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Abstract

Cannabis sativa L. contains more than 100 phytocannabinoids that can interact with cannabinoid receptors CB1 and CB2. None of the cannabinoid receptor ligands is entirely CB1- or CB2-specific. The effects of cannabinoids therefore differ not just because of different potency at cannabinoid receptors but also because they can interact with other non-CB1 and non-CB2 targets, such as TRPV1, GPR55, and GPR119. The most studied phytocannabinoid is Δ9-tetrahydrocannabinol (THC). THC is a partial agonist at both cannabinoid receptors, but its psychotomimetic effect is produced primarily via activation of the CB1 receptor, which is strongly expressed in the central nervous system, with the noteworthy exception of the brain stem. Although acute cognitive and other effects of THC are well known, the risk of irreversible neuropsychological effects of THC needs further research to elucidate the association. Unlike THC, phytocannabinoid cannabidiol (CBD) does not appear to have psychotomimetic effects but may interact with some of the effects of THC if taken concomitantly. CBD administered orally has recently undergone well-controlled clinical trials to assess its safety in the treatment of paediatric epilepsy syndromes. Their findings point to increased transaminase levels as a safety issue that calls for postmarketing surveillance for liver toxicity. The aim of this review is to summarise what is known about acute and chronic toxicological effects of both compounds and address the gaps in knowledge about the safety of exogenous cannabinoids that are still open.
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Review DOI: 10.2478/aiht-2020-71-3301
Toxicological properties of Δ9-tetrahydrocannabinol and
cannabidiol
Katarina Černe
Department of Pharmacology and Experimental Toxicology, Faculty of Medicine, University of Ljubljana, Ljubljana,
Slovenia
[Received in June 2019; Similarity Check in June 2019; Accepted in March 2020]
Cannabis sativa L. contains more than 100 phytocannabinoids that can interact with cannabinoid receptors CB1 and CB2.
None of the cannabinoid receptor ligands is entirely CB1- or CB2-specic. The effects of cannabinoids therefore differ
not just because of different potency at cannabinoid receptors but also because they can interact with other non-CB1 and
non-CB2 targets, such as TRPV1, GPR55, and GPR119. The most studied phytocannabinoid is Δ9-tetrahydrocannabinol
(THC). THC is a partial agonist at both cannabinoid receptors, but its psychotomimetic effect is produced primarily via
activation of the CB1 receptor, which is strongly expressed in the central nervous system, with the noteworthy exception
of the brain stem. Although acute cognitive and other effects of THC are well known, the risk of irreversible
neuropsychological effects of THC needs further research to elucidate the association. Unlike THC, phytocannabinoid
cannabidiol (CBD) does not appear to have psychotomimetic effects but may interact with some of the effects of THC if
taken concomitantly. CBD administered orally has recently undergone well-controlled clinical trials to assess its safety
in the treatment of paediatric epilepsy syndromes. Their ndings point to increased transaminase levels as a safety issue
that calls for postmarketing surveillance for liver toxicity. The aim of this review is to summarise what is known about
acute and chronic toxicological effects of both compounds and address the gaps in knowledge about the safety of exogenous
cannabinoids that are still open.
KEY WORDS: acute toxicity; animal studies; cannabidiol; CB1; CB2; CBD; chronic toxicity; clinical trials; Δ9-
tetrahydrocannabinol; phytocannabinoids; THC
Černe K. Toxicological properties of Δ9-tetrahydrocannabinol and cannabidiol
Arh Hig Rada Toksikol 2020;71:1-11
With the growing interest in the use of cannabinoids for
medicinal purposes grows a need for a systematic review
of their toxicological properties. There are still many
uncertainties and contradictions remaining from the
increasing number of published cannabinoid safety studies.
This is because these studies vary to extremes in their
methodology and quality, rendering results difcult to
compare. Moreover, toxicity is not systematically covered,
and there are no chronic toxicity data from well-dened
exposure settings. Higher quality toxicological data are
available for cannabinoid-based medicines that are
manufactured today as approved drugs. However, the main
indications for their use are serious and/or rare diseases,
mostly after all other treatment has failed, so their
toxicological prole is less detailed than that of the drugs
of rst choice (1).
Cannabinoid receptor ligands are a varied group of over
100 chemical compounds isolated from Cannabis sativa L.
(2). The best-characterised cannabinoids found in the
cannabis plant are Δ9-tetrahydrocannabinol (THC) and
cannabidiol (CBD). They can interact with two types of
Corresponding author: author: Katarina Černe, Department of
Pharmacology and Experimental Toxicology, Faculty of Medicine, University
of Ljubljana, Korytkova 2, Ljubljana, Slovenia
E-mail: katarina.cerne@mf.uni-lj.si
cannabinoid receptors – cannabinoid type 1 (CB1) and
cannabinoid type 2 (CB2) that both belonging to the
superfamily of G protein-coupled, seven-transmembrane
(7TM) domain receptors (3). None of the cannabinoid
receptor ligands, however, are entirely CB1- or CB2-specic.
Each of these ligands therefore differs in effect, not only
because they have different potency at cannabinoid
receptors but also because they can interact with other non-
CB1/non-CB2 targets, such as transient receptor potential
channel, vanilloid subfamily member 1 (TRPV1, aka
capsaicin or vanilloid receptor), G protein-coupled receptors
(GPR55 and GPR119), voltage-gated ion channels, and
neuronal transporters of catecholamines (4–6). Despite such
diversity, there are only four cannabinoid-based medicines
currently on the market: nabiximols (Sativex®), nabilone
(Cesamet® or Canemes®), dronabinol (Marinol® or
Syndros®), and cannabidiol (Epidiolex®) (7). Still being
developed are selective synthetic cannabinoid receptor
agonists, antagonists, and modulators, metabolism
inhibitors [such as fatty acid amide hydrolase (FAAH)
inhibitors] or inhibitors of endocannabinoid reuptake (8).
The aim of this review is to summarise what is known
about acute and chronic cannabinoid toxicity, primarily
based on animal and clinical studies of medicinal product
safety (9). Particular attention will be paid to identifying
future studies that could ll in current gaps in knowledge
2
Černe K. Toxicological properties of Δ9-tetrahydrocannabinol and cannabidiol
Arh Hig Rada Toksikol 2020;71:1-11
and uncertainties surrounding the safety of exogenous
cannabinoids. This review will discuss the toxicology of
chemically defined, single compounds that are either
synthetic, semisynthetic, or plant-derived. We will also
discuss why the combination of THC with CBD has fewer
adverse effects than THC alone.
What this review will not discuss is the toxicology of
medicinal or recreational cannabis use or the health issues
associated with contaminants in plant extracts obtained
from uncontrolled sources.
CANNABINOID RECEPTORS
THC shares the ability of endocannabinoid ligands
anandamide (AEA) and 2-arachidonoylglycerol to activate
both the CB1 and CB2 receptor. It is their partial agonist, as
it binds to them with Ki values in the low nanomolar range.
Both receptors are coupled through Gi/o proteins, negatively
to adenylate cyclase and positively to mitogen-activated
protein kinase (3). CB1 receptors are mainly located at the
terminals of central and peripheral neurons, where they
usually mediate inhibition of neurotransmitter release. CB1
is one of the G protein-coupled receptors expressed at the
highest level in the central nervous system, with the notable
exception of the brain stem (4, 10). This may be why THC
is not associated with sudden death due to respiratory
depression, which indicates its low acute toxicity. In the
brain, CB1 receptors are particularly concentrated in the
hippocampus and cerebral cortex (areas involved in memory
and cognition), olfactory areas, basal ganglia and cerebellum
(areas involved in motor activity and posture control),
hypothalamus (area involved in appetite regulation and
energy homeostasis), limbic cortex (area involved in
sedation), and neocortex (area involved in the executive
function). CB1 is also found in peripheral nervous organs
(lungs, liver, bowel, thyroid, uterus, placenta, and testicles).
Therefore, these sites can also be the targets of cannabinoid
effects. CB2 receptors are primarily associated with cells
governing the immune function, such as splenocytes,
macrophages, monocytes, microglia, and B- and T-cells.
Recently, CB2 receptors have also been reported in other
cells, often up-regulated under pathological conditions (5).
The functions of these receptors include modulation of
cytokine release and immune cell migration. CB2 receptors
are expressed in the brain by microglia, blood vessels, and
by some neurons (4, 10). However, their action has not been
elucidated.
In contrast to THC, CBD does not seem to be
psychoactive and has low afnity for CB1 and CB2 receptors
(4). This is why its research has focused on non-CB1/non-
CB2 targets (see THC/CBD interactions below). When
interpreting the effects of cannabinoids, we should bear in
mind that cannabinoid receptors are members of the
rhodopsin-like family of 7TM receptors, at which,
according to Kenakin (11), the efcacy of agonist depends
on cell type and its condition. Therefore, it is difcult to
predict the therapeutic behaviour of cannabinoid receptor
agonists. This is probably why higher release of
endocannabinoids can be protective in one and damaging
in another case.
TOXICOLOGICAL PROPERTIES OF THC
Apart from natural THC, the most reliable toxicological
data available to date are for synthetic THC dronabinol and
synthetic THC analogue nabilone. Nabilone has a similar
chemical structure and is twice as potent as THC at the CB1
and CB2 receptors (12). The main indication for dronabinol
and nabilone is nausea and vomiting in adult patients
receiving chemotherapy when conventional antiemetics fail
to do the job. Dronabinol is also indicated for anorexia in
adults with AIDS. There are no safety proles for dronabinol
and nabilone in paediatric (<18 years) and elderly (>65
years) populations. The starting dose of dronabinol is
2.5 mg, administered twice daily as capsules for oral use.
