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39th WHO Expert Committee on Drug Dependence: Joint EIHA-FAAAT contribution to the evaluation of Cannabidiol

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Abstract

From 2016 to 2019 the World Health Organization undertook a thorough review and assessment of Cannabis and cannabis-related substances. This one of the few substantial and official contributions provided for the first of the three Expert meetings dedicated to the review, the "Pre-review" of Cannabidiol (CBD). Responsible under press legislation (V.i.S.d.P.): Michael Carus | EIHA co/ nova ISBN 979-10-97087-08-1 | EAN 979109708708
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Joint EIHA – FAAAT contribution to the
39th ECDD evaluation of Cannabidiol
World Health Organization, Geneva (Switzerland), November 6th, 2017
Main authors: Boris Baňas, Dr. Bernard Beitzke, Dr. Giuseppe Cannazza, Michael Carus,
Hana Gabrielová, Farid Ghehioueche, Kerstin Iffl and, Michael Krawitz, Daniel Kruse,
Eberhard Pirich, M.D., Kenzi Riboulet Zemouli
Download this paper and further documents at: www.eiha.org
Responsible under press legislation (V.i.S.d.P.): Michael Carus | EIHA co/ nova-Institut GmbH |
Industriestraße 300 | 50354 Hürth | Germany | michael.carus@eiha.org | www.eiha.org
ISBN 979-10-97087-08-1 | EAN 979109708708
Abstract
Cannabidiol, specifically (-)-trans-Cannabidiol (CBD), can
be isolated from plants of genus Cannabis, or produced
synthetically. This chemical substance has a wide variety
of uses, from maintaining, supporting and optimizing
homeostasis to restoring, correcting and modifying it.
There is no scientific justification or rationale to amalgamate
CBD with substances under international control, even
though it may be extracted from the Cannabis sativa L.
plant – if indeed done so (usually from industrial hemp
varieties as registered by the OECD scheme), the substance
can easily be chemically purified and isolated as a pure
compound, practically free from other cannabinoids (in
particular free from THC) and therefore free from any
psychotropic or narcotic properties. Moreover, it is possible
to produce naturally occurring CBD, namely (-)-trans-
Cannabidiol, by chemical synthesis from small building
blocks, a method that really has nothing to do with
Cannabis1. The crude product (mostly a mixture of optical
isomers) may be purified by known chromatographic
methods, which results in nature-identical CBD.
This fact is acknowledged by the classification of CBD
as an API (active pharmaceutical ingredient), and by the
description of Cannabidiol in the substance’s monograph
C-052 in the German Drug Codex, DAC/NRF, which does
not differentiate between products of synthetic or natural
origin: “The substance [(-)-trans-CBD] can also be produced
synthetically”2. It also is the basis for the use of this pure
substance as an ingredient for cosmetics, food supplements,
and electronic cigarette liquids in lower concentrations.
Therefore the “CBD” substance under pre-review should
be understood solely as pure Cannabidiol of whatever
origin, i.e. CAS Number 13956-29-1, IUPAC name 2-[(1R,6R)-
3-methyl-6-prop-1-en-2-yl-1-cyclohex-2-enyl]-5-
pentylbenzene-1,3-diol.
There is no more scientific justification or rationale
for scheduling CBD based on its assumed psychotropic
properties: contrary to (-)-trans-∆9-Tetrahydrocannabinol
(THC), which is also present in Cannabis sativa L., CBD does
not have any psychotropic effects and does not exert an
euphoriant action. Furthermore, there is evidence from
scientific literature that CBD moderates and reduces the
psychotropic effects of THC. During its 38th meeting,
the WHO’s Expert Committee on Drug Dependence
acknowledged that “cannabidiol [...] has little or no
potential for abuse”3.
United Nations Office on Drugs and Crime differentiates
between drug-type versus fibre-type cannabis by a formula
where sum of THC and CBN (Cannabinol) are divided by
CBD. “If the peak area ratio of [THC+CBN] : [CBD] is <1,
then the cannabis plant is considered to be a fibre-type. If
the ratio is >1, it is considered a drug-type”4.
