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An Overview of Major and Minor Phytocannabinoids

  • Marcu & Arora

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In the 1960s several interesting compounds were isolated from the Cannabis plant. Today over 100 cannabinoids have been identified, across numerous varieties of Cannabis, which are structurally related to the main psychoactive ingredient ?9-tetrahydrocannabinol. This plant is a treasure trove of pharmacological compounds. Many of these compounds demonstrate unique properties and mechanisms apart from those of ?9-tetrahydrocannabinol; nonpsychotropic cannabidiol especially is being explored in pediatric clinical trials for the treatment of epilepsy. Cannabidiol and other cannabinoids may also represent nontoxic treatments with an exceedingly low potential for developing drug-addiction-related disorders. The aroma of Cannabis comprises over 120 terpenoid compounds, which are potent mediators of mammalian behavior when delivered at ambient air levels. ?-Caryophyllene is one of the most abundant terpenoids in the plant kingdom with cannabinoid receptor activity and has been shown to reduce cocaine self-administration in animals. The active ingredients on the Cannabis plant interact with or stimulate the endocannabinoid system, which underlies the mechanisms explaining potential benefits in drug abuse and addiction treatments.
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Chapter 62
An Overview of Major and Minor
Jahan P. Marcu
Americans for Safe Access, Washington, DC, USA; Green Standard Diagnostics, Inc., Las Vegas, NV, USA
BCP β-Caryophyllene
CBC Cannabichromene
CBG Cannabigerol
ECS Endocannabinoid system
THC Δ9-tetrahydrocannabinol
THCA Tetrahydrocannabinol acid
THCV Tetracannabivarin
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.
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)
(Sirikantaramas, 2004)
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
endogenous cannabinoids.
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
(A) (B)
(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
References Finding
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, &
Duncombe, 2010).
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
animal models.
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,
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).
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.
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
endogenous CBs.
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
opiate pharmacodynamics.
Abrams, D. I., Couey, P., Shade, S. B., Kelly, M. E., & Benowitz, N. L.
(2011). Cannabinoid–opioid interaction in chronic pain. Clinical
Pharmacology and Therapeutics, 90(6), 844–851.
Aggarwal, S. K. (2008). The medical geography of cannabinoid botanicals
in Washington State: Access, delivery, and distress. ProQuest.
Appendino, G., Chianese, G., & Taglialatela-Scafati, O. (2011). Cannabi-
noids: occurrence and medicinal chemistry. Current Medicinal Chem-
istry, 18(7), 1085–1099.
Bachhuber, M. A., Saloner, B., Cunningham, C. O., & Barry, C. L. (2014).
Medical cannabis laws and opioid analgesic overdose mortality in
the United States, 1999–2010. JAMA Internal Medicine, 174(10),
Bahi, A., Mansouri, Al, S., Memari, Al, E., Ameri, Al, M., Nurulain, S. M.,
& Ojha, S. (2014). β-Caryophyllene, a CB2 receptor agonist produces
multiple behavioral changes relevant to anxiety and depression in mice.
Physiology and Behavior, 135C, 119–124.
Ballard, M. E., Bedi, G., & de Wit, H. (2012). Effects of delta-9-
tetrahydrocannabinol on evaluation of emotional images. Journal of
Psychopharmacology, 26(10), 1289–1298.
Barann, M., Molderings, G., Brüss, M., Bönisch, H., Urban, B. W., & Göthert,
M. (2002). Direct inhibition by cannabinoids of human 5HT3A
receptors: probable involvement of an allosteric modulatory site. Brit-
ish Journal of Pharmacology, 137(5), 589–596.
Ben Amar, M. (2006). Cannabinoids in medicine: a review of their thera-
peutic potential. Journal of Ethnopharmacology, 105(1–2), 1–25.
Brown, N. K., & Harvey, D. J. (1990). In vitro metabolism of cannabi-
chromene in seven common laboratory animals. Drug Metabolism and
Disposition, 18(6), 1065–1070.
Campos, A. C., Ortega, Z., Palazuelos, J., Fogaça, M. V., Aguiar, D. C.,
Díaz-Alonso, J., … Galve-Roperh, I. (2013). The anxiolytic effect
of cannabidiol on chronically stressed mice depends on hippocampal
neurogenesis: involvement of the endocannabinoid system. The Inter-
national Journal of Neuropsychopharmacology, 16(06), 1407–1419.
TABLE 2 Chemical Types and Numbers
of Cannabinoids
Chemical Class or Type Number of Compounds
THC 18
CBG 17
Cannabidiol (CBD) 8
Other CBs 61
Non-CBs >400
This table represents a simple breakdown of compounds found in Cannabis.
There are several isomers of each class or type, as well as hundreds of
non-CB components, including terpenes, flavonoids, vitamin K, fatty
acids, nitrogenous compounds, etc.
An Overview of Major and Minor Phytocannabinoids Chapter
| 62 677
Cascio, M. G., Gauson, L. A., Stevenson, L. A., Ross, R. A., & Pertwee,
R. G. (2010). Evidence that the plant cannabinoid cannabigerol is a
highly potent α2adrenoceptor agonist and moderately potent 5HT1A
receptor antagonist. British Journal of Pharmacology, 159(1),
Crippa, J. A., Zuardi, A. W., Martín-Santos, R., Bhattacharyya, S., Atakan,
Z., McGuire, P., & Fusar-Poli, P. (2009). Cannabis and anxiety: a criti-
cal review of the evidence. Human Psychopharmacology: Clinical and
Experimental, 24(7), 515–523.
