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Cannabis has been used for more than 4000 years. The earliest documentation of the therapeutic use of marijuana is the fourth century b.c. in China.156 Cannabis use spread from China to India to North Africa, reaching Europe around a.d. 500.126 In colonial North America, cannabis was cultivated as a source of fiber. Like 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.91 This is due to the fact that the active compounds of morphine and cocaine 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 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 1967.92

Marijuana was used as an intoxicant from the 1850s until the 1930s when the US Federal Bureau of Narcotics began to portray marijuana as a powerful, addicting substance. Despite this, marijuana was listed in the US Pharmacopoeia from 1850–1942. In 1970, the Controlled Substances Act classified marijuana as a Schedule I drug.

In all populations, cannabis use by males exceeds use by females. Currently, marijuana is the most commonly used illicit xenobiotic in the United States, yet it is legal in states such as Colorado and Washington. A study by the Substance Abuse and Mental Health Services Administration reported that in 2006 in the United States, 6.0% (14.8 million persons) 12 years of age or older used marijuana in the month prior to the survey; this prevalence is unchanged from previous years. The prevalence of past-month users aged 12 to 17 years was 6.7% (down from 8.2% in 2002). The number of first-time users was estimated to be 2.1 million, with 63.3% younger than 18 years of age.

Interest in synthetic cannabinoid receptor agonists (SCRAs) as potential therapeutics increased following the progress of the late 1960’s, and ­several SCRAs 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 affinity 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.63 Despite its efforts, no drugs came to market; new agents retained unwanted psychoactive side effects. During this period, extensive structure activity relationships for cannabinoids were developed.62


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