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REVIEW
463Pharmazie 75 (2020)
Department of Pharmaceutical Technology and Cosmetology1, Department of Pharmaceutical Chemistry2, Department of
Analytical Chemistry and Drug Analysis3, Faculty of Pharmacy, “George Emil Palade” University of Medicine, Pharmacy,
Science and Technology of Târgu Mureș, Târgu Mureș, Romania
Cannabidiol - therapeutic and legal aspects
R. A. VLAD1, G. HANCU2,*, A. CIURBA1, P. ANTONOAEA1, E. M. RÉDAI1, N. TODORAN1, O. SILAȘI1, D. L. MUNTEAN3
Received June 16, 2020, accepted August 11, 2010
*Corresponding author: Gabriel Hancu, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, “George
Emil Palade” University of Medicine, Pharmacy, Science and Technology of Târgu Mureș, Târgu Mureș, Romania,
540142.
gabriel.hancu@umfst.ro
Pharmazie 75: 463-469 (2020) doi: 10.1691/ph.2020.0076
Cannabidiol (CBD) is an alkaloid present in Cannabis sativa, along with tetrahydrocannabinol (THC) and more
than 100 other substances belonging to a group of compounds called cannabinoids. Whereas the legal status
and medical use of Cannabis is a controversial issue in many countries, inconsistent legislation makes CBD
status even more complicated. Some CBD products are legal in some countries, while banned in other coun-
tries, further compounding the confusion. In 2018, the Food and Drug Administration (FDA) approved the first
CBD containing medical product, Epidiolex®, for the treatment of paediatric seizures. Currently, several clinical
trials are in progress for the potential treatment of neurologic and behavioural disorders. CBD’s current legal
and regulatory status is a continuously evolving issue; the current review is presenting historical and present
information regarding the use of CBD products worldwide.
1. Introduction
The Cannabis family comprises the Cannabis sativa and Cannabis
indica species. Cannabis plant has been used for ages to produce
hemp fibre (for clothing, rope and paper), seeds which can be
used as animal feed and also as a medicinal plant. Cannabidiol
(CBD) is one of the main alkaloids found in the composition of
the Cannabis plants together with other 103 identified alkaloids
(Lafaye et al. 2017).
The two major neuroactive components in Cannabis plants are:
the main psychoactive alkaloid, tetrahydrocannabinol (THC) and
the non-psychoactive alkaloid, CBD (Ibarra-Lecue et al. 2018).
Taking into consideration the current legislation there are small
differences regarding the amounts of THC admitted in the hemp
preparations, ranging between 0.05 and 0.6%. As a result, if the
plant contains THC it presents a high illicit use and interest, conse-
quently, its cultivation is prohibited by national laws (Wilkinson et
al. 2016). Among the Cannabis illicit preparations, we can mention
the following: marijuana (a mixture of leaves, flowers, and seeds
of the hemp plant), hashish (obtained from unfertilized buds) and
also oils which can be prepared easily because the alkaloids are
lipophilic (Chandra et al. 2019).
Currently, CBD is used as an active ingredient in the following
preparations, Epidiolex® – oral solution (contains only CBD)
and Sativex® – oromucosal spray (contains both CBD and THC)
(Giacoppo et al. 2017, Rekand 2014, Bartner et al. 2018, Lucas et
al. 2018).
The legal status of Cannabis alkaloids is different from one country
to another, as there are countries in which the THC and CBD are
classified in the same class of prohibited substances while in other
countries CBD products are legal (Corroon and Kight 2018).
Taking into consideration that on the legal market via the internet
or in different shops, CBD can be found in many pharmaceutical
and cosmetical formulations we consider that a systematic review
of CBD therapeutic use and legal status around the world can be an
interesting topic for the professionals in the pharmaceutical field.
2. CBD chemical and pharmacological characterization
The chemical structures of CBD and THC are presented in Fig. 1.
CBD has a molecular mass of 314.5 g/mol, the same as THC.
Structurally the two alkaloids differ as CBD is a bicyclic compound
while THC is tricyclic. CBD is a white crystalline powder with an
Fig. 1: Chemical structure of CBD and THC.
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464 Pharmazie 75 (2020)
extremely low solubility in water of approximatively 1 mg/L being
included in the second class using the Biopharmaceutical Classifi-
cation System (BCS II), with low solubility and high permeability
(https://www.drugbank.ca/drugs/DB09061).
There are several routes of administration for CBD, each with its
advantages and disadvantages. After oral administration of CBD,
the maximum concentration is reached after 3 hours, however,
bioavailability is low; gastrointestinal absorption is also low and
unpredictable because of its low water solubility. The low bioavail-
ability after oral administration is linked also with its metabolization
into the main metabolites 11-hydroxycannabidiol (11-OH-CBD) and
7-hydroxycannabidiol (7-OH-CBD) while the transformation of CBD
into 1’-hydroxycannabidiol (1’-OH-CBD), 2-hydroxycannabidiol
(2’-OH-CBD), 3’-hydroxycannabidiol (3’-OH-CBD), 4’-hydroxy-
cannabidiol (4’-OH-CBD), 5’-hydroxycannabidiol (5’-OH-CBD),
6α-hydroxycannabidiol (6α-OH-CBD) and 6β-hydroxycannabidiol
(6β-OH-CBD) ensues less often. By inhaling or by smoking higher
concentrations are reached in comparison with oral administration.
Due to the lipophilic character, it can be administered sublingually.
Sublingual administration has a similar bioavailability to oral admin-
istration but presents less variability (Huestis 2007).
