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Modern History of Medical Cannabis: From Widespread Use to Prohibitionism and Back

Article in Trends in Pharmacological Sciences · January 2017 DOI: 10.1016/j.tips.2016.12.002

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Simona Pisanti Maurizio Bifulco Università degli Studi di Salerno Università degli Studi di Salerno

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Science & Society cannabinoid-based drugs. Until very of Cannabis efficacy, as reported by an Modern History of recently, the destiny of Cannabis seemed extensive systematic meta-analysis of all that of a substance of abuse, powerful the randomized clinical trials conducted Medical Cannabis[2_TD$IF]: resource for the racketeering, demonized on cannabinoids up to date, are spasticity From Widespread by the public opinion, condemned by associated with multiple sclerosis, governments, and neglected by the med- chronic pain, nausea and vomiting Use to ical community. It has not always been caused by chemotherapy, and appetite Prohibitionism this way and knowing its history is useful stimulation in cancer or HIV patients [1]. to understand the reasons for its con- Anecdotal data from patients and physi- and Back torted course. The millennial history of cians suggest future uses for medical Cannabis, which effectively goes along Cannabis that need to be verified in clini- Simona Pisanti1,* and that of human kind, testifies to its exten- cal trials. Indeed, many of Cannabis’s Maurizio Bifulco1,2,* sive usefulness for many purposes, as therapeutic properties do not arise from fiber, food, and medicine, beyond new discoveries but rely upon the revival Over the history of[3_TD$IF] pharmacology there its use as a psychotropic substance. of empirical observations made through are numerous examples of drugs being Now, the perception of Cannabis’s value its use for medical purposes through the widely distributed, almost ‘trendy’, pre- and potential is changing all over the centuries in all the main ancient cultures scribed by physicians in a certain period world with a return to the past. In particu- (Chinese, Indian, Scythian, Egyptian, as a sort of panacea, and then neglected, lar, medical Cannabis is receiving an Greek, Latin, Arabic) [2]. forgotten, or even forbidden as they increased attention from patients, physi- become considered dangerous in the cians, and governmental regulations, The first modern descriptions of thera- light of clinical observations. One of these thanks to research efforts that have peutic properties of Cannabis, dating drugs is Cannabis, which was very popu- deduced the chemical characterization back to the 19th century with the work lar in the 19th century until disappearing of the cannabinoids in the 1960s and of the Irish physician William Brooke from the official Pharmacopoeia at the discovered their natural target, the endo- O’shaughnessy (1839) who, thanks to beginning of the 20th century and reviving cannabinoid system, in the 1990s. These his work in India and his experimentation, again in the new millennium. However, its new studies provided evidence of the more thoroughly made known to the modern history is peculiar since its medi- safety and effectiveness of Cannabis in European medical community the cal use has been deeply influenced and the treatment of numerous pathologies, countless pharmacological properties of hampered by economic, social, and ethi- using extracts with a known content Cannabis [3] (Figure 1). He noticed the cal issues that are now being reconsid- of cannabinoids, or purified (or even beneficial therapeutic effects of Indian ered owing to recently collected scientific synthesized) active molecules. The main Cannabis that he named Indian cannabis evidence about the efficacy and safety of conditions with the current best evidence or Cannabis indica, which in his opinion

First concern in the UK First experimentations about hemp abuse: Gaoni and Marijuana tax act in on mental patients ‘The Indian Hemp Mechoulam discover the USA by Moreau Drugs Commission Δ9-THC Report’ Cannabis legalization in Colorado and Discontinuation of Washington ‘Cannabis Pharmacology of medical studies on experiences’ inhaled Cannabis Cannabis

1839 1840 1844 1847 1887 1894 1899 1906 1925 1937 1941 1945 1960 1964 1990 2012

‘Club des Hashischins’ International drug Cannabis classified control treaty Endocannabinoid substance of abuse system discovery First experimentations Cannabis sativa on Cannabis indica Regulation of inhalation used by Cannabis out from by O’Shaughnessy Valieri to treat patients Cannabis medicinal products labeling USA Pharmacopoeia in the USA

Figure 1. Timeline of Cannabis Modern History.

