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Review Not peer-reviewed version
Elucidating the Neuroinflammatory and
Neuroprotective Activity of
Phytochemicals in Cannabis sativa and
their potential Entourage Effects
Ahmad K Al-Khazaleh * , Xian Zhou , Deep Jyoti Bhuyan , Gerald W Münch , Elaf Adel Al-Dalabeeh ,
Kayla Jaye , Dennis Chang *
Posted Date: 13 December 2023
doi: 10.20944/preprints202312.0954.v1
Keywords: Neuroinflammatory; Neuroprotective diseases; Phytochemicals; Cannabis Sativa; Entourage
effects; Synergistic effects; Terpenes; Flavonoids; Cannabinoids
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Review
Elucidating the Neuroinflammatory and
Neuroprotective Activity of Phytochemicals in
Cannabis sativa and Their Potential Entourage
Effects
Ahmad K. Al-Khazaleh 1, *, Xian Zhou 1, Deep Jyoti Bhuyan 1, 3, Gerald W. Münch 1,2,
Elaf Adel Al-Dalabeeh 4, Kayla Jaye 1 and Dennis Chang 1,*
1 NICM Health Research Institute, Western Sydney University, Penrith, NSW 2751, Australia
2 Pharmacology Unit, School of Medicine, Western Sydney University, Penrith, NSW 2751, Australia
3 School of Science, Western Sydney University, Penrith, NSW 2751, Australia
4 Department of Biological Sciences, School of Science, University of Jordan, Amman, Jordan
* Correspondence: Professor Dennis Chang; d.chang@westernsydney.edu.au; Tel.: +61 404 453 682; Ahmad
K. Al-Khazaleh; 19316068@student.westernsydney.edu.au
Abstract: Cannabis, renowned for its historical medicinal use, harbours various bioactive compounds—
cannabinoids, terpenes, and flavonoids. While major cannabinoids like THC and CBD have received extensive
scrutiny for their pharmacological properties, emerging evidence underscores the collaborative interactions
among these constituents, suggesting a collective therapeutic potential. This comprehensive review explores
the intricate relationships and synergies between cannabinoids, terpenes, and flavonoids in cannabis.
Cannabinoids, pivotal in cannabis's bioactivity, exhibit well-documented analgesic, anti-inflammatory, and
neuroprotective effects. Terpenes, aromatic compounds imbuing distinct flavours, not only contribute to
cannabis's sensory profile but also modulate cannabinoid effects through diverse molecular mechanisms.
Flavonoids, another cannabis component, demonstrate anti-inflammatory, antioxidant, and neuroprotective
properties, particularly relevant to neuroinflammation. The entourage hypothesis posits that combined
cannabinoid, terpene, and flavonoid action yields synergistic or additive effects, surpassing individual
compound efficacy. Recognizing the nuanced interactions is crucial for unravelling cannabis's complete
therapeutic potential. Tailoring treatments based on the holistic composition of cannabis strains allows
optimization of therapeutic outcomes while minimizing potential side effects. This review underscores the
imperative to delve into the intricate roles of cannabinoids, terpenes, and flavonoids, offering promising
prospects for innovative therapeutic interventions and advocating continued research to unlock cannabis's full
therapeutic potential within the realm of natural plant-based medicine.
Keywords: neuroinflammatory; neuroprotective diseases; phytochemicals; Cannabis sativa;
entourage effects; synergistic effects; terpenes; flavonoids; cannabinoids
Introduction
Cannabis, known by various names such as marijuana, ganja, hashish, pot, and hemp, is an
ancient plant cultivated and exploited for its various properties. It is a versatile plant, being used as
a fibre source, food ingredient, and medicinal substance (Pisanti & Bifulco, 2019). This annual
flowering herb can be classified into three primary species: Cannabis sativa, which is taller and more
fibrous, and Cannabis indica, which is shorter and more psychoactive. Both species exist in both wild
and cultivated forms. Additionally, some taxonomists propose including a third putative species,
Cannabis ruderalis, which is solely wild (Pisanti & Bifulco, 2019).
Cannabis is a genus within the Cannabaceae plant family, including hops. A defining characteristic
of all Cannabis plants is the presence of secondary substances called cannabinoids or phytocannabinoids
(Schilling et al., 2020). At the same time, the genus comprises three species C. sativa, C. ruderalis, and
C. indica. C. sativa is the most extensively studied species in terms of its medicinal potential, unlike C.
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2
ruderalis and C. indica, which require further elucidation regarding their therapeutic properties
(Schilling et al., 2020).
C. sativa holds significant value as a medicinal plant and has garnered increasing interest in the
research and manufacturing sectors. To date, over 150 cannabinoids and numerous other
compounds, including terpenoids, flavonoids, and alkaloids, have been identified in C. sativa (Bonini
et al., 2018; Hanuš et al., 2016; Jin et al., 2020). Many traditional medicinal uses of C. sativa have been
studied (Jin et al., 2020). Furthermore, cannabis has historically been employed in treating various
ailments, including pain, inflammation, and mental illnesses. However, it is important to note that
discrepancies in terminology between historical texts and modern scientific literature, as well as
potential nuances lost in translation between Chinese and English, may exist (Jin et al., 2020).
Combining biomechanics research and investigations into the therapeutic effects of specific
substances can facilitate the development of applications utilising different plant parts (Amar, 2006).
For instance, 9-THC, known for its antiemetic and appetite-stimulating properties, has been utilised
in approved medications such as Marinol (dronabinol, synthetic 9-THC) and Cesamet to address
chemotherapy-induced nausea or vomiting and anorexia associated with AIDS-related weight loss
(nabilone, a THC derivative) (Amar, 2006).
Neuroinflammation is a multifaceted response in the brain following injury, involving the
activation of glial cells, the release of inflammatory mediators like cytokines and chemokines, and
the production of reactive oxygen and nitrogen species (Agostinho et al., 2010; Mosley et al., 2006).