CBD is strongly distributed in highly vascularized organs such
as the heart, lungs, and liver (Gaston et al. 2017; Dinis-Oliveira
2016). If it is administered for a longer period, there is a high risk
of accumulation in the fatty tissue especially in obese patients
(Hunt and Jones 1980). The distribution volume is over 30 L when
CBD is administered intravenously while, when administered by
inhalation, decreases to a maximum of 4 L (Lucas et al. 2018).
The isoenzymes responsible for the CBD metabolization are
CYP2C19, CYP3A4, CYP1A1, CYP1A2, CYP2C9, CYP2D6
(Huestis 2007, Zendulka et al. 2016). A scheme of CBD metabo-
lism is presented in Fig. 2.
Elimination of CBD occurs usually after 24-36 hours varying as a
function of the administration route (Gamble et al. 2018; Consroe
et al. 1991).
Many types of effects have been associated with CBD and they
seem to be related to a complex pharmacodynamic mechanism.
CBD does not activate the cannabinoid receptors (CB1 and
CB2), acting more like an antagonist for the CB2 receptor and
antagonist modulator for CB1. This may explain the lack of
psychotropic effects. Depending on the concentration it can be
an antagonist for the G protein-coupled receptor 55 (GPR55).
It also has an agonist effect on the following receptors: sero-
tonin 1A receptor (5-HT1A), adrenergic receptors (α3, α1) and,
transient receptor potential ankyrin 1 (TRPA1). At high concen-
trations, it can act as an agonist on peroxisome proliferator-acti-
vated receptor gamma (PPAR-γ) and on the vanilloid receptors:
transient receptor potential cation channel subfamily V member
1 and member 2 (TRPV1 and TRPV2). Due to the polyphenolic
structural characteristics, CBD can act as a strong antioxidant
(Szaflarski and Bebin 2014; Tham et al. 2019; Smith and Zheng
2016).
CBD is one of the cannabinoids found in the Cannabis plant
with a high pharmacologic and therapeutic potential (Zuardi et
al. 1982). CBD has some obvious advantages in comparison with
THC as it does not present addiction risks and tachyphylaxis.
Recent studies on both substances showed that CBD has an anxi-
olytic effect while THC may induce anxiety (Niesink and van
Laar 2013).
Another advantage of CBD is related to the absence of psychotic
effects during administration. Some studies showed that CBD
might be used for the patient suffering from schizophrenia while
others pointed out the fact that THC might induce sleepiness
(Nicholson et al. 2004; Mao et al. 2015).
Fig. 2: CBD metabolic pathways.
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465Pharmazie 75 (2020)
3. CBD therapeutic use
CBD was administered in many studies to verify its potential
effects in epilepsy treatment; the results showed that it was more
effective on partial and generalized seizures than in seizures local-
ized in the temporal lobe. Intraperitoneal administration of 100
mg/body weight (bw) of CBD decreased the probability of tonic-
clonic seizures (Mao et al. 2015).
As in the other diseases, the way the seizures are induced is
important. CBD has positive effects in the treatment of seizures
induced by administrating pentylenetetrazol (PTZ), picrotoxin,
or penicillin G while when pilocarpine was used to induce the
seizures no effects were observed. The mortality rate decreased
while administrating PTZ, picrotoxin and, penicillin G, while in
the case of pilocarpine remained the same (Mao et al. 2015).
In a clinical trial including 15 patients (11 females) with temporal
lobe epilepsy, patients received 300 mg CBD for 18 weeks; 4
Gastaut and Dravet syndromes associated with seizures for patients
older than 2 years. The dosage starts with 2.5 mg/bw twice daily
and it can increase up to 20 mg/bw/day (Sekar and Pack 2019;
Abu-Sawwa and Stehling 2020).
CBD products might be used off-label for the treatment of other
medical conditions. Epidiolex® can be prescribed for epilepsy-re-
lated diseases but in the future other curative effects might be
approved. At this point, if a physician is prescribing CBD-con-
taining drugs off label might encounter several issues since insur-
ance companies might not cover the costs of the drug. Possible
off-label use of CBD includes also pain relief (Cohen and Sharf-
stein 2019). Various dietary supplements are sold on the market
and many of them are containing CBD. The dietary supplements
are used as adjuvants in the treatment of Parkinson disease, various
types of epilepsy, or anxiety (Trudeau et al. 2019). Also, anti-aging
effect has been related to CBD (Tura et al. 2019).
Table 1: Approved pharmaceutical products which contain only CBD
Name Substances
contained
Approval year Website/Reference Approved by
Epidiolex (Greenwich,
United States of
America (USA).
Contains
100 mg/ml CBD
June 2018 https://www.fda.gov/news-events/public-health-focus/
fda-regulation-cannabis-and-cannabis-derived-
products-including-cannabidiol-cbd
https://www.ema.europa.eu/en
FDA and European Medicines
Agency (EMA)
Table 2: Studies of CBD potential anxiolytic effects
Study design and duration CBD pharmaceutical formulation,
control dose and route
Results Reference
47 subjects (humans) with an anxiety disorder.
Diagnosis established by clinical evaluation.
Study duration: 3 months. Analysis of the results using the
Hamilton Anxiety Rating Scale
Capsules
Oral route
25 mg/day
and
75 mg/day
The anxiety score decreases
from 13 to less than 10 after 2
months and it remained under
10 after 3 months which indi-
cates a mild severity.
Shannon et al. (2019)
24 subjects with Parkinson disease.
Anxiety was induced by a Simulated Public Speaking Test
(SPST).
Study duration: the interval between the first and the second
experiment was 15 days.
Analysis of the results: The Unified Parkinson’s Disease
Rating Scale, Hoehn and Yahr Scale, Schwab and
England Scale
Gelatine capsules
Oral route
300 mg/day
CBD decreased the anxiety
induced by the SPST
De Faria et al. (2020)
36 subjects (Male mice and C57/6J controls.