The maximum recommended dosage is 20 mg/day (4–6
doses a day). Dronabinol is also administered as a 5 mg/
mL oral solution. The usual nabilone dose is 1 or 2 mg twice
a day, and the maximum recommended dosage is 6 mg/day,
administered as capsules for oral use (13, 14). Since both
are used short-term, data on chronic effects in humans are
not available.
Pharmacokinetics/toxicokinetics of THC
The bioavailability of dronabinol is low (4–20 %)
because of its high lipid solubility and extensive rst-pass
hepatic metabolism (15, 16). Its effects do not show clear
dose dependence (17). Due to lipid solubility, the apparent
volume of distribution is high (10 L/kg). Dronabinol is
extensively metabolised in the liver, primarily by
cytochrome P450 enzymes CYP2C9 and CYP3A4.
CYP2C9 is probably responsible for the formation of the
primary active metabolite hydroxy-Δ9-THC.
Pharmacogenomics studies indicate two to three times
higher plasma THC in individuals with a less active form
of CYP2C9, so adverse drug reaction in these individuals
may be more frequent and/or severe. The major route of
excretion is faeces (65 %), and the minor is urine (20 %)
(16). Urinary metabolites of dronabinol are identical to
those of marijuana and may be excreted over long time (18).
Nabilone has better bioavailability (at least 60 %) than
dronabinol and demonstrates dose linearity (15, 19).
Multiple cytochrome P450 enzymes extensively metabolise
nabilone to various metabolites, which have not been fully
characterised yet. Two major metabolic pathways are
probably involved in the biotransformation of nabilone: 1)
enzymatic reduction of the 9-keto group to form carbinol
metabolites; and 2) direct enzymatic oxidation of the
aliphatic side-chain to produce carboxylic and hydroxylic
analogues. The formation of carbinol metabolites is a major
3
nabilone metabolic pathway in dog. Hydroxylic analogues
appear to be more important in rhesus monkey and man.
Carbinols are long-lived metabolites that accumulate in the
plasma and concentrate in the brains of treated dogs over
time (see chronic toxicity) (20). Nabilone and its metabolites
are primarily eliminated in faeces (~65 %) and to a lesser
extent in urine (~20 %) (14, 17). Although no accumulation
of nabilone was observed after repeated doses, some
accumulation was observed for its metabolites (21).
Non-clinical toxicity of THC
Acute oral toxicity of THC in rats is lower in males
(LD50=1910 mg/kg) than in females (LD50=1040 mg/kg)
(22). The LD50 of oral nabilone is >1000 mg/kg in rats of
both sexes (21). The signs of acute toxicity of THC and
nabilone are similar and include lower respiratory rate,
ataxia, decreased activity, catatonia, hypothermia,
hypersensitivity to touch, and generalised body twitching.
Death was reported to be due to respiratory arrest (21, 22).
Sub-chronic and chronic effects of THC (5, 15, 50, 150,
and 500 mg/kg/day) administered by gavage were assessed
in rats in a 13-week study followed by a 9-week recovery
period and in a 2-year study (12.5, 25, and 50 mg/kg/day)
(23). Briey, THC-treated rats had lower body weight than
controls and exhibited convulsions, hyperactivity, and
changes in the reproductive organs of both male and female
rats. Reduced body weight was notable even at low dose
exposure and was attributed to metabolic changes caused
by THC. Weight loss was not associated with lower feed
consumption but with increased energy consumption
(evidenced by higher plasma corticosterone levels) needed
for hyperactivity, adaptation, and detoxication from THC.
Convulsions and hyperactivity were observed at all doses.
The onset and frequency of convulsions were also dose-
related. However, Chan et al. (23) observed no histological
changes in brain tissue of rats with a history of THC-related
convulsion or seizures. Luthra et al. (24) reported
generalised depression, followed by hyperactivity,
irritability, aggressiveness, and convulsion in rats treated
with THC for 119 days. The highest dose of THC in a sub-
chronic study in rats induced testicular atrophy and uterine
and ovarian hypoplasia (23). This study also found higher
serum FSH and LH at all doses.
Nabilone was assessed in two chronic toxicity studies
(21). The one in beagle dogs (0.5, 1.0, 2.0 mg/kg/day) was
planned to last one year but was terminated after seven
months due to high mortality. Most deaths were preceded
by convulsions, and toxicity was attributed to accumulation
of carbinol metabolites in the brain over time. In contrast
to dogs, nabilone chronic toxicity was minimal in rhesus
monkeys receiving doses of up to 2.0 mg/kg/day for one
year. Transient periods of anorexia, emesis, and ataxia were
observed only at the highest dose.
Chan et al. (23) also evaluated THC carcinogenicity in
rats and mice and found no evidence in rats at doses of up
Černe K. Toxicological properties of Δ9-tetrahydrocannabinol and cannabidiol
Arh Hig Rada Toksikol 2020;71:1-11
to 50 mg/kg/day [~20 times the maximal human
recommended dose (MHRD)]. In mice, THC produced
thyroid follicular cell adenoma (a common benign neoplasm
of the thyroid) in both sexes, but the effect was not dose-
dependent, as the hyperplasia was increased compared to
control at all doses and in both sexes. It is unclear what
these ndings mean. Carcinogenicity studies have not been
performed with nabilone.
Genotoxicity
THC and nabilone have no mutagenic potential (11–13,
23). Positive Ames and skin test results in mice for THC in
some in vitro tests are attributed to cytotoxic rather than
mutagenic action (25).
Reproductive toxicity
THC was evaluated in an oral embryo-foetal
developmental study in rats (at doses ranging from 12.5 to
50 mg/kg/day) (26) and in rabbits (0.5, 1.5, 5 and 15 mg/
kg/day) (27). No teratogenic effects were observed in rats.
Increased foetal mortality and early resorption were
associated with maternal toxicity, which manifested itself
as lower weight gain. In rabbits, one third of the foetuses
in the high-dose group had multiple anomalies (such as
acrania and spina bida). In a single-generation reproductive
study (28), male and female rats received 0.5, 1.5, and 5 mg/
kg/day of THC by gavage. Offspring to mothers receiving
1.5 and 5 mg/kg/day showed a dose-related drop in survival
at day 12 of lactation and at weaning.
A reproduction study of nabilone in rats (1.4, and 12 mg/
kg/day) and rabbits (0.7, 1.6, and 3.3 mg/kg/day) (29)
showed no teratogenic effects. However, it did nd dose-
related developmental toxicity, such as embryo death, foetal
resorption, decreased foetal weight, and disrupted
pregnancy. Another study in rats (24) revealed postnatal
developmental toxicity of nabilone at 1.4 and 12 mg/kg/
day), manifested by smaller litter size and lower survival
as well as lower initial body weight and hypothermia in
pups from the high-dose group.
There are no sufcient data on pregnancy outcomes in
women exposed to dronabinol (THC) or nabilone.
THC toxicity in clinical trials
Safety data on dronabinol come from 10 randomised,
double-blind, placebo-controlled clinical trials. In one trial
(30) patients with AIDS-related anorexia (N=139) were
receiving dronabinol as appetite stimulant (5 mg/day), and
in nine trials patients with cancer (N=454) were receiving
dronabinol as antiemetic in the dose range of 2.5–40 mg/
day (31–39) for no longer than six weeks. The most
frequently reported adverse events (33 %) in patients with
AIDS were euphoria, dizziness, somnolence, and thinking
abnormalities. The most common adverse events in patients
receiving the antiemetic dronabinol were drowsiness,
dizziness and transient impairment of sensory and
4
Černe K. Toxicological properties of Δ9-tetrahydrocannabinol and cannabidiol
Arh Hig Rada Toksikol 2020;71:1-11
perceptual functions. Patients from both studies (24% in
antiemetic and 8% in appetite stimulant) reported dose-
related “highs” (elation, laughter, and heightened
awareness). The frequency of adverse effects on the central
nervous system (CNS) increased with doses, and their
severity greatly varied between patients. After oral
administration, dronabinol had an action onset of
approximately 30 min to one hour and a peak effect at two
to four hours (40). Psychoactive effects lasted four to six
hours. Other than those affecting the nervous system, the
most frequent adverse effects were gastrointestinal
(abdominal pain, nausea, and vomiting) and cardiovascular
(palpitation, tachycardia, vasodilatation/facial ush) (30–
39). The following were the most serious adverse effects
of dronabinol: neuropsychiatric, haemodynamic instability,
seizure, paradoxical nausea, vomiting, and abdominal pain.
Dronabinol should be discontinued in patients experiencing
a psychotic reaction or showing cardiovascular effects
(tachycardia, transient changes in blood pressure) and used
with caution in patients with a history of epilepsy or
recurrent seizures (13).
Nabilone has systematically been evaluated in
controlled clinical trials that lasted up to nine weeks (41–
43). The lowest nabilone dose (2 mg) had a few adverse
effects, whereas a 3–5 mg dose closely mirrored dronabinol’s
(25 mg) effects (18).
THC addiction and dependence
High levels of CB1 receptors are found in the brain areas
that are part of the mesocorticolimbic dopaminergic
pathway and are implicated in motivational and reward
processes (44). Being partial CB1 receptor agonists, THC
and its analogues should be tested for their addictive
potential (45). Many abused drugs that can lead to addiction
increase synaptic dopamine levels in the human limbic
striatum. The same was reported for THC in human studies
in healthy participants (46–48). Dopamine release was small
compared to amphetamine, cocaine, alcohol (10–15 %),
and nicotine (~10 %).