Although it is considered a secondary event to neuronal dysfunction or death, neuroinflammation
plays a significant role in the onset and progression of neurodegenerative diseases such as
Alzheimer's Disease (AD), Parkinson's Disease (PD), Multiple Sclerosis (MS), Chronic Traumatic
Encephalopathy (CTE) (Agostinho et al., 2010; Mosley et al., 2006). Due to the limited efficacy of
current treatments for these conditions, neuroinflammation has emerged as a promising therapeutic
target in drug discovery (Agostinho et al., 2010; Mosley et al., 2006). Consequently, various in vivo
and in vitro models of neuroinflammation have been developed to study its mechanisms and
potential interventions.
2. Phytochemicals in medicinal cannabis
C. sativa contains a wide range of phytocannabinoids, which are oxygenated aromatic
hydrocarbons derived from meroterpenoids with various substitutions in the resorcinol core (Figure
1) (Gulck et al., 2020; Hanuš et al., 2016). These phytocannabinoids often have alkyl side chains with
an odd number of carbon atoms and are initially produced in their acid form (Figure 1). Through
decarboxylation, they are converted into their active forms (Gulck et al., 2020). The two most
abundant phytocannabinoids in C. sativa are cannabidiols (CBD) and Δ9-trans-tetrahydrocannabinol
(Δ9-THCs) (Figure 1). Additionally, cannabigerol (CBG) and its acid form (CBGA) serve as core
intermediates and provide phytocannabinolic acids (Figure 1) (Hanuš et al., 2016; Tahir et al., 2021).
Terpenes, which are the second-largest class of cannabis constituents after phytocannabinoids,
are also present in C. sativa and many other non-cannabinoid plants such as tea, thyme, Spanish sage,
and citrus fruits (ElSohly et al., 2017). The major terpenes in C. sativa include myrcene, alpha-pinene,
linalool, and limonene (ElSohly et al., 2017). In addition, C. sativa also biosynthesises flavonoids,
including cannflavins, which are prenylated (C5) and geranylated (C10) flavones (Ubeed et al., 2022).
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(a)
(b)
(c)
Figure 1. Chemical structures and molecular formula of the main selected (a) cannabinoids, (b)
terpenes, and (c) prenylflavonoids in C. sativa. .
3. The endocannabinoid system and neuroinflammation
Neuroinflammation refers to a broad spectrum of immune responses in the central nervous
system that stem from peripheral inflammation (Lyman et al., 2014). Key cellular players in this
process include microglia and astrocytes, which are primary cells involved in the immune reactions
within the central nervous system (Lyman et al., 2014). The activation of a neuroinflammatory
response occurs due to peripheral inflammation affecting various components, such as the blood-
brain barrier (BBB), glial cells, and neurons (Lyman et al., 2014). Previously, it was widely believed
that BBB, a specialised type of endothelium, ultimately separated the central nervous system from
the peripheral immune system (Lyman et al., 2014). However, it has been discovered that the BBB
can become permeable to pro-inflammatory molecules generated during peripheral inflammation
and facilitate their release and transport into the brain (De Vries et al., 1996; Laflamme & Rivest, 1999).
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This neuroinflammatory reaction leads to synaptic dysfunction, neuronal loss, and exacerbation of
various brain disorders (Kitazawa et al., 2005; Marquette et al., 1996; Micheau & Tschopp, 2003).
Microglial cells are a crucial component of the central nervous system (CNS) immune defence
and maintenance of homeostasis (Aloisi, 2001; Cardona et al., 2006; Filiano et al., 2015; Wirenfeldt et
al., 2011). They act as resident macrophages, responding to pathogenic invasion, tissue damage, and
protein aggregates by recognising danger-associated molecular patterns (DAMPs) or pathogen-
associated molecular patterns (PAMPs) through specific receptors (Filiano et al., 2015; Kettenmann
et al., 2011; Wirenfeldt et al., 2011).
Microglia can migrate to the injury site and initiate an innate immune response when activated
(Ji et al., 2013). Additionally, they play a critical role in preserving synaptic plasticity and contribute
significantly to learning and memory processes by modifying synapses associated with learning
(Parkhurst et al., 2013). Recent advances in single-cell RNA sequencing have revealed a distinct
subtype of microglia known as disease-associated microglia (DAM), which has been implicated in
the progression of Alzheimer's disease (AD) (Keren-Shaul et al., 2017). The blood-brain barrier (BBB),
consisting of tight junctions between brain endothelial cells, restricts the entry of pathogenic
microorganisms into the CNS. However, certain head injuries or infections can significantly change
brain function and behaviour. Inflammatory responses involving pro-inflammatory cytokines are
observed when brain tissue is damaged or infected, and microglial activation plays a key role in this
process (Konsman, 2022).
In neurodegenerative diseases, microglia are associated with neuroinflammation by activating
cell surface receptors, such as toll-like receptors (TLRs), scavenger receptors, and NLRP3
inflammasome (Bamberger et al., 2003; El Khoury et al., 2003; Fassbender et al., 2004; Kagan & Horng,
2013; Stewart et al., 2010). Impaired microglial phagocytic ability and reduced amyloid-beta (Aβ)
clearance are observed in these conditions, characterised by altered expression of Aβ phagocytosis
receptors and elevated cytokine levels. The dysregulation of immune receptors, such as TREM2 and
CD33, further highlights the significant role of neuroinflammation in neurodegenerative diseases
(Bradshaw et al., 2013; Griciuc et al., 2013; Guerreiro et al., 2013; Heneka et al., 2013; Hickman et al.,
2008; Liu & Jiang, 2016; Mawuenyega et al., 2010; Saresella et al., 2016; Sheedy et al., 2013).
Tetrahydrocannabinol (THC) and cannabidiol (CBD) are phytocannabinoids in C. sativa. They
exert their effects on neuroinflammation primarily through activating CB1 and CB2 cannabinoid
receptors (Figure 2) (Baker et al., 2007). In addition to these receptors, the endocannabinoid system
(ECS) includes proteins involved in the synthesis, inactivation and other endocannabinoid molecular
targets. Key components of the ECS include endogenous ligands such as arachidonyl ethanolamide
(AEA) and 2-arachidonylglycerol (2-AG), which are derivatives of the polyunsaturated fatty acid
arachidonic acid (Piomelli et al., 1998).
