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‘Cannabis’ ontologies I: Conceptual issues with Cannabis and cannabinoids terminology

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‘Cannabis’ ontologies I: Conceptual issues with Cannabis and cannabinoids terminology

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Objective: Identify a coherent nomenclature of products containing cannabinoids (whether derived from Cannabis sativa L. or not). Design: Research undertaken in parallel to the three-year assessment of Cannabis derivatives by the World Health Organisation. The scope is limited to Cannabis products intended for human incorporation (internal and topical con- sumption). Primarily embedded in pharmacognosy, the study incorporates a wide range of scholarly and grey literature, folk knowledge, archives, pharmacopœias, international law, field pharmacy, clinical and herbal medicine data, under a philosophical scrutiny. Generic and Cannabis-specific nomenclatural frames are compared to determine the extent to which they coincide or conflict. Results: All lexica reviewed use weak, ambiguous, or inconsistent terms. There is insufficient scientific basis for terms and concepts related to Cannabis at all levels. No sound classification exists: current models conflict by adopting idiosyncratic, partial, outdated, or utilitarian schemes to arrange the extraordinarily numerous and diverse derivatives of the C. sativa plant. In law and policy, no clear or unequivocal boundary between herbal and non-herbal drugs, nor natural and synthetic cannabinoids was found; current nomenclatures used need updates. In science, the botanical Cannabis lexicon overlooks parthenocarpy, and wide disagreement remains as to the taxonomy and systematics of the plant; chemical research should address differences in kinds between synthetic cannabinoids; pharmacopœias include little information related to Cannabis, and disagree on broader classes of herbal medicines, virtually failing to embrace many known Cannabis medicines. Since existing products and compounds fail to be categorised in an evidence-based manner, confusions will likely increase as novel cannabinoid compounds, genetic and biotechnological modifications surge. Conclusions: The lack of clarity is comprehensive: for patients, physicians, and regulators. The study proposes an update of terms at several levels. It points at gaps in morphological descriptions in botany and pharmacognosy and a need for a metaphysical address of cannabinoids. Methods of obtention are identified as a common criterion to distinguish products; the way forward suggests a mutually exclusive nomenclatural pattern based on the smallest common denominator of obtention methods. In the context of a swelling number of Cannabis products being consumed (be it via medical prescription, adult-use, ‘hemp’ foodstuff and cosmetics, or other purposes), this study can assist research, contribute to transparent labelling of products, consumer safety and awareness, pharmacovigilance, medical standards of care, and an update of prevention and harm reduction approaches. It can also better inform regulatory policies surrounding C. sativa, its derivatives, and other cannabinoid-containing products. Original article available at: https://journals.sagepub.com/doi/full/10.1177/2050324520945797
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Article
‘Cannabis’ ontologies I: Conceptual
issues with Cannabis and
cannabinoids terminology
Kenzi Riboulet-Zemouli
Abstract
Objective: Identify a coherent nomenclature for Cannabis sativa L. derived products and their analogues.
Design: Research undertaken in parallel to the three-year assessment of Cannabis derivatives by the World Health
Organisation. The scope is limited to Cannabis products intended for human incorporation (internal and topical con-
sumption). Primarily embedded in pharmacognosy, the study incorporates a wide range of scholarly and grey literature,
folk knowledge, archives, pharmacopœias, international law, field pharmacy, clinical and herbal medicine data, under a
philosophical scrutiny. Generic and Cannabis-specific nomenclatural frames are compared to determine the extent to
which they coincide or conflict.
Results: All lexica reviewed use weak, ambiguous, or inconsistent terms. There is insufficient scientific basis for terms
and concepts related to Cannabis at all levels. No sound classification exists: current models conflict by adopting
idiosyncratic, partial, outdated, or utilitarian schemes to arrange the extraordinarily numerous and diverse derivatives
of the C. sativa plant. In law and policy, no clear or unequivocal boundary between herbal and non-herbal drugs, nor natural
and synthetic cannabinoids was found; current nomenclatures need updates. In science, the botanical Cannabis lexicon
overlooks parthenocarpy, and wide disagreement remains as to the taxonomy and systematics of the plant; chemical
research should address differences in kinds between synthetic cannabinoids; pharmacopœias include little information
related to Cannabis, and disagree on broader classes of herbal medicines, virtually failing to embrace many known
Cannabis medicines. Since existing products and compounds fail to be categorised in an evidence-based manner, con-
fusions will likely increase as novel cannabinoid compounds, genetic and biotechnological modifications surge.
Conclusions: The lack of clarity is comprehensive: for patients, physicians, and regulators. This study proposes an
update of terms at several levels. It points at gaps in morphological descriptions in botany and pharmacognosy and a
need for a metaphysical address of cannabinoids. Methods of obtention are identified as a common criterion to distin-
guish products; the way forward suggests a mutually exclusive nomenclatural pattern based on the smallest common
denominator of obtention methods. In the context of a swelling number of Cannabis products being consumed (be it via
medical prescription, adult-use, ‘hemp’ foodstuff and cosmetics, or other purposes), this study can assist research,
contribute to transparent labelling of products, consumer safety and awareness, pharmacovigilance, medical standards of
care, and an update of prevention and harm reduction approaches. It can also better inform regulatory policies
surrounding C. sativa, its derivatives, and other cannabinoid-containing products.
Keywords
botany, cannabinoids, cannabis, drug control, epistemology, hemp, herbal medicine, nomenclature, pharmacognosy,
synthetic cannabinoids
“What’s the use of their having names”, the Gnat said,
“if they won’t answer to them?”
“No use to them”, said Alice; “but it’s useful to the
people that name them, I suppose. If not, why do
things have names at all?”
– Lewis Caroll, Through the Looking-Glass, and What
Alice Found There
Independent researcher, Spain
Corresponding author:
Kenzi Riboulet-Zemouli, Independent researcher, Carrer de l’Hospital 99,
Barcelona 08001, Spain.
Email: kenzi@zemou.li
Drug Science, Policy and Law
Volume 6: 1–37
!The Author(s) 2020
Article reuse guidelines:
sagepub.com/journals-permissions
DOI: 10.1177/2050324520945797
journals.sagepub.com/home/dsp
Introduction
The World Health Organisation’s (WHO) Expert
Committee on Drug Dependence (ECDD) is mandated
under the International Drug Control Conventions
(IDCC) to conduct ‘medical, scientific and public
health evaluation of substances’. It advises in a
manner that is ‘determinative as to medical and scien-
tific matters’, on ‘whether or not the substances
assessed should be placed under international control’
(ECDD, 2018; Riboulet-Zemouli, 2018; World Health
Organisation, 2015). In 2015, the ECDD started
a series of assessments of ‘cannabis-related drugs’.
Despite significant efforts, goodwill, and resources,
obstacles prevented the Experts from providing a
fully clear, complete, and methodologically sound
assessment. Among the barriers, a significant one
relates to the ‘specific provisions and terms used in
the [IDCC]’ (Room, 2013) and in particular the way
Cannabis and its derived products are referenced.
Primarily relied on at the national level, the nomencla-
ture of the IDCC aggregates pharmaceutically distinct
products under the same labels that correspond to
abstract concepts rather than to classes of products
found in real life. In science, the botanical ‘cannabis
confusions’ (McPartland, 2018; McPartland and Guy,
2017; Watts, 2006) in the taxonomic ranking of the
plant are echoed by unclear morphological designa-
tions of ‘cannabis’ and ‘cannabis resin’ in pharmacy,
all within the context of a complex pharmacological
activity. Aware of that lack of conceptual and termi-
nological consistency, the ECDD included, in its out-
come recommendations sent to the United Nations
(UN) Secretary-General in 2019, elements suggesting
a renewed, modernised, clarified terminology for ‘can-
nabis drugs’ in the IDCC.
Beyond international organisations, unscientific or
connotated epithets such as ‘marijuana’ continue to
be used, including in policy or research papers, without
proper justification. The terms ‘industrial cannabis’,
‘industrial hemp’, and ‘hemp’ remain commonly
employed as synonyms. However, in some parts of
the world, ‘cannabis industry’ refers to companies
undertaking activities related to adult-uses of
Cannabis products (e.g. for recreational purposes). In
contrast, in others, it applies only to fibre-related
industries. The most studied active phytoconstituent
of Cannabis is interchangeably called ‘THC’, ‘delta-
9-THC’, and ‘dronabinol’, although these terms corre-
spond to different chemical entities. Many other
impractical terminological habits arise from the use
of similar words to designate products that are essen-
tially different and have no comparison in terms of
pharmacological effects. The ‘fibres’ which compose
the stems of Cannabis plants, used to produce paper,
clothing, or concrete, are often confused with ‘protein
fibres’ obtained from seeds. The word ‘oil’ refers to the
non-psychoactive fatty oil obtained from seeds (popu-
larly called ‘hemp seed oil’, ‘hemp oil’, or ‘cannabis
seed oil’). Yet, it is also used to denote some prepara-
tions of extracted/concentrated active compounds
(‘hash oil’, ‘butane honey oil’, ‘cannabis oil’, ‘Rick
Simpson Oil’, etc.; see Chandra et al., 2017; Krawitz
et al., 2018; Szendrei, 1997). The current increase in
innovation and diversification in production, distribu-
tion, and transformation of ‘cannabis’ into medical,
pharmaceutical, nutraceuticals, food, cosmetic, and
adult-use products will only accentuate that tendency
to confusion.
Jurisdictions around the world are increasingly
reviewing policies on medicine-related or adult-use
‘cannabis products’, or on derivatives of Cannabis for
which purposes are not related to psychoactivity
(‘hemp’). The analysis of cannabinoid content is
useful, but not sufficient to distinguish types of prod-
ucts: a traditional ‘hashish’ and an oromucosal spray
can indeed have similar thresholds. Policies are
expected to be grounded in consensual customs, con-
ventions, and standards, when not directly based on
substantial science. Nevertheless, the potential bias
implied by weak lexica, a non-scientific nomenclature,
and numerous sociocultural terminological variants,
might hinder efficient decisions in the field of
Cannabis policymaking. The need to establish defini-
tions, categories, limits, and boundaries between the
different products, preparations, and substances
derived from Cannabis has only become more urgent
after the WHO’s assessment. Beyond the IDCC, other
standards of reference should allow for a better under-
standing of the subject matter over which regulators
are starting to work. In continuation of the multidisci-
plinary work undertaken by the ECDD, a comprehen-
sive public health approach guided by evidence, urges.
This study reviews the scope, basis, and limitations of
the nomenclatures and semantics currently used as
references in the legal and public health debate on
Cannabis, parsing their relevance and their gaps and
discussing approaches towards possible updates.
Materials and methods
The problematisation and design of the study emerged
during discussions held at the UN Commission on nar-
cotic drugs meetings from 2014 onwards. A common
conclusion was shared by patients, physicians, pharma-
cists, pharmacologists, toxicologists, chemists, biolo-
gists, botanists, UN and WHO staff, national or local
health authorities, diplomats, parliamentarians, law-
yers, traditional healers, farmers, and people crafting
C. sativa derivatives in various contexts, from all
2Drug Science, Policy and Law
corners of the world: difficulties in understanding one
another due to critical linguistic inconsistencies with
‘cannabis-specific’ terms, and the extreme challenge to
overcome this stalemate from a single science, disci-
pline, field, or focus.
The initial workstream, which sought to propose an
evidence-based nomenclature of Cannabis products,
turned out to be insoluble before a first address of
existing terms and concepts from the perspectives of
the philosophies of science and language. Ontology,
both traditionally as a metaphysical address of the
nature and essence of ‘things’ and, in its modern under-
standing, as an applied discipline of knowledge man-
agement (Merrill, 2011) provided methodological
guidance in this regard. ‘The big task for the new
“ontology”’ as Smith (2003) notes, ‘derives from what
we might call the Tower of Babel problem. Different
groups of data- and knowledge-base system designers
have their own idiosyncratic terms and concepts by
means of which they build frameworks for information
representation’ (158). The assessments of the ECDD,
progressively unfolding, emphasised this problem (see
Krawitz et al., 2018). Their work (data collection, pre-
liminary documentation, meeting outcomes) served as
the basis to identify areas where ‘cannabis’ ontologies
and terminologies seemed inconsistent, insufficient, or
lacking scientific background. Complementary research
identified existing nomenclatures for C. sativa
derivatives within international legal instruments
and documentation from a wide range of institutions.
These sources were also consulted concerning non-
Cannabis herbal drugs (i.e. phytopharmaceuticals).
Phytopharmaceutical nomenclatures and herbal drugs
categorification criteria were searched in manuals and
guides of herbal pharmacy, herbal medical practice,
and pharmacognosy. Research was undertaken at
Biblioteca de Catalunya, Jard!
ı Bota
`nic, and CRAI of
the Universitat de Barcelona (Barcelona, Spain),
Conservatoire et Jardin Botanique de Gen"
eve,
Facult!
e de M!
edecine of the Universit!
e de Gen"
eve,
Archives of the League of Nations, Libraries of the
UN and of the WHO (Geneva, Switzerland), Dag
Hammarskj
old Library (New York, USA, remotely),
the library of the UN Office on Drugs and Crime
(UNODC) (Vienna, Austria), and at the Acad!
emie
Nationale de M!
edecine, Acad!
emie de Pharmacie,
Acad!
emie des sciences, Mus!
eum National d’Histoire
Naturelle and Universit!
e de Paris (France).
References used in the 2019–2020 courses of the uni-
versities visited were favoured. Drug codifying com-
pendia and other relevant references were also
consulted at this stage.
Searches were then performed in a corpus of phar-
macopœias from 26 different jurisdictions (identified in
WHO, 2013a, 2013b, 2018a), detailed in Table 1.
Except where indicated otherwise, all abbreviations of
pharmacopœias used along the article refer to the latest
edition consulted, as referenced in Table 1. The first
stream of queries focused on whether pharmacopœias
included C. sativa phytopharmaceuticals or other
derivatives, and if so, how they were categorised. A
second stream searched for general frameworks catego-
rising phytopharmaceuticals in notices, monographs,
and glossaries, and for other categorisation patterns
emerging from individual monographs.
Literature searches were carried out up to 1 October
2019, in ProQuest, PubMedV
R, PMI, and Scopus
TM
using database-specific search strategies and appropri-
ate keywords, truncation, symbols, and reference index
terms, as appropriate. In addition, Google,
DuckDuckGo, Archive.org, Google Scholar, and
ResearchGate were employed to hand search addition-
al articles and references. The door to serendipity
stayed open.
The ‘Discussion’ section introduces neologisms: sup-
plementary Appendix I exposes the methods followed
to craft them.