First studies in monkeys (49, 50) failed to show the
rewarding effects of THC, but newer studies with
intravenous dronabinol injection (1–6 µg/kg) conrmed it
in squirrel monkeys (51, 52). Another widely used predictor
of a reinforcing (and therefore addictive) effect is the
conditional place preference (CCP) test, in which a
compartment in a cage is associated (paired) with a tested
substance. Lepore et. al. (53) reported that CCP depended
on the dose and intervals between administration and that
dronabinol doses of 2 or 4 mg/kg every 24 h produced a
reliable shift in favour of the dronabinol-paired compartment.
Reinforcing effects have also been observed in humans
(12). Nabilone (4–8 mg/day) and dronabinol (10–20 mg/
day) produced stronger marijuana-like subjective effects,
such as feeling good, feeling “high”, and feeling “stoned”
than placebo. Nabilone had a slower onset of the peak
subjective effects.
Chronic therapy with dronabinol can lead to physical
dependence. One human study (17) showed that dronabinol
doses of 210 mg/day (~10 times higher than MHRD)
administered for 12 to 16 consecutive days produced
withdrawal syndrome within 12 h after discontinuation.
Initial symptoms were irritability, insomnia, and restlessness.
By hour 24 of discontinuation, withdrawal symptoms
intensied to include “hot ashes”, sweating, rhinorrhoea,
loose stool, hiccoughs, and anorexia. We still do not know
whether nabilone can also lead to physical dependence.
Patients that participated in clinical trials for up to ve days
showed no withdrawal symptoms after discontinuation of
dosing (54).
TOXICOLOGICAL PROPERTIES OF CBD
As a 99 % pure extract from C. sativa, active substance
cannabidiol was first approved in June 2018 under
proprietary name Epidiolex® (55). The United States Food
and Drug Administration (US FDA) and European
Medicines Agency (EMA) approved it for the treatment of
seizures associated with Lennox-Gestaut (LGS) and Dravet
syndrome (DS) in patients two years of age or older.
Epidiolex® is administered as a 100 mg/mL oral solution.
The starting dose is 2.5 mg/kg twice a day and the maximum
recommended dose is 10 mg/kg twice a day (20 mg/kg/day)
(55, 56). Considering that Epidiolex® has been approved
for treatment in children, CBD has become the most
extensively toxicologically tested cannabinoid, and thus the
most reliable source of toxicological data. However,
because of the seriousness of the indications and failure of
patients to respond to existing medication, Epidiolex® was
approved in spite of certain deficiencies in the safety
assessment (e.g., inadequate safety assessment of major
human metabolite 7-COOH-CBD). Additional studies listed
in Table 1 should therefore be carried out as part of post-
marketing surveillance to obtain a complete safety prole
of CBD. Furthermore, no clinical trial with Epidiolex® has
been conducted in patients older than 55 years, so its safety
prole does not cover the elderly population. General
recommendation is to start with the lowest dose (56).
Since CBD is derived from C. sativa, Table 2 presents
a thorough assessment of the abuse and dependence
potential of Epidiolex® (4, 57–59). A human study (58)
found marginal abuse potential at a higher therapeutic dose
(1500 mg/day) and supratherapeutic dose (4500 mg/day),
but there is little other evidence that CBD could cause
addiction. The results of a human dependence study of CBD
were negative (59).
Pharmacokinetics/toxicokinetics of CBD
Plasma CBD concentrations show a nonlinear increase
with dose and 6.5 % bioavailability at a 3000-mg dose (60).
5
Černe K. Toxicological properties of Δ9-tetrahydrocannabinol and cannabidiol
Arh Hig Rada Toksikol 2020;71:1-11
CBD absorption increases three times with a high-fat meal
and six times with new oral delivery system for lipophilic
active compounds (61, 62). Its high estimated volume of
distribution (18,800—30,959 L) indicates accumulation of
CBD in body fat (63). CBD is extensively metabolised in
the liver and gut, mainly by the CYP2C19, CYP3A4,
UGT1A7, UGT1A9, and UGT2B7 enzymes (64). Drug
interaction trials to assess the effect of CBD on these
enzymes in healthy volunteers will be conducted during the
post-marketing period (Table 1) (55, 56). The metabolism
of CBD is very complex, especially in hepatocytes. The
main human metabolite is 7-carboxy-cannabidiol (7-COOH-
CBD; ~90 % of all drug-related substances measured in the
plasma) (64). Its toxicological profile has not been
investigated because experimental animals for toxicological
studies (mice, rats, and dogs) do not metabolise CBD to a
comparable extent as humans (65). The major concern with
7-COOH-CBD could be its reactive acyl-glucuronide (66)
The primary excretion route of CBD is through faeces
(84 %), followed by urine (8 %) (63).
Non-clinical toxicology of CBD
In a study of acute effects in rhesus monkeys (67),
intravenous CBD caused death by respiratory arrest and
cardiac failure at doses above 200 mg/kg (LD50=212 mg/
kg). At the lower dose of 150 mg/kg, survivors recovered
in one to three days, and liver weights increased from 19
to 142 %. In the part of the study investigating subchronic
effects (after 90 days of oral administration), the authors
reported inhibition of spermatogenesis at the highest oral
dose of 300 mg/kg (67).
Animal studies of CBD alone described below make
part of the Epidiolex® European Public Assessment Report
(EPAR, EMA’s scientic monography) (56). To the best of
my knowledge, they have not been published and therefore
no further detail or original references are currently
available. All these studies were conducted in accordance
with medicinal product safety standards and protocols and
reviewed by the EMA committee (9).
Two oral chronic toxicity studies (referred to in 56) have
assessed CBD in Wistar rats (receiving 15, 50, or 150 mg/
kg/day for 6 months) and Beagle dogs (receiving 10, 50,
100 mg/kg/day for 9 months). In both species the primary
target organ was the liver. Hepatocellular hypertrophy was
detected at all doses, accompanied by an increase in alanine
transferase (ALT) and alkaline phosphatase (ALP).
A 104-week oral carcinogenicity study in Wistar rats
(referred to in 56) revealed no drug-related neoplastic
findings. However, the study had several drawbacks,
including impure active substance, excessive effect of body
weight, and unknown exposure to the two major human
metabolites.
Table 1 Recommended post-marketing studies to obtain a complete safety prole of cannabidiol (CBD)
Non-clinical toxicity studies
Toxicity studies with CBD metabolite 7-COOH-cannabidiol in rat:
- embryo-foetal developmental study
- pre- and postnatal developmental study
- juvenile animal toxicity study
- 2-year carcinogenicity study with gavage
Toxicity studies with CBD
- 2-year carcinogenicity study in mouse
- 2-year carcinogenicity study in rat with gavage
Clinical studies
- Potential for chronic liver injury
- Effect on glomerular ltration rate
- Pregnancy outcome study
- QT interval prolongation trial at the maximum tolerable dose
Drug-drug interaction trials in healthy volunteers
CBD effect on the pharmacokinetics of:
- caffeine
- sensitive CYP2B6* and CYP2C9 substrate
- sensitive UGP1A9** and UGTB7 substrate
Strong CYP3A inhibitor effects on pharmacokinetics of CBD
Strong 2C9 inhibitor effects on pharmacokinetics of CBD
Rifampin effects on pharmacokinetics of CBD
* cytochrome P450; ** UDP-glucuronosyltransferase
6
The genotoxic potential of CBD was also investigated
in a standard battery of tests, but their results were negative
for mutagenicity and clastogenicity (referred to in 56).
A full battery of oral reproductive and developmental
studies has been conducted with purified CBD. In an
embryo-foetal development study in Wistar rats, litter loss
was noted at the highest applied dose of 250 mg/kg. In a
prenatal and postnatal development study (referred to in
56) rat exposure to the highest doses (150 and 200 mg/kg/
day) affected reproductive organs (smaller testes in males,
reduced fertility index in females). A high dose of 125 mg/
kg also reduced foetal body weight in New Zealand white
rabbit, which was related to maternal toxicity. The
developmental toxicity in rabbits occurred at maternal
plasma concentration similar to human at therapeutic doses
(referred to in 56). In rats these concentrations were much
higher. No adequate data are available on pregnancy
outcome in women exposed to CBD.
A juvenile toxicity study in Wistar rats (referred to in
56) showed neurobehavioral decits and delayed sexual
maturation in males. A no observed effect level (NOAEL)
was 150 mg/kg/day.
Clinical toxicology of CBD
Safety data on Epidiolex® were obtained from four
randomised, double-blind, placebo-controlled multicentre
trials with exposure to CBD doses of 5, 10, and 20 mg/kg/
day (68–70). These phase II studies were conducted in 2 to
55 year-old patients with LGS (N=235) and DS (N=88) for
up to 14 weeks.
Additional non-controlled safety data have been
obtained from an ongoing open-label Phase III study (Study
1415) in LGS and DS patients (N=644), which is being
conducted at 38 sites in the USA and Australia. Since this
trial is not nished, an interim analysis of long-term safety
was conducted (71, 72).
The most common adverse events in CBD-treated
patients affected the following systems: CNS (somnolence,
sedation), gastrointestinal tract (lower appetite, diarrhoea),
liver (higher transaminase), and the lungs (pneumonia). The
severity of these events was generally mild to moderate.