De Petrocellis, L., & Di Marzo, V. (2009). An introduction to the endocan-
nabinoid system: from the early to the latest concepts. Best Practice
and Research Clinical Endocrinology and Metabolism, 23(1), 1–15.
De Petrocellis, L., & Di Marzo, V. (2010). Non-CB1, non-CB2 receptors
for endocannabinoids, plant cannabinoids, and synthetic cannabimi-
metics: focus on G-protein-coupled receptors and transient receptor
potential channels. Journal of Neuroimmune Pharmacology, 5(1),
De Petrocellis, L., Ligresti, A., Moriello, A. S., Allarà, M., Bisogno, T.,
Petrosino, S., … Di Marzo, V. (2011). Effects of cannabinoids and can-
nabinoid-enriched Cannabis extracts on TRP channels and endocan-
nabinoid metabolic enzymes. British Journal of Pharmacology, 163(7),
De Petrocellis, L., Orlando, P., Moriello, A. S., Aviello, G., Stott, C., Izzo,
A. A., & Di Marzo, V. (2012). Cannabinoid actions at TRPV chan-
nels: effects on TRPV3 and TRPV4 and their potential relevance to
gastrointestinal inflammation. Acta Physiologica, 204(2), 255–266.
De Petrocellis, L., Vellani, V., Schiano-Moriello, A., Marini, P., Magherini,
P. C., Orlando, P., & Di Marzo, V. (2008). Plant-derived cannabinoids
modulate the activity of transient receptor potential channels of ankyrin
type-1 and melastatin type-8. The Journal of Pharmacology and Experi-
mental Therapeutics, 325(3), 1007–1015.
DeLong, G. T., Wolf, C. E., Poklis, A., & Lichtman, A. H. (2010). Phar-
macological evaluation of the natural constituent of Cannabis sativa,
cannabichromene and its modulation by Δ9-tetrahydrocannabinol.
Drug and Alcohol Dependence, 112(1–2), 126–133.
Flachenecker, P., Henze, T., & Zettl, U. K. (2014). Nabiximols (THC/
CBD oromucosal Spray, Sativex®) in clinical Practice - results of
a Multicenter, non-Interventional Study (MOVE 2) in patients with
multiple sclerosis spasticity. European Neurology, 71(5–6), 271–279.
Gaoni, Y., & Mechoulam, R. (1964). Structure+ synthesis of cannabigerol new
hashish constituent. Proceedings of the Chemical Society of London, 82.
Gardner, E. L. (2013). CB2 agonist and antagonist effects on cocaine self-
administration and other cocaine-induced actions. Substance Abuse.
Gertsch, J., Leonti, M., Raduner, S., Racz, I., Chen, J.-Z., Xie, X.-Q., …
Zimmer, A. (2008). Beta-caryophyllene is a dietary cannabinoid. Pro-
ceedings of the National Academy of Sciences, 105(26), 9099–9104.
Grunfeld, Y., & Edery, H. (1969a). Psychopharmacological activity of
some substances extracted from Cannabis sativa L. (hashish). Elec-
troencephalography and Clinical Neurophysiology, 27(2), 219–220.
Grunfeld, Y., & Edery, H. (1969b). Psychopharmacological activity of
the active constituents of hashish and some related cannabinoids.
Psychopharmacologia, 14(3), 200–210.
Grunfeld, Y., & Edery, H. (1969c). Psychopharmacological activity of the
active constituents of hashish and some related cannabinoids. Audio and
Electroacoustics Newsletter, IEEE, 14(3), 200–210.
Hazekamp, A., & Grotenhermen, F. (2010). Review on clinical studies with
cannabis and cannabinoids 2005–2009. Cannabinoids, 5(special), 1–21.
Hejazi, N., Zhou, C., Oz, M., Sun, H., Ye, J. H., & Zhang, L. (2006).
Delta9-tetrahydrocannabinol and endogenous cannabinoid anan-
damide directly potentiate the function of glycine receptors. Molec-
ular Pharmacology, 69(3), 991–997.
Hofmann, M. E., & Frazier, C. J. (2013). Marijuana, endocannabinoids,
and epilepsy: potential and challenges for improved therapeutic inter-
vention. Experimental Neurology, 244, 43–50.
Holley, J. H., Hadley, K. W., & Turner, C. E. (1975). Constituents of Cannabis
sativa L. XI: cannabidiol and cannabichromene in samples of known geo-
graphical origin. Journal of Pharmaceutical Sciences, 64(5), 892–894.
de Lago, E., & Fernández-Ruiz, J. (2007). Cannabinoids and neuropro-
tection in motor-related disorders. CNS and Neurological Disorders
Drug Targets, 6(6), 377–387.
Lichtman, A. H., & Martin, B. R. (2005). Cannabinoid tolerance and depen-
dence. Handbook of Experimental Pharmacology, 168, 691–717.
Martin-Moreno, A. M., Reigada, D., Ramirez, B. G., Mechoulam, R.,
Innamorato, N., Cuadrado, A., & de Ceballos, M. L. (2011). Cannabi-
diol and other cannabinoids reduce microglial activation in vitro and
in vivo: relevance to Alzheimer’s disease. Molecular Pharmacology,
79(6), 964–973.
