Medicinal cannabidiol: pharmacology and neurotherapeutic implications
1
Contents
Table of abbreviations ........................................................................................................... 3
Lay abstract .......................................................................................................................... 4
Scientific abstract .................................................................................................................. 4
Introduction ........................................................................................................................... 5
Methods ................................................................................................................................ 6
Discussion ............................................................................................................................ 6
Pharmacology of CBD ....................................................................................................... 6
Chemical structure of CBD in relation to other cannabinoids. ......................................... 6
Pharmacokinetics of CBD .............................................................................................. 7
pharmacodynamics of CBD............................................................................................ 8
Therapeutic Potential of CBD .......................................................................................... 10
As an antipsychotic. ..................................................................................................... 10
As an anxiolytic. ........................................................................................................... 11
As an antiepileptic. ....................................................................................................... 12
As an intervention for addictive behaviours. ................................................................. 13
As a neuroprotective and neurogenic agent. ................................................................ 14
Pharmacokinetic limitations .......................................................................................... 14
Conclusion .......................................................................................................................... 15
Table of Figures and Tables................................................................................................ 16
References ......................................................................................................................... 20
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Table of abbreviations
Abbreviation
C. Sativa
Δ9-THC
(−)-CBD
CBR
CNS
A1
2-AG
Cmax
Varea/F
T1/2
GPCR
CB1
CB2
FAAH
CYP
AC
cAMP
GPR55
IP3
D2
5-HT1A
MOR
Ca2+
ENT
PPAR
AD
TRPV1
Na+
RCT
SAD
OUD
PNL
Meaning
Cannabis Sativa
(-)-Trans-Δ9-Tetrahydrocannabinol
Cannabidiol
Cannabinoid receptor
Central nervous system
Adenosine 1 receptor
2-arachidononolygylcerol
Peak plasma concentration
Volume of distribution
Elimination half-life
G-protein coupled receptor
Cannabinoid receptor 1
Cannabinoid receptor 2
fatty acid amide hydrolase
Cytochrome P450
adenylyl cyclase
cyclic adenosine monophosphate
G-protein receptor 55
inositol 1,4,5-triphosphate
Dopamine 2
Serotonin 1A
µ-opioid receptor
Ionic calcium
equilibrative nucleoside transporter
Peroxisome-proliferator-activated receptor
Alzheimer’s disease
Transient receptor potential vanilloid 1
Ionic sodium
Randomised controlled trial
Social anxiety disorder
Opioid use disorder
piperine-pro-nanolipospheres (PNL).(122)
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Lay abstract
The cannabis plant has two major compounds: THC and CBD. THC gives the “high” feeling of
cannabis use. Despite its fame today as an alternative medicine, little is known about CBD.
Early animal and clinical studies have found a range of properties associated with CBD. These
properties range from a reduction in anxiety and pain, to the treatment of symptoms in major
neurological disorders such as schizophrenia and epilepsy. New studies claim protective effects in
the brains of Alzheimer’s and Parkinson’s disease patients, or as an intervention to addiction and
substance abuse.
The strongest supporting evidence for medicinal CBD is in treatment of epilepsy. Large, high-quality
clinical trials show a reduction of seizures in patients unresponsive to normal antiepileptic
medication. Legalisation of cannabis-based medication in the United Kingdom, has led to the
approval of CBD in treating epilepsy, under the name Epidiolex®.
However, a lot is still unknown with CBD, for example, the long-term effects of prolonged high
doses, interactions with other drugs, and its effectiveness in treating non-approved disorders.
Because of this, more studies are required to improve current knowledge on CBD medicinal
biochemistry, before its approval of use in clinical practice.
Scientific abstract
Two major active compounds are found in the Cannabis Sativa plant: psychoactive (−)-trans-Δ⁹tetrahydrocannabinol (Δ9-THC) and cannabidiol ((−)-CBD). Legalisation of cannabis-based medicines
allowed for the approval of two (−)-CBD-containing drugs, a (−)-CBD oral formulation (Epidiolex®)
and a CBD:THC oromucosal spray (Sativex®). (−)-CBD as a therapeutic has become a popular
alternative medicine, however, it is still not fully understood.
Pharmacokinetic research shows that oral use, the most common form of administration, lacks
dosage efficiency because of its relatively low bioavailability (31%) due to high levels of hepatic
metabolism before entering circulation. Pharmacological findings include endocannabinoid,
serotonergic, dopaminergic, and opioid system modulation. Nuclear transcription and ionic gradient
regulation have also been suggested.
Animal studies, case reports, and preliminary trials report antiepileptic, anxiolytic, antiaddictive, and
antipsychotic effects. Neuroprotection against β-amyloid neurotoxicity is a novel finding, suggesting
Alzheimer’s disease therapeutic potential. Clinical use has only been approved as an antiepileptic,
with powered phase 3 trials showing effective, well tolerated treatment in patients.
A lot is still not known however, there is a lack of high-powered research into drug-drug interactions,
long-term dosage effects, and effectiveness amongst other suggested therapeutics. More clinical
trials must be conducted on these suggested limitations to improve current knowledge into
therapeutic (−)-CBD.
4
Introduction
Cannabis is a psychoactive plant that has been cultivated and used by humanity for thousands of
years.(1) Archaeological findings of cannabis agriculture in China date as far back as the 40th century
BC, making Cannabis Sativa (C. sativa) one of the earliest known plants to be manipulated by
mankind.(1) Medical use of cannabis can be seen first reported in ancient China.(1) First isolated
from the plant C. sativa in 1940 by American chemist Roger Adams, cannabidiol ((−)-CBD) is a
crystalline solid at room temperature, having the molecular formula C21H30O2.(2) This was then
followed with discoveries of the psychoactive cannabinoid, (−)-trans-Δ⁹-tetrahydrocannabinol (Δ9THC)(3). The focus of this narrative review will be on the pharmacology and possible therapeutic
implications of compound (−)-CBD.
