285

Ann Ist Super Sanità 2020 | Vol. 56, No. 3: 285-291

DOI: 10.4415/ANN_20_03_06

Pharmacology and legal status

of cannabidiol

articles and reviews

Pietro Brunetti1, Alfredo Fabrizio Lo Faro1, Filippo Pirani1, Paolo Berretta2,
Roberta Pacifici2, Simona Pichini2 and Francesco Paolo Busardò1
1 Dipartimento di Scienze Biomediche e Sanità Pubblica, Università Politecnica delle Marche, Ancona, Italy
2 Centro Nazionale Dipendenze e Doping, Istituto Superiore di Sanità, Rome, Italy

Abstract Key words

O riginal
Cannabidiol (CBD) is the second most abundant cannabinoid present in Cannabis sativa • cannabidiol (CBD)
L. It is not associated with psychotropic activity and is capable to mitigate the psychoto- • epilepsy
mimetic effects produced by tetrahydrocannabinol (THC). The latest cannabis decrimi- • law
nalization policies and the high applicability in therapeutic and technologic-industrial • legal status
fields, have determined an exponential marketing growth of foods, cosmetics and in • policies
particularly medicinal products containing CBD, which are easily available for consum-
ers. Most importantly, on 2018 United States Food and Drug Administration approved
CBD oral solution with the trade name of Epidiolex® for the treatment of two rare and
severe forms of epilepsy, “Lennox-Gastaut syndrome” and “Dravet syndrome”, in pedi-
atric patients. The aim of this review was to focus on pharmacology and on legal status
of CBD, to highlight the lack of harmonization of international regulatory laws over the
marketing authorization of CBD-based products.

INTRODUCTION MATERIALS AND METHODS

Cannabidiol (CBD) or 2-[(6R)-6-Isopropenyl- A literature search was performed on multidisci-
3-methyl-2-cyclohexen-1-yl]-5-pentyl-1,3-benzene-di- plinary databases such as PubMed, Web of Science, in-
ol [1] is one of the more 100 phytocannabinoids pres- ternational agencies or institutional websites including:
ent in Cannabis sativa L. [2-4]. It is the second major World Health Organization, US Food and Drug Ad-
pharmacologically active component of the plant and ministration (FDA), US Drug Enforcement Adminis-
the most prevalent in the fibre-type hemp [4]. It was tration (DEA), European Monitoring Centre for Drugs
isolated for the first time in 1940, and its structure was and Drug Addiction, European Medicines Agency, Eu-
described by Mechoulam et al. in 1963 [1, 5]. CBD ropean Food Safety Authority (EFSA), Italian Medi-
is a meroterpenoid obtained from the alkylation of an cines Agency, Italian Public Administration, National
alkyl resorcinol with a monoterpene unit [6]a lot of Academies of Sciences, Engineering, and Medicine to
attention has been paid to the compounds present in identify the most relevant literature (up to November
medicinal Cannabis sativa L., such as Δ 9 -Tetrahydro- 2019). The search terms used only or in combination
cannabinol (Δ 9 -THC, it is substituted in position 1 were: cannabidiol, CBD, phytochemistry, pharmacol-
by a methyl group, in position 3 by a 2,6-dihydroxy- ogy, pharmacokinetics, pharmacodynamics, medical
4-pentylphenyl group, and in position 4 with a prop- use, adverse effects, reactions, toxicity, legal and regu-
1-en-2-yl group [2]. From the chemical structure of latory. The main keywords cannabidiol and CBD were
CBD (Table 1), it is easy to recognize the presence of searched alone and in association to each of the others.
two hydroxyl groups and according to Borges et al. Only scientific articles written in English were included,
2013, CBD has potential antioxidant activity because whereas for institutional websites both Italian and Eng-
of the cation free radicals show several resonance lish sources were taken into consideration. All sources
structures in which the unpaired electrons are mainly were screened independently by two of the authors to
distributed on the ether and alkyl groups, as well as on determine their relevance and appropriateness in the
the benzene ring [2]. framework of the current report.
In this review, we described the pharmacology and
legal status of CBD in different countries, drawing at- RESULTS AND DISCUSSION
tention to the lack of harmonization of international The initial search produced about 2800 sources, but
regulatory laws over the marketing authorization of only 29 were included for the purposes of this review.
CBD-based foods, cosmetics and medicinals. The first aim of this manuscript was focused on: 1)