There were several limitations in the research. The
main limitation is contained in substance in the axis of
research: the unsuitable, or nonexistent language and
terminology for ‘cannabis’ derivatives. False cognates
and other similar words relating to different concepts
or different objects were overwhelmingly found
between different authors or references, imposing the
use of a vocabulary proper to the article as a manner of
distinguishability (e.g. the use of phytopharmaceuticals,
instead of herbal drugs whose meaning varies impor-
tantly among regions and areas of expertise). Another
significant limitation is rooted in the Western embed of
international pharmaceutical and medical standards;
those could only partially be balanced due to language
limitations.
A self-imposed limitation consisted in excluding
from the scope of the article those products of
C. sativa for which the purpose of use is not related
to incorporation (internal or external consumption).
C. sativa is a plant also used for the production of
fibre, processed into paper, clothing, biocomposite
materials, etc. These products are often processed in
a manner that renders them unsuitable for incorpora-
tion, although they can be consumed (e.g. clothes are
worn, paper is used, but not incorporated). Relying on
the criteria of exemption by purpose present in the
IDCC (i.e. products for which the purpose of use is
not in relation to its potential psychoactive properties
are exempt from drug control, see Riboulet-Zemouli,
2019) the products whose purpose is not that of human
incorporation are excluded from the scope of this
study. Because the products that can be incorporated
are still numerous, the specific downstream criteria of
Riboulet-Zemouli 3
Table 1. Pharmacopœias consulted.
Legally-binding pharmacopœial references consulted.
Jurisdiction concerned Vernacular name / English name Abbreviation Previous editions (date) Last edition (date)
Argentina Farmacopea Argentina / Argentinian Pharmacopœia FA n/a 7th (2013)
1
Brazil Farmacop!
eia Brasileira / Brazilian Pharmacopœia FB 5th (2010) 6th (2019)
2
China /Pharmacopœia of the People’s
Republic of China
Ch.P 7th (2000)9th (2010) 10th (2015)
3
Egypt Egyptian Pharmacopœia Ph.Eg. n/a 3rd (1984)
4
France Pharmacop!
ee Franc¸aise / French Pharmacopœia Ph.Fr. n/a 11th (2012)
5
Germany Deutsches Arzneibuch / German Commission E’s Monographs DAB n/a 10th (1991)
6
Greece Ekkg!ij!
gUaqlajopoi!
ia /Hellenic Pharmacopœia Ph.Gr. n/a 5th (1998)
7
India Indian Pharmacopœia IP 6th (2010) 8th (2018)
8
Indonesia Farmakope Indonesia / Indonesian Pharmacopœia Ph.Indo. n/a 2nd (1972)
9
Japan /Japanese Pharmacopœia JP 16th (2011) 17th (2016)
10
Mexico Farmacopea Mexicana / Mexican Pharmacopœia n/a n/a 5th (1925)
11
Farmacopea Herbolaria de los Estados Unidos Mexicanos / Herbal
Pharmacopœia of the United Mexican States
FHEUM n/a 2nd (2013)
12
The Netherlands Analytical Monograph Cannabis Flos (flowers /
granulated)
n/a n/a 7.1 (2014)
13
Paneuropean Pharmacopœia Europæa / European Pharmacopœia Ph.Eur. 8th (2014) 9th (2016)
14
Poland Farmakopea Polska / Polish Pharmacopœia Ph.Pl. n/a 5th (1993)
15
Romania Farmacopeea Roma
ˆn$
a/Romanian Pharmacopœia FR n/a 10th (1993)
16
Russian Federation Ujcelahcndeyyazaah!arjgez!jccbqcrjqAelehaçbb /
State Pharmacopœia of the Russian Federation
SPRF n/a 13th (2015)
17
Spain Farmacopea Espa~
nola / Spanish Pharmacopœia n/a 5th (1865)
18
8th (1930)
19
Real Farmacopea Espa~
nola / Royal Spanish Pharmacopœia RFE n/a 5th (2015)
20
Switzerland Pharmacopœia Helvetica / Swiss Pharmacopœia Ph.Helv. n/a 11th (2017)
21
11.3 (2019)
22
(continued)
4Drug Science, Policy and Law
Table 1. Continued
Legally-binding pharmacopœial references consulted.
Jurisdiction concerned Vernacular name / English name Abbreviation Previous editions (date) Last edition (date)
United Kingdom British Pharmacopœia BP (1914)
23
(1968)
24
(2009)
25
(2017)
26
United States of America United States Pharmacopœia USP n/a 42nd (2019)
27
Vietnam Dưcd
-ie
ˆn Vie
ˆt Nam / Pharmacopœia of Vietnam VP n/a 3rd (2002)
28
Non- or partially legally-binding pharmacopœial references, and other compendia of reference consulted.
Area concerned Name Abbreviation Date
African continent African Herbal Pharmacopœia AfrHP 2010
29
African Pharmacopœia AfrP 1986
30
African continent
(North-Western)
M!
edecine arabe ancienne et savoirs populaires: La pharmacop!
ee maro-
caine traditionnelle
n/a 1997
31
African continent
(Western)
Medicinal plants in tropical West Africa n/a 1986
32
West African Herbal Pharmacopœia WAHP 2013
33
India Ayurvedic Pharmacopœia of India IPA 1989
34
International The International Pharmacopœia Ph.Int. 2018
35
Martindale: the complete drug reference 2005
36
Taiwan The illustration of common medicinal plants in Taiwan 2009
37
United Kingdom British Herbal Pharmacopœia BHP 1996
38
United States
of America
American Herbal Pharmacopœia (monograph on Cannabis spp.) USHP 2014
39
Pharmacopoeias underlined are those legally in force at the date of redaction of this article. References:
1
Administraci!
on Nacional de Medicamentos, Alimentos y Tecnolog
!
ıa M!
edica, 2013;
2
Age
ˆncia
Nacional de Vigila
ˆncia Sanita
´ria, 2019;
3
Chinese Pharmacopoeia Commission, 2015;
4
Permanent Commission of the Egyptian Pharmacopœia, 1984;
5
Agence nationale de s!
ecurit!
e du m!
edicament et des
produits de sant!
e, 2017;
6
Blumenthal et al., 1998;
7
Tr!
oja and Biok!
ajg1, 1998;
8
Indian Pharmacopoeia Commission, 2018;
9
Departemen Kesehatan Republik Indonesia, 1972;
10
Ministry of Health, Labour
and Welfare, 2016;
11
Uni!
on Nacional de Farmac!
euticos Cient
!
ıfico-Cooperativa, 1925;
12
Comisi!
on Permanente de la Farmacopea de los Estados Unidos Mexicanos, 2013;
13
Ministerie van Volksgezondheid
Welzijn en Sport, 2019;
14
European Directorate for the Quality of Medicines, 2016;
15
Komisji Farmakopei Polskiej, 1993;
16
Institutul pentru Controlul de stat al Medicamentului s
,i Cercet$
ari Farmaceutice,
1993;
17
"bybcnehcndj Ålhadjj[hayeybz !jccbqcrjq Aelehaçbb, 2015;
18
Real Academia de Medicina de Madrid, 1865;
19
Real Academia Nacional de Medicina, 1930;
20
Agencia Espa~
nola de
Medicamentos y Productos Sanitarios, 2011;
21
Swiss Agency for Therapeutic Products, 2012,
22
2019;
23
General Council of Medical Education and Registration of the United Kingdom, 1914;
24
General
Medical Council, 1968;
25
Medicines and Healthcare products Regulatory Agency, 2009,
26
2017;
27
United States Pharmacopeial Convention, 2019;
28
C^
o
:ng Ho
`aX
~
aH
^
o
:i ChNgh
~
ia Vi^
e
:t Nam, 2002;
29
Brendler et al., 2010;
30
Organisation of African Unity, 1986;
31
Bellakhdar, 1997;
32
Oliver-Bever, 1986;
33
Organisation Ouest-Africaine de la Sant!
e, 2013;
34
Ministry of Health and Family Welfare of India,
1989;
35
World Health Organisation, 2018b;
36
Sweetman, 2005;
37
Huang et al., 2009;
38
Willoughby et al., 1996;
39
Upton et al., 2014.
Riboulet-Zemouli 5
the route of administration (which often vary among
consumers, sometimes overlapping for the same prod-
uct; and which are difficult to assess in a context of
partial illegality) have been ignored, and left for further
studies.
The IDCC, a set of treaties almost universally rati-
fied, has shaped national laws, regulate research, and
impose thorough obligations to Member States. Hence,
the IDCC has been used as the paradigmatic point of
departure for the study; however, all other classifica-
tion criteria or existing Cannabis-related nomenclatures
reviewed were given a comparable weight, and
addressed with a similar approach, in an attempt to
unearth a denominator.
The length of the article reflects the over three years
of research involved in its production. The plan reflects
the incremental aspect in which unfolded the research:
it explores, from the most simple to the most sophisti-
cated products, the limitations of existing terminology,
why these limitations are rooted, beyond the terms, in
conceptual confusions; the conclusion discusses lessons
to be drawn, in view of possible new evidence-based
terminologies to be proposed.
Results
The Home Medical Encyclopedia defines ‘cannabis’ as
‘[a]ny of the numerous psychoactive preparations
derived from the hemp plant Cannabis sativa (such as
hashish and marijuana)’ (American Medical
Association, 1989: 230). Although commonly accepted,
this is the perfect example of a circular definition: it
explains the term ‘cannabis’ using this same word in
the text of its definition (Kripke, 1980: 67–70, 1982).
This ‘two cannabises’ approach is symptomatic of a
fundamentally dichotomous vision of the word, used
daily to designate two conceptually different concepts:
either a plant genus, ‘Cannabis’, or a series of (mind-
altering) products from that plant, ‘cannabis’ (Cherney
and Small, 2016; Small, 2017: 1–5). This double-edged
meaning affects and complicates the understanding of
both ‘Cannabis’ as a plant and ‘cannabis’ as a product.
Polysemic acceptances of this word are profuse,
worldwide, including in law. Legislations relating to
Cannabis’ and/or ‘cannabis’ often follow the codifica-
tion of the IDCC (UNODC, 2013), particularly the
Single Convention on Narcotic Drugs of 1961 as
amended in 1972 (C61) and the Convention on
Psychotropic Substances of 1971 (C71). This latter
treaty does not directly mention ‘cannabis’; it com-
prises only pure compounds and includes dronabinol
(ECDD, 2019: 41–44) as well as its stereochemical var-
iants and isomers. Dronabinol is the international non-
proprietary name (INN) for the (–)-trans stereoisomer
of the delta-9 isomer of tetrahydrocannabinol (THC).
Two confusions often arise (Figure 1): while the INN
seems to only designate (–)-trans-delta-9-tetrahydro-
cannabinol, some references like United States
Pharmacopœia (USP), recognise as dronabinol all
four enantiomers of delta-9-tetrahydrocannabinol.
For others, the word dronabinol is understood as refer-
ring only to delta-9-tetrahydrocannabinol obtained
ex vivo. According to WHO, however, ‘dronabinol’
corresponds to (–)-trans-delta-9-THC, either obtained
in vivo or ex vivo (ECDD, 2018: 33).
The C61, on its side, includes four occurrences of
the word in its Article 1 on definitions (UNODC,
2013: 24–26):
a. ‘Cannabis plant’ that is ‘any plant of the genus
Cannabis’ (art. 1[c]),
tetrahydrocannabinol
delta-6a(10a) delta-6a(7) delta-7 delta-8 delta-9 delta-10 delta-9(11)
(+)-cis (+)-trans (–)-cis (–)-trans
Popular belief
‘dronabinol is only ex vivo, whether (–)-trans or other’
International Nonproprietary Name
‘dronabinol is only (–)-trans-delta-9-THC, whether in vivo or ex vivo
United States Pharmacopœia
‘dronabinol is delta-9-THC, whether in vivo or ex vivo
Figure 1. Conflicting ontologies: dronabinol and THC. THC: tetrahydrocannabinol.
6Drug Science, Policy and Law
b. ‘Cannabis’, defined as ‘the flowering or fruiting tops
of the cannabis plant (excluding the seeds and leaves
when not accompanied by the tops) from which the
resin has not been extracted, by whatever name they
may be designated’ (art. 1[b]). The Commentary on
the C61 treaty, prepared by the office of the UN
Secretary-General (hereinafter called Commentary,
see UN, 1973), explains that ‘the term “cannabis”
[...] covers all tops including those which are not
yet dried, as well as those of the male plants’ (UN,
1973: 2 §1).
c. ‘Cannabis resin’ defined as ‘the separated resin,
whether crude or purified, obtained from the canna-
bis plant’ (art. 1[d]). The Commentary further
explains (UN, 1973: 5 §3) that ‘resin, however,
becomes “cannabis resin” only when it is
“separated” from the plant; without such separation,
it remains a part of the cannabis plant, and if in the
top part, of “canna bis”’.
d. ‘Extracts and tinctures of cannabis’, for which no
definition is provided.
The C61 treaty is a delicate equilibrium between the
labour of merging several previous international legal
instruments into a new, single text, and the geopolitical
developments of the postwar era (Jelsma et al., 2014;
Krawitz et al., 2018: 6–11; Riboulet-Zemouli, 2018).
The limited knowledge of the active constituents of
the plant at the time contributed such imprecise lan-
guage. A background paper to ECDD’s 2012 meeting
explains: ‘in the half-century since the 1961 Convention
was adopted, there has been considerable developments
in the terminology used’ (Room, 2013). Today the effi-
ciency of this nomenclature, used globally for several
decades, seems to be backed by weak evidence. It is,
however, representative of a trend in regulatory termi-
nological shortcuts, as well as in the legal polysemy of
the very word cannabis. C61 defines drugs as ‘any of the
substances in Schedules I and II, whether natural or
synthetic’ (art.1(j)). Only ‘cannabis’, ‘cannabis resin’,
and ‘extracts and tinctures of cannabis’ are listed in
these Schedules (UN, 1961: 239). Consequently, ‘can-
nabis plant’ is not seen as a drug as per the C61
regulations.
‘Cannabis’ as a plant
Beyond the ancient uses of the word ‘cannabis’ to refer
to this particular plant, modern science legitimises the
word with Linnæus (1753: 1027; see also and Watts,
2006) describing a monogeneric plant under this
name. At the higher family level, its belonging to
Cannabaceae is nowadays generally accepted
(McPartland, 2018; Stevens, 2001a onwards, 2001b
onwards; Watts, 2006). However, although unrivalled
at the genus level, the systematic classification of
Cannabis at lower taxonomic levels continues to be
an essential subject of controversy (Chopra and
Chopra, 1957; Clarke and Merlin, 2013; Lynch et al.,
2016; McPartland, 2018; Small, 2017; Stevens, 2001a
onwards; Yang et al., 2013). Contemporary findings
tend to show C. sativa as the only monospecific expres-
sion of the genus Cannabis; the rich genetic diversity
responsible for the numerous types of C. sativa would
be expressed at a lower level (in the taxonomic ranks of
subspecies, variety, forma, or cultivar, see Lynch et al.,
2016; McPartland, 2018). While no consensus arises,
none of the findings matches the traditional distinction
between drug-type and fibre-type Cannabis mimicked
in folk language by the use of terms such as ‘marijuana’
and ‘hemp’. Hazekamp et al. (2010) even state that
such a ‘distinction between the two types may have
limited relevance for medicinal research’ (1037).
