672 Neuropathology of Drug Addictions and Substance Misuse, Volume 1. http://dx.doi.org/10.1016/B978-0-12-800213-1.00062-6
Copyright © 2016 Elsevier Inc. All rights reserved.
An Overview of Major and Minor
Jahan P. Marcu
Americans for Safe Access, Washington, DC, USA; Green Standard Diagnostics, Inc., Las Vegas, NV, USA
ECS Endocannabinoid system
THCA Tetrahydrocannabinol acid
TRP Transient receptor potential
TRPV Transient receptor potential vanilloid type
For nearly five millennia, Cannabis has been documented as a med-
icine with unmatched applicability (Russo, 2011). The mechanism
of action of Cannabis remained a mystery until fairly recently, with
the discovery of phytocannabinoids, or plant cannabinoids, and the
receptor system known as the endocannabinoid system (ECS). Phy-
tocannabinoids are terpenophenolic compounds associated with
the effects of the Cannabis plant and mimic the effects of endog-
enous cannabinoids. These phytocannabinoids are biosynthesized
and secreted by glandular trichomes found on the flower tops of
the Cannabis plant (Figure 1). In the 1960s a host of cannabinoids
were discovered, including cannabigerol (CBG), tetracannabiva-
rin (THCV), and cannabichromene (CBC) (Figure 2). More than
100 cannabinoids have been identified in Cannabis and reports
are emerging of their occurrence in other plants (Appendino,
Chianese, & Taglialatela-Scafati, 2011; Pertwee, 2014). The great
bulk of clinical cannabinoid research focuses on the psychotropic
Δ9-tetrahydrocannabinol (THC), inadvertently marginalizing the
roles of other cannabinoids in altering the pharmacological activi-
ties of Cannabis compounds. Many compounds in the plant can
enhance or inhibit various aspects of THC pharmacology, for exam-
ple, the inhibition of unwanted side effects such as with the coad-
ministration of cannabidiol (CBD) (Russo & Guy, 2006). Major
and minor phytocannabinoids can have remarkably positive effects
in mammalian behavior related to anxiety and drug acquisition and
may offer novel drug abuse treatment options.
The ratios of these major and minor compounds can vary
greatly and some compounds are not often detected or tested for or
reported. Furthermore, the Cannabis plant is not the only source
of phytocannabinoids. Excellent in-depth reviews of the phytocan-
nabinoids have been published (Pertwee, 2014; Pharmacopoeia,
2013). The following is an overview of the major and minor phy-
tocannabinoids that can be found in Cannabis.
AND CANNABIGEROL ACID
Cannabinoid acids are found as primary metabolites in Cannabis
plants. For example, tetrahydrocannabinol acid (THCA) is synthe-
sized in glandular trichomes of the Cannabis plant and forms THC
after the parent compound is decarboxylated by UV exposure,
prolonged storage, or heat (Figure 3). The cannabinoid acids do
not produce any significant or documented psychotropic effects.
THCA, tetrahydrocannabivarinic acid, and cannabigerol acid
(CBGA) are the immediate natural precursors of THC, THCV,
and CBG. THCA and CBGA are the primary phytocannabinoid
metabolites and can cause apoptosis of insect cells (Figure 3)
Basic research has shown that these acidic compounds can
efficiently activate TRPM8 channels and stimulate or desensitize a
range of other transient receptor potential (TRP) cation channels.
THCA and CBGA have been found to inhibit enzymes respon-
sible for the breakdown of endocannabinoids, as well as cyclooxy-
genase-1 and -2, thus stimulating the ECS by increasing levels of
This compound was the first cannabinoid purified from Cannabis
(Gaoni & Mechoulam, 1964). CBG lacks the psychotropic effects
of THC (Grunfeld & Edery, 1969a, 1969b, 1969c). This compound
does not have a significant subjective psychotropic effect in humans
but CBG may stimulate a range of receptors important for pain,
inflammation, and heat sensitization. This compound can antago-
nize transient receptor potential vanilloid type (TRPV) 8 receptors
and stimulates TRPV1, TRPV2, TRPA1, TRPV3, TRPV4, and
α2-adrenoceptor activity (Cascio, Gauson, Stevenson, Ross, &
Pertwee, 2010; De Petrocellis & Di Marzo, 2009; De Petrocellis &
An Overview of Major and Minor Phytocannabinoids Chapter
| 62 673
(D) (E) (F)
FIGURE 1 The Cannabis plant and its trichomes. Immature Cannabis plants are seen in (A), while in (B) there is an example of flowering plants. An
example of a harvested and dried flower from a Cannabis plant is shown in (C), while (D and E) display close-ups of the trichomes, visible as pale stalks.
A glandular cystolic trichome can be seen in (F); these are found in Cannabis flowers and biosynthesize cannabinoids. A cannabinoid-rich oil is secreted
out of the top of trichomes in a waxy layer. Photos A–C, courtesy of J.P.M., photos D–F, courtesy of E.R.
