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Cannabidiol (CBD) and its analogs: A review of their effects on inflammation

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Review
Cannabidiol (CBD) and its analogs: a review of their effects
on inflammation
Sumner Burstein
Department of Biochemistry & Molecular Pharmacology, University of Massachusetts Medical School, 364 Plantation St., Worcester, MA 01605, United States
article info
Article history:
Received 24 December 2014
Revised 23 January 2015
Accepted 30 January 2015
Available online 7 February 2015
Keywords:
Cannabidiol
D
9
-Tetrahydrocannabinol
Anti-inflammatory
CBD receptor binding
Signaling events
Downstream events
Functional effects
abstract
First isolated from Cannabis in 1940 by Roger Adams, the structure of CBD was not completely elucidated
until 1963. Subsequent studies resulted in the pronouncement that THC was the ‘active’ principle of
Cannabis and research then focused primarily on it to the virtual exclusion of CBD. This was no doubt
due to the belief that activity meant psychoactivity that was shown by THC and not by CBD. In retrospect
this must be seen as unfortunate since a number of actions of CBD with potential therapeutic benefit
were downplayed for many years. In this review, attention will be focused on the effects of CBD in the
broad area of inflammation where such benefits seem likely to be developed. Topics covered in this
review are; the medicinal chemistry of CBD, CBD receptor binding involved in controlling Inflammation,
signaling events generated by CBD, downstream events affected by CBD (gene expression and transcrip-
tion), functional effects reported for CBD and combined THC plus CBD treatment.
Ó2015 Elsevier Ltd. All rights reserved.
Contents
1. Introduction . . . ..................................................................................................... 1378
2. Medicinal chemistry of CBD . . . . . . . . . .................................................................................. 1378
2.1. Conformation. . . . . . . . . . ....... ............................................................................ ..... 1378
2.2. Natural homologs and synthetic analogs . . . . ............................. ........................................... 1378
3. Receptor binding involved in controlling inflammation . . . . . . ............................................................... 1379
3.1. CB1 cannabinoid receptor.................... .................................................................... 1379
3.2. CB2 cannabinoid receptor.................... .................................................................... 1379
3.3. Adenosine A2A receptors ............. ........................................................................... 1379
3.4. CB2/5HT(1A) heterodimerization . . . . . . . . . . ................................................................ ........ 1380
3.5. TRPV1 receptor . . . . . . . . .......... .............................................................................. 1380
3.6. GPR55 Receptor . . . . . . . . .................... .................................................................... 1380
4. Signaling events generated by CBD. . . . .................................................................................. 1380
4.1. Eicosanoids . . . . . . . . . . . ....................................... ................................................. 1380
4.1.1. Arachidonic acid release. . . . . ............................................................................. 1380
4.1.2. Cyclooxygenase and products ............................................................................. 1380
4.1.3. Lipid storage diseases. . . . . . . ............................................................................. 1381
http://dx.doi.org/10.1016/j.bmc.2015.01.059
0968-0896/Ó2015 Elsevier Ltd. All rights reserved.
Abbreviations: CBD, cannabidiol; CBCy, cannabicyclol; CBCR, cannabichromene;
CBGA, cannabigerolic acid; CBGV, cannabigerovarin; CBN, cannabinol; CBG,
cannabigerol; DMH, dimethylheptyl; LPS, lipopolysaccharide; NBMPR, S-(4-ni-
trobenzyl)-6-thioinosine; NFAT, nuclear factor of activated T-cells; PLA
2
, phospho-
lipase A
2
; THC,
D
9
-tetrahydrocannabinol; THCV, tetrahydrocannabivarin; TNF-
a
,
tumor necrosis factor-
a
; ROI, reactive oxygen intermediates; NAgly, N-arachidonoyl
glycine; CIA, collagen-induced arthritis; FAAH, fatty acid amide hydrolase; OPC,
oligodendrocyte progenitor cells.
Tel.: +1 508 856 2850; fax: +1 508 856 2003.
E-mail address: sumner.burstein@umassmed.edu
Bioorganic & Medicinal Chemistry 23 (2015) 1377–1385
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
4.2. Cytokines . . . . . . . ................................................................... ........................... 1381
4.3. Effects of CBD on intracellular Ca
++
levels ............................................. .............................. 1381
5. Downstream events affected by CBD: gene expression and transcription . . . . . .................................................. 1381
5.1. Comparative microarray analysis . . . . . . . ................ ........................................................... 1381
5.2. Expression of glial fibrillary acidic protein mRNA. . . . . . . . . . ............. .............................................. 1382
5.3. PPAR
c
involvement . . . . . . . . . . . . . . . . . . .... ....................................................................... 1382
5.4. Production of reactive oxygen intermediates . . . . . . . . . . . . . ................................................ ........... 1382
6. Functional effects reported for CBD . . . . . . . . . . . . . . . . ..................................................................... 1382
6.1. Anti-arthritic effect in CIA . . . . . . . . . . . . .......................... ................................................. 1382
6.2. Anti-inflammatory clinical effects of HU-320 (Fig. 2).......................................... ........................ 1382
6.3. Edema and hyperalgesia . . . . . . . . . . . . . . ...................................................................... ..... 1382
6.4. Arachidonic acid-induced ear inflammation . . . . . . . . . . . . . . .......... ................................................. 1382
6.5. Inflammatory bowel disease. . . . . . . . . . . ................ ........................................................... 1382
6.6. Chemically induced colitis . . . . . . . . . . . . .......... ................................................................. 1383
6.7. Human neutrophil migration . . . . . . . . . . ............................. .............................................. 1383
6.8. Type I diabetic cardiomyopathy . . . . . . . . ................ ........................................................... 1383
6.9. Elevation of cytokine production . . . . . . . .......................................... ................................. 1383
6.10. Pneumococcal meningitis . . . . . . . . . . . . ................................................................ ........... 1383
6.11. Treatment of demyelinating pathologies .... ....................................................................... 1383
6.12. Hepatic ischemia-reperfusion injury . . . ....... .................................................................... 1384
6.13. Sepsis-related encephalitis . . . . . . . . . . . ................................................ ........................... 1384
6.14. Autoimmune encephalomyelitis. . . . . . . ....... .................................................................... 1384
6.15. Inflammatory lung diseases . . . . . . . . . . .......... ................................................................. 1384
7. Combined THC and CBD treatment . . . . . . . . . . . . . . . . . ..................................................................... 1384
8. Summary . . ........................................................................................................ 1384
Acknowledgement . . . . . . . . . . . ........................................................................................ 1385
References and notes . . . . . . . . . ........................................................................................ 1385
1. Introduction
Recent years have seen a dramatic increase in interest in the
major phytocannabinoid, cannabidiol. For the period 2008 to the
present, 1205 publications can be found in a PubMed search using
the keyword cannabidiol. This compares with lists of 225 reports
for the years 2003–2007 and 50 for 1999–2002.
1
First isolated from
Cannabis in 1940,
2
the structure shown in Figure 1 was not report-
ed until 1963.
3
Subsequent studies on Cannabis resulted in the pro-
nouncement that THC was the ‘active’ principle and research then
focused primarily on it to the virtual exclusion of CBD. This was no
doubt due to the belief that activity meant psychoactivity that was
shown by THC and not by CBD. In retrospect, this must be seen as
unfortunate since a number of actions of CBD with potential
therapeutic benefit were overlooked for many years. In this review,
attention will be focused on the effects of CBD on the broad area of
inflammation where such benefits seem likely to be realized.
2. Medicinal chemistry of CBD
2.1. Conformation
Although there is considerable structural overlap between CBD
and THC (Fig. 1), the conformational structures shown in Figure 1A
differ significantly.
4
Whereas THC exists in an essentially planar
conformation, CBD adopts a conformation in which the two rings
are more or less at right angles to each other (Fig. 1). A result of this
is the observation that CBD does not bind to or activate the CB1
receptor an action that THC is capable of doing. This in turn leads
to a complete lack of psychoactivity by CBD unlike THC, which is
the psychoactive principle of Cannabis. The basis of this is a so-
called ‘region of steric interference’
5
on the CB1 receptor that
allows THC to bind but interferes with CBD binding.
2.2. Natural homologs and synthetic analogs
There are four known side-chain homologs of CBD; methyl,
n-propyl, n-butyl and n-pentyl groups.
6
Of these, until recently,
only the pentyl homolog, CBD itself, has been extensively studied
in terms of biological activity.
7
The syntheses of the CBD deriva-
tives, ()-11-hydroxy-CBD, ()-CBD-11-oic acid and their
CBD THC
A
B
Figure 1. The minimal energy conformations of CBD and
D
9
-tetrahydrocannabinol
(THC) are shown in 1A. THC has a fairly planar conformation whereas CBD has a
bent conformation. This difference results in different pharmacological profiles
even though there is considerable structural overlap of both when viewed in a two-
dimensional as shown in 1B. CBD refers to ()-CBD here and throughout this paper.
