From the very beginning of time, a middle-aged European-looking man was discovered with a sizable stash of cannabis in the Flaming Mountains, a well-known tourist destination in the Xinjiang-Uighur autonomous region of China. The individual was carrying about 800 g of cultivated cannabis with a high 9-tetrahydrocannabinol (THC) level, according to additional testing.
Contrary to first impressions, this is an academic archeological study on excavating the grave of a 45-year-old guy of high social rank who was likely a shaman and buried around 750 bc, not a thrilling news story about an adventurous tourist facing a prison sentence far from home. The tomb was connected to the Tocharian culture, a nomadic people who spoke an extinct Indo-European language and were pictured in ancient Chinese documents as having blue eyes and light hair.
The results of the botanical and phytochemical tests showed that the marijuana wasn't just picked up off the ground; rather, it was cultivated from cannabis breeds that people had chosen for their high THC concentration. Because the male cannabis plant components are pharmacologically less psychotropic, they have been eliminated. According to Russo et al., cannabis was cultivated for its psychotropic qualities rather than merely as food or fiber. This narrative demonstrates the long-standing relationship between people and cannabis as a psychoactive substance.
According to paleobotanical research, cannabis was present in Central Asia around the Altai Mountains about 11,700 years ago. Another suggested place for the initial domestication of cannabis is South-East Asia. Cannabis produced food, seeds for oil, and fibers for ropes and nets.
Our ancestors would have discovered the euphoric effects of heated cannabis, and the resin generated by the unusual female plants would have been recognized. In one conceivable scenario, four humans transitioned from collecting cannabis to cultivating it, and they subsequently began choosing strains based on their fiber or THC content. After the last glacial period, about 12,000 years ago, cannabis seeds traveled with nomadic peoples and were traded.
This cooperative migration illustrates a mutually beneficial symbiosis in which people and a plant helped spread each other over the earth. We developed a similar evolutionary connection with the canids, an animal species that likewise assisted humans in planet colonization.
The fact that comparable words know the plant in the majority of the languages of this enormous landmass reflects the idea that cannabis spread throughout Eurasia from a single geographic location.
Greek, Latin cannăbis, Italian Canada, and Russian konoplja are etymologically related to English hemp and German Hanf. Even non-Indo-European languages use words with similar meanings, such as the Semitic language qunnab, the Turkish kendir, and the Caucasian language kanap'is.
Some mythologies in India depict cannabis as emerging as a divine component in the earliest moments of cosmogony, known as the churning of the seas, reflecting the historical link between cannabis and mankind.
Cannabis had a religious purpose as a conduit for mystic inspiration, and the god Shiva was said to favor it. Cannabis has been used in Ayurveda medicine for thousands of years under names like Vijaya to alleviate pain, nausea, and anxiety, enhance appetite and sleep, relax muscles, and provide a euphoric effect.
When the plant made it to Africa and eventually America, the spread of cannabis ended. Within a decade of the Conquista, Spain introduced hemp farming to Quillota, a town close to Valparaiso in central Chile. Hemp was originally cultivated in Acadia in 1606 by Louis Hébert, a pharmacist with a practice in Paris (today, Nova Scotia).
Historical Accounts of Cannabis's Therapeutic + Euphoric Effects
Some of the earliest documentation of cannabis use for medical purposes may be found in China. Shén Nóng (), a mythological emperor whose name means the Divine Farmer, is credited with discovering the medicinal benefits of plants (c 2000 bc). It has been asserted because of him that therapeutic cannabis was discovered two millennia before the present. However, given that the compendium (Jng) of 365 medicinal herbs (BnCo), attributed to Shén Nóng, was composed much later, during the Han dynasty, this is likely inflated (221 bc-ad 220).
Chinese words for numbness or anesthesia can contain the character Má (), also used to refer to hemp and cannabis. In Japanese, this character is used and has the same meaning. Although the precise recipe for this concoction was lost, it is believed that Huà Tuó, a Chinese surgeon of the Han period, conducted surgery under general anesthesia using a concoction of wine and herbal extracts that may have contained cannabis.
In the Ebers papyrus, which was recorded in Egypt around 1500 BC, it is mentioned that cannabis can be applied topically to treat inflammation. There is evidence of the therapeutic use of cannabis on Assyrian clay tablets. Cannabis, known as azallû in Akkadian, was reportedly used as medicine, ostensibly for depression, according to Scurlock and Andersen.
Homer's Odyssey (Book IV), pages 9 and 10, contain a historical but uncertain remark from the late seventh or early eighth-century bc. Helen, the daughter of Zeus, served wine that had been laced with npenthés, a narcotic that calms all pain and struggle and causes forgetfulness of all sins. Helen provided this concoction to Greek soldiers suffering from posttraumatic stress disorder after Telemachus' arrival brought up terrible memories of their colleagues who had been killed in the Trojan War. Literally, "N-Penthés" means "No-Grief." According to Homer's text, this medicine originates in Egypt; it may have been opium or cannabis.
