CENTER ON BEHAVIORAL MEDICINE

ADDITIONAL MATERIAL

EFFECTIVE TREATMENTS

    Alternative Approaches-Psychopharmacognosy:  Related Paper

Effective Treatments Index



Psychotropic Medications from Natural Products


Permission graciously given by the author to reproduce this paper

ALTERNATIVE THERAPIES, MAY 2000, VOL. 6, NO. 3

PSYCHOTROPIC MEDICATIONS FROM
NATURAL PRODUCTS: A REVIEW OF PROMISING
RESEARCH AND RECOMMENDATIONS

James Lake, MD

James Lake is a psychiatrist in private practice in Pacific Grove, Calif

t psychotropic agents employed in allopathic medicine have limited efficacy and significant side effects. Although usually beneficial, synthetic pychotropics are unavailable to approximately 80% of the world's population. Improved understanding of appropriate and safe uses of naturally occurring substances as psychotropic agents will greatly contribute to global mental healthcare. Empirical validation of nonallopathic treatments to ensure safety and efficacy is important because increasing numbers of patients in economically developed countries are using natural substances as medicinal agents. Patients and clinicians often lack accurate information, resulting in poor treatment outcomes or the possibility of drug drug interactions when herbal medications are used with synthetic psychotropic medications. An important objective of this paper is to distinguish compelling scientific evidence supporting the use of natural products in psychiatry from political or institutional biases that have been misrepresented as scientific arguments. Following an overview of historical, legal, and regulatory, issues, this paper presents findings of a systematic literature review on natural products used to treat neuropsychiatric disorders. Significant recent research is reviewed, including emerging treatments of seizure disorders, schizophrenia, dementia and age-related cognitive decline, depression, anxiety states, and substance abuse. Substantial evidence is advanced for safety and efficacy of many natural products used to treat neuropsychiatric symptoms or disorders. Preliminary findings suggest that several treatments based on natural substances are as effective and safe as synthetic pharmaceuticals in current use. Additional studies are indicated to confirm these findings, to elucidate mechanisms of action, and to elaborate standards for safe and appropriate treatment indications. In conclusion, strategic approaches aimed at facilitating improved networking, accelerating promising research directions, and enhancing quality standards of ongoing investigations into putative psychotropic agents from natural sources are recommended. (Altern Ther Health Med. 2000;6(3):36 60). 60).

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ALTERNATIVE THERAPIES, MAY 2000, VOL. 6, NO. 3

INTRODUCTION
An Urgent Unmet Need for
Better Psychotropic Medications

 In 1988, in response to the urgent unmet need for better psychotropic medications, and in view of limited ongoing progress in the development of novel or more efficacious psychotropic drugs,1 the National Advisory Mental Health Council recommended that the National Institutes of Mental Health (NIMH) collaborate with the National Cancer Institute to develop a program that would perform central nervous system (CNS) receptor assays on natural products then under investigation at the National Cancer Institute for determination of their potential anticancer effects. In response to this federal mandate, the National Institutes of Health (NIH) formed the Psychotherapeutic Drug Discovery and Development Program in 1991. In the same year, the NIH established a contractual agreement with private firm, NovaScreen, Inc, to provide approximately 100 in vitro CNS receptor assays for use in screening natural substances for possible psychotropic efficacy. In addition, the Office of Alternative Medicine was created at NIH in 1991 to systematically evaluate promising "alternative" treatments for all disorders, including mental illness. Initial results of NovaScreen assays have been promising! The director of NIMH Pharmacologic Treatment Research Program, where the above project was instituted, has argued that the pharmaceutical industry should renew efforts to investigate natural products as prospective sources for new psychotropic drugs, because major breakthroughs have historically resulted from the study of natural products. Other compelling reasons to evaluate natural products as prospective sources for novel CNS agents include the following2,3:

•    a vast ethnographic literature describing clinically relevant effects of plant derived medicines used in indigenous healing practices;

•   rapidly declining biodiversity in geographic regions where natural sources of medicinal agents are endemic;

•    a consensus that no significant breakthroughs in psychotropic drug development have taken place in the past 30 years. The World Health Organization (WHO) List of Essential Drugs has continued to list only 6 psychotropic drugs based on data from randomized controlled clinical trials1; and

•    an urgent need to document and to preserve knowledge pertaining to treatment approaches employed by traditional healing systems, because of the continuing decline in numbers of practicing healers in many indigenous healing traditions.

Unfortunately, because of cuts in NIMH funding for new program development, the NovaScreen contract was discontinued in 1995. Subsequently, no similar government sponsored program has been created in the United States. A number of pharmaceutical manufacturers continue to maintain CNS receptor screening programs dedicated to assaying natural products for potential value as prospective psychotropic agents.4,5  However, during the past several years, there has been a growing trend away from natural product screening using voucher specimens toward high throughput automated combinatorial chemistry assays of large families of synthetic biomolecules. The goal is to perform a fixed number of assays on as many naturally occurring substances in the shortest time. When not guided by ethnopharmacologic information from field studies, this approach has met with limited success. Despite increasing openness from the Food and Drug Administration (FDA) toward botanical pharmaceuticals, no clear institutional commitment to a program for the scientific validation of emerging plant derived medicinals exists. Therefore, excellent candidates for novel psychotropic agents are being overlooked because they do not fit current FDA criteria for investigational new drugs, and are therefore not eligible for rigorous empirical evaluation of safety or efficacy as alternative medicines.6

Overview of Historical and Cultural Issues in Allopathic Pharmacy

From earliest recorded history, all traditions of healing have used naturally occurring substances as sources of medicines. Currently, more than 20,000 plant species have medicinal uses in the world's cultures.7 The Materia Medica of ancient medical paradigms and recently evolved Western technological approaches continue to rely on natural substances including plant, animal, or mineral products as medicines or sources of substances that are modified or combined to yield medicines. The recent history of allopathic medicine is notable for its shift away from eclectic treatment strategies incorporating plant derived preparations, toward treatments based on synthetic pharmaceuticals optimized to target specific biological markers of pathology. This shift reflects an evolutionary process that is replacing a paradigm informed by indigenous healing practices with a technology-based paradigm derived from Cartesian dualism.8

In many Occidental cultures, the gradual historical paradigm shift in models of healing and illness is mirrored in a parallel evolution from the use of complex mixtures of herbal or other natural product derived ingredients, to preparations of single herbs or other natural substances, to purified single molecular moieties as active ingredients, and finally, today, to synthesized analogues of isolated active molecular species engineered to optimize a desired biological effect on a specific target receptor or other discrete molecular level process underlying a discrete, biologically unambiguous disease state.  Movement away from mainstream medical use of compound herbal preparations or crude extracts with nonspecific use indications has also been accelerated by impressive advances in understanding of biochemical, metabolic, immunologic, or other empirically verifiable biological bases of infectious diseases and several chronic medical disorders. Despite this trend, the world's largest pharmaceutical companies have continued to invest in new drug discovery programs dedicated to investigating the efficacy of naturally occurring products for the treatment of a broad range of diseases.4,5  The concept of "active ingredient" is now an axiom of Western pharmacy and the allopathic medical model of biological treatment. The concept of a most suitable or optimum discrete biological agent as the appropriate or optimum treatment for a specific disease is largely the result of oversimplification of a theory that purified uniform chemical substances would predictably yield desirable physiological effects. This theory emerged from early work in the field of analytic chemistry to isolate "pure active ingredients" from "crude" plant abstracts based on the assumption that such "pure" isolates would correlate with a highly selective or amplified and therefore optimum pharmacologic effect. In a recent review of the history of pharmacy,9 it is argued that the concept of the active ingredient is an implicit assumption or necessary conclusion of reasoning toward linear causality that is embedded in Western scientific tradition. It has been further argued that the "active ingredient" model has led, in recent historical times, to the systematic exclusion of complex herbal formulas from rigorous scientific investigation. Some believe that as a result of this simplistic model, potentially valuable compound herbal formulas in the Ayurvedic, Kampo, or other traditions have been overlooked or not fully investigated.

The efficacy of compound herbal formulas likely rests on pharmacologically more complex mechanisms than single active ingredients, because specific "active" molecules may interact with other "active" moieties in additive, antagonistic, or synergestic ways. For a given compound herbal preparation, each discrete "active" molecular species may simultaneously have antagonistic, additive, and synergestic interactions with any or all molecules present in the herbal preparation," or with a variety of physiological processes in the organism subjected to treatment. Indeed, present analytic techniques may lack the capacity for complete analysis of pharmacologic effects caused by complex dynamic interactions of multiple biologically active molecules, and existing technological constraints may afford no more viable alternative than the isolation of single "active" ingredients. Progress has recently been made in this area with the development and patenting of a process that uses assays of all biologically active molecules in a compound herbal formula.