Martin, B. R., Compton, D. R., Thomas, B. F., Prescott, W. R., Little, P. J.,
Razdan, R. K., … Ward, S. J. (1991). Behavioral, biochemical, and
molecular modeling evaluations of cannabinoid analogs. Pharmacol-
ogy, Biochemistry, and Behavior, 40(3), 471–478.
McHugh, D., Page, J., Dunn, E., & Bradshaw, H. B. (2012). Δ(9) -Tetrahy-
drocannabinol and N-arachidonyl glycine are full agonists at GPR18
receptors and induce migration in human endometrial HEC-1B cells.
British Journal of Pharmacology, 165(8), 2414–2424.
McLaughlin, P. J. (2012). Reports of the death of CB1 antagonists have
been greatly exaggerated. Behavioural Pharmacology, 23(5 and 6),
Mechoulam, R., Parker, L. A., & Gallily, R. (2002). Cannabidiol: an over-
view of some pharmacological aspects. Journal of Clinical Pharma-
cology, 42, 11S–19S.
Morel, L. J., Giros, B., & Daugé, V. (2009). Adolescent exposure to
chronic delta-9-tetrahydrocannabinol blocks opiate dependence in
maternally deprived rats. Neuropsychopharmacology, 34, 2469–2476.
O’Sullivan, S. E., Tarling, E. J., Bennett, A. J., Kendall, D. A., & Randall,
M. D. (2005). Novel time-dependent vascular actions of Delta9-
tetrahydrocannabinol mediated by peroxisome proliferator-activated
receptor gamma. Biochemical and Biophysical Research Communica-
tions, 337(3), 824–831.
Onaivi, E. S., Ishiguro, H., Gong, J.-P., Patel, S., Meozzi, P. A., Myers, L.,
… Uhl, G. R. (2008). Brain neuronal CB2 cannabinoid receptors in
drug abuse and depression: from mice to human subjects. PLoS One,
3(2), e1640.
Otto, M. A. (2012). Medical marijuana often used as a prescrip-
tion drug substitute. Clinical Psychiatry News, 40(1), 33.
678 PART | IV Cannabinoids
Pacher, P., Bátkai, S., & Kunos, G. (2006). The endocannabinoid system
as an emerging target of pharmacotherapy. Pharmacological Reviews,
58(3), 389–462.
Pertwee, R. G. (2008). The diverse CB 1 and CB 2 receptor pharmacology
of three plant cannabinoids: Δ 9-tetrahydrocannabinol, cannabidiol
and Δ 9-tetrahydrocannabivarin. British Journal of Pharmacology,
153(2), 199–215.
Pertwee, R. (2014). Handbook of cannabis. Oxford University Press.
Pertwee, R. G., & Cascio, M. G. (2014). Known pharmacological actions of
delta-9-Tetrahydrocannabinol and of four other chemical constituents of
cannabis that activate cannabinoid receptors. In Handbook of cannabis
(pp. 115–136).
Pharmacopoeia, A. H. (2013). Cannabis inflorescence.
Pope, H. G., Gruber, A. J., Hudson, J. I., Huestis, M. A., & Yurgelun-Todd,
D. (2001). Neuropsychological performance in long-term cannabis
users. Archives of General Psychiatry, 58(10), 909–915.
Reiman, A. (2009). Cannabis as a substitute for alcohol and other drugs. Harm
Reduction Journal, 6, 35.
Rog, D. J. (2010). Cannabis-based medicines in multiple sclerosis – a review
of clinical studies. Immunobiology, 215(8), 658–672.
Russo, E. B. (2008). Cannabinoids in the management of difficult to treat
pain. Therapeutics and Clinical Risk Management, 4(1), 245–259.
Russo, E. B. (2011). Taming THC: potential cannabis synergy and
phytocannabinoid-terpenoid entourage effects. British Journal
of Pharmacology, 163(7), 1344–1364.
Russo, E. B., Burnett, A., Hall, B., & Parker, K. K. (2005). Agonistic prop-
erties of cannabidiol at 5-HT1a receptors. Neurochemical Research,
30(8), 1037–1043.
Russo, E., & Guy, G. W. (2006). A tale of two cannabinoids: the thera-
peutic rationale for combining tetrahydrocannabinol and can-
nabidiol. Medical Hypotheses, 66(2), 234–246.
Russo, E. B., Jiang, H. E., Li, X., Sutton, A., Carboni, A., del Bianco, F.,
… Li, C. S. (2008). Phytochemical and genetic analyses of ancient
cannabis from Central Asia. Journal of Experimental Botany, 59(15),
Sastre-Garriga, J., Vila, C., Clissold, S., & Montalban, X. (2014). THC and
CBD oromucosal spray (Sativex®) in the management of spasticity
associated with multiple sclerosis. Expert Review of Neurotherapeu-
tics, 11(5), 627–637.
Scuderi, C., De Filippis, D., Iuvone, T., Blasio, A., Steardo, A., & Esposito,
G. (2009). Cannabidiol in medicine: a review of its therapeutic poten-
tial in CNS disorders. Phytotherapy Research, 23(5), 597–602.
Sirikantaramas, S. (2004). The gene controlling marijuana psychoac-
tivity: molecular cloning and heterologous expression of delta-1-
tetrahydrocannabinolic acid synthase from Cannabis sativa L. Journal
of Biological Chemistry, 279(38), 39767–39774.
Subbaraman, M. S. (2014). Can cannabis be considered a substitute
medication for alcohol? Alcohol and Alcoholism, 49(3), 292–298.
