The Importance of Pharmacological Synergy in Psychoactive Herbal Medicines Marcello Spinella, Phd

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Herbal Synergy Review

The Importance of Pharmacological Synergy in Psychoactive Herbal Medicines Marcello Spinella, PhD

Abstract a plant may contain the appropriate constituents, The therapeutic effects of many herbal they may be in insufficient amounts to account medicines have been well established; for the observed effects. Pharmacological synergy however, definitive mechanisms of action should also be investigated to explain the actions remain to be elucidated for many psychoactive of an herbal medicine. Significant interactions may herbal medications. Although several occur which are not evident when single constitu- mechanisms have been identified, they are ents are studied in isolation. In other cases, a pre- often insufficient to account for the observed dominant mechanism may be potentiated by lesser effects of the plant or its extracts. This review mechanisms. Thus, some herbal medications may emphasizes that, in addition to searching for produce a more favorable response when an ex- more potent mechanisms, one must consider tract is given versus an isolated single constitu- the additive and supra-additive effects of a ent. However, the advantages of single constitu- plant’s multiple constituents. Synergy may ents versus extracts should be considered on a occur through pharmacokinetic and/or case-by-case basis. pharmacodynamic interactions. Examples are given that illustrate synergistic actions in St. Mechanisms of Synergy John’s wort (Hypericum perforatum), kava kava Two broad types of synergy can be dis- (Piper methysticum), and valerian (Valeriana tinguished, based on the nature of the interaction: officinalis). pharmacodynamic or pharmacokinetic. Pharma- (Altern Med Rev 2002;7(2):130-137) codynamic synergy results from two drugs di- rected at a similar receptor target or physiological Introduction system. For example, combinations of allosteric Determining the pharmacological mecha- modifiers at the gamma-aminobutyric acidA nisms of herbal medicines presents certain chal- (GABAA) receptor create potent synergistic inter- 2-4 lenges distinct from the study of synthetic drugs. actions. Pharmacokinetic synergy results from For example, synthetic drugs are studied in isola- the processes of drug absorption, distribution, tion; whereas, herbal medicines often contain biotransformation, or elimination. For example, multiple active substances that act in combination. combined administration of drugs which compete A single drug may have several pharma- for albumin binding will elevate the free drug con- 5 cological actions, but it is only those that occur in centrations, and thus potentiate their actions. concentrations reached by standard doses that are considered relevant. In many cases, it may be a single action that is believed to account for its ef-

fects. For example, caffeine has multiple actions, Marcello Spinella, PhD – Assistant professor of but only antagonism of adenosine receptors oc- psychology, Richard Stockton College of New Jersey; 1 postdoctoral training in clinical neuropsychology; research curs at normally-reached concentrations. Some on the neuropharmacology of analgesia. psychoactive herbal medicines have had several Correspondence address: Division of Social and Behavioral Sciences, Richard Stockton College of New Jersey, P.O. of their chemical constituents identified. Although Box 195, Pomona, NJ 08240. E-mail: [email protected]

St. John’s Wort The phloroglucinol hyperforin is a St. John’s wort (Hypericum perforatum) reuptake inhibitor of serotonin, norepinephrine, 17 is traditionally known for treatment of depression, and dopamine in the nanomolar range. Radio- insomnia, and anxiety. A large body of animal and labeled hyperforin crosses the blood-brain barrier 18 human clinical research supports its antidepres- and penetrates brain tissue. Human and animal sant effects.6-10 studies support hyperforin as an essential and per- haps sufficient element for antidepressant effects 6,7,19 Pharmacodynamic Synergy of St. John’s wort. While hyperforin may be sufficient to Several classes of chemical constituents explain the antidepressant effects of St. John’s of St. John’s wort have been identified: wort, synergistic effects on monoamines is pos- naphtodianthrones, flavonoids, phloroglucinols, sible.20 Combined reuptake and enzyme inhibition phenolic acids, xanthones, and terpenes (Figure 11,12 can similarly be seen with conventional antide- 1). The naphtodianthrone hypericin, flavonols, pressants drugs (MAO inhibitors, tricyclic anti- and xanthones have been shown to inhibit both depressants, and selective serotonin reuptake in- monoamine oxidase (MAO) and/or catechol-o- 13-16 hibitors) to potentiate each other’s effects in cases methyltransferase (COMT). While some phar- of treatment-resistant depression.21,22 This must be maceutical antidepressants significantly inhibit done with caution, selecting the appropriate drugs MAO, St. John’s wort extracts only do so in milli- and doses, to avoid an overdose and serotonin syn- molar concentrations; therefore, this mechanism drome. In the case of St. John’s wort, however, appears inadequate to explain the full antidepres- effects which are individually sub-therapeutic (i.e., sant effect of the herb. MAO and COMT inhibition) may combine to

