Introduction
The herbal use of Cannabis sativa plant extract (also known as
cannabis, hemp or marijuana) can be tracked back to ancient China,
around 2900 BC. Cannabis was used in variety of ways by the ancient
Chinese people to treat ailments, including joint pain, muscle spasms,
gout and malaria(Ethan B. Russo, 2007). Around 1000 B.C., cannabis was
used as an analgesic, hypnotic, tranquilizer and anti-inflammatory agent
in India(Touw, 1981). The therapeutic use of cannabis was explored in
the early 19th century in Western medicine. Due to the
psychoactive properties, research and uses of cannabis has been hindered
by decede-long debates over its legality. Despite restrictive
legislation, interest in the recreational use of cannabis intensified in
the 1960s and 1970s, and scientists were able to isolate its
psychoactive and therapeutic constituents. The psychoactive property of
cannabis was generated from one of its extracts,
delta-9-tetrahydrocannabinol (delta-9-THC). As research progressed,
global policies have increased access to medical cannabis or
cannabinoid-based treatments. Canada officially legalized cannabis for
recreational and medical use in 2018 and Mexico legalized the
recreational use of cannabis in early 2021. In 2018, the US Agriculture
Improvement Act of 2018 was approved in the United States (US). Hemp
(defined in US as cannabis with less than 0.3% of delta-9-THC) and hemp
products are no longer considered controlled substances by the US Drug
Enforcement Administration. As of August 2021, medical cannabis use is
legal in 37 states and the District of Columbia (D.C.), and non-medical
cannabis use is legal in 18 states in the United States(”State Medical
Marijuana/Cannabis Program Laws,” 2021).
Cannabidiol (CBD) is one of the most abundant extracts fromCannabis sativa ; it has multiple bioactivities and wide health
benefits without psychoactive properties. Studies suggest that the
molecular mechanism of CBD largely relates to the human endocannabinoid
system(Mouslech & Valla, 2009). The human endocannabinoid system was
discovered soon after the identification of cannabinoid receptor 1
(CB1). This system includes two main cannabinoid receptors (CB1 and
CB2)(Pertwee, 2008) and endogenous ligands called endocannabinoids.
There are two endocannabinoids anandamide (AEA) and
2-arachidonoylglycerol (2-AG); both of them derive from arachidonic
acid(Fagundo et al., 2013). Both endogenous endocannabinoids, anandamide
(AEA, also known as N-arachidonoylethanolamide and
arachidonoylethanolamide) and 2-arachidonoylglycerol (2-AG) are
derivatives of arachidonic acid and modulate CB1 and CB2
activities(Tsuboi, Uyama, Okamoto, & Ueda, 2018). The concentration of
endocannabinoids is regulated by the enzymes fatty acid amide hydrolase
(FAAH, also known as oleamide hydrolase, anandamide amidohydrolase and
EC 3.5.1.99) and monoacylglycerol lipase (MAGL), which act by degrading
AEA and 2-AG, respectively(Luchicchi & Pistis, 2012). The CB1 receptor
is highly expressed in central nervous system (CNS) and is particularly
abundant in brain areas associated with motor control, emotional
responses, motivated behavior and energy homeostasis.
CB1 is also expressed in the heart, liver, pancreas, muscles, adipose
tissue, and reproduction system. The CB2 receptor is mainly expressed in
cells related to the immune system, such as leukocytes, but it is also
found in the spleen, thymus, bone marrow, and other tissues related to
immune functions.
CBD (Epidiolex®) was approved by the US Food and Drug
Administration (FDA) in 2018 and European Medicines Agency (EMA) in
2019, as an add-on treatment for two rare epilepsies: Dravet Syndrome
(DS) and Lennox-Gastaut Syndrome (LGS) in patients 1 year of age and
older(”FDA Approves New Indication for Drug Containing an Active
Ingredient Derived from Cannabis to Treat Seizures in Rare Genetic
Disease,”). Epidiolex® oral solution was also approved
for tuberous sclerosis complex (TSC) by the FDA in 2020 and by the EMA
in 2021(”Epidiolex,”). Sativex®, an oral spray
containing CBD and delta-9 THC in a 1 :1 ratio, is approved in several
countries including, United Kingdom (UK), European Union (EU) and Canada
for the treatment of multiple sclerosis associated
spasticity(”Sativex®,”). CBD has also exhibited tremendous treatment
potential toward multiple disease states, including psychotic disorder,
anxiety, diabetes and pain.
