Cannabidiol Adverse Effects and Toxicity

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974 Current Neuropharmacology, 2019, 17, 974-989
REVIEW ARTICLE
Cannabidiol Adverse Effects and Toxicity
Marilyn A. Huestis1, Renata Solimini2, Simona Pichini2, Roberta Pacifici2, Jeremy Carlier3 and
Francesco Paolo Busardò4,*
1
Lambert Center for the Study of Medicinal Cannabis and Hemp, Institute of Emerging Health Professions, Thomas
Jefferson University, Philadelphia, PA, USA; 2National Centre on Addiction and Doping, Istituto Superiore di Sanità,
Rome, Italy; 3Unit of Forensic Toxicology (UoFT), Department of Anatomical, Histological, Forensic and Orthopedic
Sciences, Sapienza University of Rome, Rome, Italy; 4Section of Legal Medicine, Università Politecnica delle Marche,
Ancona, Italy
Abstract: Background: Currently, there is a great interest in the potential medical use of can-
nabidiol (CBD), a non-intoxicating cannabinoid. Productive pharmacological research on CBD
occurred in the 1970s and intensified recently with many discoveries about the endocannabinoid
system. Multiple preclinical and clinical studies led to FDA-approval of Epidiolex®, a purified CBD
medicine formulated for oral administration for the treatment of infantile refractory epileptic
syndromes, by the US Food and Drug Administration in 2018. The World Health Organization
considers rescheduling cannabis and cannabinoids. CBD use around the world is expanding for
diseases that lack scientific evidence of the drug’s efficacy. Preclinical and clinical studies also
A R T I C L E H I S T O R Y report adverse effects (AEs) and toxicity following CBD intake.
Methods: Relevant studies reporting CBD’s AEs or toxicity were identified from PubMed, Coch-
Received: December 04, 2018 rane Central, and EMBASE through January 2019. Studies defining CBD’s beneficial effects were
Revised: April 16, 2019
Accepted: May 31, 2019 included to provide balance in estimating risk/benefit.
Results: CBD is not risk-free. In animals, CBD AEs included developmental toxicity, embryo-fetal
DOI:
10.2174/1570159X17666190603171901 mortality, central nervous system inhibition and neurotoxicity, hepatocellular injuries, spermato-
genesis reduction, organ weight alterations, male reproductive system alterations, and hypotension,
although at doses higher than recommended for human pharmacotherapies. Human CBD studies for
epilepsy and psychiatric disorders reported CBD-induced drug-drug interactions, hepatic abnormali-
ties, diarrhea, fatigue, vomiting, and somnolence.
Conclusion: CBD has proven therapeutic efficacy for serious conditions such as Dravet and
Lennox-Gastaut syndromes and is likely to be recommended off label by physicians for other con-
ditions. However, AEs and potential drug-drug interactions must be taken into consideration by
clinicians prior to recommending off-label CBD.
Keywords: Cannabidiol, adverse effects, toxicity, animal studies, in vitro studies, in vivo studies, studies in humans.
1. INTRODUCTION cannabinoid receptors were cloned by Matsuda et al. in 1992

[4] and Munro et al. in 1993 [3], respectively. However, the
1.1. Cannabinoid Pharmacology
endogenous cannabinoid system may include additional can-
Δ9-tetrahydrocannabinol (THC) was shown to be the nabinoid G protein-coupled receptors (GPCR) GPR55,
primary psychoactive compound in cannabis (marijuana) in GPR18, and GPR119, transient receptor potential cation
1964 by Gaoni and Mechoulam [1]. There were few ad- channels (TRP) TRPV, TRPA, TRPM, and TRPC and nu-
vances in cannabinoid pharmacology until 1988, when clear peroxisome proliferator-activated receptors (PPAR)
Devane et al. identified the first CB1 cannabinoid receptor [5]. Anandamide was the first identified endogenous can-
[2], quickly followed by the discovery of the CB2 peripheral nabinoid ligand [6], but there are many other endocannabi-
receptor by Munro et al. in 1990 [3]. The CB1 and CB2 noids including 2-arachidonylglycerol, N-palmitoyl ethano-
lamide, and N-oleoyl ethanolamide.
*Address correspondence to this author at the Section of Legal Medicine, Cannabidiol (CBD or 2-[(6R)-6-isopropenyl-3-methyl-2-
Università Politecnica delle Marche, Ancona, Italy; Tel: 3932244667; cyclohexen-1-yl]-5-pentyl-1,3-benzene-diol) was identified
E-mail: [email protected] in an extract of Minnesota wild hemp by Adams et al. at the
1570-159X/19 $58.00+.00 ©2019 Bentham Science Publishers

