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The Anti-Inflammatory Properties of Terpenoids from Cannabis

  • School of Pharmacy, Ein Kerem Campus, Hebrew University of Jerusalem

Abstract and Figures

Introduction: Cannabinoids are well known to have anti-inflammatory effects in mammalians; however, the Cannabis plant also contains other compounds such as terpenoids, whose biological effects have not yet been characterized. The aim of this study was to compare the anti-inflammatory properties of terpenoids with those of cannabidiol (CBD). Materials and Methods: Essential oils prepared from three monoecious nonpsychoactive chemotypes of Cannabis were analyzed for their terpenoid content and subsequently studied pharmacologically for their anti-inflammatory properties in vitro and in vivo. Results:In vitro, the three essential oils rich in terpenoids partly inhibited reactive oxygen intermediate and nitric oxide radical (NO•) production in RAW 264.7 stimulated macrophages. The three terpenoid-rich oils exerted moderate anti-inflammatory activities in an in vivo anti-inflammatory model without affecting tumor necrosis factor alpha (TNFα) serum levels. Conclusions: The different Cannabis chemotypes showed distinct compositions of terpenoids. The terpenoid-rich essential oils exert anti-inflammatory and antinociceptive activities in vitro and in vivo, which vary according to their composition. Their effects seem to act independent of TNFα. None of the essential oils was as effective as purified CBD. In contrast to CBD that exerts prolonged immunosuppression and might be used in chronic inflammation, the terpenoids showed only a transient immunosuppression and might thus be used to relieve acute inflammation.
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The Anti-Inflammatory Properties of Terpenoids
from Cannabis
Ruth Gallily,
*Zhannah Yekhtin,
and Lumı
´r Ondr
ˇej Hanus
Introduction: Cannabinoids are well known to have anti-inflammatory effects in mammalians; however, the Cannabis
plant also contains other compounds such as terpenoids, whose biological effects have not yet been characterized.
The aim of this study was to compare the anti-inflammatory properties of terpenoids with those of cannabidiol (CBD).
Materials and Methods: Essential oils prepared from three monoecious nonpsychoactive chemotypes of Can-
nabis were analyzed for their terpenoid content and subsequently studied pharmacologically for their anti-
inflammatory properties in vitro and in vivo.
Results: In vitro, the three essential oils rich in terpenoids partly inhibited reactive oxygen intermediate and nitric
oxide radical (NO
) production in RAW 264.7 stimulated macrophages. The three terpenoid-rich oils exerted
moderate anti-inflammatory activities in an in vivo anti-inflammatory model without affecting tumor necrosis
factor alpha (TNFa) serum levels.
Conclusions: The different Cannabis chemotypes showed distinct compositions of terpenoids. The terpenoid-rich
essential oils exert anti-inflammatory and antinociceptive activities in vitro and in vivo, which vary according to their
composition. Their effects seem to act independent of TNFa. None of the essential oils was as effective as purified
CBD. In contrast to CBD that exerts prolonged immunosuppression and might be used in chronic inflammation, the
terpenoids showed only a transient immunosuppression and might thus be used to relieve acute inflammation.
Keywords: cannabis; terpenoids; anti-inflammation; antinociceptive; CBD
Human beings have used Cannabis or Cannabis prod-
ucts in various forms for thousands of years
and refer-
ences to therapeutic use of the plant are found in Hieratic
script on papyri dated around 1700 BC.
More recent re-
ports have reviewed the history and characteristics of the
and determined their clinical and biological
The Cannabis plant contains hundreds
of different compounds apart from the major psycho-
active compound D
-tetrahydrocannabinol (THC).
Some of these are unique to the Cannabis plant,
while others are shared with other members of the
plant kingdom.
This century has seen a wealth of literature reports
on the therapeutic potential of Cannabis and/or its
constituents and a comprehensive review conducted
by the Committee on the Health Effects of Marijuana:
An Evidence Review and Research
considered more
than 10,700 relevant abstracts on this subject. They
concluded that there was moderate to conclusive evi-
dence for beneficial effects on chronic pain, and for a
variety of other uses in different autoimmune and in-
flammatory diseases. While studies have focused on
THC and the anti-inflammatory effects of the other
major constituent, the nonpsychoactive cannabinoid
cannabidiol (CBD),
the effects of the aromatic
The Lautenberg Center for General and Tumor Immunology, The Hadassah Medical School, The Hebrew University of Jerusalem, Jerusalem, Israel.
Department of Medicinal and Natural Products, Institute for Drug Research, The Hadassah Medical School, The Hebrew University of Jerusalem, Jerusalem, Israel.
*Address correspondence to: Ruth Gallily, PhD, The Lautenberg Center for General and Tumor Immunology, The Hadassah Medical School, The Hebrew University of
Jerusalem, P.O.B. 11272, Jerusalem 9112102, Israel, E-mail:
ªRuth Gallily et al. 2018; Published by Mary Ann Liebert, Inc. This Open Access article is distributed under the terms of the Creative Commons
License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the
original work is properly cited.
Cannabis and Cannabinoid Research
Volume 3.1, 2018
DOI: 10.1089/can.2018.0014
Cannabis and
Cannabinoid Research
terpene constituents have been largely neglected.
Many of the terpenoids are of pharmacological val-
About 200 terpenoids have been described in
Cannabis and constitute the essential oil of the plant,
being responsible for the characteristic odor of the
The biochemical profiles of the terpenoids
in a given plant are more closely associated to the ge-
netics than the environment.
Physiologically, they
are responsible for protecting the plant from predators
and attracting pollinating insects among other func-
tions. Pharmacologically, they have been implicated
in influencing the properties of the cannabinoids, pos-
sibly by a so-called entourage effect.
Effects on anxiety
have been noted as well as positive or negative influences
on the antibacterial, anti-inflammatory, and sedative
properties of Cannabis components.
However, there
is no consensus on the mechanism by which this is
achieved and as to whether the terpenoids themselves
possess pharmacologically significant properties.
We have previously demonstrated the ability of a tri-
ple assay, measuring swelling, pain, and tumor necrosis
factor alpha (TNFa) serum titers, to measure the anti-
inflammatory properties of CBD.
In this study, we
used a similar approach to investigate the antioxidant
and anti-inflammatory properties of three different
preparations of terpenoid-rich essential oils.
Materials and Methods
Essential oil samples
Samples rich in terpenoids were prepared from three
monoecious nonpsychoactive chemotypes of hemp
(legal in Europe). Tisza is a Hungarian variety, and
Felina and Ferimon are chemotypes adapted to the cli-
mate in France.