Wade, D. T., Collin, C., Stott, C., & Duncombe, P. (2010). Meta-analysis of
the efficacy and safety of Sativex (nabiximols), on spasticity in people
with multiple sclerosis. Multiple Sclerosis, 16(6), 707–714.
Xi, Z.-X., Peng, X.-Q., Li, X., Song, R., Zhang, H.-Y., Liu, Q.-R., …
Gardner, E. L. (2011). Brain cannabinoid CB2 receptors modulate
cocaine’s actions in mice. Nature Neuroscience, 14(9), 1160–1166.
Yamamoto, I., Watanabe, K., Matsunaga, T., Kimura, T., Funahashi, T., &
Yoshimura, H. (2003). Pharmacology and toxicology of major constit-
uents of Marijuana—On the metabolic activation of cannabinoids and
its mechanism. Journal of Toxicology: Toxin Reviews, 22(4), 577–589.
... No ano de 1960 em Israel, o químico Raphael Mechoulam e seu grupo descobriram e isolaram compostos derivados da Cannabis sativa L., como o canabidiol (CBD), delta-9-tetrahidrocanabinol (THC), canabigerol (CBG) entre outros (3). Atualmente existem centenas de fi tocanabinoides conhecidos, apesar da maioria não ser encontrada em grande quantidade no vegetal (5). O THC é o componente principal e responsável pela maioria dos efeitos psicoativos característicos da planta. ...
... Apesar do estigma que o THC carrega, sua relevância medicinal não deve ser descartada (3). O CBD é o segundo derivado mais abundante na planta sendo que diversos estudos suportam a ideia de uma perceptível efetividade no tratamento de diversas patologias, com a vantagem de não ser uma substância psicoativa (4,5). ...
... Os fi tocanabinoides interagem com o sistema endocanabinóide. Em suma, o sistema endocanabinoide (SE) é o sistema biológico encontrado em mamíferos, constituido de receptores canabinoides CB1 e CB2 que se associam aos compostos anandamida e 2-AG, produzidos endogenamente e responsáveis por inibir e/ou estimular tais receptores e proteínas que realizam a síntese, quebra e transporte desses canabinoides endógenos (5,8). ...
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O uso da Cannabis sativa para fi ns medicinais é um assunto bastante polêmico no Brasil, por isso é necessário se aprofundar no tema para elucidar as principais dúvidas e possíveis benefícios. A epilepsia é uma doença que causa alterações neurológicas, como crises epilépticas, disfagia e convulsões. Pode levar a danos cognitivos, psicológicos e comorbidades, piorando a qualidade de vida do paciente. Neste estudo foi realizada uma revisão integrativa sobre os diferentes tipos de canabinóides de C. sativa e seu uso no tratamento da epilepsia. Os dados foram obtidos a partir de artigos de pesquisa publicados em periódicos entre 1963 e 2020. Atenção especial foi dada a diferentes metabólitos, como o canabidiol (CBD). Aspectos gerais da epilepsia, uso de fi tocanabinóides em casos refratários e ensaios clínicos e pré-clínicos foram abordados nesta revisão, enfatizando seus efeitos biológicos. Como alvo futuro para o tratamento da epilepsia, o uso terapêutico do CBD em neurologia mostra resultados promissores nos casos em que a medicação convencional não tem efeito. Uma contribuição da pesquisa sobre outros fi tocanabinóides e sua inter-relação é essencial para avançar no tratamento da epilepsia e outras patologias.
... The properties of selected neutral cannabinoids are listed in Table 2. [25,44] The strongest psychoactive cannabinoid, ∆9-THC, belongs to a group of compounds that are subject to very strict international control. This was the first phytocannabinoid isolated from Cannabis sativa L. [54,56,57] and is a degradation product of ∆9-THCA [58]. It occurs in the highest concentrations in Cannabis sativa L. var. ...
... indica. ∆9-THCV is a partial agonist of the CB2 receptor, whose activity has been measured both in vitro and in vivo [25,44,58]. ...
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Scientific demonstrations of the beneficial effects of non-psychoactive cannabinoids on the human body have increased the interest in foods containing hemp components. This review systematizes the latest discoveries relating to the characteristics of cannabinoids from Cannabis sativa L. var. sativa, it also presents a characterization of the mentioned plant. In this review, we present data on the opportunities and limitations of cannabinoids in food production. This article systematizes the data on the legal aspects, mainly the limits of Δ9-THC in food, the most popular analytical techniques (LC-MS and GC-MS) applied to assay cannabinoids in finished products, and the available data on the stability of cannabinoids during heating, storage, and access to light and oxygen. This may constitute a major challenge to their common use in food processing, as well as the potential formation of undesirable degradation products. Hemp-containing foods have great potential to become commercially popular among functional foods, provided that our understanding of cannabinoid stability in different food matrices and cannabinoid interactions with particular food ingredients are expanded. There remains a need for more data on the effects of technological processes and storage on cannabinoid degradation.
... CBN is considered a degradation product of ∆ 9 -and ∆ 8 -THC (2). When the Cannabis plant is aging, or marijuana is not properly stored, and exposed to UV lighting and oxygen, THC gradually undergoes oxidation into CBN (40). Clinical studies showed that CBN had ∼10% of the potency of ∆ 9 -THC (25). ...