In any discussion of the history of natural product derived medicines, it is relevant to consider the role of cultural variables that determine which behaviors (signs) or internal experiential states (symptoms) are regarded within a specific cultural belief system as aberrant, classified as a "disorder" or "illness," which may then be viewed as an indication for treatment.  Major differences exist between divergent cultural paradigms as to rules employed for the classification or construction of considered signs or symptoms into normative or pathological behavior. 11,12 Specific patterns of signs or symptoms regarded in allopathic medicine as serious, therefore treatable psychopathology presumably reflecting an underlying neurochemical disorder may be viewed within a divergent cultural context as an idiom of distress that is accepted as appropriate, even prescribed behavior as conceptualized by the indigenous healing system prevailing within the cultural context in question.13

Regulatory Constraints Differ Internationally

To date, efforts in most Western nations to identify or to rigorously characterize natural product derived treatments with psychotropic efficacy have been sporadic at best. The reasons for this are complex and include the following:

•    Natural products are not patentable in the present US regulatory environment, and therefore not profitable for large pharmaceutical firms to manufacture. By definition, natural products are not the exclusive legal domain of the individual or corporate entity developing them. Therefore, there is little or no financial incentive to develop natural product based treatments within existing federal regulatory environment in the United States.

•    As presently conceptualized by the FDA, plant derived products are labeled as food additives or dietary supplements, and may not legally be marketed or recommended for use by physicians as medicines for the treatment of medical or psychiatric disorders.

•    In the United States and other technologically developed countries, allopathic medicine is the dominant healing paradigm that perpetuates a "culture" of synthetic pharmaceuticals.

Rigorous empirical evaluation of prospective psychotropic agents is more difficult, and the results more ambiguous than assays of prospective anticancer agents. Unlike biological or biochemical assays for anticancer drugs or antimicrobials, existing in vitro CNS receptor assays are typically not highly predictive of clinical efficacy in the treatment of neuropsychiatric disorders.

Major legal and institutional differences between the United States and most European and Asian countries have severely limited US based research on herbal or other natural product derived medicines, whereas a strong tradition of scientific investigations on European and Asian herbal medicines continues. The German market for the 3 best known botanical medicinals (valerian extract, Ginkgo Biloba preparations, and St John's Wort) that are most frequently recommended or prescribed by medical doctors for treatment of neuropsychiatric symptoms has exceeded DM 100 million every year for more than a decade, and continues to grow rapidly.14 Although the FDA has considered adopting new regulatory approaches that would treat herbal products as medicinal pharmaceuticals,15 it is unlikely that the US pharmaceutical industry and its lobbyists would endorse any proposed legislative changes that might serve to rapidly open the US marketplace to plant derived substances labeled as medicines that are manufactured in Europe or Asia. To date, there is no clear FDA policy with respect to this issue.

A great deal has been written about the relevance of traditional healing approaches to contemporary medical treatment and new drug discovery strategies. Farnsworth16 and COX17 have identified 2 principle arguments for the reasonableness of continued efforts to develop pharmaceuticals from natural products employing ethnopharmacologic approaches:

•    Successful new drug development programs have historically relied on plant derived pharmaceuticals. The majority of natural product derived pharmaceuticals were "discovered" following examination of their uses in the indigenous context.

•    Out of economic necessity, the population residing in developing countries (about 80% of the world's population or roughly 3.2 billion people) must rely on natural products as the sole source of medicinal agents. Since most plant derived medicines have yet to be scientifically studied, it is incumbent on governments of technologically more developed nations to validate and to promote treatments that are effective, while at the same time identifying plant derived medicines that have no apparent treatment efficacy for the traditionally indicated use.

METHODOLOGY

Overview

Two principle resources were examined to provide a thorough review of established and prospective natural product-derived treatments of neuropsychiatric symptoms or syndromes. The Napralert database is currently acknowledged to be the single most authoritative source of data pertaining to empirically validated studies on medicinal agents derived from natural products. In 1975, Napralert was created at the University of Illinois, Chicago. Since that time the database has been maintained under the direction of Norman Farnsworth, PhD at the Program for Collaborative Research in the Pharmaceutical Sciences. This program has continued to conduct systematic annual reviews of the world's scientific literature on pharmacological activities and medicinal applications of naturally occurring substances. At present, Napralert indexes approximately 150,000 citations and abstracts corresponding to 19 major pharmacological activities. Existing or emerging natural product derived treatments that appear to be efficacious for treating neuropsychiatric symptoms are discussed by major symptom or syndrome in this paper.

The Lloyd Library in Cincinnati, Ohio, is the other major source of information reviewed in this paper. The Lloyd Library is a unique repository of classical and contemporary information on nonallopathic treatments from the world's indigenous healing systems. Its holdings include monographs, journals, and books pertaining to anthropological, botanical, pharmacological, and medical aspects of nonallopathic healing systems for the range of medical and neuropsychiatric disorders. A thorough review was performed of the library's holdings pertaining to treatments of mental illness in indigenous healing systems for which there is published information in English and other major languages. More than 100 contemporary journals covering a 10 year period were reviewed, as well as books and classical manuscripts.

Limitations of Method

Significant findings of neuropharmacologic activity or demonstrated clinical efficacy of specific natural substances are discussed by major neuropsychiatric symptom or syndrome, and are intended as representative of general trends. Findings discussed in this paper obviously do not reflect all significant ongoing discovery and development efforts in ethnopharmacology pertaining to neuropsychiatry, as many ongoing studies are in proprietary or preliminary stages that have not yet been described in the technical or medical literature. This review is intentionally biased toward studies that purport to show efficacy of plant derived substances in the treatment of neuropsychiatric symptoms. Such deliberate positive bias comes from the author's goal of developing an argument for the scientific value of continued studies of natural substances in cases where preliminary findings are inconclusive but promising.

Analysis of Use Trends of Natural Products as Psychotropic Medications

The Napralert database is widely regarded as the most comprehensive source of empirically validated information pertaining to research on the biological efficacy of natural products in the treatment of disease. Annual reviews of the world's scientific literature have been ongoing without interruption since 1975. Citations on studies published before 1975 continue to be added to the database from retrospective reviews of newly identified studies performed before that year. Many disparate approaches have been employed to classify CNS effects of pharmaceuticals.18 Some databases group compounds according to presumed correlations between identified active molecular species and specific neuroanatomical sites or neurochernical activities believed to mediate observed CNS effects. Most classification schemes rely on major observed CNS mediated activity associated with a substance under investigation.

Pharmacological actions affecting the CNS have historically been grouped as stimulants (agents that induce wakefulness or arousal), depressants (agents that induce calming or sedation), autonomic agents (those that mediate involuntary physiological processes), and psychotropics (those having an effect on psychological functioning or mood). Although the majority of natural substances employed as medicines originate in plants, many unique biologically active molecules are found in fungi and various animal species ranging from bacteria to vertebrates.19

The data set for CNS effects is further broken down according to 114 specific CNS functional or clinical effects, including an initial category labeled "CNS effects (general)." Most subheadings under CNS biological activity codes refer to citations of studies showing empirically observable or clinically measurable efficacy of specific single or combined natural product-derived substances.

As technology required to perform CNS assays has become more widely available and more affordable during the past few decades, novel preparations of naturally occurring substances with putative CNS activity have been investigated at an increasing rate. Of 5,680 individual citations falling under 114 specific CNS activity subcodes in the data set on CNS effects, 10 activity codes are especially germane to the goal of assessing potential efficacy of natural product derived substances in the treatment of neuropsychiatric symptoms and disorders. (Napralert citations included under CNS activity categories for antipsychotic and neuroleptic were combined into one set. Citations included under activity categories anxiolytic and antianxiety were also combined into one set.) Table 1 shows cumulative citations for these 10 CNS activities.

Citations included under selected CNS activity codes shown in Table I were analyzed in 2 stages. Initially, statistical trends in numbers of citations were examined. This simple numerical approach provided a rough indication of trends in natural product research pertaining to each of the clinically relevant CNS activity categories examined. Subsequently, actual citations and corresponding studies were examined to identify trends in research progress in the identification and characterization of naturally occurring substances as prospective psychotropic agents. Citation tracking was used to reduce inflation in the data set through multiple inclusions of the same citation in different CNS activity categories. In cases where a citation was included in 2 or more Napralert Categories, for purposes of this review it was assigned to the CNS activity code reflecting its principle research or clinical emphasis. However, due to the large number of citations, a finite number of duplicate citations was inevitably overlooked.

TABLE 1  Selected Napralert CNS activity codes relevant to neuropsychiatry

Selected CNS Activity
Cumulative Citations
Napralert codes
Antiseizure activity
591
Narcotic antagonist activity  
33
Antipsychotic activity 48
Tranquilizing effect (includes 
Sedatives and anxiolytics)
194
Memory enhancing effect
68
Antiaggression effect 
16
Antidepressant activity 
44
Antianxiety effect 33
Antimanic activity  
   1
Psychotropic activity
42

Total citations are therefore probably slightly inflated. Studies cited in the exhibits were selected on the basis of methodological quality and clinical significance of reported findings. Several included citations describe limited open human trials or animal studies. Findings from these studies are included as representative of emerging research trends in natural products with potential efficacy against neuropsychiatric symptoms. Although included in the exhibits, the findings of such studies are not discussed or interpreted in the text because of limited available human trials data to corroborate them. The above approach makes the assumption that it is reasonable and germane to differentially weight studies depending on the objective significance of findings, as well as the potential future clinical importance based on preliminary findings.