Cannabidiol Adverse Effects and Toxicity Current Neuropharmacology, 2019, Vol. 17, No. 10 975
University of Illinois in 1940 [7], but its structure was not that may accompany CBD therapeutics and that must be
fully elucidated until 1963 [8]. To date, CBD’s mechanisms considered prior to off-label use of CBD for pathophysiology
of action are not fully elucidated [9]. CBD modulates central that has not yet been shown to respond effectively to CBD.
nervous system (CNS) receptors such as CB1, CB2, sero- However, to enable the reader to independently evaluate
tonin 1A receptor (5-HT1A), TRPV1, and PPARγ, although CBD’s AEs and toxicity, we briefly highlight some current
it binds poorly to the THC-binding site on CB1 and CB2 research supporting CBD therapeutics.
cannabinoid receptors [10]. CBD may antagonize CB1 re-
ceptor function by negative allosteric modulation of the or- 1.3. Anti-epileptic
thosteric receptor site [11-14]. CBD may be an inverse ago- As early as 1980, the potential therapeutic effect of 200-
nist at the CB2 receptor, partially explaining its anti- 300 mg/day CBD in patients with uncontrolled epilepsy was
inflammatory properties [15], which also are supported by evaluated [25]. Patients tolerated CBD well, with no signs of
CBD PPARɤ activation [16]. High CBD doses activate toxicity or serious side effects detected. Seven of 8 subjects
TRPV1 receptors promoting anxiolytic effects [17]. CBD receiving CBD had fewer convulsive episodes, with 3 only
also increases serotoninergic and glutamatergic transmission partially improved. A 2018 meta-analysis concluded that CBD
through a positive allosteric modulation of 5-HT1A sero- in conjunction with other anti-epileptic drugs decreased sei-
tonin receptors [10]. 5-HT1A receptor activation is also in- zure frequency in patients with Dravet’s and Lennox-Gastaut
volved in CBD neuroprotection in in vitro adult and rat new- syndromes or who experienced intractable seizures, although
born models of the acute hypoxic-ischemic brain [18]. AEs occurred more frequently than placebo [26]. The US
CBD is metabolized in the liver and the intestine by cy- Food and Drug Administration (FDA) approved Epidiolex ®
tochrome P450 (CYP) CYP2C19 and CYP3A4, and 5'- for the treatment of refractory epilepsy in 2018 [19, 27].
diphosphoglucuronosyltransferase (UGT) UGT1A7,
1.4. Anxiolytic
UGT1A9, and UGT2B7 isoforms, mainly producing hy-
droxylated and carboxylated metabolites [19]. CBD inhibited Multiple studies evaluated the potential therapeutic effect
barbiturate metabolism, increasing barbiturate-induced sleep of CBD on anxiety, psychotic symptoms, and depression in
duration in mice, and also phenazone hepatic metabolism humans since the 1980s, mostly showing mild AEs [28-35].
[20] due to the inhibition of CYP3A and CYP2C microsomal CBD effectively treated anxiety by activating limbic and
enzymes [21]. Other research suggested that CBD also in- paralimbic regions of the brain [30].
duced hepatic CYP3A, CYP2B, and CYP2C [22]. Later,
CBD was shown to inhibit THC metabolic hydroxylation in Interestingly, a single acute administration of a low 3
humans. The pharmacokinetic interaction between THC and mg/kg CBD dose in mice had an anxiolytic effect, while
CBD may explain why CBD administration prior to THC repeated administration of a 3 or 10 mg/kg dose exerted an-
potentiates THC effects [23]. tidepressant effects by cell proliferation and neurogenesis
[36]. Conversely, CBD anxiolytic effects were not observed
The complexity of CBD pharmacology offers tremen- at higher 10 and 30 mg/kg CBD doses or after 15 days of 30
dous therapeutic potential but also the potential for AEs and mg/kg/day dosing. The authors suggest that there is an in-
drug-drug interactions. verted U-shaped dose-response curve for CBD’s effects on
anxiety.
1.2. Potential Therapeutic Effects of CBD
In 2017, the National Academies of Science, Engineering 1.5. Antipsychotic Properties
and Medicine evaluated all the published literature through CBD is extensively studied for its antipsychotic effects
August, 2016 on the potential therapeutic uses of cannabi- on schizophrenia [35, 37]. Leweke et al. noted that CBD
noids [24]. They determined if there was conclusive evi- moderately inhibits degradation of the endocannabinoid
dence, substantial evidence, moderate evidence, limited evi- anandamide [38]. They performed a double-blind, random-
dence, or insufficient evidence for cannabinoids being an ized clinical trial of CBD vs. amisulpride, a potent antipsy-
effective or ineffective therapy to treat chronic pain, cancer, chotic, in acute schizophrenia. Both treatments were safe and
chemotherapy-induced nausea/vomiting, appetite and weight significant clinical improvement was achieved, but CBD had
loss, irritable bowel syndrome, epilepsy, spasticity of multi- a better side effect profile. CBD treatment significantly in-
ple sclerosis, Tourette syndrome, amyotrophic lateral sclero- creased serum anandamide concentrations.
sis, Huntington’s disease, Parkinson’s disease, dystonia,
Alzheimer’s disease/dementia, glaucoma, traumatic brain The safety and effectiveness of 1000 mg/day CBD in
injury/spinal cord injury, addiction, anxiety, depression, patients with schizophrenia were assessed [35]. These
sleep disorders, posttraumatic stress disorder, and schizo- patients (n=43) with schizophrenia received 1000 mg/day
phrenia. In addition, they reviewed the knowledge base using CBD in addition to their existing antipsychotic medications.
the same evidence categories for the health effects of can- After 6 weeks of treatment, the CBD group had lower levels
nabinoids and cancer, cardiometabolic risk, acute myocardial of positive psychotic symptoms (positive and negative
infarction, stroke, metabolic dysregulation, metabolic syn- syndrome scale (PANSS): treatment difference=21.4, 95%
drome, diabetes, respiratory disease, immunity, injury and CI=22.5,20.2). CBD was well tolerated, and AEs were simi-
death, prenatal, perinatal, and postnatal exposure to cannabis, lar between the CBD and placebo groups.
psychosocial, mental health, and problem cannabis use. Six-hundred mg oral CBD was evaluated for its effects
This review is not focused on therapeutic indications but on persecutory ideation and anxiety in a high paranoid trait
rather on potential AEs, toxicities and drug-drug interactions group (n=32) 130 min before entering a virtual-reality sce-
976 Current Neuropharmacology, 2019, Vol. 17, No. 10 Huestis et al.
nario [39]. CBD had no impact on anxiety (Beck's anxiety improving psychological symptoms and cognition in regular
inventory), or cortisol concentration, systolic blood pressure, cannabis users, and suggested that CBD may be a useful
and heart rate. In fact, in this study, a strong trend towards adjunct treatment for cannabis dependence. CBD improved
increased anxiety was documented and CBD had no effect subicular and CA1 subfields volumes in the brains of chronic
on persecutory ideation. cannabis users, suggesting a protective role of CBD against
brain structural harms conferred by chronic cannabis use
1.6. CBD Neuroprotection [40]. Moreover, CBD was shown to have low abuse liability
CBD’s anti-inflammatory and antioxidant properties may [50, 51] and to be effective in decreasing cannabis addiction
offer a new pharmacological approach for neuroprotection [52, 53].
and a reduction in hippocampal volume loss [23, 40, 41].
CBD protects against hippocampal pathology following 1.11. The Current Context
chronic frequent THC use [42]. This CBD restorative effect In June 2018, the US FDA approved the marketing
on hippocampal substructures suggests a therapeutic poten- of Epidiolex®, a CBD-rich whole cannabis plant extract, for
tial for other pathologies such as schizophrenia, Alzheimer’s the treatment of seizures in patients over age two suffering
disease, and major depressive disorder [40]. Indeed, in human from Lennox-Gastaut and Dravet syndromes, two drug-
studies for schizophrenia [35, 38] and Parkinson’s disease resistant forms of epilepsy with a higher early mortality
[43], and in animal studies for symptoms of Alzheimer’s rate [27]. The studies that led to FDA approval of Epidiolex ®
disease [44], CBD was shown to be an effective treatment. for the treatment of severe forms of epilepsy, used CBD as
an adjunct to clobazam, valproate, levetiracetam, and topi-
1.7. Spasticity ramate, resulting in seizures reduction with few AEs, com-
Many of the double-blinded, placebo-controlled studies pared to other drugs.
for the effects of cannabinoids on spasticity used whole plant In January 2019, the World Health Organization (WHO)
cannabis extracts or Sativex® that is a 1:1 THC:CBD extract changed position after 60 years and proposed rescheduling of
containing 2.5 to 120 mg THC and CBD/day. Visual Ana- cannabis and cannabinoids for therapeutic purposes [54, 55].
logue Scale (VAS) scores for each patient's most trouble- Three months after FDA Epidiolex® approval, the U.S. Drug
some symptom were significantly reduced [45]. Enforcement Administration (DEA) removed Epidiolex ®
from the most restricted Schedule 1 (no approved medical
1.8. Chronic Pain use and high abuse liability) to Schedule V with low abuse
In adults with chronic pain, patients treated with cannabis potential [56].
or cannabinoids are more likely to experience a clinically In the wake of growing medical and public interest in
significant reduction in pain symptoms [24]. A recent review medical cannabis and cannabinoids, we aimed to evaluate
of specific cannabinoids and cannabinoid extracts on multi- current knowledge of CBD’s AEs and toxicities by the rele-
ple pain types investigates both the preclinical and clinical vant scientific literature from preclinical and clinical studies.
data supporting cannabinoid pharmacotherapy for pain [46]. Clinicians should be aware of CBD AEs and potential drug-
drug interactions prior to recommending off-label CBD.
1.9. Cancer
There is tremendous interest in CBD as an anticancer 2. METHODS
agent. Aviello et al. showed that CBD had multiple chemo- A literature search, from inception to January 2019, was
preventive effects in murine colorectal carcinoma cell lines performed on PubMed, EMBASE, and CENTRAL (Coch-
by protecting DNA from oxidative damage, increasing endo- rane Central Register of Controlled Trials) using the key-
cannabinoid concentrations and reducing cell proliferation in words cannabidiol, Epidiolex, adverse or side effects, ad-
a CB1-, TRPV1- and PPARγ-antagonists sensitive manner verse reactions or events, safety, complications, toxicity, and
[47]. De Petrocellis et al. found that 1-10 µM CBD signifi- toxicology. Relevant articles were selected by the following
cantly inhibited human prostate carcinoma cell viability, criteria: articles acknowledging CBD AEs or toxicity, in-
inducing apoptosis and elevation of reactive oxygen species cluding studies focusing on the beneficial effects of the drug,
(ROS) [48]. Exciting new developments for enhancing CBD and published in English. Several studies defining CBD’s
effects in inducing cell death and enhancing radiosensitivity beneficial effects were included to provide balance and aid
of glioblastoma (GBM) cells were recently published [49]. the readers’ ability to weigh risk/benefit.
GBM cells treated with CBD, γ-irradiation, and KU60019, Further research manuscripts were retrieved through the
an ATM kinase inhibitor, increased apoptosis and with reference lists of selected articles, and reports were found on
strongly upregulated arrested cells, blockade of cell prolif- international agencies or institutional websites including US
eration, and production of pro-inflammatory cytokines, im- FDA, WHO, US DEA, and US National Academies of Sci-
proving CBD effectiveness. ences, Engineering, and Medicine. All articles were screened
independently by three co-authors to determine their rele-
1.10. Addiction Disorders vance and included if selected by at least two co-authors.
Recently, Solowij et al. described a 10-week study of
daily 200 mg CBD in cannabis dependence to improve psy- 3. RESULTS
chological symptoms and cognition [41]. CBD was well tol- CBD clearly has great potential as a new pharmacother-
erated with no serious AE, promising therapeutic effects for apy based on novel mechanisms of action for currently un-
met clinical needs. However, CBD, like almost all medica- hydroxydopamine, and hydrogen peroxide. During SH-
tions, also produces AEs and toxicity. Two previous reviews SY5Y cell differentiation, CBD did not induce changes in
focused on the therapeutic effects but also included AEs. In antioxidant potential, nor neurite density. CBD exposure
2011, Bergamaschi et al. reviewed CBD AEs in animals and during neuronal differentiation may sensitize immature cells
humans, concluding that CBD is generally safe, but further to redox-active drug neurotoxicity.
research is needed to investigate in-depth the observed in
vitro and in vivo AEs [57]. In 2017, Iffland and Grotenher- 3.1.2. In Vivo Neurological Effects
men confirmed CBD’s safety profile, especially compared to In 1981, Rosenkrantz and Hayden investigated acute
other antiepileptics and antipsychotics [58]. These authors cannabinoid toxicity in rhesus monkeys following 150, 200,
suggested that research should pursue AEs of chronic ad- 225, 250, or 300 mg/kg intravenous (IV) CBD for 9 days
ministration, hormonal effects, enzyme inhibition or induc- [61]. The LD50 was 212 mg/kg CBD. Tremors were ob-
tion, genotoxicity, drug transporters, and interactions with served at all doses and CNS inhibition (depression, sedation,
other drugs. and prostration) was evident within 30 min.
Currently, CBD is the focus of mass marketing cam- There is considerable interest in the CBD treatment of
paigns and the subject of anecdotal reports claiming that schizophrenia. In a randomized, double-blind CBD versus
CBD provides the answer for multiple illnesses from chronic amisulpride clinical trial (42 patients, CBD or amisulpride
pain to depression. Despite its Schedule I status in the US by 200 mg/day increasing to 800 mg/day over 28 days), both
the DEA, and lack of control by the FDA, CBD products are treatments were shown to be safe and significantly associ-
sold across the US and the internet. No medication should be ated with clinical improvement [38]. There were signifi-
prescribed or recommended until it is proven safe and effec- cantly fewer CBD AEs than for amisulpride, including fewer
tive for each indication under consideration. In addition, it is extrapyramidal symptoms (acute dyskinesias and dystonic
important to reflect whether the medication is safe for each reactions, tardive dyskinesia, Parkinsonism, akinesia,
individual based on his or her health, age, genetics, chronic akathisia, and neuroleptic malignant syndrome). CBD treat-
illnesses, and other medications (due to the problem of drug- ment increased serum anandamide concentrations, possibly
drug interactions). Now that Epidiolex® is FDA-approved, due to CBD inhibition of fatty acid amide hydrolase
off-label prescriptions will increase. The goal of this review (FAAH).
is to inform clinicians, pharmacists, nurses, patients, public
health authorities, and policymakers about CBD’s AEs, tox- McGuire et al. also found a low incidence (≥4%) of mild
icities, and drug-drug interactions that should be evaluated AEs including headache, with a frequency similar to placebo
prior to prescribing CBD. in schizophrenic patients [35]. However, a meta-analysis of
CBD efficacy and safety in schizophrenia concluded that
Table 1 lists AEs identified in preclinical research, and there was “moderate evidence” that CBD did not decrease
Table 2, AEs identified in clinical research. Both Tables 1 symptoms and produced frequent AEs in patients, as meas-
and 2 list AEs in chronological order. ured by the PANSS, brief psychiatric rating scale (BPRS),
and Stroop color-word test (SCWT) [62].
3.1. Neurological Effects
3.1.1. In Vitro Neurological Effects In 2017, Garberg et al. administered 50 mg/kg IV CBD
to four piglets to evaluate drug safety and potential neuro-
In vitro CBD toxicity was identified in Sprague Dawley protective effects. CBD significantly reduced brain-derived
rats’ oligodendrocytes, the cells responsible for CNS white neurotrophic factor (BDNF) expression and other signaling
matter myelination [59]. Following incubation with 100 nM- proteins in the hippocampus and frontal cortex with no effect
10 µM CBD for 20-30 min, a concentration-dependent de- in the striatum. It was concluded that CBD did not provide
crease in oligodendrocyte viability was observed. The neuroprotection during early global hypoxia-ischemia [63].
mechanism appeared to be through increases in intracellular However, in a study investigating possible treatments for
Ca2+. If there was no extracellular Ca2+, CBD-induced cell neonatal hypoxic-ischemic encephalopathy, low 1 mg/kg IV
death was reduced at 1 µM by 50.4%±18%. Furthermore, the CBD dose in combination with hypothermia, found neuro-
disruption of mitochondrial membrane potential (MMP), protective effects and modulation of excitotoxicity and in-
and ROS production were reduced. CB1, CB2, TRPV1, flammation in newborn hypoxic-ischemic encephalopathy
adenosine A2A, PPARγ, ryanodine, and inositol triphosphate animal models [64].
(IP3) receptor antagonists did not prevent CBD-induced
intracellular Ca2+ increase, suggesting that these receptors The greatest success for CBD treatment is the reduction
did not mediate these CBD actions. However, CBD toxicity in seizures in children with refractive epilepsy. In a random-
at 1 µM was significantly impaired by caspase-inhibitors, ized, double-blind, placebo-controlled trial, CBD reduced
poly(ADP-ribose) polymerase PARP-1 and calpain, suggest- atonic seizures in Lennox-Gastaut patients, who also re-
ing caspase-dependent and -independent cell death pathway ceived clobazam, valproate, lamotrigine, levetiracetam, or
activation. rufinamide [65]. Severe AEs occurred in 20 (23%) of 86
patients in the CBD group including sleep apnea. Twelve
CBD's neuroprotective effect was investigated in human (14%) patients treated with CBD and one (1%) treated with
neuroblastoma SH-SY5Y cells during and after neuronal placebo withdrew from the study.
differentiation [60]. Terminally-differentiated cells incubated
with 2.5 µM CBD were not protected against ROS produced Long-term CBD safety and efficacy were evaluated in
by exposure to glycolaldehyde, methylglyoxal, 6- children and adults with intractable epilepsies administered
Table 1. CBD adverse effects in preclinical studies.
Species CBD Dose Route Reported Adverse Effects (AEs) Refs.
Acute AEs
Organ weight elevation; Seminiferous tubule degeneration, Rosenkrantz and