FIGURE 2 Structures of cannabinoids found in the Cannabis plant. These compounds are the secondary metabolites of Cannabis. These compounds
are synthesized as acidic versions and decarboxylate over time or when heat is applied. All images generated by J.P.M. using ChemDraw software.
674 PART | IV Cannabinoids
Di Marzo, 2010; De Petrocellis et al., 2011, 2012). CBG can also
antagonize the stimulation of serotonin 5-HT1A and cannabinoid
type 1 (CB1) receptors with significant efficiency.
THC is the degradation product of nonpsychotropic THCA, which
is synthesized from CBGA by THCA synthase. THC is a partial
agonist at CB1 and CB2 receptors with a high affinity for both
receptors. Stimulation of CB1 receptors by THC can lead to a tet-
rad of effects in assays with laboratory animals; these effects are
documented as suppression of locomotor activity, hypothermia,
catalepsy (ring test), and antinociceptive effects in tail flick test
(Martin et al., 1991). THC can stimulate CB2 receptors, which
may decrease the growth of some cancers and reduce arthritic
pain and edema in models of arthritis. Perhaps most surprising is
that direct stimulation of CB2 receptors can result in significantly
reducing cocaine self-administration in animals (Gardner, 2013).
Stimulation of CB2 receptors is not associated with the psychotro-
pic effects of Cannabis use.
THC also has several non-CB receptor mechanisms that have
been reported; these include inhibiting the 5-HT3A receptor,
enhancing glycine receptor activation by allosteric modification,
elevating calcium levels via TRPA1 or TRPV2, reducing elevated
intracellular calcium levels from TRPM8 activity, stimulating
nuclear receptors, and stimulating G Protein Receptor 18 (Barann
et al., 2002; De Petrocellis et al., 2012, 2008; Hejazi et al., 2006;
McHugh, Page, Dunn, & Bradshaw, 2012; O’Sullivan, Tarling, Ben-
nett, Kendall, & Randall, 2005).
Oral THC administration can have significant effects on anxi-
ety, depression, and mood. The effects of THC in humans can vary
depending on the experience of the subject. The oral administra-
tion of pure THC to naïve subjects can induce anxiety but this is
not reported with experienced users, and use of the drug is not
significantly associated with developing anxiety and depressive
disorders later in life (Bahi et al., 2014; Ballard, Bedi, & de Wit,
2012; Campos et al., 2013; Crippa et al., 2009). Oral administra-
tion of THC results in its metabolism to 11-hydroxy-THC, which
possesses up to10 times greater potency. This metabolism can
explain some discrepancies between the observed effects in groups
administered oral or inhaled forms of THC.
THC-predominant Cannabis is reported to be a commonly
abused or misused substance. Street Cannabis can be contaminated
or adulterated and this may underlie the negative health aspects of
lifelong use. THC can cause temporary impairments to neuropsy-
chomotor performance. All observable negative effects of THC
administration on neurocognitive tasks disappear within 30 days
regardless of the amount or length of use (Pope, Gruber, Hudson,
Huestis, & Yurgelun-Todd, 2001). The proposed treatment for so-
called Cannabis addiction or withdrawal is oral THC (Lichtman &
Martin, 2005). CBD may also be considered an antidote for THC,
as CBD and compounds in the plant tame or inhibit the psychotro-
pic effects of THC (Russo, 2011). Excellent reviews are available
covering numerous clinical trials with oral and inhaled THC for
the treatment of over 10 pathologies (Ben Amar, 2006; Hazekamp
& Grotenhermen, 2010; Pacher et al., 2006).
THC, the ECS, and the endorphin/opiate system can interact
in remarkable ways (Table 1). Animal research has demonstrated
a potential prophylactic effect on developing opiate dependence,
as adolescent exposure to chronic THC blocks opiate dependence
in maternally deprived rats (Morel, Giros, & Daugé, 2009). The
ECS is proposed to interact with endorphins, through the release
of opioid peptides from CB receptor activation and the synthe-
sis of endocannabinoids induced by opiate receptor stimulation
FIGURE 3 Products of biosynthesis and decarboxylation.
Phytocannabinoids are biosynthesized as acidic precursors, such as
THCA. Acidic phytocannabinoids are decarboxylated to form neutral can-
nabinoids. The conversion of acidic to neutral cannabinoid can occur from
prolonged storage and when heat is applied, generating carbon dioxide and
water. CBDA, cannabidiolic acid.
TABLE 1 The ECS Is Proposed to Interact with Opioids through a Few Mechanisms
Morel et al. (2009) Adolescent exposure to THC may impart resistance to opiate dependence in maternally deprived
Abrams et al. (2011) and
Russo et al. (2008)
CB receptor stimulation can result in endorphin release, and opioid receptor stimulation may
increase synthesis of endogenous cannabinoids.
