The treatment of mood and anxiety disorders with botanical medicine goes back to antiquity, with various cultures applying energetic models such as humoral medicine or traditional Chinese medicine models to prescribe a range of plant-based medicines. Until recently, understanding of depression and anxiety was rudimentary, with such conditions classified broadly as “melancholia” or “hysteria.” In present times, use of herbal medicine and complementary and alternative medicine (CAM) is prevalent among sufferers of mood and anxiety disorders. Data from a nationally representative sample of 2055 people interviewed during 1997–1998 revealed that 57% of those with anxiety attacks and 54% of those with severe depression reported using CAM therapies during the previous 12 months to treat their disorder. Twenty percent of the sample with anxiety and 19% of those with severe depression visited a CAM practitioner for treatment during the year. Interviews of 82 psychiatric North American inpatients hospitalized for acute care for various psychiatric disorders revealed that 63% had used one or more CAM modalities within the previous 12 months. The most frequently used CAM intervention was herbal medicine, with 44% using the therapy during the previous 12 months. Most did not discuss this use with their medical practitioner. A study involving 52 patients from an Australian psychiatric teaching hospital revealed that 52% used CAM treatments over the preceding 18 months. Eighty-five CAM treatments were used by the sample, and 37% did not inform their medical practitioner of this use. Research on CAM or herbal medicine in psychiatry is still in its infancy, although there has been a 50% increase in the literature over the last quinquennium in the combined area of herbal medicine and psychiatry. A Medline search in late 2009 of controlled and uncontrolled clinical trials using the terms “Complementary Medicine” AND “Depression” OR “Anxiety” OR “Psychiatry” revealed 1663 hits. This compares with 10828 hits when the search term “Antidepressants” OR “Cognitive Behavioral Therapy” was substituted for “Complementary Medicine.”
Herbal medicine products contribute to a significant part of the modern “CAM industry,” and are a vital component of CAM practice. Phytotherapy (the practice of herbal medicine) today is as much science as it is art, with our understanding of herbal psychopharmacology advancing over the past two centuries after the isolation of active constituents such as morphine from opium poppies. Research into psychoactive plants that may affect the CNS has since flourished with an abundance of preclinical in vitro and in vivo studies validating many phytotherapies as having profound biopsychological effects. Aside from notable psychoactive plants (usu-ally containing alkaloids) such as cocaine from Erythroxylon coca (coca), morphine from Papaver somniferum (opium poppy), or arecoline from Areca catechu (betel nut), other less potent plants are developing over the last several decades, which is rich evidence of beneficial therapeutic activity.
Mechanisms of action for herbal medicines used for the treatment of psychiatric disorders primarily involve modulation of neuroreceptor binding and alteration of neurotransmitter formation and activity. Other actions may involve stimulating or sedating CNS activity, and regulating or supporting the healthy function of the hypothalamic pituitary adrenal axis (HPA-axis). Herbal medicines have a range of psychotherapeutic actions that include antidepressant, anxiolytic, nootropic (cognitive enhancing), sedative, hypnotic, and analgesic effects. Other tradi-tional actions that may not follow orthodox pharmacy include adaptogens and tonics, which provide increased adaptation to exogenous stressors and enhance vitality of Muscular tension (dysmenorrhea, irritable bowel syndrome, headaches), visceral spasm, pain Cognitive decline, dementia body/mind via complex effects on neurochemistry and the HPA-axis. These actions may be applied clinically in a range of psychiatric disorders, including generalized anxiety, depression, and insomnia. These conditions are the focus of this post, as they are prevalent psychiatric disorders that often comorbidly occur, having a marked socioeconomic effect.
Clinical depression is diagnosed by Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV) criteria as a condition uncomplicated by grief, comorbid medical conditions, or substance misuse, presenting with 2 weeks or more of low mood (dysphoria) and/or loss of pleasure (anhedonia), in combination with various somatic and psychological effects (e.g., fatigue, sleep disturbance, digestive changes, excessive guilt, and suicidality). Some antidepressant herbal medicines offer promise for the treatment of this disorder via psychoactive actions such as re-uptake of monoamines such as serotonin, dopamine, and noradrenaline, enhanced binding and sensitization of serotonin receptors, monoamine oxidase inhibition, and HPA-axis modulation. Other pathways of activity may include GABAergic effects, cytokine modulation (especially in depressive disorders with a comorbid inflammatory condition), and opioid and cannabinoid system effects.10 Anxiety disorders such as generalized anxiety disorder (GAD), social phobia, and post-traumatic stress dis-order present with a marked element of psychological anxiety and distress, and are accompanied by a range of somatic symptoms such as palpitations, hyperthermia, shortness of breath, dizziness, and digestive disturbance.
