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The Native American Church (NAC) evolved from the Peyote religion, one of the most important religious developments in the post-contact history of North American Indians. For thousands of years, natives of northern Mexico have ingested the peyote cactus, which grows wild in specific desert locales, for its medical and visionary properties. Consisting of two alkaloids—strychnine (producing short-term nausea, hunger cramps, and anxiety) and morphine (producing euphoria, colorful fantasies, and meditative relaxation for several hours)—peyote has long appealed to its consumers as a powerful source of religious experiences, and thus cultic activity grew around its use. Huichol Indians, for example, made regular pilgrimages to peyote-rich lands, engaging in dreamy ceremonials under peyote's influence.

In the 1800s, peyote use spread northward to Indian Territory (now Oklahoma) and coalesced into a religious complex with identifiable mythology, theology, ritual, leadership, paraphernalia, ethics, and organization. Espousing the unity of American Indian peoples, it featured the sacramental eating of peyote, often in combination with Christian aspects, including cross imagery, biblical references, devotion to Jesus, and moralistic concern for sinfulness.

The Peyote religion's myths of origin depicted peyote's power to save the lost, strengthen the sick, rejoin separated relatives, and promote peace. Its cosmology envisioned a spiritual world that pitied Indians and delivered supernatural aid through the peyote plant. Peyote thus provided the means of sustaining life, gaining grace, attaining insight, and establishing meaning. Peyotists viewed peyote as a compassionate, redemptive agent, bringing Indians into communion with their ultimate sources of existence.

Peyotism featured a comforting ritual, giving Indians opportunity to experience the holy directly by partaking of the divine cactus. During the all-night rituals, peyotists reinforced their sense of commonality as a people, exhorting each other to moral reformation and sharing Earth's plentitude. Ideally, the ceremonies took place in a tepee, surrounding an altar symbolizing the Peyote Road in the form of a crescent or cross, with a Chief Peyote button set in place and a fire in the center. The participants sat all night in a circle, swallowing peyote and contemplating their condition in reverential fervor. Toward morning, they ate a communal meal and shared their tales of peyote's benefits.

Peyotists attested to the thrilling sense of personal significance under peyote's effect. By means of ordeal and exhilaration, peyote triggered a mystical experience, a perceived contact with awe-inspiring holiness that had the power to transform the peyotists through direct revelation. For them, peyote was a medicine, a food, and a spiritual sustenance that aided clairvoyance and overcame evil, leading to ethical regeneration. Peyotists testified to its enduring effects in everyday life, strengthening familial, tribal, and American Indian identities.

A Cheyenne peyote leader photographed In 1927 by Edward S. Curtis. The Native American Church and Peyote religion have survived decades of legal challenges. As of 2013, the church had as many as 300,000 followers in North America.

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Peyotists exhibited evangelical zeal for their newly developed faith. As the Peyote religion spread across the western United States to more than 70 tribes, Christian and government agencies sought to stem its tide, terming peyote a dangerous drug and its use an incitement to immorality. Although no scientific evidence has been produced to demonstrate harmful or addictive effects of peyote, bureaucrats overseeing Indian reservations in the late 1800s and early 1900s prohibited its use. Unable to convince the U.S. Congress to outlaw peyote traffic, more than a dozen states created anti-peyote legislation beginning in 1917.

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