Address for correspondence: Roberta Pacifici, Centro Nazionale Dipendenze e Doping, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161
Rome, Italy. E-mail: [email protected].
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Pietro Brunetti, Alfredo Fabrizio Lo Faro, Filippo Pirani et al.

Table 1
Cannabidiol (CBD) and main metabolites in human

Molecular
Structure Chemical names
formula
articles and reviews

H OH CAS 13956-29-1
C21H30O2 Cannabidiol
H

HO

Main metabolites in human

O riginal

Molecular
Structure Chemical names CYP 450 isoform
formula

C21H30O3
7-Hydroxy Cannabidiol CYP2C19 CYP3A4

C21H30O3 6a-Hydroxy-
CYP2C19 CYP3A4
cannabidiol

C21H30O3 6 β-Hydroxy-
CYP2C19 CYP3A4
cannabidiol

C27H38O8 Cannabidiol β-D- UGT1A7, UGT1A9,

Glucuronide UGT2B7

C21H28O4 7-Nor-7-
CYP2C19 CYP3A4
carboxycannabidiol

pharmacology and toxicology of CBD including phar- Pharmacokinetics

macokinetics, pharmacodynamics, adverse effects and Pharmacokinetics processes of CBD are dynamic
interactions, while the second aim was to describe 2) and may change over time, depending on the route of
the legal status of CBD and to provide an overview administration and the frequency or magnitude of ex-
about American and European legislation, with a spe- posure [7]. CBD is highly lipophilic and for that reason
cial focus on the Italian scenario. can easily pass across biological barriers and it is rapidly
 287
Cannabidiol (CBD) and legal status

absorbed. Inhalatory and oral administrations are the smokers could confirm or deny that possibility. Indeed,
most common routes for drug formulation containing CBD pharmaceutical preparation are based on tablets
CBD [7, 8]. Oral absorption seems to have more vari- and oily drops [17].
ability and less bioavailability compared to inhalatory
one, probably due to an intensive first-pass metabolism Pharmacodynamics

articles and reviews

[9]. Distribution of CBD is time dependent and begins To date CBD mechanisms of action are not fully elu-
upon absorption, into fatty tissues and highly perfused cidated. Thanks to its high lipophilicity CBD crosses
organs such as: brain, heart, lung, and liver, quickly the blood-brain barrier (BBB) [4] modulating central
decreasing its plasma concentrations [7, 9]. Plasma nervous system (CNS) [1]. Most central CBD effects
protein binding, primarily to lipoproteins, of CBD, is are mediated by the activation of endocannabinoid sys-
similar to the one of THC and is about 97%. For this tem through the modulation of cannabinoids (CBr) 1,2
reason, CBD intake can cause concentration increase receptors, which are Gi/o protein-coupled receptors [11,
of co-administered drugs, displacing them from protein 18] present at a high density in the frontal cortex, basal
linkage [10] and causing possible adverse effects. CBD ganglia, hippocampus, and cerebellum, and at a minor
is extensively metabolized in liver and in intestine by density in the hypothalamus, nucleus accumbens, and
different isoforms of cytochrome P450 (CYP) such as: amygdala [11, 19]. CB1r are located predominantly at