After a king is buried, the Scythians create little rooms that are hermetically sealed with woolen blankets spread out on three posts sloping toward one another, according to Herodotus (c. 484–c. 425 bc). The participants throw hemp seeds () onto hot stones while hiding under the blankets. They are "delighted" (o) by the aromatic smoke. Hemp is either grown and cultivated by the Scythians, according to Herodotus, or it grows naturally.
Pliny the Elder, Dioscorides, and Galen all referred to the usage of cannabis for medical purposes during the Roman Empire. The latter only covered the psychological impacts. The oldest surviving encyclopedia from the Graeco-Roman world, Pliny the Elder's Naturalis Historia (c. ad. 23–79), is a thorough compendium of the knowledge that was known at the time. The author discussed the growing of hemp for use in constructing ropes and nets in Book 19.
In Book 20, Pliny highlighted the therapeutic benefits of cannabis, defining both the cultivated version and the wild variety that grows in forests (probably, Althaea cannabina , a different plant). A decoction of the roots in water soothes arthritis, and treats gout, and other conditions, according to Pliny, who also noted that they have analgesic and anti-inflammatory qualities ( radix articulos contractos emollit in aqua cocta, item podagras et similes impetus ). Pliny made no mention of the euphoric or intoxicated effects. In his pharmacopeia "De Materia Medica," the Greek physician Dioscorides (c. ad 40-90) also attested to the anti-inflammatory properties of cannabis treatments produced from the boiling root.
It was usual in Italy to serve tiny cakes containing marijuana as dessert, according to Claudius Galen (ad 129–199/217). Galen stated that the seeds provide a warm sensation and, when taken in large quantities, affect the head by producing a warm and toxic vapor, according to Brunner.
Eastern-West Divan
The poems of Goethe's West-östlicher Divan (1814–1819), which were inspired by the Persian poet Hafez, heralded a period of flourishing cultural contact between the Christian and Muslim worlds. The scientific observations of physicians during the era of European colonial adventures, such as O'Shaughnessy in India and Jacques-Joseph Moreau de Tours in the Middle East, led to the rediscovery of cannabis' therapeutic and psychoactive properties in Europe. This was accomplished through the translation of Arabic books and manuscripts by scholars like Sylvestre de Sacy.
The dedication to Silvestre de Sacy, the most renowned orientalist of his time and the author of a bilingual "chrestomathy" culled from the best passages of Arabic authors from various eras, appears at the end of Goethe's West-östlicher Divan. Silvestre de Sacy was born in Paris in 1758 and died there in 1838.
The following details and incidents from Sacy's chapter on cannabis (also known as qunnab or qinnab or kaff) have been frequently recounted by later authors, such as O'Shaughnessy.
The discovery of cannabis' invigorating effects is generally attributed to Haydar (), a devoted shaikh who passed away in Khorasan in ad 1221 and who taught the many "fakirs" who gathered around him. Ibn al-Bayr (AD 1197-1248), the compiler of a renowned pharmacopeia in Andalusia, Compendium on Simple Medicaments and Foods, identified a strain of cannabis known as Qinnab hind (Cannabis indica) that he had only ever seen in Egypt, where it was cultivated in gardens.
This remark anticipated O'Shaughnessy's claim that eastern cannabis cultivars have far more intoxicating compounds. Sacy describes the selling of potently intoxicating hashish at a location known as al-Junayna (the tiny garden), in the area of Cairo once known as abba (i.e., the Drummer-Girl, or la Timbalière), in the fantasy setting of One Thousand and One Nights.
Hashish overuse caused a form of dementia (ru'na) and eventually agitated psychoses (zhnn), which are analogous to the apathy and psychoses later described by Moreau de Tours. Eras of tolerance and periods of repression had already been seen to alternate; for instance, in 1378, an emir ordered that hashish consumers would have their teeth pulled.
After completing his medical studies at the University of Edinburgh, William Brooke O'Shaughnessy (1809 Limerick, Ireland–1889 England) relocated to Calcutta, where he published the findings of his research on cannabis in 1839. He stated that, save from a few young people experimenting with "hasheesh" at Marseilles (cannabis was brought back from the Egyptian war by Napoleon's soldiers), the intoxicating effect of cannabis was then unknown in Europe.
O'Shaughnessy observed that the effects of cannabis depended on a "resinous secretion" that appeared absent in European hemp, probably due to climatic differences since the European and South-Asian plants appeared to be the same. He discussed a number of Indian dishes that are traditional, such as Gunjah, Bang, and Majoon—a green buttery electuary that is made by boiling in fat and adding sugar and gets its name from the Arabic participle ma'jn (kneaded).