For GAD to be diagnosed according to DSM-IV criteria, in addition to uncontrollable worrying, there must also be at least three of six somatic symptoms (restlessness, fatigue, concentration problems, irritability, tension, or sleep disturbance) occurring for a period of at least 6 months. Significant distress or impaired functioning from the condition must also be present. Phytotherapies that may benefit anxiety disorders are classed as “anxiolytics,” and usually have effects on the y-aminobutyric acid (GABA) system, either via inducing ionic channel transmission by voltage-gated blockage or alteration of membrane structures, or less commonly via binding with benzodiazepine receptor sites (e.g., GABA-a). Primary chronic insomnia, as opposed to transient insomnia caused by acute stress or environmental change, is diagnosed in the DSM-IV as 1 month or more of sleep disturbance (long latency, poor maintenance, and unrestorative sleep), which causes a marked personal cost, e.g., in work and social functioning and must not be caused by drugs or alcohol, psychiatric or medical conditions, or environmental factors. Herbal hypnotics and sedatives usually work via modulation of the adenosine receptors, melatoninergic effects, or via GABAergic activity.
The significance of depression, anxiety, and insomnia being covered in the post concerns a common comorbidity between them. Mechanisms of action to treat these disorders, while varied, still interface with each other, and often when certain underlying neurological, endocrine, or circadian factors are addressed, a beneficial effect may occur on the nervous system as a whole. This may impact the treatment of other comorbid psychiatric disorders, e.g., if depression is treated then anxiety may resolve, or if insomnia is addressed depression may be relieved. In the following sec-tion, the current evidence base of botanical medicines in the treatment of these major psychiatric disorders is outlined. Mechanisms of action are detailed in addition to a review of major clinical evidence and suggestions for clinical potential application.
As evidenced in a study by Wittchen, GAD was found in 22% of primary care patients who complained of anxiety problems. Consistent with the DSM-IV manual’s description of the 1 year prevalence of GAD as approximately 3%, a sample of 10,641 Australians interviewed in 1997 had a 1 month prevalence of 2.8%, and a 12 month prevalence of 3.6%. Lifetime prevalence of GAD is approximated at 5%–6%. The socioeconomic burden of GAD is immense, with sufferers more likely than any other patient group to make frequent medical appointments and utilize medical resources. As in major depressive disorder, only about 40% of sufferers seek treatment, and only 60% achieve full or partial remission for over 5 years.
The pathophysiology of GAD is still being unraveled, although current evidence indicates that the neurobiological influence involves abnormalities of serotonergic, noradrenergic, and GABA transmission.19 The involvement of these pathways is reflected in the efficacy of selective serotonin re-uptake inhibitors (SSRIs), selective serotonin and noradrenalin reuptake inhibitors (SNRIs), and benzodiazepines.The main neurocircuitry in the panic, fear, or anxiety responses in humans involves the prefrontal cortex, hippocampus, and amygdala. Psychological determinants may also exist, such as a cognitive bias to increased attention and misinterpretation of ambiguous stimuli, which are perceived as threatening.
As detailed in the introduction, plant medicines that possess anxiolytic proper-ties usually have effects on GABA pathways either via direct receptor binding, ionic channel modulation or effects on the cell membranes of the cells. The subsequent increased GABA neurotransmission has a damping effect of stimulatory pathways, which ultimately provides a psychologically calming effect. Eight herbal medicines with known anxiolytic effects are detailed. The mechanisms of action of these phytomedicines have been detailed, as elucidated via in vitro and in vivo studies. As outlined in the “clinical applications” section, aside from treating anxiety disorders, many of these anxiolytic plant medicines have additional applications. These include improving mood (such as Melissa officinalis [lemon balm] or Piper methysticum [kava]), providing a sedative or hypnotic action for insomnia (e.g., Passiflora incarnata [passionflower] or Scutellaria lateriflora [scullcap]), reducing muscle tension or pain (e.g., Eschscholzia californica [Californian poppy]), or enhancing cognition via nootropic activities (e.g., Bacopa monniera [Bacopa] or Ginkgo biloba [Ginkgo]).10,12 Herbal medicines (such as Withania somnifera [Withania]) may also provide an adaptogenic effect applicable in cases of comorbid fatigue.