Genetic diversity happening below the species rank
reflects substantial variabilities of C. sativa crops,
which might explain the reported use of ‘drug-type’
varieties for the obtention of fibres, and vice versa
(Clarke and Merlin, 2013; Lynch et al., 2016;
Szendrei, 1997). The UNODC (2009) finds:
Chemical and morphological distinctions by which
Cannabis has been divided into these subspecies are
often not readily discernible, appear to be environmen-
tally modifiable, and vary in a continuous fashion. For
most purposes, it suffices to apply the name Cannabis
sativa to all Cannabis plants encountered. (7)
‘Cannabis’ as phytopharmaceuticals
Surprisingly, evidence-based definitions of the word
‘cannabis’ understood as a series of products obtained
from the C. sativa plant are absent from scientific lit-
erature. Besides the living plant, the word is also used
to refer to one of the products of the harvest of
C. sativa plants, a particular botanical part used for
human consumption in relation to a sought-after phar-
macological activity. This ‘cannabis’ is often referred to
as buds,flowers,inflorescences,bracts,heads, or tops.
Additionally, an important number of extracts or
transformed derivatives of the C. sativa plant, at differ-
ent stages of elaboration, are commonly referred to as
‘cannabis’. In the 1950s, the Multilingual list of narcotic
drugs under international control (UN, 1958: 13–14)
defined ‘cannabis’ as both raw herbal parts, and more
elaborate products such as confections, beverages, and
preparations. Sixty years later, the WHO also consid-
ered a number of prepared, compounded, or elaborate
products, mostly traditional ones, under the agenda
item ‘cannabis’ rather than under that of ‘extracts
Riboulet-Zemouli 7
and tinctures of cannabis’ (Cannazza and Citti, 2018a:
5, 2018b).
The C61 recognises differences between simple
botanical ‘cannabis’, the processed ‘cannabis resin’,
and ‘extracts and tinctures of cannabis’. However, no
clear distinction between the two latter entities is men-
tioned in the Convention, the processes to obtain one
or the other are sometimes similar (Table 2); the entities
‘cannabis’, ‘cannabis resin’, and ‘extract and tinctures’
are sometimes considered interchangeably (UN, 1973:
2 §5) even though they are listed in different Schedules
and eventually subject to a distinct policy r!
egime.
In literature, neither simple ‘cannabis’ nor elaborate
products are defined in a better way. In other interna-
tional instruments, Cannabis and its derivatives are
present under limited functional appellations, not
always reconcilable with the ones used in the IDCC.
For example, the World Trade Organisation’s
Harmonised Tariff System contemplates a category
(No. 1302.19) titled ‘Cannabis flower/Cannabis extract’
(Krawitz et al., 2018: 20).
Defining the basic botanical ‘cannabis product’. Scientifically
identifying the ‘buds’, ‘tops’, ‘ganja’, ‘heads’, or ‘flow-
ers’ is not an easy task, and consensus lacks on their
precise botanical designation. C. sativa is an annual
dioecious (although sometimes monoecious or her-
maphrodite) flowering herb (Clarke, 1981; Evans,
2009) producing geniculate achenes as fruits (Evans,
2009; Upton et al., 2014: 8). Reproduction occurs
through wind-dispersed pollen liberated from the flow-
ers of staminate (i.e. male) plants (Chandra et al., 2017;
Small and Antle, 2003). Chopra and Chopra (1957)
described the parts of C. sativa used for the production
of drugs as ‘flowers, leaves (and the resinous matter
derived therefrom), fruit, young twigs, and bark of
the stem’. Twenty-three years later, Kimura and
Okamoto found that traces of active compounds were
present at all stages of the plant’s life, in both staminate
and pistillate (i.e. female) C. sativa, although mainly
‘contained in the parts in prosperous growth, and espe-
cially concentrated at the bractlet in the period when
the seeds are at the peak of ripening’ (Kimura and
Okamoto, 1970). They refer interchangeably to these
botanical parts, containing the most active phytochem-
icals, as pistillate ‘tops’, ‘flowers’, ‘inflorescences’, or
‘fruits’. More accurately, the active ingredients
(mostly phytocannabinoids, terpenoids, phenols) are
biosynthesised inside the multicellular, glandular
heads of epidermal multiseriate stalk trichomes
(Chandra et al., 2017; Clarke, 1981; ECDD, 2018;
Evans, 2009: 525–527, 553–557; Flemming et al.,
2007: 8; Frank, 2018; Happyana et al., 2013; Heinrich
et al., 2017: 18, 149–150; Turner et al., 1981). While
these epidermal glandular trichomes (EGT) are also
present in a much lesser extent on leaves, stem, and
other parts of the plants (explaining the results of
Kimura and Okamoto, 1970; see also Turner et al.,
1981), their dense concentration around the reproduc-
tive parts of pistillate plants (the so-called ‘buds’ or
‘heads’) is a major factor in the choice of the parts to
harvest and transform for psychoactive purposes.
Hence, the most common and well-characterised phy-
toconstituents are found only in trace amounts outside
of the EGT found on the leaves, flowers, and fruits
(Jin et al., 2020).
‘Flowers’ is the name for the preferred harvested
parts bearing phytopharmaceutical ingredients and is
the most commonly encountered designation in the lit-
erature as well as references like USHP, Ph.Helv,
UNODC (2009), or in the various ECDD (2018,
2019) reports. C61 accepts both flowering and
fruiting tops in its definition but excludes seeds,
which, however, are sometimes referred to as fruits,
such as in Pharmacopœia of the People’s Republic of
China (Ch.P) and Japanese Pharmacopœia (JP)
(Chinese Pharmacopoeia Commission, 2015; Ministry
of Health, Labour and Welfare, 2016).
Numerous references use imaginative formulations
to mean that flowers have seeds, without directly ver-
balising ‘seeded flowers’. This would indeed oppose the
basics of botany where seeded flowers are not an
option. As early as 1894 it was noted that the materials
used for the production of a local extract in India were
‘flower heads, which are now full of seed, discarding
the coarser leaves’ (Indian Hemp Drugs Commission,
1894). 123 years later, a paper describes the botanical
parts harvested for their psychoactivity, in Nepal, as
the ‘mature seeded female inflorescences’ (Clarke,
2007). Creative alternatives, such as buds,bractlets,
calyxes (Frank, 2018), ‘bracts which surround the ova-
ries’ (Dewick, 2012), or seedless floral clusters were
found, reflecting a lack of consensus around the desig-
nation of these parts. The sentence describing the fron-
tispiece photograph of Cannabis and Health (Graham,
1976: III) achieves the feat of referring to the same
specimen simultaneously as a ‘fresh flowering top’
and a ‘developing fruit’. These curious phraseologies
can be explained by the fact that, in traditional outdoor
cultivation, staminate and hermaphrodite plants can
occur in the field, thus resulting in the pollination of
some flowers, and their transformation into fruits bear-
ing seeds (Chopra and Chopra, 1957; Clarke, 2007).
C. sativa farmers have developed strategies to avoid
this and reduce the presence of seeds in harvestable
crops, mostly by impeding pollination. Chopra and
Chopra (1957) noted that an important operation of
India’s 1950’s C. sativa farmers consisted of going
‘through the field cutting down all staminate plants’
for ‘preventing seed formation’. Hamayun and
8Drug Science, Policy and Law
Shinwari (2004) explain that the early flowering stage
of pistillate flowers allows for easy removal from the
fields. They note that ‘even the young fruit of the
female cannabis plant’ is used for the production of
psychoactive products. The plants resulting from
crops where such sexual selection has taken place are
known as ‘sinsemilla’ (Clarke and Merlin, 2013;
ECDD, 2018: 18), derived from Spanish sin semilla,
literally meaning ‘without seed’. The UNODC (2009)
explains:
Cannabis with the highest level of THC is comprised
exclusively of the female flower heads (“buds”) that
remain unfertilized throughout maturity and which,
consequently, contain no seeds. The production of sin-
semilla requires identifying the female plants and
ensuring that they are not exposed to pollen. (11)
‘Ganja’, the traditional word used in many parts of the
globe to refer to psychoactive C. sativa tops, was
described by the UN (1958) as ‘the prototype of the
pharmacopœial cannabis or “Indian hemp”, defined
as the flowering tops of the pistillate plants of
Cannabis sativa L. (sometimes required to be unfertil-
ised)’ (13).
The consideration of buds as flowers conflicts with
the repeated mentions of a seemingly needed maturity
of flowers to be harvestable. Flowers do not ripen: they
wilt (senescence) and turn into fruits which, on their
turn, do mature. Literature repeatedly suggests that
the optimal moments for the harvest of seeds, and of
content rich in cannabinoids, occur simultaneously.
Dewick (2012: 120) explains that ‘resin is produced
from the time flowers first appear until the seeds
reach maturity’, as confirmed by Clarke (1981: 12).
Kimura and Okamoto (1970) go in the same direction:
although they do not refer to the word fruit, they dis-
tinguish ‘bractlet’ from ‘flowers’, the former appearing
chronologically after the latter. They explain that
bractlets bear a higher concentration of cannabinoids
two months after analysing the staminate flowers,
which are known to appear slightly before pistillate
flowers and to have a maximum life duration of three
weeks (Small and Antle, 2003). These observations
could mean that pistillate flowers would survive five
weeks or more after their staminate counterparts have
lost the ability to pollinate them. That would be an
unprecedented form of dioecism in the Plantæ king-
dom, with the only known seeded flowers ever, and
where male and female iterations would enter flowering
at different periods.
From a different angle, yet fully aligned with
modern botanical sciences, considering ‘bud’ not as
bractlets, flowers, or inflorescences, but as fruits or
infructescences, might be insightful. In the past defined
as ‘structures bearing seeds’, fruits are currently
described in a more sensible way as ‘matured pistil or
ovary of the flower, with or without accessory struc-
tures’ (Blumenthal et al., 1998: 59) or as ‘a derivative of
the gynoecium or whatever extracarpellary part it may
be united with during the fruiting stage’ (Esau, 1977:
430; Scagel et al., 1967: 559). Botanical sciences do
contemplate the development of fruits from unfertilised
female flowers, a mechanism termed ‘parthenocarpy’
and widely spread among dicots (supplementary
Appendix II).
These observations suggest that the basic ‘cannabis
product’ might not be composed of flowers, but fruits –
more precisely, parthenocarpic fruits. Because C. sativa
naturally has both abilities to produce seeded and seed-
less fruits, the genus would be more accurately classi-
fied as a ‘facultative parthenocarpic plant’ (Koltunow
et al., 2002), and when some seeds remain in an other-
wise seedless Cannabis ‘top’ it would be called a ‘par-
tially parthenocarpic infructescence’.
The phenomenon of parthenocarpy in C. sativa and
possible reasons for its oversight in literature are dis-
cussed and illustrated in supplementary Appendix II.
In this study, the expression ‘parthenocarpic fruits’, or
‘parthenocarpic infructescence of C. sativa’ (which can
be abbreviated as ‘pioC’), is therefore preferred to
‘inflorescence’, ‘top’, ‘bract’, or other terms, when
referring to the mature seedless reproductive parts of
pistillate C. sativa plants.
Defining products derived from the Cannabis plant. In popu-
lar and folk lexica of extracts, tinctures, resins, and
other derivatives of C. sativa for human consumption
(except pioC themselves), a seemingly standard corpus
of terms is used globally (Backes, 2014; Cannazza and
Citti, 2018a, 2018b; Chambers, 2019; Daniulaityte
et al., 2017; Jaffe, 1995: 982–989; Ministry of Health
and Family Welfare of India, 1989; Nicoletti Motta,
2018; Oliver-Bever, 1986; UN, 1958; UNODC, 2009;
World Health Organisation, 2016; Zav%
relova
´, 2017)
although it refers to different concepts, depending on
sources, area, and time. No universally accepted termi-
nology is used, but some terms recur. For instance,
while the word ‘hashish’ in Morocco refers to the
living plant from which resin is extracted (Bellakhdar,
1997: 233), the Encyclopedia of Drugs and Alcohol
explains it is ‘the Arabic word for a particular form
of Cannabis sativa ...the resin derived principally
from the flowers, bracts and young leaves’ (Jaffe,
1995: 541). For Oliver-Bever (1986: 78) it is a ‘purified
alcoholic extract’ and for the UNODC (2009: 16) hash-
ish consists of ‘resinous secretions of the plant, pro-
duced in glandular trichomes’. The Martindale
explains that the word ‘is often applied to the resin,
although in some countries, hashish is applied to any
Riboulet-Zemouli 9
cannabis preparation’ (Sweetman, 2005: 1666). Many
C. sativa products linked to traditional medical practice
or entheogenic uses, still partially undocumented
(Abbott, 2014; Abdool, 2013; Bellakhdar, 1997: 232–
234; Kutesa, 2018) are victims of similar terminological
confusions. Another example is the inappropriate use
of the word ‘oil’ (Daniulaityte et al., 2017; Szendrei,
1997; WHO, 2016) to describe all sorts of products
very distinct from the common understanding of ‘oil’,
mostly limited to fatty oils and essential oils. Although
a lot of these ‘cannabis’-specific terms seem universally
known and used, they have no consistent, nor universal
definition.
Generally, folk distinctions between ‘resin’ and
‘extracts’ recur (Nicoletti Motta, 2018; Satchel, s.d).
Resin is often described as the product of a simple and
often traditional extraction process. The Encyclopedia
of Drugs and Alcohol sees hashish as ‘a concentrated
resin containing increased amounts of D9-THC’,
‘derived principally from the flowers, bracts, and
young leaves of the female hemp plant’, and that ‘con-
tains cannabinoids’ (Jaffe, 1995: 429, 541). Some
Table 2. Nomenclature of methods of obtention of Cannabis products in the 1961 Convention on narcotic drugs.
Starting material Method of obtention Resulting drug
cannabis plant Production (1(t)) cannabis
cannabis plant Production (1(t))
Separation (1(c))
cannabis resin
cannabis Manufacture (1(t))
Extraction (1(b))
Manufacture (1(t)) extracts and tinctures
cannabis plant Manufacture (1(t))
cannabis resin Manufacture (1(t))
crude cannabis resin Manufacture (Art. 1(t), 1(j)) refined cannabis resin
not a scheduled drug
(e.g.,in vitro synthesis)
Manufacture (Art. 1(t), 1(j)) cannabis resin
Manufacture (Art. 1(t), 1(j)) extracts and tinctures
The products in bold are those defined as ‘drugs’ in the Convention (Art. 1[j]), as of 2020.
