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The pharmacological properties of cannabis


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The efforts to understand the nature of how the consumption of cannabis affects the human body are ongoing, complex, and multifaceted. Documentation on the use of cannabis dates back thousands of years; however, it is only now with the recent softening of legal restrictions that modern research approaches have been able to initiate an appropriate level of detailed investigations For clinicians, researchers and policy makers, this paper reviews the general structure of cannabinoids, the current understanding of cannabinoids on cellular systems, the deference of inhalation and oral consumption on cannabinoid bioavailability, the variance among purified cannabinoids versus whole plant extract, and the potential activities of another prominent family of secondary metabolites found in cannabis, the terpenes.
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J Pain Manage 2016;9(4):481-491 ISSN: 1939-5914
© Nova Science Publishers, Inc.
The pharmacological properties of cannabis
Istok Nahtigal, MSc,
Alexia Blake, MSc, Andrew Hand, MSc,
Angelique Florentinus-Mefailoski, MSc,
Haleh Hashemi, PhD,
and Jeremy Friedberg*, PhD
MedReleaf Corp, Markham Industrial Park,
Markham, Ontario, Canada
* Correspondence: Jeremy Friedberg, PhD, MedReleaf Corp,
Markham Industrial Park, POBox 3040, Markham,
Ontario, L3R 6C4, Canada.
The efforts to understand the nature of how the
consumption of cannabis affects the human body are
ongoing, complex, and multifaceted. Documentation on the
use of cannabis dates back thousands of years; however, it
is only now with the recent softening of legal restrictions
that modern research approaches have been able to initiate
an appropriate level of detailed investigations. For
clinicians, researchers and policy makers, this chapter
reviews the general structure of cannabinoids, the current
understanding of cannabinoids on cellular systems, the
difference between inhalation and oral consumption on
cannabinoid bioavailability, the variance among purified
cannabinoids versus whole plant extract, and the potential
activities of another prominent family of secondary
metabolites found in cannabis, the terpenes.
Keywords: Cannabis, cannabinoids, terpenes
The efforts to understand the nature of how the
consumption of cannabis affects the human body
is an ongoing and complex process. Although
documentation of cannabis’ use dates back thousands
of years, it was only the recent amelioration of legal
restrictions that allowed modern research approaches
to initiate an appropriate level of detailed
investigations, as with other plant species. For
clinicians, researchers and policy makers, this chapter
reviews the general structure of cannabinoids, the
current understanding of cannabinoids within cellular
systems, the differences of inhalation and oral
consumption on cannabinoid bioavailability, the
therapeutic efficacy of purified cannabinoids versus
whole plant extract, and the potential activities of
another prominent family of secondary metabolites
found in cannabis, the terpenes.
Istok Nahtigal, Alexia Blake, Andrew Hand et al.
Structure, expression and production
of known cannabinoids
Phytocannabinoids are represented by a number
of compounds that exhibit potent bioactivities
on human physiology (1) and make up the most
studied group of chemicals from the Cannabis
sativa plant (see Table 1 for a list of predominant
cannabinoids). Phytocannabinoids have also been
discovered in plants from the genus Radula
(liverworts) and Helichrysum (sunflower family)
(2). Notwithstanding the long history of cannabis
use and research, the cannabinoid biosynthesis
pathways have only been recently elucidated.
Cannabigerol type compounds (CBG, CBGa)
were the first cannabinoids identified (3), and it
is CBGa that is converted into THCa, CBDa
and CBCa via the action of oxidocyclase THCa-,
CBDa- or CBCa-synthase (4). Cannabigerol is
synthesized from olivetolic acid (OLA) and geranyl
diphosphate (GPP), products of the polyketide
and non-mevalonate pathways, respectively. The
cannabinoids THC, CBD and CBC possess a
C5 side chain, and versions also exist wherein a
C3 group is substituted and the compounds are
otherwise identical. These analogous cannabinoids
are THCVa, CBDVa and CBCVa, whose precursors
are divarinolic acid (DVA) and GPP.
Cannabinoids are not present plant-wide.
They are produced and primarily localized to
specialized structures called trichomes. Trichomes are
epidermal protuberances that cover the flower, leaves
and parts of the stem (1, 5). The cannabinoids are
synthesized in secretory cells and translocated
to a storage cavity within the trichome (6).
Compartmentalization is necessary due to the
cytotoxic nature of cannabinoids. It is from these
trichomes that the cannabinoids are harvested or
vaporized, depending on the end use or mode of
consumption. The natural form of the cannabinoids as
they exist in the trichome are the acid forms, however,
neutral cannabinoids are the pharmacologically
active forms responsible for the partial agonistic
effects on both the CB1 and CB2 type receptors.
Consequently, moderate heating is required to drive a
decarboxylation reaction where the carboxylic acid
moiety of the acid cannabinoids is removed, leaving
the neutral forms (7).
Known cannabinoids and their effects
on cellular and system physiology
Cannabis sativa produces a wide range of secondary
metabolites, with the total number of identified and
reported compounds increasing steadily since Gaoni
and Mechoulam first isolated (-)-trans-delta-9-
tetrahydrocannabinol 9-THC) in 1964 (8). In total,
545 different compounds have been isolated, of which
104 belong to a group of compounds unique to
Cannabis sativa, referred to as cannabinoids (9-17)
(see Table 1). However, this number is considered by
many researchers to be dynamic and is a subject of
debate, with the number of cannabinoid-like
compounds possibly exceeding 130 (18). Most of
these compounds are typically present only in trace
quantities, and the pharmacological value of only a
small number has been researched. The focus of this
paper is the pharmacological action of Δ9-THC and
cannabidiol (CBD).
