The Clinical And Pharmacological Actions Of The TCM Formula “Yi Gan San” (Restrain The Liver Powder)

Introduction

The traditional Chinese herbal formula Yi Gan San (YGS) was recorded by Xue Kai (a.k.a. Xue Liang-wu) in the Bao Ying Cuo Yao (Synopsis of Caring for Infants), 1555. It was originally intended for pediatric use in cases with spasms, feverishness, bruxism, anxiety with palpitations, and restless sleep with terrifying nightmares. In contemporary practice its clinical applications have been expanded to include temper tantrums, irritability, impatience aggressiveness and insomnia. (1) In Japan, it is approved for clinical use by the Ministry of Health Labour and Welfare and is covered for reimbursement under the National Health Insurance program. (2) The conditions for which this formula is approved are: neurosis and insomnia (in adults or children), as well as irritability and night crying in children. (2, 3)

In recent years this formula has been the subject of considerable clinical research in Japan, centred on its application in patients with dementia. There is a growing body of evidence confirming its efficacy in the treatment of the extreme emotional symptoms exhibited by dementia patients, including aggression, agitation, irritability, screaming, wandering, disinhibition, apathy, hallucinations and delusions. These symptoms are collectively referred to as ‘behavioural and psychological symptoms of dementia’ (BPSD). (2, 4, 10)

The formula appears to be one of the few available treatments (both Western and traditional) that is able to provide clinically significant results in dementia patients. As a result, the Japanese Society of Neurology has listed it in the Japanese Guidelines for the Management of Dementia, 2010. Additionally, Japanese research has been providing evidence that it may also be effective in the following conditions: sleep disorders, anxiety disorders, pre-operative anxiety, tardive dyskinesia, borderline personality disorder, diseases related to schizophrenia, depression and neuropathic pain. (2) Concurrent with the accumulating clinical evidence, Japanese and other Asian researchers have also been exploring the neuropharmacological effects of this formula. This paper aims to summarise the clinical as well as the neuro- and psycho-pharmacological actions of this unique herbal formula.

The Formula: Yi Gan San (Restrain the Liver Powder)

The original formula was made up of seven ingredients: Bupleurum, Uncaria, Chinese Angelica, Ligusticum Chuanxiong, Atractylodes, Poria and Chinese Glycyrrhiza, to which Cirus peel and Pinellia are generally added.

Yi Gan San Ingredients

Bupleurum falcatum, root (chai hu)

Uncaria rhyncophylla, stem (gou teng)

Angelica polymorpha, root (dang gui)

Ligusticum wallichii (a.k.a. Ligusticum striatum), rhizome (chuan xiong)

Atractylodes macrocephala, rhiz. (bai zhu)

Poria cocos, hyphae (fu ling)

Pinellia ternata, tuber (ban xia)

Citrus reticulata, fruit pericarp (chen pi)

Glycyrrhiza uralensis, root (gan cao)

In TCM, this formula has the following actions: calms the Liver and clears Liver Heat to extinguish interior Wind; nourishes the Liver Blood and strengthens the Spleen. (5) The synergistic actions of the individual ingredients are as follows: (1, 5)

• Bupleurum and Uncaria: calm the Liver and clear Liver Heat, to extinguish interior Wind
• Chinese Angelica and Ligusticum: nourish the Liver Blood and soften the Liver.
• Bupleurum and Citrus peel: disperse stagnant Qi
• Atractylodes and Poria: strengthen the Spleen
• Citrus peel and Pinellia: dry Damp and resolve Phlegm
• Chinese Glycyrrhiza: harmonises the formula and protects the Stomach from the harsh actions of the other herbal ingredients.

In terms of pathogenesis, the formula is directed at conditions due to deficiency of the Liver Blood. As a result of this deficiency, the Liver is unable to adequately perform its function of regulating the Qi, which then tends to become stagnant. Stagnation of the Qi may lead to the development of Heat (referred to as ‘stagnant Heat’) as well as Damp and Phlegm (due to stagnation within the fluid pathways). Concurrently, the state of Blood deficiency within the Liver may generate interior Wind, as well as Heat. Thus, we have a pattern of mixed deficiency and excess: Liver deficiency on the one hand and a combination of Heat, interior Wind, Phlegm and Damp on the other. The pathogenic Heat tends to exacerbate the interior Wind and Phlegm, creating a vicious cycle. Because of their unique physiology and life-stage experiences, both children and the elderly are particularly susceptible to this kind of imbalance.