(−)-CBD is an active non-psychotropic cannabinoid found in cannabis.(1) The structure of (−)-CBD
was discovered and confirmed in 1963 by Mechoulam et al., using organic chemical analysis
methods such as nuclear magnetic resonance spectroscopy.(4) As a cannabinoid, (−)-CBD interacts
and modulates signalling in the endocannabinoid system, through cannabinoid receptor (CBR)
signalling, which in turn alters neural activity of different regions of the central nervous system
(CNS). (5–7) (−)-CBD has also been reported to alter activity in the striatal, limbic, and raphe nuclei
areas of the brain, through interactions with serotonin and dopamine receptor systems.(8,9)
Interactions with opioid and pain signalling systems have also been attributed to (−)-CBD.(10,11) (−)CBD activity at adenosine receptors (A1) has also been studied.(12) (−)-CBD has also been
implicated in regulation of ionic concentrations and intracellular actions.(13–15) Due to all these
proposed methods of action, the clinical relevance of (−)-CBD is being investigated.
An ever-growing body of research is ongoing into the therapeutic potential of (−)-CBD (1). Public
interest has also greatly increased over the past decade as it has been implicated to hold many
therapeutic benefits. Many positive pharmacological actions have been attributed to (−)-CBD
including its use in: antipsychotics,(16–19) anxiolytics,(20–22) antiepileptics,(23,24) substance abuse
interventions,(25–27), and a novel findings suggest (−)-CBD use as a neuroprotective
agent.(14,28,29)
However, (−)-CBD is currently only recommended for use in one of the listed illnesses, as an
antiepileptic for treatment-resistant forms of epilepsy.(30) In the United Kingdom, only two
approved (−)-CBD medicines exist: Epidiolex® (oral oil solution) and Sativex® (Oromucosal THC:CBD
spray).(30) The reason for this is the lack of well powered clinical trials on most of the proposed
therapeutic properties of (−)-CBD. Pharmacological limitations as a drug also exist, with oral
administration, the favored method of delivery, resulting in low circulatory levels due to hepatic
metabolism.(31) In this literature review, preclinical and clinical findings on CBD’s pharmacological
properties and therapeutic potential shall be investigated, to assess the clinical relevance of the
cannabis extract (−)-CBD.
5
Methods
For case studies, clinical trials, and review papers were found on research databases such as
PubMed, PubMed Central, and Google Scholar. Search parameters consisted of essential terms such
as “Cannabidiol”, “Endocannabinoid”, “(−)-trans-Δ⁹-tetrahydrocannabinol”, “Sativex”, and
“Epidiolex”. When searching for pharmacological properties, searches were paired with
“Pharmacodynamics” or “Pharmacokinetics”. When searching for therapeutic uses, essential terms
included “antipsychotic”, “anxiolytic”, “antiepileptic”, “anticonvulsant”, “substance abuse
intervention”, “reward”, “dependence”, “neuroprotective”, and “neurogenic”. No limit was given on
the dates of included studies as research dates to 1940.(2)
Chemical formulae and structures were obtained from PubChem databases, CIDs included were:
2978,(32) 644019,(33) 700,(34) 753,(35) 444899,(36) 5281969,(37) 5282280, 6449999,(38)
160570,(39) and 98523,(40).(41) Two future studies were obtained from ClinicalTrials.gov, identifier
numbers: NCT03813095,(42) and NCT04205682.(43)
Discussion
Pharmacology of CBD
Chemical structure of CBD in relation to other cannabinoids.
Both Δ9-THC and (−)-CBD have similar biosynthesis pathways; being produced via the conversion of
cannabigerolic acid into cannabidiolic acid or Δ9-tetrahydrocannabinolic acid.(44) These acid forms is
both compounds are stored in the C. sativa plant, heating of the plant causes spontaneous
decarboxylation of these acidic compounds into the active drugs Δ9-THC and (−)-CBD (Fig 1.).(44)
Whilst identical in molecular formulae to its psychoactive counterpart Δ9-THC,(3) (−)-CBD has a
hydroxyl group in place of the pyran core seen in Δ9-THC (Fig. 2).(2–4) The biosynthesis of
endogenous cannabinoids differs from that of C. sativa cannabinoids. Instead of alkylation and
decarboxylation seen in Δ9-THC and (−)-CBD, endogenous cannabinoids are synthesised via the
enzymatic oxidation of arachidonic acid (Fig. 3), this places them into a group of signalling molecules
known as eicosanoids.(5,45) Two of the first eicosanoids of the cannabinoid system discovered are
anandamide, a arachidonic acid amide formed by phosphodiesterase conversion of N-arachidonoyl
phosphatidylethanolamine,(46,47) and 2-arachidononolygylcerol (2-AG), an ester of arachidonic acid
that can be formed by diacylglycerol lipase converting diacylglycerol (Fig 3.).(47–49) (−)-CBD is
unique in a way, as unlike Δ9-THC and endogenous cannabinoids, it does not seem to bind to the
orthosteric sites of the CBRs, having extremely low affinity for both receptors,(50,51) how this might
impact the pharmacology and action of (−)-CBD will be discussed in later sections. (−)-CBD does not
share the common benzo[c]chromene motif seen in Δ9-THC and it’s analogues (Fig. 2), instead it is
made up of three parts: limonene, resorcinol, and a C4’-alkyl chain (Fig. 2).(51) These three
structures that make up (−)-CBD allow for structural analogues to be divided into three categories
based on moieties.(51)
Whilst, the focus of this review is on possible therapeutic effects of (−)-CBD, understanding its
structure and how analogues may be synthesised from its different moieties may lead to future
developments of CBD-based therapeutics. Some examples have been researched previously, such as
the creation C4’ alkyl group analogues of (−)-CBD to increase permeability, oral bioavailability, and
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neuroprotective potency, essentially “drugifying” natural (−)-CBD.(52) Halogenation of the resorcinol
ring in (−)-CBD with fluorine was also tested on mice for therapeutic effects, findings presented
significantly enhanced potency of anxiolytic, antidepressant and antipsychotic effects.(53) (−)-CBD’s
possible therapeutic effects will be analysed in the later section of this review, which will further
discuss the idea that some of (−)-CBD’s limitations in its effects may resolved through structural
alterations.