The therapeutic benefits of CBD are mainly generated from CBD’s role in
the endocannabinoid system. However, CBD does not bind to the
orthostatic binding site of the CB1 and CB2 receptors(McPartland, Glass,
& Pertwee, 2007; Tham et al., 2019; Thomas et al., 2007). An allosteric
binding activity of CBD on these two receptors has been
reported(”Allosteric Modulators of the CB1 Cannabinoid Receptor: A
Structural Update Review,” 2016; Laprairie, Bagher, Kelly, &
Denovan-Wright, 2015; Martínez-Pinilla et al., 2017). CBD was shown to
influence endocannabinoid balance via binding to fatty acid-binding
proteins(Elmes et al., 2015). Except for the endocannabinoids receptor,
many other potential molecular targets have been investigated, including
GPR55(Ryberg et al., 2007; Whyte et al., 2009), TRPVs(Luciano De
Petrocellis et al., 2011; L. De Petrocellis et al., 2012), 5-HT
receptors(Rock et al., 2012; Ethan B. Russo, Burnett, Hall, & Parker,
2005; Yang et al., 2010), GABAA receptors(Bakas et al.,
2017), TRPM8 receptor(Luciano De Petrocellis et al., 2008), PPARγ
nuclear receptors(Esposito et al., 2011; Granja et al., 2012;
O’Sullivan, Sun, Bennett, Randall, & Kendall, 2009; Caterina Scuderi,
Steardo, & Esposito, 2014), and glycine receptors(Ahrens et al., 2009;
Xiong et al., 2012) (Fig. 1). In Table 1, the affinity and action of the
CBD related receptors are summarized. However, the underlying mechanisms
for the effects of CBD remain largely elusive(Morales, Reggio, &
Jagerovic, 2017).
Previously there were some excellent reviews on CBD, such as pain
management(Kevin P. Hill, 2017; Mlost, Bryk, & Starowicz, 2020; Urits
et al., 2020), CNS disorders(C. Scuderi et al., 2009), anti-cancer(Paola
Massi, Solinas, Cinquina, & Parolaro, 2013; Seltzer, Watters,
MacKenzie, Granat, & Zhang, 2020), pharmacology and
pharmacokinetics(Millar, Stone, Yates, & O’Sullivan, 2018; Pertwee,
2008), and clinical trials(Kevin P. Hill, 2017; Sholler, Schoene, &
Spindle, 2020; White, 2019). This review will discuss the molecular
mechanisms of action of the therapeutic effects of CBD within different
disease contexts. We focus on disease in which there is human
experiments or clinical studies with CBD (Table 2).
Psychotic disorder
Schizophrenia is a psychotic disorder characterized by distortions of
reality, disturbances of thought and language, and withdrawal from
social contact. Its heterogeneous symptoms can be grouped into three
main categories: (1) positive symptoms (delusions, thought disorder and
hallucinations), (2) negative symptoms (anhedonia, blunted affect and
social withdrawal), and (3) cognitive impairment (sensory information
processing attention, working memory and executive functions)(Freedman,
2003).
First-line antipsychotic drugs for schizophrenia act by blocking the
central dopamine D2 receptors via receptor antagonism(Miyamoto, Duncan,
Marx, & Lieberman, 2005). However, up to one-third of patients are
unresponsive to these drugs. This may be attributed to the fact that
some schizophrenia symptoms are not driven by elevated dopamine
function. Exploring compounds with alternative molecular mechanisms
might be a way to meet the unmet need for improved schizophrenia
therapies. Research in both animals and humans indicates that CBD binds
to various molecular targets to exerts its antipsychotic properties. CBD
may bind to FAAH and FLAT (FAAH-like anandamide transporter) to inhibit
anandamide degradation and uptake(F. M. Leweke et al., 2012; Schuelert
& McDougall, 2011), facilitate 5-HT1A receptor mediated
serotonergic neurotransmission(Long et al., 2012; Ethan B. Russo et al.,
2005), and activate transient receptor potential vanilloid type 1
(Bisogno et al., 2001) (Fig. 2).
An clinical study conducted in 1995 by Zuardi et al. demonstrated that
daily administration of up to 1500 mg/day of CBD over 4 weeks resulted
an overall improvement of psychotic symptoms(A. W. Zuardi, Morais,
Guimarães, & Mechoulam, 1995) (Table 2). However, a study investigated
the effects of CBD on selective attention of schizophrenic patients
discovered that single and acute administration of CBD (300 mg or 600
mg) seems to have no beneficial effects on the performance of
schizophrenic patients in the Stroop Color Word Test(Hallak et al.,
2010) (Table 2). The first controlled, randomized, double blind clinical
trial was conducted in 2012(F. M. Leweke et al., 2012) (Table 2);
schizophrenic patients were treated with 600-800 mg/day of CBD,
resulting in a significant clinical improvement. Moreover, a significant
increase in serum anandamide levels was associated with clinical
improvement following CBD treatment. Furthermore, a phase 2 trial
demonstrated that schizophrenia patients who received 1000 mg/day of CBD
(n = 43) for 6 weeks can clinically benefit compared to those who
received the placebo (n = 45). The CBD group had lower levels of
positive psychotic symptoms and tolerated the high dose of CBD(Philip
McGuire et al., 2018) (Table 2). These preliminary evidence supports
that CBD may be effective in the treatment of psychotic disorders.
