The Impact of Cannabidiol on Psychiatric and Medical Conditions

Abstract

Cannabidiol (CBD) is a substance chemically derived from Cannabis sativa and discussed to be non-psychoactive. According to the FDA, marijuana is classified as a schedule I substance; however, hemp which is defined as extracts from marijuana including cannabinoids containing less than 0.3% tetrahydrocannabinol (THC), is excluded from that controlled substance act and available at local convenience stores in the US as it is seen as an herbal supplement. CBD is purported to be used for various medical and psychiatric conditions: depression, anxiety, post-traumatic stress disorder, Alzheimer's or other cognitive illnesses as well as pain. There is also a new trend to use CBD for the treatment of opioid use disorder. The one CBD product on the market that is FDA approved for the treatment of childhood epilepsy forms Dravet and Lennox-Gastaut syndromes is available under the name Epidiolex. There is a significant difference between this medication and the over-the-counter CBD products that contain very inconsistent strengths of CBD, if they contain it at all, and vary in percentage even from sample to sample. Frequently the so-called CBD products are not containing any CBD at all, but mostly containing THC. This article is a systematic review of literature reviewing the available clinical data on CBD, for use in various medical and psychiatric conditions with focus on a review of the pharmacology and toxicity. Resources used were ORVID, PubMed, MEDLINE, PsychINFO, EMBASE with keywords CBD, cannabidiol, hemp and cannabinoids.

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Review J Clin Med Res. 2020;12(7):393-403
The Impact of Cannabidiol on Psychiatric and
Medical Conditions
Thersilla Oberbarnscheidta, c, Norman S. Millerb
Abstract
Cannabidiol (CBD) is a substance chemically derived from Cannabis
sativa and discussed to be non-psychoactive. According to the FDA,
marijuana is classied as a schedule I substance; however, hemp which
is dened as extracts from marijuana including cannabinoids contain-
ing less than 0.3% tetrahydrocannabinol (THC), is excluded from that
controlled substance act and available at local convenience stores in
the US as it is seen as an herbal supplement. CBD is purported to
be used for various medical and psychiatric conditions: depression,
anxiety, post-traumatic stress disorder, Alzheimer’s or other cognitive
illnesses as well as pain. There is also a new trend to use CBD for the
treatment of opioid use disorder. The one CBD product on the market
that is FDA approved for the treatment of childhood epilepsy forms
Dravet and Lennox-Gastaut syndromes is available under the name
Epidiolex. There is a signicant dierence between this medication
and the over-the-counter CBD products that contain very inconsistent
strengths of CBD, if they contain it at all, and vary in percentage even
from sample to sample. Frequently the so-called CBD products are not
containing any CBD at all, but mostly containing THC. This article is a
systematic review of literature reviewing the available clinical data on
CBD, for use in various medical and psychiatric conditions with focus
on a review of the pharmacology and toxicity. Resources used were
ORVID, PubMed, MEDLINE, PsychINFO, EMBASE with keywords
CBD, cannabidiol, hemp and cannabinoids.
Keywords: Cannabidiol; THC; Cannabis sativa
Introduction
CBD, also called cannabidiol, is chemically derived from
hemp (Cannabis sativa), which is the most commonly used il-
licit drug both nationally and internationally [1].
It was rst obtained from American hemp and Egyptian
hashish in 1940 [2]. In its natural form cannabis consists of the
two most well-known active chemicals tetrahydrocannabinol
(THC) and CBD as well as about 480 other active cannabi-
noids (CBs) that are not yet well researched. The THC in the
cannabis is the psychoactive ingredient with toxicity. The THC
content in a product labeled as CBD is supposed to contain less
than 0.3% dry weight of THC in its leaves and buds [3].
Even though CBD use is a global problem, this article will
focus on the current situation and trend within the US. Mari-
juana as well as CBD is purported for use in the US for the
self-treatment of numerous medical and psychiatric conditions
as a so-called “medicine”. It is commonly used for depression,
anxiety, seizures, nausea, appetite enhancer, anti-inammato-
ry, pain or the new trend to self-treat opioid use disorder [4].
Against the usual course of a medication development,
both substances have not been scientically investigated or
developed prior to their use, but were determined by claims in
the general public of their medicinal value [5]. Possible toxic
eects and drug-drug interactions should be considered, and
consumers should be educated about the risks and safety con-
cerns regarding this substance, which are currently not publi-
cized.
Due to CBD being exempt from federal regulations by the
in 2018 passed US farm bill, it is easily accessible and avail-
able at convenience stores throughout the US [6].
The sale and marketing of CBD and CBD-containing
products are very important economic factors as sales reached
$2 billion US dollars in 2018 and are rising [7].
Of the US population, 9% of the people less than 35 years
of age reported the use of CBD at least once, 6.4% of the peo-
ple between 45 and 55 years and 3.7% of the people over 55
years of age [8].
The question for public health is if CBD is really non-psy-
choactive and as safe as it is advertised in the general-public?
Pharmacological Action of CBD
CBD can be ingested in various routes. It is available in the
form of oils, lotions, edibles, teas or smoked (Figs. 1, 2) [9]. It
is rarely administered intravenously but that route is possible
[10].
CBD undergoes a signicant rst pass metabolism in the
liver after ingestion. The bioavailability after oral consumption
Manuscript submitted April 9, 2020, accepted May 25, 2020
Published online June 25, 2020
aDepartment of Psychiatry, Western Psychiatric Hospital, University of Pitts-
burgh, UPMC Health, Pittsburgh, PA, USA
bDepartment of Psychiatry, Augusta University, Health Advocates PLLC, East
Lansing, MI, USA
cCorresponding Author: Thersilla Oberbarnscheidt, Department of Psychiatry,
Western Psychiatric Hospital, University of Pittsburgh, UPMC Health, Pitts-
burgh, PA, USA. Email: Toberbarnscheidt@gmail.com
doi: https://doi.org/10.14740/jocmr4159

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Impact of CBD on Psychiatry Conditions J Clin Med Res. 2020;12(7):393-403
is estimated 6%, and after smoking is estimated to be about
6-31% [11].
CBD’s primary active metabolite is 7-hydroxy-CBD
(7-OH-CBD) [12]. The half-life of CBD depends on the route
of administration. Smoked, the half-life is about 27 - 35 h, af-
ter oral ingestion 2 - 5 days and the shortest after intravenous
injection with about 18 - 33 h [13].
CBD is very lipophilic, similar to cannabis, and easily
passes the blood-brain barrier. It gets quickly distributed into
adipose tissue and other organs. Due to its lipophilic quality,
CBD accumulates in the adipose tissue particularly in patients
with high adiposity and is redistributed into the circulation at
a later point [14]. The amount used varies in a wide spectrum:
administered doses in studies range from 5 - 1,500 mg/day
orally up to 30 mg intravenously [15].
CBD does bind to the CB receptors, normally activated by
endogenous CBs including anandamide and 2-arachidonylg-
lycerol. There are two specic CB receptors identied. Unlike
THC that binds to CB1 receptors that are mostly located in the
brain, CBD binds mostly to CB2 receptors that are found on
cells of the immune system, which include T and B lympho-
cytes, macrophages and monocytes which are not as highly
expressed in the central nervous system [16].
The activation of those receptors decreases the release
of neurotransmitters glutamate, gamma-aminobutyric acid
(GABA), serotonin and norepinephrine and provides synaptic
control of upstream neurotransmission [17-19].
CBD acts on several other receptor types. Those include
receptors of the serotonin system 5HT 1A/2A/3A, glutamate,
TRPV-a (vanilloid) receptors, agonist activity on alpha-1 adr-
energic receptors as well as mu-opioid receptors [20].
