CANNABIDIOL (CBD)
Pre-Review Report
Agenda Item 5.2

Expert Committee on Drug Dependence
Thirty-ninth Meeting
Geneva, 6-10 November 2017

39th ECDD (2017) Agenda item 5.2

Cannabidiol (CBD)

Contents
Acknowledgements .................................................................................................................. 4
Summary ................................................................................................................................... 5
1.

Substance identification ........................................................................................................ 6
A.
B.
C.
D.
E.
F.
G.

2.

International Nonproprietary Name (INN) ............................................................................ 6
Chemical Abstract Service (CAS) Registry Number .............................................................. 6
Other Chemical Names .......................................................................................................... 6
Trade Names .......................................................................................................................... 6Street Names........................................................................................................................... 6
Physical Appearance .............................................................................................................. 6
WHO Review History ............................................................................................................. 6
Chemistry ............................................................................................................................... 6

A.
B.
C.
D.
E.
F.

Chemical Name ...................................................................................................................... 6
Chemical Structure................................................................................................................. 7
Stereoisomers ......................................................................................................................... 7
Methods and Ease of Illicit Manufacturing ............................................................................ 7
Chemical Properties ............................................................................................................... 9
Identification and Analysis ..................................................................................................... 93.

Ease of Convertibility Into Controlled Substances ............................................................ 10

4.

General Pharmacology........................................................................................................ 11
A.
B.
C.

Routes of administration and dosage ................................................................................... 11
Pharmacokinetics ................................................................................................................. 11
Pharmacodynamics .............................................................................................................. 12

5.

Toxicology............................................................................................................................ 13

6.

Adverse Reactions in Humans ............................................................................................ 13

7.

Dependence Potential .......................................................................................................... 14
A.
B.

8.

Animal Studies ...................................................................................................................... 14
Human Studies...................................................................................................................... 14
Abuse Potential .................................................................................................................... 14

A.
B.
9.

Animal Studies ...................................................................................................................... 14
Human Studies...................................................................................................................... 14
Therapeutic Applications and Extent of Therapeutic Use and Epidemiology of Medical
Use........................................................................................................................................ 15

10.

Listing on the WHO Model List of Essential Medicines .................................................... 19

11.

Marketing Authorizations (as a Medicinal Product) ......................................................... 19

12.

Industrial Use ...................................................................................................................... 19

13.

Non-Medical Use, Abuse and Dependence ........................................................................ 19

14.

Nature and Magnitude of Public Health Problems Related to Misuse, Abuse and
Dependence.......................................................................................................................... 20

15.

Licit Production, Consumption and International Trade .................................................. 20

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39th ECDD (2017) Agenda item 5.2

Cannabidiol (CBD)16.

Illicit Manufacture and Traffic and Related Information ................................................. 20

17.

Current International Controls and Their Impact ............................................................. 20

18.

Current and Past National Controls ................................................................................... 20

19.

Other Medical and Scientific Matters Relevant for a Recommendation on the Schedulingof the Substance................................................................................................................... 21

References ............................................................................................................................... 22
Annex 1: Report on WHO Questionnaire for Review of Psychoactive Substances for the39th ECDD: Evaluation of Cannabidiol .............................................................................. 27

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Cannabidiol (CBD)

Acknowledgements

This report has been drafted under the responsibility of the WHO Secretariat, Department ofEssential Medicines and Health Products, Teams of Innovation, Access and Use and Policy,
Governance and Knowledge. The WHO Secretariat would like to thank the following people
for their contribution in producing this review report: Professor Jason White, Adelaide,
Australia (literature search, review and drafting), Ms. Dilkushi Poovendran, Geneva,
Switzerland (questionnaire analysis and report drafting) and Dr. Stephanie Kershaw, Adelaide,
Australia (review report editing, questionnaire analysis and report drafting).

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Cannabidiol (CBD)

Summary

Cannabidiol (CBD) is one of the naturally occurring cannabinoids found in cannabis plants. It
is a 21-carbon terpenophenolic compound which is formed following decarboxylation from acannabidiolic acid precursor, although it can also be produced synthetically.
CBD can be converted to tetrahydrocannabinol (THC) under experimental conditions;however, this does not appear to occur to any significant effect in patients undergoing CBDtreatment.
In experimental models of abuse liability, CBD appears to have little effect on conditioned
place preference or intracranial self-stimulation. In an animal drug discrimination model CBD
failed to substitute for THC. In humans, CBD exhibits no effects indicative of any abuse ordependence potential.
CBD has been demonstrated as an effective treatment of epilepsy in several clinical trials, with
one pure CBD product (Epidiolex®) currently in Phase III trials. There is also preliminary
evidence that CBD may be a useful treatment for a number of other medical conditions.
There is unsanctioned medical use of CBD based products with oils, supplements, gums, andhigh concentration extracts available online for the treatment of many ailments.
CBD is generally well tolerated with a good safety profile. Reported adverse effects may be asa result of drug-drug interactions between CBD and patients’ existing medications.
Several countries have modified their national controls to accommodate CBD as a medicinal
product.
To date, there is no evidence of recreational use of CBD or any public health related problems
associated with the use of pure CBD.