Kept for 12h:12h light-dark schedule, food and water
provided ad libitum).
Mice received intraperitoneal injection 30 min before
starting the behavioural testing.
Alcoholic solution (Tween
80, Absolute alcohol and
NaCl 0.9% - 1:1:18)
5mg/bw
20 mg/bw
CBD
5 mg/bw did not influence the
anxiety effect while the higher
concentration decreased the
anxiety.
Zieba et al. (2019)
440 male and female mice C57BL/6J (B6).
Kept on a 12:12 h reverse light cycle.
The injections were made during the active dark phase.
Alcoholic solution
(Tween 80, absolute alcohol
and NaCl 0.9% - 1:1:18)
5 mg/bw
10 mg/bw
20 mg/bw
THC produces an anxiogenic ef-
fect while CBD does not present
an anxiolytic effect.
Kasten et al. (2019)
patients did not present any seizures during the trials (Carlini and
Cunha 1981).
In another study conducted on 34 patients, the effect of CBD in
Dravet Syndrome was verified at concentrations of 5-10-20 mg/
bw. During the 4-week treatment, it has been observed that less
than 4 seizures occurred (Devinsky et al. 2018a). In another study,
120 patients were enrolled, among them, 58% were women aged
between 2-18 years old. The patients received a CBD dose of 20
mg/bw orally for 14 weeks (Devinsky et al. 2018b). During both
trials, it has been observed that the frequency of seizures decreased
but the levels of liver aminotransferases increased which may
conduct to hepatic pathologies (Devinsky et al. 2018a, b).
Epidiolex® is an oily solution where sesame oil and alcohol are
used as solvents and it is utilized for the treatment of Lennox
4. CBD potential pharmaceutical use
It has been proven that CBD can be used therapeutically to treat
anxiety; high concentrations of 300-1500 mg/day of CBD have
been well-tolerated without the occurrence of side effects. The
receptor responsible for the antianxiety effect is 5 HT1, CBD acting
as an agonist on this receptor (Linge et al. 2016).
It can be observed that the results regarding CBD use in anxiety
management are mixed; some of them showing the fact that CBD
might reduce anxiety in higher doses while in others an anxiolytic
effect was not noticed.
The results of the studies that linked to the possible use of CBD
in Parkinson disease are also mixed. In a study, Parkinson disease
was induced by the administration of 6-hydroxy-dopamine
(6-OH-dopamine) to rats. After the administration of 3 mg/bw
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466 Pharmazie 75 (2020)
CBD, it has been observed that the dopamine levels in the putamen
have increased. CBD may be used in the early stages of Parkinson
disease and its therapeutic effect may be linked to the antioxidant
effect which is tissue specific. For example, when N18TG murine
neuroblastoma cell was used, no effect occurred, while when
mesencephalic murine was used the CBD had the antioxidant
effect and the glutathione level increased, too (Lastres-Becker et
al. 2005).
CBD has been used in clinical trials and the results showed signif-
icant reductions in the positive and negative effects while no effect
was seen on the cognitive function (Zuardi et al. 2009).
Hyperactivity is one of the symptoms of schizophrenia, which can
be induced in animals by using amphetamine or ketamine. Admin-
istration of doses between 50 and 60 mg/bw of CBD in animal
experiments conducted to the normalization of the hyperlocomo-
tion previously induced by using dopamine receptors agonists
(Moreira and Guimaraes 2005; Long et al. 2010; Gururajan et
al. 2011). Another symptom that may occur in patients with
schizophrenia is the inability of processing/filtering unnecessary
information. In animal studies, this effect is measured by using the
pre-pulse inhibition (PPI) of the startle response. Studies showed
that CBD attenuates the PPI induced by amphetamine adminis-
tration in Swiss mice and Sprague-Dawley rats (Gururajan et al.
2012). Concentrations between 3 and 30 mg/bw showed to be less
effective on the PPI while concentrations between 1 and 3 mg/bw
normalized hyperlocomotion (Deiana et al. 2015).
In a case-control study, patients between 22 and 33 years old,
received placebo from day 1 to day 5; 1280 mg of oral CBD from
day 6 to day 35, placebo from day 36-40 and in the end olanzapine
for 15 days; mixed results were obtained. In some cases, CBD
showed improvement while in other cases no improvement was
observed (Zuardi et al. 2006).