However, CBD failed to demonstrate efficacy in cognitive impairments
associated with schizophrenia (CIAS) as an add-on treatment in a
randomized placebo—controlled trial in chronically ill patients(Boggs
et al., 2018) (Table 2). In a explorative clinical trial, CBD
demonstrated efficacy in improving neurocognitive functioning in young
and acutely ill schizophrenia patients(F. Markus Leweke et al., 2021)
(Table 2).
Currently, there are only five clinical records on CBD treatment for
schizophrenics available from Clinical Trial website(”ClinicalTrials.
gov,”) (Table 2). Large-scale controlled and randomized clinical trials
are still needed to evaluate the long-term efficacy and safety of this
putative new antipsychotic agent.
Anxiety
Anxiety disorders have the highest lifetime prevalence of any mental
illness worldwide, leading to high social and economic burden(Bandelow
& Michaelis, 2015). Anxiety is an emotional disorder characterized by
feelings of tension, worried thoughts and changes such as increased
blood pressure and heart rate. People with anxiety disorders usually
have intrusive thoughts or concerns(Tovote, Fadok, & Lüthi, 2015).
Results from neuroimaging and biochemical studies(Freitas-Ferrari et
al., 2010; Martin, Ressler, Binder, & Nemeroff, 2009; Michelle G.
Craske et al., 2011) suggest that the pathophysiology of anxiety-related
disorders is largely related to key neurotransmitters, including
dopamine(DA)(Dunlop & Nemeroff, 2007), norepinephrine (NE)(Goddard et
al., 2010), γ-aminobutyric acid (GABA)(Nemeroff, 2003), and serotonin
(5-HT)(Ressler & Nemeroff, 2000). Multiple mechanisms may account for
the anti-depressive and anxiolytic activities of CBD. The proposed
anti-anxiety activity may result from CBD inhibiting the inactivation of
anandamide, a neurotransmitter(Blessing, Steenkamp, Manzanares, &
Marmar, 2015; Murrough, Yaqubi, Sayed, & Charney, 2015) and/or CBD
interacting with 5-HT1A receptors (Campos, Ferreira, &
Guimarães, 2012; Patel, Hill, Cheer, Wotjak, & Holmes, 2017).
Although the mechanism by which CBD decreases anxiety remains unclear,
prior clinical experience has preliminarily demonstrated the anxiolytic
effects of CBD (Table 2). One double-blind, cross-over study
investigated the neural effects of CBD on human pathological anxiety by
treating 10 men with generalized social anxiety disorder (SAD) were
given an oral dose of CBD (400 mg) or placebo(Crippa et al., 2011)
(Table 2). Subjective states were evaluated using the Visual Analogue
Mood Scale (VAMS) and the Regional Cerebral Blood Flow (RCBF) at rest
was measured twice using Single Photon Emission Computed Tomography
(SPECT) neuroimaging with a Technetium-99m-ethyl cysteinate diethylester
(99mTc-ECD) tracer. Subjective anxiety was
significantly reduced with CBD treatment compared to placebo. SPECT
results revealed that CBD significantly reduced ECD uptake in the left
para-hippocampal gyrus, hippocampus, and inferior temporal gyrus, and
increased ECD uptake in the right posterior cingulate gyrus. Thus, the
anxiolytic effects of CBD are exerted via the modulation of the limbic
and paralimbic brain areas(Crippa et al., 2011).
Further, a double-blind, placebo-controlled study was conducted to
compare the effects of ipsapirone and CBD on healthy volunteers
submitted to a stressful simulated public speaking (SPS) test. The
results revealed that CBD treatment (300 mg) can decrease anxiety after
SPS test(A. W. Zuardi, Cosme, Graeff, & Guimaraes, 1993) (Table 2). A
similar study aimed to compare the treatment of CBD on healthy control
patients and treatment-naïve social anxiety disorder (SAD) in SPS test.
The results showed that pretreatment with CBD (600 mg) can significantly
reduce anxiety, cognitive impairment and discomfort in their speech
performance(Bergamaschi et al., 2011) (Table 2).
Additionally, CBD induced anxiolytic effects show an inverted U-shaped
curve dose response in healthy volunteers who underwent a public
speaking test. In this study, anxiety was significantly reduced in the
300 mg CBD cohort compared to the 100 mg or 900 mg CBD cohort(Antonio W.
Zuardi et al., 2017). A subsequent
double-blind study, 57 healthy males were allocated to receive oral CBD
at doses of 150 mg, 300 mg or 600 mg; only the cohort receiving the 300
mg CBD dose had significantly reduced anxiety during the SPS test(I. M.
Linares et al., 2019).