As we are mainly concerned with mental-emotional effects, let us now focus on the psychological aspects of this formula’s clinical actions and the specific pattern of imbalance that it treats. The syndrome-pattern, towards which this formula is directed, is a combination of Liver excess and deficiency. Thus, it represents both polar extremes of Liver functioning. This may be understood in reference to the Wood phase of the Five Elements. The Wood aspect of our psyche is concerned with the ability to make plans and decisions based on a sense of one’s place and purpose in life. This group of related psychological functions provides the impetus for self-assertion, and the capacity to forcefully push through obstacles and other types of inertia. The central concept here is one of smooth and effective movement carried out in a forceful, but not harsh, manner. When balanced and harmonious, Liver-Wood fosters patience and endurance, allowing the expression of kindness towards oneself and others. The feeling of righteous indignation that leads to constructive action is also within this sphere. It follows that once these functions become extreme, we have low self-esteem on the one hand and anger on the other. Moving further away from the harmonious center, we have a sense of shrinking anxiety (the deficiency state) and unbridled rage (the excess state). (6,7)

Thus, when Liver Blood deficiency has reached a stage where it begins to generate interior Wind, we have the psychological manifestations of severe anxiety, centered around a lack of self-esteem. One can readily understand how people at the two extremes of life may experience this condition. The very young are confronted with a strange new world, interacting with which they find that only very few of their actions meet with parental approval, while the vast majority are pronounced as either ‘bad’ or ‘wrong’; nor are they physically able to do most of the things that the adults around them appear to accomplish with ease. The elderly, on the other hand, and particularly those with dementia, find that their grasp on the world around them is inexorably slipping away, as they understand less and less of it and their ability to do things progressively diminishes.

Considering the excess side of the equation, Liver Heat tends to rise up and disturb the Spirit and may also exacerbate the interior Wind; these pathogenetic pathways correlate with extreme irritability, restlessness and angry outbursts. The Phlegm, which is directed to the upper body due to the influence of both Heat and Wind, correlates with the loss of a rational perspective and self-control that generally accompanies such emotional disturbances.

The Clinical Efficacy of Yi Gan San (Restrain the Liver Powder)

A search on PubMed, in January 2020, for articles published since 2005 that include the name of this formula in the title, brought up 207 papers (using the Japanese or Chinese names: yokukansan, yokukan-san, yi-gan san, yi gan san). Mostly from Japanese researchers, these papers explore the formula’s clinical efficacy, potential applications, neuropharmacology and interactions.

Dementia

As discussed previously, although there are several different pathological processes that may underlie a patient’s dementia, e.g. amyloid plaques or cerebral infarct, the diagnosis of dementia is a clinical one and for the most part the diagnosis of ‘Alzheimer’s disease’, ‘vascular dementia’, etc. may neither be valid nor clinically useful. (8) Dementia is currently diagnosed according to the clinical features of Neurocognitive Disorder (NCD) in the Diagnostic and Statistical Manual of Mental Disorders – fifth edition (DSM-5). NCD is subdivided into two types: Minor and Major. Minor NCD is the same as ‘mild cognitive impairment’ (MCI), while Major NCD is synonymous with dementia. Major NCD is defined as a substantial decline from a previous level in one or more of six cognitive domains; the cognitive deficits are sufficient to interfere with independence; and the cognitive deficits are not attributable to other physical or mental causes (e.g. delirium or schizophrenia). (8, 9) While earlier definitions of dementia, privileged memory loss, it should be noted that according to the most recent definition, the cognitive deficit does not need to be in the domain of ‘learning and memory’ for the diagnosis of dementia to be valid. Thus, if a patient’s executive ability is the only domain affected, and if the deficit is sufficient to curtail independence, requiring assistance with the instrumental activities of daily living, then the patient may be diagnosed with dementia. (9)

As discussed previously, the current pharmaceutical interventions for dementia (i.e. cholinesterase inhibitors such as donepezil, and memantine, a noncompetitive N-methyl-D-aspartate receptor antagonist, which prevents neuronal excitotoxicity), do not provide clinically significant improvement in any of the various signs and symptoms of dementia – in spite of the multitude of industry sponsored clinical trials that purport to find statistically significant outcomes. (8, 14) The important thing to bear in mind when assessing a study on an intervention for dementia is this: does the intervention give clinically significant results? Complicated statistical analyses that show a statistically significant outcome (often less than or equal to the margin of error in measuring that outcome) are all too common. (11-14) In these instances the ‘improvements’ do not make an appreciable difference to the course of the illness nor do they ease the burden on the patient’s caregivers.