O riginal
CYP2C19 and CYP3A4 [1, 10, 11] (all main metabo- the presynaptic terminals of neurons while postsyn-
lites are reported in Table 1), forming predominantly aptic localization has rarely been observed [11]. Their
7-hydroxy-cannabidiol (7-OH-CBD) and 7-carboxy- activation inhibits the presynaptic release of many neu-
cannabidiol (7-COOHCBD), and 6-hydroxy-cannabi- rotransmitters such as: γ-aminobutyric acid (GABA),
diol as minor metabolite [1, 8]. The metabolic pathway glutamate, acetylcholine, serotonin, and noradrenaline
of CBD may involve other isoforms of CYP450 such [18]. CB2r are principally expressed in peripheral tissues
as CYP1A2, -2B6, -2C8, -2C9, -2E1, -2J2, and -3A5/7 [18] and are associated with cells governing immune
[1, 9]. The hydroxylation reactions occur furthermore function [19], although the receptorial density in brain
at positions 1”-5” of the aliphatic pentyl- and position is very low and predominantly located at mesolimbic
10 on the propenyl- substituent [8, 11]. These me- DA (DopAminergic) system [18]. CBD possesses a
tabolites may be further oxidized to form dihydroxyl- very low affinity for the CB1 and CB2 receptors [3, 20,
ated metabolites and CBDoic acid derivatives [11]. 21] acting as negative allosteric modulator of the CB1r
At last UGT1A7, UGT1A9, and UGT2B7 isoforms [1] of [22] or inverse agonist of CB2r [23]. Moreover, it can
5’-diphosphoglucuronosyltransferase (UGT), which increase concentrations of anandamide through the in-
catalyze glucuronidation of xenobiotics, create more hibition of fatty acid amide hydrolase (FAAH), its main
easily excreted products [12]. Metabolites are primarily degradative enzyme [4, 22], and the blockade of its re-
excreted with feces and in a minor amount (16% ca.) uptake, promoted by fatty acid-binding protein (FABP)
[13] with urine, while a large proportion of CBD (33%) [4, 18, 22]. For that reason CBD can modulate, through
is excreted unchanged in feces [8]. The slow release, presynaptic CB1rs, the release of certain neurotransmit-
the redistribution phenomenon from deep lipid-storage ters in particular key brain zones. The dampen of neu-
compartments and the significant enterohepatic circu- ronal excitability through the reduction of glutamate
lation contribute to a long terminal half-life elimination release, indirectly protects against the development of
of CBD, with the average amount post inhalation of cannabis use disorder (CUD ) [22] and attenuates psy-
31±4 hours and from 2 to 5 days after repeated daily chotomimetic and anxiogenic effects induced by high
administrations in chronic cannabis users [7, 9]. In a doses of THC in humans. These observations suggested
series of recent studies involving the smoking of “light that this cannabinoid could possess antipsychotic and
cannabis” containing 0.16% THC and 5.8% CBD [14- anxiolytic properties [5, 18, 20, 22]. Experimentally,
16], the highest CBD concentrations in oral fluid (OF), CBD was successfully used in humans for reducing psy-
serum and blood were observed on the samples col- chotic symptoms of schizophrenia, thanks to its partial
lected 0.5 h after the start of smoking and the com- agonist activity on dopamine D2 receptors similarly to
pound was measurable in those biological fluids up to atypical antipsychotics [20]. It also reduces anxiety and
4 hours after administration [14]. Following smoking stress symptoms [3, 20]. In this regard, the anxiolytic
of four “light cannabis” cigarettes with a one h inter- effect exerted by CBD has been mainly related to its
val between each cigarette, CBD concentrations in agonist activity towards serotonin type 1A (5HT1A) re-
blood serum and OF overlapped with those obtained ceptors [3]. Botanical preparation containing THC acid
after smoking a single cigarette, suggesting that CBD precursor (THCA-A) CBD acid precursor (CBDA) and
is poorly absorbed after repeated smoking and that this cannabigerol acid (CBGA) were successfully used for
is not the preferential route to administer it. As a jus- the treatment of neurodegenerative diseases such as
tification to this result, it has to be said that this is the Huntington and possibly Alzheimer and Parkinson [3,
first-time that a product containing negligible amounts 20]. These evidences suggest that acute administration
of psychotropic THC and significant concentration of of CBD may reduce withdrawal symptoms of drugs de-
CBD (58 mg per cigarette) was smoked in a controlled pendence and may also contribute to improve cogni-
clinical trial, and that participants were cigarette smok- tive performances [3]. CBD is a promising therapeutic
ers with some “light cannabis” experience. In fact, given agent approved for reducing seizures in many children
that CBD does not preferentially volatilize compared with Dravet syndrome, a severe treatment-resistant
to THC, a trial on more experienced “light cannabis” form of childhood epilepsy [24]. Analgesic myorelaxant
288
Pietro Brunetti, Alfredo Fabrizio Lo Faro, Filippo Pirani et al.

