Cannabis has been used for thousands of years for industrial, recreational, religious, and medicinal purposes. Once valued as a versatile herbal medicine, cannabis has held a volatile place in the medical field since the beginning of the twentieth century. Its decline was deeply influenced by economic, social, and ethical factors. Until recently, it seemed the flowering plant was destined to fall by the wayside: it was classified as a substance of abuse, condemned by governments, and contributed to the problems of drug trafficking. However, in recent years, a growing body of research has begun to demonstrate the medicinal potential of cannabis in the treatment of numerous pathologies. These findings are starting to change public perceptions and cannabis is now receiving increased attention from patients, physicians, and governmental regulators across the globe (Pain, Nature, 2015; Pisanti, Trends Pharmacol Sci, 2017). Cannabis’ path from praised healing agent to dismissed substance of abuse has now come full circle.
Early History of Cannabis
Historians and archeologists believe Cannabis sativa has been grown for at least 12,000 years. It was initially cultivated for its fiber and grain. The fibers and stalks of hemp, a non-psychoactive variety of Cannabis sativa, was found to be particularly useful in the development of numerous products including paper, textiles, and rope (Pain, Nature, 2015; Baron, Headache, 2015). The exact geographic origin of cannabis is unknown, but it is believed that the plant arose in Central Asia and subsequently spread throughout Asia and Europe, following the migration patterns of humans (Russo, Chem Biodivers, 2007). Carbon dating of archeologic remains from the Yang-shao culture in China has confirmed the use of cannabis fibers in the form of hemp dating as far back as 4,000 BC (Li, Economic Botany, 1974). Cannabis spread to the United States after the arrival of Columbus, and the industrial benefits were capitalized in the country. In fact, in 1619, Virginia passed a law requiring hemp to be grown on every farm in the colony (history.com 2018).
Fibers of a hemp plant stalk.
The earliest evidence of the medical use of cannabis dates back to 2,700 BC, where the Chinese Emperor Shen Nung described it as a remedy for gout, malaria, rheumatism, and constipation (Liu, Lett Drug Disc Des, 2006). In Egypt, starting around 1700 BC, scholars began to outline medical remedies for a number of ophthalmic, gynecologic, and infectious disorders using marijuana, indicating suspected antibacterial, antipyretic, analgesic, and anti-inflammatory effects (Russo, Chem Biodivers, 2007). A number of ancient societies in Asia and Europe, including the Greeks, Romans, and Mesopotamians provided medical indications for the use of cannabis. Some historians even argue references can be found in the original Biblical texts (Russo, Chem Biodivers, 2007). In India, literary descriptions of cannabis were outlined as early as the sixth and seventh centuries. By the tenth century, scholars were clearly describing the narcotic and pain-relieving properties of the plant (Chopra, Bull. Narcotics, 1957). The first archeologic evidence supporting the medical use of cannabis came from a burial cave near Jerusalem. The skeleton of a 14-year-old girl who had presumably died during childbirth in the fourth century was found to have burnt plant remains on her abdomen. Chemical analysis showed the remains contained THC. Archaeologists concluded that cannabis had been burnt in a vessel and that the girl inhaled cannabis smoke during her efforts to deliver the baby (Pain, Nature, 2015). Cannabis has long held an important role in human culture, across a variety of cultures and regions. It was well-known before the modern era to be a potent, versatile therapeutic.
The Rise of Modern Western Medicinal Interest
The Western world was first introduced to the medicinal uses of cannabis in 1839 by Irish physician William Brooke O’Shaughnessy. Dr. O’Shaughnessy had spent time in Calcutta, where he observed people using cannabis for a number of purposes including digestive system support, improvement of their over-all sense of well-being, and as a narcotic. Impressed, he began to test the plant’s effects in animals, becoming the first person to apply the experimental methods to the study of cannabis. Based on his experiments, he ascertained that the plant was safe for use and made extracts of cannabis resin which he placed in pills or dissolved in alcohol. He administered these preparations to select patients who suffered from epilepsy, rheumatisms, cholera, or tetanus. He deduced the plant had analgesic and myorelaxant properties. His work was of critical importance in introducing Indian hemp to British and North American physicians (O’Shaughnessey, Prov Med J Retrosp Med Sci, 1843; Pisanti, Trends Pharmacol Sci, 2017; Pain, Nature, 2015).