Table 3: Legal status of CBD, CBD oil and industrial hemp worldwide
Country CBD CBD oil Hemp Approved pharmaceutical
product containing
cannabinoids
Organisation /Legislative
Instrument
Reference website
Australia LegalaLegalaLegal Sativex®The Poisons Standard https://www.legislation.gov.au/Details/
F2020L00017
Austria LegalbLegalcLegaldSativex®
Dronabinol®
Nabilone®
EMCDDA http://www.emcdda.europa.eu/countries/
drug-reports/2019/austria/drug-laws-
and-drug-law-offences_en
Canada LegalaLegalaLegal
a, d
Sativex®Controlled Drug and
Substances Act
http://laws-lois.justice.gc.ca
Czech Republic LegaldLegaldLegaldSativex®EMCDDA
Criminal Code of the
Czech Republic
http://www.emcdda.europa.eu/countries/
drug-reports/2019/czechia_en
http://www.ejtn.eu/PageFiles/6533/
Criminal%20Code%20of%20the%20
Czech%20Republic.pdf
France LegaleLegaleLegal Sativex®EMCDDA http://www.emcdda.europa.eu/countries/
drug-reports/2019/france_en
Germany LegaleLegaleLegaleSativex®
Dronabinol®
Nabilone®
EMCDDA http://www.emcdda.europa.eu/countries/
drug-reports/2019/germany_en
Greece LegaleLegaleLegaleNone approved yet EMCDDA http://www.emcdda.europa.eu/publica-
tions/topic-overviews/cannabis-policy/
html_en
Hungary LegaleLegaleLegaleMarinol®EMCDDA http://www.emcdda.europa.eu/countries/
drug-reports/2019/hungary_en
Italy LegalfLegalfLegalgSativex®EMCDDA http://www.emcdda.europa.eu/countries/
drug-reports/2019/italy_en
Romania Legal Legal Legal None approved yet Law No. 339/2005. https://cmvro.ro/files/download/
legislatie/stupefiante-psihotrope/
Legea_339_2005_stupefiante_psiho-
trope-consolidata.pdf
Russia Illegal Illegal Legal None approved yet Government of the
Russian Federation
https://www.wto.org/english/thewto_e/
acc_e/rus_e/WTACCRUS48A5_
LEG_56.pdf
Spain LegaleLegaleLegaleSativex®
Dronabinol®
Nabilone®
Epidiolex®
EMCDDA http://www.emcdda.europa.eu/countries/
drug-reports/2019/spain_en
The Netherlands LegalhLegalhLegaleStandardised medicinal
Cannabis flower
EMCDDA http://www.emcdda.europa.eu/countries/
drug-reports/2019/netherlands_en
The United
Kingdom
LegaleLegaleLegalaSativex®EMCDDA http://www.emcdda.europa.eu/system/
files/publications/11355/united-
kingdom-cdr-2019.pdf
United States of
America
IllegaliIllegaliLegaldSativex®
Dronabinol®
Epidiolex®
FDA - Regulation of
Cannabis and
Cannabis-Derived
Products.
https://www.fda.gov/news-events/
public-health-focus/fda-regulation-
cannabis-and-cannabis-derived-
products-including-cannabidiol-cbd
a Legal as long as you have a government license b In Austria CBD is legal to be used in aromatherapy. It is forbidden to be used in food or cosmetics. c Only if it is prepared in a pharmacy as magistral prepa-
rations, otherwise in supplements it is strongly prohibited d Legal as long as THC concentration is below 0.3, in the Czech Republic this implies for technical hemp while medicinal hemp with higher THC
values is legal with a medical prescription. e Legal as long as THC concentration is below 0.2%. f Legal as long as THC concentration is below 0.6%. Available with prescription. g Legal as long as THC is
lower than 0.2%, also if it is higher but is not exceeding 0.6% it is not punishable by laws. h Legal as long as THC concentration is below 0.05%. i It is illegal under federal law
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467Pharmazie 75 (2020)
In a clinical study, 88 patients received 1000 mg of CBD daily
and an antipsychotic for 6 weeks. The patients that received CBD
beside the usual antipsychotic treatment showed no improvements
in negative and cognitive symptoms of schizophrenia while an
improvement in the positive symptoms was observed (McGuire et
al. 2018).
Alzheimer disease can be induced in mice by using β-amyloid
administered in the right dorsal hippocampus. Doses between 2.5
mg and 10 mg showed that CBD blocks the nitric oxide synthase
with the result of decreased Reactive Oxygen and Nitrogen Species
(ROS, RNS) levels and interleukin 1 β which is associated with
the neurodegenerative process. In a study, when Alzheimer disease
was induced using β-amyloid, CBD showed improved cognitive
performance and lower levels of pro-inflammatory cytokines (TNF
α and IL-6) (Martin-Moreno et al. 2011).
5. CBD legal status
As a result of their high popularity, many dietary supplements
containing CBD were developed and marketed, starting from soft
capsules containing both CBD and CBDA (cannabidiolic acid)
continuing with hard capsules containing a lipophilic gel and ending
with various oily solutions with different concentrations of CBD.
It is expected that in future years, the CBD dietary supplements
business will reach billions of euros worldwide. Dietary supple-
ments are defined as nutritional products whose purpose is to fill
a normal diet. They are concentrated sources of nutrients or other
substances with physiological and nutritional effects marketed
as capsules, tablets, pills, ampoules with liquid or powder. The
nutrients are defined as vitamins and minerals. Because CBD is an
active pharmaceutical ingredient and it cannot be included in the
vitamin class nor it has any physiological effects, the use of CBD
in dietary supplements is not legal in all countries. In the USA
there are lots of supplements containing CBD which have been
prohibited as a result of the lack or absence of the declared amount
of CBD (Cogan 2019; Wheeler et al. 2020).
According to the Controlled Substance Act, CBD is listed in Schedule
I of prohibited substances (together with both THC and mari-
juana) while the newly approved product Epidiolex® that contains
CBD is listed in Schedule V. Schedule V includes pharmaceutical
formulations with limited amounts of certain narcotics (Controlled
Substances Act, 2018; Hudak and Stenglein 2017). The import,
acquisition, distribution, and possession of THC and marijuana is
prohibited by law. As a result of the Farm Bill Act, hemp has become
legal with the following amendment, it cannot have a concentration
of THC higher than 0.3% so that hemp would not exert psychotropic
effects. Also, CBD can be extracted from the plant, but CBD limits
are not provided (Hemp Farming Act 2018). Even though the hemp
has become legal, FDA maintains the authority in verifying the prod-
ucts containing hemp or hemp-derived compounds. Considering that
in the USA, many dietary supplements are sold which contain CBD,
FDA stated that beside Epidiolex® there is no other pharmaceutical
formulation accepted which contains only CBD and does not recom-
mend the use of the supplements found on the market because CBD
is a drug with restricted use and it cannot be found legally in dietary
supplements. However, by accepting the Epidiolex® solution FDA
recognizes the benefit and therapeutically effect of CBD (Controlled
Substances Act 2018).