... CBN is both a native compound in the Cannabis plant and a degradation product of THC and CBD. Originally, the percentage of CBN in marijuana was an indicator of improper storage (2,40). The 108 positive CBN samples had a concentration range from 0.1 to 403.6 ng/mL. ...
Quantitative analysis of Δ9-tetrahydrocannabinol (Δ9-THC) in oral fluid has gained increasing interest in clinical and forensic toxicology laboratories. New medicinal and/or recreational cannabinoid products require laboratories to distinguish different patterns of cannabinoid use. This study validated a high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method for 13 different cannabinoids, including (-)-trans-Δ8-tetrahydrocannabinol (Δ8-THC), (-)-trans-Δ9-tetrahydrocannabinol (Δ9-THC), cannabidiol (CBD), Δ9-tetrahydrocannabinolic acid-A (Δ9-THCA-A), cannabidiolic acid (CBDA), 11-hydroxy-Δ9-tetrahydrocannabinol (11-OH-Δ9-THC), 11-nor-9-carboxy-Δ9-tetrahydrocannabinol (Δ9-THCCOOH), tetrahydrocannabivarin (THCV), cannabidivarin (CBDV), cannabidiorcol (CBD-C1), cannabichromene (CBC), cannabinol (CBN) and cannabigerol (CBG) in oral fluid. Baseline separation was achieved in the entire quantitation range between Δ9-THC and its isomer Δ8-THC. The quantitation range of Δ9-THC, Δ8-THC, and CBD was from 0.1 ng/mL to 800 ng/mL. Two hundred human subject oral fluid samples were analyzed with this method after solid phase extraction (SPE). Among the 200 human subject oral fluid samples, all 13 cannabinoid analytes were confirmed in at least one sample. Δ8-THC was confirmed in 11 samples, with or without the present of Δ9-THC. A high concentration of 11-OH-Δ9-THC or Δ9-THCCOOH (>400 ng/mL) was confirmed in three samples. CBD, Δ9-THCA-A, THCV, CBN, and CBG were confirmed in 74, 39, 44, 107, and 112 of the 179 confirmed Δ9-THC positive samples, respectively. The quantitation of multiple cannabinoids and metabolites in oral fluid simultaneously provides valuable information for revealing cannabinoid consumption and interpreting cannabinoid-induced driving impairment.
... Out of the cannabinoids present in Cannabis, tetrahydrocannabinol (THC) and cannabidiol (CBD) are the most studied and are the main biologically active cannabinoids [24][25][26]. Along with cannabinoids, the plant is also rich in terpenoids and flavonoids and other secondary metabolites with more than 540 phytochemicals identified including but not limited to CBD, THC, cannabigerol (CBG), cannabinol (CBN), and cannabichromene (CBC) [27]. ...
... Since cannabinoids can modulate the immune response through binding CB1 and CB2 receptors (a G-protein-coupled receptor densely located in the immune tissue, nervous tissue and brain), their role in infectious diseases has been discussed critically in many scientific publications [27][28][29][30][31][32]. However, the antimicrobial activity of cannabinoids, extracts and EOs from C. sativa is not unexpected, as many secondary metabolites of plants exhibit bioactivity against numerous pathogenic bacteria and fungi [33][34][35]. There is also fragmentary evidence in the literatures that cannabis compounds have efficacy against some viruses [25,32]. ...
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Abstract: Antimicrobial resistance has emerged as a global health crisis and, therefore, new drug discovery is a paramount need. Cannabis sativa contains hundreds of chemical constituents produced by secondary metabolism, exerting outstanding antimicrobial, antiviral, and therapeutic properties. This paper comprehensively reviews the antimicrobial and antiviral (particularly against SARS-CoV-2) properties of C. sativa with the potential for new antibiotic drug and/or natural antimicrobial agents for industrial or agricultural use, and their therapeutic potential against the newly emerged coron-avirus disease (COVID-19). Cannabis compounds have good potential as drug candidates for new antibiotics, even for some of the WHO's current priority list of resistant pathogens. Recent studies revealed that cannabinoids seem to have stable conformations with the binding pocket of the M pro enzyme of SARS-CoV-2, which has a pivotal role in viral replication and transcription. They are found to be suppressive of viral entry and viral activation by downregulating the ACE2 receptor and TMPRSS2 enzymes in the host cellular system. The therapeutic potential of cannabinoids as anti-inflammatory compounds is hypothesized for the treatment of COVID-19. However, more systemic investigations are warranted to establish the best efficacy and their toxic effects, followed by preclinical trials on a large number of participants.
... Cannabis (cannabis, hemp) plants have been used since millennial times as a rich source of food, fibers and oil as well as for medicinal, recreational or religious purposes [1,2]. Cannabis flowers are reported to contain a very complex phytochemical composition of at least 540 diverse metabolites, including more than 150 identified cannabinoids, such as Δ 9 -tetrahydrocannabinol (THC) and cannabidiol (CBD), two of the most popular cannabinoids with incontestable pharmacological properties [3][4][5][6][7][8][9]. However, other cannabinoids, such as cannabigerol (CBG), cannabidivarin (CBDV), cannabinol (CBN) and cannabichromene (CBC), have been scarcely investigated [3]. ...
