Clinical Trials Indicate Value of Herbal Medicines

(This is the second of two articles regarding herbal medicines as discussed at the American Psychiatric Association's annual meeting in Toronto. The first article, "Herbal Medicines Pose Potential Drug Interaction Hazard," appeared in the August issue-Ed.)

Potential benefits and risks of kava, St. John's wort and hoasca were considered at the recent American Psychiatric Association's symposium on herbal medicine.

Dennis McKenna, Ph.D., director of ethnopharmacology at the Heffter Research Institute, presented "Kava: Ancient Beverage to Modern Psychotherapeutic Medicine." Although McKenna's primary research interest is in the usage of psychedelic substances in indigenous cultures, he emphasized that kava exerts anxiolytic, rather than hallucinogenic, effects. McKenna's work with kava has occurred in projects funded by the health supplement industry to characterize the variety of kava plant sources and chemical composition.

According to a review in the Hawaii Medical Journal, there are approximately 200 varieties of kava plant in the Pacific, each differing in the potency of psychoactive components, which are yielded primarily from lower stems and upper roots (Norton, 1998). The plants, closely related to black pepper, were categorized Piper methysticum, "intoxicating pepper," by naturalists on English explorer Captain James Cook's 1768 voyage on the Endeavor.

McKenna reported that approximately 17 kava-lactones have been isolated and chemically characterized, with only six considered major constituents. He attributes the variation in psychotropic activity of the different plant sources to their varying amounts and proportions of these components.

In a review paper, Scott Norton, M.D., M.P.H., M.Sc., described the traditional context for kava use in the South Pacific islands as occurring within a ceremony, attended only by men, which has been "unchanged for the millennia." Norton describes the kava drink, which is prepared by grinding the stems and roots with water in mortars, as a "nonfermented depressant that causes tranquil intoxication in which thoughts and memory remain clear."

In the ceremony, Norton wrote, "All members sit, usually barefoot and cross-legged, on the ground. The presiding members and honored guests have their places, as do men who prepare, mix and serve the kava. Cups of kava are filled, passed to an individual for consumption, returned and refilled in several-to-dozens of rounds in an evening."

McKenna pointed out that the apparent safety of kava's use in traditional contexts may not necessarily apply to different usage in other cultures, or with the concentrated and purified extracts that are marketed outside these traditional settings. He offered the example of its introduction to aboriginal communities in Australia to serve as an alternative to alcohol, which was being widely abused.

"It [kava] became the alternative to alcohol, and was similarly abused because these people couldn't get alcohol," McKenna said.

The safety of kava also may be compromised, as Michael Smith, M.D., symposium chair, indicated is the case with other herbal medicines when used in combination with other pharmacologically active substances. One case report in the U.S. literature describes its adverse interaction with alprazolam (Xanax) (Almeida and Grimsley, 1996).

In two studies comparing a standardized extract of kava roots (WS 1490) to the benzodiazepine anxiolytic oxazepam (Serax), results from a battery of standardized tests indicated a tendency for cognitive improvement with kava and some reduced cognitive function with oxazepam (Heinze et al., 1994). Anxiolytic effect of a kava extract has been demonstrated against placebo in at least three controlled trials conducted in Germany (Kinzler et al., 1991; Warnecke, 1995; Volz and Kieser, 1997).

St. John's Wort

Jerry Cott, Ph.D., chief, Adult Psychopharmacology Research Program, Adult and Geriatric Treatment and Prevention Branch, National Institute for Mental Health (NIMH), described the investigations with St. John's wort (Hypericum perforatum) in his presentation, "Antidepressant Activity of Hypericum perforatum: St. John's Wort." Cott indicated that, despite the popularity of preparations from the plant, much remains to be elucidated about the active components, mechanism and clinical effects. While more research is needed, investigators (Linde et al., 1996) who conducted a meta-analysis of clinical trials with extracts of St. John's wort concluded that it "was significantly superior to placebo, and appeared comparable to standardized anti-depressants while producing fewer side effects."

Cott said this meta-analysis comprised 23 trials in a total of 1,757 outpatients with mild to moderately severe depressive disorders. The trials differed in methodology and in the preparations and dosages of the plant product. Each trial was either randomized or "quasi-randomized" through alternation and, in each, the herb was compared alone or in combination with other plant extracts to placebo and/or a standard antidepressant.