Rats 0.6, 0.8, or 1.2 mg/kg Inhaled
interference in sperm maturation Hayden, 1979 [100]
Tremors, central nervous system inhibition, convulsions,
Rhesus mon- 150, 200, 225, 250, or bradycardia, hypopnea, cardiac failure at higher doses; Liver Rosenkrantz and
Intravenous
keys 300 mg/kg/day (9 days) weight increase and testicular weights decrease, inhibition of Hayden, 1981 [61]
spermatogenesis
Sea urchin eggs Incubation in CBD- Dose-dependent decreased fertility of eggs & sperms & fertili- Schuel et al., 1987
0.1, 0.5, 1.0, or 10 µM
and sperms enriched sea water zation inhibition [101]
Decrease of testosterone metabolism; Decrease of CYP aniline
Narimatsu et al., 1990
Rats 10 mg/kg Intraperitoneal hydroxylation and p-nitroanisole demethylation, alteration of
[86]
CYP contents
Sea urchin Incubation in CBD- Dose and time-dependent acrosome reaction inhibition, motil- Schuel et al., 1991
0.1–100 µM
sperms enriched sea water ity not reduced [102]
Garberg et al., 2017

Piglets 10, 25, or 50 mg/kg Intravenous Hypotension, cardiac arrest
[63]
THC metabolism inhibition with higher THC concentrations

10 mg/kg + 10 mg/kg & lower CBD concentrations in serum and brain; Hypoloco- Hložek et al., 2017
Rats Subcutaneous
THC motion: THC metabolism inhibition shows little to no impact [96]
on THC-induced behavior
THC metabolism inhibition with higher THC concentrations

& lower CBD concentrations in serum and brain; Almost total
10 mg/kg + 10 mg/kg Hložek et al., 2017
Rats Oral immobility (10 mg/kg CBD alone caused mild hyperlocomo-
THC [96]
tion): THC metabolism inhibition shows little to no impact on
THC-induced behavior
10 mg + 10 mg THC (5 Hložek et al., 2017
Rats Inhaled No THC metabolism inhibition
min vaporization) [96]
Chronic AEs
Rhesus mon- 30, 100, or 300 Liver, heart, kidney, and thyroid weight increase; Decrease in Rosenkrantz and
Oral
keys mg/kg/day (90 days) testicular size, spermatogenesis inhibition Hayden, 1981 [61]
Anxiogenic-like effect, decreased brain-derived neurotrophic

factor (BDNF) expression & related signaling proteins in the
ElBatsh et al., 2012
Rats 10 mg/kg (14 days) Intraperitoneal hippocampus and frontal cortex; Protein expression decrease
[79]
in animals with enhanced protein expression following chronic
antidepressant/anxiolytic drug treatment
Decreased cell proliferation and neurogenesis in the hippo- Schiavon et al., 2016
Mice 30 mg/kg (15 days) Intraperitoneal
campus and in subgranular zone [36]
75, 150, or 250 Center for Drug

Rats (pregnant) mg/kg/day (during or- Oral Developmental toxicity, increased embryofetal mortality Evaluation and Re-
ganogenesis) search, 2018 [103]
75, 150, or 250 Decreased growth, delayed sexual maturation, neurobehav- Center for Drug
Rats (pregnant) mg/kg/day (during preg- Oral ioral changes, alterations of male reproductive organ devel- Evaluation and Re-
nancy and lactation) opment & fertility in offspring search, 2018 [103]
Center for Drug

Rabbits (preg- 50, 80, or 125 mg/kg/day Decreased fetal body weight, increased fetal
Oral Evaluation and
nant) (during organogenesis) structural variations
Research, 2018 [103]
Decreased circulating testosterone, increased frequency of
mitotic stages I-VI, decrease in spermiation stages VII-VIII &
meiotic stage XII, decrease in number of Sertoli cells at mei- Carvalho et al., 2018
Mice 15 or 30 mg/kg (34 days) Oral
otic stage (XII), decrease in number of spermatozoa in the [104]
epididymis tail, head abnormalities in sperm, cytoplasmic
droplets in the flagella medial region
Table 2. CBD adverse effects in clinical studies.
Simultaneous
Study Patients'
Oral CBD Dose Drug Reported Adverse Effects (AEs) Refs.
Characteristic Characteristic
Administration
Neurological studies
Age 2-16; 18 patients

with Dravet syndrome, Moderate (defined as: sufficiently discomforting so
0.5–28.6 Porter and
Parental report: Lennox-Gastaut syn- as to limit or interfere with daily activities and may
mg/kg/day (2 Not reported Jacobson,
online survey drome, Doose syn- require interventional treatment): drowsiness (37%),
weeks–12 months) 2013 [68]
drome, or idiopathic fatigue (16%)
epilepsy

with Dravet syndrome, Median of 4.3 Clobazam, other Hussain et
Parental report: AEs in 59% patients; Moderate: increased appetite,
Lennox-Gastaut syn- mg/kg/day (6.8 not-specified al., 2015
online survey weight gain, drowsiness
drome, or infantile months) antiepileptics [67]
spasms
Age 1-30; Patients with AEs in 79% safety group patients (128/162); Mod-
2–5 mg/kg/day
Open-label study, treatment-resistant epi- erate: somnolence, fatigue, lethargy, sedation, de-
increased until
expanded-access lepsy; 162 patients in creased or changes in appetite, diarrhea, transa- Devinsky et
intolerance or to a Clobazam,
trial in 11 inde- safety analysis group minases increase, changes of antiepileptics serum al., 2016
maximum of 25–50 valproate
pendent epilepsy (33 with Dravet syn- concentration; Severe: status epilepticus, convul- [70]
mg/kg/day (12
centers drome, 31 with Lennox- sions, diarrhea, weight loss, thrombocytopenia,
weeks)
Gastaut syndrome) hyperammonaemia, hepatotoxicity
1–20 mg/kg/day;
81% patients
AEs reported in 47% patients (34/74); Moderate:
Retrospective Age 1-18; 74 patients (60/74) with < 10 Tzadok et
seizure aggravation (5 patients stopped CBD treat-
study with no with treatment-resistant mg/kg, 19% Not reported al., 2016
ment due to seizure aggravation), somnolence,
control group epilepsy (14/74) with >10 [69]
fatigue, gastrointestinal disturbances, irritability
mg/kg (> 3 months,
average 6 months)
AEs in 93% patients; Moderate: diarrhea, loss of

Double-blind, Median of 3 appetite, lethargy, fatigue, pyrexia, convulsion,
Devinsky et
randomized, pla- Age 2-18; 120 patients 20 mg/kg/day (14 antiepileptics elevated aminotransferase levels, somnolence;
al., 2017
cebo-controlled with Dravet syndrome weeks) (e.g., clobazam, Severe (10 patients): elevated levels of liver
[71]
trial valproate) aminotransferase enzymes (n=3), status epilepticus
(n=3)
Treatment-emergent AEs (TEAEs) reported in 80%

5, 10, or 20
Clobazam, patients with 5 mg/kg (8/10), 63% patients with 10
Double-blind, mg/kg/day (4-week
valproate, mg/kg (6/8), 78% patients with 20 mg/kg (7/9), Devinsky et
randomized, pla- Age 4-10; 34 patients baseline, 3-week
levetiracetam, 86% patients with placebo (6/7); Moderate: pyrexia, al., 2018
cebo-controlled with Dravet syndrome treatment, 10-day
topiramate, sedation, somnolence, appetite loss, vomiting, [74]
trial taper, and 4-week
stiripentol ataxia, abnormal behavior, rash; Severe: pyrexia,
follow-up)
maculopapular rash, elevated transaminases
AEs in 84% patients with 10 mg/kg (56/67), in 94%

patients with 20 mg/kg (77/82); Moderate: somno-
lence, decreased appetite, diarrhea, upper respira-
Double-blind, tory tract infection, pyrexia, vomiting; Severe:
Age 2-55; 225 patients Devinsky et
randomized, pla- 10 or 20/mg/kg/day Not-specified elevated aspartate aminotransferase (AST) concen-
with Lennox-Gastaut al., 2018
cebo-controlled (28 days) antiepileptics tration, elevated alanine aminotransferase (ALT)
syndrome [75]
trial concentration, elevated γ-glutamyltransferase con-
centration, somnolence, increased seizures during
weaning, nonconvulsive status epilepticus, lethargy,
constipation, worsening chronic cholecystitis
(Table 2) contd….
Study Patients' Simultaneous Drug