In addition, CBD acts on the adenosine levels by reducing
the adenosine reuptake, which has been associated with neuro-
protection and anti-inammatory processes in the brain [21].
CBD also acts directly on the cerebral vasculature by in-
hibiting the nitric oxide synthase protein expression as well
as inhibition of calcium transport across membranes. Through
this mechanism it causes vasodilatation [22].
CBD has shown in vitro studies to be a potent inhibitor
with cytochrome P450 enzymes such as CYP1A2, CYP2B6,
CYP2C9, CYP2D6 and CYP3A4 [23-36]. These enzymes are
also responsible for the metabolization of various other med-
ications. Therefore, CBD will most likely interfere with the
serum levels of other medications such as antibiotics, antip-
sychotics, antidepressants and blood thinners as well as many
more. Studies about these interactions are yet lacking. The in-
teractions with CBD and other medications are summarized in
Table 1 [23-36].
Lethality Risk
It is possible to ingest quantities of CBD that will cause a fatal
overdose but very large doses are required for that to occur
in human [36]. The toxicity levels for CBD can be found in
the federal government’s Toxicology Data Network [36]. The
lethality risk with toxic substances is usually measured in the
LD50 which is the amount of substance needed to kill 50% of
the population [37].
There are three studies citied regarding the LD50 deter-
mination of CBD [37-12]: 1) In 1946, the LD50 for CBD in
dogs was determined to be greater than 254 mg per kg of body
weight, when administered intravenously. 2) In 1975, an LD50
was established in mice at 50 mg per kg of body weight, when
administered intravenously. 3) In 1981, a report in Toxicol-
ogy and Applied Pharmacology showed the LD50 for CBD to
be 212 mg per kg of body weight when administered intrave-
nously in monkeys.
More recently, a 2011 article in the journal “Current Drug
Safety” observed toxic levels of CBD in rhesus monkeys when
administered orally. Doses over 200 mg per kg of body weight
proved to be fatal in some monkeys by way of respiratory ar-
rest and cardiac failure, while 300 mg per kg of body weight
resulted in “rapid death” [12].
For reference, consider a relatively “average sized” human
at 75 kg (approximately 165 lbs). By these numbers, it would
take roughly 18,750 mg (18.75 g) of CBD consumed within a
very short amount of time to result in any potentially fatal ef-
fects. By comparison, most typical CBD oil users consume no
more than 100 mg of the compound, and that is throughout the
course of an entire day [41].
CBD’s Eect on Medical and Psychiatric Condi-
tions
Table 2 [14, 42-85] gives an overview of the toxic eects of
CBD that are further discussed more in detail.
Some of the listed eects are more acute in nature, and
others are more chronic.
Anaphylaxis and rashes are usually occurring immediately
Figure 1. CBD chemical structure (source: PUBCHEM [9]). CBD: can-
nabidiol. Figure 2. Chemical structure of THC for comparison (source:
PUBCHEM [9]). THC: tetrahydrocannabinol.

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Oberbarnscheidt et al J Clin Med Res. 2020;12(7):393-403
after ingestion. Also, dizziness as well as vomiting, diarrhea
and dry mouth occur shortly after ingestion.
Depending on the route of ingestion, the toxic eects oc-
cur faster with increased bio-availability. The eects on mood
and thoughts as well as sleep and immune-system will be dis-
cussed more in detail below. The toxic eects can occur even
with very small doses of CBD depending on the user’s sensi-
tivity but are more like to occur in higher doses. Users with
impaired liver function are at higher risk to experience toxic
eects than healthy individuals. There are no data available
yet to dierentiate reliably between the risks of dierent age
groups, gender or ethnicity.
Anxiety/post-traumatic stress disorder (PTSD)
Anxiety and PTSD are very common psychiatric disorders in
the US and are associated with substance use. While cannabis
with its THC content has shown to be anxiogenic during in-
toxication as well as withdrawal, CBD has been discussed to
have some anxiolytic potential [42, 43].
In animal studies, the systemic administration of CBD had
caused a decrease in neurons associated with fear (c-Fos posi-
tive neurons) and a direct infusion of CBD in the amygdala
neurons has led to decreased anxiety-related behaviors [44].
Another animal model showed that CBD modies the cerebral
blood ow in brain areas that play a role in anxiety symptoms:
amygdala, hippocampus, hypothalamus as well as cingulate
cortex [45].
Several human studies have shown some positive results
of CBD in anxiety conditions as well. The eect of CBD on
the amygdala was studied in brain imaging studies and showed
a decrease in activation in the amygdala after administration
of CBD [46].
A placebo-controlled study by Crippa et al showed a de-
crease in social anxiety symptoms but also sedation in a small
group of 10 patients receiving CBD. The patients in this clini-
cal study were treatment naive and with 10 participants the
study was small [47].
Another study by Bergamaschi among 24 treatment naive
patients looked at the eect of 600 mg CBD during a public
speaking test and noticed a reduction in anxiety, cognitive im-
pairment as well as discomfort in speech performance [48].
Furthermore, a study by Das et al including 48 healthy
volunteers was evaluated for anxiety provoking electric shock
anticipation and received either pure CBD without THC or
placebo. The results showed that CBD increases extinction
learning which might play a role in therapeutic approaches for
anxiety disorder treatment [49].
The lifetime prevalence for PTSD in the US is about 6.1%
of the population. The treatment has been mostly consistent
of antidepressants as well as Prazosin for nightmares. CBD
has been reported in case-control studies to be benecial for
nightmare symptoms associated with PTSD [50].
In another small study of 11 patients with PTSD, oral
CBD was administered open-labeled and the patient’s PTSD
symptoms were evaluated initially and on consecutive days up
to 8 weeks after utilizing the PCL-5 test and score. Ninety-one
percent of the patients reported a decrease in nightmare symp-
toms. None of the patients reported side eects [51].
However, despite these studies with small patient num-
bers, utilizing the pure form of CBD, there are also several
case reports of CBD-induced anxiety symptoms as a toxic side
eect from the substance.
Table 1. CYP 450 Enzymes and Medication Interaction [23-36]
Enzyme Medication that interacts Eect
CYP3A4 substrate Immunosuppressants, antidepressants, opioids, statins,
benzodiazepines
Increases toxic eects/levels of substrate
CYP3A4 inhibitor Ketoconazole, loperamide, nefazodone, cimetidine, verapamil Increases level/toxicity of CBD
CYP3A4 inducer Phenytoin, topiramate, carbamazepine, rifampicin, efavirenz,
pioglitazone
Decreases bioavailability of CBD
Reduces eect/level of CBD
CYP2C19 substrate Proton pump inhibitor, antidepressants, antiepileptics, clopidogrel,
propranolol, warfarin, cyclophosphamide
Increases toxic eects/level of substrate
CYP2C19 inhibitor Cimetidine, proton pump inhibitors, uvoxamine, clopidogrel,
uconazole
Increases level/toxicity of CBD
CYP2C19 inducer Phenobarbital, phenytoin, St. John’s Wort, rifampicin,
carbamazepine
Decreases bioavailability of CBD
Reduces eect/level of CBD
CYP2C8/9 Buprenorphine, montelukast, celecoxib,
phenobarbital, phenytoin, warfarin, valsartan
Increases toxic eects/levels of substrate
CBD: cannabidiol.
Table 2. List of Toxic Eects From CBD Use [14, 42-85]
Anxiety Depression Suicidal ideation Psychosis Sedation Anaphylaxis Rash
Insomnia Nausea Diarrhea Vomiting Dry mouth Dizziness Infections/immunosuppression
CBD: cannabidiol.