Studies evaluating antiseizure activity of natural product-derived agents constitute the CNS activity category with the greatest number of citations, even when a certain finite number of repeat or double citations is assumed. Napralert citations of studies investigating possible antiseizure activity represent the single largest subset of natural product derived substances evaluated for CNS activity throughout the entire period examined in the literature search. There is roughly a twofold difference between total citations of antiseizure studies and total citations of studies included in the next largest subcategory, tranquilizing agents. Only 29 studies of putative tranquilizing effects of naturally occurring substances are cited before 1975, and 165 additional studies published since then are cited in the Napralert data.

Among the other CNS activity categories examined, citations of studies on memory enhancing agents represent the third largest subset (after antiseizure effects and tranquilization effects), with 68 citations. The number of controlled studies published in the area of natural product derived memory enhancing agents has grown periodically faster than any other CNS activity category. Only 1 citation in this category, dated before 1975, was included by Napralert and 67 studies were added subsequently. Although the earliest cited study of a putative narcotic antagonist dates to 1892, there were 33 cumulative citations in this CNS activity category in 1997. This trend stands in marked contrast to growth in published studies on tranquilizing agents, which has continued to increase at a robust rate throughout the period examined. It is significant that this has been the case despite the fact that the earliest cited study on putative tranquilizing effects of a natural substance dates to 1898, only 6 years after publication of the earliest included study on narcotic antagonist activity. Another interesting pattern that emerges from cursory review of the number of published studies in Napralert is the complete absence of cited studies prior to 1975 in 4 principle CNS activity categories: antiaggression, antidepressant, antianxiety, and antimanic.

Citations of studies pertaining to antiseizure or tranquilizing effects represent 73% of total cumulative citations in the 10 CNS activity codes examined. These 2 CNS effects were reported or scientifically investigated significantly earlier than 8 other selected CNS effects, according to Napralert inclusion criteria. It is instructive to consider possible explanations for these dramatic apparent differences in numbers of scientific studies on natural substances evaluated for possible CNS activity. Seizure disorders correspond to discrete observable symptoms that are typically unambiguous. Therefore, the planned or accidental efficacy of a putative antiseizure medicinal will be clearly observable. The quality of empirical evidence supporting an antiseizure effect is superior to observational data attesting to the efficacy of antidepressants or other agents used to treat symptoms that are inherently more subjective than discrete neurologic signs that typically accompany seizure disorders. Accurate diagnosis of epilepsy depends on observation of abnormal behaviors or discrete neurologic signs, in contrast to most neuropsychiatric disorders, for which correct diagnosis relies on accurate assessment of subjective states, or symptoms. Physical signs of most types of epilepsy are objectively observable, and readily subject to detailed description and quantification in terms of specific types of associated abnormal involuntary tonic clonic movements, duration and frequency of seizure episodes, and electroencephalogram (EEG) abnormalities. This predictable repetition of co occurring physical signs historically permitted the naming and systematic study of epilepsy as a discrete disorder. Changes in any of the objective signs of seizure activity that are associated with administration of a substance in efforts to "treat," are likewise quantifiable, permitting empirical assessment of the efficacy of treatments explored for the disorder. Signs that allopathic medicine presently systematizes under the pathologic descriptor, "seizure disorder," were likely observed from earliest recorded history. The first known systematic report of a possible anticonvulsant agent cited by Napralert was published in 1650.

A factor that has probably significantly biased the number of Napralert citations pertaining to antiseizure or tranquilizing effects is the large number of studies on plant derived substances included under CNS activity codes that merely allude to efforts to characterize the possible antiseizure or tranquilizing efficacy of specific treatments. The disproportionately large numbers of citations pertaining to these 2 CNS activities, antiseizure activity and tranquilizing activity, is therefore due partly to a trend in ethnobotany that has emphasized the importance of identifying naturally occurring substances exhibiting these clearly observable effects on global functioning of the CNS. Furthermore, as studies or controlled observations of seizure disorders go back several centuries, many Napralert citations comment on earlier original work but do not include new findings, resulting in a finite amount of redundancy in the data set. Careful citation tracking partially corrects for this source of error.

Significant cross cultural differences exist between empirically grounded but philosophically and socioculturally distinct paradigms for diagnosing and treating signs and symptoms of human distress, or maladaptive emotional or cognitive functioning. However, many parallels exist between distinct paradigms,20 which has led to dialog between healers from divergent backgrounds and efforts to construct a common paradigm in order to facilitate understanding and cooperation in the investigation of promising new treatments for neuropsychiatric disorders.

Many reports of mental illness or response of specific symptoms to putative CNS agents are ambiguous and unverifiable at best. For example, as constellated and systematized in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, major depressive disorder is a subjective state of continuous distress lasting at least 2 weeks during which the depressed individual must report experiencing at least 5 or more of 9 specific subjective symptoms throughout the same 2 week period, including either depressed mood or loss of interest or pleasure.21 Criteria sets employed to operationalize specific symptom patterns as psychiatric "disorders" according to the Diagnostic and Statistical Manual of Mental Disorders are based on working consensus of committees that are comprised largely of academic psychiatrists. Other diagnostic systems are similarly arbitrary in that they necessarily reflect particular biases and theoretical constructs of the tradition from which they originate. By definition, any approach that formalizes strict diagnostic criteria excludes the legitimate diagnosis of symptom patterns outside of those criteria. Many nonallopathic healing systems do not recognize depression as a distinct diagnostic entity, or employ labels for subjective experiences like depression without attaching pathological meanings to those experiences.

Another interesting and related issue that requires careful consideration by researchers investigating CNS effects of plant-derived treatments used within the pharmacopeia of a given culture is the significant biological variability that exists between different ethnic groups. Several studies have demonstrated a high degree of genetically controlled variability in enzymes that are necessary to metabolize common synthetic psychotropics, including tricyclic antidepressants and phenothiazines.22 Interethnic genetic variability will probably lead to a corresponding variability in local selection of cultural preferences in botanical medicinals reflecting enzymatic or other biologically mediated differences in metabolic pathways or CNS neuropharmacologic mechanisms that mediate sought after CNS effects. Because of these issues, it has only recently been possible to formulate field methods for rigorous observation of psychiatric symptornatology across cultures, and to therefore assess the efficacy of specific treatments used in the world's indigenous healing traditions. The union of anthropology, botany, and medicine has yielded the new science of ethnopharmacology, which has as its subject the empirical study of natural product derived treatments and their effects while taking into account complicated nonpharmacological dimensions of culture that influence the phenomenology of human illness and the effectiveness of traditional healing approaches.

NATURAL SUBSTANCES INVESTIGATED FOR SELECTED CNS ACTIVITIES

The remaining part of this paper is a review and synthesis of representative promising natural product research of particular relevance to development of novel CNS agents for the treatment of common neuropsychiatric symptoms or syndromes. Because of constraints on length, a complete review of significant ongoing natural product research in all selected CNS activity categories is not included. Most reviewed studies were conducted by PhDs or allopathically trained physicians, and were typically published in professional journals of pharmacology or medicine. Included studies represent the range of well known and obscure healing systems, including traditional Chinese medicine (TCM), Ayurveda, traditional European naturopathic medicine, as well as Unani Tibb, traditional approaches used in the former Soviet Union, various African tribal healing systems, Oceania, Japan, and Korea.

Approximately 200 studies were reviewed, representing an initial core collection of empirically validated clinical observations or research on behavioral and CNS effects of naturally occurring substances that have prospective significance for development of novel treatments targeting common neuropsychiatric symptoms or disorders. Significant findings of promising natural product derived treatments are summarized in table form. Although the literature reviewed included studies with the full range of positive and negative outcomes, tables emphasize significant positive findings. As such, this review is intentionally biased towards promising directions in current natural product research that will serve as a scientifically informed starting place for efforts to further validate the efficacy of nonallopathic treatments of neuropsychiatric disorders. As future studies are screened and included in the Napralert database, results of core studies on selected substances with CNS activity will be expanded, further elucidating the mechanism of action and efficacy of natural products used to treat the range of neurologic and psychiatric disorders.

Seizure Disorders

Natural substances have probably been employed to treat seizures for millennia. The earliest Napralert identified empirically grounded observation of antiseizure effects attributable to a herbal preparation dates to the early 17th century. Synthetic drugs that prevent or interrupt seizure activity typically work by elevating CNS levels of gamma aminobutyric acid (GABA), one of the principle inhibitory neurotransmitters, or by reducing available glutamate and aspartate, 2 major excitatory neurotransmitters implicated in seizure disorders. Although many novel antiseizure drugs are currently undergoing clinical trials, there is an unmet need for safe and effective therapies. Available antiseizure medications effectively control symptoms in most seizure disorders, but are ineffective in severe cases of complex partial epilepsy, and no conventional treatment corrects the underlying pathophysiology of seizure disorders. Other issues that warrant the continuing high priority on discovery or development of new antiseizure medications include the following23:

•    Many therapies are withdrawn due to toxic
     reactions.

