only 3% found unbound in the plasma. it distributes rapidly to highly vascularized organs such as the heart, lungs, liver, spleen, and kidneys, as well as to various glands. low levels can be detected in the brain, testes, and unborn fetuses, all of which are protected from systemic circulation via barriers. thc further distributes into fatty tissues a few days after administration due to its high lipophilicity, and is found deposited in the spleen and fat after redistribution. metabolism delta-9-thc is the primary molecule responsible for the effects of cannabis. delta-9-thc is metabolized in the liver and turns into 11-oh-thc. 11-oh-thc is the first metabolic product in this pathway. both delta-9-thc and 11-oh-thc are psychoactive. the metabolism of thc into 11-oh-thc plays a part in the heightened psychoactive effects of edible cannabis. next, 11-oh-thc is metabolized in the liver into 11-cooh-thc, which is the second metabolic product of thc. 11-cooh-thc is not psychoactive. ingestion of edible cannabis products lead to a slower onset of effect than the inhalation of it because the thc travels to the liver first through the blood before it travels to the rest of the body. inhaled cannabis can result in thc going directly to the brain, where it then travels from the brain back to the liver in recirculation for metabolism. eventually, both routes of metabolism result in the metabolism of psychoactive thc to inactive 11-cooh-thc. excretion due to substantial metabolism of thc and cbd, their metabolites are excreted mostly via feces, rather than by urine. after delta-9-thc is hydroxylated into 11-oh-thc via cyp2c9, cyp2c19, and cyp3a4, it undergoes phase ii metabolism into more than 30 metabolites, a majority of which are products of glucuronidation. approximately 65% of thc is excreted in feces and 25% in the urine, while the remaining 10% is excreted by other means. the terminal half-life of thc is 25 to 36 hours, whereas for cbd it is 18 to 32 hours. cbd is hydroxylated by p450 liver enzymes into 7-oh-cbd. its metabolites are products of primarily cyp2c19 and cyp3a4 activity, with potential activity of cyp1a1, cyp1a2, cyp2c9, and cyp2d6. similar to delta-9-thc, a majority of cbd is excreted in feces and some in the urine. the terminal half-life is approximately 18–32 hours. administration illustrating various forms of medicinal cannabis smoking has been the means of administration of cannabis for many users, but it is not suitable for the use of cannabis as a medicine. it was the most common method of medical cannabis consumption in the us as of 2013. it is difficult to predict the pharmacological response to cannabis because concentration of cannabinoids varies widely, as there are different ways of preparing it for consumption (smoked, applied as oils, eaten, infused into other foods, or drunk) and a lack of production controls. the potential for adverse effects from smoke inhalation makes smoking a less viable option than oral preparations. cannabis vaporizers have gained popularity because of a perception among users that fewer harmful chemicals are ingested when components are inhaled via aerosol rather than smoke. cannabinoid medicines are available in pill form (dronabinol and nabilone) and liquid extracts formulated into an oromucosal spray (nabiximols). oral preparations are "problematic due to the uptake of cannabinoids into fatty tissue, from which they are released slowly, and the significant first-pass liver metabolism, which breaks down δ9thc and contributes further to the variability of plasma concentrations". the us food and drug administration (fda) has not approved smoked cannabis for any condition or disease, as it deems that evidence is lacking concerning safety and efficacy. the fda issued a 2006 advisory against smoked medical cannabis stating: "marijuana has a high potential for abuse, has no currently accepted medical use in treatment in the united states, and has a lack of accepted safety for use under medical supervision." history ancient cannabis, called má 麻 (meaning "hemp; cannabis; numbness") or dàmá 大麻 (with "big; great") in chinese, was used in taiwan for fiber starting about 10,000 years ago. the botanist hui-lin li wrote that in china, "the use of cannabis in medicine was probably a very early development. since ancient humans used hemp seed as food, it was quite natural for them to also discover the medicinal properties of the plant." emperor shen-nung, who was also a pharmacologist, wrote a book on treatment methods in 2737 bce that