Pharmacokinetics of CBD.
The pharmacokinetics of (−)-CBD has been researched extensively in preclinical animal
models,(54,55) however this review will be focussing on human-CBD pharmacokinetics. Major
avenues of administration of (−)-CBD are: 1) Oral administration(56–58) 2) Oromucosal spray(59,60)
3) intravenous administration(61) and 4) controlled smoking and inhalation.(62,63) Topical (−)-CBD is
also used, but as it is mostly used for dermatological purposes.(64) However, in 2020 Xu et al.(65)
did find significant relief of painful symptoms in peripheral neuropathy patients using topically
administered (−)-CBD, suggesting use in localised algesia. Here we assess the absorption,
distribution, metabolism, and elimination of (−)-CBD.
Absorption. Absorption into body’s systemic circulation is determined by the route of drug
delivery.(66) Smoking is the primary method of C. sativa administration,(67) and a study by Ohlsson
et al.(62) found plasma concentrations of (−)-CBD were rapidly increased after smoking a 18.8-19.4
mg deuterium-labelled (−)-CBD cigarette, reaching an average maximal concentration (Cmax) of
110ng/mL 3 minutes after intake, dropping down to 10.2ng/mL an hour later.(62) The average
bioavailability, the percentage of drug present in circulation after administration, after smoking was
31%±13.4% between participants,(62) which is relatively high compared to the low availability of the
clinically used oral formulations (<20%).(56,61) Haney et al.(56) reported varied oral Cmax, ranging
from 1.6 to 271ng/ml, reached after an average of 180 minutes. Intravenous administration
disregards absorption as dose is given directly into circulation.
Distribution. There is a lack of published data on differences in tissue distributions in humans,(68)
however the volume of distribution (Varea/F) for some methods of administration has been
reported.(59,62) Stott et al.(59) found a high Varea/F after a single dose of oromucosal spray
(22,169, 18,800, and 30,595L after two, four, and eight spray doses respectively). Ohlsson et al.(62)
reported Varea/F of 2,520L after Intravenous administration, suggesting that very little (−)-CBD is left
in the plasma, with most of the drug being in tissues.(69) The high volume of distribution seen in (−)CBD, does not necessarily indicate that the (−)-CBD is reaching its site of action for therapeutic
effects,(69) it does indicate however that (−)-CBD does not stay in plasma. More research is needed
into the distribution patterns of (−)-CBD in different tissues, and how it may be optimised to provide
therapeutic benefits.
Metabolism. Oral (−)-CBD is metabolised by enzymes in both the intestines and the liver, lowering its
concentration significantly before it reaches circulation.(70) First-pass metabolism still occurs during
smoking and inhalation, albeit to a much reduced extent due to the lower levels of metabolising
enzymes in the lungs.(66) Oromucosal sprays set to bypass first-pass metabolism, being
administered directly to membrane surfaces in the mouth such as under the tongue (sublingually)
and being absorbed by the mucosa, but lesions and other adverse side effects have been associated
with sprays.(59,70) The enzymes involved in hepatic metabolism of (−)-CBD are isozymes of
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cytochrome P450 (CYPs), specifically 7 of the known 14 CYPs may be involved in (−)-CBD metabolism:
CYP1A1, CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5 (31). Results from Jiang et al.(31)
suggest that CYP3A4 and CYP2C19 play the primary role in metabolising (−)-CBD. Some metabolites
of CBD also seem to present pharmacological properties, such as anticonvulsant properties, further
research into CBD metabolite interactions is needed.(31)
Elimination. Excretion from the body may differ dependent on route of administration.(59,61–63) An
important aspect of elimination is the half-life (t1/2), time taken for the elimination of half the initial
drug concentration in the blood.(71) Ohlsson et al.(62) found that after receiving (−)-CBD
intravenously, the mean t1/2 was 24h, with smoking giving a t1/2 of 31h, both of which fall into a
desirable range for daily dosing.(71) Oromucosal sprays, whilst seemingly a promising alternative to
oral administration for bioavailability, showed a low t1/2 in a study by Stott et al., ranging from 5.28
to 9.36h depending on single dose range (two to eight sprays of 5-20 mg doses).(59) A low t1/2
suggests a fast acting, short lasting effect, alongside the relatively low dosages of Oromucosal
sprays, means multiple sprays daily are needed to see any lasting effects. Oral administration of a 10
mg (−)-CBD dose resulted in a mean t1/2 value of 1.09h.(63) Very high oral dosages (1500-6000 mg),
studied by Taylor et al.(72), showed half-lives ranging between 14-17 hours, but seemed
independent of dose, other factors such as a higher Varea/F effects t1/2. Consroe et al.(73) reported a
t1/2 of 2-5 days after repeated daily oral doses of (−)-CBD, suggesting its use in the treatment of
chronic diseases such as epilepsy.(74) (−)-CBD is excreted from the body as both metabolites and its
unchanged form through the kidneys and urinary excretion, as well as the liver and faecal
excretion.(75)
pharmacodynamics of CBD.
Whilst understanding the pathway of (−)-CBD within the body is essential for pharmaceutical
research, it is also important to explain the effect on the body caused by (−)-CBD and how this done,
i.e., its role as a ligand, the receptors it may bind to, and how these chemical interactions elicit
biological responses. (−)-CBD modulation of receptor systems is still poorly understood, however
current research is trying to elucidate mechanisms of action.