Diarrhoea, weight loss, higher ALT, and somnolence/
sedation/lethargy were all dose-related. There were two
serious cases of transaminase elevation, two severe events
with rash (one consistent with a hypersensitivity reaction)
and three severe cases of appetite loss. The CBD-treated
and the placebo group did not differ in the rate of respiratory
failure. Children had lower weight, which was associated
to a certain extent with appetite loss (68–71).
Treatment with CBD is clearly associated with an
increased risk of hepatotoxicity (68–71). Higher doses of
CBD and concomitant use of valproate increase the risk of
transaminase elevation in patients. Two patients
concomitantly treated with valproate experienced toxic
Černe K. Toxicological properties of Δ9-tetrahydrocannabinol and cannabidiol
Arh Hig Rada Toksikol 2020;71:1-11
Table 2 Cannabidiol (CBD) abuse potential
TYPE OF STUDY RESULTS
Receptor binding studies
- cannabinoid receptors no signicant afnity
- opioid receptors no signicant afnity
Non-clinical studies evaluating general behaviour (similarity to THC)
- tetrad test no meaningful abuse related signal
- drug discrimination study no meaningful abuse related signal
- self-administration study no meaningful abuse related signal
Clinical studies evaluating efcacy and safety in patients with LGS* or DS*
- Phase I clinical study no euphoria or other abuse-related signals
- Phase II/III studies could not be evaluated***
Phase I human abuse potential (HAP) study (N=40, with 35 completers)
randomized, double blind, placebo-controlled trial
subjects: healthy recreational poly-drug users
positive control: THC (10, 30 mg), alprazolam (2 mg)
negative control: placebo
mean DRUG LIKING SCORE
lower therapeutic dose: 750 mg/day not signicantly different
higher therapeutic dose: 1500 mg/day signicantly different (very small increase)
supra-therapeutic dose: 4500 mg/day signicantly different (very small increase)
Human physical dependence study following chronic administration
3 days after discontinuation no withdrawal signs and symptoms
*Lennox-Gastaut syndrome; **Dravet syndrome; ***concomitant use of other seizure drugs and limited capacity of patients
7
hepatocellular injury, metabolic acidosis, and
encephalopathy. There appears to be no pharmacokinetic
interaction between CBD and valproate, although a
pharmacodynamical interaction is currently being
investigated. The potential of CBD to cause chronic liver
injury should be evaluated in the post-marketing period (55,
56) (Table 1).
MECHANISMS OF THC/CBD
INTERACTIONS
In spite of its low afnity for the CB1 and CB2 receptors,
CBD can interfere with some THC adverse effects,
particularly in the brain, without interfering with the
intended THC effects, such as muscle relaxation (73).
Understanding pharmacodynamic interactions between
THC and CBD can be quite a challenge. CBD is a ligand
with very low afnity for the CB1 receptor but can still
increase CB1 constitutional or endocannabinoid activity (5),
which has been conrmed by. thermodynamic ndings that
CBD increases membrane uidity and thereby the activity
of the CB1 receptor (74). Another mechanism of action is
that CBD increases the levels of primary endocannabinoids
AEA and 2-arachidonyl-glycerol (2-AG) (5). CBD may
also interfere with THC through interaction with other non-
CB1 receptors and enzymes in the ‘expanded
endocannabinoid system’ (5). In their systematic review
McPartland et al. (5) propose several non-CB1 receptor
mechanisms of CBD antagonising or potentiating THC
effects. For example, CBD may attenuate the anxiogenic
effect of THC by acting as a direct or indirect agonist on
serotonin 1A receptors (5-HT1A). In contrast, it can
potentiate THC action on CB1 receptors by reducing
peripheral hyperalgesia via TRPV1 channels (75). Sativex®,
as a mixture of THC and CBD, consequently provided better
antinociception than THC given on its own 76).
In terms of pharmacokinetic CBD/THC interaction,
CBD may impair THC hydrolysis by CYP450 enzymes
(77). The inhibition of THC metabolism may vary with
species, timing of administration (CBD pre-administration
vs co-administration), and CYP isoenzymes. In rats or mice
THC effects are potentiated when CBD is administered
30 min to 24 h before THC but mitigated if co-administered
(78). In humans, no pharmacokinetic interactions between
THC and CBD at clinically relevant doses have been
reported (79). Co-administration of CBD with THC in one
study (80) yielded similar maximum plasma levels of THC
as when it was administered alone. Whether CBD will
antagonise or potentiate THC effects also seems to depend
on their administration ratio, and this ratio varies with
species (5).
TOXICOLOGY OF CBD+THC
COMBINATIONS
The combination of THC and CBD in a 1:1 ratio makes
the active substance nabiximols of the cannabinoid-based
medicine Sativex® (81). It is an oromucosal spray approved
for the treatment of multiple sclerosis-associated spasticity
in adult patients when all other treatment has failed. There
is no safety prole of nabiximols in children (>18 years)
and the elderly, even though clinical trials included patients
up to 90 years of age. Elderly patients may be more
susceptible to some adverse effects in the CNS. The
oromucosal (e.g. sub-lingual) route resolves the problem
of variable bioavailability (typically 6 to 20 %) of orally
administered cannabinoids due to rst-pass metabolism.
Each 100 µL spray contains 2.7 mg THC and 2.5 mg CBD.
The starting dose is two sprays per day and the maximum
dose is 10–12 sprays per day (corresponding to 32.4 mg
THC and 30 mg CBD) (81).
A study using a rat model of Huntington’s disease
showed that nabiximols can up-regulate CB1 gene
expression (82). CBD increases the levels of the primary
endocannabinoids AEA and 2-arachidonyl-glycerol (2-AG)
(6).
The most common adverse effects of nabiximols in
clinical trials conducted in patients with multiple sclerosis
were dizziness, fatigue and gastrointestinal disorders (e.g.
nausea, vomiting, diarrhoea) (82–92). These adverse effects
and poor efcacy were the main reasons for some patients
to discontinue therapy (88, 90). In patients with multiple
sclerosis the risk of accidental injury may be increased (83,
87, 92–94). There is little evidence of abuse (addiction) or
dependence, and the risk of either to develop is small.
However, trials to date have mainly used therapeutic doses,
and it is possible that supratherapeutic doses could cause
addiction and/or dependence (85, 87, 92–94).
CONCLUSION
In spite of uncertainties about the safety of cannabinoids,
there are no doubts about the acute neurological and
cardiovascular effects of THC. However, THC is not
associated with sudden death due to respiratory depression
as is the case with opioid analgesics. Long-term cognitive,
psychological, and endocrine effects of THC are still being
investigated.
As for CBD, it can be toxic to the liver and increases
the risk of somnolence and sedation, but the most commonly
observed adverse events in controlled clinical trials were
mild to moderate. However, these clinical trials included a
small number of subjects and some aspects require
continued pharmacovigilance. Regardless of different views
on the subject, cannabinoid-based medicines need to be
assessed just as any other substance in terms of quality,
efcacy, and safety.
Černe K. Toxicological properties of Δ9-tetrahydrocannabinol and cannabidiol
Arh Hig Rada Toksikol 2020;71:1-11
8
Conicts of interest
None to declare.
Acknowledgements
This work was supported by research grants from the
Slovenian Research Agency (P3-067). I wish to thank
Nevenka Dolžan for technical assistance and Martin
Cregeen for translating sections of the text into English.
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Toksikološke lastnosti kanabinoidov
Iz rastline Cannabis sativa L. so do sedaj izolirali že več kot 100 tokanabinoidov, poleg njih pa obstaja več kot 550
sintetičnih spojin, ki delujejo na kanabinoidne receptorje CB1 in CB2. Prav tako je treba omeniti, da nobeden od ligandov
kanabinoidnih receptorjev ni popolnoma CB1- ali CB2-specičen. Zato se učinki vsakega od njih razlikujejo ne le zaradi
različne moči na kanabinoidnih receptorjih, ampak tudi zato, ker lahko delujejo na druga ne-CB1 in ne-CB2 prijemališča.
Najpogosteje proučevani kanabinoid je Δ9-tetrahidrokanabinol (THC). THC je delni agonist na obeh kanabinoidnih
receptorjih, vendar je njegov psihoaktivni učinek povezan predvsem z aktivacijo receptorjev CB1. Receptor CB1 je eden
izmed metabotropnih receptorjev z največjo ekspresijo v osrednjem živčevju, z izjemo možganskega debla. Čeprav so
akutni učinki na osrednji živčni sistem THC jasno opredeljeni, je tveganje za ireverzibilne nevropsihološke učinke THC
kot neodvisnega dejavnika potrebno nadalje raziskati za pojasnitev povezave. Za razliko od THC, tokanabinoid kanabidiol
(CBD) nima psihoaktivnih učinkov, vendar lahko pri sočasni uporabi vpliva na nekatere učinke THC. CBD, ki nima
pomembne anitete za CB1 in CB2, aktivira ali zavira številne uveljavljene in domnevne farmakološke tarče. CBD je kot
aktivna snov v zdravilu Epidiolex® pred kratkim opravil nadzorovana klinična preskušanja, da so ocenili njegovo varnost
pri zdravljenju redkih epileptičnih sindromov pri otrocih. Največjo zaskrbljenost glede varnosti so predstavljale povišane
vrednosti transaminaz. Zato je treba izvesti postmarketinški nadzor toksičnosti za jetra. Članek bo povzel kar je znano o
akutnih in kroničnih toksikoloških učinkih, katere študije še manjkajo in kaj so negotovosti v zvezi z varnostjo eksogenih
kanabinoidov.
