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The history of saffron cultivation reaches back more than 3,000 years.The wild precursor of domesticated saffron crocus was Crocus cartwrightianus. Human cultivators bred wild specimens by selecting for unusually long stigmas. Thus, a sterile mutant form of C. cartwrightianus, C. sativus, emerged in late Bronze Age Crete. Experts believe saffron was first documented in a 7th century BC Assyrian botanical reference compiled under Ashurbanipal. Documentation of saffron's use over the span of 4,000 years in the treatment of some 90 illnesses has been uncovered.
The 17.8 metres (58 ft) monolith of Gomateshwara, dating to 978–993 AD, is anointed with saffron every 12 years by thousands of devotees as part of the Mahamastakabhisheka festival.

Saffron-based pigments have been found in 50,000 year-old depictions of prehistoric places in northwest Iran. Later, the Sumerians used wild-growing saffron in their remedies and magical potions. Saffron was an article of long-distance trade before the Minoan palace culture's 2nd millennium BC peak. Ancient Persians cultivated Persian saffron (Crocus sativus 'Hausknechtii') in Derbena, Isfahan, and Khorasan by the 10th century BC. At such sites, saffron threads were woven into textiles, ritually offered to divinities, and used in dyes, perfumes, medicines, and body washes.Thus, saffron threads would be scattered across beds and mixed into hot teas as a curative for bouts of melancholy. Non-Persians also feared the Persians' usage of saffron as a drugging agent and aphrodisiac.During his Asian campaigns, Alexander the Great used Persian saffron in his infusions, rice, and baths as a curative for battle wounds. Alexander's troops imitated the practice from the Persians and brought saffron-bathing to Greece.

Conflicting theories explain saffron's arrival in South Asia. Kashmiri and Chinese accounts date its arrival anywhere between 900–2500 years  or to a Persian invasion and colonization of Kashmir. Phoenicians then marketed Kashmiri saffron as a dye and a treatment for melancholy. From there, saffron use in foods and dyes spread throughout South Asia. Buddhist monks in India adopted saffron-coloured robes after the Gautama Buddha's death. However, the robes were not dyed with costly saffron but turmeric, a less expensive dye, or jackfruit.The Tamils have been using saffron for more than 2000 years. In Tamil it is called "gnaazhal poo".It is used to cure head ache, for painless labor etc.

Some historians believe that saffron came to China with Mongol invaders from Persia.On the other hand, saffron is mentioned in ancient Chinese medical texts, including the forty-volume Shennong Bencaojing "Shennong's Great Herbal", also known as Pen Ts'ao or Pun Tsao) pharmacopoeia, a tome dating from 200–300 BC. Traditionally attributed to the legendary Yan ("Fire") Emperor Shennong, it documents 252 phytochemical-based medical treatments for various disorders. Yet around the 3rd century AD, the Chinese were referring to saffron as having a Kashmiri provenance. For example, Wan Zhen, a Chinese medical expert, reported that he habitat of saffron is in Kashmir, where people grow it principally to offer it to the Buddha." Wan also reflected on how saffron was used in his time: "The [saffron crocus] flower withers after a few days, and then the saffron is obtained. It is valued for its uniform yellow colour. It can be used to aromatise wine.