The main interactions that were first researched between (−)-CBD and receptors in our body was
with cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2).(5,6) CBRs, endocannabinoids,
and enzymes such as fatty acid amide hydrolase (FAAH), make up the endocannabinoid system.(5)
CBRs are the most abundant G protein-coupled receptors (GPCRs) in the CNS.(5,6) Dove Pettit et
al.(76) reported that the CB1 protein was primarily detected in neural tissue in rodents,(76) involved
in regulating presynaptic neurotransmitter release.(5) CB2 is commonly found on immune tissues
and are involved in the regulation of cytokine release.(5,45) CBR activation leads to the inhibition of
intracellular protein adenylyl cyclase (AC), reducing the AC-mediated production of cyclic adenosine
monophosphate (cAMP) (Fig.4), whilst stimulating mitogen-activated protein kinase.(45,77) Ion
channel regulation also occurs (Fig.4).(77) CB1 mechanisms work to inhibit the release of
neurotransmitters from the presynaptic neuron, whilst also decreasing firing from adjacent neurons
as well.(5,76,77) (−)-CBD acts as a CBR antagonist.(78) In vitro analysis of whole-brain mice
membranes expressing human CBRs, reported low affinity for orthosteric sites by (−)-CBD compared
to phytocannabinoid Δ9-THC.(78) (−)-CBD displays high potency ((−)-CBD concentration of 10µM)
antagonistic effects on CB1 receptors and their agonists.(78) The low affinity seen suggests (−)-CBD
may exert its antagonistic effect through allosteric modulation.(78) Laprairie et al.(6) reported (−)8
CBD interacts through negative allosteric modulation, at a site distinct from the orthosteric site
where agonists such as Δ9-THC bind to. A novel cannabinoid receptor discovered is G-protein
receptor 55 (GPR55), that increases intracellular calcium (Ca2+) via the Gq pathway, increasing
cellular inositol 1,4,5-triphosphate (IP3) which in turn release Ca2+ stores sensitive to IP3.(79) (−)-CBD
seemingly antagonises GRP55 function.(7) Enhanced function of the GPR55 has been related to
epileptic symptoms due to the increase of cellular Ca2+, promoting excitability in hippocampal
pyramidal neurons, an effect that was inhibited by (−)-CBD in vitro.(7)
(−)-CBD also seems to interact with other major CNS receptors such as dopamine 2 (D2),(8)
serotonin 1A (5-HT1A),(80–82) and µ-opioid (MOR) receptors.(10,83) Supersensitivity to dopamine by
an heightened affinity state of D2 is a hypothesised contributing factor to psychosis.(84) In vitro (−)CBD studies have shown that (−)-CBD may act as a partial competitive agonist with dopamine at D2
receptor binding sites, this can also be seen in vivo with preclinical models.(8,85) The method in
which (−)-CBD exerts its partial agonistic effect on D2 receptors is similar to that of aripiprazole an
antipsychotic drug, inducing dopaminergic signalling at a diminished strength, suggesting possible
clinical benefits.(8)
5-HT1A is a serotonin receptor subtype involved in many areas of the brain, dysfunction contributes
to neurological disorders such as general anxiety disorder.(86) (−)-CBD in vitro has been shown to act
as a direct agonist of 5-HT1A receptors.(9) As physiologically activated 5-HT1A by serotonin elicits a
reduction in intracellular cAMP productions, (−)-CBD acting as a full agonist would reduce cAMP
production, which has been shown in vitro by Russo et al.(9). In vivo studies looking at mammalian
behaviour report that 5-HT1A agonism via intraperitoneal injections leads to anxiolytic qualities that
may be clinically relevant.(82) Antiaddictive effects associated with (−)-CBD have also been linked to
5-HT1A agonism, as blocking the receptor with a antagonist, such as WAY-100635, reverses these
effects.(80,81)
MOR has also been studied for interactions with (−)-CBD.(10) Kathmann et al.(10) found agonist
dissociation from MORs was accelerated twofold by (−)-CBD, suggesting a form of negative allosteric
modulation. High concentrations would be needed to see similar effects in-vivo.(10) MOR
interactions with CB1 may exist, as reduced CB1 expression reduces reward effects from opioid
administration; a CB1 antagonist such as (−)-CBD may offer clinical advantages in antiaddictive
interventions.(87) (−)-CBD administration may also directly inhibit the expression of MOR in the
nucleus accumbens, an important area of the CNS involved in reward signalling, opening up the
discussion into clinical uses.(88)
(−)-CBD also seems to have intracellular interactions.(14,15,89) Peroxisome-proliferator-activated
receptor γ (PPARγ) agonism by (−)-CBD may elicit neuroprotective effects, reducing an increase in
blood-brain barrier permeability that usually occurs with oxygen and glucose deprivation.(14) Invitro, (−)-CBD reduces expression of β-amyloid in Alzheimer’s disease (AD) neuronal cell models, all
of this is reversed by PPARγ antagonists.(14) (−)-CBD may regulate cellular Ca2+ concentration via
mitochondrial Ca2+ channels, seemingly protecting against hydrogen peroxide toxicity and other
mitochondrial malfunction.(15) Another important action of (−)-CBD is direct inhibition of FAAH,
which reduces the degradation of endocannabinoids such as anandamide.(89) Changes in
anandamide serum levels may suggest antipsychotic properties of (−)-CBD.(19)
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Evidence also exists that (−)-CBD can modulate A1 and equilibrative nucleoside transporters (ENT),
as well as ion channels, including transient receptor potential vanilloid 1 (TRPV1)
channels.(11,12,90,91) A single dose of (−)-CBD in rodents seemed to activate A1 receptors.(12) (−)CBD also inhibits adenosine uptake by ENT, increasing interstitial adenosine concentration.(12,92)
A1 regulation may explain antiepileptic action associated with (−)-CBD.(93) TRPV1 channels are
ligand-gated Ca2+ channels involved in nociception and capsaicin-induced spicy sensations.(94)
Interactions exist between TRPV1 and (−)-CBD , as Ca2+ influxes were seen in vitro after the
application of (−)-CBD, followed by nociceptor desensitization, a characteristic associated with
analgesic effects, which was abolished by TRPV1 antagonists.(11) 1µMol/L (−)-CBD desensitized
TRPV1 activation via the inhibition of cAMP production, higher concentrations of (−)-CBD (10
µMol/L) seem to elicit more agonistic effects of TRPV1, lowering its subsequent desensitisation.(11)
CBD also seems to inhibit sodium (Na+) channels,(91) dysfunction and sensitivity of these has been
causally associated with types of epilepsies,(95) opening up another debate on the clinical
functionality of (−)-CBD, which will be addressed in the next section.