A large retrospective case series analysis revealed that within the
clinical context, CBD adjuvant therapy (25 mg/day to 175 mg/day) may
also benefit the outpatient psychiatric population suffering from
anxiety-related disorders(S. Shannon, Lewis, Lee, & Hughes, 2019). The
sample size consisted of 72 psychiatric patients presenting with primary
concern of anxiety (n = 47) and anxiety levels were monitored monthly
over the course of 3 months using the validated anxiety instrument the
Hamilton Anxiety Rating Scale (HARS); anxiety scores decreased within
the first month in 57 patients (79.2%) and remained decreased
throughout the 3-month study duration(S. Shannon et al., 2019).
Overall, current clinical studies support CBD as a promising therapy for
the anxiety treatment. However, there were some conflicting study
results(I. M. Linares et al., 2019; Antonio W. Zuardi et al., 2017), so
further research is necessary to evaluate the efficacy of CBD in
treating other anxiety disorders through placebo-controlled clinical
trial and determine both the appropriate dose of CBD for the anxiety
treatment and the long-term safety of CBD use.
Epilepsy/seizures
Epilepsy is a central neurological system disorder associated with
abnormal electrical activity in the brain. According to reported data,
more than 50 million people suffer from epilepsy worldwide. The main
symptom of epilepsy is recurrent
seizures, but other symptoms
include periods of unusual behavior, sensations, and sometimes loss of
awareness(”Epilepsy ”). A seizure is an uncontrolled abnormal excessive
or synchronous neuronal activity in the brain that causes temporary
abnormalities in muscle tone or movements, behaviors, sensations or
states of awareness(Fisher et al., 2014). There are three main types of
seizures recognized by the International League Against Epilepsy,
namely, focal, generalized and unknown seizures. For epilepsy patients,
being able to control seizure determines quality of life(Fisher et al.,
2017; E. L. Johnson, 2019).
Throughout the long history of cannabis’s use, CBD has exhibited the
ability to reduce seizures(von Wrede, Helmstaedter, & Surges, 2021). In
recent years, several studies revealed that CBD has a high affinity for
some receptors and channels related to epilepsy, including Transient
Receptor Potential Vanilloid (TRPV)(Vilela et al., 2017), T-Type
Ca2+ channels(Catterall, 2017), serotonin receptors
(5-HT1A and 5-HT2A)(Gharedaghi, Seyedabadi, Ghia, Dehpour, & Rahimian,
2014), Opioid receptors(Chu Sin Chung & Kieffer, 2013) and
GPR55(Kaplan, Stella, Catterall, & Westenbroek, 2017). TRPV1, an ion
channel, has been implicated in the modulation of seizures and epilepsy
by influencing the release of glutamate and modulating
Ca2+ concentrations resulting in changes in neuronal
activity(Mustafa, 2015). In vitro studies show that CBD reduced
epileptiform activity and promoted desensitization of TRPV1 channels
with consequent normalization of intracellular
Ca2+(Vilela et al., 2017). The low-voltage T-Type
Ca2+ channels
are also linked to the pathogenesis of absence epilepsy(Shin, 2006). In
response to small depolarizations of the plasma membrane, T-Type
Ca2+ channels transiently regulate neuronal
Ca2+ entry leading to further membrane depolarization
and increased neuronal excitability(Perez-Reyes, 2003). CBD may exert
antiepileptic action by interacting with and blocking the T-type
Ca2+ channels(Ross, Napier, & Connor, 2008). CBD also
shows a high affinity towards serotonin receptors
(5-HT1A and 5-HT2A)(Martinez-Aguirre et
al., 2020; Ethan B. Russo et al., 2005). These receptors may be involved
in epilepsy even though their role is still not entirely
clear(Gharedaghi et al., 2014).
In the past few decades, several clinical studies have been conducted to
evaluate the safety, tolerability and efficacy of CBD in the treatment
of epilepsy(Silvestro, Mammana, Cavalli, Bramanti, & Mazzon, 2019). An
open-label expanded-access trial has evaluated the preliminary efficacy
and safety of CBD as adjuvant antiepileptic therapy at varying doses
(2-5mg/kg/day titrated up to a maximum dose of 25 or 50 mg/kg/day) in
214 patients with treatment-resistant epilepsy. Clinically meaningful
reductions in seizure frequency observed in the study
population(Devinsky et al., 2016) (Table 2). Additionally, CBD was
demonstrated to be safe and effective as an adjuvant antiepileptic
therapy for the treatment of drop seizures in patients with the
Lennox-Gastaut syndrome (n = 225) in a double-blind, placebo-controlled
trial(Devinsky et al., 2018) (Table 2). Patients who received an oral
CBD dose of 10 or 20 mg/kg/day for 14 weeks experienced a reduction in
the frequency of drop seizures compared to the placebo group(Devinsky et
al., 2018). CBD is also an effective adjuvant antiepileptic therapy for
the treatment of drug-resistant seizures in patients with the Dravet
syndrome (n = 120). The double-blind, placebo-controlled, randomized
trial showed that compared to placebo, oral CBD up to a maximum dose of
20 mg/kg/day for 14-weeks was effective at reducing the frequency of
convulsive-seizures Dravet syndrome patients(Devinsky et al., 2017).