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Impact of CBD on Psychiatry Conditions J Clin Med Res. 2020;12(7):393-403
Depression
As part of CBD’s ability to control the cerebral neurotransmis-
sion of serotonin and norepinephrine and its active binding to
5HT-1 A receptors [17], CBD is thought to also have an eect
on depression. In addition, CBD stimulates the synaptic plas-
ticity and neurogenesis which also plays a role in the develop-
ment and treatment of depression [17-20].
Some animal models have shown some promising results.
A mouse depression model showed signicant antidepressant-
like eect after administration of CBD. The animals showed
increased engagement on pleasurable activities [53].
However, in humans, there are very limited studies avail-
able. In vitro, CBD is found to be a microglial stabilizer which
is similar to the medication lithium which could be benecial
for depression and mood stabilization [54].
In humans, there are only few case studies published of
individual patients with a history of depression who have pre-
viously been on traditional treatment with selective serotonin
reuptake inhibitor (SSRI) who successfully tried CBD prod-
ucts and experienced a signicant improvement in their de-
pressive symptoms [55].
Caution with these studies is warranted. The studies are
utilizing a controlled CBD form without any signicant THC
content, studies have small patient numbers and the follow-up
windows are short. Major toxic eects have been reported with
the use of CBD, being more depressed one of them and even
suicidal ideations [52, 56].
The pack insert of the FDA approved form of CBD Epidi-
olex lists depression and suicidal ideation as a possible ad-
verse reaction. In the largest placebo-controlled clinical trial
among 27,863 patients treated with Epidiolex and 16,029 pa-
tients treated with placebo, the risk of suicidal ideations was
increased 1 in every 530 patient and four suicides occurred in
the Epidiolex treated group versus none in the placebo group
[57].
There are no compatible data available comparing OTC
CBD with placebo regarding increased risk of suicidality.
Psychosis
In studies using animal models for schizophrenia, CBD has
shown to improve psychotic symptoms [58]. Zuardi et al
looked at the eect of CBD on stereotypy induced by dopa-
minergic agonist in rodents and found that CBD decreased
those similarly to haldol [59]. In a mice model, CBD was
compared with haloperidol and clozapine and was found to
be equivalent in inhibition of the hyperlocomotion induced
by amphetamines and ketamines [60]. In comparison to the
conventional medication haloperidol and clozapine, CBD
did not induce any catatonia, not even in doses as high as
480 mg/kg. Most commonly, doses of 120 - 240 mg/kg were
needed to show any eect, which points to a lower potency
of CBD [60].
There are very few and limited studies available in hu-
mans. Boggs et al looked at the eect of CBD at 600 mg in
schizophrenia and reported that the medication was well toler-
ated and did not worsen mood or suicidality but was ineec-
tive in treating cognitive impairment and other neuropsychiat-
ric complications of schizophrenia [61].
Another double-blind, randomized clinical trial compared
CBD with amisulpride and noted similar clinical improvement
with less side eects [62]. In the study, 33 patients with schiz-
ophrenia were followed over a 4-week period and received
either amisulpride or CBD. Both patient groups improved
similarly utilizing the positive and negative syndrome scale
(PANSS) score with some superiority in improvement of the
negative symptoms in the CBD group [62].
Leweke et al conducted a study looking at the eect of
CBD on visual hallucinations induced by nabilone in healthy
volunteers. CBD showed to decrease the degree in visual hal-
lucinations [63]. This study since it uses a synthetic form of
THC to induce psychosis, as well as other research groups, has
raised the questions if CBD might have antagonizing eects to
the negative psychotropic eects of THC and might be poten-
tially protective of the side eects of THC [64].
The study populations in these studies are mostly small
and the follow-up is short or only monitored in a one-time
event. The number of available studies is very limited, and
mostly there are individual case reports published [61, 65-67].
Alzheimer’s disease (AD)
CBD has some pharmacological characteristics that might point
to be benet in the treatment of AD. Libro at al showed that
CBD is able to prevent the development of amyloid plaques in
vitro. The group pre-treated a gingiva tissue sample with CBD
and looked at the change in mesenchymal stem cells, mean-
ing that it could possibly be benecial in the treatment of AD.
Also, CBD regulates the expression of GDK3b a central factor
implemented in the molecular pathogenesis of AD [68].
In animal models, CBD has shown to prevent glutamate-
induced excitotoxicity and to reduce inammatory mediators
and well as reduce lipid peroxidase. In addition, the active
binding to CB2 receptors was causing a down-regulation in
microglial activation in animal in vivo studies. In a mouse
model with hippocampal gliosis induced by injection of hu-
man Aβ-fragment, CBD inhibited the glial cell activation and
proinammatory mediator release in a dose-dependent man-
ner.
In a rat model, CBD stimulated the hippocampal neuro-
genesis which would technically mean that CBD reverses the
disease [69].
In case reports of traumatic brain injuries, CBD has been
found to reduce brain damage after cerebral trauma by im-
proving the metabolic activity [70]. Those ndings have been
conrmed in magnetic resonance imaging (MRI) and positron
emission tomography (PET) studies. Studies are ongoing that
evaluate this eect in persons with high risk concussion rates,
for example, football players.
CBD has been frequently associated with the side eect
of sedation which would be very negative in patients with AD
and lead to other medical complications due to decreased ac-
tivity in this elderly population. More studies need to be done
to show ecacy of CBD in AD or other forms of dementia.

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Oberbarnscheidt et al J Clin Med Res. 2020;12(7):393-403
Epilepsy and seizures
The use of CBD for the treatment of seizures has been re-
searched since the 1970s. Overall the idea is to utilize CBD’s
eect on neuronal hyperactivity which means excessive neu-
ronal ring as it occurs in seizure disorders [72]. The exact
mechanism of CBD’s action on epilepsy is unknown. In vitro,
CBD has shown to decrease epileptiform local eld potentials,
their amplitude and duration [14].
In animal models, predominantly mice, it has shown some
positive eects in few studies but no eect in most others. Stud-
ies performed in rats by Jones et al have shown anticonvulsant
eects in partial pilocarpine and penicillin-induced seizures. In
chronic epilepsy studies in animals have been less optimistic,
showing little to no eect on the seizure activity [73].
In humans, the data are very limited for the natural form of
CBD. The only FDA approved CBD medication for childhood
seizures, Dravet and Lennox-Gastaut syndromes, is Epidi-
olex, which is a synthetic substance with a purity of 98% CBD
and less than 0.15% THC. Dierence to the over-the-counter
(OTC) CBDs is that Epidiolex is showing the same content of
CBD and dose in one unit to the other. The two FDA approved
conditions are both very severe and devastating forms of child-
hood seizures where seizures are most commonly refractory to
traditional pharmaceutical treatment forms and children devel-
op encephalopathy with intellectual disability and neurodevel-
opmental problems early on in their lives [74-77]. Epidiolex is
an FDA approved medication, prescribed by physicians, and
patients will be evaluated and monitored. In contrast this is not
the case with the OTC form of CBD.
Sleep
Researches regarding the eect of CBD on sleep are still in its
infancy. Endocannabinoids have been shown to play a role in
the circadian rhythm, therefore CBD is thought to have an ef-
fect on sleep [78-80].
In animal models, studies have been performed to show
the eect of CBD on the sleep quality as well as the sleep cy-
cle [43]. In rats, studies have shown that high doses of CBD
lead to increased total percentage of sleep. In another rodent
model, high dose CBD led to increased rapid eye movement
(REM) sleep latency, while the low dose CBD showed a de-
crease with no eect shown on the non-rapid eye movement
(NREM) sleep [78].