In Hungary, distribution and use of Cannabis are prohibited. The
cultivation is permitted only on restricted areas and only seeds
that are metallically sealed can be used. The testing of Cannabis
plants and the experimental and scientific cultivation can be done
with the approval of the National Institute of Pharmacy and Nutri-
tion. Possession of quantities higher than 100 g of cannabis are
illicit and can be punished with imprisonment (162/2003. (X. 16.)
Government Decree, Hungary).
In Austria, the industrial hemp with concentrations below 0.3%
after blossoming can be used for industrial and medicinal purposes.
The recreational use of cannabis is not prohibited while buying and
possession are considered illegal. CBD oil is considered licit and
there are also a few formulations that are used such as Dronabinol
which contains also 2.5 mg THC and Sativex which contains CBD
(2.7 mg) and THC (2.5 mg) that can be used with prescription.
The products derived from flowers and fruits are excluded by the
narcotics law. Like in the USA, dietary supplements are prohibited
(Pohl and Natterer 2019).
The information found on the European Monitoring Centre for
Drugs and Drug Addiction (EMCDDA) showed that in the Czech
Republic, hemp is not prohibited but there is a maximum amount
of 0.3% of THC admitted by law enforcement for the production of
fibres and seeds. Here also appear age restrictions, as only subjects
over 18 years old can receive medical hemp. There is a maximum
weight of Cannabis of 180 g/month admitted that a person can
have but if a person is caught having over 10 g of cannabis or
possessing medicinal hemp without a prescription (with the
amount of THC larger than 0.3 %) there is a huge risk of imprison-
ment. The country from which the Czech Republic usually imports
Cannabis is the Netherlands, however few other countries such as
Canada are mentioned as countries from which the Czech Republic
admits importing. Prescribing CBD and THC is very difficult due
to bureaucracy so there are a few physicians that can prescribe the
cannabinoids or the pharmaceutical formulations due to the restric-
tions regarding the diagnosis and medical specialization (Act No.
167/1998 Coll., Czech Republic; EMCDDA, 2019).
In Romania, THC and 5 other isomers can be found in Table I in the
class of narcotics. This table realized in 2005 and updated in 2018
contains prohibited plants and substances without a therapeutic
effect. CBD is not included. The cannabis plant, Cannabis resins,
tinctures, extracts, and Dronabinol can be found in Table II which
includes narcotic plants and substances which have an interest in
medicine but are the subject of strict control. As a result of the high
popularity, we can find a lot of dietary supplements with CBD but
their concentration might be very low (Law No. 339/2005).
Currently, in Romania, no pharmaceutical formulation containing
CBD has been approved by the National Drug Agency. Many prod-
ucts containing CBD refer to the fact that CBD is not found in the
prohibited list, so it is considered that CBD is legal (https://www.
anm.ro/nomenclator/medicamente).
Numerous supplements containing CBD are marketed worldwide
and none of the producers has received any bans, excepts for the
USA where the FDA does not recommend using CBD supplements
due to the unknown concentration of CBD. Another fact that has to
be taken into consideration is that the hemp seeds contain only traces
of THC and CBD while the hemp plant contains on average less than
0.3% THC (depending on the country). The average concentration
of CBD is between 12-18% (Cohen and Sharfstein 2019).
By evaluation of the studies in which both the THC and CBD
levels were established, it has been observed that the concentra-
tion of THC in the resins increased in the United Kingdom, Italy,
and France while in the Netherlands the concentration remained
Table 4: THC: CBD ratios in cannabis resins in different countries
Country THC:CBD ratio/year References
Netherlands 2.66 (2005) 6.5 (2009) 3.95 (2015) Niesink et al. (2015)
United Kingdom 0.86 (2005) 1 (2009) 2.74 (2015) Potter et al. (2008)
Italy - 2.18 (2010) 3.66 (2013) Zamengo et al. (2013, 2014)
France 2(2005) 2 (2009) 6 (2016) Dujourdy and Besacier (2017)
Romania 4.1 (2011) Trofin et al. (2012)
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468 Pharmazie 75 (2020)
constant. We can also mention the fact that resins tend to have
an increased concentration of THC while the CBD concentration
is small or missing. We can conclude that the THC:CBD ratio is
increased because the THC concentration in the resins has been
increasing while the CBD concentration remains the same or
decreased dramatically (Freeman et al. 2019; Potter et al. 2008;
Dujourdy and Besacier 2017; Pijlman et al. 2005).
Another study which had as a central theme the quantification of
CBD in the cannabis plant showed a descending slope of the CBD
concentration, decreasing from 0.37 to 0.17%. The same situation
emerged in the case of hashish samples. Also, the CBD concentra-
tions in the hashish at the end of the study (2017) were higher than
in the cannabis plant at the beginning of the study (2008). The only
product in which the concentration of CBD increased was the hash
oil where the concentration almost doubled from 0.2% in 2008 to
0.39 in 2017 (Chandra et al. 2019).
As can be seen in the Table in most of the countries the THC:CBD
ratio is increasing. The only country where the ratio decreased is
the Netherlands that can be explained as a result of strict regula-
tions (even though using for recreational purposes is legal) since
they rarely import cannabis from other countries and they have
strict amounts of cannabis available for recreational use. In the
United Kingdom, the ratio has tripled from 2005 up to 2015 the
same as in France from 2009 until 2016, while in Italy in 3 years
the ratio almost doubled. (Niesink et al. 2015, Potter et al. 2008,
Zamengo et al. 2013, 2014, Dujourdy and Besacier 2017).