The primary cannabinoid that is responsible for
the psychotropic effects of Cannabis sativa is Δ9-
THC (19) (see figure 1). Similar to endogenous post-
synaptic released endocannabinoids anandamide and
2-arachidonoylglycerol, Δ9-THC interacts with and
activates G protein-coupled CB1 and CB2 cannabinoid
receptors (20-22). CB1 receptors are found in a high
concentration in many tissue types throughout the
body, including most brain regions and the peripheral
nervous system (23), as well as some non-neuronal
tissues such as the liver, stomach, heart, testes, and fat
tissue (24-28). Presynaptic activation of CB1 receptors
in neuronal tissue inhibits release of neurotransmitters
such as gamma-Aminobutyric acid and glutamate by
releasing βγ-subunits from the G protein complex,
leading to inhibition of voltage-gated calcium
channels and vesicle release (29-30). However, while
activation of CB1 receptors typically inhibits release
of neuronal transmitters, in vivo activation of CB1
with Δ9-THC has been observed to occasionally
increase release of acetylcholine, dopamine and
glutamate in various regions of the brain in rats (31-
34). It is likely that this is due to selective antagonism
by Δ9-THC of endocannabinoids, as reported by Patel
and Hillard (35) when observing anti-anxiolytic
effects of Δ9-THC administration in mice. It is this
inhibitory-stimulation modulation of neurotransmitter
release mediated by Δ9-THC that is thought to be
Pharmacology and cannabis
responsible for the psychotropic effects of Cannabis,
both depressant and excitatory in nature. Cannabidiol,
however, does not share psychotropic activity with
Δ9-THC, instead acting as a CB1 inverse agonist or
even antagonist, thereby attenuating in vivo response
to Δ9-THC in multiple model species (36).
Cannabinoid CB2 receptors, on the other hand, are
more typically located on organs related to the
immune system, and when activated attenuate pro-
inflammatory responses such as cytokine release and
immune cell response (37-38) (see Figure 1). There is
evidence that CBD interacts with CB2 receptors as an
inverse agonist, leading to the well-documented
reduction of clinical pro-inflammatory markers such
as TNF-α, iNOS and COX-2 expression (39). In
addition to the effects on CB2, CBD has also been
reported to interact with additional receptors related to
the immune system. For example, CBD has been
found to potently inhibit uptake of adenosine at A2A
receptors, the mechanism by which adenosine
signaling terminates, thereby enhancing the anti-
inflammatory effects of adenosine agonists (40). CB2
receptors are also found in both brain and peripheral
neuronal tissue in a lower concentration relative to
CB1 receptors, however their role has yet to be
elucidated (41).
Figure 1. The human endocannabinoid system.
Table 1. Predominant cannabinoids with clinical relevance
Molecule Clinical Relavance Molecule Clinical Relavance
Δ9-THCAAntiemeti c (Hernandez et al. 2015) CBDAAntipsychotic (Leweke et al. 2012)
C21H30O2Treatment of PTSD (Roitman et al. 2014) C21H30O2Palliative Care of Parkinson's (Chagas et al. 2014)
314.47 g/mol
Treatment of Sleep Disorders (Gorelick et al. 2013) 314.46 g/mol Anxiol ytic (Bergamaschi et al. 2011)
Acidic Form
Palliative Treatment of Dementia (Woodward et al. 2014) Acidic Form Treatment of PTSD (Das et al. 2013)
C22H30O4Treatment of IBS (Wong et al. 2011) C22H30O4Treatment of Epilepsy (Pe lliccia et al. 2005)
358.47 g/mol
Appetite Stimulant (Costiniuk et al. 2008) 358.46 g/mol Anti-Inflammatory/Anti-nociceptive (Gallily et al. 2015)
Δ9-THCVATreatment of Obesity (Tudge et al. 2014) CBDVAAntiemetic (Rock et al. 2013)
C19H26O2Anti-Inflammatory/Anti-nocicepti ve (Bolognini et al. 2010) C19H26O2Anticonvulsant in Mice (Hill et al. 2012)
286.41 g/mol
Treatment of Epilepsy (Hill et al. 2010) 286.40 g/mol Treatment of Epilepsy (Amada et al. 2013)
Acidic Form
Treatment of Insulin Sensitivity (Wargent et al. 2013) Acidic Form Anti-Acne (Olah et al. 2016)
C20H26O4C20H28O4Treatment of Bladder Dysfunctions (Pagano et al. 2015)
330.41 g/mol 330.40 g/mol
Δ8-THCAImprovement of Appeti te (Avraham et al. 2004) CBCAAnti-Acne (Olah et al. 2016)
C21H30O2Antineopl astic Activity (Munson et al. 1975) C21H30O2Anti-Inflammatory (Wirth et al. 1980)
314.47 g/mol
Antieme tic (Abrahamov et al. 1995) 314.46 g/mol Treatment of Colitis (Romano et al. 2013)
Acidic Form Acidic Form
Treatment of Hypertension (O'Neil et al. 1979)
C22H30O4C22H30O4Treatment of Hypermotility (Izzo et al. 2012)
358.47 g/mol 358.46 g/mol
Reduction of Intraocular Pressure (Colasanti et al. 1984)
CBGAAppetite Stimulant (Brierle y et al. 2016) CBCVANo Clinical Research Preformed
C21H32O2Treatment of Huntington's Disease (Diaz-Alonso et al. 2016) C19H26O2
316.48 g/mol
Reduction of Intraocular Pressure (Szczesni ak et al. 2011) 286.40 g/mol
Acidic Form
Treatment of Dry-Skin Syndrome (Ol ah et al. 2016) Acidic Form
C22H32O4Anti-Cancer (Scott et al. 2013) C20H30O4
360.48 g/mol 330.40 g/mol
CBGVATreatment of Dry-Skin Syndrome (Olah et al. 2016) CBNAAnalgesia (Sofia et al. 1975)
C19H28O2Anti-Cancer (Scott et al. 2013) C21H26O2Reduction of Intraocular Pressure (Colasanti et al. 1984)
288.42 g/mol 310.43 g/mol
Appetite Stimulant (Farrimond et al. 2012)
Acidic Form Acidic Form
332.42 g/mol 354.43 g/mol
Pharmacology and cannabis
Inhalation versus oral consumption
and bioavailability
As with all drugs, the pharmacokinetics (PK) of
cannabis are dependent on the route of administration.