1378 S. Burstein/ Bioorg. Med. Chem. 23 (2015) 1377–1385
dimethylheptyl (DMH) analogs, as well as of the enantiomeric (+)-
CBD series have been reported (Fig. 2).
8
The affinities of these com-
pounds for both the CB1 and CB2 receptors were measured with
unexpected results. Whereas the naturally occurring ()-CBD ser-
ies showed no affinity, the (+)-CBD series displayed affinities in the
nano molar range. Regarding anti inflammatory action, ()-DMH-
CBD-11-oic acid showed anti inflammatory activity in a preclinical
study (Section 6.2).
9,10
Hydrogenation of both CBD and DMH-CBD (Fig. 2) yielded mix-
tures of dihydro and tetrathydro reduction products that were
separated and structurally characterized.
11
Using murine macro-
phages, their effects on the production of reactive oxygen interme-
diates (ROI), nitric oxide (NO), and tumor necrosis factor (TNF-R)
were determined. Unexpectedly, the reduced compounds showed
affinities for CB1 in contrast to CBD and DMH-CBD that do not bind
to this receptor.
As part of a study to characterize the CB1 receptor binding site,
desoxy-CBD (Fig. 2), a CBD analog with only one hydroxy group
was prepared.
4
Based primarily on computational studies, it was
concluded that the analog would be able to occupy this site. Des-
oxy-CBD behaves as a partial agonist with an IC-50 of 30.9 nM in
the mouse vas deferens assay. This type of activity is considered
to be an indication of CB1 activation that would be predicted by
the theoretical considerations. No direct measurement of receptor
binding was reported.
3. Receptor binding involved in controlling inflammation
3.1. CB1 cannabinoid receptor
CBD itself has no affinity for CB1, however, several of its hydro-
genated analogs bind with nano molar affinity. The most active
analog was tetrahydro-DMH-CBD when tested using a synaptoso-
mal membrane preparation derived from rat brain. It was reported
to bind to this CNS cannabinoid receptor with a K
i
of 17 nM.
11
The
enantiomeric CBD derivatives, (+)-11-hydroxy-CBD, (+)-CBD-11-
oic acid and their dimethylheptyl (DMH) analogs exhibit binding
to CB1 in the low nano molar range.
8
These findings are difficult
to reconcile with the earlier report on desoxy-CBD cited above in
Section 2.2.
4
Arguments were presented that the non planar
conformation of CBD prevents it from reaching the ligand binding
site in CB1 since a planar structure is needed for this to occur. The
analogs described here all contain two phenolic hydroxy groups
that would prevent such a planar conformation.
3.2. CB2 cannabinoid receptor
A CBD analog with a modified terpene ring, HU-308 (Fig. 2) was
reported to be a specific ligand for CB2 with low nano molar affi-
nity (K
i
= 22.7 ± 3.9 nM).
12,13
It did not bind to CB1 (K
i
>10
l
M)
and did not elicit CB1 mediated responses either in vitro or in vivo.
However, forskolin stimulated cyclic AMP production in CB2
transfected cells was potently inhibited. An inflammatory effect,
arachidonic acid-induced ear edema in mice, was inhibited, which
was reversed by the CB2 antagonist SR144528 but not by the CB1
antagonist SR141716a.
The actions of CBD were studied in hypoxic–ischemic immature
brain, forebrain slices from newborn mice.
14
At a concentration of
l
M, it produced significant reductions in IL-6 concentration, and
TNF-
a
, COX-2, and iNOS expression. The use of selective antago-
nists for the CB2 and adenosine A2A receptors suggested their
mediation in these actions. However, the high concentration of
CBD needed makes the pharmacological relevance of these findings
somewhat questionable. Functional heteromers composed of a
mixture of A2A subunits with subunits from other unrelated
G-protein coupled receptors have been found in the brain. In a sub-
sequent report, using a hypoxic ischemic brain injury model in
newborn pigs, CBD reduced IL-1 levels in lesioned animals; more-
over, this effect was reduced when it was administered together
with CB2 or 5HT1A receptor antagonists.
15
The CBD was given iv
at 1 mg/kg and the levels of IL-1 were measured by Western blot
analysis.
3.3. Adenosine A2A receptors
It has been suggested that A2A receptors can down regulate
over-reactive immune cells, resulting in protection of tissues from
Figure 2. The structures of CBD analogs and related substances.
S. Burstein/ Bioorg. Med. Chem. 23 (2015) 1377–1385 1379
collateral inflammatory damage.
16
Also, it has been reported that
CBD has the ability to enhance adenosine signaling through inhibi-
tion of uptake and provide a non cannabinoid receptor mechanism
by which CBD can decrease inflammation.
17
They reported that
in vivo treatment with a low dose of CBD (1 mg/kg, ip) decreases
TNF-
a
production in LPS-treated mice; this effect was reversed
by an A2A adenosine receptor antagonist and was abolished in
A2A receptor knockout mice. The possible involvement of this
receptor in CBD anti-inflammatory actions was also mentioned in
the preceding section.
14
The A2A antagonist SCH58261 abolished
the modulation by CBD of cytokine production and COX-2 induc-
tion, suggesting that A2A activation participates in the anti-inflam-
matory activity of CBD.
CBD has anti-inflammatory effects in a murine model of acute
lung injury that appear to be mediated by the A2A receptor
injury.
18
LPS-induced inflammation in mice was reduced by the
administration of a single dose of 20 mg/kg of CBD. The effects
included neutrophil migration into the lungs, albumin concentra-
tion in the bronchoalveolar lavage fluid, myeloperoxidase activity
in the lung tissue, and production of TNF and IL-6 and chemokines
(MCP-1 and MIP-2). The A2A antagonist ZM241385 inhibited all of
these actions implicating this receptor in the anti-inflammatory
effects of CBD.
One of the animal models for multiple sclerosis, Theiler’s mur-
ine encephalomyelitis virus-induced demyelinating disease
(TMEV), is accompanied by inflammation. In this model, CBD
decreased leukocyte infiltration in the brains of TMEV-infected ani-
mals and it also significantly reduced microglial activation in the
cerebral cortex.
19
In addition, the levels of the pro inflammatory
cytokines TNF-
a
and IL-1bwere reduced. These actions of CBD
appear to be partially mediated by the A2A receptor based on inhi-
bition of the effects by prior administration of the antagonist
ZM241385. The authors concluded that CBD, ‘can limit the harmful
effects of an exacerbated inflammatory response, likely by increas-
ing adenosine signaling, and prevent the development of sec-
ondary and irreversible damage’.
3.4. CB2/5HT(1A) heterodimerization
In an interesting recent study, evidence was found that CB2 and
5HT1A receptors may form hetero dimers in HEK-293T cells.
15
The
study was focused on mechanisms of CBD neuroprotection (vide
infra) in hypoxic-ischemic newborn pigs involving a possible role
for 5HT(1A) and/or CB2 receptors. Bioluminescence resonance
energy transfer assays were used to support the conclusion that
CB2/5HT(1A) hetero dimerization is responsible for the observed
actions of CBD in this model. Further evidence was provided by
the cross-antagonism shown by the CB2 receptor antagonist
(AM630) and a serotonin 5HT1A receptor antagonist
(WAY100635). These findings have implications for receptor med-
iation in other actions of CBD and the actions of several other
cannabinoids as well.
3.5. TRPV1 receptor
Injection of mice with the plant lectin Concanavalin A (Con A),
results in polyclonal activation of T lymphocytes leading to a liver
inflammatory response that can be reduced by the administration
of 25 mg/kg of CBD.
20
Specifically, the levels of the pro-inflamma-
tory cytokines IL-2, TNF-
a
, IFN-c, IL-6, IL-12 (p-40), IL-17, MCP-1
and eotaxin-1 (CCL11) were significantly decreased by CBD in
Con A treated mice. By the use of vanilloid receptor knock-out
mice, the authors showed that CBD induced suppression of
inflammation in Con A-hepatitis was dependent on TRPV1. The
data strongly support this conclusion, however, independent
confirmation, possibly by the use of antagonists, is needed to
firmly establish a role for TRPV1.
3.6. GPR55 Receptor
CBD has been reported to act as a functional antagonist to the
GPR55 receptor.
21
The orphan receptor GPR55 was activated by
the CBD analog O-1602 (Fig. 2) resulting in increased IL-12 and
TNF-
a
production, and increased endocytic activity in LPS-activat-
ed monocytes. These effects of GPR55 were antagonized by CBD
acting as a selective antagonist.