KLJUČNE BESEDE: Δ9-tetrahidrokanabinol; akutna in kronična toksičnost; kanabidiol; podatki od ljudi; študije na živalih
... Černe (2020) [130] Review of studies on cannabis effects on humans and animals, in vivo and in vitro. ...
... Cannabidiol has been approved for years for the treatment of seizures associated with Lennox-Gastaut syndrome (LGS) and Dravet syndrome (DS) in children two years of age or older [130] and for refractory epilepsy, resulting in a widely tested cannabinoid. ...
... Although CBD has been reported to reduce the frequency of seizures in pediatric patients with drug-resistant epilepsy, almost a half of them experienced secondary effects such as seizure aggravation (18%), somnolence/fatigue (22%), gas-trointestinal problems and irritability (7%) [131]. Same effects, such as somnolence, sedation, and lethargy, were also reported in other studies, at therapeutic dosage (maximum recommended dose is 10 mg/kg twice a day), in a doserelated manner [130]. ...
Article
Background Although cannabinoids consumption represents a current social and health problem, especially in a historical context characterized by an open orientation for recreational and therapeutic purposes, risks regarding neurotoxicity of such substances is a frequently overlooked issue. Objective The present systematic review aims to summarize the available evidence regarding the mechanism of cannabinoids-induced brain damage as a substrate of neurological, psychiatric, and behavioral effects. Another objective is to provide support for future investigations and for legislative choices. Methods The systematic literature search through PubMed and Scopus and a critical appraisal of the collected studies were conducted. Search terms were “(("Cannabinoids" OR "THC" OR "CBD") AND "Brain” AND ("Damage" OR "Toxicity"))” in title and abstracts. Studies examining toxic effects on the brain potentially induced by cannabinoids on human subjects were included. Results At the end of the literature selection process, 30 papers were considered for the present review. The consumption of cannabinoids is associated with the development of psychiatric, neurocognitive, neurological disorders and, in some cases of acute consumption, even death. In this sense, the greatest risks have been related to the consumption of high-potency synthetic cannabinoids, although the consumption of phytocannabinoids is not devoid of risks. Conclusion The research carried out has allowed to highlight some critical points to focus on, such as the need to reinforce the toxic-epidemiologic monitor of new substances market and the importance of information for both medical personnel and general population, with particular attention to the mostly involved age groups.
... Pre-clinical studies, carried out on animal models, reported acute and chronic adverse effects of CBD on different organs and systems (Table A2) [112][113][114][115][116][117][118][119][120][121][122]. There are several highly recommended comprehensive reviews, which critically analyzed the CBD safety and toxicity experiments carried out in animal pre-clinical and human clinical trials [53,[123][124][125][126][127]. The following important observations should be mentioned: (1) regarding the administration route, in most human trials, CBD was administrated orally or by inhalation, whereas predominantly intraperitoneal (i.p.) and intravenous (i.v.) injections and sometimes the oral route were used in animals; (2) CBD pharmacokinetics and molecular targets seem to differ between humans and rodents; these differences should be taken into consideration when extrapolating results obtained in pre-clinical models to humans; (3) regarding the composition, in numerous CBD toxicity reports in humans, patients consumed not pure CBD but different preparations of CBD of unknown concentration and uncertain composition. ...
... Many preparations marketed as CBD contain also variable quantities of THC [77]. Since the toxicity profile and side effects caused by THC and CBD are different and THC seems to be more toxic [126], the data obtained in these studies are misleading, reporting the net effect of THC, CBD, and their interaction. Drug-drug interactions represent a very important issue in the case of CBD, because it targets enzymes implicated in drug metabolism and excretion [8]. ...
... Since CBD is suggested to be included in combined anticancer chemotherapy protocols, CBD's hepatotoxicity, which can cause changes in drug metabolism, is an issue of special importance. A hepatotoxic effect was documented in pre-clinical and clinical studies when relatively high CBD doses were administrated for a prolonged time [53,[123][124][125][126][127]. As was revealed by a randomized, double-blind trial that included 171 patients, hepatocellular injury represents the most frequent adverse effect, so it was recommended to test serum transaminases and total bilirubin levels in all patients prior to starting the treatment with Epidiolex ® , which is CBD in an oral solution [132,133]. ...
Article
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Cannabidiol (CBD), a major non-psychotropic component of cannabis, is receiving growing attention as a potential anticancer agent. CBD suppresses the development of cancer in both in vitro (cancer cell culture) and in vivo (xenografts in immunodeficient mice) models. For critical evaluation of the advances of CBD on its path from laboratory research to practical application, in this review, we wish to call the attention of scientists and clinicians to the following issues: (a) the biological effects of CBD in cancer and healthy cells; (b) the anticancer effects of CBD in animal models and clinical case reports; (c) CBD’s interaction with conventional anticancer drugs; (d) CBD’s potential in palliative care for cancer patients; (e) CBD’s tolerability and reported side effects; (f) CBD delivery for anticancer treatment.
... In addition, careful examination of whether the influence of CBD on the immune system could exacerbate viral infection is required (reviews [64,65]). Indeed, viral, fungal infections and pneumonia infections are listed among the side effects of CBD [166][167][168][169]. ...
... However, the authors of the latter two reviews postulated the need to conduct additional clinical trials. Indeed, various side effects of CBD have recently been described [166][167][168][169]. In addition to the increased risk of infection mentioned above, the increased tendency for respiratory depression and aspiration to occur, that is, symptoms also occurring in COVID-19, should be considered. ...
Article
Full-text available
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may lead to coronavirus disease 2019 (COVID-19) which, in turn, may be associated with multiple organ dysfunction. In this review, we present advantages and disadvantages of cannabidiol (CBD), a non-intoxicating phytocannabinoid from the cannabis plant, as a potential agent for the treatment of COVID-19. CBD has been shown to downregulate proteins responsible for viral entry and to inhibit SARS-CoV-2 replication. Preclinical studies have demonstrated its effectiveness against diseases of the respiratory system as well as its cardioprotective, nephroprotective, hepatoprotective, neuroprotective and anti-convulsant properties, that is, effects that may be beneficial for COVID-19. Only the latter two properties have been demonstrated in clinical studies, which also revealed anxiolytic and antinociceptive effects of CBD (given alone or together with Δ9-tetrahydrocannabinol), which may be important for an adjuvant treatment to improve the quality of life in patients with COVID-19 and to limit post-traumatic stress symptoms. However, one should be aware of side effects of CBD (which are rarely serious), drug interactions (also extending to drugs acting against COVID-19) and the proper route of its administration (vaping may be dangerous). Clearly, further clinical studies are necessary to prove the suitability of CBD for the treatment of COVID-19.
... As explicitly excluded by the definition of cannabis in the UN single convention [4], seed products (e.g., hemp seed oil), without the cannabinoid-rich resin, are generally regarded as safe and may be marketed in the EU [5,6]. Besides Δ 9 -THC, the non-psychotropic cannabidiol (CBD, Figure 1c) gained increasing popularity due to a broad spectrum of health-promoting effects ascribed to it with several reviews on safety and efficacy available [7][8][9][10][11][12][13][14][15][16][17][18]. In recent years, this culminated in extensive consumer interest with heavily increasing numbers starting in 2018 ( Figure 2). ...
... In fact, CBD is described as "non-psychotropic" [45] or even "anti-psychotropic" [11,12] as it does not show effects comparable to Δ 9 -THC, neither in studies on animals as already reported by Mechoulam et al. [46] in 1970 nor in humans as reviewed by Iseger et al. [12]. However, a multitude of psychological and physiological effects (some examples are anti-inflammatory, antiemetic, antipsychotic, anticarcinogenic, anxiolytic and analgesic effects, effects on appetite, positive effects on multiple sclerosis and spinal cord, as well as on Gilles de la Tourette's syndrome, epilepsy, glaucoma, diabetes, Parkinson disease and dystonia) were associated with CBD and reviewed in a number of articles [7][8][9][10][11][12][13][14][15][16][17][18]. In agreement with the hypothesis by Compton et al. [44], a physiological explanation for the different pharmacology was presented by Pertwee et al. [47], when they reported on the unexpectedly high potency of CBD to act as the antagonist of CB1/CB2 receptors in cells or tissues expressing these receptors. ...
Article
Full-text available
Cannabidiol (CBD) is a naturally occurring, non-psychotropic cannabinoid of the hemp plant Cannabis sativa L. and has been known to induce several physiological and pharmacological effects. While CBD is approved as a medicinal product subject to prescription, it is also widely sold over the counter (OTC) in the form of food supplements, cosmetics and electronic cigarette liquids. However, regulatory difficulties arise from its origin being a narcotic plant or its status as an unapproved novel food ingredient. Regarding the consumer safety of these OTC products, the question whether or not CBD might be degraded into psychotropic cannabinoids, most prominently tetrahydrocannabinol (THC), under in vivo conditions initiated an ongoing scientific debate. This feature review aims to summarize the current knowledge of CBD degradation processes, specifically the results of in vitro and in vivo studies. Additionally, the literature on psychotropic effects of cannabinoids was carefully studied with a focus on the degradants and metabolites of CBD, but data were found to be sparse. While the literature is contradictory, most studies suggest that CBD is not converted to psychotropic THC under in vivo conditions. Nevertheless, it is certain that CBD degrades to psychotropic products in acidic environments. Hence, the storage stability of commercial formulations requires more attention in the future.
