For thousands of years cannabis has been valued as a versatile herbal medicine. In the twentieth century, prescription gave way to proscription. Might this ancient remedy be about to regain its healing reputation? By Stephanie Pain
Earliest evidence: ∼2700 BC
Cannabis sativa is thought to have been grown for at least 12,000 years, initially for fibre and grain. “The plant arose in Central Asia, but once people began growing it, it spread very quickly,” says Ethan Russo, a psychopharmacologist at biotechnology firm Phytecs, based in Los Angeles, California, and a historian of medical cannabis. The earliest use of cannabis as a medicine is attributed to the legendary Chinese Emperor Shen Nung (pictured), who is thought to have lived around 2700 BC. His teachings were passed down by word of mouth before appearing in writing in the Shen Nung Pen-ts'ao Ching, a second-century Chinese book of herbal remedies.
Archaeologists excavating the Yanghai Tombs in northwest China in the early 2000s identified one grave as that of a shaman buried 2,700 years ago. In the grave was a stash of well-preserved C. sativa. Later analysis of the plant remains confirmed the presence of the psychoactive tetrahydrocannabinol (THC). “This is the oldest physical evidence of pharmacologically active cannabis,” says Russo.
Scythia's stoners: ∼450 BC
The Scythians of the Central Eurasian steppes erect a woollen tent, place a dish of red-hot stones inside and throw on hemp seeds, said Greek historian Herodotus. As the seeds begin to smoke, they inhale. “The Scythians enjoy it so much that they howl with pleasure,” he recorded.
Pot boiler: ∼190
The Chinese physician Hua T'o regularly anaesthetized his patients with a mixture of “hemp-boiling-compound” in wine before performing abdominal surgery.
The first evidence of medical use of cannabis came from a fourth-century burial in a cave near Beit Shemesh, 30 kilometres west of Jerusalem. Archaeologists excavating the cave in 1989 found the skeleton of a 14-year-old girl who had apparently died during childbirth. On her abdomen were burnt plant remains, which chemical analysis showed contained THC. The archaeologists concluded that cannabis had been burnt in a vessel and that the girl inhaled cannabis smoke during her efforts to deliver the baby.
European interest: ∼800
In Western Europe, remedies were based on hemp, which has more non-psychoactive, but biologically useful, cannabidiol and less THC than Asian cannabis. Archaeological finds suggest that hemp was grown in Roman Britain for grain and fibre, but it was probably the later Saxons who used it as a medicine. The ninth-century medical text the Old English Herbarium advised pounded hemp for dressing wounds and a liquid concoction “for pain of the innards”.
Westward bound: 1545
Spanish colonists introduced cannabis to Chile, initially growing it for fibre. In 1611, English settlers took hemp to Jamestown, Virginia. Hemp went on to become an important crop in North America.
Snack attack: 1563
Portuguese physician Garcia da Orta, who lived in Goa, India, was the first Western observer to record the appetite-stimulating effects of cannabis: “Those of my servants who took it ... said that it made them so as not to feel work, to be very happy, and to have a craving for food.”
Getting hooked: 1689
The Royal Society's Robert Hooke was given, by a friend, “a drug from India called Bangue”. Addressing the society, Hooke described it as “so like to hemp ... that it may be said to be only Indian hemp”. He added that it might “possibly be of considerable use for Lunaticks, or for other Distempers of the Head and Stomach”.
Modern medical interest in cannabis is traced to Irish physician William Brooke O'Shaughnessy. While in India, he saw how people used Indian hemp as a narcotic and medicine. Impressed, he tested it on animals before beginning trials in patients. O'Shaughnessy made extracts of cannabis resin and either rolled it into pills or dissolved it in alcohol to produce a tincture to treat conditions such as cholera, infantile convulsions and even tetanus. “O'Shaughnessy was of critical importance in introducing Indian hemp to British and North American physicians,” says Russo.
War on drugs: 1863
At the height of the American Civil War, a Union army soldier developed tetanus and gangrene after his shattered arm was amputated. He was treated with a tincture of cannabis and survived. Army doctors also prescribed cannabis with opium in an attempt to reduce the staggering death toll from diarrhoea and dysentery.
British chemists isolated cannabinol, the first cannabinoid identified, but their discovery came just as medical cannabis was falling out of favour. Advances in chemistry made it possible to isolate and synthesize the active ingredients of medicinal plants, and tinctures gave way to drugs of guaranteed consistency. The hypodermic syringe accelerated the move to water-soluble drugs that could be injected for faster pain relief.
Viper's drag: 1923
New Orleans was one of the first US cities to ban marijuana. Its popularity among the jazz musicians of Storyville, the city's historic red-light district, fuelled a moral crusade by organizations who saw the place, the drug and the music as a menace to society.
The law steps in: 1925
An international treaty brokered by the League of Nations to control the opium trade was extended at the last minute to include cannabis. Signatories were required to control the trade in cannabis and prevent trafficking. The 1961 United Nations Single Convention on Narcotic Drugs clamped down still further, and a decade later the UN Convention on Psychotropic Substances made it all but impossible to carry out research on cannabis; only authorized people in supervised laboratories could work with it.
In Israel, chemist Raphael Mechoulam isolated THC, kick-starting research into the plant's pharmacology (see page S12). “The main focus of research in the UK was in exploring the possible harmful effects of recreational cannabis,” says neuropharmacologist Roger Pertwee of the University of Aberdeen, UK. “But gradually people got interested in the potential medical use of synthetic cannabis-like chemicals.” Research led to nabilone and dronabinol, synthetic versions of THC, which were approved in the 1980s to suppress nausea during chemotherapy.
The cannabinoids within: 1988
Researchers discovered a new receptor in the brain, named CB1, through which THC exerts its psychoactive effects. “That led us to wonder if we have substances in our bodies that target this receptor,” says Pertwee. The first of these so-called endocannabinoids, anandamide, was found in 1992. More followed, along with a second receptor (CB2) in 1993. “The discovery that everyone has cannabinoids in their bodies led to a change in attitude,” says Pertwee. “It made our research much more respectable.
California dreamin': 1996
California passed Proposition 215 (the Compassionate Use Act), which allowed the sale and medical use of cannabis for patients with HIV/AIDS, cancer and other serious and painful diseases.
By the 1990s, growing numbers of people with conditions that failed to respond to prescription drugs were turning to cannabis. “We did a survey in the UK and the US, asking people with multiple sclerosis how they thought it helped them,” says Pertwee. Based partly on the findings, an inquiry by the UK House of Lords concluded in 1998 that there was strong evidence that cannabis had a medical value, and in 2000 the government supported a trial of cannabis in multiple sclerosis.
The first cannabis-based product Sativex (nabiximols) — a mouth spray of whole-cannabis extract, containing equal amounts of THC and cannabidiol — was given its first approval in Canada. The spray was developed by GW Pharmaceuticals, which was set up by Geoffrey Guy and Brian Whittle following the UK report. Today, nabiximols is approved in 27 countries to treat spasticity in patients with multiple sclerosis (see page S6).
High hopes 2011
The first draft genome of C. sativa was published (see go.nature.com/g1kffb), allowing researchers to explore its 100-plus cannabinoids and paving the way for the development of cannabis strains tailored to different medical uses.
Design by Mohamed Ashour/Nature
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Nature Reviews Rheumatology (2018)