4. Signaling events generated by CBD
4.1. Eicosanoids
4.1.1. Arachidonic acid release
The initiating event in all eicosanoid biosynthesis is the release
of free arachidonic acid from phospholipid storage sites where it
exists in an esterified form. Thus, drugs affecting this process, pre-
sumably involving PLA
2
, can have a profound effect on the physio-
logical status of a variety of systems. Both CBD and THC produce a
significant stimulation of arachidonic acid release in intact human
platelets.
22
Interestingly, CBD is roughly 1.5 times more potent
than THC suggesting that this action may not be involved in the
psychotropic activity of THC. It was also found that a product shift
from cyclooxygenase to lipoxygenase products occurs as a result of
cannabinoid exposure. This probably involves action(s) on down-
stream events in the arachidonic acid cascade. Stimulated arachi-
donic acid release was also observed in neuroblastoma cells
(NBA2). The arachidonic acid release effect was extended to a ser-
ies of six primary phytocannabinoids to produce the following rank
order of hydrolytic activity: CBD CBCy > THC = CBCR =
CBN CBG.
23
The model used to obtain these data was the WI-
38 human lung fibroblast that had been radiolabelled by equilibra-
tion with free arachidonic acid. Again, CBD was more active than
THC in stimulating phospholipid hydrolysis. By way of comparison,
the anti inflammatory actions of cannabinoid analogs such as NAg-
ly
24
and ajulemic acid (Fig. 2)
25
have been attributed to their ability
to promote the release of free arachidonic acid. In these examples,
a result of this action was the elevation of pro resolving substances
such as lipoxin A
4
and 15d-PGJ
2.26
A similar mechanism may
explain some of the anti inflammatory actions of CBD.
4.1.2. Cyclooxygenase and products
A group of six cannabinoids, including CBD and THC, were test-
ed for their ability to inhibit both COX-1 (ram seminal vesicles) and
COX-2 (sheep placental cotyledons) activity.
27
THC actually
stimulated COX-1 whereas CBD had very little effect on its activity.
In the case of COX-2, both THC and CBD stimulated activity with
CBD being more than twice as potent. This agrees with the effects
of these cannabinoids on the release of arachidonic acid mentioned
above. Moreover, COX-2 likely mediates the synthesis of lipoxin A
4
and 15d-PGJ
2
.
CBD was administered orally (5–40 mg/kg) once a day for
3 days following intraplantar injection of 0.1 ml carrageenan (1%
w/v in saline) in the rat.
28
Measurements were made of
prostaglandin E
2
(PGE
2
) in plasma, cyclooxygenase (COX) activity,
production of nitric oxide (NO; nitrite/nitrate content), and of
other oxygen-derived free radicals (malondialdehyde) in inflamed
paw tissues. All three markers, which were elevated by car-
rageenan treatment, were reduced in a dose-dependent fashion
by CBD when compared to vehicle treated controls. In addition
there was a dose related decrease in paw edema. These findings
1380 S. Burstein/ Bioorg. Med. Chem. 23 (2015) 1377–1385
strongly support the view that CBD has anti-inflammatory activity
and may find a use in treating clinical inflammation.
The report cited above was subsequently extended using a dif-
ferent model of inflammation; complete Freund’s adjuvant intra-
plantar injection in rats.
29
Again, CBD effected a reduction in the
levels of several mediators, such as prostaglandin E
2
, lipid peroxide
and nitric oxide, and in the over-activity of glutathione-related
enzymes. CBD’s efficacy was not accompanied by any reduction
in nuclear factor-kappa B activation and tumor necrosis factor
alpha concentration. These latter two markers are common indica-
tors for anti-inflammatory action suggesting that CBD may act by a
novel mechanism.
4.1.3. Lipid storage diseases
The hydrolytic actions of CBD have been extended to the prob-
lem of the lipid storage diseases, for example, Niemann–Pick
Disease.
30
Fibroblasts obtained from a Niemann-Pick patient were
treated with 30
l
M CBD and chromatographically analyzed for
lecithin and sphingomyelin content. The former was decreased
by 21% whereas the latter was reduced by 77%; excess sphin-
gomyelin is a feature of Niemann–Pick Disease. A control experi-
ment was done using fibroblasts from normal subjects that were
treated in a comparable manner. Lecithin and sphingomyelin con-
tent in the control was reduced by 21% and 17% respectively sug-
gesting a selective action of CBD on disease cells.
4.2. Cytokines
LPS-induced TNF-
a
production by RAW 264.7 mouse macro-
phage cells was completely inhibited by treatment with 8
l
M
CBD and its analog DMH-CBD (Fig. 2).
11
Surprisingly, the dihydro
and tetrahydro derivatives of each cited in Section 2.1 showed very
different effects on TNF-
a
synthesis; the reduced CBD analogs were
inhibitory whereas the reduced DMH-CBD compounds were mod-
erately stimulatory. There is no obvious explanation for this obser-
vation; however, full dose-response measurements may reveal
biphasic responses for all of these substances accompanied by
shifts in their potencies.
In a model of Alzheimer’s disease-related neuroinflammation,
where mice were inoculated with human Ab(1–42) peptide, CBD
reduced both iNOS and IL-1bprotein expression, and also decreased
related NO and IL-1bproduction.
31
A 50% reduction of each was
found in hippocampal homogenates following treatment with
10
l
g/kg of CBD. A smaller but significant effect was shown by
treatment with 2.5
l
g/kg of CBD. The authors suggested that CB2
may mediate these actions, however, no direct evidence was
presented.
Endotoxin-induced uveitis induced by systemic or local injec-
tion of LPS in rats was used an in vivo model to study the effects
of CBD on acute ocular inflammation.
32
The in vivo study was com-
plemented by in vitro experiments using microglial cells that were
isolated from the retinae of newborn rats. It was shown that
LPS-induced release of TNF-
a
is inhibited almost entirely by
the addition of 1
l
M CBD. Data are also reported suggesting that
the inhibition of p38 MAPK phosphorylation in responsible for this
action. In vivo it was shown CBD at 5 mg/kg prevents retinal
microglial activation or macrophage infiltration and inhibits serum
and retinal TNF-
a
release in the LPS-treated rat. These findings
provide compelling evidence for the use of CBD in the treatment
of retinal inflammation and neuroprotection both in terms of its
efficacy and safety.
The anti inflammatory action of CBD on cisplatin-induced
inflammation, and tissue injury in the kidney was studied using
an established mouse model of cisplatin-induced nephropathy.
33
CBD treatment (10 mg/kg/day ip) reduced mRNA expression of
TNF-
a
and IL-1bin the kidneys 72 h after its administration to
mice. Interestingly, several markers of nephrotoxicity were also
reduced, however, little was offered by way of mechanism to
explain these interesting findings.
It was reported that CBD, studied at 1, 5 and 10
l
M, decreased
the production and release of pro inflammatory cytokines such as
interleukin-1b, interleukin-6, and interferon-b, from LPS-activated
BV-2 microglial cells.
34
Neither CB1 or CB2 cannabinoid receptors,
nor the abn-CBD-sensitive receptors, were involved in this action.
In addition, CBD reduced the activity of the NF-
j
B pathway and
up-regulated the activation of the STAT3 transcription factor. Par-
allel experiments with THC revealed substantial differences in
their actions.
The effect of CBD on LPS-induced TNF-
a
expression was exam-
ined in intestinal homogenates of LPS-treated mice.
35
Western blot
analysis showed a 50% reduction in protein levels from CBD mice
treated with 10 mg/kg given ip Similar results were obtained in
ex vivo human derived colonic biopsies cultured for 24 h in the
presence of LPS plus IFN-
c
. Treatment of the cultures with a con-
centration of 1
l
M CBD gave a >50% reduction in iNOS protein
expression, nitrate levels and S100B protein expression. Evidence
for possible PPAR-
c
partial involvement was also reported. It was
suggested that pharmacological control of glial cell activity repre-
sents a novel approach for the treatment of intestinal inflammato-
ry pathologies.
Some data have been reported suggesting that CBD is a GPR55
antagonist.
36
In a more recent study, it was found that pretreat-
ment of rat cerebellar granule cells (CGCs) with CBD inhibited
LPS-induced cytokine mRNA expression.
37
RT-PCR analysis of cells
that were treated with 50
l
M CBD for 30 min, and then stimulated
with LPS (3
l
g/ml) for 4 h, showed reduced mRNA levels of IL-1b,
IL-6, and TNF-
a
. The high concentration of CBD used reduces to
some degree the significance of these findings.
CBD and its analog O-1602 showed anti-inflammatory activity
in mice with cerulein-induced acute pancreatitis accompanied by
an increased expression of GPR55 receptor in pancreatic tissues.