6. Conclusions
Because CBD has a complex mechanism of action there is a
great potential of using it in the treatment of different medical
conditions. The first and the only FDA-approved CBD prepara-
tion – Epidiolex® is used for the treatment of seizures associated
with Dravet and Lennox-Gastaut Syndromes. The main problem
in obtaining other pharmaceutical products is the high lipophilic
profile and strict legislation. In many countries CBD is legal, but
in others its regulatory status is not clear.
The organizations responsible for the presence and occurrence of
new products containing CBD are having a strict position, most of
them denying the therapeutic in the effect of dietary supplements
because the CBD concentration is smaller than declared.
In some European countries the medicinal use of cannabis is
legal so also the use of CBD products is legal, but legislation is
also strict; consequently, availability of the drug being slowed by
bureaucracy. However, cannabis legal status has changed recently
in many countries.
The THC:CBD ratio is an important parameter; in many EU countries
the THC level has increased while the CBD level decreased. The Neth-
erlands is one of the few countries where the THC:CBD ratio decreased.
The legal status of the CBD was presented in numerous countries.
It has been shown that even if the countries from Europe are part of
the European Union, the legislation regarding the THC maximum
amount differs from country to country; each country has its strict
legislation. In the future, many diseases could be included in the
list of the illnesses treated with CBD.
Conflicts of interest: None declared.
References
Abu-Sawwa R, Stehling C (2020) Epidiolex (Cannabidiol) primer: frequently asked
questions for patients and caregivers. J Pediatr Pharmacol Ther 25: 75–77.
Act No. 167/1998 Coll., on Dependency Producing Substances and on Amending
Certain Other Acts, as subsequently amended, Czech Republic. (Zákon č.
167/1998 Sb.o návykových látkách a o změně některých dalších zákonů, České
republice) Available from https://www.mzcr.cz/act-no-167-1998-coll/. Accessed
May 05, 2020.
Bartner LR, McGrath S, Rao S, Hyatt LK, Wittenburg LA (2018) Pharmacokinetics
of cannabidiol administered by 3 delivery methods at 2 different dosages to healthy
dogs. Can J Vet Res 82: 178–183.
Carlini EA, Cunha JM (1981) Hypnotic and antiepileptic effects of cannabidiol. J Clin
Pharmacol 21: 417S–427S.
Chandra S, Radwan MM, Majumdar CG, Church JC, Freeman TP, El Sohly MA
(2019) New trends in cannabis potency in USA and Europe during the last decade
(2008–2017). Eur Arch Psychiatry Clin Neurosci 269: 5–15.
Cogan PS (2019) On healthcare by popular appeal: critical assessment of benefit and
risk in cannabidiol based dietary supplements. Expert Rev Clin Pharmacol 12:
501-511.
Cohen PA, Sharfstein J (2019) The opportunity of CBD – reforming the law. N Engl
J Med 381: 297–299.
Consroe P, Laguna J, Allender J, Snider S, Stern L, Sandyk R (1991) Controlled clin-
ical trial of cannabidiol in Huntington’s disease. Pharmacol Biochem Behav 40:
701–708.
Corroon J, Kight R (2018) Regulatory status of cannabidiol in the United States: a
perspective. Cannabis Cannabinoid Res 3: 190–194.
de Faria SM, de Morais Fabricio D, Tumas V, Castro PC, Ponti MA, Hallak, JE,
Zuardi AW, Crippa, J, Chagas M (2020) Effects of acute cannabidiol administra-
tion on anxiety and tremors induced by a simulated public speaking test in patients
with Parkinson’s disease. J Psychopharmacol 34: 189–196.
Decision of the Government of the Russian Federation No. 681 of June 30, 1998
on the approval of the list of Narcotic Drugs, Psychotropic substances and their
precursors that shall be subject to control in the Russian Federation. (Postanov-
leniye Pravitel’stva Rossiyskoy Federatsii No 681 ot 30 iyunya 1998 g. ob utver-
zhdenii perechnya narkoticheskikh sredstv, psikhotropnykh veshchestv i ikh
prekursorov, podlezhashchikh kontrolyu v Rossiyskoy Federatsii. Available from
https://www.wto.org/english/thewto_e/acc_e/rus_e/WTACCRUS48A5_LEG_56.
pdf Accessed May 07, 2020.
Deiana S, Watanabe A, Yamasaki Y, Amada N, Kikuchi T, Stott C, Riedel G (2015)
MK-801-induced deficits in social recognition in rats: reversal by aripiprazole, but
not olanzapine, risperidone, or cannabidiol. Behav Pharmacol 26: 748–765.
Devinsky O, Patel AD, Thiele EA, Wong MH, Appleton R, Harden CL, Greenwood
S, Morrison G, Sommerville K (2018a) Randomized, dose-ranging safety trial of
cannabidiol in Dravet syndrome. Neurology 90: 1204–1211.
Devinsky O, Patel AD, Cross JH, Villanueva V, Wirrell EC, Privitera M, Greenwood SM,
Roberts C, Checketts D, Van Landingham KE, Zuberi SM (2018b) Effect of cannabi-
diol on drop seizures in the Lennox-Gastaut syndrome. N Engl J Med 378: 1888–1897.
Dinis-Oliveira RJ (2016) Metabolomics of delta9-tetrahydrocannabinol: implications
in toxicity. Drug Metab Rev 48: 80–87.
Dujourdy L, Besacier F (2017) A study of cannabis potency in France over a 25 years
period (1992–2016). Forensic Sci Int 27: 72–80.
Esposito G, Scuderi C, Savani C, Steardo LJ, Filippis D De, Cottone P, Iuvone T,
Cuomo V, Steardo L (2007) Cannabidiol in vivo blunts beta-amyloid induced
neuroinflammation by suppressing IL-1beta and iNOS expression. Br J Pharmacol
151(8): 1272–1279.