Between 1836 and 1840, Jacques-Joseph Moreau de Tours, an Esquirol student, accompanied one of his mentor's patients around the Middle East. Louis Aubert-study Roche's on the use of cannabis to treat the plague in Egypt was cited by Moreau. He conducted cannabis experiments on himself, creating an electuary somewhat reminiscent to O'Shaughnessy's majoon by boiling cannabis leaves and blossoms in a liquid that also contained butter and then flavoring it with rose, jasmine, or honey. In addition, he shared dawamesk with a group of poets and writers from Paris, including Théophile Gautier.
In addition to absolute happiness, Moreau observed that hashish also caused mental disarray and temporal anomalies. He anticipated that researching how cannabis affected the mind would enable him to understand the causes of crazy and delusions better. The psychoses and euphoria brought on by cannabis were discussed in Moreau's writing.
The First Golden Age of Cannabis for Medical Use
In the late 19th and early 20th centuries, cannabis gained a bad reputation in Western medicine. Empress Elisabeth (Sissi) of Austria and Queen Victoria used cannabis for painful menstrual periods, coughs, and probably appetite stimulation. Sissi loved that cannabis was a natural therapy because she was generally skeptical about medications.
In 1878, the highly regarded British doctor J. Russel Reynolds was chosen to serve as Queen Victoria's household doctor-in-ordinary. He reported more than 30 years of cannabis research in the Lancet in 1890. The fact that the active component of cannabis had not yet been isolated—THC would not be discovered until 1964—posed a significant barrier to its usage. As a result, it could not uniformly extract plants because "the amount of the medicinal substance varies in the hemp grown during different seasons, and in different regions."
The patient's unique sensitivity rendered the overdosing-related toxicity even more unexpected. Reynolds therefore made an effort to always buy cannabis from the same supplier in order to make a "tincture." The dose would gradually increase by placing drops on a tiny piece of sugar or bread. For several unpleasant conditions, including facial neuralgia, migraine, dysmenorrhea, and "numbness and other paresthesiae so common in the limbs of gouty individuals" (a symptom first mentioned by Pliny, the Elder), the author considered cannabis to be an extremely helpful medication.
Modern investigations of medicinal cannabis registries suggest that pain syndromes account for 42.4% of instances, which is consistent with Reynolds' observations. Reynolds alluded to a pediatric cannabis use that we would avoid today: teething issues.
When new sedative and analgesic medications like aspirin were discovered, cannabis was replaced in several medical applications. Cannabis was used less frequently throughout the 20th century, especially in the United States, due to several barriers. The Marihuana Tax Act of 1937, the withdrawal of cannabis from the American Pharmacopeia a few years later, and the 1961 Single Convention on Narcotic Drugs put cannabis and heroin under the harshest regulatory framework (Schedule IV), were these subsequent actions.
When cannabis was classified as a Schedule 1 narcotic in the United States in 1970, the Golden Age of cannabis ended, and further study of its effects was effectively prohibited. The discovery that cannabis is an independent risk factor for schizophrenia after a 15-year follow-up in a cohort of a Swedish conscripts gave psychiatric professionals another reason to be suspicious of the drug. Instead of cannabis being a direct cause of schizophrenia, one alternative explanation for the link between cannabis use and the disorder could be that schizophrenia patients' cannabinoid system pathologies are linked to both higher rates of cannabis use and a higher likelihood of developing the disorder.
The Endocannabinoid System's Discovery
and the reopened discussion of cannabis legalization
There are more than 100 cannabinoids that have been identified from cannabis, but cannabidiol (CBD) and 9-THC are the two most important ones. In 1940, CBD was initially extracted from marijuana; in 1963, its structural details were revealed. But because CBD had no psychotropic effects, THC overshadowed it and was ignored. THC, the primary psychoactive phytocannabinoid, was structurally characterized by Mechoulam and Gaoni in Israel in 1964.
Raphael Mechoulam, who immigrated to Israel and worked at the Weizmann Institute, had survived the Holocaust as a youngster in Bulgaria. He got 5 kg of police-seized cannabis, separated the various chemicals into a column, and tested one of these compounds on monkeys to determine that it was psychotropic. He then fed healthy participants some cake to describe that chemical further.
As a result, he saw a range of psychological responses (laughter, panic attacks, openness to dialogue) depending on the subjects' personalities. Because of Mechoulam's groundbreaking discovery, the endocannabinoid system has been studied in depth (ECS). Devane et al. subsequently identified the CB 1 R, the first cannabinoid receptor, in the brains of rats and people. Only four years later, arachidonoylethanolamide, the first endocannabinoid, was discovered by the same author (AEA).