Oral CBD Dose Reported Adverse Effects (AEs) Refs.
Characteristic Characteristic Administration
Neurological studies
AEs in 62% patients (53/86); Moderate:

Double-blind, diarrhea, somnolence, pyrexia, decreased
Age 2-55; 171 patients Clobazam, valproate,
randomized, pla- 20/mg/kg/day appetite, vomiting; Severe: increased ALT Thiele et al.,
with Lennox-Gastaut lamotrigine,
cebo-controlled (14 weeks) concentration, increased AST concentra- 2018 [65]
syndrome levetiracetam, rufinamide
trial tions, increased γ-glutamyltransferase
concentrations
2-10 mg/kg/day Up to 10, including

Age 0.4-62 AEs in 88% patients; Moderate: diarrhea,
Ongoing ex- increased to a clobazam, lamotrigine, Szaflarski et
(average 13); somnolence, convulsions; Severe (33%):
panded‐access maximum of 25-50 topiramate, rufinamide, al., 2018
607 patients with treat- convulsions, status epilepticus, liver ab-
program (EAP) mg/kg/day; median valproate, levetiracetam, [66]
ment-resistant epilepsy normalities (10%)
duration 48 weeks stiripentol, felbamate
Psychiatric studies and psychiatric AEs
Double-blind, Age 18-50; 42 patients 200 mg/day

Leweke et
randomized CBD with acute paranoid increased to a Fewer motor disturbances, weight gain,
Lorazepam al., 2012
versus amisulpride schizophrenia or schizo- maximum of 800 and sexual dysfunction than amisulpride
[38]
trial phreniform psychosis mg/day (28 days)
Meta-analysis of
studies & reviews Guinguis et
57 patients with Does not decrease anxiety; Frequent AEs
on CBD efficacy & 300–600 mg Not reported al., 2017
schizophrenia (not reported)
safety in schizo- [62]
phrenia
AEs in 31% patients (5/16); Tired-

ness/sedation (n=5), lightheaded/dizziness
Double-blind,
Age 18-50; 32 patients (n=2), nausea (n=2), abdominal discomfort Hundal et
randomized, pla-
with persecutory idea- 600 mg Not reported (n=1), increased appetite/hunger al., 2018
cebo-controlled
tion and anxiety (n=2); A strong trend toward increased [39]
trial
anxiety was documented; no effect on
persecution ideation