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1.

Cannabidiol (CBD)

Substance identification
A.

International Nonproprietary Name (INN)
Cannabidiol

B.

Chemical Abstract Service (CAS) Registry Number
13956-29-1 [1]C.

Other Chemical Names
CBD;
2-[1R-3-methyl-6R-(1-methylethenyl)-2-cyclohexen-1-yl]-5-pentyl-1,3benzenediol; [2]D.

Trade Names
Epidiolex® (in development)
Arvisol® (in development)

E.

Street Names
No data available

F.

Physical Appearance
A crystalline solid [2]G.

WHO Review History
Cannabidiol has not been previously pre-reviewed or critically reviewed by
the WHO Expert Committee on Drug Dependence (ECDD). The current
review is based on the recommendation from the 38th ECDD that pre-review
documentation on cannabis-related substances, including cannabidiol, be
prepared and evaluated at a subsequent committee meeting[3].

2.

ChemistryA.

Chemical NameIUPAC Name: 2-[(6R)-3-methyl-6-prop-1-en-2-ylcyclohex-2-en-1yl]-5-pentylbenzene-1,3-diol

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B.

Cannabidiol (CBD)

Chemical Structure

Molecular Formula: C21H30O2
Molecular Weight: 314.469 g/molC.

Stereoisomers
Cannabidiol (CBD) is normally taken to refer to the naturally occurring (-)enantiomer. (+) CBD has been synthesised [4], but has received little attention.
(+) CBD has been shown to have modest affinity at CB1 and CB2 receptors
unlike (-) CBD ((+)-CBD Ki= 0.84 µM at CB1), whereas both compounds
inhibited anandamide hydrolysis and were agonists at the vanilloid type 1(VR1) receptor at which capsaicin acts. [5] The (+)-CBD isomer was more
active than the (-)-CBD-isomer as an anticonvulsant agent in a mouse seizure
model. [6] However, to date, there is no substantive evidence as to whether(+)-CBD is likely to cause THC-like psychoactive effects.

D.

Methods and Ease of Illicit Manufacturing
Synthesis of CBD in vitro:
Synthetic routes are available for the production of CBD, but some of the
published methods yield only small amounts of CBD. The two most efficientroutes are:1) The condensation of (+)-e-mentha-diene-l-01 with olivetol in the presenceof weak acids (oxalic, picric or maleic acid). The isomer obtained in thisreaction may be converted to CBD with BF3-etherate by a retro-FriedelCrafts reaction, followed by recombination. However, with this reagent thereaction proceeds further causing cyclisation of CBD to delta-1-THC andiso-THC [7]2) A one step reaction for CBD synthesis utilizes boron trifluoride (BF3)etherate on alumina as condensing reagent in the reaction of (+)-e-menthadiene-l-01 with olivetol on a 0.8mmol scale (refer to Figure 1). This resultsin CBD as the major product, with 55% yield as chromatographically pure

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Cannabidiol (CBD)

oil or 41% yield as crystalline material. On a 100mmol scale, the yields
were 46% as an oil, and 37% as crystalline material. [8]

CBD (major product)

Figure 1: Synthesis of CBD with boron trifluoride (BF3)-etherate takenfrom Mechoulam et al 2002 [9]Synthesis of CBD in plants:
Cannabis cultivars range from those grown to produce cannabis forrecreational purposes to those produced in order to use hemp fibre derived
from the stems of the plant. In cultivars utilized for recreational purposes, thequantity of THC exceeds that of CBD in the dried female inflorescences used
for smoking and oral administration. Hemp cultivars produce substantially less
THC and higher levels of CBD. [10] Unsanctioned production of cannabis
cultivars with high CBD levels does occur for purposes of medical treatment
rather than recreational use (refer to Section 13).
In plants, THC and CBD are derived from their acidic precursors Δ9tetrahydrocannabinolic acid (THCA) and cannabidiolic acid (CBDA) (refer toFigure 2). THCA and CBDA are both derived from cannabigerolic acid
(CBGA). The final step differs, with THCA synthase and CBDA synthase
producing THCA or CBDA, respectively, from CBGA. Subsequent
decarboxylation of THCA and CBDA via light exposure, heating, or aging,
results in THC or CBD.[10-12]

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Cannabidiol (CBD)

Figure 2: Biogenesis of THC and CBD adapted from Taura et al. (2007)
THCA synthase and CBDA synthase catalyze oxidative cyclization of themonoterpene moiety of CBGA to form THCA and CBDA, respectively. THC
and CBD are generated from THCA and CBDA by non‐enzymatic
decarboxylation. [11]In addition to genetic characteristics, cultivated plants are influenced byenvironmental conditions and production technology during their life cycle. A
study evaluating the effects of ambient temperature and humidity, soil
temperature and precipitation on the content of THC and CBD in industrial
hemp noted that these agroclimatic conditions have differing effects on THC
and CBD. For example, CBD content is positively affected by soil temperature
and ambient temperature, but negatively influenced by precipitation [13]E.

Chemical Properties
Melting point: 62-63°C
Solubility: approx. 23.6 mg/mL in DSMO and ethanol [14]F.