•    Treatment of severe cases using available medications fails 50% of the time.

•    Limited safe choices are available for children.

•    Few effective treatments exist for absence (petit mal) seizures.

•   Adverse drug reactions often result in poor compliance.

More scientific studies have been performed on natural product derived treatments for seizure disorders than the other common neuropsychiatric disorders examined in this paper, including depression, anxiety disorders, and dementia. Table 2 displays results from recent studies on naturally occurring substances that are being explored for possible efficacy in the treatment of seizure disorders.

Most studies investigated reported antiseizure activity of a specific nonallopathic preparation using animal models of epilepsy. The usual experimental protocol evaluated the efficacy of a specific substance or preparation in preventing electroshock versus PTZ induced seizures.

TABLE 2 Selected natural products investigated for antiseizure activity

Natural Product
Comments

Rosmarinus officinalis 24

Controlled animal study showed delayed seizure onset and reduced mortality in mice pretreated with aqueous extract before picrotoxin induced seizure.

Insignificant transient increase in brain GABA correlated with delayed seizure onset.

Brahmighritham 25 <>Ayurvedic compound herbal traditionally used to treat seizures and "insanity."

Chronic treatment prevented pentylenetetrazole (PTZ) induced 
seizures or EEG changes in rats.

No significant adverse effects or toxicities were noted.

Seizure protection was comparable to benzodiazepine pretreatment group.

Maprounea Afticana 26

Used in Congo traditional medicine to treat seizures.

<>Standardized extract significantly delayed onset of PTZ induced  tonic clonic seizures but did not effectively block seizures or reduce  mortality in pretreated mice.

Slight sedative hypnotic effect demonstrated in mice.
Unknown mechanism of action.

Substance Abuse and Addiction

Natural and synthetic substances that have been associated with syndromes of abuse have varied tremendously across time and cultures. Abuse of certain substances (eg, ethanol, opiates, and benzodiazepines) results in addiction or chemical dependency on the substance such that its continued use is associated with a diminished effect at a given dose (tolerance), and sudden discontinuation leads to specific signs of physiological dysregulation (withdrawal). Because of differences in CNS receptor pharmacology, abuse of other substances (eg, marijuana and methamphetamines) does not result in physiological dependence. Although patterns of abuse in different geographic regions have evolved in relation to local changes in sociocultural institutions, substances that have historically resulted in patterns of abuse or dependence consistently fall into a few major categories: depressants, stimulants, and euphoriants. Recent WHO statistics estimate the worldwide incidence rates of illicit drug abuse, as shown in Table 3.27

Abuse of legally obtainable substances is also of growing concern worldwide. Alcohol and tobacco abuse continue to create a major burden on the economies and healthcare systems of most developed countries because of high rates of morbidity and mortality caused by associated diseases, including cancer, chronic obstructive pulmonary disease, and hepatic cirrhosis. In addition, there is substantial anecdotal evidence that abuse of prescription psychoactive drugs continues to increase as use of these synthetic pharmaceuticals becomes more widespread in many countries where they are frequently available in over the counter forms in the absence of professional medical advice or supervision.

Epiderniologic studies have identified significant interethnic differences in patterns of substance abuse within the United States.27  However, local indigenous substance abuse trends in other world regions are difficult to identify because of sociocultural differences in acceptable uses of psychoactive substances that preclude objective universal criteria for defining abuse.

Many pharmacologic and behavioral therapies have been tried, with varying degrees of success, in efforts to break the cycle of craving and self destructive use that characterizes substance abuse. Existing pharmacologic approaches have demonstrated limited efficacy in the prevention of relapse. Because of this, researchers continue to explore nonallopathic treatment approaches based on naturally occurring substances employed by indigenous healers. A few innovative detoxification programs have incorporated herbal treatment protocols for management of acute benzodiazepine or opiate withdrawal, reportedly with positive results."

Several controlled studies appear to support the use of certain herbal preparations in rational detoxification treatment programs. Table 4 displays preliminary findings of selected studies on natural products with apparent efficacy in treating syndromes of substance abuse, withdrawal, or addiction.

TABLE 3 Estimated worldwide illicit substance abuse
         
Substance of Abuse

Millions of Abusers Worldwide (est.)
Cannabis 30
Coca leaf 
 1.6
Opium   
1.7
Heroin  
0.7
Cocaine
Unknown
Amphetamines Unknown


TABLE 4 
Selected natural products investigated for efficacy in treatment of substance abuse

Natural Product Comments
Camellia japonica 29

Used in traditional Chinese and Japanese (Kampo) healing for treatment of hematemasis, and to prevent     or lessen alcohol intoxication during heavy drinking.

Single low dose oral administration caused inhibitory effect on ethanol  absorption.

Aralia elata 30 Used in traditional Chinese medicine to prevent or lessen ethanol  intoxication.

Active ingredient inhibiting ethanol absorption identifies as the elatoside: oleanolic acid oligoglycoside.

Likely mechanism involves inhibition of alcohol obsorption across cell 
membranes in digestive tract.
Ginseng 
(ginseng total saponin) 31

Used in traditional Chinese medicine for at least 5000 years for many  indications.

Controlled animal study showed prevention of development of dopamine receptor supersensitivity induced by chronic ethamphetamine  administration, therefore may provide therapy for adverse effects of chronic  methamphetamine use.

Mechanism not established, but likely related to presynaptic dopamine.

Cannabis indica 32

Anecdotal case reports claiming effective rapid treatment of delirium  tremens using oral preparation.

No reported complications or adverse drug reactions.
Withania somnifera 33 Used in Ayurvedic tradition to enhance memory and lessen age related  cognitive deficits.



Controlled animal study showed prevention of tolerance and dependence on morphine with chronic treatment concurrent with morphine administration.

No significant toxicities or adverse reactions reported.
Mentat 28 Ayurvedic compound herbal preparation.

Controlled animal study showed efficacy in reversing acute  benzodiazepine withdrawal effects.

Innovative research is also ongoing to characterize natural product derived substances that prevent the gastrointestinal absorption of alcohol, and limit CNS receptor supersensitivity responses to chronic methamphetamine abuse. Development of pharmacologic treatments that could effectively and safely achieve either goal would be of enormous potential consequence in the management of 2 of the most intractable and costly substance abuse problems in the United States, namely alcoholism and methamphetamine abuse.

Schizophrenia and Other Psychotic Disorders

Schizophrenia and other psychotic disorders are characterized by significant cross cultural variation in symptom type, as well as relative symptom duration and severity. This variability has been attributed to sociocultural differences affecting beliefs about normative behavior.34 Several studies conducted by the WHO over a 25 year period support the view that in underdeveloped countries, schizophrenia and other psychotic disorders tend to be less severe, resolve more rapidly, and have a better overall prognosis compared to technologically more developed nations.35 These differences have not yet been clearly explained, but the WHO studies suggest a strong relationship between cultural factors, including differences in expressed emotion, and frequency or severity of many symptoms that have been operationally defined by allopathic medicine as schizophrenia or other psychotic disorders. In cross cultural comparisons of psychotic disorders, efforts to interpret effect, thought process and content are confounded by basic differences in culturally determined concepts or values that bias or define perceptions of normal psychological and behavioral patterns. Because of these differences, an assessment of schizophrenia must take into account the patient's sociocultural background. The scientific investigation of cross cultural patterns in psychosis has proven to be an extremely difficult exercise, and the extent to which specific cultural variables influence formation of specific symptom patterns is unclear.33 It has been shown that cross cultural variability in treatment response is related, in part, to differences in metabolic pathways regulating plasma concentrations of antipsychotic drugs.22 There has also been interesting speculation about possible interethnic differences in CNS receptor pharmacology mediating psychotic symptornatology. Both factors would be expected to influence the relative efficacy of different synthetic or natural product derived antipsychotic medications. Although allopathic psychiatry has operationalized the clinical diagnosis of several discrete schizophrenia subtypes,21 significant cross cultural differences in phenomenology of psychotic symptoms typically are not congruent with these allopathically defined categories of psychosis  Despite these differences, however, there is evidence that schizophrenia and other psychotic disorders are present at roughly equivalent incidence rates in all major geographic regions of the world.37

TABLE 5  Selected natural products investigated for antipsychotic activity

Natural Product Comments
Glycin 39

Open clinical trial using oral glycine augmentation of ongoing antipsychotic therapy in treatment refractory patients showed significant improvement in negative symptoms.

Double blind 6 week study showed a 30% reduction in negative symptoms at doses of 800 mg/kg/day.

Patients who had responded to glycine in a previous double blind study showed greatest response to glycine in follow up study.

No adverse effects observed during an 8 week trial with 60 9 daily

Putative mechanism is N methyl D aspartate augmentation.
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Cannabidiol 40 Attenuated apomorphine-induced stereotypy  in animal model of psychosis-simular to effect of other antipsychotic drugs.


Animal study showed increased prolactin secretion similar to described antipsychotic effect.

Based on observed effects, mechanism of action may be similar to atypical antipsychotics, although no data are available on specific neurotransmitters involved.