It is estimated that by the year 2020, depression is projected to cause the second greatest increase in morbidity after cardiovascular disease, presenting a significant socio-economic burden. The lifetime prevalence of depressive disorders varies depending on the country, age, sex, and socioeconomic group, and approximates about one in six people. The 12 month prevalence of clinical depression (also known as major depressive disorder [MDD]) is approximately 5%–8%, with women being approximately twice as likely as men to experience an episode.
Botanical Anxiolytics: Mechanisms of Action and Clinical Applications
Potential Clinical
Botanical Medicine Mechanisms of Action Application
GABA-mimetic activity (enhanced Anxietyflunitrazepam binding) Insomnia
Anxiolytic effect comparable to that Fatigue
produced by lorazepam in animal models Nervous exhaustion
(elevated plus-maze, social interaction and feeding latency in an unfamiliar environment, tests)
The pathophysiology of MDD is complex, and it appears that a variety of biological causations exist. The main premise concerning the biopathophysiology of MDD has in the last several decades focused on monoamine impairment (dysfunction in monoamine expression and receptor activity, lowering of monoamine production, or secondary messenger system malfunction [e.g., G proteins or cyclic AMP]). In recent years, added attention has focused on neuro-endocrinological abnormality concerning the HPA-axis, cortisol production and brain-derived neurotropic factor (this interface affects neurogenesis), impaired endogenous opioid function, changes in GABAergic and/or glutamatergic transmission, cytokine or steroidal alterations, and abnormal circadian rhythm. From a psychological perspective, cognitive and behavioral causations (or manifestations) of MDD include negative or erroneous thought patterns or schemas, impaired self-efficacy, challenged social roles, and depressogenic behaviors or lifestyle choices.
As a recent review by Fournier et al. in JAMA details, emerging evidence has revealed that synthetic antidepressants (such as SSRIs, tricyclics, and MAOIs) have limited efficacy in persons with milder forms of depression. Furthermore, clinical guidelines often do not endorse antidepressants as the primary first-line intervention for milder forms of MDD, and are often regarded as widely over-prescribed.65 Furthermore, only 30%–40% of people achieve a satisfactory response to first-line antidepressant prescriptions thus approximately 40% do not achieve remission after several antidepressant prescriptions, thus further pharmacotherapeutic developments are required. Many herbal medicines have been revealed to provide antidepressant activity. Some plant medicines provide strong thymoleptic effects (as in the case of E. coca), however, due to pronounced dopaminergic effects (which may cause addiction) are not viable clinical options. Others, however, such as Hypericum perforatum (St. John’s wort) have thymoleptic effects that are mediated primarily via modulation of monoamine transmission. It should be noted that as in the case of most phyto-medicines H. perforatum’s antidepressant mechanism of action is not as clearly defined as SSRIs, having a multitude of biological effects on re-uptake and receptor binding of various monoamines, in addition to HPA-axis modulation.
Comorbidity between MDD and anxiety disorders is the rule, not the exception. Several herbal medicines with mood elevating effects (such as Rhodiola rosea [rhodiola] or Crocus sativus [saffron]) may also have anxiolytic effects. This may be due to modulation of neurological pathways that have both antidepressant and anxio-lytic effects (e.g., GABA, serotonin, noradrenaline, or dopamine systems), or this may be due to a “halo effect” whereby when depression is successfully treated, anxiety may also be reduced.This was found in the case of a recent RCT involving participants with generalized anxiety, which found that P. methysticum (an established anxiolytic), in addition to anxiety reduction, also provided a statistically significant reduction of comorbid depression on the Montgomery–Asberg depression rating scale.
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