Therapeutic Potential of CBD
Clinical relevance of the pharmacological effects seen from (−)-CBD remains controversial. This
section will appraise current clinical evidence for the use of (−)-CBD as an antipsychotic, anxiolytic,
and antiepileptic. It will also analyse clinical research into more novel therapeutic potentials such as
antiaddictive interventions, and as a neuroprotective and neurogenic agent.
As an antipsychotic.
As shown in the previous section, pharmacological properties such as FAAH inhibition,(19) CBR
allosteric antagonism,(6) and D2 partial agonism(8) opens discussion into potential therapeutic uses
of (−)-CBD in the treatment of psychotic symptoms in disorders like schizophrenia.
Clinical research on the effects of (−)-CBD on both healthy individuals and patients with psychosis
does exist. An early open case report by Zuardi et al.(16) showed that after treatment orally with (−)CBD, psychiatric assessments of the patient saw a reduction in psychotic symptoms, withdrawal of
(−)-CBD saw a worsening trend of symptoms.(16) A follow-up in 2006 on the results of early case
reports tested the use of (−)-CBD as a monotherapy (single drug intervention) for patients with
treatment-resistant schizophrenia.(96) progressive increase of (−)-CBD doses from 40mg to
1280mg/day were given over a four week period, finding no efficacy in treatment in two of the three
patients.(96) The lack of effect may be due to several reasons, such as the low starting dosages of
40mg over a short amount of time or the lack of a larger group size meaning the real general effects
cannot be seen.(96) This early evidence suggests that whilst (−)-CBD may not offer support as a
monotherapy in schizophrenic patients, it is well tolerated at low to high doses, alongside its
mechanism of action, (−)-CBD may still have a role in psychosis treatment.(96) An issue with case
reports is that the low group sizes means that the findings cannot be generalised, as individual
differences to treatment cannot be ruled out.
As monotherapy of (−)-CBD was shown to not be effective in treatment-resistant schizophrenia, a
randomised controlled trial (RCT) by McGuire et al. assessed 42 patients were prescribed a
1000mg/day (−)-CBD orally over six weeks as an adjunctive treatment.(18) Significant improvements
were seen in psychotic symptoms and clinician assessments of illness severity.(18) These offer
stronger and clinically relevant evidence from the previous tests, as more participants measured
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against placebo groups allow for more powered data.(18) (−)-CBD drug interactions with the varied
primary medications of schizophrenic patients may have altered the results seen in the study,
limiting the precision of their findings.(18)
Single dose 600mg trials on patients with a clinically high risk of psychosis also found that (−)-CBD
modulated striatal and parahippocampal activation in a way that indicated reversal of
dysfunction.(97) This dose also seemingly modulated mediotemporal-striatal circuitry, dysfunction of
which is directly associated with psychosis.(97,98)
Promising support exists for (−)-CBD as an antipsychotic. Limitations need to be considered before
implementation into medical practice. One example is the lack of significant effect seen in the
improvement of negative psychotic symptoms.(18) Psychotic symptoms can be categorised distinctly
into positive or negative symptoms.(99) Positive symptoms, the ones seemingly effected by (−)CBD,(18) consist of distortions in behaviours, for example hallucinations and delusions.(99) Negative
symptoms defines the decrease or complete absence of normal behaviours, such as a lack of
motivations, and speech.(99) As explained in McGuire et al.(18) negative symptoms were not
altered; positive symptoms, whilst significant, were only moderately improved.
(−)-CBD, however modest, may still provide beneficial antipsychotic therapy, more large-scale clinical
trials are required to increase the body of evidence to support the use of (−)-CBD in medical practice.
As an anxiolytic.
Clinically, anxiety and stress disorders can be described as excess fear responses and worry that
impairs general functioning and causes distress.(100) Examples are generalised anxiety disorder,
social anxiety disorder (SAD), and post-traumatic stress disorder.(100) Symptoms include fear,
worrisome thoughts, sweating, and gastrointestinal distress.(100,101) The overlap between (−)-CBD
activity in the CNS and neurological dysfunction in anxiety,(97) may indicate (−)-CBD as a possible
candidate for a clinical anxiolytic agent.
Anxiolytic action has been reported since the early 1980’s.(102) These early findings suggested (−)CBD counteracted anxiogenic effects of Δ9-THC, no anxiolytic effects were felt with independent
administration of (−)-CBD.(102) This effect may be attributable to the antagonistic effect (−)-CBD has
on Δ9-THC receptor binding to CB1.(6) In 1989, behavioural analysis of mice showed that significant
antianxiety effects from (−)-CBD were present up until higher dosages (20mg/kg).(103) Combined,
these studies offered early interesting knowledge on anxiolytic properties of (−)-CBD.
Few clinical trials on anxiolytic activity of (−)-CBD exist. Crippa et al.(20) found after acute oral
administration of 400mg (−)-CBD in SAD patients, anxiety scores were significantly decreased
compared to placebo, suggesting possible anxiolytic effects with little adverse effects. The study also
correlated (−)-CBD administration to parahippocampal gyrus and hippocampus activity.(20)
Interestingly, this effect was found to be inhibitory to neural activity, unlike the increases seen in
healthy individuals in previous studies with (−)-CBD, suggesting differences in neural excitatory levels
between healthy and SAD individuals.(20) This may mean anxiolytic (−)-CBD action is through
inhibition of dysfunctional hyperactivity of parahippocampal gyrus and hippocampus in SAD.(20)
Another double-blind study measured the effect of 600mg (−)-CBD doses on SAD patients with
anxiety by simulated public speaking.(21) Treatment seemed to significantly reduce anxiety and
improve their speech performance.(21)
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In healthy subjects, one study found an oral dose of 300mg significantly reduced anxiety during a
simulated public speaking test, but this effect was not seen at lower doses (100mg) and higher doses
(900mg),(104) another study shortly after also found this same U-shaped curve of effective
concentration in (−)-CBD dosage, with 300mg being optimal to 150 and 600mg.(22) Implicating a
narrow dosage range must be met to achieve effective anxiolytic action. Possible activation of TRPV1
receptors at higher dosages, increasing glutamate release, may reduce anxiolytic effects seen from
CB1 and 5-HT1A interactions with (−)-CBD.(105)
These complexity between receptor systems and (−)-CBD, makes the application as an effective
anxiolytic more difficult. More trials on both patient and healthy groups are needed to establish (−)CBD anxiolytic mechanisms.