38
4.3. Effects of CBD on intracellular Ca
++
levels
Mast cells can contribute to chronic airway inflammatory
responses, remodeling and symptomatology, involving the produc-
tion of several of the eicosanoids and cytokines. Activation and
degranulation of mast cells is triggered by an increase of [Ca
++
]i.
Using flow cytometry in a time-resolved mode, it was reported that
CBD evoked, in a concentration dependent manner (1–10
l
M), a
persistent rise of [Ca++]i in RBL-2H3 cells.
39
The initiation of the
arachidonic acid cascade is strongly dependent on [Ca
++
]i. No evi-
dence was presented for a specific receptor involvement, however,
both cannabinoid receptors and the vanilloid receptor were
excluded.
CBD stimulated TRPV3-mediated [Ca
2+
]i with high efficacy
showing 50–70% of the effect of ionomycin and a potency of
EC
50
= 3.7
l
M in TRPV3-mediated elevation in transfected
HEK-293 cells.
40
CBD ranked high in efficacy when compared to a
number Cannabis components including; THCV > CBD > carvacrol >
THCVA > CBGV > CBC > CBG > THC > CBGA > CBDV > CBN > CBDA =
THCA.
5. Downstream events affected by CBD: gene expression and
transcription
5.1. Comparative microarray analysis
The transcriptional effects of CBD and THC were studied in BV-2
microglial cells in a comparative microarray analysis using the Illu-
mina MouseRef-8 BeadChip platform Ingenuity Pathway Analysis
S. Burstein/ Bioorg. Med. Chem. 23 (2015) 1377–1385 1381
was performed to identify functional subsets of genes and net-
works regulated by CBD and/or THC.
41
It was reported that CBD
affected the expression of many more genes, than those affected
by THC. It was also found that CBD induced a robust response relat-
ed to oxidative stress and GSH deprivation apparently controlled
by Nrf2 and ATF4 transcription factors. The mechanism underlying
the CBD actions involves depletion of intracellular GSH, activating
the GCN2/eIF2a/p8/ATF4/ CHOP-TRIB3 pathway accompanied by
generation of ROS via the (EpRE/ARE)-Nrf2/ATF4 system, and
regulation of the Nrf2/Hmox1 axis. The anti-inflammatory effects
of CBD were correlated with up-regulations of the expression of
Hmox1 and IFNb1, and down-regulation of the expression of Ccl2,
via the IFN-b-STAT pathway.
41,42
5.2. Expression of glial fibrillary acidic protein mRNA
The anti-inflammatory properties of CBD were demonstrated in
a mouse model of Alzheimer’s disease-related neuroinflamma-
tion.
31,43
Compared to vehicle controls, CBD (2.5 or 10 mg/kg, ip)
dose-dependently inhibited glial fibrillary acidic protein mRNA
and protein expression in beta-amyloid injected mice. In addition,
under the same experimental conditions, CBD reduced iNOS and
IL-1bprotein expression, and NO and IL-1brelease as well. The
results of this study suggest that CBD can effectively inhibit beta-
amyloid evoked neuro inflammatory reactions and may be effec-
tive in the treatment of Alzheimer’s disease.
5.3. PPAR
c
involvement
An inhibitory effect of CBD on the release of inflammatory med-
iators by in vitro cultured astrocytes has been reported.
43
In this
study, beta-amyloid challenged astrocytes (1 mg/ml) were treated
with CBD (10
9
to 10
7
M) in the presence or absence of a PPAR-
a
antagonist (MK886, 3
l
M) or a PPAR-
c
antagonist (GW9662,
9 nM). After 24 h, NO production was determined by measuring
nitrite (NO
2
) accumulation in the culture medium, in addition,
IL-1b, TNF-
a
, and S100B calcium binding protein release was
determined by ELISA assay. The PPAR-
c
antagonist was able to
significantly reverse the CBD inhibitory effects on reactive gliosis,
an important feature of many autoimmune inflammatory
disorders, and, as a further result, on neuronal damage. It was
concluded that CBD reduces beta-amyloid-induced neuroinflam-
mation and promotes hippocampal neurogenesis through PPAR-
c
involvement.
5.4. Production of reactive oxygen intermediates
The unusual receptor affinity of several CBD analogs was men-
tioned above in Section 3.1.
11
Cannabidiol (CBD) and cannabidiol
dimethylheptyl (CBD-DMH) were hydrogenated to give four differ-
ent epimers. These new derivatives were studied for their ability to
modulate the production of reactive oxygen intermediates (ROI),
nitric oxide (NO), and TNF-
a
by murine macrophages. Over a lim-
ited concentration range, variable effects were observed from inhi-
bition to stimulation of the levels of these mediators of
inflammation. It seems likely that biphasic responses would be
seen if the compounds were tested at wider concentration ranges.
6. Functional effects reported for CBD
6.1. Anti-arthritic effect in CIA
In collagen-induced arthritis (CIA), pro-inflammatory cytokines,
such as TNF-
a
and IL-1b, are highly expressed in the arthritic joints
of mice with CIA, and inhibition of the levels of these molecules can
result in a reduction of clinical symptoms. Experimental evidence
that CBD given at 25 mg/kg per day orally in murine collagen-in-
duced arthritis was efficacious in achieving such a response.
9
A
modest reduction in TNF-
a
production by synovial cells from
CBD treated mice was observed, however, a more robust reduction
was reported in the LPS-induced rise in serum TNF-
a
. The authors
concluded that the ‘data show that CBD, through its combined
immunosuppressive and anti-inflammatory actions, has a potent
anti-arthritic effect in CIA’.
6.2. Anti-inflammatory clinical effects of HU-320 (Fig. 2)
Modifications of the structure of CBD, namely the introduction
of a carboxy group and replacement of the n-pentyl side-chain
with a 1,1-dimethylheptyl group, resulted in an anti-inflammatory
agent called HU-320 (Fig. 2).
10
An earlier publication
44
where the
same changes were made on
D
8
-THC also produced a molecule
with potent anti-inflammatory actions named ajulemic acid (HU-
239) (Fig. 2) that in some preclinical studies showed apparent
CB1 activity.
45
However, it was recently reported that a carefully
executed synthesis of ajulemic acid resulted in a product that
was essentially free of CB1 activity but still retained anti-inflam-
matory action.
46
In vivo, HU-320 like HU-239 did not exhibit a
cannabimimetic profile but did produce anti-inflammatory clinical
effects in a murine, collagen-induced arthritis model. In vitro, it
inhibited production of TNF-
a
by mouse macrophages and of ROIs
from RAW 264.7 cells and, in addition, suppressed the rise in
serum TNF-
a
levels following an LPS challenge.
6.3. Edema and hyperalgesia
The anti-inflammatory and anti-hyperalgesic effects of CBD,
administered orally (5–40 mg/kg) once a day for 3 days after the
onset of acute inflammation induced by intraplantar injection of
0.1 ml carrageenan (1% w/v in saline) in the rat were reported.
28
Prostaglandin E
2
(PGE
2
) was assayed in the plasma, and cyclooxy-
genase (COX) activity, production of nitric oxide (NO; nitrite/ni-
trate content), and other oxygen-derived free radicals
(malondialdehyde) in inflamed paw tissues were significantly
increased following carrageenan paw injection. CBD treatment
produced decreases in PGE
2
plasma levels, tissue COX activity, pro-
duction of oxygen-derived free radicals, and NO after three succes-
sive doses of CBD. Thus, oral CBD exhibited a beneficial action on
two symptoms of inflammation: edema and hyperalgesia.
6.4. Arachidonic acid-induced ear inflammation
The CBD metabolite CBD-11-oic acid (Fig. 2) and its synthetic
analog CBD-dimethylheptyl-11-oic acid (HU-320) (Fig. 2) were
reported to exhibit anti-inflammatory activity in a model of arachi-
donic acid-induced ear inflammation in the mouse.
47
The latter
gave a potent response at a dose of 0.1 mg/kg given ip, which
was comparable to that shown by indomethacin. A major metabo-
lite of CBD is CBD-11-oic acid
48
suggesting the possibility that this
in vivo bioconversion can enhance and may even be required for
anti- inflammatory activity. A similar argument has been made
for THC-11-oic acid, a major metabolite of THC.
49
6.5. Inflammatory bowel disease
A review of the possible use of CBD to treat inflammatory
bowel diseases has recently been published.
50
CBD selectively
decreases croton oil-induced hypermotility in mice, a model for
inflammatory bowel disease, in vivo.
