Both yokukan-san and orengedoku-to are extract granules manufactured as aqueous extracts containing herbs by strictly licensed pharmaceutical companies in Japan. The Japanese Ministry of Health, Labor, and Welfare has approved 148 orally administered Kampo formulae, composed of herbal extract granules, for clinical use in the same way as conventional medicines are used. Therapy based on Kampo medicine was the main medical treatment in Japan until Western medicine was introduced from Europe several hundred years ago. Recently, Kampo medicine has begun to receive increasing renewed attention because it provides a valid alternative approach to treating symptoms refractory to conventional medicine.7
Yokukan-san, which is comprised of seven herbs (Angelicae Radix, Atractylodis Lanceae Rhizoma, Bupleuri Radix, Poria, Glycyrrhizae Radix, Cnidii Rhizoma, and Uncariae Uncis Cum Ramlus) (), was listed in a Chinese medical book in 1555 AD for the first time and thereafter came to Japan. The name “yokukan-san” originally meant “medicine suppressing the liver.” The original Chinese description states that yokukan-san treats spasms, feverishness, clenching, terrified/simmering mental state, or intolerance to heat and cold caused by pseudo-hyperfunction of the liver and expectoration of sputum, abdominal fullness, loss of appetite, and sleep disorders caused by dysfunction of the spleen, which has a restraining relationship with the liver and is consequently damaged by the liver’s pseudo-hyperfunction.
According to the Five Phases theory, the liver is considered to be the organ that stabilizes mental activities and ameliorates involuntary muscle movements, and thus the liver often produces anger and/or involuntary muscle movement when its regular functioning is impaired.8
Many famous Kampo medicine doctors agreed with the use of yokukan-san for these indications. For example, Dotaku Meguro (1739–1798 AD) wrote that yokukan-san must have some efficacy if the patient feels anger, and Sohaku Asada (1815–1894 AD) wrote that yokukan-san can be used to treat a patient who has muscle spasms and anger, and all of his symptoms are likely to be caused by pseudo-hyperfunction of the liver. Based on these indications, yokukan-san has been used in Japan for more than 400 years as a treatment for insomnia, irritability, impulsivity, aggression, blepharospasm, tremor or fasciculation of the facial muscles, convulsions, and similar symptoms.7
It is not surprising that yokukan-san has lately been reported to have ameliorating effects in such a wide variety of diseases because it has long been considered in China and Japan to exert these, irrespective of conventional diagnosis, at any time patients exhibit aggressiveness, impulsive behaviors, and/or involuntary movements.
Orengedoku-to, which consists of four herbs (Coptidis Rhizoma, Scutellariae Radix, Phellodendri Cortex, and Gardeniae Fructus) (), was described in a Chinese medical book of 752 AD as being able to treat patients suffering from excessive body heat, mental conflict, confusion, insomnia, thirst, and nausea. In ancient times, orengedoku-to was used by soldiers before battle, both to reduce their anger so they would not become confused as well as to prevent excessive bleeding.7
As might be expected from its history, this compound has come to be used for the treatment of ailments involving bleeding (eg, nosebleeds, hemorrhoids), hypertension, irritation, and face fushing, as well as for infammatory diseases such as gastritis.7
In fact, it has been proven in animal models that orengedoku-to has protective effects against stress-induced gastric ulcers and gastritis.10
Thus, orengedoku-to has a “cooling” effect on infammatory symptoms, whether they have mental or physical causes, and is often used to treat irritability, impulsivity, aggression, pruritus, dermatitis, and other diseases, irrespective of conventional diagnosis, in which patients are considered to have excessive heat in their bodies and/or hearts. In most cases in which orengedoku-to is effective, patients have a tendency to have a reddish face and feelings of being increasingly hot.7
Thus, based on past use, both yokukan-san and orengedoku-to are thought to be effective for treating irritability, impulsivity, and aggression. Nevertheless, today yokukan-san tends to be chosen first due to its reputation for effectively treating many psychiatric symptoms. This is simply because orengedoku-to is still not known among conventional medical doctors due to the lack of evidence for its effectiveness. As already suggested, orengedoku-to by itself is more likely to be effective in cases in which patients suffer not only from irritability, impulsivity, and aggression, but also a reddish face and feelings of being increasingly hot.7
However, even in cases in which patients do not have a reddish face or feelings of being increasingly hot, orengedoku-to should be considered as an alternative treatment for irritability, impulsivity, and aggression, given that the patients with those symptoms have excessive heat not in their bodies but in their hearts. Therefore, in patients who do not feel physically cold, the addition of orengedoku-to’s cooling effect to yokukan-san can be an effective option in cases that are partially responsive to yokukan-san treatment. In fact, Coptis
rhizome and Gardenia
fruit, two of the four components of orengedoku-to, are often added to the decoction medicine of yokukan-san to augment its efficacy, as described in classic Japanese medical books. In particular, Coptis
rhizome, the common name of which is “oren” in Japanese and which is the main component of orengedoku-to, is frequently added to yokukan-san. Therefore, orengedoku-to augmentation in cases that are partially responsive to yokukan-san is also very reasonable when granule prescriptions but not the decoction medicines are available.
Three open-label studies support the notion that the use of yokukan-san is benefcial in BPSD and in treating behaviors of Alzheimer’s-type dementia,11
and our results suggest that the addition of orengedoku-to to yokukan-san may be more effective in treating Alzheimer’s-type dementia than yokukan-san alone, especially in cases showing aggression. Further, a recent report has shown that orengedoku-to may have therapeutic potential in patients with Alzheimer’s disease by inhibiting indoleamine 2,3-dioxygenase activity.14
In addition, the combination therapy involving yokukan-san and orengedoku-to is likely to be effective, irrespective of conventional diagnosis, under conditions suitable for both yokukan-san and orengedoku-to as described, because Kampo medicine often shows remarkable effectiveness in cases that, according to the Kampo diagnosis, meet the criteria for choosing each Kampo prescription.7