Identification and Analysis
There are a number of published methods for the analytical detection of CBD
in various biological samples. For example,▪

spectrophotometric determination [15];▪

liquid chromatography–tandem mass spectrometry (LC–MS/MS)
detection of CBD in whole blood [16, 17] samples;

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3.

Cannabidiol (CBD)▪

high performance (HP) LC-MS/MS methods for CBD detection in hair[18], urine [19] and plasma [20] samples;▪

gas chromatography mass spectrometry (GC-MS) detection of CBD inhair [21, 22], oral [23] and plasma [24] samples;▪

2-dimensional-GC-MS methods for detection in oral fluid [25], plasma[26] and post mortem blood samples [27].

Ease of Convertibility Into Controlled Substances
There is some evidence that CBD can be converted to tetrahydrocannabinol (THC), a
Schedule 1 substance under the United Nations Convention on Psychotropic
Substances 1971. Two main methods have been reported and there has been someinvestigation into whether this occurs spontaneously in vivo.
Conversion in the laboratory
Under experimental conditions, it has been demonstrated that heating CBD insolutions of some acids catalyses cyclizations within the CBD molecule resulting indelta-9-THC [28]. Gaoni and Mechoulam have published several papers regarding
methods of converting CBD to other cannabinoids including THC, however the yields
vary and purity is unclear. [9]A version of this method has been reported on a drug user forum. It suggests
dissolving CBD in sulphuric acid/acetic acid and leaving it for anywhere from 3 hours
to 3 days to obtain delta-9-THC and delta-8-THC. After 3 hours, the author states that
CBD has been converted into 52% delta-9-THC and 2% delta-8-THC [31].
A patent (US 2004/0143126 A1) on the conversion of CBD to delta-9-THC details amethod involving the addition of BF3Et2O (50 µl), under nitrogen atmosphere, to an
ice cold solution of CBD (300 mg) in dry methylene chloride (15 ml). The solution isstirred at 0° C for 1 hour, followed by the addition of saturated aqueous solution of
NaHCO3 (2 ml) until the red colour fades. The organic layer is removed, washed withwater, dried over MgSO4 and evaporated. The composition of the oil obtained(determined by HPLC) is: trans-delta8-isoTHC 27%, delta-9-THC 66.7%. The oil isthen chromatographed on silica gel column (20 g) and eluted with petroleum ether
followed by graded mixtures, up to 2:98 of ether in petroleum ether. The first fraction
eluted was the delta8-isoTHC (30 mg, 9.5%) followed by a mixture of delta8-iso THC
and delta-9-THC (100 mg). The last compound to be eluted was the delta-9-THC (172
mg, 57%). The purity of delta-9-THC (as determined by HPLC) is 98.7%. [29]Spontaneous conversion
It has been proposed that the conversion of CBD to delta-9-THC in the presence ofacid could occur in the human gut. Such conversion could be of importance if CBD isadministered orally. Two in vitro studies have used simulated gastric fluid todemonstrate the potential for this conversion. The first reported the formation ofanalytically confirmed delta-9-THC and delta-8-THC when CBD was exposed tosimulated gastric fluid without enzymes at 37ºC. The authors concluded that that theacidic environment during normal gastrointestinal transit could expose orally CBD-

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Cannabidiol (CBD)

treated patients to levels of THC and other psychoactive cannabinoids that may
exceed the threshold for a physiological response. [30] The second in vitro study also
reported the formation of delta-9-THC along with other cannabinoid products in
artificial gastric juice without pepsin. The conversion rate of CBD to THC was only
2.9%. [31]The predictive value of these in vitro studies for humans administering cannabidiol
orally has been questioned as simulated gastric ﬂuid does not exactly replicate
physiological conditions in the stomach. [32] Furthermore, spontaneous conversion of
CBD to delta-9-THC has not been demonstrated in humans undergoing CBDtreatment. For example, in a six week clinical study in Huntington’s disease patients
who were administered CBD 700 mg/day, the CBD average plasma concentration
range was 5.9-11.2 ng/mL with no delta-9-THC detected. [33]In humans, THC effects are characterised by impairment of psychomotor andcognitive performance, and a range of physical effects including increased heart rateand dry mouth. In general, clinical studies have reported that even high doses of oral
CBD do not cause the those effects that are characteristic for THC and for cannabisrich in THC.[34] For example, in a study of healthy volunteers administered 200mg
oral CBD, CBD did not produce any impairments of motor or psychomotor
performance.[35] A number of other studies involving high doses of CBD wererecently summarized by Grotenhermen et al.[34]; they concluded that high doses oforal CBD consistently fail to demonstrate significant effects or demonstrate effects
opposite to those of THC.
While it has been suggested that further large-scale human studies are needed to
explore the gastric conversion and potential THC-like side effects following oral CBDadministration [36], it is very unlikely that oral cannabidiol will be shown to result in
THC concentrations sufficient to induce any meaningful effects.

4.

General Pharmacology
A.

