Neurological Sciences

https://doi.org/10.1007/s10072-020-04514-2

REVIEW ARTICLE

Current application of cannabidiol (CBD) in the management

and treatment of neurological disorders
Brian Fiani 1 & Kasra John Sarhadi 2 & Marisol Soula 3 & Atif Zafar 4 & Syed A. Quadri 5

Received: 10 January 2020 / Accepted: 2 June 2020

# Fondazione Società Italiana di Neurologia 2020

Abstract
Cannabidiol (CBD), which is nonintoxicating pharmacologically relevant constituents of Cannabis, demonstrates several ben-
eficial effects. It has been found to have antioxidative, anti-inflammatory, and neuroprotective effects. As the medicinal use of
CBD is gaining popularity for treatment of various disorders, the recent flare-up of largely unproven and unregulated cannabis-
based preparations on medical therapeutics may have its greatest impact in the field of neurology. Currently, as lot of clinical
trials are underway, CBD demonstrates remarkable potential to become a supplemental therapy in various neurological condi-
tions. It has shown promise in the treatment of neurological disorders such as anxiety, chronic pain, trigeminal neuralgia,
epilepsy, and essential tremors as well as psychiatric disorders. While recent FDA-approved prescription drugs have demon-
strated safety, efficacy, and consistency enough for regulatory approval in spasticity in multiple sclerosis (MS) and in Dravet and
Lennox-Gastaut Syndromes (LGS), many therapeutic challenges still remain. In the current review, the authors have shed light on
the application of CBD in the management and treatment of various neurological disorders.

Keywords Cannabidiol . Efficacy . Ethicality . Neurologic disorders

Introduction It is the current opinion of many that neurology is facing a

therapeutic dead end. The existing single target receptor phar-
Cannabis (marijuana) is a psychoactive drug used for recrea- macotherapy has not proven generally useful in the face of
tional purposes and is known to have adverse health effects complex neurological diseases. As the medicinal use of
[1–3]. However, since past several years, pharmacologically CBD is expanding worldwide, it is gaining popularity for
relevant constituents of the Cannabis, apart from THC, have treatment of various neurologic disorders such as anxiety,
gained attention of research and legislation. The most promi- chronic pain, trigeminal neuralgia, epilepsy, and essential
nent of those is cannabidiol (CBD), which is nonintoxicating tremors as well as psychiatric disorders. In the current review,
but demonstrates several beneficial pharmacological effects. It the authors have shed light on the application of CBD in the
has been found to have physiological effects such as antioxi- management and treatment of various neurological disorders.
dative, anti-inflammatory, and neuroprotection [4–7].

Historical perspective on CBD

* Syed A. Quadri
[email protected] Cannabis is a genus of flowering plants that has had a long
history of usefulness since 1000 BC. There is early evidence
1
Department of Neurosurgery, Desert Regional Medical Center, Palm suggesting that the Chinese and Indian populations used it for
Springs, CA, USA
religious and medicinal purposes [8]. It was not until 1839 that
2
Miller School of Medicine, University of Miami, Miami, FL, USA Cannabis was introduced into western medicine by W.B.
3
New York University School of Medicine, New York, NY, USA O’Shaughessy. During this time Cannabis was being used
4
Department of Neurology, University of New Mexico, for its analgesic and sedative properties in arthritic and epilep-
Albuquerque, NM, USA tic patients, respectively [8]. The increasing positive outcomes
5
Department of Neurology, Massachusetts General Hospital, Harvard on patients’ health and the paucity of side effects highlighted
Medical School, Boston, MA 02114, USA the practical therapeutic application of Cannabis. This
 Neurol Sci

