Near the Flaming Mountains, a popular tourist spot in the Xinjiang-Uighur autonomous region of China, a middle-aged European-looking man was found with a large cache of cannabis. Further analysis revealed that the man carried almost 800 g of cultivated cannabis with a high Δ 9 -tetrahydrocannabinol (THC) content.

Contrary to a first impression, this is not a sensational news item about an adventurous tourist facing a prison sentence far away from home, but a scholarly archeological report about the excavation of the grave of a 45-year old male of high social status, probably a shaman, buried around 750 bc.1 The tomb was associated with the Tocharian culture, a nomadic population speaking a now extinct Indo-European language, depicted as blue-eyed and fair-haired in ancient Chinese records.

The botanical and phytochemical analyses indicated that the cannabis was not merely gathered from wild plants, but instead cultivated from strains of cannabis selected by humans based on their potent THC content.

This story illustrates the long-standing link between human beings and cannabis as a psychotropic drug.
 Paleobotanical studies attest that cannabis was already present about 11,700 years ago in Central Asia near the Altai Mountains. 2 South-East Asia has also been proposed as an alternative region for the primary domestication of cannabis. 3 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. In this plausible scenario,4 humans moved from gathering to cultivating cannabis and then started selecting strains either for fibers or for THC content. Some 12,000 years ago, after the last glacial period, cannabis seeds followed the migration of nomadic peoples and commercial exchanges.

The dispersal of cannabis over Eurasia from a central point is reflected by the fact that the plant is designated by related words in most languages of this huge landmass.5 English hemp and German Hanf are etymologically cognate with Greek κάνναβις, Latin cannăbis, Italian canapa, and Russian konoplja.


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.6 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.


Classical records of the medicinal and psychoactive properties of cannabis


The common name for hemp and cannabis in China is Má, and this character can appear in word compositions meaning numbness or anesthesia. 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 8 was probably used as a medicine, apparently for depression. 
A classical but ambiguous mention is found in Homer’s Odyssey (Book IV), 9,10 around the late 7th century bc. Zeus’ daughter, Helen, served wine mixed with a drug called nēpenthés 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 PTSD.

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.11 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, described the cultivation of hemp for making ropes and nets. In Book 20, Pliny discussed the medicinal uses of cannabis, differentiating cultivated cannabis and a wild variety growing in forests. Pliny discussed its anti-inflammatory properties: a decoction of the roots in water relieves arthritis and cures gout and similar maladies.
 

Cannabis became persona grata in Western medicine in the late 19th, early 20th century. 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.21 


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”. Reynolds’ indications agree with modern studies of medicinal cannabis registries, which show that pain syndromes account for 42.4% of cases.23 

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 (Schedule IV) along with heroin. The Golden Age of cannabis came to a definite end in 1970 when it was declared a Schedule 1 drug in the USA, and research into the effects of cannabis was practically made impossible. 

The discovery of the endocannabinoid system, and the renewed debate on cannabis liberalization


More than 100 cannabinoids have been isolated from cannabis; the two significant compounds are cannabidiol (CBD) and Δ 9 -THC. CBD was first isolated from marijuana in 1940, and its structure was reported in 1963.26 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 1964.27,28 Raphael Mechoulam had survived the Holocaust as a child in Bulgaria and emigrated to Israel, where he worked at the Weizmann Institute. He managed to obtain 5 kg of seized cannabis from the police, separated several compounds on a column, and identified one of these compounds as psychoactive by testing it on monkeys.29 

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 (CB 1 R) in rat and human brains.30 

Only 4 years later, the same author isolated the first endocannabinoid, arachidonoylethanolamide (AEA). 31 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. The long association of humans with cannabis made sense now that it was shown that our brain produced its own cannabinoid, although anandamide is entirely different from cannabis by its chemical class.


Today, the ECS is understood as comprising a few known endocannabinoids (principally, AEA and 2-arachidonoylglycerol [2-AG]), and the two primary cannabinoid receptors (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).32 
A singularity of the ECS is retrograde signaling, ie, the signaling initiates in postsynaptic neurons and acts upon presynaptic terminals. AEA and 2-AG are produced in the postsynaptic neuron and released into the synaptic space, then travel in a retrograde direction to the presynaptic terminal to interact with CB 1 Rs, which leads to a decrease in neurotransmitter release by the presynaptic neuron. 

The discovery of the ECS also sheds light on the human fascination for cannabis, which appears to be the only plant that produces a potent phytocannabinoid activator of the CB1 receptor.34 
The debate about the relaxation of cannabis prohibition, or even its legalization, had resurfaced in the 1960s. It was carried in Western societies by a generation that came of age after the deprivations of WWII. It culminated with the hippie philosophy on a background of opposition to the Vietnam War.