Table 3. Ontological conflicts: ‘extracts and tinctures of cannabis’ according to different authors of the pre-review documentation
used at the 40th ECDD meeting.
Chemistry Pharmacology Toxicology Therapeutic use Epidemiology
Cannabis tinctures Cannabis tinctures Cannabis extracts,
tinctures, oils and tea
Cannabis Sativa Extract Extracts and tinctures
Cannabis extracts Cannabis oils
Cannabis oils
Aqueous extracts Aqueous extracts n/a n/a
n/a Hemp seed oil Hemp seed, ‘Evening
Primrose Oils’
n/a
Nabiximols / cannabidiol in
preparation with other
cannabis-related
ingredients
Nabiximols Nabiximols Nabiximols Nabiximols
n/a n/a Oral-mucosal cannabinoid
extract
n/a n/a Cannabis resin n/a n/a
Adapted from Krawitz et al., 2018.
10 Drug Science, Policy and Law
products like rosin,dry sift, or bubble hash are alterna-
tively referred to as either a form of hashish or as
extracts (Cannazza and Citti, 2018a, 2018b;
Medicaljane, s.d). This confusion is absent from another
widely used approach, which distinguishes products in
two complementary categories based on the use of sol-
vent during the extraction process, or not (Zav%
relova
´,
2017; see also supplementary Appendix III).
Defining resin. Because ‘cannabis’ is defined in C61
as tops of C. sativa ‘from which the resin has not been
extracted’, it is suggested that extraction is the method
of obtention of ‘resin’ from ‘cannabis’. Such definition
corresponds to ‘manufacture’ in Article 1(n): ‘all pro-
cesses, other than production, by which drugs may be
obtained [including] refining as well as the transforma-
tion of drugs into other drugs’. Additionally, Article 1
(d) explains that resin is ‘separated’ from C. sativa,
which conflicts with Article 1(t) for which this opera-
tion is ‘production’ (‘the separation of [...] cannabis
and cannabis resin from the plants from which they
are obtained’). ‘Resin’ can therefore, under the
Convention, be obtained by extraction, by manufac-
ture, and by separation, as outlined in Table 2.
An additional detail about ‘resin’ is its state of being
either ‘crude or purified’. The Commentary notes: ‘the
separated resin is “cannabis resin” not only when it is
“purified”, but also in its “crude” state, i.e. when it is
still mixed with other parts of the plant’ (UN, 1973: 5
§3). The concept of purification is invoked to mean the
elimination of residual botanical elements. It relates to
the processes of refining described in Article 1(n) as
being ‘manufacture’. Production and manufacturing
are the two genuine ‘operations by which “drugs”
[...] are obtained’ (UN, 1973: 15 §2). However, a
more complex set of terminology, summarised in
Table 2, is used to refer to the processes of elaboration
of C. sativa and pioC derivatives. Boundaries in C61
are unclear and leave a margin for bias and errors of
interpretations. Because a different r!
egime of control
under the IDCC is currently applied to these products,
this may have non-negligible legal implications.
Besides the language of the IDCC, the word resin is
widely used to describe complex mixtures of phyto-
chemicals secreted by plants (Evans, 2009: 298).
Bone’s Principles of herbal pharmacology (2013)
explains the polysemy of the word resin:
The term is used in several contexts. When certain
plants are damaged, either by incision or naturally
due to the action of animals or the environment, they
secrete a viscous fluid that soon hardens ...Such resins
are often associated with essential oils (oleoresins), with
gums (gum resins) or with oil and gum (oleo-gum
resins). Their resin components, which mainly
comprise diterpenes known as resin acids, resin alco-
hols and resin phenols, are soluble in alcohol and ether
but are insoluble in water and hexane. In another con-
text, the term ‘resin’ (or occasionally ‘resinoid’) means
the part of the plant that is soluble in ether or
alcohol ...These resins are chemically diverse and can
contain resin acids, pyrones, lignans, esters and glyco-
sides amongst others. (38)
Plants generally biosynthesise their phenols, terpenes,
and terpenoids in specific glands. These are the classes
of organic compounds to which phytocannabinoids are
associated with, also including a large number of aro-
matic molecules. These secreting glands are mainly
located inside the plants’ organs like in conifers
(Kutchan et al., 2015: 1132–1135, 1147–1148) but can
sometimes appear externally, like in EGT in the case of
C. sativa plants (Evans, 2009: 298) and others
(Chrispeels and Sadava, 1994: 345; Swiss Agency for
Therapeutic Products, 2012: 134).
The WHO ECDD (2018: 18) considers that ‘resin’
originates from ‘resinous secretions’ of the plant’s EGT
which contain, in addition to numerous phenols and
terpenoids, dronabinol and other phytocannabinoids.
Analytical explorations of the exudate secreted by
EGT show the most present components numerically
are terpenoids, phytocannabinoids, hydrocarbons,
sugars, nitrogenous compounds, phenols, and flavo-
noids, with fatty, simple and amino acids, ketones,
esters, lactones, aldehydes present in a much less sig-
nificant yield. These substances ‘have all been identified
as a constituent of some preparation of Cannabis:
herbal plant material, whole extracts, and chromato-
graphic fractions, or illicit material such as hashish’
(Hazekamp et al., 2010: 1038–1039).
All of these compounds correspond to those
described as characteristics of plant resins in literature.
They are obtained by the secretion from a plant’s
glands and are all known for their ether soluble prop-
erties (Clarke, 1981; Evans, 2009: 525–527, 557;
Happyana et al., 2013). In other words, all acceptations
of ‘resin’ (glandular origin, composition, solubility in
alcohol) match with the material contained in C. sativa
trichomes’ glandular heads. The systematic and sub-
stantial yield of aromatic metabolites in addition to
phytocannabinoids suggests oleoresin might be a more
accurate term than resin to describe the ether soluble
separable content from EGTs.
It is generally assumed that the authors of the C61
agreed to use ‘resin’ in the absence of more advanced
knowledge about its chemical composition, as a way to
ensure dronabinol, by then unidentified, would fall
under control in all circumstances. The assumption
that the active compound(s) of C. sativa were included
in resin is reflected in the Commentary, which refers,
Riboulet-Zemouli 11
for instance, to the ‘pharmacologically strongly active
resin’ (UN, 1973: 2 §1). Pure THC/dronabinol itself
was eventually placed in the schedules of another
IDCC treaty: the C71. Interestingly, countries’ author-
ities have been encouraged by the International
Narcotics Control Board (INCB) to consider dronabi-
nol of synthetic origin under the r!
egime of C71, while
dronabinol derived from the C. sativa plant would be
considered under C61 rules (INCB, 2019: 8). A gross
inconsistency (see Figures 1 and 2) which has been pro-
posed a solution in the ECDD (2019: 45–47, 49–50)
recommendations: placing all dronabinol-related iso-
mers and stereoisomers within the same Schedule.
Notably, since 1961, the chemical composition of C.
sativa oleoresin has been figured out: it was found to be
exceptionally diverse and variable (Baram et al., 2019),
with components interacting and interplaying above
and beyond their individual pharmacological activity
(Ben-Shabat et al., 1998; Rather et al., 2013; Russo,
2011). This dramatically influences the oleoresin’s over-
all therapeutic effects far beyond that of dronabinol,
dependent on ‘complex interaction between molecules
and multiple targets’ (Atakan, 2012; Baker et al., 2000;
Baram et al., 2019; Russo, 2011) – a phenomenon
which is typical of herbal medicines (Rather et al.,
2013), called ‘cooperative effect’ or ‘entourage effect’
(Ben-Shabat et al., 1998; O~
na and Bouso, 2019). This
entourage effect results in C. sativa drugs binding
to different neuronal targets, an effect in turn called
‘polypharmacology’ (Gertsch, 2011; O~
na and Bouso,
2019).
In other words, ‘cannabis resin’ in IDCC as well as
folk language, relates to a single concept: the sum of all
ingredients contained in the material separated from
the glands of the epidermal capitate trichomes from
C. sativa plants. In Water is not H
2
O, Weisberg
(2006) warns that there are not always ‘a straightfor-
ward connection between scientific kinds and the nat-
ural kinds recognised by ordinary language users’
(337). Similarly it can be stated that resin is not THC,
refraining from amalgamating ‘cannabis resin’ with
THC/dronabinol (or any other single cannabinoid
or simplified composition) as an epistemological
precondition.
Defining extracts. A changing nomenclature at the
level of the IDCC. ‘Extracts and tinctures of cannabis’,
although present in the Schedules of C61 since its
inception (UN, 1961: 239) are nowhere defined in the
Treaty. No additional information is provided in the
Commentary. To document the ECDD assessment of
that particular category of Cannabis products, the
WHO tasked five teams of authors to draft reports
on, respectively, the chemistry, pharmacology, toxicol-
ogy, therapeutic use, and epidemiology of the products
(Krawitz et al., 2018: 17–22). The five documents result
in different understandings of the products covered
(or not) by this category, as presented in Table 3.
The word ‘extraction’ derives from Latin extraho/
extrahere, formed by the lemmas ex- (‘out of’) and
trah&
o(‘to pull’, ‘raw’, ‘drag’), meaning together: to
withdraw, drag-out, remove. Popular meaning covered
by the word ‘extraction’ is often that of a process
consisting in ‘the separation of a substance from a
matrix’ (Wikipedia, s.d). Separation is defined in the
Encyclopedia of Separation Sciences as a ‘process of
C71 IIa
C61 IVb
C61 Ib
tetrahydrocannabinol
delta-6a(10a) delta-6a(7) delta-7 delta-8 delta-9 delta-10 delta-9(11)
(+)-cis (+)-trans (–)-cis (–)-trans
C71 II C71 IC71 I
C61 I
C61 IIIc
Current
international
controls on THC
Changes
recommended
by the ECDD
Figure 2. Conflicting ontologies of dronabinol and THC: impact on international control. C61 I: Schedule I of the 1961 Single
Convention; C61 III: Schedule III of the 1961 Single Convention; C61 IV: Schedule IV of the 1961 Single Convention; C71 I: Schedule I
of the 1971 Convention; C71 II: Schedule II of the 1971 Convention; THC: tetrahydrocannabinol.
a
Only when ‘from synthetic origin’
(INCB, 2019: 8);
b
Only when obtained from C. sativa (INCB, 2019: 8);
c
Only for some preparations for medical use (ECDD, 2019: 55).
12 Drug Science, Policy and Law
any scale by which the components of a mixture are
separated from each other without substantial chemical
modification’ (Wilson, 2000: VIII); in this approach,
‘extraction’ is seen as a subset of ‘separation’, and
defined as ‘the process of moving one or more com-
pounds from one phase to another’. (Wilson, 2000:
1372). The concept of separation also seems to corre-
spond to all four methods of obtention used in C61 (see
Table 2). Products can also involve actual separation
without properly extracting: an illustration is the prep-
aration of traditional ‘dry’ hashish where trichome
heads are separated from the rest of the plant, but
where the glands’ external layers are not broken to lib-
erate (extract) the oleoresin contained in the cavity of
the trichome’s head.
Associated with ‘extraction’ in C61, the word tinc-
ture seems to denote with common understanding like-
wise with etymology. A tincture is indeed generally a
mixture, a dilution of a herbal matrix in alcohol. This
process increases the mass of the original matrix by
diluting it in a solvent, in apparent divergence from
the extracts produced by separation which inevitably
involve a reduction in the mass or volume of the final
material compared to the starting matrix.
In order for the ECDD (2018, 2019: 2–3, 34–36) to
review C. sativa, the WHO collected data, using the
nomenclature of C61 as terms of reference (Riboulet-
Zemouli and Krawitz, 2019: 4). This explains why
products known for their total absence of similarity
with dronabinol or other phytocannabinoids’ effects
were de facto included. ‘Hemp oil’ and ‘essential oil’
were indeed considered in the scope of the review
(WHO, 2016) aside products such as ‘CO
2
oil’,
‘butane hash oil, propane hash oil and solvent
extracts’, ‘wax’, ‘budder’, ‘live resin’, ‘shatter’, ‘taffy’,
‘distillate’, ‘pie crust/honeycomb’, ‘caviar’, ‘jelly hash’,
‘rosin’, ‘edibles’, ‘e-liquids’ (Cannazza and Citti, 2018b:
5–7). On the other hand, the ECDD (2019) noted that
‘some preparations with high D9-THC concentrations
are produced in such a way that they are not captured
within the definition of an extract or tincture’ (35).
The results of the ECDD assessments suggested edit-
ing the Schedules of the C61 to replace the terminology
extracts and tinctures with that of preparations. In the
Convention’s Article 1(s), preparations are defined as
any ‘mixture, solid or liquid, containing a drug’ and
subject to the same dispositions as the drug they con-
tain. Such a move makes the definition more accurate
by covering processes other than extraction/separation,
such as dilution (mixing, compounding, composition,
emulsion) or concentration (further mechanical or
chemical processing). It would also provide a consistent
division of C. sativa derivatives in three clear categories
able to match evidence-based definitions:
a. ‘Cannabis’ as pioC and other botanical material of
minor importance,
b. ‘Cannabis resin’ as the raw, unprocessed oleoresin
separated from EGTs,
c. ‘Preparations of cannabis’ as those products
obtained by further processing (a) or (b).
C. sativa derivatives, defined as drugs in the IDCC
(i.e. products whose ‘medical use continues to be indis-
pensable for the relief of pain and suffering’, UN, 1961:
Preamble), also correspond to the definition of a ‘med-
ical product’ laid out in BP (Medicine and Healthcare
products Regulatory Agency, 2017: I-22):
(a) Any substance or combination of substances pre-
sented as having properties for treating or preventing
disease in human beings and/or animals; or (b) any
substance or combination of substances that may be
used in or administered to human beings and/or ani-
mals with a view either to restoring, correcting or mod-
ifying physiological functions by exerting a pharmaco-
logical, immunological or metabolic action, or to
making a medical diagnosis.
This definition eventually captures several purposes of
use: the supervised therapeutic (a C. sativa product pre-
scribed by a physician), the conscious or unconscious
auto-therapeutic (self-medicated uses), but it also
encompasses so-called recreational purposes of use
(adult-use) as well as other purposes of consumption
such as the entheogenic (spiritual), nutraceutical, or
cosmetic. Even though pharmacopœias are only partial
standardisation references, thought mostly for the first
of these purposes of consumption, their contents can
provide useful guidance when mapping existing C.
sativa phytopharmaceuticals, for whatever their pur-
pose of use may be.
