Psychoactive Herbal Medications

Psychoactive Herbal Medications

Marcello Spinella

How Do We Know They Work?

Numerous psychoactive herbal medications are available to treat cognitive and emotional conditions. This article examines the evidence for their effectiveness and our assurances that it’s not “all in our minds.”

The use of psychoactive plants is a phenomenon common to all human civilizations. The psychological and behavioral effects of such plants were likely recognized in prehistoric times, and their uses have been passed down across generations. Plants are the oldest and perhaps still the primary source of medicines. We are now able to synthesize novel drugs, but the bulk of psychoactive drugs still derive from plant sources. For example, caffeine is perhaps the most frequently used stimulant in the world, consumed in the form of soft drinks, tea, and coffee. Many herbal medications with reputations for treating illnesses are freely available to the public, but the empirical basis for their effectiveness often remains obscure. This article examines the evidence for psychoactive herbal medicines.

The Prevalence of Alternative Herbal Medications

Large surveys indicate that the use of alternative medicine is prevalent in the United States (Eisenberg et al. 1998). Forty-two percent of the population acknowledged trying at least one form of alternative medicine during the previous year, most commonly to treat chronic conditions such as back problems, anxiety, depression, and headache. The popularity of herbal medicine has enormous implications for medical professionals. Only about 40 percent of those patients surveyed informed their physician of their use of alternative medicine, and it was estimated that 15 million took prescription medications concurrently with herbal medications and/or high-dose vitamins. This presents an enormous potential for adverse interactions. For example, ginkgo biloba is known to prevent clotting and can interact with blood-thinning medications. At present, herbal medicines are sold as supplements as long as they are not represented as treatment for a disease (Dietary Supplement Health and Education Act of 1994). While this m ay meet legal standards, it leaves consumers with little information to guide them.

Alternative Herbal Medicine

Several alternative medicine systems employ plant drugs to cure ailments. Homeopathy posits that “like cures like,” so medications aim to mimic the symptoms of the illness and provoke a compensatory reaction. Chinese herbal medicine suggests that the illness arises from imbalances of the yin and yang energy within a person. Thus, treatment consists of bringing these two energies back into balance. Ayurvedic medicine is an ancient Hindu medical system that also employs herbs to treat illnesses.

While such philosophies surrounding herbal medicine may seem innocuous as long as the treatments are effective, an accurate conceptual model can impede further understanding of how they work and hamper the discovery of potential novel uses. Pharmacognosy is a scientific discipline that seeks empirical validation of the therapeutic use of plants through experimental and clinical research (Robbers et al. 1996). This research requires money, time, and effort, but it yields results that are proven and reliable. Such research seeks to minimize personal biases, extraneous influences, or pure chance.

Traditional Acquisition of Knowledge About Herbal Medicines

Traditional herbal medicine systems grew out of our serendipitous discoveries from interactions with plants. While traditional systems have arisen to explain their therapeutic effects, the beneficial effects of herbs were originally discovered by trial and error. One does not need to know why an herbal medicine works in order to derive benefit from it. The herb’s biochemical effects occur whether or not one has an accurate understanding of them. If the biochemical effects of an herb bring some form of benefit to an organism, its use will be behaviorally reinforced, provided that beneficial consequences are reasonably contiguous (occur close in time) and contingent (have a predictive relationship). This does not require any explicit knowledge about the plant other than an ability to identify it. An extreme example of this comes from the nascent field of zoopharmacognosy, which studies the therapeutic uses of plants among animals. Tanzanian chimpanzees are observed to use the Aspilia plant, from which they deri ve no apparent nutritional benefit (Rodrigues et al. 1985; Page et al. 1992). However, the plant contains a chemical called thiarubine-A, which protects against certain gastrointestinal parasites and microorganisms. Although the chimpanzees presumably do not have any detailed, formalized information about the plants, they derive some noticeable benefit from eating it and the behavior is reinforced.

Do Psychoactive Herbal Medications Work and How?

Several scientific disciplines contribute to our understanding of the herbal medicines (table 1). To fully understand the effects of a herbal medication, we must obtain a botanical description of the various parts of the plant and perform biochemical analyses to identify the constituents responsible for its effects. Pharmacological studies of the constituents determine their physiological effects and how the body metabolizes and eliminates them. Of particular concern is whether the ingredients cross the blood-brain barrier in sufficient quantities to enter the brain. Ethnobotany and ethnopharmacology study the cultural context of plant drugs showing how they are used and how beliefs are instilled about what they do.