Routes of administration and dosage
Currently there are no approved marketed pure CBD medicinal products,
although two are in development (refer to Section 11).
In clinical trials and research studies, CBD is generally administered orally as
either a capsule, or dissolved in an oil solution (e.g. olive or sesame oil). It canalso be administered through sublingual or intranasal routes. A wide range oforal doses have been reported in the literature, with most from 100800mg/day. [37]B.

Pharmacokinetics
Oral delivery of an oil-based capsule formulation of CBD has been assessed inhumans. Probably due to its poor aqueous solubility, the absorption of CBDfrom the gastrointestinal tract is erratic, and the resulting pharmacokinetic
profile is variable. Bioavailability from oral delivery was estimated to be 6%
due to significant first-pass metabolism.[38] In healthy male volunteers, themean±SD whole blood levels of CBD at 1, 2 and 3 hours after administration

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Cannabidiol (CBD)of 600mg oral CBD were reported to be 0.36 (0.64) ng/mL, 1.62 (2.98) ng/mL
and 3.4 (6.42) ng/mL, respectively. [39] Aerosolized CBD has been reported
to yield rapid peak plasma concentrations in 5–10 minutes and higher
bioavailability than oral administration.
CBD is rapidly distributed into the tissues with a high volume of distributionof ~32L/kg. Like THC, CBD may preferentially accumulate in adipose tissues
due to its high lipophilicity. [37, 40]
CBD is extensively metabolised in the liver. The primary route ishydroxylation to 7-OH-CBD which is then metabolised further resulting in a
number of metabolites that are excreted in faeces and urine.[38] A study inhuman liver microsomes (HLMs) demonstrated that CBD was metabolized bypooled HLMs to eight monohydroxylated metabolites (6α-OH-, 6β-OH-,7OH-, 1”-OH-, 2”-OH-, 3”-OH-, 4”-OH-, and 5”-OH-CBDs). Among thesemetabolites, 6α-OH-, 6β-OH-, 7-OH-, and 4”-OH-CBDs were the major ones.
Seven recombinant human CYP enzymes were identified as capable ofmetabolising CBD: CYP1A1, CYP1A2, CYP2C9, CYP2C19, CYP2D6,
CYP3A4, and CYP3A5. The two main isoforms involved are CYP3A4 andCYP2C19. [41]In a number of studies, CBD has been shown to inhibit CYP isozymes in vitro,
but it is not clear that this occurs at concentrations achieved with doses usedclinically.
C.

Pharmacodynamics
There are two main cannabinoid (CB) receptors, CB1 which is primarily
located in the central nervous system with some expression in peripheral
tissues and CB2 receptors, which can be found in the periphery on cells withimmune function and in the gastrointestinal tract and at low densities in thecentral nervous system.
CBD does not appear to act directly at CB1 receptors, with a number of studies
reporting that there is no measurable response in binding assays. In studies
examining potential agonist effects at CB1 receptors, most find no effect, with
one report of a weak agonist and one of a weak antagonist effect, each at highconcentrations (>10uM). CBD also shows low affinity at CB2 receptors. [42]Across a range of measures in humans and animals, CBD had been shown tohave very different effects from those of THC. In mice, CBD failed to produce
the behavioral characteristics (e.g. suppression of locomotor activity,
hypothermia, antinociception) associated with CB1 activation, whereas THC
generated all of the effects which occur when CB1 is activated. [43, 44]
Neuroimaging studies in humans and animals have shown that CBD has
effects which are generally opposite to those of THC.[45] In contrast to THC,
CBD has no effect on heart rate or blood pressure under normal conditions, but
in animal models of stress it reduces heart rate and blood pressure.[46] Other
differences between THC and CBD are discussed below.
Some studies have shown that CBD may reduce or antagonize some of theeffects of THC. The mechanism for this is unclear, with some suggesting that

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Cannabidiol (CBD)

it may be a weak CB1 antagonist. Recent evidence suggests that it may be anegative allosteric modulator of the CB1 receptor, thereby acting as a noncompetitive antagonist of the actions of THC and other CB1 agonists.[42, 47]
CBD may also interact with the endocannabinoid system through indirect
mechanisms such as enhanced action of the endogenous cannabinoid ligand
anandamide. This results from blockade of anandamide reuptake and theinhibition of its enzymatic degradation. [5, 9, 41]
CBD has been shown to modulate several non-endocannabinoid signaling
systems. It is not clear which, if any, of these mechanisms are responsible forany of CBD’s potential clinical or other effects. Some of these mechanism
include [48]:• Inhibition of adenosine uptake, possibly resulting in indirect
agonist activity at adenosine receptors.
• Enhanced activity at the 5-HT1a receptor.
• Enhanced activity at glycine receptor subtypes• Blockade of the orphan G-protein-coupled receptor GPR55

5.