Oral CBD is also indicated for the treatment of drug-resistant seizures
in Tuberous Sclerosis Complex (TSC). Recently, CBD doses of 25 mg/kg/day
or 50 mg/kg/day was shown to be effective at reducing TSC-associated
seizures in a double-blind, placebo controlled randomized clinical trial
(n = 224 patients)(Thiele et al., 2021) (Table 2). However, as has been
previously documented(Devinsky et al., 2017; Devinsky et al., 2016;
Devinsky et al., 2018; Silvestro et al., 2019), CBD use as an adjuvant
antiepileptic therapy within the TSC context is associated with a higher
frequency of adverse events such as diarrhea and elevated liver
transaminase levels compared to placebo(Thiele et al., 2021).
The pharmacokinetics (PK) and tolerability of discontinuous oral CBD
(single dosing at 5, 10, or 20 mg/kg and multiple dosing at 10
mg/kg/day, 20 mg/kg/day or 40 mg/kg/day, respectively) was investigated
in a phase1/2 dose-escalation, open-label study for treatment-resistant
epilepsy (n = 61 patients aged from 1 to 17 years)(Wheless et al., 2019)
(Table 2). The PK data indicated variable inter-individual CBD exposure
with single-dose administration; this variability was reduced with
multiple dose administration(Wheless et al., 2019). Short-term
administration was generally safe and well tolerated although a higher
frequency of diarrhea, increased weight, somnolence, and psychomotor
hyperactivity were observed with increased CBD dose(Wheless et al.,
2019).
Sleep/Insomnia
Insomnia is a common sleep disorder that can present in either isolation
or comorbid to other medical or psychiatric conditions(Suraev et al.,
2020). There has been extensive interest in the use of cannabis as a
therapy for the treatment of insomnia(Kesner & Lovinger, 2020). The
endocannabinoids (2-AG and AEA) produce neuro-modulatory actions mainly
through the actions on the CB1 receptor(Tsuboi et al., 2018). 2-AG and
AEA are found in brain and throughout the body and can be produced by
almost all types of cells in the body(C. J. Hillard, 2015; Cecilia J.
Hillard, 2018). The interaction between cannabis and endocannabinoids
with CB1 seems to be important in sleep stablity(Pava, Makriyannis, &
Lovinger, 2016). CBD has been shown to increase concentrations of the
major endogenous cannabinoid, AEA, by inhibiting the enzyme degrading
it, fatty acid amid hydrolase (FAAH)(Bisogno et al., 2001). Increasing
endogenous anandamide via FAAH inhibition normalized deficits in stage
N3 sleep in cannabis-dependent men experiencing withdrawal(D’Souza et
al., 2019). This is consistent with preclinical data showing that
anandamide promotes slow wave sleep, possibly through correlated
increase of extracellular adenosine(Murillo-Rodriguez, Blanco-Centurion,
Sanchez, Daniele, & Shiromani, 2003). Furthermore, CBD is a promiscuous
molecule that exhibits activity on a wide array of molecular targets
beyond CB1 and CB2 receptors such as inhibitory GABAAreceptors(Bakas et al., 2017), which may also influence
sleep(Gottesmann, 2002).
To date, well-designed randomized controlled trials employing objective
measures to assess the effects of cannabis on sleep duration and quality
is lacking in the clinical insomnia population. Previous
studies(Ethan B. Russo, Guy, & Robson, 2007) have shown potential
benefits in the therapeutic use of Sativex®, a spray
containing equal parts THC and CBD, in the relief of pain and other
chronic symptoms including improved sleep, with the latter only being
assessed as a secondary outcome using subjective rating scales. One case
study showed that 25 mg CBD daily reduced anxiety symptoms and improved
sleep disturbances in a young child with post-traumatic stress
disorder(Scott Shannon & Opila-Lehman, 2016) (Table 2). Indeed,
preclinical evidence(Hsiao, Yi, Li, & Chang, 2012) has demonstrated
that the anxiolytic effects of CBD likely dependent on CB1 and
5-HT1A receptor action, with early human experimental
evidence supporting preclinical findings. Previously, 72 psychiatric
adult patients were given oral doses of CBD at 25 mg/day and sleep
quality was measured using by The Pittsburg Sleep Quality Index, which
is a self-report measure that assesses the quality of sleep during a
1-month period. Sleep scores improved within the first month in 48
patients (66.7%) but fluctuated over time(S. Shannon et al., 2019).