To date, most human clinical trials have evaluated the
PK activity of cannabis after inhalation or ingestion.
While different studies report a wide range of PK
parameters due to differences in dosing, it is still clear
that the onset, rate of absorption, and bioavailability
of THC and CBD are significantly higher after
inhalation than after ingestion or oral administration
(42, 43) (see Table 2).
Table 2. Pharmacokinectics of cannabis based on route of administration
Route of Administration
% Dose Consumed
~ 50% (loss due to pyrolysis)
Trajectory to Circulation
Lungs Bronchi-Bronchiole -
Stomach Small Intestines Portal Vein - Liver
Other Factors Affecting
Intake upon inhalation
(puff duration, intake volume,
holding time)
Absorption (stomach contents, metabolic rate,
genetic variants in CYP 450 enzyme activity,
enzyme regulation by other drugs)
First-Pass Hepatic
First-Pass Hepatic Metabolism by CYP450
2 56%
30 90 minutes
Time of Peak Plasma
5 10 minutes
1 6 hours
2 - 4 hours
4 8 hours
THC is detectable in blood almost immediately
after smoking, with peak plasma concentrations
measurable after 5 10 minutes (42, 44-46). Reported
peak values vary with administered dose. For
instance, one study reported that inhalation of
cigarettes containing 1.75% THC (equivalent to 16
mg THC) and 3.55% THC (34 mg THC) resulted in
mean peak plasma concentrations of 84.3 ng/ml and
162.2 ng/ml, respectively (42). However, the range of
measured peak plasma concentrations for the low
dose cigarette was 50-129 ng/ml and 76-267 ng/ml for
the high dose cigarette.
Such wide ranges are also found when comparing
reported bioavailability values. Some studies have
reported the bioavailability of inhaled THC as 30%
(46), 1035% (43), and 18% (47). One study
comparing the pharmacokinetics of THC between
frequent and occasional users concluded that the
bioavailability was 2327% for frequent users, and
1014% for occasional users (45). These differences
arise from variances in smoking technique, with
factors such as puff duration, intake volume, and
holding time determining drug intake (42, 43, 48).
Furthermore, up to 30% of THC has been shown to be
lost during the pyrolysis process, with additional loss
occurring in the side stream smoke and incomplete
absorption in the lungs (43, 45, 49). As a conservative
calculation, the bioavailability of THC after smoking
is reported as 2-56% (42, 48).
Fewer studies have focused exclusively on the PK
activity of CBD. One study reported that the
bioavailability of CBD after inhalation was 31%,
while others remark on the similarity in PK activity
between THC and CBD (43, 50). However, it has
been reported that CBD may alter the PK activity of
THC and can mediate some of its adverse effects,
such as paranoia and anxiety (42, 50-53). The exact
reason for this modulatory effect is unknown, but
current scientific opinion is that CBD inhibits the
activity of cytochrome P450 enzymes, which in turn
effects THC metabolism, particularly after oral
administration (42, 48, 51).
The PK activity of cannabis after oral
administration is rather different. Absorption is much
slower and irreproducible, with the onset of action
ranging between 3090 minutes. Peak THC plasma
Istok Nahtigal, Alexia Blake, Andrew Hand et al.
concentrations may be reached as early as 1-2 hours
after ingestion or as late as 46 hours (42, 45). Also,
the duration of effects is noticeably longer after oral
administration than after inhalation (48).
Oral administration is known to diminish the
bioavailability of both THC and CBD compared to
inhalation. Several studies have reported that the
bioavailability of THC after ingestion is 4-20% (42),
4-12% (43), 3-14% (50), and 6% (52). Similarly, the
oral bioavailability of CBD has been reported as 13
19% (54) and 6% (55).
The major explanation for this reduction in oral
bioavailability is that cannabinoids undergo extensive
first pass hepatic metabolism by CYP 450 genes prior
to reaching systemic circulation (42, 43, 50).
Oxidation into 11-OH-THC and other metabolites
diminishes the amount of THC that reaches systemic
circulation, thereby reducing oral bioavailability. For
the same reason, plasma levels of 11-OH-THC are
significantly higher after oral administration
compared to inhalation (43). With inhalation, first
pass hepatic metabolism is avoided since the
cannabinoids enter system circulation via the lungs.
Overall, these differences in PK activity allow
patients to customize their treatment based on their
therapeutic needs. For example, a patient in need of
instant pain relief may prefer to smoke or vape
cannabis. Conversely, a patient with insomnia may be
less interested in instant effects, and instead may
prefer to ingest cannabis and experience its effects
throughout the night.
The cocktail versus the individual
The use and efficacy of herbal drugs in traditional
medicine has been documented for centuries among
many cultures. Recently published data has presented
evidence for the therapeutic benefits of whole
botanical extracts over single isolated constituents,
as well as their bioequivalence with synthetic
chemotherapeutics (56, 57).
Different molecules and metabolic pathway
components such as enzymes, substrates, receptors,
ion channels, transport proteins, DNA/RNA,
ribosomes, monoclonal antibodies and physico-
chemical mechanisms are the possible targets for
different bio-chemical molecules that are present in a
plant extract (59). Synergistic effects of plant extracts
result in the following ways: (i) Constituents of a
plant extract affect different targets. (ii) Constituents
interact with one another to improve their solubility,
thereby enhancing the bioavailability of one or several
substances of an extract. (iii) Compounds may also
have their efficacy enhanced with agents that
antagonize mechanisms of resistance (58).
A given synergistic effect can be tested by
comparing the pharmacological effects of the mono-
substances versus the combination of substances by
analyzing isobole curves based on data from several
dose combinations (60). This analysis enables one to
discriminate effects between simple additive,
antagonistic interactions or real synergism with
potentiated or over-additive effects (56).