Toxicology
The potential toxic effects of CBD have been extensively reviewed [49] with a recent
update of the literature. [50] In general, CBD has been found to have relatively low
toxicity, although not all potential effects have been explored. The following are someof the relevant findings to date from in vitro and animal studies:• CBD affects growth of tumoral cell lines, but has no effect in most nontumour cells. However, a pro-apoptotic effect has been observed inlymphocytes.
• It has no effect on embryonic development (limited research)• Evidence on potential hormonal changes is mixed, with some evidence ofpossible effects and other studies suggesting no effect, depending on themethod used and the particular hormone• It has no effect on a wide range of physiological and biochemical parameters
or significant effects on animal behaviour unless extremely high doses areadministered (eg, in excess of 150 mg/kg iv as an acute dose or in excess of
30 mg/kg orally daily for 90 days in monkeys)• Effects on the immune system are unclear; there is evidence of immune
suppression at higher concentrations, but immune stimulation may occur at
lower concentrations.
• There is potential for CBD to be associated with drug interactions throughinhibition of some cytochrome P450 enzymes, but it is not yet clear whether
these effects occur at physiological concentrations.

6.

Adverse Reactions in Humans
As noted above, CBD does not produce the effects that are typically seen withcannabinoids such as THC. It also failed to produce significant effects in a humanstudy of abuse potential discussed below.[39] Across a number of controlled and open
label trials CBD of the potential therapeutic effects of CBD it is generally well

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Cannabidiol (CBD)

tolerated, with a good safety profile. [37, 50] Clinical trials involving use of CBD fortreatment of epilepsy will be discussed in Section 9: Therapeutic Applications.

7.

Dependence Potential
A.

Animal Studies
Male mice were injected i.p once a day for 14 days with either CBD (0.1, 1, or
3mg/kg) or delta-9-THC (1, 3, or 10mg/kg). Tolerance to the effects of THC
was observed, however no tolerance to CBD at any of the dosages wasobserved. [51] No studies of the physical dependence potential of CBD inanimals were identified.

B.

Human Studies
Controlled, human studies regarding the potential physical dependence effects(e.g. withdrawal and tolerance) of cannabidiol have not been reported

8.

Abuse Potential
A.

Animal Studies
In male Sprague-Dawley rats, administration of low dose (5 mg/kg) CBD did
not change the threshold frequency required for intracranial self-stimulation(ICSS). However, high dose (10 mg/kg and 20 mg/kg) CBD resulted in anelevation of the threshold suggestive of diminished reward activity. This effectis opposite to that of drugs of abuse such as cocaine, methamphetamine andopioids which lower the threshold.[52]Increased dopamine release in cells of the mesolimbic ventral tegmental area –nucleus accumbens pathway is a common effect characteristic of almost all
drugs of abuse. While THC has been shown to increase the firing rate of thesecells, cannabidiol had no effect. [53]It appears that CBD given alone has little effect on conditioned place
preference (CPP). For example, Long-Evans rats treated with 10 mg/kg CBDshowed neither CPP nor CPA.[54] However, rats treated with increasing dosesof CBD and THC (1, 3, and 10 mg/kg) exhibited a trend towards CPP not seenin those given THC alone. [55] The authors attributed this to apharmacokinetic interaction leading to higher THC concentrations rather thana change in receptor action.
CBD appears not to exhibit THC-like discriminative stimulus effects. For
example, in rats trained to discriminate THC from vehicle, CBD did not
substitute for THC at any dose tested [54]. CBD also failed to substitute for
THC in pigeons trained to discriminate THC from vehicle. [56]B.

Human Studies
While the number of studies is limited, the evidence from well controlledhuman experimental research indicates that CBD is not associated with abusepotential.

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Cannabidiol (CBD)Single dose administration of cannabidiol has been evaluated in healthy
volunteers using a variety of tests of abuse potential as well as physiologicaleffects in a randomised double blind placebo controlled trial.[39] An orally
administered dose of 600mg of CBD did not differ from placebo on the scalesof the Addiction Research Centre Inventory, a 16 item Visual Analogue Mood
Scale, subjective level of intoxication or psychotic symptoms. In contrast,
THC (10mg oral) administration was associated with subjective intoxicationand euphoria as well as changes in ARCI scales reflecting sedation andhallucinogenic activity. THC also increased psychotic symptoms and anxiety.
While THC increased heart rate, CBD had no physiological effects.
A randomized, double-blind, within-subject laboratory study was undertaken
to assess the influence of CBD (0, 200, 400, 800mg, p.o.) pre-treatment on theeffects of inactive (0.01% THC) and active (5.30–5.80% THC) smokedcannabis. Healthy cannabis smokers (n=31) completed eight outpatientsessions with CBD administered 90min prior to cannabis administration.
Under placebo CBD conditions, active cannabis was self-administered bysignificantly more participants and produced significant, time-dependent
increases in subjective ratings and heart rate relative to inactive cannabis.
CBD alone produced no significant psychoactive, cardiovascular or othereffects. Cannabis self-administration, subjective effects, and cannabis ratings
did not vary as a function of CBD dose relative to placebo capsules. Thesefindings suggest that oral CBD does not reduce the reinforcing, physiological,
or positive subjective effects of smoked cannabis.[57]The authors of the study then undertook a second analysis of this data to
examine the abuse liability profile of oral cannabidiol in comparison to oral
placebo and active smoked cannabis. The results of this analysis demonstrated
that CBD was placebo-like on all measures (including visual analogue scales,
psychomotor performance such as the digit symbol substitution task, heart rate
and blood pressure) compared to active cannabis, which produced abuserelated subjective effects as well as a range of other effects. [58]9.