and antiepileptic actions of CBD are achieved through most recent evidence on cannabinoids effectiveness on
the increasing of inhibitory tone in cortical and stria- sleep refer to CBD therapeutic potential for the treat-
tal membranes obtained from the inhibition of GABA ment of insomnia [29]. This capability is due to its anx-
reuptake and the positive allosteric modulation of GA- iolytic, antipsychotic and neuroprotective properties,
BAA receptor [25]. Thanks to its lack of psychoactivity, which prompted for its potential use in epilepsy, sub-
articles and reviews

CBD is one of the most interesting compounds poten- stance abuse and dependence, post-traumatic stress,
tially useful in various models of pathologies such as depression, and finally sleep disorders [5]. However,
inflammatory and autoimmune disorders like multiple this beneficial CBD feature should be considered when
sclerosis, arthritis, and cancer [6]a lot of attention has the substance is used by healthy individuals, where this
been paid to the compounds present in medicinal Can- anxiolytic and relaxing effects may be dangerous in nor-
nabis sativa L., such as Δ 9 -Tetrahydrocannabinol (Δ mal daily activities such as driving or working.
9 -THC. The agonist activity on peroxisome prolif-
erator-activated receptor gamma (PPARγ) [26], the Legal status in United States of America
competitive inhibition of adenosine uptake [23], the As cannabis compound, CBD was reported in the
antagonism over adenosine receptor A2A [27] and the schedule I of Controlled Substances Act (CSA) which
activation of Transient Receptor Potential Subfamily V prohibits “manufacture, distribution, or dispensation,
O riginal

