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

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Modern History of
Medical Cannabis[2_TD$DIFF]:
From Widespread
Use to
Prohibitionism
and Back
Simona Pisanti
1,
*and
Maurizio Bifulco
1,2,
*
Over the history [3_TD$DIFF]of pharmacology there
are numerous examples of drugs being
widely distributed, almost ‘trendy’, pre-
scribed by physicians in a certain period
as a sort of panacea, and then neglected,
forgotten, or even forbidden as they
become considered dangerous in the
light of clinical observations. One of these
drugs is Cannabis, which was very popu-
lar in the 19th century until disappearing
from the official Pharmacopoeia at the
beginning of the 20th century and reviving
again in the new millennium. However, its
modern history is peculiar since its medi-
cal use has been deeply influenced and
hampered by economic, social, and ethi-
cal issues that are now being reconsid-
ered owing to recently collected scientific
evidence about the efficacy and safety of
cannabinoid-based drugs. Until very
recently, the destiny of Cannabis seemed
that of a substance of abuse, powerful
resource for the racketeering, demonized
by the public opinion, condemned by
governments, and neglected by the med-
ical community. It has not always been
this way and knowing its history is useful
to understand the reasons for its con-
torted course. The millennial history of
Cannabis, which effectively goes along
that of human kind, testifies to its exten-
sive usefulness for many purposes, as
fiber, food, and medicine, beyond
its use as a psychotropic substance.
Now, the perception of Cannabis’s value
and potential is changing all over the
world with a return to the past. In particu-
lar, medical Cannabis is receiving an
increased attention from patients, physi-
cians, and governmental regulations,
thanks to research efforts that have
deduced the chemical characterization
of the cannabinoids in the 1960s and
discovered their natural target, the endo-
cannabinoid system, in the 1990s. These
new studies provided evidence of the
safety and effectiveness of Cannabis in
the treatment of numerous pathologies,
using extracts with a known content
of cannabinoids, or purified (or even
synthesized) active molecules. The main
conditions with the current best evidence
of Cannabis efficacy, as reported by an
extensive systematic meta-analysis of all
the randomized clinical trials conducted
on cannabinoids up to date, are spasticity
associated with multiple sclerosis,
chronic pain, nausea and vomiting
caused by chemotherapy, and appetite
stimulation in cancer or HIV patients [1].
Anecdotal data from patients and physi-
cians suggest future uses for medical
Cannabis that need to be verified in clini-
cal trials. Indeed, many of Cannabis’s
therapeutic properties do not arise from
new discoveries but rely upon the revival
of empirical observations made through
its use for medical purposes through the
centuries in all the main ancient cultures
(Chinese, Indian, Scythian, Egyptian,
Greek, Latin, Arabic) [2].
The first modern descriptions of thera-
peutic properties of Cannabis, dating
back to the 19th century with the work
of the Irish physician William Brooke
O’shaughnessy (1839) who, thanks to
his work in India and his experimentation,
more thoroughly made known to the
European medical community the
countless pharmacological properties of
Cannabis [3] (Figure 1). He noticed the
beneficial therapeutic effects of Indian
Cannabis that he named Indian cannabis
or Cannabis indica, which in his opinion
TIPS 1400 No. of Pages 4
First experimentations
on mental patients
by Moreau
First concern in the UK
about hemp abuse:
‘The Indian Hemp
Drugs Commission
Report’
Pharmacology of
inhaled Cannabis
Marijuana tax act in
the USA
Gaoni and
Mechoulam discover
Δ9-THC Cannabis legalization
in Colorado and
Washington
Endocannabinoid
system discovery
Cannabis classified
substance of abuse
Cannabis out from
USA Pharmacopoeia
International drug
control treaty
Regulation of
Cannabis medicinal
products labeling
in the USA
‘Club des
Hashischins’
First experimentations
on Cannabis indica
by O’Shaughnessy
Cannabis sativa
inhalation used by
Valieri to treat patients
Discontinuation of
medical studies on
Cannabis
‘Cannabis
experiences’
1839 1840 1844 1847 1887 1894 1899 1906 1925 1937 1941 1945 1960 1964 1990 2012
Figure 1. Timeline of Cannabis Modern History.
Trends in Pharmacological Sciences, Month Year, Vol. xx, No. yy 1

TIPS 1400 No. of Pages 4
showed better medicinal properties than
Cannabis sativa, the variety common in
Europe. He made a rigorous study of
Cannabis properties, first testing it in vari-
ous animal species, thus being the first,
to our knowledge, to apply the experi-
mental method in studying Cannabis.
Having ascertained its safety in animals,
he administered alcoholic tinctures of
Cannabis to some selected patients
who suffered from epilepsy, rheuma-
tisms, cholera, or tetanus and deduced
that the plant had interesting analgesic
and myorelaxant properties. Based on
this observation, he proposed that Can-
nabis could be a powerful remedy for
seizures. Moreover, he investigated its
effects on tetanus; although Cannabis
was not able to cure the infection,
it relieved some serious symptoms,
suggesting that it could be used as an
adjuvant. A similar experimental and sys-
tematic approach was employed also by
the French psychiatrist Jacques-Joseph
Moreau, considered the father of modern
psychopharmacology, who in 1840 tried
Cannabis on himself and later on his stu-
dents and described in detail its acute
psychoactive effects, which he had pre-
viously observed in Arabic people who
were customary to hashish use. Moreau
also treated his mental patients at the
Hôpital de Bicêtre, observing that hashish
in moderate doses calmed patients,
helped them to sleep, suppressed head-
aches, and increased appetite [4].