CB1 receptors are predominantly found in the central nervous system, while CB2 receptors are
primarily expressed peripherally in lymphoid organs, peripheral blood leukocytes, mast cells, and to
a lesser extent in the pancreas(Howlett et al., 2019; Sinha et al., 1998). CB1 mRNA and protein
expression have been observed in various immune cells, including B cells, NK cells, neutrophils,
CD8+ T cells, monocytes, and CD4+ T cells, albeit in decreasing order, whereas CB2 is expressed at
higher levels in these immune cells, approximately 10-100 times more than CB1 (Galiègue et al., 1995).
Given their widespread expression in the immune system, these receptors may play a crucial role in
immunomodulation.
Endocannabinoids, such as 2-AG and AEA, are produced in large quantities by microglia,
macrophages, astrocytes, and neurons during inflammation. These endocannabinoids bind to CB
receptors and have been shown to reduce neuronal damage by protecting the nervous system from
excitotoxicity (Figure 2) (Table 1) (Eljaschewitsch et al., 2006; Marinelli et al., 2008; Walter et al., 2004;
Walter et al., 2002).
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Furthermore, cannabinoid treatment has been demonstrated to attenuate the inflammatory
effects of IL-1 and protect glial cells from death (Aguado et al., 2006; Sheng et al., 2005). Overall, the
cannabinoid system plays a protective role by combating CNS excitotoxicity and neuroinflammation.
The evidence primarily supports the anti-inflammatory benefits of cannabis, although some studies
suggest potential pro-inflammatory effects, creating a more nuanced understanding (Killestein et al.,
2003; Maestroni, 2004).
The endocannabinoid system (ECS) modulates multiple physiological processes within the
nervous system, and dysregulation of ECS has been associated with various pathological conditions,
including neuroinflammation (Di Marzo & Piscitelli, 2015; Hillard, 2018). Therapeutic modulation of
ECS activity has shown beneficial effects on medical conditions related to neuroinflammation
(Ambrose & Simmons, 2019; Giacobbe et al., 2021). The ECS comprises multiple receptors, including
peroxisome proliferator-activated receptors (PPARs) and ion channels (such as the transient receptor
potential ankyrin [TRPA] family and the transient receptor potential vanilloid [TRPV] family), as well
as cannabinoid receptor types 1 and 2 (CB1 and CB2, respectively) (Biringer, 2021). The ECS also
involves endocannabinoids derived from arachidonic acid, receptor ligands, and enzymes
responsible for endocannabinoid metabolism (Di Marzo & Piscitelli, 2015).
Endocannabinoids, the enzymes involved in their biosynthesis and degradation, and
endocannabinoid receptors are expressed by most immune cells (Chiurchiù et al., 2015). CB1 and CB2
receptors are present in immune cells, with CB2 being expressed at higher levels than CB1 (Jean-
Gilles et al., 2010; Rahaman & Ganguly, 2021). Activation of CB receptors regulates anti-inflammatory
responses, as evidenced by increased release of the anti-inflammatory cytokine IL-10 and decreased
release of pro-inflammatory cytokines IL-12 and IL-23 upon CB2 receptor activation in activated
macrophages (Figure 2) (Correa et al., 2009; Correa et al., 2010). The CB2 receptor system has also
been implicated in anxiety, depression, and substance abuse, suggesting its involvement in
modulating dopamine reward pathways (Al Mansouri et al., 2014; Gertsch et al., 2008; Xi et al., 2011).
Trans-caryophyllene has demonstrated neuroinflammatory inhibition and lipid regulation
properties (Zhang et al., 2017).
4. Anti-neuroinflammatory activity of phytochemicals in C. Sativa
4.1. CBD
CBD has been extensively studied for its potential anti-neuroinflammatory properties in various
in vitro and in vivo models of degenerative diseases (Table 1). However, the precise mechanism
underlying its anti-neuroinflammatory activity still needs to be understood. In the context of hypoxic-
ischemic (HI) immature brains in newborn mice, CBD treatment was found to significantly decrease
the expression of inflammatory markers such as IL-6, TNF-α, COX-2, and iNOS in brain slices (Figure
3). It has been suggested that this effect may be mediated through the CB2 and adenosine A2A
receptors (Castillo et al., 2010). Similarly, low doses of CBD were observed to reduce TNF-α
production in mice treated with lipopolysaccharide, and this effect was abolished in mice lacking the
A2A receptor and restored by an A2A adenosine receptor, indicating a potential modulation of
adenosine signalling by CBD (Carrier et al., 2006).
Furthermore, CBD selectively inhibits GPR55, another G protein-coupled receptor in human
macrophages. In microglial cells isolated from the retinas of newborn rats treated with endotoxin or
LPS for acute ocular inflammation, CBD treatment inhibited TNF-α production via the p38 MAPK
pathway. In rat retinas exposed to LPS, CBD administration prevented the development of
macrophage accumulation, activated microglia, increased levels of reactive oxygen species (ROS) and
nitrotyrosine, activated p38 MAPK, and neuronal apoptosis (Figure 3) (El-Remessy et al., 2008).
In LPS-activated microglial cells (BV-2 cells), CBD has been shown to reduce the production and
release of inflammatory cytokines such as IL-1, IL-6, and IFN-β. This reduction is associated with a
decrease in the activity of the NF-κB pathway and the levels of IL-1β and IL-6. Additionally, CBD
downregulates the expression of the SOCS3 gene, which regulates cytokine and hormone signalling.
CBD treatment leads to increased phosphorylation of the STAT3 transcription factor, which is
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required for activation. In contrast, CBD decreases the phosphorylation of STAT1, a transcription
factor involved in IFN-β-dependent pro-inflammatory processes (Carow & Rottenberg, 2014; Kozela
et al., 2010). NF-κB and STAT3 have important and sometimes overlapping roles in pro-inflammatory
responses, while STAT1 plays a significant role in IFN-β-mediated inflammation (Carow &
Rottenberg, 2014; Kozela et al., 2010).
Figure 3. The anti-neuroinflammatory activity of CBD.
4.2. THC
Since its synthesis in 1964, delta-9-tetrahydrocannabinol (THC) has been the most extensively
studied phytocannabinoid, primarily due to its pharmacological effects. THC primarily interacts with
the endocannabinoid receptors CB1 and CB2, acting as a partial agonist at sub-micromolar doses.