member 1 and 2 (TRPV1,2) [21, 28], mediated by CBD as well as its possession with intent to manufacture,
produce several changes. Namely, significant reduction distribute, or dispense” of all those substances, that
in release of IL-2 (Interleukin), TNF-α (Tumor Necro- have a high potential for abuse or have no currently ac-
sis Factor), IFN-c (Interferon), IL-6, IL-12, IL-17, eo- cepted medical use in treatment in the United States
taxin-1 (CCL11) and COX-2 (Cyclooxygenase), and of America (US) [30]. On June 25th, 2018 FDA ap-
iNOS (inducible Nitric Oxide Synthases) expression proved Epidiolex® (CBD) oral solution for the treat-
[27], decreasing the inflammatory event and exerting ment of two rare and severe forms of epilepsy, Lennox-
neuroprotective actions after hypoxic ischemic expo- Gastaut syndrome and Dravet syndrome, in pediatric
sure [6] or decreasing the leukocyte infiltration in brain patients [31]. This is the first FDA-approved drug that
in some autoimmune diseases, like multiple sclerosis contains a purified drug substance derived from mari-
[27]. As regards cancer, CBD has exhibited antiprolif- juana, schedule I of CSA [32]. For that reason, FDA
erative and proapoptotic activities through the antago- prepared and transmitted a report of CBD to justify the
nism over G protein-coupled receptors (GPR) 55 [3], necessity of re-scheduling CBD, due to scientific evi-
modulating the tumorigenesis in different types of can- dences of its therapeutic benefits. On September 27th,
cer, including breast, lung, colon, brain, and others [6]. 2018 the Department of Justice and DEA announced
that Epidiolex®, was placed in schedule V, as a “drug
Adverse effects and interactions with lower potential for abuse than Schedule IV con-
CBD is by definition: the major nonpsychoactive phy- taining limited quantities of certain narcotics”, the least
tocannabinoid derived from cannabis [5] and, thanks to restrictive schedule of the CSA [33]. It is necessary to
its good safety profile and the lack of euphoric effects, is underline that CSA did not distinguish between CBD
the most interesting cannabinoid [4]. However, CBD is obtained from recreational, medical or industrial can-
not a biologically inert compound and its complex phar- nabis (hemp). On December 20th, 2018, with the Agri-
macology offers tremendous therapeutic potential but, culture Improvement Act, hemp was definitely removed
also, the potential for adverse effects and drug-drug in- from schedule I and became legal, so any cannabinoid
teractions. Pharmacodynamics and pharmacokinetics or derivatives, including CBD, obtained from hemp are
interactions from cannabinoids may occur via simple legal, if and only if that hemp is produced under the fed-
competitive inhibition, noncompetitive (allosteric) inhi- eral law, while all other cannabinoids, produced in any
bition, or at the level of gene expression of the cannabi- other setting, remain illegal and scheduled in the first
noid receptors, biotransformation enzymes, and trans- table of CSA [34], except for the limited circumstances
port proteins [9]. The metabolic routes of cannabinoids e.g. a medically approved benefit. On June 16th 2019,
primarily involve cytochrome P450 oxidases (CYP) en- the FDA released a document recognizing the signifi-
zymes which are implicated in the primary metabolism cant public interest in cannabis-derived compounds,
and biotransformation of the majority of therapeutic expressing, at the same time, concern for the exponen-
agents and xenobiotics [12]. It is easy to understand tial increase of illegal products that violate the Federal
that these compounds are susceptible to, or complicit Food, Drug and Cosmetic Act (FD&C Act) [35]. From
as, inhibitors or inducers of these enzymes. The de- 2015 to 2019 FDA sent several warring letters to com-
crease in the metabolic activity of individual CYPs can panies that commercialized products containing CBD
increase the plasma levels of their substrates, and symp- because they were marketed as unapproved new drugs
toms of toxicity could appear. In the opposite direction, adding CBD to food [36]. It is essential to underline
increased CYP activity will decrease the efficacy of its that aside Epidiolex ®, no other CBD drug products
substrates, and can lead to the failure of a therapy [10]. were FDA-approved and for that reason they cannot
The above reported studies on “light cannabis” smoking be distributed or sold in interstate commerce [35].
showed that after smoking up to 232 mg CBD in four CBD products are excluded from the dietary supple-
hours time caused sleepiness. It has to be said that few ment definition under section 201(ff) of the FD&C Act
data exist in the international literature concerning the [35, 37]. Nonetheless, ingredients as hulled hemp seed,
side effects of CBD intake in healthy individuals. The hemp seed proteins powder and hemp seed oil, that are
 289
Cannabidiol (CBD) and legal status

derived from parts of the cannabis plant that do not are “safe for human health when used under normal or
contain CBD, might be able to be marketed as dietary reasonably foreseeable conditions of use” in accordance
supplements or be added to food [35]. In the first case, with articles 3 and 4 of the Chapter II of the Cosmetic
this can happen only if dietary supplements comply re- Regulation (Regulation (EU) No 1223/2009) [44], as
quirements related to Current Good Manufacturing to say: if they not contain any substances listed in the

articles and reviews

Practices and are correctly labeled to eliminate any pos- Annex II and are “obtained from cannabis, cannabis
sible risk of illness or injury [37]. In the second case, resin, cannabis extracts and cannabis tinctures originat-
only after approval by FDA or if CBD addition to food ing from the seeds and leaves that are not accompanied
is generally recognized as safe [35]. At last, cosmetics by the fruiting tops of the cannabis plant” [43]. There-
containing CBD are not restricted by any regulation. fore, whereas US legal status of CBD is currently well
However, all ingredients must comply with all appli- defined throughout Federal States, EU one is not ho-
cable requirements and cannot be used if they cause mogeneous at moment, nor extensively regulated, with
adulteration or misbranding of the product or could be some countries, such as Italy, with no legal measures
injurious to users [37]. So it seems that the 2018 Farm at all.
Bill, the primary agricultural and food policy tool of the
federal government explicitly preserved FDA’s author- Legal status in Italy