In conclusion, CBD is a substance that is beneficial
to human health and public welfare. Subjecting it to
appropriate legal sanitary regulation is justified, but it
does not fit any of the requirements for inclusion in the
international drug control treaty schedules.
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1 Steup, C. (2015): Method for producing synthetic Cannabinoids. European Patent 2 314 580 B1
2 DAC/NRF 2016/2 C-052
3 White, J. (2016): Abuse dependence potential of Cannabis sativa and nabiximols, 38th ECDD (2016) Agenda item 5.1, page 20
4 UNODC (2009): Recommended methods for the identifi cation and analysis of cannabis and cannabis products. page 20
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Introduction
Cannabidiol (CBD) is one of the non-psychotropic and
non-intoxicating active compounds in Cannabis sativa L., a
plant called “hemp” in vernacular English.
The last couple of years have seen a growing interest in CBD.
Not only does Cannabidiol offer a plethora of beneficial
health applications, it also has no relevant side effects, even
when administered at high doses. It is increasingly used as
an ingredient in cosmetics, in electronic cigarette liquids,
and as a food supplement ingredient, thereby generating
investment and creating employment in the fields of
cultivation and processing of hemp and hemp-derived
products. In 2016, 30,000 ha of industrial hemp were
cultivated in the European countries, some 75,000 ha of
hemp are cultivated in Canada and about 100,000 hectares
in China.
We welcome WHO’s comprehensive review of all cannabis-
related substances but we strongly oppose classification
of Cannabidiol as a psychotropic substance under
international control. All scientific evidence shows that
CBD has no intoxicating effects (Iffland and Grotenhermen,
2017 and references therein). Based on findings in scientific
literature (Iffland and Grotenhermen, 2017 and references
therein), scheduling CBD among the controlled substances
does not hold up at all.
Researchers have also clearly shown that CBD is safe to use
in a broad range of concentrations and indications, and
has insignificant side effects compared to other similar
nutraceutical products which are not included in the
international treaties schedules.
Scheduling CBD would also have devastating implications
on a worldwide hemp agriculture and industry reborn after
almost a century of open or hidden oppression. Industrial
segments, such as European automotive industry, would
also greatly suffer if, a new psychotropic substance innate
to hemp plant would have to be controlled.
I. Variety of Applications of
Cannabidiol
1. Absence of abuse liability and dependence-
producing effects
Contemporary evidence from the pharmacological sciences
clearly shows that Cannabidiol is non-intoxicating and
does not have any abuse potential or negative side effects
on individual or public health and welfare. (Iffland and
Grotenhermen, 2017).
Another comprehensive review on the safety and side
effects of CBD has shown that even very high doses of the
substance are safe and well tolerated, without significant
side effects (Bergamaschi et al., 2011). In their meta-analysis
of a total of 132 reviewed publications, it was found that
CBD did not induce catalepsy, did not affect critical
physiological parameters such as heart rate, blood pressure,
body temperature, or gastrointestinal transit, nor did it
alter psychomotor and cognitive functions.
The article by Russo (2017) explains that “CBD is frequently
mischaracterized in lay, electronic, and scientific sources as
‘non-psychoactive’ or ‘non-psychotropic’ in comparison
to (-)-trans-∆9-Tetrahydrocannabinol (THC), but these
terms are inaccurate, given its prominent pharmacological
benefits on anxiety, schizophrenia, addiction, and possibly
even depression.” Therefore, CBD should preferably and
more accurately be labelled as ‘non-intoxicating’, seeing
that it does not affect addiction parameters such as
“reinforcement, craving, compulsive use etc.”. The relevance
of a drug abuse liability assessment can only be grounded
on the existence of alterations of these factors produced or
induced by the substance.
It has also been shown in various reports (such as the Czech
Scientific Phytosanitary and Environmental Committee5)
that “the toxicological studies on CBD products, and on
comparable products, provided sufficient reassurance that
the novel ingredient could be safe for the proposed uses.”
