, the family felt it might help if the girl was in a different environment. The girl and the grandmother had always had a close and loving relationship. Quite incidentally the grandmother tells you that even the special tea she has been making for her has not helped.

VALARIAN

A 50-year-old woman in good health comes to your office for her yearly GYN appointment. In answer to your inquiry about her current medications she discloses that she drinks a cup of tea with Chamomile and Valerian before she goes to bed every night because it helps here sleep a little better. She also lists Vitamin C, Vitamin E and Glucosamine with Chondroiton as daily medications. The woman states that she is pleased that she has taken far fewer doses of Ibuprofen or Naprosyn since she started this regimen. Additionally, she reveals that she occasionally uses Kessyl Glycol as needed for muscle strain.

Evaluation
The students will be expected to include specific questions about patients’ self-medication behaviors in their subsequent exercises in patient interviewing. Additionally, they will be expected to demonstrate an understanding that while herbal medications and other alternative medications can exert useful pharmacological actions, they can have dangerous side effects and may compete or enhance the effects of allopathic medications.

CONCLUSIONS

Learning module on herbal medications will:
* Emphasize the necessity for physicians to obtain a full medication history from each patient specifically inquiring about use of herbal medications, dietary supplements and “over-the-counter” preparations.
* Encourage students to consider evidence presented in well-controlled basic and clinical studies that demonstrate the advantages and dangers of herbal medications.
* Provide students a better understanding of the cellular and molecular mechanisms of action of herbal medications.
* Alert students to important untoward effects and significant interactions that can occur when herbal medication is combined with conventional drug therapy.

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