Abrams et al. (2011) Clinical research demonstrates that THC can enhance the pain-relieving effects of suboptimal
doses of opiates.
Bachhuber et al. (2014) The state of Colorado has experienced a signiﬁcant decrease in opiate-related deaths since the
implementation of medical and commercial Cannabis laws.
The release of opioid peptides by CBs and the release of endocannabinoids by opioids may be one mechanism (Abrams et al., 2011; Russo, 2008). Clini-
cally, THC may enhance the pain-relieving effects of opiates, lowering the amount of an opiate necessary for relief. Drug abuse studies demonstrate that
adolescent exposure to chronic THC blocks opiate dependence in maternally deprived rats. There is evidence of the existence of a direct receptor–receptor
interaction and cellular pathways, such as via allosteric modiﬁcation of heterodimers.
An Overview of Major and Minor Phytocannabinoids Chapter
| 62 675
(Abrams, Couey, Shade, Kelly, & Benowitz, 2011; Russo et al.,
2008). Clinically, THC may enhance the pain-relieving effects
of opiates, lowering the amount of an opiate necessary for relief.
Surveys suggest Cannabis is used to decrease the use of other
drugs (alcohol, nicotine, and opiates) (Reiman, 2009). In the
United States, the state governments that have passed commer-
cial Cannabis/marijuana laws report lower opiate overdose and
related death statistics; these populations may reflect what has
been observed in surveys and clinical studies of THC and opiates
(Bachhuber, Saloner, Cunningham, & Barry, 2014).
THCV is a propyl analogue of THC and most often occurs as a
small percentage of dried plant material, and THCV-rich plants
that are 16% THCV by dry weight have been developed by a phar-
maceutical company (Pharmacopoeia, 2013). Mechanistically
speaking, THCV can behave as both an agonist and an antagonist
at CB receptors depending on the concentration (Pertwee, 2008).
Antagonizing CB receptors can suppress appetite and the
intoxicating effects of THC. However, caution must be empha-
sized when developing CB1 receptor antagonists. Clinical studies
in human populations studying the antagonists of CB receptors
with the drug rimonabant (SR141716A) led to depressive epi-
sodes and potentially worsened neurodegenerative disease out-
comes, and ultimately this drug was withdrawn from the market
(McLaughlin, 2012). Despite this setback, SR141716A remains a
very important research tool for unlocking potential medical treat-
ments targeting the CB receptors and deepening the understanding
of the ECS.
The main nonpsychotropic phytocannabinoids are CBD and its
acidic precursor cannabidiolic acid. These are the most abundant
phytocannabinoids in European hemp (Pharmacopoeia, 2013).
CBD has a very low affinity for CB receptors but may have sig-
nificant CB1- and CB2-independent mechanisms of action. CBD
is reported to be an agonist at TRPV1 and 5-HT1A receptors and
to enhance adenosine receptor signaling (Russo, Burnett, Hall,
& Parker, 2005). Exceptional tolerability of CBD in humans has
been demonstrated (Mechoulam, Parker, & Gallily, 2002). CBD
can produce a wide range of pharmacological activity including
anticonvulsive, anti-inflammatory, antioxidant, and antipsychotic
effects. These effects underlie the neuroprotective properties
of this CB and support its role in the treatment of a number of
neurological and neurodegenerative disorders, including epi-
lepsy, seizures, Parkinson disease, amyotrophic lateral sclerosis,
Huntington disease, Alzheimer disease, and multiple sclerosis
(Hofmann & Frazier, 2013; de Lago & Fernández-Ruiz, 2007;
Martin-Moreno et al., 2011; Scuderi et al., 2009).
CBD possesses the unique ability to counteract the intoxi-
cating effects of Cannabis (Russo & Guy, 2006). The benefits
of CBD include reducing the unwanted side effects of THC, a
dynamic pharmacological effect that has been fairly well studied
in clinical trials. CBD is included in a specific ratio of 1/1 in
the medicinal Cannabis preparation and licensed pharmaceutical
known as Sativex®, which has been studied in numerous properly
controlled clinical trials representing some 30,000 patient years
(Flachenecker, Henze, & Zettl, 2014; Rog, 2010; Sastre-Gar-
riga, Vila, Clissold, & Montalban, 2014; Wade, Collin, Stott, &
CBC can be one of the most abundant nonpsychotropic CBs
found in strains or varieties of Cannabis (Brown & Harvey,
1990; Holley, Hadley, & Turner, 1975). CBC can cause strong
anti-inflammatory effects in animal models of edema through
non-CB receptor mechanisms (DeLong, Wolf, Poklis, & Licht-
man, 2010). CBC has been shown to significantly interact with
TRP cation channels, including TRPA1, TRPV1–4, and TRPV8
(Pertwee, 2014). CBC can also produce behavioral activity in the
Billy Martin tetrad assay for the effects of CB administration.