Korean traditional
Preparations 41

Thirty one naturally occurring substances used to treat psychosis in Korean traditional medicine were subjected to in vitro CNS screening assays using crude plant extracts.

In vitro assays revealed several CNS receptor selectivities and affinities. More constituents had strong binding affinities with monoamine receptors than other CNS receptors.

Controlled animal studies are needed to elucidate specific behavioral effects of different preparations.
Brahmyadiyoga 42 Ayurvedic traditional compound herbal formula used to treat madness.

Controlled study showed antipsychotic efficacy comparable to chlorpromazine.

Mechanism of action remains unknown, but in vitro assays confirmed D 2 activity and GABA agonist activity.


In the history of ethnopharmacology, a most significant event was the isolation and clinical application of the alkaloid reserpine from Rauwolfia spp, a plant that had been used for millennia in the Ayurvedic tradition to treat madness. Although     reserpine had clearly demonstrated antipsychotic efficacy, it was     soon replaced by the first synthetic antipsychotic, chlorpromazine which proved more effective, had fewer side effects and was relatively inexpensive to manufacture.38  Table 5 provides overviews for representative studies on natural products with putative antipsychotic effects.    Compared to other psychiatric indications for treatment,     a disproportionately small number of studies has investigated natural substances used to treat psychosis. There are many possible kinds of reasons for this apparent discrepancy. It is possible that reported differences between developed and technologically less developed nations in phenomenology, severity, and duration of psychotic states translates into relatively lower priority assigned to treating these symptoms in indigenous healing systems. Another explanation is the possibility that a significant percentage of individuals experiencing symptoms that would be categorized as psychotic behavior in the domain of allopathic psychiatry are regarded as exhibiting normal variants of behavior or thought in their indigenous cultural contexts. When or if such psychotic behavior is interpreted by local healers as distress or illness warranting treatment, a range of other plant derived treatments targeting symptoms such as anxiety and agitation that frequently accompany psychosis would likely be used.

Another kind of explanation for the apparent paucity of indigenous herbal preparations targeting psychosis is the possibility that such treatments would in fact prove useful and desirable within indigenous contexts, but that few naturally occurring substances with antipsychotic efficacy have been successfully identified or developed into effective treatments. Finally, vagueness surrounding this issue may be clarified through a comparative historical review of healing traditions in disparate geographic regions. The goal of such a review would be examination of ethnographic studies for evidence of differences in indigenous treatments of psychotic like conditions before the widespread availability of chlorpromazine starting in the late 1950s.43 The displacement of effective indigenous therapies by introduced synthetic drugs is a well studied phenomemon in ethnographic research.

Dementia and other Disorders of Cognitive Decline

Because of the ongoing demographic shift toward an increasing elderly population, age related disorders, including senile dementia, are expected to become more prevalent in coming decades. Dementia is broadly defined as global impairment of intellect and personality in the absence of changes in the level of consciousness. Numerous discrete and overlapping etiologies of dementia have been identified. The 2 most prevalent forms of dementia are etiologically distinct. Alzheimer's disease, which accounts for roughly 50% of dementias, is correlated with loss of cholinergic neurons in specific brain regions. Multi infarct dementia, which accounts for 20% to 30% of dementia cases, has been attributed to microvascular disease causing restricted cerebral circulation, eventually reading to regional ischemic CNS damage. Many putative biological and environmental causes of dementia have been investigated. It is likely that most cases of dementia have etiologies that are complex and multifactorial. A particular etiology typically correlates with a characteristic age at onset, course, and symptom pattern; however, accurate diagnosis of a specific underlying cause or causes is often problematic without sophisticated brain imaging technologies, which are generally unavailable outside of research settings. Therefore, in most cases the diagnosis of dementia is largely presumptive, based predominantly on clinical history.

Many cross cultural studies reveal inherent methodological difficulties in efforts to operationalize diagnostic criteria for various dementing disorders. Because of differences in what is regarded as normative behavior or indicators of impaired cognitive functioning, prevalence estimates of dementia in different geographic regions range from less than 1% to approximately 11%.22 Future research is necessary to clarify these issues.

The following discussion will not separately review studies on the efficacy of synthetic drugs currently being marketed for the treatment of Alzheimer's disease. Both drugs that are available in the United States inhibit acetylcholinesterase, incrementally increasing available acetylcholine in certain brain regions implicated in dementia. Many studies provide evidence that these synthetic agents, tacrine hydrochloride (cognex) and donepezil hydrochloride (aricept), offer transient symptomatic relief in senile dementia of the Alzheimer's type of mild to moderate severity. Unfortunately, because of toxicities or adverse side effects, both drugs have experienced limited success due to significant medication discontinuation rates, or because of marginal clinical improvements believed to be due to excessive central cholinergic activity.

This section will briefly review research progress on natural substances investigated for possible efficacy against dementia. The botanical that is best known in this regard is the ancient species Ginkgo biloba, which has been employed in TCM for treatment of memory loss and other indications for more than 5 millennia. More than 400 clinical studies have been performed to assess cognitive enhancing or dementia reversing characteristics of herbal preparations based on Ginkgo biloba. In Europe, a standardized extract has been available as a nonprescription formula for oral use, and a prescription formula for parenteral use for more than a decade. That preparation (EGb 761) is the most frequently prescribed plant derived medicine in Europe and one of the most frequently prescribed pharmaceuticals overall. Table 6 summarizes significant findings of controlled studies on cognitive enhancing activities of Ginkgo biloha.

Other than Ginkgo biloba, several herbal preparations or nutritional supplements are presently used by practitioners from diverse traditions to treat age related memory loss or dementia.

TABLE 6  Ginkgo biloba preparations  investigated for cognitive enhancing activity 44-48

Controlled studies demonstrate improvement in mild to moderate symptoms of memory loss, depression, and disorientation associated with CNS vascular deficiency or senile dementia of the Alzheimer's type in elderly populations.

A controlled study demonstrated efficacy against treatment resistant depression associated with cognitive decline in elderly patients who had previously failed to respond to therapeutic trials of standard synthetic antidepressants or other phytomedicinal preparations, including St John's Wort. Patients experienced significant sustained improvements in mood and cognitive performance.

Improvements in cognitive performance typically start after 6 weeks of treatment at recommended dosages of standardized preparation (EGb 761).

Mechanism of action is complex. Several active ingredients have been identified; principally flavonoids and terpenoids.

Putative mechanism of action contributing to observed cognitiveenhancing effects include: 1) suppression of platelet activating factor, by terpenoid fraction, resulting in reduced capillary endothelial damage and reportedly decreased glutamate release following neuronal injury; and 2) strong free radical scavenging, by flavonoid fraction, reducing oxidative damage of membranes of CNS neurons resulting in improved membrane dopamine transport and reduction in serotonin receptor density.

Controlled studies have demonstrated a consistent reversal of EEG associated changes in dementia, optimized after several months of treatment with standardized preparations, most notably alpha EEG enhancing effects and decreased slow wave activity associated with improved cognitive activation.

Open trial on 19 patients with mild to moderate dementia compared EEG changes in patients treated with Ginkgo biloba extract and tacrine. Both groups showed improved activity; however, more patients showed improvement in the Ginkgo biloha group.

Alpha EEG enhancing effects observed more for certain preparations (EGb 761) than for others.

No clear evidence from controlled human trials that Ginkgo biloba preparations have significant memory enhancing or cognitionenhancing effect in nonimpaired individuals.

Controlled animal studies have demonstrated neuroprotective effect with prolonged use of standardized preparations associated with reduced infarct size after focal CNS ischemic damage. Mechanism unknown.

TABLE 7  Selected natural products investigated for antipsychotic activity

Natural Product Comments
Garlic (Allium sativa) Extract 49 Used in many indigenous traditions to treat age‑related memory loss. 

Certain preparations documented to have antioxidative activity.

Controlled animal study showed immunomodulatory effect that may positively impact age‑related changes in antibody production and prolonged longevity. <> 

Controlled animal study showed enhanced spatial learning and reduced age‑related memory deficits in senescence‑accelerated mice. 
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Thiamine50 Potentiates CNS effects of acetylcholine. 

Improved cognitive functioning patients with Alzheimer's disease or age‑related memory loss taking 3‑8 g/day.

Chronic thiamin diphosphate deficiency may contribute to cognitive     impairment in Alzheimer's disease
Kami‑untan‑to51,52

Kampo traditional preparation for treating age‑related memory loss and dementia.

Oral administration increased choline acetyltransferase activity in frontoparietal cortex and reduced cognitive  impairment in forebrain‑lesioned rats.


Indirectly increases available achetylcholine by inducing increased transcription of choline acetyltransferase and nerve growth factor mRNA.


Putative mechanism is stimulated nerve growth factor production resulting in increased choline acetyltransferase production, and indirectly, increased acetylcholine production.
Peony root extract
(Peonea lactiflora)53

Used in traditional Chinese herbal preparations to treat dementia.

Oral preparation significantly improved spatial learning deficits in basal forebrain‑lesioned rats.

