From the Earliest Dawn of History
Cannabis has accompanied human civilization for thousands of years, evolving from a versatile agricultural crop into one of the most extensively studied medicinal plants. Over time, cultivation spread across the world. Today, this long history provides the foundation for modern scientific research into cannabinoids and the development of evidence-based pharmaceutical medicines.
Paleobotanical studies attest that cannabis was already present about 11700 years ago in Central Asia near the Altai Mountains. South-East Asia has also been proposed as an alternative region for the primary domestication of cannabis. Cannabis provided fibers for ropes and nets, food, and seeds for oil. Our ancestors would have chanced upon the euphoriant properties of heated cannabis and would have easily identified the resin produced by the distinctive female plants. Gradually humans moved from gathering to cultivating cannabis and then started selecting strains either for fibers or for THC content.
Reflecting the long association of cannabis and humans, some myths in India have cannabis emerge, as a divine ingredient, in the earliest stages of cosmogony, known as the churning of the ocean. The god Shiva supposedly favored cannabis, which had a religious role as an agent for mystic inspiration. Under names such as Vijaya , cannabis has been used for thousands of years in ayurvedic medicine to reduce pain, nausea, and anxiety, improve appetite and sleep, relax muscles, and produce a feeling of euphoria. The global dissemination of cannabis came to an end when the plant reached Africa, and ultimately America. Spain introduced the cultivation of hemp in central Chile, in Quillota near Valparaíso, within the first decade after the Conquista . Louis Hébert, an apothecary with a practice in Paris, is credited as being the first colonist to grow hemp in 1606 in Acadia (today, Nova Scotia).
Classical Records of the Medicinal Properties
Historical records from ancient civilizations suggest that cannabis has been recognized for its medicinal properties for thousands of years. Early medical texts from China, Egypt, Assyria, Greece, and the Roman Empire describe the use of cannabis preparations for a variety of therapeutic purposes.
China has some of the earliest records of the medicinal use of cannabis. The discovery of the curative virtues of plants is attributed to Shén Nóng, a mythical emperor whose name means the Divine Farmer (2000 BC). Because of him, it has been claimed that the discovery of medicinal cannabis dates back to two millennia BC. However, this is probably exaggerated since the compendium of 365 medical herbs, ascribed to Shén Nóng, was written much later, during the Han dynasty (221 bc-ad 220). The common name for hemp and cannabis in China is Má, and this character can appear in word compositions meaning numbness or anesthesia. Huà Tuó, a Chinese surgeon of the Han dynasty, is said to have performed surgery under general anesthesia using a mixture of wine and herbal extracts, which might have contained cannabis, although the exact formula for this potion was not passed on.
The topical application of cannabis for inflammation is mentioned in the Ebers papyrus, written in Egypt in about 1500 bc. The medicinal use of cannabis has been reported on Assyrian clay tablets. According to Scurlock and Andersen, cannabis, called azallû in Akkadian, was probably used as a medicine, apparently for depression.
A classical but ambiguous mention is found in Homer’s Odyssey (Book IV), around the late 7 th or early 8 th century bc. Zeus’ daughter, Helen, served wine mixed with a drug called nēpenthés (νηπενθές) that quiets all pain and strife and brings forgetfulness of every ill. Helen served this mixture to Greek soldiers who had painful reminiscences of their comrades slain during the Trojan war, triggered by Telemachus’ visit—a case of posttraumatic stress disorder. “Nē–Penthés” literally means “No–Grief.” Homer’s text tells us that this medication comes from Egypt; it might have been cannabis or opium.
Herodotus (c. 484-c. 425 bc) describes how Scythians, after a King’s burial, prepare small chambers that are hermetically closed with woolen blankets laid on three posts sloping toward each other. The participants crawl under the blankets and throw hemp seeds (κάνναβις) on red hot stones and are “delighted” (ἀγάμενοι) by the fragrant smoke. Herodotus remarks that hemp either grows spontaneously or is sown and cultivated by the Scythians.
In the Roman Empire, the medical use of cannabis was mentioned by Pliny the Elder, Dioscorides, and Galen. Only the latter discussed the psychoactive effects. The Naturalis Historia by Pliny the Elder (c ad 23-79), the oldest extant encyclopedia from the Graeco-Roman world, is an exhaustive compilation of the knowledge available at the time. In Book, the author described the cultivation of hemp for making ropes and nets. Pliny discussed the medicinal uses of cannabis, differentiating cultivated cannabis and a wild variety growing in forests (probably, Althaea cannabina, a different plant). Pliny indicated antalgic and anti-inflammatory properties: a decoction of the roots in water relieves arthritis and cures gout and similar maladies. Pliny did not mention the intoxicating or euphoriant properties.
