Enel Health®Atlas
Sign in
Enel Health®Atlas
Browse libraries

Not medical advice. The Atlas is not a substitute for a clinician who can examine you.

Yokukansan (抑肝散, TJ-54)

The Ming formula for a fretful child, now given to agitated elders

Evidence grade 3 of 5, Mixed. Read how the Atlas grades evidence.

Matsunaga, Kishi and Iwata (J Alzheimers Dis, 2016) pooled five RCTs and 381 patients. Yokukansan reduced BPSD total scores against placebo plus usual care (SMD -0.32), with benefit on agitation and aggression (-0.37), delusions (-0.51) and hallucinations (-0.54), improved daily living scores, and no excess adverse events. The qualifier is in the same paper: yokukansan was not superior to placebo on BPSD total or any subscale in Alzheimer's patients specifically. Furukawa's double-blind trial (Geriatr Gerontol Int, 2017), the largest at 145 Alzheimer's patients, missed its primary outcome. The positive signal rests largely on non-Alzheimer's dementia, especially Lewy body disease, in trials run almost entirely in Japan.

Reference only. Not medical advice.

What can go wrong

The licorice is the problem. Glycyrrhizin inhibits 11β-hydroxysteroid dehydrogenase type 2, letting cortisol act on mineralocorticoid receptors and producing pseudoaldosteronism, with hypokalemia, hypertension and muscle weakness, and in reported cases rhabdomyolysis and death. This is not theoretical for yokukansan. An analysis of Japan's JADER adverse-event database found it carried a higher reported pseudoaldosteronism signal than other licorice-containing Kampo formulas (ROR 2.4, 95% CI 1.9 to 2.8) despite containing relatively less licorice. Case reports document severe hypokalemia, particularly when it is combined with a second licorice formula such as shakuyakukanzoto. Risk climbs with dose, duration, older age and female sex, which describes the dementia population it is most often given to. Potassium and blood pressure warrant monitoring.

Yokukansan is a seven-herb Kampo formula, sold in Japan as Tsumura's TJ-54 granules, combining Atractylodes lancea rhizome, Poria, Cnidium rhizome, Uncaria hook, Angelica acutiloba root, Bupleurum root and licorice. It was written in 1555 for restless, irritable, night-crying children, and Japanese practice has quietly repurposed it over the last twenty years for the behavioral and psychological symptoms of dementia, particularly agitation, aggression and hallucinations. That repurposing rests on more genuine randomized evidence than almost anything else in the traditional-formula category, and the evidence is also genuinely mixed. A 2016 meta-analysis of five RCTs found a modest overall benefit, driven substantially by dementia with Lewy bodies, while the same analysis found no benefit in Alzheimer's patients specifically, and the largest double-blind Alzheimer's trial missed its primary endpoint. The licorice in it is not decorative and has caused severe hypokalemia.

Kampo formula with real randomized data for agitation in dementia, though null in the largest Alzheimer's trial; its licorice carries a real pseudoaldosteronism risk.

How it is supposed to work

Geissoschizine methyl ether, an indole alkaloid from Uncaria hook, is a potent partial agonist at serotonin 5-HT1A receptors and an antagonist at 5-HT2A and 5-HT7, and animal work links it to reduced aggression in socially isolated mice. Glycyrrhizin from licorice is metabolized to 18β-glycyrrhetinic acid, which enhances astrocytic glutamate uptake in the hippocampus. Reviews list further effects across several other neurotransmitter systems, typical of multi-herb extracts and hard to attribute.

What people get wrong

  • Often saidYokukansan is proven for agitation in dementia.

    ActuallyIt is approved in Japan for neurosis, insomnia and childhood night crying, and not for dementia, so that use is off-label. The 2016 meta-analysis found benefit overall but none in Alzheimer's patients, and the largest double-blind Alzheimer's trial missed its primary endpoint. The real signal sits in Lewy body dementia.

  • Often saidBeing herbal and licorice-sweetened, it is gentle.

    ActuallyThe licorice inhibits 11β-HSD2 and can cause pseudoaldosteronism with severe hypokalemia, hypertension and muscle weakness. Japan's own adverse-event database gives yokukansan a higher reported signal than other licorice-containing Kampo formulas, even though it contains comparatively less licorice.

  • Often saidIt is a Japanese invention.

    ActuallyIt is Chinese. Xue Kai published it as Yi Gan San in Bao Ying Cuo Yao in 1555 for irritable children. Japan adopted the same three characters under a Japanese reading, standardized it as TJ-54 granules, and then ran the trials that made it internationally known.

Who profits, and who pushes back

  • Shinji Matsunaga, Taro Kishi and Nakao Iwata

    caveatsPsychiatrists, Fujita Health University; authors of the 2016 meta-analysis in Journal of Alzheimer's Disease

    Report that yokukansan significantly decreased BPSD total scores (SMD -0.32) and agitation/aggression (SMD -0.37) with no significant difference in adverse events or discontinuation, while stating that yokukansan was not superior to placebo plus usual care for BPSD total or any subscale in Alzheimer's disease patients.