included the medical benefits of cannabis. he recommended the substance for many ailments, including constipation, gout, rheumatism, and absent-mindedness. cannabis is one of the 50 "fundamental" herbs in traditional chinese medicine. the ebers papyrus (c. 1550 bce) from ancient egypt describes medical cannabis. the ancient egyptians used hemp (cannabis) in suppositories for relieving the pain of hemorrhoids. surviving texts from ancient india confirm that cannabis' psychoactive properties were recognized, and doctors used it for treating a variety of illnesses and ailments, including insomnia, headaches, gastrointestinal disorders, and pain, including during childbirth. the ancient greeks used cannabis to dress wounds and sores on their horses, and in humans, dried leaves of cannabis were used to treat nose bleeds, and cannabis seeds were used to expel tapeworms. in the medieval islamic world, arabic physicians made use of the diuretic, antiemetic, antiepileptic, anti-inflammatory, analgesic and antipyretic properties of cannabis sativa, and used it extensively as medication from the 8th to 18th centuries. landrace strains evolution of cultivated cannabis strains. the cultivar, cannabis ruderalis, still grows wild today. cannabis seeds may have been used for food, rituals or religious practices in ancient europe and china.: 19–22 harvesting the plant led to the spread of cannabis throughout eurasia about 10,000 to 5,000 years ago, with further distribution to the middle east and africa about 2,000 to 500 years ago.: 18–19 a landrace strain of cannabis developed over centuries. they are cultivars of the plant that originated in one specific region. widely cultivated strains of cannabis, such as "afghani" or "hindu kush", are indigenous to the pakistan and afghanistan regions, while "durban poison" is native to africa.: 45–48 there are approximately 16 landrace strains of cannabis identified from pakistan, jamaica, africa, mexico, central america and asia. modern an irish physician, william brooke o'shaughnessy, is credited with introducing cannabis to western medicine. o'shaughnessy discovered cannabis in the 1830s while living abroad in india, where he conducted numerous experiments investigating the drug's medical utility (noting in particular its analgesic and anticonvulsant effects). he returned to england with a supply of cannabis in 1842, after which its use spread through europe and the united states. in 1845 french physician jacques-joseph moreau published a book about the use of cannabis in psychiatry. in 1850 cannabis was entered into the united states pharmacopeia. an anecdotal report of cannabis indica as a treatment for tetanus appeared in scientific american in 1880. the use of cannabis in medicine began to decline by the end of the 19th century, due to difficulty in controlling dosages and the rise in popularity of synthetic and opium-derived drugs. also, the advent of the hypodermic syringe allowed these drugs to be injected for immediate effect, in contrast to cannabis which is not water-soluble and therefore cannot be injected. in the united states, the medical use of cannabis further declined with the passage of the marihuana tax act of 1937, which imposed new regulations and fees on physicians prescribing cannabis. cannabis was removed from the u.s. pharmacopeia in 1941, and officially banned for any use with the passage of the controlled substances act of 1970. cannabis began to attract renewed interest as medicine in the 1970s and 1980s, in particular due to its use by cancer and aids patients who reported relief from the effects of chemotherapy and wasting syndrome. in 1996, california became the first u.s. state to legalize medical cannabis in defiance of federal law. in 2001, canada became the first country to adopt a system regulating the medical use of cannabis. the use of cannabis, at least as fiber, has been shown to go back at least 10,000 years in taiwan. "dà má" (pinyin pronunciation) is the chinese expression for cannabis, the first character meaning "big" and the second character meaning "hemp". cannabis indica fluid extract, american druggists syndicate, pre-1937 an advertisement for cannabis americana distributed by a pharmacist in new york in 1917 the ebers papyrus (c. 1550 bce) from ancient egypt has a prescription for medical marijuana applied directly for inflammation. society and culture legal status legal status of (whole-plant) medical cannabis worldwide legal as authorized by a physician legal for any use (no prescription required)