As an antiepileptic.
Epilepsy is a neurological disorder characterised by recurrent, spontaneous seizures.(106) These
seizures may be brought on by disruptions in the balance of neural activity in the brain, leading to
excessive neuronal excitation.(106) Ion channel dysregulation, a common factor in seizures,(106) is
an important target for the production of novel antiepileptics. Of the therapeutic properties
mentioned, only the use of (−)-CBD as an antiepileptic is recommended by the national institute of
clinical excellence, and can be prescribed for cases of treatment-resistant epilepsy.(30)
Anticonvulsant action in rodents was one of the earliest properties attributed to (−)-CBD.(107,108)
Small trials on epileptic patients found similar results, with moderate to higher doses (−)CBD.(74,109) Two phase 3 trials were essential contributors to the approval of (−)-CBD in the
treatment of epilepsy.(23,110) Both trials found that very high (−)-CBD dosages of 20mg/kg body
weight was well tolerated in epileptic patients, seizures were greatly reduced, with increased levels
of liver aminotransferase being the main adverse side effect.(23,110) Drug trials analysing the use of
(−)-CBD as a long-term antiepileptic found that treatment was well tolerated with limited side
effects, sustained significant reductions in seizure frequency was also reported.(111)
Drug-Drug interactions between (−)-CBD and known antiepileptics are being investigated currently.
Clobazam, stiripentol, and valproate are all commonly used antiepileptic medication.(112) In two
phase one trials investigating (−)-CBD interactions with antiepileptics, bidirectional interactions
between clobazam and (−)-CBD were present.(112,113) The active metabolite of clobazam (Nclobazam) was increased, alongside an increased exposure to (−)-CBD.(112,113) Stiripentol exposure
was also increased, whilst valproate didn’t have any major interactions.(112) Safety in both trials
were not compromised by drug interactions, however the increase of N-clobazam will need more
research, as this may mean (−)-CBD adjunct treatment may increase clobazam side effects.
(−)-CBD antiepileptic action is still not fully understood. A wide range of receptor interactions (Fig. 4)
may play a role in the regulating neural excitation.(13) Na+ channel mutations have been associated
with epilepsies, modulation by (−)-CBD may ameliorate dysfunction.(91) GRP55 inhibition by (−)-CBD
reduces downstream cellular signalling involved in excitation in cells.(7) TRPV1 expression is
increased epileptic disorders, so increased desensitisation by (−)-CBD, reducing Ca2+ influx in
neurons, may be another mechanism behind antiepileptic effects.(93) Adenosine also modulates
neuronal excitability, the ability of (−)-CBD to increase adenosine interstitial concentration by
inhibition of ENT, may allow adenosine to mediate and reduce neuronal signalling.(93) Whilst it is
not sure what mechanism (−)-CBD mediates antiepileptic effects through, it is possible a
12
combination of these effects allow for effective anticonvulsant properties, and whilst use as an
antiepileptic has been approved,(30) more research into its mechanism of action, long-term
treatment, and its use as a combined therapy with other drugs, is needed to optimise clinical
effectiveness.
As an intervention for addictive behaviours.
(−)-CBD shows inhibition of the rewarding effects of ethanol and morphine in rodents.(80,88) A body
of research into the potential of (−)-CBD as a novel intervention for substance abuse disorders is
currently growing.
Case reports have reported the use of (−)-CBD to reduce withdrawal symptoms in cannabis
dependent patients.(25) Crippa et al.(25) reported a significant reduction in withdrawal symptoms
after a cannabis dependent patient was treated with 600mg (−)-CBD doses over 10 days. Another
study investigating similar effects found marijuana strains with higher (−)-CBD content modulated
the reinforcing and addictive nature of Δ9-THC.(26) THC:CBD oromucosal spray was used to treat
cannabis dependence, finding that combination of the spray with behavioral therapy, decreased
cannabis use and helped with cravings.(114) A mechanism of action of (−)-CBD may prevent cannabis
dependency, and the modulation of addictive activity may be generalisable to other substances such
as morphine, alcohol, and cocaine. However, no known trials into the effect of (−)-CBD on addictive
behaviours and substance abuse have been published. One clinical double-blinded RCT from the
University of Sydney, currently set to begin this year, will be investigating the effectiveness of (−)CBD on alcohol withdrawal symptoms.(43)
Opioid user disorder (OUD) is a chronic illness characterised by an addiction to opioids such as
morphine or heroin.(115) The action of (−)-CBD as an agonist of 5-HT1A receptors in the dorsal raphe
nucleus has shown it to inhibit reward behaviour in rodents, indicating its clinical potential for
OUD.(80) Trials into (−)-CBD as an OUD intervention are underway. One study by Hurd et al.(27)
found that (−)-CBD doses of 400mg and 800mg, reduced cravings and anxiety caused by drug cues in
heroin use disorder patients, the strongest effect were apparent acutely (within 24 hours of
administration), but were still apparent a week after final administration, suggesting long-lasting
antiaddictive properties. A Phase 2 trial on OUD patients investigating the effects of (−)-CBD is
expected to take place in 2023 by the pharmaceutical company Aphios.(42) With the current
published findings, not enough information exists to confirm antiaddictive effects of (−)-CBD, more
clinical trials into effective dosage ranges, and the possibility of any drug interactions with already
existing interventions, are needed before approval of clinical application.