These receptors have been the focus of considerable research in understanding the psychoactive
effects of THC. The development of synthetic high-affinity counterparts has facilitated the
identification of the endocannabinoid system and its central nervous system targets (Gaston &
Friedman, 2017). The metabolic precursor of THC, delta-9-tetrahydrocannabinolic acid (THCA), is
present in high concentrations in cannabis plants. Upon drying or burning, THCA is decarboxylated
to THC. THCA is believed to have less psychoactive properties than THC (Gaston & Friedman, 2017).
However, at concentrations exceeding 10 µM, THC inhibits cyclooxygenases-1 and 2, as well as
diacylglycerol lipase alpha (DLG), an essential enzyme in the biosynthesis of the endocannabinoid 2-
arachidonoylglycerol (2-AG). In vitro, experiments have shown activation of TRPA1 and TRPV4
channels, while TRPM8 channels are blocked at low micromolar concentrations (Gaston & Friedman,
2017).
Another cannabinoid present in varying levels of cannabis is delta-9-tetrahydrocannabivarin
(THCV). Similar to THC, THCV acts as a partial agonist of CB1/2 receptors and exhibits activity on
GPR55, TRPA1, and TRPV1-4 receptors at sub-micromolar or low micromolar doses (Pertwee &
Cascio, 2014). In vitro and in vivo animal models have demonstrated the anti-seizure effects of THCV
in one study (Hill et al., 2010).
THC has been shown in numerous studies to possess anti-neuroinflammatory properties (Table
1). For instance, it increases the production of anti-inflammatory cytokines while decreasing pro-
inflammatory cytokine production in multiple sclerosis (MS). THC also promotes apoptosis in T cell-
driven inflammation and increases the population of FoxP3+ regulatory T cells through miRNA
induction and epigenetic modifications (Figure 4) (Rao et al., 2014; Sido et al., 2016).
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Figure 4. The Anti-neuroinflammatory activity of THC.
Moreover, THC has been found to inhibit acetylcholine esterase (AchE)-induced aggregation of
amyloid-beta (Aβ), improve motor coordination deficits in R6/2 mice, mitigate striatal atrophy and
huntingtin aggregate accumulation, and exacerbate malonate lesions in Alzheimer's disease (AD)
(Table 1) (Blazquez et al., 2011; Dowie et al., 2010; Eubanks et al., 2006; Lastres-Becker et al., 2003).
THC, THCA, and the metabolite cannabinol (CBN) have been described to possess analgesic, anti-
inflammatory, and neuroprotective effects (Baron, 2018; De Petrocellis et al., 2011; Pugazhendhi et
al., 2021).
4.3. CBG
While there is still a need for further research on the anti-neuroinflammatory effects of
cannabigerol (CBG) compared to cannabidiol (CBD), several studies have discussed the
neuroprotective properties of CBG against neuroinflammation (Table 1). For instance, in cultured
motor neurons, CBG pretreatment was found to reduce the levels of pro-inflammatory cytokines such
as IL-1β, TNFα, and IFN-γ, and prevent apoptosis in LPS-stimulated macrophages by inhibiting the
expression of caspase-3 and Bax, while increasing Bcl-2 levels (Gugliandolo et al., 2018). Similarly, in
an in vivo study using a 3-nitro propionate model to examine the effects of CBG on Huntington's
disease pathology, treatment with CBG significantly attenuated the upregulation of COX-2, iNOS,
and pro-inflammatory cytokines such as TNF-α and IL-6 (Figure 5) (Valdeolivas et al., 2015).
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Figure 5. The Anti-neuroinflammatory activity of CBG.
These findings highlight the potential of CBG as a neuroprotective agent against
neuroinflammation, but further investigation is necessary to understand its mechanisms and
therapeutic potential fully.
Table 1. A summary of preclinical evidence of cannabinoids on microglial activation and
neuroinflammatory signalling.
Compoun
d
Model
Concentration
/
Dose
indicated
neurodegenerativ
e diseases
Outcome
References
CBD
in vitro glutamate
neuronal toxicity
model
N/A
N/A
CBD was shown to
be more protective
than either α-
tocopherol or
vitamin C and
comparable to
butylated
hydroxytoluene
(BHT).
(Saito et al.,
2012; Yousaf
et al., 2022)
THC
in vivo in
hemiparkinsonia
n rats
N/A
PD
neuroprotective
effect
(Lastres-
Becker et al.,
2005)
CBD
in vivo in
hemiparkinsonia
n rats
3 mg/kg
PD
exhibited a potent
neuroprotective
effect in this rat
model
(Lastres-
Becker et al.,
2005)
CBD
N/A
< 1 μM
N/A
inhibit activated
microglial cell
migration by
antagonising the
abnormal-
cannabidiol (Abn-
CBD)-sensitive
receptor
(Walter et al.,
2003)
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CBD
in vitro
PC12 cells
N/A
AD
Neuroprotective
against the
neuronal damage
induced by the β-
amyloid peptide
(Aβ) inhibits Aβ-
induced
neurotoxicity.
(Esposito et
al., 2006)
CBD
In vivo
mouse model
N/A
AD
Attenuated the
expression of
several glial pro-
inflammatory
proteins, including
glial fibrillary
acidic protein,
inducible nitric
oxide synthase
(iNOS) and
interleukin 1β (IL-
1β), which are
major contributors
to the propagation
of
neuroinflammatio
n and oxidative
stress.
(Esposito et
al., 2007)
CBD
in vivo
mouse model
100-200 mg/kg
Dravet Syndrome
It has beneficial
effects on seizures
and social deficits
(Kaplan et
al., 2017)
CBD
in vivo
mouse model
10 mg/kg
twice- daily
schizophrenia
improves the
social
and cognitive
dysfunctions
(Osborne et
al., 2017)
CBDV
Clinical trial
Single oral
dose
ASD
It modulates
glutamatergic but
not γ-
aminobutyric acid
(GABA)
neurotransmission
in adult male
patients, although
the biological
response may
differ between
autistic
individuals.
(Pretzsch et
al., 2019)
THCV
in vivo
mouse model
<3 mg/kg
PD
alleviates motor
inhibition in 6-
OHDA-lesioned
rodents by
blocking
CB1 receptors at
low doses
(Espadas et
al., 2020)
THC
N/A
N/A
PD
It reduced
levodopa-induced
dyskinesia
(Cristino et
al., 2020)
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CBN
in vitro
C6 glioma cells
0.3–30000 nM
EC50: 700 nM
N/A
It inhibited NO
production and
iNOS expression
(Esposito et
al., 2001)
CBN
N/A
N/A
MS
It may antagonise
the 2-AG-induced
recruitment of
microglial cells
and produces
minimal palliative.