However, other compounds in plant extracts
could enhance the overall efficacy if negative
symptoms or ‘‘lateral damages’’ have developed
during a disease. Many plant extracts are rich in other
secondary metabolites, such as polyphenols and
terpenoids. These have an important role in this way,
specifically when their bioavailability is high.
Polyphenols possess a strong ability to bind with
proteins or glycoproteins, and terpenoids have great
affinities for cell membranes because of their
lipophilicity and thus a high potential to permeate
through cell walls of the body or bacteria (56).
For example, a study clearly illustrated that
cannabis plant extracts are superior to pure
cannabidiol for the treatment of inflammatory disease.
This higher efficiency might be explained by additive
or synergistic interactions between CBD and minor
phytocannabinoids or non-cannabinoids presented in
the extracts (61). A study of efficacy of the whole
plant Artemisia annua and pure artemisinin (the active
compound) in the treatment of malaria showed the
whole plant to be clinically efficacious, well tolerated,
and oftentimes more effective than purified
compounds used to reduce malaria morbidity and
mortality (62). While the synergism between
compounds in the whole plant extract increases the
extracts efficacy, there are also concerns about
adverse drug reactions (ADRs). Adverse drug
reactions tend to be more apparent with combinations
of prescribed synthetic medicines, but clinical
manifestations of ADRs do not seem to be common
Pharmacology and cannabis
for botanical extracts. This may be due, in part, to a
lack of reporting of adverse reactions for herbal
medicines (63).
Terpene biochemistry and free
radical scavenging
Terpenes comprise a diverse class of organic
compounds which are produced by a variety of plants.
Their functions range from plant protection by
deterring herbivores to attracting predators and
pollinating insects. In addition to their roles as end-
products or secondary metabolites, terpenes are
biosynthetic building blocks within nearly every
living creature. Steroids, as an example, are derived
from the terpene squalene.
When terpenes are modified chemically through
oxidation or structural rearrangement, the resulting
compounds are generally referred to as terpenoids.
More often than not, the term terpene is used to
include all terpenoids. The difference between
terpenes and terpenoids is that terpenes are
hydrocarbons, whereas terpenoids contain additional
functional groups such as oxygen moieties or
branching methyl groups. Terpenes and terpenoids are
the primary constituents of the essential oils of plants
and flowers (64). They are a chief constituent of the
Cannabis sativa plant; as of 2011, more than 200
terpenoids have been identified in cannabis, with
little being known about how they affect the
pharmacological properties (65). The synergistic
relationship between terpenes and cannabinoids can
occur through four different mechanisms: (i) multi-
target physiological effects, (ii) pharmacokinetics,
(iii) bacterial resistance, and (iv) side-effect
modulation. The synergistic potential of terpenes adds
weight to the idea that plants can be better drugs than
singular compounds derived from them (65).
Terpenoids are pharmacologically versatile
due to their lipophilic nature, enabling interaction
with cell membranes, neuronal and muscle ion
channels, neurotransmitter receptors, G-protein
coupled receptors, second messenger systems and
enzymes (66). These substances have immensely
broad biochemical effects, influencing some of the
most critical enzyme systems, while affecting
neurotransmitter levels and other fundamental
processes. These effects are exactly what
pharmaceutical drugs are designed to do. One of the
most important and captivating aspects of these novel
compounds is that they are pharmacologically
active in extremely minute quantities well below
toxic levels. Terpenoids are bioavailable in high
percentages due to their lipophilic properties,
permitting passive migration across biological
membranes and entrance into the blood stream,
influencing activities of the brain, heart or other
Some of the most commonly found terpenes in
Cannabis sativa are:
D-limonene: Studies using citrus oils in mice
and humans showed profound anxiolytic and
antidepressant effects (67, 68).
β-Myrcene: anti-inflammatory, analgesic and
sedative properties (69).
α-Pinene: anti-inflammatory, antibacterial
and a bronchodilator, as well as being able
to counteract short-term memory deficits
induced by THC intoxication (65, 68).
D-Linalool: anxiolytic activity (68, 70).
β-Caryophyllene: is the most common
sesquiterpenoid encountered in cannabis.
While these compounds are the major
representatives by mass, it is important to note that
there are significantly more chemical species present
in small quantities each with its own and compounded
Plant antioxidants are composed of a broad
variety of compounds, such as ascorbic acid,
polyphenolic compounds, and terpenoids. Terpenes
are the main components of essential oils, their anti-
oxidative capacity contributing to the beneficial
properties of fruits and vegetables. Three main modes
of antioxidant action have been detected to date: (i)
quenching of singlet oxygen, (i) hydrogen transfer,
and (iii) electron transfer. Several investigations have
studied reactive oxygen species and the antioxidant
activity of monoterpenes and diterpenes or essential
oils in vitro (71). Reactive oxygen species (ROS) are
created from free radicals generated during energy
metabolism and by environmental deterioration,
inadequate nutrition, exposure to irradiation and stress
involved in the pathological development of many
Istok Nahtigal, Alexia Blake, Andrew Hand et al.
human diseases such as neurodegeneration,
cardiovascular deterioration, diabetes and others. The
most promising strategy to avert oxidative damage
caused by these reactive species is the use of
antioxidant molecules. Antioxidants play an important
role in defending the body against free radical attack
by delaying or inhibiting the oxidation of lipids or
other biomolecules, preventing, or facilitating the
repairing of the damage to cells (72). These
compounds can act as direct antioxidants through free
radical scavenging mechanisms and/or as indirect
antioxidants by enhancing the antioxidant status
(enzymatic and non-enzymatic). Terpenes, one of the
most extensive and varied structural compounds
occurring in nature, display a wide range of biological
and pharmacological activities. Due to their
antioxidant behaviour, terpenes have been shown to
provide relevant protection under oxidative stress
conditions in different diseases including liver, renal,
neurodegenerative and cardiovascular diseases,
cancer and diabetes, as well as in aging processes
Cannabis is a plant rich with diverse compounds that
exhibits a range of effects on human physiology.