All three chemotypes of Cannabis were harvested in
August/September 2016 in the pre-Alpine region of
Slovenia (Upper Savinja Valley), latitude NS 4620¢
29.525 and longitude E 1450¢0.777. Samples of essen-
tial oil were prepared by steam distillation of female
flowers (upper third of the plant).
Terpenoid analysis
Samples (1 lL) of essential oil were analyzed by gas
chromatography/mass spectrometry (GC/MS) in a Hew-
lett Packard G 1800B GCD system with an HP-5971
gas chromatograph, with an electron ionization detec-
tor. The software used was GCD Plus ChemStation
and the column was an Rtx
5MS Low bleed GC/MS
column (30 m ·0.25 mm ·0.25 lmfilmthickness).For
then the temperature was programmed from 50Cto
280Cat8C/min; inlet 250C; detector 280C; splitless
injection/purge time 1.0 min; initial temperature 100C;
and with initial time 4.0 min. The helium flow rate was
1 mL/min. Compound constituents were identified by
comparison with standards and by the retention times,
Kovats indices and by comparison with mass spectra
from computerized libraries (HPCH2205, Wiley7N, and
The terpenoids isolated by steam distillation
as essential oil from each of the cannabis chemotypes
gave the test samples T1 (Tisza chemotype), T2 (Felina
chemotype), and T3 (Ferimon chemotype), whose an-
algesic and anti-inflammatory properties were charac-
terized in vitro and in vivo.
Cell culture
(BALB/c) was obtained from the American Type Culture
Collection (ATCC, Rockville, MD) and cultured in Dul-
becco’s modified Eagle’s medium (DMEM) supple-
mented with 5% fetal calf serum (FCS), 1 mM sodium
pyruvate and 100 lg/L streptomycin, and 100 IU/mL
penicillin. The cell line is adherent and the cells were pas-
saged by scraping from the culture dish.
Reactive oxygen intermediate production
For reactive oxygen intermediate (ROI) assay, RAW
264.7 cells were removed from the culture dish by
scraping, and were washed and resuspended at 10
cells/mL in Hank’s balanced salt solution without phe-
nol red. Cells (5 ·10
) were added to a luminometer
tube together with various concentrations of the essen-
tial oils (5, 10, 20, or 40 lg/mL). After 5 min, 10 lL
luminol (Sigma) and 30 lL zymosan (Sigma) were
added to each tube and the chemiluminescence was
measured immediately in a luminometer (Biolumate
LB 95; Berhold, Wilbad, Germany). A second set of
samples was incubated for 24 h with the essential oils
before adding luminol and zymosan. All experiments
were done in duplicates.
Nitric oxide (NO
) determination
and MTT evaluation of viability
RAW 264.7 cells were seeded at a density of 1 ·10
well in 24-well plates and incubated overnight at 37C
and 5% CO
. On the following day, the medium was
changed to fresh DMEM without FCS, containing vari-
ous concentrations of the essential oils. The cells were
then stimulated by the addition of lipopolysaccharide
(LPS) to a concentration of 1 lg/mL. Cell supernatants
Gallily et al.; Cannabis and Cannabinoid Research 2018, 3.1
(SNs) were harvested after 24 h for nitric oxide radical
) assay by addition of 100 lLSNtoanequalvolume
of Griess reagent (1% sulfanilamide, 0.1% naphthalene
diamine, and 2% H
). After 10 min of incubation,
the resultant color was measured at 550 nm. The amount
of NO
produced, and any inhibition by the test materi-
als, was calculated from a standard curve prepared with
The viability of the cells after incubation with the test
materials was determined by MTT viability staining.
The absorbance was measured at 550 nm on a micro-
plate reader.
Female Sabra mice (Israel), 7–8 weeks old, were main-
tained in the specific-pathogen-free unit of the Hadas-
sah Medical School, Hebrew University, Jerusalem,
Israel. The experimental protocols were approved by
the Institutional Animal Care Ethics Committee. The
animals were maintained at a constant temperature
(20–21C) and a 12-h light/12-h dark cycle, and were
provided a standard pellet diet with water ad libitum.
Induction and treatment of paw inflammation
Inflammation was induced by injection of 40 lLofa
suspension of 1.5% w/v zymosan A (Sigma) in saline
into the subplanter surface of the right hind paw of
the mice. This was followed immediately by an injec-
tion of the sample intraperitoneally (10, 25, or 50 mg/
kg). For injection, the terpenoids were dissolved in ve-
hicle containing ethanol:Cremophore:saline at a ratio
of 1:1:18. CBD was used as a positive control. Paw
swelling and pain perception were assessed after 2, 6,
and 24 h. Blood was collected after 24 h for analysis
of TNFaserum levels.
Evaluation of edema
Calibrated calipers were used to measure paw swelling
(thickness) 2, 6, and 24 h after injection of zymosan.
Pain assay
Pain at 2, 6, and 24 h after zymosan injection was
assessed by the von Frey nociceptive filament assay,
where 1.4–60 g filaments, corresponding to 4.17–5.88 log
of force, was used to test the sensitivity of the swollen
paw. The untreated hind paw served as a control.
The measurements were performed in a quiet room
and the animals were handled for 10 s before the test.
A trained investigator then applied the filament, pok-
ing the middle of the hind paw to provoke a flexion re-
flex, followed by a clear finch response after paw
withdrawal. Filaments of increasing size were each ap-
plied for about 3–4 s. The mechanical threshold force
in grams was defined as the lowest force required to ob-
tain a paw retraction response.
FIG. 1. GC/MS spectra of essential oils from three
different chemotypes of Cannabis—Tisza (T1), Felina
(T2), and Ferimon (T3). Each chemotype displays an
individual, characteristic profile. The identity of each
peak is summarized in Table 1. GC/MS, gas
chromatography/mass spectrometry.
Gallily et al.; Cannabis and Cannabinoid Research 2018, 3.1
Measurement of TNFa
Blood was collected 24 h after zymosan injection, and
the sera were assayed for TNFausing a mouse TNFa
ELISA kit (R&D System), according to the manufactur-
er’s instructions.
Statistical analysis
Statistical calculations used the nonparametric Mann-
Whitney Utest and Wilcoxon signed-rank test. The re-
sults are presented as average standard error.