The conclusion of the 2017 report from the US National Academy of Medicine on “The Health Effects of Cannabis and Cannabinoids—The Current State of Evidence and Recommendations for Research” confirmed the limitation of scientific knowledge.35 The National Academy of Medicine report stated that conclusive or substantial evidence that cannabis or cannabinoids are effective is limited to only three domains. The recognized therapeutic uses were as follows: (i) alleviation of chronic pain in adults (cannabis); (ii) as antiemetics in the treatment of chemotherapy-induced nausea and vomiting (oral cannabinoids); and (iii) the improvement in patient-reported multiple sclerosis spasticity symptoms (oral cannabinoids).

At a time of cannabis liberalization, essential unsolved questions persist. For instance, we know little about the psychotomimetic effect of THC, even in persons without a history of mental disorders. 
Although considered a congener of heroin by the 1961 UN Single Convention, cannabis naturally belongs to the class of substances such as tobacco, alcohol, and caffeine, which are used regularly by all humanity. Mechoulam’s milestone discovery that Δ 9 -THC is the primary psychoactive principle, and the ensuing elucidation of the ECS, opened the gate for a new era in cannabis history.

---------

Source:

• Crocq MA. History of cannabis and the endocannabinoid system
. Dialogues Clin Neurosci. 2020 Sep;22(3):223-228. doi: 10.31887/DCNS.2020.22.3/mcrocq. PMID: 33162765; PMCID: PMC7605027.

References:

1. Russo EB, Jiang HE, Li X, et al Phytochemical and genetic analyses of ancient cannabis from Central Asia. J Exp Bot. 2008;59(15):4171–4182. [PMC free article] [PubMed] [Google Scholar]

2. Pisanti S, Bifulco M. Medical cannabis: a plurimillenial history of an evergreen. J Cell Physiol. 2019;234:8342–8351. [PubMed] [Google Scholar]

3. Bonini SA, Premoli M, Tambaro S, et al Review. Cannabis sativa: a comprehensive ethnopharmacological review of a medicinal plant with a long history. J Ethnopharmacol. 2018;227:300–315. [PubMed] [Google Scholar]

4. Clarke RC, Merlin MD. Cannabis. Evolution and Ethnobotany . Berkeley, CA: University of California Press; 2013. [Google Scholar]

5. Barbera M. Wanderworten, etymological format: a ‘Hemp’ case study, starting from Votic and Baltofinnic. . Proceedings of the XVII EURALEX International Congress [Internet] . Available at: https://pdfs.semanticscholar.org/673c/4b8b05f1c8a87e322bdcc34784b248ae3f5c.pdf. [Google Scholar]

6. Samorini G. Roma, Italia: Edizioni Studio Tesi; 2016. Mitologia delle piante inebrianti [Google Scholar]

7. Quilodrán Jiménez H. Cáñamo Quillotano. Una Herencia Española en Desuso. El Boletín Histórico. Año III No 11 [May 17, 2020]; Available at: http://www.boletinhistoricoshgchile.com/Boletin/Boletin11/5%20Cañamo%20quillotano%20(Hugo%20Quilodrán).pdf. [Google Scholar]

8. Scurlock JA, Andersen BR. Chicago, IL: University of Illinois; 2005. Diagnoses in Assyrian and Babylonian Medicine: Ancient Sources, Translations, and Modern Medical Analyses p. 82. [Google Scholar]

9. Homer . Loeb Classical Library . Book I. Cambridge, MA: Harvard University Press; 1998. Odyssey; p. 220 sqq. [Google Scholar]

10. Homer . New York, NY: Norton and Company; 2018. The Odyssey [Google Scholar]

11. Herodotus . Book IV. Paris, France: Les Belles Lettres; 1985. Histories pp. 73–75. Greek text with French translation. [Google Scholar]

12. Pliny the Elder [Pline l’Ancien] Books XIX and XX. Paris, France: Les Belles Lettres; 1965, 2003. Histoire Naturelle [Google Scholar]

13. Dunn D. New York, NY: Norton and Company; 2019. The shadow of Vesuvius. A life of Pliny [Google Scholar]

14. Brunner TF. Marijuana in ancient Greece and Rome? The literary evidence. Bull Hist Med. 1973;47(4):344–355. [PubMed] [Google Scholar]

15. Grotenhermen F, Russo E. New York, NY: The Haworth Press; 2002. Cannabis and Cannabinoids. Pharmacology, Toxicology, and Therapeutic Potential [Google Scholar]