Following O’Shaughnessy’s work, systematic research on marijuana began to proliferate in the Western World. During the second half of the nineteenth century and the first decades of the twentieth, over a hundred studies were published in Europe and the United States. Researchers explored the impact of cannabis on pathologies ranging from migraine, neuropathic pain, insomnia, hysteria, and stroke to asthma, emphysema, tetanus, and uterine hemorrhage. Pharmaceutical companies such as Merck and Eli Lily developed analgesic, anti-inflammatory, and anti-spastic drugs using cannabis extracts (Pisanti, Trends Pharmacol Sci, 2017; Russo, Cannabis sativa L. – Botany and Biotechnology, Chap 2, 2017). The presumed impact of cannabis on migraine relief was so promising that in 1915 Dr. William Osler, considered the “Father of Modern Medicine”, stated that when treating migraine, “Cannabis indica is probably the most satisfactory remedy” (Baron, Headache, 2015). It was an exciting time in marijuana research. Unfortunately, just as the research was starting to show promising results, it was about to suffer major legal and social setbacks.
William Brooke O’Shaughnessy (circa 1836).
Growing Restrictions and Fear of Reefer Madness
Even though the body of research on the benefits of marijuana was reaching its peak at the end of the nineteenth century, the use of medical cannabis was starting to decline. The pharmacologically active components of marijuana were still unknown, and therefore the drug preparations suffered from standardization difficulties. Manufacturers were unable to accurately titrate clinical dosing or ensure quality control. Due to the variable effect cannabis medications had on patients, it failed to gain broad acceptance (Pisanti, Trends Pharmacol Sci, 2017; Russo, Chem Biodivers, 2007).
While medicinal use started to decline, recreational use was growing in Western cultures. The new research helped to popularize the exploration of the psychoactive properties of marijuana. For instance, French psychiatrist Jacques-Joseph Moreau trialed cannabis on himself and his students in 1840 and detailed the psychoactive effects in research journals. Soon after, use of cannabis grew among the intellectual elite in Europe. The Club des Hashischins (Club of Hashish Eaters) emerged in Paris and was frequented by famous poets and authors like Victor Hugo, Alexandre Dumas, Charles Baudelaire, and Honoré de Balzac. The group was dedicated to exploring the drug-induced experiences caused by hashish (Pisanti, Trends Pharmacol Sci, 2017).
Public and government concerns began to emerge about the uncontrolled circulation of cannabis for recreational purposes. This concern was driven in part by economic worries that cannabis use was impacting the productivity of slaves and indentured colonial workers and in part by propaganda that cannabis was a drug of abuse used by minority and low-income communities that lead to psychosis, mental deterioration, addiction, and violent crimes (Pisanti, Trends Pharmacol Sci, 2017; Baron, Headache, 2015).
Hôtel de Lauzun, meeting place of The Club des Hashischins.
The British government was so worried about the economic effects of hemp use by the Indian people in its colonies that it commissioned “The Indian Hemp Drugs Commission Report” in 1894. The report established “the occasional use or hemp in moderate doses may be beneficial, but this use may be regarded as medicinal in character… The excessive use may certainly be accepted as very injurious, though it must be admitted that in many excessive consumers the injury is not clearly marked. The injury done by the excessive use is, however, confined almost exclusively to the consumer himself; the effect on society is rarely appreciable’ (Pisanti, Trends Pharmacol Sci, 2017; Report of the Indian Hemp Drugs Commission, 1893-94. [CH. XIII]).
Throughout the Western world, governments began working to restrict cannabis use. In the U.S., local laws started to emerge after 1860 requiring medicines to indicate if marijuana was found in the preparation, and requiring prescriptions from doctors for use. The Pure Food and Drug Act of 1906 enacted the first national regulation that medical preparations containing cannabis be labeled. In 1925, international drug control treaties between the U.S., Germany, the UK, France, Italy, the Netherlands, Portugal, Russia, China, Japan, Persia, and Siam banned the exportation of Cannabis indica to countries that prohibited its use. Recreational use of cannabis was banned in the UK in 1928. In 1937, the U.S. government passed the “Marijuana Tax Act”, which did not forbid the use of cannabis, but made the purchase and preparation of the plant so expensive that experimentation into the medical uses of cannabis were all but discontinued. In 1941, despite protest from the medical community, cannabis was removed from the United States Pharmacopoeia and National Formulary (Pisanti, Trends Pharmacol Sci, 2017; Baron, Headache, 2015).
The Indian Hemp Drugs Commission Report (1894).