encouraged scientists to explore the mechanisms responsible inflammation [14]. However, it is the CB2 receptor-
for its molecular and cellular actions. However, multiple independent actions that have a significant role in modulating
shortcomings halted its therapeutic potential and scientific inflammation. CBD is an analog to capsaicin and as a result
progress. These obstacles included pharmacodynamics, lack behaves like a transient potential vanilloid receptor type 1
of standardized production protocols, governmental regula- (TRPV1) agonist. Because TRPV1 is a nonspecific cation
tions, and the discovery of more effective treatments such as channel that has anti-inflammatory, pain-relieving, and
opiates [9]. sebum-producing effects, the TRPV1 properties of CBD can
Cannabis sativa contains hundreds of chemical entities be isolated for its therapeutic potential [15]. Similarly, through
known as phytocannabinoids many of which contain psycho- CBD activity on the adenosine receptor (A2A) and tumor
tropic properties. Effects like impaired memory, learning, mo- necrosis factor-alpha (TNF-α), CBD can be used for the treat-
tor function, temperature regulation, and psychosis have lim- ment of inflammatory diseases like rheumatoid arthritis [9].
ited the use of Cannabis sativa in clinical practice [10]. Their action here involves the modulation of pathways in the
However, isolation of cannabidiol (CBD) in 1963 by inflammatory process. In addition to its anti-inflammatory
Mechoulam and Shvo and subsequent studies on the molecule properties, CBD has antioxidant properties that have been
and its activity motivated the robust start of clinical trials in shown to be neuroprotective. Agonistic properties of seroto-
2005 [11]. CBD is non-psychoactive and the second most nin (5- hydroxytryptamine (5-HT)1A) have been shown to
prevalent bioactive compound in Cannabis sativa. Because modulate brain excitotoxicity, oxidative stress, and inflamma-
of its non-psychoactive properties and its relatively low tox- tion [16]. Additionally, CBD’s effect on serotonin receptors
icity and addiction profile, it has been considered for the treat- has anti-anxiety and anti-nausea properties [17, 18].
ment of various pathologies including chronic pain, essential Due to the diversity of CBD pharmacological applications,
tremor (ET), Parkinson’s (PD), obsessive compulsive disor- multiple drug delivery modalities are being considered for
der, and epilepsy [9]. Recent clinical trials assessing the role of treatment. CBD is extracted from hemp and its bioavailability
CBD in the abovementioned conditions are delineating the differs significantly with the mode of administration. If taken
potential role of CBD as adjuvant therapy where existing orally, CBD bioavailability ranges between 13 and 19%, as
treatments are not entirely satisfactory. opposed to 31% when inhaled [19]. The difference is mostly
due to a first pass metabolism effect occurring in the liver by
cytochrome P450 [20]. High fat and calorie meals dramatical-
Principles and mechanism of action of CBD ly increase the mean plasma concentration of CBD when tak-
en orally and can be considered when developing a treatment
CBD is a cyclohexane with a broad pharmacological profile plan. For faster bioavailability, especially when considering
including interactions with several receptors, enzymes, trans- neurological treatments where the blood-brain barrier must be
porters, and ion channels. Its multidimensionality has made crossed, intravenous administration is preferred. Although the
studying CBD a difficult task, but at the same time, it is this toxicity index of CBD is very low, CBD’s terminal half-life is
property that gives CBD a plethora of actions making it an about 9 h. This prolonged elimination has to be taken into
anti-inflammatory, antioxidant, pain relieving, and anxiolytic consideration when trying to avoid unwanted side effects such
molecule. as diarrhea, nausea, and vomiting [21].
CBD’s anti-inflammatory actions can be explained by its
activity on various receptors that decrease the migration of
leukocytes, inhibit the COX1 and COX2 pathways, and de- Initial challenges with CBD legality and ethics
crease the production of pro-inflammatory cytokines [12]. The
human nervous system is impregnated with cannabinoid re- Due to the multiple constituents in Cannabis, regulation of its
ceptors, cannabinoid type 1 (CB1), and cannabinoid type 2 use has proven to be difficult. This lack of consistency has
(CB2). Both CB1 and CB2 are G-coupled protein receptors caused significant confusion for patients, doctors, and scien-
that are located presynaptically thereby controlling the release tists when trying to determine the potential use of CBD in the
of neurotransmitters at the synapse. CB1 is concentrated in the clinic. In the USA, recreational smoking of Cannabis began in
central nervous system and is believed to be responsible for New Orleans in 1910, but it was not until 1937 that the federal
psychologic effects on pleasure, memory, thought, concentra- government began regulating it. The Marihuana Tax Act of
tion, sensory and time perceptions, and coordinated move- 1937 established the use of medical and recreational marijua-
ment [13]. CB2 receptors are expressed mostly in peripheral na as illegal [22]. Since, the legality of CBD has varied from
tissues and immune cells thereby playing a role in inflamma- state to state and federally. Additionally, legality can vary
tion [13]. Although CBD has low affinity for the CB2 recep- depending on numerous factors such as whether it is used
tor, at low doses it functions as an inverse agonist and antag- for recreational or medicinal purposes or even based on what
onist that can block migration of immune cells and decrease part of the plant is used. The recent Agricultural Improvement
Neurol Sci

Act of 2018 removed hemp as a schedule 1 substance and significant improvements in analgesia and sleep quality in
reclassified it as an “agricultural commodity.” Hemp or the patients (as measured through the RA Disease Activity
stalk, fiber, and sterilized seeds of Cannabis contains a Score-28, or DAS-28) receiving nabiximols vs. the placebo-
CBD:THC ratio of 10:1 or higher. A schedule 1 substance is controlled group [27]. Overall, these promising results thus far
classified based on its high potential for abuse and lack of along with the favorable safety profile warrant further research
accepted safety profile [23]. Evidence for the lack of a psy- into the use of nabiximols for chronic non-cancer-related pain.
choactive component in hemp and ongoing research Pain secondary to malignancy is a significant cause of mor-
supporting CBD’s safety has cleared hemp from its previous bidity and diminished quality of life in many patients with
classification and regulations. The recent federal legalization advanced disease. Although opioids are today’s mainstay of
of CBD that contains less than 0.3% of THC will aid in our treatment, they carry a slew of adverse effects and significant
ongoing scientific endeavors to fully understanding the thera- risk of dependence. Thus, in search of more practical and safe
peutic potential of CBD. solutions, researchers have turned to CBD with its mild side
effect profile and proven anti-inflammatory effects as a cur-
rent target of research into cancer-related pain management.
Current applications in neurology The published studies exploring the use of CBD in cancer
patients have researched nabiximols as an adjunctive therapy
Chronic pain in cancer patients receiving ongoing opioid therapy. Although
results across several studies have shown either
Chronic pain is a significant source of morbidity in the USA. nonstatistically significant or only mildly significant improve-
Common causes like small neural fiber involvement in chron- ments in subjective pain scores, a more consistently signifi-
ic diseases like diabetes mellitus, nerve impingement like in cant effect has been improvement in sleep quality and reduc-
radiculopathy or sciatica, or inflammation caused by autoim- tion in sleep disturbances [24]. Though not the primary end-
mune processes or advanced malignancy often require crea- point of these studies, preliminary results demonstrating im-
tive medical solutions to adequately address and control. To provements in sleep certainly justify further research into the
date, there have been a variety of analgesic medications de- use of CBD to improve quality of life in cancer patients. As
veloped and widely utilized for the treatment of chronic pain. these studies had relatively small sample sizes and thus were
In the case of chronic neuropathic pain, standard medical ther- inadequately powered, more research is required to explore
apy includes options like antiepileptic drugs, SSRIs, NSAIDs, the effectiveness of nabiximols in reducing cancer-related
and often opioids in refractory cases, all of which have vary- pain and helping address the daily burden that these patients
ing efficacy and harbor their own specific adverse effects as- endure. Prominent pain studies and their findings have been
sociated with long-term use. In the population of individuals summarized in the table (see Table 1).
with cancer-related chronic pain, the need for novel solutions
is more pronounced: chronic pain occurs in up to 90% of ET
patients with advanced disease, and opioids are often the pri-
mary analgesic agent prescribed by physicians [24]. In the With the growing field of research exploring the potential
field of research geared towards improving chronic pain man- therapeutic applications of CBD in the treatment of neuro-
agement, CBD has sparked great interest as a potentially new logical disorders, there has been a lot of interest in devel-
solution with a safer side-effect profile and minimal concern oping a greater understanding of how CBD can be used in
for abuse when compared with the mainstay of treatment. the treatment of movement disorders. Essential tremor
Current research into the applications of CBD in non- (ET) is the most prevalent movement disorder in the
cancer-related pain have been based mostly on nabiximols, USA. The clinical symptoms of upper extremity or axial
an oromucosal CBD spray with a 1:1 ratio of THC:CBD that tremor both at rest and worsened with movement can be
has been studied as a new solution to alleviate pain secondary quite debilitating. First-line medical therapy for ET usually
to conditions like neuropathy and arthritis [24]. For example, involves beta blockers (like propranolol) or barbiturates
an early study in 2007 by Nurmikko et al. illustrated > 30% (like primadone), but approximately one-third of individ-
improvement in subjective peripheral neuropathy pain ratings uals with ET are medication non-responders, and thus re-
in 26% of patients receiving analgesic therapy with quire unique solutions to address their ET. As a potential
nabiximols [25]. In addition, a more recent systematic review alternative, CBD seems promising as a novel therapy given
of studies utilizing nabiximols for pain control corroborated the high expression of CB1 receptors (CB1R) expressed in
this finding by reporting improved analgesia with the the cerebellum, which have been shown to modulate input
oromucosal spray, though long-term effects still require fur- from inhibitory basket and stellate interneurons onto excit-
ther research [26]. In the realm of arthritis pain relief, an RCT atory Purkinje cells [28]. Several studies utilizing rodent
in patients with rheumatoid arthritis reported statistically models have demonstrated that essential tremors arise from
 Neurol Sci