Figure 1. Chemical Structures of Hypericin and Hyperforin

augment the primary pharmacological mechanism extract containing naphtodianthrones is inactive (monoamine reuptake inhibition). in a water suspension, but very effective when another constituent, procyanidin, is present. Pharmacokinetic Synergy Procyanidin increases the water solubility of Pharmacokinetic synergy may also occur naphtodianthrones, thus increasing their pharma- 8 with St. John’s wort, where a combination of con- cokinetic availability. stituents improves its oral bioavailability. An

Figure 2. The Major Kava Lactones

OMe

O O

O O O O

CH2 Dihydromethysticin 7,8-Dihydrokavain

OMe OMe

O O O O

OMe

Kavain Yangonin

OMe OMe

O O O O

OMe O OMe O

CH3 11-Methoxy-yangonin Methysticin

Kava Kava Kava kava (Piper methysticum) is a plant Pharmacokinetic Synergy native to the South Pacific islands with anxiolytic Administering combined kava lactones and sedative effects.23 Controlled human clinical allows for greater access to the brain than when studies show it to be superior to placebo for treat- they are given individually.26 For example, ment of anxiety, and equivalent in efficacy to the yangonin given with other kava lactones (admin- benzodiazepine oxazepam (Serax¨).24,25 istered i.p.) reaches levels 20 times higher in the The active chemical constituents from brain than when it is given alone. Similarly, kavain kava are the kava lactones, principally kavain, levels in the brain are doubled when given in com- dihydrokavain, yangonin, dimethoxyyangonin, bination with other kava lactones, compared to methysticin, and dihydromethysticin (Figure 2).23 levels reached when given alone. The reason for Kava lactones pass the blood-brain barrier and this pharmacokinetic synergy is not certain. One behavioral effects occur at micromolar concentra- possibility is that kava lactones are competing for tions.25,26 plasma binding sites. Thus, giving them in com- Kava lactones enhance binding to the bination occupies more plasma binding sites, al-

GABAA receptor in the low micromolar range, lowing for greater free plasma concentrations of through a non-benzodiazepine mechanism.27,28 the remaining kava lactones. With higher plasma Kava lactones also block voltage-gated Na+ and concentrations, there is greater access to the brain. Ca2+ channels in micromolar concentrations.29-31 Another possible reason for this pharmacokinetic Further, kava lactones interact with monoamine synergy is that administering combined kava lac- systems by blocking the reuptake of norepineph- tones improves intestinal absorption. While 32,33 rine and inhibiting MAOB. yangonin and desmethoxyyangonin are ineffective orally when given alone, they increase the potency Pharmacodynamic Synergy of a combination of kava lactones.40 The central nervous system depressant effects of kava lactones occur through actions on Valerian + 2+ GABAA and Na and Ca channels, which occur Valerian (Valeriana officinalis) has a tra- at normally-reached concentrations. Combined ditional reputation for treating anxiety, insomnia, kava lactones, kavain and dihydromethysticin, act and seizures.41,42 Animal studies of valerian sup- in an additive manner to inhibit Ca2+ channels.34 port it as a central nervous system depressant.43-47 However, combined GABAergic and Na+/ Ca2+ Studies in humans demonstrate that valerian ex- channel inhibition are likely to produce additive tracts increase slow wave sleep, improve sleep or synergistic depressant effects. For example, quality, and decrease sleep latency.48-52 Valerian’s pharmaceutical Ca2+ channel blockers potentiate main chemical constituents are categorized as the sedative effects of benzodiazepines.35 Ethanol monoterpenes and sesquiterpenes (Figure 3).43 and barbiturates are also noted to potentiate the sedative and cognitive-impairing effects of Pharmacodynamic Synergy 28,36,37 kava. Several GABAergic mechanisms of action The monoamine actions of kava may also have been proposed for valerian. There is some contribute to its therapeutic effects. Monoamine debate whether oral valerian reverses uptake of mechanisms are more commonly associated with GABA. In support of this, low microgram con- antidepressants, but they can be effective in treat- centrations of an aqueous valerian extract inhibit 38,39 ing generalized anxiety. Kava lactone actions uptake and stimulate release of GABA from syn- on norepinephrine reuptake and MAO are indi- 53,54 + B aptosomes. This effect is Na -dependent and vidually less potent than pharmaceutical antide- Ca2+-independent, suggesting it is due to reversal pressants, but their combination may potentiate of the neuronal GABA transporter. Some research- each other’s effects. ers report GABA is present in valerian, which