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showed better medicinal properties than the others, by famous poets and writers anti-inflammatory, and antispastic drugs. Cannabis sativa, the variety common in like , , In 1899, the pharmacologist Walter Ernest Europe. He made a rigorous study of , Honoré de Balzac, Dixon pointed out the particular efficacy Cannabis properties, first testing it in vari- Théophile Gautier, and the painter Ferdi- of inhaled Cannabis to obtain a consistent ous animal species, thus being the first, nand Boissard, who ingested to and rapid pharmacological effect, to our knowledge, to apply the experi- experiment its psychotropic properties on whereas Shoemaker reported its efficacy mental method in studying Cannabis. themselves [5]. In addition, some Italian in a large number of patients treated for Having ascertained its safety in animals, scientists were leading in the medical neuralgia, migraine, gastralgia, enteralgia, he administered alcoholic tinctures of experimentation on Cannabis. Giovanni brain tumors, and herpes zoster. Cannabis to some selected patients Polli, physician and director of the scien- who suffered from epilepsy, rheuma- tific journal Annals of Chemistry Applied to However, around the end of 19th century, tisms, cholera, or tetanus and deduced Medicine, and Carlo Erba, a pharmacist, the use of medical Cannabis started to that the plant had interesting analgesic introduced in Italy the knowledge on Can- decline, because there was a remarkable and myorelaxant properties. Based on nabis properties. Both Giovanni Polli and variability in its effects among patients and this observation, he proposed that Can- Carlo Erba tested themselves its effects, also among different preparations of Can- nabis could be a powerful remedy for psychoactive and not, in a reported nabis, as their pharmacologically active seizures. Moreover, he investigated its experiment carried out in Milan on June principles were not known and thus not effects on tetanus; although Cannabis 19, 1847 [6]. Successively, several inquis- quantifiable. However, as reported in an was not able to cure the infection, itive doctors made similar ‘Cannabis editorial from the Medical and Surgical it relieved some serious symptoms, experiences’ in Italy. Such sessions of Reporter, published in New York, there suggesting that it could be used as an hashish ingestion were precisely followed has never been a case of poisoning adjuvant. A similar experimental and sys- and observed by an ample audience of recorded from Cannabis use, so its safety tematic approach was employed also by scientists and doctors, who promptly and was not a matter of discussion [7]. the French psychiatrist Jacques-Joseph accurately described its effects on the Beyond such pharmacological concerns, Moreau, considered the father of modern body. The Neapolitan physician Raffaele there was the emergence of the first wor- psychopharmacology, who in 1840 tried Valieri was a confident supporter of the ries about an uncontrolled diffusion of Cannabis on himself and later on his stu- medical properties of Cannabis. In 1887, Cannabis for recreational purposes dents and described in detail its acute he published a booklet entitled ‘About beyond its therapeutic value, fostered psychoactive effects, which he had pre- local hemp and its preparations in place by economic reasons. Indeed, the British viously observed in Arabic people who of Cannabis indica’ and launched a pro- government that had huge economic were customary to hashish use. Moreau gram for the inhalation of local C. sativa, interests in India was really worried about also treated his mental patients at the which was produced in Italy, particularly the effects of drug abuse, first of opium Hôpital de Bicêtre, observing that hashish in Campania, for patients with several and then of hemp used by Indian in moderate doses calmed patients, pathologies ranging from migraine, neu- people, so it commissioned a study helped them to sleep, suppressed head- ralgia, insomnia, hysteria to asthma, pul- ‘The Indian Hemp Drugs Commission aches, and increased appetite [4]. monary emphysema, and exophthalmic Report’, which was published in 1894 goiter, reporting good therapeutic results establishing that, ‘the occasional use or Thanks to the studies and the knowledge [6]. The second part of the 19th century hemp in moderate doses may be benefi- made by O’shaughnessy in Britain and up to the first decades of the 20th was cial, but this use may be regarded as Moreau in France, the interest for C. ind- certainly the Golden age of Cannabis in medicinal in character . . . The exces- ica, and mainly for its resin named ‘hash- medicine. Numerous studies were con- sive use may certainly be accepted as ish’, increased and disseminated from ducted in a short time, both in Europe very injurious, though it must be admitted England to the rest of Europe [5].In and in the United States, that rapidly that in many excessive consumers the France, beyond its medical use, the increased the number of publications injury is not clearly marked. The injury employment of Cannabis and hashish about Cannabis (>100) and its use in done by the excessive use is, however, for their psychoactive properties rapidly commercial preparations produced by confined almost exclusively to the con- became fashionable. Very soon, its use several pharmaceutical laboratories sumer himself; the effect on society is extended mainly to the artistic milieus around the world (Merck in Germany, rarely appreciable’. In 1912, in response of that time and soon in arose Burroughs Wellcome in England, and to the increasing criticism of the opium the so-called Club des Hashischins (The Bristol-Meyers Squibb and Eli Lilly in the trade, the first international drug control Hashish-Eaters’ club) at the Hôtel de USA), including in tinctures, pills, and treaties on opium and coca were agreed Pimodan, which was frequented, among extracts used mainly as analgesic, upon by the USA, Germany, the UK,