Neuropharmacological mechanism unclear, but may be independent of cholinergic dysfunction and related tostimulated adrenergic activity.
Mentat54

Compound herbal formula used in Ayurvedic tradition to treat age‑related

memory and cognitive deficits.

Controlled animal study showed improved cognitive performance in brain‑lesioned rats.

Likely mechanism is improved cholinergic activity.

Bu lai cas
(Boschniakia rossica)55

Used in traditional Chinese medicine to treat senile dementia.

Has strong free‑radical scavenging activity.

Animal study showed improved learning discrimination performance andnormalization of behavior in basal forebrain‑lesioned rats.
Qian Jin Yi Fang
 (S‑113m)56
Compound herbal formula containing ginseng, biota, and schizandra spp used in traditional Chinese medi­cine to enhance memory and prevent memory loss

Controlled animal study using senescence‑accelerated mice showed

signifantly improved new memory acquisition and retention.

Controlled animal study suggests efficacy in improving normal age‑related memory loss.
Phosphatidylserine57 Twenty controlled double‑blind trials consistently show mild to moderate improvement in age‑related cognitive decline and early (mild) Alzheimer's disease.

Likely mechanisms involve enhanced nerve cell membrane homeostasis and stimulation of dopaminergic activity.

Does not improve cognitive decline associated with‑CNS vascular disease.

Open clinical trial suggests efficacy against depression in elderly males.

Rare adverse drug reactions and no known contraindications.

Docosahexaenoic acid58

Lower serum docosahexaenoic acid levels predicted significantly increased risk of developing Alzheimer's disease.

Controlled clinical trials showed cognitive improvement in patients with vascular dementia or Alzheimer's disease.

<Table 7 displays significant promising findings of controlled studies for selected natural products under investigation for cognitive‑enhancing or dementia‑reversing activities. 

Although many traditional treatment approaches have been in continuous use among the world's major nonallopathic healing systems for centuries or longer, with apparent positive clinical results, systematic laboratory studies or controlled human clinical trials assessing indigenous treatments are only beginning. At present, limited conclusive evidence supports clinical efficacy or a neurophysiological mechanism of action that might explain putative memory‑enhancing properties of these traditional treatments.

Depression and other Mood Disorders

  Allopathic psychiatry has operationally defined a family of mood disorders, many of which have an unequivocal biological basis and have been empirically demonstrated to respond to treatments following rigorous control conditions. Major depressive disorder, as defined in the Diagnostic and Statistical Manual,21 is a serious mood disorder resulting in significant social and occupational impairment. The international cost in terms losses in productivity resulting from major depression is enormous. Therefore, considerable research is ongoing to synthesize or to discover novel pharmacologic treatments for depression. These efforts include programs to identify herbal compounds from the world's indigenous healing systems that offer effective treatment for mood disorders, including major depressive disorder. Currently available antidepressant medications do not offer cures for major mood disorders, have delayed onset of action, frequent side effects resulting in poor compliance, or premature discontinuation, and generally offer relief in only 60% to 70% of cases. Patients who respond to currently available treatments seldom experience complete remission of depressive symptoms and frequently relapse while compliant with recommended pharmacologic treatment protocols. Although considerable progress has been made in reducing side effects and improving overall safety, little progress has been achieved in overall efficacy of synthetically manufactured antidepressant medications.59

Recently, a popular herbal treatment, long‑used for diverse indications in European traditional naturopathic medicine,60 has experienced widespread acceptance in the United States because of a renewed media campaign. St John's Wort (Hypericum perforatum) has been used in diverse European traditional healing systems for more than a millennium. At different times in diverse traditions, it has been used to treat diabetes, ulcers, gastrointestinal disorders, as a wound‑healing and anticancer agent, and for a variety of neurologic indications.

Preparations of St John's Wort have been recommended or prescribed by European medical doctors and naturopaths for the treatment of depression and certain anxiety states for centuries, although questions as to its efficacy and mechanism of action remain unresolved. In addition to the putative efficacy of St John's Wort preparations for the treatment of unipolar depression, a few studies have shown promising results for its use in the treatment of seasonal affective disorder.61 More than a dozen preparations containing St John's Wort alone or in combination with other botanicals are marketed in European countries as prescription or over‑the‑counter drugs. Equivalent preparations are rapidly becoming available in the United States.

  Although the precise neuropharmacological mechanisms of several active constituents in St John's Wort are not yet completely elucidated, the common clinical understanding is that discrete molecules within the raw herb extract function as serotonin reuptake inhibitors or monoamine oxidase (MAO) inhibitors. However, a 1997 study62 conducted by one of Germany's principle manufacturers of herbal medicines, revealed insignificant inhibition of MAO‑A or MAO‑B, while confirming reuptake inhibition of dopamine, serotonin, and norepinephrine. The researchers in this study also concluded that the active constituent responsible for reuptake inhibition of all 3 neurotransmitters is not hypericin, as previously assumed, but a poorly characterized constituent called hyperforin.62 This finding has practical clinical significance because most commercially available preparations of St John's Wort continue to be standardized to a specific percent of hypericin . However, a major German‑based pharmaceutical firm, Schwabe, recently started to manufacture a St John's Wort preparation standardized to 5% hyperforin after reportedly conducting an in‑house clinical trial demonstrating superior efficacy compared to preparations standardized to 0.3% hypericin.63 In another study,64 clinical improvement in depression was demonstrated to be dependent on percent composition of hyperforin. Recent in vitro research also demonstrates that crude St John's Wort extract has a modulatory effect on central GABA‑B receptors. At present, specific dose‑response characteristics of depression to hype hyperforin­standardized extracts of St John's Wort are being investigated. In addition to direct effects on several neurotransmitters, there is evidence that preparations of St John's wort may inhibit interleukin‑6, indirectly resulting in increased cortisol production, possibly resulting in an additional indirect antidepressant effect.

In 1996, a meta‑analysis of 23 randomized trials comparing St John's Wort with placebo or other drug treatment regimens for depression was published in the British Medical Journal.65 The studies included 2 controlled trials matching St John's Wort against imiprimine and maprotiline, respectively.66 Based on self-completed and physician‑administered symptom inventories, no significant response difference was found between St John's Wort and either synthetic drug. However, time to onset of clinically significant response appeared to be longer for St John's Wort, which was also notable for significantly fewer side effects than imiprimine and maprotiline. Because of difficulties comparing studies due to methodological differences and the absence of a standard herbal preparation across studies, no strong conclusions were reached about the efficacy of St John's Wort for treatment of depressive disorders. However, "good evidence" suggested that St John's Wort was more effective than placebo for treatment of mild or moderate depressive symptoms. Researchers at the Center for Complementary Health Studies at the University of Exeter, the United Kingdom, performed another meta‑analysis of trials on St John's Wort.67 Their analysis developed a series of criteria to evaluate the rigor of randomized clinical trials on St John's Wort mono‑preparations, ie, herbal preparations were evaluated that contained St John's Wort only. Nine controlled studies that satisfied criteria for methodological rigor were identified and included in the metaanalysis. These included 3 studies comparing St John's wort to synthetic antidepressants. Unlike the meta‑analysis published in the British Medical Journal, this more focused analysis concluded that St John's Wort is superior to placebo for treatment of depression. Reasons for the discrepancy in findings of these 2 meta‑analyses clearly relate to methodological differences that led to ambiguous results due to the impossibility of making rigorous comparisons between trials using criteria employed in the British Medical Journal study. In the hope of resolving ambiguities, several studies using standardized preparations and improved controls are presently under way, and a large multicenter study sponsored by the National Center for Complementary and Alternative Medicine, NIH, began in mid‑1998.

TABLE 8 Selected natural products investigated for antidepressant activity

Natural product Comments
S‑adenosyl
methionine 62,69-71
Several double-blind placebo-controlled studies, using daily doses of 800-1600 mg, show antidepressant efficacy comparable to imiprimine and superior to placebo.

Mechanism of action is facilitation of neurotransmitter biosynthetic pathways (dopamine and serotonin) assisted by vitamin B12 and folic acid.

Reported to exacerbate mania in bipolar patients.
St John's Wort (Hypericum   perforatum)63,64,72‑78 Many controlled double-blind trials show efficacy similar to standard synthetic antidepressants.

Principle active ingredient recently clarified as hyperforin, but several constituents likely contribute to effect,

Mechanism of action likely combined synaptosomal reputake inhibition of serotonin, norepinephrine, and dopamine, possible weak MAO inhibitor effect.

Some evidence that interleukin-6 inhibition is involved in antidepressant mechanism.

More studies ongoing to clarify mechanism, elucidate efficacy for treatment of specific mood disorders.
Ginkgo biloba79 Positive response in depressed elderly patients. with mild-to-moderate cognitive dysfunction and nonresponse history to therapeutic trials on tricyclic antidepressants.

Additional research ongoing to clarify mechanism, efficacy in depression.
L‑tryptophan80‑82 As effective as imiprimine and amitriptylene in treatment of unipolar depression.

Fewer side effects than tricyclic drugs.

More effective than light therapy for treatment of seasonal affective disorder.    