51
Surprisingly, it was
observed that the effect appeared to involve CB1 since it is
1382 S. Burstein / Bioorg. Med. Chem. 23 (2015) 1377–1385
believed that CBD does not bind to the CB1 receptor. It was also
reported that CBD did not reduce motility in mice treated with
the FAAH inhibitor N-arachidonoyl-5-hydroxytryptamine. It was
suggested that CBD might indirectly activate (via FAAH
inhibition) enteric CB1 receptors and thus reduce motility. Inhibi-
tion of FAAH would elevate levels of anandamide a well-
documented CB1 ligand.
6.6. Chemically induced colitis
In a murine model in mice, colitis was induced by intracolonic
administration of trinitrobenzene sulfonic acid (TNB).
52
In the
inflamed colon, the effects of CBD on COX-2 and inducible nitric
oxide synthase (iNOS) were measured by Western blot; changes
in interleukin-1band interleukin-10 were assayed using ELISA,
and endocannabinoids determined by isotope dilution liquid chro-
matography-mass spectrometry. Human colon adenocarcinoma
(Caco-2) cells were used to study the effect of CBD on oxidative
stress. CBD was reported to reduce colon injury, inducible iNOS
(but not COX-2) expression, and IL-1b, interleukin-10, and endo-
cannabinoid changes associated with TNB administration. CBD also
reduced reactive oxygen species production and lipid peroxidation
in Caco-2 cells.
The route of administration of CBD was studied in chemically
induced colitis.
53
In this study, the efficacy of CBD administered
either orally (20 mg/kg) or rectally (20 mg/kg) in the TNB mouse
model of colitis was determined with a view toward possible clin-
ical use in humans. These were compared with mice that received
CBD (10 mg/kg) given intraperitoneally. The extent of colitis was
evaluated by macroscopic scoring, histopathology and the
myeloperoxidase (MPO) assay. Oral administration was not effec-
tive, however, both rectal and intraperitoneal treatment reduced
the extent of colitis in this model.
6.7. Human neutrophil migration
The inhibition of human neutrophil chemotaxis by CBD and
related molecules has been reported.
54
It was found that ()-CBD
(Fig. 1) is a partial agonist with an IC-50 value of 0.45 nM, being
about 40 fold more potent than (+)-CBD (Fig. 2); abnormal-canna-
bidiol, an isomer of CBD, is a full agonist. In addition, it was
observed that the abnormal-cannabidiol analog O-1602 (Fig. 2) inhi-
bits migration with an IC-50 value of 33 nM. Moreover, ()-CBD and
related ligands showed potent inhibition of human neutrophil
migration, and the data implicated a novel receptor that was dis-
tinct from cannabinoid CB1 and CB2 receptors. The endogenous
lipoamino acid N-arachidonoyl-l-serine antagonized this receptor.
The possibility that GPR55 is this novel receptor is discussed in
the report.
6.8. Type I diabetic cardiomyopathy
Beneficial effects of CBD were reported in a study using a mouse
model of type I diabetic cardiomyopathy and primary human car-
diomyocytes exposed to high glucose.
55
CBD showed beneficial
effects on myocardial dysfunction, cardiac fibrosis, oxidative/ni-
trosative stress, inflammation, cell death, and interrelated signal-
ing pathways. Markers that were measured included NF-
j
B and
MAPK (JNK and p-38, p38
a
), expression of adhesion molecules
(ICAM-1, VCAM-1), TNF-
a
, markers of fibrosis (TGF-b, CTGF,
fibronectin, collagen-1, MMP-2 and MMP-9), cell death (caspase
3/7 and PARP activity), chromatin fragmentation and Akt phospho-
rylation. This very comprehensive report provides yet another
example of the anti-inflammatory actions of CBD.
A review paper on the therapeutic uses for CBD in inflamma-
tion, oxidative stress, the immune system, the metabolic syndrome
and the endocannabinoids was recently published.
56
In the paper,
recent studies reporting that CBD may have utility in treating sev-
eral diseases and disorders believed to involve activation of the
immune system and associated oxidative stress as a contributor
to their etiology and progression are presented. Included are
rheumatoid arthritis, types I and II diabetes, atherosclerosis, Alz-
heimer’s disease, hypertension, the metabolic syndrome, ische-
mia-reperfusion injury, depression, and neuropathic pain. It is
suggested that CBD’s therapeutic actions are a result of the fact
that inflammation and oxidative stress are intimately involved in
many human diseases.
6.9. Elevation of cytokine production
CBD is generally anti-inflammatory and immuno-suppressive,
however under certain conditions, it can elevate cytokine produc-
tion.
57
Both THC and CBD suppressed or enhanced IFN-
c
and IL-2
production by mouse splenocytes under optimal or suboptimal
stimulation, respectively. It was reported that these two cannabi-
noids suppressed or enhanced HIVgp120-specific T cell responses.
It was further demonstrated that THC and CBD differentially
regulated NFAT nuclear translocation and cytokine production. In
all cases, intracellular calcium was elevated regardless of the
degree of cellular activation. These studies provide a possible
explanation for the widely reported discrepancies regarding
cannabinoid actions on immune responses.
In support of the previous report it was later found that CBD
exacerbates LPS-induced pulmonary inflammation.
58
This effect
of CBD in vivo likely involves the parent compound, metabolites,
inhibition of certain metabolizing enzymes, and inhibition of NFAT
activity. It was concluded that CBD should be considered an
immune modulator, rather than only an immune suppressive
agent.
6.10. Pneumococcal meningitis
CBD has anti-inflammatory effects in pneumococcal meningitis
and reduces cognitive sequelae.
59
The intense inflammatory
response generated is accompanied by a significant mortality rate
and neurologic sequelae, such as, seizures, sensory-motor deficits
and impairment of learning and memory. Male Wistar rats under-
went a cisterna magna tap and received either 10 ml of sterile sal-
ine as a control or an equivalent volume of Streptococcus
pneumoniae suspension. Rats subjected to meningitis were treated
by intraperitoneal injection with CBD (2.5, 5, or 10 mg/kg once, or
daily for 9 days after meningitis induction). Controls were sham
operated and vehicle treated rats. The chronic administration of
CBD at several doses reduced the TNF-
a
level in the frontal cortex.
Prolonged treatment with CBD at 10 mg/kg, reduced memory
impairment in rats with pneumococcal meningitis.
6.11. Treatment of demyelinating pathologies
The protective effect of CBD against damage to oligodendrocyte
progenitor cells (OPCs) mediated by the immune system has been
reported.
19,60
Treatment of cells with 1
l
M CBD protects them
from oxidative stress by decreasing the production of reactive oxy-
gen species. CBD also protects OPCs from apoptosis induced by
LPS/IFN
c
through the decrease of caspase-3 induction by mechan-
isms not involving CB1, CB2, TRPV1 or PPAR-
c
receptors. In addi-
tion, tunicamycin-induced cell death was reduced by CBD,
suggesting a role for endoplasmic reticulum stress in the mode of
action of CBD. This protection against endoplasmic reticulum
stress-induced apoptosis was related to the reduced phosphoryla-
tion of eiF2
a
, one of the initiators of the endoplasmic reticulum
S. Burstein / Bioorg. Med. Chem. 23 (2015) 1377–1385 1383
stress pathway. Moreover CBD diminished the phosphorylation of
PKR and eiF2
a
induced by LPS/IFN
c
. The data suggest that inhibi-
tion of the endoplasmic reticulum stress pathway is a factor in
the ‘oligoprotective’ effects of CBD during inflammation. It was
further suggested that CBD has therapeutic potential for the treat-
ment of demyelinating pathologies.
6.12. Hepatic ischemia-reperfusion injury
Hepatic ischemia-reperfusion (I/R) injury is a major clinical
problem believed to be responsible for liver failure following trans-
plantation, hepatic surgery and circulatory shock. The beneficial
effects of CBD treatment in a mouse model of hepatic I/R injury
were described in a recent study.
61
Several markers of liver injury
(serum trans aminases), hepatic oxidative/nitrative stress (4-hy-
droxy-2-nonenal, nitrotyrosine content/staining, gp91phox and
inducible nitric oxide synthase mRNA), mitochondrial dysfunction
(decreased complex I activity), inflammation (TNF-
a
), COX-2,
macrophage inflammatory protein-1
a
/2, intercellular adhesion
molecule mRNA levels, tissue neutrophil infiltration, nuclear factor
kappa B (NF-
j
B) activation, stress signaling (p38MAPK and JNK)
and cell death (DNA fragmentation, PARP activity, and TUNEL)
were studied. The inhibitory effects of CBD were retained in CB2
knockout mice and were not reduced by CB1 or CB2 antagonists
in vitro suggesting a novel mechanism of action.
6.13. Sepsis-related encephalitis
The effects of CBD in a mouse model of sepsis-related
encephalitis induced by intravenous administration of lipopolysac-
charide (LPS) have been described.