The terpenoid content of essential oils from three
different Cannabis chemotypes
The essential oils from each of the three different che-
motypes of Cannabis—Tisza (T1), Felina (T2), and
Ferimon (T3)—were analyzed by GC/MS analyses,
and up to 50 different compounds were identified
(Fig. 1 and Table 1). The spectra show similarities
and differences between the different Cannabis chemo-
types. As the amounts of the identified terpenoids were
Table 1. Terpenoid Content in the Three Chemotypes of Cannabis: The Results Are Presented as the Relative
Ratio to the Main Terpene in the Sample, Which Was Set to 100.00%
Terpene Kovats Index Tisza chemotype (T1) % Felina chemotype (T2) % Ferimon chemotype (T3) %
a-Pinene 5.85 31.420 14.007 19.413
Camphene 6.26 0.640 0.108
b-Pinene 7.04 20.461 13.434 10.153
Myrcene 7.43 100.000 100.000 52.755
a-Phellandrene 7.85 1.316 2.693 1.163
-Carene 8.10 13.020 2.240 2.103
a-Terpinene 8.30 1.094 2.376 1.018
o-Cymene 8.59 0.221 0.564
p-Cymene 8.53 0.105 0.396
Limonene 8.69 10.482 3.379 7.142
b-Phellandrene 8.70 3.537 6.794 2.668
cis-b-Ocimene 8.96 4.043 4.005 2.520
trans-b-Ocimene 9.42 51.700 39.864 32.634
c-Terpinene 9.78 1.151 2.041 0.880
Terpinolene 10.98 32.842 81.256 38.728
Linalool 11.32 0.905
1,3,8-para-Menthatriene 11.86 0.449 0.377
endo-Fenchol 12.10 0.263
allo-Ocimene 12.70 1.517 1.918 1.179
Terpinen-4-ol 14.66 0.294 0.665
p-Cymen-8-ol 14.91 0.421
Hexyl butanoate 15.40 0.362
a-Terpineol 15.21 0.303 0.466
Eugenol 22.70 1.199
a-Ylangene 23.43 0.191 0.148 0.205
a-Copaene 23.49 0.144 0.204
Hexyl hexanoate 23.83 0.411
7-epi-Sesquithujene 24.19 0.288 0.222
Sesquithujene 24.84 0.231
cis-Caryophyllene 24.95 1.778 1.669 2.072
cis-a-Bergamotene 25.10 0.148 1.517 0.846
trans-Caryophyllene 25.36 75.569 68.099 100.000
trans-a-Bergamotene 25.99 3.578 11.867 11.100
a-Guaiene 26.20 0.387
trans-b-Farnesene 26.92 3.157 14.176 11.811
a-Humulene 26.82 28.338 25.453 33.158
allo-Aromadendrene 27.07 1.744 3.130
ar-Curcumene 27.96 0.310 0.323
b-Selinene 28.37 4.745 6.653 6.007
a-Selinene 28.74 3.785 4.654 4.747
cis-a-Bisabolene 29.09 1.719
trans-a-Bisabolene 1.524
d-Cadinene 29.72 0.621
b-Sesquiphellandrene 29.70 2.011
Selina-3,7(11)-diene 30.66 2.343 2.577 2.813
Caryophyllene oxide 32.16 4.437 5.523
Humulene epoxide II 33.20 1.151 1.176
allo-Aromadendrene epoxide 34.42 0.426
a-Bisabolol 36.17 0.226
Gallily et al.; Cannabis and Cannabinoid Research 2018, 3.1
not quantified, the results in Table 1 are presented as
the relative ratio to the main terpene in the sample,
which was set to 100.00%.
In vitro studies
Suppression of ROI and NO
production by RAW mac-
rophages incubated with the terpenoid-rich essential
oils. To study the effects of terpenoids on essential mac-
rophage functions, the RAW 264.7 macrophage cell line
was either untreated or incubated with the essential oils
at indicated concentrations, before stimulation with zy-
mosan to induce ROIs or LPS to induce NO
The ROI production was measured by luminol chemilu-
minescence, while NO
production was measured by
resulting nitrite concentration in the supernatant. The
generation of ROI by RAW 264.7 macrophages was sig-
nificantly suppressed following a short 5 min-incubation
with 40 lg/mL terpenoids from chemotypes T1 and T2
(Fig. 2), while lower concentrations had barely any effect.
T3 terpenoids, however, showed only a moderate inhibi-
tion at 40 lg/mL (Fig. 2). When the macrophages were
incubated with terpenoids for 24 h before zymosan in-
duction of ROI, the terpenoids had barely any inhibitory
effect (Fig. 2). This observation suggests for a transient
inhibitory effect of terpenoids.
Similar to ROI inhibition, the T1 and T2 essential
oils significantly suppressed LPS-induced NO
tion by RAW macrophages when applied at a concen-
tration of 40 lg/mL (Fig. 3). Lower concentrations of
T1 and T2 had almost no effect. The T3 essential oil
had barely any effect at the concentrations used.
The MTT assay showed that the inhibition of NO
and ROI by terpenoids was not due to cytotoxicity,
since all the cells remained over 80% viable with all
concentrations tested (data not shown).
In vivo studies
Anti-inflammatory and antinociceptive effects of
terpenoid-rich essential oils. In this study, we used
the well-accepted mouse model of zymosan-induced
inflammation to investigate the anti-inflammatory
and antinociceptive activities of the three terpenoid
preparations. The extent of hind paw swelling was de-
termined 2, 6, and 24 h following paw injection of
60 lg zymosan alone (control) or together with intra-
peritoneal injection of various concentrations of
FIG. 2. Zymosan-induced generation of ROIs by
RAW 264.7 macrophages was inhibited by essential
Cannabis oils from each of the three chemotypes
Tisza (T1), Felina (T2), and Ferimon (T3). RAW 264.7
macrophages (5 ·10
/500 lLHBSS)wereeither
untreated (Control) or incubated with 20 or 40lL
by zymosan. The ROI was measured by luminol
chemiluminescence. The percentage inhibition of
ROI production is presented. *p<0.05. ROI, reactive
oxygen intermediate; HBSS, Hank’s Balanced Salt
FIG. 3. LPS-induced generation of NO
by RAW
264.7 macrophages was inhibited by essential
Cannabis oils from each of the three chemotypes
Tisza (T1), Felina (T2), and Ferimon (T3). RAW 264.7
macrophages were incubated in serum-free
medium alone or in the presence of various
amounts of the essential oils, as indicated in the
figure. After 5 min, the macrophages were exposed
to LPS (1 lg/mL) for 24 h and the nitrite
concentration in the supernatant reflecting NO
production was measured using the Griess reagent.
*p<0.05, **p<0.01. LPS, lipopolysaccharide.
Gallily et al.; Cannabis and Cannabinoid Research 2018, 3.1
essential oils from each of the three chemotypes Tisza
(T1), Felina (T2), and Ferimon (T3). For comparison,
a mouse group was treated with CBD (5 mg/kg), which
is well known to exert anti-inflammatory and antino-
ciceptive effects.
Intraperitoneal injection of each
of the three terpenoid preparations significantly re-
duced zymosan-induced paw swelling at all three con-
centrations tested (10, 25, and 50 mg/kg) (Fig. 4A).