Historical nomenclatures of Cannabis in pharma-
copœias. C. sativa was considered a valuable drug (i.e.
essential drug) at the moment of the first International
conference on the unification of formulæ of potent med-
icaments held at Brussels in 1906, which resulted in an
Agreement seen as an early basis for the harmonisation
of pharmacopœias, and later for The International
Pharmacopœia (Ph.Int.) (WHO Expert Committee on
Specifications for Pharmaceutical Preparations, 2008:
6). Remarkably, C. sativa drugs were not included in
the first harmonised list because too little of their phy-
toconstituents were known (Power, 1903: 9). In
contrast, the second conference, and Agreement, of
September 1925 (International Agreement revising the
Agreement signed at Brussels, 29 November 1906, on
the Unification of Pharmacopoeial Formulas for Potent
Drugs, see: Seconde conf!
erence internationale pour
Riboulet-Zemouli 13
l’unification de la formule des m!
edicaments h!
eroı
¨ques,
1925a, 1926; Indian Med Gaz, 1932) did incorporate
three C. sativa-based ‘formulæ’ (Real Academia
Nacional de Medicina, 1930: 897–905; Seconde con-
f!
erence internationale pour l’unification de la formule
des m!
edicaments h!
eroı
¨ques, 1925b): Cannabis indicæ
herba (raw plant), Extractum cannabis indicæ and
Tinctura cannabis indicæ. The proceedings of the con-
ference show that prior to 1925, extractum cannabis
was found in the pharmacopœias of at least 10 coun-
tries (detailed in Table 4), and that Cannabis tincturæ
were present in very diverse formulations in all coun-
tries reviewed except in the Austrian, Belgian, and
Dutch pharmacopœias (General Council of Medical
Education and Registration of the United Kingdom,
1914; Seconde conf!
erence internationale pour l’unifica-
tion de la formule des m!
edicaments h!
eroı
¨ques, 1925a,
1926). After the entry into force of the Agreement in
1929, monographs of internationally standardised for-
mulations were progressively included in most national
pharmacopœias. While the 1865 edition of the Spanish
pharmacopœia only included ‘Ca~
namo – Cannabis
sativa L.’ as a crude drug, pointing at the seeds as the
preferred material for formulations (Real Academia de
Medicina de Madrid, 1865: 25), the 1930 revision har-
monises on the Agreement’s standard by adding
extractum (Real Academia Nacional de Medicina,
1930: 335) and tincturæ (Real Academia Nacional de
Medicina, 1930: 857). In the UK, the British
Pharmacopœia Commission followed in 1932, although
with some changes (Cartwright, 2015: 50–51; Indian
Med Gaz, 1932). It is safe to assume that C61 partially
inherited this nomenclature.
Conversely, in the 1950s, the body within the recent-
ly created WHO with a similar mandate to that of the
ECDD today (Danenberg et al., 2013) stated that ‘there
is no justification for the medical use of cannabis prep-
arations’ (in 1952 and 1953), adding that ‘there should
also be extension of the effort towards the abolition of
cannabis from all legitimate medical practice’ (in 1954),
and that ‘Cannabis and its preparations are practically
obsolete and there is no justification for their medical
use’ in 1960 (Riboulet-Zemouli, 2018: 37–39). The
records of their meetings on Cannabis feature cherry-
picked documentation, and no trace of methodology
seems to have been used to reach these conclusions.
After receiving the first draft of C61, ‘the Committee
was pleased to note the decision ...to place cannabis
drugs together with diacetylmorphine (heroin) ...in the
list of prohibited drugs’ although it seems that such
decision had not been consulted with them as, in the
next paragraph, the Experts ‘expressed the view that
[they] would welcome an opportunity to consider,
and give advice on, substances that might be placed
in that schedule’ (WHO Expert Committee on Drugs
Liable to Produce Addiction, 1956: 3–4). Once the
Convention was in force, they continued in 1965, and
again in 1968, to declare that ‘medical need’ for C.
sativa drugs ‘no longer exist’. The placement of C.
sativa-related medicines in the Schedules of C61
which involve the most stringent controls, obviously
‘with insufficient scientific support to substantiate
those classifications’ (Committee on Economic, Social
and Cultural Rights, 2020: 15), but also the subsequent
withdrawal of Cannabis drugs from pharmacopœias
and pharmacy shelves, was undoubtedly influenced by
these statements.
Monographs on Cannabis disappeared from BP in
1932, and 10 years later from USP (Giancaspro et al.,
2016). Nonetheless, the UN (1958: 111) still reports, in
the 1950s, C. sativa pharmaceuticals in at least 16 legal-
ly binding pharmacopœias, on all continents. With the
entry into force of the C61 in 1964, these phytophar-
maceuticals started to disappear from pharmacopœias
as well as from mainstream medical practice, following
the gradual decline in the use of phytomedicines in
modern healthcare along the latter 20th century (see
Table 4, and Chandra et al., 2017).
At the time of writing this article, C. sativa phyto-
pharmaceuticals were almost totally absent from phar-
macopœias worldwide, even in jurisdictions where it
was allowed for medical prescription. In Asia, Ch.P
and JP include monographs of C. sativa fruits (raising
questions with regards to pioCs), while in North
America, USP has two monographs on dronabinol.
In Europe, German Commission E’s monographs
(DAB) and Swiss Pharmacopœia reincluded in 2019
monographs of Cannabis parthenocarpic infructescen-
ces (although titled ‘Cannabis flos’ [flower], see Swiss
Agency for Therapeutic Products, 2019: 115, 263–266).
Besides the mere presence of Cannabis or not in phar-
macopœias, the way medical products of herbal origin
are addressed and classified provides useful guidance
on how to approach C. sativa derivatives.
Pharmacopœial nomenclatures of phytopharmaceuti-
cals. All current pharmacopœias reviewed contemplated
phytopharmaceuticals, in individual monographs, in
general notices/appendices, or both. One pattern of
categorification for plant-based medication was found
recurrent from the 1865 edition of the Spanish pharma-
copœia onwards to the latest edition of European
Pharmacopœia (Ph.Eur). It is based on the observation
of the physical consistency of phytopharmaceuticals,
divided between:
solid/dry (extracta sicca),
semisolid/soft (extracta spissa) or
fluid/liquid extracts (extracta fluida).
14 Drug Science, Policy and Law
The latest editions of Argentina’s, Brazil’s, Ph.Eur.,
Russia’s State Pharmacopœia of the Russian
Federation (SPRF), and Spain’s pharmacopœia consis-
tently use this model. Others like Herbal
Pharmacopœia of Mexico (FHEUM), Indian
Pharmacopœia (IP), JP, and French Pharmacopœia
(Ph.Fr.) occasionally refer to these terms without sys-
tematising them. Most pharmacopœias consider tinc-
tures (tincturæ) distinct from extracta, while others
such as Argentinian Pharmacopœia and Ph.Eur. con-
sider tincturæ a subset of extracta fluida.
Pharmacopœial monographs however never mention
that other alcohols like glycerol, propylene glycol, or
polyethylene glycol are increasingly replacing ethanol
in the preparations of tincturæ (Schulz et al., 2004: 11).
Ph.Eur. separates oleoresina (oleoresins), defined as
‘semi-solid extracts composed of a resin in solution in
an essential and/or fatty oil ...obtained by evaporation
of the solvent(s)’, from extracta spissa that it defines as
‘semi-solid preparations obtained by evaporation or
partial evaporation of the solvent’.
In the 2000s, new models of classification were intro-
duced to complement the traditional one (Gaedcke and
Steinhoff, 2003: 4–7, 26). One of these newer models
divides phytopharmaceuticals between drugs that are
genuine extractable matter, termed ‘native extracts’,
and drugs that contain added ingredients (whether
active compounds or excipients) with regard to the
starting botanical material, termed ‘non-native’
(European Directorate for the Quality of Medicines,
2016: 6519, 6521; Gaedcke and Steinhoff, 2003: 6–7).
In 1988, Menßen (Gaedcke and Steinhoff, 2003: 26–27)
proposed to distinguish between ‘primary extracts’ and
‘refined extracts’ as the refinement process (also
referred to as purification or enrichment) produces
phytopharmaceuticals with a reduced spectrum of
constituents.
Another complementary model pushed forward by
Ph.Eur. is that of ordering phytopharmaceuticals
according to content standardisation criteria, distin-
guishing them according to the level of precise knowl-
edge of their composition in active compounds.
According to this model rapidly expanding, phytophar-
maceuticals are either ‘standardised extracts’, ‘quanti-
fied extracts’, or ‘other extracts’ (European Directorate
for the Quality of Medicines, 2016: 25–26). Ph.Eur.
explains:
Standardised extracts are adjusted to a defined content
of one or more constituents with known therapeutic
activity. This is achieved by adjustment of the extract
with inert excipients or by blending batches of the
extract. Quantified extracts are adjusted to one or
more active markers, the content of which is controlled
within a limited, specified range. Adjustments are made
by blending batches of the extract. Other extracts are
not adjusted to a particular content of constituents.
(European Directorate for the Quality of Medicines,
2016: 6515–6516, 6519)
This latter standardisation-based distinction is current-
ly included in BP, DAB, Brazilian Pharmacopœia, Ph.
Eur., and Royal Spanish Pharmacopœia (RFE). Evans
(2009: 72) cites nabiximols (the generic name for a for-
mulation of dronabinol and cannabidiol (CBD), of
which a well known marketed example is SativexV
R) as
an example of standardised C. sativa drug.
Ch.P., FHEUM, FP, Romanian Pharmacopœia
(FR), IP, JP, Egyptian Pharmacopœia, Ph.Fr.,
Hellenic (Greek) Pharmacopœia, Polish
Pharmacopœia, SPRF, USP, and Pharmacopœia of
Vietnam (VP) adopted sui generis approaches, often
in complement to one of the above patterns. Ch.P
references none of the previous models: instead, it sep-
arates crude drugs from preparations, which are sub-
divided into 26 specific formulations (e.g. pills,
powders, granules, concentrated decoctions, plasters,
ointments, etc.). In the same spirit, JP regards ‘crude
drugs’ (including drugs of herbal, animal, or mineral
origin), only distinguishing between ‘whole’, ‘cut’, or
‘powdered’ crude drugs (Ministry of Health, Labour
and Welfare, 2016: 1, 5–6). It classifies crude drugs
simultaneously in eight subcategories: ‘extracts’ (corre-
sponding to both extracta sicca and spissa), ‘fluid
extracts’, ‘tinctures’, ‘spirits’, ‘infusions or decoctions’,
‘teabags’, ‘aromatic waters’, and ‘pills’ (Ministry of
Health, Labour and Welfare, 2016: 21–23). FHEUM
separates ‘vegetal drugs’, ‘triturated herbs’, ‘teas’, ‘tinc-
tures and extracts’, and ‘essential oils’ (Comisi!
on
Permanente de la Farmacopea de los Estados Unidos
Mexicanos, 2013: 7–8). IP distinguishes ‘crude herbs’
and ‘processed herbs’ (covering either intermediary or
traditional preparations), ‘botanical extracts’ which
includes fluid, powdered, and semisolid extracts, sepa-
rates the ‘tinctures’, and presents ‘herbal formulations’
as readily available products for consumers, and poten-
tially for non-medical uses (e.g. food supplement,
nutraceutical, cosmetic, see Indian Pharmacopoeia
Commission, 2018: 3725–3729). Numerous references
such as Ph.Eg, Ph.Indo, Ph.Pl, FR, and VP use long
lists of traditional formulations (e.g. elixirs, ointment,
potion, granulate, powder, suppository, syrups, etc.),
with a rationale mostly reliant on historical addition
of marketed formulations types rather than on the
intrinsic physical characteristics of the products. USP
makes mention of ‘herbals’, ‘crude products of plant
origin’, as well as ‘botanical-containing products’ with-
out further definition, nor consistent use throughout
the different pharmacopœial monographs. A different
detailed scheme of categorification was found in the
Riboulet-Zemouli 15
former USSR pharmacopœia (USSRSP, see Shikov
et al., 2014) in force until 2007. Phytopharmaceuticals
were distinguished between ‘medicinal plant’, ‘summar-
ised non-refined (or galenic) formulations’ (which
includes infusions, decoctions, tinctures, concentrated
extractions, and elixirs), ‘novo-galenic formulations’
(herbal material mixed with non-herbal ingredients),
‘combined phyto-preparations’ (mixtures of only
herbal ingredients), and ‘active pharmaceutical ingre-
dients’ (APIs).
Finally, among the non- or partially legally binding
pharmacopœias reviewed (Table 1), Ph.Int. did not
contemplate herbal medicines at all, while others such
as British Herbal Pharmacopœia, Ayurvedic
Pharmacopœia of India, USHP, and African Herbal
Pharmacopœia did not rely on any orderly meta-
category for phytopharmaceuticals.
Other kinds of medical products of herbal origin
were found in a number of pharmacopœias, particu-
larly those following Ph.Eur. standards. Some of
these eventually correspond to C. sativa-derived phyto-
pharmaceuticals, such as:
Essential oils, termed ætherolea (European
Directorate for the Quality of Medicines, 2016: 814–
815),
Teas, plantæ ad ptisanam, and instant herbal teas,
præparationes celeres ad ptisanam (European
Directorate for the Quality of Medicines, 2016: 820),
Products obtained from organisms with recombi-
nant deoxyribonucleic acid (rDNA) biotechnologies,
Table 4. Presence of C. sativa pharmaceuticals in pharmacopœias, 1925-2020; non-exhaustive.
\\ Cannabis Cannabis extractum Cannabis tincturæ Cannabis flos (fructus) Cannabis fructus (semen) Dronabinol
1925 Undocumented Austria
a,c
Belgium
a,c
France
a,c
Hungary
a,c
Italy
a,c
Japan
a,c
Mexico
e
Netherlands
a,c
Switzerland
a,c
UK
a
USA
a,b
(extractum fluidum)
France
b,c
Hungary
b,c
Italy
b,c
Japan
b
Switzerland
b,c
UK
b
USA
b
Mexico
e
Mexico
f
n/a
1958 Argentina
d
Belgium
d
Brazil
d
China
d
Egypt
d
Finland
d
France
d
India
d
Italy
d
Netherlands
d
Portugal
d
Romania
d
Spain
d
Switzerland
d
USSR
d
Venezuela
d
Undocumented Undocumented Undocumented Undocumented n/a
2020 Undocumented Undocumented Undocumented Germany
g
Netherlands
h
Ph.Helv
i
ChP
j
JP
k
USP
l
a
Seconde conf!
erence internationale..., 1925a: 48;
b
Seconde conf!
erence internationale..., 1925a: 49;
c
Seconde conf!
erence internationale..., 1926;
d
United Nations, 1958: 111;
e
Uni!
on Nacional de Farmac!
euticos Cient
!
ıfico-Cooperativa, 1925: 406–407;
f
Uni!
on Nacional de Farmac!
euticos Cient
!