Table 1 Prominent pain studies and findings

Author Country Study design Population Sample size Main findings

and year of
publication

Portenoy 84 centers Randomized, Patients with active cancer 260 patients completed; 71 Combined median reduction
et al., across double-blinded, and moderate to severe in the low-dose, 67 in the of 10.5% in subjective
2012 North placebo-controlled trial chronic pain that persisted medium-dose, and 59 in pain levels in the low-dose
America, studying the efficacy and despite a stable opioid the high-dose Nabiximols and medium-dose treat-
Europe, safety of CBD in the form regimen groups, with 66 patients in ment groups compared
Latin of dose-graded the placebo group with placebo (p = 0.035)
America, Nabiximols compared
and South with placebo in patients
Africa with advanced
cancer-related and
opioid-refractory pain
over a 4-week study peri-
od
Fallon 101 centers Phase 3, randomized, Patients 18 years and older 294 patients completed; 136 Primary efficacy endpoint of
et al., across double-blinded, who had a diagnosis of patients in the Sativex percent improvement in
2017 Europe and placebo-controlled trial cancer-related pain that group and 158 patients in average daily pain
the USA; studying the effect of was unalleviated by opti- the placebo group numerical rating scale was
Study 2 Sativex oromucosal spray mized opioid therapy not met; post-hoc analyses
as adjunctive therapy in identified 8.8% improve-
advanced cancer patients ment in scores on QOL
with chronic questionnaires for Sativex
opioid-resistant pain in US patients < 65 years
old (p = 0.04), which was
not observed in patients
from the rest of the world
Fallon 65 centers in Phase 3, randomized, Patients 18 years and older 166 patients completed; 78 Primary efficacy endpoint of
et al., Australia, double-blinded, who had a diagnosis of patients in the Sativex mean change in average
2017 Europe, and placebo-controlled trial cancer-related pain that group and 88 patients in daily pain numerical
Asia studying the effect of was unalleviated by opti- the placebo group rating scale was not met;
Sativex oromucosal spray mized opioid therapy mean average pain scores
as adjunctive therapy in increased equally in both
advanced cancer patients the Sativex and placebo
with chronic groups
opioid-resistant pain
Lichtman 114 centers Phase 3, randomized, Patients 18 years and older 291 patients completed; 141 Nabiximols were statistically
et al., across double-blinded, who had a diagnosis of patients in the nabiximols superior to placebo in
2018 Europe and placebo-controlled trial cancer-related pain that group and 150 patients in improving pain assessed
the USA studying the effect of was unalleviated by opti- the placebo group by the average daily pain
nabiximols as adjunctive mized opioid therapy numerical rating scale,
therapy in advanced can- with 15.5% improvement
cer patients with chronic in the nabiximols group
pain unalleviated by opti- vs. 6.3% in the placebo
mized opioid therapy group (p = 0.04); US
patients appeared to
benefit from nabiximols
on multiple secondary
endpoints compared with
patients from the rest of
the world
Nurmikko 6 centers in Randomized, Patients 18 years and older 103 patients completed; 47 Mean reduction in pain
et al., the UK and double-blinded, with a history of unilateral patients in the Sativex intensity scores on a pain
2007 Belgium placebo-controlled trial peripheral neuropathic group and 56 patients in numerical rating scale was
studying the effect of pain and allodyna the placebo group greater in the Sativex
oro-mucosal Sativex on group compared with
pain and allodyna in pa- placebo (p = 0.004);
tients with neuropathic secondary outcomes of
pain of peripheral origin improvements in various
other scores like a
neuropathic pain scale and
Neurol Sci

Table 1 (continued)