Thanks to the studies and the knowledge
made by O’shaughnessy in Britain and
Moreau in France, the interest for C. ind-
ica, and mainly for its resin named ‘hash-
ish’, increased and disseminated from
England to the rest of Europe [5].In
France, beyond its medical use, the
employment of Cannabis and hashish
for their psychoactive properties rapidly
became fashionable. Very soon, its use
extended mainly to the artistic milieus
of that time and soon in Paris arose
the so-called Club des Hashischins (The
Hashish-Eaters’club) at the Hôtel de
Pimodan, which was frequented, among
the others, by famous poets and writers
like Victor Hugo, Alexandre Dumas,
Charles Baudelaire, Honoré de Balzac,
Théophile Gautier, and the painter Ferdi-
nand Boissard, who ingested hashish to
experiment its psychotropic properties on
themselves [5]. In addition, some Italian
scientists were leading in the medical
experimentation on Cannabis. Giovanni
Polli, physician and director of the scien-
tific journal Annals of Chemistry Applied to
Medicine, and Carlo Erba, a pharmacist,
introduced in Italy the knowledge on Can-
nabis properties. Both Giovanni Polli and
Carlo Erba tested themselves its effects,
psychoactive and not, in a reported
experiment carried out in Milan on June
19, 1847 [6]. Successively, several inquis-
itive doctors made similar ‘Cannabis
experiences’in Italy. Such sessions of
hashish ingestion were precisely followed
and observed by an ample audience of
scientists and doctors, who promptly and
accurately described its effects on the
body. The Neapolitan physician Raffaele
Valieri was a confident supporter of the
medical properties of Cannabis. In 1887,
he published a booklet entitled ‘About
local hemp and its preparations in place
of Cannabis indica’and launched a pro-
gram for the inhalation of local C. sativa,
which was produced in Italy, particularly
in Campania, for patients with several
pathologies ranging from migraine, neu-
ralgia, insomnia, hysteria to asthma, pul-
monary emphysema, and exophthalmic
goiter, reporting good therapeutic results
[6]. The second part of the 19th century
up to the first decades of the 20th was
certainly the Golden age of Cannabis in
medicine. Numerous studies were con-
ducted in a short time, both in Europe
and in the United States, that rapidly
increased the number of publications
about Cannabis (>100) and its use in
commercial preparations produced by
several pharmaceutical laboratories
around the world (Merck in Germany,
Burroughs Wellcome in England, and
Bristol-Meyers Squibb and Eli Lilly in the
USA), including in tinctures, pills, and
extracts used mainly as analgesic,
anti-inflammatory, and antispastic drugs.
In 1899, the pharmacologist Walter Ernest
Dixon pointed out the particular efficacy
of inhaled Cannabis to obtain a consistent
and rapid pharmacological effect,
whereas Shoemaker reported its efficacy
in a large number of patients treated for
neuralgia, migraine, gastralgia, enteralgia,
brain tumors, and herpes zoster.
However, around the end of 19th century,
the use of medical Cannabis started to
decline, because there was a remarkable
variability in its effects among patients and
also among different preparations of Can-
nabis, as their pharmacologically active
principles were not known and thus not
quantifiable. However, as reported in an
editorial from the Medical and Surgical
Reporter, published in New York, there
has never been a case of poisoning
recorded from Cannabis use, so its safety
was not a matter of discussion [7].
Beyond such pharmacological concerns,
there was the emergence of the first wor-
ries about an uncontrolled diffusion of
Cannabis for recreational purposes
beyond its therapeutic value, fostered
by economic reasons. Indeed, the British
government that had huge economic
interests in India was really worried about
the effects of drug abuse, first of opium
and then of hemp used by Indian
people, so it commissioned a study
‘The Indian Hemp Drugs Commission
Report’, which was published in 1894
establishing that, ‘the occasional use or
hemp in moderate doses may be benefi-
cial, but this use may be regarded as
medicinal in character . . . The exces-
sive 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 con-
sumer himself; the effect on society is
rarely appreciable’. In 1912, in response
to the increasing criticism of the opium
trade, the first international drug control
treaties on opium and coca were agreed
upon by the USA, Germany, the UK,
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TIPS 1400 No. of Pages 4
France, Italy, the Netherlands, Portugal,
Russia, China, Japan, Persia, and Siam to
regulate and control both their commerce
and use. In the revision of the agreement,
signed in 1925 in Ginevra, because of the
efforts of Egypt, USA, and China, hashish
in all preparations was proposed among
the drugs to be restrained. Thanks to the
opposition of India where Cannabis use
was deeply rooted in the culture and pop-
ular traditions, the proposal was not
approved but the nations settled for a
compromise to forbid the export of C.