Figure 3. Some Constituents of Valerian Conclusions There are multiple

CH3 examples of pharmacodynamic and pharmacokinetic CH2Olv synergy at work in psychoactive herbal medicines CH3 (Table 1). St. John’s wort O shows evidence of pharma- O CH CH3 3 codynamic synergy through CHO monoamine neurotransmit- Valeranone Dihydrovaltrate ter systems, preventing neu-

CH rotransmitter breakdown, 3 and blocking reuptake. CH 3 lv= CO - Pharmacokinetic synergy is H evident in St. John’s wort CH3 since procyanidin increases the bioavailability of the CH3 naphtodianthrones. Kava COOH kava’s effects on GABA and CH3 CH3 voltage-gated ion channels CH3 (and possible monoamine COOH systems) create pharmaco- Isovaleric Acid dynamic synergy. Kava Valerenic Acid kava also shows evidence of pharmacokinetic synergy since administration of combined kava lactones in- 55 could account for these results. If so, this does creases brain bioavailability of each, compared to not explain the effects of oral valerian, since individual administration. Valerian shows evidence GABA does not readily cross the blood-brain bar- of pharmacodynamic synergy since multiple con- rier. However, other researchers have failed to find stituents of the herb are acting on GABAergic sys- GABA in valerian preparations, so reversal of tems, both pre- and post-synaptically. Pharmaco- reuptake may still be considered a possible mecha- kinetic synergy in valerian is possible, but has not 56 nism of valerian’s sedative effects. yet been investigated. There is additional evidence for other The above examples of synergy are di- GABAergic effects of valerian. For example, rectly relevant to the therapeutic benefits of these valerenic acid inhibits enzymatic breakdown of herbal medicines. The synergistic effects of St. GABA, and low concentrations of valerian ex- John’s wort likely enhance its effects on monoam- tracts enhance benzodiazepine binding at the ine neurotransmitter systems, the predominant GABA receptor ([3H]flunitrazepam).43,56,57 Ortiz A mechanism of most antidepressant drugs. The syn- and colleagues found there are at least two con- ergistic interactions of kava kava occur through stituents of valerian acting at the GABA recep- A GABA, voltage-gated ion channel, and monoam- 56 tor. Valerian extracts also potentiate the behav- ine systems. All of these mechanisms help account 47 ioral actions of barbiturates. It is not clear which for kava kava’s demonstrated anti-anxiety effects. of these GABA mechanisms account for valerian’s Finally, the synergistic effects of valerian’s con- effects, but additive or synergistic interactions are stituents on GABA transmission would explain its likely, especially since they all affect GABAergic demonstrated effects on sleep. transmission.

Table 1. Summary of Synergistic Mechanisms

Pharmacodynamic Synergy Pharmacokinetic Synergy

St. John’s Monoamine reuptake inhibition; Procyanidin increases Wort MAO inhibition; bioavailability of hypericin COMT inhibition

Kava kava GABAA facilitation; Kavalactones increase each Na+ and Ca2+channel inhibition; other’s bioavailability MAO inhibition; Reuptake inhibition of NE

Valerian Multiple GABA mechanisms Not yet investigated

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