... Hemp seed oil is rich in a variety of nutrients and has high edible and medicinal value, however, it contains delta-9tetrahydrocannabinol acid (Δ9-THCA). At certain concentrations in the body, it may produce symptoms such as abdominal distension, sweating, and vomiting which are the main adverse reactions [31][32][33]. ...
Preprint
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Background: The incidence of colorectal cancer among the middle-aged and elderly is gradually increasing in China. Colonoscopy is an effective method for early diagnosis of colorectal cancer, and bowel preparation is one of many important factors affecting colonoscopy. Although there are many studies on intestinal cleansers, the results are not ideal. There is evidence that hemp seed oil has certain potential effects in intestinal cleansing, but prospective studies in this area are still lacking. Methods: This is a randomized, double-blind, single-center clinical study. We randomly assigned 690 subjects to a combination of 3L PEG; 30 mL hemp seed oil and 2L PEG; or 30 mL hempseed oil, 2L PEG, and 1000 ml 5% sugar brine. Boston Bowel Preparation Scale (BBPS) was considered the primary outcome measure. We evaluated the interval between consumption of the bowel preparation and the first bowel movement. Secondary indicators were evaluated after the total number of bowel movements; these included the time of cecal intubation, the detection rate of polyps and adenomas, the willingness to repeat the same bowel preparation, whether the protocol is tolerated, and whether there were adverse reactions during bowel preparation. Discussion: This study aimed to test the hypotheses that hemp seed oil (30 ml) increases the quality of bowel preparation while reducing the amount of polyethylene glycol (PEG), and its combination with 5% sugar saline can reduce the occurrence of adverse reactions. Trial registration: The study was prospectively registered on March 15, 2022, Chinese Clinical Trial Registry (www.chictr.org.cn, ChiCTR2200057626); Pre-results.
... The main human metabolite is 7-carboxy-cannabidiol (7-COOHCBD) and represents the~90% of all drugrelated substances measured in the plasma. The primary excretion route of CBD is through feces (84%), followed by urine (8%) [19,20]. ...
Article
Full-text available
Medical case reports suggest that cannabinoids extracted from Cannabis sativa have therapeutic effects; however, the therapeutic employment is limited due to the psychotropic effect of its major component, Δ9-tetrahydrocannabinol (THC). The new scientific discoveries related to the endocannabinoid system, including new receptors, ligands, and mediators, allowed the development of new therapeutic targets for the treatment of several pathological disorders minimizing the undesirable psychotropic effects of some constituents of this plant. Today, FDA-approved drugs, such as nabiximols (a mixture of THC and non-psychoactive cannabidiol (CBD)), are employed in alleviating pain and spasticity in multiple sclerosis. Dronabinol and nabilone are used for the treatment of chemotherapy-induced nausea and vomiting in cancer patients. Dronabinol was approved for the treatment of anorexia in patients with AIDS (acquired immune deficiency syndrome). In this review, we highlighted the potential therapeutic efficacy of natural and synthetic cannabinoids and their clinical relevance in cancer, neurodegenerative and dermatological diseases, and viral infections.
... Cannabidiol (CBD) was isolated in 1940 [68], and its structure was elucidated by Raphael Mechoulam in 1963 [69]. CBD presents low affinity for the CBs and acts as an inverse agonist, which may explain its lack of psychotropic activity and its ability to antagonize some THC-induced effects, such as anxiety, hunger, sedation and tachycardia [10,70]. Additionally, this phytocannabinoid can also act as an allosteric modulator of the CB receptors [71,72] or bind to other receptors, including GPR55 ( Figure 2) [10,61]. ...
Article
Full-text available
Although cannabinoids have been used for centuries for diverse pathological conditions, recently, their clinical interest and application have emerged due to their diverse pharmacological properties. Indeed, it is well established that cannabinoids exert important actions on multiple sclerosis, epilepsy and pain relief. Regarding cancer, cannabinoids were first introduced to manage chemotherapy-related side effects, though several studies demonstrated that they could modulate the proliferation and death of different cancer cells, as well as angiogenesis, making them attractive agents for cancer treatment. In relation to breast cancer, it has been suggested that estrogen receptor-negative (ER−) cells are more sensitive to cannabinoids than estrogen receptor-positive (ER+) cells. In fact, most of the studies regarding their effects on breast tumors have been conducted on triple-negative breast cancer (TNBC). Nonetheless, the number of studies on human epidermal growth factor receptor 2-positive (HER2+) and ER+ breast tumors has been rising in recent years. However, besides the optimistic results obtained thus far, there is still a long way to go to fully understand the role of these molecules. This review intends to help clarify the clinical potential of cannabinoids for each breast cancer subtype.
... Although responses of the heart to cannabinoids depend highly on the individual, in general, an acute increase in heart rate is followed by decreased heart function [1]. Among naturally occurring cannabinoids, Δ 9 -tetrahydrocannabinol (Δ 9 -THC) is the most potent psychoactive constituent of marijuana [9]. Δ 9 -THC elicits its effects by binding to cell surface G-protein coupled receptors, referred to as type-1 and -2 cannabinoid receptors (CB-R1 and CB-R2), both of which are expressed in cardiomyocytes [10,11]. ...
Article
Full-text available
Cannabinoids are some of the most popular recreationally used illicit drugs, and are frequently consumed along with alcoholic beverages. Although the whole body effects of cannabinoids depend largely on their effects on the central nerve system, cannabinoids could harm the heart directly, due to the presence of the endocannabinoid system including cannabinoid receptor1 and 2 (CB-R1 and CB-R2) in the heart. The aim of this study is to examine the mechanism of direct cardiotoxicity of Δ⁹-tetrahydrocannabinol (Δ⁹-THC), the main psychoactive ingredient of cannabis. For this purpose, HL-1 murine atrial cardiac muscle cells were treated with 10 or 30 µM Δ⁹-THC, along with 100 mM ethanol to examine the possible synergistic effects of Δ⁹-THC and ethanol. Transcriptome analysis showed upregulation of the genes involved in the unfolded protein response (UPR), including Bip, CHOP, ATF4 and ATF6, in cells treated with Δ⁹-THC. Immunoblot analysis showed caspase3 activation, indicating apoptosis caused by ER stress in Δ⁹-THC-treated cells. Microscopic analysis showed that Δ⁹-THC enhances macropinocytosis, a process involved in the uptake of extracellular fluids including nutrients. Moreover Δ⁹-THC seemed to activate AMPK, a sensor of intracellular energy status and an activator of macropinocytosis. Finally, we found that compound C (AMPK inhibitor) aggravated cell death by Δ⁹-THC while AICAR (AMPK activator) ameliorated it. Collectively, these results indicate that the activation of AMPK is necessary for the survival of HL-1 cells against Δ⁹-THC toxicity. Macropinocytosis might serve as one of the survival pathways downstream of AMPK.
... This reclassification identifies hemp and hemp-derived products, such as cannabidiol (CBD), as a substance of medicinal value with no addictive properties and legalizes it nationally. CBD's appeal as a medicinal agent is based upon its favorable tolerance in both human and animal models (3)(4)(5). These models found a lack of habit-forming potential (6,7) and rare incidents of adverse side-effects (8) from CBD use compared to THC (9)(10)(11). ...
Article
Full-text available
Background: With the passing of the 2018 Agriculture Improvement Act that legalized hemp-derived products, i.e., cannabidiol (CBD), the use of CBD has increased exponentially. To date, the few studies that have characterized individuals who use CBD suggest that co-use of CBD and tetrahydrocannabinol (THC)-dominant cannabis, i.e., marijuana, is highly prevalent. It is, therefore, important to investigate the relationship between CBD use and marijuana use to understand the antecedents and consequences of co-use of these two cannabis products. Methods: We conducted an online survey using structured questionnaires to determine differences in CBD users with (CBD+MJ) and without co-morbid marijuana use. Group comparisons were carried out using chi-square tests and ANOVA. Multiple correspondence analysis (MCA) with bootstrap ratio testing was performed to examine the relationship between the categorical data. Results: We received 182 survey responses from current CBD users. CBD+MJ had more types of CBD administration ( F = 17.07, p < 0.001) and longer lifetime duration of CBD use (χ2 = 12.85, p < 0.05). Results from the MCA yielded two statistically significant dimensions that accounted for 77% of the total variance. Dimension 1 (representing 57% of the variance) associated CBD+MJ with indication of CBD use for medical ailments, use of CBD for more than once a day for longer than 2 years, applying CBD topically or consuming it via vaping or edibles, being female, and, having lower educational attainment. Dimension 2 (representing 20% of the variance) separated the groups primarily on smoking-related behaviors where CBD+MJ was associated with smoking CBD and nicotine. Conclusions: Identifying the factors that influence use of CBD and marijuana can inform future studies on the risks and benefits associated with each substance as well as the impacts of policies related to cannabis-based products.
Article
Due to the resistance to drugs, studies involving the combination and controlled release of different agents are gradually increasing. In this study, two different active ingredients, known to have antibacterial and antiparasitic activities, were encapsulated into a single polymeric nanoparticles. After co-encapsulation their antibacterial and antileishmanial activity was enhanced approximately 5 and 250 times, respectively. Antibacterial and antileishmanial activities of caffeic acid phenethyl ester and juglone loaded, multifunctional nanoformulations (CJ4-CJ6-CJ8) were also evaluated for the first time in the literature comparatively with their combined free formulations. The antibacterial activity of the multifunctional nanoformulation (CJ8) were found to have a much higher activity (MIC values 6.25 and 12.5 µg/mL for S. aureus and E. coli, respectively) than all other formulations. Similar efficacy for CJ8 was obtained in the antiparasitic study against the Leishmania promastigotes and the IC50 was reduced to 0.1263 µg/mL. The high activity of multifunctional nanoparticles is not only due to the synergistic effect of the active molecules but also by the encapsulation into polymeric nanoparticles. Therefore, it has been shown in the literature for the first time that the biological activity of molecules whose activity is increased by the synergistic effect can be improved with nanosystems.