The method of action that (−)-CBD may reduce addictive behaviours is through modulation of the
striatal and mesolimbic pathways, and the dorsal raphe nucleus.(80) One hypothesis on how (−)-CBD
may work to reduce addictive behaviour, is through inhibiting the reward system in the brain via 5HT1A.(9,80) 5-HT1A agonism has been shown to counteract the effects of opioid administration.(116)
This same agonism may be responsible for the inhibition of morphine-induced reward signalling.(80)
(−)-CBD may also inhibit MOR expression in the striatum, reducing the reward signalling.(88) D2
activity in the mesolimbic system may also play a role in (−)-CBD action.(8) Competitive binding to D2
receptors of the striatum may lead to a reduced signalling effect by the partial agonism of (−)CBD,(8) therefore reducing the reward signalling from dopaminergic stimulation. A similar effect is
seen from another D2 partial agonist, aripiprazole.(117) This however is still hypothetical, and more
13
research into the multifaceted mechanisms of (−)-CBD is needed to fully understand how it may
work as an substance abuse intervention.
As a neuroprotective and neurogenic agent.
(−)-CBD studies into interactions with intracellular targets such as mitochondrial Ca2+ channels and
transcription factor PPARγ, have ignited interest into another potential use of (−)-CBD, as a
neuroprotective and neurogenic agent.(14,15) Suggestions of use to treat neurodegenerative
disease such as AD, have led to investigations into this potential property. In vitro research has
shown that PPARγ activity may reduce β-amyloid in AD cells, which can be enhanced by (−)-CBD
administration.(14) Evidence of hippocampal neurogenesis altering behaviours and disorders have
been associated with the action of (−)-CBD.(118) Modulation of mitochondrial Ca2+ channels have
also been implicated in the neuroprotective capabilities of (−)-CBD.(15)
AD rodent models investigating neuroprotective effects found that (−)-CBD activates PPARγ,
reducing β-amyloid-related protein expression, alongside the downregulation of inflammatory
cytokines.(29) Reduction in neurogenesis of rodent hippocampal neurons due to β-amyloid exposure
was reversed in the presence of (−)-CBD, this mechanism was suggested to be through CB1
receptors.(29)
One preliminary double-blind trial by Chagas et al.(28) found that after 300mg (−)-CBD dosages,
patients with Parkinson’s disease did not see any significant improvement in symptoms, but did see
improvements in quality of life, which may be due to anxiolytic effects of (−)-CBD, instead of the
proposed neuroprotective effects.(28) PPARγ antagonists also seemed to reverse neuroprotective
abilities of (−)-CBD.(14) Research into neuroprotective and neurogenic potential is still new, with a
very few amount of in vivo trials.(14) More in-vivo research into how nuclear modulation may
effectively be used in neurodegenerative treatment is still needed, with an emphasis on human
trials; preliminary trials on healthy individuals need to be conducted, as with current research, not
enough evidence exists to confidently state (−)-CBD as a neuroprotective agent.
Pharmacokinetic limitations
Whilst most clinical trials have stated that sufficient tolerability, mild side effects are still apparent.
In phase 3 antiepileptic trials, elevated levels of aminotransferase in the liver was reported.(23,24)
Another study looking into abnormal liver chemistry after oral (−)-CBD doses, reported findings
consistent with drug-induced liver injury.(119) Whilst trials still found the dosages of (−)-CBD given
to be tolerable, a serious risk to account for is what the long-term effects on hepatic function may be
with chronic (−)-CBD consumption. A common adverse effect shared amongst (−)-CBD trials was
diarrhoea, a trait associated with heightened aminotransferase .(18,23,114) When taken chronically,
a possibility of long-term minor side effects like diarrhoea leading worse conditions may exist. For
example, Irritable bowel syndrome, which shows elevated aminotransferase.(120)
These adverse effects on hepatic function may be due to the high doses of (−)-CBD needed to
achieve therapeutic effects. Oral (−)-CBD formulations, like Epidiolex®,(30) are subject to first-pass
metabolism, interacting with hepatic enzymatic actions.(31) Having to pass through the liver greatly
lowers the bioavailability of (−)-CBD; higher doses are needed to achieve clinically relevant
concentrations.(121) Lowering the amount of first-place metabolism that takes place with orally
administered (−)-CBD, would increase bioavailability and lower the effective doses needed, maybe
preventing hepatic risks.
14
Possible methods to improve (−)-CBD bioavailability would be to use novel drug delivery
systems(122) or the use of chemical derivatives of (−)-CBD with higher potency.(52) Self-emulsifying
drug delivery systems are being investigated to improve bioavailability, for example piperine-pronanolipospheres (PNL).(122) PNL-based (−)-CBD formulations seem to improve on current food oil
formulations used in research, as it improves bioavailability through increased solubility, and
inhibition of first-pass metabolism enzymes such as Cytochrome P450.(122) KLS-13019, a resorcinol
analogue of (−)-CBD, has been seen to be more potent and soluble than (−)-CBD, as a
neuroprotective agent, it was also seen to be over 400-fold safer, leading to less adverse effects.(52)
This is important for treatment of patients with comorbid disease or disorders with multiple
prescribed medication, as drug-drug interactions with (−)-CBD are quite high, as it targets proteins
involved in drug metabolism, such as cytochrome enzymes.(123) As current clinical
recommendations is to lower dosage,(123) a potent, low dose variation of (−)-CBD medication or
new administration routes that avoid first-pass metabolism, may help limit any possible adverse
effects.
Conclusion
The objective of this review was to outline current findings into the pharmacology of (−)-CBD, and to
assess its utility as a therapeutic agent for a range of disorders. (−)-CBD seems to be able to
modulate many different biological mechanisms in the human body. Oral administration is the most
preferred method of administration, with (−)-CBD being the only approved pure (−)-CBD solution
available for prescription.(30) First-pass metabolism by the liver reduces bioavailability of oral (−)CBD, so whilst being the most preferred method, it is not efficient relative to dosage size.(70) Ways
to optimise bioavailability are being produced for example, self-emulsifying drug delivery systems
like PNL.(70) The diverse possible targets of (−)-CBD makes its mechanism of action highly complex,
effecting multiple different systems in the CNS.(124) This same feature makes (−)-CBD an interesting
compound for dug research.