Freeman TP, Groshkova T, Cunningham A, Sedefov R, Griffiths P, Lynskey MT
(2019) Increasing potency and price of cannabis in Europe, 2006-16. Addiction
114: 1015–1023.
Gamble LJ, Boesch JM, Frye CW, Schwark WS, Mann S, Wolfe L, Brown H, Berth-
elsen ES, Wakshlag JJ (2018) Pharmacokinetics, safety, and clinical efficacy of
cannabidiol treatment in osteoarthritic dogs. Front Vet Sci 5: 1-9.
Gaston TE, Friedman D (2017) Pharmacology of cannabinoids in the treatment of
epilepsy. Epilepsy Behav 70: 313–318.
Giacoppo S, Bramanti P, Mazzon E (2017) Sativex in the management of multiple
sclerosis-related spasticity: An overview of the last decade of clinical evaluation.
Multiple Sclerosis and Related Disorders 17: 22–31.
Government Decree 162/2003. (X. 16.) on the arrangements for cultivation, marketing
and use of plants suitable for drug production, Hungary. (Korm. Rendelet a
kábítószer előállítására alkalmas növények termesztésének, forgalmazásának és
felhasználásának rendjéről, Magyarország) Available from https://net.jogtar.hu/
jogszabaly?docid=a0300162.kor Accessed May 04, 2020
Gururajan A, Taylor DA, Malone DT (2011) Effect of cannabidiol in a MK-801-ro-
dent model of aspects of schizophrenia. Behav Brain Res 222: 299–308.
Gururajan A, Taylor DA, Malone DT (2012) Cannabidiol and clozapine reverse
MK-801- induced deficits in social interaction and hyperactivity in Sprague-
Dawley rats. J Psychopharmacol 26: 1317–1332.
House of Representatives - H.R. 5485, 115th Congress, Hemp Farming Act of 2018,
Section 2, 297A, 297B and 297C - Subtitle G - Hemp Production.
Hudak J, Stenglein C (2017) DEA guidance is clear: cannabidiol is illegal and always
has been. 2017. Available at: https://www.brookings.edu/blog/ fixgov/2017/02/06/
cannabidiol-illegal-and-always-has-been accessed May, 8 2020.
Huestis MA (2007) Human cannabinoid pharmacokinetics. Chem Biodivers 4: 1770–
1804.
Hunt CA, Jones RT (1980) Tolerance and disposition of tetrahydrocannabinol in man.
J Pharmacol Exp Ther 215: 35–44.
Ibarra-Lecue I, Mollinedo-Gajate I, Meana JJ, Callado LF, Diez-Alarcia R, Urigüen L
(2018) Chronic cannabis promotes pro-hallucinogenic signaling of 5-HT2A recep-
tors through Akt/mTOR pathway. Neuropsychopharmacology 43: 2028–2035.
Kasten CR, Zhang Y, Boehm SL 2nd (2019) Acute cannabinoids produce robust anxi-
ety-like and locomotor effects in mice, but long-term consequences are age and
sex-dependent. Front Behav Neurosci 13: 1-18.
Lafaye G, Karila L, Blecha L, Benyamina (2017) Cannabis, cannabinoids, and health.
Dialogues Clin Neurosci 19: 309–316.
Lastres-Becker I, Molina-Holgado F, Ramos JA, Mechoulam R, Fernandez-Ruiz J
(2005) Cannabinoids provide neuroprotection against 6-hydroxydopamine toxicity
in vivo and in vitro: relevance to Parkinson’s disease. Neurobiol Dis 19: 96–107.
Romanian Parliament, Law No nr.339/2005 on the legal regime for narcotic and
psychotropic plants, substances and preparations, Romanian Official Gazette,
nr. 1095/05.12.2005. (Parlamentul României Legea nr 339/29.11.2005 privind
regimul juridic al plantelor, substanțelor și preparatelor psihotrope, Monitorul
Oficial al României, nr. 1095/05.12.2005).
Linge R, Jiménez-Sánchez L, Campa L, Pilar-Cuéllar F, Vidal R, Pazos A, Adell A,
Díaz Á (2016) Cannabidiol induces rapid-acting antidepressant-like effects and
enhances cortical 5-HT/glutamate neurotransmission: role of 5-HT1A receptors.
Neuropharmacology 103: 16-26.
REVIEW
469Pharmazie 75 (2020)
Long LE, Chesworth R, Huang X-F, McGregor IS, Arnold JC, Karl TA (2010)
Behavioural comparison of acute and chronic Δ9-tetrahydrocannabinol and canna-
bidiol in C57BL/ 6JArc mice. Int J Neuropsychopharmacol 13: 861–876.
Lucas CJ, Galettis P, Schneider J (2018) The pharmacokinetics and the pharmacody-
namics of cannabinoids. Br J Clin Pharmacol 84: 2477–2482.
Mao K, You C, Lei D, Zhang H (2015) High dosage of cannabidiol (CBD) alleviates
pentylenetetrazole-induced epilepsy in rats by exerting an anticonvulsive effect. Int
J Clin Exp Med 8: 8820–8827.
Martín-Moreno AM, Reigada D, Ramírez BG, Mechoulam R, Innamorato N,
Cuadrado A, de Ceballos ML (2011) Cannabidiol and other cannabinoids reduce
microglial activation in vitro and in vivo: relevance to Alzheimer’s disease. Mol
Pharmacol 79: 964–973.
McGuire P, Robson P, Cubala WJ, Vasile D, Morrison PD, Barron R, Taylor A, Wright
S (2018) Cannabidiol (CBD) as an adjunctive therapy in schizophrenia: a multi-
center randomized controlled trial. Am J Psychiatry 175: 225–231.