Therapeutic Applications and Extent of Therapeutic Use andEpidemiology of Medical Use
Epilepsy
The clinical use of CBD is most advanced in the treatment of epilepsy. In clinical
trials, CBD has been demonstrated as an effective treatment for at least some forms of
epilepsy, with one pure CBD product (Epidiolex®) currently in Phase III trials.
The use of CBD for this purpose is based on a number of studies in animals datingback to the 1970s. [59] These studies demonstrated the anti-seizure activity ofcannabidiol in a number of animal models. Based on this research, cannabidiol has
been trialled in patients with epilepsy.
In a very early small-scale double-blind placebo controlled trial, patients received
either 200 mg CBD daily (4 patients) or placebo (5 patients) for a 3-month period, in
addition to their habitual medication. In the CBD group, two patients had no seizures
for the entire 3-month period, one partially improved, and the fourth had no

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Cannabidiol (CBD)

improvement. No improvements were observed in the placebo group and no toxic
effects were reported for either group. This study has a number of limitations,
including the small sample size, unclear design as to blinding, and lack of definitionof partial improvement. [60]In another study, 15 patients with “secondarily generalized epilepsy with temporalfocus,” were randomly divided into two groups. In a double-blind procedure, eachpatient received 200-300 mg daily of CBD or placebo for up to four and a half months
in combination with their existing prescribed antiepileptic medications (which wereno longer effective in the control of their symptoms). CBD was tolerated in all
patients, with no signs of toxicity or serious side effects. Of the eight participants in
the CBD treatment group, four were reported to be almost free of seizure episodes
throughout the trial, whereas three others showed partial clinical improvement. CBD
was ineffective in one patient. In comparison, the clinical condition of seven placebo
patients remained unchanged with one patient showing improvement.[61]There have also been some negative reports regarding the effectiveness of CBD. In atrial reported in 1986, a dose of CBD of 200–300 mg/day for a month resulted in no
significant differences between the treatment and placebo groups. [62] Similarly, a 6month double blind study administering CBD 100 mg 3 times each day did not resultin any changes in seizure frequency or improvement in cognition or behaviour. [63]The results of two trials examining the effects of CBD in patients with severe,
intractable, childhood-onset, treatment-resistant epilepsy have been reported. The firstwas an open label study of 214 patients (aged 1–30 years) who were receiving stable
doses of antiepileptic drugs before study entry. Patients were given oral cannabidiol,
initially at 2–5 mg/kg per day, and then titrated until intolerance or to a maximum
dose of 25 mg/kg or 50 mg/kg per day, dependent on study site. The primary measure
was the percentage change in the frequency of seizures. In the CBD group, the medianmonthly frequency of motor seizures reduced from 30·0 at baseline to 15·8 over the
12 week treatment period. The trial was also designed to assess safety, but the absenceof a control group means that the results cannot be used to assess the likelihood of
CBD producing particular effects. Adverse events reported in more than 10% of
patients were somnolence, decreased appetite, diarrhoea, fatigue, and convulsion. Five(3%) patients discontinued treatment because of an adverse event. Serious adverse
events were reported in 48 (30%) patients, of which 20 (12%) experienced severe
adverse events possibly related to cannabidiol use, the most common of which was
status epilepticus (n=9 [6%]). [64]The same research group recently reported the results of a controlled trial of CBDtreatment for Dravet syndrome, a complex childhood epilepsy disorder that is
associated with drug-resistant seizures and a high mortality rate. In a double-blind,placebo-controlled trial, 120 children and young adults with Dravet syndrome wererandomly assigned to receive either cannabidiol oral solution (20 mg per kilogram perday) or placebo, in addition to standard antiepileptic treatment (a median of 3.0
drugs). The authors reported that cannabidiol decreased the median frequency of
convulsive seizures per month from 12.4 to 5.9, as compared with a decrease from
14.9 to 14.1 with placebo. A small percentage (5%) of patients in the CBD groupbecame seizure free as compared to zero in the placebo group. Adverse events that
occurred more frequently in the cannabidiol group than in the placebo group included
diarrhoea (31% vs 10%), loss of appetite (28% vs 5%) and somnolence (36% vs10%). Other adverse effects noticed were vomiting, fatigue, pyrexia and abnormal