In conclusion, the popularity of (−)-CBD as a treatment for a diverse range of ailments is still quite
premature. Research into its possible therapeutic uses seem promising, however, not enough large
clinical trials exist for most of the assigned uses. Many popular effects, such as anxiolytic and
antipsychotic factors, are based on in vitro and pre-clinical research, with minimal phase 3 high
powered clinical trials. Effects of consistent high-dose usage still needs to be studied, as the
presence of heightened levels of aminotransferase in the liver, possibly leading to IBS may be a longterm risk to investigate.(23) Novel properties, such as neuroprotectivity, require more initial
research, before moving onto trial phases. It is of the utmost importance to produce more research
before any recommendations are made for prescribing (−)-CBD medically for neurological disorders.
15
Table of Figures and Tables
Figure 1. Biosynthesis and decarboxylation of Cannabis Sativa compounds (−)-CBD and Δ9-THC.
Inside Cannabis Sativa (C. Sativa), cannabigerolic acid is (CBGA) is converted into Cannabidiolic acid
(CBDA) and Δ9-tetrahydrocannabinolic acid (Δ9-THCA). CBGA and Δ9-THCA is how the compounds are
stored within the C. Sativa plant. Once C. Sativa is heated, decarboxylation occurs, converting CBGA
and Δ9-THCA into the active compounds cannabidiol ((−)-CBD) and (-)-trans-Δ9-tetrahydrocannabinol
(Δ9-THC)). Structures adapted from PubChem CIDs: 6449999,(38) 160570,(39) 98523,(40) 2978,(32)
644019(33).
16
Δ9-THC
(−)-CBD
Figure 2. 2D Chemical structure of Δ9-THC and (−)-CBD. Both meroterpenoids structures look similar
when compared.(44) However, a key difference, circled in red, is the presence of a hydroxyl group
on (−)-CBD (left). Δ9-THC instead has a pyran ring, bound at the oxygen, present. This difference in
structure leads to vastly different pharmacological effects between the two drugs.(44) The main
structural group in Δ9-THC is it’s hexahydro-6H-benzo[c]chromene core, which is not present in the
structure of (−)-CBD, instead (−)-CBD structural moieties consist of resorcinol, limonene, a terpene
present in C. sativa, and a C4’-alykl chain.(51) Structures adapted from PubChem CIDs: 2978,(32)
644019(33)
17
Figure 3. Biosynthesis pathways of eicosanoids 2-Arachidonoylglycerol (2-AG) and Narachidonoylethanolamine (anandamide). Enzymatic hydrolysis of diacylglycerol (DAG) by glycerol
lipase synthesises 2-AG, which can then be metabolised into arachidonic acid and glycerol via
anandamide amidohydrolase.(47) Free arachidonic acid and ethanolamine synthesis into
anandamide is catalysed through the reverse reaction of anandamide amidohydrolase, however high
concentrations of both substrates are needed for this reaction to occur.(47) Another formation
pathway of anandamide seen in neurons is the hydrolysis of N-arachidonoyl
phosphatidylethanolamine (NAPE) into anandamide via the enzyme phosphodiesterase.(47)
Anandamide is also degraded via the enzymatic activity of anandamide amidohydrolase, yielding
arachidonic acid and ethanolamine as products.(47) Chemical structures adapted from PubChem
CIDs: 700,(34) 753,(35) 444899,(36) 5281969,(37) and 5282280.(41)
18
Figure 4. Pharmacological targets of (−)-CBD. (1.) Cannabidiol ((−)-CBD) acts as an antagonist,
allosterically binding to cannabinoid receptors (CBRs): CB1 and CB2.(77) Under physiological
conditions, anandamide (AEA) binds to presynaptic CBRs, triggering the inhibitory (αi) G proteincoupled receptor (GPCRs) pathway, leading to inhibition of Adenylyl cyclase (AC), reducing
adenosine monophosphate (cAMP) production from Adenosine triphosphate (ATP).(77) CBR
activation also stimulates inwardly rectifying potassium (K+) channels and inhibit voltage-gated
calcium channels (Ca2+), inhibiting neurotransmitters (NT) release from vesicles.(77) (−)-CBD also
interacts with cannabinoid receptor GPR55, activation increases intracellular calcium levels through
G-protein Q signalling (αq), (−)-CBD antagonism prevents GPR55 signalling.(7) Negative allosteric
modulation of µ-opioid receptors (MOR) greatly increases the dissociation of ligands, (−)-CBD.(10)
(2) (−)-CBD Receptor agonism. (−)-CBD agonism of transient receptor potential vanilloid 1 (TRPV1)
causes an influx of Ca2+ followed by TRPV1 nociceptor desensitization.(11) (−)-CBD induces partial
agonism in D2 receptors, similar to functioning seen in aripiprazole.(8,85) 5-HT1A direct agonism by
(−)-CBD has been associated with different therapeutic effects.(80–82) (−)-CBD also has weak
agonistic effects to adenosine receptor 1 (A1) signalling and inhibits equilibrative nucleoside
transporters(ENT), increasing the interstitial concentration of adenosine, and in turn, adenosine
signalling.(93) (−)-CBD also may inhibit Na+ channels.(91,95) (3) Intracellular actions of (−)-CBD also
exist. Fatty acid amide hydrolase (FAAH) inhibition by (−)-CBD prevents AEA degradation into
arachidonic acid (AA) and ethanolamine.(19,89) Peroxisome-proliferator-activated receptors (PPARs)
are activated by (−)-CBD, increasing PPAR transcriptional activity.(14) (−)-CBD may also inhibit
mitochondrial Ca2+ channels.(15) Diagram made using www.biorender.com
19
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