62
Intravital microscopy was
used to measure vascular responses of pial vessels and inflamma-
tory parameters were measured by qRT-PCR. It was seen that
CBD prevented LPS-induced arteriolar and venular vasodilation as
well as leukocyte margination. CBD also reduced LPS-induced
increases in TNF-
a
and COX-2 expression as measured by quanti-
tative real time PCR. In addition, the expression of inducible-nitric
oxide synthase was reduced. These observations demonstrate both
the anti-inflammatory and the vascular-stabilizing effects of CBD
in endotoxic shock.
6.14. Autoimmune encephalomyelitis
CBD reduced the severity of the clinical signs of autoimmune
encephalomyelitis (EAE) when administered to myelin oligoden-
drocyte glycoprotein-immunized C57BL/6 mice at the onset of
the disease.
34,63
It also decreased axonal loss and reduced inflam-
mation as shown by reductions in the infiltration of T cells and
microglial activation. In addition, CBD inhibited myelin oligoden-
drocyte glycoprotein (MOG)-induced T-cell proliferation in vitro
at both low and high concentrations of the myelin antigen and
the effect was not mediated by either the CB1 or the CB2 receptors.
Suppression of microglial activity and T-cell proliferation by CBD
was suggested to contribute to these beneficial effects.
6.15. Inflammatory lung diseases
This report
64
is an extension of an earlier one where it was
shown that prophylactic treatment with CBD reduces inflamma-
tion in a model of acute lung injury (ALI).
18
In the current publi-
cation, the effects of therapeutic treatment with CBD (20 and
80 mg/kg) in a mouse model of lipopolysaccharide-induced ALI
on pulmonary mechanics and inflammation was reported. CBD
decreased total lung resistance and elastance, leukocyte migration
into the lungs, myeloperoxidase activity in the lung tissue, pro-
tein concentration and production of the pro-inflammatory
cytokines (TNF and IL-6) and chemokines (MCP-1 and MIP-2) in
the bronchoalveolar lavage supernatant. It was concluded that
CBD could be efficacious in the treatment of inflammatory lung
diseases.
7. Combined THC and CBD treatment
It has been suggested that the combination of THC and CBD has
a better therapeutic profile in a variety of actions than each
cannabinoid component alone.
65,66
A example of such synergism in the area of inflammation has
been reported in a mouse model of Alzheimer’s disease.
67
They
observed reduced astrogliosis, microgliosis, and inflammatory-re-
lated molecules in treated AbPP/PS1 mice that were more marked
after treatment with THC + CBD than with either THC or CBD alone.
It was suggested that the anti-inflammatory effects had a role in
the positive cognitive effects that were seen as a result of cannabi-
noid treatment.
A combination of phytocannabinoids that is primarily com-
posed of THC and CBD, is neuroprotective in malonate-lesioned
rats, an inflammatory model of Huntington’s disease.
68
Evidence
was presented that suggested a role for both CB1 and CB2 receptors
in the anti-inflammatory actions of the cannabinoid mixture.
8. Summary
Although it was discovered early on, CBD has become a major
area of research only in recent years. In particular, its biological
Table 1
Anti-inflammatory actions of CBD
Response Model Reference
Reduces immune response Rats subjected to pneumococcal meningitis 59
Prevents experimental colitis Murine model of colitis 52
Reduced iNOS and IL-1bexpression Mouse model of Alzheimer’s disease 31,43
Reduces b-amyloid-induced neuroinflammation Cultured astrocytes 43
TNF-
a
and IL-1blevels reduced Murine collagen-induced arthritis 9
Decreases in PGE
2
plasma levels Carrageenan paw injection in the rat 28
Reduced the extent of colitis TNB mouse model of colitis 53
Inhibition of neutrophil chemotaxis Human neutrophil migration 54
Effects on NF-
j
B, MAPK, ICAM-1, VCAM-1, TNF-
a
Mouse model of type I diabetic cardiomyopathy 55
Enhanced IFN-
c
and IL-2 production Mouse splenocytes 57
Exacerbates LPS-induced pulmonary inflammation Pulmonary inflammation in C57BL/6 mice 58
Reduced the TNF-
a
level in the frontal cortex Pneumococcal meningitis in rats 59
Decreases hepatic ischemia-reperfusion (I/R) injury Mouse model of hepatic I/R 61
Reduced LPS-induced increase in TNF
a
and COX-2 Mouse model of sepsis-related encephalitis 62
Reduced effects of autoimmune encephalomyelitis Immunized C57BL/6 mice 34,63
Reduces inflammation in acute lung injury (ALI) Mouse model of lipopolysaccharide-induced ALI 64,18
1384 S. Burstein / Bioorg. Med. Chem. 23 (2015) 1377–1385
actions are a topic of many interesting reports that suggest possible
therapeutic applications. Included are its anti inflammatory actions
in a variety of preclinical models (Table 1). Some examples are
experimental colitis, collagen-induced arthritis, b-amyloid-induced
neuroinflammation, neutrophil chemotaxis, hepatic ischemia-
reperfusion (I/R) injury, autoimmune encephalomyelitis, acute
lung injury (ALI), etc. These and others need to be pursued in
human trials with a view toward clinical applications where CBD’s
absence of psychotropic effects and other adverse events offers a
major advantage over other cannabinoids. Another area in need
of new research is the discovery of synthetic analogs with greater
potency than CBD that still retain a favorable therapeutic ratio. A
review covering other areas of CBD actions has recently been pub-
lished by Hill et al.
7
Acknowledgement
The author thanks Dr. Akbar Ali for his assistance in preparing
the graphical abstract and Figure 1.
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... CBD can interfere with the detrimental actions of Δ9-THC in terms of psychotic proneness and cognitive dysfunction [153]. On the other hand, CBD is a particularly interesting target as a novel approach for cognitive improvement in schizophrenia, in part, due to its strong anti-inflammatory properties [154]. CBD has the potential to limit Δ9THC-induced cognitive impairment and to improve cognitive function in different pathological conditions, but there is limited evidence investigating the therapeutic efficacy of CBD as treatment for cognitive deficits in schizophrenia [155,156]. ...
Chapter
Cognitive impairment, in past decades, has been consistently reported in patients with schizophrenia [1]. Neurocognitive disability appears early in the course of the disease, even in prodromal phases, and these deficits are widely present in different stages of the illness whether in patients or in their first-degree family members [2]. In 2004, the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) project has identified seven distinct cognitive domains that are impaired in patients with schizophrenia: speed of processing, attention/vigilance, working memory, verbal and visual learning, reasoning and problem solving, and social cognition [3–5]. Moreover, in the third meeting of the Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia (CNTRICS) project, it was cleared that six areas of cognitive domains are damaged in patients with schizophrenia: perception, working memory, attention, executive functions, long-term memory, and social cognition [6]. Regarding social cognitive deficits, they include impairments in facial affect recognition, in perceiving and interpreting social cues, in theory of mind (ToM), and in the ability to make appropriate causal attributions for events [7]. Several studies have shown that both neurocognitive and social cognitive deficits are among the major causes of severe functional disabilities in patients with schizophrenia and they are also related to a worse outcome of the disorder [8–10]. In a comprehensive literature review, Green et al. [10] underlined that different cognitive deficits might have an impact on specific areas of psychosocial functioning. As a matter of fact, cognitive deficits seem to explain 20–60% of the variance of everyday functioning [3, 4, 11]. The influence of cognition on functional outcomes may happen through its influence on functional capacity, the ability to perform critical everyday living skills [12]. Thus, functional capacity may actually be considered as a proxy measure between neurocognition and everyday functioning and it has been found to be quite strongly associated with cognitive performance [13]. Recent studies have shown how cognitive impairment predicts functional outcomes even more than positive and negative symptoms and how it is associated with disability in phases of clinical remission too [2, 14]. From the greater and detailed knowledge of the role and meaning of cognitive impairment in schizophrenia, its improvement became an essential target in the treatment and in the clinical management of the illness [15]. In order to restore cognitive deficits in schizophrenic patients, there are different pharmacological and non-pharmacological approaches developed. Whereas pharmacological interventions include approved treatments (e.g., antipsychotics and antidepressants) and under-study treatments, non-pharmacological interventions include cognitive remediation, noninvasive brain stimulation techniques, and physical activity techniques [16–20].
... Cannabidiol (C 21 H 30 O 2 ) is a phytocannabinoid that has been gaining attention for the treatment of neuropathic pain due to its high affinity for cannabinoid receptors and consequently its side effects, while exercising anti-inflammatory and analgesic activities (Burstein, 2015;Britch et al., 2021). Studies on the activity of this compound in chemotherapy-induced peripheral neuropathy have already evaluated its antinociceptive effect against the causative agents PTX, OXL, and VIN. ...