Only few and small numbered human studies are avail-
able to show the eect of CBD on sleep. The sedating eect of
CBD appears to be dose dependent. Low dose of CBD has been
found to be more stimulating, while higher doses have a sedat-
ing eect. Two studies by Nicholson and Zuadi et al showed
that a CBD dose of 160 mg/day to increase sleep time in per-
sons suering insomnia as well as decrease nightly arousals
while a lower dose again showed increased wakefulness [79,
80]. Basic research in humans showed an overall increase in
the total amount of sleep with several sleep disorders [79, 80].
There are no data available yet to show the eects of CBD
abstinence syndrome on sleep as it is described with THC to
cause prolonged insomnia as a symptom or prolonged with-
drawal [81]. Long-term and chronic use for insomnia bears the
risk for development of dependence to CBD.
Huntington’s disease
From pre-clinical studies, CBD is discussed to have protec-
tive eects against striatal degeneration [82]. In animal stud-
ies CBD has shown promising capabilities to reduce striatal
dopamine hypersensitivity which is mediating chorea [83, 84].
This has been shown predominantly in rats. CBD also reduced
the aggressive behaviors in rats treated with neurotoxin L-py-
roglutamate which is one possible pathophysiological model
for the aggressive behaviors seen in Huntington’s disease [83].
A genetic mouse model has shown neuroprotective prop-
erties of CBD towards the striatal degeneration through selec-
tive binding to CB2 receptors [84].
Few clinical studies have looked at the eect of CBD on
Huntington’s disease and not shown benecial value in the me-
dicinal properties of CBD in the treatment of this devastating
disease [85].
A study done by Consroe et al compared CBD versus pla-
cebo. The group used a mean dose of 700 mg CBD daily on 15
patients with Huntington’s disease. The group did not nd any
signicant dierence in chorea severity, side eects and lab
tests after 6 weeks of treatment [85].
Pain
CBD is commonly used for pain without any scientic evi-
dence nor FDA approval. Preclinical studies have proposed hat
CBD might be useful in the treatment of chronic pain condi-
tions [86].
However, clinical studies have been unconvincing so far.
In Naftali’s study, CBD at 10 mg per day dose was shown inef-
fective in the treatment of Chron’s disease [87]. Also, another
study by Ben showed that CBD was ineective at 40 mg per
day dose in the treatment of chronic neuropathic pain. Other
people suggested CBD to be useful in the treatment of cancer
pain but studies supporting this statement are yet to be done
[88]. None of the available studies are long-term and show-
ing relevant benecial clinical eect to advocate for the use of
CBD in pain conditions.
Opioid use disorder (OUD)
In the US approximately 2.5 million people have been diag-
nosed with an OUD and about 80 people each day die of over-
dose. OUD is a burden for each individual person, their fami-
lies and the society. The annual costs associated with OUD are
estimated 78 billon US dollars [1].
The conventional medication assisted treatments available
for OUD including methadone, buprenorphine as well as nal-
trexone, have been of value but also associated with their own
challenges. Those medications are regulated and require the

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Impact of CBD on Psychiatry Conditions J Clin Med Res. 2020;12(7):393-403
person to be enrolled in a treatment program, which is time-
consuming and associated with a negative stigma. This bears
grounds to investigate for alternatives, easier accessible and
less controlled treatment options for OUD [89].
Blogs on the internet are attracting an increasing num-
ber of people with OUD and discuss the use of CBD during
withdrawal as well as ongoing maintenance treatment. CBD is
advertised as safe and with low lethality even in combination
with strong opioid agonists [90].
In animal studies, CBD has been shown to reduce the
rewarding eects of opioids and it also reduces the heroin-
seeking behaviors. CBD acts on the same receptors that heroin
does and antagonizes the heroin’s eect on CB1 and glutamate
receptors [91].
The data from Colorado are concerning, with the increased
use of CBs and THC, there has been a corresponding increase
in opioid use and no decrease in opioid use since the legaliza-
tion [92, 93].
However, there are only limited case reports available in
humans regarding the use of CBD in OUD or small numbered
clinical studies that are not allowing a broad statement regard-
ing CBD’s ecacy in the treatment of OUD.
The treatment of OUD with CBD bears particularly a risk,
as the amount of CBD taken is not dosed in a controlled setting
and for someone who has lost control over a substance prior
might have diculties dosing CBD as well.
CBD and addiction
CBD is unlike THC not binding to the cerebral CB1 receptor
which is responsible for the rewarding eects of cannabis in
its natural form and for the feeling of euphoria. Many articles
state that CBD is a non-psycho-active substance [3-5]. How-
ever, it must have some degree of psycho-activity if it alters
people’s mood, anxiety as well as cognition.
As with many other substances listed in the DSM V for
substance use disorders, it is also possible with CBD to experi-
ence a loss of control and a compulsive use. Even though the
risk of lethality is very low, it does not mean it is impossible to
become addicted to the substance [37, 38, 94].
Withdrawal symptoms are not well described in the lit-
erature but however, most likely a person who takes CBD
regularly for insomnia, will experience rebound insomnia if
he stops [81].
Similar exacerbating eects are to be expected when CBD
is no longer taken for depression or anxiety [12, 42]. Studies
about the withdrawal symptoms from CBD and their course
are yet to be published. Only case reports exist.
Federal regulation
Under Federal Law, marijuana is still listed as a schedule I
substance which means that the substance is not accepted for
medical use and has a high potential for abuse. In comparison,
cocaine is a schedule II substance since it is used as an anes-
thetic medically [95].
The Drug Enforcement Administration (DEA) has specic
criteria for a drug to be considered a medication [3, 6]: 1) The
drugs chemistry must be known and reproducible; 2) The drug
must have shown ecacy in well-controlled clinical study; 3)
The drug must have shown safety; 4) It must be accepted by
qualied experts and scientic evidence must be widely avail-
able.
CBD falls under the regulation of the “Farm Bill” (the ag-
riculture improvement act of 2018, Pub. L. 115-334) which
was signed in December 2018. This bill denes hemp as the
cannabis plant, any part of it including extracts and cannabi-
noids with a THC concentration of less than 0.3% dry weight.
“Hemp” was removed from the controlled substance act under
federal law and is federally not considered a controlled sub-
stance [95, 96].
Especially problematic is the purity of the content that can
be purchased currently. The requirements for quality control as
well as labeling vary signicantly from state to state. For ex-
ample, California requires laboratory testing for medical and
recreational cannabis and cannabis products while other states,
for example, Arizona, do not mandate any laboratory testing
[97, 98].
Over the last several years, including 2019, the FDA has
issued several warning letters about unapproved new drugs on
the market that allegedly contain CBD. The FDA had tested
the content of these products and found a discrepancy of the
claimed ingredients on the label and the actual content. Ninety
percent of the tested CBD products contained much less CBD
that what was posted on the label or no CBD at all, but the ma-
jority of tested products did contain a greater content of THC
than claimed [99-103].
The FDA explicitly writes on their webpage that these prod-
ucts are not FDA approved for the diagnosis, cure, mitigation,
treatment, or prevention of any disease and warns customers to
beware purchasing or using any such products [37, 38].
The FDA further states that no food products can enter
inter-state commerce and that CBD is not a safe food additive.
CBD and other CBD or cannabis derived products should not
be considered as dietary supplements as they contain pharma-
cologically active ingredients. Also, the FDA warns about the
various dosing contents as there have been potentially toxic
doses reported in certain food, for example, gummi bears con-
taining 1,500 mg of CBD [37, 38].
Discussion
The interest in cannabis products and CBD has exploded na-
tionally over the last decade and the current trend is to legalize
marijuana and make CBD available without strict regulations
or control to the general public. CBD can nowadays be pur-
chased online, in natural food stores, pet stores or retail out-
let without a physician prescription despite claims for use in
medical conditions.