Patients with normal or high urinary methoxyhydrophenylgylcol levels more likely to respond.
L‑tyrosine83,84 Isolated case reports of significant symptom reduction in individuals refractory to standard drug therapies.

Patients with low urinary methoxyhydrophenylgylcol levels more likely to respond.
D,L phenylalanine85,86
80% response rate in 1 open clinical trial.

Likely mechanism similar to imiprimine.

D-phenylalanine isomer probably has greater mood-elevating effects than L-isomer.
Pyridoxine 
(vitamin B6)87,88
Significant number of depressed patients have documented vitamin B6 deficiency.

Functions as enzyme cofactor for conversion of L-tryptophan to serotonin and L-tyrosine to norepinephrine.

Depression more frequent in patients with gastrointestinal pathology causing reduced vitamin B6 absorption.

Depressed patients with celiac disease responded to high-dose exogenous vitamin B6 therapy.
Folic acid89,90 Deficiency states associated with conditions such as depression, apathy, fatigue, and anxiety. Depressed psychiatric patients had consistently lower serum folate levels.
Vitamin B1291,92 Deficiency states associated with depression that responds dramatically to replacement therapy.
Vitamin C93 Case reports suggest association between response to vitamin C in depression with documented low cerebrospinal fluid serotonin levels.

Double-blind study of chronic psychiatric inpatients showed improvements in depressed mood and other psychiatric symptoms.
Magnesium94,95 Numerous case reports of improvement in depressed mood or chronic pain with intravenous magnesium administration.

Double-blind study showed significant improvement in premenstrual mood symptoms.
Inositol96 Evidence that lithium carbonate treats mania by reducing CNS inositol levels.

Cerebrospinal fluid inositol levels are low in depressed patients.

Double-blind study showed inositol mono-therapy effective in treatment of depression including significant improvements in mood, agitation, and anxiety symptoms.
Valerian (Valeriana officinalis)97 Evidence from animal studies suggests possible antidepressant effect.


In addition to St John's Wort, controlled clinical trials have investigated a variety of naturally occurring substances for antidepressant activity. Popular attention has been attracted by S-adenosyl-methionine (SAMe), which has recently been introduced to the US market as a dietary supplement. When activated by vitamin B12 and folic acid, SAMe indirectly supports biosynthetic pathways for serotonin and dopamine production, changing available CNS levels of 2 neurotransmitters centrally implicated in depression and other neuropsychiatric disorders. Numerous double-blind studies have demonstrated favorable results when compared with imiprimine or placebo. There is also accumulating evidence that SAMe is effective against chronic pain disorders frequently seen in depressed patients, including fibromyalgia. Preparations of Ginkgo biloba have also been found effective in treating a population of elderly patients suffering from depression comorbid with mild to moderate cognitive impairment" that were refractory to therapeutic trials on conventional synthetic antidepressants. Table 8 summarizes significant findings of published controlled studies investigating the efficacy of selected naturally occurring substances for the treatment of unipolar depression or other mood disorders.

Anxiety and Sleep Disorders

Anxiety is caused by psychological distress or physiological factors associated with metabolic, endocrinologic, or neurochemical changes that are experienced as subjective anxiety states. Three long-established systems of healing, Western allopathic medicine, Ayurvedic medicine, and TCM conceptualize anxiety symptoms and syndromes as acute or chronic conditions. Different syndromes are differentially related to ongoing or episodic distress and numerous other underlying causitive factors depending on the acuity or chronicity of symptoms, and specific symptom patterns.100 As for mood disorders, allopathic psychiatry has advanced the concept of a family of anxiety disorders in which a particular psychopathological state is constellated from a specific symptom pattern. Though viewed as discrete diagnostic entities, many anxiety disorders are conceptualized as existing on a continuum reflecting measurable differences in, for example, severity, chronicity, and symptom type.

TABLE 9 Kava-kava used to treat anxiety

First scientific studies examining anxiolytic properties from 18th century.

Active ingredients are 5 kava lactones isolated from root extract. Combined action underlies anxiolytic effect.

Likely CNS site of action is brainsterm reticular activating system.

Total recommended daily dose of kava lactones is 200 to 250 mg in 2 to 3 divided doses.

Chronic use of recommended therapeutic doses does not result in tolerance or dependence.

Significant anxiety reduction demonstrated after I week in placebocontrolled trial using standardized kava extract.

Uncommon side effects at typical doses include mild gastrointestinal disturbance and allergic dermatitis.99

Unresolved issue of reported kava-induced dermopathy (dry scaly skin rash) seen only after ingestion of large quantities (does higher than several grams daily).

German Commission E advises against use during pregnancy or lactation or with concomitant use of other CNS depressants, including EtOH, barbiturates, and antidepressants.

Double-blind placebo- controlled study (N = 58) using 100 mg extract standardized at 70% kava lactones 3 times daily showed significant anxiety reduction measured by HAM-A and global improvement in well-being measured by CGI after 1 week, which progressed during the 4-week study period.100

Comparison studies with benzodiazepines showed anxiolytic activity without impairment of cognitive functioning.101

Observed therapeutic effects include muscle relaxation, analgesia, and anticonvulsant properties; may protect brain during transient ischemia (N. N. Sing, unpublished data, 1998).

State anxiety level due to interpersonal problems or cognitive and environmental stressors decreased for the Kava group on 240 mg daily dose; trait anxiety level did not improve.

Double-blind study (N = 40) on the effects of Kava extract 100 mg 3 times daily (70% kava lactones) on climacteric-associated anxiety in women showed significant decrease in anxiety (HAM-A) and enhanced well-being (CGI). No adverse reactions were reported.102

Multicenter 25-week placebo-controlled double-blind study (N = 101) of outpatients with anxiety or tension of nonpsychotic origin meeting DSM-III-R criteria for social or specific phobias, agoraphobia, or adjustment disorder/anxious, 100 mg 3 times daily (70% lactones), HAM-A measured at weeks 0, 4, 8, 12, 16, and 24, CGI measured pretest and at weeks 12 and 24, showed significant overall anxiety reduction from week 8 and significant improvement in daily functioning throughout. Nine patients dropped-out (6 from control group, 3 from Kava group).103

Multicenter double-blind (N = 172) study compared kava extract 210 mg/day to oxazepam and bromazapam for treatment of anxiety or agitation of nonpsychotic origin. Patients randomized to receive kava extract 100 mg, oxazepam 5 mg, or bromazepam 3 mg 3 times daily for 6 weeks. Anxiety and tension were measured at baseline and at 1, 3, and 6 weeks. All medications had equivalent antianxiety effects and rare or mild side effects.104

CGI indicates Clinical Global Impression scale; HAM-A, Hamilton Anxiety scale.

Many herbal preparations that are widely used to treat anxiety states in nonallopathic or allopathic medicine, are also employed, but at significantly higher doses, to induce sedation. In these cases, herbal preparations used to treat anxiety are likewise employed when inducing sleep is clinically indicated to relieve insomnia or other symptoms of distress or fatigue. However, certain preparations selectively function as anxiolytics without causing sedation, whereas others cause sedation to an extent that makes their use as anxiolytic agents inappropriate or unsafe.

As noted in the introduction, human behavior reflecting distress that is regarded as illness is highly variable across cultures. Many so-called culture-bound syndromes have been identified that appear to reflect culture-specific patterns of psychological symptom formation around acute anxiety states.13 Studies have attempted to identify possible common underlying neurochemical or other biological changes associated with anxiety states in divergent cultural settings. To date, a common biological cause has not been elucidated. However, the existence of a common neurobiological basis for anxiety is supported by evidence that traditional herbal preparations used to treat anxiety states in one culture often have comparable efficacy against phenomenologically similar anxiety symptoms in a culture characterized by markedly different idioms of distress. It is also clear that benzodiazepines (potent GABA receptor agonists) typically have a predictable calming or sedating effect regardless of cultural context or symptom pattern. This finding lends support to the dominant allopathic model that relates excessive or maladaptive anxiety states to dysfunction at the level of CNS GABA receptors.

Among natural substances used in the world's indigenous healing systems to treat anxiety states or to induce sedation, preparations of 4 herbals are best known: valerian root, ginseng, Kava-kava, and Chamomile. Table 9 reviews significant research findings pertaining to Kava-kava, a traditional medicine from Polynesia, which has recently come into widespread use in Europe and the United States. In China, preparations of ginseng have been used in the treatment of anxiety and many other psychological and physical symptoms for at least 5,000 years. Table 10 reviews recent studies of natural products with putative anxiolytic or sedating properties.

TABLE 10 Selected natural products investigated for antianxiety activity

Natural Product

Comments

Valerian root extract                   

  (Valeriana officinalis)105
Reduces sleep latency and improves sleep efficiency.
Shown effective in diminishing mild to moderate anxiety states.
Effect likely mediated through GABA antagonist activity.
Patients do not develop tolerance or dependence with chronic use.
May be useful adjunct in treatment of benzodiazepine withdrawal.
May potentiate CNS alcohol effects.
Often combined with extract of lemon balm M. officinalis) for enhanced sedation effect.
Ginseng (Panax ginseng)106        
Ginsenosides are active molecules with putative anxiolytic effect.
Indirect evidence of MAO inhibition as possible underlying
mechanism for anxiolysis.
Evidence that ginseng improves human performance under stress.
Does not impair motor performance or memory.
Tolerance or dependence do not develop with chronic use.