There were no significant differences between the
three concentrations, meaning that a plateau effect
FIG. 4. Anti-inflammatory (A) and antinociceptive (B) effects of intraperitoneally injected CBD or essential oils
from each of the three Cannabis chemotypes Tisza (T1), Felina (T2), and Ferimon (T3). (A) Prevention of
zymosan-induced swelling of hind paw; 1.5% zymosan in 40 lL was injected into the subplanter surface of the
right hind paw. Immediately thereafter, CBD (5 mg/kg) or essential oils (10, 25, or 50 mg/kg) dissolved in vehicle
containing ethanol:Cremophore:saline at a ratio of 1:1:18 was injected intraperitoneally. The paw thickness
indicative for paw swelling was measured 2, 6, and 24 h thereafter. The paw thickness of untreated mice was
2.3 mm, which made the baseline of the graph. N=9 in each treatment group. *p<0.05, **p<0.01. (B) The
hyperalgesia occurring after zymosan injection in control and treated mice as described in (A) was measured
by using the von Frey nociceptive filament assay. The higher the paw withdrawal threshold, the higher is the
antinociceptive effect of the drug. N=9 in each treatment group. *p<0.05, **p<0.01. CBD, cannabidiol.
Gallily et al.; Cannabis and Cannabinoid Research 2018, 3.1
has been reached and no further inhibition can be
achieved by increasing the dose. Also, it should be
noted that the three terpenoids were less potent than
Next, we studied the antinociceptive effects of the
three terpenoid preparations in comparison to CBD.
To this end, the same mice described above for zymosan-
induced paw swelling were used to determine the paw
withdrawal threshold by applying von Frey filaments
on the paws. Higher paw withdrawal threshold is indic-
ative for better pain-relieving effects. As expected, CBD
significantly increased the paw withdrawal threshold
could significantly increase the pain threshold (Fig. 4B),
although less potent than CBD. T1 showed a correlative
doseresponseat6h,whileno significant difference
and 24 h (Fig. 4B).
In contrast, only a moderate pain inhibition could
be achieved with the T2 and T3 terpenoid prepara-
tions (Fig. 4B). No correlative dose–response could
be seen for T2 and T3, suggesting for having reached
a maximum effect. The more potent pain-relieving ef-
fects of T1 in comparison to T2 and T3 is correlative
to the better prevention of paw swelling by T1 (com-
pare Fig. 4B with 4A). Of note, the antinociceptive ef-
fects of all compounds, including CBD, were most
TNFaserum titer. TNFais one of the proinflamma-
tory cytokines that is produced during inflammation
and activates the nociceptive terminals that innervate
the inflamed tissue.
It was therefore important to
study the effect of terpenoids on TNFaserum levels.
However, none of the terpenoid preparations had any
significant effect on the TNFaserum level 24 h after zy-
mosan injection (Fig. 5). Under the same conditions,
CBD reduced the level of TNFasignificantly by about
48% (Fig. 5).
The terpenoids provide the cannabis plant with its
characteristic fragrance and it is generally accepted
that they provide protection from marauding in-
sects. Although more than 230 different named ter-
penoids have been identified, in Cannabis, only
about 50 known terpenoids have been identified in
a single plant sample, and the profile may be character-
istic of a given chemotype (Hanus
ˇLO, unpublished
data). This variety is reflected in the differences noted
between the three cannabis chemotypes used in this
study. Despite suggestions that differences in the
FIG. 5. TNFain the sera of mice treated with zymosan and essential oils. Twenty-four hours after injecting
zymosan and/or an intraperitoneal dose of CBD (5 mg/kg) or essential oils (10, 25, or 50 mg/kg) dissolved in
vehicle containing ethanol:Cremophore:saline at a ratio of 1:1:18, the TNFaconcentration in the serum was
determined by ELISA. N=3 for each treatment group. **p<0.01. TNFa, tumor necrosis factor alpha.
Gallily et al.; Cannabis and Cannabinoid Research 2018, 3.1
pharmaceutical properties of different chemotypes may
be a consequence of the variety of terpenoids present,
there is almost no information about the biological
and medical properties of cannabis-derived terpenoids.
We have previously developed a triple assay to
demonstrate the anti-inflammatory and antinocicep-
tive properties of CBD.
This assay measures the
ability of any compound to inhibit zymosan-induced
paw swelling and to relieve zymosan-induced pain. In
addition, by collecting blood 24 h after zymosan in-
jection, the assay enables us to determine the effects
of the compounds on zymosan-induced TNFapro-
duction. We adapted this method to study the anti-
inflammatory properties of terpenoid-rich essential
oils from three different chemotypes of Cannabis.
Our data show that the three essential oils, which
contain various ratios of 48 identified terpenoids,
show moderate anti-inflammatory properties in an
induced paw swelling model in mice. All three prepa-
rations were much less potent than CBD. Also, no
correlative dose–response was observed, suggesting
that a maximum effect was observed already with
the lower dose. T2 was somewhat less potent than
T1 and T3 with regard to their paw swelling inhibitory
effects. T1, but not T2 and T3, exhibited moderate
antipain effects, but still, T1 was less potent than
CBD. The differences between terpenoids and CBD
might be explained by their different effect on TNFa
production. While CBD strongly reduces TNFapro-
duction in vivo, the terpenoids barely had any effect.
In vitro, the terpenoids only affected macrophage
production at high
concentration (40 lg/mL), which is in contrast to
6lg/mL CBD required to inhibit 90% of granulocyte-
induced ROI production
and 8 lg/mL CBD to in-
hibit 50% of zymosan-induced ROI in RAW 264.7
The effects were chemotype specific to a certain extent,
which is in agreement with the individuality of the es-
sential oils with terpenoids. Interestingly, in contrast to
CBD, none of the chemotype essential oil had any effect
on the levels of zymosan-induced TNFa.Thismightsug-
gest the terpenoids exert their anti-inflammatory effects
through a mechanism other than that employed by the
Different chemotypes of cannabis have a distinctive
composition of terpenoids. These essential oils do
have anti-inflammatory and antinociceptive activities
that vary according to their composition, but they
had no effect on TNFatiters. None of the essential
oils was as effective as CBD. We suggest that terpenoids
may be used to diminute acute inflammation effect,
whereas the cannabinoids to inhibit chronic inflamma-
tion symptoms.
The authors would like to thank Dr. Ronit Sionov for
her valuable editorial assistance.
Author Disclosure Statement
The authors declare no conflicts of interest.
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Cite this article as: Gallily R, Yekhtin Z, Hanus
ˇLO (2018) The anti-
inflammatory properties of terpenoids from Cannabis,Cannabis and
Cannabinoid Research 3:1, 282–290, DOI: 10.1089/can.2018.0014.