The World Anti-Doping Agency (WADA) has recently
exempted Cannabidiol from its list of Substances
and Methods Prohibited “In-Competition”. The note
says: “Cannabidiol is no longer prohibited. Synthetic
cannabidiol is not a cannabimimetic; however, cannabidiol
extracted from cannabis plants may also contain varying
concentrations of THC, which remains a prohibited
substance.”
In addition, The Novel Food catalogue published by the
European Commission designates Cannabidiol as a “major
nonpsychotropic constituent of the Cannabis sativa plant”.6
Two renowned medicine control agencies testify to the
absence of adverse or psychoactive properties of CBD:
The European Medicines Agency (EMA), which declared
that “Cannabidiol is present in the cannabis plant but it
is not expected to have effects on mood, mental activity
or behaviour.”7; and the Australian Therapeutic Goods
Administration (TGA), which claimed that “there is low
risk of misuse or abuse as cannabidiol does not possess
psychoactive properties.”8
__________
5 Scientifi c Phytosanitary and Environmental Committee, Czech Republic, Expert opinion 2/2017: Evaluation of “Cannabidiol CBDex” as novel food ingredient, March 27,
2017, page 17-18
6 http://ec.europa.eu/food/safety/novel_food/catalogue/search/public/index.cfm#
7 EMA/COMP/252372/2016, European Medicines Agency, Committee for Orphan Medicinal Products, 27 May 2016
8 TGA, Interim decisions on matters referred to an expert advisory committee: ACMS out-of-session, November 2014
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2. Examples of health-related uses of CBD
The last INN listing from 20169 defines Cannabidiolum
as a “cannabinoid receptor antagonist”. This is further
evidence of it actually reducing THC’s effects, for example.
Corroboration is provided by a letter from the Institute of
Chemical Processes Fundamentals of the Czech Academy
of Sciences: “Effects of ligands on CB1 receptors result in
psychoactive effects evident with intake of d9-THC acting
as CB1 receptor agonist. As per available sources CBD is a
partial CB1 antagonist and his bonding on the receptor
does not invoke psychoactive effect.”
On another possible medical application, evidence is
given in the 2016 EMA Committee for Orphan Medicinal
Products report10 titled “Public summary of opinion on
orphan designation: Cannabidiol for the prevention of
graft-versus-host disease”, where Cannabidiol is described
as acting “to reduce inflammation and other damaging
immune effects and it is thereby expected to protect the
patient’s organs from injury.”
3. Cosmetic applications of CBD
Amongst others, CBD can be used in several cosmetic
applications. In the unofficial EU database for information
on cosmetic substances and ingredients, CosIng, Cannabidiol
is listed with four functional claims11:
antioxidant,
antiseborrhoeic,
skin conditioning,
skin protecting.
A letter by the Public Health Authority of the Slovak
Republic12 to EIHA states that “cannabidiol can be added
to cosmetic products as a pure substance (natural* or
synthetic) as well as a part of extracts from the plants
or seeds of Cannabis sativa”. Additionally, several CBD-
containing products have already been certified and
properly registered in INCI.13.
4. Food applications of CBD
Cannabidiol is frequently used in food or food
supplement products. The substance has even been listed
in the European Union’s Novel Food Catalogue14, and the
European Commission acknowledges that Cannabidiol is
a cannabinoid and a major non-psychotropic constituent
of the Cannabis sativa plant. At least one application for
authorization of Cannabidiol use in food supplements is
currently under evaluation.
5. Use of CBD in electronic cigarette liquids
There are no restrictions concerning the use of CBD in
electronic cigarette liquids in many European countries
as long as end-user products conform to the provisions
of Directive 2001/95/EC on general product safety. These
legal provisions acknowledge the fact that CBD helps fight
nicotine addiction as a substitution product (Iffland and
Grotenhermen, 2017 and references therein).