Moreira FA, Guimaraes FS (2005) Cannabidiol inhibits the hyperlocomotion induced
by psychotomimetic drugs in mice. Eur J Pharmacol 512: 199–205.
Nicholson AN, Turner C, Stone BM (2004) Effect of Delta-9-tetrahydrocannabinol
and cannabidiol on nocturnal sleep and early-morning behavior in young adults. J
Clin Psychopharmacol 24: 305-313.
Niesink RJM, van Laar MW (2013) Does cannabidiol protect against adverse psycho-
logical effects of THC?. Front Psychiatry 4: 1–8.
Niesink RJM, Rigter S, Koeter MW, Brunt TM (2015) Potency trends of Δ9-tetrahy-
drocannabinol, cannabidiol and cannabinol in cannabis in the Netherlands: 2005–
15. Addiction 110: 1941–1950.
Pijlman F, Rigter S, Hoek J, Goldschmidt H, Niesink R (2005) Strong increase in
total delta-THC in cannabis preparations sold in Dutch coffee shops. Addict Biol
10: 171–180.
Pohl M, Natterer A (2019) Cannabidiols in Austria. European Food and Feed Law
Review 14: 58–60.
Potter DJ, Clark P, Brown MB (2008) Potency of Δ9-THC and other cannabinoids in
cannabis in England in 2005: implications for psychoactivity and pharmacology.
J Forensic Sci 53: 90–94.
Rekand T (2014) THC:CBD spray and MS spasticity symptoms: data from latest
studies. Eur Neurol 71: 4–9.
Sekar K, Pack A (2019) Epidiolex as adjunct therapy for treatment of refractory
epilepsy: a comprehensive review with a focus on adverse effects. F 1000 Research
8: 1–8. https://doi.org/10.12688/f1000research.16515.1.
Shannon S, Lewis N, Lee H, Hughes S (2019) Cannabidiol in anxiety and sleep: a
large case series. Perm J 23: 18–41.
Smith PF, Zheng Y (2016) Cannabinoids, cannabinoid receptors and tinnitus. Hear
Res 332: 210-216.
Szaflarski JP, Bebin EM (2014) Cannabis, cannabidiol, and epilepsy-from receptors
to clinical response. Epilepsy Behav 41: 277–282.
Tham M, Yilmaz O, Alaverdashvili M, Kelly MEM, Denovan-Wright EM, Laprairie
RB (2019) Allosteric and orthosteric pharmacology of cannabidiol and cannabidi-
ol-dimethylheptyl at the type 1 and type 2 cannabinoid receptors. Br J Pharmacol
176: 1455–1146.
Title 21 United States Code (USC) Controlled Substances Act, Chapter 13 – Drug
abuse prevention and control, Subchapter I, Part A, Section 802. (2018) Available
from https://www.deadiversion.usdoj.gov/21cfr/21usc/. Accessed May 05, 2020.
Trofin IG, Dabija G, Văireanu DI, Filipescu L (2012) The influence of long-term
storage conditions on the stability of cannabinoids derived from cannabis resin.
Rev. Chim 63: 422–427.
Trudeau MS, Madden RF, Parnell JA, Gibbard WB, Shearer J (2019) Dietary and
supplement-based complementary and alternative medicine use in pediatric autism
spectrum disorder. Nutrients 11: 1–11.
Tura M, Mandrioli M, Gallina Toschi T (2019) Preliminary study: comparison of anti-
oxidant activity of cannabidiol (CBD) and α-tocopherol added to refined olive and
sunflower oils. Molecules 24: 1–15.
Wheeler M, Merten JW, Gordon BT, Hamadi H (2020) CBD (Cannabidiol) product
attitudes, knowledge, and use among young adults. Subst Use Misuse 24: 1–8.
Wilkinson ST, Yarnell S, Radhakrishnan R, Ball SA, D’Souza DC (2016) Marijuana
legalization: impact on physicians and public health. Annu Rev Med 67: 453–466.
Zamengo L, Frison G, Bettin C, Sciarrone R (2013) Cannabis potency in the Venice
area (Italy): update 2013. Drug Test Anal 7: 255–258.
Zamengo L, Frison G, Bettin C, Sciarrone R (2014) Understanding the risks asso-
ciated with the use of new psychoactive substances (NPS): high variability of
active ingredients concentration, mislabelled preparations, multiple psychoactive
substances in single products. Toxicol Lett 229: 220–228.
Zendulka O, Dovrtelova G, Noskova K, Turjap M, Sulcova A, Hanus L, Jurica (2016)
Cannabinoids and cytochrome P450 interactions. Curr Drug Metab 17: 206–226.
Zieba J, Sinclair D, Sebreec T, Bonn-Miller M, Gutterman D, Siegeld S, Karl T (2019)
Cannabidiol (CBD) reduces anxiety-related behavior in mice via an FMRP inde-
pendent mechanism. Pharmacol Biochem Behav 181: 93–100.
Zuardi AW, Shirakawa I, Finkelfarb E, Karniol IG (1982) Action of cannabidiol on
the anxiety and other effects produced by delta 9-THC in normal subjects. Psycho-
pharmacology 76: 245–250.
Zuardi AW, Hallak JEC, Dursun SM, Morais SL, Sanches RF, Musty RE, Crippa JA
(2006) Cannabidiol monotherapy for treatment resistant schizophrenia. J Psycho-
pharmacol 20: 683–686.
Zuardi AW, Crippa JA, Hallak JE, Pinto JP, Chagas MH, Rodrigues GG, Dursun SM,
Tumas V (2009) Cannabidiol for the treatment of psychosis in Parkinsons disease.
J Psychopharmacol 23: 979–983.