Aside from Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), other less common cannabinoids have recently gained an increasing popularity, mostly due to their promising biological potential. However, time-saving and cost-effective methods for their preparative purification are missing. In this study, trapping multiple dual mode (MDM), a flow-reversal liquid-liquid chromatography (LLC) operating mode, was used for the separation of different minor cannabinoids from a hemp extract. Separation task specific biphasic solvent systems were selected for the purification of the target constituents, as follows: n-hexane/methanol/water 10/6.5/3.5 for cannabielsoin (CBE); n-hexane/methanol/water 10/7/3 for cannabidivarin (CBDV) and cannabigerol (CBG); n-hexane/methanol/water 10/8/2 for cannabinol (CBN) and n-hexane/methanol/water 10/9/1 for cannabichromene (CBC) and cannabicylol (CBL). For each separation task, the concentration of the hemp extract in the feed stream and mobile phase flow rate were selected by shake-flask and stationary phase retention experiments, respectively. For the determination of the trapping MDM operating parameters, the short-cut method was implemented and followed by equilibrium-cell model-based simulations. The trapping MDM allowed the separation of the targeted cannabinoids with purities of 93-99%, yields of 73-95%, solvent consumption 2-4-fold lower and productivities almost double than those obtained using batch separation.
... The endocannabinoid system and cannabinoids have started to get more and more considerable interests for therapeutic claims (Ryan et al. 2009) which could be observed by varieties of biological activities (Marcu 2016). Cannabis and cannabinoids can play the role of antinociceptive, anti-inflammatory, immunosuppressant antiemetogenic activity, and anticonvulsant activity (Mensah and Adu-Gyamfi 2019). ...
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Background There is a worldwide interest in the use of Cannabis sativa for biomedicine purposes. Cannabis has ethnomedicinal usage as a natural medicine in Bangladesh and cultivated during the British Empire period for revenues. Objective Folk medicine practitioners (FMPs) from different districts of Bangladesh have been using Cannabis sativa , but until now there have not been any compiled studies particularly regarding this practice. Hence, this review is an effort to retrieve the traditional usage of Cannabis sativa as a phytomedicine from published ethnomedicinal studies. Methods and materials Information was searched by using the search terms “ethnomedicinal Cannabis sativa and Bangladesh”; “Bangladesh cannabaceae and ethnomedicinal survey”; “ganja, bhang and folk medicine Bangladesh”; “tetrahydrocannabinol (THC), cannabinoid and therapeutic, clinical trial”; and “cannabis and pharmacological/biological” and retrieved from ethnobotanical articles available on PubMed, Scopus, Science Direct, and Google Scholar databases. A search of the relevant scientific literature also was conducted to assess the efficacy of the ethnomedicinal usage of Cannabis sativa. Results While reviewing over 200 ethnomedicinal plants’ survey articles, we found that FMPs of Bangladesh from 12 different districts used Cannabis sativa to treat cited ailments like sleep-associated problems ( n =5), neuropsychiatric and CNS problems ( n =5), and infections and respiratory problems ( n =5) followed by rheumatism, gastrointestinal, gynecological ( n =4 each), cancer, sexual, and other ailments including hypertension, headache, itch, increases bile secretion, abortifacient, dandruff, fever, and urinary problems ( n =1 each). There are a total of 15 formulations identified from the 11 out of 18 ethnomedicinal plant survey reports. The leaf was the main plant part used (53.8%), followed by root (23%), seed (7.7%) and flower, inflorescence, resin, and all parts 3.8% respectively. Conclusions Sales and cultivation of Cannabis are illegal at present in Bangladesh, but the use of Cannabis sativa as a natural phytomedicine has been practiced traditionally by folk medicine practitioners of Bangladesh for many years and validated through relevant pharmacological justification. Although Cannabis sativa possesses ethnomedicinal properties in the folk medicine of Bangladesh, it is, furthermore, needed to conduct biological research to consolidate pharmacological justification about the prospects and challenges of Cannabis and cannabinoids’ use in Bangladesh as safer biomedicine in the future.
... In addition to the common cannabinoids, CBD, THC, and their acid forms, three other cannabinoids (i.e., cannabichromene (CBC), cannabinol (CBN), and cannabigerolic acid (CBGA)) were selected for analysis. The latter were selected due to their importance in phytocannabinoid biosynthesis [33] and their bioactive properties [34]. Since all the chosen extraction methods also lead to the extraction of a certain fraction of phenols known to possess antioxidative properties, these were also evaluated. ...
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Cannabis sativa is one of the oldest medicinal plants used by humans, containing hundreds of bioactive compounds. The biological effects and interplay of these compounds are far from fully understood, although the plant’s therapeutic effects are beyond doubt. Extraction methods for these compounds are becoming an integral part of modern Cannabis-based medicine. Still, little is known about how different methods affect the final composition of Cannabis extracts and thus, their therapeutic effects. In this study, different extraction methods were tested, namely maceration, Soxhlet, ultrasound-assisted extraction (UAE), and supercritical CO2 extraction methods. The obtained extracts were evaluated for their cannabinoid content, antioxidant properties, and in vitro bioactivity on human colon cancer and healthy colon cells. Our data suggest that Cannabis extracts, when properly prepared, can significantly decrease cancer cell viability while protecting healthy cells from cytotoxic effects. However, post-processing of extracts poses a significant limitation in predicting therapeutic response based on the composition of the crude extract, as it affects not only the actual amounts of the respective cannabinoids but also their relative ratio to the primary extracts. These effects must be carefully considered in the future preparations of new therapeutic extracts.