Although these results demonstrated that the beneficial effect of CBD on
sleep, research on the impacts of CBD on sleep is still lacking. One
study revealed that acute administration of CBD (300 mg) doesn’t seem to
alter the sleep cycle of healthy volunteers(I. M. P. Linares et al.,
2018) (Table 2).
Cannabis is commonly believed to be a useful sleep aid(Vigil et al.,
2018). However, there are no published studies to-date assessing its
effects on sleep in people with physician-confirmed chronic insomnia
disorder. Given the increased consumer interest and expansion of legal
prescription for cannabis globally, it is important to better understand
how cannabis-based medicines affect sleep and next-day function prior to
becoming a routine clinical intervention.
Cardiovascular System/Blood pressure/vasorelaxant
The complex mechanism of action of CBD makes it possible to have
multidirectional influence on the cardiovascular system(Kicman &
Toczek, 2020). A number of preclinical studies have shown beneficial
effects of CBD on the cardiovascular system(Stanley, Hind, &
O’Sullivan, 2013). Mechanistic studies showed that CBD affects
cardiovascular function by interacting with a variety of receptors,
including CB1(Mukhopadhyay, Mohanraj, Bátkai, & Pacher, 2008),
CB2(Steffens & Pacher, 2012), TRPV1(Peng & Li, 2010), PPARs(”PPARs and
the Cardiovascular System,” 2009) and 5-HT1A(Kaumann &
Levy, 2006).
A few clinical trials have assessed the effects of CBD on the
cardiovascular system. A randomized crossover trial assessed the
influence of a single 600 mg CBD dose on cardiovascular parameters,
including blood pressure in healthy male volunteers (n = 9)(Jadoon, Tan,
& O’Sullivan, 2017) (Table 2). The acute administration of CBD was
shown to reduce resting systolic blood pressure and stroke volume, while
increasing the heart rate and maintaining cardiac output. Furthermore,
cardiovascular parameters in response to various stress stimuli was
modified following CBD administration(Jadoon et al., 2017). Further
studies are required to see whether CBD can play a role in the treatment
of cardiovascular disorders.
However, studies carried out in animals and humans largely indicate
little to no effects on resting blood pressure or heart rate following
CBD administration. Still, CBD treatment was shown to reduce the
cardiovascular response to various types of stress. Taken together, the
cardiovascular system may benefit from CBD treatment, but targets sites
for CBD remain to be elucidated.
Diabetes
Type 1 diabetes mellitus is an autoimmune disease resulting in
destruction of pancreatic beta cells, a process assumed to be mediated
mainly by CD4 Th1 and CD8 T lymphocytes(MANDRUP-POULSEN, 2003). CBD is a
potent anti-inflammatory agent(Nichols & Kaplan, 2020). It is effective
in suppressing IFN-γ and TNF-α production and progression of autoimmune
Th1-mediated rheumatoid arthritis by inhibition of T cell
proliferation(Malfait et al., 2000). Studies have shown that CBD
significantly inhibited insulitis in Non-Obese Diabetic (NOD) mice(L.
Weiss et al., 2006; Lola Weiss et al., 2008). CBD has multiple desirable
effects in the context of hyperglycemia, mainly through its
anti-inflammatory(Burstein, 2015) and antioxidant properties(Hammell et
al., 2016). Interestingly, a chronic overactivation of the
endocannabinoid system has been identified in obesity and type 2
diabetes, (Di Marzo, 2008) suggesting a potential therapeutic use for
CBD in treating type 2 diabetes also.
The safety and effectiveness of CBD and Δ(9)-tetrahydrocannabivarin
(THCV, a naturally occurring analog of THC) in insulin naïve patients
with type 2 diabetes (n=62) was investigated in a randomized,
double-blind, placebo-controlled, parallel group pilot study five
treatment arms were assessed: CBD (100 mg twice daily), THCV (5 mg twice
daily), 1:1 ratio of CBD and THCV (5 mg/5 mg, twice daily), 20:1 ratio
of CBD and THCV (100 mg/5 mg, twice daily), or matched placebo for 13
weeks(Jadoon et al., 2016) (Table 2). The trial failed to meet the
primary efficacy endpoint which was a change in HDL cholesterol
concentrations from baseline. While both agents were well tolerated, a
majority of patients experienced adverse events. Interestingly, THCV
significantly decreased fasting plasma glucose and improved pancreatic
beta-cell function while CBD decreased resistin and increased
glucose-dependent insulin tropic peptide(Jadoon et al., 2016).
Pain
management
Pain has long been characterized as a subjective experience encompassing
sensory-physiological, motivational-affective and cognitive-evaluative
components(Melzack & Wall, 1965). Nociceptive pain is caused by damage
to body tissues and is usually described as sharp, aching, or throbbing
pain. Neuropathic pain is caused by damage to sensory or spinal nerves,
which send inaccurate pain messages to higher centers.(Kremer, Salvat,
Muller, Yalcin, & Barrot, 2016) Inflammatory pain is caused by noxious
stimuli that occur during the inflammatory or immune response(Vasko,
2009). Chronic pain is defined as recurrent or constant pain that lasts
or recurs for longer than three months and can result in disability,
suffering, and a physical disturbance(Cathy M. Russo & William G.