II. Recommendations
6. Policy perspectives for Cannabidiol
Of all the criteria considered in the Guidance on the
WHO review of psychoactive substances for international
control15 (similarity with substances already in Schedules
I or II of the 1961 Convention or Schedules I, II, III or IV
of the 1971 Convention; convertibility into a substance
scheduled under 1961 Convention; or the capacity of
the substance to produce a “state of dependence” and “a
central nervous system stimulation or depression, resulting
in hallucinations, disturbances in motor function, in
thinking, in behaviour or perception or mood”), none
matches Cannabidiol.
Therefore, rather than applying the provisions of the
international drug control conventions, obviously irrelevant
in this case, national regulations related to Cannabidiol
production and use should apply a comprehensive three-
tier model16 of doses and applications as outlined below:
 At high doses, over 200mg/average adult per day, the
promising pharmaceutical applications of CBD require
further clinical research. Policy makers should use the
results of clinical research to allow evidence-based
medicinal use of CBD.
At physiological doses, between 20-200 mg/day, CBD
should be regarded as an over the counter product, or
a food supplement, similar to many substances, such as
some vitamins and iron products, Valerian, glucosamine,
chondroitin (sulphate), Ginkgo biloba, etc.
Low CBD concentrations and doses below 20 mg/day
should keep being allowed in food products without any
restrictions.
__________
9 WHO Drug Information, Vol. 30, No. 2, 2016, Proposed INN: List 115
10 ibid. EMA/COMP/252372/2016
11 http://ec.europa.eu/growth/tools-databases/cosing/index.cfm?fuseaction=search.details_v2&id=93486
12 Ref. OHVBPKV/9810/2016/Kr, November 30, 2016
* Emphasis added
13 EU CPNP: Cosmetic Products Notifi cation Portal, https://webgate.ec.europa.eu/cpnp/public/tutorial.cfm
14 http://ec.europa.eu/food/safety/novel_food/catalogue/search/public/index.cfm
15 World Health Organization, 2010, ISBN 978 92 4 150055 5
16 http://eiha.org/media/2014/08/17-01-EIHA-CBD-position-paper.pdf
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7. International classifi cation of Cannabidiol
and nomenclature issues
There is no reason to differentiate between Cannabidiol
produced synthetically and by isolation from the
cannabis plants. For example, DAC/NRF monograph
C-052 mentions chromatographic purity between 98-
102% and defines ∆9-THC, ∆8-THC and Cannabinol (CBN)
as “specified impurities”. Without prejudice of other legal
requirements concerning the manufacture of the extracts
of cannabis, considering “Cannabidiol” of natural origin
as an “extract of cannabis” does not hold up to principles
of the nomenclature of organic chemistry (IUPAC) system,
Chemical Abstracts Service (CAS) as well as Harmonized
System (HS Codes) of the World Trade Organization:
Cannabis extract: CAS#: 89958-21-4, HS Code: 1302 19
– Vegetable saps and extracts
Cannabidiol: CAS#: 13956-29-1, HS Code: 2907 29
– Phenols, phenol-alcohols
We can further substantiate our opinion based on the
following citation: A chemical substance (e.g., plant extract)
used to produce a semisynthetic drug substance or a crude
drug substance derived from a plant ... starting material is
considered an intermediate”17. This statement makes clear
that a plant extract used for isolating a pure chemical
substance as an API is NOT the API itself, neither it is the
medicinal product made from it. The plant extract is only
an intermediate in the processing to yield to pure API.
Another important issue – although this point is of greater
relevance for the Secretariat than for the experts is the
incorrectly translated wording of the biological effect of
CBD in some of the WHO’s official documents. Critically,
the document entitled “WHO Drug Information, Vol. 30,
No. 2, 2016, Proposed INN: List 115” mentions cannabidiolum
as the International Nonproprietary Name for CBD on
page 17, and states:
“EN: cannabinoid receptor antagonist
FR: agoniste des récepteurs aux cannabinoïdes
ES: agonista del receptor de cannabinoids”
We hereby formally object to the attributes “agoniste”
in French and “agonista” in Spanish, because CBD is an
antagonist of cannabinoid receptors. This should be
rectified in the forthcoming List of Proposed INNs 115. We
call on the Secretariat and the EMP department to attend
to this confusing mistake with particular care.
