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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.
E-mail: jfriedberg@medreleaf.com
Abstract
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
Introduction
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.
482
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 (Δ9-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
483
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
C21H28O4C21H26O2
332.42 g/mol 354.43 g/mol
Pharmacology and cannabis
485
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
Inhalation
Oral
% Dose Consumed
~ 50% (loss due to pyrolysis)
100%
Trajectory to Circulation
Lungs – Bronchi-Bronchiole -
Alveoli
Stomach – Small Intestines – Portal Vein - Liver
Other Factors Affecting
Uptake
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
Metabolism
Bypassed
First-Pass Hepatic Metabolism by CYP450
enzymes
Bioavailability
2 – 56%
<20%
Onset
Immediate
30 – 90 minutes
Time of Peak Plasma
5 – 10 minutes
1 – 6 hours
Duration
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), 10–35% (43), and 18% (47). One study
comparing the pharmacokinetics of THC between
frequent and occasional users concluded that the
bioavailability was 23–27% for frequent users, and
10–14% 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 30–90 minutes. Peak THC plasma
Istok Nahtigal, Alexia Blake, Andrew Hand et al.
486
concentrations may be reached as early as 1-2 hours
after ingestion or as late as 4–6 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
compounds
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
extract’s 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
487
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
organs.
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
effects.
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.
488
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
(73).
Conclusion
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
utility.
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
interest.
Acknowledgments
We thank Dean Pelkonen for assistance with graphic
design for Figure 1.
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Submitted: August 08, 2016. Revised: August 27, 2016.
Accepted: September 04, 2016.