Double-blind, AEs in 35% patients (15/43) (similar as
with no treatment- Mc Guire et
randomized, pla- 1,000 mg/day Not-specified placebo); Moderate: diarrhea (n=4; pla-
resistant schizophrenia al., 2018
cebo-controlled (43±3 days) antipsychotics cebo, n=2), nausea (n=3), headache (n=2,
or related psychotic [35]
trial placebo, n=2)
disorder
up to 10 antiepileptic drugs including clobazam, valproic dromes. The most common AEs were sedation, somnolence,
acid, levetiracetam, lamotrigine, stiripentol, rufinamide, topi- fatigue, lethargy, and malaise. In an online survey of 117
ramate, and felbamate [66]. The starting oral CBD dose was parents who administered CBD cannabis preparations to
2-‐10 mg/kg/day, escalating to 25-‐50 mg/kg/day for a median their children with uncontrolled epilepsy, the median dose
48-week duration. Twenty-four percent of 607 patients in the was 4.3 mg/kg/day for a median duration of 6.8 months [67].
safety dataset (mean age 13 years) withdrew, primarily due AEs were reported in 59% of children, but there were no
to failed efficacy (n=89, 61%) and AEs (n=32, 22%). AEs controls. Porter and Jacobson reported similar findings in
were reported in 88% of all patients, severe AEs such as another smaller online survey including 18 parents [68].
convulsions and status epilepticus were reported for 33% of Drowsiness and fatigue reportedly affected 37% and 16% of
patients. children, respectively. In a retrospective study of 74 children
1–18 years old with seizures, the CBD dose ranged from 1 to
In the Epidiolex® FDA approval notification [27] and
20 mg/kg/day for more than 3 months (average 6 months)
Epidiolex® prescription information [19], CBD’s in vivo AEs
[69]. AEs were reported in 47% of children. Status epilepti-
in humans included, similar to other anti-epileptics, suicidal
cus was attributed to the disease, and drowsiness and fatigue
thoughts, suicide attempts, agitation, depression, aggression,
could have been due to the other administered anti-epileptic
and panic attacks.
drugs, making it difficult to assign AEs to the CBD treat-
3.2. Changes in Behavior ment.
Most clinical CBD research focused on reduction in sei- From 2016-2018, Devinsky et al. investigated CBD effi-
zures in patients with Dravet’s or Lennox-Gastaut syn- cacy for the treatment of Dravet syndrome and Lennox-
Gastaut syndrome and reported associated AEs. In a 2016 Long-term CBD safety and efficacy were evaluated in an
open-label clinical trial of 214 patients 1-30 years old with ongoing expanded-‐access program in children and adults
treatment-resistant epilepsy, patients received up to 25-50 with treatment-‐resistant epilepsies receiving up to 10 antiepi-
mg/kg/day CBD for 12 weeks [70]. Of the 162 patients in the leptic drugs including clobazam, lamotrigine, topiramate,
safety and tolerability analysis, 79% reported AEs, 25% rufinamide, valproic acid, levetiracetam, stiripentol, and fel-
somnolence, 11% convulsions, and more than 5% reported bamate [66]. The starting oral CBD dose was 2-‐10
somnolence, fatigue, lethargy, convulsions, status epilepti- mg/kg/day, escalating to 25-‐50 mg/kg/day for a median 48-
cus, changes in concentrations of concomitant antiepileptic week duration. Twenty-four percent of 607 patients in the
drugs, gait disturbance, and sedation. Serious adverse events safety dataset (mean age 13 years) withdrew, mostly for lack
were reported in 30% patients, including one unexpected of efficacy (n=89, 61%) and AEs (n=32, 22%). Eighty-eight
death regarded as unrelated to study drug. Twelve percent percent experienced treatment-‐emergent AEs, with the most
had severe adverse events possibly related to CBD use, the common AE being somnolence (22%).
most common (6%) was status epilepticus. Ten percent re-
In a study on the efficacy of CBD in schizophrenia, there
ceiving the highest dose had to lower the dose prior to the
was a low incidence (≥4%) of mild AEs including somno-
end of the trial and 4% stopped treatment, most likely due to
lence and insomnia, with a frequency similar to that found in
AEs. The median reduction in monthly motor seizures was
placebo [35].
36.5% (IQR 0–64.7).
In a 2017, randomized, double-blind, placebo-controlled Several preclinical and clinical studies documented CBD’s
acute anxiolytic effects [76-78], although more recently
CBD trial on Dravet’s syndrome, 120 children received 20
ElBatsh et al. demonstrated that 10 mg/kg intraperitoneal (IP)
mg/kg/day oral CBD or placebo for 14 weeks, in conjunction
CBD over 14 days produced an anxiogenic effect in rats [79].
with their standard treatment (1 to 5 antiepileptic drugs) [71].
AEs occurred more frequently in the CBD than the placebo CBD AEs in humans reported in the Epidiolex® FDA
group, with somnolence (36% vs 10%) being the most com- approval notification [27] and the Epidiolex® prescription
mon AE. Another less common AE was fatigue. information [19] included somnolence, sedation and leth-
argy, insomnia, sleep disorder and poor quality sleep, fa-
Adverse reactions were reported in 199 children and
tigue, malaise, and asthenia.
young adults treated with 2-5 mg/kg/day CBD for uncon-
trolled seizures [72] and in 424 children and young adults
3.3. Hepatic Effects
treated with 0.5-50 mg/kg/day CBD for refractory epilepsy
[73]. The most common AEs were drowsiness, somnolence, Following 90 days of oral CBD (30-300 mg/kg/day),
and fatigue. liver and kidney weights in rhesus monkeys were 13-56%
greater than controls, without morphological changes in the
In a 3-week 2018 treatment trial in 4 to 10-year-old chil-
organs [61].
dren with Dravet’s syndrome receiving 5, 10, or 20
mg/kg/day CBD, there were more AEs following CBD than In 214 patients 1-30 years old with treatment-resistant
placebo [74]. Children were concomitantly taking clobazam, epilepsy receiving up to 25-50 mg/kg/day CBD for 12
valproate, levetiracetam, topiramate, and stiripentol. The weeks, 7% had slightly elevated liver function tests, but one
most frequent AEs were somnolence, sedation, ataxia, and had a significant increase in transaminases (considered hepa-
abnormal behavior. totoxic), leading to CBD withdrawal [70]. All patients with
hepatic or platelet abnormalities were also taking valproate.
In a 2018 randomized double-blind trial investigating
In a 3-week treatment trial in 4 to 10-year-old children with
CBD effect on atonic seizures in 225 patients 2-55 years old
Dravet’s syndrome receiving 5, 10, or 20 mg/kg/day CBD
with Lennox-Gastaut syndrome, patients received 10 and 20
and concomitant anti-epileptic drugs, 6 patients taking CBD
mg/kg/day oral CBD for 28 days [75]. In conjunction with and valproate developed elevated transaminases, but not
other antiepileptic drugs, seizure frequency was reduced
liver injury [74]. In a 2017, double-blind, randomized, pla-
compared to placebo. This most common AE was somno-
cebo-controlled CBD trial on Dravet’s syndrome, 120 chil-
lence. Serious AEs included somnolence and lethargy. Som-
dren and young adults received 20 mg/kg/day oral CBD or
nolence occurred more frequently in those receiving 20
placebo for 14 weeks, along with standard treatment of 1 to 5
mg/kg/day CBD than 10 mg/kg/day. AEs were reported in 6
antiepileptic drugs [71]. AEs occurred more frequently in the
patients following 20 mg/kg/day CBD, one following the CBD than placebo group including increases in liver-
lower dose, and one receiving a placebo.
function tests. Patients with Lennox-Gastaut syndrome
In a randomized, double-blind, placebo-controlled trial, (n=225) receiving 10 and 20 mg/kg/day oral CBD for 28
CBD was efficacious in reducing atonic seizures in patients days, reported serious AEs with elevated aspartate
with Lennox-Gastaut syndrome, also taking clobazam, val- aminotransferase (AST), alanine aminotransferase (ALT), γ-
proate, lamotrigine, levetiracetam, or rufinamide [65]. glutamyltransferase (GGT) concentrations, and worsening
Treatment-related AEs, including somnolence, were mostly chronic cholecystitis [75]. The most common AE was AST
mild and occurred in 62% of 86 patients treated with 20 or ALT increases 3.2-12.2 times the upper limit of normal in
mg/kg/day CBD for 14 weeks. Severe AEs included sedation 4 of 6 patients receiving 20-mg/kg/day CBD, one receiving
occurring in 23% of 86 patients receiving CBD; 14% pa- 10-mg/kg/day CBD, and among patients concomitantly re-
tients treated with CBD and one (1%) treated with placebo ceiving valproate (79%, 9 in the 20 mg/kg/day group and 2
withdrew from the study. in the 10 mg/kg/day group). Overall, 9% receiving CBD had
elevated liver AST concentrations and none in the placebo common AEs were diarrhea (29%), and decreased appetite
group. Severe AEs in Lennox-Gastaut patients receiving 12%). In clinical studies of schizophrenia, mild AEs, diar-
CBD treatment included increased ALT, AST, and GGT rhea and nausea, occurred with a low incidence of ≥4%, with
concentrations [65]. In children and adults with treat- a frequency similar to placebo [35].