Brose, 1998). Chronic pain affects 20% of the population, with
musculoskeletal disorders being the most common cause(Mills, Nicolson,
& Smith, 2019). The International Classification of Diseases 11
(ICD-11) has developed a systematic classification of chronic pain into
seven different categories: chronic primary pain, chronic cancer-related
pain, chronic postsurgical or posttraumatic pain, chronic neuropathic
pain, chronic secondary headache or orofacial pain, chronic secondary
visceral pain, and chronic secondary musculoskeletal pain(Treede et al.,
2015).
CBD can be therapeutically beneficial in managing chronic pain. As
presented before, CBD has low affinity to the orthosteric binding site
of the CB1 and CB2 receptors(McPartland
et al., 2007), and has allosteric activity on both CB1and CB2 receptors(Laprairie et al., 2015;
Martínez-Pinilla et al., 2017). The CB1 receptor is
mainly expressed in the CNS, particularly in the regions of the midbrain
and spinal cord that are both responsible for pain
perception(Manzanares, Julian, & Carrascosa, 2006). The antagonistic
effects of CBD on CB2 play an important role in the anti-inflammatory
response of suppression of mast cell degranulation and neutrophil
propagation in the vicinity of pain centers(Pertwee, 2008). Another
putative CBD target is GPR2, which is expressed in the brain and spinal
cord and is involved in pain reception(Ruiz-Medina, Ledent, & Valverde,
2011). CBD may also relieve pain by regulating the serotonin
5-HT1A receptor(Ethan B. Russo et al., 2005) and
TRPV1(Di Marzo, Bifulco, & De Petrocellis, 2004).
The therapeutic analgesic potential of a sublingual CBD spray for
uncontrolled neuropathic pain was investigated previously in 34 patients
(Table 2). The patients were given 2.5 mg CBD, 2.5 mg THC, 2.5 mg THC
with 2.5 mg CBD mixture (THC:CBD) or placebo in 1-week intervals
following an open-label 2-week THC : CBD run-in period. Pain assessments
were made using a visual analog scale (VAS). During the run-in period,
16 of 34 patients had a greater than 50% decrease in VAS for either one
of their two main symptoms sites. Furthermore, 10 of 16 patients
reported greater than 50% reduction in VAS for both symptoms(Notcutt et
al., 2004).
In another prospective cohort study, the impact of CBD on opioid use was
investigated in 97 patients with a diagnosis of chronic pain and on
stable opioids use for at least 1 year(Capano, Weaver, & Burkman, 2020)
(Table 2). Ninety-four patients were able to tolerate twice-daily, hemp
derived CBD-rich soft gels, which contained 15.7 mg CBD, 0.5 mg THC, 0.3
mg cannabidivarin, 0.9 mg cannabidiolic acid, 0.8 mg cannabichromene,
and >1% botanical terpene blend. The improvement was
evaluated by Pain Disability Index (PDI-4), Pittsburgh Sleep Quality
Index (PSQI), Pain Intensity and Interference (PEG) and Patient Health
Questionnaire (PHQ-4). Fifty of the 94 patients using the CBD extract
were successfully able to reduce their dependence on opioids for pain
control and 94% of CBD users reported improvements of life
quality(Capano et al., 2020). There is also moderate evidence from a
meta-analysis to support the analgesic use of cannabinoids in treating
chronic, non-cancer pain defined as as fibromyalgia, rheumatoid
arthritis, neuropathic pain, or mixed pain (Table 2). The mean treatment
duration was 2.8 weeks.(Johal et al., 2020)
Cancer pain is a common problem, and 70% to 90% of patients with
advanced cancer experience significant pain(Quigley, 2005). Opioids
remain the keystone for the treatment of moderate to severe cancer
pain(Kalso, Edwards, Moore, & McQuay, 2004). Evidence for pain control
with CBD in the cancer setting comes from a Phase 2 study that recruited
177 patients with cancer pain, who experienced inadequate analgesia
despite chronic opioid dosing(J. R. Johnson et al., 2010) (Table 2). In
this study, patients received either THC:CBD extract (n = 60), THC
extract (n = 58), or placebo (n = 59) for 2-weeks as an oromucosal
spray. With regards to pain, 43% of patients taking the THC:CBD extract
achieved a 30% or greater improvement in their pain score. Furthermore,
the THC:CBD combination showed a more promising efficacy compared to THC
alone(J. R. Johnson et al., 2010).