Neurochemical and neurophysiological studies of herbal medicines can characterize the detailed effects of the drug on neurons. Psychology and psychiatry assess the mental and behavioral effects of the herbal medicine through clinical studies. Neuropsychology is particularly equipped to quantify and evaluate the specific cognitive effects of plant drugs with batteries of psychometric tests. Ideally, functional brain imaging techniques can be used to investigate psychoactive herbal medicines. The electroencephalogram (EEG) can grossly measure changes in the brain’s electrical patterns after a herbal medicine is given (Itil et al. 1998). More recent neuroimaging techniques such as positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) can detect regional changes in cerebral blood flow or glucose metabolism caused by a herb.

Thus, a psychoactive herbal medicine can be examined on multiple levels, from molecular interactions to behavioral and cognitive effects. Such results provide convergent evidence for the herb’s proposed mechanism of action.

Essential Features of Herbal Drug Studies

In addition to understanding how an herbal medication might work, we must also evaluate whether the herbal medication really works. Experimental studies of drugs must have certain critical elements (see table 2). Many studies done on herbal medications lack proper methodology, making their potentially useful results unreliable. Studies need to have a placebo control group, in which some subjects receive an inactive treatment that closely resembles the active treatment. Placebos create powerful expectations that influence the results of the study, especially when one is studying psychoactive drugs (Straus and von Ammon 1996; Gordon 1996). For example, placebos can create temporary antidepressant effects, but they differ from real antidepressants in terms of the pattern and persistence of the effect. In cases where it is difficult to ethically justify a placebo group, and thus deprive subjects of needed treatment, one can instead compare the herbal medication with an established treatment.

It is also useful to employ several doses of the drug and establish a dose-response relationship, showing that the magnitude of effect varies with the size of the dose. This strengthens the pharmacological nature of the effect and helps determine the appropriate dose for clinical use.

Another key element in the experimental study of psychoactive herbs is randomized assignment of subjects to the various control and experimental groups. Double-blindedness is also an essential facet of a controlled study. These features eliminate potential bias by the researcher and any self-selection effects by the subjects. Finally, statistical analysis of the results is needed to ensure they are not likely due to chance occurrence.

Clinical Decisions: Quality of Evidence

When evaluating a treatment for clinical use, one must consider the quality of evidence that supports it. A Canadian task force developed such guidelines (table 3), which have subsequently been adopted by other regulatory panels (Canadian Task Force on the Periodic Health Examination 1979; Woolf 1992).

The quality of evidence is categorized into three classes: Class I means that the treatment has at least one randomized, controlled study to support it. Class II evidence covers studies without randomization, cohort or case-control studies, or uncontrolled research with dramatic results. Class III evidence includes the expert opinions based on research and experience.

While the latter classes of evidence provide useful information, Class I evidence should be sought for all herbal medicines used clinically. Case studies and anecdotal reports can provide useful information and should be treated seriously, but they should also be followed up with verification by empirical research.

Psychoactive Herbal Medicines

The remainder of this article examines the research surrounding a few selected psychoactive herbs to illustrate some of the above topics:

St. John’s Wort

St. John’s Wort (Hypericum perforatum) is an herb traditionally used to treat depression, insomnia, and anxiety (Kowalchik and Hylton 1987; Heiligenstein et al. 1998). It contains several classes of chemical constituents that may contribute to its pharmacologic effects (Nahrstedt et al. 1997; Erdelmeier 1998).

There are several possible neurochemical mechanisms by which St. John’s Wort alleviates depression. Initial attention was drawn to hypericin and pseudohypericin since they inhibit the enzyme monoamine oxidase (MAO), as do several pharmaceutical antidepressants. However this effect is small at normal oral doses (Muller et al. 1997; Thiede and Walper 1994). Another constituent, hyperforin, blocks reuptake of the neurotransmitrers serotonin, norepinephrine and dopamine (Muller et al. 1998). This mechanism is also common to other pharmaceutical antidepressants, which similarly prolong the activity of those neurotransmitters. For example, fluoxetine (Prozac) and sertraline (Zoloft) block reuptake of seroronin. Hyperforin also similarly causes adaptive changes in the brain over time (Muller et al. 1994, 1997, 1998). Other neurochemical actions of St. John’s Wort have been discovered, but the actions of hyperforin may be sufficient to account for the antidepressant effect.