ment-‐resistant epilepsies receiving up to 25-‐50 mg/kg/day
for a median 48-week duration, AEs related to ALT/AST CBD AEs in humans listed in the Epidiolex® FDA ap-
proval notification [27] and in Epidiolex® prescription in-
abnormalities (higher than three times the upper limit of
formation [19] include decreased appetite, diarrhea, nausea,
normal) were reported for 10% of patients; 75% of these also
vomiting, and abdominal pain.
received valproate [66].
CBD AEs in humans presented in the Epidiolex® FDA 3.5. Drug-drug Interactions
approval notification [27] and Epidiolex® prescription in- CBD’s interaction with CYP enzymes can reduce or po-
formation [19] include transaminase elevation (especially
tentiate the effects of other drugs [19, 22, 80]. In 1974,
with concomitant valproate). Epidiolex® can also cause liver
Karniol et al. investigated effects of oral 0, 15, 30, and 60
injury, usually mild, but more severe injury with related
mg CBD alone, 0 and 30 mg THC alone, and CBD and THC
symptoms such as jaundice can occur although rarely.
combinations to study potential drug-drug interactions in a
double-blind trial in 40 healthy male volunteers [81]. THC
3.4. Gastrointestinal Effects
alone disturbed time estimations, increased pulse rate, and
In an online survey of 117 parents who administered a induced strong psychological reactions, while up to 60 mg
median CBD-enriched cannabis preparation of 4.3 CBD alone produced no effects. Thirty to 60 mg CBD weak-
mg/kg/day for a median duration of 6.8 months for treatment ened or blocked time production impairment, psychological
of their children's epilepsy, 59% reported AEs, primarily disturbances, and pulse rate acceleration produced by THC,
gastrointestinal disturbances; however, there was no control when co-administered. CBD also decreased anxiety follow-
group [67]. In a retrospective study of 74 patients, age range ing THC, with subjects reporting more pleasurable effects.
1-18 years, CBD dosage ranged from 1 to 20 mg/kg/day for
In 1995, CBD effects on THC pharmacokinetics were
more than 3 months (average 6 months), 47% AEs were re-
investigated in mice receiving 120 mg/kg IV CBD 2 h before
ported, prominently [69]. Gastrointestinal disturbances could
12 mg/kg IV THC [82]. CBD inhibited hepatic microsomal
be due to other co-administered anti-epileptic drugs making
THC metabolism reducing THC clearance. 7-OH-THC and
it difficult to assign responsibility to CBD.
6α-OH-THC concentrations were increased in brain, with
In 162 participants included in a clinical trial of 25-50 few changes in blood. CBD-induced changes in metabolite
mg/kg/day CBD for 12 weeks for treatment-resistant epi- profile and brain pharmacokinetics might change pharma-
lepsy, serious AEs included diarrhea, weight loss, and gas- cological effects. Bergamaschi reviewed research on animal
trointestinal intolerance (n=1) [70]. In a CBD trial on models in 2011 showing that CBD did not induce changes in
Dravet’s syndrome, 120 children and young adults were ran- food intake, catalepsy, or physiology in rats and mice [57].
domly receiving 20 mg/kg/day oral CBD or placebo for 14 Chronic low and high CBD doses inhibited hepatic drug me-
weeks, AEs included diarrhea (31% vs 10%), loss of appetite tabolism producing drug-drug interactions in vivo in mice
(28% vs. 5%), and much less commonly vomiting [71]. Diar- and rats following 10-120 mg/kg IP CBD [83-93]. However,
rhea and weight and appetite loss were also reported in 199 more recently, when equal amounts of CBD and THC were
children and young adults treated with 2-5 mg/kg/day CBD co-administered, CBD did not modify THC blood concentra-
for uncontrolled seizures [72], and in 424 children and young tions in humans [94]. In addition, Karschner et al. found no
adults treated with 0.5-50 mg/kg/day CBD for refractory changes in THC’s subjective and physiological effects when
epilepsy [73]. equivalent doses of THC alone or CBD and THC (Sativex®)
were given via oromucosal spray [95].
Similarly, in 4 to 10-year-old children with Dravet’s syn-
drome, CBD treatment with 5, 10, or 20 mg/kg/day reported In a clinical trial of treatment-resistant epilepsy, 162 par-
appetite loss and vomiting as the most frequent AE [74]. ticipants included in the safety and tolerability analysis re-
Devinsky et al. reported AEs of decreased appetite, diarrhea, ceived 25-50 mg/kg/day CBD for 12 weeks and sustained
and vomiting, and a serious AE constipation in 2 to 55-year- changes in concentrations of concomitant antiepileptic drugs
old patients (n=225) with Lennox-Gastaut syndrome, receiv- that may have led to status epilepticus [70]. Similarly, in
ing 10 and 20 mg/kg/day oral CBD for 28 days [75]. De- patients with CBD-reduced atonic seizures, severe AEs in-
creased appetite and diarrhea occurred more frequently in the creased concomitant antiepileptic concentrations in 23% of
high-dose group than the low-dose group (10 mg/kg/day). 86 patients in the CBD group; 14% of patients treated with
CBD significantly reduced atonic seizures in patients with CBD and one (1%) treated with placebo withdrew from the
Lennox-Gastaut syndrome, with mostly mild AEs diarrhea, study [65].
decreased appetite, and vomiting in 62% of 86 patients
THC, CBD, and THC and CBD effects via vaporization
treated with 20 mg/kg/day CBD for 14 weeks [65]. Vomiting
of 20 mg THC, CBD, or 1:1 THC:CBD, oral, and subcuta-
was among the severe AEs reported.
neous (SC) administration of 10 mg/kg THC or CBD, or 20
Following 25-‐50 mg/kg/day for a median of 48 weeks in mg/kg 1:1 THC:CBD, or oral gavage were investigated in
children and adults with treatment-‐resistant epilepsies, 88% Wistar rats [96]. Although no statistical analyses were per-
of all patients experienced treatment-‐emergent AEs and 33% formed, SC CBD inhibited THC metabolism resulting in 4
experienced severe AEs, including vomiting [66]. The most times higher serum and brain THC concentrations when
CBD and THC were simultaneously administered compared weeks, including pyrexia in patients with Lennox-Gastaut
to THC alone. Serum and brain CBD concentrations were syndrome, with concomitant clobazam, valproate, lamo-
half the concentration when CBD and THC were co- trigine, levetiracetam, or rufinamide [65].
administered compared to CBD alone. Oral CBD inhibited
THC metabolism with 2 to 3 times higher serum and brain 3.8. Cardiovascular Effects
THC concentrations and two-fold lower serum and brain
After rhesus monkeys received 150, 200, 225, 250, or
CBD concentrations when CBD and THC were administered
300 mg/kg IV CBD for 9 days, higher CBD doses elicited
together. CBD did not inhibit THC metabolism after pulmo-
hypopnea, bradycardia, and cardiac failure [61]. In 162 pa-
nary THC and CBD administration. SC cannabinoids ad-
tients with treatment-resistant epilepsy administered 25-50
ministration (THC and CBD and THC and CBD alone) pro-
mg/kg/day CBD for 12 weeks, serious AEs included diar-
duced hypolocomotion. Oral THC and THC and CBD pro-
duced almost total immobility, but oral CBD produced mild rhea, weight loss, and gastrointestinal intolerance (n=1) [70].
hyperlocomotion. The apparent CBD inhibition of THC me- Five (3%) patients experienced mild to moderate and one
tabolism after oral and SC administration had little impact on case of severe thrombocytopenia, resolving after stopping
THC-induced behavior. valproate. One patient also taking valproate developed hy-
perammonemia leading to stopping CBD intake. AEs were
In a CBD versus amisulpride trial, 42 patients signifi- clearly related to dose and anti-epileptic drug intake. All
cantly improved seizure control, with significantly higher patients receiving CBD and valproate had liver or blood ab-
serum anandamide concentrations, perhaps due to CBD inhi- normalities.
bition of the enzyme FAAH [38].
CBD was evaluated as a neuroprotectant after perinatal
Epidiolex® and concomitant clobazam administration, hypoxia-ischemia in piglets [63]. Piglets were randomized to
produced a 3-fold increase in plasma concentrations of N- 50 mg/kg IV CBD (n=13) or vehicle (n=9). CBD induced
desmethylclobazam, the active metabolite of clobazam, in- severe hypotension in two piglets; one suffered fatal cardiac
creasing the risk of AEs such as excessive sedation [19, 97]. arrest (50 mg/kg, IV). CBD (25 mg/kg, n=4) induced signifi-
Epidiolex® increases plasma concentrations of drugs metabo- cant hypotension in one piglet, while 10 mg/kg (n=5) was
lized by CYP2C19 such as diazepam or clobazam. well tolerated. A significant negative correlation between
In 137 patients in the efficacy analysis receiving 25-50 plasma CBD concentration and blood pressure during drug
mg/kg/day CBD for 12 weeks for treatment-resistant infusion was observed (p<0.005).
epilepsy, 11 withdrew due to AEs including allergy to sesame
oil vehicle (n=1) [70]. In the Epidiolex® FDA approval 3.9. Reproductive Effects
notification [27] and in Epidiolex® prescription information 3.9.1. In Vitro Reproductive Effects