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France, Italy, the Netherlands, Portugal, the National Formulary, as a final victory has increased the consumption of mari- Russia, China, Japan, Persia, and Siam to of the prohibitionist campaign of Anslinger juana for medical use, also creating a new regulate and control both their commerce who, in 1944 and 1945, forced the Amer- business with the retail of marijuana edi- and use. In the revision of the agreement, ican Medical Association to deny the La bles. Indeed, in contrast to some popular signed in 1925 in Ginevra, because of the Guardia report and declared forbidden beliefs, a high percentage of patients, for efforts of Egypt, USA, and China, hashish every study on Cannabis medical use. psychological and/or cultural reasons, are in all preparations was proposed among In the 1960s, due to the popularization not comfortable with marijuana smoke or the drugs to be restrained. Thanks to the of Cannabis for recreational purposes, it inhalation, preferring edible products, opposition of India where Cannabis use was definitively classified as a substance which also offer a more potent and longer was deeply rooted in the culture and pop- of abuse [5]. THC therapeutic effect [13]. Marketing ular traditions, the proposal was not strategies for these products, far from approved but the nations settled for a However, the scientific research on Can- being ingenuous or hasty, have been compromise to forbid the export of C. nabis did not completely stop, and a new carefully planned with packaging resem- indica to those countries where it was era started thanks to the discoveries of bling children-friendly popular sweets. explicitly outlawed. Already from 1860 in the scientists Yehiel Gaoni and Raphael Since sweets, cakes, chocolate are ‘com- New York and then in other states, local Mechoulam, who in 1964 in Israel identi- fort food’, their psychological effect may laws started to restrict Cannabis use. The fied for the first time the chemical struc- even add an extra beneficial value to mari- Pure Food and Drug Act of 1906 for the ture of the main cannabinoid, active juana therapy. By contrast, specific regu- first time regulated the labeling of medical substances present in the plant, named lations, up-to-date still lacking, should deal preparations containing Cannabis.InD9-tetrahydrocannabinol[6_TD$IF] (D9-THC) [9]. with health dangers, especially for chil- 1937 in the USA, on specific request by The studies continued up to the 1970s, dren, and with a clear labeling of THC the supervisor of the Federal Bureau of when a new scientific lull occurred, since doses and recommended serving sizes. Narcotics Harry Anslinger, a personality the active compounds of Cannabis had that had a crucial role in the destiny of been characterized but their biological In conclusion, we are facing an epoch of Cannabis, initiated the ‘Marihuana Tax target was still unknown. Then in the great cultural and scientific changes Act’, which prescribed the payment of a 1990s, discovery of the receptors for can- regarding medical Cannabis. Its history US$1 tax for each business deal regard- nabinoids and characterization of the teaches us how a drug can have wide ing Cannabis for medical or industrial use endocannabinoids (first of all anandamide popularity and immediately afterward a and of US$100 for all the other purposes, and 2-arachidonoylglycerol) and the sudden decline, depending on social, cul- starting the prohibitionist era [8]. Even if endocannabinoid system (enzymes for tural, and economic reasons. Now that the the law did not forbid the use of Cannabis, endocannabinoids synthesis and degra- scientific evidence collected on the phar- its purchase was so expensive, and the dation), the effective biological target of macological potential of Cannabis is in violations to the rules so punitive, with phytocannabinoids, renewed scientific agreement with the economic interests fines up to US$2000 or even 5-year interest in Cannabis, leading to the publi- linked to this enormous new market, moral imprisonment, that all experimentations cation of thousands of papers that clearly and social concerns have been bypassed. about the medical use of Cannabis were highlighted the pharmacological potential Exactly now, the lesson from the past is discontinued. The Medical American of this plant [10,11]. In the last two dec- pivotal to manage the Cannabis affair in Association through Dr William Wood- ades, beyond studying the pharmacolog- the right way, emphasizing first of all the ward was firmly contrary to such policy, ical properties of phytocannabinoids, health benefits for patients. continuing to assert the pharmacological research efforts have focused on the 1 ‘ potential of this plant in numerous patho- development of synthetic drugs able to Department of Medicine Surgery and Dentistry Medical School of Salerno’, University of Salerno, Salerno, Italy logical conditions, despite its adverse interfere with the endocannabinoid sys- 2Corporea, Fondazione Idis Città della Scienza, Napoli, psychotropic effects. In addition, Fiorello tem, enhancing or blocking its functions Italy La Guardia, the Mayor of New York, depending on the physiopathological *Correspondence: strongly opposed against Cannabis pro- context. Meanwhile, several countries [email protected] (S. Pisanti) and hibitionism and commissioned to the have changed their policy on Cannabis, [email protected] (M. Bifulco). New York Academy of Medicine a report endorsing laws that allow its well-docu- http://dx.doi.org/10.1016/j.tips.2016.12.002 known as ‘La Guardia Committee’, mented therapeutic use and decriminal- References which repudiated the risk of marijuana izing or even legalizing it for recreational 1. Whiting, P.F. et al. (2015) Cannabinoids for medical use: a addiction and detrimental effects. In purpose, as in Uruguay and in the states systematic review and meta-analysis. JAMA 313, 2456– 2473 1941, Cannabis was removed by the of Washington, Colorado, Oregon, and 2. Clark, R. and Merlin, M. (2013) Cannabis: Evolution and United States Pharmacopeia and from Alaska in the USA [12]. Such policy reform Ethnobotany, University of California Press

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