Electroencephalographic studies have shown St. John’s Wort creates changes in the brain activity consistent with those of other antidepressant drugs (Sharpley et al. 1998). A cognitive study in humans shows St. John’s Wort to lack any negative effects on attention, concentration, or reaction time (Schmidt and Sommer 1993). The antidepressant effects of St. John’s Wort have been supported in both animal and human research. A number of antidepressant-like effects are seen in animal models of depression (Chatterjee et al. 1998a, 1998b; Okpanyi and Weischer 1987). Meta-analyses have evaluated methodologically controlled human trials of St. John’s Wort, in which it proved superior to placebo (Linde et al., 1996; Kim et al. 1999). Hyperforin was shown to be a responsible ingredient in some studies, and a dose-response relationship was obtained. A few studies found St. John’s Wort to be equivalent in effectiveness to other standard antidepressants, including two selective serotonin reuptake inhibitors (Linde 1996; Vorbach 1994, 1997; Harrer et al. 1994; Brenner et al. 2000; Schrader 2000).

Although long-term safety of Sr. John’s Wort has nor been evaluated, it has not shown any serious toxicity in published reports (Heiligenstein et al. 1998). Side effect are generally mild and occur at a rate comparable to placebo (Ernst et al. 1998). Further, it may have a better side effect profile than pharmaceutical antidepressants (Kim et al. 1999; Schrader 2000; Linde et al. 1996). Phototoxicity has occurred in animals grazing on the plant, but this does not appear to be a problem in humans raking therapeutic doses (Brockmoller et al. 1997). However, pharmacokinetic interactions have been noted with the drugs warfarin, digoxin, theophylline, cyclosporin, and the protease inhibitor indinavir (Nebel et al. 1999; Ruschitzka et al. 2000; Johne et al. 1999; Yue et al. 2000; Miller 2000). Given their common mechanism of action, concurrent use of St. John’s Wort with other antidepressants is not recommended (Gordon 1998).

Thus, St. John’s Wort’s traditional reputation as an antidepressant is supported by neurochemical, animal, and human clinical studies. Although much research remains to be done, St. John’s Won is a prime example of a traditional herbal treatment verified by multiple levels of scientific research.

Ginkgo

Ginkgo biloba is a tree that grows characteristic fin-shaped leaves. It has been known in the Chinese medical literature as a treatment for memory loss for hundreds of years (Field and Vadnal 1998). A class of chemicals have been found unique to gingko, termed ginkgolides A, B, C, M and J, and bilobalide. Gingko extracts alter a number of neurotransmitter systems in the brain. They increase the activity of acetylcholine, at concentrations likely to be reached with normal doses (Kristofikova et al. 1992; Kristofikova et al. 1997; Taylor 1986). Acetylcholine is a crucial neurorransmitrer in memory and other cognitive abilities. Ginkgo may also produce cognitive effects by interacting with the neurotransmitters serotonin and norepinephrine (White et al. 1996; Ramassamy et al. 1992; Huguet et al. 1994; Brunello et al. 1985). It relaxes arteries and prevents blood platelet-formation, which would allow for increased blood flow

to the brain (Chen et al. 1997; Lamant et al. 1987). Finally, ginkgo has antioxidant and neuroprotective effects (Maitra et al. 1995; Lugasi et al. 1999).

EEG studies show that ginkgo creates electrical changes in the brain consistent with cognitive activation (Kunkel et al. 1993; Itil et al. 1998). These effects are comparable to those of the drug tacrine (Cognex), which is prescribed for Alzheimer’s disease. Ginkgo improves learning in several animal models, and several studies have assessed the cognitive effects of ginkgo in humans with Alzheimer’s disease, vascular dementia, and age-related cognitive decline. A meta-analysis of controlled studies showed that ginkgo produces statistically significant improvements in people with Alzheimer’s disease (Oken et al. 1998). While the magnitude of improvement with ginkgo is modest, it is comparable in size to the drug donezepil (Aricept), a standard treatment for Alzheimer’s disease. Preliminary results indicate that ginkgo may also improve cognitive function in normal adults as well (Subhan and Hindmarch 1984; Warotetal. 1991).

Clinical studies of ginkgo have not reported any serious side effects, and the incidence of side effects is equivalent to placebo (Field and Vadnal 1998; Le Bars et al. 1997). The primary concern with ginkgo seems to be interactions with other blood-thinning medications (Fugh-Berman 2000).

Ginseng

Ginseng (referring here to Panax ginseng) is a plant with a long history of use. Ancient Chinese writings note cognitive improvement to be among its uses.

The major pharmacologically active constituents of ginseng are the ginsenosides (Gillis et al. 1997; Robbers et al. 1996). Ginsenosides increase production of the neurotransmitter acetylcholine and stimulate its receptors (Benishinm 1992; Lewis et al. 1999). It also dilates blood vessels, which could increase blood flow to the brain (Kim et al. 1992; Ko et al. 1996). Two ginsenosides enhance electrical changes in the brain which are thought to underly the formation of memories (Abe et al. 1994). Ginseng may also have neuroprotective effects, guarding neurons from damage caused by lack of blood flow (Wen et al. 1996).