  • Furukawa and colleagues

    caveatsInvestigators of the 2017 multicenter double-blind placebo-controlled trial, Geriatrics and Gerontology International

    Report that across 145 randomized Alzheimer's patients the data did not reach statistical significance for yokukansan against BPSD, while agitation/aggression and hallucinations improved and adverse events were infrequent.

  • Japanese Ministry of Health, Labour and Welfare

    neutralNational drug regulator, Japan

    Approves yokukansan, and covers it under national health insurance, for neurosis, insomnia, and night crying and irritability in children. Dementia is not an approved indication, making BPSD prescribing off-label.

  • Authors of the JADER pseudoaldosteronism analysis, Biological and Pharmaceutical Bulletin, 2020

    caveatsJapanese pharmacovigilance researchers

    Report that yokukansan carried a higher reported odds ratio for pseudoaldosteronism (ROR 2.4, 95% CI 1.9 to 2.8) than other licorice-containing Kampo formulas despite its relatively lower licorice content, and note that the resulting hypertension, hypokalemia and muscle weakness may result in death.

Where the research comes from

Most of the published research on this comes from one place. 100% of it is from Written in Ming China in 1555, adopted into Japanese Kampo, and today prescribed almost entirely within Japan. Findings that no unrelated group has reproduced are weaker than the study count makes them look.

Share of published research by country of origin.
PlaceShare of published research
Written in Ming China in 1555, adopted into Japanese Kampo, and today prescribed almost entirely within Japan100%

How we got here

The formula kept its characters and changed its reading. 抑肝散 is Yi Gan San in Chinese and yokukansan in Japanese, so the Ming original and the Kampo product are literally the same three graphs, and English papers pick whichever name matches the country of the study, which fragments literature searches. The clinical literature mostly says TJ-54, a Tsumura catalog number rather than a drug name, an artifact of one manufacturer supplying nearly all the trial material and a reminder that the tested article is a specific standardized extract rather than the classical decoction. A documented variant, yokukansankachimpihange, adds citrus peel and pinellia for weaker or more debilitated patients and is sold separately as TJ-83.

The formula was written by Xue Kai, a Ming physician, and published in Bao Ying Cuo Yao (Synopsis for Protecting Infants) in 1555 as Yi Gan San, the powder to restrain the liver. Its target was the fretful, convulsive, night-crying child, and it belongs to a Chinese pediatric tradition that read such symptoms as liver wind and constrained liver qi. Japanese physicians brought it into the Kampo repertoire, where it has been used for roughly four centuries, gradually widening it toward adult neurosis and insomnia. Japan's Ministry of Health, Labour and Welfare approves and reimburses it for neurosis, insomnia, and night crying and irritability in children. Dementia is not among the approved indications, so the use it is best known for internationally is off-label in the one country that prescribes it seriously. The dementia literature begins with Japanese trials in the mid-2000s.

  1. 1555Xue Kai publishes Yi Gan San in Bao Ying Cuo Yao, for restlessness and night crying in children
  2. 17th to 19th centuriesJapanese Kampo adopts the formula as yokukansan and extends it toward adult neurosis and insomnia
  3. mid-2000sJapanese open and observer-blind trials first report yokukansan improving BPSD in dementia patients
  4. 2009A 106-patient crossover trial in International Journal of Neuropsychopharmacology reports improved NPI scores in Alzheimer's and Lewy body dementia, with effects persisting one month and no withdrawal symptoms
  5. 2012Geissoschizine methyl ether identified as a potent 5-HT1A agonist and the candidate for the anti-aggression effect
  6. 2016Matsunaga, Kishi and Iwata meta-analysis: 5 RCTs, benefit overall, none in Alzheimer's disease specifically
  7. 2017Furukawa's 145-patient double-blind Alzheimer's trial misses its primary endpoint
  8. 2020JADER database analysis finds yokukansan's pseudoaldosteronism signal exceeds that of other licorice-containing Kampo formulas

How it is understood

Yokukansan's original use is bound up with boshi dofuku, mother and child taking the same medicine together. The formula was given for night crying, irritability and convulsions in infants, and the nursing mother drank it too, on the reasoning that her liver constraint reached the child through her milk and her manner. Yoku-kan-san is the powder that restrains the liver, liver meaning the Kampo system governing anger, tension and the free flow of emotion rather than the organ. Its use in agitated elderly patients extends that logic.

At a glance

Composition
Seven herbs: Atractylodes, Poria, Cnidium, Uncaria, Angelica, Bupleurum, licorice
Key compound
Geissoschizine methyl ether from Uncaria hook, a 5-HT1A partial agonist
Japanese approved use
Neurosis, insomnia, night crying and irritability in children; not dementia
Best evidence
5 RCTs, n=381, BPSD total SMD -0.32; null in the Alzheimer's subgroup

What this entry does not yet cover

What follows is unfinished work on our side, not a finding about Yokukansan (抑肝散, TJ-54). A short entry is not a safe entry.

  • Cost and market. We have not documented what it sells for or who sells it.
  • Supply chain. We have not mapped where it is made.
  • Who uses it. We have not documented the user groups.
  • What could change. No forward-looking summary yet.
  • How it compares. We have not set it against the alternatives.
  • Children and teenagers. We have not checked what is known about younger people.
  • What people take it for. We have not catalogued the claims made for it.

Sources