[19], CBD AEs in humans included allergic reactions and
rash. In 1982, the effects of 100-200 µM CBD reduced the
basal accumulation of progesterone, testosterone, and estra-
3.6. Respiratory Effects diol-17β in preovulatory rat follicles by up to 60% [98]. Lu-
teinizing hormone-stimulated increase in progesterone and
In 162 patients with treatment-resistant epilepsy receiv-
testosterone was reduced by 75-88% following 50-200 µM
ing 25-50 mg/kg/day CBD for 12 weeks, a serious AE of
CBD and estradiol-17β accumulation was inhibited by 40%.
pneumonia was reported [70]. In a trial investigating the ef-
fects of 10 and 20 mg/kg/day oral CBD for 28 days on atonic Progesterone 17α-hydroxylase activity was significantly
seizures in 2 to 55-year-old patients with Lennox-Gastaut inhibited by 100-1000 µM CBD [99]. Testosterone 6β and
syndrome (n=225), common AEs included upper respiratory 16α-hydroxylase activity and androstenedione formation
tract infection [75]. In children and adults with treat- from testosterone in rat liver microsomes also were signifi-
ment-‐resistant epilepsies receiving up to 25-‐50 mg/kg/day cantly reduced by CBD.
for a median 48-week duration, 33% experienced severe AEs
including pneumonia [66]. The most common AEs were 3.9.2. In Vivo Reproductive Effects
upper respiratory tract infection in 12%. Following oral 30, 100, and 300 mg/kg CBD for 90 days
®
CBD AEs in humans in the Epidiolex FDA approval in rhesus monkeys, significant 57% decreases in testicular
notification [27] and in the Epidiolex® prescription informa- weights were observed after 200 mg/kg CBD that continued
tion [19] included viral, fungal, and pneumonia infections. after the end of treatment [61]. Similarly, acute and sub-
chronic 0.6, 0.8, and 1.2 mg/kg smoked CBD exposure in
3.7. Pyrexia rats showed a severe dose-related seminiferous tubule de-
generation with interference in sperm maturation [100]. In
The most frequent AE was pyrexia in a 3-week treatment addition, testicular weight decreases correlated with a dose-
trial of 5, 10, or 20 mg/kg/day CBD in 4 to 10-year-old chil- related inhibition of spermatogenesis.
dren with Dravet’s syndrome [74]. In the same manner, 2 to
55-year-old patients with Lennox-Gastaut syndrome In 42 patients administered 200 mg/day gradually in-
(n=225), receiving 10 and 20 mg/kg/day oral CBD for 28 creased to 800 mg/day CBD or amisulpride over 28 days,
days for atonic seizures had pyrexia amongst common AEs there were significantly fewer CBD-related AEs compared to
[75]. Treatment-related AEs were mostly mild and occurred amisulpride, including lower prolactin release, and less sex-
in 62% of 86 patients treated with 20 mg/kg/day CBD for 14 ual dysfunction [38].
Fertility also was affected by CBD. In sea urchins, in from 1.0 to 0.50 µg/L (-52%), while antifungal ketoconazole
vivo fertilization was inhibited by 0.1-100 µM CBD due to a (400 mg), a CYP3A4 inhibitor, almost doubled peak plasma
decreased acrosome reaction in sperm [101, 102]. CBD from 0.7 to 1.3 µg/L (+89%) [112].
When pregnant rats were administered 0, 75, 150, or 250 4. DISCUSSION
mg/kg/day oral CBD during organogenesis, developmental
toxicity including increased embryofetal mortality at the This is an exciting time for CBD research and medicine.
highest dose was observed [103]. Oral 0, 50, 80, or 125 Epidiolex®, containing 98% CBD, was approved by the FDA
mg/kg/day CBD administration during organogenesis in for the treatment of intractable epilepsy in patients with
pregnant rabbits decreased fetal body weights and increased Dravet’s or Lennox-Gastaut syndromes, showing that a plant
fetal structural variations were shown following the highest extract containing primarily CBD can provide the reproduci-
dose [103]. Also, following 150 and 250 mg/kg/day oral bility needed for pharmacotherapies. There is active in vitro
CBD to pregnant and lactating rats, decreased growth, de- and preclinical research into the mechanisms of action of
layed sexual maturation, neurobehavioral changes with de- CBD in efforts to better understand its pharmacodynamics
creased activity, and AEs for male reproductive organ devel- and pharmacokinetics and therapeutic potential. Clinical
opment and fertility in offspring were noted. No maternal research is proceeding for multiple indications for CBD in
toxicity was reported [103]. well-designed, randomized, placebo-controlled clinical trials,
by a variety of routes of administration. Pharmaceutical
When Swiss mice received 30 mg/kg oral CBD or pla- companies pursue synthetic CBD and plant extracts as CBD
cebo in sunflower oil for 34 consecutive days, CBD de- sources. CBD may provide a new approach as a stand-alone-
creased total circulating testosterone by 76% (still within drug and as an adjunct to other medications for unmet clini-
normal ranges), significantly increased abnormalities in cal needs.
spermiation and meiotic stages [104]. CBD-treated mice had
a 38% reduction in spermatozoa in the epididymis tail and Amongst all of these positive developments, unapproved
more head abnormalities in the sperm and cytoplasmic drop- CBD products are being sold across the US and in other
lets in the flagella medial region. countries without rigorous standardization of CBD potency,
the content of other constituents, and with unproven claims
3.10. Cellular Effects of health effects. Now that Epidiolex® is approved, it is
likely that off-label prescriptions will increase. It is impor-
In vitro toxicity was observed in the production of cyto-
tant that physicians and patients understand that CBD, like
kines in human eosinophil leukemia cells, peripheral blood
any other medication, is not appropriate for every individual
mononuclear cells, human T-lymphotropic virus-1 (HTLV-
and every disease and that it has side effects that are not neg-
1) positive B cells, and T cells following 1-10 µg/mL CBD
ligible and must be considered prior to use.
[105]. CBD suppressed T-cell activities in splenocytes ex-
posed to CBD in vitro or isolated from CBD-administered The most important consideration is whether or not there
mice [106]. Exposure of splenocytes to CBD produced ROS, is sufficient scientific data that CBD is efficacious in treating
reduced cellular glutathione (GSH) content, and significantly a patient’s disease or condition. The field is changing rap-
stimulated caspase-8 activation. Pretreatment with a caspase- idly, but proof of efficacy is limited currently to CBD as an
8 inhibitor significantly reduced, in a concentration- anti-epileptic. A second critical factor is dose, route, and
dependent manner, CBD-mediated apoptosis, but not ROS frequency of administration. In many of the preclinical stud-
production, suggesting that CBD’s apoptotic effects in pri- ies, much higher CBD concentrations were administered. For
mary lymphocytes are associated with oxidative stress- example, many of the cardiovascular, hepatocellular damage,
dependent activation of caspase-8. inhibition of P450 systems, hormone changes, decreased
fertility, alterations of in vitro cell viability, and reduced P-
In vitro apoptosis was induced in mouse thymus and
glycoprotein activities effects occurred at doses of >200
spleen cells exposed to 4-16 µM CBD [106, 107], and a pro-
mg/kg/day [61], far above the current up to 50 mg/kg/day
apoptotic effect was noted in lymphocytes following 10
doses suggested in recent anti-epileptic clinical studies.
mg/kg IP CBD [106].
However, in the clinical trial data to date, few cardiovascular
ATP-binding cassette transporter (ABC) ABCG2 activity and reproductive effects were reported. Other in vivo pre-
in mouse embryonic fibroblasts was reduced after in vitro clinical studies utilized lower doses similar to those used in
exposure to 10-50 µM CBD [108]. humans, but the route of administration, IP or IV, provided
higher bioavailability and hence, a greater chance of AEs
Following exposure to 3-100 µM CBD, in vitro P- and toxicity.
glycoprotein activity was reduced in human T lymphoblas-
toid leukemia cells [109]. In addition, ABCC1 transporter Drug interactions are an important issue to be carefully
was inhibited in human ovarian carcinoma cells with a CBD considered when prescribing CBD. CBD is often added to a
IC50 of 128.3 µM [110]. CBD was also shown to interact regimen of other medications, especially other anti-epileptics
with P-glycoprotein efflux transporters involved in multidrug and the potential for drug-drug interactions could lead to
resistance [111] and may also affect placental permeability serious health consequences. In vitro and in vivo data suggest
and pharmacokinetics of other drugs. In humans, 600 mg of that CBD interacts with pharmaceuticals, specifically drugs
the antibiotic rifampicin, a CYP3A4 inducer involved in metabolized by the liver. Drug-drug interactions with
CBD metabolism, significantly reduced peak plasma CBD CYP1A2 substrates (theophylline, caffeine), CYP2B6 sub-
strates (bupropion, efavirenz), UGT1A9 (diflunisal, propo- REFERENCES