By referencing the Sanskrit word Nanda, which signifies bliss, happiness, or pleasure, and is a fitting description of what the Scythians experienced when inhaling cannabis vapors in the above paragraph from Herodotus, AEA was also known as anandamide. Once it was established that humans could manufacture their cannabinoids in the brain—anandamide, which belongs to a completely different chemical class than cannabis—the long-standing relationship between humans and cannabis began to make sense.
Today, it is believed that the ECS consists of the two primary cannabinoid receptors, AEA and 2-arachidonoylglycerol [2-AG], as well as a few known endocannabinoids (CB 1 R, present mainly in the central nervous system and also in digestive organs, and CB 2 R, implicated in the regulation of immunity and inflammation). Retrograde signaling, which starts in postsynaptic neurons and affects presynaptic terminals, is a unique feature of the ECS.
After being created in the postsynaptic neuron and released into the synaptic space, AEA and 2-AG move backward to the presynaptic terminal where they interact with CB 1 Rs and cause the presynaptic neuron to release less neurotransmitter. The pieces by Di Marzo, Maldonado et al., and Morrison and Murray in this edition of Dialogues in Clinical Neuroscience (DCNS) illustrate the remarkable growth in our understanding of the ECS over the past several years.
The ECS emerges as a sophisticated and pervasive brain signaling system that affects cognitive and affective processes and psychotic diseases. It may also be the target of many therapeutic drugs. Since cannabis appears to be the only plant that can create a strong phytocannabinoid that activates the CB 1 R, understanding the ECS also highlights why people are so fascinated by it.
In the 1960s, the discussion of loosening or even legalizing cannabis prohibition had returned. A generation that came of age after the hardships of WWII carried it in Western countries. It culminated in resistance to the Vietnam War and the hippie philosophy. This ongoing discussion now has a new perspective thanks to the enormous improvements in scientific understanding of the ECS.
Hall and Marcu talk about the drawbacks of legalizing cannabis and allowing its recreational or medical usage in this issue of DCNS. These choices ought to be supported by scientific data. The US National Academy of Medicine's 2017 report, "The Health Effects of Cannabis and Cannabinoids—The Current State of Evidence and Recommendations for Research," concluded that science has its limitations. According to the National Academy of Medicine report, there are just three sectors in which there is conclusive or significant evidence that cannabis or cannabinoids are beneficial.
The following known medical benefits included: I reducing adult-onset chronic pain; (ii) treating chemotherapy-related nausea and vomiting with oral marijuana; and (iii) reducing patient-reported multiple sclerosis spasticity symptoms (oral cannabinoids). There are still important unanswered questions about cannabis in this period of legalization. For instance, even in those without a history of mental illnesses, nothing is known about the psychotomimetic effects of THC. Additionally, contrary to initial assumptions, there is no evidence supporting the protective effects of CBD when combined with THC.
Cannabis naturally falls into the same category as chemicals like cigarettes, alcohol, and caffeine, which are used regularly by everyone, despite being classified as a congener of heroin by the 1961 UN Single Convention. Compared to alcohol and tobacco, it could not be as hazardous to the body. When marijuana is used during the neurodevelopmental stage, there is a chance that it will cause psychosis or cognitive impairment. A new era in cannabis history began with Mechoulam's seminal discovery that 9-THC is the main psychoactive component and the subsequent clarification of the ECS.
The Scientist Who Discovered CBD
Everyone should be aware that the main psychoactive ingredients in marijuana are ()-trans-9-tetrahydrocannabinol (THC) and numerous of its cannabinoid isomers (Cannabis sativa). However, some THC isomers are not psychoactive and can be helpful in specific situations.
This group includes those who use cannabinoids. The structure displayed is that of cannabidiol, which is also known as (-)-cannabidiol, 1(2)-trans-cannabidiol, and cannabidiol (7CI). Cannabidiol has at least seven recognized isomers.
The famous organic chemist Roger Adams and his team discovered cannabidiol from C. sativa, sometimes known as "Minnesota wild hemp," as it's bis(3,5-dinitrobenzene) ester in 1940. The isomerism of cannabidiol was unknown at the time. Its isomers' absolute configurations weren't known; some were only synthesized in the 1960s.
Cannabidiol and most other cannabinoids are not psychoactive, as was found in 1970 by Israeli researchers under Raphael Mechoulam. Since then, cannabidiol has been researched for potential medical applications, such as treating severe epilepsy. It is an ingredient in certain cosmetics and dietary supplements. Scientists are trying to create marijuana strains that produce more cannabidiol while having less THC.
The legal position of cannabidiol differs from one jurisdiction to another. The laws are such an ad hoc that the European Industrial Hemp Association published a position paper in 2016 proposing a regulatory protocol to ensure uniformity across all European Union member states.