Abbreviations Used
CBD ¼cannabidiol
DMEM ¼Dulbecco’s modified Eagle’s medium
FCS ¼fetal calf serum
GC/MS ¼gas chromatography/mass spectrometry
KI ¼Kovats Index
LPS ¼lipopolysaccharide
NO ¼nitric oxide
ROI ¼reactive oxygen intermediate
SNs ¼supernatants
THC ¼tetrahydrocannabinol
TNFa¼tumor necrosis factor alpha
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... For example, cis-p-menth-2-en-1-ol, a stereoisomer of trans-p-menth-2-en-1ol, has been reported to be present in the essential oil from dried inflorescences and floral bracts of industrial hemp [44]. The stereoisomers of aromadendrene oxide (alloaromadendrene, aromadendrene epoxide, and isoaromadendrene epoxide) have been found in the essential oils of various cannabis chemotypes [49] and industrial hemp [44]. All these newly identified compounds have previously been found in the essential oils of flowers and aerial parts of other medicinal plants [50][51][52][53][54][55]. ...
... Even though each study design was different, we were able to detect around four times more terpenes and terpenoids using GC × GC as compared to the reported GC studies [4,[18][19][20]30,35,38,43,44,46,47,49,[56][57][58][59]. The number of terpenes and terpenoids detected in the reported GC studies ranged from 23 to 109. ...
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Cannabis contains a wide range of terpenes and terpenoids that are mainly responsible for their distinctive aroma and flavor. These compounds have also demonstrated therapeutic effects either alone and/or as synergistic compounds with other terpenes, terpenoids, and/or cannabinoids. Several studies have attempted to fully characterize terpenes and terpenoids in cannabis; however, most of these studies used one-dimensional gas chromatography, which often results in the co-elution of the compounds. In the present study, we analyzed terpenes and terpenoids in the dried flowers of six cannabis strains using a two-dimensional gas chromatograph time-of-flight mass spectrometer (GC × GC-TOFMS). A total of 146 terpenes and terpenoids were detected across all six cannabis strains with an enhanced separation of 16 terpenes and terpenoids in the second dimension. Additionally, we achieved enhanced separation of four terpenes and terpenoids from a standard mixture in the second dimension. Chemical differences were observed in the number and relative abundance of monoterpenes, monoterpenoids, sesquiterpenes, and sesquiterpenoids in all six strains. We were also able to identify four new terpenoids in cannabis, which are reported here for the first time.
... Introduction Cannabis sativa L. plant is a member of the Cannabaceae family (Muscara et al. 2021) that has been used since the beginning of human species evolution (Gallily et al. 2018;Russo 2007). It has several applications, for example, for recreational purposes (Petrocellis et al. 2011), in religious traditions (Pattnaik et al. 2022), as nutrients and other compounds source, and as a natural fiber for textiles (Muscara et al. 2021). ...
... It has several applications, for example, for recreational purposes (Petrocellis et al. 2011), in religious traditions (Pattnaik et al. 2022), as nutrients and other compounds source, and as a natural fiber for textiles (Muscara et al. 2021). Nevertheless, cannabis stands out by its therapeutical applications, mainly for pain relief and in different autoimmune and inflammatory diseases (Gallily et al. 2018). It is also known by its topical uses in skin disorders, such as atopic dermatitis (ATD) (Zeng et al. 2021), psoriasis (Yeroushalmi et al. 2020), eczema, pruritus (Biernacki et al. 2021), skin cancer (Rio et al. 2018a), acne (Olah et al. 2014), skin inflammatory disease (Mugnaini et al. 2019), amongst others. ...
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In recent decades, the therapeutic potential of cannabinoids and analogous compounds has been intensively investigated. The endocannabinoid system has already been identified in the skin and, although much remains to be discovered about its contribution and importance for the maintenance of skin homeostasis, it has been increasingly associated as promising for dermatological disorders’ management. Cannabidiol (CBD), the main non-intoxicating phytocannabinoid in cannabis, has been shown to have hydrating, sebostatic, antipruritic, antimicrobial, anti-inflammatory, antioxidant, wound healing, photoprotective, anti-fibrotic and antitumoral, as well as modulating hair growth. Thus, CBD has gained attention concerning its application in cutaneous pathologies such as atopic dermatitis, psoriasis, acne, epidermolysis bullosa, systemic sclerosis, seborrheic dermatitis, androgenetic alopecia and cutaneous melanoma, although its bioactivities still lack scientific evidence and some of its mechanisms of action remain to be elucidated. Given its physicochemical characteristics, its topical administration becomes challenging, and it is necessary to develop new technological strategies to overcome the skin intact barrier. This review describes the latest evidence that exists on the application of CBD to the skin, the problems inherent to its chemical structure and that compromise its cutaneous administration, and the different strategies and formulations that have been studied to improve it, also clarifying some CBD-containing cosmetics products that are already available on the market.
... Because of their capacity to block toll like receptor-4, these compounds are employed for neuroprotection, skin homeostasis, and antiinflammatory actions [70]. The increased paw diameter and volume in arthritic mice were found to be reduced after application of CBD, suggesting its involvement in the treatment of inflammation; however, the impact was not contingent on a drop in TNF-a level [71]. Additionally, the downregulation of angiotensin-converting enzyme II gene expression by Cannabis sativa extract showed that it might be a viable technique for lowering COVID-19 susceptibility [72]. ...
... In a 2018 report by Gallily et al., the anti-inflammatory potential of terpenoid extracts derived from C. sativa [5-40 µg/mL] was demonstrated by a reduction in NO· levels following application onto LPS-stimulated RAW 264.7 cells. However, the same study reported no significant effect on TNF-α levels in an in vivo model of zymosan-induced paw swelling in mice [76]. In this study, we opted to use terpenes derived from H. lupulus (hops) as an alternative source, in order to avoid the possibility of THC residues in the extracts. ...
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This study investigates the potential of cannabidiol (CBD), one major cannabinoid of the plant Cannabis sativa, alone and in combination with a terpene-enriched extract from Humulus lupulus (“Hops 1”), on the LPS-response of RAW 264.7 macrophages as an established in vitro model of inflammation. With the present study, we could support earlier findings of the anti-inflammatory potential of CBD, which showed a dose-dependent [0–5 µM] reduction in nitric oxide and tumor necrosis factor-alpha (TNF-α) released by LPS-stimulated RAW 264.7 macrophages. Moreover, we observed an additive anti-inflammatory effect after combined CBD [5 µM] and hops extract [40 µg/mL] treatment. The combination of CBD and Hops 1 showed effects in LPS-stimulated RAW 264.7 cells superior to the single substance treatments and akin to the control hydrocortisone. Furthermore, cellular CBD uptake increased dose-dependently in the presence of terpenes from Hops 1 extract. The anti-inflammatory effect of CBD and its cellular uptake positively correlated with terpene concentration, as indicated by comparison with a hemp extract containing both CBD and terpenes. These findings may contribute to the postulations for the so-called “entourage effect” between cannabinoids and terpenes and support the potential of CBD combined with phytomolecules from a non-cannabinoid source, such as hops, for the treatment of inflammatory diseases. Supplementary Information The online version contains supplementary material available at 10.1007/s13659-023-00382-3.