(Walter et al.,
2003)
THC
in vitro
BV-2 murine
microglial cell
line
10 μM
N/A
It decreases the
production and
release of
proinflammatory
cytokines,
including
interleukin-1β,
interleukin-6, and
interferon (IFN)β,
from LPS-
activated
microglial cells.
(Kozela et al.,
2010)
CBG
in vitro
murine
microglial cell
line
25 μM
MS
It has inhibited the
microglia-driven
inflammatory
response,
protected neurons
from toxic insults
in vitro, and
restored motor
function
impairment by
inhibiting the
synthesis of IL-1β,
IL-6, TNF-α, the
chemokine, MIP-
1α and
prostaglandin E2
(PGE2).
(Carrillo-
Salinas et al.,
2014; Granja
et al., 2012)
CBG
in vitro
NSC-34 motor
neurons
7.5 µM
N/A
CBG pre-treatment
has REDUCED IL-
1β, TNF-α, IFN-γ
and PPARγ
protein levels and
reduced
nitrotyrosine,
SOD1 and iNOS
protein levels and
restored Nrf-2
levels.
(Gugliandol
o et al., 2018)
CBG
In vivo and
in vitro
N/A
PD
It shows a
neuroprotective
against
inflammation-
driven neuronal
damage, acting
through the
activation of the
canonic binding
(García et al.,
2018)
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site in PPARγ
receptors.
CBG
In vivo and
In vitro
neuroblastoma
Neuro-2a (N2a)
2 g/ 6.319 mM
HD
It has improved
motor deficits,
reactive
astrogliosis and
microglial
activation,
inhibiting the
upregulation of
proinflammatory
markers and
improving
antioxidant
defences in the
brain.
(Díaz-Alonso
et al., 2016)
CBDA
In vitro
Neuro-2a (N2a)
cells
25 μM
HD
CBDA shows
potent
neuroprotective
activity by
activating PPARγ
with higher
potency than their
decarboxylated
products
(Nadal et al.,
2017)
CBDA
in vivo
10 and
30 mg/kg
Dravet syndrome
It has an
anticonvulsant
against
pentylenetetrazol-
induced seizures
and hyperthermia-
induced seizures.
(Anderson et
al., 2019)
CBDV
in vivo
mouse model
CBDV
Rett syndrome
(RTT), a rare
neurological
disorder affecting
predominantly
females
It improves
behavioural and
functional deficits.
(Hagberg et
al., 2002;
Ricceri et al.,
2013; Vigli et
al., 2018;
Zamberletti
et al., 2019)
CBC
In vitro
1 μM
N/A
CBC exert
potential actions
on brain health
through effects on
adult neural stem
cells using whole
brain-derived
neural
stem progenitor
cells (NSPCs).
(Shinjyo & Di
Marzo, 2013)
THC
In vitro
10 μM
N/A
THC reduces IL-
1β, IL-6, and
TNFα production
in LPS-stimulated
rat microglial cells.
(Puffenbarge
r et al., 2000)
THC
In vitro
0 – 15 μM
AD
It inhibits the
enzyme
acetylcholinesteras
e (AChE) and
(Eubanks et
al., 2006)
Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 13 December 2023 doi:10.20944/preprints202312.0954.v1
13
prevents AChE-
induced amyloid
β-peptide (Aβ)
aggregation,
which is
considered the key
pathological
marker of
Alzheimer's
disease.
THC
in vivo
R6/1 mouse model
10 mg/kg
HD
It inhibits
acetylcholine
esterase (AchE)-
induced
aggregation of Aβ
and attenuates the
motor
coordination
deficits of R6/1
mice.
(Dowie et al.,
2010)
THCA
In vitro
N2a cells
10 μM
IC50 of
0.47 μM
HD
It has
neuroprotective
activity by activate
PPARγ
transcriptional
activity.
(Nadal et al.,
2017)
4.4. Terpenes
Terpenes and terpenoids, found in plant resins and essential oils, are significant components
responsible for the pharmacological effects of various medicinal plants, including cannabis. Terpenes
are hydrocarbons, while terpenoids contain additional functional groups derived from different
chemical elements, making them the most abundant class of phytochemicals. In cannabis, there are
approximately 200 unique terpenes, focusing on the primary terpenes found in the highest
concentrations. These aromatic essential oils contribute to the distinctive aromas, flavours, and
characteristics of different cannabis strains (Cox-Georgian et al., 2019; Ludwiczuk et al., 2017).
Terpenes have lipophilic properties and interact with various bodily targets, including
neurotransmitter receptors, ion channels in muscles and neurons, G-protein receptors, enzymes, cell
membranes, and second messenger systems. They work independently and synergistically with
cannabinoids to produce various therapeutic effects. Additionally, terpenes can enhance the
permeability of the blood-brain barrier, leading to the development of transdermal cannabinoid
patches containing terpenes as permeation agents. They also influence the binding of THC to CB1
receptors, contributing to the analgesic effects of cannabinoids (Baron, 2018).
While terpenes have been associated with health benefits such as analgesia, anxiolytic and
antidepressant effects, skin penetration enhancement, cancer chemoprevention, and antimicrobial
activities, their anti-neuroinflammatory activities have not been extensively studied. It is important
to note that most available data come from preclinical studies conducted using animal models or in
vitro experiments. Some reported benefits of specific terpenes are based on studies evaluating whole
essential oils or plants, where the specified terpene may be the most abundant constituent.
Additionally, the potential therapeutic contributions of minor terpenes should be considered. Among
the primary terpenes found in cannabis are -caryophyllene, myrcene, -pinene, humulene, linalool,
limonene, terpinolene, terpineol, ocimene, valencene, and geraniol (Abd Rashed et al., 2021; He et al.,
2022).
