Takamine Tokumei from Shuri, Ryūkyū Kingdom, is reported to have made a general anesthesia in 1689 in the Ryukyus, now known as Okinawa. He passed on his knowledge to the Satsuma doctors in 1690 and to Ryūkyūan doctors in 1714.
Hanaoka Seishū (華岡 青洲, 1760–1835) of Osaka was a Japanese surgeon of the Edo period with a knowledge of Chinese herbal medicine, as well as Western surgical techniques he had learned through Rangaku (literally "Dutch learning", and by extension "Western learning"). Beginning in about 1785, Hanaoka embarked on a quest to re-create a compound that would have pharmacologic properties similar to Hua Tuos mafeisan. After years of research and experimentation, he finally developed a formula which he named tsūsensan (also known as mafutsu-san'). Like that of Hua Tuo, this compound was composed of extracts of several different plants, including:
* 2 parts bai zhi (Chinese:白芷，Angelica dahurica);
* 2 parts cao wu (Chinese:草烏，Aconitum sp., monkshood or wolfsbane);
* 2 parts chuān ban xia (Pinellia ternata);
* 2 parts chuān xiōng (Ligusticum wallichii, Cnidium rhizome, Cnidium officinale or Szechuan lovage);
* 2 parts dong quai (Angelica sinensis or female ginseng);
* 1 part tian nan xing (Arisaema rhizomatum or cobra lily)
* 8 parts yang jin hua (Datura stramonium, Korean morning glory, thorn apple, jimson weed, devils trumpet, stinkweed, or locoweed').
The active ingredients in tsūsensan are scopolamine, hyoscyamine, atropine, aconitine and angelicotoxin. When consumed in sufficient quantity, tsūsensan produces a state of general anesthesia and skeletal muscle paralysis. Shutei Nakagawa (1773–1850), a close friend of Hanaoka, wrote a small pamphlet titled "Mayaku-ko" ("narcotic powder") in 1796. Although the original manuscript was lost in a fire in 1867, this brochure described the current state of Hanaoka's research on general anesthesia.
On 13 October 1804, Hanaoka performed a partial mastectomy for breast cancer on a 60-year-old woman named Kan Aiya, using tsūsensan as a general anaesthetic. This is generally regarded today as the first reliable documentation of an operation to be performed under general anesthesia. Hanaoka went on to perform many operations using tsūsensan, including resection of malignant tumors, extraction of bladder stones, and extremity amputations. Before his death in 1835, Hanaoka performed more than 150 operations for breast cancer.