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type 1 and type 2 cannabinoid receptors. Br. J. Pharmacol., 2018.
Not applicable.
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None.
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Cannabidiol Adverse Effects and Toxicity

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Cannabidiol Adverse Effects and Toxicity

1. INTRODUCTION cannabinoid receptors were cloned by Matsuda et al. in 1992

1570-159X/19 $58.00+.00 ©2019 Bentham Science Publishers

Table 1. CBD adverse effects in preclinical studies.

Species CBD Dose Route Reported Adverse Effects (AEs) Refs.

Organ weight elevation; Seminiferous tubule degeneration, Rosenkrantz and

Garberg et al., 2017

THC metabolism inhibition with higher THC concentrations

THC metabolism inhibition with higher THC concentrations

Anxiogenic-like effect, decreased brain-derived neurotrophic

75, 150, or 250 Center for Drug

Center for Drug

Table 2. CBD adverse effects in clinical studies.

Age 2-16; 18 patients

Age 3-10; 117 patients

AEs in 93% patients; Moderate: diarrhea, loss of

Treatment-emergent AEs (TEAEs) reported in 80%

AEs in 84% patients with 10 mg/kg (56/67), in 94%

Study Patients' Simultaneous Drug

AEs in 62% patients (53/86); Moderate:

2-10 mg/kg/day Up to 10, including

Psychiatric studies and psychiatric AEs

Double-blind, Age 18-50; 42 patients 200 mg/day

AEs in 31% patients (5/16); Tired-

Age 18-65; 88 patients

strates (bupropion, efavirenz), UGT1A9 (diflunisal, propo- REFERENCES

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ated with oxidative stress-dependent activation of caspase-8. Toxi- [http://dx.doi.org/10.1016/j.bcp.2005.12.033]

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