Myrcene is commonly found in aromatic plants such as sweet basil, bay leaves, lemongrass, and
mango. It is utilized in the cosmetic industry due to its remarkable anti-inflammatory, analgesic, and
anxiolytic properties (Van Cleemput et al., 2009). The analgesic effects of myrcene appear to be
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14
mediated through an opioid mechanism, as they were inhibited by naloxone (Lorenzetti et al., 1991).
Additionally, myrcene exhibits muscle relaxant, hypnotic, sedative, sleep aid, and antioxidant
properties (De-Oliveira et al., 1997).
Alpha-pinene contributes to the distinctive scent of fresh pine needles, conifers, and sage. It is
also present in various herbs, including parsley, rosemary, basil, and dill, making it the most
prevalent natural terpenes (Noma et al., 2010). Studies have demonstrated its antioxidant activity
(Wang et al., 2008) and anti-inflammatory effects in human chondrocytes (Neves et al., 2010; Rufino
et al., 2014), suggesting its potential for anti-osteoarthritic activity (Rufino et al., 2014). Alpha-pinene
also acts as an acetylcholinesterase inhibitor, enhancing memory and counteracting the short-term
memory loss caused by THC (Kennedy et al., 2011).
Extensive research indicates that linalool, a monoterpene, possesses anti-ischemic, antioxidant,
and anti-inflammatory properties. It enhances the activities of antioxidant enzymes superoxide
dismutase (SOD) and catalase in vitro, inhibits LPS-induced MCP-1 in airway epithelia, scavenges
reactive oxygen species (ROS) in neurons after oxygen-glucose deprivation/reoxygenation, and
inhibits MCP-1-induced microglia migration. Linalool also protects neurons from glutamate-induced
oxidative stress by preventing mitochondrial ROS and calcium synthesis. Furthermore, it can
potentially block LPS-induced PGE2 synthesis and NF-κB/TNF-α expression in macrophages and
microglia (Downer, 2020).
Limonene, a monoterpene, exhibits significant anti-inflammatory and antioxidant effects both
in vitro and in vivo. It reduces IL-1-induced nitric oxide synthesis in human chondrocytes and
decreases the production of prostaglandin E2, nitric oxide, and TNF-α/IL-1 in macrophages
stimulated with lipopolysaccharide (LPS). Moreover, in animal models of colitis, limonene has been
shown to alleviate intestinal inflammation when administered in vivo. It also demonstrates
nonprotective effects by targeting COX-2 and nitric oxide, preventing renal injury. Additionally,
limonene enhances the activity of antioxidant enzymes superoxide dismutase (SOD), catalase, and
glutathione in the central nervous system during cerebral ischemia models, while reducing the
generation of IL-1 and reactive oxygen species (ROS), thus exhibiting its antioxidant potential
(Downer, 2020).
4.5. Flavonoids
Flavonoids are a class of phenolic compounds characterized by the presence of a phenol ring in
their molecular structure. These compounds are known to possess various health benefits, although
most of the research conducted so far has been in preclinical models (Andre et al., 2016). Among the
flavonoids found in cannabis, three cannflavins, namely cannflavin A (CFL-A), B (CFL-B), and C
(CFL-C), have been identified. These cannflavins exhibit promising therapeutic properties,
particularly as anti-neuroinflammatory agents (Erridge et al., 2020). In a series of studies conducted
in the mid-1980s, Barret et al. investigated the ability of these compounds to inhibit the release of
prostaglandin E2 (PGE2) from human rheumatoid synovial cells (Figure 6). The results showed that
cannflavins were approximately 30 times more potent than aspirin in ex vivo experiments (Erridge
et al., 2020).
Figure 6. The Anti-neuroinflammatory activity of Flavonoids in Cannabis.
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5. Entourage effects among the phytochemicals in C. Sativa
In 1998, a groundbreaking study conducted by Mechoulam et al. unveiled a pair of
monoacylglycerols that influenced the activity of the endogenous cannabinoid 2-arachidonoyl-
glycerol through inhibiting its metabolism (Ben-Shabat et al., 1998; Mechoulam & Ben-Shabat, 1999).
Despite being pharmacologically inert on their own, these compounds exhibited a significant impact
on the activity of the target compound, giving rise to the concept known as the "entourage effect."
This effect refers to modifying the pharmacological properties of individual molecules through
interactions with co-existing metabolites, even if these metabolites lack inherent pharmacological
activity (Cogan, 2020).
Throughout history, cannabis has been utilized as a medicinal plant, and its crude extracts have
been found to contain various phytomolecules, such as flavonoids, terpenes, and phytocannabinoids.
Recent research has emphasized the preference for combining these phytomolecules in medical
therapies due to the observed entourage effect. This phenomenon encompasses two types of
interactions: "intra-entourage," arising from interactions among phytocannabinoids or terpenes, and
"inter-entourage," resulting from interactions between phytocannabinoids and terpenes (Koltai &
Namdar, 2020). Investigating the combinations of phytomolecules exhibiting entourage effects is
crucial for developing novel drugs (Koltai & Namdar, 2020).
5.1. The preclinical and clinical evidence
Preclinical studies have demonstrated the interaction between phytocannabinoids and terpenes,
suggesting that the enhanced medical benefits of full-spectrum cannabis extracts, compared to
isolated molecules, can be attributed to the entourage effect (Mazuz et al., 2020; Namdar et al., 2019).
However, it is essential to note that unfavorable interactions, referred to as the "parasitage effect," can
also occur in specific in vitro molecular interactions (Namdar et al., 2019).
Careful selection of active phytomolecules and reduction of inactive or potentially pro-
inflammatory compounds hold promise for optimizing therapeutic activity. Research has shown that
the THCA-rich fraction of a cannabis strain exhibits superior anti-inflammatory activity compared to
the crude extract, suggesting the potential benefit of selectively choosing compounds (Nallathambi
et al., 2018).
Moreover, recent studies have demonstrated the suppressive effect of a combination of THC and
CBD on neuroinflammation in animal models of multiple sclerosis (Feliú et al., 2015; Moreno-Martet
et al., 2015). Phytocannabinoids, including THC and CBD, exhibit immunomodulatory and anti-
inflammatory properties, acting through distinct signaling pathways. For example, in LPS-activated
microglial cells, THC and CBD were found to exert different mechanisms of action, with THC
controlling the IFNβ pathway activity and CBD inhibiting the NF-κB-dependent pathway (Figure 7)
(Kozela et al., 2010).