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results on liver-function tests. Adverse effects led to the withdrawal of eight patientsin the cannabidiol group compared with one in the placebo group.[65]It has been suggested that some of the adverse effects of cannabidiol observed in theclinical studies may relate to interactions with other antiepileptic drugs. For example,
a recent study evaluated thirteen subjects with refractory epilepsy concomitantly
taking clobazam and CBD. Nine of 13 subjects had a >50% decrease in seizures,
corresponding to a responder rate of 70%. Side effects were reported in 10 (77%) of
the 13 subjects, but were alleviated with clobazam dose reduction. All subjects
tolerated CBD well. [66]It has been suggested that cannabidiol (as Epidiolex) is likely to be submitted forregulatory approval by GW Pharmaceuticals for epilepsy treatment in 2017 following
the successful outcomes reported in treatment of Dravet syndrome.
Other indications
There is also evidence that CBD may be a useful treatment for a number of othermedical conditions. However, this research is considerably less advanced than fortreatment of epilepsy. For most indications, there is only pre-clinical evidence, while
for some there is a combination of pre-clinical and limited clinical evidence. The
range of conditions for which CBD has been assessed is diverse, consistent with its
neuroprotective, antiepileptic, hypoxia-ischemia, anxiolytic, antipsychotic, analgesic,
anti-inflammatory, anti-asthmatic, and antitumor properties.[37, 50, 67] The evidence
for CBD’s various therapeutic applications was recently reviewed by Pisanti et al(2017), refer to Table 1.
Another possible therapeutic application which has been investigated is the use of
CBD to treat drug addiction. A recent systematic review concluded that there were alimited number of preclinical studies which suggest that CBD may have therapeutic
properties on opioid, cocaine, and psychostimulant addiction, and some preliminary
data suggest that it may be beneficial in cannabis and tobacco addiction in humans.
However, considerably more research is required to evaluate CBD as a potential
treatment. [68]Page 17 of 27

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Table 1. Overview of diseases for which CBD may have therapeutic benefits taken from
Pisanti et al (2017) [69]DiseaseAlzheimer's disease
Parkinson's disease

Multiple sclerosis
Huntington's
diseaseHypoxia-ischemia
injuryPain
Psychosis
Anxiety

Depression
CancerNauseaInflammatory
diseases
Rheumatoid
arthritis
Infection
Inflammatory
bowel and Crohn's
diseases
Cardiovasculardiseases
Diabetic
complications

Effects
Antinflammatory, antioxidant, antiapoptotic in in vitro and in vivo modelsof Aβ-evoked neuroinflammatory and neurodegenerative responses.
Attenuation of the dopaminergic impairment in vivo; neuroprotection;
improvement of psychiatric rating and reduction of agitation, nightmare
and aggressive behaviour in patients.
Improved signs of EAE in mice, antinflammatory and immunomodulatory
properties.
Neuroprotective and antioxidant in mice transgenic models; no significant
clinically important differences in patients.
Short term neuroprotective effects; inhibition of excitotoxicity, oxidative
stress and inflammation in vitro and in rodent models.
Analgesic effect in patients with neuropathic pain resistant to othertreatments.
Attenuation of the behavioural and glial changes in animal models of
schizophrenia; anti-psychotic properties on ketamine-induced symptoms
Reduction of muscular tension, restlessness, fatigue, problems inconcentration, improvement of social interactions in rodent models ofanxiety and stress; reduced social anxiety in patients.
Anti-depressant effect in genetic rodent model of depression.
Antiproliferative and anti-invasive actions in a large range of cancer types;
induction of autophagy-mediated cancer cell death; chemopreventive
effects.
Suppression of nausea and conditioned gaping in rats
Antinflammatory properties in several in vitro and in vivo models;
inhibition of inflammatory cytokines and pathways.
Inhibition of TNF-α in an animal model
Activity against methicillin-resistant Staphylococcus aureus
Inhibition of macrophage recruitment and TNF-α secretion in vivo and ex
vivo; reduction in disease activity index in Crohn's patients.
Reduced infarct size through anti-oxidant and anti-inflammatory
properties in vitro and in vivo.
Attenuation of fibrosis and myocardial dysfunction

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10. Listing on the WHO Model List of Essential Medicines
Cannabidiol is not listed on the WHO Model List of Essential Medicines (20th List) or
the WHO Model List of Essential Medicines for Children (6th List).[70]11. Marketing Authorizations (as a Medicinal Product)
CBD is present in nabiximols (Sativex®) which is marketed by GW Pharmaceuticals
in a number of countries. [71] As nabiximols also contains an equal amount of THC,
it will be covered in a separate ECDD review.
There are no currently authorized pure CBD products. However, there are several indevelopment including Epidiolex® and Arvisol®.
Epidiolex® is a liquid formulation of pure plant-derived CBD. It is produced by GW
Pharmaceuticals and has shown positive results in phase 3 trials for Dravet andLennox-Gastaut syndromes which are both treatment resistant seizure disorders. The
published results related to this therapeutic application are covered in Section 9:
Therapeutic Applications. [72], [73]Arvisol® is an oral tablet containing pure CBD. It has been developed by Echo
Pharmaceuticals in the Netherlands and is intended to be registered in the treatment ofdisorders such as schizophrenia and epilepsy. Arvisol® is still undergoing Phase I
clinical trials and is not yet available as a medicinal product. [74]
In 2015, the US Food and Drug Administration (FDA) granted GW Pharmaceuticals
Fast Track designation for intravenous CBD to treat Neonatal Hypoxic-Ischemic
Encephalopathy (NHIE).[75] The European Commission also granted orphan
designation (EU/3/15/1520) for cannabidiol to be used in the treatment of perinatal
asphyxia.[76] NHIE and Perinatal Asphyxia are forms of acute or sub-acute brain
injury due to asphyxia caused during the birth process and resulting from deprivationof oxygen during birth (hypoxia). Currently there are no other treatments available forthese conditions, but there is evidence of the effectiveness of cannabidiol in animalmodels. [77]12. Industrial Use
Pure CBD has no legitimate industrial uses.