indica to those countries where it was
explicitly outlawed. Already from 1860 in
New York and then in other states, local
laws started to restrict Cannabis use. The
Pure Food and Drug Act of 1906 for the
first time regulated the labeling of medical
preparations containing Cannabis.In
1937 in the USA, on specific request by
the supervisor of the Federal Bureau of
Narcotics Harry Anslinger, a personality
that had a crucial role in the destiny of
Cannabis, initiated the ‘Marihuana Tax
Act’, which prescribed the payment of a
US$1 tax for each business deal regard-
ing Cannabis for medical or industrial use
and of US$100 for all the other purposes,
starting the prohibitionist era [8]. Even if
the law did not forbid the use of Cannabis,
its purchase was so expensive, and the
violations to the rules so punitive, with
fines up to US$2000 or even 5-year
imprisonment, that all experimentations
about the medical use of Cannabis were
discontinued. The Medical American
Association through Dr William Wood-
ward was firmly contrary to such policy,
continuing to assert the pharmacological
potential of this plant in numerous patho-
logical conditions, despite its adverse
psychotropic effects. In addition, Fiorello
La Guardia, the Mayor of New York,
strongly opposed against Cannabis pro-
hibitionism and commissioned to the
New York Academy of Medicine a report
known as ‘La Guardia Committee’,
which repudiated the risk of marijuana
addiction and detrimental effects. In
1941, Cannabis was removed by the
United States Pharmacopeia and from
the National Formulary, as a final victory
of the prohibitionist campaign of Anslinger
who, in 1944 and 1945, forced the Amer-
ican Medical Association to deny the La
Guardia report and declared forbidden
every study on Cannabis medical use.
In the 1960s, due to the popularization
of Cannabis for recreational purposes, it
was definitively classified as a substance
of abuse [5].
However, the scientific research on Can-
nabis did not completely stop, and a new
era started thanks to the discoveries of
the scientists Yehiel Gaoni and Raphael
Mechoulam, who in 1964 in Israel identi-
fied for the first time the chemical struc-
ture of the main cannabinoid, active
substances present in the plant, named
D
9
[6_TD$DIFF]-tetrahydrocannabinol (D
9
-THC) [9].
The studies continued up to the 1970s,
when a new scientific lull occurred, since
the active compounds of Cannabis had
been characterized but their biological
target was still unknown. Then in the
1990s, discovery of the receptors for can-
nabinoids and characterization of the
endocannabinoids (first of all anandamide
and 2-arachidonoylglycerol) and the
endocannabinoid system (enzymes for
endocannabinoids synthesis and degra-
dation), the effective biological target of
phytocannabinoids, renewed scientific
interest in Cannabis, leading to the publi-
cation of thousands of papers that clearly
highlighted the pharmacological potential
of this plant [10,11]. In the last two dec-
ades, beyond studying the pharmacolog-
ical properties of phytocannabinoids,
research efforts have focused on the
development of synthetic drugs able to
interfere with the endocannabinoid sys-
tem, enhancing or blocking its functions
depending on the physiopathological
context. Meanwhile, several countries
have changed their policy on Cannabis,
endorsing laws that allow its well-docu-
mented therapeutic use and decriminal-
izing or even legalizing it for recreational
purpose, as in Uruguay and in the states
of Washington, Colorado, Oregon, and
Alaska in the USA [12]. Such policy reform
has increased the consumption of mari-
juana for medical use, also creating a new
business with the retail of marijuana edi-
bles. Indeed, in contrast to some popular
beliefs, a high percentage of patients, for
psychological and/or cultural reasons, are
not comfortable with marijuana smoke or
inhalation, preferring edible products,
which also offer a more potent and longer
THC therapeutic effect [13]. Marketing
strategies for these products, far from
being ingenuous or hasty, have been
carefully planned with packaging resem-
bling children-friendly popular sweets.
Since sweets, cakes, chocolate are ‘com-
fort food’, their psychological effect may
even add an extra beneficial value to mari-
juana therapy. By contrast, specific regu-
lations, up-to-date still lacking, should deal
with health dangers, especially for chil-
dren, and with a clear labeling of THC
doses and recommended serving sizes.
In conclusion, we are facing an epoch of
great cultural and scientific changes
regarding medical Cannabis. Its history
teaches us how a drug can have wide
popularity and immediately afterward a
sudden decline, depending on social, cul-
tural, and economic reasons. Now that the
scientific evidence collected on the phar-
macological potential of Cannabis is in
agreement with the economic interests
linked to this enormous new market, moral
and social concerns have been bypassed.
Exactly now, the lesson from the past is
pivotal to manage the Cannabis affair in
the right way, emphasizing first of all the
health benefits for patients.
1
Department of Medicine Surgery and Dentistry ‘Medical
School of Salerno’, University of Salerno, Salerno, Italy
2
Corporea, Fondazione Idis Città della Scienza, Napoli,
Italy
*Correspondence:
spisanti@unisa.it (S. Pisanti) and
mbifulco@unisa.it (M. Bifulco).
http://dx.doi.org/10.1016/j.tips.2016.12.002
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