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Background: Since 2014, patients with severe treatment-resistant epilepsies (TREs) have been receiving add-on cannabidiol (CBD) in an ongoing, expanded access program (EAP), which closely reflects clinical practice. We conducted an interim analysis of long-term efficacy and tolerability in patients with Lennox-Gastaut syndrome (LGS) or Dravet syndrome (DS) who received CBD treatment through December 2016. Methods: Children and adults with LGS/DS taking stable doses of antiepileptic drugs (AEDs) at baseline were included from 25 EAP sites across the United States. During the 4-week baseline period, parents/caregivers kept diaries of all countable seizure types. Patients received a pharmaceutical formulation of highly purified CBD (Epidiolex®; 100 mg/mL) in oral solution at 2-10 mg/kg/day, titrated until tolerability limit or a maximum dose of 25-50 mg/kg/day. Patient visits were every 2-4 weeks. The percentage change from baseline in median monthly convulsive (ie, major motor) and total seizures was evaluated at 12-week intervals through 96 weeks. The percentages of patients who had ≥50%, ≥75%, and 100% reduction in monthly seizures relative to the baseline period were also evaluated. Adverse events (AEs) were monitored and summarized for the safety analysis set (SAS) through 144 weeks. Results: Of the 607 patients in the SAS, 58 had DS and 94 had LGS (N = 152); 455 patients had other TREs. Twenty-eight percent of LGS/DS patients withdrew, primarily owing to lack of efficacy (20%). LGS/DS patients were taking a median of 3 (0-10) concomitant AEDs. Median treatment duration was 78.3 (range, 4.1-146.4) weeks. Between weeks 12 and 96, median CBD dose ranged from 21 to 25 mg/kg/day. At 12 weeks, add-on CBD reduced median monthly major motor seizures by 50% and total seizures by 44%, with consistent reductions in both seizure types through 96 weeks. At 12 weeks, the proportions of patients with ≥50%, ≥75%, and 100% reductions in major motor seizures were 53%, 23%, and 6%; the proportions with corresponding reductions in total seizures were 46%, 26%, and 5%. Responder rates for both seizure types were consistent through 96 weeks. CBD had an acceptable safety profile; the most common AEs were somnolence (30%) and diarrhea (24%). Conclusions: Results from this interim analysis support add-on CBD as an effective long-term treatment option in LGS or DS.
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Cannabidiol (CBD), the main nonpsychoactive constituent of Cannabis sativa, has shown a wide range of therapeutically promising pharmacological effects either as a sole drug or in combination with other drugs in adjunctive therapy. However, the targets involved in the therapeutic effects of CBD appear to be elusive. Furthermore, scarce information is available on the biological activity of its human metabolites which, when formed in pharmacologically relevant concentration, might contribute to or even account for the observed therapeutic effects. The present overview summarizes our current knowledge on the pharmacokinetics and metabolic fate of CBD in humans, reviews studies on the biological activity of CBD metabolites either in vitro or in vivo, and discusses relevant drug-drug interactions. To facilitate further research in the area, the reported syntheses of CBD metabolites are also catalogued.
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Introduction: There is a large variation in cannabidiol (CBD) pharmacokinetics and little information on its bioavailability. This study aims to establish the CBD dose-exposure relationship and to evaluate the effects of dosage forms, food, and doses on CBD absorption. Methods: Single-dose (range: 5-6000 mg) CBD plasma concentration-time profiles administered as oral solution (OS), oral capsule (OC), or oromucosal spray/drop (OM) from healthy volunteers were extracted from 15 published clinical studies. A dose-exposure proportionality assessment was performed, and a population-based meta-analysis of CBD pharmacokinetics and systemic bioavailability was conducted with a nonlinear mixed-effect modeling. A three-compartment model with a Weibull or zero-order absorption model was used to describe CBD disposition and absorption kinetics. Dosage form, food, and dose were assessed for covariation. Results: Oral solution CBD exposures increased less than proportionally with doses of 750 mg or greater, and bioavailability (6.5% at 3000 mg) decreased with increasing dose. The bioavailability of OC (5.6%) and fed-state OM (6.2%) were similar, whereas it was lower in fasted-state OM (0.9%). The Weibull absorption model best described OS, OC, and fed-state OM profiles. The slowest absorption rate was observed in OS, resulting in a time of maximum concentration of 4.75 hours, followed by fed-state OM (3.13 hrs) and OC (2.1 hrs). The absorption kinetics of fasted-state OM was best described by a zero-order absorption for the duration of 1.71 hours. Conclusion: The effects of doses, dosage forms, and feeding status on CBD pharmacokinetics were quantified and should be taken into consideration for dose optimization.
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Rationale: Treatment with a highly purified oral solution of cannabidiol (CBD), derived from the plant Cannabis sativa L., demonstrated some evidence of central nervous system (CNS)-related adverse events in patients enrolled in phase 3 trials for treatment of childhood-onset epilepsy. Cannabidiol was categorized as a Schedule 1 substance by the United States Drug Enforcement Administration; therefore, it was important to test CBD for human abuse potential. Methods: This was a single-dose, randomized, double-blind, double-dummy, placebo- and active-controlled crossover trial. The abuse potential of single oral doses of plant-derived pharmaceutical formulations of highly purified CBD (Epidiolex®; 750 mg, 1500 mg, and 4500 mg) was compared with that of single oral doses of alprazolam (2 mg), dronabinol (10 mg and 30 mg), and placebo in healthy recreational polydrug users. The primary endpoint to assess abuse potential was the maximum effect (Emax) on Drug-Liking visual analog scale (VAS). Other measurements included Emax on Overall Drug-Liking VAS, Take Drug Again VAS, positive and negative effects, other subjective effects, and Drug Similarity VAS. Cognitive and psychomotor functions were assessed using the Divided Attention Test, the Hopkins Verbal Learning Test-Revised, and the Digit-Symbol Substitution Task. Pharmacokinetic parameters were determined for CBD and its major metabolites. Standard safety measures and adverse events were assessed. Principal results: Of 95 eligible subjects, 43 qualified for the treatment phase, received at least 1 dose of investigational medicinal product, and were included in safety assessments; 35 subjects were included in the pharmacodynamic analysis. Subjects receiving alprazolam and dronabinol had significantly higher Drug-Liking Emax (P < 0.0001) compared with those receiving placebo, confirming study validity. Compared with placebo, Drug-Liking was not significantly different for subjects taking 750-mg CBD (P = 0.51). Drug-Liking Emax values for 1500-mg and 4500-mg CBD were significantly different from placebo (P = 0.04 and 0.002, respectively); however, the mean differences were <10 points on VAS compared with >18-point differences between positive controls and placebo. Alprazolam and dronabinol had significantly higher Drug-Liking, Overall-Liking, and Take Drug Again VAS Emax values compared with all doses of CBD (P ≤ 0.004). In contrast to alprazolam, CBD administration had no observable effect on cognitive/psychomotor tests. Pharmacokinetic parameters for CBD in this trial were consistent with previous studies. The majority of adverse events reported during the trial were of mild or moderate severity; no serious adverse events or deaths were reported. Conclusion: Administration of a therapeutic dose of CBD (750 mg) showed significantly low abuse potential in a highly sensitive population of polydrug users. Although high and supratherapeutic doses of CBD (1500 mg and 4500 mg, respectively) had detectable subjective effects compared with placebo; the effects were significantly lower than those observed with alprazolam and dronabinol.
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Background Cannabidiol has been used for treatment-resistant seizures in patients with severe early-onset epilepsy. We investigated the efficacy and safety of cannabidiol added to a regimen of conventional antiepileptic medication to treat drop seizures in patients with the Lennox–Gastaut syndrome, a severe developmental epileptic encephalopathy. Methods In this double-blind, placebo-controlled trial conducted at 30 clinical centers, we randomly assigned patients with the Lennox–Gastaut syndrome (age range, 2 to 55 years) who had had two or more drop seizures per week during a 28-day baseline period to receive cannabidiol oral solution at a dose of either 20 mg per kilogram of body weight (20-mg cannabidiol group) or 10 mg per kilogram (10-mg cannabidiol group) or matching placebo, administered in two equally divided doses daily for 14 weeks. The primary outcome was the percentage change from baseline in the frequency of drop seizures (average per 28 days) during the treatment period. Results A total of 225 patients were enrolled; 76 patients were assigned to the 20-mg cannabidiol group, 73 to the 10-mg cannabidiol group, and 76 to the placebo group. During the 28-day baseline period, the median number of drop seizures was 85 in all trial groups combined. The median percent reduction from baseline in drop-seizure frequency during the treatment period was 41.9% in the 20-mg cannabidiol group, 37.2% in the 10-mg cannabidiol group, and 17.2% in the placebo group (P=0.005 for the 20-mg cannabidiol group vs. placebo group, and P=0.002 for the 10-mg cannabidiol group vs. placebo group). The most common adverse events among the patients in the cannabidiol groups were somnolence, decreased appetite, and diarrhea; these events occurred more frequently in the higher-dose group. Six patients in the 20-mg cannabidiol group and 1 patient in the 10-mg cannabidiol group discontinued the trial medication because of adverse events and were withdrawn from the trial. Fourteen patients who received cannabidiol (9%) had elevated liver aminotransferase concentrations. Conclusions Among children and adults with the Lennox–Gastaut syndrome, the addition of cannabidiol at a dose of 10 mg or 20 mg per kilogram per day to a conventional antiepileptic regimen resulted in greater reductions in the frequency of drop seizures than placebo. Adverse events with cannabidiol included elevated liver aminotransferase concentrations. (Funded by GW Pharmaceuticals; GWPCARE3 ClinicalTrials.gov number, NCT02224560.)