Chamomile (Matricaria
     reenters)107
Active ingredient is apigenin, shown to competitively inhibit CNS benzodiazepine binding without sedation.
No known contraindications.
Tilia species (Tilia tomentosa)108 Used in preparations for treating anxiety states in Latin America.
In vitro assays confirm active ingredients are benzodiazepine
receptor ligands.
Animal studies show clear anxiolytic effect without accompanying
sedation.
Jasmine (Jasminurn
officinale)109
Many traditional medicinal uses over centuries including sedating arid anesthetic effects Animal studies demonstrate sedative and antiaggression effect of ethanolic extract.
No evidence of toxicity.
Mikania cordata110 Used for many indications in several indigenous traditions.
Controlled animal study showed reduction in stress-induced decrease in norepinephrine and epinephrine; increase in dopamine, and normalization of serotonin,
Investigators concluded that the extract selectively prevents or normalizes stress-induced changes in several different neurotransmitters.


SUMMARY 

Based on controlled studies or other empirically validated information, there is substantial, in many cases unequivocal scientific evidence supporting the efficacy of naturally occurring substances as clinically useful and safe psychotropic agents for the treatment of a range of neuropsychiatric symptoms or disorders. Informed by ethnographic studies on indigenous healing practices, researchers at major universities, government‑sponsored institutes, and in the pharmaceutical industry continue to identify natural product‑derived substances that are prospective candidates for novel psychopharmacologic agents. Table 11 displays selected promising research findings pertaining to natural substances with demonstrated efficacy for treatment of the neuropsychiatric disorders discussed in this review. These disorders are seizure disorders; dementia and age‑related cognitive decline; anxiety disorders; unipolar depression and other mood disorders; schizophrenia and other psychoses; and substance abuse and addiction.

TABLE 11 Natural products as treatments of neuropsychiatric disorders: summary of significant promising findings

Disorder

Natural product
Healing paradigm
Promising results
Seizures
Brahmighritham (com-pound formula)

Ayurveda
Seizure protection comparable to 
  benzodiazepines
Substance abuse
Camellia japonica
Aralia elata
Panax ginseng
Withania somnifera

Mentat (compound formula)
Kampo
TCM
TCM
Ayurveda

Ayurveda
Inhibits alcohol absorption
Inhibits alcohol absorption
Diminishes adverse CNS effects chronic
Prevents tolerance and dependence to
  morphine
Reverses symptoms of acute benzodiazepine
  withdrawal
Psychotic disorders
Glycine
Brahmyadiyoga (compound formula)

Ayurveda
Improves negative psychotic symptoms
Antipsychotic activity comparable to
  chlorpromazine
Dementia (or cognitive decline)
Thiamin

Kami-untan-to (com-pound formula)
Mentat (compound formula)
Qlan Jin Yi Fang (compound formula)
Phosphatidylserine
Docosahexaenoic acid

Ginkgo hiloha


Kampo

Ayurveda
TCM




TCM
Improves cognitive functioning in Alzheimer's
  patients taking 3-8 gm/day
Improves performance in dementia and
  age-related memory loss
Improves overall cognitive performance
Improves normal age-related memory loss

Improves age-related cognitive decline
Improves cognitive performance in multi-infarct dementia or Alzheimer's disease
Improves mild to moderate memory loss in Alzheimer's disease and multi-infarct
dementia
Depression
Hypericum perforatum

L-tryptophan

D-phenylalanine
Magnesium

Inositol
S-adenosyl methionine
Naturopathy
Several controlled studies demonstrate
  efficacy for mild to moderate depression
As effective as some tricyclics for unipolar
  depression
Excellent response rate in open trial
Improves depressed mood and premenstrual
  mood symptoms
Improves mood, agitation and anxiety
  symptoms
Antidepressant efficacy comparable to
  imiprimine
Anxiety
Piper methysticum


Valeriana officinalis
Polynesia


Naturopathy
Improvement equivalent to
 benzodiazepines for generalized
 anxiety, social and specific phobias
  and agoraphobia
Effective for mild to moderate anxiety

Note: Simple herbal formulas include Latin binomials in italics, and compound herbal formulas or other naturally occurring substances are designated as such.

   Many natural products reviewed in this paper have been systematically employed in indigenous healing systems for centuries or longer and are presently being investigated within allopathic medicine to assess their efficacy in the treatment of symptoms or illnesses that bear phenomenological resemblance to allopathic concepts of neuropsychiatric disease. In many cases, this process is tantamount to the rediscovery by allopathic medicine of empirically validated nonallopathic therapies. Many putative psychotropic substances reviewed above have efficacies that are comparable to existing synthetic drugs, similar or superior side effect and toxicity profiles, and (unlike most synthetic psychotropic agents) are potentially available and affordable to the majority of the world's population. These reasons are a sufficient basis for mandating the continued conservation of tropical biodiversity in regions where plants or other natural sources of promising medicinal agents are indigenous. The continuing pursuit of thoughtful investigations into medicinal uses of these and other natural substances will eventually lead to their widespread clinical applications in many regions of the world, addressing the urgent unmet demand for improved global mental healthcare.

RECOMMENDATIONS

Establishment of a Cooperative International Research Program

Significant ethnopharmacologic research efforts are ongoing in diverse settings around the world to characterize the psychotropic efficacy of naturally occurring substances. In many cases, there is limited contact between research centers performing related, sometimes identical studies. This absence of communication and liaison has resulted in redundancy, missed opportunities for cooperative research, and delayed research progress. The establishment of a task force with strong international representation will significantly improve progress in all stages of natural product research and development of novel psychotropic medications. To permit the development of an effective network of researchers, the task force should be multidisciplinary in make-up, and include pharmacists, anthropologists, botanists, and pharmacognosists, as well as Western-trained medical doctors and recognized practitioners of indigenous healing systems. Ideally, this task force will have the support and cooperation of the Office of Traditional Medicine of the WHO as well as government-sponsored institutes in participating countries, including the NIH, Office of Alternative Medicine. The recently established International Cooperative Biodiversity Group Programs, jointly established by the NIH, the National Science Foundation, and US Agency for International Development in 1995 to promote pharmaceutical discovery while conserving global biodiversity, might provide structure and initial funding for the proposed research program.

Establishment of a Center for Alternative Medicine for Psychiatry

The National Center for Complementary and Alternative Medicine has already established several centers for alternative medicine to promote research and education regarding alternative therapies for a variety of medical illnesses. A center for alternative medicine should be established with the parallel objective Live of facilitating research programs that will empirically evaluate the efficacy of alternative (nonallopathic) treatments in psychiatry, including studies on natural substances with putative psychotropic activity. An initial task in this effort should be a systematic comprehensive review of the scientific and ethnographic literature on treatments of neuropsychiatric symptoms using natural substances. The literature review on which the present paper is based represents a first rough effort toward that end.

Global Ethnopharmacological Survey Emphasizing Treatments of Neuropsychiatric Symptoms and  Syndromes

The TRAMIL Program (Applied Research on the Traditional Popular Medicine in the Caribbean Basin)... has been ongoing since 1983 with the objectives of establishing a "regional applied research program toward the improvement and rationalization of folk medicinal practices..." in the Caribbean basin. The program enlists the collaborative aid of a network of established research centers in order to plan and carry out surveys on uses of traditional medicines and to provide feedback of accurate information about treatments to indigenous Caribbean populations. An analogous program with parallel objectives, should be established on a global scale with the sole purpose of investigating, and preserving indigenous knowledge pertaining to treatments of neuropsychiatric disorders.

Development of Improved Standards for Ethnopharmacologic Research

It is an unfortunate historical fact that many investigations of the pharmacologic efficacy of natural products are anything but scientific.112 There is little uniformity of standards defining precise experimental protocol including sample collection, preparation or defining of controls surrounding the performance of in vitro assays, animal studies or human trials investigating the efficacy of natural substances. There is also inadequate use of computerized databases for correlative data analysis, resulting in missed opportunities for synthesis of related ethnopharmacologic data. The systematic critique and reformulation of standards for ethnopharmacologic research should be an initial task of the proposed International Cooperative Biodiversity Group on psychiatry or the proposed center for alternative medicine on psychiatry (see Establishment of a Center for Alternative Medicine for Psychiatry).

Improved Networking Among Indigenous Healers

With the global availability of the Internet, opportunities for networking and liaison have achieved an unprecedented level. A few years ago it would have taken months and significant funds to locate and efficiently communicate with individuals in geographically remote parts of the world. Today, the Internet affords almost real-time access to researchers and healers in most countries who are exploring shared interests in investigating the efficacy of naturally occurring substances as psychotropic agents. Communication and international collaboration via the Internet will lead to consolidation of many local research efforts and acceleration of progress in ethnopharmacology research in general.

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