These effects are primarily attributed to cannabinoids
and terpenes, large families of metabolites that can
interact with many cellular and physiological systems
in the body. Although much research still needs to be
done, the effects of these metabolites provide an
important tool in managing a range of clinical
symptoms. Among cultivars of the plant, varying
levels of these compounds create different
physiological effects and, depending on how the plant
is administered to patients, can alter the clinical
Conflict of interest
The authors are all employees of MedReleaf, an
authorized grower and distributor of medical cannabis
in Canada. The authors report no other conflicts of
We thank Dean Pelkonen for assistance with graphic
design for Figure 1.
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... Upon binding of the endocannabinoids to the CB1R, an intracellular signaling cascade is initiated, which ultimately inhibits neurotransmitter release, thereby blocking pain signaling ( Figure 2) [32,33]. AEA has been observed to bind as a partial agonist at the CB1R and CB2R, with a higher affinity at the CB1R, where 2-AG has been observed to be an agonist of both the CB1R and CB2R, binding with low to moderate affinity [28,32,34]. ...
... Upon binding of the endocannabinoids to the CB1R, an intracellular signaling cascade is initiated, which ultimately inhibits neurotransmitter release, thereby blocking pain signaling ( Figure 2) [32,33]. AEA has been observed to bind as a partial agonist at the CB1R and CB2R, with a higher affinity at the CB1R, where 2-AG has been observed to be an agonist of both the CB1R and CB2R, binding with low to moderate affinity [28,32,34]. The opioid-and cannabinoid systems implicated in the modulation of neuronal activity and pain signal. ...
... Both pathways, when activated by their respective agonists, modulate the intracellular release of neurotransmitters (e.g., GABA and glutamate) through calcium (Ca 2+ )-dependent vesicular release blockade, by blocking Ca 2+ and kalium (K + ) channels. Hereby is the neuronal activity decreased and results in dampening of the pain signaling [28,33,34]. Created with Figure 2. The opioid-and cannabinoid systems implicated in the modulation of neuronal activity and pain signal. ...
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The analgesic potential of Cannabis sativa L.—based medicinal cannabis products for treatment of cancer associated chronic pains has gained increased interest in recent years. To ensure a controlled distribution of these products and investigate their therapeutic potential, several countries have established so-called pilot trials. Many doctors, however, are hesitant to prescribe medicinal cannabis primarily due to lack of research evidence regarding the products’ efficacy, safety and thus questionable dosing guidelines. This review aims to elucidate clinical research supporting administration of medicinal cannabis in cancer patients for analgesic purposes. The cannabinoids’ effects on the endocannabinoid system (ECS) and its implication in pain regulation is included to illustrate the complexity related to this research field. Published clinical studies on medicinal cannabis primarily consist of observational studies and only one pilot randomized controlled trial (RCT), where more RCTs exist on the cannabis-based product, Sativex® (GW Pharma Ltd., Cambridge, UK). The studies indicate analgesic potential, however non-significantly, for most patients and with acceptable safety profile. Summarizing, high-quality RCTs are scarce in this research field, and the limitations of the observational studies complicates interpretation of clinical outcomes. Despite discrepancy among the studies, they do show indications for administration and dosing regimens providing analgesic effects for some cancer patients.
... The cannabinoid THC, CBD and CBC contains C5 side chain and substituted moiety as C3. The THCVa, CBDVa and CBCVa cannabinoids are produced from the same reactant of divarinolic acid (DVA) and GPP [10]. ...
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This study investigated the formulation of a product prototype RMUTI-SKC by using the legal part of cannabis plants (leaves). Five product prototypes were composed of cannabis (leaves), stevia and mint. The herbs were added to improve the taste, smell and physical appearance properties of the product prototype which was yellowish-green. The analysis of the chemical properties found no heavy metals (Cd, As, and Pb) were observed (based on THAI community product standard, and demonstrated a moderate antioxidant activity, total phenolic content and total flavonoid content. The GC-MS profile of crude extracts analysis revealed the phytochemicals based on pharmacological action of essential oil, flavoring substance, anti-inflammatory, antioxidant, anti-bacterial, antidiabetic, antifungal and anti-cancer, respectively. The experimental results showed the pharmacological properties of the product prototype which can be a guideline for applying cannabis plants to other products. Further study on pathogen testing and product aging should be carried out to satisfy the quality of production. HIGHLIGHTS The formulation of a product prototype RMUTI-SKC by using the legal part of cannabis plants (leaves). The analysis of the chemical properties found no heavy metals (Cd, As and Pb) were observed (based on THAI community product standard, and demonstrated a moderate antioxidant activity, total phenolic content and total flavonoid content. GRAPHICAL ABSTRACT
... CBD counteracts some THC-induced effects (e.g., tachycardia, anxiety, etc.), probably due to its low affinity for CB-R (45). Several pre-clinical and clinical studies have highlighted many biological effects (e.g., antiinflammatory, neuroprotective, antioxidative, antiemetic, and analgesic effects) associated with CBD, varying according to its concentration and the study models adopted (46,47). ...
Triple negative breast cancer (TNBC) represents an aggressive subtype of breast cancer, which is deficient in estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression. Thus, TNBC cells are unable to respond to the conventional hormonal therapies, making chemotherapy the only therapeutic choice. Patients with TNBC develop metastasis and recurrence over time and have reduced survival compared to patients with other subtypes of breast cancer. Therefore, there is a need for innovative therapies. Data emerged from pre-clinical studies, highlighted various antitumor activities of plant-derived Cannabis sativa and synthetic cannabinoids (CBs), including delta-9-tetrahydrocannabinol (THC) and non-psychoactive cannabidiol (CBD). On the contrary, some studies indicated that CBs might also promote tumor progression. At present, clinical studies on the effects of CBs from Cannabis sativa in cancer patients are few. In the present study, we reviewed known and possible interactions between cannabinoids and TNBC therapies.