... Such an effect could suggest that cannabis may have beneficial effects on brain function in those with cognitive impairment, advancing age, and/or other conditions where brain inflammation is thought to be central to changes in cognition (Lew et al. 2018(Lew et al. , 2021bWilson et al. 2019;Spooner et al. 2021Spooner et al. , 2023. Cannabidiol (CBD), a passive (i.e., non-psychoactive) ingredient in cannabis (Burstein 2015), has previously been shown to have antioxidant and anti-inflammatory properties (Gallily et al. 2018;Atalay et al. 2019), therefore possibly reducing inflammation in certain pathologies mentioned above. However, whether the same anti-inflammatory properties are embodied by cannabis more broadly (Hampson et al. 2000;Marsicano et al. 2002;Centonze et al. 2007) will be important to identify in future studies. ...
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Rationale and objectives Cannabis use is often associated with the use of other psychoactive substances, which is subsequently linked to an increased risk for addiction. While there is a growing body of neuroimaging literature investigating the cognitive effect of long-term cannabis use, very little is known about the potential additive effects of cannabis polysubstance use. Methods Fifty-six adults composed of 18 polysubstance users (i.e., cannabis plus at least one other illicit substance), 19 cannabis-only users, and 19 nonusers completed a visuospatial attention task while undergoing magnetoencephalography. A data-driven approach was used to identify oscillatory neural responses, which were imaged using a beamforming approach. The resulting cortical regions were probed for group differences and used as seeds for whole-brain connectivity analysis. Results Participants exhibited robust theta, alpha, beta, and gamma responses during visuospatial processing. Statistical analyses indicated that the cannabis-only group had weaker occipital theta relative to the nonusers, and that both polysubstance and cannabis-only users had reduced spontaneous gamma in the occipital cortices during the pre-stimulus baseline period relative to nonusers. Finally, functional connectivity analyses revealed that polysubstance users had sharply reduced beta connectivity between occipital and prefrontal, as well as occipital and left temporal cortices. Conclusions Cannabis use should be considered in a polysubstance context, as our correlational design suggests differences in functional connectivity among those who reported cannabis-only versus polysubstance use in occipital to prefrontal pathways critical to visuospatial processing and attention function. Future work should distinguish the effect of different polysubstance combinations and use more causal designs.
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Diversos estudios recientes concuerdan en que la investigación, el desarrollo, la innovación y la creación (I+D+I+C) son la base para el crecimiento sostenible de toda sociedad. Los diferentes sectores de desarrollo de la sociedad, han logrado avances revolucionarios con base en los importantes esfuerzos que realizan investigadores, profesores-investigadores, estudiantes en diferentes grados de escolaridad (doctorado, maestría, pregrado, bachillerato y primaria), innovadores, empresas de base científica o tecnológica, y otros. En el reciente concepto de Sociedad 5.0 donde la sociedad utiliza las tecnologías de la Industria 4.0 para el bien del planeta y la vida de las personas, se señala que la I+D+I+C son necesarias y de suma importancia para el diseño de nuevos y mejores modelos económicos y de productos con alto valor agregado que sean sostenibles en el tiempo. Asimismo, son la base para la generación de grandes oportunidades económicas y comerciales para el desarrollo tecnológico de los países. Para lograr estas capacidades en I+D+I+C, los países han aumentado año tras año la inversión económica en la formación de talento humano especializado en investigación. En este sentido, el Programa Nacional de Formación de Investigadores del Ministerio de Ciencia, Tecnología e Innovación (Minciencias) de Colombia, contempla tres líneas de acción clave: el Programa Ondas orientado a la formación de población infantil y juvenil, la Formación de Jóvenes Investigadores e Innovadores orientado a jóvenes estudiantes de últimos semestres de pregrado o recién graduados y la Formación de Doctores orientado a profesionales que buscan realizar su formación doctoral en el país o en el exterior. El papel de las Instituciones de Educación Superior (en especial de las Universidades y de las Instituciones Universitarias o Escuelas Tecnológicas) colombianas en el Programa Nacional de Formación de Investigadores de Minciencias ha sido fundamental, ya que en gran medida son las ejecutoras directas de diferentes procesos relacionados con este objetivo, reafirmando su misión no sólo en educación y formación, sino también, en investigación, desarrollo, innovación, creación, transferencia y aporte social. En estas instituciones es donde los jóvenes comprenden la importancia de estos temas y cómo pueden impactar de forma significativa en sus procesos formativos y profesionales, para de esta manera propender no sólo por la adquisición y generación de nuevos conocimientos, sino también, por la aplicación de esos conocimientos en las comunidades en las cuales estarán inmersos como futuros profesionales. Los jóvenes y futuros profesionales están llamados a aprender los procesos y métodos de investigación, así como desarrollar una conciencia crítica, científica y racional, que les permita convertir las necesidades y problemáticas en oportunidades para investigar, innovar y crear soluciones desde sus disciplinas, aportando al desarrollo social de su entorno. Así como la Formación de Investigadores es clave para el desarrollo social, también lo es la comunicación de la I+D+I+C. Este trabajo se logra con la publicación y divulgación de los avances y resultados de los diferentes proyectos e iniciativas a través de diversos medios como, por ejemplo: los artículos en revistas o las ponencias en eventos locales, nacionales o internacionales, los registros de propiedad intelectual, los libros, los capítulos de libro, el desarrollo de software, la generación de hardware, las patentes, el registro de nuevas variedades vegetales o razas animales, entre otras. Esta comunicación desarrolla, impulsa y mejora el nivel educativo tanto formativo de los jóvenes y estudiantes como el de las mismas universidades, además, motiva a más jóvenes a iniciar este proceso de formación como una oportunidad para trabajar y aportar resultados que permitirán la innovación en los procesos de las empresas en las cuales están o estarán inmersos. Teniendo en cuenta lo anterior, el comité organizador de las I Jornadas de Reflexión del Proyecto Jóvenes Investigadores e Innovadores en el Departamento del Cauca 2022, presentó su primer evento en siete (7) focos de interés los cuales agrupan las ponencias de treinta (30) jóvenes investigadores beneficiarios de la primera convocatoria del proyecto “Implementación del proyecto de Jóvenes Investigadores e Innovadores en departamento del Cauca”, buscando divulgar los resultados de sus investigaciones y recibir realimentación de la comunidad en general. Los focos de interés son: Territorio y Ambiente, Industria, Biotecnología, Tecnologías de la Información y las Comunicaciones (TIC), Sociocultural, Salud y Educación. Esta primera jornada tuvo una duración de 8 horas y fue celebrada el 15 de noviembre de 2022 en el Centro de Convenciones Casa De La Moneda en Popayán (Cauca, Colombia). En este libro se compendian las memorias de los 30 artículos de reflexión (cada uno como un capítulo del libro) en los tópicos del evento, de los cuales, 8 corresponden al foco de Territorio y Ambiente, 7 a Salud, 4 a TIC, 4 a Biotecnología, 3 a Industria, 2 a Sociocultura y 2 a Educación. Los jóvenes investigadores e innovadores que participaron en este evento han sido apoyados institucionalmente por la Universidad del Cauca (18), la Corporación Universitaria Comfacauca (6), la Universidad Cooperativa de Colombia seccional Cauca (3), la Fundación Universitaria María Cano seccional Cauca (2) y la Corporación Autónoma del Cauca (1), y han sido apoyados financieramente por parte del Departamento del Cauca a través del Sistema General de Regalías con el proyecto titulado “Implementación Del Proyecto De Jóvenes Investigadores E Innovadores En El Departamento Del Cauca” e identificado con BPIN: 2020000100043. Es así como las Jornadas de Reflexión del Proyecto Jóvenes Investigadores e Innovadores en el Departamento del Cauca inician su proceso de consolidación como un espacio de divulgación y debate sobre los resultados de investigación de los trabajos realizados por los jóvenes beneficiados y su formación en I+D+I+C.