In 13 placebo-controlled studies, 55.1% (225) of patients were improved with St. John's wort compared to 23.3% (94) of those receiving placebo. In comparison with a standard antidepressant, the single plant extract was associated with improvement in 63.9% (101) compared to 58.5% (93) on the standard medication. The plant employed in a combination product in another trial produced improvement in 67.7% (88) compared to 60% (66) so improved on the standard antidepressant. Side effects occurred in 50 (19.8%) patients on Hypericum and 84 (52.8%) patients on standard antidepressants.

While the conclusions from this meta-analysis are based upon small studies of varying methodology conducted primarily in Europe, Cott indicated that the effectiveness of the product will soon be ascertained in a large clinical trial in the United States. This study is jointly sponsored by NIMH, the Office of Alternative Medicine and the Office of Dietary Supplements. The three-arm study design will compare the plant product to placebo and to the selective serotonin reuptake inhibitor (SSRI) antidepressant sertraline (Zoloft) in more than 300 patients with major depression in an eight-week acute treatment phase (PT February 1998).

Cott pointed out that while it is generally assumed that hypericin and related compounds are the psychoactive component of Hypericum, the pharmacologic evidence for this is lacking. Cott indicated that recent data suggest that hyperforin may be an important constituent. A mechanism of action also remains elusive, according to Cott.

"The most often cited effects, monoamine uptake inhibition and MAO [monoamine oxidase] inhibition, have not been shown in vivo, and no drug interactions or side effects have been reported that are consistent with either mechanism," he said.

Cott has found with in vitro screening that the crude plant extract, but not pure hypericin, inhibits monoamine oxidase (MAOA and MAOB), and binds to receptors of adenosine, benzodiazepine, inositol triphosphate (IP3) and gamma aminobutyric acid (GABAA and GABAB). The binding to GABA receptors at relatively low concentration is particularly indicative, according to Cott, of its likely occurrence in humans at pharmacologic dosages. In contrast, Cott has found that the initial European reports of in vitro mono-amine reuptake inhibition and of inhibition of serotonin receptor expression with St. John's wort only occurs at concentrations unlikely to be attained in humans.

Despite a recent European study characterizing the plant product as a "rather potent" inhibitor of the uptake of serotonin, norepinephrine and dopamine (Mller et al., 1997), Cott related, "while several mechanisms of action have been proposed for Hypericum, none are particularly convincing."

Researching Hallucinogens

In seeking therapeutic herbal medicines, researchers are increasingly examining how indigenous peoples utilize botanicals, including hallucinogenic substances.

Charles Grob, M.D., associate professor of psychiatry at the University of California, Los Angeles (UCLA) School of Medicine, and director of the Division of Child and Adolescent Psychiatry at Harbor-UCLA Medical Center, indicated in his presentation, "Plant Entheogens as Medicine," that formal psychiatric research with hallucinogens has recently resumed after a 25-year period of "virtual prohibition" on such scientific inquiry.

Grob attributes the quarter century absence of research with hallucinogens to a backlash response to unscientific experimentation and illicit use of hallucinogens in the 1960s. He pointed out, however, that suppression of research with these substances has earlier precedents.

"The shamanistic use of hallucinogenic plants as agents designed to facilitate healing, acquire knowledge and enhance societal cohesion [was] brutally repressed in both the Old and New Worlds by the progenitors of our own contemporary Euro-American cultures, often with the complicity of the medical professions [Grob, 1994]."

The recent improved support and attitude toward this field of research was marked by a technical meeting of the National Institute of Drug Abuse in 1992, attended by Grob. It was the consensus of that meeting that it is now appropriate, with the technology available to perform functional brain imaging and neuroendocrine and neuroreceptor assessments, to progress from animal studies to, again, studies of the effects of these substances in humans.

"The strategy of pursuing such biological investigations will likely not only yield valuable new information in the neurosciences," Grob has written, "but facilitate the relegitimization of human research with hallucinogens and ultimately become prelude to the re-exploration of their effects on perception, cognition and emotion [Grob, 1994]."