Several animal studies have shown ginseng to facilitate learning and memory (Gillis 1997; Wang et al. 1995; Nitta et al. 1995; Petkov and Mosharrof 1987; Petkov et al. 1992). Unfortunately, very few cognitive studies of ginseng have been performed in humans. One study assessed several cognitive functions, but found improvement only in mental arithmetic (D’Angelo et al. 1986). Thus, ginseng has potential to serve as a cognition-enhancing herbal medicine, based on its pharmacology and animal studies. However, there is a severe lack of controlled human trials that would need to be done before any conclusions can be drawn.

Typical doses of ginseng are not usually associated with serious adverse effects (Robbers and Tyler 1999). A “ginseng abuse syndrome” consisting of hypertension, irritability, nervousness, and sleeplessness has been reported in people taking inappropriately large doses (Siegel, 1979). Little is known about the interaction of ginseng and other medications, but interaction with the anticoagulant warfarin and antidepressant phenelzine have been reported (Janetzky and Morreale 1997; Jones and Runikis 1987).

Kava

Kava (Piper methysticum) is a plant native to the South Pacific islands. It is known traditionally for its relaxing properties, and producing a calm but alert state.

The pharmacologically active chemicals from kava are the kavapyrones, also referred to as kavalactones (Lebot et al. 1997). Kavalactones enhance the actions of the neurotransmitter GABA, which has a calming effect on brain activity. Similarly, pharmaceutical antianxiety drugs such as Valium and Xanax also enhance the actions of GABA (Boonen and Heberlein 1998; Jussofie et al. 1994; Davies 1992). Kavalactones also block sodium and calcium channels in the brain, which additionally dampens excitation in the brain (Gleitz et al., 1995; Gleitz et al. 1996; Magura et al. 1997; Schirrmacher et al. 1999). Kava may also increase the activity of monoamine neurotransmitters such as norepinephrine (Seitz et al. 1997; Uebelhack et al. 1998).

EEG studies of kava show that it slows down activity in the brain, similar to other sedative drugs (Frey 1991). However, it does not seem to impair cognition at lower doses (Foo and Lemon 1997). A review and meta-analysis of methodologically controlled studies of kava for treating of anxiety has shown kava to be consistently superior to placebo (Pittler and Ernst 2000). One study additionally found it equivalent in efficacy to the benzodiazepine oxazepam (Serax) (Lindenberg and Pitule-Schodel 1990). While it is likely that kava improves sleep, no clinical studies have yet been conducted to assess this. Given its neuropharmacological mechanisms, combination of kava with other sedative drugs, including ethanol, is not recommended.

Conclusions

Several types of research provide information about the mechanisms and effectiveness of psychoactive herbal medicines. St. John’s Wort and Ginkgo biloba are probably at the forefront in this respect, having the greatest bodies of research to support their use. Properly investigated, herbal medicines may be a valuable ally in the treatment of brain disorders.

To obtain such research requires time, money, and effort. Unlike pharmaceutical drugs, herbal medications are not patentable, so private companies lack an incentive to fund the research to establish their safety and effectiveness. Herbal research at present is largely limited to private endowments and government funding.

Despite this fact, the popularity of herbal medicines persists. It is therefore necessary to pool knowledge about herbal medicines and coordinate research efforts. Education of the public and health professionals is the best way to ensure optimal and safe use of psychoactive herbs.

Marcello Spinella, Ph.D. is an assistant professor of psychology at Richard Stockton College in Pomona, New Jersey. He has conducted research in the neuropharmacology of analgesia and his forthcoming book, The Psychopharmacology of Herbal Medications, will be published in 2001 by MIT Press.

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Quality of evidence for evaluating a treatment

Class I

At least one properly designed, randomized controlled trial

Class II

II-1 Well-designed, control led trials without randomization

II-2 Well-designed, cohort or case-control analytic studies, preferably from more than one center or research group

II-3 Comparisons between times or places without intervention; dramatic results in uncontrolled experiments

Class III

Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees

(Canadian Task Force on the Periodic Health Examination, 1979)

Necessary Elements

Control groups (e.g., placebo)

Randomization

Double-blind

Other Useful Elements

Dose-response relationship

Comparison to an existing, established treatment

Key methodological elements in herbal drug studies

Class I: At least one properly designed, randomized controlled trial

Class II

II-1: Well-designed, controlled trials without randomization

II-2: Well-designed, cohort or case-control analytic studies, preferably from more than one center or research group

II-3: Comparisons between times or places with-out intervention; dramatic results in uncontrolled experiments

Class III: Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees

(Canadian Task Force on the Periodic Health Examination, 1979)

Quality of evidence for evaluating a treatment

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