ıfico-
Cooperativa, 1925: 163;
g
Swiss Agency for Therapeutic Products, 2019: 115;
h
Ministerie van Volksgezondheid Welzijn en Sport, 2019;
i
Swiss Agency
for Therapeutic Products, 2019: 263–266;
j
Chinese Pharmacopœia Commission, 2015: 93;
k
Ministry of Health, Labour and Welfare, 2016: 1876;
l
United States Pharmacopeial Convention, 2019.
16 Drug Science, Policy and Law
Table 5. Ontological conflicts in the pharmacopœial classification of phytopharmaceuticals: comparison between different models and the classification of C. sativa phytopharmaceuticals
in international law.
Riboulet-Zemouli 17
producta ab arte ADN recombinandorum (European
Directorate for the Quality of Medicines, 2016:
6526–6528)
Products of fermentation, producta ab fermentatione
(European Directorate for the Quality of Medicines,
2016: 5909–5910),
Vegetable fatty oils, olea herbaria (European
Directorate for the Quality of Medicines, 2016:
848–850).
European regulatory nomenclature of phytopharma-
ceuticals. Alternatively, the European Union (EU) in
its Community code relating to medicinal products for
human use (European Commission, 2001) considers a
simplified approach where all phytopharmaceuticals
are termed ‘herbal medicinal products’ and subdivided
between substances and preparations:
Herbal medicinal products: Any medicinal product,
exclusively containing as active ingredients one or
more herbal substances or one or more herbal prepa-
rations, or one or more such herbal substances in com-
bination with one or more such herbal preparations,
Herbal substances: All mainly whole, fragmented or cut
plants, plant parts, algae, fungi, lichen in an unpro-
cessed, usually dried, form, but sometimes fresh.
Certain exudates that have not been subjected to a
specific treatment are also considered to be herbal sub-
stances. Herbal substances are precisely defined by the
plant part used and the botanical name according to
the binomial system (genus, species, variety and
author),
Herbal preparations: Preparations obtained by subject-
ing herbal substances to treatments such as extraction,
distillation, expression, fractionation, purification, con-
centration or fermentation. These include comminuted
or powdered herbal substances, tinctures, extracts,
essential oils, expressed juices and processed exudates.
Even so, this model is not particularly relied upon in
pharmacopœias, as shown in Table 5.
Nomenclature of Traditional & Complementary
Medicine (T&CM) by the WHO. Unrelated to
C. sativa, to the ECDD and to its mandate under the
IDCC, the T&CM unit of WHO classifies phytophar-
maceuticals according to their pharmacological prop-
erties, while staying consistent with the processes of
obtention that are often firmly embedded into tradi-
tional processing methods (Abbott, 2014; Bellakhdar,
1997; Kutesa, 2018; World Health Organisation, 2011).
Their approach distinguishes phytopharmaceuticals
according to processing stages (World Health
Organisation, 2011: 129–130):
Herbal medicines include herbs, herbal materials,
herbal preparations and finished herbal products:
Herbs include crude plant material such as leaves,
flowers, fruit, seed, stems, wood, bark, roots, rhi-
zomes or other plant parts, which may be entire,
fragmented or powdered.
Herbal materials are either whole plants or parts of
medicinal plants in the crude state. They include
herbs, fresh juices, gums, fixed oils, essential oils,
resins and dry powders of herbs. In some countries,
these materials may be processed by various local
procedures, such as steaming, roasting, or stir-
baking with honey, alcoholic beverages or other
materials.
Herbal preparations are the basis for finished herbal
products and may include comminuted or powdered
herbal materials, or extracts, tinctures and fatty oils
of herbal materials. They are produced by extraction,
fractionation, purification, concentration, or other
physical or biological processes. They also include
preparations made by steeping or heating herbal
materials in alcoholic beverages and/or honey, or in
other materials.
Finished herbal products consist of herbal prepara-
tions made from one or more herbs. If more than
one herb is used, the term mixture herbal product
can also be used. Finished herbal products and mix-
ture herbal products may contain excipients in addi-
tion to the active ingredients finished products or
mixture products to which chemically defined active
substances have been added, including synthetic
compounds and/or isolated constituents from
herbal materials, are not considered to be herbal.
The definition of ‘herbs’ provided by WHO seems to
correspond to EU’s ‘herbal substance’, while EU’s
‘herbal preparations’ include WHO’s ‘herbal materi-
als’, ‘herbal preparations’, and ‘finished herbal prod-
ucts’ (Table 5). The T&CM classification proposed by
WHO seems more detailed than EU’s, even though
some products could fall under the scope of two of
the proposed categories. For instance, a product can
match both ‘stir-baking with honey, alcoholic bever-
ages or other materials’ (herbal materials) and ‘steeping
or heating herbal materials in alcoholic beverages and/
or honey, or in other materials’ (herbal preparations).
Regrettably, the WHO T&CM model has not been
more followed in pharmacopœias than EU’s.
Often, the same wording is used to encompass dif-
ferent definitions. BP adopted a dichotomous approach
to phytopharmaceuticals: on the one hand, it fully fol-
lows Ph.Eur. considering ‘herbal drugs’ as non-
18 Drug Science, Policy and Law
processed material while it labels processed herbs as
‘herbal drug extracts’ and ‘herbal drug preparation’
for the further homogenised – and eventually standar-
dised – phytopharmaceuticals (Medicines and
Healthcare products Regulatory Agency, 2017: I-17,
VII-A837). On the other hand, BP maintains in parallel
a monograph for what is called ‘processed herbal
drugs’, corresponding to those phytopharmaceuticals
obtained via traditional processing methods’
(Medicines and Healthcare products Regulatory
Agency, 2017: IV-43–49).
Defining an upper limit to phytomedicine. The only
consensus that seems to be shared is that of excluding
from the category of phytopharmaceutical some fin-
ished products that, however, originate from plant
material: those herbal derivatives to which non-herbal
active compounds have been added. BP (Medicines and
Healthcare products Regulatory Agency, 2017: I-22),
in a similar fashion to that of DAB and RFE, the
EU with the supra category ‘herbal medicinal products’
or the WHO T&CM with ‘herbal medicines’, groups as
phytopharmaceuticals only those drugs:
exclusively containing as active ingredients one or
more herbal drugs,
exclusively containing as active ingredients one or
more herbal drug preparations,
exclusively containing as active ingredients one or
more such herbal drugs in combination with one
or more such herbal drug preparations.
WHO (2011) specifies that ‘products to which chem-
ically defined active substances have been added,
including synthetic compounds and/or isolated constit-
uents from herbal materials, are not considered to be
herbal’ (130). Consequently, herbal-based products
containing non-herbal active compounds, or contain-
ing non-herbal compounds as excipients, are not
regarded as phytotherapy. Gaedcke and Steinhoff
(2003: 1) explain that because phytopharmaceuticals
‘are always mixtures of a number of substances’, a
medicinal plant (entirely or by parts) is considered as
a single active ingredient regardless of the composition
(Gaedcke and Steinhoff, 2003; Rather et al., 2013).
Besides their multiple constituents, phytopharmaceuti-
cals, working in a synergical ‘entourage’ fashion, are
viewed as one single substance (Atakan, 2012).
Also, fully isolated compounds or ‘refined extracts’
(Gaedcke and Steinhoff, 2003: 2–7) obtained from
botanical material are not regarded as phytopharma-
ceuticals. These are rather considered as common APIs
for the formulation of conventional pharmaceutical
preparations. As an example, in the USSRSP model
(Table 5) ‘combined phyto-preparations’ would be
considered phytopharmaceuticals, while ‘standardised
extracts’ and ‘novo-galenic formulations’ would fall
out of this category.
‘Others’: Non-phyto cannabinoid
pharmaceuticals, non-Cannabis cannabinoid
phytopharmaceuticals, etc
The uppermost limitation of the scope of phytomedi-
cine on which pharmacopœias rely is not complete, as it
would not exclude one particular (and diverse) corpus
of compounds commonly referred to as synthetic can-
nabinoids. This broad category encompasses some ‘syn-
thetic’ molecules that can be derived from plant
material, without being mixed with non-herbal com-
pounds; hence, pharmacopœial models currently de
facto embrace some ‘synthetic cannabinoids’ as phyto-
medicines, which is problematic.
Alonso (1998) explains that botanical materials can,
in addition to their use as a source of active com-
pounds, be utilised as non-active starting materials in
laboratory processes in order to obtain compounds
that were not genuinely present in the plant. Halfway
between natural compounds and molecules designed
fully in vitro, these drugs have been referred to as semi-
naturals (Feher and Schmidt, 2003) or more recently as
semisynthetics (Cragg and Newman, 2013; Jones et al.,
2006). Mathur and Hoskins (2017) describe them as
‘generally produced by transforming starting materials
from natural sources into final products via chemical
reactions’, clarifying that these reactions consist in the
‘rearrangement of chemical entities or structural iso-
mers of naturally occurring products in order to gen-
erate new molecules’. Chrispeels and Sadava (1994)
mention the example of saponins which are structurally
‘so much like human steroids that saponins are used as
the starting material for synthetizing steroids used for
making birth control pills’ (136).
At the API level, in order to explore the implications
for C. sativa medicines, a safe analogy can be estab-
lished with the extensively studied Papaver somniferum
L. from which originate naturally occurring opioids
(i.e. opiates). Six primary natural secondary metabo-
lites are biosynthesised in P. somniferum: morphine,
codeine, thebaine, papaverine, noscapine, and narceine.
Semisynthetic opioids, in comparison, are those
obtained by human intervention over the chemical
structure of these compounds: diacetylmorphine
(heroin) is a well-known example of semisynthetic
opioid obtained from morphine (Novak et al., 2000;
Solimini et al., 2018); oxycodone is a semisynthetic
derivative of thebaine (Cortazzo et al., 2013: 502;
Elkader and Sproule, 2005). In what concerns
C. sativa, semisynthetics consist of derivatives from
naturally obtained phytocannabinoid molecules
Riboulet-Zemouli 19
(Fahrenholtz et al., 1967), having undergone modifica-
tions of some of their pharmacophores with significant
binding affinity to brain receptors (Bow and Rimoldi,
2016; Razdan and Zitko, 1969; Shevyrin et al., 2016). It
is generally accepted that structural modifications cor-
responding to the natural pathways of cannabinoids
biosynthesis and degradation within the C. sativa
plant (e.g. decarboxylation, see Baram et al., 2019;
Caspi et al., 2017; Hanu%
s et al., 2016) are not consid-
ered products of semisynthesis. However, the product
of a semisynthesis can be another, different naturally
occurring compound (as in the example of human ste-
roids mentioned). For instance, the process to trans-
form cannabidiol (CBD) into dronabinol, because it
does not occur in vivo (not corresponding to the natu-
ral biosynthetic pathways of C. sativa, see Caspi et al.,
2017) but is possible in vitro (ECDD, 2018: 13; Merrick
et al., 2016), is considered a semisynthesis.
Importantly, semisynthetic compounds should not
be confused with the second subset of synthetic canna-
binoids, the naturally occurring ones obtained only by
synthesis in vitro. In the case of opioids, morphine can
either be extracted from P. somniferum or created by
full chemical synthesis (Gates and Tschudi, 1956;
Mechoulam and Hanu%
s, 2000; Novak et al., 2000).
The same goes with molecules structurally identical to
naturally occurring phytocannabinoids such as drona-
binol or cannabidiol (CBD is the INN of (–)-CBD,
whether natural or synthetic) that are designed in
vitro without involving initial plant material (Adam
Ametovski and Lupton, 2019; Mechoulam and
Gaoni, 1965; Petrzilka et al., 1967; Razdan et al.,
1974; Trost and Dogra, 2007). Analytically indistin-
guishable, fully synthesised in vitro phytocannabinoids
and naturally obtained in vivo phytocannabinoids were
not distinguished by the ECDD which considers them
in all points pharmacologically identical (ECDD, 2019:
54–55; Riboulet-Zemouli and Krawitz, 2019).
Yet another class of compounds termed ‘synthetic
cannabinoids’ is that of synthetic analogues, also
(mostly) obtained via laboratory synthesis without
C. sativa botanical ingredients. The resulting substan-
ces, however, are not phytocannabinoids found in the
environment but novel compounds, mimicking their
pharmacological effects without being derived from,
nor directly relatable to them. Firman et al. (2019)
find that out of the ‘223 compounds identified,
a mere ten ...bear structural relation to THC’.
Examples of synthetic cannabinoid analogues are nabi-
lone (Blanchard and Ryan, 1977a, 1977b; Flemming
et al., 2007: 22–23) or the HU- and JWH-type compo-
nents found in ‘spice’ (National Institute on Drug
Abuse, 2018; Seely et al., 2012), while fentanyl and
methadone are well-known synthetic opioid analogues.
Synthetic cannabinoid analogues have been exten-
sively studied, resulting in the invention of a wide
array of substances. A proposal of a classification
system for cannabinoids (Shevyrin et al., 2016) found
few compounds structurally related to C. sativa phyto-
cannabinoids – HU-210 and dexanabinol, for instance
– and termed them ‘classical cannabinoids’. Shevyrin
et al. identified numerous other groups of synthetic
compounds with no direct structural relationship to
the plant’s phytoconstituents: nonclassical and hybrid
synthetic cannabinoid analogues, naphthoylindoles,
phenylacetylindoles, benzoylindoles, naphthylmethy-
lindoles, diarylpyrazoles, 3-naphthoylpyrroles, synthet-
ic endocannabinoid analogues, etc. To distinguish these
molecules from naturally occurring phytocannabinoids
obtained in vitro and from semisynthetics, the expres-
sion ‘synthetic analogues’ (Biernat, 2018; European
Monitoring Centre for Drugs and Drug Addiction,
2017; Flemming et al., 2007; Luo et al., 2019; Pop,
1999; Shevyrin et al., 2016; Trost and Dogra, 2007)
has been proposed. However, the confusing use of the
phraseology ‘synthetic cannabinoids’ continues (Bonn-
Miller et al., 2018; Carvalho et al., 2017; ECDD, 2019:
19–25; Fattore and Fratta, 2011; National Institute on
Drug Abuse, 2018; Pop, 1999; Reekie et al., 2018; Seely
et al., 2012). Some authors placed ‘semisynthetics’ as a
subset of ‘analogues’ (Bow and Rimoldi, 2016) making
the case of the inexistence of both semisynthetics and
analogues in a natural environment – the only differ-
ence being the use of botanical C. sativa material to
obtain the former, not the latter. Nevertheless, some
compounds existing in nature can be obtained by the
semisynthesis process of chemically altering starting
botanical material containing phytocannabinoids,
when these alterations are different from those of the
natural biosynthetic pathways of the plant. This is illus-
trated by cases such as the transformation of CBD into
dronabinol: both compounds are found in nature, but
such transformation has not been reported in natural
environments – there is limited evidence that CBD can
be processed into some compounds defined thus far as
metabolites of dronabinol (Huestis, 2007) in an in vitro
environment simulating gastric acids (Bonn-Miller
et al., 2017; Grotenhermen et al., 2017; Merrick
et al., 2016; White, 2018:10–11), but no confirmation
of conversion in animal or human models has been
reported (Crippa et al., 2020; ECDD, 2018: 13;
Grotenhermen et al., 2017; White, 2018: 10–11; Wray
et al., 2017).