Grob described his own recent investigation of the botanical hallucinogen mixture hoasca, also known as yag and daime (Grob et al., 1996). The hallucinogen is brewed from a woody vine the Mazan and Zaparo Indians call ayahuasca (Quechua for "vine of the souls" or "vine of the dead") and the leaves of the hallucinogenic tryptamine-containing plant Psychotria viridis (chacarona plant). The botanical designation of ayahuasca (Banisteriopsis caapi) was originally documented by English botanist Richard Spruce in the mid-1800s, who also identified Hevea, the genus of the rubber tree, and Cinchona calisaya, the source for quinine. Analysis of ayahuasca has revealed the psychoactive beta-carboline alkaloids harmine, harmaline and tetrahydroharmine; and N,N-dimethyltryptamine (DMT) is yielded from the Psychotria viridis(Callaway et al., 1996).

The combination of ayahuasca and Psychotria viridis by the Indians of the Amazon-like the addition of Piper longum or Piper nigrum to an active herb in Ayurvedic medicine as described in the August article-is another example of an ancient, empirical enhancement of pharmacological effect by drug metabolism inhibition.

James Callaway, Ph.D., of the department of pharmacology and toxicology, University of Kuopio, Finland, has noted that DMT from the Psychotria is a short-acting psychotropic agent when administered parenterally, but it is not orally active because of its degradation by MAOA in the gastrointestinal tract. When combined with ayahuasca, however, the harmala alkaloids serve to inhibit the activity of MAOA, and psychoactive effects are exerted by the orally administered DMT (Callaway et al., 1996).

Grob's investigation of the use of hoasca among peoples of the Brazilian Amazon was sponsored in part by the Heffter Research Institute, and was conducted with McKenna, Callaway and other colleagues, including medical faculty in Brazil from the Centro De Estudos Medicos, So Paulo, and psychiatry faculty from the Departamento Psiquiatria of the Universidade Estudial do Rio De Janeiro and of the Escola Paulista de Medecina, So Paulo (Grob et al., 1996).

Grob had explained the rationale for such research earlier, in the Yearbook of Ethnomedicine: "If we are to develop optimal research design for evaluating the therapeutic utility of hallucinogens, it will not be sufficient to adhere to strict standards of scientific methodology alone. We must also pay heed to the examples provided us by such successful applications of the shamanic paradigm [Grob, 1994]."

Grob described the application of a rigorous research protocol, including blood draws for pharmacokinetic studies, in the primitive setting of the Amazon as "a fascinating experience." The project was featured in the British Broadcasting Corporation documentary "Psychedelic Science," which recently aired in the United States on the Arts and Entertainment cable channel in their "Unexplored Mysteries" series.

The researchers selected 15 long-term members of the syncretic church, Unino do Vegetal (UDV), chosen randomly from among volunteers in the town of Manaus. These individuals had utilized ayahuasca in the context of their church rituals a minimum of twice monthly, and some as often as several times per week. Grob noted that their adherence to the rituals necessitated abstinence from all other psychoactive substances, including alcohol, tobacco, marijuana, cocaine and amphetamines. An additional 15 subjects who did not consume ayahuasca, but were demographically matched, served as controls.

The investigators applied a battery of tests to assess past and current psychological functioning, including the Composite International Diagnostic Interview, the Tridimensional Personality Questionnaire and the WHO-UCLA Auditory Verbal Learning test of neuropsychological functioning. The users of the hallucinogen also completed the Hallucinogen Rating Scale.

Grob and colleagues reported that despite a number of the subjects having had alcohol, depressive or anxiety disorders prior to their participation in the church ritual use of the hallucinogen, "all disorders had remitted without recurrence after entry into the UDV." The researchers qualify this finding as preliminary and tentative, and acknowledge the salutatory effects of support from religious affiliation. Nevertheless, they opine, "It is not inconceivable that the long-term use of the hoasca itself may have had a direct positive and therapeutic effect on our subjects' psychiatric and functional status."

Grob commented to Psychiatric Times, "We think this should be a reputable area of investigation for contemporary medical psychiatric researchers...it is possible to research this area in an objective, scientific manner and come back with valuable information."

References:

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