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Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most prevalent and difficult-to-treat symptoms in cancer patients. For this reason, the explore for unused helpful choices able of filling these impediments is essential. Natural products from plants stand out as a valuable source of therapeutic agents, being options for the treatment of this growing public health problem. Therefore, the objective of this study was to report the effects of natural products from plants and the mechanisms of action involved in the reduction of neuropathy caused by chemotherapy. The search was performed in PubMed, Scopus and Web of Science in March/2021. Two reviewers independently selected the articles and extracted data on characteristics, methods, study results and methodological quality (SYRCLE). Twenty-two studies were selected, describing the potential effect of 22 different phytochemicals in the treatment of CIPN, with emphasis on terpenes, flavonoids and alkaloids. The effect of these compounds was demonstrated in different experimental protocols, with several action targets being proposed, such as modulation of inflammatory mediators and reduction of oxidative stress. The studies demonstrated a predominance of the risk of uncertain bias for randomization, baseline characteristics and concealment of the experimental groups. Our findings suggest a potential antinociceptive effect of natural products from plants on CIPN, probably acting in several places of action, being strategic for the development of new therapeutic options for this multifactorial condition.
... 23,24 The safe, pain-relieving, and anti-inflammatory properties of CBD have been considered of special interest as a novel therapeutic agent in the dermatology and cosmetics market. [25][26][27][28] Although there is evidence suggests that the application of CBD may have a similar anti-inflammatory property to other immuone-suppressant drugs for some skin disorders and inflammatory condition, the underlying molecular mechanisms of CBD still need fully identified. The similarities and dissimilarities of their inflammatory response pathways need additional comparative study. ...
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Background: Cannabidiol (CBD) is a non-psychoactive phytocannabinoid constituent of Cannabis sativa with pain-relieving and anti-inflammatory properties. With the emphasis on natural ingredients in cosmetics, CBD has become a new cosmetic ingredient due to its ability to alleviate inflammation. However, in-depth studies that directly compare the effective mechanism and the therapeutic potential of CBD are still needed. Purpose: The aim of the present study was to investigate the anti-inflammatory effect of CBD in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages and compare it to dexamethasone (DEX). Methods: RAW264.7 macrophages in the logarithmic growth phase were incubated in the presence or absence of LPS. After that, the production of nitric oxide (NO), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) were measured. A luciferase reporter assay for nuclear factor kappa B (NF-κB) was performed, and the phosphorylation levels of the mitogen-activated protein kinase (MAPK) and NF-κB signaling pathways were measured. Results: The present study indicated that CBD had a similar anti-inflammatory effect to DEX by attenuating the LPS-induced production of NO, IL-6, and TNF-α. However, only CBD attenuated JNK phosphorylation levels, and only DEX attenuated IKK phosphorylation levels. Conclusion: These results suggested that CBD and DEX exhibit similar anti-inflammatory effects on LPS-induced RAW264.7 macrophages mainly through suppressing the MAPK and NF-κB signaling pathways, but with different intracellular mechanisms. These findings suggested that CBD may be considered a natural anti-inflammatory agent for protecting skin from immune disorders.
... [3] Mechanism of action Of the two significant phytocannabinoids, CBD was the first compound discovered from marijuana in 1940, and the structure was documented by 1963. [31] In 1941, the THC structure was identified by Mechoulam and Gaoni in Israel. [32,33] Raphael Mechoulam would later discover that the cannabis-spiced cake he fed healthy volunteers in his experiment triggered psychological reactions depending on their personality. ...
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Cannabis sativa is a complex domesticated plant that has an unstable taxonomy. It is the most utilised illicit substance that has gained prominence in some parts of the world as it is used for therapeutic and recreational purposes. C. Sativa has also been used to manage numerous medical conditions since antiquity. The pharmacological benefits of C. sativa are still subject to intense research due to inconsistent outcomes. C. sativa, like other psychoactive substances, has both medical and psychological side effects. Despite the lack of knowledge, medical practitioners continue to recommend this substance. This review aims to highlight the effects of legalisation and liberalisation on the global trend of cannabis use. A search was conducted on Google Scholar and Medline from 2012 to date. The results showed that cannabis was found to be effective in the management of some medical conditions, though more work is required. Recreational use is rising due to a reduced perception of harm and the availability of more potent species. Cannabis use persists despite the several medical and psychological side effects. It is concluded that there is a shortage of information on the safety and pharmacological properties of C. sativa, and more work is required.
... Among all cannabinoids, ∆9-tetrahydrocannabinol (∆9 -THC) and cannabidiol (CBD) are the most represented. While ∆9-THC is best known for the psychotropic effect associated with Cannabis consumption, CBD is non-psychoactive phytocannabinoid that shows interesting biological properties, including neuroprotective, anti-inflammatory, anti-oxidant, and anti-apoptotic effects [10][11][12]. The molecule CBD (C 21 H 30 O 2 ) is a cyclohexene with a methyl group in position 1, a 2,6-dihydroxy-4-pentylphenyl group at position 3 and a prop-1-en-2-yl group at position 4 ( Figure 1). ...
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Recently, the scientific community has started to focus on the neurogenic potential of cannabinoids. The phytocompound cannabidiol (CBD) shows different mechanism of signaling on cannabinoid receptor 1 (CB1), depending on its concentration. In this study, we investigated if CBD may induce in vitro neuronal differentiation after treatment at 5 µM and 10 µM. For this purpose, we decided to use the spinal cord × neuroblastoma hybrid cell line (NSC-34) because of its proliferative and undifferentiated state. The messenger RNAs (mRNAs) expression profiles were tested using high-throughput sequencing technology and Western blot assay was used to determine the number of main proteins in different pathways. Interestingly, the treatment shows different genes associated with neurodifferentiation statistically significant, such as Rbfox3, Tubb3, Pax6 and Eno2. The CB1 signaling pathway is responsible for neuronal differentiation at 10 µM, as suggested by the presence of p-ERK and p-AKT, but not at 5 µM. A new correlation between CBD, neurodifferentiation and retinoic acid receptor-related orphan receptors (RORs) has been observed.
... • low content of toxic and allergenic components, due to the cultivation of crops without the use of pesticides are considered promising natural compounds in the treatment of epilepsy, depression, anorexia, cancer and other diseases and disorders [10,12]. The relatively high content of cannabidiol in the plant biomass of hemp varieties allowed for cultivation in the Russian Federation, and the normatively low content of THC in them, allow to consider industrial hemp as a potential crop for the production of biologically active substances in the future [3]. ...
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Cannabis sativa L. hemp seeds are recommended as a resource of essential components in food technology, as they contain more than 30% oil and 25% protein, a significant amount of dietary fiber, vitamins and minerals. Hemp oil contains more than 80% polyunsaturated fatty acids and it is considered as a rich source of essential fatty acids - linoleic and α-linolenic acid. The protein fraction of hemp seeds (edestin and albumin) is highly digestible and has a balanced amino acid composition. Hemp seeds contain a list of physiologically valuable components, due to which they are a priority raw material in the functional food production. Taking into account the population’s need of the for functional and specialized food products, it is reasonable to produce innovative products of high nutritional and biological value from industrial hemp seeds. The high protein content in products and raw materials produced from hemp seeds “Nadezhda” has been experimentally established. The degree of daily protein requirement is satisfied on 20.8–53.5% (hemp flour pasta and natural hemp protein) while consuming 100 g of the product. A significant content of dietary fiber in products from hemp seeds was found, the degree of satisfaction of the daily need for which is 13.2–144.8%. The protein fraction of the hemp seed is characterized by a high biological value, it has been established that the limiting amino acid is lysine, the amino acid score is 88.2%, the protein rationality coefficient is 69.3%, and the protein amino acid number adjusted for digestibility is 79%.
Article
Cannabidiol (CBD) is an important natural compound of hemp. Cyclodextrin-assisted extraction of CBD from hemp leaves was optimized by single-factor experiments and response surface methodology. The highest extraction yield of CBD was 1.075 ± 0.012 mg/g and the recovery yield was 87.19 % using dimethyl-β-cyclodextrin (DM-βCD), which showed that the extract had a higher proportion of CBD. The optimal conditions were as follows: extraction temperature was 40 ℃, liquid-to-solid ratio was 25.17 mL/g, extraction time was 74.4 min, mass ratio of DM-βCD to hemp leaves was 1.17, and ethanol concentration was 60 %. Different characterizations demonstrated that complexation of DM-βCD promoted CBD extraction and increased the proportion of CBD in the extract. The cumulative release rate of CBD (67.98%) from the extract by DM-βCD-assisted extraction (DAHE) was much higher than that (2.62%) without DM-βCD-assisted extraction (HE). The permeability, bioactivity, and stability of DAHE were also better than that of HE. The better results of DAHE could be due to the inclusion by DM-βCD and the higher proportion of CBD. In conclusion, DM-βCD-assisted extraction was an appropriate method for CBD extraction and the obtained extract with higher CBD proportion and better bioactivity and stability could be applied in many fields.