III. Conclusions
CBD is a safe to use substance that is beneficial to human
health and public welfare and has numerous applications
in industry and nutrition, cosmetics as well as health
and wellbeing products, besides its promising benefits in
diverse indications such as reducing anxiety or helping
people to quit smoking.
Applying the measures laid down in the international drug
control treaties to Cannabidiol would severely restrict its
availability for the non-problematic consumers of CBD
and CBD-related products, as well as undermining safe
access for many patients who already profit from CBD’s
manifold health-related and homeostasis-supporting
effects. In addition to diminishing public welfare,
employment in the blooming hemp industry would be
actively destroyed, and the already existing and regulated
market of non-therapeutical hemp-based products would
shrink significantly, despite just having experienced a
rebirth after almost a century of oppression.
Finally, Cannabidiol does not fit any of the requirements
or criteria for inclusion in the international drug control
treaty schedules, and it lacks the properties usually
attributed to psychotropic substances or narcotic drugs.
Therefore we strongly urge the WHO to clearly recommend
the exclusion of Cannabidiol from the scope of the
international control measures, and reaffirm its unbelonging
to the lists of internationally controlled substances.
Selected and cited references
Bergamaschi, M. M., Queiroz, R. H. C., Chagas, M. H. N., De Oliveira, D. C.
G., De Martinis, B. S., Kapczinski, F., ... & Martín-Santos, R. (2011):
Cannabidiol reduces the anxiety induced by simulated
public speaking in treatment-naive social phobia
patients. Neuropsychopharmacology, 36(6), 1219-1226.
CosIng database, accessed on Otober 2nd, 2017: http://ec.europa.
eu/growth/tools-databases/cosing/index.
cfm?fuseaction=search.details_v2&id=93486.
DAC/NRF (Deutscher Arzneimittel-Codex, Neues Rezeptur-Formularium) 2016/2
(C-052): Cannabidiol (Cannabidiolum), Mediengruppe
Deutscher Apotheker GmbH.
Niesink, R. et al. (2013): Does cannabidiol protect against adverse
psychological effects of THC? Frontiers in psychiatry,
October 2013, Article 130.
Iffl and, K., & Grotenhermen, F. (2017): An Update on Safety and Side
Effects of Cannabidiol: A Review of Clinical Data and
Relevant Animal Studies. Cannabis and Cannabinoid
Research, 2(1), 139-154.
Russo, E. B. (2017): Cannabidiol Claims and Misconceptions.
Trends in pharmacological sciences, 38(3), 198-201.
Scientifi c Phytosanitary and Environmental Committee, Czech Republic, Expert
opinion 2/2017: Evaluation of “Cannabidiol CBDex” as
novel food ingredient, March 27, 2017, page 17-18.
Scuderi, C., Filippis, D. D., Iuvone, T., Blasio, A., Steardo, A., & Esposito, G. (2009):
Cannabidiol in medicine: a review of its therapeutic
potential in CNS disorders. Phytotherapy Research,
23(5), 597-602.
A plethora of additional empirical evidence may be obtained
from EIHA.org, Dr. Bernhard Beitzke and Boris Baňas;
moreover, digital copies of the cited material are available
upon request.
__________
17 FDA (2010): Guidance for Industry, Drug Substance Chemistry, Manufacturing, and Controls Information. Page 52
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EIHA and FAAAT would like to thank the following companies for their support of this campaign:
Bluebird Botanicals Buddingtech CannaWell CBD life UK
CBD oils UK CBDepot.eu Deep Nature Project EIHA
Greenindustries.shop Hemp and humanity HempConsult GmbH Hempflax
Hempire Ltd Hempoint.cz Hempura MCU Botanicals
MeetHarmony MH medical hemp GmbH
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