Cannabis and CBD are almost seen as a “wonder drug” in
the eye of the general public and claimed to help with condi-
tions that are dicult to treat with established medications:
AIDS, multiple sclerosis (MS), amyotrophic lateral sclerosis

Articles © The authors | Journal compilation © J Clin Med Res and Elmer Press Inc™ | www.jocmr.org 399
Oberbarnscheidt et al J Clin Med Res. 2020;12(7):393-403
(ALS), Huntington’s disease and might also mirror some mis-
trust and frustration in the medications that are currently avail-
able as FDA approved medications.
In the case of OUD treatment, people might try to use
CBD to avoid being associated with the stigma of treatment
for OUD. Buprenorphine and methadone clinics are still seen
with some degree of negative stigma even amongst physicians.
Aected people try to self-treat with other substances and con-
sult blogs on the internet rather than professional treatment.
There are also cases reported of CBD use for other use disor-
der for example alcohol or tobacco. The use of CBD in these
cases bears the risk of potentially developing a new addiction
or dependence in the process of substituting one drug with an-
other. Data from Colorado since legalization are alarming and
pointing to an increase of opioid use since the increased use
of CBs and since legalization of marijuana. Well-established
treatments for OUDs are available and should be preferred and
advertised.
CBD might have some medicinal value, but main prob-
lem is that there is little established research nor control or
regulation over the CBD product and people do not know what
they are getting when they purchase CBD. CBD products vary
highly in compositions and concentrations even from one unit
to the other. The FDA issued warning letters about CBD prod-
ucts being falsely labeled and distributed.
The THC content is legally limited to be less than 0.3%
but the reality shows that CBD products often contain higher
amounts of THC and therefore the user gets put at risk to ex-
perience all the toxic side eects that are associated with mari-
juana and THC. The list of those toxic side eects includes at-
tention-decit/hyperactivity disorder (ADHD) like symptoms,
cognitive impairment, aggression, behavior changes, paranoia,
depression, anxiety, cancers and more.
The studies looking at the clinical eect of CBD on certain
psychiatric and medical conditions utilize pure forms of CBD
that had prior been tested of its contents for its ingredients and
concentration, but this is not the form that the general public
purchases in a convenience store.
The only form that is FDA approved CBD product that
is considered a medication is the Epidiolex. The dierence in
calling it a “medication” is that one unit is consistent with the
next and that it contains always the same dose. For OTC CBD
this is not the case, the content varies as well as the psychoac-
tive eect.
Given the inconsistency in the OTC CBD product, there
are no dosing recommendations available for each claimed
condition and they are not prescribed like a FDA approved
medication and there is no physician follow-up.
Also, the use of CBD bears a risk for the user to develop
toxic side eects from other medications that they are taking
as prescribed as those might develop higher serum concentra-
tions through the interaction of CBD with several CYP P 450
enzymes.
Persons with organ transplants are at risk of increased tox-
ic eects from their immunosuppressant which might lead to
organ failure, toxic levels of anticoagulants might lead to acute
bleeding, and someone who is prescribed suboxone might ex-
perience sedation or respiratory depression even though he/she
was previously on a stable dose.
After reviewing the literature, CBD is claimed as a psy-
choactive substance with eects on mood and behaviors and
therefore bears the risk to develop an addiction.
Long-term studies in larger patient cohorts are needed to
investigate the addictive potential of CBD.
Conclusion
More studies need to be done in humans in a controlled setting
to determine the medicinal value of CBD for various diagnoses
in order to be able to make clear recommendations.
Preclinical studies have shown some promising data re-
garding the medicinal value of CBD but studies in human are
not consistent in outcome and controversial in their design.
More studies need to be performed in human with larger sam-
ple sizes and longer follow-up periods.
Dosing guidelines for CBD need to be established for dif-
ferent indications and follow-up with a physician. The current
situation, where the user does not know what they are actually
getting in the product, makes CBD unsafe and the risk out-
weighs the benet of recommending or using that substance.
Especially the content of CBD needs to be under stricter regu-
lations with lab monitoring to determine and guarantee a par-
ticular dose or content or CBD and to exclude a higher content
of THC than the 0.3% that are allowed by law. Currently there
is no consistency in the content of the CBD product.
It is dangerous to assume that the CBD is a “miracle drug”
without any safety concerns given the list of potential toxic
reactions. Particularly the sedating eect appears to be con-
cerning and limiting in its use.
Cross-interactions with other medications need to be in-
vestigated to rule out toxicity in co-morbid patients taken nu-
merous prescribed medications.
A possible development of an addictive disorder to CBD
can from the current knowledge not be excluded and further
data on long-term administration, the eects of tolerance and
toxicity with administration of higher doses need to be investi-
gated. From experience, if a substance is used over a prolonged
period of time, there is a process of habituation involved and
consecutively an increase in consumption of the substance.
Also, the claimed absence of psycho-active eects and ab-
sence of withdrawal symptoms upon discontinuation of CBD
is from current point of view, subject to speculation.
The current trend of decriminalization of marijuana and its
products bear the risk to further increase the CBD consump-
tion with associated increase in health problems, violence,
criminality and lethality.
Acknowledgments
None to declare.
Financial Disclosure
None to declare.

Articles © The authors | Journal compilation © J Clin Med Res and Elmer Press Inc™ | www.jocmr.org
400
Impact of CBD on Psychiatry Conditions J Clin Med Res. 2020;12(7):393-403
Conict of Interest
There is no conict of interest.
Author Contributions
Thersilla Oberbarnscheidt contributed to the writing of article
and literature research. Norman Miller contributed to research
and editing of article.
Data Availability
The authors declare that data supporting the ndings of this
study are available within the article.
References
1. Oce of the Surgeon General Facing Addiction in Amer-
ica: The Surgeon General's Report on Alcohol, Drugs,
and Health. U.S. Department of Health and Human Ser-
vices (HHS), Oce of the Surgeon General; 2016.
2. FDA 2016. Botanical drug development guidance for
industry. Available at: https://www.fda.gov/downloads/
Drugs/Guidances/UCM458484.pdf.
3. Grotenhermen F, Russo E. Cannabis and Cannabinoids:
pharmacology, toxicology, and therapeutic potential.
New York: Haworth press Inc; 2008.
4. Devinsky O, Cilio MR, Cross H, Fernandez-Ruiz J,
French J, Hill C, Katz R, et al. Cannabidiol: pharmacol-
ogy and potential therapeutic role in epilepsy and other
neuropsychiatric disorders. Epilepsia. 2014;55(6):791-
802.
5. Zhornitsky S, Potvin S. Cannabidiol in humans-the
quest for therapeutic targets. Pharmaceuticals (Basel).
2012;5(5):529-552.
6. https://www.federalregister.gov/documents/2016/12/14/2
016-29941/ establishment-of-a-new-drug-code-for-marih
uana-extract.
7. Azer V, et al. Cowen's collective view of CBD. Cowen's
Research. Available online: https://www.cowen.com/re-
ports/cowen-collective-view-of-cbd/.
8. Bonaccorso S, Ricciardi A, Zangani C, Chiappini S, Schi-
fano F. Cannabidiol (CBD) use in psychiatric disorders: a
systematic review. Neurotoxicology. 2019;74:282-298.
9. Gaoni Y, Hashish MR. VII The isomerization of canna-
bidiol to tetrahydrocannabinols. Tetrahedron. 1996;22(4).
10. Lafaye G, Karila L, Blecha L, Benyamina A. Canna-
bis, cannabinoids, and health. Dialogues Clin Neurosci.
2017;19(3):309-316.
11. Agurell S, Halldin M, Lindgren JE, Ohlsson A, Wid-
man M, Gillespie H, Hollister L. Pharmacokinetics and
metabolism of delta 1-tetrahydrocannabinol and other
cannabinoids with emphasis on man. Pharmacol Rev.