Marijuana started to be considered a drug of abuse and resurgence of recreational marijuana in the early 1960s and early 1970s by anti-establishment groups further drove this perception. Cannabis came to be associated with the psychedelic hippie counterculture movement. In August 1970, the U.S. Assistant Secretary of Health, Dr. Roger O. Egeberg recommended that marijuana be classified a Schedule 1 substance, in the same category as heroin and lysergic acid diethylamide (LSD). Dr. Egeberg’s reasoned, “Since there is still a considerable void in our knowledge of the plant and effects of the active drug contained in it, our recommendation is that marijuana be retained within Schedule 1 at least until the completion of certain studies now underway to resolve the issue.” The Controlled Substances Act of 1970 was passed shortly after this recommendation was published and marijuana was classified as a Schedule 1 substance, not because of scientific evidence, but due to lack of scientific knowledge. Ironically, this classification made research in the U.S. illegal at that time (Pisanti, Trends Pharmacol Sci, 2017; Baron, Headache, 2015). Shortly after, in the UK, under the Misuse of Drugs Act of 1971, cannabis was classified as a class B drug, making it illegal to grow, process, produce or supply the drug (Liu, Lett Drug Disc Des, 2006). That same year, the UN Convention on Psychotropic Substances determined that only authorized people in supervised laboratories could carry out research on cannabis (Pain, Nature, 2015). The growing body of restrictions and regulations were making it all but impossible to do reputable research on cannabis and its components.
A New Era of Medical Research
With the growing legal barriers to research and the widespread negative opinion of marijuana as a narcotic, it looked like medicinal research of cannabis was destined to end. However, small groups of researchers continued to study the plant and their findings at the end of the twentieth century helped to be propel research forward in new and exciting directions.
This change in the direction of research was driven in part by the discovery of the phytocannabinoids (the components that act on receptors in the human body, found in the cannabis plant). Cannabidiol was the first phytocannabinoid isolated from cannabis at the end of the nineteenth century. Its structure was elucidated in the early 1930s. It was first synthesized by Dr. Roger Adams and his team at the University of Illinois in 1940 (Pertwee, Br J Pharmacol, 2006; Adams, J. Am. Chem. Soc., 1940). THC, the psychoactive cannabinoid found in cannabis, was isolated and synthesized in 1964 by Israli scientists Yehiel Gaoni and Raphael Mechoulam (Gaoni and Mechoulam, J. Am. Chem. Soc., 1964). Then, in the 1990s, the discovery of the receptors for cannabinoids and the characterization of the endocannabinoids and the endocannabinoid system, the effective biologic target of phytocannabinoids, renewed scientific interest in cannabis, leading to the publication of thousands of papers over the following decades highlighting the pharmacologic potential of the plant and its components (Russo, Chem Biodivers, 2007; Pertwee, Br J Pharmacol, 2006; Pisanti, Trends Pharmacol Sci, 2017).
Professor Raphael Mechoulam.
As medical research resumed, public perceptions of medicinal marijuana began to change. Patients with conditions that failed to respond to prescription drugs started to turn to cannabis for results (Liu, Lett Drug Disc Des, 2006; Pain, Nature, 2015). Physicians began to take a closer look at research and advocate for change and legalization (Gupta, CNN, 2013; WebMD 2014). Public pressure forced government bodies to rethink their regulations. Cannabis was decriminalized in the Netherlands in 1976. In 1996, California became the first state to legalize medical cannabis under the Compassionate Use Act. The UK House of Lords started to re-examine the medicinal value of marijuana in 1998 and approved a trial of cannabis in multiple sclerosis in 2000. In 2004, under the UK Misuse of Drugs Act, cannabis was downgraded to a class C drug (Liu, Lett Drug Disc Des, 2006; Pain, Nature, 2015; Pisanti, Trends Pharmacol Sci, 2017). In 2001, Canada became the first country to adopt a system regulating the medical use of marijuana (CBC News) and several other countries followed suit, endorsing laws that allowed for well-documented therapeutic use and decimalization or even legalization for recreational purposes (Pisanti, Trends Pharmacol Sci, 2017). In the U.S., although federal law still deems possession of cannabis illegal, the medical use of cannabis is legal in 33 states and the territories of Guam and Puerto Rico. The recreational use of cannabis is legal in 10 states and the District of Columbia and it has been decriminalized in three additional states (NCLS – Marijuana Overview; NCLS – State Medical Marijuana Laws).
Cannabis was one of the first plants harvested by humans and has actively shaped the development of cultures and societies for thousands of years. The versatile plant has been used for medicinal, industrial, religious, and nutritional purposes. Some have even argued the case that cannabis co-evolved with the human species (Clarke & Merlin, Cannabis: Evolution and Ethnobotany, 2016). Perceptions of cannabis declined at the start of the twentieth century due to social, cultural, and economic factors. However, the growing body of scientific evidence over the past three decades shows that the use of cannabinoids and manipulation of the endocannabinoid system could offer therapeutic options for pathologies that were previously considered refractory to treatment. Factors such as increased social acceptance, greater levels of legalization, and improved technology have allowed cannabis to re-emerge as a medicine in the modern era.