Cannabis has been used for over 3000 years with the management of pain being one of the most common reasons for its use. However, research has lagged purported benefit. In the United States, federal law classifies cannabis as a substance with no currently accepted medical use, a lack of accepted safety for use under medical supervision, and a high potential for abuse. Along with a complicated political and social backdrop, this classification has driven difficulties in conducting clinical trials into the benefits of cannabis-based medicine (CBM) in the treatment of various pain conditions. However, most states have legalized cannabis for medicinal use, recreational use, or both. Pain remains the most common reason patients obtain medical cannabis certification. Studies are needed to not only evaluate whether CBM are beneficial in various pain states, but if so at what doses, formulations, and cannabinoid ratios.
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Key message Three novel transcription factors were successfully identified and shown to interact with the trichome-specific THCAS promoter regulatory region. Abstract Cannabinoids are important secondary metabolites present in Cannabis sativa L. (cannabis). One cannabinoid that has received considerable attention, 9-tetrahydrocannabinol (THC), is derived from Delta-9-Tetrahydrocannabinolic acid (THCA) and responsible for the mood-altering and pain-relieving effects of cannabis. A detailed understanding of transcriptional control of THCA synthase (THCAS) is currently lacking. The primary site of cannabinoid biosynthesis is the glandular trichomes that form on female flowers. Transcription factors (TFs) have been shown to play an important role in secondary-metabolite biosynthesis and glandular trichome formation in Artemisia annua, Solanum lycopersicum and Humulus lupulus. However, analogous information is not available for cannabis. Here, we characterize a 548 bp fragment of the THCAS promoter and regulatory region that drives trichome-specific expression. Using this promoter fragment in a yeast-one-hybrid screen, we identified 3 novel TFs (CsAP2L1, CsWRKY1 and CsMYB1) and provided evidence that these 3 TFs regulate the THCAS promoter in planta. The O-Box element within the proximal region of the THCAS promoter is necessary for CsAP2L1-induced transcriptional activation of THCAS promoter. Similar to THCAS, the genes for all three TFs have trichome-specific expression, and subcellular localization of the TFs indicates that all three proteins are in the nucleus. CsAP2L1 and THCAS exhibit a similar temporal, spatial and strain-specific gene expression profiles, while those expression patterns of CsWRKY1 and CsMYB1 are opposite from THCAS. Our results identify CsAP2L1 playing a positive role in the regulation of THCAS expression, while CsWRKY1 and CsMYB1 may serve as negative regulators of THCAS expression.
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This article reviews recent research on cannabinoid analgesia via the endocannabinoid system and non-receptor mechanisms, as well as randomized clinical trials employing canna- binoids in pain treatment. Tetrahydrocannabinol (THC, Marinol ® ) and nabilone (Cesamet ® ) are currently approved in the United States and other countries, but not for pain indications. Other synthetic cannabinoids, such as ajulemic acid, are in development. Crude herbal cannabis remains illegal in most jurisdictions but is also under investigation. Sativex ® , a cannabis derived oromucosal spray containing equal proportions of THC (partial CB 1 receptor agonist ) and can- nabidiol (CBD, a non-euphoriant, anti-infl ammatory analgesic with CB 1 receptor antagonist and endocannabinoid modulating effects) was approved in Canada in 2005 for treatment of central neuropathic pain in multiple sclerosis, and in 2007 for intractable cancer pain. Numer- ous randomized clinical trials have demonstrated safety and effi cacy for Sativex in central and peripheral neuropathic pain, rheumatoid arthritis and cancer pain. An Investigational New Drug application to conduct advanced clinical trials for cancer pain was approved by the US FDA in January 2006. Cannabinoid analgesics have generally been well tolerated in clinical trials with acceptable adverse event profi les. Their adjunctive addition to the pharmacological armamentarium for treatment of pain shows great promise.
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To date, a large number of controlled clinical trials have been done evaluating the therapeutic ap- plications of cannabis and cannabis-based preparations. In 2006, an excellent review was pub- lished, discussing the clinical trials performed in the period 1975 to June 2005 (Ben Amar 2006). The current review reports on the more recent clinical data available. A systematic search was per- formed in the scientific database of PubMed, focused on clinical studies that were randomized, (double) blinded, and placebo-controlled. The period screened was from July 1, 2005 up to August 1, 2009. The key words used were: cannabis, marijuana, marihuana, hashish, cannabinoid(s), tetrahydro- cannabinol, THC, CBD, dronabinol, Marinol, nabilone, Cannador and Sativex. For the final selec- tion, only properly controlled clinical trials were retained. Open-label studies were excluded, ex- cept if they were a direct continuation of a study discussed here. Thirty-seven controlled studies evaluating the therapeutic effects of cannabinoids were identified. For each clinical trial, the country where the project was held, the number of patients assessed, the type of study and comparisons done, the products and the dosages used, their efficacy and their adverse effects are described. Based on the clinical results, cannabinoids present an interesting therapeutic potential mainly as analgesics in chronic neuropathic pain, appetite stimulants in de- bilitating diseases (cancer and AIDS), as well as in the treatment of multiple sclerosis.