The Greek physician Dioscorides (c. ad 40-90) also confirmed, in his pharmacopeia, “ De Materia Medica ,” that applications made with the boiled root of cannabis could lessen inflammation. Claudius Galen (ad 129-199/217) wrote that it was customary in Italy to serve small cakes containing marijuana for dessert. As cited by Brunner, Galen remarked that the seeds create a feeling of warmth, and if consumed in large amounts, affect the head by emitting a warm and toxic vapor.
Introduction to Modern Western Medicine
During the 19th century, cannabis began to attract the attention of Western medicine through systematic clinical observations. In 1839, Irish physician Sir William Brooke O’Shaughnessy published one of the first comprehensive scientific reports describing the medicinal potential of cannabis based on his work in India, introducing the plant to European medical practice.
William Brooke O’Shaughnessy (1809 Limerick, Ireland-1889 England) studied medicine at the University of Edinburgh and moved to Calcutta, where he published the results of his observations on cannabis in 1839. He noted that the intoxicating effect of cannabis was then unknown in Europe, except a few youths experimenting with “hasheesh” in Marseilles (Napoleon’s soldiers brought back cannabis from the Egypt campaign). O’Shaughnessy noted that the effects of cannabis depended on a “resinous secretion” that seemed absent in European hemp, likely because of differences of climate since the European and South-Asian plants looked identical.
Queen Victoria took cannabis for painful menses, and Empress Elisabeth (Sissi) of Austria took it for cough, and possibly also to stimulate the appetite. Sissi was generally wary of medicines and appreciated that cannabis was a natural remedy.
J. Russel Reynolds, a very influential British physician, was appointed in 1878 as physician-in-ordinary to Queen Victoria’s household. In 1890, he summarized more than 30 years’ experience with cannabis in the Lancet. A major obstacle to the use of cannabis was the fact that the active ingredient had not yet been isolated—THC would be identified only in 1964. Therefore, plant extracts could not be made uniform, because “the hemp grown during different seasons, and in different places, varies in the amount that it contains of the therapeutic agent.” The toxicity due to overdosing was made all the more unpredictable by the idiosyncratic sensitivity of the patient. Therefore, Reynolds tried to always obtain cannabis from the same source to prepare a “tincture.” The dose, taken in drops on a small piece of sugar or bread, would be increased cautiously.
The author found cannabis a most useful drug in a variety of painful illnesses (facial neuralgia, migraine, dysmenorrhea, and “numbness and other paresthesiae so common in the limbs of gouty people” [an indication already mentioned by Pliny the Elder]). Reynolds’ indications agree with modern studies of medicinal cannabis registries, which show that pain syndromes account for 42.4% of cases. Reynolds mentioned a pediatric use of cannabis that we would refrain from today: teething problems.
In several medical indications, cannabis was displaced by the discovery of other sedative and analgesic drugs such as aspirin. Throughout the 20th century, a series of obstacles restricted the use of cannabis, particularly in the United States. These successive measures were the Marihuana Tax Act in 1937; the removal of cannabis from the American pharmacopeia a few years later; and the 1961 United Nations Single Convention on Narcotic Drugs that placed cannabis under the strictest control regime along with heroin.
The Discovery of the Endocannabinoid System
The modern era of cannabinoid science began with the identification and structural characterization of the principal phytocannabinoids found in Cannabis sativa. These discoveries transformed cannabinoid research into a multidisciplinary field and continue to drive the development of evidence-based cannabinoid medicines.
More than 100 cannabinoids have been isolated from cannabis; the two significant compounds are cannabidiol (CBD) and Δ9 -THC. CBD was first isolated from marijuana in 1940, and its structure was reported in 1963. However, since CBD was not psychoactive, it was neglected and eclipsed by THC. The structure of the main psychoactive phytocannabinoid, THC, was determined in Israel by Mechoulam and Gaoni in 1964.
Raphael Mechoulam separated several compounds on a column, and identified one of these compounds as psychoactive by testing it on monkeys. Afterward, he further characterized that compound by feeding it with cake to healthy volunteers. He thereby observed a variety of psychological reactions (laughing, panic attacks, openness to discussion) according to the subjects’ personalities. Mechoulam’s seminal discovery gave the impetus for the exploration of a novel receptor system, the endocannabinoid system (ECS). Subsequently, Devane et al characterized a first cannabinoid receptor (CB1) in rat and human brains. Only 4 years later, the same author isolated the first endocannabinoid, arachidonoylethanolamide (AEA). AEA was also termed anandamide by reference to the Sanskrit word ānanda, which means bliss, happiness, or pleasure, and is a good description of what the Scythians experienced when inhaling cannabis fumes in Herodotus’ excerpt quoted earlier.
Reference:
Crocq, M.A. (2020). History of cannabis and the endocannabinoid system. Dialogues in Clinical Neuroscience, 2020:22(3), 223–228.