Author Country Study design Population Sample size Main findings

and year of
publication

sleep score were similarly

greater in the Sativex
group vs. the placebo
group
Lynch Canada Randomized, Patients 18 years or older 16 patients completed; 8 No statistically significant
et al., double-blinded, with neuropathic pain patients in the nabiximols difference between the
2014 placebo-controlled trial persisting for 3 months group and 8 patients in the treatment and placebo
studying the effect of after completing placebo group groups on the numeric
oro-mucosal nabiximols chemotherapy with rating scale for pain
in the treatment of paclitaxel, vincristine, or intensity
chemotherapy-induced cisplatin
neuropathic pain
Mondello Italy Retrospective cohort study Patients with documented 11 patients completed, aged Statistically significant
et al., evaluating the effect of failed back surgery 49 to 77 years old reduction in pain
2018 THC/CBD on pain in pa- syndrome suffering from perception, evaluated
tients experiencing neuro- moderate to severe through a numeric rating
pathic pain secondary to chronic pain not scale, in all patients treated
failed back surgery syn- responsive to other with cannabinoid agonists
drome treatment regimens during the entire 12-month
period of treatment
(p < 0.001)

conductance of activity through T-type voltage-gated cal- indeed play a role in modulating tremor. The animal model
cium channels, as evidenced by the abolishment of tremors results are indeed promising, but given that harmaline-induced
through utilization of antagonists at these ion channels tremor is an acute process and only about half of the pharma-
[29]. Given that CBD is a potent antagonist at T-type volt- cologic therapies reported to diminish harmaline-induced
age-gated calcium channels and requires very low doses to tremor have been efficacious in suppression of tremor in
block conduction, CBD is poised to become a growing humans, there is still a significant need for further research
target of research into new therapies for alleviating tremor into how CBD can be manufactured and harnessed to treat
[29]. ET in humans [32].
Although the biological feasibility of using CBD to allevi-
ate essential tremor has been elucidated through prior re- PD
search, there have yet to be any studies exploring the efficacy
of CBD in reducing essential tremor in humans. However, a Parkinson’s disease (PD) is a neurological disorder character-
2016 study completed in rats demonstrated that harmaline- ized by significant movement impairment mediated by degen-
induced essential tremor could be reduced via antagonism at eration of dopaminergic neurons in the substantia nigra pars
the CB1 receptor [30]. Through systemic IV administration of compacta. These movement problems often manifest in the
harmaline, which has been shown to produce excitotoxic ef- form of symptoms like a resting “pill-rolling” tremor, “cog-
fects in rodents that manifest as tremor, the researchers were wheel” rigidity, akinesia, postural instability, and a character-
able to induce a stable tremor in the test subjects that lasted istic shuffling gait. Although no cure has been developed, the
from 2.5–3 h. The etiology of this harmaline-induced tremor gold standard of medical therapy to alleviate the symptoms
has been shown to be via interference of the activating signal secondary to dopamine deficiency has been the dopamine
sent through climbing fibers from the inferior olive to the precursor, levodopa. Although levodopa can be highly effec-
Purkinje cells in the cerebellum [31]. The results of the study tive, especially when paired with a DOPA-decarboxylase in-
demonstrated that CB1R antagonism improved ET symptoms hibitor like carbidopa that prevents metabolic degradation of
(as measured through a multifaceted tremor scoring system), levodopa in the periphery prior to delivery to the CNS, chronic
while agonism at this receptor led to exacerbation of tremor use is often met with decreased efficacy and difficulty in titra-
symptoms [30]. Although further studies in humans are re- tion as the therapeutic window narrows. These “on-off” ef-
quired to clarify the effects of CBD on ET, these murine fects associated with long-term levodopa therapy have
studies have elucidated that the endocannabinoid system does prompted alternate solutions including both medical and
 Neurol Sci

surgical options. With the growing body of research surround- Anxiety-related disorders
ing clinical uses for CBD, PD is among the movement disor-
ders of interest to researchers attempting to uncover potential Anxiety-related disorders span a spectrum of symptoms and
therapeutic uses for CBD given its growing popularity and presentations that can have extremely deleterious and devastat-
favorable side-effect profile. ing effects on one’s quality of life and ability to carry out ac-
The molecular role of CBD in alleviating tremor and move- tivities of daily living. Post-traumatic stress disorder (PTSD),
ment disability secondary to PD has been the focus of several generalized anxiety disorder (GAD), panic disorder, social anx-
recent studies. One prevailing theory is that CBD exerts its iety disorder, and obsessive-compulsive disorder (OCD) are all
potential therapeutic effects in movement disorders like PD conditions that present with significantly impairing levels of
through neuroprotection and attenuation of dopaminergic neu- anxiety that can leave individuals helpless and unable to func-
ron degradation [33]. A 2005 study by Lastres-Becker et al. tion without proper medical management. Altogether, they
experimented with the neurotoxic effects of 6- have a lifetime prevalence of 29% in the general population,
hydroxydopamine and demonstrated that in vitro dopaminergic which is the highest of any of mental disorder and a significant
neurodegeneration and in vivo hemi-parkinsonism induced in cause of burden not only to the individuals coping with these
rodents through intranigral adm inistration of 6- illnesses, but also the healthcare system as a whole [37].
hydroxydopamine were both reduced via administration of Although the mainstay of therapy in this group of disorders is
CBD [34]. These researchers postulated that the antioxidant usually a selection or combination of psychotherapy, selective
properties of CBD along with the observed regulation of glial serotonin reuptake inhibitors (SSRIs)/serotonin norepinephrine
functioning accounted for the neuroprotective effects against reuptake inhibitors (SNRIs), benzodiazepines, monoamine-
the neurotoxin. Subsequently, research in human patients has oxidase inhibitors (MAOIs), and/or tricyclic antidepressants
been conducted to build on these findings, but current reports (TCAs), all of these pharmacologic solutions carry highly var-
are controversial and at best suggest mildly beneficial effects of iable rates of efficacy as well as their own risk of adverse ef-
CBD on PD-related tremor. Of the few studies completed, most fects, some of which can even be life-threatening. For this rea-
of the statistically significant benefits of CBD in PD patients son, there is an ever-developing need for alternative pharmaco-
have been related to subjective quality of life improvements and logic solutions that can potentially provide these patients with
reductions in symptoms related to PD-related psychosis [9]. A more consistent relief while carrying milder side effects. Thus,
2014 case report in 4 PD patients revealed reduction (and in researchers have recently turned to CBD as a novel solution in
some cases complete elimination) of agitation, kicking, night- the field of treating anxiety disorders.
mare, and/or aggressive behavior in PD patients with comorbid Although CBD has been shown to have a variety of molec-
REM sleep behavior disorder who were treated with oral doses ular targets and therefore carries a great deal of variability in its
of CBD [35]. When it comes to the effectiveness of CBD in exact mechanism of action, it has been found to be a potent
alleviating PD-related tremor, an early study in PD patients activator of the 5-HT1A and 5-HT2A receptors, both of which
reported dose-related improvements in movement symptoms are targets of current anxiolytic medications like buspirone for
(ranging from 20 to 50%) in patients treated over a 6-week generalized anxiety disorder [29]. Following these findings,
period with oral doses of CBD, while another study failed to various preclinical studies have examined the anxiolytic effects
show any significant benefit in PD patients treated with oral of CBD in rodent models. A review of the current body of
CBD compared with the placebo-controlled group [33]. Some literature demonstrates that intraperitoneal administration of
prominent studies in PD patients and their findings have been CBD produces anxiolytic effects in rats following a bell-
summarized in the table (see Table 2). shaped dose-response curve, with low to moderate doses pro-
Although preliminary results in human trials assessing the ducing the most reproducible anxiolytic effects, while higher
effectiveness of CBD in alleviating symptoms of PD have doses often produced no significant change [37]. These effects
been unconvincing, the molecular feasibility of CBD therapy were observed in a variety of animal model settings aimed to
in PD, contentious initial results in human trials, and lack of replicate different forms of anxiety like what would be seen in
more robust clinical trials with larger sample sizes signify that GAD, PTSD, panic disorder, and OCD. For instance, CBD
CBD deserves further exploration into its potential as an ad- administration led to observed reductions in the rodents’ ex-
junctive therapy for PD. In fact, a prospective cohort study pression of predator-related stress (as one might expect to be
evaluating the effect of a 2-week course of cannabis use on the cause of PTSD and panic disorder) and marble-burying
PD-related tremor has been completed and results are pending behavior (meant to mimic OCD-type behavior) [37].
[36]. Further studies into the effect of cannabinoid products on Stemming from these preclinical results, human trials have
PD symptoms will hopefully provide a more definitive answer been conducted to assess the anxiolytic effects of CBD and
to the question of whether this novel therapy can provide relief have shown promising results (see Table 4). For instance, an
for so many patients who have exhausted other therapeutic early study in 1982 by Zuardi et al. demonstrated that oral
options. administration of CBD in healthy volunteers reduced the
Neurol Sci