Importance Opioid analgesic overdose mortality continues to rise in the United States, driven by increases in prescribing for chronic pain. Because chronic pain is a major indication for medical cannabis, laws that establish access to medical cannabis may change overdose mortality related to opioid analgesics in states that have enacted them.Objective To determine the association between the presence of state medical cannabis laws and opioid analgesic overdose mortality.Design, Setting, and Participants A time-series analysis was conducted of medical cannabis laws and state-level death certificate data in the United States from 1999 to 2010; all 50 states were included.Exposures Presence of a law establishing a medical cannabis program in the state.Main Outcomes and Measures Age-adjusted opioid analgesic overdose death rate per 100 000 population in each state. Regression models were developed including state and year fixed effects, the presence of 3 different policies regarding opioid analgesics, and the state-specific unemployment rate.Results Three states (California, Oregon, and Washington) had medical cannabis laws effective prior to 1999. Ten states (Alaska, Colorado, Hawaii, Maine, Michigan, Montana, Nevada, New Mexico, Rhode Island, and Vermont) enacted medical cannabis laws between 1999 and 2010. States with medical cannabis laws had a 24.8% lower mean annual opioid overdose mortality rate (95% CI, −37.5% to −9.5%; P = .003) compared with states without medical cannabis laws. Examination of the association between medical cannabis laws and opioid analgesic overdose mortality in each year after implementation of the law showed that such laws were associated with a lower rate of overdose mortality that generally strengthened over time: year 1 (−19.9%; 95% CI, −30.6% to −7.7%; P = .002), year 2 (−25.2%; 95% CI, −40.6% to −5.9%; P = .01), year 3 (−23.6%; 95% CI, −41.1% to −1.0%; P = .04), year 4 (−20.2%; 95% CI, −33.6% to −4.0%; P = .02), year 5 (−33.7%; 95% CI, −50.9% to −10.4%; P = .008), and year 6 (−33.3%; 95% CI, −44.7% to −19.6%; P < .001). In secondary analyses, the findings remained similar.Conclusions and Relevance Medical cannabis laws are associated with significantly lower state-level opioid overdose mortality rates. Further investigation is required to determine how medical cannabis laws may interact with policies aimed at preventing opioid analgesic overdose.
Background: Nabiximols (Sativex®), a cannabinoid-based oromucosal spray, is an add-on therapy for patients with moderate to severe multiple sclerosis spasticity (MSS) resistant to other medications. The primary objective was to provide real-life observational data of clinical experience of nabiximols in contrast to formal clinical trials of effectiveness. Methods: This was an observational, prospective, multicenter, non-interventional study with a follow-up period of 3-4 months, conducted in routine care setting in Germany. Patients with moderate to severe MSS were included at nabiximols' initiation. Structured documentation forms, questionnaires and validated instruments were used for data collection at inclusion, 1 and 3 months after inclusion. Results: Overall, 335 patients were assessed of whom 276 fitted the criteria and were included in the effectiveness analysis. After 1 month, nabiximols provided relief of resistant MSS in 74.6% of patients according to specialist assessment; mean spasticity 0-10 numerical rating scale (NRS) score decreased from 6.1 ± 1.8 to 5.2 ± 2.0 points; in patients with NRS improvement ≥20% mean NRS score decreased by 40%. After 3 months, 55.3% of patients had continued to use nabiximols and the mean NRS score had decreased by 25% from baseline. 17% of patients reported adverse events. Conclusion: Real-life data confirm nabiximols as an effective and well-tolerated treatment option for resistant MSS in clinical practice.
Substituting cannabis for alcohol may reduce drinking and related problems among alcohol-dependent individuals. Some even recommend prescribing medical cannabis to individuals attempting to reduce drinking. The primary aim of this review is to assess whether cannabis satisfies the seven previously published criteria for substitute medications for alcohol [e.g. 'reduces alcohol-related harms'; 'is safer in overdose than alcohol'; 'should offer significant health economic benefits'; see Chick and Nutt ((2012) Substitution therapy for alcoholism: time for a reappraisal? J Psychopharmacol 26:205-12)]. Literature review. All criteria appear either satisfied or partially satisfied, though studies relying on medical cannabis patients may be limited by selection bias and/or retrospective designs. Individual-level factors, such as severity of alcohol problems, may also moderate substitution. There is no clear pattern of outcomes related to cannabis substitution. Most importantly, the recommendation to prescribe alcohol-dependent individuals cannabis to help reduce drinking is premature. Future studies should use longitudinal data to better understand the consequences of cannabis substitution.
Numerous cannabinoids have been synthesized that are extremely potent in all of the behavioral assays conducted in our laboratory. An important feature in increasing potency has been the substitution of a dimethylheptyl (DMH) side chain for the pentyl side chain. Our previous studies have shown that (−)-11-OH-Δ8-THC-dimethylheptyl was 80–1150 times more potent than Δ9-THC. Stereospecificity was demonstrated by its (+)- enantiomer which was more than 1400–7500 times less potent. A related series of DMH cannabinoid analogs has recently been synthesized and preliminary evaluations reported here. (−)-11-OH-Δ9-THC-DMH was found to be equipotent with (−)-11-OH-Δ8-THC-DMH. The aldehyde (−)-11-oxo-Δ9-THC-DMH was 15–50 times more potent than Δ9-THC. Surprisingly, (−)-11-carboxy-Δ9-THC-DMH was also active, being slightly more potent than Δ9-THC. In the bicyclic cannabinoid series, the length and bulk of the side chain were found to be equally important. Aminoalkylindoles, which are structurally dissimilar from classical cannabinoids, have been found to exhibit a pharmacological profile similar to Δ9-THC. Though not extremely potent in vivo, they appear to represent an entirely new approach to studying the actions of the cannabinoids. The structural diversity and wide-ranging potencies of the analogs described herein provide the opportunity to develop a pharmacophore for the cannabinoids using molecular modeling techniques.