While there are no available treatments that are able to slow, stop or reverse the cognitive deficits in patients with Major NCD (i.e. full blown dementia), there is one medicine that has been shown to dramatically (in comparison to other pharmaceutical ‘treatments’ for dementia) improve the behavioural and psychological symptoms of dementia (BPSD) as well as the activities of daily living (ADL). This was shown in the first controlled study of the formula Yi Gan San (YGS) in Japan in 2005. (15) Since this time there have been several high-quality studies that have confirmed these findings, showing efficacy in improving sleep, and in reducing delusions, hallucinations, agitation and aggressive behavior in dementia patients. (2, 10, 16) Additionally, YGS has fewer and much less severe adverse effects compared to the antipsychotic and antidepressant drugs that may be used to control BPSD, as well as compared with the standard pharmaceutical regimens. (17, 18)

Anxiety

Since 2008 there have been many studies supporting the role of YGS in the alleviation of anxiety (due to a variety of causes), stabilization of mood and reduction in aggressive behaviour. Studies on pre-operative anxiety have found that YGS was as effective as diazepam, without causing undesirable sedation. (19, 20) Moreover, the use of the herbal formula was without serious adverse effects. Animal studies have demonstrated that the anti-anxiety action of YGS may be due to its effect on cerebral serotonin receptors and glucocorticoid receptors, normalizing HPA axis activity following stress exposure. (21, 22)

Other conditions

Controlled studies in humans have demonstrated the effectiveness of YGS to ameliorate symptoms in the following conditions: schizophrenia, the extrapyramidal side effects of antipsychotic drugs, borderline personality disorder (positive effect on low mood, impulsivity and aggression), pervasive developmental disorders and Asperger’s syndrome. (23 – 28)

Neuropharmacology

Most of the neuropharmacological studies conducted on YGS are on rats and mice (for obvious reasons), so there are a number of caveats when assessing the major findings. These caveats may be summarized as: differences in metabolism between animals and humans, inferring a psychological state based upon the animal’s behavior, assuming that a receptor agonist or antagonist that has been administered to the animal only affects one specific receptor (i.e. not taking into account the possibility of multiple or unforeseen effects), assuming that the herbal medicine’s actions are only due to the effects on the neurotransmitters and receptors that are being considered in a particular study. Therefore, we need to bear in mind that these studies can only provide an incomplete and possibly misleading picture of the herbal formula’s effects.

The neurotransmitter systems affected by YGS include the glutamatergic, serotonergic, cholinergic, dopaminergic, adrenergic and GABAergic. In addition, it has neuroprotective effects and promoting effects on neuroplasticity, including neurogenesis. (29) Specific effects of YGS are as follows: (17, 29 – 31)

• Increasing the density of serotonin (5-HT) 1A receptors in the prefrontal cortex (PFC) to reduce anxiety and aggressiveness.
• Reversing the age-related decrease in dopamine neurotransmission in the prelimbic region of the PFC to preserve or restore working memory and learning.
• Increasing neuronal activity in the prelimbic region of the PFC to reduce stress related anxiety
• Suppression of stress induced neuronal activity in the amygdala, to alleviate anxiety
• Amelioration of neuronal and astroglial degeneration in the hippocampus (which may occur in patients with dementia), to alleviate aggressive behavior.
• Inhibition of the inflammatory response, oxidative stress and subsequent neuronal death in the hippocampus due to transient ischaemia, preserving spatial memory and reducing locomotor hyperactivity after ischaemic injury.
• Amelioration of the age-related decrease in the proliferation and migration of neuronal stem cells in the hippocampus, to preserve emotional balance and reduce over-excitation.
• Reducing stress induced changes within the corpus callosum.
• Neuroprotection within the basal ganglia, to reduce dyskinsesia
• Protection against stress induced changes within the thalamus and hypothalamus.
• Attenuation of glutamate neurotransmission within the spinal cord to alleviate neurophathic pain.

The pharmacological effects of YGS on various types of brain cells may be summarized as follows (30, 31):

• Actions on neurons: neuroprotective, neurogenic, promotes neurite outgrowth, prevents stress induced apoptosis and facilitates autophagy (for recycling of nutrients).
• Actions on astrocytes: promotes removal of excess glutamate.
• Actions on oligodendrocytes: promotes proliferation and differentiation.
• Actions on the microglia: reduces the inflammation that is associated with microglial activation (i.e. suppresses excessive activation of microglia in response to injury)

Taken together, the above actions of YGS on the various aspects of cerebral functioning help to provide possible mechanisms for the formula’s efficacy in reducing aggression, anxiety and excitability, particularly in conditions involving injury (i.e. dementia) or stress (i.e. mood disturbances).

Dosage

Most of the studies on humans have used water soluble concentrated granules, provided by Tsumura & Co., Tokyo, Japan, referred to as Yokukansan ‘TJ-54’. (2, 16, 17, 19 – 26). Dosage is in the range of 2.5g for a single dose and 5 – 7.5 g for a daily dose. (31) This is equivalent to 8 capsules for a single dose and 16 – 25 capsules for a daily dose of the prepared formula, *Yi Gan San. (33) Pediatric doses are generally half to ¾ of the adult dose; adjustments to the dose in adults may be made in accordance with body size; (32, 34) a higher dose is generally given initially, and then reduced to a maintenance dose one clinical results have become apparent. (33, 34)

* Yi Gan San is available as ‘Settle the Emotions formula (CM187)’ from Sun Herbal Pty Ltd.

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