Table 2 Summary of studies on PD patients

Author Country Study design Population Sample size Main findings

and year of
publication

Carroll USA Randomized, double-blinded, Patients with Parkinson’s 17 patients completed, with There was no evidence for a
et al., placebo-controlled cross- Disease with randomization to receive treatment effect on
2004 over trial to examine the hy- levodopa-induced dyskine- oral cannabis extract levodopa-induced dyskine-
pothesis that cannabis may sia followed by placebo or sia as assessed by the
have a beneficial effect on vice versa UPDRS, or any of the sec-
dyskinesia in PD ondary outcome measures
Zuardi Brazil Open-label pilot study to Patients with Parkinson’s 6 patients completed There was a significant
et al., evaluate the efficacy, Disease who had psychosis decrease in psychotic
2008 tolerability, and safety of for at least 3 months that symptoms evaluated by the
CBD on PD patients with could not be controlled with Brief Psychiatric Rating
psychotic symptoms reduction of PD medications Scale and the Parkinson
and that were using stable Psychosis Questionnaire
doses of PD medications for under CBD treatment
at least 7 days
Chagas Brazil Randomized, double-blinded, Patients above 45 years old 21 patients completed; 7 No statistically significant
et al., placebo-controlled trial to with idiopathic PD on stable patients in the low-dose differences in UPDRS
2014 examine the effects of CBD doses of anti-PD medication CBD group, 7 patients in scores, plasma BDNF or
in PD globally, including for at least 30 days the high-dose CBD group, H1-MRS levels; the group
assessments of motor and and 7 patients in the pla- treated with high-dose CBD
functional symptoms, a psy- cebo group demonstrated reductions in
chiatric assessment, and the PDQ-39 assessment
complementary tests evalu- compared with placebo
ating serological factors as- (p < 0.05)
sociated with neurodegener-
ation

anxiogenic effects of THC [38]. Moreover, a follow-up study unilaterally in the distribution of one or more of the branches
by the same group in 1993 showed that healthy volunteers of the trigeminal nerve. This debilitating pain is usually trig-
given CBD prior to an anxiety-inducing public speaking test gered by coming in contact with traditionally nonpainful sen-
exhibited anxiolytic effects on par in efficacy with diazepam sory stimuli such as light touch, water, or wind. First-line
and ipsapirone [39]. More recent neuroimaging studies have therapy is often medical through mono- or combination ther-
attempted to explain these clinical results by exploring how apy of antiepileptic drugs like carbamazepine, oxcarbazepine,
CBD affects neuronal activity. These studies have illustrated and lamotrigine. For the individuals who are refractory to
through SPECT and fMRI that CBD modulates neuronal ac- medical treatment, surgical options often include highly inva-
tivity in limbic and paralimbic areas, including orbitofrontal, sive ablative, decompressive, or resection approaches. In or-
cingulate, and medial temporal cortex as well as the insula, all der to expand the gambit of potential alternative medical ther-
of which play a role in regulating emotional response and have apies for TN, research throughout the last couple decades has
been implicated in various anxiety-related disorders [11]. explored how CBD, which has demonstrated analgesic prop-
Overall, the promise of CBD as an effective treatment for erties in both animal models and human clinical trials, may
anxiety-related disorders is supported by some of the strongest play a role in helping alleviate pain secondary to TN.
evidence currently in the field of CBD-related research. One main mechanism by which CBD exerts its anti-
Nevertheless, as these studies have had generally small sam- nociceptive properties is through binding CB1R and subse-
ple sizes and have mostly assessed only acute administration quently modulating the descending pathway from the
of CBD for anxiety relief, more studies are required to build periaqueductal gray (PAG) and rostral ventral medulla in the
on this evidence and determine whether CBD is a feasible midbrain through the spinal cord [40]. Animal models have
solution for chronic therapy in anxiety-related disorders. been conducted to build support for this finding and have
shown that the synthetic cannabinoid drug WIN55,212-2 ef-
Trigeminal neuralgia fectively binds CB1R and leads to inhibition of allodynia and
hyperalgesia resulting from constriction injury of the
Trigeminal neuralgia (TN) is a rare form of neuropathic pain infraorbital branch of the trigeminal nerve [41]. Other preclin-
that is characterized by facial, electrical-like pain often ical studies have highlighted the ability of this synthetic
 Neurol Sci