The criterion of similarity in the molecular structure
of compounds is not always related to the final phar-
macological effect, organoleptic properties, the consis-
tency of the product, or to other characteristics, and it
is not yet entirely mapped at this time. Hence, if that
variable is discarded, a double dichotomous distinction
20 Drug Science, Policy and Law
stands out: occurrence in nature versus novelty of the
compound; obtention from the transformation of
C. sativa material versus that of other material. This
allows for cannabinoid APIs to be arranged in four
meta-categories:
In vivo phytocannabinoids: naturally occurring com-
pounds, derived:
- from C. sativa plant material (e.g. dronabinol pre-
sent in EGTs),
- from other plant genera (e.g. (!)-cis-perrottetinene
present in some plants of the genus Radula; see
Gertsch, 2018),
In vitro phytocannabinoids: the same naturally occur-
ring compounds as above, obtained by full ‘chemical
synthesis’,
Synthetic cannabinoid analogues (e.g. nabilone, HU-
210, dexanabinol): non-naturally occurring com-
pounds, obtained by full chemical synthesis,
Semisynthetic cannabinoids:
- Semisynthetic phytocannabinoids, i.e. naturally
occurring compounds, derived from C. sativa
plant material, obtained by partial chemical syn-
thesis different than those of the plant’s natural
phytocannabinoid biosynthetic pathways (e.g.
CBD transformed into dronabinol),
- Semisynthetic cannabinoid analogues, i.e. non-
naturally occurring compounds, derived from
C. sativa plant material, obtained by partial chem-
ical synthesis (e.g. the (þ)-enantiomer of CBD, not
found in natural environments).
An additional layer of complexity is brought by
modern biotechnologies and also relates to the
method of obtention used (Sirikantaramas et al.,
2007). Serious questioning of the traditional
Aristotelian breach between nature and artefacts
(Bhushan, 2006; Cragg and Newman, 2013; Feher
and Schmidt, 2003; Schummer, 2002) arise while
innovations such as gene editing, genome mining, and
combinatorial biosynthesis (e.g. rDNA) thrive. What
were thought to be ‘fundamental differences between
combinatorial synthesis and biosynthesis’ (Feher and
Schmidt, 2003) are being overcome, also for C. sativa.
Already, cannabinoid compounds, just like opioids
(Galanie et al., 2015) can be obtained from the design
of heterologous expression of biosynthetic pathways,
such as in genetically modified (GM) organisms
(Carvalho et al., 2017; Luo et al., 2019; Siddiqui
et al., 2012; Sirikantaramas et al., 2007). Both naturally
occurring and novel cannabinoids were obtained by
Luo et al. (2019) from genetically engineered yeasts, a
feat achieved by introducing selected C. sativa genes in
Saccharomyces cerevisiae using rDNA technologies.
Different classes of GM organisms, including GM
C. sativa plants (Berahmand et al., 2016; Feeney and
Punja, 2003; Sayre et al., 2019) are currently being
engineered to produce different yields or ratios of var-
ious cannabinoid compounds. All the four meta-
categories of cannabinoids listed above can, or will
likely soon, be obtainable via genetically engineered
organisms, complicating the distinction between the
natural and the artificial. This is echoed in pharma-
copœial nomenclatures, increasingly tending to distin-
guish drugs obtained via organisms having been
genetically recombined, adding them special require-
ments such as PhEur (monograph 0784).
Noteworthily, GM in C. sativa can also be unrelated
to the biosynthetic mechanisms of the plant. GM can
indeed be limited to specific characters, such as resis-
tance to pests, salinity and drought, or tolerance
to herbicides or insecticides (Catacora-Vargas, 2011:
10–11, 85–86) which in theory do not alter, or affect
only indirectly, the production of phytocannabinoids
within EGTs. A distinction is therefore needed between
a GM which alters the plant’s biosynthetic pathways
and a GM which does not.
Finally, if this was not a complex enough panorama,
cannabinoids are naturally produced by other living
organisms. Beyond Cannabis, other plant genera natu-
rally biosynthesise cannabinoid compounds (Gertsch,
2018; Hanu%
s et al., 2016). Beyond the Plantae kingdom,
Homo sapiens also produce ‘endocannabinoids’
(Hanu%
s et al., 2016; Huestis, 2007; Pacioni et al., 2015;
Shevyrin et al., 2016) and a series of living organisms
(Hanu%
s et al., 2016) are found to produce their own
endogenous cannabinoid substances, similar or not to
those known to be biosynthesised in H. sapiens or C.
sativa (e.g. anandamide is naturally secreted in humans
and in black truffle fungi, see Pacioni et al., 2015).
Discussion
This study is the first to examine the interrelation
between different nomenclatures of natural and artifi-
cial drugs containing cannabinoids, and between these
and the products available nowadays. The study finds
mostly confusing terminology, where four salient trou-
bling aspects (which sometimes overlap) recur: terms
comprising various distinct ‘relata’ (a relatum is the
thing or entity to which a word relates and which it
designates); terms whose relata vary according to con-
text, time, or geography; terms inherited from socially
constructed, utilitarian, non-science-based language;
terms overly specific to a defined field of scientific
research.
Terminologies used for synthetic cannabinoids rep-
resent useful frameworks for research but are limited in
their potential applications outside of the biochemical
sectors. Nomenclatures used in international law rely
Riboulet-Zemouli 21
on broad, utilitarian categories that expand, beyond
the products targeted for control, to other similar
peripheral products, even if they are not relevant to
drug control criteria. This is the case for pioC, con-
trolled as ‘fruiting tops’ alongside ‘flowering tops’
from either male, female, hermaphrodite, and monoe-
cious plants, although they might contain insignificant
amounts of phytocannabinoids. It is also the case for
dronabinol, the ‘main psychoactive substance in the
cannabis plant’ (ECDD, 2019: 45): while only dronabi-
nol, the (–)-trans enantiomer of the delta-9 isomer of
THC, is a target for public health scrutiny, the three
other stereochemical variants, as well as the six other
delta isomers of THC are grouped with dronabinol as
tetrahydrocannabinols – as a collateral damage –
besides the fact that the ECDD (2018) recognised dro-
nabinol ‘is the only [stereochemical variant] that occurs
naturally in the cannabis plant’ and that ‘the limited
information on the pharmacology of [its] stereochemi-
cal variants ...suggests that they have little activity’
(33–34). It conflicts, also, with the statement that
‘there are no reports that the THC isomers ...induce
physical dependence, or that they are being abused or
are likely to be abused so as to constitute a public
health or social problem’ and ‘there are no reported
medical or veterinary uses of these isomers’ (ECDD,
2019: 49).
Way forward: A non-conflicting framework for the
nomenclature of ‘cannabis’ products
Besides approximations and scientific inconsistencies,
the four-tiered ontology used in C61 is consistent. It
can be interpreted as an incremental and mutually
exclusive scheme composed of: ‘cannabis plant’ (the
living or freshly harvested plant, staminate and pistil-
late iterations), ‘cannabis’ (pioCs and inflorescences of
the former), ‘cannabis resin’ (material separated from
EGT found on one of the former), and ‘preparations’
(or ‘extracts and tinctures’ any processed drug derived
from either one of the former). Consistency is reached
at the expense of clear relata, at least concerning the
last three categories, which include everything other
than what is in the previous category. Such a catego-
risation does not carry any practical pharmaceutical
information, since it aggregates products of all kinds.
It also leaves room for conflicting interpretations: some
products are virtually included within this ontological
class (because they are prepared from ‘cannabis’ or
‘cannabis plant’) even though they do not comply
with the criteria for international drug control (e.g.
essential oils, or non-medical cosmetics containing
CBD). The IDCC corrects this ontological conflict
applying a different, transversal criterion: that of the
purpose of use (Riboulet-Zemouli, 2019). As C. sativa
products, and their methods of obtention, become
increasingly more diverse, the four-tiered categorifica-
tion of C61 will continue to lose relevance.
While the first two categories, ‘cannabis plant’ and
‘cannabis’ (starting materials, see Table 2) can be easily
further defined by modern botanical research, elements
are missing to distinguish products within the last two
categories, ‘cannabis resin’ and ‘preparations’ (see
Table 5). The uniquely complex phytochemical compo-
sition of C. sativa, the variability in patterns and routes
of administration, and the still uncaptured phytophar-
macological mechanisms of action of C. sativa products
render insufficient the analytical identification of the
composition in phytocannabinoids. It suggests the
need for complementary elements of differentiation
between products. This study finds that a consideration
of the ‘methods of obtention’ (i.e. transformation,
processing, and formulation of the products) in addi-
tion to the very composition of the final product, might
be insightful. Alas, the four terms present in the C61
treaty to describe obtention processes (‘production’,
‘manufacture’, ‘separation’, and ‘extraction’) are used
interchangeably (Table 2) and do not convey additional
information about the pharmacognosy of the drugs. In
popular culture, the most solid distinction criterion –
which relates to the methods of obtention – is a dichot-
omy discriminating the addition of foreign matter (sol-
vent extraction) to the thermomechanical processing of
the plant’s EGTs (solventless extraction). Such addi-
tional determinant, complementing the four-tiered
basis provided by C61, could help tweak a method of
differentiation between products.
The criterion relying on the addition or not of elu-
ents (i.e. solvents), although useful, does not provide
full coverage of the potential products obtained: within
the two subgroups, variations in techniques and result-
ing products often happen (see supplementary
Appendix III). Lu and Luthria (2014: 5, 12) inform
that ‘postharvest storage and processing (such as grind-
ing and drying) influence the quantity of phenolic phy-
tochemicals’ and of phytocannabinoids. Concerning
the processing methods based on the addition of for-
eign matter, all basic and widely used techniques to
extract and isolate natural biocompounds are reported
for obtaining C. sativa derivatives (supplementary
Appendix III provides details of these techniques).
A series of other secondary methods of extraction
exist, likely to be increasingly used in the future.
Minor changes in extraction parameters have shown
to result in significant chemical and pharmacological
differences between final products (for instance canna-
binoidless essential oils and high-dronabinol ‘concen-
trates’ which can both be obtained by distillation).
Solventless extraction or processing techniques,
although less numerous, also showed substantial
22 Drug Science, Policy and Law
variability; additionally, many of these are embedded
in traditional folk knowledge and intangible assets, still
fully or partially undocumented (Abbott, 2014;
Abdool, 2013; Bellakhdar, 1997: 232–234; Clarke,
2007; Kutesa, 2018). Variables such as the size of
filter pores, the amount of pressure exerted, the tem-
perature, or the type of movement applied are also
determinative in characterising the final product
(Devi and Khanam, 2018; Hamayun and Shinwari,
2004; Upton et al., 2014; supplementary Appendix
IV). With or without eluent, all extraction or process-
ing techniques report different thresholds of acid or
decarboxylated phytocannabinoids depending on trivi-
al variations in parameters along the process.
Laying out in detail the processes of obtention of
drugs is a core objective of pharmacopœias.
Nevertheless, even going more in-depth than the
IDCC, neither the monographs related to Cannabis
nor general nomenclature for phytopharmaceuticals
provided any thorough pattern for an orderly, non-
overlapping and non-arbitrary classification of
C. sativa derivatives. Pharmacopœias either focus on
precise traditional formulations, like in Ch.P and
FHEUM, falling short of including all known products
(and in particular the most recent ones, e.g. liquid mix-
tures for electrical vaporisation devices), or they rely,
like Ph.Eur., on wide-ranging categories that would
include, in the case of C. sativa, an heterogeneous
array of products with different pharmacological
effects (varying concentrations, different formulations,
different routes of administration).
Ph.Eur’s extracta sicca,extracta spissa,extracta
fluida,oleoresina,tincturæ,ætherolea,olea herbaria,
plantæ ad ptisanam,præparationes celeres ad ptisanam,
producta ab fermentatione, and producta ab arte ADN
recombinandorum are relevant to Cannabis, but insuffi-
cient. The derivative of C. sativa called ‘rosin’, obtained
via a solventless extraction process relying on heat and
pressure; ‘butane hash oil’, obtained by percolation of
dry pioC using pressurised butane as eluent (Beal,
2019); and ‘supercritical CO
2
oil’ (Naz et al., 2017;
Omar et al., 2013) have a similar consistency. They
could be considered as extracta spissa although their
composition and methods of obtention vary greatly;
they could also be seen as oleoresina. Another prepa-
ration reported already in 1848 (Mechoulam and
Hanu%
s, 2000) and nowadays known as ‘Rick Simpson
oil’ or full ethanol-extracted cannabis oil, obtained by
maceration of pioC in alcohols followed by partial or
total evaporation (mechanically or via distillation),
could be viewed either as tincturæ,extracta spissa, or
oleoresina. ‘Dry sift’ or ‘dry sieve’ (Beal, 2019,
Daniulaityte et al., 2017), a type of ‘hashish’ obtained
via repeated microfiltrations of ground dry pioCs,
without involving the use of solvent, is another
illustration. The process results in a fine dry powder
almost entirely made of capitate heads of EGTs. As
such, it corresponds to extracta sicca. However,
under very light pressure and heat (e.g. from fingers)
it immediately takes the consistency of an extracta
spissa or oleoresina, since EGTs’ external layers
(cuticles) break and liberate the content of the glands,
which then stick together (Graham, 1976: 6; Nicoletti
Motta, 2018). The UNODC (2009) talks about a res-
inous secretion that ‘appears as loose or pressed sticky
powder, depending on the method of production’ (16).
Two pharmacopœial categories, oleoresina and extracta
spissa, likely apply to these four very different products
that have (or can have under certain thermophysical
conditions) a consistency in appearance similar.
Among all these products, many are popularly referred
to as ‘oils’ although none correspond to the pharma-
copoeial category of herbal fatty oils olea herbaria.
Not only the method of obtention seem to be a
common blind spot in IDCC and pharmacopoeial
nomenclatures (notably, with the exception of WHO
T&CM’s), but this criterion is also a determinative
element of a drug’s pharmacological effect, since ‘prep-
arations with different therapeutic properties can be
made from the same herbal material, depending on
the manufacturing process employed’ (Schulz et al.,
2004: 5). The fitness of a phytopharmaceutical to one
route of administration or another also relates to the
processes involved to prepare it (European Directorate
for the Quality of Medicines, 2016: 6519; Gaedcke and
Steinhoff, 2003).