... To date, modern clinical studies that have investigated the medicinal properties of cannabis substances have focused primarily on the pharmacological potential of single cannabinoids to treat specific medical disorders [31,32], such as CBD for palliative care of Parkinson disease [33] or THC for the suppression of nausea in patients with cancer who are undergoing chemotherapy treatments [34]. However, over the years, a large number of publications have indicated that the therapeutic effect of whole-plant-based remedies is often superior to the effect obtained from drugs containing a single purified cannabinoid. ...
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Maintaining specific and reproducible cannabinoid compositions (type and quantity) is essential for the production of cannabis-based remedies that are therapeutically effective. The current study investigates factors that determine the plant’s cannabinoid profile and examines interrelationships between plant features (growth rate, phenology and biomass), inflorescence morphology (size, shape and distribution) and cannabinoid content. An examination of differences in cannabinoid profile within genotypes revealed that across the cultivation facility, cannabinoids’ qualitative traits (ratios between cannabinoid quantities) remain fairly stable, while quantitative traits (the absolute amount of Δ9-tetrahydrocannabinol (THC), cannabidiol (CBD), cannabichromene (CBC), cannabigerol (CBG), Δ9-tetrahydrocannabivarin (THCV) and cannabidivarin (CBDV)) can significantly vary. The calculated broad-sense heritability values imply that cannabinoid composition will have a strong response to selection in comparison to the morphological and phenological traits of the plant and its inflorescences. Moreover, it is proposed that selection in favour of a vigorous growth rate, high-stature plants and wide inflorescences is expected to increase overall cannabinoid production. Finally, a range of physiological and phenological features was utilised for generating a successful model for the prediction of cannabinoid production. The holistic approach presented in the current study provides a better understanding of the interaction between the key features of the cannabis plant and facilitates the production of advanced plant-based medicinal substances.
... Since the turn of the century, the potential of medicinal cannabis has been scientifically reacknowledged through a large number of studies (Nahtigal et al., 2016). These have suggested that cannabis-based remedies can alleviate and treat a wide range of medical disorders (Cascio et al., 2017) such as nausea (Parker et al., 2002), psychotic symptoms of schizophrenia (Leweke et al., 2012), pediatric epilepsy (Goldstein, 2015) and pain (Baron, 2018). ...
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In recent decades with the reacknowledgment of the medicinal properties of Cannabis sativa L. (cannabis) plants, there is an increased demand for high performing cultivars that can deliver quality products for various applications. However, scientific knowledge that can facilitate the generation of advanced cannabis cultivars is scarce. In order to improve cannabis breeding and optimize cultivation techniques, the current study aimed to examine the morphological attributes of cannabis inflorescences using novel image analysis practices. The investigated plant population comprises 478 plants ascribed to 119 genotypes of high−THC or blended THC−CBD ratio that was cultivated under a controlled environment facility. Following harvest, all plants were manually processed and an image of the trimmed and refined inflorescences extracted from each plant was captured. Image analysis was then performed using in-house custom-made software which extracted 8 morphological features (such as size, shape and perimeter) for each of the 127,000 extracted inflorescences. Our findings suggest that environmental factors play an important role in the determination of inflorescences’ morphology. Therefore, further studies that focus on genotype X environment interactions are required in order to generate inflorescences with desired characteristics. An examination of the intra-plant inflorescences weight distribution revealed that processing 75% of the plant’s largest inflorescences will gain 90% of its overall yield weight. Therefore, for the optimization of post-harvest tasks, it is suggested to evaluate if the benefits from extracting and processing the plant’s smaller inflorescences outweigh its operational costs. To advance selection efficacy for breeding purposes, a prediction equation for forecasting the plant’s production biomass through width measurements of specific inflorescences, formed under the current experimental methodology, was generated. Thus, it is anticipated that findings from the current study will contribute to the field of medicinal cannabis by improving targeted breeding programs, advancing crop productivity and enhancing the efficacy of post-harvest procedures.
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Cannabis sativa L. is a phenotypically diverse and multi-use plant used in the production of fiber, seed, oils, and a class of specialized metabolites known as phytocannabinoids. The last decade has seen a rapid increase in the licit cultivation and processing of C. sativa for medical end-use. Medical morphotypes produce highly branched compact inflorescences which support a high density of glandular trichomes, specialized epidermal hair-like structures that are the site of phytocannabinoid biosynthesis and accumulation. While there is a focus on the regulation of phytocannabinoid pathways, the genetic determinants that govern flowering time and inflorescence structure in C. sativa are less well-defined but equally important. Understanding the molecular mechanisms that underly flowering behavior is key to maximizing phytocannabinoid production. The genetic basis of flowering regulation in C. sativa has been examined using genome-wide association studies, quantitative trait loci mapping and selection analysis, although the lack of a consistent reference genome has confounded attempts to directly compare candidate loci. Here we review the existing knowledge of flowering time control in C. sativa , and, using a common reference genome, we generate an integrated map. The co-location of known and putative flowering time loci within this resource will be essential to improve the understanding of C. sativa phenology.
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Cannabis is an herbal medicine that contains two essential cannabinoids: Cannabidiol (CBD) and Delta-9-Tet-rahydrocannabinol (THC). CBD acts as an anti-inflammatory agent, helps improve sleep quality, and provides antiepi-leptic effects while THC has psychoactive effects and inhibits brain growth, especially in children and adolescents with developing brains. Currently, only pure CBD and CBD-enriched cannabis extracts are used in children and adolescents only for treating uncontrolled severe epilepsy. On the other hand, children and adolescents who use cannabis and cannabis products containing a large amount of THC can experience physical, mental health, and cognitive problems. Physical symptoms of cannabis use include restlessness or lethargy, abdominal pain, and severe nausea and vomiting while mental health issues are depression, anxiety, suicidal thoughts and behaviors, and severe aggressive behavior. Additionally, the use of cannabis also has negative impacts on cognitive functions and learning processes which include decreased cogni-tive levels, poor memory, and impaired executive functions, leading to failure in future academic and work performances. Therefore, all healthcare professionals should provide accurate information about cannabis to parents, children, and adolescents to prevent the adverse effects of cannabis use in children and adolescents after the implementation of "cannabis legalization."