Table 3 Some prominent studies on epilepsy and their findings

Author Country Study design Population Sample size Main findings

and year of
publication

Thiele USA, Randomized, double-blinded, Patients 2–55 years old with 171 patients enrolled; Median percentage reduction in
et al., Netherlan- placebo-controlled trial LGS refractory to treat- 86 in the CBD group monthly drop seizure
2018 ds, Poland studying the effect of CBD as ment with at least two and 85 in the placebo frequency of 43.9% in the
an add-on therapy for drop AEDs group CBD group and 21.8% in the
seizures in patients with placebo group
Lennox-Gastaut Syndrome
over a 14-week study period
Devinsky 12 centers in Randomized, double-blinded, Patients 4–10 years old with 34 patients enrolled; 27 CBD exposure did not affect
et al., the USA placebo-controlled trial Dravet Syndrome on AED in the CBD group concomitant AED levels
2018 and UK studying the effect of CBD as therapy experiencing < 4 (stratified by three (apart from an increase in
an add-on therapy to AEDs convulsive seizures at dosages) and 7 in the N-desmethylclobazam) and
in patients with Dravet baseline placebo group was generally well-tolerated
Syndrome over a 3-week
study period
Devinsky 30 centers in Randomized, double-blinded, Patients 2–55 years old with 225 patients enrolled; Median percentage reduction in
et al., the USA, placebo-controlled trial LGS refractory to treat- 149 in the CBD monthly drop seizure
2018 Spain, studying the effect of CBD as ment with at least two group (stratified by frequency of 41.9% in the
UK, and an add-on therapy in patients AEDs two dosages) and 76 20-mg CBD group, 37.2% in
France with Lennox-Gastaut in the placebo group the 10-mg CBD group, and
Syndrome over a 14-week 17.2% in the placebo group
study period (p = 0.005, p = 0.002)
Devinsky 23 centers in Randomized, double-blinded, Patients 2–18 years old with 120 patients enrolled; Median reduction in monthly
et al., the USA placebo-controlled trial medication-refractory 61 in the CBD group convulsive seizures
2017 and studying the effect of CBD as Dravet Syndrome and 59 in the placebo frequency of 6.5% in the
Europe an add-on therapy in patients group CBD group and 0.8% in the
with Dravet Syndrome over a placebo group (p = 0.01)
14-week study period
Tzadok Israel Multicenter retrospective Patients 1–18 years old with 74 patients included in 89% of patients reported some
et al., cohort study evaluating the medication-refractory epi- cohort, with varying reduction in seizure
2016 effect of CBD-enriched lepsy resistant to > 7 AEDs levels of cognitive frequency, with 52%
medical cannabis on children who received cannabis oil impairment, experiencing at least a 50%
with medication-refractory treatment for at least treatment duration, reduction in seizure
epilepsy over an average of 3 months and CBD dosage frequency
6 months

cannabinoid to modulate signaling via N-type calcium chan- Epilepsy

nels, GABA receptor ion channels, and 5-HT3 receptor-
activated ion channels, all of which have been shown to play Epilepsy is another lifelong disorder that unfortunately carries
a role in the manifestation of TN pain [40]. Although trials in a staggering rate of cases refractory to current pharmaceutical
humans are lacking given the controversy surrounding therapies: it is estimated that between 28 and 37% of the
cannabis-related medical research, one trial of 112 patients approximately 50 million people worldwide with epilepsy
who smoked cannabis demonstrated relief of trigeminal neu- are troubled by what has been classified as “drug-resistant
ralgia associated with MS in over 70% of study participants epilepsy,” which is determined via an inadequate response to
[42]. It is important to acknowledge that the cannabis utilized two or more trials of appropriate antiepileptic agents [43].
by participants in this study is different than traditional CBD These patients often face a life full of tribulation secondary
in that it contains a specific percentage of THC, a substance to increased emergency room visits, regular neurologic care,
that has its own psychotropic and neurologic effects. and even prolonged hospital admissions. For patients who
Nevertheless, this study highlighted a remarkable degree of develop epilepsy in childhood, this disorder can even impair
effectiveness of a cannabis-related substance in alleviated TN proper neurological and cognitive development. Not only is
pain in humans, which certainly merits further study. The this taxing on individual patients and their families but it also
variety of molecular mechanisms by which CBD can achieve drives a large degree of cost to the healthcare system. Given
analgesic effects illustrates its undeniable potential as an alter- the highly variable nature of the possible causes of epilepsy
native solution to treat patients suffering from refractory TN. (whether genetic, structural, metabolic, idiopathic, etc.), new
Neurol Sci

Table 4 Human trials conducted to assess the anxiolytic effects of CBD

Author and Country Study design Population Sample size Main findings
year of
publication