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Figure 7. The activity of THC and CBD combination in mediating anti-neuroinflammatory
properties.
5.2. The entourage effects in the context of neuroinflammation
The entourage effect of cannabis in the context of neuroinflammation and neurodegenerative
disorders is a fascinating phenomenon that underscores the complex interplay between various
phytochemicals found in C. Sativa (Hazzah et al., 2020). Extensive research has demonstrated that
the therapeutic potential of cannabis extends beyond the individual effects of its primary
cannabinoids, such as cannabidiol (CBD) and tetrahydrocannabinol (THC) (Marsh, 2022). Instead, it
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is the combined action of these cannabinoids, along with a diverse array of terpenes and flavonoids,
contributing to the entourage effect, leading to a more comprehensive and robust therapeutic
response (Marsh, 2022).
The endocannabinoid system (ECS) is central to the impact of the entourage effect on
neuroinflammation and neuroprotection (ECS), a crucial physiological system involved in
maintaining homeostasis throughout the body (Soundara Rajan et al., 2017). Cannabinoids, such as
CBD and THC, interact with the ECS receptors, CB1 and CB2, modulating inflammatory responses
and exerting neuroprotective effects (Soundara Rajan et al., 2017).
In addition to cannabinoids, terpenes play a pivotal role in the entourage effect by enhancing
the overall therapeutic potential of cannabis. Terpenes, responsible for the plant's distinctive aroma
and flavor, have been found to possess anti-inflammatory, analgesic, and anxiolytic properties
(Chacon et al., 2022; Fidyt et al., 2016). For example, β-caryophyllene, a common terpene in Cannabis
sativa, has been identified as a selective CB2 receptor agonist with potential anti-inflammatory effects
(Fidyt et al., 2016). Moreover, these compounds can influence the blood-brain barrier's permeability,
potentially facilitating the passage of cannabinoids into the brain and central nervous system, where
they can exert their neuroprotective effects more effectively.
5.3. The mechanisms underpin the entourage effects
The therapeutic synergies between phytocannabinoids and various cannabis phytochemicals
remain inadequately investigated, with a limited understanding of the underlying mechanisms and
pharmacological basis. Santiago et al. (2019) demonstrated that the dominant terpenes in Cannabis
sativa, namely α-pinene, β-pinene, β-caryophyllene, linalool, limonene, and myrcene, either
individually or in combinations, did not impact the hyperpolarization induced by Δ9-THC,
suggesting that if phytocannabinoid synergies exist, they do not operate through CB1R or CB2R
activation (Santiago et al., 2019). However, Cheng et al. (2014) reported that β-caryophyllene prefers
binding to CB2R, potentially contributing to synergistic effects within the phytochemical matrix of C.
sativa to mitigate Alzheimer's disease (AD)-related neurotoxicity (Cheng et al., 2014).
In enhancing bioavailability, the role of terpenoids, particularly their interaction with
phytocannabinoids, warrants further exploration. Namdar et al. (2019) highlighted the need for a
comprehensive understanding of potential synergistic actions (Namdar et al., 2019). Terpenes like
limonene serve as permeation enhancers for lipophilic compounds through the skin. At the same
time, linalool demonstrated the ability to enhance the permeability of hydrophilic compounds via the
same route (El Maghraby et al., 2004). Moreover, myrcene's potential to enhance the transport of Δ9-
THC across the blood-brain barrier presents a promising avenue for developing centrally penetrant
AD therapeutics (Hartsel et al., 2016). The bioavailability of hydrophobic bioactives, such as
phytocannabinoids, is notably low through ingestion compared to smoking. Goulle et al. (2008)
reported ingestion rates of 6–7%, whereas smoking exhibited higher bioavailability ranging from 10–
35% (Goulle et al., 2008). Co-ingestion of triglycerides, particularly long-chain fatty acids, has been
identified as a strategy to improve the absorption of ingested lipophilic compounds through the
gastrointestinal tract (Wu et al., 2018). Additionally, flavonoids, alkaloids, and other polyphenols
have shown potential in increasing phytocannabinoid bioavailability by inhibiting major drug-
metabolizing enzymes of the cytochrome P450 family, reducing Phase II-metabolism through
inhibition of uridine 5′-diphospho-glucuronosyltransferase, and inhibiting P-glycoprotein 1 efflux
pumps (Cherniakov et al., 2017).
Furthermore, flavonoids, another group of phytochemicals in cannabis, have gained increasing
attention for their antioxidative and neuroprotective properties. These compounds have shown
promise in combating oxidative stress and neurodegeneration, making them valuable contributors to
the entourage effect's neuroprotective capabilities (Wang et al., 2021). A review published in the
journal Frontiers in Aging Neuroscience highlighted the neuroprotective effects of various
flavonoids, including quercetin and apigenin, which have been shown to attenuate
neuroinflammation and reduce neurodegenerative processes (Costa et al., 2016).
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Positive potentiating interactions, commonly referred to as synergies, occur when the combined
effects of compounds exceed the anticipated benefits derived from individual constituents (Caesar &
Cech, 2019). The botanical synergies of C. sativa phytochemicals, colloquially known as 'entourage
effects,' purportedly demonstrate greater efficacy clinically, in vivo, and in vitro compared to a single
or predominant phytocannabinoid molecule (Russo, 2019). Numerous studies have highlighted
beneficial combinations for AD prevention. In a mouse model of tauopathy, Sativex (1:1 THC/CBD)
reduced Aβ and tau deposition in the hippocampus and cerebral cortex (Casarejos et al., 2013). A
CBD-THC combination in the APPxPS1 mouse model also decreased soluble Aβ42 and plaque
composition, whereas CBD and THC individually did not (Aso & Ferrer, 2014). Another study using
APPxPS1 mice demonstrated that a combination of CBD and THC may improve cognition in aged
transgenic AD mice by normalizing synaptosome-associated protein 25, glutamate receptors 2 and 3,
and γ-aminobutyric acid receptor A subunit α1 expression (Aso & Ferrer, 2016). Schubert and
colleagues also demonstrated significant synergistic in vitro enhancement of neuroprotection
between Δ9-THC and CBN in an oxytosis cell death assay (Schubert et al., 2019).