16. Booth M. New York, NY: Thomas Dunne Books; 2015. Cannabis. A History [Google Scholar]

17. Silvestre de Sacy AI. Paris, France: Presses Universitaires de France; 2008. La Chrestomatie arabe pp. 448–473. Original edition 1826. New bilingual French-Arabic edition by Académie tunisienne des Sciences, des Lettres et des Arts. [Google Scholar]

18. O’Shaughnessy WB. The Journal of the Asiatic Society of Bengal. Calcutta, India: Bishop’s College Press; 1840. Extract from a memoir on the preparations of the Indian hemp, or gunjah (Cannabis Indica), their effects on the animal system in health, and their utility in the treatment of tetanus and other convulsive diseases; p. 732 sqq. Vol. VIII. No. 93 September 1839. [PMC free article] [PubMed] [Google Scholar]

19. Aubert-Roche L. Paris, France: Librairie des sciences médicale de Just Rouvier; 1843. Essai sur le hachisch et son bon emploi dans le traitement de la peste [On hashish and its proper use in the treatment of the plague] [Google Scholar]

20. Moreau de Tours J. Paris, France: Fortin, Masson and Cie; 1845. Du hachisch et de l’aliénation mentale [Hashish and insanity] [Google Scholar]

21. Fellner S , Unterreiner K. Wien, Austria: Amalthea; 2008. Morphium, Cannabis und Cocain. Medizin und Rezepte im Wien des 19. Jahrhunderts [Google Scholar]

22. Reynolds JR. Therapeutical uses and toxic effects of Cannabis Indica. Lancet. 1890;1:637–638. [Google Scholar]

23. Baron EP, Lucas P, Eades J, Hogue O. Patterns of medicinal cannabis use, strain analysis, and substitution effect among patients with migraine, headache, arthritis, and chronic pain in a medicinal cannabis cohort. J Headache Pain. 2018;19(1):37. [PMC free article] [PubMed] [Google Scholar]

24. Andréasson S, Allebeck A, Engström A, Rydberg U. Cannabis and schizophrenia. A longitudinal study of Swedish conscripts. Lancet. 1987;2(8574):1483–1486. [PubMed] [Google Scholar]

25. Weiser M, Noy S. Interpreting the association between cannabis use and increased risk for schizophrenia. Dialogues Clin Neurosci. 2005;7(1):81–85. [PMC free article] [PubMed] [Google Scholar]

26. Burstein S. Review. Cannabidiol (CBD) and its analogs: a review of their effects on inflammation. Bioorg Med Chem. 2015;23:1377–1385. [PubMed] [Google Scholar]

27. Mechoulam R, Gaoni Y. A total synthesis of dl-Δ1-tetrahydrocannabinol, the active constituent of hashish. J Am Chem Soc. 1965;87:3273–3275. [PubMed] [Google Scholar]

28. Pertwee RG. Cannabinoid pharmacology: the first 66 years. Br J Pharmacol. 2006;147:S163–S171. [PMC free article] [PubMed] [Google Scholar]

29. The Scientist . Spain: Fundación Canna; [March 18, 2020]. (video of interview of Mechoulam) Available at: http://mechoulamthescientist.com. [Google Scholar]

30. Devane WA, Dysarz FA, Johnson MR, Melvin LS, Howlett AC. Determination and characterization of a cannabinoid receptor in rat brain. Mol Pharmacol. 1988;34:605–613. [PubMed] [Google Scholar]

31. Devane WA, Hanus L, Breuer A, et al Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science. 1992;258(5090):1946–1949. [PubMed] [Google Scholar]

32. Zou SL, Kumar U. Review. Cannabinoid receptors and the endocannabinoid system: signaling and function in the central nervous system. Int J Mol Sci. 2018;19(3):833. doi: 10.3390/ijms19030833. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

33. Jarvis S, Rassmussen S, Winters B. Role of the endocannabinoid system and medical cannabis. J Nurse Pract. 2017;13(8):525–531. [Google Scholar]

34. Gertsch J, Pertwee RG, Di Marzo V. Phytocannabinoids beyond the Cannabis plant – do they exist? Br J Pharmacol. 2010;160:523–529. [PMC free article] [PubMed] [Google Scholar]

35. National Academies of Sciences, Engineering, and Medicine 2017 . Washington, DC: The National Academies Press; The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. [CrossRef] [Google Scholar]

36. Hindley G, Beck K, Borgan F, et al Psychiatric symptoms caused by cannabis constituents: a systematic review and meta-analysis. Lancet Psychiatry. 2020;7:344–353. doi: 10.1016/S2215-0366(20)30074-2. [PMC free article] [PubMed] [CrossRef] [Google Scholar]