1986;38(1):21-43.
12. Bergamaschi MM, Queiroz RH, Zuardi AW, Crippa JA.
Safety and side eects of cannabidiol, a Cannabis sativa
constituent. Curr Drug Saf. 2011;6(4):237-249.
13. Guy GW, Whittle BA, Robson P. The Medicinal uses of
cannabis and cannabinoids. TJ International: Cronwall,
UK. 2004.
14. Cunha JM, Carlini EA, Pereira AE, Ramos OL, Pimentel
C, Gagliardi R, Sanvito WL, et al. Chronic administra-
tion of cannabidiol to healthy volunteers and epileptic
patients. Pharmacology. 1980;21(3):175-185.
15. Rabgay K, Waranuch N, Chaiyakunapruk N, Sawangjit
R, Ingkaninan K, Dilokthornsakul P. The eects of can-
nabis, cannabinoids, and their administration routes on
pain control ecacy and safety: A systematic review
and network meta-analysis. J Am Pharm Assoc (2003).
2020;60(1):225-234 e226.
16. Pertwee RG. The diverse CB1 and CB2 receptor pharma-
cology of three plant cannabinoids: delta9-tetrahydrocan-
nabinol, cannabidiol and delta9-tetrahydrocannabivarin.
Br J Pharmacol. 2008;153(2):199-215.
17. Russo EB, Burnett A, Hall B, Parker KK. Agonistic prop-
erties of cannabidiol at 5-HT1a receptors. Neurochem
Res. 2005;30(8):1037-1043.
18. Pertwee RG, Ross RA, Craib SJ, Thomas A. -)-Canna-
bidiol antagonizes cannabinoid receptor agonists and no-
radrenaline in the mouse vas deferens. Eur J Pharmacol.
2002;456(1-3):99-106.
19. Bisogno T, Hanus L, De Petrocellis L, Tchilibon S, Pon-
de DE, Brandi I, Moriello AS, et al. Molecular targets
for cannabidiol and its synthetic analogues: eect on
vanilloid VR1 receptors and on the cellular uptake and
enzymatic hydrolysis of anandamide. Br J Pharmacol.
2001;134(4):845-852.
20. De Petrocellis L, Ligresti A, Moriello AS, Allara M,
Bisogno T, Petrosino S, Stott CG, et al. Eects of can-
nabinoids and cannabinoid-enriched Cannabis extracts on
TRP channels and endocannabinoid metabolic enzymes.
Br J Pharmacol. 2011;163(7):1479-1494.
21. Ross HR, Napier I, Connor M. Inhibition of recom-
binant human T-type calcium channels by Delta9-
tetrahydrocannabinol and cannabidiol. J Biol Chem.
2008;283(23):16124-16134.
22. Ahrens J, Demir R, Leuwer M, de la Roche J, Kramp K,
Foadi N, Karst M, et al. The nonpsychotropic cannabi-
noid cannabidiol modulates and directly activates alpha-1
and alpha-1-Beta glycine receptor function. Pharmacol-
ogy. 2009;83(4):217-222.
23. Brown AJ. Novel cannabinoid receptors. Br J Pharmacol.
2007;152(5):567-575.
24. Zanger UM, Schwab M. Cytochrome P450 enzymes in
drug metabolism: regulation of gene expression, enzyme
activities, and impact of genetic variation. Pharmacol
Ther. 2013;138(1):103-141.
25. Stott C, White L, Wright S, Wilbraham D, Guy G. A Phase
I, open-label, randomized, crossover study in three paral-
lel groups to evaluate the eect of Rifampicin, Ketocona-
zole, and Omeprazole on the pharmacokinetics of THC/
CBD oromucosal spray in healthy volunteers. Springer-
plus. 2013;2(1):236.
26. Gerey AL, Pollack SF, Bruno PL, Thiele EA. Drug-drug

Articles © The authors | Journal compilation © J Clin Med Res and Elmer Press Inc™ | www.jocmr.org 401
Oberbarnscheidt et al J Clin Med Res. 2020;12(7):393-403
interaction between clobazam and cannabidiol in children
with refractory epilepsy. Epilepsia. 2015;56(8):1246-
1251.
27. Gaston TE, Bebin EM, Cutter GR, Liu Y, Szaar-
ski JP, Program UC. Interactions between cannabidiol
and commonly used antiepileptic drugs. Epilepsia.
2017;58(9):1586-1592.
28. Jiang R, Yamaori S, Okamoto Y, Yamamoto I, Watanabe
K. Cannabidiol is a potent inhibitor of the catalytic activ-
ity of cytochrome P450 2C19. Drug Metab Pharmacoki-
net. 2013;28(4):332-338.
29. Yamaori S, Okamoto Y, Yamamoto I, Watanabe K.
Cannabidiol, a major phytocannabinoid, as a potent
atypical inhibitor for CYP2D6. Drug Metab Dispos.
2011;39(11):2049-2056.
30. Yamaori S, Kushihara M, Yamamoto I, Watanabe K.
Characterization of major phytocannabinoids, canna-
bidiol and cannabinol, as isoform-selective and potent in-
hibitors of human CYP1 enzymes. Biochem Pharmacol.
2010;79(11):1691-1698.
31. Yamaori S, Okushima Y, Yamamoto I, Watanabe K.
Characterization of the structural determinants required
for potent mechanism-based inhibition of human cyto-
chrome P450 1A1 by cannabidiol. Chem Biol Interact.
2014;215:62-68.
32. Yamaori S, Koeda K, Kushihara M, Hada Y, Yamamoto
I, Watanabe K. Comparison in the in vitro inhibitory ef-
fects of major phytocannabinoids and polycyclic aromat-
ic hydrocarbons contained in marijuana smoke on cyto-
chrome P450 2C9 activity. Drug Metab Pharmacokinet.
2012;27(3):294-300.
33. Yamaori S, Ebisawa J, Okushima Y, Yamamoto I, Wa-
tanabe K. Potent inhibition of human cytochrome P450
3A isoforms by cannabidiol: role of phenolic hydroxyl
groups in the resorcinol moiety. Life Sci. 2011;88(15-
16):730-736.
34. Arnold WR, Weigle AT, Das A. Cross-talk of cannabinoid
and endocannabinoid metabolism is mediated via human
cardiac CYP2J2. J Inorg Biochem. 2018;184:88-99.
35. Zhou ZW, Chen XW, Sneed KB, Yang YX, Zhang X,
He ZX, Chow K, et al. Clinical association between
pharmacogenomics and adverse drug reactions. Drugs.
2015;75(6):589-631.
36. Van Driest SL, Shi Y, Bowton EA, Schildcrout JS, Pe-
terson JF, Pulley J, Denny JC, et al. Clinically action-
able genotypes among 10,000 patients with preemp-
tive pharmacogenomic testing. Clin Pharmacol Ther.
2014;95(4):423-431.
37. Federal Government Toxicology Data Network (https://
toxnet.nlm.nih.gov).
38. Current Drug Safety. https://www.medicinalgenomics.
com/wpcontent/uploads/2013/01/Bergamaschi_2011.pdf.
39. WHO. CANNABIDIOL (CBD). Critical review report.
Expert Committee on Drug Dependence Fortieth Meet-
ing. Geneva, June 4-7, 2018.
40. Ibeas Bih C, Chen T, Nunn AV, Bazelot M, Dallas M,
Whalley BJ. Molecular Targets of Cannabidiol in Neu-
rological Disorders. Neurotherapeutics. 2015;12(4):699-
730.
41. Iand K, Grotenhermen F. An update on safety and
side eects of cannabidiol: a review of clinical data and
relevant animal studies. Cannabis Cannabinoid Res.