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Abstract Serevenia buxifolia is an evergreen citrus plant and has attracted considerable attention due to its bioactive components and biological activities. In the present study, the essential oil (EO) from S. buxifolia cultivated in Vietnam was demonstrated to exhibit the in vitro antioxidant, thrombolytic, anti‐hemolysis, anti‐inflammatory, and antidiabetic activities. Briefly, the gas chromatography coupled to mass spectrometry analysis revealed that the leaf EO of S. buxifolia was composed of 33 components, with the main constituents being β‐carypphyllene (32.5%), and elixene (9.8%). The extracted oil possessed a fairly high free radical scavenging activity against 2, 2‐diphenyl‐1‐picrylhydrazyl (DPPH), with an IC50 value of 190.7 μg/mL compared with positive control, α‐tocopherol, IC50 value of 42.6 μg/mL. The EO also exhibited thrombolytic activity: the percentage of inhibition was found to be 70.75% at 100 μL, in comparison with 87.2% for the positive control, streptokinase. For hemolytic activity, the percentage of inhibition of the EO was from 27.4% to 59.6% at concentrations from 10 to 100 μg/mL, respectively. The results of in vitro anti‐inflammatory activity indicated that the EO of S. buxifolia leaves effectively protects the heat‐induced denaturation, with an IC50 value of 40.25 μg/mL. The EO also exhibited antidiabetic potential, with IC50 values of 87.8 and 134.9 μg/mL against α‐amylase and α‐glucosidase, respectively. It is noteworthy that the potent biological activities of the obtained S. buxifolia oil increased in a dose‐dependent manner. The results achieved show that the EO of S. buxifolia leaves can be a potential source for oxidative stress, inflammatory, and diabetic management.
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Medicinal and aromatic plants have been one of the most important sources of medicine since the dawn of human civilization. Indigenous communities have used products from these plants in different conditions throughout history. Cannabis sativa L. is one of the most widely employed herbaceous medicinal plants for textiles, and fibers, in medicine, as a source of food, animal food, animal bedding, and agriculture for seeds. This paper highlights the traditional applications, botany, phytochemistry, and pharmacological properties of C. sativa. Extensive database retrieval, such as Google Scholar, Semantic Scholar, ResearchGate,, PubMed, SciFinder, ChemSpider, CNKI, PubFacts was performed using the keywords “Hemp” and “Cannabis,” as well as the scientific name of this plant species (Cannabis sativa). Besides, reviews of relevant textbooks, documents, and patents were also employed to collect sufficient information. This study revealed numerous pharmacological activities of C. sativa that could help with several health issues. Additionally, more than 565 bioactive constituents have been isolated and identified from diverse parts of C. sativa. This could help discover potential therapeutic effects and develop new medications to benefit human health.
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Rodents are commonly used to study the pathophysiological mechanisms of pain as studies in humans may be difficult to perform and ethically limited. As pain cannot be directly measured in rodents, many methods that quantify “pain-like” behaviors or nociception have been developed. These behavioral methods can be divided into stimulus-evoked or non-stimulus evoked (spontaneous) nociception, based on whether or not application of an external stimulus is used to elicit a withdrawal response. Stimulus-evoked methods, which include manual and electronic von Frey, Randall-Selitto and the Hargreaves test, were the first to be developed and continue to be in widespread use. However, concerns over the clinical translatability of stimulus-evoked nociception in recent years has led to the development and increasing implementation of non-stimulus evoked methods, such as grimace scales, burrowing, weight bearing and gait analysis. This review article provides an overview, as well as discussion of the advantages and disadvantages of the most commonly used behavioral methods of stimulus-evoked and non-stimulus-evoked nociception used in rodents.
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Cannabis (Cannabis sativa) plants produce and accumulate a terpene-rich resin in glandular trichomes, which are abundant on the surface of the female inflorescence. Bouquets of different monoterpenes and sesquiterpenes are important components of cannabis resin as they define some of the unique organoleptic properties and may also influence medicinal qualities of different cannabis strains and varieties. Transcriptome analysis of trichomes of the cannabis hemp variety 'Finola' revealed sequences of all stages of terpene biosynthesis. Nine cannabis terpene synthases (CsTPS) were identified in subfamilies TPS-a and TPS-b. Functional characterization identified mono-and sesqui-TPS, whose products collectively comprise most of the terpenes of 'Finola' resin, including major compounds such as β-myr-cene, (E)-β-ocimene, (-)-limonene, (+)-α-pinene, β-caryophyllene, and α-humulene. Transcripts associated with terpene biosynthesis are highly expressed in trichomes compared to non-resin producing tissues. Knowledge of the CsTPS gene family may offer opportunities for selection and improvement of terpene profiles of interest in different cannabis strains and varieties.