Zuardi et al., Brazil Randomized, double-blind, Healthy 8 patients, with random selection to CBD blocks the anxiety
1982 placebo-controlled, crossover patients receive either THC, CBD, and provoked by THC when
study looking to assess whether aged THC-CBD mixture, or a placebo administered simultaneously,
CBD reduces the anxiety 20–38 years and diazepam mixture as well as several other effects
provoked by THC in normal old evoked by THC use (p < 0.05)
volunteers
Zuardi et al., Brazil Randomized, double-blind, Healthy 40 patients, with 10 patients in each Diazepam significantly
1993 placebo-controlled study looking patients of 4 subgroups receiving either decreased pre-stress and
to assess the effects of ipsapirone aged CBD, ipsapirone, diazepam, or post-stress anxiety (p = 0.042,
and CBD on healthy volunteers 20–30 years placebo p = 0.002); ipsapirone signifi-
submitted to a simulated public old cantly decreased performance
speaking test compared with anxiety (p = 0.037), and CBD
those using diazepam and place- significantly decreased
bo post-stress anxiety (p = 0.017)
Bergamaschi Brazil Randomized, double-blind, Participants 24 patients with SAD, with 12 Pretreatment with CBD
et al., 2011 placebo-controlled, crossover with either patients randomly assigned to significantly reduced anxiety,
study looking to assess whether generalized receive CBD and 12 patients cognitive impairment, and
CBD reduces the anxiety SAD or assigned to receive placebo; 12 discomfort in speech
provoked by public speaking in healthy healthy subjects did not receive performance, and significantly
healthy volunteers and volunteers any medication throughout the decreased alert in anticipatory
treatment-naive social anxiety trial speech, while the placebo
disorder patients group presented with higher
anxiety, cognitive impairment,
discomfort, and alert levels
when compared with the
healthy control group

treatment options continue to be sought out by researchers Building on this early clinical trial data, the FDA approved
hoping to reduce the fraction of refractory cases, improve the first cannabis-derived pharmaceutical solution for the
patients’ quality of life, and diminish the burden on the treatment of drug-resistant epilepsy in 2018 with the release
healthcare system. of Epidiolex [19]. This medication was targeted towards chil-
Over the last decade, growing numbers of studies have illus- dren with Dravet Syndrome or Lennox-Gaustat Syndrome,
trated the potential benefit of CBD in treating refractory cases of two rare and devastating forms of genetic treatment-resistant
epilepsy in both adults and children (see Table 3). Although the pediatric epilepsy. Early trials leading to the FDA approval of
exact mechanism by which CBD can exert antiepileptic effects is Epidiolex demonstrated highly statistically significant reduc-
yet to be clarified, several in vitro studies have demonstrated the tions in seizure frequency in patients receiving CBD com-
neuroprotective effects of CBD and its ability to reduce pared with placebo over a 14-week trial period, with only mild
excitotoxicity, which can manifest as seizures. For example, a to moderate adverse effects that were well-tolerated [19]. With
1998 study by Hampson et al. elucidated that CBD reduced the these groundbreaking findings, the field of research surround-
level of glutamate in rat cortical neuron cultures that had been ing cannabis-derived products and therapy for refractory epi-
exposed to toxic levels of this excitatory neurotransmitter [44]. lepsy has taken off, as many more human trials are currently
Although preclinical studies like this have shown promising re- being conducted to further clarify the role that CBD can play
sults supporting the feasibility of using CBD in epilepsy, not in epilepsy therapy. In due time, many of the individuals who
enough placebo-controlled trials in humans have been conducted have become accustomed to a life with treatment-resistant
to make a more definitive conclusion regarding this alternative epilepsy may gain a novel opportunity to lead a life free from
treatment option. However, a 2016 clinical trial conducted by suffering once and for all.
Devinsky et al. evaluated CBD as an adjunctive therapy to
existing antiepileptic regimens in children and young adults with Chronic back pain and failed back syndrome
treatment-resistant epilepsy. This study found that oral adminis-
tration of 2–5 mg/kg/day of CBD reduced seizure frequency Failed back surgery syndrome (FBSS) refers to spinal pain
while maintaining an acceptable safety profile [6]. that is either persistent despite surgical intervention or that
 Neurol Sci

occurs de novo secondary to spinal surgery [45]. The inci- lifetime risk of one in 400, predominantly affecting young
dence of the onset of chronic pain after spinal surgery ranges females [48]. It is considered the leading cause of neurological
considerably from 5 to 74.6%, with about one-quarter of cases disability in young and middle-aged individuals in northern
undergoing re-operation [46]. The etiology underlying the industrialized countries, and is characterized by progressive
new-onset of postoperative pain can vary widely and include stages of demyelination that can manifest in an innumerable
inflammatory and mechanical causes including but not limited amount of ways related to the location and extent of demye-
to epidural fibrosis, canal/foraminal stenosis, joint inflamma- lination [33]. The current gold standard of treatment is, like
tion, and disc herniation/degeneration. Thus, therapeutic op- many autoimmune diseases, maintenance therapy achieved
tions are equally variable and depend on the underlying etiol- with immunosuppression while reserving the use of steroids
ogy. Currently, therapies that exist for FBSS include conser- to control and curb acute episodes. However, as many indi-
vative options like exercise, physical therapy, and weight loss; viduals often experience frequent relapsing symptoms even
pharmacological options like antidepressant medication and when receiving a standard treatment regimen, a 1997 study
antiepileptic medication; and more invasive and surgical op- explored the MS patient experience further by interviewing a
tions like deep brain stimulation, spinal cord stimulation, glu- sample of 112 individuals. From this study, it was reported
cocorticoid injections, and sometimes repeat surgery [46]. that one-third of the MS patients in this sample self-medicated
Even with these available avenues of therapy, many patients with cannabis and perceived significant symptom relief with
have persistent pain despite multiple attempts at treatment. reduced frequency of flare-ups [42].
Thus, there is need for further exploration of other therapeutic Given this intriguing anecdotal finding, follow-up studies
options, and CBD is one option that has garnered more inter- in animals looked to evaluate whether there existed a feasible
est given its early promise as a relatively safe analgesic. molecular basis for this response. In turn, several preclinical
As the incidence of FBSS in the general population is esti- studies in rodents found that the agonistic action of CBD on
mated to be as low as 0.02% to 2%, the drive of researchers to CB1R was able to improve signs and symptoms of neurolog-
expand the current literature exploring alternative treatments for ical disability such as tremor and spasticity through the sup-
FBSS is still wanting [47]. Nevertheless, one retrospective pression of pro-inflammatory microglial activity and T cell
study completed between 2014 and 2016 recruited 11 patients proliferation [9]. This was followed by clinical trials in
with a clinical diagnosis of FBSS who were reportedly suffer- humans, most notable of which was a collection of five ran-
ing from moderate to severe chronic pain that was unresponsive domized controlled trials including 368 patients with a variety
to other treatment modalities. Patients enrolled in this study of neurological disorders [49]. These studies assigned individ-
were treated with a daily oral combination of THC/CBD for a uals to either receive an oro-mucosal THC:CBD spray (in a
period of 12 months, with baseline and concluding assessments 1:1 ratio) or a placebo and followed them for assessment of
conducted to evaluate changes in perceived pain, mood, and symptom severity, ultimately reporting statistically significant
activity level. Of the 11 patients, 4 reported an analgesic effect reductions in neuropathic pain, spasticity, muscle spasms, and
secondary to the THC/CBD treatment as early as in the first sleep disturbances in the intervention group, all with very mild
month, an effect that lasted for the duration of the study period and self-limited adverse effects. These results led to the devel-
[46]. Moreover, the researchers observed statistically signifi- opment of Sativex, a pharmaceutical oro-mucosal spray con-
cant decreases in mean pain perception in this group at the taining a 1:1 ratio of THC:CBD, which was approved in 2005
end of the study compared with baseline, with specific mention as an adjunctive treatment for neuropathic pain in patients
of reductions in burning sensation and paresthesia associated with MS [49].
with FBSS. Although these results were limited to a select few As more clinical trials in humans with MS have been con-
patients in the cohort, all 11 patients reported statistically sig- ducted to attempt to replicate and build on these initial find-
nificant improvements in sleep quality, mood, and general ac- ings, results have not been as reassuring as initially perceived.
tivity level [46]. Over the course of the study, adverse events Studies observing the effects of cannabis-based medicinal ex-
were mild, self-limited, and never required medical attention. tracts on MS-related tremor have reported controversial and
Although the results of this study are based on a small sample mixed results, with some groups finding effective reduction of
size with a particular THC/CBD formulation and lacked a prop- tremor and pain with CBD/THC combinations and others
er control group, the positive analgesic effects demonstrated in reporting an absence of statistically significant effects com-
this study certainly warrant further exploration into CBD as a pared with placebo [28] (see Table 5). This discrepancy led to
potential alternative treatment for FBSS. the conduction of a 2011 systematic review by Koppel et al.
surveying the published literature in this field, which led to the
Multiple sclerosis and muscle spasticity conclusion that oral cannabis extract and THC were “probably
ineffective,” while Sativex was “possibly ineffective” for the
Multiple sclerosis (MS) is an autoimmune, inflammatory, de- treatment of MS-related tremors [50]. Altogether, research
myelinating condition that affects the CNS and carries a into the application of CBD as an adjunctive therapy for MS
Neurol Sci