2017;2(1):139-154.
42. Blessing EM, Steenkamp MM, Manzanares J, Marmar
CR. Cannabidiol as a potential treatment for anxiety dis-
orders. Neurotherapeutics. 2015;12(4):825-836.
43. Hsiao YT, Yi PL, Li CL, Chang FC. Eect of cannabidiol
on sleep disruption induced by the repeated combination
tests consisting of open eld and elevated plus-maze in
rats. Neuropharmacology. 2012;62(1):373-384.
44. Zuardi AW, Cosme RA, Grae FG, Guimaraes FS. Ef-
fects of ipsapirone and cannabidiol on human experimen-
tal anxiety. J Psychopharmacol. 1993;7(1 Suppl):82-88.
45. Crippa JA, Zuardi AW, Garrido GE, Wichert-Ana L,
Guarnieri R, Ferrari L, Azevedo-Marques PM, et al. Ef-
fects of cannabidiol (CBD) on regional cerebral blood
ow. Neuropsychopharmacology. 2004;29(2):417-426.
46. Fusar-Poli P, Crippa JA, Bhattacharyya S, Borgwardt SJ,
Allen P, Martin-Santos R, Seal M, et al. Distinct eects of
{delta}9-tetrahydrocannabinol and cannabidiol on neural
activation during emotional processing. Arch Gen Psy-
chiatry. 2009;66(1):95-105.
47. Crippa JA, Derenusson GN, Ferrari TB, Wichert-Ana L,
Duran FL, Martin-Santos R, Simoes MV, et al. Neural ba-
sis of anxiolytic eects of cannabidiol (CBD) in general-
ized social anxiety disorder: a preliminary report. J Psy-
chopharmacol. 2011;25(1):121-130.
48. Bergamaschi MM, Queiroz RH, Chagas MH, de Oliveira
DC, De Martinis BS, Kapczinski F, Quevedo J, et al. Can-
nabidiol reduces the anxiety induced by simulated public
speaking in treatment-naive social phobia patients. Neu-
ropsychopharmacology. 2011;36(6):1219-1226.
49. Das RK, Kamboj SK, Ramadas M, Yogan K, Gupta V,
Redman E, Curran HV, et al. Cannabidiol enhances con-
solidation of explicit fear extinction in humans. Psychop-
harmacology (Berl). 2013;226(4):781-792.
50. Zuardi AW, Shirakawa I, Finkelfarb E, Karniol IG. Action
of cannabidiol on the anxiety and other eects produced
by delta 9-THC in normal subjects. Psychopharmacology
(Berl). 1982;76(3):245-250.
51. Campos AC, Guimaraes FS. Activation of 5HT1A recep-
tors mediates the anxiolytic eects of cannabidiol in a
PTSD model. Behav Pharmacol. 2009;(20):S54.
52. Brown JD, Winterstein AG. Potential adverse drug events
and drug-drug interactions with medical and consumer
cannabidiol (CBD) use. Journal of Clinical Medicine.
2019;(8):989.
53. Xu C, Chang T, Du Y, Yu C, Tan X, Li X. Pharmacoki-
netics of oral and intravenous cannabidiol and its antide-
pressant-like eects in chronic mild stress mouse model.
Environ Toxicol Pharmacol. 2019;70:103202.
54. Rock EM, Bolognini D, Limebeer CL, Cascio MG, Ana-
vi-Goer S, Fletcher PJ, Mechoulam R, et al. Cannabidi-
ol, a non-psychotropic component of cannabis, attenuates
vomiting and nausea-like behaviour via indirect agonism
of 5-HT(1A) somatodendritic autoreceptors in the dorsal
raphe nucleus. Br J Pharmacol. 2012;165(8):2620-2634.
55. Hegazy O, Platnick H. Cannabidiol (CBD) for Treatment

Articles © The authors | Journal compilation © J Clin Med Res and Elmer Press Inc™ | www.jocmr.org
402
Impact of CBD on Psychiatry Conditions J Clin Med Res. 2020;12(7):393-403
of Neurobromatosis-related Pain and Concomitant Mood
Disorder: A Case Report. Cureus. 2019;11(12):e6312.
56. van Ours JC, Williams J, Fergusson D, Horwood LJ.
Cannabis use and suicidal ideation. J Health Econ.
2013;32(3):524-537.
57. EPIDIOLEX Cannabidiol prescribing Information. Avail-
able online at: https://www.epidiolex.com.
58. Rohleder C, Muller JK, Lange B, Leweke FM. Canna-
bidiol as a potential new type of an antipsychotic. a criti-
cal review of the evidence. Front Pharmacol. 2016;7:422.
59. Zuardi AW, Rodrigues JA, Cunha JM. Eects of canna-
bidiol in animal models predictive of antipsychotic activ-
ity. Psychopharmacology (Berl). 1991;104(2):260-264.
60. Moreira FA, Guimaraes FS. Cannabidiol inhibits the
hyperlocomotion induced by psychotomimetic drugs in
mice. Eur J Pharmacol. 2005;512(2-3):199-205.
61. Zuardi AW, Hallak JE, Dursun SM, Morais SL, Sanches
RF, Musty RE, Crippa JA. Cannabidiol monotherapy for
treatment-resistant schizophrenia. J Psychopharmacol.
2006;20(5):683-686.
62. Leweke FM, Koethe D, Gerth CW, et al. Cannabidiol as
an antipsychotic. A double-blind, controlled clinical trial
on cannabidiol vs amisulpride in acute schizophrenia. Eur
Psychiatry. 2007;22:S14.02.
63. Leweke FM, Koethe D, Pahlisch F, Schreiber D, Gerth
CW, Nolden BM, Klosterkotter J, et al. S39-02 An-
tipsychotic eects of cannabidiol. Eur. Psychiatry.
2009;24:S207.
64. Bhattacharyya S, Morrison PD, Fusar-Poli P, Martin-
Santos R, Borgwardt S, Winton-Brown T, Nosarti C, et
al. Opposite eects of delta-9-tetrahydrocannabinol and
cannabidiol on human brain function and psychopathol-
ogy. Neuropsychopharmacology. 2010;35(3):764-774.
65. Zuardi AW, Morais SL, Guimaraes FS, Mechoulam R.
Antipsychotic eect of cannabidiol. J Clin Psychiatry.
1995;56(10):485-486.
66. Zuardi AW, Crippa JA, Hallak JE, Pinto JP, Chagas MH,
Rodrigues GG, Dursun SM, et al. Cannabidiol for the
treatment of psychosis in Parkinson's disease. J Psychop-
harmacol. 2009;23(8):979-983.
67. Hallak JE, Machado-de-Sousa JP, Crippa JA, Sanches
RF, Trzesniak C, Chaves C, Bernardo SA, et al. Per-
formance of schizophrenic patients in the Stroop Color
Word Test and electrodermal responsiveness after acute
administration of cannabidiol (CBD). Braz J Psychiatry.
2010;32(1):56-61.
68. Libro R, Diomede F, Scionti D, Piattelli A, Grassi G,
Pollastro F, Bramanti P, et al. Cannabidiol modulates the
expression of Alzheimer's disease-related genes in mes-
enchymal stem cells. Int J Mol Sci. 2016;18(1).
69. Wolf SA, Bick-Sander A, Fabel K, Leal-Galicia P, Tauber
S, Ramirez-Rodriguez G, Muller A, et al. Cannabinoid
receptor CB1 mediates baseline and activity-induced sur-
vival of new neurons in adult hippocampal neurogenesis.
Cell Commun Signal. 2010;8:12.