O riginal
ity to regulate products other than medicines contain- Currently, in Italy, there are no laws that ban CBD
ing cannabis or cannabis-derived compounds (CBD in and at moment CBD is not yet registered as a medici-
particular) under the FD&C Act. On the other hand, nal. Due to this law vacancy, some hemp shops freely
the Farm Bill has no effect on state-legal cannabis offer CBD products (oil, crystals, etc).
programs, in which cannabis and derived compounds
(CBD in particular) were legalized for medical and rec- CONCLUSIONS
reational purposes, that are declaimed illegal under the Thanks to its safe therapeutic profile and its lack of
federal law [38]. psychoactivity, CBD is one of the most interesting com-
pounds, with a lot of reported pharmacological effects
Legal status in European Union in different models of pathologies, from inflammatory
In European Union (EU) there is no harmonized and neurodegenerative diseases, to epilepsy, autoim-
law on CBD use. Indeed, currently the criminal or mune disorders like multiple sclerosis, arthritis, schizo-
administrative response towards CBD use is under phrenia, cancer and many others. Even if pharmaceuti-
the responsibility of each EU Member State. Actu- cal and therapeutic profile of CBD is deeply notorious,
ally, medicinal products containing CBD, such as: Sa- its legal status, in different countries around the world,
tivex® and Epidiolex® (since September 19th, 2019), isn’t clear and harmonized. The widespread growth of
are authorized in many EU countries, and, in some of markets selling products containing CBD (medicinal
them, under certain conditions, are reimbursed by the products, foods and cosmetics) is not only an “Ameri-
national health insurance system [39, 40]. Any medici- can” reality, but also involves many Europeans Coun-
nal product containing CBD placed for sale or distri- tries, and according to recent market research studies
bution on the market in a Member State must require it will continue growing exponentially over the next few
a Community marketing authorization, released by the years. Actual legislative acts of different governments
European Agency for the Evaluation of EMA, in ac- to control drugs, foods and cosmetics containing CBD,
cordance with the Title I article 3 of Regulation (EEC) which are easily available for consumers, are nowadays
N. 2309/93 [41]. The marketing authorization shall be inappropriate to support the international and intrana-
valid throughout the Community. On the contrary, the tional market without a systematic revision and could
rejection of a Community marketing authorization shall cause an important public health threat.
constitute a prohibition on the placing on the market
of the medicinal product throughout the Community Funding
in compliance with the Title II article 12 of Regulation The study was partly supported by Department for
(EEC) N. 2309/93 [41]. In the past few years there has Anti-Drug Policies, Presidency of the Council of Min-
been an increase in the availability of cannabis based isters of Italian Government.
products (herb, hemp, oils) that contain CBD, referred
as “light cannabis” [17]. All extracts of Cannabis sativa Acknowledgements
L. and any product to which CBD, synthetically ob- The authors thank Michele Sciotti, Laura Martucci,
tained or not, is added as ingredient, have to be con- Antonella Bacosi and Simonetta Di Carlo for technical
sidered as novel foods and strictly controlled under the assistance.
novel food Regulation ((EU) 2015/2283) [42]. As in
case of medicinal products, novel foods require a com- Conflict of interest statement
munity authorization for the suppling in EU Member None of the authors have any conflict of interest.
States market which is released by the EFSA [42, 43].
Others Cannabis based products containing CBD may Received on 15 December 2019.
be used in cosmetics placed on the EU market if they Accepted on 17 March 2020.
290
Pietro Brunetti, Alfredo Fabrizio Lo Faro, Filippo Pirani et al.

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