Table 5 Studies observing the effects of cannabis-based medicinal extracts on MS-related tremor

Author Country Study design Population Sample size Main findings

and year of
publication

Zajicek UK Randomized, Patients 18–64 years old with 611 patients completed; 207 No treatment effect of
et al., placebo-controlled trial clinical definite or patients in the cannabis cannabinoids on the
2003 studying the effect of can- laboratory-supported MS extract group, 197 patients primary outcome of change
nabinoids for the treatment with stable disease for the in the THC group, and 207 in spasticity as measured by
of spasticity and other previous 6 months and patients in the placebo the Ashworth score of
symptoms related to MS problematic spasticity group spasticity; however, there
was evidence of a treatment
effect on patient-reported
pain and spasticity, with
improvement in spasticity
reported in 61%, 60%, and
46% of patients on canna-
bis extract, THC, and
placebo, respectively
Vaney Switzerland Randomized, Patients over 18 years old 57 patients completed; 28 No statistically significant
et al., placebo-controlled, with clinically confirmed patients in the first group differences associated with
2004 crossover trial studying the MS and clinically stable receiving cannabis-extract active treatment compared
effect of orally spasticity capsules followed by with placebo, but trends in
administered Cannabis placebo, and 29 patients in favor of active treatment
extract in MS patients with the second group receiving were seen for spasm
poorly-controlled spastici- placebo followed by can- frequency, mobility, and
ty nabis extract getting to sleep
Rog et al., UK Randomized, double-blind, Patients over 18 years old 64 patients completed; 32 Sativex was superior to
2005 placebo-controlled trial to with a diagnosis of MS for patients in the Sativex placebo in reducing the
study effect of Sativex at least 6 months with group and 32 patients in mean intensity of pain
oromucosal spray in cen- central neuropathic pain the placebo group (p = 0.005) and sleep
tral neuropathic pain asso- for at least 3 months and disturbance (p = 0.003)
ciated with MS attributed to MS
Wade UK Randomized, double-blind, Patients over 18 years old 154 patients completed; 77 The primary outcome
et al., placebo-controlled trial to with clinically confirmed patients in the cannabis measure was a Visual
2004 study effect of cannabis MS that has been stable for extract group, and 77 Analogue Scale score for
extract on a range of the preceding 4 weeks and patients in the placebo each patient’s most
symptoms due to MS on a stable medication group troublesome symptom, and
regimen the cannabis extract group
demonstrated significant
reduction in spasticity VAS
scores compared with
placebo (p = 0.001)
Fox et al., UK Randomized, double-blind, Patients between 18 and 14 patients completed, No significant improvement
2004 placebo-controlled, 64 years old with clinically starting with a cannabis in any of the objective
crossover trial to study definite MS and a visible extract capsule followed measures of upper limb
effect of cannabis extract upper limb tremor by placebo, or vice versa tremor with cannabis
for tremor associated with extract compared with
MS placebo; finger tapping was
faster on placebo compared
with cannabis extract
(p < 0.02)

has demonstrated a discrepancy between the findings of Specifics on usage in pediatric patient
early animal models and subsequent human trials. population versus adults
Although feasible in its application for the treatment
of MS symptoms, CBD remains a controversial therapy Special attention must be given to pediatric patients due to the
and requires further research to elucidate proper molec- severity of the side effects and the potential for Cannabis
ular targets and optimal formulations for treatment. induced seizures at higher concentrations [51]. Studies in
 Neurol Sci

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