Chapter
In the last decade there has been an increasing demand for hemp derivatives from legal Cannabis sativa L. (THC content < 0.3%) to be used in different industrial applications, because of the spread of its cultivation and preference in sustainable agricultural systems. In the European Union about 25,000 hectares are cultivated, and more than seventy cultivars are allowed to be grown in agricultural systems. During hemp processing a huge amount of biomass, mostly given by leaves and inflorescences, can be generated, and be reused to produce niche products. Among the latter, the essential oil, a liquid, odorous product composed mainly of monoterpenes and sesquiterpenes, represents a promising future candidate in different fields such as pest management science, pharmaceuticals, cosmetics, and others. In this chapter we review scientific literature dealing with the chemical compositions of the essential oil obtained from different cultivars of industrial hemp highlighting the potential use of their constituents as pharmaceutically active drugs, insecticides, acaricides, and antimicrobials.
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Cannabis sativa L has a long history as a medicinal plant, dating back more than two millennia. Preclinical studies using both pharmacological and genetic approaches have increased the understanding of this plant and its importance in providing therapeutic strategies for a variety of conditions. The cannabis plant comprises hundreds of different active compounds with potential therapeutic properties, with cannabinoids being the main class of active compounds. Recent drug development has produced cannabinoid-rich cannabis-based medicinal products, which were legalised in November 2018 in the UK. They are increasingly prescribed for conditions, including multiple sclerosis, epilepsy and chronic pain. This article aims to review the current literature on the therapeutic effects and applications of the two main cannabinoids found in cannabis-based medicinal products.
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Similarity-based search has been a hot research topic for a long history, which is widely used in many applications. The large scale Restricted Floating Sensor (RFS) network is an important mod-el in offshore data collection [1]. Due to the mobility and the large number of sensors, improved techniques are needed to deal with uncertainty and mass queries. As a theoretical basis, this paper constructs a new fuzzy similarity measure based on distance. With examples we illustrate that many common similarity functions can be constructed from these measures. From [2] we know our work over distance and similarity is a reasonable generalization and extension of other Fuzzy Sets. This work provides a theoretical guidance for constructing a fuzzy query processing strategy for our RFS networks.
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Background: Pelvic floor (PF) hypertonic disorders are a group of conditions that present with muscular hypertonia or spasticity, resulting in a diminished capacity to isolate, contract and relax an individual muscle. Their presentation includes voiding and sexual dysfunctions, pelvic/perineal pain and constipation. Various factors are associated with these conditions, such as complicated vaginal birth, muscular injury, scar tissue formation and neuropathies. Study Design: the case of a single patient will be presented, together with the management strategies employed. Case Description: The case of a woman with hereditary spastic paraplegia/paraparesis is presented, with a history of muscle spasticity, urinary and fecal complaints since childhood. She presented to this institution seeking treatment for pelvic pain, pain during intercourse, constipation and micturition problems. A physical therapy protocol was developed, with the trial of several treatment modalities. Thiele’s perineal massage, abdominal massage and pelvic floor strengthening were first tried, followed by cryotherapy, which had low adherence, and by pelvic floor muscles stretching exercises using an insufflated vaginal probe. Outcome: after some failed attempts, perineal and pelvic floor stretching proved to be very efficacious therapies for this patient´s complaint, leading to improved pain during intercourse, constipation, pelvic pain and urinary stream.Discussion: pelvic floor spasticity can lead to severe disability and interfere with daily basic functions, such as micturition and evacuation. Physical therapy plays an essential role in the management of these patients, and can lead to significant improvement in quality of life.
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Inflammation in the central nervous system (CNS) is a complex process that involves a multitude of molecules and effectors, and it requires the transmigration of blood leukocytes across the blood-brain barrier (BBB) and the activation of resident immune cells. Cannabidiol (CBD), a non-psychotropic cannabinoid constituent of Cannabis sativa, has potent anti-inflammatory and immunosuppressive properties. Yet, how this compound modifies the deleterious effects of inflammation in TMEV-induced demyelinating disease (TMEV-IDD) remains unknown. Using this viral model of multiple sclerosis (MS), we demonstrate that CBD decreases the transmigration of blood leukocytes by downregulating the expression of vascular cell adhesion molecule-1 (VCAM-1), chemokines (CCL2 and CCL5) and the proinflammatory cytokine IL-1β, as well as by attenuating the activation of microglia. Moreover, CBD administration at the time of viral infection exerts long-lasting effects, ameliorating motor deficits in the chronic phase of the disease in conjunction with reduced microglial activation and pro-inflammatory cytokine production. Adenosine A2A receptors participate in some of the anti-inflammatory effects of CBD, as the A2A antagonist ZM241385 partially blocks the protective effects of CBD in the initial stages of inflammation. Together, our findings highlight the anti-inflammatory effects of CBD in this viral model of MS, and demonstrate the significant therapeutic potential of this compound for the treatment of pathologies with an inflammatory component.
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The mechanisms underlying the neuroprotective effects of cannabidiol (CBD) were studied in vivo using a hypoxic-ischemic (HI) brain injury model in newborn pigs. One- to two-day-old piglets were exposed to HI for 30 min by interrupting carotid blood flow and reducing the fraction of inspired oxygen to 10%. Thirty minutes after HI, the piglets were treated with vehicle (HV) or 1 mg/kg CBD, alone (HC) or in combination with 1 mg/kg of a CB2 receptor antagonist (AM630) or a serotonin 5HT1A receptor antagonist (WAY100635). HI decreased the number of viable neurons and affected the amplitude-integrated EEG background activity as well as different prognostic proton-magnetic-resonance-spectroscopy (H±-MRS)-detectable biomarkers (lactate/N-acetylaspartate and N-acetylaspartate/choline ratios). HI brain damage was also associated with increases in excitotoxicity (increased glutamate/N-acetylaspartate ratio), oxidative stress (decreased glutathione/creatine ratio and increased protein carbonylation) and inflammation (increased brain IL-1 levels). CBD administration after HI prevented all these alterations, although this CBD-mediated neuroprotection was reversed by co-administration of either WAY100635 or AM630, suggesting the involvement of CB2 and 5HT1A receptors. The involvement of CB2 receptors was not dependent on a CBD-mediated increase in endocannabinoids. Finally, bioluminescence resonance energy transfer studies indicated that CB2 and 5HT1A receptors may form heteromers in living HEK-293T cells. In conclusion, our findings demonstrate that CBD exerts robust neuroprotective effects in vivo in HI piglets, modulating excitotoxicity, oxidative stress and inflammation, and that both CB2 and 5HT1A receptors are implicated in these effects.
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The discovery of carboxylic acid metabolites of the cannabinoids (CBs) dates back more than three decades. Their lack of psychotropic activity was noted early on, and this resulted in a total absence of further research on their possible role in the actions of the CBs. More recent studies have revealed that the acids possess both analgesic and anti-inflammatory properties and may contribute to the actions of the parent drug. A synthetic analog showed similar actions at considerably lower doses. In this review, a brief survey of the extensive literature on metabolism of Δ9-tetrahydrocannabinol to the acids is presented, while more emphasis is given to the recent findings on the biological actions of this class of CBs. A possible mechanism involving effects on eicosanoids for some of these actions is also suggested. Finally, an analogy with a putative metabolite of anandamide, an endogenous CB, is discussed.
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Cannabidiol (CBD) is a plant-derived cannabinoid that has been predominantly characterized as anti-inflammatory. However, it is clear that immune effects of cannabinoids can vary with cannabinoid concentration, or type or magnitude of immune stimulus. The present studies demonstrate that oral administration of CBD enhanced lipopolysaccharide (LPS)-induced pulmonary inflammation in C57BL/6 mice. The enhanced inflammatory cell infiltrate as observed in bronchoalveolar lavage fluid (BALF) was comprised mainly of neutrophils, with some monocytes. Concomitantly, CBD enhanced pro-inflammatory cytokine mRNA production, including tumor necrosis factor-α (Tnfa), interleukins (IL)-5 and -23 (Il6, Il23), and granulocyte colony stimulating factor (Gcsf). These results demonstrate that the CBD-mediated enhancement of LPS-induced pulmonary inflammation is mediated at the level of transcription of a variety of pro-inflammatory genes. The significance of these studies is that CBD is part of a therapeutic currently in use for spasticity and pain in multiple sclerosis patients, and therefore it is important to further understand mechanisms by which CBD alters immune function.
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