Phytocannabinoids modulate inflammatory responses by regulating the production of cytokines in several experimental models of inflammation. Cannabinoid type-2 (CB2) receptor activation was shown to reduce the production of the monocyte chemotactic protein-2 (MCP-2) chemokine in polyinosinic-polycytidylic acid [poly-(I:C)]-stimulated human keratinocyte (HaCaT) cells, an in vitro model of allergic contact dermatitis (ACD). We investigated if non-psychotropic cannabinoids like cannabidiol (CBD) produced similar effects in this experimental model of ACD. HaCaT cells were stimulated with poly-(I:C) and the release of chemokines and cytokines was measured in the presence of CBD or other phytocannabinoids (such as CBDA, CBDV, CBDVA, CBC, CBG, CBGA, CBGV, THCV, THCVA) and antagonists of cannabinoid type-1 (CB1), CB2 or transient receptor potential vanilloid type 1 (TRPV1) receptors. HaCaT cell viability following phytocannabinoid treatment was also measured. The cellular levels of endocannabinoids [anandamide (AEA), 2-arachidonoylglycerol (2-AG)] and related molecules [palmitoylethanolamide (PEA), oleoylethanolamide (OEA)] were quantified in poly-(I:C)-stimulated HaCaT cells treated with CBD. We showed that in poly-(I:C)-stimulated HaCaT cells, CBD elevated the levels of AEA and dose-dependently inhibited poly-(I:C)-induced release of MCP-2, IL-6, IL-8 and TNF-α in a manner reversed by CB2 and TRPV1 antagonists, AM630 and I-RTX, respectively, with no cytotoxic effect. This is the first demonstration of the anti-inflammatory properties of CBD in an experimental model of ACD.
An advanced Mendelian Cannabis breeding program has been developed utilizing chemical markers to maximize the yield of phytocannabinoids and terpenoids with the aim to improve therapeutic efficacy and safety. Cannabis is often divided into several categories based on cannabinoid content. Type I, Δ 9-tetrahydrocannabinol-predominant, is the prevalent offering in both medical and recreational marketplaces. In recent years, the therapeutic benefits of cannabidiol have been better recognized, leading to the promotion of additional chemovars: Type II, Cannabis that contains both Δ 9-tetrahydrocannabinol and cannabidiol, and cannabidiol-predominant Type III Cannabis. While high-Δ 9-tetrahydrocannabinol and high-myrcene chemovars dominate markets, these may not be optimal for patients who require distinct chemical profiles to achieve symptomatic relief. Type II Cannabis chemovars that display cannabidiol- and terpenoid-rich profiles have the potential to improve both efficacy and minimize adverse events associated with Δ 9-tetrahydrocannabinol exposure. Cannabis samples were analyzed for cannabinoid and terpenoid content, and analytical results are presented via PhytoFacts, a patent-pending method of graphically displaying phytocannabinoid and terpenoid content, as well as scent, taste, and subjective therapeutic effect data. Examples from the breeding program are highlighted and include Type I, II, and III Cannabis chemovars, those highly potent in terpenoids in general, or single components, for example, limonene, pinene, terpinolene, and linalool. Additionally, it is demonstrated how Type I – III chemovars have been developed with conserved terpenoid proportions. Specific chemovars may produce enhanced analgesia, anti-inflammatory, anticonvulsant, antidepressant, and anti-anxiety effects, while simultaneously reducing sequelae of Δ 9-tetrahydrocannabinol such as panic, toxic psychosis, and short-term memory impairment.
The golden age of cannabis pharmacology began in the 1960s as Raphael Mechoulam and his colleagues in Israel isolated and synthesized cannabidiol, tetrahydrocannabinol, and other phytocannabinoids. Initially, THC garnered most research interest with sporadic attention to cannabidiol, which has only rekindled in the last 15 years through a demonstration of its remarkably versatile pharmacology and synergy with THC. Gradually a cognizance of the potential of other phytocannabinoids has developed. Contemporaneous assessment of cannabis pharmacology must be even far more inclusive. Medical and recreational consumers alike have long believed in unique attributes of certain cannabis chemovars despite their similarity in cannabinoid profiles. This has focused additional research on the pharmacological contributions of mono- and sesquiterpenoids to the effects of cannabis flower preparations. Investigation reveals these aromatic compounds to contribute modulatory and therapeutic roles in the cannabis entourage far beyond expectations considering their modest concentrations in the plant. Synergistic relationships of the terpenoids to cannabinoids will be highlighted and include many complementary roles to boost therapeutic efficacy in treatment of pain, psychiatric disorders, cancer, and numerous other areas. Additional parts of the cannabis plant provide a wide and distinct variety of other compounds of pharmacological interest, including the triterpenoid friedelin from the roots, canniprene from the fan leaves, cannabisin from seed coats, and cannflavin A from seed sprouts. This chapter will explore the unique attributes of these agents and demonstrate how cannabis may yet fulfil its potential as Mechoulam's professed “pharmacological treasure trove.”
Cannabis sativa L. is a prolific, but not exclusive, producer of a diverse group of isoprenylated resorcinyl polyketides collectively known as phytocannabinoids. The modular nature of the pathways that merge into the phytocannabinoid chemotype translates in differences in the nature of the resorcinyl side-chain and the degree of oligomerization of the isoprenyl residue, making the definition of phytocannabinoid elusive from a structural standpoint. A biogenetic definition is therefore proposed, splitting the phytocannabinoid chemotype into an alkyl-and a b-aralklyl version, and discussing the relationships between phytocannabinoids from different sources (higher plants, liverworts, fungi). The startling diversity of cannabis phytocannabinoids might be, at least in part, the result of non-enzymatic transformations induced by heat, light, and atmospheric oxygen on a limited set of major constituents (CBG, CBD, D 9-THC and CBC and their corresponding acidic versions), whose degradation is detailed to emphasize this possibility. The diversity of metabotropic (cannabinoid receptors), ionotropic (thermos-TRPs), and transcription factors (PPARs) targeted by phytocannabinoids is discussed. The integrated inventory of these compounds and their biological macromolecular end-points highlights the opportunities that phytocannabinoids offer to access desirable drug-like space beyond the one associated to the narcotic target CB 1 .
This chapter reviews the enzymatic pathways involved in the biosynthesis of cannabis constituents and the variety of phytocannabinoids and terpenoids that are produced. While phytocannabinoids are often referred to as the “active” ingredients in cannabis, the other chemical constituents have a broad spectrum of pharmacological properties and can contribute to the effects seen upon cannabis ingestion or combustion and inhalation, and may also be contained within and contribute to the activity of extracts, tinctures, and other cannabis formulations. The chapter concludes with a focus on the detailed ways in which these processes are manifested in vitro, in laboratory animals, and in the therapeutic use of cannabis preparations.
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