70. Campos AC, Fogaca MV, Scarante FF, Joca SRL, Sales
AJ, Gomes FV, Sonego AB, et al. Plastic and neuropro-
tective mechanisms involved in the therapeutic eects of
cannabidiol in psychiatric disorders. Front Pharmacol.
2017;8:269.
71. Izquierdo I, Orsingher OA, Berardi AC. Eect of canna-
bidiol and of other cannabis sativa compounds on hip-
pocampal seizure discharges. Psychopharmacologia.
1973;28(1):95-102.
72. Carlini EA, Leite JR, Tanhauser M, Berardi AC. Can-
nabidiol and Cannabis sativa extract protect mice and
rats against convulsive agents. J Pharm Pharmacol.
1973;25:664-665.
73. Do Val-da Silva RA, Peixoto-Santos JE, Kandratavicius
L, De Ross JB, Esteves I, De Martinis BS, Alves MN, et
al. Protective eects of cannabidiol against seizures and
neuronal death in a rat model of mesial temporal lobe epi-
lepsy. Front Pharmacol. 2017;8:131.
74. Devinsky O, Marsh E, Friedman D, Thiele E, Laux L,
Sullivan J, Miller I, et al. Cannabidiol in patients with
treatment-resistant epilepsy: an open-label interventional
trial. Lancet Neurol. 2016;15(3):270-278.
75. Nabbout R, Thiele EA. The role of cannabinoids in epi-
lepsy treatment: a critical review of ecacy results from
clinical trials. Epileptic Disord. 2020;22(S1):23-28.
76. Devinsky O, Cross JH, Laux L, Marsh E, Miller I, Nab-
bout R, Scheer IE, et al. Trial of cannabidiol for drug-
resistant seizures in the dravet syndrome. N Engl J Med.
2017;376(21):2011-2020.
77. Thiele EA, Marsh ED, French JA, Mazurkiewicz-Beldz-
inska M, Benbadis SR, Joshi C, Lyons PD, et al. Can-
nabidiol in patients with seizures associated with Len-
nox-Gastaut syndrome (GWPCARE4): a randomised,
double-blind, placebo-controlled phase 3 trial. Lancet.
2018;391(10125):1085-1096.
78. Chagas MH, Crippa JA, Zuardi AW, Hallak JE, Machado-
de-Sousa JP, Hirotsu C, Maia L, et al. Eects of acute sys-
temic administration of cannabidiol on sleep-wake cycle
in rats. J Psychopharmacol. 2013;27(3):312-316.
79. Nicholson AN, Turner C, Stone BM, Robson PJ. Eect
of Delta-9-tetrahydrocannabinol and cannabidiol on noc-
turnal sleep and early-morning behavior in young adults.
J Clin Psychopharmacol. 2004;24(3):305-313.
80. Zuardi AW. Cannabidiol: from an inactive cannabinoid to
a drug with wide spectrum of action. Braz J Psychiatry.
2008;30(3):271-280.
81. Budney AJ, Moore BA, Vandrey RG, Hughes JR. The
time course and signicance of cannabis withdrawal.
J Abnorm Psychol. 2003;112(3):393-402.
82. Sagredo O, Pazos MR, Satta V, Ramos JA, Pertwee RG,
Fernandez-Ruiz J. Neuroprotective eects of phytocan-
nabinoid-based medicines in experimental models of
Huntington's disease. J Neurosci Res. 2011;89(9):1509-
1518.
83. Consroe P, Musty R, Conti L. Eects of cannabidiol in
animal mdodels of neurologic dysfunction. An interna-
tional research report. National campaign against drug
abuse monograph series no.7. Canberra: Australian Gov-
ernment Publishing Service. 1988:147-152.
84. Campos AC, Ortega Z, Palazuelos J, Fogaca MV, Aguiar
DC, Diaz-Alonso J, Ortega-Gutierrez S, et al. The anxio-
lytic eect of cannabidiol on chronically stressed mice
depends on hippocampal neurogenesis: involvement of

Articles © The authors | Journal compilation © J Clin Med Res and Elmer Press Inc™ | www.jocmr.org 403
Oberbarnscheidt et al J Clin Med Res. 2020;12(7):393-403
the endocannabinoid system. Int J Neuropsychopharma-
col. 2013;16(6):1407-1419.
85. Consroe P, Laguna J, Allender J, Snider S, Stern L,
Sandyk R, Kennedy K, et al. Controlled clinical trial of
cannabidiol in Huntington's disease. Pharmacol Biochem
Behav. 1991;40(3):701-708.
86. Ferguson G, Ware M. Review article: sleep, pain
and cannabis. Journal of Sleep Disorders & Therapy.
2015;4(2):191.
87. Naftali T, Bar-Lev Schleider L, Dotan I, Lansky EP,
Sklerovsky Benjaminov F, Koniko FM. Cannabis in-
duces a clinical response in patients with Crohn's disease:
a prospective placebo-controlled study. Clin Gastroen-
terol Hepatol. 2013;11(10):1276-1280 e1271.
88. Chakravarti B, Ravi J, Ganju RK. Cannabinoids as thera-
peutic agents in cancer: current status and future implica-
tions. Oncotarget. 2014;5(15):5852-5872.
89. https://store.samhsa.gov/system/les/pep15-fedguideotp.
pdf. Federal guidelines for opioid treatment programs.
90. Wiese B, Wilson-Poe AR. Emerging Evidence for Canna-
bis' Role in Opioid Use Disorder. Cannabis Cannabinoid
Res. 2018;3(1):179-189.
91. Katsidoni V, Anagnostou I, Panagis G. Cannabidiol in-
hibits the reward-facilitating eect of morphine: involve-
ment of 5-HT1A receptors in the dorsal raphe nucleus.
Addict Biol. 2013;18(2):286-296.
92. https://www.sos.state.co.us/pubs/info_center/laws/CO-
Constitution/ColoradoConstitution.pdf. Article XVIII
Section 14.
93. http://www.sos.state.co.us/CCR/NumericalCCRDocList.
do?deptID=19&deptName=200%20Revenue&agencyI
D=185&agencyName=212%A0Marijuana%20Enforce-
ment%20Division.
94. Schoedel KA, Szeto I, Setnik B, Sellers EM, Levy-
Cooperman N, Mills C, Etges T, et al. Abuse potential as-
sessment of cannabidiol (CBD) in recreational polydrug
users: A randomized, double-blind, controlled trial. Epi-
lepsy Behav. 2018;88:162-171.
95. https://www.federalregister.gov/documents/2016/12/14/2
016-29941/establishment-of-a-new-drug-code-for-marih
uana-extract. Accessed on April 22, 2018.
96. Bonn-Miller MO, Loin MJE, Thomas BF, Marcu JP,
Hyke T, Vandrey R. Labeling accuracy of cannabidiol ex-
tracts sold online. JAMA. 2017;318(17):1708-1709.
97. https://www.sos.state.co.us/pubs/info_center/laws/CO-
Constitution/ColoradoConstitution.pdf. Article XVIII,
Section 16.
98. Cole JM. Memorandum for all United States Attorneys.
Guidance Regarding Marijuana Enforcement, Oce of
the Deputy Attorney General, August 29, 2013.
99. https://www.fda.gov/ICECI/EnforcementActions/Warn-
ingLetters/2017/ucm583192.htm.
100. https://www.fda.gov/ICECI/EnforcementActions/Warn-
ingLetters/2017/ucm583197.htm.
101. https://www.fda.gov/ICECI/EnforcementActions/Warn-
ingLetters/2017/ucm583205.htm.
102. https://www.fda.gov/ICECI/EnforcementActions/Warn-
ingLetters/2017/ucm583188.htm.
103. http://www.denvergov.org/content/dam/denvergov/Por-
tals/771/documents/PHI/Food/CBDdocument.pdf.