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Abstract Metabolic syndrome (MetS), an epidemic defined as a group of interconnected physiological, biochemistry, clinical, and metabolic factors, directly increases the risk of cardiovascular disease, atherosclerosis, type 2 diabetes, and death. MetS therapy includes diet, physical exercise, and a poly-pharmacological intervention. Cannabis is mainly recognized for its recreational uses and has several medical applications for neurological diseases, due to its hypnotic, anxiolytic, antinociceptive, anti-inflammatory, and anticonvulsant activities. Although several clinical observations in Cannabis smokers suggest metabolic effects, its utility in metabolic disorders is unclear. This review aims to determine under what conditions Cannabis might be useful in the treatment of MetS. Cannabis contains 120 phytocannabinoids, of which Δ9-THC mediates its psychoactive effects. Cannabinoids exert biological effects through interactions with the endocannabinoid system, which modulates several physiologic and metabolic pathways through cannabinoid receptors (CB1/CB2). Signaling through both receptors inhibits neurotransmitter release. In general, endocannabinoid system stimulation in Cannabis smokers and Δ9-THC signaling through CB1 have been implicated in MetS development, obesity, and type 2 diabetes. In contrast, CB1 antagonists and non-psychotropic phytocannabinoids like cannabidiol reduce these effects through interactions with both cannabinoid and non-cannabinoid receptors. These pharmacological approaches represent a source of new therapeutic agents for MetS. However, more studies are necessary to support the therapeutic potential of Cannabis and cannabinoids in metabolic abnormalities.
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Cannabis: The journey from medical to Intoxicant and back again
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Sativex(®), a cannabis extract oromucosal spray containing Δ(9)-tetrahydrocannabinol (THC) and cannabidiol (CBD), is currently in phase III trials as an adjunct to opioids for cancer pain treatment, and recently received United Kingdom approval for treatment of spasticity. There are indications that CBD modulates THC's effects, but it is unclear if this is due to a pharmacokinetic and/or pharmacodynamic interaction. Cannabis smokers provided written informed consent to participate in this randomized, controlled, double-blind, double-dummy institutional review board-approved study. Participants received 5 and 15 mg synthetic oral THC, low-dose (5.4 mg THC and 5.0 mg CBD) and high-dose (16.2 mg THC and 15.0 mg CBD) Sativex, and placebo over 5 sessions. CBD, THC, 11-hydroxy-THC, and 11-nor- 9-carboxy-THC were quantified in plasma by 2-dimensional GC-MS. Lower limits of quantification were ≤0.25 μg/L. Nine cannabis smokers completed all 5 dosing sessions. Significant differences (P < 0.05) in maximum plasma concentrations (C(max)) and areas under the curve from 0-10.5 h postdose (AUC(0→10.5)) for all analytes were found between low and high doses of synthetic THC and Sativex. There were no statistically significant differences in C(max), time to maximum concentration or in the AUC(0→10.5) between similar oral THC and Sativex doses. Relative bioavailability was calculated to determine the relative rate and extent of THC absorption; 5 and 15 mg oral THC bioavailability was 92.6% (13.1%) and 98.8% (11.0%) of low- and high-dose Sativex, respectively. These data suggest that CBD modulation of THC's effects is not due to a pharmacokinetic interaction at these therapeutic doses.
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Cannabis sativa L. is an important herbaceous species originating from Central Asia, which has been used in folk medicine and as a source of textile fibre since the dawn of times. This fast-growing plant has recently seen a resurgence of interest because of its multi-purpose applications: it is indeed a treasure trove of phytochemicals and a rich source of both cellulosic and woody fibres. Equally highly interested in this plant are the pharmaceutical and construction sectors, since its metabolites show potent bioactivities on human health and its outer and inner stem tissues can be used to make bioplastics and concrete-like material, respectively. In this review, the rich spectrum of hemp phytochemicals is discussed by putting a special emphasis on molecules of industrial interest, including cannabinoids, terpenoids and phenolic compounds, and their biosynthetic routes. Cannabinoids represent the most studied group of compounds, mainly due to their wide range of pharmaceutical effects in humans, including psychotropic activities. The therapeutic and commercial interests of some terpenoids and phenolic compounds, and in particular stilbenoids and lignans, are also highlighted in view of the most recent literature data. Biotechnological avenues to enhance the production and bioactivity of hemp secondary metabolites are proposed by discussing the power of plant genetic engineering and tissue culture. In particular two systems are reviewed, i.e. cell suspension and hairy root cultures. Additionally, an entire section is devoted to hemp trichomes, in the light of their importance as phytochemical factories. Ultimately, prospects on the benefits linked to the use of the -omics technologies, such as metabolomics and transcriptomics to speed up the identification and the large-scale production of lead agents from bioengineered Cannabis cell culture, are presented.
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Marijuana (Cannabis sativa) has long been known to contain antibacterial cannabinoids, whose potential to address antibiotic resistance has not yet been investigated. All five major cannabinoids (cannabidiol (1b), cannabichromene (2), cannabigerol (3b), Delta (9)-tetrahydrocannabinol (4b), and cannabinol (5)) showed potent activity against a variety of methicillin-resistant Staphylococcus aureus (MRSA) strains of current clinical relevance. Activity was remarkably tolerant to the nature of the prenyl moiety, to its relative position compared to the n-pentyl moiety (abnormal cannabinoids), and to carboxylation of the resorcinyl moiety (pre-cannabinoids). Conversely, methylation and acetylation of the phenolic hydroxyls, esterification of the carboxylic group of pre-cannabinoids, and introduction of a second prenyl moiety were all detrimental for antibacterial activity. Taken together, these observations suggest that the prenyl moiety of cannabinoids serves mainly as a modulator of lipid affinity for the olivetol core, a per se poorly active antibacterial pharmacophore, while their high potency definitely suggests a specific, but yet elusive, mechanism of activity.