Clinically, a randomized controlled trial showed that oral mucosal C. sativa-based extracts,
specifically Δ9-THC and CBD-based whole plant extract, were more effective than placebo or Δ9-
THC-predominant extract for treating cancer pain (Johnson et al., 2010). Observations in patients with
severe epilepsy indicated notable improvements with lower CBD extract doses than purified CBD
(Pamplona et al., 2018). In mice with seizures induced by pentylenetetrazol, the botanical synergy of
minor phytocannabinoids was statistically relevant for treating tonic-clonic seizures and improving
survival rates (Berman et al., 2018). In non-neurogenic therapeutic areas, Blasco-Benito and
colleagues demonstrated that C. sativa extract treatment was more efficient than pure Δ9-THC in
producing antitumor responses in vitro and in vivo (Blasco-Benito et al., 2018), while humulene was
shown to synergize with β-caryophyllene for enhanced anticancer activities (Legault & Pichette,
2007).
Recent evidence by Finlay and colleagues suggested that terpenoids did not alter the binding of
Δ9-THC, CBD, and CBR radioligand ([3H]-CP55,940) or exert functional effects on CB1R or CB2R,
indicating that phytocannabinoid synergies may involve pathways beyond direct effects on these
receptors (Finlay et al., 2020).
To further understand entourage pathways, investigations into the effects of terpenoids on
cannabinoid metabolism and distribution are warranted, as current studies primarily focus on CB1R
and CB2R signalling through the Gi/o protein-coupled receptors pathway (Santiago et al., 2019).
Notably, Δ9-THC may influence signalling at non-cannabinoid receptor targets (Banister et al.,
2019).
Regular consumption of C. sativa seeds may elevate endocannabinoid levels due to their high
linoleic acid content (Callaway, 2004; Maccarrone et al., 2010). with potential neuroprotective effects
explored in preclinical studies (Bilkei-Gorzo, 2012). This consumption may also be an absorption
enhancer due to the high phytochemical content in seeds, sprouts, and leaves (Frassinetti et al., 2018).
Cannflavin A, a neuroprotective prenylflavonoid in C. sativa, has a prolonged elimination half-life,
suggesting that regular hemp sprouts may extend their presence in plasma and tissues (Werz et al.,
2014). Further studies are needed to explore the potential synergies of whole plant C. sativa extracts
in preventing neuroinflammatory diseases.
The significance of the entourage effect in the context of neuroinflammation and neuroprotective
disorders offers a novel perspective for developing therapeutic interventions. By harnessing the
collective strength of various phytochemicals present in C. Sativa, researchers and medical
practitioners can explore innovative treatment approaches that capitalise on the synergistic
interactions of these compounds. Furthermore, understanding the entourage effect can guide the
development of targeted cannabis-based formulations tailored to specific neuroinflammatory
conditions and neuroprotective disorders, potentially leading to more effective and well-tolerated
treatments for those in need.
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6. Conclusion
In cannabis science, cannabinoids, terpenes, and flavonoids have often been overlooked, with
much of the literature focusing predominantly on the major cannabinoids THC and CBD. However,
emerging evidence suggests that these constituents, particularly cannabinoids and terpenes, play a
substantial role in interacting and collaborating. This interplay gives rise to the diverse effects,
benefits, and side effects observed among different cannabis strains, which can vary in the ratios of
these components (Moulin et al., 2014). Moreover, they are both interact with the endocannabinoid
system and exert various effects on the body, including analgesic, anti-inflammatory, and
neuroprotective actions. However, it is becoming increasingly clear that their effects are not solely
attributed to their actions but are modulated by other compounds in the plant.
Terpenes, aromatic compounds found in cannabis and other plants, contribute to the distinct
flavours and aromas associated with different strains. They have been shown to have
pharmacological properties and can interact with neurotransmitter receptors, enzymes, and cell
membranes, among other targets. Moreover, terpenes can influence the pharmacokinetics and
pharmacodynamics of cannabinoids, potentially enhancing or modulating their effects. The concept
of the entourage effect suggests that the combined action of cannabinoids and terpenes may result in
a synergistic or additive therapeutic effect greater than the sum of their individual effects.
Flavonoids, another class of compounds found in cannabis, have also demonstrated therapeutic
potential. Although research on cannabis flavonoids is limited, studies have suggested their anti-
inflammatory, antioxidant, and neuroprotective properties. Furthermore, specific flavonoids, such as
cannflavins, have shown potent anti-inflammatory effects, particularly in neuroinflammation.
Understanding the intricate interplay between cannabinoids, terpenes, and flavonoids is
paramount for realizing the full therapeutic benefits of cannabis. This paper outlines critical research
directions and identifies key evidence gaps necessitating immediate attention.
Firstly, elucidating the synergistic effects and underlying mechanisms of cannabinoids, terpenes,
and flavonoids demands a focused investigation.
Secondly, comprehending the intricacies of cannabis phytochemical production and
accumulation mechanisms, particularly under varying lighting conditions, is pivotal for advancing
medicinal applications.
Thirdly, conducting comprehensive phytochemical characterization of cannabis strains,
including their distinct ratios of cannabinoids, terpenes, and flavonoids, holds promise for refining
treatment strategies. Such endeavours can pave the way for developing more personalized and
productive medicinal interventions.
Moreover, addressing regulatory barriers obstructing cannabis research is imperative.
Overcoming these obstacles, stemming from the classification of cannabis as a Schedule I substance
is crucial to expanding access to cannabis products for research purposes. Furthermore, this would
enable a more comprehensive exploration of the therapeutic and adverse effects of cannabis and
cannabinoids, fostering informed decision-making in public health initiatives.
Finally, recognizing the value of non-phytocannabinoid compounds, such as terpenes and
flavonoids, in therapeutic development necessitates a broader research focus. Exploring these
compounds' biosynthesis, bioactivities, and biotechnological applications is pivotal for harnessing
their therapeutic potential and diversifying treatment options.
In conclusion, a comprehensive exploration of the synergies between cannabinoids, terpenes,
and flavonoids, coupled with advancements in phytochemical research and the removal of
regulatory barriers, holds the key to unlocking the full therapeutic potential of cannabis. Addressing
these gaps is crucial for advancing the field and fostering evidence-based, personalized treatment
modalities.
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