13. Non-Medical Use, Abuse and Dependence
At present, there are no case reports of abuse or dependence relating to the use of pure
CBD. There are also no published statistics on non-medical use of pure CBD.
There is unsanctioned medical use of CBD based products. These are produced fromhigh CBD content plants and distributed in a variety of forms, including oils andcapsules. These products are sold online as unapproved treatments for a variety ofdisorders including epilepsy, cancer, AIDS/HIV, anxiety, arthritis, pain, and posttraumatic stress disorder (PTSD). Additionally, CBD is being used in skin and beauty
products such as shampoos and skin creams.[78, 79] Also see Annex 1: Report on
WHO questionnaire for review of psychoactive substances.

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14. Nature and Magnitude of Public Health Problems Related to Misuse,
Abuse and Dependence
At present no public health problems (e.g. driving under the influence of drugs cases,
comorbidities) have been associated with the use of pure CBD.
Also refer to Annex 1: Report on WHO questionnaire for review of psychoactive
substances.

15. Licit Production, Consumption and International Trade
Licit production of CBD for medical purposes is described in Section 11. Also refer toAnnex 1: Report on WHO questionnaire for review of psychoactive substances.

16. Illicit Manufacture and Traffic and Related Information
There are no published statistics (e.g. country data on seizures of illicit CBD)
currently available. Refer to Annex 1: Report on WHO questionnaire for review ofpsychoactive substances.

17. Current International Controls and Their Impact
Cannabidiol is not listed in the schedules of the 1961, 1971 or 1988 United Nations
International Drug Control Conventions.[80]However, cannabidiol is being produced for pharmaceutical purposes as an extract of
cannabis by GW Pharmaceuticals. Cannabidiol that is produced as an extract of
cannabis is currently included in Schedule I of the 1961 Convention.

18. Current and Past National Controls
United Kingdom: A statement was issued by the Medicines and Healthcare products
Regulatory Agency (MHRA) in 2016 that products containing CBD used for medical
purposes are considered as a medicine subject to standard licensing requirements. [81]United States: CBD is one of many cannabinoids present in cannabis, and as such is inschedule I of the Controlled Substances Act. However in December 2015, the FDA
eased the regulatory requirements to allow researchers to conduct CBD trials. The
Drug Enforcement Agency (DEA) stated that these modifications are intended to
streamline the research process regarding CBD’s possible medicinal value and help
foster ongoing scientific studies. [82]Canada: CBD is specifically listed in ‘Cannabis, its preparations and derivatives’ as acontrolled substance listed in Schedule II Controlled Drugs and Substances Act.
However, in 2016 Canada’s Access to Cannabis for Medical Purposes Regulations
came into effect. These regulations improve access to cannabis used for medicinal
purposes, including CBD. [83]Page 20 of 27

39th ECDD (2017) Agenda item 5.2

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Australia: In 2015, CBD in preparations for therapeutic use containing 2 per cent orless of other cannabinoids found in cannabis was placed in Schedule 4 as a
‘Prescription Only Medicine OR Prescription Animal Remedy’. Previous to this it
was captured in Schedule 9 as a prohibited substance.[84]New Zealand CBD is a controlled drug, however many of the restrictions currently
imposed by the regulations will be removed by the end of 2017. The changes will
mean that CBD products, where the level of other naturally occurring cannabinoids isless than 2% of the cannabinoid content, will be easier to access for medical use. [85]
Switzerland: CBD is not subject to the Narcotics Act because it does not produce a
psychoactive effect. It is still subject to standard Swiss legislation. [86]Also refer to Annex 1: Report on WHO questionnaire for review of psychoactive
substances.

19. Other Medical and Scientific Matters Relevant for a Recommendationon the Scheduling of the Substance
None

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from: https://www.gov.uk/government/news/mhra-statement-on-products-containingcannabidiol-cbd
United States Department of Justice Drug Enforcement Administration. 1 August2017]; Available from: https://www.dea.gov/divisions/hq/2015/hq122315.shtml.
Goverment of Canada Justice Laws Website. 1 August 2017]; Available from:http://laws-lois.justice.gc.ca/eng/acts/c-38.8/FullText.html.
Australian Goverment Department of Health Therapeutic Goods Administration. 1
August 2017]; Available from: https://www.tga.gov.au/book/part-final-decisionsmatters-referred-expert-advisory-committee-2.
New Zealand Goverment Ministry of Health. 1 August 2017]; Available from:http://www.health.govt.nz/our-work/regulation-health-and-disabilitysystem/medicines-control/cannabidiol.
Swiss Agency for Therapeutic Products. 1 August 2017]; Available from:https://www.swissmedic.ch/aktuell/00673/03778/index.html?lang=en.

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39th ECDD (2017) Agenda item 5.2

Cannabidiol (CBD)

Annex 1: Report on WHO Questionnaire for Review of
Psychoactive Substances for the 39th ECDD: Evaluation ofCannabidiol
Please refer to separate Annex 1 document published on ECDD website

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