Cannabis sativa L., one of the oldest plants known in medicine, is the most widely used illicit drug in the world today. A total of almost 500 natural constituents have been isolated and/or identified from cannabis [1], with Δ⁹-THC the main biologically active component [2]. The availability of high potency marijuana on the illicit market with unprecedented Δ⁹-THC concentrations (> 20% by dry weight)[3] has renewed our interest in the discovery of new constituents from cannabis. Phytochemical investigation of a high potency variety of C sativa L. resulted in the isolation of six new metabolites, (±)-6,7-trans-epoxycannabigerolic acid (1), (±)-6,7-cis-epoxycannabigerolic acid (2), (±)-6,7-cis-epoxycannabigerol (3), (±)-6,7-trans-epoxycannabigerol (4), 5ʹ-methyl-4-pentylbiphenyl-2,2ʹ,6-triol (5), and 7-methoxycannabispirone (5), along with seven known compounds (cannabigerolic acid, 5ʹ-methoxycannabigerolic acid, cannabispirone, β-cannabispiranol, dehydrocannabifuran, cannaflavin B and cannabigerol). The antimicrobial and antileishmanial activities were investigated. Acknowledgements: This work is supported by the Center of Research Excellence in Natural Products Neuroscience, The University of Mississippi, contract # 1P20RR021929-01, and by the National Institute on Drug Abuse, contract # N01DA-5-7746. We are grateful to Dr. Bharathi Avula for assistance with the HR-ESI-MS, and to Dr. Melissa Jacob and Ms. Marsha Wright for conducting the antimicrobial testing. References: [1] Grotenhermen F, Russo E, In Cannabis and Cannabinoids: Pharmacology, Toxicology, and Therapeutic Potential. Grotenhermen F, Russo E, Ed.; The Haworth Press, Inc.: Binghamton, New York, 2002; Definitions and Explanations, pp. xxvii–xxxi. [2] Clarke RC, Watson DP, In Cannabis and Cannabinoids: Pharmacology, Toxicology, and Therapeutic Potential. Grotenhermen F, Russo E, Ed.; The Haworth Press, Inc.: Binghamton, New York, 2002; Chapter 1 – Botany of Natural Cannabis Medicines, p.3–14.
Cannabis, the only genus in the plant family Cannabaceae, consists of only one highly variable species, Cannabis sativa L. More than 535 constituents have been isolated and/or identified from Cannabis sativa L., [1–3] with Δ⁹-THC being recognized as the main biologically active component [4]. Cannabisol (1), a unique dimer of Δ⁹-tetrahydrocannabinol (Δ⁹-THC) with a methylene bridge, was isolated from Cannabis sativa. This is the first example of a C-bridged dimeric cannabinoid. The structure of cannabisol (1) was unambiguously deduced by HRESIMS, GCMS and NMR spectroscopy. A plausible biogenesis of 1 will be presented. Fig.1: Cannabisol (1) Acknowledgement: The project was supported by Grant No. 5P20RR021929 from the National Center for Research Resources and grant # N01DA-05–7746 from NIDA. References: [1] ElSohly MA, Slade D (2005) Life Sci 78: 539–548. [2] Radwan M, ElSohly MA, et al. (2009)J Nat Prod 72(5): 906–911. [3] Pollastro F, Orazio T, et al. (2011)J Nat Prod 74(9): 2019–2022. [4] Williamson EM, Evans FJ (2000) Drugs 60: 1303–1314.
Marijuana and other exogenous cannabinoids alter immune function and decrease host resistance to microbial infections in experimental animal models and in vitro. Two modes of action by which Δ9-tetrahydrocannabinol (THC) and other cannabinoids affect immune responses have been proposed. First, cannabinoids may signal through the cannabinoid receptors CB1 and CB2. Second, at sites of direct exposure to high concentrations of cannabinoids, such as the lung, membrane perturbation may be involved. In addition, endogenous cannabinoids or endocannabinoids have been identified and have been proposed as native modulators of immune functions through cannabinoid receptors. Exogenously introduced cannabinoids may disturb this homoeostatic immune balance. A mode by which cannabinoids may affect immune responses and host resistance may be by perturbing the balance of T helper (Th)1 pro-inflammatory versus Th2 anti-inflammatory cytokines. While marijuana and various cannabinoids have been documented to alter immune functions in vitro and in experimental animals, no controlled longitudinal epidemiological studies have yet definitively correlated immunosuppressive effects with increased incidence of infections or immune disorders in humans. However, cannabinoids by virtue of their immunomodulatory properties have the potential to serve as therapeutic agents for ablation of untoward immune responses.
Background and purpose: It has been proposed that medicinal strains of cannabis and therapeutic preparations would be safer with a more balanced concentration ratio of Δ9-tetrahydrocannabinol (THC) to cannabidiol (CBD), as CBD reduces the adverse psychotropic effects of THC. However, our understanding of CBD and THC interactions is limited and the brain circuitry mediating interactions between CBD and THC are unknown. The aim of this study is to investigate whether CBD modulates THC-induced functional effects and c-Fos expression in a 1:1 dose ratio that approximates therapeutic strains of cannabis and nabiximols. Experimental approach: Male C57BL/6 mice were treated with vehicle, CBD, THC, or a combination of CBD and THC (10 i.p. for both cannabinoids) to examine effects on locomotor activity, anxiety-related behaviour, body temperature, and brain c-Fos expression (a marker of neuronal activation). Key results: CBD potentiated THC-induced locomotor suppression but reduced the hypothermic and anxiogenic effects of THC. CBD alone had no effect on these measures. THC increased brain activation as measured by c-Fos expression in 11 of the 35 brain regions studied; CBD co-administration suppressed THC-induced c-Fos expression in 6 of these brains regions. This effect was most pronounced in the medial preoptic nucleus and lateral PAG. CBD alone treatment diminished c-Fos expression only in the central nucleus of the amygdala compared to vehicle. Conclusions and implications: These data re-affirm that CBD modulates the pharmacological actions of THC and provide information regarding brain regions involved in the interaction between CBD and THC.