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Background: Patients with Lennox-Gastaut syndrome, a rare, severe form of epileptic encephalopathy, are frequently treatment resistant to available medications. No controlled studies have investigated the use of cannabidiol for patients with seizures associated with Lennox-Gastaut syndrome. We therefore assessed the efficacy and safety of cannabidiol as an add-on anticonvulsant therapy in this population of patients. Methods: In this randomised, double-blind, placebo-controlled trial done at 24 clinical sites in the USA, the Netherlands, and Poland, we investigated the efficacy of cannabidiol as add-on therapy for drop seizures in patients with treatment-resistant Lennox-Gastaut syndrome. Eligible patients (aged 2-55 years) had Lennox-Gastaut syndrome, including a history of slow (<3 Hz) spike-and-wave patterns on electroencephalogram, evidence of more than one type of generalised seizure for at least 6 months, at least two drop seizures per week during the 4-week baseline period, and had not responded to treatment with at least two antiepileptic drugs. Patients were randomly assigned (1:1) using an interactive voice response system, stratified by age group, to receive 20 mg/kg oral cannabidiol daily or matched placebo for 14 weeks. All patients, caregivers, investigators, and individuals assessing data were masked to group assignment. The primary endpoint was percentage change from baseline in monthly frequency of drop seizures during the treatment period, analysed in all patients who received at least one dose of study drug and had post-baseline efficacy data. All randomly assigned patients were included in the safety analyses. This study is registered with ClinicalTrials.gov, number NCT02224690. Findings: Between April 28, 2015, and Oct 15, 2015, we randomly assigned 171 patients to receive cannabidiol (n=86) or placebo (n=85). 14 patients in the cannabidiol group and one in the placebo group discontinued study treatment; all randomly assigned patients received at least one dose of study treatment and had post-baseline efficacy data. The median percentage reduction in monthly drop seizure frequency from baseline was 43·9% (IQR -69·6 to -1·9) in the cannibidiol group and 21·8% (IQR -45·7 to 1·7) in the placebo group. The estimated median difference between the treatment groups was -17·21 (95% CI -30·32 to -4·09; p=0·0135) during the 14-week treatment period. Adverse events occurred in 74 (86%) of 86 patients in the cannabidiol group and 59 (69%) of 85 patients in the placebo group; most were mild or moderate. The most common adverse events were diarrhoea, somnolence, pyrexia, decreased appetite, and vomiting. 12 (14%) patients in the cannabidiol group and one (1%) patient in the placebo group withdrew from the study because of adverse events. One patient (1%) died in the cannabidiol group, but this was considered unrelated to treatment. Interpretation: Add-on cannabidiol is efficacious for the treatment of patients with drop seizures associated with Lennox-Gastaut syndrome and is generally well tolerated. The long-term efficacy and safety of cannabidiol is currently being assessed in the open-label extension of this trial. Funding: GW Pharmaceuticals.
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In 1937, the United States of America criminalized the use of cannabis and as a result its use decreased rapidly. In recent decades, there is a growing interest in the wide range of medical uses of cannabis and its constituents; however, the laws and regulations are substantially different between countries. Laws differentiate between raw herbal cannabis, cannabis extracts, and cannabinoid-based medicines. Both the European Medicines Agency (EMA) and the United States Food and Drug Administration (FDA) do not approve the use of herbal cannabis or its extracts. The FDA approved several cannabinoid-based medicines, so did 23 European countries and Canada. However, only four of the reviewed countries have fully authorized the medical use of herbal cannabis - Canada, Germany, Israel and the Netherlands, together with more than 50% of the states in the United States. Most of the regulators allow the physicians to decide what specific indications they will prescribe cannabis for, but some regulators dictate only specific indications. The aim of this article is to review the current (as of November 2017) regulations of medical cannabis use in Europe and North America.
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The plant Cannabis sativa, commonly called cannabis or marijuana, has been used for its psychotropic and mind-altering side effects for millennia. There has been growing attention in recent years on its potential therapeutic efficacy as municipalities and legislative bodies in the United States, Canada, and other countries grapple with enacting policy to facilitate the use of cannabis or its constituents for medical purposes. There are over 550 chemical compounds and over 100 phytocannabinoids isolated from cannabis, including Δ(9)-tetrahydrocannabinol (THC) and Cannabidiol (CBD). THC is thought to produce the main psychoactive effects of cannabis, while CBD does not appear to have similar effects. Studies conflict as to whether CBD attenuates or exacerbates the behavioral and cognitive effects of THC. This includes effects of CBD on THC induced anxiety, psychosis and cognitive deficits. In this article, we review the available evidence on the pharmacology and behavioral interactions of THC and CBD from pre-clinical and human studies particularly with reference to anxiety and psychosis like symptoms. Both THC and CBD, as well as other cannabinoid molecules, are currently being evaluated for medicinal purposes, separately and in combination. Future cannabis-related policy decisions should include consideration of scientific findings including the individual and interactive effects of CBD and THC.Neuropsychopharmacology accepted article preview online, 06 September 2017. doi:10.1038/npp.2017.209.
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The lipophilic phytocannabinoids cannabidiol (CBD) and Δ⁹-tetrahydrocannabinol (THC) show therapeutic efficacy in various medical conditions. Both molecules are poorly water soluble and subjected to extensive first pass metabolism in the gastrointestinal tract, leading to a limited oral bioavailability of approximately 9%. We have developed an advanced lipid based Self-Emulsifying Drug Delivery System termed Advanced Pro-NanoLiposphere (PNL) pre-concentrate. The PNL is composed of lipid and emulsifying excipients of GRAS status and are known to increase solubility and reduce Phase I metabolism of lipophilic active compounds. Advanced PNLs are PNLs with an incorporated natural absorption enhancers. These molecules are natural alkaloids and phenolic compounds which were reported to inhibit certain phase I and phase II metabolism processes. Here we use piperine, curcumin and resveratrol to formulate the Advanced-PNL formulations. Consequently, we have explored the utility of these Advanced-PNLs on CBD and THC oral bioavailability. Oral administration of CBD-piperine-PNL resulted in 6-fold in AUC compared to CBD solution, proving to be the most effective of the screened formulations. The same trend was found in pharmacokinetic experiments of THC-piperine-PNL with resulted in a 9.3-fold increase in AUC as compared to THC solution. Our Piperine-PNL can be used as a platform for synchronized delivery of piperine and CBD or THC to the enterocyte site. This co-localization provides an increase in CBD and THC bioavailability by its effect at the pre-enterocyte and the enterocyte levels of the absorption process. The extra augmentation in the absorption of CBD and THC by incorporating piperine into PNL is attributed to the inhibition of Phase I and phase II metabolism by piperine in addition to the Phase I metabolism and P-gp inhibition by PNL. These novel results pave the way to utilize piperine-PNL delivery system for other poorly soluble, highly metabolized compounds that currently cannot be administered orally.
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Background The Dravet syndrome is a complex childhood epilepsy disorder that is associated with drug-resistant seizures and a high mortality rate. We studied cannabidiol for the treatment of drug-resistant seizures in the Dravet syndrome. Methods In this double-blind, placebo-controlled trial, we randomly assigned 120 children and young adults with the Dravet syndrome and drug-resistant seizures to receive either cannabidiol oral solution at a dose of 20 mg per kilogram of body weight per day or placebo, in addition to standard antiepileptic treatment. The primary end point was the change in convulsive-seizure frequency over a 14-week treatment period, as compared with a 4-week baseline period. Results The median frequency of convulsive seizures per month decreased from 12.4 to 5.9 with cannabidiol, as compared with a decrease from 14.9 to 14.1 with placebo (adjusted median difference between the cannabidiol group and the placebo group in change in seizure frequency, −22.8 percentage points; 95% confidence interval [CI], −41.1 to −5.4; P=0.01). The percentage of patients who had at least a 50% reduction in convulsive-seizure frequency was 43% with cannabidiol and 27% with placebo (odds ratio, 2.00; 95% CI, 0.93 to 4.30; P=0.08). The patient’s overall condition improved by at least one category on the seven-category Caregiver Global Impression of Change scale in 62% of the cannabidiol group as compared with 34% of the placebo group (P=0.02). The frequency of total seizures of all types was significantly reduced with cannabidiol (P=0.03), but there was no significant reduction in nonconvulsive seizures. The percentage of patients who became seizure-free was 5% with cannabidiol and 0% with placebo (P=0.08). Adverse events that occurred more frequently in the cannabidiol group than in the placebo group included diarrhea, vomiting, fatigue, pyrexia, somnolence, and abnormal results on liver-function tests. There were more withdrawals from the trial in the cannabidiol group. Conclusions Among patients with the Dravet syndrome, cannabidiol resulted in a greater reduction in convulsive-seizure frequency than placebo and was associated with higher rates of adverse events. (Funded by GW Pharmaceuticals; ClinicalTrials.gov number, NCT02091375.)