Treatment of cancer
It has been hypothesized that CBD has robust anti-proliferative and
pro-apoptotic effects. In addition, it may inhibit cancer cell
migration, invasion, and metastasis.(Moreno, Cavic, Krivokuca, Casadó,
& Canela, 2019; Piomelli, 2003)
The anti-tumor effects of CBD may primarily be mediated through the TRPV
channels(Bujak, Kosmala, Szopa, Majchrzak, & Bednarczyk, 2019). These
channels play an important role in regulating the cytoplasmic calcium
concentration from the extracellular sources as well as the calcium
stored within the endoplastic reticulum. Disruption of cellular calcium
homeostasis can lead to increased production of reactive oxygen species
(ROS), ER stress, and cell death.(Haustrate, Prevarskaya, & Lehen’kyi,
2020) (Fig. 3). For a more in-depth understanding of the mechanism of
the CBD in the treatment of cancer, we refer you to other excellent
reviews on the topic(Paola Massi et al., 2013; Seltzer et al., 2020).
Multiple cancer-related studies demonstrated that CBD exhibits
pro-apoptotic and anti-proliferative actions(McAllister et al., 2011) in
different types of tumors, and may also exert anti-migratory,
anti-invasive(Ramer & Hinz, 2008; Ramer, Merkord, Rohde, & Hinz,
2010), anti-metastatic and perhaps anti-angiogenic properties. CBD
potently inhibited the growth of different tumors, including those of
breast cancer(McAllister, Christian, Horowitz, Garcia, & Desprez,
2007), lung cancer(Ramer, Rohde, Merkord, Rohde, & Hinz, 2010), colon
cancer(Aviello et al., 2012), prostate cancer(Luciano De Petrocellis et
al., 2013), colorectal cancer(Jeong et al., 2019; Ligresti et al., 2003;
SREEVALSAN, JOSEPH, JUTOORU, CHADALAPAKA, & SAFE, 2011),
glioma(Jacobsson, Rongård, Stridh, Tiger, & Fowler, 2000; P. Massi et
al., 2006; Paola Massi et al., 2004), leukemia/lymphoma(Gallily et al.,
2003; McKallip et al., 2006) and endocrine cancer(Lee et al., 2008; Wu
et al., 2008). Interestingly, the anticancer effect of this compound
seems to be selective for cancer cells, at least in vitro , since
it did not affect normal cell lines.
Currently, there are no large efficacy clinical studies on exploring CBD
treatment for cancer. Clinical evidence supporting CBD’s anticancer
activity comes from a case analysis study of 119 solid tumor patients
enrolled under the Pharmaceutical Specials scheme; of the 119 patients,
28 received CBD oil as the only treatment(Kenyon, Liu, & Dalgleish,
2018) (Table 2). CBD was administered on a three days on and three days
off basis, which clinically was found to be more effective than giving
it as a continuous dose. The average dose was 10 mg twice daily and in
some cases the dose was increased up to 30 mg twice daily. Anti-tumor
effect was observed when the CBD treatment duration was at least 6
months. In the case of a five-year-old male patient with an anaplastic
ependymoma who had failed all standard treatments with no further
treatment options, CBD was applied as the only treatment and tumor
volume had decreased by around 60% after 10 months of treatment. Other
patients with prostate cancer, breast cancer, esophageal cancer, and
lymphoma also saw a reduction in circulating tumor cells and tumor size.
No side effects of any kind were observed when using CBD. These results
strongly support the development of CBD-based products for cancer
patients who have exhausted all standard treatments.(Kenyon et al.,
2018)
Other than directly being used to treat cancer, CBD has also used to
reduce the adverse effects associated with cancer treatment.
Chemotherapy-induced nausea and vomiting (CINV) remain major adverse
effects of cancer chemotherapy(Rao & Faso, 2012). The lack of adequate
CINV control may be partly attributed to the fact that antiemetic
treatment regimens are guided by risk factors, including level of
emetogenicity of chemotherapeutic agents(Yokoe et al., 2019). CINV
adversely impacts patients’ quality of life. Patients rated nausea as
their first most feared symptom and vomiting as their
third(Bloechl-Daum, Deuson, Mavros, Hansen, &
Herrstedt, 2006). A phase 2 clinical trial designed to evaluate the
efficacy of cannabis-based medicine containing 2.7 mg of THC and 2.5 mg
of CBD, taken in conjunction with standard anti-emetic treatment in the
control of CINV was conducted in 16 patients; a higher proportion of
patients in the cannabis group experienced a complete response during
the overall observation period(Duran et al., 2010) (Table 2). Similarly,
a phase 2 study with 78 cancer patients showed that the addition of oral
cannabis extract (THC 2.5 mg/CBD 2.5 mg) to standard antimetric
treatment during chemotherapy was associated with an increased
proportion of patients achieving complete responses, and a lower
incidence of nausea and vomiting(Grimison et al.,
2020) (Table 2).