From harvest to the last stage of product formula-
tion, processes of obtention are of singular relevance in
the case of C. sativa phytopharmaceuticals, regarding
the large variety of pharmacologically active secondary
metabolites present in the plant as well as the complex
molecular interactions involved. The presence and yield
of flavonoids, phytocannabinoids, and other terpenoids
can be subject to variations depending on the method
employed. In this regard, C. sativa derivatives appear
to be chemically unstable since straightforward factors
(temperature, time, humidity, light) target degradation
or other types of chemical reactions. Variations dra-
matically affecting the pharmacological properties of
a product can be induced by basic thermomechanical
stimuli (Agarwal et al., 2018; Naz et al., 2017), for
instance, heating at 200#C for seven minutes
(Verhoeckx et al., 2006) or ageing (Fairbairn,
1976: 15; Mechoulam and Hanu%
s, 2000; Zamengo
et al., 2019). This is the case when phytocannabinoids,
obtained in acidic form when separated from the plant
(Happyana et al., 2013; Kimura and Okamoto, 1970;
Perrotin-Brunel et al., 2010, 2011, Pertwee, 2006)
decarboxylate into compounds with enhanced
Riboulet-Zemouli 23
psychopharmacological effects (Reekie et al., 2018;
Verhoeckx et al., 2006).
From many perspectives, the most compelling evi-
dence suggests the ‘method of obtention’ is a common,
and overlooked criterion in classification systems that
fail to overarch C. sativa products. Significantly, this
study shows that, if the identification of different meth-
ods of extraction, separation, fractionation, isolation,
purification, refinement and concentration (terms
somehow used interchangeably) and of crucial param-
eters within those processes, might not per se provide
all sufficient information on C. sativa products, it seems
likely to provide a consistent and useful complement of
information on the characteristics and properties of
C. sativa products, to achieve a thinner, more precise
cartography of them. The variabilities could be used
to frame the lowest taxon of ‘products’, the smallest
common denominator, in such hypothetical
classification.
A metachemistry of cannabinoids (and beyond)
The very same methods which are used to extract or
separate phytopharmaceutical material from pioC and
C. sativa are also sometimes employed to transform
botanical C. sativa material into ‘semisynthetic’ ingre-
dients. Moreover, these same techniques can also be
used to process GM C. sativa material, and even bio-
technologically crafted EGT containing non-natural
cannabinoid analogues. Borrow limitations between
herbal drugs and non-herbal drugs could lead to even
greater confusion in the future. Such reversibility and
porosity between natural and unnatural cannabinoid-
containing products was determinative for including
‘synthetic’ products in the scope of this study: limiting
the study only to natural herbal drugs would have
required preexisting boundaries that neither the
IDCC nor the pharmaceutical references provided for.
Historically, the myriad of new cannabinoid mole-
cules discovered in the last decades (Firman et al.,
2019; Shevyrin et al., 2016) have been termed ‘synthetic
cannabinoids’ by opposition to ‘phytocannabinoids’,
the naturally occurring cannabinoids found in
Cannabis plants. While the word ‘phytocannabinoid’
links to an unambiguous and delimited relatum, the
expression ‘synthetic cannabinoids’ is given by ostenta-
tion rather than by description. Eighty years ago,
Adams et al. (1940) were the first to synthesise a can-
nabinoid compound ex vivo: the phytocannabinoid
CBN (see Mechoulam and Hanu%
s, 2000; Pertwee,
2006). The first compounds to be named ‘synthetic can-
nabinoid’ in the 1960s were all closely related to the
molecules found in C. sativa, either phytocannabinoids
obtained in vitro or closely related byproducts,
obtained during attempts to synthesise and describe
naturally occurring phytocannabinoids (Bow and
Rimoldi, 2016; Fahrenholtz et al., 1967; Mechoulam
and Gaoni, 1965; Mechoulam and Hanu%
s, 2000;
Pertwee, 2006; Petrzilka et al., 1967; Razdan and
Zitko, 1969). Hence their definition by the negative
insofar they were, by then, the only non-natural, not
wholly-phyto cannabinoids. With the years, dozens of
new structurally heterogeneous compounds were
described, obtained via varying synthesis routes, using
different starting materials, and resulting in an increas-
ingly diverse class of molecular structures within what
continued to be a single ontological entity: synthetic
cannabinoids, encompassing each time more different
relata.
A compressive arrangement of those ‘synthetic ago-
nists active at cannabinoid CB1 and CB2 receptors’
(Firman et al., 2019) is still to be found. Shevyrin
et al. (2016) made insightful proposals (classifying
these substances in six groups: ‘classical’, ‘nonclassical’,
‘hybrid cannabinoids’, ‘aminoalkylindoles’, ‘eicosa-
noids’, and ‘other cannabinoids’), and Biernat (2018)
proposed three categories (‘cannabinoids derived
directly from cannabis’, ‘synthetic versions of cannabi-
noids found in cannabis’, and ‘compounds that are
similar to cannabinoids found in cannabis’), among
others. It appears however that the six-tiered categories
continue to rely on a definition by ostentation, group-
ing under others a variety of structurally diverse mole-
cules. The suggestion made by Biernat falls in a similar
stalemate with the class ‘compounds that are similar to
cannabinoids found in cannabis’, probably too
heterogeneous, encompassing novel artificial ana-
logues, semisynthetics, endocannabinoids, and any
other cannabinoid.
Beyond their ability to bind to the human endocan-
nabinoid receptor system, what brings together canna-
binoid compounds is the difficulty in classifying them
rightly. Relying solely on their chemical structure
might not be the best approach, as, again, the category
other will always exist and potentially grow as an
increased number of substances may be found to
have some interaction with CB1 or CB2 (it is already
the case for non-cannabinoid phytoconstituents
(Gertsch et al., 2010) and for paracetamol (Klinger-
Gratz et al., 2018), suggesting the need for a real meta-
physical address of the endocannabinoid system).
Heretofore, the lemma cannabinoid itself has not been
discussed. Basis of all neologisms in chemistry, the
word ‘cannabinoid’ is nonetheless much more a
neuro-pharmacological term than a chemical one.
From its etymology – appeared in the 1940s (Google
Books Ngram Viewer, s.d) built as a derivative of ‘can-
nabis’ to which was added the suffix -oid derived from
classical Greek edo1,ˆdos: ‘kind’, ‘form’, ‘type’, ‘like-
ness’ – it designates substances that are of the cannabis
24 Drug Science, Policy and Law
kind, that relate, that are similar to ‘cannabis’, from a
wholly subjective, empirical point of view. The relatum
associated with ‘cannabinoid’ does not necessarily
imply a structural resemblance at the molecular level,
but rather a similarity in terms of the overall pharma-
cological effects observed, deemed akin to those pro-
duced by botanical Cannabis products. Dewick (2012)
makes an enlightening statement:
Natural products structures are usually quite complex,
some exceedingly so, and fully systematic nomenclature
becomes impracticable. Names are thus typically based
on so-called trivial nomenclature, in which the discov-
erer of the natural product exerts their right to name
the compound. (3)
Driven beyond epistemology, Bachelard (1966) deepens
the reflection on chemical nomenclatures, addressing
the metaphysics of chemistry (or as Nordmann, 2006
puts it, metachemistry), suggesting a ‘rationalised’ use
of scientific language ‘which takes substance to be a
category of the understanding’ (Nordmann, 2006:
348–350) rather conceptual. This approach considers
that the term ‘substance ...designates the stability of
an assemblage’, or what gathers together ‘a multiplicity
of agents into a stable and coherent whole’.Naming in
chemistry is perhaps the most challenging contempo-
rary classification playground – or, as Schummer
(2002) resumed it ‘imagine the tremendous efforts
that were necessary to distinguish carefully between
millions of substances today, most of them being
white powders indistinguishable to the naked eye’.
Because advancements in chemistry make language
continuously drift away from compounds, the need to
‘define and stress the differences between terms that
may appear to be synonyms’ (Santal!
o and Casado,
2016: 39) becomes pressing, particularly for the class
(es) of ‘synthetic cannabinoids’, neither stable nor con-
sistent. Such demand is outstanding, not only because
of the need for accurate language to match understand-
ing, but also in terms of the strong ethical concerns
which arise from the debates around the uses of
Cannabis products (Zarhin et al., 2019) presently
amplified in the context of moral and epistemological
upheaval driven by two ongoing parallel revolution(s):
the Cannabis policy reforms one, and the biotechnolog-
ical one (Perron-Welch, 2019).
Extrapolations from other well-known classes of
psychoactive phytoconstituents and their analogues
do not seem to provide comprehensive solutions. For
instance, cannabinoids differ from opioids on at least
three levels: hundreds of different phytocannabinoids
have been identified in C. sativa plants (while only a
dozen of phyto-opioids are known); the human body
naturally produces endogenous cannabinoids;
cannabinoids are also naturally secreted by other
living organisms (whether plant, animal, or fungus).
This latter point is subject, again, to further scrutiny
of the metaphysics of animal endocannabinoid systems.
Besides come the novel, human-conceived cannabinoid
compounds, raising the absolute list of cannabinoids
kinds (or taxa), but also virtually the complexity of
their systematics, above that of opioids, and most
other well-studied classes of molecules.
A bioethical nomenclature for cannabinoid compounds. The
exploration of a new classification of cannabinoid sub-
stances, in a bioethical rather than purely biochemical
fashion, might be a solution. In the same fashion that
the methods of obtention of C. sativa derivatives which
bring additional analytical information on the compo-
sition of a product, a bioethical nomenclature of com-
pounds does not per se conflict with nomenclatures
arranged according to chemical structures. It could
very well be a complementary tool, in line with
Bhushan’s (2006) suggestion to overcome the difficul-
ties in classifying chemical substances by using ‘a kind
for every occasion’ on the basis that ‘kinds are real but
particular to the occasion of the individuals who
choose to work with them, their choices of models
and strategies, and what happens to function best in
the environment in question’ (327–328). In this direc-
tion, kinds, or nomenclatures, used by chemists, might
not be the best approach for an environment of law
and public health policy, or for clinical contexts.
As exposed, a pattern in four classes of cannabi-
noids showed two main axes useful to start discrimi-
nating compounds: occurrence in nature or not, and
obtention from C. sativa material or not.
The first axis, regarding the prevalence of a com-
pound in natural environments, appears to be easily
divisible in two clear mutually exclusive groups: one
comprises novel and artificial substances, not present
in nature, that could be labelled as human inventions.
A comparison can be done with the artificial analogues
of nicotine: initially defined under a chemical nomen-
clature as chloronicotinyls, they have been renamed
neonicotinoids by Tomizawa and Yamamoto (1993:
97–98) and Sheets (2002) adding the prefix !!
eo1(n!
eos:
‘new’, ‘young’) to ‘nicotine’ followed by the suffix -oid.
Likewise, the group of cannabinoid compounds not
present in nature could be grouped under the term neo-
cannabinoids. The second group would include canna-
binoids occurring in nature (either in raw state, such as
dronabinol, or as secondary metabolites processed by a
living organism, like THC-COOH; see Huestis, 2007),
whether they are derived from living organisms or
obtained by processes of human-made synthetic chem-
istry reproducing the natural biosynthesis pathways of
a living organism. These include phytocannabinoids,
Riboulet-Zemouli 25
human endocannabinoids, as well as naturally occur-
ring endogenous cannabinoid substances found in
other living, genetically unmodified organisms.
Medical and scientific terminologies often articulate
the prefix neo- in opposition to paleo- (derived from
pakai!
o1,palai!
os: ‘old’, ‘ancient’); as such, this second
group, mutually exclusive with the previous one, could
be termed paleocannabinoids.
The second axis relies on the methods of obtention.
The first level of opposition is found between substan-
ces derived from living organisms (the mechanism
called biosynthesis), whether GM or not, and substan-
ces derived from an inert material, in vitro, via different
laboratory processes (traditionally called ‘synthesis’ or
‘chemical synthesis’). The use of the word ‘synthesis’
alone, as a synonym of ‘chemical synthesis’, sometimes
in vitro, sometimes ex vivo, is exceptionally confusing:
‘synthesis’ derives from r!
t!heri1 (s!
unthesis: ‘arrange-
ment’, ‘putting together’, ‘composition’, ‘combination’)
and is the generic, general term to refer to any obten-
tion of a complex chemical compound from simpler
precursors, whether in living organisms or not. The
Oxford Dictionary of Biology defines synthesis as ‘the
formation of chemical compounds from more simple
compounds’ (Martin and Hine, 2015: 577).
In order to avoid using ‘synthesis’, ‘laboratory syn-
thesis’, or ‘chemical synthesis’ to oppose ‘biosynthesis’,
the neologism poesynthesis is suggested. It is created
from poi!
ex,poie&
o: ‘to make’, ‘produce’, ‘create’, ‘com-
pose’, ‘bring into existence’; arranged for phonetic and
legibility purposes according to lemmas formed with
the same prefix, like poetry. ‘Poesynthesis’ would aggre-
gate all those molecules obtained via in vitro synthesis;
it would complement and oppose ‘biosynthesis’ refer-
ring only to molecules obtained in laboratory chemical
synthesis processes. A cannabinoid obtained in vitro
would accordingly be called poesynthetic cannabinoid.
Looking at the holdups, this axis deserves a more
complex than a dual approach, in particular in the con-
text of the surge of gene editing technologies targeting
and altering biosynthesis pathways. While both paleo-
cannabinoids and neocannabinoids can be poesyn-
thetic, neocannabinoids can, by definition, not be
derived from natural biosynthesis . Or can they? Luo
et al. (2019), among others, have shown that neocan-
nabinoids can be obtained through a biosynthesis
altered by biotechnological means. This suggests the
need for a subdivision within biosynthesis, discriminat-
ing GM from non-GM biosynthesis. To distinguish
between natural biosynthesis and biosynthesis induced
artificially (sometimes called ‘synthetic biology’ [sic] in
the context of policy, see Perron-Welch, 2019), the use
of lemmas inspired in ancient Greek can again bring
terminological clarity. Cannabinoids which are
obtained by processes of biosynthesis not naturally
occurring, having been induced by biotechnological
genetic modifications, could be termed dysbiosynthetic
cannabinoids as per the prefix dtr-(dus: ‘disordered’,
‘difficult’, ‘abnormal’) to the existing ‘biosynthesis’
(formed with b!
io1,bios: ‘life’). By opposition, the
prefix e-(e^
u: ‘true’, ‘real’) could form the terms eubio-
synthesis and eubiosynthetic cannabinoids to cover com-
pounds obtained entirely by natural biosynthesis in
unmodified environments, and their natural metabo-
lites. Figure 3 details the interrelation between the
terms proposed.
Figure 3 shows that the only of these neologisms
coveri