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Cannabis has been used for more than 4,000 years. The earliest documentation of the therapeutic use of marijuana is the fourth century B.C. in China.172 Cannabis use spread from China to India to North Africa, reaching Europe around A.D. 500.138 In colonial North America, cannabis was cultivated as a source of fiber. Similar to cocaine and morphine, cannabis was the focus of research efforts in the 19th century. Although the active chemical constituents of the former were isolated during this time, that of cannabis remained elusive.97 This was because the active compounds of opium poppy and coca leaf are both alkaloids and were possible to extract with the technological means of the time, whereas the methods to isolate the active terpenes in cannabis were not available to researchers until several decades later.

The first pure phytocannabinoid to be isolated was cannabinol, in 1898. Synthesis of its structural isomers yielded the first synthetic cannabinoid (SC) years later—Δ9-tetrahydrocannabinol (THC). Cannabinol was previously shown to lack psychoactive effects, but this new compound demonstrated similar effects to cannabis in a model of ataxia in dogs. Pure Δ9-THC was subsequently isolated from hashish extract in 1964, and the structure was elucidated in 1967.98

Cannabis was used in the United States as a substance of abuse from the 1850s until the 1930s when the US Federal Bureau of Narcotics began to portray marijuana as a powerful, addictive substance. Despite this, marijuana was listed in the US Pharmacopoeia from 1850 to 1942. In 1970, the Controlled Substances Act classified marijuana as a Schedule I drug.

In all populations, cannabis use by men exceeds use by women. Currently, marijuana is the most commonly used illicit xenobiotic in the United States; however, it is legal for recreational use in an increasing number of states, including at the time of this writing Colorado, Washington, California, Oregon, and Alaska. In 2015 in the United States, 8.2% (22 million persons) 12 years of age or older used marijuana in the month before the survey; this prevalence is increased from 6% in previous years. The prevalence of past-month users aged 12 to 17 years was 7% (increased from 6.8% in 2006). The number of first-time users was estimated to be 2.1 million, with 63.3% younger than 18 years of age.128

Interest in SCs as potential therapeutics increased after the progress of the late 1960s, and several SCs similar in structure to THC were created. These semisynthetic compounds were based on the dibenzopyran ring structure of THC and had varying cannabinoid receptor binding affinities relative to THC. The search for a nonopioid analgesic sparked research and development efforts by pharmaceutical companies, most notably Pfizer, from the 1960s to 1980s.67 Despite its efforts, no medications came to market; new analgesics retained unwanted psychoactive side effects. During this period, an extensive understanding of ...

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