The effects of CBC can be augmented for additive results when
THC is coadministered. CBC administration can induce nocicep-
tion by itself and can potentiate the nociceptive effects of THC in
CBN is a degradation product of THC and its presence in the Can-
nabis plant may indicate the relative age of the harvested plant
material or how well the material was stored. CBN binds less effi-
ciently than THC to CB1 and CB2 receptors. CBN binds more
tightly to CB2 receptors than to CB1 receptors. The metabolite of
CBN is 11-hydroxy-CBN, which is reported to be more potent at
CB1 receptors (Yamamoto et al., 2003).
A recent review of phytocannabinoids summarized the
ability of CBN to inhibit the activity of a number of enzymes,
including cyclooxygenase, lipoxygenase, and a host of cyto-
chrome P450 (CYP) enzymes (e.g., CYP1A1, CYP1A2,
CYP2B6, CYP2C9, CYP3A4, CYP3A5, CYP2A6, CYP2D6,
CYP1B1, and CYP3A7) (Pertwee & Cascio, 2014). CBN may
also stimulate the activity of phospholipases.
BCP is a volatile terpene with CB receptor activity, found ubiq-
uitously throughout nature and in great abundance in Cannabis,
cloves, and black pepper (Figure 4). This terpene is an efficient
CB2 receptor agonist, is generally regarded as safe by the US Food
and Drug Administration, and is available commercially (Gertsch
et al., 2008). BCP binds and stimulates CB2 receptors, causing
analgesic and anti-inflammatory activity without psychotropic
effects. BCP has also been shown to reduce drug administration,
FIGURE 4 Structure and key facts regarding BCP. BCP is a volatile
terpene that activates CB2 receptors and may be a useful therapeutic com-
pound. Structure generated with ChemDraw by J.P.M.
676 PART | IV Cannabinoids
improving scores of depression and anxiety in mammals (Bahi
et al., 2014; Onaivi et al., 2008; Xi et al., 2011).
APPLICATIONS TO OTHER ADDICTIONS
AND SUBSTANCE MISUSE
Medical Cannabis and Cannabis-based medicines could poten-
tially be developed as drug addiction disorder treatments or used as
a substitute for alcohol and other drugs such as opiates and cocaine
(Aggarwal, 2008; Otto, 2012; Reiman, 2009; Subbaraman, 2014).
BCP and other CBs that activate the CB2 receptor may provide a
safe treatment for drug addiction and withdrawal symptoms by
providing anti-inflammatory effects and pain relief and improving
mood, but without any intoxicating effects. CB1 receptor-based
therapies may be appropriate for patients who have previous expe-
rience with Cannabis, as naïve patients have been shown to be less
tolerant of the side effects of CB1 activation compared to experi-
enced users in clinical settings.
DEFINITION OF TERMS
l Cannabinoids: This is a group of closely related compounds,
similar to THC or other compounds found in plants.
l CB1 receptor: This is a G-protein-coupled receptor densely
located in the brain and nervous tissue.
l CB2 receptor: This is a G-protein-coupled receptor densely
located in immune tissue and also found in the brain.
l Endocannabinoid system: This is a mammalian biological system
consisting of receptors (i.e., CB1, CB2), endogenously produced
compounds (i.e., anandamide, 2- arachidonoylglycerol), and pro-
teins responsible for the synthesis, breakdown, and transport of
l Phytocannabinoid: These are CB compounds that are found in
This chapter focuses on a group of terpenophenolic compounds
found in the Cannabis plant (Table 2). Cannabis is a plant that has
been documented as a medicine for millennia. Neurocognitive defi-
cits related to Cannabis use are reversible regardless of the amount
or duration of use over a lifetime. CBs such as BCP and CBD may
offer novel therapeutic strategies to develop treatments for drug
abuse-related disorders. BCP, CBD, and other phytocannabinoids
are nonpsychotropic and do not cause intoxication. CBD is well
tolerated in humans and can reduce anxiety. Furthermore, the
administration of CB2 agonists reduces anxiety and depression in
animal models, with supporting, but limited, evidence in humans.
THC and the ECS can interact with the opiate system. Clini-
cally coadministration of THC with opiates allows the adminis-
tration of significantly less opiate to reach the desired analgesic
effects. Additionally, administration of CB2 agonists reduces drug-
seeking behavior and signs of withdrawal in animal models. Can-
nabis and its pharmacological agents may have a potential role in
drug abuse treatment programs; evidence exists from animal and
human research suggesting clinical benefits related to cocaine and
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TABLE 2 Chemical Types and Numbers
Chemical Class or Type Number of Compounds
Cannabidiol (CBD) 8
Other CBs 61
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